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Environmentally friendly microwave enhanced syntheses of important cyclic imides and their derivatives

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E N V IR O N M E N T A L L Y FR IE N D L Y M IC R O W A V E E N H A N C E D
S Y N T H E S E S O F IM P O R T A N T C Y C LIC IM ID E S A N D T H E IR
D E R IV A TIV E S
by
Ellis T. Benjamin
A Dissertation Submitted in Partial Fulfillment
of the Requirements for the Degree
Doctor of Philosophy
M O R G A N STA TE U N IV E R S IT Y
M ay 200 7
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UMI N um ber: 3258457
Copyright 2007 by
Benjamin, Ellis T.
All rights reserved.
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ABSTRACT
Title of Dissertation:
E N V IR O N M E N T A L L Y F R IE N D L Y
M IC R O W A V E E N H A N C E D S Y N T H E S E S OF
IM P O R T A N T C Y C LIC IM ID E S A N D T H E IR
D E R IV A TIV E S
Ellis T. Benjamin, Doctor of Philosophy,
M ay 2007
Dissertation advisor:
Yousef Hijji Ph.D.
Departm ent of Chemistry
The developm ent of efficient environmentally friendly techniques is
a desired objective in organic chemistry. The application of microwaves in
organic synthesis provides excellent benefits; while being green chemistry
it is efficient and
simple.
The
application
of microwaves for the
manufacture of important moieties such as cyclic imides, their derivatives,
thalidomide and its analogues, and enaminones and its derivatives are the
objectives of this study.
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The synthesis of the cyclic imides starts with cyclic anhydrides,
such as substituted succinic anhydride obtained via the solventless
m icrowave-enhanced
Diels-Alder reaction of m aleic anhydride.
The
nitrogen source utilized ammonium salts such as ammonium chloride
(N H 4 CI),
ammonium
acetate
(N H 4 OAc),
hydroxylamine
hydrochloride
(N H 2 O H /H C I) and A/-methoxyamine hydrochloride (N H 2 O C H 3 /HCI).
The use of multimode microwave and the monomode microwave
with controlled temperature, pressure, and microwave power provided a
comparison between the two available types of microwave ovens.
The
strategy used N H 4CI in the presence of dimethylaminopyridine (D M A P) as
a base, which seem ed to be efficient in providing the unsubstituted cyclic
imides within minutes.
Another alternative is ammonium acetate, which
reacted without the addition of the base and provided the cyclic imides in
shorter time in com parable yields under the microwave conditions. W hile
A/-hydroxy
imides
unsubstituted
protocol.
w ere
not obtained
in good
cyclic imides were achieved
yields
in good
using
yield
DMAP,
using this
Analogously, /V-methoxy cyclic imides w ere acquired from N-
methoxyamine, hydrochloride/ DMAP.
In application of this strategy to compounds of importance, the
synthesis of thalidomide and its analogues was a focus of this study and
were achieved
ammonium
in good yield
chloride,
and
using cyclic anhydride,
DM AP
in
a
one-pot
glutamic acid,
reaction
under the
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solventless conditions developed. Another application w as the synthesis
of enam inones
and
its derivatives
from
1,3-cycloalkanediones
and
ammonium acetate in the soventless conditions which w ere obtained in
excellent yields.
This study provided efficient, easy, eco-friendly synthetic methods
to a variety of cyclic imides,
A/-methoxyimides, thalidomide and
its
analogues, enaminones and its derivatives that can be of value for the
synthesis of natural products and pharmaceutical drugs.
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ENVIRONMENTALLY FRIENDLY MICROWAVE ENHANCED
SYNTHESES OF IMPORTANT CYCLIC IMIDES AND THEIR
DERIVATIVES
by
Ellis T. Benjamin
has been approved
February 2007
DISSERTATION COMMITTEE APPROVAL:
Chair
I'ousef Hljji, PKD.
Santosh Mandal, Ph.D.
■j
C i
Arthur L. Williams, Ph.D.
LaVentrice Taylor, P
MauriceJwunze, Pn.D
Oladapo Bakare, Ph.D
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D E D IC A TIO N
This work is dedicated to God, Jon Fletcher Ellis Cummings, Daisy
Bell Jeffers,
Earl
Benjamin
Sr.,
Mabel
Reynolds,
Earl
Benjamin
Jr.,
Gertrude Benjamin, Earl Benjamin III, Ericka Benjamin, Benjamin Samuel
Schottenfeld, Alexander Jon Schottenfeld and to all of those who have lifted
m e high enough to touch the sky.
I would
like to give a special
acknowledgem ent to Earl Benjamin III for his dedication.
W ords cannot
express w hat you m ean to me, you really are the best part of me. For this
and so much more, I thank you.
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ACKNOW LEDG EM ENTS
I would like to acknowledge Dr. Yousef Hijji for his support and
guidance of m e during a very difficult time in my life. W ithout you, I do not
believe I would have ever graduated from this program. I would also like to
acknowledge my parents Earl Benjamin Jr. and Gertrude CummingsBenjamin for all their financial support.
and the R C M I (N IH ) Grant (R R 17581).
I would like to also thank Title III
I would also acknowledge the
special teachers and instructors who have guided m e through my education
specifically, Dr. M andal, Dr. Sowers, Dr. W asfi, and Dr. Johnson.
I would
also like to thank Dr. Rogers Barlatt, Dr. Williams, Dr. Iwunze, Dr. Taylor,
Dr. Bakare, and Dr. Franklin O. Smith who showed me w hat it m eans to be
a black professor.
Your dignity and dedication to your student gave me
something to aspire to.
I would also like to give a special thank you to Mr.
Samuel Dublin. Mr. Dublin you were always there when I needed you. You
gave so much of yourself to me and other students.
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TABLE O F C O N T E N T S
T O P IC _____________________________________________________ PA G E NO.
List of Tables
viii
List of Figures
ix
List of Schem es
x
List of Abbreviations
xii
Structures of Compounds Used or Synthesized in
This W ork
Chapter I:
Introduction
Introduction to the Problem
Specific Aims
G reen Chemistry and Environmental Toxicology
Environmental and Biological Toxicology
Solvent W aste as Pollutants
Techniques to Decrease Pollution from Solvent W aste
Introduction to Microwave Radiation
Introduction to Microwave Chemistry
Introduction to Microwave Organic Chemistry
Multimode and Monomode Microwave Instruments
Microwave Reactions
Cyclic Imides
Importance of Cyclic Imide Moieties
Unsubstituted Cyclic Imides
Bicyclic Dicarboxylic Acid Anhydrides
A/-Hydroxy Cyclic Imides
A/-Methoxy Cyclic Imides
Thalidom ide and its Derivatives
Cyclic Enam inones
Enam inone - Imide Conjugates
Problems with the Current Conventional Synthesis
of Cyclic Imides
The Use of Harmful Solvents
Complicated Reactions and W orkup
Long Reaction Tim es
T he Use of Lewis Acids as Catalyst
Synthetic Improvements of Microwave
Enhanced Synthesis
Solventless Systems
v
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xiii
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Improved Reaction Conditions
Decreased Reaction Tim es
Dissertation Research
Chapter II:
R E S U LTS
Microwave Synthesis of Bicyclic Anhydrides
Multimode Synthesis of Bicyclic Anhydrides
M onom ode Microwave Synthesis of Bicyclic Anhydrides
Microwave Synthesis of Unsubstituted Cyclic Imides
Multimode Microwave Synthesis of Cyclic Imides
D M A P /N H 4 CI
M onom ode Microwave Synthesis of Cyclic Imides
D M A P /N H 4 CI
Multimode Microwave Synthesis of Cyclic Imides
N H 4 O Ac
M onom ode Microwave Synthesis of Cyclic Imides
NH 4 O Ac
Multimode Microwave Synthesis of Cyclic Imides
N H 2 O H (H C I)
M onom ode Microwave Synthesis of Cyclic Imides
N H 2 O H (H C I)
Microwave Synthesis of N -Methoxy Cyclic Imides
Multimode Microwave Synthesis of N -Methoxy
Cyclic Imides
M onom ode Microwave Synthesis of A/-Methoxy
Cyclic Imides
Microwave Synthesis of Thalidomide and Derivatives
Multimode Microwave Synthesis of Thalidomide and
Derivatives
M onom ode Microwave Synthesis of Thalidomide and
Derivatives
Comparison of Thalidomide Microwave Synthetic
Techniques
M icrowave Synthesis of Cyclic Enaminones
Multimode Microwave Synthesis of Cyclic Enam inones
M onom ode Microwave Synthesis of Cyclic Enam inones
Microwave Synthesis of Enoneimides
Multimode Microwave Synthesis of Enoneimides
M onom ode Microwave Synthesis of Enoneimides
vi
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Chapter III:
D IS C U S S IO N
The M icrowave Assisted Diels-Alder Synthesis of Cyclic
Anhydrides
The Synthesis of Unsubstituted Cyclic Imides
Unsubstituted Cyclic Imides from DM AP,
Ammonium Chloride, Cyclic Anhydrides
Unsubstituted Cyclic Imides from Ammonium Acetate
and Cyclic Anhydrides
The Reaction of Hydroxylamine(HCI) and
Cyclic Anhydrides
Structural Identification of Unsubstituted Cyclic Imides
Advantages and Comparison of the Three Novel
Techniques for the Synthesis of Unsubstituted
Cyclic Imides
The M icrowave Synthesis of N-M ethoxy Cyclic Imides
The M icrowave Synthesis of Thalidomide and
its Analogs
The M icrowave of Cyclic Enaminones
The Synthesis of Enaminone Imide Conjugates
Conclusions about the Microwave Synthesis of
Cyclic Imides and their Derivatives
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1 0 2
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107
Chapter IV:
M A TE R IA L A N D M E TH O D S
Material and Methods
Monom ode Discover Param eters
Shim adazu G C M S Param eters
Varian G C M S Param eters
109
109
Chapter V:
E X P E R IM E N T A L
117
Chapter VI:
REFERENCES
159
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LIST OF TABLES
PAGE NO.
TABLE
1. Multimode M icrowave Synthesis of Bicyclic Anhydrides
2. Monom ode Microwave Synthesis of Anhydrides
3. Multimode M icrowave Synthesis of Unsubstituted Imides
D M A P /N H 4 CI
4. Monom ode Synthesis of Unsubstituted Imides Using D M A P and
N H 4 CI
5. Multimode Synthesis of Unsubstituted Imides Using N H 4O Ac
6 . Monom ode Synthesis of Unsubstituted Imides Using N H 4OAc
7. Multimode Synthesis of Unsubstituted Imides Using
N H 2 O H (H C I) and DM A P
8 . Monom ode Synthesis of Unsubstituted Imides Using
N H 2 O H (H C I)
9. Multimode Synthesis of Unsubstituted Imides Using
NH 2 O C H 3 (HCI)
10.Monom ode Synthesis of Unsubstituted Imides Using
NH 2 O C H 3 (HCI) at 5 min and 125 °C
11.Monom ode Synthesis of Unsubstituted Imides Using
NH 2 O C H 3 (HCI) at 7 min and 180 °C
12. Multimode Microwave Synthesis of Thalidomide
Derivatives
13. Monom ode Microwave Synthesis of Thalidomide
Derivatives
14. Comparison of Thalidomide Synthesis using Phthalic Anhydride
and Glutam ic Acid, with D M A P /N H 4 CI, N H 4 OAc, and Thiourea
in the Multimode Microwave
15. Comparison of Thalidomide Synthesis using Phthalic Anhydride
and Glutam ic Acid with DMAP/NH4CI, NH4OAC, and Thiourea
in the M onom ode Microwave
16. Multimode Microwave Synthesis of Cyclic Enam inones
17. Monomode Microwave Synthesis of Cyclic Enam inones
18. Multimode Microwave Synthesis of Enoneimides
19. Monomode Microwave Synthesis of Enoneimides
20. 1H and 13C N M R Signals for the Bicyclic Carboxylic Acid
Anhydrides
21. - N H - Proton shift difference using DM SO -c /6 and C D C I 3
viii
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LIST OF FIGURES
FIGURE
PAGE NO.
1. Structures of Cyclic Anhydrides and Unsubstituted Imides
2. Structures of Cyclic N-Methoxyim ide and Thalidomide Analogs
3. Structures of Enaminones, Enaminone Imide Conjugates and
1,3-diketones
4. Som e Comm on Harmful Solvents
5. Electromagnetic Spectrum
6 . Microwave Oven Diagram
7. The Rotational Motion of Molecules under Microwave Irradiation
8 . The Translational Motion of Molecules under Microwave
Irradiation
9. The Structure of Cyclic Imides
10. Important Cyclic Imide Moieties
11. The G eneral Structure of Unsubstituted Cyclic Imides
12. The G eneral Structure of Bicyclic Dicarboxylic Acid Anhydrides
13. The G eneral Structure of A/-Hydroxy Cyclic Imides
14. The Structure of Flutimide
15. The G eneral Structure of A/-Methoxy Cyclic Imides
16. The Structure of Thalidomide
17. The G eneral Structure of Cyclic Enaminones
18. The G eneral Structure of Enaminone - Imide Conjugates.
19. The O R T E P structure of c/'s-1,2-Cyclobutanedicarboximide
20. The O R T E P structure of 1-Methoxy-pyrrolidine-2,5-dione
21. The O R T E P structure of 3-Am ino-2-cyclopenten-1-one
ix
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94
105
LIST OF SCHEMES
SCHEMES
1.
2.
3.
4.
5.
6 .
7.
.
9.
10.
11.
8
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
PAGE NO.
General M icrowave Imides Synthesis
Microwave Michael Addition Reaction
Microwave Acridine Reaction
Microwave Barbiturate Reaction
Cyclic Imide Synthesis using Ammonia and Cyclic Anhydrides
Cyclic Imide Synthesis using amide-acid with (C D I) and D M A P
Cyclic Imide Synthesis using Diacid Chlorides with Lithium
Nitride
Cyclic Imide Synthesis using Urea and Thiourea
Cyclic Imide Synthesis using Formamide
Cyclic Imide Synthesis using Urea and Glutaric Acid
Cyclic Imide Synthesis using Potassium Cyanide and 1,3Dibromopropane
Cyclic Imide Synthesis using 1,3-dicyanopropane
Microwave Cyclic Imide Synthesis using Benzonitrile
Microwave Cyclic Imide Synthesis using Cyclic Anhydrides
and Cyanate/Thiocyanate
Conventional N-Methoxyim ide Synthesis using AlkylHalide
Conventional N-Methoxyimide Synthesis using Methoxyam ine
Conventional Thalidom ide Synthesis using Glutamine and
Phthalic Anhydride
Conventional Thalidomide Synthesis using a Protected
Glutamine and Phthalic Anhydride
Conventional Thalidomide Synthesis using a Protected
Glutamine and Phytolglutamine
Conventional Thalidomide Synthesis using a Glutamic
Anhydride and Phthalic Anhydride
Microwave Thalidom ide Synthesis using Glutamic Acid,
Phthalic Anhydride, and Urea and Thiourea
Thalidomide Derivatives Synthesis using Glutamic Acid
and Substituted Phthalic Anhydride
Conventional Enaminone Synthesis using Ammonium Acetate
Conventional Enaminone Synthesis using Am m onia
Conventional Enaminone Synthesis using H2/Pd with KOH
Microwave Enam inone Synthesis
The Microwave Diels-Alder Synthesis
Mechanism Unsubstituted Cyclic Imides Synthesis using
Am m onia
Microwave Cyclic Imide Synthesis using DM A P and N H 4CI
Unsubstituted Cyclic Imides Synthesis Mechanism using
x
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31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
DM AP and N H 4CI
Microwave Cyclic Imide Synthesis using N H 4O Ac
Cyclic Imide formation Mechanism using N H 4OAc
N-Hydroxy Cyclic Imide Formation Mechanism
Alternate Mechanism s for the Hydroxylamine and Cyclic
Anhydride
The Synthesis of A/-Methoxyimides using M ethoxyam ine(HCI)
Thalidom ide and its Derivatives Synthesis
M echanism s of Thalidomide and its Derivatives Formation
Possible M echanism s of Thalidomide and its Derivatives
Synthesis
The Synthesis of Cyclic Enaminones using N H 4OAc
The Mechanism of Cyclic Enaminones Formation using
76
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NH4OA c
104
106
41. The Microwave Synthesis of Enoneimides Conjugate
xi
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LIST OF ABBREVIATIONS
A B B R E V IA TIO N
FULL W O R D
CDI
OEM
Con
Dioxane
DM AP
DM F
DM A
Enoneimides
EPA
KOH
M eO H
Mono
MW
N H 4 CI
N H 4 OAc
N H 2 O H (H C I)
N H 2 O C H 3 (HCI)
OSHA
TH F
’-carbonyldiimidazole
C E M Discover Monom ode Microwave
Multimode Microwave
1,4-Dioxane
4-A/,A/-Dimethylaminopyridine
A/,A/-Dimethylformamide
A/,A/-Dimethylacetamide
Enaminone Imide Conjugates
Environmental Protection Agency
Potassium Hydroxide
Methanol
Monomode Microwave
Microwave
Ammonium Chloride
Ammonium Acetate
Hydroxylamine Hydrochloride
Methoxyamine Hydrochloride
Occupational Safety and Health Administration
Tetrahydrofuran
TNFa
Tum or Necrosis Factor alpha
1 ,1
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Structures of Compounds Used or Synthesized in This Work:
.0
"f
Y
(D o
°
encfo-Bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride
1-lsopropyl-4-methyl-encfo-bicydo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride
O
O
NH
O
(3)
Succinimide
.0
O
(I)
3a,4,5,6,7,7a-Hexahydro-1H-isoindole-1,3(2H)-dione
NH
O
" 'f
(4 )
Phthalimide
(5)
H
VN
H
O
3a,4,7,7a-Tetrahydro-4,7-ethano-1H-isoindole-1,3(2H)dione
U
(5)
Glutarimide
O
AN
HN
3a,4,7,7a-Tetrahydro-4-isopropyl-7-methyl-4,7-Ethano-1
H-isoindole-1,3(2H)-dione
(6 )
c/s-1,2-Cyclobutanedicarboximide
Figure 1. Structures of Cyclic Anhydrides and Unsubstituted Imides
xiii
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( 10 )
2-Methoxy-isoindole-1,3-dione
(1Z) °
O
1-lsopropyl-4-methoxy-7-methyl-4-aza-tricyclo[
5.2.2.02,6]undec-8-ene-3,5-dione
N -0
CH3
a ir
1-Methoxy-piperidine-2,6-dione
NH
.0
( 18)
N-q
CH3
2-(2,6-Dioxo-piperidin-3-yl)-isoindole-1,3-dione
(12) O
2-Methoxy-hexahydro-isoindole-1,3-dione
NH
S \
o
( 19)
2-(2,6-Dioxo-piperidin-3-yl)-hexahydro-isoindole-1,3-dione
'CH3
(12)
1-M ethoxy-pyrrolidine-2,5-dione
O
NH
N -O
^
CH3
(20)
O
(14 )
3-(2,6-Dioxo-piperidin-3-yl)-3-aza-bicyclo[3.2.0]heptane-2,4-dione
3-Methoxy-3-aza-bicyclo[3.2.0]heptane-2,4-dione
f
NH
"rN"?
(15 )
O
(21)
CH3
3-(2,5-Dioxo-pyrrolidin-1-yl)-piperidine-2,6-dione
4-Methoxy-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione
N02
o
u
ch3
(16 )
(2 2 )
o
2-Methoxy-4-nitro-isoindole-1,3-dione
4-(2,6-Dioxo-piperidin-3-yl)-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3
,5-dione
Figure 2. Structures of Cyclic N-Methoxyimide and Thalidom ide Analogs
xiv
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(2 3 )
3-Amino-cyclohex-2-enone
( 29 )
3-(5,5-Dimethyl-3-oxo-cyclohex-1-enyl)-3-aza-bicyclo[3.2.0]heptane-2,4-dione
H2 N^
O
N
( 24 )
3-Amino-5,5-dimethyl-cyclohex-2-enone
O
h2 n ^ ^ _ o
(30 )
2-(5,5-Dimethyl-3-oxo-cyclohex-1-enyl)-hexahydro-isoindole-1,3-dione
( 25 )
3-Amino-cyclopent-2-enone
0
H2 N -~^n^O
>
(31)
Cyclohexane-1,3-dione
( 26 )
3-Amino-2-methyl-cyclopent-2-enone
,0
N
( 32)
5,5-Dimethyl-cyclohexane-1,3-dione
O
( 27)
;0
1-(5,5-Dimethyl-3-oxo-cyclohex-1-enyl)-pyrrolidine-2,5-dione
( 33 )
Cyclopentane-1,3-dione
O
N
O
(28 )
2-(5,5-Dimethyl-3-oxo-cyclohex-1 -enyl)-isoindole-1,3-dione
( 34 )
2-M ethyl-cyclopentane-1,3-dione
Figure 3. Structures of Enaminones, Enaminone Imide Conjugates, and
1,3-diketones
xv
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I. IN T R O D U C T IO N
Introduction to the Problem
R ecent acknowledgements of the harmful effects of pollutants have
led the United States governm ent to enact the W ater Pollution Control Act
(W P C A ) of 1972 and Pollution Prevention Act (PPA ) of 1990, which
established national policies to prevent or reduce pollution at its source
w henever feasible .
1 ,2
Currently, the largest amount of harmful pollutants
stems from industrial processing and manufacturing . 3 O ne w ay scientists
endeavor to decrease the large am ount of harmful pollutants released into
the environment is by the introduction of “green chemistry.”
Green
chemistry is the use of chemical techniques to limit or eliminate the
release of environmentally and biologically harmful pollutants into the
environm ent . 4
Solventless m icrowave-enhanced synthesis has recently
been found to be a novel green chemical process that has been able to
limit the use of harmful solvents in many industrial processes.
microwave-enhanced
chemistry
has been
Although
used to synthesize
many
functional groups, other important syntheses have yet to be explored.
O ne such functional group, that is of interest, is that of cyclic imides
and their derivatives.
Cyclic imides and their derivatives are important
moieties used in many fields of science and industrial manufacturing. An
1
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application of microwave-enhanced synthesis as a green chemical method
to the synthesis of cyclic imides would contribute to reduction of harmful
pollutants.
Specific Aims
In view of the importance of cyclic imides and their derivatives, and
the developm ent of microwave organic synthesis, it is surprising that only
a few reports have appeared in the literature addressing their expeditious
synthesis.
The
overall goal of this project was to develop
solventless
microwave-assisted
organic
syntheses
as
techniques to produce cyclic imides and their derivatives.
novel
eco-friendly
The specific
aims of this dissertation are:
1.
The use of solventless microwave-enhanced synthesis to replace
conventional
methods,
and
thereby
reduce
the
release
of
synthesis
of
environmentally harmful solvents.
2.
The
introduction
of
efficient
methods
for
the
unsubstituted, N -hydroxy, N -methoxy cyclic imides of important
applications for the synthesis of many biological, photochemical,
and polymeric materials.
3.
The m icrowave-enhanced synthesis of thalidomide, thalidomide
analogs, enaminones, and enaminone imide conjugates.
2
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Green Chemistry and Environmental Toxicology
The concept of "green chemistry" has been widely adopted to m eet
the fundam ental scientific challenges of protecting human health and the
environment, while simultaneously achieving commercial viability . 5 Green
chemical processes have as their goal the minimization of hazardous
conditions while providing similar product yields. O ne of the thrusts for
achieving this target is to explore alternative reaction conditions and
reaction m edia to accomplish the desired chemical transformations with
minimum byproducts and waste generation . 6 ,7 ,8 ,9
Although the manufacturing of new materials has helped advance
our society overall, several major dilemmas accom pany the wide-scale
production and use of these materials.
material
storage
and
breakdown,
Problems such as innate effects,
waste
removal/remediation,
and
excessive costs are often concerns which plague society in the fabrication
and use of these materials.
O ne major problem is the release of harmful byproducts and
solvents
into
our
environment
manipulation of these materials.
from
the
production,
isolation,
and
Solvents such as trichloroethylene,
dichloromethane, chloroform, ethyl ether, dioxane, and benzene are found
throughout the literature for the synthesis of many organic m aterials . 10,11
3
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However, these chemicals have also been found to be environmental
toxicants.
Environmental and Biological Toxicology
Often, solvents such as dichloromethane, dioxane, and benzene
are regarded as environmentally and biologically harmful materials (Figure
4).
The toxic effects of these solvents are well documented in the
literature and have been shown to be detrimental to the environment.
Recent studies found that common
dichloromethane
microorganisms . 1 2
elicited
severe
solvents such
side
effects
on
as acetone and
indigenous
soil
Another study found that the introduction of benzene
and similar arom atic compounds were able to kill or disrupt the function of
m ethanogens,
M ethanosaeta
concilii GP6,
Methanospirillum hungatei
G P 1 , Methanobacterium espanolae GP9, and Methanobacterium bryantii,
which are used for the environmental breakdown of toxic waste (i.e.,
bioremediation ) . 1 3
Heavy metals and hydrocarbons have been found to
disrupt chemotaxis of marine organisms . 14
4
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<-H3
h
1) /V,/V-Dimethylacetamide
ch 3
2) A/,/V-Dimethylformamide
o
o.
Cl
O
3) Dichloromethane
5) Dioxane
4) Benzene
Figure 4. Som e Common Harmful Solvents
Although the detrimental effects of organic solvent waste in the
environment are of note, the greatest impacts have been found on
biological systems.
increase
virus
Studies have indicated that certain solvents may
penetration,
reduce
interferon,
and
disrupt
immunity
response leading to increased morbidity . 1 5 It also has been demonstrated
that solvents such as trichloroethylene caused connective tissue diseases
such as, systemic sclerosis, scleroderma, undifferentiated connective
tissue disease, systemic lupus erythematosis, and rheumatoid arthritis
with the m ajor focus on systemic sclerosis . 1 6 Benzene (Figure 4) has been
found to react with DNA to form benzetheno adducts which promote the
breaking of DN A leading to cancerous conditions . 1 7
Dichloromethane
(methylene chloride) has been associated with carcinogenic potential,
corneal
thickening,
cytomegaly,
intraocular
cytoplasmic
tension,
vacuolization,
inflammation, and bile duct fibrosis . 1 8 ,1 9 ,2 0 ,2 1
hepatic
hemosiderosis,
necrosis,
granulomatous
Laboratory studies show that
5
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prolonged exposure to dioxane causes cancer in anim als . 2 2 Additionally,
studies indicated that repeated exposure to large amounts of dioxane in
drinking water, air, or on the skin causes liver and kidney dam age in
anim als . 2 3
Although these materials have been found to be harmful to both
biological and environmental sources, they are commonly used throughout
multiple industries.
