Investigations in the imidazole series

The catalytic dechlorination of 1-alkyl-5-chloro-, 1-alkyl-4-chloro-, and 1-alkyl(aralkyl)-2-alkyl(aryl)-5-chloroimidazoles in the presence of Raney nickel, which makes it possible to simplify the synthesis of a number of 1-alkyl- and 1-alkyl(aralkyl)-2-alkyl(aryl)imidazoles, was investigated.See [1] for communication LXXV.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 820–822, June, 1972.     

Synthesis and properties of 1,3-diaza-2-phospholo[4,5-d]pyrimidines

Reaction of 5-amino-4-alkyl(aryl or aralkyl)aminopyrimidines with PCl₅ gives 2,2-dichloro-3-alkyl(aryl or aralkyl)-1,3-diaza-2-phospholo[4,5-d]pyrimidines, which on treatment with piperidine or morpholine are converted into the corresponding 2,2-diamino derivatives. The latter, on boiling in water or aqueous alcohol, give the dipiperidides or dimorpholides of the corresponding 5-pyrimidylamidophosphoric acids.Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 6, No. 5, pp. 710–712, May, 1970.     

Studies in the imidazole series

By quaternization of 1-alkyl(aryl, aralkyl)-2-methyl-4, 5-diarylimidazoles with -bromo ketones and by subsequent cyclization of the quaternary salts of imidazole, a number of arylpyrrolo[1,2-a]imida~ zoles were obtained. A study was made of the effect of different bases on the process of cyclization and the yield of pyrroloimidazole derivatives. The structure was established of certain intermediate products of the reaction involving the closure of the pyrrole ring.For Part XXXVI, see [11].     

Synthesis of 2-alkyl(aralkyl)sulfanyl-6-methylpyrimidin-4(3<Emphasis Type="Italic">H</Emphasis>)-ones and 4-alkyl(aralkyl)oxy-2-alkyl(aralkyl)sulfanyl-6-methylpyrimidines

2-Alkyl(aralkyl)sulfanyl-6-methylpyrimidin-4(3H)-ones and 4-alkyl(aralkyl)oxy-2-alkyl(aralkyl)-sulfanyl-6-methylpyrimidines having similar or different substituents on the sulfur and oxygen atoms were synthesized by alkylation of sodium salts derived from 6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-4-one and 2-alkyl(aralkyl)sulfanyl-6-methylpyrimidin-4(3H)-ones with alkyl (propyl, ethyl, allyl) and aralkyl [benzyl, m-phenoxybenzyl, p-(1-adamantylbenzyl)] halides. The effects of the alkyl (aralkyl) halide nature and solvent polarity on the rate of nucleophilic substitution and product yield were studied.     

Unusual cleavage of phenacyl-substituted benzimidazolium salts. Synthesis of 1,4-diarylimidazoles

The action of ammonium acetate in acetic acid on 1-alkyl(aralkyl)-3-phenacylbenzimidazolium bromides leads, in addition to the formation of a new imidazole ring, to cleavage of the benzimidazole fragment of the molecule at the 1,2 bond to give 1-alkyl(aralkyl)aminoaryl-4-arylimidazoles. 1,2-Dimethyl-3-(p-nitrophenacyl)benzimidazolium bromide is converted under similar conditions to the corresponding 2-methylimidazole. 4,4-Dimethyl-2,2-bis(p-nitrophenyl)-1,1-dipyrrolo[1,2-a]benzimidazole was isolated as a side product of this reaction.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 388–392, March, 1982.     

