Nitrenes in Heterocyclic Ring Synthesis

The insertion of a nitrene (a monovalent, six-electron, neutral nitrogen, most often generated by thermolysis or photolysis of an azide (RN3 RN -I- N2), or by deoxygenation of a nitro group) into a C-H bond has been made the key step in several synthetic routes to both five- and six-membered aromatic systems. The process can be written in a general way  

The preparation of an indole (which was elaborated into the coenzyme, methoxatin (see also section 6.16.2.4), and of carbazole illustrate the power of the method. 

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The synthesis of metal-coordinated 1-azirines and the reactions of azirines induced by metals have opened a new area in the chemistry of this small ring heterocycle. Many of the reactions encountered bear resemblance to previously discussed thermally and photo-chemically induced reactions of 1-azirines. The reaction of a series of diiron enneacarbonyls in benzene results in coupling and insertion to give diimine complexes and ureadiiron complexes as well as pyrroles and ketones (76CC191). A mechanism for the formation of these products which involves initial 1,3-bond cleavage and generation of a nitrene-iron carbonyl complex as an intermediate was proposed. 

The formation of five- and six-membered heterocycles by radical cyclization is discussed in a comprehensive review <2004H(63)1903>. Representative examples of ring syntheses involving carbenoid (Table 6) or nitrenoid (Table 7) intermediates are given. In many cases, the free carbene or nitrene is probably not involved, and the distinction between insertion and addition reactions given in the tables is not always clear cut. Such reactions are particularly useful for the preparation of tricyclic compounds. The application of carbenes and carbenoids in the synthesis of heterocyles is summarized in a review <1996AHC(65)93>. 

Even if no nitrenes are produced as intermediates, the isocyanates formed in Curtius-type rearrangements are of value for the synthesis of heterocyclic compounds. For example, transient isocyanates cyclize unto azine rings, giving imidazoazines (Scheme 21).161 N,N-Diphenylcarbamoyl azide rearranges thermally to 1-phenylindazolone (Eq. 35) via the elusive diphenyla-mino isocyanate.162 Further examples have been summarized by Reichen.163... 

Staurosporine and related molecules are under active investigation as potential anti-tumour agents. The synthesis illustrates several aspects of heterocyclic chemistry, including a 2-pyrone acting as a diene in an intramolecular Diels-Alder reaction, and the use of nitrene insertion for the formation of 5-membered nitrogen rings. 

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... 

As with several indole-ring syntheses to be discussed, transition metals have been adapted to the Sundberg azide indole-carbazole synthesis. These include rhodium, ruthenium, palladium, and iron. Rather than discuss these elegant methods in the present chapter, 1 have relegated them to the respective chapters on metal-promoted indole synthesis. Two excellent reviews discuss the synthesis of nitrogen heterocycles via azides [59] and nitrenes [60]. 

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