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MICROWAVE-ASSISTED AND FLUOROUS BENZALDEHYDE-BASED
SYNTHESIS OF HETEROCYCLES
A Thesis Presented
by
SHAN DING
Submitted to the Office of Graduate Studies,
University of Massachusetts Boston,
in partial fulfillment of the requirements for the degree of
MASTER OF SCIENCE
June 2011
Chemistry Program
UMI Number: 1494027
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MICROWAVE-ASSISTED AND FLUOROUS BENZALDEHYDE-BASED
SYNTHESIS OF HETEROCYCLES
A Thesis Presented
by
SHAN DING
Approved as to style and content by:
_____________________________________________
Wei Zhang, Associate Professor
Chairperson of Committee
_____________________________________________
Marianna Torok, Assistant Professor
Member
_____________________________________________
Jonathan Rochford, Assistant Professor
Member
__________________________________________
Jason Evans, Program Director
Chemistry Graduate Program
__________________________________________
Robert L. Carter, Chairperson
Chemistry Department
ABSTRACT
MICROWAVE-ASSISTED AND FLUOROUS BENZALDEHYDE-BASED
SYNTHESIS OF HETEROCYCLES
June 2011
Shan Ding, B.S., Shenyang Pharmaceutical University, China
M.S., University of Massachusetts Boston
Directed by Professor Wei Zhang
Green chemistry integrates the environmental benign and sustainable protocols for
chemical research and production. Recently, many synthetic approaches with green
chemistry aspects have been developed. For example, microwave irradiation applies
energy directly to solvents and reactants, which significantly reduces the reaction time.
Multicomponent reactions (MCRs) incorporate reactants for the rapid construction of
complex molecules. Fluorous solid-phase extraction (F-SPE) is a chromatography-free
purification method that reduces the amount of solvent used.
These new techniques have been applied to construct a series of heterocyclic
molecules: bridged oxazabicycle, which has been found to be an example of a bicyclebased photochromic colorant and the ideal substrate to study the molecular switch;
pyranopyrazole, which is considered to be an important pharmaceutical scaffold; and
iv
1,4-dihydropyridine, which has been reported as a multi-drug resistance (MDR) reversing
agent.
A combination of advanced green techniques is applied to our
perfluorooctanesulfonyl benzaldehyde-based synthesis to assemble a series of
heterocyclic scaffolds. Perfluorooctanesulfonyl (C8F17O2SO-) protected benzaldehyde is
used as a limiting reagent for MCRs to form the condensed product. MCRs are performed
under microwave irradiation to quickly assemble the heterocyclic skeleton, and
microwave-assisted Suzuki-Miyaura cross-coupling reactions remove the fluorous tag
and introduce biaryl functionality to the heterocyclic compounds. The intermediates are
isolated from the reaction mixtures by F-SPE. Our synthetic routes demonstrate the green
chemistry approaches of microwave-assisted fast reactions; high atom economic MCRs;
and chromatography-free F-SPE that could significantly improve the synthetic efficiency.
v
DEDICATION
This work is dedicated to my family, particularly to my mother who
educated me with all of her love
and lead my way to where I am right now
vi
ACKNOWLEDGMENTS
It is a pleasure to thank the people who contributed and extended their valuable
assistance along my journey and made this thesis possible.
First and foremost, I owe my deepest gratitude to my advisor, Dr. Wei Zhang for
his continuous support through my study and research. It has been an honor to be his first
Master student. He has helped lead my way to the fluorous chemistry world, and the
enthusiasm he has for the research has been the motivation for me to hurdle all the
obstacles toward the completion of this research work. I am grateful for his time and
inspiration.
I gratefully thank Dr. M. Torok and Dr. Rochford for being my committee
members and for using their precious time to read this thesis with the constructive
comments.
I appreciatively thank Dr. Carter, Dr. Anastas, Dr. Torok, Dr. Foster and Dr.
Dransfield for their valuable insights on the courses. Their excellent teachings provide
me a fundamental base for my research work.
I gratefully acknowledge Dr. Evans for his advice and support to complete Master
study, thanks to Dr. Schwartz, Dr. Cerny, Dr. Evans for their instructions on my TA work.
My thesis would not have been possible without the greatest help from my lab
buddies at Dr. Wei Zhang’s research group. Many thanks go particularly to Asha, Bruno,
Zijuan and Liang, for giving me such a pleasant time when working together. I would
never forget the days we worked on the LC-MS and microwave. Thanks to Minh-Thu,
Min, Minhgiao, Tao, Weiyi and April, for their tremendous help on my research projects.
vii
It is a pleasure to mention Hong, Stephanie, Trinh, Sargis, Angela, David and Ryan for
creating a pleasant working atmosphere in the lab.
I am grateful to Liliana, James, Ginny, Paul, and Karyn who support and make
our daily research possible and are always ready to help.
My time at UMASS Boston was made enjoyable largely due to the many friends I
have. Thanks to Aditya, Dmitry, Dong and Chris for their inspirational suggestions on the
research work and their specialties on NMR and LC-MS. Special thanks go to Jerry for
guiding me on the scientific writing; the thesis would be unintelligible to read without his
help. Thanks to Yufei, Wei, Fengying, June and Qi for the delightful lunch break
discussions and their humors about scientists’ lives. Thanks to my colleagues Alex, John,
Steven, Katie, Cat, Lan, Quan, Ronny, Josh, Sam and Samson for the greatest time we
worked together on teaching the undergraduate labs.
I owe my deepest gratitude to my family for all their love and encouragement. For
my parents who raised me with their care and love. My mom has always been my
spiritual support through my tough days and my best friend to share my good news.
Thanks to my grandpa for showing me the joy of intellectual pursuit ever since I was a
child. Thanks to my uncle Byron for his inspiration on the planning of my studies and
career. He has set up a great example of becoming a successful scientist. Thanks to my
auntie Song for being supportive through my days in the United States. Thanks to a
special man Chris for supporting me through my desperate days and for me to lend to
whenever I need. I would also thank Zhou’s family for inviting me to spend time at their
home. Finally, I would like to thank all my dear friends who are important to my life and
I apologize for not mentioning them personally one by one.
viii
TABLE OF CONTENTS
DEDICATION ............................................................................................................vi
ACKNOWLEDGMENTS ........................................................................................ vii
LIST OF TABLES ......................................................................................................xi
LIST OF SCHEMES................................................................................................ xiii
LIST OF ABBREVIATIONS ...................................................................................xvi
CHAPTER
Page
1. INTRODUCTION ..................................................................................... 1
2. LITERATURE OVERVIEW..................................................................... 4
2.1. Fluorous technology.................................................................... 4
2.2. Microwave-assisted organic synthesis (MAOS) ....................... 11
2.3. Multicomponent reactions (MCRs) .......................................... 16
2.4. Suzuki-Miyaura cross-coupling reactions................................. 20
3. RESULTS AND DISCUSSION .............................................................. 25
3.1. Introduction ............................................................................... 25
3.2. Synthesis of perfluorooctanesulfonyl benzaldehydes ............... 26
3.2.1. Introduction ............................................................. 26
3.2.2. Results and discussion ............................................ 26
3.3. A green approach toward the synthesis of polycyclic
oxazabicyclo[3,3,1]nonanes ...................................................... 27
3.3.1. Introduction ............................................................. 27
3.3.2. Results and discussion ............................................ 30
3.4. An environmentally benign approach to synthesize
pyranopyrazole derivatives ....................................................... 40
3.4.1. Introduction ............................................................. 40
3.4.2. Results and discussion ............................................ 42
3.5. Synthesis of pyridine derivatives via microwave-assisted
MCRs ........................................................................................ 49
3.5.1. Introduction ............................................................ 49
3.5.2. Results and discussion ............................................ 50
3.6. Perfluorooctanesulfonyl benzaldehyde-assisted synthesis of
dihydropyridine ......................................................................... 55
3.6.1. Introduction ............................................................ 55
3.6.2. Results and discussion ............................................ 58
ix
CHAPTER
Page
4. CONCLUSIONS...................................................................................... 60
5. EXPERIMENTAL PROCEDURES ........................................................ 62
5.1. General experimental procedure for synthesis of
perfluorooctanesulfonyl benzaldehydes (Chapter 3.2) ............. 62
5.2. General experimental procedure for a green approach toward the
synthesis of polycyclic
oxazabicyclo[3,3,1]nonanes (Chapter 3.3) ............................... 62
5.3. General experimental procedure for synthesis of pyranopyrazole
derivatives by an environmentally benign
approach (Chapter 3.4).............................................................. 64
5.4. General experimental procedure for synthesis of pyridine
derivatives via microwave-assisted MCRs (Chapter 3.5) ......... 65
5.5. General experimental procedure for perfluorooctanesulfonyl
benzaldehyde-assisted synthesis of dihydropyridine
(Chapter 3.6) ............................................................................. 66
APPENDIX
A. ANALYTICAL METHODS................................................................... 67
B. SUPPORTING INFORMATION AND PRODUCT
CHARACTERIZATION FOR CHAPTER 3.2 . ................................. 68
C.
SUPPORTING INFORMATION AND PRODUCT
CHARACTERIZATION FOR CHAPTER 3.3. .................................. 71
D. SUPPORTING INFORMATION AND PRODUCT
CHARACTERIZATION FOR CHAPTER 3.4 . ............................... 110
E.
SUPPORTING INFORMATION AND PRODUCT
CHARACTERIZATION FOR CHAPTER 3.5 . ............................... 119
F.
