Gold(I)-catalyzed synthesis of 1,5-benzodiazepines directly from o-phenylenediamines and alkynes

Article abstract of DOI:10.1021/jo300543n

A unique gold(I)-catalyzed highly atom-economic synthesis of 1,5-benzodiazepines directly from o-phenylenediamines and alkynes has been achieved for the first time.

Full text of DOI:10.1021/jo300543n

Note
pubs.acs.org/joc
Gold(I)-Catalyzed Synthesis of 1,5-Benzodiazepines Directly from
o‑Phenylenediamines and Alkynes
Jianqiang Qian,† Yunkui Liu,*,†,‡ Jianhai Cui,† and Zhenyuan Xu*,†
†State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou
310014, People’s Republic of China
‡College of Chemistry & Materials Engineering, Wenzhou University, Zhejiang Province, Wenzhou 325027, People’s Republic of
China
S
* Supporting Information
ABSTRACT: A unique gold(I)-catalyzed highly atom-eco-
nomic synthesis of 1,5-benzodiazepines directly from o-
phenylenediamines and alkynes has been achieved for the
first time.
enzodiazepines have recently received much attention as
an important class of N-heterocyclic compounds exhibiting
a broad spectrum of biological and pharmacological activities,
such as anti-inflammatory, anticonvulsant, antianxiety, sedative,
antidepressive, and hypnotic activities.1 Several representative
medicinal candidates containing a 1,5-benzodiazepine scaffold
are exemplified in Figure 1 including compounds I and II,2 two
the construction of carbon−carbon or carbon−heteroatom
bonds (e.g., C−N bonds10,11) with high selectivity and
efficiency. In light of the easy availability of alkynes and the
extraordinary ability of gold to activate alkynes, we envisioned
that alkynes would be alternative precursors for the synthesis of
1,5-benzodiazepines. As part of our ongoing project devoted
toward the development of efficient and highly atom-economic
synthesis of heterocycles via gold-catalyzed reactions,12,13 we
herein report a unique gold(I)-catalyzed synthesis of 1,5-
benzodiazepines directly from o-phenylenediamines and
alkynes. To the best of our knowledge, this is the first example
of an alkyne-based and a highly atom-economic synthesis of
1,5-benzodiazepines (Scheme 1, path d).
B
Initially, o-phenylenediamine 1a and phenylacetylene 2a were
chosen as the model substrates to optimize suitable conditions
for this reaction (Table 1). When the reaction was tested with
Ph3PAuNTf2 (2.5 mol % based on 1a) in CH2Cl2 at room
temperature for 24 h, the desired 1,5-benzodiazepine 3a was
indeed isolated in 41% yield, and the yield of 3a was further
increased to 46% at 40 °C for 6 h (entry 1, Table 1). When
Figure 1. Representative compounds containing a 1,5-benzodiazepine
scaffold.
drugs for the treatment of schizophrenia, and compound III,3
an inhibitor of HIV-1 capsid assembly. In addition, 1,5-
benzodiazepines are also useful intermediates for the synthesis
of some fused ring compounds.4
The traditional strategies for the synthesis of 1,5-
benzodiazepines basically rely on the condensation reactions
of o-phenylenediamines with α,β-unsaturated carbonyl com-
pounds,5 β-haloketones,6 or ketones5a,7 (Scheme 1, paths a−c).
These reactions can offer effective methods for the synthesis of
1,5-benzodiazepines. However, they inevitably suffer from
unsatisfactory atom economy. Therefore, from the sustainable
and atom-economic synthesis point of view, it is still highly
desirable to develop alternative approaches for the synthesis of
1,5-benzodiazepines with higher atom economy.
Alkynes are ubiquitous and easily available structures in
organic synthesis, serving as important synthetic precursors and
subunits for various useful organic compounds.8 In the past
decade, gold9 has emerged as a powerful catalyst for the
electrophilic activation of alkynes toward a variety of
nucleophiles under homogeneous conditions, thus enabling
14
IMesAuNTf2 (IMes = 1,3-bis(mesityl)imidazol-2-ylidene)
was used as a catalyst in CH2Cl2 or CHCl3 at 40 °C for 6 h,
3a was obtained in 49 and 59% yield, respectively (entries 2 and
3, Table 1). Employing the same catalyst, this yield could be
further improved up to 90% by increasing the temperature and
using a higher catalyst loading (5 mol %, entry 3, Table 1). It
15
was found that (2-biphenyl)Cy2PAuNTf2 was the most
effective catalyst for the reaction, in which case 3a could be
produced in 93% yield in CHCl3 at 60 °C for 6 h (entry 4,
Table 1). A combination of (2-biphenyl)Cy2PAuCl with
AgNTf2 gave almost the same result (entry 5, Table 1).
However, the use of (2-biphenyl)Cy2PAuCl or AgNTf2 alone
led to a very poor result (entries 6 and 7, Table 1).
