The Julia Olefination Reaction

The Julia olefination involves the addition of a sulfonyl-stabilized carbanion to a carbonyl compound, followed by elimination to form an alkene.277 In the initial versions of the reaction, the elimination was done under reductive conditions. More recently, a modified version that avoids this step was developed. The former version is sometimes referred to as the Julia-Lythgoe olefination, whereas the latter is called the Julia-Kocienski olefination. In the reductive variant, the adduct is usually acylated and then treated with a reducing agent, such as sodium amalgam or samarium diiodide.278 

In the modified procedure one of several heteroaromatic sulfones is used. The crucial role of the heterocyclic ring is to provide a nonreductive mechanism for the elimination step, which occurs by an addition-elimination mechanism that results in fragmentation to the alkene. The original example used a benzothiazole ring,279 but more recently tetrazoles have been developed for this purpose.280 

Other aryl sulfones that can accommodate the nucleophilic addition step also react in the same way. For example, excellent results have been obtained using 3,5-bis-(trifluoromethyl)phenyl sulfones.281 

As is the case with the Wittig and Peterson olefinations, there is more than one point at which the stereoselectivity of the reaction can be determined, depending on the details of the mechanism. Adduct formation can be product determining or reversible. Furthermore, in the reductive mechanism, there is the potential for stereorandomization if radical intermediates are involved. As a result, there is a degree of variability in the stereoselectivity. Fortunately, the modified version using tetrazolyl sulfones usually gives a predominance of the E-isomer. 

Reactions of Carbon Nucleophiles with Carbonyl Compounds 

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There are several new methodologies based on the Julia olefination reaction. For example, 2-(benzo[t/Jthiazol-2-ylsulfonyl)-j -methoxy-i -methylacetamide 178, prepared in two steps from 2-chloro-iV-methoxy-jV-methylacetamide, reacts with a variety of aldehydes in the presence of sodium hydride to furnish the ajl-unsaturated Weinreb amides 179 <06EJOC2851>. An efficient synthesis of fluorinated olefins 182 features the Julia olefination of aldehydes or ketones with a-fluoro l,3-benzothiazol-2-yl sulfones 181, readily available from l,3-benzothiazol-2-yl sulfones 180 via electrophilic fluorination <06OL1553>. A similar strategy has been applied to the synthesis of a-fluoro acrylates 185 <06OL4457>. 

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. 

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). 

A second paper161 describes the use of the same base in either THF or t-butanol for the elimination of a-acetoxy phenyl sulphones as outlined in equation (68), in essence a reaction sequence very similar to the Julia olefin synthesis (Section III.B.3) except in the method by which the sulphonyl group is finally removed. 

Scheme 2.20 gives some examples of the application of the Julia olefination in synthesis. Entry 1 demonstrates the reductive elimination conditions. This reaction gave a good E.Z ratio under the conditions shown. Entry 2 is an example of the use of the modified reaction that gave a good E.Z ratio in the synthesis of vinyl chlorides. Entry 3 uses the tetrazole version of the reaction in the synthesis of a long-chain ester. Entries 4 to 7 illustrate the use of modified conditions for the synthesis of polyfunctional molecules. 

Chapters 1 and 2 focus on enolates and other carbon nucleophiles in synthesis. Chapter 1 discusses enolate formation and alkylation. Chapter 2 broadens the discussion to other carbon nucleophiles in the context of the generalized aldol reaction, which includes the Wittig, Peterson, and Julia olefination reactions. The chapter and considers the stereochemistry of the aldol reaction in some detail, including the use of chiral auxiliaries and enantioselective catalysts. 

Sulfonylation of aromatic hydrocarbons in the presence of a Lewis acid and the reaction of sodium benzenesulfinate with alkyl halides proved to be particularly easy and useful to prepare starting materials for the Julia olefination procedure (see Section 4.3.2). 

The Julia olefin synthesis consists of the reaction of a sulfonyl anion with an aldehyde or ketone. The resulting alcohol is usually acetylated and the olefin formed by aluminum-amalgam reduction. The yield of / -hydroxysulfone is usually good, but the subsequent reductive elimination is more... 

However, reactions like this are of limited use—their success relies on the base s lack of choice of protons to attack provide an alternative H and we are back with the situation in the reaction on p. 810. Logic dictates, therefore, that only trisubstituted double bonds can be made stereospecifically in this way, because the reaction must not have a choice of hydrogen atoms to participate in the elimination. The answer is, of course, to move away from eliminations involving H, as we did with the Julia olefination. We shall look at this type of reaction for much of the rest of this chapter. 

I hc key intermediates in the synthesis of the E- and the Z-isomers of capsaicin were the E and Z unsaturated esters shown below. By using a Wittig reaction with an unstabilized ylid it was possible to make the Z-isomer selectively, whilst the Julia olefination gave the -isomer. 

This chapter gathers together the principles behind these examples together with a discussion of what makes organosulfur chemistry special and also introduces new reactions. We have a lot to explain In Chapter 31 we introduced you to the Julia olefination, a reaction whose first step is the deprotonation of a sulfone. 

The S. Julia olefination reaction modified and optimized by P. Kocien-ski [10] became the premiere fragment linkage reaction in construction of functionally complex targets. It has frequently been referred to as the Julia-Kocienski reaction. 

In a pivotal modification of the direct olefination reaction Kocienski and his coworkers [10] showed that the use of l-phenyl-lff-tetrazol-5-yl sulfones, preferentially with NaHMDS or KHMDS as the base and DME as the solvent, provides olefins in excellent yields and stereoselectivity with respect to -isomers. The modified version of the direct olefination reaction has frequently been referred to as the Julia-Kocienski olefination reaction. 

The Wittig, Horner-Wadsworth-Emmons, Peterson, and Julia Olefination Reactions... 

The Julia olefin synthesis is rather like the Wittig reaction with a sulfone instead of a phosphonium salt but with one other important difference the elimination step is stereoselective and both dia-stereoisomers of the intermediate can give the same isomer of the alkene. Treatment of the sulfone 147 with a strong base gives the anion 148 (or a metal derivative) that combines with an aldehyde to give a diastereomeric mixture of adducts 149. Elimination by various methods gives, in open chain compounds, mostly -150 but, in cyclic compounds, mostly the Z-alkene.29... 

The best version of the Julia olefin synthesis (so far) is probably that introduced by Kocienski.33 It uses /V-phenyl tetrazolyl sulfones 167 easily prepared from the available thiol 165 by a Mitsunobu reaction with a simple alcohol followed by oxidation. 

Under the mild reaction conditions associated with this reducing agent, it is possible to perform reductive desulfonylations of p-hydroxy sulfones without formation of the Julia olefination products (Eq. 88).148... 

Since its original publication,94 the Julia olefination has become a very important tool in organic synthesis for the site- and stereoselective synthesis of alkenes. The synthetic importance of the process is reflected by its numerous applications in the synthesis of a diverse range of functionalized alkenes such as allylic alcohols,198 allylic amines,199-201 homoallylic alcohols,202 homoallylic amines,203 and allylsilanes.204,129 The reaction has also been used as a key step in many... 

An interesting variation of the Julia olefination is the reductive elimination of 2 3 e oxy sulf°nes- This reaction, which leads to allylic alcohols,198 consists of alk lation of a sulfone-stabilized allylic carbanion followed by epoxidation of the... 

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