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Microwave-induced bismuth nitrate-catalyzed multicomponent reaction toward heterocycles

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MICROWAVE-INDUCED BISMUTH NITRATE-CATALYZED MULTICOMPONENT
REACTION TOWARD HETEROCYCLES
A Thesis
by
ASHWINI BOBBALA
Submitted to the Graduate School of the
University of Texas-Pan American
In partial fulfillment of the requirements for the degree of
MASTER OF SCIENCE
August 2012
Major Subject: Chemistry
UMI Number: 1529143
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MICROWAVE-INDUCED BISMUTH NITRATE-CATALYZED MULTICOMPONENT
REACTION TOWARD HETEROCYCLES
A Thesis
by
ASHWINI BOBBALA
COMMITTEE MEMBERS
Professor Bimal K. Banik
Chair of the Committee
Dr. Jason Parsons
Committee Member
Dr. Jose J. Gutierrez
Committee Member
Dr. K. Christopher Smith
Committee Member
August 2012
Copyright 2012 Ashwini Bobbala
All Rights Reserved
ABSTRACT
Bobbala, Ashwini, Microwave-Induced Bismuth Nitrate-Catalyzed Multicomponent Reaction
Toward Heterocycles. Master of Science (MS), August, 2012, 59 pp., 1 table.
The microwave-induced reaction for the synthesis of nitrogen containing heterocyclesis
very important in medicinal chemistry. The synthesis of various other valuable compounds is
also done by employing this reaction. The aza Diels-Alder reaction is one of the most powerful
synthetic tools for the synthesis of nitrogen containing heterocycles. The main goal of the
research is to synthesize the nitrogen containing heterocycles using Bismuth nitrate as the
catalyst in the presence of microwave irradiation. In the present study we explore the catalytic
activity of bismuth nitrate and the role of microwave reactor in the synthesis of 2, 3-diaryl
substituted bicyclic octanone which is the integral part of various biologically active natural
products. Compared to conventional heating the microwave reaction was found to be more
effective and efficient.These molecules posses acetyl cholinesterase inhibitory properties.
iii
DEDICATION
The completion of my master studies would not have been possible without the love and
support of my family. My mother, Sarojini Bobbala, my father, Narsimha Reddy Bobbala, my
brother, Rakesh Reddy Bobbala, who has wholeheartedly inspired, motivated and supported me
by all means to accomplish this degree. Thank you for your love and patience.
iv
ACKNOWLEDGMENTS
I will always be grateful to Dr. Bimal K. Banik, chair of my thesis, for all his mentoring
and advice. From database funding, research design, and data processing, to manuscript editing,
he encouraged me to complete this process through his infinite patience and guidance. I would
also like to express my gratitude to my thesis committee members: Dr. Jason Parsons, and Dr.
Jose J. Gutierrez and Dr. Chris Smith. Their advice, input, and comments on my dissertation
helped to ensure the quality of my intellectual work. I would finally like to thank all of the
dedicated researchers of Dr. Banik’s laboratory, Dr. DebashishBandopadhyay, and Dr. Ram
NareshYadav. My thanks to Jessica Cruz for helping me with the instrumentation.
Finally I would like to gratefully acknowledge the financial support I received from the Kleberg
Foundation and the University of Texas Pan-American. Thanks to their support which helped me
to focus all of my time and effort towards this research project.
v
TABLE OF CONTENTS
Page
ABSTRACT………………………………………………………………………………
iii
DEDICATION…………………………………………………………….……………...
iv
ACKNOWLEDGEMENTS………………………………………………………………
v
TABLE OF CONTENTS………………………………………………………………
vi
LIST OF TABLES……………………………………………………………………….. viii
CHAPTER I. INTRODUCTION…………………………………………………………
1
1.1 Multi-component Reaction……………………………………………………
1
1.2 Aza Diels-Alder Reaction……………………………………………………..
5
1.3 Catalytic role of Bismuth nitrate and Bismuth salts in Organic synthesis….…. 8
1.4 Microwave Reaction…………………………………………………………. 12
CHAPTER II. EXPERIMENTAL METHODS…………………..……………………… 17
2.1 General Experimental Procedure………………………….………………….. 18
2.2 Methodology………………………………………………………………….. 19
2.2.1 Extraction…………………………………………………………… 19
2.2.2 Purification………………………………………………………….. 20
CHAPTER III. RESULTS, DISCUSSION AND CONCLUSION….………..................... 24
3.1 Spectrum 51a………………………………………………………………….. 24
3.2 Spectrum 51b………………………………………………………………….. 28
3.3 Spectrum 51c…………………………………………………………………… 32
vi
3.4 Spectrum 51d…………………………………………………………………… 36
3.5 Spectrum 51e………………………………………………………………….. 40
3.6 Spectrum 51f…………………………………………………………………… 44
3.7 Spectrum 51g…………………………………………………………………… 48
3.8 Conclusion……………………………………………………………………… 53
REFERENCES…………………………………………………………………………...... 54
BIOGRAPHICAL SKETCH…………………………………………………………….... 59
vii
LIST OF TABLES
Page
Table 1: Bismuth nitrate- catalyzed synthesis of 2, 3-diaryl-2-azabicylo [2.2.2] octan5-ones of monocyclic amine…………………………………………………………….
viii
21
CHAPTER I
INTRODUCTION
The main concepts of this chapter are to introduce the different reactions and
methodology such as: multi-component reactions that are most promising powerful tool for
synthetic organic chemists. The importance of aza Diels-alder reaction and the results obtained
by using this reaction are demonstrated. The performance of the automated microwave reactor
for performing the reaction is also included.
1.1 Multi-component Reaction
Multi-component reaction (MCR) is a chemical reaction where three or more organic
molecules react to form a product in a single operation. Multi-component reactions have been
known for over 150 years. The first documented multi component reaction was the “Strecker
synthesis of alpha amino cyanides” in 1850 from which alpha amino acids could be derived. In
modern synthetic organic field multi-component reactions draw the much attention. Thus, in
principle architecturally complex structures can be generated in a single reaction step. MCR’s
minimizes the cost in the form of time and material by generating complex targets in a single
convergent step. Multi-component reactions typically run at milder reaction condition and do not
require multiple steps for completing the target oriented synthesis. Multi-component reactions
play a pivotal role in pharmaceutical, agrochemical and other various industrial applications.
