Sulfones Julia olefination reactions

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). 

Recently, fluoro-Julia olefination reaction using a-fluorinated heteroaryl sulfone has been actively studied for the synthesis of fluoroaUcene [38]. Fluorinated... 

Tributyltin-1,3-dienes have been synthesized from tributyltin substituted benzothiazolyl sulfones and aldehydes via a Julia olefination reaction. The selectivity of the process proved higher in the presence of KHMDS as base (Scheme 96) [190]. 

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. 

Lythgoe, Kocienski and their coworkers investigated the scope, stereochemistry and mechanism of the classical Julia olefination (also called the Juha-Lythgoe olefination) and paved the way for its broad application in target-oriented synthesis [87-90]. The bias towards fi-olefins, with the isomer ratio being typically in the range 7/3 to 9/1 for primary unhindered sulfones and aldehydes, marks a distinctive stereochemical feature of the 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. 

Table 10 Heterocyclic and aromatic sulfones used in the Julia-Kocienski olefination reaction ...

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. 

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. 

Among the different methods for the formation of C-C double bonds, the reductive elimination of (3-functionalized (mainly P-hydroxy or (3-carboxy) sulfones, is one of the most widely used ones in organic synthesis. The reductive elimination of (3-hydroxy sulfones and derivatives is the so-called Julia,94 or Julia-Lythgoe olefination reaction (Eq. 2). It usually involves a condensation between the anion of an alkyl sulfone and a carbonyl compound to afford a (3-hydroxy sulfone (Eq. 47). The metal alkoxide intermediate is typically transformed in situ into a carboxylic or sulfonic ester derivative, which is then reduced... 

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... 

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... 

These olefination reactions can be applied with confidence to the stereoselective synthesis of alkenes. Both isomers of a wide variety of alkenes can be obtained with very high stereoselectivities when suitable reaction conditions are selected. Compared with other methods, the Julia reductive elimination has some advantages. First, sulfones are more readily available and easily purified than the corresponding phosphorus and silicon derivatives. There is a wide range of mild and high-yielding routes to synthesize sulfones.3 Furthermore, the sulfone group also confers stability and frequently crystalline properties to the substrate. 

The reaction between a carbanion derived from alkyl 3,5-bis(trifluoromethyl)phenyl sulfones and aldehydes affords, with good yields and stereoselectivities, the corresponding 1,2-disubstituted alkene through the Julia-Kocienski olefination reaction. This one-pot protocol can be performed using the phosphazene base at —78 °C and has been successfully used in a high yielding and stereoselective synthesis of various stilbenes such as resveratrol [47] (Scheme 5.28). 

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 Ylides Julia Olefination and Related Processes. Recently, the modified Julia olefination, which employed certain heteroarylsulfones instead of the traditional phenyl-sulfones, has emerged as a powerful tool for alkene synthesis. Although the reaction was first reported with LDA, bases such as LHMDS, NaHMDS, and KHMDS are now commonly used. In addition, solvent as well as base counter-cation have been shown to markedly affect the stereochemical outcome of the olefination reaction. For instance, KHMDS was less selective than NaHMDS for the coupling between benzothiazoylsulfone (1) and cyclopropane carboxaldehyde (2) in toluene, furnishing a 3.7 1 ratio compared to a 10 1 ratio favoring the Z-isomer. However, both bases provided a 1 1 mixture of isomers when the reaction was run in DMF (eq 54). ... 

The one-step heterocyclic modification of the Julia olefination was discovered by Marc Julia s brother, Sylvestre Julia, who also worked at the Ecole Normale Superieure. The use of tetrazolyl-sulfones was a contribution of Philip Kociehski, and the reaction is sometimes known as the Julia-Kocieilski reaction. 

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