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A novel synthesis of functionalized gem-difluoro-penta-1,4-dienes
Journal of Fluorine Chemistry 109 (2001) 141±144
A novel synthesis of functionalized gem-di¯uoro-penta-1,4-dienes Yanchang Shen*, Guo-Fang Jiang, Guoping Wang, Yuming Zhang Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Academia Sinica, 345 Linglin Lu, Shanghai 200032, China Received 20 December 2000; accepted 22 February 2001
Abstract The 2,2-di¯uoro-1-tosyloxyvinyl anion 2, generated from the 2,2,2-tri¯uoroethyl p-toluenesulfonate 1 and 2 eq of n-butyllithium, reacted with a-ethoxycarbonyl vinylphosphonate 3 to give the phosphoryl-stabilized carbanion 4 which reacted further with a variety of aldehydes affording functionalized gem-di¯uoro-penta-1,4-dienes in 69±96% yields. # 2001 Elsevier Science B.V. All rights reserved. Keywords: Sequential transformations of phosphonates; Vinyl-phosphonate; 1,4-Dienes; Functionalized gem-di¯uoro-penta-1,4-dienes
1. Introduction The introduction of ¯uorine into an organic molecule has often been accompanied with profound changes in biological activities of the ¯uorinated compound when compared to its hydrocarbon one, and hence, organo¯uorine compounds have been applied increasingly in pharmaceuticals, agrochemicals and other ®elds [1±6]. gem-Di¯uoroalkenes bearing terminal di¯uoromethylene groups have remarkable reactivity toward nucleophilic addition±elimination processes [7] and could be used as useful synthetic building blocks in organic synthesis [8,9]. They also exhibit potent antiparasitic and anticonvulsant activities [10]. Few methods for their preparation are known [10±12], but multiple steps are necessary or else the starting materials are not easily available. Alka-1,4-dienes and their functionalized derivatives are important parts of the structure of a number of naturally occurring compounds which show biological activities and have been employed as useful intermediates for their synthesis, hence, such compounds have attracted much interest [13±16]. They are capable of undergoing synthetic transformation, such as cyclization to various six- or sevenmembered carbo- or hetero-cycles [17,18]. The 1,1-di¯uoro-1,3-dienes via coupling reaction have been reported [19] which are thermodynamically stable regioisomers. Nevertheless, 1,1-di¯uoro-1,4-dienes are not easy to obtain, because they are thermodynamically unstable with respect to 1,3-dienes. To the best of our knowledge, the *
Corresponding author. Fax: 86-21-64166128. E-mail address: [email protected] (Y. Shen).
synthesis of gem-di¯uor-1,4-dienes has not been reported in the literature except the synthesis of gem-di¯uorostyrenes [7]. Therefore, to develop an effective method for their preparation would be valuable. 2. Results and discussion In our continuing investigation of the sequential transformations of phosphonates in organic synthesis [20±23], herein we report sequential transformations of vinyl-phosphonate and its application to the synthesis of functionalized gem-di¯uoro-penta-1,4-dienes in 69±96% yields. The reaction sequence is shown in Scheme 1. The 2,2-di¯uoro-1-tosyloxyvinyl anion 2, generated from the 2,2,2-tri¯uoroethyl p-toluenesulfonate 1 and 2 eq of nbutyllithium, reacted with a-ethoxycarbonyl vinylphosphonate 3 to give the phosphoryl-stabilized carbanions 4 which reacted further with aldehydes affording functionalized gem-di¯uoro-penta-1,4-dienes. The results are summarized in Table 1. On the basis of data reported in [24], the chemical shift of the vinyl proton in the (E)-unsaturated ester will appear at lower ®eld than that for the corresponding (Z)isomer. Hence, the con®guration of the product could be ascertained. 3. Experimental The IR spectra of liquid products were obtained as ®lms on a Digilab FTS-20E spectrometer. 1 H NMR spectra were recorded on a Bruker AM-300 (300 MHz) spectrometer
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 1 1 3 9 ( 0 1 ) 0 0 3 9 3 - 1
142
Y. Shen et al. / Journal of Fluorine Chemistry 109 (2001) 141±144
that the aldehyde had disappeared. The mixture was poured into water (20 ml) and extracted with ethyl ether (3 10 ml). The organic layer was combined, washed with water (3 10 ml) and dried over Na2SO4. Evaporation of the solvent gave a residue, which was puri®ed by ion chromatography using silica gel eluting with petroleum ether (60±908C)-ethyl acetate (92:8) to give the products 5.
Scheme 1.
