Terminal alkynes as keto-methyl equivalent toward one pot synthesis of 1,5-benzodiazepine derivatives under catalysis of Hg(OTf)2

Article abstract of DOI:10.1016/j.tetlet.2012.01.036

Mercuric triflate catalyzes the reaction between 1,2-diaminobenzene and terminal alkynes to afford 2,4-disubstituted 2-methyl-2,3-dihydro-1H-benzo[b][1, 4]diazepine in an excellent yield. The terminal alkynes function as a source of keto-methyl equivalent.

Full text of DOI:10.1016/j.tetlet.2012.01.036

Tetrahedron Letters 53 (2012) 1460–1463
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Tetrahedron Letters
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Terminal alkynes as keto-methyl equivalent toward one pot synthesis
of 1,5-benzodiazepine derivatives under catalysis of Hg(OTf)2
⇑
Gourhari Maiti , Utpal Kayal, Rajiv Karmakar, Rudraksha N. Bhattacharya
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Mercuric triflate catalyzes the reaction between 1,2-diaminobenzene and terminal alkynes to afford 2,4-
disubstituted 2-methyl-2,3-dihydro-1H-benzo[b][1,4]diazepine in an excellent yield. The terminal
alkynes function as a source of keto-methyl equivalent.
Received 30 September 2011
Revised 6 January 2012
Accepted 9 January 2012
Available online 15 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Alkynes
1,5-Benzodiazepines
o-Phenylenediamines
Mercuric triflate
Benzodiazepines and its derivatives constitute an important
class of heterocyclic compounds, which possess a wide range of
therapeutic and pharmacological properties. Benzodiazepines en-
hance the effect of the neurotransmitter gamma-aminobutyric acid
(GABA), which results in sedative, hypnotic, anxiolytic, anticonvul-
sant, muscle-relaxant, and amnesic action.1 These properties make
benzodiazepines useful in treating anxiety, insomnia, agitation,
seizures, muscle spasms, alcohol withdrawal, and as a premedica-
tion for medical or dental procedures.2 Depending on the substitu-
tion pattern and nature of substituents, benzodiazepines can have
a wide range of half life. Short- and intermediate-acting benzodi-
azepines are preferred for the treatment of insomnia whereas
longer-acting benzodiazepines are recommended for the treat-
ment of anxiety.3 Although the benzodiazepine was first intro-
duced as a drug candidate nearly 40 years ago, the research in
this area is very active and is directed toward the synthesis of com-
pounds of enhanced pharmacological activity. In the last decade,
the area of biological interest of 1,5-benzodiazepines has been ex-
tended to several diseases such as cancer, viral infection, and car-
diovascular disorders.4 Moreover, 1,5-benzodiazepines are key
intermediates for the synthesis of various fused ring systems such
as triazolo-, oxadiazolo-, oxazino-, or furanobenzodiazepines.5 In
addition, benzodiazepine derivatives also have also of commercial
their importance as dyes for acrylic fibers in photography.6 Owing
to versatile applications, several methods for the synthesis of ben-
zodiazepines have been reported in the literature.
Most of the methods reported in the literature either involve (i)
condensation of o-phenylenediamines with a,b-unsaturated keto-
nes7a,b or (ii) the reaction of o-phenylenediamines with various
ketones using varieties of reagents and catalysts. These include
BF3ꢀEt2O,8a NaBH4,8b polyphosphoric acid,8c CAN,8d TCT,8e and also
under solvent-free conditions using MgO and POCl3,9a Yb(OTf)3,9b
CeCl3ꢀ7H2O/NaI supported on silica gel,9c Sc(OTf)3,9d InBr3,9e sul-
fated zirconia,9f ZnCl2,9g and SiO2/ZnCl2.9h Al2O3/P2O5
or
10a
AcOH10b under microwave conditions, Amberlyst-15 in ionic
liquids10c and 1,3-di-n-butylimidazolium bromide10d as solvent
without any catalyst have also been reported for this reaction.
Apart from these, various other catalysts have also been explored
under solvent-free conditions.11a–d
Recently, there is a report of [4+2+1] cycloaddition of o-pheny-
lene diamines with 2 equiv of alkynoate ester under solvent-free
ultrasonic irradiation conditions which afforded the 3,4-disubsti-
tuted 1,5-benzodiazepines in a good yield.12 Srinivasan and co-
workers disclosed a multicomponent reaction involving an acyl
chloride, aryl acetylene, and phenylenediamine to obtain 2,4-disub-
stituted-3H-benzo[b][1,4]diazepines.13 However, to the best of our
knowledge there is no report of employing aryl or alkyl substituted
terminal acetylenes directly as keto-methyl equivalent for this
transformations. We were interested to develop new synthetic
route to benzodiazepines from o-phenylenediamines and terminal
alkynes as delineated in Scheme 1.
