Chapter-I Brief introduction of heterocycles
1
CHAPTER - I
Brief introduction of heterocycles
1.1 Introduction of heterocyclic chemistry
The chemistry of heterocyclic compounds is of great interest both from the
theoretical as well as practical standpoint. Heterocyclic compounds occur
widely in nature and in a variety of non-naturally occurring material.
Moreover, they are of immense importance not only both biologically and
industrially but also to the functioning of developed society as well. It has
become one of the largest areas of the research in Organic Chemistry. Their
participation in a wide range of areas cannot be underestimated. A significant
part of large number of compounds such as alkaloids, antibiotics, essential
amino acids, vitamins, haemoglobin, the hormones, synthetic drugs and dyes
composed of heterocyclic ring systems and have significant importance for
human and animal health. Therefore, researchers are on continuous pursuit to
design and produce better pharmaceuticals, pesticides, and insecticides. Other
important practical applications of heterocycles can also be cited, for instance,
additives and modifiers in wide variety of industries including cosmetics,
reprography, information storage, plastics, solvents, antioxidants. Finally as the
applied science, Heterocyclic Chemistry is an inexhaustible resource of novel
compounds. It is therefore easy to understand why both the developments of
new methods and the strategic deployment of known methods for the synthesis
of complex heterocyclic compounds continue to drive the field of Synthetic
Organic Chemistry.
Organic compounds have a variety of structures. These structures can be
acyclic or cyclic. The cyclic systems containing only carbon atoms are called
carbocyclic and the cyclic systems containing carbons and at least one other
element are called heterocyclic. Though the number of heteroatoms are known
to be part of the heterocyclic rings, the most common are nitrogen, oxygen or
sulphur. A heterocyclic ring may contain one or more heteroatom’s which may
or may not be same. Also the rings may be saturated or unsaturated. Nearly half
2
of the known organic compounds contain at least one heterocyclic ring. Many
heterocyclic compounds occur naturally and are actively involved in biology
e.g., nucleic acids (purine and pyrimidine bases), vitamins (Thiamine B1,
Riboflavin B2, Nicotinamide B3, Pyridoxol B6 and Ascorbic acid), heme and
chlorophyll, penicillins, cephalosporins, macrolides etc. The study of
heterocycles is a vast and expanding area of chemistry because of their
applications in medicine, agriculture, photodiodes and other fields.
Heterocyclic compounds are classified as alicyclic and aromatic
heterocycles. The alicyclic heterocycles are the cyclic analogues of amines,
ethers and thioethers and their properties are influenced by the ring strain. The
three and four membered alicyclic heterocyclic rings are more strained and
reactive compared to five and six membered rings. The common alicyclic
heterocyclic compounds are aziridine (I), oxirane (II), thirane (III), azetidine
(IV), oxetane (V), thietane (VI), pyrrolidine (VII), tetrahydrofuran (VIII),
tetrahydrothiophene (IX) and piperidine (X).
The heterocycles which show aromatic behavior as in benzene are called
the aromatic heterocyclic compounds. These compounds follow the Hückel’s
rule which states that cyclic conjugated and planar systems having (4n+2) π
electrons are aromatic. Some simple aromatic heterocyclic compounds are
pyrrole (XI), furan (XII), thiophene (XIII), imidazole (XIV), pyrazole (XV),
oxazole (XVI), thiazole (XVII) and pyridine (XVIII).
3
1.2 Medicinal Chemistry
Medicinal chemistry is of great academic and intellectual interest. The
elucidation of the arachidonic acid cascade is one of the most fascinating bits
of chemistry of our generation. The study of the chemistry of the brain is one of
the great frontiers of science. Unlike astrophysics and evolutionary theory,
however, medicinal chemistry is an applied science. It is lavishly funded not
because of its philosophical centrality, but because it provides the hope that
human disease can be cured or alleviated. Its paymasters intend that mankind,
or at least those sections of it with access to advanced medical care, live longer
and more comfortably. Its practitioners are judged by this criterion. There are
few Nobel prizes for those who discover, say, the biochemical origins of
rodent-specific dermatitis. As the test of success is pragmatic, serendipity plays
an important role in medicinal chemistry. The discoverers of sulfonamides
thought that dye stuffs might prove efficacious because they bonded
specifically to certain tissues, as in Ehrlich’s classic experiment. In the end,
Prontosil worked not because it was a dye but because it cleaved in the gut to
p-aminobenzenesulfonic acid. Fleming, whose chance discovery of penicillin
would have been meaningless, had not Florey and Chain solved the problem of
its purification and Coghill and his co-workers (who did not get Nobel prizes)
solved the problem of its large-scale production. Medicines are thus judged by
their results. A successful drug can be manufactured reasonably easily, has
negligible side effects, is widely prescribed, makes a lot of money and is
perceived as making a major contribution to health care.
4
1.3 Overview of Nitrogen and Sulfur heterocycles
For more than a century, heterocycles have constituted one the largest
areas of research in organic chemistry. They have contributed to the
development of society from a biological and industrial point of view as well as
to the understanding of life processes and to the efforts to improve the quality
of life. Heterocycles play an important role in biochemical processes because
the side groups of the most typical and essential constituents of living cells,
DNA and RNA, are based on aromatic heterocycles.[1]
Among the
approximately 20 million chemical compounds identified by the end of the
second millennium, more than two-thirds are fully or partially aromatic, and
approximately half are heterocyclic. The presence of heterocycles in all kinds
of organic compounds of interest in biology, pharmacology, optics, electronics,
material sciences, and so on is very well known.
Among them, sulfur and nitrogen-containing heterocyclic compounds
have maintained their interest of researchers through decades of historical
development of organic synthesis. Nitrogen-containing compounds are
ubiquitous in nature and many of them are biologically active. The grounds of
this interest were their biological activities and unique structures that led to
several applications in different areas of pharmaceutical and agrochemical
research or, more recently, in material sciences.[2]
The family of sulfur–nitrogen
heterocycles includes highly stable aromatic compounds that display
physicochemical properties with relevance in the design of new materials,
especially those relating to molecular conductors and magnets. During the past
few decades, interest has been rapidly growing in gaining insight into the
properties and transformations of these heterocycles. The interesting
characteristics found in many of them have led to the development of modern
synthetic methods that are the subject of this special issue. Nitrogen and sulfur
organic aromatic heterocycles are formally derived from aromatic carbon
cycles with a heteroatom taking the place of a ring carbon atom or a complete -
CH=CH- group. The presence of heteroatoms results in significant changes in
the cyclic molecular structure due to the availability of unshared pairs of
5
electrons and the difference in electronegativity between hetero-atoms and
carbon. Therefore, nitrogen and sulfur heterocyclic compounds display
physicochemical characteristics and reactivity quite different from the parent
aromatic hydrocarbons. On the other hand, the presence of many nitrogen and
sulfur atoms in a ring is normally associated with instability and difficulties in
the synthesis but, in fact, surprisingly stable heterocycles with unusual
properties can be frequently obtained from simple organic substrates and the
appropriate inorganic reagent. Carbon atoms confer high stability to such rings,
according to the aromaticity and anti-aromaticity rules. The nitrogen-sulfur
core gives unusual properties to the compounds, in accordance with their
electron rich p-excessive nature. The physicochemical properties of this family
of compounds have relevance in the design of new materials, especially
concerning organic conductors.
In contrast with the number and variety of such heterocycles, the
numbers of synthetic methods to afford them are in practice, restricted to the
availability of the appropriate sulfur or nitrogen reagent. Sometimes, the
preparation of new heterocyclic systems by conventional ways is a hard work
that implies many synthetic steps and expensive starting materials. Moreover,
many heterocyclic systems, predicted to be stable, are impossible to prepare
because the required synthetic approach simply does not exist. For this reason,
new approaches to obtaining complex heterocyclic systems by using simple
organic starting materials and reagents generate reactive intermediates that can
be trapped by selected nucleophiles in tandem or sequential processes, have
been developed. A good combination of reagents and reaction sequences
permits the preparation of heterocycles that imply several reaction steps by
rational design. An example of this chemistry is the reaction of N-
alkyldiisopropylamines with disulfur dichloride, which is able to give several
different heterocyclic structures, depending on the reaction conditions.[3]
Multicomponent reactions constitute another important synthetic tool that is
now growing fast in the development of new heterocyclic processes.
Multicomponent condensations of isocyanides are extremely powerful
6
synthetic tools for the preparation of structurally diverse complex molecules,
which can be further modified by post-condensation transformations.[4]
Among
the post-condensation transformations, those leading to the formation of
heterocyclic cores are very important since it permits the preparation, often in a
very simple manner, of heterocyclic compounds with substitution patterns that
are not easily obtainable by other synthetic routes. Furthermore, these
transformations permit a facile access to the constrained peptides and
peptidemimetics, which are of great interest in drug discovery programs. These
and other areas are now currently under intense research, especially those
relating to pharmaceutical and new materials chemistry. The interesting
characteristics found in many of these heterocycles is the development of rapid
synthetic methods from easily available materials, and the very wide range of
products obtainable by modern methods offer wide scope for the synthesis of
new sulfur-nitrogen heterocycles. The chapters in this thesis reflect the new
strategies that are now being developed for the synthesis of these heterocycles.
1.4 Synthesis of Nitrogen and Sulphur heterocycles
Heating of acetyl acetone and benzaldehyde in presence of two
equivalent of ammonium acetate yielded the pyrimidine derivatives[5]
(Scheme
1.1) via the intermediate.
MeCO2NH4
4 5
CH3
CH3
O
O
DMSO/AcOH
NH
NH2
CH3
H3C
H C6H5
O
N
N
CH3
CH3H5C6
Scheme 1.1
The reaction of 1,3-diaminopropane with formaldehyde yielded
perhydropyrimidine and with diethylcarbonate to yield the 2-oxo derivative and
with carboxylic acid it gives tetrahydropyrimidine[6]
(Scheme 1.2).
7
NH2
NH2
O=C.(CO2C2H5)2
RCOOH
o-xylene
HCHO
N
NH
H
N
NH
H
O
N
N
H
R
6a
6b
6c
Scheme 1.2
Cyclocondensation of enaminonitrile with CS2 in the presence of sodium
methoxide gave pyrimidinethione derivative[7]
(Scheme 1.3).
RCH2S-C=
NH2 CN
CN+ CS2
MeOH/MeONa
5M
N
N
S
H
S
H
SCH2R
CN
8
7
Scheme 1.3
Cyanocrotonamide derivatives condensed with diethoxyalkyl-amine to
yield the pyrimidine derivative[8]
(Scheme 1.4).
N
N
CH3
R1
N O
CN
CH3
CH3
NH2
O
NC
R1HN+ R
OC2H5
OC2H5
NCH3
CH3 H3C
9 10 11
Scheme 1.4
The reaction of malonodiamide with an ester such as malonic ester
yielded the 4,6-dihydroxypyrimidine derivative[9]
(Scheme 1.5).
8
N
N OH
CH3
OH
H3C
OMeO
NH2
NH2
O
H3C
O
+
OMe
OMe
O
H3C
O
12 1314
Scheme 1.5
The reaction of -aminocrotonamide with succinic anhydride yielded -
succinamido-crotonamide, which in turn undergoes cyclization in basic
medium to give 3,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl-propanoic acid[10]
(Scheme 1.6).
