Cyanoacetamide Derivatives As Synthons in Heterocyclic Synthesis

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Turk J Chem 32 (2008) , 259 – 286. c TUB¨ ITAK˙ Review

Cyanoacetamide Derivatives as Synthons in Heterocyclic Synthesis

Ahmed Ali FADDA, Samir BONDOCK∗,RamyRABIE, Hassan Ali ETMAN Department of Chemistry, Faculty of Science, Mansoura University, ET-35516 Mansoura-EGYPT e-mail: [email protected]

Received 09.10.2007

This review presents a systematic and comprehensive survey of the methods of preparation and the chemical reactivity of cyanoacetamide derivatives. These compounds are important intermediates for the synthesis of a variety of otherwise diﬃcult to obtain synthetically useful and novel heterocyclic systems.

Key Words: Cyanoacetanilide, thiophene, pyrazole, thiazole, pyridine, pyridazine, pyrimidine, heterocycles

Introduction

Cyanoacetamides are highly reactive compounds. They are extensively utilized as reactants or reaction intermediates since the carbonyl and the cyano functions of these compounds are suitably situated to enable reactions with common bidentate reagents to form a variety of heterocyclic compounds. Moreover, the active hydrogen on C-2 of these compounds can take part in a variety of condensation and substitution reactions. In addition, the diverse biological activities reported for many derivatives of cyanoacetamide have also drawn the attention of biochemists in the last decade. The literature covering the chemistry of cyanoacetamide derivatives has been limited. However, a review of the chemistry and reactions of cyanothioacetamide (in Russian) was published in 1999.1 The main objective of the present survey is to provide a comprehensive account of the synthetic utility of N-aryl and/or heteryl cyanoacetamides in building various organic heterocycles and to highlight their potential in evolving better chemotherapeutic agents.

Synthesis

The synthesis of cyanoacetamides may be carried out in several ways. The most versatile and economical method involves the treatment of various substituted aryl or heteryl amines with alkyl cyanoacetates using ∗Corresponding author

259 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al., diﬀerent reaction conditions to yield cyanoacetamide derivatives. The following are some of the methods that have been used to prepare N-aryl or N-heteryl cyanoacetamides.

Fusion Metho d

The solvent-free reaction of arylamines with ethyl cyanoacetate constitutes one of the most widely used methods for the preparation of cyanoacetanilides. Thus, fusion of aromatic amines with an excess amount of ethyl cyanoacetate at 150 ◦C aﬀorded cyanoacetanilide derivatives 1.2

O O CN Ar CN ArNH2 + EtO N 150 °C H 1 1 Ar 1 Ar a C H 6 5 h 4-CF3-C6H4 b 2-NO -C H 2 6 4 i 4-Br-C6H4

c 4-MeO-C6H4 j 2,4,6-Cl3-C6H2 4-Cl-C H d 6 4 k 2-F-C6H4 e antipyryl l 4-F-C6H4 f 4-Me-C6H4 m Pyridyl

g 3-Cl-4-F-C6H3 n 2-OCF3-C6H4

Scheme 1

Using Diﬀerent Basic Medium Conditions

Sodium ethoxide solution

Metwally and coworkers have recently reported that the base catalyzed condensation of 2-aminothiazole derivatives 2 with ethyl cyanoacetate aﬀorded N-(thiazol-2-yl) cyanoacetamide derivatives 3.3

R1 R1 N O N O CN NaOEt CN NH + R R2 S 2 EtO EtOH 2 S N H 2 3

3 R1 R2 a Ph H

b C4H4

Scheme 2

260 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

Butyl lithium/THF

Bhawal et al. reported that the reaction of benzylamine with ethyl cyanoacetate in THF containing butyl lithium as a basic catalyst aﬀorded N-benzylcyanoacetamide 4 in 91% yield.4

O O CN CN NH EtO THF N 2 + H BuLi

4 Scheme 3

Dicyclohexyl carbodiimide (DCC) & 4-N,N-dimethylaminopyridine (DMAP)

2-Cyano−N-(4-nitrophenyl)acetamide 1b was obtained by condensation of 2-nitroaniline with cyanoacetic acid in dimethylforamide containing dicyclohexyl carbodiimide and 4-N,N-dimethylaminopyridine.5

NO2 NO2 H NH2 HO N CN + CN DCC / DMAP O DMF O

1b Scheme 4

Microwave method

Microwave irradiation has become an important method in organic synthesis that can be applied to a wide range of reactions within short reaction times and with high yields. The microwave irradiation of p-anisidine with ethyl cyanoacetate in trichlorobenzene aﬀorded 2-cyano-N-(4-methoxyphenyl) acetamide 1c in 90% yield.6

