Condensation of 1-Substituted 1,2,3,9a-Tetrahydro-9H-imidazo[1,2-a]indol-2-one Derivatives with Aromatic Aldehydes

Condensation of 1-alkyl-, 1-allyl-, and 1-benzyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones with benzaldehydes in acetic acid and subsequent treatment of the reaction mixture with potassium hydroxide afforded 1-substituted 9a-(2-phenylethenyl)-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one derivatives. 1-Methyl- and 1-ethyl-9a-[2-(4-dimethylaminophenyl)ethenyl]-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones were synthesized by alkylation of 9a-[2-(4-dimethylaminophenyl)ethenyl]-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one with methyl- and ethyl iodides in DMF in the presence of a strong base.     

A thermal cascade route to pyrroloisoindolone and pyrroloimidazolones

Flash vacuum pyrolysis (FVP) of indol-1-ylacrylate derivatives 11 and 15 or the isomeric indol-3-ylacrylates 21, 22, and 24 at 925 degrees C (0.05 Torr) provides pyrrolo[1,2-a]indol-3-ones 2, 18, 28, and 29 in 53-90% yield by a cascade mechanism that involves a sigmatropic migration, elimination, electrocyclization sequence. Pyrrolo[1,2-a]imidazol-5-ones 3 and pyrrolo[1,2-c]imidazol-5-ones 4 were similarly obtained by FVP of corresponding 2,5-unsubstituted imidazol-1-ylacrylates (e.g., 33), with the former isomer predominating in ca. 80:20 ratio. Migration to the 2-position is therefore favored in the initial sigmatropic shift. FVP of 2-substituted imidazol-1-ylacrylates 35, 37, and 51 (825-875 degrees C) instead give pyrrolo[1,2-c]imidazol-5-ones 56-58 only (88-91%), and that of 4,5-disubstituted imidazol-1-ylacrylates 39 and 41 (825-850 degrees C) provide pyrrolo[1,2-a]imidazol-5-ones 59 and 60 exclusively (93-95%), and thus the selectivity of the initial shift can be controlled by the presence of substituents on the imidazole 2- and 5-positions. FVP of the benzimidazole analogues 61 and 62 at 950 degrees C gave the pyrrolo[1,2-a]benzimidazol-1-ones 6 (71%) and 63 (36%), respectively.     

Novel synthesis of bicycles with fused pyrrole, indole, oxazole, and imidazole rings

Reactions of benzotriazol-1-yl(1H-pyrrol-2-yl)methanone 10 and benzotriazol-1-yl(1H-indol-2-yl)methanone 11 with diverse ketones, isocyanates, and isothiocyanates in the presence of base afforded pyrrolo[1,2-c]oxazol-1-ones 1, oxazolo[3,4-a]indol-1-ones 2, pyrrolo[1,2-c]imidazoles 3, and imidazo[1,5-a]indoles 4 by a simple one-step procedure.     

Reaction of 2,3,3-trimethyl-3H-indole salts with acrylamide. Synthesis of 1,2,3,4,10,10a-hexahydropyrimido[1,2-a]indol-2-one derivatives

Methyl derivatives of pyrimido[1,2-a]indol-2-one were obtained by the reaction of 2,3,3-trimethyl-3H-indole salts with acrylamide in a proton-containing solvent. The products were condensed with aromatic aldehydes. The interconversion of pyrimido[1,2-a]indol-2-ones and 1-(2-carbamoylethyl)-3H-indolium salts under the influence of acids and bases was studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1056–1059, August, 1986.     

Alkylation of 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones

Reaction of 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones with dimethyl sulfate and haloalkanes in DMF or DMSO in the presence of potassium hydroxide gives the 1-substituted 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones (N-substituted products) and 9,9a-dihydro-3H-imidazo[1,2-a]indoles (O-substituted products). The latter, on treatment with acids and bases, are converted into 1-alkoxycarbonylmethyl-2,3-dihydro-1H-indoles. 1-Ethoxycarbonyl-methyl-2,3-dihydro-1H-indoles on treatment with lithium aluminohydride undergoes cyclization to 2,3,9,9a-tetrahydrooxazolo[3,2-a]indole.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 49–53, January, 1988.     

