Chuang et al.
JOCArticle
Conclusion
CDCl3) δ 3.83 (6H, s), 7.04 (4H, m), 7.36 (4H, m), 8.02 (1H, br s),
8.72 (2H, br s); 13C NMR (75 MHz, CDCl3) δ 55.5, 111.2, 121.0,
127.1, 129.4, 130.7, 133.3, 137.6, 148.4, 156.6; IR (KBr) 3003,
1601, 1582 cm-1; EIMS m/z (rel int) 291 (100, Mþ). Anal. Calcd
for C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found: C, 78.30; H,
5.76; N, 4.65.
In summary, a series of pyridine derivatives was synthe-
sized from the corresponding acryloyl azides by the acetic
acid-promoted cycloaddition. The reaction involved a tri-
molecular condensation mechanism. The yield of the pyr-
idine product depends on the substituent on the double bond
and the solvent used. The reactivity of the acid-promoted
cycloaddition increases with the presence of aryl groups,
such as phenyl and pyridinyl. Here, we report a novel and
convenient synthetic approach to the symmetrical 3,5-disub-
stituted pyridines from acryloyl azides.
3,5-Bis(4-nitrophenyl)pyridine (5e). Yield 48%; white solid,
1
mp 315-317 °C (EtOAc) (lit.12b mp 222-224 °C); H NMR
(300 MHz, DMSO-d6) δ 8.21 (4H, d, J = 8.4 Hz), 8.37 (4H, d,
J = 8.4 Hz), 8.60 (1H, br s), 9.10 (2H, br s); 13C NMR (75 MHz,
CDCl3) δ 124.1, 128.6, 133.5, 133.7, 143.2, 147.4, 148.3; IR
(KBr) 3030, 1672, 1601, 1512 cm-1; EIMS m/z (rel int) 321 (100,
Mþ). Anal. Calcd for C17H11N3O4: C, 63.55; H, 3.45; N, 13.08.
Found: C, 63.34; H, 3.45; N, 13.23.
Experimental Section
3,5-Bis(3-nitrophenyl)pyridine (5f). Yield 66%; white solid,
mp 257-259 °C (EtOAc-CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 7.74 (2H, t, J = 8.0 Hz), 8.01 (2H, dt, J = 8.0, 1.9
Hz), 8.15 (1H, t, J = 2.2 Hz), 8.34 (2H, dt, J = 8.0, 1.9 Hz), 8.53
(2H, t, J = 1.9 Hz), 8.96 (2H, d, J = 2.2 Hz); 13C NMR (75
MHz, CDCl3) δ 122.2, 123.3, 130.4, 133.0, 132.2, 134.7, 138.9,
148.0, 148.9; IR (KBr) 3049, 1521, 1352 cm-1; EIMS m/z (rel int)
321 (100, Mþ). Anal. Calcd for C17H11N3O4: C, 63.55; H, 3.45;
N, 13.08. Found: C, 63.40; H, 3.39; N, 12.92.
3,5-Bis(2-nitrophenyl)pyridine (5g). Yield 58%; white solid,
mp 141-142 °C (hexane-EtOAc); 1H NMR (300 MHz, CDCl3)
δ 7.50 (2H, d, J = 7.4 Hz), 7.59 (3H, m), 7.72 (2H, t, J = 7.4 Hz),
8.03 (2H, d, J = 8.2 Hz), 8.62 (2H, br s); 13C NMR (75 MHz,
CDCl3) δ 124.8, 129.4, 132.4, 132.5, 133.0, 133.3, 135.0, 148.0,
148.7; IR (KBr) 3032, 1530, 1348 cm-1; EIMS m/z (rel int) 321
(100, Mþ). Anal. Calcd for C17H11N3O4: C, 63.55; H, 3.45; N,
13.08. Found: C, 63.41; H, 3.27; N, 12.77.
General Procedure for the Acid-Promoted Cycloaddition of an
Acryloyl Azide, 4. A mixture of acryloyl azide 4 (4 mmol) and
HOAc (3.00 g, 40 mmol) in DMSO (4 mL) was heated under N2
at 150 °C for 4 h. After cooling, the resulting solution was
diluted with ethyl acetate (400 mL), washed with 4 N aqueous
NaOH (16 mL) and water (8 ꢀ 25 mL), dried with anhydrous
MgSO4, and filtered. The filtrate was concentrated, and the
residue was purified by column chromatography over Al2O3
eluting with hexane-EtOAc (5:1) to give pyridine derivatives
5a-j, 6a-d, 6j, and 7, as well as the pyrimidinone 8a and
pyridinone 9a when 4a was used. The full spectral data of these
compounds are described as follows.