Counteranion and solvent screening experiments showed that
both parameters had a significant effect on the outcome of the
Received: March 14, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo300543n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. Strategies for the Synthesis of 1,5-Benzodiazepines
a
Table 1. Optimization of Reaction Conditions
To investigate the scope of the reaction, we first examined
the cycloaddition of 1a with various terminal alkynes 2 under
the optimal reaction conditions (Table 2). In the participation
of aromatic terminal alkynes, the reaction proceeded smoothly
to furnish 1,5-benzodiazepines 3 in moderate to excellent yields
(51−97%, entries 1−11, Table 2). The reaction of 1a with
aliphatic terminal alkynes also occurred, albeit it generally
required longer reaction times and gave lower yields of desired
products (entries 13 and 14, Table 2). Surprisingly, when
cyclopropyl acetylene 2l was used, the reaction underwent
smoothly to furnish target product 3l in an unexpectedly high
yield of 96% (entry 12, Table 2). Among the alkynes bearing
para-substituted aryl groups, it was found that those substituted
with electron-withdrawing groups gave better yields of 3 than
those substituted with electron-donating ones (entries 6, 9, 10
vs 2−5, Table 2). Note that the ortho- or meta-substituted
phenylalkynes generally gave slightly lower yields of target
products compared with the para-substituted phenylalkynes
(entries 7, 8 vs 2−6, 9, and 10, Table 2). Besides, a heterocycle-
substituted terminal alkyne 2k could be well tolerated under the
reaction conditions, and the corresponding product 3k was
obtained in 97% yield (entry 11, Table 2). An attempt to
employ internal alkyne 2o as a substrate failed to give any
desired product (entry 15, Table 2).
Then, further investigations were undertaken to examine the
capability of the catalysis system to catalyze the tandem
amination/cyclization reaction of various o-phenylenediamines
with alkynes under the optimized reaction conditions. As seen
from Table 3, both mono- and disubstituted o-phenylenedi-
amines could react with alkynes to afford the corresponding
1,5-benzodiazepines in moderate to excellent yields (66−98%,
entries 1−10, Table 3). It was found that electron-rich o-
phenylenediamines 1 reacted with alkynes more smoothly to
furnish the corresponding products 3 in higher yields (91−
98%, entries 1−4 and 7, Table 3) than those electron-deficient
o-phenylenediamines (66−80%, entries 5, 6, and 8−10, Table
3). Unfortunately, two regioisomeric products were obtained
when an unsymmetrical o-phenylenediamine was employed as a
substrate (entries 7−10, Table 3). It seemed that the electronic
situation of o-phenylenediamines had a significant effect on the
resulting regioselectivity apart from the resulting yield. For
example, a 4-methyl-substituted o-phenylenediamine 1d could
give two regioisomers in high yield (total yield of 95%), albeit
at the expense of low regioselectivity (3v:3′v = 62:38, entry 7,
Table 3). In contrast, when a 4-chloro-substituted o-phenyl-
enediamine 1e was used, the reaction gave two regioisomers in
a total yield of 66%, albeit with a regioselectivity as high as 94:6
(3w:3′w, entry 8, Table 3). Similar results were obtained in the
case of 4-bromo- or 4-nitro-substituted o-phenylenediamine
(entries 9, 10, Table 3).
b
entry
catalyst
PPh3AuNTf2
solvent
yield (%)
cd ce
,
,
1
CH2Cl2
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
41, 46
ce
,
2
IMesAuNTf2
49
ce
,
c
3
IMesAuNTf2
59, 73, 90
h
4
(2-biphenyl)Cy2PAuNTf2
(2-biphenyl)Cy2PAuCl/AgNTf2
(2-biphenyl)Cy2PAuCl
AgNTf2
93, 67
5
92
6
trace
i
7
_
8
(2-biphenyl)Cy2PAuCl/AgOTf
(2-biphenyl)Cy2PAuCl/AgSbF6
(2-biphenyl)Cy2PAuCl/AgNO2
(2-biphenyl)Cy2PAuCl/AgCN
(2-biphenyl)Cy2PAuCl/AgF
AuCl
89
9
86
10
11
12
13
14
15
16
17
18
19
20
21
22
23
trace
trace
trace
i
_
i
IMesAuCl
_
i
PPh3AuCl
_
i
AuCl3
_
AuCl/AgNTf2
trace
i
AuCl3/3AgNTf2
_
i
NaAuCl4·2H2O
_
i
HAuCl4·4H2O
_
f
i
Lewis acids
_
g
i
Brϕnsted acids
_
i
none
_
a
All the reactions were carried out with 1a (0.2 mmol) and 2a (0.5
mmol) in the presence of catalyst (5.0 mol % based on 1a) in solvent
(2.0 mL) at 60 °C for 6 h unless otherwise noted. Isolated yields. 2.5
mol % of catalyst was used. The reaction was carried out at room
temperature for 24 h. The reaction temperature was 40 °C. Lewis
acids, such as CuI, PdCl2, BiCl3, ZnCl2, FeCl3, and Cu(OTf)2.
Brϕnsted acids, such as HOTf, HNTf2, and aqueous HCl (37 wt %).
