Enantioselective synthesis of 4-substituted 4,5-dihydro-1 H-[1,5]benzodiazepin-2(3 H)-ones by the Lewis base-catalyzed hydrosilylation

Article abstract of DOI:10.1021/jo201334n

Enantioselective synthesis of 4-substituted 4,5-dihydro-1H-[1,5] benzodiazepin-2(3H)-ones has been accomplished through chiral Lewis base-catalyzed hydrosilylation. The corresponding products were obtained in excellent yields (up to 99%) and enantioselect

Full text of DOI:10.1021/jo201334n

Note
pubs.acs.org/joc
Enantioselective Synthesis of 4-Substituted 4,5-Dihydro-1H-
[1,5]benzodiazepin-2(3H)-ones by the Lewis Base-Catalyzed
Hydrosilylation
Xing Chen,†,‡,§ Yongsheng Zheng,†,§ Chang Shu,†,§ Weicheng Yuan,† Bo Liu,*,‡ and Xiaomei Zhang*,†
†Key Laboratory for Asymmetric Synthesis and Chiraltechnology of Sichuan Province, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, China
‡Sichuan University, Chengdu 610041, China
§Graduate School of the Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: Enantioselective synthesis of 4-substituted 4,5-
dihydro-1H-[1,5]benzodiazepin-2(3H)-ones has been accom-
plished through chiral Lewis base-catalyzed hydrosilylation.
The corresponding products were obtained in excellent yields
(up to 99%) and enantioselectivities (up to 98%). The
absolute configuration of product 3n has been determined as S
by X-ray crystallographic analysis.
ducted under microwave irradiation at high temperature to
achieve satisfactory yields.
large number of pharmaceutical and biologically active
Aagents incorporate heterocycles as substructural units. 1,5-
Benzodiazepines belong to this family, and their derivatives are
important compounds with various biological properties.1 In
this class of compounds, the 1,5-benzodiazepin-2-ones have
been clinically used as antisecretory agents and anxiolytic
agents, such as telenzepine,2 arfendazam,3 lofendazam,4
triflubazam,5 and clobazam.6 In addition, some compounds of
this kind have exhibited a wide range of biological activities,
including interleukin-1β-converting enzyme inhibition, antiar-
rhythmic properties,7 and delayed rectifier potassium current
blocking.8 Because of the aforementioned biological activities,
1,5-benzodiazepin-2-ones are considered as “privileged” scaf-
folds in drug development.9
The important biological properties of these compounds
have led to considerable interest in their synthesis and
biological study. Solid-phase synthetic strategies have been
applied to prepare 4,5-dihydro-1H-[1,5]benzodiazepin-2-one
derivatives.8,10 Xiaoxia Wang and co-workers have demon-
strated that o-phenylenediamine reacted with N-cinnamoylben-
zotriazoles via 1,4-addition to afford 1,3,4,5-tetrahydro-1,5-
benzodiazepin-2-ones.11 In addition, several other groups also
reported their studies on this subject.12 However, to the best of
our knowledge, only one example of enantioselective synthesis
of these compounds has been described. Rueping and co-
workers employed chiral phosphoric acids in promoting
enantioselective transfer hydrogenation of 4-substituted 1,5-
benzodiazepin-2-ones to afford the chiral 4-substituted 4,5-
dihydro-1H-[1,5]benzodiazepin-2(3H)-ones in good yields and
excellent enantioselectivities.13 The reactions must be con-
Recently, asymmetric reaction involving the strategy of Lewis
base activation of Lewis acids has attracted much attention.14
Among these reactions, Lewis base-catalyzed enantioselective
hydrosilylation of ketimines has become an important approach
to obtaining chiral amines.15,16 This organocatalytic method-
ology has many properties, including mild reaction conditions,
atom economy, and operational simplicity. During our
continuing research on the enantioselective Lewis base-
catalyzed hydrosilylation of CN bond compounds,16m−o we
have developed several chiral picolinoylamide Lewis base
catalysts that were appropriate for different types of substrates.
Ephedrine-derived catalyst 1a was found to succeed in
promoting the enantioselective hydrosilylation of ketimines,16p
benzoxazinones, and quinoxalinones.16n Proline-derived cata-
lysts 1b and 1c accelerated the hydrosilylation of N-aryl β-
enamino esters with good yields and enantioselectivities.16m
Meanwhile, trans-4-hydroxy-L-proline-derived catalysts 1d and
1e delivered good yields and enantioselectivities in the
hydrosilylation of α-ketimino esters.16o With these catalysts in
hand, we extended their application in the hydrosilylation of 4-
substituted 1,5-benzodiazepin-2-ones to prepare chiral 4,5-
dihydro-1H-[1,5]benzodiazepin-2-ones. Herein, we describe
the general, enantioselective hydrosilylation of 4-substituted
1,5-benzodiazepin-2-ones promoted by these catalysts.
First, catalysts 1a−e (Figure 1) were evaluated in the
hydrosilylation of 4-phenyl-1H-benzo[b][1,4]diazepin-2(3H)-
Received: July 13, 2011
Published: September 29, 2011
© 2011 American Chemical Society
9109
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The Journal of Organic Chemistry
Note
Because of the poor solubility of substrate 2a, sometimes the
reaction suffered from poor reproducibility. To improve the
solubility, several substituents were introduced at N1 of 2a to
generate substrates 2b−d. Interestingly, the substituents
affected the enantioselection remarkably. Both N-methyl
substrate 2b and N-allyl substrate 2c gave very poor ee values
(Table 2, entries 2 and 3, respectively). On the other hand, N-
Figure 1. Chiral Lewis base organocatalysts evaluated in this study.
one (2a) in methylene dichloride at −10 °C. The results are
summarized in Table 1. In our initial investigations, we
Table 2. Influence of the N1 Substituents of 4-Phenyl-1H-
benzo[b][1,4]diazepin-2(3H)-one
a
Table 1. Influence of Different Chiral Lewis Base
Organocatalysts, Solvents, and Temperatures on the
Enantioselective Hydrosilylation of 4-Phenyl-1H-
a
benzo[b][1,4]diazepin-2(3H)-one 2a
b
c
entry
2
R
T (h)
yield (%)
ee (%)
1
2
3
4
2a
2b
2c
2d
2d
2d
2d
H
2
1
98
95
96
97
98
98
50
90
42
55
90
96
83
−
Me
allyl
Bn
Bn
Bn
Bn
1
b
c
2
entry
1
solvent
T (°C)
t (h)
yield (%)
ee (%)
d
5
2
1
1a
1b
1c
1d
1e
1d
1d
1d
1d
1d
1d
1d
DCM
−10
−10
−10
−10
−10
−10
−10
−10
−10
−10
0
4
2
99
98
97
98
98
82
84
82
88
87
−
de
,
6
7
2
2
DCM
f
24
3
DCM
1
a
Unless specified otherwise, the reaction was conducted with 2 (0.25
mmol), trichlorosilane (0.5 mmol), and 1d (0.025 mmol) in 3 mL of
(CH2Cl)2. Yield based on 2. The ee value was determined by chiral-
phase HPLC analysis. The reaction was conducted under an inert
atmosphere. The catalyst loading was 5 mol %. The reaction was
conducted in the absence of catalyst.
4
DCM
4
5
DCM
2.5
−
−
2
b
c
d
6
CHCl3
CH3CCl3
(CH2Cl)2
(CHCl2)2
THF
NR
d
d
7
NR
−
e
f
8
98
97
97
95
97
90
88
87
88
85
9
2
10
11
12
2
benzyl substrate 2d afforded a high enantioselectivity of 90%
(Table 2, entry 4). Furthermore, we found that the ee value
rose to 96% when the reaction was conducted under an inert
atmosphere (Table 2, entry 5). It was suggested that the
presence of water affected the enantioselectivity. Finally, we
tried to lower the catalyst loading. Unfortunately, the ee value
decreased (Table 2, entry 6), perhaps because of the
background reaction. When the reaction was conducted in
the absence of the catalyst, 50% of the product was obtained
after 24 h (Table 2, entry 7).
