A novel synthesis of beta;-perfluoroalkylated alpha;,beta;-unsaturated nitriles

摘要

J. CHEM. SOC. PERKIN TRANS. i 1991 A Novel Synthesis of p-Perfluoroalkylated a,p-Unsaturated Nitriles Yanchang Shen * and Tielin Wang Shanghai Institute of Organic Chemistry, Academia Sinica 345Lingling L u, Shanghai 200032,China A novel intramolecular Wittig reaction proceeding via ylide-anion formation and protonation and its application to the synthesis of p-perfluoroalkyl-a,P- u nsaturated nitriles is described. x,P-Unsaturated nitriles and their fluoro species have much potential, particularly in the synthesis of biologically active compounds, since they can serve as useful intermediates and undergo many organic transformations.' However, to the best of our knowledge, the synthesis of P-perfluoroalkyl-a$-unsaturated nitriles has not been reported. Perfluoroacylmethylenetriphenylphosphoraneswere found to be very stable and did not react with aldehydes because of the strong electron-withdrawing effect of the perfluoroacyl groups; only the intramolecular Wittig reaction occurred, at 250 "C, giving fluoro acetylenes.2 We recently reported an ylide-anion formation resulting from nucleophilic addition to the p-perfluoroacyl group to activate trifluoroacetylmethylenetri-phenylphosphorane and its application to the synthesis of X-trifluoromethyl trans-allylic alcohol^.^ We now wish to report a novel intramolecular Wittig reaction proceeding via ylide-anion formation resulting from nucleophilic addition and protonation and its application to the synthesis of P-perfluoro-a,P-unsaturated nitriles. The nucleophilic reagents could regiospecifically attack the perfluoroacyl group of perfluoroacylcyanomethylenetriphenyl-phosphorane 1 to form ylide-anion 2 and, after protonation with acetic acid, the intramolecular Wittig reaction occurred spontaneously to give product 4 in 90-96 yield.The E and 2 isomers of 4 could be. separated conveniently by column 1 2 3 /-Ph,P= 0 Rbsol; ,H + Rbsol;,c=c /CN,c=c R , ' CN R, bsol;H 2-4 E-4 chromatography on silica gel and E isomers were the major products (8amp;100). The results are shown in Table 1. All products are new and characterized by microanalyses, IR, NMR and mass spectroscopy. It is noteworthy that this reaction is of wide scope; the R groups may be aryl, alkynyl or heterocyclic.The nucleophilic attack was regiospecific at the perfluoroacyl groups while the cyano group was not attacked. When the alkynyl lithium was used as the nucleophilic reagent, a l-cyano-2-en-4-yne was obtained. The synthesis of fluorine-containing conjugated enyne is not easy,4 therefore, this new methodology should be useful in the synthesis of biologically active compounds. Experimental The general procedure was as follows: lithium reagent (4 mmol) Table 1 Synthesis of compounds 4 4 R Rf taI0C Yield" E-Zh ~~ a Ph CF3 -60 91 88:12 c d b . 2-thienyl 2-thienyl Ph n-C,F, n-C3F7 CF3 -60 0 0 90 90 96 87:131oo:o1oo:o e PhCS CF, 0 98 92: 8 f PhCS n-C,F, 0 93 95:5 g hex-1-ynyl CF, 0 90 86:14 h hex-1-ynyl n-C,F7 0 93 87:73 'Reaction temperature of 1 with RLi." Isolated results. was added dropwise with stirring to a solution of ylide I (4 mmol) in dry THF (16 ml) at -60 or 0 "C under nitrogen. The reaction mixture was stirred for 1 h at the same temperature, forming ylide-anion 2, and acetic acid (1 ml) was added. The mixture was warmed to 20 "C, stirred for 2 h and diethyl ether (20 ml) was added. The organic layer was washed repeatedly with water to neutral pH and dried. Evaporation of the solvent gave a residue which was separated by a column chromato- graphy on silica gel eluting with light petroleum (b.p. 6CL 90 "CMthyl acetate (97: 3) to afford product 4. 4,4,4-TriJluoro-3-phenylbut-2-enenitrile 4a.-E isomer, b.p. 110 "C/2 mmHg; vmax/cm-' 2190, 1620 and 845; 6, 7.56 (5 H, m) and 6.16 (1 H, s); G,(TFA,,,) -10.9(s, 3 F). 