0.4 mmol of 2a was used. No desired product was detected.
b
c
d
e
f
g
h
i
reaction (entries 4, 5, 8−12, Table 1; Table S2 in the
Supporting Information). The activity of other gold catalysts on
the reaction was examined, and all failed to give the desired
product (entries 13−20, Table 1). Control experiments showed
that no reaction occurred in the absence of a gold catalyst
(entry 23, Table 1). Moreover, treatments of the model
substrates with some conventional Lewis or Brϕnsted acids,
such as CuI, PdCl2, BiCl3, ZnCl2, FeCl3, Cu(OTf)2, HOTf,
HNTf2, or HCl were done, and all failed to give the desired
product (entries 21 and 22, Table 1), indicating that (2-
biphenyl)Cy2PAuNTf2 had a unique ability to achieve a high
reactivity for the reaction.
B
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Note
a
Table 2. Gold(I)-Catalyzed Reaction of o-Phenylenediamine 1a with Terminal Alkynes 2
a
All reactions were carried out with 1a (0.2 mmol) and 2 (0.5 mmol) in the presence of (2-biphenyl)Cy2PAuNTf2 (5.0 mol % based on 1a) in
b
c
CHCl3 (2.0 mL) at 60 °C for 6 h unless otherwise noted. Isolated yields. The reaction time was 10 h.
All solvents for the reactions were dried and distilled prior to use
To elucidate the mechanism of the reaction, we synthesized
compound 6a according to reported procedures.16 When 6a
was subjected to the standard reaction conditions, 3a could also
be obtained in 95% yield (Scheme 2), suggesting that 6a was
likely a key intermediate for the reaction. Based on this result
and previous reports,7b,11b−d a proposed mechanism regarding
the gold(I)-catalyzed tandem amination/cyclization reaction of
o-phenylenediamines with alkynes is depicted in Scheme 3.
First, the hydroamination reaction between o-phenylenedi-
amines and two molecules of alkynes to produce dienamine 5
occurs in the presence of gold(I).11b,c Then, dienamine 5 may
undergo isomerization to form diimine 6 or monoimine 7 via
double- or mono-1,3-shift of the hydrogen of the amino
group.11b,c Finally, an intramolecular cyclization of monoimine
7 occurs to furnish seven-membered ring product 3.7b,f,g,17c
In summary, for the first time we have realized a new access
to 1,5-benzodiazepines directly from o-phenylenediamines and
alkynes with high atom-economy wherein (2-biphenyl)-
Cy2PAuNTf2 displays a crucial role in achieving high efficiency
for the reaction.
according to standard methods. Melting points were uncorrected. The
1H NMR and 13C NMR spectra were recorded at 25 °C in CDCl3 at
500 and 125 MHz, respectively, with TMS as the internal standard.
Chemical shifts (δ) are expressed in ppm, and coupling constants J are
given in Hz. The IR spectra were recorded on an FT-IR spectrometer.
GC−MS experiments were performed with EI source; high resolution
mass spectra (HRMS) were obtained on a TOF MS instrument with
EI source.
General Procedure for the Gold(I)-Catalyzed Cycloaddition
Reaction of o-Phenylenediamine (1) with Alkynes (2). To a
solution of o-phenylenediamine 1 (0.2 mmol) and alkynes 2 (0.5
mmol) in CHCl3 (2.0 mL), (2-biphenyl)Cy2PAuNTf2 (0.01 mmol)
was added. Then the reaction mixture was stirred at 60 °C for 6 h.
Upon completion, the resulting mixture was diluted with CH2Cl2 and
filtered through Celite. After evaporation of the solvent under vacuum,
the residue was purified by column chromatography on silica gel
(100−200 mesh) using petroleum ether−EtOAc (10:1, v/v) as eluent
to give pure 3.
2-Methyl-2,4-diphenyl-2,3-dihydro-1H-1,5-benzodiazepine
(3a).17a Purification by column chromatography (petroleum ether/
EtOAc, 10/1) as a yellow soild (58.1 mg, 93%): IR (KBr) ν = 3336,
1
3057, 2971, 1606, 1469, 1331 cm−1; H NMR (CDCl3, 500 MHz) δ
EXPERIMENTAL SECTION
7.60−7.57 (m, 4H), 7.33−7.15 (m, 7H), 7.07−7.03 (m, 2H), 6.83 (dd,
J1 = 1.5 Hz, J2 = 7.5 Hz, 1H), 3.51 (br s, 1H), 3.13 (d, J = 13.0 Hz,
1H), 2.97 (d, J = 13.5 Hz, 1H), 1.75 (s, 3H); MS (EI, 70 eV) m/z (%)
■
General Methods. Unless otherwise stated, all reagents were
purchased from commercial suppliers and used without purifications.
C
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The Journal of Organic Chemistry
Note
a
Table 3. Gold(I)-Catalyzed Synthesis of Other Substituted 1,5-Benzodiazepines
a
All reactions were carried out with 1 (0.2 mmol) and 2 (0.5 mmol) in the presence of (2-biphenyl)Cy2PAuNTf2 (5.0 mol % based on 1) in CHCl3
b
c
d
(2.0 mL) at 60 °C for 6 h unless otherwise noted. Isolated yields. The reaction time was 10 h. The ratio was determined on the basis of 1H NMR
analysis.
