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Development of “metal-coated” microreactors as a new methodology for Microwave-Assisted, Continuous Flow Organic Synthesis (MACOS) and its application in synthetic chemistry

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Development of "Metal-Coated" Microreactors as a New Methodology
for Microwave-Assisted, Continuous Flow Organic Synthesis (MACOS)
and its Application in Synthetic Chemistry
Gjergji Shore
A Dissertation Submitted to the Faculty of Graduate Studies
in Partial Fulfillment of the Requirements
for the Degree of
Doctor of Philosophy
Graduate Program in Chemistry
York University
Toronto, Ontario
December 2009
1*1
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ABSTRACT
A new method for conducting chemical reactions in flow has been developed. The
method is based upon the use of capillary microreactors, that have been internally coated
with thin metallic films, which are irradiated with microwaves while the reaction solution
is flowed through it. The technology has been coined Microwave-Assisted, Continuous
Flow Organic Synthesis (MACOS). The thin metal films displayed catalytic activity
under microwave irradiation. In addition, the chemical processes conducted with this
method were tremendously accelerated due to the heat released by coupling of
microwaves to metallic films.
A number of protocols were developed for coating capillary reactors with different metal
films. The morphologies of the metal films were studied using Scanning Electron
Microscopy and Energy Dispersive X-ray analysis and the temperatures on the surface of
films under microwave irradiation were accurately measured by a high definition infrared
camera. The catalytic activity of metallic films under microwave irradiation was utilized
in a number of applications, including Suzuki-Miyaura and Heck cross-coupling using
thin Pd films, hydrosilylation of terminal alkynes using thin Au films, Diels-Alder
reactions using thin Pd films. The scope of catalysis by thin films was extended
effectively to difficult, multi-step reactions including the synthesis of indoles, naphthyl
ketones and propargyl amines using Pd, Au and Cu-coated capillary reactors,
respectively.
iv
ACKNOWLEDGEMENT
/ would like to express my deep gratitude to all those who helped and inspired me during
my doctoral studies. I especially want to thank Prof. Michael G. Organ for his detailed
comments and constructive guidance throughout this work. Prof Sergey Krylov, Prof
Edward Lee-Ruff Prof. William Pietro, Prof. Pierre Potvin, Prof. William A. van
Wijngaarden and Prof Mats Larhed deserve special thanks as my thesis committee
members and advisors. I would like to thank all my lab colleagues for their support and
friendship, especially Dr.N. Hadei, Dr. S. Calimsiz, M. Tsimmerman, S. Bremner etc.
Special thanks to Dr. Howard Hunter for his help with NMR spectroscopy. I owe a debt
of gratitude to my wife Viola; without her support and understanding it would have been
impossible for me to finish this work.
v
TABLE OF CONTENTS
Page
Abstract
iv
Acknowledgment
v
Table of Contents
vi
List of Figures
x
ListofTables
xiii
List of Abbreviations
xiv
Chapter One: Introduction
1
1.1 Continuous flow reactors and microwave-assisted synthesis as "enabling
technologies"
1.2 Continuous flow technology and its advantages
2
3
1.3 Operational features of flow microreactors
5
1.3.1 Diffusion-controlled mass transfer
5
1.3.2 High surface area-to-volume ratio
6
1.3.3 Electro-osmotic flow (EOF)
6
1.3.4 Surface functionalization
7
1.3.5 Heat and mass transfer
8
1.3.6 In-line integration of chemical analysis and automated processing
equipment
1.4 Microreactor design and fabrication
8
10
1.5 The S cope of Applications
12
1.5.1 Liquid phase reactions
12
1.5.2 Liquid-Solid reactions
13
1.5.3 Liquid-Gas reactions
14
1.5.4 Liquid-Gas-Solid reactions
15
1.5.5 Natural product synthesis
16
1.6 Limitations of continuous flow reactors
17
1.7 Microwave irradiation theory
18
vi
1.8 Microwave thermal effects
20
1.9 Microwave-induced dielectric heating
23
1.10 Microwave heating of metals
28
1.11 Advantages of microwave heating over conventional thermal heating
29
1.12 Microwave effects
35
1.12.1 Thermal effects and specific microwave effects
35
1.12.2 Non-thermal effects
35
1.13 Dedicated Microwave Reactors
41
1.13.1 Microwave-assisted continuous flow technique as technological
solution to batch microwave scale-up problems
1.14 Micro wave-assisted fluidic systems and their applications
43
46
1.14.1 Microscale fluidic systems
46
1.14.2 The Stop-Flow protocol
53
1.14.3 Microwave-Assisted Continuous Flow Organic Synthesis
(MACOS)
1.15 Plan of study
1.15.1 The use of Pd and Ag-coated glass capillaries as reaction vessels
for flow chemistry
1.15.2 Synthesis in flow using the Au and Cu-coated glass capillaries as
reaction vessels
Chapter Two: Preparation and characterization of thin metal films on glass
capillary reactors. Thermal images of thin Pd, Ag, Au, Cu
films under microwave irradiation
2. Results and Discussion
54
59
59
60
61
62
2.1 The development of thin Pd and Ag films inside glass capillary reactors
62
2.1.1 Thin Pd films
62
2.1.2 Thin Ag films
65
2.2 The development of methodologies for coating glass capillary reactors
with thin Au and Cu films
67
2.2.1 The development of thin Au
films
68
2.2.2 The development of thin Cu
films
71
vu
2.3 The development of Rh and Pt thin films inside the glass capillary
reactors
2.3.1 The development of Rh thin films
2.3.2 The development of Pt thin films
2.4 The development of protocols for coating capillary reactors with
bimetallic layers of Ru-on-Pd and Rh-on-Pd
2.5 Measuring the temperature of metal film surfaces
73
74
75
77
79
Chapter Three: In-flow catalysis by thin Pd films. Applications to SuzukiMiyaura and Heck cross-couplings, Diels-AIder reactions
and indole synthesis
87
3.1 Suzuki-Miyaura and Heck cross-coupling reactions conducted in flow
using Pd-coated capillaries as reaction vessels with MACOS
3.2 Diels-Alder reactions in continuous flow format
88
93
3.3 Indole synthesis in MACOS utilizing a Pd-PEPPSI-IPr catalyzed
sequential aryl amination/Heck coupling sequence
Chapter Four: In-flow catalysis by thin Au and Cu films. Applications to
hydrosilylation and benzannulation reactions and propargyl
amine synthesis
101
4.1 Hydrosilylation of terminal alkynes in flow format using Au-coated
capillaries as reaction vessels in MACOS
4.2 Benzannulation reactions in flow format using Au-coated capillaries as
reaction vessels in MACOS
4.3 In-flow synthesis of propargyl amines utilizing Cu-coated capillaries as
reaction vessels in MACOS
4.4 "Metals-In-Microwave": a successful approach that can be extended to
other applications
Chapter Five: Experimental
113
5.1 Microwave irradiation experiments and metal coating protocols for the
borosilicate glass capillary reactors
5.1.1 Micro wave irradiation experiments
5.1.2 General procedure for the preparation the Pd- and Ag-film coating
inside of 1200 micron and 1700 micron (ID) capillaries
5.1.3 General procedure for the preparation of the Au-on-Au and Au-onAg film coating inside of 1200 micron andi700 micron (ID)
capillaries
5.1.4 General procedure for the preparation of the Cu-film coating inside
of 1700 micron (ID) glass capillaries
5.1.5 General procedure for the preparation of the Rh-film coating inside
of 1200 micron and 1700 micron (ID) capillaries
vin
112
120
129
138
141
142
142
143
144
145
145
5.1.6 General procedure for the preparation of the Pt-film coating inside
of 1200 micron and 1700 micron (ID) capillaries
5.1.7 General procedure for the preparation of the Ru-on-Pd and Rh-onPd coating inside of 1200 micron and 1700 micron (ID) capillaries
5.1.8 Measurements of the metal film temperature using an IR camera
5.2 Suzuki-Miyaura and Heck coupling reactions in flow
145
146
146
147
5.2.1 General procedure for the Suzuki-Miyaura coupling reactions
147
5.2.2 General procedure for the Heck coupling reactions
152
5.3 Diels- Alder reactions in flow
156
5.3.1 General procedure for Diels-Alder reactions in flow with
microwave heating
5.3.2 General procedure for Diels-Alder reactions in flow with oil bath
heating
5.4 Indole synthesis in continuous flow format
156
156
159
5.4.1 General procedure for the indole synthesis
159
5.5 Hydrosilylation reactions in continuous flow format
171
5.5.1 General procedure for the hydrosilylation by MACOS
5.6 Benzannulation reactions in continuous flow format
5.6.1 General procedure for the benzannulation reactions by MACOS
5.7 Synthesis of propargyl amines in continuous flow format
5.7.1 General procedure for the synthesis of propargyl amines in MACOS
References
171
185
185
195
195
208
IX
LIST OF FIGURES
Page
Figure 1.1 Schematic representation of enabling techniques and possible
combinations of such techniques for developing new synthetic
platforms
2
Figure 1.2 Voltage-driven mobility of different charged species and EOF
generated by the diffuse layer of cations adsorbed on the negatively
charged glass wall
7
Figure 1.3 A lead discovery and optimization system based on microreactor
technology, incorporating in-line analytical and purification
instruments
10
Figure 1.4 Continuous flow microreactors
11
Figure 1.5 The Electromagnetic Spectrum
19
Figure 1.6 Electric (E) and magnetic (M) field components in microwave
21
irradiation
Figure 1.7 Effects of surrounding electric field on dipole orientation
22
Figure 1.8 Applied sinusoidal electric field (top) and out-of-phase induced
24
Maxwell displacement current
Figure 1.9 Dielectric properties of water plotted against irradiation frequency
27
Figure 1.10 Schematic comparison of conventional and microwave heating
30
Figure 1.11 The temperature-time profiles for conventional and microwave
dielectric heating (using similar power setting)
Figure 1.12 Intramolecular imide formation of polyamic acid and first order
kinetic plots for the imide formation via microwave irradiation and
conventional heating
Figure 1.13 Proposed stabilization of reaction intermediate species under
microwave irradiation via lowering of transition state energy
32
Figure 1.14 Cross-sectional view of a magnetron depicting the pathway of
electrons under the applied magnetic field and cross-sectional view
of a single-mode microwave cavity
x
38
38
42
Figure 1.15 Single-mode microwave instruments
43
Figure 1.16 Schematic design of the continuous flow system developed by
Strauss
47
Figure 1.17 Continuous flow reactors built by Haswell
48
Figure 1.18 Isothermal continuous flow reactor built by Jachuck
48
Figure 1.19 U-shaped tubular microreactor built by Ley filled with Pd EnCat
catalyst
49
Figure 1.20 Continuous flow reactor designed by Kappe
50
Figure 1.21 The composite ring reactor designed by Kirschning
51
Figure 1.22 The coiled glass reactor designed by Wilson
52
Figure 1.23 MACOS system capillary microreactors
Figure 1.24 Cross-sectional view of MACOS multireactor system for preparing
libraries in parallel synthesis
55
56
Figure 2.1 SEM images of Pd film morphology
63
Figure 2.2 The morphology of Pd film prepared inside a glass capillary
compared to a Pd film prepared on a glass slide
64
Figure 2.3 SEM images of Ag mirror film morphology
65
Figure 2.4 SEM and EDX analysis of Ag film prepared from Ag20 colloids
67
Figure 2.5 SEM and EDX analysis of the gold
69
film
Figure 2.6 SEM analysis of the double layer of gold supported on a thin Ag
film
71
Figure 2.7 SEM and EDX analysis of Cu film morphology
72
Figure 2.8 SEM and EDX analysis of Rh thin film morphology
75
Figure 2.9 SEM and EDX analysis of Pt film morphology
76
Figure 2.10 SEM and EDX analysis of Ru-on-Pd bi-metallic layer
78
Figure 2.11 SEM and EDX analysis of Rh-on-Pd bi-metallic layer
79
XI
Figure 2.12 Metal-coated glass capillary reactors (1700 um ID), after prolonged
exposure to microwave irradiation
80
Figure 2.13 Schematic presentation of the built-in IR sensor measuring the
temperature on surface of a) a standard vial and b) a tubular capillary
reactor
81
Figure 2.14 MACOS set up for obtaining thermal IR images of metal-coated
capillaries while the flowed reaction is irradiated with microwaves
82
Figure 2.15 A metal-coated capillary (1700 \xm) positioned in the microwave
instrument cavity with a machined window
83
Figure 2.16 Thermal images of metal-coated capillaries, exposed to microwave
irradiation, in the cavity
85
Figure 2.17 Thermal images of the non-irradiated part of capillaries, outside of
86
the cavity.
Figure 3.1 Diels-Alder reactions conducted in continuous flow format
94
Figure 3.2 The dropwise ratio of maleic anhydride vs. 1-bromooctane in a
solution flowed through a Pd-coated capillary
Figure 3.3 The kinetic curve obtained during the investigation of the batch
microwave reaction of 2-bromoaniline, with 1-bromo-lphenylethylene
100
104
Figure 4.1 Distribution of conversion for the hydrosilylation reaction between
triphenylsilane and methylpropargyl ether conducted in different
gold-coated capillary microreactors
118
Figure 4.2 Distribution of conversion for the hydrosilylation reaction between
triphenyl silane and methylpropargyl ether conducted in a recycled
gold-coated capillary microreactor
119
Figure 4.3 A formal [4+2] benzannulation reaction between an enynal or
enynone unit and alkynes
120
Figure 4.4 The proposed mechanism of the benzannulation reaction between
aromatic carbonyls and alkynes catalyzed by Au111 complexes
127
Figure 4.5 Zwitterionic intermediates involved in benzanuulation mechanism
catalyzed by Au111 catalysts
128
XII
LIST OF TABLES
Page
Table 1.1 Radiation photon energies compared to chemical bond energies
20
Table 1.2 Loss tangent values for some common solvents used in organic
synthesis
25
Table 3.1 Suzuki-Miyara cross-coupling reactions of aryl boronic acids and
aryl bromides using MACOS with Pd-coated capillaries
89
Table 3.2 Heck cross-coupling reactions of aryl iodides with acrylates using
MACOS with Pd-coated capillaries
90
Table 3.3 Diels-Alder cycloaddition reactions of 80 and 81, 83 and 84, 86 and
87 employing Pd-coated and clear capillaries as reaction vessel
95
Table 3.4 Indole synthesis in MACOS via Pd-PEPPSI IPr-catalyzed coupling
of 2-bromoalkenes and 2-bromoaniline, using both clear capillaries
and metal-coated ones
103
Table 3.5 An indole library synthesized using a continuous-flow format with
Pd-PEPPSI-IPr catalyst in a Pd-coated capillary reactor
109
Table 4.1 Vinylsilane products synthesized in flow with MACOS via catalysis
by Au thin films
116
Table 4.2 Optimization studies for benzannulation reaction using MACOS
122
Table 4.3 Substituted naphthyl ketones synthesized in flow format using
MACOS.
125
Table 4.4 Optimization studies for the three-component coupling of propargyl
amines in MACOS
131
Table 4.5 Propargyl amines synthesized in-flow using Cu-coated capillaries as
reaction vessels in MACOS
134
Table 4.6 Control experiments for the synthesis of propargyl amines in flow
format
136
xiii
LIST OF ABBREVIATIONS
AES
atomic emission spectrometry
atm
atmosphere
bp
boiling point
Conv
conventional
Cu(OAc)2
copper acetate
DMA
dimethylacetamide
DME
dimethoxyethane
DMAD
dimethylacetylenedicarboxylate
DMF
dimethylformamide
DMSO
dimethylsulfoxide
°C
degree Celsius
EDG
electron-donating group
EDX
energy-disspersive X-ray
EOF
electro osmotic flow
equiv
equivalent
EtOAc
ethylacetate
Et3N
triethylamine
EWG
electron-withdrawing group
FR
flow rate
FTIR
fourier transform infrared
gram
XIV
GHz
gigahertz(10 hertz)
h
hour
HPLC
high pressure liquid chromatography
HRMS
high resolution mass spectrometry
ICP-MS
inductively coupled plasma mass spectrometry
ID
internal diameter
ISM
industrial, scientific and medical
IPr
isopropyl
IR
infrared
LLD
lower level of detection
MACOS
microwave-assisted continuous flow organic synthesis
MAOS
microwave-assisted organic synthesis
mg
milligram (10" gram)
MHz
megahertz (IO6 hertz)
min
minute
mL
mililiter (losliter)
(im
micrometer (IO"6 meter)
MVK
methylvinyl ketone
MW
microwave
nm
nanometer (10" meter)
NMP
N-methyl-2-pyrrolidone
NMR
nuclear magnetic resonance
xv
Pd EnCat
Pd catalyst encapsulated in polyurea
PEPPSI™
pyridine-Enhanced Precatalyst Preparation, Stabilization and Initiation
Pd(OAc)2
palladium acetate
ppm
parts per million
ps
picosecond (10" second)
psi
pounds per square inch
PTFE
polytetrafluoroethylene
rt
room temperature
s
second
SEM
scanning electron microscopy
t
tertiary
tan
tangent
'BuONa
sodiumbutoxide
TMS
trimethylsilyl
TMSOTf
trimethylsilyl triflate
UV
ultraviolet
w
watt
wt
weight
XVI
Chapter One
Introduction
1.1 Continuous flow reactors and microwave-assisted synthesis as
"enabling technologies"
Advancements in synthetic methodology, from a technological perspective, have
occurred primarily in a traditional vessel format, regardless of the specific chemistry
selected. Today, the issue of developing new technological approaches in organic
synthesis has become important because of the impact that new technolgies have on the
chemical and pharmaceutical industries. These new approaches have been lumped
together and called "enabling technology", an area that has received increasing attention,
as such technology does influence the way in which organic synthesis is being conducted.
The broader defmition of "enabling technology" includes traditional techniques such as
"solid phase synthesis" as well as relatively new ones such as "microwave-assisted
synthesis", "continuous flow reactors" etc, (Figure 1.1) which were developed to speed
up synthetic transformations and ease process workup.1 It is likely that modern syntheses
will not be based on the individual use of new technologies, but will likely require the
integration of several enabling technologies into a versatile synthetic platform.
Solid Ph 11 se
iissisted Catalvsis
Continuous Flow
Reactors
New Solvent
Svstems
M W assisted
Sviithesis
Figure 1.1 Schematic representation of enabling techniques and possible combinations of
such techniques for developing new synthetic platforms
2
The combination of the techniques shown in Figure 1.1 is one of several possible;
different synthetic platforms will require not only different combination sequences, but
also the inclusion of new techniques, as the best combination will have to be determined
and optimized. "Continuous flow reactors" and "microwave assisted synthesis" will be
discussed in detail in this chapter, as our own technological approach presented in this
work is based on the integral combination of these two technologies.
1.2 Continuous flow technology and its advantages
The development of continuous flow systems based on microfluidic technology has seen
huge steps forward over the last decade, mainly driven by the need to address an
important concern. Both small-scale chemical research and large-scale industrial
applications are conducted mainly in a batch-wise manner, using conventional glassware,
whereas flow-through processes are used primarily to satisfy specific industrial
production needs.1'2 This arrangement makes it difficult to adapt the batch protocols to
flow-through industrial applications, because the accumulated research data from batch
protocols cannot be transferred readily to industrial systems. Continuous flow processes
are considered a universal tool to fill this technological gap; such processes allow the
quick transition from research platforms to industrial process development, thus
eliminating the time and material-consuming optimization process from bench-top
reactions to a full production scale.2
In particular, continuous flow systems based on microfluidic technology, known as
microreactors, are becoming commonly employed in organic synthesis, both on the
research scale and process development.3
3
Continuous flow systems do offer several advantages when compared to batch based
protocols, such as:
Process reproducibility and reliability.3,4 Flow processes are characterized by
constant mixture composition; also, the accumulation of unreacted reagents is avoided
due to their fast removal from the reaction zone. Because of the small cross-sectional
dimensions of the reactor, the heat and mass transfer efficiency is increased and the
effects of erratic mixing and thermal gradients are largely avoided.5
Facile automation. Not only are considerable amounts of time, materials and
human labour involved in identifying the optimal reaction conditions for batch reactions
on a small scale, but oftentimes these conditions cannot be readily transferred to a scaledup process. The small dimensions of microstructured continuous flow systems, on the
other hand, allow for the use of minimal amounts of reagents and make possible the rapid
screening of reaction conditions. The automation of such systems ensures tighter quality
control, by allowing immediate information feedback from the in-line analytical modules
and the rapid application of this feedback in order to optimize reaction conditions.6
Increased process safety. In general, process automation in these devices requires
very little human intervention, and this manner of conducting potentially explosive
reactions greatly improves safety for individuals.
Process diversification. Linear, divergent, as well as convergent multistep
syntheses are also feasible by assembling a series of flow reactors, provided that solvent
switching is not required and that full conversion of starting materials in each step is
ensured.
4
These positive features of flowed synthesis can be utilized successfully by synthetic
chemists in order to overcome the hurdles associated with the optimization of chemical
transformations conducted in round-bottomed flasks. Furthermore, in order to obtain
significant amounts of product, the reactors are simply run longer (the scale-out
principle) e or, alternatively, several reactors can be placed in parallel (numbering-up)
all using identical reaction conditions.6'8
1.3 Operational features of flow microreactors
In addition to the advantages stated above, the use of microfluidic continuous flow
technology brings with it several unique features from an engineering standpoint that
significantly enhance the application of such systems.
1.3.1 Diffusion-controlled mass transfer
It is known that the flow regime in microchannels is laminar, the typical Reynolds
number representing the ratio of inertia forces to viscous forces is below 10, as compared
to a Reynolds number greater than 3000 typically associated with turbulent flow in
channels. Under laminar flow conditions, the mass transfer across a channel section will
be dominated by diffusion, which allows for relatively accurate predictions of the flow
behaviour, leading in turn to a highly controlled manipulation of the flow regime within a
microfluidic channel network. This feature of the flow systems enables the operator to
accurately control the reaction progress by initiating or quenching reactions in a
controlled manner.2'6
A close estimate of the time t needed for diffusion across the entire width of the channel
w is calculated based on Fick's law9 as shown in Equation 1
5
t = 5w2/D
(1)
(D is the diffusion coefficient).
It is clear that by scaling down the dimensions of the channel there is going to be a
significant reduction in time needed for complete diffusion-based mixing. However, even
for microchannel-based systems, the time needed for the complete mixing of two streams
can be high (for a typical channel width of lOOum and an average value of D of 5x10"10
9
1
m s" the time is about 100s). Considering the small dimensions of microreactors, the
incomplete mixing of reagent streams can lead to poor reactivity.
1.3.2 High surface area-to-volume ratio
Scaling-down of reactor size increases the surface area-to-volume ratio considerably (for
example, the surface area-to-volume ratio of a tubular channel follows a 2r.r
relationship, where r is the radius) to the extent that it plays an active role by influencing
several parameters of the process.
1.3.3 Electro-osmotic flow (EOF)
EOF is one of the main surface-dependent applications in these reactors (due to the high
surface-to-volume ratio). The operating principle of EOF is shown in Figure 1.2. The
negative charge of the glass channel wall (created through ionization of immobile surface
groups) attracts a nanometers-thick layer of counter-ions, which, under the influence of
an electrical field applied along the channel, moves at a constant speed towards the
negative electrode, thus dragging the solution in the channel along.6
6
O
^e-ph(+)
Æ>ø~ø
v(+>
©
w
v(-)
e
^
„
0 0 ffi ©
©© ©^ ©
EOF
•
©ø
Figure 1.2 Voltage-driven mobility of different charged species and EOF generated by
the diffuse layer of cations adsorbed on the negatively charged glass wall.
In addition to EOF, the charged species within the electric field also have an additional
electrophoretic velocity (e-ph vector), with a magnitude comparable to EOF velocity.10
This application, although limited to glass and high polarity solvents, has several
advantages over alternative pumping methods: it can be miniaturized easily as there are
no mechanical parts involved, and the voltage sequence can be applied under automated
computer control.
This feature of using voltage sequences to direct reagents to selected
points at specified times, provides the ability to control the spatial and temporal evolution
of chemical processes.6'11
1.3.4 Surface functionalization
The relatively large surface area of microstructured channels can be utilized in several
ways: a) The surface can be modified with specific chemical groups (such as amines) that
can bind biologically active molecules, such as antibodies. This bio-functionalized
surface can be a rapid, fiexible tool for bioanalysis.12 b) The electrical charge of the
surface can be altered by either plasma treatment13 or surface coating with silanising
agents.
The charge alteration can in turn alter the EOF direction within the channel.
7
Loading the channel surface with different chargés can result in counter-flows within the
same channel, which can improve mixing significantly.15 c) The surface can be coated
with either hydrophilic or hydrophobic groups (usually by treating the surface with
silanising reagents), in order to change the contact behaviour of reagents with the
surface.14
1.3.5 Heat and mass transfer
The heat and mass transfer in channels with a high surface-to-volume ratio is
significantly improved due to a significantly higher heat and mass transfer area per unit
volume. Furthermore, the heat and mass transfer within a small volume occurs in a
shorter time, enabling the quick formation of a homogeneous reaction medium, a factor
that will have a positive impact on reaction kinetics and conversion rates. As a specific
example, highly exothermic reactions are safely handled in these systems due to
relatively small thermal mass and rapid heat dissipation.
1.3.6 In-line integration of chemical analysis and automated processing
equipment
The capability to integrate in-line analytical and processing equipment (purification etc)
with microreactors for rapid monitoring of reaction conditions is considered a very
important feature of such reactors. Using these capabilities, assessing chemical kinetics
and identifying optimal conditions of multistep processes is possible in a controlled
fashion.16
8
As an added benefit, feedback-controlled optimization of reaction conditions with
automated methodology can greatly reduce the time and labour costs associated with
development of synthetic protocols." The availability of UV and FTIR detectors has
made possible the integration of spectroscopic measurements in microreactors, although
the FTIR spectrometers can only be used with silicon reactors which are IR
transparent.183 Råman spectroscopy has been incorporated also into the microreactor
design as an effective monitoring device.18b A recent report describes the successful use
of NMR spectroscopy to assess the reaction progress during catalytic hydrogenation in
microreactors.
a
Such multiple modules within one microreactor design (Figure 1.3) can
clearly make these systems attractive tools for the pharmaceutical industry, where high
throughput and information-rich techniques are constantly being sought for the rapid
evaluation of reaction arrays.2
A practical example of a lead discovery and optimization system is shown in Figure 1.3.
In normal use, the reagents are injected into the system by the pumping array. When the
reagents reach the microreactor they mix and react. The reaction time depends on the
combination of flow rate and channel size and length. After exiting the reactor, the
product slug is detected by an UV-Visible detector. The detection of the slug triggers an
injection of part of the slug into the HPLC system, where reaction components are timeresolved. Then, the appearance of a product with appropriate properties, as identified by a
mass spectrometer, triggers an entry into the automated flow assay system.19b
9
system
MS
HPLC
UV Detectof
Pump
Figure 1.3 A lead discovery and optimization system based onflow microreactor
technology, incorporating in-line analytical and purification instruments1915
1.4 Microreactor design and fabrication
Microreactors are continuous flow devices with built-in fluid channels, with channel
internal diameters (ID) ranging from fractions of a millimeter up to several millimeters
(Figure 1.4). The basic reactor design includes an inlet, mixing and reaction and an outlet.
A more advanced design can include built-in chemical or physical sensors and additional
sections for concentrating and capturing reagents.I7'20a
Stainless steel is a popular material for these reactors, due to its robustness and
availability. The configuration can be modified easily, due to the wide availability of
micromixers and heat exchangers that can easily fit into such systems. These reactors are
compatible with organic solvents and can be operated under elevated temperature and
pressure conditions; however, they are not compatible with reactions involving corrosive
agents such as strong acids or bases.20b
10
Figure 1.4 Continuous flow microreactors. a) Silicon-based Jensen microreactor;
stainless steel microreactor system;23 c) glass chip microreactor8d
b)
Although polymer-based microreactors are easy to manufacture and relatively
inexpensive, they show low thermal conductivity and can be affected adversely by
reactions involving organic solvents that can dissolve the polymeric material or cause
swelling,200 thus the application of these reactors is restricted to ambient temperature
aqueous chemistry and biochemical processes.20d'f Ceramic-based microreactors are
stable at high temperatures and chemically inert, but their manufacturing process is
complicated by the thermal expansion/shrinkage of ceramic materials during baking.208
Glass, is also a popular choice as a material for microreactors, since fabrication methods
are well-established; glass is chemically inert and enables the use of visible light
detection, however, creating three-dimensional channels in glass is a difficult and costly
process.6'2011 Silicon is receiving wide attention as a material with high mechanical
strength and good chemical compatibility. Well-established wet and dry etching
techniques enable the controlled creation of microchannels. Also, the oxidation of silicon
surface forms a glass layer, making silicon chips functionally equivalent to glass
11
reactors.20lJ A protective coating process, such as Ni electroplating, can be applied to
silicon surfaces in order to increase the chemical resistance of such reactors.20k
1.5 The Scope of Applications
The majority of reactions conducted in continuous-flow microstructured reactors involve
homogeneous liquid solutions, as the design of such devices is best suited for handling
liquids. However, recent examples have shown that multiphase reactions can be
conducted successfully in flow as well.
1.5.1 Liquid phase reactions
A wide range of liquid-phase reactions have been performed in microreactor devices,
91
including epoxidations,
94
reactions,
99
9S
nitrations,
91 9^
aldol reactions, cross coupling reactions, '
91
glycosylations,
98
multicomponent
91 9ft
olefinations, '
97
peptide couplings,
Grignard
9Q
reactions, and Swern oxidations to nåme a few. Liquid-phase reactions carried out in
flow format benefit from the efficient mass and heat transfer inside microreactors, and
also from the fact that only small amounts of reactants are in the system at any given
time.
BnO-
\
OAc
tL,
BnCr"
BnO
BnO
TMSOTf
nO-"-"\
BnO-4
1
"Tl
cci3
2
1
BnO—x
Schem(5 1 . 1
12
o ^ \
An example of a glycosylation reaction is shown in Scheme 1.1, where more than 40
reactions for a coupling between mannoside 1 and galactoside 2 (Scheme 1.1) performed
in a Jensen microreactor system (Figure 1.4a) were observed within a day, using as little
as 2.0 mg of glycosylating reagent for each reaction. A conventional batch procedure for
the same protocol required significantly larger quantities of starting materials and was
limited to three reactions per day.
1.5.2 Liquid-Solid reactions
Chemical processes that require solid reactants that do not dissolve are difficult to carry
out in microreactors, since solids may clog the channel network. Several different
approaches have been used in order to carry out reactions that use solid catalysts.
Catalytically-active metals may be immobilized on the inner walls of a reactor or may be
placed on miniaturized poles in the reactor channels. Another approach is to load the
catalyst on polymer beads in pre-packed reaction cartridges that are placed in the reactor
channel. '
In these processes, effective interaction between the phases take place due to
a high surface to volume ratio which can lead to considerable reaction rate enhancement.
Scheme 1.2
As an example, Heck reactions
have been carried out in the stainless steel reactor
shown in Figure 1.4b; a solution of phenyl iodide 5 and ethyl acrylate 6 has been passed
13
through a cartridge loaded with a 10 % Pd on charcoal (Scheme 1.2). The product (ethyl
cinamate 7) was isolated in 95% yield after 30 min at 150 °C, compared to a batch
strategy for the same reaction that gave 100% conversion after 10 min at 130 °C using an
homogeneous catalyst.
1.5.3 Liquid-Gas reactions
Continuous flow microreactors are particularly suited for liquid-gas reactions, which are
generally difficult to perform because of the hazardous nature of reactive gases. The high
mass transfer rates promote gas-liquid reactions that are limited by the transport of gas
I T
species into the liquid reaction medium in larger vessels.
However, reactor design has
to incorporate engineering features that allow for the careful control of gas flow in the
reactor, as well as the regulation of contact time between gas and liquid, and the
separation of the gaseous phase at the end of the reaction.34 The utility of microreactors
for this chemistry has been illustrated for reactions such as fluorination,35 chlorination,36
mtration etc.
CHq
F2, CH3OH, rt
Scheme 1.3
As an example, the direct fluorination of toluene (Scheme 1.3) was performed at room
temperature in a silicon microreactor that was internally coated with nickel to render it
compatible with the corrosive fluorine gas.2
14
Taking advantage of highly efficient heat
transfer enables this exothermic reaction to be manageably conducted under flow
conditions; monofluorination of toluene was achieved with very good selectivity. By
using five equivalents of elemental fluorine in methanol as solvent, 96% conversion was
reported, yielding the monofluorinated toluenes 9, 10 and 11 in a ratio of 3:1:2,
respectively.
1.5.4 Liquid-Gas-Solid reactions
Important multiphase catalytic processes, such as catalytic hydrogenation and oxidation
reactions often suffer from long reaction times due to poor interactions between the
different phases. Again, continuous flow microreactor technology ensures higher reaction
rates due to an increased surface-to-volume ratio and allows for accurate control of
crucial parameters such as temperature and residence time.
HCk
^ \
HO.
15
Scheme 1.4. a) A chemoselective reductive amination conducted in an H-Cube
hydrogenation reactor; b) H-Cube® flow hydrogenation reactor
As an example, hydrogenation of imine 12 (Scheme 1.4a) was conducted in an H-Cube®,
a commercially-available continuous flow hydrogenation reactor (Scheme 1.4b), by
employing a catalyst cartridge loaded with 10% palladium on charcoal at 20 bar
hydrogen pressure. The reaction yielded the desired amine 13 quantitatively and in high
purity, without affecting other functional groups such as the nitrile and the phenol.
37
1.5.5 Natural product synthesis
The technological scope of the flow microreactor approach has been tested in the
synthesis of natural products. Not only has this technology been able to handle
multicomponent and multistep operations in order to construct architecturally diverse
natural product molecules such as grossamide3 and oxomaritidine.39 The synthesis of
grossamide 18 was eventually achieved in less than a day (Scheme 1.5).
MeO.
COOH
Reagent1
H7N„
16
Reagent 2
MeO
Reagent3
Reagent 1
18
OMe
-Enzyme
(peroxidase)
Grossamide
OH
Scheme 1.5
1.6 Limitations of continuous flow reactors
Continuous flow technology is often superior to batch processing in efficiency and
practicability,
however, a critical viewing of continuous flow systems is often
necessiated, by the need to define limitations of such systems. Such limitations include:
Continuous flow reactors often face cost-related issues. The fabrication of chip
microreactors requires specialized facilities with fabrication costs running into the
thousands of dollars.
These reactors often possess a complex engineering design that requires inclusion
of complex heating and mixing modules. Although the laminar flow regime has often
17
been considered a favorable feature due to diffusion-controlled mass transfer, it does
slow the kinetics of chemical transformations. Also, connecting microreactors to external
fluid reservoirs under pressurized conditions is considered a challenging task technically
due to potential leakage problems or mechanical stress on the system.40
In order to be fully automated the system design has to incorporate in-line
facilities for purification of intermediates or final products: a solution which is both
expensive and technically challenging (Figure 1.3).
Chemical transformations that require solid starting materials or yield solid
intermediates and/or products are difficult to carry out, since solids can clog the channels
and potentially incapacitate the entire system.
These reactors often face problems associated with different kinetics of reactions
and the necessity for different solvents when performing multistep syntheses in the flowthroughmode.1
1.7 Microwave irradiation theory
Microwave irradiation is normally considered the part of the electromagnetic spectrum
occurring between infrared and radiofrequency radiation (Figure 1.5); the wavelengths lie
between 0.1 cm and 100 cm and the frequencies between 300 GHz and 300 MHz. Two
major applications of microwave emitting devices are telecommunications and heating.