Condensed imidazo-1,2,4-azines. 21. Synthesis of 2-arylfuro(pyrrolo-, thieno-)[2,3-e]-1,2,4-triazino[2,3-a]benzimidazoles by cyclization of 2-aroyl-1,2,4-triazino[2,3-a]benzimidazol-4H-3-ones

2-[(-Ethyl-, arylimino)phenethyl]-1,2,4-triazino[2,3-a]benzimidazoles were obtained by reaction of 2-aroylmethyl-1,2,4-triazino[2,3-a]benzimidazol-4H-3-ones with ethyl(aryl)amines or urea. By the action of phosphorus oxychloride, these benzimidazoles cyclize into substituted pyrrolo[2,3-e]-1,2,4-triazino[2,3-a]benzimidazoles, heating of which in polyphosphoric acid leads to the formation of furo[2,3-e]-1,2,4-triazino[2,3-a]benzimidazoles, while by the action of P₄S₁₀, they are transformed into thieno[2,3-e]-1,2,4-triazino[2,3-a]benzimidazoles.For Communication 20, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1109–1113, August, 1989.     

Research on imidazo[1,2-a]benzimidazole derivatives XII. 3-Acyl-substituted imidazo[1,2-a]benzimidazoles

Stable 3-acetyl derivatives of imidazo[1,2-a]benzimidazole were synthesized by the action of acetic anhydride on 2,9-disubstituted imidazo[1,2-a]benzimidazole. The former were also obtained by cyclization of 1-alkyl (aralkyl) -3-acylmethyl-2-iminobenzimidazoline hydrobromides in acetic anhydride in the presence of anhydrous sodium acetate. 3-Benzoyl-substituted imidazo[1,2-a]benzimidazoles, which are unstable in acidic media, were synthesized by the action of benzoyl chloride in the presence of pyridine or excess starting imidazo [1,2-a] benzimidazole.See [1] for communication XI.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 121– 125, January, 1976.     

Heterocyclic Analogs of Prostaglandins: I. Synthesis of 3-Alkyl(Aralkyl)-2,5-dihydrofuran-2-ones as Synthons for 11-Deoxy-10-oxaprostanoids

3-Acyl(arylmethyleneacyl)tetronic acids were synthesized. Selective hydrogenation of the carbonyl group in the acyl fragment and reduction of the conjugated double bond afforded in high yield the corresponding 3-alkyl(aralkyl) derivatives possessing either natural or modified prostaglandin -chain. Reduction of the conjugated double bond in vinylogous 3-alkyl(aralkyl)tetronic acid amides with sodium cyanotrihydridoborate gave a mixture of stereoisomeric -amino lactones which underwent retro-Michael elimination of the amine residue, leading to 3-alkyl(aralkyl)-2,5-dihydrofuran-2-ones. The latter can be regarded as synthons for 11-deoxy-10-oxaprostanoids.     

Imidazo[1,2-a]benzimidazole derivatives

3-Amino derivatives of 9-alkyl(benzyl)-2-arylimidazo[1,2-a]benzimidazoles, obtained by the reduction of the appropriate 3-nitro(nitroso) derivatives, are extremely unstable, and the imidazole ring opens readily resulting in conversion to 2-(-carboxybenzylamino)benzimidazoles. The reaction apparently proceeds through the intermediate formation of 2-(-cyanobenzylamino)benzimidazole, which is a tautomeric form of the 3-amino compound and can react as such to form 3-acylamino derivatives and anils. If there is a methyl group in the 3-position of the ring, the amine is quite stable and can be isolated in free form.See [1] for communication IV.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 673–677, May, 1971.     

Thebaine Adducts with Maleimides. Synthesis and Transformations

Diels-Alder reaction of thebaine with maleimides is structurally specific and yields [7,8,3′,4′ ]-succinimido-endo-ethenotetrahydrothebaines containing N′-alkyl, cycloalkyl, aralkyl or aryl substituents. N′-[1(S)-hydroxymethyl-2-methylpropyl]-succinimido-6,14-endo-ethenotetrahydrothebaine formed in reaction of S-valinol with (7α,8α)-anhydrido-6,14-endo-ethenotetrahydrothebaine. The reduction of the adducts by LiAlH₄ afforded N′-substituted 7,8-pyrrolidino-endo-ethenotetrahydrothebaines. The reduction of fused succinimides by NaBH₄ resulted in the corresponding 2′α-hydroxylactam derivatives. O-Demethylation of the tetrahydrothebaine pyrrolidine derivatives effected by BBr₃ afforded compounds of the tetrahydrooripavine series. The O-demethylation of tetrahydrothebaine succinimide derivatives gave rise to the corresponding 6-demethyl-endo-ethenotetrahydrooripavines. Alkylation conditions were found for N′-(4-hydroxyphenethyl)-substituted tetrahydrothebaine succinimide derivatives.     

