Russian Chemical Reviews 68 (9) 737 ± 763 (1999) Cyanoacetamides and their thio- and selenocarbonyl analogues as promising reagents for fine organic synthesis V P Litvinov Contents I. Introduction II. Synthesis of cyanoacetamides, their thio- and selenocarbonyl analogues and aryl- and hetarylmethylidene derivatives III. The use of cyanoacetamides and their thio- and selenocarbonyl analogues in the synthesis of heterocyclic compounds IV. Conclusion Abstract. Published data on the use of cyanoacetamides, cyano- thio- and -selenoacetamides in fine organic synthesis and the prospects of application of these compounds in combinatorial synthesis are analysed and generalised. The bibliography includes 653 references. I. Introduction Cyanoacetic acid derivatives are important intermediates for preparation of various organic and, especially, heterocyclic compounds possessing diverse biological activities and many other practically useful properties.In this group of compounds, cyanoacetamides and their thio- and selenocarbonyl analogues are of particular interest as very promising reagents for cascade heterocyclisation, which will undoubtedly become one of the main approaches to the targeted synthesis of heterocycles in the near future, and for combinatorial chemistry experiencing nowadays a sharp rise (see, for example, Refs 1 ± 26). This new methodology based on automatic, high-tech synthetic methods enables syn- thesis of a large number (up to several thousand) of novel organic compounds as subjects for biological screening.The present review systematises for the first time published data on the reactivity of cyanoacetamides and their thio- and selenocarbonyl analogues (for selected aspects of the chemistry of these compounds, see reviews 27 ± 34). The presence of several reactive centres in the molecules of these reagents provides ample opportunities to synthesise a great variety of novel compounds under relatively mild conditions and using rather simple labora- tory equipment. Syntheses of many polyfunctional heterocyclic compounds, including those prepared by multicomponent con- densations, are based on cyanoacetamides and their S- and Se- containing analogues. The reactions involving these reagents occur, as a rule, with high regioselectivity (often, stereoselec- tively) and their course can easily be controlled by changing reaction conditions and varying substituents in the molecules of initial compounds.All this makes cyanoacetamides and their S- and Se-analogues very useful reagents for combinatorial synthesis aimed at the design of novel biologically active compounds with a targeted mode of action. V P Litvinov N D Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 117913 Moscow, Russian Federation. Fax (7-095) 135 53 28. Tel. (7-095) 135 88 37. E-mail: vpl@carc.ioc.ac.ru Received 13 May 1999 Uspekhi Khimii 68 (9) 817 ± 844 (1999); translated by S V Chapyshev #1999 Russian Academy of Sciences and Turpion Ltd UDC 547.7/8 737 737 738 755 The present review aims to demonstrate the synthetic poten- tial of cyanoacetamides in the synthesis of novel heterocyclic compounds. Primary attention is paid to the methods for preparation of the final products and much less to mechanistic aspects of the reactions surveyed. The structures of the feasible intermediates are considered only in the most synthetically important reactions.II. Synthesis of cyanoacetamides, their thio- and selenocarbonyl analogues and aryl- and hetarylmethylidene derivatives Cyanoacetamide (1a) can readily be obtained by several methods, viz., using the reactions of cyanoacetates (2) with ammonia,35 of cyanoacetic acid (3) with NH4OH36 and of chloroacetamide (4) with NaCN.37 EtOH BuOH TsOH NCCH2COOR+NH3 2 NCCH2COOH+NH4OH 3 NCCH2C(O)NH2 1a ClCH2C(O)NH2+NaCN 4 There are several methods for the preparation of cyanothio- acetamide (1b), viz., treatment of an ethanolic solution of malononitrile with H2S in the presence of triethylamine 38 ± 41 or triethanolamine,42, 43 the reaction of cyanoacetamide (1a) with phosphorus pentasulfide in pyridine or ethyl acetate 44 ± 46 (the yield in the latter reaction does not exceed 36%), and the reaction of 1-ethoxyethylidenemalononitrile (6) with H2S in ethanol.39 B CH2(CN)2+H2S 5 NCCH2C(S)NH2 1b NCCH2C(O)NH2+P2S5 1a EtO(Me)C C(CN)2+H2S 6 B=Et3N, (HOCH2CH2)3N.Cyanoselenoacetamide (1c) was synthesised for the first time in 1985 by the reaction of malononitrile with H2Se in diethyl ether in the presence of triethylamine at 5 8C under argon in 75% yield.47738 Et3N NCCH2C(Se)NH2 1c CH2(CN)2+H2Se 5 Aryl- and hetarylmethylidene cyanoacetamides 7 are also promising reagents for the synthesis of functionally substituted heterocycles.These compounds are obtained by the reactions of aromatic or heteroaromatic aldehydes 8 with amides 1a ± c in the presence of organic bases, under argon in the case of cyanosele- noacetamide (1c).39, 44, 45, 48 ± 56 Thioamides 7b can also be pre- pared by the reactions of arylmethylidenemalononitriles 9 with H2S.48 In some cases, amides 7b (R=Ph, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-NO2C6H4) readily undergo spontaneous [2+4]- cycloaddition to give 3,4-dihydro-2H-thiopyrans 10.48 RCHO +NCCH2C(X)NH2 8 C(X)NH2 1a ± c B CN RCH 7a ± c CN RCH + H2S CN 9 R=Ar, Het; X=O (a), S (b), Se (c).C6H4Y-4 NC C(S)NH2 CN 4-YC6H4CH H2N(S)C CN R NH2 S 10 Y=H, F, Cl, Br, NO2. 1-[(4-Alkoxycarbonylphenyl)pyrrolidin-3-ylidene]cyanothio- acetamide (11) has been obtained by the reaction of pyrrolidone 12 with cyanothioacetamide (1b). The reaction of the same reactants in the presence of b-alanine with azeotropic distillation of water from the reaction mixture results in tetrahydrothieno- [2,3-b]pyrrole 13.57 NC C(S)NH2 1b B N O C6H4COOAlk-4 11 CN N NH2 C6H4COOAlk-4 1b S 12 H2N(CH2)2COOH NC6H4COOAlk-4 13 Cycloalkylidenecyanothioacetamides 14 were synthesised in a similar way.58 NC O C(S)NH2 1b (H2C)n (H2C)n B 14 n=1, 2.Some other reactions involving the methylene group of cyanothioacetamide (1b) are known. Thus the condensation of this amide with nitroso-arenes affords the corresponding arylimi- nocyanothioacetamides 1533 and the reaction with aryldiazonium salts affords compounds 16.59 The latter were used in the synthesis of thiazolidin-3-one and pyrimidine-2-thione derivatives.59 C(S)NH2 ArNO ArN CN 15 NCCH2C(S)NH2 + C(S)NH2 1b ArN2Cl7 ArNHN CN 16 V P Litvinov Cyanoacetamide 1b adds unsaturated compounds. Thus its reaction with 3b-acetoxy pregna-5,16-dien-20-one (17) in the presence of sodium ethoxide involves the double bond of the ring D yielding (3b-hydroxy-20-oxopregn-5-en-16a-yl)cyanothio- acetamide (18).60 ± 62 Ac 1b EtONa, D 17 RO Ac CH(CN)C(S)NH2 RO 18 R=H, Ac.Arylmethylidenecyanothioacetamides 7b are alkylated with methyl iodide to give the corresponding methyl thioimidates 19, which can be used in the synthesis of heterocyclic systems.63, 64 CN CN MeI ArCH ArCH EtONa NH C(SMe) C(S)NH2 19 7b III. The use of cyanoacetamides and their thio- and selenocarbonyl analogues in the synthesis of heterocyclic compounds Owing to the presence of several highly reactive centres, first of all, the methylene and carbonyl or thio(seleno)carbonyl groups, cyanoacetamides have found wide use in the synthesis of diverse five- and six-membered heterocycles and their annelated ana- logues.All reactions in this Section are systematised in accord with the size of the heterocycle, while each Subsection deals with a certain type of the reacting substrates. 1. Synthesis of five-membered heterocycles a. Five-membered heterocycles with one heteroatom in the ring Reactions of the a-mercapto carbonyl compounds 20 with nitriles that contain an active methylene group, including cyanoacet- amide (1a), in the presence of bases at room temperature afford 2-aminothiophenes 21 in good yields (the Gewald reaction).65 ± 74 The first stage of these reactions presumably involves the condensation of a nitrile with the carbonyl group of compounds 20 (the Knoevenagel-like reaction) and formation of 4-mercapto nitriles (path a) the structures of which are suitable for intra- molecular cyclisation. However, two other possible mechanisms involving the initial nucleophilic attack on the cyano group by thiolate (path b) and the concerted cyclocondensation (path c) cannot also be excluded from consideration.Z R2 H Nu O R2 a CHZ C R1 SH R1 SH CN N 20 Nu H O R2 O R2 CH2Z b Z C S R1 S R1 N H Nu O R2 c NHHCHZ C SH R1 NCyanoacetamides and their thio- and selenocarbonyl analogues as promising reagents for fine organic synthesis Z R2 Z R2 R1 NH R1 NH2 S S 21 R1, R2=H, Alk, Ar; Z=CN, CO2R3, CONH2, COAr, 4-NO2C6H4SO2R4; R3, R4=H, Alk, Ar. The use of dimeric 2,5-dihydroxy-1,4-dithianes 73 instead of the a-mercapto carbonyl compounds 20 in the reactions with amides 1a,b and other CH acids essentially simplifies the synthesis of substituted 2-aminothiophenes 21.A yet more efficient version