H NH2 EtO N + CN M.W CN O trichlorobenzene O MeO MeO

1c Scheme 5

Utilization of 1-Cyanoacetyl-3,5-Dimethylpyrazole as Cyanoacetylation Reagent

Cyanoacetylpyrazole 5 is a very handy and cheap cyanoacetylation reagent, which was ﬁrst synthesized and introduced in common practice in the late 1950s by Ried and Scheimer.7 It was successfully applied for the synthesis of various N-alkyl and N-aryl cyanoacetamides. Thus, treatment of 2-amino-6- methoxybenzothiazole 6 with 5 in boiling dry toluene resulted in the formation of the corresponding N-(6- methoxybenzothiazol-2-yl) cyanoacetamide 7 in 85% yields. 8,9,48

261 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

Me H MeO S NH MeO S N 2 N CN + Me N CN N N O O toluene

6 5 7 Scheme 6

N,N-Bis[2-oxo-3-oxazolidenyl]phosphorodiamidic Chloride Reagent

The reaction of cyanoacetic acid with aniline in boiling ethanol containing N, N− bis[2-oxo-3-oxazolidenyl] phosphorodiamidic chloride 8 and triethylamine furnished cyanoacetamide derivative 1a.10

O H NH2 HO N Et N CN + CN + ONP NO 3 O EtOH O Cl O O 8 1a Scheme 7

Typical Reactivity of Cyanoacetamide Derivatives

Cyanoacetamides are polyfunctional compounds possessing both electrophilic and nucleophilic properties. Typical nucleophilic positions are NH andC − 2 with reactivity order C-2 > NH. These chemical properties have been used to design diﬀerent heterocyclic moiety with diﬀerent ring sizes such as azirine, pyrrole, thiophene, pyrazole, imidazole, thiazole, thiadiazole, pyridine, pyrane, pyridazine, pyrimidine, and triazine. On the other hand, cyanoacetamide possesses electrophilic positions, especially at C −3,C−1 with reactivity order C3 > C1.

O R 2 CN N H 1 3

Reactions of Cyanoacetamide Derivatives

Synthesis of 3 Membered Ring with 1Hetero Atom

Azirine derivatives

Treatment of cyanoacetanilide 1a with hydroxylamine in the presence of sodium methoxide as a basic catalyst aﬀorded the oxime 9, which upon treating with p-toluene sulfonyl chloride, gave compound 10.In- tramolecular nucleophilic substitution of 10 in sodium methoxide furnished 3-amino-N-phenyl−1H−azirine- 2-carboxamide 11.11

262 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

CN CN H H N N NaOCH3 + NH2OH.HCl NOH O O

1a 9 O Cl S Me O N CN H H O N N O NH2 NaOMe N S -p-TsOH O O O Me 11 10

Scheme 8

Synthesis of 5 Membered Ring with 1Heteroatom

Pyrrole derivatives

Reaction of p-chlorocyanoacetanilide 1d with carbon disulﬁde in DMF and potassium hydroxide, followed by addition of methyl iodide, has been reported to aﬀord the ketene dithioacetals 12, which were transformed by the action of formamide into 4-amino-2-(methylsulfanyl)-5-oxo-N-phenyl-5H-pyrrole-3-carboxamide 13.12

CN CN H H N N SMe 1-KOH/DMF + CS2 2-MeI O O SMe Cl Cl 1d 12d

H2N H2N -N H O N O H

O SMe Cl 13 Scheme 9

Thiophene and its fused derivatives

The reaction of cyanoacetanilide 1a with phenyl isothiocyanate in DMF containing potassium hydroxide gave the non-isolable intermediate 14a, which underwent heterocyclization with 3-(2-bromoacetyl)-2H-chromen- 2-one 15 to give thiophene derivative 16.13

263 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

O O DMF NC R NC R + PhNCS N KOH N H H - +K S NHPh

1a 14a O Br O NH2 O O O S HN R O O 15 NHPh 16 Scheme 10

Condensation of 4-antipyrinylcyanoacetamide 1e with cyclohexanone in boiling ethanol containing a catalytic amount of piperidine aﬀorded arylidene derivative 17. Heterocyclization of 17 with elemental sulfur in warming ethanol containing a few drops of morpholine as a basic catalyst under Gewald reaction conditions aﬀorded the corresponding thiophene derivative 18.14

