Cyclization azirines

The pyrazole ring is resistant to oxidation and reduction. Only ozonolysis, electrolytic oxidations, or strong base can cause ring fission. On photolysis, pyrazoles undergo an unusual rearrangement to yield imidazoles via cleavage of the N —N2 bond, followed by cyclization of the radical iatermediate to azirine (27). 

The course of the photochemically mediated isomerization of vinylazirines is dependent on the stereochemistry of the vinyl group, as is illustrated in Scheme 94a (75JA4682). Under thermal conditions the isomerization proceeds through formation of the butadienylnitrene and subsequent pyrrole formation. Analogous conversions of azirines to indoles have also been effected (Scheme 94b). It is possible that some of the vinyl azide cyclizations discussed in Section 3.03.2.1 proceed via the azirine indeed, such an intermediate has been observed... 

Important synthetic paths to azirines and aziridines involve bond reorganization, or internal addition, of vinylnitrenes. Indeed, the vinylnitrene-azirine equilibrium has been demonstrated in the case of trans-2-methyl-3-phenyl-l-azirine, which at 110 °C racemizes 2000 times faster than it rearranges to 2-methylindole (80CC1252). Created in the Neber rearrangement or by decomposition of vinyl azides, the nitrene can cyclize to the p -carbon to give azirines (Scheme 4 Section 5.04.4.1). 

The protonated azirine system has also been utilized for the synthesis of heterocyclic compounds (67JA44S6). Thus, treatment of (199) with anhydrous perchloric acid and acetone or acetonitrile gave the oxazolinium perchlorate (207) and the imidazolinium perchlorate (209), respectively. The mechanism of these reactions involves 1,3-bond cleavage of the protonated azirine and reaction with the carbonyl group (or nitrile) to produce a resonance-stabilized carbonium-oxonium ion (or carbonium-nitrilium ion), followed by attack of the nitrogen unshared pair jf electrons to complete the cyclization. 

Azirines react with enolate anions. Initial nucleophilic attack on phenyl 1-azirine by the enolate anion derived from acetophenone gives intermediate (223) which undergoes 1,2-bond cleavage, cyclization and hydroxyl group elimination to give pyrrole (226). 

Carbanions in the form of ylides also add to azirines. For example, treatment of 1-azirine (227) with dimethylsulfonium methylide gives 1-azabicyclobutane (229) in good yield (72JA2758). The addition of the methylene group occurs by initial nucleophilic attack by the ylide to give intermediate (228) which cyclizes with expulsion of dimethyl sulfide. 

Addition of trichloromethide ion to azirine (210) generates aziridine (230). When this aziridine was treated with base, cyclization and rearrangement occurred and the azetidine (233) was isolated (73JA2982). 

Preparative routes to aziridines and 1-azirines are derived from cycloelimination processes in which one, and sometimes two, bonds are formed directly to the nitrogen atom (Scheme 1). For aziridines these include the two intramolecular cyclization pathways involving either nucleophilic displacement by the amine nitrogen (or nitrenium anion) on the /3-carbon (route a) or nucleophilic displacement by a /3-carbanionic centre on the amine nitrogen... 

In some cases, the /3-haloamine undergoes spontaneous cyclization to the aziridine <70TL1125>. Most of these routes, however, require either reductive or base-induced cyclization to the aziridine. Access to a vast number of aziridines and 1-azirines has been... 

A related synthesis of vinylaziridines 88 by treatment of ot, 3-unsaturated hydra-zones 85 with Grignard reagents has also been reported (Scheme 2.23) [39]. Ni-trenes 86 were proposed as plausible intermediates, their cyclization to azirine 87... 

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

The presence of a 2-substitutent in 3-phenylazirines (17, R —H in Scheme 21) modifies the mode of reaction with molybdenum carbonyl.47 In contrast to pyrazine formation for (17, R =H see Section V,C,2), the alkenyl azirine (18, Scheme 22) is transformed in excellent yield into 2-phenyl-5-carboxy-methylpyrrole. This product probably arises by intramolecular cyclization within an intermediate dienylnitrene intermediate, and related reactions have been devised to synthesize isoxazoles (see Section IV,E,2) and pyrazoles (see Section IV,D,1).47 The molybdenum carbonyl-promoted formation of 2,5-disubstituted pyrroles47 has analogy in uncatalyzed thermal, but not photochemical decomposition of 3-phenyl-2//-azirine 2-acrylate.49... 

Taber and Tian have employed the Neber protocol to prepare a-aryl azirines that underwent thermal rearrangement to afford substituted indoles via a unique Ie type ring closure <06JACS1058>. A variety of substituted N-alkyl and N-aryl indoles have been prepared by Zhao and co-workers who observed Ie cyclization of 2-aryl-3-arylamino-2-... 

The first step — cyclization of lb to the azirine 2b — is predicted to be the rate-determining step. The CASPT2 calculated barrier of 9.2 kcal/mol is... 

Formation of 2//-azirines by thermal decomposition of vinyl azides has been shown to exhibit small entropy of activation and insensitivity to solvent polarity acyclic vinyl azides decompose more readily than analogous cyclic ones and it is advantageous to have a hydrogen atom cis to the azido group ( -are more reactive than Z-isomers). These results and the linear correlation found for ring-substiment effects on decomposition of a-styryl azides are consistent with a nonconcerted mechanism in which elimination of nitrogen and cyclization into a three-membered ring proceeds synchronously. 

These intermediates with benzyhnagnesinm bromides gave 2-benzyl-2/7-azirines 8 in 50-80% yields, bnt potassinm phthahmide and sodium salt of benzenethiol converted them into the corresponding azirines 9 and 10 in good yields (equation 4). Similar Neber-type cyclization of a-hthio oxime ethers to highly reactive azirines was recently reported. ... 

A single o- or p-methyl substituent has no influence on the rate of cyclization of the singlet tolylnitrene to the favored azirine. ° The methyl group has no bystander effect on benzazirine formation. Cyclization of 2,6-dimethylphenyl or 2,4,6-tri-methylphenylnitrenes necessarily proceeds toward a carbon bearing a substituent. A steric effect raises the barrier to cyclization by 1.5-2.0 kcal/mol, in excellent agreement with the predictions of Karney and Borden. The steric effect extends the lifetime of 2,6-dimethylphenylnitrene at ambient temperature to 13 ns in Freon-113 and of 2,4,6-trimethylphenylnitrene to 8 ns, in the same solvent (Table 11.4). ° ... 

In principle, singlet 1-naphthylnitrene can cyclize to two distinct azirines 43 and 44, but 43 is clearly much lower in energy than isomer 44, which lacks aromaticity in either ring. One can therefore predict that 43 will be formed preferentially. 

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