Wavelengths between 1-25 cm are used extensively for radar and telecommunication
purposes, whereas the heating applications use Industrial, Scientific and Medical (ISM)
frequencies which are 27.12 MHz (11.05 m), 915 MHz (37.24 cm) and 2.45 GHz (12.24
cm) respectively. All domestic microwave ovens and dedicated microwave reactors for
18
chemical synthesis use a frequency of 2.45 GHz in order to avoid interference with
telecommunications and radar frequencies.
It is known that Gamma Ray and X-Ray photons have sufficient energy to cause
excitation of core electrons. Ultraviolet and visible irradiation are also used in
photochemical reactions to excite valence electrons. However, by comparing the data in
Table 1.1, it is clear that microwave irradiation cannot induce chemical reactions 41
Wavelength (m)
Radio
13
IO
Microwave Infrared Visible Ultraviolet X-Ray
I2
IO
•
r5 — H
KT
10-*
1
- f -8
IO'
10"'°
7-Ray
I
IO'2
Frequency (Hz)
10*
108
1015
10»2
10 16
mW
iQiQ
Figure 1.5 The Electromagnetic Spectrum
The microwave photon (calculated by using Planck's law E = hcA.) at a frequency of
2.45 GHz carries insufficient energy to cleave chemical bonds.
19
Radiation
Frequency
(MHz)
Quantum Energy
(eV)
Bond Type
Bond Energy
(eV)
Gamma Rays
3.0 x IO14
1.24 x IO6
C-C
3.61
X - Rays
3.0 x IO13
1.24 x IO5
C=C
6.35
Ultraviolet
9
1.0 x IO
4.1
C O
3.74
Visible light
6.0 x IO8
2.5
c=o
7.71
C-H
4.28
O-H
4.80
Hydrogen
bond
0.04-0.44
Brownian
motion
0.0017
6
Infrared light
3.0 x IO
0.012
Microwaves
2450
0.0016
Radiofrequencies
1
9
4.0 x IO"
Table 1.1 Radiation photon energies compared to chemical bond energies42
1.8 Microwave thermal effects
Microwave-related chemistry relies on the ability of materials to convert microwave
irradiation into heat; the "heat generation" mechanism is related to the interaction of the
molecules of a given material with microwaves. Microwaves are electromagnetic waves
which consist of an electric wave and a magnetic wave, with the magnetic wave
oscillating at a 90° angle to the electric wave (Figure 1.6). The electric wave has been
shown to be the more important in these interactions,43b'44 although in some instances the
magnetic field component has been shown to play a significant role (magnetic field
interactions with transition metal oxides).45
20
Figure 1.6 Electric (E) and magnetic (M) field components in microwave irradiation
The main effect derived from the interaction of the electric field component with material
molecules is heating. Two main mechanisms41 are recognized today for this type of
interaction: dipolar polarization and ionic conduction.
The dipolar polarization mechanism43 applies only to polar materials and is based on the
tendency of the dipoles to follow the inversion of the oscillating electric field (Figure
1.7). Molecules, possessing dipole moment, align themselves in the applied electric field
in a certain pattern, and as the field oscillates the dipole matrix attempts to retain the
induced pattern by realigning itself with the alternating electric field. This generates heat
in the process through molecular friction and dielectric loss.41 The amount of heat
generated is proportional to the ability of the applied electric field to generate an optimal
phase difference between the orientation of the electric field and that of the dipole matrix.
If the phase difference is too large (the dipole matrix has no time to realign under high
frequency irradiation) or too small (the dipole matrix re-aligns too quickly under low
frequency irradiation), minimal heat is generated. The frequency of 2.45GHz, used in
21
dedicated microwave equipment, allows the dipole matrix to re-align without following
the alternating field precisely. The phase difference thus generated causes thermal energy
to be gained through molecular friction and collisions, in the form of dielectric heating.
The frequency of microwave irradiation is close to that of the rotational relaxation
process, however, it is important to emphasize that the microwave-solvent interaction is
not considered a quantum resonance phenomenon. There is no evidence to indicate the
involvement of quantized rotational bands; microwave-induced dielectric heating is a
collective property involving aggregates of molecules. ' '
The ionic conduction mechanism43 applies to materials containing charged particles (such
as ionic liquids etc). The dissolved charged particles, involved in an oscillatory motion
under the influence of an alternating electric field, collide with adjacent molecules,
generating heat in the process. The ionic conduction mechanism is considered to be just
as efficient as the dipolar polarization mechanism in the heat-generating process.41
b)
'\
x \
V
/ x .
+ + + + + +
Figure 1.7 Effects of surrounding electric field on dipole orientation: a) static electric
field; b) alternating electric field
22
1.9 Microwave-induced dielectric heating
Microwave-induced heating efficiency for different materials is dependent on the
dielectric properties of each material. A dielectric material contains either permanent or
induced dipoles, such that the material acts as a capacitor when placed in an electric field
i.e., the material allows an electrical charge to be stored with no conductivity observed.
The polarization of dielectric materials arises from the charge displacement or rotation of
dipoles in an electric field. At the molecular level, polarization involves either the
distortion of the distribution of the electron cloud within a molecule, or the physical
rotation of molecular dipoles, 7 which are particularly important in the mechanism of
microwave dielectric heating. The permittivity of a material c is a physical property
which describes the polarizability of that material, whereas the dielectric constant or
relative permittivity E' is the permittivity of the material relative to that of free space.
Dielectric polarization depends primarily on the ability of dipoles to reorient in an
applied electric field. In a liquid phase, molecules rotate so rapidly that they are able to
respond to field oscillations occurring at a frequency of IO6 times per second. However,
when the material is exposed to electromagnetic radiation, the electric field component is
reversed much more rapidly and the dipoles are no longer able to keep up with the
oscillating field, at frequencies of IO9 times per second or higher, thus creating a phase
difference. The re-orientation of the dipoles and displacement of charge is equivalent to
an electric current, known as the Maxwell displacement current,43b which is at 90° phase
difference with regard to the oscillating electric field (Figure 1.8a).
23
Electric field
Current I
b)
Time
90°
Maxwell displacement current
Electric field E
d)
c)
Electric field E
Figure 1.8 a) Applied sinusoidal electric field (top) and out-of-phase induced Maxwell
displacement current (bottom);43 b) phase diagram for an ideal dielectric where the
energy is transmitted without loss; c) phase diagram showing a phase displacement 6 and
generation of Maxwell displacement current (I x sina); d) diagram illustrating the
relationship between £*, s' and s"; tan 8 = s"/ s \
In an ideal scenario, where there is no phase difference between the orientation of the
molecules and the variations of the alternating electric field, the Maxwell displacement
current is zero (Figure 1.8b), and therefore no heating occurs. If the frequency of the
electromagnetic radiation reaches that of the microwave, the rotations of the polar
molecules in the liquid begin to lag behind the electric field oscillations, and as a result a
phase difference 5 is generated (Figure 1.8c). This phase displacement contains a
component / x sin å aligned with the electric field, and so resistive heating occurs in the
24
irradiated material (formally described as dielectric loss). The total relative permittivity is
characterized as shown in Equation 2
£* = £' - j 8"
(2)
"
(E' is the dielectric constant and E" is the loss factor that reflects the conductance of the
material).43b
As shown in Figure 1.8d, tan å = E"/E' is defined as the loss tangent or energy dissipation
factor, whose values provide a convenient parameter for comparing the efficiency of
conversion of microwave energy into thermal energy. A material with a high tan å is
required for an efficient absorption of microwaves. A general classification based on tan
5 values can identify materials as high {tan å > 0.5), medium {tan å 0.1-0.5) and low {tan
å < 0.1) microwave absorbers.41 The loss tangents for several organic solvents are shown
inTablel.2. 48
Solvent
tan 5
Solvent
tan 5
Solvent
tan 5
Ethylene glycol
1.350
2-butanol
0.447
Chloroform
0.091
Ethanol
0.941
0.280
Aceton itri le
0.062
DMSO
0.825
1,2-dichlorobenzene
1-Me -2-pyrroIidone
0.275
Ethyl acetate
0.059
2-propanol
0.799
Acetic acid
0.174
Acetone
0.054
Formic acid
0.722
N,N - DMF
0.161
THF
0.047
Methanol
0.659
1,2-dichloroethane
0.127
Dichloromethane
0.042
Nitrobenzene
0.589
Water
0.123
Toluene
0.040
1-butanol
0.571
Chlorobenzene
0.101
Hexane
0.020
Table 1.2 Loss tangent values for some common solvents used in organic synthesis
Materials without a permanent dipole moment have no relaxation process in the
microwave region, and are therefore considered microwave-transparent. However, the
overall dielectric properties of the reaction medium can change due to the polar nature of
reagents and/or catalysts, allowing sufficient heating by microwave irradiation.
25
Alternatively, polar additives
a
(ionic liquids or alcohols) or passive heating elements
(chemically inert, strong microwave-absorbing materials such as SiC) can be included in
the reaction medium in order to increase the microwave-absorbing capacity of the
medium. The energy transfer between the polar molecules, capable of coupling with
microwaves, and the non-polar molecules is rapid,
a
and therefore provides an effective
mechanism for heating non-polar solvents. The frequency dependence of £*, E' and s"
functions is described by the following Debye equations43b
S* = Eco + (S s - R») / ( l + JCOX)
(3)
e' = £oc + (ss - Eoc) /(l + © V )
(4)
£" = (ES - £oo)G>T / ( l + © V )
(5)
(x is the relaxation time - the time interval needed for the aligned dipolar molecules to
achieve a randomized state after the applied electric field is removed, co = 2nv is the
angular frequency of the electromagnetic radiation and ES and ex are the values of relative
permittivity at frequencies v « T"1 and v » T"1 respectively).
Equations 4 and 5 demonstrate the dependency of the dielectric properties of a given
material on the irradiation frequency. As an example, the dielectric properties of water at
25°C are plotted against the irradiation frequency in Figure 1.9 (most organic solvents
behave similarly to water).41 The loss factor E" reaches a maximum at about 18 GHz as
the dielectric constant E' falls. Although dedicated microwave generators operate at a
much lower frequency (2.45 GHz), the appreciable E" value at this frequency still allows
for rapid microwave heating; microwaves at this frequency can penetrate the water layer
deeper43a as compared to irradiation at an optimal frequency of 18 GHz .
26
80
60
40
20
1
15
30
Frequency (GHz)
Figure 1.9 Dielectric properties of water plotted against irradiation frequency
The penetration depth is an important consideration in microwave theory, and is
calculated based on the standardized value of l/e, that represents the point where the
microwave power has been reduced to 36.8% of the initial value.42 Penetration depth is
inversely proportional to tan å; for this reason materials with high tan å values have low
penetration depths for microwave irradiation as it is absorbed in the outer layers of
materials. The inner part of the material will then be heated by a conventional convection
mechanism (Figure 1.10a).
The average relaxation time is also an important parameter in determining the suitability
of materials for efficient heating under microwave irradiation. The operating frequency of
2.45 GHz corresponds to a relaxation time of 65 ps; therefore all organic molecules with
relaxation profiles that incorporate a relaxation time of 65 ps are able to couple efficiently
with microwave irradiation at that frequency. This conclusion has been supported by
experimental observations for a range of polar organic solvents that satisfy this
27
condition. The average relaxation time is temperature-dependent, as it decreases with an
increase of temperature; this directly affect the loss tangent which increases with
temperature. On this basis, some organic solvents that appear to be unsuitable candidates
for dielectric heating due to long relaxation times at room temperature can begin heating
very rapidly as the temperature increases.46a Therefore, temperature increase will bring a
loss tangent increase, thus enabling the solvent to convert more of the microwave energy
into thermal energy. The resulting phenomenon is described as thermal runaway.50 This
situation can potentially compromise process safety; however, if the necessary
precautions are tåken, the temperature of the reaction medium can rise well above
conventional boiling temperature (superheating), leading to substantially enhanced
reaction rates.46a
1.10 Microwave heating of metals
A somewhat different heating mechanism, defined as charge space polarization, has been
described for materials possessing free conducting electrons, such as semiconductors or
metals. 4 3 "' 4 4 3 ' 5 1 ^ microwave irradiation can induce a flow of electrons on the surface,
that can heat the material via a resistance heating mechanism. The electrons move under
a microwave-induced magnetic field, which then induces eddy currents, causing heat in a
material due to its resistivity. These eddy currents create a secondary magnetic field
opposite to the excitation field, generating a repelling force that opposes the original
microwave. This means most of the microwave energy is reflected off the surface of the
metallic layer.
28
Skin depth Sd (see Equation 6) is the parameter that quantifies the penetration of metals
by microwave irradiation, defined as the depth from the surface at which the current
density is l/e (0.368) of the surface value;53 the value of Sd is very small, typieally on the
order of l-6um.54
Sd = (2/ton<r)1/2
(6)
(ca is the angular frequency, ]i is the permittivity and <r the conductivity of the metal).
One major problem associated with microwave irradiation of metals is the severe
electrical arcing caused by charge accumulation on metal surfaces, which can have a
potentially destructive effect on the equipment. The extent of arcing can be influenced by
several factors such as metal morphology, particle size, metal conductivity, solvent
system, etc.55a The solvent superheating (see Section 1.11) is not observed under these
conditions due to partial evaporation occurring on the metal's surface. However, the
generation of gas pockets in this manner can lead to plasma formation, the existence of
which increases the possibility of electrical discharges to the equipment.51'56
These considerations become particularly important for microwave-assisted applications
with thin metallic layers.
1.11 Advantages of microwave heating over conventional
heating
thermal
The traditional conductive heating of organic processes by external heat sources still
plays a dominant role in organic chemistry. This process relies on the thermal
conductivity of the reaction vessel materials, as well as convection currents within the
29
vessel (Figure 1.10, a). The conductive heating is generally considered an inefficient
method for transferring energy into the reaction; the temperature of the heat source and
that of the vessel walls must necessarily be higher than the reaction medium, increasing
the possibility of a temperature gradient being developed within the reaction medium
from the vessel wall into the reaction bulk and this can lead to local overheating. In
contrast, microwave heating is an irradiation process that raises the temperature of the
vessel volume simultaneously, provided that the reaction vessels are not large (Figure
1.10, b). The reaction vessel itself is not affected thermally by microwave irradiation
since it is made of microwave transparent materials, thus an inverted thermal gradient
exists from the reaction bulk into the vessel wall, resulting in greatly reduced hot wall
effects.41
b)
Magnetron
Figure 1.10 Schematic comparison of conventional (a) and microwave heating (b).41
30
Several other advantages displayed by microwave dielectric heating over conventional
thermal heating are known:
The introduction of microwave energy into a reaction medium can lead to much
higher heating rates than those achieved conventionally. Heating rates of 2-4 °Cs_1 can be
achieved readily for common organic solvents; such heating rates would require furnaces
heated over 1000 °C using conventional heating methods.46'57
The microwave-based technology allows for the remote introduction of
microwave energy into the reactor; there is no direct contact between the energy source
and the reaction vessel. Not only does it lead to faster heating rates, it also generates a
significantly different temperature profile for the reaction (Figure 1.11). At higher
temperatures, the rate of chemical reactions using microwave irradiation is much higher
and the reaction times shorter, so consequently the products also need remain a relatively
shorter time in the process vessel. The "hot wall" effects are also eliminated as the
temperature of the reactor walls is lower than that of the inner liquid volume. There are
assumptions in the literature that temperature-sensitive reagents or catalysts may rapidly
deteriorate at the hot vessel surface under conventional heating conditions. The
elimination of such "hot wall" effects when heating using a microwave can increase the
lifetime of catalysts and lead to berter conversions. However, the lack of dedicated
studies in this area to date makes it hard to quantify such effects.41
31
Temperature
Microwave heating
.
Conventional heating
Time
Figure 1.11 The temperature-time profiles for conventional and microwave dielectric
heating (using similar power setting) 46a
Microwave dielectric heating is a suitable method for accelerating chemical
reactions under pressurized vessel conditions. It is possible to increase the temperature of
a reaction in cornmon organic solvents over 100 °C above the conventional boiling point
of the solvent using microwave irradiation443,58 Studies have shown that although the
enthalpy of vaporization is the same under microwave and conventional heating
conditions,
microwave-heated liquids boil at temperatures above their conventional
boiling points at atmospheric pressure, mainly due to the remotely introduced massheating mechanism, that eliminates the role of nucleation points on reactor's surface.41'50
For example, the microwave dielectric heating of ethanol (bp = 79 °C) in a closed vessel
at 164 °C lead to a pressure of 12 atm. Heating at this temperature will lead to an
32
enhancement of about 10 in the reaction rate, as calculated by the Arrenius kinetic
equation (7).
K= A e (Ea/RT)
(7)
(K is the reaction rate constant, R is the gas constant, A is the Arrenius pre-exponential
factor and Ea is the activation energy of the reaction)
Components of a reaction medium can have different interactions with microwave
irradiation, therefore selective heating of such a medium can be achieved. This
phenomenon can be exploited in several applications.
Hetet-ogeneous reactions involving metal powders and gases. The metal particles interact
very strongly with microwaves, whereas gases are transparent to microwave irradiation.
Under microwave irradiation conditions, the metal particles begin to heat up rapidly,
causing a rapid reaction between the metal and gas components. Formation of
macroscopic hot spots (with temperatures of 100-150 °C above bulk temperature) have
been shown to have a pronounced effect on reaction rates.60'61a This strategy has proven
effective in the preparation of oxides, halides, sulphides, etc. of transition metals.55
Heterogeneous reactions in liquid solvents. Although precautions have to be tåken in
order to prevent electrical arcing, such as the use of low-microwave settings, high-boiling
solvents and small well-dispersed metal particles,463 the formation of "hot spots" due to
the powerful
coupling of microwave irradiation with metal nanoparticles or
heterogeneous materials can accelerate greatly reaction rates.60 It is presumed that the
temperature of the catalysfs surface is significantly higher than the bulk reaction
medium,
and these localized "hot spots" can have an important impact on the outcome
33
of the process. It has been shown that a very small number of superheated areas is
sufficient to induce a substantial rate enhancement (2% of hot spots can increase reaction
yield by up to 60%), even if their effects on the averaged process temperatures cannot be
detected.46b'62a Several successful strategies have also been reported detailing synthetic
protocols that involve reagents on solid supports such as silica and alumina.
As an
example, the selective heating of Pd/C catalyst was utilized in the hydrogenation of
diphenylbutadiene 19 (Scheme 1.6). Microwave irradiation of this heterogeneous
transformation gave complete conversion after 5 minutes, whereas the same reaction
performed under conventional heating proceeded with only 55% conversion. The use of a
fiberoptic
sensor
ensured
accurate
temperature
monitoring
in both cases.62b
Pd/C, H2 (4 bar), EtOAc
19
MW or conventional
heating, 80 °C, 5 min
Ph'
20
MW heating: > 99% conversion
Conventional
heating: 55% conversion
Scheme 1.6
Homogeneous reactions containing polar additives. The scope of microwave dielectric
heating can be extended to solvents, normally transparent to microwaves, that contain
polar additives.643'65 The energy of such polar molecules, known as "molecular radiators",
is assumed to dissipate extremely fast into cooler surroundings43'46 because it has been
shown that is not possible to store the microwave energy in a specific part of the polar
molecule by selectively activating the polar functional groups.43b'66 The inclusion of only
2% methanol in benzene (a microwave transparent solvent) ensures rapid heating of the
solvent mixture under microwave irradiation, which couples effectively only with the
34
methanol molecules. However, the rate of energy transfer through molecular collisions is
so fast that the benzene molecules are also heated rapidly.
a
1.12 Microwave effects
1.12.1 Thermal effects and specific microwave effects
It is now generally accepted that the major contribution of microwave irradiation
technology to chemical synthesis is the generation of thermal effects, that are responsible
for the dramatic rate enhancements.64 Such rate enhancement can be rationalized by
purely thermal/kinetic considerations43a on the basis of the Arrhenius kinetic law
(Equation 7). The pre-exponential factor A and activation energy Ea remain unchanged
for the purpose of the thermal effects.41
In addition, microwave effects that are caused by the uniqueness of the microwave
dielectric heating mechanisms are also recognized. These effects, known as "specific
microwave effects", are capable of accelerating the process kinetics in a manner that
cannot be duplicated by conventional heating (see Section 1.10). However, these effects
essentially
remain
thermal
effects.64a
1.12.2 Non-thermal effects
In addition to the thermal effects mentioned above, there are believed to be unique effects
associated with microwave irradiation that cannot be explained by purely thermal
considerations. These non-thermal, or athermal effects, result from the direct interaction
of the electric field with specific molecules in the reaction medium. This affects the
35
orientation of polar molecules, which affects either the pre-exponential factor (A) or the
activation energy (Ea) in the Arrhenius equation (7).
It has been argued that the application of a microwave field to dielectric materials induces
rapid rotation of molecular dipoles, which increases the probability of contact between
molecules and then collision efficiency. The pre-exponential factor A, which represents
the probability of efficient molecular collisions, is descibed by Equation 9.
A = yX2T
(9)
(y is a geometric factor which includes the number of nearest-neighbour jump sites, X the
distance between adjacent lattice planes (the jump distance), and r the jump frequency,
which is directly proportional to the vibration frequency of atoms at the reaction
interface).
An increase in molecular mobility under microwave irradiation increases the preexponential factor A, therefore increasing the rate of reaction.63
A typical example is provided in the microwave synthesis of titanium carbide.67a (Scheme
1.7).
MW or conyentional
Ti0 2 + 3C
heatmg
^ TiC + 2CO
1300-1550 °C
Scheme 1.7
The reaction rate using microwave irradiation was 3.4 times higher than the rate found
with conventional heating, which could be explained by the pre-exponential factor being
3.4 times higher during microwave heating with no change in activation energy.
The decrease in the free activation energy AG* is considered another major non-thermal
effect of microwave irradiation. Considering that AG* consists of an enthalpy and an
entropy term (AG* = AH* - TAS*), it has been predicted that microwave irradiation
36
generates a more "ordered" environment as a consequence of dipolar polarization; as a
result, the entropy term TAS* would increase in a microwave-irradiated medium, in turn
decreasing AG*.63,67c'68 Experimental evidence for this assumption has been provided in
the microwave-assisted intramolecular imide formation of polyamic acid68c (Figure 1.12).
The AG* factor is clearly reduced in the case of microwave heating and that has been
attributed to a non-thermal microwave effect. It has been argued that when the polarity of
reaction intermediates or transition state species is increased on going from starting
materials to the transition state, the stabilization of the transition state species is more
effective that that of the starting materials, resulting in an enhancement of reactivity by a
decrease in the activation energy 41'63>67c'69 (Figure 1.13).
a)
NMP
37
b)
* Ink
-2.0
Microwave heating
-3.0
-4.0
-5.0
Conventional heating
-6.0
-7.0
J
I
I
1
I
L
AG* (kJ/kmol)
Microwave
57 ± 5
Conventional
_1_
2.20 2.25 2.30 2.35 2.40 2.45 2.50
Activation
mode
105 ± 14
1000AT(K)
68c
Figure 1.12 a) Intramolecular imide formation of polyamic acid; b) Arrhenius plots for
the imide formation via microwave irradiation and conventional heating
A+ B — -
Reaction coordinate
Figure 1.13 Proposed stabilization of reaction intermediate species under microwave
irradiation via lowering of transition state energy
38
Similarly, it has been argued that a non-thermal microwave effect should be more
pronounced for reactions that occur via a late transition state with an high activation
energy. The transition state in this case is more prone to developing increased polarity,
when compared to a reaction that occurs via an early transition state with only a small
difference in polarity from the starting materials.41'63'670'69
A typical example to support this effect has been provided in the form of two irreversible
Diels-Alder cycloadditions, performed over an extended time interval under both
conventional heating and microwave irradiation conditions in order to balance any
uneven thermal effects (Scheme 1.8). 70
a)
COOEt
COOEt
COOEt
COOEt
150 °C, 2.5hours, neat
MW or conventional
heating
23
24
v
COOEt
COOEt
26
No development of chargés
in transition state intermediate
MW heating: 37% yield (52:48)
Conv. heating: 36% yield (53:47)
b)
COOMe
Ph
COOMe
150 °C, 3 hours, neat
MW or conventional
heating
28
MW heating: 64% yield
Conv. heating: 19% yield
Development of chargés
in transition state intermediate
Scheme 1.8
39
Detailed ab initio calculations of the two reactions revealed a concerted isopolar
mechanism for the first reaction in Scheme 1.8a, with no chargés and therefore no
polarity developed in the transition state. Performed under microwave irradiation
conditions, the yield of this reaction was the same when heated by microwave or
conventional heating. On the contrary, the second reaction in Scheme 1.8b, for which the
ab initio calculations revealed a significant charge development in the transition state,
performed significantly berter under microwave irradiation conditions. According to the
authors, the difference in the reaction yield for the second reaction is a clear indication of
the existence of non-thermal effects that stabilize the polar transition state, thus lowering
the activation energy of the microwave-assisted reaction pathway. This consequence does
not exist in the first reaction due to the lack of electrostatic interactions of electric field
with the transition state. However, a re-investigation of the second Diels-Alder reaction
in Scheme 1.8b, using a fiber-optic sensor technology in order to obtain accurate
temperature readings, revealed no differences in yield between oil-bath and microwave
irradiation conditions. This result was attributed to thermal effects playing the same role
in both heating methods (conducted at an accurately-recorded temperature), rather than
invoking a special non-thermal microwave effect.71
The above example, as well as other arguments that support the existence of non-thermal
microwave effects are still the subject of considerable debate and controversy.72 It is the
opinion of some of the leading experts in this field that the concept of non-thermal
microwave effects has to be critically re-examined, and further evidence presented in
order to reach a definite conclusion about the existence of such effects.64
40
1.13 Dedicated Microwave Reactors
The practice in the latel980s and early 1990s of conducting microwave-assisted synthesis
in domestic microwave ovens has been abandoned today due to safety concerns.41
Heating organic solvents in open vessels can lead to explosions induced by electric arcing
and the lack of real-time pressure monitoring can lead to vessel rupture. Furthermore
synthetic protocols often suffer from reproducibility problems due to the inhomogeneous
nature of pulsed microwave irradiation.
Today, domestic microwave ovens have been replaced by dedicated microwave
applicators in most research laboratories, which feature built-in temperature and pressure
sensors and software that enables on-line temperature or pressure control. The main
components of a dedicated microwave reactor are the magnetron (microwave generator),
the waveguide (a transmission line that guides the microwave irradiation into the
microwave cavity), and the cavity itself, which accommodates the reaction vessel. The
magnetron (Figure 1.14a), consists of a cylindrical cathode in the centre of a circular
chamber, surrounded by an anode block possessing small cavities and the system is
operated under vacuum. The electrons emitted from the cathode due to a high-voltage
electric field are defiected by a magnetic field applied parallel to the cathode axis which
causes electrons to spiral outwardly instead of gravitating straight into the anode.
Sweeping inside the cavity, these electrons induce a high-frequency electromagnetic
field, a portion of which is extracted by a short antenna connected to the waveguide. This
in turn directs the induced microwave field into the instrument cavity and the microwavegenerating efficiency of these devices is in the 65-70% range (Figure 1.14b).
41
Figure 1.14 a) Cross-sectional view of a magnetron depicting the pathway of electrons
under the applied magnetic field; b) cross-sectional view of a single-mode microwave
cavity41
Early microwave applicators were multi-mode instruments, where the microwaves were
reflected by the walls over a large cavity (similar to a domestic microwave oven) and
interacted with the sample in a random manner. Although the samples were rotated inside
the cavity, the density of the field around individual samples was low, despite the high
microwave power being used (1000-1600 W) resulting in poor performance for smallscale reactions. This was addressed to a large extent in modern multi-mode instruments
that can accommodate multiple reaction vessels in the presence of a homogeneous field.
The more recent single-mode microwave applicators also generate a homogeneous
energy field of high density around the smaller cavity (Figure 1.14b) despite relatively
low power levels (typically 300-400 W). The homogeneity of the microwave field
ensures sustained equipment performance and process reproducibility. The temperature
on the surface of reaction vessels can be measured by a remote, built-in IR sensor, that
does not always represent the actual temperature of the reaction bulk. The more
42
expensive fiber-optic temperature probes, that can be immersed directly into the reaction
vessel, are mainly available in larger, multi-mode microwave instruments.
Figure 1.15 Single-mode microwave instruments a) Biotage Initiator 60, equipped with a
rack and robotic arm; b) CEM Voyager (flow instrument) and its flow cell; c) CEM
liberty peptide synthesizer.
The steady performance of single-mode microwave instruments has been the driving
force behind their design development. A number of instruments are now commercially
available and in use in research laboratories, offering, among other features, flow-through
systems and solid phase peptide synthesis (Figure 1.15).41
1.13.1 Microwave-assisted continuous flow technique as technological
solution to batch microwave scale-up problems
Reported initially in 1986
the advantages of microwave-assisted organic synthesis
(MAOS) as an enabling technology1 has led to its use in a wide variety of
applications.41'64'74 The publication of more than 3500 manuscripts in this field64b is a
strong indicator of the impact that this technique has had on synthetic organic
methodology. MAOS protocols have been exploited successfully in drug discovery,75
43
total synthesis,
biochemical processes,
polymer synthesis,
nanotechnology
and
materials science.80
The main technical limitation for single-mode microwave devices is the small cavity size,
which generally allows the use of vessels no larger than 1-5.0 mL; for that reason the
majority of microwave-assisted reactions published to date have been conducted on a
scale of less than 1.0 g.64'81 However, in order to fulfill the demands of pharmaceutical
and industrial applications, there is a need to develop larger-scale microwave-assisted
protocols that can ultimately provide products on a multi-gram or even kilogram scale.
The limited penetration depth of microwave irradiation is perhaps the biggest challenge
in scaling-up microwave-promoted protocols since it limits the size of the reaction vessel
that can be used. Depending on the dielectric properties of particular solvents, the
maximum penetration depth of 2.45 GHz microwaves is on the order of few
/-Q-T
centimeters.
t
Therefore microwave power density inside a large reaction volume may
be negligible when compared to the surface density, thus invoking a convection heating
mechanism (Figure 1.10a) as opposed to microwave dielectric heating.81 Consequently,
as the size of the reaction vessel increases, it becomes more difficult to heat the larger
reaction volume, requiring additional microwave power. However, as the capacity of the
microwave reactor increases to 5000 W power levels, the standard air-cooling in
magnetrons is replaced by more sophisticated oil-based cooling, a factor that introduces
more complexity and cost into the system. *' 2 This consideration, the low energy
efficiency of converting electricity into microwave power (65-70%), and safety concerns
such as potential rupturing of large pressurized reactors, make the microwave approach
44
less
attractive
experts ' '
for
large-scale
processing.
'
It is the opinion
of several
' ' ' in this field that the solution to this problem is the combination of two
"enabling" technologies: microwave heating and flow processing, in the form of
microwave-assisted continuous flow technology.
In addition to advantages associated with continuous flow methodology (Section 1.2), the
microwave-assisted, continuous flow approach is an appealing alternative to scaling-up
MAOS protocols for several reasons:
It solves the scalability issues without the need for further optimization, by using
the scale-out and/or numbering-up approach (see Section 1.2). Once the reaction
conditions are optimized for the continuous flow protocol, substantial amounts of product
can be obtained by operating the system for a long time interval or running several
reactors in parallel under identical conditions.83b
It eliminates the safety concerns associated with powerful microwave heating of
large pressurized reactors. These concerns are negligible due to lower reaction volumes,
smaller instrument cavities and small scale reactors.
It bypasses the physical limitations of batch MW instruments such as penetration
depth and power constraints. Moreover, energy transmission is higher in smaller cavities;
low power magnetrons are suitable and therefore the process is more economical.
It offers the possibility of full system automation, resulting in a considerable
reduction of processing time and labour.
One problem associated with the continuous flow approach is the limited "residence
time" that any one plug of a reaction mixture experiences under microwave irradiation.
45
Further, processing heterogeneous mixtures in flow poses its own hurdles. The former
problem can be dealt with to a great extent by using coil-based designs for flow reactors
that can increase the residence time. As for handling slurries and solid reagents,
peristaltic pumps have been demonstrated to be effective in this regard.41'81
1.14 Microwave-assisted fluidic systems and their applications
1.14.1 Microscale fluidic systems
The numerous microwave-assisted, continuous flow systems in operation today
exemplify the successful application of the two "enabling" technologies in conjunction,
microwave heating and flow processing.
Strauss et al. were the first to develop and utilize a microwave-assisted continuous flow
quartz reactor (Figure 1.16) that provided accurate pressure and temperature control. The
reactor was operational at 200 °C, incorporating a back-pressure of 14 bar. In order to
prove the reliability of the microwave-assisted continuous flow concept, over 20
reactions,
including
nucleophilic
substitutions,
Diels-Alder
cycloadditions,
esterifications, base- and acid-catalyzed hydrolyses, isomerizations, decarboxylations,
eliminations etc, were performed at temperatures up to 100 °C higher than the boiling
point of the solvents at standard conditions, which accelerated the reactions by as much
as three orders of magnitude.
46
1—I 6
Sr-,
P 3
T
1 - Reaction mixturc
2 - Pump
3 - Pressure sensor
T
4
LAAAAJ
vVvv
;~3
7
N
4 - Microwave cavity
^
5 - Micro processor
6 - Temperature sensor
7 - Heat exchanger
8 - Pressure control
valve
9 - Collection vessel
5
_
Figure 1.16 Schematic design of the continuous flow system developed by Strauss84
A custom-built glass-chip reactor was designed by Haswell et al. (Figure 1.17a) that
incorporated an immobilized Pd catalyst (Pd/AbC^), which was re-used several times in a
heterogeneous Suzuki-Miyaura cross-coupling protocol (Figure 1.17b).
Coating the
outside of the catalyst channel with a strongly microwave-absorbent gold layer proved to
be effective in generating the necessary heat for the reaction.
a
'
^ø***~\
i****Sz:
Teflon tube
Fitting connectors
Glass reactor
Glass
reactor
Supported
Pd catalyst
Microwave
cavity
Gold coating
Temperature
sensor
47
b)
-X
R30
+
ArB(OH)2
31
Pd/Al 2 0 3; K 2 C0 3
DMF/H 2 0
R^VA,
*
MW, 44s, 3 mL/min
32
X= Br, I
R= CN, N0 2 , CHO, OCH 3 , CH 3
5 reactions
58-99% conversion
Figure 1.17 a) Continuous flow reactor built by Haswell; b) Suzuki-Miyaura crosscoupling reactions conducted in flow using the above reactor
Of
Jachuck et al. have reported the use of an isothermal continuous flow microreactor
(Figure 1.18a) in the oxidation reaction of benzyl alcohol by Fe(N03)3#9H20 (Figure
1.18b). The sealed polytetrafluoroethylene (PTFE) microreactor consists of reaction zone
microchannels (270 uL) that interface with heat exchange microchannels (600 uL). The
reactor is placed in a microwave cavity, and the heat generated in the reaction zone is
absorbed by water flowing inside the heat exchanger. This approach allowed the system
to operate under isothermal conditions where the reaction temperature fluctuated by less
0
86
than 0.3 °C during the process.
a)
XHO
Fe(N0 3 ) 3 9H 2 0
1
MW, 17s, 1 mL/min
V^
^
34
75% conversion
33
Figure 1.18 a) Isothermal continuous flow reactor built by Jachuck; b) oxidation of
benzyl alcohol conducted in flow using the above reactor86
48
Ley et al. employed successfully a U-shaped continuous flow reactor (Figure 1.19a) in
Suzuki-Miyaura cross-couplings (Figure 1.19b), using a polyurea microencapsulated Pd
catalyst (Pd EnCat).87 Applying pulsed microwave irradiation followed by short gas-jet
cooling extended the life of the catalyst to the point that cross-coupling products were
synthesized without the need for catalyst regeneration.
a)
5 reactions
81-92% conversion
Figure 1.19 a) U-shaped tubular microreactor built by Ley filled with Pd EnCat catalyst;
b) Suzuki-Miyaura cross-coupling protocol conducted in flow using the above reactor.