SUPPORTING INFORMATION AND PRODUCT
CHARACTERIZATION FOR CHAPTER 3.6 . ............................... 124
CITATIONS ............................................................................................................ 127
REFERENCES ........................................................................................................ 137
x
LIST OF TABLES
Table
Page
1. Microwave heating profile of different solvents ......................................... 12
2. Synthesis of perfluorooctanesulfonyl benzaldehydes ................................. 27
3. Effect of solvent, time and temperature on the microwave-assisted MCRs
to synthesize tetrahydroquinolines .............................................................. 31
4. Effect of equivalence of starting materials on the microwave-assisted
MCRs to synthesize tetrahydroquinolines .................................................. 31
5. Microwave-assisted MCRs to synthesize tetrahydroquinolines ................. 33
6. Effect of catalyst, solvent, reaction time and temperature on the
microwave-assisted synthesis of fluorous oxazabicyclo[3.3.1]nonanes ..... 34
7. Effect of equivalence of starting materials on microwave-assisted
synthesis of fluorous oxazabicyclo[3.3.1]nonanes ..................................... 34
8. Microwave-assisted synthesis of fluorous oxazabicyclo[3.3.1]nonanes .... 35
9. Effect of reaction time and temperature on microwave-assisted SuzukiMiyaura cross-coupling reaction to synthesize biaryl-substituted
oxazabicyclo[3.3.1]nonanes ........................................................................ 37
10. Microwave-assisted Suzuki-Miyaura cross-coupling reaction to synthesize
biaryl-substituted oxazabicyclo[3.3.1]nonanes ........................................... 38
11. Effect of the catalyst, solvent, reaction time and temperature on
microwave-assisted MCRs to synthesize 43 ............................................... 42
12. Effect of reaction time and temperature on microwave-assisted SuzukiMiyaura cross-coupling reaction to synthesize 45 ...................................... 43
13. Effect of reaction time and temperature for microwave-assisted SuzukiMiyaura cross-coupling reaction of 47 ....................................................... 45
14. Effect of reaction time and temperature on microwave-assisted
cycloaddition reaction of 50 and 52 ............................................................ 47
15. Effect of equivalence of starting materials on microwave-assisted
cycloaddition reaction of 46 and 50 ........................................................... 48
xi
Table
Page
16. Microwave-assisted MCRs to synthesize of 53 .......................................... 51
17. Effect of reaction time and temperature on microwave-assisted SuzukiMiyaura cross- coupling reaction of 53 ...................................................... 52
18. Effect of reaction time and temperature on microwave-assisted SuzukiMiyaura cross- coupling reaction on 57...................................................... 53
19. Microwave-assisted amination reaction of 57 ............................................ 54
20. Effect of reaction time and temperature on microwave-assisted MCRs to
synthesize fluorous dihydropyridine 65 ...................................................... 58
xii
LIST OF SCHEMES
Scheme
Page
1. Perfluorooctylethylsiyl bonded phase in fluorous cartridge ......................... 5
2. Typical procedure of F-SPE.......................................................................... 6
3. Fluorous THP protective group to protect hydroxyl groups ......................... 7
4. Fluorous Boc protective group to protect amine groups ............................... 8
5. Perfluoroalkyl protective group to protect amino ester groups .................... 8
6. Displace fluorous tag to form new a carbon-carbon bond ............................ 9
7. Displace fluorous tag to form new a carbon-nitrogen bond ......................... 9
8. Displace fluorous tag to form new a carbon-sulfur bond ........................... 10
9. Microwave-assisted solvent-free Suzuki-Miyaura cross-coupling
reaction ........................................................................................................ 13
10. Microwave-assisted phase-transfer catalysis reaction ................................ 14
11. Microwave-assisted Heck coupling reaction .............................................. 14
12. Microwave-assisted AAD MCRs ............................................................... 15
13. Microwave-assisted solvent-free and catalyst-free amination reaction ...... 15
14. Microwave-assisted hydrogenation reaction............................................... 15
15. MCRs to synthesize amino acids ................................................................ 16
16. Hantzsch reaction to synthesize dihydropyridines ...................................... 17
17. Biginelli reaction to synthesize dihydropyrimidinones .............................. 17
18. Atwal modification of Biginelli reaction to synthesize dihydropyridines .. 18
19. Mannich reaction to synthesize β-amino-carbonyls ................................... 18
20. Passerini reaction to synthesize α-hydroxyl carboxamides ........................ 18
xiii
Scheme
Page
21. Bucherer-Berges reaction to synthesize hydantoins ................................... 19
22. Gewald reaction to synthesize poly-substituted 2-amino-thiophenes ......... 19
23. Ugi reaction to synthesize amides............................................................... 19
24. Suzuki-Miyaura cross-coupling reaction .................................................... 20
25. Regio-selectivity of conjugated dienes via Suzuki-Miyaura cross-coupling
reaction ........................................................................................................ 20
26. Synthesis of enyne via Suzuki-Miyaura cross-coupling reaction ............... 20
27. Suzuki-Miyaura cross-coupling reaction in water ...................................... 22
28. Suzuki-Miyaura cross-coupling reaction in supercritical carbon
dioxide......................................................................................................... 22
29. Suzuki-Miyaura cross-coupling reaction in solvent-free condition ............ 22
30. Suzuki-Miyaura cross-coupling reaction via microwave irradiation .......... 23
31. Suzuki-Miyaura cross-coupling reaction via ultrasonic irradiation ............ 23
32. Suzuki-Miyaura cross-coupling reaction under continuous-flow
condition ..................................................................................................... 23
33. Palladium nanoparticle-catalyzed Suzuki-Miyaura cross-coupling
reaction ........................................................................................................ 24
34. Suzuki-Miyaura cross-coupling reaction between organoboronic acid the
organotriflates ............................................................................................. 24
35. Perfluorooctanesulfonyl benzaldehyde products ........................................ 27
36. Examples of Tröger’s base, Tröger’s base analogue 5 and the molecular
recognition process 6 ................................................................................. 28
37. Examples of diazabicyclo[3.3.1]nonane 7, oxazabicyclo[3.3.1]nonane 8 and
its photochromism process 9 ....................................................................... 29
38. MCR to synthesize the oxazabicycle .......................................................... 29
xiv
Scheme
Page
39. Building blocks for preparation of biaryl-substituted
oxazabicyclo[3.3.1]nonanes ........................................................................ 30
40. Proposed mechanism for microwave-assisted MCRs to synthesize
tetrahydroquinolines .................................................................................... 32
41. Tetrahydroquinolines .................................................................................. 32
42. Fluorous oxazabicyclo[3.3.1]nonanes ........................................................ 36
43. Biaryl-substituted oxazabicyclo[3.3.1]nonanes .......................................... 39
44. Synthesis of the pyranopyrazole ................................................................. 40
45. MCR to synthesize pyranopyrazole in aqueous medium ............................ 41
46. Base-promoted MCR to synthesize pyranopyrazole................................... 41
47. Microwave-assisted cycloaddition reaction of 43 and 46 ........................... 44
48. Microwave-assisted MCRs to synthesize 50 .............................................. 46
49. Microwave-assisted cycloaddition reaction of 50 and 46 ........................... 47
50. Examples of first, second and third generations of MDR reversal agents .. 49
51. Synthesis of 3,5-dibenzoyl-1,4-diydropyridines ......................................... 50
52. Microwave-assisted oxidation reaction of 53 ............................................. 52
53. Selected examples of pyrazole/quinolizine-containing drugs..................... 55
54. MCRs of benzaldehyde, diketone and pyrazole to form 59 and 60 ............ 56
55. MCRs of benzaldehyde, diketone and pyrazole and strong base
to form pyrazoloquinozinones 61 ............................................................... 56
56. Mechanism for the formation of pyrazoloquinozinones 61 ........................ 57
57. Decomposition of pyrazoloquinolizinone to form dihydropyridine 65 ...... 59
xv
LIST OF ABBREVIATIONS
DMF
Dimethylformamide
F-SPE
Fluorous Solid-Phase Extraction
HFE
Hydrofluoroether
IPA
Isopropanol
LC-MS
Liquid chromatography-mass spectrometer
LLE
Liquid-liquid extraction
MAOS
Microwave-assisted organic synthesis
MCRs
Multicomponent reactions
MDR
Multidrug resistance
MW
Microwave
NADH
Nicotinamide adenine dinucleotide
NMP
Methylpyrrolidone
NMR
Nuclear magnetic resonance
TBAB
Tetrabucylammonium bromide
THF
Tetrahydrofuran
THP
Tetrahydropyranyl
TLC
Thin layer chromatography
xvi
CHAPTER 1
INTRODUCTION
This thesis, written in partial fulfillment for the degree of Master of Science in
Chemistry, describes the work and research carried out under the guidance and
supervision of Dr. Wei Zhang at the University of Massachusetts Boston from September
2008 to February 2011. The main focus of the research was based on the synthesis of a
series of heterocycles that exhibit potential biological activities. Heterocyclic molecules
are popular compounds for the study of biological activities and for the development of
new synthetic chemistries.1 Our interests have focused on the following heterocyclic
systems.
The first example of the heterocycles is biaryl-substituted
oxazabicyclo[3.3.1]nonane. It is a well-studied scaffold in chelating and biomimetic
systems.2 It has also been found to be the target molecule in the re-synthesis of natural
products3-6 and in medicinal chemistry.7-8
The second example of the heterocycles is pyranopyrazole. Pyranopyrazole and
its derivatives are important biologically active ingredients.9 They have been used as anticancer,10 anti-bacterial,11 anti-inflammatory,12 anti-fungal,13 antimicrobial,14 herbicidal,15
1
molluscicidal,16 analgesic17 and anti-platelet agents.18 They have also been reported as
biodegradable agrochemicals19 and potential inhibitors of human Chk1 kinase.20-21
The third example is the pyridine type compounds. 1,4-Dihydropyridines have
been categorized as multi-drug resistance (MDR) reversing agents.22 As they mimic
nicotinamide adenine dinucleotide (NADH) in the reduction process in vitro, they have
also been classified as calcium channel antagonists and are used to decrease the blood
pressure and vascular resistance in patients with hypertension.23 However, 1,4dhydropyridines bearing calcium channel-blocking activity eliminate their MDR reversal
activity as it poses a therapeutic issue with pharmacodynamic and pharmacokinetic
limitations.24 Thus, the modification of 1,4-dhydropyridine derivatives to eliminate Ca++
channel antagonist behavior while maintaining a high ability to reverse MDR in cancer
therapy has become an important goal in synthetic applications.
Because of their important pharmaceutical activities, the synthetic challenges of
heterocycles have also been addressed. For example, the synthesis of
pyrazoloquinolizinone combined with different heterocyclic fragments to construct a new
heterocyclic ring.25
All of the examples shown above provide a brief overview of the importance of
heterocycles in chemical and biological applications. Many synthetic approaches toward
various heterocycles have been reported in literature. However, most of the reactions
involve multistep synthesis along with the purification of intermediates in each step.
More importantly, a significant amount of waste was generated during the timeconsuming purification processes. Thus, the design of more efficient and environmentally
benign synthetic routes for heterocycles is highly demanded. The ideals of green
2
chemistry, which aim to minimize pollution and maximize efficiency in chemical
synthesis26, can fulfill these goals. First, direct and rapid microwave heating is a novel
source of energy for driving the reaction.27 “Microwave flash heating” shows high
efficiency in quick chemical transformations, and it also improves the yields by reducing
the byproducts.28 Second, microwave-assisted MCRs achieve not only fast reactions, but
also convergent reactions where the majority of the atoms from the starting materials are
converted into products.29 In addition, fewer intermediates are purified from the reaction
mixture. Finally, since flash chromatography is a time-consuming process and generates
a significant amount of waste, the novel purification technique of F-SPE is applied to our
research. This easy purification tool is highly efficient and a significant time-saver.30
Fluorophobic solvents elute non-fluorous compounds while fluorophilic solutions elute
the fluorous compounds.31 This simple operation generates a limited amount of waste,
which is more similar to filtration than to chromatography.32
Overall, the combination of fluorous techniques with atom economic MCRs and
fast microwave reactions provided an efficient way to construct our target molecules,
while also allowing us to overcome the purification challenges. The power of this
integrated platform technology is environmentally benign and it could have broad
applications in organic synthesis and medicinal chemistry.33
3
CHAPTER 2
LITERATURE REVIEW
2.1.
Fluorous Technology
Fluorous chemistry was first introduced to chemists’ vocabulary in 1994. It has
been developed as a new technique to facilitate synthesis and purification of compounds
that have broad applications in chemistry and biology. The fluorous compounds that
contain perfluorocarbon alkyl moieties, which are often abbreviated as (CH)mRfn, have
different lengths of ponytails that impart special characteristic to the compounds.34 The
most important feature of the fluorous chain is that it is both hydrophobic and lipophobic,
but fluorous molecules can also dissolve in fluorous solvents, such as hydrofluoroethers
(HFEs).33 The fluorous ponytails can be grouped into two categories: permanent fluorous
chains and temporary fluorous chains. The permanent fluorous moiety is designed as part
of the final product that helps to achieve simple purification via F-SPE. While the
temporary fluorous tag serves not only as the phase tag, but also as the protecting and
activating group of the parent molecule for post-modification reactions. Chemists also
have defined two different fluorous chains based on fluorine content. There are “heavy”
fluorous chains and “light” fluorous chains.35 “Heavy” fluorous tags always bear 39 or
more fluorines, in comparison to their lighter cousins that contain 21 fluorines or fewer.32
4
For a typical organic reaction, good solubility of reactants into solvents is important for a
successful reaction. Although “heavy” fluorous chains are easier to dissolve in highly
fluorinated solvents, they may have lower solubility in common organic solvents.
However, this issue can be addressed by using “light” fluorous tags with their broad
miscibility in standard organic solvents.32 Moreover, the replacement of expensive
fluorous solvents will also lower the cost. At the early stage of fluorous chemistry, liquidliquid extractions (LLEs) were designed for “heavy” fluorous chains by using fluorous
solvents. However as “light” fluorous chains are less soluble in fluorous media, the LLEs
have been replaced by a more recent and environmentally benign separation technique: FSPE.36
F-SPE utilizes fluorous silica gel (Scheme 1)32 as the stationary phase to separate
all fluorous molecules from non-fluorous excess reagents or unexpected products. The
new technique is not time-dependent, but rather based on the different solvent systems
employed.33 In other words, it primarily depends on the presence of fluorous tags but not
on the polarity of the compounds. It reflects a “like dissolves like” effect.33 Compared to
traditional flash chromatography, F-SPE significantly lowers the amount of waste
generated, and its operational convenience tremendously lowers the workload of the
chemists.
Scheme 1. Perfluorooctylethylsiyl bonded phase in fluorous cartridge
5
The most popular F-SPE system consists of 24 manifolds. The process of F-SPE
(Scheme 2) starts with the activation/washing of the cartridge. This can be done when
one applies either positive pressure on the top or negative pressure at the bottom to drive
the solvents down into 10-15 mL test tubes.32 Dimethylformamide (DMF) is a typical
solvent to activate new cartridges. As the cartridges are also reusable, 3-5 cartridge
volumes of fluorophilic solvent can be used to wash recycled cartridges. The next step is
to precondition the cartridges with 80:20 MeOH-H2O. After dissolving in a minimum
amount of solvent, the sample is loaded onto the silica gel cartridge to be completely
absorbed. The sample loading capacity is typically between 5-10% by weight of fluorous
silica gel. Next, the non-fluorous compounds are washed out by a fluorophobic solvent:
80:20 MeOH-H2O. Then the fluorous compound is eluted by fluorophilic solvents,
typically anhydrous methanol, acetone or tetrahydrofuran (THF). Depending on the size
of the cartridge employed, there can be more than one fraction collected in each elution
process. Finally the same fractions are condensed to dryness.