Specifically, dichloromethane is currently used as a
solvent in paint removal, degreasing agents, aerosol propellants, triacetate
solutions, as a process solvent in the m anufacture of steroids, antibiotics,
vitamins, and tablet coatings and as an extraction solvent for spice
oleoresins, hops, and caffeine . 1 6
the
pharmaceutical
industry
Dioxane is a commonly used solvent in
for
the
synthesis
of
necessary
interm ediates . 2 4
Solvent Waste as Pollutants
The scale of the solvent production and w aste released into
environment is in the millions of pounds per year. Dioxane as an example
is commonly produced between
1 0
million and 18 million pounds a year by
three companies in the United States . 3
Much of the concern about
dioxane waste in the United States is focused on air and w ater stores,
because it is a liquid that does adhere to soil, and easily evaporates or
6
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enters the groundwater. O f the total 1.13 million pounds of dioxane
released
into the
U.S.
environment in 1992, 6 8 0 ,0 0 0
pounds were
released into the atmosphere, 4 5 0 ,00 0 pounds were released into surface
waters,
and
3,300
w ere
released
onto the
land . 3
Dioxane
at a
concentration of 1 microgram/L has been detected in drinking w ater in the
U.S. (no specific locations given); the chemical was detected in 37% of
well w ater sam ples collected near a solid waste landfill located 60 miles
southwest of Wilmington, DE. dioxane at 1 microgram/L was detected in
the Chicago Sanitary and Ship Channel . 3
With the understanding of the toxic nature of these solvents, the
United States Occupational Safety and Health Administration (O SHA)
established exposure limits for many commonly used solvents.
For
exam ple, the O S H A permissible exposure limit for dioxane is 100 parts
per million of air (ppm) as an
8
-hour time-weighted average.
Although
acute toxicity is rare for dioxane, the National Institute for Occupational
Safety and Health (N IO S H ) set contact limits at 1 ppm or 3.6 m g/m 3 for a
30
minute
exposure . 2 5
The
American
Conference
of Governmental
Industrial Hygienists (A C G IH ) set the contact limit for dioxane at 25 ppm
or 90 m g/m 3 . 2 6
M any synthetic processes used for the manufacturing of numerous
materials are often the responsibility of organic chemists.
As scientists,
7
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synthetic organic chemists manipulate carbon based molecules under
specific
conditions
pharmaceuticals.
synthesize and
to
form
materials
ranging
from
plastics
to
Often, these manufacturing processes use solvents to
isolate the desired materials from starting reactants
through final purification and packing, leading to the loss of solvents and
byproducts as waste. This large am ount of waste has encouraged many
synthetic organic chemists to search for new and novel techniques for the
elimination of solvents in organic reactions while maintaining high product
yields.
Techniques to Decrease Pollution from Solvent Waste
Currently there are several remediation methods used to decrease
the large amounts of harmful pollutants. Remediation techniques such as
electrochem ical , 2 7
ultrasound , 2 8
bioremediation , 2 9
phytoremediation , 3 0
activated carbon , 31 and microwave 3 2 are currently being used to remove
harmful waste from the environment.
M any of these techniques focus on
the breakdown of harmful materials into innocuous products such as
hydrocarbons.
Even more effective is the exclusion of these harmful chemicals
from chemical reactions, which is a far more important remedy for solvent
waste as compared to remediation techniques. Novel techniques such as
8
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solid
state
chemistry , 3 3
photochemistry , 3 4
sonic
chemistry , 3 5
and
microwave chemistry 3 6 are currently used as alternatives to conventional
organic syntheses. The advantages of these techniques have been found
to increase reaction yield, decrease energy input, decrease reaction time,
synthesize desired stereoselective products and reduce or eliminate the
solvent waste commonly found in the classical synthetic processing of
m aterials .
3 7 '3 8 3 9
Recent
decrease
advances
or eliminate
have
the
shown
need
for
that
microwave
reaction
solvents
radiation
while
can
giving
com parable or better reaction yields compared to that of conventional
synthesis
40
This advancem ent spurred organic chemists to find novel
microwave techniques for the synthesis of the molecular functionalities
necessary for the production and manipulation of desired materials. The
interest in microwave chemistry centers on its ability to adapt to a number
of conventional reactions .4 1 4 2 ,4 3
Introduction to Microwave Radiation
Microwave
radiation
lies within the
electromagnetic spectrum,
whose wavelengths lie in the range of 1 mm to 25 urn with corresponding
frequencies of 0.3 to 300 G H z (Figure 5). A large part of the microwave
spectrum is used for communication purposes, and only narrow frequency
9
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windows centered at 900 M H z and 2.45 G H z are allowed for microwave
heating purposes.
Very few microwave applications involving heating
have been reported w here frequencies of 28, 30, 60, and 83 G H z have
been used . 4 4
Visible
Gamma
Rays
^
*
I
UV
IR
^ I—
'
H
Radio
•< ----------- 1
I
I
1______ I______I
1 0 * 111
10**
>
I______ I______1
1 0 '7
10*s
10*3
10*1
10
10
w avelength (cm)
Figure 5. Electromagnetic Spectrum
It has been known for over 50 years that microwave radiation has
the ability to induce the heating of m aterials . 4 5 Although microwave units
were capable of heating materials, improvements in the late 197 0’s of the
microwave generator called the m agnetron , 4 6 , 4 7 '4 8 and the microwave
cavity 4 9 ,5 0 allowed for wide-scale distribution of domestic and monomode
microwaves.
Since the late 1980’s, microwave radiation has been
incorporated into multiple technologies, ranging from food preparation to
chemical synthetic techniques.
10
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Introduction to Microwave Chemistry
The last 20 years have seen a dram atic increase of microwave
applications in organic syntheses . 5 1 ,5 2 Several reasons why microwave
chemistry has becom e an important tool is due to its ability to be profitably
applied even when unfavorable crystal packing and low melting points
impede solid-state reactions . 5 3 Additionally, benefits are found when the
microwave reaction can improve product yields over conventional melt
reactions without direct crystallization do not provide
product . 5 4
1 0 0
% yield of one
Finally, microwave reactions have been found to work under
solventless conditions, thereby decreasing the amount of harmful solvents
used in many conventional reactions.
Current
microwave
technology
uses
magnetrons
as
energy
generators, which principally use thermionic diodes with heated cathodes
as sources of electrons. As the electrons are released from the cathode,
lower energy microwaves are produced as a result of the high-energy
ejection of the electron. The microwaves are directed toward a microwave
cavity with the use of micro-waveguides, usually m ade of sheet metal for
directional and protective purposes.
The microwave radiation enters the
microcavity and transfers its energy into the material, thereby allowing the
material to receive its energy
44
(Figure
6
)
11
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Microwaveguides
Microwave Cavity
Microwaveguides
Figure
6
. Microwave Oven Diagram
T he transfer of microwave energy into materials relies on its
dielectric constant, or relative permittivity, which represents the ability of a
dielectric material to store electric potential energy under the influence of
an electric field
materials
44
induce
corresponding
W hen irradiated in the microwave, polar and charged
the
rotational
molecules.
Since
and
the
translational
m ovem ent
of
motion
the
of
the
molecules
increases, so does the collisional deactivation of the molecules, which in
turn releases its energy in the form of heat . 5 5
Microwave radiation can interact with organic materials through two
different mechanisms.
The first mechanism centers on the interaction of
organic molecules that maintain a dipole moment. This dipole interaction
causes the molecules to move rotationally with respect to each other and
the microwave pattern . 5 6 ,5 7 (Figure 7)
12
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Microwaves
Rotational Motion
Figure 7. T h e Rotational Motion of Molecules under Microwave Irradiation
Th e second mechanism uses charged molecules as a basis for
m ovem ent under microwave irradiation. The diverse orientation of organic
molecules allows for neutral, dipole containing, and charged molecules
formations.
Functionalities such as salts of carboxylates and quaternary
amines are charged species that allow for the translational m ovem ent of
molecules along the microwave (Figure
a translational
trajectory
8
). These molecules move along
corresponding
to the
microwave
formation
allowing for collisions to occur thereby producing heat . 5 8 ,5 9
Microwave Chamber
Microwave Output
Microwave Input
= Charged Molecules
Figure
8
. The Translational Motion of Molecules under Microwave
Irradiation.
13
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Introduction to Microwave Organic Chemistry
Microwave radiation has been used in inorganic chemistry since the
late 197 0’s while the advent of microwave organic chemistry did not
appear until the late 198 0’s.
to control
reaction
organic chemistry.
Problems with reproducibility and the ability
conditions slowed the progression
of microwave
These concerns centered on the inability of the
scientist to control the tem perature thereby limiting product breakdown.
Magnetron improvements in the mid 1980’s decreased hot spot formation
allowing
for
improved
temperature
control
and
enhanced
reaction
conditions.
Microwave organic chemistry maintains many advantages over
conventional techniques . 6 0 Microwave chemistry occurs through the rapid
absorption of energy giving quicker transitions into desired products often
within minutes instead of hours . 6 1 ,6 2
chemistry
permits
enantiomerically
The rapid reaction time of microwave
stereoselectivity
pure
products.
of
chiral
Microwave
molecules
heating
adds
yielding
energy
specifically into the reactants thereby decreasing thermal gradients found
in many conventional reactions permitting solventless conditions.
14
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Multimode and Monomode Microwave Instruments
Early microwave organic reactions w ere carried out in a multimode
microwave oven commonly used for household food preparation purposes
with
synthetic
conditions
similar to
conventional
reactions.
These
reactions normally involved solvents such as dimethylformamide (DM F),
/V,/V-dimethylacetamide (DM A), tetrahydrofuran (TH F), and pyridine to
dissolve the reactants, and to distribute heat evenly throughout the
reaction mixture preventing burning and/or acting as catalysts.
Although
these reactions w ere found to be successful, several problems w ere still
apparent.
Hot spot formations produced the need for motion in the
microwave to evenly distribute the energy. The energy used to heat food
was often greater than that of the organic reaction activation energy, often
causing product breakdown.
increased
Uncontrolled pressure still allowed for
byproduct formations and explosive possibilities.
Heating
control used interval heating instead of power percentage heating, causing
non-standard reaction times to vary greatly.
New m onomode microwave models, by Biotage®, CEM®, and
o th er m ic ro w a v e m a n u factu rers gave scientists increased control over
pressure and tem perature of the reaction environment. Pressure controls
w ere
added to limit the possibility of explosions of the microwave
reactions.
Tem perature and time parameters w ere standardized through
15
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even energy distributions.
Microwave Reactions
M any organic transformations have been done in the microwave
since the late 198 0’s. Reactions such as cylic imides synthesis (Nacylation),
(Schem e
1 ) , 6 3 ,6 4
M ichael’s
addition
(Schem e
2 ) , 65
condensations ,6 6 acetalization and ketalization of carbonyls (deprotection/
protection)
3) ,69
67
polymer transesterification
barbiturate
cycloadditions , 7 2
synthesis
(Schem e
Sonogashira
acridine synthesis, (Schem e
68
4 ) , 70
coupling
nucleophillic substitution , 71
(organometallic
reactions ) , 7 3
oxidation of primary/secondary alcohols , 7 4 Beckmann rearrangements,
and the reduction of aldehydes/ketones
microwave environment.
These
76
75
have been found to work in the
reactions have been
used for the
synthesis of multiple types of polymers, biologically active molecules,
photochemical materials, and many starting reactants.
synthesis
of substituted
cyclic
imides
using
O f note is the
cyclic anhydrides
(1 ,2
dicarboxylic acid anhydrides) reacted with primary am ine molecules giving
good
yields
under
solventless
conditions
(Schem e
1) . 6 3
Another
interesting synthesis is the reaction of 5,5-dim ethyl-1,3-cyclohexadione
under microwave irradiation to form heterocyclic compounds (Schem e
3) . 69
16
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82-96% (7 examples)
Schem e 1. G eneral Microwave Cyclic Imides Synthesis 6 3
O
R^
o n
2
♦ ^
R)
-
5
^
-
^3
^1
o^
r4
O
o
Michael Additions
8 examples (54- 95% yield)
Schem e 2. Microwave Michael Addition Reaction 6 5
NH4OAc
ai2o 3
ArCHO
+
+
MW
50-70% (5 examples)
Schem e 3. Microwave Acridine Reaction 6 9
'C 0 2H
C 02H
CO(NH2)2
NaOEt
Et0H
O
mw
Barbiturate (80% yield)
Schem e 4. Microwave Barbiturate Reaction .
70
17
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3 H20
Solventless (neat) reactions center on synthetic systems which do
not need solvents to evenly heat and mix reactants . 7 7
N eat reactions are
rare in conventional syntheses due to the reactants ability to easily burn
without even heat distribution.
Few techniques have the ability to react
under neat conditions and are often limited to very specific reactions. With
the advent of microwave chemistry energy was placed directly into
reactants thereby reducing the possibility of product breakdown, allowing
for the wide-scale use of solventless reactions.
Although many conventional and microwave techniques are well
known, very few microwave techniques under neat conditions have been
explored.
multiple
Scientists are now exploring novel solventless synthesis of
molecules
and
functionalities
using
microwave
technology;
however the exploration into many others moieties are still lacking.
An
important moiety whose usefulness in multiple applications is the cyclic
imide functionality.
Cyclic Imides
The
structure of the cyclic imide moiety has
many powerful
properties that can be exploited for its incorporation into many natural and
synthetic m aterials . 7 8 ,7 9
Structurally, the cyclic imide moiety is an amine
flanked by two carbonyls, cyclized to form a ring structure and bound by
18
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the nitrogen to a vast number of other R groups such as H, methoxy,
hydroxyl, and various organic groups (Figure 9).
R
i
X = Carbon rings structures (1, 2, 3, 4, etc...)
R = H, Me, MeO, OH, Alkyl, etc...
Figure 9. The Structure of Cyclic Imides
Cyclic imide moiety maintains increased w ater solubility when
compared to hydrocarbons due to the hydrogen bonding character of the
carbonyl and the nitrogen moiety.
The cyclic ring can be incorporated
into a number of molecules allowing for increased molecular diversity. As
one of the first well characterized organic molecules , 8 0 cyclic imides have
been found in the literature as early as the mid 183 0’s.81
Cyclic imides and their derivatives are found in many important
molecules
of
medicinal , 8 2 ,8 3
polymeric , 8 4
sensor , 8 8 and antibacterial products . 8 9
molecules
are
oxidatively
physically
strong,
stable,
fluorescent,
electronic , 8 7
Often, cyclic imide-containing
heat
and
photonic , 8 5 ,8 6
retardant,
solvent
redox-active . 9 0
resistant,
Cyclic
imide
functionalities are also commonly found in natural products playing a
major role in the biological activity of these m olecules . 91
This m akes the
enhanced synthesis of cyclic imides of central importance for improved
19
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incorporation into biological active materials.
Importance of Cyclic Imide Moieties
W ork on cyclic imide-containing molecules varies widely throughout
many fields of chemistry, biology, material science, and pharmaceutical
science . 9 2
Current work in pharmaceutical science
ranges from the
formation of alkaloids like unnatural (+)-5-epi-nojirimycin lactam and
bromogranulatimide 9 3
for the
synthesis
of anti-cancer
medicines, to the synthesis of cyclic imide-containing
and
6
-
anti-HIV
molecules as
adrenergic receptor antagonists . 9 4 ,9 5 (Figure 10) Microbiological work has
focused on the antifungal and antimicrobial properties of streptimidone , 9 6 a
glutarimide
antibiotic.
The
photochemical
properties
of cyclic
imide
containing molecules have been well studied as a reactive reduction
center for photon absorbing materials.
Current research in polymeric
science is determining the ion conducting properties of cyclic imide
containing molecules towards the optoelectronic use of these m aterials . 8 6
Cyclic imide containing molecules as polymers are also currently used as
novel drug delivery system s . 9 7
20
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6-Bromogranulatimide
H
Granulatimide
analgesics ligands
N-amino-4-(N-piperidyl)naphthalene-1,8-dicarboximide conjugate
O
O
NAN-190
Streptimidone
O
Figure 10. Important Cyclic Imide Moieties
Although important, very few synthetic pathways for cyclic imide
moieties
and
its
derivatives
have
been
developed.
Conventional
techniques which use solvents are often used for the synthesis of cyclic
imides and their derivatives. Historically these processes are effective but
are often limited by harsh conditions.
21
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Unsubstituted Cyclic Imides
The structure of an unsubstituted cyclic imide consists of an amine
flanked by two carbonyls connected through a ring structure (Figure 11).
H
i
Figure 11. The G eneral Structure of Unsubstituted Cyclic Imides
This moiety retains many useful properties such as its hydrogen
bond character and its ability to be bound to numerous cyclic structures. It
is also found in several important pharmaceuticals and anti-microbial
agents such as
6
-bromogranulatimide 9 3 and streptimidone 9 6 (Figure 10).
Although it is found in many materials only a handful synthetic techniques
are currently used for the synthesis of unsubstituted cyclic imides.
Currently, there are several conventional synthetic techniques for
cyclic imides commonly reported in the literature.
These conditions
include the condensation of liquid and/or gas am m onia with
cyclic
anhydrides (Schem e 5 ) , 9 8 the cyclicization of an am ide-acid with 1,1’carbonyldiimidazole (C D I) and DM AP (Schem e
6 ) , 9 9 ,1 0 0
the reaction of
phthaloyl dichloride with lithium nitride (Schem e 7 ) , 101 the reaction of a
primary am ide with a secondary am ide catalyzed by AICI3 ,102 the reaction
of cyclic anhydrides with urea , 1 0 3 thiourea , 1 0 4 (Schem e
8
) and formamide
22
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(Scheme 9).105
+ N H 3 ------------------------- ► C ^ NH
0
+
H2°
0
Schem e 5. Cyclic Imide Synthesis using am m onia and cyclic anhydrides
81,98
CDI, 4-DMAP
1
j
o'
Schem e
6
n
H
Y0 V.i 0H THF, reflux - >r| Y" rI r L
+ h20
76%
^
nh2
. Cyclic Imide Synthesis using amide-acid with CDI and DM AP
99
cc
/''T^r ''C0CI
DME
NH +
Schem e 7. Cyclic Imide Synthesis using Diacid Chlorides with Lithium
Nitride
+
Y
—
■ Y
X=s, o
Schem e
8
101
+
h>°
o
. Cyclic Imide Synthesis using Urea and Thiourea
1 0 3 ' 104
23
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Scheme 9. Cyclic Imide Synthesis using Formamide 105
The conventional syntheses of unsubstituted cyclic imides also
used glutaric acid with urea , 1 0 6
1,5-pentanedioic acid with ammonia
(Schem e 10 ) , 1 0 7 1,3-dibromopropane with potassium cyanide (Schem e
11 ) , 1 0 8 and 1,3-dicyanopropane with trifluroacetic acid (Schem e 12 ) . 1 0 8
TT +
|_|
Urea
H 02c - (C H 2)3-C 02H ------------------ ^
h 2o
89%
Schem e 10. Cyclic Imide Synthesis using Urea and Glutaric Acid
106
1:KCN,H20,EtOH
2:CF3C 02H,Ac0H
Br—(CH2)3-Br
h
3:H20,Me0H,110° C, 65 h
Schem e 11. Cyclic Imide Synthesis using Potassium Cyanide and 1,3dibromopropane
N r w m .v o i
107
i . c f 3c q 2h ,a c O H __________ _
2. H20, MeOH
56 %
Schem e 12. Cyclic Imide Synthesis using 1,3-dicyanopropane
24
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108
Several conventional syntheses of cyclic imides have been shown
to give good yields. However, these syntheses are often limited due to the
harsh conditions necessary, relatively long reaction times, and harmful
solvents (TH F, M eO H ) commonly used . 1 0 8
Conventional unsubstituted
cyclic imide syntheses commonly include the condensation of liquid and/or
gas am m onia, a known corrosive, with cyclic anhydrides.
Reaction times
have been found to be as long as 65 hours.
To
our
best
knowledge,
only
five
microwave
syntheses
unsubstituted cyclic imides are currently found in the literature.
of
These
syntheses of unsubstituted cyclic imides use 1,5-pentanedioic acid with
benzonitrile (Schem e 1 3),109 cyclic anhydrides with urea/thiourea , 1 1 0 cyclic
anhydrides with form am ide , 111
cyanate
and
syntheses
of
sodium
and cyclic anhydrides with potassium
thiocyanate
unsubstituted
(Schem e
cyclic
imides
14).112
using
The
microwave
benzonitrile
and
cyanate/thiocyanate are limited by the specific reactants necessary to
fabricate the desired product.
This limits the ability of som e microwave
syntheses to effectively work on many reactants.
H 0 2C - ( C H 2)3-C 02H
— PhCN
►
MW
° ^
I
N^ °
I
89%
Schem e 13. Microwave Cyclic Imide Synthesis using Benzonitrile
25
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109
Schem e 14. Microwave Cyclic Imide Synthesis using Cyclic Anhydrides
and Cyanate/Thiocyanate
112
Overall problems with these syntheses are:
1. The use of benzene, DMA, and DM F as solvents.
2. The corrosive nature of gaseous am monia and ammonium
hydroxide that are released into the environment.
3. The use of Lewis acids as catalysts in these reactions.
4. The release of sulfur byproducts.
Bicyclic Dicarboxylic Acid Anhydrides
Cyclic dicarboxylic acid anhydrides are often used as starting
reactants for the synthesis of unsubstituted cyclic imides which are often
good reaction centers and easily undergo nucleophillic attack. Cyclic
anhydrides are commonly formed from the dehydration of diacids bound
on a ring structure, which can also vary greatly from alkyl, bicyclic, and
aromatic rings.
Once formed, cyclic anhydrides can be bound into large
molecules through several techniques.
The most common of these
techniques is the Diels-Alder reaction of maleic anhydride with dienes.
Specifically, the reaction of 1,3-cyclohexadiene and a-terpinene (dienes)
26
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with m aleic anhydride (dieneophile) forms bicyclic succinic anhydrides
which maintains increased complexity to that of m aleic anhydride (Figure
12).113
o
R-i = H, R2 = H
R 1 = CH3, R2 = C H(CH3)2
Figure 12. The G eneral Structure of Bicyclic Dicarboxylic Acid Anhydride
To determ ine if microwave synthetic processes are universally
effective, the synthesis of bicyclic anhydride under solventless microwave
conditions
w as
performed
cyclohexadiene with
anhydride . 1 1 4
The
using
the
maleic anhydride,
bicyclic synthesis
Diels-Alder
and
synthesis
a-terpinene with
is conducted
of
1,3-
maleic
by conventional
methods using m aleic anhydride with a catalyst . 1 1 5 , 1 1 6 , 1 1 7
W-Hydroxy Cyclic Imides
Structurally the N -hydroxy cyclic imide (Figure 13) is similar to that
of the unsubstituted cyclic imide, maintaining a hydroxyamine flanked by
two carbonyls, cyclized to form a ring structure.
27
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OH
O
N
O
Figure 13. The G eneral Structure of A/-Hydroxy Cyclic Imides
A/-hydroxy cyclic imides are important moieties currently found in
natural
products
such
as flutimide
(Figure
14),118 oxidizers , 1 1 9
pharm aceuticals . 1 2 0 They are also used as free radical initiators
121
and
and for
the synthesis of crown ethers . 1 2 2
OH
Figure 14. The Structure of Flutimide
The novel anti-influenza virus compound, flutimide (1-Hydroxy-5isobutyl-3-isobutylidene-3H-pyrazine-2,6-dione), was recently identified in
extracts of fungal species that selectively inhibited the cap-dependent
transcriptase of influenza A and B viruses. Flutimide has no effect on the
activities of other polymerases thereby making it a powerful anti-influenza
agent.
Although, A/-hydroxy cyclic imides are found in many important
materials, few synthetic techniques for its synthesis are found in the
literature. The synthesis of cyclic A/-hydroxyimides used cyclic anhydrides
with hydroxylam ine(HCI ) . 1 2 3 ,1 2 4
The use of a base catalyst such as
pyridine has also been used to aid the progress of the reaction . 1 2 5
28
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N-Methoxy Cyclic Imides
The structure of A/-methoxy cyclic imide contains a methoxyamine
flanked by two carbonyls, cyclized to form a ring structure (Figure 15). Nmethoxy cyclic imides have been used as protecting groups , 1 2 6 in the
synthesis of crown ethers , 1 2 2 and tested as anticonvulsants . 1 2 0 Only three
conventional synthetic techniques have been found to produce N-methoxy
cyclic imides, with no microwave techniques.
i
Figure 15. The G eneral Structure of N-M ethoxy Cyclic Imides
The synthesis of A/-methoxyimides often use A/-hydroxy cyclic
imides with methyl iodide to form the cyclic A/-methoxyimide (Schem e
15).127,128,129’130 A second synthetic technique for A/-methoxyimide uses a
cyclic anhydride with methoxyamine to produce A/-methoxyimide and
water (Schem e 1 6).131'132
o
.0
THF
N- ° H * CH’ '
TEA
o
^
N' ° \
+
H'
o
Schem e 15. Conventional /V-Methoxyimide Synthesis using Alkyl Halide 1 2 0
29
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o
o
p
+
NH2OCH3
o
o
Schem e 16. Conventional /V-Methoxyimide Synthesis using
M ethoxyamine
131
Thalidomide and its Derivatives
Thalidom ide, a sedative isolated in the late 19 6 0 ’s, has been
recently found to exhibit biological activity centering on the modulation of
the autoim mune response.
This has led to the w ide-scale testing of
thalidomide and its derivatives as possible therapeutic agents for diseases
such as leprosy, HIV, and certain forms of cancer . 1 3 3 , 1 3 4 ,1 3 5 ,1 3 6 Structurally,
thalidomide maintains both phthalic and glutarimide rings while containing
both an unsubstituted and substituted cyclic imides (Figure 16).
