Stevens rearrangements

If the Stevens rearrangement is a concerted reaction, it is a symmetry-forbidden process based on the Woodward-Hoffmann rules. Indeed, it was shown to occur via an intramolecular hemolytic cleavage-radical pair recombination process, which explains the lack of crossover products and the observed retention of configuration at the migrating 

A new approach to the morphine skeleton was demonstrated by the total synthesis of (+)-desoxycodeine-D by C.-Y. Cheng and co-workers. The key step was the formation of the B ring by the Stevens rearrangement of a tetrahydroisoquinoline-derived quaternary ammonium salt upon treatment with phenyllithium. 

Raju Ranjith Kumar, K. Angaiyarkanni Vanitha and Subbu Perumal 1.3.8.1 D cription 

The transformation of quaternary ammonium salts 1 and sulfonium salts 3 to the corresponding amines 2 and sulfides 4 in the presence of a strong base is known as Stevens rearrangement. The salts are usually obtained by the alkylation of the corresponding amines and sulfides. The competing reaction is the Sommelet-Hauser rearrangement. 

In 1928, T. S. Stevens reported the reaction of 1-phenyl-l-(iV,iV-dimethyl) ethanone 5 with benzyl bromide to afford the ammonium salt 6 which upon treatment with sodium hydroxide, resulted in the formation of rearranged amine 7. The reaction of corresponding sulfur analog reaction was reported in 1932.  

The mechanism of Stevens rearrangement for the nitrogen reaction is shown below. The key step is the formation of an ylide 8 resulting from the deprotonation of the ammonium salt 1 by a strong base, which is also supported by the electron withdrawing nature of R. The ylide 8 is converted into the rearranged product 2 either by an ionic mechanism or a radical mechanism. The former involves the formation of a cation-anion pair 9, whilst the latter proceeds through di-radical pair 10. 

The reaction of l-phenyl-3,4-dihydro-l/f-2-benzothiopyran 12 with (trimethylsilyl)methyl triflate afforded the trans 2-benzothiopyran triflate 13, which upon treatment with cesium fluoride in dimethyl sulfoxide gave 

Since the corresponding nitro derivative is not always available, other oxidants have also found application—e.g. arsenic pentoxide. 

The Skraup reaction is of wide scope for the synthesis of substituted quinolines. Certain primary amines, bearing a cyano, acetyl or methyl group, may however be subject to decomposition under the usual reaction conditions. 

Quinolines substituted at the pyridine ring may be obtained by using a substituted a ,/3-unsaturated aldehyde or ketone instead of the glycerol as starting material. However often a large amount of the carbonyl component polymerizes under the reaction conditions. 

Tertiary amines from quaternary ammonium salts by migration of an alkyl group 

A quaternary ammonium species 1, bearing an electron-withdrawing group Z a to the nitrogen center, can rearrange to a tertiary amine 3, when treated with a strong base. This reaction is known as the Stevens rearrangement.  

A substituent migrates from nitrogen to the -carbon atom of certain quaternary ammonium salts under the influence of strong bases the reaction may be exemplified as follows when R is, for instance, phenyl 96 

According to Wittig,97 the base (sodium alkoxide, phenyllithium, or sod-amide) removes a proton from the -carbon atom, yielding the unstable ylide in which the benzyl group then migrates from nitrogen to carbon. 

As a preparative example we reproduce the directions of Heffe and Krohnke98 for conversion of diphenacylammonium bromides into dibenzoyl-ethylene it is brought about by even relatively weak bases such as aqueous dimethylamine or dilute sodium hydroxide solution  

A N-Dimethyldiphenacylammonium bromide is stirred in aqueous 33% dimethylamine solution (10 parts) at room temperature. After a short time the yellow color fades and the solution becomes milky. The mixture is cooled to 0° and crystallization is brought about by seeding. After being kept for 8 h at 0°, the A,A-dimethyl-l-benzoyl-3-oxo-3-phenylpropyl-amine is filtered off (yield 78%), washed with water, and recrystallized from methanol, forming crystals of m.p. 65°. 

Warming this amine in neutral or weakly acidic solution leads to loss of dimethylamine and formation of dibenzoylethylene. 

A quatemaiy ammonium salt containing an electron-withdrawing group Z on one of the caibons attached to the nitrogen is treated with a strong base to give a rearranged tertiary amine. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 262, Springer International Publishing Switzerland 2014 

Schdllkopf, U. Ludwig, U. Ostermann, G. Paysch, M. Tetrahedron Lett. 1969, 3415. 

