Rearrangements 2,3-Wittig

The first example of a [l,2]-Wittig-type rearrangement was reported in 1924 by Schorigin, and was discovered during studies on the reactivity of benzyl ethers towards alkali metals. Schorigin found that heating a mixture of benzyl ethyl ether (4) with metallic sodium to 130-210 °C generated a small amount (13%) of phenyl ethyl carbinol (5). 

A related [l,2]-rearrangement was described by Schlenk and Bergman in 1928. As shown below, reduction of benzophenone dimethyl acetal (6) with metallic sodium led to the formation of diphenyl methyl carbinol (8), presumably via intermediate organosodium species 7.  

Subsequent studies by Wittig demonstrated that deprotonation of benzyl alkyl ether derivatives with phenyllithium could provide the requisite carbanion and induce [1,2]-Wittig rearrangement. For example, treatment of benzyl methyl ether (9) with phenyllithium provided a-methyl benzyl alcohol (10) in 35% yield upon workup. 

The [1,2]-Wittig rearrangement is believed to proceed via a radical mechanism,which is illustrated in the example shown below. The reaction of 11 with MeLi provides organolithium intermediate 12, which imdergoes C-0 bond homolysis to form radicals 13 and 14. Radical 13 is converted to 15 via 1,2-lithium migration, and a subsequent intermolecular radical coupling of 15 with 14 yields alkoxide 16. The alcohol product 17 is obtained after an aqueous workup. The homolysis/recombination events are believed to occur inside a solvent cage. 

In addition to the trends noted above, scrambling of stereochemistry at the metallated carbon is observed in transformations that involve alkenyl migrating groups. This observation provides additional evidence for the intermediacy of radical species in these reactions. 

The rearrangement of an ether 1 when treated with a strong base, e.g. an organo-lithium compound RLi, to give an alcohol 3 via the intermediate a-metallated ether 2, is called the Wittig rearrangement. The product obtained is a secondary or tertiary alcohol. R R can be alkyl, aryl and vinyl. Especially suitable substrates are ethers where the intermediate carbanion can be stabilized by one of the substituents R R e.g. benzyl or allyl ethers. 

In certain cases the reaction may proceed by a concerted mechanism. With allyl ethers a concerted [2,3]-sigmatropic rearrangement via a five-membered six-electron transition state is possible  

Recently this [2,3]-Wittig rearrangement has received much attention and has been developed into a useful method for the stereoselective synthesis of homoal-lylic alcohols. 

Kallmerten, in Houben-Weyl, 4th Ed, Vol. E2ld (Eds. G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann), Thieme, Stuttgart, 1995, p. 3758 and 3821. Eor recent examples, see D. Enders, D. Backhaus, J. Runsink, Tetrahedron 1996, 52, 1503-1528, and references therein. 

An interesting example of chemistry involving a radical dissociation-recombination mechanism is the 1,2-Wittig rearrangement [17]. The general scheme for the Wittig rearrangement is shown in Eq. (12). 

The enantioselective variant employs a bisoxazoline ligand (39) which coordinates the lithium in a similar fashion to other known asymmetric lithiation protocols (Eq. 13) [18], 

It was observed that when 2.0 equivalents of BuLi were introduced, yields of the desired product (S )-40 reached a maximum of 94% while maintaining moderate levels of enantioselectivity (approximately 62% ee). The use of substoichiometric amounts of chiral ligand did not have a significant effect on either the selectivity or yield. It was postulated that the second equivalent of /-BuLi was needed in order to facilitate dissociation of initial Li-ligand complex resulting in a /-BuLi dimer which coordinates the substrate. This process serves to regenerate the active chiral catalyst species and allow for this reaction to proceed with substoichiometric amounts of ligand. 

Treatment of ethers with alkyl lithium results in alcohols. 

The radical mechanism is also possible as radical intermediates have been identified. 

Kitagawa, O. Momose, S. Yamada, Y. Shiro, M. Taguchi, T. Tetrahedron Lett. 2001,42, 4865. 

The [1,2]-Wittig rearrangement is believed to proceed via a radical mechanism  

Name Reactions 4th ed., DOI 10.1007/978-3-642-01053-8 270, Springer-Verlag Berlin Heidelberg 2009 

9 Miyata, O. Asai, H. Naito, T. Chem. Pharm. Bull. 2005, 53, 355-360. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 289, Springer International Publishing Switzerland 2014 

Tomooka, K. Yamamoto, H. Nakai, T. Justus Liebigs Ann. Chem. 1997, 1275. 

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Antithetic conversion of a TGT by molecular rearrangement into a symmetrical precursor with the possibility for disconnection into two identical molecules. This case can be illustrated by the application of the Wittig rearrangement transform which converts 139 to 140 or the pinacol rearrangement transform which changes spiro ketone 141 into diol 142. 

The aza-Wittig rearrangement in synthesis and transformations of N-hetero-cycles 97S497. 

Wittig rearrangement with participation of 0-heterocycles 97LA1275. 

Isomerization of vinylaziridines is widely used in organic synthesis. Six types of isomerization of vinylaziridines are shown in Scheme 2.40. Outlined in this section are i) azepine formation by aza-[3,3]-Claisen rearrangement of 1,2-divinyl- or 2,3-divinylaziridines 153 (Section 2.4.1), ii) pyrroline formation from 155 (Section 2.4.2), Hi) aza-[2,3]-Wittig rearrangement of anionic species 157 (Section 2.4.3),... 

Scheme 2.52 Aza-[2,3]-Wittig rearrangements of vinylaziridines 213 and alkaloid syntheses.

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. 

In contrast to the intermediate hydroxystannanes, O-protected stannanes 7 are stable compounds which can be distilled or chromatographed and stored under nitrogen for months. Treatment of 7 with butyllithium in tetrahydrofuran at — 78,JC results in rapid tin/lithium exchange (< 1 min). No products resulting from Wittig rearrangement or formation of an ate complex 8 could be detected9. 

A proton can be removed from an allylic ether by treatment with an alkyllithium at about -70°C [at higher temperatures the Wittig rearrangement (18-22) takes place] to give the ion 130, which reacts with alkyl halides to give the two products... 

Of these reactions, the [2,3] Wittig rearrangement in particular has often been used as a means of transferring chirality. The product of this reaction has potential chiral centers at C-3 and C-4 (if R ), and if the starting... 

The aza-[2,3]-Wittig rearrangement [47] and the related aza-[3,3]-Claisen rearrangement [48] of vinylaziridines are elegant examples of expansion of the aziridine ring in a stereocontrolled fashion (Scheme 38). 

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