A facile synthesis of pyrrolo[1,2-a]benzimidazoles and pyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazole derivatives

Reaction of 2-cyanomethylbenzimidazole 1 with hydrazonoyl halides 2 led to formation of pyrrolo[1,2-a]benzimidazole derivatives 7. Similar reaction of 1 with halides 3 afforded 5-amino-4-(benzimidazol-2-yl)pyrazole derivatives 11 or 1-amino-2-arylpyrazolo[3,4:4′,3′]pyrrolo[1,2-a]benzimidazol-4-one 14 depending on the reaction conditions. The mechanisms of the studied reactions are discussed.     

An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

Facile synthesis of 4-phenylquinolin-2(1H)-one derivatives from N-acyl-o-aminobenzophenones

An efficient synthesis of 4-phenylquinolin-2(1H)-one derivatives has been achieved in a one-pot reaction from N-acyl-o-aminobenzophenones 1a-c (a: acyl=acetyl; b: acyl=propanoyl; c: acyl=heptanoyl) using NaH as a base. Treatment of 1 with NaH provided the quinolones 2a-c with 62-83% yields, whereas the reaction in the presence of alkyl iodide (alkyl=methyl, ethyl, n-octyl) gave the corresponding N-alkylated quinolones 3a-g in 75-95% yields. The alkylation reaction of 4-phenylquinolin-2(1H)-one 2a with alkyl halide gave a mixture of N-alkylated and O-alkylated products. Comparison of IR and NMR data of the N-alkylated and O-alkylated compounds with those of 2a-c indicated that 2a-c exist as the lactam form.     

Microwave-assisted synthesis of novel bis(2-thioxothiazolidin-4-one) derivatives as potential GSK-3 inhibitors

(5Z,5′Z)-3,3′-(1,4-Phenylenebis(methylene)-bis-(5-arylidene-2-thioxothiazolidin-4-one) derivatives (5a-r) have been synthesized by the condensation reaction of 3,3′-(1,4- or 1,3-phenylenebis(methylene))bis(2-thioxothiazolidin-4-ones) (3a,b) with suitably substituted aldehydes (4a-f) or 2-(1H-indol-3-yl)2-oxoacetaldehydes (8a-c) under microwave conditions. The bis(2-thioxothiazolidin-4-ones) were prepared from the corresponding primary alkyl amines (1a,b) and di-(carboxymethyl)-trithiocarbonyl (2). The 2-(1H-indol-3-yl)-2-oxoacetaldehydes (8a-c) were synthesized from the corresponding acid chlorides (7a-c) using HSnBu₃.     

An unexpected formation of pyrazolopyrimidines during the attempted to obtain 5-substituted tetrazoles from carbonitriles

In this Letter, we described the synthesis of new 5-(5-amino-1-aryl-1H-pyrazole-4-yl)-1H-tetrazoles 2a–c from 5-amino-1-aryl-1H-pyrazole-4-carbonitriles 1a–c as well as the unexpected 1H-pyrazolo[3,4-d]pyrimidine derivatives 6a–c from 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles 4a–c, instead of 5-(5-amino-1-aryl-3-methyl-1H-pyrazole-4-yl)-1H-tetrazoles 5a–c as desired. In an attempt to obtain these tetrazole derivatives containing the methyl group at C3-position in the pyrazole ring, the amino group in 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile 4c was protected by the reaction with sodium hydride and di-tert-butyl-dicarbonate (Boc). The tetrazole derivative 5c was synthesized from the protected compound 7c using analogue methodology to obtain 2a–c and 6a–c.     

