Access to Stable Quaternary Phosphiranium Salts by P-Alkylation and P-Arylation of Phosphiranes

Abstract

We report the preparation of phosphiranium salts by quaternarization of phosphiranes, a class of sensitive, highly strained, and poorly nucleophilic cyclic phosphines. High-yielding introduction of a varied set of alkyl groups including methylene ester arms was accomplished under mild conditions. A Cu-catalyzed electrophilic arylation of phosphiranes using diaryl iodonium reagents was also achieved to yield unprecedented P,P-diaryl phosphiranium salts with good efficiency.

Key words

alkylation - arylation - phosphirane - phosphiranium salt - ­alkylating agent - diaryliodonium salt

• References and Notes

• 1 Berchel M, Jaffrès P.-A. In Organophosphorus Chemistry: From Molecules to Applications, 1st ed. Iaroshenko V. Wiley- VCH; Weinheim: 2019: 59-111 ; and references cited therein
• 2a Virieux D, Volle J.-N, Pirat J.-L. In Science of Synthesis, Vol. 42. Mathey F, Trost BM. Thieme; Stuttgart: 2009: 503-594
• 2b Tebby JC, Allen DW. In Science of Synthesis, Vol. 31. Ramsden CA. Thieme; Stuttgart: 2007: 2083-2104
• 2c For the first example of QPS synthesis utilizing phosphine oxides as electrophilic partners and Grignard reagents as nucleophiles, see: Vetter AC, Nikitin K, Gilheany DG. Chem. Commun. 2018; 54: 5843
• 3a Mathey F. Chem. Rev. 1990; 90: 997
• 3b Quin LD. In A Guide to Organophosphorus Chemistry . Quin LD. John Wiley & Sons; New York: 2000: 234
• 3c Mathey F, Regitz M. In Phosphorus-Carbon Heterocyclic Chemistry: The Rise of a New Domain . Mathey F. Elsevier Science; Amsterdam: 2001: 17
• 4 Henderson WA, Buckler SA. J. Am. Chem. Soc. 1960; 82: 5794
• 5a Hockless DC. R, McDonald MA, Pabel M, Wild SB. J. Chem. Soc., Chem. Commun. 1995; 257
• 5b Hockless DC. R, McDonald MA, Pabel M, Wild SB. J. Organomet. Chem. 1997; 529: 189

For another recent example of isolated QPrS, see:
• 5c Ficks A, Martinez-Botella I, Stewart B, Harrington RW, Clegg W, Higham LJ. Chem. Commun. 2011; 47: 8274

