Facile synthesis of 1,4-benzodiazepin-3-ones from o-bromobenzylamines and amino acids via a cascade coupling/condensation process

Article abstract of DOI:10.1016/j.tet.2009.06.104

CuI-catalyzed coupling of 2-bromobenzylamines and α-amino acids and subsequent condensative cyclization (directly or mediated with DPPA) provides 1,4-benzodiazepin-3-ones in moderate yields. Using l-proline and l-valine as the starting materials enantiopu

Full text of DOI:10.1016/j.tet.2009.06.104

Tetrahedron 65 (2009) 8956–8960
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journal homepage: www.elsevier.com/locate/tet
Facile synthesis of 1,4-benzodiazepin-3-ones from o-bromobenzylamines
and amino acids via a cascade coupling/condensation process
,
b,
*
Hexiang Wang a, Yongwen Jiang b, Kun Gao a , Dawei Ma
*
a State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
CuI-catalyzed coupling of 2-bromobenzylamines and a-amino acids and subsequent condensative cy-
Received 29 April 2009
Received in revised form 16 June 2009
Accepted 26 June 2009
clization (directly or mediated with DPPA) provides 1,4-benzodiazepin-3-ones in moderate yields. Using
-proline and -valine as the starting materials enantiopure products are obtained although partial ra-
cemization occurs for other amino acids.
L
L
Available online 2 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cascade reaction
Coupling
1,4-Benzoazepin-3-one
Heterocycles
Amino acids
1. Introduction
addition, several 1,4-benzoazepin-3-ones1e–g such as compound 3
have been employed as -turn mimetics for drug discovery.
b
1,4-Benzodiazepin-3-one is an unique core structure for de-
veloping bioactive molecules.1 The known compounds with this
skeleton include SB-214857 (Fig.1) that has been used for treatment
of cardiovascular diseases in clinic trials,1a,b vasopressin V2 receptor
agonist 1,1c and mitochondrial F1F0 ATP hydrolase inhibitor 2.1d In
For most existing approaches to 1,4-benzoazepin-3-ones, the
closure of the hetereocyclic ring is the key step.1–4 One method is
via the intramolecular nucleophilic aromatic substitution.1a,2 To
accelerate the substitution, a carboxyl ester or nitro group is usually
placed para or ortho to the leaving group, which is only suitable for
preparing some special 1,4-benzoazepin-3-ones. Another popular
method is through the formation of the amide bond, which requires
to prepare available precursor through multiple steps reactions.1h,3
Recently developed metal-catalyzed N-arylation5,6 provides an
alternative approach to 1,4-benzoazepin-3-ones. Using Pd/bidentate
phosphine as a catalyst, Ferraccioli and co-workers achieved seven-
membered ring formation through an intramolecular N-arylation.7
Our group revealed that CuI-catalyzed intramolecular N-arylation of
an aspartic acid derivative proceeded smoothly to provide a pre-
cursor for assembly of SB-214857.6b In this paper, we wish to report
a one-pot procedure to 1,4-benzoazepin-3-ones, which relies on an
intermolecular N-arylation and subsequent condensative cyclization
of N-substituted 2-bromobenzyl-amines and amino acids.
Me
O
N
Me
O
N
N
O
N
Me
N
H
O
CO2H
HN
xHCl
SB-214857
Cl
N
1
HO
t-Bu
N
O
H
N
N
O
N
2. Results and discussion
N
H2N
Ph
CO2H
HN
2
3
2.1. CuI-catalyzed coupling reaction of 2-halobenzylamines
with L-proline and subsequent condensative cyclization
Figure 1. Structures of some 1,4-benzoazepin-3-ones.
As indicated in Table 1, we started our investigations by carrying
* Corresponding authors.
E-mail address: madw@mail.sioc.ac.cn (K. Gao).
out a coupling reaction of N-benzyl-2-bromo-benzylamine with
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.104

H. Wang et al. / Tetrahedron 65 (2009) 8956–8960
8957
Table 2
L
-proline.6a It was found that under the effect of 10 mol % CuI and
Synthesis of 1,4-benzoazepin-3-ones from other amino acidsa
Cs2CO3, this reaction worked in DMF at 90 ꢀC to give the coupling/
condensative cyclization product directly. However, the desired
product 5a was isolated in only moderate yield (entry 1). We
wondered if the condensative cyclization was a rate-determining
step for this process, and therefore decided to improve the yield by
increasing reaction temperatures after the coupling step was
completed. To our delight, a 64% yield was observed by heating at
110 ꢀC (entry 2).