Kappe et al. used a rather unique reactor design (Figure 1.20a) to conduct a Dimroth
rearrangement of 1,3-thiazines into substituted dihydropyrimidines (Figure 1.20b). The
reactor was designed by fitting a standard 10 mL Pyrex tube with a custom-built steel
head. The inner space of the reactor was filled with 2 mm-sized glass beads in order to
create microchannels that would increase the residence time of the reaction mixture in the
microwave heating zone. The system was placed in the cavity of a CEM Voyager (Figure
49
1.15b), and the reaction mixture was pumped from the bottom of the reaction vessel and
forced to mo ve upwards through the glass beads.
a)
Inflow
Outflow
Back-pressure
regulator
Glass beads
Steel attenuator
10 mL glass
reactor
„
IR temperature
<•—' sensor
b)
Ph
i
EtOOC.
NMP
Me
U€
N
EtOOC
MW, 200°C, 66min
330ml_/min
H
38
88% conversion
Figure 1.20 a) Continuous flow reactor designed by Kappe; b) Dimroth rearrangement
conducted in flow using the above reactor88
Using a similar reactor design to the one shown in Figure 1.20a, although their reactor
was filled with sand instead of glass beads, Bagley et al. successfully conducted the
Bohlmann-Rahtz synthesis of pyridines by cyclodehydration of the corresponding
aminodienones. 89
50
Kirschning et al. also developed a unique continuous flow reactor_90 composed of
composite polymer materials in the form of rings, supported by a steel frame (Figure
1.21a). Immobilization of the Pd catalyst on the inner reactor surface was carried out by
pumping a Pd solution through the ring wall then reducing Pd with a sodium borohydride
solution, that led to the formation of Pd nanoclusters on the reactor surface (Figure
1.21b). The palladated reactor was placed in the cavity of a CEM Voyager (Figure 1.15b)
and was utilized in several synthetic applications, including a Heck cross-coupling
reaction (Figure 1.20c).
a)
b)
c)
Pd0
J
V
/
\
/
NEt3130 °C
39
41
40
75% yield
Figure 1.21 a) The composite ring reactor designed by Kirschning; b) SEM image of Pd
nanoclusters on the reactor surface (scale shown is 100 nm); c) Heck cross-coupling
conducted in flow using the above reactor64b'90
Another custom-made flow reactor was reported by Wilson et al.91 The flow cell,
consisting of a glass coil encased in a protective glass sheath (Figure 1.22a), was
51
designed to process reaction mixtures on a multi-gram scale (4.0 mL total flow cell
volume). Inserted into the cavity of a single-mode microwave reactor (Emrys
Synthesizer, similar to the one shown in Figure 1.15a), the system was operated either in
open- or closed-loop mode. Temperature measurements were performed by the internal
IR sensor of the instrument and pressure fluctuations were prevented by the use of a
back-pressure regulator mounted at the outlet tubing. A variety of Suzuki-Miyaura crosscoupling reactions, esterifications and nucleophilic aromatic substitution (Figure 1.22b)
were efficiently performed under microwave irradiation conditions
a)
b)
DIEA, EtOH
MW, 1mL/min, 5h
120°C
81% conversion
Figure 1.22 a) The coiled glass reactor designed by Wilson; b) microwave-assisted
nucleophilic aromatic substitution conducted in flow using the above reactor91
52
1.14.2 The Stop-FIow protocol
The Stop-FIow protocol is a microwave-assisted technique developed recently64 in order
to facilitate microwave processing on a gram scale; the technique is mainly suited to
process heterogeneous mixtures that can be incompatible with other fluidic systems. The
standard equipment for this technique is the CEM Voyager used in conjunction with the
flow cell, as shown in Figure 1.15b. The reagent mixtures are pumped into the vessel
using peristaltic pumps capable of processing slurries of reagents. The system is sealed
and all processing occurs under pressurized conditions; afterwards the processed mixture
is discharged from the vessel automatically and the system is ready to receive the next
batch.
Using the stop-flow approach, Leadbeater et al. successfully scaled-up the SuzukiMiyaura coupling of phenyl boronic acid and 4-bromoacetophenone as well as the Heck
09
cross-coupling of styrene with 4-bromoanisole.
The optimized reaction conditions on a
1.0 mmol scale for both protocols were introduced readily to a stop-flow strategy on a 10
mmol scale using the CEM Voyager instrument. A process cycle of 10 consecutive runs
provided, respectively, 18.5 g the Suzuki-Miyaura product (95% yield, 50 min total time)
and 14.9 g of the Heck product (71% yield, 200 min total time).
In a similar manner, Maes et al. performed several Pd-catalyzed amination reactions of 4chloroanisole with morpholine using the CEM Voyager reactor.93 The stop-flow
approach allowed for the smooth transition of optimized reaction conditions, from a 1.0
mmol to a 20 mmol scale. A process cycle of 12 consecutive runs provided an overall
yield of 76% for the amination product (190 minutes).
53
These examples, as well as several others '
detailing the utility of microwave assisted
continuous flow technology for larger scale processes in semi-pilot and pilot plant
industrial applications, indicate the great potential of the microwave-assisted continuous
flow approach in combinatorial chemistry and other synthetic applications.
1.14.3 Microwave-Assisted
(MACOS)
Continuous
Flow
Organic
Synthesis
The Microwave-Assisted Continuous Flow Organic Synthesis (MACOS) technique has
been developed recently by Organ et al.83 The technological core of this technique is a
custom-made continuous flow reactor that can operate in conjunction with a single-mode
microwave instrument. The basic continuous flow reactor design (Figure 1.23a) consists
of a stainless steel mixing chamber with three inlet ports, that are connected to an
external syringe pump, which merge into one outlet. Glass capillary reactors of varying
internal diameters (200-1180 //m) can be attached to the steel chamber by Microtight
fittings. After exiting the reaction capillary, the reaction mixture flows directly to a
monitoring device or collection vessel. The steel chamber sits atop a microwave
instrument cavity, and thus the capillary is kept in place within the irradiation chamber.
The capillary is irradiated with 2.45 GHz of single mode microwave energy that can be
varied between 0 and 400 W and the reaction temperature is monitored by an internal IR
sensor.
54
Re a gent leads from
. syringe pump
c)
b)
a)
/
Microtight
fittings
/9QR
u
PEEK tubing
Sinlets in total
_Stainless steel
mixing chamber
Stainless steel
mixing chamber
with mach in ed
channels
Microtight
fittings
Microwave
chamber
Microwave
chamber
Microwave
chamber
Microwave
chamber
Microwave
chamber
n
1-
To collectionvessel
Glass capillary
reactor
To collection
vessel
4Capillary reactors
in total
PEEK tubing
Figure 1.23 MACOS system capillary microreactors. a) schematic of the single capillary
reactor system; b) schematic of the parallel, multicapillary microreactor system, c)
photograph of the parallel, multicapillary microreactor system.
The utility of this design has been displayed in several chemical transformations
including Suzuki-Miyaura cross-couplings, Wittig reactions, nucleophilic aromatic
substitutions etc (Scheme 1.9). All transformations proceeded with very good conversion,
considering the brief time that the reaction mixture spent under microwave irradiation (45 minutes).
Furthermore, by changing the design of the steel mixing chamber the MACOS system
can be modified to incorporate several capillary reactors in parallel. The multi-reactor
chamber (Figure 1.23b,c) contains four pairs of inlet ports (8 ports in total), with the
channels of each pair merging to afford four outlet ports (Figure 1.24).
55
a)
R-X
45
+
Pd(OAc)2, base,
DMF/H2Q
MW, 100-170W
5-10 min
ArB(OH)2
46
R-Ar
47
10 reactions
65-99% conversion
R=Aryl or alkyl
b)
O
MeO-
/
DMSO
\
H
48
+
PPh3
EtO'
_ ^ MeOMW, 170W, 4 min
/ Y X
50
49
P
OEt
89% conversion
c)
OMe
.OMe
DMF, Hunigs base
MW, 170W, 5 min
51
~NO2
H 2 N'
OMe
OMe
52
53
>99% conversion
Scheme 1.9
ProductA1B1
ProductA2B2
ProductA1B2
ProductA2B1
Figure 1.24 Cross-sectional view of MACOS multireactor system for preparing libraries
in parallel synthesis
56
The four capillaries connected to each outlet form a multireactor system that is heated
simultaneously while the reaction mixture flowes through each capillary. Using this
technique, four streams containing all possible combinations were collected; the total
number of products obtained is only limited by the number of reagents involved. Several
libraries based upon Suzuki-Miyaura and nucleophilic aromatic substitution protocols
were collected this way in one of the first-ever examples of parallel synthesis in
continuous flow format involving microwave irradiation.
The scope of the MACOS application has also been extended to incorporate
multicomponent reaction strategies. Tetrasubstituted furans and quinolinones were
successfully synthesized in flow by employing a three-component reaction protocol
(Scheme 1.10) in which the three components were introduced separately into the single
capillary MACOS system.94 The short residence time (under 2 min) had no impact on the
reaction outcome, as both products were isolated in a very good yield.
57
a)
CHO
V^
DMSO
+ HN
\
54
MW, 170W, 2 min
55
R= CN, Br, OH, OMe, COOMe, N(CH3)2
5 examples
71-94% conversion
b)
NC
CHO
DMF, DMAD
MW, 170W, 2 min
58
MeOOC
R= H, Cl, F, OMe, N0 2 ,
C0 2 Me, CF3
R'= H, N0 2
COOMe
60
7 examples
30-79% isol. yield
Scheme 1.10 Multicomponent reaction strategies conducted in MACOS: a) synthesis of
quinolinones 57 from aldehydes 54, pyrazole 55 and dimedone 56; b) synthesis of
tetrasubstituted furans 60 from DMAD, isocyanide 58 and aldehydes 59.
58
1.15 Plan of Study
1.15.1 The use of Pd and Ag-coated glass capillaries as reaction vessels
for flow chemistry
Significant efforts have been made to integrate flow methods in synthetic chemistry as a
way to address the limitations associated with batch-based synthetic methodologies. The
combination of MAOS with flow techniques is considered a powerful combination for
this purpose because it exploits the benefits of both approaches. Microwave-Assisted
Continuous-Flow Organic Synthesis (MACOS) has demonstrated the power of
combining these technologies in several applications.83
The goal of this research is to develop new catalysts, immobilized on the reactor surface,
capable of catalyzing a variety of chemical transformations in flow. The new catalysts
must be capable also of operating under pressurized flow conditions and high
temperatures caused by microwave irradiation. Initially research will focus on the
development of thin metal films, such as Pd and Ag, deposited on the inner surface of
glass capillary reactors. Then the new reactors will be evaluated for MACOS. This
approach would expand the scope of synthetic applications for this recently developed
technology.
The metal films have to be thin enough so the glass vessels can withstand the high
temperatures generated under microwave irradiation; the films also have to be porous to
provide the highest surface area possible, which is an important consideration in
heterogeneous catalysis.
59
The newly designed capillary reactors will be tested initially in cross-coupling reactions,
such as Suzuki-Miyaura and Heck protocols. In previously reported MACOS protocols it
was briefly noted that an unevenly distributed thin Pd film, deposited on the inner
capillary surface due to the "blacking out" of the homogeneous Pd catalyst, was capable
of catalyzing the Suzuki-Miyaura cross-coupling on its own.83a The utility of metalcoated capillaries will then be tested in a more complex protocol such as indole synthesis
in continuous flow format.
1.15.2 Synthesis in flow using the Au and Cu-coated glass capillaries as
reaction vessels
Both Au and Cu nanoparticles have been used as heterogeneous catalysts in several
applications and for that reason we envisioned that thin films of these metals could
display catalytic activity under microwave irradiation. The Au-coated capillaries will be
investigated in the flow synthesis of vinyl silanes and naphthyl ketones while Cu-coated
capillaries will be used in the flow synthesis of propargyl amines.
60
Chapter Two
Preparation and characterization of thin metal films on glass capillary
reactors. Thermal images of thin Pd, Ag, Au, Cu films under microwave
irradiation
61
2. Results and Discussion
2.1 The development of thin Pd and Ag films inside glass capillary
reactors
2.1.1 Thin Pd films
The preparation of Pd films is based on methods for preparation of palladium particles by
thermal decomposition of organometallic compounds in organic solvents.
Thin Pd films were prepared by flowing a 0.1 mmol/mL solution of Pd(OAc)2 into a glass
capillary reactor, capping the ends, and heating the capillary at 120 °C for 30 min. During
this time, Pd0 was gradually deposited on the wall of the capillary, producing a black
film. Although the film formed uniformly around the entire glass surface, the capillaries
were rotated during heating to ensure an even thickness and to counter any effects of
gravity on the deposition process. To remove any residual organic matter and to improve
the adherence of the Pd to the glass, the coated capillaries were calcinated by heating
them at 400 °C (3 x 1 min) in a muffle furnace.
The morpholgy of thin Pd films was investigated by Scanning Electron Microscopy
(SEM) analysis and elemental composition was determined by Energy-Dispersive X-ray
(EDX) analysis. Close inspection of the Pd film morphology on the basis of SEMgenerated images reveals that these films are highly porous and consist of nanometer-size
Pd crystallites (Figure 2.1). Images in panels b-e show the extensively porous Pd film
morphology with increasing magnification. The higher magnification in panels 2.Id and
2.le reveals that the films consist of small Pd dusters ranging between 60 to 140 nm in
diameter. The Pd film thickness is approximately 2-3 (im as shown by the cross-sectional
view in panel 2.1b.
62
Figure 2.1 SEM images of Pd film morphology. a) Image of a Pd film removed from a
Pd-coated capillary at x 50 magnification; b) cross-sectional view of the same sample at x
5000 magnification; c) image obtained from the central portion of the film at x 1500
magnification d) image obtained from the central portion of the film at x 30000
magnification; e) image obtained from the central portion of the film at x 100000
magnification.
In order to study the effect of high-temperature calcinations on film morphology, several
Pd films were prepared on glass slides. After the film had been deposited and washed, it
was calcinated three separate times (1 min each time) at 400 °C.
EDX analysis was performed on the film formed in the capillary as well as on films that
had been prepared on glass slides. The non-calcinated slide films were found to contain
an average of 28.0 wt % of carbon, which dropped to 15.0 wt % for the calcinated slide
samples; the amount of elemental carbon dropped even further, to 5.5 wt %, for the
calcinated capillary films. This could indicate that the residual carbonaceous material is
63
most likely located on the surface of the Pd grains. SEM analysis of the Pd film on a
glass slide show a somewhat less developed morphology when compared to capillary
films (Figure 2.2).
Figure 2.2 The morphology of Pd film prepared inside a glass capillary (a) compared to a
Pd film prepared on a glass slide (b). Both images were obtained by SEM at 5000
magnification
The chemical composition of films prepared in capillaries consists primarily of Pd (94.0
wt %), C (5.5 wt %) and O (0.3 wt %). The oxygen could be associated with the presence
of a thin surface oxide on the Pd grains, although this was never confirmed. The presence
of such a small amount of carbon and oxygen indicates that the film is mostly metallic.
Based on the difference in weight of the capillary before and after the film preparation,
the film thickness as evaluated by SEM and the dimensions of the capillary, the density
of the porous Pd film was calculated to be around 3 g/cm3, corresponding to a porosity of
approximately 75%.
64
2.1.2 Thin Ag films
Thin Ag films were prepared using the well-known Ag mirror protocol. The glass
capillary reactors were filled with a freshly-prepared
solution consisting of
equivolumetric amounts of Tollen's reagent and 5% D-glucose solution, capped at both
ends and left to develop at rt. After the Ag coating was fully developed (5-10 min), the
capillaries were rinsed with acetone and placed inside the muffle furnace for calcination
at 400 °C before use.
The morphology of the Ag-mirror film was also investigated by SEM (Figure 2.3).
Figure 2.3 SEM images of Ag mirror film morphology. a) Top view of Ag-mirror film at
x 5000 magnification; b) and c) cross-sectional view of Ag-mirror film on the glass edge
at x 60000 magnification; d) cross-sectional view of Ag-mirror film on the glass edge at x
60000 magnification form a different angle.
65
In contrast to the porous morphology of the Pd film, the Ag-mirror film is very compact,
with only small voids between the grains. This morphology gives the Ag film its mirrorlike appearance, while the porous nature of the Pd film leads to a dark grey appearance,
despite the fact that both films contained the same quantity of metal by weight. Although
the Ag-mirror film was subjected to the same calcination process as the Pd films, this
appears not to have had a visible impact on the Ag film morphology, which remains
compact after the thermal treatment. The thickness of the Ag layer is also much less than
that of the Pd film (approximately 75 nm, Figure 2.3c), despite the fact that both films
contained the same quantity of metal by weight.
On the basis of this contrast, we re-examined the morphology of the Ag film and tried to
create a microstructure which would simulate the porous Pd film. This was achieved by
depositing Ag20 colloids from ethylene glycol onto the glass surface. For this purpose,
the glass capillaries were filled with a 0.5 mmol/mL colloidal solution of silver oxide in
ethylene glycol and then placed inside a muffle furnace and the temperature was
gradually increased to 140 °C. After the Ag coating was fully developed (30 min), the
capillaries were calcinated at 400 °C (3 x 1 min) before use.
SEM analysis, performed on the Ag layer, confirmed that the Ag colloidal films have a
larger surface area than the corresponding silver-mirror films (Figure 2.4, panels a, b and
d); EDX analysis of the film, performed in the area shown in panel 2.4c, confirmed that
they contained mostly Ag . However, the surface area is still much less than that of the
Pd films (see Figure 2.1 to compare images obtained at the same magnification).
66
Figure 2.4 SEM and EDX analysis of Ag film prepared from Ag20 colloids. a) Image
obtained at x 10000 magnification; b) image obtained at x 30000 magnification; c) EDX
analysis of Ag film conducted in the indicated area; d) cross-sectional image obtained at
x 50000 magnification
2.2 The development of methodologies for coating glass capillary
reactors with thin Au and Cu films
The initial success that we had in utilizing the Pd-coated capillaries for conducting
chemistry in flow with MACOS served as basis for extending the "catalysis by thin
films" concept to other metals such as Au and Cu. Both Au and Cu nanoparticles have
been used as heterogeneous catalysts in several applications (Chapter four); for that
reason we suspected that thin films of these metals with developed morphologies could
display catalytic activity under microwave irradiation conditions.
67
2.2.1 The development of thin Au films
We began our investigation with the development of a method to deposit robust gold
films on the surface of capillaries, capable of withstanding the heat and physical wearand-tear associated with MACOS technology.96 After several trials, it was determined
that the most robust and porous films resulted from a two-step deposition process that
utilizes two protocols known to generate Au nanoparticles, the polyol method97a and
sodium citrate method.
Firstly, a very fine layer of densely-packed gold particles was deposited directly on the
capillary wall from a 0.1 mmol/mL solution of AUCI3 in diethylene glycol. The clear
capillaries were filled with this solution, capped at both ends and left to develop at 180°C
inside a muffle furnace for 30 minutes. At the end of this deposition method, which can
be repeated several times in order to achieve a sufficient thickness of the first gold layer,
the capillaries were calcinated at 500 °C (3 x 1 min) in order to forge a strong bond of the
gold film with the glass surface.
A second layer of gold nanoparticle dusters was then deposited on top of the first layer
from an aqueous sodium citrate solution containing AuCb, prepared by mixing equal
volumes of a 0.2 mmol/mL aqueous solution of AUCI3 with a 1% aqueous solution of
sodium citrate. The capillaries, coated initially with a thin Au layer, were filled with this
solution and left to develop at room temperature. In approximately 90-120 min the
second gold layer would be fully developed and then the Au-coated capillaries were
calcinated at 400 °C (3 x 1 min) for a second time in order to forge a stronger link
between the two gold layers.
68
The gold film surface was investigated by SEM analysis (Figure 2.5) that clearly shows
the presence of two layers of gold with differing morphologies. The underlying layer
(Figure 2.5a) developed from the polyol method, although very thin, appears to be very
robust, compact and strongly attached to the glass surface. It serves as a foundation for
the second layer developed from the sodium citrate method, which grows vertically and
displays higher porosity (Figure 2.5b, c, d and e), a very important feature of the film that
can potentially influence its catalytic activity. The EDX analysis of the gold layer
indicates that the chemical composition of the film consists mainly of Au0 atoms (Figure
2.5f).
Figure 2.5 SEM and EDX analysis of the gold film. a) Image of the first Au layer
directly attached to the glass obtained at x 60000 magnification; b) image of Au
nanoparticle dusters of the second layer obtained at x 60000 magnification; c) image of a
different nanoparticle duster of the second layer obtained at x 30000 magnification; d)
image of the second Au layer obtained at x 5000 magnification; e) image of the second
Au layer obtained at x 1500 magnification; f) EDX analysis of the Au layer performed in
the area indicated
69
This protocol however is unusually long as it takes several hours to develop the two gold
coatings inside the glass capillary reactors. For this reason we started to investigate
alternative protocols for coating capillaries with gold. We experimented with the use of
bimetallic films and found that optimal results were achieved by laying down a porous
gold film on top of a thin silver mirror. This new approach shortened considerably the
time needed for generating the Au/Ag bimetallic coating and also allowed us to improve
dramatically the morphology of the gold layer. It has previously been demonstrated
(Section 2.1) that the Ag mirror films can be strongly attached to the glass surface by the
calcinations process. This feature allowed us to deposit up to two layers of gold on the
thin silver layer, using the sodium citrate protocol. To this purpose, the glass capillaries
were initially coated with a very thin Ag mirror layer, using the method described in
Section 2.1. After the calcinations process at 500 °C (3 x 1 min) in a muffie furnace, these
capillaries were filled with an aqueous sodium citrate solution containing AuCb
(prepared as described earlier in this section) and left to develop at rt. In approximately
20 min, the gold layer would be developed and this process would be repeated for the
second time. Then the capillaries coated with this Au/Ag bimetallic layer were calcinated
at 500 °C (3 x 1 min).
The SEM generated images of the bimetallic layer, shown in Figure 2.6, indicate that the
morphology of this double layer of gold consists of more developed gold nanoparticle
dusters (Figure 2.6a,c) than the Au-on-Au film (Figure 2.5). There are clearly two layers
of gold with a developed surface morphology (Figure 2.6b,d). The bottom Au layer is
70
supported on a very thin Ag layer (barely visible in the panel 2.6d) which is directly
attached to the glass surface.
Two gold
layers
Two gold
layers
Very thin silver layer
Figure 2.6 SEM analysis of the double layer of gold supported on a thin Ag film. a)
Image from the top obtained at x 50000 magnification; b) cross-sectional image obtained
at x 30000 magnification; c) image from the top obtained at x 30000 magnification; d)
cross-sectional image obtained at x 100000 magnification
2.2.2 The development of thin Cu films
Håving invested considerable time in developing protocols for coating capillary reaction
vessels with noble metals such as Pd, Au and Ag, we decided to investigate base metals
such as Cu as well, considering the rich chemistry associated with Cu-based catalytic
systems.
98
71
The method for deposition of Cu on the glass surface of capillaries is relatively simple
when compared to the gold-coating protocol as there is a single step that utilizes a
precursor solution of copper acetate in hydrazine. The clear capillaries were filled with
0.5 mmol/mL solution of Cu(OAc)2 in hydrazine, capped at both ends and left to develop
at 60 °C inside a muffle furnace for 5-10 minutes. This protocol generates a Cu
monolayer which is strongly attached to the glass surface. The subsequent calcination
methodology at 400 °C is used to further strengthen the metal film-glass bond and
possibly improve the porosity of the Cu layer.
Figure 2.7 SEM and EDX analysis of Cu film morphology. a) Image from the top
obtained at x 30000 magnification; b) image from the top obtained at x 60000
magnification; c) cross-sectional view of the Cu film on the glass edge obtained at x
100000 magnification; d) EDX analysis of the Cu layer.
72
The SEM technique was used to investigate the Cu layer morphology (Figure 2.7). The
images generated by this technique point to a surface morphology characterized by
smaller and relatively undeveloped dusters (Figure 2.7a,b) as opposed to the very
developed nanoparticle clusters of Au or Pd films. However the close-up cross-sectional
image shown in the Figure 3.1c indicates the presence of cavities in the film, a factor that
points to a considerable inner surface area.
EDX analysis demonstrates that the Cu film is primarily metallic in composition (Figure
2.7d). The film is normally produced in the presence of air, thus the existence of oxygen
detected by the EDX method could be explained by the presence of copper oxides on the
surface of the film. These metal oxides, which certainly exist in all previously discussed
metal films, could also play a role in catalysis.
2.3 The development of Rh and Pt thin films inside the glass capillary
reactors
The successful deployment of metal-coated capillaries (such as Pd, Au and Cu) as
reaction vessels in MACOS encouraged us to develop protocols for the deposition of
other transition metals that could display catalytic activity under microwave irradiation.
Our efforts were focused on developing thin metallic layers for Pt and Rh, whose
nanoparticles supported on inert materials have been used as heterogeneous catalysts in
industrial applications" and also organic reactions.100
73
2.3.1. The development of Rh thin films
The protocol for developing Rh thin films on the inner surface of glass capillary reactors
uses a solution of RI1CI3 in hydrazine. Films were prepared by filling glass capillaries
with a 0.5 mmol/mL solution of RI1CI3 in hydrazine and placing the capillaries in a
muffle furnace at 80°C for 15 min. During this time, metallic Rh gradually deposited on
the inner surface of the capillary producing a dark film, strongly attached to the glass.
Capillaries were then calcinated at 400 °C (3 x 1 min) in order to enhance film porosity,
drive off any residual organic matter, and improve metal adherence to the glass wall. The
Rh film morphology was examined using SEM technique and the chemical composition
of the film was determined by EDX analysis. The SEM images (Figure 2.8) showed that
the Rh thin films are very similar to Pd films in their morphology, possessing a high
degree of porosity and inner surface area (Figure 2.8, panels a,b,c). The chemical
composition of the film is Rh to a great extent as indicated by EDX analysis shown in
Figure 2.8d.
74
Figure 2.8 SEM and EDX analysis of Rh thin film morphology. a) Image obtained at x
1500 magnification; b) image obtained at x 5000 magnification; c) image obtained at x
60000 magnification; d) EDX analysis of the Rh layer
2.3.2 The development of Pt thin films
The method of preparation of Pt thin films on the capillary surface is based also on the
quick reduction of H2PtCl6 in hydrazine. The capillaries were filled with a 0.3 mmol/mL
solution of H2PtCl6 in hydrazine; the capillary ends were capped at both ends and the film
was left to develop at 60-80 °C inside a muffle furnace for 30 minutes. The subsequent
calcination process at 400 °C (3 x 1 min) generates a Pt layer strongly attached to the
glass surface.
The SEM technique was also used to investigate the Pt layer morphology. The images
generated by this technique point to a surface morphology characterized by dusters of Pt
75
grains forming a regular layer (Figure 2.9, panels a, b and c). The film thickness is
approximately 100 nm (Figure 2.9b). The close-up image in Figure 2.9c shows the
presence of cavities between grains in the film that can probably enhance the inner
surface area.
EDX analysis showed that the Pt film is primarily metallic in composition (Figure 2.9d).
There is a small percentage of oxygen also detected by the EDX method that could be
explained by the fact that the entire process occurs in the presence of air.
Figure 2.9 SEM and EDX analysis of Pt film morphology. a) Image obtained at x 20000
magnification; b) image obtained at x 30000 magnification; c) image obtained at x 60000
magnification; d) EDX analysis of the Pt layer.
76
2.4 The development of protocols for coating capillary reactors with
bimetallic layers of Ru-on-Pd and Rh-on-Pd
The development of bimetallic layer of Au-on-Ag (Section 2.2.1) prompted us to
investigate bi-metallic layers of other metals. This approach is convenient for developing
layers of metals that have low affinity for the glass surface and also represents a largely
unexplored field for heterogeneous catalysis in continuous flow format.
The glass capillaries were initially coated with a very thin Pd layer that forms a robust
link with the glass surface. These thinly coated capillaries contained less than 10% Pd by
weight (0.3-0.4 mg) when compared to a normally coated Pd capillary, the Pd film of
which can weigh 4-5 mg (Section 2.1.1). The Ru and Rh films were prepared by filling
the Pd-coated capillary reactors with a 0.3 mmol/mL diethylene glycol solution of RUCI3
and RJ1CI3 respectively, and heating them at 150 °C for 30 minutes in a muffle furnace.
This was followed by the calcination process at 400 °C (3 x 1 min) in the muffle furnace.
It was initially thought that the very thin Pd layer would serve as supporting platform for
the subsequent Ru and Rh structures, linking them to the glass surface; indeed this
procedure gave rise to a robust bi-metallic coating of the two metals (Pd-Ru and Pd-Rh)..
Surface characterization by SEM and EDX analysis for both the Ru-on-Pd and Rh-on-Pd
structures are shown in Figures 2.10 and 2.11 respectively.
77
Figure 2.10 SEM and EDX analysis of Ru-on-Pd bi-metallic layer. a) Image obtained at
x 60000 magnification; b) image obtained at x 30000 magnification; c) image obtained at
x 10000 magnification; d) EDX analysis of Ru nanoclusters performed in the area
indicated
Both sets of pictures show the random distribution of Rh and Ru structures on the thin Pd
film. The Pd thin film is shown as a non-porous layer (Figure 2.1 la) and serves simply
as a support for Rh and Ru "islands" to build upon. EDX analysis of both supported
layers confirmed the mainly metallic composition of both Ru and Rd structures as shown
in Figure 2.1 Od and 2.1 Id respectively.
The catalytic performance of both bi-metallic layers is yet to be explored.
78
Figure 2.11 SEM and EDX analysis of Rh-on-Pd bi-metallic layer. a) Cross-sectional
image obtained at x 30000 magnification; b) image from the top obtained at x 10000
magnification; c) image from the top obtained at x 50000 magnification; d) EDX analysis
of Rh nanoclusters performed in the area indicated
2.5 Measuring the temperature of metal film surfaces
In all studies described in the following chapters, we did not have an accurate
measurement of the actual temperature of the metal-coated reactor where conversion
occurred, as the temperature of the metal film could only be estimated. In all protocols
reported hereafter the temperature represents the value measured by the built-in IR
sensor. We suspected that the temperatures achieved inside the metal-coated glass
capillary reactors were much higher than those recorded by the IR sensor (180-230 °C as
79
reported under the reaction conditions below). After spending an average of 30-40 min
under microwave irradiation, the metal-coated glass capillaries often would be distorted
out of shape (Figure 2.12). For these physical changes to occur, the temperature of
capillary would have to exceed 850 °C which is the melting temperature of borosilicate
glass (for comparison purposes the temperatures obtained on the non-coated capillaries
are in the range of 80-100 °C).
Figure 2.12 Metal-coated glass capillary reactors (1700 um ID), after prolonged
exposure to microwave irradiation
The problem with the built-in IR sensor in the Biotage Initiator Synthesizer is that it was
designed to read the temperature of the vials that were designed for the irradiation
chamber. The sensor is comprised of a number of individual pixels and the temperature
that is read is the average of all the pixels. When a standard microwave vial is used, the
temperature is accurate because the sensor is small relative to the diameter of the tube;
80
capillaries only cover a small percentage of the area of the sensor, which means that most
of the pixels are targeting the air surrounding the tube (Figure 2.13).
tø i
Figure 2.13 Schematic presentation of the built-in IR sensor measuring the temperature
on surface of a) a standard vial and b) a tubular capillary reactor
Only recently we came into the means of assessing accurately the temperature on the
surface of metal-coated glass capillaries under microwave irradiation by employing a
FLIR Systems Thermovision™ A320 high definition IR camera. The temperature
measured by this camera can be focused down to the level of only a few pixels, which is
far narrower than the diameter of the capillary, meaning that the temperature of isolated
areas within the film can be accurately assessed. The set up shown in Figure 2.14 was
used where a small window was machined at the end of the waveguide to allow access to
the surface of the capillary in the irradiation zone by the camera.
81
Figure 2.14 MACOS set up for obtaining thermal IR images of metal-coated capillaries
while the flowed reaction is irradiated with microwaves. A small window (arrow) has
been machined into the end of the Initiator waveguide through which the FLIR Systems
Thermovision™ A320 camera is focused on the metal coated capillary. No microwave
irradiation escapes the irradiation zone, which is constantly monitored with a portable IR
sensor.
The camera's field of vision could be focused to measure the temperature on 3 cm of
capillary length inside the instrument cavity (Figure 2.15a). Thermal images of other
parts of the system were also obtained, such as a metal-coated capillary length,
protruding from the lower end of the cavity (Figure 2.15b).
82
Figure 2.15 A metal-coated capillary (1700 um) positioned in the microwave instrument
cavity with a machined window. a) The length of the capillary in the window is 3 cm,
positioned approximately 2cm below the end of the waveguide; b) part of the capillary
protruding out of the cavity, positioned approximately 12 cm below the end of the
waveguide.
83
Using this setup, accurate IR images of metal films were obtained for several metalcoated capillary reactors whose utility in several continuous flow applications has been
detailed in the following chapters (Figure 2.16).
1200.0°C
1000
800
600
400
200
199.9°C
1200.0°C
1199.8°C
1000
800
600
400
200
199.9°C
84
273.4°C
1199.8°C
1300.8°C
1000
Spol
6D4
S|)()2
7|7
800
600
l
N|)o3 )27
400
Spo4 ()5<>
>p<>5 SOI
200
199.9°C
- 200
306. 4°C
Figure 2.16 Thermal images of metal-coated capillaries, exposed to microwave
irradiation, in the cavity. a) Pd-coated capillary (1200 (am); b) Au-on-Au coated capillary
(1200 (im); c) Ag mirror-coated capillary (1200 (am) which appears distorted from
excessive heat; d) Ag (colloid)-coated capillary (1200 (am); e) Cu-coated capillary (1700
(am); f) Au-on-Ag coated capillary (1700 |am).
It is clear from all the thermal IR images shown above that the range of temperatures
within the metal-coated capillaries far exceeds the values indicated by the built-in IR
sensor; the temperature in the middle of the capillary exceeds 900 °C and while the
temperature steadily decreases moving away from the middle of the waveguide, it was
never less than 700 °C.
Interestingly, using the same IR camera, unusually high temperatures were observed in
the part of metal coating of the glass reactor which is not subjected to microwave
irradiation. Figure 2.17 shows the thermal images of two metal-coated capillaries (coated
with a thin Cu layer and Au-on-Ag layer respectively), protruding out of the microwave
chamber as shown visually in Figure 2.15b (there is no microwave irradiation at this
85
point as indicated by the portable IR sensor). Although there is a noticeable drop in the
temperature of metallic layer when compared to the temperatures generated inside the
irradiation chamber in the middle of the capillary, the temperatures of the bottom end of
capillary are still very high perhaps due to high thermal conductivity of metals. It is a
good indication that this part of the capillary reactor could still have a considerable
impact on reaction speed and catalysis.
Figure 2.17 Thermal images of the non-irradiated part of capillaries, outside of the
cavity. The actual length is approximately 3cm. a) Cu-coated capillary (1700 um); Auon-Ag coated capillary (1700 um).
86
Chapter Three
In-flow catalysis by thin Pd films
Applications to Suzuki-Miyaura and Heck cross-couplings, DielsAlder reactions and indole synthesis
87
3.1 Suzuki-Miyaura and Heck cross-coupling reactions conducted in
flow using Pd-coated capillaries as reaction vessels with M A C O S
The Pd-coated capillaries were initially used as reaction vessels with MACOS in SuzukiMiyaura coupling reactions, using a similar set-up to the one shown in Figure 1.22a.
