Salt-free Wittig reactions

B. Reactions.—(/) Halides. Whereas ylides are alkylated in the normal way on treatment with a-bromo- or a-iodo-esters, quite different reactions occur with a-fluoro- and a-chloro-acetates. When salt-free ylides were refluxed in benzene with ethyl fluoroacetate or trifluoroacetate normal Wittig olefin synthesis took place with the carbonyls of the ester groups to give vinyl ethers, e.g. (14). On the other hand, methyl chloroacetate with... 

This accounts for the considerable discrepancy between the alkene Z/E ratio found on work-up and the initial oxaphosphetan ais/trans ratio. By approaching the problem from the starting point of the diastereomeric phosphonium salts (19) and (20), deprotonation studies and crossover experiments showed that the retro-Wittig reaction was only detectable with the erythreo isomer (19) via the cis-oxaphosphetan (17). Furthermore, it was shown that under lithium-salt-free conditions, mixtures of (19) and (20) exhibited stereochemical drift because of a synergistic effect (of undefined mechanism) between the oxaphosphetans (17) and (18) during their decomposition to alkenes. 

E Selective Wittig reagents. The reaction of 1 with lithium in THF provides LiDBP, which on reaction with an alkyl halide (2 equiv.) and NaNH2 in THF gives a salt-free ylide such as 2 or 3, formed by reaction with ethyl iodide or butyl iodide, respectively. These ylides react readily with aldehydes at —78°, but the intermediate oxaphosphetanes are unusually stable and require temperatures of 70-110° for conversion to the phosphine oxide and the alkene, which is obtained in E/Z ratios of 6-124 1. Highest (E)-selectivity is observed with a-branched aldehydes. 

The overall sequence of three steps may be called the Wittig reaction, or only the final step. Phosphonium salts are also prepared by addition of phosphines to Michael olefins (like 5-7) and in other ways. The phosphonium salts are most often converted to the ylides by treatment with a strong base such as butyllithium, sodium amide,640 sodium hydride, or a sodium alkoxide, though weaker bases can be used if the salt is acidic enough. For (PhjP CHj, sodium carbonate is a strong enough base.641 When the base used does not contain lithium, the ylide is said to be prepared under "salt-free conditions.642... 

Wittig reactions employing microwave heating have been published several times both in solution and under solvent-free conditions. They have been performed using stable ylides27, as well as using the pre-formed phosphonium salts, which under basic conditions forms the ylides in situ1. ... 

The carbonyl- 14C KIEs in the title reaction system (equation 225), which gives a nearly 50 50 mixture of cis-trans isomers, depends very much on the ylide used430, and indicate that the reactions proceed via cycloaddition TS of considerable nucleophilic character, inferred also from the substituent effects studied. Positive p values indicate that the Wittig reaction is nucleophilic in nature. Assuming as before the four-centered TS, the authors430 conclude that the C—C bond formation is much advanced of the P—O bond formation in the TS and that the carbonyl-carbon KIE are expected to be larger for later TS salt-free reaction410 (more reactant-like for Li salt present in reaction). 

The salt-free Wittig reaction of non-, semi-, and stabilized ylides has been investigated on realistic systems using density functional theory (DFT) calculations, including... 

Methylene trimethylarsorane (the term trimethylarsonium methylide is equally correct) had already been formulated in 1953 by Wittig and Torssell (104) who studied the reaction of tetramethylarsonium salts with organolithium compounds. Although this method cannot be used for the preparation of the salt-free material due to the strong complexation by the lithium cations, it is clear from reactions of the product mixture that the ylide is present in solution. The formation of arsonium salts upon addition of alkyl halides is a typical example ... 

All P ylides for Wittig reactions are obtained by deprotonation of phosphonium salts. Depending on whether one wants to prepare a nonstabilized, a semistabilized, or a stabilized ylide, certain bases are especially suitable (see Table 11.1 an unusual, i.e., base-free, generation of ylides is described in Side Note 11.1). In stereogenic Wittig reactions with aldehydes, P ylides exhibit characteristic stereoselectivities. These depend mainly on whether the ylide involved is nonstabilized, semistabilized, or stabilized. This can also be seen in Table 11.1. 

Under salt-free conditions, the cw-oxaphosphetanes formed from nonstabilized ylides can be kept from participating in the stereochemical drift and left intact until they decompose to give the alkene in the terminating step. This alkene is then a pure ci.s-isomer. In other words, salt-free Wittig reactions of nonstabilized ylides represent a stereoselective synthesis of cis-alkenes. 

