Carbazoles nitrene cyclization

Thermolysis or photolysis of 2-azidobiphenyl produces a nitrene, as does deoxygenation of 2-nitrobi-phenyl with triethyl phosphite. The nitrene cyclizes immediately to give carbazole. Carbazoles can also be made by cyclodehydrogenation of diphenylamines. 

Fuostifoline (47), a furo[3,2-a]carbazole, was isolated from Murraya euchrestifolia. Timdri s total synthesis of 47 commenced with alkylation of bromocresol 43 with bromoacetaldehyde diethyl acetal and P4Oio-promoted cyclization to furnish 5-bromo-7-methylbenzofuran (44) [47]. The Suzuki coupling of boronic acid 45, derived from 44, with o-bromonitrobenzene yielded biaryl 46. Nitrene generation, achieved via deoxygenation of nitro compound 46 using triethyl phosphite, was followed by cyclization to fuostifoline (47). 

The direct photolysis of o-isocyanatobiphenyls 278 is yet another means for the generation of nitrene, which leads via cyclization to a carbazole. How-... 

The prototype reactions for synthesis of pyrrole, indole and carbazole by processes involving electrophilic nitrogen are outlined in Scheme 3 with a nitrene as the electrophilic form of nitrogen. This conceptual scheme must be generalized to include nitrenoids and nitrene equivalents to accomodate the range of cyclizations which can proceed by this mechanism. In practice, this mechanistic pattern is rare for pyrroles, known but only of moderate utility for indoles, and among the most efficient methods for the synthesis of carbazoles. 

Nonoxidative photocyclization also occurs in 2-diphenyl isocyanate (367) to form carbazole (368) and phenanthridone (369).390 The mechanism of this transformation is uncertain, and, in fact, little attention has been given to the photochemistry of isocyanates. Carbazole is also the principal product of nonsensitized photolysis of 2-azidobiphenyl391 the reaction presumably involves the cyclization of an intermediate nitrene. 

In two papers, Miller and co-workers (45,46) have extended their intramolecular ring B cyclization strategy (47) to the use of aryl nitrenes in the synthesis of pyridocarbazoles. Thus, in the first paper, isoquinoline azide 39 was heated at 180-200°C to aiford ellipticine (1) as the minor product (20%) (Scheme 7). The major product was the isomeric pyrido[3,4-a]carbazole 40 (60%). This result is consistent with the relative nucleophilicities of C-6 and C-8 of isoquinoline. The isomeric azido isoquinoline 41 exhibited comparable re-gioselectivity in the cyclization of the corresponding nitrene to yield isoellipticine (27) as the minor product (Scheme 7). 

Deoxygeuation of N-fonetions (1, I2IS-12I6 2, 433). Brooke and.co-workers have presented evidence that the cyclization of (1) to the carbazole (2) by triethyl phosphite does not proceed by way of a nitrene as originally believed, but probably through the bipolar species (a). 

Lehmann and Berry303 reported a flash photolysis study of the carbazole formation from 2-azidobiphenyl in the gas phase and in solution. The rate constant for cyclization of the nitrene was measured in solution at 300 K as 2.1B x 103 sec-1, and an activation enthalpy of 11.46 + 0.76 kcal/mol was derived. The rate in the gas phase at 75°C was unmeasurably fast (i.e., > 1.4 x 106 sec" ). It was concluded that a singlet nitrene was first formed, but that it was the triplet that underwent cyclization. 

Although the cyclization of nitrenes to indoles via ortho-azidostyrenes justifiably is associated with Sundberg, several earlier workers described and studied this reaction. Notably, the researches of Smith [1-5], SmoUnsky [6-8], Abramovitch [9], Coffin and Robbins [10], and Isomura colleagues [11] describe the pyrolysis of ort/io-azidobiphenyls to carbazoles and, in a few cases, ort/io-azidostyrenes to indoles. A sampling of these pre-Sundberg reactions from the work of Smith and coworkers is shown in Scheme 1. The typical solvent used was kerosene, and the conversion of azides to carbazoles was also accomplished photochemically, albeit in lower yield. Other carbazoles prepared thermally were 1-4 in excellent yields. These workers also synthesized 4H-thieno[3,2-ii]indole (5) from 2-(o-azidophenyl)thiophene [3]. 

The Cadogan reaction refers to the deoxygenation of o-nitrostyrenes 1 or o-nitrostilbenes with trialkyl phosphite or trialkylphosphine and subsequent cyclization of the resulting intermediate nitrene 2 to form indoles 3. The reductive cyclization protocol has also been exploited to prepare a variety of A -containing heterocyclic compounds including carbazoles, indazoles, benzimidazole, benzotriazoles, anthranils, phenazines, phenothiazines, quinolines, and related compounds. 

Intramolecular substitution by arylnitrenes has been known for a long time and the cyclization of o-azidobiphenyls to carbazoles is representative of an important series of nitrene reactions that yield heterocycles. Only fairly recently has an intermolecular counterpart of these reactions been observed. Originally when phenyl azide was thermolyzed in benzene only azobenzene (11%), aniline (18%), and tars were obtained, and no diphenylamine was found. Abramovitch considered that phenylnitrene is not sufficiently electrophilic to attack benzene, so he decomposed a series of aryl azides (bearing strongly electron-withdrawing substituents, NO2, CN, CF3) in solvents activated... 

Cyclization of o-azidobiphenyls to carbazoles is one of the oldest and best studied arylnitrene reactions. Carbazole formation (67) has finally been shown " to involve cyclization of a singlet nitrene (68), generated by photolysis or thermolysis of 2-azidobiphenyl, settling a controversy of some standing. ... 

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