Scheme 2. Conversion of 6a to 3a under the Standard Reaction Conditions
= 312(35) [M+], 297(38), 235(74), 194(100), 115(26), 77(64); mp
150−152 °C (lit.17a mp 150−152 °C).
138.4, 131.0, 128.6, 128.5, 128.1, 127.8, 127.6, 127.4, 126.3, 125.4,
121.6, 121.4, 77.5, 43.1, 29.8, 28.7, 28.4, 15.8, 15.4; MS (EI, 70 eV) m/
z (%) = 368(36) [M+], 353(48), 263(42), 222(100), 131(18), 77(6);
HRMS (EI) for C26H28N2 calcd. 368.2252, found 368.2249.
2-Methyl-2,4-bis(4-methoxyphenyl)-2,3-dihydro-1H-1,5-benzo-
diazepine (3d).17a Purification by column chromatography (petro-
leum ether/EtOAc, 10/1) as a yellow solid (60.3 mg, 81%): IR (KBr)
ν = 3338, 3052, 2963, 1604, 1510, 1250 cm−1; 1H NMR (CDCl3, 500
MHz) δ 7.63−7.32 (m, 5H), 7.07−7.06 (m, 2H), 6.84−6.78 (m, 5H),
3.82 (s, 3H), 3.78 (s, 3H), 3.44 (br s, 1H), 3.07 (d, J = 13.5 Hz, 1H),
2.94 (d, J = 13.5 Hz, 1H), 1.75 (s, 3H); MS (EI, 70 eV) m/z (%) =
372(17) [M+], 357(26), 253(10), 224(53), 207(100), 77(14); mp
118−120 °C (lit.17a mp 114−116 °C).
2-Methyl-2,4-ditoluyl-2,3-dihydro-1H-1,5-benzodiazepine
(3b).17a Purification by column chromatography (petroleum ether/
EtOAc, 10/1) as a yellow solid (62.6 mg, 92%): IR (KBr) ν = 3336,
1
2969, 2921, 1604, 1415, 1329 cm−1; H NMR (CDCl3, 500 MHz) δ
7.59−7.35 (m, 5H), 7.11−7.04 (m, 6H), 6.84 (dd, J1 = 1.5 Hz, J2 = 7.5
Hz, 1H), 3.54 (br s, 1H), 3.10 (d, J = 13.5 Hz, 1H), 3.00 (d, J = 13.5
Hz, 1H), 2.36 (s, 3H), 2.32 (s, 3H), 1.75 (s, 3H); MS (EI, 70 eV) m/z
(%) = 340(34) [M+], 325(42), 249(45), 208(100), 91(16), 77(24);
mp 99−100 °C (lit.17a mp 98−99 °C).
2-Methyl-2,4-bis(4-ethylphenyl)-2,3-dihydro-1H-1,5-benzodiaze-
pine (3c). Purification by column chromatography (petroleum ether/
EtOAc, 10/1) as a yellow oil (61.2 mg, 83%): IR (neat) ν = 3337,
2-Methyl-2,4-bis(4-ethoxyphenyl)-2,3-dihydro-1H-1,5-benzodia-
zepine (3e). Purification by column chromatography (petroleum
ether/EtOAc, 10/1) as a brown solid (68.1 mg, 85%): IR (KBr) ν =
1
3050, 2966, 1606, 1510, 1315 cm−1; H NMR (CDCl3, 500 MHz) δ
7.59−7.52 (m, 4H), 7.37−7.30 (m, 1H), 7.12−7.04 (m, 6H), 6.85 (dd,
J1 = 1.5 Hz, J2 = 7.5 Hz, 1H), 3.56 (br s, 1H), 3.11 (d, J = 13.0 Hz,
1H), 3.0 (d, J = 13.0 Hz, 1H), 2.65−2.60 (m, 4H), 1.77 (s, 3H), 1.25−
1.19 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 170.0, 145.2, 143.2,
1
3347, 2977, 2927, 1604, 1510, 1469 cm−1; H NMR (CDCl3, 500
MHz) δ 7.62−7.31 (m, 5H), 7.08−7.04 (m, 2H), 6.84−6.76 (m, 5H),
4.06−3.98 (m, 4H), 3.43 (br s, 1H), 3.06 (d, J = 13.0 Hz, 1H), 2.93 (d,
D
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Note
253(39), 213(100), 95(10), 77(4); mp 106−107 °C (lit.17a mp 104−
105 °C).
Scheme 3. Proposed Mechanism
2-Methyl-2,4-bis(thiophen-2-yl)-2,3-dihydro-1H-1,5-benzodiaze-
pine (3k).17c Purification by column chromatography (petroleum
ether/EtOAc, 10/1) as a brown solid (62.9 mg, 97%): IR (KBr) ν =
1
3335, 3072, 2971, 1593, 1467, 1429 cm−1; H NMR (CDCl3, 500
MHz) δ 7.42−7.35 (m, 2H), 7.13−6.94 (m, 7H), 6.85−6.84 (m, 1H),
3.64 (br s, 1H), 3.08 (d, J = 13.5 Hz, 1H), 3.01 (d, J = 13.5 Hz, 1H),
1.86 (s, 3H); MS (EI, 70 eV) m/z (%) = 324(34) [M+], 309(27),
241(10), 200(100), 109(2), 77(4); mp 90−91 °C (lit.17c mp 92−93
°C).
