Beckmann rearrangements addition

The intermediate may be trapped by other nucleophiles (different from water) and diverse products may be obtained. The interception of the intermediate may occur inter- or intra-moleculary, the latter providing a helpful tool to produce a new ring system (Scheme 9, pathway 2). These reactions are sometimes referred to, respectively, as Beckmann rearrangement-addition and Beckmann rearrangement-cyclization reactions. 

Imidates, or even nitrogen compounds produced from imidates by the addition of nucleophiles, may be obtained from oximes by a Beckmann rearrangement-addition process. 

Although the Schmidt reaction is formally analogous to the Beckmann rearrangement, it is less versatile in the 20-keto steroid series since only 1,4-addition to the double bond has been observed with the important A -derivatives. 

Regioselective Beckmann rearrangements were used as key steps in the synthesis of phosphonoalkyl azepinones (Scheme 36) [43b] and in a formal total synthesis of the protein kinase C inhibitor balanol (Scheme 37) the optically active azide 197 derived from cyclohexadiene mono-oxide was converted into ketone 198 in several steps. After preparation of the oxime tosylates 199 (2.3 1 mixture), a Lewis acid mediated regioselective Beckmann rearrangement gave the lactams 200 and 201 in 66% and 9% yield, respectively. Lactam 201 underwent a 3-e im-ination to give additional 200, which served as a key intermediate in a balanol precursor synthesis (Scheme 37) [43 cj. 

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. 

The oxime nitrogen can also participate in cycloamination reactions to give pyrroles. Thus, treatment of oxime esters such as 185 with Pd(Ph3P)4 readily affords 186 [129]. The pentafluorophenyl group is necessary for good results otherwise a Beckmann rearrangement can unfavorably enter the picture. The oxime stereochemistry makes no difference on the outcome of the reaction. In addition to 186, pyrroles 187 and 188 were also prepared in this study (among others) [129]. 

The Beckmann rearrangement of oximes to produce amides is promoted by perrhenate ions under phase-transfer catalytic conditions, in the presence of trifluoro-methanesulphonic acid in nitromethane [6]. Under these conditions, the rearrangement reaction is frequently accompanied by the solvolysis of the oxime to the ketone. This can be obviated by the addition of hydroxylamine hydrochloride. No reaction occurs in the absence of the ammonium catalyst or with the O-acetyl oximes. 

Beckmann, E. Chem. Ber. 1886, 89, 988. Ernst Otto Beckmann (1853—1923) was bom in Solingen, Germany. He studied chemistry and pharmacy at Leipzig. In addition to the Beckmann rearrangement of oximes to amides, his name is associated with the Beckmann thermometer, used to measure freezing and hoihng point depressions. Mazur, R. H. J. Org. Chem. 1961,26, 1289. 

The main intermediate of the rearrangement may be a nitrilium ion (225) in some cases or an imidate (226) in others. The resulting intermediate reacts with water to produce the amide (218) after tautomerization. If other nucleophiles (Nu ) are present, they can intercept the reactive intermediates (both inter- or intra-molecularly) and several different imino-substituted derivatives (227) can be formed. These rearrangement-addition reactions will be analysed later in this chapter as they can effectively broaden the scope of the Beckmann rearrangement reaction (Sections VI.D.2 and VI.E.2). 

A similar mechanism to the previous ones was proposed by Deng, Shi and coworkers for the bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl, 269) catalytic Beckmann rearrangement (equation 82). Addition of the Lewis acid zinc chloride improved the catalyst performance and amides were synthesized in excellent yields (92-99%). 

A multigram preparation of a useful chiral building block was developed, using the Beckmann rearrangement as a key synthetic step (equation 115) °. The enantiomeric addition of thiophenol to a chalcone 313, catalysed by (+)-cinchonine, provided the chiral enantiomeric carbonyl compound 314. The Beckmann rearrangement of its oxime 315 gives the anilide of (R)-(- -)-3-phenyl-3-phenylsulfanylpropanoic acid 316. Alcoholysis produced the expected enantiomerically pure ethyl ester 317. 

Acetaminothiophene has been prepared by a Hofmann rearrangement of thiophene-3-carboxamide (equation 49), or by a Beckmann rearrangement of the 3-acetylthiophene oxime (Section 3.14.3.4). Dimethyl 4-amino-2,3-thiophenedicarboxylate was formed in excellent yield from the oxime of the 4-ketotetrahydrothiophene diester, which is readily available by addition of thioglycolate to dimethyl fumarate, followed by a Dieckmann cyclization (equation 50 Section 3.15.2.2.2). 

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