The mannich reaction in the synthesis of N,S-containing heterocycles 4. Aminomethylation of 6-amino-3,5-dicyano-1,4-dihydropyridine-2-thiolates: A convenient regioselective route to 3,5,7,11-tetraazatricyclo[7.3.1.02,7]tridec-2-ene derivatives

Treatment of N-methylmorpholinium 4-R-6-amino-3,5-dicyano-1,4-dihydropyridine-2-thiolates (R = 2-ClC₆H₄ and 2-MeOC₆H₄) with primary amines in the presence of an excess of formaldehyde gave 13-R-8-thioxo-3,5,7,11-tetraazatricyclo[7.3.1.0^2,7]tridec-2-ene-1,9-dicarbonitrile derivatives in high yields (66–95%). In a similar way, aminomethylation of 3-R-10-amino-7,11-dicyano-9-aza-3-azoniaspiro[5.5]undeca-7,10-diene-8-thiolates (R = Me and Et) afforded 1′-alkyl-8-thioxospiro[3,5,7,11-tetraazatricyclo[7.3.1.0^2,7]tridec-2-ene-13,4′-piperidine]-1,9-dicarbonitriles in 43–91% yields. Alternatively, these compounds were obtained by multicomponent cyclocondensation of N-alkylpiperidin-4-ones, cyanothioacetamide, primary amines, and aqueous formaldehyde. The starting 3-R-10-amino-7,11-dicyano-9-aza-3-azoniaspiro[5.5]undeca-7,10-diene-8-thiolates were prepared by a new method from N-alkylpiperidin-4-ones and cyanothioacetamide. The structure of 5,11-bis(4-ethoxyphenyl)-13-(2-methoxyphenyl)-8-thioxo-3,5,7,11-tetraazatricyclo[7.3.1.0^2,7]tridec-2-ene-1,9-dicarbonitrile was examined by X-ray diffraction analysis. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1014–1022, May, 2007.     

Synthesis of pyrazole- and thiazole-annulated 3-R-1,5-dinitro-3-azabicyclo[3.3.1]nonanes

The previously unknown 3-R-1,5-dinitro-3-azabicyclo[3.3.1]nonanes fused to the pyrazole or thiazole rings were synthesized by the reductive cyclization of m-dinitroindazoles and benzothiazoles. The method is based on the reduction of carbon-carbon bonds in the benzene ring, which are activated by the meta-nitro groups, with NaBH₄ followed by the Mannich reaction with formaldehyde and primary amines.     

Purines, pyrimidines, and related fused systems. 21. Oxidative amination of 3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione

Oxidative amination of 3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione with primary alkylamines and potassium amide in liquid ammonia gives rise to the corresponding 4-amino derivatives as the major products. The reactions with acyclic secondary amines are accompanied by annelation of the pyrrole moiety to the starting heterosystem to form 1-R-3-R"-6,8-dimethylpyrrolo[2",3";3,4]pyrimido[4,5-c]pyridazine-7,9(6H,8H)-diones. The reaction with piperidine as the aminating agent occurs exclusively as aminodehalogenation. The Sonogashira cross-coupling of 4-amino-3-chloro-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones with terminal alkynes affords 1-R-2-R"-6,8-dimethylpyrrolo[3",2";3,4]pyrimido[4,5-c]pyridazine-7,9(6H,8H)-diones.     

The Mannich reaction in the synthesis of N,S-containing heterocycles 10. Recyclization of stable cyclic michael adducts,N-methylmorpholinium 6-R-6-hydroxy-1,4,5,6-tetrahydropyridine-2-thiolates,to pyrimido[4,3-b][1,3,5]thiadiazines under conditions of aminomethylation reaction

5-Substituted N-methylmorpholinium 4-aryl-6-R-3-cyano-6-hydroxy-1,4,5,6-tetrahydro-pyridine-2-thiolates upon the action of primary amines and HCHO in ethanol undergo recyclization to 3,7-disubstituted 8-aryl-3,4,7,8-tetrahydro-2H,6H-pyrimido[4,3-b][1,3,5]thiadiazine-9-carbonitriles in low yields (5–28%). The latter were also obtained by alternative method, viz., by sequential condensation of cyanothioacetamide with aromatic aldehydes, primary amines, and HCHO.     

Dual reactivity of diazonium salts derived from 1-amino-2-ethynyl-9,10-anthraquinones

Diazotization of vicinal 1-amino-2-ethynyl-4-R-9,10-anthraquinones followed by a reaction with NaN₃ gave 5-hydroxy-3-R-1H-naphtho[2,3-g]indazole-6,11-diones or 3-ethynyl-5-R-6H-anthra[1,9-cd]isoxazol-6-ones, depending on the substituents at the triply bonded C atom and in position 4 of the anthraquinone framework.     

