Efficient TCT-catalyzed synthesis of 1,5-benzodiazepine derivatives under mild conditions

Article abstract of DOI:10.3390/molecules13092313

2,4,6-Trichloro-1,3,5-triazine (TCT) efficiently catalyzed the condensation reactions between 1,2-diamines and various enolizable ketones to afford 1,5-benzodiazepines in good to excellent yields. Simple and mild reaction conditions, the use of a cheap ca

Full text of DOI:10.3390/molecules13092313

Molecules 2008, 13, 2313-2325; DOI: 10.3390/molecules13092313
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.org/molecules
Article
Efficient TCT-catalyzed Synthesis of 1,5-Benzodiazepine
Derivatives under Mild Conditions
Chun-Wei Kuo, Chun-Chao Wang, Veerababurao Kavala and Ching-Fa Yao *
Department of Chemistry, National Taiwan Normal University, 88, Section 4, Tingchow Road, Taipei
1
16, Taiwan, ROC
*
Author to whom correspondence should be addressed; E-mail: cheyaocf@ntnu.edu.tw;
Tel.: +886-2-2930-9092; Fax: +886-2-2932-4249.
Received: 22 August 2008; in revised form: 10 September 2008 / Accepted: 10 September 2008 /
Published: 25 September 2008
Abstract: 2,4,6-Trichloro-1,3,5-triazine (TCT) efficiently catalyzed the condensation
reactions between 1,2-diamines and various enolizable ketones to afford
1
,5-benzodiazepines in good to excellent yields. Simple and mild reaction conditions, the
use of a cheap catalyst and easy workup and isolation are notable features of this method.
Keywords: Benzodiazepines, 2,4,6-trichloro-1,3,5-triazine, enolizable ketones,
o-phenylenediamines.
Introduction
Benzodiazepines and its derivatives constitute an important class of heterocyclic compounds which
possess a wide range of therapeutic and pharmacological properties. Derivatives of benzodiazepines
are widely used as anticonvulsant, antianxiety, analgesic, sedative, antidepressive, and hypnotic agents
[
1-2]. In the last decade, the area of biological interest of 1,5-benzodiazepines has been extended to
several diseases such as cancer, viral infection and cardiovascular disorders [3-4]. In addition,
,5-benzodiazepines are key intermediates for the synthesis of various fused ring systems such as
1
triazolo-, oxadiazolo-, oxazino- or furanobenzodiazepines [5-8]. Besides, benzodiazepine derivatives
are also of commercial importance as dyes for acrylic fibers in photography [9]. Owing to their

Molecules 2008, 13
2314
versatile applications various methods for the synthesis of benzodiazepines have been reported in the
literature. These include condensation reactions of o-phenylenediamines with α,β-unsaturated carbonyl
compounds [10], with ketones in the presence of BF
MgO/POCl , Yb(OTf) , Al /P or AcOH under microwave conditions, Amberlyst-15 in the ionic
liquid 1-butyl-3-methylimidazolium bromide ([bmim]Br), CeCl ·7H O/NaI supported on silica gel,
InBr , Sc(OTf) , sulfated zirconia InCl , CAN, ZnCl under thermal conditions, AgNO3. [11-26]. These
3 2 4 2
·Et O, NaBH , polyphosphoric acid or SiO ,
3
3
2
O
3
2 5
O
3
2
3
3
,
3
2
reactions also occur with various catalysts under solvent free conditions [27-30]. Nevertheless, many
of these methods suffer from shortcomings such as long reaction times, harsh reaction conditions, low
product yields, occurrence of several side products and difficulties in recovery of the products.
Moreover, some of the reagents employed are very expensive. Consequently, the search continues for
better catalysts in terms of operational simplicity and economic viability to synthesize
1
,5-benzodiazepines.
In recent years, 2,4.6-trichloro-1,3,5-triazine (TCT) has received considerable attention due to its
commercial availability and efficient delivery of anhydrous HCl in reaction media. It is inexpensive,
and has been found to be versatile in functional group transformations such as conversions of alcohols
to alkyl chlorides, oxidations of sulfides to sulfoxides, oxidative couplings of thiols and selenols,
cleavage of thioacetals, etc. [31-36]. TCT reacts with ‘incipient’ moisture and produces three moles of
HCl and cyanuric acid as a by-product (removable by simple washing with water). The HCl generated
in situ acts as a protic acid, activates the carbonyl oxygen to promote the condensation to give the
products [37]. In continuation to our efforts for the development of simple and novel methods for the
synthesis of different heterocyclics [38-44], we report herein a simple and efficient method for the
synthesis of 1,5-benzodiazepines using TCT as catalyst. While this paper was under peer review,
3
Khodaei et al. [45] reported a similar procedure, differing from ours in the preferred solvent – CH CN
vs. MeOH – and the amount of solvent required, 10 mol % vs. 4 mol %; the yields were similar
although their reported reaction times were shorter, possibly due to the higher catalyst load used.