Multicomponent reactions (MCRs) offer the elegance of one-pot
reaction, atom-economy, and the possibility of introducing maxi-
mum diversity in the product in one chemical operation and have
become an integral part of drug discovery program.14 As a part of
our continuing program15 we were interested to explore the MCR
⇑
Corresponding author. Tel./fax: +91 33 2414 6223.
E-mail address: ghmaiti123@yahoo.co.in (G. Maiti).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.036

G. Maiti et al. / Tetrahedron Letters 53 (2012) 1460–1463
1461
Table 2
H
N
R
Synthesis of benzodiazepinesa
NH2
NH2
R
H
N
N
R1
R1
NH2
R
Hg(OTf)2
R
R
ethanol, rt
NH2
N
R1
R1
Scheme 1. Route to benzodiazepines.
1(a-d)
2(a-h)
3aa-3ch
Entry 1,2-Diamine
R1=
Time
(h)
Yieldb
(%)
Productc
methods toward the synthesis of biologically relevant heterocy-
cles. Herein, we wish to report a new synthetic route to 2-
methyl-2,4-disubstituted-2,3-dihydro-1H-benzo[b][1,4]diazepine
starting from various phenylenediamines and terminal alkyne
derivatives in the presence of Hg(OTf)2 at room temperature in
dry ethanol solution in an excellent yield.
We began our investigation by the reactions of o-phenylenedi-
amine 1a and phenyl acetylene 2a as model substrate to optimize
the reaction conditions by using various Lewis acid catalysts, sol-
vents, and catalyst-solvent combination. We put a special empha-
sis on Au(III) and Hg(II) salts as catalysts in an effort to standardize
the reaction due to their ability to polarize the carbon–carbon
triple bonds making them more susceptible to nucleophilic attack.
Moreover, in recent times there had been a trend to explore the
catalytic properties of Hg(II) triflate.16 The results are summarized
in Table 1.
From the Table 1, it is evident that mercuric triflate and ethanol
were found to be the most effective catalyst and solvent respec-
tively both in terms of reaction time and yield. The optimum quan-
tity of catalyst was screened and it was found that on increasing
the amount of catalyst from 0.5 to 2 mol %, yield of the reaction in-
creases gradually but beyond 2 mol %, there is no significant
improvement of the rate as well as yield of the reaction. Employing
HAuCl4 as catalyst, a product of polymeric nature was obtained
which could not be characterized.
Encouraged by these results, we tried to generalize the scope
and versatility of this methodology. Various 1,2-diamines and dif-
ferently substituted terminal aryl- and alkyl acetylenes were used
for the synthesis of substituted 1,5-benzodiazepines.17 In case of
internal alkynes such as methyl phenyl acetylene the reaction
did not proceed at all under similar reaction condition. The out-
come of our endeavors is summarized in Table 2.
NH2
1
Phenyl 2a
6.5
8.0
6.0
24
90
89
80
49
3aa
3ab
3ac
3ad
NH2
1a
2
3
4
1a
1a
1a
4-Bromophenyl
2b
4-Chlorophenyl
2c
4-
Methoxyphenyl
2d
3-Nitrophenyl 2e
n-Hexyl 2f
n-Butyl 2g
5
6
7
1a
1a
1a
24
8.5
5.0
43
84
84
3ae
3af
3ag
NH2
NH2
8
2a
1.0
97
3ba
1b
9
10
11
12
13
14
1b
1b
1b
1b
1b
1b
2b
2e
2d
2c
2g
2h
1.5
24
2.5
2.5
5.5
1.0
92
51
62
83
87
93
3bb
3be
3bd
3bc
3bg
3bh
4-Methylphenyl
NH2
NH2
15d
2a
4.5
84
3ca
1c
1e
16d
17d
18d
1c
1c
1c
2b
2e
2h
2.0
2.0
3.5
97
45
81
3cb
3ce
3ch
NH2
NH2
19
20
2a
2a
24
24
00
00
NRe
O2N
N
NH2
NRe
NH2
1d
a
Reaction condition: o-phenylenediamine (1.0 mmol), terminal acetylene
(2.2 mmol) in 3 mL ethanol, mercuric triflate (0.02 mmol), rt.
b
Pure, isolated yield after column chromatography.
Table 1
c
All products were characterized by IR, 1H NMR, 13C NMR.
Screening of reaction conditions for the synthesis of 1,5-benzodiazepines with 1a and
d
Mixture of regioisomers are formed in the ratio of approximately 2:3.
