Synthesis of 2,3-Benzodiazepines and 2,3-Benzodiazepin-4-ones

from Arynes and β-Diketones

Kentaro Okuma,* Yukiko Tanabe, Noriyoshi Nagahora, and Kosei Shioji

Department of Chemistry, Fukuoka University, Jonan-ku, Fukuoka 814-0180

E-mail: kokuma@[Link]
Received: February 27, 2015; Accepted: April 12, 2015; Web Released: April 28, 2015

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 C­C 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.

Arynes are highly reactive intermediates that have been aroylacetones (3), and hydrazine hydrate.10 The advantages of
widely used in organic synthesis.1 Reaction of aryne with β- this method include concise reaction, commercial availability
keto compounds provides a useful tool on the synthesis of of starting materials (triflates, β-diketones, and β-ketoesters),
ortho-substituted ketones via carbon­carbon insertion reac- and the possibility of one-pot synthesis. Herein, we report the
tion.2 Benzodiazepines have received considerable attention in full details of one-pot synthesis of 2,3-benzodiazepines and
recent times because of their psychoactive ability.3 Especially, 2,3-benzodiazepin-4-ones such as Tofisopam, Girisopam and
2,3-benzodiazepines (1) act as tranquillizing agents without Girisopam derivatives starting from triflates 2, aroylacetones 3,
any muscle relaxant and anti convulsant activity in rodents.4 and β-ketoesters as shown in Figure 2.
Synthesis of 2,3-benzodiazepines (1) was first aimed at finding
active papaveine-related derivatives with cardiovascular activ- R
R R
ity. The most active derivative, Tofisopam (Grandaxin) 1a
N O R
was found to be a highly active non-sedative, anxiolytic in R O
N R
humans.5 Other 2,3-benzodiazepines and 2,3-benzodiazepin-3- O O
Ar Ar
ones such as Girisopam, Nerisopam, and BDZ-2 were also +
found to be biologically active (Figure 1).6 Ar
These 2,3-benzodiazepines were previously synthesized by
four-step reactions starting from arylacetones or arylethanols.7 O
O R
Recently, we have reported the synthesis of 4-aryl-2-naphthols R R
by the reaction of 2-(trimethylsilyl)phenyl triflate (2) with β- OEt
NH R
diketones and CsF via intramolecular cyclization.8 Given our R R Ar
N
interest in the synthesis of nitrogen-containing heterocycles,9 O O
Ar O
we speculated on the possibility of a short step synthesis of + EtO Ar
2,3-benzodiazepines and communicated the synthesis of 2,3-
benzodiazepines starting from 2-(trimethylsilyl)aryl triflates 2, Figure 2. Retrosynthetic analysis of 2,3-benzodiazepines.
Et O
MeO MeO MeO O
N N N NH
MeO MeO N O N
MeO N N

OMe Cl NH2
MeO NH2

Tofisopam Girisopam Nerisopam BDZ-2

Figure 1. Biologically active 2,3-benzodiazepines.

1064 | Bull. Chem. Soc. Jpn. 2015, 88, 1064–1073 | doi:10.1246/bcsj.20150064 © 2015 The Chemical Society of Japan
 Table 1. Reaction of 2a with Benzoylacetone 3a and 3b
MeO TMS
O
MeO
MeO MeO
OTf O
2a CsF MeO O + OH
MeO
O O CH3CN

+
R
R
3a: R= p-NO2 R 4a: R= p-NO2
3b: R= H 5a: R= p-NO2
4b: R= H 5b: R= H

2a 3a Temp Time Products, Yield/%

Entry
/equiv or 3b /°C /h 4 5
1 0.7 3a rt 18 4a 21 5a 0
2 1.1 3a rt 12 4a 32 5a 0
3 1.1 3a 40 8 4a 43 5a 0
4 1.7 3a rt 8 4a 63 5a 0
5 1.7 3a 40 8 4a 56 5a 0
6 1.7 3b rt 8 4b 61 5b 8

O
Results and Discussion O
Synthesis of ortho-Substituted Acetophenones. To stand- CsF
2a
ardize the reaction conditions, a series of experiments were
performed under varying reaction parameters, such as time and Cl