Me O Me H H Me N Me N N CN EtOH / pip. N CN + N O N O Ph O Ph O 1e 17

H2N Me S H Me N S / DMF N morpholine N O Ph O 18 Scheme 11

Huang and coworkers have reported a simple and convenient synthesis of thiophene derivatives via a solvent-free microwave assisted reaction. The microwave irradiation of cyanoacetamides 1c,f,g,h with cyclohexanone, sulfur, and aluminum oxide as a solid support in the presence of morpholine as a basic catalyst under solvent-free conditions for several minutes gave thiophene derivatives 19 in high yields.15 Reaction of substituted cyanoacetanilide derivatives 1 with carbon disulfide in boiling sodium ethoxide gave the sodium dithiolate salts 20. Compounds 20 are readily alkylated with phenacyl bromide to give the stable sodium salts of monoalkylthio derivatives 21. Acidification of 21 with hydrochloric acid gave the mercapto products 22. The sodium α-cyanoketene dithiolates 21 were cyclized on refluxing in sodium

264 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al., ethoxide to give the corresponding sodium thiophene thiolates 23, which were acidiﬁed with hydrochloric acid to give 2-mercaptothiophenes 24.16

O O O Ar Ar N morpholine /Al2O3 N H + + S H M.W/ 160W/ 10min CN S H2N 1c,f,g,h 19

19 Ar M.W yield%

a 4-MeO-C6H4 93

b 4-Me-C6H4 95

c 3-Cl-4-F-C 6H3 86

d 4-CF3-C6H4 84

Scheme 12

O O O NaS SNa H Br NaS S HS S N CS Ph Ph HCl Ph R CN 2 H N H H EtONa R CN EtONa N N O R CN R CN O O O 12120 22

EtONa

24 Ryield% HS NaS S O S O a C6H5 70 H H b 4-Cl-C6H4 80 N HCl N R Ph R Ph c 4-Me-C6H4 78

O NH2 O NH2 d 4-Br-C6H4 80 24 23 Scheme 13

Walser and coworkers have reported that treatment of 2-cyano−N−(2-nitrophenyl) acetamide 1b with 1,4-dithiane-2,5-diol in boiling ethanol containing a catalytic amount of triethylamine furnished 2-amino-N- (2-nitrophenyl)thiophene-3-carboxamide 25.5

S OH

O O HO S CN N EtOH / Et3N N H H NO NO2 2 S H2N 1b 25 Scheme 14

265 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

Synthesis of 5 Membered Ring with 2 Hetero Atoms

Pyrazole derivatives

Treatment of N-(2,4,6-trichlorophenyl) cyanoacetamide 1j with hydroxylamine in boiling ethanol containing a catalytic amount of sodium acetate furnished amidoxime 26. Acetylation of 26 with acetic anhydride aﬀorded o-acetyltion product 27. Thermal cyclization of 27 delivered 1,2,4-oxadiazole derivatives 28.Acid catalyzed rearrangement of 1,2,4-oxadiazole 28 led to the formation of pyrazolin-5-one derivative 29.17

R R OH R O Me NH NH N NH2OH.HCl Ac2O NH N CN EtOH/AcONa O O O NH2 O NH2

1j 26 27

R R NN NH N O H+ Me O NH2 O N 29 28

Scheme 15

The 1,3-dipolar cycloaddition of nitrile imine 31 (generated in situ from the treatment of hydrozonyl halide 30 with triethylamine) with cyanoacetanilide 1a furnished pyrazole derivative 32.18

O O O O H Ph O N 2 2 R Cl R N 2 Ph N N + H R EtOH CN N H H H NH N TEA N - 2 NH N N N R1 R1 R1 30 31 32 1 R =4-Cl-C6H4 2 R =4-CH3-C6H4

Scheme 16

The coupling reaction of 4-antipyrinyl diazonium chloride 33 with cyanoacetanilide 1a in ethanol buﬀered with sodium acetate gave the corresponding antipyrinyl hydrazone derivative 34, which upon treatment with a mixture of acetic acid and hydrochloric acid gave 3a,4,5,6-tetrahydro-3a,4-dimethyl-6- oxo−N,5-diphenylpyrazolo[4,3-c]pyrazole-3-carboxamide 35. The reaction mechanism for the formation of 35 involved the intramolecular addition of enamine to the azomethine group of 34, followed by elimination of HCN.19

266 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

O CN O CN H H H + - Ph N NCl N Ph N N N EtOH N N + N O AcONa N O Me Me Me Me 33 1a 34 O

Ph N N HCl ACOH N N Me Me O N H 35 Scheme 17

Reaction of cyanoacetamide 1a with carbon disulﬁde in DMF and potassium hydroxide, followed by alkylation with methyl iodide, gave dimethylsulfanyl acrylamide 12a. The reactivity of 12a towards nitrogen nucleophilies was reported. Treatment of 12a with aniline gave acrylamide 36 through Michael addition of the amino group to the ethylenic bond in 12a followed by elimination of methanethiol. The acrylamide 12a was converted to pyrazole derivative 37 (R1 = SMe) by treatment with hydrazine hydrate. Compound 37 (R1 = NHPh) could be also obtained via heating of 36 with hydrazine hydrate in ethanol.20

