Synthesis of Allenyl Esters by Horner–Wadsworth–Emmons-Type Reactions of Methyl 2-[Bis(benzylthio)phosphoryl]acetate and Ketenes Using Grignard Reagents

Abstract

Methyl 2-[bis(benzylthio)phosphoryl]acetate and its analogues have proven to be efficient Horner–Wadsworth–Emmons (HWE)-type reagents for synthesizing conjugated allenyl esters and their analogues through reactions with disubstituted ketenes using Grignard reagents. A series of HWE-type reagents containing the bis(benzylthio)phosphoryl group showed better reactivity than the corresponding HWE reagents, where two phosphorus–sulfur bonds were substituted with phosphorus–oxygen bonds.

Keywords

Horner–Wadsworth–Emmons reagents - Phosphorus–sulfur bond - Conjugated allenyl esters - Ketenes - Allenes - Grignard reagents - Olefination

Publikationsverlauf

Eingereicht: 20. Mai 2025

Angenommen nach Revision: 08. August 2025

Accepted Manuscript online:
11. August 2025

Artikel online veröffentlicht:
03. September 2025

• References

• 1a Bisceglia JÁ, Orelli LR. Curr Org Chem 2012; 16: 2206
• 1b Jasem YA, El-Esawi R, Thiemann T. J Chem Res 2014; 38: 453
• 1c Bisceglia JÁ, Orelli LR. Curr Org Chem 2015; 19: 744
• 1d Kobayashi K, Tanaka III K, Kogen H. Tetrahedron Lett 2018; 59: 568
• 1e Roman D, Sauer M, Beemelmanns C. Synthesis 2021; 53: 2713
• 1f Bilska-Markowska M, Kaźmierczak M. Org Biomol Chem 2023; 21: 1095
• 1g Babar J, Ahmad S, Parveen B. et al. Top Curr Chem 2025; 383: 20
• 2a Runge W, Kresze G. Liebigs Ann Chem 1975; 1361
• 2b Tanaka K, Otsubo K, Fuji K. Tetrahedron Lett 1996; 37: 3735
• 2c Yamazaki J, Watanabe T, Tanaka K. Tetrahedron-Asymmetry 2001; 12: 669
• 2d Nagaoka Y, Inoue H, Tomioka K. Phosphorus Sulfur Silicon Relat Elem 1843; 2002: 177
• 2e Inoue H, Tsubouchi H, Nagaoka Y, Tomioka K. Tetrahedron 2002; 58: 83
• 2f Huang X, Xiong Z-C. Chem Commun 2003; 1714
• 2g Plunkett S, Dahms K, Senge MO. Eur J Org Chem 2013; 1566