+
15 16
NH2
NH2
O
Me
O
O
(CH2)n O
N
NH2
O
Me
H
COR
HN
N
O
R Me
R = (CH2)2COOH
n = 2
Scheme 1.6
Treatment of 3-amino-2-(methylamino)propionaldehyde-O-methyl-
oxime 2HCl with trimethyl orthoformate gave Z and E-1,2,5,6-tetrahydro-5-
pyrimidine carboxaldehyde-O-methyl oxime[11]
(Scheme 1.7).
+
17
HN N
CH=N-OR
HCl.H2N
HCl.H2N
C=N
H
OMe HC(OMe)2
Scheme 1.7
N-Methyl-2-thiocarbamoylacetamide reacts with ethyl formate to form
the 6-thioxo-4-(3H)-pyrimidinone[12]
(Scheme 1.8).
18
NHMe
NH2
S
O
HCO2Et
39% N
N
O
Me
S
Scheme 1.8
9
Malondiamide derivative condensed with ethyl chloroformate to
produce methylthio-2,4-(1H, 3H)-pyrimidin-dione cyclization of -
aminothiocrotamide with dimethyl formamide dimethylacetal yielded 4-(3H)-
pyrimidinethione[13]
(Scheme 1.9 and Scheme 1.10).
+NH
NHEt
O
MeS N
N
O
Et
MeS O
H
Cl-C-OC2H5
OOH
19
20
Scheme 1.9
+NH2
NH2
S
Me N
N
S
H
Me
21 22
HC(OMe)2NMe2ref
68%
Scheme 1.10
A number of substituted pyrimidine-5-carbonitriles and ethyl
pyrimidine-5-carboxylate were prepared by the reaction of methyl-N-
aminocarbonyl or N-aminothiocarbonyl imidates with malononitriles, methyl,
cyanoacetate or diethyl malonate by refluxing with alkoxide in alcohol[14]
(Scheme 1.11 and Scheme 1.12).
+R'
OMe
NH
R-N= C = X
HN
N
R'
X
R23a,b
a) X= O b) X= S
Scheme 1.11
10
25
CN
CNMeONa
N
N
R'
X
R
H2N
NC
N
N
R'
X
R
O
NCH
N
N
R'
X
R
O
H5C2O2CH
CN
CO2CH3CH3ONa
OEt
OEt
O
O
EtONa
23a,b
23a, X= O 23b, X = S
24a
24b
Scheme 1.12
Reaction of 1,3-dicarbonyl compound with N-Cyano-guanidine in the
presence of Ni(OAc)2 gave the pyrimidine derivatives[15]
(Scheme 1.13).
R
R'
O
O
+
H2N
H2N
N-C NNi(OAc)2 N
N
R
COR'
NH2H2N
26 27a,b
a, R=R'=Me b, R=Me, Ph, R'= Me, OEt
Scheme 1.13
Reaction of 1,3-diaza derivative with keten derivative afforded the
pyrimidine derivatives[16]
(Scheme 1.14).
+
H
C
R'''
C ON
N
Ph'
O
R'''
R'
R''28 30
Ph'-N=C-N=CHR'
R''
29
R'=Ph, MeS-, R''= Me2N-, R'''= Cl, Ph, Ph'= Ph, p-MePh, p-BrPh, p-ClPh, p-MeOPH
Scheme 1.14
11
Cycloaddition between diazadiene and alkynes derivatives afforded
pyrimidine derivative[17]
(Scheme 1.15).
+
R'
HN
N
NMe2
CCl3
R'' C C COR'''N
N
R'
COR'''
R''Cl3C
3231
38-98%
Scheme 1.15
Reversed polarization as in 2-trimethylsilyloxy and 2-trimethylsilylthio-
1,3-diene allow percyclic reaction with acyclic enamines from pyrrolidines or
morpholinopyrimidinones and pyrimidinethione[18]
are formed in high yields in
dichloromethane (Scheme 1.16).
+
Ar2N
N
XSiMe3
Ar1
HN
N
R2
NR12X
Ar2
Ar1
33
R2
NR12
34
-25oC
80-93%
X = O, S
PtSOH HN
N
R2
X
Ar2
Ar1
Scheme 1.16
The first synthesis of pyrimidine nucleus is achieved from the
condensation of urea with malonic acid in the presence of phosphoryl chloride,
it was named barbituric acid[19]
(Scheme 1.17).
+
35
NH2
NH2
O
OH
OH
O
O
N
N
OH
OHHO
Scheme 1.17
Condensation of benzamidine with ethylacetoacetate in alkaline solution
yielded 4-hydroxy-6-methyl-2-phenyl-pyrimidine[20]
(Scheme 1.18).
+
36
N
N
OH
CH3H5H6H5C6 NH
NH2 H5C2O
NaO
O
H
CH3
Scheme 1.18
12
The enamino ester condensed with amidine derivatives yielded ethyl
pyrimidine-5-carboxylate derivative[21]
(Scheme 1.19).
+
39
N
N RR'
CO2C2H5
R' NH2
NH
R
O
CO2C2H5
N
CH3
CH3
3837
Scheme No. 1.19
4-Carbethoxy-2, 6-dihydroxypyrimidine was obtained by the reaction of
urea with diethyloxaloacetate presumably via intermediacy of 5-
carbethoxymethylene hydention[22]
that rearranged to give pyrimidine
derivative[23]
(Scheme 1.20).
+
OC2H5
CH2CO2C2H5
O
O
NH2
NH2
OHN
NO O
CHCO2C2H5
H
N
N
OH
HO CO2C2H5
4041
42
Scheme 1.20
The reaction of ethylcyanoacetate derivatives with S-alkyl isothiourea
derivatives yielded pyrimidine derivatives[24]
(Scheme 1.21).
+
NH2
NH
R'S .HCl
H5C2O2C
NC
RN
N
OH
R
NH2R'S
43 44a,b
44a, R=NHCOCH3 44b, R=NHCH2C6H5
Scheme 1.21
The reaction of bromopyruvate esters with urea yielded 71-89% of the
corresponding uracil derivatives [25]
(Scheme 1.22).
+
H2N
H2N
O
HN
N
O
OH
O
RH
45 46
CO2C2H5
O
Br
R
Scheme 1.22
13
The reaction of diethylmalonate derivative with urea gave the
pyrimidine derivative [26]
(Scheme 1.23).
+
H2N
H2N
O
HN
N
O
OO
CH2R
C2H5
H
47 48
OC2H5
OC2H5RH2C
H5C2
O
O
Scheme 1.23
S-(p-Methoxybenzyl)thiourea hydrochloride reacts with -acetyl-
cinnamic esters in presence of sodium hydroxide to yield 1,3-dihydro-6-
methyl-5-pyrimidine carboxylic acid esters[27]
(Scheme 1.24).
+
HN
H2N
RHN
N
Ar
CH3R
CO2C2H5
CO2C2H5
COCH3
CHAr
49 50CH2SMeOR=
Scheme 1.24
The ketoester reacted with guanidine derivative to yield 2-ureido-6-
triflouromethyl-3,4-dihydropyrimidine-4-one[28]
(Scheme 1.25).
+HN
N CF3NH2N
O
H
O
OR
CF3
O
O H
NH2N NH2
ONH
51 38 52
Scheme No. 1.25
The guanidine derivatives reacted with the ketoesters to yield the
corresponding pyrimidine derivatives[29]
(Scheme 1.26).
OC2H5
CH2
O
O
OCH3R NH2
NHHN
N CH2 OCH3
O
R
+
53 54
Scheme 1.26
14
The reaction of diaminoguanidine with -ketoester yielded 3-amino-2-
hydrazino-6-phenyl-3,4-dihydro-4-pyrimidin-one[30]
(Scheme 1.27).
OC2H5
C6H5
O
O
N
N C6H5
O
NH2N
H
H2N
H
+
5556
H2NN
NH2N
NH
HH
Scheme 1.27
The condensation of diethylmalonate with formamidine acetate in basic
medium led to the formation of 4,6-dihydroxy-5-ethylpyrimidine[31]
(Scheme
1.28).
OC2H5
OC2H5
O
O
H5C2N
N OH
OH
C2H5
+
57
H2N H
NH
.CH3COO
Scheme 1.28
Heating a mixture of ethyl cyanoacetate with aldehydes and S-methyl
isothiourea gave the corresponding 4-aryl-5-cyano-2-methylthio-6-oxo
pyrimidine derivative[32]
(Scheme 1.29).
OC2H5
CN
O
Ar H
O
+ SCH3
HN
H2N
NH
NAr SCH3
O
NC
61
Scheme 1.29
Condensation of ethyl--bromoacetoacetate with S-methyl or S-benzyl
isothiourea yielded the corresponding pyrimidine derivatives[33]
(Scheme 1.30).
CH2Br
OC2H5
O
O
+ SR
HN
H2N
N
NHO SR
CH2Br
62a,b
a, R= CH3 b, R= C6H5CH2-
HCO3
-
Scheme 1.30
15
The reaction of cyanoolefine with guandine, urea, thiourea or S-methyl-
thiourea yielded the corresponding 4-aminopyrimidine derivatives[34]
(Scheme
1.31).
+ X
H2N
H2N
NH
NH2N X
R'
R
H
64a,b
X= NH, O, S or MeSR'
CN
R
H
63aa, R=Ph R'=CONH2 b, R= p-ClC6H4 R'=PhCO
Scheme 1.31
Cyclocondensation of acetamidine hyrochloride with cyano olefin
yielded 4-amino-5-aminomethyl-2-methyl-pyrimidine[35]
(Scheme 1.32).
+ NH
N CH3
H2NH2C
NH2
65
CH2NH-CH
OMe
NC
H
O
63b
H2N CH3
NH.HCl
Scheme 1.32
The reaction of formyl acetic acid with urea yielded uracil[36]
(Scheme
1.33).
H
OH
O
O
H2N NH2
O
+
66
N
NH
O
O
H
Scheme 1.33
Heating a mixture of 2,3-diphenyl cyclopropanone with amidoxime
yielded the corresponding 2,5,6-triphenylpyrimidine-4-one[37]
(Scheme 1.34).
H5C6 NH2
NOH
+
67
N
NH
O
C6H5
H5C6
H5C6
O
C6H5
H5C6
Scheme 1.34
16
The reaction of acetophenone semicarbazone with ethylacetoacetate
gave N-alkylidineaminouracil[38]
(Scheme 1.35).
CH3
OC2H5
O
O
H5C6 CH3
NNH-C-NH2
O
+
68
N NH
O
O
N
H3C
H3C
H5C6
Scheme 1.35
Condensation of phenylacetylene with benzaldehyde and urea in butanol
containing dry hydrochloric acid forming 2-hydroxy-4,6-diphenylpyrimidine[39]
(Scheme 1.36).
H2N NH2
O
+
69
N
N
C6H5
C6H5HO
H5C6
BuOH/HCl
H5C6CHO
Scheme 1.36
Acetyl acetone condensed with acetamidine, p-methyl-phenylguanidine,
urea, thiourea or nitroguanidine to give the corresponding pyrimidine
derivatives[40]
(Scheme 1.37).
CH3
CH3
O
O
H2N R
NH
+
70 a-e
N
N
CH3
CH3R
a, R= CH3 b, R= HNC6H4CH3 (p) c, R= OHd, R= SH e, R= NHNO2
Scheme 1.37
The reaction of thiobenzamide with 3-alkoxy-3-aryl (or alkyl)-2-
cyanoacrylo-nitriles and sodium isopropoxide in 2-propanol afforded 4-thioxo-
3,4-dihydro-pyrimidine derivatives[41]
through formation of the 3-aryl (or
alkyl)-2-cyano-3-thiobenzamide acrylonitriles (Scheme 1.38).
