Phosphinate-containing heterocycles: A mini-review

Summary This review provides an overview of recent efforts towards the synthesis of phosphinate heterocycles R1R2P(O)(OR). Our laboratory and others’ have been involved in this field and as a result new P–C, P–N, and P–O containing heterocyclic motifs are now available through a variety of methods. While developing rapidly, this area is still in its infancy so that biological testing of the compounds has not yet been conducted and applications are rare. The growing availability of synthetic methods will undoubtedly change this situation in the near future.


Introduction
The preparation of P-heterocycles has been the subject of many studies over the years, and the field has been extensively reviewed [1][2][3][4][5][6][7][8]. Typically, accessing P-heterocycles involves multistep sequences with low overall yields [1][2][3][4][5][6][7][8]. In the past 20 years, significant effort has been devoted to synthetic and reactivity studies of a particular family of organophosphorus compounds: the phosphinates R 1 R 2 P(O)(OR) [9]. Because the phosphinic acid moiety P(O)OH can mimic carboxylic acids, its incorporation into heterocycles may offer new opportunities for the discovery of biologically active analogs. However, little or no biological data is available at this time. Selected recent synthetic work by us and others is presented below.

Review Phospholes
Several compounds have been prepared in this series. Keglevich and coworkers realized the synthesis of phosphole derivatives 2a-f based on the McCormack reaction [10] followed by microwave-assisted esterification of the phosphinic acid using different alcohols in large excess (Scheme 1) [11,12]. Six phospholes 2a-f were prepared in yields up to 94%.
Chen and Duan have synthesized one phosphinoline 17 in 60% yield by the alkyne-arene annulation of ethyl phenyl-H-phosphinate (15) using 2 equivalents of Ag 2 O (Scheme 7) [21]. Miura et al. simultaneously reported the same reaction but with 4 equivalents of AgOAc instead, delivering the heterocycle 17 in 53% yield (Scheme 8) [22]. Both reactions used 4 equivalents of Ag(I) as well as an excess of H-phosphinate.
In this particular study phosphinates 26 and 29 were tested as inhibitors of aspartate transcarbamoylase (ATCase).

1,3-Azaphosphindoles and 1,3-benzazaphosphorines
Several compounds in this series were synthesized by Montchamp and coworkers using two different approaches. The first one is the reaction between an imine 34 and 2-bromophenyl-substituted H-phosphinate esters 36 in the presence of Cs 2 CO 3 , and catalytic Pd(PPh 3 ) 4 in refluxing toluene to generate the corresponding cyclized products 37a-h in yields up to 76% (Scheme 15) [29].

Scheme 15: Tandem Kabacknik-Fields/C-N cross-coupling reaction.
The second way is the formation of the imine first by reacting an amine 39a,b with an aldehyde 38, then the phosphinate is introduced and the mixture stirred for 24 h at reflux to generate the corresponding H-phosphinate esters. Addition of DIPEA and catalytic Pd/dppf in a mixture DMF/DME to the intermediates generated the corresponding cyclized derivatives 40a,b in yields up to 53% (Scheme 16) [18]. For these compounds, the authors were able to separate the different diastereoisomers generated during the reaction by simple column chromatography on silica gel.

1,4-Azaphosphorines
In this series, only a few examples have been reported in the literature. One derivative has been prepared by Manthey and coworkers in 50% yield as a precursor to a dihydroorotase inhibitor (Scheme 17) [30].
In this example, the amino acid 41 was first cyclized using 1-(3dimethylaminopropyl)-3-ethylcarbodiimide (42) at pH 5.6 followed by protection of the carboxylic acid and phosphinic acid moieties by diphenylmethyl group using a slight excess of diphenyldiazomethane. The two diastereoisomers obtained were readily separable by column chromatography.
To prepare the required phosphinate 45 a double allylation of H 3 PO 2 was performed using 2 equivalents of cinnamyl alcohol 44 in the presence of 2 mol % of Pd/Xanthpos followed by an esterification using benzyl bromide. Ozonolysis, and reductive amination using excess benzylamine in the presence of sodium cyanoborohydride completed the synthesis.
Compound 51 was subsequently converted into the corresponding analog of cyclic AMP, but no biological activity was reported.

1,2-Oxaphosphorines
Gouverneur and coworkers have realized the synthesis of several 1,2-oxaphosphorine derivatives 53a-k using diastereoselective ring closing metathesis with 2 to 4 mol % of various catalysts (Scheme 22) [34]. During this work, they obtained 11 different compounds in yields up to 100% and diastereomeric excesses up to 86%. The starting phosphinates 52a-k were prepared using classical chemistry involving Grignard addition to EtOP(O)Cl 2 .

Phenoxaphosphine
Scheme 23 shows the synthesis of one phenoxaphosphine 56 in 55% yield by Li and coworkers via the reaction between diethyl 2-oxocyclohexylphosphonate (54) and benzyne generated from 2-(trimethylsilyl)phenyl triflate (55) and cesium fluoride [35]. This oxazaphosphinane 61 was synthesized in two steps at room temperature, first, by a nucleophilic attack of methyl hypophosphite on oxazolidine 60 followed by an intramolecular cyclization, this time without base catalyzed transesterification. The authors explained this difference of reactivity by the Thorpe-Ingold effect [38]. Indeed, the presence of four methyl groups allows the hydroxy function to be spatially closer to the reactive phosphinate, facilitating the intramolecular cyclization of this product.

Conclusion
Phosphinate heterocycles are becoming routine products in the literature. Classical approaches such as the McCormack reaction of conjugated dienes, the sila-Arbuzov reaction of bis(trimethylsiloxy)phosphine with dihalides, etc. continue to be useful. However, novel approaches in both the preparation of acyclic precursors and the reactions to achieve their heterocyclization, have led to more efficient synthesis and broader structural diversity. While, like with any other P-heterocycles the phosphinates can be employed for the synthesis of novel phosphine ligands, their potential for the discovery of novel biologically active motifs is tantalizing.