Azides Beckmann reaction

In addition to the Beckmann reaction, the Schmidt rearrangement is used to generate M-alkylated lactams, too. Alkyl azides 231 react with the cyclic ketones (and aldehydes) in the presence of proton or Lewis acids. On running the inter-molecular reactions, in most cases symmetric ketals 230 have been converted... 

Azide ion has been shown to be an effective trap for a Beckmann intermediate. Treatment of acetophenone oxime with thionyl cloride in the presence of hydrazoic acid gave tetrazole (37), as shown in equation (23). Thiolates participate efficiendy in Beckmann reactions, and the sulW nucleophile may be incorporated into a Lewis acidic reagent, as demonstrated in equation (24). ... 

Other useful tetrazole syntheses involving nitrilium ions include Beckmann reaction of oximes in the presence of azide ion (83JCR(S)18) and the reaction between ketones and 2 mol of hydrazoic acid in acidic media, the Schmidt reaction (Scheme 37). For example, treatment... 

The Schmidt reaction is closely related to the Beckmann reaction (equation 34). Acyclic and cyclic ketones are transformed to amides and lactams by treatment with hydrogen azide. With bridged bi-cyclic ketones, the regioselectivity of the migration is opposite to the direction of the Beckmann reaction. The Schmidt reaction has been applied to asymmetric synthesis starting from optically active a,a-dialkylated -keto esters. High chemical and optical yields have been obtained (equation 35). ... 

Treatment of ketones with azide derivatives affords amides by a Schmidt reaction [389]. Its mechanism is similar to that of the Beckmann rearrangement The key intermediate is an iminodiazonium ion [390]. In transformations of bridged bicycHc ketones both the Schmidt and the Beckmann reaction are complementary [391] since inverse selectivities have been observed [392]. 

Of equal importance to the Beckmann rearrangement for the preparation of azepines and azepinones is the Schmidt reaction of ketones. Again, however, with unsymmetrically substituted cyclohexanones or with bicyclic ketones such as a-tetralone, two azepines are possible, a -Substituted cyclohexanones invariably yield the product of attack by azide ion at the least hindered side of the protonated ketone as exemplified in Scheme 19 (B-67MI51600). 

The lactam (2) is obtained in 87% yield by treating cycloheptanone with sodium azide and concentrated hydrochloric acid (54JA2317). Beckmann rearrangement of cycloheptanone oxime with concentrated sulfuric acid gives (2) in 88% yield (58JA1510). Alternatively, the ketone gives (2) directly by reaction with hydroxylamine sulfonate in 95% formic acid (79S537). 

Amides lactams. Dimethyl thioketals of cyclic or acyclic ketones react with iodine azide to form an a-azido sulfide in 75-95% yield. The product rearranges to an amide or a lactam in high yield in the presence of trifluoroacctic acid. This sequence is an attractive alternative to the Beckmann rearrangement or Schmidt reaction. 

Six-membered rings can also serve as precursors to seven-membered rings by ring-transformation processes. Thus, Beckmann rearrangement of 308 selectively afforded the azepinones 309 (e.g., R=R = R2 = H, R3 = Me 50%) (Equation 45) <1998JGM198>, while reaction of 310 with azide gave the azido azepine 311 (Equation 46) <1998H(48)427>. 

Nitrilium ions are generally indicated as discrete intermediates in the Beckmann rearrangement of oximes (equation 37, Y = OH2) and in the Schmidt rearrangement (equation 37, Y = N2) of ketones and aldehydes with hydrogen azide. The first stage of these reactions has been defined as an ionization by rearrangement process through a transition state of type 183 (Smith, 1963). 

Analogously with the reaction depicted in equation (37), a-N-morpholino oxime (59) underwent oxidative ring cleavage under standard Beckmann conditions (equation 39). Azide nitrogen assisted cleavage of the steroidal azido oxime (60) gave a dinitrile (equation 40). ... 

Rearrangements. Cyclic ketones undergo ring expansion on reaction with hydroxyalkyl azides." Regioselectivity is dependent on steric and electronic factors. Beckmann rearrangement of ketoxime carbonates has been observed at room temperature. 

The present chapter is not intended to be a catalogue of all aspects of azepine chemistry which have been published since CHEC-I. Thus, for example, many established areas such as the Beckmann and Schmidt reactions for the preparation of reduced azepines are discussed only in respect to newer developments. The Beckmann rearrangement has been reviewed <870R(35)i>. The emphasis is to take forward the knowledge of azepine chemistry, to describe new chemistry and to develop earlier aspects which were just emerging when CHEC-I was being prepared. Such aspects include the synthesis and properties of azepine-3(2//) Ones, the formation of bicyclic and tricyclic azepines by the cyclization of diene-conjugated nitrile ylides and those results since 1984, theoretical and experimental, on the mechanism and synthetic applications of aryl azide chemistry. 

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