(CH2Cl)2
(CH2Cl)2
1.5
4
−20
a
Unless specified otherwise, the reaction was conducted with 2a (0.3
mmol), trichlorosilane (0.6 mmol), and catalyst (0.03 mmol) in 3 mL
of solvent. Yield based on 2a. The ee value was determined by chiral-
b
c
d
phase HPLC analysis. No reaction.
observed that 2a was rather active in this reaction system.
Catalyst 1a promoted the reaction efficiently to generate the
product in excellent yield with considerably good enantiose-
lectivity within only 4 h (Table 1, entry 1). Proline-derived
catalysts 1b and 1c were found to result in almost the same
yields and ee values (Table 1, entries 2 and 3, respectively). In
addition, trans-4-hydroxy-L-proline-derived catalyst 1d dis-
played a slightly higher enantioselectivity (Table 1, entry 4).
Introduction of methyl groups at the para position of the two
phenyl groups did not improve the enantioselectivity (Table 1,
entry 5). Therefore, 1d was determined to be the optimal
catalyst and employed in further investigations.
With the optimized conditions in hand, we explored the
scope of the Lewis base-catalyzed hydrosilylation of 4-
substituted 1-benzyl-1H-benzo[b][1,4]diazepin-2(3H)-ones
(Figure 2 and Table 3).
Subsequently, several solvents were evaluated. Among the
chlorinated solvents, 1,2-dichloroethane gave an ee value of up
to 90% (Table 1, entry 8). Surprisingly, the reactions in
chloroform and 1,1,1-trichloroethane failed to give any product
(Table 1, entries 6 and 7, respectively). Meanwhile, THF gave
the product with good yield and enantioselection (Table 1,
entry 10). Then the temperature of the reaction was also
investigated. When the reaction was conducted at 0 °C, the ee
value dropped slightly (Table 1, entry 11). When the
temperature was lowered to −20 °C, the ee value dropped
even more (Table 1, entry 12).
Figure 2. Various 4-substituted 1-benzyl-1H-benzo[b][1,4]diazepin-
2(3H)-ones hydrosilylated in this study.
9110
dx.doi.org/10.1021/jo201334n|J. Org. Chem. 2011, 76, 9109−9115

The Journal of Organic Chemistry
Note
chiral tetrahydro-1,5-benzodiazepines in excellent yields (up to
99%) and enantioselectivities (up to 98%). The absolute
configuration of one of the products has been determined to be
S by X-ray crystallographic analysis.
Table 3. Enantioselective Hydrosilylation of 4-Substituted 1-
Benzyl-1H-benzo[b][1,4]diazepin-2(3H)-ones 2d−u
a
Catalyzed by 1d
b
c
entry
2
3/yield (%)
3d/96
ee (%)
1
2d
2e
2f
96
96
94
94
5
EXPERIMENTAL SECTION
■
2
3e/98
3f/97
3g/97
3h/99
3i/98
3j/97
3k/97
3l/96
3m/98
3n/97
3o/98
3p/97
3q/98
3r/97
3s/99
3t/98
1
All the chlorinated solvents were distilled from CaH2. All H NMR
3
(300 MHz) and 13C NMR (75 MHz) spectra were recorded in CDCl3
using TMS as an internal standard. Catalysts 1a−e were prepared
according to the literature procedure.16i,m,o,p Compounds 2a17a and
2b−t17b,c were prepared according to the literature procedure.
General Procedure for the Preparation of Compounds 2b−
s. A mixture of o-phenylenediamine (10 mmol) and β-keto ester (15
mmol) in toluene (70 mL) was heated to reflux for 4−8 h, while water
was removed with a Dean-stark trap. Once the sample had cooled to
ambient temperature, the product crystallized and was collected by
filtration, washed with toluene (100 mL), dried, and used in the next
step without further purification.
4
2g
2h
2i
5
6
98
91
54
92
93
7
2j
8
2k
2l
9
10
11
12
13
14
15
16
17
18
2m
2n
2o
2p
2q
2r
2s
2t
d
94 (S)
92
97
To a solution of the product mentioned above (2 mmol) in DMF
(20 mL) were added cesium carbonate (0.78 g, 2.4 mmol) and methyl
iodide, allyl bromide, or benzyl bromide (2.4 mmol). The mixture was
stirred at ambient temperature for 2 h, then diluted with EtOAc (100
mL) and washed with water (100 mL), dried over Na2SO4, filtered,
and concentrated. The residue was purified by flash chromatography
(10:1 petroleum ether:ethyl acetate) to give pure compounds 2b−s.
1-Allyl-4-phenyl-1H-benzo[b][1,4]diazepin-2(3H)-one17d (2c):
95
74
89
72
e
2u
3u/97 (93:7 dr)
36
a
Unless specified otherwise, the reaction was conducted with 2 (0.25
mmol), trichlorosilane (0.5 mmol), and 1d (0.025 mmol) in 3 mL of
b
c
1
white solid; 68% yield; H NMR δ 3.04 (d, J = 11.9 Hz, 1H), 4.16
(CH2Cl)2 at −10 °C for 2−3 h. Yield based on 2. The ee value was
d
(d, J = 11.8 Hz, 1H), 4.41−4.55 (m, 2H), 5.10−5.17 (m, 2H), 5.80−
5.93 (m, 1H), 7.23−7.27 (m, 2H), 7.42−7.50 (m, 5H), 8.13−8.16 (m,
2H); 13C NMR δ 39.7, 50.5, 116.6, 121.9, 125.3, 125.9, 127.2, 127.6,
128.6, 130.9, 133.1, 134.2, 137.3, 141.8, 160.8, 165.2; HRMS (ESI)
calcd for C18H16N2OH 277.1335, found 277.1333.
determined by chiral-phase HPLC analysis. The absolute config-
uration was determined by X-ray crystallographic analysis. The ee
e
value of the major diastereomer.
Generally, 4-para- or meta-substituted phenyl substrates
afforded the products in excellent yields (>96%) with good
enantioselectivities (91−98%), no matter whether the sub-
stituents were electron-donating or electron-withdrawing
(Table 3, entries 1−4, 6, 7, 9−12). However, ortho substitution
of the phenyl group decreased the degree of enantioselection
dramatically. The o-methoxy substrate 2h generated almost
racemic product (Table 3, entry 5). Meanwhile, o-fluoro
substrate 2k afforded the product with a 54% ee value perhaps
because of less steric hindrance of fluoride compared with the
methoxy group (Table 3, entry 8). In addition, 1-benzyl-4-
(naphthalen-2-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one 2p
and 1-benzyl-4-(6-methoxynaphthalen-2-yl)-1H-benzo[b][1,4]-
diazepin-2(3H)-one 2q underwent the reaction smoothly to
afford the corresponding product with excellent yields and ee
values (Table 3, entries 13 and 14, respectively). 4-Heteroaryl
substrates were also employed in this transformation to afford
high yields of corresponding products with moderate to good
ee values (Table 3, entries 15 and 16). With regard to the
substitution of the benzene ring, the 7-chloro substrate gave the
corresponding product in excellent yields, but moderate ee
value (Table 3, entry 17). Finally, 3,4-disubstituted substrate 2u
was also subjected to the enantioselective hydrosilylation to
provide the desired product with excellent yields and good
diastereoselectivity (93:7 dr), but very poor enantioselectivity
(Table 3, entry 18). Furthermore, the absolute configuration of
product 3n was determined to be S by X-ray crystallographic
analysis (see the Supporting Information for details).
1-Benzyl-4-p-tolyl-1H-benzo[b][1,4]diazepin-2(3H)-one (2e):
white solid; 75% yield; H NMR δ 2.45 (s, 3H), 3.16 (d, J = 11.9
1
Hz, 1H), 4.24 (d, J = 11.8 Hz, 1H), 5.08−5.20 (m, 2H), 7.09−7.34
(m, 10H), 7.44 (dd, J1 = 1.6 Hz, J2 = 7.9 Hz, 1H), 8.7(d, J = 8.1 Hz,
2H); 13C NMR δ 21.3, 39.6, 51.0, 122.0, 125.3, 125.7, 126.5, 126.9,
127.1, 127.7, 128.4, 129.3, 133.9, 134.5, 137.1, 141.4, 142.1, 160.8,
165.7; HRMS (ESI) calcd for C23H20N2ONa 363.1468, found
363.1471.
