A concise synthesis of 6,7-dihydro-5H-dibenz[c,e]azepin-5-one

Article abstract of DOI:10.3987/COM-09-S(S)65

A concise and efficient strategy for the synthesis of dibenz[c,e]azepin-5-ones has been developed. The approach relies on a key transformation involving Suzuki-Miyaura coupling of 2-bromobenzyl azides with 2-(methoxycarbonyl)phenylboronic acid, followed b

Full text of DOI:10.3987/COM-09-S(S)65

HETEROCYCLES, Vol. 80, No. 1, 2010
669
HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 669 - 677. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd July, 2009, Accepted, 25th August, 2009, Published online, 25th August, 2009
DOI: 10.3987/COM-09-S(S)65
A CONCISE SYNTHESIS OF 6,7-DIHYDRO-5H-DIBENZ[c,e]AZEPIN-5-
ONE‡
Young-Hyoung Goh,a,b Guncheol Kim,b Bum Tae Kim,a and Jung-Nyoung
Heoa,*
aMedicinal Chemistry Research Center, Korea Research Institute of Chemical
b
Technology, Daejeon 305-600 Korea. Department of Chemistry, Chungnam
National University, Daejeon 305-764 Korea; E-mail: heojn@krict.re.kr
Abstract – A concise and efficient strategy for the synthesis of
dibenz[c,e]azepin-5-ones has been developed. The approach relies on a key
transformation involving Suzuki-Miyaura coupling of 2-bromobenzyl azides with
2-(methoxycarbonyl)phenylboronic acid, followed by either a stepwise sequence
involving Staudinger reaction and lactam formation or one-pot
hydrogenation/base-mediated intramolecular lactam formation.
Natural products and natural product based substances play pivotal roles in modern drug discovery.1
Consequently, the unique, often complex structural motifs of many drugs are inspired by or derived from
those found in natural products. For example, the potent tubulin assembly inhibitors N-acetylcolchinol (2)
and its prodrug ZD 6126 (3) have structural features that are found in the highly toxic natural product
colchicine (1) (Figure 1).2 In ongoing investigations, our efforts have focused on the development of
substances whose designs are based on scaffolds found in the novel dibenzo[a,c]cycloheptene-5-one (4)
and dibenz[c,e]azepin-5-one (5) natural products. Dibenzazepine derivatives are structural platforms for
an interesting array of pharmacologically active substances, including those that possess anxiolytic3 and
hypolipidemic4 activities, as well as inhibitors of tubulin assembly5 and protein kinase C.6
Recent studies in our laboratory have concentrated on routes for the preparation of novel polycyclic
substances that are based on Suzuki-Miyaura coupling and aldol condensation strategies.7 Recently, we
uncovered an efficient catalytic system for the preparation of dibenzo[a,c]cyclohepten-5-ones 4.8 In an
extension of this protocol, we envisioned that the process could be used for the synthesis of
‡ This paper is dedicated to Prof. Akira Suzuki on the occasion of his 80th birthday.

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HETEROCYCLES, Vol. 80, No. 1, 2010
dibenz[c,e]azepin-5-ones 5 which bear an amide moiety in the central 7-membered ring. Although a
number of approaches for the synthesis of dibenz[c,e]azepin-5-ones have been reported,9 the need for
concise and rapid routes to access these compounds still exists. Herein, we describe a new route for the
synthesis of dibenzazepines that employs a Suzuki-Miyaura coupling process between 2-bromobenzyl
azides
and
2-(methoxycarbonyl)phenylboronic
acid,
followed
by
either
a
one-pot
hydrogenation/base-mediated intramolecular lactam formation process or a stepwise sequence involving
Staudinger reaction and lactam formation.
MeO
MeO
MeO
MeO
MeO
MeO
NH
O
NHAc
NHAc
O
MeO
colchicine (1)
O
R
N-acetylcolchinol (2): R = OH
ZD 6126 (3): R = OPO3H2
4
5
Figure 1. Tricyclic compounds possessing a central 7-membered ring such as colchicines (1),
N-acetylcolchinol (2), ZD 6126 (3), dibenzo[a,c]cycloheptene-5-one (4) and dibenz[c,e]azepin-5-one (5)
frameworks.