Results and Discussion
In the first instance, o-phenylenediamine (1 equiv.) and acetone (2.5 equiv.) were stirred at ambient
temperature in dichloromethane with 4 mol% of TCT (Scheme 1). The reaction was complete within
5.5 h. After screening various solvents like methanol, ethanol, isopropanol, ethyl acetate and
acetonitrile, we found that the reaction proceeds well in polar solvents, giving slight variations in
reaction time and that methanol was the best choice for this reaction (Table 1).
Scheme 1. Synthesis of 1,5-benzodiazepines.

Molecules 2008, 13
2315
We assume that in the reaction medium TCT generates anhydrous HCl, which would be the active
catalyst. When a similar reaction was performed using 10 mol% of aqueous HCl, the reaction took
longer time (24 h) for completion, whereas the same conversion was achieved in 1 h with anhydrous
1
0% HCl in methanol. This further supports the proposed in-situ generation of anhydrous HCl in the
reaction as the source of the catalytic action.
Table 1. Solvent effects in the reaction.
Entrya
Yield (%)b
Solvent
Time (h)
1
2
MeOH
EtOH
1
2
99
96
3
4
5
IPA
1.5
5.5
6
95
94
84
CH Cl
2
2
THF
6
7
EA
4
7
92
93
CH CN
3
a
The reaction was performed with acetone (2.5 mmol) and
diamine (1 mmol) in 1 mL of solvent catalyzed by TCT.
Isolated yield.
b
Under the optimized conditions, aliphatic ketones such as acetone reacted with
,2-phenylenediamine in methanol (Scheme 2) to form the corresponding benzodiazepine in excellent
1
yield (Table 2, entry 1). However, the reaction was sluggish with the substrates 2-butanone and
-pentanone (Table 2, entries 2 and 3), resulting in poor yields. This may be due to the steric hindrance
3
of a methyl group in the proximity of the carbonyl carbon. Alicyclic ketones such as cyclopentanone,
cyclohexanone and cycloheptanone (Table 2, entries 4-6) gave excellent yields of products. With the
present methodology, aromatic ketones such as acetophenone (Table 2, entry 7) and substituted
acetophenones with both electron-donating and withdrawing groups generally produced the
corresponding benzodiazepines in good to excellent yields, with the latter performing somewhat better.
Thus, for example, an acetophenone bearing a OMe electron-releasing group such as 4-methoxy-
acetophenone (Table 2, entry 8) resulted in a poorer yield after a longer period of time, whereas an
2
acetophenone possessing a NO electron-withdrawing group, such as 4-nitroacetophenone (Table 2,
entry 11) underwent a smooth reaction to afford a good yield of the corresponding product 3k.

Molecules 2008, 13
2316
Scheme 2. Reaction of o-phenylenediamines with various ketones in the presence of 4 mol
of TCT.
%
Table 2. The results of the reaction of o-phenylenediamines with various ketones.
Entry
R
R1
H
Time (h) Yield (%)a References
1
2
3
CH3
C H
1
3a / 99
3b / 71
3c / 23
[21]
[21]
[21]
H
21
21
2
5
C H
CH3
2
5
4
5
6
7
(CH2)3
(CH2)4
(CH2)5
2
3d / 95
3e / 95
3f / 99
3g / 99
[21]
[21]
[21]
4.5
5.5
C H
H
12
[21]
6
5
8
9
4-OMe-C H
H
H
H
H
72
20
25
8
3h / 52
3i / 81
3j / 75
3k / 87
[21]
[40]
[40]
[25]
6
4
4-Me-C H
6
4
1
1
0
1
4-Cl-C H
6
4
4-NO -C H
4
2
6
1
2
2-thienyl
H
26
3l / 96
[40]
a
Isolated yields.
Having successfully performed the reactions of 1,2-phenylenediamine with a wide range of ketones,
we focused our attention on examining the reactions of various ketones and structurally diverse
diamines (Scheme 3). The results revealed that both mono- and disubstituted phenylenediamines
reacted with ketones to produce the corresponding benzodiazepines in excellent yields. Diamines
bearing substituents with various electronic effects reacted with acetone with equal ease (Table 3,

Molecules 2008, 13
2317
entries 1, 3, 5 and 8). The reactions of aromatic ketones with monosubstituted diamines furnished the
corresponding benzodiazepines in shorter times (Table 3, entries 2 and 4), whereas disubstituted
diamines took relatively longer times to afford good yields of products (Table 3, entries 6, 7 and 9). All
the monosubstituted diamines gave 1:1 mixtures of regioisomers. The results are summarized in Table
3
.