Alkylation of 1,2,3,4,10,10a-hexahydropyrimido[1,2-a]indol-2-one

A mixture of N- and O-alkylation products is formed in the reaction of 1,2,3,4,10,-10a-hexahydropyrimido[1,2-a]indol-2-ones with ethyl iodide, allyl bromide, or benzyl chloride in DMFA (dimethylformamide) in the presence of potassium hydroxide. In the presence of aqueous solutions of acids with subsequent treatment with bases, the alkylation products are converted to 1-[2-(alkoxycarbonyl)-ethyl]-2-methylene-2,3-dehydro-1H-indoles. The reaction of 1,2,3,4,10,10a-hexahydropyrimido[1,2-a]indol-2-one with triethyloxonium fluoroborate gives 1-[2-(ethoxycarbonyl)ethyl]-2-methylene-2,3-dihydro-1H-indole.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1224–1227, September, 1989.     

Triazino-1,2,4-[4,5-a] indoles IV. Etude des triazinoindolethiones

The 1,2-dihy dro-1,2,4-triazino[4,5-a] indole-1-thiones 2 and 3 obtained by sulphurization of the 1,2-dihydro-1,2,4-triazino-[4,5-a] indol-1-ones 1 and 4 with phosphorus pentasulphide are intermediate products in the synthesis of 1,2,4-triazino[4,5-a]-indolc 10 and 4-methyl-1,2,4 omdp;e 19. The thiolactam-thiolactim tautomerism was studied using the ir and nmr spectra and allowed N. and S.substitutions. The methylation with dimethyl sulphate afforded mixtures of N. and S. methyl derivatives which were separated by chromatographic analysis and identified by |21|0H nmr and unequivocal synthesis.     

Syntheses of optically active tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones and hexahydroimidazo[1,2-a]pyridin-2(3H)-ones

The reactions of (2S)-2-amino-2-substituted-N-(4-nitrophenyl)acetamides 16a-c, succindialdehyde (13), and benzotriazole afforded enantiopure (3S,5R,7aR)-5-(1H-1,2,3-benzotriazol-1-yl)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 17a-c, which were converted by sodium borohydride into (3S,7aR)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 18a-c. Chiral (2S)-2-amino-2-substituted-N-(4-methylphenyl)acetamides 12a-d, easily prepared in two steps from N-Boc-alpha-amino acids 10a-d, similarly reacted with glutaraldehyde (20) and benzotriazole to generate 5-benzotriazolyl-3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 21a-d, which were converted by sodium borohydride directly into optically active 3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 22a-d.     

Condensation of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium chloride with aromatic aldehydes

The reaction of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium chloride with various aromatic aldehydes in acetic acid and the subsequent workup of the intermediate styrylic derivatives with strong bases yielded 9a-(2-arylethenyl)-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one derivatives. Condensation of the mentioned salt with salicylaldehyde in acidic or basic medium afforded the derivative of l-carbamoylmethylspiro[benzopyran-2,2-indole]. Alkylation of the latter compound with benzyl chloride in the presence of potassium hydroxide gave 9a-[2-(2-benzyloxyphenyl)ethenyl]-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one.Department of Organic Chemistry, Kaunas University of Technology, LT-3028 Kaunas, Lithuania Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 761–769, June, 2000.     

新型环烷烯并嘧啶并噻唑-3-酮类化合物的合成

以环戊酮、环庚酮为起始原料合成的环烷烯并[1,2-d]嘧啶-2-硫酮(2)与氯乙酸、芳香醛反应, 合成具有潜在抗癌活性的稠合杂环化合物5-芳基-2,8-二芳亚甲基-2,3,6,7-四氢-5H,8H-环戊烯并[1,2-d]噻唑并[3,2-a]嘧啶-3-酮(3)以及5-芳基-2,10-二芳亚甲基-2,3,6,7,8,9-六氢-5H,10H-环庚烯并[1,2-d]噻唑并[3,2-a]嘧啶-3-酮(4). 3和4的结构经¹H NMR, IR, MS分析确认.     

New method for the annelation of a pyridine ring on derivatives of imidazole and benzimidazole

The interaction of (Z)-1,3-diaryl-4-bromo-2-buten-1-ones with 1-substituted (benz)imidazoles in benzene gave (Z)-1-R-3-(2,4-diaryl-4-oxo-2-butenyl)-1H-imidazolium bromides and (Z)-1-R-3-(2,4-diaryl-4-oxo-2-butenyl)-1H-benzimidazolium bromides which readily cyclize in the presence of base to form derivatives of 7,9-diarylpyrido[1,2-a]benzimidazole and 6,8-diarylpyrimidazo[1,2-a]pyridine. The effects of the nature of substituents in the benzene ring of the diarylbutenones and the substituent at N(1) in the (benz)imidazoles on the alkylation and cyclization reactions has been studied. The optimum conditions for the synthesis of the 5-R-4-hydroxy-2,4-diphenyl-4,5-dihydro-1H-pyrido[1,2-a]benz-imidazol-10-ium, 5-R-2,4-diaryl-4-hydroxy-4,5-dihydro-3H-pyrido[1,2-a]benzimidazol-10-ium, and 5-R-2,4-diaryl-5H-pyrido[1,2-a]benzimidazol-10-ium have been found.     

