Phosphine-Catalysed Cyclisation of β-Hydroxy-α,α-Difluoroynones

Abstract

2-Benzylidene-4,4-difluorodihydrofuran-3(2H)-ones were synthesised in 58-86% yield via phosphine-promoted cyclisation of β-hydroxy-α,α-difluoroynones. The benzylidene group was found to be a suitable masked carbonyl group, thereby allowing for the validation of a novel route to 3,3-difluoro-2-hydroxy-γ-lactols.

Key words

phosphine - fluorine - furanone - catalysis

References and Notes

• 1a Trost BM. Kazmaier U. J. Am. Chem. Soc.  1992,  114:  7933 
• 1b Guo C. Lu X. J. Chem. Soc., Perkin Trans. 1  1993,  1921 
• 1c Trost BM. Li C.-J. J. Am. Chem. Soc.  1994,  116:  10819 
• For selected examples, see:
• 2a Lu X. Du Y. Lu C. Pure Appl. Chem.  2005,  77:  1985 
• 2b Ludovic J. Marinetti A. Tetrahedron Lett.  2006,  47:  2141 
• 2c Fleury-Brégeot N. Ludovic J. Retailleau P. Marinetti A. Tetrahedron  2007,  63:  11920 
• 2d Kuroda H. Tomita I. Endo T. Org. Lett.  2003,  5:  129 
• 2e Xia Y. Liang Y. Chen Y. Wang M. Jiao L. Huang F. Liu S. Li Y. Yu Z.-X. J. Am. Chem. Soc.  2007,  129:  3470 
• 2f Wilson JE. Fu GC. Angew. Chem. Int. Ed.  2006,  45:  1426 
• 2g Wurz RP. Fu GC. J. Am. Chem. Soc.  2005,  127:  12234 
• 2h Cowen BJ. Miller SJ. J. Am. Chem. Soc.  2007,  129:  10988 
• 2i Castelano S. Fiji HDG. Kinderman SS. Watanabe M. de Leon P. Tamanoi F. Kwon O. J. Am. Chem. Soc.  2007,  129:  5843 
• 2j Ye L.-W. Sun X.-L. Wang Q.-G. Tang Y. Angew. Chem. Int. Ed.  2007,  46:  5951 
• 2k Nair V. Mathew SC. Biju AT. Suresh E. Angew. Chem. Int. Ed.  2007,  46:  2070 
• 2l McDougal NT. Shaus SE. Angew. Chem. Int. Ed.  2006,  45:  3117 
• 2m Sriramurthy V. Barcan GA. Kwon O. J. Am. Chem. Soc.  2007,  129:  12928 
• 3a Gabillet S. Lecercle D. Loreau O. Carboni M. Dezard S. Gomis J.-M. Taran F. Org. Lett.  2007,  9:  3925 
• 3b Carboni M. Gomis J.-M. Loreau O. Taran F. Synthesis  2008,  417 
• 4 Methot JL. Roush WR. Adv. Synth. Catal.  2004,  346:  1035 
• 5 Ye L.-W. Zhou J. Tang Y. Chem. Soc. Rev.  2008,  37:  1140 
• 6 Kwong CK.-W. Fu MY. Lam CS.-L. Toy PH. Synthesis  2008,  2307 
• 7 Schuler M. Silva F. Bobbio C. Tessier A. Gouverneur V. Angew. Chem. Int. Ed.  2008,  47:  7927 
• 8a Hertel LW. Kroin JS. Misner JW. Tustin JM. J. Org. Chem.  1988,  53:  2406 
• 8b Chou TS. Heath PC. Patterson LE. Poteet LM. Lakin RE. Hunt AH. Synthesis  1992,  565 
• 8c Kotra JP. Xiang Y. Newton MG. Schinazi RF. Cheng Y.-C. Chu CK. J. Med. Chem.  1997,  40:  3635 
• 8d Fernández R. Matheu MI. Echarri R. Castillón S. Tetrahedron  1998,  54:  3523 
• 8e Gumina G. Schinazi RF. Chu CK. Org. Lett.  2001,  3:  4177 
• 8f Zhang XG. Xia H.-R. Dong X.-C. Jin J. Meng W.-D. Qing F.-L. J. Org. Chem.  2003,  68:  9026 
• 8g Zhou W. Gumina G. Chong Y. Wang J. Schinazi RF. Chu CK. J. Med. Chem.  2004,  47:  3399 
• 8h Xu X.-H. Qiu X.-L. Zhang X. Qing F.-L. J. Org. Chem.  2006,  71:  2820 
• 8i Xu X.-H. Trunkfield AE. Bugg DH. Qing F.-L. Org. Biomol. Chem.  2008,  6:  157 
• 10a Hallinan EA. Fried J. Tetrahedron Lett.  1984,  25:  2301 
• 10b Kuroboshi M. Ishihara T. Bull. Chem. Soc. Jpn.  1990,  63428 
• 10c Yamaguchi M. Shibato K. Fujiwara S. Hirao I. Synthesis  1986,  421 
• 10d Iseki K. Asada D. Kuroki Y. J. Fluorine Chem.  1999,  97:  85 
• 11 Silva F. Sawicki M. Gouverneur V. Org. Lett.  2006,  8:  5417 

9

For additional details on the synthesis of β-hydroxy-α,α-difluoroynones, see the Electronic Supporting Information of ref. 7.

