Synthesis of 2,3-benzodiazepines and 2,3-benzodiazepin-4-ones from arynes and β-diketones

Article abstract of DOI:10.1246/bcsj.20150064

2,3-Benzodiazepines were synthesized by two-step or one-pot reactions from aryne precursors. Reaction of 2- (trimethylsilyl)aryl triflates with β-diketones in the presence of CsF gave ortho-substituted benzophenones. Treatment of benzophenones with hydrazine hydrate resulted in the formation of 2,3-benzodiazepines in moderate yields. Tofisopam, a well known anxiolytic, could be synthesized via C-C bond insertion of 3,4-dimethoxybenzyne with 2-ethyl-1-(3,4-dimethoxyphenyl)butane-1,3-dione, followed by the reaction with hydrazine hydrate in one-pot operation. 2,3-Benzodiazepin-4-ones were also synthesized by the reaction of β-keto esters with triflates in the presence of CsF, followed by the addition of hydrazine hydrate. Substituted isoquinolines were synthesized by the reaction of ortho-substituted benzophenones with ammonium hydroxide.

Full text of DOI:10.1246/bcsj.20150064

Advance Publication Cover Page
Synthesis of 2,3-Benzodiazepines and 2,3-Benzodiazepin-4-ones from Arynes and
-Diketones
Kentaro Okuma,* Yukiko Tanabe, Noriyoshi Nagahora, and Kosei Shioji
Advance Publication on the web April 28, 2015 by J-STAGE
doi:10.1246/bcsj.20150064
© 2015 The Chemical Society of Japan

Synthesis of 2,3-Benzodiazepines and 2,3-Benzodiazepin-4-ones from Arynes and
-Diketones
Kentaro Okuma,* Yukiko Tanabe, Noriyoshi Nagahora, and Kosei Shioji
Department of Chemistry, Fukuoka University
Jonan-ku, Fukuoka 814-0180, Japan
Received: February, 27, 2015; E-mail: kokuma@fukuoka-u.ac.jp
Abstract: 2,3-Benzodiazepines were synthesized by two step or one-pot reactions from
aryne precursors. Reaction of 2-(trimethylsilyl)aryl triflates with -diketones in the
presence of CsF gave ortho-substituted benzophenones. Treatment of
benzophenones with hydrazine hydrate resulted in the formation of
2,3-benzodiazepines in moderate yields. Tofisopam, well known anxiolytics,
could be synthesized via C-C bond insertion of 3,4-dimethoxybenzyne with
2-ethyl-1-(3,4-dimethoxyphenyl)butane-1,3-dione, followed by the reaction with
hydrazine hydrate in one pot operation.
2,3-Benzodiazepin-4-ones were also
synthesized by the reaction of -keto esters with triflates in the presence of CsF,
followed by the addition of hydrazine hydrate. Substituted isoquinolines were
synthesized by the reaction of ortho substituted benzophenones with ammonium
hydroxide.
Introduction
Arynes are highly reactive intermediates that have been widely used in organic
synthesis.1 Reaction of aryne with -keto compounds provides a useful tool on the
1

synthesis of ortho-substituted ketones via carbon-carbon insertion reaction.2
Benzodiazepines have received considerable attention in recent times because of their
psychoactive ability.3 Especially, 2,3-benzodiazepines (1) act as tranquillizing agents
without any muscle relaxant and anti convulsant character in rodents.4 Synthesis of
2,3-benzodiazepines 1 was firstly aimed at finding active papaveine-related derivatives
with cardiovascular activity. The most active derivative, Tofisopam (Grandaxin) 1a
was found to be a highly active non-sedative, anxiolytic in humans.5 Other
2,3-benzodiazepines and 2,3-benzodiazepin-3-ones such as Girisopam, Nerisopam, and
BDZ-2 were also found to be biologically active (Figure 1).6
Et
O
NH
MeO
MeO
MeO
MeO
O
O
MeO
MeO
N
N
N
N
N
N
N
OMe
Cl
Girisopam
NH2
NH2
MeO
Tofisopam
Nerisopam
BDZ-2
Figure 1. Biologically active 2,3-benzodiazepines
These 2,3-benzodiazepines were previously synthesized by four-step reactions
starting from arylacetones or arylethanols.7 Recently, we have reported the synthesis
of 4-aryl-2-naphthols by the reaction of 2-(trimethylsilyl)phenyl triflate (2) with
-diketones and CsF via intramolecular cyclization.8 Given our interest in the
synthesis of nitrogen-containing heterocycles,9 we speculated on the possibility of a
short step synthesis of 2,3-benzodiazepines and communicated the synthesis of
2,3-benzodiazepines starting from 2-(trimethylsilyl)aryl triflates 2, aroylacetones (3),
and hydrazine hydrate.10 The advantage of this method include short step reaction,
commercial availability of starting materials (triflates, -diketones, and -ketoesters),
and the possibility of one-pot synthesis. Herein, we report the full details of one-pot
2

synthesis of 2,3-benzodiazepines and 2,3-benzodiazepin-4-ones such as Tofisopam,
Girisopam and Girisopam derivatives starting from triflates 2, aroylacetones 3,
and-ketoesters as shown in Figure 2.
R
R
R
R
R
N
O
R
O
O
N
O
Ar
Ar
+
Ar
O
O
R
R
O
R
R
OEt
NH
R
Ar
R
N
O
Ar
O
+
EtO
Ar
Figure 2. Retrosynthetic analysis of 2,3-benzodiazepines
Results and Discussion
Synthesis of ortho-substituted acetophenones
To standardize the reaction conditions, a series of experiments were performed
under varying reaction parameters, such as time and temperature for a representative
reaction of 4,5-dimethoxy-2-trimethylsilylphenyl triflate (2a). Treatment of 2a with
4-nitrobenzoylacetone 3a in the presence of CsF in acetonitrile at rt for 18 h resulted in
the formation of 2-acetylmethylbenzophenone (4a) in 21% yield (Table 1, Entry 1).
The results are shown in Table 1.
3

Table 1. Reaction of 2a with benzoylacetone 3a and 3b
TMS
OTf
MeO
MeO
O
MeO
MeO
MeO
MeO
O
+
O
CsF
OH
2a
O
O
CH3CN
+
R
R
R
3a: R= p-NO2
3b: R= H
4a: R= p-NO2
4b: R= H
5a: R= p-NO2
5b: R= H
Entry
2a
3a
Temp
(oC)
rt
Time
(h)
18
12
8
Products
(%)
(equiv) or 3b
4
5
1
2
3
4
5
6
0.7
1.1
1.1
1.7
1.7
1.7
3a
3a
3a
3a
3a
3b
4a
4a
4a
4a
4a
4b
21
32
43
63
56
61
0
0
0
0
0
8
5a
5a
5a
5a
5a
5b
rt
40
rt
8
40
8
rt
8
When 1.1 equiv. of 2a was treated with 3a at rt for 12 h, 4a was obtained in 32% yield
(Entry 2). When the reaction was carried out at 40oC, 4a was obtained in 43% yield
(Entry 3). When 1.7 equiv. of 2a was reacted with 3a at rt, 4a was obtained in 63%
yield, whereas elevated temperature resulted in the formation of 4a in 56% yield
(Entries 4 and 5). When 3b was used as a substrate, 4b was obtained in 61% along
with 5b (8%, Entry 6), which might be formed via intramolecular aldol condensation of
regioisomer (a’) as shown in Scheme 1.
4