Historically the syntheses of thalidomide focused on the cyclic
imide moieties found inside the molecule. Although several conventional
syntheses are known, few techniques have been successful for the rapid,
high yield production of thalidomide under non harsh or complex systems.
o
o
o
Figure 16. The Structure of Thalidomide
30
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Conventional synthesis of thalidomide uses (S)-glutam ine reaction
with phthalic anhydride in dioxane, acetone, and w ater for
2
hours with
24% yield (Schem e 1 7 ) .137
o
o
o
^COzH
nh
0
0
2
O O
40 min, 1 2 0 ° C ;2 h , 200°C
24%
Schem e 17. Conventional Thalidomide Synthesis using Glutamine
and Phthalic Anhydride
137
Secondarily, thalidomides can be synthesized using 2-(1,3-D ioxo1,3-dihydro-isoindol-2-yl)-acrylic acid ethyl ester with (toluene-4-sulfonyl)acetic acid in D M F /H 2 O /T H F reacted with piperidine, benzotriazole, NaH,
NH 4 CI, trifluroacetic acid, and Na am algam over
thalidom ide . 138
8
hours to produce
A third synthesis used 2-terf-butoxycarbonylamino-4-
carbamoyl-butyric acid (A/-protected glutamine) with CD I, trifloroacetic
acid, phthalic anhydride, and triethylamine using solvents of T H F and
dichloromethane for 22 hours to obtain thalidomide (Schem e 1 8 ) .139
NH
o
,0
1. CDI,TH F,16 h (reflux)
2. CF3C 0 2H, CH2CI2, 4 h, rt
3. Et3N,THF, 2 d, reflux
O
OO
O
31%
Schem e 18. Conventional Thalidomide Synthesis using a Protected
Glutamine and Phthalic Anhydride
139
31
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A fourth synthesis of thalidomide used a mixture of 4-m ethoxybenzylamine, A/-(4-m ethoxy-benzyl)-2-(toluene-4-sulfonyl)-acetam ide, and
phthalimide reacted with sodium acetate, triphenyl phosphine, sodium
phosphate, Na am algam , N H 4CI, and triethylamine dissolved in TH F, H 2 O,
methanol, dichloromethane and d io x a n e .140 In a fifth synthetic techniques
thalidomide w as synthesized by reacting S-4-carbam oyl-2-(1,3-dioxo-1,3dihydro-isoindol-2-yl)-butyric acid with CDI and 4-dimethylaminopyridine in
T H F to produce thalidomide in 90% (Schem e 1 9 ).141
o
° V nh2
P
90 %
Schem e 19. Conventional Thalidomide Synthesis using a Protected
Phytolglutamine 141
A sixth conventional synthesis of thalidomide used the mixture of
trifloroacetic acid with 3-am ino-dihydro-pyran-2,6-dione in triethylamine for
2 hours in refluxing T H F to produce thalidomide in 69% yield (Schem e
20).139
o
CF3CONH2, Et3N, THF, 2 h, reflux
0
+
NH
NH2
o
69%
Schem e 20. Conventional Thalidomide Synthesis using a Glutamic
Anhydride and Phthalic Anhydride 139
32
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A seventh method and the only microwave assisted synthesis of
thalidomide used glutamic acid, phthalic anhydride, catalyzed by urea and
thiourea solventless yielding 60% (Schem e 21 ).142 Although thalidomide
derivatives are highly sought, only one conventional synthesis was found
using
(S)-glutam ine
reacted
with
substituted
phthalic
anhydrides
in
dioxane, acetone, and w ater between 2 and 20 hours with 24% yield
(Schem e 2 2 ) . 143
O
60%
Urea, MW or
H02C
C02H
Thiourea, MW
y - o = °
// NH
0
0 0
Schem e 21. Microwave Thalidomide Synthesis using Glutamic
Acid, Phthalic Anhydride, and Urea and Thiourea 142
24%
0
h 2n
^ /C 0 2H
NH2
1,4-dioxane, acetone, w a te r
NH
20-40 min, 120°C; 2-20 h,160- 200°C
R = H, Me, Et, MeO, F, Cl, Br, N 0 2
24.1 %
Schem e 22. Thalidomide Derivatives Synthesis using Glutamic
Acid and Substituted Phthalic Anhydride 143
33
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Cyclic Enaminones
Cyclic enam inones are currently used in many biological, and
optical-electronic materials including non-linear optical m aterials144 and
anticonvulsants.145 Although cyclic enaminones are found in many useful
materials, few conventional syntheses and only one microwave report was
found for their synthesis.
Structurally, cyclic enam inones maintain an
amine bound through a double bond to a carbonyl on the adjacent carbon
(Figure
17).
This functionality can be linear or bound into a ring.
Specifically, cyclic enam inones have been used to induce biological
activity, indicating the importance of their synthesis.
Figure 17. The General Structure of Cyclic Enam inones
Common conventional synthesis of cyclic enam inones include 1,3
cyclic diketones with ammonium acetate (Schem e 2 3 ),146,147,148 1,3 cyclic
diketones
with
am m onia
(Schem e
2 4 ),149,150 the
reduction
of
3-
aminoaniline with t V P d then reacted with KOH (high pressure) (Schem e
2 5 ),151 and the reaction of 4-oxo-pentanenitrile with sodium butyan oate.152
Reaction times varied from 3 hours to 17 hours under reflux conditions.
Cyclic
enam inones
have
also
been
synthesized
in the
microwave
environment using N H 4OAc with a montmorillonite solid support (Schem e
34
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26).
153
NH4OAc, PhMe, 5 h, reflux
° ^
^
' NH2
90 %
Schem e 23. Conventional Enam inone Synthesis using Ammonium
A cetate 146
NH3 .Benzene
CK ^
„N H ,
+ HoO
50%
Schem e 24. Conventional Enam inone Synthesis using Am m onia 149
H,N
NH,
1:H2, Pd, AcOH, H20
2: KOH (High Pressure)
°Y ^
y
NH2
+ H20
87%
Schem e 25. Conventional Enam inone Synthesis using H2/Pd with KOH
H,N
N H 4O A c ,
3 min, MW
Montmorillonite solid support
+ H ,0
O
90%
Schem e 26. Microwave Enam inone Synthesis
153
35
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151
Enaminone - Imide Conjugates
Figure 18. The G eneral Structure of Enaminone - Imide Conjugates
Although
cyclic
enam inones
are
used
as
pharmaceuptical
intermediates for their biologically activity, their incorporation with cyclic
imides has not been seen in the literature.
The coupling of the cyclic
imides with cyclic enam inones to form the conjugate has the possibility of
increasing the biological activity of both moieties (Figure 18).
Problems with the Current Conventional Synthesis of Cyclic Imides
T h e conventional syntheses of cyclic imides and their derivatives
are well documented in the literature; however, these syntheses are often
limited due to the harsh conditions necessary, relatively long reaction
times, and harmful solvents.
Although there are multiple syntheses of
cyclic imides and its derivates, several problems arise with m any of these
syntheses. A few problems are:
1. The use of d io xan e,154 D M A 155, and D M F 156 as solvents.
2.
Increased complexity using exotic and expensive materials such
as platinum, and increasing byproduct formations.
36
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3. Long reaction times.
4. The use of Lewis Acids.
1) The Use of Harmful Solvents
Although solvents are necessary for the conventional synthesis of
cyclic imides and their derivatives, many solvents currently used have
been found to be biologically and environmentally harmful.
Specifically
the use of dioxane,154 D M A ,157 and D M F 158 has been found to induce toxic
effects on reproductive system s159 while also being carcinogenic.
These
effects are frequently balanced with the importance of the materials
produced from these imides and their derivatives.
2) Complicated Reactions and Workup
Often, the syntheses of cyclic imides containing molecules are
multi-step processes with complicated workups.
These processes can
maintain up to six solvents with five reactants for the synthesis of a single
imide containing m olecule.140 Additionally many expensive reactants such
as platinum are used for cyclic imides and their derivatives syntheses
which are often expensive or hard to synthesize. Finally, complicated
processing can lead to lower yields if procedural errors occur.
37
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3) Long Reaction Times
Long reaction times often play a large part in byproduct formation
and energy consumption for the synthesis of materials.
Conventional
reactions of imides and their derivatives have been found to range from 2
to 22 hours.139'143
During this time, multiple chemical processes and
byproduct formation can occur.
In the case of thalidomide, racemization
has been found to increase over time, thereby decreasing its efficacy. As
a consequence, short reaction times favorable. Long reaction times of
conventional synthesis are also costly when describing overall energy
usage compared to microwave and alternative chemical techniques.
4) The Use of Lewis Acids as Catalyst
T he use of Lewis acids are often common to initiate many chemical
reactions such as ketoesters and epoxides synthesis.160,161,162 Cyclic
imides and their derivatives are among some of these products which
have used Lewis acids as a catalyst.163,164 Although Lewis acids are
common in many reactions, their use promotes conditions that causes
byproduct formation.
Reactions by the Lewis acid can occur both at the
imide reaction site as well as other regions of the molecules, which forces
the protection of sensitive reactions sites. This causes the reaction to
occur in multi-steps, to protect sensitive functional groups, instead of a
38
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one-step process thereby limiting product yield.
Synthetic Improvements of Microwave Enhanced Synthesis
Although
many
conventional
syntheses
have
been
found
throughout the literature,108,139 very few novel and environmentally friendly
techniques have been noted. This work seeks to explore microwave
chemistry as a synthetic pathway for cyclic imides and their derivatives.
The exploitation of solventless systems, decreased reaction times, and
improved
reaction
conditions
commonly
found
in
many
microwave
reactions are explored for the single and multi-step processing of cyclic
imides and their derivatives for improvement over current techniques.
These improvements are:
1. Solventless systems
2.
Improved reaction conditions
3. Decreased reaction times
1) Solventless Systems
Microwave chemistry has allowed for decreased usage or removal
of environmentally and biologically harmful solvents.
Due to specific
properties of microwave radiation, the melting point of the material is able
to be obtained without burning.63,64 This allows for a molten mixture of
39
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reactants to becom e the pseudo-solvent mixing the reactant and the
catalyst.
Cyclic imides and their derivatives often maintain melting
tem peratures well within the range used in microwave chemistry, allowing
for reactions to occur. These solventless microwave systems remove the
need
for
solvent
for
many
organic
reactions;
thereby
decreasing
environmental and biological harm.
2) Improved Reaction Conditions
Favorable reaction conditions for microwave chemistry are also an
improvement over conventional synthesis.63'75
M icrowave
chemistry
allows for both tem perature and pressure control of the reaction.
The
ability to control tem perature and pressure is not easily accomplished with
conventional synthetic techniques, with special apparatus necessary.
Pressure
and tem perature control has been
microwaves with easy control of both parameters.
coupled
in monomode
Direct control of these
parameters is important in cyclic imides and their derivatives synthesis
due to increased pressure. This pressure increase results due to w ater
formation
and
completion.
am m onia
production
as
the
reaction
proceeds
to
If not controlled the loss of a reactant am m onia can limit
product yield.
40
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3) Decreased Reaction Times
Reaction
times
of
the
microwave
chemistry
compared
to
conventional techniques is probably its most unique feature. The ability to
synthesize materials in minutes instead hours reduces reaction times,
reduces time for byproduct formation and other chemical process, and
allows for easier workups.63-75 This reduction in time assists in the rapid
determination of synthetic viability and quantified product yield. Scaling up
this process can allow the industrial manufacturing of cyclic imide to
increase production yield.
Dissertation Research
Specifically these novel microwave syntheses will focus on the
synthesis of:
1. Bicyclic succinic anhydrides.
2. Unsubstituted cyclic imides.
3. A/-hydroxy cyclic imides.
4. A/-methoxy cyclic imides.
5. Thalidom ide and its derivatives.
6. Cyclic enaminones.
41
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7. Enaminone imide conjugates.
The novel m icrowave-enhanced Diels-Alder reaction will use maleic
anhydride with a-terpenine and 1,3-cyclohexadiene to produce bicyclic
and substituted succinic anhydrides.
These anhydrides will be used as
reactants for the synthesis of specific cyclic imides and their derivatives.
This synthesis will be performed neat with only the reactants inside the
microwave vessel.
Tw o microwave assisted techniques will be used for the synthesis
of unsubstituted cyclic imides.
The first technique will use DM A P as a
base catalyst, ammonium chloride as a nitrogen source, and a series of
cyclic anhydrides in a neat reaction for the production of unsubstituted
cyclic imides.
The second technique will use ammonium acetate as a
nitrogen source and a series of cyclic anhydrides.
The release of
am monia allows for its reaction with the cyclic anhydride producing the
desired cyclic imide. These reactions should allow for the nitrogen source
to breakdown into am m onia to aid the formation of the unsubstituted cyclic
imides.
The microwave assisted synthesis of A/-hydroxy cyclic imide will
use
cyclic
anhydrides
with
hydroxylamine(HCI)
under
neat
reaction
conditions. This synthesis should work in a two-step process with the first
42
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step being the reaction of hydroxylamine with the cyclic anhydride to form
an acid and A/-hydroxylamide functionality. T h e second step will be a
dehydration and cyclization of these functionalities into the desired cyclic
/V-hydroxyimide product.
The microwave assisted synthesis of A/-methoxy cyclic imide will
use a series of cyclic anhydrides with m ethoxyam ine(HCI).
This neat
reaction will use only cyclic anhydride and m ethoxyam ine(HCI).
microwave
assisted
synthesis
methoxyamide functionality.
will
initially
form
an
acid
The
and
N-
Cyclization occurs through a dehydration of
the acid and A/-methoxyamide functionality forming the desired product.
Thalidom ide
is
a
current
pharmaceutical
maintains two cyclic imide functionalities.
novel unsubstituted
which
structurally
The incorporation of earlier
cyclic imide syntheses will be used to produce
thalidomide and a series of its derivatives. The thalidomide syntheses will
use a series of cyclic anhydrides and glutamic acid with ammonium
acetate or D M A P / ammonium chloride.
Cyclic
enam inones
are
useful
currently used as anticonvulsants.
biologically
active
molecules
The novel microwave synthesis of
cyclic enam inones will use ammonium acetate with cycloalkanediones.
This neat reaction will work through the breakdown of ammonium acetate
into am m onia and acetic acid.
43
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Since both cyclic enaminones and cyclic imides have shown to
have biological activity the synthesis of their conjugates should potentiate
their activity. T h e microwave assisted synthesis of enam inone imide
conjugates
will
use
the
reaction
of
cyclic
anhydrides
with
enaminones under basic conditions.
44
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cyclic
II. RESULTS
Microwave Synthesis of Bicyclic Anhydrides
The Diels-Alder reaction of 1,3-cyclohexadiene and a-terpinene
with m aleic anhydride in the multimode and m onomode microwave under
solventless conditions, are shown in tables 1 and 2, respectively.
The
reaction times for multimode microwave conditions w ere set at 1 minute,
while m onom ode microwave conditions w ere set at 5 minutes at 150 °C.
Isolated product yields for the multimode and monomode reactions ranged
from 72 to 92% and 63 to 82% , respectively finding stereoselectivity that
maintained the endo as the major product for both syntheses.
45
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Multimode Synthesis of Bicyclic Anhydrides
Table 1. Multimode Microwave Synthesis of Anhydrides
Diels-Alder Synthesis (Multimode)
Entry
Diene
Anhydride
Tim e (min)
Yield (% )
Endo/Exo
/fJL. / " f °
(i) y o
1
72
8 /1
92
15/1
f
"r°
o
Monomode Microwave Synthesis of Bicyclic Anhydrides
Table 2. M onom ode Microwave Synthesis of Anhydrides (Monom ode)
Diels-Alder Synthesis (Monom ode)
Entry
Diene
Anhydride
Tim e (min)
Yield (% )
Endo/Exo
63
8 /1
82
13/1
a,y>
■
• f
46
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Microwave Synthesis of Unsubstituted Cyclic Imides
The
anhydrides,
synthesis
DM AP,
of
unsubstituted
and NH4CI
in
the
cyclic
imides
multimode
and
using
cyclic
monomode
microwave under solvent-less conditions, is shown in tables 3 and 4,
respectively. The reaction times for the multimode reaction ranged from 2
to 5 minutes, with the monomode conditions set for 10 minutes at 150 °C.
Isolated product yields were found between 69 to 90% and 81 to 91% for
the multimode and monomode microwave, respectively.
The synthesis of unsubstituted cyclic imides using cyclic anhydrides
and ammonium acetate (N H 4OAc) in the multimode and monomode
microwave under solvent-less conditions, is shown in tables 5 and 6,
respectively. Reaction times for the multimode reaction ranged from 15 to
100 seconds, with the monomode conditions set for 5 minutes at 150 °C.
Isolated percent yields were found between 50 to 98% and 4 0 to 91% for
the multimode and monomode microwave, respectively.
The
anhydrides,
synthesis
DM A P
and
of
unsubstituted cyclic
hydroxylamine (HCI)
imides
in the
using
multimode
cyclic
and
monomode microwave under solvent-less conditions, is shown in tables 7
and 8, respectively.
Reaction times for the multimode reaction ranged
from 72 to 161 seconds, with the monomode conditions set for 5 minutes
47
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at 150 °C.
Isolated product yields were found between 84 to 97% and 61
to 81% for the multimode and monomode microwave, respectively.
48
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Multimode Microwave Synthesis of Cyclic Imides using DMAP/NH 4 CI
Table 3 .M icrowave Synthesis of Unsubstituted Imides using DMAP/NH4CI
DMAP/NH4CI (Multimode)
Entry
Imide
Tim e (min)
Yield (% )
o
69
NH
(3) O
81
NH
O
H
Q ^N^O
90
(5)
- A
(W
81
NH
O
69
0
82
(§) y NH
O
0
' nh
unknown dark
product
o
8
~5
(s)>rNH
o
49
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Monomode
Microwave
Synthesis
of
Cyclic
Imides
using
DMAP/NH4CI
Table 4. M onom ode Synthesis of Unsubstituted Imides using DM A P and
NH4CI
NH4CI/ DM AP (Monom ode)
Tim e (min)
T (°C)
Entry
Imides
o
NH
1
Yield (%)
150
91
150
91
150
81
150
91
150
81
(3)
0
NH
H
Q ^N ^O
(5)
A
5
K
b
o
o
f
(8) y
o
150
91
150
~ 5
m
50
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Multimode Microwave Synthesis of Cyclic Imides using NH4OAc
Table 5. Multimode Synthesis of Unsubstituted Imides using N H 4OAc
N H 4OAc
Entry
Imide
s<
6
-
Tim e (sec)
Yield (% )
45
73
45
50
15
92
100
78
45
90
60
98
240
72
O
NH
H
O ^N^O
(5)
O
A
NH
(§ T ^
Qj"
(8)
O
(9
) 'r m
O
51
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Monomode Microwave Synthesis of Cyclic Imides using NH4OAc
Table 6. Monom ode Synthesis of Unsubstituted Imides using N H 4OAc
N H 4O A c_________________________
Tim e (min)
T (°C)
Yield (%)
Entry
NH
6
150
81
150
81
150
53
150
71
150
51
150
91
150
40
52
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Multimode Microwave Synthesis of Cyclic Imides using NH20H(HCI)
Table 7. Multimode Synthesis of Unsubstituted Imides using N H 20H (H C I)
and DM AP
Entry
N H 2O H and DM A P (Multimode)
Tim e (sec)
Imide
o
Yield (% )
110
96
160
97
72
96
94
84
(2) o
0
NH
O
O
A
NH
Of
\_ / Q
53
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Monomode Microwave Synthesis of Cyclic Imides using NH20H(HCI)
Table 8. Monom ode Synthesis of Unsubstituted Imides using N H 2O H (H C I)
Entry
N H 2O H (H C I)/ DM AP (Monom ode)______________
Tim e (min)
T (°C)
Yield (%)
Imide
o
(s) y
5
150
71
5
150
70
5
150
61
5
150
61
5
150
61
5
150
81
NH
54
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Microwave Synthesis of A/-Methoxy Cyclic Imides
Tables 9, 10, and 11 present the microwave enhanced synthesis of
A/-methoxy cyclic imides using cyclic anhydrides and methoxyam ine (HCI)
under solvent-less conditions in the multimode, m onomode at 125 °C for 5
minutes, and m onomode
at 180 °C for 7 minutes, respectively.
The
reaction times for the multimode reaction ranged from 17 to 100 seconds,
with the monom ode conditions set for 5 minutes at 125 °C and 7 minutes
at 180 °C.
Isolated product yields w ere between 61 to 99% , 4 0 to 54%
(mono, 5 min at 125 °C), and 75 - 84% (7 min at 180 °C).
Isolated
product yields of 4 7 % and 40% were found for N-m ethoxy cyclic imides
(15) and 17% for (17) w ere lower than the rest of the products.
55
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Multimode Microwave Synthesis of N-Methoxy Cyclic Imides
Table 9. Multimode Synthesis of Unsubstituted Imides using NH2OCH3
(HC1)
Entry
N H 2O C H 3(HCI) (Multimode)
A/-Methoxy imides
Tim e (sec)
N—0N
CH3
~
Yield (%)
41
72
17
99
28
61
48
96
74
98
100
47
94
66
65
17
.0
CH,
N -i
CH,
O
o
\|-0
ch3
(1 3 )0
- A
,N—Q\
CH,
f
Oil
f
'0
0
NO'2
CH,
O
,N—Q
CH,
f
...^
8
m
f
o
ch3
56
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Monomode Microwave Synthesis of A/-Methoxy Cyclic Imides
Table 10. Monomode Synthesis of Unsubstituted Imides using
NH2OCH3(HCI) at 5 min and 125 °C
Entry
NH2OCH3 (Monomode)
Tim e (min)
/V-Methoxyimides
0
n—o
m
Y
o
T ( C)
Yield (%)
125
50
125
48
125
54
125
54
125
40
Tc h 3
57
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Table 11. Monomode Synthesis of Unsubstituted Imides using
NH2OCH3(HCI) at 7 min and 180 °C
Entry
NH2OCH3 (Monomode)
Tim e (min)
N-Methoxyim ides
N—Q
\
CH3
CH,
N-Ox
CH3
T (°C)
Yield (%)
180
75
180
79
180
84
180
70
180
81
180
49
O
(13)
CH,
o
,0
A
N—0,
'CH>
...^
(IB Y
o
f
-o
ch3
58
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Microwave Synthesis of Thalidomide and Derivatives
Tables 12 and 13 present the microwave enhanced synthesis of
thalidomide and its derivatives using cyclic anhydrides, glutamic acid,
DMAP, NH4CI under solvent-less conditions in both a multimode and
monomode microwave, respectively.
Multimode reaction times ranged
from 2.5 to 7.25 minutes, while the monomode reaction conditions were
set to 10 minutes at 150 °C. Isolated product yields in the multimode were
between 4 0 to 53% while monomode yields ranged from 4 7 to 86% .
59
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Multimode Microwave Synthesis of Thalidomide and Derivatives
Table 12. Multimode Microwave Synthesis of Thalidomide Derivatives
Thalidomide Derivatives (Multimode)
Entry
Imide
o
^NH
o
o
o
6.5
53
2.5
40
2.0
32
4.2 5
52
7.25
51
\
) ^ NH
o
o
( 21) o
Yield (% )
o
/
N (
"(20)^
o
o
Tim e (min)
o
60
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Monomode Microwave Synthesis of Thalidomide and Derivatives
Table 13. Monomode Microwave Synthesis of Thalidomide Derivatives
Thalidomide Derivatives (Monomode)
Entry
Imide
Tim e (min)
T (°C)
Yield (%)
10
150
86
10
150
47
10
150
59
10
150
48
10
150
62
o
:n - ^ > = o
v
o
o
O
0
N—(
m
( 21)
i
o
o
o
nh
)= 0
o
^NH
o
61
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Comparison of Thalidomide Microwave Synthetic Techniques
Tables 14 and 15 compare microwave synthetic techniques of
thalidomide
using
thiourea,
D M A P /N H 4 CI,
and
multimode and monomode microwave, respectively.
N H 4OAc
in
both
a
These comparisons
sought to determ ine the percent of the products found in the thalidomide
synthesis, thalidomide to the phthalimide, by using G C - M S to obtain the
percent produced.
Table 14. Comparison of Thalidomide using Phthalic Anhydride and
Glutamic Acid, with D M A P /N H 4 CI, N H 4 OAc, and Thiourea in the
Multimode Microwave
R eagent
Tim e (min)
Power
Phthalimide
Thalidomide
Thiourea
1 0
40 %
61.31
28.54
D M A P / NH4CI
1 0
40 %
66.28
33.72
Ammonium Acetate
1 0
40 %
84.98
2.98
62
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Table 15. Comparison of Thalidomide Synthesis using Phthalic Anhydride
and Glutamic Acid with D M A P /N H 4 CI, N H 4 OAc, and Thiourea in the
Monom ode Microwave
R eagent
Tem p (°C)
Tim e
Phthalimide
Thalidomide
Thiourea
150
1 0
min
59%
40%
DM A P N H 4CI
150
1 0
min
57%
43%
Ammonium Acetate
150
1 0
min
90%
7%
Microwave Synthesis of Cyclic Enaminones
The microwave assisted synthesis of cyclic enam inones using
cyclic 1,3 diones and NH4OAc under solvent-less conditions in both a
multimode and monomode microwave, is shown in tables 16 and 17,
respectively.
Multimode reaction times w ere 4 5 seconds for all reactions,
while the m onomode reaction conditions w ere set to 5 minutes at 150 °C.
Isolated product yields in the multimode w ere between 71 to 91% while
m onomode yields ranged from 76 to 92% .
63
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Multimode Microwave Synthesis of Cyclic Enaminones
Table 16. Multimode Microwave Synthesis of Cyclic Enam inones
Enam inone Synthesis using N H 4O Ac (Multimode)
Dione
Enaminone
Tim e (sec)
Yield (%)
h 2n
Entry
(2 3 )
45
81
45
91
45
71
45
82
H2N
(2 4 )
2
H2N ^
(3 3 )V J
3
O
(2 5 )
h2n ^ A ^ o
(26)
\_ r
Monomode Microwave Synthesis of Cyclic Enaminones
Table 17. Monom ode Microwave Synthesis of Cyclic Enam inones
___________ Enam inone Synthesis using NH4OAc (Monom ode)
Entry
Dione
Enaminone
Tim e (min)
T (°C)
h 2n
1
<a,U
(2 3 )
o
Yield (%)
150
92
150
92
150
81
150
76
h 2n
H2N ^
O
(33)
(2 5 )
o
h 2n ~
^
(2 6 )
64
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Microwave Synthesis of Enaminone Imide Conjugates
Tables 18 and
enoneimides
using
cyclohexen-1-one
less
conditions
respectively.
19 present the microwave enhanced synthesis
previously
produced
5,5-dim ethyl-1-am ino-2-
(24) and a series of cyclic anhydrides under solventin
both
a
multimode
and
m onomode
microwave,
Multimode reaction times ranged between 2 .15 and 3.15
minutes, while the m onomode reaction conditions w ere set to 5 minutes at
150 °C. Isolated product yields in the multimode w ere between 70 to 88%
while monom ode yields ranged from 54 to 84% .