(d values in ppm from tetramethylsilane, in CDCl3, J-values are given in Hz). 19 F NMR spectra were taken on a Varian EM-360 (60 MHz) spectrometer (d in ppm from external tri¯uoroacetic acid, in CDCl3, positive for up ®eld shifts). Mass spectra were measured on a Finnigan GC±MS-4021 mass spectrometer. 3.1. a-Ethoxycarbonyl vinylphosphonate (1) The compound a-ethoxycarbonyl vinylphosphonate (1) was prepared according to the published procedure in [25]. 3.2. General procedure for the preparation of functionalized gem-difluoro-penta-1,4-dienes (5) The 2,2-di¯uoro-1-tosyloxyvinyl anion 2, generated from the 2,2,2-tri¯uoroethyl p-toluenesulfonate 1 (1 mmol) and n-butyllithium (2 mmol) in tetrahydrofuran (THF, 10 ml) were held at 788C for 30 min. To this solution a-ethoxycarbonyl vinylphosphonate (3, 1 mmol) was slowly added. After addition the reaction mixture was allowed to warm to 208C, stirred for 30 min and the aldehyde (0.8 mmol) was added. The mixture was further stirred for 2 h, TLC showed Table 1 Preparation of functionalized gem-difluoro-penta-1,4-dienes Compound
R
Yield (%)a
E:Zb
5a 5b 5c 5d 5e 5f 5g 5h
4-NO2C6H4 C6H5 4-FC6H4 3-BrC6H4 2,4-Cl2C6H3 4-ClC6H4 3-CF3OC6H4 3-Furyl
79 69 91 96 84 74 92 75
40:60 50:50 48:52 48:52 77:23 43:57 59:41 85:15
a b
data.
Isolated yields. The ratio of E- and Z-isomer was estimated on the basis of NMR
3.2.1. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(4-nitrophenyl)-1,4-pentadiene (5a) Yield 79%; mp 69±718C; E:Z 40:60. IR (®lm) (cm 1) 2990, 1770, 1640, 1600, 1520, 1380, 1300, 1200, 1080. 1 H NMR(CDCl3/TMS): d 1.09(Z) (t, J 7.1 Hz, 0:60 3H), 1.34(E) (t, J 7.1 Hz, 0:40 3H), 2.42(E) (s, 0:40 3H), 2.46(Z) (s, 0:60 3H), 3.46±3.51(m, 2H), 4.09(Z) (q, J 7.2 Hz, 0:60 2H), 4.30(E) (q, J 7.2 Hz, 0:40 2H), 6.93(Z) (s, 0:60 1H), 7.91(E) (s, 0:40 1H), 7.29±8.28(m, 8H). 19 F NMR(CDCl3/TFA): d 14.6(E) (d, J 54.5 Hz, 0:40 1F), 15.3(Z) (d, J 54.5 Hz, 0:60 1F), 28.7(d, J 54.5 Hz, 1F). MS m/z (rel. int.) 468 (M 1, 2), 312 (M Ts, 51), 284 (35), 155 (100), 139 (25), 115 (22), 91 (97). Analysis: calculated for C21H19F2NO7S (467.44): C, 53.96, H, 4.10, N, 3.00%; found: C, 54.07, H, 4.12, N, 3.03%. 3.2.2. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-phenyl-1,4-pentadiene (5b) Yield 69%; oil; E:Z 50:50. IR (®lm) (cm 1) 2990, 1770, 1710, 1640, 1600, 1380, 1300, 1230, 1180, 1110. 1 H NMR(CDCl3/TMS): d 1.09(Z) (t, J 7.1 Hz, 0:50 3H), 1.34(E) (t, J 7.1 Hz, 0:50 3H), 2.39(E) (s, 0:50 3H), 2.44(Z) (s, 0:50 3H), 3.39±3.54 (m, 2H), 4.09(Z) (q, J 7.2 Hz, 0:50 2H), 4.28(E) (q, J 7.2 Hz, 0:50 2H), 6.77(Z) (s, 0:50 1H), 7.24±7.43 (m, 7H), 7.72±7.80 (m, 2H), 7.86(E) (s, 0:50 1H). 19 F NMR(CDCl3/TFA): d 14.0(E) (d, J 54.5 Hz, 0:50 1F), 14.7(Z) (d, J 54.5 Hz, 0:50 1F), 27.7(E) (d, J 54.5 Hz, 0:50 1F), 28.0(Z) (d, J 54.5 Hz, 0:50 1F). MS m/z (rel. int.) 423 (M 1, 5), 377 (19), 335 (1), 311 (2), 267 (100), 239 (79), 221 (1). Analysis: calculated for C21H20F2O5S (422.44): C, 59.71, H, 4.77%; found: C, 59.43, H, 4.84%. 3.2.3. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(4-fluorophenyl)-1,4-pentadiene (5c) Yield 91%; oil; E:Z 48:52. IR (®lm) (cm 1) 2990, 1770, 1720, 1600, 1510, 1380, 1300, 1230, 1180, 1070. 