Julia alkenation

The Julia alkene synthesis has been applied to allylsilane synthesis, including the synthesis of 2-cyclopentylidene- and 2-cyclobutylideneethyl(trimethyl)silanes30. 

Julia alkenation and modified Julia alkenation (Julia-Kocienski alkenation)... 

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. 

Alternatively, the classical Julia alkenation of acetoxy sulfones C with sodium amalgam in MeOH might possibly proceed via an initial formation of an alkenyl sulfone F, which would then undergo homolytic cleavage involving single electron transfer (Scheme 4.34). This mechanism is proposed on the basis of deuterium incorporation studies performed by Keck et al . ... 

In contrast to the classical Julia alkenation, the modified Julia alkenation offers the possibility of saving one or two steps. The /Z-selectivity can be controlled by varying the sulfonyl group, solvent and base. 

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. 

A disadvantage of this procedure is that reductive cleavage of the epoxy sulfones leading to trisub-stituted alkenes, e.g. (95), is not stereoselective. However, formation of disubsituted alkenes follows the trends found in the standard Julia alkenation in that rrani-alkenes are favored (equation 24) and proximate branching increases the stereoselectivity (equation 25). Unlike the standard Julia alkenation, the stereochemistry of the epoxy sulfone reductive elimination depends on the stereochemistry of the precur-... 

A connective synthesis of alkynes inspired by the Julia alkenation was developed by Lythgoe and coworkers for the synthesis of la-hydroxy vitamin D3, as shown in Scheme 34. The P-keto sulfone (101) derived by condensation of the the metalated sulfone (99) with the ester (100) was converted to the enol phosphate (102), which on reductive elimination gave the enynene (103). 

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... 

There are two further variants of the Julia alkenation which deserve wider recognition. Both methods surmount the inherent limitation in scale of the reductive elimination step imposed hy the use of Na(Hg). The first method involves a radical-induced... 

Problem 9.13. Write curved arrow mechanisms shown in each step in the Julia alkenation. ... 

General Considerations. A sequence involving metalation, alkylation, and fluoride-induced elimination of benzenesulfinate allows the conversion of (2) to a terminal alkene. An analogous sequence involving a double alkylation of (2) provides a 1,1-disubstituted alkene (eq 2). The Uthio derivative of (2) has also been used to prepare cyclopropyUdene derivatives, homo-allylic alcohols, and aUyl silanes via the Julia alkenation. ... 

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