2-Methyl-2,4-dicyclopropyl-2,3-dihydro-1H-1,5-benzodiazepine
(3l). Purification by column chromatography (petroleum ether/EtOAc,
10/1) as a pale-yellow oil (46.1 mg, 96%): IR (neat) ν = 3341, 3078,
1
3004, 2961, 1628, 1471, 1307 cm−1; H NMR (CDCl3, 500 MHz) δ
7.08−7.06 (m, 1H), 6.94−6.93 (m, 2H), 6.70−6.69 (m, 1H), 2.88 (br
s, 1H), 2.36 (d, J = 12.5 Hz, 1H), 2.28 (d, J = 13.0 Hz, 1H), 1.88−1.84
(m, 1H), 1.17 (s, 3H), 1.16−1.12 (m, 3H), 0.97−0.95 (m, 2H), 0.64−
0.61 (m, 1H), 0.49−0.41 (m, 2H), 0.28−0.26 (m, 1H); 13C NMR
(CDCl3, 125 MHz) δ 175.7, 140.0, 137.8, 126.9, 124.9, 121.33, 121.28,
69.8, 43.5, 26.6, 22.4, 20.5, 9.8, 9.4, 1.2, 0.4; MS (EI, 70 eV) m/z (%) =
240(45) [M+], 225(32), 199(77), 183(16), 171(16), 158(100),
132(22), 77(12); HRMS (EI) for C16H20N2 calcd. 240.1626, found
240.1624.
J = 13.5 Hz, 1H), 1.74 (s, 3H), 1.44−1.38 (m, 6H); 13C NMR
(CDCl3, 125 MHz) δ 167.3, 160.5, 157.9, 140.6, 140.0, 138.1, 132.1,
128.9, 128.2, 126.6, 125.9, 121.8, 121.5, 114.2, 113.9, 73.4, 63.5, 42.8,
29.7, 14.8, 14.7; MS (EI, 70 eV) m/z (%) = 400(32) [M+], 385(43),
238(100), 207(28), 119(27), 77(6); HRMS (EI) for C26H28N2O2
calcd. 400.2151, found 400.2155; mp 104−106 °C.
2-Methyl-2,4-dibutyl-2,3-dihydro-1H-1,5-benzodiazepine
(3m).17d Purification by column chromatography (petroleum ether/
EtOAc, 10/1) as a yellow oil (25.1 mg, 46%): IR (neat) ν = 3343,
1
2958, 2929, 2865, 1681, 1638, 1468 cm−1; H NMR (CDCl3, 500
MHz) δ 7.15−7.13 (m, 1H), 6.99−6.97 (m, 2H), 6.73−6.71 (m, 1H),
3.10 (br s, 1H), 2.57 (t, J = 7.8 Hz, 2H), 2.23 (d, J = 13.0 Hz, 1H),
2.15 (d, J = 12.5 Hz, 1H), 1.73−1.55 (m, 4H), 1.46−1.42 (m, 2H),
1.36−1.32 (m, 4H), 1.28 (s, 3H), 0.99−0.93 (m, 6H); MS (EI, 70 eV)
m/z (%) = 272(11) [M+], 257(7), 175(44), 132(22), 92(7), 77(4).
2-Methyl-2,4-dihexyl-2,3-dihydro-1H-1,5-benzodiazepine (3n).
Purification by column chromatography (petroleum ether/EtOAc,
10/1) as a yellow oil (31.5 mg, 48%): IR (neat) ν = 3354, 2954, 2927,
2-Methyl-2,4-bis(4-chlorophenyl)-2,3-dihydro-1H-1,5-benzodia-
zepine (3f).17a Purification by column chromatography (petroleum
ether/EtOAc, 10/1) as a yellow solid (73.2 mg, 96%): IR (KBr) ν =
1
3338, 3061, 2972, 1599, 1481, 1328 cm−1; H NMR (CDCl3, 500
MHz) δ 7.56−7.49 (m, 4H), 7.33−7.31 (m, 1H), 7.24−7.21 (m, 4H),
7.13−7.06 (m, 2H), 6.85 (dd, J1 =1.5, J2 = 7.5 Hz, 1H), 3.45 (br s,
1H), 3.09 (d, J = 13.5 Hz, 1H), 2.91 (d, J = 13.5 Hz, 1H), 1.76 (s,
3H); MS (EI, 70 eV) m/z (%) = 380(25) [M+], 365(38), 228(100),
207(32), 102(13), 77(9); mp 144−146 °C (lit.17a mp 146−147 °C).
