K. C. Prousis, A. Tzani, N. Avlonitis, T. Calogeropoulou, and A. Detsi
Vol 000
(2a) (161 mg, 1.0 mmol) and propan-2-ol (300mg, 5.0mmol). After
work-up as described for compound 6b, the title compound was
obtained as a white solid. Yield: 184 mg, 83%. mp 58–59ꢀC (lit.
[45] mp 62–63ꢀC). 1H-NMR (300 MHz, CDCl3): d = 1.41
(d, J = 6.3 Hz, 6H), 2.25 (s, 3H), 5.18–5.31 (m, 1H), 7.06,
(t, J= 7.5 Hz, 1H), 7.51 (t, J= 7.5 Hz, 1H), 8.02 (d, J= 7.8 Hz, 1H),
8.68 (d, J= 8.4 Hz, 1H), 11.13 (br s, 1H). 13C-NMR (75 MHz,
CDCl3): d = 23.7, 25.6, 31.6, 73.9, 115.5, 120.4, 122.4, 130.9,
134.5, 141.7, 167.9, 169.2 ppm. ESI–MS: m/z 221.89 [M + H]+.
Ethyl 2-acetamido-4,5-dimethoxybenzoate (6f). Compound
6f was prepared via Method B using 6,7-dimethoxy-2-methyl-
4H-benzo[d][3,1]oxazin-4-one (2d) (221 mg, 1.0 mmol) and
ethanol (230 mg, 5.0 mmol). After work-up as described for
compound 6b, compound 6f was obtained as a white solid.
Yield: 227 mg, 85%. mp 131–133ꢀC (lit.[49] mp 130ꢀC dec.).
1H-NMR (300 MHz, CDCl3): d = 1.42 (t, J = 7.2 Hz, 3H), 2.22
(s, 3H), 3.88 (s, 3H), 3.95 (s, 3H), 4.30 (q, J = 7.2 Hz, 2H), 7.43
(s, 1H), 8.43 (s, 1H), 11.14 (br s, 1H) ppm. 13C-NMR (75 MHz,
CDCl3): d = 14.4, 25.6, 56.2, 61.2, 103.4, 106.7, 112.2, 138.0,
143.8, 154.0, 168.1, 169.1 ppm. ESI–MS: m/z 267.89 [M + Na]+.
Prop-2-ynyl 2-acetamido-4,5-dimethoxybenzoate (6g). Compound
6g was prepared via Method B using 6,7-dimethoxy-2-methyl-4H-benzo
[d][3,1]oxazin-4-one (2d) (221 mg, 1.0 mmol) and prop-2-yn-1-ol
(propargyl alcohol) (280 mg, 5.0 mmol). After work-up as described for
compound 6b, compound 6g was obtained as a white solid. Yield:
was obtained as a white solid Yield: 166 mg, 80%. mp 63–65ꢀC
(lit.[50] mp 59–60ꢀC.) 1H-NMR (600 MHz, CDCl3): d = 1.41
(t, J = 7.2 Hz, 3H), 2.41 (s, 3H), 4.40 (q, J = 7.2 Hz, 2H), 7.04
(dd, J = 7.8, 4.8 Hz, 1H), 8.31 (dd, J = 7.8, 1.8 Hz, 1H), 8.57
(d, J = 4.8, 1.8 Hz, 1H), 10.77 (br s, 1H) ppm..13C-NMR
(75 MHz, CDCl3): d = 14.3, 26.1, 62.1, 111.3, 118.1, 140.1,
152.6, 153.0, 166.7, 169.8 ppm. ESI–MS: m/z 208.92 [M + H]+.
