988
J. Holt, F. Tjosås, J. M. Bakke and A. Fiksdahl
Vol. 41
Scheme 2
(100 MHz, D O): δ 55.7, 59.8, 126.9, 129.7, 138.9, 145.5, 156.5,
168.3; ms: m/z 167 (M , 100 %), 152 (17), 136 (21), 134 (29),
This one-step nitro substitution reaction represents a
2
+
superior alternative to the traditional three-step procedure
going via the amine and the standard substitution of a dia-
zonium salt.
106 (2); HRMS: calcd for C H NO ; 167.05824, observed
8
9
3
167.05849.
Methyl 3-Phenoxypyridine-4-carboxylate (2c).
Methyl 3-nitropyridine-4-carboxylate (1, 100 mg, 0.55 mmol)
and phenol (66.43 mg, 0.062 ml, 0.7 mmol, 1.2 equivalent) were
dissolved in dry DMSO (2 ml) and NaH (19.76 mg, 0.82 mmol,
1.5 equivalent) was added. The reaction mixture was heated to
EXPERIMENTAL
Chemicals: NaN , phenol (Merck), thiophenol, NaOMe
(Fluka), NaH (Sigma-Aldrich); Solvents: pro analysi quality. H
3
1
1
85 °C for 20 minutes. H nmr showed complete conversion of the
13
/
C nmr: Bruker Avance DPX 300 and 400 MHz spectrometers,
starting material. The reaction mixture was added HCl (10 %),
extracted with EtOAc and concentrated in vacuo. The crude
product was purified by flash chromatography (diethyl
ether/dichloromethane 1:1) yielding 37 mg (30 %) oily product,
chemical shifts are reported in ppm downfield from TMS. J val-
ues are given in Hz. ms: Finnigan MAT 95 XL (EI / 70 eV). ir:
Nicolet 20SXC FT-IR spectrophotometer. All melting points are
uncorrected, measured by Griffin apparatus. Flash chromatogra-
phy: Silica (sds, 60 A, 40-63 µm). Methyl 3-nitropyridine-4-car-
boxylate (1) was prepared from methyl pyridine-4-carboxylate
by nitration according to the literature [11,12].
1
-1 1
pure by H nmr; ir (film) 3015w, 1716s, 1362m, 1222m cm ; H
nmr (300 MHz, CDCl ): δ 3.85 (s, 3H), 6.99 (d, J 6.0, 2H, o-
3
PhH), 7.15 (m, 1H, p-PhH), 7.36, (d, J 6.0, 2H, m-PhH), 7.73 (d,
13
J 5.2, H-5), 8.03 (s, 1H, H-2), 8.48 (d, J 5.2, 1H, H-6); C nmr
Methyl 3-Azidopyridine-4-carboxylate (2a).
(75 MHz, CDCl ): δ 52.8, 115.3, 118.1, 124.0, 124.2, 130.0,
3
143.5, 144.7, 151.2, 156.9, 164.7; ms: m/z 230 (M+1, 12 %), 229
(M , 100 %), 197 (55), 170 (11), 115 (11), 108 (12); HRMS:
A solution of methyl 3-nitropyridine-4-carboxylate (1, 100
+
mg, 0.55 mmol) and NaN (117 mg, 3.27 mmol, 3.3 equivalents)
3
calcd for C H NO ; 229.0739, observed 229.0741.
13 11
3
in dry DMSO (2 ml) was heated to 85 °C for 20 min.
Alternatively, the solution was left stirring for 16 hrs. at 45 °C.
Addition of acetone (2 ml) followed by flash chromatography
Anal. Calcd. for C H NO : C, 68.11; H, 4.84; N, 6.11.
13 11
3
Found: C, 67.57; H, 4.90; N, 6.18.