O
O
CsF
2a
Cl
O
O
O
O
4b
Cl
a
Cl
Cl
Cl
O
O
O
O
a'
Cl
Cl
O
O
H
5b
C
H
H
C
H
H
O
O
Scheme 1. Formation mechanism of 4b and 5b from triflate 2a and diketone 3b.
Since the optimum conditions were obtained (rt, 1.7 eq of 2, 8 h), we then tried the
synthesis of other 2-acetylmethylbenzophenones 4.
4-nitrobenzoylacetone 3a and CsF resulted
Treatment of 2b with
the formation of
in
2-acetylmethyl-4,5-dimethoxybenzophenone 4c in 42% yield. By using substituted
triflates 2a-2e, other benzophenones 4a-4h were synthesized in moderate yields (Table
2).
5

Table 2. Synthesis of compounds 4 from 2, 3, and CsF.
Table 2.
R
O
O
TMS
OTf
R
R
CsF
O
+
Ar
CH3CN
rt, 8h
R
Ar
O
3a: Ar=p-NO2C6H4
3b: R= m-ClC6H4
3c: R= C6H5
2a: R= OMe
2b: R= H
2c: R= Me
2d: R= OCH2O
2e: E= F
4
O
O
Cl
NO2
O
O
4b
4a
63%
51%
MeO
MeO
MeO
MeO
Cl
O
O
NO2
O
O
4d
42%
4c
42%
O
O
Me
Me
O
O
NO2
NO2
O
O
4e
41%
O
41%
4f
F
F
F
F
O
Cl
NO2
O
O
4g
42%
4h
56%
Similarly, CsF mediated reaction of -ketoesters (6) with triflates 2, following the
conditions reported by Stoltz et al.,2 afforded the 2-aroylarylacetate esters (7).
(Table
3.) Yields were better than those using aroylacetones 3 as substrates due to
regioselective addition to the aroyl carbons of -ketoesters (Table 1).
6

Table 3. Synthesis of ethyl 2-aroylarylacetates 7 from 2,6, and CsF.
O
O
O
TMS
OTf
R
R
R
R
Ar
O
CsF
+
Ar
6a: Ar= Ph
6b: Ar= m-ClC6H4
6c: Ar= 3,4-(MeO)2C6H3
OEt
CH3CN
OEt
2a-2d
7
Cl
O
O
MeO
MeO
O
O
MeO
MeO
OEt
OEt
82%
O
7a
56%
7b
O
OMe
OMe
MeO
O
O
MeO
OEt
OEt
7c 52%
quant.
O
7d
OMe
OMe
O
Me
O
OEt
O
Me
OEt
47%
7f
56%
O
7e
O
Cl
O
O
Me
Me
O
O
OEt
OEt
7g
7h
53%
95%
O
Cl
O
F
F
O
O
O
O
OEt
OEt
7j
7i
81%
70%
O
Cl
F
O
F
OEt
7k quant.
7

Reaction of ortho-substituted benzophenones with hydrazone
To confirm the present method provides a general short-step synthesis of
2,3-benzodiazepines, reaction of 4a with hydrazine hydrate in refluxing butanol was
tried. As expected, benzodiazepine 1a was obtained in 63% yield. Other diazepines
1b-1f were synthesized in moderate yields (Table 3).
Table 4. Synthesis of benzodiazepines
R
R
R
R
O
NH2NH2 .H2O
N
N
BuOH
reflux
O
R'
4a: R = H, R' = p-NO2
4b: R = H, R' = m-Cl
4c: R = OMe, R' = p-NO2
4d: R = OMe, R' = m-Cl
4e: R = Me, R' = H
R
1a-1f
4f: R = OCH2O, R' = p-NO2
N
N
N
N
Cl
1b 45%
NO2
1a
32%
MeO
MeO
MeO
MeO
N
N
N
N
Cl
NO2
63%
1c
1d
65%
Me
Me
O
O
N
N
N
N
NO2
43%
NO2
1e
1f
55%
8

Nerisopam (1c’) has also shown anxiolytic and neuroleptic activity in animal
studies,4 which could be easily synthesized by reduction of 1c by Sn/HCl in 86% yield
(Scheme 2).
MeO
MeO
MeO
MeO
Sn/HCl
N
N
N
N
EtOH/H2O
NO2
NH2
1c' (Nerisopam)
1c
Scheme 2. Synthesis of Nerisopam 1c’.
Since our method provides a short-step synthesis of benzodiazepines, we have tried
the preparation of Tofisopam (1g) in one-pot operation. Treatment of triflate 2a with
2-ethyl-1-(3,4-dimethoxyphenyl)butane-1,3-dione (3d) in the presence of CsF for 8 h
followed by the addition of hydrazine hydrate in refluxing EtOH resulted in the
formation of Tofisopam 1g and 2-ethyl-1,2-bis(3,4-dimethoxyphenyl)butane-1,3-dione
(8) in 45% and 32% yields, respectively. Similarly, Girisopam 1b was synthesized in
one-pot operation (33％) (Scheme 3).
9

TMS
OTf
MeO
MeO
MeO
MeO
N
NH2NH2
CsF
N
2a
CH3CN
rt, 8h
EtOH
reflux
6h
O
O
OMe
OMe
MeO
1g 45%
OMe
O
O
3d
OMe
+
OMe
OMe
MeO
8
32%
TMS
MeO
MeO
MeO
MeO
OTf
NH2NH2
N
CsF
2a
N
CH3CN
rt, 8h
EtOH
reflux
6h
O
O
Cl
Cl
3b
1b (Girisopam)
Scheme 3. Synthesis of Tofisopam 1g and Girisopam 1b.
Previously, Müllar et al. synthesized Tofisopam 1g starting from
1-(3,4-dimethoxyphenyl)-1,3-dibromobutane via four-step reaction (Scheme 4).11
Thus, the present method provides a versatile synthesis of benzodiazepines in one-pot
operation.
Br
Br Br
MeO
MeO
MeO
MeO
OMe
OMe
MeO
MeO
MeO
MeO
MeO
MeO
O
O
N
N
OMe
OMe
OMe
OMe
OMe
OMe
1g
10

Scheme 4. Reported synthesis of Tofisopam 1g
Synthesis of 2,3-benzodiazepin-4-ones
Since 2,3-benzodiazepin-4-ones (9) were generally synthesized from substituted
arylacetic acid via 4 step reactions,6 we have tried the two-step synthesis of 9 from
aryne precursors. First step was already shown in Table 3, thus, the reaction of ethyl
2-aroylphenylacetate 7 with hydrazine hydrate was tried. Treatment of aroylacetate
ester 7a with hydrazine hydrate in refluxing butanol for 8 h resulted in the formation of
2,3-benzodiazepin-4-one 9a in 83% yield. As shown in Table 5, other reaction of ethyl
aroylacetates7b-7g
with
hydrazine
hydrate
gave
the
corresponding
2,3-benzodiazepin-4-ones 9 in 53-83% yields.
Table 5. Synthesis of 2,3-benzodiazepine-4-ones.
OEt
O
R
R
H2N-NH2 . H2O (18 eq)
O
NH
O
R
Solvent
N
R
Ar
Ar
7
9
9
7
R
Ar
Solv. Temp./oC
Yield/%
7a
7b
MeO
MeO
C6H5
BuOH
BuOH
reflux
reflux
9a
9b
83
53
m-ClC6H4
7c
H
3,4-(MeO)2C6H3 EG
160
9c
60
7d
Me
m-ClC6H4
C6H5
EG
160
9d
9e
9f
72
59
60
29
7e -OCH2O-
BuOH
BuOH
BuOH
reflux
reflux
reflux
7f
-OCH2O-
F
m-ClC6H4
C6H5
7g
9g
Synthesis of substituted isoquinolines
Since Stoltz et al. synthesized one-pot synthesis of 3-hydroxyisoquinolines from
aryne precursors 2b and -keto esters,12 we applied this method to the one-pot synthesis
11

