Regioselective synthesis of 1,2,4,5-tetrasubstituted pyridines from Baylis-Hillman adducts via consecutive [3+2+1] annulation protocol

Article abstract of DOI:10.1016/j.tetlet.2008.01.110

An efficient synthetic method of poly-substituted pyridines was developed. Various poly-substituted pyridines were prepared from the combination of Baylis-Hillman adducts (3 carbons), activated methylene compounds (2 carbons) and ammonium acetate (1 nitro

Full text of DOI:10.1016/j.tetlet.2008.01.110

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1948–1951
Regioselective synthesis of 1,2,4,5-tetrasubstituted pyridines from
Baylis–Hillman adducts via consecutive [3+2+1] annulation protocol
Sung Hwan Kim, Ko Hoon Kim, Hoo Sook Kim, Jae Nyoung Kim *
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
Received 10 January 2008; accepted 21 January 2008
Available online 30 January 2008
Abstract
An efficient synthetic method of poly-substituted pyridines was developed. Various poly-substituted pyridines were prepared from the
combination of Baylis–Hillman adducts (3 carbons), activated methylene compounds (2 carbons) and ammonium acetate (1 nitrogen) via
[3+2+1] annulation protocol in good yields, regioselectively.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Poly-substituted pyridines; Baylis–Hillman adducts; [3+2+1] Annulation; NH4OAc
Poly-substituted pyridines are an important class of
compounds due to their abundance in biologically impor-
tant natural substances and their usefulness as synthetic
intermediates in organic synthesis.1–4 Thus, various
synthetic approaches have been examined and a variety
of efficient and practical methods have been developed.1–4
However, new and efficient synthetic procedures are still
required for the synthesis of poly-substituted pyridines in
a regioselective manner.3
Recently, we reported the synthesis of poly-substituted
pyridine derivatives regioselectively starting from the easily
available Baylis–Hillman adducts by way of [3+1+2] annu-
lation process (Scheme 1).3a The pyridine ring was con-
structed in a consecutive manner: (i) introduction of
tosylamide (one nitrogen source) at the primary position
of the Baylis–Hillman adduct (three carbon source), (ii)
reaction with Michael acceptor (two carbon source) and
the following aldol cyclization and aromatization pro-
cesses.3a Meantime, we imagined the possibility for the con-
struction of pyridine skeleton in a different annulation
protocol, namely [3+2+1] annulation (Scheme 1). As
shown in Scheme 1, the introduction of activated methylene
compounds 2 at the primary position of Baylis–Hillman
adduct 1 could provide the starting material 3 easily.5 The
reaction of 3 and a suitable ammonia source would provide
the desired 1,2,4,5-tetrasubstituted pyridine compound 4
via the corresponding enamine intermediate.2b,4
Thus, we synthesized 3a by the reaction of Baylis–
Hillman acetate 1a and methyl acetoacetate (2a) in 82%
yield in the presence of K2CO3 in CH3CN at room temper-
ature.5 With this compound 3a in our hand, we examined
the reaction conditions and found that the use of NH4OAc
in acetic acid produced desired pyridine 4a in good yield in
short time (73%, entry 1 in Table 1).6–8 Encouraged by the
results, we synthesized starting materials 3b–h by the reac-
tions of Baylis–Hillman acetates 1a–c and various activated
methylene compounds 2a–f in 63–81% yields as shown in
Table 1.5 The syntheses of poly-substituted pyridines
4b–h were carried out under the same conditions of entry
1 and we obtained the products in good to moderate yields
(52–72%) except compound 4h (entry 8, vide infra). The
reaction mechanism could be explained as the sequential
enamine formation,2b,4,7 cyclization, dehydration and the
following double bond isomerization processes as depicted
in Scheme 1.
*
As shown in Scheme 2 (entry 8 in Table 1), the reaction
of compound 3h under the same reaction conditions
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 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.110