temperature for a representative reaction of 4,5-dimethoxy-2-

O
trimethylsilylphenyl triflate (2a). Treatment of 2a with 4-
O
nitrobenzoylacetone (3a) in the presence of CsF in acetonitrile O
at rt for 18 h resulted in the formation of 2-acetylmethylbenzo- O 4b
phenone (4a) in 21% yield (Table 1, Entry 1). The results are Cl
shown in Table 1. a
Cl
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 40 °C, 4a was obtained in 43% yield (Entry 3). Cl O Cl
When 1.7 equiv of 2a was reacted with 3a at rt, 4a was O
obtained in 63% yield, whereas elevated temperature resulted O
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 a'
O
(8%, Entry 6), which might be formed via intramolecular aldol
Cl
condensation of regioisomer (a¤) as shown in Scheme 1.
Since the optimum conditions were obtained (rt, 1.7 equiv Cl O
of 2, 8 h), we then tried the synthesis of other 2-acetylmethyl-
benzophenones 4. Treatment of 2a with 4-nitrobenzoylacetone H
O
(3a) and CsF resulted in the formation of 2-acetylmethyl-4,5- C
5b
H
dimethoxybenzophenone 4c in 42% yield. By using substituted H C
H H
triflates 2a­2e, other benzophenones 4a­4h were synthesized O O
in moderate yields (Table 2).
Similarly, CsF-mediated reaction of β-ketoesters 6 with Scheme 1. Formation mechanism of 4b and 5b from triflate
triflates 2, following the conditions reported by Stoltz et al.,2 2a and diketone 3b.
afforded the 2-aroylarylacetate esters 7 (Table 3). Yields were
better than those using aroylacetones 3 as substrates due to benzodiazepine 1a was obtained in 63% yield. Other diaze-
regioselective addition to the aroyl carbons of β-ketoesters pines 1b­1f were synthesized in moderate yields (Table 4).
(Table 1). Nerisopam (1c¤) has also shown anxiolytic and neuroleptic
Reaction of ortho-Substituted Benzophenones with Hy- activity in animal studies,4 which could be easily synthesized
drazone. To confirm the present method provides a general by reduction of 1c by Sn/HCl in 86% yield (Scheme 2).
short-step synthesis of 2,3-benzodiazepines, reaction of 4a with Since our method provides a short-step synthesis of benzo-
hydrazine hydrate in refluxing butanol was tried. As expected, diazepines, we have tried the preparation of Tofisopam (1g)

Bull. Chem. Soc. Jpn. 2015, 88, 1064–1073 | doi:10.1246/bcsj.20150064 © 2015 The Chemical Society of Japan | 1065
Table 2. Synthesis of Compounds 4 from 2, 3, and CsF Table 3. Synthesis of Ethyl 2-Aroylarylacetates 7 from 2, 6,
and CsF
TMS O O R
R CsF O
O
+ R TMS O O R
OTf Ar CH3CN R Ar
R CsF
Ar
rt, 8h O + Ar OEt O
R OTf CH3CN R
2a: R= OMe 3a: Ar=p-NO2C6H4
3b: R= m-ClC6H4 6a: Ar= Ph
2b: R= H 4 2a-2d 6b: Ar= m -ClC6H4 OEt
2c: R= Me 3c: R= C6H5 7
6c: Ar= 3,4-(MeO)2C6H3
2d: R= OCH2O
2e: E= F
O Cl
O
MeO MeO
O O Cl

O NO2 MeO O O
O MeO
4a 63% 4b 51% 82% OEt OEt
7a 7b 56%
MeO MeO
OMe O
O O Cl O
MeO MeO MeO
NO2 OMe
O O
O
O
4d 42% MeO
4c 42% OEt
O OEt
Me 7c 52% 7d quant.
O O
Me O OMe O
NO2 O
O NO2 O Me
OMe
4e 41% 4f 41%
O
O Me
F F
O OEt OEt
O Cl
F 7e 56% 7f 47%
NO2 F
O O Cl O
O
4g 42% 4h 56% O
Me

O O O
Me
in one-pot operation. Treatment of triflate 2a with 2-ethyl-1- OEt
OEt
(3,4-dimethoxyphenyl)butane-1,3-dione (3d) in the presence of 7g 53% 7h 95%
CsF for 8 h followed by the addition of hydrazine hydrate O
Cl
in refluxing EtOH resulted in the formation of Tofisopam 1g O
F
and 2-ethyl-1,2-bis(3,4-dimethoxyphenyl)butane-1,3-dione (8) O
in 45% and 32% yields, respectively. Similarly, Girisopam 1b
was synthesized in one-pot operation (33%) (Scheme 3). F O
O O
Previously, Müller et al. synthesized Tofisopam 1g starting OEt
from 1-(3,4-dimethoxyphenyl)-1,3-dibromobutane via four- 7i 70% OEt 7j 81%
step reaction (Scheme 4).11 Thus, the present method provides Cl
O
a versatile synthesis of benzodiazepines in one-pot operation.
Synthesis of 2,3-Benzodiazepin-4-ones. Since 2,3-benzo- F
diazepin-4-ones (9) have generally been synthesized from
substituted arylacetic acid via 4 step reactions,6 we have tried F O
the two-step synthesis of 9 from aryne precursors. First step
OEt
was already shown in Table 3, thus, the reaction of ethyl 2- 7k quant.
aroylphenylacetate 7 with hydrazine hydrate was tried. Treat-
ment of aroylacetate ester 7a with hydrazine hydrate in refluxing
butanol for 8 h resulted in the formation of 2,3-benzodiazepin- aryne precursors 2b and β-keto esters,12 we applied this method
4-one 9a in 83% yield. As shown in Table 5, other reaction to the one-pot synthesis of 1-aryl-3-alkyl-substituted isoquio-
of ethyl aroylacetates 7b­7g with hydrazine hydrate gave the nolines. 1-Phenylisoquinolines are important ligands for the
corresponding 2,3-benzodiazepin-4-ones 9 in 29­83% yields. synthesis of palladium, platinum, and iridium complexes,
Synthesis of Substituted Isoquinolines. Since Stoltz et al. which show novel red phosphorescence and are applied to the
synthesized one-pot synthesis of 3-hydroxyisoquinolines from synthesis of organic electroluminescent devices.13 Treatment of

