2. review of literature 2.1. benzamide -...

Chapter 2 Review of Literature

33 | Design, Synthesis and Biological Evaluation of Novel Anti-Fungal Agents

2. REVIEW OF LITERATURE

2.1. Benzamide

Priya BS and et al 1

reported, a compound with an amide-bond backbone have a wide

range of biological activities. Among the natural and synthetic substituted amide

derivatives, there are compounds possessing anti-proliferative, antiviral, antimalarial,

general anesthetics, anti-inflammatory, antimicrobials and in the treatment of

Alzheimer’s diseases

Amide moiety is versatile in organic compounds since all the three atoms in the O–C–

N chain are potentially reactive. Several efficient methods have been exploited for the

amidation using specific dehydrating reagents under mild liquid-phase condition. The

synthesis of substituted amides (3) began with the synthesis of various acid chlorides

(1), where the acid chloride undergoes condensation reaction with different amines (2)

in presence of triethylamine as acid scavenger in dichloroethane as solvent.

Nilo Zanatta et al., 2 synthesized furan-3-carboxamides (5) as antifungal agents,

reaction of 2,2,2-trichloro-1-(furan-3-yl)ethanone (4), with benzamidine, primary and

secondary amines, furnished a series of furan-3-carboxamides, in good yields. It is

interesting to note that, probably, due to the higher boiling point of the amines used in

these reactions, the use of a sealed tube was not necessary. For the reaction of 2, 2, 2-

trichloro-1-(furan-3-yl)ethanone, with benzamidine hydrochloride, the use of an

equivalent amount of sodium hydroxide solution was necessary to obtain the amidine

free base.

Esin Ak Sener et al., 3 reported, the synthesis and antimicrobial activity of some N-(o-

hydroxyphenyl)benzamides (8) synthesized by reacting suitable 2-aminophenols (7)

with appropriate carboxylic acid chlorides, (6) and their antimicrobial activity.



Ozlem Temiz-Arpaci et al., 4 had developed, a series of novel 2-[p-substituted-

phenyl]benzoxazole-5-yl-arylcarboxyamide (11), obtained by treating 5-amino-2-

phenyl-or 5-amino-2-(substituted-phenyl)benzoxazoles (10) with substituted benzoic

acids or furan-2-carboxylic acid or thiophene-2-carboxylic acid chlorides (9) and

examine their microbiological activity against various Gram-positive and Gram-

negative bacteria and against the yeast C. albicans in comparison.

Tugba Ertan et al., 5 reported, a series of N-(2-hydroxy-4(or 5)-nitrophenyl)

benzamides/ phenylacetamides (14) derivatives by reacting suitable 2-aminophenols

(13) with appropriate carboxylic acid chlorides, (12). The derivatives which have a

nitro group attached on position 4 or 5 of N-(2-hydroxyphenyl) binding them as a new

class of synthetic antimicrobial agents along with their in vitro antimicrobial activity.

Additionally, they also put an electron donating group such as amine instead of nitro

which is an electron withdrawing group for the same position in order to be able to

discuss the effect of substituent for biological activity. According to these studies they

conclude that benzamide structure played a noticeable role for increasing the activity.

When compared to the effect of nitro and amine group for this activity, it can be

concluded that compounds including a nitro group on the phenolic ring slightly

enhanced the activity.



Benzamide Scaffold incorporated with heterocyclic residue like thiazole, furan and

phenyl ring substituted with electron-donating and electron-withdrawing groups were

found to prove antifungal activity.

B. Narayana et al., 6 synthesized, new 2-hydroxy-5-(1,3-thiazol-5-yl) benzamide (18),

were prepared by reacting 5-(bromoacetyl) salicylamide (16) with thiourea,

thioformamide, thioalkylamide (17) and substituted thioureas in absolute ethanol and

investigate their antifungal activity.

Thiazoles and their derivatives have attracted continuing interest over the years

because of their varied biological activities.

Desai N.C. and et al.,7 synthesized N-(5-(2-(5-(arylidene)-4-oxo-3-phenylthiazolidin-

2-ylidene)hydrazinecarbonyl)-4-methylthiazol-2-yl)-4-fluorobenzamides (20)by con

densation of 4-fluoro-N-(4-methyl-5-(2-(4-oxo-3- phenylthiazolidin-2-ylidene) hy -

drazinecarbonyl)thiazol-2-yl)benzamide (19) and Knoevenagel condensation with

aromatic aldehydes through conventional and microwave methods and evaluated

for antifungal activity.

Anil Kumar et al, 8 had reported, a series of new substituted benzamides (23),

synthesized by were generated by the reaction of substituted benzoic acid (21) with 2-

aminophenol (22), using carbonyldiimidazole (CDI) in THF in one pot.



Furthermore the compounds comprising olefins shows good antifungal activity.

William F. Wood et al., 9 reported, long-chain (E)-3-alken-2-ones (24), synthesiz -ed

by condensation of an appropriate aldehyde with acetone using piperidine and acetic

acid as a catalyst and evaluated for antimicrobial activity.

Sarveswari S. et al., 10

had synthesized 1-(6-Chloro-2- methyl-4-phenyl quinolin-3-

yl)-(aryl) prop-2-en-1-ones (27), by stirring the mixture of 3-Acetyl-6-chloro-2-

methyl-4-phenyl quinoline (25) and arylaldehyde (26) into a KOH and evaluated for

atifungal activity.

