Hydrazones 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-toluenesulphonyl hydrazones can be converted to alkenes on treatment with strong bases such as alkyl lithium or lithium dialkylamides. This reaction is known as the Shapiro reaction68. When w./i-LinsaUi rated ketones are the substrates, the products are dienes. This reaction is generally applied to the generation of dienes in cyclic systems where stereochemistry of the double bond is fixed. A few examples where dienes have been generated by the Shapiro reaction have been gathered in Table 669. 

Preparation of gem-difluoroallenes. gem-Difluoroallenes can be synthetized by metal-promoted reduction of dihalogenolefins, or by Shapiro reaction of trifluoro-methylketone hydrazones. ... 

Remarkably, some hydrazones may be doubly lithiated with the second lithiation occurring a to N at the trigonal carbon atom (101).68 Doubly lithiated hydroazones of a different kind are intermediates in the Shapiro reaction (section 8.1). 

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... 

Hydrazones based upon l-amino-2-phenylaziridine 23 have also been described. Use of excess base leads to the usual Shapiro reaction 15 however, a unique feature of hydrazones like 24 is that they form alkenes in the presence of only catalytic amounts of LDA.16 For example,... 

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. 

Conversion of ketones into arylsulfbnylhydrazones allows preparation of the corresponding vinyl lithiums by base-promoted decomposition ofthe hydrazone. This is known as the Shapiro reaction. 

Vinylsilanes may be prepared from the corresponding ketones by formation of the hydrazone followed by Shapiro reaction, quenching the vinylic anion with chlorosilanes. An equally effective process derives the vinylsilane from the vinyl chloride, in turn prepared simply from the ketone. The crucial oxidative transformation may be achieved in two ways. Firstly, ozonolysis in dichloromethane/methanol at approximately 0 C followed by reductive work-up affords the a-hy xy ketone, e.g. (96) to (97), via the intermediates (98) and (99). The outcome of the reaction varies with the solvent and work-up conditions, but using the combination indicated, good yields of the desired products are available. 

Direct transition from level 2 to level 0 can be achieved by way of the Wolff-Kishner reaction (treatment of the respective hydrazones with alkali), a classical pathway for the reduction of carbonyl compounds. At the same time, a direct conversion of aldehydes and ketones into alkenes is also feasible via reductive cleavage of their tosylhydrazones under the action of MeLi, the Shapiro reaction (Scheme 2.63). "... 

As mentioned, LiAlH4 in refluxing THF was the initial system introduced to reduce preformed tosyl-hydrazones to hydrocarbons and a number of successful conversions have been reported, representative examples of which are presented in Table 5. Alkene side products often accompany the hydrocarbon products,a result attributed to proton abstraction from the a-carbon of intermediate (59), leading to a vinyldiimide anion (64), followed by N2 expulsion and protonation during work-up (Scheme 3). With certain ketones, including 17-keto steroids, alkenes are the major s or sole product (entries 7-9, Table 5). This side reaction mimics the elimination obtained upon treatment of to-sylhydrazones with other strong bases (i.e. alkyllithiums, the Shapiro reaction 29). Note that use of LiAlD4 introduces one deuterium (with H2O work-up) or two deuteriums (with D2O work-up entries 5 and 6, Table 5, respectively). 

The reaction of alkyllithium reagents with acyclic and cyclic tosylhydrazones can lead to mixtures of elimination (route A) and addition (route B) products (Scheme 22). The predominant formation of the less-substituted alkene product in the former reaction (Shapiro Reaction) is a result of the strong preference for deprotonation syn to the N-tosyl group. Nucleophilic addition to the carbon-nitrogen tosyl-hydrazone double bond competes effectively wiA a-deprotonation (and alkene formation) if abstraction of the a-hydrogens is slow and excess organolithium reagent is employed. Nucleophilic substitution is consistent with an Su2 addition of alkyllithium followed by electrophilic capture of the resultant carbanion. 