1 H NMR(CDCl3/TMS): d 1.12(Z) (t, J 7.1 Hz, 0:52 3H), 1.33(E) (t, J 7.1 Hz, 0:48 3H), 2.41(E) (s, 0:48 3H), 2.45(Z) (s, 0:52 3H), 3.39±3.52(m, 2H), 4.11(Z) (q, J 7.1 Hz, 0:52 2H), 4.28(E) (q, J 7.1 Hz, 0:48 2H), 6.76(Z) (s, 0:52 1H), 6.97±7.12(m, 2H), 7.24±7.43(m, 4H), 7.83(E) (s, 0:48 1H), 7.73±7.86(m, 2H). 19 F NMR(CDCl3/TFA): d 14.1(E) (d, J 54.5 Hz, 0:48 1F), 15.2(Z) (d, J 54.5 Hz, 0:52 1F), 27.9(d, J 54.5 Hz, 1F), 35.0(d, J 77.0 Hz, 1F). MS m/z (rel. int.) 441 (M 1, 2), 394 (11), 284 (100), 256 (35), 238 (97), 155 (63), 133 (38),
Y. Shen et al. / Journal of Fluorine Chemistry 109 (2001) 141±144
91 (73). Analysis: calculated for C21H19F3O5S (440.43): C, 57.27, H, 4.35; found: C, 57.15, H, 4.45%. 3.2.4. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(3-bromophenyl)-1,4-pentadiene (5d) Yield 96%; oil; E:Z 48:52. IR (®lm) (cm 1) 2980, 1720, 1600, 1560, 1380, 1300, 1200, 1180, 1070. 1 H NMR(CDCl3/TMS): d 1.08(Z) (t, J 7.1 Hz, 0:52 3H), 1.31(E) (t, J 7.1 Hz, 0:48 3H), 2.37(E) (s, 0:48 3H), 2.42(Z) (s, 0:52 3H), 3.39±3.47(m, 2H), 4.08(Z) (q, J 7.1 Hz, 0:52 2H), 4.26(E) (q, J 7.1 Hz, 0:48 2H), 6.69(Z) (s, 0:52 1H), 7.15±7.46(m, 6H), 7.75(E) (s, 0:48 1H), 7.71±7.82(m, 2H). 19 F NMR(CDCl3/TFA): d 14.2(E) (d, J 48.0 Hz, 0:48 1F), 15.2(Z) (d, J 48.0 Hz, 0:52 1F), 27.8(d, J 48.0 Hz, 1F). MS m/z (rel. int.) 501 (M, 2), 455 (7), 346 (37), 318 (25), 298 (13), 155 (65), 139 (28), 115 (21) 91 (100), 65 (23). Analysis: calculated for C21H19BrF2O5S (501.33): C, 50.31, H, 3.82; found: C, 49.83, H, 3.80%. 3.2.5. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(2,4-dichlorophenyl)-1,4-pentadiene (5e) Yield 84%; oil; E:Z 77:23. IR (®lm) (cm 1) 2990, 1770, 1710, 1600, 1470, 1390, 1300, 1230, 1180, 1100. 1 H NMR(CDCl3/TMS): d 1.04(Z) (t, J 7.1 Hz, 0:23 3H), 1.31(E) (t, J 7.2 Hz, 0:77 3H), 2.41(E) (s, 0:77 3H), 2.43(Z) (s, 0:23 3H), 3.37±3.42 (m, 2H), 4.03(Z) (q, J 7.1 Hz, 0:23 2H), 4.27(E) (q, J 7.2 Hz, 0:77 2H), 6.85(Z) (s, 0:23 1H), 7.83(E) (s, 0:77 1H), 7.18± 7.85(m, 7H). 19 F NMR(CDCl3/TFA): d 15.1(E) (d, J 54.0 Hz, 0:77 1F), 15.7(Z) (d, J 54.0 Hz, 0:23 1F), 28.0(d, J 54.0 Hz, 1F). MS m/z (rel. int.) 491 (M 1, 2), 445 (5), 335 (65), 307 (27), 289 (48), 155 (85), 139 (26), 91 (100). Analysis: calculated for C21H18Cl2F2O5S (491.33): C, 51.34, H, 3.69; found: C, 51.39, H, 3.82%. 3.2.6. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(4-chlorophenyl)-1,4-pentadiene (5f) Yield 74%; oil; E:Z 43:57. IR (®lm) (cm 1) 2990, 1770, 1710, 1490, 1380, 1300, 1230, 1200, 1180. 1 H NMR(CDCl3/TMS):d 1.12(Z) (t, J 7.1 Hz, 0:57 3H), 1.33(E) (t, J 7.2 Hz, 0:43 3H), 2.41(E) (s, 0:43 3H), 2.44(Z) (s, 0:57 3H), 3.40±3.49 (m, 2H), 4.10(Z) (q, J 7.1 Hz, 0:57 2H), 4.28(E) (q, J 7.2 Hz, 0:43 2H), 6.75(Z) (s, 0:57 1H), 7.18(E) (s, 0:43 1H), 7.19± 7.86(m, 8H). 19 F NMR(CDCl3/TFA): d 13.9(E) (d, J 55.0 Hz, 0:43 1F), 14.8(Z) (d, J 55.0 Hz, 0:57 1F), 28.0(d, J 55.0 Hz, 1F). MS m/z (rel. int.) 457 (M 1, 25), 411 (33), 351 (59), 301 (100), 273 (9), 255 (62). Analysis: calculated for C21H19ClF2O5S (456.88): C, 55.21, H, 4.19; found: C, 55.41, H, 4.60%. 3.2.7. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(3-trifluromethoxyphenyl)-1,4-pentadiene (5g) Yield 92%; oil; E:Z 59:41. IR (®lm) (cm 1) 2990, 1770, 1720, 1380, 1300, 1260, 1220, 1180. 1 H NMR(CDCl3/
