Julia alkenation reaction

The Julia alkenation, also known as the Julia-Lythgoe alkenation is a reaction of phenyl sulfones 4.54 with aldehydes or ketones followed by reductive elimination with sodium amalgam to give alkenes. 

The Julia olefination reaction is highly regioselective and ( )-stereoselective, providing a valuable alternative to the Schlosser reaction for making rrans -disubstituted olefins. The reaction involves condensation of a metalated alkyl phenyl sulfone with an aldehyde to yield a P-hydroxysulfone, which is then subjected to a reductive elimination to produce the alkene. There are limitations to the preparation of tri- and tetra-substituted alkenes via the sulfone route because the P-alkoxy sulfones derived from addition of the sulfone anion to ketones may be difficult to trap and isolate or they may revert back to their ketone and sulfone precursors. 

In this chapter we deal with the tegio- and stereo-controlled synthesis of alkenes by reductive elimination of 1,2-disubstituted alkanes. Where appropriate the related 1,4-elimination reactions leading to conjugated dienes will also be considered. The principal criterion for inclusion here is synthetic utility, and reactions such as the Julia alkenation are given prominence because they incorporate a reductive elimination as a key step in a sequence which is connective. Consequently such reductive eliminations should not be considered in isolation, but as an integral part of a sequence which achieves regio- and stereo-con-... 

At the end of the chapter we briefly consider some reactions such as the fluoride-induced elimination of 3-silyl sulfones, which are not reductive eliminations but which have been included because of their relation to the Julia alkenation. 

By comparison with the Homer-Wittig reaction, the Julia alkenation has two principal assets. First, as the nucleophilic partner in the connective step (stage 2), sulfones are used, which are often more readily available and more easily purified than the corresponding phosphonium salts. Secondly, the 1,2-disub-stituted alkenes produced in the key reductive elimination step have predominantly ( )-stereochemistry. One detraction of the Julia alkenation is its length — it can be foiled at any one of the four stages. In practice, stage 2, the condensation of the metalated sulfone with the carbonyl, is usually the most problematic but in certain circumstances all of the stages have their pitfalls. These will be examined individually below. 

The addition of metalated sulfones to aldehydes or ketones is a reversible reaction and the principal cause of failure in the Julia alkenation results from an unfavorable equilibrium at this stage. The reverse reaction is favored when the P-alkoxy sulfone adduct is sterically encumbered. Adducts derived from ketones are more vulnerable than those derived from aldehydes. Stabilization of the sulfone anion by conjugation with an aromatic ring or chelation with a proximate heteroatom are also important contributors to favoring the reverse reaction. However, by varying the metal counterion, the position of equilibrium can be adjusted. For example, the lithio derivative of the sulfone (61 Scheme 24) failed to... 

In many cases functionalization of the adduct (stage 3) is superfluous since 3-bydroxy sulfones undergo reductive elimination under the usual Julia alkenation conditions. However, the yields are usually lower than the corresponding reductive elimination with the more reactive 3-acetoxy, 3-benzoyloxy or 3-methanesulfonyloxy sulfones owing to competing retroaldolization under the basic conditions of the reaction. A further complication is reductive desulfonylation, as shown in equation (18). ... 

A serious obstacle to the use of the Julia alkenation for the synthesis of trisubstituted alkenes is illustrated in Scheme 31. Addition of cyclohexanone to the lithiated sulfone (86) gave intermediate (87), which could not be acylated under the reaction conditions because of the sterically hindered tertiary alk-oxide. Owing to an unfavorable equilibrium, (87) reverted back to starting materials. However, by reversing the functionality of the fragments a stable adduct (88) was formed in which the less hindered secondary alkoxide was acylated and the resultant -benzoyloxy sulfone (89) reductively eliminated to the alkene (90) in 54% overall yield. Trisubstimted alkenes have been generated by reductive elimination of 3-hydroxy sulfones ° but, in general, retroaldol reactions compete. 