1-Benzyl-4-(4-methoxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-
one (2f): white solid; 68% yield; 1H NMR δ 3.15 (d, J = 11.8 Hz, 1H),
3.90 (s, 3H), 4.22 (d, J = 11.8 Hz, 1H), 5.14 (s, 2H), 7.02 (dd, J1 = 1.9
Hz, J2 = 7.0 Hz, 2H), 7.09−7.33 (m, 8H), 7.43 (dd, J1 = 1.6 Hz, J2 =
7.9 Hz, 1H), 8.13−8.17 (m, 2H); 13C NMR δ 39.4, 51.0, 55.3, 113.9,
121.9, 125.3, 125.5, 126.5, 126.9, 127.1, 128.4, 129.5, 129.8, 133.9,
137.1, 142.2, 160.2, 162.0, 165.7; HRMS (ESI) calcd for C23H21N2O2
357.1598, found 357.1586.
1-Benzyl-4-(3-methoxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-
1
one (2g): white solid; 69% yield; H NMR δ 3.15 (d, J = 11.9 Hz,
1H), 4.21 (d, J = 11.7 Hz, 1H), 5.12 (s, 2H), 7.04−7.10 (m, 3H),
7.12−7.27 (m, 5H), 7.31 (dd, J1 = 1.3 Hz, J2 = 7.9 Hz, 1H), 7.38−7.45
(m, 2H), 7.69−7.72 (m, 2H); 13C NMR δ 39.9, 51.1, 55.3, 112.1,
117.6, 120.3, 122.0, 125.4, 126.0, 126.5, 127.0, 127.2, 128.5, 129.6,
134.0, 137.1, 138.7, 142.0, 159.8, 160.7, 165.6; HRMS (ESI) calcd for
C23H20N2O2Na 379.1417, found 379.1405.
1-Benzyl-4-(2-methoxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-
1
one (2h): white solid; 59% yield; H NMR δ 3.23 (d, J = 11.8 Hz,
1H), 3.88 (s, 3H), 4.22 (d, J = 11.9 Hz, 1H), 5.02 (d, J = 15.6 Hz, 1H),
5.31 (d, J = 15.6 Hz, 1H), 6.95−6.98 (m, 1H), 7.02 (dd, J1 = 0.8 Hz, J2
= 7.5 Hz, 1H), 7.09−7.34 (m, 8H), 7.39−7.45 (m, 2H), 7.47 (dd, J1 =
1.6 Hz, J2 = 7.5 Hz, 1H); 13C NMR δ 42.8, 50.9, 55.2, 111.1, 120.7,
122.1, 125.2, 126.0, 126.7, 127.0, 127.4, 128.4, 130.3, 131.7, 133.5,
137.2, 141.9, 158.0, 163.9, 166.6; HRMS (ESI) calcd for
C23H20N2O2Na 379.1417, found 379.1407.
In summary, we have developed a general, enantioselective
hydrosilylation of 4-substituted 1-benzyl-1H-benzo[b][1,4]-
diazepin-2(3H)-ones catalyzed by chiral Lewis base organo-
catalysts that are derived from trans-4-hydroxy-L-proline. This
transformation allows a mild and efficient synthesis of various
1-Benzyl-4-(3,4-dimethoxyphenyl)-1H-benzo[b][1,4]diazepin-
1
2(3H)-one (2i): white solid; 78% yield; H NMR δ 3.12 (d, J = 11.8
Hz, 1H), 4.20 (d, J = 11.7 Hz, 1H), 5.11 (s, 2H), 6.95 (d, J = 8.4 Hz,
1H), 7.08−7.27 (m, 7H), 7.30 (dd, J1 = 1.3 Hz, J2 = 8.0 Hz, 1H), 7.42
9111
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The Journal of Organic Chemistry
Note
(dd, J1 = 1.6 Hz, J2 = 7.9 Hz, 1H), 7.70 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz,
1H), 7.79 (d, J = 2.0 Hz, 1H); 13C NMR δ 39.3, 51.1, 55.9, 109.9,
110.4, 121.7, 121.9, 125.3, 125.6, 126.5, 126.9, 127.1, 128.4, 129.9,
134.0, 137.1, 142.1, 149.0, 151.8, 160.0, 165.6; HRMS (ESI) calcd for
C24H23N2O3 387.1703, found 387.1693.
142.3, 159.0, 160.7, 165.8; HRMS (ESI) calcd for C27H23N2O2
407.1754, found 407.1750.
1-Benzyl-4-(furan-2-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one
1
(2r): white solid; 66% yield; H NMR δ 3.13 (d, J = 11.9 Hz, 1H),
4.02 (d, J = 12.0 Hz, 1H), 5.10 (s, 2H), 6.58 (q, J = 1.7 Hz, 1H), 7.08−
7.29 (m, 9H), 7.44 (dd, J1 = 1.6 Hz, J2 = 8.0 Hz, 1H), 7.65 (dd, J1 = 0.6
Hz, J2 = 1.6 Hz, 1H); 13C NMR δ 39.2, 51.3, 112.3, 115.8, 122.2,
125.5, 126.1, 126.5, 127.0, 127.5, 128.5, 133.9, 137.0, 141.6, 146.3,
150.9, 151.2, 165.4; HRMS (ESI) calcd for C20H16N2O2Na 339.1104,
found 339.1107.
1-Benzyl-4-(4-fluorophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one
1
(2j): white solid; 73% yield; H NMR δ 3.15 (d, J = 11.8 Hz, 1H),
4.18 (d, J = 11.8 Hz, 1H), 5.12 (s, 2H), 7.08 (d, J = 6.9 Hz, 2H), 7.14−
7.26 (m, 7H), 7.32 (d, J = 8.0 Hz, 1H), 7.4 (dd, J1 = 1.3 Hz, J2 = 8.0
Hz, 1H), 8.14−8.18 (m, 2H); 13C NMR δ 39.8, 51.1, 115.5, 115.8,
122.1, 125.5, 126.1, 126.5, 127.1, 127.2, 128.5, 129.9, 130.0, 133.5,
133.5, 134.0, 137.0, 141.9, 159.7, 163.0, 165.5, 166.3; HRMS (ESI)
calcd for C22H18FN2O 345.1398, found 345.1394.
1-Benzyl-4-(2-fluorophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one
(2k): yellowish solid; 45% yield; 1H NMR δ 3.30 (d, J = 11.9 Hz, 1H),
4.20 (d, J = 11.9 Hz, 1H), 5.04 (d, J = 15.3 Hz, 1H), 5.28 (d, J = 15.6
Hz, 1H), 7.08−7.10 (m, 2H), 7.13−7.28 (m, 7H), 7.32−7.35 (m, 1H),
7.40−7.49 (m, 2H), 7.69−7.74 (m, 1H); 13C NMR δ 42.4, 42.5, 51.0,
116.3, 116.6, 122.2, 124.4, 124.4, 125.5, 126.5, 126.7, 127.1, 127.4,
128.5, 130.6, 130.7, 132.3, 132.4, 133.4, 137.0, 141.7, 159.5, 159.7,
162.9, 165.7; HRMS (ESI) calcd for C22H18FN2O 345.1398, found
345.1397.
1-Benzyl-4-(4-chlorophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one
(2l): white solid; 71% yield; 1H NMR δ 3.14 (d, J = 11.9 Hz, 1H), 4.17
(d, J = 11.9 Hz, 1H), 5.07−5.18 (m, 2H), 7.07−7.09 (m, 2H), 7.13−
7.26 (m, 5H), 7.32 (dd, J1 = 1.3 Hz, J2 = 7.9 Hz, 1H), 7.40−7.47 (m,
3H), 8.07−8.11 (m, 2H); 13C NMR δ 39.7, 51.1, 122.1, 125.5, 126.2,
126.5, 127.1, 127.2, 128.5, 128.8, 129.0, 134.0, 135.7, 137.0, 137.3,
141.8, 159.6, 165.4; HRMS (ESI) calcd for C22H18ClN2O 361.1102,
found 361.1098.