For the synthesis of phosphirane substrates, see:
• 6a Mézailles N, Fanwick PE, Kubiak CP. Organometallics 1997; 16: 1526
• 6b Yang F, Fanwick PE, Kubiak CP. Organometallics 1999; 18: 4222
• 7 Partial conversions of phosphirane 1a to the corresponding P-methyl phosphiranium salts were observed after prolonged reaction times using other methylating agents by ³¹P NMR monitoring. Attempts to complete the methylation reactions all failed to give the products in satisfactory yields. Prolonged reaction times and heating were rather found to favor degradation of both substrate 1a and quaternarization products. Results not shown.
• 8 General Procedure for the Preparation of P-Me Phosphiranium Salts 2 (Conditions A or B) To a solution of phosphirane 1 (1.0 equiv) in CH₂Cl₂ (0.5 M) was added methyl trifluoromethanesulfonate or trimethyloxonium tetrafluoroborate (1.0–2.0 equiv) dropwise at room temperature. The mixture was then stirred at room temperature and conversion of the starting material was monitored by ³¹P NMR (approx. 2 h). The reaction mixture was then concentrated under reduced pressure to give the title compounds 2. 1-Mesityl-1-methylphosphiran-1-ium Trifluoromethanesulfonate (2a) Prepared from 1-mesitylphosphirane (1a, 0.84 mmol) using the general procedure with methyl trifluoromethanesulfonate (2.0 equiv). Reaction time: 2 h. The title compound 2a was isolated as a white solid (290 mg, 99% yield). R_f  = 0.40 (CH₂Cl₂/EtOAc = 60:40); mp 58–60 °C. IR (neat): ν = 2941, 1604, 1250, 1031, 940 cm^–1. ¹H NMR (300 MHz, CDCl₃, 20 °C): δ = 6.99 (d, ⁴ J_H–P  = 6.0 Hz, 2 H), 2.74–2.60 (m, 2 H), 2.57 (d, ⁴ J_H–P  = 1.6 Hz, 6 H), 2.26 (s, 3 H), 2.20 (d, ² J_H–P  = 17.8 Hz, 3 H), 2.15–2.03 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃, 20 °C): δ = 146.9 (d, ⁴ J_C–P  = 3.0 Hz, Cq), 144.5 (d, ³ J_C–P  = 11.0 Hz, 2 CH), 130.0 (d, ² J_C–P  = 13.2 Hz, 2 Cq), 120.3 (q, ¹ J_C–F  = 320.2 Hz, Cq), 110.7 (d, ¹ J_C–P  = 93.8 Hz, Cq), 22.0 (d, ³ J_C–P  = 9.1 Hz, 2 CH₃), 21.3 (d, ⁵ J_C–P  = 1.7 Hz, CH₃), 9.3 (d, ¹ J_C–P  = 4.4 Hz, 2 CH₂P), 5.4 (d, ¹ J_C–P  = 50.1 Hz, CH₃P). ³¹P NMR (121 MHz, CDCl₃, 20 °C): δ = –116.1. ¹⁹F NMR (282 MHz, CDCl₃, 20 °C): δ = –78.4. HRMS (ESI): m/z calcd for C₁₂H₁₈P [M]⁺: 193.1146; found: 193.1144.
• 9 The ³¹P NMR spectrum shows a single peak at –116.4 ppm for 2a, while the methyl group on P appears as a doublet at 2.20 ppm (² J_P–H  = 17.8 Hz) in the ¹H NMR spectrum. In comparison, the acyclic phosphonium analogue of 2a gives a signal at +21.2 ppm in the ³¹P NMR spectrum, see: Sattler A, Parkin G. Chem. Commun. 2011; 47: 12828
• 10 Similarly, phosphiranes give the most upfield ³¹P NMR signals known for tertiary phosphines. As a representative example, our model phosphirane 1a gives a signal at –240.4 ppm in the ³¹P NMR spectrum.
• 11a The stereochemistry anti and syn refers to the relative position of the substituent on the ring carbon to the mesityl substituent at phosphorus. The reaction was performed from a diastereosiomeric mixture of syn- and anti-1-mesityl-2-methylphosphirane (1d).
• 11b The reaction was performed from the racemic trans-1-mesityl-2,3-dimethylphosphirane (1e).
• 12a Stereochemistry of the products 2d and 2e are proposed by analogy and in accordance with Gaspar and co-workers’ work who described the stereoselective synthesis of the parent phosphiranes 1d and 1e, see: Li X, Robinson KD, Gaspar PP. J. Org. Chem. 1996; 61: 7702
• 12b It is worth noting that due to instability issues, which differ from one diastereomer to another in both the phosphirane and the phosphiranium series, significant variations in the dr values of the isolated products may be observed.