No reaction.
2aa
e
H
Ph
N
NH2
NH2
Ph
Catalyst (2 mol%)
solvent, rt
From Table 2, it is evident that the reaction proceeds smoothly
with the terminal alkynes. Electronic nature of functional groups
on aryl rings of both diamine and terminal acetylene had a marked
effect on the rate as well as yield of the reaction. 4-Methoxyphenyl-
acetylene (Table 2, entry 4) reacted much slower compared to phe-
nyl acetylene (Table 2, entry 1) itself and yield was also lower.
These observations may be explained by considering the nucleo-
philic addition of amino group to the Hg(II)–alkyne complex to be
slow in case of 4-methoxyphenylacetylene. The electron donating
ability of the aryl ring, which is highest for the methoxyl group
and least for the nitro group, may explain this observation. How-
ever, under the similar reaction condition, we observed that in case
of 3-nitrophenylacetylene, reaction was sluggish and also low
yielding. Moreover, along with the desired benzodiazepine, it fur-
nished 3-nitroacetophenone as by product. To account for the
above observation and to understand the mechanistic pathway,
various aryl acetylenes were subjected to react with wet ethanol
in the presence of mercuric triflate. Only in case of 3-nirophenyl-
acetylene we were able to isolate 3-nitroacetophenone in a 25%
N
Ph
Ph
1a
3aa
2a
Entry
Catalyst
Solvent
Time (h)
Yieldb (%)
c
c
c
1
2
3
4
5
6
7
8
9
10
11
12
13
HAuCl4
HAuCl4
HAuCl4
Hg(OTf)2
Hg(OTf)2
Hg(OTf)2
HgCl2
HgCl2
FeCl3
Yb(OTf)3
Cu(OTf)2
Cu(OTf)2
TfOH
DCM
THF
Ethanol
THF
Ethanol
DCM
12
12
12
24
6.5
24
12
10
24
24
24
24
24
65
90
46
54
82
THF
Ethanol
Ethanol
Ethanol
Ethanol
THF
3
c
c
c
c
Ethanol
a
Reaction condition: o-phenylenediamine (1.0 mmol), phenylacetylene
(2.2 mmol) in 3 mL solvent, catalyst (0.02 mmol), rt.
b
Pure, isolated yield after column chromatography.
Product not formed.
c

1462
G. Maiti et al. / Tetrahedron Letters 53 (2012) 1460–1463
Ph
regioisomeric mixture showed the presence of two regioisomers
in 1:1.65 ratio, the same proportion in which 3bh and 3bd were
formed.
In summary, we have developed a mild and efficient reaction
between o-phenylenediamines and terminal alkynes leading to 2-
methyl-2,4-disubstituted-2,3-dihydro-1H-benzo[b][1,4]diazepines
using Hg(OTf)2 catalyst with high atom economy. The notable
advantages of this method are operational simplicity, mild reaction
conditions, low catalyst loading, ease of isolation of products, and
non-toxic ethanol as solvent.
TfOH
Ph
NH
Ph
NH2
NH2
NH
NH2
HgOTf
Hg(OTf)2
HgOTf
NH2
Ph
Ph
H
Ph
Ph
N
NH
N
Ph
Ph
Ph
NH2
N
H
NH2
HgOTf
HgOTf
Ph
HgOTf
Ph
Acknowledgments
N
N
TfOH
Ph
N
H
We gratefully acknowledge the financial and infrastructural
support from UGC-CAS and PURSE-DST program of the Department
of Chemistry, Jadavpur University. U.K. (JRF) and R.K. (SRF) thanks
CSIR, New Delhi for the award of their research fellowships.
Ph
N
H
HgOTf
3aa
Figure 1. Plausible mechanism of the reaction.
Supplementary data
yield but in all other cases only trace amount of acetophenone
derivatives were obtained. This observation suggests that for all
other aryl acetylenes, the reaction occurs between Hg(II)–alkynes
complex and phenylenediamine. However, for 3-nitrophenylacety-
lene, at least in part, the reaction may proceed through an aceto-
phenone intermediate. This is further supported by the fact that
when substituted acetophenones were made to react with o-phen-
ylenediamine under similar reaction condition, yields were low
even after prolonged stirring at room temperature. On the basis of
the above observations we suggest the following major reaction
pathway for this transformation (Fig. 1).
1,2-Diamines containing an electron withdrawing group as well
as electron deficient aromatic ring such as 4-nitro-o-phenylenedi-
amine (Table 2, entry 19) and 2,3-diaminopyridine (Table 2, entry
20) did not react under this reaction condition. On the other hand
reactions with 4,5-dimethyl-o-phenylenediamine was much faster
than the corresponding 1,2-phenylenediamine.
