4896
M.-Y. Chang et al. / Tetrahedron 67 (2011) 4892e4896
acetate); IR (CHCl3) 3418, 2940,1768,1133 cmꢂ1; HRMS (ESI, Mþþ1)
ethyl acetate¼4/1 to 2/1) afforded compound 4 (65 mg, 66%). Vis-
cous oil; IR (CHCl3) 3434, 2938, 2158, 1777, 1145 cmꢂ1; HRMS (ESI,
Mþþ1) calcd for C16H19N2O4S 335.1066, found 335.1068; 1H NMR
calcd for C15H18NO4S 308.0957, found 308.0961; 1H NMR
(400 MHz):
d
7.78e7.74 (m, 2H), 7.62e7.48 (m, 3H), 6.98 (dd, J¼1.2,
8.4 Hz, 1H), 6.81 (dd, J¼0.4, 8.4 Hz, 1H), 5.29 (t, J¼0.4 Hz, 1H), 4.08
(400 MHz): d 7.92e7.89 (m, 2H), 7.68e7.63 (m, 1H), 7.59e7.52 (m,
(q, J¼7.2 Hz, 2H), 3.39 (t, J¼6.4 Hz, 2H), 2.48 (dt, J¼1.2, 6.8 Hz, 2H),
2H), 6.06 (d, J¼3.6 Hz, 1H), 4.11 (q, J¼7.2 Hz, 2H), 3.72 (ddd, J¼3.6,
6.4, 14.0 Hz, 1H), 3.43 (ddd, J¼2.8, 9.6, 14.0 Hz, 1H), 2.74e2.66 (m,
1H), 2.23 (dd, J¼6.4, 16.0 Hz, 1H), 2.15 (dd, J¼8.0, 16.0 Hz, 1H), 1.75
(ddt, J¼2.8, 6.4, 13.2 Hz, 1H), 1.23 (t, J¼7.2 Hz, 3H), 1.19e1.16 (m, 1H);
1.19 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz):
d 166.55, 146.56, 136.89,
133.38, 129.32 (2ꢁ), 126.88 (2ꢁ), 112.58, 110.44, 105.88, 59.59,
42.66, 24.71, 14.07. Anal. Calcd for C15H17NO4S: C, 58.61; H, 5.57; N,
4.56. Found: C, 58.88; H, 5.90; N, 4.89. Single-crystal X-ray diagram:
crystal of compound 8 was grown by slow diffusion of ethyl acetate
into a solution of compound 8 in dichloromethane to yield colorless
prism. The compound crystallizes in the triclinic crystal system,
13C NMR (100 MHz):
127.51 (2ꢁ), 114.51, 113.57, 60.93, 44.18, 38.36, 30.35, 25.94, 14.11.
d
170.65, 162.82, 137.77, 133.71, 129.45 (2ꢁ),
Acknowledgements
ꢀ
ꢀ
ꢀ
space group Pꢂ1, a¼8.1105 (3) A, b¼8.1143 (3) A, c¼12.6883 (4) A,
V¼730.14 (4) A , Z¼2, Dcalcd¼1.398 g/cm3, F(000)¼324, 2
q
range
3
ꢀ
The authors would like to thank the National Science Council of
the Republic of China for its financial support (NSC 99-2113-M-037-
006-MY3). The project is also supported by a grant from the
Kaohsiung Medical Research Foundation (KMU-Q100004).
1.65e26.40ꢀ, R indices (all data) R1¼0.0348, wR2¼0.0930.
4.5. (1-Benzenesulfonyl-6-cyano-2,3-dihydro-1H-pyridin-4-
ylidene)acetic acid ethyl ester (9) and (1-benzenesulfonyl-2,3-
dihydro-1H-pyridin-4-ylidene)-bromo-acetic acid ethyl ester (9a)
References and notes
N-Bromosuccinimide (90 mg, 0.5 mmol) was added to a solution
of compound 8 (123 mg, 0.4 mmol) with trimethylsilyl cyanide
(3 mL) in dichloromethane (10 mL) at rt. The reaction mixture was
stirred at rt for 5 min. Boron trifluoride etherate (w0.1 mL) was
added to the reaction mixture. The reaction mixture was stirred at
rt for 3 h. Saturated sodium bicarbonate solution (2 mL) was added
to the reaction mixture and the solvent was concentrated under
reduced pressure. The residue was extracted with ethyl acetate
(3ꢁ30 mL). The combined organic layers were washed with brine,
dried, filtered, and evaporated to afford crude product under re-
duced pressure. Purification on silica gel (hexane/ethyl acetate¼6/1
to 3/1) afforded compounds 9 (96 mg, 72%) and 9a (16 mg, 10%). For
compound 9: white solid; mp¼64e65 ꢀC (recrystallized from
hexane and ethyl acetate); IR (CHCl3) 3424, 2948, 2134, 1771,
1138 cmꢂ1; HRMS (ESI, Mþþ1) calcd for C16H17N2O4S 333.0909,
1. For reviews on the synthesis of piperidine, see:(a)Buffat, M. G. P. Tetrahedron 2004,
60,1701; (b) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron
2003, 59, 2953; (c) Sorbera, L. A.; Serradell, N.; Bolos, J.; Rosa, E.; Bozzo, J. Drugs
Future 2007, 32, 674; (d) Laschat, S.; Dickner, T. Synthesis 2000, 1781.