Hasan Kucukbay et al., 11

reported, electron-rich olefins (29) derived benzimidazole

compound synthesized from appropriate benzimidazolium salts (28) and NaH and

screened for antifungal activity.



In the present study we synthesized N-subtituted benzamides and subjected them to

antifungal and molecular docking studies to examine their biological activities,

possible interactions and binding patterns with the proteins in relation to their activity.

2.1.1. Amide bond formation: methods and strategies

Carboxy components can be activated as acyl halides, acyl azides, acylimidazoles,

anhydrides, esters etc. There are different ways of coupling reactive carboxy

derivatives with

an amine:

an intermediate acylating agent is formed and isolated then subjected to

aminolysis.

a reactive acylating agent is formed from the acid in a separate step(s), followed

by immediate treatment with the amine.

the acylating agent is generated in situ from the acid in the presence of the amine,

by the addition of an activating or coupling agent.

In nature, protein synthesis involving a sequence of peptide coupling reactions (amide

bond formation between two α-amino acids or peptides), which is very complex,

supported by selective activation process catalyzed by enzymes.13

Laboratory

synthesis of amides historically involves condensation reaction between carboxylic

acids and amines. On mixing an amine with a carboxylic acid, an acid base reaction

occurs first to form a stable salt.The amide bond formation has to fight against

adverse thermodynamics as the equilibrium lies on the side of hydrolysis rather than

synthesis.14

Figure 8.Reaction of carboxylic acid with amine to form salt.

The direct condensation of the salt is reported to take place at high temperature (160-

180ºC),15

which is usually quite incompatible with the presence of other



functionalities. Therefore, activation of the acid, attachment of a leaving group to the

acyl carbon of the acid, to allow attack by the amino group is necessary.

Figure 9.Acid activation and aminolysis.

2.1.1.1. Acyl azides

The acyl azide route is one of the first developed for peptide coupling by Curtius.

16

Acyl azides can be prepared from the corresponding methyl esters via a two step

synthesis. The methoxy group is displaced with hydrazine to generate the acyl

hydrazide, which then undergoes a nitrosation reaction to yield the final acyl azide.

This is usually an efficient coupling method, but an occasional side reaction is a

Curtius rearrangement, leading to the formation of the unwanted corresponding

isocyanate.

The acyl azide route is one of the first developed for peptide coupling by Curtius.

Acyl azides can be prepared from the corresponding methyl esters via a two-step

synthesis. The methoxy group is displaced with hydrazine to generate the acyl

hydrazide, which then undergoes a nitrosation reaction to yield the final acyl azide

Figure 10. Amide synthesis via acyl azide

2.1.1.2. Acyl halides

Acyl chlorides (acid chlorides) are one of the easiest methods to activate an acid and

numerous acyl chlorides are commercially available. This is usually a two-step

process, involving first the conversion of the acid into the acyl halide followed by the

coupling itself.

Thionyl chloride SOCl2, 17

oxalyl chloride (COCl)2, 18

phosphorus trichloride PCl3 , 19

phosphorus oxychloride POCl3 20

and phosphorus pentachloride PCl5 21

are commonly



used to generate acyl chlorides from their corresponding acids. Phoshonium

pentachloride is generally used for aromatic acids, which contains electron

withdrawing substituents and which do not react readily with thionyl chloride.22

The

amide bond is formed by reacting the acyl chloride with the desired amine. An

additional base is usually required to trap the formed HCl and to avoid the conversion

of the amine into its unreactive HCl salt. Couplings are usually performed in inert dry

solvents.

Figure 11. Mechanism for acyl chloride formation using oxalyl chloride or thionyl

chloride

Nevertheless, acyl chlorides are moisture sensitive, hazardous and may pose danger of

hydrolysis, racemisation, cleavage of protecting groups and other side reactions

during coupling reaction.23

Use of acyl bromides and acyl fluorides to generate amide

bonds is also reported.24,25

2.1.1.3. Anhydrides

Anhydrides are species that readily react with a vast range of nucleophiles including

amines. Simple symmetric anhydrides and refined mixed anhydrides are utilized for

the preparation of amides.

2.1.1.3.1. Symmetric anhydrides The diversity of commercially available anhydrides

is rather limited and, quite often, the desired anhydride has to be prepared. Symmetric

anhydrides are formed either by heating the corresponding acid or, in milder

conditions, by reacting two molecules of acid in the presence of one equivalent of

dicyclohexyl carbodiimide (DCC).26

The anhydride is then reacted in a second step

with the selected amine (Fig.6). No additional base is required, as the addition

generates a carboxylate anion in situ. The main limitation is that only half of the acid

is effectively coupled and the other half is wasted.



Figure 12. Anhydride preparation and consecutive coupling with amines.

2.1.1.3.2. Mixed carboxylic anhydrides To overcome this waste problem, mixed

anhydride methods have been developed where the second carboxylic moiety is cheap

and easy to couple onto the acid. Mixed pivalic anhydrides 27

are one of the rare

examples. The desired aminolysis selectivity is believed to be due to the steric

hindrance of the t-Bu group.

Figure 13. Two step coupling procedure via pivalic anhydride.