Multimode Microwave Synthesis of Enoneimides
Table 18. Multimode Microwave Synthesis of Enoneimides
_________________ Microwave Synthesis of Enoneimides
Entry
Anhydrides
Tim e (min)
Enoneimides
O
o
Yield (%)
2.75
88
3.15
75
65
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Monomode Microwave Synthesis of Enoneimides
Table 19. Monomode Microwave Synthesis of Enoneimides
Microwave Synthesis of Enoneimides
Entry
Anhydrides
Enoneimides
Tim e
(min)
Tem p
(°C)
Yield
150
54
150
82
150
62
150
84
( 0/.
o
1
0 (30)
o
66
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III. DISCUSSION
This
study
illustrates
several
novel
solventless
microwave
syntheses of cyclic imides and their derivatives that are eco-friendly
alternatives
to
conventional
syntheses
using
both
conventional
(multimode) and focused (monomode) reactors. This research introduces
novel
synthetic
synthesis
of
techniques
unsubstituted
for
the
cyclic
solventless
imides,
microwave
A/-methoxy
cyclic
assisted
imides,
thalidomide and its derivatives, cyclic enaminones, and imide - enaminone
conjugates. The following classes of compounds have been synthesized:
1. Bicyclic carboxylic acid anhydrides.
2. Unsubstituted cyclic imides.
3. A/-methoxy imides.
4. Thalidom ide and its analogues.
5. Cyclic Enaminones.
6
. Imide - enam inone conjugates.
The Microwave Assisted Dieis-Alder Synthesis of Cyclic Anhydrides
Anhydrides are an important class of compounds often used as a
starting reactant for the synthesis of cyclic imides. To increase the
molecular complexity and diversity of the anhydrides used for the cyclic
67
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imide syntheses, bicyclic carboxylic acid anhydrides w ere produced using
the microwave assisted Diels-Alder reaction of m aleic anhydride with a terpinene and 1,3-cyclohexadiene. Although conventional and microwave
assisted Diels-Alder syntheses are found throughout the literature, few
reports
have
been
found
on the
microwave
assisted
synthesis
of
molecules (1) and (2 ) . 1 1 5 ,1 1 6 These reactions used only the mixture of the
functionalized diene with maleic anhydride under solventless microwave
conditions (see Schem e 27).
R1 = H, CH3 R2 = H, Isopropyl
Schem e 27. The Diels-Alder Synthesis
M any advantages w ere found for our microwave assisted DielsAlder synthesis of bicyclic carboxylic acid anhydrides over conventional
synthetic techniques. A conventional synthesis of this reaction has been
found to react over 5 hours , 1 1 6 w hereas our microwave assisted reactions
occur between 1 and 5 minutes. Isolated Diels-Alder product yields for
bicyclic anhydrides for our technique ranged between 63 and 92 (Table
2 0
) percent with yields comparable to literature value of 82 percent . 1 1 6
Catalyst such as bauxite, ion exchange resin, and activated clay has been
used to aid the previous conventional reactions; however our microwave
68
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reaction needed no catalyst for the reaction to occur . 1 1 4 Solvents such as
methanol and chloroform have been used in the conventional synthesis of
these bicyclic systems while the microwave assisted synthesis reacted
without solvents. Finally the reactants w ere effortlessly mixed and heated
followed by easy flash chromatographic isolation giving excellent product
yields (Tables 1 and 2).
The endo form was found to be the major product of the Diels-Alder
reaction.
This
was
confirmed
through
Bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic
a
co-injection
anhydride
(1_)
of
with
endothe
commercially available endo sample from Aldrich chemical company into a
gas
chromatograph
mass spectrometer (G C
retention times and mass spectra.
- M S)
showing
similar
Ratios w ere determined through 1H
N M R (400 M H z Bruker) by looking at the integration of the endo/exo
protons.
T h e ratios of the endo to exo product of (1) w ere 8/1 for the
multimode and monomode microwave while ratios of the endo/exo product
for (2) w ere found to be 13/1 and 15/1. This result seem s to be in line with
the current understanding of endo product formation being favored (1 ).
Higher endo selectivity is observed with the more sterically hindered (2)
which almost completely forms the endo product.
The m onomode microwave reactions w ere used to standardize the
microwave process for both bicyclic anhydrides.
The standardization
69
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parameters w ere set for 5 minutes at 150 °C.
Yields w ere comparable
between the m onomode and multimode microwave reactions with only
slight differences found. Alternative isolation techniques m ay account for
differences in isolated product yields since the initial G C - M S indicates
almost
1 0 0
% conversion into the desired product.
Identification of the bicyclic carboxylic acid anhydrides used NM R,
GC - MS, IR, and melting point temperature. The data indicates a well
defined structure of molecule (1) that is symmetric as demonstrated by 4
signals in the 1H N M R and 5 signals in the 13C N M R (Table 20). Signals in
the 1H N M R indicated 2 olefinic protons at 6.30 ppm, 4 bridging protons at
1.61 ppm, 2 a-protons (to the carbonyl) at 3.17 ppm, and 2 p-protons at
1.39 ppm. Tw o equivalent olefinic protons of molecule (1_) gave one signal
at 6.30 ppm.
Similarly, the 13C showed 5 signals with the carbonyl
carbons at 173.89 ppm, the olefinic carbons at 132.82, and 3 (C H 2 )
carbons at 4 4 .5 3 ppm, 31.42 ppm, and 22.69 ppm. T h e IR indicated the
presence of carbonyls with signals at 1715.5 and 1780.9 cm '1. (1_). The GC
- M S showed the proper mass of 178 which corresponds to the molecular
weight.
Unlike molecule (1), molecule (2) is unsymmetrical maintaining 10
signals in the 1H N M R and 14 signals in the 13C N M R (Table 20). Signals
in the 1H N M R are two signals at 6.014 ppm and 6 .0 6 7 ppm indicated
70
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olefinic protons and a proton signal at 2.51 ppm indicated a septet, while
signals at 1.45 ppm, 1.031 ppm, and 0.958 ppm indicated all of the C H 3 in
molecule (2) without overlapping of the isopropyl methyls due to the
anisotropic effect of neighboring chiral centers. The 13C N M R maintained
two signals for the carbonyl carbons at 171.47 ppm and 170.84 ppm, two
olefinic carbons at 136.64 ppm and 135.89 ppm, and three methyl groups
at 21.75 ppm, 17.90 ppm, and 16.26 ppm.
Two bands at 1770.6 and
1834.2 cm ' 1 in the IR indicated the presence of the carbonyls in (2). The
GC - M S gave the mass of 234 which corresponds to the molecular weight
of (2).
Table 20. 1H and 13C N M R Signals for the Bicyclic Carboxylic Acid
Anhydrides
1H and 13C N M R Signals for the Bicyclic carboxylic acid anhydrides
Molecule
1H N M R Signals
13C N M R Signals
6 .3 0 (dd, J = 3.16, 4.5 Hz,
2H ), 3.23 (m, 2H), 3.12 (t,
J = 1.7 Hz, 2 H), 1.60 (m,
2H), 1.41 (m, 2H),
172.75 (C = 0 ), 133.04 (CH),
4 4 .7 7
(C H ),
3 1.63
(CH),
22.98 (C H 2)
(d, J = 8.12 Hz, 1 H),
(d, J = 8.52 Hz, 1 H),
(d, J = 8.75 Hz, 1 H),
(d, J = 8.75 Hz, 1 H),
(septet, J = 6.85 i Hz,
1.51 (s, 3H), 1.:31 (m, 4H ), 1.09 (d , J =
Hz,, 3H), 1.02 (d , J =
Hz , 3 H )
171.47 (C = 0 ), 170.85 (C = 0 ),
136.96 (CH), 136.28 (CH),
(CH),
50.94
4 7 .2 0
(CH),
43.50 (C), 36. 69 (C), 33.61
2 2 .6 6
29.32
(C H 2),
(C),
(C H 2), 2 2 .1 7 (C H 3), 18.27
(C H 3), 16.64 (C H 3)
6 .1 1
6 .0 2
3.23
2 .8 6
2.57
1 H),
1.48
6.9 6
6.80
71
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The Synthesis of Unsubstituted Cyclic Imides
The
synthesis of unsubstituted
imides
is important for many
different materials used in photochemical, biochemical, and polymeric
science . 6 6 , 6 7 , 6 8 ' 7 3
The conventional synthesis of cyclic imides commonly
uses cyclic anhydrides with am monia or a primary am ine containing
compounds in solvated systems.
Although there are m any synthetic
techniques for the production of cyclic imides, many reactions result in
harsh conditions, long reaction times, and low product yield.
problems
plague
many
cyclic
unsubstituted cyclic imides.
imide
synthesis
especially
These
that
of
Although important few novel techniques
have been able to limit many of the problems frequently found in
unsubstituted cyclic imide syntheses.
Decrease reaction times, easy
workup, solventless condition are just a few advantages of microwave
chemistry.
Currently, only four novel techniques for the synthesis of
unsubstituted
cyclic
imides
have
been
found
to
utilize
microwave
irradiation reacting benzonitrile with diacids , 1 0 9 urea/thiourea with cyclic
anhydrides , 1 1 0
formamide
with
cyclic
anhydrides , 111
and
cyanate/thiocyanate with diacids 1 1 2 to produce unsubstituted cyclic imides.
Several of these microwave techniques are limited because they can only
react with either anhydrides or with diacids. This limits their ability to react
72
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with a
broad
array of starting
materials, thereby,
adding
additional
synthetic steps to many syntheses. This dissertation research introduces
three different microwave assisted synthetic techniques for the production
of
unsubstituted
cyclic
NH 2 O H (H C I)/D M A P
syntheses
of
imides
under
unsubstituted
using
N H 4 C I/D M A P,
solventless
cyclic
conditions.
imides
N H 4 OAc,
O ur
improves
and
microwave
over
previous
syntheses because it is faster, high yielding, utilizes one-pot reactions,
and uses solventless conditions thereby reducing solvent waste.
O ur synthesis of unsubstituted cyclic imides in the solventless
environment uses the in situ production of ammonia.
Am m onia reacts
with anhydrides to form both an am ide and an acid functionality.
completion
of the
reaction
occurs
through
a
cyclization
from
The
the
dehydration of the acid and am ide forming an unsubstituted cyclic imide
(Schem e 28).
has
the
The incorporation of ammonium salts with a base catalyst
ability
to
produce
ammonia.
Ammonium
chloride
and
hydroxylamine w ere used as ammonium salts for the production of
ammonia.
The base catalyst that was used was DM A P w here imidazole
was used in som e cases for comparison.
Ammonium acetate has been
found to form am m onia as a reactive species, thereby, achieving the first
step in cyclic imide formation.
Since ammonium acetate maintains
conjugate base moiety no additional base was added.
Although not
73
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thoroughly tested, several of our microwave techniques for the synthesis
of unsubstituted cyclic imides w ere also able to work with diacids to form
cyclic imides improving over several given microwave techniques.
o
o
o
NH2
NH3
Dehydration
,NH + H20
proton Transfer
o
O
O
Schem e 28: The Mechanism Unsubstituted Cyclic Imides Synthesis using
Ammonia
Conditions for the
monomode
microwave
reactions w ere
relative to the multimode reactions conditions (see Tables 3-8).
set
Those
multimode reactions which gave good yields over short periods of time
were given shorter time frames in the monomode microwave. Conversely,
if a
reaction w as longer in duration to give good yields, then the
m onomode conditions w ere set accordingly.
The tem perature for the
microwave assisted reactions were set at 150 °C slightly above the
melting point of all cyclic anhydrides to allow for proper mixing of the
reactants, while minimizing thermal decompositions of the reactants or
products at higher temperatures.
74
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Unsubstituted Cyclic Imides from DMAP, Ammonium Chloride,
Cyclic Anhydrides
This first technique for the
microwave
assisted
synthesis
of
unsubstituted cyclic imides used ammonium chloride as a source for
nitrogen, D M A P as a base catalyst, and cyclic anhydrides for the cyclic
carbon backbone (Schem e 29).
Ammonium chloride w as chosen as a
source of nitrogen because under basic conditions it releases ammonia
and hydrochloric acid.
DM AP was chosen to initiate the reaction through
the removal of a proton of the ammonium salt.
, -cyclohexane
1 2
dicarboxylic
acid
Phthalic anhydride, cis-
anhydride,
c/s- 1 ,2 -cyclobutane
dicarboxylic acid anhydride, succinic anhydride, maleic anhydride, glutaric
anhydride, endo-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride and 1isopropyl-4-methyl-enc/o-bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic
anhydride w ere chosen to experimentally test the effectiveness of this
process. These reactions were done in a solventless system.
0
;0
O
+
NH4CI
Ammonium
Chloride
o
DMAP
(Base C atalyst).
MW
X ''''/
'q
+ Hz0 + HC|
Schem e 29. Microwave Cyclic Imide Synthesis using D M A P and N H 4 CI
The addition of a base catalyst seem s necessary to promote the
unsubstituted cyclic imide reaction.
Testing of ammonium chloride with
75
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anhydrides excluding DM AP did not produce a reaction.
DM A P also
seem s to increase microwave absorption allowing for increased heating
and melting of the reactants initiating am m onia formation.
An alternate
synthesis using imidazole as a base catalyst showed that cyclic imides
were formed with ammonium
percent yield.
chloride and phthalic anhydride in 40
Although imidazole worked as a base catalyst, isolated
product yields from DM AP w ere similar or better yields. (Schem e 30)
O
P
+ NH3
N
O
0
OH
NH2
+ nh3
O
NH4CI
o
o
- h 2o
o
-OH
nh2
NH
O
O
O
Schem e 30. Unsubstituted Cyclic Imides Synthesis Mechanism using
D M AP and NH4CI
Results from the microwave assisted unsubstituted cyclic imides
synthesis using cyclic anhydrides, DMAP, and ammonium chloride in a
multimode microwave ranged from 69 to 90 isolated percent yields with
reactions times between 2 to 5 minutes for six cyclic imides (Table 3).
These results are comparable to those for conventional conditions found
76
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in the literature.101
Six of the cyclic imide syntheses seem ed to give
reasonable isolated percent yields with the exception of m aleic anhydride
producing a dark unidentifiable solid. Tests which mixed m aleic anhydride
and D M A P produced a dark unidentified brown solid. As other anhydrides
reacted without complications only maleic anhydride seem s to be effected
by this synthetic technique.
Polymerization of the alkene in the maleic
anhydride m ay have occurred through a M ichael’s reaction as one
possible reason for byproduct formation. Also, approximately 5 % product
yields w ere obtained for compound (9) with steric crowding around the
reaction center as a possible cause of the low isolated yields (Tables 3
and 4).
To standardize this technique cyclic anhydrides, DM AP, and N H 4CI,
were irradiated in a monomode microwave under solventless conditions at
150 °C for 10 minutes.
To test the effectiveness of the monomode
synthetic technique similar cyclic anhydrides from the multimode reactions
were used.
Isolated unsubstituted cyclic imides percent yields were
between 81- 91 percent comparable to our multimode synthesis. (Table 4)
Both the m onomode and multimode reactions maintained similar trends
and yields for (9) showing approximately 5 percent yield.
77
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Unsubstituted Cyclic Imides from Ammonium Acetate and Cyclic
Anhydrides
This second microwave assisted synthesis of unsubstituted cyclic
imides utilized cyclic anhydrides using ammonium acetate as a source for
nitrogen.165,166
Since the first step of synthesizing unsubstituted cyclic
imides is the production of an amide-acid from an anhydride which can
also be considered an amidation.
No additional base catalysts were
added for the microwave synthesis using ammonium acetate unlike similar
microwave reactions done in this dissertation. (Schem e 31)
o
,0 +
O
0
---------- ►
Ammonium
MW
Acetate
N H 4O A c
I N nHh + H2
h 20
o + AcOH
|
AceticAcid
O
Schem e 31. Microwave Cyclic Imide Synthesis using N H 4OAc
The reaction mechanism for the use of N H 4O Ac was described by
Climent Montoliu et. al. to form acetic acid and am m onia.167 Ammonia is
then able to attack the anhydride allowing for ring opening into acid amide
functionalities.
group
attacking
Cyclization occurs through dehydration with the amide
the acid
group thereby producing the
cyclic imide
functionality. (Schem e 32)
78
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O
o
o
O
,0
Ammonium
Acetate
OH
NH2
+ NH3
O
O
O
O
O
NH
o
o
o
Schem e 32. Microwave Cyclic Imide Formation Mechanism using
NH4O A c .
The
multimode
synthesis of unsubstituted
cyclic
imides with
ammonium acetate used seven cyclic anhydrides similar to that of the
D M A P \N H 4CI reactions to experimentally test this method (Table 5).
Reaction times in the multimode microwave ranged between 15 to 240
seconds with sterically hindered (9) maintaining the longest reaction time.
Multimode microwave isolated percent ranged from 50 to 98 percent and
were considered excellent yields when compared to literature values.101
The lowest isolated product was the synthesis of phthalimide which seem s
to be an anom aly with
higher yields in the m onomode microwave
synthesis. Isolation techniques or an incomplete reaction m ay account for
this difference. Excluding this result the isolated product yield ranged from
72 to 98 percent. Although not shown in table 4 the microwave reaction of
79
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maleic anhydride and ammonium acetate was attempted with little desired
product formed.
Standardization
of
this
microwave
assisted
synthesis
of
unsubstituted cyclic imides used ammonium acetate and cyclic anhydrides
in a monom ode microwave with param eters of 5 minutes at 150 °C (Table
6).
This technique produced between 51 and 81 isolated percent yields
with com parable isolated percent yields in both the monomode and
multimode m icrowave-enhanced reactions.
The lowest isolated percent
yield w as for compound (9), although gave reasonable yield in the
multimode microwave.
The Reaction of Hydroxylamine (HCI) and Cyclic Anhydrides
The synthesis of cyclic A/-hydroxy imides was attempted using both
multimode and monomode microwaves.
Multiple techniques using an
array of reactants varying from the use of base catalysts such as
triethylamime with cyclic anhydrides and hydroxylamine (HCI) to the
synthesis
attempted.
of cyclic
anhydrides
with
hydroxylamine
phosphate
were
Although the desired products w ere occasionally formed no
consistent product yields w ere obtained.
Reactions repeated under
similar conditions w ere found to give different product yields, ultimately
producing the unsubstituted cyclic imides as the major product. Additional
80
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heating and increased base (catalyst) enhanced unsubstituted cyclic imide
formation.
Although not our intention, w e were able to use this technique to
synthesize unsubstituted imides using hydroxylamine as a source for
nitrogen, DM AP, and cyclic anhydrides for the cyclic carbon backbone
(Schem e 33).
Although this synthesis was found to produce the
unsubstituted cyclic imide a definite mechanism has yet to be determined,
although several possible mechanisms exist.
P + NH2OH (HCI) + DMAP
NH +
N-OH
O
Major Product Minor Product
Schem e 33. Microwave A/-Hydroxy Cyclic Imides Synthesis
A possible mechanism for unsubstituted cyclic imide formation is
the decomposition of hydroxylamine (HCI) into am m onia (Schem e 34).
The production of am monia then promotes unsubstituted cyclic imide
formation. This reaction seem s to be a faster alternate mechanism to that
of the predicted cyclic A/-hydroximide formation, or the direct reaction of
hydroxyl
am ine
with
anhydride.
The
mechanism
which
forms
the
unsubstituted cyclic imide from NH2O H (H C I) and cyclic anhydrides seems
to be aided by the addition of a base catalyst and additional heating.
81
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o
.0
NH3
Fast
NH2OH(HCI)
+
0
DMAP
Hydrolysis
o
NH
+
H20
0
Major Product
O
O
Slow
N-OH
P
NH2OH(HCI)
+ DMAP
O
Minor Product
O
Schem e 34. Alternate Mechanisms for the Hydroxylamine and Cyclic
Anhydride
The multimode microwave synthesis of this reaction used four
cyclic
anhydrides.
Specifically,
phthalic
anhydride,
c/s-1,2-
cyclohexanedicarboxylic acid anhydride, c/'s-1,2-cyclobutanedicarboxylic
acid anhydride, succinic anhydride w ere used to experimentally test this
synthetic technique (Table 7). The monomode microwave synthesis of this
techniques
used
glutaric
anhydride,
phthalic
anhydride,
c/'s-1,2-
cyclohexanedicarboxylic acid anhydride, c/s-1,2-cyclobutanedicarboxylic
acid
anhydride,
succinic
anhydride
(Table
8).
Comparisons
of the
multimode and monomode microwave used 4 of the sam e 5 anhydrides.
Multimode microwave reactions gave isolated product yields of
unsubstituted cyclic imides from 84 and 97 isolated percent yield.
The
yields which is equal to or better than that of conventional techniques.
82
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Reaction times ranges from 72 to 160 seconds or between 1 to 3 minutes.
Standardization of this technique used a m onomode microwave
with param eters of 5 minutes at 150 °C, (Table 8).
synthesis gave between 61
and 81
The monomode
isolated percent yields with no
anomalies found between unsubstituted cyclic product yields. Isolated
product yields w ere com parable to the multimode counterpart (Table7).
Differences in microwave power between the multimode and monomode
microwaves m ay play a part in the decomposition of the hydroxylamine.
The rapid increase in temperature of the multimode microwave may
increase the
conversion
of the
hydroxylamine
(HCI)
into ammonia,
thereby, giving slightly better yields.
Structural Identification of Unsubstituted Cyclic Imides
Several identification techniques such as NMR, G C - MS, IR,
melting
tem perature,
cyclobutanedicarboximide
and
w ere
X-ray
used
crystallography
to
establish
the
of
cis-1,2-
structure
of
unsubstituted cyclic imides synthesized from DM AP/NH4CI, ammonium
acetate, or hydroxylamine (HCI). These techniques w ere not only used to
identify the proper structure for the given cyclic imide, but as a comparison
between
products
of different synthetic techniques.
For example,
comparisons w ere m ade for the succinimide synthesized by DMAP/NH4CI,
83
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ammonium acetate, or hydroxylamine (HCI) to identify purity and the
proper structure. Structural identification of the unsubstituted cyclic imides
used 1H, 13C, and D E P T-C N M R which indicated the proper structure for
each cyclic imide. 1H N M R was done on the 4 0 0 M H z N M R indicating well
defined structures of the unsubstituted cyclic imides with little to no
impurities. Since many of the unsubstituted cyclic imides are simple
molecules 13C, D E P T-C NM R, and G C - M S w ere used as the primary
identification techniques for the cyclic imides. 13C and D E P T -C N M R gave
good structural identification of the given molecule, while retention time,
purity, and structure w ere determined by G C - MS.
The spectral data of
all molecules is reported in the experimental section.
Full characterization of the c/s-1,2-cyclobutanedicarboximide (4)
using NM R, G C - MS, IR, melting tem perature, and X -ray crystallography
identified the proper structure.
The 1H N M R indicates a symmetric
molecule that maintains 4 proton signals.
The 1H N M R showed proton
signals at 9.49 ppm for the -N H - proton, 3.324 ppm for 2 a-protons, 2.687
ppm for 2 alkyl protons, and 2.273 ppm for 2 alkyl protons. The 13C NM R
shows 3 signals at 181.49 ppm for the 2 carbonyl carbons, 39.77 ppm for
2 - C H - carbons, and 22.04 ppm for the 2 -C H 2- carbons as confirmed by
D E P T-C NM R.
The gas chromatograph indicated a single peak with the
m /z num ber of 125 corresponded to the molecular weight of c/s-1,2-
84
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cyclobutanedicarboximide.
The carbonyl absorption peaks are clearly
shown in the IR at 1723.8, 1781.2 and 320 8.9 cm '1. T h e melting point of
135-137 °C matched that of the literature value of 1 3 7 .5 -1 3 8 ° c . 176 A
single crystal of c/'s-1,2-cyclobutanedicarboximide w as isolated and sent
for x-ray analysis.
The x-ray analysis found a well structured cis-
cyclobutane and cyclic imide ring structure with an Ri value of 0.0491
(Figure 19). This crystal structure was published.168
Figure 19. The O R T E P structure of c/'s-1,2Cyclobutanedicarboximide
Additionally, characterizations of the unsubstituted cyclic imides in
the 1H N M R found a broad peak of the - N H - ranging from 7.88 ppm and
9.49 ppm for all unsubstituted cyclic imides tested.
Comparisons of the
85
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13C N M R of multiple unsubstituted cyclic imides using different synthetic
techniques w ere similar with peak differences within 1 ppm.
Carbonyl
carbons are well defined with 13C peaks ranging from 169.07 ppm to
182.11
ppm.
Tested melting points matched given literature values,
succinimide 122-124 °C (123-125 °C )169, phthalimide 2 2 6 -2 2 8 °C (232-235
°C ) 169, and glutarimide 154-156 °C (155-157 °C ).169 G C - M S was tested
on all sam ples to determ ine purity and molecular structure. The molecular
mass given by the Mass Spectrometer matched the molecular weights of
the unsubstituted cyclic imides.
M any of the cyclic imides 1H N M R w ere run on the Bruker 4 00 M Hz
N M R in both DMSO-cfe and CDCI3.
Differences - N H - chemical shift in
both solvents indicated the relative acidity of these imides to each other.
Because D M S O -d 6 is more polar than CDCI3 there seem s to be shifts in
the - N H - proton of between 1 and 4 ppm indicating the acidity of the
moiety.
Phthalimide seem s to be the most acidic with chemical shift
change of 3.6 and non-aromatic moieties of glutarimide and cis-1,2cyclohexanimide maintaining 1.52 and 1.54, respectively. (Table 21)
86
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Table 21. -N H - Proton shift difference using DMSO-ck and CDCI3
Entry
Imide
O
NH
-N H - (DMSO-dg)
-N H - (CDCI3)
11.05
8.98
11.31
7.71
10.58
9.06
11.25
9.49
10.93
9.53
10.98
8.49
10.91
8.04
til
NH
NH
NH
.0
(8 )
ym
O
87
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Advantages and Comparison of the Three Novel Techniques for the
Synthesis of Unsubstituted Cyclic Imides
Several advantages of these synthetic techniques are clearly seen.
The first advantage is a fast reaction allowing for rapid product production.
Reactions using N H 4OAc, N H 20H (H C I)/D M A P , NH4C I/D M A P occur within
seconds instead of hours limiting byproduct formation.
Secondly, these
reactions w ere done in a one-pot reaction in both a monomode and
multimode
microwave
producing
high
isolated
percent yields
under
solventless conditions removing any solvent waste. Multiple cyclic imides
were achieved with little workup and good yields that w ere comparable to
given literature values.
NH4OAc, DM AP, N H 4CI and N H 2O H (H C I) are
inexpensive reagents that are commonly found in organic laboratories.
NH4O A c , and N H 4C I/D M A P have also been found to work on both
anhydrides as shown in (Tables 3 through 8) and on diacids (Tables 12
and 13), respectively.
