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Y. Zhou et al. / Tetrahedron Letters 49 (2008) 3757–3761
4. (a) Botella, L.; Najera, C. Angew. Chem. Int. Ed. 2002, 41, 179; (b)
Based on the above experiments, the reaction mecha-
Solodenko, W.; Brochwitz, C.; Wartchow, Rudolf, et al Molecular
Diversity. 2005, 9, 333; (c) Zhou, Y. C.; Kijima, T; Izumi, T. 14th
IUPAC International Symposium on Organometallic Chemistry
Directed Towards Organic Synthesis (OMCOS 14), August, 2007.
Nara, Japan.
nism was proposed as shown in Scheme 4. Ammonium ace-
tate kept at equilibrium during the reaction as a base to
supply ammonium. In the first stage it was concerning
the two competitive reactions. One is shown in Scheme 3.
The aldehyde reacted with cyanoacetate ester to give 7,
but 7 did not react with 6 like the mechanism of Knoevena-
gel-condensation reaction. This pathway is over. The other
is shown in Scheme 4. The aldehyde reacted with acetoac-
etate ester to give the key intermediate like Knoevenagel
condensation, which reacted with ammonium to give the
second key intermediate, ester enamine. Then a-hydrogens
of cyanoacetate ester were activated enough to permit the
deprotonation with a weak base, acetate. Further conden-
sation between cyanoacetate ester and ester enamine was
carried out and then went on to give the dihydropyridine
derivative by intramolecular cycloaddition. The protons
of NH at 4-position and methyl group at 2-position were
cleaved, respectively, to give the product by aromatization.
The structure of the product of 5c was conclusively
proved by X-ray Crystallographic Analysis.10 Figure 2
shows a general view of 5c.
In conclusion, the synthesis of 5c, pyridine derivatives
containing multiple functional groups with axial chirality,
was illustrated. The structure was conclusively determined
by X-ray Crystallographic Analysis. The analyst data of 5
were consistent with each other. Because the purpose to
synthesize the title compounds was to use it as an asymmet-
ric ligand, further researches on the optical resolution of
compounds 5b and 5c using enzymes are currently
underway.
5. (a) Chai, L. Z.; Zhao, Y. K.; Sheng, Q. J.; Liu, Z. Q. Tetrahedron Lett.
2006, 47, 9283; (b) Peng, L. J.; Wang, J. T.; Lu, Z.; Liu, Z. Q.; Wu, L.
M. Tetrahedron Lett. 2008, 49, 1586; (c) Kumar, S.; Sharma, P.;
Kapoor, K. K.; Hundal, M. S. Tetrahedron 2008, 64, 536; (d) Kikuchi,
S.; Iwai, Ma.; Murayama, H.; Fukuzawa, S. Tetrahedron Lett. 2008,
49, 116.
6. Typical procedure: To a mixture of methanol (30 ml) and toluene
(30 ml), ethyl acetoacetate (5.20 g, 40 mmol), 1-naphthaldehyde
(6.24 g, 40 mmol), methyl 2-cyanoacetate (3.96 g, 40 mmol) and
Ammonium acetate (3.24 g, 42 mmol) were added. The mixture was
heated to reflux under stirring for 24 h. The resulting solution were
workuped by azeotropic distillation to separate off all toluene, to which
water (3 ml) was added. The resulting solvent was kept for refluxing for
24 h and then allowed to cool to room temperature. The light yellow
crystals were formed and filtered to give the title compound, and then
purified by recrystallization from chloroform-ethyl acetate.
7. Data for 5-cyano-6-hydroxy-2-methyl-4-phenyl-nicotinate (5a): Yield
22%; slight yellow solid; crystallized from chloroform-ethyl acetate;
MS(EI): m/z: 268 [M+]; MS (FAB+) m/z: 269 (MH+); mp 147–
150 °C. 1H NMR (400 MHz, DMSO, d, ppm): 2.58 (s, 3H, 2-CH3),
3.43(s, 3H, –OCH3), 7.27–7.29 (m, 2H, HAr), 7.46–7.47 (m, 3H, HAr),
12.97 (s, 1H, –OH); 13C NMR (400 MHz, DMSO, d, ppm):18.73,
52.46, 57.74, 85.58, 116.67, 127.62, 129.07, 130.27, 136.38, 147.54,
153.85, 160.14, 166.24; IR (KBr, m, cmÀ1): 3441, 2226, 1733, 1431,
1324, 1288.