Arthur R. Giumanini, Angelo G. Mech. Mol. Migr. 1971, 3, 291. 

Kitagaki, S. Yanamoto, Y. Tsutsui, H. Anada, M. Nakajima, M. Hashimoto, S. Tetrahedron Lett. 2001, 42, 6361. 

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Two efficient syntheses of strained cyclophanes indicate the synthetic potential of allyl or benzyl sulfide intermediates, in which the combined nucleophilicity and redox activity of the sulfur atom can be used. The dibenzylic sulfides from xylylene dihalides and -dithiols can be methylated with dimethoxycarbenium tetrafiuoroborate (H. Meerwein, 1960 R.F. Borch, 1968, 1969 from trimethyl orthoformate and BFj, 3 4). The sulfonium salts are deprotonated and rearrange to methyl sulfides (Stevens rearrangement). Repeated methylation and Hofmann elimination yields double bonds (R.H. Mitchell, 1974). 

Such reductive ring contractions of sulfones are formally similar to two other methods capable of supplanting a sulfur atom by a carbon-carbon double bond the Ramberg-Backlundand Stevens rearrangements. The distinguishing feature of this novel approach to cyclobutenes consists in the resultant higher level of alkyl substitution at the sp -hybridized centers. 

In the preparation of C-nor-D-homosteroid hormone analogs Mitsuhashi and Harada extended the Bamford-Stevens rearrangement to the cholanic acid series. Treatment of 3a-hydroxy-12-oxocholanic acid /j-toluene-... 

Sommelet rearrangement, intermediate temperatures favor Stevens rearrangement,- and high temperatures promote elimination to form isoindoles. Treatment of 2-methyl-2-o-tolylmethylisoindolinium... 

Scheme 2.53 [2,3]-Stevens rearrangement of a vinylaziridine-derived ammonium ylide 219.

The aza-[2,3]-Wittig rearrangement of a vinylaziridine-derived quaternary azir-idinium ylide (i.e., [2,3]-Stevens rearrangement) has recently been reported (Scheme 2.53) [86], The aziridinium ylide 219, generated by the intramolecular reaction of a copper carbenoid tethered to a vinylaziridine, underwent a [2,3]-Ste-vens rearrangement to furnish the bicydic amine 220 with the indolizidine skeleton. 

The mechanism as we have pictured it can lead only to an ortho product. However, a small amount of para product has been obtained in some cases. A mechanism in which there is a dissociation of the ArC—N bond (similar to the ion-pair mechanism of the Stevens rearrangement, p. 1419) has been invoked to explain the para products that are observed. 

For a method that uses nonbasic conditions, and gives high yields of the Sommelet-Hauser product, with little or no Stevens rearrangement, see Nakano, M. Sato, Y. J. Org. Chem., 1987, 52, 1844 Shirai, N. Sato, Y. J. Org. Chem., 1988, 53, 194. 

Sulfur ylids containing a Z group give an analogous rearrangement, often also referred to as a Stevens rearrangement. In this case too, there is much evidence... 

Rearrangements closely resembling the Stevens rearrangement have been investigated by applying Grignard reagents or potassium t-butoxide in dimethyl-formamide (low availability of protons) to cis- and trans-2,4-diphenylthietane oxides and dioxides . The main results are summarized in equation 97 and 98. 

Scheme 52). The reaction will proceed via the enolate 292 and the quinodimethide 293 as key intermediates. Basic treatment of 291 did not cause the Stevens rearrangement but gave the Hofmann degradation product 295. 

Scheme 55. Stevens rearrangement to spirobenzylisoquinolines. Reagents a, PhLi, LAH, or NaCH2SOCH3.

Kano et al. (161,162) also investigated the Stevens rearrangement of tetrahydroprotoberberine metho salts 302 with dimsylsodium and obtained the spirobenzylisoquinolines 303 in high yield (Scheme 56). Similarly C-homoprotoberberine 304 gave the new spiro compound 305, whereas B-homoprotoberberine 306 afforded only the Hofmann degradation product 307. 

Kametani et al. (163-165) studied the Stevens rearrangement using sodium bis(2-methoxyethoxy)aluminum hydride as the base in dioxane. It became clear from studies using deuterium-labeled or optically active compounds that quasi-axially oriented hydrogens at C-8 and C-14 were independently abstracted by the base, leading to a spirobenzylisoquinoline and an 8-... 

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