Scheme 2. Typical procedure of F-SPE
6
Just as automated chromatography has been developed in recent years to replace
traditional flash chromatography, advanced F-SPE systems such as the automated F-SPE
and plate-to-plate F-SPE have been introduced as well. Those advanced systems increase
the throughput of organic synthesis.
There has been significant number of applications of F-SPE performed in
synthetic work through combination with the fluorous-tagging technique. To prepare a
dedicated organic compound, it is important to control diverse undesired reactive sites to
allow chemical transformation to happen at the specific functional group. The fluoroustagging technique protects reactive functional groups from undesired reactions and allows
fluorous purification. Also, since the fluorinated group is attached to the reactive
functional groups through a linker, the strong electronegativity of the perfluoroalkyl
group does not affect the reactivity of the functional groups.38
For example, Wipf and coworkers39 reported the use of fluorous-labeled
tetrahydropyranyl (THP) ether to protect hydroxyl groups (Scheme 3). Purification was
done by F-SPE for larger or more polar molecules.
Scheme 3. Fluorous THP protective group to protect hydroxyl groups
7
Curran and coworkers40 developed the first fluorous Boc (tert-butyloxycarbonyl) groups
with different linkers and various fluorous chains to protect amine groups (Scheme 4).
Parallel F-SPE and preparative Fluofix HPLC column separation were used for the
purification of the products.
Scheme 4. Fluorous Boc protective group to protect amine groups
Zhang and coworkers41 synthesized perfluoroalkyl group to protect amino esters, which
has the potential utility for constructing a large variety of small molecules (Scheme 5).
The intermediate and product were purified by F-SPE.
Scheme 5. Perfluoroalkyl protective group to protect amino ester groups
The displaceable fluorous tags are also applied in cross-coupling reactions for
post-modification of fluorous intermediates, where the fluorous group is replaced by a
new group that increases the molecular complexity of the final product. Typical postmodification reactions include carbon-carbon bond formation (Suzuki-Miyaura cross-
8
coupling reaction), carbon-nitrogen bond formation, carbon-hydrogen and carbon-sulfur
bond formation.
For example, Zhang and coworkers42 developed the Suzuki-Miyaura cross-coupling
reaction to displace a fluorous tag to form a new carbon-carbon bond (Scheme 6). The
perfluorooctylsulfonate tagged molecules were subjected to aryl boronic acids with a
palladium catalyst to form biaryls. The separation was done by F-SPE over FluoroFlash
silica gel.
Scheme 6. Displace fluorous tag to form a new carbon-carbon bond
Zhang and coworkers43 further published a synthetic route for the palladium-catalyzed
Buchwald-Hartwig type amination of fluorous arylsulfonates (Scheme 7). Most
compounds were purified by F-SPE, while others were purified by crystallization.
Scheme 7. Displace fluorous tag to form a new carbon-nitrogen bond
9
Zhang and coworkers44 reported on the fluorous synthesis of aryl
perfluoroalkylsulfonates with thiols in a palladium-catalyzed cross-coupling reaction
(Scheme 8). F-SPE was applied for the purification of the reaction mixture.
Scheme 8. Displace fluorous tag to form a new carbon-sulfur bond
10
2.2.
Microwave-assisted organic reactions (MAOS)
Microwaves serve as the Bunsen burner in chemistry for the 21st century.45
Microwave heating has attracted a significant amount of attentions as it provides internal
heating46 to reduce reaction times from days and hours to minutes and seconds. Plus, the
fast microwave reaction affects the distribution of the products to achieve the desired
chemical transformation by increasing reaction yields and minimizing the formation of
byproducts.29
There has always been a disagreement surrounding the “black box” associated
with the rapid heating effect of microwave irradiation. While speculations focused on
“specific” or “non-thermal” effects in the early days, more recent investigations showed
that the fast microwave heating phenomena is based purely on thermal effects.46 Under
microwave irradiation, solvents and the reagents absorb microwave energy and convert it
to heat. The energy transformation is achieved by microwave dielectric heating. In an
electromagnetic field, electric components such as dipoles or ions become aligned.
Microwave frequencies cause oscillations and a certain amount of energy is lost due to
the realignment of dipoles or ions through dipolar polarization or ionic conduction.47
Solvents that bear dielectric properties contribute to the rapid heating associated with
microwave irradiation. The loss factor, tanδ (Table 1),48 is related to the dielectric
properties of different solvents, and so tanδ is evaluated to compare a solvent’s heating
power. For example, ethanol (0.941) bears a higher tanδ than toluene (0.040), which is an
indication of its better heating power.
11
Table 1. Microwave heating profile of different solvents
Solvent
tanδ
Solvent
tanδ
ethylene glycol
1.350
DMF
0.161
ethanol
0.941
1,2-dichloroethane
0.127
DMSO
0.825
water
0.123
2-propanol
0.799
chlorobenzene
0.101
formic acid
0.722
chloroform
0.091
methanol
0.659
acetonitrile
0.062
nitrobenzene
0.589
ethyl acetate
0.059
1-butanol
0.571
acetone
0.054
2-butanol
0.447
tetrahydrofuran
0.047
1,2-dichlorobenzene
0.280
dichloromethane
0.042
NMP
0.275
toluene
0.040
acetic acid
0.174
hexane
0.020
In the past decades, organic reactions were conducted by using an external heat
source, such as a hot plate or an oil bath. This relatively time-consuming and hard to
control energy transformation method depended on the ability of heat to penetrate the
walls of the reaction vessels.49 Under conventional methods, the heat reaches the vessel
walls first and then the reaction mixture. However, microwave transparent materials have
been employed for microwave reaction vessels to minimize wall effects.50 Therefore,
microwaves can apply energy directly to the internal mixture which results in consistently
high temperatures. Furthermore, under microwave irradiation, solvents with high loss
factors show the capability of reaching temperatures above their boiling points, which is
impossible to reproduce using conventional heating methods.47
In recent years, microwave-assisted organic synthesis has been applied to a wide
12
range of reactions. By employing environmentally benign reaction media, the greenness
of the microwave reactions has been emphasized.46 For example, solvent-free reactions
have become popular since the early 1990s.51 In addition, water is a safe, non-toxic and
cheap solvent compared to common organic solvents. Another example is ionic liquids,
which contain exclusively ions. Ionic liquids are non-flammable and have low vapor
pressures and high boiling points. They can bear a wide range of reaction temperatures,
and their high polarity can significantly decrease the reaction time without any significant
pressure build-up.52 Another advantage of ionic liquids is that they are immiscible with
common organic solvents.53-54 This specific feature allows easy for separation.
For example, Leadbeater and coworkers55 reported microwave-assisted solvent-free
Suzuki-Miyaura cross-coupling reactions with good yields obtained (Scheme 9).
Scheme 9. Microwave-assisted solvent-free Suzuki-Miyaura cross-coupling reaction
Bogdal and coworkers56 developed the N-alkylation of azaheterocycles under phasetransfer-catalysis microwave irradiation (Scheme 10). The tetrabutylammonium bromide
(TBAB) was used as the phase-transfer catalyst. Excellent yields were achieved as well.
13
Scheme 10. Microwave-assisted phase-transfer catalysis reaction
Kormos and coworkers57 developed a strategy of a one-pot, two-step, Heck coupling
reaction for the synthesis of asymmetrically substituted stilbenes (Scheme 11). Good to
excellent yields were achieved.
Scheme 11. Microwave-assisted Heck coupling reaction
Strübing and coworkers58 reported on AAD (aldehydes, amides and dienophiles) MCRs
under microwave irradiation (Scheme 12). Highly selective yields of endo N-acyl
cyclohexenylamines were achieved. Furthermore, the reaction time was 50 times faster
than the conventional heating by employing acetic anhydride as both reagent and solvent.
14
Scheme 12. Microwave-assisted AAD MCRs
Baqi and coworkers59 reported on the amination of 5-nitroanthranilic acid with a wide
range of amines under microwave irradiation (Scheme 13). No solvent or catalysts were
involved in this reaction. Good to excellent yields were achieved as well.
Scheme 13. Microwave-assisted solvent-free and catalyst-free amination reaction
Piras and coworkers60 disclosed the hydrogenation of pyridines via microwave heating.
Good to excellent yields were also obtained (Scheme 14).
Scheme 14. Microwave-assisted hydrogenation reaction
15
2.3.
Multicomponent reactions (MCRs)
The tradition of linear organic synthesis is to form multiple chemical bonds from
consecutive reactions. These reactions involve purifications at each step and show low
yields for final products. The challenge for highly efficient synthesis can be addressed by
MCRs to minimize the yield loss in each step. Therefore the linear synthetic strategy has
come to be less fashionable with MCRs now the superior synthetic approach for the new
millennium.61 Multicomponent reactions, as the name indicates, is a convergent reaction,
in which more than two reagents are combined in a single operation to form products that
incorporate most or all of the atoms from the components.62 So large compound libraries
can be built up from a small group of starting materials in a relatively short time period.30
MCRs were first introduced in the 19th century.63-64 In 1838, Laurent and Gerhardt
isolated the crystalline product “benzoyl azotide” from the reaction of bitter almond oil,
ammonia and hydrogen cyanide.63,65 It opened a new chapter for organic synthesis. Over
the last 170 years, many MCRs had been developed, and many important MCRs have
been highly developed in both academia and industry.
For example, in 1850, Adolph Strecker66 developed a serious of chemical reactions to
form amino acids from carbonyl, hydrogen cyanide and ammonia (Scheme 15).
Scheme 15. MCRs to synthesize amino acids
16
Almost 130 years ago, a German chemist Arthur Rudolf Hantzsch67-68 developed MCRs
to prepare 1,4-dihydropyridine and its derivatives from ammonia, aldehyde and 2 equiv.
β-ketoester (Scheme 16).
Scheme 16. Hantzsch reaction to synthesize dihydropyridines
In 1893, Italian chemist Pietro Biginelli69-70 first reported the synthesis of 3,4dihydropyrimidin-2(1H)-ones from condensation of aryl aldehyde, β-ketoester (ethyl
acetoacetate) and urea (Scheme 17).
Scheme 17. Biginelli reaction to synthesize dihydropyrimidinones
The alternative synthetic routes of Biginelli reactions have been developed and the most
favorable one is the “Atwal modification”.71 Atwal and coworkers condensed enone and
protected urea/thiourea derivatives to form the desired dihydropyrimidines (Scheme 18).
17
Scheme 18. Atwal modification of Biginelli reaction to synthesize dihydropyridines
When it comes to the twenty century, many well-known MCRs were developed.
In 1912, another German chemist Carl Mannich72 developed three-component reactions
to construct β-amino-carbonyls from nonenolizable aldehydes, non-tertiary amines and
enolizable carbonyls (Scheme 19).
Scheme 19. Mannich reaction to synthesize β-amino-carbonyls
In 1921, Italian chemist Mario Passerini73,74 reported on MCRs of carboxylic acids,
carbonyls and isocyanides to form α-hydroxyl carboxamides (Scheme 20).
Scheme 20. Passerini reaction to synthesize α-hydroxyl carboxamides
18
In 1929, Bergs75,76 first published the synthesis of hydantoin derivatives and Bucherer77
improved on his synthetic route with a lower temperature and pressure (Scheme 21). As a
result, these three component reactions from carbonyls or cyanohydrins, ammonium
carbonates and potassium cyanides were named the Bucherer-Bergs reaction.
Scheme 21. Bucherer-Berges reaction to synthesize hydantoins
In 1966, Gewald and coworkers78 reported on reactions for the synthesis of polysubstituted 2-amino-thiophenes (Scheme 22). The condensation happens between ketones
and α-cyanoesters in the presence of sulfur and base.
Scheme 22. Gewald reaction to synthesize poly-substituted 2-amino-thiophenes
The Ugi reaction79 presented a four-component reaction to construct amides from the
conversion of carbonyls, amines, isocyanides and carboxylic acids (Scheme 23).
Scheme 23. Ugi reaction to synthesize amides
19
2.4.