Aminomethylation of N-methylmorpholinium 6-amino-4-aryl-3,5-dicyano-1,4-dihydropyridine-2-selenolates as an approach to the preparation of 3,5,7,11-tetraazatricyclo[7.3.1.02,7]tridec-2-ene-8-selenone derivatives

A reaction of N-methylmorpholinium 6-amino-4-aryl-3,5-dicyano-1,4-dihydropyridine-2-selenolates with primary amines and excess of formaldehyde leads to 3,5,7,11-tetraazatricyclo[7.3.1.0^2,7]tridec-2-ene-8-selenone derivatives. The same compounds were obtained by a multicomponent cascade cyclocondensation of benzaldehyde, cyanoselenoacetamide, primary amine, and excess of formaldehyde.     

2-Alkyl-4-amino-5-(tert-butyl-NNO-azoxy)-2H-1,2,3-triazole 1-oxides: synthesis and reduction

A new approach to the synthesis of 4-amino-5-(tert-butyl-NNO-azoxy)-2-R-2H-1,2,3-triazole 1-oxides 1 was developed. Compounds 1 were obtained by reactions of 3-amino-4-(tert-butyl-NNO-azoxy)furoxan with aliphatic amines RNH₂ (R = Me, Et, Prⁱ, Bu, and Bu^t). 4-Amino-5-(tert-butyl-NNO-azoxy)-2-tert-butyl-2H-1,2,3-triazole 1-oxide was transformed under the action of acids into 4-amino-5-(tert-butyl-NNO-azoxy)-1-hydroxy-1H-1,2,3-triazole. Methylation of the latter with diazomethane mainly involves the O atom of the triazole oxide ring. Reduction of compounds 1 gave 4-amino-5-(tert-butyl-NNO-azoxy)-2-R-2H-1,2,3-triazoles and 4-amino-5-(tert-butyldiazenyl)-2-R-2H-1,2,3-triazoles (R = Me, Prⁱ, and Bu^t). The structures of the compounds obtained were confirmed by ¹H, ¹³C, and ¹⁴N NMR spectroscopy.     

Synthesis of a novel series of 3-substituted [1]benzothieno[3,2-d]pyrimidine derivatives

A series of 3-substituted [1]benzothieno[3,2-d]pyrimidine derivatives has been synthesized as possible antileukemic agents by condensation of methyl 3-(ethoxymethylene)amino-2-benzothiophene carboxylate (II) with a variety of amines to afford the corresponding 3-aryl and 3-alkyl [I]benzothieno[3,2-d]pyrimidin-4(3H)-ones, Ill and IV, respectively. In addition, Mannich reactions of [I]benzothieno[3,2-d]pyrimidin-4(3H)-one (VIII) with formaldehyde and secondary amines gave the expected derivatives, IX. 3-Amino[I]benzothieno[3,2-d]-pyrimidin-4(3H)-one (VI) reacted with substituted aromatic aldehydes in the presence of boron trifluoride to yield the corresponding imines VII.     

Reaction of organozine reagents derived from dialkyl 2,2-dibromomalonates and methyl 4,4-dibromo-3-oxoalkanoates with 2-oxochromene-3-carboxamides

Organozinc compounds obtained by treatment of dialkyl 2,2-dibromomalonates with zinc reacted with N-substituted 2-oxochromene-3-carboxamides to give dialkyl 1a-R-carbamoyl-2-oxo-1a,7b-dihydro-2H-cyclopropa[c]chromene-1,1-dicarboxylates or alkyl 2-R-1,3,4-trioxo-2,3-dihydro-1H,9bH-chromeno[3′,4′:1,3]-cyclopropa[1,2-c]pyrrole-9c-carboxylates. Reactions of N-substituted 2-oxochromene-3-carboxamides with zinc enolates derived from methyl 4,4-dibromo-3-oxoalkanoates led to the formation of the corresponding 9c-alkyl-2-R-2,3-dihydrochromeno[3′,4′:1,3]cyclopropa[1,2-c]pyrrole-1,3,4-triones.     