of the Gewald reaction consists in the use of a mixture of a carbonyl compound 22 (aldehyde, ketone or b-dicarbonyl compound) and sulfur in the presence of an organic base in ethanol or DMF instead of the a-mercapto carbonyl compounds 20. This method results in higher yields of 2-aminothiophenes 21.66, 68, 69, 73 ± 77 B 21 R1CH2COR2+NCCH2Z+S8 22 Treatment of cyanothioacetamide (1b) or its N-aryl deriva- tives with sulfur in the presence of bases affords 2,5-diaminothio- phenes 23 78 or 24.79 NC C(S)NH2 R=H NH2 H2N S8, B S 23 NCCH2C(S)NHR NC C(S)NHAr R=Ar ArHN NH2 S 24 Heating of solutions of equimolar amounts of 2-cyano- methylbenzothiazole (25a) or 2-cyanomethyl-1H-benzoimida- zole (25b) and sulfur in dry DMF in the presence of a base affords 3,5-diamino-4-[benzothiazol(or imidazol)-2-yl]-2-cyano- thiophenes 26a,b in 61%± 64% yields.80 H2N CN N N 1a, S8 CH2CN Et3N, DMF S X X 25a,b H2N 26a,b X = S (a), NH (b).Treatment of a mixture of cyanothioacetamide (1b) and cyclic ketones 27 with sulfur in the presence of a base gives rise to thieno[2,3-d]pyrimidine-4-thiones 28. Compounds 29 are assumed to be the intermediates of this reaction.78 C(S)NH2 O 27 1b, S8 (H2C)n (H2C)n NH2 B 27 S29 S NH (H2C)n S (CH2)n NH 28 n=2, 3. A series of thiophene derivatives 30 ± 32 has been obtained by the reactions of cyanothioacetamide (1b) with ethyl 3-chloro-2,4- dioxopentanoate (33)81 or ethyl bromopyruvate (34).82 In ethanol in the presence of a base, the reaction of the amide 1b with compound 33 involves its acetyl group, whereas the reaction of the same compounds in a mixture of pyridine and acetic acid involves 739 the a-carbonyl group of compound 33 and results in ethyl 5-acetyl-2-amino-3-cyanothiophene-4-carboxylate (31).81 Me CN EtOH, D EtO2C(O)C NH2 1b S 30 MeCOCH(Cl)COCO2Et 33 CN EtO2C Py, AcOH Ac NH2 S 31 The course of the reaction of the amide 1b with ethyl bromopyruvate (34) also depends on the solvent.Thus the reaction of these compounds in a mixture of pyridine and acetic acid results in ethyl 2-amino-3-cyanothiophene-4-carboxylate (32), whereas ethyl 2-cyanomethylthiazole-4-carboxylate (35) is formed in DMF.81 CN EtO2C 1b, B, EtOH NH2 S 32 BrCH2COCO2Et 34 EtO2C N 1b, DMF D CH2CN S 35 The use of pyridinium ylides in reactions with nitriles containing the activated methylene group has led to the creation, in recent years, of methods of regio- and stereoselective synthesis of partially hydrogenated five-membered heterocycles.83 ± 91 The course of the reactions of pyridinium ylides 36 (prepared in situ by treatment of the corresponding pyridinium salts with an equimolar amount of triethylamine) with aryl- or hetarylmethyli- dene cyanothioacetamides 7b depends on the temperature.Thus the condensations of these compounds at 20 8C follow the AdN-E1,6 mechanism to yield stereoselectively substituted 3,4- trans-1,2,3,4-tetrahydropyridines 37, whereas the reactions of these compounds under reflux follow the AdN-E1,5 mechanism and give rise to 2,3-dihydrothiophenes 38.83 ± 89 Ar R1=Ph + CN 20 8C R2 S7 R2 C(S)NH2 NH +ArCH NH HOPh37 CN N + CN Ar 7b 7CHCOR1 D 36 R1CO NH2 S 38 Ar=4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-MeOC6H4, ; N ; R2=H, Br.R1=Ph, Compounds 38 were also obtained by a three-component condensation of pyridinium ylide 36 (R1=1-adamantyl) with aromatic or heteroaromatic aldehydes and cyanothioacetamide (1b).83, 84, 87, 88 A novel stereoselective method for the preparation of trans- dihydrothiophenes 38 and trans-dihydrofurans 39 has been developed based on the three-component condensation of ylides 40 with aldehydes and amides 1a,b in ethanol in the presence of triethylamine.89740 Et3N + NCCH2C(X)NH2 + ArCHO + EtOH 1a,b N N 7CHCOR 40 CN Ar RCO NH2 X 38, 39 R=MeO, Ph; Ar=2-MeOC6H4, 4-FC6H4, , N N ; X = S (38), O (39).Functionally substituted trans-dihydrothiophenes 38 have also been obtained by the reactions of arylmethylidenecyano- thioacetamides 7b with stabilised sulfonium ylides generated in situ from bromides 41. Cyclopropanethiocarboxamides 42 were found to be the minor products of these reactions.92, 93 + Et3N MeOH Me2SCH2COR Br7+7b 41 NC C(S)NH2 CN Ar + COR Ar RCO NH2 S 42 (11% ± 24%) 38 (19% ± 70%) ; R=Ph, S Ar=2-MeC6H4, 2-NO2C6H4, 4-MeOC6H4, , .N S First publications on the use of the Gewald reaction in the synthesis of sulfur-, selenium- and tellurium-containing five- membered heterocycles have appeared recently.65 ± 74 Com- pounds 43 ± 45 were prepared in 60% ±85% yields by treating mixtures of ethyl cyanoacetate (cyanoacetamide, malononitrile) and isothiocyanates, cyclohexanone or camphor with sulfur, selenium or tellurium. It has been found that ultrasound or microwave irradiation considerably accelerate these reac- tions.94, 95 Y X NR RN C S+YCH2CN Et3N, DMF S H2N X 43 Y O X +YCH2CN NH2 Et3N, DMF X 44 Me Me Y O X +YCH2CN NH2 Et3N, DMF X 45 R=Ph, PhCO, CH2=CHCH2, ButCO; X=S, Se, Te; Y=CO2Et, CONH2, CN.The addition of cyanoacetamide (1a) to 1,1-diphenylethylene in acetic acid in the presence of Mn(OAc)3 results in a complex mixture of amides 46 and 47, lactones 48 ± 50, lactam 51 and benzophenone.96 1a, Mn(OAc)3 Ph2C CH2 Ph2CHCH(OAc) C(CN)C(O)NH2+ AcOH 46 (22%) O O NC H2N(O)C Ph2C(OAc)CH2CHCN + + + O O + 47 (3%) C(O)NH2 Ph Ph Ph 48 (15%) Ph 49 (2%) V P Litvinov O O CH CH Ph2C Ph2C NC NH + Ph2CO NC O + + (2%) Ph Ph Ph Ph 50 (3%) 51 (5%) A new approach to the synthesis of substituted pyrrolinone derivatives has been developed using the Knoevenagel condensa- tion of a-hydroxy ketones 52 with substituted cyanoacetamides aimed at comparing biological activities of oxygen- and nitrogen- containing five-membered heterocycles.These reactions occur via iminolactams 53, which are readily converted into the correspond- ing pyrrolinones 54 under the reaction conditions.97 R1MeC(OH)Ac+NCCH2C(O)NHR2 52 C(O)NHR2 C(O)NHR2 Me Me Me Me O NH O R1 R1 NH 54 53 R1=Alk, CH2=CHCH2, Bn; R2=H, Alk, Bn, Het. The condensation of cyanothioacetamide (1b) with diethyl oxalate results in 4-cyano-5-thioxopyrrolidine-2,3-dione (55). The latter reacts with arylmethylidene malonates yielding pyrroli- dino[1,2-b]-1,3-thiazine-5,6-diones 56.42, 43, 98 (CO2Et)2+NCCH2C(S)NH2 1b O CN Z CN O ArCH O CN S N S O NH NH2 Ar Z 55 56 Z=CN, C(S)NH2, CO2Et. The reactions of amide 1b with maleic anhydride or N-(2- chlorophenyl)maleimide afford pyrrolidine (57) or pyrrolo- [3,2-b]pyrrole (58) derivatives.99 NC CH2CO2H 1b OH S O O N O 57 NH 1b S O O O N N CN 2-ClC6H4 C6H4Cl-2 58 2,3,6-Trimethylbenzoquinone (59) reacts with cyanoaceta- mide (1a) in the presence of sodium methoxide yielding 5-hydroxy-4,6,7-trimethyl-3-cyanoindolin-2-one (60).100, 101 Me Me CN HO O 1a, MeONa O NH Me Me O Me Me 59 60 (78%) Polysubstituted phthalimide 61 has been obtained by conden- sation of methyl acetylenedicarboxylate with the amide 1a in the presence of Cu2(OAc)4 in dioxane.102Cyanoacetamides and their thio- and selenocarbonyl analogues as promising reagents for fine organic synthesis NH2 O MeO2C 1a, Cu2(OAc)4 NH MeO2CC CCO2Me MeO2C O CO2Me 61 (16%) Cyanoacetamide (1a) has been used as the starting material in the synthesis of dye 62.The cyclocondensation of phthalonitrile with the amide 1a was carried out in methanol in the presence of NaOMe and then the reaction mixture was treated with barbituric acid at 65 8C.103, 104 C(CN)C(O)NH2 CN a, b NH CN O O NH HN 62 (96.5%) O OC NH ( H a) 1a, MeONa, MeOH; (b) , 2C CO658C. OC NH The reaction of enamino ketone of the indoline series 63 with the amide 1a (refluxing in benzene in the presence of triethyl- amine) gives rise to 3-amino-2-carbamoyl-9-oxopyrrolo[1,2- a]indole 64.105 O O 1a, Et3N CHNMe2 PhH, D, 6 h N CONH2 NH 63 64 (14%) NH2 A series of pyrrolothiolates has been synthesised by reaction of the amide 1a with sulfur in the presence of catalytic amount of diethylamine.106 b. Five-membered heterocycles with two heteroatoms in the ring Cyanoacetamides and their chalcogen analogues have been successfully used in syntheses of five-membered heterocycles with two heteroatoms in the ring: thiazoles, isothiazoles, thiazo- linones, oxazoles, pyrazoles, imidazoles, dithioles, etc. Thus the condensation of cyanothioacetamide (1b) with a-halogeno carbonyl compounds involving their methylene group has been employed in the synthesis of 2-thiazolylacetoni- triles 65 as well as thiazolylthiones and other five-membered heterocycles.34, 59, 80, 81, 107 R N 1b HalCH2COR CH2CN S 65 R=Alk, Ar, CO2Et.Thiazole derivatives 66 were synthesised by the reaction of 2-acetyl-2-cyanothioacetamide 67 (prepared by the acetylation of the amide 1b) with ethyl bromoacetate or 1-chloroacetonitrile in good yields.108 R BrCH2CO2Et N 67 CH(CN)Ac S ClCH2CN 66 R=OH, NH2.3-(Bromoacetyl)coumarins 68 react with activated thioamides 69 on heating in ethanol to give substituted thiazoles 70 in yields of up to 93%.109 741 S X R1 R1 COCH2Br N +H2NC(S)X 69 O O O O R2 R2 70 68 