1
A multitude of multi-component reactions
examples of reactions are as below:
1. Mannich pyridine reaction
2. Biginelli reaction
3. Bucherer-bergs reaction
4. Gewald reaction
5. Hantzsch pyridine reaction
6. Strecker amino acid synthesis
7. Kindler Thioamide Synthesis
8. Passerine Reaction
9. Ugi Reaction
10. aza Diels-Alder Reaction
1. Mannich pyridine reaction
2. Biginelli Reation:
2
[1]
exist today. Some of the representative
3. Bucherer-Bergs Reaction:
4. Gewald reaction:
5. Hantzsch Dihydropyridine (Pyridine) Synthesis:
6. Streker Synthesis:
3
7. Kindler Thioamide Synthesis:
8. Passerine Reaction:
9. Ugi Reaction:
In connection to our study we under took a program for the synthesis the nitrogen
containing bicyclic hetro aromatic molecules. In this perspective we had chosen the aza Diels
Alder reaction. The aza Diels -Alder reaction is a class of pericyclic reaction and high atom
economic carbon –carbon and carbon-nitrogen bond forming reaction.
4
1.2 Aza Diels-alder Reaction
Aza-Diels-Alder reaction ranks among the most powerful methodologies for the
construction of nitrogen-containing six-membered ring compounds.[2] The N-containing
heterocyclic compounds are emerging great importance in the field of organic synthesis. The
asymmetric aza Diels-Alder reaction is one of the most efficient transformations to approach
chiral piperidine derivatives, the precursors of a large family of biologically important
compounds such as alkaloids, peptides, and aza-sugars.[3] Pyranoquinolines are known to exhibit
various biological properties
[4]
such as psychotropic, antiallergic, anti-inflammatory and
estrogenic activities.[5-8] In addition to this, they are used as pharmaceuticals.[9] Furoquinolines
function as antagonists
[10]
of 5-hydroxytryptamine receptors in animals and have been found to
be most potent anti-inflammatory agents.[11] Some alkaloids possess the furoquinoline
skeleton.[12] Generally these compounds are prepared by aza-Diels-Alder reaction. Many Lewis
acids cannot be utilized for the single-step coupling of aldehydes, amines and enol because they
will be decomposed or deactivated by the amines and water formed in the intermediate imineformation step. Most imines are hydroscopic, unstable at high temperature, and difficult to
purify, so mulicomponent coupling protocol is highly desirable. Owing to the potential biological
activities of pyranio- and furo-quinolines, mild and more efficient multicomponent protocol for
the synthesis of these compounds are still in great demand in organic synthesis.
A brief account of the role of aza Diels –Alder reaction is described here.
1)
Vanadium chloride catalyzed reaction:
Sabitha et al. group reported the synthesis of pyrano- and furo[3,2-c]quinolines in high
yields using vanadium chloride as catalyst following aza Diels-Alder reaction.[13] The author
reported the role of vanadium chloride as a catalyst for the reaction in respect to both catalytic
5
as well as selectivity. They performed this reaction at room temperature under milder reaction
condition.
Scheme 1:
1
2
3
4a
4b
First chiral Bronsted acid-catalyzed direct aza hetero-Diels-Alder Reaction:
2)
Liu-Zhu Gong et al. group reported bicyclic N-atom containing compounds by aza Diels-Alder
reaction using chiral phosphoric acid derivative catalyst. [14]
Scheme 2:
5
3)
6
7a
7b
Enzyme-Catalyzed Direct Three-Component Aza-Diels−Alder Reaction:
Zhi Guan reported the direct three-component aza-Diels−Alder reaction of aromatic aldehyde,
aromatic amine, and 2-cyclohexen-1-one by hen egg white lysozyme for the first time. [15] This
group also reported the role of Enzyme catalysts, as efficient and green biotransformation tools
6
in organic synthesis. This method showed immense advantages such as mild reaction conditions,
simple separation, good selectivity, and high yields.
Scheme 3:
8
4)
9a
9b
Asymmetric Three-Component Inverse Electron-Demand Aza-Diels–Alder Reaction:
Feng et al. group reported the asymmetric one-pot three-component Inverse Electron-
Demand aza-Diels-Alder reaction with cyclopentdiene, promoted by 5 mol% of an N,N’-dioxideSc(OTf)3 complex, to afford ring-fused tetrahydroquinoline derivatives in high yields, excellent
diastereoselectivities and enantioselectivities.[16]
Scheme 4:
10
11
12
7
13
L5
Acid-mediated three-component aza Diels-Alder reaction:
5)
Dai et al. group reported the aza Diels-Alder reaction of 2-aminophenol in combination
with substituted benzaldehydes and electron-rich cyclic alkenes under controlled microwave
irradiation. The reactions were performed in the presence of a catalytic amount of CF3CO2H in
MeCN at 60°C for 15min. and afforded highly functionalized 8-hydroxy-1, 2, 3, 4tetrahydroquinolines. [17]
Scheme 5:
14
15
1.3
16
17a
17b
Catalytic role of Bismuth nitrate and Bismuth salts in Organic synthesis
The word bismuth is derived from the German word Weissmuth or white substance.
Bismuth is the 83rd element in the periodic table with an atomic mass of 208.980 and is the
heaviest stable element on the Periodic Table. In spite of its heavy metal status, bismuth is
8
considered to be safe, as it is non-toxic and noncarcinogenic.
[18]
Bismuth and its compounds
have been used in medicinal preparations for over four hundred years. Several bismuth
compounds have been found for the treatment for gastric disorders.