1-Benzyl-4-(thiophen-2-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one
1
(2s): white solid; 64% yield; H NMR δ 3.20 (d, J = 11.6 Hz, 1H),
4.12 (d, J = 11.3 Hz, 1H), 5.06−5.14 (m, 2H), 7.09−7.30 (m, 9H),
7.40 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 4.8 Hz, 1H), 7.74 (d, J = 3.1 Hz,
1H); 13C NMR δ 40.0, 51.4, 122.1, 125.5, 126.0, 126.5, 127.0, 127.3,
128.0, 128.5, 130.6, 131.7, 134.1, 137.1, 141.5, 143.3, 155.3, 165.2;
HRMS (ESI) calcd for C20H16N2OSNa 355.0876, found 355.0868.
1-Benzyl-7-chloro-4-phenyl-1H-benzo[b][1,4]diazepin-2(3H)-one
(2t). 2t was prepared from 7-chloro-4-phenyl-1H-benzo[b][1,4]-
diazepin-2(3H)-one17e according to the general procedure: colorless
oil; 38% yield; 1H NMR δ 3.13 (d, J = 11.9 Hz, 1H), 4.26 (d, J = 11.9
Hz, 1H), 5.02−5.18 (m, 2H), 7.05−7.13 (m, 3H), 7.20−7.25 (m, 4H),
7.43 (d, J = 2.4 Hz, 1H), 7.50−7.53 (m, 3H), 8.13−8.16 (m, 2H); 13
C
NMR δ 39.9, 51.0, 123.3, 126.0, 126.6, 126.7, 127.3, 127.8, 128.6,
128.7, 130.6, 131.4, 132.6, 136.7, 137.0, 143.1, 161.9, 165.4; HRMS
(ESI) calcd for C22H17ClN2ONa 383.0922, found 383.0922.
Synthesis of Compound 2u. To a solution of compound 2d
(0.626 g, 1.92 mmol) in THF (30 mL) was added t-BuOK (0.28 g, 2.5
mmol) at room temperature. The mixture was stirred for 10 min, and
then MeI (0.14 mL) was added dropwise. The mixture was stirred at
room temperature for 24 h. The reaction was quenched with saturated
NH4Cl (100 mL), and the mixture was extracted with DCM (3 × 80
mL), washed with brine, dried over Na2SO4, filtered, and concentrated.
The residue was purified by flash chromatography (10:1 petroleum
ether:ethyl acetate) to give a colorless oil (0.45 g, 69%).
1-Benzyl-4-(3-chlorophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one
1
(2m): white solid; 68% yield; H NMR δ 3.15 (d, J = 11.9 Hz, 1H),
4.17 (d, J = 11.9 Hz, 1H), 5.06−5.18 (m, 2H), 7.06−7.09 (m, 2H),
7.15−7.25 (m, 5H), 7.32 (dd, J1 = 1.5 Hz, J2 = 7.9 Hz, 1H), 7.40−7.50
(m, 3H), 9.97−8.01 (m, 1H), 8.15−8.17 (m, 1H); 13C NMR δ 39.7,
51.1, 122.1, 125.5, 125.8, 126.4, 126.6, 127.1, 127.2, 127.7, 128.5,
129.9, 131.0, 134.0, 134.9, 136.9, 139.0, 141.7, 159.4, 165.4; HRMS
(ESI) calcd for C22H18ClN2O 361.1102, found 361.1095.
1-Benzyl-3-methyl-4-phenyl-1H-benzo[b][1,4]diazepin-2(3H)-one
(2u): colorless oil; 69% yield; 1H NMR δ 1.03 (d, J = 7.5 Hz, 0.38H),
1.50 (d, J = 6.9 Hz, 2.62H), 3.33 (q, J = 6.9 Hz, 0.98H), 4.84 (q, J =
7.5 Hz, 0.12H), 5.02−5.15 (m, 1H), 5.26−5.37 (m, 1H), 7.08−7.50
(m, 12H), 7.77 (m, 2H), 8.05−8.08 (m, 0.19H); 13C NMR δ 9.8, 12.4,
42.7, 47.4, 51.0, 52.3, 121.2, 121.8, 125.0, 125.3, 125.9, 125.9, 126.0,
126.1, 126.3, 126.4, 126.6, 126.8, 126.8, 126.9, 127.1, 127.3, 127.7,
127.9, 128.3, 128.3, 128.4, 129.3, 130.5, 132.2, 133.6, 136.9, 137.0,
137.5, 138.6, 141.1, 164.8, 166.7, 168.1, 168.4; HRMS (ESI) calcd for
C23H20N2ONa 363.1468, found 363.1476.
General Procedure for the Enantioselective Hydrosilylation
of Compounds 2a−u. A solution of trichlorosilane in 1,2-dichloro-
ethane (1:4, v/v, 0.25 mL, 2.0 equiv) was added to a solution of the
catalyst (10 mol %) and compound 2 (0.25 mmol) in dry 1,2-
dichloroethane (3 mL) at −10 °C. The mixture was stirred at −10 °C
until the reaction was completed. Then the reaction was quenched
with a saturated aqueous solution of NaHCO3 (1 mL). The mixture
was filtered through a pad of Celite, washed with DCM (70 mL), dried
over Na2SO4, filtered, and concentrated. The residue was purified by
flash chromatography (5:1 petroleum ether:ethyl acetate) to afford the
pure product.
1-Benzyl-4-(4-bromophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-
1
one (2n): white solid; 65% yield; H NMR δ 3.14 (d, J = 11.9 Hz,
1H), 4.16 (d, J = 11.8 Hz, 1H), 5.06−5.18 (m, 2H), 7.06 (d, J = 6.7
Hz, 2H), 7.17−7.26 (m, 5H), 7.30 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 1.6
Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H), 8.00−8.03 (m, 2H); 13C NMR δ
39.6, 51.1, 122.1, 125.5, 125.9, 126.2, 126.5, 127.1, 127.2, 128.5, 129.2,
131.8, 134.0, 136.2, 137.0, 141.9, 159.7, 165.4; HRMS (ESI) calcd for
C22H18BrN2O 405.0597, found 405.0591.
1-Benzyl-4-(3-bromophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-
1
one (2o): white solid; 67% yield; H NMR δ 3.15 (d, J = 11.9 Hz,
1H), 4.17 (d, J = 11.9 Hz, 1H), 5.07−5.18 (m, 2H), 7.07−7.09 (m,
2H), 7.17−7.27 (m, 5H), 7.31−7.43 (m, 3H), 7.62−7.65 (m, 1H),
8.02−8.05 (m, 1H), 8.33 (t, J = 1.7 Hz, 1H); 13C NMR δ 39.7, 51.1,
122.1, 123.0, 125.5, 126.3, 126.4, 126.6, 127.1, 127.2, 128.5, 130.1,
130.6, 133.9, 133.9, 136.9, 139.2, 141.7, 159.3, 165.3; HRMS (ESI)
calcd for C22H18BrN2O 405.0597, found 405.0584.
1-Benzyl-4-(naphthalen-2-yl)-1H-benzo[b][1,4]diazepin-2(3H)-
1
one (2p): white solid; 71% yield; H NMR δ 3.24 (d, J = 11.9 Hz,
1H), 4.41 (d, J = 11.9 Hz, 1H), 5.09−5.20 (m, 2H), 7.09−7.28 (m,
7H), 7.35 (dd, J1 = 1.3 Hz, J2 = 8.0 Hz, 1H), 7.50 (dd, J1 = 1.5 Hz, J2 =
7.9 Hz, 1H), 7.54−7.59 (m, 2H), 7.87−8.03 (m, 3H), 8.36 (dd, J1 =
1.5 Hz, J2 = 8.6 Hz, 1H), 8.58 (s, 1H); 13C NMR δ 39.7, 51.1, 122.1,
124.2, 125.5, 126.0, 126.5, 126.6, 127.0, 127.3, 127.6, 127.6, 128.4,
128.5, 128.6, 129.2, 132.9, 134.5, 134.6, 137.1, 142.2, 160.7, 165.8;
HRMS (ESI) calcd for C26H21N2O 377.1648, found 377.1645.
