1974 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10
Touzeau et al.
Eth yl 7-Oxo-2,3-d ih yd r o-7H-[1,4]oxa zin o[2,3,4-ij]qu in -
olin e-2-ca r boxyla te (25a ). Obtained in 11% yield during the
cyclization of 23a . Mp 149-150 °C. IR (KBr) υ(cm-1) 1756
113.1 (CH); 119.1 (CH); 122.0 (C); 129.0 (C); 132.2 (C); 140.1
(C); 167.4 (CdN). MS m/z 257 (M)+. Anal. (C15H19N3O, C2H2O4)
C, H, N.
1
(CO), 1636 (CO); H (CDCl3) δ 1.25 (t, 3H, J ) 7.2 Hz, CH3);
3-[2-(E t h oxyca r b on yl)-3,4-d ih yd r o-1,4-b en zoxa zin -4-
yl]-3-oxop r op a n oic a cid (27a ). Ben zyl 3-[2-(Eth oxyca r -
b o n y l)-3,4-d ih y d r o -1,4-b e n zo x a zin e -4-y l]-3-o x o p r o -
p a n oa te. To a solution of compound 2a (3.53 g, 17.1 mmol)
in CH2Cl2 (35 mL) was dropwise added at 0 °C a solution of
triethylamine (7.6 mL, 54.6 mmol) and benzyl 3-chloro-3-
oxopropanoate (7.64 g, 35.9 mmol) in CH2Cl2 (35 mL), and the
mixture was stirred for 1 h at room temperature. Water was
added, and the organic layer was decanted and washed with
water. Drying over MgSO4 and evaporation left a residue
which was chromatographed on a silica gel column using
EtOAc/PE 2:8 as eluent to give an oil (3.50 g, 53%). IR (film)
υ(cm-1) 1750 (CO), 1672 (CO); 1H NMR (CDCl3) δ 1.30 (t, 3H,
J ) 7.0 Hz, CH3); 3.60-3.65 (m, 1H, CH2CO); 3.85-3.97 (m,
2H, CH2CO, H3a); 4.50-4.55 (m, 1H, H3b); 4.25 (q, 2H, J ) 7.0
Hz, OCH2); 4.94 (t, 1H, J ) 4.0 Hz, H2); 5.22 (s, 2H, CH2);
6.90-7.23 (m, 4H, Har); 7.40 (s, 5H, Har). Anal. (C21H21NO6)
C, H, N.
4.24 (q, 2H, J ) 7.2 Hz, OCH2); 4.30-4.40 (m, 2H, H3a, H3b);
5.04 (dd, 1H, J ) 3.8 Hz, 5.6.Hz, H2); 6.21 (d, 1H, J ) 7.5 Hz,
dCH); 7.25-7.33 (m, 2H, Har); 7.39 (d, 1H, J ) 7.5 Hz, dCH);
7.93 (dd, 1H, J ) 2.6 Hz, 6.9 Hz, Har). Ms m/z 260 (M + H)+.
Anal. (C14H13NO4) C, H, N.
E t h yl 8-Met h yl-7-oxo-2,3-d ih yd r o-7H -[1,4]-oxa zin o-
[2,3,4-ij]qu in olin e-2-ca r boxyla te (25c). Obtained during the
cyclization of 23c as an oil; yield 16%. IR: (film) υ(cm-1) 1756
1
(CO), 1626 (CO); H NMR (CDCl3) δ 1.30 (t, 3H, J ) 7.0 Hz,
CH3); 2.91 (s, 3H, CH3); 4.33 (q, 2H, J ) 7.0 Hz, OCH2); 4.34
(m, 2H, H3a, H3b); 5.00 (dd, 1H, J ) 4.0 Hz, 5.4 Hz, H2); 6.22
(d, 1H, J ) 7.8 Hz, dCH); 7.00 (d, 1H, J ) 8.0 Hz, H9ar); 7.18
(d, 1H, J ) 8.0 Hz, H10ar); 7.30 (d, 1H, J ) 7.8 Hz, dCH). 13C
NMR (CDCl3) δ 14,1 (CH3); 23.2 (CH3); 50.1 (CH2); 62.0 (CH2);
70.7 (CH); 112.3 (CH); 117.8 (CH); 125.4 (C); 126.3 (CH); 129.0
(C); 134.2 (C); 139.5 (CH); 141.7 (C); 167.4 (CO); 180.4 (CO).