It should be noted that due to their increased instability:
• 13a HRMS and IR data are missing from the characterization of phosphiranium 2d.
• 13b neither determination of a reliable chemical yield nor full characterization of the quaternarization product 2e could be done.
• 14 Isolation of both allyl and benzyl triflate could not be realized. Therefore, in situ formation of the triflate reagents and direct addition of the reaction mixture onto a dichloromethane solution of phosphirane 1a at –30 °C was realized. For a similar procedure involving formation and direct use of allyl triflate, see: Corey EJ, Helal CJ. Tetrahedron Lett. 1996; 37: 5675
• 15 General Procedure for the Preparation of P-Alkyl Phosphiranium Triflate 3 (Conditions C) To a solution of diisopropylethylamine (1.2 equiv) and the corresponding alkyl alcohol (1.2 equiv) in dry CH₂Cl₂ (0.6 M) at –30 °C was added dropwise trifluoromethanesulfonic anhydride (1.2 equiv) under argon atmosphere. The reaction mixture was successively stirred 10 min at –30 °C, warmed to 0 °C, and stirred for 10 min. The reaction mixture was again cooled to –30 °C. Then, dry Et₂O was added to precipitate the ammonium salts. After decantation, the supernatant solution was added dropwise to a solution of phosphirane 1 (1 equiv) in dry CH₂Cl₂ (1 M) at –50 °C. The reaction mixture was then allowed to warm to room temperature over a period of 4 h, and stirring was pursued at room temperature. Conversion of the starting material was monitored by ³¹P NMR spectroscopy. Evaporation of the solvent under reduced pressure then afforded the title product 3. 1-Allyl-1-mesitylphosphiranium Trifluoromethanesulfonate (3a) Prepared from 1-mesitylphosphirane (1a, 0.84 mmol) using the general procedure with allyl alcohol (1.2 equiv). Reaction time: 4 h. The title compound 3a was isolated as a thick colorless oil (350 mg, 95% crude yield). R_f  = 0.15 (EtOAc). IR (neat): ν = 2944, 1605, 1250, 1153, 1025, 940 cm^–1. ¹H NMR (300 MHz, CDCl₃, 20 °C): δ = 7.03 (d, ⁴ J_H–P  = 5.7 Hz, 2 H), 5.70 (m, 1 H), 5.55–5.39 (m, 2 H), 3.41 (dd, ² J_H–P  = 18.7 Hz and ³ J_H–H  = 7.6 Hz, 2 H), 2.78–2.68 (m, 2 H), 2.58 (br s, 6 H), 2.31 (s, 3 H), 2.20–2.10 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃, 20 °C): δ = 147.3 (d, ⁴ J_C–P  = 3.2 Hz, Cq), 145.2 (d, ³ J_C–P  = 10.8 Hz, 2 CH), 130.2 (d, ² J_C–P  = 13.3 Hz, 2 Cq), 125.3 (d, ³ J_C–P  = 16.2 Hz, CH₂), 123.5 (d, ² J_C–P  = 14.0 Hz, CH), 120.3 (q, ¹ J_C–F  = 319.6 Hz, CF₃), 109.3 (d, ¹ J_C–P  = 86.1 Hz, Cq), 25.8 (d, ¹ J_C–P  = 42.6 Hz, CH₂P), 22.5 (d, ³ J_C–P  = 7.9 Hz, 2 CH₃), 21.5 (d, ⁵ J_C–P  = 1.2 Hz, CH₃), 9.0 (m, 2 CH₂P). ³¹P NMR (121 MHz, CDCl₃, 20 °C): δ = –114.1. ¹⁹F NMR (282 MHz, CDCl₃, 20 °C): δ = –78.5. HRMS (ESI): m/z calcd for C₁₄H₂₀P [M]⁺: 219.1303; found: 219.1298.
• 16 Crude yield estimated from ¹H NMR analysis of the crude mixture.