With increasing environmental concerns and the need for ‘green reagents’, the interest in
bismuth and its compounds has increased tremendously in the last decade. Several review
articles and a monograph has focused on the applications of bismuth and its compounds in
organic synthesis. [19-22]
Bismuth nitrate is used as the catalyst in the aza Diels-Alder Reaction. Bismuth nitratecatalyzed, automated microwave-assisted expeditious synthesis of Heterocycles has been carried
out in an efficient manner. Bismuth salts have emerged as efficient Lewis acids due to their
relatively low toxicity, ready availability at a low cost and tolerance of moisture. In the previous
research among several bismuth salts, bismuth nitrate pentahydrate was chosen as the best
catalyst for the reaction.
An example for the bismuth nitrate-catalyzed microwave reaction is the formation of
“4-(phenylamino) pent-3-ene-2-one” in 99% yield and the reaction was completed within 3
minutes.
18
Encouraged by that result, who also reacted the acetyl acetone with cyclohexyl amine,
morpholine and benzylamine in presence of bismuth nitrate and produced the corresponding
products in excellent yields.
9
They also confirmed the role of catalyst by doing a blank reaction under similar
conditions in the absence of catalyst. Only 50% completion was found even after 1 hour. It has
clearly showed that the role of catalyst bismuth nitrate pentahydrate for activation of the
reaction.
Some of the synthetic applications of bismuth nitrate-catalyzed reactions are:
1)
Synthesis of Glucose Peracetate via bismuth nitrate produced two isomers.
Scheme 6:
19a, 19b
From this reaction it has been demonstrated that bismuth nitrate can be used for the
peracetylation of glucose under environmentally benign conditions. [23]
2)
Microwave-induced bismuth nitrate-catalyzed electrophilic substitution of indole with
keto ester under solvent-free condition.
Scheme 7:
20
21
22
10
This method using microwave irradiation with catalytic amounts of bismuth nitrate was
attractive for the synthesis of this novel type of molecule. [24]
3)
Microwave-induced Bismuth nitrate-catalyzed Pechman reaction:
Scheme 8:
R1 = H, OCH3, Me
23
24
Bismuth nitrate catalyst was used for the synthesis of 4-substituted-coumarins under solvent
free condition. [25]
4)
Oxidative cleavage of olefins:
Suzuki, et al. group reported the insoluble bismuth sulphate catalyzed autooxidation of
cyclohexene in acidic solvents. [26]
Scheme 9:
25
26
27
11
28
29
30
5)
Oxidation of epoxides:
Scheme 10:
31
32
Le Boisselier, et al. group reported the oxidation of epoxides to cyclic carbonates using
molecular oxygen as the oxidant and BiBr3 as the catalyst. [27]
6)
Deprotection of O,O-acetals:
Scheme 11:
33
34
35
Sabitha, et al. group reported the catalytic activity of BiCl3 in CH3OH as a solvent for
deprotection of acetals. [28]
1.4 Microwave Reaction
This issue on microwave-induced reaction provides the ideal platform to bringing
together researchers and leading scientists from academia and industries to address the acute
problems that the chemical industry faces and to provide viable pollution preventive strategies
12
and realistic solutions. Higher activation energy transformations that are difficult and impossible
to complete with conventional heating (oil bath, steam bath, and mantle) can be performed very
easily with microwave irradiation because of the facile energy transfer process. Heat is applied
externally and it passes through the walls of the reaction vessel and solvent during thermallyassisted chemical reactions. Therefore, some of the reactions may not prove efficient. However,
microwave-induced reactions have a number of advantages because of microwave coupling,
microwave heating, microwave irradiation and molecular heating. Microwave coupling is the
direct transfer of microwave energy to a substrate that results in instantaneous heating.
Microwave heating is the direct energy transfer process to the reaction mixtures; this raises
kinetic excitation and is characterized by rapid energy transfer. Microwave irradiation is a form
of non-ionizing radiation that transfers energy by interacting with polar molecules. In addition,
the direct energy transfer from microwave to the molecules will greatly enhance the speed of the
chemical reaction (solvent free reaction).
Much of the drug discovery research has been depended on green chemistry: synthesis of
useful molecules in the absence of any solvents, microwave-induced reactions, ultrasoundassisted reaction, solar energy-mediated reactions and by catalytic methods. Advancing new and
existing processes that are highly stereoselective and environmentally benign are one of the most
important challenges. Homogeneous and heterogeneous catalysis, organocatalysis, biocatalysts
and asymmetric catalysis targeted toward organic synthesis of complex natural products and
medicinally important drug have received an increasing role in recent years.
Thus, the microwave induced reactions opens up a new era in the synthesis and chemistry/
biology of medicinally active molecules.
Some of the synthetically useful transformation performed under microwave is stated as: [29]
13

Organometallic cross-coupling reactions

Cycloadditions

Heterocyclic reaction

Nucleophilic additions and substitutions

Electrophilic substitutions

Oxidations

Reductions

Condensations

Hydrolysis

Dehydration

Protection and Deprotection

Miscellaneous reactions
Heterocyclic Reaction:
Heterocyclic chemistry was found to be an area of importance in synthetic chemistry. A
large number of compounds both natural and target drug compounds contains heterocyclic core.
Synthesis of these kinds of compounds was found to be challenging.
The Biginelli three-component condensation reaction is a one-pot synthesis to
dihydropyrimidines. These heterocyclic systems have enhanced pharmacological efficiency in a
variety of biological activity including antiviral, antitumor, antibacterial and anti-inflammatory
activities. The reaction was found to complete in five minutes with microwave irradiation with
an yield of 60-90%.[30] With normal conventional heating these reactions can take approximately
24 hours for complete transformation with low to moderate yields.