S. H. Kim et al. / Tetrahedron Letters 49 (2008) 1948–1951
1949
O
TsNH2
EWG
EWG
Ph
Ph
Ph
Ref. 3a
[3+1+2] route
NHTs
N
OAc O
O
R
Ph
O
1a
N
NH4OAc
(2)
EWG
Ph
O
R
this work
[3+2+1] route
EWG
R
EWG
4
3
O
N
Ph
Ph
NH2
R
R
EWG
EWG
Scheme 1.
Table 1
Synthesis of poly-substituted pyridines
O
O
OAc O
OAc O
OAc O
COMe
CO2Et
COMe
COMe
COMe
2c
COMe
COPh
Ph
Entry
1
Ph
CO2Me
2a
SO2Me
SO2Ph
2b
1a
1b
1c
2d
2f
2e
Substrates
Product 3a (%)
Product 4b (%)
Entry
5
Substrates
Product 3a (%)
Product 4b (%)
O
O
Bn
N
Bn
N
Ph
Ph
1a + 2a
1a + 2b
1a + 2c
1a + 2e
1a + 2f
1b + 2a
COMe
COPh
Ph
4a (73) CO2Me
4e (58)c SO2Ph
3a (82)
3e (63)
CO2Me
O
SO2Ph
O
O
Bn
N
Bn
N
Ph
Ph
2
3
6
7
COMe
4f (52)d
3f (65)
4b (72) CO2Et
3b (78)
CO2Et
O
O
O
O
Bn
N
Bn
N
Ph
Ph
COMe
COMe
4c (71) COMe
3g (81)
CO2Me
3c (81)
COMe
4g (65) CO2Me
O
O
Bn
N
N
Ph
4
1a + 2d
8
1c + 2a
COMe
SO2Me
COMe
CO2Me
4d (63) SO2Me
4h (19)eCO2Me
3d (78)
3h (67)
a
Conditions: compound 1 (1.0 equiv), compound 2 (1.0 equiv), K2CO3 (1.1 equiv), CH3CN, rt, 3–5 h.
Conditions: compound 3 (1.0 equiv), NH4OAc (3.0 equiv), AcOH, reflux, 1–2 h.
Reaction time is 15 h.
b
c
d
e
Reaction time is 5 h.
Hexenyl substituted compound 5 was obtained in 54% isolated yield (see Scheme 2).