1-Benzyl-4-(6-methoxynaphthalen-2-yl)-1H-benzo[b][1,4]-
diazepin-2(3H)-one (2q): white solid; 67% yield; 1H NMR δ 3.20 (d,
J = 11.6 Hz, 1H), 3.94 (s, 3H), 4.38 (d, J = 11.8 Hz, 1H), 5.13−5.15
(m, 2H), 7.09−7.26 (m, 9H), 7.33 (d, J = 8.0 Hz, 1H), 7.47 (dd, J1 =
1.3 Hz, J2 = 7.9 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 8.8 Hz,
1H), 8.32 (dd, J1 = 1.6 Hz, J2 = 8.7 Hz, 1H), 8.51 (s, 1H); 13C NMR δ
39.5, 51.1, 55.3, 105.7, 119.3, 122.1, 124.9, 125.4, 125.8, 126.6, 127.0,
127.2, 127.2, 128.3, 128.5, 128.5, 130.7, 132.5, 134.0, 136.1, 137.1,
The racemates were synthesized using DMF as a catalyst.
1-Methyl-4-phenyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-
one18 (3b): white solid; 97% yield; HPLC analysis 42% ee, Chiralcel
AD-H (80:20 hexane:iPrOH, 1.0 mL/min, tr‑major = 9.3 min, tr‑minor
7.9 min).
=
1-Allyl-4-phenyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-
1
one (3c): white solid; 96% yield; H NMR δ 2.65 (dd, J1 = 4.8 Hz, J2
= 12.7 Hz, 1H), 2.82 (dd, J1 = 10.3 Hz, J2 = 12.7 Hz, 1H), 3.68 (s,
1H), 4.45−4.52 (m, 2H), 5.13 (dd, J1 = 1.4 Hz, J2 = 10.3 Hz, 1H),
5.15−5.29 (m, 2H), 5.85−5.97 (m, 1H), 6.83−6.86 (m, 1H), 7.01−
7.13 (m, 2H), 7.26−7.36 (m, 6H); 13C NMR δ 41.0, 50.8, 65.4, 116.1,
122.4, 122.5, 122.9, 125.9, 126.5, 127.9, 128.7, 133.4, 135.0, 139.3,
144.3, 170.0; HPLC analysis 55% ee, Chiralcel AD-H (80:20
hexane:iPrOH, 1.0 mL/min, tr‑major = 9.7 min, tr‑minor = 8.5 min);
HRMS (ESI) calcd for C18H18N2ONa 301.1397, found 301.1392.
9112
dx.doi.org/10.1021/jo201334n|J. Org. Chem. 2011, 76, 9109−9115

The Journal of Organic Chemistry
Note
1-Benzyl-4-phenyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-
one (3d): white solid; 96% yield; 1H NMR δ 2.75 (dd, J1 = 4.9 Hz, J2
= 12.7 Hz, 1H), 2.92 (dd, J1 = 10.1 Hz, J2 = 12.6 Hz, 1H), 3.69 (s,
1H), 5.09 (dd, J1 = 4.8 Hz, J2 = 10.0 Hz, 1H), 5.16−5.22 (m, 2H), 6.85
(dd, J1 = 1.4 Hz, J2 = 6.8 Hz, 1H), 6.98−7.04 (m, 1H), 7.08−7.13 (m,
1H), 7.22−7.40 (m, 10H); 13C NMR δ 41.0, 51.4, 65.5, 122.6, 122.6,
123.0, 125.9, 126.5, 126.8, 127.0, 127.9, 128.3, 128.8, 134.9, 137.6,
139.4, 144.3, 170.5; HPLC analysis 96% ee, Chiralcel AD-H (80:20
hexane:iPrOH, 1.0 mL/min, tr‑minor = 13.8 min, tr‑major = 15.8 min);
127.6, 127.7, 128.2, 135.1, 137.6, 139.4, 139.8, 139.8, 160.6, 163.9,
170.2; HPLC analysis 91% ee, Chiralcel OD-H (80:20 hexane:iPrOH,
1.0 mL/min, tr‑major = 8.3 min, tr‑minor = 18.6 min); [α]20D +82.5 (c 0.86,
CHCl3); HRMS (ESI) calcd for C22H19FN2ONa 369.1374, found
369.1366.
1-Benzyl-4-(2-fluorophenyl)-4,5-dihydro-1H-benzo[b][1,4]-
1
diazepin-2(3H)-one (3k): colorless oil; 97% yield; H NMR δ 2.80−
2.89 (m, 2H), 3.57 (s, 1H), 5.03−5.19 (m, 2H), 5.40−5.44 (m, 1H),
6.82 (dd, J1 = 1.6 Hz, J2 = 7.6 Hz, 1H), 6.96−7.12 (m, 4H), 7.18−7.32
(m, 7H), 7.41−7.47 (m, 1H).; 13C NMR δ 39.0, 51.4, 58.1, 58.1,
115.3, 115.6, 122.7, 122.9, 124.2, 124.3, 126.5, 126.8, 127.1, 127.5,
127.5, 128.2, 129.1, 129.3, 130.1, 130.3, 135.3, 137.6, 139.6, 157.9,
161.1, 170.3; HPLC analysis 55% ee, Chiralcel AD-H (80:20
hexane:iPrOH, 1.0 mL/min, tr‑major = 10.9 min, tr‑minor = 22.1 min);
[α]20 +132.6 (c 0.632, CHCl3); HRMS (ESI) calcd for
D
C22H20N2ONa 351.1468, found 351.1463.
1-Benzyl-4-p-tolyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-
1
one (3e): colorless oil; 98% yield; H NMR δ 2.35 (s, 3H), 2.70 (dd,
J1 = 4.8 Hz, J2 = 12.6 Hz, 1H), 2.88 (dd, J1 = 10.2 Hz, J2 = 12.6 Hz,
1H), 3.62 (s, 1H), 5.03 (dd, J1 = 4.8 Hz, J2 = 10.1 Hz, 1H), 5.13 (s,
2H), 6.81 (dd, J1 = 1.5 Hz, J2 = 7.7 Hz, 1H), 7.06−7.07 (m, 1H),
7.13−7.16 (m, 1H), 7.18−7.21 (m, 6H), 7.25−7.30 (m, 4H); 13C
NMR δ 21.1, 41.1, 51.5, 65.3, 122.6, 122.6, 123.1, 125.9, 126.6, 126.9,
127.1, 128.4, 129.5, 135.0, 137.7, 137.7, 139.6, 141.4, 170.7; HPLC
analysis 96% ee, Chiralcel AD-H (80:20 hexane:iPrOH, 1.0 mL/min,
[α]20 +26.1 (c 1.072, CHCl3); HRMS (ESI) calcd for
D
C22H19FN2ONa 369.1374, found 369.1374.
1-Benzyl-4-(4-chlorophenyl)-4,5-dihydro-1H-benzo[b][1,4]-
1
diazepin-2(3H)-one (3l): white solid; 96% yield; H NMR δ 2.74−
2.76 (m, 2H), 3.66 (s, 1H), 4.98−5.03 (m, 1H), 5.08−5.17 (m, 2H),
6.83−7.00 (m, 1H), 7.00−7.08 (m, 2H), 7.19−7.30 (m, 10H); 13C
NMR δ 40.8, 51.4, 64.8, 122.5, 122.9, 123.0, 126.6, 126.8, 127.0, 127.4,
128.2, 128.8, 133.5, 135.1, 137.5, 139.3, 142.3, 170.1; HPLC analysis
t
r‑major = 15.1 min, tr‑minor = 12.1 min); [α]20D +155.3 (c 0.656, CHCl3);
HRMS (ESI) calcd for C23H22N2ONa 365.1624, found 365.1622.