14
Scheme 12:
36
1)
37
38
39
The Paal-Knorr condensation reaction/ cyclization reacts 1, 4-diketones with
primary amines to form N-susbstituted pyrroles. This synthesis requires at least twelve hours of
prolonged thermal heating and Lewis acids to activate the diketones. With microwaves,
transformation occurred within 30 seconds to two minutes with very high yields (75-90%).[31]
Scheme 10:
40
2)
The
Hantzsch
41
pyridine
reaction
42
was
used
to
synthsize
susbstituted
dihydropyridines. These are known to act as a calcium channel blockers and are biologically
active. In this reaction an aldehyde, two equivalents of a beta-ketoester, and ammonium
hydroxide are combined in the same reaction vessel, one equivalent of the beta-ketoester and the
aldehyde undergo an aldol condensation. The other equivalent reacts with the ammonium
15
hydroxide to yield enamine.
[32-34]
Classical thermal heating takes over 24h, whereas these
reactions occur in five minutes with microwave irradiation.
Scheme 13:
43, 44
45, 46
47
Importance of Nitrogen Heterocycles:
Nitrogen containing compounds are the key building blocks for the construction of
valuable compounds. They are very important biomodels in drug research. The aza Diels-Alder
reaction was the most powerful reaction for the synthesis of nitrogen heterocycles. Some of the
examples are.
The 2-azabicyclo [2.2.2] octane skeleton is found in natural products which act as a
potent acetyl cholinesterase inhibitors. Therefore they are used in the treatment of Alzheimers
disease. There is still a need to find molecules which possess this skeleton that have not been
tested for this inhibitory activity.
16
CHAPTER II
EXPERIMENTAL METHODS
In this section, a detailed description of the multi-component reaction process along with
the plausible mechanism of the reaction was outlined. The general experimental procedure was
done by using the chemicals from Sigma-Aldrich. The automated microwave used for this
reaction was from CEM Corporation.
Multi-component reaction is a chemical reaction where three or more compounds react to
form a single product. In our method this reaction involves coupling of anilines, benzaldehydes,
and cyclohexenone in the presence of catalytic amounts of bismuth nitrate in N, Ndimethylformamide. The reaction was found to proceed smoothly to afford the corresponding
mixture of endo/ exo- isomers in a ratio of 20:80, in an overall yield of 90%. These isomers were
separated by column chromatography over silica gel. [35]
Scheme 14: Bi (NO3)3.5H2O catalyzed one pot three component aza Diels-Alder Reaction
48
49
50
51
52
Three component bismuth nitrate catalyzed aza Diels-Alder reaction to give 2, 3-diaryl-2azabicyclo [2.2.2] octan-5-ones.
17
Their structures were established based on 1H NMR data. Similarly, various other amines
were reacted with aldehydes and the results are listed in the Table 1. In all the cases, the imines
generated in situ from aldehydes and amines react immediately with cyclohexenone, and the
multi component reaction proceeded to give the corresponding heterocycles in high yields. The
ratio of the each isomers obtained in each reaction was determined from 1H NMR spectrum of
the crude product, and the gross structures of the products were established on the basis of
spectroscopic (IR, 1H NMR, and 13C NMR) data of the pure compounds.
The plausible reaction mechanism of aza-Diels-Alder Reaction of Cyclohexenone with
amines and aldehydes. [36]
Scheme 15:
2.1 General Experimental Procedure
A mixture of aniline (1mmol), benzaldehyde (1mmol), cyclohexenone (1mmol) and 10
mol% of Bismuth nitrate in 2ml of N, N-dimethylformamide were placed into the microwave
vial. To this vial a small magnet was added and placed in the microwave. The temperature was
set at 60°C and 300W power was applied. The reaction was then conducted for 20-40min.and
monitored by TLC. Once the completion of the reaction was indicated by TLC, the reaction was
18
stopped and extraction was performed. The reaction mixture was poured into a separating funnel
and diluted with DCM and extracted with 50mL of saturated sodium bicarbonate, brine and
water and dried over anhydrous sodium sulphate. The solvent was evaporated by using
rotavapour. The crude mass was subjected to the flash chromatography. Proton NMR was taken
to determine the ratio of the isomers.
A small vial of silica gel was added to the compound to prepare the slurry. The slurry was
dried by using vacuum for half an hour. The column was packed with silica gel and the dried
slurry was added over silica gel column. The compound was eluted by using hexane and ethyl
acetate as elutant.
2.2 Methodology
2.2.1 Extraction
Extraction was performed by taking the reaction mixture in a separating funnel. The
reaction mixture was added through the top with the stopcock at the bottom closed and dispensed
into a separating funnel. To this compound, a saturated sodium bicarbonate solution was added,
the funnel was then closed and shaken gently by inverting the funnel multiple times; the two
solutions were mixed together too vigorously to form an emulsion. The funnel was then inverted
and the tap carefully opened to release excess vapor pressure. The separating funnel was set
aside to allow for the complete separation of the phases. The top and the bottom tap were then
opened and the two phases released by gravitation. The organic layer was collected and to this
10mL of brine solution was added and the same procedure was followed as with the sodium
bicarbonate. Once again, the organic layer was collected and to this water was added and shaken
vigorously and sodium sulphate was added to the solvent collected. The solvent was filtered and
evaporated.
19
2.2.2 Purification
Flash Chromatography:
The reaction mixture obtained after the evaporation was checked using TLC followed by
the separation of the reaction mixture using the column chromatography. Initially the slurry was
prepared by adding the silica gel to the mixture and then allowed to dry for some time. The
column was packed with the silica gel and the dried mixture was added above the packed column
and 100% hexane was added initially to wet the column. Then, the same method was performed
by adding solvents with increasing polarity (hexane: ethyl acetate mixture). After eluting the
product, the solvent was evaporated. The compound was crystallized, filtered, dried and then
NMR, IR data was obtained for characterization of the structures. The summary of the result of
these reactions are shown in table 1.
20
Table 1. Bismuth nitrate- catalyzed synthesis of 2, 3-diaryl-2-azabicylo [2.2.2] octan-5-ones of
monocyclic amine.
entry
Amine (R)
Aldehyde (R)
a)
H
b)
Cyclic-enone
Time
(min.)
