10.1002/ejoc.201901511
European Journal of Organic Chemistry
FULL PAPER
N-(tert-butyl)-5-ethylidene-7-(4-methoxybenzyl)-6-oxo-5,6,7,8-
N-(tert-butyl)-8-(3,4-dichlorobenzyl)-7-oxo-8,9-dihydro-7H-
tetrahydroimidazo[1,5-a]pyrazine-8-carboxamide (6j): White solid,
59% yield, melting point: 92–93 oC. The product 6j appears as an
unseparated mixture of Z/E isomers with a ratio of 2:3. 1H NMR (500
MHz, CDCl3) δ 7.86 (s, 0.4H), 7.67 (s, 0.6H), 7.23 – 7.11 (m, 2H), 6.92 –
6.82 (m, 3.4H), 6.41 (q, J = 7.5 Hz, 0.6H), 5.92 (s, 0.6H), 5.82 (s, 0.4H),
5.28 – 5.22 (m, 1H), 4.84 (s, 1H), 4.12 (d, J = 14.9 Hz, 0.4H), 4.08 (d, J =
14.9 Hz, 0.6H), 3.78 (s, 3H), 2.38 (d, J = 7.5 Hz, 1.7H), 2.13 (d, J = 7.7
Hz, 1.3H), 1.26 – 1.20 (m, 9H). 13C NMR (126 MHz, CDCl3) δ 166.3,
166.2, 161.8, 161.1, 159.5(2C), 135.0, 131.9, 130.4, 130.1, 130.0, 127.4,
127.3, 127.2, 125.4, 125.0, 124.3, 123.9, 122.5, 122.2, 121.9, 114.4,
56.3, 56.1, 55.4, 52.1(2C), 49.4, 48.6, 28.5(2C), 13.9(2C). HRMS (ESI)
calculated for C21H26N4NaO3 [M+Na]+: 405.1897; found: 405.1890.
imidazo[1,5-a][1,4]diazepine-9-carboxamide (7d): White solid, 53%
yield, melting point: 202–203 oC. 1H NMR (500 MHz, CDCl3) δ 7.70 (s,
1H), 7.44 (d, J = 2.1 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.18 (dd, J = 8.2,
2.1 Hz, 1H), 7.08 (d, J = 9.9 Hz, 1H), 6.98 (s, 1H), 5.88 (d, J = 9.9 Hz,
1H), 5.00 (s, 1H), 4.91 (s, 1H), 4.89 (d, J = 15.5 Hz, 1H), 4.65 (d, J = 15.2
Hz, 1H), 1.16 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 165.2, 164.3, 137.5,
136.3, 133.1, 132.4, 131.0, 130.4, 129.1, 127.9, 127.7, 125.7, 115.0,
56.4, 52.2, 51.7, 28.4. HRMS (ESI) calculated for C19H20Cl2N4NaO2
[M+Na]+: 429.0856; found: 429.0847.
N-(tert-butyl)-8-butyl-7-oxo-8,9-dihydro-7H-imidazo[1,5-
a][1,4]diazepine-9-carboxamide (7e): White solid, 52% yield, melting
point: 150–151 oC. 1H NMR (500 MHz, CDCl3) δ 7.70 (s, 1H), 7.15 (s,
1H), 7.03 (d, J = 9.9 Hz, 1H), 5.82 (d, J = 9.8 Hz, 1H), 5.30 (s, 1H), 4.98
(s, 1H), 3.86 – 3.77 (m, 1H), 3.43 – 3.38 (m, 1H), 1.69 – 1.49 (m, 2H),
1.36 – 1.29 (m, 2H), 1.26 (s, 9H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (126
MHz, CDCl3) δ 164.9, 164.6, 137.2, 128.8, 128.5, 125.1, 115.7, 57.3,
52.2, 49.6, 30.0, 28.5, 20.1, 13.8. HRMS (ESI) calculated for C16H24N4
NaO2 [M+H]+: 327.1791; found: 327.1799.
(Z)-5-benzylidene-N-(tert-butyl)-7-(4-methoxybenzyl)-6-oxo-5,6,7,8-
tetrahydroimidazo[1,5-a]pyrazine-8-carboxamide (6k): White solid,
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1
68% yield, melting point: 233–235 C. H NMR (500 MHz, CDCl3) δ 7.81
(s, 1H), 7.70 (d, J = 7.5 Hz, 2H), 7.40 (t, J = 7.3 Hz, 2H), 7.35 (t, J = 7.3
Hz, 1H), 7.17 (s, 1H), 7.15 (d, J = 3.7 Hz, 2H), 6.88 (s, 1H), 6.84 (d, J =
8.6 Hz, 2H), 6.32 – 6.17 (m, 1H), 5.22 (d, J = 14.9 Hz, 1H), 4.95 (s, 1H),
4.14 (d, J = 14.9 Hz, 1H), 3.74 (s, 3H), 1.23 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 166.0, 160.3, 159.5, 132.9, 132.1, 130.2, 130.1, 128.9, 128.0,
127.4, 126.7, 124.7, 124.5, 123.1, 114.4, 56.2, 55.3, 52.0, 49.0, 28.5.