1-Benzyl-4-(4-methoxyphenyl)-4,5-dihydro-1H-benzo[b][1,4]-
diazepin-2(3H)-one (3f): white solid; 97% yield; 1H NMR δ 2.70 (dd,
J1 = 4.9 Hz, J2 = 12.6 Hz, 1H), 2.85 (dd, J1 = 10.0 Hz, J2 = 12.6 Hz,
1H), 3.62 (s, 1H), 3.79 (s, 3H), 5.03 (dd, J1 = 4.9 Hz, J2 = 9.8 Hz,
1H), 5.03−5.12 (m, 2H), 6.78−6.87 (m, 3H), 6.94−7.08 (m, 2H),
7.18−7.32 (m, 8H); 13C NMR δ 41.2, 51.5, 55.3, 65.0, 114.1, 122.6,
122.7, 123.1, 126.6, 126.9, 127.1, 127.2, 128.4, 135.0, 136.6, 137.7,
139.6, 159.3, 170.7; HPLC analysis 94% ee, Chiralcel AD-H (80:20
hexane:iPrOH, 1.0 mL/min, tr‑major = 21.2 min, tr‑minor = 16.9 min);
92% ee, Chiralcel AD-H (80:20 hexane:iPrOH, 1.0 mL/min, tr‑major
=
14.5 min, tr‑minor = 16.9 min); [α]20D +100.6 (c 0.596, CHCl3); HRMS
(ESI) calcd for C22H19ClN2ONa 385.1078, found 385.1075.
1-Benzyl-4-(3-chlorophenyl)-4,5-dihydro-1H-benzo[b][1,4]-
1
diazepin-2(3H)-one (3m): white solid; 98% yield; H NMR δ 2.72−
2.84 (m, 2H), 3.63 (s, 1H), 4.98−5.18 (m, 3H), 6.82−6.85 (m, 1H),
7.00−7.08 (m, 2H), 7.18−7.31 (m, 10H); 13C NMR δ 40.7, 51.4, 64.9,
122.6, 122.9, 123.1, 124.2, 126.3, 126.6, 126.9, 127.1, 128.0, 128.3,
130.0, 134.5, 135.0, 137.5, 139.3, 145.9, 170.0; HPLC analysis 93% ee,
Chiralcel AD-H (80:20 hexane:iPrOH, 1.0 mL/min, tr‑major = 14.0 min,
[α]20 +149.2 (c 0.752, CHCl3); HRMS (ESI) calcd for
D
C23H22N2NaO2 381.1573, found 381.1564.
t
r‑minor = 15.8 min); [α]20D +133.2 (c 0.6, CHCl3); HRMS (ESI) calcd
1-Benzyl-4-(3-methoxyphenyl)-4,5-dihydro-1H-benzo[b][1,4]-
for C22H19ClN2ONa 385.1078, found 385.1078.
(S)-1-Benzyl-4-(4-bromophenyl)-4,5-dihydro-1H-benzo[b][1,4]-
diazepin-2(3H)-one (3n): white solid; 97% yield; H NMR δ 2.74−
1
diazepin-2(3H)-one (3g): white solid; 97% yield; H NMR δ 2.73
1
(dd, J1 = 4.9 Hz, J2 = 12.6 Hz, 1H), 2.87 (dd, J1 = 10.1 Hz, J2 = 12.6
Hz, 1H), 3.69 (s, 1H), 3.75 (s, 3H), 5.02 (dd, J1 = 4.9 Hz, J2 = 10.0 Hz,
1H), 5.07−5.18 (m, 2H), 6.82−6.90 (m, 4H), 6.97−7.07 (m, 2H),
7.18−7.30 (m, 7H); 13C NMR δ 40.9, 51.4, 55.0, 65.4, 111.4, 113.3,
118.1, 122.5, 122.6, 123.0, 126.5, 126.8, 126.9, 128.2, 129.8, 134.9,
137.6, 139.4, 145.9, 159.8, 170.5; HPLC analysis 95% ee, Chiralcel
2.76 (m, 2H), 3.63 (s, 1H), 4.96−5.03 (m, 1H), 5.08−5.17 (m, 2H),
6.08−6.82 (m, 1H), 6.83−7.08 (m, 2H), 7.15−7.29 (m, 8H), 7.43−
7.45 (m, 2H); 13C NMR δ 40.7, 51.4, 64.8, 121.7, 122.5, 122.9, 123.1,
126.6, 126.9, 127.1, 127.8, 128.2, 131.8, 135.1, 137.5, 139.3, 142.8,
170.1; HPLC analysis 94% ee, Chiralcel AD-H (80:20 hexane:iPrOH,
AD-H (80:20 hexane:iPrOH, 1.0 mL/min, tr‑major = 22.2 min, tr‑minor
=
1.0 mL/min, tr‑major = 15.3 min, tr‑minor = 18.6 min).; [α]20 +98.6 (c
D
17.1 min); [α]20 +116.2 (c 1.02, CHCl3); HRMS (ESI) calcd for
0.596, CHCl3); HRMS (ESI) calcd for C22H19BrN2ONa 429.0573,
found 429.0562.
D
C23H22N2O2Na 381.1573, found 381.1572.
1-Benzyl-4-(2-methoxyphenyl)-4,5-dihydro-1H-benzo[b][1,4]-
1-Benzyl-4-(3-bromophenyl)-4,5-dihydro-1H-benzo[b][1,4]-
1
1
diazepin-2(3H)-one (3h): white solid; 99% yield; H NMR δ 2.77
diazepin-2(3H)-one (3o): white solid; 98% yield; H NMR δ 2.72−
(dd, J1 = 5.3 Hz, J2 = 12.5 Hz, 1H), 2.91 (dd, J1 = 8.9 Hz, J2 = 12.5 Hz,
1H), 3.60 (brs, 1H), 3.83 (s, 3H), 5.12 (q, J = 15.6 Hz, 2H), 5.49 (dd,
J1 = 5.3 Hz, J2 = 8.9 Hz, 1H), 6.77 (dd, J1 = 1.5 Hz, J2 = 7.6 Hz, 1H),
6.89−7.06 (m, 4H), 7.17−7.39 (m, 8H); 13C NMR δ 38.3, 51.3, 55.1,
58.8, 110.3, 120.4, 122.3, 122.6, 122.6, 126.2, 126.3, 126.7, 127.0,
128.1, 128.6, 131.3, 135.2, 137.7, 139.9, 156.0, 171.1; HPLC analysis
2.82 (m, 2H), 3.66 (s, 1H), 4.95−5.02 (m, 1H), 5.07 (m, 2H), 6.82−
6.84 (m, 1H), 7.08−7.19 (m, 2H), 7.20−7.29 (m, 8H), 7.40−7.47 (m,
1H); 13C NMR δ 40.7, 51.4, 64.8, 122.6, 122.6, 122.9, 123.1, 124.6,
126.6, 126.9, 127.0, 128.3, 129.2, 130.3, 130.9, 135.0, 137.5, 139.2,
146.1, 170.0; HPLC analysis 92% ee, Chiralcel AD-H (80:20
hexane:iPrOH, 1.0 mL/min, tr‑major = 15.3 min, tr‑minor = 16.7 min);
5% ee, Chiralcel AD-H (80:20 hexane:iPrOH, 1.0 mL/min, tr‑major
=
[α]20 +62.9 (c 1.888, CHCl3); HRMS (ESI) calcd for
D
26.5 min, tr‑minor = 13.5 min); HRMS (ESI) calcd for C23H22N2O2Na
381.1573, found 381.1582.
C22H19BrN2ONa 429.0573, found 429.0562.