Yield
(%)
Product
ratio
H
30-40
90
7:3
OCH3
H
20-30
88
8:2
c)
OCH3
F
25-30
80
7:3
d)
OCH3
CH3
15-20
82
9:1
e)
CH3
2 OCH3
20-25
90
7:3
f)
CH3
CH3
15-20
92
9:1
g)
H
2 OCH3
15-20
92
8:2
The aza Diles-Alder reaction with polycyclic amine:
The reaction was performed by taking 6-amino chrysene (1mmol), benzaldehyde
(1mmol), cyclohexenone (1mmol), 75mg of bismuth nitrate and 2ml of DMF. The reaction was
performed at 65°C for 1-2h. A new spot was observed. The reaction mixture was taken into a
separatory funnel and extraction was performed. After the extraction, the compound was isolated
using column chromatography. After observing the results (IR, NMR) it came to conclusion that
the correct compound was not formed. The desired compound was not formed probably because
of the stearic bulk of the ring in the 6-aminocheysene.
21
Scheme 16:
53
54
Scheme 17:
Synthesis of 9, 10-Dihydrophenanthrene amine:
10-15gm of clay, 8gm of bismuth nitrate was taken in 100ml of round bottomed flask. To
this dichloromethane was added and the solvent was evaporated using the rotavapour. In the next
step the round bottomed flask was place in the microwave along with a beaker of ice. The
reaction was run for 2min. and the TLC was performed to check the completion of the reaction.
After the completion of the reaction, the compound was dissolved in the DCM and filtered. The
solvent collected after the filtration was taken into a separatory funnel and extracted using
saturated sodium bicarbonate, brine and water. The solvent was evaporated and isolated, the
solid compound was collected. The solid was dried completely and used to perform the reaction.
22
The reaction was performed by taking 1mmol of the compound, 1mmol of the
Benzaldehyde, 1mmol of the cyclohexenone, 75 mg of bismuth nitrate and 2ml of DMF.
The reaction was run at 65°C for 1hr 30min-45min. after the completion of reaction
extraction was performed and the solvent was evaporated by using rotavapour. The pure
compound was isolated by column chromatography. After observing the results (IR, NMR) it
came to conclusion that the desired compound was formed.
Scheme 18:
55
56
23
CHAPTER III
RESULTS, DISCUSSION AND CONCLUSION
In this chapter the results of the experiments were explained.
Melting points were
determined in a Fisher Scientific electrochemical Mel-Temp® manual melting point apparatus
(Model 1001D) equipped with a 400 °C thermometer. FT-IR spectra were registered on a Bruker
IFS 55 Equinox FTIR spectrophotometer. Spectra were obtained with TOPSPIN Bruker
superconducting UltrashieldTM plus 600 MHz NMR spectrometer using CDCl3 as solvent. All
chemicals were purchased from Sigma-Aldrich Corporation. All solvents used in the project
were purchased from Fisher-Scientific.
3.1 Spectrum 51a:This spectrum shows the reaction of Aniline and Benzaldehyde with Cyclohexenone.
24
Entry a, Table 1). Solid, mp 144-146 °C (n-hexane); IR (KBr): ν 1721, 1593, 1497, 1283
cm-1; 1H-NMR (600 MHz, CDCl3) δ 7.35-7.30 (2H, m), 7.24-7.20 (2H, m), 7.20-7.10 (2H, m),
6.65-6.63 (2H, m), 6.53-6.52 (2H, m), 4.71 (1H, d, J = 2.3 Hz), 4.48 (1H, t, J = 3.1 Hz), 2.63
(1H, q, J = 3.0 Hz), 2.34 (1H, dd, J = 1.8, 18.7 Hz), 2.19-2.18 (1H, m), 1.84-1.83 (1H, m), 1.651.49 (2H, m);
13
C-NMR (150 MHz, CDCl3) δ 16.4 (CH2), 26.0 (CH2), 42.3 (CH2), 48.2 (CH),
51.0 (CH), 62.4 (CH), 113.1 (CH), 117.7 (CH), 126.2 (2CH), 127.4 (2CH), 128.4 (2CH), 129.3
(2CH), 140.1 (C), 148.2 (C), 213.6 (C).
1.0 proton ab aus .txt
0.9
O
H
0.8
N
Normalized Intensity
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
3.90 1.29 1.92 0.98 1.96
10
9
8
7
1.00 1.01
6
5
Chemical Shift (ppm)
25
1.98 1.00 0.99 0.06 0.99 1.00 1.04 0.97
4
3
2
1
0
1.0 c13 ab aus.txt
0.9
O
0.8
H
N
Normalized Intensity
0.7
0.6
0.5
0.4
0.3
0.2
0.1
220
200
180
160
140
120
100
Chemical Shift (ppm)
26
80
60
40
20
0
1.0 dept ab aus.txt
0.9
O
0.8
0.7
H
N
0.6
Normalized Intensity
0.5
0.4
0.3
0.2
0.1
0
-0.1
-0.2
-0.3
-0.4
-0.5
160
150
140
130
120
110
100
90
80
Chemical Shift (ppm)
27
70
60
50
40
30
20
10
The IR Spectrum of aniline with benzaldehyde
ab aus
O
1497
1593
1283
N
40
3500
749
H
1221
60
1721
% Transmittance
80
3000
2500
2000
1500
-1
Wavenumber (cm )
3.2 Spectrum 51b:-
28
1000
500
Entry b, Table 1). Solid, mp 112-115 °C (n-hexane); IR (KBr): ν 1726, 1509, 1279, 1223
cm-1;1H-NMR (600MHz, CDCl3) δ 7.36-7.19 (5H, m), 6.67-6.65 (2H, m), 6.49-6.46 (2H, m),
4.63 (1H, d, J = 1.7 Hz), 4.37-4.36 (1H, m), 3.62 (3H, s), 2.70 (1H, qt, J = 2.9 Hz), 2.30 (1H, dd,
J = 1.8, 16.7 Hz), 2.23-2.10 (1H, m), 1.84-1.78 (1H, m), 1.78-1.53 (1H, m);
13
C-NMR (150
MHz, CDCl3) δ 16.3 (CH2), 26.3 (CH2), 41.9 (CH2), 48.9 (CH), 51.1 (CH), 55.6 (OCH3), 62.7
(CH3), 114.3 (CH), 114.8 (2CH), 126.2 (2CH), 127.3 (2CH), 128.8 (2CH), 140.4 (C), 142.7 (C),
52.2 (C), 213.9 (C).