R1=R2=H;R1±R2= ;R1=7-NEt2, R2=H; X=CH2CN, NH2, NHNH2, C(S)NMe2. The reaction of the pregnenolone derivative 18 containing the cyanothioacetamide fragment with phenacyl bromide was employed for the synthesis of thiazolyl-substituted steroids 71 (yields 85%± 97%).60, 62, 110 Ac 4-XC6H4COCH2Br CH(CN)C(S)NH2 KOH, EtOH 18 RO Ac C6H4X-4 N CH(CN) S 71 HO R =Alk; X=H, Cl, Br. Cyanothioacetamide (1b) reacts with sulfur and isothiocya- nates in the presence of bases yielding thiazoline-2-thione deriva- tives 72.The latter are cyclised on treatment with formic acid to give thiazolo[4,5-d]pyrimidine-2,7-dithiones 73.78 Similar reaction of the amide 1b with sulfur and hydrogen sulfide affords 1,2- dithiol-3-thione derivative 74, which is converted into 5-amino-4- cyano-1,2-dithiol-3-thione (75) on treatment with formic acid rather than undergoes cyclisation.78 H2N N NR RNCS, S8 HCOOH NR S EtONa HN S H2N(S)C S S 72 S 73 1b S S NC H2N(S)C CS2, S8 HCOOH EtONa S S H2N H2N S 74 S 75 R=Me, Ph, CH2=CHCH2. Reactions of the amide 1a and its derivatives with isothiocya- nates have also been employed in the synthesis of other substituted thiazoles.111, 112 Thiazolyl-substituted acrylonitriles 76 can be prepared in two ways.The first one is the reaction of phenacyl bromide with salts 77. The latter are obtained by the reaction of Meldrum's acid (78) with aromatic aldehydes and cyanothioacetamide (1b) or with arylmethylidenecyanothioacetamides 7b (ethanol, 20 ± 25 8C, equimolar amount of the secondary amine). The second method of preparation of acrylonitriles 76 is based on the reaction of phenacyl bromide with amides 7b.113 ± 117 Ar O Ph CHCHC(S)NH2 Ar N O 7 +PhCOCH2Br CN Me + CN S O O H2NR1R2 Me 76 77V P Litvinov 742 O O 1b The condensation of the amide 1a with CS2 in the presence of KOH results in 3,5-dimercaptoisothiazole-4-carboxamide 85.125 KS CN +ArCHO Me MeI KOH O O Me NHR1R2 KS NCCH2C(O)NH2+CS2 1a C(O)NH2 78 77 C(S)NH2 SH H2N(O)C CN MeS S8 78 +ArCH CN 7b N MeS C(O)NH2 HS S 85 C(S)NH2 76 ArCH +PhCOCH2Br CN 7b 5-Amino-3-methyl-4-cyanoisothiazole (87) has been synthes- ised by the reaction of the amide 1b with methyl dithioacetate (86).126 EtOK MeI KSC CC(S)NH2 HCl EtOH Thiazolinone 79 was obtained by the reaction of cyanoacet- amide (1a) with mercaptoacetic acid or its ester.118, 119 This compound can also be synthesised from cyanothioacetamide (1b) and ethyl chloroacetate.120 MeC(S)SMe +NCCH2C(S)NH2 86 1b Me CN 1a, Et3N Me NC HSCH2CO2R O AcOH 1) NH3 2) H2O MeSC CC(S)NH2 N N Me CN H2N CH2C(O)NH2 1b S ClCH2CO2Et S 87 79 R=H, Alk.Thiazole derivatives 80 and 81 also have been synthesised using the amide (1b).81, 82, 109 Ar N-Substituted cyanothioacetamides 88 were prepared from ethyl cyanoacetates and aryl isothiocyanates,127 their reactions with hydrazines 89 yielded 5-amino-3-arylaminopyrazoles 90.128 The analogous reaction of the amide 1a with hydrazonoyl chloride 91 afforded 5-amino-1,3-diphenylpyrazole-4-carboxamide.129 N 1b NHR1 ArCOCH2Hal CH2CN POCl3, DMF EtOH S N 80 H2N 7H2S R1NHC(S)CH2CN+H2NNHR2 89 88 NR2 90 EtO2C 1b N R1=Ar; R2=H, Ar. DMF BrCH2COCO2Et 34 H2NCO Ph H2N CH2CN S 1a Ph(Cl)C NNHPh 81 N H2N 91 NPh Cyanoacetamide derivatives 92 on heating with hydrazine give pyrazoles 93, while their reactions with mercaptoacetic acid result in thiazolinones 94.130 N ArN NH2 NH2NH2 4-Thiazoline-2-thione derivatives 82 were obtained by the reaction of cyanoacetamide (1a) with isothiocyanates in the presence of elemental sulfur.121 The reaction of the same amide with 2-mercaptoaniline gives 2-carbamoylmethylbenzothiazole (83a).122 The latter is employed in light- and waterproof azo- dyes used in polycaprolactam manufacture.Benzooxazole 83b is obtained in a similar way from the amide 1a and 2-aminophe- nol.123 N HO H2N(O)C 1a, S8 NH 93 NR RN C S O S H2N ArNHN C(CN)C(O)NH2 92 H2NCO N S 82 HSCH2CO2H ArNHN C R=Ar, Alk. S 94 NH2 N 1a Ar=Ph, 4-MeC6H4, 4-ClC6H4.CH2C(O)NH2 X XH 83a,b X = S (a), O (b). The reaction of N-[bis(methylthio)methylidene]toluene-4-sul- fonamide (95) with the amide 1a affords compound 96 in 94% yield. The latter gives pyrazoles 97 in yields of up to 98% on treatment with hydrazines.131 SMe 1a, K2CO3 4-MeC6H4SO2N DMSO SMe 95 SMe 4-MeC6H4SO2N Reactions of the amide 1a with phenacyl benzoates in boiling xylene in the presence of BF3 afford 2-aryl-4-phenyloxazoles in 75%± 90% yields.124 Isothiazole 84 has been obtained in good yield by bromination of acetyl(cyano)thioacetamide 67.108 Ac Br CH(CN)C(O)NH2 Br2 AcCH(CN)C(S)NH2 7HBr N 67 H2N S 84Cyanoacetamides and their thio- and selenocarbonyl analogues as promising reagents for fine organic synthesis H2NCO NHSO2C6H4Me-4 CN MeS H2NNHR N C(O)NH2 H2N NR97 4-MeC6H4SO2NH96 R=H, Ph, 4-ClC6H4, 4-NO2C6H4. Phenylhydrazone 98 reacts with the amide 1a in methanol in the presence of sodium methoxide yielding pyrazole 99.132 An analogous reaction of hydrazone 100 with a bulky substituent affords pyrazole 101 in only 6% yield.133 Isooxazole 103 is obtained from hydroximoyl bromide etherate under similar conditions.132 H2NCO CF3 Br 1a, MeONa N H2N NNHPh MeOH F3C 98 NPh 99 (53%) NC CF3 Cl H2N N N Br 1a, EtONa NNH CF3 Cl Cl EtOH F3C Cl 100 101 CF3 H2NCO CF3 Br 1a, MeONa NOH.OEt2 MeOH N F3C H2N 102 O 103 (30%) High yields of isoxazoloquinazolines 104 were obtained upon cyclocondensation of 4-methylthioquinazoline 3-oxides 105 with the amide 1a in the presence of ButOK.134 R N N R 1a, ButOK N O N O SMe H2N(O)C NH 105 104 R=Ph, 4-MeC6H4.Reactions of 1-oxa-2-azaspiro[2.5]octane (106) with cyano- amides 107 give spiroimidazoline derivatives 108 in high yields.135 O NH B O R +NCCH(R)C(O)NH2 HN H2N(O)C NH 107 108 106 R=cyclo-C5H9, cyclo-C6H11, Me(CH2)7, PhCH2. A four-step synthesis of a xanthine analogue, viz., 5,6,7,8- tetrahydro-4H-imidazo[4,5-c]-1,4-diazepine-5,8-dione (109), has been developed starting from cyanoacetamide (1a).136 O C(O)NH2 NH N a, b, c d e N NCCH2C(O)NH2 NH2 O 1a NH NBn NBn O NH HN O NH N109 (a) HNO2; (b) [H]; (c) CH2(OEt)2, BnNH2; (d) KOH; (e) H2/Pd.743 2-Cyanomethylbenzoimidazole (110) has been obtained by condensation of cyanoacetamide (1a) with o-phenylenediamine in good yield.137 This reaction, carried out in the presence of concentrated sulfuric acid, was accompanied by hydrolysis of the cyano group resulting in 2-carbamoylmethylbenzoimidazole 111.138, 139 NH2 NH2 NH2 NH 1a CH2CN TsOH, PhNO2 N NHC(O)CH2CN 110 NH 1a, H2SO4 CH2C(O)NH2 N 111 The reaction of o-phenylenediamine with substituted cyanoacet- amide 112 under similar conditions gives rise to benzimidazole derivative 113.140 NH2 CN + NHN C(O)NH2 NH2 112 NO2 O2N NNH N C(O)NH2 NH113 c. Five-membered heterocycles with three heteroatoms in the ring The amide (1a) and thioamide (1b) are widely used in the synthesis of five-membered heterocycles with three heteroatoms in the ring, in particular, of 1,2,3-triazoles possessing a wide range of bio- logical activities.Synthesis of substituted 1,2,3-triazoles by the reactions of cyanoacetamide (1a) with alkyl-, aryl- and hetaryla- zides can be mentioned as an example.141 ± 145 It is noteworthy that the preparation of 1,2,3-triazole derivatives from compounds with an activated methylene group and phenyl azide was first reported by Dimroth in 1902.146, 147 1-Azidoglycosides 114 react with the amide 1a in aqueous DMF in the presence of KOH to give triazolonucleosides 115 in high yields. The reactions proceed with inversion of configuration yielding 1,2-trans adducts from 1,2-cis azides.144 H2NCO KOH DMF, H2O NN RN3+NCCH2C(O)NH2 114 1a H2N NR 115 (70% ± 80%) ButPh2SiO Ph3CO O O O , , O O O .R= O O O O O The synthesis of 2-substituted 9-b-D-ribofuranosyl-8-azahy- poxanthines 116 from b-D-ribofuranosyl azide, sodium salt of the amide 1a and carboxylic acid esters has also been described.145744 O N HN N N R N HOH2C O O O 116 (R=H, Alk, Ar) Synthesis of nucleosides with 1,2,3-triazoles and 8-azapurines as aglycones by reactions of azides 117 with the amide 1a has been undertaken aimed at access to novel potential pharmaceutical preparations. In the presence of KOH in aqueous DMF at 0 8C, these reactions gave rise to 1,2,3-triazole derivatives 118. The latter were readily converted into 8-azapurine derivatives 119 on treatment with ethyl formate.148, 149 KOH DMF, H2O, 0 8C N3CH2XR+NCCH2C(O)NH2 1a 117 O H2NCO N HN HCO2Et N NNH HN EtONa, EtOH N N N 119 118 CH2XR CH2XR R=PhCH2O(CH2)2, (PhCH2OCH2)2CH; X =O, S.The reaction of benzyl azide with the amide 1a in EtOH in the presence of NaOEt followed by treatment of the reaction mixture with carboxylic acid esters affords 3,5-disubstituted 7-hydroxy- 3H-1,2.3-triazolo[4,5-d]pyrimidines 120. 