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Chapter-I Brief introduction of heterocycles

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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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