The Journal of Organic Chemistry
Article
DMSO) δ 160.7, 152.1, 145.6, 144.3 (q, J = 35.6 Hz), 138.0, 136.0,
129.5, 128.9, 127.8, 126.6, 126.3, 123.8, 118.8 (q, J = 277.8 Hz), 48.4.
140.0, 136.0, 128.9, 127.7, 127.6, 126.3, 119.4 (q, J = 277.6 Hz), 119.2,
48.4. 19F NMR (375 MHz, DMSO) δ −64.81. MS [M + H]+ 305.92
m/z. IR 1703 (s), 1401 (s), 1202 (s), 693 (s) cm−1. (ESI-TOF), m/z
[M + H]+ calcd for C15H11F3N3O 306.0849, found 306.0852
+
19F NMR (375 MHz, DMSO) δ −64.90. MS [M + H]+ + NH4
366.99 m/z. IR 1698 (s), 1529 (s), 1404 (s), 1199 (s), 982 (s), 687 (s)
cm−1. (ESI-TOF), m/z [M + H]+ calcd for C16H11F3N3O3 350.0747,
found 350.0746.
3-(o-Tolyl)-2-(trifluoromethyl)quinazolin-4-(3H)-one (4r). The
reaction was performed according to the general procedure with
anthranilic acid 1r as starting material, o-toluidine and trifluoroacetic
acid. The crude compound was purified by flash chromatography (n-
heptane/EtOAc: from 100/0 to 70/30) yielding compound 4r as a
white solid (0.92 g, 42%). mp 144 °C. 1H NMR (500 MHz, CDCl3) δ
8.38−8.40 (m, 1 H), 7.91−7.96 (m, 2 H), 7.69 (m, 1 H), 7.36−7.48
(m, 3 H), 7.23 (d, J = 7.8 Hz, 1 H), 2.16 (s, 3 H). 13C NMR (125
MHz, CDCl3) δ 161.0, 145.4, 142.4 (q, J = 35.5 Hz), 136.9, 135.3,
133.9, 131.0, 130.3, 129.6, 129.1, 128.8, 127.5, 126.9, 122.2, 117.8 (q, J
= 277.5 Hz), 17.51. 19F NMR (375 MHz, CDCl3) δ −65.58. MS [M +
H]+ 305.21 m/z. IR 1692 (s), 1375 (s), 1202 (s), 965 (s), 693 (s)
cm−1. (ESI-TOF), m/z [M + H]+ calcd for C16H12F3N2O 305.0896,
found 305.0898.
3-Pentyl-2-(trifluoromethyl)quinazolin-4(3H)-one (4s). The reac-
tion was performed according to the general procedure with
anthranilic acid 1s as starting material, n-pentylamine and trifluoro-
acetic acid. The crude compound was purified by flash chromatog-
raphy (n-heptane/EtOAc: from 100/0 to 70/30) yielding compound
4s as a transparent oil (1.23 g, 59%). 1H NMR (500 MHz, DMSO) δ
8.23 (d, J = 7.7 Hz, 1 H), 7.94−7.97 (m, 1 H), 7.85 (d, J = 8.1 Hz, 1
H), 7.73 (t, J = 7.7 Hz, 1 H), 4.01 (t, J = 8.0 Hz, 2 H), 1.67−1.72 (m, 2
H), 1.35 (m, 4 H), 0.88−0.91 (m, 3 H). 13C NMR (125 MHz,
DMSO) δ 161.1, 145.0, 142.1 (q, J = 34.9 Hz), 135.7, 130.0, 128.6,
127.0, 122.1, 118.7 (q, J = 276.8 Hz), 45.4, 28.9, 28.0, 22.1, 14.3. 19F
NMR (375 MHz, DMSO) δ −64.88. MS [M + H]+ 285.26. IR 2933
(m), 1690 (s), 1609 (s), 1467 (s), 1404 (s), 1321 (s), 1238 (s), 1202
(s), 1092 (s), 772 (s), 695 (s) cm−1. (ESI-TOF), m/z [M + H]+ calcd
for C14H16F3N2O 285.1209, found 285.1216.