5-Amino-1-benzyl-1,2,3- triazole-5-carboxamide (121) has been postulated as an intermedi- ate.150 O H2NCO N NH 1a, EtONa R1CO2R2 N BnN3 NN EtOH H2N R1 N Bn N120 (43% ± 95%) NBn 121 R1=H, Me, Et, Pr, CH2OCH2Me, CH(OCH2Me)2, (CH2)2CO2H, CO2Et, Ph, PhCO, CH2NHCOPh; R2=Me, Et.Many other 1,2,3-triazole derivatives possessing coccidio- static, anticonvulsive, antiproliferative and other types of bio- logical activities have been synthesised using the reactions of aromatic and aliphatic azides with the amide 1a.151 ± 157 The reaction of 6-nitroazolo[1,5-a]pyrimidines 122 with the amide 1a in refluxing ethanol involves transformation of the pyrimidine ring into the pyridine ring and affords substituted 2-azolyl-2-pyridylamines 123. The latter are converted into 7- nitro-9-oxo-4,9-dihydroazolo[1,5-a]pyrido[2,3-d]pyrimidines 124 on subsequent treatment with sodium carbonate in ethanol and acidification with HCl.158, 159 NO2 N 1a, EtOH, B N R X N 122 C(O)NH2 X HN R 1) Na2CO3, EtOH 2) HCl N NH N NO2 123 O N N R X N NH 124 R=H, Me, SMe, CF3, Cl, NH2, NMe2, Ph; X=N, CH, CNO2.Synthesis of 5-amino-4-cyano-1,2,3-thiadiazole (126) by the reaction of tosyl azide 125 with cyanothioacetamide (1b) has been described.160 NC 1b 4-MeC6H4SO2N3 H2N 125 Later,161 1,2,3-thiadiazolium bromides 127 were obtained by bromination of arylhydrazonocyanothioacetamides 16. NC NC C(S)NH2 Br2 ArNHN H2N CN 16 A group of Japanese scientists 162 have developed a nine-step method of synthesis of an useful chemical modificator of cepha- losporin antibiotics, viz., (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2- [(fluoromethoxy)imino]acetic acid (128), from cyanoacetamide (1a) according to the scheme shown below. The yield of the target product with respect to the initial cyanoacetamide was 17.6%.CN a HON NCCH2C(O)NH2 1a C(O)NH2 CN d FCH2ON FCH2ON CN CN FCH2ON g N N NH2 S CO2Me FCH2ON i N N NH2 S CO2H FCH2ON N N NH2 128 S (a) HNO2 (81%); (b) BrCH2F, Et3N (75%); (c) POCl3 (72%); (d) NH4OH, NH4Cl (84%); (e) Br2; ( f ) KSCN, Et3N (88%); (g) MeONa, MeOH (92%); (h) H2SO4, H2O (84%); (i) HCO2H, Ac2O (84%); ( j) NaOH, H2O (84%). 2. Synthesis of six-membered carbo- and heterocycles Of six-membered heterocycles synthesised on the basis of cyano- acetamides, pyridin-2-one (-thione and -selenone) derivatives are of major interest (see, for example, reviews 27, 28, 30 ± 34, 74 and papers 163 ± 175).Many of these compounds have been found to be highly effective cardiotonics 176 ± 251 (e.g., `amrinone' and `milrinone' 242 ± 251), non-nucleoside inhibitors of HIV reverse transcriptase (potential pharmaceuticals for treatment of V P Litvinov NO2NN S 126 Br7 Br7 + + NNAr NNAr H2N S S 127CN b c FCH2ON C(O)NH2 CN e, f C(NH2) NH MeO NH FCH2ON h N N NH2 S CO2Me FCH2ON j N N NHCHO SCyanoacetamides and their thio- and selenocarbonyl analogues as promising reagents for fine organic synthesis AIDS 252 ± 265), tranquilisers,266 ± 278 compounds with antiinflama- tory, hypoglycemic, anticonvulsant, antiulcerous, fungicidal, bactericidal, pesticidal and many other types of biological activity.272 ± 308 Pyridin-2-ones are also very useful starting mate- rials in the design of novel calcium antagonists,309, 310 CH antioxidants,311 ± 315 folic acid analogues,316 vitamin B6,317 and other biologically active compounds,311, 316 ± 324 as well as models of redox coenzymes NAD and NADP.285 As an example, the use of substituted spiro[cyclopentane-piperidone] in the synthesis of `buspirone', which is an antidepressant and an analgesic, and also prevents an affection to narcotics,269 can be mentioned.The only known natural alkaloid with the cyano group in a molecule is a representative of the class of pyridones (`ricyane', 3-cyano-4- methoxy-1-methylpyridin-2-one).325 Pyridin-2-one derivatives are employed as stabilisers of polymers and lacquers,326 as pigments and diazo-components in the synthesis of dyes,327 ± 334 as acid ± base indicators in titrimetric analysis;335 they possess liquid-crystalline 336 and some other practically useful properties.The simplest and most convenient methods for the prepara- tion of functionally substituted pyridin-2(1H)-ones, -thiones and -selenones are based on the use of cyclisation reactions of carbonyl compounds and their enamines with compounds containing the activated methylene group, first of all, malononitrile and cyano- acetamides. This opens an indirect route to regioselective synthesis of functionally substituted pyridines. Direct functional- isation of the rather inert pyridine ring by electrophilic substitu- tion reactions is quite difficult.Condensations of symmetrical 1,3-dicarbonyl compounds with cyano(chalcogeno)acetamides 1a ± c occur smoothly in the presence of basic catalysts to give 3-cyanopyridin-2(1H)-ones, -thiones and selenones 129 in high yields.28, 85, 337 ± 352 Similar reaction of monothiodibenzoylmethane (130) with cyanothioacet- amide (1b) in ethanol in the presence of piperidine gives rise to 3-cyano-4,6-diphenylpyridine-2(1H)-thione.353 R R CN CN RCOCH2COR 1a7c, B 7H2O R X X R NH O NH2 129a ± c R=Alk, Ar, Het; X =O (a), S (b), Se (c). Ph CN 1b, B PhC(S)CH2COPh S Ph 130 NH (87%) It is noteworthy that pyridin-2(1H)-ones 129a were obtained by the above method as far back as the end of the past century, while the first thione analogue, viz., 3-cyano-4,6-dimethylpyri- dine-2(1H)-thione, was synthesised by condensation of acetylace- tone with the amide 1b at the end of the 1950's,338, 341 and the first selenone analogue was prepared in a similar way from the amide 1c only in 1985.47 Reactions of cyanothioacetamide (1b) occur under milder conditions and give higher yields of pyridines than with cyanoacetamide (1a).The reactions of cyanoselenoacetamide (1c) also occur under mild conditions, though an inert atmosphere is required in this case. The reaction of 1,3-diketones with dimethylformamide dimethyl acetal affords b-enamino carbonyl compounds 131, which are condensed with amides 1a,b yielding functionally substituted pyridones and pyridinethiones 132.232, 235, 354 ± 356 R1CO DMF 1a,b R1COCH2COR2+Me2NCH(OMe)2 R2CO NMe2 131 745 CN R2CO R1CO R2CO R1 X CH(CN)C(X)NH2 NH 132 R1=Me, Et, CH2CO2Et; R2=Me, MeO, EtO; X=O, S.Synthesis of pyridinethiones 133 by the reaction of ethoxyme- thylidene diketones 134 with the amide 1b in ethanol in the presence of piperidine has also been described.357 R1 R1CO CN R2CO 1b, B OEt R2CO S 134 133 NH Condensations of unsymmetrical 1,3-dicarbonyl compounds with cyano(thio, seleno)acetamides 1a-c leads to two isomeric pyridines with different substituents in positions 4 and 6, which allows one to elucidate the effect of the reactivities of the carbonyl groups on the regioselectivity of reactions. Thus it was shown 85, 337, 347, 358 that the condensation of benzoylacetone with the amide 1b gives both isomeric pyridinethiones 135b and 136b (Ar=Ph) in the ratio 2 : 1.Earlier, only the isomer 135b was thought to be the reaction product.341 However, the analogous reaction of benzoylacetone with cyanoselenoacetamide (1c) occurs with high regioselectivity to give only one isomer, viz., 3-cyano-4-methyl-6-phenylpyridine-2(1H)-selenone (135c, Ar= Ph).358, 359 Reactions of cyanothioacetamide (1b) with other unsymmet- rical 1,3-diketones 137 (Ar=4-MeC6H4, 4-MeOC6H4, 4-BrC6H4, 2-thienyl) also give rise to mixtures of the correspond- ing isomers 135b and 136b.360, 361 Only the isomer 135a (Ar=Ph) was earlier assumed 362, 363 to be the reaction product of benzoylacetone with cyanoacetamide (1a) or ethyl cyanoacetate in the presence of ammonia or diethyl- amine. In the condensation of nicotinoylacetone with cyanoace- tamide (1a), a mixture of isomers 135a and 136a (Ar=3-pyridyl) in the ratio 3 : 2 is formed, while in the reaction of 4-pyridylcarbo- nylacetone, the isomer 136a (Ar=4-pyridyl) is the major prod- uct.167 1a ± c ArCOCH2COMe Ar Me CN CN + MeC(O)CH2 C(X)NH2 C(X)NH2 ArC(O)CH2 Ar Me CN CN + X Me X Ar NH NH 136a ± c 135a ± c Ar=Ph, 4-MeC6H4, 4-MeOC6H4, 4-BrC6H4, , , S N ; X = O (a), S (b), Se (c).N The regioselectivity of the reaction is the higher the stronger are the electron-withdrawing properties of a substituent at one of the carbonyl groups. Thus 1,3-diketones with the trifluoromethyl group 137 react with cyanoacetamides 1b,c to give only 3-cyano-6- R-4-trifluoromethylpyridine-2(1H)-thiones and -selenones 138 in fairly high yields.345, 364 ± 366 The change in the order of operations, i.e., the preliminary generation of a carbanion from the thioamide 1b by treating it with sodium ethoxide followed by the addition of trifluoroacetylacetone has led to the other isomer, viz., 3-cyano-4- methyl-6-trifluoromethylpyridine-2(1H)-thione, in 94% yield.365, 367746 CF3 CN 1b, c, B CF3COCH2COR EtOH X R 137 NH 138 ; X =S, Se.R=Alk, Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, S Reactions of cyanoacetamide (1a) with 1,3-dicarbonyl com- pounds and their derivatives have successfully been employed in the synthesis of pyrimidines, pyrazines and other hetero- cycles.368 ± 380 Thus the condensation of the amide (1a) with methyl 2-acetylpent-4-ynoate (139) in concentrated aqueous ammonia solution gives rise to pyridone 140.An analogous reaction