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H. S. Lee et al. / Tetrahedron Letters 50 (2009) 2274–2277
Ph
EtOOC
Ph
SnBu3
n-Bu3SnH
COOEt
COOEt
COOEt
(2.5 equiv)
3a
+
H
N
Ph
N
Ph
AIBN, benzene
reflux, 1 h
K2CO3 (2.0 equiv)
DMF, rt, 48 h
N
Ph
Br
Br
N
Ph
2d (68%)
4g (85%)
(77%)
5g (50%), 3:2 mixture
6 (21%), 1:1 mixture
aniline (3 equiv)
THF, reflux, 36 h
4g'
COOEt
COOEt
Ph
1b
N
Ph
N
Ph
SnBu3
4g'
Scheme 4.
Ph
MeOOC
Ph
COOMe
SnBu3
+
N
Ph
N
Ph
n-Bu3SnH
COOMe
H
COOMe
5h (31%)
7 (24%), 1:1 mixture
(2.5 equiv)
3b
AIBN, benzene
reflux, 2 h
K2CO3 (2.0 equiv)
DMF, rt, 48 h
Br
2e (62%)
N
Br
4h (86%)
N
Ph
Ph
Ph
Ph
MeOOC
MeOOC
N
Ph
N
Ph
aniline (3 equiv)
THF, reflux, 48 h
8 (12%)
9 (28%)
1a
Scheme 5.
2008, EP 1908471 A1; Chem. Abstr. 2008, 148, 449462.; (c) Bursavich, M. G.;
West, C. W.; Rich, D. H. Org. Lett. 2001, 3, 2317–2320; (d) Bezencon, O.; Bur, D.;
Fischli, W.; Remen, L.; Richard-Bildstein, S.; Weller, T. 2004, WO 002957 A1;
Chem. Abstr. 2004, 140, 93928.
consecutive 1,5-hydrogen transfer and double bond isomerization
process. Applications of this methodology are currently underway
for the synthesis of paroxetine derivatives having 5-alkyls.
6. For the general review on Baylis–Hillman reaction, see: (a) Basavaiah, D.; Rao,
A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–891; (b) Kim, J. N.; Lee, K. Y.
Curr. Org. Chem. 2002, 6, 627–645; (c) Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Bull.
Korean Chem. Soc. 2005, 26, 1481–1490; (d) Singh, V.; Batra, S. Tetrahedron
2008, 64, 4511–4574. and further references cited therein.
Acknowledgments
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD, KRF-2008-
313-C00487). Spectroscopic data were obtained from the Korea Ba-
sic Science Institute, Gwangju branch.
7. For the radical cyclizations involving the Baylis–Hillman adducts, see: (a)
Singh, V.; Batra, S. Tetrahedron Lett. 2006, 47, 7043–7045; (b) Majhi, T. P.; Neogi,
A.; Ghosh, S.; Mukherjee, A. K.; Chattopadhyay, P. Tetrahedron 2006, 62, 12003–
12010; (c) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Commun. 1999,
1913–1914; (d) Alcaide, B.; Almendros, P.; Aragoncillo, C. J. Org. Chem. 2001, 66,
1612–1620; (e) Gowrisankar, S.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2007, 48,
3105–3108; (f) Gowrisankar, S.; Lee, K. Y.; Kim, T. H.; Kim, J. N. Tetrahedron Lett.
2006, 47, 5785–5788; (g) Gowrisankar, S.; Lee, H. S.; Kim, J. N. Bull. Korean
Chem. Soc. 2006, 27, 2097–2100; (h) Gowrisankar, S.; Lee, K. Y.; Kim, J. N. Bull.
Korean Chem. Soc. 2006, 27, 929–932; (i) Park, D. Y.; Gowrisankar, S.; Kim, J. N.
Bull. Korean Chem. Soc. 2005, 26, 1440–1442; (j) Gowrisankar, S.; Lee, K. Y.; Kim,
J. N. Tetrahedron Lett. 2005, 46, 4859–4863; (k) Lee, H. S.; Kim, H. S.; Kim, J. M.;
Kim, J. N. Tetrahedron 2008, 64, 2397–2404. and further references cited
therein.
References and notes
1. For the radical cyclizations involving 1,5-hydrogen transfer, see: (a)
Gowrisankar, S.; Kim, S. J.; Lee, J.-E.; Kim, J. N. Tetrahedron Lett. 2007, 48,
4419–4422; (b) Rancourt, J.; Gorys, V.; Jolicoeur, E. Tetrahedron Lett. 1998, 39,
5339–5342.