(S)-3-Isobutyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione
(6).15c To a suspension of anthranilic acid 1a (1.0 g, 7.22 mmol, 1.0
equiv) in toluene (4 mL) at rt was added Et3N (1.5 mL, 10.8 mmol,
1.5 equiv) followed by T3P (50% w/w in toluene, 4.38 mL, 7.22
mmol, 1.0 equiv). The resulting mixture was kept at rt for 2.5 h then
heated to 70 °C and L-leucine methyl ester hydrochloride (1.3 g, 7.07
mmol, 0.98 equiv) added in one portion. After 20 h at 70 °C, the
reaction mixture was cooled to rt, diluted with EtOAc (25 mL) and
quenched by slow addition of aq. sat. NaHCO3 (25 mL, Caution! Gas
evolution). Aqueous phase was extracted with EtOAc (25 mL) and
collected organic phases were washed with aq. sat. NaHCO3 (25 mL)
and brine (25 mL), dried over anhydrous MgSO4, filtered and
evaporated under reduced pressure to afford desired crude 6. After
trituration with TBME (10 mL), purified benzodiazepine dione 6 was
obtained as a white powder (0.53 g, 32%). mp 242 °C. 1H NMR (500
MHz, DMSO) δ 10.38 (s, 1 H), 8.45 (d, J = 5.8 Hz, 1 H), 7.74 (dd, J1
= 1.5 Hz, J2 = 7.8 Hz, 1 H), 7.52 (m, 1 H), 7.21−7.24 (m, 1 H), 7.10
(d, J = 8.0 Hz, 1 H), 3.61 (q, J = 7.2 Hz, 1 H), 1.66−1.75 (m, 1 H),
1.56 (t, J = 7.2 Hz, 2 H), 0.86 (d, J = 6.6 Hz, 3 H), 0.78 (d, J = 6.6 Hz,
3 H). 13C NMR (125 MHz, DMSO) δ 172.1, 168.2, 137.2, 132.7,
130.8, 126.8, 124.4, 121.4, 36.6, 24.3, 23.3, 22.0. MS [M + H]+ 233.20.
The analytical data are consistent with reported data.
3-Benzyl-2-(chlorodifluoromethyl)quinazolin-4-(3H)-one (4t).
The reaction was performed according to the general procedure
with anthranilic acid 1t as starting material, benzylamine and
chlorodifluoroacetic acid. The crude compound was purified by flash
chromatography (n-heptane/EtOAc: from 100/0 to 80/20) yielding
compound 4t as a transparent oil (1.13 g, 49%). 1H NMR (500 MHz,
CDCl3) δ 8.36 (dt, J1 = 1.0 Hz, J2 = 8.0 Hz, 1 H), 7.88−7.89 (m, 2 H),
7.63−7.67 (m, 1 H), 7.26−7.35 (m, 3 H), 7.17 (d, J = 7.3 Hz, 2 H),
5.57 (s, 2 H). 13C NMR (125 MHz, CDCl3) δ 161.8, 145.8, 145.6 (t, J
= 28.7 Hz), 145.0, 135.6, 135.1, 129.3, 128.7, 127.5, 127.4, 126.1,
121.6, 119.5 (t, J = 294.3 Hz), 48.3. 19F NMR (375 MHz, CDCl3) δ
−53.79. MS [M + H]+ 321.16. IR 1690 (s), 1602 (s), 1167 (s), 1114
(s), 924 (s), 809 (m), 772 (s) cm−1. (ESI-TOF), m/z [M + H]+ calcd
for C16H12ClF2N2O 321.0601, found 321.0603.
3-Benzyl-2-(trifluoromethyl)benzoquinazolin-4-(3H)-one (4k).
The reaction was performed according to the general procedure
with anthranilic acid 1k as starting material, benzylamine and
trifluoroacetic acid. The crude compound was purified by flash
chromatography (n-heptane/EtOAc: 100/0 to 70/30) yielding
1
compound 4k as a white solid (1.04 g, 55%). mp 129 °C. H NMR
(500 MHz, DMSO) δ 8.97 (s, 1 H), 8.56 (s, 1 H), 8.33 (d, J = 8.2 Hz,
1 H), 8.23 (d, J = 8.2 Hz, 1 H), 7.75 (m, 2 H), 7.21−7.34 (m, 5 H),
5.40 (s, 2 H). 13C NMR (125 MHz, DMSO) δ 162.0, 141.5 (q, J =
35.1 Hz), 140.3, 136.8, 136.6, 132.8, 129.9, 129.7, 128.9, 128.8, 128.2,
127.5, 127.5, 126.1, 118.7 (q, J = 277.1 Hz), 47.6. 19F NMR (375
MHz, DMSO) δ −64.60. MS [M + H]+ 355.13 m/z. IR 1693 (s), 1609
(s), 1186 (s), 905 (s), 698 (s) cm−1. (ESI-TOF), m/z [M + H]+ calcd
for C20H14F3N2O 355.1053, found 355.1061.