3,5-Diphenylpyridine (5a). Yield 62%; white solid, mp 137-
138 °C (hexane-EtOAc) (lit.20 mp 137-138 °C); 1H NMR (300
MHz, CDCl3) δ 7.43 (2H, t, J = 7.5 Hz, 2 ꢀ H-40), 7.51 (4H, t,
J = 7.5 Hz, 4 ꢀ H-30), 7.65 (4H, d, J = 7.5 Hz, 4 ꢀ H-20), 8.05
3,5-Bis(pyridine-3-yl)pyridine (5h). Yield 70%; white solid,
(1H, t, J = 2.2 Hz, H-4), 8.83 (2H, d, J = 2.2 Hz, 2 ꢀ H-2); 13
C
1
mp 157-158 °C (hexane-EtOAc) (lit.22 mp 159-160 °C); H
NMR (75 MHz, CDCl3) δ 127.3 (4 ꢀ C-20), 128.2 (2 ꢀ C-40),
129.1 (4 ꢀ C-30), 132.9 (C-4), 136.7 (2 ꢀ C-3), 137.8 (2 ꢀ C-10),
147.0 (2 ꢀ C-2); IR (KBr) 3021, 1598, 1584 cm-1; EIMS m/z (rel
int) 231 (100, Mþ). Anal. Calcd for C17H13N: C, 88.28; H, 5.67;
N, 6.06. Found: C, 88.20; H, 5.67; N, 6.02.
NMR (300 MHz, CDCl3) δ 7.47 (2H, dd, J = 8.0, 4.8 Hz), 7.96
(2H, m), 8.06 (1H, t, J = 2.0 Hz), 8.71 (2H, m), 8.91 (4H, m); 13
C
NMR (75 MHz, CDCl3) δ 123.9, 132.9, 133.1, 133.8, 134.6,
147.7, 148.3, 149.7; IR (KBr) 3026, 1568, 1481, 1447, 1400 cm-1
;
EIMS m/z (rel int) 233 (100, Mþ). Anal. Calcd for C15H11N3: C,
77.23; H, 4.75; N, 18.01. Found: C, 77.03; H, 4.65; N, 17.71.
3,5-Bis(ethoxycarbonyl)pyridine (5i). Yield 33%; white solid,
mp 48-48.5 °C (hexane) (lit.23 mp 48.5-50 °C); 1H NMR
(300 MHz, CDCl3) δ 1.44 (6H, t, J = 7.1 Hz), 4.46 (4H, q,
J = 7.1 Hz), 8.86 (1H, t, J = 1.9 Hz), 9.37 (2H, d, J = 1.9 Hz);
13C NMR (75 MHz, CDCl3) δ 14.2, 61.8, 126.3, 137.9, 154.1,
164.5; IR (KBr) 2988, 1717, 1605 cm-1; EIMS m/z (rel int) 223
(100, Mþ); HREIMS m/z calcd for C11H13NO4 223.0845, found
223.0842 [M]þ.
3,5-Diphenyl-[2,4,6-13C3]pyridine (5a-13C). Yield 51%; white
solid, mp 139-140 °C (hexane-EtOAc); 1H NMR (300 MHz,
CDCl3) δ 7.47 (6H, m), 7.65 (4H, m), 8.05 (1H, dtt, J = 159.3,
5.6, 2.2 Hz, H-4), 8.82 (2H, dddd, J = 165.4, 10.2, 5.5, 2.2 Hz,
2 ꢀ H-2); 13C NMR (75 MHz, CDCl3) two labeled signals
δ 132.9 (C-4), 147.0 (2 ꢀ C-2); IR (KBr) 3035, 1599, 1578 cm-1
;
EIMS m/z (rel int) 234 (100, Mþ); HREIMS m/z calcd for
12
C
13C3H13N 234.1148, found 234.1145 [M]þ.
