1-Trifluoromethyl-1-diethoxyphosphoryl Carbene: A New Synthon for the Preparation of CF₃-Containing α-Hydroxy and α-Amino Phosphonic Acid Derivatives

Abstract

The first synthesis of diethyl 1-diazo-2,2,2-trifluoroethylphosphonate has been developed starting from readily available compounds. The synthetic utility of this compound is demonstrated via its Rh-catalyzed insertion into O-H and N-H bonds to produce CF₃-substituted α-hydroxy phosphonic and α-amino phosphonic acid derivatives

diazo compounds - fluorine - aminophosphonates - hydroxyphoshonate - insertion reactions

References and Notes

1a Field SC. Tetrahedron  1999,  55:  12237 

1b Heaney F. In Comprehensive Organic Functional Group Transformations   Vol. 4:  Katritzky AR. Meth-Kohn O. Rees CW. Elsevier Science; Oxford UK: 1995.  Chap. 4. p.10 

2a Atherton FR. Hassall CH. Lambert RW. J. Med. Chem.  1986,  29:  29 ; and references cited therein

2b Kafarski P. Lejcazk B. Phosphorus, Sulfur Silicon Relat. Elem.  1991,  63:  193 

2c Bird J. De Mello RC. Harper HP. Hunter DJ. Karran EH. Markwell ER. Miles-Williams AJ. Rahman SS. Ward RW. J. Med. Chem.  1994,  37:  158 

2d McLeod DA. Brinkworth RI. Ashley JA. Janda KD. Wirsching P. Bioorg. Med. Chem. Lett.  1991,  1:  653 

2e Hirschmann R. Smith AB. Taylor CM. Benkovic PA. Taylor SD. Yager KM. Sprengeler PA. Benkovic SJ. Science (Washington, D.C.)  1994,  265:  234 

2f Grembecka J. Mucha A. Cierpicki T. Kafarski P. J. Med. Chem.  2003,  46:  2641 

3a Filler R. Kobayashi Y. Yagupolski LM. In Organofluorine Compounds in Medicinal Chemistry and Biomedicinal Applications   Elsevier Science; Amsterdam: 1993. 

3b Ojima I. McCarthy J. Welch JT. Biomedicinal Frontiers of Fluorine Chemistry, ACS Symposium Series 639   ACS; Washington, D.C.: 1996. 

4 Banks RE. Tatlow JC. Smart BE. In Organofluorine Chemistry: Principles and Commercial Applications   Plenum Press; New York: 1994. 

5a Osipov SN. Kolomiets AF. Fokin AV. Russ. Chem. Rev.  1992,  61:  798 ; and references cited therein

5b Osipov SN. Golubev AG. Sewald N. Kolomiets AF. Fokin AV. Burger K. Synlett  1995,  1269 

5c Osipov SN. Golubev AS. Sewald N. Michel T. Kolomiets AF. Fokin AV. Burger K. J. Org. Chem.  1996,  61:  7521 

5d Osipov SN. Artyushin OI. Kolomiets AF. Mendeleev Commun.  2000,  5:  192 

5e Kobel’kova NM. Osipov SN. Kolomiets AF. Russ. Chem. Bull.  2002,  7:  1298 

6a Shi G. Xu Y. Chem. Commun.  1989,  607 

6b Shi G. Xu Y. J. Org. Chem.  1990,  55:  3383 

6c Shi G. Xu Y. Xu M. Tetrahedron  1991,  47:  1629 

6d Shi G. Xu Y. Xu M. J. Fluorine Chem.  1991,  52:  149 

6e Shi G. Cao Z. Cai W. Tetrahedron  1995,  51:  5011 

6f Paulini K. Reissig H.-U. J. Prakt. Chem./Chem.-Ztg.  1995,  337:  55 

6g Osipov SN. Sewald N. Burger K. Kolomiets AF. Fokin AV. Tetrahedron Lett.  1996,  37:  615 

6h Jiang B. Zhang Z. Luo Z. Org. Lett.  2002,  4:  2453 

6i Mueller P. Grass S. Shahi SP. Bernardinelli G. Tetrahedron  2004,  60:  4755 

6j Vorob’eva DV. Titanyuk ID. Beletskaya IP. Osipov SN. Mendeleev Commun.  2005,  6:  222 