O O NC NC DMF/KOH + CS2 N N MeI H H MeS SMe 1a 12a

NH2.NH2.H2O PhNH2

R1 O O

NH NH H O NC N N 2. 2. 2 N H H HN NH2 MeS NHPh

37 36 R1 =SMe,NHPh Scheme 18

Heating of fluorosubstituted cyanoacetanilide derivatives 1k, l with aryl isothiocyanate in ethanolic potassium hydroxide gave the corresponding potassium 2-cyanoethylene-1-thiolate salts 14. The latter, on alkylation with methyl iodide, afforded keteneN, S−acetals 38. Reaction of compounds 38 with hydrazine hydrates in refluxing ethanol containing a catalytic amount of piperidine gave the corresponding pyrazole derivatives 39.21

267 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

SCN CN CN H H H N N N X KOH/EtOH O O SK R R X 1 14 39 RX yield% a 2-F H 78 b 4-F H 85 MeI c 4-F 2-F 80 d 2-F 4-Cl 79 X CN H H O N N NH2.NH2 R N H EtOH / O SMe N R X H2N N H 39 38 Scheme 19

Isothiazole derivatives

Elgemeie and coworkers have recently reported that the reaction of cyanoacetamide derivatives 1a, 1c, 1f with carbon disulﬁde containing sodium ethoxide gave the ketene dithioacetal derivatives 20.Heatingof 20 in ethanol with sulfur and piperidine acetate gave the corresponding disodium isothiazole-3,5-dithiolates 41, which were acidiﬁed with acetic acid to give the 3,5-disulfanylisothiazoles 42.22

H NaS SNa NaS S N Sx CS2 H / S H - R CN N N N EtONa R C N pip.acetate R O - O O S 1a,1c,1f 20 40

S HS S N NaS N H ACOH H N H2O N R SH R SNa O O

42 41 Scheme 20

Imidazole and its derivatives

Schmitz and coworkers have reported that the reaction of cyanoacetanilide 1a with 1-oxo-2-aza-spiro[2,5]octane 43 in boiling dry toluene containing sodium hydroxide as a basic catalyst gave the spiro imidazole derivative 44.23

268 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

H N NaOH + Ph Ph CN Toulene N NH O O HN O O NH2 NH2 1a 43 44

Scheme 21

The reaction of cyanoacetamide derivatives 1a, 12c with carbon disulﬁde and dimethyl sulfate in DMF containing potassium hydroxide gave the ketene S, S−dithioacetals 12a, c,which,ontreatment with bifunctional nucleophilic reagents such as ethylene diamine, o-phenylenediamine, 2-aminophenol, and 2-aminothiophenol gave the imidazole 45, benzimidazole 46a, benzoxazole 46b, and benzothiazole 46c derivatives.20,24,25.

O O NC NC DMF/KOH + CS2 N N (Me) SO H H 2 4 MeS SMe 1a 12a NH2

XH NH2(CH2)2NH2

O O NC N NC 46 x H N H a NH HN X b O HN NH c S

46 45 Scheme 22

Thiazole and its derivatives

Rad and coworkers have prepared the thiazolidin-4-one48 with high regioselectivity via the base catalyzed cyclocondensation of cyanoacetanilide 1a with diethyl 2-sulfanyl-1,4-butandioate 47 in boiling ethanol.26 In viewof the growing biological importance of fused thiazoles, and particularly of thiazolo[4,5- d]pyrimidines, it was considered of interest to synthesize 51. Thus, the reaction of 49 with sulfur and an appropriate aryl isothiocyanate in ethanol containing a catalytic amount of triethyl amine furnished thiazole derivatives 50. Heterocyclization of 50 with a mixture of triethylorthoformate and acetic anhydride delivered thiazolo[5,4-d]pyrimidine derivatives 51.27

269 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

EtO O O O O HN EtOH Ph CN + COOEt Ph COOEt N HS TEA N S H H 1a47 48

Scheme 23

Ar Ar CN N NH2 N N H ArNCS HC(OEt) N S H 3 S R S TEA N AC2O / N S R S R O O O 49 50 51

51 RAr a piperidino Ph b piperidino PhCH2 c piperidino Tolyl

Scheme 24

Cyclocondensation of cyanoacetanilide 1a with thioglycolic acid in boiling glacial acetic acid furnished the thiazolinone derivatives 52 in 95% yields. Formation of 52 is assumed to proceed via the initial nucleophilic addition of the mercapto function to the nitrile group, followed by intramolecular cyclization by the elimination of the water molecule to aﬀord 52. The thiazolinone 52 was condensed with aromatic aldehydes in boiling ethanol containing a catalytic amount of piperidine to give compounds 53.28,29