17
H2N Ph
S+
73
N
S NHPh
CN
R
CN
RR'O
NC
PrONa
HCl
N
N SPh
CN
R
H
71
72
HN
C6H5
R
CN
CNS
Scheme 1.38
Treatment of thioazolyl thiourea derivative with malonic acid in the
presence of acetyl chloride gave the pyrimidine derivative[42]
(Scheme 1.39).
+ N N
OO
SN
S
EtO2C
Me
7475
N
S
EtO2C
NH-C-NH-Me
SHOOC
HOOC
AcCl
Scheme 1.39
Reaction of 1,1-cycloalkanedicarboxylic acid diethyl esters with
thiourea gave barbituric acid derivative[43]
(Scheme 1.40).
(CH2)n
COOEt
COOEt+ S
H2N
H2N
(CH2)n
N
N
O
O
H
H
S
76
n= 1-3
Scheme 1.40
Condensation of the O-ethylthiourea with diethylmalonate gave the
pyrimidine derivative[44]
(Scheme 1.41).
+ OEt
HN
H2N
77
CO2Et
CO2Et
N
N
OH
OEtHO
EtONa
Scheme 1.41
18
Heterocyclization of thiourea derivative with the enolate of 1,3-
dicarbonyl derivative afforded hydroxyl hexahydropyrimidinthiones, which
upon dehydration afforded tetrahydropyrimidinthiones[45]
(Scheme 1.42).
+S
XH2CHN
H2NNaAc
ONa
HN NH
S
COR
OH
Me
HN N
S
COR
Me- H2O
78 79 80 81
+S
XH2CHN
H2NNaAc
ONa
R
HN NH
S
COR
OH
Me
HN N
S
COR
Me- H2O
78 79 80 81
Scheme 1.42
Reaction of 1,3-dicarbonyl compound with (azidomethyl) thiourea or
[(P.tolylsulphonyl)methyl]-thiourea gave pyrimidine derivative[46]
(Scheme
1.43).
+ HN NH
R'R''
S
84
R'
R''
ONa
O
H2N
HN
SCH2N3
83
Scheme 1.43
Treatment of 2-methylpyrimidine derivatives with POCl3/ DMF
afforded diformyl derivative that treated with formamidine derivative to give
2,5-bipyrimidine derivative[47]
(Scheme 1.44).
N
N
MeR POCl/DMF
N
N
R
CHO
CHO
R'NH2
NH2
.HCl
N
N
R
N
N
R'
85 86
87
R= substituted phenyl R'= substituted phenyl, C7H5
Scheme 1.44
19
Cyclocondensation of 1,3-dicarbonyl derivatives with urea gave
pyrimidines[48]
(Scheme 1.45).
+
89
H2N
H2N
O
88
R4
R3
R2
R5
R6O
R1
R
O
R4
R3
R2
R5
R6N N
R
R1
OH
Scheme 1.45
Treatment of guanidine nitrate with acetylacetone in the presence of
potassium carbonate gave 2-amino-4,6-dimethyl pyrimidine[49]
(Scheme 1.46).
+
90
H3C
H3C
O
O
H2N
H2N
NH2
NO3
N N
CH3
NH2
H3C
K2CO3/H2O
24h/room temp
Scheme 1.46
Cyclocondensation of benzaldehyde derivatives with urea or thiourea
and acetoacetate derivative in the presence of HCl according to Biginelli
reaction gave pyrimidine derivatives[50]
(Scheme 1.47).
HX
NH
NH2
91 92
CHO
R1
R4 R2
R3
+
H3C
RO2C
O
R1
R4
R3
R2
HN
N
H
X
CO2R
CH3
93X= O or S
Scheme 1.47
20
Reaction of aldehyde with ketomethylene derivatives and urea or N-
alkylurea in presence of HCl afforded 2-oxopyrimidine derivatives[51]
(Scheme
1.48).
94 95
+
H3C
R1
O
96a,b
R-CHOR2NH-C-CH3
OHN
N
R2
O
R1
CH3
R
a, R= alkyl R1= NO2 b, R= Ph R1= acetyl
R2=H, alkyl
Scheme 1.48
Reaction of 3-pyridinecarboxyaldehyde, thiourea and ethyl cyanoacetate
gave 5-cyano-2-mercapto-6-(3-pyridyl-2-thiouracil) derivative[52]
(Scheme
1.49).
+
100
N
CHO HN
N
O
HS N
H2N NH2
S
CO2Et
CN
Scheme 1.49
Condensation of ethyl guanidium nitrate and ethyl acetoacetate ester in
presence of sodium hydroxide in alcohol gave two isomers pyrimidines[53]
(Scheme 1.50).
H2N
H2N
NEt+
H3C
BuO2C
O
101
N
N
Me
EtHN OH
BuNO2
N
N
Me
H2N O
Bu
Etab
reflux
alc. +
Scheme 1.50
Cyclocondensation of methyl methoxyacetate, S-methylthiourea
sulphate and ethyl formate gave 2-methylthio-5-methoxy-3,4-
dihydropyrimidin-4-one[54]
(Scheme 1.51).
21
MeS
H2N
NH +
102
N
NH
SMe
MeO
O
HSO4
CO2Me
OMeHCOOEt
Scheme 1.51
Cyclocondensation of 1,3-dicarbonyl derivative with formamidine
derivatives afforded pyrimidine derivatives[55]
(Scheme 1.52).
H2N
R'
NH
105
CH2
CO2R
Bu
OR''
N
N
CH2
R''Bu
OH
R'
103
+
104a,b
a, R'=Et b, R'=Me Scheme 1.52
Condensation of benzamide with propargyl amine and subsequent
cyclocondensation of obtained product with 1,3-dicarbonyl compound gives
pyrimidine derivative[56]
(Scheme 1.53).
EtO
F3C
O
O
Et
106
NH
OMe
+
NH2
NH
NH N
N
CF3
Et
O Ph
Scheme 1.53
Reaction of ethyl 4-(acetyloxy)-2-[2-(methylthio)-3-nitrophenyl]
methylene-3-oxobutanoate and 2-methyl-2-thio-pseudourea sulphate in the
presence of sodium acetate afforded ethyl (hydroxymethyl)pyrimidine
carboxylate derivative which was cyclized in NaOH to give corresponding
pyrimidine derivative[57]
(Scheme 1.54).
22
MeS
NH
NH2
HSO4 +
O2N SMe
OCO2Et
CH2OHHO
AcONa
DMFN
N
R
CO2Et
H
CH2OHMeS
MeOH/DMSO
NaOH
O
N
N
R
H
MeS
O
107
108
Scheme 1.54
Treatment of acrylonitrile derivatives with N-acetylurea led to the
formation of ureido acrylonitrile derivatives which undergo intramolecular
cyclization upon treatment with alkali to give pyrimidine derivatives[58]
(Scheme 1.55).
+
111a,b
H
CNR
Me2NMe
H2N
N
O
HO
N
HNRNC
H
Me
O
O N
NNC
X
Me
O
O
110a,b109a,b
a, R= CHOb, R= CO2Et
a, X = H
b, X = OH
Scheme 1.55
1,3-Dicarbonyl compound were condensed with formamidine acetate to
give pyrimidine derivatives[59]
(Scheme 1.56).
R
ClF2C
O
O
CHEtN
N
Et
CF2Cl
R
OH2N
H2N
+EtONa
EtOH
112a,b 113a,ba, R = CHO b, R = p-C6H4-Cl
OOCCH3.
Scheme 1.56
23
Cyclocondensation of aniline formamidine derivative with ketone
compound gave pyrimidine derivative[60]
(Scheme 1.57).
N NH2
NH
H
Cl
R
Me2N
O
N
N
N
N
Cl
H
Cl
+
114115R=2-Cl-4-pyridyl
Scheme 1.57
Cyclocondensation of p-methoxybenzamidine HCl with 2-
methoxycarbonyl-3-dimethylaminoacroline in presence of EtONa in refluxing
EtOH afforded the 2-p-anisyl pyrimidine[61]
(Scheme 1.58).
+
116
N
NEtO2C
OMe
MeO
NH
NH2
.HCl
H
O
OEt
H
(CH3)2N
O
EtONa
EtOH
Scheme 1.58
Ethyl 3-oxo-2-(4-flourobenzylidene)-4-methylpentanoate was refluxed
with benzamidine hydrochloride and potassium acetate to give 4-(4-
flurophenyl)-6-isopropyl-2-phenyl-5-ethoxycarbonyl-1,2-dihydro-
pyrimidine[62]
(Scheme 1.59).
+
117
.HCl AcOKPh
NH
NH2
Me2CH-C-C
O CO2Et
F
HN N
Ph
CO2EtMe
Me
F
toluene
Scheme 1.59
A mixture of O-methyl isourea hydrogensulphate, chalcone and
NaHCO3 in DMF when heated gave dihydropyrimidine. Treatment of S-[3-(3-
methoxyphenoxy)propyl]-isothio-urea hydrobromide with ethoxy methylidine
24
malonate in H2O/EtOH and K2CO3 was heated to give pyrimidine
derivatives[63]
(Scheme 1.60 and Scheme 1.61).
+
118
119
.HSO4MeO
NH2
NH2
Cl
CO2Et
O
N
N N
Cl
CO2Et
N
N
MeO
H
N
N N
NaHCO3
DMF
70oC
Scheme 1.60
+
120
K2CO3
H2O/EtOEtO CO2Et
CO2Et
HBr(H2C)2-CH2-S
NH
NH2O
OMe
O
NH
SN (CH2)3-O
OMe
EtO2C
70oC, 2h
Scheme 1.61
Ethyl (3-triflouromethylbenzoyl) acetate was refluxed with N,N-
dimethyl formamide dimethyl acetal in tetrahydrofuran to give the 1-(3-
triflouro-methylbenzoyl)-1-ethoxy-carbonyl-2-(N,N-dimet-h-ylamino) ethene
which was refluxed with benzamidine HCl in the presence of potassium
ethoxide and gave 2-phenyl-4-(3-triflouromethylphenyl)-5-ethoxy-
carbonylpyrimidine[64]
(Scheme 1.62).
25
CF3
C-CH2CO2Et
O
MeO OMe
NMeMe
+THF
CO2Et
NCH3
CH3
O
CF3
NH
NH2
HCl
N N
CO2Et
Ph
CF3
C2H5OK
121reflux, 5h
Scheme 1.62
Condensation of 2-chloro-3-nitrobenzaldehyde with acetoacetate
derivative and MeS-C(=NH)NH2 yielded 3,4-dihydropyrimidine carboxylate[65]
(Scheme 1.63).
NO2
CHO
Cl
+
123
Me-C-CH2-CO2(CH2)2SiMe3
O MeS
NH
NH2
HN
N
NO2
Cl
CO2(CH2)2SiMe
MeMeS122
Scheme 1.63
Condensation of benzylacetoacetate with N-methylurea and 2-
naphthaldehyde gave Biginelli compound[66]
(Scheme 1.64).
O
NHCH3
NH2
O
+
H3C- C-CH2-C-OCH2C6H5
O O
N
NHRO2C
O
Me
Me
124
R=CH2.C6H5
Scheme 1.64
26
Reflux of benzoylethylene and benzamidine derivative gave pyrimidine
derivative[67]
(Scheme 1.65).
+
N
N
SMe
CF3
Cl
127
C-CH=C
O SMe
SMe H2N
HN
CF3
K2CO3
Me2CHOH
126125
reflux
Scheme 1.65
Treatment of pyridylamidine salt with enamines and sodium methoxide
in presence of methanol gave the pryidyl pyrimidine derivative[68]
(Scheme
1.66).