1066 | Bull. Chem. Soc. Jpn. 2015, 88, 1064–1073 | doi:10.1246/bcsj.20150064 © 2015 The Chemical Society of Japan
Table 4. Synthesis of Benzodiazepines
MeO MeO
N Sn/HCl N
R R
O NH2NH2 .H2O MeO N MeO N
N EtOH/H2O
R BuOH R N
reflux
O
R'
4a: R = H, R' = p-NO2
4b: R = H, R' = m-Cl NO2 NH2
4c: R = OMe, R' = p-NO2 R
4d: R = OMe, R' = m-Cl
4e: R = Me, R' = H 1c 1c' (Nerisopam)
1a-1f
4f: R = OCH2O, R' = p-NO2
Scheme 2. Synthesis of Nerisopam 1c¤.

N
N
Experimental
N
N
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,
NO2
Cl F254) and flash column chromatography was performed with
silica (Merck, 70­230 mesh). NMR spectra (1H at 400 MHz;
1a 32% 1b 45% 13
C at 100 MHz) were recorded in CDCl3, and chemical shifts
are expressed in ppm relative to internal TMS for 1H and
13
MeO C NMR. Melting points are uncorrected.
MeO Reaction of Triflate 2a with 4-Nitrobenzoylacetone at rt.
N
N To a solution of 4-nitrobenzoylacetone 3a (79 mg, 0.22 mmol)
MeO N MeO N 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
Cl
reaction mixture and the mixture was concentrated to 6 mL,
NO2 extracted with dichloromethane (5 mL © 3). The combined
1c 63% 1d 65% 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-acetyl-
Me O methyl-4,5-dimethoxy-(4¤-nitro)benzophenone 4a (22 mg,
N N
Me
0.064 mmol).
N O N When 1.7 equiv 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
15 h, 4a (65 mg, 0.19 mmol) was obtained in 63% yield. Other
reaction was carried out in a similar manner.
NO2 NO2 4a: Yellow oil; 1H NMR (CDCl3): ¤ 2.26 (s, 3H, CH3), 4.12
1e
(s, 2H, CH2), 7.30 (d, J = 7 Hz, 1H, ArH), 7.34­7.36 (m, 2H,
43% 1f 55%
ArH), 7.51­7.55 (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, 123.4, 126.5, 126.5, 130.3, 131.1, 131.9, 132.2, 134.8,
triflate 2a with 4-nitrobenzoylacetone 3a in the presence of CsF 136.9, 143.0, 150.0, 196.4, 205.1; HRMS: m/z Calcd for
at rt for 8 h followed by the addition of ammonium hydroxide C16H13NO4 283.0845. Found: 283.0835 (M+).
for an additional 10 h at 60 °C resulted in the formation of 1- 4b: Yellow oil; 1H NMR (CDCl3): ¤ 2.20 (s, 3H, CH3), 4.02
(4¤-nitrorophenyl)-3-methyl-6,7-dimethoxyisoquinoline (10a) (s, 2H, CH2), 7.33­7.42 (m, 4H, ArH), 7.51 (t, J = 8 Hz, 1H,
in 32% yield. As shown in Table 6, substituted isoquinolines ArH), 7.55 (d, J = 8 Hz, 1H, ArH), 7.67 (d, J = 8 Hz, 1H,
10 were synthesized in one-pot operation starting from com- ArH), 7.80 (s, 1H, ArH); 13C NMR (CDCl3): ¤ 29.9, 48.1,
mercially available 2 and diketones 3. 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
Conclusion C16H13ClO2 m/z (%) = 272.0604 (M+, 100), 274.0575 (M2+,
We have developed a completely new method for the syn- 32). Found m/z = 272.0604 (M+, 100), 274.0583 (M2+, 32).
thesis of 2,3-benzodiazepines and 2,3-benzodiazepin-4-ones 5b: Yellow oil; 1H NMR (CDCl3): ¤ 2.12 (s, 1H, OH), 3.02
from (2-trimethylsilyl)aryltriflates. The reaction requires only (d, J = 17 Hz, 1H, CH2), 3.21 (d, J = 16 Hz, 1H, CH2), 3.28
a two-step reaction. A completely different strategy for the (d, J = 16 Hz, 1H, CH2), 3.58 (d, J = 17 Hz, 1H, CH2), 7.28­
one-pot synthesis 1-arylisoquinolines from aryne precursors 7.42 (m, 5H, ArH), 7.54 (d, J = 7 Hz, 1H, ArH), 7.57 (s,
was accomplished. 1H, ArH), 8.08 (d, J = 8 Hz, 1H, ArH); 13C NMR (CDCl3):