H
N
R'
R
1. 10 mol % CuI, amino acid
X
Cs2CO3, DMF, 90 °C
O
H
N
2. DPPA, 0-5 °C
N
Y
Y
R
4
6
Entry
1
Product
Yieldb (%)
H
N
Table 1
CuI-catalyzed coupling reaction of 2-halobenzyl-amines with
sequent condensative cyclizationa
L-proline and sub-
O
58
N
R
Y
10 mol % CuI, L-proline
Cs2CO3, DMF, 90 °C
6a: Y = H, R = Bn
X
N
2
3
4
5
6
7
6b: Y¼NO2, R¼Bn
6c: Y¼OMe, R¼Bn
6d: Y¼F, R¼Bn
44
35
48
60
52
57
H
O
N
N
then 110 °C
Y
R
Y
4
R
6e: Y¼CO2Me, R¼Bn
6f: Y¼H, R¼allyl
6g: Y¼H, R¼n-Bu
5
Entry
X
Y
R
Product
Yieldb (%)
1c
2
3
4
Br
Br
I
Br
Br
Br
Br
Br
Br
H
H
H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
allyl
n-Bu
5a
5a
5a
5b
5c
5d
5e
5f
47
64
63
48
12
55
65
60
63
H
N
8
9
O
N
50c
NO2
OMe
CO2Me
F
H
H
Bn
5
6h
6d
7
H
N
Ph
8d
9d
51
O
5g
N
a
Reaction conditions: 2-halobenzylamine (2 mmol),
L
-proline (3 mmol), CuI
Bn
6i
(0.2 mmol), Cs2CO3 (2 mmol), DMF (4 mL), 90 ꢀC, 21 h; 110 ꢀC, 24 h.
b
Isolated yield.
c
The reaction was conducted at 90 ꢀC for 24 h.
H
N
OH
d
The coupling was conducted at 90 ꢀC for 21 h, then DPPA (3 mmol), 0–5 ꢀC, 8 h.
10
46
40
O
N
Switching aryl bromide to aryl iodide gave a similar result (entry 3),
which led us to utilize aryl bromides as our substrates (aryl chlo-
rides have not be attempted) in the subsequent studies. Other 2-
bromobenzylamines with a substituent group on the benzene ring
were also compatible with this process, delivering the corre-
sponding tricyclic compounds 5b–5e (entries 4–7). But the elec-
tronic-rich substrate provided low yield (entry 5), indicating that
the electronic nature at the benzene ring plays an important role
for this process. Next, we tried to change N-substituents, and found
that both allyl and n-butyl substituted products were isolated in
satisfactory yields (entries 8 and 9). Noteworthy is that similar
yields could be observed if the condensative cyclization step was
prompted by adding diphenyl phosphoryl azide (DPPA), after cou-
Bn
6j
H
N
11
NH
O
N
Bn
6k
a
Reaction conditions: 2-bromobenzylamine (2 mmol), amino acid (3 mmol), CuI
(0.2 mmol), Cs2CO3 (2 mmol), DMF (4 mL), 90 ꢀC, 24 h, then DPPA (3 mmol), 0–5 ꢀC,
8 h.
b
Isolated yield.
c
The ee value for 6h was only 49%.
pling of 2-bromobenzylamines and L-proline (entries 6, 8 and 9).
process, as evident from that 1,4-benzoazepin-3-ones 6f and 6g
were isolated in 52–57% yields (entries 6 and 7). Four other amino
acids were also compatible with this process (entries 8–11),
2.2. Elaboration of 1,4-benzoazepin-3-ones via coupling with
other amino acids
although L-tryptophane and L-tyrosine gave slightly lower yields.
Thus, we concluded that this method is suitable for preparing
a considerable range of substituted 1,4-benzoazepin-3-ones.
To further explore the reaction scope, other
tested under the optimized reaction conditions and the results are
summarized in Table 2. When -valine was employed, coupling step
a-amino acids were
L
worked well. However, no direct condensative cyclization product
was determined, and this step had to be conducted under the ac-
tion of DPPA (entry 1). This difference illustrated that the coupling
2.3. Determination of the optical purity of the 1,4-
benzodiazepin-3-ones
product from
L
-proline might have a favored conformation for di-
Because the coupling reaction was carried in the presence of
base and at relatively high reaction temperatures, we wondered if
racemization at this step. Accordingly, we attempted to determine
the enantiomer excess values for all 1,4-benzoazepin-3-ones.
However, only some of them were found applicable to chiral HPLC
determination, and their enantiomer excess values were indicated
in Table 3. It looked that no racemization took place for both
rect condensative cyclization step. Using this two-step procedure,
several 2-bromobenzylamines bearing electron-donating and
electron-withdrawing groups were then checked. We were pleased
to find that they provided the corresponding 1,4-benzoazepin-3-
ones in moderate yields (entries 2–5). The additional functional
groups in the benzene ring are ready for further conversions, and
therefore allowing assembly of more diverse 1,4-benzoazepin-3-
ones. Changing N-substituent had no influence to the reaction
L-proline and
L-valine derived products, as they have greater than
99% ee. However, some racemization occurred for
L-phenyl alanine

8958
H. Wang et al. / Tetrahedron 65 (2009) 8956–8960
derived product and serious racemization was observed in case of
L
-
1H), 5.17 (d, J¼15.0 Hz, 1H), 5.07–5.10 (m, 1H), 4.19 (d, J¼15.0 Hz,
1H), 3.71 (d, J¼16.5 Hz, 1H), 3.29–3.38 (m, 2H), 2.65–2.70 (m, 1H),
alanine. These results demonstrated that steric hindrance plays an
essential role for prevention of racemization. This trend is consis-
tent to that observed in CuI-catalyzed coupling reaction of aryl
halides and amino acids.6a
1.95–2.13 (m, 3H); 13C NMR (100 MHz, CDCl3)
d 170.1, 146.2, 137.3,
129.4, 129.2, 128.5 (2C), 128.1 (2C), 127.3, 119.0, 115.8, 113.2, 58.7,
51.5, 49.6, 49.5, 28.0, 23.5; ESI-MS m/z 293.0 (MþH)þ; ESI-HRMS
calcd for C19H21N2O (MþH)þ m/z 293.1648, found 293.1645; HPLC:
chiracel IB-H column (250 mm); detected at 254 nm; n-hexane/i-
propanol: 90/10; flow: 0.7 mL/min; retention time: 16.5 min (ma-
jor), 15.6 min (minor), ee¼99%.