1950
S. H. Kim et al. / Tetrahedron Letters 49 (2008) 1948–1951
N
N
+
3h
CO2Me
CO2Me
4h (19%)
5 (54%)
- H2O
air oxidation
N
N
N
OH
HO
CO2Me
CO2Me
CO2Me
Scheme 2.
O
NH4OAc (3.0 equiv)
AcOH, reflux, 10 h
COMe
COPh
Bn
Ph
Ph
(2g)
N
Ph
1a
Ph
K2CO3 (1.5 equiv)
DMF, rt, 5 h
Ph
Ph
4i (88%)
3i (77%)
Scheme 3.
(b) Xiong, X.; Bagley, M. C.; Chapaneri, K. Tetrahedron Lett. 2004,
45, 6121–6124; (c) Sainz, Y. F.; Raw, S. A.; Taylor, R. J. K. J. Org.
Chem. 2005, 70, 10086–10095; (d) Palacios, F.; Herran, E.; Rubiales,
G. J. Org. Chem. 1999, 64, 6239–6246; (e) Palacios, F.; Alonso, C.;
Rubiales, G.; Villegas, M. Tetrahedron 2005, 61, 2779–2794.
3. For the synthesis of pyridines from Baylis–Hillman adducts, see: (a)
Park, D. Y.; Lee, M. J.; Kim, T. H.; Kim, J. N. Tetrahedron Lett.
2005, 46, 8799–8803; (b) Lee, M. J.; Kim, S. C.; Kim, J. N. Bull.
Korean Chem. Soc. 2006, 27, 439–442.
4. For some examples for the synthesis of pyridine derivatives using
ammonium acetate as the nitrogen source, see: (a) Ladouceur, G. H.;
Cook, J. H.; Doherty, E. M.; Schoen, W. R.; MacDougall, M. L.;
Livingston, J. N. Bioorg. Med. Chem. Lett. 2002, 12, 461–464; (b)
Rodriguez, H.; Suarez, M.; Perez, R.; Petit, A.; Loupy, A. Tetra-
hedron Lett. 2003, 44, 3709–3712; (c) Bowman, M. D.; Jacobson, M.
M.; Pujanauski, B. G.; Blackwell, H. E. Tetrahedron 2006, 62, 4715–
4727.
5. For the synthesis of starting materials and their synthetic applica-
tions, see: (a) Lee, M. J.; Park, D. Y.; Lee, K. Y.; Kim, J. N.
Tetrahedron Lett. 2006, 47, 1833–1837; (b) Kim, J. N.; Kim, J. M.;
Lee, K. Y. Synlett 2003, 821–824; (c) Im, Y. J.; Lee, C. G.; Kim, H.
R.; Kim, J. N. Tetrahedron Lett. 2003, 44, 2987–2990; (d) Kim, J. N.;
Im, Y. J.; Kim, J. M. Tetrahedron Lett. 2002, 43, 6597–6600; (e) Im,
Y. J.; Lee, K. Y.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2002, 43,
4675–4678.
produced expected compound 4h in low yield (19%).
Instead, we obtained hexenyl compound 5, which might
be produced via air oxidation9 followed by acid-catalyzed
dehydration, as the major product (54%). As a next step,
we examined the synthesis of 1,2-diarylpyridine compound
4i. Synthesis of starting material 3i was inefficient in
CH3CN; however, we prepared 3i in good yield (77%)
when we used DMF as solvent. With this compound 3i,
we synthesized 1,2-diarylpyridine 4i in high yield (88%)
for 10 h. It is interesting to note that relatively longer reac-
tion time was required for the synthesis of 4e (entry 5), 4f
(entry 6), and 4i (Scheme 3). The lower reactivity in these
cases might be due to the larger steric crowdedness during
the cyclization between enamine and carbonyl moieties.
In summary, we disclosed an efficient synthetic method
of poly-substituted pyridines starting from the Baylis–
Hillman adducts via [3+2+1] annulation protocol in good
yields, regioselectively.10
References and notes
6. The use of propionic acid or butyric acid can reduce the reaction time
and the use of montmorillonite K10 as an additive did not improve
the yield. The use of ammonium chloride or ammonium hydroxide
did not afford the product in reasonable yield and the use of different
solvents was less effective.
7. For the synthesis of pyridine and quinoline derivatives from Baylis–
Hillman adducts using similar strategy including the reaction of
anilines and enaminoketones, see: (a) Gowrisankar, S.; Na, J. E.; Lee,
M. J.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26, 319–322; (b) Lee,
C. G.; Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Tetrahedron Lett.
2004, 45, 7409–7413; (c) Lee, C. G.; Lee, K. Y.; Lee, S.; Kim, J. N.
Tetrahedron 2005, 61, 1493–1499; (d) Kim, S. C.; Gowrisankar, S.;
Kim, J. N. Bull. Korean Chem. Soc. 2005, 26, 1001–1004.
1. For the transition metal-catalyzed synthesis of poly-substituted
pyridines, see: (a) McCormick, M. M.; Duong, H. A.; Zuo, G.;
Louie, J. J. Am. Chem. Soc. 2005, 127, 5030–5031; (b) Heller, B.;
Sundermann, B.; Fischer, C.; You, J.; Chen, W.; Drexler, H. J.;
Knochel, P.; Bonrath, W.; Gutnov, A. J. Org. Chem. 2003, 68, 9221–
9225; (c) Tanaka, R.; Yuza, A.; Watai, Y.; Suzuki, D.; Takayama, Y.;
Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7774–7780; (d)
Heller, B.; Sundermann, B.; Buschmann, H.; Drexler, H. J.; You, J.;
Holzgrabe, U.; Heller, E.; Oehme, G. J. Org. Chem. 2002, 67, 4414–
4422; (e) Young, D. D.; Deiters, A. Angew. Chem. Int. Ed. 2007, 46,
5187–5190.
2. For the synthesis of poly-substituted pyridines via condensation
reactions or Diels–Alder type reactions, see: (a) Wang, C.; Wang, Z.;
Liu, L.; Wang, C.; Liu, G.; Xi, Z. J. Org. Chem. 2006, 71, 8565–8571;
8. Typical procedure for the synthesis of compounds 3a and 4a: To a
solution of Baylis–Hillman acetate 1a (436 mg, 2.0 mmol) and methyl