of 1-aryl-3-alkylsubstituted isoquionolines. 1-Phenylisoquinolines are important
ligands for the synthesis of palladium, platinum, iridium complexes, which show novel
red phosphorescence and applied to the synthesis of organic electroluminescent
devices.13 Treatment of triflate 2a with 4-nitrobenzoylacetone 3a in the presence of
CsF at rt for 8 h followed by the addition of ammonium hydroxide for additional 10 h at
60 oC resulted in the formation of
1-(4’-nitrorophenyl)-3-methyl-6,7-dimethoxyisoquinoline (10a) in 32% yield. As
shown in Table 6, substituted isoquinolines 10 were synthesized in one-pot operation
starting from commercially available 2 and diketones 3.
Table 6. One-pot synthesis of substituted isoquinolines
1) CsF (3.0 eq)
O
O
2)
R
R
TMS
OTf
R
R
Ar
3
NH4OH
60 oC
N
MeCN
rt
Ar
2a: R= OMe
2b: R= H
2d: R= OCH2O
3a: Ar=p-NO2C6H4
3b: Ar= m-ClC6H4
10a: R= OMe, Ar= p-NO2C6H4
10b: R= OMe, Ar= m-ClC6H4
10c: R= H, Ar= p-NO2C6H4
10d: R= OCH2O, Ar= p-NO2C6H4
Entry
2
Time 1
3
Time 2/ hr
10
Yield /%
1
2
3
4
2a
2a
2b
2d
8
3a
3b
3a
3a
10
48
24
2
10a
10b
10c
10d
32
25
54
30
1.4
1
1.5
Conclusion
We have developed a completely new method on the synthesis of
2,3-benzodiazepines and 2,3-benzodiazepin-4-ones from (2-trimethylsilyl)aryltriflates.
The reaction requires only two-step reaction. A completely different strategy for the
one-pot synthesis 1-arylisoquinolines from aryne precursors was accomplished.
12

Experimental Section
General: All chemicals were obtained from commercial suppliers and were used
without further purification. Analytical TLC was carried out on precoated plates
(Merck silica gel 60, F254) and flash column chromatography was performed with
13
silica (Merck, 70-230 mesh). NMR spectra (1H at 400 MHz; C at 100 MHz) were
recorded in CDCl3, and chemical shifts are expressed in ppm relative to internal TMS
for 1H and 13C NMR. Melting points were uncorrected.
Reaction of Triflate 2a with 4-Nitrobenzoylacetone at rt
To a solution of 4-nitrobenzoylacetone 3a (79 mg, 0.22 mmol) and CsF (100 mg, 0.66
mmol) in acetonitrile (3 mL) was added triflate 2a (86 mg, 0.24 mmol) in acetonitrile (2
mL). After being stirred for 15 h at rt, 5 mL of water was added to the reaction
mixture and the mixture was concentrated to 6 mL, extracted with dichloromethane (5
mL x 3). The combined extract was dried over sodium sulfate, filtered, and evaporated
to give brown oil, which was chromatographed over silica gel by elution with
hexane-ethyl
acetate
(3:1)
to
afford
2-acetylmethyl-4,5-dimethoxy-(4’-nitro)benzophenone 4a (22 mg, 0.064 mmol).
When 1.7 eq of 2a (182 mg, 0.51 mmol), CsF (227 mg, 1.5 mmol), and 3a (62 mg, 0.30
mmol) were used at rt for 15h, 4a (65 mg, 0.19 mmol) was obtained in 63% yield.
Other reaction was carried out in a similar manner.
4a: Yellow oil; 1H NMR (CDCl3)= 2.26 (s, 3H, CH3), 4.12 (s, 2H, CH2), 7.30 (d, J =
7 Hz, 1H, ArH), 7.34-7.36 (m, 2H, ArH), 7.51-7.55 (m, 1H, ArH), 7.98 (d, J = 9 Hz, 2H,
ArH), 8.31 (d, J = 9 Hz, 2H, ArH). 13C NMR (CDCl3) = 30.0, 48.0, 123.4, 126.5,
123.4, 126.5, 130.3, 131.1, 131.9, 132.2, 134.8, 136.9, 143.0, 150.0, 196.4, 205.1;
13

HRMS: m/z Calcd for C16H13NO4 283.0845. Found: 283.0835 (M+).
4b: Yellow oil; 1H NMR (CDCl3)  = 2.20 (s, 3H, CH3), 4.02 (s, 2H, CH2), 7.33 - 7.42
(m, 4H, ArH), 7.51 (t, J = 8 Hz, 1H, ArH), 7.55 (d, J = 8 Hz, 1H, ArH), 7.67 (d, J = 8
Hz, 1H, ArH), 7.80 (s, 1H, ArH). 13C NMR (CDCl3) = 29.9, 48.1, 126.5, 128.5, 129.6,
130.1, 130.3, 131.4, 132.1, 132.7, 134.6, 134.7, 137.2, 139.5, 196.8, 205.3; HRMS:
Calcd for C16H13ClO2 m/z (%)= 272.0604 (M+, 100), 274.0575 (M+2, 32). Found m/z =
272.0604 (M+, 100), 274.0583 (M+2, 32).
1
5b: Yellow oil; H NMR (CDCl3) = 2.12 (s, 1H, OH), 3.02 (d, J = 17 Hz, 1H, CH2),
3.21 (d, J = 16 Hz, 1H, CH2), 3.28 (d, J = 16 Hz, 1H, CH2), 3.58 (d, J = 17 Hz, 1H,
CH2), 7.28-7.42 (m, 5H, ArH), 7.54 (d, J = 7 Hz, 1H, ArH), 7.57 (s, 1H, ArH), 8.08 (d, J
= 8 Hz, 1H, ArH); 13C NMR (CDCl3) = 43.5, 51.33, 74.98, 122.9, 125.3, 127.0, 127.2,
128.0, 129.5, 130.0, 131.6, 134.3, 134.7, 140.0, 147.8, 196.2 (s, C=O). HRMS: Calcd
for C16H13ClO2 m/z (%)= 272.0604 (M+, 100), 274.0575 (M+2, 32). Found m/z =
272.0601 (M+, 100), 274.0553 (M+2, 32).
4c: pale yellow solid. mp 157-159oC (ref14 mp 156-158oC. 1H NMR (CDCl3)  = 2.25 (s,
3H, CH3), 3.75 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 4.02 (s, 2H, CH2), 6.75 (s, 1H, Ar),
6.85 (s, 1H, Ar), 7.92 (d, 2H, J= 8 Hz, Ar), 8.31 (d, 2H, J = 8 Hz, Ar); 13C NMR
(CDCl3)= 30.1 (CH3), 48.4 (CH2), 56.4 (OCH3), 56.4 (OCH3), 114.7, 115.3, 123.7,
128.5, 130.3, 131.0, 144.2, 147.1, 150.1, 152.3 (Ar), 195.5 (C=O), 205.8 (C=O). Anal.
Calcd for C18H17NO6; C, 62.97; H, 4.99; N, 4.08. Found; C, 62.89; H, 4.91; N, 4.20.
1
4d: Pale yellow solid; mp 100-101oC (ref.4 mp 108-110oC. H NMR (CDCl3)= 2.23
(s, 3H, CH3), 3.78 (s, 3H, CH3O), 3.94 (s, 2H, CH2), 3.96 (s, 3H, OCH3), 6.76 (s, 1H,
ArH), 6.93 (s, 1H, ArH), 7.40(t, J = 8 Hz, 1H, ArH), 7.56 (d, J = 8 Hz, 1H, ArH), 7.64
(d, J = 8.0 Hz, 1H, ArH), 7.77 ( s, 1H, ArH).
14