The reaction of various arylacetylene derivatives with 4-methyl-
o-phenylenediamine furnished the corresponding benzodiazepines
as a mixture of two regioisomers, which could not be separated by
usual column chromatography. In contrast to the earlier report of
regioisomer in equimolecular proportion by Yao and co-workers 8e
in case of 4-methyl-o-phenylenediamine, we obtained a mixture
of inseparable regioisomers approximately in the ratio of 2:3 and
it was almost independent on the substitutions pattern in the aro-
matic ring of aryl acetylenes (Table 2, entries 15–18). The ratio
was determined from the 1H NMR spectrum by comparison of the
integrations of C-7 and/or C-10 aromatic proton signals at d 6.64–
6.67 and at d 7.13–7.16 for the two regioisomers.
In an effort to explore the scope of the reaction using two differ-
ent alkynes, 4,5-dimethyl-o-phenylenediamine (1b) was made to
react with 2d and 2h under Hg(OTf)2 catalysis (Scheme 2). Pure
3bh (yield 25%) and 3bd (yield 15%) were formed in 1:1.65 ratio
along with regioisomeric mixture (yield 53%) of 4bdh and 4bd0h0.
The regioisomeric mixture of 4bdh and 4bd0h0 could not be sepa-
rated by usual column chromatography. 1H NMR spectrum of the
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.036.
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Scheme 2. Formation of mixed benzodiazepines.

G. Maiti et al. / Tetrahedron Letters 53 (2012) 1460–1463
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7.65 (m, 8H, major + minor isomers). 13C NMR (75 MHz, CDCl3): d 20.6, 21.0,
29.7, 30.0, 43.0, 43.3, 72.9, 73.9, 121.5, 122.3, 125.4, 127.0, 127.1, 128.0, 128.3,
128.6, 128.9, 129.6, 129.7, 131.3, 135.5, 136.4, 137.1, 138.0, 139.5, 139.7, 140.3,
147.6, 147.7, 166.8, 167.9. HRMS calculated for C23H22N2Na+ 349.1681 found
349.1685.
Spectral data of 2-methyl-2,4-bis(4-bromophenyl)-2,3-dihydro-8-methyl-1H-
1,5-benzodiazepine 3cb (approximately 2:3 regioisomeric mixture): Yellow
crystalline solid. mp 127–129 °C. Rf = 0.4 (silica: petroleum ether/ethyl acetate,
9:1). 1H NMR (300 MHz, CDCl3): d 1.72 (s, 3H, minor isomer), 1.73 (s, 3H, major
isomer), 2.34 (s, 3H, major isomer), 2.35 (s, 3H, minor isomer), 2.86 (d,
J = 13.2 Hz, 1H, minor isomer), 2.88 (d, J = 13.2 Hz, 1H, major isomer), 3.03 (d,
J = 13.2 Hz, 1H, minor isomer), 3.09 (d, J = 13.2 Hz, 1H, major isomer), 3.45 (br
s, 2H, major + minor isomers), 6.65 (s, 1H, major isomer), 6.75 (d, J = 7.9 Hz, 1H,
minor isomer), 6.86 (dd, J = 1.5, 8.0 Hz, 1H, major isomer), 6.91 (dd, J = 1.9,
8.0 Hz, 1H, minor isomer), 7.13 (d, J = 1.5 Hz, 1H, minor isomer), 7.22 (d,
J = 8.0 Hz, 1H, major isomer), 7.34-7.50 (m, 16H, major + minor isomer). 13C
NMR (75 MHz, CDCl3): d 20.5, 21.0, 29.5, 29.9, 42.8, 43.1, 72.7, 73.7, 121.1,
121.5, 122.7, 124.4, 124.6, 127.4, 128.4, 128.5 128.6, 128.9, 131.2, 131.3, 131.7,
135.0, 136.7, 136.8, 137.5, 138.0, 138.3, 140.0, 146.3, 146.4, 165.2, 166.3. HRMS
calculated for C23H20Br2N2Na+ 504.9885 found 504.9890.