2. For the radical cyclizations involving 1,6-hydrogen transfer, see: (a) Prediger, I.;
Weiss, T.; Reiser, O. Synthesis 2008, 2191–2198; (b) Lin, H.; Schall, A.; Reiser, O.
Synlett 2005, 2603–2606.
3. For the synthesis and the synthetic applications of 1,4,5,6-tetrahydropyridine
derivatives, see: (a) Kim, M. G.; Bodor, E. T.; Wang, C.; Harden, T. K.; Kohn, H. J.
Med. Chem. 2003, 46, 2216–2226; (b) Tingoli, M.; Tiecco, M.; Testaferri, L.;
Andrenacci, R.; Balducci, R. J. Org. Chem. 1993, 58, 6097–6102; (c) Carranco, I.;
Diaz, J. L.; Jimenez, O.; Lavilla, R. Tetrahedron Lett. 2003, 44, 8449–8452; (d)
Jiang, J.; Yu, J.; Sun, X.-X.; Rao, Q.-Q.; Gong, L.-Z. Angew. Chem., Int. Ed. 2008, 47,
2458–2462.
4. For the synthesis of antidepressant paroxetine and its analogs from 1,4,5,6-
tetrahydropyridine intermediate, see: (a) Pastre, J. C.; Correia, C. R. D. Org. Lett.
2006, 8, 1657–1660; (b) Shih, K.-S.; Liu, C.-W.; Hsieh, Y.-J.; Chen, S.-F.; Ku, H.;
Liu, L. T.; Lin, Y.-C.; Huang, H.-L.; Jeff Wang, C.-L. Heterocycles 1999, 51, 2439–
2444; (c) Correia, C. R. D.; Pastre, J. C. 2006, BR 002109 A; Chem. Abstr. 2008,
149, 425798.; (d) Hughes, M. J.; Kitteringham, J.; Jacewicz, V. W.; Smith, G. E.;
Voyle, M.; Shapiro, E. 2002, U.S. 0010155 A1; Chem. Abstr. 2002, 136, 134679.;
(e) Wehinger, E.; Kazda, S.; Knorr, A. 1984, DE 3239273 A1; Chem. Abstr. 1984,
101, 72619.
8. For the synthesis of starting materials, see: (a) Nag, S.; Yadav, G. P.; Maulik, P.
R.; Batra, S. Synthesis 2007, 911–917; (b) Park, Y. S.; Cho, M. Y.; Kwon, Y. B.; Yoo,
B. W.; Yoon, C. M. Synth. Commun. 2007, 37, 2677–2685.
9. Typical experimental procedure for the synthesis of 4b and 5b: To a stirred
mixture of 2a (424 mg, 1.0 mmol) and 3b (203 mg, 1.5 mmol) in DMF (3 mL)
was added K2CO3 (166 mg, 1.2 mmol) and stirred at room temperature for 4 h.
After the usual aqueous workup and column chromatographic purification
process (hexanes/ether, 2:1) compound 4b was isolated as colorless oil, 445 mg
(93%). A mixture of 4b (239 mg, 0.5 mmol), Bu3SnH (175 mg, 0.6 mmol), and
AIBN (8 mg, 0.05 mmol) in benzene (3 mL) was heated to reflux for 1 h. After
removal of solvent, the residue was purified by column chromatography
(hexanes/ether, 4:1) to obtain compound 5b as a white solid, 279 mg (70%).
Selected spectroscopic data of compound 4b, 5b, 5f, and
follows.Compound 4b: 93%; colorless oil; IR (film) 1720, 1436, 1339, 1248,
1159 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 1.62 (s, 3H), 2.41 (s, 3H), 3.65 (s, 3H),
6 are as
;
3.71 (s, 2H), 4.15 (s, 2H), 4.77 (s, 1H), 4.78 (s, 1H), 7.20–7.27 (m, 3H), 7.37 (t,
J = 7.5 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.56–7.65 (m, 3H), 7.76 (s, 1H); 13C NMR
(CDCl3, 75 MHz) d 19.93, 21.46, 44.09, 52.06, 54.89, 113.58, 124.11, 127.36,
127.38, 129.40, 129.55, 130.33, 130.98, 132.81, 134.63, 136.59, 140.82, 142.32,
143.00, 167.29; TSIMS m/z 478 (M++1), 480 (M++3).Compound 5b: 70%; white
5. (a) For the synthesis and biological activities of 4-arylpiperidines and
tetrahydropyridines, see: Almirante, N.; Biondi, S.; Ongini, E. 2007, WO
104652 A2; Chem. Abstr. 2007, 147, 378417.; (b) Herold, P.; Mah, R.; Marti, C.