Scheme 3 Reaction of various o-phenylenediamines with ketones in the presence of 4 mol
of TCT.
%
H R
N
O
R1
NH2
R1
4
mol% TCT/MeOH
rt
+
R
R2
NH2
R2
N
R
3
m-3v
Table 3. The results of the reaction of various o-phenylenediamines with ketones.
Yield(%)a
Entry
1b
R
R1
Cl
R2
H
Time(h)
2
References
[40]
CH3
3m / 99
2b
3b
6
5
C H
Cl
H
H
14
2
3n / 71
3o / 99
[40]
[40]
CH3
C H
CH3
4b
5
6
5
CH3
CH3
H
14
2
3p / 70
3q / 99
[40]
[21]
CH3
C H
CH3
6
7
CH3
CH3
CH3
CH3
23
5
3r / 88
3s / 76
[21]
[40]
[40]
[25]
6
5
4-Cl-C H
6
4
8
9
CH3
C H
Cl
Cl
Cl
Cl
7.5
26
8
3t / 72
3u / 51
6
5
1
0
CH3
(CH)4
3v / 65
a
Isolated yields.
b
1
:1 mixture of two regioisomers.
Finally, the reaction of acetone with a bisdiamine in the presence of 8 mol % TCT gave the
corresponding bisbenzodiazepine in moderate yield (Scheme 4). The product 3w thus obtained proved
unstable in solution and readily decomposed in methanol when it was subjected to crystallization.

Molecules 2008, 13
Scheme 4. Reaction of bisdiamine with acetone in the presence of TCT.
2318
H
N
NH2
NH2
2
8
mL acetone
mol% TCT
N
N
H N
2
rt, 15 h
NH2
NH
2
w
3w
Conclusions
In summary, we have disclosed an efficient and economic method for the synthesis of
,5-benzodiazepines. We also demonstrated the electronic effects on the reaction of various
1
substitutions on the ketone and the diamine participants. Electron withdrawing groups like the (NO2)
group stimulate the reaction rate, whereas electron releasing groups reduce the reactivity of the ketone.
Simple workup and easy isolation under mild reaction conditions are the best features of the present
methodology.
Experimental
General
All reagents and chemicals were purchased from Sigma-Aldrich Chemical Company, Acros
organics and Merck and were used as received. Analytical thin layer chromatography was performed
with E. Merck silica gel 60F glass plates and flash chromatography by the use of E. Merck silica gel 60
1
13
(
230–400 mesh). H-NMR and C-NMR spectra were recorded at 400 and 100 MHz, respectively, on
a Bruker Avance EX 400 FT-NMR instrument. Chloroform-d was used as the solvent and TMS (δ =
.00 ppm) as an internal standard. Chemical shift values are reported in ppm relative to TMS in delta
δ) units. Multiplicities are recorded as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of
0
(
doublet), br (broadened), m (multiplet). Coupling constants (J) are expressed in Hz. MS and HRMS
were measured on JEOL JMS-D300 and JEOL JMS-HX110 spectrometers, respectively.
General procedure for the preparation of 1,5-benzodiazepines
To a stirred solution of o-phenylenediamine (1 mmol) in MeOH (1 mL), a ketone (2.5 mmol) and 4
mol% TCT were added. The reaction mixture was stirred at room temperature until the reaction was
complete, as judged by TLC analysis. The reaction mixture was then concentrated and washed with
water to give the crude product, which was further purified by flash chromatography on silica gel
(eluent: hexane-EtOAc= 5:1).

Molecules 2008, 13
2319
1
2
,2,4-Trimethyl-2,3-dihydro-1H-benzo[b][1,4]diazepine (3a): H-NMR δ 7.14–7.12 (m, 1H),
7
.00–6.96 (m, 2H), 6.74–6.72 (m, 1H), 2.97 (br s, 1H, NH), 2.37 (s, 3H), 2.23 (s, 2H), 1.35 (s, 6H);
1
3
C-NMR δ 172.4, 140.8, 137.9, 126.9, 125.5, 122.1, 121.7, 68.3, 45.2, 30.5, 29.9; MS (EI) m/z
+
(
(
relative intensity) 188 (M , 38), 173 (100), 133 (39), 132 (50); HRMS (EI) m/z calcd. for C H N
1
2
16
2
+
M ) 188.1314, found 188.1314.