17. Representative experimental procedure: To a solution of phenylacetylene
(225 mg, 2.2 mmol) in 3 mL ethanol, o-phenylenediamine (108 mg, 1.0 mmol)
and Hg(OTf)2 (10 mg, 0.02 mmol) were added and stirred at room temperature
for 6.5 h. Completion of the reaction was monitored by TLC. After completion of
reaction, the reaction mixture was quenched with water, extracted with
dichloromethane, dried over anhydrous sodium sulphate, and volatiles were
removed. The crude residue was purified by short column chromatography
over silica-gel (60–120 mesh) using 5% ethylacetate/petroleum ether mixture
afforded 2-methyl-2,4-diphenyl-2,3-dihydro-1H-benzo[b][1,4]diazepine (3aa)
(281 mg, 90%) as
a
yellow crystalline solid; mp 148–150 °C (lit.9e150–
152 °C). Rf = 0.5 (silica: petroleum ether/ethyl acetate, 9:1) 1H NMR
(300 MHz, CDCl3): d 1.77 (s, 3H), 2.99 (d, J = 13.1 Hz, 1H), 3.17 (d, J = 13.1 Hz,
1H), 3.60 (br s, 1H), 6.86 (dd, J = 1.8, 7.5 Hz, 1H), 7.03–7.13 (m, 2H), 7.16–7.20
Spectral data of 2-methyl-2,4-bis(4-methylphenyl)-2,3-dihydro-8-methyl-1H-
1,5-benzodiazepine 3ch (2:3 regioisomeric mixture): Yellow crystalline solid.
mp 85–87 °C. Rf = 0.6 (silica: petroleum ether/ethyl acetate, 9:1). 1H NMR
(300 MHz, CDCl3): d 1.72 (s, 3H, minor regioisomer), 1.73 (s, 3H, major isomer),
2.32 (br s, 9H, minor isomer), 2.35 (s, 9H, major isomer), 2.96 (d, J = 13.1 Hz,
1H, minor isomer), 2.98 (d, J = 13.2 Hz, 1H, major isomer), 3.06 (d, J = 13.2 Hz,
1H, minor isomer), 3.09 (d, J = 13.2 Hz, 1H, major isomer), 3.49 (br s, 2H,
major + minor isomers), 6.64 (d, J = 1.2 Hz, 1H, major isomer), 6.74 (d,
J = 7.9 Hz, 1H, minor isomer), 6.83–6.92 (m, 2H, major + minor isomers),
7.07–7.12 (m, 8H, minor + minor isomer), 7.16–7.17 (m, 1H, minor isomer),
7.25 (d, J = 7.9 Hz, 1H, major isomer), 7.45–7.52 (m, 4H, major + minor
(m, 1H), 7.20–7.34 (m, 5H), 7.39 (dd, J = 1.8, 7.2 Hz, 1H), 7.57–7.63 (m, 4H). 13
C
NMR (75 MHz, CDCl3): d 29.9, 43.2, 73.9, 121.3, 121.6, 125.4, 126.3, 127.0,
128.0, 128.3, 128.6, 129.7, 138.0, 139.4, 140.1, 147.6, 168.0. HRMS calculated
for C22H20N2Na+ 335.1519 found 335.1517.
Spectral
data
of
2-methyl-2,4-diphenyl-2,3-dihydro-8-methyl-1H-1,5-
benzodiazepine 3ca (approximately 2:3 regioisomeric mixture): Yellow
crystalline solid. mp 86–88 °C. Rf = 0.5 (silica: petroleum ether/ethyl acetate,
9:1). 1H NMR (300 MHz, CDCl3): d 1.76 (s, 3H, minor regioisomer), 1.77 (s, 3H,
major regioisomer), 2.36 (s, 3H, major isomer), 2.37 (s, 3H, minor isomer), 2.97
(d, J = 13.2 Hz, 1H, minor isomer), 2.99 (d, J = 13.2 Hz, 1H, major isomer), 3.12
(d, J = 13.0 Hz, 1H, minor isomer), 3.17 (d, J = 13.2 Hz, 1H, major isomer), 3.52
(br s, 2H, major + minor isomers), 6.67 (s, 1H, major isomer), 6.77 (d, J = 7.9 Hz,
1H, minor isomer), 6.87 (dd, J = 1.2, 8.0 Hz, 1H, major isomer), 6.92 (dd, J = 1.5,
7.9 Hz, 1H, minor isomer), 7.16–7.34 (m, 14H, major + minor isomers), 7.57–
isomers), 7.54–7.60 (m, 4H, major + minor). 13C NMR (75 MHz, CDCl3):
d
20.6, 20.9, 21.0, 21.3, 29.7, 29.9, 42.7, 43.1, 72.6, 73.5, 121.4, 121.5, 122.3,
125.2, 125.2, 126.8, 127.1, 127.2, 127.6, 128.5, 128.8, 128.9, 131.2, 135.6, 136.1,
136.4, 136.6, 136.9, 137.1, 137.3, 138.1, 139.8, 140.0, 140.5, 145.1, 166.7, 167.8.
HRMS calculated for C25H26N2Na+ 377.1988 found 377.1984.