R. Morrin Acheson

1-Hydroxypyrroles, 1-Hydroxyindoles and 9-Hydroxycarbazoles

Publisher Summary This chapter focuses on 1-hydroxypyrroles, 1-hydroxyindoles, and 9-hydroxycarbazoles. 1-Hydroxypyrrole is a colorless liquid, which has not been analyzed, and which decomposed on attempted distillation under high vacuum. 1-Hydroxyindole is a reactive compound that has only been obtained in solution; it polymerizes to a green powder on attempted isolation. Its 4-benzyloxy derivative also could not be isolated and these compounds are more difficult to handle than 1-hydroxypyrrole. Reduction of a 1-hydroxyindole to the corresponding indole is always effected by zinc and acetic acid if sufficiently vigorous conditions are employed by other reagents, including trimethyl phosphate titanium(III) chloride under the correct conditions and by Raney nickel/sodium hypophosphite. The instability of 1-hydroxyindole itself may well be due, in part, to radical formation and polymerization. N- Hydroxycarbazole was first postulated as an intermediate in the reaction of benzyne with nitrosobenzene, which gave N-phenylcarbazole. Carbazole can be oxidized to the 9-oxyl radical, which has been identified in fish liver; it may be related to tumor production. A small number of 9-hydroxycarbazoles has been made.

Transformations involving the pyrrolidine ring of nicotine

Nicotine was oxidised to cotinine and this successively alkylated and reduced to a series of 4′-mono- and 4′,4′-di-alkylnicotines, the mass spectra of which are discussed. The pyrrolidine ring has been opened with ethyl chloroformate and the product both recyclised to S-nicotine without loss of optical activity and converted to metanicotine. The dihydrochloride of the last, on successive treatment with bromine and sodium hydrogencarbonate, yielded 3′-bromonicotine. Cotinine has been converted into various derivatives, and the demethylation of nicotine has been investigated.

The synthesis, reactions, and spectra of 1-acetoxy-, 1-hydroxy-, and 1-methoxy-indoles

Reduction of 2-nitrophenylacetaldehyde gave the unstable 1-hydroxyindole, trapped as 1-acetoxyindole. Concurrent alkaline hydrolysis with methyl iodide present yielded 1-methoxyindole which was substituted by electrophiles at position 3. The 3-carbaldehyde, from a Vilsmeier reaction, was converted into 1-methoxy-NN-dimethyl-tryptamine. 1,5-Dimethoxyindole underwent the Mannich reaction forming the 3-dimethylaminomethyl derivative. 1-Acetoxyindole with dimethylformamide and phosphoryl chloride yielded 2-chloroindole-3-carbaldehyde and 1-hydroxyindole-3-carbaldehyde, while (1-hydroxyindol-3-yl)glyoxylic acid with hydroxylamine gave 3-cyano-1-hydroxyindole or indole-3-nitrile oxide. The u.v.,i.r.,n.m.r., and mass spectra of the 1-hydroxyindole derivatives are discussed.

Addition reactions of heterocyclic compounds. Part 74. Products from dimethyl acetylenedicarboxylate with thiourea, thioamide, and guanidine derivatives

Benzimidazole-2-thione with dimethyl acetylenedicarboxylate (DMAD) in acetonitrile gave a fused thiazolidinone derivative, but in methanol a fused thiazinone was obtained. Structures were assigned to adducts from other thioureas by comparison with the 13C n.m.r. spectra for these compounds. A method has been developed for distinguishing between the possible structural types of adducts for guanidine and amidine derivatives with DMAD using 1H and 13C n.m.r. spectroscopy. Products from various thioamides and DMAD were identified from their n.m.r. and other spectra.

An ester migration in the rearrangement of a diels–alder adduct of a furan and a phenyl migration in the rearrangement of methyl 3,3,5-triphenylpyrazole-4-carboxylate

Methyl 5-methoxyfuran-2-carboxylate reacts with dimethyl acetylenedicarboxylate to give trimethyl 3-hydroxy-6-methoxybenzene-1,2,4-tricarboxylate, identified from its spectra and its conversion into diethyl 2,5-dihydroxyterephthalate. The thermal rearrangement of methyl 3,3,5-triphenyl-3H-pyrazole-4-carboxylate proceeds by a phenyl, and not by an ester, migration.