1
2
6
1
1
,2-Dimethyl-2-methyl-2,3-dihydro-1H-1,5-benzodiazepine (3b): H-NMR δ 7.16–7.14 (m, 1H),
.99–6.95 (m, 2H), 6.73–6.71 (m, 1H) 3.10 (br s, 1H, NH), 2.61–2.57 (m, 2H), 2.22 (d, J = 12.9 Hz,
1
3
H), 2.14 (d, J = 12.9 Hz, 1H), 1.63 (m, 2H), 1.24 (m, 5H), 0.95 (t, J = 7.5 Hz, 1H); C-NMR δ 175.9,
40.7, 137.9, 127.1, 125.4, 121.8, 121.7, 70.7, 42.1, 35.7, 26.9, 10.6, 10.6, 8.5; MS (EI) m/z (relative
+
+
intensity) 216 (M , 19), 201 (20), 187 (100), 145 (18); HRMS (EI) m/z calcd. for C H N (M )
1
4
20
2
2
16.1627, found 216.1623.
1
2
,2,4-Triethyl-3-methyl-2,3-dihydro-1H-1,5-benzodiazepine (3c): H-NMR δ 7.35 (dd, 1H, J = 7.9, 1.1
Hz), 6.97 (t, J = 8.1 Hz, 1H), 6.74 (t, J = 7.1 Hz, 1H), 6.62 (dd, J = 8.0, 0.5 Hz, 1H), 3.86 (br s, 1H,
NH), 2.85 (q, J = 7.0 Hz, 1H), 2.60–2.49 (m, 2H), 1.61–1.51 (m, 2H), 1.37 (q, J = 7.4 Hz, 2H), 1.24 (t,
1
3
J = 7.4 Hz, 3H), 0.96–0.88 (m, 6H), 0.79 (t, J = 7.3 Hz, 3H); C-NMR δ 173.6, 139.0, 132.8, 132.2,
1
2
2
26.7, 117.9, 117.5, 60.3, 46.1, 35.7, 28.4, 28.0, 12.3, 11.5, 7.8, 7.3; MS (EI) m/z (relative intensity)
+
+
44 (M , 14), 216 (12), 215 (100), 147 (23); HRMS (EI) m/z calcd. for C16
H
24
N
2
(M ) 244.1940, found
44.1940.
1
2
,3,9,10a-Tetrahydro-1H-spiro[benzo[b]cyclopenta[e][1,4]diazepine-10,1’-cyclopentane] (3d): H-
NMR δ 7.32 (dd, J = 1.2, 1.1 Hz, 1H), 6.99–6.76 (m, 2H), 6.57 (dd, J = 1.0, 1.0 Hz, 1H), 3.98 (s, 1H),
.77 (t, J = 9.0 Hz, 1H), 2.63–2.59 (m, 2H), 2.15–2.06 (m, 1H), 2.00–1.92 (m, 1H), 1.87–1.56 (m, 9
2
1
3
H), 1.48–1.42 (m, 1H); C-NMR δ 178.2, 139.3, 134.1, 132.4, 127.1, 119.5, 118.9, 67.5, 54.4, 39.5,
+
3
1
8.7, 33.6, 29.1, 24.4, 24.2, 23.6; MS (EI) m/z (relative intensity) 240 (M , 39), 211 (87), 183 (42),
+
45 (41), 132 (100); HRMS (EI) m/z calcd. for C16
H
20
N
2
(M ) 240.1626, found 240.1629.
1
2
',3',4',10'-Tetrahydro-1'H-spiro[cyclohexane-1,11'-dibenzo[b,e][1,4]diazepine] (3e): H-NMR δ
7
.29–7.26 (m, 1H), 6.99–6.92 (m, 2H), 6.70 (d, J = 1.4 Hz, 1H), 3.78 (br s, 1H, NH), 2.59 (t, J = 6.6
1
3
Hz, 2H), 2.4–2.36 (m, 1H), 1.86–1.18 (m, 16H); C-NMR δ 176.2, 138.6, 138.3, 129.4, 126.0, 121.2,
21.1, 51.9, 41.9, 40.9, 40.6, 34.2, 33.0, 27.2, 26.9, 26.7, 25.3, 24.2, 21.9; MS (EI) m/z (relative
1
+
+
24 2
intensity) 268 (M , 39), 225 (100), 145 (53), 132 (39); HRMS (EI) m/z calcd. for C18H N (M )
2
68.1940, found 268.1945.
,8,9,10,10a,12-Hexahydro-6H-spiro[benzo[b]cyclohepta[e][1,4]diazepine-11,1'-cycloheptane] (3f):
7
1
H-NMR δ 7.21–7.19 (m, 1H), 7.01–6.96 (m, 2H), 6.73–6.71 (m, 1H), 3.59 (br s, 1H, NH), 2.80–2.64
1
3
(
m, 2H), 2.36–2.32 (m, 1H), 2.05–0.99 (m, 20H); C-NMR δ 179.9, 137.1, 127.1, 125.5, 121.8, 121.6,
4.0, 40.6, 38.3, 37.9, 30.2, 29.8, 29.7, 29.0, 28.3, 26.2, 23.2, 22.4; MS (EI) m/z (relative intensity) 296
5
+
+
(
M , 39), 239 (100), 145 (29), 132 (35); HRMS (EI) m/z calcd. for C20
96.2250.