0.50 proton pab paus.txt
0.45
O
H
0.40
N
Normalized Intensity
0.35
0.30
OMe
0.25
0.20
0.15
0.10
0.05
0
1.96 1.97 0.97 0.43 1.94 1.99
10
9
8
7
6
1.00 1.01
5
Chemical Shift (ppm)
29
3.00 0.99 0.97 0.51 0.97 1.02 0.98 1.88
4
3
2
1
0
1.0 carbon pab paus.txt
0.9
O
0.8
H
N
Normalized Intensity
0.7
0.6
OMe
0.5
0.4
0.3
0.2
0.1
220
200
180
160
140
120
100
Chemical Shift (ppm)
30
80
60
40
20
0
1.0 c13 dept pab us.txt
0.9
O
0.8
0.7
H
N
0.6
Normalized Intensity
0.5
0.4
OMe
0.3
0.2
0.1
0
-0.1
-0.2
-0.3
-0.4
-0.5
160
150
140
130
120
110
100
90
80
Chemical Shift (ppm)
31
70
60
50
40
30
20
10
The IR Spectrum of P-Anisidine with Benzldehyde.
pab paus
80
OMe
30
3500
3000
2500
1509
1248
40
2000
1500
-1
Wavenumber (cm )
3.3 Spectrum 51c:-
32
1000
810
1279
N
1041
H
50
1223
O
1114
60
1726
%Transmittance
70
Entry c, Table 1). Solid, mp 94-96 °C (n-hexane); IR (KBr): ν 1724, 1506, 1249, 1223
cm-1; 1H-NMR (600 MHz, CDCl3) δ 7.32-7.30 (2H, m), 7.01-6.97 (2H, m), 6.67-6.65 (2H,m),
6.64 (2H, m) 4.61 (1H, brs), 2.69 (3H, s), 2.69-2.65 (2h, m), 2.55-2.53 (1H, m), 2.50 (1H, dd, J =
1.8, J = 18.7Hz), 2.19-2.13 (1H, m), 1.84-1.79 (1H, m), 1.66-1.55 (1H, m);
13
C-NMR (150
MHz, CDCl3) δ 16.3 (CH2), 6.4 (CH2), 41.9 (CH2), 49.1 (CH), 51.1 (CH), 55.6 (OCH3), 62.1
(CH), 114.4 (CH), 114.9 (CH), 115.6 (CH), 115.6), 115.8 (CH), 127.8 (2CH), 127.9 (2CH),
142.5 (C), 152.2 (C), 161.3 (C), 163.0 (C), 214.0 (C).
0.50 proton pafb paus.txt
0.45
O
H
0.40
F
N
Normalized Intensity
0.35
0.30
0.25
OMe
0.20
0.15
0.10
0.05
0
1.95 0.21 1.92 1.96 2.00
10
9
8
7
1.00 0.98
6
5
Chemical Shift (ppm)
33
3.00 1.00 1.00 1.01 1.01 1.01 1.05 1.60
4
3
2
1
0
1.0 c13 pafb paus.txt
0.9
O
H
0.8
F
N
Normalized Intensity
0.7
0.6
OMe
0.5
0.4
0.3
0.2
0.1
220
200
180
160
140
120
100
Chemical Shift (ppm)
34
80
60
40
20
0
1.0 dept pafb paus.txt
0.9
O
0.8
H
F
N
0.7
0.6
Normalized Intensity
0.5
OMe
0.4
0.3
0.2
0.1
0
-0.1
-0.2
-0.3
-0.4
-0.5
160
150
140
130
120
110
100
90
80
Chemical Shift (ppm)
35
70
60
50
40
30
20
10
The IR Spectrum of P-Anisidine with 4-fluoro benzaldehyde
pafb paus
80
60
O
40
30
3500
3000
2500
2000
1500
-1
Wavenumber (cm )
3.4 Spectrum 51d:-
36
811
1041
OMe
1249
1223
F
N
1505
50
H
1724
%Transmittance
70
1000
500
Entry d, Table 1). Solid, mp 149-154 °C (n-hexane); IR (KBr): ν 1726, 1512, 1275, 1242
cm-1; 1H-NMR (600 MHz, CDCl3) δ 7.23-7.22 (2H, m), 7.11-7.10 (2H, m), 6.67-6.65 (2H, m),
6.49-6.47 (2H, m), 4.59 (1H, brs), 4.35 (1H, t, J = 2.3 Hz), 3.62 (3H, s), 2.68 (1H, t, J = 3.1 Hz),
2.65 (1H, t, J = 3.1 Hz), 2.55 (1H, q, J = 2.9 Hz), 2.31 (1H, d, J = 1.7 Hz), 2.28 (3H, s), 2.212.15 (1H, m), 1.82-1.77 (1H, m), 1.69-1.64 (1H, m);
13
C-NMR (150 MHz, CDCl3) δ 16.4
(CH2), 21.1 (CH3), 26.3 (CH2), 41.9 (CH2), 48.9 (CH), 51.2 (CH), 55.7 (OCH3), 62.5 (CH),
114.3 (2CH), 114.8 (2CH), 126.2 (2CH), 129.5 (2CH), 137.0 (C), 137.0 (C), 142.8 (C), 152.0
(C), 214.1 (C).