Synthesis of 3-alkyl(aryl)-3-aminoquinuclidines

A series of 3-alkyl(aryl)-3-aminoquinuclidines was synthesized by means of the interaction between 3-alkyl(aryl)-3-oxyquinuclidines and acetonitrile in the presence of concentrated sulfuric acid with subsequent hydrolysis of the 3-alkyl(aryl)-3-acetaminoquinuclidines. It was shown that in addition to acetamino derivatives 3-alkyl-²-dehydroquinuclidines and 3-alkylidenequinuclidines are formed, the structure of which was established by the method of NMR.     

Multicomponent Synthesis of 4-Alkyl(Aryl,Hetaryl)-2-alkoxycarbonyl(aroyl,carbamoyl)- 3,6-diamino-5-cyanothieno[2,3-<Emphasis Type="Italic">b</Emphasis>]pyridines

The condensation of malononitrile with hydrogen sulfide and aldehydes in the presence of triethylamine in ethanol at room temperature afforded 4-alkyl(aryl, hetaryl)-2,6-diamino-3,5-dicyano-4H-thiopyrans. Treatment of the latter in situ with alkali in DMF, followed by addition of an alkylating agent, led to the formation of 4-alkyl(aryl, hetaryl)-2-alkoxycarbonyl(aroyl, carbamoyl)-3,6-diamino-5-cyanothieno[2,3-b]- pyridines.     

Efficient synthesis of new 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrol-2(5H)-ones

The synthesis of 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrol-2(5H)-ones 5, 6a-d from 1-alkyl(aryl)-4-bromo-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 3, 4a-d is reported. The 1-alkyl(aryl)-4-bromo-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 3, 4a-d were obtained from regiospecific bromination of 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones 1, 2a-d with molecular bromine. The NMR and X-ray diffraction data showed that 1-alkyl(aryl)-5-(3,3,3-trihalo-2-oxopropylidene)-1H-pyrrolidin-2-ones were brominated at 4-position in the pyrrolidin-2-one ring.     

A new route to pyrimido[1,6‐a]benzimidazole derivatives

Cyclocondensation of orthophenylendiamines with 3‐bromopropionic acid in PPA afforded 2‐vinylbenzimidazoles which were subsequently converted to their corresponding 2‐(1,2‐dibromoethyl)‐1H‐benzimidazoles on treatment with bromine. Reaction of these compounds with aryl nitriles or aryl isocyanates in basic chloroform yielded 1‐arylpyrimido[1,6‐a]benzimidazoles and 2‐arylpyrimido[1,6‐a]‐benzimidazol‐3‐ones respectively.     

S-烃基-1-烃基-3-[4-(苯并咪唑-2-巯基)苯基]异硫脲的合成及其iNOS抑制活性

以2-巯基苯并咪唑(1)为原料,经缩合和还原得到2-(4-氨基苯硫基)苯并咪唑(3),再与异硫氰酸苯甲酰酯或异硫氰酸烃基酯反应得到取代硫脲(5和7),最后与卤代烃反应得到20个新的S-烃基-1-烃基-3-[4-(苯并咪唑-2-巯基)苯基]异硫脲化合物(6和8),其结构经IR,¹HNMR,MS及元素分析确证.初步的药理试验表明,20个目标化合物均有不同程度的iNOS抑制活性,其中化合物6b,8d和8f的iNOS抑制活性与阳性对照药氨基胍相当.     