4e: Yellow oil; 1H NMR (CDCl3)= 2.23 (s, 6H, CH3), 2.30 (s, 3H, CH3), 4.03 (s, 2H,
CH2), 7.05 (s, 1H, ArH), 7.10 (s, 1H, ArH), 7.94 (d, J = 9 Hz, 2H, ArH), 8.31 (d, J = 9
13
Hz, 2H,ArH). C NMR (CDCl3)= 19.3, 19.8, 29.9, 47.8, 123.4, 130.9, 132.1, 132.7,
133.8, 134.1, 135.0, 141.5, 143.7, 149.8, 196.4, 205.7. HRMS: m/z Calcd for
C18H17N3O2 307.1321. Found: 307.1322 (M+).
1
4f: Yellow solid; mp 150-152oC (ref.15 mp 151-154oC). H NMR (CDCl3)= 2.25 (s,
3H, CH3), 4.01 (s, 2H, CH2), 6.06 (s, 2H, OCH2O), 6.76 (s, 1H, ArH), 6.81 (s, 1H, ArH),
7.91 (d, J = 8 Hz, 2H, ArH), 8.31 (d, J = 8 Hz, 2H, ArH).
1
4g: Orange oil; H NMR (CDCl3)  = 2.24 (s, 3H, CH3), 4.09 (s, 2H, CH2), 7.12
(dd,3JHF = 11 Hz, 4JHF = 7 Hz, 1H, ArH), 7.19 (dd,3JHF = 10 Hz, 4JHF = 8 Hz, 1H, ArH),
7.96 (d, J = 9 Hz, 2H), 8.33 (d, J = 9 Hz); 13C NMR (CDCl3)  = 30.0, 47.2, 119.7 (d, J
= 18 Hz,), 121.4 (d, J = 18 Hz), 123.6, 131.0, 132.7 (dd, J = 5 Hz), 133.3 (dd, J = 5 Hz),
142.2, 148.8 (dd, 1JCF = 365 Hz, 2JCF = 13 Hz), 150.3, 151.3 (dd, 1JCF = 370 Hz, 2JCF
=
19
3
3
13 Hz), 194.4, 204.4. F NMR (CDCl3)  = -138.66 (ddd, JFF = 21 Hz, JFH = 10 Hz,
4JFH = 9 Hz), -138.63 (ddd, 3JFF = 21 Hz, 3JFH = 11 Hz, 4JFH = 9 Hz). HRMS: m/z; Calcd
for C16H11F2NO4; 319.0656. Found: 319.0644 (M+).
4h: Brown oil; 1H NMR (CDCl3)  = 2.22 (s, 3H, CH3), 3.99 (s, 2H, CH2), 7.10 (dd,3JHF
= 11 Hz, 4JHF = 8 Hz, 1H, ArH), 7.24 (dd,3JHF = 9 Hz, 4JHF = 8 Hz, 1H, ArH), 7.43 (t, J
= 8 Hz, 1H, ArH), 7.58 (d, J = 8 Hz, 1H, ArH), 7.63 (d, J = 8 Hz, 1H, ArH), 7.77 (s, 1H,
ArH). 13C NMR (CDCl3)  = 30.3, 47.4, 120.0 (d, J = 18 Hz), 121.5 (d, J = 18 Hz),
128.6, 130.1, 130.2, 132.7 (dd, 1JCF = 3 Hz, 2JCF = 4 Hz), 133.4, 133.9 (dd, 1JCF = 2 Hz,
1
2
1
2JCF = 4 Hz), 135.1, 139.0, 148.9 (dd, JCF = 345 Hz, JCF = 13 Hz), 151.9 (dd, JCF
=
350 Hz, 2JCF = 13 Hz), 197.8, 204.5. 19F NMR (CDCl3)  = -139.07 (ddd, 3JFF = 21 Hz,
4
3
3
4
3JFH = 10 Hz, JFH = 9 Hz), -132.58 (ddd, JFF = 21.3 Hz, JFH = 10 Hz, JFH = 9 Hz);
15

HRMS: m/z Calcd for C16H11ClF2O2; 308.0416. Found; 308.0415 (M+).
Reaction of triflate 2a with ethyl benzoylacetate
To a solution of ethyl benzoyl acetate 6a (35 mg, 0.18 mmol) and CsF (136 mg, 0.90
mmol) in acetonitrile (3 mL) was added triflate 2a (106 mg, 0.30 mmol) in acetonitrile
(2 mL). After being stirred for 8 h at rt, 5 mL of water was added to the reaction
mixture and the mixture was concentrated to 6 mL, extracted with dichloromethane (5
mL x 3). The combined extract was dried over sodium sulfate, filtered, and evaporated
to give brown oil, which was chromatographed over silica gel by elution with
hexane-ethyl acetate (3:1) to afford ethyl 2-benzoyl-4,5-dimethoxyphenylacetate 7a (44
1
mg, 0.15 mmol). 7a: colorless solid; mp 78-79oC (Ref.16 mp 78-79oC). H NMR
(CDCl3) = 1.15 (t, J = 7 Hz, 3H, CH3), 3.79 (s, 3H, OMe), 3.82 (s, 2H, CH2), 3.96 (s,
3H, OMe), 4.06 (q, J = 7 Hz, 2H, CH2), 6.86 (s, 1H, ArH), 6.94 (s, 1H, ArH), 7.46 (t, J =
8 Hz, 2H, ArH), 7.57 (t, J = 8 Hz, 1H, ArH), 7.80 (d, J = 8 Hz, 2H, ArH). 13C NMR
(CDCl3)  = 14.1, 38.7, 56.0, 56.1, 60.8, 113.9, 114.5, 128.2, 128.2, 130.2, 130.3, 132.6,
138.4, 146.9, 151.0, 171.4, 197.1. HRMS: calcd for C19H20O5 m/z = 328.1311 (M+).
Found m/z = 328.1304 (M+).
1
7b: yellow oil; H NMR (CDCl3)  = 1.17 (t, J =7 Hz, 3H, CH3), 3.80 (s, 3H, OMe),
3.82 (s, 2H, CH2), 3.96 (s, 3H, OMe), 4.08 (q, J = 7 Hz, 2H, CH2), 6.87 (s, 1H, ArH),
6.91 (s, 1H, ArH), 7.40 (t, J = 8 Hz, 1H, ArH), 7.54 (d, J = 8 Hz, 1H, ArH), 7.65 (d, J =
9 Hz, 1H, ArH), 7.66 (s, 1H, ArH). 13C NMR (CDCl3)  = 14.1, 38.8, 56.1, 56.2, 60.8,
113.9, 114.7, 128.2, 128.5, 129.6, 129.6, 130.0, 132.5, 134.6, 140.1, 147.0, 151.3, 171.3,
195.7. HRMS: calcd for C19H19ClO5 m/z = 36.09212 (M+). Found m/z = 362.0925
(M+).
16