1-Benzyl-4-(naphthalen-2-yl)-4,5-dihydro-1H-benzo[b][1,4]-
diazepin-2(3H)-one (3p): white solid; 97% yield; H NMR δ 2.82
1
1-Benzyl-4-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-benzo[b][1,4]-
diazepin-2(3H)-one (3i): white solid; 98% yield; 1H NMR δ 2.73 (dd,
J1 = 5.2 Hz, J2 = 12.7 Hz, 1H), 2.83 (dd, J1 = 9.5 Hz, J2 = 12.7 Hz, 1H),
3.60 (s, 1H), 3.79 (s, 3H), 3.86 (s, 3H), 5.00 (dd, J1 = 5.2 Hz, J2 = 9.4
Hz, 1H), 5.06−5.20 (m, 2H), 6.82 (m, 4H), 6.98−6.70 (m, 1H),
7.06−7.07 (m, 1H), 7.19 (m, 7H); 13C NMR δ 29.5, 41.1, 51.3, 55.6,
55.8, 65.3, 109.1, 111.1, 118.0, 122.5, 122.6, 122.9, 126.4, 126.7, 126.9,
128.2, 135.0, 136.9, 137.6, 139.6, 148.5, 149.0, 170.5; HPLC analysis
(dd, J1 = 4.8 Hz, J2 = 12.6 Hz, 1H), 3.00 (dd, J1 = 10.0 Hz, J2 = 12.6
Hz, 1H), 3.73 (s, 1H), 5.09−5.20 (m, 2H), 5.23 (dd, J1 = 4.9 Hz, J2 =
9.8 Hz, 1H), 6.86 (dd, J1 = 1.5 Hz, J2 = 7.6 Hz, 1H), 6.99−7.13 (m,
2H), 7.22−7.53 (m, 9H), 7.76−7.85 (m, 4H); 13C NMR δ 40.8, 51.5,
65.5, 122.6, 123.0, 123.9, 124.7, 126.0, 126.2, 126.6, 126.8, 127.0,
127.6, 127.9, 128.3, 128.7, 133.0, 133.2, 134.9, 137.6, 139.5, 141.4,
170.4; HPLC analysis 97% ee, Chiralcel OD-H (80:20 hexane:iPrOH,
98% ee, Chiralcel AD-H (80:20 hexane:iPrOH, 1.0 mL/min, tr‑minor
=
1.0 mL/min, tr‑major = 19.2 min, tr‑minor = 27.8 min); [α]20 +187.8 (c
D
34.0 min, tr‑major = 19.6 min); [α]20 +63.7 (c 0.43, CHCl3); HRMS
0.86, CHCl3); HRMS (ESI) calcd for C26H22N2ONa 401.1608, found
401.1614.
D
(ESI) calcd for C24H24N2O3Na 411.1679, found 411.1679.
1-Benzyl-4-(4-fluorophenyl)-4,5-dihydro-1H-benzo[b][1,4]-
diazepin-2(3H)-one (3j): colorless oil; 1H NMR δ 2.71−2.83 (m,
2H), 3.63 (s, 1H), 5.00−5.05 (m, 2H), 5.12−5.17 (m, 1H), 6.83 (d, J
= 1.5 Hz, 1H), 6.98−7.04 (m, 4H), 7.19−7.29 (m, 8H); 13C NMR δ
41.0, 51.4, 64.8, 115.4, 115.6, 122.5, 122.8, 123.0, 126.6, 126.9, 127.0,
1-Benzyl-4-(6-methoxynaphthalen-2-yl)-4,5-dihydro-1H-benzo-
1
[b][1,4]diazepin-2(3H)-one (3q): white solid; 98% yield; H NMR δ
2.78 (dd, J1 = 4.8 Hz, J2 = 12.8 Hz, 1H), 2.99 (dd, J1 = 10.2 Hz, J2 =
12.7 Hz, 1H), 3.69 (s, 1H), 3.91 (s, 3H), 5.08−5.21 (m, 3H), 6.84 (dd,
J1 = 1.4 Hz, J2 = 7.7 Hz, 1H), 6.96−7.37 (m, 11H), 7.67−7.71 (m,
9113
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Note
3H); 13C NMR δ 41.0, 51.6, 55.3, 65.6, 105.7, 119.2, 122.6, 122.7,
123.1, 124.5, 124.6, 126.7, 126.9, 127.1, 127.6, 128.4, 128.7, 129.5,
134.2, 135.0, 137.8, 139.4, 139.6, 157.9, 170.6; HPLC analysis 95% ee,
Chiralcel AD-H (80:20 hexane:iPrOH, 1.0 mL/min, tr‑major = 29.3 min,
W.; Miranda, M.; Rodgers, J. D.; Hitchens, T. K.; Leo, G.; Gauthier, D.
A.; Ho, C. Y.; Scott, M. K.; De Clercq, E.; Pauwels, R.; Andries, K.;
Janssen, M. A. C.; Janssen, P. A. J. Med. Chem. 1995, 38, 771−793.
(c) Castro, J. L.; Broughton, H. B.; Russell, M. G. N.; Rathbone, D.;
Watt, A. P.; Ball, R. G.; Chapman, K. L.; Patel, S.; Smith, A. J.;
Marshall, G. R.; Matassa, V. G. J. Med. Chem. 1997, 40, 2491−2501.
tr‑minor = 24.0 min); [α]20 +182.9 (c 0.886, CHCl3); HRMS (ESI)
D
calcd for C27H24N2O2Na 431.1730, found 431.1723.
1-Benzyl-4-(furan-2-yl)-4,5-dihydro-1H-benzo[b][1,4]diazepin-
(2) Eltze, M.; Gonne, S.; Riedel, R.; Schlotke, B.; Schudt, C.; Simon,
̈
1
2(3H)-one (3r): white solid; 97% yield; H NMR δ 2.77 (dd, J1 = 5.4
W. A. Eur. J. Pharmacol. 1985, 112, 211−224.
(3) Hofmann, H. P.; Ereiskott, H.; Kretzschmar, R. Naunyn-
Schmiedeberg’s Arch. Pharmacol. 1982, 32 (Suppl.), R44.
Hz, J2 = 12.6 Hz, 1H), 2.90 (dd, J1 = 10.5 Hz, J2 = 12.6 Hz, 1H), 3.69
(s, 1H), 5.09−5.14 (m, 3H), 6.14 (d, J = 3.2 Hz, 1H), 6.29−6.31 (m,
1H), 6.75−6.76 (m, 1H), 6.98−7.00 (m, 2H), 7.15−7.36 (m, 7H); 13
C
(4) Muller, W. E.; Groh, B.; Bub, O. Pharmacopsychiatry 1986, 10,
̈
NMR δ 37.6, 51.4, 58.6, 105.4, 110.2, 122.7, 123.4, 123.5, 126.5, 126.9,
314−315.
127.0, 128.3, 136.0, 137.6, 138.6, 142.0, 155.7, 170.5; HPLC analysis
(5) Nicholson, A. N.; Stone, B. M.; Clarke, C. H. Br. J. Clin.
Pharmacol. 1977, 4, 567−572.
75% ee, Chiralcel AD-H (80:20 hexane:iPrOH, 1.0 mL/min, tr‑major
=
19.3 min, tr‑minor = 12.9 min); [α]20D +187.5 (c 0.778, CHCl3); HRMS
(ESI) calcd for C20H18N2O2Na 341.1260, found 341.1254.
(6) Kruse, H. Drug Dev. Res. 1982, 2 (Suppl.), 145−151.
(7) Claremon, D. A.; Frieidinger, R. M.; Liverton, N.; Selnick, H. G.;
Smith, G. R. PCT Int. Appl. WO 9640656, 1996.
1-Benzyl-4-(thiophen-2-yl)-4,5-dihydro-1H-benzo[b][1,4]-
1
diazepin-2(3H)-one (3s): white solid; 99% yield; H NMR δ 2.79−
(8) Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.;
Labaudiniere, R. F. J. Comb. Chem. 2000, 2, 513−521.
(9) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.;
Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem.
1988, 31, 2235−2246.
(10) Lee, J.; Rivero, D. R. A. J. Org. Chem. 1999, 64, 3060−3065.
(11) (a) Wang, X.; Zou, X.; Li, J.; Hu, Q. Synlett 2005, 3042−3046.
