Synthesis of poly-substituted tetrahydropyridines from Baylis-Hillman adducts modified with N-allylamino group via radical cyclization

Article abstract of DOI:10.1016/j.tetlet.2009.02.225

An expedient method was developed for the synthesis of 1,4,5,6-tetrahydropyridines by radical cyclization protocol involving consecutive 1,5-hydrogen transfer and double bond isomerization process starting from Baylis-Hillman adducts.

Full text of DOI:10.1016/j.tetlet.2009.02.225

Tetrahedron Letters 50 (2009) 2274–2277
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Tetrahedron Letters
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Synthesis of poly-substituted tetrahydropyridines from Baylis–Hillman
adducts modified with N-allylamino group via radical cyclization
*
Hyun Seung Lee, Eun Sun Kim, Sung Hwan Kim, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An expedient method was developed for the synthesis of 1,4,5,6-tetrahydropyridines by radical cycliza-
tion protocol involving consecutive 1,5-hydrogen transfer and double bond isomerization process start-
ing from Baylis–Hillman adducts.
Received 19 February 2009
Accepted 27 February 2009
Available online 6 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Radical cyclization
Tetrahydropyridines
Baylis–Hillman adducts
Radical cyclizations have been used for the synthesis of various
cyclic compounds. In some instances initial radical species under-
went 1,n-H transfer to form another radical before cyclization reac-
tion.1,2 Among the 1,n-H transfers, 1,5- and 1,6-H transfers are the
most common.1,2 Very recently we observed an interesting radical
cyclization procedure for the synthesis of tricyclic lactam deriva-
tives involving 1,5-H transfer and concomitant isomerization.1a
Suitably substituted dihydro- and tetrahydropyridine deriva-
tives have been regarded as important synthetic intermediates
for the synthesis of various important compounds.3 Especially,
1,4,5,6-tetrahydropyridine derivative A has been used for the syn-
thesis of antidepressant drug paroxetine (B)4 and many paroxe-
tine-like PSSRIs (phenylpiperidine selective Serotonin reuptake
inhibitors) including femoxetine (B0).4,5 In addition, many 1,2,5,6-
tetrahydropyridine derivatives C have been reported as renin
inhibitors ( Fig. 1).5 During our recent studies on the chemical
transformations of Baylis–Hillman adducts,6,7 we imagined that
we could synthesize tetrahydropyridine skeleton4,5 via the radical
cyclization of 4a–e as in Scheme 1. N-Tosyl-N-allyl derivatives
4a–e were prepared in good to moderate yields from the acetates
of Baylis–Hillman adducts 1a and 1b as summarized in Scheme 2
in two steps.7,8
ture in a ratio of 3:2–4:1. However, we could not separate each iso-
mer in their pure form. The mechanism for the formation of 5 could
be regarded as in Scheme 1: (i) 1,5-hydrogen transfer from the ini-
tial radical (I) to form (II),1a isomerization to more stable benzylic
radical (III), the following cyclization in a 6-exo-trig mode to (IV),
and final hydrogen radical abstraction to 5.
However, the reaction of N-benzyl derivative 4f showed low
yield of product 5f (38%) under the same conditions (1.2 equiv of
n-Bu3SnH) due to the formation of many intractable side products.
Fortunately, we obtained 5f in an improved yield (76%) when we
used n-Bu3SnH in excess amounts (2.5 equiv) presumably due to
rapid hydrogen abstraction of the corresponding radical intermedi-
ate (IV) from n-Bu3SnH (Scheme 3). Similarly, the reaction of N-
phenyl derivative 4g showed similar pattern. When we used 1.2–
1.5 equiv of n-Bu3SnH, pyrrolidine derivative 6 was formed in
appreciable amounts with low yield of 5g. The desired compound
5g was isolated in moderate yield (50%) with 2.5 equiv of n-
Bu3SnH, together with pyrrolidine derivative 6 in 21% yield as a
syn/anti (1:1) mixture (Scheme 4). The formation of 6 could be ex-
plained as sequential hydrostannylation at the allyl group10 and
following radical cyclization in a 5-exo-trig mode. The reduction
of bromophenyl moiety might occur independently with excess
Bu3SnH. Compound 6 was also prepared from 4g0 under the same
conditions (2.5 equiv of n-Bu3SnH) in good yield (77%). We
obtained compounds 5h (31%) and 7 (24%) from the reaction of
N-methallyl derivative 4h, similarly. In the reaction, two minor
compounds 8 (12%) and 9 (28%) were isolated together as side
products and we did not confirm the geometry of double bond
Scheme 5.
With the substrates 4a–e we examined the radical cyclization
reaction under the conditions of n-Bu3SnH (1.2 equiv)/AIBN in
refluxing benzene.7 As expected, we obtained 1,4,5,6-tetrahydro-
pyridines 5a–e in good to moderate yields (56–82%) in short time
(Table 1).9 Compounds having two stereogenic centers including
5a, 5c, and 5d were isolated as their syn/anti diastereomeric mix-
In summary, we disclosed an efficient synthetic way for 1,4,5,6-
tetrahydropyridines by radical cyclization protocol involving
* Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.225