7c: pale yellow oil; (Ref.16 mp 113-114°C). 1H NMR (CDCl3) = 1.15 (t, J = 7 Hz, 3H,
CH3), 3.77 (s, 2H, CH2), 3.82 (s, 2H, OMe), 3.93 (s, 3H, OMe), 3.95 (s, 3H, OMe), 3.95
(s, 3H, OMe), 4.06 (q, J = 7 Hz, 2H, CH3), 6.86 (s, 1H, ArH), 6.87 (d, J = 9 Hz, 1H,
ArH), 6.94 (s, 1H, ArH), 7.33 (d, J = 9 Hz, 1H, ArH), 7.49 (s, 1H,ArH). HRMS: Calcd
for C21H24O7 m/z = 388.1522 (M+). Found m/z = 388.1520 (M+).
1
7d: yellow oil; H NMR (CDCl3) = 1.11 (t, J = 7 Hz, 3H, CH3), 3.88 (s, 2H, CH2),
4.02 (q, J =7 Hz, 2H, OCH2), 7.30-7.39 (m, 3H, ArH), 7.43-7.48 (m, 3H, ArH), 7.57 (t,
J = 8 Hz, 1H, ArH), 7.81 (d, J =7 Hz, 2H, ArH). 13C NMR (CDCl3) = 14.5 (CH3),
39.3 (CH2), C, 61.2 (CH2), 126.7, 128.5, 130.2, 130.6, 131.0, 132.0, 133.1, 134.2, 138.0,
138.4 (Ar), 171.3 (C=O), 198.1 (C=O). HRMS: Calcd for C17H16O3 m/z = 268.1099
(M+). Found m/z = 268.1090 (M+).
7e: Pale yellow oil; 1H NMR (CDCl3) = 1.12 (t, J =8 Hz, 3H, CH3), 3.82 (s, 2H, CH2),
3.93 (s, 3H, OMe), 3.95 (s, 3H, OMe), 4.02 (q, J = 8 Hz, 2H, OCH2), 6.85 (d, J = 8 Hz,
1H, ArH), 7.30-7.40 (m, 4H, ArH), 7.46 (t, J = 8 Hz, 1H, ArH), 7.53 (s, 1H, ArH). 13C
NMR (CDCl3) = 14.0 (CH3), 38.7 (CH2), 56.0 (OMe), 56.1 (OMe), 60.8 (CH2), 109.7,
111.7, 126.1, 126.3, 129.3, 130.3, 130.6, 131.5, 133.5, 138.8, 149.0, 153.4, 171.2 (C=O),
196.7 (C=O). HRMS: Calcd for C19H20O5 m/z = 328.1311 (M+). Found m/z =
329.1320 (M+).
1
7f : Colorles oil; H NMR (CDCl3) = 1.12 (t, J = 7 Hz, 3H, CH3), 2.24 (s, 3H, CH3),
2.31 (s, 3H, CH3), 3.81 (s, 2H, CH2), 4.03 (q, J = 7 Hz, 2H, OCH2), 7.12 (s, 1H, ArH),
7.16 (s, 1H, ArH), 7.44 (t, J = 7 Hz, 2H, ArH), 7.56 (t, J = 7 Hz, 1H, ArH), 8.00 (d, J =
7 Hz, 2H, ArH). 13C NMR (CDCl3)  = 14.0 (CH3), 19.2 (CH3), 19.7 (CH3), 38.5 (CH2),
60.7 (CH2), 128.4, 130.2, 131.5, 131.6, 132.5, 133.1, 134.7, 135.6, 138.2, 139.9, 171.6
(C=O), 198.1 (C=O). HRMS: Calcd for C19H20O3 m/z = 296.1412 (M+). Found m/z =
17

296.1421 (M+).
1
7g: Colorles oil; H NMR (CDCl3) = 1.14 (t, J =8 Hz, 3H, CH3), 2.25 (s, 3H, CH3),
2.32 (s, 3H, CH3), 3.82 (s, 2H, CH2), 4.04 (q, J = 8 Hz, 2H, CH2), 7.13 (s, 1H, ArH),
7.14 (s, 1H, ArH), 7.39 (t, J = 8 Hz, 1H, ArH), 7.54 (d, J = 8 Hz, 1H, ArH), 7.66 (d, J =
8 Hz, 1H, ArH), 7.78 (s, 1H, ArH). 13C NMR (CDCl3) = 14.1, 19.3, 19.8, 38.5, 60.8,
128.4, 129.5, 130.0, 130.9, 131.6, 131.8, 132.5, 133.3, 133.6, 134.5, 134.9, 135.0, 140.0,
140.5, 171.5, 196.6. HRMS: Calcd for C19H19ClO3 m/z = 330.1023 (M+). Found m/z =
330.1020 (M+).
7h: Colorless oil; 1H NMR (CDCl3)  = 1.15 (t, J =7 Hz, 3H, CH3), 3.79 (s, 2H, CH2),
4.06 (q, J = 7 Hz, 2H, CH2), 6.03 (s, 2H, OCH2O), 6.84 (s, 1H, ArH), 6.88 (s, 1H, ArH),
7.45 (t, J =7 Hz, 2H, ArH), 7.56 (t, J = 8 Hz, 1H, ArH), 7.78 (d, J = 8 Hz, 2H, ArH).
13C NMR (CDCl3)  = 14.0 (CH3), 38.9 (CH2), 60.7 (CH2), 101.7, 110.6, 111.9, 128.2,
129.8, 130.1, 131.7, 132.6, 138.1, 145.9, 149.6, 171.3 (C=O), 196.8 (C=O). HRMS:
Calcd for C18H16O5 m/z = 312.0998 (M+). Found m/z = 312.1005 (M+).
1
7i: Colorles oil; H NMR (CDCl3) = 1.17 (t, J =7 Hz, 3H, CH3), 3.79 (s, 2H, CH2),
4.08 (q, J = 7 Hz, 2H, CH2), 6.05 (s, 2H, OCH2O), 6.84 (s, 1H, ArH), 6.85 (s, 1H, ArH),
7.39 (t, J = 9 Hz, 1H, ArH), 7.54 (d, J = 7 Hz, 1H, ArH), 7.65 (d, J = 9 Hz, 1H, ArH),
7.75 (s, 1H, ArH). 13C NMR (CDCl3)  = 14.6 (CH3), 39.4 (CH2), 61.3 (CH2), 102.2,
110.8, 112.4, 128.5, 129.8, 130.2, 130.4, 131.2, 132.8, 134.7, 140.1, 146.2, 150.1, 171.3
(C=O), 195.4 (C=O). HRMS: Calcd for C18H15ClO5 m/z = 346.0608 (M+). Found m/z
= 346.0610 (M+).
7j: Pale yellow oil; 1H NMR (CDCl3) = 1.14 (t, J = 7 Hz, 3H, CH3), 3.82 (s, 2H, CH2),
4.04 (q, J = 7 Hz, 2H, CH2), 7.18-7.24 (m, 2H, ArH ×2), 7.48 (t, J = 8 Hz, 2H, ArH),
7.61 (t, J = 8 Hz, 1H, ArH), 7.78 (d, J = 8 Hz, 2H, ArH). 13C NMR (CDCl3)  = 14.0
18