Synthesis of substituted diazines,diazoles, and condensed thia- and oxadiazoles

The corresponding 2-arylhydrazono-3-oxoimidazo[1,2-a]pyridines, 3-arylhydrazono-2-oxoimidazo [1,2-a]benzothiazoles, 2-oxoimidazolidino[3,2-a]benzimidazoles, 2-oxoimidazo[1,2-a]benzoxazoles, and 2-arylhydrazono-3-oxothiazolo[2,3-a]benzimidazoles were obtained by the condensation of arylazochloroacetyl chlorides with 2-aminopyridine, 2-aminobenzothiazole, 2-aminobenzoxazole, 2-aminobenzimidazole, and 2-mercaptobenzimidazole. 5-Arylhydrazono-1,2-diphenylimidazole-4-ones and 5-arylhydrazono-3,4-diaryl-1,2,4-oxidiazine-6-ones were synthesized by the reaction of arylazochloroacetyl chlorides with N-phenylbenzamidine and N-phenylamidoxime.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 930–936, July, 1971.     

1,2,3,9a-Tetrahydro-9H-imidazo[1,2-a]indoles

When derivatives of 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-one or 1-carbamoylmethyl-2-methylene-2,3-dihydroindole are reacted with lithium aluminum hydride, derivatives of 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indole are formed. Under the same conditions 1-(N-phenylcarbamoylmethyl)-2-methylene-2,3-dihydroindole is not cyclized to an imidazo[1,2-a]indole. WHen treated with proton acids imidazo[1,2-a]indoles are converted to 3H-indolium salts. Opening of the imidazolidine ring is also found when imidazo[1,2-a]indole is acylated with benzoyl chloride.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 227–230, February, 1987.     

Reaction of dihalocarbenes with 2-(benzylideneamino)pyridines. Cyclization of 2-(benzylideneamino)pyridinium dihalomethylids to give 2-aryl-3-haloimidazo[1,2-α]pyridines

Pyridinium dichloromethylids, formed in the reaction of dichlorocarbene with 2-(benzylideneamino)pyridines, undergo intramolecular 1,5-cyclization to give 2-aryl-3-chloroimidazo[1,2-a]pyridines, which undergo partial conversion to 2-aryl-3-chloro-4H-pyrido[1,2-a]pyrimidin-4-ones under the reaction conditions. 2-Aryl-3-bromoimidazo[1,2-a]pyridines and 2-[N-(1-aryl-2,2,2-tribromoethyl)amino]pyridines, respectively, are obtained in the reaction of dibromocarbene and the tribromomethyl onion generated in the reaction of bromoform with potassium hydroxide.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 810–816, June, 1991.     

NMR spectroscopic structure elucidation of the products of the reaction of 3-(3-aryl-3-oxopropenyl)- chromen-4-ones with 1,2-phenylenediamine

The reaction of 3-(3-aryl-3-oxopropenyl)chromen-4-ones with 1,2-phenylenediamine resulted in the unexpected formation of 10a-aryl-1,2,10,10a-tetrahydrobenzo-[4,5]-imidazo[1,2-a]pyridin-3-yl(2-hydroxyphenyl)-1-methanones. Their structure elucidation and complete 1H and 13C assignments have been performed by a combination of various one- and two-dimensional NMR experiments.     

Unusual reactions of 5,5-dimethyl-2-(indenyl-2)-3-pyrazolidinone with acetylenedicarboxylates

[reaction: see text] Reaction of 5,5-dimethyl-3-pyrazolidinone (1) with 2-indanone (2) gave 5,5-dimethyl-2-(1H-indenyl-2)-3-pyrazolidinone (3) instead of the expected azomethine imine 4. Although reaction of 2-substituted 3-pyrazolidinones with acetylenedicarboxylates usually gives ring expansion products, such as 1,2-diazepines, treatment of 3 with dialkyl acetylenedicarboxylates (5, R = Me; 6 R = Et) resulted in the formation of rel-(7aR,12aS)-6,7-bis(alkoxycarbonyl)-3,4-dihydro-4,4-dimethyl-7aH-indano[1,2-b]pyrrolo[1,2-a]pyrimidin-2-ones (7, R = Me; 9, R = Et) as major products and 3,4-bis(alkoxycarbonyl)-7,7-dimethyl-2-(indenyl-2)-6,7-dihydro-2H,6H-1,2-diazepin-5-ones (8, R = Me: 10, R = Et) as minor products.     