Table 1. Preparation of biaryl ester-azides 9a-f
B(OH)2
R2
R2
R2
CO2Me
R1
R1
R1
8
NaN3 (1.1 equiv)
DMF, rt, 3-6 h
N3
X
N3
Pd(OAc)2 (4 mol %)
XPhos (8 mol %)
KF (3.0 equiv)
THF, 80 oC, 1 h
CO2Me
Br
Br
6a-f
7a-f
9a-f
entry
R1
R2
H
X
7 (yield, %)a
7a (94)
7b (89)
7c (86)
9 (yield, %)a
1
2
3
4
5
6
H
H
H
F
Br
Br
Br
Br
Br
Cl
9a (99)
9b (92)
9c (94)
9d (94)
9e (97)
9f (93)
Cl
F
H
7d (90)
7e (92)
CO2Me
OMe
H
OMe
7f (92)
aIsolated yield.
The 2-bromobenzyl azides 7a-f, required for the synthetic pathway, were prepared by reactions of the
corresponding benzyl halides 6a-f with NaN3 in DMF. These processes proceeded smoothly to furnish

HETEROCYCLES, Vol. 80, No. 1, 2010
671
7a-f in 86%-94% yields (Table 1). We next explored the Suzuki-Miyaura coupling reaction of 7a with
2-(methoxycarbonyl)phenylboronic acid (8) in order to generate the biaryl ester-azide 9a. A wide range of
ligands (DavePhos, JohnPhos, SPhos, XPhos, Cyclohexyl JohnPhos, DPEPhos, XantPhos, and
CataCXium PIntB), bases (Cs2CO3, K3PO4, Na2CO3, and KF), and solvents (dioxane, THF, toluene, DMF,
and CH3CN) were examined in order to develop optimum conditions of the coupling reaction (Table 1).
This investigation led to the finding that the use of XPhos as ligand with KF as base in THF solvent
provided an optimal yield for this process. It is noteworthy that in reactions with azides 7a-f, both
electron-withdrawing and –donating group substituted groups are well tolerated and the processes afford
biaryl ester-azides 9a-f in excellent yields.
Table 2. Synthesis of 6,7-dihydro-5H-dibenz[c,e]azepin-5-ones
R2
R2
R1
R1
Method A
N3
or
NH
O
Method B
CO2Me
9a-f
5a-f
yield (%)a
Method Ab
entry
R1
R2
product (5)
Method Bc
1
2
3
4
5
6
H
H
H
Cl
5a
5b
5c
5d
5e
5f
99
90
92
96
47e
89
99
30d
94
92
70
88
H
F
F
H
CO2Me
OMe
H
OMe
b
c
a Isolated yield. Method A: i) PPh3 (2 equiv), THF, rt, 10 h; ii) NaOMe (1.0 equiv), MeOH, rt, 6 h. Method B: H2 (1 atm),
10% Pd/C (20 wt %), NaOMe (1.0 equiv), MeOH, rt, 2 h. d Dechlorination occurred. e Although starting material 8e was
completely consumed (TLC monitoring), it was difficult to separate the by-product (Ph3P=O) from the 4e by column
chromatography.
The availability of the biaryl ester-azides enabled us to investigate a method for the construction of
dibenzazepines that employs reduction of the azide to produce the corresponding amine followed by
lactam ring formation. Azides can be transformed to amines under mild conditions by using either
hydrogenation processes or the Staudinger reaction. Indeed, treatment of ester-azide 9a with PPh3 under
standard Staudinger conditions, followed by addition of NaOMe, led to the formation of the desired
dibenzazepine 5a in quantitative yield (Table 2, entry 1, Method A). The Staudinger based methodology

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HETEROCYCLES, Vol. 80, No. 1, 2010
was applied to reaction of the other substituted biaryl ester-azides. In all but one case, reactions were
found to take place efficiently to afford the desired products in excellent yields. The exception is reaction
of 9e that produces 5e in a low yield owing to difficulties associated with chromatographic separation of
the by-product Ph3PO (Table 2, entry 5, Method A).
