2410
N. Henry et al. / Tetrahedron 62 (2006) 2405–2412
2,3-dibromopropionate ethyl ester (0.72 mmol) was added
dropwise in a twice separated by 1 h. The mixture was
stirred at reflux for 2–24 h. The solvent was evaporated, the
residue was suspended in cold water (20 mL), and the
aqueous solution was further extracted with CH2Cl2 (3!
15 mL). The combined organic phases were washed with
0.5% NaHCO3, dried (Na2SO4), and concentrated to
providing crude nitrile or ester. The residue was purified
by column chromatography on silica gel eluting with
mixtures of hexane/ethyl acetate. The yields reported
correspond to analytically pure isolated compounds.
amide). Anal. Calcd for C11H11N3O3: C, 56.65%; H, 4.75%;
N, 18.02%. Found: C, 56.34%; H, 4.43%; N, 17.69%.
The minor isomer 4-ethoxycarbonyl-3,4-dihydro-2H-
pyrido[3,2-b][1,4]oxazine-3-nitrile (7b) was obtained as
a white solid in 40% yield. Mp 199–201 8C. IR (KBr) y
(cmK1), 2280 (CN); 1784 (CO); 1556 (CN); 1210 (Ar–O);
1046 (C–O). 1H NMR (CDCl3, 200 MHz) d (ppm), 1.26 (t,
JZ7 Hz, 3H, CH3); 4.12 (m, 3H, CHN and CH2–O); 4.72
(d, JZ14.2 Hz, 1H, CH2O); 7.08–7.12 (m, 1H, H-7); 7.41
(dd, JZ1.0, 8.0 Hz, 1H, H-8); 8.18 (dd, JZ1.0, 4.8 Hz, 1H,
H-6). 13C NMR (CDCl3, 50.3 MHz) d (ppm), 14.8 (CH3);
40.8 (CH, CH–N); 62.8 (CH2, CH2–O); 63.5 (CH2–O);
115.9 (C, CN); 121.8 (CH, C-7); 126.7 (CH, C-8); 138.5 (C,
C-8a); 141.5 (C, C-8a); 153.2 (C, C-4a); 168.2 (CO, amide).
Anal. Calcd for C11H11N3O3: C, 56.65%; H, 4.75%; N,
18.02%. Found: C, 56.87%; H, 5.02%; N, 17.71%.
4.2.1. 4-Acetyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-2-
nitrile (6a). Following the general procedure described
above starting from 2-acetamido-3-hydroxypyridine
(100 mg, 0.66 mmol) and 2-chloroacrylonitrile (63 mg,
0.72 mmol) a mixture of two isomeres was obtained. The
4-Acetyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-2-
nitrile was obtained as a white solid in 70% yield. Mp 113–
115 8C. IR (KBr) y (cmK1), 2230 (CN); 1671 (CO); 1580
(CN); 1268 (Ar–O); 1081 (C–O). 1H NMR (CDCl3,
200 MHz) d (ppm), 2.66 (s, 3H, CH3); 3.95 (dd, JZ4.4,
14.2 Hz, 1H, CH2N); 4.93 (dd, JZ4.4, 14.2 Hz, 1H, CH2N);
5.21 (dd, JZ1.0, 6.8 Hz, 1H, H-2); 7.13 (dd, JZ4.6, 7.9 Hz,
1H, H-7); 7.38 (dd, JZ1.0, 7.9 Hz, 1H, H-8); 8.18 (dd, JZ
1.0, 4.6 Hz, 1H, H-6). 13C NMR (CDCl3, 50.3 MHz) d
(ppm), 24.8 (CH3); 40.9 (CH2); 63.5 (CH–O); 114.6 (C,
CN); 121.5 (CH, C-7); 125.3 (CH, C-8); 138.8 (C, C-8a);
141.2 (C, C-8); 151.2 (C, C-4a); 170.1 (CO, amide). Anal.
Calcd for C10H9N3O2: C, 59.11%; H, 4.46%; N, 20.68%.
Found: C, 59.34%; H, 4.63%; N, 20.54%. The 4-Acetyl-3,4-
dihydro-2H-pyrido[3,2-b][1,4]oxazine-3-nitrile (7a) was
obtained as a white solid in 36% yield when acetone was
used as a solvent (see Table 1). Mp 110–112 8C. IR (KBr) y
(cmK1), 2236 (CN); 1675 (CO); 1567 (CN); 1243 (Ar–O);
4.2.3. 4-tertButylcarbonyl-2,3-dihydro-4H-pyrido[3,2-b]-
[1,4]oxazine-2-nitrile (6c). From 2-tertbutylcarbonyl-
amino-3-hydroxypyridine (100 mg, 0.52 mmol) and
2-chloroacrylonitrile (50 mg, 0.57 mmol) the 2-substituted
pyrido-oxazine was obtained with 50% yield as a yellow
pale instable solid. IR (KBr) y (cmK1), 2242 (CN); 1717
(CO); 1568 (CN); 1254 (Ar–O); 1097 (C–O). 1H NMR
(CDCl3, 200 MHz) d (ppm), 1.55 (s, 9H, CH3); 3.81–3.85
(m, 1H, H-3); 4.50–4.61 (m, 1H, H-3); 5.10–5.19 (m, 1H, H-
2); 7.05–7.09 (m, 1H, H-7); 7.24–7.28 (m, 1H, H-8); 8.21
(dd, JZ1.8, 4.8 Hz, 1H, H-6). 13C NMR (CDCl3,
50.3 MHz) d(ppm), 28.1 (CH3); 43.9 (CH2, CH2–N); 63.2
(CH, CH–O); 83.2 (C); 116.8 (C, CN); 121.2 (CH, C-7);
124.9 (CH, C-8); 138.9 (C, C-8a); 141.9 (CH, C-6); 150.0
(C, C-4a); 168.1 (C, CO). Anal. Calcd for C13H15N3O2: C,
63.66%; H, 6.16%; N, 17.13%. Found: C, 63.99%; H,
6.54%; N, 16.08%.
