Vinyllithium, Shapiro reaction

Removal of the carbonate ring from 7 (Scheme 1) and further functional group manipulations lead to allylic alcohol 8 which can be dissected, as shown, via a retro-Shapiro reaction to give vinyl-lithium 9 and aldehyde 10 as precursors. Vinyllithium 9 can be derived from sulfonyl hydrazone 11, which in turn can be traced back to unsaturated compounds 13 and 14 via a retro-Diels-Alder reaction. In keeping with the Diels-Alder theme, the cyclohexene aldehyde 10 can be traced to compounds 16 and 17 via sequential retrosynthetic manipulations which defined compounds 12 and 15 as possible key intermediates. In both Diels-Alder reactions, the regiochemical outcome is important, and special considerations had to be taken into account for the desired outcome to. prevail. These and other regio- and stereochemical issues will be discussed in more detail in the following section. 

Ketone p-toluenesulfonylhydrazones are converted to alkenes on treatment with strong bases such as an alkyllithium or lithium dialkylamide.286 Known as the Shapiro reaction,2 7 this proceeds through the anion of a vinyldiimide, which decomposes to a vinyllithium reagent. Treatment of this intermediate with a proton source gives the alkene. 

Alkenyllithium compounds are intermediates in the Shapiro reaction, which is discussed in Section 5.7.2. The reaction can be run in such a way that the organolithium compound is generated in high yield and subsequently allowed to react with a variety of electrophiles.64 This method provides a route to vinyllithium compounds starting from a ketone. 

Conjugated dienes can be prepared from certain ketones via their trisylhydrazones (386) by the Shapiro reaction (equation 102). This involves a reductive metallation to a vinyllithium intermediate, transmetallation, for example, with Cu(I) iodide, and oxidative coupling. ... 

The Shapiro reaction provides a convenient, easy and straightforward method to convert ketones into a plethora of olefinic substances in high yields. Many of these vinyllithium derivatives are useful for further synthetic manipulations. No attempt is made in this chapter to cover all the applications of the Shapiro reaction and only few representative examples will be described. A variety of polyolefins such as 119, used for cation olefin cyclization, can be stereospecifically formed in a concise and modular approach in a single step from the components shown in equation 42 via the Shapiro reaction . 

Making the vinyllithium by a Shapiro reaction (section 8.1) from 164 bypasses the chemoselectivity problem altogether, and provides a useful cyclisation route to exo-methylene derivatives of five-, six- and seven-membered rings 165.78 The main by-products 166 are the result of protonating the vinyllithium. 

The decomposition of the dianions of arenesulfonylhydrazones, known as the Shapiro reaction,4 is one of the most reliable ways of making vinyllithium reagents. In the earliest, and still widely used, version of the reaction,1 a ketone is condensed with p-toluenesulfonylhydrazine 1 to yield a crystalline hydrazone such as 2. Deprotonation of 2 with base (usually BuLi) gives a monoanion 3, which, if heated, decomposes to a carbene 4 in... 

Geometrical stereoselectivity can often be achieved in the condensation of unsymmetrical ketones 8 with tosylhydrazine l,2 and this feature means Shapiro reactions direct from an unsymmetrical ketone 8 via E-9 lead to the less substituted vinyllithium 11. On the other hand, a sequential alkylation-Shapiro sequence from a starting symmetrical hydrazone 12 will reliably form the more substituted vinyllithium 14 via Z-9 Retention of Z stereochemistry in Z-9 is dependent on its re-use almost immediately on standing, for example, Z-9 (R = vinyl) equilibrates to an 85 15 ratio E Z-9J ... 

Usable vinyllithiums are obtained if (a) ortholithiation-resistant hydrazones derived from triisopropylphenylsulfonylhydrazine 15 are used,9 and (b) if the Shapiro reaction is carried out in a TMEDA-hexane mixture, which avoids protonation of the vinyllithium.10 For example, 16 forms stereoselectively from 15, with steric hindrance directing formation of the E hydrazone. The dianion of 16 decomposes at 0 °C to yield the vinyllithium 17 which reacts with electrophiles to yield products such as 18.11... 

The Shapiro reaction has been used as a method for the initiation of anionic cyclisations, as described in section 7.2. Hydrazones derived from 23 are particularly valuable in this area, not only as the source of vinyllithiums but also as carbene equivalents. Nucleophilic addition to 26 promotes the collapse of the product lithioamine to give the organolithium 27. 

The first vinyllithium carbolithiation reaction was reported by Chamberlin and Bloom15, who showed that Shapiro-derived organolithium 10 cyclized onto a terminal alkene giving stereoselectively (>50 1) bicyclic compounds 11, after treatment with electrophiles (Scheme 4). The intermediate alkyllithiums 12 are generated via a 5-exo-trig cyclization reaction from 10, which undergo the carbolithiation reaction at approximately the same rate as reported by Bailey for the simple parent compound 5-hexenylIithium, i.e. with a half-life of a few minutes at 0 °C. 

A complementary approach, developed by Paquette, - uses substituted acryloyl chlorides as addends in reaction with structii ly embellished vinylsilanes. A general route to the vinylsilanes (87) was found in the silylation of vinyllithiums generated by the Shapiro reaction.The acylation with acryloyl chlorides takes place readily with aluminum trichloride to afford the divinyl ketones which are subsequently cyclized with tin tetrachloride. The Nazarov cyclization products were formed as a mixture of double tend isomers (equation 47). The best results were obtained with p,p-dimethylacryloyl chloride. Crotonyl chloride could be employed, but acryloyl chloride proved impractical. This metl owes much of its utility to the regiocontroUed synthesis of Ae vinylsilmes, thereby clearly establishing the loci of cyclopentannulation. 