Reactions of zinc enolates derived from α,α-dibromo carbonyl compounds with 3-(2-oxo-4a,8a-dihydro-2H-chromene-3-carbonyl)chromen-2-one

Zinc enolates derived from 1-R-2,2-dibromoethanone reacted with 3-(2-oxo-4a,8a-dihydro-2H-chromene-3-carbonyl)chromen-2-one to give the corresponding 1-R-1a-{(1-R-2-oxo-1,7b-dihydrocyclopropa[c]chromen-1(2H)-yl)carbonyl}-1a,7b-dihydrocyclopropa[c]chromen-2(1H]-ones as a single diastereoisomer with cis arrangement of the hydrogen atoms with respect to the cyclopropane ring plane. Reactions of the same electrophilic substrate with zinc enolates obtained from 1-aryl-2,2-dibromoalkanones led to the formation of 1-alkyl-1a-{(1-alkyl-1-aroyl-2-oxo-1,7b-dihydrocyclopropa[c]chromen-1(2H)-yl)carbonyl}-1-aroyl-1a,7b-dihydrocyclopropa[c]chromen-2(1H)-ones as a single diastereoisomer with trans arrangement of the alkyl group and hydrogen atom with respect to the cyclopropane ring plane.     

Reactions of some pyranylidene esters with amines

The reactions of 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2,6-diphenyl-4H-pyran ( 1 ) with primary amines gave the corresponding 1-substituted 1,4-dihydropyridine derivatives. The related benzo derivative of 1 (12) and primary amines gave 3-substituted 3,4-dihydro-2-phenyl-5H-[1]benzopyrano[3,4-c] pyridine-4,5-dione derivatives. With secondary amines, 12 gave 2-phenyl-4H,5H-pyrano[3,4-c] [1]benzopyrane-4,5-dione, and with isopropylamine, N,N-dimethylhydra-zine, and methanolic potassium hydroxide, 12 gave 4-phenacylcoumarin. Some reaction intermediates were isolated which indicate probable reaction paths. The reactions with amines were extended to a naphtho derivative of 1 (19) and to a thia homolog of 12 (24).     

Iodocyclization of 6-allylamino-4,5-dihydropyrazolo[3,4-d]pyrimidines

6-Allylamino-1-R-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidines treated with iodine in the presence of potassium carbonate are converted into 6-allylamino-1-R-1H-pyrazolo[3,4-d]pyrimidines that at further reaction with iodine undergo the cyclization into 6-iodomethyl-1-R-1,6,7,8-tetrahydroimidazo [1,2-a]pyrazolo[3,4-d]-pyrimidin-5-ium iodide of a linear structure. In the absence of potassium carbonate alongside the mentioned linear products 8-iodo-methyl-1-R-1,4,5,6,7,8-hexahydroimidazo[1,2-a]pyrazolo[4,3-e] pyrimidin-9-ium iodides of an angular structure have been obtained.     

Synthesis of methyl 2-aryl-5-chlorosulfonyl-1,3-oxazole-4-carboxylates and their reactions with amines and amidines

Previously unknown methyl 2-aryl-5-chlorosulfonyl-1,3-oxazole-4-carboxylates have been synthesized. Their reactions with amines and amidines have yielded the corresponding sulfonamides and 6H,7H-[1,3]oxazolo-[5,4-d]pyrimidin-7-ones.     

The reactions of 4-dicyanomethylene-2-phenyl-4H-1-benzopyran and some benzologs with nucleophiles

4-Dicyanomethylene-2-phenyl-4H-1-benzopyran (1) reacts with primary amines under mild conditions to give 4-imino-3-alkyl-5-alkylimino-2-phenyl-3,4-dihydro-5H-[1]benzopyrano[3,4-c]-pyridine derivatives which, in turn, are hydrolyzed with acid to 4-imino-3-alkyl-2-phenyl-3,4-dihydro-5H-[1]benzopyrano[3,4-c]pyridin-5-ones. When more vigorous conditions are employed for the reactions of 1 with primary amines, Dimroth rearrangements take place and the products are derivatives of 4-alkyl- (or aryl)amino-5-alkyl- (or aryl)imino-2-phenyl-5H-[1]benzopyrano-[3,4-c]pyridine. The latter compounds are hydrolyzed by acid to the corresponding 5-pyridone derivatives. The reaction of 1 with piperidine gives 2-phenyl-4-piperidyl-5H-[1]benzopyrano-[3,4-c]pyridin-5-one. Sodium methoxide reacts with 1 to give 3-cyano-2-methoxy-4-(2-hydroxyphenyl)-6-phenylpyridine. Two benzologs of 1 have been allowed to react with primary and secondary amines and the products are analogous to those obtained from 1 .     