For some syntheses of conjugated allenyl esters, see:
• 3a Nagao Y, Kim K, Sano S. et al. Tetrahedron Lett 1996; 37: 861
• 3b Lepore SD, He Y, Damisse P. J Org Chem 2004; 69: 9171
• 3c Sano S, Shimizu H, Nagao Y. Tetrahedron Lett 2005; 46: 2883
• 3d Sano S, Shimizu H, Kim K, Lee WS, Shiro M, Nagao Y. Chem Pharm Bull 2006; 54: 196
• 3e Maity P, Lepore SD. J Org Chem 2009; 74: 158
• 3f Neff RK, Frantz DE. ACS Catal 2014; 4: 519
• 4 Sano S, Matsumoto T, Toguchi M, Nakao M. Synlett 2018; 29: 1461
• 5a Still WC, Gennari C. Tetrahedron Lett 1983; 24: 4405
• 5b Messik F, Oberthür M. Synthesis 2013; 45: 167
• 5c Molnár K, Takács L, Kádár M, Kardos Z, Faigl F. Synthesis 2015; 47: 1085
• 5d Janicki I, Kiełbasiński P. Adv Synth Catal 2020; 362: 2552
• 5e Janicki I, Kiełbasiński P. Synthesis 2022; 54: 378
• 5f Janicki I, Kiełbasiński P. Molecules 2022; 27: 7138
• 5g Janicki I. J Org Chem 2025; 90: 5725
• 6 Sano S, Matsumoto T, Yano T, Toguchi M, Nakao M. Synlett 2015; 26: 2135
• 7a Pinho e Melo TMVD, Cardoso AL, d’A. Rocha Gonsalves AM, Costa Pessoa J, Paixão JA, Beja AM. Eur J Org Chem. 2004: 4830
• 7b Li C-Y, Zhu B-H, Ye L-W. et al. Tetrahedron 2007; 63: 8046
• 7c Allen AD, Tidwell TT. Chem Rev 2013; 113: 7287
• 7d Radhoff N, Studer A. Nat Commun 2022; 13: 3083
• 8a Sano S, Yamada S, Ihara T, Seki K, Kitaike S, Nakao M. Synlett 2025; 36: 546
• 8b Nakao M, Okamoto M, Isetani S, Imai A, Kitaike S, Sano S. SynOpen 2025; 9: 131
• 9 Preparation of Methyl 4-Phenylpenta-2,3-dienoate (4a): To a solution of methyl 2-[bis(benzylthio)phosphoryl]acetate (2) (65.7 mg, 0.179 mmol) in anhydrous THF (1.5 mL) was added i-PrMgBr (0.67 mol/L in THF, 294 μL, 0.197 mmol), and the solution was stirred at 0 °C for 10 min under argon. After adding triethylamine (100 μL, 0.717 mmol) and 2-phenylpropionyl chloride (3a) (53.1 μL, 0.359 mmol), the mixture was stirred at 0 °C for 10 min under argon. The reaction mixture was quenched with sat. aq NH₄Cl (4 mL) and then extracted with CHCl₃ (20 mL x 3). The extract was dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The oily residue was purified by flash column chromatography [Silica Gel PSQ 60B (Fuji Silysia Chemical): n-hexane–EtOAc (20:1)] to afford 4a (33.5 mg, 99%) as a yellow oil. IR (neat): 2951, 1948, 1721, 1495, 1437, 1392, 1263, 1210, 1152, 1028 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.41–7.33 (m, 4 H), 7.29–7.25 (m, 1 H), 5.90 (q, J = 2.9 Hz, 1 H), 3.75 (s, 3 H), 2.21 (d, J = 2.9 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 214.0, 166.1, 134.2, 128.6, 127.9, 126.2, 105.4, 89.5, 52.0, 16.2. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₁₂O₂Na: 211.0735; found: 211.0736
• 10 Ao Y-F, Wang D-X, Zhao L, Wang M-X. J Org Chem 2014; 79: 3103
• 11 Isopropyl 2-phenylpropanoate was prepared from acid chloride 3a and isopropanol in the presence of triethylamine, and the chemical structure of the by-product was confirmed to have the same chemical structure through comparison of the ¹H NMR spectrum.
• 12 Mitchell AG, Nicholls D, Walker I, Irwin WJ, Freeman S. J Chem Soc Perkin Trans 2 1991; 1297

For allenyl ketones, see:
• 13a Chen L, Wang J, Lin C, Zhu Y, Du D. Org Lett 2022; 24: 7047
• 13b Xia J, Ma R, Wang L, Sun J, Zheng G, Zhang Q. Org Chem Front 2024; 11: 3089
• 13c Teng B-H, Kuai C-S, Zhao Y, Wu X-F. Tetrahedron 2024; 157: 133965

For allenyl amides, see:
• 14 Wang J, Zheng W-F, Li Y, Guo Y-L, Quian H, Ma S. Org Chem Front 2024; 11: 2477

For allenylphosphonates, see:
• 15a Kalek M, Stawinski J. Adv Synth Catal 2011; 353: 1741
• 15b Guo L, Zhao W, Li M, Dong S, Gong J, Chen S. Appl Organomet Chem 2019; 33: e5003