Development of a Novel Horner–Wadsworth–Emmons Reagent for the Facile Preparation of Mixed Phosphonoacetates

Abstract

A novel Horner–Wadsworth–Emmons (HWE) reagent, methyl 2-[bis(3,4,5-trifluorophenoxy)phosphoryl]acetate, was synthesized by the reaction of methyl 2-(dichlorophosphoryl)acetate and 3,4,5-trifluorophenol. Sequential alcoholysis of this HWE reagent with isopropyl alcohol and benzyl alcohol on the phosphorus atom afforded the mixed phosphonoacetate, methyl 2-[(benzyloxy)(isopropoxy)phosphoryl]acetate, in 89% yield for the two steps.

Key words

Horner–Wadsworth–Emmons reagents - methyl 2-[bis(3,4,5-trifluorophenoxy)phosphoryl]acetate - alcoholysis - fluorophenols - mixed phosphonoacetates - phosphorus–sulfur bonds - phosphonothioate

• References

• 1a Bisceglia J. Á, Orelli LR. Curr. Org. Chem. 2012; 16: 2206
• 1b Jasem YA, El-Esawi R, Thiemann T. J. Chem. Res. 2014; 38: 453
• 1c Bisceglia J. Á, Orelli LR. Curr. Org. Chem. 2015; 19: 744
• 1d Kobayashi K, Tanaka KIII, Kogen H. Tetrahedron Lett. 2018; 59: 568
• 1e Janicki I, Kiełbasiński P. Adv. Synth. Catal. 2020; 362: 2552
• 1f Roman D, Sauer M, Beemelmanns C. Synthesis 2021; 53: 2713
• 1g Bilska-Markowska M, Kaźmierczak M. Org. Biomol. Chem. 2023; 21: 1095
• 2 Angelastro A, Barkhanskiy A, Journeaux T, Sivapalan R, King TA, Rodríguez Pérez L, Goundry WR. F, Barran P, Flitsch SL. Nat. Synth. 2024; 3: 976
• 3 Motoyoshiya J, Kusaura T, Kokin K, Yokoya S, Takaguchi Y, Narita S, Aoyama H. Tetrahedron 2001; 57: 1715
• 4a Sano S, Kujime E, Takemoto Y, Shiro M, Nagao Y. Chem. Pharm. Bull. 2005; 53: 131
• 4b Sano S, Kujime E, Tanaka H, Kitaike S, Nakao M. Chem. Data Collect. 2016; 5/6: 12
• 5a Sano S, Sumiyoshi H, Handa A, Tokizane R, Nakao M. Tetrahedron Lett. 2015; 56: 4686
• 5b Nakao M, Tanaka K, Kitaike S, Sano S. Synthesis 2017; 49: 3654
• 6a Molnár K, Takács L, Kádár M, Kardos Z, Faigl F. Synthesis 2015; 47: 1085
• 6b Janicki I, Kiełbasiński P. Synthesis 2022; 54: 378
• 7a Kokin K, Motoyoshiya J, Hayashi S, Aoyama H. Synth. Commun. 1997; 27: 2387
• 7b Kokin K, Iitake K, Takaguchi Y, Aoyama H, Hayashi S, Motoyoshiya J. Phosphorus, Sulfur Silicon Relat. Elem. 1998; 133: 21
• 7c Motoyoshiya J. Trends Org. Chem. 1998; 7: 63
• 8a Jones DJ, O’Leary EM, O’Sullivan TP. Tetrahedron Lett. 2018; 59: 4279
• 8b Kostov O, Liboska R, Páv O, Novák P, Rosenberg I. Molecules 2019; 24: 1872
• 8c Jones DJ, O’Leary EM, O’Sullivan TP. Adv. Synth. Catal. 2020; 362: 1825
• 8d Jones DJ, O’Leary EM, O’Sullivan TP. Adv. Synth. Catal. 2020; 362: 2801
• 9 Sano S, Matsumoto T, Toguchi M, Nakao M. Synlett 2018; 29: 1461
• 10 Sano S, Takemoto Y, Nagao Y. ARKIVOC 2003; (viii): 93
• 11 Sano S, Yamada S, Ihara T, Seki K, Kitaike S, Nakao M. Synlett 2025; 36: 546
• 12 Mino T, Shibuya M, Suzuki S, Hirai K, Sakamoto M, Fujita T. Tetrahedron 2012; 68: 429
• 13 Shang W, Duan D, Liu Y, Lv J. Org. Lett. 2019; 21: 8013