Cyclocondensation of <Emphasis Type="Italic">N</Emphasis>-aryl-3-oxobutanethioamides with 2-aminoimidazole and 2-aminobenzimidazole

Cyclization of N-aryl-3-oxobutanethioamides with 2-aminoimidazole and 2-aminobenzimidazole gave 7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-5-thione or 2-methylpyrimido[1,2-a]benzimidazole-4(1H)-thione and 4-(arylamino)-2-methylpyrimido[1,2-a]benzimidazoles whose ratio depends on the nature of aryl substituents in the initial butanethioamides and on the presence of a protic solvent.     

Reaction of Ethyl 6-Alkyl(aryl)-4-chloromethyl-2-methylpyridine-3-carboxylates with Ammonia and Primary Amines

Ethyl 6-alkyl(aryl)-4-chloromethyl-2-methylpyridine-3-carboxylates react with ammonia andprimary amines to give 6-substituted 3-alkyl(aryl)-1-methyl-1'2-dihydropyrrolo[3'4-c]pyridin-7-ones.The reactions with 4-aminopyridine yield ethyl 6-alkyl(aryl)-2-methyl-4-(4-pyridylaminomethyl)pyridine-3-carboxylates.     

Novel route of the reaction of trifluoromethyl-containing N-methyl(4-ethoxyphenyl)imidazolidin-2-ones with urea

The reactions of perfluorobiacetyl with N-(4-ethoxyphenyl)- and N-methylurea afforded cis- and trans-isomers of 1-methyl-4,5-dihydroxy-4,5-bis(trifluoromethyl)imidazolidin-2-one and 1-(4-ethoxyphenyl)-4,5-dihydroxy-4,5-bis(trifluoromethyl)imidazolidin-2-one in a yield of ～60—75%. N-Alkyl(aryl)bis(trifluoromethyl)imidazooxazoles were obtained as unexpected products in the reaction of 1-alkyl(aryl)-4,5-dihydroxy-4,5-bis(trifluoromethyl)imidazolidin-2-ones with urea in dimethylacetamide. The reaction is accompanied by the rearrangement of imidazolidin-2-ones to N-alkyl(aryl)-5,5-bis(trifluoromethyl)hydantoins with CF₃ group migration from position 5 to position 4 of the starting heterocycle. A similar rearrangement is observed on boiling of the studied imidazolidin-2-ones in dimethylacetamide. The molecular structures of 3-(4-ethoxyphenyl)-5,5-bis(trifluoromethyl)imidazolidine-2,4-dione and 6-(4-ethoxyphenyl)-3a,6a-bis(trifluoromethyl)tetrahydroimidazo[4,5-d]oxazole-2,5-dione were studied by X-ray diffraction analysis.     

Synthesis of new polyfunctional 5,6,7,8-tetrahydroimidazo-[1,5-<Emphasis Type="Italic">c</Emphasis>]pyrimidin-5-ones by the aza-Wittig reaction followed by intramolecular cyclization and 1,3-prototropic shift

Ethyl 2-oxo-6-[(triphenyl-λ⁵-phosphanylidene)aminomethyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylates reacted with organic isocyanates according to the aza-Wittig pattern, and the subsequent intramolecular ring closure and 1,3-H shift resulted in the formation of ethyl 3-alkyl(aryl)amino-5-oxo-5,6,7,8-tetrahydroimidazo[1,5-c]pyrimidine-8-carboxylates.     

3-α-Halocarbonyl derivatives of pyrazolo[1,5-a] benzimidazole and their reactions

3-(-haloacyl)-2,4-dialkylpyrazolo[1,5-a]benzimidazoles can be obtained either by brominating 3-acetylpyrazolo[1,5-a]benzimidazoles with bromine in acetic acid, or by acylating the 3-unsubstituted pyrazolobenzimidazoles with haloacetic halides. Halogenation of 3-acetylpyrazolo[1,5-a]benzimidazoles with bromine in acetic acid in the presence of sodium acetate, and bromination with N-bromosuccinimide or 1-chlorobenzotriazole, result in deacylation to give 3,6(7)-dibromo- and 3-chloropyrazolo[1,5-a]benzimidazoles. The mono- and trihaloketones obtained have been used to prepare the corresponding aminoketones, the 3-carboxylic acid, and its derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 43–48, January, 1988.