The First Synthesis of Diethyl α,α-Chlorofluorobenzylphosphonates

Abstract

Starting from α-hydroxyphosphonates, a wide variety of diethyl α,α-chlorofluorobenzylphosphonates have been obtained in pure form in a two-step procedure. The first step was chlorination of α-hydroxyphosphonates with Ph₃P and CCl₄, while the second step was fluorination with N-fluorobisbenzenesulfonimide.

Key words

fluorinated phosphonates - chlorination - fluorination - diethyl α,α-chlorofluorobenzylphosphonates

References and Notes

• 1a Romanenko VD. Kukhar VP. Chem. Rev.  2006,  106:  3868 
• 1b Romanenko VD. Kukhar VP. Tetrahedron  2008,  64:  6153 
• 2a Blackburn GM. Chem. Ind. (London)  1981,  5:  134 
• 2b Berkowitz DB. Bose M. J. Fluorine Chem.  2001,  112:  13 
• 3a Frank AW. J. Org. Chem.  1965,  30:  3663 
• 3b Fonong T. Burton DJ. Pietrzyk DJ. Anal. Chem.  1983,  55:  1089 
• 4a Martin SF. Wong YL. Wagman AS. J. Org. Chem.  1994,  59:  4821 
• 4b Halazy S. Ehrhard A. Danzin C.
  J. Am. Chem. Soc.  1991,  113:  315 
• 4c McLennan AG. Taylor GE. Prescott M. Blackburn GM. Biochemistry  1989,  28:  3868 
• 4d Blackburn GM. Perree TD. Rashid A. Bisbal C. Lebleu B. Chem. Scr.  1986,  26:  21 
• 4e Caplan NA. Pogson CI. Hayes DJ. Blackburn GM. Bioorg. Med. Chem. Lett.  1998,  8:  515 
• 4f Wang G. Boyle N. Chen F. Rajappan V. Fagan P. Brooks JL. Hurd T. Leeds JM. Rajwanshi VK. Jin Y. Prhavc M. Bruice TW. Cook PD. J. Med. Chem.  2004,  47:  6902 
• 4g Liu DG. Gao Y. Voigt JH. Lee K. Nicklaus MC. Wu L. Zhang ZY. Terrence R. Burke J. Bioorg. Med. Chem. Lett.  2003,  13:  3005 
• 4h Yao ZJ. Ye B. Wu XW. Wang S. Wu L. Zhang ZY. Terrence R. Burke J. Bioorg. Med. Chem.  1998,  6:  1799 
• 5a Thenappan A. Burton DJ. J. Org. Chem.  1990,  55:  2311 
• 5b Burton DJ. Sprague LG. Pietrzyk DJ. Edelmuth SH. J. Org. Chem.  1984,  49:  3437 
• 6a Wang Q. Huang Z. Ramachandran C. Dinaut AN. Taylor SD. Bioorg. Med. Chem. Lett.  1998,  8:  345 
• 6b Taylor SD. Kotoris CC. Dinaut AN. Chen MJ. Tetrahedron  1998,  54:  1691 
• 6c Iorga B. Eymery F. Savignac P. Tetrahedron  1999,  55:  2671 
• 6d Xu Y. Qian L. Prestwich GD. Org. Lett.  2003,  5:  2267 
• 7a Caplan NA. Pogson CI. Hayes DJ. Blackburn GM. J. Chem. Soc., Perkin Trans. 1  2000,  3:  421 
• 7b Pham V. Zhang W. Chen V. Whitney T. Yao J. Froese D. Friesen AD. Diakur JM. Haque W. J. Med. Chem.  2003,  46:  3680 
• 7c Benayoud F. deMendonca DJ. Digits CA. Moniz GA. Sanders TC. Hammond GB. J. Org. Chem.  1996,  61:  5159 
• 8a Piettre SR. Tetrahedron Lett.  1996,  37:  2233 
• 8b Piettre SR. Tetrahedron Lett.  1996,  37:  4707 
• 9a Blackburn GM. Brown D. Martin SJ. Parratt MJ. J. Chem. Soc., Perkin Trans. 1  1987,  1:  181 
• 9b Inukai K. Ueda T. Muramatsu H. J. Org. Chem.  1964,  29:  2224 
• 9c McKenna CE. Khawli LA. J. Org. Chem.  1986,  51:  5467 
• 10 Iorga B. Eymery F. Savignac P. Tetrahedron Lett.  1998,  39:  3693 
• 13a Differding E. Ruegg GM. Tetrahedron Lett.  1991,  32:  3815 
• 13b Differding E. Bersier PM. Tetrahedron  1992,  48:  1595 
• 13c Gilicinski AG. Pez GP. Syvret RG. Lal GS. J. Fluorine Chem.  1992,  59:  157 
• 13d Christe KO. J. Fluorine Chem.  1984,  25:  269 
• 13e Cartwright MM. Woolf AA. J. Fluorine Chem.  1984,  25:  263 