of ethyl 2-acetylpent-4-enoate (141) with the amide 1a in piperidine yields pyridone 142.371 Me Ac NC CH2C CH 1a, NH3, H2O CH CHCH2C MeO2C OH O 139 NH 140 (74%) Me Ac NC CH2CH CH2 NH 1a, CH2 CHCH2CH EtO2C OH O 141 NH 142 (51%) Substituted dispiro(dipyrano[2,40 : 6,40]bisdithiolo[4,5-b : 40,50- e])-4,8-benzoquinone 144 was obtained by the reaction of 2,6-bis(diacetylmethylidene)bisdithiolo[4,5-b : 40,50-e]benzoquinone (143) with a twofold excess of the amide 1a in ethanol in the presence of piperidine.380 O NH Ac 1a, Ac S S D, 3±5 h S S Ac Ac 143 O C(O)NH2 O Me H2N S S O O S S Me NH2 O H2N(O)C 144 (68%) The kinetics of condensation of symmetrical and unsymmet- rical 1,3-diketones (pentane-2,4-dione, 5-methylhexane-2,4- dione, 5,5-dimethylhexane-2,4-dione) with cyanoacetamide (1a) in the presence of piperidine as a catalyst under various reaction conditions has been studied. Judging from the rate constants and activation parameters as well as the structure of unsymmetrical 4,6-disubstituted 3-cyanopyridin-2(1H)-ones obtained, a plausi- ble scheme for the reaction mechanism was suggested, which gives a rationale for the regioselectivity of the condensation and the positions of the substituents in the reaction products.381 Cyclic 1,3-diketones have been successfully employed as substrates in the reactions with cyanoacetamides 1a-c, and regioselective syntheses of bicyclic 3-cyanopyridin-2(1H)-ones, -thiones and -selenones 146 were proposed.85, 346, 382 ± 394 (H2C)n (H2C)n O CN CN 1a ± c, B (H2C)n R 7H2O R X COR X 145 O NH2 NH 146 n=1, 2; R=Alk, Ar; X=O, S, Se.V P Litvinov This approach has also been applied to the preparation of pyridone 147 having the skeleton of the alkaloid papaverine.386 CN CN 1b Bn 7H2O S COBn Bn S O NH2 NH 147 7-Acetyl-8-aryl-4-cyano-1,6-dimethyl-6-hydroxy-5,6,7,8-tet- rahydroisoquinolin-2(1H)-ones 149a, -thiones 149b and their sodium salts 150a,b were obtained in high yields in reactions of the amides 1a,b with 2,4-diacetyl-3-aryl-5-hydroxy-5-methyl- cyclohexanones 148.394 Ar CN Ac HO Ac 1a C(O)NH2 Me Me O HO Ac Ac Ar 148 CN HO O Me NH Et3N Ac Me Ar 149aOH7 H+ CN HO O MeONa 7 Me Na+ N Ac Me Ar 150aCN HO HO S S 7 Me Me H+ 1b 148 NH N MeONa Ac Ac OH7 Na+ Me Me Ar 149b Ar150b Of reactions of cyclic 1,3-diketones with cyanoacetamide (1a),277, 280, 395 ± 399 the condensations of pyrans or thiopyrans 151 in ethanol in the presence of triethylamine can be noted as the method for preparation of 3-oxopyrano(thiopyrano)[3,4-c]- pyridines 152.277, 395, 396 CN O Me COR 1a, Et3N C(O)NH2 Me Me EtOH X COR X Me 151 CN Me O Me NH X 152 R=Alk, Ar; X=O, S.It is known that substituted coumarins and their annelated analogues exhibit bactericidal, spasmolytic and hypothermic activities. In order to develop methods of synthesis of substituted coumarins, which could be used in design of novel pharma- ceuticals, it was necessary to study reactions of 3-acetylcoumarin747 Cyanoacetamides and their thio- and selenocarbonyl analogues as promising reagents for fine organic synthesis ONa O O Me Me C(S)NH2 NH 1b, AcOH (153) with the amides 1a,b in the presence of bases.This resulted in oxo- and thioxo-derivatives of benzopyrano[3,4-c]pyridines 154.280 X CN EtOH EtOH NC Me Me N NMe Me N 163 162 Ac Me 1a,b, Et3N Me EtOH O O O O C(S)NH2 EtO2C 154 153 Me N CN Me X = O (a), S (b). Me Me MeN MeN CN CN 7H2 CHC(S)NH2 Me EtO2C Me S O Compared with cyclic 1,3-diketones, cyclic b-oxo aldehydes react with cyanoacetamides more selectively.Thus the condensa- tions of sodium salts of 2-hydroxymethylidenecycloalkanones 155 with amides 1b,c occur regioselectively to give only one of two possible isomers, viz., 5,6-annelated 3-cyanopyridine-2(1H)-thio- nes 156a and -selenones 156b.85, 387, 400 ± 406 HN Me CN MeN CHONa CN 1b,c X (H2C)n (H2C)n Me O O O NH2 155 HN S 164 CN (H2C)n X NH 156a,b n=1, 2; X = S (a), Se (b). Similarly to cyclic b-oxo aldehydes, their acyclic analogues also react with high regioselectivity.38, 85, 174, 395, 410 ± 422 Thus 6-substituted 3-cyanopyridine-2(1H)-thiones and -selenones (166) are formed in the reaction of amides 1b,c with sodium enolates of b-oxo aldehydes (165).The regioselectivity of the reaction is independent of the nature of substituents (electron- donating or electron-withdrawing) in the benzene ring of the substrates 165.85, 397 ± 399, 402 CN CN Yet another example of high regioselectivity is the reaction of sodium salt of 2-formylquinuclidone (157) with cyanothioacet- amide (1b), which affords only bridged 3-cyano-1,5-naphthyri- dine-2(1H)-thione (158).407 RCO ONa 1b,c, AcOH CN N O X R X R 1b 165 O NH2 NH 166 S CHONa N R=Pr, Ph, 4-ClC6H4, 4-BrC6H4, 3,4-Cl2C6H3, 4-MeOC6H4, NH 157 158 2,4-(MeO)2C6H3, N ; X=S, Se. Cyanothioacetamide has been used in the synthesis of steroids annelated with the pyridine ring.Thus pyridinethione 161 was obtained in 80% yield by condensation of the amide 1b with the sodium enolate of 16-formyl-5a-androstan-17-one (159).60, 408 The latter has been prepared by formylation of 5a-androstan-17- one (160) with methyl formate. The key step in the synthesis of 2-pyridinone derivatives 167 possessing high anti-HIV activity 253, 257 is the condensation of sodium enolate of 2-ethyl-3-oxobutane (168) with cyanoacet- amide (1a) in the presence of piperidinium acetate. Et CN O CHO Et ONa Ac 1a O Me OMe Me N Et 1) MeONa 2) HCO2Me 168 NH R Et (CH2)2R 160 Et S HN O CN O Me O Me NH NH 1) NaH 2) 1b, AcOH CHO 167 161 159 O N N , , , , R= O NH O N N , .O S An example of recyclisation of (1,2,5-trimethyl-4-oxopiperid- 3-ylmethylidene)cyanothioacetamide (162), prepared from the sodium salt of 1,2,5-trimethyl-3-formylpiperid-4-one (163) and the amide 1b, into 4-cyano-6,7,8a-trimethyl-3-thioxo- 1,2,3,5,6,7,8,8a-octahydro-2,7-naphthyridin-1-one (164) has been described.173, 409 The regioselective reaction of sodium enolates of 2- and 3-thenoylacetaldehydes 169 with cyanothioacetamide (1b) in ethanol in the presence of acetic acid, giving rise to the corre- 170,421 3-cyano-6-thienylpyridine-2(1H)-thiones sponding748 presents yet another example of successful synthesis of substituted pyridine-2-chalcogenones using condensations of oxo aldehydes with cyanoacetamides. COCH CHONa S 169 The condensations of cyanoacetamides with aliphatic, aro- matic and heterocyclic aldehydes also lead to functionalised heterocycles.423 ± 436 Among this type of the reactions, cyclo- condensations of 5-chloro-3-methyl-1-phenylpyrazole-4-carbox- aldehyde (171) with amides 1a,b, giving rise to pyrazolopyridines 172a,b,426 and of 5-aminopyrazole-4-carboxaldehydes 173 with the amide 1a, which makes possible the preparation of amino- substituted pyrazolo[3,4-b]pyridines 174,429 are worth mention- ing.Me CHO 1a,b N Cl NPh 171 X = O (a), S (b).R CHO 1a N NH2 NPh 173 R=Me, Pr, Ph. 6-amino-3,5-dicyanopyridine-2(1H)-thiones 4-Substituted 175 are convenient building blocks in the synthesis of biologically active compounds. It is remarkable that they can be prepared from aliphatic or aromatic aldehydes, cyanothioacetamide (1b) and malononitrile in a one-pot preparative step including three consecutive reactions.432, 434 ± 442 RCHO + NCCH2C(S)NH2 1b R=Alk, Ar.Analogous reactions of aromatic and heterocyclic aldehydes with cyanoacetamide (1a) in the presence of ammonium acetate had earlier been employed for the synthesis of 4-substituted 3,5- dicyano-6-hydroxypyridin-2(1H)-ones 176.437 RCHO + NCCH2C(O)NH2 1a R=Ar, Het. The cyclisation of glutaraldehyde with cyanoacetamide (1a) occurs in aqueous dioxane in the presence of triethylamine to give 1-cyano-2,6-dihydroxycyclohexane-1-carboxamide (177) in 75% yield.425 1a, Et3N OCH(CH2)3CHO CN 1b, AcOH S NH EtOH S 170 (60% ± 72%) Me CN N X NH NPh172a,b R C(O)NH2 N N NH2 NPh 174 R CN NC CH2(CN)2, Et3N S H2N NH 175 R CN NC NH4OAc O HO NH 176 CN H2N(O)C HO OH 177 V P Litvinov Reactions of the amide 1a with 2-nitro- and 2-aminobenz- aldehyde have been successfully used in the synthesis of 2-amino- quinoline-3-carboxamide 178.438 CN CH CHO 1a Fe C(O)NH2 AcOH NO2 NO2 C(O)NH2 N NH2 178 CHO 1a 178 NH2 Analogous reactions of amides 1a,b with hydroxybenz- aldehyde and hydroxybenzo[b]thiophenecarbaldehyde have led to coumarin derivatives 179a,b and 180a,b.439 ± 442 C(X)NH2 CHO 1a,b NH OH O 179a,b CHO HO 1a,b S C(X)NH2 C(X)NH2 O HN HCl, H2O O O S S 180a,b X = O (a), S (b).b-Enamino carbonyl compounds are widely used in the synthesis of various heterocyclic compounds. They are succes- sfully employed for regioselective synthesis of 3-cyanopyridin-2- (1H)-ones, -thiones and -selenones 129a ± c (see, for example, reviews 28, 30, 85 and papers 443 ± 454). R1 CN NR2R3 R1CO 1a ± c X R1 R1 NH 129a ± c R1=Alk, Ar, Het; R2, R3=H, Ph; R2±R3=(CH2)5, (CH2)2O(CH2)2; X = O (a), S (b), Se (c). It was found 47, 85, 341 ± 343, 349, 353, 387 that unlike the condensa- tions of 1,3-dicarbonyl compounds, the reactions of the corre- sponding symmetrical