Premixed solutions containing the aryl boronic acid, aryl bromide, base, and solvent were
put through the Pd-coated capillary while it was subjected to microwave irradiation. The
instrument's magnetron was turned on and off so as to maintain a temperature of 200 °C,
which was controlled by the internal infrared (IR) sensor in the microwave cavity. The
coupling of both electron-rich and electron-poor aryl halides with boronic acids was
achieved with good to excellent conversion (Table 3.1).96 In an interesting example, the
reaction with the highly-hindered 2-bromo-l,3,5-trimethylbenzene (Table 3.1, entry 6)
proceeded very well, although the reaction presumably took place at the surface of the Pd
film.
88
A r - Br
61
1 Equiv
Entry
+
A. KOH, DMF/H20, 200-205 °C
FR=15 ul/min
Ar' - B(OH)2
62
1.2 Equiv
Ar'B(OH)2
B(OH)2
/^B(OH) 2
Ar" - Ar"
B. K 2 C0 3 or CsF, DMA/H20
FR=15nL/min, 215-225 °C
Ar"Br
Conditionsa
\ j ' CHO
B r _
Br-
Product
Prod No
Convers b d.
(Isol. Yield)
\ />-\
/-CHO
63
88%
\ //X
//
64
95%
3
65
97%
3
65
7%
3
65
58%
2
^
3
(^B(OH)2
Br-\jHOCH3
4
C=)^B(OH)2
Br^l^OCH3
Batche / ^ W ^ V
MW
5
(^B(OH)2
Br-<Q^OCH3
° ^
< ^ ^ ^ O C H
6
Q^B(OH)2
B |
B
(\ / M \
h-
66
92%
7
I\QKB(OH)2
B
\ J ~ \
^CHO
67
93%
68
59%
69
73%
70
81%
(74%)d
71
84%
(76%)d
- G ^
Br^_J-CHO
A
Br
C
8
<Q^Q^OCH
0
CH
OHC
N^jKB(OH) 2
Brv
9C
Nr = VB(OH) 2
<\ />CHO
10
N^J-B(OH)2
Br
11C
r^^V-Q
Br^/-CHO
-B(OH)2
B
AJ
B
/^CHO
ff//-\ xx 7/
Table 3.1 Suzuki-Miyara cross-coupling reactions of aryl boronic acids and aryl
bromides using MACOS with Pd-coated capillaries. aTemperature is measured by the IR
sensor of the microwave. bConversion was determined as a ratio between product and
Ar"Br starting material on a crude sample obtained from the effluent from the capillary
by analyzing it by ] H NMR spectroscopy. cIn this case, 2.0 equiv aryl boronic acid was
used. Yield was determined by collecting a known volume of effluent from the capillary
and purifying the product by silica gel chromatography. eReaction conducted in batch
microwave at 200 °C, using reagents specified in condition A. Reaction flowed into a Pdcoated capillary, immersed into an heated oil bath, using condition A.
89
The Heck reaction was also investigated, and once again the Pd film was found to be very
effective in promoting this transformation under microwave irradiation conditions (Table
3.2).96 Again, pre-mixed solutions of aryl iodides and acrylates containing bases were run
in the MACOS system while the temperature was kept at 200 °C. Electron-deficient and
neutral aryl iodides were successfully coupled to different acrylates with good conversion
producing the E-isomer.
«..«,.«
CH 2 =CH-R
72
1 Equiv
Entry
1
Ari
^x ) - \
. , Et3N> D M A - T = 2 2 0 "225 °Ca
:
+ Ar-I
—
• Ar-CH = CH-R
73
FR=15 ul_/min
1.2 Equiv
R
Product
C0 2 CH 3
Product
No
^ ^ c O O M e
Conversion"
(Isol. Yield)
74
80%
75
58%
76
88%
77
$$>e
78
99%
MeCL^
2
MeO-^J-l
3
_
~^\-\
C0 2 CH 3
C0 2 CH 3
^ ^
C
Me^\
U ^
O O M e
r n n M o
COOMe
F
4
F^>,
\J-\
XX 7
C02CH3
UU
C02C(CH3)3
U l ^ ™
C 0 0 M e
t o
^^^C=N
(82%)c
Table 3.2 Heck cross-coupling reactions of aryl iodides with acrylates using MACOS
with Pd-coated capillaries. aTemperature is measured by the IR sensor of the microwave.
b
Conversion was determined as a ratio between product and alkene starting material on a
crude sample obtained from the effluent from the capillary by analyzing it by *H NMR
spectroscopy. cYield was determined by collecting a known volume of effluent from the
capillary and purifying the product by silica gel chromatography.
90
In order to shed some light on the mechanism of Pd film-catalyzed cross-coupling
reactions in flow, several control experiments were performed. One of the several
possibilities considered was that metal nanoclusters were liberated from the surface of the
superheated metal film, and that catalysis takes place with these clusters in solution. To
explore this possibility, DMF solvent was flowed through a Pd-coated capillary while it
was microwaved under identical conditions to those used during a typical coupling
reaction. After 2 mL of DMF was collected, half of it was placed in a standard batch
microwave vessel together with the remaining reaction components in analogy with the
coupling detailed in entry 3 (Table 3.1). The mixture was then heated under MW batchmode conditions for 20 min at the same temperature as that recorded under flow
conditions (200 °C). The batch reaction scarcely proceeded at all, as the measured
conversion was only about 7% (Table 3.1, entry 4). Additionally, a sample from the other
half of the effluent was analyzed for Pd content by atomic emission spectrometry (AES)
to determine if Pd was liberated from the film during prolonged heating; no Pd could be
detected (Pd content was less than 2 ppm). This strongly suggests that the reaction mainly
occurs at the metal surface and that little conversion results from solubilized Pd
nanoclusters. Analysis of the crude cross-coupling product mixture did show slightly
elevated levels of Pd (19.2 ppm). It is possible that the oxidative addition step takes place
at the surface, in so doing liberating Pd atoms, and then transmetalation and reductive
elimination occur in solution away from the surface.
The second control experiment was conducted in order to ascertain the need for
microwave irradiation of Pd films. Assuming that heating the Pd film to 200 °C is
91
responsible for the conversion observed, then heating the Pd film to the same temperature
by any other method should lead to similar conversions. The reaction in entry 3 (Table
3.1) was repeated, with the exception that the capillary was immersed in an oil bath set at
200 °C. The capillary was allowed to come to that temperature, and the flow reaction was
carried out under otherwise identical conditions. The conversion obtained was just over
half of that obtained by heating with microwave irradiation (Table 3.1, entry 5). Thus, in
the absence of irradiation, the same conversion rate cannot be achieved, meaning that the
microwave is essential for this process. An obvious question in this case would be: how
does irradiation cause these tremendous rate enhancements? With simple heat transfer,
the highest temperature that the film can obtain is the same as that of the heat source, in
this case 200 °C with the oil bath.
The number of previous reports that describe the utility of thin films under microwave
irradiation in catalysis is very limited. There are only two publications that describe
briefly the deposition of Pd black on the surface of batch reaction vessels, where the
metal films themselves proved suitable to catalyze Heck and Sonogashira couplings101 as
well as C-P coupling,
however no special heat effects due to coupling of microwaves
to the film were noticed. The involvement of "microwave effects" in reaction-rate
enhancement has been debated and many argue that microwave just heats more
effectively than conventional methods such as an oil bath, and that microwaves
themselves do nothing to improve reaction performance. The recent IR image of a Pdcoated capillary under microwave irradiation (Figure 2.16a) gives support to this
argument; the "hot areas" generated on the surface of the Pd film are well above the
92
average temperature of 200 °C recorded by the built-in IR sensor and it is quite possible
that these areas of the film are responsible for the tremendous rate enhancements
observed in these couplings.
3.2 Diels-Alder reactions in continuous flow format
In order to differentiate the role of heating from that of catalysis with metal films under
microwave irradiation conditions, we decided to investigate in-flow protocols for
chemical transformations that are not necessarily metal-catalyzed, such as Diels-Alder
reactions. A typical Diels-Alder reaction such as "Reaction 1" shown in Figure 3.1 was
initially selected; it was reported to proceed very slowly under batch heating conditions
without catalysis (80% yield after 24 h refluxing in toluene).
This reaction, using
microwave irradiation, was examined in-flow and the results are displayed in Table
3.3
104
Reaction 1
O
.0
.0
80
O
+
DMSQ, FR=10nL/min
1200 (im capillary
b
z
/
82
1 Equiv
93
>
Reaction 2
^
^
,0001-13
-CH 3
^ C H
hUC
DMSO, FR=10nL/min
1200 (im capillary
3
H,C
83
1 Equiv
84
1.5 Equiv
85
Reaction 3
COOCH3
.CX
COOCH3
DMSO, FR=10^L/min
1200 |im capillary
COOCH,
COOCH3
86
88
87
1 Equiv
1.5 Equiv
Figure 3.1 Diels-Alder reactions conducted in continuous flow format
Entry
Capillary
(1200 nm ID)
Pressure
(atm)
Temperature
(°C)
Conversion b
[Isol. Yield](%)
Reaction 1, Product82J
1
Clear
2
Clear
3
1
115
12
5
110
39
1
205
50
3
Pd-coated outside
4
Pd-coated inside
1
205
93 [80] c
5
Pd-coated inside
5
180
99
6
Clear
1
205 (oil batn)
50
7
Pd-coated inside
1
205 (oil bath)
75
8
Pd-coated inside
1
23 (No MW)
16
9
Clear
1
23 (No MW)
0
94
Entry
Capillary
(1200 nm ID)
Press ure
(atm)
r
\.
Reaction 2, Product 85
J
Clear
10
11
Clear
Temperature
(°C)
Conversion b
[Isol. Yield](%)
1
115
10
5
110
70
205
58
205
86 [70] c
180
96
3
12
Pd-coated outside
13
Pd-coated inside
14
Pd-coated inside
15
Clear
205 (oil bath)
46
16
Pd-coated inside
205 (oil bath)
64
17
Pd-coated inside
23 (No MW)
5
18
Clear
23 (No MW)
0
5
Reaction 3, Product 88
v
J
19
Clear
20
Clear
21
115
10
110
50
Pd-coated outside3
205
47
22
Pd-coated inside
205
90 [74] c
23
Pd-coated inside
180
87
24
Clear
205 (oil bath)
54
25
Pd-coated inside
205 (oil bath)
72
26
Pd-coated inside
23 (No MW)
1
27
Clear
23 (No MW)
0
5
5
Table 3.3 Diels-Alder cycloaddition reactions of 80 and 81, 83 and 84, 86 and 87
employing Pd-coated and clear capillaries as reaction vessel aA Pd thin film was
deposited on the outer surface of the capillary; the inner surface of the capillary had no
metal coating. bConversion was determined as a ratio between the product and dienophile
starting material 80 in Reaction 1 (dienes 83 and 86 for Reaction 2 and Reaction 3,
respectively) on a crude sample obtained from the effluent from the capillary by
analyzing it by 'H NMR spectroscopy. cPercent yield following silica gel
chromatography.
95
In a typical reaction protocol, the homogeneous mixture of dienophile 80 and diene 81 in
DMSO were flowed in the MACOS system using Pd-coated capillaries as reaction
vessels. Remarkably, almost quantitative conversion was achieved (Table 3.3, entry 4),
which meant that a reaction that had once proceeded to only 80% conversion under 24 h
of constant reflux in toluene solvent under batch conditions could now reach completion
in less than 3 minutes with MACOS (that is the residence time that a reaction plug spends
in the microwave zone).
Several control experiments were conducted in order to look at different aspects of this
synthesis under flow conditions. Compounds 80 and 81 in DMSO were initially flowed
together in MACOS through a clear glass capillary (Table 3.3, entry 1), while being
irradiated with sufficient energy to attain the same temperature as was reported during the
batch oil bath (approx. 110 °C).
Considering the short residence time in flow (the
reacting solution spends approximately 3 min in the irradiation zone of the microwave), it
is notable that even 12% conversion was attained; a similar control experiment conducted
in the absence of microwave irradiation led to no detectable conversion (Table 3.3, entry
9). To investigate the role of the Pd film as a source of intense heat, additional control
experiments were carried out. The clear capillary was submerged in an oil bath heated to
205 °C and the same mixture of 80 and 81 were flowed through, simulating the
conditions employed in the MACOS system; a considerable increase in conversion to
50% was observed (Table 3.3, entry 6).
The MACOS in-flow strategy was then extended to two other difficult Diels-Alder
cycloadditions (Figure 3.1, Reactions 2 and 3), which proceeded with a high conversion
96
when conducted in Pd-coated capillaries (Table 3.3, entries 13 and 22).104 Similarly, all
control experiments with new substrates in a clear capillary followed the same pattern.
To probe any catalytic role of the thin Pd film, several experiments were carried out.
In order to dissect the role of microwave irradiation, the three reactions were
performed in a Pd-coated capillary submerged in an oil bath heated to 205 °C.
Substantially lower conversion was noticed under these conditions: 75% for substrates 80
and 81, 64% for substrates 83 and 84 and 72% for substrates 86 and 87 (Table 3.3, entries
7, 16 and 25, respectively) suggesting that microwave irradiation is necessary and that
simple bulk heating of the film in the oil bath does not suffice to promote the highest
possible conversion.
To see if the Pd film had a stand-alone heating effect, we covered the outside of a
glass capillary with a Pd metal coating and performed the reactions in MACOS under
microwave irradiation. The IR sensor in the irradiation chamber recorded a temperature
of 205 °C. Conversion of 50% was attained for substrates 80 and 81 and similar
conversion was obtained for the reaction between 83 and 84, and 86 and 87 (Table 3.3,
entries 3, 12 and 21 respectively). With such thin glass walls and small reaction volumes,
heat transfer is generally accepted to be immediate. Thus, the temperature of the reaction
in the capillary would also be expected to be 205 °C, although the temperature reading
could be inaccurate as the IR emissivity of glass is different from that of Pd film.
Interestingly, when the same transformation was simply flowed through the same
Pd-coated capillary with no microwave irradiation, only 16% conversion was achieved
for substrates 80 and 81 whereas the other two reactions proceeded with much lower
97
conversion (Table 3.3 entries 8, 17 and 26). The same experiment, conducted in a clear
glass capillary, yielded 0% conversion for all transformations (Table 3.3, entries 9, 18
and 27). These results indicate that the Pd metal film must be playing a catalytic role in
these cycloaddition reactions in the absence of microwave irradiation and may also have
a catalytic role in the presence of microwaves.
As mentioned in section 2.1.1, EDX analysis of the Pd film indicates that its composition
is 94% Pd, 5.5% C, and 0.3% O by weight; therefore it is presumed that the vast majority
of the film is Pd0. To verify this, hydrogen gas was flowed inside a Pd-coated capillary,
which resulted in significant sparking, implying that a significant portion of the film's
surface is indeed metallic Pd. Trying to invoke a Lewis acid-type role for the film,
analogous to the well-established role of conventional electron-deficient metals105 in
homogeneous catalysis such as complexes of boron or aluminium, might seem
counterintuitive in this case, given the electron-rich nature of the Pd0 film. However,
reduced metals are definitely known to coordinate suitable substrates, for example, in
catalytic hydrogenation of olefins using Pd/C. It is possible that a similar mechanism
might be active under our conditions.
In order to further investigate such a coordinative role of the Pd0 film in the above
MACOS reactions, a solution was prepared containing an equimolar amount of maleic
anhydride and 1-bromooctane as internal standard (0.2 M in each), and it was flowed
through a Pd-coated capillary at rt (with no microwave irradiation); the effluent was
collected dropwise and each drop was analyzed for its composition. The results are
display ed graphically in Figure 3.2. Whereas 1-bromooctane, which presumably could
98
not coordinate to the film, came straight through the capillary, a portion of maleic
anhydride was retained in the capillary. This is clearly seen when one notes the amount of
maleic anhydride in drops 1 through 5. When the available sites on the film became
saturated, the maleic anhydride came straight through, and the slight over-concentration
seen in drops 5 through 10 was caused by the retained material being returned to the
infusing stream. After flowing the solution for a sufficient time, the concentration of
maleic anhydride equalled the initial concentration; i.e. 0.2 mmol/mL. Thus, it would be
reasonable to attribute a catalytic role to the Pd0 film, at least in part, that involves
coordination of the dienophile to the metal surface.
The effect of pressure within the flow system on reaction progress was also investigated.
All the experiments previously discussed were conducted with MACOS operating as an
isolated system under standard atmospheric pressure (latm or 15 psi); the only pressure
generated under these conditions came from the heat of the reacting solution, the
mechanical pressure exerted by syringe pumps and the walls of the system.
99
0.24
Conc
mmol/mL
0.22
•
0.20
1-bromooctane concentration
0.18
0.16
0.14
1
2
3
4
5
6
7
8
9
10
Drop number
Figure 3.2 The dropwise ratio of maleic anhydride vs. 1-bromooctane in a solution
flowed through a Pd-coated capillary
Under these conditions, the solvent cannot exceed its boiling point and thus, no
overpressure is possible; when the boiling point is reached, the solvent changes rapidly to
the gas state and the plug of reactant in the irradiation zone is expelled rapidly from the
capillary. With 5 atm (75 psi) of backpressure in the MACOS set-up, the formation of gas
bubbles in the liquid is likely supressed and the reaction flows as a continuous stream.
The effect of pressure was more notable in the case of clear capillaries, where a dramatic
increase in conversion was observed for all substrates (Table 3.3, entries 2 vs. 1, 11 vs. 10
and 20 vs. 19). With Pd-coated capillaries, a slight increase in conversion was also
noticed, however the effect of pressure in this case was probably secondary to the effect
100
of immense heat generated inside the capillary as indicated by the thermal image of Pdcoated capillary discussed in section 2.5 (Figure 2.16a).
3.3 Indole synthesis in M A C O S utilizing a Pd-PEPPSI-IPr catalyzed
sequential aryl amination/Heck coupling sequence
Multicomponent and multi-step reaction protocols play an important role in synthetic
chemistry, and the suitability of MACOS for accommodating such strategies has already
been shown.94 Developing a continuous-flow protocol for the synthesis of indoles, which
are compounds of significant pharmacological importance,106 would certainly extend the
scope of its applications in this area.
We started our development of the in-flow protocol for synthesizing indoles by
considering a recently-reported conventional batch synthesis based on an amination/Heck
coupling sequence.107 This Pd-catalyzed protocol was adapted for flow conditions by
flowing a homogenized mixture of 2-bromoalkenes with 2-bromoaniline in the presence
•I A O
of a small amount of Pd-PEPPSI-IPr as homogeneous catalyst
into the MACOS set-up
(Scheme 3.1). The reaction components, under microwave irradiation, were initially
flowed into clear capillaries, which were then replaced by metal-coated ones (Table 3.4).
101
IPr / = \ Prl
N N
IPrTprl
cr£ ei
R
Br
1.2 Equiv
89a (R = Et)
89b (R = Me;
Me)
89c (R = Ph)
^.
H2N~~^^
B r - ^ ^
Cl
Pd-PEPPSI-IPr (2.5mol%)
'BuONa (3.0 Equiv),Toluene
1200 |j.m capillary
1.0 Equiv
H
N
^
91a (R = Et)
91b (R = Me)
91c (R = Ph)
90
Scheme 3.1
The in-flow reaction showed no conversion when we initially employed a simple glass
capillary as the flow tube (Table 3.4, entries 1 and 2), which posed a number of questions
for us. It has been previously demonstrated that catalyzed reactions, such as SuzukiMiyaura coupling and ring-closing metathesis, can be driven to completion in a MACOS
set-up in the brief time (approximately 120 seconds) that the sample resides in the
irradiation chamber of the microwave;
a
is it possible that the Pd-PEPPSI-Ipr catalyst is
ineffective for this particular sequence? Alternately, if the catalyst is active for this
particular sequence, perhaps the time interval of 120 seconds is insufficient for the
catalyst to show appreciable activity? To probe these queries, batch microwave
experiments with the same substrates were performed, which demonstrated that the
catalyst was in fact active, but that the transformation required 20 minutes to reach a
conversion above the 80% mark (Table 3.4, entries 3 and 4).
102
Entry
Vinyl
Bromide
Mode
Conditions3
Product
ConversionD
(Yield)c
1
89c
Flow
FR = 15|il_/min, P = 75 psi
T=100°C
Clear 1200 um capillary
91c
0% (0%)
2
89a
Flow
FR = 15uUmin, P = 75 psi
T = 105°C
Clear 1200 fim capillary
91a
0% (0%)
3
89c
Batch
240 W, T = 1 7 5 ° C
20 min
91c
85% (74%)
4
89b
Batch
91b
83% (70%)
5
89c
Flow
91c
0% (0%)
6
89a
Flow
240 W, T = 1 7 5 ° C
20 min
FR = 15 uUmin, P = 75 psi
T = 205 °C
Pd-coated 1200 |itm capillaryd
No Pd PEPPSI-lPr catalyst
FR = 15 i^L/min, P = 75 psi
T = 205 °C ,Ag mirror-coated
1200nmcapillary d
91a
48% (32%)
7
89a
Flow
FR = 15 uL/min, P = 75 psi
91a
T = 205 °C ,Ag colloidal-coated
1200umcapillary d
62% (47%)
8
89a
Flow
FR = 15 uL/min, P = 75 psi
T = 205 °C
Pd-coated 1200 um capillaryd
91a
95% (81%)
9
89a
Flow
FR = 15 uUmin, P = 75 psi
T = 200 °C, oil bath
Pd-coated 1200 um capillaryd
91a
57%
Table 3.4 Indole synthesis in MACOS via Pd-PEPPSI IPr-catalyzed coupling of 2bromoalkenes and 2-bromoaniline, using both clear capillaries and metal-coated ones.
a
Temperature is measured by the IR sensor of the microwave. bConversion was
determined by measuring the ratio of indole product to starting material in an aliquot
obtained from the effluent from the capillary and analyzing it by ! H NMR spectroscopy.
c
Yield was determined following purification of the product by silica gel
chromatography. dAll metal-coated capillaries were prepared so as to contain the same
weight of metal.
103
In order to determine whether catalyst activation under these particular conditions was
slow, we decided to explore the kinetics of the reaction performed in entry 3 (Table 3.4).
Such a lag phase might account for the prolonged reaction times necessary for reaction
completion under MAOS, which for most cross-coupling reactions occurs much more
quickly.64 To determine this, the entry 3 reaction under batch microwave conditions was
evaluated at multiple time intervals after the start of the microwave run, and the samples
were analyzed immediately by ! H NMR spectroscopy. The resulting kinetic curve is
shown in Figure 3.3.
100
-2.5
• 98
2.5
7.5
10
12.5
15
17.5
20
22.5
25
Time (minute)
Figure 3.3 The kinetic curve obtained during the investigation of the batch microwave
reaction of 2-bromoaniline, with 1-bromo-l-phenylethylene (the reactions were sampled
right after the end of the run and the samples were analyzed immediately by ! H NMR
spectroscopy).
104
The reaction mixture under batch conditions takes approximately 2 min to reach the
desired temperature (175 °C) and, assuming that this temperature is necessary to initiate
the catalytic cycle, we began taking readings at that time. Interestingly, there appears to
be no lag phase and conversion followed almost linear kinetics. This fact was concerning,
because it implied that the sequence might not be suitable for MACOS, as the coupling
sequence must proceed at an accelerated pace to complete during the 3 minutes that the
sample resides in the irradiation zone of the microwave cavity, otherwise the sample
would have to be passed through the zone several times to reach an acceptable level of
conversion, a situation which compromises some of the advantages of working in a
continuous flow format.91
The poor MACOS results with the clear capillaries, as compared to the batch reactions,
suggested that perhaps the heating was a decisive factor in enabling the amination/Heck
coupling sequence to proceed satisfactorily. The temperature of the clear vessels did not
exceed 100 °C during the flow experiments, so in order to address this problem we
decided to use metal-coated capillaries as reaction vessels. We have shown previously
that such capillaries can achieve high temperatures, due to effective microwave coupling
to the metallic layer in addition to catalytic activity for cross-coupling reactions.98
However, in this case, when the reaction mixture was irradiated in a Pd-coated capillary,
no conversion was obtained in the absence of Pd-PEPSSI-IPr catalyst (Table 3.4, entry
5). In light of this result, we decided to flow the Pd-PEPPSI-IPr-containing solution
through a metal-coated capillary to see if the superior heating might help promote
catalyst activation and/or turnover. We had previously found that Ag films absorb
105
microwave irradiation suitably, so we tried such a capillary first (Table 3.4, entry 6). For
the first time we began to see appreciable conversion with MACOS (48%), as the
reaction proceeded to the indole product. However, when the same reaction was tried
using a Pd-coated capillary (Table 3.4, entry 8), the improvement in conversion was
significant (95%).
According to our mechanistic understanding of this particular coupling sequence, the
only role that the Ag mirror film is capable of serving is that of an effective heat source;
it is also not obvious why the Pd film provided considerably better results than the Ag
mirror film when the Pd-PEPPSI-IPr catalyst was employed. This was especially
perplexing considering the fact that the Pd film by itself did not yield any product.
Perhaps a better explanation could be provided by considering the morphology of both
films; the Pd film consists of nanoparticle dusters (Figure 2.1) and is highly porous, in
contrast to the Ag mirror film which is compact, with only small voids between the grains
(Figure 2.3). Both films are capable of generating very high temperatures under MW
irradiation (Section 2.5). The IR sensor temperature readings in the microwave cavity
(Table 3.4, entries 6 and 8) indicated that the same temperature was reached in both
systems and this was confirmed recently from the thermal images of both films (Figure
2.16a,c). However the Pd film, possessing more morphological irregularities, could
potentially have hotter sites (known as "hot spots") at the microscopic level, possibly
leading to a much higher reactivity of the Pd-PEPPSI-IPr catalyst in those regions.
To probe this notion further, we decided to employ capillaries coated with the more
porous Ag colloidal films (Figure 2.4). The porous Ag film (Table 3.4, entry 7) did result
106
in significantly better conversion (62%) when compared to the silver mirror (entry 6,
48% conversion), indicating that the film's morphology in fact does play an important
role in this sequence.
The considerably higher conversion achieved in the case of the Pd film does indicate that
the Pd film could be doing more than just providing heat. The Ag film can provide high
temperatures but no catalytic role, whereas the Pd film is capable of providing both heat
and catalytic activity, leading to the high conversion in the Pd case that is absent with Ag.
Perhaps Pd-PEPPSI-IPr catalyzes one of the steps quite efficiently when a metal film is
present, but catalyzes the other step less effectively. It has been shown previously that
Pd-PEPPSI-IPr can be highly efficient in sp3-sp3 coupling reactions108 b'c with little or no
P-hydride elimination occurring, which is a requisite for the Heck reaction in this
sequence. Perhaps it is possible that the Heck component of this sequence is responsible
for the prolonged reaction times in batch mode employing Pd-PEPPSI-IPr, in which full
conversion to product required more than 20 min, whereas the flowed reactions through
Pd-coated capillaries were complete in approximately 120 s.
In several attempted Heck reactions utilizing Pd-PEPPSI-IPr, conducted in a flask in our
laboratories, the Heck product was only observed after prolonged batch heating at 120 °C
in an oil bath. Product formation always occurred after significant darkening of the
solution that may well have been the result of the blacking-out of the Pd catalyst; there is
a strong possibility that the conversions in these Heck reactions were catalyzed by Pd
black and not by Pd-PEPPSI-IPr. In an analogous manner, then, it is also possible that the
107
highly-developed Pd film nanoclusters are promoting the second step under the extremely
high thermal conditions, whereas Pd-PEPPSI-IPr is only catalyzing the amination step.
The experience gained through these control experiments was put to use in building an
indole library (Table 3.5)109 by subjecting a variety of coupling partners to the MACOS
protocol, which utilizes Pd-coated capillaries as outlined in entry 8 (Table 3.4). The
protocol worked smoothly, as all reactions proceeded with minimal, if any by-products.
108
v
r
Me^Br
89b
T
89a
ar OD
91a
^
J
Et-
95(81)
90a
Cl'
CC
Et-
a
a
92a
ta
MeCl
-ar
-ar hy
Me-
Et-
F
a
Oy-NH2
—
—
H
)
Me-
I
95a
*
H
H
I
(95c)
J
Ph-
Ula
94 (82)a
(96b)
H
1
(96c)
J
Me-
Et-
(94c)
95 (85)a
V
96a
90g
Ph-
92 (85)
\
ax
oa
H
a
92 (72)
"F
F
Ph-
74 (65)a
74 (64)a
Et-
94b
95b
I
I 93c I
88 (78)a
N-a**,
a
ar ta
Ph-
-ta
Me-
F
F' ^ - ^ B r
90f
H
98 (82)a
*-
Et-
90e
i-Pr"
ia
93b
94a
90 (75)a
90d
82 (70)a
84 (73)
Et-
—
—
Ph-
Cl
a
85 (76)
90c
(92cJ
H
82 (70)a
93a
OD
(91c)
85 (74)a
92 (72)
H
F'
ta
92b)
H
Ph-
Me~
79(71)a
90b
to
(91b)
la
Me~
-i-Pr
85 (79)a
88 (83)a
72 (65)a
H
97b
Ph~i-Pr
(97c)
<a,Pr
85 (80)a
Table 3.5 An indole library synthesized using a continuous-flow format with Pd-PEPPSIIPr catalyst in a Pd-coated capillary reactor. aConversion was calculated as the *H NMR
ratio of indole product to 2-bromoaniline starting material, whereas yield was determined
following purification of a known volume of reaction mixture by silica gel
chromatography.
109
The control experiments outlined above do suggest a co-dependence of Pd-PEPPSI-IPr
catalyst with a metal surface, in order to successfully catalyze the amination/Heck
sequence. This was re-affirmed by the fact that an independent amination or Heck
reaction performed in the absence of either Pd coating or Pd-PEPPSI-IPr catalyst did not
yield any results (Scheme 3.2).
Heck Reaction Control
^
\
COO'Bu
Condition A or B
toluene
99
1.0 equiv
^ 3 8
1.5 equiv
No product observed
under either reaction conditions
Pd-coated capillary, 'BuONa (3.0 Equiv),
FR = 15 uL/min. P = 75 psi. T = 205 "C
B
Pd-PEPPSI IPr(2.5mol%), clear capillary, 'BuONa (3.0 Equiv),
FR = 15 uL/min, P = 75 psi, T = 70 °C
Amination Reaction Control
Condition A or B
toluene
^
1
00
No product observed
under either reaction conditions
101
1.0 equiv
1.5 equiv
Pd-Coated capillary, 'BuONa (3.0 Equiv),
FR = 15 nl_/min, P = 75 psi, T = 195 °C
B
Pd-PEPPSI IPr(2.5mol%), clear capillary, 'BuONa (3.0 Equiv),
FR = 15 uL/min, P = 75 psi, T = 75 °C
Scheme 3.2
110
The Heck coupling between substrates 98 and 99 did not proceed in the presence of the
Pd film, although we have shown previously that the same reaction can be catalyzed by
thin Pd films in DMA solvent.
Similarly, the amination reaction between 100 and 101
also failed, although the utility of Pd-PEPPSI-IPr catalyst for batch amination reactions in
DME solvent has been previously detailed.
Therefore, there definitely appears to be a
co-dependence between the Pd-PEPPSI-IPr catalyst and the metallic layer for this
particular in-flow indole protocol.
Finally, a significant reduction in conversion was observed when the same transformation
in flow, as depicted by entry 8 in Table 3.4, was conducted using an oil bath (Table 3.4,
entry 9), although the oil bath temperature was kept the same as the temperature
measured by the IR sensor of the microwave instrument, 205 °C. This result points again
to the important effect of superior heating, generated by microwave coupling to metal
films, that as we have managed to determine in more recent experiments, exceeds by far
any amount of heat conveyed into the system by a conventional oil bath (Section 2.5).
111
Chapter Four
In-flow catalysis by thin Au and Cu films
Applications to hydrosilylation and benzannulation reactions and
propargyl amine synthesis
112
4.1 Hydrosilylation of terminal alkynes in flow format using Au-coated
capillaries as reaction vessels in M A C O S
We were interested in developing a continuous flow protocol for the hydrosilylation of
terminal alkynes that was suitable for MACOS, because of the usefulness of the process.
Vinylsilanes (in addition to alkylsilanes) as products of this atom-economical reaction111
are very important for the silicon industry112 because they are used to produce silicon
polymers which in turn are basic materials for the manufacture of commodities such as
lubricating oils, resins, pressure-sensitive adhesives etc.113 Additionally, vinylsilanes are
used as building blocks in organic synthesis,114 finding use as organometallic crosscoupling partners1 5 and to generate carbonyl derivatives by Tamao oxidation.116
The most commonly used metal to catalyse hydrosilylation is Pt (i.e. Karsted's catalyst117
and Speier's catalyst
), which is one of the most expensive precious metals. Recently,
Au, a less costly metal, has been investigated for its suitability as a hydrosilylation
catalyst. While generally less reactive than Pt, Au has been applied to the hydrosilylation
of alkynes, carbonyls and imines.119 However, while supported gold nanoparticles have
been shown to be active in some preliminary hydrosilylation studies,120 metallic gold was
observed to be essentially inactive with the same substrates. Corma and co-workers
showed that Au111 from KAuCU was quite reactive in the hydrosilylation of styrene, but
reactivity ceased as the salt decomposed over time to metallic Au.121
Our efforts in developing an efficient in-flow strategy for alkyne hydrosilylations were
focused upon the utility of the gold-coated capillaries as reaction vessels (Section 2.2.1)
with the metallic gold layer being the potential catalyst for this application.
113
The need for the double-layered Au films was confirmed in the initial testing of the goldcoated capillary prototypes in hydrosilylation reactions. It was found that the first dense
layer is necessary for good adhesion of the second, more porous film to the glass (Figure
2.5), which makes the overall film suitably robust for MACOS applications.
The general hydrosilylation protocol outlined in Table 4.1 was tried on a variety of
terminal alkynes.
Typically, the mixture of alkynes and hydrosilylating reagents in
toluene was flowed through gold-coated capillaries under microwave irradiation. The
catalysis by gold film appeared tolerant of many functional groups including cyano,
alcohols, chlorides, aromatics/heteroaromatics and ethers (Table 4.1). Also free alcohols
that were remote from the alkyne (entries 3 and 4), or right next to it (entries 13, 14, 17
and 18), were equally well tolerated. Triethyl-, triphenyl- and chlorodiphenyl silane all
proved
equally
efficacious
as hydrosilylating
agents. Regioselectivity
of the
hydrometallation was high for placement of the silicon moiety on the terminal carbon of
the alkyne. The reactions of alkynes with alkyl chains proceeded with somewhat lower
selectivity compared to other substrates (entries 1-6) and E selectivity for the vinylsilane
product was greater than 90 percent for the majority of alkyne substrates.
114
R.3SiH
+
R
1 Equiv
Au-coated 1200 (im
capillary, toluene
FR=20^il/min P=75psi
T=175-185°C
= =
2 Equiv
102a (R'= Et)
102b (R' = Ph)
102c(R'=Ph 2 CI)
R
^
^
^
^
^
S i R
K
+
.
