Beckmann rearrangement substrates

Substituents R, R at the starting oxime 1 can be H, alkyl, or aryl. The reaction conditions for the Beckmann rearrangement often are quite drastic (e.g. concentrated sulfuric acid at 120 °C), which generally limits the scope to less sensitive substrates. The required oxime can be easily prepared from the respective aldehyde or ketone and hydroxylamine. 

The reaction that normally occurs on treatment of a ketoxime with a Lewis or proton acid is the Beckmann rearrangement (18-17) fragmentations are considered side reactions, often called abnormal or second-order Beckmann rearrangements. Obviously, the substrates mentioned are much more susceptible to fragmentation than are ordinary ketoximes, since in each case an unshared pair is available to assist in removal of the group cleaving from the carbon. However, fragmentation is a side reaction even with ordinary ketoximes and, in cases where a particularly stable carbocation can be cleaved, may be the main reaction. ... 

Not only do oximes undergo the Beckmann rearrangement, but so also do esters of oximes with many acids, organic and inorganic. A side reaction with many substrates is the formation of nitriles (the abnormal Beckmann rearrangement, 17-31). Cyclic ketones can be converted directly to lactams in one laboratory step by... 

The ammoximation reaction involves the in situ formation of hydroxylamine via TS-1 catalysed oxidation of NH3 with H2O2. Hence, there are no size restrictions with regard to the ketone substrate, because the reaction of NH2OH with the latter occurs in the bulk solution. For example, TS-1 catalyses the ammoximation of / -hydroxyacetophenone (Le Bars et al., 1996). Beckmann rearrangement of the oxime product (see Fig. 2.18) affords the analgesic paracetamol (4-acetaminophenol). 

Oximes are also good substrates for allylsamarium bromide addition.25 The Beckmann rearrangement product 44 was produced from oxime 43 in good yields when the ratio of allysamarium bromide to oximes was more than 3 1 (Equation (8)). This type of product was also obtained when the other allylic organometallic compounds were used. The reaction mechanism was proposed as shown in Scheme 13. 

A serious shortcoming of TS-1, in the context of fine chemicals manufacture, is the restriction to substrates that can be accommodated in the relatively small (5.lx5.5 A2) pores of this molecular sieve, e.g. cyclohexene is not epoxidised. This is not the case, however, with ketone ammoximation which involves in situ formation of hydroxylamine by titanium-catalysed oxidation of NH3 with H202. The NH2OH then reacts with the ketone in the bulk solution, which means that the reaction is, in principle, applicable to any ketone (or aldehyde). Indeed it was applied to the synthesis of the oxime of p-hydroxyacetophenone, which is converted, via Beckmann rearrangement, to the analgesic, paracetamol (Fig. 1.24) [75]. 

One of the classical reductive aldehyde syntheses is the Sonn-MUller reduction of imidoyl chlorides. The method is closely related to the Stephen reduction described in the previous section. As shown in Scheme 16, substrates (53) may be prepared either by the treatment of anilides with phosphorus pentachloride or sulfinyl chloride, or less usually via the Beckmann rearrangement. They are... 

The Beckmann rearrangement proceeds through a transition state represented by structure (59) in equation (27). Thus, the organoaluminum-catalyzed protocol presents an opportunity to convert a ketone regiospecifically and stereospecifically into a chain-extended amino substrate. 

Dimethyl [a-(hydroxyimino)benzyl]phosphonate is stable in mineral acid but decomposes in formic acid containing formate with the liberation of benzonitrile, but otherwise the behaviour is different from that in boiling acetic acid when an additional product, a phosphoramidate ester, is obtained by a Beckmann rearrangement. For the oximes of the (4-methoxybenzoyl)- or (4-chlorobenzoyl)-phosphonic esters, only the phosphoramidate diester 127 is obtained, but for all the substrates examined [additionally the unsubstituted benzoyl- as well as the (4-methylbenzoyl)phosphonic derivatives], the formation of the phosphoramidate ester demonstrates a high migratory aptitude of the phosphinoyl group (Scheme 22) ... 

This reaction, like all Neber rearrangements, is limited by availability of the appropriate oxime tosylate. Substrates in which the aryl group contain an electron-donating function are unstable, since they have a propensity to undergo Beckmann rearrangement. However, this difficulty can be resolved by subsequent conversion of the a-amino acetals. For example, catalytic hydrogenation of 2,2-diethoxy-2-(p-bromophenyl)ethylaraine yields the known parent compound, 2,2-diethoxy-2-phenylethylamine These two a-amino acetals readily undergo hydrolysis and should be protected from moisture. 

Kinetic evidence for such a dynamic path bifurcation in the mechanism of the Beckmann rearrangement has also been presented for reactions of oxime sulfonates (43, R /R = H/Me). In addition to the rearrangement product (amide), these substrates can also fragment (to alcohols), with the bifurcation in the mechanism apparently occurring after the rate-determining transition state. 

TsCl has recently been identified as a suitable organocatalyst for the Beckmann rearrangement. This requires a Lewis acid additive, ZnCl2, and only requires 1 hour to result in reaction completion. Few substrates were tested, although less successful substrates included l-(4-cbloro-phenyl)etha-none oxime which only proceeded to 40% conversion. The potential for scale up was also demonstrated with the reaction being conducted on a 100 mmol scale yielding quantitative amide. Other organocatalytic methods include the use of cyclopropenium ions. ... 

Recently, ah initio calculations on the mechanism of the Beckmann rearrangement of various substrates have been performed [357]. 

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