ienc Sc es al J c o i u m r e n a h l C Chemical Sciences Journal Keglevich et al., Chem Sci J 2014, 5:2 ISSN: 2150-3494 DOI: 10.4172/2150-3494.1000088 Research Article Article OpenOpen Access Access Synthesis of Phosphinic Acid Derivatives; Traditional Versus up-to-Date Synthetic Procedures Gyorgy Keglevich*, Nora Zsuzsa Kiss and Zoltan Mucsi Dept of Organic Chemistry and Technology, Budapest University of Technology and Economics, Hungary Abstract Synthetic methods for the preparation of phosphinic derivatives (esters and amides) are summarized. The basic method is, when phosphinic chlorides are reacted with alcohols or amines. These reactions take place under mild conditions, but utilize expensive chlorides, need a solvent, and a base has to be added to remove the HCl formed. On conventional heating, the phosphinic acids resist undergoing derivatizations by nucleophiles. However, on microwave (MW) irradiation, the phosphinic acids could be esterified by alcohols. The direct esterification does not require an extra solvent, it is atomic efficient, but needs a relatively higher temperature. The similar amidations were reluctant. Phosphinic acids may also be esterified by alkylation that may be promoted by combined phase transfer catalysis and MW irradiation. It is also possible to convert the phosphinic acids by different reagents (e.g. by the T3P reactant) to a more reactive intermediate that is ready to react with alcohols or amines. Other methods, such as preparation by the Arbuzov reaction or by fragmentation-related phosphorylation are also discussed. Keywords: Phosphinic derivatives; Esterification; Amidation; phosphinic acid with an excess of ethanol gave 12% of the ethyl phenyl Microwave; Phase transfer catalysis phosphinate after a reflux of 42h (Scheme 3). Introduction Ph O 80 °C / 42 h Ph O P + EtOH P Phosphinic derivatives (acids, chlorides, esters, amides etc.) are H OH (excess) H OEt important building blocks (starting materials and intermediates) in 12% Scheme 3 synthetic organic chemistry [1]. They are produced on an industrial scale, and utilized in the synthesis of fine chemicals, plant protecting One patent reports the esterification of dialkylphosphinic acids in agents and medicines. Until now, there has been no comprehensive the presence of different catalysts under quite extreme conditions and review on the synthesis of phosphinic derivatives. For this we prolonged reaction times (Scheme 4) [5]. undertook to compile this review including also our quite experiences. 1 1 R O 190-250 °C / 2-7 days R O The discussion has been grouped around two major point of views: P + R2OH P catalyst 2 traditional syntheses and green chemical aspects. R1 OH (3 equiv.) R1 OR 60-97% 1 Traditional Methods for the Synthesis of Phosphinate R = C9 olefin cat: p-toluenesulfonic acid, p-naphthol sulfonic acid, R2 = 2-ethylhexyl, Ph benzenesulfonic acid, etc. irect Esterification Scheme 4 It is known, that phosphinic acids cannot be esterified by alcohols In another patent, authors claimed that two phosphinates were (Scheme 1). 1 1 synthesized from the corresponding phosphinic acids by reaction with Y O Y O 2 equiv. of allyl or crotyl alcohol in the presence of p-toluenesulfonic P + ROH P Y2 OH Y2 OR acid in aromatics with water removal. However, there was no evidence for the formation of the esters [6]. Y1, Y2 = alkyl or aryl It is remarkable, that no other example for the direct Scheme 1 esterifications of phosphinic acids have been reported. However, Only a few examples are known for direct esterification. Nifant’ev diphenylphosphinothioates were prepared by the direct esterification reported the direct esterification of hypophosphorous acid in the of diphenylphosphinodithioic acid with certain alcohols and phenols in presence of acidic catalysts under azeotropic water removal in benzene the absence of a catalyst [7].The reaction required long reaction times. or toluene (Scheme 2) [2,3]. ∆ / 2 h *Corresponding author: Dept of Organic Chemistry and Technology, Budapest H O cat: ZnCl , AlCl , CH COONa H O 2 3 3 University of Technology and Economics, 1521 Budapest PO Box 91, Hungary, Tel: P + ROH P ArH 36-1-463-1111/5883; E-mail: [email protected] H OH (3 equiv.) H OR R = iPr, Bu Received November 04, 2014; Accepted November 22, 2014; Published Desember 03, 2014 Scheme 2 Citation: Keglevich G, Kiss NZ, Mucsi Z (2014) Synthesis of Phosphinic Acid Cherbuliez substantiated that the direct esterification of Derivatives; Traditional Versus up-to-Date Synthetic Procedures. Chem Sci J 5: tetracoordinated P-acids with at least one P-H bond is only possible 088. doi: 10.4172/2150-3494.1000088 via the tautomeric tri