A different reaction mode of lithiobetaines is used in the Schlosser variant of the Wittig reaction. Here, too, one starts from a nonstabilized ylide and works under non-salt-free conditions. However, the Schlosser variant is an olefination which gives a pure frans-alkene rather than a trans.cis mixture. The experimental procedure looks like magic at first ... 

By this method (Z)-monounsaturated fatty acids and esters could be obtained with an ( )-isomer content of less than 10% this stereoselectivity being however inferior to that of the commonly used acetylenic approach 55,56). However, the salt-free techniques used today in Wittig reactions allow (Z)-alkenoic acids to be synthesized with less than 2% of the ( )-isomers. Thus, Bestmann et al. prepared methyl and ethyl esters of (Z)-4,5,6,7,8,9,ll- and 13-alkenoic acids of different chain lengths 35,57 62), which served as intermediates in the synthesis of insect pheromones, both by reaction of co-alkoxycarbonyl-substituted alkyl-triphenyl-phosphonium salts with simple alkanals and of co-formylalkanoic esters with alkylidenephosphoranes. As the starting material for the synthesis of -substituted alkyl-phosphonium salts co-chloro- and -bromocarboxylic esters were used. The corresponding -substituted aldehydes can usually be obtained by ozone cleavage of suitable olefin derivatives or by oxidation of alkohols 57,58). 

The possibility of synthesizing pure (Z)-olefins by means of reactive salt-free ylides predestinates the (Z)-double bond at C-5 in e.g. 106 and 107 to be introduced into the corresponding aldehyde via the Wittig reaction. The ( )-configurated double bond at C-13 (105,106 and 107) with its vicinal hydroxy group was frequently formed by the phosphonate method (cf. Chapter 2). In some cases, however, it could also be obtained by ( )-selective Wittig olefination using resonance-stabilized phosphoranes. 

Among insect pheromones a great number of mono- and polyolefinic compounds are found a lot of them can be obtained by the Wittig reaction. Especially the syntheses of sex attractants of female butterflies and moths, which are mostly mono- and bisunsaturated alcohols, acetates or aldehydes 168), offer a broad field for the application of the Wittig reaction and have stimulated the development of many new stereoselective variants. Thus, the methods of salt-free Wittig reactions (Chapter 2) like the sodium amide method11 31 32, the silazide technique33, potassium in HMPA 34,35 or the use of dipolar aprotic solvents like dimethyl formamide 169>, dimethyl sulfoxide 51,170) or hexamethylphosphoric triamide 51 170) were often used. 

A brominated polystyrene is reacted with sodium diphenylphosphan to form the polymeric Wittig reagent. Reaction with a halide and a base form the ylid which reacts with the carbonyl compound to the olefin. Wittig olefination can be made stereoselective (33). The formation of cis-olefins is accomplished in salt-free solu-... 

Protic solvents shift the alkene E)j Z) ratio in the direction of the (E)-form. The alkene [E)I Z) ratio of salt-free Wittig reactions is thus influenced not only by the electronic character of R, but also by the solvent and the stereochemistry of the formation of the 1,2-oxaphosphetane in the first rate-determining step. According to Eq. (5-48), the thermodynamically less stable (Z)-l,2-oxaphosphetane is formed in the first activation step. A conformational analysis of the activated complex leading to the 1,2-oxaphosphetane intermediate provides a reasonable explanation for this unexpected cis-selectivity [143, 556]. 

Scheme 4.22 Mechanism of the Wittig reaction of non-stabilized ylides under salt-free conditions...

Currently accepted mechanism of the Wittig reaction of aldehydes with non-stabilized ylides involves the formation of oxaphosphetanes through a [2-I-2]-cycloaddition-like reaction . The oxaphosphetanes are thermally unstable and collapse to alkene and phosphine oxide below room temperature. Under salt-free conditions there is no formation of betaine intermediates. The salt-free ylides can be prepared by the reaction of phosphines with carbenes generated in situ. Vedejs etal proposed a puckered 4-centre cyclic transition state I for sy -oxaphosphetane and planar structure J for anff-oxaphosphetane. In general, the flnfi-oxaphosphetane J is more stable than the syn-oxaphosphetane I, and under equilibrium conditions (when stabilized ylides are used) the E-alkene product is favoured (Scheme 4.24). However, kinetic control conditions, which appear to dominate when non-stabilized ylides are used, would lead to Z-alkene. 

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