O OH O NH O

NC Ph HSCH2COOH Ph N S N H ACOH H 1a

-H2O

O O

N O N O Ph ArCHO Ph Ar S N EtOH /pip. S N H H 53 Ar = 4-Me-C6H4,4-MeO-C6H4 52 Scheme 25

The active methylene group in the cyanoacetamides 1a, 1e, 3a, 3b readily adds to isothiocyanate derivatives in DMF containing potassium hydroxide to give the non-isolable enaminonitrile 54,which underwent heterocyclization upon treatment with α-halocarbonyl compounds to give the corresponding thiazole derivatives 55 and 56.3,13,30−32

270 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

O O R1 CN R2NCS N R1 CN H N DMF/ KOH H R 2 N SK H 1a,1e,3a,3b 54

R COCH Br 55 R1 R2 R3 3 2 XCOCH2X a Ph Ph Ph X=Cl,Br b Ph PhCO Ph c antipyrine Ph Ph O O d Ph Ph R1 CN R1 CN O O N N H H 56 R1 R2 R R a Ph Ph 2 N S 2 N S Ph N Ph b R O S 3 N 55 56 c Ph S

Scheme 26

CN CN CN O H H H BrCH COOC H N CS2 N SNa 2 2 5 N S A Ar Ar r EtONa EtOH OEt O O NaS O NaS

1c,1f 20

+ ClCH2COOH H

CN O CN O H H N S N S Ar OH Ar OEt O NaS O HS 58

H+

CN O CN H H N S EtONa N S Ar OH Ar O HS O S 57 59 O Scheme 27

A novel and eﬃcient method for the synthesis of 1,3-dithiolan-2-ones 59 was recently reported by Elgemeie and coworkers. Thus, treatment of cyanoacetamides 1c, f with carbon disulﬁed and sodium ethoxide gave the corresponding ketene diothioacetals 20. Alkylation of 20 with chloroacetic acid furnished the

271 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al., monoalkylated product 57.When57 was reﬂuxed in ethanolic sodium ethoxide, it underwent heterocyclization to give the corresponding 1,3-dithiolane derivatives 59. Compound 59 can also be obtained by alkylation of the dithiolate 20 with ethyl bromoacetate, followed by heterocyclization of the resulting acyclic product 58.33

Synthesis of 5 Membered Ring with 3 Hetero Atoms

Thiadiazole derivatives

Dankova and coworkers have reported that cyanothioacetanilide 60 could be obtained by boiling 1a with

P4S10 in dioxane. Treatment of 60 with azidobenzenesulﬁte gave 5-anilino-1,2,3-thiadiazole-4-carbonitrile 61.Thiationof61 with hydrogen sulﬁde furnished 5-anilino-1,2,3-thiadiazole-4-carbothioamide 62.34,35

O S N CN P S PhSO N NC Ph 4 10 NC Ph 3 3 N N Dioxane N S Ph H H N H 1a 60 61 S

N NH2 H S N 2 S Ph N H 62

Scheme 28

Synthesis of 6 Membered Ring with 1Hetero Atom

Pyridine derivatives

The Friedlander cyclocondensation of 2-amino-4,6-dimethyl nicotinaldehyde 64 with cyanoacetamide derivatives 63 in boiling ethanol containing a catalytic amount of piperidine gave 1,8-naphthyridine derivatives 65.36

O Me O Me R OHC R N EtOH/pip N H + H CN H2N N Me H2N N N Me 63 64 65 R=Me,Et,n-Pr

Scheme 29

The Knoevengel condensation of N-benzyl-2-cyanoacetamide 4 with o-nitrobenzaldehyde 66 afforded cyanocinnamides 67. Reductive cyclization of 67 with iron in boiling acetic acid gave 2-amino- N-benzylquinoline-3-carboxamide 68.37

272 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

NO2 CN Ph N NO2 O OHC H CN EtOH/pip Ph N + H 4 66 67

O NH2

Ph N N H Fe/AcOH

68 Scheme 30

Treatment of cyanoacetamide derivative 63 with 2-formylcyclopentanone 69 in boiling ethanol afforded 2,5,6,7-tetrahydro-1-methyl-2-oxo-1H-cyclopenta[b] pyridine-3-carbonitrile 70.38