• 17 Formation of P-ethyl phosphiranium triflate 3c as a major product was observed by monitoring progress of the quaternarization reaction starting from phosphirane 1a by ¹H NMR and ³¹P NMR spectroscopy. The ³¹P NMR spectrum shows a single peak at δ = –109.6 ppm for 3c, while the ethyl group on P appears as a dt at δ = 1.42 ppm (3 H, ³ J_P–H  = 27.0 Hz and ³ J_H–H  = 7.6 Hz) and a multiplet at δ = 2.50–2.25 ppm (2 H) in the ¹H NMR ­spectrum.
• 18 General procedure for the preparation of P-methylene ester phosphiranium triflates 5: a) Triflate Reagents Formation: To a solution of the corresponding glycolic ester (1 equiv) and pyridine (1.3 equiv) in CH₂Cl₂ (0.25 M) at –10 °C, was added triflic anhydride (1.15 equiv) dropwise, under argon atmosphere. Reaction was stirred 1 h at –10 °C and 3.5 h at room temperature. Degassed water (0.2 M) was next added to the reaction mixture. After decantation, the aqueous layer was extracted with CH₂Cl₂ (3 × 5 mL/mmol). The combined organic layers were then combined, dried over MgSO₄, filtered, and concentrated under vacuum to give the corresponding triflate reagents 4.b) Alkylation of Phosphirane 1: To a solution of phosphirane (1 equiv) in MeCN (0.2 M) was added the corresponding triflate reagent 4 (1 equiv). The reaction mixture was then stirred at room temperature under argon atmosphere until complete conversion of phosphirane 1 (³¹P NMR monitoring, approx. 24 h). The solvent was then removed under vacuum to give the crude methylene ester phosphiranium salts 5. 1-Mesityl-1-(2-ethoxy-2-oxoethyl)phosphiran-1-ium Trifluoromethanesulfonate (5b) Prepared from 1-mesitylphosphirane (1a, 0.40 mmol) using the general procedure with the triflate reagent derived from ethyl glycolate (1.0 equiv). Reaction time: 24 h. The title compound 5b was isolated as a thick colorless oil (394 mg, 95% crude yield). R_f  = 0.23 (CH₂Cl₂/acetone = 50:50). IR (neat): ν = 2985, 1724, 1606, 1243, 1223, 1156, 1027 cm^–1. ¹H NMR (300 MHz, CDCl₃, 20 °C): δ = 7.09 (d, ⁴J_P–H  = 6.2 Hz, 2 H), 4.19 (q, ³J_H–H  = 7.2 Hz, 2 H), 4.03 (d, ²J_P–H  = 16.8 Hz, 2 H), 3.17–3.07 (m, 2 H), 2.71 (s, 6 H), 2.37 (s, 3 H), 2.28–2.18 (m, 2 H), 1.24 (t, ³J_H–H  = 7.2 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃, 20 °C): δ = 164.6 (d, ²J_P–C  = 5.1 Hz, C=O), 147.7 (d, ⁴J_P–C  = 3.2 Hz, Cq), 145.7 (d, ³J_P–C  = 11.4 Hz, 2 CH), 130.5 (d, ²J_P–C  = 14.0 Hz, 2 Cq), 120.4 (q, ¹J_F–C  = 319.4 Hz, CF₃), 109.1 (d, ¹J_P–C  = 93.0 Hz, Cq), 63.5 (CH₂), 30.0 (d, ¹J_P–C  = 56.2 Hz, CH₂P), 22.4 (d, ³J_P–C  = 8.5 Hz, 2 CH₃), 21.7 (d, ⁵J_P–C  = 1.6 Hz, CH₃), 13.8 (CH₃), 10.3 (d, ¹J_P–C  = 2.7 Hz, 2 CH₂P). ³¹P NMR (121 MHz, CDCl₃, 20 °C): δ = –118.6. ¹⁹F NMR (282 MHz, CDCl₃, 20 °C): δ = –78.5. HRMS (ESI): m/z calcd for C₁₅H₂₂O₂P [M]⁺: 265.1357; found: 265.1360.
• 19 Crude yields are given since purification attempts only led to the decomposition of the products.