2-Methyl-2,4-bis(3-chlorophenyl)-2,3-dihydro-1H-1,5-benzodia-
zepine (3g).7e Purification by column chromatography (petroleum
ether/EtOAc, 10/1) as a yellow solid (60.2 mg, 79%): IR (KBr) ν =
1
2859, 1679, 1465, 1375 cm−1; H NMR (CDCl3, 500 MHz) δ 7.15−
7.14 (m, 1H), 7.00−6.96 (m, 2H), 6.73−6.72 (m, 1H), 3.10 (br s,
1H), 2.57 (t, J = 8.0 Hz, 2H), 2.23 (d, J = 13.0 Hz, 1H), 2.15 (d, J =
13.0 Hz, 1H), 1.74−1.53 (m, 4H), 1.43−1.38 (m, 2H), 1.35−1.31 (m,
12H), 1.28 (s, 3H), 0.92−0.89 (m, 6H); 13C NMR (CDCl3, 125
MHz) δ 175.3, 140.8, 137.9, 127.1, 125.4, 121.8, 121.7, 70.7, 43.4,
42.9, 42.5, 31.8, 31.7, 29.8, 29.2, 27.6, 26.5, 24.2, 22.6, 14.1, 14.0; MS
(EI, 70 eV) m/z (%) = 328 (9) [M+], 313(9), 243(100), 203(16),
173(67), 133(23), 77(4); HRMS (EI) for C22H36N2 calcd. 328.2878,
found 328.2875.
1
3338, 3066, 2972, 1601, 1566, 1471 cm−1; H NMR (CDCl3, 500
MHz) δ 7.62−7.08 (m, 11H), 6.87 (dd, J1 = 1.5 Hz, J2 = 7.5 Hz, 1H),
3.48 (br s, 1H), 3.10 (d, J = 13.5 Hz, 1H), 2.92 (d, J = 13.0 Hz, 1H),
1.77 (s, 3H); MS (EI, 70 eV) m/z (%) = 380(31) [M+], 365(38),
269(78), 228(100), 102(12), 77(8); mp 104−106 °C.
2-Methyl-2,4-bis(2-chlorophenyl)-2,3-dihydro-1H-1,5-benzodia-
zepine (3h).17b Purification by column chromatography (petroleum
ether/EtOAc, 10/1) as a yellow solid (38.9 mg, 51%): IR (KBr) ν =
2,7,8-Trimethyl-2,4-diphenyl-2,3-dihydro-1H-1,5-benzodiazepine
(3p).17e Purification by column chromatography (petroleum ether/
EtOAc, 10/1) as a yellow solid (62.0 mg, 91%): IR (KBr) ν = 3332,
1
3293, 3061, 2967, 1619, 1476, 1432 cm−1; H NMR (CDCl3, 500
1
2969, 2922, 1613, 1466, 1325 cm−1; H NMR (CDCl3, 500 MHz) δ
MHz) δ 7.77−7.75 (m, 1H), 7.31−6.85 (m, 10H), 6.26 (dd, J1 = 1.5
Hz, J2 = 7.5 Hz, 1H), 4.42 (d, J = 13.5 Hz, 1H), 4.12 (br s, 1H), 2.97
(d, J = 13.5 Hz, 1H), 1.90 (s, 3H); MS (EI, 70 eV) m/z (%) =
380(37) [M+], 365(100), 269(93), 152(54), 102(25), 77(20); mp
115−116 °C (lit.17b mp 114−115 °C).
7.63−7.59 (m, 4H), 7.32−7.16 (m, 7H), 6.66 (s, 1H), 3.44 (br s, 1H),
3.15 (d, J = 13.0 Hz, 1H), 2.98 (d, J = 13.5 Hz, 1H), 2.28 (s, 6H), 1.77
(s, 3H); MS (EI, 70 eV) m/z (%) = 340(45) [M+], 325(68), 263(74),
222(100), 207(28), 77(23); mp 137−139 °C (lit.17e mp 136−138
°C).
2-Methyl-2,4-bis(4-bromophenyl)-2,3-dihydro-1H-1,5-benzodia-
zepine (3i).17a Purification by column chromatography (petroleum
ether/EtOAc, 10/1) as a brown solid (91.2 mg, 97%): IR (KBr) ν =
2,7,8-Trimethyl-2,4-ditoluyl-2,3-dihydro-1H-1,5-benzodiazepine
(3q).17c Purification by column chromatography (petroleum ether/
EtOAc, 10/1) as a yellow solid (70.0 mg, 95%): IR (KBr) ν = 3286,
1
3337, 3059, 2970, 1607, 1478, 1392 cm−1; H NMR (CDCl3, 500
1
2969, 2918, 1608, 1471, 1324 cm−1; H NMR (CDCl3, 500 MHz) δ
MHz) δ 7.49−7.31 (m, 9H), 7.28−7.06 (m, 2H), 6.85 (dd, J1 = 1.5
Hz, J2 = 7.5 Hz, 1H), 3.45 (br s, 1H), 3.08 (d, J = 13.5 Hz, 1H), 2.90
(d, J = 13.0 Hz, 1H), 1.75 (s, 3H); MS (EI, 70 eV) m/z (%) = 470
(48) [M+], 455(48), 274(100), 207 (56), 115(12), 77(6); mp 148−
150 °C (lit.17a mp 145−146 °C).