coordinated form [4]. The direct esterification Copyright: © 2014 Keglevich G, et al. This is an open-access article distributed of orthophosphoric acid with ethanol yielded 2.5% of the monoethyl under the terms of the Creative Commons Attribution License, which permits ester after 22 days, at the same time, the esterification of phenyl-H- unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Chem Sci J Volume 5 • Issue 2 • 1000088 ISSN: 2150-3494 CSJ, an open access journal Citation: Keglevich G, Kiss NZ, Mucsi Z (2014) Synthesis of Phosphinic Acid Derivatives; Traditional Versus up-to-Date Synthetic Procedures. Chem Sci J 5: 088. doi: 10.4172/2150-3494.1000088 Page 2 of 14 Esterification of Phosphinic Chlorides with Alcohols Under phase transfer catalytic (PTC) conditions, the acids may be transformed directly to the corresponding phosphinates. It is also The usual synthesis of phosphinic esters involves the reaction of possible to use an alkali salt as the starting material [21]. phosphinic chlorides with alcohols (Scheme 5) [1,8-10], It is drawback that this method applies chlorides and an aromatic solvent, the The addition of unsaturated compounds, such as terminal acylation is not atomic efficient and environmentally problematic due acetylenes to phosphinic acids may also lead to phosphinates [22]. to the formation of hydrochloric acid. A few laboratory methods utilize diazomethane or diazoalkanes O O for the esterification of phosphinic acids [23-29]. The first alkyl di 3 base (e.g. TEA) 1 P + R OH 1 P R Cl - HCl R OR3 H-phosphinates was also prepared by this approach [30]. R2 R2 Scheme 5 Esterification of Phosphinic Acids using Activating Agents In most cases a tertiary amine [11], an alcoholate [12] or a phenolate Since the nucleophilic substitution on the phosphorus atom is used in a polar solvent [13]. Despite the disadvantages, this method is of phosphinic acids by alcohols does not take place, the acid should widely used due to its general applicability. be transformed to a more active species. Such procedure is when the phosphinic acid is reacted by a carbodiimide. Karanewsky A few examples were described for the esterification of chloro- reported the esterification of phosphinic acids in the presence of phospholene oxides by alcohols in the presence of NEt3 or NaOMe as dicyclohexylcarbodiimide (DCC), 10% of N, N-dimethylaminopyridine the base in different solvents. The preparative details can be seen (Table (DMAP) and a slight excess of alcohol in THF to give the corresponding 1). The yields were variable (27-85%) [14-18]. phosphinates in good yields (Scheme 7) [31-33]. Alkylating Esterification of Phosphinic Acids O O DCC (1.1 eq) / DMAP (0.1 eq.) 2 R1 P + R OH R1 P Phosphinates may also be obtained by O-alkylation [7-9]. In the OH OR2 H THF H first step, the acid is transformed into the corresponding sodium or 64-89% potassium salt that is then reacted with an alkyl halide. However, only R1 = aryl, aralkyl 2 i t a few examples were described (Scheme 6) [19, 20]. R OH = EtOH, PrOH, BuOH, BuOH, etc. M / MOH or 1 1 R O 3 2 Scheme 7 R O M2CO3 R X R O P P P 1 2 2 - MX 3 R2 OH R OM R1 OR Mixed anhydrides of Y Y P (O)O-C(O)OR type can be formed 1 2 1 2 R , R = alkyl, aryl M = Na, K R3 = alkyl, aminoalkyl easily that undergo CO2 elimination to provide the Y Y P(O)OR phosphinate [34]. Scheme 6 Conditions Phosphinic chloride Yield [%]ref Product Reagents Solvent R 14 Me Me MeOH/NEt3 Et2O Me 64 neo neo 15 PentOH/NEt3 PhH Pent 85 P P EtOH/NEt CH Cl Et 4716 O Cl 3 2 2 O OR Me Me 14 MeOH/NEt3 Et2O Me 62 P P O Cl O OMe R Me R Me P NaOMe PhMe Me 80–8117 O Cl P O OMe R=H, Me R1 R2 R1 R2 ROH/NEt CH Cl C -C alkyl 27–7216 P 3 2 2 1 12 O Cl P O OR R1, R2=H, Me Table 1: Esterification of chloro-phospholene oxides Chem Sci J Volume 5 • Issue 2 • 10000088 ISSN: 2150-3494 CSJ, an open access journal Citation: Keglevich G, Kiss NZ, Mucsi Z (2014) Synthesis of Phosphinic Acid Derivatives; Traditional Versus up-to-Date Synthetic Procedures. Chem Sci J 5: 088. doi: 10.4172/2150-3494.1000088 Page 3 of 14 Esterification of Phosphinic Acids by Orthocarbonyl the coupling of aryl halides or other derivatives with >P(O)H reagents, Compounds mainly dialkyl phosphites in the presence of a complex catalyst [50]. In a modification, alkyl-H-phosphinic acids were coupled with aryl Alkyl hypophosphinates (H2P(O)OR) that are starting materials halides to give phosphinates (Scheme 11) [51]. in the synthesis of alkyl- and aryl phosphinates, are prepared through reflux or 110 °C the alkaline hydrolysis of P4 in an industrial scale, [35] however, a few O Pd(OAc)2 / L O alternative methods were also described for their preparation.