Bull. Chem. Soc. Jpn. 2015, 88, 1064–1073 | doi:10.1246/bcsj.20150064 © 2015 The Chemical Society of Japan | 1067
 MeO TMS
MeO
N
MeO OTf NH2NH2
CsF MeO N
2a
O O CH3CN EtOH
rt, 8h reflux
OMe 6h OMe
MeO
1g 45%
OMe
3d O O
OMe
+

OMe

MeO OMe

8 32%

MeO TMS

MeO
MeO OTf NH2NH2 N
CsF
2a MeO N
CH3CN EtOH
O O rt, 8h reflux
Cl 6h
Cl
3b
1b (Girisopam)

Scheme 3. Synthesis of Tofisopam 1g and Girisopam 1b.

Br Br Br
MeO
MeO
MeO
MeO
OMe

OMe

MeO
MeO MeO
MeO O N
MeO O MeO N
OMe

OMe
OMe OMe
OMe OMe
1g

Scheme 4. Reported synthesis of Tofisopam 1g.

¤ 43.5, 51.33, 74.98, 122.9, 125.3, 127.0, 127.2, 128.0, 129.5, OCH3), 3.96 (s, 3H, OCH3), 4.02 (s, 2H, CH2), 6.75 (s, 1H,
130.0, 131.6, 134.3, 134.7, 140.0, 147.8, 196.2 (s, C=O). Ar), 6.85 (s, 1H, Ar), 7.92 (d, 2H, J = 8 Hz, Ar), 8.31 (d, 2H,
HRMS: Calcd for C16H13ClO2 m/z (%) = 272.0604 (M+, J = 8 Hz, Ar); 13C NMR (CDCl3): ¤ 30.1 (CH3), 48.4 (CH2),
100), 274.0575 (M2+, 32). Found m/z = 272.0601 (M+, 100), 56.4 (OCH3), 56.4 (OCH3), 114.7, 115.3, 123.7, 128.5, 130.3,
274.0553 (M2+, 32). 131.0, 144.2, 147.1, 150.1, 152.3 (Ar), 195.5 (C=O), 205.8
4c: Pale yellow solid; mp 157­159 °C (ref 14, mp 156­ (C=O). Anal. Calcd for C18H17NO6: C, 62.97; H, 4.99; N,
158 °C); 1H NMR (CDCl3): ¤ 2.25 (s, 3H, CH3), 3.75 (s, 3H, 4.08%. Found; C, 62.89; H, 4.91; N, 4.20%.