Excellent selectivity is observed with mixed carbonic anhydrides. 28

The carbonate

electrophilic centre a is more reactive than the carboxylic site b as the reactive centre

a is less stabilized by resonance.

Figure 14. Two-step coupling via ethyl carbonic anhydride.

2.1.1.4. Acylimidazoles using CDICarbonyl diimidazole (CDI) is a useful coupling

reagent that allows one pot amide formation. 29

Acyl carboxy imidazole and imidazole

are initially formed but readily react together to yield the activated species as the

acylimidazole. Practically, the acylimidazole is preformed for 1 h and then the amine

is added. This reaction, which generates imidazole in situ, does not need an additional

base and is even compatible with HCl salts of the amine.30



Figure 15. One pot amide preparation using CDI

2.1.1.5. Acyloxyboron intermediates

Acyloxyboron species 31

generated from carboxylic acids and boron reagents often

react with amines to give amides. Boron reagents readily react with carboxylic acids

to yield acyloxyboron intermediates, which are coupled to amines in moderate yields.

The main drawback of this procedure is the low conversion rate usually observed

during the aminolysis step.

Figure 16. Acylboronate formation and aminolysis

2.1.1.6. Esters

Alkyl esters (e.g., methyl, ethyl, benzyl esters) cannot be considered as activated

species and are commonly used as protecting groups in peptide synthesis. Alkyl esters

can, however, be displaced occasionally by amines under forcing conditions such as

the use of high temperatures or the addition of a Lewis acid (e.g., TiCl4).32

Activated

esters such as aromatic esters are usually easier to hydrolyze than alkyl esters and are

prone to react with a wide range of nucleophiles. More importantly, they cleanly react

with amines under mild conditions. 33



Figure 17. Conversion of activated esters to amide

2.1.1.7. Phosphonium salts

Benzotriazol-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (Fig.

14), also called Castro’s reagent, 34

is the first published example of these HOBt-based

onium salt reagents. The one-pot coupling is performed mixing the desired acid and

amine in the presence of BOP 60 and triethylamine or Hu¨nig’s base. The

deprotonated acid first reacts with BOP 60 to generate both an activated

acylphosphonium species and HOBt. HOBt readily reacts with the activated acid to

produce a reactive Bt ester, which finally undergoes aminolysis. The driving force of

this phosphonium-based reaction is to generate the correspondingoxide

Figure 18. One-pot coupling procedure using BOP

2.1.1.8. Microwave activation

In several cases, microwave irradiation has been a successful alternative to

conventional high temperatures to perform direct condensation of amines to

carboxylic acids without prior activation. The use of direct microwave heating is

reported to reduce the chemical reaction time, reduce side reactions, increase yields

and improve reproducibility. 35

The microwave irradiation may be run with or without

catalyst.



2.2. Thienopyrimidin-4(3H)-thiones

Fused pyrimidines continue to attract considerable attention of researchers in different

countries because of their great practical usefulness, primarily, due to a very wide

spectrum of their biological activities.

Thieno[2,3-d]pyrimidines are considered to be bioisosteres of quinazolines. The

concept of bioisosterism has been exploited by medicinal chemists as an approach to

the drug design. This has lead to the synthesis of various types of condensed

pyrimidines, which show a wide range of biological activities.

Following are the few examples of various biological activities exhibited by the

thienopyrimidines.

Richard Luke et al.,36

reported the improvement in potency against Tie2 of novel

thieno pyrimidine (30) and thiazolopyrimidine kinase inhibitors. These compounds

have moderate potency in cellular assays of Tie-2 inhibition, good physical properties,

DMPK, and show evidence of in vivo inhibition of Tie-2.

Jeroen C. et al., 37

synthesized 2-Aryl-4-morpholinothieno[3,2-d]pyrimidines (31)

which are known as PI3K inhibitors. This class of compounds also potently inhibited

the homologous enzyme mTOR. Replacement of the morpholine group in these

compounds with 8-oxa-3-azabicyclo [3.2.1] octane group led to mTOR inhibitors with

selectivity over PI3K. Optimization of the 2-aryl substituent led to the discovery of 2-

(4-ureidophenyl)-thienopyrimidines as highly potent (IC50<1nM) mTOR inhibitors

with excellent selectivity (upto >1,000-fold) over PI3K and good potency in a cellular

proliferation assay (IC50 <50 nM).



Hans-Georg Häcker et al., 38

synthesized a series of 2-alkylthio-4-amino thieno[2,3-d]

pyrimidines (32) and tested in a daunorubicin accumulation assay.

Chen Yu Lu et al., 39

synthesized 5,6-Dihydrothieno[3,2:4,5]thieno[2,3-d]pyrimidin-

4(3H)-ones (33) in yields of 71–87% by a consecutive method, which includes aza-

Wittig reaction of iminophosphorane with aromatic isocynate to give carbodiimide

and subsequent reaction with various amines, phenols or alcohols in the presence of

catalytic amount of sodium ethoxide or solid potassium carbonate.