143
TMS): d 1.08(Z) (t, J 7.2 Hz, 0:41 3H), 1.34(E) (t, J 7.1 Hz, 0:59 3H), 2.40(E) (s, 0:59 3H), 2.45(Z) (s, 0:41 3H), 3.46±3.51(m, 2H), 4.09(Z) (q, J 7.2 Hz, 0:41 2H), 4.30(E) (q, J 7.2 Hz, 0:59 2H), 6.77(Z) (s, 0:41 1H), 7.13(E) (s, 0:59 1H), 7.12±8.85(m, 8H). 19 F NMR(CDCl3/TFA): d 19.8 (s,3F), 14.4(E) (d, J 54.0 Hz, 0:59 1F), 15.2(Z) (d, J 54.0 Hz, 0:41 1F), 28.2(d, J 54 Hz, 0:41 1F), 28.4(d, J 54 Hz, 0:59 1F) MS m/z (rel. int.) 507 (M 1, 22), 461 (28), 351 (100), 323 (13), 305 (23). Analysis: calculated for C22H19 F5O6S (506.44): C, 52.18, H, 3.78; found: C, 52.48, H, 4.19%. 3.2.8. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(4-furlyphenyl)-1,4-pentadiene (5h) Yield 75%; oil; E:Z 85:15. IR (®lm) (cm 1) 2990, 1770, 1710,1640, 1600, 1380, 1290, 1230, 1210, 1180. 1 H NMR(CDCl3/TMS): d 1.12(Z) (t, J 7.1 Hz, 0:15 3H), 1.28(E) (t, J 7.1 Hz, 0:85 3H), 2.41(E) (s, 3H), 3.80±3.86(m, 2H), 4.12(Z) (q, J 7.2 Hz, 0:15 2H), 4.22(E) (q, J 7.2 Hz, 0:85 2H), 6.44(Z) (dd, J 3.20, 2.80 Hz, 0:15 1H), 6.48(E) (dd, J 3.27, 2.27 Hz, 0:85 1H), 6.60(Z) (d, J 3.38 Hz, 0:15 1H), 6.64(E) (d, J 3.43 Hz, 0:85 1H), 7.27 (d, J 8.0, 2H), 7.36(Z) (s, 0:15 1H), 7.42(Z) (s, 0:15 1H), 7.46(E) (s, 0:85 1H), 7.55(E) (s, 0:85 1H), 7.76 (d, J 8.2 Hz, 2H). 19 F NMR(CDCl3/TFA): d 13.9(Z) (d, J 54.0 Hz, 0:15 1F), 14.5(E) (d, J 54.0 Hz, 0:85 1F), 27.4(d, J 54.0 Hz, 0:15 1F), 28.0(E) (d, J 54.0 Hz, 0:85 1F). MS m/z (rel. int.) 413 (M 1, 9), 367 (26), 299 (9), 257 (100), 229 (27), 211 (41). Analysis: calculated for C19H18F2O6S (412.40): C, 55.34, H, 4.40; found: C, 55.86, H, 4.71%. Acknowledgements Thanks are due to the National Natural Science Foundation of China and Academia Sinica for ®nancial support. References [1] J.T. Welch, Tetrahedron 43 (1987) 3123. [2] J.T. Welch, S. Eswarakrishnan, Fluorine in Biorganic Chemistry, Wiley, New York, 1991. [3] G. Resnati, Tetrahedron 49 (1993) 9385. [4] R. Filler, Y. Kobayashi, L.M. Yagupolskii (Eds.), Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications, Elsevier, Amsterdam, 1993. [5] A. Becker (Ed.), Inventory of Industrial Fluorobiochemicals, Eyrolles, PA, 1996. [6] R. Filler, Fluorine-containing chiral compounds of biomedical interest, ACS Symp. Ser. 746 (2000) 1±20. [7] J. Ichikawa, Y. Wada, T. Okauchi, T. Minami, Chem. Commun. (1997) 1537 and references cited therein. [8] J. Ichikawa, T. Sonoda, H. Kobayashi, Tetrahedron Lett. 30 (1989) 1641. [9] M.J. Tozer, T.F. Herpin, Tetrahedron 52 (1996) 8619.
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[10] P.T. Meinke, W.L. Shoop, B.F. Michael, T.A. Blizzard, G.R. Dawson, M.H. Fisher, H. Mroxik, Bioorg. Med. Chem. Lett. 8 (1998) 3643. [11] J. Ichikawa, M. Fujiwara, H. Nawata, T. Okauchi, T. Minami, Tetrahedron Lett. 37 (1996) 8799. [12] J.-P. Begue, D. Bonnet-Delpon, M.H. Rock, J. Chem. Soc., Perkin Trans. 1 (1996) 1409. [13] T. Cuvigny, C.H. Du Penhoat, M. Julia, Tetrahedron 42 (1986) 5329. [14] K. Mori, in: J. ApSimon (Ed.), The Total Synthesis of Natural Products, Vol. 4, Wiley, New York, 1981, p. 42. [15] P.A. Wender, P.E. Floreancig, T.E. GlassM, G. Natchus, A.J. Shuker, J.C. Sutton, Tetrahedron Lett. 36 (1995) 4939.
