1260
Published on the web July 13, 2013
One-pot Synthesis of 2,3-Benzodiazepines from Arynes and ¢-Diketones
Kentaro Okuma,* Yukiko Tanabe, Ryoichi Itoyama, Noriyoshi Nagahora, and Kosei Shioji
Department of Chemistry, Fukuoka University, Jonan-ku, Fukuoka 814-0180
(Received June 22, 2013; CL-130580; E-mail: kokuma@fukuoka-u.ac.jp)
Novel one-pot synthesis of 2,3-benzodiazepines from aryne
CH3
CH3
N
CH3
N
H2C
precursors was accomplished. Tofisopam, well-known anxio-
lytics, could be synthesized via C-C bond insertion of 4,5-
dimethoxybenzyne with 2-ethyl-1-(3,4-dimethoxyphenyl)-
butane-1,3-dione, followed by the reaction with hydrazine
hydrate in a one-pot operation. This protocol is applicable to
the synthesis of other biologically active 2,3-benzodiazepines,
such as Girisopam and Nerisopam.
CH3
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
N
OMe
Cl
1b Girisopam
NH2
MeO
1a Tofisopam
1c Nerisopam
Figure 1.
Synthesis of 2,3-benzodiazepines 1 was first aimed at finding
active papaverine-related derivatives with cardiovascular activ-
ity. These substances act as tranquillizing agents, and they show
no muscle-relaxant and anticonvulsant character in rodents.1 The
most active derivative, Tofisopam (Grandaxin1) (1a) was found
to be a highly active nonsedative, anxiolytic in humans.2 Other
2,3-benzodiazepines such as Girisopam (1b) and Nerisopam (1c)
were also found to be biologically active (Figure 1).
O
R
R
R
R
R
N
R
Ar
N
O
O
Ar
O
+
Ar
These 2,3-benzodiazepines were generally synthesized by
four-step reactions starting from arylacetones or arylethanols.3
Although synthesis of 1,4-dimethyl-2,3,4,5-tetrahydro-(1H)-1,4-
benzodiazepin-5-one by reaction of benzyne prepared from
o-trimethylsilylphenyl triflate 2 and KF with 1,3-dimethyl-2-
imidazolidinone was reported by Yoshida et al., there is no
report on the straightforward synthesis of 2,3-benzodiazepines
1.4 Recently, we have reported the direct synthesis of
4-substituted 2-naphthols by the reaction of benzyne with
1,3-diketones, intermediates of which were 2-acetylmethylben-
zophenones.5 Given our interest in the synthesis of nitrogen-
containing heterocycles,6 we speculated on the possibility of a
short-step synthesis of 2,3-benzodiazepines such as 1a, 1b, and
1c from arynes as shown in Figure 2. Herein, we report the one-
pot synthesis of 2,3-benzodiazepines 1 by sequential two-step
reaction starting from 2-trimethylsilylphenyl triflates 2 and
aroylacetones 3.
We first attempted the reaction of 4,5-dimethoxy-2-trime-
thylsilylphenyl triflate (2a) with 4-nitrobenzoylacetone (3a)7 in
the presence of CsF in acetonitrile to optimize the reaction
conditions. Treatment of 2a with 3a in the presence of CsF in
acetonitrile at rt resulted in the formation of 2-acetylmethyl-4,5-
dimethoxy-4¤-nitrobenzophenone (4a) in 21% yield (Table 1,
Entry 1). The results are shown in Table 1.
Figure 2.
Table 1. Reaction of 2a with p-nitrobenzoylacetone (3a)
MeO
TMS
MeO
MeO
MeO
OTf
O
CsF
2a
O
CH3CN
r.t.
O
O
+
NO2
NO2
3a
4a
2
Temp
/°C
Time
/h
Product 4a
/%
Entry
/equiv
1
2
3
4
5
6
0.7
1.1
1.1
1.7
1.7
2.0
rt
rt
40
rt
40
rt
18
15
8
10
6
21
32
43
61
56
52
10
When 1.1 equiv of 2a was treated with 3a at rt for 15 h, 4a
was obtained in 32% yield (Entry 2). When the reaction was
carried out at 40 °C, 4a was obtained in 43% yield (Entry 3).
When 1.7 equiv of 2a was reacted with 3a at rt, 4a was obtained
in 61% yield,8 whereas elevated temperature resulted in the
formation of 4a in 56% yield (Entries 4 and 5). Using excess
amount of 2a resulted in the formation of less amount of 4a
(Entry 6).
intramolecularly attacked aroyl carbonyl carbon to give four-
membered intermediate b. Ring-opening of the intermediate b
gave ortho-substituted benzophenone 4a (Scheme 1).
When the reaction was carried out in refluxing acetonitrile,
an intramolecular aldol reaction followed by dehydration
proceeded to give 6,7-dimethoxy-4-(4-nitrophenyl)-2-naphthol
(5a) in 52% yield (Scheme 2).
Since the optimum conditions were obtained (rt, 1.7 equiv of
2a, 10 h), we then tried the synthesis of other 2-(acetylmethyl)-
benzophenones 4. Treatment of 2a with 3-chlorobenzoylacetone
The reaction would proceed as follows: fluoride-induced
enolate attacked aryne to give the corresponding anion a, which
Chem. Lett. 2013, 42, 1260-1262
© 2013 The Chemical Society of Japan