N
NH2
NH
Cl
+
H2C-C(Me)2-C-CH=CH-N(Me)2
Me
O
N
N
N
N(Me)2
QAr
MeOH
MeONa
128
129
Q= CMe2-CH3 Ar = 4-MeC6H4
Scheme 1.66
The dihydropyrimidine was obtained by the reaction of thiourea with
benzoyl ethylene derivative[69]
(Scheme 1.67).
O
Cl
Me
+ S
H2N
H2N N
N
Ar'
Ar S
130 131
Scheme 1.67
Cyclocondensation of amidino-oxoimidazolidine derivative with
acrylamide derivative gave 4-amino-pyrimidine derivative[70]
(Scheme 1.68).
27
+
132 134
NHN NH
NH2O
Me
MeHC = C - C-NMe
OCN
CF3OEt
NHN
O
Me
Me
N
N
NCH3
O
NH2
CF3133
Scheme 1.68
Reaction of acrylonitrile derivative with nitro-guanidine gave (3,4,5-
trimethoxy benzyl) pyrimidine[71]
(Scheme 1.69).
+
136135
H
HN
CN
MeOOMe
OMe
HN
H2N
N
NO2
CN
NN
NHPh
OMe
OMe
OMe
H2N
NHNO2
MeONa
EtOH
Scheme 1.69
Cyclocondensation of acrylate derivative with guanidine gave
pyrimidine derivative[72]
(Scheme 1.70).
+
138137
HN
H2N
NH2N-CH= CH-C
O
OMeR2
R1
N
N
NH2O
N
H
R2R1
Scheme 1.70
Reaction of acrylate derivative with formamidine yielded the
cyanopyrimidine derivative[73]
(Scheme 1.71).
+
141139
HN
H2N
RNHN
SMe2O
CN
R
CO2Et
CN
MeS
MeS
140
Scheme 1.71
28
Treatment of benzamidine derivative with acrolein derivative under
basic condition in methanol gave pyrimidine derivative[74]
(Scheme 1.72).
+
144142
NN
FF
Bu143
NH2
NH2
F
F
Cl
H5C2O
O
Bu
MeONa
MeOH
Scheme 1.72
Reaction of acrylonitrile derivative with guanidine and thiourea led to 2-
amino-5-cyanopyrimidine and 2-formyl-2-thiopyrimidine[75]
(Scheme 1.73).
S
H2N
H2N
146
147
HN
H2N
NH2
N
N
NH2
NC
145
CHO
CN
H
Me2N
N
N
SH
H
O NH2
Scheme 1.73
Condensation of acrylate with O-methyl isourea gave
methoxypyrimidine and subsequent ammonolysis give amino-pyrimidine[76]
(Scheme 1.74).
149
Me3C-Si-O-(CH2)3-C-C= CH-(CH2)11-Me
Me
Me O
COMe
+
H2N OMe
NHHN N
OMe
(CH2)11.Me
COCH3
HO.(CH2)3
amonolysisHN N
(CH2)11.Me
COCH3
HO.(CH2)3
NH2
148
150
Scheme 1.74
29
Cyclization of piperazinyl amidine salt with dimethyl-amino
acraldehyde in presence of base afforded pyrimidine derivative[77]
(Scheme
1.75).
+
151 152
HN N
NH2
NH2
Xn
H
Me2N
O
N
N
N NH
R'
R'= H, C-4 alkyl, X = salt anion, n = charge of X
Scheme 1.75
Treatment of guanidine derivative with dimethyl acetylene dicarboxylate
in toluene under heating overnight gave pyrimidine derivative[78]
(Scheme
1.76).
+
153 154
N
H
H2N
NH
R1
R2
CO2Me
CO2Me
CO2Me/
Ph.MeN N
HN
O
CO2Me
H
R2
R1
R1=2-OBu R2=H
Scheme 1.76
Cyclocondensation of benzamidines with amino allylidene dimethyl
ammonium perchlorates gave the pyrimidine derivative[79]
(Scheme 1.77).
156
+
155157
NH
NH2
HO NMe2H2N
Bu
ClO4N N
OH
H2N
Bu
Scheme 1.77
Cyclocondensation of R1CH2CH(CN)CH(OR)2 with guanidine gave 2,4-
diaminopyrimidine derivative[80]
(Scheme 1.78).
30
+
158
N
N
NH2
R'
NH2RO OR
R'CN
NH
H2N
H2N
R'= (unsubstituted p-naphthyl..)
Scheme 1.78
A mixture of 1-(3-triflouromethylphenyl)-2-(N,N-dimethylamino-
methylene)-1-butanone benzamidine hydrochloride and sodium carbonate in
refluxing in ethanol gave pyrimidine derivatives[81]
(Scheme 1.79).
+
159
NH2
NH2C2H5
O
CF3
N
CH3
CH3
ClN
N
C2H5
Ph
CF3
Na2CO3
EtOH
reflux 6h
Scheme 1.79
Condensation of malonic acid with thiourea in acetic acid/acetic
anhydride gave the mixture of 5-acetylthiobarbituric acid and condensed with
5-N,N-diphenyl-N-thiourea in phosphoryl chloride give 1,3-diphenyl-2-
thiobarbituric acid, 1-[1--naphthylethyl-2-thiobarbituric acid was obtained
from condensation of malonic acid with N-aryl-2[1--naphthyl]
ethylthiourea[82]
(Scheme 1.80).
S
H2N
H2N
CO2H
CO2H
S
PhHN
PhHN
S
ArHN
HN
H7C10
CH3
N
N
Ar
S
O
O
CH3
C10H7
160c
N
N S
O
O
Ph
Ph
NH
N S
O
O
H
Ac
160a
160b
AcOH/Ac2O
Scheme 1.80
31
Condensation of 4-ethoxy-3-formyl-3-butene-2-one with methyl-
thiourea gave mixture of acetyl-2-methylthiopyrimidine and isomeric 5-formyl-
4-methyl-2-methyl-thiopyrimidine respectively[83]
(Scheme 1.81). The yield
and isomer ratio depends on the reaction condition.
161
OMe
CHO
OEt
+ SCH3
HN
H2N N
NH3C
O
SCH3 N
N
SCH3H3C
OHC
+
a b
Scheme 1.81
Thiourea condensed with 2-amino-1-cyanopropene or -imi-
nopropionitrile to give 4-amino-2-mercapto-6-methyl pyrimidine, also
diethoxymethylenemalononitrile when reacted with S-methyl thiourea gave 4-
amino-5-cyano-6-ethoxy-2-methylthio-pyrimidine[84]
(Scheme 1.82).
162a163
CN
H3C NH2
+ S
H2N
H2NN
N
SHH3C
NH2CN
H3C NH
162b
164 165
CN
EtO OEt
NC
+ SCH3
HN
H2NN
N
SCH3EtO
NH2
NC
Scheme 1.82
Variety of heterocyclic chalcones were used in the synthesis of
pyrimidine with heterocyclic moiety to 4 or 6 position, thus the use of benzal-
-acetothienone, 2-cinnamoylbenzimidazole and 4-cinnamoyl-3-methyl-1,5-
diphenylpyrazol afforded pyrimidine-2-thione[85]
(Scheme 1.83).
32
S
H2N
H2N
SCOCH=CHPh
N
N
H
COCH=CHAr
NN
Ph
Ph
COCH=CHPhH3C
166c
166b
166a
N
N
H
N
NH
S
Ar
SN
NH
S
Ph
NN
Ph
Ph
H3C N
N
S
Ar H
167a
167b
167c
Scheme 1.83
Fusion of arylmethylene 2,3,4,5-tetrahydrobenzo(b)-oxepin-5-one with
thiourea at about 185°C lead to the formation of aryl 6,7,8,4,10,11-hexahydro-
5H-benzo(b)oxepino-[5,4-d]pyrimidine[86]
(Scheme 1.84).
S
H2N
H2NO O
CHAr
O
N
N S
HAr
H
168169
a, Ar = C6H5 b, Ar = C6H4OCH3(p) c, Ar = C6H3O2CH2(p)
Scheme 1.84
Bis-arylmethylene cycloalkanone, bis-arylmethylene cyclo-heptanone,
were refluxed with thiourea in ethanolic potassium hydroxide to give the
corresponding condensed pyrimidine derivative respectively[87]
(Scheme 1.85).
33
S
H2N
H2N
170a n = 1 171a n = 1
(CH2)n
O
ArHC CHAr
(CH2)n
O
ArHC N
N
H
S
Ar
170b n = 2 171b n = 2
Ar=C6H5, C6H4OCH3(p), C6H4Cl(p), C6H4CH=CH2, C6H4.NHe2(p)
Scheme 1.85
Thiourea reacts with malonitriles to give 4,6-diamino-2-
mercaptopyrimidine, ethylmalononitrile and diethyl malononitrile give 5-ethyl
and 5,5-diethyl, derivatives[88]
(Scheme 1.86).
S
NH2
NH2
NC
NC
NC
NC
Et
NC
NC
Et
Et
N
N
NH2
H2N SH172a
N
N
NH2
H2N SH
Et
Et
172c
N
N
NH2
H2N SH
Et
172b
Scheme 1.86
S-Benzylisothiourea hydrochloride reacted with p-chlorobenzoyl-
phenylacetylene to give 2-benzylthio-4-p-chlorophenyl pyrimidine[89]
(Scheme
1.87).
HN
H2N
SCH2PhN
N
C6H4Cl(p)
Ph SCH2Ph
173
Ph
COC6H4Cl(p)
+-H2O
Scheme 1.87
The reaction may proceed via Michael addition of thiourea followed
by cyclization. Mesityl oxide reacts with thiourea for 8 hr to give 3,4-
dihydro-4,4,6-trimethyl-2-(1H)pyrimidine[90]
(Scheme 1.88).
34
NH
N
Me
S
H
Me
Me
178
+ S
H2N
H2N
O
Me
Me
Me
177
Scheme 1.88
Acetylacetone reacts with thiourea to give 2-mercapto-4,6-dimethyl-
pyrimidine and with N-methyl thiourea to give 1,2-dihydro-1,4,6-trimethyl-2-
thiopyrimidine.The condensation with S-alkyl isothiourea gave 4,6-dimethyl-2-
alkylthiopyrimidine respectively[91]
(Scheme 1.89).
NH
N
CH3
H3C S182a
182b
S
H2N
H2N
182c
S
HN
H2N
CH3
SR
HN
H2N
N
N
CH3
H3C S
CH3
N
N
CH3
H3C SR
O
O
H3C
H3C
Scheme 1.89
Thiourea react readily with -diketones to give pyrimidine of higher
yields than urea, as a typical example, reaction of thiourea with benzoylacetone
in acidic ethanol gives 6-methyl-4-phenyl-2(1H)-pyrimidinethione[92]
(Scheme
1.90).
191
+ S
H2N
H2NO
O
Ph
H3CN
N
S
H
H3C
PH
80%
Scheme 1.90
35
Reaction of aroyl isothiocyanate with cyanothioacetamide yielded the
pyrimidinethione derivatives[93]
(Scheme 1.91).
R-C-N= C =S
O
+
CN
H2N S
N
N
S
CN
R
H
S
H
214215a-c
a, R=C6H4Cl(p) b, R=C6H5 c, R=C6H4OMe (p)
Scheme 1.91
Heating ethyl 2-amino-4-methyl-5-phenylthiophene-3-carboxylate with
potassium thiocyanate in dioxane in presence of conc. HCl followed by
cyclization with acetic acid yield compound[94]
(Scheme 1.92).