Suzuki-Miyaura cross-coupling reactions
Palladium-catalyzed cross-coupling reactions between organoboronic acids and
the halides were first reported on by Japanese chemist Akira Suzuki and coworkers in
1979.80 The intermediates formed by the hydroboration of alkynes and boronic acids
were reacted with halides in the presence of a catalytic amount of tetrakis
(triphenylphosphine) palladium and strong base to yield the desired conjugated dienes
(Schemes 24,25) or enynes (Scheme 26) with high regio- and stereo-specificity.
Scheme 24. Suzuki-Miyaura cross-coupling reaction
Scheme 25. Regio-selectivity of conjugated dienes via Suzuki-Miyaura cross-coupling
reaction
Scheme 26. Synthesis of enyne via Suzuki-Miyaura cross-coupling reaction
20
Nowadays the scope of this classic reaction has been extended to form additional
molecules, such as poly-olefins, styrenes and biaryls, and has also been applied in the
formation of ligands,81 polymers,82 pharmacologically active molecules83 and various
materials.84 Additional boron reagents85, such as arylboron, potassium trifluoroborates,
and alkyboron derivatives, can also be reacted with various organo halides, organo
triflates and organo fluorous compounds41 as well. Suzuki-Miyaura cross-coupling
reaction has advantages over the traditional coupling reactions. The Suzuki reactants are
easily accessible, air-stable, water-stable, non-toxic and tolerated by a majority of
functional groups. The reaction can achieve high regio- and stereo-selectivity. The
inorganic by-products are easily removed and are non-toxic to environment.86 Moreover
the Suzuki-Miyaura cross-coupling reaction can be achieved in a variety of green reaction
media such as water, supercritical carbon dioxide, ionic liquids or in a solvent-free
system. The reaction can proceed under novel synthetic tools, such as microwave
reactions, ultrasound irradiation reactions or continuous flow processes. Also, reusable
and recoverable polymer-supported catalysts have been designed to simplify the
purification process.81
For example, Basu and coworkers87 have established ligand-free Suzuki-Miyaura crosscoupling reaction in water at room temperature (Scheme 27). The reaction was achieved
by using sodium aryl trihydroxyborates as an alternative source of organoboron
compounds.
21
Scheme 27. Suzuki-Miyaura cross-coupling reaction in water
Feng and coworkers88 have reported on the SBA-15-supported Suzuki-Miyaura crosscoupling reaction in supercritical carbon dioxide (Scheme 28). Palladium was anchored
into the Ph-SBA-15-PPh3 to form a stable and reusable Ph-SBA-15-PPh3-Pd catalyst.
Supercritical carbon dioxide served as the environmentally benign solvent, which also
prevented the leaching of the palladium from its support.
Scheme 28. Suzuki-Miyaura cross-coupling reaction in supercritical carbon dioxide
Bernhardt and coworkers89 reported on a solvent-free and time-efficient Suzuki-Miyaura
cross-coupling reaction in ball milling (Scheme 29). The solid reagent system KF-Al2O3
was used to mediate the reaction and provide the solvent-free conditions.
Scheme 29. Suzuki-Miyaura cross-coupling reaction in solvent-free condition
22
Akkaoui and coworkers90 reported on a microwave-assisted, one-pot, two-step, SuzukiMiyaura cross-coupling reaction (Scheme 30). Microwave irradiation was employed as
an alternative strategy to overcome low yields associated with conventional heating
methods.
Scheme 30. Suzuki-Miyaura cross-coupling reaction via microwave irradiation
Silva and coworkers91 published ultrasound-assisted Suzuki-Miyaura cross-coupling
reactions (Scheme 31). These reactions were carried out without employing phosphate.
Scheme 31. Suzuki-Miyaura cross-coupling reaction via ultrasonic irradiation
Singh and coworkers92 reported on a Suzuki-Miyaura cross-coupling reaction under
continuous-flow conditions (Scheme 32).
Scheme 32. Suzuki-Miyaura cross-coupling reaction under continuous-flow condition
23
Liu and coworkers93 reported on a palladium nanoparticle-catalyzed Suzuki-Miyaura
cross-coupling reaction (Scheme 33). Due to the small size, narrow-size distribution and
high surface area of the palladium nanoparticles, the reaction achieved high selectivities
and excellent yields.
Scheme 33. Palladium nanoparticle-catalyzed Suzuki-Miyaura cross-coupling reaction
Long and coworkers94 achieved a Suzuki-Miyaura cross-coupling reaction between
boronic acids and organic triflates (Scheme 34). The efficient substitution of triflates to
halides diversified the substrates and extended the original reaction scheme.
Scheme 34. Suzuki-Miyaura cross-coupling reaction between organoboronic acid the
organotriflates
24
CHAPTER 3
RESULTS AND DISCUSSION
3.1.
Introduction
The broad biological activities of target heterocyclic molecules have already been
discussed in chapter 2, which emphasized the designing of environmentally benign
protocols to synthesize heterocycles by green synthetic tools. Our protocols were inspired
by previously developed microwave-assisted fluorous syntheses of heterocyclic
compound libraries95-97 and focused on the assembly of different heterocyclic ring
skeletons. The three previously described approaches were utilized to the end: microwave
irradiation, which significantly reduced reaction times; and MCRs, which were useful for
constructing multiple bonds in a single reaction to achieve high synthetic efficiency.
Perfluorooctanesulfonyl (C8F17O2SO-) protected benzaldehyde was employed as the
convertible linker for F-SPE that dramatically reduced the amount of solvent generated in
comparison to column purification. The post-modification of fluorous intermediates was
achieved by Suzuki-Miyaura cross-coupling reactions that removed the fluorous linker
and increased the complexity and diversity of the final product. These sustainable
synthetic approaches have been combined in the preparation of the target molecules. A
detailed description of the newly developed synthetic routes can be found in this chapter.
25
3.2.
Synthesis of perfluorooctanesulfonyl benzaldehydes
3.2.1. Introduction
Perfluorooctanesulfonyl benzaldehydes provide the fluorous linker to facilitate FSPE. Intermediates with a perfluoroalkyl “phase tag” can be quickly isolated from the
reaction mixture while generating a limited amount of waste. These aryl
perfluoroalkylsulfonates are also employed as protecting groups to mask active functional
groups in unstable reaction conditions.99-102 Fluorous linkers are analogues to triflates.
They are also good substrates for metal-catalyzed coupling reactions, so new chemical
bonds such as carbon-carbon bonds, carbon-sulfur bonds and carbon-nitrogen bonds are
formed by cleaving perfluorosulfonate groups. For example, Suzuki-Miyaura crosscoupling reactions were applied in our protocols to produce biaryl products.
3.2.2. Results and discussion
Perfluorooctanesulfonyl benzaldehydes were synthesized by employing an
established synthetic route.42
Phenols were mixed with perfluorooctanesulfonyl fluoride 1 and Na2CO3 in
dimethylformamide (DMF) and the mixture was heated at 70 oC for 5 h. The reaction
mixture was then extracted from 1:1 ethyl acetate AcOEt/H2O and evaporated to dryness.
The crude perfluorooctanesulfonyl benzaldehydes 2 and 3 (Scheme 35) were further
purified by F-SPE (Table 2).
26
Table 2. Synthesis of perfluorooctanesulfonyl benzaldehydesa
Entry
-OH
Time (h)
Product
Yield (%)b
1
p-OH
5
2
90
2
m-OH
5
3
85
a
Reagents and conditions: hydroxybenzaldehyde (6.0 mmole), Na2CO3 (6.3 mmole), 1
(5.0 mmole), DMF (5.0 mL),bIsolated yield after F-SPE
Scheme 35. Perfluorooctanesulfonyl benzaldehyde products
3.3.
A green approach toward the synthesis of polycyclic oxazabicyclo[3,3,1]nonanes
3.3.1. Introduction
In 1887, Tröger’s base103 was reported as the first heterobicyclo[3.3.1]nonane 4
(Scheme 34). In this molecule, two bridged-head stereogenic nitrogens construct the
bicyclic skeleton and lock the whole conformation. Later, Tröger’s base 4 derivatives
were applied as molecular clips in molecular recognition.104 For example, Tröger’s
base105 analog 5, in which two alkyl groups were substituted by pyridine amides to form
hydrogen bonds with dicarboxylic acids to fulfill the recognition process 6 (Scheme 36).
27
Scheme 36. Examples of Tröger’s base, Tröger’s base analogue 5 and the molecular
recognition process 6
Recently, Yang and coworkers107,108 reported the synthesis of
diazabicyclo[3.3.1]nonane 7 and oxazabicyclo[3.3.1]nonane 8 (Scheme 37).
Diazabicyclo[3.3.1]nonane 7 is a potent inhibitor of vitamin K epoxide reductase
(VKOR)106 and oxazabicyclo[3.3.1]nonane 8 is the first example of a biaryl-fused
heterobicyclo[3.3.1]nonane107 photochromic colorant. Under UV radiation, the cleavage
of the C-O bond converts the molecule from colorless 9a to pale red 9b and the reversed
formation of the C-O bond happens at high temperature108 (Scheme 35). Therefore, this
novel molecular structure can be further utilized in organic photochromic dyes.
28
Scheme 37. Examples of diazabicyclo[3.3.1]nonane 7, oxazabicyclo[3.3.1]nonane 8 and
its photochromism process 9a and 9b
More recently, Yang and coworkers109 applied MCRs to synthesize cleft-shaped
oxazabicyclo[3.3.1]nonanes (Scheme 38).
Scheme 38. MCR to synthesize the oxazabicycle
Although this MCR strategy achieved a high atom economy, the relatively long
reaction time and time-consuming purification process needed to be improved. By our
approach, microwave-assisted MCRs were applied to reduce the reaction time and
29
perfluorooctanesulfonyl benzaldehydes were employed for easy separation. Moreover,
the post-modifications achieved by Suzuki-Miyaura cross-coupling increased the
molecular complexity of the library scaffold. The building blocks of our protocol are
listed below (Scheme 39).
Scheme 39. Building blocks for preparation of biaryl-substituted
oxazabicyclo[3.3.1]nonanes
3.3.2. Results and discussion
The first step was the one-pot MCR of aniline, perfluorooctanesulfonyl
benzaldehyde, isobutyraldehyde 10 and catalytic amount of ytterbium
trifluoromethanesulfonate Yb(OTf)3 11 (OTf = OSO2CF3) to form tetrahydroquinolines.
Microwave-heated reactions using equal amounts of aniline and 2, an excess amount of
10 and a catalytic amount of 11 were performed in either ethanol (EtOH) or 1,2dicholoroethane (CH2Cl2) at different times and temperatures (Table 3). Reactions were
monitored by LC-MS. The results indicated the best yield was achieved when using
EtOH as the solvent and reaction was heated at 50 oC for 15 min.
30
Table 3. Effect of solvent, time and temperature on the microwave-assisted MCRs to
synthesize tetrahydroquinolines
a
Solvent
Time (min)
Temp (oC)
Yield (%)a
CH2Cl2
10
100
NRb
CH2Cl2
10
50
20
CH2Cl2
20
50
20
EtOH
10
50
60
EtOH
15
50
80
Yield was detected by LC-MS,bNR-no reaction
The equivalences of the starting materials were optimized (Table 4) and 2 was
used as the limiting reagent. Aniline and 10 were in excess (1.5 eq.) to consume 2
completely and the minimum amount of 11 (0.4 eq.) was applied, as well. It was
important to discover when 10 was replaced by cyclohexanecarbaldehyde, as there was
no product formed because of the bulkiness of 10 impeded the cyclization of imine and
cyclohexanecarbaldehyde.
Table 4. Effect of equivalence of starting materials on the microwave-assisted MCRs to
synthesize tetrahydroquinolines
a
Aniline (eq.)
10 (eq.)
11 (eq.)
Yield (%)a
1.0
1.5
1.5
1.5
1.5
1.5
0.4
0.4
0.2
60
80
60
Yield was detected by LC-MS
31
For further interest, the initial MCR product was further reacted with EtOH to
form O-ethylated ether (Scheme 40).
Scheme 40. Proposed mechanism for microwave-assisted MCRs to synthesize
tetrahydroquinolines
Four tetrahydroquinolines (Scheme 41) were prepared (Table 5) in 74-88% yield.
A longer reaction time (20 min) was required for scale-up (1.0 mmole of 2). The reaction
mixtures were purified by F-SPE.
