(Methylcarboxymethylene)tripropylphosphorane: A Stabilized Ylide for Rapid Formation of Methyl Vinyl Ketones and Applications in Medicinal Chemistry and Natural Product Synthesis

Abstract

The synthesis of (methylcarboxymethylene)tripropylphosphorane, a new air-, water- and light-stable phosphonium ylide for the rapid formation of methyl vinyl ketones from various aldehyde starting materials is reported. This stabilized ylide provides high reaction yields and an excellent degree of E/Z stereoselectivity (>20:1). Furthermore, removal of phosphine oxide is accomplished during aqueous work-up, thus bypassing the need for column chromatography. The versatility of this ylide is demonstrated by the synthesis of methyl vinyl ketones from aryl as well as sensitive enolizable and functionalized aliphatic aldehydes, along with applications of these in the synthesis of olivetol, olivetolic acid, hygroline, and hygrine.

Key words

Wittig reactions - olefination - stabilized ylides - enones - methyl vinyl ketone - polyketides - alkaloids

Publikationsverlauf

Eingereicht: 21. Februar 2025

Angenommen nach Revision: 14. Juli 2025

Accepted Manuscript online:
14. Juli 2025

Artikel online veröffentlicht:
28. Juli 2025

• References and Notes

• 1 Zu L, Xie H, Li H, Wang J, Wang W. Adv. Synth. Catal. 2007; 349: 2660
• 2 Ji L, Ma Y, Li J, Zhang L, Zhang L. Tetrahedron Lett. 2009; 50: 6166
• 3 Szanto G, Hegedus V, Mattyasovszky L, Simon A, Simon A, Bitter I, Toth G, Toke L, Kadas I. Tetrahedron 2009; 65: 8412
• 4 Guo L.-D, Huang X.-Z, Luo S.-P, Cao W.-S, Ruan Y.-P, Ye J.-L, Huang P.-Q. Angew. Chem. Int. Ed. 2016; 55: 4064 ; Angew. Chem., 2016, 128, 4132
• 5 Gu X, Dai Y, Guo T, Franchino A, Dixon DJ, Ye J. Org. Lett. 2016; 17: 1505
• 6 Liu S, Wang Q, Ye L, Shi Z, Zhao Z, Yang X, Ding K, Li X. Tetrahedron 2016; 72: 5120
• 7 Focella A, Teitel S, Brossi A. J. Org. Chem. 1977; 42: 3456
• 8 Procopio A, De Nino A, Nardi M, Oliverio M, Paonessa R, Pasceria R. Synlett 2010; 1849
• 9 Chen W, Du W, Yue L, Li R, Wu Y, Ding L.-S, Chen Y.-C. Org. Biomol. Chem. 2007; 5: 816
• 10 Lin A, Wang J, Mao H, Ge H, Tan R, Zhu C, Cheng Y. Org. Lett. 2011; 13: 4176
• 11 Lu X, Deng L. Angew. Chem. Int. Ed. 2008; 47: 7710
• 12 Reisinger CM, Wang X, List B. Angew. Chem. Int. Ed. 2008; 47: 8112
• 13 Ricci P, Carlone A, Bartoli G, Bosco M, Sambri L, Melchiorre P. Adv. Synth. Catal. 2008; 350: 49
• 14 Vamisetti GB, Chowdhury R, Kumar M, Ghosh SK. Tetrahedron: Asymmetry 2017; 28: 317
• 15 Thayumanavan R, Dhevalapally B, Sakthivel K, Tanaka F, Barbas CF. III. Tetrahedron Lett. 2002; 43: 3817
• 16 Wu L.-Y, Bencivenni G, Mancinelli M, Mazzanti A, Bartoli G, Melchiorre P. Angew. Chem. Int. Ed. 2009; 48: 7196 ; Angew. Chem., 2009, 121, 7332
• 17 Horvath KL, Newton CG, Roper KA, Ward JS, Sherburn MS. Chem. Eur. J. 2019; 25: 4072
• 18 Rapson WS, Robinson R. J. Chem. Soc. 1935; 1285
• 19 Weiland P, Miescher K. Helv. Chim. Acta 1950; 33: 2215
• 20 Ramachandran S, Newman MS. Org. Synth. 1961; 41: 38