28 2
H N (M ) 296.2253, found
2

Molecules 2008, 13
2320
1
2
-Methyl-2,4-diphenyl-2,3-dihydro-1H-benzo[b][1,4]diazepine (3g): H-NMR δ 7.59–7.57 (m, 4H,),
.31–7.16 (m, 7H), 7.05–7.03 (m, 2H), 6.83 (d, J = 1.7 Hz, 1H), 3.50 (br s, 1H, NH), 3.12 (d, J = 13.2
7
1
3
Hz, 1H), 2.95 (d, J = 13.2 Hz, 1H), 1.74 (s, 3H); C-NMR δ 167.6, 147.6, 140.1, 139.6, 138.0, 129.7,
28.6, 128.3, 128.0, 127.0, 127.0, 126.3, 125.4, 121.6, 121.4, 73.6, 43.0, 29.8; MS (EI) m/z (relative
1
+
+
intensity) 312 (M , 24), 297 (25), 235 (23), 194 (100); HRMS (EI) m/z calcd. for C H N (M )
2
2
20
2
3
12.1627, found 312.1632.
1
2
8
5
1
1
,3-Dihydro-2-methyl-2,4-di(4'-methoxyphenyl)-1H-1,5-benzodiazepine (3h): H-NMR δ 7.59 (d, J =
.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.29 (t, J = 5.2 Hz, 1H), 7.03 (t, J = 4.4 Hz, 2H), 6.81–6.75 (m,
H), 3.78 (s, 3H), 3.74 (s, 3H), 3.41 (br s, 1H, NH), 3.03 (d, J = 13.2 Hz, 1H), 2.90 (d, J = 13.2 Hz,
1
3
H), 171 (s, 3H); C-NMR δ 167.1, 161.0, 158.5, 140.6, 140.1, 138.0, 132.3, 128.8, 128.2, 126.5,
25.8, 121.7, 121.5, 113.5, 113.3, 73.3, 55.3, 55.2, 42.8, 29.7; MS (EI) m/z (relative intensity) 372
+
+
(
M , 9), 357 (8), 225 (23), 224 (100), 133 (14); HRMS (EI) m/z calcd. for C H N O (M ) 372.1838,
24 24 2 2
found 372.1832.
1
2
,3-Dihydro-2-methyl-2,4-di(4'-methoxyphenyl)-1H-1,5-benzodiazepine (3i): H-NMR δ 7.53 (d, J =
.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.31–7.28 (m, 1H), 7.05–6.99 (m, 6H), 6.76–6.74 (m, 1H), 3.44
8
(
br s, 1H, NH), 3.03 (d, J = 13.2 Hz, 1H), 2.92 (d, J = 13.2 Hz, 1H), 2.30 (s, 3H), 2.27 (s, 3H), 1.67 (s,
1
3
3
1
3
H); C-NMR δ 167.3, 144.9, 140.2, 139.8, 138.1, 136.9, 136.5, 129.1, 128.9, 128.7, 128.4, 127.1,
+
26.0, 125.1, 121.5, 121.3, 73.2, 42.7, 29.7, 21.2, 20.8; MS (EI) m/z (relative intensity) 340 (M , 9),
25 (7), 209 (40), 208 (100), 207 (14), 133 (15), 117 (55), 92 (26), 91 (18), 65 (10); HRMS (EI) m/z
+
calcd. for C24
H
24
N
2
(M ) 340.1940, found 340.1944.
1
2
-Methyl-2,4-di(4-chlorophenyl)-2,3-dihydro-1H-1,5-benzodiazepine (3j): H-NMR δ 7.52–7.46 (m,
4
H), 7.28 (d, J = 2.0 Hz, 1H), 7.21–7.18 (m, 4H), 7.08–7.04 (m, 2H), 6.82 (d, J = 8.8 Hz, 1H), 3.42 (br
1
3
s, 1H, NH), 3.08–3.04 (d, J = 13.2 Hz, 1H), 2.87 (d, J = 13.2 Hz, 1H), 1.72 (s, 3H); C-NMR δ 166.0,
1
45.8, 139.9, 137.7, 137.6, 136.0, 133.0, 128.6, 128.3, 128.2, 127.0, 126.6, 122.0, 121.5, 73.4, 42.9,
+
2
9.7; MS (EI) m/z (relative intensity) 380 (M , 4), 365 (5), 231 (18), 230 (40), 229 (60), 228 (100), 193
+
(12), 137 (12), 133 (11); HRMS (EI) m/z calcd. for C22
H
18
2
N Cl
2
(M ) 380.0847, found 380.0849.
