Barrie C. Uff

Formation of Cyanohydrin Carbonates of Aromatic Aldehydes and Aryl Heteroaryl Ketones

Abstract Cyanohydrin derivatives cannot be made by direct addition to diaryl ketones due to the unfavourable equilibrium for the addition process.1 We required a route to cyanohydrin carbonates of type (1, R1=heteroaryl, R2=a1kyl), and approached their formation via the aromatic aldehyde analogues (2). Such derivatives (2) have been made using a single aqueous phase method,2 and acyl analogues have been made using also a two-phase (water/ether) procedure.3 To obtain the carbonates (2) we have found the former method unreliable and that a satisfactory procedure is to stir an aqueous solution of KCN with the aldehyde and alkyl chloroformate in methylene chloride at 10°C (Table 1). Where necessary yields can be increased by the inclusion of a phase transfer catalyst,4 benzyltrimethylammonium chloride. A similar procedure, for addition to (heterocyclic) c=N, has recently been reported5 for the formation of certain Reissert compounds.

Studies with Reissert compounds. Part 17. Mono-Reissert compound formation at the 1,2-position of the quinazoline system

4-Substituted quinazolines have been selectively converted into mono-Reissert compounds at the 1,2-position by use of acid chlorides and trimethylsilyl cyanide. Various reactions of the quinazoline Reissert compounds are reported. For example, conjugate base generation at the 2-position leads to a 1,2-rearrangement, whereas substitution occurs in the presence of an alkyl halide, providing, after hydrolysis, 2-alkyl-4-phenylquinazolines in good yield. Ring annellation by intramolecular alkylation is also reported. The quinazoline Reissert compound conjugate base reacts with aldehydes to give alcohol esters which can further be converted, via the alcohol and use of phosgene, to novel oxazolo[4,3-a]quinazoline derivatives.

Benzologous Reissert Compound Formation from 2-Methylindazole

Abstract 2-Methylindazole undergoes 1, 4-addition on treatment under Reissert conditions. Methylation of the product in strong base leads to 2, 3-dimethylindazole.

Reissert compound chemistry. Part IV. N-acyl pseudo-base formation and stereochemistry

The formation is reported of a series of heterocyclic N-acyl pseudo-bases from 5-nitroisoquinoline, 3-methyl-5-nitroisoquinoline, and 6-nitroquinoline. The compounds were obtained under conditions for Reissert compound formation, only small yields of the latter being present in most cases. The N-acyl pseudo-bases appear to be covalent in character, and do not, in general, display tautomerism with an open chain or ionic form, in contrast to N-alkyl pseudo-bases. Long-range coupling observed in the n.m.r. of the N-acyl pseudo-bases and 1,2-dihydroisoquinolines and -quinolines of the Reissert type suggests the stereochemistry to be such that the substituent at the saturated carbon is adopting a quasi-axial position, analogous to substituted 1,2-dihydronaphthalenes. Characteristic resonance frequencies are indicated.

Reissert compound chemistry. Part 5. Formation of pyrrolo[1,2-a]-quinolines and pyrrolo[2,1-a]isoquinolines

Treatment of a quinoline Reissert compound carrying a blocking group at the 4-position with base in the presence of acrylonitrile can lead in modest yield to the pyrrolo[1,2-a]quinoline system (8) and to an open chain ketone (11) derived via an intermediate tetrahydropyrrolo[1,2-a]quinoline. This behaviour contrasts with the more ready formation of the pyrrolo[2,1-a]isoquinoline system (3) by a similar process.

Reissert compound chemistry. Part III. Some rearrangement and substitution reactions

Reissert anion alkylation has led to a new synthesis of petaline, and a 1-benzoyl-8-hydroxyisoquinoline derivative has been obtained by rearrangement of the corresponding 8-benzoyloxy Reissert compound. Competitive reactions of the anion of 3-methylisoquinoline Reissert compound are described.

Reissert compound formation with five-membered ring heterocycles using trimethylsilyl cyanide

Treatment of benzothiazole with trimethylsilyl cyanide and an acid chloride in CH2Cl2 gives the N-acyl-2-cyano-2,3-dihydrobenzothiazole in good yield; benzoxazole similarly is converted into a five-membered ring Reissert compound, providing the first examples in these series.

Halohydrins of isoquinoline reissert compounds: base-induced rearrangement reactions providing isochromenes and new isoquinolines

Various 3- or 4-methyl and unsubstituted 2-acyl-1-cyano-1,2-dihydroisoquinolines (Reissert compounds) have been converted into the corresponding chloro- or bromo-hydrins by treatment with aqueous hypochlorous acid or aqueous 1,3-dibromo-5,5-dimethylhydantoin, respectively. These 4-halo- 3-hydroxy-derivatives were generally convertible with base into the corresponding 1-acyliminoisochromenes and thence into the related isocoumarins. The chlorohydrin of 2-acetyl-1 -cyano-1,2-dihydroisoquinoline was transformed by sodium ethoxide into 1-ethoxy-4-formyl-3-methylisoquinoline, in the expected manner. However, the bromohydrin of 2-benzoyl-1-cyano-1,2dihydro-3-methylisoquinoline, which exists as the tautomeric bromoketone, gave, as the major product, 4-benzoyl-1-ethoxy-3-methylisoquinoline rather than 4-acetyl-1 -ethoxy-3-phenylisoquinoline. The mechanism of this new rearrangement is discussed.

Cyanochlorination and cyanation of isoquinolines

Treatment of isoquinoline with sulphuryl chloride and potassium cyanide gave, in one preparative step, 4-chloro-1-cyanoisoquinoline and 1-carbamoyl-3-cyanoisoquinoline in yields dependent upon the proportions of reagents. 4-Chloroisoquinoline, 1,3-dicyanoisoquinoline, 3-cyanoisoquinoline, and 1-cyanoisoquinoline were also produced under different reaction conditions. The formation of the various products is explained in terms of successive electrophilic and nucleophilic attack by the reagents on the hetero-ring of isoquinoline followed by elimination reactions to regenerate an aromatic system. Cyanochlorination and cyanation of several isoquinoline derivatives and of quinoline were briefly studied.

Rearrangement reactions of a Reissert compound chlorohydrin

The Reissert compound, 2-benzoyl-1-cyano-1,2-dihydroisoquinoline, reacted with hypochlorous acid to yield a crystalline chlorohydrin. Base-catalysed elimination of hydrogen chloride from this led to an array of rearranged products in a controlled manner. In this way, simple preparative routes to 1-benzoylamino-1-cyanoisochromene, 1-benzoyliminoisochromene (and thence isocoumarin), 1-ethoxy-4-formyl-3-phenylisoquinoline, and 1-ethoxy-3-phenylisoquinoline were devised. The mechanism of the consecutive rearrangements is discussed.