• 21 Eder U, Sauer G, Wiechert R. Angew. Chem. Int. Ed. 1971; 10: 486
• 22a Hajos ZG, Parrish DR. DE 2102623, 1971
• 22b Hajos ZG, Parrish DR. US 3975440, 1976 (see Example 21).
• 23 Zhou P, Zhang L, Luo S, Cheng J.-P. J. Org. Chem. 2012; 77: 2526
• 24 Vetica F, Pandolfi F, Pettazzoni L, Leonelli F, Bortolami M. Symmetry 2022; 14: 355
• 25 Gallier F, Martel A, Dujardin G. Angew. Chem. Int. Ed. 2017; 56: 12424
• 26 Li P, Payette JN, Yamamoto H. J. Am. Chem. Soc. 2007; 129: 9534
• 27 Nicolaou KC, Li A, Edmonds DJ. Angew. Chem. Int. Ed. 2006; 45: 7086
• 28 Dzierba CD, Zandi KS, Mollers T, Shea KJ. J. Am. Chem. Soc. 1996; 118: 4711
• 29 Danishefsky SJ, Masters JJ, Young WB, Link JT, Snyder LB, Magee TV, Jung DK, Isaacs RC. A, Bornmann WG, Alaimo CA, Coburn CA, Di Grandi MJ. J. Am. Chem. Soc. 1996; 118: 2843
• 30 Marques-Lopez E, Herrera RP, Christmann M. Nat. Prod. Rep. 2010; 27: 1138
• 31 Moyano A, Rios R. Chem. Rev. 2011; 111: 4703
• 32 Melchiorre P. Angew. Chem. Int. Ed. 2012; 51: 9748
• 33 Michaelis A, Kohler E. Chem. Ber. 1898; 1566
• 34 Ramirez F, Dershowitz S. J. Am. Chem. Soc. 1957; 79: 41
• 35 El-Batta A, Jiang C, Zhao W, Anness R, Cooksy AL, Bergdahl M. J. Org. Chem. 2007; 72: 5244
• 36 McNulty J, Das P, Gosciniak D. Tetrahedron Lett. 2008; 49: 281
• 37 McNulty J, Das P. Tetrahedron 2009; 65: 7794
• 38 McNulty J, Zepeda-Velazquez C, McLeod D. Green Chem. 2013; 15: 3146
• 39 McLeod D, McNulty J. R. Soc. Open Sci. 2016; 3: 160374
• 40 McNulty J, Zepeda-Velazquez C. Angew. Chem. Int. Ed. 2014; 53: 8450
• 41 McNulty J, McLeod D, Jenkins HA. Eur. J. Org. Chem. 2016; 688
• 42 Nielsen AJ, Jenkins HA, McNulty J. Chem. Eur. J. 2016; 22: 9111
• 43 Revu O, Zepeda-Velazquez C, Nielsen AJ, McNulty J, Yolken RH, Jones-Bando L. ChemistrySelect 2016; 1: 5895
• 44 McNulty J, McLeod D. Eur. J. Org. Chem. 2017; 29
• 45 McNulty J, D’Aiuto L, Zhi Y, McClain L, Zepeda-Velázquez C, Ler S, Jenkins HA, Yee MB, Piazza P, Yolken RH, Kinchington PR, Nimgaonkar VL. ACS Med. Chem. Lett.. 2016; 7: 46
• 46 McNulty J, Babu-Dokuburra C, Scattolon J, Zepeda-Velazquez C, Wesesky MA, Caldwell JK, Zheng W, Milosevic J, Kinchington PR, Bloom DC, Nimgaonkar VL, D’Aiuto L. Sci. Rep. 2023; 13: 1639
• 47a McNulty J, Das P. Eur. J. Org. Chem. 2009; 4031
• 47b McNulty J, McLeod D. Tetrahedron Lett. 2013; 54: 6303
• 47c Calzavara J, McNulty J. Tetrahedron Lett. 2011; 52: 5672
• 47d McNulty J, Das P, McLeod D. Chem. Eur. J. 2010; 16: 6756
• 47e McNulty J, McLeod D. Tetrahedron Lett. 2011; 52: 5467
• 47f McNulty J, Das P. Tetrahedron Lett. 2009; 50: 5737
• 47g Das P, McNulty J. Tetrahedron Lett. 2010; 51: 3197
• 47h McNulty J, McLeod D. Chem. Eur. J. 2011; 17: 8794
• 47i Das P, McLeod D, McNulty J. Tetrahedron Lett. 2011; 52: 199
• 48 Narayanappa A, Hurem D, McNulty J. Synlett 2017; 28: 2961
• 49 Hurem D, McNulty J. Phosphorus Reagents for Two-, Three-, and Four-Carbon Homologation of Carbonyl Compounds to Functionalized Olefins. In Homologation Reactions: Reagents, Applications, and Mechanisms. Pace V. Wiley-VCH; Weinheim: 2023: 401-427