S
CO2EtH3C
Ph NH2N
N
S
O
H
S
H
Ph
H3C
KSCN
232231
Scheme 1.92
Cyanothioacetamide react with in ethanol containing ethoxide followed
by aqueous HCl to give pyrimidinethione derivatives[95]
(Scheme 1.93).
CN
SH2N
+N-CN
MeS
MeS
EtOH/EtONa
N
N
SMe
CN
H
H2N S
250
aq. HCl
249
Scheme 1.93
Intramolecular cycloaddition of amino group to the activated double
bond in the thiourea derivative yielded perhydropyrimidine[96]
(Scheme 1.94).
NH
R HN S
Ph
O
N
NH
O
Ph
SR
NaOEt, EtOH
258 259
DMF
Scheme 1.94
36
Pyrimidine formation from thiazine may involve a Dimroth like
rearrangement of thiazinamine, an aminolytic displacement of the ring sulphur
atom or combination of both, aqueous ethanol in methylamine converts 4-
phenyl-5-phenylsulfonyl-2H-1,3-thiazine-2,6(3H)-dithione into pyrimidine[97]
by displacement of the ring sulfur and a nucleophilic substitution of the thioxo
sulfur in the 2-position (Scheme 1.95).
291
N
N
Ph
PhSO2
NHMeS
H290
S
NH
Ph
PhSO2
S S
MeNH2, EtOH
H2O, r.t., 33%
Scheme 1.95
5-Aryl or alkylsulphonyl 1,3-thiazine on treatment with β-iminonitriles
or sulfones in presence of sodium 1,1-dimethyl peroxide in tetrahydrofurane
gave 2,5,6-trisubstituted pyrimidine derivatives[98]
(Scheme 1.96).
Scheme 1.96
5-Amino-3-phenylisoxazole was hydrogenated which then cyclized by
warming in aqueous alkali to 4-hydroxy-2,6-phenylpyrimidine[99]
(Scheme
1.97).
296
N
N
OH
PhPh
293b
NO
NH2
Ph
H+
PhCOClN
O
NH2
H
Ph
O
Ph
295
Scheme 1.97
S
H N
S
P h
S H 3 C O 2 S
+ H N
P h
C H 2 C N N
N
H
P h S
C N
P h
37
1.5 Multicomponent Cyclocondensation Strategy
1.5.1 Introduction
Organic chemistry is the science of the rules of how chemical entities
react with each other to form new molecules. The length of the synthesis is
dependent upon the average molecular complexity produced per operation,
which in turn depends upon the number of chemical bonds being created.
Therefore, devising reactions that achieve multi-bond formation in one
operation is becoming one of the major challenges in searching for step of
economic synthesis. An ideal multi-bond forming process should satisfy the
following criteria: a) readily available starting materials b) operational
simplicity c) resource effective d) atom economical e) ecologically benign. The
importance of such a multi-bond formation lies in its ability to deliver products
with high yields with, chemo, regio, stereo or enantioselectivity and its general
applicability over a wide range of starting materials.
Multi-component reactions (MCRs) are convergent reactions, in which
three or more starting materials react to from a product, where basically all or
most of the atoms contribute to the newly formed product. In an MCR, a
product is assembled according to a cascade of elementary chemical reactions.
In the light of chemical productivity and generation of molecular diversity, an
“ideal” MCR should not only compromise more than two starting materials but
also these would be different and all or most of the atoms of those starting
materials would be incorporated into the final product. The challenge is to
conduct such an ideal MCR in such a way that the network of the pre-
equilibrated reactions channel into the main desired product and don not yield
side products. The result is clearly dependent upon the reaction conditions such
as solvent, temperature, catalyst, concentration, the nature of starting materials
and the functional groups. Such MCRs will occupy an outstanding position
among all other reactions, making them especially interesting for the concept of
combinatorial chemistry.[100]
The development of a ideal MCR is a challenging
task as, it requires careful consideration of the reactivity match of the starting
materials and the reactivities of the intermediates generated in situ, their
38
compatibility and their compartmentalization. This chapter has been devoted to
the detailed aspect of multi-component reactions from their origin to the design
of an ideal MCR and their application in heterocyclic synthesis.
1.5.2 History and origin of MCRs
The origin of MCRs is closely linked to isocyanide chemistry. The
chemistry of multicomponent reactions and isocyanides belonged to three
periods. In the century 1859-1958, isocyanide chemistry was moderately active
and was separate from the classical name reactions of MCRs. In the next
period, isocyanides became well available, and MCRs of isocyanides became
the most variable way of forming chemical compounds.[101]
The first MCRs
were accomplished in 1838 when Laurent and Gerhardt[102]
formed the
“benzoylazotide” from bitter almond oil and ammonia via benzaldehyde and
hydrogen cyanide. The chemistry of MCRs officially began 12 years later,
when Strecker[103]
introduced the general formation of α-aminocyanides from
ammonia, carbonyl compounds and hydrogen cyanide. The preparation of
heterocyclic compounds by MCRs was introduced in early 1880s.[104]
This
ended in 1960, when Hellmann and Optiz[105]
demonstrated that all these
reactions are α-aminoalkylations of nucleophiles, including the preparations of
heterocyclic products by MCRs that are α-aminoalkylations and subsequent
ring-forming reactions of bifunctional adducts.
The chemistry of isocyanides began in 1859, when Lieke[106]
formed the
allylisocyanide from allyl iodide and silver cyanide. Later Hoffmann[107]
introduced the formation of isocyanide from chloroform, primary amines and
potassium hydroxide. The chemistry of isocyanides is fundamentally distinct
from the rest of organic chemistry, since they are the only chemical entities
with divalent carbon atoms C(II), and all their chemical reactions correspond to
the conversion of this divalent carbon into tetravalent carbon atoms, C(IV). In
1921, Passerini[108-109]
introduced the first MCRs of the isoscyanides. They
react with carboxylic acids and carbonyl compounds to give acyloxy-
carbonamides. The first century of isocyanide chemistry contained important
progress, but overall was an empty part of chemistry.
39
In 1958, the isocyanides became generally well available and shortly
after that, Ugi et. al,[110]
introduced the four component reaction of the
isocyanides, which is since 1962 referred to as the Ugi reaction (U-4CR).[111]
The U-4CRs are one-pot reactions of amines, carbonyl compounds, acids and
isocyanides that form products from any educts while other chemical reactions
and MCRs have limitations.[112]
This can be illustrated by the following
example (Scheme 1.98).
Ph Ph
NH
PhPh
COOH
PG
PhPh
NC COOMeNH
O
O
NH
Ph PhPh
COOMe
Ph Ph
Ph
PG
+ +
Scheme 1.98
The sterically hindered product can be formed by a U-4CR[113]
, but it
cannot be prepared by any other method. Many natural products have been
formed by the U-4CR[114]
, and it was known that cyclic products can be formed
by the U-4CR.[115]
A great variety of β-lactam derivatives have since then
produced by the U-4CR.[116]
Since 1963, stereoselective U-4CRs are
developed.[117]
Kunz and Pfrengle[118]
introduced the formation of α-aminoacid
derivatives by stereoselective U-4CRs with o-pivalyl-1-amino-carbohydrates,
which indeed did have many preparative advantages, but they were yet not
suitable components for peptide synthesis by U-4CR. More recently, Ugi and
Ross introduced o-acylated -1-amino-carbohydrate derivatives whose oxygen
was replaced by sulfur. Thus peptide derivatives can be stereoselectively
formed by the U-4CR, and their products can be cleaved in a desired way under
mild conditions.
1.5.3 Defining MCR
In principle, all chemical reactions correspond to equilibria between one
or two educts and products. However, in practice the preferred chemical
reactions form their products irreversibly, and without competing formation of
by-products with quantitative yields of product. An exception are some
reactions, in which three components can react in a single step, and it was also
40
found that cations and anions can directly undergo α-additions onto
isocyanides, due to formally divalent carbon C(II) of the latter. If more than
two edducts are converted into the products, usually such syntheses require
sequences of chemical reactions. Typically after each step, the intermediate or
the final product must be isolated, purified and then used for next step. The
more steps are needed, the more preparative work is needed, and with each step
the yield of the product decreases.
Multicomponent reactions of three or more different starting materials
can directly form their products.[119]
Also educts with three and more different
functional groups can be thus converted into corresponding products. The
MCR product must contain each educt or at least a part of the educt with its
functional group. MCRs are accomplished just by mixing the educts. Highly
complex and diversified product can thus be formed in a higher yield, via a
single operation than by conventional multistep synthesis. The MCRs do not
directly convert their educts into the products, but they are sequences of sub
reactions that proceed stepwise. Usually, the starting materials of MCRs are
readily available or can be easily prepared.
To discover an ideal MCR, it is necessary to understand the specific
characteristics and logic of these reactions. Ugi, the most productive
protagonist and the inventor of MCRs, distinguishes 3 idealized types of MCR
considering the reversibility of reactions leading to intermediary products P1,
P2……. and the final product P
N.
1.5.3.1 Type I MCR
A + B P1 + C P2 + D..... PN
MCRs of this type are collections of equilibria between all participating
sub-reactions, including the last step which forms the final product. The MCRs
of type I are usually three component reactions that form their products from
ammonia or amines, carbonyl compounds and neutral nucleophilic compounds
or anions of weak acids. The Strecker reaction (S-3CR)4 (Scheme 1.99) and the
Mannich reaction (Scheme 1.100)[120]
are the best examples of type I MCRs.
41
R H
O NH3/HCN
R
NH2
HCN R
NH2
HCOOH
H+/ H2O
Scheme 1.99
H
H
O R2NH
O
R
R2N
O
R+ ++R1
R1
Scheme 1.100
1.5.3.2 Type II MCRs
A + B P1 + C P2 + D..... .......O PN
In this type, the educts and the intermediate products equilibrate, but the
final product results from a practically irreversible final reaction step. In 1882,
Hantzsch[121]
and Radziszewski[122]
introduced the formation of heterocycles by
MCRs of type II from bifunctional educts (Scheme 1.101). Shortly later
Biginelli also prepared related heterocycles[123]
(Scheme 1.102). In 1920,
Bucherer and Bergs[124]
made hydantoin derivatives by the BB-4CRs, which led
to the industrially preferred method of preparing α-aminoacids as these
compounds can be obtained in much higher yields via the hydantoin route than
by the S-3CR (Scheme 1.103). The MCRs of the isocyanides are also type II
reactions, whose irreversible step is always an α-addition of a cation and an
anion onto the CII of the isocyanides. Subsequently their α-adducts rearrange
into their final products. In 1956, Asinger et. al, published the preparation of
thiazole derivatives by the A-MCR of three or four components.[125]
42
R-CHOR'
O
OR'
O
NH3
NH
R
COOR'
R'R'
R'OOC
+ 2 ++
Hantzsch Synthesis (Scheme 1.101)
Me O
EtOOC
H O
Ph NH2
NH2
ON
N
H
OMe
EtOOC
Ph
H
+ +
EtOH,
H+
Biginelli Reaction (Scheme 1.102)
O
R
R'
KCN
(NH4)2CO
3 NH
NH
R
R'
O
O
Bucherer-Bergs Reaction (Scheme 1.103)
1.5.3.3 Type III MCRs
P1 + C P2 + D..... .......O PNA + B
MCRs of this type correspond to sequences of irreversible reactions that
all proceed towards the product. In preparative chemistry rather few MCR of
type III are known, whereas in living cells, most products are formed by
biochemical MCRs of this type.[126]
1.5.4 Designing an ideal MCR
Using the above logic an ideal MCR can be deigned, so that highly
complex product can be obtained in short reaction time, thereby making the
process highly efficient and feasible. Thus, ideally in a type II reaction
sequence, it would be favorable if starting material C would react only with P1
but not with A or B, or alternatively, the reaction of C with A or B should be
reversible. An excellent example for this rational design strategy, is the 3CR of
43
aromatic amines with aldehydes and the subsequent aza-Diels-Alder cyclo-
addition of the resulting azomethine with electron rich dienophiles giving
tetrahydroquinoline derivatives under mild conditions (Scheme 1.104).
