Cyclic phosphinic acids

An entirely different method for the preparation of X -phosphorins utilizes phosphine chlorides 36 or 40. Treatment with bases leads to HCI elimination and to the formation of the X -phosphorins 37 and 41, respectively. The phosphine chlorides can be prepared from cyclic phosphinic acids 34 by reduction with diphenylsilane to the cyclic phosphines 35 followed by chlorination with phosgene. Alternatively,... 

Trisubstituted X -phosphorins or X -phosphorins can be isolated unchanged even after long periods of irradiation when oxygen is excluded. Stade discovered that cyclic phosphinic acid esters 208 a-c which contain a cyclic butadiene (1.3)-moiety, photochemically rearrange smoothly to the tricyclic compounds 214 a-c. 

The cyclic phosphinic acids, the 4-hydroxy-1,4-oxaphosphinine 4-oxides (312), may be made by acid-promoted cyclization of bis-(j8-chlorostyryl)-phosphinic acids (Equation (22)) <84ZOB1481, 85ZOB780), and their esters (313) result from the reaction of bromomethyl ketones with dialkyl alkynylphosphonites (Equation (23)) <89DOK(304)625>. 

Reaction of di-p-tolyl ether with PC13/A1C13 gives the cyclic phosphinic acid (8) in high yield. Ring closure does not occur with diphenyl ether. 

A simple example to illustrate the procedure is the thermal dehydration of 2-biphenyl-methylphosphonic acid (311) to the cyclic acid 312" whilst the thermolysis of the di(phos-phonomethyl)biphenyl (313) yields two cyclic phosphinic acids in 30% overall yield with 314 as the major product 2-Biphenylvl- and 2-phenoxyphenyl-phosphinic acids fail to cyclize under a variety of conditions, nor does (2-biphenylyl)phenylphosphinic acid cyclize with H2SO4 or polyphosphoric acid, although the corresponding phosphinic chloride does so in nitrobenzene. 

Strained Cyclic Phosphinic Acids, Inhibitors of Glutamate Racemase (GR)... 3... 

In 2010, Chebib et al. investigated y-aminobutyric acid analogues based on cyclic phosphonic and phosphinic acids in order to obtain selective GABAc receptor antagonists [73]. In the series, two cyclic phosphinic acids. 3-AMOHP 70 and 3-GOHP 74, showed selectivity at pi GABAc receptors (Fig. 13). 

Hydroxymethyl phosphinate 105 was prepared in three steps from hydroxymethyl-//-phosphinic acid 115 [102]. //-Phosphinic acid 115 was silylated to give the P ° intermediate, which reacted in a silyl-Arbusov reaction with the bromoacetyl derivative of aspartic acid to give 116. A deprotective step using hydrogen afforded phosphinic acid 105. From intermediate 116, cyclic phosphinic acid 106 was also accessible in two steps. First, a 5-exo-tet cyclization under... 

Bis(a-hydroxyalkyl)phosphinic acid diastereoisomers (242) have been readily separated via the formation of a new cyclic phosphinic acid (243) formed by the reaction of various aldehydes with hypophosphorous acid under microwave irradiation (Scheme 99). ° ... 

Direct Esterification and Amidation of Cyclic Phosphinic Acids... 

The esterification of cyclic phosphinic acids such as l-hydroxy-3-phospholene oxides (7 and 8), 1-hydroxy-phospholane oxides (11 and 13), and l-hydroxy-l,2,3,4,5,6-hexahydrophosphinine oxide (15) was carried out in the presence of c. 15-fold excess of the alcohols in a closed vessel to afford the phosphinates (9,10,12,14, and 16) in acceptable to excellent (44-95%) yields [33-37]. The method elaborated seems to be of general value. It was foxmd that the esterification of phosphinic acids is thermoneutral and kinetically controlled, and also represented as an irreversible process [35]. 

Thioalcohols could also be used as reaction components with l-hydroxy-3-phospholene oxides (7 and 8) xmder MW conditions. It was not a sxuprise that the products were thioesters (17) and not esters (9/10) (Scheme 4) [38]. Hence, indeed the alcohol/thioalcohol is phosphinoylated by reaction with the cyclic phosphinic acid and not the phosphinic acid is alkylated by the alcohol or thioalcohol. Quantum chemical calculations revealed that the esterification with thioalcohols is rather endothermic (48.5kJ/mol) and the enthalpy of activation is rather high (cfl. 145 kj/mol), higher than that is for esterifications ca. 102 kj/mol) [38]. 

After the esterifications and thioesterifications, the direct amidation of cyclic phosphinic acids was also attempted. The interaction of l-hydroxy-3-phospholene oxide (7) and 1-hydroxy-phospholane oxides (11 and 13) with primary amines under MW conditions took place in conversions of ca. 33% (Scheme 5). The amides (18-20) were isolated with 23-29% yields [37,39]. 

SCHEME 3 MW-assisted direct esterification of cyclic phosphinic acids. 

Gavande N, Yamamoto I, Salam NK, Ai TH, Burden PM, Johnston GAR, Hanrahan JR, Chebib M. Novel cyclic phosphinic acids as GABA p receptor antagonists design, synthesis, and pharmacology. ACS Med. Chem. Lett. 2011 2 11-16. 

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