0.50 proton pat paus.txt
0.45
O
H
0.40
Normalized Intensity
Me
N
0.35
0.30
0.25
OMe
0.20
0.15
0.10
0.05
0
1.99 0.22 1.96 1.96 1.99
10
9
8
7
1.00 1.01
6
5
Chemical Shift (ppm)
37
3.00 1.00 0.99 4.02 1.03 1.01 1.04 1.59
4
3
2
1
0
1.0 carbon pat paus.txt
0.9
O
0.8
H
Me
N
Normalized Intensity
0.7
0.6
OMe
0.5
0.4
0.3
0.2
0.1
220
200
180
160
140
120
100
Chemical Shift (ppm)
38
80
60
40
20
0
1.0 c13dept pat paus.txt
0.9
O
0.8
H
Me
N
0.7
0.6
Normalized Intensity
0.5
OMe
0.4
0.3
0.2
0.1
0
-0.1
-0.2
-0.3
-0.4
-0.5
160
150
140
130
120
110
100
90
80
Chemical Shift (ppm)
39
70
60
50
40
30
20
10
The IR Spectrum of P-Anisidine with Toulaldehyde
pat paus
80
75
65
60
1341
H
1241
1034
Me
N
50
3500
OMe
3000
2500
2000
1509
45
40
1500
-1
Wavenumber (cm )
3.5 Spectrum 51e:-
40
826
O
55
1726
%Transmittance
70
1000
500
Entry e, Table 1). Solid, mp 128-130 °C (n-hexane); IR (KBr): ν 1723, 1514, 1256, 1235
cm-1; 1H-NMR (600 MHz, CDCl3) δ 7.18 (1H, s), 6.92-6.91 (2H, m), 6.83-6.78 (2H, m), 6.476.45 (2H, m), 2.16 (1H, d, J = 4.5 Hz), 4.41 (1H, qt, J = 2.1 Hz), 3.80 (3H, s), 3.79 (3H, s), 2.68
(1H, t, J = 3.1), 2.65 (1H, t, J = 3.1), 2.90 (1H, qt, J = 2.5 Hz), 2.31 (1H, dd, J = 1.7, J = 18.1Hz),
2.13 (3H, s), 1.85-1.79 (1H, m), 1.71 (1H, m), 1.58-1.53 (1H, m); 13C-NMR (150 MHz, CDCl3)
δ 16.4 (CH2), 20.2 (CH3), 26.2 (CH2), 42.0 (CH2), 48.4 (CH), 51.2 (CH), 56.0 (20CH3), 62.4
(CH), 109.1 (CH), 111.4 (CH), 113.3 (CH), 118.3 (CH), 127.0 (2CH), 129.8 (CH), 132.7 (2C),
146.2 (C), 148.2 (C), 149.4 (C), 214.0 (C).
1.0 proton tdb tus.txt
0.9
0.8
O
H
OMe
0.7
OMe
Normalized Intensity
N
0.6
0.5
0.4
Me
0.3
0.2
0.1
0
0.23 2.96 1.98 1.98
10
9
8
7
0.99 1.01
6
5
Chemical Shift (ppm)
41
6.00 1.01 1.00 1.02 3.95 1.01 0.03 1.01 1.55
4
3
2
1
0
1.0 c13 tdb tus.txt
0.9
O
H
0.8
OMe
OMe
N
Normalized Intensity
0.7
0.6
Me
0.5
0.4
0.3
0.2
0.1
220
200
180
160
140
120
100
Chemical Shift (ppm)
42
80
60
40
20
0
1.0 dept tdb tus.txt
0.9
0.8
O
0.7
H
OMe
OMe
N
0.6
Normalized Intensity
0.5
0.4
Me
0.3
0.2
0.1
0
-0.1
-0.2
-0.3
-0.4
160
150
140
130
120
110
100
90
80
Chemical Shift (ppm)
43
70
60
50
40
30
20
10
The IR Spectrum of Toulidine with 3,4 Dimethoxybenzaldehyde.
tdb tus
60
3500
3000
1514
809
Me
1025
20
OMe
1285
N
1256
40
OMe
1133
H
1614
O
1722
% Transmittance
80
2500
2000
1500
-1
Wavenumber (cm )
3.6 Spectrum 51f:-
44
1000
500
Entry f, Table 1). Solid, mp 132-134 °C (n-hexane); IR (KBr): ν 1725, 1511, 1275, 1221
cm-1; 1H-NMR (600 MHz, CDCl3) δ 7.32 (2H, d, J = 7.3 Hz), 7.21 (2H, d, J = 7.3 Hz), 6.98
(2H, d, J = 7.7 Hz), 6.55 (2H, d, J = 7.8 Hz), 4.74 (1H, brs), 4.53 (1H, brs), 2.89-2.86 (1H, m),
2.78-2.75 (1H, m), 2.42 (1H, m), 2.39 (3H, s), 2.35 (1H, m), 2.33 (3H, s), 1.93-1.89 (1H, m),
1.78-1.74 (1H, m), 1.66-1.62 (1H, m); 13C-NMR (150 MHz, CDCl3) δ 16.4 (CH2), 20.24 (CH3),
21.1 (CH3), 26.1 (CH2), 42.2 (CH2), 48.4 (CH), 51.1 (CH), 62.2 (CH), 13.2 (CH), 126.1 (2CH),
127.0 (2CH), 129.5 (2CH), 130.0 (CH), 137.0 (2C), 137.2 (C), 146.1 (C), 214.0 (C).