(b) Wang, X.; Li, Z.; Zhu, X.; Mao, H.; Zou, X.; Kong, L.; Li, X.
Tetrahedron 2008, 64, 6510−6521.
2.91 (m, 2H), 3.66 (s, 1H), 5.06−5.18 (m, 2H), 5.38 (dd, J1 = 6.1 Hz,
J2 = 9.2 Hz, 1H), 6.81−6.83 (m, 1H), 6.95−7.04 (m, 4H), 7.18−7.30
(m, 7H); 13C NMR δ 41.6, 51.4, 61.0, 122.9, 123.4, 123.6, 123.6,
124.5, 126.6, 126.8, 126.9, 127.1, 128.1, 128.4, 135.7, 137.6, 138.3,
147.5, 170.2; HPLC analysis 90% ee, Chiralcel AD-H (80:20
hexane:iPrOH, 1.0 mL/min. tr‑major = 20.2 min, tr‑minor = 16.5 min);
[α]20 +174.5 (c 0.638, CHCl3); HRMS (ESI) calcd for
D
C20H18N2OSNa 357.1022, found 357.1032.
1-Benzyl-7-chloro-4-phenyl-4,5-dihydro-1H-benzo[b][1,4]-
1
diazepin-2(3H)-one (3t). colorless oil; 98% yield; H NMR δ 2.72
(dd, J1 = 4.6 Hz, J2 = 12.8 Hz, 1H), 2.88 (dd, J1 = 10.2 Hz, J2 = 12.8
Hz, 1H), 3.72 (s, 1H), 5.02−5.15 (m, 3H), 6.82 (d, J = 2.3 Hz, 1H),
6.91−6.95 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.22−7.36 (m, 10H);
13C NMR δ 40.8, 51.4, 65.2, 121.9, 122.3, 124.1, 125.8, 127.0, 128.1,
128.4, 128.9, 131.3, 133.2, 137.2, 140.7, 143.8, 170.2; HPLC analysis
(12) (a) Pathak, R.; Nag, S.; Batra, S. Synthesis 2006, 4205−4211.
(b) Liu, G.; Zhao, H. Y. J. Comb. Chem. 2007, 9, 1164−1176. (c) Rida,
M.; El Meslouhi, H.; Ahabchane, N. H.; Garrigues, B.; Es-Safi, N.;
Essassi, E. M. Open Org. Chem. J. 2008, 2, 83−87. (d) Hoyt, S. B.;
London, C.; Wyvratt, M. J.; Fisher, M. H.; Cashen, D. E.; Felix, J. P.;
Garcia, M. L.; Li, X.; Lyons, K. A.; MacIntyre, D. E.; Martin, W. J.;
Priest, B. T.; Smith, M. M.; Warren, V. A.; Williams, B. S.;
Kaczorowski, G. J.; Parson, W. H. Bioorg. Med. Chem. Lett. 2008, 18,
1963−1966.
73% ee, Chiralcel AD-H (80:20 hexane:iPrOH, 1.0 mL/min, tr‑major
=
17.0 min, tr‑minor = 14.2 min).; [α]20 +75.3 (c 0.96, CHCl3); HRMS
D
(ESI) calcd for C22H19ClN2ONa 385.1078, found 385.1071.
1-Benzyl-3-methyl-4-phenyl-4,5-dihydro-1H-benzo[b][1,4]-
diazepin-2(3H)-one (3u): white solid; 97% yield; 1H NMR δ 0.82 (d,
J1 = 6.8 Hz, 3H), 3.13−3.22 (m, 1H), 3.66 (s, 1H), 4.72 (d, J = 6.4 Hz,
1H), 5.00 (d, J = 15.3 Hz, 1H), 5.32 (d, J = 15.3 Hz, 1H), 6.94−6.98
(m, 1H), 7.04−7.11 (m, 2H), 7.22−7.37 (m, 10H); 13C NMR δ 12.8,
38.9, 51.6, 72.7, 122.1, 122.7, 123.3, 126.3, 126.8, 127.5, 128.0, 128.2,
128.4, 136.5, 137.9, 139.6, 140.9, 172.7; HPLC analysis 93:7 dr, 36%
ee, Chiralcel AD-H (80:20 hexane:iPrOH, 1.0 mL/min, t = 5.3, 7.0,
8.0, 8.6 min); HRMS (ESI) calcd for C23H23N2O 343.1805, found
343.1800.
(13) Rueping, M.; Merino, E.; Koenigs, R. M. Adv. Synth. Catal.
2010, 352, 2629−2634.
(14) For reviews on Lewis base activation of Lewis acids, see:
(a) Rendler, S.; Oestreich, M. Synthesis 2005, 1727−1747. (b) Orito,
Y.; Nakajima, M. Synthesis 2006, 1391−1401. (c) Denmark, S. E.;
Beutner, G. L. Angew. Chem. 2008, 120, 1584−1663. Angew. Chem.,
Int. Ed. 2008, 47, 1560−1638.
̌
́
(15) For reviews, see: (a) Kocovsky, P.; Malkov, A. V. Chiral Lewis
Bases as Catalysts. In Enantioselective Organocatalysis; Dalko, P. I., Ed.;
Wiley-VCH: Weinheim, Germany, 2007; p 255. (b) Kagan, H. B.
Organocatalytic Enantioselective Reduction of Olefins, Ketones and
Imines. In Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley-
VCH: Weinheim, Germany, 2007; p 391. (c) Guizzetti, S.; Benaglia,
M. Eur. J. Org. Chem. 2010, 5529−5541.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all new compounds and chiral
HPLC analysis spectra and single-crystal X-ray diffraction data
of compound 3n. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) For representative examples, see: (a) Malkov, A. V.; Liddon, A.
J. P. S.; Ramirez-Lopez, P.; Bendova, L.; Haigh, D.; Koco
Angew. Chem. 2006, 118, 1460−1463. Angew. Chem., Int. Ed. 2006, 45,
1432−1435. (b) Malkov, A. V.; Stoncius, S.; Kocovsky, P. Angew.
Chem. 2007, 119, 3796−3798. Angew. Chem., Int. Ed. 2007, 46, 3722−
3724. (c) Malkov, A. V.; Stoncius, S.; Vrankova, K.; Arndt, M.;
Koco
vsky, P. Chem.Eur. J. 2008, 14, 8082−8085. (d) Malkov, A. V.;
Vrankova,
̌
́
vsky, P.
AUTHOR INFORMATION
Corresponding Author
*E-mail: xmzhang@cioc.ac.cn; chembliu@scu.edu.cn.
̌
̌
́
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̌
́
̌
́
́
̌ ̌
́
K.; Stoncius, S.; Kocovsky, P. J. Org. Chem. 2009, 74, 5839−
ACKNOWLEDGMENTS
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5849. (e) Pei, D.; Wang, Z. Y.; Wei, S. Y.; Zhang, Y.; Sun, J. Org. Lett.
2006, 8, 5913−5915. (f) Zhou, L.; Wang, Z.; Wei, S.; Sun, J. Chem.
Commun. 2007, 2977−2979. (g) Pei, D.; Zhang, Y.; Wei, S. Y.; Wang,
M.; Sun, J. Adv. Synth. Catal. 2008, 350, 619−632. (h) Wu, X. J.; Li, Y.;
Wang, C.; Zhou, L.; Lu, X. X.; Sun, J. Chem.Eur. J. 2011, 17, 2846−
2848. (i) Onomura, O.; Kouchi, Y.; Iwasaki, F.; Matsumura, Y.
Tetrahedron Lett. 2006, 47, 3751−3754. (j) Guizzetti, S.; Benaglia, M.;
Rossi, S. Org. Lett. 2009, 11, 2928−2931. (k) Guizzetti, S.; Benaglia,
M.; Bonsignore, M.; Raimondi, L. Org. Biomol. Chem. 2011, 9, 739−
743. (l) Sugiura, M.; Kumahara, M.; Nakajima, M. Chem. Commun.
We are grateful for financial support from the National Sciences
Foundation of China (20972155) and the National Basic
Research Program of China (973 Program) (2010CB833300).
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