b-enamines with cyanoacetamides occur under mild conditions (20 ± 40 8C) and in the absence of basic catalysts to give selectively and in higher yields 4,6-disubstituted 3-cyanopyridin-2(1H)-ones, -thiones and -selenones 129a ± c.Synthesis of 5-substituted 3-cyanopyridin-2(1H)-ones 181 is based on the use of the reactions of b-enamino aldehydes 182 with cyanoacetamide (1a) in the presence of a base.272, 455 ± 462 R CN OHC NMe2 1a, B R O NH 181 182 R=Ar, Het.Cyanoacetamides and their thio- and selenocarbonyl analogues as promising reagents for fine organic synthesis Condensations of b-enamines prepared from unsymmetrical 1,3-diketones with amides 1a ± c can afford isomeric 4,6-disubsti- tuted 3-cyanopyridin-2(1H)-ones, -thiones and -selenones depending on whether the keto or the amino group of enamines is subjected to the initial nucleophilic attack by amides.85, 339, 345, 347, 358, 387, 446, 463 ± 467 Varying the substituents in initial enamines and the reaction conditions, one may control the direction of these reactions leading to one particular isomer or to a mixture of both isomers.Thus 2-amino-1-benzoylpropene (183) reacts with cyanoacet- amide (1a) in the presence of sodium ethoxide to give 3-cyano-6- methyl-4-phenylpyridin-2(1H)-one (184),339, 464, 466, 467 while the condensation of these compounds at 150 8C for 1 h results in the isomeric 3-cyano-4-methyl-6-phenylpyridin-2(1H)-one (185a).464, 465 Ph CN EtONa EtOH, D, 6 h O Me NH Me 184 1a Me COPh H2N 183 CN 150 8C, 1 h O Ph NH 185a Only 3-cyanopyridine-2(1H)-thione 185b and -selenone 185c are obtained on brief refluxing of a mixture of b-enamino ketones 186 or 187 and amide 1b or 1c in ethanol in the presence of acetic acid.85, 347, 358, 446, 463 Ph Me N O CN 1b,c MeC(O) 186 Ph X Me O N NH 185b,c 187 PhC(O) X = S (b), Se (c).The stronger the electron-withdrawing properties of the substituent at the sp2 hybridised carbon atom linked with the amino group, the higher the regioselectivity of the reaction. This is true even for those enamines which have the phenyl and 2-thienyl substituents at the carbonyl group. Thus condensations of trifluoromethyl-substituted enamino ketones 188 with amides 1b,c in ethanol at 25 ± 30 8C in the absence of a catalyst afford 3-cyano-6-phenyl- or -6-(2-thienyl)-4-trifluoromethylpyridine- 2(1H)-thiones and -selenones 138.85, 345 CF3 CN CF3 1b,c R O N X R NH O 138 188 ; X=S, Se.R=Ph, S b-Enamino ketones can also be used for the preparation of 5,6-disubstituted 3-cyanopyridin-2(1H)-ones. Thus 6-alkyl-5- aryl-3-cyanopyridin-2(1H)-ones 189 possessing cardiotonic activ- ity have been obtained by condensation of enamino ketones 190 (R1=R2=Me) with cyanoacetamide (1a) in the presence of sodium methoxide.86, 87, 468 ± 472 3-Cyano-5-aryl-6-methylpy- 749 ridine-2(1H)-thiones 189 (X=S) were synthesised in a similar way from the enamino ketone 190 [R17R2=(CH2)2O(CH2)2].473 Ar CN Ar 1a,b R1R2NCH X R3 COR3 NH 190 189 Ar=Ph, 4-MeSC6H4, 4-SO2C6H4, 3,4-(MeO)2C6H3; R1, R2=Alk; R1±R2=(CH2)2O(CH2)2; R3=Me, CH(OMe)2, cyclo-Alk; X=O, S.The well-known cardiotonic preparation `milrinone' (192) is obtained by the condensation of the enamine 191 with cyanoace- tamide (1a) or malononitrile (5).474 Me Ac NH 1a O N N NHMe 191 192 CN The reaction of enamine 193 with the amide 1a in isopropyl alcohol in the presence of sodium alkoxides is nonselective and results in a mixture of pyridones 194 and 195.475Me Me N N 1a Ac CN + Pri(Ac)N N(Ac)Pri S S Me2NCH Me O 193 Me 194 NH N + C(O)NH2 Pri(Ac)N SMe O NH 195 5,6-Disubstituted 3-cyanopyridin-2(1H)-ones 132 have been obtained by the reactions of 2-aminomethylidene derivatives of 1,3-dicarbonyl compounds 196 with the amide 1a in the presence of sodium hydride in THF369 or sodium methoxide in DMF.476 Both symmetrical 369, 476 and unsymmetrical 477 ± 479 b-diketones were used in these reactions.Compounds 196 with substituents R1=Bun, OEt and R2=Me react regioselectively yielding only one isomer. CN R2CO COR1 1a Me2NCH COR2 O R1 HN 196 132 R1, R2=Me, Pri, But, Bun, OEt, Ph. 3-Cyano-4,4,6-trimethylpyridin-2(1H)-one (197) has been obtained by the reaction of 4-amino-3-methylpent-3-en-2-one (198) with the amide 1a at 150 8C for 30 min.465 This compound was also synthesised by the condensation of the enamine 198 with malononitrile (5) in THF in the presence of triethylamine at 20 8C.454 Me Me Me CN Me 1a Ac H2N Me O 198 HN 197 The condensations of b-enamino carbonyl compounds 199 with substituted cyanoacetamides 200a,b occur with the elimina- tion of methanethiol and result in 4-dialkylaminopyridones 201a,b bearing the b-enamino amide fragment.Compound 201b reacts with N-methylcyanoacetamide 200b to give naphthyridine- dione 202.480750 NR3R4CN R2 SMe R1CO PriONa PriOH +NCCH2C(O)NHR5 200a,b NR3R4 R2 O R1 RN5 199 201a,b O NC NMe 200b 201b NH2 PriONa, PriOH O 202 Me N R1=Me, Ph, 4-ClC6H4, 4-MeOC6H4; R2=H; R3=Et, Ph, CH2CH(OEt)2, Bn; R4=H; R3±R4=(CH2)2O(CH2)2; R5 = H (a), Me (b). Synthesis of fused pyridinones, -thiones and selenones to with takes advantage of the high reactivity of cyclic b-enamino ketones respect 1a ± c.28, 30, 85, 346, 349, 382, 384 ± 387, 446, 481, 482 cyanoacetamides Condensations of enamino ketones 203 with amides 1a ± c occur regioselectively to give in each case only one of two possible isomers in the absence of basic catalysts and afford the products in higher yields (on average, by 10%) than those obtained from 1,3-dicarbonyl compounds.Condensations of b-enamino ketones 203 bearing an aryl substituent instead of an alkyl one, demand more drastic reaction conditions. Thus 3-cyano-6-phenyltetrahydroiso- quinolin-3-one 146 (n=4, X=O, R=Ph) can be obtained on refluxing of the equimolar amounts of the starting compounds in isopropyl alcohol for 1.5 h.384 CN COR COR Z NCCH2Y (H2C)n (H2C)n (H2C)n NH CN N Y R 146 X 203 n=1, 2; R=Alk, Ar; X=O, CH2; Y=CN, C(Z)NH2; Z=O, S, Se. It has been noted 369, 481 that condensations of enamines prepared from cyclic oxo aldehydes and secondary amines are more regioselective.Hydrogenated 3-cyanoquinoline-2(1H)-thiones and -selen- ones 156a,b were obtained by the condensation of 2-piperidino- methylidenecycloalkanones 204 with amides 1b,c in ethanol in the presence of acetic acid in high yields.85, 352, 387, 402 ± 404, 446 CN CHN 1b,c (H2C)n (H2C)n X NH 156a,b O 204 n=2, 3; X = S (a), Se (b). The reaction of 2-dimethylaminomethylidenenecyclohexane- diones 205 with cyanoacetamide (1a) in THF in the presence of NaOH gives rise to a mixture of cyanopyridones 206 and carbamoylpyrones 207. When enamines 205 are made to react with the amide 1a in ethanol under reflux, only carbamoyl- pyridones 208 are obtained in high yields.369 O CHNMe2 1a R1 O R2 205 V P Litvinov CN C(O)NH2 O O O O NaOH, THF + O NH R1 R1 207 206 R2 R2 C(O)NH2 O O EtOH, D NH R1 R2 208 R1=H, Me; R2=H, Me, Ph.The reaction of the enamine 209 prepared from dimedone with N,N-dimethylacetamide diethyl acetal (210) affords diaminodiene 211 in high yield. The latter reacts with amides 1a,b with the elimination of dimedone to give 3-cyano-6-dimethylamino- pyridin-2(1H)-one (212a) or -thione 212b, respectively.449 CHCH C(NMe2)2 CHNMe2 O O O O 1a,b + Me2 NC(Me)(OEt)2 210 Me Me Me Me 209 211 O O CN + X Me2N NH Me Me 212a,b X = O (a), S (b). 3-Cyanopyridin-2(1H)-ones, -thiones and -selenones can also be synthesised from b-enamino esters.Thus the condensation of the b-enamino ester 214 with the amide 1a affords 3-cyano-6- hydroxy-4-methylpyridin-2(1H)-one (213), which is employed in the synthesis of dyes.465 Me CN 1a H2N(Me)C CHCO2Et 214 HO O 213 NH It was found 447, 483, 484 that enamines 215a and 215b prepared from ethyl acetoacetate or acetoacetanilide are more reactive toward amides 1a ± c than ethyl acetoacetate itself. Thus the reactions of enamines 215a,b with amides 1a ± c in ethanol at room temperature afford salts 216 in high yields. The latter are readily converted into the corresponding pyridinones, -thiones or -selenones 217 on treatment with HCl. The pyridone 217 (X=O) was also prepared by the reaction of the enamine 215a (X=CH2) with the amide 1a in water followed by acidification of the reaction mixture.Me COR CN HCl 1a ± c + X H2N N Me Y7 O X NH 216 215a,b Me CN Y HO NH 217 R=OEt (215a), NHPh (215b); X=O, CH2; Y=O, S, Se.Cyanoacetamides and their thio- and selenocarbonyl analogues as promising reagents for fine organic synthesis The b-enamino ester 215a (X=CH2) reacts with benzylide- necyanoacetamide 218 to give substituted 3,4-dihydropyridone 219. The latter is transformed into ethyl 3-cyano-6-methyl-4- phenyl-1,2-dihydropyridine-5-carboxylate (220) on treatment with dilute nitric acid.485 CO2Et N Me +PhCH C(CN)CONH2 218 215a Ph Ph CN CN EtO2C EtO2C HNO3 O Me O Me NH NH 220 219 Tetrahydroisoquinolinone 222 has been obtained by the condensation of b-enamino ester 221 with cyanoacetamide (1a).465 CO2Et CN 1a NH2 O HO HN 221 222 a,b-Unsaturated