LiAlH₄-Induced Reductive Dephosphonylation of α,α-Dialkyl Triethyl β-Phosphonyl Esters: Mechanistic Study and Synthetic Application

Abstract

Treatment of α,α-dialkyl triethyl β-phosphonyl esters with LiAlH₄ in CH₂Cl₂–THF caused the one-pot dephosphonylation and reduction to yield the corresponding primary alcohols bearing a controllable β secondary carbon center. Mechanistic study has revealed that the LiAlH₄-induced dephosphonylation should occur first with the assistance of the carboxylate group, and the hydrogen source of the resultant new C–H bond is LiAlH₄.

Key words

reductive dephosphonylation - β-phosphonyl esters - C–P bond cleavage - lithium aluminum hydride - primary alcohols

• References and Notes

• 1 Savignac P, Iorga B In Modern Phosphonate Chemistry. CPR Press; London: 2003. 217-375
• 2 Liao CC, Zhu JL. J. Org. Chem. 2009; 74: 7873
• 3 For characterization of 2, see: Driver TG, Franz AK, Woerpel KA. J. Am. Chem. Soc. 2002; 124: 6524
• 4 We previously observed that treatment of 1 with DIBAL-H in toluene or Li(t-BuO)₃AlH in THF did not cause the dephosphonylation but only afforded the phosphono aldehyde

• For examples on synthetic application of racemic 2, see:

• 5a Smith CD, Gavrilyuk JI, Lough AL, Batey RA. J. Org. Chem. 2010; 75: 702
• 5b Harned AM, Mukherjee S, Flynn DL, Hanson PR. Org. Lett. 2003; 5: 15
• 5c Chavan SP, Sharma AK. Tetrahedron Lett. 2001; 42: 4923
• 5d Rawal VH, Singh SP, Dufour C, Michoud C. J. Org. Chem. 1993; 58: 7718
• 5e Janssen AJ. M, Klunder AJ. H, Zwanenburg B. Tetrahedron 1991; 47: 5513
• 6a Cabioch JL, Pellerin B, Denis JM. Phosphorus, Sulfur Silicon Relat. Elem. 1989; 27
• 6b Katti KV, Pillarsetty N, Raghuraman K. Top. Curr. Chem. 2003; 229: 121
• 6c Stulz E, Maue M, Scott SM, Mann BE, Sanders JK. M. New J. Chem. 2004; 28: 1066 ; and references cited therein
• 7 Denmark SE, Marlin JE. J. Org. Chem. 1991; 56: 1003
• 8a Hong JE, Shin WS, Jang WB, Oh DY. J. Org. Chem. 1996; 61: 2199
• 8b Lee SY, Hong JE, Jang WB, Oh DY. Tetrahedron Lett. 1997; 38: 4567
• 8c Lee SY, Lee CW, Oh DY. J. Org. Chem. 1999; 64: 7017
• 8d Oh SY, Lee CW, Oh DY. J. Org. Chem. 2000; 65: 245
• 8e For a synthetic application, see: Yang H, Hong YT, Kim S. Org. Lett. 2007; 9: 2281
• 9 Amedjkouh M, Grimaldi J. Tetrahedron Lett. 2002; 43: 3761
• 10 For characterization of 3, see: Fringuelli F, Girotti R, Pizzo F, Vaccaro L. Org. Lett. 2006; 8: 2487
• 11 The endo stereochemistry of 5 was assigned on the basis of 2D NOESY experiments as well as the coupling constant of the C-1 signal on the ¹³C NMR spectrum (δ = 43.6 ppm, ³ J _P–C = 0 Hz), see: Defacqz N, Touillaux R, Tinant B, Declercq J.-P, Peeters D, Marchand-Brynaert J. J. Chem. Soc., Perkin Trans. 2 1977; 1965
• 12 Krawczyk H, Albrecht L. Synthesis 2005; 2887
• 13 Compound 6 was found to be extremely air-sensitive and decomposed quickly upon usual workup and purification. Only the IR, ³¹P (δ = –115.4 ppm) and ¹H NMR spectra of the crude products were obtained. For the instability of similar type of phosphines, see: Lasne MC, Ripoll JL, Thuillier A. J. Chem. Soc., Perkin Trans. 1 1988; 99
• 14a House HO In Modern Synthetic Reaction. 2nd ed. W. A. Benjamin, Inc; New York: 1972: 492-628
• 14b Carey FA, Sundberg RJ In Advanced Organic Chemistry. 4th ed., Part B Plenum Press; New York: 2000: 13-15
• 15 Nasser J, About-Jaudet E, Collignon N. Phosphorus, Sulfur Silicon Relat. Elem. 1990; 171
• 16 Stritzke K, Schulz S, Nishida R. Eur. J. Org. Chem. 2002; 3884
• 17 Such solvent effect was not observed for other substrates
• 18 Formation of 2 (Table 1, Entry 4) as a Typical Procedure for the LiAlH₄-Mediated Reductive Dephosphonylation To a stirred suspension of LiAlH₄ (95%, 169 mg, 4.23 mmol) in dry CH₂Cl₂ (5 mL) and THF (5 mL) precooled at 0 °C in an ice bath, a solution of 1 (213 mg, 0.705 mmol) in CH₂Cl₂–THF (5 mL, v/v = 1:1) was added dropwise in 2 min via a syringe under a nitrogen atmosphere. The ice bath was then removed and stirring was continued for an additional 2 h at r.t. The reaction mixture was recooled in an ice bath and cautiously quenched with 5% NaOH aq solution (2 mL). The resulting pale grey suspension was diluted with CH₂Cl₂ (30 mL) and successively washed with H₂O (2 × 8 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (hexane–EtOAc = 5:1) to afford 66 mg (75%) of 2 with the NMR spectral data agreeing well with the literature.^{3 1}H NMR (400 MHz, CDCl₃): δ = 6.15 (dd, J = 5.7, 3.0 Hz, 1 H), 5.96 (dd, J = 5.7, 2.9 Hz, 1 H), 3.40 (dd, J = 10.4, 6.5 Hz, 1 H), 3.26 (dd, J = 10.4, 8.9 Hz, 1 H), 2.93 (br s, 1 H), 2.81(br s, 1 H), 2.34–2.25 (m, 1 H), 1.82 (ddd, J = 11.6, 9.2, 3.9 Hz, 1 H), 1.45 (dm, J = 8.2 Hz, 1 H), 1.27 (br d, J = 8.6 Hz, 2 H), 0.53 (ddd, J = 11.6, 4.4, 2.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 137.5, 132.1, 66.5, 49.5, 43.6, 42.2, 41.7, 28.8