H NC NC O EtOH + TEA O NH O O N Me Me 63 69 70 Scheme 31

Taking the advantages of microwave irradiation such as short reaction times, the absence of solvent reduces the risk of explosion, simpliﬁes the workup and the products are high in yield and purity, which encouraged Mijin and coworkers to investigate the yields % of the reaction of 1 with acetylacetone. Thus, reﬂuxing of cyanoacetanilides 1 with acetylacetone furnished 4-substituted phenyl-4,6-dimethyl-3-cyano–2- pyridones 71.39

Me Me NC NC O M.W / 200 W /7min + piperidine O NH O Me O N Me R R 1 M.W conven.method 71 71 R yield% yield% a ph 96 75 b 4-MeO-C6H4 95 72 c 4-Me-C6H4 97 75 d 4-NO2-C6H4 84 64 Scheme 32

The cyclocondensation of cyanoacetamide derivatives 1 with β-diketones in boiling ethanol containing a catalytic amount of a base yielded pyridine-2-ones 72, 73,and74.40−42

273 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

HN O R 1 O O O O Me Me R R Me 2 1

EAA KOH

Me R1 R1 Me CN NC COOH

O Me N O KO N O R2 N R R R

74 73 72 R = Ph, 4-Me-Ph, 4-MeO-Ph R = Ph, R1 = Me R = Ph, R1 = R2 = Me

Scheme 33

The Michael addition of cyanoacetamides 1a, 1m to arylidene malononitrile in reﬂuxing ethanol containing a catalytic amount of triethylamine furnished the pyridinone derivatives 76.43,44

NH2 NC H NH H NC NC NC Ar + Ar EtOH Ar O NH TEA CN O N NH R1 O N N H R1 R1 1a,1m 73 76 75 76 R1 Ar a Ph 3-Pyridyl b Ph 2-furyl c 2-Pyridyl 3-Pyridyl d Ph Ph

Scheme 34

In addition, it has been reported that the pyridine-2-ones 78 and 79 were obtained via the treatment of cyanoacetamide derivatives 1a, 1e with acrylonitrile derivatives 77 in a basic medium. The reaction mechanism for the formation of 78 and 79 was assumed to proceed via the initial Michael addition of the activated methylene group to the double bond of the arylidene 77 to aﬀord the non-isolable Michael adduct, which cyclized to give pyridine-2-ones 78 and 79.30,45,46

274 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

The Knoevenagel condensation of (N-pyridyl)-2-cyanoacetamide 1m with benzaldehyde in refluxing ethanol containing a catalytic amount of piperidine resulted in the formation of (E) − N-pyridyl-2- cyanoacrylamide 80. The reaction of 80 as a Michael acceptor with malononitrile in boiling ethanol containing a fewdrops of piperidine afforded N-pyridylpyridinone derivative 81.47,48 Condensation of cyanoacetamide derivatives 82 with ketene dithioacetals 83 in DMF catalyzed by anhydrous potassium carbonate afforded pyridine-2–one derivatives 84.49,50

NC R3 EtOH TEA O N NH2 R NC R2 1 78 R3 + H O NH CN R2 R1 1a,1e 77 NC CN EtOH

O N NH2

R1 79

78 79 R R1 R2 R3 R1 R2 3 a PhPh CONHPh a antipyrine Ph CN b Ph p-MeOPh CONHPh b antipyrine p-Me Ph CN c antipyrine p-MeOPh CN S S d p-BrPh CN N An S S e N 2-thienyl CN An Scheme 35

O CN O CN N N EtOH pip. NH + OHC NH

1m 80

O CN N CH2(CN)2 N EtOH pip.

H2N CN

81 Scheme 36

Cyclocondensation of cyanoacetanilide 1a with ethyl 3-cyano-2-methyl-but-2-enate 85 in a basic medium gave pyridine-2,6-dione derivative 86. Reductive cyclization 86 with lithium aluminum hydride

275 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al., aﬀorded bispidine derivative 87.51 Treatment of cyanoacetanilide 1a with 2-(2-bromo-2-thiocyanate-1-phenyldiene)malononitrile 88 in a basic medium furnished pyridinone 89.52 The base catalyzed cyclocondensation of cyanoacetanilide 1a with 3,5-diphenyl-1,2-dithiolium per- chlorate 90 delivered the pyridinone derivative 91 in good yield.53

SMe NC SMe NC R2 R2 DMF + MeS O NH K2CO3 CN O N NH2 R1 R1 82 83 84

84 R1 R2

a O Me O NHCO b CN O Me

Scheme 37

Me Me NC Me NC CN CN NaOEt + Me O NH O N O COEt Ph Ph 1a 85 86

Me Me Ph 1-DMF N 2-LiAlH4 NH 87

Scheme 38

Ph NC Ph NC CN NaOEt + NCS CN O NH Br CN O N NH2 Ph Ph 1a 88 89

Scheme 39

276 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

Ph NC Ph O NC Ph NaOMe + + SH O NH Ph O Cl O MeOH S O N Ph O Ph 1a 90 91 Scheme 40