Comparison
assisted
synthesis
between the three techniques for the microwave
of
unsubstituted
cyclic
imides
found
all
three
techniques gave isolated percent yields of 50-98 % in the multimode and
4 1-91 %
in
the
monomode
microwave
excluding
several
products.
Although yields w ere relatively close, reaction times for each technique
seem ed to vary greatly between the three microwave techniques.
88
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The
fastest multimode microwave technique used ammonium acetate and
cyclic anhydrides giving isolated unsubstituted cyclic imides yields of 50 to
98 % within 15 to 100 seconds (Table 5). The second fastest multimode
microwave technique is the reaction of DM AP, hydroxylamine(HCI), and
cyclic anhydrides producing isolated unsubstituted cyclic imides yields of
42 to 97 % within 72 to 160 seconds. The slowest multimode microwave
techniques used DM AP, ammonium chloride, and cyclic anhydrides giving
isolated unsubstituted cyclic imides yields of 60 to 90 percent within 2 to 5
minutes. O ne specific exam ple of this is a time comparison of all three of
the microwave synthetic techniques of phthalimide. Multimode microwave
reaction times w ere 4 5 seconds, 160 seconds, and 5 minutes for the
NH 4 OAc, D M A P /N H 2
5, 7).
0
H(HCI), and D M A P /N H 4 CI, respectively (Tables 3,
O ne reason for the rapid reaction of ammonium acetate may lie in
its ability to readily breakdown and react under microwave radiation to
form am m onia and acetic acid initiating the reaction.
W hile all three microwave reactions gave good yields for the
synthesis of unsubstituted cyclic imides the reaction of ammonium acetate
seem s to generate unsubstituted cyclic imides that w ere not produced with
D M A P /N H 4 CI.
Specifically, imide (9) was generated in 4 2 and 72 %
isolated yield using ammonium acetate while D M A P /N H 4 CI produced
approximately 5 % isolated yields in both the m onomode and multimode
89
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microwave, respectively.
For its speed and ability to generate a wider
variety
cyclic
of
unsubstituted
imides
the
microwave
reaction
with
ammonium acetate seem s to be the best choice of all three techniques.
The Microwave Synthesis of Af-Methoxy Cyclic Imides
Cyclic A/-methoxyimides are important molecules currently found in
several biologically relevant m olecules.110 Structurally, A/-methoxyimides
are similar to unsubstituted cyclic imides making their synthesis and
incorporation into biologically relevant molecules of importance.
One
advantage of cyclic A/-methoxyimides over unsubstituted cyclic imides is
its
increased
w ater solubility
over
unsubstituted
imides,122 thereby,
increasing w ater absorption increasing its pharmaceutical benefit.
The
solventless microwave synthesis of A/-methoxyimides is explored for
decreased reaction times, the elimination of solvent waste, and easy
workups (Schem e 35).
0 +
O
,NOCH3 +
NH2OCH3 HCI
H20 +
HCI
MW
Schem e 35: Synthesis of /V-Methoxyimides using M ethoxyam ine (HCI)
Eight anhydrides w ere chosen to experimentally test this method in
the multimode microwave. Specifically, 3-nitrophthalic anhydride, phthalic
anhydride,
c/'s-1,2-cyclohexanedicarboxylic
acid
anhydride,
90
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c/s-1,2-
cyclobutanedicarboxylic
acid
anhydride,
anhydride,
glutaric
anhydride,
succinic
anhydride,
maleic
endo-bicyclo[2.2.2]oct-5-ene-2,3-
dicarboxylic anhydride and 1-isopropyl-4-methyl-endo-bicyclo[2.2.2]oct-5ene-2,3-dicarboxylic
anhydride
w ere
selected
to
test
this
synthetic
process. (Table 9) Additionally, six of the eight anhydrides w ere chosen to
standardize this method in the monomode microwave. (Table 10) These
five anhydrides w ere phthalic anhydride, succinic anhydride, glutaric
anhydride,
cis-1,2-cyclobutanedicarboxylic acid
anhydride,
and
endo-
bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic anhydride.
The multimode microwave synthesis of cyclic N-methoxyimides
using cyclic anhydride and m ethoxyam ine(HCI) produced good isolated
product yields of 4 7 to 98 percent, excluding (18). Yields w ere the lowest
for the bicyclic /V-methoxy cyclic imides with (16) and (18) yields are 47
and 17 percent, respectively (Table 9).
Lower yields m ay have resulted
from steric crowding of the beta carbon adjacent to the carbonyl carbons.
Increased reaction time and m ethoxyam ine(HCI) seem ed to increase
product yield when steric crowding occurred. Reaction times for the
synthesis of the cyclic A/-methoxyimides ranged from 17 to 100 seconds
(Table 9). These reaction times were short with all reactions occurring
within 2 minutes com parable to subsequent microwave syntheses of
unsubstituted cyclic imides and their derivatives.
T h e melting process
91
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seem s to work rapidly allowing the reaction to occur within seconds.
Standardization of this process used the monomode microwave for
5 minutes at 125 °C and 7 minutes at 180 °C. W hen conditions were set at
125 °C for 5 minutes isolated yields of the cyclic A/-methoxyimide product
were found to range between 40 and 54 percent (Table 10), while an
increase in tem perature and time resulted in an increase in yields to range
from 49 to 84 percent (Table 11).
This increase in tem perature and/or
time w as necessary to improve isolated product yields.
There is little
difference in product yield between the monomode reaction done for 7
minutes at 180 °C and the multimode synthesis.
An
advantage
of
the
microwave
synthesis
of
cyclic
N-
methoxyimides is that it is one of the first microwave assisted synthesis
found in the literature.
This solventless reaction reduces the need for
harmful solvent such as T H F .120 Shorter reaction times and high yields are
as also advantages of this microwave assisted synthesis.
Structural identification of the cyclic /V-methoxyimides, presented in
the experimental section, used such techniques as 1H NM R, 13C NMR,
D E P T-C
NMR,
GC
crystallography for
-
MS,
IR,
melting
tem perature,
and
X-ray
1-Methoxy-pyrrolidine-2,5-dione which indicated the
proper structure for each cyclic /V-methoxyimides.
1H N M R w as done on
the 4 0 0 M H z N M R indicating well defined structures with a singlet for the
92
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methoxy group approximately at 3.90 ppm.
Specifically, the full characterization of 1-Methoxy-pyrrolidine-2,5dione
indicated the proper structure. The 1H N M R maintained 2 signals,
with a singlet with 4 protons at 2.669 ppm that accounts for the protons on
the succinic ring, while a second singlet at 3.864 ppm indicated the
methoxy protons. Three signals were found in the 13C and D E P T-C N M R
which accounted for the carbonyl carbons at 171.19 ppm, the methoxy
carbon at 6 4 .1 6 ppm and the alkane carbon at 25.42 ppm. A carbonyl
band w as clearly seen at 1711.9 cm '1 in the IR spectrum. W hile the G C M S showed a single peak, in the G C and with the mass spectra giving m /z
number of 129 corresponded to the proper molecular weight.
The X-ray
crystal structure of 1-methoxy-pyrrolidine-2,5-dione confirmed the well
formed structure with a R-i of 0.0347 (Figure 20).
93
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T3
,C2
Figure 20. The O R T E P structure of 1-Methoxy-pyrrolidine-2,5-dione
Similar to 1-Methoxy-pyrrolidine-2,5-dione all remaining compounds
closely match the structural data.
Generally, the methoxy groups are
slightly shifted residing at approximately 64 ppm in the 13C N M R for all
cyclic A/-methoxyimides.
Since many of the cyclic N-methoxyimides are
symmetric signal overlapping is found in both the 13C and D E P T -C NMR.
The carbonyl carbons are clearly seen in the 13C N M R at approximately
172 ppm for all cyclic /V-methoxyimides.
The Microwave Synthesis of Thalidomide and its Analogs
Thalidom ide
and
its analogs
are
pharmaceuticals
which
are
currently under investigation for effects on the modulation of the immune
system.
Currently, thalidomide is a C O X -2, T N F a , and angiogenesis
94
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inhibitors and is used to treat diseases such as H IV /A ID S , Crohn’s
disease, Leprosy, Behcet’s disease, graft-versus-host disease (G VH D ),
and multiple forms of cancers.170,171172,173
M any thalidomide syntheses
are tedious, give low product yields, use expensive reagents, and maintain
long reaction times. Secondly, thalidomide derivatization centers on the
glutaric ring which limits easy alterations for the syntheses of thalidomide
analogs.
Microwave organic chemistry has expanded exponentially, over the
last twenty years due to its easy workups, rapid turn around, and high
yields.63'69 The speed at which microwave reactions are done, matches
well with combinatory processes to synthesize analogs for improved
biological activity when compared to low-yielding conventional synthesis
especially
that
of thalidomide
and
its
analogs
(2 4 % ).143 Although
microwave technology is being used for many important compounds, only
one reference has applied microwave assisted reactions to thalidom ide.142
This synthesis focused only on thalidomide and
not the systematic
production of its analogs. Due to the increased interest in thalidomide and
its analogs no synthesis has focused on the systematic high yield
synthesis of thalidomide and its analogs.
The novel microwave assisted synthesis of thalidomide and its
analogs was improved over current conventional and microwave assisted
95
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synthesis by the high yield production of thalidomide and its systematic
derivatization within minutes. Previous derivatives modified the glutarimide
ring w here this work focuses on the phthalic rings allowing for the addition
of many carbon skeletons including bicyclic systems.
This method is
simple using inexpensive materials in a one pot reaction mixture.
This
method can be applied to produce countless thalidomide analogs in high
yield with easy scale up. The microwave assisted synthesis uses DM AP
as a base catalyst, glutamic acid to form the glutarimide ring, ammonium
chloride as a source of nitrogen, and a series of cyclic anhydrides for the
carbon backbone in a one-pot reaction (Schem e 36). To synthesize
derivatives of thalidomide several anhydrides w ere chosen to modify the
structure
of
thalidomide.
Specifically,
phthalic
anhydride,
c/s-1,2-
cyclohexanedicarboxylic acid anhydride, c/'s-1,2-cyclobutanedicarboxylic
acid anhydride, succinic anhydride, and endo-bicyclo[2.2.2]oct-5-ene-2,3dicarboxylic anhydride w ere chosen for the microwave assisted synthesis
of thalidomide and its derivatives.
o
DMAP
CatalyticBase
O
Microwave
O
Schem e 36: Thalidomide and its Derivatives Synthesis
The
microwave assisted
synthesis of thalidomides found that
DMAP/NH4CI gave the best yields with modification of the cyclic imides
96
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
rings.
Although only one process is discussed three processes for the
synthesis of unsubstituted cyclic imides w ere tested along with another
published microwave thalidomide synthesis142 (Tables 3, 5, 7).
The
techniques for unsubstituted cyclic imide formation in this dissertation
used ammonium acetate and hydroxylamine(HCI) gave good yields of the
unsubstituted cyclic imides but did not work well in a multi-step process to
form
thalidomide.
The
speed
of these
reactions
disadvantage for the synthesis of thalidomide.
seem s
to
be a
There are two competing
reactions which occur in the synthesis of thalidomide, with unsubstituted
cyclic imide formation is favored over thalidomide synthesis. Thalidomide
formation in a one-pot is a slow process due to the need for a specific
progression of reactions.
formation
requires
fewer
However, the unsubstituted cyclic imides
mechanistic
steps
only
needing
ammonia
formation to initiate the reaction. Faster imides synthetic processes using
NH4O A c and D M A P /N H 2O H (H C I) seem s to drive unsubstituted cyclic
imide production with thalidomide yields found between 4 and 10 percent.
Only the synthesis using D M A P /N H 4CI allows enough time for thalidomide
formation to occur (Schem e 37).
97
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o
h 2n
o
c o 2h
n h 4o a c
p
NH
+
c o 2h
O
O
+
other Products
Fast
H2N
COzH
O
O
NH4CI
DMAP
P +
c o 2h
o
o
Slow
o
o
Schem e 37: Thalidomide and its Derivatives Formation
The synthesis of thalidomides and its derivatives used glutamic
acid, DM AP, ammonium chloride, and cyclic anhydrides for the cyclic
carbon backbone.
One possible mechanism uses the primary am ine of
the glutamic acid to form a cyclic imide.
The reaction of the DM AP and
ammonium chloride produces ammonia which reacts with the diacid
moiety of the glutamic acid forming thalidomide. (Schem e 38) A second
possible
mechanism
produces
the
unsubstituted
cyclic
imide
from
glutamic acid using the ammonia generated by DM A P and N H 4CI in the
microwave.
T h e primary am ine of the 3-Am ino-piperidine-2,6-dione is
then able to react with the phthalic anhydride forming thalidomide.
(Schem e
38)
This
process
is applicable
with
different
anhydride
derivatives yielding those derivatives.
98
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DMAP
O
P
+
H2N v ,C 0 2H
P
n h 4ci
un
+
r ---c o 2H
o
\ /\
^
N -0 = °
fr
o
o
NH
OH
OR
h 2n
c o 2h
DMAP
+
h 2n
r1
C 02H
o
" O VNH —
TVC
^
> -N H
O
0
O
Schem e 38: Possible Mechanisms of formation of Thalidom ide and its
Derivatives
The
multimode
microwave
synthesis
of
thalidomide
and
its
derivatives used glutamic acid, DMAP, NH4CI, and cyclic anhydrides
thoroughly mixed in an 8 ml Teflon capped vial.
This mixture was
irradiated in a multimode microwave until vigorous bubbling occurred and
a dark brown color w as noticed. The reaction vial w as allowed to cool to
room tem perature and purified.
The multimode microwave synthesis of
thalidomide resulted in isolated product yields from 32 to 53 percent with
reaction times between 2 and 7.25 minutes (Table 12).
The lowest
isolated product yield w as that of thalidomide derivative (21 ) with the other
compounds maintaining approximately 50 percent isolated yield.
Standardization of the microwave synthesis of thalidomide set the
monomode microwave reaction conditions at 150 °C for 10 minutes with
isolated yields ranging from 47 to 86 percent (Table 13).
This process
99
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seem s to give better yields compared to the multimode microwave
synthesis, giving an isolated product yield of thalidomide at
percent.
8 6
The eighty-six percent yield is extremely high when synthesized in a onepot reaction.
O ther thalidomides derivatives percent yields were also
slightly increased with a range from 4 7 to 59 percent.
Column chromatography of these samples w as unsuccessful in
separating the unsubstituted cyclic imides and thalidomide analogs.
A
novel technique for the isolation of thalidomide and its analogs was
utilized to provide
pure compounds.
Thalidomide w as
isolated
by
dissolving the mixture in a minimum amount of ethyl acetate: acetone
(50:50) then washing with saturated sodium bicarbonate solution.
The
organic layer w as concentrated and the thalidomide w as precipitated with
hexanes.
The remaining unsubstituted cyclic imides remained in the
solution while the thalidomide analogs precipitated out of the solution as a
light brown solid. All thalidomide derivatives w ere isolated similarly.
Structural identification used
1
H,
13
C, D E P T -C N M R , G C - MS, IR,
and melting tem perature which indicated the proper structure for each
thalidomide derivative.
The
1
H,
13
C, and D E P T-C N M R of thalidomide
corresponded well with literature values. The 1H N M R showed
6
signals
with the - N H - proton peak at 11.14 ppm, 4 aromatic protons at 7.94 ppm,
the -C H -N proton at 5.17 ppm(dd), one proton at 2.92 ppm, 2 protons at
100
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2.57 ppm and 1 proton at 2.09 ppm.
This corresponds well with the
published values of thalidomide with the -N H - proton at 11.16 ppm, 4
aromatic protons between 8.05-7.80 ppm, a proton at 5.18 ppm, 1 proton
between 3 .0 5 -2 .8 5 ppm, 2 protons between 2 .7 0 -2 .4 5 ppm, and 1 proton
between 2 .1 5 -2 .0 0 ppm . 1 7 4 The 13C N M R gave 9 signal with 3 carbonyls
at 172.7 ppm, 169.8 ppm, and 167.1 ppm, the aromatic carbons at 134.9
ppm, 131.2 ppm, 123.4 ppm, the - C H - carbon at 49 .0 ppm, and the two
remaining C H 2 at 30.9 ppm and 22.0 ppm. The literature 13C N M R values
of thalidomides found 3 carbonyls at 172.8 ppm, 169.8 ppm, and 167.1
ppm, 3 aromatic carbons at 134.9, 131.2, and 123.4 ppm, a chiral carbon
at 49 .0 ppm and two C H 2 at 30.9 ppm and 22 .0 ppm . 1 7 4
G C - M S gave
the proper m olecular mass of 258 with the melting point between 268-270
°C (269 - 271 °C ) . 141 All other derivatives w ere determined similarly.
Comparison
studies
which
used
thiourea,
D M A P /N H 4 CI,
and
NH4OAc w ere done using similar molar ratios in both the multimode and
m onomode microwaves (Tables 14, 15).
These studies used the gas
chromatographic ratio of unsubstituted cyclic imides (phthalimide) to
thalidomide obtained from the G C -M S spectra with identification using a
matching of N IS T 98 database. Comparisons in both the monomode and
multimode microwave produced in all instances slightly higher percent
yields of thalidomide for the D M A P /N H 4 CI reaction than that of the
101
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thiourea reaction.
The Microwave Synthesis of Cyclic Enaminones
Cyclic enam inone are moieties which are found in many biologically
active molecules. Although cyclic enaminones are common few synthetic
techniques which combine the speed, high yield, and easy workup of
microwave synthesis have been done.
Currently, there is only one
microwave synthesis of cyclic enaminones which uses N H 4OAc and a
montmorillonite solid support . 1 5 3
Advantages
of
our
microwave
assisted
synthesis
for
cyclic
enam inone over current synthetic techniques are in time, reaction done
within minutes instead of hours,
reducing agents,
and the
146
simple workup with the use of
lack of reagents such as palladium
montmorillonite solid support . 151
and
This approach uses the microwave
reaction of 1,3 cyclohexadiones as a carbon backbone with ammonium
acetate as a source of nitrogen to form the enam inone moiety without the
use of expensive montmorillonite solid support (Schem e 39).
102
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D
K
h
NH4OAc
R1 = H, CH3
R2=H, CH3 n = 0 , 1
Schem e 39. The Synthesis of Cyclic Enaminones using N H 4OAc
Four 1,3 cycloalkanediones were used to experimentally
test the
validity of microwave synthesis of cyclic enam inones in the multimode
microwave.
Specifically,
cyclohexanedione,
5,5-dim ethyl-1,3-
2-m ethyl-1,3-cyclopentadione,
cyclopentanedione w ere
cyclohexadione,
1,3-cyclohexanedione,
used.
1,3-cyclohexadione,
2-m ethyl-1,3-cyclopentanedione
and
5,5-dim ethyl-1,3-
w ere
standardize this reaction in monomode microwave.
1,3-
chosen
Each
to
molecule
structurally maintains 2 ketone functionalities separated by one carbon on
a cyclic ring backbone.
The microwave enhanced synthesis of cyclic enam inones used
ammonium acetate and 1,3 cycloalkanediones. Ammonium acetate is
used as a base to remove a proton from the ammonium salt producing
gaseous am m onia.
Am m onia is then able to attack the carbonyl carbon
allowing for the production of a primary am ine and alcohol functionalities.
A dehydration of the alcohol forms an alkene yielding the enaminone
moiety (Schem e 40).
1 03
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-0
o.
NH4OAC
n h 2 + A C 0H
Schem e 40. The Mechanism of Cyclic Enam inones Formation using
NH4OAc
The multimode microwave synthesis of cyclic enam inones reacted
1,3 cyclic diones with ammonium acetate in an 8 ml Teflon capped vial.
This was irradiated in a multimode microwave until vigorous bubbling
occurred and a dark yellow to brown mixture was noticed. The sample
isolation used column chromatography with a methanol: acetone (80:20)
mobile phase. The microwave reaction times w ere steady at 45 second
with
isolated
product
yields
from
71
to
91
percent.
(Table
16)
Synthetically, the synthesis of cyclic enam inones w as easy with simple
isolations.
Standardization of this method used the conditions of 150 °C for 5
minutes with isolated product yields ranging from 76 to 92 percent (Table
17).
Isolation used column chromatography similar to the multimode
isolation.
and
Isolated product yields w ere com parable in both the multimode
m onomode
microwave
with
yields
consistent
to
conventional
techniques and microwave techniques.
Structural
identification
of the
cyclic
enam inones
used
such
techniques as 1H N M R , 13C NM R, D E P T-C NM R, G C - MS, IR, melting
tem perature,
and
X-ray
crystallography
which
indicated
the
1 04
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proper
structure for each enam inone of 3-am ino-2-cyclopenten-1-one. The 13C
N M R and D E P T -C N M R showed five signals with the carbonyl carbon at
202.61 ppm, the
N H 2-C = C at 178.71 ppm, C = C -H carbon at 99.30 ppm,
and 2 - C H 2- at 3 4 .0 0 ppm and 27.62 ppm. The G C - M S showed a single
peak with a m /z num ber of 97 which corresponds to the proper molecular
weight of 3-am ino-2-cyclopenten-1-one. The X-ray crystal structure of 3am ino-2-cyclopenten-1-one provided well defined structure with a Ri value
of 0.0554. This structure has been published.175 (Figure 21)
Figure 21. The O R T E P structure of 3-am ino-2-cyclopenten-1-one
The remaining compounds w ere also properly identified using
spectral data presented in the experimental section.
105
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The Synthesis of Enaminone - Imide Conjugates
Enam inone - imide conjugates are the coupling products of cyclic
anhydride with biologically important cyclic enam inones.145 This process
sought to synthesize these novel materials for possible biological testing.
Although the syntheses of cyclic enaminones and som e derivatives are
well
known this
is the first synthesis of this series
derivatives found in the literature.
of enaminone
This microwave synthesis used the
reaction of cyclic enaminones, cyclic anhydrides, with D M A P as a base
catalyst under solventless microwave conditions to produce enoneimides
(Schem e 41).
These reactions used enaminones produced earlier by
solventless microwave synthesis (Tables 16 and 17).
DMAP
O
O
Schem e 41. The Microwave Synthesis of Enoneimides conjugate
The
synthesis
of
enoneimides
used
anhydrides for the cyclic carbon backbone.
enam inone
and
cyclic
This synthesis used the
primary am ine of the enaminones to open the cyclic anhydride to an
amide acid functionality.
This is accomplished through a nucleophillic
attack at the carbonyl of the anhydride.
Ring closure occurs with the
amide group attacking at the acid group, thereby, removing the hydroxyl
functionality yielding the cyclic imide product (enoneimides).
1 06
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The
multimode
microwave
gave
isolated
product
yields
of
enoneimides between 7 5 -88 percent with reaction times ranging from 2 to
3 minutes (Table 18). The products w ere identified by G C - MS. Isolation
used
column
Standardization
chromatography
of
the
with
microwave
pure
synthesis
acetone
of
as
enoneimides
eluent.
used
m onomode microwave conditions of 150 °C for 10 minutes with isolated
product yields between 54 to 84 percent (Table
19).
Yields were
com parable to that of the multimode synthesis.
Conclusions about the Microwave Assisted Synthesis of Cyclic
Imides and their Derivatives
In this dissertation, several novel solventless microwave syntheses
of cyclic imides and their derivatives w ere produced. These methods used
the advantages of microwave chemistry producing the products in high
yields, within minutes, easy workup and eliminating of the use of solvents,
exotic reagents, or catalysts.
Three novel microwave assisted syntheses of unsubstituted cyclic
imides w ere developed in both monomode and multi m ode microwaves.
The anhydrides w ere converted to the unsubstituted cyclic imides either
by reaction with:
1) Ammonium chloride and DMAP.
107
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2) Am monium acetate.
3) Hydroxylamine (HCI), DMAP.
The novel microwave assisted synthesis of cyclic A/-methoxy imides
was revealed in high-yield using cyclic anhydrides and methoxylamine
(HCI). M icrowave reactions conditions for the m onomode microwave were
set at 180°C and 7 minutes to find isolated product yields comparable to
that of the multimode synthesis.
The reaction conditions w ere optimized
to provide good yields. A novel one pot microwave assisted synthesis of
thalidomide and its analogs was developed using cyclic anhydrides,
glutamic acid, DM AP, and N H 4CI.
Cyclic enam inones can be produced,
through a microwave assisted reaction using cyclic 1,3-cycloalkanediones
and ammonium acetate, in good isolated yields with drastic reduction in
reaction time. The enam inone can also be converted to enaminone-im ide
conjugates.
108
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IV. MATERIAL AND METHODS
Both multimode and monomode microwave systems are currently
used
for
microwave
enhanced
organic
synthesis.
The
multimode
microwave is a conventional Kennmore Microwave Oven (Household)
Output: 1100 W atts (Frequency: 245 0 M Hz). Tw o m onomode microwaves,
CEM Discover and Personal Chemistry Optimizer, are used as industrial
standards. Reactions in the multimode (commercial) microwave use an 8
ml Teflon capped vial.
Isolation
procedures
use
TLC
as
a
basis
for
the
column
chromatography of the materials. Addition procedures will be purification
through solubility. G as Chromatography Mass Spectrometry (G C - MS)
will be used to quantify and identify the amounts of product and possible
byproducts found in the purified materials.
Standardized methods for the identification of cyclic imide products
will consist of (G C - M S), 1H NM R, 13C NM R, D E P T -C N M R , Melting Point,
and Infrared Spectroscopy (IR).
completely
analyzed
Chromatograph
M ass
by
all
Every new compound synthesized was
corresponding
Spectrometry
was
techniques.
performed
using
All
Gas
either
a
Shimadzu G C -17A and G C - M S -Q P 5050A labsolutions system or a
Varian C P 380 0 and Saturn 2200 system.
109
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All IR spectra w ere performed on a Perkin-Elm er Spectrum R X I IR
system. All melting points determinations w ere performed on a Laboratory
Devices M el-Tem p
II instrument.
1H, 13C and D E P T -C
N M R were
performed on both a Bruker 4 0 0 M H z and a rebuilt 90 M H z N M R Anasazi
Instruments.
Scientific
All solvent (HPLC grade) w ere purchased from Fisher
Corporation.
All
reagents
w ere
purchased
from
Chemical Com pany and were used without purification.