A one-pot procedure for preparation of dibenzazepines that relies on hydrogenation of biaryl ester-azides
in MeOH solutions containing NaOMe was also explored (Table 2, Method B). By using this procedure,
reactions of azides 9a and 9c-f resulted in efficient conversion to dibenzazepines 5a and 5c-f.
Unfortunately, the chloroarene containing azide 9b was found to undergo one-pot reaction to produce 5b
in very low yield (Table 2, entry 2, Method B).
In summary, the investigation described above has led to the development of a concise and efficient
procedure to synthesize dibenz[c,e]azepin-5-ones, starting from 2-bromobenzyl halide. The key step in
this
approach
involves
Suzuki-Miyaura
coupling
of
2-bromobenzyl
azides
with
2-(methoxycarbonyl)phenylboronic acid, which is then followed by either stepwise Staudinger reaction
and lactam formation or a one-pot hydrogenation/base-mediated lactam forming process. Further studies
are in progress to probe applications of this protocol to the synthesis of pharmaceutically interesting
dibenzazepines.
EXPERIMENTAL
Starting Materials. 2-Bromobenzyl bromide (6a) is commercially available. 6b–6e were prepared by
reaction of the corresponding 2-bromotoluenes with NBS in the presence of AIBN.10 6f was synthesized
from 2-bromo-4,5-dimethoxybenzyl alcohol following the literature method.11
General Procedure for preparation of 2-bromobezyl azides 7.12 To a solution of benzyl bromide 6 (5.3
mmol) in DMF (5.5 mL) was added NaN3 (377 mg, 5.8 mmol). The mixture was stirred at room
temperature for 4–24 h, quenched with H2O (200 mL), and extracted with CH2Cl2 (3 × 20 mL). The
organic extracts were washed with brine (70 mL), dried over MgSO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography to give benzyl azide 7.
1
1-(Azidomethyl)-2-bromobenzene (7a).13 rt 4 h, Yield 94%, yellow oil; H NMR (300 MHz, CDCl3) δ
13
7.61 (d, 1H, J = 8.0 Hz), 7.42–7.32 (m, 2H), 7.21 (td, 1H, J = 7.6, 1.5 Hz), 4.50 (s, 2H); C NMR (75
MHz, CDCl3) δ 135.2, 133.29, 130.26, 128.02, 123.97, 104.99, 54.84; IR (neat) 3058, 2849, 2097, 1555,
1438 cm-1; MS (EI) m/z 212 (M+ + 2, 9), 210 (M+, 7), 184 (66), 182 (62), 170 (52), 169 (40), 148 (19), 76
(88), 55 (100).
1
2-(Azidomethyl)-1-bromo-4-chlorobenzene (7b). rt 3 h, Yield 89%, yellow oil; H NMR (300 MHz,
CDCl3) δ 7.52 (d, 1H, J = 8.5 Hz), 7.41 (d, 1H, J = 2.6 Hz), 7.19 (dd, 1H, J = 8.5, 2.6 Hz), 4.48 (s, 2H);

HETEROCYCLES, Vol. 80, No. 1, 2010
673
13C NMR (75 MHz, CDCl3) δ 137.0, 134.2, 134.1, 130.0, 129.9, 121.4, 54.4; IR (neat) 3075, 2853, 2100,
1459, 1393, 888, 811 cm-1; MS (EI) m/z 247 (M+ + 2, 23), 245 (M+, 23), 189 (11), 155 (19), 149 (52), 111
(34), 83 (57), 71 (80), 57 (100).
1
2-(Azidomethyl)-1-bromo-4-fluorobenzene (7c). rt 3 h, Yield 86%, yellow oil; H NMR (300 MHz,
CDCl3) δ 7.55 (dd, 1H, J = 8.8, 5.3 Hz), 7.17 (dd, 1H, J = 9.1, 3.0 Hz), 6.94 (td, 1H, J = 8.3, 3.0 Hz), 4.48
13
(s, 2H); C NMR (75 MHz, CDCl3) δ 162.1 (d, J = 246.5 Hz), 137.3 (d, J = 7.3 Hz), 134.1 (d, J = 8.0
Hz), 117.2 (d, J = 3.3 Hz), 116.9 (d, J = 4.5 Hz), 116.6 (d, J = 3.0 Hz), 54.2; IR (neat) 3080, 2097, 1584,
1437, 1271, 1236, 1044 cm-1; MS (EI) m/z 231 (M+ + 2, 83), 229 (M+, 82), 201 (98), 199 (100), 186 (72),
120 (79), 94 (98), 74 (27).