HRMS (ESI) calculated for C26H29N4O3 [M+H]+: 445.2234; found:
445.2239.
N-benzyl-8-(4-methoxybenzyl)-7-oxo-8,9-dihydro-7H-imidazo[1,5-
a][1,4]diazepine-9-carboxamide (7f): White solid, 60% yield, melting
point: 184–185 oC. 1H NMR (500 MHz, CDCl3) δ 7.54 (s, 1H), 7.25 (p, J =
3.7 Hz, 3H), 7.20 (d, J = 8.6 Hz, 2H), 7.01 (dd, J = 7.2, 2.3 Hz, 2H), 6.98
(d, J = 9.9 Hz, 1H), 6.82 (s, 1H), 6.79 (d, J = 8.6 Hz, 2H), 6.07 (s, 1H),
5.79 (d, J = 9.9 Hz, 1H), 5.05 (s, 1H), 4.73 (q, J = 14.7 Hz, 2H), 4.26 (dd,
J = 14.7, 6.1 Hz, 1H), 4.19 (dd, J = 14.7, 5.7 Hz, 1H), 3.76 (s, 3H). 13C
NMR (126 MHz, CDCl3) δ 166.1, 165.0, 159.6, 137.4, 137.2, 130.2,
128.9, 128.6, 127.6, 127.5, 125.9, 114.9, 114.4, 55.2, 55.1, 51.6, 44.1.
HRMS (ESI) calculated for C23H22N4NaO3 [M+Na]+: 425.1584; found:
425.1581.
General Procedure for the Synthesis of Imidazodiazepinone
Scaffold 7: In an oven-dried 10 mL screw-cap vial were charged with Ugi
adduct 5 (0.25 mmol) and dry chloroform (2 mL). The reaction mixture
was stirred at 80 oC until it is complete. The reaction mixture was then
purified by column chromatography (2–4% MeOH in DCM) to afford
imidazopyrazinone scaffold 7.
N-(tert-butyl)-8-(4-methoxybenzyl)-7-oxo-8,9-dihydro-7H-
8-(4-methoxybenzyl)-N-(4-methoxyphenyl)-7-oxo-8,9-dihydro-7H-
imidazo[1,5-a][1,4]diazepine-9-carboxamide (7g): White solid, 55%
yield, melting point: 215–216 oC. 1H NMR (500 MHz, CDCl3) δ 7.70 (s,
1H), 7.35 (d, J = 8.4 Hz, 2H), 7.08 (t, J = 10.0 Hz, 3H), 7.01 (s, 1H), 6.93
(d, J = 8.5 Hz, 2H), 6.85 (s, 1H), 6.76 (d, J = 8.9 Hz, 2H), 5.89 (d, J = 9.8
Hz, 1H), 5.17 (s, 1H), 4.91 (d, J = 14.6 Hz, 1H), 4.68 (d, J = 14.6 Hz, 1H),
3.81 (s, 3H), 3.75 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.0, 163.9,
159.9, 156.9, 137.4, 130.5, 129.7, 129.3, 127.8, 127.4, 126.3, 121.4,
114.9, 114.8, 114.1, 55.8, 55.5, 55.4, 51.8. HRMS (ESI) calculated for
C23H22N4NaO4 [M+Na]+: 441.1533; found: 441.1530.
imidazo[1,5-a][1,4]diazepine-9-carboxamide (7a): White solid, 63%
yield, melting point: 176–178 oC. 1H NMR (500 MHz, CDCl3) δ 7.67 (s,
1H), 7.33 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 9.9 Hz, 1H), 6.96 (s, 1H), 6.91
(d, J = 8.6 Hz, 2H), 5.84 (d, J = 9.8 Hz, 1H), 5.07 (s, 1H), 4.98 (s, 1H),
4.95 (d, J = 14.5 Hz, 1H), 4.46 (d, J = 14.5 Hz, 1H), 3.81 (s, 3H), 1.09 (s,
9H). 13C NMR (126 MHz, CDCl3) δ 165.0, 164.9, 159.8, 137.1, 130.4,
129.0, 128.0, 126.3, 114.7, 114.5, 56.0, 55.4, 52.0, 51.7, 28.3. HRMS
(ESI) calculated for C20H24N4NaO3 [M+Na]+: 391.1741; found: 391.1744.
