Noritaka Abe

THE CHEMISTRY OF AZAAZULENES

This review describes the synthetic methods and reactions of azaazulenes including some of their dihydro-, oxo-derivatives and hetero fused derivatives published during 2000 to early in 2010. The biological and physical properties of azaazulenes are also described.

Palladium-catalyzed heteroarylamination of ethyl 2-chloro-1-azaazulene-3-carboxylate and annulation of heteroarylamino-1-azaazulenes

The palladium catalyzed heteroarylamination of ethyl 2-chloro-l-azaazulene-3-carboxylate was achieved using a catalyst based on Pd 2 (dba) 3 / Xantphos system. Treatment of ethyl 2-(heteroarylamino)-1-aza-azulene-3-carboxylates with a PPA-POCl 3 mixture gave corresponding annulation products. 2-(2-Benzothiazolylamino)-l-azaazulene (3h) showed anticancer activity against HeLa S3 cells (IC 50 : 6.5 μM).

Synthesis and Some Reactions of Ethyl (2-Alkylimino-1,2-dihydro-1-azaazulen-1-yl)acetates

Ethyl (2-alkylimino-1,2-dihydro-1-azaazulen-1-yl)acetates (3) were synthesized from 2-alkylamino-1-ethoxycarbonylmethyl-1-azaazulenium salts, which were produced from 2-alkylamino-1-azaazulenes with ethyl bromoacetate. Reaction of 3 with acid anhydrides gave the mesoionic anhydro-3-acyl-1-alkyl-2-hydroxy-1,3a-diazacyclopent[a]azulenium hydroxide. Polar cycloaddition of 3 with methyl propiolate gave methyl 2-alkyl-1-oxo-1,2-dihydro-2,9b-diazaindeno[3,3a,4,5-bcd]azulene-8-carboxylate and 3-ethyl 5-methyl 2-alkylamino-2a-azabenz[cd]azulene-3,5-dicarboxylate.

Studies on heterocyclic chemistry. Part 21. Reactions of 3-mercapto- and 3-acylthio-3-isothiazoline-5-thiones: ring transformations, a base-induced ring cleavage, and thiol-ester–thioxo-ester rearrangements

Acylation of 4-aryl-3-mercapto-3-isothiazoline-5-thiones (1) with acid chloride in pyridine or alternatively with acid anhydride leads exclusively to 3-acylthio-4-aryl-3-isothiazoline-5-thiones (2). Reactions of (1) with reactive acetylenes afford 2-[aryl(thiocarbamoyl)methylene]-1,3-dithiole derivatives (3) whereas those of (2) with the acetylenes are accompanied by an S → N acyl migration giving N-benzoyl-[4,5-bis(methoxycarbonyl)-1,3-dithiol-2-ylidene]arylethanethioamides (4). 13C N.m.r. spectra and some chemical reactions of (3) and (4) are described. The ring-cleavage of (1) with base and the thiol-ester–thioxo-ester rearrangements of (2) induced by diazoalkane, alkyl iodide, or triethyloxonium tetrafluoroborate are also reported.

Heteroarylamination and heteroarylsulfidation of 2-chloro-1-azaazulenes

Heteroarylamination and heteroarylsulfidation of 2-chloro-1-azaazulenes (1) were investigated. Palladium catalyzed coupling of 2-amino-1-azaazulenes (2) with 1 underwent to give bis(1-azaazulen-2-yl)amine derivatives in good yields, but the reaction of 2-mercapto-1-azaazulenes (4) with 1 did not give good results in the same conditions. The reaction of 4 with 1 under basic conditions gave bis(1-azaazulen-2-yl) sulfide derivatives in good yields. Heteroarylamino-substitution was proceeded on the reaction of 4-amino-3-mercapto-4H-1,2,4-triazoles (6) with 1 in BuOH under reflux, whereas heteroarylsulfido-substitution was proceeded on the reaction of 6 with 1 in the presence of NaH in dioxane. The chemistry of azaazulenes is of interest for their physiological properties as well as physical and chemical properties. Aryl amines have a potential functionality in pharmaceutical drug candidates, therefore Pd-catalyzed amination of aryl halides has attracted attention. Recently, we reported that heteroarylaminatition of ethyl 2-chloro-1-azaazulene-3-carboxylate proceeded well by Pd-catalyzed amination. In the extension of the chemistry, we examined the reaction of 2-chloro-1-azaazulenes with 2-amino-1-azaazulenes, mercapto-1-azaazulenes, and 4-amino-3-mercapto-4H-1,2,4-triazoles. Treatment of 2-chloro-1-azaazulene (1a) with 2-amino-1-azaazulene (2a) in the presence of Pd2(dba)3, Xantphos, and Cs2CO3 in dioxane under reflux for 4 h gave bis(1-azaazulen-2-yl)amine (3aa) in 39% yield. The H NMR spectrum of 3aa was symmetrical and the C NMR spectrum showed 9 signals; this showed that heteroarylamination occurred at amino group at C-2, and not at N-1 of 1-azaazulene nuclei. Similar treatment of 1b, 1c, and 1d with 2a and 2b gave 3ba (70%), 3ca (63%), and 3db (43%), respectively. Although the yields were slightly low as the case, the usefulness of Pd-catalyzed heteroarylamination was certified for the synthesis of bis(1-azaazulen-2-yl)amine derivatives.