1
1-(Azidomethyl)-2-bromo-4-fluorobenzene (7d). rt 3 h, Yield 90%, yellow oil; H NMR (300 MHz,
13
CDCl3) δ 7.40–7.34 (m, 2H), 7.07 (td, 1H, J = 8.2, 2.6 Hz), 4.47 (s, 2H); C NMR (75 MHz, CDCl3) δ
162.1 (d, J = 250.3 Hz), 131.09 (d, J = 3.4 Hz), 131.06 (d, J = 8.5 Hz), 123.9 (d, J = 9.7 Hz), 120.4 (d, J =
24.5 Hz), 114.9 (d, J = 20.9 Hz), 53.9; IR (neat) 3062, 2102, 1653, 1600, 1487, 1436, 1398, 1229, 1034,
861 cm-1; MS (EI) m/z 231 (M+ + 2, 30), 229 (M+, 30), 201 (57), 188 (100), 148 (76), 121 (61), 110 (41),
94 (69), 85 (71), 71 (82), 56 (83).
Methyl 4-(azidomethyl)-3-bromobenzoate (7e). rt 24 h, Yield 92%, white solid; mp 64–67 °C; 1H NMR
(300 MHz, CDCl3) δ 8.26 (d, 1H, J = 1.7 Hz), 8.01 (dd, 1H, J = 8.0, 1.7 Hz), 7.50 (d, 1H, J = 8.0 Hz),
4.55 (s, 2H), 3.94 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.9, 137.4, 131.6, 129.1, 127.0, 126.4, 120.8,
51.9, 50.1; IR (neat) 3080, 2958, 2122, 1714, 1604, 1560, 1431, 1283, 1251, 1120 cm-1; MS (EI) m/z 271
(M+ + 2, 18), 269 (M+, 18), 240 (25), 227 (51), 210 (100), 199 (28), 181 (27), 155 (31), 103 (57), 74 (40).
1-(Azidomethyl)-2-bromo-4,5-dimethoxybenzene (7f). 2-Bromo-4,5-dimethoxybenzyl chloride was
used as a starting material. rt 5 h, Yield 92%, yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.06 (s, 1H), 6.88
(s, 1H), 4.43 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 148.6, 147.7, 125.9, 114.7,
113.1, 111.8, 55.3, 55.2, 53.5; IR (neat) 3005, 2935, 2093, 1601, 1504, 1438, 1384, 1258, 1219, 1163,
1029 cm-1; MS (EI) m/z 273 (M+ + 2, 21), 271 (M+, 21), 231 (99), 199 (28), 184 (32), 120 (86), 105 (98),
92 (86), 79 (100), 62 (78).
General Procedure for preparation of azido-ester biaryls 9. To a vial (3 mL) were added benzyl azide
7 (0.47 mmol), boronic acid 8 (121 mg, 0.71 mmol), Pd(OAc)2 (4.2 mg, 4.0 mol %), KF (82 mg, 1.4
mmol) , and X-Phos (17.9 mg, 8.0 mol %) sequentially. The mixture was suspended in THF (1.0 mL) and
stirred at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was purified by column
chromatography (2% → 10% EtOAc/hexanes) to afford azido-ester biaryl 9.