Lakshmi N. et al., 40

reported the diazotization of 3-amino-2-sulfanyl-2,3,5,6,7,8-

hexahydro[1] benzothieno[2,3-d]pyrimidin-4(1H)-one (34) to give the diazonium salt

of 3-amino-2-sulfanyl-2,3,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-4(1H)-

one. Various Schiff bases are then treated with the above to give 3(phenylhydrazono)

(substitutedphenyl) ethyl]-2-sulfanyl-2,3,5,6,7,8-hexahydro[1] benzothieno [2,3-d]

pyrimidin-4-(1H)-ones. All the compounds have shown promising antibacterial and

antifungal activities.



Salahuddin et al., 41

carried out the synthesis of some novel benzothienopyrimidines

(35) by using Gewald reaction and further cyclization and chlorination of 2-amino-5-

benzyl-4,5,6,7-tetrahydrothieno-pyridine-3-carboxamide. All the synthesized compo -

unds were tested against bacterial strains (Gram +ve and Gram–ve).

Ahmeda et al., 42

synthesized a series of fused pyrimidopyrazolo theinopyrimidine

derivatives using 2-(1-methyl-1H-indol-ylmethyl)-4-methyl-5-ethoxycarbonyl-6-

mercapto pyrimidine (36) as a starting material. The pharmacological screening

showed that many of these compounds have good anti-inflammatory and analgesic

activities comparable to Prednisolone and valdecoxib as reference drugs.

Salahuddin et al., 43

carried out the synthesis of novel thieno[2,3-d]pyrimidines (37)

by using Gewald reaction and further bromination of intermediate 1-[4-(6,7-dihydro-

5Hcyclopenta[4,5]thieno[2,3-d]pyrimidin-4-yl-amino)phenyl]ethanone. Which upon

reaction with different substituted benzothiazoles give a novel series of thieno -

pyrimidines. All the synthesized compounds were tested against Gram +ve and Gram

-ve bacterial strains.



Nitinkumar et al., 44

reported the synthesis of novel tricyclic thienopyrimidines and

triazole (38) fused tetracyclic thienopyrimidines from 2-amino-6-methyl-4,5,6,7-tetra

-hydro-1-benzothiophene-3-carbonitrile and 2-amino-7-oxo-4,5,6,7-tetrahydro-1-ben -

zothio-phene-3-carbonitrile respectively. The corresponding precursors were prepared

by employing the Gewald reaction. The compounds displayed promising antibacterial

and antifungal activities.

Ahmed M.M. et al., 45

reported the synthesis of 3-amino-2-(4-bromo benzoyl)-4-

cyano-5-phenyl-aminothiophene (39) and 2-acetyl-3-amino-4-cyano-5-phenylamino-

thiophene with a variety of active methylene compounds, such as ethyl cyanoacetate,

ethylacetoacetate, ethylbenzoylacetate and diethylmalonate, yielded the corresponding

thieno[3,2-b]pyridine-2-one derivatives. Also the reaction with formamide and formic

acid, afforded the corresponding thieno[3,2-d]pyrimidine derivatives. While the

reaction of compound with phenyl-isothiocyanate, yielded thieno[3,2-b]pyrimidin-2-

thione derivative.

Robert D Hubbard et al., 46

synthesized a novel class of substituted pyrrolidinyl

acetylenic thieno[3,2-d]pyrimidines (40) that are potent and selective inhibitors of

both EGFR/ErbB-2 receptor tyrosine kinases. Selected molecules, including

compound, were found to be potent in enzymatic and cellular assays while also

demonstrating exposure in the mouse from an oral dose



Manisha S. Phoujdar et al., 47

reported a series of novel 2-unsubstituted 4-(sub -

stituted)anilinothieno[2,3-d]pyrimidines, which are synthesized through the

chlorination of the corresponding 2-unsubstituted-thieno[2,3-d]pyrimidin-4-ones ( 41)

followed by the nucleophilic displacement of the 4-Cl group, with a variety of

Anilines. All four steps of this synthesis involved microwave irradiation (MWI).

Ming-Guo Liu et al., 48

the mono (iminophosphorane) was selectively prepared from

the reaction of 3,4-diaminothieno[2,3-b]thiophene (42) with excess triphenyl

phosphine, and Et3N due to intramolecular double hydrogen bond formation.

mono(iminophosphorane) reacted with aromatic isocyanates to give stable

carbodiimides, which were further treated with aliphatic secondary or primary amines

to give 2-amino substituted thieno[3,2:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones in the

presence of a catalytic amounts of EtO-Naþ. The reaction of carbodiimides with

phenols in the presence of a catalytic amounts of potassium carbonate gave a mixture

of 2-aryloxy substituted thieno[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones.



Roger J. Gillespie et al., 49

reported that the (-)-(11R, 2S)-enantiomer of the

antimalarial drug mefloquine has been found to be a reasonably potent and

moderately selective adenosine A2A receptor antagonist. Further investigation of this

compound has led to the discovery of a series of keto-aryl thieno [3,2-d]pyrimidine

(43) derivatives, which are potent and selective antagonists of the adenosine A2A

receptor. These derivatives show selectivity against the A1 receptor.

Agathe Begouin et al.,50

has employed DDQ as a dehydrogenation reagent synthesize

polyaromatic compounds benzothieno pyrido pyrimidinones and benzothieno

pyrimido isoquinolinone (44) by microwave-assisted process which allows shorter

reaction times and easier purification as fewer degradation products were formed.