In addition to carbon-carbon bond forming reactions of derived anions, hydrazones and oximes are important derivatives of carbonyl groups for the Beckmann rearrangement (of oximes to amides, equation 55)203.204 jmd the Shapiro reaction (tosylhydrazones to alkenes, equation 56). ° Of historical... 

The original Shapiro reaction involves the preparation of unfiinctionalized alkenes from ketone tosyl-hydrazones by quenching of the in situ generated alkenyllithium reagents with water. Recent applications of this reaction in natural product synthesis include the synthesis of 9(0)-methanoprostacyclin (Scheme 12), the in vitro conversion of humulene to A ( -capnellene (Scheme 13), the synthesis of die basic skeleton of isoadsirene (equation S2) ° and the total synthesis of the eudesmanolides rothin A and rothin B (equation 53). ... 

The synthon of the a-acrylate anion is available from a secondary a-keto carboxamide by the Shapiro reaction. The secondary a-ketoamide trisylhydrazones ate ptepar in a one-pot synthesis by reaction of the isocyanides with acid chloride, water and trisylhydrazine in sequence. In DME solvent, the hydra-zone (103) is smoothly metallated with BuLi to give Ae trianion (KH). Allylation of the trianion (104) gives the hydrazone (105). Alternatively, warming (104) up to room temperature yields the dianion (106) which can be intercepted with several electrophiles (Scheme 23). The adduct (107) is readily transformed into the rran -iodo lactone (108) stereospecifically (equation 56). This chemistry also has been applied to a new synthesis of -lactams (Scheme 24). ... 

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. 

Kang, J., Kim, J. H., Jang, G. S. A Shapiro reaction with [(diethylamino)sulfonyl]hydrazones. Bull. Korean Chem. Soc. 1992, 13,192-199. 

It can be quenched with electrophiles in the usual way. In this example prenyl bromide is the first electrophile giving the stable lithiated hydrazone 50 the Shapiro reaction gives Z-51 trapped as the vinyl stannane7 E-52. The vinyl silane 39 and stannane 52 products from these reactions can be used to make more elaborate alkenes with control over geometry as we shall see later. 

Addition of vinyl metals to aldehydes and ketones (chapter 16) also allows control over stereochemistry. The stereospecific vinyl anion equivalent 24 is one we made in chapter 16 by the Shapiro reaction. We repeat this scheme because it uses prenylation of a hydrazone aza-enolate to make the starting material for the vinyl-tin compound 25. 

The mechanism of the Shapiro reaction is believed to involve initial deprotonation of the NH proton from tosylhydrazone 5 to generate 6, which undergoes a second deprotonation adjacent to the hydrazone group to afford dianion 7. Elimination of lithium p-toluene-... 

In most cases the regiochemistry of the Shapiro reaction is controlled by steric factors, with the second metalation occurring at the less-substituted a-carbon atom of the hydrazone.2 For example, a-methyl ketone 10 was transformed to disubstituted alkene 11 in 69% yield as a single regioisomer via conversion to a tosylhydrazone followed by treatment with -BuLi. However, the regiochemical outcome of Shapiro reactions involving a,p-unsaturated hydrazones is difficult to predict in the absence of data obtained from reactions of structurally related substrates, as the second metalation can occur at either the a - or y-position. 

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. 

The Bamford-Stevens synthesis is related to the Shapiro reaction (Shapiro and Heath, 1967 reviews Shapiro, 1976 Adlington and Barrett, 1983), in which a 4-toluenesulfonyl hydrazone of an aldehyde or a ketone is treated with at least two equivalents of a very strong base, usually, methyllithium (see Organic Syntheses examples of Chamberlin et al., 1983, and Shapiro et al., 1988). The Shapiro reaction leads to an olefin by a hydrogen shift. The mechanism has been proposed by Casanova and Waegell (1975) as given in (2-34). This mechanism involves a diazenide anion 2.81 as intermediate. 

Catalytic Shapiro reaction. Small amounts of LDA in ether successfully promote the decomposition of hydrazones derived from Af-amino-2-phenylaziridine. fZl-Alkenes are the major products. 

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