1068 | Bull. Chem. Soc. Jpn. 2015, 88, 1064–1073 | doi:10.1246/bcsj.20150064 © 2015 The Chemical Society of Japan
 4d: Pale yellow solid; mp 100­101 °C (ref 4, mp 108­ 131.0, 132.7 (dd, JCF = 5 Hz and JCF = 5 Hz), 133.3 (dd,
110 °C); 1H NMR (CDCl3): ¤ 2.23 (s, 3H, CH3), 3.78 (s, 3H, JCF = 5 Hz and JCF = 5 Hz), 142.2, 148.8 (dd, 1JCF = 365 Hz,
CH3O), 3.94 (s, 2H, CH2), 3.96 (s, 3H, OCH3), 6.76 (s, 1H, 2
JCF = 13 Hz), 150.3, 151.3 (dd, 1JCF = 370 Hz, 2JCF = 13 Hz),
ArH), 6.93 (s, 1H, ArH), 7.40 (t, J = 8 Hz, 1H, ArH), 7.56 194.4, 204.4; 19F NMR (CDCl3): ¤ ¹138.66 (ddd, 3JFF = 21
(d, J = 8 Hz, 1H, ArH), 7.64 (d, J = 8.0 Hz, 1H, ArH), 7.77 Hz, 3JFH = 10 Hz, 4JFH = 9 Hz), ¹138.63 (ddd, 3JFF = 21 Hz,
(s, 1H, ArH). 3
JFH = 11 Hz, 4JFH = 9 Hz). HRMS: m/z; Calcd for C16H11-
4e: Yellow oil; 1H NMR (CDCl3): ¤ 2.23 (s, 6H, CH3), 2.30 F2NO4; 319.0656. Found: 319.0644 (M+).
(s, 3H, CH3), 4.03 (s, 2H, CH2), 7.05 (s, 1H, ArH), 7.10 (s, 1H, 4h: Brown oil; 1H NMR (CDCl3): ¤ 2.22 (s, 3H, CH3), 3.99
ArH), 7.94 (d, J = 9 Hz, 2H, ArH), 8.31 (d, J = 9 Hz, 2H, (s, 2H, CH2), 7.10 (dd, 3JHF = 11 Hz, 4JHF = 8 Hz, 1H, ArH),
ArH); 13C NMR (CDCl3): ¤ 19.3, 19.8, 29.9, 47.8, 123.4, 7.24 (dd, 3JHF = 9 Hz, 4JHF = 8 Hz, 1H, ArH), 7.43 (t, J = 8 Hz,
130.9, 132.1, 132.7, 133.8, 134.1, 135.0, 141.5, 143.7, 149.8, 1H, ArH), 7.58 (d, J = 8 Hz, 1H, ArH), 7.63 (d, J = 8 Hz, 1H,
196.4, 205.7. HRMS: m/z Calcd for C18H17N3O2 307.1321. ArH), 7.77 (s, 1H, ArH); 13C NMR (CDCl3): ¤ 30.3, 47.4, 120.0
Found: 307.1322 (M+). (d, J = 18 Hz), 121.5 (d, J = 18 Hz), 128.6, 130.1, 130.2, 132.7
4f: Yellow solid; mp 150­152 °C (ref 15, mp 151­154 °C); (dd, 1JCF = 3 Hz, 2JCF = 4 Hz), 133.4, 133.9 (dd, 1JCF = 2 Hz,
1
H NMR (CDCl3): ¤ 2.25 (s, 3H, CH3), 4.01 (s, 2H, CH2), 6.06 2
JCF = 4 Hz), 135.1, 139.0, 148.9 (dd, 1JCF = 345 Hz, 2JCF =
(s, 2H, OCH2O), 6.76 (s, 1H, ArH), 6.81 (s, 1H, ArH), 7.91 13 Hz), 151.9 (dd, 1JCF = 350 Hz, 2JCF = 13 Hz), 197.8, 204.5;
(d, J = 8 Hz, 2H, ArH), 8.31 (d, J = 8 Hz, 2H, ArH). 19
F NMR (CDCl3): ¤ ¹139.07 (ddd, 3JFF = 21 Hz, 3JFH =
4g: Orange oil; 1H NMR (CDCl3): ¤ 2.24 (s, 3H, CH3), 4.09 10 Hz, 4JFH = 9 Hz), ¹132.58 (ddd, 3JFF = 21.3 Hz, 3JFH =
(s, 2H, CH2), 7.12 (dd, 3JHF = 11 Hz, 4JHF = 7 Hz, 1H, ArH), 10 Hz, 4JFH = 9 Hz); HRMS: m/z Calcd for C16H11ClF2O2;
7.19 (dd, 3JHF = 10 Hz, 4JHF = 8 Hz, 1H, ArH), 7.96 (d, 308.0416. Found; 308.0415 (M+).
J = 9 Hz, 2H), 8.33 (d, J = 9 Hz, 2H); 13C NMR (CDCl3): ¤ Reaction of Triflate 2a with Ethyl Benzoylacetate. To a
30.0, 47.2, 119.7 (d, J = 18 Hz), 121.4 (d, J = 18 Hz), 123.6, solution of ethyl benzoyl acetate 6a (35 mg, 0.18 mmol) and
CsF (136 mg, 0.90 mmol) in acetonitrile (3 mL) was added
Table 5. Synthesis of 2,3-Benzodiazepine-4-ones triflate 2a (106 mg, 0.30 mmol) in acetonitrile (2 mL). After
OEt O being stirred for 8 h at rt, 5 mL of water was added to the
R R
H2N-NH2 . H2O (18 equiv) reaction mixture and the mixture was concentrated to 6 mL,
O NH extracted with dichloromethane (5 mL © 3). The combined
R O Solvent R N extract was dried over sodium sulfate, filtered, and evaporated
Ar Ar to give brown oil, which was chromatographed over silica gel
7 9
by elution with hexane­ethyl acetate (3:1) to afford ethyl 2-
benzoyl-4,5-dimethoxyphenylacetate 7a (44 mg, 0.15 mmol).
Temp. Yield 7a: colorless solid; mp 78­79 °C (ref 16, mp 78­79 °C).
7 R Ar Solv. 9
/°C /% 1
H NMR (CDCl3): ¤ 1.15 (t, J = 7 Hz, 3H, CH3), 3.79 (s, 3H,
7a MeO C6H5 BuOH reflux 9a 83 OMe), 3.82 (s, 2H, CH2), 3.96 (s, 3H, OMe), 4.06 (q, J = 7 Hz,
7b MeO m-ClC6H4 BuOH reflux 9b 53 2H, CH2), 6.86 (s, 1H, ArH), 6.94 (s, 1H, ArH), 7.46 (t, J =
7c H 3,4-(MeO)2C6H3 EG 160 9c 60 8 Hz, 2H, ArH), 7.57 (t, J = 8 Hz, 1H, ArH), 7.80 (d, J = 8 Hz,
7d Me m-ClC6H4 EG 160 9d 72 2H, ArH); 13C NMR (CDCl3): ¤ 14.1, 38.7, 56.0, 56.1, 60.8,
7e ­OCH2O­ C6H5 BuOH reflux 9e 59 113.9, 114.5, 128.2, 128.2, 130.2, 130.3, 132.6, 138.4, 146.9,
7f ­OCH2O­ m-ClC6H4 BuOH reflux 9f 60 151.0, 171.4, 197.1. HRMS: calcd for C19H20O5 m/z =
7g F C6H5 BuOH reflux 9g 29 328.1311 (M+). Found m/z = 328.1304 (M+).
Table 6. One-Pot Synthesis of Substituted Isoquinolines
1) CsF (3.0 equiv)
O O
2)
R TMS Ar R
3 NH4OH
60 oC N
R OTf MeCN R
rt
Ar

