Sodium hydride, reaction with phosphonate esters

Phosphonate esters can be deprotonated with sodium hydride or alkoxide anions to give enolate-type anions that react well with aldehydes or ketones to give -alkenes. Alkene-forming reactions with phosphonates are called Horner-Wadsworth-Emmons (or Horner-Emmons, Wadsworth-Emmons, or even Horner-Wittig) reactions. This example is a reaction that was used by some Japanese chemists in the synthesis of polyzonimine, a natural insect repellent produced by millipedes. 

In the case of HWE reactions of phosphonate esters containing a charge-stabilizing electron-withdrawing group, for example, as in trimethyl phosphono-acetate, the carbanion is often generated by reaction with potassium fcrf-butoxide, sodium hydride, n-butyllithium or similar base. Direct reaction with an aldehyde or ketone then gives the ( )-a,P-unsaturated ester as the major product (see Protocol 6). The nature of the phosphonate (see Section 3), and the substitution of the aldehyde or ketone, can influence the stereochemical outcome of these reactions as can, to a lesser extent, the reaction temperature and solvent.16... 

Dialkoxyphosphoryl-substituted carbanions, usually generated by the reaction of methyl-substituted phosphonic acid dialkyl esters with sodium hydride, react with a variety of oxiranes to give substituted cyclopropanes in moderate to good yield. Whereas the reaction of A5-phos-phanes with oxiranes (see Section 1.2.2.1.) gives cyclopropanes under forcing reaction conditions (200 °C, 8 hours), the phosphoryl-substituted carbanions give cyclopropanes under relatively mild conditions by a similar reaction mechanism (Houben-Weyl, Vol4/3, p 138). 

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 protected methyl glycoside 3 is converted to the corresponding aldehyde by Swern oxidation using oxalyl chloride activated DMSO. Further reaction with triethyl phosphonoacetate and sodium hydride -known as the Horner-Wadsworth-Emmons reaction - provides selectively the trans et /Tun saturated ester 4 in 72 % yield. This valuable alternative to the Wittig olefination protocol uses phosphonate esters as substrates which are readily available from alkyl halides and trialkyl phosphites via the Arbuzov rearrangement.9 co2Et Reaction of the phosphonate with a suitable base gives the... 

Preparation of Derivatives. A -Acyl- and A-enoylsul-tam derivatives are routinely prepared in good yields using either sodium hydride-acid chloride or trimethyl-aluminum-methyl ester single-step protocols. A variant of the former method employing in situ stabilization of labile enoyl chlorides with CuCl/Cu has also been reported. A two-step procedure via the A-TMS derivative (1) is useful when a nonaqueous work-up is desirable and for synthesis of the A-acryloyl derivative. A-Enoyl derivatives may also be prepared via the phosphonate derivative (2) by means of an Homer-Wadsworth-Emmons reaction (eq... 

Whether a Michael or a Horner reaction occurs when an a)3-unsaturated ketone is treated with a phosphonate carbanion depends upon the conditions. Chalcone and the ester phosphonate (135) gave the product of a Horner reaction with sodium hydride in diglyme, but Michael addition occurred with sodamide in ether. 

Cyclopentenones. Heathcock et al have developed a cyclopentenone synthesis that involves an intramolecular Wittig-Horner reaction of 3,e-diketo-phosphonates. For example, the reaction of 2 eq. of (1) with the ester(2)inTHF gives the diketone (3), after hydrolysis of the protective group. When treated with sodium hydride in DME at 20°, (3) cyclizes to the cyclopentenone (4) in 80% yield. 

The stability of the phosphonlum-stabiUzed enolates also means that, although they react well with aldehydes, their reactions with ketones are often poor, and it is better in these cases to use phosphonate-stabilized enolates. Being anionic, rather than neutral, these enolates are more nucleophilic. If an ester enolate equivalent is being used, the best base is the alkoxide ion belonging to the ester with a ketone enolate equivalent, use sodium hydride or an alkoxide. 

In the case of aromatic spacers, the synthesis was carried out in five steps with an overall yield of 56%. 4-(Bromomethyl)benzonitrile was first reduced using diisobutylaluminium hydride and followed by hydrolysis, to obtain the corresponding aldehyde. The latter was then reacted with triethyl phosphite. Subsequent reaction with methylamine and reduction with sodium borohydride of the resulting phosphonate allowed synthesis of the phosphonated secondary amine. Finally, the 4-(iV-methylaciylamido-methyl)benzylphosphonic acid monomer was obtained by an aciyloylation reaction, and hydrolysis of the phosphonated ester group with bromo-trimethylsilane and methanol finally led to the desired phosphonic acid moiety. 

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