1
Methyl 6'-(azidomethyl)biphenyl-2-carboxylate (9a). Yield 99%, yellow oil; H NMR (300 MHz,
CDCl3) δ 8.00 (dd, 1H, J = 7.8, 1.2 Hz), 7.57 (td, 1H, J = 7.5, 1.5 Hz), 7.47 (td, 1H, J = 7.6, 1.4 Hz),

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HETEROCYCLES, Vol. 80, No. 1, 2010
7.42–7.33 (m, 3H), 7.28–7.26 (m, 1H), 7.16–7.14 (m, 1H), 4.14 (A of ABq, 1H, J = 13.7 Hz), 4.09 (B of
13
ABq, 1H, J = 13.7 Hz), 3.61 (s, 3H); C NMR (75 MHz, CDCl3) δ 167.3, 141.7, 141.3, 133.1, 131.9,
131.3, 130.6, 130.5, 129.5, 128.8, 128.0, 127.9, 105.0, 52.9, 52.3; IR (neat) 2954, 2090, 1715, 1571, 1431,
1259, 1189 cm-1; MS (EI) m/z 267 (M+, 3), 180 (100), 164 (13), 152 (19), 105 (10).
1
Methyl 6'-(azidomethyl)-4'-chlorobiphenyl-2-carboxylate (9b). Yield 83%, yellow oil; H NMR (300
MHz, CDCl3) δ 8.02 (dd, 1H, J = 7.8 Hz, 1.3 Hz), 7.58 (td, 1H, J = 7.5 Hz, 1.5 Hz), 7.49 (td, 1H, J = 7.2
Hz, 1.4 Hz), 7.44 (d, 1H, J = 2.2 Hz), 7.32 (dd, 1H, J = 8.2 Hz, 2.2 Hz), 7.22 (dd, 1H, J = 7.6 Hz, 1.3 Hz),
7.07 (d, 1H, J = 8.2 Hz), 4.12 (A of ABq, 1H, J = 14.1 Hz), 4.06 (B of ABq, 1H, J = 14.0 Hz), 3.66 (s,
13
3H); C NMR (75 MHz, CDCl3) δ 165.9, 138.9, 138.6, 133.9, 132.4, 130.8, 129.9, 129.4, 129.3, 128.9,
127.2, 127.1, 126.6, 51.1, 50.9; IR (neat) 3066, 2954, 2926, 2098, 1722, 1472, 1433, 1253, 764 cm-1; MS
(EI) m/z 301 (M+, 0.1), 216 (24), 214 (100), 179 (20), 165 (22), 152 (42).
1
Methyl 6'-(azidomethyl)-4'-fluorobiphenyl-2-carboxylate (9c). Yield 94%, yellow oil; H NMR (300
MHz, CDCl3) δ 8.01 (dd, 1H, J = 7.7, 1.1 Hz), 7.57 (td, 1H, J = 7.5, 1.4 Hz), 7.48 (td, 1H, J = 7.6, 1.3
Hz), 7.26–7.04 (m, 4H), 4.13 (A of ABq, 1H, J = 14.1 Hz), 4.07 (B of ABq, 1H, J = 14.1 Hz), 3.64 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 167.3, 162.1 (d, J = 245.2 Hz), 140.1, 137.0 (d, J = 3.4 Hz), 135.5 (d,
J = 7.3 Hz), 131.8, 131.3, 130.7 (d, J = 7.9 Hz), 130.4, 130.5, 128.1, 115.1 (d, J = 22.3 Hz), 114.5 (d, J =
21.1 Hz), 52.3, 52.0; IR (neat) 3071, 2958, 2923, 2096, 1723, 1610, 1591, 1434, 1247 cm-1; MS (EI) m/z
285 (M+, 0.1), 256 (23), 224 (15), 198 (100), 183 (39), 170 (91), 151 (22).