Sachin et al., 51

reported the synthesis of novel 1,2,9,11-tetrasubstituted-7Hthieno

[2,3:4,5]pyrimido[6,1-b]quinazolin-7-ones starting from 5,6-disubstituted-3Hthieno

[2,3-d]pyrimidin-4-ones (45) which could be reached in two steps through a von

Niementowski reaction, which involves condensation of substituted anthranilic acids

with a 4-chloro-5,6-disubstituted-3H-thieno[2,3-d]pyrimidines.



Alagarsamya et al.,52

designed and synthesized some of 2-methylthio-3-substituted-

5,6-dimethylthieno[2,3-d]Pyrimidin-4(3H)-ones (46). The synthesized compounds

were investigated for analgesic, anti-inflammatory and antibacterial activities.

Veerachamy et al., 53

synthesised a new series of 2-mercapto-3-substituted-5,6-di -

methylthieno[2,3-d]pyrimidin-4(3H)-ones by reacting 3-amino-2-mercapto-5,6-dimet

-hylthieno[2,3-d]pyrimidin-4(3H)-one with different aldehydes and ketones. The

starting material 3-amino-2-mercapto-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one

(47) was synthesised from 2-amino-3-carbethoxy-4,5-dimethyl thiophene by a novel

innovative route. The title compounds were investigated for analgesic, anti-

inflammatory and ulcerogenic index activities.

Ashalatha et al., 54

synthesized nine new 2-(substituted phenyl) /alky [1,3,4]

thiadiazolo[2,3-b]6,7,8,9-tetrahydrobenzo(b)thieno[3,2-e]pyrimidin-5(4H)-ones(48).

Six new 3-amino-2-[(2-oxo-2-(aryl)ethyl)thio]-5,6,7,8-tetrahydro [1] benzothieno[2,3-

d]pyrimidin-4(3H)-ones, one 2-mercapto[1,3,4]thiadiazolo[2,3-b]-6,7,8,9-tetrahydro -

benzo(b) thieno[3,2-e]pyrimidin-5(4H)-one and one 2-chloromethyl [1,3,4] thiadi -

azolo[2,3-b]-6,7,8,9-tetrahydrobenzo(b)thieno[3,2-e]pyrimidin-5(4H)-one.

Compounds were screened for anti-inflammatory and antimicrobial activities.



Davoodnia A. et al., 55 has carried out a one-pot synthesis of new 3-arylthieno[2,3-d]

pyrimidine-2,4(1H,3H)-diones (49)viabase-catalyzed cyclocondensation of ethyl 2-

amino-4,5-dimethylthiophene-3-carboxylate with aryl isocyanates is described.

Abdel-Rahman et al.,56

has reacted 5-Methyl-6-phenyl-2-thioxo thieno[2,3-d]

pyrimidone derivative with hydrazonoyl chloride derivatives to afford triazolo

thienopyrimidines(50). Also, acetone-1-(2-amino-5-isopropyl-thiophene-3-carbonitr-

ile) which was reacted with functional and bifunctional groups to yield the correspond

-ing compounds. The new products showed anti-inflammatory, analgesic and

ulcerogenic activities comparable to that of Indomethacin and acetylsalicylic acid.

Gerardo Blanco et al.,57

described a simple one-pot and efficient method for the

synthesis of pyrazino[2,3,4,5]thieno[3,2-d]pyrimidinone (51) derivatives via a tandem

aza-Wittig/heterocumulene-mediated annulation process. The effects of the nucleo phi

-les and isocyanates on the regioselectivity of the cyclization have been investigated.



Alagarsamy et al.,58

reported a variety of novel 2-methylthio-3-substituted-5,6,7,8-

tetrahydrobenzo(b)thieno[2,3-d]pyrimidin-4(3H)-ones (52) which have been synthesiz

-ed by reacting (2-methylthio-4-oxo-3H-5,6,7,8-etrahydrobenzo(b)thieno[2,3-d] pyri -

midin-3-yl)dithiocarbamic acid methyl ester with a variety of amines. The starting

material dithiocarbamate was synthesized from 2-amino-3-carbethoxy-4,5,6,7 tetrahy

-drobenzo(b)thiophene by a novel innovative route. The title compounds were

investigated for analgesic, anti-inflammatory, ulcerogenicity index and antibacterial

activities.

Riyadh et al.,59 reported two convenient methods for synthesis of novel pyrido

[3,2:4,5] thieno[3,2-d][1,2,4] triazolo[5,4-a] pyrimidin-5-ones were developed. The

first route involved the reaction between 2,3-dihydro-7,9-dimethyl-2-thioxopyrido

[3,2:4,5]thieno[3,2-d] pyrimidin-4(1H)-one ( 53) or its 2-methylthio derivative with

hydrazonoyl halides in dioxane under reflux in presence of triethylamine. The

alternative route proceeded via reaction of the appropriate active chloromethylene

compounds followed by coupling the products with benzene diazonium chloride

which afforded the azo coupling products and then was converted in situ to.