14
3,5-Bis(4-methoxyphenyl)pyridine (5b). Yield 47%; white
solid, mp 233-235 °C (hexane-EtOAc) (lit.21 mp 229 °C); 1H
NMR (CDCl3) δ 3.87 (6H, s), 7.03 (4H, d, J = 8.7 Hz), 7.58 (4H,
d, J = 8.7 Hz), 7.96 (1H, t, J = 2.0 Hz), 8.74 (2H, d, J = 2.0 Hz);
13C NMR (CDCl3) δ 55.4, 114.6, 128.3, 130.3, 131.9, 136.2,
146.1, 159.8; IR (KBr) 3013, 1609, 1513 cm-1; EIMS m/z (rel int)
291 (100, Mþ). Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88;
N, 4.81. Found: C, 78.02; H, 5.80; N, 4.67.
3,5-Bis(3-methoxyphenyl)pyridine (5c). Yield 58%; white
solid, mp 110-111 °C (hexane-EtOAc) (lit.,10e mp 111 °C);
1H NMR (300 MHz, CDCl3) δ 3.86 (6H, s), 6.96 (2H, dd, J =
8.0, 2.1 Hz), 7.15 (2H, br s), 7.21 (2H, d, J = 8.0 Hz), 7.40 (2H, t,
J = 8.0 Hz), 8.02 (1H, br s), 8.81 (2H, br s); 13C NMR (75 MHz,
CDCl3) δ 55.3, 112.9, 113.4, 119.6, 130.1, 132.8, 136.4, 139.1,
147.0, 160.1; IR (KBr) 3001, 1607, 1584 cm-1; EIMS m/z (rel int)
291 (100, Mþ). Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88;
N, 4.81. Found: C, 77.95; H, 5.97; N, 4.80.
3,5-Dipropylpyridine (5j). Yield 2%; colorless liquid; 1H
NMR (300 MHz, CDCl3) δ 0.95 (6H, t, J = 7.4 Hz), 1.64
(4H, sextet, J = 7.4 Hz), 2.56 (4H, t, J = 7.4 Hz), 7.29 (1H, t,
J = 1.9 Hz), 8.26 (2H, d, J = 1.9 Hz); 13C NMR (75 MHz,
CDCl3) δ 13.7, 24.3, 34.9, 135.9, 137.2, 147.4; IR (KBr) 2961,
1456 cm-1; EIMS m/z (rel int) 163 (43, Mþ); HREIMS m/z calcd
for C11H17N 163.1361, found 163.1365 [M]þ.
2-Benzyl-3,5-diphenylpyridine (6a). Yield 12%; white solid,
mp 72-73 °C (hexane-EtOAc) (lit.24 mp 74-75 °C); 1H NMR
(300 MHz, CDCl3) δ 4.19 (2H, s, CH2), 7.05 (2H, d, J = 7.4 Hz,
2 ꢀ H-2000), 7.14 (1H, t, J = 7.4 Hz, H-4000), 7.20 (2H, t, J =
7.4 Hz, 2 ꢀ H-3000), 7.28 (2H, d, J = 7.4 Hz, 2 ꢀ H-20), 7.40 (4H,
m, 2 ꢀ H-30 and H-40, H-400), 7.46 (2H, t, J = 7.4 Hz, 2 ꢀ H-300),
7.61 (2H, d, J = 7.4 Hz, 2 ꢀ H-200), 7.75 (1H, d, J = 2.0 Hz, H-4),
8.83 (1H, d, J = 2.0 Hz, H-6); 13C NMR (75 MHz, CDCl3) δ
41.3 (CH2), 126.0 (C-4000), 127.0 (2 ꢀ C-200), 127.7 (C-40), 128.0
3,5-Bis(2-methoxyphenyl)pyridine (5d). Yield 51%; white
solid, mp 125-126 °C (hexane-EtOAc); 1H NMR (300 MHz,
(22) Ishikura, M.; Ohta, T.; Terashima, M. Chem. Pharm. Bull. 1985, 33,
4755–4763.
(23) Dieterich, D. Synthesis 1972, 631–632.
(20) Gopinath, K. W.;Govindachari, T. R.;Nagarajan, K.;Purushothaman,
K. K. J. Chem. Soc. 1957, 1144–1148.
(21) Brown, D. J.; England, B. T. Aust. J. Chem. 1970, 23, 625–627.
(24) Folkers, K.; Johnson, J. B. J. Am. Chem. Soc. 1933, 55, 3361–3368.
J. Org. Chem. Vol. 75, No. 19, 2010 6629