Monomode Parameters
Bicvclic Anhydrides
Power:
150 mw
Ramp:
10 minutes
Hold:
5 minutes
Tem perature: 150 °C
Pressure:
2 50 psi
Stirring:
On
Unsubstituted Cyclic Imides (D M A P / NH^CI)
Power:
150 mw
Ramp:
20 minutes
Hold:
10 minutes
110
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Aldrich
Tem perature: 150 °C
Pressure:
2 50 psi
Stirring:
On
Unsubstituted Cyclic Imides (NhbOAc)
Power:
150 mw
Ramp:
10 minutes
Hold:
5 minutes
Tem perature: 150 °C
Pressure:
2 50 psi
Stirring:
On
Unsubstituted Cyclic Imides (D M A P / NH?O H(HCm
Power:
150 mw
Ramp:
10 minutes
Hold:
5 minutes
Tem perature: 150 °C
Pressure:
2 50 psi
Stirring:
On
A/-Methoxvimides
111
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Power:
150 mw
Ramp:
10 minutes
Hold:
7 minutes
Tem perature: 180 °C
Pressure:
2 50 psi
Stirring:
On
Cyclic Enam inones
Power:
150 mw
Ramp:
10 minutes
Hold:
5 minutes
Tem perature: 150 °C
Pressure:
2 50 psi
Stirring:
On
Enam inone Imide Conjugates
Power:
150 mw
Ramp:
20 minutes
Hold:
10 minutes
Tem perature: 150 °C
Pressure:
2 50 psi
112
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Stirring:
On
Thalidom ides D M A P / NhUCI
Power:
150 mw
Ramp:
20 minutes
Hold:
10 minutes
Tem perature: 150 °C
Pressure:
2 5 0 psi
Stirring:
On
Shimadazu GC - MS Parameters
Sampling Time:
0.8 min
Injection Tem perature:
250°C
Interface Tem perature:
280°C
Column Mode:
Splitless
Column Inlet Pressure:
8.2 psi
Column flow:
1 ml/min
Linear Velocity:
36.4 cm/sec
Split Ratio:
48
Total Flow:
50 ml/min
113
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Column information:
X T I-5
Serial:
# 203641
Thickness:
0.25 urn
Length:
30 m
Diameter:
0.25 urn
Max use:
325 C
Shim adazu G C Param eters
GC program time:
20.63 min
1) Start 60°C (hold 1min)
2) Ram p from 60°C to 250°C (rate 20°C per minute)
3) Hold 250 °C (10 min)
Shim adazu M S Param eters
Acquisition Mode:
Detector Voltage :
Scan
Relative to Tuning result
0.1 kV
Threshold:
1000
Interval:
0.5 sec
Solvent Cut off Time:
4 min
Start time:
4 min
1 14
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End time:
20 min
Start:
40 m/z
End:
350 m /z
Scan Speed:
1000
Shim adazu Pressure Param eters
1) Start 8.2 psi (hold 1 min)
2) Rate 8.2 psi to 18.7 psi (rate 1.1 psi)
3 )1 8 .7 (hold 10 min)
Varian GC - MS Parameters
Sampling Time:
0.8 min
Injection Tem perature:
250°C
Interface Tem perature:
280°C
Column Mode:
Splitless
Thickness:
0.25 urn
Length:
30 m
Diameter:
0.25 urn
Max use:
325 °C
115
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Varian G C M S Param eters
G C program time:
20.00 min
1) Start 50°C (hold 1min)
2) Ram p from 50°C to 250°C (rate 20°C per minute)
3) Hold 250°C (10 min)
Varian M S Param eters
Acquisition Mode:
Scan
Detector Voltage :
Relative to Tuning result
Solvent Cut off Time:
4 min
Start time:
4 min
End time:
20 min
Start:
40 m/z
End:
350 m /z
Varian Pressure Param eters
1) Start 8.2 psi (hold 1 min)
2) Rate 8.2 psi to 18.7 psi (rate 1.1 psi)
3) 18.7 (hold 10 min)
116
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V. EXPERIMENTAL
endo-Bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylic
anhydride
cyclohexadiene (0.40 g, 5.1 mmol) and maleic anhydride
mmol) w ere mixed in an 8 ml Teflon capped vial.
(1):
1,3-
(0.50 g, 5.1
The mixture was
allowed to heat for 57 seconds at full power in the multi mode microwave
and then cooled to room temperature. A sample was isolated and injected
into the G C - M S to determine purity of the anhydride sample.
The
sample w as purified with a silica column (30 g) using AcOEt: acetone
(1:1).
Fractions 6 -1 3 w ere isolated yielding a white solid (0.65 g, 72% ).
The endo product w as verified with an authentic sam ple of the endo
product sold by Aldrich Chemical Company, mp 132-134 °C; 1H -N M R (400
M Hz) in C D C b : 5 (ppm) = 6.31 (dd, J = 3.16, 4 .5 Hz, 2H ), 3.23 (m, 2H),
3.12 (t, J = 1.7 Hz, 2H ), 1.60 (m, 2H), 1.41 (m, 2H ), 13C -N M R (100 M Hz) in
CDCb: .5 (ppm) = 172.75 (C = 0 ), 133.04 (CH), 4 4 .7 7 (C H ), 31.63 (CH),
22.98
(C H 2); M S m /z 178 (M +) 149, 91,78; IR (chloroform) (v, cm '1):
1715.5, 1780.9 (C = 0 ).
e n d o - Bicyclo[2.2.2]oct-5-ene-2,3-
dicarboxylic anhydride
cyclohexadiene (0.10 g, 1.24 mmol) and maleic anhydride
(1): 1,3-
(0.12 g, 1.24
mmol) w ere thoroughly mixed in a CEM -sealed vial with a magnetic stirrer.
117
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The mixture w as capped and heated in a C EM Discover microwave for 5
minutes at 150 °C.
The sample was rapidly cooled to room temperature
yielding a white solid. The sample was dissolved in 4 ml of ethyl acetate
and w as precipitated with 2 ml of hexanes to afford a white solid (0.14 g,
63% ) M S m /z 178 (M +) 149, 91, 78.
1-lsopropyl-4-methyl-e/ido-bicyclo[2.2.2]oct-5-ene-2,3anhydride (2):
dicarboxylic
a-Terpenine (1.0 g, 7.33 mmol) and m aleic anhydride
(0.72 g, 7.34 mmol) w ere mixed in an 8 ml Teflon capped vial.
The
mixture w as allowed to heat for 1 minute at full power in the multi mode
microwave and then cooled to room tem perature.
T h e sample was
purified with a silica column (30 g) using ethyl acetate: hexanes (1:1)
yielding a white solid (1.60 g, 92% )
mp 50-52 °C. 1H -N M R (400 M Hz)
(C D C I3): 6 (ppm) = 6.11 (d, J = 8.12 Hz, 1H), 6.02 (d, J = 8.52 Hz, 1H),
3.23 (d, J = 8.75 Hz, 1H), 2.86 (d, J = 8.75 Hz, 1H), 2 .5 7 (septet, J = 6.85
Hz, 1H), 1.51 (s, 3H), 1.31 - 1.48 (m, 4H ), 1.09 (d, J = 6.9 6 Hz, 3H), 1.02
(d, J = 6.8 0 Hz , 3H); 13C -N M R (100 M H z) in C D C I3: 5 (ppm) = 171.47
(C = 0 ), 170.85 (C = 0 ), 136.96 (CH), 136.28 (CH), 5 0.94 (C H ), 4 7 .2 0 (CH),
4 3.50 (C), 36.69 (C), 33.61 (C H 2), 29.32 (C), 22.66 (C H 2), 2 2.17 (C H 3),
18.27 (C H 3), 16.64 (C H 3); M S m /z 234 (M +) 163, 135, 119, 91; IR
(chloroform) (v, cm’1): 1770.6, 1834.2 (C = 0 ).
118
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1-lsopropyl-4-methyl-endo-bicyclo[2.2.2]oct-5-ene-2,3anhydride (2):
dicarboxylic
a - Terpenine (0.10 g, 0.73 mmol) and maleic anhydride
(0.07 g, 0.7 3 mmol) w ere thoroughly mixed in a C E M -sealed vial with a
magnetic stirrer. The mixture was capped and heated in a C E M Discover
microwave for 5 minutes at 150°C.
The sam ple w as rapidly cooled to
room tem perature yielding a white solid. The sam ple w as dissolved in 4
ml of ethyl acetate and was precipitated with 2 ml of hexanes to afford a
white solid (0.1 4 g, 82% ) M S m /z 234 (M +) 163, 135, 119, 91.
Succinimide (3): Succinic anhydride (1.0 g, 10 mmol), D M A P (0.17 g, 1.4
mmol), and N H 4CI (0.68 g, 13 mmol) w ere mixed in an 8 ml Teflon capped
vial. The mixture was allowed to heat for 2 minutes at full power in the
multi mode microwave and then cooled to room temperature. The sample
was extracted with ethyl acetate: acetone (1:1) and aq. NaHCOs solution.
The organic layer was concentrated affording a white solid (0.68 g, 69% ).
mp 122-124 °C. [123-125 °C ]169; 1H -N M R (400M H z) in C D C I3: 5 (ppm) =
8.98 (bs, 1H, NH), 2.76 (s, 4H); 13C -N M R (100 M H z) in C D C I3: .5 (ppm) =
178.07 (C = 0 ), 2 9 .5 7 (C H 2); M S m /z 99 (M +) 56; IR (chloroform) (v , cm '1):
3199.05, 1711.0, 1775.14 (C = 0 ).
119
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Succinimide (3): Succinic anhydride (0.50 g, 4 .9 9 mmol) and ammonium
acetate (N H 4OAc) (0.38 g, 4 .929 mmol) w ere mixed in an 8 ml Teflon
capped vial. The mixture was allowed to heat for 38 seconds at full
percent power in the multi mode microwave and then cooled to room
temperature.
The sample was dissolved in A cO E t and washed with aq.
N a H C 0 3 solution. The organic layer was concentrated affording a white
solid (0.36 g, 73% ).
13C N M R (90 M Hz, C D C I3) 6 178.1, 29.6; M S m /z 99
(M +) 56.
Succinimide (3): Succinic anhydride (0.50 g, 3.37 mmol) and ammonium
acetate (0.42 g, 7.8 5 mmol) were mixed in a C E M -sealed vial with a
magnetic stirrer. The mixture was allowed in a C E M Discover microwave
to heat for 5 minutes at 200 °C and allowed to cool to 4 0°C affording a
white solid. The sample was extracted with ethyl acetate (40 ml) and aq.
N a H C 0 3 (10 ml) solution. The organic layer was isolated and dried
affording a white solid (0.40 g, 43% ). M S m /z 99 (M +) 56.
Succinimide (3): Succinic anhydride (0.20 g, 2.00 mmol), hydroxylamine
hydrochloride (0.1 4 g, 2.0 0 mmol), and DM A P (0.04 g, 0.34 mmol) were
thoroughly mixed in a CEM -sealed vial with a magnetic stirrer.
The
mixture was capped and heated in a C EM Discover microwave for 5
120
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
minutes at 150 °C.
The sample was rapidly cooled to room temperature
yielding a dark brown solid.
The sample was dissolved in 4 ml of ethyl
acetate and w as washed with (2x) 2ml of aq. NaHCC >3 solution.
The
organic layer w as dried to afford a white solid (0.14 g, 7 1% ) M S m /z 99 (M
+) 56.
S u c c in im id e (3):
Succinic anhydride (0.10 g, 1.00 mmol), ammonium
chloride (0.05 g, 1.00 mmol), and DM A P (0.04 g, 0.34 mmol) were
thoroughly mixed in a CEM -sealed vial with a magnetic stirrer.
The
mixture w as capped and heated in a C E M Discover microwave for 5
minutes at 150 °C.
The sample was rapidly cooled to room temperature
yielding a dark brown solid.
The sample was dissolved in 4 ml of ethyl
acetate and w as washed with (2x) 2ml of aq. NaHCOs solution.
The
organic layer was dried to afford a white solid (0.09 g, 91% ) M S m /z 99 (M
+) 56.
S u c c in im id e (3): Succinic anhydride (1.0 g, 10 mmol), DM A P (0.12 g,
0.99 mmol), and N H 2O H (H C I) (0.80 g, 11 mmol) w ere mixed in an 8 ml
Teflon capped vial. The mixture was allowed to heat for 1 minute 49
seconds at full power in the multi mode microwave and then cooled to
room tem perature.
The sample was dissolved in acetone and flashed
121
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chromatographed using a silica column (30 grams) with pure acetone.
The organic layer was concentrated affording a yellow solid (0.95 g, 96% )
MS m /z 99 (M +) 56.
Phthalimide (4): Phthalic anhydride (1.0 g, 6.7 5 mmol), D M A P (0.17 g,
1.4 mmol), and N H 4CI (0.42 g, 7.85 mmol) w ere mixed in an
capped vial.
ml Teflon
8
The mixture was allowed to heat for 4 minutes and 11
seconds at 30 percent power in the multi mode microwave and then
cooled to room temperature.
The sample was washed down a short
column ( - 3 0 g) with pure acetone.
The organic layer was concentrated
affording a yellow solid (0.80 g, 81% ).
1
mp 2 2 6 -2 2 8 °C. [232-235 °C 169];
H -N M R (40 0 M H z) in C D C I3: 5 (ppm) = 7.88 (m, 2H), 7.7 7 (m, 2H ), 7.71
(bs, 1H, NH):
13
C -N M R (100 M Hz) in D M S O -d 6): 5(ppm) = 169.07 (C = 0 ),
134.07 (C H ), 132.56 (C), 122.77 (CH); M S m /z 147 (M +) 104, 76, 50; IR
(chloroform) (v, cm '1): 3271.70, 1740.9, 1778.2 (C = 0 ).
Phthalimide (4): Phthalic anhydride (0.50 g, 3.37 mmol) and ammonium
acetate (N H 4 OAc) (0.30 g, 3.89 mmol) w ere mixed in an
8
ml Teflon
capped vial. The mixture was allowed to heat for 4 7 seconds at full
percent power in the multi mode microwave and then cooled to room
temperature.
The sam ple was dissolved in ethyl acetate (30 ml) and
122
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washed with aq. N a H C 0
3
solution. The organic layer w as concentrated
affording a white solid (0.25 g, 50% ). mp 2 2 6 -2 2 8 °C. 13C N M R (90 MHz,
C D C I3) 5 169.3, 134.2, 132.6, 122.9; D E P T-C N M R (90 M Hz, C D C I3) 5
169.3 (C = 0 ), 134.2 (CH), 132.6 (C), 122.9 (CH); M S m /z 147 (M +) 104,
76, 50; IR (chloroform) (v, cm’1): 3274.07, 1739.7, 1776.8 (C = 0 ).
Phthalimide (4): Phthalic anhydride (1.0 g, 6 .75 mmol), Imidazole (0.08 g,
1.35 mmol), and N H 4CI (0.49 g, 9.16 mmol) w ere mixed in an 8 ml Teflon
capped vial. T h e mixture was allowed to heat for 1 min 10 seconds at full
percent power, 3 minutes at 20% power, and 2 minutes at 30% power in
the multi m ode microwave then cooled to room temperature. The sample
was dissolved in acetone
(1 0
ml) and washed down a short silica column
(30 grams). The organic layer was concentrated affording a yellow solid
(0.40 g, 41% ). mp 2 2 6 -2 28 °C. M S m /z 147 (M +) 104, 76, 50.
Phthalimide (4): Phthalic anhydride (0.50 g, 3.37 mmol) and ammonium
acetate (0.42 g, 7.8 5 mmol) w ere mixed in a C E M -sealed vial with a
magnetic stirrer.
The mixture was allowed to heat in a C E M Discover
microwave for 5 minutes at 150 °C and allowed to cool to 4 0 °C affording a
white solid. The sam ple was extracted with ethyl acetate (40 ml) and aq.
NaHC0
3
solution (10 ml). The organic layer was isolated and dried
123
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
affording a white solid (0.40 g, 81% ). mp 2 2 6 -2 2 8 °C. 13C N M R (90 MHz,
C D C b) 5 169.1, 133.7, 132.7, 122.7; M S m /z 147 (M +) 104, 76, 50.
Phthalimide (4): Phthalic anhydride (0.10 g, 0 .675 mmol), ammonium
chloride (0 .0 3 6 g, 0.675 mmol), and DM A P (0.04 g, 0.34 mmol) were
thoroughly mixed in a CEM -sealed vial with a magnetic stirrer.
The
mixture w as capped and heated in a C E M Discover microwave for 5
minutes at 150 °C.
The sample was rapidly cooled to room temperature
yielding a dark brown solid. The sample was dissolved in 4 ml of AcOEt
and was w ashed with (2x) 2ml of aq. N a H C 0 3 solution. The organic layer
was dried to afford a white solid (0.09 g, 91% ) M S m /z 147 (M +) 104, 76,
50.
Phthalimide (4): Phthalic anhydride (1.0 g, 6.7 5 mmol), DM A P (0.08 g,
0.6 mmol), and N H 2 O H (H C I) (0.54 g, 7.7 mmol) w ere mixed in an
8
ml
Teflon capped vial. The mixture was allowed to heat for 4 minutes and 11
seconds at 30 percent power in the multi m ode microwave and then
cooled to room temperature. The sample was dissolved in acetone flash
chromatographed using silica (~30 g) with pure acetone as the mobile
phase. The organic layer was concentrated affording a yellow solid (0.96
g, 97% ). M S m /z 147 (M +) 104, 76, 50.
124
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Phthalimide (4): Phthalic anhydride (0.20 g, 1.35 mmol), hydroxylamine
hydrochloride (0.9 g, 1.35 mmol), and DM A P (0.04 g, 0.34 mmol) were
thoroughly mixed in a CEM -sealed vial with a magnetic stirrer.
The
mixture w as capped and heated in a C EM Discover microwave for 5
minutes at 150 °C.
The sample was rapidly cooled to room temperature
yielding a dark brown solid.
The sample w as dissolved in 4 ml of ethyl
acetate and w as washed with (2x) 2ml of aq. N a H C 0 3 solution.
The
organic layer was dried to afford a white solid (0.14 g, 7 0% ) M S m /z 147
(M +) 104, 76, 50.
Glutarimide (5): Glutaric anhydride (1.0 g, 8.76 mmol), D M A P (0.21 g,
1.71 mmol), and N H 4CI (0.54 g, 10 mmol) w ere mixed in an
8
ml Teflon
capped vial. The mixture was allowed to heat for 59 seconds at full power
in the multi m ode microwave and then cooled to room tem perature. The
sample was w ashed down a short column (~30 g) with acetone and dried.
The sam ple w as dissolved in (20 ml) chloroform, filtered, dried, and
washed with (1 ml) ethyl acetate. This yielded white crystals (0.89 g,
90% ). mp 154-156 °C. [155-157 °C 169]; 1H -N M R (400 M H z) in C D C I3: 5
(ppm) = 9.06 (bs, 1 H, NH), 2.59 (t, J =
6
.6 Hz, 2H);
13
6 .6
Hz, 4H ), 2.0 2 (quintet, J =
C -N M R (100 M Hz) in C D C I3: 5 (ppm) = 173.45 (C = 0 ), 32.43
1 25
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
(C H 2), 17.68 (C H 2 ); M S m /z 113 (M +) 70, 42; IR (chloroform) (v, cm '1):
3208.88, 1710.0, 1795.0 (C = 0 ).
Glutarimide (5): Glutaric anhydride (0.50 g, 4 .38 mmol) and ammonium
acetate (N H 4 OAc) (0.33 g, 4.2 8 mmol) w ere mixed in an
8
ml Teflon
capped vial. The mixture was allowed to heat for 22 seconds at full
percent power in the multi mode microwave and then cooled to room
tem perature. The sam ple was dissolved in ethyl acetate and washed with
aq. N a H C 0 3 solution. The organic layer w as concentrated affording a
white solid (0.4 5 g, 92% ). M S m /z 113 (M +) 70, 42.
Glutarimide (5): Glutaric anhydride (0.50 g, 4 .3 8 mmol) and ammonium
acetate (0.33 g, 4 .3 8 mmol) w ere mixed in a C E M -sealed vial with a
magnetic stirrer. The mixture was allowed to heat in a C E M Discover
microwave for 5 minutes at 150 °C and allowed to cool to 40 °C affording a
dark brown solid.
The sample was extracted with ethyl acetate (40 ml)
and aq. N a H C 0 3 solution (10 ml). The organic layer w as isolated and
dried affording a light brown solid (0.26 g, 53% ). 13C N M R (90 MHz,
C D C I3) 5 173.9, 31.4, 17.6; D E P T-C N M R (90 M Hz, C D C I3) 5 173.9
(C = 0 ), 31.4 (C H 2), 17.6 (C H 2); M S m /z 113 (M +) 70, 42.
126
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Glutarimide (5): Glutaric anhydride (0.20 g, 1.75 mmol), hydroxylamine
hydrochloride (0.12 g, 2.0 0 mmol), and DM A P (0.04 g, 0.34 mmol) were
thoroughly mixed in a CEM -sealed vial with a magnetic stirrer.
The
mixture w as capped and heated in a C E M Discover microwave for 5
minutes at 150 °C.
The sample was rapidly cooled to room temperature
yielding a dark brown solid.
The sample was dissolved in 4 ml of ethyl
acetate and was washed with (2x) 2ml of aq. NaHCC >3 solution.
The
organic layer was dried to afford a light brown solid (0.12 g, 61% ) M S m /z
113 ( M + ) 70, 42.
Glutarimide (5): Glutaric anhydride (0.10 g, 0 .876 mmol), DM A P (0.04 g,
0.34 mmol), and N H 4CI (0.05 g, 0.876 mmol) w ere thoroughly mixed in a
C E M -sealed vial with a magnetic stirrer.
The mixture w as capped and
heated in a C E M Discover microwave for 5 minutes at 150°C. The sample
was rapidly cooled to room tem perature yielding a dark brown solid. The
sample w as dissolved in 4 ml of ethyl acetate and w as w ashed with (2x)
2ml of aq. N a H C 0
3
solution. The organic layer was dried to afford a light
brown solid (0.0 8 g, 81% ) M S m /z 113 (M +) 70, 42.
crs-1,2-Cyclobutanedicarboximide (6): cis-1,2-Cyclobutane dicarboxylic
acid anhydride
(0.50 g, 3.96 mmol), DM AP (0.11 g, 0.90 mmol), and
127
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
NH4CI (0.2 5 g, 4 .6 7 mmol) w ere mixed in an
8
mixture w as allowed to heat for
seconds at full power in the
1
minute
6
ml Teflon capped vial. The
multi mode microwave and then cooled to room tem perature. The sample
was extracted with ethyl acetate: Acetone (1:1) and aq. N a H C 0 3 solution.
The organic layer was concentrated affording a white solid (0.40 g, 81% ).
13C N M R (90 M Hz, C D C I3) 5 181.4, 39.7, 22.7; M S m /z 125 (M +) 82, 54;
IR (chloroform) (v, cm '1): 3214.81, 1723.8, 1781.2 (C = 0 ).
c/s-1,2-Cyclobutanedicarboximide (6): cis-1,2-cyclobutane dicarboxylic
acid anhydride (0.20 g, 1.59 mmol) and ammonium acetate (N H 4 OAc,
0.15 g, 1.95 mmol) w ere mixed thoroughly in a C E M -sealed vial with a
magnetic stirrer. The mixture was heated for 5 min at 150 °C in a CEM
Discover microwave powered at 150 W . The sample w as then cooled
rapidly to 40 °C and dissolved in 25 ml of ethyl acetate. The organic layer
was washed with aq. N a H C 0 3 solution (25 ml) and dried over sodium
sulfate (anhydrous). The organic layer was dried affording a white solid
(0.14 g, 71% ). M S m/z: 125 (M +), 82, 54.
c/s-1,2-Cyclobutanedicarboximide (6): c/s-1,2-Cyclobutane dicarboxylic
acid anhydride
(1.0 g, 7.90 mmol) and ammonium acetate (N H 4 OAc)
(0.60 g, 7.9 mmol) w ere mixed in an
8
ml Teflon capped vial. The mixture
128
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
was allowed to heat for
1 0 0
seconds at full percent power in the multi
mode microwave and then cooled to room tem perature. For purification a
column of silica (30 g) was washed (1:1) ethyl acetate and hexanes
yielding a white solid (0.77 g, 78% ).
°C 176];
1
mp 135-137 °C [mp 1 3 7 .5 -1 3 8
H -N M R (400 M H z) (C D C I3): 5 (ppm) = 9.49 (bs, 1H, NH), 3.324
(m, 2H ), 2 .6 8 7 (m, 2H ), 2.273 (m, 2H);
13
C -N M R (100 M H z) in C D C I3:
8
(ppm) = 181.49 (C = 0 ), 39.77 (CH), 2 2.04 (C H 2); M S m /z 125 (M +) 82, 54;
IR (chloroform) (v, cm '1): 3208.9, 1723.8, 1781.2 (C = 0 ).
c/s-1,2-Cyclobutanedicarboximide (6): cis-1,2-Cyclobutane dicarboxylic
acid anhydride
(1.0 g, 7.9 mmol), DM AP (0.10 g, 0.8 mmol), and
N H 2 O H (H C I) (0.6 3 g, 9.1 mmol) were mixed in an
8
ml Teflon capped vial.
The mixture w as allowed to heat for 1 minute 12 seconds at full power in
the multi mode microwave and then cooled to room temperature.
The
sample was dissolved in acetone flash chromatographed using silica (~30
g) with pure acetone as the mobile phase.
The organic layer was
concentrated affording a light brown solid (0.95 g, 96% ) M S m /z 125 (M +)
82, 54.
c/s-1,2-Cyclobutanedicarboximide (6): c/s-1,2-Cyclobutane dicarboxylic
acid anhydride (0.20 g, 1.59 mmol) hydroxylamine hydrochloride (0.11 g,
129
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
1.59 mmol), and DM A P (0.04 g, 0.34 mmol) w ere thoroughly mixed in a
C EM vial with a stirrer.
The mixture was capped and heated in a CEM
Discover microwave for 5 minutes at 150°C.
The sam ple was rapidly
cooled to room tem perature yielding a white solid.
The sample was
dissolved in 4 ml of ethyl acetate and was w ashed with (2x) 2ml of aq.
NaHC0
3
solution. The organic layer was dried to afford a white solid (0.12
g, 6 1% ) M S m /z 125 (M +) 82, 54.
c/s-1,2-Cyclobutanedicarboximide (6): c/s-1,2-Cyclobutane dicarboxylic
acid anhydride
(0.1 0 g, 0.73 mmol) ammonium chloride (0.04 g, 0.73
mmol), and D M A P (0.04 g, 0.34 mmol) w ere thoroughly mixed in a CEM
vial with a stirrer. T h e mixture was capped and heated in a C E M Discover
microwave for 5 minutes at 150 °C.
The sam ple w as rapidly cooled to
room tem perature yielding a white solid. The material w as dissolved in 4
ml of ethyl acetate and was washed with ( 2 x)
2
ml of aq. N a H C 0
solution.