The reaction of a tosylhydrazone with at least 2 equiv. of an alkyllithium reagent in ether or hexane generates the dianion (Shapiro reaction) this gives, after loss of Ts" and N2, the vinyllithium compound, which can be trapped by a variety of electrophiles, e.g. H", CO2, DMF (Scheme 27). The less-substituted alkene is formed predominantly under these conditions. 

A novel class of chiral indenes (verbindenes) was prepared from enantiopure verbenone by K.C. Rupert and coworkers who utilized the Shapiro reaction and the Nazarov cyciization as the key transformations. The bicyclic ketone substrate was treated with triisopropylbenzenesulfonyl hydrazide to prepare the trisyl hydrazone that was then exposed to n-BuLi. The resulting vinyllithium intermediate was reacted with various aromatic aldehydes to afford the corresponding allylic alcohols. 

P. Quayle and co-workers utilized the Dotz benzannulation reaction for the synthesis of diterpenoid quinones." The authors developed a novel synthetic approach to 12-O-methyl royleanone using a simple vinyl chromium carbene complex along with a disubstituted oxygenated acetylene. The bicyclic hydrazone was converted to the corresponding vinyllithium derivative by the Shapiro reaction and then functionalized to give the desired crude Fischer chromium carbene complex. The benzannulation took place in refluxing THF with excellent regioselectivity, and the natural product was obtained in 37% overall yield from the hydrazone. 

Another fragmentation reaction especially useful for the synthesis of vinyllithium compounds is the well-known Shapiro reaction We were successful in preparing 2,3-dilithio-l,3-butadiene 166 by a double Shapiro reaction although in 12% yield only The main reaction product was 2-butyne. 

Most Shapiro reactions of acyclic sulfonylhydrazones or cyclic sulfonylhydra-zones derived from larger rings proceed with selectivity for the formation of the E-vinyllithium reagent. For example, the trisylhydrazone generated from 4-heptanone (12)... 

The conditions originally employed for the Shapiro reaction involved treatment of the sulfonylhydrazone derivative with an alkyllithium reagent in hexane or ether solvent. Although these conditions are quite effective for the conversion of sulfonylhydrazones to alkenes (e.g., 1—>2), efforts to capture the intermediate vinyllithium reagent with electrophiles other than H+ are often met with limited success due to competing deprotonation of the solvent or the sulfonyl aryl group by the basic vinyllithium species. For example, treatment of 15a with >2 equiv of n-BuLi in hexane followed by quenching with D2O provided 16 in quantitative yield but with only -10% deuterium incorporation. A solution to this problem was developed independently by Shapiro and Bond that employs TMEDA (tetramethylethylenediamine) as an additive for Shapiro reactions.7,10 As shown below, use of TMEDA (4.0 equiv) as a cosolvent led to the conversion of 15b to 16 in quantitative yield with 95% deuterium incorporation. 

The two modifications described above have allowed for the efficient capture of vinyllithium intermediates generated in Shapiro reactions with a wide variety of electrophiles. For example, the alkyllithium reagent 20 prepared from treatment of trisylhydrazone 18 with n-BuLi was effectively trapped with benzaldehyde (62% yield, 21), 1 -bromobutane (58% yield, 22), and bromine from 1,2-dibromoethane (43% yield, 23)." Similarly, formation of 20 from tosylhydrazone 19 followed by trapping with CO2 afforded 24 (52% yield). The reaction of intermediate 20 (generated from 19) with cyclohexenone provided 25, the product of 1,2-addition, in 61% yield.13... 

As noted above, the classical Shapiro reaction requires the use of >2 equiv of base to effect the conversion of an arylsulfonylhydrazone to an alkene. However, in recent work Yamamoto has described a catalytic version of the Shapiro reaction that employs aziridinyl hydrazones and is effective with only 5-30 mol% of added base.21 As shown above, treatment of hydrazone 34 with 5 mol% of LDA affords a 93% isolated yield of 35 with >99 1 stereoselectivity. This reaction is believed to proceed via metalation of 34 with LDA to yield 36. This intermediate decomposes with loss of styrene and nitrogen to provide vinyllithium reagent 37, which is protonated by diisopropylamine, regenerating the LDA base. Unfortunately this method is not amenable to the capture of the intermediate vinyllithium species with electrophiles. 

As an example of the Shapiro reaction, the 2,4,6-triisopropylphenylsulphonylhydrazone of (-)-(3/ )-3-hydroxy-P-ionone (34) is treated with an excess of -BuLi in hexane in the presence of TMEDA to give the vinyllithium reagent 35 which, on condensation with the C27-aldehyde 36, furnishes the C4o-allylic alcohol 37 in 75% yield, en route to (3/ ,6 / )-P,E-carotene-3,19-diol [20] (Scheme 9). 

The Shapiro reaction has been utilized in the functionalization of phenanthroline to obtain chiral ligands. The vinyllithium generated with 2 equiv of s-BuLi was trapped with phenanthroline. 

Alpha alkylation of hydrazones and Shapiro reaction in a one-pot process provides a versatile route to tetrasubstituted alkenes. The addition of 2 equiv of butyllithium to a trisyUiydrazone generates a dianion, which may be trapped at low temperature with different electrophiles such as methyl iodide. An additional equivalent of butyllithium generates a dianion species that decomposes at room temperature to yield the vinyllithium intermediate of the Shapiro reaction. This t)q)e of compound can react with different electrophiles as commented before. In this example, the final addition of paraformaldehyde gave rise to the tetrasubstituted alkene represented in eq 22. ... 

When the Shapiro reaction is carried out on trifluoro-methylhydrazones, the vinyllithium intermediate undergoes defluorination prior to trapping to give 1,1-difluoroaUenes (eq 25). ... 

---