\
= =
^
b l K
,
3
+
K
„
P-(E)
3bl
p-(Z)
103a-k
Entry
Alkyne
R'3SiH
Product
p-(E) p-(Z)
a
Conversion3
(Isol. yield)b
Product
No
1
C4H9
^ ^
Et3SiH
82
9
9
82(70)
104
2
C4H9
=
Ph3SiH
80
6
14
78(68)
105
3
HO—C2H4^^
Et3SiH
84
6
10
82(69)
106
4
HO—C2H4^^
Ph3SiH
85
4
11
85(74)
107
5
Cl
C
=
Et3SiH
75
4
21
77(68)
108
6
Cl
C
^^
Ph3SiH
93
3
4
78(70)
109
3
3
H
H
6
6
7
Ph
= =
Et3SiH
92
4
4
86(78)
110
8
Ph
^ =
Ph3SiH
90
2
8
91 (80)
111
SEEE
Et3SiH
96
4
-
84(76)
112
9
a
MeO-
=
MeO^
E
11
MeO^
=
Ph3SiH
98
1
1
88(80)
113
12
MeO^
===
Ph3SiH
98
1
1
20 (Oil bath)c
113
13
H O ^
===
Et3siH
90
14
HO-
E
Et3sJH
Ph3SiH
96
98
115
4
28 (Oil bath)c
10
1
1
_
g
87(75)
1
85(74)
112
1 U
115
Entry
Alkyne
R'3SiH
Product
p-(E) p-(Z)
a
Conversion3
(Isol. yield)b
p ro duct
No
15
NC—C3H6^
Et3SiH
93
1
6
82(74)
116
16
NC—C 3 H 6 t
Ph3SiH
97
1
2
86(78)
117
> —
Et3SiH
81
2
17
62(54)
118
;
Ph3SiH
98
1
1
68(58)
119
Et3SiH
97
1
2
88 (80)
120
Ph3SiH
97
1
2
82 (72)
121
56 (45)
122
17
HO
18
^ >
HO
19
BnO-
20
BnO^
21
Cl
22
NC—C3H6
C3H6-
Ph 2 CISiH d 100
Ph 2 CISiH d
96
4
80 (66)
123
-
75 (60)
124
66 (60)
125
23
MeO.
\
Ph 2 CISiH d
100
24
BnO.
\
Ph 2 CISiH d
100
Ph 2 CISiH d
70
30
72 (62)
126e
Ph2CISiHd
76
24
58 (50)
127e
• o26
Me3Si
Table 4.1 Vinylsilane products synthesized in flow with MACOS via catalysis by Au
thin films. aPercent conversion was determined by analyzing the }H NMR spectrum of
the crude reaction mixture as it exited the MACOS system. Percentage yield was
determined by collecting a known volume of reaction effluent and purifying the crude
product by silica-gel chromatography. (3-(E) isomer was isolated in entries 1-24. cGoldcoated capillaries were submerged in a heated oil bath (192 °C) for 20 min before the run
started to ensure that the film achieved the temperature of the oil bath.dThe silanol
corresponding to the silyl chloride (-SiPhiOH) was isolated following silica-gel
chromatography and yields were calculated on this basis. eBoth P-(E) and d isomers were
isolated.
116
The temperatures indicated in Table 4.1 reflect the values estimated by the IR sensor in
the Biotage Initiator; the real temperatures generated as a result of Au film-microwave
coupling were much higher as determined by the thermal imaging of the Au-coated
capillaries (Figure 2.16b). The necessity for microwave irradiation however was
confirmed at that time by conducting the same protocol in flow in the presence of a
conventional heating source such as an oil bath. Two control experiments were conducted
in flow (simulating the reactions conducted in entries 9 and 11, Table 4.1) by using the
same Au capillaries placed in an oil bath set to deliver the same temperature as recorded
during the MACOS runs. In both cases, percentage conversion was significantly curtailed
as these runs produced approximately 25% of the product that was obtained with
microwave irradiation (Table 4.1, entries 10 and 12). The temperature effects aside, there
could also be an electronic effect that positively promotes the reaction by the current that
is being generated in the metal film by the oscillating microwave field.
The reproducibility of this flowed process in Au-coated capillary microreactors was
investigated by conducting the reaction between triphenylsilane and methylpropargyl
ether (Table 4.1, entry 11) five separate times, using a freshly Au-coated capillary each
time. The reaction proceeded with remarkable consistency in all cases (Figure 4.1); the
average conversion was 82.8 % corresponding to a standard deviation of 3.4 %.
117
t Conversion %
100
90
'88
• 85
80
• 78
• 81
«82
70
60 50 "
40 "
1
2
3
4
5
*x
r*
•
.
No of trials
Figure 4.1 Distribution of conversion for the hydrosilylation reaction between
triphenylsilane and methylpropargyl ether conducted in different gold-coated capillary
microreactors
The robustness of the gold film and its potential to be re-used was also investigated by
conducting the same reaction (Table 4.1, entry 11) five separate times using the same
capillary. With the exception of the first trial, the catalytic performance of the gold film
decreased very slowly with time (Figure 4.2).
118
1k
100
Conversion %
-
• 91
90
• 80
80
• 75
70
• 72
:
60
50
• 52
40
1
1
i
i
•
No of trials
Figure 4.2 Distribution of conversion for the hydrosilylation reaction between triphenyl
silane and methylpropargyl ether conducted in a recycled gold-coated capillary
microreactor
It was noticed in several cases the gold film darkened over time, however we did not
identify degradation matter from the film in the effluent, thus perhaps the dark patches
are organic matter in the flow stream that is being gradually deposited on the surface of
this intensely hot metal film, where it chars. Also it has been reported previously that a
very thin gold layer deposited on the outside of glass reactors "evaporates" during
microwave irradiation.85a The same phenomenon could be happening in our case also,
although this is difficult to assess visually. To try to assess any Au loss, we took the postreaction capillaries and re-calcinated them at 400 °C (in order to dispose of any organic
matter attached to the film's surface). After weighing, we found no significant difference
119
in the weight of the used capillary when compared to the weight of the just-prepared
capillary. It is possible that flowing solution is cooling the film sufficiently to increase its
lifetime and reactivity. Additionally, several product samples were collected directly
from the capillary (crude) and submitted to inductively coupled plasma mass
spectrometry (ICP-MS). The technique has a lower level of detection (LLD) of 50 ppm;
no gold was detected in any of the product samples.
4.2 Benzannulation reactions in flow format using Au-coated capillaries
as reaction vessels in M A C O S
Several relatively new synthetic methodologies for the creation of new benzene rings,
called benzannulation reactions, have received increasing attention in recent years.
One
of the most common reactions in this group proceeds via a formal [4+2] cycloaddition
between an enynal or enynone unit 129 and alkynes, to generate substituted naphthyl
ketones 130, which are biologically active agents and important compounds in synthetic
chemistry124 (Figure 4.3).
Figure 4.3 A formal [4+2] benzannulation reaction between an enynal or enynone unit
and alkynes
120
This transformation has been shown to be promoted by Lewis acids, copper
complexes125a and various gold species,125 such as AuX and A11X3 (X=C1, Br); only
recently it was also shown that Au nanoparticles dispersed on different supports can
catalyze this reaction as well.
and Au
Further, it has been shown computationally that both Au
can perform this catalytic cycle with similar energy profiles.
This raises the
possibility that the actual active species in these transformations could be either species,
providing that the possibility exists for the starting Au complex to be oxidized or reduced
under a specific set of reaction conditions. Given the complexity of this process, we were
interested in finding out whether our metal films would be suitable catalysts for
benzannulation.
We started the investigation of the benzannulation reaction by assessing different types of
metal films for their suitability as a catalyst.128 The films of Pd, Ag, Au and Cu are
generally prepared in a reducing environment, thus they are expected to be largely M°,
which has been confirmed by EDX analysis of these films (Sections 2.1 and 2.2).
However, film preparation was not conducted under a strictly inert environment, thus
oxygen in the air could play a role in the film's composition leading to the formation
metal oxides on the surface.
With these metal-coated capillaries in hand, benzannulation reaction was investigated
using the substrates in Table 4.2.
121
LOEquiv
Entry
3.0 Equiv
Film
133 A
Heat Source
133 B
Temperature Conversion3
TO (Isol. Yield %) b
Pd
microwave
240
0
Ag mirror
microwave
240
0
Cu
microwave
240
trace
Au-on-Au
microwave
220
75
Au-on-Ag
microwave
240
90 (78)
Au-on-Ag
microwave
190
68
Au-on-Ag
oil bath
190
14
A:B Ratio
Table 4.2 Optimization studies for benzannulation reaction using MACOS. aPercent
conversion was determined by analyzing the H NMR spectrum of the crude reaction
mixture as it exited the MACOS system. bPercentage yield was determined by collecting
a known volume of reaction effluent and purifying the crude product by silica-gel
chromatography
Films of Pd (Table 4.2, entry 1) and Ag (Table 4.2, entry 2) showed no conversion into
product at all. Surprisingly, the reaction conducted in a Cu-coated vessel (Cu is reported
to be a suitable catalyst for benzannulation), could not be optimized beyond the formation
of only trace amounts of product (Table 4.2, entry 3).
This benzannulation reaction is reported using homogeneous and heterogeneous gold
catalysts, and indeed we found that a pure Au film provided good conversion for a short
period (Table 4.2, entry 4). However, we found that these Au films performed poorly
122
when subjected to the rigors of MACOS and had a short lifespan. This technical problem,
coupled to unusually long protocols for coating capillaries with two layers of gold
(Section 2.2.1) made progress slow, therefore we decided to try the capillary reactors
coated with a Au-on-Ag bimetallic layer.
The robustness of Au-on-Ag capillaries under microwave irradiation conditions was
considerably higher than that of the stand-alone Au-coated capillaries. When the
benzannulation reaction was run at a high temperature (Table 4.2, entry 5), as read by the
IR sensor in the Biotage Initiator microwave, excellent conversion was achieved that
diminished as the temperature was reduced (Table 4.2, entry 6). It is noteworthy that
under batch conditions, these reactions are reported to require an average time of 6 hours
to obtain similar conversion levels
to those obtained in about 120 s using MACOS (the
residence time of reaction mixture in the flow reactor).
To make a direct comparison to a conventional heating source the identical
transformation in entry 6 was performed using an oil bath to achieve the same
temperature (i.e. 190 °C, entry 7) and the conversion was dramatically reduced from 68%
to 14%. It is now known that the temperature of the Au-on-Ag bimetallic film is well
above the bulk temperature recorded by the IR sensor of the instrument (Figure 2.16f).
The oil bath experiment confirmed the fact that high temperatures are necessary for this
benzannulation in flow and the Au-on-Ag film is capable of generating such temperatures
under microwave irradiation.
123
With optimized conditions in hand (Scheme 4.1) we set out to examine the substrate
scope of this reaction using capillaries lined with the Au-on-Ag films. The results are
shown in Table 4.3.
CHO
Au-on-Ag 1700 |im capillary
FR=25n_L/min, T=240 °C,
P=75psi, 1,2-dichlorobenzene
R"
132
OT
R'
0
3.0 Equiv
Scheme 4.1
The optimized reaction protocol was initially applied to the 2-(2-phenylethynyl)
benzaldehyde 131a, used in the optimization studies (Table 4.3, entries 1, 2, 3), and was
also useful in the case of heteroatom-containing aldehydes (Table 4.3, entries 4-10). The
continuous flow protocol catalyzed by metallic gold revealed a broad functional group
tolerance including silyl groups ( Table 4.3, entries 2 and 8), halides (Table 4.3, entries 7
and 9), ethers (Table 4.3, entry 3), amides (Table 4.3, entry 10), and even free carboxylic
acids (Table 4.3, entry 5). Interestingly, switching the position of nitrogen from the
benzaldehyde ring to the alkyne ring resulted in no reaction at all (Table 4.3, entry 11). In
all cases where reactions did not fully complete, the starting materials accounted for the
mass balance; crude 'H NMR spectra were very clean showing only a trace of
byproducts.
124
Entry
R'
X
TMS
Conversion a
(Isol. Yield %) b
A:B Ratio
Product
No
CH
90(78)
75:25
133 A,B
CH
75(62)
Bonly
134 B
CH
62(52)
58:42
135 A,B
CH
76(62)
Aonly
136 A
CH
72(60)
Bonly
137 B
N
78(64)
70:30
138 A,B
N
68(54)
Bonly
139 B
N
65(58)
Bonly
140 B
65(52)
B only
141 B
50(40)
Bonly
142 B
OCH-,
V
COOH
TMS
f\
Br
N
10
JPr
x
O
11
iPr
CH
Table 4.3 Substituted naphthyl ketones synthesized in flow format using MACOS.
125
a
Percent conversion was determined by analyzing the ! H NMR spectrum of the crude
reaction mixture as it exited MACOS system. bPercent yield was determined by
collecting a known volume of reaction effluent and purifying the crude product by silicagel chromatography.
On a typical run, conducted over 30-35 minutes, approximately 0.7-0.8 mL of crude
mixture would be collected, which generated 70-80 mg of final product after purification,
an ample quantity for evaluation in biological screens. The current approach however, is
suitable for producing larger quantities of the benzannulation product. In order to
demonstrate this, a larger-scale benzannulation was performed, using the substrates in
Table 4.3, entry 1. To improve efficiency and reduce solvent consumption and hence
waste production, the concentration of both starting materials was tripled. After running
the flow reactor for 90 min, 750 mg of product (133A and 133B, 3:1) were collected.
Under these conditions the concentration of phenylacetylene was 4.5 M, demonstrating
that MACOS can easily handle alkyne concentrations that are far above the typical levels
(0.1-0.5 M) commonly used in conventionally-heated batch reactors.
In most cases, the reactions displayed a high level of regioselectivity. The homogeneous
benzannulation reaction, catalyzed by Au111 catalysts has been proposed to proceed via the
formation of several organogold intermediates125 (Figure 4.4).
126
Figure 4.4 The proposed mechanism of the benzannulation reaction between aromatic
carbonyls and alkynes catalyzed by Au111 complexes
The regioselectivities observed in Table 4.3 can be explained by invoking a zwitterionic
intermediate shown in Figure 4.5, the existence of which has been suggested under
homogeneous reaction conditions125 involving the Diels-Alder type cycloaddition shown
in Figure 4.4.
127
AuX3
i
*>
AuX3
ii
J
Figure 4.5 Zwitterionic intermediates involved in benzanuulation mechanism catalyzed
by Au10 catalysts
For the benzannulation reactions involving phenylacetylene (Table 4.3, entries 1, 4, 6) the
predominant formation of the A-regioisomer (133A, 136A and 138A, respectively) can
be explained by the resonance effect of the phenyl ring at C7 position which stabilizes the
corresponding vinyl cation.
The predominant formation of the B-regioisomer for entries 5, 7, 9 and 10 (137B, 139B,
141B and 142B, respectively) can be explained by the positioning of EWG-substituted
phenyl moiety on the C6, away from the positively charged C7 center. The same
reasoning can be applied to explain the exclusive formation of 134B and 140B in the
reactions of TMS acetyl ene in entries 2 and 8; the TMS group can significantly stabilize
P carbocations.129
The reaction conditions in MACOS are not homogeneous, however the observed product
regioselectivity could suggest a similar mechanism in operation to the one depicted in
Figure 4.4.
128
4.3 In-flow synthesis of propargyl amines utilizing Cu-coated capillaries
as reaction vessels in M A C O S
1 ^0
Propargylamines are versatile synthetic intermediates in organic synthesis
and are also
key structural elements in natural products and therapeutic drug molecules.131A
conventional approach for synthesizing propargylamines is nucleophilic attack of lithium
1 ^9
or Grignard acetylides onto imines and their derivatives.
However there are problems
with this strategy such as the necessity of moisture-free reaction conditions,
stoichiometric use or reagents and protection of sensitive functionalities such as alcohols,
esters etc, which limits its wider application. Over the last decade there has been
increasing interest in developing transition-metal catalysts to accomplish the synthesis of
propargyl amines using a Mannich-type three-component coupling reaction of aldehydes,
secondary amines and terminal alkynes via C-H bond activation. Li and co-workers have
reported the use of noble transition-metal salts, such as Au, Ag, Ir, Ru-Cu, Ru-In for this
reaction.
Environmentally-friendly strategies have also been carried out in water, ionic
liquids and without solvent. 133c'd'134
Recently the Mannich three-component coupling strategy has been shown to be promoted
by supported Au,135b'c Cu,135d'e and Ag,135a CuO,135f and Ag 2 0 135g nanoparticles. In all
cases the metal-acetylide intermediate has been assumed to play a key role in the reaction
sequence.
Multicomponent reaction protocols have been successfully developed for MACOS in the
past,94 however those protocols were not metal-catalyzed. This three-component coupling
reaction would be a good example to investigate the catalytic role of transition-metal
129
films in the MACOS system with respect to multicomponent reaction strategies in flow
format.
The investigation began by assessing the catalytic properties of several metal films. The
chemical composition of our films consists mainly of metal(O) atoms as determined by
EDX analysis; the presence of oxygen indicates that a small amount of electron-deficient
metal atoms bound to oxygen could also exist in the layer, possibly distributed
sporadically on the surface. This could have a positive role in the catalytic activity of the
metallic layer as the CuO and Ag20 nanoparticles have been shown to catalyze this
reaction.
The optimization studies for the in-flow synthesis of propargyl amines, are shown in
Table 4.4. This reaction is not known to be catalyzed by Pd catalysts so it was not
unexpected to find that the Pd film showed no conversion of starting materials at all
(entry 1). Surprisingly, the Ag-mirror film showed no catalytic activity for this reaction
as well (entry 2). Initially we thought that the determining factor for this result was the
lack of porosity of the Ag mirror layer (Figure 2.3) therefore the same reaction was
conducted using the more porous Ag colloidal film (Figure 2.4). However after receiving
the same negative result (entry 3), it was made clear that the Ag is not a suitable catalyst
for this chemistry.
130
CHO
Metal-coated 1700 jim
Capillary, Toluene
FR=20 nL/min, P=75 psi
T=175°C
N
H
1 Equiv
1.2 Equiv
143a (R = H)
143b (R = 4-Br)
143c (R = 3-Br)
Entry
146 (R = H)
147 (R = 4-Br)
148 (R = 3-Br)
144a
Film
Aldehyde
Heat Source
Temperature
T£)
Conversion3
(Isol. Yield %)b
1
Pd
143a
microwave
200
0
2
Ag mirror
143a
microwave
200
0
3
Ag colloid
143a
microwave
200
0
4
Au-on-Ag
143a
microwave
235
72
5
Au-on-Ag
143b
microwave
235
78
6
Au-on-Ag
143c
microwave
235
70
7
Cu
143a
microwave
175
82 (76)
8
Cu
143b
microwave
175
84 (78)
9
Cu
143c
microwave
175
90 (84)
Table 4.4 Optimization studies for the three-component coupling of propargylamines in
MACOS. aPercent conversion was determined by analyzing the *H NMR spectrum of the
crude reaction mixture as it exited the MACOS system. bPercentage yield was determined
by collecting a known volume of reaction effluent and purifying the crude product by
silica-gel chromatography
It was not surprising to find that the Au film, supported on a very thin Ag layer could
serve as active catalyst for this reaction sequence (entries 4-6). However consistently
higher conversions were obtained when a Cu film was used in the same application
131
(entries 7-9). Furthermore the Cu-coated capillaries were generated in mere minutes
using a very fast and facile coating protocol, compared to a considerably longer and
complex procedure for generating Au-on-Ag films; from a cost perspective the capillaries
containing the Au-on-Ag films were approximately 10 times costlier than the Cu-coated
ones. For these reasons, the Cu-coated capillaries were finally chosen to prepare the
library of propargyl amines (Table 4.5)136 using the protocol in Scheme 4.2.
CHO
+
^1 li
R3
R
Cu-coated 1700 |im
Capillary, Toluene
N
H
•
FR=20 nL/min, P=75 psi
170-180 °C
143
144
145
1 Equiv
1.2 Equiv
1.5 Equiv
Scheme 4.2
132
D
K
II
1 IT
Entry
Aldehyde
Amine
Alkyne
Product
er o "D
2
)
Br
Convers3
(Yield%)b
Product
No
82 (76)
146
84 (78)
147
90 (84)
148
85 (74)
149
82 (76)
150
90 (82)
151
81 (75)
152
80 (75)
153
H
Br^
H
H
F,C
MeO'
CHO
0 "O
CHO
H
CHO
H
0 "O
133
Entry
10
Aldehyde
Amine
Alkyne
Convers3
(Yield%)b
Product
er o "ID
11
H
Product
No
83(74)
154
90(82)
155
78 (70)
156
75(67)
157
68 (60)
158
74 (68)
159
72(65)
160
72 (67)
161
Br
12
|
H
H
13
H
MeO'
14
B r ^ ^
N
H
^ S
Br'
CH0
15
a o
N—Me
N==/
H
16
XT 0 V>
N—Me
Br'
N—Me
Table 4.5 Propargyl amines synthesized in-flow using Cu-coated capillaries as reaction
134
vessels in MACOS. aPercent conversion was determined by analyzing the ! H NMR
spectrum of the crude reaction mixture as it exited MACOS system. Percent yield was
determined by collecting a known volume of reaction effluent and purifying the crude
product by silica-gel chromatography
The reaction was applicable to the aromatic as well as aliphatic aldehydes. A survey of
different functional groups on the benzaldehyde ring revealed good functional group
tolerance including halides (entries 2,3,9,11,14,16), methoxy (entries 5,13), and
trifluoromethyl group (entry 4). Several secondary amines were tolerated as were a
number of heterocycle-containing alkynes (entries 12-16). In all cases where reactions
did not fully complete, the starting materials accounted for the mass balance; crude H
NMR spectra were very clean showing only product and residual starting materials.
All of the runs shown in Table 4.5 were conducted on approximately 0.9-1.0 mL of an
infusing starting material solution (30 min. per run), which, after purification, generated
150-200 mg of final product. Such quantities are ample for evaluation in biological
screens.
It was also demonstrated that the starting materials could be infused into the mixing
chamber separately, rather than as premixed solutions, which improves the combinatorial
efficiency of the process. The propargylamine 146 was prepared by flowing the aldehyde
143a, amine 144a, and alkyne 145a into the mixing chamber from three separate
syringes. The reaction proceeded equally well as when premixed solutions were used
(Table 4.6, entry 1).
135
Entry Product
Reaction
Conditions
Heat Source Temp (°C)
Convers
(Is. Yield %)
1
146
Starting materials a
infused separately
microwave
175
80
2
150
Flow rate a n d b
reagent concentr.
were doubled
microwave
175
60(55)
495 mg
collected
3
146
Standard reaction
conditions
oil bath
185
29
4
148
Standard reaction
conditions
oil bath
185
34
Table 4.6 Control experiments for the synthesis of propargyl amines in flow format. aThe
three reaction components were dissolved separately, tåken up into three separate
syringes, and infused into a MACOS reactor head equipped with three inlet ports. The
streams flowed down the attached capillary through the microwave chamber. The
concentration of the aldehyde, amine, and alkyne were 3.0, 3.6 and 4.5 mmol/mL,
respectively and the flow rate of each syringe was set at 7 uL/min. bA larger-scale run
was performed by infusing the aldehyde (2.0 mmol/mL), amine (2.4 mmol/mL), and
alkyne (3.0 mmol/mL) into the reactor at a rate of 40 uL/min for 40 min leading to the
isolation of 495 mg of product 150.
In order to investigate MACOS capacity to prepare compounds on a larger scale, which is
desirable for any application, the reaction shown in entry 2 was performed. Good
conversion to product 150 was achieved when the reaction was performed under standard
conditions for 30 minutes (Table 4.5, entry 5) yielding 213 mg of 150 after purification.
To improve throughput, the concentration of the starting materials and the flow rate were
doubled; this lowered conversion, but allowed for the collection of half a gram of product
in just 40 min. Running the reaction for a longer period of time and/or through multiple
capillaries in parallel (scaling out) will lead to the production of even larger quantities.
136
To assess the performance of this protocol using a conventional heating source, the
protocol for propargyl amines 146 and 148 was repeated using an oil bath (Table 4.6,
entries 3 and 4). The Cu-coated capillaries were allowed to sit in an oil bath set to 185 °C
for 20 minutes to come to temperature, after which the reaction mixtures were flowed
through them in the usual way and the product collected; dramatic reductions in
conversion were observed (29% and 34%, respectively). An explanation can be provided
by the fact that the actual temperatures reached in the Cu-coated capillary reactors under
microwave irradiation surpasses the oil bath temperature by several hundred degrees as
confirmed by the thermal image in Figure 2.16e.
137
4.4 "Metals-In-Microwave": a successful approach that can be extended
to other applications
In summary, a novel methodology has been developed for conducting chemistry in
continuous flow format; the method utilizes glass microreactors coated with thin metallic
films, as reaction vessels under microwave irradiation conditions. Our technological
approach, based on the new method, allows chemical deposition of several noble and
base metals on the inner surface of glass microreactors in the form of thin metallic layers.
The SEM analysis indicates that these metallic layers possess unique morphological
features as the morphology of a typical film consists of dusters of nanoparticles as
opposed to regular crystalline lattice of corresponding metal; these dusters possess an
enormous surface area due to high film porosity.
The working principle of the new technology is a carefully orchestrated balance between
the metal film thickness and MW power which transforms the metal-microwave coupling
from potentially "harmful" into a beneficial and very important relationship for this
system. There are two distinguishing features that set apart our system from other
continuous flow systems in use today:
•
Thin metal films are catalytically active under MW irradiation conditions in a
wide variety of chemical reactions
•
Due to the enormous amount of heat generated on the metal film in very brief
time (with temperatures reaching levels of 300-900 °C) these chemical reactions
are tremendously accelerated
138
The metal-coated capillary reactors were used as reaction vessels with MACOS reactor in
a series of chemical transformations conducted in-flow, aimed at demonstrating the
versatility of the new technological approach. The metal film can supply extremely high
temperatures to address high transition state barrier transformations, but it can also
pro vide a catalytically-active metal surface. The catalytic activity of metallic films under
microwave irradiation was utilized in a number of applications, including SuzukiMiyaura and Heck cross-couplings, hydrosilylation of terminal alkynes, and also DielsAlder reactions. The scope of catalysis by thin films was extended effectively to difficult,
multi-step reactions including the synthesis of indoles, naphthyl ketones and propargyl
amines in flow. The process can be conducted using separate streams of reactants, or by
premixing the reaction components and infusing the reaction through one single syringe
and larger quantities of product can be attained readily by scaling out. In terms of
sustainability the temperatures attained in the MACOS set up are reached with the lowest
possible power setting available on the microwave instrument (10-30W).
The initial success achieved in these practical examples of "Metals-In-Microwave"
approach points to the possibility of a wider scope of applications for this technology.
This approach can be extended to several other metals which are capable of providing a
catalytically-active surface; it can be used to catalyze an even greater number of
transformations in-flow, excluding the need of homogeneous catalysts.
139
The tremendous acceleration of chemical reactions in flow can make this approach
attractive for a great number of homogeneously-catalyzed reactions which are presently
conducted in batch conditions.
This remote generation of high levels of thermal energy using only a minimal amount of
energy from the magnetron constitutes a much "greener" alternative in terms of energy
savings when compared to electrical heating devices. From the engineering perspective
this approach is also attractive because it eliminates the need for complex "heating" and
"mixing" components in the design of flow micro-reactors.
The possible development of a pilot plant using this technology can be very interesting
from an industrial perspective. The remote introduction of high levels of thermal energy
that can be activated and de-activated instantaneously can increase remarkably process
safety and efficiency.
140
Chapter Five
Experimental
141
5.1 Microwave irradiation experiments and metal coating protocols for
the borosilicate glass capillary reactors
5.1.1 Microwave irradiation experiments
All MACOS experiments were performed inl200 um or 1700 um (ID) borosilicate glass
tubes, using a single mode Biotage Smith Creator Synthesizer, operating at a frequency
of 2.45 GHz with irradiation power from 0 to 300 W. The glass reactor was fed reactants
from Hamilton gastight syringes attached to a Harvard 22 syringe pump pre-set to the
desired flow rate. The system was connected to a sealed collection vial, where a
pressurized airline was attached to create backpressure (pressure inside the system
reached 75 psi). The temperature read on the surface of the capillary by the built-in IR
sensor of the microwave controlled the operation of the magnetron. All reagents and
solvents were purchased from commercial sources and used without additional
purification. Column chromatography purifications were carried out using the flash
technique on silica gel 60 (200-400 mesh). NMR spectroscopy was run using a Bruker
Advance 400 MHz instrument. Proton NMR spectra were calibrated to 7.26 ppm for the
signal from the residual proton of the deuterated chloroform solvent, while carbon NMR
spectra were calibrated to 77.00 ppm for the signal from the central peak in the triplet for
deuterated chloroform.
142
5.1.2 General procedure for the preparation of the Pd- and Ag-film
coating inside of 1200 micron and 1700 micron (ID) capillaries
Pd-film coating: The 1200 um and 1700 um glass capillaries (ID) were filled with a 0.1
mmol/mL solution of palladium acetate in DMF, capped at both ends with Teflon tape
and placed inside a muffle furnace; the temperature was increased to 120° C. After 10-30
min., metallic Pd began to be released from the solution and deposited on the surface of
the glass wall. The reactors were rinsed with acetone and then calcinated in the same
furnace for 3 x 1 min. at 400°C before use in MACOS.
Ag-film coating (the "silver mirror" layer): Tollens' reagent was prepared as follows:
2.0 mL of 4M NaOH solution was added drop-wise into 20 mL of a 3% AgNC>3 solution,
forming a gray precipitate that was titrated with a 4M solution of NH4OH until the
solution became clear.
Tollens' reagent (0.5 mL) was added to a 2 mL vial containing 0.5 mL of a 5% D-glucose
solution. The glass capillaries were filled with this mixture, capped at both ends with
Teflon tape and left to develop at rt. After the Ag coating was fully developed (5-10 min),
the capillaries were rinsed with acetone and placed inside a muffle furnace for calcination
at 400°C (3 x 1 min) before use.
Ag film coating (the "colloidal silver" layer): Capillaries were filled with a 0.5
mmol/mL colloidal solution of silver oxide in ethylene glycol and then both ends were
capped with Teflon tape. Capillaries were then placed inside a muffle furnace and the
temperature was gradually increased to 140° C. After the Ag coating was fully developed
143
(30 min), the capillaries were rinsed with acetone and placed inside a muffle furnace for
calcination at 400°C ( 3 x 1 min) before use.
5.1.3 General procedure for the preparation of the Au-on-Au and Auon-Ag film coating inside of 1200 micron and 1700 micron (ID)
capillaries.
Au-on-Au bimetallic film. Boronsilicate capillaries were filled with a 0.1 mmol/mL
solution of A11CI3 in diethylene glycol, capped at both ends and placed inside a muffle
furnace; the temperature was gradually increased to 180 °C. After 30 min. capillaries
were tåken out and rinsed with acetone. The procedure was repeated several times.
A second deposition mixture was prepared by mixing a 0.2 mmol/mL aqueous solution of
AUCI3 (0.5 mL) with a 0.15 mmol/mL aqueous solution of sodium citrate,
Na3C6Hs07-2H20 (0.5 mL). The mono-coated capillaries were filled with this mixture,
capped at both ends and left to develop at room temperature for another 30 min.
Afterwards, capillaries were calcinated at 400°C ( 3 x 1 min) before use in MACOS.
Au-on-Ag bimetallic film. Tollen's reagent (0.5 mL) was added to a 2 mL vial
containing 0.5 mL of a 5% D-glucose solution. Capillaries were filled with this mixture,
capped at both ends, and left to develop at rt. After the Ag coating was fully developed
(15 min), the capillaries were rinsed with acetone and placed inside a muffle furnace for
calcination at 500°C ( 3 x 1 min).
The gold-coating solution was prepared by mixing a 0.4 mmol/mL aqueous solution of
AUCI3 (0.5 mL) with a 0.1 mmol/mL aqueous solution of sodium citrate,
144
Na3C6HsCV2H20 (0.5 mL). The Ag-lined capillaries were filled with the mixture, capped
at both ends, and left to develop at rt for 30 min. After emptying the reactors and rinsing
them with acetone, they were calcinated at 500°C (3 x 1 min) before use in MACOS.
5.1.4 General procedure for the preparation of the Cu-film coating
inside of 1200 micron and 1700 micron (ID) capillaries
Capillaries were filled with a 0.5 mmol/mL solution of Cu(OAc)2 in hydrazine, capped at
both ends, and placed inside a muffle furnace (120° C). After 10 min. metallic Cu was
gradually released from the solution and deposited on the glass surface. After rinsing with
acetone, the capillaries were placed inside a muffle furnace for calcination at 400°C (3 x
1 min) before use in MACOS.
5.1.5 General procedure for the preparation of the Rh-film coating
inside of 1200 micron and 1700 micron (ID) capillaries
Borosilicate capillaries were filled with a 0.5 mmol/mL solution of RI1CI3 in hydrazine,
capped at both ends, and placed inside a muffle furnace. The furnace temperature was
gradually raised to 80 °C. Over a 15 min. interval, metallic Rh was gradually deposited
on the inner side of capillary wall. After rinsing with acetone, the capillaries were placed
inside a muffle furnace for calcination at 400°C (3 x 1 min).
5.1.6 General procedure for the preparation of the Pt-film coating inside
of 1200 micron and 1700 micron (ID) capillaries
Borosilicate capillaries were filled with a 0.3 mmol/mL solution of L^PtC^ in hydrazine,
capped at both ends, and placed inside a muffle furnace. The furnace temperature was
gradually raised to 80 °C. After 30 min. metallic Pt was gradually released from the
145
solution and deposited on the inner side of capillary wall. After rinsing with acetone, the
capillaries were placed inside a muffie furnace for calcination at 400°C ( 3 x 1 min).
5.1.7 General procedure for the preparation of the Rh-on-Pd and Ruon-Pd coating inside of 1200 micron and 1700 micron (ID) capillaries
Borosilicate capillaries were initially coated with a very thin Pd layer using a 0.02
mmol/niL solution of Pd(OAc)2 in DMF on the basis of procedure described in Section
5.1.2. These Pd-coated capillaries were filled with a 0.3 mmol/mL solution of RI1CI3
(R.UCI3) in diethylene glycol, capped at both ends and placed inside a muffle furnace; the
temperature was gradually increased to 150°C. After 30 min. metallic Rh (Ru) was
gradually released from the solution and deposited on the inner side of capillaries. After
rinsing with acetone, capillaries were calcinated in the furnace for 3 x 1 min. at 400 °C.
5.1.8 Measurements of the metal film temperature using an IR camera
A FLIR Systems Thermovision™ A320 high definition IR camera was used to obtain
live images of the metal coated capillaries under microwave irradiation. The IR camera
was set-up approximately 20 cm away from the window in the irradiation chamber
(Figure 2.14). The recording started after the power on the microwave instrument was
turned on and the temperature of the instrument's built-in IR sensor was kept at 180 °C
for all films. The IR images were recorded and processed on "ThermaCAM™
Researcher" program.
146
5.2 Suzuki-Miyaura and Heck coupling reactions in flow
5.2.1 General procedure for the Suzuki-Miyaura coupling reactions
A stock solution containing the aryl halide 61 (0.6 mmol, 1 equiv.), arylboronic acid 62
(0.72 mmol, 1.2 equiv.), base (2M KOH, 1.8 mmol, 3 equiv.) in 2.0-2.2 mL DMF was
prepared (the mixture volume is 3.0 mL and the solution concentration is 0.2 mmol/mL
with respect to aryl halide, Table 3.1). In reactions with pyridine boronic acid, the stock
solution was prepared by dissolving the aryl halide 61 (0.6 mmol, 1 equiv.), pyridine
boronic acid 62 (0.72 mmol, 1.2 equiv.) and base (K2CO3, 120 mg, 1.5 equiv. or CsF,
217 mg, 2.4 equiv.) in DMA/H2O (2:1). The continuous flow microwave system was
primed with the same solvent as the stock solution. An aliquot from the homogenous
stock solution (1-3 mL) was tåken up in a Hamilton gastight syringe, which was
connected to the reactor system with the aid of Microtight fittings. The syringe was
placed in a Harvard 22 syringe pump that was set to deliver 15 uL/min and the single
mode microwave was programmed to heat constantly; the power level was adjusted
manually so as to keep the temperature constant at the specified values in Table 3.1. The
effluent from the reactor was fed into a collection tube and then analyzed by lH NMR
spectroscopy immediately after the reaction. A known volume of crude reaction mixture
was collected and partitioned between ethyl acetate (50 mL) and water (50 mL) and the
aqueous layer was extracted with ethyl acetate (3 x 25 mL). The combined organic layers
were dried over magnesium sulfate and solvent was removed under reduced pressure.