Reaction of polychloroacetaldehyde arylsulfonylimines with 2-amino-6<Emphasis Type="Italic">H</Emphasis>-1,3-thiazine-6-thiones and 2-amino-4-phenyl-6<Emphasis Type="Italic">H</Emphasis>-1,3-thiazin-6-one

2-Amino-4-R-6H-1,3-thiazine-6-thiones and 2-amino-4-phenyl-6H-1,3-thiazin-6-one react with highly electrophilic N-arylsulfonylimines of chloral and phenyldichloroacetic aldehyde at the exocyclic amino group affording in good yields products of nucleophilic addition to the azomethine group of imines: N-[2-polychloro-1-(6-thioxo-4-R-6H-1,3-thiazin-2-ylamino)ethyl]- or -[2-polychloro-1-(6-oxo-4-phenyl-6H-1,3-thiazin-2-ylamino)ethyl]arenesulfonamides.     

Mechanism of formation of carbene complexes by reaction of cis-[PdCl2(PPh3)(CNR)] with secondary amines

A kinetic study is reported for the reactions of secondary aromatic amines p-YC₆H₄NHR (Y = MeO, Me, H; R = Me, Et) with the isocyanide complexes cis-[PdCl₂(p-XC₆H₄NC)(PPh₃)] (X = Me, H, Cl) leading to the carbene derivatives cis-[PdCl₂ {C(NH-p-C₆H₄X)NR-p-C₆H₄Y} (PPh₃)] in 1,2-dichloroethane at 25°C. A stepwise mechanism is proposed which involves a direct nucleophilic attack of the entering amine on the isocyanide carbon followed by proton transfers to the final carbene complexes. These take place both intramolecularly in a four-membered cyclic transition state and by the agency of one further amine molecule serving as a proton acceptor-donor in a six-membered transition state. Competition experiments with primary amines and trends in rate parameters are discussed to support the mechanism.     

Synthesis of heterocycles based on arylation products of unsaturated compounds: XVII. Arylation of 2-acetylfuran and synthesis of 3-R-6-(5-aryl-2-furyl)-7<Emphasis Type="Italic">H</Emphasis>-[1,2,4]triazolo[3,4-<Emphasis Type="Italic">b</Emphasis>][1,3,4]thiadiazines

Reaction of 2-acetylfuran with arenediazonium chlorides under Meerwein reaction conditions led to the formation of 5-aryl-2-acetylfurans. The bromination of these compounds gave 2-bromo-1-(5-aryl-2-furyl)-ethanones that reacted with 4-amino-4H-5-R-1,2,4-triazole-3-thiols to form 3-R-6-(5-aryl-2-furyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines.     

The Mannich-type interaction of sulfur-containing CH acids with formaldehyde and primary amines

One-pot reactions of dimethyl sulfonyldiacetate and N-methyl-2r,6c-di(methoxycarbonyl)-3t,5t-diphenyltetrahydro-1,4-thiazine 1,1-dioxide with formaldehyde and primary amines lead to derivatives of 9-thia-3,7-diazabicyclo[3.3.1]nonane 9,9-dioxide resulted from decarboxylation of the ester groups at the positions 1 and 5. The effects of the reaction conditions and structure of the starting reagents on the yields of 9-thia-3,7-diazabicyclo[3.3.1]nonane 9,9-dioxides were studied.     

Azines and azoles: CXXVI. First example of a novel heterocyclic system: Pyrimido[1,6-<Emphasis Type="Italic">a</Emphasis>][1,5]benzodiazepines

4-Hydroxy-5-(2-R-2,3-dihydro-1H-1,5-benzodiazepin-4-yl)-2H-1,3-thiazine-2,6-diones readily undergo acylation at the N¹ atom of the benzodiazepine system by the action of acetic anhydride. Heating of the acetylated products in boiling dimethylformamide leads to the formation of 75–93% of the corresponding 7-acetyl-6-R-6,7-dihydropyrimido[1,6-a][1,5]benzodiazepine-1,3-diones that are derivatives of hitherto unknown fused heterocyclic system, pyrimido[1,6-a][1,5]benzodiazepine. 4-Hydroxy-5-(2-R-2,3-dihydro-1H-1,5-benzodiazepin-4-yl)-2H-1,3-thiazine-2,6-diones are converted into 1-(2-aminophenyl)-6-(2-R-vinyl)uracils on heating in boiling DMF.     

VI. Synthesis of Heterocyclic Analogs of γ-Aminobutyric Acid from 3,5-Dinitrobenzoic Acid

A series of 7-carboxy-3-R-1,5-dinitro-3-azabicyclo[3.3.1]non-6-enes was synthesized by reduction of 3,5-dinitrobenzoic acid with sodium borohydride followed by Mannich reaction with formaldehyde and primary amines. The mechanism of decomposition under electron impact of the 3-azabicyclo[3.3.1]nonane was established. Enthalpies of formation of compounds synthesized were calculated by semiempirical PM3 method.