1
Methyl 6'-(azidomethyl)-3'-fluorobiphenyl-2-carboxylate (9d). Yield 94%, yellow oil; H NMR (300
MHz, CDCl3) δ 8.03 (dd, 1H, J = 7.7, 1.1 Hz), 7.59 (td, 1H, J = 7.4, 1.4 Hz), 7.50 (td, 1H, J = 7.6, 1.2
Hz), 7.39 (dd, 1H, J = 8.4, 5.7 Hz), 7.26–7.24 (m, 1H), 7.09 (td, 1H, J = 8.4, 2.6 Hz), 6.89 (dd, 1H, J =
9.1, 2.6 Hz), 4.09 (A of ABq, 1H, J = 14.0 Hz), 4.04 (B of ABq, 1H, J = 14.0 Hz), 3.66 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 165.5, 160.3 (d, J = 246.3 Hz), 142.2 (d, J = 8.2 Hz), 138.4 (d, J = 1.6 Hz), 130.4,
129.4, 128.9, 128.8 (d, J = 8.6 Hz), 128.4, 127.5 (d, J = 3.3 Hz), 126.7, 114.8 (d, J = 21.9 Hz), 113.0, (d,
J = 21.0 Hz), 50.53, 50.50; IR (neat) 3066, 2958, 2093, 1726, 1612, 1587, 1479, 1434, 1286, 1251 cm-1;
MS (EI) m/z 285 (M+, 0.01), 256 (9), 198 (100), 183 (31), 169 (63), 151 (21), 85 (22), 59 (19).
1
Dimethyl 6'-(azidomethyl)biphenyl-2,3'-dicarboxylate (9e). Yield 97%, yellow oil; H NMR (300
MHz, CDCl3) δ 8.09–8.04 (m, 2H), 7.82 (d, 1H, J = 1.5 Hz), 7.60 (td, 1H, J = 7.5, 1.4 Hz), 7.53–7.48 (m,
2H), 7.26–7.23 (m, 1H), 4.20 (A of ABq, 1H, J = 14.2 Hz), 4.13 (B of ABq, 1H, J = 14.0 Hz), 3.90 (s,
13
3H), 3.63 (s, 3H); C NMR (75 MHz, CDCl3) δ 166.9, 166.6, 141.5, 140.3, 138.2, 132.1, 131.1, 130.6,
130.2, 129.8, 129.5, 128.9, 128.25, 128.21, 52.4, 52.1, 52.0; IR (neat) 3019, 2949, 2097, 1718, 1434,
1288, 1234 cm-1; MS (EI) m/z 325 (M+, 0.1), 296 (22), 269 (17), 238 (100), 211 (85), 179 (59), 165 (44),
151 (47), 139(22).
Methyl 6'-(azidomethyl)-3',4'-dimethoxybiphenyl-2-carboxylate (9f). Yield 93%, brown oil; 1H NMR

HETEROCYCLES, Vol. 80, No. 1, 2010
675
(300 MHz, CDCl3) δ 7.96 (dd, 1H, J = 7.7, 1.3 Hz), 7.56 (td, 1H, J = 7.5, 1.5 Hz), 7.46 (td, 1H, J = 7.6,
1.4 Hz), 7.29–7.26 (m, 1H), 6.92 (s, 1H), 6.66 (s, 1H), 4.10 (A of ABq, 1H, J = 13.9 Hz), 4.05 (A of ABq,
13
1H, J = 13.7 Hz), 3.96 (s, 3H), 3.84 (s, 3H), 3.65 (s, 3H); C NMR (75 MHz, CDCl3) δ 167.6, 148.3,
148.1, 140.7, 133.8, 131.6, 131.5, 130.8, 130.1, 127.7, 125.2, 112.4, 111.6, 55.96, 55.95, 52.5, 52.1; IR
(neat) 3080, 2932, 2092, 1715, 1607, 1516, 1440, 1249, 1237 cm-1; MS (EI) m/z 327 (M+, 5), 298 (10),
253 (9), 240 (100), 224 (14).
Method A: General Procedure for preparation of 6,7-dihydro-5H-dibenz[c,e]azepin-5-ones 5. To a
solution of azido-ester biaryl 9 (0.18 mmol) in THF (18 mL) was added PPh3 (94 mg, 0.36 mmol) and
stirred at rt for 10 h. The solvent was evaporated in vacuo and dissolve in MeOH (18 mL). The resulting
solution was treated with NaOMe (0.36 mL, 0.18 mmol, 0.5 M in MeOH) and stirred at rt for 6 h. The
mixture was concentrated in vacuo and purified by column chromatography (50% EtOAc/hexanes) to
afford dibenz[c,e]azepin-7-one 5.