[16] M.B. Roe, M. Whittaker, G. Procter, Tetrahedron Lett. 36 (1995) 8103. [17] P. Knochel, J.F. Normant, Tetrahedron Lett. 25 (1984) 1475. [18] H.M.L. Davies, T.J. Clark, H.D. Smith, J. Org. Chem. 56 (1991) 3817. [19] J. Ichikawa, C. Ikeura, T. Minami, Synlett (1992) 739. [20] Y. Shen, J. Ni, J. Org. Chem. 62 (1997) 7260. [21] Y. Shen, P. Li, J. Ni, J. Sun, J. Org. Chem. 63 (1998) 9363. [22] Y. Shen, J. Ni, P. Li, J. Sun, J. Chem. Soc., Perkin Trans. 1 (1999) 509. [23] Y. Shen, G.-F. Jiang, Synthesis (2000) 502. [24] W.A. Kleschick, C.H. Heathcock, J. Org. Chem. 43 (1978) 1256. [25] J.M. McIntosh, R.A. Sieler, Can. J. Chem. 56 (1978) 226.
A novel synthesis of functionalized gem-di¯uoro-penta-1,4-dienes Yanchang Shen*, Guo-Fang Jiang, Guoping Wang, Yuming Zhang Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Academia Sinica, 345 Linglin Lu, Shanghai 200032, China Received 20 December 2000; accepted 22 February 2001
Abstract The 2,2-di¯uoro-1-tosyloxyvinyl anion 2, generated from the 2,2,2-tri¯uoroethyl p-toluenesulfonate 1 and 2 eq of n-butyllithium, reacted with a-ethoxycarbonyl vinylphosphonate 3 to give the phosphoryl-stabilized carbanion 4 which reacted further with a variety of aldehydes affording functionalized gem-di¯uoro-penta-1,4-dienes in 69±96% yields. # 2001 Elsevier Science B.V. All rights reserved. Keywords: Sequential transformations of phosphonates; Vinyl-phosphonate; 1,4-Dienes; Functionalized gem-di¯uoro-penta-1,4-dienes
1. Introduction The introduction of ¯uorine into an organic molecule has often been accompanied with profound changes in biological activities of the ¯uorinated compound when compared to its hydrocarbon one, and hence, organo¯uorine compounds have been applied increasingly in pharmaceuticals, agrochemicals and other ®elds [1±6]. gem-Di¯uoroalkenes bearing terminal di¯uoromethylene groups have remarkable reactivity toward nucleophilic addition±elimination processes [7] and could be used as useful synthetic building blocks in organic synthesis [8,9]. They also exhibit potent antiparasitic and anticonvulsant activities [10]. Few methods for their preparation are known [10±12], but multiple steps are necessary or else the starting materials are not easily available. Alka-1,4-dienes and their functionalized derivatives are important parts of the structure of a number of naturally occurring compounds which show biological activities and have been employed as useful intermediates for their synthesis, hence, such compounds have attracted much interest [13±16]. They are capable of undergoing synthetic transformation, such as cyclization to various six- or sevenmembered carbo- or hetero-cycles [17,18]. The 1,1-di¯uoro-1,3-dienes via coupling reaction have been reported [19] which are thermodynamically stable regioisomers. Nevertheless, 1,1-di¯uoro-1,4-dienes are not easy to obtain, because they are thermodynamically unstable with respect to 1,3-dienes. To the best of our knowledge, the *
Corresponding author. Fax: 86-21-64166128. E-mail address: [email protected] (Y. Shen).
synthesis of gem-di¯uor-1,4-dienes has not been reported in the literature except the synthesis of gem-di¯uorostyrenes [7]. Therefore, to develop an effective method for their preparation would be valuable. 2. Results and discussion In our continuing investigation of the sequential transformations of phosphonates in organic synthesis [20±23], herein we report sequential transformations of vinyl-phosphonate and its application to the synthesis of functionalized gem-di¯uoro-penta-1,4-dienes in 69±96% yields. The reaction sequence is shown in Scheme 1. The 2,2-di¯uoro-1-tosyloxyvinyl anion 2, generated from the 2,2,2-tri¯uoroethyl p-toluenesulfonate 1 and 2 eq of nbutyllithium, reacted with a-ethoxycarbonyl vinylphosphonate 3 to give the phosphoryl-stabilized carbanions 4 which reacted further with aldehydes affording functionalized gem-di¯uoro-penta-1,4-dienes. The results are summarized in Table 1. On the basis of data reported in [24], the chemical shift of the vinyl proton in the (E)-unsaturated ester will appear at lower ®eld than that for the corresponding (Z)isomer. Hence, the con®guration of the product could be ascertained. 3. Experimental The IR spectra of liquid products were obtained as ®lms on a Digilab FTS-20E spectrometer. 1 H NMR spectra were recorded on a Bruker AM-300 (300 MHz) spectrometer
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 1 1 3 9 ( 0 1 ) 0 0 3 9 3 - 1
142
Y. Shen et al. / Journal of Fluorine Chemistry 109 (2001) 141±144
that the aldehyde had disappeared. The mixture was poured into water (20 ml) and extracted with ethyl ether (3 10 ml). The organic layer was combined, washed with water (3 10 ml) and dried over Na2SO4. Evaporation of the solvent gave a residue, which was puri®ed by ion chromatography using silica gel eluting with petroleum ether (60±908C)-ethyl acetate (92:8) to give the products 5.