Table 3
The ee values of some 1,4-benzoazepin-3-onesa
Compound
5a
6f
6g
6i
6h
ee (%)
99
99
99
90
49
a
4.2.2. (S)-5-Benzyl-8-nitro-3,3a,5,6-tetrahydro-1H-benzo-
Determined by chiral HPLC.
[f]pyrrolo[1,2-a][1,4]diazepin-4(2H)-one (5b)
1H NMR (300 MHz, CDCl3)
d
8.01 (dd, J¼9.0, 2.7 Hz, 1H), 7.62 (d,
3. Conclusions
J¼2.7 Hz, 1H), 7.24–7.31 (m, 5H), 6.44 (d, J¼9.0 Hz, 1H), 5.21–5.30
(m, 2H), 5.02 (d, J¼14.7 Hz, 1H), 4.36 (d, J¼14.7 Hz, 1H), 3.79 (d,
J¼16.8 Hz, 1H), 3.41–3.52 (m, 2H), 2.72–2.83 (m, 1H), 2.00–2.19 (m,
In summary, we have developed a CuI-catalyzed cascade process
to synthesize 2-substituted 1,4-benzodiazepin-3-one. Changing the
substituents at the benzene ring and N-position of 2-bromo-
benzylamines, and their amino acid coupling partners were dem-
onstrated possible. Although in some cases partial racemization
3H); 13C NMR (100 MHz, DMSO-d6)
d 168.5, 151.1, 136.5, 129.3, 128.7
(2C), 128.3, 128.0, 127.8, 126.0, 125.6, 118.5, 112.5, 59.3, 50.7, 50.6,
49.6, 28.1, 23.4; EIMS m/z 333 (Mþ); EI-HRMS calcd for C19H19N3O3
(Mþ) m/z 333.1426, found 337.1433.
occurred, enantiopure products could be obtained by using
L-proline
and -valine as the coupling partners. The present result provides
L
another example to illustrate the potential for assembling hetero-
cycles by using recently developed Ullmann-type coupling reaction
conditions.8
4.2.3. (S)-5-Benzyl-8-methoxy-3,3a,5,6-tetrahydro-1H-benzo[f]-
pyrrolo[1,2-a][1,4]diazepin-4(2H)-one (5c)
1H NMR (300 MHz, CDCl3)
d
7.23–7.35 (m, 5H), 6.74 (dd, J¼8.7,
2.7 Hz, 1H), 6.46 (d, J¼8.7 Hz, 1H), 6.37 (d, J¼2.7 Hz, 1H), 5.23 (d,
J¼16.5 Hz, 1H), 5.12 (d, J¼15.0 Hz, 1H), 4.91–4.94 (m, 1H), 4.24 (d,
J¼15.0 Hz, 1H), 3.77 (d, J¼16.5 Hz, 1H), 3.69 (s, 3H), 3.22–3.36 (m,
2H), 2.62–2.67 (m, 1H), 1.93–2.12 (m, 3H); 13C NMR (100 MHz,
4. Experimental
4.1. General remarks
CDCl3)
d 170.5, 150.6, 140.8, 137.3, 128.6, 128.4, 128.2, 128.1, 127.4,
All solvents were purified and dried prior to use. Optical rotations
were measured by used a Perkin–Elmer 241MC polarimeter in the
solvent indicated. 1H NMR spectra were recorded at Bruker Avance
300 MHz, and 13C NMR spectra were recorded at Bruker Avance
120.5, 115.9, 114.1, 114.0, 59.3, 55.9, 51.4, 49.9, 49.7, 28.1, 23.5. EIMS
m/z 322 (Mþ); EI-HRMS calcd for C20H22N2O2 (Mþ) m/z 322.1681,
found 322.1683.