Formation of new 4-isocyanobut-2-enenitriles by thermal ring cleavage of 3-pyridyl azides

A new thermal ring cleavage of 3-pyridyl nitrenes for the formation of 4-isocyanobut-2-enenitrile products is reported. Thermolysis of 4-(thien-3-yl)-3-pyridyl azide 1 and 3-azido-4-(1-TIPS-1H-pyrrol-3-yl)pyridine 5 afforded two new isonitrile-nitrile products by ring cleavage; 4-isocyano-2-(thiophen-3-yl)but-2-enenitrile (3, 27%) and 4-isocyano-2-(1-TIPS-1H-pyrrol-3-yl)but-2-enenitrile (7, 20%), in addition to our previously reported pyrido[3,4-b]thienopyrrole (2, 29%) and pyrido[3,4-b]pyrrolo[3,2-d]pyrrole (6, 71%) products. Minor amounts of 2-(thien-3-yl)-1H-pyrrole-3-carbonitrile (4, 6%), formed by ring contraction, were also isolated after thermolysis of azide 1. Isonitriles 3 and 7 underwent degradation into amine 3b and formamide 7a by acidic hydrolysis. The nature and chemistry of compounds 3, 4 and 7 were investigated.     

Synthesis of 4-thiaharmalan analogue 4-aryl-1,3-thiazino[5,6-b]indole derivatives by prevention of rearrangements to position two of the indole moiety

An efficient and selective non-acidic protocol has been developed for the synthesis of derivatives of a new ring system: 4-aryl-1,3-thiazino[5,6-b]indole, a 4-thiaharmalan analogue. The convenient amidomethylation of indole-3-thiol (5) afforded 3-benzoylaminomethylthio-1H-indole (7a), with ortho-amidomethylated 2-benzoylamino-methyl-3-benzoylaminomethylthio-1H-indole (8) as side product. Following the Bischler-Napieralski reaction of 7a the rearranged 2-benzoylaminomethylthio-1H-indole 11 could be isolated. In order to prevent such rearrangements the target thiazinoindoles were prepared via 3-thiobenzoylaminomethylthioindole (13) via a modified Bischler-Napieralski reaction.     

A novel and convenient method for the synthesis of new derivatives of pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione

A novel methodology has been developed for the efficient synthesis of 1,4-pyridopyrrolodiazepine derivatives. The key reaction is the bromination under mild conditions by NBS of compounds resulting via peptide coupling of l-proline methyl ester with 3-aminopyridine-2-carboxylic acid 1, then intramolecular cyclization in the construction of 2-bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione 4. This latter is then engaged in cross-coupling reactions to generate 1,4-pyridopyrrolodiazepines derivatives 5a-m, 6a-i, 7, and 8a-c. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.     

The reaction of 2-(1-hydropolyfluoro-1-alkenyl)-4H-3,1-benzoxin-4-ones with dinucleophilic reagents: a convenient route to fluoroalkylated nitrogen-containing tricyclic compounds

The reactions of 2-(1-hydropolyfluoro-1-alkenyl)-4H-3,1-benzoxin-4-ones (2) with hydrazine hydrate and phenyl hydrazine were investigated. The reaction of 2 with hydrazine hydrate in ethanol under reflux condition readily gave 2-fluoroalkyl-4H-pyrazolo[5,1-b]quinazolin-9-ones (3) in high yields. The reaction of 2 with phenyl hydrazine, however, resulted in the formation of 2-(2-phenyl-5-fluoroalkyl-2H-pyrazol-3-yl) benzoic acids (7). Further treatment of 7 with PPA gave 1-phenyl-4,9-dihydro-3-fluoroalkyl-1H-pyrozolo[3,4-b]quinolin-4-ones (4) in 65-80% overall yields.     

Synthesis of functional Δ-1,3,5-oxazaphospholene and 2H-1,4,2-diazaphosphole complexes via catalytic ring expansion reactions of a 2H-azaphosphirene complex

Catalytically-induced ring expansion of 2H-azaphosphirene complex 1 using ferrocenium hexafluorophosphate and acetone (2), diethylketone (3), cyclohexanone (4), benzaldehyde (5) or para-hydroxy-benzaldehyde (6) furnished selectively the Δ³-1,3,5-oxazaphospholene complexes 7-11, whereas with ortho- and para-hydroxy- or ortho- and para-amino-substituted benzonitriles the 2H-1,4,2-diazaphosphole complexes 16-19 were obtained. Two further findings are noteworthy: (1) The significant decreased reaction time in the case of the sterically more demanding carbonyl derivatives 2-4 and (2) the formation of diastereomers in the case of 10 and 11 with a ratio of 8:1 and 9:1, respectively. All products were characterized by NMR, MS and elemental analysis and the configuration of complexes 7 and 10a were determined by X-ray single-crystal diffraction analysis.     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