Scheme 1.
(d values in ppm from tetramethylsilane, in CDCl3, J-values are given in Hz). 19 F NMR spectra were taken on a Varian EM-360 (60 MHz) spectrometer (d in ppm from external tri¯uoroacetic acid, in CDCl3, positive for up ®eld shifts). Mass spectra were measured on a Finnigan GC±MS-4021 mass spectrometer. 3.1. a-Ethoxycarbonyl vinylphosphonate (1) The compound a-ethoxycarbonyl vinylphosphonate (1) was prepared according to the published procedure in [25]. 3.2. General procedure for the preparation of functionalized gem-difluoro-penta-1,4-dienes (5) The 2,2-di¯uoro-1-tosyloxyvinyl anion 2, generated from the 2,2,2-tri¯uoroethyl p-toluenesulfonate 1 (1 mmol) and n-butyllithium (2 mmol) in tetrahydrofuran (THF, 10 ml) were held at 788C for 30 min. To this solution a-ethoxycarbonyl vinylphosphonate (3, 1 mmol) was slowly added. After addition the reaction mixture was allowed to warm to 208C, stirred for 30 min and the aldehyde (0.8 mmol) was added. The mixture was further stirred for 2 h, TLC showed Table 1 Preparation of functionalized gem-difluoro-penta-1,4-dienes Compound
R
Yield (%)a
E:Zb
5a 5b 5c 5d 5e 5f 5g 5h
4-NO2C6H4 C6H5 4-FC6H4 3-BrC6H4 2,4-Cl2C6H3 4-ClC6H4 3-CF3OC6H4 3-Furyl
79 69 91 96 84 74 92 75
40:60 50:50 48:52 48:52 77:23 43:57 59:41 85:15
a b
data.
Isolated yields. The ratio of E- and Z-isomer was estimated on the basis of NMR
3.2.1. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(4-nitrophenyl)-1,4-pentadiene (5a) Yield 79%; mp 69±718C; E:Z 40:60. IR (®lm) (cm 1) 2990, 1770, 1640, 1600, 1520, 1380, 1300, 1200, 1080. 1 H NMR(CDCl3/TMS): d 1.09(Z) (t, J 7.1 Hz, 0:60 3H), 1.34(E) (t, J 7.1 Hz, 0:40 3H), 2.42(E) (s, 0:40 3H), 2.46(Z) (s, 0:60 3H), 3.46±3.51(m, 2H), 4.09(Z) (q, J 7.2 Hz, 0:60 2H), 4.30(E) (q, J 7.2 Hz, 0:40 2H), 6.93(Z) (s, 0:60 1H), 7.91(E) (s, 0:40 1H), 7.29±8.28(m, 8H). 19 F NMR(CDCl3/TFA): d 14.6(E) (d, J 54.5 Hz, 0:40 1F), 15.3(Z) (d, J 54.5 Hz, 0:60 1F), 28.7(d, J 54.5 Hz, 1F). MS m/z (rel. int.) 468 (M 1, 2), 312 (M Ts, 51), 284 (35), 155 (100), 139 (25), 115 (22), 91 (97). Analysis: calculated for C21H19F2NO7S (467.44): C, 53.96, H, 4.10, N, 3.00%; found: C, 54.07, H, 4.12, N, 3.03%. 3.2.2. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-phenyl-1,4-pentadiene (5b) Yield 69%; oil; E:Z 50:50. IR (®lm) (cm 1) 2990, 1770, 1710, 1640, 1600, 1380, 1300, 1230, 1180, 1110. 1 H NMR(CDCl3/TMS): d 1.09(Z) (t, J 7.1 Hz, 0:50 3H), 1.34(E) (t, J 7.1 Hz, 0:50 3H), 2.39(E) (s, 0:50 3H), 2.44(Z) (s, 0:50 3H), 3.39±3.54 (m, 2H), 4.09(Z) (q, J 7.2 Hz, 0:50 2H), 4.28(E) (q, J 7.2 Hz, 0:50 2H), 6.77(Z) (s, 0:50 1H), 7.24±7.43 (m, 7H), 7.72±7.80 (m, 2H), 7.86(E) (s, 0:50 1H). 19 F NMR(CDCl3/TFA): d 14.0(E) (d, J 54.5 Hz, 0:50 1F), 14.7(Z) (d, J 54.5 Hz, 0:50 1F), 27.7(E) (d, J 54.5 Hz, 0:50 1F), 28.0(Z) (d, J 54.5 Hz, 0:50 1F). MS m/z (rel. int.) 423 (M 1, 5), 377 (19), 335 (1), 311 (2), 267 (100), 239 (79), 221 (1). Analysis: calculated for C21H20F2O5S (422.44): C, 59.71, H, 4.77%; found: C, 59.43, H, 4.84%. 