• 50 2-(Oxopropyl)tripropylphosphonium Chloride (4b) To an oven-dried two-neck flask charged with tripropylphosphine (4.0 mL, 20 mmol) in dry diethyl ether (10 mL) was added chloroacetone (1.7 mL, 21 mmol) dropwise over 15 min under nitrogen at 0 °C. Upon addition of chloroacetone, the mixture was stirred at 0 °C for an additional 15 min. The flask was then removed from the ice-bath and allowed to slowly warm to room temperature while stirring over 1 h. The obtained white precipitate was carefully washed with dry diethyl ether by decantation (5 × 10 mL). The volatiles were removed under a stream of nitrogen, and then under reduced pressure (~0.1 mmHg) to give 4b as a crystalline white solid (4.35 g, 86%). Mp 57–59 °C (CH₂Cl₂). ¹H NMR (600 MHz, CDCl₃): δ = 4.64 (d, J = 12.2 Hz, 2 H), 2.34–2.29 (m, 9H), 1.58–1.47 (m, 6 H), 0.98 (t, J = 7.3 Hz, 9 H). ¹³C NMR DEPTQ (151 MHz, CDCl₃): δ = 202.35, 202.30, 35.48, 35.13, 32.08, 32.04, 21.70, 21.39, 15.77, 15.74, 15.53, 15.42. ³¹P NMR (243 MHz, CDCl₃): δ = 29.47. HRMS (ESI): m/z [M]⁺ calcd for C₁₂H₂₆OP: 217.1716; found: 217.1715.
• 51 (Methylcarboxymethylene)tripropylphosphorane (3b) To a flask charged with 4b (4.05 g, 16.0 mmol) was added water (3 mL) and CH₂Cl₂ (2 mL) and the mixture was stirred until all the solid had dissolved. To the colorless mixture was added 1 M NaOH solution (10 mL, 20 mmol) and the mixture was stirred at room temperature over 0.5 h. The mixture was extracted into CH₂Cl₂ (4 × 10 mL). The combined organic extract was washed with brine (10 mL), dried with sodium sulfate and the solvent was removed under reduced pressure to give the title compound as a white solid (3.29 g, 95%). Mp 57–59 °C (CH₂Cl₂). ¹H NMR (600 MHz, CDCl₃): δ = 2.87 (d, J = 23.8 Hz, 1 H), 1.84–1.76 (m, 9 H), 1.45–1.35 (m, 6 H), 0.93 (td, J = 7.3, 0.9 Hz, 9 H). ¹³C NMR DEPTQ (151 MHz, CDCl₃): δ = 190.28, 49.06, 48.39, 28.17, 28.07, 24.10, 23.74, 15.81, 15.79, 15.63, 15.53. ³¹P NMR (243 MHz, CDCl₃): δ = 16.51. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₂₆OP: 217.1716; found: 217.1718.
• 52 Direct Homologation Procedure To a vial charged with phosphorane 3b (1.2 equiv) in diethyl ether was added the corresponding aldehyde 2 (1.0 equiv, 1.0 mmol/mL). The solution was stirred at room temperature until the disappearance of aldehyde was observed by TLC. The mixture was then diluted with diethyl ether (2 mL) and the solution was extracted with 1% aq HCl (4 × 1 mL), water (1 mL), and then brine (1 mL). The organic solution was dried (MgSO₄), concentrated and trace solvent was removed under reduced pressure (~1 mmHg) to afford the target compound as described in Table 1.
• 53 (E)-4-(4-Chlorophenyl)-3-buten-2-one (1a) Following the direct homologation procedure, the phosphorane 3b (83.8 mg, 0.397 mmol) was reacted with 4-chlorobenzaldehyde (2a) (46.5 mg, 0.331 mmol) over 2 h. The product 1a was isolated as a white solid (52.0 mg, 87%, E/Z > 20:1). Mp 51–52 °C (Et₂O). ¹H NMR (600 MHz, CDCl₃): δ = 7.43 (m, 3 H), 7.34–7.30 (m, 2 H), 6.64 (d, J = 16.25 Hz, 1 H), 2.35–2.33 (m, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 198.1, 141.9, 136.4, 132.9, 129.4, 127.5, 27.7. See Ref. 60a.