MS m/z 274 (M + H)+. Anal. (C15H15NO4) C, H, N.
3-[2-(E t h oxyca r b on yl)-3,4-d ih yd r o-1,4-b en zoxa zin -4-
yl]-3-oxop r op a n oic Acid (27a ). Benzyl 3-[2-(ethoxycarbo-
nyl)-3,4-dihydro-1,4-benzoxazine-4-yl]-3-oxopropanoate was hy-
drogenolyzed as for 22a to afford the acid 27a in 97% yield;
oil. IR: (film) υ(cm-1) 3500-2700 (OH), 1760 (CO), 1670 (CO);
1H NMR (CDCl3) δ 1.28 (t, 3H, J ) 7.0 Hz, CH3); 3.55-3.94
(m, 3H, CH2CO, H3a); 4.20 (q, 2H, J ) 7.0 Hz, OCH2); 4.62-
4.81 (m, 1H, H3b); 5.01 (s large, 1H, H2); 6.85-7.19 (m, 4H,
2-(4,5-Dih yd r o-1H -im id a zol-2-yl)-2,3,6,7-t et r a h yd r o-
5H-[1,4]oxa zin o[2,3,4-ij]qu in olin e (26a ). Eth yl 2,3,6,7-
Tetr a h yd r o-5H-[1,4]oxa zin o[2,3,4-ij]qu in olin e-2-ca r box-
yla te. Compound 24a (200 mg, 0.76 mmol) in ethanol (20 mL)
was stirred with Pd/C 10% (50 mg) under hydrogen (3 atm)
for 48 h. After filtration over a filter aid, the solvent was
evaporated and the residue was purified by column chroma-
tography using CH2Cl2 as eluent. An oil was obtained (131 mg,
70%). IR (film) υ(cm-1) 1742 (CO); 1H NMR (CDCl3) δ 1.28 (t,
3H, J ) 7.1 Hz, CH3); 1.99-2.06 (m, 2H, CH2); 2.76 (t, 2H, J
) 6.5 Hz, CH2); 3.08 (t, 2H, J ) 6.5 Hz, CH2N); 3.33-3.35 (m,
2H, H3a, H3b); 4.27 (q, 2H, J ) 7.1 Hz, OCH2); 4.86 (dd, 1H, J
) 3.7 Hz, 4.7 Hz, H2); 6.58-6.61 (m, 2H, Har); 6.74 (t, 1H, J )
6.0 Hz, H9). Anal. (C14H17NO3) C, H, N.
H
ar); 9.64 (br s, 1H, OH). Anal. (C14H15NO6) C, H, N.
3-[2-(E t h oxyca r b on yl)-6-m et h yl-3,4-d ih yd r o-1,4-b en -
zoxa zin -4-yl]-3-oxop r op a n oic Acid (27c). Ben zyl 3-[2-
(Eth oxyca r bon yl)-6-m eth yl-3,4-d ih yd r o-1,4-ben zoxa zin -
4-yl]-3-oxop r op a n oa te. This ester was similarly obtained in
61% yield as for benzyl 3-[2-(ethoxycarbonyl)-3,4-dihydro-1,4-
benzoxazin-4-yl]-3-oxopropanoate, starting from compound 2c.
Oil. IR (film) υ(cm-1) 1744 (CO), 1668 (CO); 1H NMR (CDCl3)
δ 1.27 (t, 3H, J ) 7.0 Hz, CH3); 2.26 (s, 3H, CH3); 3.59-3.65
(m, 1H, CH2CO); 3.81-3.90 (mas, 2H, CH2CO, H3a); 4.20 (q,
2H, J ) 7.0 Hz, OCH2); 4.43-4.55 (m, 1H, H3b); 4.90 (t, 1H, J
) 4.0 Hz, H2); 5.22 (s, 2H, CH2); 6.94-6.98 (m, 3H, Har);. 7.39
(s, 5H, Har). Anal. (C22H23NO6) C, H, N.