Method B: General Procedure for preparation of 6,7-dihydro-5H-dibenz[c,e]azepin-5-ones 5. To a
solution of azido-ester biaryl 9 (0.37 mmol) in MeOH (37 mL) was added 10% Pd/C (20 mg, 20 wt%)
and NaOMe (0.74 mL, 0.37 mmol, 0.5 M in MeOH). The suspension was stirred under H2 (1 atm) for 2 h.
The resulting mixture was filtered through a Celite pad while rinsing with EtOAc. The solution was
concentrated in vacuo and purified by column chromatography (50% EtOAc/hexanes) to give
dibenz[c,e]azepin-5-one 5.
6,7-Dihydro-5H-dibenz[c,e]azepin-5-one (5a). Method A: 99%, Method B: 99%, white solid; mp
1
194–197 °C (lit.9a 190–191 °C); H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H, J = 8.0 Hz), 7.69–7.56 (m,
3H), 7.53–7.48 (m, 1H), 7.45 (td, 1H, J = 7.6, 1.4 Hz), 7.37 (td, 1H, J = 7.4, 1.4 Hz), 7.29 (dd, 1H, J = 7.4,
13
1.2 Hz), 6.66 (brs, 1H), 4.25 (dd, 1H, J = 13.6, 6.1 Hz), 3.96 (dd, 1H, J = 14.7, 7.0 Hz); C NMR (75
MHz, CDCl3) δ 171.3, 139.2, 138.8, 137.7, 133.7, 131.2, 130.2, 129.4, 129.1, 128.5, 128.1, 127.9, 126.8,
44.9; IR (neat) 3282, 3167, 3022, 2918, 1642, 1599, 1452, 1404, 1346 cm-1; MS (EI) m/z 209 (M+, 39),
180 (100), 165 (6), 152 (30); HRMS (EI) calcd for C14H11NO [M+] 209.0841, found 209.0846.
9- Chloro-6,7-dihydro-5H-dibenz[c,e]azepin-5-one (5b). Method A: 90%, Method B: 30%, white solid;
mp 195–197 °C; 1H NMR (300 MHz, CDCl3) δ 8.01 (d, 1H, J = 7.4 Hz), 7.63–7.49 (m, 4H), 7.43 (dd, 1H,
J = 8.3, 2.0 Hz), 7.30 (d, 1H, J = 1.8 Hz), 6.78 (brs, 1H), 4.21 (dd, 1H, J = 14.7, 5.9 Hz), 3.92 (dd, 1H, J
13
= 14.8, 6.9 Hz); C NMR (75 MHz, CDCl3) δ 171.0, 140.5, 137.3, 136.6, 134.1, 133.4, 131.4, 130.7,
130.3, 128.9, 128.6, 128.3, 126.8, 44.5; IR (neat) 3177, 3058, 2919, 1663, 1600, 1473, 1440, 1392, 774
cm-1; MS (EI) m/z 243 (M+, 100), 214 (88), 208 (28), 180 (30), 165 (12), 152 (64); HRMS (EI) calcd for
C14H10ClNO [M+] 243.0451, found 243.0448.
9-Fluoro-6,7-dihydro-5H-dibenz[c,e]azepin-5-one (5c). Method A: 92%, Method B: 94%, white yellow

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solid; mp 198–200 °C; H NMR (300 MHz, CDCl3) δ 8.00 (d, 1H, J = 7.8 Hz), 7.63–7.48 (m, 4H), 7.15
(td, 1H, J = 8.5 Hz, 2.6 Hz), 7.02 (dd, 1H, J = 8.4, 2.6 Hz), 6.85 (brs, 1H), 4.22 (dd, 1H, J = 14.7, 6.0 Hz),
3.99 (dd, 1H, J = 14.8, 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 169.9, 161.1 (d, J = 247.6 Hz), 139.7 (d, J
= 7.2 Hz), 135.5, 133.6 (d, J = 3.3 Hz), 132.1, 130.1, 129.8 (d, J = 8.3 Hz), 128.9, 127.6, 126.7, 114.1 (d,
J = 21.2 Hz), 112.5 (d, J = 21.7 Hz), 43.3; IR (neat) 3276, 2921, 1671, 1615, 1502, 1459, 1444, 1335,
1240, 1145, 970, 823 cm-1; MS (EI) m/z 227 (M+, 97), 198 (100), 169 (34), 98 (10); HRMS (EI) calcd for
C14H10FNO [M+] 227.0746, found 227.0742.