1
1032 (C–O). H NMR (CDCl3, 200 MHz) d (ppm), 3.67–
4.2.4. 4-Acetyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-
2-carboxylic acid ethyl ester (8). Following the general
procedure described above starting from 2-acetamido-3-
hydroxypyridine (100 mg, 0.66 mmol) and 2,3-dibromo-
propionate ethyl ester (188 mg, 0.72 mmol) the 4-acetyl-
3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-2-carboxylic
acid ethyl ester was obtained in 56% yield. Colorless oil. IR
(KBr) y (cmK1), 1745 (CO); 1653 (CO), 1228 (Ar–O); 1059
3.78 (m, 1H, CHN); 3.80 (s, 3H, CH3); 4.80–4.90 (m, 2H, H-
2); 6.61 (dd, JZ4.5, 8.0 Hz, 1H, H-7); 7.18 (dd, JZ1.0,
8.0 Hz, 1H, H-8); 7.72 (dd, JZ1.0, 8 Hz, 1H, H-6). 13C
NMR (CDCl3, 50.3 MHz) d (ppm), 27.2 (CH3); 42.5 (CH2);
61.2 (CH2–O); 115.9 (C, CN); 122.3 (CH, C-7); 126.2 (CH,
C-8); 137.5 (C, C-8a); 141.8 (C, CH-6); 150.8 (C, C-4a);
168.2 (CO, amide). Anal. Calcd for C10H9N3O2: C, 59.11%;
H, 4.46%; N, 20.68%. Found: C, 59.02%; H, 4.72%; N,
20.72%.
1
(C–O). H NMR (CDCl3, 200 MHz) d (ppm), 1.28 (t, JZ
7.0 Hz, 3H, CH3); 2.54 (s, 3H, CH3); 3.98 (dd, JZ4.0,
7.0 Hz, 2H, CH–N); 4.24 (q, JZ7.0 Hz, 2H, CH2–O); 4.94–
4.99 (m, 1H, CH–O), 7.09 (dd, JZ1.4, 4.7 Hz, 1H, H-7);
7.18 (dd, JZ1.3, 8.0 Hz, 1H, H-8); 8.01 (dd, JZ1.4, 4 Hz,
1H, H-6). 13C NMR (CDCl3, 50.3 MHz) d (ppm), 14.1
(CH3); 24.5 (CH3); 40.3 (CH2–N); 62.0 (CH2–O); 73.1
(CH–O); 121.4 (CH, C-7); 124.6 (CH, C-8); 139.7 (CH, C-
6); 141.1 (C, C-8a); 141.3 (C, C-4a); 168.1 (CO, ester);
170.1 (CO, amide). Anal. Calcd for C12H14N2O4: C,
57.59%; H, 5.64%; N, 11.19%. Found: C, 57.78%;
H, 5.89%; N, 11.40%. 4-Acetyl-3,4-dihydro-2H-pyrido[3,2-b]-
[1,4]oxazine-3-carboxylic acid ethyl ester (9) the 4-acetyl-
3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-3-carboxylic
acid ethyl ester was obtained in 14% yield. Colorless oil. IR
(KBr) y (cmK1), 1756 (CO); 1667 (CO), 1232 (Ar–O); 1045
4.2.2. 4-Ethoxycarbonyl-3,4-dihydro-2H-pyrido[3,2-b]-
[1,4]oxazine-2-nitrile (6b). From 2-ethoxycarbonyl-3-
hydroxypyridine (100 mg, 0.55 mmol) and 2-chloroacrylo-
nitrile (53 mg, 0.60 mmol) a mixture of two isomers was
obtained. Themajorityisomer4-ethoxycarbonyl-3,4-dihydro-
2H-pyrido[3,2-b][1,4]oxazine-2-nitrile was obtained as a
yellow pale solid in 40% yield. Mp 103–104 8C. IR (KBr) y
(cmK1), 2251 (CN); 1784 (CO); 1576 (CN); 1151 (Ar–O);
1080 (C–O). 1H NMR (CDCl3, 200 MHz) d (ppm), 1.26 (s,
3H, CH3); 2.20 (dd, JZ1.0, 8.4 Hz, 1H, CHN); 2.73 (dd,
JZ1.0, 8.5 Hz, 1H, CHN); 4.07–4.19 (m, 2H, CH2–O); 4.81
(dd, JZ1.0, 9.1 Hz, 1H, H-2); 7.20 (dd, JZ4.5, 8.0 Hz, 1H,
H-7); 7.41 (dd, JZ1.0, 8.0 Hz, 1H, H-8); 8.21 (dd, JZ1.0,
8 Hz, 1H, H-6). 13C NMR (CDCl3, 50.3 MHz) d (ppm), 14.4
(CH3); 43.4 (CH2); 62.8 (CH2–O); 72.9 (CH, C-2); 119.2
(C, CN); 121.2 (CH, C-7); 124.6 (CH, C-8); 138.5 (C,
C-8a); 140.6 (CH, C-6); 153.2 (C, C-4a); 168.4 (CO,
1
(C–O). H NMR (CDCl3, 200 MHz) d (ppm), 1.30 (t, JZ
7.0 Hz, 3H, CH3); 2.53 (s, 3H, CH3); 3.97 (m, 1H, CH–N);
4.24 (q, JZ7.0 Hz, 2H, CH2–O); 4.87–4.95 (m, 2H,
CH2–O), 6.83 (m, 1H, H-7); 7.21 (dd, JZ1.3, 8.0 Hz, 1H,