1.0 proton ttltus.txt
0.9
0.8
O
H
0.7
Me
Normalized Intensity
N
0.6
0.5
0.4
Me
0.3
0.2
0.1
0
1.90 1.68 1.70 1.72
10
9
8
7
0.86 0.87
6
5
Chemical Shift (ppm)
45
0.87 0.87 3.54 3.01 0.76 0.91 1.25
4
3
2
1
0
1.0 c13 ttl tus.txt
0.9
O
0.8
H
Me
N
Normalized Intensity
0.7
0.6
Me
0.5
0.4
0.3
0.2
0.1
220
200
180
160
140
120
100
Chemical Shift (ppm)
46
80
60
40
20
0
1.0 dept ttl tus.txt
0.9
O
0.8
0.7
H
N
Me
0.6
Normalized Intensity
0.5
0.4
Me
0.3
0.2
0.1
0
-0.1
-0.2
-0.3
-0.4
-0.5
160
150
140
130
120
110
100
90
80
Chemical Shift (ppm)
47
70
60
50
40
30
20
10
The IR Spectrum of Toulidine with Toulaldehyde.
ttl tus
80
60
50
O
1275
Me
20
3500
3000
2500
2000
1500
-1
Wavenumber (cm )
3.7 Spectrum 51g:-
48
801
1113
1511
30
1221
Me
N
1340
1614
40
H
1725
% Transmittance
70
1000
500
Entry g, Table 1). Solid, mp 150-154 °C (n-hexane); IR (KBr): ν 1724, 1595, 1515, 1255
cm-1;1H-NMR (600 MHz, CDCl3) δ 7.09-7.06 (2H, m), 6.91-6.78 (4H, m), 6.61-6.54 (2H, m),
4.63 (1H, d, J = 2.2 Hz) 4.46 (1H, qt, J = 1.9 Hz), 3.81 (3H, s), 3.80 (3H, s), 2.70-2.65 (1H, m),
2.59 (1H, t, J = 2.9 Hz), 2.32 (1H, dd, J = 1.7Hz, J = 18.7 Hz), 2.19-2.14 (1H, m), 2.18-2.81 (2H,
m), 1.71-1.66 (1H, m), 1.59-1.56 (1H, m);
13
C-NMR (150 MHz, CDCl3) δ16.4 (CH2), 26.1
(CH2), 42.2 (CH2), 48.2 (CH), 51.2 (CH), 55.8 (OCH3), 55.9 (OCH3), 62.3 (CH), 109.1 (CH),
111.4 (CH), 113.2 (CH), 117.8 (CH), 118.2 (CH), 129.3 (2CH), 132.4 (C), 148.2 (C), 148.3 (C),
149.3 (C), 213.8 (C).
1.0 proton adb aus.txt
0.9
0.8
O
Normalized Intensity
0.7
H
OMe
N
0.6
OMe
0.5
0.4
0.3
0.2
0.1
0
0.21 1.97 1.00 1.98 1.01 1.14
10
9
8
7
6
0.99 1.00
5
Chemical Shift (ppm)
49
6.01 0.70 1.00 0.98 0.91 1.01 1.01 1.55
4
3
2
1
0
1.0 c13 adb aus.txt
0.9
O
H
OMe
0.8
OMe
N
Normalized Intensity
0.7
0.6
0.5
0.4
0.3
0.2
0.1
220
200
180
160
140
120
100
Chemical Shift (ppm)
50
80
60
40
20
0
1.0 dept adb aus.txt
0.9
0.8
O
H
OMe
0.7
OMe
N
0.6
Normalized Intensity
0.5
0.4
0.3
0.2
0.1
0
-0.1
-0.2
-0.3
-0.4
160
150
140
130
120
110
100
90
80
Chemical Shift (ppm)
51
70
60
50
40
30
20
10
The IR Spectrum of aniline with 3, 4-dimethoxybenzaldehyde
adb aus
85
80
70
65
45
3500
3000
2500
2000
1500
-1
Wavenumber (cm )
52
749
1024
1127
50
1255
OMe
N
55
694
OMe
1416
H
1310
O
1595
1515
60
1724
% Transmittance
75
1000
500
3.8 Conclusion
We have developed a highly efficient bismuth nitrate catalyzed microwave induced one pot three
component aza Diels-Alder reaction for the synthesis of 2-aza bicycle [222] octane 5-one. We
have also explored the diverse catalytic activity of environmentally-friendly bismuth nitrate in
aza Diels-Alder reaction. The reaction proceeds in good yield with monocyclic aromatic amines.
However, because of the steric crowding of the polycyclic aromatic amines, the reaction has not
produced any desired product. Interestingly, a preference for the formation of the endo isomer
has been observed.
53
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Hefei National Laboratory for Physical Sciences at the Microscale and Department of
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b
Department of Chemistry, The Hong Kong University of Science and Technology, Clear
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Heterocyclic Letters Vol. 1, special issue, July (2011), 73-74.
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(2011), 95-96.
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35. Luis Astudillo S.,a, Gabriel A. Vallejosa, Néstor Correaa, Margarita Gutiérrez C.a,
Walesca de la Guardaa and Vladimir V. Kouznetsovb
a
Laboratorio de Síntesis Orgánica, Instituto de Química de Recursos Naturales, Universidad
de Talca, Casilla 747,Talca, Chile.
b
Laboratorio de Química Orgánica y Biomolecular, Escuela de Química, Universidad
Industrial de Santander, A.A.678, Bucaramanga, Colombia.
57
36. Hua Liu, Lin-Feng Cun, Ai-Qiao Mi, Yao-Zhong Jiang, and Liu-Zhu Gong,
Hefei National Laboratory for Physical Sciences at the Microscale and Department of
Chemistry, UniVersity of Science and Technology of China, Hefei, 230026, China, Key
Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan ProVince,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu,
610041, China, and Graduate School of Chinese Academy of Sciences, Beijing, China.
58
BIOGRAPHICAL SKETCH
Ashwini Bobbala, was born in 1988 in Nakrekal, Nalgonda (Dist.), Andhra Pradesh
India. She obtained her school diploma from St Anne’s High School in 2003. Then she attended
Osmania University in 2003 for her Undergraduate studies. She finished her studies in 2009 and
obtained Bachelors in Pharmacy. She was accepted to University of Texas Pan American
(UTPA) in 2010 in order to pursue a Master’s degree in chemistry. She began to work as
Graduate assistant while working on research with Professor Bimal K. Banik related to her thesis
topic:
microwave-induced
bismuth
nitrate-catalyzed
multicomponent
reaction
heterocycles. She finished her studies by August 2012. Her permanent address is:
Ashwini Bobbala
D/o Narsimha Reddy Bobbala
Nakrekal, Nalgonda (Dist.)
P.O Box 508211
Andhra Pradesh, India.
59
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