2-(4,5-Dih yd r o-1H -im id a zol-2-yl)-2,3,6,7-t et r a h yd r o-
5H-[1,4]oxa zin o[2,3,4-ij]qu in olin e (26a ). Obtained from
ethyl 2,3,6,7-tetrahydro-5H-[1,4]oxazino[2,3,4-ij]quinoline-2-
carboxylate as for 4. Yield 61%; oil. IR (film) υ(cm-1) 3395
(NH), 1667, 1633(CdN); 1H (CDCl3) δ 1.98 (m, 2H, CH2); 2.76
(t, 2H, J ) 7.0 Hz, CH2); 3.08-3.12 (m, 2H, CH2N); 3.31 (dd,
1H, J ) 7.5 Hz, 11.8 Hz, H3a,); 3.49 (dd, 1H, J ) 2.6 Hz, 11.8
Hz, H3b); 3.70 (s, 4H, NCH2); 4.70 (br s, 1H, NH); 5.02 (dd,
1H, J ) 2.6 Hz, 7.5 Hz, H2); 6.51-6.58 (m, 3H, Har). MS m/z
244 (M + H)+. Anal. (C14H17N3O, C2H2O4) C, H, N.
3-[2-(E t h oxyca r b on yl)-6-m et h yl-3,4-d ih yd r o-1,4-b en -
zoxa zin -4-yl]-3-oxop r op a n oic Acid (27c). Obtained by hy-
drogenolysis, as for 22a , of benzyl 3-[2-(ethoxycarbonyl)-6-
methyl-3,4-dihydro-1,4-benzoxazin-4-yl]-3-oxopropanoate. Yield
90%; oil. IR (film) υ(cm-1) 3400-2700 (OH), 1738 (CO), 1670
2-(4,5-Dih yd r o-1H -im id a zol-2-yl)-8-m et h yl-2,3,6,7-t et -
r a h yd r o-5H-[1,4]oxa zin o[2,3,4-ij]qu in olin e (26c). Same
procedure as for 26a , starting from 24c. Eth yl 8-Meth yl-
2,3,6,7-t et r a h yd r o-5H -[1,4]oxa zin o[2,3,4-ij]q u in olin e-2-
ca r boxyla te. This compound was obtained from 24c by
hydrogenation under 3 atm of hydrogen; yield 31%; oil. IR
1
(CO); H NMR (CDCl3) δ 1.28 (t, 3H, J ) 7.0 Hz, CH3); 2.35
(s, 3H, CH3); 3.65-3.85 (m, 3H, CH2CO, H3a); 4.24 (q, 2H, J )
7.0 Hz, OCH2); 4.67-4.93 (m, 1H, H3b); 4.98 (br s, 1H, H2);
6.94-7.01 (m, 3H, Har); 7.52 (br s, 1H, OH). 13C NMR (CDCl3)
δ 14.1 (CH3); 20.8 (CH3); 38.7 (CH2); 41.7 (CH2); 62.3 (CH2);
73.5 (CH); 117.8 (CH); 123.9 (CH); 124.2 (C); 129.1 (C); 130.8
(CH); 144.6 (C); 168.2 (CO); 168.9 (2CO). Anal. (C15H17NO6)
C, H, N.