3
The organic layer w as dried to afford a white solid (0.0 9 g, 91% ) M S m/z
125 (M +) 82, 54.
3a,4,5,6,7,7a-Hexahydro-1 H-isoindole-1,3(2H)-dione
(7):
c/s-1,2-
Cyclohexane dicarboxylic acid anhydride (1.0 g, 6.4 9 mmol), DM A P (0.16
g, 1.3 mmol), and N H 4CI (0.40 g, 7.48 mmol) w ere mixed in an
8
ml Teflon
130
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
capped vial. T h e mixture was allowed to heat for 2 minutes at full power in
the multi m ode microwave and then cooled to room tem perature.
The
sample w as extracted with ethyl acetate:acetone (1:1) and aq. N a H C 0 3
solution. The organic layer was concentrated affording a white solid (0.68
g, 69% ). 13C N M R (90 M Hz, C D C I3) 5 180.0, 40.1, 22.7, 20.8; M S m /z 153
(M +) 125, 99, 82, 67, 54, 41; IR (chloroform) (v, cm '1): 3220.14, 1725.4,
1781.6 (C = 0 ).
3a,4,5,6,7,7a-Hexahydro-1 H-isoindole-1,3(2H)-dione
Cyclohexane dicarboxylic acid anhydride
(0.50
(7):
g, 3.24
cis-1,2mmol) and
ammonium acetate (N H 4 OAc) (0.25 g, 3.24 mmol) w ere mixed in an
8
ml
Teflon capped vial. The mixture was allowed to heat for 4 7 seconds at full
percent power in the multi mode microwave and then cooled to room
temperature. The sam ple was dissolved in ethyl acetate and washed with
aq. N a H C 0 3 solution. The organic layer was concentrated affording a
white solid (0.48 g, 99% ). 13C N M R (90 M Hz, C D C I3) 5 181.0, 40.4, 23.4,
21.6; D E P T -C N M R (90 MHz, C D C I3) 5 181.0 (C = 0 ), 4 0 .4 (CH), 23.3
(C H 2), 21 .5 (C H 2); M S m /z 153 (M +) 125, 99, 82, 67, 54, 41; IR
(chloroform) (v, cm '1): 3210.1, 1711.9, 1780.4 (C = 0 ).
3a,4,5,6,7,7a-Hexahydro-1 H-isoindole-1,3(2H)-dione
(7):
131
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
c/s-1,2-
cyclohexane
dicarboxylic
acid
anhydride
(0.5
g,
3.2 5
mmol)
and
ammonium acetate (0.25 g, 3.25 mmol) were mixed in a C E M -sealed vial
with a m agnetic stirrer.
The mixture was allowed to heat in a CEM
Discover microwave for 5 minutes at 150 °C and allowed to cool to 40 °C
affording a white solid. The sample was extracted with ethyl acetate (40
ml) and aq. N a H C 0
3
solution (10 ml). The organic layer was isolated and
dried affording a white solid (0.25 g, 51% ). M P 131-133 °C. [1 3 4 .5 -1 3 5
°C 176]; 1H -N M R (400M H z) in C D C I3: 5 (ppm) = 9.525 (bs,1H, NH), 2.924
(m, 2H ), 1.83 (m, 4H ), 1.47 (m, 4H);
13
C -N M R (100 M H z) in C D C I3:
8
(ppm) = 180.867 (C = 0 ), 4 0 .7 3 (CH), 2 3 .4 5 (C H 2), 2 1 .4 4 (C H 2); M S m /z
153 (M +) 125, 99, 8 2 ,6 7 , 5 4 ,4 1 .
3a,4,5,6,7,7a-Hexahydro-1H-isoindole-1,3(2H)-dione
(7):
c/s-1,2-
Cyclohexane dicarboxylic acid anhydride (1.0 g, 6.5 mmol), DM AP (0.08
g, 0.65 mmol), and N H 2 O H (H C I) (0.51 g, 7.3 mmol) w ere mixed in an
8
ml
Teflon capped vial. The mixture was allowed to heat for 1 minute 49
seconds at full power in the multi mode microwave and then cooled to
room
tem perature.
The
sample
was
dissolved
in
acetone
flash
chromatographed using silica (~30 g) with pure acetone as the mobile
phase.
The organic layer was concentrated affording a white solid (0.83
g, 84% ) M S m /z 153 (M +) 125, 99, 82, 67, 54, 41.
132
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
3a,4,5,6,7,7a-Hexahydro-1H-isoindole-1,3(2H)-dione
Cyclohexane
dicarboxylic
acid
anhydride
(0.20
(7):
g,
c/'s-1,2-
1.29
mmol)
hydroxylamine hydrochloride (0.09 g, 1.29 mmol), and D M A P (0.04 g, 0.34
mmol) w ere thoroughly mixed in a CEM -sealed vial with a magnetic stirrer.
The mixture w as capped and heated in a C E M Discover microwave for 5
minutes at 150 °C.
The sample was rapidly cooled to room temperature
yielding a white solid. The sample was dissolved in 4 ml of ethyl acetate
and was w ashed with (2x) 2ml of aq. N a H C 0 3 solution. The organic layer
was dried to afford a white solid (0.12 g, 61% ) M S m /z 153 (M +) 125, 99,
82, 67, 54, 41.
3a,4,5,6,7,7a-Hexahydro-1 H-isoindole-1,3(2H)-dione
(7):
c/s-1,2-
cyclohexane dicarboxylic acid anhydride (0.10 g, 0.64 mmol), ammonium
chloride (0.0 3 g, 0.64 mmol), and DM AP (0.04 g, 0.34 mmol) were
thoroughly mixed in a CEM -sealed vial with a magnetic stirrer.
The
mixture was capped and heated in a CEM Discover microwave for 5
minutes at 150 °C.
The sample was rapidly cooled to room temperature
yielding a white solid. The material was dissolved in 4 ml of ethyl acetate
and was w ashed with (2x) 2ml of aq. NaHCOs solution. The organic layer
was dried to afford a white solid (0.08 g, 81% ) M S m /z 153 (M +) 125, 99,
1 33
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
82, 67, 54, 41.
3a,4,7,7a-Tetrahydro-4,7-ethano-1 H-isoindole-1,3(2H)-dione (8):
bicyclo[2.2.2]oct-5-en-2,3-dicarboxylic
acid
anhydride
(0.5 0
mmol), D M A P (0.07 g, 0.57 mmol), and NH4CI w ere mixed in
8
g,
cis2.80
ml Teflon
capped glass vial. The mixture was allowed to heat for 2 minute 14
seconds
in the
multi
m ode
microwave
tem perature affording a dark brown solid.
and
then
cooled
to
room
For purification a column 30
gram silica was washed with acetone yielding a white solid (0.41 g, 82 %).
13C N M R (90 M Hz, C D C I 3 ) 5173.94, 132.49, 41.20, 31.37, 23.56; D E P T-C
N M R (90 M Hz, C D C I3) 5 173.94 (C = 0 ), 132.49(C H ), 41 .2 0 (C H ), 31.37
(CH), 2 3 .5 6 (C H 2); M S m /z 179 (M +) 149, 99, 78, 51; IR (chloroform) (v,
cm '1): 3208.88, 1714.68, 1784.61 (C = 0 ).
3a,4,7,7a-Tetrahydro-4,7-ethano-1 H-isoindole-1,3(2H)-dione
bicyclo [2.2.2]oct-5-en-2,3-dicarboxylic acid anhydride
(8):
cis-
(0.10 g, 0.56
mmol) and ammonium acetate (0.04 g, 0.56 mmol) w ere mixed thoroughly
in a C E M -sealed vial with a magnetic stirrer. The mixture was heated for 5
min at 150 °C in a C E M Discover microwave powered at 150 W . The
sample was then cooled rapidly to 40 °C and dissolved in 25 ml of ethyl
acetate. The organic layer was washed down a flash column (30g silica).
134
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
The dried organic layer afforded 0.09 g of a white solid (0.0 9 g, 91 %) MS
m /z 177 (M +) 149, 99, 78, 51.
3a,4,7,7a-Tetrahydro-4,7-ethano-1 H-isoindole-1,3(2H)-dione (8):
bicyclo [2.2.2]oct-5-en-2,3-dicarboxylic acid anhydride
c/s-
(0.50 g, 2.80
mmol) and ammonium acetate ( 0 . 2 2 g, 2.80 mmol) w ere mixed in
8
ml
Teflon capped glass vial. The mixture was allowed to heat for 1 minute in
the multi m ode microwave and then cooled to room tem perature affording
a yellow translucent solid. For purification a silica column (30 grams) was
washed with acetone yielding a white solid (0.48g, 98 % ). mp 200 -2 02 °C;
1
H -N M R (400 M H z) in C D C I3:
8
(ppm.) = 8.49 (bs, 1H, NH), 6.23 (dd J=
3.0, 4 .5 Hz, 2H ), 3.14 (m, 2H ), 2.88 (m, 2H ), 1.58 (bd, J = 7.5 Hz, 2H),
1.14 (bd, J = 7.5 Hz, 2H ),
13
C -N M R (100 M H z) in C D C I3: .8 (ppm) = 179.39
(C = 0 ), 132.30 (C H ), 4 5 .5 3 (CH), 31.57 (CH), 23.46 (C H 2); M S m /z 177 (M
+) 149, 91, 78; IR (chloroform) (v, cm '1): 3255.9, 1716.31, 1780.14 (C = 0 ).
3a,4,7,7a-Tetrahydro-4-isopropyl-7-methyl-4,7-Ethano-1H-isoindole1,3(2H)-dione (9): cis-BicycIo [2.2.2] 5-m ethyl-8-isopropyl-oct-5-en-2,3dicarboxylic acid anhydride
(0.50 g, 2.13 mmol), ammonium chloride
(0.13 g, 2.4 mmol) and DM AP (0.05 g, 0.41 mmol) w ere mixed in
8
ml
Teflon capped glass vial. The mixture was allowed to heat for 4 minute in
135
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
the multi m ode microwave and then cooled to room tem perature affording
a dark brown solid. For purification a column of silica (30 g) was washed
with 1:1 ethyl acetate and Hexanes yielding a white solid. A G C - M S and
TLC found that the reaction mixture had less than 5% of the product with
the remaining being starting material.
3a,4,7,7a-Tetrahydro-4-isopropyl-7-methyl-4,7-Ethano-1H-isoindole1,3(2H)-dione (9): cis-bicyclo [2.2.2]-6-m ethyl-8-isopropyl-oct-5-en-2,3dicarboxylic acid anhydride
(0.50 g, 2.13 mmol) and ammonium acetate
(0.50 g, 6.4 8 mmol) w ere mixed in
8
ml Teflon capped glass vial. The
mixture w as allowed to heat for 4 minutes in the multi m ode microwave
and then cooled to room tem perature affording a yellow translucent solid.
For purification a column of silica (30 g) w as washed with of 1:1 ethyl
acetate and hexanes yielding a white solid (0.35 g, 72% ).
M H z) in C D C I3:
8
1
H -N M R (400
(ppm) = 8.04 (bs, 1H, NH), 6 .067 (d, J = 8.3 Hz, 1H),
5.94 (d, J = 8.3 Hz, 1H), 2.99 (d, J = 7.5 Hz, 1H), 2 .5 9 (m, 2H ), 1.47 (s,
3H), 1.4-1.2 (m, 2H ) 1.07 (d, J = 6.5 Hz, 3H), 1.0-0.8 (m, 2H ), 0.98 (d, J =
6.5 Hz, 3H);
13
C -N M R (100 M Hz) in C D C I3: 5 (ppm) = 177.98 (C = 0 ),
177.57 (C = 0 ), 136.31 (CH), 135.60 (CH), 51.57 (CH), 4 7 .7 3 (CH), 43.51
(C), 36.74 (C), 3 4 .2 4 (C H 2), 29.47 (CH), 22.85 (C H 2), 22.51 (C H 3), 18.36
(C H 3), 16.82 (C H 3); M S m /z 233 (M +) 163, 135, 119, 91; IR (C H C I3) (v,
136
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
cm'1): 3250.37, 1709.2, 1761.4(C=0).
2-Methoxy-isoindole-1,3-dione (10): Phthalic anhydride (0.10 g, 0.675
mmol) and m ethoxyam ine (HCI) (0.0 56 g, 0.675 mmol) w ere thoroughly
mixed in a C E M vial with a stirrer. The mixture was capped and heated in
a C EM Discover microwave for 7 minutes at 180 °C.
The sample was
rapidly cooled to room tem perature yielding a white solid.
The material
was dissolved in 4 ml of ethyl acetate washed with an aq. N a H C 0 3
solution and dried under vacuum to afford a white solid (0.10 g, 75 %). MS
m /z 177 (M +) 147, 130, 105, 90, 76, 50.
2-Methoxy-isoindole-1,3-dione (10):
Phthalic anhydride (0.50 g, 3.37
mmol) and m ethoxyam ine (HCI) (0.28 g, 3.37 mmol) w ere thoroughly
mixed in a C E M vial with a stirrer. The mixture was capped and heated in
a C E M Discover microwave for 5 minutes at 125 °C.
The sample was
rapidly cooled to room tem perature yielding a white solid.
The sample
was dissolved in 4 ml of ethyl acetate and was w ashed with (2x) 2ml of aq.
N a H C 0 3 solution. The organic layer was dried to afford a white solid (0.30
g, 50 % ) M S m /z 177 (M +) 147, 130, 105, 90, 76, 50.
2-Methoxy-isoindole-1,3-dione (10):
Phthalic anhydride (1.0 g, 6.75
137
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
mmol) and methoxyam ine (HCI) (0.56 g, 6.7 5 mmol) w ere mixed in
8
ml
Teflon capped glass vial. The mixture was allowed to heat for 41 seconds
in the multi m ode microwave and allowed to cool to room tem perature
affording a white solid.
The sample was extracted with ethyl acetate
isolated and dried affording a white solid (0.8 6 g, 72% ). 13C N M R (90
M Hz, CDCIs) 5 65.6, 123.3, 134.3; D E P T-C N M R (90 M Hz, C D C I3) 5 65.6
(C H 3), 123.3 (CH), 134.3(C H ); M S m /z 177 (M +) 147, 130, 105, 90, 76,
50; IR (chloroform) ( v , cm '1): 1733.0, 1790.1 (C = 0 ).
1-Methoxy-piperidine-2,6-dione (JM):
Glutaric anhydride (1.0 g, 8.76
mmol) and m ethoxyam ine (HCI) (0.73 g, 6 .75 mmol) w ere mixed in
8
ml
Teflon capped glass vial. The mixture was allowed to heat for 17 seconds
in the multi m ode microwave and allowed to cool to room temperature
affording a dark brown solid. The sample was dissolved with ethyl acetate
washed with an aq. N a H C 0 3 solution and dried affording a brown solid
(1.26 g, 99 %). mp 7 2 -74 °C. 13C N M R (90 M Hz, C D C I3)
6
16.5, 32.9, 63.7;
D E P T-C N M R (90 M Hz, C D C I3) 5 16.5(C H 2), 3 2 .9 (C H 2), 6 3 .7 (C H 3); MS
m /z 143 (M +) 113, 85, 70, 55, 42; IR (chloroform) ( v , cm '1): 1705.4 (C = 0 ).
1-Methoxy-piperidine-2,6-dione (11.): Glutaric anhydride (0.10 g, 0.88
mmol) and m ethoxyam ine (HCI) (0.07 g, 0 .675 mmol) w ere thoroughly
138
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
mixed in a C E M vial with a stirrer. The mixture was capped and heated in
a C EM Discover microwave for 7 minutes at 180 °C.
The sample was
rapidly cooled to room temperature yielding a white solid.
The sample
was dissolved in 4 ml of ethyl acetate and dried under vacuum to afford a
white solid (0.1 0 g, 79% ). M S m /z 143 (M +) 113, 85, 70, 55, 42.
1-Methoxy-piperidine-2,6-dione (11): Glutaric Anhydride (0.50 g, 4.38
mmol) and m ethoxyam ine (HCI) (0.36 g, 4 .3 8 mmol) w ere thoroughly
mixed in a C E M vial with a stirrer. The mixture was capped and heated in
a C E M Discover microwave for 5 minutes at 125 °C.
The sample was
rapidly cooled to room temperature yielding a white solid.
The sample
was dissolved in 4 ml of ethyl acetate and was washed with (2x) 2ml of aq.
NaHCC >3 solution. The organic layer was dried to afford a white solid (0.30
g, 4 8% ) M S m /z 143 (M +) 113, 85, 70, 55, 42.
2-Methoxy-hexahydro-isoindole-1,3-dione (12):
dicarboxylic acid anhydride
c/s-1,2-Cyclohexane
(1.0 g, 6.49 mmol) and m ethoxyam ine (HCI)
(0.54 g, 6.4 9 mm) w ere mixed in
8
ml Teflon capped glass vial. The
mixture w as allowed to heat for 28 seconds in the multi mode microwave
and allowed to cool to room temperature affording a white solid.
The
sample w as extracted with ethyl acetate isolated and dried affording a
139
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
white solid (0.7 3 g, 61 %). mp 126-130 °C. 13C N M R (90 M Hz, C D C I3) 5
21.05, 23.25, 37.11, 64.19; D E P T-C N M R (90 M Hz, C D C I3) 5 2 1 .0 5 (C H 2),
2 3 .2 5 (C H 2), 3 7 .1 1(CH), 64.19 (C H 3); M S m /z 183 (M +) 153, 124, 112, 96,
81, 67, 54, 41 ;IR (chloroform) (v, cm '1): 170 5.4 ,1 788.6 (C = 0 ).
2-Methoxy-hexahydro-isoindole-1,3-dione (12):
dicarboxylic acid anhydride
c/s-1,2-Cyclohexane
(0.10 g, 0.649 mmol) and methoxyamine
(HCI) (0 .0 5 4 g, 0.649 mmol) were thoroughly mixed in a C E M vial with a
stirrer.
The
mixture was capped
microwave for 7 minutes at 180 °C.
and
heated
in a
CEM
Discover
The sam ple w as rapidly cooled to
room tem perature yielding a white solid. The material w as dissolved in 4
ml of ethyl acetate and dried under vacuum to afford a white solid ( 0
.1 0
g,
84% ) M S m /z 183 (M +) 153, 124, 112, 96, 81, 67, 54, 41.
2-Methoxy-hexahydro-isoindole-1,3-dione (12):
c/s-1,2-cyclohexane
dicarboxylic acid anhydride (0.50 g, 3.24 mmol) and methoxyamine (HCI)
(0.27 g, 3.24 mmol) were thoroughly mixed in a C E M vial with a stirrer.
The mixture was capped and heated in a C E M Discover microwave for 5
minutes at 125 °C.
The sample was rapidly cooled to room temperature
yielding a white solid. The sample was dissolved in 4 ml of ethyl acetate
and was washed with (2x) 2ml of aq. N a H C 0 3 solution. The organic layer
140
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
was dried to afford a white solid (0.32 g, 54% ) M S m /z 183 (M +) 153, 124,
112, 96, 81, 67, 54, 41.
1-Methoxy-pyrrolidine-2,5-dione (13): Succinic anhydride (1.0 g, 9.99
mmol) and m ethoxyam ine (HCI) (0.92 g, 11.0 mmol) w ere mixed in
8
ml
Teflon capped glass vial. The mixture was allowed to heat for 4 8 seconds
in the multi m ode microwave and allowed to cool to room temperature
affording a translucent yellow solid. The sam ple was dissolved in 4 ml of
ethyl acetate washed with (2x) 2ml of aq. N a H C 0 3 solution and dried
affording a white solid (1.25 g, 96 %). M P 102-104 °C 1H N M R (400 MHz,
C D C I3) 3 .8 8 4 (s, 3H), 2.670 (s, 4H); 13C N M R (90 M Hz, C D C I3)
8
171.19,
64.16, 25.42; D E P T -C N M R (90 M Hz, C D C I3) 2 5.42 (C H 2), 6 4 .1 6 (C H 3),
171.19 (C = 0 ); M S m /z 129 (M +) 99, 70, 55, 42; IR (chloroform) (v, cm '1):
1727.7, 1790.6 (C = 0 ).
1-Methoxy-pyrrolidine-2,5-dione (13): Succinic anhydride (0.10 g, 0.99
mmol) and methoxyamine (HCI) (0.092 g, 1.10 mmol) w ere thoroughly
mixed in a C E M vial with a stirrer. The mixture was capped and heated in
a C E M Discover microwave for 7 minutes at 180 °C.
The sample was
rapidly cooled to room temperature yielding a white solid.
The sample
was dissolved in 4 ml of ethyl acetate and washed with (2x) 2ml of aq.
141
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
NaHC0
3
solution and dried under vacuum to afford a white solid (0.09 g,
70% ) M S m /z 129 (M +) 99, 70, 55, 42.
1-Methoxy-pyrrolidine-2,5-dione (13): Succinic anhydride (0.50 g, 4.99
mmol) and m ethoxyam ine (HCI) (0.41 g, 4 .9 9 mmol) w ere thoroughly
mixed in a C E M vial with a stirrer. The mixture was capped and heated in
a C E M Discover microwave for 5 minutes at 125 °C.
The sample was
rapidly cooled to room temperature yielding a white solid.
The sample
was dissolved in 4 ml of ethyl acetate and was washed with (2x) 2ml of aq.
N a H C 0 3 solution. The organic layer was dried to afford a white solid (0.35
g, 54% ) M S m /z 129 (M +) 99, 70, 55, 42.
3-Methoxy-3-aza-bicyclo[3.2.0]heptane-2,4-dione
(14):
Cis-1,2-
Cyclobutane anhydride (0.10 g, 0.8 mmol) and methoxyamine (HCI) (0.07
g, 0.84 mmol) w ere thoroughly mixed in a C E M vial with a stirrer.
The
mixture w as capped and heated in a C E M Discover microwave for 7
minutes at 180 °C.
The sample was rapidly cooled to room temperature
yielding a white solid. The sample was dissolved in 4 ml of ethyl acetate
and dried under vacuum to afford a white solid (0.10 g, 81% ) M S m/z 155
(M +) 125, 96, 83, 69, 5 4 ,4 1 .
142
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3-Methoxy-3-aza-bicyclo[3.2.0]heptane-2,4-dione
(14):
Cis-1,2-
Cyclobutane anhydride (0.50 g, 3.96 mmol) and m ethoxyam ine (HCI)
(0.33 g, 3.96 mmol) w ere mixed in
8
ml Teflon capped
glass vial. The
mixture w as allowed to heat for 1 min 14 seconds in the multi mode
microwave and allowed to cool to room tem perature affording a white
solid.
The sam ple was extracted with 4 0 ml ethyl acetate: acetone (9:1)
isolated and dried affording a light yellow solid (0.60 g, 98 %).
1
H -N M R
(400 M H z) in C D C I3: 5 (ppm) = 4.02 (bs, 3H, C H 3), 3.27 (m, 2H ), 2.67 (m,
2H), 2 .19 (m, 2H); 13C N M R (100 MHz, C D C I3) 5 173.5, 64.3, 35.4, 22.6;
D E P T -C N M R (90 M Hz, C D C I3) 5 21.9 (C H 2), 35.3 (C H ), 63.8 (CH),
1 7 3 .8 (C = 0 );
M S m /z 155 (M +); IR (chloroform) (v, cm '1): 1720.47,
1777.73 (C = 0 ).
4-Methoxy-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione
(15): cis-
bicyclo[2.2.2]-oct-5-en-2,3-dicarboxylic acid anhydride (0.5 0 g, 2 .80 mmol)
and methoxyam ine (HCI) (0.23 g, 2.80 mmol) w ere thoroughly mixed in a
C EM vial with a stirrer.
The mixture was capped and heated in a CEM
Discover microwave for 5 minutes at 125 °C.
The sam ple was rapidly
cooled to room tem perature yielding a white solid.
The sample was
dissolved in 4 ml of ethyl acetate and was washed with (2x) 2ml of aq.
N a H C 0 3 solution. The organic layer was dried to afford a white solid (0.23
1 43
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
g. 4 0 % ) M S m /z 207 (M +); 177, 134, 106, 9 1 ,8 0 , 5 1 ,4 1 .
4-Methoxy-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione
(15):
cis-
bicyclo[2.2.2]-oct-5-en-2,3-dicarboxylic acid anhydride (0.50 g, 2.80 mmol)
and methoxyam ine (HCI) (0.26 g, 3.11 mmol) w ere mixed in
8
ml Teflon
capped glass vial. The mixture was allowed to heat for 1 minute 40
seconds in the multi mode microwave and allowed to cool to room
tem perature affording a brownish yellow solid. The sam ple w as dissolved
with ethyl acetate isolated washed with an aq. N a H C 0 3 solution dried
affording a white solid 0.41
grams
(71
%).
For purification flash
chromatography w as done on a silica column (30 gram) (AcOEt: hexanes,
1:1) yielding a white solid (0.27 g, 4 7% ) 13C N M R (90 M Hz, C D C I3)
523.34, 31.31, 41.14, 64.23, 132.29; D E P T-C N M R (90 M Hz, C D C I3) 5
23.34 (C H 2), 31.31 (CH), 41.14(C H ), 6 4 .2 3 (C H 3), 132.29(C H ); M S m /z
207 (M +) 177, 134, 106, 91, 80, 51, 41; IR (chloroform) (v, cm’1): 1720.74,
1780.54 (C = 0 ).
4-Methoxy-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5-dione
(15): cis-
bicyclo[2.2.2]-oct-5-en-2,3-dicarboxylic acid anhydride (0.1 0 g, 0.56 mmol)
and methoxyam ine (0.05 g, 0.59 mmol) w ere thoroughly mixed in a CEM
vial with a stirrer. The mixture was capped and heated in a C E M Discover
144
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
microwave for 7 minutes at 180 °C.
The sample w as rapidly cooled to
room tem perature yielding a white solid. The sam ple was dissolved in 5
ml of methanol and washed down a silica column (ethyl acetate, 30 g)
yielding a white solid (0.1 0 g, 85% ); M S m /z 208 (M +); 177, 134, 106, 91,
80, 5 1 ,4 1 .
2-Methoxy-4-nitro-isoindole-1,3-dione (16):
3-Nitrophthalic anhydride
(0.50 g, 2.5 8 mmol) and methoxyamine (0.24 g, 2.87 mmol) w ere mixed in
8
ml Teflon capped glass vial. The mixture was allowed to heat for 1
minute 34 seconds in the multi mode microwave and allowed to cool to
room tem perature affording a dark yellow solid.