carbonyl compounds, owing to the substan- tial difference in reactivities of their nucleophilic centres, react with cyanothioacetamides yet more regioselectively than the corresponding enamino carbonyl compounds.In this case, the synthetic strategy consists in the condensation of unsaturated carbonyl compounds with cyanothioacetamide (1b) leading to 5-oxo thioamides 223. The reason for regioselectivity is that Michael addition occurs preferentially, rather than the Knoeve- nagel condensation involving the carbonyl group. Further intra- molecular cyclisation of the adducts 223 and dehydrogenation of pyridinethiones 224 result in 3-cyanopyridine-2(1H)-thiones 225 (see reviews 28, 41 and papers 486 ± 500).R3 CN R2 R1 R2 1b R1 S O R3 O NH2 223 R3 R3 CN R2 CN R2 S S R1 R1 NH NH 224 225 R1=H, Alk, Ph, Bn, ; R2=H;R3=Ph, 4-ClC6H4, N 4-MeOC6H4, 4-NO2C6H4, 4-MeNC6H4; R2±R3=(CH2)4. These reactions were initially used in the synthesis of 4,5- diaryl-3-cyanopyridine-2(1H)-thiones.343, 486, 488 Later, a series of 4,6-dihetaryl-pyridinethiones was obtained.352, 491, 492 a,b-Unsa- turated carbonyl compounds were also employed in the synthesis of 4-aryl-6-methyl- 347, 358 and 4,5,6-trisubstituted 3-cyanopyr- idine-2(1H)-thiones.41, 346, 385, 386, 487, 490 The direction of any par- ticular reaction depends on the structure of the initial compounds, reaction conditions and catalyst.Thus reactions with the amide 1b in boiling ethanol or methanol in the presence of sodium alkoxides result in the formation of substituted 3-cyanopyridine-2(1H)- thiones 225.41, 343, 346, 347, 352, 358, 385, 386, 486, 487, 491, 492 However, if the sodium alkoxide catalyst is replaced by an equimolar amount of an organic base and the reaction is carried out at 20 8C, only tetrahydropyridines 224 are formed.489, 493 ± 498 In this case, an 751 organic base acts not only as a catalyst but also as a stabiliser of the partially hydrogenated pyridinethiones, which can be isolated as stable salts. The latter are converted into pyridinethiones 225 on treatment with HCl and oxidation with atmospheric oxygen. Although the condensations of a,b-unsaturated ketones with cyanothioacetamide (1b) afford the final products in somewhat lower yields compared to those obtained from 1,3-dicarbonyl compounds, this is counterbalanced by the selectivity of the reaction.Thus only the corresponding 3,4- or 4,4-bipyridines are formed from 1-(3- or 4-pyridyl)but-1-en-3-ones, respectively.167 The reactions of 2-arylidenecyclopentan(or -hexan)ones 226 and of 2,5-dibenzylidenecyclopentanone (228) with the amide 1b give rise to 5,6-annelated 4-aryl±3-cyanopyridine-2(1H)-thiones 227 499 and 229,501 respectively. Ar CHAr CN 1b (H2C)n (H2C)n S 226 NH 227 n=1, 2; Ar=Ph, 4-ClC6H4. Ph CN 1b CHPh PhCH S NH PhCH O 229 228 Pyridinethiones annelated with steroids were obtained using the reactions of the amide 1b with a,b-unsaturated ketones 17 and 230.The condensation of the amide 1b with the ketone 17 is accompanied by hydrolysis of the acetoxy group and results in pyridinethione 231. The reaction of the amide 1b with arylidene- ketone 230 affords 4-arylpyridinethione 232.60, 62 Me NH Ac S 1b CN HO AcO 17 231 (76%) S O HN CN CHAr 1b Ar 230 232 (81%) Ar=Ph, 3-FC6H4, . N The condensations of 2-arylmethylidene-3-oxoquinuclidines 233 with the amide 1b lead to the formation of stable salts 235, which are converted into partially hydrogenated 4-aryl-3-cyano- 1,5-naphthyridine-2(1H)-thiones 234 or 236 on treatment with HCl.502 Ar N O 1b, B BH+ S7 CHAr 235 NH N233 HClAr Ar N N CN CN S NH NH S 236 234752 Reactions of cyanoacetamides with aroyl- and hetaroylimino dithioethers have been described.273, 503 ± 506 Thus reactions of compounds 237 with cyanoacetamide (1a) in methanol in the presence of sodium methoxide afford 2-aryl(hetaryl)-5-cyano-6- methylthio-3,4-dihydropyrimidin-4-ones 238 in 40%± 60% yields. However, a vinylogue of compounds 237, viz., iminodi- thioether 239, gives under similar conditions 5-cyano-6-methyl- thio-4-phenyl-3,4-dihydropyridin-2-one (240) in 70% yield.504SMe R N SMe R HN1a RCON C(SMe)2 HN N CN CN 237 O O 238 R=Ar, Het.O Ph 1a NH PhCH CH2CON C(SMe)2 239 NC SMe 240 2-(Diacetylmethylidene)benzooxazole (241) prepared from dimethyl dithio acetal 242 and 2-aminophenol reacts with the amide 1a in boiling methanol in the presence of piperidine to give spiro compound 243 in 58% yield.505 NH2 NH 1a EtOH CAc2 Ac2C C(SMe)2+ 242 O OH 241 Me NH ONH2 O H2N(O)C 243 O,S-Acetals 244 react with the amide 1a on heating in ethanol in the presence of sodium alkoxides yielding 4-alkoxy-3-cyano- pyridin-2(1H)-ones 245.Similar reactions of cyclic O,S-acetals 246 give rise to annelated 4-alkoxy-3-cyanopyridin-2(1H)-ones 247.507 OR1 CN 1a, NaOR1 ArCOCH C(OR1)SR2 R1OH, 10 ± 12 h Ar O 244 NH 245 (74% ± 83%) Ar=Ph, 4-MeOC6H4, 4-ClC6H4, ;R1=Me, Et, Prn; R2=Me, Et. O CN SMe O HN 1a, NaOR OR OR ROH (CH2)n (CH2)n X X 247 (61% ± 74%) 246 n=1, 2; R=Me, Et; X=S, CH2.Salt 248 prepared by the reaction of diacetyl dimethyl ketal 249 with methyl formate in the presence of sodium methoxide reacts with the amide 1a to give trimethyl orthopicolinate 250.508 1a H2O HCO2Et 249 MeC(OMe)2Ac NaOMe MeC(OMe)2COCH CHONa 248 CN O Me(MeO)2C NH 250 V P Litvinov The use of a,b-ynones as substrates in the reactions with cyanoacetamides has been described.85, 347, 463, 509 3-Cyano-6- methyl-4-phenylpyridine-2(1H)-thione (136b) was obtained on stirring a solution of acetylphenylacetylene (251) with cyanothio- acetamide (1b) in ethanol in the presence of morpholine at 25 8C.85, 347, 463 However, the reaction of equimolar amounts of the ketone 251 with morpholine followed by the addition of the amide 1b to the reaction mixture gave isomeric 3-cyano-4-methyl- 6-phenylpyridine-2(1H)-thione 135b.It was concluded 85 that the Michael addition of the amide 1b to the ketone 251 is realised in the first reaction (path a) in which morpholine plays the role of a basic catalyst increasing the nucleophilicity of the methylene group in the amide 1b. In the latter case (path b), b-enamino ketone 252 is initially formed, which then reacts with the amide 1b in a selective manner to give the isomer 135b. This mechanism was proved by isolation of intermediate b-enamino ketone 252.85 AcC CPh 251 b a b, c Ph Me Ph AcCH CN CN N c 135b S Ph S Me O 252 NH 135b NH 136b O, EtOH; (b)HN (a) 1b, HN O, EtOH, 25 8C, 3 ± 4 h; (c) 1b. The use of a,b-unsaturated nitriles in reactions with amides 1b,c for the preparation of 3-cyanopyridine-2(1H)-thiones and selenones is based on the formation of d-oxothio- and d-oxo- selenoamide intermediates, which easily cyclise into a pyridine ring under the reaction conditions.49, 115, 353, 447, 498, 510 ± 521 This is exemplified in the preparation of 6-amino-4-aryl(hetaryl)-3,5- dicyanopyridine-2(1H)-thiones and -selenones 253 by the reac- tions of arylmethylidenecyanothioacetamides 7b with malononi- trile (5) or of arylmethylidenemalononitriles 254 with thio- and selenoamides 1b,c.Pyridinethiones and -selenones 253 can also be prepared by recyclisation of intermediate 2,6-diamino-4-aryl-3,5- dicyanothio(or -seleno)pyranones 255.The latter were isolated in some cases.49, 510, 512, 515 ± 518 4-Aryl-3,5-dicyano-6-hydroxypyri- dine-2(1H)-thiones and -selenones 257 are synthesised by analo- gous reactions of arylmethylidenecyanoacetates 256 with amides 1b,c.519 ± 521 5 ArCH C(CN)C(S)NH2 7b 1b,c ArCH C(CN)2 254 Ar Ar CN NC CN NC C C X X NH2 N N H2 N 258 259 Ar Ar CN NC NC CN D X X NH2 H2N H2N NH 255 253 ; X=S, Se. , Ar=Ph, 4-BrC6H4, N NCyanoacetamides and their thio- and selenocarbonyl analogues as promising reagents for fine organic synthesis Ar CN NC CN 1b,c ArCH CO2Et X HO 256 NH 257 X=S, Se. The ambident nature of the thioamide and selenoamide groups in intermediates 258 and 259 is believed to be the reason for the formation of pyridinechalcogenones 253 or thio(seleno)pyrans 255, the outcome of the reactions depends on the reaction conditions.Thio(seleno)pyrans 255 are formed under kinetically controlled conditions, while pyridinechalcogenones 253 are formed under thermodynamic control. Such a dual chemical behaviour of intermediates 258 and 258 often prevents the unambiguous elucidation of the structure of the reaction products and often leads to misinterpretations. Thus the struc- ture of 5-arylmethylidenpyridinethione has been erroneously attributed to the products of thermodynamically controlled reactions of arylmethylidenemalononitriles 254 with cyanothio- acetamide 1b.520, 521 This incorrect structure was then reproduced in reviews.34, 166 Another similar mistake has been made with respect to the product obtained in the reaction of (1-amino-2,2,2- trichloroethylidene)malononitrile with the amide 1b;522 this is not pyridinethione derivative 253 (X=S), but rather the thiopyran derivative 255.523 Once again, no evidence in favour of earlier 524 postulated