2a: R= OMe 3a: Ar=p-NO2C6H4 10a: R= OMe, Ar= p-NO2C6H4

2b: R= H 3b: Ar= m-ClC6H4 10b: R= OMe, Ar= m-ClC6H4
2d: R= OCH2O 10c: R= H, Ar= p-NO2C6H4
10d: R= OCH 2O, Ar= p-NO2C6H4

Entry 2 Time 1/h 3 Time 2/h 10 Yield/%

1 2a 8 3a 10 10a 32
2 2a 1.4 3b 48 10b 25
3 2b 1 3a 24 10c 54
4 2d 1.5 3a 2 10d 30

Bull. Chem. Soc. Jpn. 2015, 88, 1064–1073 | doi:10.1246/bcsj.20150064 © 2015 The Chemical Society of Japan | 1069
 7b: yellow oil; 1H NMR (CDCl3): ¤ 1.17 (t, J = 7 Hz, 3H, m/z = 312.1005 (M+).
CH3), 3.80 (s, 3H, OMe), 3.82 (s, 2H, CH2), 3.96 (s, 3H, OMe), 7i: Colorles oil; 1H NMR (CDCl3): ¤ 1.17 (t, J = 7 Hz, 3H,
4.08 (q, J = 7 Hz, 2H, CH2), 6.87 (s, 1H, ArH), 6.91 (s, 1H, CH3), 3.79 (s, 2H, CH2), 4.08 (q, J = 7 Hz, 2H, CH2), 6.05
ArH), 7.40 (t, J = 8 Hz, 1H, ArH), 7.54 (d, J = 8 Hz, 1H, ArH), (s, 2H, OCH2O), 6.84 (s, 1H, ArH), 6.85 (s, 1H, ArH), 7.39
7.65 (d, J = 9 Hz, 1H, ArH), 7.66 (s, 1H, ArH); 13C NMR (t, J = 9 Hz, 1H, ArH), 7.54 (d, J = 7 Hz, 1H, ArH), 7.65
(CDCl3): ¤ 14.1, 38.8, 56.1, 56.2, 60.8, 113.9, 114.7, 128.2, (d, J = 9 Hz, 1H, ArH), 7.75 (s, 1H, ArH); 13C NMR (CDCl3): ¤
128.5, 129.6, 129.6, 130.0, 132.5, 134.6, 140.1, 147.0, 151.3, 14.6 (CH3), 39.4 (CH2), 61.3 (CH2), 102.2, 110.8, 112.4, 128.5,
171.3, 195.7. HRMS: calcd for C19H19ClO5 m/z = 36.09212 129.8, 130.2, 130.4, 131.2, 132.8, 134.7, 140.1, 146.2, 150.1,
(M+). Found m/z = 362.0925 (M+). 171.3 (C=O), 195.4 (C=O). HRMS: Calcd for C18H15ClO5
7c: pale yellow oil; 1H NMR (CDCl3): ¤ 1.15 (t, J = 7 Hz, m/z = 346.0608 (M+). Found m/z = 346.0610 (M+).
3H, CH3), 3.77 (s, 2H, CH2), 3.82 (s, 2H, OMe), 3.93 (s, 3H, 7j: Pale yellow oil; 1H NMR (CDCl3): ¤ 1.14 (t, J = 7 Hz,
OMe), 3.95 (s, 3H, OMe), 3.95 (s, 3H, OMe), 4.06 (q, J = 3H, CH3), 3.82 (s, 2H, CH2), 4.04 (q, J = 7 Hz, 2H, CH2),
7 Hz, 2H, CH3), 6.86 (s, 1H, ArH), 6.87 (d, J = 9 Hz, 1H, 7.18­7.24 (m, 2H, ArH © 2), 7.48 (t, J = 8 Hz, 2H, ArH), 7.61
ArH), 6.94 (s, 1H, ArH), 7.33 (d, J = 9 Hz, 1H, ArH), 7.49 (s, (t, J = 8 Hz, 1H, ArH), 7.78 (d, J = 8 Hz, 2H, ArH); 13C NMR
1H, ArH). HRMS: Calcd for C21H24O7 m/z = 388.1522 (M+). (CDCl3): ¤ 14.0 (CH3), 38.1 (CH2), 61.1 (CH2), 119.2 (d, J =
Found m/z = 388.1520 (M+). 18 Hz), 120.8 (d, J = 18 Hz), 128.5, 130.2, 131.7 (dd, J =