The monothiomalonamide 93 was prepared from the reaction of 2-cyano-N‘-phenylacetohydrazide 92 with hydrogen sulﬁde. Treatment of 93 with acetylacetone in reﬂuxing ethanol containing a catalytic amount of triethylamine gave pyridine-2-thione derivative 94.54

O O R R N pyridine N H + H2S H CN TEA H2N S 92 93 Me O R O O N H Me Me Me N S TEA 94 R=PhCH2CH2 Scheme 41

The one-pot reaction of cyanoacetanilide 1a, 4-chlorobenzaldehyde, cyanothioacetamide 95,and methyl iodide in boiling ethanol in the presence of piperidine gave the isolable intermediate ketene N, S-acetal 96, which underwent heterocyclization upon prolonged heating to give the pyridine derivative 97.55

O Ar O CN Ph CN Ph MeI / EtOH N N ++ArCHO H H piperidine CN H N S CN 2 H2N SMe 1a 95 96 O Ar Ph CN N H

H2N N SMe

97 Ar = 4-Cl-C6H4 Scheme 42

Heating of 1a with malononitrile dimer under solvent-free conditions gave the pyridine derivative 98, which could also be obtained when 1a was heated with 2 moles of malononitrile in boiling ethanol containing a fewdrops of triethyl amine. 56

277 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

NH2 O NH2 NC CN NC CN O Ph CN + N 150 oC Ph H N N NH2 CN H 1a 98 Scheme 43

Enaminonitriles 100 were prepared in 75% yields from the reaction of cyanoacetamide derivatives 1a, 4, and 3,4-dihydro-5-methoxy-2H-pyrrole 99 in a basic medium. Treatment of 100 with dimethylformamide dimethylacetal (DMF-DMA) in boiling dry toluene furnished pyrrolo[2,3−c]pyridinone derivatives 101.57

R R NH NH NaOMe + O MeO N O N H CN CN 1a,4 99 100 R N DMF-DMA O N toluene H CN

101 Scheme 44

Pyrane derivatives

El-Taweel et al. have reported that heating of cyanoacetamide derivative 102 with enaminone 103 in boiling ethanol containing a fewdrops of acetic acid delivered α-pyrone derivatives 104.46

O S O H R2 N N NC NS Me EtOH H + R3 N O ACOH Me R3 O O An 102 103 104 S

R2 = An=antipyrine R3 = NS O O An Scheme 45

The interaction of an equimolar amounts of pyridoxal hydrochloride 105 with cyanoacetanilides 1a, 1c in reﬂuxing absolute methanol containing a catalytic amount of piperidine aﬀorded the 2-H-pyrano[2,3-c] pyridine 107. The reaction mechanism proceeds smoothly via the formation of the non-isolable intermediate 106. 5-Hydroxymethyl-2-imino-8-methyl-2H-pyrano[2,3−c]pyridine-3-carboxamide 107 can readily react with nucleophilic reagents such as aromatic amines in boiling acetic acid to give the N-arylimino- pyrano[2,3−c]pyridine derivatives 108.58

278 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

OH OH H O O R R O piperidine N + H N + - NH Cl CN N H HO CN HO Me Me 1a,1c 105 106

OH OH O O R R

N PhNH2 N H H Ph N AcOH N N O HN O H Me Me 108 107 Scheme 46

Six Membered Ring with 2 Hetero Atoms

Pyridazine derivatives

Elrady and coworkers have recently reported a convenient and facile synthesis of pyridazine 112 and pyridindione 113 derivatives via the reaction of cyanoactamide derivatives 1f, 109 with ethyl 2-arylhydrazono-3- butyrates 110 in a boiling mixture of benzene/acetic acid. The key precursor for the products is the expected Knoevnagel condensation intermediate 111. Elimination of the ethanol molecule yielded the isolable intermediate pyridindione 113, while an intramolecular cycloaddition of hydrazohydrogen to the cyano group aﬀorded the pyridazine derivative 112.59

Me NC Me NC N Ar N Ar PhH N + H O N AcOH O NH H CO2Et CO2Et O NH R R 1f,109 110 111

112, 113 R Ar a 4-Me-ph phenyl b 2-thiazolyl 4-MeO-C6H4 Me O Me

NC N Ar CO2Et N RHN H N O N O HN N R Ar 113 112 Scheme 47

279 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

Pyrimidine derivatives

The interaction of cyanoacetanilide 1a with ethyl 2-amino-3-ethoxycarbonylthiophenes carboxylate 114 in boiling pyridine gave the dihydrothieno [2,3-d]pyrimidinones 115.60,61