2. For reviews, see: (a) Kallstrom, S.; Leino, R. Bioorg. Med. Chem. 2008, 16, 601; (b)
Wijdeven, M. A.; Willemsen, J.; Rutjes, F. P. J. T. Eur. J. Org. Chem. 2010, 2831.
3. (a) Bursavich, M. G.; West, C. W.; Rich, D. H. Org. Lett. 2001, 3, 2317; (b) Plietker,
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Lett. 2005, 46, 447; (d) Surmont, R.; Verniest, G.; de Groot, A.; Thuring, J. W.; de
Kimpe, N. Adv. Synth. Catal. 2010, 352, 2751.
4. (a) Kadouri-Puchot, C.; Comesse, S. Amino Acids 2005, 29, 101; (b) Watanabe, L.
A.; Haranaka, S.; Jose, B.; Yoshida, M.; Kato, T.; Moriguchi, M.; Soda, S.; Nishino,
N. Tetrahedron: Asymmetry 2005, 16, 903 and references cited herein; (c) Car-
ballo, R. M.; Valdomir, G.; Purino, M.; Martin, V. S.; Padron, J. I. Eur. J. Org. Chem.
2010, 2304; (d) Leon, L. G.; Carballo, R. M.; Vega-Hernandez, M. C.; Martín, V. S.;
Padron, J. I.; Padron, J. M. Bioorg. Med. Chem. Lett. 2007, 17, 2681; (e) Enders, D.;
Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359 and references cited herein.
5. For synthesis of LY233053, see: (a) Ornstein, P. L.; Schoepp, D. D.; Arnold, M. B.;
Leander, J. D.; Lodge, D.; Paschal, J. W.; Elzey, T. J. Med. Chem. 1991, 34, 90; (b)
Ornstein, P. L.; Schaus, J. M.; Chambers, J. W.; Huser, D. L.; Leander, J. D.; Wong,
D. T.; Paschal, J. W.; Jones, N. D.; Deeter, J. B. J. Med. Chem. 1989, 32, 827; (c)
Ornstein, P. L.; Schoepp, D. D.; Arnold, M. B.; Jones, N. D.; Deeter, J. B.; Lodge, D.;
Leander, J. D. J. Med. Chem. 1992, 35, 3111; (d) Ornstein, P. L. U.S. Patent
4,968,678, 1990.
6. For synthesis of selfotel (CGS 19755), see: Hutchison, A. J.; Williams, M.; Angst,
C.; de Jesus, R.; Blanchard, L.; Jackson, R. H.; Wilusz, E. J.; Murphy, D. E.; Ber-
nard, P. S.; Scheider, J.; Campbell, T.; Guida, W.; Sills, M. A. J. Med. Chem. 1989,
32, 2171.
7. (a) Skiles, J. W.; Giannousis, P. P.; Fales, K. R. Bioorg. Med. Chem. Lett. 1996, 6,
963; (b) Ooi, H.; Urushibara, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett.
2001, 3, 953; (c) Pilli, R. A.; Correa, I. R., Jr.; Maldaner, A. O.; Rosso, G. B. Pure
Appl. Chem. 2005, 77, 1153; (d) Etayo, P.; Badorrey, R.; Diaz-Villegas, M. D.;
Galvez, J. A. Synlett 2010, 2799.
8. Etayo, P.;Badorrey, R.;Diaz-Villegas, M. D.;Galvez, J. A. Eur. J. Org. Chem. 2008, 3474.
9. (a) Ganorkar, R.; Natarajan, A.; Mamai, A.; Madalengoitia, J. S. J. Org. Chem. 2006,
71, 5004; (b) Barkallah, S.; Schneider, S. L.; McCafferty, D. G. Tetrahedron Lett.
2005, 46, 4985; (c) Quancard, J.; Labonne, A.; Jacquot, Y.; Chassaing, G.; Lavielle,
S.; Karoyan, P. J. Org. Chem. 2004, 69, 7940.