7d: yellow oil; 1H NMR (CDCl3): ¤ 1.11 (t, J = 7 Hz, 3H, 3 and 4 Hz), 133.3, 134.8 (dd, J = 2 and 4 Hz), 137.1, 148.5
CH3), 3.88 (s, 2H, CH2), 4.02 (q, J = 7 Hz, 2H, OCH2), 7.30­ (dd, J = 290 and 12 Hz), 151.0 (d, J = 293 and 12 Hz), 170.4
7.39 (m, 3H, ArH), 7.43­7.48 (m, 3H, ArH), 7.57 (t, J = 8 Hz, (C=O), 195.6 (C=O); 19F NMR (376 MHz, CDCl3): ¤ ¹138.9
1H, ArH), 7.81 (d, J = 7 Hz, 2H, ArH); 13C NMR (CDCl3): ¤ (d, 3JFF = 21 Hz), ¹133.3 (d, 3JFF = 21 Hz). HRMS: Calcd for
14.5 (CH3), 39.3 (CH2), 61.2 (CH2), 126.7, 128.5, 130.2, 130.6, C17H14F2O3 m/z = 304.0911 (M+). Found m/z = 304.0924
131.0, 132.0, 133.1, 134.2, 138.0, 138.4 (Ar), 171.3 (C=O), (M+).
198.1 (C=O). HRMS: Calcd for C17H16O3 m/z = 268.1099 7k: Yellow oil; 1H NMR (CDCl3): ¤ 1.16 (t, J = 7 Hz, 3H,
(M+). Found m/z = 268.1090 (M+). CH3), 3.84 (s, 2H, CH2), 4.05 (q, J = 7 Hz, 2H, CH2), 7.18­
7e: Pale yellow oil; 1H NMR (CDCl3): ¤ 1.12 (t, J = 8 Hz, 7.26 (m, 2H, ArH © 2), 7.42 (t, J = 8 Hz, 1H, ArH), 7.57
3H, CH3), 3.82 (s, 2H, CH2), 3.93 (s, 3H, OMe), 3.95 (s, 3H, (d, J = 8 Hz, 1H, ArH), 7.64 (d, J = 8 Hz, 1H, ArH), 7.77
OMe), 4.02 (q, J = 8 Hz, 2H, OCH2), 6.85 (d, J = 8 Hz, 1H, (s, 1H, ArH); 13C NMR (CDCl3): ¤ 14.5 (CH3), 38.5 (CH2),
ArH), 7.30­7.40 (m, 4H, ArH), 7.46 (t, J = 8 Hz, 1H, ArH), 61.4 (CH2), 119.6 (d, J = 18 Hz), 121.3 (d, J = 18 Hz), 128.5,
7.53 (s, 1H, ArH); 13C NMR (CDCl3): ¤ 14.0 (CH3), 38.7 (CH2), 130.0, 130.2, 132.2 (dd, J = 3 and 4 Hz), 133.4, 134.2 (dd,
56.0 (OMe), 56.1 (OMe), 60.8 (CH2), 109.7, 111.7, 126.1, J = 2 and 4 Hz), 135.0, 138.9, 148.8 (dd, J = 308 and 13 Hz),
126.3, 129.3, 130.3, 130.6, 131.5, 133.5, 138.8, 149.0, 153.4, 151.3 (dd, J = 312 and 13 Hz), 170.5 (C=O), 194.3 (C=O);
171.2 (C=O), 196.7 (C=O). HRMS: Calcd for C19H20O5 19
F NMR (376 MHz, CDCl3): ¤ ¹138.4 (ddd, 3JFF = 18 Hz,
m/z = 328.1311 (M+). Found m/z = 329.1320 (M+). 3
JFH = 10 Hz, 4JFH = 8 Hz), ¹132.4 (ddd, 3JFF = 18 Hz,
7f: Colorles oil; 1H NMR (CDCl3): ¤ 1.12 (t, J = 7 Hz, 3H, 3
JFH = 11 Hz, 4JFH = 8 Hz). HRMS: Calcd for C17H13ClF2O3
CH3), 2.24 (s, 3H, CH3), 2.31 (s, 3H, CH3), 3.81 (s, 2H, CH2), m/z = 338.0521 (M+). Found m/z = 338.0531 (M+).
4.03 (q, J = 7 Hz, 2H, OCH2), 7.12 (s, 1H, ArH), 7.16 (s, 1H, Reaction of 4a with Hydrazine Hydrate. To a solution of
