Copper‐Catalyzed Synthesis of α‐Hydroxy Phosphonates from H‐Phosphonates and Alcohols or Ethers

Abstract

a-Hydroxy phosphonates have attracted considerable attention owing to their critical roles in anticancer drugs, plant growth regulators, and enzyme inhibitors. [1] The traditional way to synthesize a-hydroxy phosphonates is an addition reaction of monobasic phosphorus (the Pudovik reaction) or odorous trialkyl phosphite (the Abramov reaction) to an aldehyde or ketone. [2] Moreover, the reactions based on phosphonate derivatives such as oxidation of alkyl phosphonates [3] or reduction or addition of keto phosphonates [4] have also been found to be effective methods to form a-hydroxy phosphonates. Recently, great efforts have been made to develop metal-catalytic [5] or metal-free [6] syntheses of ahydroxy phosphonates involving the condensation of Hphosphonates with carbonyls.Catalytic functionalization of alcohols and ethers have garnered much interest owing to the ease of generating carbon-carbon [7] and carbon-heteroatom bonds. [8] Typical catalysts for this reaction are Ru, [9] Ir, [10] Pd, [11] Cu, [8a] and Fe [8c, 12] ; furthermore, it has been accomplished under transition-metal-free conditions. [13] Although many heteroatomic (oxygen, nitrogen) nucleophilic reagents are used in the alkylation catalyzed by these complexes, H-phosphonates as the substrates have not been investigated for the preparation of a-hydroxy phosphonates.Herein, we present a facile method for the phosphonation of alcohols or ethers catalyzed by CuCl 2 /TBHP (tert-butyl hydroperoxide) with moderate to good yields. Compared with aldehydes, the corresponding alcohols are readily available, highly stable, cheaper, and less toxic. The direct condensation of simple H-phosphonates with alcohols is found to be a more environmentally friendly route than reactions in which aldehydes and trivalent phosphorus compounds are used as reagents.The a-hydroxyphosphonation reaction catalyzed by copper depends greatly on the reaction conditions. The scope and limitation of the reaction is illustrated in Table 1, with benzyl alcohol (1 a) and diisopropyl H-phosphonate (2 a) as selected substrates. The yield of 3 a was determined by 31 P NMR spectroscopy. Treament of 2 a (1.0 mmol, 31 P NMR: d = 7.0 ppm) with 1 a (1.2 mmol) in the presence of CuCl 2 (5 mol %) with TBHP (1.2 mmol) and K 2 CO 3 (0.6 mmol) in 1,2-dichloroethane (DCE) at 80 8C for 24 hours produced diisopropyl a-hydroxybenzyl phosphonate (3 a, 31 P NMR: d = 19.5 ppm) in 80 % yield (Table 1, [a] Z.

Metal‐Free Hydroxyalkylation‐Initiated Radical Cyclization of 1,6‐Enynes with Alcohols

“…Direct α ‐C(sp 3 )−H functionalization of alcohols by oxidative radical reaction leading to the construction of C−C bonds still belongs to a vital and challenging area in modern synthetic chemistry . In this context, a variety of effective α ‐C(sp 3 )−H functionalization of alcohols strategies, including the reaction with alkynes, alkenes, carboxylic acids, phosphonates, vinyl isocyanides and quinoxalin‐2(1 H )‐ones, have been well documented. Among these, the oxidative functionalization of alkenes is of particular synthetic value because of its simple and efficient nature.…”

Recent Advances in H-Phosphonate Chemistry. Part 2. Synthesis of C-Phosphonate Derivatives

“…A new approach to α-hydroxyphosphonates was recently reported [67]. It makes use of alcohols or ethers as starting materials which are oxidized with CuCl 2 /tertbutyl hydroperoxide to form in situ the corresponding carbonyl compounds.…”

Copper-Catalyzed Alkenylation of Alcohols with β-Nitrostyrenes via a Radical Addition–Elimination Process

“…1 Over the past decades, impressive progress has been made in developing this transformation including transition-metal-catalyzed cross-coupling of alcohols with N-heterocycles, 2 alkenes, 3 alkynes, 4 cinnamic acids, 5 and H-phosphonates. 6 In addition, a few metal-free catalytic systems have also been reported. 7 However, this kind of transformation using simple alcohols as reactants still remains a challenge to chemists, and the α-C(sp 3 )-H bond functionalization of alcohols for the formation of allylic alcohol derivatives has not been thoroughly investigated although much progress has been achieved in the field of direct oxidative C(sp 3 )-H bond functionalization.…”

“…Alcohols could be used as ideal alkylation reagents via αhydroxy carbon centered radical mechanism under oxidative conditions. [1][2][3][4][5][6][7] We envisioned that such a radical procedure might be applicable to (E)-β-nitrostyrenes, so we herein present a facile copper-catalyzed radical additionelimination alkenylation of alcohol α-C(sp 3 )-H bond for the first time (Scheme 1, b).…”