2
1
,4-bis(4-Nitrophenyl)-2,3-dihydro-1H-benzo[b][1,4]diazepine (3k): yellow solid; m.p. 152—154°C;
H-NMR δ 8.05 (d, J = 8.5 Hz, 4H), 7.75 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 7.6
Hz, 1H), 7.16 (t, J = 7.5, 7.4 Hz, 1H), 7.09 (t, J = 7.6, 7.3 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 3.67 (br s,
1
3
1
1
3
H), 3.31 (d, J = 13.6 Hz, 1H), 3.00 (d, J = 13.6 Hz, 1H), δ 1.84 (s, 3H); C-NMR δ 164.0, 154.2,
48.6, 147.1, 144.9, 139.0, 137.4, 129.8, 127.9, 127.8, 127.0, 123.7, 123.6, 122.3, 121.5, 73.5, 43.1,
+
0.4; MS (EI) m/z (relative intensity) 402 (M , 18), 387 (17), 280 (18), 239 (100), 193 (20); HRMS
+
(
EI) m/z calcd for C22
H
18
N
4
O
4
(M ) 402.1328, found 402.1323.
1
2
-Methyl-2,4-di-thiophen-2-yl-2,3-dihydro-1H-benzo[b][1,4]diazepine (3l): H-NMR δ 7.39 (d, J = 4.8
Hz, 1H), 7.30–7.28 (m, 1H), 7.12–7.11 (m, 1H), 7.08–7.03 (m, 4H), 6.94–6.91 (m, 2H), 6.83–6.80 (m,
1
3
1
H), 3.60 (br s, 1H, NH), 3.06 (d, J = 13.2 Hz, 1H), 3.00 (d, J = 13.2 Hz, 1H), 1.84 (s, 3H); C-NMR

Molecules 2008, 13
2321
δ 162.4, 153.2, 137.2, 130.4, 128.6, 127.9, 127.6, 126.8, 126.3, 124.2, 122.8, 122.6, 122.0, 72.6, 44.4,
+
3
0.6; MS (EI) m/z (relative intensity) 324 (M , 11), 201 (32), 200 (100), 109 (18); HRMS (EI) m/z
+
calcd. for C18
H
16
N
2
S
2
(M ) 324.0755, found 324.0761.
1
2
,2,4-Trimethyl-2,3-dihydro-8-chloro-1H-1,5-benzodiazepine (3m): H-NMR δ 7.07 (s, 1H), 7.00 (d, J
=
8.4 Hz, 1H), 6.89–6.85 (m, 2H), 6.67 (s, 1H), 6.60 (d, J = 8.3 Hz, 1H), 3.02 (br s, 2H, NH),
1
3
2
1
3
.30–2.29 (m, 6H), 2.19–2.16 (d, J = 12.3 Hz, 4H), 1.27 (s, 12H); C-NMR δ 173.8, 172.6, 141.4,
39.1, 138.4, 136.5, 130.0, 128.1, 126.4, 126.3, 125.1, 122.5, 121.3, 120.7, 68.2, 67.6, 45.1, 45.0, 30.4,
+
0.2, 29.64, 29.62; MS (EI) m/z (relative intensity) 222 (M , 35), 209 (28), 207 (100), 167 (39), 166
+
(
56); HRMS (EI) m/z calcd. for C H ClN (M ) 222.0924, found 222.0924.
1
2
15
2
1
2
-Methyl-2,4-diphenyl-8-chloro-2,3-dihydro-1H-1,5-benzodiazepine (3n): H-NMR δ 7.60–7.56 (m,
H), 7.35–7.18 (m, 14H), 7.05 (dd, J = 8.4, 2.4 Hz, 0.7H), 7.01–6.98 (dd, J = 8.4, 2.4 Hz, 1.3H), 6.85
8
(
d, J = 2.4 Hz, 1.3H), 6.78 (d, J = 8.4 Hz, 0.7H), 3.62 (br s, 1.3H, NH), 3.52 (br s, 0.7H, NH), 3.17 (t, J
13
=
13.4 Hz, 2H), 3.00–2.96 (m, 2H), 1.78 (s, 3H), 1.77 (s, 3H); C-NMR δ 168.7, 167.6, 147.1, 139.4,
1
1
2
3
39.1, 138.1, 131.0, 130.1, 130.1, 129.9, 128.4, 128.4, 128.1, 128.0, 127.2, 127.1, 127.0, 126.0, 125.3,
+
22.4, 121.3, 120.5, 73.7, 72.9, 43.2, 43.0, 30.0, 29.8; MS (EI) m/z (relative intensity) 346 (M , 12),
+
30 (35), 229 (32), 228 (100), 167 (19), 103 (53); HRMS (EI) m/z calcd. for C22
H19ClN
2
(M )
46.1237, found 346.1229.