• 54 (E)-3-Nonen-2-one (1h) Following the direct homologation procedure, the phosphorane 3b (83.8 mg, 0.397 mmol) was reacted with hexanal (2h) (39 μL, 0.324 mmol) over 2 h. The product 1h was isolated as a colorless oil (41.4 mg, 91%, E/Z > 20:1). ¹H NMR (600 MHz, CDCl₃): δ = 6.78 (dt, J = 15.9, 6.9 Hz, 1 H), 6.04 (dt, J = 15.9, 1.4 Hz, 1 H), 2.21 (s, 3 H), 2.21–2.17 (m, 2 H), 1.47–1.41 (m, 2 H), 1.32–1.26 (m, 4 H), 0.87 (t, J = 7.0 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 198.69, 148.60, 131.26, 32.40, 31.32, 27.74, 26.78, 22.39, 13.91. See Ref. 60b.
• 55a Hurem D, MacPhail BJ, Carlini R, Lewis J, McNulty J. SynOpen 2021; 5: 86
• 55b Cascio MG, Bisogno T, Palazzo E, Thomas A, van der Stelt M, Brizzi A, de Novellis V, Marabese I, Ross R, van de Doelen T, Brizzi V, Pertwee R, Maione S, Di Marzo V. Br. J. Pharmacol. 2006; 149: 431
• 55c Carberry JJ. WO 2017/091755 A1, 2017
• 56a McNulty J, Hurem D. Curr. Org. Chem. 2023; 27: 645
• 56b Adams R, Loewe S, Jelinek C, Wolff H. J. Am. Chem. Soc. 1941; 63: 1971
• 56c Welling MT, Liu L, Raymond CU, Ansari O, King GJ. Front. Plant Sci. 2018; 9: 1510
• 56d Citti C, Linciano P, Russo F, Luongo L, Iannotta M, Maione S, Lagana A, Caprioti AL, Forni F, Vandelli MA, Gigli G, Cannazza G. Sci. Rep. 2019; 9: 20335
• 56e Linciano P, Citti C, Luongo L, Belardo C, Maione S, Vandelli MA, Forni F, Gigli G, Lagana A, Montone CM, Cannazza G. J. Nat. Prod. 2020; 83: 88
• 56f For a summary of developing drug candidates containing modified side chains, see: Erickson BE. Chem. Eng. News 2020; 98: 16
• 56g Anderson LL, Low IK, Banister SD, McGregor IS, Arnold JC. J. Nat. Prod. 2019; 82: 3047
• 57a Kim JH, Hart HT, Stevens JF. Phytochemistry 1996; 41: 1319
• 57b Todd FG, Stermitz FR, Schultheis P, Knight AP, Traub-Dargatz J. Phytochemistry 1995; 39: 303
• 57c Cretton S, Munoz O, Tapia J, Marcourt L, Maes L, Christen P. Nat. Prod. Commun. 2017; 12: 355
• 57d Petri GL, Ralmondi MV, Spano V, Holl R, Barraja P, Montalbano A. Top. Curr. Chem. 2021; 379: 34
• 57e Cretton S, Genta-Jouve G, Kaiser M, Maser P, Munoz O, Burgi T, Cuendet M, Christen P. Phytochemistry 2021; 192: 112957
• 58a Celis S, Gorrea E, Nolis P, Illa O, Ortuño RM. Org. Biomol. Chem. 2012; 10: 861
• 58b Kane BE, Grant MK.O, El-Fakahany EE, Ferguson DM. Bioorg. Med. Chem. 2008; 16: 1376
• 58c Zhao T, Kurpiewska K, Kalinowska-Tłuścik J, Herdtweck E, Dömling A. Chem. Eur. J. 2016; 22: 3009
• 59a Davies SG, Fletcher AM, Roberts PM, Smith AD. Tetrahedron 2009; 65: 10192
• 59b Liniger M, Estermann K, Altmann KH. J. Org. Chem. 2013; 78: 11066
• 59c Bhat C, Tilve SG. Tetrahedron 2013; 69: 6129
• 59d Arѐvalo-Garcίa EB, Colmenares JC. Q. Tetrahedron 2008; 49: 3995
• 60a Brethome AV, Paton RS, Fletcher SP. ACS Catal. 2019; 9: 7179
• 60b Kourouli T, Kefalas P, Ragoussia N, Ragoussis V. J. Org. Chem. 2002; 67: 4615