(CH3), 38.1 (CH2), 61.1 (CH2), 119.2 (d, J = 18 Hz), 120.8 (d, J = 18 Hz), 128.5, 130.2,
131.7 (dd, J = 3 and 4 Hz), 133.3, 134.8 (dd, J = 2 and 4 Hz), 137.1, 148.5 (dd, J = 290
and 12 Hz), 151.0 (d, J = 293 and 12 Hz), 170.4 (C=O), 195.6 (C=O). 19F NMR (376
MHz, CDCl3) = -138.9 (d, 3JFF = 21 Hz), -133.3 (d, 3JFF = 21 Hz). HRMS: Calcd for
C17H14F2O3 m/z =304.0911 (M+). Found m/z = 304.0924 (M+).
7k : Yellow oil; 1H NMR (CDCl3) = 1.16 (t, J = 7 Hz, 3H, CH3), 3.84 (s, 2H, CH2),
4.05 (q, J = 7 Hz, 2H, CH2), 7.18-7.26 (m, 2H, ArH×2), 7.42 (t, J = 8 Hz, 1H, ArH),
7.57 (d, J = 8 Hz, 1H, ArH), 7.64 (d, J = 8 Hz, 1H, ArH), 7.77 (s, 1H, ArH). 13C NMR
(CDCl3)  = 14.5 (CH3), 38.5 (CH2), 61.4 (CH2), 119.6 (d, J = 18 Hz), 121.3 (d, J = 18
Hz), 128.5, 130.0, 130.2, 132.2 (dd, J = 3 and 4 Hz), 133.4, 134.2 (dd, J = 2 and 4 Hz),
135.0, 138.9, 148.8 (dd, J = 308 and 13 Hz), 151.3 (dd, J = 312 and 13 Hz), 170.5
(C=O), 194.3 (C=O). 19F NMR (376 MHz, CDCl3) = -138.4 (ddd, 3JFF = 18 Hz, 3JFH
= 10 Hz, 4JFH = 8 Hz), -132.4 (ddd, 3JFF = 18 Hz, 3JFH = 11 Hz, 4JFH = 8 Hz). HRMS:
Calcd for C17H13ClF2O3 m/z =338.0521 (M+). Found m/z = 338.0531 (M+).
Reaction of 4a with hydrazine hydrate
To a solution of 4a (34 mg, 0.10 mmol) in EtOH (4.0 mL) was added a solution of
hydrazine hydrate (50 mg, 1.0 mmol). After stirring at rt for 16h, the mixture was
poured into water and extracted with dichloromethane.
The separated
dichloromethane solution was dried over magnesium sulfate, filtered, and evaporated to
give pale orange oil, which was chromatographed over silica gel by elution with
hexane-dichloromethane (1:1) to give 2,3-benzodiazepine 1a (20 mg, 0.06 mmol).
1a: Colorless solid; mp 175-176oC. 1H NMR (CDCl3) = 2.18 (s, 3H, CH3), 3.06 ( d,
J = 12 Hz, 1H, CH2), 3.42 (d, J = 12 Hz, 1H, CH2), 7.29 (d, J = 8 Hz, 1H, ArH), 7.34 (d,
J = 8 Hz, 1H, ArH), 7.41 (t, J = 8 Hz, 1H, ArH), 7.58 (t, J = 8 Hz, 1H, ArH), 7.86 (d, J =
19

9 Hz, 2H, ArH), 8.26 (d, J = 9 Hz, 2H, ArH). 13C NMR (CDCl3) = 23.0 (CH3), 38.8
(CH2), 123.4, 126.6, 127.3, 129.2, 129.8, 130.3, 132.1, 139.7, 144.6, 148.6, 155.2
(C=N), 157.1 (C=N). HRMS: Calcd for C16H13N3O2 m/z = 279.1008 (M+). Found m/z
= 279.1004 (M+).
1b: Pale yellow solid; mp 141-142oC. 1H NMR (CDCl3)  = 2.17 (s, 3H, CH3), 3.08 (d,
J = 12 Hz, 1H, CH2), 3.38 (d, J = 12 Hz, 1H, CH2), 7.29 - 7.38 (m, 4H, ArH), 7.40 (m,
2H, ArH), 7.54 (d, J = 8 Hz, 1H, ArH), 7.57 (d, J = 8 Hz, 1H, ArH), 7.66 (s, 1H, ArH).
13C NMR (CDCl3)  = 23.3 (CH3), 39.0 (CH2), 126.6, 127.4, 127.9, 129.7, 129.7, 129.8,
130.0, 130.4, 132.0, 134.5, 139.8, 140.8, 155.6 (C=N), 158.0 (C=N). HRMS: Calcd
for C16H13ClN2 m/z = 268.0767 (M+). Found m/z = 268.0765 (M+).
1c: Yellow solid; mp 236-238oC (ref4 mp 238-240oC). 1H NMR (CDCl3)= 2.18 (s,
3H, CH3), 2.99 (d, J =12 Hz, 1H, CH2), 3.34 (d, J = 12 Hz, 1H, CH2), 3.75 (s, 3H,
OCH3), 3.99 (s, 3H, OCH3), 6.70 (s, 1H, ArH), 6.76 (s, 1H, ArH), 7.89 (d, J = 8 Hz, 2H,
ArH), 8.27 (d, J = 8 Hz, 2H, ArH). 13C NMR (CD3CN) = 23.0 (CH3), 38.5 (CH2),
56.2 (OMe), 56.2 (OMe), 108.8, 111.8, 121.5, 123.4, 130.3, 133.2, 144.9, 148.3, 148.6,
152.6, 154.6 (C=N), 156.6 (C=N).
1d: Pale yellow crystal; mp 172-173oC (ref.4 mp 167-169oC). 1H NMR (CDCl3)  =
2.16 (s, 3H, CH3), 2.99 (d, J =12 Hz, 1H, CH2), 3.28 (d, J = 12 Hz, 1H, CH2), 3.76 (s,
3H, OCH3), 3.98 (s, 3H, OCH3), 6.74 (s, 1H, ArH), 6.76 (s, 1H, ArH), 7.34 (t, J = 8 Hz,
1H, ArH), 7.41 (d, J = 8 Hz, 1H, ArH), 7.58 (d, J = 8 Hz, 1H, ArH), 7.72 (s, 1H, ArH).
13C NMR (CDCl3) = 22.1 (CH3), 37.4 (CH2), 52.2 (OMe), 55.3 (OMe), 107.9, 111.2,
120.9, 126.9, 128.4, 128.6, 128.8, 132.3, 133.3, 139.9, 147.2, 151.4, 154.1 (C=N), 156.3
(C=N). HRMS: Calcd for C18H17ClN2O2 m/z (%)= 328.0979 (M+, 100), 330.0949
(M+2, 32). Found m/z = 328.0971 (M+, 100), 330.0948 (M+2, 32).
20