1
2
6
3
,2,4,8-Tetramethyl-2,3-dihydro-1H-1,5-benzodiazepine (3o): H-NMR δ 7.00 (d, J = 7.8 Hz, 1H),
.93 (s, 1H), 6.77–6.75 (m, 2H), 6.62 (d, J = 7.8 Hz, 1H), 6.50 (s, 1H), 2.87 (br s, 1H, NH), 2.33 (s,
1
3
H), 2.32 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H), 2.19 (s, 2H), 2.16 (s, 2H), 1.30 (s, 6H), 1.29 (s, 6H); C-
NMR δ 172.4, 171.3, 140.9, 137.8, 137.7, 135.2, 135.1, 131.6, 126.9, 126.8, 126.0, 122.6, 121.9,
+
1
1
21.7, 68.3, 67.5, 45.1, 45.0, 30.4, 30.1, 29.7, 20.8, 20.5; MS (EI) m/z (relative intensity) 202 (M , 30),
+
87 (100), 147 (23), 146 (38); HRMS (EI) m/z calcd. for C13
H
18
N
2
(M ) 202.1470, found 202.1469.
1
2
8
0
-Methyl-2,4-diphenyl-2,3-dihydro-8-methyl-1H-1,5-benzodiazepine (3p): H-NMR δ 7.65–7.59 (m,
H), 7.32–7.18 (m, 14H), 6.93 (d, J = 7.8 Hz , 0.8H), 6.88 (d, J = 7.8 Hz, 1.2H), 6.78 (d, J = 7.8 Hz,
.8 H), 6.67 (s, 1.2H), 3.51 (br s, 2H, NH), 3.15 (t, J = 13.2 Hz, 2H), 2.98 (q, J = 7.2 Hz, 2H), 2.37 (d,
1
3
J = 3.6 Hz, 6H), 1.77 (d, J = 4.2 Hz, 6H); C-NMR δ 167.8, 166.6, 147.7, 140.4, 139.8, 139.5, 137.9,
1
1
37.2, 136.2, 135.4, 131.2, 129.7, 129.5, 128.9, 128.6, 128.2, 128.0, 127.9, 127.0, 126.9, 125.4, 125.4,
25.3, 122.3, 121.4, 121.5, 73.8, 72.8, 43.3, 42.9, 29.9, 29.6, 21.0, 20.5; MS (EI) m/z (relative
+
intensity) 326 (M , 16), 311 (19), 209 (40), 208 (100), 207 (27), 200 (21), 103 (17), 77 (23); HRMS
+
(
EI) m/z calcd. for C23
H
22
N
2
(M ) 326.1783, found 326.1780.
1
2
1
1
2
2
,2,4,7,8-Pentamethyl-2,3-dihydro-1H-banzo[b][1,4]diazepine (3q): H-NMR δ 6.92 (s, 1H), 6.52 (s,
1
3
H), 2.34 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 1.32 (s, 6H); C-NMR δ 171.6, 138.5,
35.5, 133.7, 130.1, 127.9, 122.8, 67.9, 45.3, 30.4, 29.8, 19.2, 18.9; MS (EI) m/z (relative intensity)
+
+
16 (M , 26), 201 (100), 161 (29), 160 (39), 145 (20); HRMS (EI) m/z calcd. for C14
H
20
N
2
(M )
16.1626, found 216.1621.

Molecules 2008, 13
2322
1
2
,7,8-Trimethyl-2,4-diphenyl-2,3-dihydro-1H-benzo[b][1,4]diazepine (3r): H-NMR δ 7.57 (t, J = 8.6
Hz, 4H), 7.23–7.12 (m, 7H), 6.62 (s, 1H), 3.40 (br s, 1H, NH), 3.09 (d, J = 8.7 Hz, 1H), 2.96 (d, J =
1
3
8
1
.7 Hz, 1H), 2.24 (s, 6H), 1.73 (s, 3H); C-NMR δ 166.8, 147.8, 139.8, 137.7, 135.8, 134.8, 129.7,
29.6, 129.4, 128.2, 127.9, 126.9, 125.4, 122.3, 73.1, 43.3, 29.8, 18.4, 18.8; MS (EI) m/z (relative
+
+
intensity) 340 (M , 19), 325 (27), 223 (47), 222 (100); HRMS (EI) m/z calcd. for C H N (M )
2
4
24
2
3
40.1939, found 340.1934.
