Tosylates, Beckmann rearrangements

The ketoxime derivatives, required as starting materials, can be prepared from the appropriate aromatic, aliphatic or heterocyclic ketone. Aldoximes (where R is H) do not undergo the rearrangement reaction, but rather an elimination of toluenesulfonic acid to yield a nitrile. With ketoxime tosylates a Beckmann rearrangement may be observed as a side-reaction. 

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. 

Lee and coworkers ", studying the Beckmann rearrangement of 1-indanone oxime derivatives 240, observed that the pure E and Z oximes isomerize under mild acidic conditions such as silica gel (equation 72). In the presence of Brpnsted or Lewis acids as silica gel or AICI3 the high rotational barrier of C=N double bond would be lowered by the formation of a complex between the tosylate and AICI3 241. This fact makes the... 

Alternatively, oximes may be converted to O-substituted oximes (typically O-tosyl oximes) making the rearrangement much easier. Sometimes, these oxime derivatives rearrange spontaneously under the condition of their formation and cannot be isolated. Usually, O -tosyl ketoximes rearrange smoothly with exclusive anti migration. Relative to the acid-promoted Beckmann rearrangement, the rearrangement of O -tosyl oximes is much milder and specific. 

Several different reaction conditions were tested to perform the Beckmann rearrangement of the substituted thiophene 323 (equation 118). The reaction of the tosyl oxime derivative was found to be the best available method, and 324 was obtained in high yield °. ... 

The synthesis of chiral, non-racemic a-amino acids remains an interesting field of investigation and the synthesis of fully protected a,a-disubstituted a-amino acids 331 via the Beckmann rearrangement of tosylated oximes was achieved (equation 123). As expected, the migrating group was able to retain the original stereochemistry and good yields and excellent enantioselectivities were observed ... 

The Neber rearrangement was discovered in 1926 during the investigation of the Beckmann rearrangement. It was reported that treatment of ketoxime tosylate 517 with potassium ethoxide followed by acetic and hydrochloric acid produced a-amino ketones 518 (equation 231). 

Beckmann rearrangement of the oxime tosylate (190) to provide the 2-oxoperhydropyrido[l,2-n]pyrimidine (193) was reported by Grob et al.1A1... 

These bicyclo[4.2.0]octanones also undergo aza-ring expansion to lactams. Beckmann rearrangement of the oxime of a typical bicyclic butanone (1) results in an octahydroisoindolone (2), whereas rearrangement of the methylnitrone (3) with tosyl chloride (4, 510 511 6, 598) proceeds in the opposite direction to give an octahydroindolone (4) as the only product.2... 

But for hormones such as oestrone and testerone two carbon atoms need cyclic substituent. Tosylation and Beckmann rearrangement gives an... 

Beckmann rearrangement of a 17-oxime has also been used to furnish A13<18)-13,17-seco-5a-androstene-17-nitrile (249), which on methylation with methyl-lithium gave the ketone (256 R = H) and thence by hydride reduction the alcohol (257 R1 = H, R2 = OH, R3 = Me).115 Conversion of this alcohol into its tosylate and further hydride reduction furnished the exocyclic olefin A13(18)-13,17-seco-D-homoandrostene (257 R1 = R2 = H, R3 = Me). Reaction of the nitrile (249) with trideuteriomethyl-lithium gave the ketone (256 R = D) and conversion into the hydrocarbon as outlined above gave the olefin (257 R1 = R2 = H, R3 = CD3). Reduction of the ketone (256 R = H) with lithium aluminium deuteride furnished the alcohol (257 R1 = D, R2 = OH, R3 = Me) which could in turn be converted into... 

Under Beckmann rearrangement conditions, O-tosyl oximes furnish the cyanoanilines, while the parent oxime gives the intermediate 2-cyanophenylisocyanate220. When the O-acetyl oximes are reacted with sodium azide, cyanoanilines are also produced. Campbell proposed a mechanism where the E-isomer of the oxime suffers elimination, forming a 2-cyanoisocyanate, which upon hydrolysis and decarboxylation gives 2-cyanoani line (Scheme... 

Photohydration of 3-oxo-A -compounds in water-methanol (4 1) gave the corresponding 5a-hydroxy-3-oxo-compounds. ° Photolysis of 3-oxo-4-tosyl-oxycholest-4-ene (204) gave the hydroxy-compound (205) whereas the simple cyclohexenone derivatives (206) afforded the 3-aryl-2-hydroxycyclohexenones (207). It was established that photo-Beckmann rearrangement of A-nor-5a-cholestan-3-one oxime proceeded with retention of configuration at C-5. 

Beckmann rearrangement. The standard Beckmann rearrangement of A -3-keto steroids is complicated by the (act that the corresponding oximes consist of syn-and anti-isomers (lb and la), but the former isomers undergo rearrangement in the presence of acid much more readily than the an/i-isomers. However, the tosylates of the isomeric oximes equilibrate in methanol very readily in the presence of acid. Thus treatment of the tosylated oxime mixture with cone. HCl at 50° results in 3-azalactams (2) in 85-95% yield. ... 

Heating 3-nitroso-2-phenyl-l//-indole with excess phosphoryl chloride or tosyl chloride in sulfolane at 200 C for 1 h, followed by dilution with water, produces 2-phenylquinazolin-4(3//)-one in 90 or 68% yield, respectively. The ring expansion proceeds via the second-order Beckmann rearrangement of the imino-oxime tautomeric form of 3-nitroso-2-phenyl-l//-indole. °... 

Nitrones (268), derived from ketones, undergo a Beckmann-like rearrangement when treated with tosyl chloride in pyridine. Unlike the Beckmann rearrangement, however, the reaction is independent of the nitrone configuration, and shows a preference for vinyl migration. The consequence, for a 4-en-3-one derivative, is the formation of the unusual enamine-lactam (270). The hydroxyl-amino-O-tosylate derivative (269) is considered a likely intermediate (see also Part II, Chap. 2, p. 353). 

The Beckmann rearrangement also allowed the preparation of cyclopropyl-amines 183-189 yy accessible in 68-77 % yield from the reaction of the oxime (76) with tosyl chloride in dioxane or with trifluoroacetic anhydride in dimethoxy-ethane (equation 13). Bicyclic- and tricyclic aminocyclopropanes (79 and 81) could be obtained from ketones (78 and 80) and hydroxylaminic reagents (equations 14 and 15). Further examples are reported in Refs 188a-j. 

The rearrangement of ketone nitrones with tosyl chloride in pyridine has been described in full. The reaction has resemblances to the Beckmann rearrangement of oximes, but does not depend upon nitrone stereochemistry, and gives N-alkyl-(usually A-methyl) lactams. 

A-aza-A-homosteroids (2). The reaction is probably initiated by p-toluenesulfonylation of the nitrone followed by capture of a nucleophile at C3. The resulting hydroxylamine O-tosylate then rearranges to (2). The rearrangement provides an alternative to the Beckmann rearrangement. 

Beckmann rearrangements applied to 2-furyl ketones are abortive there is no skeletal rearrangement. Many studies have failed to elucidate exactly what happens, but recently it has been demonstrated by methods including alternative synthesis that the products from oxime tosylates in methanol are actually 2,5-dimethoxy-2,5-dihydrofurans (e.g., Ill from 2-acetylfuran) as mixtures of geometrical isomers exactly as if they had been formed by furan oxidation techniques Section VI Part I).226... 

Tosyl chloride is also useful as a reagent for ell eciing Beckmann rearrangements," " for example of 9-geetyl>dHe6elln oxlmei"... 

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