1e: Colorless solid; mp 188-189oC. 1H NMR (CDCl3)  = 2.18 (s, 3H, CH3), 2.93 (d, J
= 12 Hz, 1H, CH2), 3.30 (d, J = 12 Hz, 1H, CH2), 6.03 (s, 1H, CH2), 6.07 (s, 1H, CH2),
6.68 (s, 1H, ArH), 6.78 (s, 1H, ArH), 7.87 (d, J = 7.9 Hz, 2H, ArH), 8.26 (d, J = 8.9 Hz,
2H, ArH). 13C NMR (CDCl3)  = 19.7 (CH3), 20.1 (CH3), 23.2 (CH3), 38.5 (CH2),
123.6, 127.0, 127.8, 130.5, 130.7, 136.3, 137.4, 141.9, 145.0, 148.7, 156.1 (C=N), 157.8
(C=N). HRMS: Calcd for C18H17N3O2; m/z = 307.1321 (M+). Found: 307.1321 (M+).
1f: Yellow crystals; mp 199-202oC (ref.15 mp 200-203oC). H NMR (CDCl ) = 2.18
1
3
(s, 3H, CH3), 2.93 (d, J = 12 Hz, 1H, CH2), 3.30 (d, J = 12 Hz, 1H, CH2), 6.03 (s, 1H,
CH2), 6.08 (s, 1H, CH2), 6.67 (s, 1H, ArH), 6.78 (s, 1H, ArH), 7.87 (d, J = 8.4 Hz, 2H,
ArH), 8.26 (d, J = 8.4 Hz, 2H, ArH).
Reduction of nitrobenzodiazepine 1c
To a suspension of 1c (13 mg, 0.038 mmol) and iron powder (9 mg, 0.16 mmol) in
ethanol-water (4:1, 5 mL) was added conc. HCl (0.02 mL, 0.18 mmol) at rt. After
refluxing for 2h, resulting mixture was extracted with dichloromethane (3 ml x 3).
Saturated sodium carbonate solution (1 mL) was added to the water layer, which was
extracted with dichloromethane ( 2 mL x 3), dried over sodium sulfate, filtered, and
evaporated to give almost pure Nerisopam 1c’ (9 mg, 0.025 mmol).
1c’: Yellow crystals; mp 223-226oC (Ref4 mp 225-227oC). 1H NMR (CDCl3)= 2.13
(s, 3H, CH3), 3.04 (d, J = 12 Hz, 1H, CH2), 3.22 (d, J = 12 Hz, 1H, CH2), 3.76 (s, 3H,
MeO), 3.97 (s, 3H, MeO), 6.55-6.75 (m, 3H, ArH), 6.85 (s, 1H, ArH), 7.52 (d, J = 8
Hz,2H, ArH).
One-pot synthesis of Tofisopam 1g
To a solution of 2-ethyl-1-(3,4-dimethoxyphenyl)butan-1,3-dione 3d (50 mg, 0.20
mmol) and CsF (152 mg, 1.0 mmol) in acetonitrile (7 mL) was added triflate 2a (122
21

mg, 0.34 mmol). After being stirred for 10 h at 60oC, the reaction mixture was
evaporated to give pale yellow oil, which was added to a solution of hydrazine hydrate
(50 mg, 1.0 mmol) in EtOH (7 mL). After atanding for 16h at rt, the reaction mixture
was evaporated to give brown oil, which was chromatographed over silica gel by
elution with hexane dichloromethane (1:1) to afford Tofisopam 1g (34.4 mg, 0.09
mmol) and diketone 8 (17 mg, 0.044 mmol).
1g: Pale yellow crystals; mp 155-157oC (ref4 mp 156-157oC). 1H NMR (CDCl )  =
3
0.55 (t, J = 8 Hz, 3H, CH ), 1.97 (s, 3H, CH ), 2.30 (m, 2H, CH ), 3.74 (s, 3H, OCH ),
3
3
2
3
3.85 (s, 3H, OCH ), 3.86 (s, 3H, OCH ), 3.88 (s, 3H, OCH ), 6.35 (s, 1H, ArH), 6.70
3
3
3
(d, J = 8 Hz, 1H, ArH), 6.87 (s, 1H, ArH), 6.94 (d, J = 8 Hz, 1H, ArH), 7.55 (s, 1H,
ArH). 13C NMR (CDCl )  = 7.8 (CH3), 12.4 (CH3), 25.5, 55.5 (OCH3), 56.0 (OCH3),
3
56.0 (OCH3), 56.0 (OCH3), 72.3 (CH), 108.9, 110.1, 110.6, 111.7, 117.9, 121.5, 122.7,
127.8, 149.0, 149.1, 149.8, 151.6, 179.8. HRMS: Calcd for C H N O m/z =
;
22 26
2
4
+
382.1893. Found: 382.1896 (M ).
8: pale yellow oil: 1H NMR (CDCl )  = 0.79 (t, 3H, J = 7 Hz, Me), 2.11 (s, 3H, Me),
3
2.24 (q, 1H, J = 7 Hz, CHH), 2.67 (q, 1H, J = 7 Hz, CHH), 3.81 (s, 6H, OMe), 3.86 (s,
3H, OMe), 3.88 (s, 3H, OMe), 6.69 (d, 1H, J = 9 Hz, 1H, Ar), 6.79 (d, 1H, J = 9 Hz, Ar),
6.95 (d, 1H, J = 9 Hz, Ar), 7.05 (s, 1H, Ar), 7.30 (d, 1H, J = 8 Hz, Ar), 7.44 (s, 1H, Ar);
13C NMR (CDCl )  = 9.6 (CH3), 28.3 (CH3), 29.6 (CH2), 56.0 (OCH3), 56.0 (OCH3),
3
56.2 (OCH3), 56.2 (OCH3), 72.3 (CH), 110.0, 111.1, 111.9, 112.3, 121.5, 125.1, 128.7,
131.6, 148.4, 148.7, 148.9, 153.2, 197.6 (C=O), 205.4 (C=O). HRMS: Calcd for
+
C H O m/z = 386.1729. Found: 386.1731 (M ).
;
22 26
6
Reaction of ethyl 2-aroylphenylacetate with hydrazine hydrate.
To a solution of 7a (34 mg, 0.20 mmol) in BuOH (4.0 mL) was added a solution of
22

hydrazine hydrate (50 mg, 1.0 mmol). After refluxing for 16h, the mixture was poured
into water and extracted with dichloromethane (5 mL x 3). The separated
dichloromethane solution was dried over magnesium sulfate, filtered, and evaporated to
give pale orange oil, which was chromatographed over silica gel by elution with
hexane-dichloromethane (1:1) to give 2,3-benzodiazepin-3-one 9a (20 mg, 0.06 mmol).
9a: Colorless solid; mp 200-202oC (ref.17 mp 202-20 oC). 1H NMR (CDCl3)  = 3.51 (s,
2H, CH2), 3.72 (s, 3H, OMe), 3.97 (s, 3H, OMe), 6.67 (s, 1H, ArH), 6.85 (s, 1H, ArH),
7.41-7.49 (m, 3H, ArH), 7.63 (d, J = 7 Hz, 2H, ArH), 8.49 (br, 1H, NH); GCMS: calcd
for C17H16N2O3 m/z = 296 (M+). Found m/z = 296 (M+).
9b: Pale yellow solid; mp 263.5-265oC (Ref.18 no mp.) 1H NMR (CDCl3) = 3.50 (s,
2H, CH2), 3.74 ( s, 3H, OMe), 3.97 (s, 3H, OMe), 6.63 (s, 1H, ArH), 6.85 (s, 1H, ArH),
7.36 (t, J = 8 Hz, ArH), 7.44 (d, J = 8 Hz, 1H, ArH), 7.48 (d, 1H, 7.28 Hz, Ar), 7.67 (s,
1H, ArH), 8.73 (br, 1H, NH). 13C NMR (CDCl3)  = 41.7 (CH2), 56.1 (OCH3), 56.2
(OCH3), 110.4, 111.6, 123.0, 127.5, 129.2, 129.6, 129.7, 130.0, 134.6, 139.7, 147.8,
152.5, 160.1 (C=N), 170.7 (C=O). HRMS: Calcd for C17H15ClN2O3 m/z = 330.0771
(M+). Found m/z = 330.0766 (M+).
1
9c: Colorless oil; H NMR (CDCl3)  3.58 (s, 2H, CH2), 3.91 (s, 3H, OMe), 3.93 (s,
3H, OMe), 6.86 (d, J = 8 Hz, 1H, ArH), 7.00 (d, J = 8 Hz, 1H, ArH), 7.28-7.41 (m, 4H,
ArH), 7.55 (t, J = 8 Hz, 1H, 8.34 (br, 1H, NH). 13C NMR (CD3CN) = 42.1, 56.0
(MeO×2), 110.3, 111.2, 123.4, 126.7, 128.0, 129.8, 130.4, 131.2, 131.9, 136.2, 149.0,
150.9, 161.9, 171.2. HRMS: Calcd for C17H16N2O3 m/z (%)= 296.1161 (M+). Found
m/z = 296.1158 (M+).
9d: Colorless solid; mp 222.5-223.5oC. 1H NMR (CDCl3)  2.22 (s, 3H, CH3), 2.33
23