R O R 1 1 CO2Et O pyridine NH O + NC Ph N R2 R2 NH2 Ph S H S N N H 114 1a 115 R1 =Ph,Me R2 =H,Me

Scheme 48

Cyclocondensation of cyanoacetanilide 1a and 2-aminopiperonal 116 in reﬂuxing ethanol gave the corresponding quinoline derivative 117. The reaction mechanism for the formation of 117 involves the formation of a non-isolable arylidene intermediate, followed by an intramolecular addition of the amino group to the nitrile function. Compound 117 was transformed to 118 by heating with a mixture of triethylorthoformate and acetic acid.62

O O CHO O Ph O Ph Et OH N + N H H O O NH2 CN N NH2 116 1a 117 O

O Ph N HC(OEt)3 (AC)2O O N N 118

Scheme 49

Reaction of 4-antipyrinylcyanoacetamide 1e with DMF-DMA in boiling dry xylene aﬀorded the corresponding enaminonitrile derivative 119 in good yield. Treatment of the enaminonitrile 119 with 5- phenyl-3-aminopyrazole in boiling DMF containing a catalytic amount of piperidine resulted in the formation of pyrazolo[1,5-a]pyrimidine derivative 120.30

280 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

Me Me Me Me MeO Me N O xylene N O + N N CN MeO Me N CN Ph N Ph N H H O O NMe 1ePh 119 2 Me Me N O N NH2 N N N Ph N N H H Ph O H2N N 120 Scheme 50

Heterocyclization of N-(benzothiazol-2-yl)cyanoacetamide 3b with triethylorthoformate in boiling nitrobenzene furnished 2-oxo-2H-pyrimido[3,1-b]benzothiazole-3-carbonitrile 121 in 79% good yield.8

H S N O S N O PhNO2 + HC(OEt)3 N 200 oC/3 h N CN CN 3b 121 Scheme 51

Thiazine derivatives

Kandeel and coworkers have reported that treatment of cyanoacetanilide 1a with 2-sulfanyl benzoic acid 122 in boiling acetic acid delivered 2-(4-oxo-4H-benzo[e][1,3]thiazin-2-yl)-N-phenylacetamide 123.63

O O O OH NC Ph AcOH N O + N H Ph SH S N H 1221a 123

Scheme 52

Liepa et al. have synthesized 2-(5,6-dihydro-4,4-dimethyl-4H-1,3-thian-2-yl)-N−(2- triﬂuoromethoxy) phenylacetamide 125 via the treatment of 2-triﬂuoromethoxy cyanoacetanilide 1n with 4-sulfanyl-2-methyl- butan-2-ol 124 in methane sulfonic acid.64

OCF3 HS OCF3 H H N N S CN MeSO H + HO 3 O Me Me O N Me Me 1n 124 125 Scheme 53

281 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

Six Membered Ring with 3 Hetero Atoms

Triazine derivatives

The diazo coupling reaction of the active methylene of cyanoacetanilide 1a with pyrazolyl diazonium chloride 126 in ethanol buﬀered with sodium acetate, at 0-5 ◦C, gave the corresponding hydrazone derivative 127. Cyclization of 127 into pyrazolo[5,1-c]triazine 128 was achieved upon reﬂuxing in acetic acid. The reaction mechanism for the formation of 128 involves the nucleophilic attack of the ring nitrogen atom on the cyano group in 127.30,65,66

+ - N Cl N H N N N N Ph N N Ph AcONa N NC Ph + H2N H H N NH EtOH NH N O 2 N N NC Ph O 1a 126 127 N N Ph N N H2N H N N AcOH N Ph

NH2 O 128

Scheme 54

Biological Activities

Cyanoacetamide derivatives and related heterocycles moieties have generated recent interest due to their interesting biological67−69 and pharmaceutical51,60,70 activities. These derivatives have anti-microbial58 activities and have been found useful as herbicidals71 and plant growth regulators;40 in addition, they have been reported to be active against neoplastic disorder.72 Furthermore, these derivatives have been used as kynurenine-3-hydroxykase inhibitors.73,74 They have also been used for their anti-inﬂammatory,72 anti-viral,14 anti-bacterial,76,77 anti-tumor,78 neoplasm inhibitory,79 tyrosine kinase inhibitory,80 and analgesic properties,81 and for the treatment of disorders related to vasculogenesis.82

Conclusion

The present survey has clearly demonstrated that cyanoacetamide may be successfully used to synthesize a wide variety of heterocycles of academic and pharmaceutical interest. Moreover, in general, the desired compounds may be obtained in a single step with high yield.

282 Cyanoacetamide Derivatives as Synthons in..., A. A. FADDA, et al.,

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