Nitrenes, cyclization

For most aryl azides, the rate constants of singlet nitrene decay and product formation (triplet nitrene and/or ketenimine) are the same. Thus, in all these phenyl-nitrenes cyclization to substituted benzazirines is the rate-limiting step of the process of isomerization to ketenimine, as is the case for the parent phenylnitrene. The only known exception, o-fluorophenylnitrene, will be discussed in the next section. 

Further applications of nitrene cyclizations have also been reported in which the intermediate nitrene inserts into a 7r-deficient heterocycle or a nitrene on a -deficient nucleus inserts into a proximal carbon-hydrogen bond. In general, the preferred source of the nitrene is the photolysis or thermolysis of an azide. The versatility of this approach is shown in two syntheses of pyrrolo[3,2-J]thiazoles (selenazoles) (177), (178), (180) (Equations (52) and (53)). Thermolysis of the / -thiazolyl (selenazolyl)-a-azido-esters (176) or the / -(4-azido-5-thiazolyl)-x,/J-enones (179) affords these bicyclic heterocycles in excellent yields (79JHC1563, 92JCS(Pi)973>. The same strategy has also been... 

The mechanism of the photochemically induced conversion of vinylazides into 2H-azirines has been examined using ab initio MO calculations. A new approach to the elusive thionitrosobenzene system has been reported. Direct irradiation of the 3-azido-2,l-benzisothiazole (88) affords a transient 2-cyanothionitrosobenzene (89) which can be trapped as the cycloadduct (90) with cyclopentadiene. Nitrene cyclization is the preferred pathway on irradiation of the 5-formyl- or 5-benzoyl-6-azidouracils (91) and yields the isoxazolo[3,4-d]pyrimidines (92). In contrast, 5-phenyl- and 5-benzyl-6-azidouracils were converted into pyrimido[4,5-b]indoles and pyrimido[4,5-ti Jquinolines, respectively, by a pathway involving photochemically induced loss of nitrogen and intramolecular nitrene insertion. 

Tertiary G—H bonds are more reactive than secondary ones, primary G—H bonds are least reactive. For example, the relative rates for insertion (corrected for the number of hydrogens of each type) into the G—H bonds of 2-methylbutane by ethoxycarbonylnitrene are about 30 10 1 297.324 Pivaloylnitrene is somewhat more selective . Ethoxycarbonylnitrene inserts readily into bridgehead G—H bonds in small bicyclic systems, such as norbomane or tricyclo[3.3.0.0 ] octane . The insertion is stereospecific, wfith retention of configuration both in intramolecular nitrene cyclizations " and in the inter-... 

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. 

When o-azidobenzoic acid and its potassium salt were photolysed in H2O, EtOH, THE, EtOH-H20 or THF-H2O, the major product was 2,1-benzisoxazo-lone, from intramolecular cyclization. Varying amounts of azepine products were observed, depending on the solvent. Intramolecular nitrene cyclization was also observed in the photolysis of the azido-functionalized cryptand (43), which afforded the benzopyrazole (44) after an aerobic workup. ... 

Intramolecular nitrene cyclization from thermolysis of 2-azidosulfonylbenzophenone affords the dibenzo[c/][l,2]thiazepine 5,5-dioxide system (47) in low yield, together with other products. The 2-methyl and 8-methyl analogues of (47) are prepared similarly, also in low yields <78JOCi2i8>. 

This chapter on nitrene cyclization is a segue to the following several chapters that employ this tactic in powerful and widely used indole ring syntheses. The use of metals, such as palladium, rhodium, and ruthenium, to generate nitrenes or their equivalent and effect indole ring construction is discussed in later chapters. Soderberg has reviewed the synthesis of heterocycles via the generation... 

Scheme 1 Klemm-Horaguchi Indole Synthesis via Nitrene Cyclization...

Although the Hemetsberger reaction is clearly a powerful synthesis of indole-2-carboxylates, some problems are encountered in addition to the occasional mixture of nitrene cyclization products. Indeed, often the aldoliza-tion route to the 2-azidocinnamates proceeds poorly. This can be obviated at lower temperatures (-30 °C) to stop the reaction at the azido alcohol stage. Subsequent dehydration with thionyl chloride in pyridine or triethylamine afforded the 2-azidocinnamates. This two-step process was superior to the conventional one-step aldolization/ dehydration reaction, as found by Murakami and coworkers [67]. Tercel s group also observed that a low temperature (-78 °C) aldol condensation, isolation of the azido... 

Kametani has reviewed the uses of nitrene cyclizations in the synthesis of heterocyclic natural products. 

Scheme 11.34 Effect of the bulky ortho-tert-butyl substituent on the reaction of singlet nitrene cyclization...

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