NH2 CHO
NH
+ +
Scheme 1.104
In the above three component reaction (3CR), both formation of
azomethines from aldehydes and amines and the hetero cycloaddition of
azomethines and dienophiles, are two individual reactions known beforehand.
The idea to carry out these two reactions in one step as a 3CR requires the
recognition that the dienophile does not react either with the amine or
aldehyde, but only with their azomethine product under the given reaction
conditions.[127]
Thus highly diverse tetrahydroquinoline derivatives can be
obtained in one single step in high yield and in short time rather than the
conventional preparation and isolation of azomethine and its reaction further
with the dienophile.
For such an ideal design of an MCR, thorough understanding about the
reactivity of various functional groups must be known, so that the sequence of
the various sub reactions can be tailored or fine tuned according to the product
which is desired. The sequence of component addition does not generally
change the course of the reaction, as the thermodynamically most stable
products are irreversible formed from a reactive intermediate. Such one-pot
classical MCRs are very valuable for parallel library synthesis. There is rapid
need to identify reactive components that would allow sequential multi-
component reactions (SMCRs) which would generate different scaffolds
depending upon the sequence of component addition. Such an approach would
be highly attractive as the same set of building blocks will generate a whole
44
range of scaffolds and thus allow synthesizing libraries with high scaffold
diversity.
True multi-component reactions should be distinguished from the so-
called tandem, cascade, domino or zipper reactions where one starting material
bears with several functionalities that react in several consecutive steps, for
example:
A + B P1 P2 ......... PN
These one-pot , multi-step synthesis procedures rely on a high conversion of
the first reversible step that will allow to add a reactant C, eventually under
different reaction conditions, where as “pure” MCRs are run under eventually
under the same conditions by adding the starting materials at the same time. In
MCRs, the products are formed by the reaction of completely different types of
educts or functional groups and form a great variety of products. MCRs may
however include reaction mechanisms that could be described with the terms
domino, tandem, zipper if some of the starting materials contain multiple
functional groups that are involved in the reaction sequence.
A method is suggested to describe the kinetics of multicomponent
reactions based on the definition of bond types, whose conversion in similar
reactions is characterized by the same rate constants, irrespective of the kind of
the component which contains the same bond.[128]
The method permits to
obtain a description sensitive to the composition of reaction mixtures and at the
same time to reduce significantly the number of kinetic parameters, since the
number of bonds is much less than the number of components.
Multi component reactions are networks of various reactions with
individual mechanisms that for the most part also require different reaction
conditions. However, it is not very likely that the actual experimental MCR
conditions will suit these reaction mechanisms. Thus, finding the right reaction
conditions for a novel MCR, such as solvent, concentration, reaction time is
likely to be more difficult than for conventional reactions. Recently L. Weber
et. al, have introduced the application of genetic algorithms to solve complex
multi dimensional problems in MCR chemistry.[129]
Based on automated
45
parallel synthesis that assures exactness and consciousness of the preparative
execution and high throughput LC, L. Weber et. al, have performed genetic
algorithm driven optimization of MCR reaction conditions.[130]
Some very important MCRs have been discovered by preparing libraries
from 10 different starting materials. By analyzing the products of each
combination (three, four , upto ten-component reactions), it is possible to select
those reactions that show single main product. HPLC and MS are useful
analytical methods, because the purity and the mass of the new compounds
help to decide whether a reaction might be interesting to investigate further.[131]
1.5.5 Applications of multicomponent reactions
1.5.5.1 Pyrroles
The syntheses of pyrroles have been described in two different methods
by Ranu et. al, It has been achieved by a three component coupling of α,β-
unsaturated aldehyde/ketone, amine and nitroalkane and also by a similar three
component coupling of aldehyde/ketone, amine and α,β-unsaturated nitroalkene
on the surface of silica gel or alumina without any solvent under microwave
irradiation[132]
(Scheme 1.105 and Scheme 1.106).
N
R1R2
R3
R4
R5
SiO2
NH2R4 NO
2R5
O
R2
R3R1+ +
MW
Scheme 1.105
NH2 NO
2
NO2
H
O
Al2O
3
N HR1R2
R3
R4
R5
+ + +MW
R1
R4
R3
R2
Scheme 1.106
1.5.5.2 Imidazoles
The classical route to the synthesis of substituted imidazoles is from the
condensation of aldehyde, diketone and ammonia. An excellent yield of
46
imidazole deriveatives have been obtained in short reaction times[133]
(Scheme
1.107).
H
O
O
O
NH4OAc
Al2O
3
NN HR2
+ +
R1
R3
MW
R1 R2
R3
75-85%130W, 10min
Scheme 1.107
A number of green chemistry related improvements to the synthesis of
tetrasubstituted imidazoles are reported. The numbers of steps are reduced to
one through an efficient four component condensation. Solvents are avoided
and reusable catalysts are employed. A four component condensation of
benzaldehyde derivatives, ammonium acetate, benzyl and primary amine
catalyzed by zeolite Hγ and silica gel under microwave irradiation has been
reported[134]
(Scheme 1.108).
O
O
Ph
PhH
O
PhNH
4OAc R-NH
2
NH
N
Ph
Ph
Ph+ + +zeolite or silica gel
MW
Scheme 1.108
1.5.5.3 Dihydropyridines
The Hantzsch synthesis by far remains the most important route to the
synthesis of the pyridine ring system. Such a three component condensation
between substituted aldehyde, acetoacetates and a nitrogen source when carried
out under microwave irradiation gives significantly high yields of the product
in short reaction times[135]
(Scheme 1.109).
MeO
OEtO
Ar H
O
NH4OH
NH
MeMe
Ar
COOEtEtOOC
+ +MW 1400C
10-15 min
51-92%
Scheme 1.109
47
3,4-dihydropyridones, which are analogues of pyridine compounds, are
synthesized by Suarez and coworkers via an efficient one-pot condensation of
Meldrum’s acid, methyl acetoacetate, substituted benzaldehyde derivatives and
ammonium acetate under solvent-free microwave irradiation conditions[136]
(Scheme 1.110).
O O
CH3
CH3
OO
O O
OMeMeOAr-CHO
NH
O
O
Ar
OMeNH
4OAC
MW+ +
Scheme 1.110
4-aryl-1,4-dihydropyridine compounds are also analogues of
dihydropyridine compounds which have a profound biological activity. They
are synthesized in high yields, by a multicomponent condensation of
substituted benzaldehyde derivatives, ethyl acetoacetate, and dimedone and
ammonium acetate in the presence of MCM-41 as a heterogeneous catalyst by
I. Nagarapu and Co-workers[137]
(Scheme 1.111).
Ar-CHO
O
O
O
O
O
NH4OAc
NH
Ar O
O
O
+ + +
MCM-41
900C
Scheme 1.111
1.5.5.4 Dihydropyrimidones
The Biginelli reaction involving the multicomponent condensation of
aromatic aldehydes, ethyl acetoacetate and urea is the most widely explored
route for the synthesis of dihydropyrimidine derivatives. A wide variety of acid
catalysts like supported ZnCl2, AlCl3, InCl3, FeCl3/ MCM-41 have been
employed for the multicomponent condensation.[138]
The products are obtained
in high yields and in short reaction times (Scheme 1.112).
48
Ar-CHONH
2NH
2
O O O
OEt NH
NH
O
ArO
EtOFeCl3/Si-MCM - 41
+ +MW
Scheme 1.112
More recently Yadav et. al, have described an efficient method of
synthesis of pyrimidinone derivatives by one-pot reactions of thiazole Schiff
bases, glycine and acetic anhydride. A pyrimidine ring on the thiazole nucleus
to yield 6,7-dihydro-5H-thiazolo[3,2-a]pyrimidin-5-ones was carried out under
solvent-free microwave conditions[139]
(Scheme 1.113).
S
N
N
Ar'
Ar
Glycine/AC2O
N S
N
OAr
Ar'
NH2
H+
Scheme 1.113
1.5.5.5 Quinazolines
2,3-dihydro-quinazolin-4(1H)-ones are important analogoues of
quinazoline with a battery of important medicinal and pharmaceutical
applications. Samant et. al, have synthesized these compounds via one pot three
component condensation between isatoic anhydride, aldehyde and amine under
solvent-free microwave conditions. [140]
The reaction time is drastically reduced
and the yields are high (Scheme 1.114).
NH
O
O
O
CHO NH2
NH
N
O
+ R1 + R2
Amberlyst-15
MWR1
R2
Scheme 1.114
1.5.5.6 Pyrans
The main interest in the 4H-pyran group is due to its biological and
pharmacological properties.[141]
Seshu Babu et. al, have synthesized 5-
substituted-2-amino-4-aryl-3-cyano-6-methyl-4H-pyrans via a multicomponent
49
condensation of aryl aldehydes, ethyl acetoacetate and malononitrile in the
presence of a strong basic Mg/La mixed oxide catalyst.[142]
The synthesis
involves the in situ generation of arylidene malononitrile and its subsequent
condensation with an active 1,3-dicarbonyl derivative (Scheme 1.115).
O HO
O
EtO
CN
CN
O NH2
O
CNEtO
R1
R2+
R2
R1
Mg/La mixed oxide
Methanol 650 C
Scheme 1.115
1.5.5.7 Chromenes
Chromenes or Benzopyrans occupy an important place in the realm of
natural and synthetic organic chemistry because of their biological and
pharmacological properties.[143]
Maggi et. al, have reported a high yielding one-
pot synthesis of 2-amino-2-chromenes by a three component condensation of
aryl aldehydes, malononitrile and an activated phenol derivative in water in the
presence of basic alumina as a heterogeneous catalyst.[144]
The process has a
high selectivity and is environmentally benign (Scheme 1.116).
R-CHO
CN
CN
OH
O
R
NH2
CN
+ +H2O reflux
alumina
Scheme 1.116
50
1.6 Indian Pharmaceutical Industry
1.6.1 Introduction
The Indian pharmaceutical industry currently tops the chart amongst
India's science-based industries with wide ranging capabilities in the complex
field of drug manufacture and technology. A highly organized sector, the
Indian pharmaceutical industry is estimated to be worth $ 4.5 billion, growing
at about 8 to 9 percent annually. It ranks very high amongst all the third world
countries, in terms of technology, quality and the vast range of medicines that
are manufactured. It ranges from simple headache pills to sophisticated
antibiotics and complex cardiac compounds; almost every type of medicine is
now made in the Indian pharmaceutical industry. The Indian pharmaceutical
sector is highly fragmented with more than 20,000 registered units. Ithas
expanded drastically in the last two decades. The pharmaceutical and chemical
industry in India is an extremely fragmented market with severe price
competition and government price control. The pharmaceutical industry in
India meets around 70% of the country's demand for bulk drugs, drug
intermediates, pharmaceutical formulations, chemicals, tablets, capsules, orals
and injectibles. There are approximately 250 large units and about 8000 small
scale units, which form the core of the pharmaceutical industry in India
(including 5 Central Public Sector Units).The government has also played a
vital role in the development of the India software industry.