12

General Procedure for Cyclisation of 1c
To a solution of 1c (200 mg, 0.64 mmol, 1 equiv) in anhydrous toluene (64 mL) was added under argon AcOH (15 µL, 0.255 mmol, 40 mol%) followed by dppp (26.3 mg, 0.064 mmol, 10 mol%). The reaction mixture was stirred at 60 ˚C for 4 h. The crude mixture was concentrated in vacuo at r.t., and the resulting solution was directly purified by column chromatography on silica gel (hexane-Et₂O, 80:20) to give the product as a yellow oil (120 mg, 0.38 mmol) in a 60% yield.



( Z )-2-Benzylidene-4,4-difluoro-5-(2-phenylethyl)-dihydrofuran-3 (2 H )-one (2c)
R _f = 0.68 (hexane-EtOAc, 80:20). ^¹H NMR (400 MHz, CDCl₃): δ = 2.25 (q, J = 7.3 Hz, 2 H, CH ₂CH), 2.91-3.04 (m, 2 H, CH₂Ph), 4.44-4.55 (m, 1 H, CF₂CH), 6.65 (s, 1 H, C=CHPh), 7.25-7.46 (m, 8 H, 8 × ArH), 7.79 (br d, J = 6.8 Hz, 2 H, 2 × ArH). ^¹³C NMR (100 MHz, CDCl₃): δ = 29.5 (d, J = 6.4 Hz, CH₂), 30.8 (CH₂), 79.7 (dd, J = 27.2, 24.0 Hz, CH), 112.7 (CH), 113.3 (dd, J = 268.8, 256.4 Hz, CF₂), 126.6 (CH), 128.6 (CH), 128.8 (CH), 129.0 (CH), 130.0 (CH), 131.3 (CH), 132.5 (C), 140.0 (C), 144.1 (dd, J = 4.8, 3.2 Hz, C), 186.5 (t, J = 25.2 Hz, C). ^¹9F NMR (377 MHz, CDCl₃): δ = -125.17 (dd, J = 282.3, 14.9 Hz, 1 F), -120.62 (dd, J = 281.7, 12.1 Hz, 1 F). IR (CH₂Cl₂): ν = 3055, 1751, 1266, 1135, 738 cm^-¹. HRMS (CI⁺): m/z calcd for C₁₉H₁₇F₂O₂ [M + H]⁺: 315.1197; found: 315.1209.

13

Procedure for the Synthesis of 6c
To a stirred solution of 5c (47.6 mg, 0.11 mmol, 1 equiv) in MeCN-CCl₄-H₂O (1.5:1:1, 1 mL) were added NaIO₄ (141 mg, 0.66 mmol, 6 equiv) and RuCl₃˙H₂O (0.9 mg, 4.4 µmol, 4 mol%). After 30 min, the reaction mixture was quenched by addition of H₂O, and it was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo. Purification by column chromatography on silica gel (hexane-Et₂O, 95:5 to 90:10) gave the product as a white solid (26.5 mg, 74 µmol) in a 68% yield. R _f = 0.23 (hexane-Et₂O, 95:5). ^¹H NMR (400 MHz, CDCl₃): δ = 0.14 and 0.17 (2 × s, 6 H), 0.92 (s, 9 H), 2.05-2.15 (m, 2 H), 2.70-2.91 (m, 2 H), 4.25-4.36 (m, 1 H), 4.48 (dd, J = 14.8, 9.4 Hz, 1 H), 7.16-7.22 (m, 3 H), 7.25-7.32 (m, 2 H). ^¹³C NMR (126 MHz, CDCl₃): δ = -4.8 (CH₃), -5.1 (CH₃), 18.5 (C), 25.5 (CH₃), 28.8 (d, J = 5.2 Hz, CH₂), 30.7 (CH₂), 71.2 (dd, J = 19.5, 19.6 Hz, CH), 77.8 (dd, J = 25.3, 24.6 Hz, CH), 120.8 (dd, J = 254.0-254.1 Hz, CF₂), 126.7 (CH), 128.7 (CH), 128.9 (CH), 139.9 (C), 169.3 (d, J = 17.1 Hz, C=O). ^¹9F{^¹H} NMR (377 MHz, CDCl₃): δ = -131.30 (d, J = 232.0 Hz, 1 F), -116.62 (d, J = 232.0 Hz, 1 F). IR (CH₂Cl₂): ν = 2950, 2900, 2833, 1810, 1263, 1153, 910, 735 cm^-¹. MS (CI⁺): m/z = 374.25 [M + NH₄]⁺.