7.58 (d, J = 7.0 Hz, 2H), 7.48 (d, J = 6.0 Hz, 2H), 7.18−7.09 (m, 5H),
6.64 (s, 1H), 3.45 (br s, 1H), 3.10 (d, J = 12.0 Hz, 1H), 2.98 (d, J =
13.0 Hz, 1H), 2.35 (s, 3H), 2.31 (s, 3H), 2.26 (s, 6H), 1.73 (s, 3H);
MS (EI, 70 eV) m/z (%) = 368(26) [M+], 353(30), 250(11),
236(100), 207(39), 77(10); mp 145−146 °C (lit.17c mp 142−144
°C).
2,7,8-Trimethyl-2,4-bis(4-chlorophenyl)-2,3-dihydro-1H-1,5-ben-
zodiazepine (3r).17c Purification by column chromatography (petro-
leum ether/EtOAc, 10/1) as a yellow solid (80.2 mg, 98%): IR (KBr)
ν = 3278, 2969, 2917, 1591, 1481, 1317 cm−1; 1H NMR (CDCl3, 500
MHz) δ 7.53−7.48 (m, 4H), 7.23−7.16 (m, 5H), 6.65 (s, 1H), 3.38
2-Methyl-2,4-bis(4-fluorophenyl)-2,3-dihydro-1H-1,5-benzodia-
zepine (3j).17a Purification by column chromatography (petroleum
ether/EtOAc, 10/1) as a yellow solid (66.9 mg, 96%): IR (KBr) ν =
1
3334, 3064, 2971, 1603, 1506, 1228 cm−1; H NMR (CDCl3, 500
MHz) δ 7.60−7.38 (m, 5H), 7.14−7.07 (m, 2H), 6.95−6.87 (m, 5H),
3.48 (br s, 1H), 3.13 (d, J = 13.5 Hz, 1H), 2.93 (d, J = 13.0 Hz, 1H),
1.78 (s, 3H); MS (EI, 70 eV) m/z (%) = 348(39) [M+], 333(87),
E
dx.doi.org/10.1021/jo300543n | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(br s, 1H), 3.09 (d, J = 13.0 Hz, 1H), 2.89 (d, J = 13.5 Hz, 1H), 2.26
(s, 6H), 1.74 (s, 3H); MS (EI, 70 eV) m/z (%) = 408(8) [M+],
393(11), 256(9), 207(100), 133(11), 77(5); mp 183−184 °C (lit.17c
mp 182−184 °C).
(petroleum ether/EtOAc, 10/1) as a yellow solid (55.8 mg, 78%,
3y:3′y > 99:1); data of 3y: 1H NMR (CDCl3, 500 MHz) δ 8.31 (d, J =
2.5 Hz, 1H), 7.95 (dd, J1 = 2.5 Hz, J2 = 8.5 Hz, 1H), 7.62−7.60 (m,
2H), 7.40−7.35 (m, 3H), 7.31−7.23 (m, 4H), 7.20−7.17 (m, 1H),
6.82 (d, J = 9.0 Hz, 1 H), 4.74 (br s, 1H), 3.43 (d, J = 13.5 Hz, 1H),
3.11 (d, J = 14.0 Hz, 1H), 1.83 (s, 3H).
2,4-Dicyclopropyl-2,7,8-trimethyl-2,3-dihydro-1H-1,5-benzodia-
zepine (3s). Purification by column chromatography (petroleum
ether/EtOAc, 10/1) as a yellow oil (52.1 mg, 97%): IR (neat) ν =
1
3441, 3081, 3003, 2923, 1628, 1450, 1305 cm−1; H NMR (CDCl3,
ASSOCIATED CONTENT
■
500 MHz) δ 6.87 (s, 1H), 6.50 (s, 1H), 2.79 (br s, 1H), 2.34 (d, J =
12.5 Hz, 1H), 2.26 (d, J = 12.5 Hz, 1H), 2.18 (s, 6H), 1.89−1.85 (m,
1H), 1.16−1.10 (m, 6H), 0.95−0.94 (m, 2H), 0.62−0.58 (m, 1H),
0.49−0.40 (s, 2H), 0.28−0.25 (m, 1H); 13C NMR (CDCl3, 125 MHz)
δ 175.2, 137.7, 135.6, 133.3, 129.5, 128.1, 122.5, 69.6, 43.6, 26.5, 22.5,
20.6, 19.2, 18.8, 9.7, 9.3, 1.3, 0.6; MS (EI, 70 eV) m/z (%) = 268(43)
[M+], 253(32), 227(29), 199(12), 186(100), 171(10), 160(12),
77(8); HRMS (EI) for C18H24N2 calcd. 268.1939, found 268.1944.
2-Methyl-2,4-diphenyl-2,3-dihydro-7,8-dichloro-1H-1,5-benzo-
diazepine (3t).17a Purification by column chromatography (petroleum
ether/EtOAc, 10/1) as a yellow solid (51.1 mg, 67%): IR (KBr) ν =
S
* Supporting Information
Optimization of reaction conditions; copies of 1H NMR and/or
13C NMR of the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ykuiliu@zjut.edu.cn; greensyn@zjut.edu.cn.
