Send Orders for Reprints to reprints@benthamscience.ae Current Green Chemistry, 2015, 2, 379-391 379 A Survey of the Palladium–Catalyzed Hirao Reaction with Emphasis on Green Chemical Aspects Erzsébet Jablonkai and György Keglevich* Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary Abstract: The Pd-catalyzed P–C couplings of aryl, hetaryl and vinyl derivatives and species with a P(O)H function, typically dialkyl phosphites and secondary phosphine oxides giving rise to phosphonates and phosphine oxides are summarized with special emphasis on the green chemical variations. A great variety of reactions are discussed to demonstrate the different conditions and catalyst systems described. environmentally friendly protocols include the use of a phase transfer catalyst and the microwave technique. The best way is to perform the P–C coupling reactions under P- ligand-free and solvent-free conditions. Keywords: Hirao reaction, P-C coupling, Pd-catalyst, phosphonates, phosphinates, phosphine oxides, P-ligand-free. 1. INTRODUCTION The P–C coupling reaction of aryl, hetaryl and vinyl halides (or other derivatives) and Y 1 Y 2 P(O)H reagents, such as dialkyl phosphites (Y 1 ,Y 2 = RO), alkyl H-phosphinates (Y 1 = RO, Y 2 = R, Ar) and secondary phosphine oxides (Y 1 ,Y 2 = R, Ar) became an important method for the synthesis of phosphonates, phosphinates and phosphine oxides, respectively [1, 2]. The preparation of arylphosphonates is especially important. Many variations of the original Hirao reaction were elaborated applying different P-reactants, preformed or in situ formed Pd(0), Pd(II), Ni(II) and Cu(II) containing catalysts with mono- and bidentate P-ligands, bases (mostly 1-2 equivalents of amines) and solvents. In this review, we focus on the Pd-catalyzed accomplishments. A special attention is given to the green chemical variations including phase transfer catalytic and microwave-assisted approaches, along with P-ligand-free and solvent-free accomplishments. 2. DISCUSSION 2.1. Hirao Reaction Using Pd(0) Catalyst Thirty four years ago, Hirao reported the P–C cross- coupling reaction of aryl- and vinyl halides with dialkyl phosphites in the presence of tetrakis(triphenylphosphine) palladium (Scheme 1). The phosphonates (1) were obtained mostly in high yields, using triethylamine, tributylamine and pyridine as the base, in toluene as a suitable solvent [3- 5]. The mechanism of the Hirao reaction is similar to the C–C coupling reactions (Scheme 2). The first step is the *Address correspondence to this author at the Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary; Tel: +36-1-463-1111(5883); Fax: +36-1-463-3648; E-mail: gkeglevich@mail.bme.hu oxidative addition of the aryl derivatives to the Pd(0) complex. The next step involves the ligand exchange, when the deprotonated Y 1 Y 2 P(O)H replaces the X – anion of species 2A. Finally, the corresponding coupled product (3) is formed by reductive elimination from intermediate 2B. The Hirao reaction was then extended to other models. The most important results are summarized in (Scheme 3) [6-37]. Substituted aryl and vinyl halides and triflates were reacted with dialkyl phosphites, alkyl H-phosphinates and secondary phosphine oxides utilizing the Pd(PPh 3 ) 4 catalyst in the presence of triethylamine, diizopropylethylamine and methylmorpholine in toluene, acetonitrile, DMF, THF and benzene as the solvent. Falling in the range of 18-98%, the yields were mostly high. The synthesis of dinucleoside pyridylphosphonates was also accomplished using Pd(PPh 3 ) 4 catalyst and triethylamine as the base in THF solution under argon atmosphere [38]. Intramolecular P–C bond formations resulted in benzooxaphosphacycloalkenes [39]. Diaryliodonium tetrafluoroborates were found to be reactive aryl derivatives in coupling reaction with dialkyl phosphites in the presence of K 2 CO 3 in DMF [40]. The corresponding arylphosphonates were obtained in 72-98% yields. A similar Pd-catalyzed method for the arylation of diethyl ethoxyphosphinylmethyl- and ethoxyphosphinylpropylphosphonate (5) with aryl derivatives was also elaborated (Scheme 4) [41, 42]. The reaction took also place in the presence of Pd 2 (dba) 3 /dppf as the catalyst. The P–C coupling was extended to the phosphorylation of borane complexes [43-46]. In this case, inorganic bases, such as K 2 CO 3 , Ag 2 CO 3 and K 3 PO 4 were applied instead of amines along with acetonitrile, or toluene as the solvent (Scheme 5). The Hirao reaction was applied successfully for the coupling of different cyclic P-reagents, such as 2213-347X/15 $58.00+.00 © 2015 Bentham Science Publishers