Deirdre M. B. Hickey

Vinyl azides in heterocyclic synthesis. Part 3. Isolation of azirine trimers (1,3,8-triazatricyclo[4.3.0.03,5]non-7-enes) and intramolecular interception of nitrile ylides by neighbouring π-bonds or nucleophiles

Photolysis of azidocinnamates (1a–e) at 300 nm in light petroleum gives exclusively the triazatricyclononenes (7a–e) in a highly stereospecific trimerisation of the corresponding azirine (2). A mechanism is proposed involving the sequence: azide (1)→ azirine (2)→ nitrile ylide (8)→ dimer (9)→ azomethine ylide (10)→ trimer (7)(Scheme 2). This mechanism not only rationalizes the formation of the trimers (7), rather than dimers or oligomers, but also their stereochemistry. Further evidence for it is provided by photolyses of the azidocinnamates (1f–h) which give the ‘dimer’(13), the cyclopropaisoquinoline (16), and the imidazopyridine (20), respectively; these three products result from intramolecular interception of the azomethine ylide or nitrile ylide intermediates.

Formation of indoles, isoquinolines, and other fused pyridines from azidoacrylates

Mild thermal decomposition in boiling toluene or xylene of the azidocinnamates (1)–(6), readily prepared from the corresponding aldehyde and ethyl azidoacetate, gives indoles in good yield when there is an unsubstituted ortho position, and dihydroisoquinolines, and hence isoquinolines, when there is an o-methyl or methylene group. In the presence of iodine, which seems to favour a radical type process, the yield of isoquinoline is increased, and isoquinoline formation can compete with the indole-forming cyclisation to a free ortho-position. Iodine also catalyses primary enamine formation by a hydrogen abstraction process. The thiophene (7) and pyrazole (8) are formed and decomposed similarly to give the corresponding c-fused pyridines (28) and (29). The 2,6-dichloro compound (9) thermolyses to the stable 2H-azirine (32) which isomerises to the nitrile (33) on stronger heating. Yields in these azide decompositions are sometimes high, though they can be variable and the reactions, though easily carried out, can be complex.

Synthesis of thyroid hormone analogues. Part 2. Oxidative coupling approach to SK&F L-94901

A synthesis of L-3,5-dibromo-3′-[(6-oxo-l,6-dihydropyridazin-3-yl)methyl]thyronine-SK&F L-94901 (1), a novel, selective and potent thyromimetic – is described. The key step in this synthesis involves the formation of a hindered diaryl ether moiety. This paper describes an approach via oxidative coupling of the hindered phenols (2) and (3). Some by-products and impurities generated during the synthesis are discussed briefly.

Vinyl azides in heterocyclic synthesis. Part 2. Selectivity in the decomposition of azidocinnamates with olefinic ortho-substituents

Thermolysis of azidocinnamates with an olefinic o-substituent gives products (isoquinolines, azepines, aziridines) formed by selective interaction of the azide, and the derived nitrene, with the olefinic substituent, cyclisation onto the unsubstituted aromatic ortho position now being a minor reaction. However when this interaction is removed by epoxidation of the alkene, cyclisation occurs exclusively to the aromatic ring to give 4-substituted indoles in high yield. Thus o-vinyl azidocinnamate (1a) gives isoquinoline (5a), and (1b) gives isoquinoline (5b) together with the 3-benzazepine (7); o-allyl azidocinnamate (2a) gives indole (12), the 3-benzazepine (13), and the tricyclic aziridines (14) and (15), and (2b) gives an analogous mixture of products from which only the indole (19) was isolated. A mechanism is proposed (Scheme 2) in which the azide partitions itself between intramolecular cycloaddition to the double bond and loss of nitrogen to give the azirine-nitrene equilibrium. This rationalises the formation of the 4 temperature-dependent products from azidocinnamate (2a), the aziridine (15) involving an intramolecular ene reaction of the imine bond. Thermolysis of the epoxy-azidocinnamates (3) and (4) gives indoles (20) and (21) respectively in high yield; treatment of (3) with triethyl phosphite gives the aziridine (8), presumably by formation of an iminophosphorane and intramolecular nucleophilic attack by this on the epoxide, the counterpart of a known intermolecular reaction.

Synthesis of isoquinolines from azidocinnamates; the effect of iodine

Iodine has a marked catalytic effect on the thermolysis of azidocinnamates; indoles, isoquinolines, 1,2-dihydroisoquinolines, or enamines are isolated depending on the conditions.

Vinyl azides in heterocyclic synthesis. Part 6. Synthesis of isoquinolines by intramolecular aza-Wittig reaction

Azidocinnamates containing ortho-carbonyl substituents are versatile intermediates for heterocyclic synthesis. Isoquinolines (8) and (9) are formed under mild neutral conditions by intramolecular aza-Wittig reactions of iminophosphoranes, readily derived from azides (1) and (2), respectively, with triethyl phosphite. The azafluoranthene (10) can also be prepared from the azide (3)via the isolable iminophosphoranes (11) and (12). Thermolysis of the azides (1) in toluene or xylene gives the 4-substituted indoles (13) in varying yield (Table 2). Similarly the indoles (14) and (19) are formed from the azides (3) and (6a and b) respectively.

Selectivity in vinyl azide reactions; decomposition of azidocinnamates with olefinic ortho-substituents

Thermal decomposition of vinyl azides (1a–c) gives isoquinolines (3), benzazepines (4), or aziridines (5) and (6) by preferential reaction at the unsaturated substituent; removal of this unsaturation as in the epoxides (1d,1e) leads exclusively to 4-substituted indoles.

Photolysis of azidocinnamates: isolation of azirine trimers; X-ray crystal structure of triethyl 2,4,9-tri-o-tolyl-1,3,8-triazatricyclo-[4.3.0.03,5]non-7-ene-5,6,7-tricarboxylate

Photolysis of the azidocinnamates (1) gives trimers of the azirines (2); X-ray crystallographic analysis establishes the triazatricyclononene structure (6) for these trimers.