In 1986, the Indian government announced a new software policy which
was designed to serve as a catalyst for the software industry. This was followed
in 1988 with the world market policy and the establishment of the Software
Technology Parks of India (STP) scheme. In addition, to attract foreign direct
investment, the Indian government permitted foreign equity of up to 100
percent and duty free import on all inputs and products.
India's pharmaceutical industry is now the third largest in the world in
terms of volume and stands 14th
in terms of value. According to data published
by the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers,
the total turnover of India's pharmaceuticals industry between September 2008
51
and September 2009 was US$ 21.04 billion. Of this the domestic market was
worth US$ 12.26 billion.The Indian pharmaceuticals market is expected to
reach US$ 55 billion in 2020 from US$ 12.6 billion in 2009. The market has
the further potential to reach US$ 70 billion by 2020 in an aggressive growth
scenario.
Moreover, the increasing population of the higher-income group in the
country will open a potential US$ 8 billion market for multinational companies
selling costly drugs by 2015. Besides, the domestic pharma market is estimated
to touch US$ 20 billion by 2015, making India a lucrative destination for
clinical trials for global giants. Further, estimates the healthcare market in India
to reach US$ 31.59 billion by 2020.
1.6.2 Diagnostics Outsourcing/Clinical Trials
The indian diagnostic services are projected to grow at a CAGR of more
than 20 per cent during 2010-2012.Some of the major indian pharmaceutical
firms, including Sun Pharma, Cadilla Healthcare and Piramal Life Sciences,
had applied for conducting clinical trials on at least 12 new drugs in 2010,
indicating a growing interest in new drug discovery research.
1.6.3 Generics
India tops the world in exporting generic medicines worth US$ 11
billion and currently, the Indian pharmaceutical industry is one of the worlds
largest and most developed. Moreover, the Indian generic drug market to grow
at a CAGR of around 17 per cent between 2010-11 and 2012-13. Union
Minister of Commerce and Industry and Minister for Trade and Industry,
Singapore, have signed a 'Special Scheme for Registration of Generic
Medicinal Products from India' in May 2010, which seeks to fast-track the
registration process for Indian generic medicines in Singapore.
1.6.4 Advantage India
1.6.4.1 Overview
The Indian Pharmaceutical Industry, particularly, has been the front
runner in a wide range ofspecialties involving complex drugs' manufacture,
development and technology. With theadvantage of being a highly organised
52
sector, the pharmaceutical companies in India are growingat the rate of $ 4.5
billion, registering further growth of 8 - 9 % annually. More than 20,000
registered units are fragmented across the country and reports say that 250
leading Indian pharmaceutical companies control 70% of the market share with
stark price competition and government price regulations.
1.6.4.2 Competent workforce
India has a pool of personnel with high managerial and technical
competence as also skilled workforce. It has an educated work force and
English is commonly used. Professional services are easily available.
1.6.4.3 Cost-effective chemical synthesis
Its track record of development, particularly in the area of improvedcost-
beneficial chemical synthesis for various drug molecules is excellent. It
provides a wide variety of bulk drugs and exports sophisticated bulk drugs.
1.6.4.4 Legal & Financial Framework
India has a 53 year old democracy and hence has a solid legal
framework and strong financial markets. There is already an established
international industry and business community.
1.6.4.5 Information & Technology
It has a good network of world-class educational institutions and
established strengths in information technology.
1.6.4.6 Globalisation
The country is committed to a free market economy and globalization.
Above all, it has a 70 million middle class market, which is continuously
growing.
1.6.4.7 Consolidation
For the first time in many years, the international pharmaceutical
industry is finding great opportunities in India. The process of consolidation
has become a generalized henomenon in the world pharmaceutical industry,
has started taking place in India.
53
1.6.5 MAJOR PHARMACEUTICAL COMPANIES IN INDIA
Some of the leading Indian players,
Cipla
Ranbaxy Lab
Dr Reddy's Labs
Sun Pharma
LupinLtd
Aurobindo Pharma
Piramal Health
Cadila Health
Matrix Labs
Wockhardt
1.6.6 CHALLENGES & FUTURE GROWTH
1.6.6.1 Challenges
Over the past decade, pharmaceutical companies have entered a difficult
period where shareholders, the market and regulators have created significant
pressures for change within the inustry. The core issues for most of drug
companies are declining productivity of in-house R &D, patent expiration of
number of block buster drugs, increasing legal and regulatory concern, and
pricing issue. As a result larger pharmaceutical companies are shifting to new
business model with greater outsourcing of discovery services, clinical research
and manufacturing.Current global financial conditions and the threat of a broad
recession accelerated the time-table for implementing transformational changes
in global organizations, as the industry confronts lower corporate stock prices
and an increasingly cost-averse customer. Leaders of the largest global
pharmaceutical companies recognize the need for transformational change in
organizations, but will need to move swiftly to ensure sustained growth.
Transformations in the business model of larger pharmaceutical industry spell
more opportunities for Indian pharmaceutical companies. Pharmaceutical
production costs are almost 50 percent lower in India than in western nations,
while overall R&D costs are about one-eighth and clinical trial expenses
54
around one-tenth of western levels. Riding on better sales in the domestic and
export markets, Indian pharmaceutical industry is expected to continue with its
good performance. Today Indian pharmaceutical industry can look forward to
the years to come, with great expectations. There are opportunities in
expanding the range of generic products as more molecule come off patent,
outsourcing, and above all, in focusing into drug discovery as more profits
come from traditional plays. At the same time, the Indian pharma industry
would have to contend with several challenges particularly the
Effects of new product patent
Drug price control
Regulatory reforms
Infrastructure development
Quality management and
Conformance to global standards.
1.6.6.2 Growth
The Indian pharmaceutical market reached US$ 10.04 billion in size,
with a value-wise growth rate of 20.4 per cent over the previous year’s
corresponding period on a Moving Annual Total (MAT) basis for the 12
months ended July 2010. Cipla maintained its leadership position in the
domestic market with 5.27 per cent share, followed by Ranbaxy. The highest
growth in the domestic market was for Mankind Pharma, which grew 37.2 per
cent. Leading companies in the domestic market such as Sun Pharma (25.7per
cent), Abbott (25 per cent), Zydus Cadila (24.1 per cent), Alkem Laboratories
(23.3 per cent), Pfizer (23.6 per cent), GSK India (19 per cent), Piramal
Healthcare (18.6 per cent) and Lupin (18.8 per cent) had impressive growth
during July 2010, shows the data. The pharmaceuticals industry in India will
grow by over 100 per cent over the next two years. The pharmaceutical
industry is currently growing at the rate of 12 per cent, but this will accelerate
soon. The sale of all types of medicines in the country stands at US$ 9.61
billion, which is expected to reach around US$ 19.22 billion by 2012.
55
1.7 Scope of the present work
A large number of important drugs have been introduced during the
period of 1940-1960. The period is known as the golden period of the drug
discovery. Thus starting from 1933, various types of drugs come in to the
market. The heterocycles are among the most common scaffolds in drugs and
pharmaceutically relevant substances. Due to the pharmacophoric character and
considerable wide structural diversity, the large libraries of several heterocyclic
compounds are typically used for high performance screening in the early
stages of drug-discovery programs.
Taking in view of applicability of heterocyclic compounds in drug
design, we have undertaken the preparation of nitrogen and sulfur containing
heterocyclic derivatives. The placement of wide variety of substitution on these
nuclei has been designed in order to
1.7.1 Aim and objective of the present investigation is,
to synthesize various nitrogen and sulfur heterocyclic derivatives.
to characterize these products for their structure elucidation using
spectroscopic techniques like IR, NMR, and Mass spectrometry.
1.7.2 Abstract
The research embodied in the thesis has been compiled in the form of a
thesis entitled “STUDIES IN SYNTHESIS OF NEW NITROGEN AND
SULPHUR HETEROCYCLES WITH PHARMACEUTICAL
APPLICATIONS’’. The main aim of this work is to design the synthesis of
nitrogen and/or sulfur containing molecules and to characterize these products
for their structure elucidation using spectroscopic techniques like IR, NMR,
and Mass spectral data. These biologically active heterocyclic molecules are
synthesized by multicomponent cyclocondensation strategies. The subject
matter included in this thesis has been divided into nine chapters.
Chapter-I: Brief introduction of heterocycles.
Chapter-II: 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) catalyzed, three-
component, one-pot synthesis of partially hydrogenated triazolopyrimidines
and benzimidazolopyrimidines
56
Chapter-III: Expedient, recyclable camphorsulphonic acid catalyzed
multicomponent cyclocondensation strategy for partially hydrogenated
azoloquinazolinones
Chapter-IV: Anhydrous HCl catalyzed three-component transformation of
aryl aldehyde, 1,3-cyclohexandione and urea into octahydroquinazolinones.
Chapter-V: Synthesis of 1,8-dioxo-decahydroacridine derivatives by low
concentration of anhydrous hydrochloric acid as a catalyst.
Chapter-VI: An eco-expedient synthesis of bis(indolyl)methanes using
cyanoacetic acid as a catalyst at ambient temperature condition.
Chapter-VII: Synthesis of some new thiazole derivatives.
Chapter-VIII: Anhydrous hydrochloric acid promoted facile three
component synthesis of 1,8-dioxo-octahydroxanthenes.
Chapter-IX: An expeditious and environmentally benign methodology for
the synthesis of substituted tetrahydro-4H-chromenes by using
hydroxypropyl-β-cyclodextrin (HP-β-CD) as a notable catalyst and host.
1.7.2.1 Chapter I: Brief Introduction of heterocycles
The chemistry of heterocyclic compounds is of great interest both from
the theoretical as well as practical standpoint. Heterocyclic compounds occur
widely in nature and in the form of variety of non-naturally occurring
materials. Moreover, these are of an immense importance not only both
biologically and industrially. It has become one of the largest areas of the
research in Organic Chemistry. Their participation in a wide range of areas
cannot be under estimated. A significant part of large number of compounds
such as alkaloids, antibiotics, essential amino acids, vitamins, haemoglobin,
hormones, synthetic drugs and dyes composed of heterocyclic ring systems and
are important for human and animal health. Therefore, researchers are on the
continuous pursuit to design and produce better pharmaceuticals, pesticides,
and insecticides.
Among approximately 20 million chemical compounds more than two-
thirds are fully or partially aromatic, and half of them are heterocyclic. The
presences of heterocycles in all kinds of organic compounds are of interest in
57
biology, pharmacology, optics, electronics and material sciences. Among these
sulfur and nitrogen containing heterocyclic compounds have maintained an
interest of researchers through decades in historical development of organic
synthesis.
Multi-component reactions (MCRs) are convergent reactions, in which
three or more starting materials react to from a product, where basically all or
most of the atoms are involved in the formation of new product. The synthesis
of heterocycles has become the cornerstone of synthetic organic chemistry.
Exploitation of these heterocycles should allow the synthetic chemist to rapidly
discover methodology for the synthesis of complex molecules in a shorter time
scale. Furthermore, multicomponent coupling reactions have received
significant research in this context and their utility in preparing libraries to
screen for functional molecules is well appreciated. Therefore they constitute a
superior tool for diversity-oriented synthesis.
The Indian pharmaceutical industry currently tops the chart amongst
India's science-based industries with wide ranging capabilities in the complex
field of drug manufacture and technology. A highly organized sector, the
Indian pharmaceutical industry is estimated to be worth $ 4.5 billion, growing
at about 8 to 9 percent annually. It ranks very high amongst all the third world
countries, in terms of technology, quality and the vast range of medicines that
are manufactured. It ranges from simple headache pills to sophisticated
antibiotics and complex cardiac compounds. Almost all types of medicines are
manufactured by Indian pharmaceutical industry.