Little is known about the stereochemistry of trisubstituted alkene formation in the Julia alkenation. In a synthesis of milbemycin 33 Barrett and coworkersgenerated intermediate (91 equation 22) as a mixture of isomers (E Z = 5 3) by reductive elimination of a 3-acetoxy sulfone however, a similar reductive elimination on the 3-hydroxy sulfone shown in equation (23) gave a single isomer. The marked difference in the yield of these two transformations reflects the advantage of suppressing the retroaldoliza-tion reaction by acylation. 

The removal of the sulfone group can be accomplished under a number of different reductive conditions. Most popular is the concomitant removal of both the sulfone and the derivatized (3-hydroxy group to give an alkene and this is commonly termed the Julia olefination reaction (see Section 2.8). 

Scheme 19.21 Julia-Kocienski reactions leading to tri- and tetra-substituted alkenes.

The Julia Alkenation and Related Reactions. In 1973, Julia and Paris reported a new connective and regioselective alkene synthesis (eq 10) based on the reductive elimination of fi-acyloxy sulfones. The Juha alkenation is now one of the principal methods for fragment linkage in complex natural product synthesis. Mono-, di-, tri-, and tetrasuhstituted alkenes can he prepared in moderate to good yield, depending on the substrate. The three-step sequence, illustrated in eq 11, entails (a) condensation of a metalated sulfone with an aldehyde or ketone, (h) O-functionalization of the adduct as the acetate, henzoate, or mesylate (to prevent retroaldohzation), and (c) reductive elimination using 6% Na(Hg) in THF-MeOH (3 1) at —20 °C. In favorable cases, step (b) can be omitted and the reductive elimination performed on a... 

In the Julia alkeuatiou reaction (Scheme 9.75) an a-lithiosulfone is allowed to condense with an aldehyde or ketone at low temperatures (e.g.,-90°C) in a ethereal solvent, for example, oxacyclopentane (THF). The resulting alcohol is acetylated (this chapter and Chapter 8, Table 8.6, item 16) and the acetoxysulfone is reduced with amalgamated sodium [Na(Hg)] and disodium hypophosphate (Na2HP04) in methanol (CH3OH). The resulting alkene forms with tram- or ( )-selectivity. ... 

The one-port olefination of Sylvestre Julia is operationally simpler and more amenable to scale up than the classical y4-step variant originally reported by Marc Julia. This reaction consists of the replacement of the phenyl sulfone moiety traditionally in the classical reaction, with different heteroaryl sulfones, such as benzothiazol-2-yl (BT, 5) sulfone. This allows the direct olefination process and eliminates the sulfone reduction step. The stereochemistry of the reaction in the synthesis of 1,2-disubstituted alkenes is dependent on the base and solvent. 

Subsequently, Julia, Uguen and Callipolitis104 105 used both lithium metal in ethyl-amine and sodium amalgam in ethanol to effect reductive cleavages of j8-hydroxysulphones or of allylic sulphones. The latter reaction is part of a synthetic sequence for the construction of alkenes that has been used with some considerable success... 

Julia and Paris120 described an olefin synthesis, based on the use of a sulphonyl group which directs the formation of a carbon-carbon bond. Subsequent reductive elimination with sodium amalgam leads to the alkene, as outlined in equation (50). The reaction sequence is similar in principle to an olefin synthesis first developed by Cornforth121. The yields of all steps are generally above 80%. 

This section deals with reactions that correspond to Pathway C, defined earlier (p. 64), that lead to formation of alkenes. The reactions discussed include those of phosphorus-stabilized nucleophiles (Wittig and related reactions), a a-silyl (Peterson reaction) and a-sulfonyl (Julia olefination) with aldehydes and ketones. These important rections can be used to convert a carbonyl group to an alkene by reaction with a carbon nucleophile. In each case, the addition step is followed by an elimination. 

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