Prop-2-ynyl 2-acetamidonicotinate (6k). Compound 6k was
prepared via Method A using 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-
4-one (2e) (162 mg, 1.0 mmol) and prop-2-yn-1-ol (propargyl alcohol),
(280 mg, 5.0 mmol). After work-up as described for compound 6a,
followed by flash column chromatography (petroleum ether/ethyl
acetate 4:6), compound 6k was obtained as a white solid. Yield:
1
144 mg, 66%. mp 77–81ꢀC. H-NMR (300 MHz, CDCl3): d =2.43
(s, 3H), 2.58 (t, J= 2.4 Hz, 1H), 4.94 (d, J= 2.4 Hz, 2H), 7.07 (dd,
J= 7.8, 4.8 Hz, 1H), 8.33 (dd, J= 7.8, 2.1 Hz, 1H), 8.58 (dd, J=1.8,
4.8 Hz, 1H), 10.52 (br s, 1H) ppm. 13C-NMR (75 MHz, CDCl3):
d = 26.1, 29.8, 53.17, 76.0, 110.6, 118.2, 140.32, 152.5, 153.4, 165.9,
169.8 ppm. ESI–MS: m/z 218.98 [M + H]+. ESI–HRMS: m/z
[M + H]+ Calcd for C11H11N2O3: 219.0764, found: 219.0756.
4-Methoxybenzyl 2-acetamidonicotinate (6l). Compound 6l
was prepared via Method A using 2-methyl-4H-pyrido[2,3-d][1,3]
oxazin-4-one (2e) (162 mg, 1.0mmol) and p-methoxybenzyl
alcohol (690 mg, 5 mmol). After work-up as described for 6a,
followed by flash column chromatography (petroleum ether/ethyl
acetate 4:6), compound 6l was obtained as a white solid. Yield:
239 mg, 72%. mp 92–95ꢀC. 1H-NMR (300MHz, CDCl3):
d = 2.43 (s, 3H), 3.83 (s, 3H), 5.31 (s, 2H), 6.92 (d, J = 8.4Hz,
2H), 7.02 (dd, J = 4.8, 8.1 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 8.30
(dd, J = 2.1, 7.8Hz, 1H), 8.55 (dd, J = 4.8, 1.8 Hz, 1H), 10.72 (br
s, 1H) ppm. 13C-NMR (75MHz, CDCl3): d = 26.1, 55.4, 67.6,
114.2, 118.1, 127.2, 130.5, 140.21, 152.6, 153.0, 160.1, 166.5,
169.8 ppm. ESI–MS: m/z 300.86 [M+ H]+. ESI–HRMS: m/z
[M+ H]+ Calcd for C16H17N2O3: 301.1183, found: 301.1181.
Isopropyl 2-acetamidonicotinate (6m). Compound 6m was
prepared via Method A using 2-methyl-4H-pyrido[2,3-d][1,3]
oxazin-4-one (2e) (162 mg, 1.0mmol) and propan-2-ol (300 mg,
5.0 mmol). After work-up as described for 6a, followed by flash
column chromatography (petroleum ether/ethyl acetate 7:3),
compound 6m was obtained as a white solid. Yield: 188 mg, 80%.
1
207 mg, 90%. mp 211–214ꢀC. H-NMR (300 MHz, CDCl3): d =2.24
(s, 3H), 2.56 (t, J=2.4Hz, 1H), 3.90 (s, 3H), 3.97 (s, 3H), 4.91
(d, J=2.4Hz, 2H), 7.45 (s, 1H), 8.45 (s, 1H), 10.94 (br s, 1H) ppm.
13C-NMR (75 MHz, CDCl3): d = 25.7, 52.5, 56.2, 56.3, 75.4, 103.4,
105.7, 112.2, 138.4, 143.9, 154.6, 167.2, 169.2 ppm. ESI–MS: m/z
300.02 [M + Na]+. ESI–HRMS: m/z [M + H]+ Calcd for C14H16NO5:
278.1023, found: 278.1019.
4-Methoxybenzyl 2-acetamido-4,5-dimethoxybenzoate (6h).Compound
6h was prepared via Method B using 6,7-dimethoxy-2-methyl-
4H-benzo[d][3,1]oxazin-4-one (2d) (221mg, 1.0 mmol) and
p-methoxybenzyl alcohol (691mg, 5.0 mmol). After work-up as
described for compound 6b, compound 6h was obtained as a
white solid. Yield: 291mg, 81%. mp 132–134ꢀC. 1H-NMR
(300 MHz, CDCl3): d = 2.22 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H),
3.96 (s, 3H), 5.29 (s, 2H), 6.92 (d, J = 7.8 Hz, 2H), 7.37
(d, J = 8.4Hz, 2H), 7.45 (s, 1H), 8.45 (s,1H), 11.08 (br s, 1H)
ppm. 13C-NMR (75 MHz, CDCl3): d = 25.6, 55.4, 56.2, 56.3,
66.7, 103.4, 106.6, 112.4, 114.2, 127.9, 130.1, 138.1, 143.9,
154.2, 159.9, 167.9, 169.1 ppm. ESI–MS: m/z 382.00 [M + Na]+.