6k Zhu S. Xing C. Zhu S. Tetrahedron  2006,  62:  829 

7a Sinitsa AD. Onisko PP. Kim TV. Kiseleva EI. Pirozhenko VV. J. Gen. Chem. USSR  1986,  52:  2372 

7b Flynn AG. Beight DW. Bohme EHW. Metcalf BW. Tetrahedron Lett.  1985,  26:  285 

7c Vaubaillon D. Giraud V. Rabiller C. Gruss U. Haas A. Haegele G. Phosphorus, Sulfur Silicon Relat. Elem.  1997,  126:  177 

8a Ingrassia L. Mulliez M. Synthesis  1999,  1731 

8b De Medina P. Ingrassia LS. Mulliez ME. J. Org. Chem.  2003,  68:  8424 

9a Yates P. J. Am. Chem. Soc.  1952,  74:  5376 

9b Ye T. McKervey A. Chem. Rev.  1994,  94:  1091 ; and references cited therein

9c Aller E. Buck RT. Drysdale MJ. Ferris L. Haigh D. Moody CJ. J. Chem. Soc., Perkin Trans. 1  1996,  2879 

9d Ferris L. Haigh D. Moody CJ. J. Chem. Soc., Perkin Trans. 1  1996,  2885 

9e Moody CJ. Ferris L. Haigh D. Swann E. Chem. Commun.  1997,  2391 

10

Diethyl (1-Diazo-2,2,2-trifluoroethyl)phosphonate ( 4) The reaction was conducted in a 500 mL flask equipped with a condenser, a funnel, and magnetic stirrer. i-PrONO (9.5 g, 0.106 mol) was added to a vigorously stirred solution of aminophosphonate (19.6 g, 0.083 mol) in CHCl₃ (300 mL). After the addition of approximately 1.0 g of i-PrONO an exothermic reaction began; the rest of the nitrite was added dropwise providing a mild refluxing reaction mixture for 20 min. After stirring for an additional 40 min (the temperature was reduced to r.t.) the solvent was removed under reduced pressure and the residue was distilled in vacuo to afford 13.7 g (67%) of diazo compound 4 as light yellow liquid. Bp 47-50 °C (1 Torr). IR (KBr): 2160, 1150 cm^-1. ¹H NMR (CDCl₃): δ = 1.40 (t, 6 H, J = 7.1 Hz), 4.15-4.30 (m, 4 H). ¹³C NMR (CDCl₃): δ = 15.9, 63.6, 118.6 (m), 124.1 (dq, J _C-F = 271.0 Hz, J _C-P = 12.1 Hz). ³¹P NMR (CDCl₃): δ = 9.23. ¹⁹F NMR (CDCl₃): δ = 23.0.