3.2.3. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(4-fluorophenyl)-1,4-pentadiene (5c) Yield 91%; oil; E:Z 48:52. IR (®lm) (cm 1) 2990, 1770, 1720, 1600, 1510, 1380, 1300, 1230, 1180, 1070. 1 H NMR(CDCl3/TMS): d 1.12(Z) (t, J 7.1 Hz, 0:52 3H), 1.33(E) (t, J 7.1 Hz, 0:48 3H), 2.41(E) (s, 0:48 3H), 2.45(Z) (s, 0:52 3H), 3.39±3.52(m, 2H), 4.11(Z) (q, J 7.1 Hz, 0:52 2H), 4.28(E) (q, J 7.1 Hz, 0:48 2H), 6.76(Z) (s, 0:52 1H), 6.97±7.12(m, 2H), 7.24±7.43(m, 4H), 7.83(E) (s, 0:48 1H), 7.73±7.86(m, 2H). 19 F NMR(CDCl3/TFA): d 14.1(E) (d, J 54.5 Hz, 0:48 1F), 15.2(Z) (d, J 54.5 Hz, 0:52 1F), 27.9(d, J 54.5 Hz, 1F), 35.0(d, J 77.0 Hz, 1F). MS m/z (rel. int.) 441 (M 1, 2), 394 (11), 284 (100), 256 (35), 238 (97), 155 (63), 133 (38),
Y. Shen et al. / Journal of Fluorine Chemistry 109 (2001) 141±144
91 (73). Analysis: calculated for C21H19F3O5S (440.43): C, 57.27, H, 4.35; found: C, 57.15, H, 4.45%. 3.2.4. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(3-bromophenyl)-1,4-pentadiene (5d) Yield 96%; oil; E:Z 48:52. IR (®lm) (cm 1) 2980, 1720, 1600, 1560, 1380, 1300, 1200, 1180, 1070. 1 H NMR(CDCl3/TMS): d 1.08(Z) (t, J 7.1 Hz, 0:52 3H), 1.31(E) (t, J 7.1 Hz, 0:48 3H), 2.37(E) (s, 0:48 3H), 2.42(Z) (s, 0:52 3H), 3.39±3.47(m, 2H), 4.08(Z) (q, J 7.1 Hz, 0:52 2H), 4.26(E) (q, J 7.1 Hz, 0:48 2H), 6.69(Z) (s, 0:52 1H), 7.15±7.46(m, 6H), 7.75(E) (s, 0:48 1H), 7.71±7.82(m, 2H). 19 F NMR(CDCl3/TFA): d 14.2(E) (d, J 48.0 Hz, 0:48 1F), 15.2(Z) (d, J 48.0 Hz, 0:52 1F), 27.8(d, J 48.0 Hz, 1F). MS m/z (rel. int.) 501 (M, 2), 455 (7), 346 (37), 318 (25), 298 (13), 155 (65), 139 (28), 115 (21) 91 (100), 65 (23). Analysis: calculated for C21H19BrF2O5S (501.33): C, 50.31, H, 3.82; found: C, 49.83, H, 3.80%. 3.2.5. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(2,4-dichlorophenyl)-1,4-pentadiene (5e) Yield 84%; oil; E:Z 77:23. IR (®lm) (cm 1) 2990, 1770, 1710, 1600, 1470, 1390, 1300, 1230, 1180, 1100. 1 H NMR(CDCl3/TMS): d 1.04(Z) (t, J 7.1 Hz, 0:23 3H), 1.31(E) (t, J 7.2 Hz, 0:77 3H), 2.41(E) (s, 0:77 3H), 2.43(Z) (s, 0:23 3H), 3.37±3.42 (m, 2H), 4.03(Z) (q, J 7.1 Hz, 0:23 2H), 4.27(E) (q, J 7.2 Hz, 0:77 2H), 6.85(Z) (s, 0:23 1H), 7.83(E) (s, 0:77 1H), 7.18± 7.85(m, 7H). 19 F NMR(CDCl3/TFA): d 15.1(E) (d, J 54.0 Hz, 0:77 1F), 15.7(Z) (d, J 54.0 Hz, 0:23 1F), 28.0(d, J 54.0 Hz, 1F). MS m/z (rel. int.) 491 (M 1, 2), 445 (5), 335 (65), 307 (27), 289 (48), 155 (85), 139 (26), 91 (100). Analysis: calculated for C21H18Cl2F2O5S (491.33): C, 51.34, H, 3.69; found: C, 51.39, H, 3.82%. 3.2.6. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(4-chlorophenyl)-1,4-pentadiene (5f) Yield 74%; oil; E:Z 43:57. IR (®lm) (cm 1) 2990, 1770, 1710, 1490, 1380, 1300, 1230, 1200, 1180. 1 H NMR(CDCl3/TMS):d 1.12(Z) (t, J 7.1 Hz, 0:57 3H), 1.33(E) (t, J 7.2 Hz, 0:43 3H), 2.41(E) (s, 0:43 3H), 2.44(Z) (s, 0:57 3H), 3.40±3.49 (m, 2H), 4.10(Z) (q, J 7.1 Hz, 0:57 2H), 4.28(E) (q, J 7.2 Hz, 0:43 2H), 6.75(Z) (s, 0:57 1H), 7.18(E) (s, 0:43 1H), 7.19± 7.86(m, 8H). 