147
C^^-"
CHO
4-BiphenyIyl aldehyde (Table 3.1, 63) Following the general procedure for the SuzukiMiyaura cross coupling using MACOS, 4-bromobenzaldehyde and phenylboronic acid
were reacted, providing crude product that was purified by flash chromatography (12%
ethyl acetate in hexane) to provide 63 (88% conversion) as a colorless oil. *H NMR (400
MHz, CDC13) 8 10.06 (s, 1H), 7.98-7.94 (m, 2H), 7.79-7.66 (m, 4H), 7.52-7.46 (m, 3H).
13
C NMR (100 MHz, CDCI3) 5 192.2, 147.4, 139.9, 135.4, 130.2, 129.1, 128.3, 127.8,
127.2. Spectra matched that reported in the literature.
4-methyIbiphenyl (Table 3.1, 64) Following the general procedure for the SuzukiMiyaura cross coupling using MACOS, 4-bromotoIuene and phenylboronic acid were
reacted, providing crude product that was purified by flash chromatography (20% ethyl
acetate in hexane) to provide 64 (95% conversion) as colorless crystals. Mp = 62-65 °C
(reported 64-66 °C). ! H NMR (300 MHz, CDC13) 8 7.60-7.54 (m, 4H), 7.44-7.40 (m, 3H),
7.37-7.32 (m, 2H), 2.37 (s, 3H). 13C NMR (100 MHz, CDCI3) 8 140.9, 138.0, 137.2,
129.5, 128.7, 127.3, 127.1, 126.9,21.2. Spectra matched that reported in the literature.138
4-methoxybiphenyl (Table 3.1, 65) Following the general procedure for the SuzukiMiyaura
cross
coupling
using
MACOS,
148
l-bromo-4-methoxybenzene
and
phenylboronic acid were reacted, providing crude product that was purified by flash
chromatography (15% ethyl acetate in hexane) to pro vide 65 (97% conversion)
as
colorless crystals. Mp = 87-88 °C (reported 85-87 °C). ! H NMR (300 MHz, CDC13) 6
7.60-7.52 (m, 4H), 7.42-7.38 (m, 2H), 7.32-7.28 (m, 1H), 6.97 (d, J= 8.8 Hz, 2H), 3.77
(s, 3H). 13C NMR (100 MHz, CDC13) 5 158.8, 140.9, 133.8, 128.9, 128.3, 126.7, 126.5,
114.2, 55.6. Spectra matched that reported in the literature.139
2,4,6-trimethylbiphenyl (Table 3.1, 66) Following the general procedure for the SuzukiMiyaura
cross
coupling
using
MACOS,
2-bromo-1.3.5-trimethylbenzene
and
phenylboronic acid were reacted, providing crude product that was purified by flash
chromatography (22% ethyl acetate in hexane) to provide 66 (92% conversion) as a
colorless oil. *H NMR (300 MHz, CDC13) 5 7.55-7.38 (m, 3H); 7.19 (d, J= 8.2 Hz, 2H);
6.84 (s, 2H), 2.38 (s, 3H), 2.10 (s, 6H). 13C NMR (100 MHz, CDC13) 6 141.0, 139.3,
136.7, 135.8, 129.4, 128.3, 128.1, 126.5, 21.1, 20.6. Spectra matched that reported in the
literature.140
4-(pyridin-4-yl)benzaIdehyde (Table 3.1, 67) Following the general procedure for the
Suzuki-Miyaura cross coupling using MACOS, 4-bromobenzaldehyde
and 4-
pyridineboronic acid were reacted, providing pure product that was purified by flash
149
chromatography (25% ethyl acetate in hexane) to provide 67 (93% conversion) as a
colorless oil. *H NMR (400 MHz, CDC13) 5 10.08 (s 1H), 8.72 (dd, J= 4.9, 1.8 Hz, 2H),
8.04 (dd, J = 6.8, 1.7 Hz, 2H), 7.78 (dd, J = 7.8, 1.9 Hz, 2H), 7.57 (dd, J = 4.9, 1.8 Hz,
2H). I3C NMR (100 MHz, CDC13) 5 191.1, 149.6, 146.8, 143.5, 136.4, 130.2, 127.5,
121.5. Spectra matched that reported in the literature.141
OHC
2-(pyridin-4-yl)benzaIdehyde (Table 3.1, 68) Following the general procedure for the
Suzuki-Miyaura cross coupling using MACOS, 2-bromobenzaldehyde
and 4-
pyridineboronic acid were reacted, providing pure product that was purified by flash
chromatography (25% ethyl acetate in hexane) to provide 68 (59% conversion) as a
colorless oil. ! H NMR (400 MHz, CDC13) 5 10.01 (s 1H), 8.68 (d, J= 6.2 Hz, 2H), 8.108.07 (m, 1H), 7.72-7.52 (m, 5H). 13C NMR (100 MHz, CDC13) 5 190.7, 149.5, 145.6,
142.2, 133.6, 133.2, 130.0, 128.6. 128.2, 124.4. Spectra matched that reported in the
literature.142
CHO
3-(pyridin-4-yl)benzaldehyde (Table 3.1, 69) Following the general procedure for the
Suzuki-Miyaura cross coupling using MACOS, 3-bromobenzaldehyde
and 4-
pyridineboronic acid were reacted, providing crude product that was purified by flash
chromatography (25% ethyl acetate in hexane) to provide 69 (73% conversion) as a
150
colorless oil. lH NMR (400 MHz, CDC13) 8 10.03 (s 1H), 8.74-8.70 (d,J= 5.0 Hz, 2H),
8.18 (s, 1H), 7.96-7.90 (m, 2H), 7.68 (t, J= 7.9Hz, 1H), 7.58-7.54 (d, J= 5.0 Hz, 2H).
13
C NMR (100 MHz, CDC13) 5 191.9, 150.5, 146.8, 139.2, 137.1, 132.5, 130.3, 129.8,
127.5, 121.3. Spectra matched that reported in the literature.142
•CMD
4-phenylpyridine (Table 3.1, 70) Following the general procedure for the Suzuki Miyaura cross coupling using MACOS, bromobenzene and 4-pyridineboronic acid
were reacted, providing 1.4 mL of crude product that was purified by flash
chromatography (24% ethyl acetate in hexane) to provide 70 (32.2 mg, 74% yield) as
light yellow crystals. Mp = 74-76 °C (reported 76-78 °C). 2H NMR (400 MHz, CDCI3) 6
8.65 (d, J= 6.1 Hz, 2H), 7.69 (d, J = 6.1Hz, 2H), 7.57-7.48 (5H, m). 13C NMR (100
MHz, CDCI3) 8 150.3, 148.5, 138.4, 129.0, 128.2, 126.6, 121.2. Spectra matched that
reported in the literature.
4-(benzofuran-2-yl) benzaldehyde (Table 3.1, 71) Following the general procedure
above for the Suzuki-Miyaura cross coupling using MACOS, 4-bromobenzaldehyde and
2-benzofuranboronic acid were reacted, providing 1.5 mL of crude product that was
purified by flash chromatography (10% ethyl acetate in hexane) to provide 71 (55.9 mg,
84% yield) as yellow crystals. Mp = 120-122 °C. *H NMR (400 MHz, CDCI3) 8 10.06
(1H, s), 8.04 (d, / = 8.1 Hz, 2H), 7.98 (d, J= 8.1 Hz, 2H), 7.65 (d, J= 8.1Hz, 1H), 7.57
151
(d, J= 8.1 Hz, 1H), 7.37 (t, J= 8 .1Hz, 1H), 7.33-7.29 (m, 1H), 7.23 (s, 1H). "C NMR
(100MHz,CDCl 3 )5 191.5, 155.3, 154.3, 135.9, 135.8, 130.3, 128.8, 125.4, 125.1, 123.4,
121.5, 111.4, 104.3. Spectra matched that reported in the literature.91
5.2.2 General Procedure for the Heck coupling reactions
A stock solution containing the acrylate 72 (1 mmol, 1 equiv.), aryl halide 73 (1.2 mmol,
1.2 equiv.), base (triethylamine, 3 mmol, 3 equiv.) in 1.5 mL DMA was prepared (the
mixture volume is 2.0 mL and the solution concentration is 0.5 mmol/mL with respect to
acrylate, Table 3.2). The continuous flow microwave system was primed with the same
solvent as the stock solution and an aliquot from the homogenous stock solution (1-3 mL)
was tåken up in a Hamilton gastight syringe, which was connected to the reactor system
with the aid of Microtight fittings. The syringe was placed in a Harvard 22 syringe pump
that was set to deliver 15 uL/min and the single mode microwave was programmed to
heat constantly; the power level was fluctuated manually so as to keep the temperature
constant at the specified values in Table 3.2. The effluent from the reactor was fed into a
collection tube and then analyzed by 'H NMR spectroscopy immediately after the
reaction. A known volume of crude reaction mixture was collected and partitioned
between diethyl ether (50 mL) and water (50 mL) and the aqueous layer was extracted
with diethyl ether (3 x 25 mL). The combined organic layers were dried over anhydrous
magnesium sulfate and solvent was removed under reduced pressure.
152
Methyl cinnamate (Table 3.2, 74) Following the general procedure for the Heck cross
coupling using MACOS, iodobenzene and methylacrylate were reacted, providing
crude product that was purified by flash chromatography (14% ethyl acetate in hexane) to
provide 74 (80% conversion) as colorless crystals. Mp = 38-40 °C (reported 39-40 °C).
l
U NMR (400 MHz, CDC13) 5 7.68 (d, J= 15.8 Hz, 1H), 7.52-7.48 (m, 2H), 7.37-7.32
(m, 3H), 6.46 (d, J = 15.8 Hz, 1H), 3.76 (s, 3H). 13C NMR (100 MHz, CDC13) 5 167.8,
144.8, 134.4, 130.0, 128.7, 127.8, 117.6, 51.8. Spectra matched that reported in the
literature.143
^-^
\ ^
^COOMe
Methyl 3-(4-methoxyphenyl)acrylate (Table 3.2, 75) Following the general procedure
for the Heck
cross
coupling using MACOS, l-iodo-4-methoxybenzene
and
methylacrylate were reacted, providing crude product that was purified by flash
chromatography (12% ethyl acetate in hexane) to provide 75 (58% conversion) as a
colorless oil. ! H NMR (400 MHz, CDC13) 6 7.94 (d, J= 15.8 Hz, 1H), 7.40-7.22 (m, 4H),
6.40 (d, J= 15.8 Hz, 1H), 3.82 (s, 3H), 3.69 (s, 3H). 13C NMR (100 MHz, CDCI3) 5
168.0, 161.2, 144.6, 129.9, 127.2, 115.5, 114.2, 55.7, 51.6. Spectra matched that reported
in the literature.144
153
Methyl 3-p-toIylacrylate (Table 3.2, 76) Following the general procedure for the Heck
cross coupling using MACOS, 4-iodotoIuene and methylacrylate were reacted,
providing crude product that was purified by flash chromatography (16% ethyl acetate in
hexane) to provide 76 (88% conversion) as colorless crystals. Mp = 51-53 °C (reported
53-55 °C). ! H NMR (400 MHz, CDC13) 8 7.66 (d,J= 15.9 Hz, 1H), 7.44-7.40 (m, 2H),
7.22-7.18 (m, 2H), 6.38 (d, J= 15.9 Hz, 1H), 3.78 (s, 3H), 2.35 (s, 3H). 13C NMR (100
MHz, CDC13) 5 167.9, 144.7, 140.5, 131.5, 129.6, 128.2, 116.6, 51.4, 21.2. Spectra
matched that reported in the literature.144
Methyl 3-(4-fluorophenyl) acrylate (Table 3.2, 77) Following the general procedure for
the Heck cross coupling using MACOS, l-fluoro-4-iodobenzene and methyl acrylate
were reacted, providing 1.2 mL of crude product that was purified by flash
chromatography (10% ethyl acetate in hexane) to provide 77 (85 mg, 79% yield) as pale
brown crystals. Mp = 47-49 °C (reported 50-51 °C). *H NMR (400 MHz, CDC13) 8 7.70
(d, J = 16.1 Hz, 1H), 7.50-7.42 (m, 2H), 7.12-7.02 (m, 2H), 6.38 (d, J= 16.1 Hz, 1H),
3.72 (s, 3H). 13C NMR (100 MHz, CDC13) 8 166.5
130.6, 129.7
(3J'3C-"F
= 8.8 Hz), 117.2, 115.9
(2J"C-"F
that reported in the literature.145
154
(V"C-"F
= 128.6 Hz), 162.2, 143.1,
= 22.5 Hz), 51.2. Spectra matched
Tert-butyl cinnamate (Table 3.2, 78) Following the general procedure for the Heck
cross coupling using MACOS, 4-iodotoluene and t-butyl acrylate were reacted,
providing crude product that was purified by flash chromatography (12% ethyl acetate in
hexane) to provide 78 (99% conversion) as pale yellow oil. 'H NMR (400 MHz, CDC13)
5 7.56 (d, J= 16.2 Hz, 1H), 7.51-7.47 (m, 2H), 7.34-7.38 (m, 3H), 6.42 (d, J= 16.2 Hz,
1H), 1.62 (s, 9H).
13
C NMR (100 MHz, CDC13) 5 166.8, 143.7, 134.5, 130.1, 128.7,
128.0, 120.3, 80.5, 27.8. Spectra matched that reported in the literature.146
(E)-3-phenylacrylonitrile (Table 3.2, 79) Following the general procedure for the Heck
cross coupling using MACOS, iodobenzene and acrylonitrile were reacted, providing
1.4 mL of crude product that was purified by flash chromatography (10% ethyl acetate in
hexane) to provide 79 (74 mg, 82% yield) as a yellow oil. 'H NMR (400 MHz, CDC13) 8
7.44-7.30 (m, 6H), 5.88 (d, J = 16.2 Hz, 1H). 13C NMR (100 MHz, CDC13) 5 151.0,
133.5, 131.2, 129.0, 127.5, 118.1, 96.8. Spectra matched that reported in the literature.146
155
5.3 Diels-Alder reactions in flow
5.3.1 General procedure
microwave heating
for
Diels-Alder
reactions
in
flow
with
A stock solution containing the diene, 83 or 86 (1.0 mmol, 1.0 equiv.) and the dienophile
84 or 87 (1.5 mmol, 1.5 equiv.) in DMSO (total mixture volume was 1.0 mL) was
prepared. For "Reaction 1" in Figure 3.1, the concentration of the dienophile 80 was 0.2
mmol (1.0 equiv.), and that of the diene 81 was 0.3 mmol (1.5 equiv.). The continuous
flow microwave system was primed with DMSO and an aliquot from the homogenous
stock solution was tåken up in a Hamilton gastight syringe and connected to the reactor
system with the aid of Microtight™ fittings. The syringe was placed in a Harvard 22
syringe pump that was set to deliver 10 uL/min and the single mode microwave was
programmed to heat constantly; the power level was fluctuated manually so as to keep the
temperature constant at the specified values in Table 3.3. The effluent from the reactor
was fed into a sealed vial and then analyzed by ! H NMR spectroscopy immediately after
the reaction. A known volume of crude reaction mixture was collected and the product
purified by silica gel chromatography.
5.3.2 General procedure for Diels-Alder reactions in flow with oil bath
heating
A Pd-coated capillary fitted on both sides with flexible Teflone™ tubing and submerged
in an oil bath that was pre-heated to the desired temperature (see Table 3.3 for specific
156
temperatures). The Diels-Alder solutions were flowed continuously at the specified flow
rate as the reactions conducted in MACOS. The effluent was collected into a sealed vial.
2,3:5,6-DibenzobicycIo[2.2.2]octane-7,8-dicarboxyIic
anhydride
(Table
3.3, 82)
Following the general procedure for the Diels-Alder reaction using MACOS, anthracene
and maleic anhydride were reacted, providing 1.4 rnL of crude product, that was
partitioned between diethyl ether (50 mL) and water (50 mL) and the aqueous layer was
extracted with diethyl ether (3 x 25 mL). The combined organic layers were dried over
anhydrous magnesium sulfate, filtered and the solvent was removed under reduced
pressure. Purification by flash chromatography (20 % ethyl acetate in hexane) provided
62 mg of 82 (80% yield) as white crystals. Mp = 261-263 °C (reported 264 °C). lH NMR
(400 MHz, CDC13) 5 7.57-7.49 (m, 2H), 7.39-7.30 (m, 2H), 7.22-7.08 (m, 4H), 4.85 (s,
2H), 3.55 (s, 2H).
13
C NMR (100 MHz, CDCI3) 5 170.5, 140.6, 138.1, 127.8, 127.1,
125.2, 124.4, 48.0, 45.4. Spectra matched that found in the literature.147
O
l-(3,4-dimethylcyck>hex-3-enyl) ethanone (Table 3.3, 85) Following the general
procedure for the Diels-Alder reaction using MACOS, dimethyl butadiene and MVK
157
were reacted, providing 1.2 mL of crude product that was partitioned between diethyl
ether (50 mL) and water (50 mL) and the aqueous layer was extracted with diethyl ether
(3 x 25 mL). The combined organic layers were dried over anhydrous magnesium sulfate,
filtered and the solvent was removed under reduced pressure. Purification by flash
chromatography (5% ethyl acetate in hexane) provided 127.5 mg of 85 (70% yield), as a
light yellow oil. ! H NMR (400 MHz, CDC13) 8 2.57-2.52 (m, 1H), 2.18 (s, 3H), 2.10-1.94
(m, 6H), 1.65 (s, 3H), 1.63 (s, 3H). 13C NMR (100 MHz, CDC13) 5 211.6, 125.4, 123.8,
48.1, 32.9, 31.0, 27.9, 25.2, 19.1, 18.7. Spectra matched that found in the literature. 148
Q
-COOCH3
COOCH3
Dimethyl
7-oxabicycIo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate
(Table
3.3,
88)
Following the general procedure for the Diels-Alder reaction using MACOS, furan and
DMAD were reacted, providing 1.0 mL of crude product that was partitioned between
diethyl ether (50 mL) and water (50 mL) and the aqueous layer was extracted with
diethyl ether (3 x 25 mL). The combined organic layers were dried over anhydrous
magnesium sulfate, filtered and the solvent was removed under reduced pressure.
Purification by flash chromatography (30% ethyl acetate in hexane) provided 155 mg of
88 (74% yield), as a yellow oil. *H NMR (400 MHz, CDC13) 8 7.25 (s, 2H), 5.71 (s, 2H),
3.85 (s, 6H). 13C NMR (100 MHz, CDC13) 8 163.3, 153.1, 143.2, 85.2, 52.2. Spectra
matched that found in the literature.149
158
5.4 Indole synthesis in continuous flow format
5.4.1 General procedure for the indole synthesis
A stock solution containing the substituted bromoalkene 89 (0.75 mmol, 1.5 equiv.), obromoaniline 90 (0.5 mmol, 1.0 equiv.), sodium t-butoxide (1.5 mmol, 3.0 equiv.), Pd
PEPPSI-IPr (18 mg, 2.6 mol %.) in 0.8 mL toluene (total mixture volume was 1.0 mL)
was prepared (Scheme 3.1). The continuous flow microwave system was primed with
toluene and a 1 mL aliquot from the homogenous stock solution was tåken up in a
Hamilton gastight syringe and connected to the reactor system with the aid of
Microtight fittings. The syringe was placed in a Harvard 22 syringe pump that was set
to deliver 15 uL/min and the single mode microwave was programmed to heat constantly;
the power level was fluctuated manually so as to keep the temperature constant at the
specified values in Table 3.4. The effluent from the reactor was fed into a sealed vial and
then analyzed by H NMR spectroscopy immediately after the reaction. A known volume
of crude reaction mixture was collected and the product purified by silica gel
chromatography.
Purity analyses were conducted on Waters 2695LC-Quattro Ultima Mass Spectrometer
(MS) using an H2O-CH3CN solvent system; the MS was run in "ESI+, dual scan" mode
(T = 350°C). The LC columns used were Synergy 4 micron Hydro RP 150mm x 4.6mm
(T = 20°C) and Gemini Cl8 4 micron 150mmX4.6mm (T = 24°C).
159
2-EthyI-lH-indole (Table 3.5, 91a) Following the general procedure for the preparation
of indoles using MACOS, 0.6 mL of crude reaction mixture, derived from 89a and 90a
were collected and purification by flash chromatography (14% ethyl acetate in hexane)
provided 35.1 mg of 91a (81% yield, 100% purity) as a brown amorphous solid. Mp =
85-87 °C (reported 82-83 °C). ! H NMR (400 MHz, CDC13) 8 7.81 (br s, 1H), 7.61 (d, J =
2.1 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.20-7.12 (m, 2H), 6.32 (s, 1H), 2.82 (q, J= 8.1
Hz, 2H), 1.39 (t, J= 8.0 Hz, 3H). 13C NMR (100 MHz, CDCI3) 5 139.5, 136.6, 129.8,
121.5, 120.2, 119.5, 111.2, 100.8, 21.2, 14.4. Spectra matched that found in the
literature
150
2-MethyI-lH-indole (Table 3.5, 91b) Following the general procedure for the
preparation of indoles using MACOS, 0.55 mL of crude reaction mixture, derived from
89b and 90a were collected and purification by flash chromatography (20% acetone in
hexane) provided 26 mg of 91b (72% yield, 100% purity) as a brown amorphous solid.
Mp = 118-120 °C (reported 117-119 °C). *H NMR (400 MHz, CDC13) 8 7.87 (br s, 1H),
7.53 (d, J= 8.1 Hz, 1H), 7.31 (d, J= 8.0 Hz, 1H), 7.12-7.05 (m, 2H), 6.24 (s, 1H), 2.47
(s, 3H). 13C NMR (100 MHz, CDC13) 8 135.5, 134.3, 129.6, 121.9, 120.3, 119.8, 110.8,
101.0, 12.8. Spectra matched that found in the literature
160
151, 152
2-Phenyl-lH-indole (Table 3.5, 91c) Following the general procedure for the preparation
of indoles using MACOS, 0.7 mL of crude reaction mixture, derived from 89c and 90a
were collected and purification by flash chromatography (12% ethyl acetate in hexane)
provided 50.0 mg of 91c (74% yield, 95% purity) white crystals. Mp = 180-182 °C
(reported 184-186 °C). ! H NMR (400 MHz, CDC13) 5 8.35 (br s, 1H), 7.72-7.60 (m, 3H),
7.52-7.40 (m, 3H), 7.36 (t,J= 8.0 Hz, 1H), 7.23 (t, J= 7.1 Hz, 1H), 7.15 (t, J= 7.1 Hz,
1H), 6.86 (s, 1H). 13C NMR (100 MHz, CDC13) 5 137.6, 136.5, 132.2, 129.0, 128.7,
127.6, 125.0, 122.2, 120.4, 120.2, 110.8, 99.8. Spectra matched that found in the
literature
152
2-Ethyl-5-Chloro-lH-indole (Table 3.5, 92a) Following the general procedure for the
preparation of indoles using MACOS, 0.82 mL of crude reaction mixture, derived from
89a and 90b were collected and purification by flash chromatography (20% ethyl acetate
in hexane) provided 52.4 mg of 92a (71% yield, 92% purity) as a brown oil. lH NMR
(400 MHz, CDC13) 5 7.91 (br s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.22 (d, J= 8.2 Hz, 1H),
7.08 (dd, J= 8.1, 2.0 Hz, 1H), 6.21 (s, 1H), 2.81 (q, J= 8.0 Hz, 2H), 1.37 (t, J = 8.0 Hz,
3H).
13
C NMR (100 MHz, CDC13) 5 142.9, 134.2, 129.9, 125.2, 121.2, 119.2, 111.2,
98.6, 21.4, 13.1. Spectra matched that found in the literature.151
161
H
Me
^^^
4.
2-Methyl-5-Chloro-lH-indole (Table 3.5, 92b) Following the general procedure for the
preparation of indoles using MACOS, 0.7 mL of crude reaction mixture, derived from
89b and 90b were collected and purification by flash chromatography (20% acetone in
hexane) provided 41.0 mg of 92b (70% yield, 93% purity) as a pale brown amorphous
solid. Mp = 112-114 °C (reported 114-116 °C). ! H NMR (400 MHz, CDC13) 8 7.88 (br s,
1H), 7.49 (d, J= 2.2 Hz, 1H), 7.20 (d, J= 8.7 Hz, 1H), 7.07 (dd, J= 8.7, 2.0 Hz, 1H),
6.19 (s, 1H), 2.49 (s, 3H). 13C NMR (100 MHz, CDC13) 5 136.6, 134.4, 130.2, 125.2,
121.1, 119.0, 111.1, 100.3, 13.8. Spectramatchedthatfoundintheliterature. 154
H
Cl
2-PhenyI-5-ChIoro-lH-indole (Table 3.5, 92c) Following the general procedure for the
preparation of indoles using MACOS, 0.5 mL of crude reaction mixture, derived from
89c and 90b were collected and purification by flash chromatography (16% ethyl acetate
in hexane) provided 39.9 mg of 92c (70% yield, 99% purity) as white crystals. Mp = 185187 °C (reported 189-191 °C). *H NMR (400 MHz, CDC13) 8 8.38 (br s, 1H), 7.68 (d, J =
8.0 Hz, 2H), 7.61 (d, J= 2.1 Hz, 1H), 7.48 (t, J= 8.1 Hz, 2H), 7.39-7.31 (m, 2H), 7.17
(dd, 7 = 8.1, 2.0 Hz, 1H), 6.79 (s, 1H). 13C NMR (100 MHz, CDC13) 8 139.1, 135.5,
132.0, 129.8, 129.1, 127.7, 125.4, 123.8, 121.4, 119.2, 112.7, 98.5. Spectra matched that
found in the literature.157
162
H
F
2-EthyI-5-fluoro-lH-indoIe (Table 3.5, 93a) Following the general procedure for the
preparation of indoles using MACOS, 0.55 mL of crude reaction mixture, derived from
89a and 90c were collected and purification by flash chromatography (30%
dichloromethane in hexane) provided 33.9 mg of 93a (76% yield, 100% purity) as pale
brown crystals. Mp = 117-119 °C. ! H NMR (400 MHz, CDC13) 5 7.88 (br s, 1H), 7.267.18 (m, 2H), 6.88 (dd, J'H-"F= 9.0, 1.0 Hz, 1H), 6.23 (s, 1H), 2.81 (q, J=
8.0 Hz,
2H),
1.37 (t, J = 8.1 Hz, 3H). 13C NMR (100 MHz, CDC13) 5 157.9 (>c-'V = 232.3 Hz),
143.2, 132.3, 129.2
Hz), 104.7
(2J"C-"F
(3J»C-"F
= 10.2 Hz), 110.6
= 23.4 Hz), 99.2
(4J"C-»F
(3J"C-"F
= 10.2 Hz), 109.0
(2J"C-"F
= 26.3
= 4.4 Hz), 21.5, 13.1. Anal. calcd. for
C10H10NF: C 73.88, H 6.19, N 8.58, F 11.64. Found: C 73.90, H 6,28, N 8.48, F 11.54.
Compound has been reported previously153 without ! H NMR or 13C NMR spectra, which
are reported here.
H
Me
^^
<\^
2-Methyl-5-fluoro-lH-indole (Table 3.5, 93b) Following the general procedure for the
preparation of indoles using MACOS, 0.58 mL of crude reaction mixture, derived from
89b and 90c were collected and purification by flash chromatography (20% ethyl acetate
in hexane) provided 40.0 mg of 93b (73% yield, 100% purity) as pale crystals. Mp = 103105 °C (reported 98-100 °C). 'H NMR (400 MHz, CDC13) 8 7.84 (br s, 1H), 7.24-7.16
163
(m, 2H), 6.87 (dd, J'H-"F = 9.0, 1.0 Hz, 1H), 6.21 (s, 1H), 2.46 (s, 3H).
U
C NMR
(100
MHz, CDC13) 8 157.7 (!J»C-"F= 233.6 Hz), 137.0, 132.5, 129.5 (3J"C-"F = 10.5 Hz), 110.5
(3J"C-"F = 9.1 Hz), 108.9 (2J"C-"F = 25.5 Hz), 104.6 (2J»C-'>F = 24.2 Hz), 100.7 (4J"C-"F =
4.5 Hz), 13.8. Spectra matched that found in the literature.154
H
F
2-Phenyl-5-fluoro-lH-indole (Table 3.5, 93c) Following the general procedure for the
preparation of indoles using MACOS, 0.78 mL of crude reaction mixture, derived from
89c and 90c were collected and purification by flash chromatography (30%
dichloromethane in hexane) provided 64.1 mg of 93c (78% yield, 100% purity) as white
crystals. Mp = 178-180 °C (reported 183 °C). *H NMR (400 MHz, CDC13) 5 8.33 (br s,
1H), 7.68 (d, J= 8.0 Hz, 2H), 7.48 (t, J= 8.0 Hz, 2H), 7.39-7.28 (m, 3H), 6.97 (dd, J'H-"F
= 9.0, 1.0 Hz, 1H), 6.81 (s, 1H). 13C NMR (100 MHz, CDC13) 5 158.3
Hz), 139.7, 133.3, 132.1, 129.6
10.4 Hz), 110.6
(2J"C-"F=
(3J"C-"F=
(1J"C-"F=
10.4 Hz), 129.1, 128.0, 125.2, 111.5
235.3
(3J"C-"F
=
25.8 Hz), 105.4 (2J»c-'V= 23.3 Hz), 100.1. Spectra matched
that found in the literature.154'155
H
^^^
2-EthyI-5-methyl-lH-indole (Table 3.5, 94a) Following the general procedure for the
preparation of indoles using MACOS, 0.66 mL of crude reaction mixture, derived from
89a and 90d were collected and purification by flash chromatography (20% ethyl acetate
164
in hexane) provided 39.5 mg of 94a (75% yield, 96% purity) as a yellow amorphous
solid. Mp = 74-75 °C (reported 75-76 °C). *H NMR (400 MHz, CDC13) 8 7.79 (br s, 1H),
7.35 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.96 (d,J= 8.1 Hz, 1H), 6.19 (s, 1H), 2.80 (q, J =
8.0 Hz, 2H), 2.46 (s, 3H), 1.36 (t, J= 8.0 Hz, 3H). 13C NMR (100 MHz, CDC13) 5 141.4,
134.6, 130.2, 128.7, 122.4, 119.5, 109.9, 98.2, 21.5, 21.3, 13.2. HRMS calcd. for
C11H13N: 159.1048; found: 159.1050. Compound has been reported previously153 without
!
H NMR or 13C NMR spectra, which are reported here.
2-MethyI-5-methyl-lH-indole (Table 3.5, 94b) Following the general procedure for the
preparation of indoles using MACOS, 0.84 mL of crude reaction mixture, derived from
89b and 90d were collected and purification by flash chromatography (20%) acetone in
hexane) provided 49.8 mg of 94b (82% yield, 100% purity) as a yellow amorphous solid.
Mp = 115-118 °C (reported 119 °C). *H NMR (400 MHz, CDC13) 5 7.76 (br s, 1H), 7.33
(s, 1H), 7.19 (d, J= 8.1 Hz, 1H), 6.96 (d, J= 8.1 Hz, 1H), 6.16 (s, 1H), 2.45 (s, 6H). 13C
NMR (100 MHz, CDCI3) 5 136.7, 134.6, 129.7, 128.4, 122.2, 119.3, 108.9, 98.7, 21.6,
14.4. Spectra matched that found in the literature.156
2-Phenyl-5-methyl-lH-indole (Table 3.5, 94c) Following the general procedure for the
preparation of indoles using MACOS, 0.75 mL of crude reaction mixture, derived from
165
89c and 90d were collected and purification by flash chromatography (12% ethyl acetate
in hexane) provided 66.1 mg of 94c (85% yield, 89% purity) as white crystals. Mp = 203205 °C (reported 209-211 °C). *H NMR (400 MHz, CDC13) 5 8.26 (br s, 1H), 7.70-7.62
(m, 2H), 7.49-7.40 (m, 3H), 7.35-7.28 (m, 2H), 7.05 (d, J= 8.0 Hz, 1H), 6.78 (s, 1H),
2.48 (s, 3H). 13C NMR (100 MHz, CDC13) 8 137.8, 135.0, 132.5, 129.6, 129.5, 129.0,
127.7, 125.1, 124.0, 120.2, 110.6, 99.5, 21.5. Spectra matched that found in the
literature
157
2-EthyI-5,7-dimethyl-lH-indole (Table 3.5, 95a) Following the general procedure for
the preparation of indoles using MACOS, 0.45 mL of crude reaction mixture, derived
from 89a and 90e were collected and purification by flash chromatography (10% acetone
in hexane) provided 27.9 mg of 95a (72% yield, 80% purity) as a brown oil. ! H NMR
(400 MHz, CDCI3) 5 7.72 (br s, 1H), 7.22 (s, 1H), 6.81 (s, 1H), 6.22 (s, 1H), 2.84 (q, J =
8.1 Hz, 2H), 2.49 (s, 3H), 2.44 (s, 3H), 1.39 (t, J = 8.1 Hz, 3H). 13C NMR (100 MHz,
CDCI3) 5 141.1, 133.7, 129.0, 128.4, 123.4, 119.2, 117.6, 99.1, 21.8, 21.3, 15.7, 13.4.
HRMS calcd. for C12H15N: 173.1204; found: 173.1205.
166
2-Methyl-5,7-dimethyI-lH-indole (Table 3.5, 95b) Following the general procedure for
the preparation of indoles using MACOS, 0.60 mL of crude reaction mixture, derived
from 89b and 90e were collected and purification by flash chromatography (20% acetone
in hexane) provided 41.0 mg of 95b (85% yield, 93% purity) as a pale brown oil. *H
NMR (400 MHz, CDC13) 5 7.70 (br s, 1H), 7.19 (s, 1H), 6.79 (s, 1H), 6.17 (s, 1H), 2.48
(s, 3H), 2.45 (s, 3H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCI3) 5 135.5, 134.0, 131.6,
128.4, 123.2, 119.3, 118.9, 100.7, 21.9, 21.3, 14.4. Spectra matched that found in the
literature.158
2-Phenyl-5,7-dimethyl-lH-indole (Table 3.5, 95c) Following the general procedure for
the preparation of indoles using MACOS, 0.40 mL of crude reaction mixture, derived
from 89c and 90e were collected and purification by flash chromatography (30%
dichloromethane in hexane) provided 36.4 mg of 95c (82% yield, 100% purity) as a
colorless oil. *H NMR (400 MHz, CDCI3) 5 8.12 (br s, 1H), 7.71 (d, J= 8.0 Hz, 2H),
7.50-7.41 (m, 2H), 7.38-7.30 (m, 2H), 6.87 (s, 1H), 6.78 (s, 1H), 2.54 (s, 3H), 2.45 (s,
3H).
13
C NMR (100 MHz, CDC13) 5 139.9, 137.2, 134.8, 132.2, 129.8, 129.1, 127.8,
167
125.1, 123.3, 118.7, 110.6, 99.5, 21.4, 20.3. Spectra matched that found in the
literature. 159
2-Ethyl-5,7-difluoro-lH-indoIe (Table 3.5, 96a) Following the general procedure for the
preparation of indoles using MACOS, 0.68 mL of crude reaction mixture, derived from
89a and 90f were collected and purification by flash chromatography (10% ethyl ether in
pentane) provided 39.3 mg of 96a (64% yield, 90% purity) as a pale yellow oil. *H NMR
(400 MHz, CDC13) 5 8.02 (br s, 1H), 7.01 (dd, J'H-"F= 9.2, 1.5 Hz, 1H), 6.68 (dd, J'H-"F
=
9.0, 1.4 Hz, 1H), 6.28 (s, 1H), 2.82 (q, J= 8.1 Hz, 2H), 1.38 (t, J= 8.1 Hz, 3H). 13C
NMR (100 MHz, CDCI3) 5 156.9
Hz), 143.8, 131.3
(2J"C-"F
21.9;16.1 Hz), 99.9
{4J"C-"F=
(]J"C-"F=
235.6; 10.2 Hz), 147.9 (!J"C-"F= 245.9; 14.6
= 19.1 Hz), 120.4
4.4 Hz), 95.9
( 3 J»C-"F
( 2 J"C-"F=
= 13.2 Hz), 100.5
{2J"C-'»F
=
48.3; 20.5 Hz), 22.2, 13.2. HRMS
calcd. for C10H9NF2: 181.0703; found: 181.0701.