ESI–HRMS: m/z [M + H]+ Calcd for C19H22NO6: 360.1442,
found: 360.1439.
Isopropyl 2-acetamido-4,5-dimethoxybenzoate (6i). Compound
6i was prepared via Method B using 6,7-dimethoxy-2-methyl-4H-
benzo[d][3,1]oxazin-4-one (2d) (221 mg 1.0 mmol) and propan-2-ol
(300 mg, 5.0 mmol). After work-up as described for compound
6b, compound 6i was obtained as a white solid. Yield: 181.5 mg,
65%. mp 127–131ꢀC. 1H-NMR (300 MHz, CDCl3): d =1.41
(d, J= 6.3 Hz, 6H), 2.24 (s, 3H), 3.89 (s, 3H), 3.96 (s, 3H), 5.23
(septet, J= 6 Hz, 1H), 7.43 (s, 1H), 8.44 (s, 1H), 11.19 (br s, 1H)
ppm. 13C-NMR (75 MHz, CDCl3): d = 22.1, 25.7, 56.2/56.3, 68.9,
103.4, 107.1, 112.4, 137.9, 143.8, 154.0, 167.6, 169.2 ppm. ESI–MS:
m/z 281.88 [M + H]+. ESI–HRMS: m/z [M + H]+ Calcd for
C14H20NO5: 282.1336, found: 282.1332.
1
mp 81–82ꢀC. H-NMR (600MHz, CDCl3): d = 1.37 (d, J =6 Hz,
6H), 2.40 (s, 3H), 5.24 (septet, J = 6 Hz, 1H), 7.04 (dd, J = 7.8,
4.8 Hz, 1H), 8.30 (dd, J = 7.8, J = 2.1 Hz, 1H), 8.56 (d, J = 4.2Hz,
1H), 10.83 (br s, 1H) ppm. 13C-NMR (75 MHz, CDCl3): d = 21.9,
26.1, 70.0, 111.7, 118.1, 140.2, 152.6, 152.8, 166.2, 169.7 ppm.
ESI–MS: m/z 222.95 [M + H]+. ESI–HRMS: m/z [M+ H]+ Calcd
for C11H15N2O3: 223.1077, found: 223.1074.
Acknowledgments. Financial support from the Basic Research
Committee Program “ΠΕΒΕ 2008” of the National Technical
University of Athens is gratefully acknowledged.
REFERENCES AND NOTES
[1] Bouillant, M. L.; Favre-Bonvin, J.; Ricci, P. Tetrahedron Lett
1983, 24, 51.
[2] Mohamed, M. S.; Kamel, M. M.; Kassem, E. M. M.; Abotaleb,
N.; Abd El-moez, S. I.; Ahmed, M. F. Eur J Med Chem 2010, 45, 3311.
[3] Mrozek-Wilczkiewicz, A.; Kalinowski, D. S.; Musiol, R.; Finster,
J.; Szurko, A.; Serafin, K.; Knas, M.; Kamalapuram, S. K.; Kovacevic, Z.;
Jampilek, J.; Ratuszna, A.; Rzeszowska-Wolny, J.; Richardson, D. R.;
Polanski, J. Bioorg Med Chem 2010, 18, 2664.
Ethyl 2-acetamidonicotinate (6j).
Compound 6j was
prepared via Method A using 2-methyl-4H-pyrido[2,3-d][1,3]
oxazin-4-one (2e) (162 mg, 1.0 mmol) and ethanol (230 mg,
5.0 mmol). After work-up as described for 6b, compound 6j
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet