Synthesis of Azole-Fused Benzodiazocines
General Procedure for the Synthesis of Compounds 5a-f, 6a,e, 8, 12, 1H NMR (CD3OD, 300 MHz): δ = 2.53 (dd, J1 = 15.8, J2 = 2.6 Hz,
13, 23, 32 as Exemplified for Compound 5a: To a solution of com-
pound 3a (0.30 g, 1.00 mmol) in AcOH (2 mL), Fe powder (0.28 g,
5.00 mmol) was added and the mixture was heated at 90 °C for
20 min. Then the reaction mixture was cooled to room temperature
and poured in ice water followed by neutralization with saturated
aqueous NaHCO3 solution. The precipitated solid was separated
by filtration through a Celite bed which was repeatedly washed
with EtOAc. The organic layers were pooled, washed with brine,
dried (Na2SO4) and concentrated to obtain a crude product. Purifi-
cation via column chromatography using EtOAc/hexanes (1:1, v/v)
as the eluent furnished 5a (0.20 g, 74%) as a white solid.
1 H, CH2), 2.82 (d, J = 10.0 Hz, 1 H, CH2), 3.28 (s, 1 H, CH), 5.03
(d, J = 10.1 Hz, 1 H, CH), 6.70–6.75 (m, 1 H, ArH), 6.83 (d, J =
8.3 Hz, 1 H, ArH), 7.07 (dd, J1 = 8.0, J2 = 1.3 Hz, 1 H, ArH),
7.14–7.20 (m, 2 H, ArH), 7.26 (d, J = 1.1 Hz, 1 H, ArH) ppm. 13C
NMR (CD3OD, 75 MHz): δ = 41.0, 65.4, 117.0, 117.7, 119.8, 121.9,
128.0, 128.1, 129.2, 142.4, 146.3 ppm. MS (ES): m/z = 241.2 [M +
1]+. DART-HRMS [ES+]: calcd. for C13H13N4O 241.1089; found
241.1089.
1-(4-Hydroxy-4,5,6,7-tetrahydroimidazo[1,2-a][1,6]benzodiazocin-
5-yl)ethan-1-one (5f): This compound was isolated in 68% yield
(0.43 g, from 0.70 g) as a yellow solid, m.p. 119–120 °C. Rf = 0.22
Methyl 4-Hydroxy-4,5,6,7-tetrahydroimidazo[1,2-a][1,6]benzodiaz-
ocine-5-carboxylate (5a): M.p. 187–188 °C. Rf = 0.25 (EtOAc/hex-
(MeOH/EtOAc, 1:9, v/v). IR (KBr): ν
= 1695 (CO), 3375 (OH)
˜
max
cm–1. H NMR (CD3OD, 300 MHz): δ = 2.30 (s, 3 H, CH3), 2.55
1
anes, 7:3, v/v). IR (KBr): ν
= 1726 (CO2Me), 3426 (OH) cm–1.
˜
(dd, J1 = 16.2, J2 = 2.8 Hz, 1 H, CH2), 2.76 (dd, J1 = 7.2, J2
=
max
1H NMR (CD3OD, 300 MHz): δ = 2.52–2.60 (m, 2 H, CH2), 3.26
(s, 1 H, CH), 3.78 (s, 3 H, OCH3), 5.29 (d, 1 H, J = 9.8 Hz, CH),
6.64–6.72 (m, 2 H, ArH), 7.02–7.14 (m, 3 H, ArH), 7.23 (d, 1 H,
J = 1.3 Hz, ArH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ = 42.8,
52.5, 53.8, 65.1, 116.8, 118.4, 129.1, 129.5, 143.8, 172.7 ppm. MS
(ES): m/z = 274.2 [M + 1]+. DART-HRMS [ES+]: calcd. for
C14H16N3O3 274.1192; found 274.1171.
2.4 Hz, 1 H, CH2), 3.34 (s, 1 H, CH), 5.32 (d, J = 9.8 Hz, 1 H,
CH), 6.64–6.69 (m, 2 H, ArH), 7.02–7.13 (m, 3 H, ArH), 7.22 (s,
1 H, ArH) ppm. 13C NMR (CD3OD, 75 MHz): δ = 30.8, 43.5,
61.7, 66.3, 118.8, 120.0, 121.1, 123.5, 129.8, 130.2, 131.2, 145.1,
151.2, 210.9 ppm. MS (ES): m/z = 258.1 [M + 1]+. DART-HRMS
[ES+]: calcd. for C14H15N3O2 258.1117; found 258.1142.
Methyl 4-Hydroxy-10-methyl-4,5,6,7-tetrahydroimidazo[1,2-a][1,6]-
benzodiazocine-5-carboxylate (6a): This compound was isolated in
68% yield (0.28 g, from 0.45 g) as a white solid, m.p. 191–192 °C.
Ethyl 4-Hydroxy-4,5,6,7-tetrahydroimidazo[1,2-a][1,6]benzodiaz-
ocine-5-carboxylate (5b): This compound was isolated in 70% yield
(0.11 g, from 0.18 g) as a white solid, m.p. 155–157 °C. Rf = 0.26
R = 0.25 (EtOAc). IR (KBr): ν
= 1726 (CO2Me), 3426 (OH)
˜
f
max
cm–1. H NMR (CDCl3, 300 MHz): δ = 2.24 (s, 3 H, CH3), 2.72–
2.76 (m, 2 H, CH2), 3.26–3.31 (m, 1 H, CH), 3.80 (m, 3 H, OCH3),
5.25 (d, J = 9.8 Hz, 1 H, CH), 6.57 (d, J = 8.3 Hz, 1 H, ArH),
6.89–6.97 (m, 2 H, ArH), 7.11 (dd, J1 = 13.8, J2 = 1.3 Hz, 2 H,
ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 19.9, 43.1, 52.2, 65.0,
120.2, 125.8, 127.2, 128.3, 128.5, 130.2, 139.5, 139.9, 166.5,
173.1 ppm. MS (ES+): m/z = 288.2 [M + 1]+. DART-HRMS [ES+]:
calcd. for C15H18N3O3: 288.1348; found 288.1128.
1
(EtOAc/hexanes, 7:3, v/v). IR (KBr): ν
= 1726 (CO2Et), 3429
˜
max
(OH) cm–1. H NMR (CD3OD, 300 MHz): δ = 1.36 (t, 3 H, J =
7.1 Hz, CH3), 2.58–2.63 (m, 2 H, CH2), 3.32 (s, 1 H, CH), 4.23–
4.33 (m, 2 H, OCH2), 5.36 (d, 1 H, J = 9.7 Hz, CH), 6.70–6.78 (m,
2 H, ArH), 7.08–7.20 (m, 3 H, ArH), 7.28 (s, 1 H, ArH) ppm. 13C
NMR (CD3OD, 75 MHz): δ = 14.6, 43.7, 54.9, 62.2, 66.2, 118.1,
119.3, 120.4, 122.9, 129.2, 129.5, 130.5, 144.5, 149.9, 173.8 ppm.
MS (ES): m/z = 288.2 [M + 1]+. DART-HRMS [ES+]: calcd. for
C15H18N3O3 288.1348; found 288.1336.
1
4-Hydroxy-10-methyl-4,5,6,7-tetrahydroimidazo[1,2-a][1,6]benzo-
diazocine-5-carbonitrile (6e): This compound was isolated in 70%
yield (0.19 g, from 0.30 g) as a white solid, m.p. 209–210 °C. Rf =
Butyl 4-Hydroxy-4,5,6,7-tetrahydroimidazo[1,2-a][1,6]benzodiaz-
ocine-5-carboxylate (5c): This compound was isolated in 68% yield
(0.22 g, from 0.35 g) as a white solid, m.p. 160–162 °C. Rf = 0.26
0.21 (EtOAc). IR (KBr): ν
= 2240 (CϵN), 3390 (OH) cm–1. 1H
˜
max
(EtOAc/hexanes, 7:3, v/v). IR (KBr): ν
= 1723 (CO2nBu), 3415
˜
max
NMR (CD3OD, 300 MHz): δ = 2.23 (s, 3 H, CH3), 2.49–2.54 (m,
1 H, CH2), 2.81 (d, J = 9.0 Hz, 1 H, CH2), 3.27 (s, 1 H, CH), 5.02
(d, J = 9.5 Hz, 1 H, CH), 6.74 (d, J = 8.4 Hz, 1 H, ArH), 6.89 (s,
1 H, ArH), 7.01 (d, J = 7.6 Hz, 1 H, ArH), 7.12 (d, J = 5.6 Hz, 1
H, ArH), 7.26 (s, 1 H, ArH) ppm. 13C NMR (DMSO, 75 MHz): δ
= 20.2, 41.7, 41.9, 66.1, 118.6, 119.2, 121.8, 122.7, 126.3, 129.1,
129.5, 130.6, 140.9, 146.6 ppm. MS (ES): m/z = 255.2 [M + 1]+.
DART-HRMS calcd. for C14H15N4O: 255.1246; found 255.1253.
(OH) cm–1. H NMR (CD3OD, 300 MHz): δ = 1.03 (t, 3 H, J =
7.3 Hz, CH3), 1.43–1.53 (m, 2 H, CH2), 1.70–1.79 (m, 2 H, CH2),
2.61–2.66 (m, 2 H, CH2), 3.33 (s, 1 H, CH), 4.17–4.34 (m, 2 H,
OCH2), 5.38 (d, 1 H, J = 9.7 Hz, CH), 6.72–6.80 (m, 2 H, ArH),
7.12 (d, 1 H, J = 8.0 Hz, ArH), 7.16–7.22 (m, 2 H, ArH), 7.30 (s,
1 H, ArH) ppm. 13C NMR (CD3OD, 75 MHz): δ = 12.7, 18.9,
30.4, 42.2, 53.5, 60.2, 64.6, 116.6, 117.8, 121.4, 127.7, 128.0, 129.0,
143.0, 149.4, 172.4 ppm. MS (ES): m/z = 316.3 [M + 1]+. DART-
HRMS [ES+]: calcd. for C17H22N3O3 316.1661; found 316.1658.
1
14-Hydroxy-9a,10,11,12,13a,14-hexahydrodibenzo[b,g]imidazo-
[1,2-d][1,4]diazocin-13(9H)-one (8): This compound was isolated in
70% yield (0.51 g, from 0.80 g) as a yellow solid, m.p. 105–106 °C.
tert-Butyl 4-Hydroxy-4,5,6,7-tetrahydroimidazo[1,2-a][1,6]benzo-
diazocine-5-carboxylate (5d): This compound was isolated in 78%
yield (0.28 g, from 0.40 g) as a white solid, m.p. 189–190 °C. Rf =
R = 0.24 (MeOH/EtOAc, 1:9, v/v). IR (KBr): ν
= 1705 (CO),
˜
f
max
3429 (OH) cm–1. 1H NMR (CDCl3, 300 MHz): δ = 1.93 (d, J =
3.4 Hz, 2 H, CH2), 2.34 (s, 4 H, 2ϫ CH2), 3.72 (s, 1 H, CH), 4.08
(s, 1 H, CH), 5.35 (d, J = 8.9 Hz, 1 H, CH), 6.80–6.90 (m, 3 H,
0.29 (EtOAc/hexanes, 7:3, v/v). IR (KBr): ν
= 1725 (CO2tBu),
˜
max
3422 (OH) cm–1. H NMR (CD3OD, 300 MHz): δ = 1.52 (s, 9 H,
3ϫ CH3), 2.50–2.55 (m, 2 H, CH2), 3.25 (s, 1 H, CH), 5.25 (s, 1
H, CH), 6.66–6.76 (m, 2 H, 7.04–7.15 (m, 4 H, ArH) ppm. 13C
NMR (DMSO, 75 MHz): δ = 19.9, 35.4, 52.2, 65.9, 120.2, 121.3,
125.9, 127.3, 128.3, 128.5, 130.3, 139.5, 148.1, 173.1 ppm. MS (ES):
m/z = 316.1 [M+ + 1]+. HR-EIMS [EI+]: calcd. for C17H21N3O3
315.1583; found 315.1571.
1
ArH), 7.02–7.12 (m, 2 H, ArH), 7.19–7.24 (m, 1 H, ArH) ppm. 13
C
NMR (CD3OD, 75 MHz): δ = 24.4, 27.5, 40.0, 64.2, 64.5, 118.7,
119.6, 123.9, 129.1, 130.7, 132.2, 140.2, 146.4, 149.3, 201.8 ppm.
MS (ES): m/z = 284.2 [M + 1]+. DART-HRMS [ES+]: calcd. for
C16H18N3O2 284.1399; found 284.1401.
Imidazo[1,2-a]quinoxaline (12): 121–122 °C (ref.[5c] 124 °C).
4-Hydroxy-4,5,6,7-tetrahydroimidazo[1,2-a][1,6]benzodiazocine-5-
carbonitrile (5e): This compound was isolated in 70% yield (0.19 g,
from 0.30 g) as a white solid, m.p. 117–118 °C. Rf = 0.27 (EtOAc/
Ethyl 2-{[1-(2-Aminophenyl)-1H-imidazol-2-yl]methyl}acrylate (13):
This compound was isolated in 74% yield (0.10 g, from 0.15 g) as
hexanes, 7:3, v/v). IR (KBr): νmax = 2224 (CϵN), 3423 (OH) cm–1. brown oil. R = 0.20 (EtOAc/hexanes, 3:2, v/v). IR (neat): ν
=
˜
˜
max
f
Eur. J. Org. Chem. 2010, 4832–4840
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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