Abdullah G. M. et al.,

60 reported the reaction of naproxanoyl chloride with some

nucleophilic reagents as ammonium thiocyanate and sodium azide to produce the

novel isothiocyanate derivatives. Interaction of isothiocyanate with 1,2-

phenylenediamine and anthranilic acid has produced the corresponding benzimidazole

derivatives and 3,1-benzoxazine derivatives respectively. In a similar manner ethyl 4,

5- disubstituted-aminothiophene-3-carboxylate were reacted with naproxenoyl

chloride in benzene to furnish corresponding amide derivatives which on treatment



with hydrazine hydrate yielded 3-amino[2,3-d]pyrimidines (54).

Narayana B. et al.,61

has converted ethyl-2-amino-4,5,6,7-tetrahydro-benzothio-

phene-3-carboxylate into 2-(acetyl amino)-5,6,7-tetrahydro-1-benzo thiophene-3-

carboxylate and ethyl 2-(propionyl amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-

carboxylate. The above compounds on treatment with hydrazine hydrate give 3-

amino-2-methyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine-4-(3H)-one and 3-

amino-2-ethyl-5,6, 7,8-tetrahydro (55) benzothieno[2,3-d]pyrimidine-4-(3H)-one

respectively. The comp -ounds screened for antibacterial and antifungal activity.

Mosharef Hossain Bhuiyan MD et al.,

62 reported the reaction of o-aminonitrile with

ethyl N-bis

thieno[3,2-e]imidazole[1,2-c]pyrimidine moiety in a one process.[1,2,4]triazolo[4,3-c]

thieno-[3,2-e]pyrimidine derivatives were prepared by initial treatment of o-amino -

nitrile with carbon disulfide, followed by methylation with methyl iodide and

subsequent reaction with benzhydrazide and thiosemicarbazide, respectively.

Hydrazino thieno(2,3-d)pyrimidine was prepared by cyclization of heteroaromatic

oaminoester with formamide, followed by chlorination and subsequent displacement

with hydrazine. Treatment of the hydrazino derivative with acetylacetone,

benzaldehyde and acetic anhydride afforded pyrazolylpyrimidine, benzylidene

hydrazonopyrimidine and triazolopyrimidine derivatives (56). Some of these

derivatives exhibited pronounced antimicrobial activity.



Fatma EM El-Baih et al.,63

prepared thioxo thienopyrimidinones, alkyl thio and aryl

alkyl thio thieno pyrimidinones, thienopyrimidinones, thienopyrimidines a thieno

pyrimidinedione and a thieno triazolo pyrimidinone (57) from 2-amino-3-carboethoxy

-4,5-disubstituted thiophenes and 2-amino-3-cyano-4,5-disubstituted thiophenes via

reactions with different reagents.

Alagarsamy et al.,64

synthesized a variety of novel 2-mercapto-3-(substituted amino)-

5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-ones(58) by reacting 3-

Amino-2-mercapto-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyramidine-4-one

with different aldehydes and ketones; the starting material 3-amino-2-mercapto-5,6,7,

8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one was synthesized from 2-

amino-3-carbethoxy-4,5,6,7-tetrahydrobenzo thiophene by a novel innovative route.

The title compounds were investigated for analgesic, anti-inflammatory and

ulcerogenic index activities.

Ming Wu Ding et al.,

65 synthesized 2-Alkylamino-5,6,7,8-tetrahydro benzo

thieno[2,3-d] pyrimidin-4(3H)-ones (59) by a new selective synthetic method, which

includes aza-wittig reaction of iminophosphorane with aromatic isocynate to give



carbodi-imide and subsequent reaction with various aliphatic primary amine in the

presence of EtO-Na+.

Sheng Zhen XU et al.,66

reported the 2,7-diaminothieno[2,3-d:5,4-d]dipyrimidine-

4,5(3H,6H) diones (60) synthesis by a facile synthetic method, which includes bisaza-

Wittig reaction of bis-iminophosphorane with aromatic isocyanate to give bis-

carbodiimide and subsequent reaction with various dialkylamine in the presence

ofsolid K2CO3 or EtONa.

Abu Zieda Hassanien et al.,67

reported the reaction of 2-acetylbenzoimidazole with

some arylaldehydes under different conditions gave chalcones, 1,5-pentanediones and

pyridines. Treatment of chalcones with various types of reagents gave the

corresponding new pyridines, thienopyridines (61) pyrido [2,3:4',5], thieno[3',2'-d]-

pyrimidin-8-ones via initial addition of active methylene or amino group to the double

bond followed by cyclization.



Michael et al., 68

synthesized new classes of thienopyrimidines and thienopyridines

(62) as potent inhibitors of VEGFR-2 kinase.

David Vazquez Vilarelle et al.,

69 reported one-pot synthesis of the hitherto unrepor

tedpyrido[5,6:4,5;3,2:4,5]dithieno[3,2-d:3,2-d]dipyrimidine-4,8(3H,9H)-dione (63)

and pyrazino[5,6:4,5;3,2:4,5]dithieno[3,2-d:3,2-d]dipyrimidine-4,8 (3H, 9H)-dione

pentaheterocyclic systems, based on the tandem aza-Wittig hetero cumulenemediated

annulations strategy is described.

Mohamed Amal Abdel Haleem Eissa et al.,

70 reported the reaction of 2-substituted or

unsubstituted-4-(4-acetylanilino)-5,6,7,8-terahydrobenzo[b]thieno [2,3-d] pyrimidines

(64) derivatives with the hydrazine derivatives, and thiosemicarbazides, provided the

corresponding hydrazones and thiosemicarbazones. Representative compounds were

tested for their antimicrobial activity against Candida Albicans and certain gram-

positive and gram-negative bacteria.



