Insertion reactions, nitrenes

The main example of a category I indole synthesis is the Hemetsberger procedure for preparation of indole-2-carboxylate esters from ot-azidocinna-mates[l]. The procedure involves condensation of an aromatic aldehyde with an azidoacetate ester, followed by thermolysis of the resulting a-azidocinna-mate. The conditions used for the base-catalysed condensation are critical since the azidoacetate enolate can decompose by elimination of nitrogen. Conditions developed by Moody usually give good yields[2]. This involves slow addition of the aldehyde and 3-5 equiv. of the azide to a cold solution of sodium ethoxide. While the thermolysis might be viewed as a nitrene insertion reaction, it has been demonstrated that azirine intermediates can be isolated at intermediate temperatures[3]. 

Intermediate arylamidine, 6S, is prepared by the aluminum chloride-catalyzed addition of aniline to the nitrile function of 4-cyanothiazole (67), Amidine, 65, is then converted to its N-chloro analog (69) by means of sodium hypochlorite. On base treatment, this apparently undergoes a nitrene insertion reaction to produce thiabendazole (70), ... 

The pyranofurooxazoline 109 can be prepared by a nitrene insertion reaction of the corresponding furan 110 upon treatment with ethyl azidoformate at — 50 °C under photolysis conditions. Compound 109 is moisture sensitive, and upon treatment with wet acidic THF was converted quantitatively to the more polar furanopyran 111. The structure and stereochemistry of 109 were proved unambiguously by X-ray diffraction, showing that the nitrene inserted anti to the bridgehead methyl group <1999JOC736> (Scheme 30). 

Baldwin has utilized an intramolecular nitrene insertion reaction in an approach to hydrolytically stable analogues of penicillin <2001T4999, 2003T8233>. Although the reaction proceeded in only moderate yields, the product is formed with excellent facial selectivity (Equation 43). 

The results have been corroborated by further studies of o-(allyloxy)phenyl azide and 14 derivatives substituted on the allyl group. The allyloxy azide in Scheme 39 underwent complete conversion to triazoline at 35°C in 3 weeks as indicated by NMR.197 Thermolysis of o-allylphenyl azides, on the other hand, required high temperatures of the order of 155-200°C, apparently suggesting nitrene insertion reactions.197 The higher rate of decomposition of ortho-substituted phenyl azides as compared to the corresponding meta or para isomers, noted primarily in those systems where the ortho substituents have... 

Attempts to achieve asymmetric nitrene insertion reactions catalyzed by chiral transition metal complexes have also been performed [41,42]. The reaction of the nosyl-imine derivative as the nitrene donor with indane 61 catalyzed by the chiral rhodium complex 63 gave the optically active allyl amine 62 in good yield and moderate ee (Eq. (15)) [41],... 

Azido-5,7-dimethyl-6-phenylisoquinoline (182) has been used to prepare ellipticine via a nitrene insertion reaction (Equation (82)) <89TL297>. 

Although intermolecular nitrene insertion reactions can be a useful way of functionalizing unactivated C—H bonds, it is the intramolecular version of the reaction that has found the widest use in synthesis. Most types of nitrene will undergo intramolecular C—H insertion, and the following discussion is organized in terms of type of nitrene, scope and selectivity of the reaction, and, finally, specific uses in synthesis. 

Intramolecular nitrene insertion reactions into sp C—H bonds have found wide use in recent years in the synthesis of indole alkaloids and related natural products. In general, the reactions are of two types. 

A similar nitrene insertion reaction was used in the synthesis of 6 -aminogentamycin C2 by functionalization of the garosamine moiety of the antibiotic. The key steps of the sequence are shown in Scheme 10 heating the azidoformate (18) to 130 C in dichloromethane results in the desired intramolecular nitrene insertion and fimctionalization of the unactivated methyl group, although some cyclization to the five-position is also observed. The synthesis was completed by hydrc enolysis of the oxazolidinone and removal of the protecting groups. 

The azabicyclononane system is a common structural feature in diterpene alkaloids, and the nitrene insertion route to the ring system has been studied in detail in model decalins as well as in steroids (Scheme 11). Thus irradiation of the rrans-acyl azide (21) gave, in addition to isocyanate (30-33%), a mixture of Ae 7- and 8-lactams (22) and (23). The y-lactam (22) predominated, dthough the overall yield was poor. > The corresponding c/s-azide (24), however, gave the 8-lactam (25) as Ae major product, again in low yield. One elegant application of this type of intramolecular nitrene insertion reaction... 

Efficient intramolecular nitrene insertion reactions have... 

Nitrene insertion. A nitrene insertion reaction is central to many syntheses of pyridoacridine alkaloids and their analogues. For example, Labarca et al. [87JCS(P1)927] have reported a three-step synthesis of a pyridoacridine 169 starting from 2-methoxyacridine-9-carboxaldehyde 165 (Scheme 26). Cyclization of the vinyl azide 166 by thermolysis is believed to involve a nitrene insertion reaction, to give either 167 or 168. 

A related nitrene insertion reaction which quite plausibly might have been expected to lead to a benzo-3,2-thiazocine was shown in fact to result in formation of a thiazepine as the result of an unusual rearrangement upon flash pyrolysis (Scheme 14) <84JOC3ii4>. 

The relative reactivity of C—bonds a to ring oxygens have been estimated, and the results are summarized in Scheme 5. The results are rationalized by invoking stabilization of the nitrene by prior coordination to die ring oxy n. Dioxane with two oxygen atoms is particularly effective at stabilizing nitrenes, and the formation of complex (4) has been proposed to explain the pronounced solvent effect that dioxane has on a number of insertion reactions of ethoxycaibonylnitrene. Nitrene insertion reactions in chlo-roalkanes tend to occur away from the chlorine atom with rrn/u-l,2-dichlorocyclohexane as substrate, the insertion product (5) is formed in good yield. ... 

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