Regioselective Baeyer-Villiger lactonization of 2-substituted pyrrolidin-4-one. Synthesis of statine

Nine 2-substituted pyrrolidin-4-ones 4a-i were obtained via a series of functional group transformation of known prolinol 5 by facile six kinds of methodologies. The target structure of 1,3-amino alcohols 2a-i was constructed in the regioselective Baeyer-Villiger lactonization of ketones 4a-i and reduction of the resulting 4-substituted tetrahydro-1,3-oxazin-6-ones 3a-i. A new and straightforward synthesis of (3S,4S)-statine (6) has been established starting from trans-(2S,4R)-4-hydroxyproline (1).     

Reactions of (E)-1,2-di(3-guaiazulenyl)ethylene and 2-(3-guaiazulenyl)-1,1-bis(4-methoxyphenyl)ethylene with tetracyanoethylene (TCNE) in benzene: comparative studies on the products and their spectroscopic properties

Reactions of the title ethylene derivatives, (E)-1,2-di(3-guaiazulenyl)ethylene (1) and 2-(3-guaiazulenyl)-1,1-bis(4-methoxyphenyl)ethylene (2), with a 2 M amount of TCNE in benzene at 25 °C for 24 h under argon give new cycloaddition compounds, 1,1,2,2,11,11,12,12-octacyano-3-(3-guaiazulenyl)-8-isopropyl-5,10-dimethyl-1,2,3,6,9,10a-hexahydro-6,9-ethanobenz[a]azulene (3) from 1 and 1,1,2,2,11,11,12,12-octacyano-8-isopropyl-3,3-bis(4-methoxyphenyl)-5,10-dimethyl-1,2,3,6,9,10a-hexahydro-6,9-ethanobenz[a]-azulene (4) from 2, respectively, in 66 and 87% isolated yields. Comparative studies on the above reactions as well as the spectroscopic properties of the unique products 3 and 4, possessing interesting molecular structures, are reported and, further, a plausible reaction pathway for the formation of these products is described.     

Reactions of 4-substituted 5H-1,2,3-dithiazoles with primary and secondary amines: fast and convenient synthesis of 1,2,5-thiadiazoles, 2-iminothioacetamides and 2-oxoacetamides

The treatment of 5H-1,2,3-dithiazole-5-thiones 1 in chloroform under reflux and 5H-1,2,3-dithiazol-5-ones 2 in THF at room temperature with primary aliphatic amines and benzylamine afforded 1,2,5-thiadiazole-3(2H)-thiones 3 and 1,2,5-thiadiazol-3(2H)-ones 6, respectively. The structure of dithiazolone 3f was confirmed by X-ray diffraction analysis. The reaction of dithiazolone 2e bearing an electron-donating methyl group in the 4-position gave 2-oxoacetamide 7e in high yield. The reaction of thiones 1 with secondary aliphatic amines in DMSO yielded 2-iminothioacetamides 8 in moderate yields together with elemental sulfur. Interestingly, the treatment of dithiazolones 2 with secondary amines under the same conditions afforded 2-oxoacetamides 9—the products of the hydrolysis of corresponding imino derivatives 10, which was isolated as 10b. A general mechanism was proposed for the formation of the products.     

A novel efficient protocol for preparation of 3-formyl-2-arylbenzo[b]furan derivatives

An efficient method for preparation of 3-formyl-2-arylbenzo[b]furan derivatives 4 from 3-chloro-2-(2-methoxyaryl)-1-arylprop-2-en-1-one 2 was developed, and the desired product was obtained in good to excellent yields. By converting 2-(2-methoxyphenyl)-3-oxo-3-phenylpropanal 1 to 2, the regioselectivity problem occurring in the reaction when using 1 as the starting material was successfully avoided. Furthermore, a one-pot procedure for the successive demethylation, cyclization, and hydrolysis was evolved, although the intermediate 3-(dibromomethyl)-2-phenylbenzo[b]furan 3a could be isolated. A plausible mechanism was proposed based on some in situ investigations.     

