Julia olefination reaction examples

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>. 

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. 

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. 

Paquette and coworkers [127], in a synthesis of the complex polyol antibiotic amfidinolu-3, made masterly use of the Julia-Kodenski olefination reaction. Two examples taken from that work are presented below. Reaction of sulfone 285 with aldehyde 284 (Scheme 92) carried out with KHMDS in THF (at - 78 °C to rt) gave the building block 286 with 90% yield but with relatively poor selectivity, EjZ 1>I. Free-radical isomerization of the mixture (benzene, AIBN, reflux) increased the isomer ratio, /2 6/1. 

Unlike the corresponding phosphonium salts, addition of sulfonium salts to aldehydes results, not in the alkene products, but in the formation of epoxides (see Section 1.1.5.2). However, sulfones can be used to prepare alkenes, by way of the a-metallo derivatives, in what is termed the Julia olefination (alkenylation). Addition of the organometallic species to an aldehyde or ketone gives a p-hydroxy sulfone which, in the form of its 0-acyl or 0-sulfonyl derivative, undergoes reductive cleavage with, for example, sodium amalgam in methanol to form the alkene. The reaction is regioselective and can be used to prepare mono-, di- and trisubstituted alkenes (2.91). 

Generation of Sulfur Ylide Julia Olefination and Related Reactions. The deprotonation at a position a to a sulfone group is effected using a strong base, t3q)ically n-butyllithium or LDA, to give an anion which then reacts with an aldehyde or a ketone leading to the corresponding 8-hydroxy sulfone. There are, however, a number of examples where LHMDS was used as a base. For instance, sulfone 19 was deprotonated with LHMDS and then reacted with aldehyde 20 to produce 8-hydroxy sulfone 21 (eq 51)P... 

This mechanistic hypothesis has since been corroborated by several experiments (Scheme 3.37). For example, reaction of substrate 192, possessing both a j8-hydroxy sulfone and a j8-benzoyloxy sulfone, with Sml2 at —78 °C, affords exclusively the olefin 193 originating from the elimination of the sulfonylbenzoate. An even more remarkable example is provided in reaction 3.30, in which exclusive formation of triene 195 from substrate 194 takes place. Despite the closer proximity of the OH and phenylsulfone substituents, only the elimination involving the benzoate is observed. This reverse elimination appears to be specific to benzoate derivatives and opens new vistas in the development of mild conditions for the Julia olefination of sensitive polyfunctional molecules. 

Interestingly, when a fi-substituted alcohol is used in the Barton-McCombie reaction and if a [3-elimination process occurs faster than the hydrogen transfer step, then the formation of a double bond is observed. We have just seen such an example with a dixanthate (see Section 3.1.3). Many others are known as in [3-hydroxy sulfides [231] and [3-hydroxysulfones [232,233] in a modified Julia synthesis of olefins. 

The olefination based upon the reaction of benzothiazolyl- and phenyltetra-zolyl sulfones with carbonyl compounds is widely used in the target-oriented synthesis. In order to illustrate the reaction scope, yields and stereoselectivities, in this section we present selected examples of these reactions. The examples include reactions of saturated sulfones with saturated aldehydes, saturated sulfones with o, j6-unsaturated carbonyl compounds, -unsaturated sulfones with saturated aldehydes, and /l,y-imsaturated sulfones with a, -unsaturated aldehydes. The emphasis is given to recent work. A complete account of earlier applications of the modified Julia reaction has been given in the Blakemore review [98]. 

The sulfone is a versatile functional group comparable to the carbonyl functionality in its ability to activate molecules for further bond construction, the main difference between these two groups being that the sulfone is usually removed once the synthetic objective is achieved. The removal most commonly involves a reductive desulfonylation process with either replacement of the sulfone by hydrogen (Eq. 1), or a process that results in the formation of a carbon-carbon multiple bond when a P-functionalized sulfone, for example a (3-hydroxy or (3-alkoxy sulfone, is employed (Eq. 2). These types of reactions are the Julia-Lythgoe or Julia-Paris-Kocienski olefination processes. Alkylative desulfonylation (substitution of the sulfone by an alkyl group, Eq. 3), oxidative desulfonylation (Eq. 4), and substitution of the sulfone by a nucleophile (nucleophilic displacement, Eq. 5) are also known. Finally, p-eliminations (Eq. 6) or sulfur dioxide extrusion processes (Eqs. 7, 8 and 9) have become very popular for the... 

Marko and co-workers also made an efforts on the modification of the classical Julia-Lythgoe olefination using sulfoxides instead of sulfones. The modified reaction, after in situ benzoylation and Sml2/HMPA- or DMPU-mediated reductive elimination, provides 1,2-di-, tri-, and tetra-substituted olefins in moderate to excellent yields and E/Z selectivity. For example benzoated sulfoxide 67 was obtained by addition of sulfoxide 66 to aldehyde 33, which was subsequently reduced into alkene 68 in 67% yield with E/Z ratio of > 95 1. 

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