Abramov reaction

In the Abramov reaction [13] a phosphite is reacted with an aldehyde to produce a compound with a P-C bond (6.346). In some cases, however, a transfer of groups is liable to occur, but the reaction can sometimes be useful for the synthesis of a specific compound with a P-C bond as, for example, in (6.347). 

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On the basis of NMR and derivatisation studies, the configuration at phosphorus in 48 was shown to be S. It phosphonylates aldehydes readily via the Abramov reaction to afford a-siloxyimidophosphonate esters 50 (Scheme 18) [41 13] with diastereomeric excess (de) up to 96% (for R=/-Bu). The reactions proceed smoothly... 

The other major approach toward overcoming the "alkyl transfer" difficulty of the Abramov reaction involves the use of silyl esters of the trivalent phosphorus acids. Unlike carbon, silicon does not have the stereochemical restraints associated with ordinary alkyl groups for intramolecular transfer.211 The preparation of mixed alkyl—silyl esters of trivalent phosphorus acids paved the way for the Abramov reaction to be of general utility.204 208 212 An example is shown in Equation 3.14. 

The use of an anionic reagent for addition at carbonyl carbon rather than a fully esterified form of a trivalent phosphorus acid obviates a troublesome aspect of the Abramov reaction. Specifically no dealkylation step is required. Mechanistic investigations257 258 indicate that the reaction proceeds much as a simple "aldol"-type reaction in which the anionic phosphorus site adds directly to the carbonyl center. While the initial efforts concerned with the "Pudovik reaction"259 were directed toward the use of sodium salts of the simple dialkyl phosphites, as shown in Equation 3.17,260 266 with a, 5-unsaturated carbonyl systems (vide infra) competition between sites for addition can occur. Addition at the carbonyl carbon site is the kinetically favored route.267-270... 

In [62] the synthesis of phosphorus-containing derivatives of 2-indolinone was reported. Thus, in 5-bromoisatin one phosphorus-containing fragment was introduced by the Abramov reaction with the formation of compound 66 [233], and a second was then introduced by the Arbuzov reaction (compound 67) ... 

Published data on the reaction of isatin with di- and trialkyl phosphites are somewhat contradictory. In particular, the authors in [78] showed that isatin with trialkyl phosphite forms 2 1 adduct, which has the structure of 1,3,2-dioxaphospholane containing a pentacoordinated phosphorus atom. More recently analogous results were obtained in the reaction of isatin with amidophosphites [79], At the same time it was shown [80] that 5-methylisatin reacts with trialkyl phosphites with the formation of 3-dialkoxyphosphoryl-3-hydroxy-2-indolinones, identical with the compounds obtained in the reaction of isatin with dialkyl phosphites [78]. In the monograph [4] with reference to the patent [61] the reaction of diethyl phosphite with isatin under the conditions of the Abramov reaction was indicated to lead to 3-dialkoxyphosphoryl-2-indolinone. In all probability this needs verification. 

The procedure of isotope effect studies will be illustrated on several examples. First one concerns studies of phosphonate-phosphate rearrangement (Scheme 1). Phosphite 3 reacts in the presence of triethylamine with o-nitrobenzaldehyde (Pudovik reaction) to form 1-hydroxyphosphonate 4 as mixture of two diastereo-isomers, 1 1. Amine also catalyses the reverse refro-phospho-aldol (retro-Abramov) reaction of 1-hydroxyphosphonate to phosphite and aldehyde and rearrangement to phosphate 5. In acetonitrile at 65°C Pudovik reaction is much faster than of retro-Abramov reaction and phosphonate-phosphate rearrangement, which rates are comparable. Important fact for the mechanism elucidation was experimental evidence that rearrangement occurs with retention of configuration at phosphorus atom.49... 

The reaction of a silyl phosphite with an a-haloaldehyde or ketone generally leads to a 1 1 adduct (i.e. addition at the carbonyl carbon atom to yield a silyloxyphosphonate by the Abramov reaction, cf. Section 5). However, both the Perkow and the Michaelis-Arbuzov pathways are significant and frequently dominate, the outcome depending on the nature of the reactants and the reaction conditions.47... 

The most successful asymmetric variants of the Abramov reaction employ chiral substrates, either chiral carbonyl compounds or aldimines, or chiral phosphorus(III) reagents.5,51,86,88 However, the Pudovik reaction using chiral catalysts is a superior route for the asymmetric synthesis of a-hydroxy- and a-aminophosphonates (Section 6). 

An alternative approach that avoids many of the difficulties of the Abramov reaction uses a bivalent phosphorus component with at least one acidic site on phosphorus. The Pudovik reaction uses a base for the removal of the acidic proton and facilitates attack by the electron-rich phosphoras anionic site on the carbonyl carbon. A variety of bases have been used for this purpose, as have phosphoras reagents with differing numbers of acidic sites on the phosphoras component. High yields of adducts are possible under very mild conditions using this approach (equation 31). The... 

Other sugars and related compounds undergo the Abramov reaction with dialkyl phosphites with much lower stereoselectivity. For example, 2,3 4,5-di-0-isopropylidene-D-xylose and dimethyl phosphite give a mixture of epimers 12 (86 14), from which the epimer formed in excess crystallizes. The absolute configuration of the newly formed stereogenic center at C-l in this epimer was found to be R33. 

The Abramov reaction of 2,3-0-isopropylidene-D-glyceraldehyde and 2,4-0-ethylidene-D-ery-throse with dialkyl phosphites proceeds with very poor stereoselectivity to give the C-l di-alkoxyphosphinyl epimers in 59 41 and 53 47 ratio, respectively33. 