2isomer, b.p.105 "C/2 mmHg; v,,,/cm-' 2 170, 16 10and 845; 6, 7.46 (5 H, m) and 5.90 (1 H, s); 6F -15.6 (3 F, s). m/z 197 (M+), 170 and 128 (Found: C, 60.85; H, 3.03; N, 7.17. C,,H,F3N requires C, 60.92; H, 3.07; N, 7.10). 4,4,5,5,6,6,6-HeptaJuoro-3-phenylhex-2-enenitrile4b.-E iso-mer, b.p. 1 10 "C/2 mmHg; v,,,/cm-' 2 160, 1620 and 845; 6, 7.45 (5 H, m) and 6.06 (1 H, s); 3.6 (3 F, s), 35.4 (2 F. s) and 47.5 (2 F, s). 2isomer, b.p. 105 "C/2 mmHg; v,,,/cm-' 2160, 1610 and 845; 6" 7.40 (5 H, m) and 5.86 (1 H, s); aF3.1 (3 F, s), 32.0 (2 F, m) and 47.5 (2 F, s). m/z 297 (M'), 178 and 128 (Found: C, 48.94; H, 1.87; N, 4.70. C,*H,F,N requires C, 48.50; H, 2.03; N, 4.7173. 4,4,4- TriJuoro-3-( 2-thienyl)but-2-enentrile4c.--E isomer, b.p.105 "C/2 mmHg; v,,,/cm-' 2160, 1600 and 846; 6, 7.367.76 (2H,m),6.9amp;7.16(1 H,m)and5.86(1 H,m);6, -12.0(3F,s); m/z 203 (M'), 135 and 134 (Found: C, 47.35; H, 1.93; N, 6.98. C8H,F3NS requires C, 47.29; H, 1.98; N, 6.98). 4,4,5,5,6,6,6-HeptaJuoro-3-(2-thienyl)hex-2-eneizitrile4d.-E isomer, b.p. 1 15 "C/2 mmHg; v,,,/cm-' 21 60, 1590and 800; 6, 7.35-7.73 (2 H, m), 6.93-7.20 (1 H, m) and 5.93 (1 H, s); 6F 3.6 (3 F, s), 34.3 (2 F, s) and 47.3 (2 F, s);m/z 303 (M +), 184 and 134 (Found: C, 39.78; H, 1.30; N, 4.78. C8H4F3NS requires C, 39.61; H, 1.33; N, 4.62). 3-Trijluoromethyl-5-phenyl-pent-2-en-4-ynenitrile4e.-E iso-mer, b.p.120 "C/2 mmHg; vmax2150,2200,1600 and 815; 6, 7.22 (5 H, m), 5.93 (1 H, s); 6, -9.2 (3 F, s). 2 isomer, b.p. 127 OC/2 mmHg; v,,,/cm-' 2140 and 850; 6, 7.30 (5 H, m), 5.78 ppm (1 H, s); 6F -12.7 ppm (3 F, s). m/z 221 (M') and 152 (Found: C, 64.98; H, 2.73; N, 6.45. C,,H,F,N requires C, 65.16; H, 2.73; N, 6.33). 4,4,5,5,6,6,6-Hep tajuoro- 3 -(pheny lethyny 1)hex-2-enenitrile 4f.--E isomer, b.p. 150 OC/2 mmHg; v,,,/cm-' 2150 and 8 10; 6, 7.33 (5 H, m) and 6.00 (1 H, s); 3.4 (3 F, s), 35.6 (2 F, s) and 48.3 (2 F, s). Z isomer, b.p. 159 "C/2 mmHg; v,,,/cm-' 2150 and 850; 6, 7.37 (5 H, m) and 580 (1 H, s); 6, 3.0 (3 F, s), 31.9 (2 F, s), 48.2 (2 F, s. m/z 321 (M'), 202 and 152 (Found C, 51.94; 2.07; N, 4.40. C1,H,F,N requires C, 52.31; H, 1.88;N, 4.36).3-TriJluoromethylnon-2-en-4-ynenitrile4g.-E isomer, b.p. 86 "C/2 mmHg; v,,,/cm-' 2150, 1600 and 830; 6, 6.07 (1 H, s), 2.55 (2 H, t, J6.0 Hz), 1.60 (4 H, m) and 0.85 (3 H, t); SF -9.0 (3 F, m). 2 isomer, b.p. 92 "C/2 mmHg; vmax/cm-' 2 150, 1600 and 820; 6, 5.85 (1 H, s), 2.75 (2 H, t, J 6 Hz), 1.60 (4 H, m) and 0.85 (3 H, t); 6, -12.3 (3 F, s). m/z 201 (M+), 200, 183, 159 and 132 (Found: C, 58.96; H, 4.81; N, 6.85. CloHl0F,N requires C, 59.69; H, 5.01; N, 6.96). 3-(1,1,2,2,3,3,3-Hepta~uoropropy~non-2-en-4-ynenitrile4h.-J. CHEM. SOC. PERKIN TRANS. 1 1991 E isomer, b.p. 110 "C/2 mmHg; vmax/cm-' 2170, 1590 and 805; 8, 6.00 (1 H, s), 2.45 (2 H, m), 1.45 (4 H, m) and 0.87 (3 H, t); 6, 3.3 (3 F, s), 35.6 (2 F, m) and 49.0 (2 F, s).Z isomer, b.p. 120 "C/2 mmHg; v,,,/cm-' 21 50,1590 and 830; 6, 5.87 (1 H, s), 2.40 (t, J6.0 Hz), 1.50 (4 H, m), 0.87 (3 H, t); 6, 3.0 (3 F, s), 33.3 (2 F, s) and 48.4 (2 F, s). m/z 301 (M'), 300,286,259 and 182(Found: C, 48.37; H, 3.36; N, 4.63. C,,H,,F,N requires C, 47.85; H, 3.34; N, 4.65). Acknowledgements The authors thank the National Natural Science Foundation of China and Academia Sinica for financial support. References 1 P. P. Bay, G. Gerbart, V. van Dorsselaer and C. Danzin, J. Med. Chem., 1983, 26, 1551; R. S. H. Liu, H. Matsumoto, A. E. Asato, M. Denny, Y. Shichida, T. Yashizawa and F. W. Dalquist, J. Am. Chem. Soc., 1986, 103, 7195. 2 Y.-Z. Huang, Y.-C. Shen, W.-Y. Ding, J.-H. Zheng, Tetrahedron Lett., 1981, 22, 5283; Y.-C. Shen, Y.-K. Lin and Y.-K. Xin, Tetruhedron Lett., 1985, 26, 5173; Y.-C. Shen and J.-H. Zheng, J. Fluorine Chem., 1987,35, 5 13 and references cited therein. 3 Y.-C. Shen and T.-L. Wang, Tetruhedron Lett., 1989,30,7203. 4 S. Fiji, Y. Make and H. Kimoto, J. Fluorine Chem., 1986,33, 329. Paper 0/04704J Receiued 19th October 1990 Accepted 29th October 1990