1
(film) υ(cm-1) 1759 (CO); H NMR (CDCl3) δ 1.29 (t, 3H, J )
7.0 Hz, CH3); 2.00-2.10 (t, 2H, m, CH2); 2.10 (s, 3H, CH3);
2.62 (t, 2H, J ) 6.5 Hz, CH2); 3.03 (t, 2H, J ) 6.5 Hz, NCH2);
3.32 (d, 2H, J ) 4.5 Hz, H3a, H3b); 4.26 (q, 2H, J ) 7.0 Hz,
OCH2); 4.84 (t, 1H, J ) 4.5 Hz, H2); 6.49 (d, 1H, J ) 8.5 Hz,
Eth yl 7-Hyd r oxy-5-oxo-2,3-d ih yd r o-5H-[1,4]-oxa zin o-
[2,3,4-ij]qu in olin e-2-ca r boxyla te (28a ). To a solution of
compound 27a (2.34 g 8 mmol) in CH2Cl2 (40 mL) was dropwise
added trifluoroacetic anhydride (5 mL, 35 mmol) at 0 °C, and
the mixture was stirred for 18 h at room temperature. Water
was added, and the pH of the aqueous layer was adjusted to
pH 4-5. The obtained solid from the mixture was filtered (1.12
g, 51%); mp 242 °C. IR (KBr) υ(cm-1) 3086 (OH), 1752 (CO),
1646 (CO); 1H (DMSO-d6) δ 1.13 (t, 3H, J ) 7.0 Hz, CH3); 4.10
(q, 2H, OCH2); 4.18 (dd, 1H, J ) 3.8 Hz, 13.6 Hz, H3a); 4.35
(dd, 1H, J ) 5.2 Hz, 13.6 Hz, H3b); 5.30 (dd, 1H, J ) 3.8 Hz,
5.2 Hz, H2); 5.85 (s, 1H, dCH); 7.12-7.25 (m, 2H, Har); 7.47
(dd, 1H, J ) 1.5 Hz, 7.8 Hz); 11.52 (s, 1H, OH). MS m/z 276
(M + H)+. Anal. (C14H13NO5) C, H, N.
H
ar); 6.69 (d, 1H, J ) 8.5 Hz, Har). 13C NMR (CDCl3) δ 14.6
(CH3); 19.5 (CH3); 22.3 (CH2); 24.8 (CH2); 49.1 (CH2); 49.7
(CH2); 68.8 (CH2); 73.3 (CH); 113.7 (CH); 120.1 (CH); 122. 7
(C); 126.3 (C); 132.5 (C); 141.2 (C); 170.0 (CO). Anal. (C15H19
NO3) C, H, N.
-
2-(4,5-Dih yd r o-1H -im id a zol-2-yl)-8-m et h yl-2,3,6,7-t et -
r a h yd r o-5H -[1,4]oxa zin o[2,3,4-ij]q u in olin e (26c). Ob-
tained from ethyl 8-methyl-2,3,6,7-tetrahydro-5H-[1,4]oxazino-
[2,3,4-ij]quinoline-2-carboxylate as for 4 as an oil; yield 77%.
IR (film) υ(cm-1) 3310 (NH), 1667, 1633 (CdN); 1H NMR
(CDCl3) δ 2.00-2.10 (m, 2H, CH2); 2.10 (s, 3H, CH3); 2.60-
2.67 (m, 2H, CH2); 2.95-3.15 (m, 2H, NCH2); 3.17 (dd, 1H, J
) 8.0 Hz, 11.5 Hz, H3a); 3.40 (dd, 1H, J ) 2.5 Hz, 11.5 Hz,
Eth yl 7-Hyd r oxy-8-m eth yl-5-oxo-2,3-d ih yd r o-5H-[1,4]-
oxa zin o[2,3,4-ij]qu in olin e-2-ca r boxyla te (28c). Same pro-
cedure as for 28a , starting from 27c; yield 70%, mp 167-168
°C. IR (KBr) υ(cm-1) 3086 (OH), 1732 (CO), 1648 (CO); 1H
NMR (DMSO-d6) δ 1.14 (t, 3H, J ) 7.0 Hz, CH3); 2.64 (s, 3H,
H
3b); 3.65 (s, 4H, NCH2); 4.96 (dd, 1H, J ) 2.5 Hz, 8.0 Hz, H2);
5.38 (br s, 1H, NH); 6.44 (d, 1H, J ) 8.0 Hz, Har); 6.58 (d, 1H,
J ) 8.0 Hz, Har). 13C NMR (CDCl3) δ 19.1 (CH3); 21.5 (CH2);
24.5 (CH2); 48.6 (CH2); 49.2 (2CH2); 49.7 (CH2); 71.2 (CH);