400 MHz, and assigned in parts per million (
shifts were given on the scale (ppm) and were referenced to in-
ternal TMS. Reference peaks for chloroform in 13C NMR spectra were
set at 77.0 ppm. For DMSO-d6, the reference peaks in 1H NMR and 13
d
). 1H NMR chemical
4.2.4. (S)-Methyl-5-benzyl-4-oxo-2,3,3a,4,5,6-hexahydro-1H-
benzo[f]pyrrolo[1,2-a][1,4]diazepin-e-8-carboxylate (5d)
d
1H NMR (300 MHz, CDCl3)
d
7.79 (dd, J¼8.7, 1.8 Hz, 1H), 7.46 (d,
C
J¼1.8 Hz, 1H), 7.25–7.33 (m, 5H), 6.45 (d, J¼8.7 Hz, 1H), 5.26 (d,
J¼16.5 Hz, 1H), 5.14–5.19 (m, 2H), 4.17 (d, J¼14.7 Hz, 1H), 3.84 (s,
3H), 3.76 (d, J¼16.5 Hz, 1H), 3.36–3.43 (m, 2H), 2.68–2.73 (m, 1H),
NMR spectra were set at 2.50 ppm and 40.0 ppm, respectively. Low-
resolution mass spectra were recorded on a GILENT5973 instrument
(EI) and a LCMS-2010EV instrument (ESI). High-resolution mass
spectra were recorded on an IonSpec 4.7 Tesla FTMS instrument.
Silica gel plate GF254 were used for thin layer chromatography (TLC)
and silica gel H or 300–400 mesh were used for flash column
chromatography. Enantiomeric excesses were determined by HPLC
using a Daicel Chiralpak IB or IC-H column (wavelength¼254 or
214 nm) with hexane/i-PrOH as the eluent.
2.00–2.14 (m, 3H); 13C NMR (100 MHz, CDCl3)
d 169.5, 167.2, 150.0,
137.1, 131.6, 131.4, 128.9 (2C), 128.4 (2C), 127.8, 118.5, 117.0, 112.8,
59.1, 51.8, 51.4, 50.3, 49.7, 28.3, 23.7. EIMS m/z 350 (Mþ); EI-HRMS
calcd for C21H22N2O3 (Mþ) m/z 350.1630, found 350.1633.
4.2.5. (S)-5-Benzyl-8-fluoro-3,3a,5,6-tetrahydro-1H-benzo[f]-
pyrrolo[1,2-a][1,4]diazepin-4(2H)-one (5e)
1H NMR (300 MHz, CDCl3)
d
7.21–7.34 (m, 5H), 6.83 (td, J¼8.4,
4.2. General procedure for coupling of 2-halobenzyl-amines
with L-proline
2.7 Hz, 1H), 6.46 (dd, J¼9.0, 2.7 Hz, 1H), 6.39 (dd, J¼9.0, 4.5 Hz, 1H),
5.23 (d, J¼16.5 Hz, 1H), 5.04 (d, J¼15.0 Hz, 1H), 4.96–4.99 (m, 1H),
4.28 (d, J¼15.0 Hz, 1H), 3.66 (d, J¼16.5 Hz, 1H), 3.23–3.33 (m, 2H),
2.62–2.68 (m, 1H), 1.94–2.11 (m, 3H); 13C NMR (100 MHz, CDCl3)
An oven-dried Schlenk tube was charged with 2-halobenzyl-
amines 4 (2 mmol), -proline (3.0 mmol), CuI (0.2 mmol), and ce-
L
d
170.1, 154.1 (d, J¼234 Hz), 142.6, 136.9, 128.5, 128.3, 128.0 (2C),
sium carbonate (2.0 mmol). The tube was evacuated and backfilled
with argon, and then DMF (4 mL). After the mixture was stirred at
90 ꢀC for 21 h and then 110 ꢀC for 24 h under argon atmosphere, the
cooled mixture was partitioned between water and ethyl acetate.
The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel to
give the corresponding tricyclic compound.
127.4, 120.0 (d, J¼5.8 Hz), 115.8 (d, J¼22.6 Hz), 115.1 (d, J¼22.1 Hz),
113.6 (d, J¼7.7 Hz), 58.8, 50.8, 49.8, 49.7, 27.9, 23.4; ESI-MS m/z 311
(MþH)þ; ESI-HRMS calcd for C19H20N2OF (MþH)þ m/z 311.1554,
found 311.1565.