Scheme 41. Tetrahydroquinolines
32
Table 5. Microwave-assisted MCRs to synthesize tetrahydroquinolinesa
Entry
1
2
3
4
-OSO2C8F17
p-OSO2C8F17
p-OSO2C8F17
m-OSO2C8F17
m-OSO2C8F17
R1
OMe
H
OMe
H
Product
12
13
14
15
Yield (%)b
84
88
88
74
a
Reagents and conditions: aniline (3.0 mmole), 2 (2.0 mmole), 10 (3.0 mmole), 11 (0.8
mmole, EtOH (4.0 mL),bIsolated yield after F-SPE
The second step was the cycloaddition of tetrahydroquinoline with coumarin or 4hydroxy-1-methylquinolin-2(1H)-one to form fluorous oxazabicyclo[3.3.1]nonanes.
Microwave-heated reactions with equal amounts of tetrahydroquinoline, coumarin and
catalytic amount of the catalyst were performed at different times and temperatures
(Table 6). Reactions were monitored by LC-MS. The results indicated the best yield was
achieved when using p-toluenesulfonic acid 16 as the catalyst, CH2Cl2 as the solvent and
reaction was heated at 85 oC for 20 min.
The equivalences of the starting materials were optimized (Table 7).
Tetrahydroquinoline was used as the limiting reagent; coumarin was in excess (1.5 eq.) to
ensure the reaction completion; and a catalytic amount of 16 (0.2 eq.) was applied.
33
Table 6. Effect of catalyst, solvent, reaction time and temperature on the microwaveassisted synthesis of fluorous oxazabicyclo[3.3.1]nonanes
a
Solvent
Time (min)
Temp (oC)
Cat. (0.4 eq.)
Yield (%)a
EtOH
20
50
11
NRb
EtOH
20
70
11
NR
EtOH
10
150
11
10
EtOH
15
150
11
10
EtOH
15
160
11
10
EtOH
20
160
11
10
CH2Cl2
10
145
11
10
CH2Cl2
10
145
16
20
CH2Cl2
5
100
16
40
CH2Cl2
10
100
16
40
CH2Cl2
5
85
16
50
CH2Cl2
10
85
16
50
CH2Cl2
15
85
16
50
CH2Cl2
20
85
16
70
CH2Cl2
35
85
16
50
CH2Cl2
45
85
16
50
Yield was detected by LC-MS,bNR-no reaction
Table 7. Effect of equivalence of starting materials on microwave-assisted synthesis of
fluorous oxazabicyclo[3.3.1]nonanes
a
Coumarin (eq.)
16 (eq.)
Yield (%)a
1.0
1.5
1.5
0.4
0.4
0.2
40
50
70
Yield was detected by LC-MS
34
Eight fluorous oxazabicyclo[3.3.1]nonanes (Scheme 42) were prepared (Table 8)
in 48-77% yields. A longer reaction time (30 min) was required for scale-up (0.6 mmole
of 2). The reaction mixtures were purified by F-SPE.
Table 8. Microwave-assisted synthesis of fluorous oxazabicyclo[3.3.1]nonanesa
a
Entry
C8F17O2SO-
R1
X
Product
Yield (%)a
1
m-OSO2C8F17
H
NMe
17
55
2
m-OSO2C8F17
OMe
NMe
18
77
3
p-OSO2C8F17
H
NMe
19
61
4
m-OSO2C8F17
H
O
20
68
5
m-OSO2C8F17
OMe
O
21
71
6
p-OSO2C8F17
H
O
22
50
7
p-OSO2C8F17
OMe
NMe
23
66
8
p-OSO2C8F17
OMe
O
24
48
Isolated yield after F-SPE
35
Scheme 42. Fluorous oxazabicyclo[3.3.1]nonanes
The final step was the Suzuki-Miyaura cross-coupling reactions to remove the
fluorous linkers and introduce biaryl groups to the oxazabicyclo[3.3.1]nonanes.
Microwave-heated reactions with the limiting reagent fluorous
36
oxazabicyclo[3.3.1]nonane, an excess amount of phenyl boronic acid (1.5 eq.), cesium
carbonate (CsCO3) 25 (2.5 eq.), and a catalytic amount of Pd(dppf)Cl2 26 were performed
in the co-solvent 4:1:4 acetone: H2O: HFE7200 at different times and temperatures
(Table 9). The fluorous solvent HFE7200 was employed to increase the solubility of
fluorous oxazabicyclo[3.3.1]nonane. Reactions were monitored by LC-MS. The results
indicated the best yield was achieved when heating the reaction at 100 oC for 25 min.
Table 9. Effect of reaction time and temperature on microwave-assisted Suzuki-Miyaura
cross-coupling reaction to synthesize biaryl-substituted oxazabicyclo[3.3.1]nonanes
a
Time (min)
Temp (oC)
Yield (%)a
10
20
25
30
15
20
25
80
80
80
80
100
100
100
NRb
10
10
10
20
20
40
Yield was detected by LC-MS,bNR-no reaction
Twelve oxazabicyclo[3.3.1]nonanes (Scheme 43) were prepared (Table 10) in 12-
65% yields. A longer reaction time (35 min) was required for scale-up (0.1 mmole of
fluorous oxazabicyclo[3.3.1]nonane). The reaction mixtures were purified by F-SPE and
flash chromatography.
37
Table 10. Microwave-assisted Suzuki-Miyaura cross-coupling reaction to synthesize
biaryl-substituted oxazabicyclo[3.3.1]nonanesa
Entry
R1
C8F17O2SO-
X
R2
Product
Yield (%)b
1
H
o-OSO2C8F17
O
Ph
27
55
2
OMe
p-OSO2C8F17
O
Ph
28
48
3
H
o-OSO2C8F17
NMe
PhOMe
29
26
4
H
o-OSO2C8F17
O
PhOMe
30
47
5
H
p-OSO2C8F17
NMe
PhOMe
31
65
6
OMe
p-OSO2C8F17
NMe
PhOMe
32
38
7
OMe
p-OSO2C8F17
O
PhOMe
33
38
8
OMe
o-OSO2C8F17
O
Ph
34
48
9
OMe
o-OSO2C8F17
NMe
PhOMe
35
12
10
OMe
o-OSO2C8F17
NMe
Ph
36
14
11
OMe
o-OSO2C8F17
O
PhOMe
37
23
12
H
p-OSO2C8F17
O
PhOMe
38
14
a
Reagents and conditions: fluorous oxazabicyclo[3.3.1]nonane (0.1 mmole), phenyl
boronic acid (0.2 mmole), 25 (0.3 mmole), 26 (0.02 mmole), co-solvent (3 mL),bIsolated
yield after flash chromatography
38
Scheme 43. Biaryl-substituted oxazabicyclo[3.3.1]nonanes
39
In summary, a perfluorooctanesulfonyl benzaldehyde-assisted synthesis of biarylsubstituted oxazabicyclo[3.3.1]nonanes has been developed. The microwave-assisted
MCRs have fast reaction times and high atom economy, F-SPE provided a method for
easy separation, and microwave-assisted Suzuki-Miyaura cross-coupling reactions
introduced the biaryl functional group to the products. This efficient and green protocol
can be expanded to construct a library scaffold using a large number of building blocks.
3.4.
An environmentally benign approach to synthesize pyranopyrazole derivatives
3.4.1. Introduction
In 1973, Junek and Aigner reported the synthesis of pyranopyrazole (Scheme
44).112 Because of their significant biological activities, more pyranopyrazoles and
derivatives were developed soon afterwards. The typical formation method for
pyranopyrazoles is a three-component reaction, in which carbonyl, malononitrile,
pyrazolone and catalytic amount of base are combined to form target molecules.113
Scheme 44. Synthesis of the pyranopyrazole
Recently, Vasuki and Kumaravel114 published a protocol of an aqueous medium,
rapid four-component reaction to synthesize pyranopyrazole. In their synthetic route,
40
benzaldehyde, malononitrile, hydrazine hydrate and ethyl acetoacetate were mixed with
catalytic amount of piperidine in distilled water, and the reaction was stirred at room
temperature for 5-10 min (Scheme 45). One year later, Litvinov and co-workers113
reported another base-promoted, four-component reaction of aldehyde, β-ketoester,
malononitrile and hydrazine hydrate in EtOH (Scheme 46) to synthesize pyrano[2,3c]pyrazole.
Scheme 45. MCR to synthesize pyranopyrazole in aqueous medium
Scheme 46. Base-promoted MCR to synthesize pyranopyrazole
Our synthetic route was inspired by this base-promoted, four-component reaction
and aimed to synthesize pyranopyrazole. By our approach, perfluorooctanesulfonyl
benzaldehyde was employed as the fluorous linker to ease separation and was later
detached via the Suzuki-Miyaura cross-coupling reaction to increase the complexity of
the final products.
41
3.4.2. Results and discussion
The first step was the one-pot MCR of 2, malononitrile 39, methyl acetoacetate 40,
hydrazine hydrate 41 and a catalytic amount of base to construct fluorous-pyranopyrazole
43. Microwave-heated reaction with equal amounts of 2 and 39, excess amounts of 40
(1.5 eq.) and 41 (1.5 eq.), and catalytic amounts of triethylamine (Et3N) 42/piperidine
(0.5 eq.) were performed at different times and temperatures (Table 11). Reactions were
monitored by LC-MS. The results indicated the best yield was achieved when Et3N was
applied as a base, EtOH as the solvent and the reaction heated at 100 oC for 20 min.
Table 11. Effect of the catalyst, solvent, reaction time and temperature on microwaveassisted MCRs to synthesize 43a
Solvent
Time (min)
Temp (oC)
Base
Yield (%)b
EtOH
15
rt
42
10
EtOH
30
rt
42
10
EtOH
20
50
42
30
EtOH
15
80
42
40
EtOH
20
100
70
EtOH
20
100
42
piperidine
EtOH
30
100
42
40
MeOH
20
100
42
20
H2O
20
100
42
10
a
10
Reagents and conditions: 2 (0.5 mmole), 39 (0.5 mmole), 40 (0.8 mmole), 41 (0.8
mmole), 42 (0.3 mmole),bYield was detected by LC-MS
42
The first step reaction was scaled up (1 mmole of 2) with 76% of 43 achieved
after F-SPE to prepare the post-modification of the fluorous linker. The Suzuki-Miyaura
cross-coupling reaction was performed under microwave heating with the limiting
reagent 43, excess amounts of 44 (1.5 eq.) and 25 (2.5 eq.), and a catalytic amount of 26
in the co-solvent 4:1:4 acetone: H2O: HFE7200 at different times and temperatures
(Table 12). Reactions were monitored by LC-MS, but no product was formed. It was
assumed that the free amine group interfered with the reaction 26.
Table 12. Effect of reaction time and temperature on microwave-assisted Suzuki-Miyaura
cross-coupling reaction to synthesize 45a
Time (min)
15
30
15
15
20
Temp (oC)
120
120
130
135
150
a
Yield (%)b
NRc
NR
NR
NR
NR
Reagents and conditions: 43 (0.1 mmole), 44 (0.2 mmole), 25 (0.3 mmole), 26 (0.02
mmole), co-solvent (3 mL),bYield was detected by LC-MS,cNR-no reaction
43
As the Suzuki-Miyaura cross-coupling reaction could not be applied to remove
the fluorous linker from 43, the alternative route18 with the cycloaddition reaction of 43
was carried out. A microwave-heated reaction of 43 (0.03 mmole) in acetic anhydride 46
(300 uL) was performed at 140 oC for 10 min (Scheme 47). Excess 46 was removed by
liquid-liquid extraction (LLE) with 1:1 NaHCO3 solution/AcOEt and the crude
compound 47 was purified by flash column chromatography over silica gel (3:1-1:1
hexane/AcOEt ). 47 was obtained in 50% yield.
Scheme 47. Microwave-assisted cycloaddition reaction of 43 and 46
Afterwards, the microwave-assisted Suzuki-Miyaura cross-coupling reaction was
applied to 47. Microwave-heated reactions with the limiting reagent 47 and excess
amounts of 44 (1.5 eq.) and 25 (2.5 eq.), and a catalytic amount of 26 were carried out in
the co-solvent 4:1:4 acetone: H2O: HFE7200 at different times and temperatures (Table
13). Reactions were monitored by LC-MS. However, no product was formed again.