7-Alkylation and 7-sulphonylation of 5,6-dihydroimidazolo[2,1-b]thiazoles

Reinvestigation of the alkylation of 3-phenyl-5,6-dihydroimidazolo[2,1-b]thiazole has shown that methylation occurs exclusively at the 7-position, and that the free base is readily solvolysed to a mixture of 1 -methylimidazolidin-2-one, 1 -methylimidazolidine-2-thione, and diphenacyl sulphide and disulphide. 3-Methyl-5,6-dihydroimidazolo[2,1-b]thiazole with methane- and arene-sulphonyl chlorides gave the corresponding 7-sulphonylthiazolium chlorides. On heating, these rearranged to 3-(2-chloroethyl)-4-methyl-3-aryl (or alkyl)sulphonylimido-2,3-dihydrothiazoles. The 7-(4-chlorophenylsulphonyl) derivative lost this substituent with aqueous base while concentrated aqueous ammonia attacked the 7a-position leading to a 3-[2-(p-chlorobenzenesulphonamido) ethyl]-2-imino-4-methyl-2,3-dihydrothiazole.

The synthesis of diethyl p-tolylsulphonylethynylphosphonate and related acetylenes, and their reactions with nucleophiles, pyridinium-1-dicyanomethylides, and dienes

Diethyl p-tolylthioethynylphosphonate (10) was synthesized from diethyl ethynylphosphonate (7) by two routes and oxidised to the corresponding sulphoxide (11) and sulphone (12). The sulphone showed no triple bond i.r. absorption, but a strong Raman band, and nucleophiles could add to either end of the triple bond. These alkynes gave indolizines with pyridinium-1-dicyanomethylides and Diels–Alder adducts with anthracenes. The orientations of the additions were deduced from 1H, 1H; 31P, 1H; and 31P, 13C coupling constants.

The crystal and molecular-structure of 1,2,3,5-Tetramethylbenzo[B]-Thiophenium Tetrafluoroborate and some theoretical calculations on the hypothetical 1H-Thiophenium Cation

The X-ray crystal structure of 1,2,3,5-tetramethylbenzo[b]thiophenium tetrafluoroborate, refined to R 0.043, shows the bonding about sulphur to be pyramidal and not planar. This structure and the 13C n.m.r. spectral data suggest that benzo[b]thiophenium salts should be considered as cyclic styrene derivatives. Theoretical calculations also showed an energy maxium for the planar configuration of the 1H-thiophenium cation.

Reduction of some 1-substituted pyridinium salts

Reductions by sodium borohydride and dithionite of four 1-substituted pyridinium salts gave in all cases mixtures of mainly 1,2- and 1,4-dihydropyridines which were analysed by n.m.r. spectroscopy. Palladium–charcoal hydrogenation catalyst isomerised certain reduced pyridines.

Addition reactions of heterocyclic compounds. Part 79. Reaction of dimethyl acetylenedicarboxylate with some cyclohept[b]indoles and cyclo-oct[b]indoles

The reactions of dimethyl acetylenedicarboxylate with N-methyl- and pyrido[3,2,1-hi]indoles which have either a penta- or hexa-methylene chain linking positions 2 and 3, have been found to give rise to a very similar array of products. Nineteen new adducts were isolated and their structures established by 1H and 13C n.m.r. spectral comparisons, and in some cases also by chemical transformations. The structures include five new classes of adducts not previously encountered: two types of (1 + 1 DMAD) adducts, one of which is a cyclobutene and the other a 3-maleate; two types of (1 + 2 DMAD) adducts, one with two side chains, and the other having a ring-expanded nine- or ten-membered ring and one side chain; and a (1 + 2 DMAD - CH4O) adduct, all examples of which exhibit fragmentation on heating to give a carbazole and a spiro-cycloalkyl-keten dimer. The isolation of the two (1 + 1 DMAD) adducts is important as both adduct types have been postulated as intermediates in the formation of more complex adducts.