19 F NMR(CDCl3/TFA): d 13.9(E) (d, J 55.0 Hz, 0:43 1F), 14.8(Z) (d, J 55.0 Hz, 0:57 1F), 28.0(d, J 55.0 Hz, 1F). MS m/z (rel. int.) 457 (M 1, 25), 411 (33), 351 (59), 301 (100), 273 (9), 255 (62). Analysis: calculated for C21H19ClF2O5S (456.88): C, 55.21, H, 4.19; found: C, 55.41, H, 4.60%. 3.2.7. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(3-trifluromethoxyphenyl)-1,4-pentadiene (5g) Yield 92%; oil; E:Z 59:41. IR (®lm) (cm 1) 2990, 1770, 1720, 1380, 1300, 1260, 1220, 1180. 1 H NMR(CDCl3/
143
TMS): d 1.08(Z) (t, J 7.2 Hz, 0:41 3H), 1.34(E) (t, J 7.1 Hz, 0:59 3H), 2.40(E) (s, 0:59 3H), 2.45(Z) (s, 0:41 3H), 3.46±3.51(m, 2H), 4.09(Z) (q, J 7.2 Hz, 0:41 2H), 4.30(E) (q, J 7.2 Hz, 0:59 2H), 6.77(Z) (s, 0:41 1H), 7.13(E) (s, 0:59 1H), 7.12±8.85(m, 8H). 19 F NMR(CDCl3/TFA): d 19.8 (s,3F), 14.4(E) (d, J 54.0 Hz, 0:59 1F), 15.2(Z) (d, J 54.0 Hz, 0:41 1F), 28.2(d, J 54 Hz, 0:41 1F), 28.4(d, J 54 Hz, 0:59 1F) MS m/z (rel. int.) 507 (M 1, 22), 461 (28), 351 (100), 323 (13), 305 (23). Analysis: calculated for C22H19 F5O6S (506.44): C, 52.18, H, 3.78; found: C, 52.48, H, 4.19%. 3.2.8. 5,5-Difluoro-4-tosyloxy-2-ethoxycarbonyl1-(4-furlyphenyl)-1,4-pentadiene (5h) Yield 75%; oil; E:Z 85:15. IR (®lm) (cm 1) 2990, 1770, 1710,1640, 1600, 1380, 1290, 1230, 1210, 1180. 1 H NMR(CDCl3/TMS): d 1.12(Z) (t, J 7.1 Hz, 0:15 3H), 1.28(E) (t, J 7.1 Hz, 0:85 3H), 2.41(E) (s, 3H), 3.80±3.86(m, 2H), 4.12(Z) (q, J 7.2 Hz, 0:15 2H), 4.22(E) (q, J 7.2 Hz, 0:85 2H), 6.44(Z) (dd, J 3.20, 2.80 Hz, 0:15 1H), 6.48(E) (dd, J 3.27, 2.27 Hz, 0:85 1H), 6.60(Z) (d, J 3.38 Hz, 0:15 1H), 6.64(E) (d, J 3.43 Hz, 0:85 1H), 7.27 (d, J 8.0, 2H), 7.36(Z) (s, 0:15 1H), 7.42(Z) (s, 0:15 1H), 7.46(E) (s, 0:85 1H), 7.55(E) (s, 0:85 1H), 7.76 (d, J 8.2 Hz, 2H). 19 F NMR(CDCl3/TFA): d 13.9(Z) (d, J 54.0 Hz, 0:15 1F), 14.5(E) (d, J 54.0 Hz, 0:85 1F), 27.4(d, J 54.0 Hz, 0:15 1F), 28.0(E) (d, J 54.0 Hz, 0:85 1F). MS m/z (rel. int.) 413 (M 1, 9), 367 (26), 299 (9), 257 (100), 229 (27), 211 (41). Analysis: calculated for C19H18F2O6S (412.40): C, 55.34, H, 4.40; found: C, 55.86, H, 4.71%. Acknowledgements Thanks are due to the National Natural Science Foundation of China and Academia Sinica for ®nancial support. References [1] J.T. Welch, Tetrahedron 43 (1987) 3123. [2] J.T. Welch, S. Eswarakrishnan, Fluorine in Biorganic Chemistry, Wiley, New York, 1991. [3] G. Resnati, Tetrahedron 49 (1993) 9385. [4] R. Filler, Y. Kobayashi, L.M. Yagupolskii (Eds.), Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications, Elsevier, Amsterdam, 1993. [5] A. Becker (Ed.), Inventory of Industrial Fluorobiochemicals, Eyrolles, PA, 1996. [6] R. Filler, Fluorine-containing chiral compounds of biomedical interest, ACS Symp. Ser. 746 (2000) 1±20. [7] J. Ichikawa, Y. Wada, T. Okauchi, T. Minami, Chem. Commun. (1997) 1537 and references cited therein. [8] J. Ichikawa, T. Sonoda, H. Kobayashi, Tetrahedron Lett. 30 (1989) 1641. [9] M.J. Tozer, T.F. Herpin, Tetrahedron 52 (1996) 8619.
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