Phosphorus III reactants

This chapter covers the main synthetically useful phosphonylation reactions, the corresponding processes of phosphinylation and tertiary phosphine oxide formation along with some related reactions. In all these reactions the phosphorus reactant (a phosphite, phosphonite, phosphinite, or derivative or tautomer thereof) is the nucleophilic component, herein these reactants are referred to collectively as phosphorus(III) reactants/acids, as appropriate in general these reagents are best used freshly distilled. Syntheses of phosphonates, phosphinates and tertiary phosphine oxides by nucleophilic substitution at phosphorus is not covered (for reviews of this area see Refs 6 and 16). 

The stereochemical outcome of the Michaelis-Arbuzov reaction of chiral phosphorus(III) reactants with a chiral phosphorus centre is retention, and such reactions have been employed in asymmetric synthesis.51... 

Since amine-phosphorus(III) halide condensation reactions are well-established low-energy routes to phosphorus-nitrogen bonds, they provide a logical starting point for examination of skeletally stabilized molecule synthesis. For our initial studies, reactants that are phenyl substituted as opposed to alkyl substituted... 

The Kabachnik-Fields reaction is the three-component condensation of an aldehyde or ketone, an amine (secondary, primary, or ammonia) and a monobasic phosphorus(III) acid to yield an a-amino organophosphorus compound (a phos-phonate, phosphinate, or tertiary phosphine oxide) Scheme 28. It was discovered independently in 1952 by Kabachnik and Medved 120 and Fields,121 and may be regarded as a variant of the Pudovik reaction (Section 6), which was discovered contemporarily. The yields of the reaction tend to be only moderate (cf. Section 6), and are generally unsatisfactory with phosphinate reactants, but it is wide in scope and simple to perform. For a recent review of the Kabachnik-Fields reaction, including discussion of the mechanism (which usually proceeds via the imine), see Ref. 102. 

It was McCormack who, in 1953, in the patent literature, first reported the cycloaddition of phosphorus(III) halides to l,3-dienes . As then represented, the sequence took the form depicted in reaction 13 (X = Cl or Br). The careful addition of water to the crystalline 1 1 adduct, formulated as a halogenophosphonium salt (92), gave the unsaturated phosphinic chloride (93, R = Br or Cl) or acid (93, R = OH). Since the original publication of the procedure, the application of modern spectroscopic techniques has demonstrated that the final products in such reactions are mixtures of the 3-phospholene (93) and 2-phospholene (94) isomers, conveniently represented, when admixed and in unknown proportions, as 95. It has since become apparent that the relative proportions of the isomeric forms 93 and 94 of any derivative depend on the nature of the halogen X and on the manner of work-up thus, in an acidic work-up medium, the products tend to have the structure 94, but neutralization during the hydrolysis step leads to derivatives of the isomeric 93. The reaction consists simply in mixing the reactants at room temperature and... 

In principle, the reaction between a dihaloalkane (9) and a phosphorus(III) ester (10 (R = alkyl, aryl or alkoxy) initially affords the haloalkyl compound 11 the use of a trialkyl phosphite would thus lead to an (co-haloalkyl)phosphonic diester 11 (R = alkoxy, R = alkyl), whilst that of a phosphonite diester (10 R = alkyl, aryl) would afford an (co-haloalkyl)alkyl(or aryl)phosphinic ester. Depending on the ratio of reactants, further reaction might then take place (pathway A), resulting in the formation of the compounds 12. Depending also on n, and on the reaction temperature, the alternative pathway B may be followed the products are then cyclic phosphonic or phosphinic acid derivatives 13, and examples following both reaction pathways have been discussed (chapter 2, Section A). 

One further reaction may be noted, although not extensively explored. In the initial report, aldehydes or ketones react with dichlorothiophosphites, when the products are ethers of (1 -mercaptoalkyl)phosphonic dichlorides (reaction 18) reactions which involved benzaldehyde or acetone proceeded with only moderate yields In a second report, use is made of combinations of carbonyl reactant, thiol and phosphorus(III) chloride, and it is conceivable that the actual reactants are essentially those mentioned in the first report ... 

A measrired quantity (normally 0.010 mol) of a volatile halide such as thionyl chloride, silicon tetrachloride, boron chloride, germanium(IV) chloride, or phosphorus(III) chloride is then dosed into the reaction vessel, with liquid nitrogen as a refrigerant. The reaction vessel is isolated from the vacuum manifold and warmed to 0° in an ice bath to bring about liquefaction of the volatile chloride. Intermittent shaking of the ice-bath-cooled reactants for a period of 1 to 4 hours usually ensures complete exchange of the radio-... 

Attracted by these results, Pilgram et a/.18 tried to intercept possible intermediates, such as RO—C(=S)N3, by trivalent phosphorus compounds. With phosphorous triamides 2,2-dihydro-l,3,4,5,2-thiatriazaphosphorines are formed, but it seems impossible to distinguish between attack of the reactant directly on the heterocyclic ring and attack on a thioacyl azide formed by ring opening (see Section III, B, 3). 

Phosphorus Halides Phosphorus reacts with all the halogens, forming phospho-rus(III) halides, PX3, or phosphorus(V) halides, PX5 (X = F, Cl, Br, or I), depending on the relative amounts of the reactants ... 

PhCHCl2 could be obtained as the temperature was raised, the yield of this decreased, and there was an increase in yield of the (a-chlorobenzyl)phosphonic dichloride, which could reach 85% before isolation. A variety of products are formed from benzaldehyde and (PhO)2PCl including the corresponding phosphorus(V) chloride and the compound 111. When the reaction conditions are changed, for example, by the inclusion of the solvent-reactant AC2O, isolation of (a-hydroxybenzyl)phosphonic acid becomes feasible (see Section III.3). 

Other reactions between cyclic phosphorochloridites or cyclic esters and dienes are summarized in Scheme here, A and B are O, S or Se, and may be different or identical, and X = Cl, Br, NCS, or OR, and the conversion is brought about when mixtures of reactants are heated together in sealed tubes for extended time periods. As in the many examples known in which the reacting system, as a whole, is sulphur-free, the nature of the intermediate can be in doubt, and probably depends on the nature of the substituents, particularly those directly connected to phosphorus thus some reactants may interact through a covalent, pentacoordinate species 27, whereas others form a pseudoquatemary intermediate 28. It may also be that one intermediate structure is transformed into the second before the ultimate formation of the 3-phospholene (29). Also, in accord with these ideas, thiophosphorus(III) halides have been obseved to react with a,j5-unsaturated ketones to give, ultimately, l,2-oxa-4-phospholenes as their 2-sulphides (30) (Scheme 3)45 8. reactions carried out in acetic acid solution the products are said to be the esters... 

Phosphorus-31 NMR was used to observe the substrates and products interconverting on the surface of the enzyme at equilibrium for the five phosphoryl transfer enzymes and one nucleotidyl-transfer enzyme discussed in Section III,A. In these experiments the concentrations of the enzyme (3-5 mAf) and all the different substrates, whether they contain P or not (2-4 mAf), are such that 80-90% of the reactants and products will be bound to the enzyme (for dissociation constants less than —200 iiM). The results obtained for the difiTerent enzymes are now summarized. 

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