Substituent-induced regioselective synthesis of 1,2-teraryls and pyrano[3,4-c]pyran-4,5-diones from 2H-pyran-2-ones

Substituent-controlled regioselective synthesis of highly functionalized 1,2-teraryls 3a-k has been achieved through ring transformation of 6-aryl-4-(pyrrolidin-1-yl/piperidin-1-yl)-2H-pyran-2-one-3-carbonitriles 1a-g by aryl acetones 2a-c in the presence of powdered KOH in DMF in very good yield. Under similar reaction conditions, 6-aryl-4-methylsulfanyl-2H-pyran-2-ones 5a-f afforded 1,7-diaryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-diones 6a-j as major products and 3,4-diaryl-2-methyl-6-methylsulfanylbenzonitriles as minor constituents 7a-j.     

A new method for the synthesis of 2-cyclopenten-1-one-5-carboxylic ester derivatives via Rh2(OAc)4-mediated intramolecular C-H insertion reaction of 4Z-β-vinyl-α-diazo β-ketoesters

2-Cyclopenten-1-one-5-carboxylic ester derivatives 14 are synthesized in a four-step-reaction sequence starting from alkynyl aldehydes 9 via 4Z-β-vinyl-α-diazo β-ketoesters intermediate 8. The synthetic method for 8 is described. When the δ substituent is an alkyl group, Rh(II)-mediated decomposition of the diazo compounds 8 led to an intramolecular C-H insertion to afford 2-cyclopenten-1-one-5-carboxylic ester derivatives 14 in high yields. When the δ substituent is an aryl group, 2-hydroxynaphthoate 15 is obtained exclusively. In both cases, no Wolff rearrangement product was observed.     

Solvent-free reactions of N,N′-thiocarbonyldiimidazole with ferrocenylcarbinols

The efficient and simple routes for the synthesis of various ferrocenyl derivatives from ferrocenylcarbinols and N,N′-thiocarbonyldiimidazole (TCDI) are described. It involves grinding the two substrates in a Pyrex tube with a glass rod at room temperature. The reaction of ferrocenylmethanol (1a) provided S,S-bis(ferrocenylmethyl)dithiocarbonate (1b), whose crystal structure and a plausible mechanism for its formation are also reported. The reaction of 1-ferrocenyl-1-phenylmethanol (2a) and 1-ferrocenylbutanol (2b) gave the products 2c and 2d, respectively. The reaction of ω-ferrocenyl alcohols 4-ferrocenylphenol (3a) and 6-ferrocenylhexan-1-ol (3b) yielded the products 3c and 3d, respectively. Reaction of 1,1′-ferrocenedimethanol (3e) afforded 3f in moderate yield, and by contrast, it was not similar to 1b. Reaction of [4-(trifluoromethyl)phenyl]methanol (4a) provided the thiocarbonate 4b in good yield.     

Synthesis of substituted 2-aroyl-3-methylchromen-4-ones from isovanillin via 2-aroyl-3-methylchroman intermediates

The synthesis of substituted 2-aroyl-3-methylchromen-4-one from isovanillin is described. O-Allylphenol (2) prepared from isovanillin (1) was allowed to react with various α-bromoacetophenone (3) to produce 2-(2-allyl-3,4-dimethoxy)phenoxy-1-aroylethanones (4). The resultant 4 were treated with 2 equiv of potassium tert-butoxide to afford the substituted 2-aroyl-3-methylchromans (5) through an isomerization of an allylic double bond and a carbanion-olefin intramolecular 6-endo-trig cyclization reaction. Subsequently, resultant 5 were oxidized with DDQ to yield the title compound 6, in good over-all yields.