1.7.2.2 Chapter II: Synthesis of Azolopyrimidines
Among the nitrogen containing heterocycles, triazolo /
benzimidazolopyrimidines represent a pharmaceutically important class of
compounds because of their diverse range of biological activities, such as
antitumor, cytotoxicity, therapeutic potentiality, potent and selective ATP site
directed inhibition of the EGF-receptor protein tyrosine kinase and
cardiovascular activities. In addition, they have been found in DNA-interactive
drugs and as useful building blocks in the synthesis of herbicidal drugs, e.g.
58
Metosulam, Flumetsulam, Azafenidin, Diclosulam, Penoxsulam,
Floransulan,Cloransulam, etc.
In this work, an efficient synthesis of triazolo/benzimidazolo-
pyrimidines, an important class of building blocks in herbicidal drugs and
pharmaceuticals, has been developed via a multicomponent condensation
reaction between binucleophilic azole, malononitrile and aldehyde by using
DBU as a novel catalyst under conventional conditions in ethanol. The
advantages such as short reaction time, enhanced yield, high selectivity and
operational simplicity render this method particularly attractive for the rapid
synthesis of triazolo/benzimidazolopyrimidines (Scheme 1.117 and Scheme
1.118).
+
NH
N
R
N
N
CN
NH2
RCHO+ DBU
CN
CNNHN
NNH2
Ethanol
Scheme 1.117
+
NH
N
R
N
CN
NH2
RCHO+NH
NNH2
DBU
CN
CN
Ethanol
Scheme 1.118
1.7.2.3 Chapter III: Synthesis of Azoloquinazolinones
The pharmacologically important heterocycles with nitrogen bridge
derived from 1,2,4-triazole paved the way toward active research in triazole
chemistry. A number of attempts were made to improve the activities of
compounds varying the substitution on the triazole nucleus. Certain 1,2,4-
triazolederivatives are of interests due to their bioactivity, including
antibacterial and antifungal properties. The 1,2,4 triazole nucleus has recently
been incorporated into a wide variety of therapeutically interesting drugs
candidates including H1/H2 histamine receptor blockers, fungicidal, anti-
59
depressant and plant growth regulator. 1,3,4-Thiadiazoles are also associated
with pharmacological activities viz. diuretic and anti-inflammatory.
We have developed a simple and highly efficient practical method for
the synthesis of benzo[4,5]imidazo[1,2-a]quinazoline derivatives using novel
catalyst camphor sulfonic acid (CSA) under conventional condition. The
notable features of this procedure are mild reaction conditions, simple
experimental procedure and excellent yields, which make it a useful and
attractive process for the synthesis of 9-aryl-dimethyl-5,6,7,9-tetrahydro-1,2,4-
triazolo-[5,1-b]quinazolin-8(4H)-ones derivatives. We believe that this
methodology will be a valuable addition to the existing methods in the field of
synthesis of 9-aryl-dimethyl-5,6,7,9-tetrahydro-1,2,4- triazolo-[5,1-
b]quinazolin-8(4H)-ones derivatives (Scheme 1.119 and Scheme 1.120).
+
NH
N
O
CH3
CH3
N
N
R
RCHO+
O
CH3
CH3
ONH2
NH
N
N
CSA
Acetonitrile
Scheme 1.119
+
NH
N
O
CH3
CH3
R
N
RCHO+
O
CH3
CH3
O
NH
NNH2
CSA
Acetonitrile
Scheme 1.120
1.7.2.4 Chapter IV: Synthesis of Octahydroquinazolinones
Octahydroquinazolinone derivatives have attracted considerable
attention since they exhibit potent antibacterial activity against Staphylococcus
aureus, Escherichia coli, Pseudomonas aeruginosa and calcium antagonist
activity.
We have developed a new convenient method for the preparation of
octahydroquinazolinones under non-basic and non-metal conditions. The
method has ability to tolerate structurally and electronically divergent
substituents in aldehydes; variable reaction conditions, shorter reaction times
and simple work-up procedure are other advantages. Further, the present
60
procedure is readily amenable to large-scale synthesis and the generation of
combinatorial octahydroquinazolinones (Scheme 1.121).
+NH2 NH2
X
TMSCl
O
O
CH3
CH3
+ RCHONH
NH
X
O
CH3
CH3
R
Ethylene Glycol
X=O,S
X=O,S
Scheme 1.121
1.7.2.4 Chapter V: Synthesis of 1,8-Dioxo-decahydroacridines
The acridine derivatives having two keto functional groups at the 1st and
8th
positions are found to be good anti-malarial agents. Substituted
hexahydroacridine-1,8-dione, a novel dihydropyridine molecule, resembles K-
channel openers, and relaxes KCl reconstructed urinary-bladder smooth muscle
in-vitro. These acridinediones were found to act as laser dyes. In acridine 1,8-
diones, electron delocalization along a stretch of nine non-H atoms facilitate
them to exhibit fluorescence and laser activity. The effectiveness of lasing can
be controlled by the substituents at C-9 and N-10 of the acridine chromophore.
Apart from the above applications, acridinediones also possess other important
photo-physical and electrochemical properties. Acridine dyes reacting with
nucleic acids have received increasing interest as mutagens in micro-
organisms.
The present study describes a convenient and an efficient process for the
synthesis of acridinedione derivatives through a three-component coupling of
various aromatic aldehydes, 5,5-dimethyl-1,3-cyclohexanedione, and
ammonium acetate by using low concentrations of anhydrous HCl as a catalyst.
Present methodology offers very attractive features such as reduced reaction
times, higher yields with wide scope in organic synthesis. This novel catalytic
strategy is highly fascinating; this could also be used for several acid catalyzed
organic transformations and could replace the existing catalysts which are
currently being used in the industry (Scheme 1.122).
61
OH
Ar
Ar
O
O
CH3
CH3
O
CH3
CH3
TMSCl
Ethylene Glycol
O
O
CH3
CH3
NH4OAc ++ 2
Scheme 1.122
1.7.2.6 Chapter VI: Synthesis of Bis(indolyl)alkanes
Bis (indolyl) alkanes and their derivatives constitute an important group
of biologically active metabolites of terrestrial and marine in origin. In the
recent years bis(indolyl)alkanes have been found in marine sources. Bis-indole
metabolites bearing imidazole or a piperazine nucleus has been isolated from
various genera of sponges. Bis(indolyl)methanes and their derivatives exhibit a
diverse biological activities which affect central nervous system and used as
the tranquilizers. The important indole derivative, 9H-pyrralo[1,2-a]indole
called fluorazine is an important compound because of its anticholinergic
activity and for the inhibition of GABA transport and Na+/ K
+- TPase. Several
synthetic routes to 9H-pyrralo[1,2-a]indoles have been inscripted in literature
however, most of them have been directed towards the synthesis of mitomycin
antibiotics .
Cyanoacetic acid was found to be a mild and an efficient catalyst for the
electrophilic substitution reaction of indole with various aromatic aldehydes
affording the corresponding bis(indolyl)methanes in an excellent yields. The
advantages of this protocol are mild reaction conditions with reduced amount
of catalyst load, high conversion, easy handling, efficient and clean synthesis,
which makes the procedure attractive (Scheme 1.123).
NH
+
H O
Ar
NCOH
O
NH
NH
Ar
WaterNH
Scheme 1.123
1.7.2.7 Chapter VII: Synthesis of various Thiazoles
62
It is well-known that a number of heterocyclic compounds containing
nitrogen and sulfur exhibit a variety of biological activities. Heterocycles
bearing isoxazole, thiazole, and thiazolidinones have been found to be
associated with diverse pharmacological activities. The chemistry of isoxazole
derivatives continues to draw the attention of synthetic organic chemists due to
their varied biological activities. Several of these derivatives are potent
antitumor, CNS-active, analgesic, antimicrobial, and chemotherapeutic agents.
Thiazole derivatives have been employed as antipsychotics, antimalarials,
antibacterials and antiparasitic agents.
In light of the synthetic methods reported herein, the synthetic strategies
and subsequent chemical transformations of the resulting thiazole containing
heterocyclic compounds provides several important classes of functionalized
diversified molecules. The simplicity and flexibility of the experimental
procedures in the generation of these classes, together with the diversity of
thiazole chemistry, make these synthetic methodologies a highly efficient and
practical method for preparation of various biologically active derivatives.
1.7.2.8 Chapter VIII: Synthesis of 1,8-Dioxo-octahydroxanthenes
Xanthene derivatives are parent compounds of a large number of
naturally occurring as well as synthetic derivatives, and occupy a prominent
position in medicinal chemistry. Xanthenes and benzoxanthenes find their use
as dyes, fluorescent materials for visualization of bio-molecules and laser
technologies due to their useful spectroscopic properties. Xanthene based
compounds are also explored for their agricultural bactericidal activity,
photodynamic therapy, anti-inflammatory effect and anti-viral activity.
Xanthenediones constitute a structural unit in many natural products. They
have been also used as versatile synthons because of their inherent reactivity of
the inbuilt pyran ring.
We have demonstrated a simple, an efficient and clean methodology for
the synthesis of substituted 1,8-dioxo-octahydroxanthenes via the one-pot
condensation of benzaldehyde and dimedone at 80°C. Anhydrous HCl is found
to be novel and an efficient catalyst amongst the other catalysts screened for
the synthesis of octahydroxanthenes. The developed protocol works with a
63
wide range of aromatic aldehydes having electron withdrawing and electron
donating substituents. The developed methodology has the advantages of
operational simplicity and easy workup procedure (Scheme 1.124).
OH
Ar
CH3
CH3
O
OCH3
CH3
O
O O
ArO O
CH3
CH3
CH3
CH3
TMSCl
Ethylene Glycol+ +
Scheme 1.124
1.7.2.9 Chapter IX: Synthesis of Tetrahydrobenzo[b]pyrans
In recent years 4H-benzo[b]pyran and their derivatives have attracted
strong interest in scientific communities due to their wide range of biological
and pharmaceutical properties such as antibacterial, anticoagulant, spasmolytic
and diuretic. Efforts have been directed on the synthesis of an anticancer,
antianaphylactic, antibacterial agents. In addition, they have been used as
cognitive enhancer for the treatment of neurogenerative disease such as
Alzheimer disease, Parkinson’s disease, AIDS associated dementia, Down’s
syndrome as well as for the treatment of schizophrenia and myoclonus. Pyrans
and benzo-condensed derivatives constitute a structural unit for the series of
natural products and are oftenly used in cosmetics, pigments and as potential
biodegradable agrochemicals.
We have developed a green procedure for the synthesis of biologically
and pharmacologically active heterocyclic compounds, benzopyran derivatives,
under supramolecular catalysis involving Hydroxypropyl-β-cyclodextrin (HP-
β-CD) as the catalyst with water as the solvent. Potential advantages of using
water as a solvent are its low cost, safety, ease of use as a environmentally
benign nature (Scheme 1.125).
O
Ar
CN
NH2
O
CH3
CH3
Hydroxypropyl cyclodextrin
O
Ar
H
O
CH3
CH3
O
CN
CN
+ +
Scheme 1.125
64
The products are obtained in almost pure form by simple filtration or, if
necessary, the products were purified by recrystallization in ethanol. This
inventive catalyzed method has advantages of easily obtained raw materials,
simple and safe operation, mild reaction conditions, high yield, simple post-
treatment, less pollution to environment, high applicability value of potential,
social and economic benefits.
65
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