Melissa L.P. et al.,71 designed and synthesized N-(2,4-dioxo-1,2,3,4-tetrahydro-

thieno[3,2-d]pyrimidin-7-yl)-guanidines (65) as a novel class of thymidine phosphory

-lase (TP)inhibitors.

Kidwai et al.,

72 synthesized novel 5-methyl-6-ethylcarboxylate-2-thioxo-thieno[3,2-d]

pyrimidine-4(1H)-ones (66) from 2-amino-3,5-diethyl carboxylate-4-methyl

thiophene and mono substituted thioureas using microwave technology under the

solid support of K2CO3.

Ammar Y. A. et al.,

73 Carried out the reactivity of quinoxaline-2,3-dicarboxylic

anhydride towards some heterocyclic amines as nitrogen nucleophiles. Thieno[2,3-d]

pyrimidine (67) is obtained by refluxing the compound with hydrazine hydrate.

Condensation of compound with aromatic aldehydes furnishes the corresponding

Schiff bases. Finally, refluxing of compound with acetic anhydride yields the

acetamido derivative

Annamaria Panico et al.,

74 reported the effects of a series of thienopyrimidine

derivatives on the prevention of cartilage destruction in articular disease. Some

thienopyrimidine derivatives (68) in the presence of IL-1, blocked the cartilage



breakdown by inhibiting both the NO production and GAGs release in a

dosedependent manner.

Magda A. Abdallah et al.,75 synthesized 1,4,7,8,9,10-Hexahydro-6H[1]benzothieno

[2,3;4,5]pyrimido[1,2-b][1,2,4,5]tetrazin-6-ones (69) via reaction of 2,3,5,6,7,8-

hexahydro-3-amino-2-thioxo[1]benzothieno[2,3-d]-pyrimidin-4(1H)-one or its 2-

methylthio derivative with hydrazonoyl halides in ethanol in the presence of

triethylamine. Some of the products were screened for their biological activity.

Ogawva K. et al.,

76 synthesized a series of 2,4-dioxo-thieno[2,3-6], [3,2-d] and [3,4-d]

pyrimidin-l-acetic acids (70) with a benzyl moiety at the N-3 position and tested in

vitro for aldose reductase inhibitory activity against partially purified enzyme from rat

lens. Some of these compounds were also evaluated for inhibition of sorbitol

accumulation in the sciatic nerve or lens of streptozotocin-induced diabetic rats in

vivo. Among the synthesized compounds, several showed potent aldose reductase

inhibitory activity.

The thieno[2,3-d]pyrimidine and fused heterocycles containing this ring system might

be expected to show close resemblance in properties to the quinazoline structure

because of the similarity between benzene and thiophene.



In view of the close association of pyrimidines with important biodynamic agents,

numerous compounds containing such a ring system have been extensively

investigated. Most of the work reported in the literature often involves fusion of

pyrimidine nucleus with thiophene heterocyclic system.

2.2.1. Synthesis of thienopyrimidines

Synthetic approaches to the construction of thienopyrimidines are sufficiently well

developed. Three possible types of annelation of thiophene to the pyrimidine ring and,

correspondingly, three isomeric thienopyrimidines are known:

(a) thieno [2,3d] pyrimidine

(b) thieno[3,2d]pyrimidine and

(c) thieno[3,4d]pyrimidine

The structures and the conventional numbering of these heterocyclic systems are

shown below.

The known approaches to the synthesis of thienopyrimidines can be divided into two

main groups:

a. The construction of the pyrimidine ring by intramolecular cyclization of

thiophene derivatives and

b. The thiophene ring closure in pyrimidine derivatives

2.2.1.1. Synthesis of thienopyrimidines by pyrimidine ring closure

Appropriately substituted aminothiophenes, which are accessible by various methods,

serve as the main starting compounds for the preparation of thienopyrimidines with

the use of this approach. 77-80

Syntheses involving the pyrimidine ring closure starting

from both 2 and 3 aminothiophenes proceed under similar conditions and in virtually

the same reaction sequences, due to which all three types of thienopyrimidi -nes

become accessible.

Hence, it is reasonable to classify the reactions leading to these compounds according

to the type of substitution in the pyrimidine rings formed.

One of the most popular approaches to the synthesis of thienopyrimidinediones (75) is

based on the pyrimidine ring closure in thienylureas (74).



Hereinafter, A is the thiophene ring bearing substituents at positions 2 and 3 or 3 and

4; thienopyrimidine structure (75) is thiophene analogously annelated to the

pyrimidine ring; the ester group is most widely used as the COX group.

The starting thienylureas are synthesized according to the known procedures based on

reactions of aminothiophenes with isocyanates, 81-85

KOCN—HCl,46 ClSO2NCO,

and some other reagents. The substituent R in thienylureas can be replaced with other

hydrocarbon groups using reactions with amines.81

Pyrimidine ring closure from thienylureas occurs easily upon treatment with bases

(generally, with ethanolic or aqueous solutions of alkalis).81-88

An example of the use

of potassium tertbutoxide as a cyclizing agent was documented. Cyclization of ureas

with a —CONH2 group in an acidic medium was also described. 86

Thienopyrimidinediones containing the hydrogenated thiophene ring were

synthesized starting from the corresponding tetrahydrothienylureas. 82, 88-90

Thienopyrimidinediones (75) unsubstituted at the nitrogen atom (R = H) were

prepared starting from aminothiophenes (76), whose successive treatment with

chloroformates (or phosgene) and primary amines 91-95

afforded the target products

(77).