H. S. Lee et al. / Tetrahedron Letters 50 (2009) 2274–2277
2275
R
N
F
F
O
O
OMe
CONR1R2
COOMe
O
O
N
H
N
Me
N
COOAr2
COOMe
A
Paroxetine (B)
Femoxetine (B')
C (renin inhibitors)
Figure 1.
R2
Ph
R3
R1
EWG
R2
n-Bu3SnH (1.2 equiv)
EWG
Br
N
R3
AIBN, benzene
reflux, 1-3 h
N
Ts
Ts R1
5a-e
4a-e
R2
Ph
Ph
R3
R1
EWG
EWG
EWG
EWG
R2
R2
Ph
R2
R3
N
Ts
(IV)
N
R3
N
R3
N
Ts R1
Ts R1
Ts R1
(I)
(II)
(III)
Scheme 1.
Table 1
Synthesis of tetrahydropyridine derivatives
Entry
Conditionsa
Substrate 4 (%)
Conditionsb (h)
Product 5 (%)
1
2
3
4
5
2a + 3a ,6 h
2a + 3b, 4 h
2a + 3c, 3 h
2a + 3d, 24 h
2b + 3b, 4 h
4a (80)
4b (93)
4c (80)
4d (87)
4e (92)
2
1
2
2
3
5a (72, syn/anti = 2:3)c
5b (70)
5c (82, syn/anti = 2:3)c
5d (80, syn/anti = 1:4)c
5e (56)
a
Conditions: Compound 2 (1.0 mmol), compound 3 (1.5 mmol), K2CO3 (1.2 equiv), DMF, rt.
Conditions: Substrate 4 (0.5 mmol), n-Bu3SnH (0.6 mmol), AIBN (cat) benzene, reflux.
The ratio of syn/anti was determined in 1H NMR and is arbitrary.
b
c
R2
Br
R3
OAc
EWG
R2
EWG
R1
EWG
TsNH2 (2.0 equiv)
Br
N
R3
H
N
Ts
K2CO3 (1.2 equiv)
DMF, rt, 3-24 h
Br
K2CO3 (2.0 equiv)
DMF, 50 ºC, 3 h
Ts R1
Br
3a: R1, R2, R3 = H
1a: EWG = COOMe
1b: EWG = COOEt
4a: EWG = COOMe, R1, R2, R3 = H
2a: EWG = COOMe (66%)
2b: EWG = COOEt (62%)
3b: R1 = Me, R2, R3 = H
3c: R1, R3 = H, R2 = Me
3d: R1 = H, R2, R3 = Me
4b: EWG = COOMe, R1 = Me, R2, R3 = H
4c: EWG = COOMe, R1, R3 = H, R2 = Me
4d: EWG = COOMe, R1 = H, R2, R3 = Me
4e: EWG = COOEt, R1 = Me, R2, R3 = H
Scheme 2.
Ph
COOMe
aq THF
COOMe
COOMe
n-Bu3SnH (2.5 equiv)
DABCO (2.0 equiv)
3b
1a
H
Br
N
Bn
AIBN, benzene
reflux, 2 h
Br
2c (80%)
N
N
Bn
K2CO3 (1.2 equiv)
DMF, rt, 4 h
BnNH2 (2.0 equiv)
50 ºC, 24 h
Bn
5f (76%)
4f (88%)
Scheme 3.

