Insertion aryl nitrenes

Aryl nitrenes also generally rearrange rather than undergo addition or insertion reactions.252... 

Formation of the product of formal insertion of nitrene 16e into the aryl and benzylic CH-bonds of toluene was observed upon photolysis of 15e in toluene ... 

Photochemically reactive molecules have often been used as labels for specific sites in proteins and nucleic acids. Psoralen derivatives serve as relatively nonspecific photochemically activated crosslinking agents for DNA and double-stranded RNA.195 Aryl azides are converted by light to aryl nitrenes, which react in a variety of ways including insertion into C-H bonds (Eq. 23-27).200 201 In some cases UV irradiation can be used to join natural substrates to enzymes or hormones to receptors. For example, progesterone, testosterone, and other steroids have been used for direct photoaffinity labeling of their receptors.202 Synthetic benzophenones have also been used widely as photoactivated probes.203... 

The photochemistry of aryl azides is quite complex, suggesting that the nitrene 14 may not be the only reactive intermediate and that insertion reactions may not be the only route to form photoconjugates.Although aryl nitrenes are much less susceptible to rearrangements than acyl nitrenes, they may still occur and lead to the formation of reactive intermediates such as azepines, which may go on to react with nucleophiles.[911 141 Addition of nitrenes to double bonds will generate azirines, while dimerization will produce azobenzenesJ11 Aryl azides are stable to most of the procedures used in the course of peptide synthesis except for reduction reactions. Non-photochemical reduction of aryl azides to the primary amines by thiols has been reported by Staros et al.[15]... 

The major intermolecular reaction of triplet aryl nitrenes in solution is hydrogen atom abstaction to form primary amines. For a photoaffinity reagent bound to a receptor, this would result in a failure to couple. However, it is possible that the intramolecular photochemistry of aryl azides is more relevant, and here numerous examples of insertion by triplets have been noted. Presumably, these are two step processes hydrogen atom abstraction, followed by radical coupling (cf. Figs. 2.1 and 2.3). 

While little work has been done to determine the nature of the photochemical adducts between aryl nitrenes and protein receptors, Westheimer and his colleagues have put considerable effort into elucidating the structure of the products formed when carbenes react with proteins. The isolation, albeit in low yields, of insertion products formed by the reactions of carbenes with the -OH of tyrosine, the CH3- of alanine and the -S2- of cystine in chymotrypsin and trypsin augers well for the formation of stable products in other systems (see Chowdhry and Westheimer, 1979 and references therein). 

The development of the chemistry of aryl nitrenes has occurred primarily over the last 20 years, even though initial forays were made nearly a century ago. This slow development can be attributed to the fact that photolysis or pyrolysis of typical aryl azides, such as phenylnitrene 1, produces polymeric tar (Reaction 5.1). This is in sharp contrast to the rich chemistry of phenylcarbene (2), which exhibits insertion into C-H bonds, addition to Jt-bonds, reaction with oxygen, and so on. ... 

Although aryl nitrenes often give poor yields of intermolecular C-H insertion products, the intramolecular reaction works well, and proceeds with retention... 

This reaction appears to be more difficult than the insertion into a vinylic C-H bond, which occurs in the synthesis of indoles from 2-nitrostyrenes (see paragraph 5.3.). The known chemical inertness of aromatic C-H bonds towards nitrene insertion [13] and the stabilisation of the intermediate aryl nitrene triply bridged in the ruthenium cluster are probably responsible for the poor yield of the heterocyclic product. 

The importance of this rearrangement pathway for nitrenes generated in a biological receptor site is not known, however, and in model systems an aryl nitrene will insert into a carbon-hydrogen bond if tiiere is one in the near neighborhood. Thus irradiation of 2-azidobiphenyl results, via both the singlet and the triplet nitrene, in the formation of carbazole ... 

Aryl nitrenes also generally rearrange rather than undergo addition or insertion reactions. A few intramolecular insertion reactions in aromatic systems go in good yield. ... 

A copper-catalyzed enantioselective aziridination of aryl cinnamyl ethers and intramolecular arylation of the in situ generated tethered aziridine was developed by Hajra and Sinha. This method provides an easy access of N-sulfonyl-protected fra s-3-amino-4-arylchromans with high regio-, diastereo- (dr > 99 1), and enantioselectivity (ee up to 95%) (Scheme 8.113). Three C(sp )-H bonds were activated in this transformation under this Cu(0Tf)2/Cu(C10 )2-6H20 catalyst system. The major side reaction is the C-H insertion of nitrene at the O-CH2 unit followed by oxidative cleavage [188]. 

Bis(aryl azide)s, such as (10), represent an important class of photocrosslinking agents. Irradiation of the aryl azide chromophore (ArN3) results in the elimination of N2 and formation of a highly reactive aryl nitrene (ArN ). Two important reactions of the nitrene group are insertion into a C-H bond, and addition to a C=C bond, as shown in Scheme 5. 

The photolysis of 2-azidobiphenyl 64 or similar aryl nitrene precursors yields carbazole 66 by insertion of the singlet nitrene 65 into the ortho C-H bond of the neighboring benzene ring. This efficient reaction may be extended to the synthesis of other heterocycles. 

Aryl and heteroaryl nitrene insertion processes have also been employed in the synthesis of heterocycles. The azide 459, for example, is converted on irradiation into the imidazole 460,383 and dihydro-10-thiaisoalloxazines are obtained in good yield on photoelimination of nitrogen from 6-(2-azido-phenylthio)uracils.384... 

Formation of l-aryl-l//-azepines is rare and occurs only with those arylnitrenes made sufficiently electrophilic by an electron-withdrawing, e.g. CN, N02 or CF3, ortho or para substituent. Even so, these docile nitrenes attack only electron-enriched arenes (e.g. mesity-lene or Af,Af-dimethylaniline) and are of minor synthetic importance (B-73MI51600). More reactive are 7r-deficient heteroarylnitrenes, and moderate yields (15-40%) of 1-heteroaryl-l//-azepines, e.g. (228 R=4,6-dimethoxy-l,3,5-triazin-2-yl), may be obtained by the photodecomposition of 2-azido-4,6-dimethoxy-l,3,5-triazine in a variety of aromatic substrates (81BCJ301). Interestingly, intramolecular insertion of arylnitrenes into arenes is more common and has been used for the synthesis of fused azepines, e.g. the azepinoindoles (229) from o-azidodiphenylmethanes (81JCS(P1)1132). 

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