Although intermediate thienylureas were not isolated,their transient formation is quite

probable. 96, 97

Substituted thienopyrimidinedione (79) was prepared in 91% yield by

heating N-N-diethyl-N-methoxycarbonyl-N-´(3-methylamino-5-phenyl-2-thenoyl )

thiourea (78) in methanol. 98



Thienylthioureas (80) prepared by reactions of vicamino (ethoxycarbonyl) thiophenes

(74) with isothiocyanates 98-101,

or by reactions of thiophenes succesively with

thiophosgene and amines 100,101

undergo, like thienylureas , the pyrimidine ring

closure upon treatment with an ethanoholic solution of HCl 100

or ethanolic alkali

followed by acidification of the reaction mixture with hydrochloric acid. 98-103

Earlier,

104,105 it has been demonstrated that for R = Acyl, the latter reactions resulted in

hydrolysis to give unsubstituted thioxopyrimidinone (81)

The reactions of aminocarbonyl derivatives of thiophene (82) with potassium

thiocyanate afforded (4-oxo3, 4dihydrothieno[2,3d]pyrimidin-2-ylthio)acetic acid

derivatives (83) in yields up to 51%. Analogously, the isomeric aminocarbonyl

derivative (84) gave ethyl (7-cyano-6-methylthio-4-oxo-3,4-dihydrothieno [3,2d]

pyrimidin-2-ylthio)acetate (85) in 85% yield. 106, 111

Thioxothienopyrimidinones (86) were prepared 107,112

by recyclization of thiazines in

an acidic medium.



A procedure was developed 108-111

, for the synthesis of thienopyrimidinedithiones (89)

involving thermal recyclization of thiazines (88), which, in turn, are prepared by the

reactions of substituted 2-amino-3-cyanothiophenes (87) with carbon disulfide in the

presence of bases.

1-Aminothieno[2,3d]pyrimidine-3(4H)-thiones (92) were prepared by cyclization of

vic cyano(thioureido)thiophenes (90) followed by the Dimroth rearrangement of

intermediates (91) under the action of bases112-116,

or by heating of 2-amino-3-

cyanothiophenes with thiourea.117

Thienopyrimidinones (94) were prepared1 118-123,

by the reactions of thiophenes (93)

containing the ethoxycarbonyl and amide groups with amines. It was postulated that

these reactions proceed via intermediate diamides 94

The third general procedure for the synthesis of thienopyrimidines (98) is based on

recyclization of thienooxazinones (96), which are generated by the reactions of amino

-carboxylic acids (95) or esters with acylating agents (Ac2O, HC(OEt)3, or PhCOCl)

in the presence of bases,under the action of amines.86, 124-136

This recyclization

proceeds through the intermediate formation of diamides (97). The reactions with

secondary amines give these diamides as the only reaction products. 135, 137



Successive treatment of 2-amino-3-cyanothiophenes (99) with carbon disulfide in the

presence of sodium methoxide and then with methyl iodide gave rise to vic-bis

(methylthio) methyl deneamino(cyano)thiophenes (100), which were transformed into

alkylthiothienopyrimidineimines (101) under the action of amines.138

It was

emphasized that it is necessary to thoroughly control the reaction conditions to

prevent the possible Dimroth rearrangement.

2.2.1.2. Synthesis of thienopyrimidines by thiophene ring closure

As earlier, procedures for the synthesis of thienopyrimidines by the thiophene ring

closure starting from the available pyrimidine system are used much more rarely than

the pyrimidine ring closure. This is attributable to the fact that the starting

appropriately substituted pyrimidines are less readily accessible. In this section, the

data are systematized according to the types of reactions giving rise to the thiophene

ring formation. Generally, the synthesis of thienopyrimidines using the Claisen,

Thorpe—Ziegler and Friedläender condensations can be represented by the following

scheme:

Another procedure for the synthesis of pyrimidines (103) involves alkylation of 5-

ethoxy carbonylpyrimidine-4(3H)thiones (102) with chloroacetic acid derivatives. In



this case, thienopyrimidines (104) were prepared without isolation of intermediate

pyrimidines. 139-142

Alternative approaches to the synthesis of thienopyrimidines by the thiophene ring

closure are also documented. For example, the thioClaisen rearrangement of proparg -

yl sulfide (104) (X = S) affords thienopyrimidinediones (105); the rearrange -ment of

sulfoxide 143

, (X = SO) gives rise to the corresponding formyl derivative 144

(R2 =

CHO).

Another approach to the construction of the thiophene ring based on functionalized

pyrimidines involves thiolation of the methyl group in vic-methylpyrimidine -

carbonitriles (106) with elemental sulfur followed by cyclization of intermediate

thiols (107) to give thienopyrimidines (108). The reactions were carried out with

pyrimidinethiones 145

and pyrimidinediones. 146



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