■
Notes
1
3305, 3059, 2969, 1605, 1454, 1324 cm−1; H NMR (CDCl3, 500
The authors declare no competing financial interest.
MHz) δ 7.57−7.55 (m, 4H), 7.43 (s, 1H), 7.36−7.20 (m, 6H), 6.95 (s,
1H), 3.63 (br s, 1H), 3.30 (d, J = 13.5 Hz, 1H), 2.99 (d, J = 13.5 Hz,
1H), 1.78 (s, 3H); MS (EI, 70 eV) m/z (%) = 380(50) [M+], 365(42),
303(74), 207(100), 103(46), 77(35); mp 161−162 °C (lit.17a mp
158−160 °C).
ACKNOWLEDGMENTS
■
Financial support from the Natural Science Foundation of
China (No. 21172197) and Zhejiang Province (No.
Y4100201), the Foundation of Science and Technology
Department of Zhejiang Province (2011R09002-09), and the
Opening Foundation of Zhejiang Provincial Top Key Discipline
is gratefully acknowledged.
2-Methyl-2,4-bis(4-fluorophenyl)-2,3-dihydro-7,8-dichloro-1H-
1,5-benzodiazepine (3u). Purification by column chromatography
(petroleum ether/EtOAc, 10/1) as a yellow solid (66.8 mg, 80%): IR
(KBr) ν = 3336, 3051, 2956, 1606, 1482, 1227 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 7.55−7.45 (m, 5H), 6.97−6.91 (m, 5H), 3.59
(br s, 1H), 3.16 (d, J = 13.5 Hz, 1H), 2.91 (d, J = 13.5 Hz, 1H), 1.78(s,
3H); 13C NMR (CDCl3, 125 MHz) δ 167.9, 164.3 (d, J = 251.3 Hz),
162.0 (d, J = 246.3 Hz), 142.2, 137.4, 134.6, 131.0 (d, J = 10.0 Hz),
129.6, 129.4 (d, J = 8.8 Hz), 127.2 (d, J = 8.8 Hz), 124.7, 122.1, 115.7
(d, J = 10.0 Hz), 115.3 (d, J = 21.3 Hz), 115.2 (d, J = 21.3 Hz), 73.0,
43.4, 30.0; MS (EI, 70 eV) m/z (%) = 416(53) [M+], 401(42),
281(100), 207(44), 95(16), 77(3); HRMS (EI) for C22H16 Cl2F2N2
calcd. 416.0659, found 416.0662; mp 179−180 °C.
2,8-Dimethyl-2,4-diphenyl-2,3-dihydro-1H-1,5-benzodiazepine
(3v) and 2,7-Dimethyl-2,4-diphenyl-2,3-dihydro-1H-1,5-benzodia-
zepine (3′v).17f Purification by column chromatography (petroleum
ether/EtOAc, 10/1) as a yellow solid (62.0 mg, 95%, 3v:3′v = 62:38):
1H NMR (CDCl3, 500 MHz) δ 7.64−7.58 (m, 4H), 7.33−7.18 (m,
7H), 6.92 (dd, J1 = 2.0 Hz, J2 = 8.0 Hz, 0.38H, 3′v), 6.87 (dd, J1 = 1.0
Hz, J2 = 8.0 Hz, 0.62H, 3v), 6.78 (d, J = 7.5 Hz, 0.38H, 3′v), 6.68 (s,
0.62H, 3v), 3.51 (br s, 1H), 3.17 (d, J = 13.0 Hz, 0.62H, 3v), 3.13 (d, J
= 13.0 Hz, 0.38H, 3′v), 3.00 (d, J = 13.0 Hz, 0.62H, 3v), 2.98 (d, J =
13.0 Hz, 0.38H, 3′v), 2.37 (s, 1.86H, 3v), 2.36 (s, 1.14H, 3′v), 1.78 (s,
1.86H, 3v), 1.76 (s, 1.14H, 3′v).
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pine (3w) and 2-Methyl-2,4-diphenyl-2,3-dihydro-7-chloro-1H-1,5-
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(petroleum ether/EtOAc, 10/1) as a yellow solid (45.8 mg, 66%,
1
3w:3′w = 94:6): H NMR (CDCl3, 500 MHz) δ 7.59−7.56 (m, 4H),
7.35−7.19 (m, 7H), 7.06−7.04 (q, 0.06H, 3′w), 7.02−7.00 (q, 0.94H,
3w), 6.87 (d, J = 2.0 Hz, 0.94H, 3w), 6.79 (d, J = 8.0 Hz, 0.06H, 3′w),
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pine (3x) and 2-Methyl-2,4-diphenyl-2,3-dihydro-7-bromo-1H-1,5-
benzodiazepine (3′x).17g Purification by column chromatography
(petroleum ether/EtOAc, 10/1) as a yellow solid (61.4 mg, 72%,
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7.34−7.14 (m, 8H), 7.01 (d, J = 2.0 Hz, 1 H), 3.61 (br s, 0.97H, 3x),
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F
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