2-Methyl-5,7-difluoro-lH-indole (Table 3.5, 96b) Following the general procedure for
the preparation of indoles using MACOS, 0.60 mL of crude reaction mixture, derived
from 89b and 90f were collected and purification by flash chromatography (10% ethyl
ether in pentane) provided 33.0 mg of 96b (65% yield, 93% purity) as a yellow oil. 'H
168
NMR (400 MHz, CDC13) 6 8.00 (br s, 1H), 6.98 (dd, J'H-"F = 9.2, 1.4 Hz, 1H), 6.66 (dd,
J'H-"F=
9.0, 1.4 Hz, 1H), 6.24 (s, 1H), 2.48 (s, 3H). 13C NMR (100 MHz, CDC13) 5 157.3
(1J"C-"F=
235.6; 10.2 Hz), 147.6
Hz), 120.8
96.1
(JJ"C-"F =
244.4; 14.6 Hz), 138.2, 131.6
C>C-"F=
(3J»C-"F = 11.7 Hz), 101.6 ( ¥ J"C-"F= 4.4 Hz), 100.3 (2J»C-"F = 23 A; 4.4
(2J"C-"F
17.5
Hz),
= 30.7; 20.5 Hz), 13.6. HRMS calcd. for C9H7NF2: 167.0547; found:
167.0544.
F
H
Ph
I
<(
2-Phenyl-5,7-difluoro-lH-indole (Table 3.5, 96c) Following the general procedure for
the preparation of indoles using MACOS, 0.50 mL of crude reaction mixture, derived
from 89c and 90f were collected and purification by flash chromatography (25%
dichloromethane in pentane) provided 37.4 mg of 96c (65% yield, 96% purity) as a
colorless oil. *H NMR (400 MHz, CDCI3) 5 8.44 (br s, 1H), 7.69 (d, J= 8.1 Hz, 2H), 7.50
(t, J= 8.0 Hz, 2H), 7.45-7.38 (m, 1H), 7.11 (dd, J'H-"F= 9.0, 1.5 Hz, 1H), 6.83 (s, 1H),
6.77 (t, J-H-"F= 10.0 Hz, 1H). 13C NMR (100 MHz, CDC13) 5 157.2 {'j»c-nF= 231 A; 10.2
Hz), 148.4 ( 1 J"C- 1 'F= 245.9; 14.6 Hz), 140.2,131.7
125.5, 121.6
(2J"C-'SF=
13.2 Hz), 101.0
(2J»C-"F=
(V»C-"F=
4.4 Hz), 131.2, 129.4, 128.1,
23A; 4.4 Hz), 100.5., 97.4
(2J'3C-"F =
30.7; 20.5 Hz). Anal. calcd. for Ci4H8NF2: C 73.36, H 3.96, N 6.11, F 16.58. Found: C
73.54, H 3.58, N 6.11, F 16.38. HRMS calcd. for Ci4H9NF2: 229.0703; found: 229.0692.
169
H
iPr
2-Ethyl-5-isopropyl-lH-indole (Table 3.5, 97a) Following the general procedure for the
preparation of indoles using MACOS, 0.61 mL of crude reaction mixture, derived from
89a and 90g were collected and purification by flash chromatography (30%
dichloromethane in hexane) provided 47.4 mg of 97a (83% yield, 96% purity) as a pale
yellow oil. *H NMR (400 MHz, CDC13) 5 7.68 (br s, 1H), 7.55 (s, 1H), 7.29 (d, J= 8.1
Hz, 1H), 7.18 (d, J= 8.1 Hz, 1H), 6.34 (s, 1H), 3.16 (septet, J=7.l Hz, 1H), 2.83 (q, J =
8.0 Hz, 2H), 1.45 (m, 9H). 13C NMR (100 MHz, CDC13) 5 141.7, 140.2, 134.5, 129.0,
120.2, 116.9, 110.1, 98.5, 34.4, 24.9, 21.5, 13.5. HRMS calcd. for C13H17N: 187.1361;
found: 187.1353.
H
Me
^ ^
4.
2-Methyl-5-isopropyl-lH-indole (Table 3.5, 97b) Following the general procedure for
the preparation of indoles using MACOS, 0.68 mL of crude reaction mixture, derived
from 89b and 90g were collected and purification by flash chromatography (30%
dichloromethane in pentane) provided 46.0 mg of 97b (79% yield, 97% purity) as a pale
yellow oil. ] H NMR (400 MHz, CDC13) 6 7.69 (br s, 1H), 7.44 (s, 1H), 7.24 (d, J= 8.1
Hz, 1H), 7.09 (d, J= 8.1 Hz, 1H), 6.24 (s, 1H), 3.07 (septet, J= 7.1 Hz, 1H), 2.45 (s, 3H),
1.38 (d,J=
7.1 Hz, 6H). 13C NMR (100 MHz, CDC13) 8 140.4, 135.3, 134.6, 129.2,
170
120.1, 116.7, 110.0, 100.1, 34.2, 24.7, 13.7. HRMS calcd. for Ci2Hi5N: 173.1204; found:
173.1206.
H
iPr
2-Phenyl-5-isopropyl-lH-indoIe (Table 3.5, 97c) Following the general procedure for
the preparation of indoles using MACOS, 0.72 mL of crude reaction mixture, derived
from 89c and 90g were collected and purification by flash chromatography (30%
dichloromethane in pentane) provided 67.9 mg of 97c (80% yield, 99% purity) as a
colorless oil. 'H NMR (400 MHz, CDC13) 6 8.27 (br s, 1H), 7.70 (d, J= 8.0 Hz, 2H), 7.56
(s, 1H), 7.49 (t, J= 8.1 Hz, 2H), 7.42-7.32 (m, 2H), 7.18 (d, J= 8.1 Hz, 1H), 6.86 (s, 1H),
3.10 (septet, J= 7.1 Hz, 1H), 1.41 (d, J= 7.1 Hz, 6H). 13C NMR (100 MHz, CDC13) 8
140.9, 138.0, 135.4, 132.6, 129.4, 128.9, 127.5, 125.1, 121.6, 117.5, 110.6, 99.8, 34.2,
24.6. HRMS calcd. for C17H17N: 235.1361; found: 235.1355.
5.5 Hydrosilylation reactions in continuous flow format
5.5.1 General procedure for the hydrosilylation by M A C O S
A stock solution containing the hydrosilane 102 (1.0 mmol, 1.0 equiv.) and the terminal
alkyne 103 (2.0 mmol, 2.0 equiv.) in 0.7 mL toluene (total mixture volume is 1.0 mL)
was prepared (Table 4.1). After the continuous flow microwave system was primed with
toluene, a 1.0 mL aliquot of the homogenous stock solution was tåken up in a Hamilton
gastight syringe and connected to the reactor system with the aid of Microtight fittings.
171
The syringe was placed in a Harvard 22 syringe pump that was set to deliver 20 uL/min
and the single mode microwave was programmed to heat constantly; the power level was
fluctuated manually so as to keep the temperature constant at the specified values in
Table 4.1. The effluent from the reactor was fed into a sealed vial that was charged with
75 psi of air to create backpressure in the system; the eluent was analyzed by lH NMR
spectroscopy immediately after the reaction to obtain chemical conversion. A known
volume of crude reaction mixture was collected and the product purified by silica gel
chromatography.
-cx
VJ
Synthesis of benzyl propargyl ether 103i (used as a substrate in Table 4.1, entries 19,
20 and 24). To a solution of KOH (10.4 g, 185 mmol) in dry DMSO (60 mL) at 0 °C was
added sequentially benzyl alcohol (5.0 g, 46.3 mmol) and propargyl bromide (13.7 g,
92.6 mmol). The mixture was left stirring at rt for 2h before being diluted with Et20 (200
mL) and H2O (100 mL). The organic layer was separated, washed with H2O (4 x 50 mL),
dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. Flash chromatography
(10% ethyl acetate in hexane) followed by distillation (2.5 mmHg, 80°C) afforded benzyl
propargyl ether (4.8g, 71%) as a clear liquid.160 ! H NMR (400 MHz, CDCI3) 5 7.42-7.22
(m, 5H), 4.64 (s, 2H), 4.21 (d, J= 2.0 Hz, 2H), 2.49 (t, J = 2.0 Hz, 1H). 13C NMR (100
MHz, CDCI3) 5 137.6, 128.4, 128.1, 127.9, 79.8, 74.5, 71.5, 57.0.
172
P-(E)-l-(Triethylsilyl)-l-hexene (Table 4.1, 104) Following the general procedure for
the hydrosilylation using MACOS, 1-hexyne and triethylsilane were reacted, providing
0.8 mL of crude product that was purified by flash chromatography (pentane) to provide
110.0 mg of 104 (70% yield including P-(Z) and ot minor isomers) as a pale yellow oil. ! H
NMR (400 MHz, CDC13) 5 6.08 (dt, J = 18.7, 6.3 Hz, 1H), 5.56 (dt, J = 18.7, 1.5 Hz,
1H), 2.21-2.14 (m, 2H), 1.49-1.32 (m, 4H), 0.96-0.88 (m, 12H), 0.60 (q, J = 7.9 Hz, 6H).
13
C NMR (100 MHz, CDCI3) 5 144.8, 125.4, 36.8, 31.0, 22.2, 14.1, 7.5, 3.6. Spectra
matched that found in the literature.161a
p-(E)-l-(Triphenylsilyl)-l-hexene (Table 4.1, 105) Following the general procedure for
the hydrosilylation using MACOS, 1-hexyne and triphenylsilane were reacted,
providing 0.75 mL of crude product that was purified by flash chromatography (5% ethyl
acetate in hexane) to provide 174.5 mg of 105 (68% yield including P-(Z) and d minor
isomers) as a yellow oil. 'H NMR (400 MHz, CDC13) 5 7.78-7.69 (m, 6H), 7.58-7.45 (m,
9H), 6.38-6.32 (m, 2H), 2.39-2.31 (m, 2H), 1.58-1.35 (m, 5H), 1.05 (t, J= 7.2 Hz, 2H).
13
C NMR (100 MHz, CDCI3) 6 154.0, 136.3,.135.3, 129.6, 128.0, 123.4,37.0,31.0,22.5,
14.2. Spectra matched that found in the literature.161b'162
^ \
^ ^
/SiEt 3
HO
^ ^
^ ^
P-(E)-l-(Triethylsilyl)-l-buten-4-ol (Table 4.1, 106) Following the general procedure
for the hydrosilylation using MACOS, 3-butyne-l-oI and triethylsilane were reacted,
173
providing 0.58 mL of crude product that was purified by flash chromatography (20%
ethyl acetate in hexane) to provide 74.2 mg of 106 (69% yield including P-(Z) and d
minor isomers) as a colorless oil. ! H NMR (400 MHz, CDC13) 5 6.05 (dt, J =18.7, 6.4
Hz, 1H), 5.72 (dt, J = 18.7, 1.3 Hz, 1H), 3.64 (t, J = 6.3 Hz, 2H), 2.48 (dd, J = 6.3, 1.2
Hz, 2H), 1.63 (br, 1H), 0.95 (t, J = 8.0 Hz, 9H), 0.59 (q, J = 8.0 Hz, 6H). 13C NMR (100
MHz, CDC13) 5 144.1, 130.3, 61.7, 40.5, 7.5, 3.5. Spectra matched that found in the
literature.
HO
^ \
^ ^
/SiPh 3
^ ^
^ ^
P-(E)-l-(TriphenylsilyI)-l-buten-4-ol (Table 4.1, 107) Following the general procedure
for the hydrosilylation using MACOS, 3-butyne-l-ol and triphenylsilane were reacted,
providing 0.65 mL of crude product that was purified by flash chromatography (25%
ethyl acetate in hexane) to provide 159 mg of 107 (74% yield including P-(Z) and d
minor isomers) as white crystals. Mp = 107-110 °C. *H NMR (400 MHz, CDCI3) 8 7.677.52 (m, 6H), 7.49-7.36 (m, 9H), 6.39 (dt, J = 18.5, 1.2 Hz, 1H), 6.19 (dt, J = 18.5, 6.4
Hz, 1H), 3.75 (t, J = 6.3 Hz, 2H), 2.60 (dd, J = 6.3, 1.2 Hz, 2H), 1.55 (br, 1H). 13C NMR
(100 MHz, CDCI3) 5 149.6, 136.4, 135.1, 130.2, 128.4, 127.9, 61.9, 40.3. Spectra
I ff)
matched that found in the literature.
p-(E)-5-Chloro-l-(triethylsilyI)-l-pentene (Table 4.1, 108) Following the general
procedure for the hydrosilylation using MACOS, 5-chloro-l-pentyne and triethylsilane
were reacted, providing 0.65 mL of crude product that was purified by flash
174
chromatography (20% dichloromethane in pentane) to provide 96.0 mg of 108 (68%
yield including P-(Z) and d minor isomers) as a colorless oil. ! H NMR (400 MHz,
CDC13) 5 6.01 (dt, J = 18.8, 6.2 Hz, 1H), 5.64 (dt, J = 18.8, 1.4 Hz, 1H), 3.63 (t, J = 6.7
Hz, 2H), 2.48 (q, J = 6.7 Hz, 2H), 1.98 (q, J = 6.7 Hz, 2H), 0.92 (t, J = 8.0 Hz, 9H), 0.58
(q, J = 8.0 Hz, 6H). 13C NMR (100 MHz, CDCI3) 5 146.2, 127.9, 44.4, 34.2, 31.7, 7.5,
3.7. Spectra matched that found in the literature.
P-(E)-5-Chloro-l-(triphenylsiIyl)-l-pentene (Table 4.1, 109) Following the general
procedure
for
the
hydrosilylation
using
MACOS,
5-chloro-l-pentyne
and
triphenylsilane were reacted, providing 0.75 mL of crude product that was purified by
flash chromatography (12% dichloromethane in hexane) to provide 189.7 mg of 109
(70% yield including P-(Z) and d minor isomers) as a colorless oil. ! H NMR (400 MHz,
CDCI3) 5 7.72-7.60 (m, 6H), 7.58-7.46 (m, 9H), 6.42 (dt, J = 18.5, 1.3 Hz, 1H), 6.28 (dt,
J = 18.5, 6.5 Hz, 1H), 3.66 (t, J = 6.7 Hz, 2H), 2.47 (q, J = 6.7 Hz, 2H), 2.05 (q, J = 6.7
Hz, 2H). 13C NMR (100 MHz, CDC13) 5 151.1, 136.1, 134.8, 129.7, 128.0, 125.4, 44.6,
34.1, 31.5. Spectra matched that found in the literature.
P-(E)-l-(Triethylsilyl)-2-phenylethene
(Table 4.1, 110) Following the
general
procedure for the hydrosilylation using MACOS, phenylacetylene and triethylsilane
were reacted, providing 0.62 mL of crude product that was purified by flash
175
chromatography (10% dichloromethane in pentane) to provide 106.0 mg of 110 (78%
yield including P-(Z) and & minor isomers) as a pale yellow oil. *H NMR (400 MHz,
CDC13) 5 7.47-7.42 (m, 2H), 7.37-7.30 (m, 2H), 7.27-7.21 (m, 1H), 6.88 (d, J = 19.5 Hz,
1H), 6.41 (d, J = 19.5 Hz, 1H), 0.98 (t, J = 8.0 Hz, 9H), 0.68 (q, J = 8.0 Hz, 6H). 13C
NMR (100 MHz, CDCI3) 5 144.8, 138.5, 128.8, 127.9, 126.5, 125.9, 7.7, 3.8. Spectra
matched that found in the literature.1 4
^
Pfi
^
.SiPh3
^ ^
p-(E)-l-(TriphenyIsilyl)-2-phenylethene
(Table 4.1, 111) Following the general
procedure for the hydrosilylation using MACOS, phenylacetylene and triphenylsilane
were reacted, providing 0.62 mL of crude product that was purified by flash
chromatography (10% dichloromethane in pentane) to provide 179 mg of 111 (80 %
yield including P-(Z) and d minor isomers) as white crystals. Mp = 138-141 °C (reported
141-143 °C). 'H NMR (400 MHz, CDC13) 5 7.68-7.61 (m, 6H), 7.56-7.28 (m, 14H), 7.1
(d, J = 2.0 Hz, 2H). 13C NMR (100 MHz, CDC13) 5 149.1, 138.1, 136.1, 134.6, 129.8,
128.8, 128.6,128.1, 127.3 122.9. Spectra matched that found in the literature.162'164a
MeCL/^.SiEt3
P-(E)-3-Methoxy-l-(triethyIsilyl)-l-propene (Table 4.1, 112) Following the general
procedure for the hydrosilylation using MACOS, methylpropargyl ether and
triethylsilane were reacted, providing 0.8 mL of crude product that was purified by flash
chromatography (15% dichloromethane in pentane) to provide 112.6 mg of 112 (76%
176
yield including p-(Z) isomer) as a yellow oil. 'H NMR (400 MHz, CDC13) 5 6.09 (dt, J =
18.9, 4.9 Hz, 1H), 5.84 (dt, J= 18.9, 1.5 Hz, 1H), 3.97 (dd, J= 4.9, 1.5 Hz, 2H), 3.34 (s,
3H), 0.93 (t, J = 8.0 Hz, 9H), 0.57 (q, J = 8.0 Hz, 6H). 13C NMR (100 MHz, CDC13) 5
143.4, 128.6, 75.8, 57.9, 7.5, 3.6. Spectra matched that found in the literature.162
P-(E)-3-Methoxy-l-(triphenyIsilyl)-l-propene (Table 4.1, 113) Following the general
procedure for the hydrosilylation using MACOS, methylpropargyl ether and
triphenylsilane were reacted, providing 0.74 mL of crude product that was purified by
flash chromatography (14% ethyl acetate in hexane) to pro vide 195 mg of 113 (80% yield
including P-(Z) and d minor isomers) as white crystals. Mp = 97-99 °C. *H NMR (400
MHz, CDCI3) 6 7.65-7.54 (m, 6H), 7.46-7.32 (m, 9H), 6.58 (dt, J = 18.6, 1.4 Hz, 1H),
6.28 (dt, J = 18.6, 4.6 Hz, 1H), 4.1 (dd, J = 4.6, 1.4 Hz, 2H), 3.45 (s, 3H). 13C NMR (100
MHz, CDCI3) 5 148.1, 136.2, 134.7, 129.7, 128.1, 125.3, 75.2, 58.5. Spectra matched that
found in the literature.162,165
H C L ^ ^ . S i E t s
P-(E)-l-(Triethylsilyl)-l-propen-3-ol (Table 4.1, 114) Following the general procedure
for the hydrosilylation using MACOS, propargyl alcohol and triethylsilane were
reacted, providing 0.9 mL of crude product that was purified by flash chromatography
(15% ethyl acetate in hexane) to provide 115.8 mg of 114 (75% yield including P-(Z) and
d minor isomers) as a colorless oil. *H NMR (400 MHz, CDC13) 5 6.16 (dt, J = 19.0, 4.1
Hz, 1H), 5.84 (dt, J = 19.0, 1.6 Hz, 1H), 4.14 (dd, J = 4.1, 1.6 Hz, 2H), 2.62 (br, 1H),
177
0.92 (t, J = 8.0 Hz, 9H), 0.56 (q, J = 8.0 Hz, 6H). U C NMR (100 MHz, CDC13) 5 146.1,
125.7, 65.4, 7.4, 3.5. Spectra matched that found in the literature.163
HO.
^ ^ ^
.SiPh 3
P-(E)-l-(TriphenyIsilyl)-l-propen-3-ol
(Table 4.1, 115) Following the general
procedure for the hydrosilylation using MACOS, propargyl alcohol and triphenylsilane
were reacted providing 0.75 mL of crude product that was purified by flash
chromatography (15% ethyl acetate in hexane) to provide 175 mg of 115 (74% yield
including |3-(Z) and d minor isomers) as white crystals. Mp = 127-129 °C. *H NMR (400
MHz, CDCI3) 5 7.60-7.52 (m, 6H), 7.50-7.38 (m, 9H), 6.26 (dt, J = 18.8, 1.7 Hz, 1H),
5.89 (dt, J = 18.8, 3.9 Hz, 1H), 4.48 (dd, J = 3.9, 1.7 Hz, 2H), 1.68 (br, 1H). 13C NMR
(100 MHz, CDCI3) 5 150.8, 136.1, 134.5, 129.8, 128.1, 122.7, 65.2. Spectra matched that
found in the literature.162'165
P-(E)-6-(triethylsilyl)hex-5-enenitrile (Table 4.1, 116) Following the general procedure
for the hydrosilylation using MACOS, 5-hexynylnitrile and triethylsilane were reacted,
providing 0.7 mL of crude product that was purified by flash chromatography (10% ethyl
acetate in hexane) to provide 108.5 mg of 116 (74% yield including |3-(Z) and d minor
isomers) as a pale yellow oil. ! H NMR (400 MHz, CDCI3) 8 5.94 {åt, J = 18.7, 6.2 Hz,
1H), 5.64 (dt, J= 18.7, 1.5 Hz, 1H), 2.35 (t, J= 7.2 Hz, 2H), 2.32-2.25 (m, 2H), 1.77 (t, J
= 7.2 Hz, 2H), 0.92 (t, J= 8.0 Hz, 9H), 0.56 (q, J= 8.0 Hz, 6H). 13C NMR (100 MHz,
178
CDC13) 5 146.1, 128.8, 119.6, 35.7, 24.6, 16.6, 7.4, 3.5. Spectra matched that found in the
literature.162
p-(E)-6-(triphenylsilyl)hex-5-enenitrile
(Table 4.1, 117) Following the general
procedure for the hydrosilylation using MACOS, 5-hexynylnitrile and triphenylsilane
were reacted, providing 0.72 mL of crude product that was purified by flash
chromatography (20% ethyl acetate in hexane) to pro vide 198 mg of 117 (78% yield
including |3-(Z) and d minor isomers) as a colorless oil. *H NMR (400 MHz, CDC13) 5
7.68-7.53 (m, 6H), 7.51-7.38 (m, 9H), 6.38 (dt, J= 18.5, 1.5 Hz, 1H), 6.18 (dt, J= 18.5,
6.0 Hz, 1H), 2.47-2.41 (m, 2H), 2.37 (t, J = 7.3 Hz, 2H), 1.87 (t, J = 7.3 Hz, 2H). 13C
NMR (100 MHz, CDC13) 5 150.0, 136.0, 134.6, 129.8, 127.9, 126.5, 119.6, 35.5, 24.3,
16.6. Spectra matched that found in the literature.
P-(E)-l-(Triethylsilyl)-l-buten-3-ol (Table 4.1, 118) Following the general procedure
for the hydrosilylation using MACOS, 3-butyne-2-ol and triethylsilane were reacted,
providing 0.9 mL of crude product that was purified by flash chromatography (15% ethyl
acetate in pentane) to pro vide 90 mg of 118 (54% yield including |3-(Z) and d minor
isomers) as a colorless oil. ! H NMR (400 MHz, CDCI3) 5 6.12 (dd, J = 19.0, 5.2 Hz, 1H),
5.74 (dd, J = 19.0, 1.5 Hz, 1H), 4.29-4.24 (m, 1H), 2.08 (br, 1H), 1.24 (d, J = 6.6 Hz,
179
3H), 0.90 (t, J = 8.0 Hz, 9H), 0.55 (q, J = 8.0 Hz, 6H). U C NMR (100 MHz, CDC13) 5
151.3, 124.2, 70.7, 23.2, 7.4, 3.5. Spectra matched that found in the literature.162
OH
P-(E)-l-(TriphenylsiIyl)-l-buten-3-ol (Table 4.1, 119) Following the general procedure
for the hydrosilylation using MACOS, 3-butyne-2-ol and triphenylsilane were reacted,
providing 0.8 mL of crude product that was purified by flash chromatography (20% ethyl
acetate in hexane) to provide 153.4 mg of 119 (58 % yield including P-(Z) and d minor
isomers) as white crystals. Mp = 122-124 °C. *H NMR (400 MHz, CDC13) 8 7.66-7.54
(m, 6H), 7.52-7.38 (m, 9H), 6.52 (dd, J = 18.7, 1.4 Hz, 1H), 6.28 (dd, J = 18.7, 4.5 Hz,
1H), 4.45-4.40 (m,lH), 1.72 (d, J = 2.6, 1H), 1.32 (d, J= 6.1 Hz, 3H). 13C NMR (100
MHz, CDC13) 8 155.5, 136.1, 134.5, 129.7, 128.1, 121.7, 70.6, 23.2. Spectra matched that
found in the literature.166
P-(E)-3-Benzyloxy-l-(triethylsilyI)-l-propene (Table 4.1, 120) Following the general
procedure for the hydrosilylation using MACOS, benzylpropargyl ether and
triethylsilane were reacted, providing 0.66 mL of crude product that was purified by
flash chromatography (20% dichloromethane in pentane) to provide 138.2 mg of 120
(80% yield including (3-(Z) and d minor isomers) as a colorless oil. 'H NMR (400 MHz,
CDCI3) 8 7.44-7.36 (m, 4H), 7.32-7.27 (m, 1H), 6.20 (dt, J = 19.0, 4.9 Hz, 1H), 5.88 (dt,
J = 19.0, 1.5 Hz, 1H), 4.57 (s, 2H), 4.10 (dd, J = 4.9, 1.5 Hz, 2H), 0.99 (t, J = 8.0 Hz,
180
9H), 0.62 (q, J = 8.0 Hz, 6H). liC NMR (100 MHz, CDC13) 5 143.6, 138.4, 128.6, 128.4,
127.8, 127.6, 73.5, 72.3, 7.4, 3.6. Spectra matched that found in the literature.167
P-(E)-3-Benzyloxy-l-(triphenylsilyl)-l-propene (Table 4.1, 121) Following the general
procedure for the hydrosilylation using MACOS, benzylpropargyl ether and
triphenylsilane were reacted providing 0.65 mL of crude product that was purified by
flash chromatography (15% ethyl acetate in hexane) to pro vide 190 mg of 121 (72% yield
including P-(Z) and d minor isomers) as a colorless oil. ! H NMR (400 MHz, CDC13) 8
7.72-7.60 (m, 6H), 7.55-7.34 (m, 14H), 6.67 (dt, J= 18.7, 1.4 Hz, 1H), 6.37 (dt, J= 18.7,
4.5 Hz, 1H), 4.7 (s, 2H), 4.26 (dd, J = 4.6, 1.4 Hz, 2H). 13C NMR (100 MHz, CDC13) 5
148.3, 138.3, 136.2, 134.5, 129.6, 128.5, 128.1, 128.0, 127.8, 125.3, 72.8, 72.5. Spectra
1 fO
matched that found in the literature.
p-(E)-5-Chloro-l-(hydroxydiphenylsiIyl)-l-pentene (Table 4.1, 122) Following the
general procedure for the hydrosilylation using MACOS, 5-chloro-pentyne-l and
chlorodiphenylsilane were reacted providing 0.64 mL of crude product that was purified
by flash chromatography (15% ethylacetate in pentane) to pro vide 87.0 mg of 122 (45%
yield, no other isomers formed) as a colorless oil. *H NMR (400 MHz, CDC13) 6 7.687.61 (m, 4H), 7.47-7.38 (m, 6H), 6.31 (dt, J = 19.2, 6.0 Hz, 1H), 6.09 (dt, J = 19.2, 1.1
Hz, 1H), 3.57 (t, J = 6.0 Hz, 2H), 2.40 (q, J = 7.0 Hz, 2H), 2.28 (br s, 1H), 1.95 (q, J =
181
7.0 Hz, 2H). liC NMR (100 MHz, CDC13) 8 150.9, 135.6, 134.5, 130.1, 127.9, 125.9,
44.4, 33.7, 31.1. HRMS calcd. for (Ci7Hi9OClSi + H): 303.0972; found: 303.0612.
P-(E)-5-Cyano-l-(hydroxydiphenylsilyl)-l-pentene (Table 4.1, 123) Following the
general procedure for the hydrosilylation using MACOS, 5-hexynylnitrile and
chlorodiphenylsilane were reacted providing 0.7 mL of crude product that was purified
by flash chromatography (20% ethylacetate in pentane) to pro vide 135 mg of 123 (66%
yield including the d minor isomer) as a colorless oil. 'H NMR (400 MHz, CDC13) 5
7.68-7.58 (m, 4H), 7.51-7.38 (m, 6H), 6.25 (dt, J = 18.2, 6.0 Hz, 1H), 6.11 (dt, J = 18.2,
1.1 Hz, 1H), 2.53 (br s, 1H), 2.44-2.32 (m, 4H), 1.82 (q, J = 7.0 Hz, 2H). 13C NMR (100
MHz, CDCI3) 8 149.7, 135.5, 134.5, 130.1, 127.9, 127.2, 119.5, 35.2, 23.9, 16.5. HRMS
calcd. for Ci8Hi9NOSi: 293.1236; found: 293.1237.
MeCX/^.SiPh2OH
p-(E)-3-Methoxy-l-(hydroxydiphenylsilyl)-l-propene (Table 4.1, 124) Following the
general procedure for the hydrosilylation using MACOS, methylpropargyl ether and
chlorodiphenylsilane were reacted providing 0.72 mL of crude product that was purified
by flash chromatography (20% ethyl acetate in hexane) to provide 116.5 mg of 124 (60%
yield, no other isomers formed) as a colorless oil. 'H NMR (400 MHz, CDCI3) 5 7.687.60 (m, 4H), 7.46-7.38 (m, 6H), 6.41-6.31 (m, 2H), 4.06 (dd, J = 3.0, 1.1 Hz, 2H), 3.39
(s, 3H), 2.49 (br s, 1H). 13C NMR (100 MHz, CDC13) 8 147.9, 135.4, 134.6, 130.3, 127.9,
182
125.7, 74.7, 58.3. Anal. Calcd. for Ci 6 Hi 8 0 2 Si: C 71.07, H 6.71; found, C 71.10, H 6.55.
HRMS calcd. for (Ci6H1802Si +NH 4 ): 288.1420; found: 288.1425.
P-(E)-((3-benzyloxy)prop-l-enyl)hydroxydiphenyIsilane (Table 4.1, 125) Following
the general procedure for the hydrosilylation using MACOS, benzylpropargyl ether and
chlorodiphenylsilane were reacted providing 0.78 mL of crude product that was purified
by flash chromatography (20% ethyl acetate in hexane) to provide 162 mg of 125 (60%
yield, no other isomers formed) as a colorless oil. ! H NMR (400 MHz, CDC13) 5 7.687.60 (m, 4H), 7.50-7.44 (m, 2H), 7.42-7.35 (m, 7H), 7.33-7.26 (m, 2H), 6.45-6.34 (m,
2H), 4.58 (s, 2H), 4.15 (dd, J = 3.8, 1.1 Hz, 2H), 3.01 (br s, 1H). 13C NMR (100 MHz,
CDCI3) 5 145.0, 138.1, 135.4, 134.6, 130.5, 128.4, 127.9, 127.8, 127.6, 125.8, 72.5, 72.3.
HRMS calcd. for (C22H2202Si + NH4): 364.1733; found: 364.1747.
P-(E)-Hydroxydiphenyl-[2-(thiophen-3-yl)]-vinylsilane (Table 4.1, 126-P) Following
the general procedure for the hydrosilylation using MACOS, 3-ethynylthiophene and
chlorodiphenylsilane were reacted providing 0.8 mL of crude product that was purified
by flash chromatography (30%) dichloromethane in pentane) to provide 118 mg of 126-P
(48% yield, minor 126-a isomer reported below) as a pale yellow oil. *H NMR (400
MHz, CDCI3) 5 7.78-7.69 (m, 4H), 7.48-7.40 (m, 6H), 7.37-7.33 (m, 1H), 7.31-7.24 (m,
2H), 7.12 (d, J = 19.2 Hz, 1H), 6.55 (d, J = 19.2 Hz, 1H), 2.51 (s, 1H). 13C NMR (100
183
MHz, CDCI3) 6 142.3, 141.5, 135.4, 134.7, 130.1, 127.9, 126.1, 124.9, 124.3, 122.8.
Anal. Calcd. for C18Hi6OSSi: C 70.09, H 5.23; found, C 69.89, H 5.21. HRMS calcd. for
Ci8Hi6OSSi: 308.0689; found: 308.0674.
SiPhoOH
1
*•
(a)-Hydroxydiphenyl-[l-(thiophen-3-yl)]-vinyIsilane (Table 4.1, 126-a) From the
above crude reaction mixture, 34.4 mg of the minor isomer 126-a was isolated (14%
yield) as a pale yellow oil. 2H NMR (400 MHz, CD2C12) 8 7.71-7.62 (m, 4H), 7.50-7.38
(m, 6H), 7.31-7.26 (m, 1H), 7.24-7.16 (m, 2H), 6.36 (d, J = 2.1 Hz, 1H), 5.69 (d, J = 2.1
Hz, 1H), 2.71 (br s, 1H). 13C NMR (150 MHz, CD2C12) 8 142.9, 141.2, 134.9, 134.7,
130.3, 130.1, 127.8, 126.2, 125.3, 121.9. Anal. Calcd. for C18H16OSSi: C 70.09, H 5.23;
found C 69.97, H 5.11. HRMS calcd. for C18Hi6OSSi: 308.0689; found: 308.0561.
/^v.
TMS
.SiPh 2 OH
^ ^
p-(E)-l-(Hydroxydiphenylsilyl)-2-(trimethylsilyl)-ethene (Table 4.1, 127-P) Following
the general procedure for the hydrosilylation using MACOS, ethynyltrimethylsilane and
chlorodiphenylsilane were reacted providing 0.9 mL of crude product that was purified
by flash chromatography (20% ethylacetate in pentane) to provide 108 mg of 127-P (40%
yield, minor 127-a isomer reported below) as a colorless oil. *H NMR (400 MHz,
CDCI3) 8 7.69-7.60 (m, 4H), 7.51-7.40 (m, 6H), 7.05-6.89 (m, 2H), 2.44 (br s, 1H), 0.16
184
(s, 9H). U C NMR (100 MHz, CDC13) 5 157.3, 143.9, 135.5, 134.6, 130.0, 127.8, -1.7.
Anal. Calcd. for C17H220Si2: C 68.40, H 7.43; found, C 68.63, H 7.37. HRMS calcd. for
Ci7H220Si2: 298.1209; found: 298.1205.
SiPh 2 OH
T M S ^
(a)-l-(Hydroxydiphenylsilyl)-l-(trimethylsilyl)-ethene (Table 4.1, 127-cc) From the
above crude reaction mixture, 26.6 mg of 127-a were also obtained (10% yield) as a
colorless oil. *H NMR (400 MHz, CDCI3) 8 7.67-7.58 (m, 4H), 7.46-7.35 (m, 6H), 6.63
(d, J = 5.0 Hz, 1H), 6.41 (d, J = 5.0 Hz, 1H), 2.30 (br s, 1H), 0.08 (s, 9H). 13C NMR (100
MHz, CDCI3) 5 150.7, 145.3, 135.9, 134.5, 129.8, 127.8, -0.48. Anal. Calcd. for
Ci7H220Si2: C 68.40, H 7.43; found, C 68.20, H 7.47. HRMS calculated for C17H22OS12:
298.1209; found: 298.1222.