1
13
(diethyl ether) afforded a crystalline product, pure by H and
C
Methyl 3-Thiophenoxypyridine-4-carboxylate (2d).
nmr (44 mg, 50 %). The reaction was also carried out in DMSO-
The reaction was carried out as above for the preparation of the
phenoxy product 2c, replacing phenol with thiophenol (56.77
mg, 0.5 mmol, 1.1 equivalent) and DMSO (2 ml) with THF (5
1
d and monitored by H nmr; mp 46.5-47 °C (diethyl ether); ir
6
(film) 3004s, 2110s, 1716m, 1643s, 1420m, 1362m, 1221s,
-1 1
1092m cm ; H nmr (300 MHz, CDCl ): δ 3.96 (s, 3H), 7.67 (d,
3
1
ml). The crystalline product (2d, 56 mg, 42 %), pure by H and
13
J 4.96, 1H, H-5), 8.48 (d, J 4.96, 1H, H-6), 8.64 (s, 1H, H-2);
C
13
C nmr, was obtained after flash chromatography (hexane/ace-
nmr (75 MHz, DMSO-d ): δ 53.2, 123.7, 129.2, 134.7, 144.0,
6
tone 3:1); mp 75 °C (hexane); ir (film) 3064w, 2948w, 1723s,
1456m, 1436s, 1396m, 1279s, 1220m, 1197m, 1178m, 1098s,
+
146.3, 164.5; ms: m/z 178 (M , 7 %), 150 (52), 147 (25), 123
(57), 119 (17), 118 (11), 108 (67), 107 (37), 64 (100). ); HRMS:
-1
1
1038m, 971m, 780s, 750s, 700s cm ; H nmr (300 MHz,
calcd for C H N O ; 178.0491; observed 178.0489.
7
6 4 2
DMSO-d ): δ 3.90 (s, 3H) 7.4-7.6 (m, 5H), 7.76 (d, J 5.0, 1H, H-
6
13
5), 8.03 (s, 1H, H-2), 8.49 (d, J 5.0, 1H, H-6); C nmr (75 MHz,
Methyl 3-methoxypyridine-4-carboxylate (2b).
DMSO-d ): δ 53.2, 123.4, 127.5, 127.9, 129.8, 129.9, 130.6,
6
Methyl 3-nitropyridine-4-carboxylate (1, 210 mg, 1.153
mmol) in freshly distilled methanol (10 ml) was added to freshly
made sodium methoxide in methanol (1.5 M, 0.945 ml, 1.417
+
131.1, 134.7, 135.7, 165.3; ms: m/z 245 (M , 51 %), 232 (16),
214 (12), 186 (19), 158 (5), 123 (100), 115 (20), 109 (14);
HRMS: calcd for C H NO S; 245.0511, observed 245.0515.
13 11
2
mmol, 1.25 equivalents) under N at –5 °C. The reaction mixture
2
Anal. Calcd. for C H NO S: C, 63.65; H, 4.52; N, 5.71.
13 11
2
1
was refluxed for 5 hrs. H nmr showed complete conversion of
Found: C, 63.68; H, 4.42; N, 5.54.
the substrate (1) into the methoxy substitution product (2b).
Ether (50 ml) and a NH Cl solution were added to the reaction
Acknowledgements.
4
mixture. After extraction, drying and concentration in vacuo, the
Financial support from the Norwegian Research Council is
gratefully acknowledged.
crystalline product was obtained (100 mg, 52 %) by flash chro-
1
matography (diethyl ether/dichloromethane 1:1) pure by H and
13
C nmr; mp 59.5 - 60 °C (hexane) (lit. [6] 58 °C); ir (KBr)
REFERENCES AND NOTES
3028w, 2958w, 1720s, 1593m, 1558m, 1498m, 1323s, 1109s,
1070s, 1018s, 958m, 838m, 786s, 713m, 665m cm ; H nmr
-1
1
(400 MHz, CDCl ): δ 3.85 (s, 3H), 3.94 (s, 3H), 7.50 (d, J 4.9,
1H, H-5), 8.27 (d, J 4.9, 1H, H-6), 8.39 (s, 1H, H-2); C nmr
[1] F. Effenberger; M. Koch and W. Streicher, Chem. Ber., 124,
163 (1991).
3
13