Synthesis of 1-substituted 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones

1-R-9,9,9a-Trimethyl-1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones and the corresponding 2-methylene-2,3-dihydroindoles were obtained by the reaction of 2,3,3-trimethyl-3H-indole with a number of N-substituted chloroacetic acid amides and subsequent reaction of the resulting quaternary salts with bases. The kinetics of intramolecular cyclization of 1-(N-alkylcarbamoylethyl)-2-methylene-2,3-dihydroindoles under the influence of acetic acid were studied. Under the influence of strong protic acids 1-R-imidazo[1,2-a]indol-2-ones undergo decyclization and are converted to 3H-indolium salts.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1485–1489, November, 1986.     

Quinolinone and pyridopyrimidinone inhibitors of DNA-dependent protein kinase

8-Substituted 2-morpholin-4-yl-quinolin-4-ones and 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones with selected aryl and heteroaryl groups as the substituent have been synthesised as potential inhibitors of DNA-dependent protein kinase. A multiple-parallel approach, employing Suzuki cross-coupling methodology, was utilised in the preparation of 8-substituted 2-morpholin-4-yl-quinolin-4-ones. For this purpose 8-bromo-2-morpholin-4-yl-quinolin-4-one was required as an intermediate. This compound was obtained by adapting a literature route in which thermal cyclocondensation of (2-bromoanilino)-morpholin-4-yl-5-methylene-2,2-dimethyl[1,3]dioxane-4,6-dione afforded 8-bromo-2-morpholin-4-yl-quinolin-4-one. A multiple-parallel approach, employing Suzuki cross-coupling methodology, was also utilised to prepare 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones using 9-hydroxy-2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-one O-trifluoromethanesulfonate as an intermediate. 8-Substituted 2-morpholin-4-yl-quinolin-4-ones and 9-substituted 2-morpholin-4-yl-pyrido[1,2-a]pyrimidin-4-ones were both inhibitors of DNA-dependent protein kinase. When the substituent was dibenzothiophen-4-yl, dibenzofuran-4-yl or biphen-3-yl, IC50 values in the low nanomolar range were observed. Interestingly, the pyridopyrimidinones and quinolinones were essentially equipotent with the corresponding 8-substituted 2-morpholin-4-yl-chromen-4-ones previously reported (I. R. Hardcastle, X. Cockcroft, N. J. Curtin, M. Desage El-Murr, J. J. J. Leahy, M. Stockley, B. T. Golding, L. Rigoreau, C. Richardson, G. C. M. Smith and R. J. Griffin, J. Med. Chem., 2005, 48, 7829-7846).     

Acetylation of pyridazino[4, 5-b]indoles and their dihydro and tetrahydro derivatives. III

Acetylation of pyridazino[4,5-b]indol-4-ones with acetic anhydride gives the O-acetyl derivatives, and acetylation of 1,2-dihydropyridazino[4,5-b]indol-4-ones leads to the 2-acetyl and 2,4-diacetyl derivatives. Tetrahydropyridazino[4,5-b]indoles, obtained by reduction of the dihydro derivatives, undergo substitution by an acetyl group at the 2 position.See [1] for communication II.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1218–1222, September, 1976.     

One-pot synthesis of polycyclic heterocyclic compounds by condensation of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium salts with pyridine-2, 3, and 4- and quinoline-4-carboxaldehydes

A one-pot synthesis of new polycyclic heterocyclic compounds was carried out via the condensation of 1-carbamoylmethyl-2,3,3-trimethyl-3H-indolium chloride with pyridine- and quinolinecarboxaldehydes. The heating of the aforementioned 3H-indolium salts with 1 eq. of pyridine-2, 3, and 4- or quinoline-4-carboxaldehyde in ethanol in the presence of piperidine as a catalyst provided 9a-[2-(pyridyl)ethenyl]- or 9a-[2-(quinolyl)ethenyl]-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one derivatives as the main products. However, reaction outcome was dramatically different for the analogous reactions in acetic acid. In this case, the heating of the chloride with 2 eq. of pyridine-2-carboxaldehyde afforded derivatives of 9a-[3-(pyridin-2-yl)indolizin-2-yl]-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-one as the major product, while the use of 2 eq. of pyridine-3 and 4- or quinoline-4-carboxaldehyde led to the formation 2-heteroaryl-1-heteroarylmethyl-9H-pyrrolo[1,2-a]indole-3-carboxamides. Plausible pathways for the cyclization reactions are discussed. The structural assignments were based on ¹H, ¹³C and ¹⁵N NMR spectroscopy, HRMS and single-crystal X-ray diffraction data.