4.2.6. (S)-5-Allyl-3,3a,5,6-tetrahydro-1H-benzo[f]pyrrolo-[1,2-
a][1,4]diazepin-4(2H)-one (5f)
1H NMR (300 MHz, CDCl3)
d
7.14 (td, J¼8.4, 1.5 Hz, 1H), 6.86 (d,
J¼7.5 Hz,1H), 6.57 (t, J¼7.5 Hz,1H), 6.48 (d, J¼8.4 Hz,1H), 5.68–5.81
(m, 1H), 5.35 (d, J¼16.5 Hz, 1H), 5.14–5.22 (m, 2H), 5.01–5.04 (m,
1H), 4.32 (dd, J¼15.3, 5.4 Hz, 1H), 3.91 (dd, J¼15.3, 6.3 Hz, 1H), 3.77
(d, J¼16.5 Hz, 1H), 3.23–3.37 (m, 2H), 2.57–2.66 (m, 1H), 1.91–2.09
4.2.1. (S)-5-Benzyl-1,2,3,3a,5,6-hexahydrobenzo[f]pyrrolo-[1,2-
a][1,4]diazepin-4-one (5a)
1H NMR (300 MHz, CDCl3)
1H), 6.76 (d, J¼6.9 Hz, 1H), 6.48–6.56 (m, 2H), 5.30 (d, J¼16.5 Hz,
d
7.26–7.34 (m, 5H), 7.14 (t, J¼8.1 Hz,
(m, 3H); 13C NMR (100 MHz, CDCl3)
d 169.5, 146.0, 133.2, 129.2,
129.0, 119.0, 117.3, 115.2, 113.0, 58.4, 51.2, 49.3, 48.8, 27.7, 23.7; EIMS

H. Wang et al. / Tetrahedron 65 (2009) 8956–8960
8959
m/z 242 (Mþ); EI-HRMS calcd for C15H18N2O (Mþ) m/z 242.1419,
4.3.4. (S)-4-Benzyl-7-fluoro-2-isopropyl-4,5-dihydro-1H-benzo-
found 242.1410.
[e][1,4]diazepin-3(2H)-one (6d)
1H NMR (300 MHz, CDCl3)
d
7.20–7.32 (m, 5H), 6.77 (td, J¼8.4,
4.2.7. (S)-5-Butyl-3,3a,5,6-tetrahydro-1H-benzo[f]pyrrolo-[1,2-
a][1,4]diazepin-4(2H)-one (5g)
3.0 Hz, 1H), 6.53 (dd, J¼4.8, 8.7 Hz, 1H), 6.43 (dd, J¼3.0, 8.7 Hz, 1H),
4.94 (d, J¼16.2 Hz, 1H), 4.90 (d, J¼15.0 Hz, 1H), 4.43 (d, J¼15.0 Hz,
1H), 4.05–4.10 (m, 1H), 3.85 (d, J¼16.2 Hz, 1H), 3.59 (d, J¼6.6 Hz,
1H), 2.25–2.32 (m, 1H), 1.12 (d, J¼6.6 Hz, 3H), 1.11 (d, J¼6.6 Hz, 3H);
1H NMR (300 MHz, CDCl3)
d
7.13 (td, J¼8.4, 1.8 Hz, 1H), 6.90 (dd,
J¼7.2, 1.2 Hz, 1H), 6.56 (t, J¼7.2 Hz, 1H), 6.46 (d, J¼8.1 Hz, 1H), 5.42
(d, J¼16.5 Hz, 1H), 4.98–5.01 (m, 1H), 3.73 (d, J¼16.5 Hz, 1H), 3.49–
3.59 (m, 1H), 3.38–3.45 (m, 1H), 3.21–3.32 (m, 2H), 2.56–2.64 (m,
1H), 1.90–2.06 (m, 3H), 1.45–1.55 (m, 2H), 1.20–1.30 (m, 2H), 0.87 (t,
13C NMR (100 MHz, CDCl3)
d
170.6, 155.3 (d, J¼237 Hz), 141.8 (d,
J¼2.4 Hz), 137.2, 128.5 (2C), 128.1 (2C), 127.4, 121.5 (d, J¼6.4 Hz),
118.4 (d, J¼7.5 Hz), 115.5 (d, J¼22.3 Hz), 115.3 (d, J¼21.3 Hz), 61.8,
50.1, 49.9, 29.5, 20.4, 18.6; ESI-MS m/z 335 (MþNa)þ; ESI-HRMS
calcd for C19H21FN2ONa (MþNa)þ m/z 335.1530, found 335.1539.
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 169.5, 146.1, 129.2, 129.1,
119.5, 115.7, 113.1, 58.6, 52.5, 49.4, 46.9, 30.3, 27.9, 23.5, 20.0, 13.7;
ESI-MS m/z 281 (MþNa)þ; ESI-HRMS calcd for C16H22N2ONa
(MþNa)þ m/z 281.1637, found 281.1624.
4.3.5. (S)-Methyl-4-benzyl-2-isopropyl-3-oxo-2,3,4,5-tetrahydro-
1H-benzo[e][1,4]diazepine-7-carboxylate (6e)
4.3. General procedure for coupling of 2-bromobenzyl-
amines with other amino acids
1H NMR (300 MHz, CDCl3)
d
7.70 (dd, J¼8.4, 2.1 Hz, 1H), 7.46 (d,
J¼2.1 Hz, 1H), 7.23–7.32 (m, 5H), 6.49 (d, J¼8.4 Hz, 1H), 5.18 (d,
J¼16.5 Hz, 1H), 5.00 (d, J¼15.0 Hz, 1H), 4.35 (d, J¼15.0 Hz, 1H), 4.27
(d, J¼8.4 Hz, 1H), 3.88 (d, J¼16.5 Hz, 1H), 3.84 (s, 3H), 2.26–2.33 (m,
1H), 1.14 (d, J¼6.3 Hz, 3H), 1.13 (d, J¼6.6 Hz, 3H); 13C NMR
An oven-dried Schlenk tube was charged with 2-bromobenzyl-
amines 4 (2 mmol), a-amino acid (3.0 mmol), CuI (0.2 mmol), and
Cs2CO3 (2.0 mmol). The tube was evacuated and backfilled with
argon before DMF (4 mL) was added. After the mixture was stirred
at 90 ꢀC for 21 h, it was cooled to 4 ꢀC, then DMF (6 mL) and DPPA
(0.68 mL, 3 mmol) were added. The resultant solution was stirred at
0–4 ꢀC overnight before it was partitioned between water and ethyl
acetate. The organic layer was separated, and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in vacuo.