To achieve asymmetric C-P bond formation in the Abramov reaction, chiral phosphoryl components can also be used in which the phosphorus atom is a stereogenic center. In this case, the main problem is the synthesis of suitable enantio- or diastereomerically pure phosphites. 

On the basis of the results presented, it has been concluded that the Abramov reaction proceeds with overall retention of configuration at phosphorus64. 

If the starting co-hydroxyalkylphosphonate is obtained via the Abramov reaction, presenting a convenient route to a-hydroxyalkylphosphonates, the final heterocycles formed in the one-pot process may possess additional functionality such as a hydroxy (compound 70, Scheme 39) [85] or phosphoryl group (compound 71, Scheme 40) [86], In the latter case, the starting carbonyl compounds of rather complex structure gave rise to directional synthesis of biologically active compounds 72 and 73. 

The use of silyl phosphite esters in the Abramov reaction is well established, but a practical modification involves the addition of MesSiCl to a mixture of triethyl phosphite and carbonyl reactant at room temperature. The addition of a silyl phosphite (R = Si-containing group) to a chiral hydroxyaldehyde derivative (138) (R is also a Si-containing group) affords a mixture of the diprotected diastereoisomeric (l,2-dihydroxyalkyl)phosphonic esters (139) and... 

The preparation of species such as a-hydroxyphosphonates has been alluded to only briefly here (see Section 3.5). We would note two direct approaches that are available for the preparation of these materials, both involving nucleophilic addition to carbonyl carbon. One of these is referred to as the Abramov reaction that involves the addition of a fully esterified trivalent phosphorus acid to a carbonyl carbon followed by a dealkylation of the phosphorus ester site. This preparation is quite inefficient when ordinary ester linkages are used, but the use of silyl esters overcomes most of these difficulties and allows facile isolation of the target compounds (equation 30). Note that reaction occurs preferentially at the carbonyl carbon and not by displacement of halogen at carbon. Addition occurs preferentially at carbonyl carbon compared to displacement at a carbon-halogen linkage, and provides product if removal of the ester linkage is facile. 

The most important reaction for the formation of those acids carrying the hydroxy group on an a-carbon atom consists in the addition of compounds possessing the P(0)H moiety across the carbonyl group (1,2-addition) of an aldehyde or ketone (reaction 5)— the so-called Abramov reaction. ... 

In the simplest form of the Abramov reaction, the phosphorus-containing reactant is hypophosphorous acid (phosphinic acid) or an ester thereof, and in the reactions between the acid and formaldehyde or benzaldehyde the initial product is the phosphinic acid 144 (R = H or Ph.). However, the reaction can proceed further to give the bis(l-hydroxyalkyl)phosphinic acid (145 R = H or Ph) the latter (R = Ph) reacts readily with yet more benzaldehyde to give its benzylidene derivative, 5-hydroxy-2,4,6-triphenyl-1,3,5-dioxaphosphorinane 5-oxide (146 R = Ph). When acted on by a second mole of cyclohexanone in the presence of acetyl chloride, (l-hydroxycyclohexyl)phosphinic acid (147) gives the novel phosphinic chloride 148, characterized as the free acid 149 following ready hydrolysis A reaction between a phosphinic acid (150) and a second (non-identical) carbonyl compound leads to an unsymmetrical phosphinic acid (151). Esters of symmetrical 1, r-dihydroxy-substituted phosphinic acids are preparable from hypophosphite esters, H2P(0)0R ". ... 

The Abramov reaction proceeds normally with polycyclic aromatic aldehydes but of other, monocyclic, benzenoid aldehydes, the behaviour of 2-hydroxybenzaldehyde is anomalous here, the reaction product 172 is evidently formed by hydrolysis of the dihydrobenzo-1,2-oxaphosph(V)ole 171, in turn the result of the expulsion of 1 mol of the alcohol ROH from the initial 1 1 adduct 170. ... 

In most instances the Abramov reaction generates an a-substituted chiral centre, but all syntheses have been considered to lead to the racemic product. Various (a-hydrox-yalkyl)phosphonic acids have been resolved through salts of a monoalkyl ester with, for... 

It is thus apparent that the formation of 2-oxo-1,2-oxaphospholanols makes an important contribution to the chemistry of the Abramov reaction when it involves aldoses, but the formation of 2-oxo-1,2-oxaphosphorinanols from appropriate substrates has also been... 

A useful method for the introduction of phosphorus-containing moieties on to the carbonyl position of furanose forms of ketohexoses is based on a modification to the Abramov reaction consisting in the addition of a hydrophosphoryl compound to a hydrazide 330 (Scheme Thus, 331b (X = H, Z = OMe) (derived from the corresponding 331a) was allowed to react with 332 (R = or to give the corresponding adducts 333 ... 

Application of the Abramov reaction has received little more attention, but it has been used in conjunction with toluenesulphonyl derivatives of hydroxyketones in the presence of dbu (Scheme 28) when acted upon by thiourea in MeOH at room temperature, the oxi-ranes 344 (R = Me or Et, R = Me or Cy) are converted into the corresponding thiiranes 345 ". The reaction between the protected oxoacetal 346 with methyl phenylphosphinate in the presence of dbu provides the epoxide 347 as a mixture of the diastereoisomeric 4RS and 4SR pairs in the ratio 7 3. Reduction of the product with H2 and Raney nickel yields the linear phosphinate ester 348 Similarly, the reactions between the ketose 349 (R = Me or CH2Ph) with either dialkyl hydrogenphosphonate or alkyl phenylphosphinate, again in the presence of dbu, gave the epoxides 350 (R = Me or CH2Ph R = R = MeO R = Ph,... 

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