The sample was
extracted with ethyl acetate isolated and dried affording a light yellow solid
(0.38 g,
6 6
% ). Mp 150-152 °C. 13C N M R (90 M Hz, C D C I3)
128.99, 136.16, 144.7; D E P T-C N M R (90 M Hz, C D C I3)
65.75, 127.24,
6
8
6 5 .7 5 (C H 3),
127.24 (C H ), 128.99 (CH), 136.16 (CH); M S m /z 221 (M +) 192, 149, 117,
103, 75, 63, 45; IR (chloroform) (v, cm '1): 1741.6, 1798.1 (C = 0 ).
1-lsopropyl-4-methoxy-7-methyl-4-aza-tricyclo[5.2.2.02,6]undec-8ene-3,5-dione (17): 1-lsopropyl-7-m ethyl-4-oxa-tricyclo[5.2.2.02,6]undec8-ene-3,5-dione (1.0 g, 4.2 7 mmol) and methoxyamine (HCI) (0.32 g, 4.27
mmol) w ere thoroughly mixed in an
8
ml Teflon capped vial. The mixture
145
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was heated for 1 minute 5 seconds in the multi mode microwave yielding a
dark brown liquid.
The sample was allowed to cool to room temperature
and a G C - M S w as taken. Approximately 10 percent of the product was
found. An additional 0.32 g of methoxyamine (HCI) was added and the
mixture w as heated for another minute. A G C - M S found ~20 percent of
the product had formed. One gram of methoxyamine (HCI) w as added and
the vial w as heated for another minute yielding ~30 percent.
Additional
heating was stopped due to the possible breakdown of the product.
silica column of ethyl acetate: hexanes ( 1 :2 )
2 0 0
A
ml was run finding the
product in fractions 10 -16. W hite solid 0.17 g (15% yield) M S 2 63 (M+);
193, 164, 135, 119, 105, 92, 7 0 ,4 1 .
2-(2,6-Dioxo-piperidin-3-yl)-isoindole-1,3-dione (18): Phthalic anhydride
(0.10 g, 0.68 mmol), glutamic acid (0.10 g, 0.68 mmol), DM A P (0.02 g,
0.14 mmol), and N H 4CI (0.04, 0.77 mmol) w ere mixed thoroughly in a
C E M -sealed vial with a magnetic stirrer. The mixture w as heated for 10
min at 150 °C in a C E M Discover microwave powered at 150 W . It was
then cooled rapidly to 4 0 °C and dissolved in 15 ml of (1:1) ethyl acetate:
acetone.
The organic layer was washed with 2x (10 ml) distilled w ater
and dried over sodium
concentrated
sulfate (anhydrous).
under vacuum
and
precipitated
The
with
organic layer was
hexanes
1 46
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
(30
ml)
affording a white solid (0.14 g, 80% ). mp 2 6 8 -2 7 0 °C. (269 - 271 °C lit.).
1H N M R (400 M Hz, D M S O -d 6) 5 11.14 (s, 1 H), 7.94 (m, 4 H), 5.17 (dd, 1
H, 12.5, 5.5 Hz), 2.9 2 (m, 1 H), 2.57 (m, 2 H), 2.0 9 (m, 1 H); 13C NM R
(100 M Hz, DMSO-cf6) 172.7, 169.8, 167.1, 134.9, 131.2,123.4, 49.0, 30.9,
22.0; M S 258 (M+); 230, 213, 202, 173, 148, 111, 76, 50; IR (nujol) (v, cm’
1): 3271.7, 1771.7, 1707.3 (C = 0 ).
2-(2,6-Dioxo-piperidin-3-yl)-isoindole-1,3-dione (18): Phthalic anhydride
(1.0g, 6.75m m ol), glutamic acid (1.0 g, 6.75m m ol), D M A P (0.17 g, 1.39
mmol), and N H 4CI (0.38, 7.1 mmol) w ere mixed in
The mixture w as heated for
6
8
ml Teflon capped vial.
minute 30 seconds at full power in the multi
mode microwave and then cooled to room temperature. The sample was
dissolved in ( 1 :1 ) ethyl acetate: acetone and washed with a small amount
of aq. NaHC O s solution. The mixture was concentrated and precipitated
with hexanes to yielding a light brown solid (0.9 0 g, 52% ). mp 2 6 8 -2 70 °C.
13C N M R (90 M Hz, D M S O ) 5 173.0, 170.1, 167.4, 135.1, 131.5, 123.6,
49.2, 31.2, 22.2; M S m /z 258 (M +) 230, 213, 202, 173, 148, 111, 76, 50.
2-(2,6-Dioxo-piperidin-3-yl)-hexahydro-isoindole-1,3-dione
I ,2-Cyclohexane
dicarboxylic
acid
anhydride
(0.10
g,
(19):
0.65
c/'s-
mmol),
glutamic acid (0.0 95 g, 0.65 mmol), DM A P (0.02 g, 0.16 mmol), and
147
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
ammonium chloride (N H 4 CI) (0.040 g, 0.75 mmol) w ere mixed thoroughly
in a C E M -sealed vial with a magnetic stirrer. The mixture w as heated for
10 min at 150 °C in a C E M Discover microwave powered at 150 W . It was
then cooled rapidly to 40 °C and dissolved in 15 ml of (1:1) ethyl acetate:
acetone.
T h e organic layer was washed with 2x (10 ml) distilled water
and dried over sodium
concentrated
sulfate (anhydrous). The organic layer was
under vacuum
and
precipitated
with
hexanes
(30
ml)
affording of a white solid (0.12 g, 70 %). Mp 152 - 154 °C; 1H N M R (400
M Hz, DMSO-cfe) 5 11.0 (s, 1 H, NH), 4.9 (dd, 1 H, 12.5, 5.5 Hz, C H C O ),
3.0 (m, 1 H), 2.8 (m, 1 H), 2.8 (m, 1 H), 2.5 (m, 1 H), 1.9 (m, 1 H) , 1.7 (m,
3 H), , 1.6 (m, 1 H), 1.4 (m, 4 H); 13C N M R (100 M Hz, D M S O -d 6) 178.8
(C = 0 ),
1 7 8 .7 (C = 0 ),
38.8(C H ),
3 0 .7 (C H 2),
1 7 2 .7 (C = 0 ),
23.1 (C H 2),
1 6 9 .4 (C = 0 ),
2 2 .9 (C H 2),
48 .7 (C H ),
2 1 .1 (C H 2),
39.1(C H ),
21 .0 5 (C H 2),
21 .0 0 (C H 2); M S 2 64 (M+); 236, 210, 179, 154, 112, 82, 67, 54, 41; IR
(nujol) (v, cm '1): 3102.57, 3213.24, 1702.95, 1725.80, 177 4.2 0 (C = 0 ).
2-(2,6-Dioxo-piperidin-3-yl)-hexahydro-isoindole-1,3-dione
(19):
c/'s-
1,2-Cyclohexane dicarboxylic acid anhydride (1.0 g, 6.4 9 mmol), glutamic
acid (0.95 g, 6.4 9 mmol), DM AP (0.16 g, 1.31 mmol), and ammonium
chloride (NH4CI) (0.40 g, 7.48 mmol) w ere thoroughly mixed in a Teflon
capped vial.
The mixture was heated in a multimode microwave for 2
148
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
minutes and 39 seconds in the multi mode microwave.
During this
process the material melted, bubbled and turned a dark brown.
The
sample w as allowed to cool to room tem perature and was dissolved in an
ethyl acetate: acetone mixture ( 2 :1 ) and washed with 5 ml of aq. N a H C 0 3
solution.
The organic layer was dried and washed with cold methanol
affording a light brown solid (0.70 g, 40% ). M S 264 (M+); 236, 210, 179,
154, 112, 82, 67, 5 4 ,4 1 .
3-(2,6-Dioxo-piperidin-3-yl)-3-aza-bicyclo[3.2.0]heptane-2,4-dione
(20): cis-1,2-Cyclobutane dicarboxylic acid anhydride (0.1 g, 0.79 mmol),
glutamic acid (0.12 g, 0.79 mmol), DM AP (0.02 g, 0.1 6
mmol), and
ammonium chloride (N H 4 CI) (0.04 g, 0.916 mmol) w ere mixed thoroughly
in a C E M -sealed vial with a magnetic stirrer. The mixture was heated for
10 min at 150 °C in a monomode microwave powered at 150 W . It was
then cooled rapidly to 40 °C and dissolved in 15 ml of (1:1) ethyl acetate:
acetone.
The organic layer was washed with 2x (10 ml) distilled w ater
and dried over sodium
concentrated
sulfate (anhydrous).
under vacuum
and
The
precipitated with
organic layer was
hexanes
(30
ml)
affording a white solid (0.10 g, 54 %). mp 2 03 -2 05 °C; 1H N M R (400 MHz,
DMSO-of6)5 11.06 (s, 1 H, NH), 4.9 5 (dd, 1 H, 12.5, 5.5 Hz, C H C O ), 2.84
(m, 1 H), 2 .52 (m, 4 H, C H 2 C H 2), 2.02 (m, 2 H, C H 2 C H 2), 1.92 (m, 1 H,
149
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C H 2);
13C
1 6 9 .4 (C = 0 ),
NMR
(100
4 9 .1 (C H ),
M Hz,
D M S O -d 6)
37.9(C H ),
179.0(C =O ),
37.7(C H ),
30.7(C H ),
1 7 2 .7 (C = 0 ),
2 2 .3 (C H 2),
2 2 .0 (C H 2), 2 1 .0(C H 2); M S m /z 236 (M +) 208, 151, 106, 112, 96, 83, 55,
41; IR (nujol) (v, cm '1): 3207.48, 1702.55, 1729.09, 1771.79 (C = 0 ).
3-(2,6-Dioxo-piperidin-3-yl)-3-aza-bicyclo[3.2.0]heptane-2,4-dione
(20): c/'s-1,2-Cyclobutane dicarboxylic acid anhydride (1.0 g, 7.93 mmol),
glutamic acid (1.17 g, 7.93 mmol), DM A P (0.19 g, 1.6 mmol), and
ammonium chloride (N H 4 CI) (0.44 g, 9.16 mmol) w ere thoroughly mixed in
a Teflon capped vial. The mixture was heated in a multimode microwave
for 1 minute and 56 seconds in the multi mode microwave.
During this
process the material melted, bubbled and turned a dark brown.
The
sample w as allowed to cool to room tem perature and w as dissolved in an
ethyl acetate: acetone mixture (2:1) and washed with 5 ml of aq. N a H C 0
solution.
3
The organic layer was dried and washed with cold methanol
affording a light brown solid (0.60 g, 32 %). M S m /z 236 (M +) 208, 151,
106, 112, 96, 83, 55, 41.
3-(2,5-Dioxo-pyrrolidin-1 -yl)-piperidine-2,6-dione
(21):
Succinic
anhydride (1.0 g, 10.0 mmol), glutamic acid (1.4 7 g, 10.0 mmol), DM AP
(0.24 g, 1.97 mmol), and ammonium chloride (N H 4 CI) (0.62 g, 11.59
150
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
mmol) w ere thoroughly mixed in a Teflon capped vial.
The mixture was
heated in a multimode microwave for 4 minute and 19 seconds in the multi
mode microwave.
turned
During this process the material melted, bubbled and
a dark brown.
The sample was allowed to cool to room
tem perature and was dissolved in an ethyl acetate: acetone mixture (2 :1 )
and washed with 5 ml of aq. N a H C 0 3 solution.
The organic layer was
dried and w ashed with cold methanol affording a light brown solid (1.09 g,
0.52% ). M S m /z 210 (M +) 182, 167, 125, 112, 83,
6 8
3-(2,5-Dioxo-pyrrolidin-1 -yl)-piperidine-2,6-dione
, 5 6 ,4 1 .
(21):
Succinic
anhydride (0.10 g, 1.0 mmol), glutamic acid (0.15 g, 1.0 mmol), DM AP
(0.02 g, 0.19 mmol), and ammonium chloride (N H 4 CI) (0.0 6 g, 1.14 mmol)
w ere mixed thoroughly in a CEM -sealed vial with a m agnetic stirrer. The
mixture w as heated for 10 min at 150 °C in a monomode microwave
powered at 150 W . It was then rapidly cooled to 4 0 °C and dissolved in 15
ml of (1 :1) ethyl acetate: acetone.
The organic layer w as w ashed with 2x
(10 ml) distilled w ater and dried over sodium sulfate (anhydrous). The
organic layer was concentrated under vacuum and precipitated with
hexanes (30 ml) affording a white solid (0.10 g, 48% ). mp 2 27 - 229 °C;
1H N M R (400 M Hz, D M S O -d 6)5 11.0 (s, 1 H, NH), 4 .9 (dd, 1 H, 12.5, 5.5
Hz, C H C O ), 3.3 (s, 1 H), 2.8 (m, 4 H), 2.5 (m, 1 H), 2.4 (m, 1 H), 1.9 (m, 1
151
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
H); 13C N M R (100 M Hz, D M S O -d 6) 176.9, 172.7, 169.3, 49.0, 30.7, 28.0,
22.1; M S m /z 2 10 (M +) 182, 167, 125, 112, 83,
6 8
, 56 41; IR (nujol) (v,
cm '1): 3119.3 2, 3210.14, 1717.99, 1727.93, 1770.23 (C = 0 ).
4-(2,6-Dioxo-piperidin-3-yl)-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5dionedione
(22):
c/s-Bicyclo[2.2.2]-oct-5-en-2,3-dicarboxylic
acid
anhydride (0.10 g, 0.56 mmol), glutamic acid (0.08 g, 0.56 mmol), DM AP
(0.02 g, 0.2 mmol), and ammonium chloride (N H 4 CI) (0.06 g, 1.14 mmol)
w ere mixed thoroughly in a CEM -sealed vial with a m agnetic stirrer. The
mixture w as heated for 10 min at 150 °C in a C E M Discover microwave
powered at 150 W . It was then rapidly cooled to 4 0 °C and dissolved in 15
ml of (1 :1) ethyl acetate: acetone.
The organic layer w as washed with 2x
(10 ml) distilled w ater and dried over sodium sulfate (anhydrous). The
organic layer was concentrated under vacuum and precipitated with
hexanes (30 ml) affording a white solid (0.10 g, 62% ). mp 128 -130 °C; 1H
N M R (400 M Hz, D M S O -d 6) 5 11.0 (s, 1 H, NH), 6.1 (m, 2 H, C H =C H ), 4.8
(dd, 1 H, 12.5, 5.5 Hz, C H C O ), 3.0 (m, 4 H, C H 2 C H 2), 2.8 (m, 1 H), 2.5 (m,
1 H), 2.3 (m, 1 H), 1.7 (m, 1 H), 1.6 (d, 2 H, 7.5 Hz),
13C (100 M Hz, D M S O -d 6)
8
1.2 (d, 2 H, 7.5 Hz);
177.75 (C = 0 ), 177.71 (C = 0 ), 172.57 (C = 0 ),
168.73 (C = 0 ), 132.09 (CH), 131.82 (CH), 4 8 .7 5 (CH), 4 3 .3 7 (CH), 31.39
(CH),
31.22
(CH),
30.48(C H ),
29.79(C H ),
2 3 .1 7 (C H 2),
2 2 .9 8 (C H 2),
152
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
2 2 .8 7 (C H 2), 2 1 .2 9 (C H 2); M S m /z 288 (M +) 260, 209, 178, 149, 136, 112,
99, 80, 78, 54, 41; IR (nujol) (v, cm’1): 3271.68, 1707.28, 1766.12 (C = 0 ).
4-(2,6-Dioxo-piperidin-3-yl)-4-aza-tricyclo[5.2.2.02,6]undec-8-ene-3,5dionedione
(22):
c/'s-Bicyclo[2.2.2]-oct-5-en-2,3-dicarboxylic
acid
anhydride (1.0 g, 5.61 mmol), glutamic acid (0.82 g, 5.61 mmol), DM AP
(0.13 g, 1.06 mmol), and ammonium chloride (N H 4 CI) (0.34 g, 6.3 5 mmol)
w ere thoroughly mixed in an
8
ml Teflon capped vial.
The mixture was
heated in a multimode microwave for 7 minutes and 15 seconds in the
multi mode microwave.
During this process the material melted, bubbled
and turned a dark brown.
The sample w as allowed to cool to room
tem perature and was dissolved in an AcOEt: acetone mixture (2:1) and
washed with 5 ml of aq. NaHCC >3 solution.
The organic layer w as dried
and washed with cold methanol affording a light brown solid (1.09 g, 51 %)
MS m /z 2 88 (M +) 260, 209, 178, 149, 136, 112, 99, 80, 78, 5 4 ,4 1 .
3-Amino-2-hexen-1-one (23): 1,3-cyclohexanedione (2.0 g, 17.8 mmol)
and N H 4 O Ac (2.0 6 g, 26.8 mmol) were thoroughly mixed in an
capped vial.
8
ml Teflon
The mixture was heated in a multimode microwave for 40
sec at full power in the multi mode microwave.
During this process the
material melted, bubbled, and turned dark brown.
The sample was
153
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
allowed to cool to room temperature.
The sam ple w as dissolved in
methanol and washed down a silica column (~50 grams) using pure
acetone. Fractions 1 5 -1 9 w ere collected to give a yellow solid (1.60 g, 81
%) M S m /z 111 (M +) 83, 54, 40.
3-Amino-2-hexen-1-one (23): 1,3-cyclohexanedione (0.2 0 g, 1.78 mmol)
and N H 4 O Ac (0.14 g, 1.78 mmol)
with a stirrer.
were thoroughly mixed in a CEM vial
The mixture was capped and heated in a C E M Discover
microwave for 5 minutes at 150 °C.
The sample w as rapidly cooled to
room tem perature yielding a white solid. The sam ple w as washed with 2
ml ethyl ether and crystallized in methanol yielding a yellow solid (0.18 g,
92% ) M S m /z 111 (M +) 83, 54, 40 13C N M R (90 M Hz, C D C I3) 5 213.49,
186.50, 115.60, 53.96, 46.19, 39.83; D E P T-C N M R (90 M Hz, C D C I3) 5
21 3 .4 9 (C = 0 ), 186.50 (C-N), 115.60 (CH), 53.96 (C H 2), 4 6 .1 9 (C H 2),
39.83 (C H 2); IR (nujol) (v, cm '1): 3126.68, 1677.41 (C = 0 ).
5,5-Dimethyl-3-amino-2-hexen-1-one
(24):
5,5-D im etyl-1,3-
cyclohexanedione (2.0 g, 14.2 mmol) and N H 4OAc (1.2 6 g, 16.3 mmol)
were thoroughly mixed in an
8
ml Teflon capped vial.
The mixture was
heated in a multimode microwave for 1 min 5 sec at full power in the multi
mode microwave.
During this process the material melted, bubbled, and
154
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
turned translucent orange yellow.
The sam ple was allowed to cool to
room tem perature. The sample was washed with ethyl ether to produce a
yellow solid.
The sample was crystallized in methanol yielding yellow
solids (1.81 g, 92% ) M S m /z 139 (M +) 83, 55, 41.
5,5-Dimethyl-3-amino-2-hexen-1-one
(24):
5,5-Dim etyl-1,3-
cyclohexanedione (0.20 g, 1.42 mmol) and N H 4OAc (0.11 g, 1.42 mmol)
w ere thoroughly mixed in a C EM vial with a stirrer.
The mixture was
capped and heated in a C E M Discover microwave for 5 minutes at 150 °C.
The sam ple was rapidly cooled to room tem perature yielding a yellow
solid.
The sam ple was washed with 2 ml ethyl ether and crystallized in
methanol yielding a yellow solid (0.18 g, 92% ) M P 1 0 2 -1 0 5 °C; M S m /z
139 (M +) 111, 83, 55, 40; 13C N M R (90 M Hz, C D C I3)
.8
195.27, 167.05,
98.89, 50.67, 42.62, 33.22, 29.03; D E P T-C N M R (90 M Hz, C D C I3) 5
195.27 (C = 0 ), 167.05 (C-N), 98.89 (C H 2), 50.67 (C H 2), 4 2 .6 2 (C H 2), 33.22
(C), 2 9 .0 3 (C H 3); IR (nujol) (v, cm '1): 3110.51, 1688.17 (C = 0 ).
3-Amino-1-penten-1-one (25): 1,3-cyclopentanedione (0.5 g, 5.1 mmol)
and N H 4 O Ac (0.45 g, 5.8 mmol) were thoroughly mixed in an
8
ml Teflon
capped vial. T h e mixture was heated in a conventional microwave for 45
sec at full power in the multi mode microwave.
During this process the
1 55
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
material melted, bubbled, and turned dark brown.
allowed to cool to room temperature.
The sample was
The sam ple w as dissolved in
methanol and w ashed down a silica column (~40 grams) using acetone:
methanol (3:1). Fractions 18-21 were collected to give light brown crystals
0.35 g (71 % ) M S m /z 97 (M +)
6 8
, 55, 41.
3-Amino-1-penten-1-one (25): 1,3-cyclopentanedione (0.1 g, 1.02 mmol)
and N H 4 O Ac (0.8 g, 1.04 mmol) w ere thoroughly mixed in a C E M vial with
a stirrer. The mixture was capped and heated in a m onomode microwave
for 5 minutes at 150 °C.
The sample was rapidly cooled to room
tem perature yielding a dark brown solid. The sample w as dissolved in
methanol and washed down a flash silica column (~40 grams) using
A cO Et (0.08 g, 81% ) M S m /z 97 (M +)
6 8
, 55, 41; 5 2 0 2 .3 5 (C = 0 ),
178.44(C -N ), 99.10 (CH), 33.80 (C H 2), 2 7.42 (C H 2); IR (nujol) (v, cm’1):
3331.52, 1677.41 (C = 0 ).
2-methyl-3-amino-2-penten-1-one (26): 2-Methyl-1,3-cyclopentanedione
(1.0 g, 8 .93 mmol) and NH4OAc (1.03 g, 13.3 mmol) w ere thoroughly
mixed in an
8
ml Teflon capped vial.
The mixture w as heated in a
multimode microwave for 40 seconds at full power in the multi mode
microwave.
During this process the material melted, bubbled, and turned
1 56
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
dark brown.
The sam ple was allowed to cool to room temperature.
material was washed with ethyl ether.
The
The sam ple w as dissolved in
methanol and washed down a silica column (~40 grams) using 1:1 ethyl
acetate: methanol.
(0.87 g,
8 8
Fractions 1 8 - 2 4 were collected to give a white solid
% ) M S m /z 112 (M +) 82, 54, 41.
2-methyl-3-amino-2-penten-1-one (26): 2-M ethyl-1,3-cyclopentanedione
(0.20 g, 1.78 mmol) and NH4OAc (0.13 g, 1.78 mmol) w ere thoroughly
mixed in a C E M vial with a stirrer. The mixture was capped and heated in
a C E M Discover microwave for 5 minutes at 150 °C.
The sample was
rapidly cooled to room tem perature yielding a white solid.
was washed with
2
The sample
ml ethyl ether and crystallized in methanol yielding a
yellow solid (0.15 g, 76% ),
M S m /z 111 (M +) 82, 54, 41; 13C N M R (90
MHz, C D C I3) 5 200.57, 173.17, 104.40, 31.44, 24.69, 4.94; D E P T -C NM R
(90 M Hz, C D C I 3 ) 5 2 0 0 .5 7 (C = 0 ), 173.17 (C -N ), 104.40 (C), 31.44 (C H 2),
24.69 (C H 2), 4 .9 4 (C H 3); IR (nujol) (v , cm '1): 3299.19, 1680.10 (C = 0 ).
1-(5,5-Dimethyl-3-oxo-cyclohex-1-enyl)-pyrrolidine-2,5-dione
(27):
Succinic anhydride (0.21 g, 2.1 mmol), 5,5-Dim ethyl-3-am ino-2-hexen-1one (24) (0.10 g, 0.71 mmol), and DM AP (0.09 g, 0.21 mmol) w ere mixed
in a C E M vial with a stir bar. The mixture w as heated in a C E M Discover
157
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
for 10 minutes at 150 °C.
tem perature.
The
sample
The sample was allowed to cool to room
was
dissolved
in
methanol
and
flash
chromatographed on a silica column (30 gram, methanol) yielding a dark
brown solid (0.15 g, 95% ). M S m /z 221 (M +) 137.
2-(5,5-Dimethyl-3-oxo-cyclohex-1 -enyl)-isoindole-1,3-dione
(28):
Phthalic anhydride (0.32 g, 2.1 mmol), 5,5-Dim ethyl-3-am ino-2-hexen-1one
(24) (0.10 g, 0.71 mmol), and DM AP (0.09 g, 0.74 mmol) w ere mixed
in a C E M vial with a stir bar. The mixture w as heated in a C E M Discover
for 10 minutes at 150 °C.
tem perature.
The
sample
The sample was allowed to cool to room
was
dissolved
in
methanol
and
flash
chromatographed using a silica column (30 gram, methanol) yielding a
dark brown solid (0.18 g, 94% ). M S m /z 2 69 (M +) 254, 185, 157, 104, 76.
3-(5,5-Dimethyl-3-oxo-cyclohex-1-enyl)-3-aza-bicyclo[3.2.0]heptane2,4-dione (29): c/'s-1,2-cyclobutanedicarboxylic anhydride (0.21 g, 1.67
mmol), 5,5-D im ethyl-3-am ino-2-hexen-1-one
(24) (0.10 g, 0.71 mmol), and
D M AP (0.09 g, 0.21 mmol) were mixed in a C E M vial with a stir bar. The
mixture w as heated in a monomode microwave for 10 minutes at 150 °C.
The sam ple w as allowed to cool to room temperature.
The sample was
dissolved in methanol and flash chromatographed in a silica column (30
1 58
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
gram, m ethanol) yielding a dark brown solid (0.1 4 g,
62% ). M S m /z 235
(M +) 208, 151, 106,112, 96, 83, 5 4 ,4 1 .
2-(5,5-Dimethyl-3-oxo-cyclohex-1-enyl)-hexahydro-isoindole-1,3dione (30): c/'s-1,2 cyclohexane
dicarboxylic anhydride (0.33 g, 2.1
mmol), 5,5-Dim ethyl-3-am ino-2-hexen-1-one
(24) (0.10 g,
0.71 mmol),
and D M A P (0.09 g, 0.74 mmol) w ere mixed in a C EM vial with a stir bar.
The mixture w as heated in a monomode microwave for 10 minutes at 150
°C.
T h e sam ple w as allowed to cool to room temperature.
The sample
was dissolved in methanol and flash chromatographed in a silica column
(30 gram, methanol) yielding a dark brown solid (0.18 g, 65 %). M S m /z
269 (M +) 254, 185, 157, 104, 76.
159
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
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