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General Procedure for the Preparation of α-Chloro-benzylphosphonates from α-Hydroxyphosphonates
A solution of 1k (1.00 g, 3.46 mmol, 1.0 equiv) and Ph₃P (1.36 g, 5.19 mmol, 1.5 equiv) in dry CCl₄ (10 mL) is refluxed for 8 h under argon. Then, the mixture is evaporated under reduced pressure, and the semisolid residue is extracted with PE. The combined extracts are filtered, and the solvent is removed under reduced pressure. The crude material was purified by flash column chromatography on silica gel to yield 3k as yellow oil (0.81 g, 76%). ^¹H NMR (300 MHz, CDCl₃): δ = 1.26 (t, J = 7.0 Hz, 3 H), 1.35 (t, J = 7.0 Hz, 3 H), 4.00-4.14 (m, 2 H), 4.15-4.28 (m, 2 H), 5.00 (d, ^² J _PH = 15.2 Hz, 1 H), 7.73 (d, J = 8.6 Hz, 2 H), 8.25 (d, J = 8.6 Hz, 2 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 16.2 (d, ^³ J _PC = 5.6 Hz), 16.4 (d, ^³ J _PC = 5.7 Hz), 52.5 (d, ^¹ J _PC = 156.4 Hz), 64.1 (d, ^² J _PC = 7.0 Hz), 64.6 (d, ^² J _PC = 7.0 Hz), 123.6, 129.8, 141.4, 148.0 ppm.

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General Procedure for the Preparation of α,α-Chloro-fluorobenzylphosphonates from α-Chlorophosphonates
To a solution of the α-chlorophosphonates 3k (0.31 g, 0.94 mmol, 1.0 equiv) in dry THF (10 mL) at -78 ˚C was added dropwise a solution of NaHMDS (1.69 mmol, 2.0 M in THF, 1.5 equiv) in dry THF (5 mL) under argon. The resulting dark green solution was stirred for 1 h at -78 ˚C. A solution of NFSI (0.41 g, 1.31 mmol, 1.3 equiv) in dry THF (5 mL) was added over a period of 10 min. After addition, the solution was stirred for 1 h and then allowed to warm to -30 ˚C. The reaction was quenched with 0.01 N HC1, and the resulting solution was extracted with CH₂Cl₂. The combined organic layer was dried over MgSO₄, and the solvent was removed under reduced pressure. The crude material was purified via flash column chromatography on silica gel to yield 4k as yellow oil (0.24 g, 77%). ^¹H NMR (300 MHz, CDCl₃): δ = 1.25 (t, J = 7.0 Hz, 3 H), 1.41 (t, J = 7.0 Hz, 3 H), 4.05-4.19 (m, 2 H), 4.32-4.41 (m, 2 H), 7.86 (d, J = 8.5 Hz, 2 H), 8.29 (d, J = 8.6 Hz, 2 H) ppm; ^¹³C NMR (75 MHz, CDCl₃): δ = 16.3 (d, ^³ J _PC = 15.0 Hz), 65.3 (d, ^² J _PC = 7.2 Hz), 66.2 (d, ^² J _PC = 7.1 Hz), 105.6 (dd, ^¹ J _PC = 193.4 Hz, ^¹ J _FC = 259.1 Hz), 123.4, 127.5 (d, ^³ J _PC = 8.4 Hz), 142.5 (d, ^² J _PC = 21.0 Hz), 148.7 ppm. ^³¹P NMR (121.5 MHz, CDCl₃): δ = 5.13 (d, ^² J _PF = 88.1 Hz) ppm.

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We thank one of the reviewers for pointing out these possibilities.