44
Table 13. Effect of reaction time and temperature for microwave-assisted SuzukiMiyaura cross-coupling reaction of 47
Time (min)
Temp (oC)
Yield (%)a
15
80
NRc
20
80
NR
15
100
NR
20
100
NR
15
120
NR
15
130
NR
15
140
NR
a
Reagents and conditions: 47 (0.1 mmole), 44 (0.2 mmole), 25 (0.3 mmole), 26 (0.02
mmole), co-solvent (3 mL),bYield was detected by LC-MS,cNR-no reaction
As the Suzuki-Miyaura cross-coupling reaction was not successful for both
substrate 43 and 47, the control reaction was conducted with the substitution of bromobenzaldehyde 49 for perfluorooctanesulfonyl benzaldehyde 2. The goal for the control
reaction was to conduct the Suzuki-Miyaura cross-coupling reaction to remove the bromo
group and then apply the same conditions to revisit compound 47. A microwave-heated
reaction with equal amounts of 49 (0.7 mmole) and 39 (0.7 mmole), excess amounts of
40 (1.0 mmole) and 41 (1.0 mmole), and a catalytic amount of 42 (0.4 mmole) mixed in
EtOH (5 mL) was carried out at 100 oC for 35 min (Scheme 48). The reaction was
45
monitored by LC-MS. The reaction mixture was evaporated and extracted with 1:1
AcOEt/H2O. The crude mixture was further purified by 5:1-1:1-1:5 hexane/AcOEt over
flash chromatography. 50 was produced in 30% yield. It was found that 50 was less
soluble in common organic solvents such as EA, acetone, MeOH and cold EtOH.
Therefore recrystallization114 from hot EtOH was used for the purification of 50 and 60%
yield was achieved.
Scheme 48. Microwave-assisted MCRs to synthesize 50
Next step was the microwave-assisted cycloaddition reaction of 50 and 46. A
microwave-heated reaction of 50 (0.03 mmole) in 46 (300 uL) was performed at 140 oC
for 10 min (Scheme 49). A significant amount of acetic acid was produced after the
reaction and it resulted in a large amount of bubbles in the LLE. The alternative synthetic
method was carried out with the replacement of 46 by acetyl chloride 52. However, the
reaction was not successful (Table 14).
46
Scheme 49. Microwave-assisted cycloaddition reaction of 50 and 46
Table 14. Effect of reaction time and temperature on microwave-assisted cycloaddition
reaction of 50 and 52a
Time (min)
Temp (oC)
Yieldb
15
50
NRc
10
80
NR
10
120
NR
a
Reagents and conditions: 50 (0.03 mmole), 52 (300 uL),bYield was detected by LCMS,cNR-no reaction
Therefore, the cycloaddition reaction of 50 and 46 was revisited with a reduced
amount of 46 involved (Table 15). The results showed that the best yield could be
achieved using microwave heating with 50 (0.03 mmole) and 46 (80 µL).
47
Table 15. Effect of equivalence of starting materials on microwave-assisted
cycloaddition reaction of 46 and 50a
50 (mmole)
0.03
0.03
0.03
0.03
a
Yield (%)a
80
80
80
NRb
46 (µL)
300
150
80
10
Yield was detected by LC-MS,bNR-no reaction
The reaction was scaled up (0.7 mmole 50) and the purification of 51 is currently
under development.
In summary, a perfluorooctanesulfonyl benzaldehyde-assisted synthesis of
pyranopyrazole and its derivatives has been developed. The fluorous pyranopyrazole and
bromo pyranopyrazole were synthesized successfully; however, the Suzuki-Miyaura
cross-coupling reactions for both substrates are still under development. Our plan is to
perform the Suzuki-Miyaura cross-coupling reaction on substrate 51 and then apply the
same conditions to compound 45. However, if the Suzuki-Miyaura cross-coupling
reaction cannot be obtained on substrate 51, the other modifications will be carried out to
fulfill the cleavage of the bromo group.
48
3.5.
Synthesis of pyridine derivatives via microwave-assisted MCRs
3.5.1. Introduction
As discussed in chapter 2, 1,4-dihydropyridines show MDR reversing effects when
the calcium channel blocking activity is eliminated. Three generations of MDR inhibitors
have been developed over the past decades, and the second and third generations are
currently used in clinical trials (Scheme 50).30
Synthetic developments of 1,4-dihydropyridines have also been reported. For
example, Kawase and coworkers115 developed the synthesis of the 3,5-diacetyl-1,4dihydropyridines (Scheme 51).
Nifedipine (first generation)
Dexniguldipine (second generation)
Tariquidar (third generation)
Scheme 50. Examples of first, second and third generations of MDR reversal agents
49
Scheme 51. Synthesis of 3,5-diacetyl-1,4-dihydropyridines
Our protocol was inspired by Kawase’s work. By our approach,
perfluorooctanesulfonyl benzaldehyde was used as the fluorous linker to facilitate F-SPE
and also as the substrate for the Suzuki-Miyaura cross-coupling reaction.
3.5.2. Results and discussion
The first step was the MCR of 2, 40, aqueous ammonia 52 and a catalytic amount
of acid to construct fluorous pyranopyrazole 53. Microwave-heated reactions with
limiting reagent 2, excess amounts of 40 (2.2 eq.) and 52 (4.0 eq.), and a catalytic amount
of 11/HCl (1 drop) were performed in isopropanol (IPA) at different times and
temperatures (Table 16). Reactions were monitored by LC-MS. The results indicated that
the best yield (80%) was achieved when 5 was used as the catalyst, IPA as the solvent
and the reaction heated at 150 oC for 20 min.
50
Table 16. Microwave-assisted MCRs to synthesize 53a
Solvent
Time (min)
Temp (oC)
Acid
Yield (%)b
IPA
IPA
MeOH
MeOH
IPA
20
20
20
20
20
120
150
150
180
150
11
11
11
11
HCl
50
80
30
10
10
a
Reagents and conditions: 2 (0.1 mmole), 40 (0.2 mmole), 52 (0.4 mmole),bYield was
detected by LC-MS
The second step was a microwave-assisted Suzuki-Miyaura cross-coupling
reaction to remove the fluorous linker and introduce biaryl functional groups to the
products. Microwave-heated reactions with limiting reagent 53, excess amounts of 44
(1.5 eq.) and 25 (2.5 eq.), and a catalytic amount of 26 were carried out in the co-solvent
4:1:4 acetone: H2O: HFE7200 at different times and temperatures (Table 17). Reactions
were monitored by LC-MS, however no product was formed. It was proposed that an
oxidation reaction happened on the non-aromatic dihydropyridine ring and was
competing with the Suzuki-Miyaura cross-coupling reaction.
51
Table 17. Effect of reaction time and temperature on microwave-assisted Suzuki-Miyaura
cross- coupling reaction of 53a
Time (min)
Temp (oC)
Yield (%)b
30
85
NRc
30
100
NR
30
120
NR
30
140
NR
a
Reagents and conditions: 48 (0.1 mmole), 38 (0.2 mmole), 25 (0.3 mmole), 26 (0.02
mmole), co-solvent (3 mL),bYield was detected by LC-MS,cNR-no reaction
Further modification was carried out by the cycloaddition reaction of 53. A
microwave-heated reaction of 53 (0.1 mmole), sodium nitrite 55 (0.6 mmole) and 56 (1.0
mmole) was performed at 130 oC for 20 min (Scheme 52). Moreover, the two separate
reactions could be optimized to one-pot two-step reaction and 70% yield of 57 was
obtained after F-SPE.
Scheme 52. Microwave-assisted oxidation reaction of 53
52
The microwave-assisted Suzuki-Miyaura cross-coupling reaction was then
applied to 57. Microwave-heated reactions with limiting reagent 57 and excess amounts
of 38 (1.5 eq.) and 25 (2.5 eq.), and a catalytic amount of 26 were carried out in the cosolvent 4:1:4 acetone: H2O: HFE7200 at different times and temperatures (Table 18).
Reactions were monitored by LC-MS. The product was only produced when the reaction
was heated at 130 oC for 60 min.
Table 18. Effect of reaction time and temperature on microwave-assisted Suzuki-Miyaura
cross- coupling reaction on 57a
Time (min)
Temp (oC)
Yield (%)b
15
140
NRc
20
140
NR
25
140
NR
15
150
NR
40
130
50
60
130
50
a
Reagents and conditions: 57 (0.1 mmole), 38 (0.2 mmole), 25 (0.3 mmole), 26 (0.02
mmole), co-solvent (3 mL),bYield was detected by LC-MS,cNR-no reaction
The product 58 was purified by F-SPE and flash chromatography. Unfortunately
the structure was not confirmed by 1H-NMR although the mass was corrected from LC-
53
MS. It was assumed that the product collected was the ligand from the palladium catalyst
but not the target molecule.
Therefore, the other coupling reaction: microwave-assisted amination coupling
reaction was performed on substrate 57. Microwave-heated reactions with limiting
reagent 57 and the amine (1.5 eq.) in excess, and a catalytic amount of methylpyrrolidone
(NMP) were carried out at different times and temperatures (Table 19). The reactions
were monitored by LC-MS, however no product was formed. It was assumed that
diisobutylamine impeded the amination reaction because of its bulkiness, but as to why
the piperidine reaction failed is still not understood.
Table 19. Microwave-assisted amination reaction of 57a
Amine
Time (min)
Temp (oC)
Yield (%)b
20
130
NRc
20
150
NR
20
100
NR
40
120
NR
20
150
NR
a
Reagents and conditions: 57 (0.1 mmole), amine (0.2 mmole), NMP (1 mL),bYield was
detected by LC-MS,cNR-no reaction
54
In summary, the perfluorooctanesulfonyl benzaldehyde-assisted synthesis of
pyridine and its derivatives has been carried out. The fluorous pyridine and fluorous
pyrimidine were synthesized successfully, however, the Suzuki-Miyaura cross-coupling
reactions for both substrates were not successful. The project is currently in process for
further development.
3.6.
Synthesis of pyrazoloquinozinones via microwave-assisted MCRs
3.6.1. Introduction
Pyrazole and quinolizine ring skeletons have been found in a variety of
biologically active molecules (Scheme 53).
Viagra
Celebrex
Protopine
Berberine
Scheme 53. Selected examples of pyrazole/quinolizine-containing drugs
55
Not only have their biological activities attracted a lot of interest, but the
construction of the heterocyclic ring skeletons from pyrazoles and quinolines have also
been investigated. It has been reported that MCRs of benzaldehyde, diketone and
pyrazole lead to the formation of pyrazoloquinolinones 59117 and pyrazoloquinazolinones
60.118 The reflux reaction in EtOH yielded mixture of 59 and 60, while higher
temperature (150 oC) formed 60 exclusively (Scheme 54).
Scheme 54. MCRs of benzaldehyde, diketone and pyrazole to form 59 and 60
More interesting, when the reaction was catalyzed by strong base, such as EtOH, the
novel pyrazoloquinozinones 61 were formed118 (Scheme 55).
Scheme 55. MCRs of benzaldehyde, diketone, pyrazole and strong base to form
pyrazoloquinozinones 61
56
The unusual formation of pyrazoloquinozinones 61 can be explained by the
initial condensation of aldehyde and diketone to form the Michael adduct 62. The
addition of 5-aminopyrazole to the Michael adduct was promoted by strong base to form
pyrazoloquinozinones (Scheme 56).
Scheme 56. Mechanism for the formation of pyrazoloquinozinones 61
Our protocol was inspired by this unique formation of pyrazoloquinozinones 61.
We utilized microwave-assisted MCRs to provide a quick reaction,
perfluorooctanesulfonyl benzaldehyde-based synthesis to afford an easy separation and
the Suzuki-Miyaura cross-coupling reaction to remove the fluorous linker and to yield
pyrazoloquinozinones.
57
3.6.2. Results and discussion
Microwave-heated reactions with limiting reagent 2, excess amounts of 3methyl-1H-pyrazol-5-amine 63 (1.2 eq.) and 5,5-dimethylcyclohexane-1,3-dione 64 (1.2
eq.), and a catalytic amount of organic/inorganic base were performed in EtOH at
different times and temperatures (Table 20). Reactions were monitored by LC-MS. The
results indicated the best yield was achieved when used 2,2-dimethoxypropane (DMP) as
the catalyst and the reaction was heated at 120 oC for 10 min. The product was purified
by F-SPE and flash chromatography with employing Et3N to stabilize the product.