5.6 Benzannulation reactions in continuous flow format
5.6.1 General procedure for the benzannulation reactions by M A C O S
A stock solution containing the acetylenic aldehyde 131 (0.5 mmol, 1.0 equiv.) and
alkyne 132 (1.5 mmol, 3.0 equiv.) in 0.7-0.8 mL of 1,2-dichloro benzene (total mixture
volume is 1.0 mL) was prepared and loaded into a Hamilton gastight syringe. The tubing
was primed with 1,2-dichloro benzene and the syringe was connected to the reactor
system with the aid of Microtight fittings after which it was placed in a Harvard 22
syringe pump that was set to deliver 20 uL/min. The single mode microwave was
programmed to heat constantly; the power level was fiuctuated manually so as to keep the
185
temperature constant at the specified levels in Table 4.2. The effluent from the reactor
was fed into a sealed vial and analyzed directly by ! H NMR spectroscopy immediately
after the reaction. Typically, 0.7-0.8 mL of the crude reaction mixture was collected and
the product was purified by silica gel column chromatography.
Phenyl-(2-phenylnaphthalen-l-yl)-methanone (Table 4.3,133A) Following the general
MACOS
benzannulation
protocol,
2-(2-phenylethynyl)-benzaldehyde
and
phenylacetylene were reacted providing 0.7 mL of crude product that was purified by
flash chromatography (15% ethyl acetate in hexane) to provide 62.6 mg of 133A (58%
yield, minor isomer reported below) as a yellow oil. ! H NMR (400 MHz, CDCI3): 5 8.2
(d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.68-7.61 (m,
2H), 7.58 (d, J = 8.3 Hz, 1H), 7.52-7.35 (m, 5H), 7.30-7.14 (m, 5H). 13C NMR (100
MHz, CDCI3): 5 199.8, 140.4, 137.9, 137.6, 137.2, 133.4, 132.5, 130.5, 129.5, 129.4,
129.3, 128.3, 128.1, 128.0, 127.6, 127.2, 127.0, 126.4, 125.5. Spectra matched that found
in the literature.168
186
Phenyl-(3-phenylnaphthalen-l-yI)-methanone (Table 4.3, 133B) From the above crude
reaction mixture, 21.4 mg of 133B were also obtained (20 % yield) as a yellow oil. 'H
NMR (400 MHz, CDC13) 6 8.15 (d, .7=1.1 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.90 (d, J
= 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 1.1 Hz, 1H), 7.58 (d, J = 8.0 Hz,
2H), 7.50 (t, J = 7.4, 1H), 7.49-7.37 (m, 6H), 7.30 (t, J = 7.5, 1H).
13
C NMR (100 MHz,
CDCI3): 5 197.7, 139.9, 138.2, 137.2, 137.0, 134.2, 133.4, 130.5, 130.1, 129.0, 128.8,
128.6, 128.3, 127.8, 127.2, 127.0, 126.9, 126.7, 125.7. Spectra matched that found in the
literature.125c
Phenyl-(3-trimethylsiIanyl-naphthalen-l-yl)-methanone (Table 4.3, 134B) Following
the general MACOS benzannulation protocol, 2-(2-phenylethynyl)-benzaldehyde and
TMS-acetylene were reacted providing 0.74 mL of crude product that was purified by
flash chromatography (15% ethyl acetate in hexane) to provide 69.6 mg of 134B (62 %
yield) as a white solid. Mp=86-87°C (reported 88°C). ! H NMR (400 MHz, CDC13): 8
8.17 (d, J = 1.1 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.95-7.84 (m, 3H), 7.68 (d, J = 1.1Hz,
187
1H), 7.60-7.45 (m, 5H), 0.35 (s, 9H). liC NMR (100 MHz, CDC13): 5 198.5, 138.3,
136.8, 136.5, 135.5, 133.3, 133.0, 131.6, 131.1, 130.5, 128.5, 128.3, 127.4, 126.4, 125.6,
-1.20. Spectra matched that found in the literature.125b
(2-(MethoxymethyI)naphthalen-l-yl)-phenylmethanone (Table 4.3, 135A) Following
the general MACOS benzannulation protocol, 2-(2-phenyIethynyl)-benzaldehyde and
methylpropargyl ether were reacted providing 0.82 mL of crude product that was
purified by flash chromatography (15% ethyl acetate in pentane) to pro vide 58.8 mg of
135A and 135B isomers (52% combined yield, 58:42, respectively) as a colorless oil.
(135A) *H NMR (400 MHz, CDCI3): 6 7.98 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H),
7.84 (d, J = 8.1Hz, 2H), 7.66-7.54 (m, 3H), 7.52-7.37 (m, 4H), 4.50 (s, 2H), 3.23 (s, 3H).
13
C NMR (100 MHz, CDC13): 8 199.2, 137.8, 135.7, 133.7, 133.3, 132.8, 130.4, 129.6,
129.4, 128.7, 128.2, 126.8, 126.2, 125.5, 125.4, 72.1, 58.3. Anal. calcd. for Ci 9 Hi 6 0 2 : C
82.58, H 5.84; found, C 82.34, H 5.60. HRMS calcd. for Ci 9 H 16 0 2 : 276.1150; found:
276.1154.
188
(3-(MethoxymethyI)naphthalen-l-yI)-phenylmethanone (Table 4.3, 135B) *H NMR
(400 MHz, CDCI3): 5 8.06 (d, J= 8.1Hz, 1H), 7.98 (d, J = 1.1 Hz, 1H), 7.93 (d,J= 8.1
Hz, 1H), 7.89 (d, J= 8.1 Hz, 2H), 7.10 (t, J= 7.1 Hz, 1H), 7.58 (d, J = 1.1 Hz, 1H),
7.56-7.44 (m, 4H), 4.66 (s, 2H), 3.46 (s, 3H). 13C NMR (100 MHz, CDC13): 8 197.9,
138.2, 136.7, 134.4, 133.7, 133.3, 130.5, 130.4, 129.4, 128.5, 128.3, 127.3, 127.1, 126.7,
125.6, 74.2, 58.3. Anal. calcd. for Ci 9 Hi 6 0 2 : C 82.58, H 5.84; found, C 82.39, H 5.62.
HRMS calcd. for Ci 9 H 16 0 2 : 276.1150; found: 276.1153.
2-(Phenylnaphthalen-l-yl)(thiophen-3-yl)-methanone (Table 4.3,136A) Following the
general MACOS benzannulation protocol, 2-(2-(thiophen-3-yl)-ethynyl)-benzaldehyde
and phenylacetylene were reacted providing 0.65 mL of crude product that was purified
by flash chromatography (15% ethyl acetate in hexane) to provide 63.4 mg of 136A
(62% yield) as a pale yellow oil. *H NMR (400 MHz, CDCI3): 8 8.04 (d, J = 8.1 Hz, 1H),
7.96 (d, J= 8.1 Hz, 1H), 7.84 (d, J= 8.1 Hz, 1H), 7.61 (d, J= 8.1 Hz, 1H), 7.59-7.48 (m,
3H), 7.47-7.38 (m, 3H), 7.34-7.21 (m, 3H), 7.15-7.10 (m, 1H). 13C NMR (100 MHz,
CDCI3): 8 198.6, 143.5, 140.3, 137.1, 136.4, 135.3, 132.4, 130.4, 129.6, 129.4, 128.3,
189
128.1, 127.6, 127.5, 127.3, 127.2, 126.4, 126.2, 125.5. Anal. calcd. for C21H14OS: C
80.22, H 4.49; found, C 79.79, H 4.13. HRMS calcd. for C2iH14OS: 314.0765; found:
314.0759.
(3-(4-(Thiophene-3-carbonyl)naphthaIen-2-yl)-benzoic
acid
(Table
4.3,
137B)
Following the general MACOS benzannulation protocol, 2-(2-(thiophen-3-yI)-ethynyl)benzaldehyde and 3-ethynylbenzoic acid were reacted providing 0.7 mL of crude
product that was purified by flash chromatography (10% methanol in dichloromethane)
to provide 75.0 mg of 137B (60% yield) as a yellow oil. *H NMR (400 MHz, CDC13): 5
8.17 (s, 1H), 8.10 (d, J = 8.1 Hz, 1H), 8.00-7.92 (m, 2H), 7.82 (d, J = 8.1 Hz, 1H), 7.67
(d, J = 8.1 Hz, 1H), 7.63-7.48 (m, 4H), 7.43-7.33 (m, 2H), 7.15 (s, 1H). 13C NMR (150
MHz, CDCI3): 5 192.7, 171.3, 143.4, 140.6, 136.7, 135.7, 135.3, 134.6, 132.6, 130.8,
130.3, 129.7,129.4, 129.1, 128.4, 128.1, 127.3, 127.2, 127.0, 126.6, 126.4, 125.5. HRMS
calcd. for C22H1403S: 358.0664; found: 358.0666.
190
Phenyl-(7-phenylquinolin-8-yl)-methanone (Table 4.3, 138A) Following the general
MACOS
benzannulation
protocol,
2-(2-phenyIethynyl)-nicotinaIdehyde
and
phenylacetylene were reacted providing 0.78 mL of crude product that was purified.by
flash chromatography (20% ethyl acetate in pentane) to provide 77.5 mg of 138A and
138B isomers (64% combined yield) as a pale yellow oil. (138A) ! H NMR (400 MHz,
CDC13): 5 8.88 (dd, J = 4.1, 1.5 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 8.1 Hz,
1H), 7.74-7.63 (m, 3H), 7.48-7.38 (m, 4H), 7.33-7.20 (m, 5H). 13C NMR (100 MHz,
CDCI3): 8 198.8, 151.1, 146.6, 140.5, 139.3, 137.9, 137.4, 135.7, 133.0, 129.6, 129.3,
128.7, 128.6, 128.3, 128.2, 127.7, 127.0, 121.4. HRMS calcd. for C22Hi5NO: 309.1154;
found: 309.1145.
Phenyl-(6-phenylquinoIin-8-yl)-methanone (Table 4.3, 138B)
l
H NMR (400 MHz,
CDCI3): 5 8.86 (dd, J = 4.1, 1.5 Hz, 1H), 8.29 (dd, J = 8.1, 1.5 Hz, 1H), 8.16 (d, J = 2.0
Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 8.1, 1.5 Hz, 2H), 7.75 (dd, J = 8.1, 1.5
Hz, 2H), 7.59 (t, J = 7.1 Hz, 1H), 7.57-7.50 (m, 2H), 7.48-7.40 (m, 4H). 13C NMR (100
MHz, CDCI3): 5 197.7, 150.8, 145.6, 139.8, 139.5, 138.7, 137.7, 136.2, 133.3, 130.3,
191
129.1, 128.5, 128.3, 128.1, 127.9, 127.5, 127.1, 122.0. Anal. calcd. for C22Hi5NO: C
85.40, N 4.53, H 4.89; found, C 84.98, N 4.32, H 4.62. HRMS calcd. for C22Hi5NO:
309.1154; found: 309.1143.
(6-(3-Fluorophenyl)quinolin-8-yl)(phenyl)methanone (Table 4.3,139B) Following the
general MACOS benzannulation protocol, 2-(2-phenylethynyl)-nicotinaldehyde and 1ethynyl-3-fluorobenzene were reacted providing 0.75 mL of crude product that was
purified by flash chromatography (25% ethyl acetate in pentane) to provide 66.0 mg of
139B (54% yield) as a colorless oil. *H NMR (400 MHz, CDC13): 8 8.87 (dd, J = 4.0,1.5
Hz, 1H), 8.29 (dd, J = 8.1, 1.5 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 2.0 Hz,
1H), 7.90 (dd, J = 8.1, 1.5 Hz, 2H), 7.60 (t, J = 7.1 Hz, 1H), 7.56-7.40 (m, 6H), 7.177.10 (m, 1H). 13C NMR (100 MHz, CDC13): 5 197.6, 163.3 ('j^F
145.7, 141.8, 141.7, 140.1, 137.6, 137.5, 136.2, 133.4, 130.6
128.4, 127.5, 127.3, 123.1, 122.1, 114.9
(2J"C-"F
= 245.0 Hz), 151.1,
(3J»C-"F
= 22.0 Hz), 114.4
= 8.5 Hz), 130.2,
(2J"C-"F
= 23.0 Hz).
Anal. calcd. for C22H14FNO: C 80.72, N 4.28, H 4.31; found, C 80.77, N 4.56, H 4.09.
HRMS calcd. for C22Hi4FNO: 327.1059; found: 327.1046.
192
Phenyl-(6-(trimethylsilyl)quinolin-8-yl)methanone (Table 4.3, 140B) Following the
general MACOS benzannulation protocol, 2-(2-phenylethynyl)-nicotinaldehyde and
TMS acetylene were reacted providing 0.8 mL of crude product that was purified by
flash chromatography (20% ethyl acetate in pentane) to provide 70.5 mg of 140B (58%
yield) as a pale brown oil. lH NMR (400 MHz, CDC13): 5 8.82 (dd, J = 4.1, 1.5 Hz, 1H),
8.21 (dd, J = 8.1, 1.5 Hz, 1H), 8.11 (d, J = 1.6 Hz, 1H), 7.87-7.82 (m, 3H), 7.55 (t, J =
7.6 Hz, 1H), 7.44-7.36 (m, 3H), 0.38 (s, 9H). 13C NMR (100 MHz, CDC13): 6 198.5,
151.0, 146.4, 138.9, 138.3, 137.9, 136.0, 135.5, 133.2, 132.1, 130.2, 128.3, 127.5, 121.7,
-0.87. Anal. calcd. for Ci9Hi9NOSi: C 74.71, N 4.59, H 6.27; found, C 74.93, N 4.62, H
6.07. HRMS calcd. for Ci9Hi9NOSi: 305.1236; found: 305.1232.
(6-(4-Bromophenyl)quinolin-8-yl)-phenylmethanone (Table 4.3, 141B) Following the
general MACOS benzannulation protocol, 2-(2-phenylethynyl)-nicotinaIdehyde and 1bromo-4-ethynylbenzene were reacted providing 0.7 mL of crude product that was
193
purified by flash chromatography (20% ethyl acetate in pentane) to provide 70.5 mg of
141B (52% yield) as a colorless oil. *H NMR (400 MHz, CD2C12): 5 8.83 (dd, J = 4.1,
1.5 Hz, 1H), 8.35 (dd,J = 8.1, 1.5 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.00 (d,J = 2.0 Hz,
1H), 7.85 (dd, J = 8.1, 1.5 Hz, 2H), 7.76-7.66 (m, 4H), 7.56-7.44 (m, 3H), 7.34 (q, J =
9.0 Hz, 1H). 13C NMR (150 MHz, CD2C12): 5 197.3, 150.7, 145.4, 140.0, 138.5, 137.8,
137.5, 136.2, 133.2, 132.1, 129.8, 128.9, 128.4, 128.3, 127.2, 126.9, 122.3, 122.1. HRMS
calcd. for C22Hi4BrNO [M+H]+: 388.0337; found: 388.0337.
3-(8-benzoylquinolin-6-yl)-N,N-diisopropylbenzamide (Table 4.3, 142B) Following
the general MACOS benzannulation protocol, 2-(2-phenylethynyI)-nicotinaldehyde and
3-ethynyI-N,N-diisopropylbenzamide were reacted providing 0.84 mL of crude product
that was purified by flash chromatography (30% ethyl acetate in pentane) to provide 73.0
mg of 142B (40% yield) as a colorless oil. 'H NMR (600 MHz, CD2C12): 5 8.81 (dd, J =
3.8, 1.6 Hz, 1H), 8.35 (dd, J= 8.1, 1.6 Hz, 1H), 8.25 (d, J= 2.1 Hz, 1H), 8.03 (d, J= 2.1
Hz, 1H), 7.84 (dd, J = 8.1, 1.6 Hz, 2H), 7.79 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.61 (t, J =
7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.52-7.44 (m, 3H), 7.35 (d, J = 8.1 Hz, 1H), 3.90
(br s, 1H), 3.54 (br s, 1H), 1.55 (s, 6H), 1.16 (s, 6H). 13C NMR (150 MHz, CD2C12 10°C):
194
5 197.6, 170.2, 150.7, 145.5, 140.2, 140.0, 139.9, 138.1, 137.8, 136.3, 133.3, 129.9,
129.2, 128.5, 128.4, 127.5, 127.4, 127.2, 124.9, 124.6, 122.2, 51.0, 45.7, 20.4. HRMS
calcd. for C29H28N2O2: 436.2151; found: 436.2147.
5.7 Synthesis of propargyl amines in continuous flow format
5.7.1 General procedure for the synthesis of propargyl amines in
MACOS
A stock solution containing the substituted benzaldehyde 143 (1.0 mmol/mL, 1.0 equiv.),
secondary amine 144 (1.2 mmol/mL, 1.2 equiv.) and alkyne 145 (1.5 mmol/mL, 1.5
equiv.) in toluene was prepared. The continuous flow microwave system was primed with
toluene and an aliquot from the homogenous stock solution (1-3 mL) was tåken up in a
Hamilton gastight syringe that was connected to the reactor system with the aid of
Microtight™ fittings. The syringe was placed in a Harvard 22 syringe pump that was set
to deliver 20 uL/min and the single mode microwave was programmed to heat
constantly; the power level was fluctuated manually so as to keep the temperature
constant at the specified levels in Table 4.4. The effluent from the reactor was fed into a
sealed vial under backpressure (75 psi); percent conversion was determined by *H NMR
spectroscopy on an aliquot tåken directly from this vial. Typically 0.8-0.9 mL of the
crude reaction mixture was collected and the product was purified by silica gel column
chromatography. .
195
(l,3-DiphenyI-2-propynyl)piperidine (Jable 4.5, 146) Following the general procedure
for the synthesis of propargylamines, benzaldehyde, piperidine, and phenylacetylene
were reacted, providing 0.95 mL of crude product that was purified by flash
chromatography (14% ethyl acetate in hexane) to pro vide 198.8 mg of 146 (76% yield) as
a colorless oil. ! H NMR (400 MHz, CDC13) 8 7.71-7.66 (m, 2H), 7.59-7.54 (m, 2H),
7.48-7.31 (m, 6H), 4.86 (s, 1H), 2.65-2.55 (m, 4H), 1.69-1.60 (m, 4H), 1.52-1.44 (m,
2H). 13C NMR (100 MHz, CDC13) 8 140.9, 132.1, 128.9, 128.6, 128.3 (two overlapping
signals), 127.8, 123.4, 87.9, 86.1, 62.4, 50.7, 26.2, 24.4. Spectra matched that found in
the literature.133b
[l-(4-Bromophenyl)-3-phenyl-2-propynyI]piperidine (Table 4.5, 147) Following the
general procedure for the synthesis of propargylamines, 4-bromobenzaldehyde,
piperidine and phenylacetylene were reacted providing, 0.90 mL of crude product that
196
was purified by flash chromatography (18% ethyl acetate in hexane) to provide 248 mg
of 147 (78 % yield) as a pale yellow oil. JH NMR (400 MHz, CDC13) 8 7.60-7.52 (m,
4H), 7.54-7.50 (m, 2H), 7.41-7.34 (m, 3H), 4.78 (s, 1H), 2.62-2.54 (m, 4H), 1.66-1.58
(m, 4H), 1.53-1.47 (m, 2H). 13C NMR (100 MHz, CDCI3) 8 137.9, 131.8, 131.1, 130.2,
128.3, 128.1, 123.1, 121.4, 88.2, 85.3, 61.8, 50.7, 26.2, 24.4. Spectra matched that found
in the literature.133b
[l-(3-Bromophenyl)-3-phenyI-2-propynyl]piperidine (Table 4.5, 148) Following the
general procedure for the synthesis of propargylamines 3-bromobenzaldehyde,
piperidine and phenylacetylene were reacted, providing 0.79 mL of crude product that
was purified by flash chromatography (14% ethyl acetate in hexane) to provide 235 mg
of 148 (84 % yield) as a pale yellow oil. *H NMR (400 MHz, CDCI3) 8 7.88 (s, 1H),
7.65-7.62 (m, 1H), 7.60-7.56 (m, 2H), 7.47-7.43 (m, 1H), 7.40-7.35 (m, 3H), 7.28-7.24
(m, 1H), 4.81 (s, 1H), 2.64-2.54 (m, 4H), 1.69-1.57 (m, 4H), 1.55-1.48 (m, 2H). 13C
NMR (100 MHz, CDCI3) 8 141.3, 131.9, 131.4, 130.9, 129.9, 128.4, 128.2, 127.1, 123.1,
122.4, 88.4, 85.1, 61.9, 50.7, 26.2, 24.7. Spectra matched that found in the literature.133b
197
[l-(4-TrifluoromethylphenyI)-3-phenyI-2-propynyl]piperidine
(Table
Following
propargylamines
the
general
procedure
(trifluoromethyl)benzaldehyde,
for
the
piperidine
synthesis
and
of
phenylacetylene
4.5,
were
149)
4-
reacted,
providing 0.80 mL of crude product that was purified by flash chromatography (16%
ethyl acetate in hexane) to provide 203 mg of 149 (74% yield) as a colorless oil. 2H NMR
(400 MHz, CDC13) 8 7.81 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1, 2H), 7.58-7.54 (m, 2H),
7.39-7.34 (m, 3H), 4.86 (s, 1H), 2.62-2.55 (m, 4H), 1.70-1.57 (m, 4H), 1.53-1.45 (m,
2H). 13C NMR (100 MHz, CDC13) 5 143.0, 131.8, 129.7 (q, 2J»C-"F= 32.2 Hz), 128.7,
128.4, 128.3, 125.1, 124.3 (q,
^"C-^F
= 271.9 Hz), 123.0, 88.6, 84.9, 62.0, 50.8, 26.2,
24.4. Spectra matched that found in the literature.133b
[l-(4-Methoxyphenyl)-3-phenyl-2-propynyl]piperidine (Table 4.5, 150) Following the
general procedure for the synthesis of propargylamines 4-methoxybenzaldehyde,
198
piperidine and phenylacetylene were reacted, providing 0.92 niL of crude product that
was purified by flash chromatography (20% ethyl acetate in hexane) to provide 213 mg
of 150 (76 % yield) as a yellow oil. ! H NMR (400 MHz, CDC13) 5 7.61-7.51 (m, 4H),
7.38-7.31 (m, 3H), 6.96-6.91 (m, 2H), 4.78 (s, 1H), 3.85 (s, 3H), 2.63-2.53 (m, 4H), 1.691.55 (m, 4H), 1.54-1.46 (m, 2H). 13C NMR (100 MHz, CDCI3) 5 158.9, 131.8, 130.7,
129.6, 128.3, 128.0, 123.4, 113.4, 87.6, 86.5, 61.8, 55.3, 50.6, 26.2, 24.5. Spectra
matched that found in the literature.133b
l-(l-Isobutyl-3-phenyl-prop-2-ynyl)-piperidine (Table 4.5, 151) Following the general
procedure for the synthesis of propargylamines, isovaleraldehyde, piperidine and
phenylacetylene were reacted, providing 0.72 mL of crude product that was purified by
flash chromatography (14% ethyl acetate in hexane) to provide 150 mg of 151 (82%
yield) as a colorless oil. lU NMR (400 MHz, CDC13) 8 7.50-7.44 (m, 2H), 7.35-7.28 (m,
3H), 3.63-3.57 (m, 1H), 2.76-2.68 (m, 2H), 2.56-2.47 (m, 2H), 1.92 (septet, J = 7.1 Hz,
1H), 1.75-1.54 (m, 6H), 1.52-1.44 (m, 2H), 1.06-0.96 (m, 6H). 13C NMR (100 MHz,
CDCI3) 5 131.7, 128.2, 127.7, 123.6, 88.1, 85.6, 56.7, 50.6, 42.3, 26.2, 25.4, 24.6, 23.2,
22.1. Spectra matched that found in the literature.169
199
N-benzyl-N-ethyl-5-methyl-l-phenylhex-l-yn-3-amine (Table 4.5, 152) Following the
general procedure for the synthesis of propargylamine, isovaleraldehyde, Nethylbenzylamine and phenylacetylene were reacted providing 0.75 mL of crude
product that was purified by flash chromatography (6% ethyl acetate in pentane) to
provide 172 mg of 152 (75% yield) as a colorless oil. *H NMR (400 MHz, CDC13) 8
7.56-7.50 (m, 2H), 7.48-7.44 (m, 2H), 7.42-7.34 (m, 5H), 7.32-7.28 (m, 1H), 3.97 (d, J =
14.2 Hz, 1H), 3.82 (t, J = 8.2 Hz, 1H), 3.53 (d, J = 14.2 Hz, 1H), 2.78-2.68 (m, 1H),
2.63-2.54 (m, 1H), 1.98 (septet, J = 7.1 Hz, 1H), 1.78-1.69 (m, 1H), 1.67-1.59 (m, 1H),
1.17 (t, J= 12 Hz, 3H), 0.98-0.90 (m, 6H). 13C NMR (100 MHz, CDC13) 5 140.5, 131.8,
128.8, 128.3, 128.1, 127.8, 126.7, 123.7, 88.9, 84.7, 55.1, 50.9, 45.0, 43.1, 24.8, 22.8,
22.3, 13.7. Anal. calcd. for C22H27N: C 86.51, H 8.91, N 4.59; found, C 86.61, H 9.13, N
4.72.
200
4-(5-methyl-l-phenylhex-l-yn-3-yl)-morphoIine (Table 4.5,153) Following the general
procedure for the synthesis of propargylamines, isovaleraldehyde, morpholine and
phenylacetylene were reacted providing 0.72 mL of crude product that was purified by
flash chromatography (20% ethyl acetate in pentane) to provide 139.0 mg of 153 (75%
yield) as a pale yellow oil. ! H NMR (300 MHz, CDC13) 5 7.49-7.41 (m, 2H), 7.34-7.27
(m, 3H), 3.84-3.70 (m, 4H), 3.64-3.57 (m, 1H), 2.82-2.72 (m, 2H), 2.64-2.54 (m, 2H),
1.93 (septet, J = 6.8 Hz, 1H), 1.72-1.52 (m, 2H), 1.03-0.94 (m, 6H). 13C NMR (100
MHz, CDC13) 6 131.7, 128.2, 127.9, 123.2, 87.1, 86.2, 67.2, 56.2, 49.7, 41.8, 25.2, 23.0,
22.2. Anal. calcd. for Ci7H23NO: C 79.33, H 9.01, N 5.44; found, C 79.53, H 8.82, N
5.48. HRMS calcd. for C17H23NO: 258.1858; found: 258.1851.
1
Ph
N-benzyl-l-(4-bromophenyl)-N-ethyI-3-phenylprop-2-yn-l-amine
Following
the
general
procedure
for
the
201
synthesis
(Table 4.5, 154)
of propargylamines,
4-
bromoaldehyde, N-ethylbenzylamine and phenylacetylene were reacted providing 0.70
mL of crude product that was purified by flash chromatography (10% ethyl acetate in
pentane) to provide 209 mg of 154 (74% yield) as a pale brown oil. lU NMR (400 MHz,
CD2C12) 5 7.70-7.60 (m, 4H), 7.58-7.52 (m, 2H), 7.49-7.41 (m, 5H), 7.40-7.34 (m, 2H),
7.32-7.27 (m, 1H), 4.99 (s, 1H), 3.88 (d, J = 14.2 Hz, 1H), 3.56 (d, J = 14.2 Hz, 1H),
2.62 (q, J= 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CD2C12) 5 139.9,
139.0, 131.8, 131.1, 130.1, 128.8, 128.4, 128.3, 128.2, 126.9, 123.0, 121.1, 88.3, 84.7,
56.1, 54.9, 44.5, 13.4. HRMS calcd. for C24H22BrN: 403.0936 ; found: 403.0908.
4-(l,3-diphenylprop-2-ynyI)-morpholine
(Table 4.5, 155) Following the general
procedure for the synthesis of propargylamines, benzaldehyde, morpholine and
phenylacetylene were reacted providing 0.75 mL of crude product that was purified by
flash chromatography (15% ethyl acetate in pentane) to provide 170 mg of 155 (82%
yield) as yellow oil. lR NMR (400 MHz, CD2C12) 5 7.72-7.67 (m, 2H), 7.61-7.56 (m,
2H), 7.46-7.33 (m, 6H), 4.86 (s, 1H), 3.79-3.69 (m, 4H), 2.70-2.64 (m, 4H). 13C NMR
(100 MHz, CD2C12) 5 138.0, 131.7, 128.6, 128.4, 128.3, 128.2, 127.7, 123.0, 88.3, 85.2,
67.0, 61.9, 49.9. Spectra matched that found in the literature.170
202
4-(l-(4-bromophenyl)-3-phenylprop-2-ynyI)-morpholine (Table 4.5, 156) Following
the general procedure for the synthesis of propargylamines, 4-bromoaldehyde,
morpholine and phenylacetylene were reacted providing 0.82 mL of crude product that
was purified by flash chromatography (15% ethyl acetate in pentane) to provide 204 mg
of 156 (70% yield) as a yellow oil. ! H NMR (400 MHz, CDC13) 5 7.61-7.47 (m, 6H),
7.40-7.32 (m, 3H), 4.77 (s, 1H), 3.81-3.69 (m, 4H), 2.68-2.59 (m, 4H). 13C NMR (100
MHz, CDCI3) 8 137.0, 131.8, 131.3, 130.3, 128.5, 128.4, 122.7, 121.8, 88.9, 84.3, 67.1,
61.4, 49.8. Spectra matched that found in the literature.170
l-(l-phenyl-3-(thiophen-3-yl)prop-2-ynyl)piperidine (Table 4.5, 157) Following the
general procedure for the synthesis of propargylamines, benzaldehyde, piperidine and
3-ethynylthiophene were reacted providing 0.82 mL of crude product that was purified
by flash chromatography (20% dichloromethane in pentane) to provide 154 mg of 157
203
(67% yield) as a yellow oil. lH NMR (400 MHz, CDC13) 6 7.69-7.64 (m, 2H), 7.52 (d, J
= 3.1 Hz, 1H), 7.43-7.36 (m, 2H), 7.35-7.29 (m, 2H), 7.23-7.20 (m, 1H), 4.81 (s, 1H),
2.64-2.52 (m, 4H), 1.69-1.56 (m, 4H), 1.53-1.44 (m, 2H). 13C NMR (100 MHz, CDC13) 5
138.6, 130.2, 128.5, 128.4, 128.0, 127.4, 125.2, 122.3, 85.7, 82.7, 62.5, 50.7, 26.2, 24.4.
Anal. calcd. for C18H19NS: C 76.82, H 6.81, N 4.98; found, C 76.90, H 6.82, N 5.04.
HRMS calcd. for d 8 H 1 9 NS: 281.1238; found: 281.1211.
Ph
—S
N-benzyI-N-ethyI-l-(4-methoxyphenyl)-3-(thiophen-3-yl)prop-2-yn-l-amine
(Table
4.5, 158) Following the general procedure for the synthesis of propargylamines, 4methoxybenzaldehyde, N-ethylbenzylamine and 3-ethynylthiophene were reacted
providing 0.62 mL of crude product that was purified by flash chromatography (30%
dichloromethane in pentane) to provide 134.5 mg of 158 (60% yield) as a yellow oil. lH
NMR (400 MHz, CD2C12) 5 7.68-7.62 (m, 2H), 7.60 (d, J = 3.0 Hz, 1H), 7.47-7.41 (m,
2H), 7.40-7.33 (m, 3H), 7.30-7.26 (m, 2H), 6.97-6.91 (m, 2H), 4.98 (s, 1H), 3.87 (d, J =
14.1 Hz, 1H), 3.84 (s, 3H), 3.53 (d,J = 14.1 Hz, 1H), 2.61 (q, J= IA Hz, 2H), 1.14 (t, J
= 7.1 Hz, 3H). 13C NMR (100 MHz, CD2C12) 8 158.9, 140.3, 131.6, 130.1, 129.3, 128.7,
128.5, 128.1, 126.7, 125.4, 122.3, 113.3, 85.2, 82.6, 55.9, 55.2, 54.6, 44.3, 13.3. Anal.
204
calcd. for C23H23NOS: C 76.42, H 6.41, N 3.87; found, C 76.12, H 6.65, N 4.02. HRMS
calcd. for C23H23NOS: 361.1500; found: 361.1508.
.0.
4-(l-(4-bromophenyl)-3-(thiophen-3-yl)prop-2-ynyl)-morpholine
Following
the
general
procedure
for
the
synthesis
(Table 4.5, 159)
of propargylamines,
4-
bromobenzaldehyde, morpholine and 3-ethynylthiophene were reacted providing 0.86
mL of crude product that was purified by flash chromatography (18% ethyl acetate in
pentane) to provide 212 mg of 159 (68% yield) as a yellow oil. 2H NMR (400 MHz,
CD2C12) 5 7.60-7.52 (m, 5H), 7.39-7.35 (m, 1H), 7.24-7.21 (m, 1H), 4.78 (s, 1H), 3.763.66 (m, 4H), 2.64-2.56 (m, 4H). 13C NMR (100 MHz, CD2C12) 5 137.3, 131.2, 130.3,
129.9, 128.9, 125.5, 121.7, 121.5, 84.0, 83.7, 67.0, 61.4, 49.8. Anal. Calcd. for
C17H16BrNOS: C 56.36, H 4.45, N 3.87; found, C 56.22, H 4.46, N 3.66. HRMS calcd.
for Ci7Hi6BrNOS: 361.0136; found: 361.0131.
205
l-(3-(l-methyl-lH-imidazol-5-yl)-l-phenylprop-2-ynyl)-piperidine (Table 4.5, 160)
Following the general procedure for the synthesis of propargylamines, benzaldehyde,
piperidine and 5-ethynyl-l-methyl-lH-imidazole were reacted providing 0.80 mL of
crude product that was purified by flash chromatography (10% methanol in acetonitrile)
to provide 145 mg of 160 (65 % yield) as a colorless oil. *H NMR (400 MHz, CD2C12) 8
7.67-7.62 (m, 2H), 7.47 (s, 1H), 7.44-7.38 (m, 2H), 7.36-7.31 (m, 1H), 7.28 (s, 1H), 4.91
(s, 1H), 3.74 (s, 3H), 2.60-2.54 (m, 4H), 1.69-1.55 (m, 4H), 1.52-1.46 (m, 2H).
13
C NMR
(100 MHz, CD2C12) 5 138.4, 138.2, 133.8, 128.3, 128.1, 127.6, 116.2, 93.0, 75.9, 62.5,
50.7, 32.1, 26.2, 24.4. Anal. calcd. for Ci8H2iN3: C 77.38, H 7.58, N 15.04; found, C
77.45, H 7.72, N 14.89. HRMS calcd. for Ci8H2iN3: 279.1735; found: 279.1731.
206
w
Me
4-(l-(4-bromophenyl)-3-(l-methyl-lH-imidazol-5-yl)prop-2-ynyI)-morpholine (Table
4.5, 161) Following the general procedure for the synthesis of propargylamines, 4bromobenzaldehyde, morpholine and 5-ethynyl-l-methyl-lH-imidazoIe were reacted
providing 0.88 mL of crude product that was purified by flash chromatography (10%
methanol in dichloromethane) to pro vide 212 mg of 161 (67% yield) as a colorless oil. ! H
NMR (400 MHz, CD2C12) 5 7.58-7.51 (m, 4H), 7.48 (s, 1H), 7.30 (s, 1H), 4.86 (s, 1H),
3.76-3.66 (m, 7H), 2.64-2.55 (m, 4H). 13C NMR (100 MHz, CD2C12) 8 138.4, 136.9,
134.3, 131.3, 130.2, 121.7, 115.6, 91.6, 76.8, 66.9, 61.5, 49.8, 32.2. Anal. calcd. for
Ci 7 Hi 8 BrN 3 0: C 56.68, H 5.04, N 11.66; found, C 56.50, H 5.05, N 11.22. HRMS calcd.
for Ci 7 H 18 BrN 3 0: 359.0633; found: 359.0630.
207
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