Phosphinic acids, synthesis

Phosphinic acids, synthesis of, 6, 6 Phosphonic acids, synthesis of, 6, 6 Phosphonium salts ... 

B. By Hydrolysis Reactions.—Details have appeared of the synthesis of dibenzophosphorin oxides (15) from 5-alkyldibenzophospholes, by reaction with methyl propiolate in the presence of water, and of confirmatory syntheses from phosphinic acid chlorides, as shown below. Evidence for the suggested mechanism of the ring-expansion reaction is presented. The hydrolysis of enamine phosphine oxides is an efficient, although somewhat indirect, method for the preparation of j8-ketoalkylphosphine oxides (16) [see Section 3(iii), for the preparation of enamine oxides]. Reasonable yields (48—66%) of trialkylphosphine oxides (17) have been obtained by the alkaline hydrolysis of the products from the pyrolysis at 220 °C of red phosphorus with alkyl halides, in the presence of iodine. 

A further method for the synthesis of a mixed anhydride between a phosphinic acid and a sulfonic acid employs a sulfonic triazolide ... 

A modification of this procedure allowed the isolation of 1,3,2-oxazaphospholidine 52a as a single diastereomer [41] and its application to asymmetric synthesis of enantiomerically and diastereomerically pure phosphinic acid derivatives 53 and 54 and tertiary phosphine oxides 55 (Scheme 20) [45], A few years later, a similar approach for the synthesis of enantiomerically pure tertiary phosphine oxides 55... 

Scheme 20 Synthesis of diastereomerically pure phosphinic acid derivatives 53...

Golubski, Z.E., Alkylation of phosphinic acid salts in the presence of crown ethers, Synthesis, 632, 1980. 

Andrew Regan was born in Rawtenstall, Lancashire and studied at the University of Cambridge, where he obtained his BA in 1981 (MA 1985), and his PhD in 1984, under the supervision of Professor Jim Staunton. From 1984-1985 he held an SERC-NATO Research Fellowship at Columbia University in the laboratories of Professor Gilbert Stork. He returned to the UK in 1985 to a lectureship in organic chemistry at the University of Kent at Canterbury, and since 1990 has been a lecturer in the Department of Chemistry at the University of Manchester. His research interests include the synthesis of phosphinic-acid hormone mimics, simplified macrolide antibiotics and anti-tumour compounds, stereoselective methodology, and the use of enzymes in synthesis. 

The usual flood of reports concerning the addition of phosphites to imines has appeared. These include the reaction of hypophosphites to give a-aminoalkyl-phosphinic acid salts possessing antibacterial activity22 and the synthesis of AM, 4,2-A5-oxazaphospholines (30) from phosphites and carboxamides.23 The addition of... 

Figure 39. Synthesis of phosphinic acid (X = OH) containing poly(arylene ether).

Such nucleophilic substitutions can also be carried out on analogous 1,1-di-arylamino-X -phosphorins and on oxy-bis -X -phosphorinsii4 or acetates 153, the latter can be viewed as mixed anhydrides in which phosphinic acid or acetic acid are easily displaced by nucleophiles. These reactions have a broad application in synthesis. 

The biological properties of phosphorus amino acid analogues (and their derivatives) depend upon their stereochemistry. Consequently, numerous methods for obtaining these compounds in stereochemically pure form have been developed. Two excellent review articles summarize the work performed prior to 1993. 3,4 Resolution of racemates continues to be a useful approach for obtaining optically pure aminoalkylphosphonic and -phosphinic acid derivatives (vide infra), but most of the newer literature describes asymmetric syntheses of these compounds.15-17 Two methods for resolution and one for asymmetric synthesis are described (vide infra) they have been selected since they are relatively easy to perform, work with a variety of side chains, can be carried out on a reasonable scale with readily available starting materials, and produce products of high stereopurity. However, just as in traditional amino acid chemistry, each side chain introduces its own complications, and in many cases, especially for more complex analogues, other methods may be preferred. 

Scheme 13 Synthesis of a-Aminoalkylphosphinates from Phosphinic Acid 56"59 ...

The most common method for the synthesis of phosphinopeptides is the addition of a nucleophilic, trivalent phosphorus species to a carbon electrophile, including conjugated double bonds, alkylating agents, imines, and carbonyl compounds. By analogy with the phosphite ester additions described above, the nucleophilic form of a phosphinic acid is the trivalent species, generated from the more stable, pentavalent PH derivative by deprotonation or by silylation (cf. Scheme 2). 

A less common approach to the synthesis of phosphinates is the reaction of electrophilic phosphonates with carbon nucleophiles such as Grignard reagents or lithium enolates. For example, the phosphinic acid analogue 71 of the amino acid statine was synthesized by displacement of tert-butyl lithioacetate on a 5-phenyl phosphonothioate 70 (Scheme 23)d104l The racemic diastereomers of the 5-phenyl phosphonothioate were obtained in pure form, and the displacement of the phenylsulfanyl moiety was found to be stereospecific, although the stereocenter at phosphorus would later be lost on hydrolysis of the ester. A similar displacement reaction has been described using the p h osp h on och I ori d ate.1711... 

Scheme 31 Synthesis of Phosphonate Monoesters by Esterification and Oxidation of H-Phosphinic Acids 63-1231...

Compounds containing phosphorus can be both valuable synthetic intermediates and target compounds of solid-phase synthesis. Important synthetic intermediates include phosphonium salts and phosphorus ylides, which are key intermediates in carbonyl olefinations. Their preparation is discussed in Section 5.2.2.1. The preparation of oligonucleotides, these being the most important phosphorus-containing target molecules in solid-phase synthesis, is considered in Section 16.2. In this chapter, the preparation of phosphines, phosphonic acid derivatives, and phosphinic acid derivatives is discussed. 

Regan and co-workers protocol for the synthesis of y-keto phosphinic acids by 1,4-addition of bis(trimethylsilyl)phosphonite (BTSP, 64) to a,p-unsaturated ketones avoids the isolation of pyrophoric BTSP 64 by generating it in situ. This procedure may be modified to synthesize disubstituted phosphinic acids by addition of a second a,p-unsaturated ketone.133 a,f)-Unsaturated esters are also suitable reactants.134 The products are isolated most conveniently as their adamantanammonium salts.133... 

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