2276
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.

H. S. Lee et al. / Tetrahedron Letters 50 (2009) 2274–2277
2277
solid, mp 110–112 °C; IR (KBr) 1709, 1633, 1168, 1096 cmꢀ1
;
1H NMR (CDCl3,
N, 4.05.Compound 6 (separated pure isomer, but syn/anti was not determined):
21%; colorless oil; IR (film) 1726, 1598, 1507, 1374 cmꢀ1 1H NMR (CDCl3,
300 MHz) d 0.59 (s, 3H), 0.88 (s, 3H), 2.49 (s, 3H), 2.80 (d, J = 12.0 Hz, 1H), 3.18
(d, J = 12.0 Hz, 1H), 3.37 (s, 1H), 3.61 (s, 3H), 6.70 (d, J = 5.7 Hz, 2H), 7.03–7.15
(m, 3H), 7.40 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 8.1 Hz, 2H), 8.16 (s, 1H); 13C NMR
(CDCl3, 75 MHz) d 21.64, 25.25, 27.03, 31.96, 48.00, 49.38, 51.43, 110.10,
126.62, 127.33, 127.76, 128.66, 130.09, 134.07, 134.44, 141.23, 144.69, 167.04;
TSIMS m/z 400 (M++1). Anal. Calcd for C22H25NO4S: C, 66.14; H, 6.31; N, 3.51.
Found: C, 66.37; H, 6.13; N, 3.45.Compound 5f: 76%; white solid, mp 123–
;
300 MHz) d 0.85–0.92 (m, 15H), 1.02–1.07 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H), 1.24–
1.55 (m, 12H), 2.46–2.53 (m, 1H), 2.74 (d, J = 13.8 Hz, 1H), 2.94 (dd, J = 8.7 and
6.3 Hz, 1H), 3.34 (d, J = 13.8 Hz, 1H), 3.41 (d, J = 9.9 Hz, 1H), 3.58 (d, J = 9.9 Hz,
1H), 3.56–3.62 (m, 1H), 4.09–4.20 (m, 2H), 6.50 (d, J = 7.5 Hz, 2H), 6.66 (t,
J = 7.5 Hz, 1H), 7.12–7.29 (m, 7H); 13C NMR (CDCl3, 75 MHz) d 9.20, 9.31, 13.69,
14.30, 27.41, 29.19, 41.24, 45.70, 51.87, 54.42, 59.34, 60.44, 111.17, 115.52,
126.66, 128.26, 129.12, 129.92, 137.67, 147.39, 173.31; TSIMS m/z 613 (M++1).
10. For the similar hydrostannylation of double bond and the following radical
cyclizations, see: (a) Gerbino, D. C.; Koll, L. C.; Mandolesi, S. D.; Podesta, J. C.
Organometallics 2008, 27, 660–665; (b) Hanessian, S.; Leger, R. J. Am. Chem. Soc.
1992, 114, 3115–3117; (c) Miura, K.; Saito, H.; Uchinokura, S.; Hosomi, A. Chem.
Lett. 1999, 659–660.
124 °C; IR (KBr) 1682, 1620, 1167, 1144 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 0.54
;
(s, 3H), 0.99 (s, 3H), 2.36 (d, J = 12.3 Hz, 1H), 2.85 (d, J = 12.3 Hz,1H), 3.35 (s,
1H), 3.56 (s, 3H), 4.37 (d, J = 15.3 Hz, 1H), 4.44 (d, J = 15.3 Hz, 1H), 7.02 (d,
J = 6.6 Hz, 2H), 7.10–7.41 (m, 8H), 7.77 (s, 1H); 13C NMR (CDCl3, 75 MHz) d
25.51, 28.07, 31.52, 47.85, 50.51, 52.41, 60.11, 97.51, 125.91, 127.46, 127.90,
127.98, 128.71, 128.78, 136.59, 144.32, 144.55, 168.89; TSIMS m/z 336 (M++1).
Anal. Calcd for C22H25NO2: C, 78.77; H, 7.51; N, 4.18. Found: C, 78.89; H, 7.76;