11

OH- and NH-Insertion; General Procedure A solution of diazo compound 4 (1.1 mmol) in anhydrous benzene (3 mL) was added to a solution of the hydroxy or amino compound (1.0 mmol) and dirhodium tetraacetate (2 mol%) in benzene (10 mL). The reaction mixture was stirred under reflux for 4 h. After evaporation of the solvent under reduced pressure the crude product was purified by column chromatography on silica gel (EtOAc-hexanes).
Diethyl (2,2,2-Trifluoro-1-methoxyethyl)phosphonate ( 5a) Yield: 88%; oil. ¹H NMR (CDCl₃): δ = 1.38 (t, 6 H, J = 7.0 Hz), 3.65 (s, 3 H), 3.78-3.9 (m, 1 H), 4.20-4.30 (m, 4 H). ³¹P NMR (CDCl₃): δ = 11.8 (app. q, J = 8.9 Hz). ¹⁹F NMR (CDCl₃): δ = 6.7 (app. t, J = 8.5 Hz). Anal. Calcd for C₇H₁₄F₃O₄P: C, 33.61; H, 5.64. Found: C, 33.75; H, 5.75.
1-(Diethoxyphosphoryl)-2,2,2-trifluoroethyl N -( tert -Butoxycarbonyl) -1-phenylalaninate ( 5f) Yield: 62%; oil; dr 1:1. ¹H NMR (CDCl₃): δ = 1.35-1.45 (m, 6 H), 1.45 (s, 9 H), 3.10 (ddd, 1 H, J = 4.1, 6.4, 14.0 Hz), 3.28 (app. dt, 1 H, J = 5.5, 14.0 Hz), 4.20-4.37 (m, 4 H), 4.78 (m, 1 H), 4.98 (m, 1 H), 5.68-5.83 (m, 1 H), 7.20-7.30 (m, 2 H), 7.30-7.41 (m, 3 H). ³¹P NMR (CDCl₃): δ = 8.7 (app. q, J = 7.4 Hz), 9.3 (app. q, J = 7.4 Hz). ¹⁹F NMR (CDCl₃): δ = 7.63 (app. t, J = 7.3 Hz), 7.84 (app. t, J = 7.3 Hz). Anal. Calcd for C₂₀H₂₉F₃NO₇P: C, 49.70; H, 6.00; N 2.90. Found: C, 49.51; H, 6.21; N 2.75.
Diethyl (2,2,2-Trifluoro-1-phenoxyethyl)phosphonate ( 5g) Yield: 78%; oil. ¹H NMR (CDCl₃): δ = 1.40 (t, 6 H, J = 7.1 Hz), 4.20-4.40 (m, 4 H), 4.88-5.00 (m, 1 H), 7.05-7.15 (m, 3 H), 7.40-7.50 (m, 2 H). ³¹P NMR (CDCl₃): δ = 10.6 (app. q, J = 8.9 Hz). ¹⁹F NMR (CDCl₃): δ = 7.10 (app. t, J = 8.2 Hz). Anal. Calcd for C₁₂H₁₆F₃O₄P: C, 46.16; H, 5.17. Found: C, 46.27; H, 5.21.
Diethyl {1-[( tert -Butoxycarbonyl)amino]-2,2,2-trifluoroethy}phosphonate ( 6a) Yield: 59%; white crystals; mp 81.5-82.5 °C. ¹H NMR (CDCl₃): δ = 1.41 (t, 6 H, J = 8.1 Hz), 1.52 (s, 9 H), 4.20-4.30 (m, 4 H), 4.65-4.80 (m, 1 H), 5.20 (m, 1 H). ³¹P NMR (CDCl₃): δ = 13.6 (app. q, J = 6 Hz). ¹⁹F NMR (CDCl₃): δ = 8.05 (app. t, J = 7.5 Hz). Anal. Calcd for C₁₁H₂₁F₃NO₅P: C, 39.41; H, 6.31; N, 4.18. Found: C, 39.47; H, 6.31; N, 4.15.
Diethyl {1-[(Phenylsulfonyl)amino]-2,2,2-trifluoroethyl}phosphonate ( 6c) Yield: 64%; white solid; mp 115-117 °C. ¹H NMR (CDCl₃): δ = 1.33 (t, 3 H, J = 7.1 Hz), 1.39 (t, 3 H, J = 7.1 Hz), 4.10-4.30 (m, 4 H), 4.35-4.57 (m, 1 H), 7.05-7.15 (m, 1 H), 7.30-7.65 (m, 3 H), 7.92-7.97 (m, 2 H). ³¹P NMR (CDCl₃): δ = 12.3 (app. q, J = 7.4 Hz). ¹⁹F NMR (CDCl₃): δ = 8.03 (app. t, J = 8.0 Hz). Anal. Calcd for C₁₂H₁₇F₃NO₅PS: C, 38.40; H, 4.57; N, 3.73. Found: C, 38.21; H, 4.44; N, 3.67.
Diethyl {1-[(Pentafluorophenyl)amino]-2,2,2-trifluoroethyl}phosphonate ( 6d) Yield: 63%; white solid; mp 55-56 °C. ¹H NMR (CDCl₃): δ = 1.40 (dt, 6 H, J = 0.7, 7.1 Hz), 4.20-4.38 (m, 4 H), 4.38-4.50 (m, 1 H). ³¹P NMR (CDCl₃): δ = 13.2 (app. q, J = 7.4 Hz). ¹⁹F NMR (CDCl₃): δ = 8.06 (app. t, J = 7.8 Hz, 3 F), -78.0 (d, J = 21.8 Hz, 2 F), -85.2 (dt, J = 5.8, 21.8 Hz, 2 F), -88.9 (t, J = 21.8 Hz, 1 F). Anal. Calcd for C₁₂H₁₂F₈NO₃P: C, 35.93; H, 3.01; N, 3.49. Found: C, 36.25; H, 3.22; N, 3.47.