3-Benzyl-2-(trifluoromethyl)pteridin-4(3H)-one (4l). The reaction
was performed according to the general procedure with anthranilic
acid 1l as starting material, benzylamine and trifluoroacetic acid. The
crude compound was purified by flash chromatography (DCM/
MeOH: 100/0 to 90/10) yielding compound 4l as a yellow foam (1.05
1
g, 48%). H NMR (400 MHz, DMSO) δ 9.18 (d, J = 2.1 Hz, 1 H),
9.05 (d, J = 2.1 Hz, 1 H), 7.27−7.35 (m, 5 H), 5.38 (s, 2 H). 13C NMR
(125 MHz, DMSO) δ 160.9, 152.1, 151.4, 147.3, 145.6 (q, J = 36 Hz),
135.9, 134.7, 128.8, 127.6, 126.3, 118.4 (q, J = 277.9 Hz), 48.6 (d, J = 3
Hz). 19F NMR (375 MHz, DMSO) δ −65.11. MS [M + H]+ 307.18
m/z. IR 1728 (m), 1347 (s), 1120 (s), 1125 (s), 731 (s), 695 (s) cm−1.
(ESI-TOF), m/z [M + H]+ calcd for C14H10F3N4O [M + H]+
307.0801, found 307.0816.
3-Benzyl-2-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4(3H)-one
(4m). The reaction was performed according to the general procedure
with anthranilic acid 1m as starting material, benzylamine and
trifluoroacetic acid. The crude compound was purified by flash
chromatography (n-heptane/EtOAc: 100/0 to 70/30) yielding
1
compound 4m as a light yellow solid (0.55 g, 25%). mp 127 °C. H
NMR (500 MHz, DMSO) δ 9.13 (dd, J1 = 4.5 Hz, J2 = 1.9 Hz, 1 H),
8.63 (dd, J1 = 7.9 Hz, J2 = 1.9 Hz, 1 H), 7.77 (dd, J1 = 7.9 Hz, J2 = 4.6
Hz, 1 H), 7.23−7.34 (m, 5 H), 5.36 (s, 2 H). 13C NMR (125 MHz,
DMSO) δ 162.1, 157.2, 155.5, 145.3 (q, J = 35.9 Hz), 136.9, 136.2,
128.9, 127.6, 126.2, 125.5, 121.7, 120.3 (q, J = 277.4 Hz), 48.2. 19F
NMR (375 MHz, DMSO) δ −65.03. MS [M + H]+ 305.88 m/z. IR
1698 (s), 1394 (s), 1211 (s), 731 (s) cm−1. (ESI-TOF), m/z [M + H]+
calcd for C15H11F3N3O 306.0849, found 306.0852.
3-Benzyl-6-bromo-2-(trifluoromethyl)pyrido[2,3-d]pyrimidin-
4(3H)-one (4n). The reaction was performed according to the general
procedure with anthranilic acid 1n as starting material, benzylamine
and trifluoroacetic acid. The crude compound was purified by flash
chromatography (n-heptane/EtOAc: 100/0 to 70/30) yielding
1
compound 4n as a light yellow thick oil (0.37 g, 21%). H NMR
(500 MHz, DMSO) δ 9.24 (d, J = 2.6 Hz, 1 H), 8.79 (d, J = 2.6 Hz, 1
H), 7.25−7.33 (m, 5 H), 5.35 (s, 2 H). 13C NMR (125 MHz, DMSO)
δ 161.3, 157.9, 154.2, 145.5 (q, J = 35.8 Hz), 138.4, 135.9, 129.0,
128.9, 127.8, 127.7, 126.3, 119.1 (q, J = 276.80 Hz), 48.4. 19F NMR
(375 MHz, DMSO) δ −65.08. MS [M + H]+ 385.75 m/z. IR 1696 (s),
1449 (s), 1308 (s), 1210 (s), 808 (s), 729, (s), 695 (s) cm−1. (ESI-
TOF), m/z [M + H]+ calcd for C15H11BrF3N3O 383.9954, found
383.9958.
3-Benzyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one
(4o). The reaction was performed according to the general procedure
with anthranilic acid 1o as starting material, benzylamine and
trifluoroacetic acid. The crude compound was purified by flash
chromatography (n-heptane/EtOAc: from 100/0 to 50/50) yielding
1
compound 4o as a light yellow solid (0.83 g, 38%). mp 106 °C. H
NMR (500 MHz, DMSO) δ 9.29 (s, 1 H), 8.88 (d, J = 5.2 Hz, 1 H),
8.09 (d, J = 5.2 Hz, 1 H), 7.23−7.33 (m, 5 H), 5.36 (s, 2 H). 13C NMR
(125 MHz, DMSO) δ 160.8, 151.7, 149.4, 144.1 (q, J = 35.7 Hz),
G
J. Org. Chem. XXXX, XXX, XXX−XXX