Alkyl halides phosphonate carbanions

Olefination Reactions Involving Phosphonate Anions. An important complement to the Wittig reaction involves the reaction of phosphonate carbanions with carbonyl compounds 253 The alkylphosphonic acid esters are made by the reaction of an alkyl halide, preferably primary, with a phosphite ester. Phosphonate carbanions are generated by treating alkylphosphonate esters with a base such as sodium hydride, n-butyllithium, or sodium ethoxide. Alumina coated with KF or KOH has also found use as the base.254... 

The alkylation reaction occurred easily with both primary and secondary halides. When R = Et in the phosphonate carbanion, the alkylated phosphonate suffers partial dealkylation to 0"(R0)P(0)GFR CCX)Et by SN2 attack of the lithium halide produced in the reaction. This side-reaction can be easily suppressed by use of the corresponding isopropyl phosphonate carbanion. Thus, this straightforward alkylation of (3) appeared promising as an entry to a-fluoroesters. Alkylation occurred only at carbon and the absence of hydrogen at the a-carbon in the phosphonate precluded any transylidation process, thus allowing total utility of the phosphonate carbanion only in the desired alkylation reaction without concomitant loss of the phosphonate carbanion in acid-base side-reactions. 

The phosphonate-stabilized carbanion is prepared from an appropriate alkyl halide. This is called ihe, Arbuzov reaction. 

A related process consists initially in the reaction between diethyl methylphosphonate carbanion and a nitrile, RCN, to give the species 318, and the alkylation (R = Me, CH2CH=CH2, CH2Ph) of the latter. Work-up of the product under basic conditions leads to the enamines 319. Work-up with acid conditions affords the (2-oxoalkyl)phosphonic diesters 320 the latter were also obtained through acidolysis (3 m H2SO4) of the enamines 319. A wide choice of alkylating species is possible alkyl halides, disulphides RSSR (R = Me or Ph), sulphenyl chlorides RSCl (R = Me or Ph), PhSeBr, MeS02SMe and PhSOoCl have all been used ". ... 

Simple alkyl ethers are readily available by appropriate alkylation with alkyl halides and, of such ethers, the allyl ethers are of special interest ". Allyl ethers from slightly more complex hydroxy acids have been obtained as carbanions by the addition of allyloxy ions to dialkyl (l,2-alkadienyl)phosphonates (Scheme 36), when the main products were the separable ketones 202 (37%) and 203 (19%) formed by Claisen rearrangements within the mesomeric ion 201 ". ... 

The stereochemistry of alkylation of chiral phosphorus-stabilised carbanions (138) has been investigated and shown to be highly sensitive to the nature of the nitrogen substituent. Phase-transfer catalysed alkylation of 2-(diethoxyphosphinyl)cyclohexanone (139) gives bothO-(140) and C-(141) alkylated products. The latter predominate when reactive, non-sterically demanding alkyl halides are used. a-Arylphosphonates (142) have been synthesised in good yields by the copper(l) salt-mediated arylation of phosphonate carbanions. Under similar conditions A-(2-iodophenyl)-substituted phosphonates provide benzoxazole-(143) and oxindole-(144) substituted phosphonates. 

A very useful modification of the Wittig reaction involves the reaction of phosphonate-stabilized carbanions with aldehydes or ketones, which is known as the Homer-Wadsworth-Emmons (HWE) reaction [7, 151,152], This reaction was originally described by Homer et al. [153, 154] and further defined by Wadsworth and Emmons [155]. Phosphonate-stabilized carbanions are more nucleophilic and more basic than phosphonium ylides. They are prepared by the addition of suitable bases to the corresponding alkylphosphonates, which are readily accessible through the Michaelis-Arbuzov reaction of trialkyl phosphites with alkyl halides (usually a-halo carbonyl compounds) [143]. In contrast to the Wittig reaction, the HWE reaction yields phosphate salt byproducts that are water-soluble and hence are readily separated from the desired alkene products by simple extraction. 

A sequence starting with methylenebis[phosphonic acid] tetraester carbanions, and consisting of alkylation with an appropriate 3-substituted-propyl halide, side-chain modification, and cyclization, ultimately affords the tetraalkyl esters of cyclopropane-1,l-bis[phosphonic acid], and from which the free acid has been obtained.The reaction between 1,2-dibromoethane and ethyl (diethoxyphosphinyl) acetate or ethyl... 

The steroidal a-(isocyanomethyl)phosphonates (130) and (133) have been synthesized by methylation of the carbanions (129) and (132), respectively.66 Compounds (130) and (133) behave as N,P-ketals in that they can be hydrolysed to the corresponding ketones (131) and (134) (Scheme 10). A range of a-substituted a-aminophosphonic acids (136) have been prepared in moderate to excellent yield by the alkylation of the protected a-aminophosphonate (135) with alkyl and aryl halides and Michael acceptors under phase transfer catalysis (Scheme 11).67 The reactions of the lithium carbanion of diethyl prop-2-enyIphosphonate (137) with a,P-unsaturated ketones and esters have been investigated.6S Attack can be at the a- or y-positions in the phosphonate although in all cases Michael addition to the a, p-unsaturated carbonyl is preferred to attack at carbonyl carbon. In some examples simple adducts (138) are formed, but in more complex cases addition is followed by cyclisation to give (139) (Scheme 12). The bisphosphonate (141), which is a potent inhibitor of myo-inositol monophosphatase, has been prepared with the phosphonylation of the carbanion of (140) as a key step.6 9... 

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