8. Data for methyl 5-cyano-6-hydroxy-2-methyl-4-(1-naphthyl)-nicotin-
ate (5b): Yield 30%; slight yellow solid; crystallized from chloroform–
ethyl acetate; MS (FAB+): m/z: 319 [MH+]; mp 162.9–164.3 °C. 1H
NMR (400 MHz, CDCl3, d, ppm): 2.58 (s, 3H, OCH3), 2.98 (s, 3H,
CH3), 7.31–7.34 (dd, J = 0.91, 1.36, 7.02, 1H, HAr), 7.42–7.50 (m, 4H,
HAr), 7.83–7.85 (d, J = 7.25, 1H, HAr), 7.86–7.88 (d, J = 8.61, 1H,
HAr), 12.27 (s, 1H, –OH); 13C NMR (400 MHz, CDCl3, d, ppm):
19.53, 52.20, 76.80, 103.53, 114.15, 115.27, 124.36, 125.16, 125.73,
126.66, 127.25, 128.77, 129.81, 130.27, 133.08, 133.35, 152.94, 160.91,
162.61, 165.16.
Acknowledgement
9. Data for ethyl 5-cyano-6-hydroxy-2-methyl-4-(1-naphthyl)-nicotinate
(5c): Yield 37%; slight yellow solid; crystallized from chloroform-ethyl
acetate; MS (EI): m/z: 332 [M+]; mp 162.9–164.3 °C. 1H NMR
(600 MHz, CDCl3, d, ppm): 0.32–0.35 (t, 3H, J = 7.14, CH2CH3),
2.70 (s, 3H, CH3), 3.49–3.56 (qq, J = 7.2, 1H, CH2), 3.58–3.64 (qq,
J = 7.2, 1H, CH2), 7.40–7.42 (dd, J = 1.50, 7.2, 1H, HAr), 7.49–7.57
(m, 4H, HAr), 7.9–7.92 (dd, J = 1.50, 7.0, 1H, HAr), 7.95–7.97 (d, J =
8.22, 1H, HAr), 12.97 (s, 1H, –OH); 13C NMR (400 MHz, DMSO, d,
ppm): 18.73, 52.46, 57.74, 85.58, 116.67, 127.62, 129.07, 130.27,
136.38, 147.54, 153.85, 160.14, 166.24. IR (KBr, m, cmÀ1): 3434, 2238,
1725, 1398, 1262, 1126, 798, 777; Anal. Calcd for C20H16N2O3: C
72.28; H 4.85; N 8.43. Found: C 72.42; H 4.90; N 8.36.
This research was financially supported by the Sasakawa
Scientific Research Grant from The Japan Science Society
under Grant number 19-314.
References and notes
1. (a) Trecourt, F.; Mallet, M.; Mongin, O. J. Org. Chem. 1994, 59,
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1982, 104, 536; (e) Bringmann, G.; Reichert, Y.; Kane, V. V.
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2. (a) Mizufune, H.; Matsumura, U.; Sera, M.; Tawada, H.; Ueda, T. J.
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10. Crystal data for 5c: CCDC 677844.
11. Synthesis of methyl 3-aminocrotonate (6). According to a modified
literature procedure,5 a solution of methyl acetoacetate (141 mg,
1.21 mmol) and ammonium acetate (550 mg, 7.14 mmol) in methanol
(20 ml) was stirred overnight. The solution was concentrated in vacuo
and partitioned between water (20 ml) and ethyl acetate (20 ml). The
aqueous layer was further extracted with ethyl acetate (3 Â 30 ml) and
the combined organic layers were washed with brine (15 ml), dried
(Na2SO4) and evaporated in vacuo to give the title compound 6 as a
pale yellow oil.
12. Data for methyl 3-aminocrotonate (6): Yield 97; MS(EI): m/z: 115
[M+]; mp 80–83 °C. 1H NMR (400 MHz, CDCl3, d, ppm): 1.90 (s, 3H,
CH3), 3.64 (s, 3H, –OCH3), 4.52 (s, 1H, @CH).
13. Synthesis of methyl 2-cyano-3-(1-naphthyl)-acrylate (7). According to
a modified literature procedure,3a To a stirred mixture of methyl 2-