For examples of metal-catalyzed arylation of tertiary phosphines, see:
• 20a Ziegler CB. Jr, Heck RF. J. Org. Chem. 1978; 43: 2941
• 20b Marcoux D, Charette AB. J. Org. Chem. 2008; 73: 590
• 20c Marcoux D, Charette AB. Adv. Synth. Catal. 2008; 350: 2967
• 20d Hanamoto T., Kiguchi Y., Shindo K., Matsuoka M., Kondo M.; Chem. Commun.; 1999, 151.

For a photoredox reaction mediated by a Ru-based photosensitizer, see:
• 20e Fearnley AF, An J, Lindovska P, Denton RM. Chem. Commun. 2016; 52: 4987

For examples of metal-free arylation methods, see:
• 21a Wittig G, Matzura H. Angew. Chem., Int. Ed. Engl. 1964; 3: 231
• 21b Rémond E, Tessier A, Leroux FR, Bayardon J, Jugé S. Org. Lett. 2010; 12: 1568
• 21c Huang W, Zhong C.-H. ACS Omega 2019; 4: 6690
• 21d Bugaenko DI, Volkov AA, Livantsov MV, Yurovskaya MA, Karchava AV. Chem. Eur. J. 2019; 25: 12502
• 22 General Procedure for the Preparation of Diaryl Phosphiranium Salts 6 To a solution of phosphirane 1 (1 equiv) in 1,1,2,2-tetrachloroethane (0.1 M) were added diphenyliodonium salt (1.2 equiv), copper chloride (10 mol%), and copper metal wire (cat.) at room temperature. The reaction mixture was then heated at 50 °C. After cooling down to room temperature, the resulting crude mixture was directly purified by flash column chromatography on silica gel (eluent: CH₂Cl₂ then CH₂Cl₂/acetone, 60:40) to yield the title product 7. 1-Mesityl-1-phenylphosphiranium Trifluoromethanesulfonate (7a) Prepared from 1-mesitylphosphirane (1a, 0.14 mmol) using the general procedure with diphenyliodonium triflate (1.2 equiv). Reaction time: 1 h. The title compound 7a was isolated as a colorless oil (42 mg, 81% crude yield). R_f  = 0.40 (CH₂Cl₂/acetone = 60:40). IR (neat): 1603, 1257, 1169, 1034, 636 cm^–1. ¹H NMR (300 MHz, acetone-d ₆, 20 °C): δ = 7.93–7.82 (m, 2 H), 7.81–7.68 (m, 3 H), 7.35 (d, ⁴ J_H–P  = 5.9 Hz, 2 H), 3.36–3.23 (m, 2 H), 3.08–2.96 (m, 2 H), 2.70 (d, d, ⁴ J_H–P  = 1.7 Hz, 6 H), 2.44 (s, 3 H). ¹³C NMR (75 MHz, acetone-d ₆, 20 °C): δ = 148.5 (d, ⁴ J_C–P  = 3.1 Hz, Cq), 147.1 (d, ² J_C–P  = 10.7 Hz, 2 Cq), 135.8 (d, ⁴ J_C–P  = 4.5 Hz, CH), 133.4 (d, ³ J_C–P  = 13.3 Hz, 2 CH), 131.6 (d, ³ J_C–P  = 16.4 Hz, 2 CH), 131.1 (d, ² J_C–P  = 13.4 Hz, 2 CH), 122.3 (q, ¹ J_C–F  = 321.8 Hz, CF₃), 115.2 (d, ¹ J_C–P  = 90.5 Hz, Cq), 109.2 (d, ¹ J_C–P  = 97.4 Hz, Cq), 22.6 (d, ³ J_C–P  = 8.9 Hz, 2 CH₃), 21.6 (d, ⁵ J_C–P  = 1.4 Hz, CH₃), 12.9 (d, ¹ J_C–P  = 3.2 Hz, 2 CH₂P). ³¹P NMR (121 MHz, acetone-d ₆, 20 °C): δ = –113.8. ¹⁹F NMR (282 MHz, acetone-d ₆, 20 °C): δ = –78.9. HRMS (ESI): m/z calcd for C₁₇H₂₀P [M]⁺: 255.1302; found: 255.1303.