S. H. Kim et al. / Tetrahedron Letters 49 (2008) 1948–1951
1951
acetoacetate (2a, 232 mg, 2.0 mmol) in CH3CN (3 mL) was added
K2CO3 (305 mg, 2.2 mmol) and stirred for 4 h at rt. After the usual
aqueous workup and column chromatographic purification process
(hexanes/EtOAc, 10:1), we obtained 3a as a colorless oil, 450 mg
(82%). A stirred mixture of compound 3a (274 mg, 1.0 mmol) and
NH4 OAc (231 mg, 3.0 mmol) in AcOH (6 mL) was heated to reflux
for 1 h. After cooling to room temperature, the usual aqueous
workup, and column chromatographic purification process (hexanes/
EtOAc, 15:1) we obtained 4a as a pale yellow oil, 187 mg (73%). Other
compounds were synthesized analogously and the spectroscopic data
of compounds 3a, 4a, 4c, 4g, and 5 are as follows.
200.18; ESIMS m/z 240 (M++1). Anal. Calcd for C16H17NO: C,
80.30; H, 7.16; N, 5.85. Found: C, 80.18; H, 7.31; N, 5.72.
Compound 4g: 65%; pale yellow oil; IR (film) 3030, 2954, 1726, 1433,
1250 cmÀ1 1H NMR (CDCl3, 300 MHz) d 1.18 (t, J = 7.5 Hz, 3H),
;
2.78 (q, J = 7.5 Hz, 2H), 2.80 (s, 3H), 3.87 (s, 3H), 4.02 (s, 2H), 7.08–
7.11 (m, 2H), 7.18–7.31 (m, 3H), 7.91 (s, 1H); 13C NMR (CDCl3,
75 MHz) d 13.21, 24.41, 28.53, 37.63, 52.00, 122.66, 126.41, 128.53,
128.60, 130.48, 139.39, 140.11, 157.43, 164.79, 167.25; ESIMS m/z 270
(M++1). Anal. Calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20.
Found: C, 75.74; H, 6.99; N, 5.22.
Compound 5: 54%; colorless oil; IR (film) 2954, 2927, 2856, 1730,
;
1433, 1279 cmÀ1 1H NMR (CDCl3, 300 MHz) d 0.94 (t, J = 7.2 Hz,
Compound 3a: 82%; colorless oil; IR (film) 2952, 1747, 1716,
1666 cmÀ1
;
1H NMR (CDCl3, 300 MHz) d 2.12 (s, 3H), 2.45 (s,
3H), 1.26–1.53 (m, 4H), 2.26 (qd, J = 7.2 and 1.5 Hz, 2H), 2.56 (s,
3H), 2.77 (s, 3H), 3.91 (s, 3H), 6.16 (dt, J = 15.6 and 6.9 Hz, 1H), 6.48
(d, J = 15.6 Hz, 1H), 8.16 (s, 1H); 13C NMR (CDCl3, 75 MHz) d
13.92, 22.25, 22.73, 24.37, 31.36, 33.01, 52.06, 122.97, 124.95, 129.74,
135.03, 135.25, 157.09, 157.86, 167.29; ESIMS m/z 248 (M++1). Anal.
Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C, 72.95; H,
8.77; N, 5.52.
3H), 3.02–3.18 (m, 2H), 3.57 (s, 3H), 3.73 (dd, J = 8.1 and
6.6 Hz, 1H), 7.32–7.45 (m, 5H), 7.61 (s, 1H); 13C NMR (CDCl3,
75 MHz) d 24.49, 25.95, 28.62, 52.23, 57.85, 128.67, 128.89, 129.01,
134.89, 138.66, 142.49, 169.81, 199.97, 202.27; ESIMS m/z 275
(M++1).
Compound 4a: 73%; pale yellow oil; IR (film) 2925, 2854, 1726, 1433,
1
1277 cmÀ1; H NMR (CDCl3, 300 MHz) d 2.48 (s, 3H), 2.79 (s, 3H),
9. For the similar air oxidation process, see: (a) Park, D. Y.; Kim, S. J.;
Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2006, 47, 6315–6319; (b)
Theeraladanon, C.; Arisawa, M.; Nishida, A.; Nakagawa, M.
Tetrahedron 2004, 60, 3017–3035; (c) Potts, K. T.; Walsh, E. B.;
Bhattacharjee, D. J. Org. Chem. 1987, 52, 2285–2292; (d) Bell, T. W.;
Rothenberger, S. D. Tetrahedron Lett. 1987, 28, 4817–4820.
10. In order to check the possibility for the synthesis of 4f in a one-pot
reaction, we examined the reaction of Baylis–Hillman acetate 1a and
3-amino-2-cyclohexen-1-one in the presence of AcOH (cat) in EtOH.
We observed the formation of the desired product 4f in only trace
amounts (4%), and instead we isolated the corresponding primary
acetate of 1a (31%).
3.88 (s, 3H), 3.99 (s, 2H), 7.08–7.11 (m, 2H), 7.19–7.32 (m, 3H),
7.92 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 22.68, 24.27, 38.22,
52.02, 122.83, 126.44, 128.51, 128.63, 131.29, 138.77, 139.69,
157.26, 160.29, 167.15; ESIMS m/z 256 (M++1). Anal. Calcd for
C
16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.44; H, 6.78; N,
5.32.
Compound 4c: 71%; pale yellow oil; IR (film) 3030, 2925, 1685, 1442,
1
1261 cmÀ1; H NMR (CDCl3, 300 MHz) d 2.50 (s, 3H), 2.51 (s, 3H),
2.72 (s, 3H), 4.01 (s, 2H), 7.09–7.12 (m, 2H), 7.21–7.34 (m, 3H), 7.64
(s, 1H); 13C NMR (CDCl3, 75 MHz) d 22.63, 24.30, 29.25, 38.23,
126.57, 128.56, 128.71, 130.50, 131.17, 138.30, 138.62, 155.56, 159.68,