10. (a) Lu, S. P.; Lewin, A. H. Tetrahedron 1998, 54, 15097; (b) Osipov, S. N.; Kolo-
miets, A. F.; Bruneau, C.; Picquet, M.; Dixneuf, P. H. Chem. Commun. 1998, 2053.
11. (a) Giblin, G. M. P.; Jones, C. D.; Simpkins, N. S. J. Chem. Soc., Perkin Trans. 1 1998,
3689; (b) Xu, R.; Chu, G.; Bai, D. Tetrahedron Lett. 1996, 37, 1463.
found 333.0912; 1H NMR (400 MHz):
d 7.96e7.93 (m, 2H),
7.69e7.65 (m, 1H), 7.60e7.56 (m, 2H), 6.32 (s, 1H), 5.74 (s, 1H), 4.14
(q, J¼7.2 Hz, 2H), 3.70 (t, J¼6.0 Hz, 2H), 2.93e2.90 (m, 2H), 1.25 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz):
d 165.36, 143.54, 137.92, 134.05,
129.68 (2ꢁ), 128.67, 127.42 (2ꢁ), 119.71, 115.86, 114.06, 60.51, 44.83,
24.97, 14.12. Anal. Calcd for C16H16N2O4S: C, 57.82; H, 4.85; N, 8.43.
Found: C, 58.01; H, 5.10; N, 8.78. For compound 9a: white solid;
mp¼107e108 ꢀC (recrystallized from hexane and ethyl acetate); IR
(CHCl3) 3432, 2931, 1760, 1122 cmꢂ1
;
1H NMR (200 MHz):
d
7.81e7.78 (m, 2H), 7.60e7.53 (m, 3H), 7.11 (d, J¼8.0 Hz, 1H), 6.01
(d, J¼8.0 Hz, 1H), 4.21 (q, J¼7.2 Hz, 2H), 3.40 (t, J¼6.6 Hz, 2H), 3.04
(t, J¼6.6 Hz, 2H), 1.28 (t, J¼7.2 Hz, 3H). Anal. Calcd for
C15H16BrNO4S: C, 46.64; H, 4.18; N, 3.63. Found: C, 46.82; H, 4.49; N,
3.79. Single-crystal X-ray diagram: crystal of compound 9a was
grown by slow diffusion of ethyl acetate into a solution of com-
pound 9a in dichloromethane to yield colorless prism. The com-
pound crystallizes in the monoclinic crystal system, space group P 1
ꢀ
ꢀ
ꢀ
21/c 1, a¼10.0231 (10) A, b¼5.4646 (6) A, c¼28.654 (3) A, V¼1568.7
(3) A , Z¼4, Dcalcd¼1.636 g/cm3, F(000)¼784, 2
q
range 1.42e26.44ꢀ,
3
ꢀ
12. CCDC 806211 (7a), 806222 (8), and 806564 (9a) contain the supplementary
crystallographic data for this paper. This data can be obtained free of charge via
13. (a) Padmapriya, A. A.; Just, G.; Lewis, N. G. Synth. Commun. 1985, 15, 1057; (b)
Rettenbacher, A. S.; Schantl, J. G. ARKIVOC 2001, v, 36.
14. (a) Koike, T.; Tanabe, M.; Takeuchi, N.; Tobinaga, S. Chem. Pharm. Bull. 1997, 45,
243; (b) Rajappa, S. Tetrahedron 1981, 37, 1453; (c) Bagley, M. C.; Glover, C.;
Merritt, E. A.; Xiong, X. Synlett 2004, 811.
15. Shao, C. L.; Wang, C. Y.; Wei, M. Y.; Gu, Y. C.; She, Z. G.; Qian, P. Y.; Lin, Y. C.
Bioorg. Med. Chem. Lett. 2011, 21, 690.
16. (a) Ohashi, A.; Imamoto, T. Org. Lett. 2001, 3, 373; (b) Shultz, C. S.; Dreher, S. D.;
Ikemoto, N.; Williams, J. M.; Grabowski, E. J. J.; Krska, S. W.; Sun, Y.; Dormer, P.
G.; DiMichele, L. Org. Lett. 2005, 7, 3405.
R indices (all data) R1¼0.0603, wR2¼0.1562.
4.6. (1-Benzenesulfonyl-6-cyano-1,2,3,4-tetrahydropyridin-4-yl)
acetic acid ethyl ester (4)
Palladium on activated carbon (10%, 5 mg) was added to a solu-
tion of compound 9 (100 mg, 0.3 mmol) in ethyl acetate (10 mL).
Then hydrogen was bubbled into the mixture for 10 min, and stirring
occurred at rt for 20 h. The reaction mixture was filtered and
evaporated to yield crude product. Purification on silica gel (hexane/