1
2
7
=
,4-bis(4-Chlorophenyl)-2,7,8-trimethyl-2,3-dihydro-1H-benzo[b][1,4]diazepine (3s): H-NMR δ
.52–7.19 (m, 8H), 7.9 (s, 1H), 6.62 (s, 1H), 3.32 (br s, 1H, NH), 3.05 (d, J = 13.2 Hz, 1H), 2.87 (d, J
1
3
13.2 Hz, 1H), 2.24 (s, 6H), 1.71 (s, 3H); C-NMR δ 165.2, 146.1, 138.1, 137.1, 135.8, 135.4, 135.3,
1
32.9, 130.0, 129.7, 128.4, 128.3, 128.2, 127.1, 122.4, 73.0, 43.1, 29.8, 19.4, 18.8; MS (EI) m/z
+
(
relative intensity) 408 (M , 3), 305 (12), 304 (70), 289 (100), 131 (18); HRMS (EI) m/z calcd. for
+
C H N Cl (M ) 408.1160, found 408.1155.
2
4
22
2
2
1
7
6
1
2
,8-Dichloro-2,2,4-trimethyl-2,3-dihydro-1H-benzo[b][1,4]diazepine (3t): H-NMR δ 7.20 (s, 1H),
1
3
.81 (s, 1H), 3.07 (br s, 1H, NH), 2.34 (s, 3H), 2.25 (s, 2H), 1.33 (s, 6H); C-NMR δ 173.9, 139.7,
+
37.7, 128.3, 128.1, 124.4, 122.2, 67.7, 45.3, 30.5, 29.9; MS (EI) m/z (relative intensity) 256 (M , 28),
58 (18), 243 (58), 241 (100), 203 (25), 202 (37), 201 (46), 200 (58); HRMS (EI) m/z calcd. for
+
C
12
H
14
N
2
Cl
2
(M ) 256.0534, found 256.0529.
1
(
E)-7,8-Dichloro-2-methyl-2,4-diphenyl-2,3-dihydro-1H-benzo[b][1.4]diazepine (3u): H-NMR δ 7.54
t, J = 6.8, 6.6 Hz, 4H), 7.40 (s, 1H), 7.33-7.17 (m, 6H), 6.92 (s, 1H), 3.59 (br s, 1H, NH), 3.17 (d, J =
(
13
1
1
3.4 Hz, 1H), 2.97 (d, J = 13.4 Hz, 1H), 1.75 (s, 3H), 1.57 (s, 1H); C-NMR δ 168.8, 146.8, 139.2,
38.9, 137.7, 130.2, 129.9, 128.8, 128.1, 127.1, 125.3, 124.1, 121.8, 72.9, 43.2, 29.9; MS (EI) m/z
+
(
relative intensity) 380 (M , 8), 260 (10), 265 (19), 264 (61), 262 (100), 103 (23), 77 (12); HRMS (EI)
+
m/z calcd. for C22
H
18
N
2
Cl
2
(M ) 380.0874, found 380.0842.
1
2
1
1
1
,2,4-Trimethyl-2,3-dihydro-1H-naphtho[2,3-b][1,4]diazepine (3v): H-NMR δ 7.72 (d, J = 7.8 Hz,
H), 7.61 (d, J = 7.9 Hz, 1H), 7.55 (s, 1H), 7.33-7.29 (m, 2H), 7.08 (s, 1H), 2.38 (s, 3H), 2.17 (s, 2H),
1
3
.33 (br s, 1H, NH); C-NMR δ 173.1, 141.9, 137.6, 131.9, 130.3, 127.4, 125.8, 125.2, 124.0, 123.6,
+
17.6, 65.9, 44.6, 29.9, 29.6; MS (EI) m/z (relative intensity) 238 (M , 25), 224 (18), 223 (100), 183
+
(42), 182 (37), 115 (17); HRMS (EI) m/z calcd. for C16
H
18
N
2
(M ) 238.1470, found 238.1465.
2
,2',4,4,4',4'-Hexamethyl-4,4',5,5'-tetrahydro-3H,3'H-7,7'-dibenzo[b][1,4]diazepine (3w): mixture of
1
two isomers; H-NMR δ 7.39 (s, 1H), 7.20 (m, 3H), 6.92 (d, 1H, J = 9.7 Hz), 6.74 (d, 1H, J = 5.0 Hz)
1
3
1
1
1
H), 3.01 (br s, 2H), 2.36 (s, 6H), 2.56 (s, 4H), 1.32 (s, 12H); C-NMR δ 172.8, 172.7, 172.5, 172.4,
38.4, 138.3, 138.1, 138.0, 137.5, 136.9, 134.4, 127.5, 127.4, 125.3, 124.8, 123.9, 123.7, 122.1, 122.0,
20.5, 120.2, 119.8, 119.6, 68.1, 67.9, 45.4, 45.3, 30.7, 30.6, 29.9, 29.8. MS (EI) m/z (relative
+
intensity) 374 (M , 40), 359 (100), 319 (23), 263 (7).

Molecules 2008, 13
2323
Acknowledgements
Financial support provided by the National Science Council of Republic of China and National
Taiwan Normal University (96TOP001) is gratefully acknowledged.
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Sample availability: Available from the authors
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