10-Fluoro-6,7-dihydro-5H-dibenz[c,e]azepin-5-one (5d). Method A: 96%, Method B: 92%, white
1
yellow solid; mp 198–200 °C; H NMR (300 MHz, CDCl3) δ 8.04–8.01 (m, 1H), 7.65–7.51 (m, 3H),
7.33–7.24 (m, 2H), 7.05 (td, 1H, J = 8.3, 2.6 Hz), 6.99 (brs, 1H), 4.19 (dd, 1H, J = 14.8, 6.0 Hz), 3.96 (dd,
1H, J = 14.8, 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 171.0, 162.6 (d, J = 244.6 Hz), 140.8 (d, J = 7.8 Hz),
136.7 (d, J = 1.9 Hz), 135.2 (d, J = 3.0 Hz), 133.7, 131.4, 130.3, 128.9, 128.5, 128.4 (d, J = 8.5 Hz),
116.2 (d, J = 22.5 Hz), 114.7 (d, J = 21.3 Hz), 44.1; IR (neat) 3288, 3171, 3058, 2921, 1657, 1561, 1392,
1264, 1177, 902, 890 cm-1; MS (EI) m/z 227 (M+, 100), 198 (97), 169 (36); HRMS (EI) calcd for
C14H10FNO [M+] 227.0746, found 227.0749.
Methyl 7-oxo-6,7-dihydro-5H-dibenzo[c,e]azepine-2-carboxylate (5e). Method A: 47%, Method B:
1
70%, white solid; mp 264–266 °C; H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 8.06–8.02 (m, 2H), 7.64
(d, 2H, J = 4.0 Hz), 7.58–7.52 (m, 1H), 7.38 (d, 1H, J = 7.8 Hz), 7.01 (brs, 1H), 4.26 (dd, 1H, J = 14.8,
6.0 Hz), 4.03 (dd, 1H, J = 14.8, 6.9 Hz), 3.95 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.6, 166.5, 143.3,
139.2, 136.7, 133.4, 131.5, 130.7, 130.6, 130.3, 129.3, 129.2, 128.6, 126.9, 52.3, 44.8; IR (neat) 3201,
3080, 1714, 1660, 1627, 1466, 1394, 1307, 1284, 1240, 1226 cm-1; MS (EI) m/z 267 (M+, 100), 238 (62),
208 (21), 180 (33), 165 (13), 150 (36); HRMS (EI) calcd for C16H13NO3 [M+] 267.0895, found 267.0898.
9,10-Dimethoxy-6,7-dihydro-5H-dibenz[c,e]azepin-5-one (5f). Method A: 89%, Method B: 88%, white
1
solid; mp 256–259 °C; H NMR (300 MHz, CDCl3) δ 8.00 (d, 1H, J = 7.7 Hz), 7.61–7.53 (m, 2H), 7.47
(td, 1H, J = 7.3, 1.7 Hz), 7.10 (s, 1H), 6.88 (brs, 1H), 6.81 (s, 1H), 4.20 (dd, 1H, J = 14.6, 6.0 Hz), 3.95 (s,
13
3H), 3.94 (s, 3H), 3.87 (dd, 1H, J = 14.8, 7.1 Hz); C NMR (75 MHz, CDCl3) δ 171.2, 149.0, 148.9,
137.8, 133.4, 131.9, 131.2, 131.1, 130.3, 128.6, 127.4, 112.6, 110.1, 56.2, 56.1, 44.7; IR (neat) 3161,
3010, 2923, 1649, 1599, 1512, 1465, 1435, 1390, 1272, 1141 cm-1; MS (EI) m/z 269 (M+, 100), 254 (32),
240 (44), 139 (34); HRMS (EI) calcd for C16H15NO3 [M+] 269.1052, found 269.1057.
ACKNOWLEDGEMENTS
We thank Korea Research Institute of Chemical Technology and the Center for Biological Modulators,

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Korea (KN-0911) for financial support.
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