The residue was purified via column chromatography to afford 1,4-
benzodiazepin-3-ones.
(100 MHz, CDCl3) d 169.6, 166.7, 149.7, 137.0, 131.8, 130.7, 128.6 (2C),
128.1 (2C), 127.5, 118.4, 118.0, 115.8, 60.9, 51.6, 50.4, 49.5, 29.2, 20.3,
18.7; EIMS m/z 352 (Mþ); EI-HRMS calcd for C21H24N2O3 (Mþ) m/z
352.1787, found 352.1786.
4.3.6. (S)-4-Allyl-2-isopropyl-4,5-dihydro-1H-
benzo[e][1,4]diazepin-3(2H)-one (6f)
1H NMR (300 MHz, CDCl3)
d
7.07 (td, J¼7.5, 1.5 Hz, 1H), 6.88 (dd,
J¼7.8, 1.2 Hz, 1H), 6.62 (td, J¼7.5, 0.9 Hz, 1H), 6.56 (dd, J¼7.8, 0.9 Hz,
1H), 5.67–5.79 (m, 1H), 5.05–5.20 (m, 3H), 4.21–4.29 (m, 1H), 4.11
(d, J¼8.4 Hz, 1H), 3.91–4.00 (m, 2H), 3.69 (br s, 1H), 2.20–2.28 (m,
1H), 1.11 (d, J¼6.9 Hz, 3H), 1.08 (d, J¼6.9 Hz, 3H); 13C NMR
4.3.1. (S)-4-Benzyl-2-isopropyl-4,5-dihydro-1H-benzo[e]-[1,4]-
diazepin-3(2H)-one (6a)
(100 MHz, CDCl3) d 170.1,145.6,133.5,129.6,128.8,119.8,117.7,117.3,
1H NMR (300 MHz, CDCl3)
d
7.25–7.34 (m, 5H), 7.05 (td, J¼8.4,
117.1, 61.3, 50.6, 49.1, 29.3, 20.3, 18.7; ESI-MS m/z 245 (MþH)þ; ESI-
HRMS calcd for C15H21N2O (MþH)þ m/z 245.16484, found 245.1654;
HPLC: chiracel IB-H column (250 mm); detected at 254 nm; n-
hexane/i-propanol: 90/10; flow: 0.7 mL/min; retention time:
8.2 min (major), 12.0 min (minor), ee¼99%.
1.2 Hz, 1H), 6.74 (d, J¼7.2 Hz, 1H), 6.55–6.58 (m, 2H), 5.06 (d,
J¼16.5 Hz, 1H), 5.00 (d, J¼15.0 Hz, 1H), 4.35 (d, J¼15.0 Hz, 1H), 4.18
(dd, J¼6.3, 8.4 Hz,1H), 3.86 (d, J¼16.5 Hz,1H), 3.72 (d, J¼6.3 Hz,1H),
2.22–2.34 (m, 1H), 1.13 (d, J¼6.6 Hz, 3H), 1.12 (d, J¼6.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 170.5, 145.6, 137.4, 129.5, 128.8, 128.5 (2C),
128.0 (2C), 127.3, 119.7, 117.7, 117.0, 61.3, 50.6, 49.7, 29.3, 20.4, 18.7;
ESI-MS m/z 295 (MþH)þ; ESI-HRMS calcd for C19H23N2O (MþH)þ
m/z 295.1805, found 295.1809.