(s, 3H, CH3), 3.51 (s, 2H, CH2), 6.94 (s, 1H, ArH), 7.16 (s, 1H, ArH), 7.35 (t, J = 8 Hz,
1H, ArH), 7.43 (d, J = 8 Hz, 1H, ArH), 7.46 (d, J = 8 Hz, 1H, ArH), 7.63 (s, 1H, ArH),
8.44 (br, 1H, NH). 13C NMR (CD3CN) = 19.5, 19.8, 41.6, 127.5, 128.4, 129.2, 129.2,
129.6, 129.9, 130.0, 133.6, 134.5, 135.7, 139.9, 141.7, 160.7, 171.1; HRMS: Calcd for
C17H15ClN2O m/z (%) = 298.0873 (M+). Found m/z = 298.0843 (M+).
9e: Colorless solid; mp 180-181oC (ref.19 mp 181.5-182.5oC). 1H NMR (CDCl3) 
3.46 (s, 2H, CH2), 6.02 (s, 2H, -OCH2O-), 6.62 (s, 1H, ArH), 6.83 (s, 1H, ArH),
7.40-7.48 (m, 3H, ArH), 7.59 (d, J = 8 Hz, 2H, ArH), 8.86 (br, 1H, NH); HRMS: calcd
for C16H12N2O3 m/z = 280.0848 (M+). Found m/z = 280.0841 (M+).
9f: Colorless oil; 1H NMR (CDCl3)  3.45 (s, 2H, CH2), 6.05 (s, 2H, -OCH2O-), 6.60
(s, 1H, ArH), 6.83 (s, 1H, ArH), 7.35 (t, J = 8 Hz, 1H, ArH), 7.43 (d, J = 8 Hz, 1H, ArH),
7.47 (d, J = 8 Hz, 1H, ArH), 7.61 (s, 1H, ArH), 8.63 (br, 1H, NH). 13C NMR (CDCl3)
 42.1 (CH2), 102.3, 108.3, 108.9, 124.6, 127.7, 129.4, 129.9, 130.3, 131.2, 134.7,
139.8, 147.0, 151.2, 160.1, 170.7 (C=O). HRMS: calcd for C16H11ClN2O3 m/z =
314.0458 (M+). Found m/z = 314.0445 (M+).
9g: Colorless oil; 1H NMR (CDCl3)  3.55 (s, 2H, CH2), 7.07 (dd, 3JHF = 10 Hz, 4JHF
=
8 Hz 1H, ArH), 7.22 (dd, 3JHF = 10 Hz,4JHF = 8 Hz, 1H, ArH), 7.43-7.49 (m, 3H, ArH),
7.57 (d, J = 7 Hz, 2H, ArH), 8.50 (br, 1H, NH). 13C NMR (CDCl3)  41.3, 116.9 (d,
1
2
J = 18 Hz), 118.5 (d, J = 18 Hz), 128.0 (dd, J CF = 4 Hz, JCF = 3 Hz), 128.6, 129.1,
1
2
2
3
130.5, 133.0 (dd, JCF = 3 Hz, JCF = 4 Hz), 137.1, 149.4 (dd, JCF = 343 Hz, JCF = 13
2
3
Hz), 151.9 (dd, JCF =349 Hz, JCF = 13 Hz), 160.0, 170.1. 19F NMR (376 MHz,
3
3
CDCl3)  -137.8 (d, JFF = 23 Hz), -131.2 (d, JFF = 23 Hz); HRMS: calcd for
C15H10F2N2O m/z =272.0761 (M+). Found m/z = 272.0765 (M+).
Synthesis of 1-(p-nitrophenyl)-3-methyl-6,7-dimethylisoquinoline
24

To a solution of 2-ethyl-1-(p-nitrophenyl)butan-1,3-dione 2d (50 mg, 0.20 mmol) and
CsF (152 mg, 1.0 mmol) in acetonitrile (7 mL) was added triflate 2a (122 mg, 0.34
mmol). After being stirred for 10 h at 60oC, the reaction mixture was evaporated to
give pale yellow oil, which was added to a solution of ammonium hydroxide (50 mg,
1.0 mmol) in EtOH (7 mL). After standing for 16h at rt, the reaction mixture was
evaporated to give brown oil, which was chromatographed over silica gel by elution
with
hexane
dichloromethane
(1:1)
to
afford
1-(p-nitrophenyl)-3-methyl-6,7-dimethylisoquinoline (17 mg, 0.044 mmol).
10a: Pale yellow solid; mp 251-251.8oC (ref.20 mp 252oC). 1H NMR (CDCl3)  2.71
(s, 3H, CH2), 3.86 (s, 3H, OMe), 4.05 (s, 3H, OMe), 7.05 (s, 1H, ArH), 7.13 (s, 1H,
ArH), 7.43 (s, 1H, ArH), 7.88 (d, J = 8 Hz, 2H, ArH), 8.39 (d, J = 8 Hz, 2H, ArH).
10b: Yellow solid; mp 161.5-162oC; 1H NMR (CDCl3) 2.71 (s, 3H, CH3), 3.86 (s,
3H, OMe), 4.04 (s, 3H, OMe), 7.05 (s, 1H, ArH), 7.21 (s, 1H, ArH), 7.38 (s, 1H, ArH),
7.45-7.46 (m, 2H, ArH), 7.57 (t, J = 5 Hz, 1H, ArH), 7.70 (s, 1H, ArH). 13C NMR
(CDCl3)  22.9 (Me), 54.9 (OMe), 55.1 (OMe), 103.5, 103.7, 116.8, 119.5, 126.8,
127.7, 128.7, 128.9, 133.5, 133.8, 140.1, 148.3, 148.8, 152.1, 154.9. HRMS: Calcd for
C18H18ClNO2 m/z (%) = 313.0870 (M+), 315.0840 (M+2). Found m/z = 313.0882 (M+),
315.0845 (M+2).
10c: Yellow solid; mp 168.2-169oC (ref.21 mp 167-168oC). 1H NMR (CDCl3)  2.76
(s, 3H, CH3), 7.50 (t, J = 7 Hz, 1H, ArH), 7.57 (s, 1H, ArH), 7.68 (t, J = 8 Hz, 1H, ArH),
7.83-7.91 (m, 4H, ArH), 8.39 (d, J = 8.8 Hz, 2H, ArH).
10d: Yellow solid; mp 198-199 oC (ref.15 mp 178-181oC). 1H NMR (CDCl3) = 2.69
(s, 3H, CH3), 6.09 (s, 2H, -OCH2O-), 7.08 (s, 1H, ArH), 7.12 (s, 1H, ArH), 7.41 (s, 1H,
25

ArH), 7.82 (d, J = 9 Hz, 2H, ArH), 8.38 (d, J = 9 Hz, 2H, ArH).
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28

Synthesis of 2,3-Benzodiazepines and 2,3-Benzodiazepin-4-ones from Arynes and
-Diketones
K. Okuma, Y. Tanabe, N. Nagahora, and K. Shioji
2,3-Benzodiazepines were synthesized by the reaction of diketones or -keto esters
with 2-(trimethylsilyl)aryl triflates in the presence of CsF, followed by the addition of
hydrazine hydrate.
O
O
R
R
TMS
OTf
R
R
NH2NH2
CsF
Ar
N
MeCN
N
O
O
Ar
Ar
O
R
R
NH2NH2
EtO
Ar
NH
N
29