Table 20. Effect of reaction time and temperature on microwave-assisted MCRs to
synthesize fluorous dihydropyridine 65a
Solvent
Base
Time (min)
Temp (oC)
Yield (%)a
EtOH
DMP
10
100
50
EtOH
NaOEt
10
100
NRc
EtOH
DMP
10
140
40
EtOH
DMP
20
160
10
EtOH
DMP
10
120
70
H2O
DMP
10
120
20
CH2Cl2
DMP
10
120
10
CH3CN
DMP
10
120
10
a
Reagents and conditions: 2 (0.03 mmole), 63 (0.04 mmole), 64 (0.04 mmole), catalyctic
amount of base, EtOH (1 mL),bYield was detected by LC-MS,cNR-no reaction
58
It was interesting to note that under this reaction condition, the unique
pyrazoloquinozinone cannot be formed (Scheme 57).
Scheme 57. Decomposition of pyrazoloquinolizinone to form dihydropyridine 65
In summary, the fluorous benzaldehyde-assisted synthesis of fluorous
dihydropyridine was carried out. However, the unique formation of
pyrazoloquinozinones cannot be achieved with employing DMP as the base.
59
CHAPTER 4
CONCLUSIONS
The design of environmentally benign and efficient protocols to synthesize target
heterocycles has been explored. High synthetic efficiencies and green chemistry
advantages were realized by conducting MCRs for atom economic reactions, microwave
irradiation for time efficiency, F-SPE for easy purification, and Suzuki-Miyaura crosscoupling reaction for introducing biaryl functional group.
The synthesis of biaryl-substituted oxazabicyclo[3.3.1]nonanes generated twelve
compounds and can be expanded to construct more analogs by using a large number of
building blocks. The results of the Suzuki-Miyaura cross-coupling reaction to remove the
fluorous linker provided a place to compare the synthesis of fluorous pyranopyrazole and
bromo pyranopyrazole, and their derivatives. The synthesis of fluorous pyridine and
fluorous pyrimidine showed that the Suzuki-Miyaura cross-coupling reaction was a
bottleneck on certain substrates. The synthesis of fluorous dihydropyridine demonstrated
that the unique formation of pyrazoloquinozinone cannot be achieved without using a
strong base.
60
The individual protocols described in the previous paragraph offer
environmentally friendly synthetic routes. The work reveals green approaches to design a
variety of biological interested heterocyclic compounds.
The above result has been published in Green Chemistry as listed below.
1.
Ding, S.; Le-Nguyen, M., Xu, T.; Zhang, W. "Fluorous Benzaldehyde-based
Synthesis of Biaryl-substituted Oxazabicyclo [3.3.1]nonanes" Green Chem.
2011, 13, 847.
61
CHAPTER 5
EXPERIMENTAL PROCEDURES
5.1.
General experimental procedure for synthesis of perfluorooctanesulfonyl
benzaldehydes (Chapter 3.2)
All reactants were purchased from Aldrich and used without further purification.
The hydroxybenzaldehyde (6 mmol) and Na2CO3 (6.3 mmol) were dissolved in
DMF (5.0 mL) at room temperature. Perfluorooctanesulfonic fluoride (5 mmol) was then
added dropwise to the mixture. The mixture was heated at 70 oC for 5 h. The reaction
optimization was monitored by LC-MS. The completed solution was cooled down and
extracted with a 1:1 AcOEt:water mixture (100 mL). The combined organic phase was
dried over anhydrous Mg2SO4 and the solvent was evaporated under vacuum. The dry
crude perfluorooctylsulfonyl benzaldehyde was further purified by F-SPE.
5.2.
General experimental procedure for a green approach toward the synthesis of
polycyclic oxazabicyclo[3,3,1]nonanes (Chapter 3.3)
All reactants except perfluorooctanesulfonyl benzaldehydes were purchased from
Aldrich and used without further purification.
62
To a solution of perfluorooctanesulfonyl benzaldehyde (2.0 mmole) in ethanol (4
mL) was added aniline (3.0 mmole), isobutyraldehyde (3.0 mmole) and Yb(OTf)3 (0.8
mmole). The resulting solution was heated under microwave (Biotage Initiator 8) at 50 oC
for 20-25 min. The completed reaction was purified by F-SPE and the methanol/acetone
fractions were concentrated to give the tetrahydroquionline. The analytical sample was
further purified by flash chromatography with 0-20% gradient of AcOEt-hexanes.
To a solution of tetrahydroquionline (0.6 mmole) in 1,2-dichloroethane (3 mL)
was added coumarin (0.9 mmole) and a catalytic amount of p-toluenesulfonic acid (0.1
mmole). The resulting solution was heated under microwave at 85 oC for 30 min. The
completed reaction mixture was purified by F-SPE and the methanol/acetone fractions
were concentrated to give polycyclic fluorous oxazabicyclo[3,3,1]nonane. The analytical
sample was further purified by flash chromatography with 0-10% gradient of AcOEthexanes.
To a solution of polycyclic fluorous oxazabicyclo[3,3,1]nonane (0.1 mmole) in
co-solvent of 4:1:4 acetone: H2O: HFE7200 (3 mL) was added phenyl boronic acid (0.15
mmole), cesium carbonate (0.25 mmole) and Pd(dppf)Cl2 (0.02 mmole). The resulting
solution was heated under microwave at 100 oC for 30 min. The reaction optimization
was monitored by LC-MS. The completed reaction mixture was purified by flash
chromatography with 0-30% gradient of AcOEt-hexanes to give the desired product.
63
5.3.
General experimental procedure for synthesis of pyranopyrazole derivatives by an
environmentally benign approach (Chapter 3.4)
All reactants except perfluorooctanesulfonyl benzaldehydes were purchased from
Aldrich and used without further purification.
To a solution of perfluorooctanesulfonyl benzaldehyde (1 mmole) in ethanol was
added 1.0 mmole of malononitrile, 1.5 mmole of methyl acetoacetate, 1.5 mmole of
hydrazine hydrate, and 0.5 mmole of triethylamine simultaneously. The reaction was
heated at 100 oC for 20 min. The completed reaction mixture was purified by F-SPE and
the methanol/acetone fractions were concentrated to yield 76% of fluorous
pyranopyrazole. The analytical sample was further purified by flash chromatography with
20-50% gradient of EA-hexanes and 100% of AcOEt.
A solution of 0.5 mmole fluorous pyranopyrazole in 5 mL acetic anhydride was
heated at 140 oC for 10 min. The reaction mixture was subjected to liquid-liquid
extraction with equal amounts of NaHCO3-AcOEt to remove the accessible acetic acid.
The crude mixture was subjected to flash chromatography over silica gel (3:1 - 1:1
hexane/AcOEt) and 50% of fluorous pyranopyrimidinone was formed.
To a solution of bromo benzaldehyde (1 mmole) in ethanol was added 1.0 mmole
of malononitrile, 1.5 mmole of methyl acetoacetate, 1.5 mmole of hydrazine hydrate, and
0.5 mmole of triethylamine simultaneously. The reaction was heated at 100 oC for 35
min. The completed reaction was cooled down to 4 oC. The resulting solid was filtered
off, washed with cold ethanol, dissolved in hot ethanol and recrystallized from ethanol.
70% of bromo pyranopyrazole was achieved after recrystallization.
64
A solution of 0.5 mmole bromo pyranopyrazole in 5 mL acetic anhydride was
heated at 140 oC for 10 min. The reaction mixture was subjected to liquid-liquid
extraction with equal amount of NaHCO3-AcOEt to remove the accessible acetic acid.
The crude mixture was recrystallized from hot ethanol to yield bromo
pyranopyrimidinone.
5.4.
General experimental procedure for synthesis of pyridine derivatives via
microwave-assisted MCRs (Chapter 3.5)
To a solution of 0.7 mmole of m-perfluorooctanesulfonyl benzaldehyde in
isopropanol was added 2.8 mmole of aqueous ammonia and 1.54 mmole of methyl
acetoacetate and 7 drops of HCl. The mixture was heated at 150 oC for 20 min. The
reaction was monitored by LC-MS and yield fluorous dihydropyridine. After the
completion of the reaction, 4.2 mmole of sodium nitrite and 7 mmole acetic acid were
added into the mixture of fluorous dihydropyridine and the reaction was heated at 130 oC
for 20 min. The completed reaction mixture was purified by F-SPE and the methanol
fraction was concentrated to yield 61% of fluorous pyrimidine.
65
5.5.
General experimental procedure for perfluorooctanesulfonyl benzaldehydeassisted synthesis of pyrazoloquinozinones (Chapter 3.6)
To a solution of 0.2 mmole of m-perfluorooctanesulfonyl benzaldehyde in ethanol
was added 2.4 mmole of 3-methyl-1H-pyrazol-5-amine and 2.4 mmole of 5,5dimethylcyclohexane-1,3-dione and 3.0 mmole of 2,2-dimethoxypropane (DMP). The
reaction was heated at 120 oC for 10 min. The completed reaction mixture was purified
by F-SPE and the methanol/acetone fractions were concentrated to yield 70% of the
product.
66
APPENDIX A
ANALYTICAL METHODS
LC-MS ANALYSIS: LC-MS were performed on an Agilent 2100 system. A C18 column
(5.0 μm, 6.0 × 50 mm) was used for the separation. The mobile phases were methanol and
water both containing 0.05% formic acid. A linear gradient was used to increase from
25:75 v/v methanol/water to 100% methanol over 7.0 min at a flow rate of 0.7 mL/min.
The routine UV detections were at 210 nm and 254.4 nm. Mass spectra were recorded in
atmospheric pressure chemical ionization.
NMR ANALYSIS: The 1H and 13C and spectra were obtained on a 300 MHz Varian NMR
spectrometer in CDCl3 solvent with tetramethylsilane as the internal standard. The
temperature was 25 °C (accuracy ±1 °C) and controlled by the Varian control unit.
67
APPENDIX B
SUPPORTING INFORMATION AND PRODUCT CHARACTERIZATION FOR
CHAPTER 3.2
3-Perfluorosulfonyl benzaldehyde (2)
LC-MS (APCI+) m/z 619.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 10.05 (s, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.81
(s, 1H), 7.68 (t, J = 15.6 Hz, 1H), 7.57 (d, J = 9.9 Hz, 1H)
68
Compound 2
69
70
APPENDIX C
SUPPORTING INFORMATION AND PRODUCT CHARACTERIZATION FOR
CHAPTER 3.3
4-Ethoxy-2-(3-perfluorosulfonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline (13)
LC-MS (APCI+) m/z 734 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 7.40-7.50 (m, 3H), 7.24 (d, J = 8.1 Hz, 1H),
7.10-7.17 (m, 2H), 6.61-6.71 (m, 2H), 4.61 (s, 1H), 4.15 (s, 1H), 3.62-3.69 (M, 2H), 3.443.50 (m, 1H), 1.20 (t, J = 13.8 Hz, 3H), 0.93 (s, 3H), 0.67 (s, 3H).
13
C NMR (75.474 MHz, CDCl3), δ (ppm) 149.7, 144.1, 143.6, 131.0, 129.6, 129.2,
129.1, 122.0, 120.5, 119.9, 116.6, 114.3, 83.0, 64.4, 59.6, 36.2, 23.4, 19.1, 15.5.
71
8-(3-Perfluorosulfonyl)-12-methoxy-15,15-dimethyl-8,9-dihydro-8,14methanobenzo[d]chromeno[3,4-g][1,3]oxazocin-1(14H)-one (21)
LC-MS (APCI+) m/z 924 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 7.81 (d, J = 4.8 Hz, 2H), 7.79 (s, 1H), 7.49 7.72 (m, 2H), 7.42 (d, J = 7.8 Hz, 1H), 7.24 - 7.32 (m, 2H), 7.09 (d, J = 2.4 Hz, 1H), 6.65
(dd, J = 2.7 Hz, 3.0 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 4.99 (s, 1H), 3.84 (s, 1H), 3.78 (s,
3H), 1.25 (s, 1H), 1.02 (s, 3H), 0.97 (s, 3H).
13
C NMR (75.474 MHz, CDCl3), δ (ppm) 153.5, 152.4, 149.7, 141.5, 132.6, 131.9,
129.9, 128.8, 125.6, 124.1, 122.7, 122.4, 122.1, 116.9, 115.5, 114.3, 113.8, 106.1, 96.0,
55.9, 42.1, 33.4, 22.9, 22.2.