4.3.7. (S)-4-Butyl-2-isopropyl-4,5-dihydro-1H-
benzo[e][1,4]diazepin-3(2H)-one (6g)
1H NMR (300 MHz, CDCl3)
d
7.06 (t, J¼7.8 Hz, 1H), 6.92 (d,
J¼7.5 Hz, 1H), 6.63 (t, J¼7.5 Hz, 1H), 6.55 (d, J¼7.8 Hz, 1H), 5.17 (d,
J¼16.5 Hz, 1H), 4.09 (dd, J¼8.1, 6.3 Hz, 1H), 3.91 (d, J¼16.5 Hz, 1H),
3.69 (d, J¼6.3 Hz, 1H, N-H), 3.48 (t, J¼7.2 Hz, 2H), 2.17–2.26 (m, 1H),
1.43–1.53 (m, 2H), 1.20–1.28 (m, 2H), 1.10 (t, J¼7.2 Hz, 3H), 1.07 (t,
J¼7.2 Hz, 3H), 0.86 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
4.3.2. (S)-4-Benzyl-2-isopropyl-7-nitro-4,5-dihydro-1H-benzo[e]-
[1,4]diazepin-3(2H)-one (6b)
1H NMR (300 MHz, CDCl3)
d
7.91 (dd, J¼9.0, 2.4 Hz, 1H), 7.60 (d,
J¼2.4 Hz, 1H), 7.21–7.30 (m, 5H), 6.50 (d, J¼9.0 Hz, 1H), 5.11 (d,
J¼16.5 Hz, 1H), 4.83 (d, J¼14.7 Hz, 1H), 4.63 (d, J¼5.4 Hz, 1H), 4.56
(d, J¼14.7 Hz, 1H), 4.13 (dd, J¼5.4, 8.7 Hz, 1H), 3.91 (d, J¼16.5 Hz,
1H), 2.29–2.36 (m, 1H), 1.15 (d, J¼6.6 Hz, 3H), 1.14 (d, J¼6.3 Hz, 3H);
d
170.0, 145.6, 129.3, 128.8, 120.2, 117.6, 117.0, 61.2, 51.7, 47.0, 30.4,
29.2, 20.4, 19.9, 18.6, 13.7; EIMS m/z 260 (Mþ); EI-HRMS calcd for
C16H24N2O (Mþ) m/z 260.1889, found 260.1883; HPLC: chiracel IB-H
column (250 mm); detected at 214 nm; n-hexane/i-propanol: 90/
10; flow: 0.7 mL/min; retention time: 7.0 min (major), 10.7 min
(minor), ee¼99%.
13C NMR (100 MHz, DMSO-d6)
d 169.5, 153.4, 138.4, 135.8, 128.7
(2C),128.2 (2C),127.5, 126.9, 125.2,118.8,115.6, 60.0, 50.1, 49.6, 28.9,
20.3, 19.4; EIMS m/z 339 (Mþ); EI-HRMS calcd for C19H21N3O3 (Mþ)
m/z 339.1583, found 339.1580.
4.3.8. (S)-4-Benzyl-2-methyl-4,5-dihydro-1H-
4.3.3. (S)-4-Benzyl-2-isopropyl-7-methoxy-4,5-dihydro-1H-
benzo[e][1,4]diazepin-3(2H)-one (6c)
benzo[e][1,4]diazepin-3(2H)-one (6h)
1H NMR (300 MHz, CDCl3)
d
7.26–7.30 (m, 5H), 7.05 (t, J¼7.8 Hz,
1H NMR (300 MHz, CDCl3)
d
7.22–7.34 (m, 5H), 6.67 (dd, J¼3.0,
1H), 6.73 (d, J¼7.2 Hz, 1H), 6.49–6.59 (m, 2H), 5.23 (d, J¼16.5 Hz,
1H), 5.07 (d, J¼15.0 Hz, 1H), 4.82 (q, J¼6.3 Hz, 1H), 4.30 (d,
J¼15.0 Hz, 1H), 3.72 (d, J¼16.5 Hz, 1H), 1.46 (d, J¼6.3 Hz, 3H); 13C
8.4 Hz, 1H), 6.57 (d, J¼8.4 Hz, 1H), 6.30 (d, J¼3.0 Hz, 1H), 4.95 (d,
J¼14.7 Hz, 1H), 4.89 (d, J¼16.5 Hz, 1H), 4.41 (d, J¼14.7 Hz, 1H), 4.03
(d, J¼7.2 Hz, 1H), 3.91 (d, J¼16.5 Hz, 1H), 3.67 (s, 3H), 3.42 (br s, 1H),
2.25–2.32 (m, 1H), 1.12 (d, J¼6.9 Hz, 3H), 1.11 (d, J¼6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 171.2, 145.6, 137.3, 129.6, 129.0, 128.6 (2C),
128.1 (2C), 127.4, 119.1, 117.5, 116.4, 50.7, 49.9 (2C), 17.4; ESI-MS m/z
267 (MþH)þ; ESI-HRMS calcd for C17H19N2O (MþH)þ m/z 267.1492,
found 267.1493; HPLC: chiracel IC-H column (250 mm); detected at
214 nm; n-hexane/i-propanol: 90/10; flow: 0.8 mL/min; retention
time: 25.3 min (minor), 38.3 min (major), ee¼49%.
NMR (100 MHz, CDCl3) d 171.0, 152.1, 139.4, 137.3, 129.4, 128.4 (2C),
128.0 (2C), 127.3, 122.3, 118.9, 114.5, 62.3, 55.6, 50.4, 50.0, 29.7, 20.3,
18.5; ESI-MS m/z 325 (MþH)þ; ESI-HRMS calcd for C20H25N2O2
(MþH)þ m/z 325.1911, found 325.1914.