Synthesis and reactions of 3- and 8-ethynyl-1-azaazulenes

3-Iodo-1-azaazulenes were easily ethynylated by Sonogashira-Hagihara reaction to give 3-ethynyl-1-azaazulenes. Cyclization of 2-amino-3- ethynyl-1-azaazulene was achieved by heating in the presence of copper(II) acetate or copper(II) trifluoromethanesulfonate, and 1,9-diaza-1H-cyclopent[a]azulene derivatives were obtained. Reaction of 2-chloro-1-azaazulene with lithium phenylacetylide gave 3-chloro-1-(2-chloro-1-azaazulen-8-yl)-2-phenyl-2a-aza-2H-cyclopent[cd]azulene together with 2-chloro-8-phenylethynyl-1-azaazulene.

Reactions of 2-triphenylphosphoimino-1-azaazulenes with aryl isocyanates and aryl isothiocyanates

Reaction of 2-triphenylphosphoimino-1-azaazulenes (4a-c), prepared from 2-amino-1-azaazulenes, with some aryl isocyanates gave 2-arylimino-3-aryl-2,3,4,4a-tetrahydro-1,3,4a-triazabenz[a]azulen-4-one (6) as major products.Reaction of aryl isothiocyanates gave 2-arylimino-3-aryl-2,3,4,4a-tetrahydro-l,3,4a-triazabenz[a]azulene-4-thiones (10).

Synthesis of 2-Chloro-8-(2-pyridyl)-1-azaazulene and Its Metal Complexes

Reaction of 2-chloro-1-azaazulenes with 2-pyridyllithium followed by dehydrogenation by chloranil gave 8-(2-pyridyl) -1-azaazulene (2). Formation of metal complexes (M = Cu, Fe, Pd) of 2 was achieved. The reaction of 2 with Cu(1) gave 1:1-complex (3) and 2:1-complex (4). Complex (3) was deduced to have a polymeric chain structure with the copper center is +1. The ESR spectrum study of 4 showed that the copper center is +2. The structure of 4 was decided by X-Ray structural analysis and it is shown that the complex takes a trigonal bi-pyramidal structure.

Synthesis and some reactions of 11-azacyclohept〔a〕azulen-3(3H)-ones and evaluation of their cytotoxic activity against HeLa S3 cells

Aldol condensation of 2,3-diformyl-1-azaazulene with acetone, methoxyacetone, and benzylacetone in aq. NaOH solution gave corresponding 11-azacyclohept[α]azulen-3(3H)-one (2a), 2-methoxy-derivative (2b) and 2-benzyl-derivative (2d) in good yields. Hydrolysis of 2b using hot HBr gave 2-hydroxy-11-azacyclohept[a]azulen-3(3H)-one (2f). Acetylation of 2f gave 2-acetoxy-11-azacyclohept[α]azulen-3(3H)-one (2g). Reaction of the compounds (2a, 2b, 2f) with diethyl malonate in Ac 2 O under heating gave 1,9(11bH)-11b-azaazuleno[1,2,3-cd]azulenedione derivatives (4a, 4b, 4f). Compounds (2b, 2f) showed weak cytotoxic activity against HeLa S3 cells.

FACILE SYNTHESIS OF (2-BENZIMIDAZOLYL)-1-AZAAZULENES, (2-BENZOTHIAZOLYL)-1-AZAAZULENES, AND RELATED COMPOUNDS AND EVALUATION OF THEIR ANTICANCER IN VITRO ACTIVITY

Facile syntheses of 2-, 3,- and 8-(2-benzimidazolyl)-1-azaazulenes (2a-c, 5, 7, 9) and 2-, 3-, and 8-(2-benzothiazolyl)-1-azaazulenes (13b-c, 16, 17, 18) were achieved by the condensation of corresponding 1-azaaazulene- carbaldehydes with o-phenylenediamine and 2-aminothiophenol in alcoholic solvents at rt or under reflux under airobic conditions. Reaction of 1-azaazulenecarbaldehyds with 2-aminophenol gave Schiffs bases (10a-c, 11, 12). Reaction of 2-chloro-1-azaazulene-3-carbaldehyde (1a) with 2-amino- thiophenol in refluxing 1-BuOH gave benzothiazapine-fused 1-azaazulene (20). Reaction of 4-amino-3-mercapto-4H-1,2,4-triazoles (21a-d) with in refluxing 1-BuOH gave triazolothiadizapine-fused 1-azaazulene (22a-d). The structure of trifluolomethyl derivative (22c) was determined by X-ray structure analysis. 3-(2-Benz- imidazolyl)-2-chloro-1-azaazulene (2a) showed anticancer activity against HeLa S3 cells (IC50: 5.3 µM).