8-([1,1'-Biphenyl]-4-yl)-12-methoxy-15,15-dimethyl-8,9-dihydro-8,14methanobenzo[d]chromeno[3,4-g][1,3]oxazocin-1(14H)-one (34)
LC-MS (APCI+) m/z 502 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 7.81-7.90 (m, 3H), 7.66-7.72 (m, 4H), 7.50 (t,
J = 14.1 Hz, 3H), 7.42 (d, J = 7.5 Hz, 1H), 7.27-7.31 (m, 2H), 7.10 (d, J = 2.7 Hz, 1H),
6.65 (dd, J = 2.4 Hz, 2.7 Hz, 1H), 6.56 (d, J = 8.7 Hz, 1H), 5.05 (s, 1H), 3.85 (s, 1H),
3.78 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H).
13
C NMR (75.474 MHz, CDCl3), δ (ppm) 162.5, 159.8, 153.1, 152.4, 142.0, 140.4,
137.3, 133.2, 131.7, 129.3, 129.1, 127.9, 127.3, 126.8, 125.5, 124.0, 123.0, 116.9, 115.8,
113.8, 113.7, 105.9, 96.9, 55.9, 42.3, 33.3, 23.1, 22.4.
72
8-([1,1'-Biphenyl]-4-yl)-15,15-dimethyl-8,9-dihydro-8,14methanobenzo[d]chromeno[3,4-g][1,3]oxazocin-1(14H)-one (27)
LC-MS (APCI+) m/z 472 [M+1]+.
8-([1,1'-Biphenyl]-3-yl)-12-methoxy-15,15-dimethyl-8,9-dihydro-8,14methanobenzo[d]chromeno[3,4-g][1,3]oxazocin-1(14H)-one (28)
LC-MS (APCI+) m/z 502 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 7.74-7.82 (m, 3H), 7.58-7.65 (m, 5H), 7.43 (t,
J = 14.7 Hz, 3H), 7.35 (d, J = 7.5 Hz, 1H), 7.20-7.24 (m, 1H), 7.03 (d, J = 2.7 Hz, 1H),
6.58 (dd, J = 2.4 Hz, 2.1 Hz, 1H), 6.49 (d, J = 8.7 Hz, 1H), 4.98 (s, 1H), 3.78 (s, 1H),
3.71 (s, 3H), 0.97 (s, 3H), 0.94 (s, 3H).
73
8-(4'-Methoxy-[1,1'-biphenyl]-4-yl)-2,15,15-trimethyl-2,8,9,14-tetrahydro-1H-8,14methanobenzo[4,5][1,3]oxazocino[7,8-c]quinolin-1-one (29)
LC-MS (APCI+) m/z 515 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 8.07 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 8.1 Hz,
2H), 7.50-7.68 (m, 5H), 7.25-7.33 (m, 4H), 6.84-6.98 (m, 3H), 6.59 (d, J = 8.1 Hz, 1H),
5.18 (s, 1H), 4.05 (s, 1H),3.88 (s, 3H), 3.76 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H).
8-(4'-Methoxy-[1,1'-biphenyl]-4-yl)-15,15-dimethyl-8,9-dihydro-8,14methanobenzo[d]chromeno[3,4-g][1,3]oxazocin-1(14H)-one (30)
LC-MS (APCI+) m/z 502 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 7.89 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 8.4 Hz,
2H), 7.60-7.69 (m, 4H),7.48-7.50 (m, 3H),7.25-7.32 (m, 3H),7.02-7.06 (m, 1H), 6.80 (t, J
= 7.8 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 5.23 (s, 1H), 3.85 (s, 1H), 3.76 (s, 3H), 1.03 (s,
3H), 1.02 (s, 3H).
74
8-(4'-Methoxy-[1,1'-biphenyl]-3-yl)-2,15,15-trimethyl-2,8,9,14-tetrahydro-1H-8,14methanobenzo[4,5][1,3]oxazocino[7,8-c]quinolin-1-one (31)
LC-MS (APCI+) m/z 514 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 8.05 (d, J = 8.1 Hz, 1H), 7.95 (s, 1H), 7.75 (d,
J = 7.5 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.51-7.58 (m, 4H),7.19-7.32 (m, 3H),7.00-7.03
(m, 3H), 6.75 (t, J = 14.7 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 5.18 (s, 1H), 4.06 (s, 1H),
3.86 (s, 3H), 3.68 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H).
12-Methoxy-8-(4'-methoxy-[1,1'-biphenyl]-3-yl)-2,15,15-trimethyl-2,8,9,14tetrahydro-1H-8,14-methanobenzo[4,5][1,3]oxazocino[7,8-c]quinolin-1-one (32)
LC-MS (APCI+) m/z 545 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 7.95 (d, J = 8.6 Hz, 1H), 7.88 (s, 1H), 7.67 (d,
J = 7.8 Hz, 1H), 7.41-7.57 (m, 6H),7.12-7.23 (m, 1H), 7.10 (d, J = 4.2 Hz, 1H ), 6.94 (d,
J = 8.7 Hz, 1H ), 6.72 (d, J = 4.5 Hz, 1H ), 6.53 (dd, J = 2.7 Hz, 2,7Hz, 1H), 6.44 (d, J =
8.4 Hz, 1H), 4.92 (s, 1H), 3.95 (s, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 3.60 (s, 3H), 0.96 (s,
3H), 0.90 (s, 3H).
13
C NMR (75.474 MHz, CDCl3), δ (ppm) 162.3, 159.2, 155.7, 152.7, 140.6, 139.8,
138.6, 134.1, 130.5, 128.5, 127.3, 126.3, 123.4, 121.7, 116.2, 116.1, 114.5, 114.3, 114.1,
113.4, 113.0, 111.2, 97.2, 94.8, 77.6, 77.2, 76.8, 56.0, 55.6, 42.5, 33.0, 29.6, 29.4, 23.2,
22.4.
75
12-Methoxy-8-(4'-methoxy-[1,1'-biphenyl]-3-yl)-15,15-dimethyl-8,9-dihydro-8,14methanobenzo[d]chromeno[3,4-g][1,3]oxazocin-1(14H)-one (33)
LC-MS (APCI+) m/z 532 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 7.85-7.91 (m, 3H), 7.64-7.72 (m, 2H), 7.487.58 (m, 4H), 7.25-7.31 (m, 2H), 7.10 (d, J = 2.7 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 6.65
(dd, J = 2.7 Hz, 2.1 Hz, 1H), 6.55 (d, J = 9.0 Hz, 1H), 5.05 (s, 1H), 3.87 (s, 3H),3.85 (s,
1H), 3.78 (s, 3H), 1.05 (s, 3H), 1.02 (s, 3H).
12-Methoxy-8-(4'-methoxy-[1,1'-biphenyl]-4-yl)-2,15,15-trimethyl-2,8,9,14tetrahydro-1H-8,14-methanobenzo[4,5][1,3]oxazocino[7,8-c]quinolin-1-one (35)
LC-MS (APCI+) m/z 545 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 8.06 (d, J = 8.7 Hz, 2H),7.84 (d, J = 7.8 Hz,
3H), 7.39-7.67 (m, 4H), 7.18-7.32 (m, 2H), 7.01-7.04 (m, 2H), 6.60 (dd, J = 2.7 Hz, 2.1
Hz, 1H), 6.52 (d, J = 7.8 Hz, 1H), 4.96 (s, 1H), 4.02 (s, 1H), 3.88 (s, 3H), 3.78 (s, 3H),
3.68 (s, 3H), 1.03 (s, 3H), 0.97 (s, 3H).
76
8-([1,1'-Biphenyl]-4-yl)-12-methoxy-2,15,15-trimethyl-2,8,9,14-tetrahydro-1H-8,14methanobenzo[4,5][1,3]oxazocino[7,8-c]quinolin-1-one (36)
LC-MS (APCI+) m/z 515 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 8.06 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.5 Hz,
2H), 7.69 (t, J = 15.9 Hz, 3H), 7.47-7.53 (m, 3H), 7.40-7.42 (m, 2H), 7.19-7.32 (m, 3H),
6.61 (dd, J = 2.4 Hz, 1.8 Hz, 1H), 6.52 (d, J = 8.7 Hz, 1H), 4.97 (s, 1H), 4.02 (s, 1H),
3.78 (s, 3H), 3.68 (s, 3H), 1.03 (s, 3H), 0.98 (s, 3H).
12-Methoxy-8-(4'-methoxy-[1,1'-biphenyl]-4-yl)-15,15-dimethyl-8,9-dihydro-8,14methanobenzo[d]chromeno[3,4-g][1,3]oxazocin-1(14H)-one (37)
LC-MS (APCI+) m/z 532 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 7.70-7.82 (m, 2H), 7.51-7.64 (m, 3H), 7.42 (t,
J = 13.8 Hz, 3H), 7.20-7.23 (m, 3H), 7.02 (d, J = 3.0 Hz, 1H), 6.90-6.96 (m, 1H), 6.56
(dd, J = 2.1 Hz, 2.3 Hz, 1H), 6.47 (d, J = 8.7 Hz, 1H), 4.96 (s, 1H), 3.81 (s, 3H), 3.78 (s,
1H), 3.72 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H).
77
8-(4'-Methoxy-[1,1'-biphenyl]-3-yl)-15,15-dimethyl-8,9-dihydro-8,14methanobenzo[d]chromeno[3,4-g][1,3]oxazocin-1(14H)-one (38)
LC-MS (APCI+) m/z 502 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 7.86-7.91 (m, 3H), 7.59-7.70 (m, 4H), 7.487.57 (m, 4H), 7.26-7.28 (m, 2H), 7.01-7.03 (m, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.62 (d, J
= 7.5 Hz, 1H), 5.24 (s, 1H), 3.87 (s, 3H), 3.42 (s, 1H), 1.06 (s, 3H), 1.04 (s, 3H).
78
Compound 13
79
80
81
Compound 21
82
83
84
Compound 34
85
86
87
Compound 27
88
Compound 28
89
90
Compound 29
91
92
Compound 30
93
94
Compound 31
95
96
Compound 32
97
98
99
Compound 33
100
101
Compound 35
102
103
Compound 36
104
105
Compound 37
106
107
Compound 38
108
109
APPENDIX D
SUPPORTING INFORMATION AND PRODUCT CHARACTERIZATION FOR
CHAPTER 3.4
6-Amino-4-(3-perfluooctanesulfonyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5carbonitrile (43)
LC-MS (APCI+) m/z 750.
110
Compound 43
111
4-(3-Perfluooctanesulfonyl)-3,7-dimethyl-4,6-dihydropyrazolo[4',3':5,6]pyrano[2,3-d
]pyrimidin-5(2H)-one (47)
LC-MS (APCI+) m/z 792.
112
Compound 47
113
6-Amino-4-(4-bromophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonit
rile (50)
LC-MS (APCI+) m/z 330 [M+1]+.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 8.21 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 8.4 Hz,
1H), 4.61 (s, 1H), 7.66(s, 2H), 5.32 (s, 1H), 2.49(s, 3H).
114
Compound 50
115
116
4-(4-Bromophenyl)-3,7-dimethyl-4,6-dihydropyrazolo[4',3':5,6]pyrano[2,3-d]pyrimi
din-5(2H)-one (51)
LC-MS (APCI+) m/z 373 [M+1]+.
117
Compound 51
118
APPENDIX E
SUPPORTING INFORMATION AND PRODUCT CHARACTERIZATION FOR
CHAPTER 3.5
Dimethyl 4-(3-perfluorooctanesulfonyl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylate (53)
LC-MS (APCI+) m/z 799.
119
Compound 53
120
Dimethyl 4-(3-perfluorooctanesulfonyl)-2,6-dimethylpyridine-3,5-dicarboxylate (57)
LC-MS (APCI+) m/z 797.
121
Compound 57
122
123
APPENDIX F
SUPPORTING INFORMATION AND PRODUCT CHARACTERIZATION FOR
CHAPTER 3.6
4-(3- Perfluorooctanesulfonyl)-3,7,7-trimethyl-6,7,8,9-tetrahydroisoxazolo[5,4b]quinolin-5(4H)-one (65)
LC-MS (APCI+) m/z 806.
1
H NMR (300.128 MHz, CDCl3), δ (ppm) 7.89 (d, J = 7.8 Hz, 1H), 7.26-7.38 (m, 1H),
7.19 (s, 1H), 7.08 (d, J = 2.1 Hz, 1H), 5.18 (s, 1H), 2.42 (d, J = 2.2 Hz, 2H), 2.23 (d, J =
3.0 Hz, 2H), 1.95 (s, 3H), 1.43 (s, 3H), 1.02 (s, 3H).
124
Compound 65
125
126
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