formation of 3,4-dihydropyridinethiones has been found later.One-step condensation of cycloalkylidenemalononitriles 260 with cyanothioacetamide (1b) or the corresponding cyanothio- amides 261 with malononitrlile proceeds via intermediates 263 and results in spirodihydropyridines 262.58 CN 1b (H2C)n CN CH(CN)2 260 (H2C)n CN CH2(CN)2 CH(CN)C(S)NH2 263 (H2C)n C(S)NH2 261 SH NC S NC NH NH (H2C)n (H2C)nNC NH2 NH2 NC262 n=1, 2.The reactions of arylmethylidenecyanothioacetamides 7b with aldehydes, ketones, esters, amides and the corresponding enam- ines are also widely used in the synthesis of 4-aryl-3-cyanopyr- idine-2(1H)-thiones. Depending on the structure of the initial carbonyl compound and the reaction conditions, these reactions can stop in the stage of either hydrogenated pyridinethiones or their oxidised forms.49, 510 ± 512, 525 ± 530 Unlike monocarbonyl compounds, acyclic 1,3-dicarbonyl compounds and b-enamino carbonyl derivatives react with the amides 7b in ethanol in the presence of an organic base (piperidine, morpholine, diethylamine, hexamethyleneimine) at 25 8C to give 1,4-dihydropyridine-2-thiolates 264.The latter are converted into 3-cyano-3,4-dihydropyridine-2(1H)-thiones 265 upon treatment with 10% HCl.49, 113, 349, 352, 446, 488, 495, 510 ± 512, 529, 531 ± 538 753 B R1COCH2COR2+ArCH C(CN)C(S)NH2 7b Ar Ar CN R1CO CN R1CO H+ HCl [O] S R2 R2 NH NH S7BH+ 264 Ar CN R1CO R2 NH S 265 R1=Me, OEt, Ph; R2=Me, CF3; Ar=4-FC6H4, 4-BrC6H4, 4-ClC N 6H4, 2-NO2C6H4, , . N The reaction of the amide 7b with a cyclic dicarbonyl compound such as dimedone allowed one to isolate the inter- mediate Michael adducts 266 as salts.113, 512 Acidification of the salts 266 affords compounds 267. Heating of the latter in ethanol in the presence of a base followed by acidification results in 3,4- dihydropyridinethiones 268.O O CH(Ar)CH(CN)C(S)NH2 HCl 7b, B Me Me EtOH O7BH+ O Me Me 266 Ar O Ar O CN CN 1) D, B 2) HCl Me Me S OH C(S)NH2 Me Me NH 267 268 Ar O CN Me SH Me NH Ar=4-FC6H4, ,N ,B=HN O,HN . N 4-Aryl-5-arylcarbamoyl-3-cyano-6-methylpyridine-2(1H)- thiones,539 stable 3-cyano-4-[2-furyl(thienyl)]-3,4-dihydro- pyridine-2(1H)-thiones,540 3-cyano-4-(2-furyl)-6-methyl-5-phe- nylcarbamoyl-1,4-dihydropyridine-2-thiolates and -selenolates 54 have been synthesised using the reactions of acetoacetanilides with the amides 7b. This approach was also used for the preparation of 60-methyl-50-phenylcarbamoyl-30,40-dihydro-spiro[cyclohexane- 1,40-pyridine]-20(10H)-thione (269) from acetoacetanilide and cyclohexylidenecyanothioacetamide.541 PhNH(O)C CN AcCH2CONHPh+ Me S NC C(S)NH2 O NH2754 PhNH(O)C CN S Me NH 269 Synthesis of 30,50-dicyano-60-oxo-spiro[cyclopentane-1,40- 10,40,50,60-tetrahydropyridine]-20-thiolate 270 by the reaction of ethyl cyclopentylidenecyanoacetate (271) with cyanothioacet- amide (1b) in the presence of N-methylmorpholine or by the reaction of cyclopentylidenecyanothioacetamide (272) with ethyl cyanoacetate under similar conditions is yet another example of the design of spiro-fused hydrogenated pyridine derivatives.542 CN 1b, B CO2Et NC CN 271 CN 7EtOH NCCH2CO2Et, B EtO S O NH2 C(S)NH2 272 S7BH+ NC NH NC O 270 All experimental results suggest that reactions of arylmethyl- idenecyanothioacetamides 7b and their carbocyclic derivatives with 1,3-dicarbonyl compounds and their enamines always involve the stage of intermediate formation of Michael adducts such as 1,4-dihydropyridine-2-thiolates and 3,4-dihydropyridine- 2(1H)-thiones. The only exception is the condensation of benzo- thiazolone 273 with the amides 7b, which results in the formation of annelated system 274.543 SH S OH S N 7b N N CHAr O NH O 273 274 As to the stereochemical aspects of reactions of cyanoacet- amides and their S- and Se-analogues, they remained unexplored until recently.Pyridinium ylides are very convenient model compounds for the study of regio- and stereoselectivity of formation of 3-cyanopyridine-2(1H)-thio- nes.58, 71, 83, 85 ± 88, 288, 492, 544 ± 559 It has been shown that condensa- tions of arylmethylidenecyanothioacetamides 7b with pyridinium ylides 275 generated in situ from the corresponding salts result in 3,4-trans-1,2,3,4-tetrahydropyridine-6-thiolates 276.The high selectivity of these reactions is due to the stereoselective addition of the ylides 275 (X=S) to the amides 7b. Subsequent cyclisation of adducts 277 into betaines 276 occurs with retention of the trans- arrangement of the hydrogen atoms.549, 554 Betaines 276 were obtained in high yields from pyridinium salts 278 and cyanothioa- cetamide (1b).551 When malononitrile (5) was used in the reaction instead of amide 1b, trans-adducts 279 were obtained from compounds (E)-278; these were isolated and examined.Treat- ment of the adducts 279 with H2S afforded trans-tetra- hydropyridines 276. The latter gave 3-cyanopyridine-2(1H)- thiones 280 upon boiling in AcOH in the presence of ammonium acetate. The condensations of amides 7b with pyridinium ylides 275 (X=O, S) give 2-oxo(thioxo)tetrahydropyridine-6-thiolates 281 in high yields. Ar H N + 7b + H N R 7 O NH2 CHC(O)R 275 277Ar H + CN D N H S7 HOR NH 276 1b 276 Y7 + Ar N ROC H Ar H ROC H 5 278 +N Y=Cl, Br. +N H Ar CN H 7b 275 S7 X NH 281 X=O, S. A great number of other examples of the use of cyanoacet- amides and their S- and Se-derivatives in the synthesis of functionalised 3-cyanopyridin-2(1H)-ones, -thiones and -sele- nones,560 ± 604 3-cyanopyridin-2-olates and -thiolates,605 ± 609 pyr- imidin-2-ones,610 ± 616 tetrahydroquinolin-2-ones,617, 618 5-cyano- 3,4-diphenylpyridazin-6-one,619 2-aryl-5-cyano-4-methylthio-1,3- oxazin-6-ones 620 and other heterocyclic compounds are also documented. Cyanoacetamides 1a,b have found application in the synthesis of substituted pyridines 282,621 quinolines 178,438 283,622 284,623, 624 isoquinolines 285,388, 389, 625 286,626 pyrazine 287,627 dihydropyrrolopyrimidines 288 628 and triazines 289.629, 630 Among other heterocyclic systems synthesised with the use of amides 1a ± c and their derivatives, thio- and selenopyr- ans,49, 510, 512, 515 ± 518, 631, 632 coumarins and thiocoumarins,439 442, 633, 634 and thiazines 635 are worth mentioning.Apart from that, the preparation of carbocyclic systems of the cyclohexane series from cyanoacetamide (1a) has been described.425, 636 NH2 CN NC N NH2 RHNC(O)CH2 282 (R=H, Ph) 283 (X=CN, CO2Et, CONH2; Ar=Ph, 4-ClC6H4, 4-BrC6H4, 3-NO2C6H4) C(O)NH2 OO N NH2 284 V P Litvinov CN S7 Ar CN S R NH 280 CN H2S 7 276 CN 279 Ar O X Me NH2 Me NPhCN OH N Me 285755 Cyanoacetamides and their thio- and selenocarbonyl analogues as promising reagents for fine organic synthesis R Me Me R N C(O)NH2 CN CN NH N CHC(O)NH2 NH2 SH O S O 286 NH NH287 292 EtO2C NH2 R1 Me N R=4-MeC MeN 6H4, , , ;B= O. S S O NH N R2 N CH2R4 NR3 N The use of pyridinium ylides 275 (X=O) in the N 288 (R1=H, Ph; R2=H, Me; R3=CO2Et; R4=OMe, OEt, NH2) three-component condensations allows one to perform a one- pot synthesis of 3-cyanopyridin-2(1H)-ones without preliminary synthesis of arylmethylidenecyanothioacetamides 7b.58, 83, 85, 288, 492, 549, 550 IV.Conclusion X 289 (X=CN, C(O)NH2, C(S)NH2) In the last decade, many derivatives of pyridin-2(1H)-ones, -thiones, -selenones and their salts have successfully been synthes- ised using a three-component condensation of cyanoacetamides or their derivatives with aliphatic, aromatic or heterocyclic aldehydes and 1,3-dicarbonyl compounds or their derivatives in the presence of an excess of organic base.495, 531, 532, 534, 535, 637 ± 653 B R1CHO+NCCH2C(X)NH2+R2COCH2COR3 1a ± c R1 R1 CN R2CO CN R2CO R3 X R3 X7BH+ NH NH R1=Alk, Ar, Het; R2=Alk, 2-MeC6H4NH; R3=Alk, NHPh; The data considered here clearly demonstrate the high synthetic potential of cyanoacetamides and their thio- and selenocarbonyl analogues.Many biologically active heterocyclic compounds have been obtained based on these reagents. This suggests that cyanoacetamides and their arylmethylidene and hetarylmethyl- idene derivatives can be particularly promising starting materials in combinatorial synthesis of functionalised carbo- and hetero- cyclic compounds used in the design of novel highly effective pharmaceuticals with a broad range of action. The great interest of chemists in these reagents is confirmed by the fact that more than 490 papers of 653 cited in this review are dated to the last 10 ± 15 years and more than 20% of them are patents.The review was written with financial support of the Russian Foundation for Basic Research (Project No. 99-03-32965). X=O, S, Se; B=HN , MeN O O, Et2NH. References Synthesis of 4-(aryl or hetaryl)-3-cyano-6-methyl-5-phenyl- carbamoyl-1,4-dihydropyridine-2-thiolates 290 from aromatic or heterocyclic aldehydes, amide 1b and acetoacetanilide in the presence of an excess of N-methylmorpholine may be regarded as an illustration of such an approach.642 ± 644 1. 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