N-(tert-butyl)-8-(4-(tert-butyl)benzyl)-7-oxo-8,9-dihydro-7H-
imidazo[1,5-a][1,4]diazepine-9-carboxamide (7b): White solid, 67%
yield, melting point: 225–226 oC. 1H NMR (500 MHz, CDCl3) δ 7.67 (s,
1H), 7.42 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 9.9 Hz,
1H), 6.99 (s, 1H), 5.83 (d, J = 9.8 Hz, 1H), 5.11 (d, J = 14.5 Hz, 1H), 5.09
(s, 1H), 5.00 (s, 1H), 4.35 (d, J = 14.5 Hz, 1H), 1.32 (s, 9H), 1.05 (s, 9H).
13C NMR (126 MHz, CDCl3) δ 165.0, 164.8, 151.7, 137.0, 133.1, 129.1,
128.9, 127.9, 126.6, 126.4, 114.3, 56.2, 51.9, 34.6, 31.3, 28.2. HRMS
(ESI) calculated for C23H30N4NaO2 [M+Na]+: 417.2261; found: 417.2264.
N-(tert-butyl)-8-(4-methoxybenzyl)-1-methyl-7-oxo-8,9-dihydro-7H-
imidazo[1,5-a][1,4]diazepine-9-carboxamide (7h): White solid, 83%
yield, melting point: 165–166 oC. 1H NMR (500 MHz, CDCl3) δ 7.57 (s,
1H), 7.26 (d, J = 7.5 Hz, 2H), 7.04 – 6.96 (m, 1H), 6.90 (d, J = 8.6 Hz,
2H), 5.78 (d, J = 9.9 Hz, 1H), 5.01 (s, 1H), 4.88 (s, 1H), 4.85 (d, J = 14.6
Hz, 1H), 4.65 (d, J = 14.5 Hz, 1H), 3.81 (s, 3H), 1.95 (s, 3H), 1.14 (s, 9H).
13C NMR (126 MHz, CDCl3) δ 165.4, 165.1, 159.7, 137.3, 135.3, 130.3,
127.9, 126.3, 126.2, 123.5, 114.7, 113.8, 55.4, 54.7, 52.0, 51.6(2C), 28.4,
12.1. HRMS (ESI) calculated for C21H26N4NaO3 [M+Na]+: 405.1897;
found: 405.1911.
N-(tert-butyl)-8-(4-fluorobenzyl)-7-oxo-8,9-dihydro-7H-imidazo[1,5-
a][1,4]diazepine-9-carboxamide (7c): White solid, 58% yield, melting
o
point: 194–196 C. 1H NMR (500 MHz, CDCl3) δ 7.69 (s, 1H), 7.35 (dd, J
N-(tert-butyl)-3-butyl-8-(4-methoxybenzyl)-7-oxo-8,9-dihydro-7H-
imidazo[1,5-a][1,4]diazepine-9-carboxamide (7i): White solid, 68%
= 8.4, 5.4 Hz, 2H), 7.10 (d, J = 9.9 Hz, 1H), 7.05 (t, J = 8.6 Hz, 2H), 6.94
(s, 1H), 5.86 (d, J = 9.9 Hz, 1H), 5.06 (s, 1H), 4.96 (s, 1H), 4.80 (d, J =
14.8 Hz, 1H), 4.74 (d, J = 14.8 Hz, 1H), 1.12 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 165.1, 164.7, 162.6 (d, J = 247.5 Hz), 137.3, 131.9 (d, J = 3.2
Hz), 130.64 (d, J = 8.2 Hz), 129.0, 127.9, 126.0, 116.0 (d, J = 21.4 Hz),
114.8, 56.9, 56.2, 52.1, 51.7, 28.3. 19F NMR (376MHz, CDCl3) δ -113.2.
HRMS (ESI) calculated for C19H22FN4O2 [M+H]+: 357.1721; found:
357.1726.
o
yield, melting point: 122–123 C. 1H NMR (500 MHz, CDCl3) δ 7.33 (d, J
= 8.5 Hz, 2H), 6.96 (d, J = 9.9 Hz,1), 6.90 (d, J = 8.6 Hz, 2H), 6.82 (s,
1H), 5.80 (d, J = 9.9 Hz, 1H), 5.08 (s, 1H), 4.96 (d, J = 14.5 Hz, 1H), 4.89
(s, 1H), 4.45 (d, J = 14.5 Hz, 1H), 3.81 (s, 3H), 2.82 – 2.47 (m, 2H), 1.74
(p, J = 7.7 Hz, 2H), 1.41 (h, J = 7.4 Hz, 2H), 1.09 (s, 9H), 0.95 (t, J = 7.4
Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.2, 165.0, 159.7, 149.2, 130.4,
128.1, 127.7, 127.1, 125.7, 114.6, 113.8, 56.3, 55.4, 51.9, 51.5, 29.6,
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