8960
H. Wang et al. / Tetrahedron 65 (2009) 8956–8960
4.3.9. (S)-2,4-Dibenzyl-4,5-dihydro-1H-benzo[e][1,4]-diazepin-
References and notes
3(2H)-one (6i)
1H NMR (300 MHz, CDCl3)
d
7.19–7.35 (m, 10H), 7.00 (t, J¼8.4 Hz,
1. (a) Keenan, R. M.; Callahan, J. F.; Samanen, J. M.; Bondinell, W. E.; Calvo, R. R.;
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F. J. Med. Chem. 1999, 42, 545; (b) Andrews, I. P.; Atkins, R. J.; Breen, G. F.; Carey, J.
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T. C.; Wells, A. S. Org. Process Res. Dev. 2003, 7, 655; (c) Yokoyama, K.; Suzuki, R.;
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1H), 6.69 (d, J¼7.2 Hz, 1H), 6.55 (t, J¼8.4 Hz, 1H), 6.42 (d, J¼8.1 Hz,
1H), 5.19 (d, J¼16.5 Hz, 1H), 5.02 (d, J¼15.0 Hz, 1H), 4.90 (m, 1H),
4.41 (d, J¼15.0 Hz, 1H), 3.77 (d, J¼16.5 Hz, 1H), 3.71 (br s, 1H), 3.46
(dd, J¼14.7, 4.5 Hz, 1H), 2.97 (dd, J¼14.7, 9.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3)
d 170.5, 145.4, 137.5, 137.1, 129.3, 129.2, 128.8,
128.7 (2C), 128.5, 128.3 (2C), 128.1, 128.0, 127.3, 126.7, 119.6, 117.9,
116.7, 55.8, 50.6, 50.1, 37.5; ESI-MS m/z 343 (MþH)þ; ESI-HRMS
calcd for C23H23N2O (MþH)þ m/z 343.1805, found 343.1801; HPLC:
chiracel IC-H column (250 mm); detected at 214 nm; n-hexane/i-
propanol: 90/10; flow: 0.6 mL/min; retention time: 34.3 min (ma-
jor), 36.3 min (minor), ee¼90%.
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4.3.10. (S)-4-Benzyl-2-(4-hydroxybenzyl)-4,5-dihydro-1H-benzo-
[e][1,4]diazepin-3(2H)-one (6j)
1H NMR (300 MHz, CDCl3)
d
7.14–7.32 (m, 9H), 6.99 (td, J¼7.8,
1.5 Hz, 1H), 6.79 (d, J¼8.7 Hz, 2H), 6.69 (d, J¼7.8 Hz, 1H), 6.55 (td,
J¼7.5, 1.2 Hz, 1H), 6.42 (d, J¼8.1 Hz, 1H), 5.16 (d, J¼16.2 Hz, 1H), 4.98
(d, J¼15.3 Hz, 1H), 4.84–4.86 (m, 1H), 4.43 (d, J¼15.3 Hz, 1H), 3.78
(d, J¼16.2 Hz, 1H), 3.71 (d, J¼3.6 Hz, 1H), 3.33 (dd, J¼14.1, 4.8 Hz,
1H), 2.88 (dd, J¼14.1, 8.7 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
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d
170.9, 156.1, 146.6, 138.5, 130.8 (2C), 130.0, 129.3, 128.7 (2C), 128.6,
128.0 (2C), 127.4, 119.7, 116.6, 116.4, 115.3 (2C), 55.4, 51.3, 49.9, 36.0;
ESI-MS m/z 359 (MþH)þ; ESI-HRMS calcd for C23H23N2O2 (MþH)þ
m/z 359.1754, found 359.1761.
4.3.11. (S)-2-((1H-Indol-3-yl)methyl)-4-benzyl-4,5-dihydro-1H-
benzo[e][1,4]diazepin-3(2H)-one (6k)
1H NMR (300 MHz, CDCl3)
d
8.16 (br s, 1H), 7.69 (d, J¼7.8 Hz, 1H),
7.13–7.41 (m, 9H), 6.99 (td, J¼7.8, 1.2 Hz, 1H), 6.68 (d, J¼6.0 Hz, 1H),
6.52 (t, J¼7.5 Hz,1H), 6.39 (d, J¼7.5,1H), 5.21 (d, J¼16.5 Hz,1H), 5.05
(d, J¼15.0 Hz, 1H), 5.02 (m, 1H), 4.43 (d, J¼15.0 Hz, 1H), 3.88 (br s,
1H), 3.74 (d, J¼16.5 Hz, 1H), 3.53 (dd, J¼15.0, 5.4 Hz, 1H), 3.18 (dd,
J¼15.0, 8.7 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
d 171.0, 146.8,
138.5, 136.6, 130.0, 129.0 (2C), 128.7, 128.3, 128.2, 128.0, 127.4, 124.3,
121.4, 119.6, 118.9, 118.8, 116.5, 116.4, 111.8, 111.3, 54.4, 51.3, 50.0,
26.9; ESI-MS m/z 404 (MþNa)þ; ESI-HRMS calcd for C25H23N3ONa
(MþNa)þ m/z 404.17333, found 404.1746.
Acknowledgements
The authors are grateful to the Chinese Academy of Sciences and
the National Natural Science Foundation of China (grant 20621062
and 20872156) for their financial support.