ArH), 7.44 (t, J = 7 Hz, 2H, ArH), 7.56 (t, J = 7 Hz, 1H, ArH), 4a (34 mg, 0.10 mmol) in EtOH (4.0 mL) was added a solution
8.00 (d, J = 7 Hz, 2H, ArH); 13C NMR (CDCl3): ¤ 14.0 (CH3), of hydrazine hydrate (50 mg, 1.0 mmol). After stirring at rt
19.2 (CH3), 19.7 (CH3), 38.5 (CH2), 60.7 (CH2), 128.4, 130.2, for 16 h, the mixture was poured into water and extracted with
131.5, 131.6, 132.5, 133.1, 134.7, 135.6, 138.2, 139.9, 171.6 dichloromethane. The separated dichloromethane solution was
(C=O), 198.1 (C=O). HRMS: Calcd for C19H20O3 m/z = dried over magnesium sulfate, filtered, and evaporated to give
296.1412 (M+). Found m/z = 296.1421 (M+). pale orange oil, which was chromatographed over silica gel by
7g: Colorles oil; 1H NMR (CDCl3): ¤ 1.14 (t, J = 8 Hz, 3H, elution with hexane­dichloromethane (1:1) to give 2,3-benzo-
CH3), 2.25 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.82 (s, 2H, CH2), diazepine 1a (20 mg, 0.06 mmol).
4.04 (q, J = 8 Hz, 2H, CH2), 7.13 (s, 1H, ArH), 7.14 (s, 1H, 1a: Colorless solid; mp 175­176 °C. 1H NMR (CDCl3):
ArH), 7.39 (t, J = 8 Hz, 1H, ArH), 7.54 (d, J = 8 Hz, 1H, ArH), ¤ 2.18 (s, 3H, CH3), 3.06 (d, J = 12 Hz, 1H, CH2), 3.42
7.66 (d, J = 8 Hz, 1H, ArH), 7.78 (s, 1H, ArH); 13C NMR (d, J = 12 Hz, 1H, CH2), 7.29 (d, J = 8 Hz, 1H, ArH), 7.34
(CDCl3): ¤ 14.1, 19.3, 19.8, 38.5, 60.8, 128.4, 129.5, 130.0, (d, J = 8 Hz, 1H, ArH), 7.41 (t, J = 8 Hz, 1H, ArH), 7.58
130.9, 131.6, 131.8, 132.5, 133.3, 133.6, 134.5, 134.9, 135.0, (t, J = 8 Hz, 1H, ArH), 7.86 (d, J = 9 Hz, 2H, ArH), 8.26
140.0, 140.5, 171.5, 196.6. HRMS: Calcd for C19H19ClO3 (d, J = 9 Hz, 2H, ArH); 13C NMR (CDCl3): ¤ 23.0 (CH3), 38.8
m/z = 330.1023 (M+). Found m/z = 330.1020 (M+). (CH2), 123.4, 126.6, 127.3, 129.2, 129.8, 130.3, 132.1, 139.7,
7h: Colorless oil; 1H NMR (CDCl3): ¤ 1.15 (t, J = 7 Hz, 3H, 144.6, 148.6, 155.2 (C=N), 157.1 (C=N). HRMS: Calcd for
CH3), 3.79 (s, 2H, CH2), 4.06 (q, J = 7 Hz, 2H, CH2), 6.03 C16H13N3O2 m/z = 279.1008 (M+). Found m/z = 279.1004
(s, 2H, OCH2O), 6.84 (s, 1H, ArH), 6.88 (s, 1H, ArH), 7.45 (M+).
(t, J = 7 Hz, 2H, ArH), 7.56 (t, J = 8 Hz, 1H, ArH), 7.78 1b: Pale yellow solid; mp 141­142 °C. 1H NMR (CDCl3):
(d, J = 8 Hz, 2H, ArH); 13C NMR (CDCl3): ¤ 14.0 (CH3), 38.9 ¤ 2.17 (s, 3H, CH3), 3.08 (d, J = 12 Hz, 1H, CH2), 3.38
(CH2), 60.7 (CH2), 101.7, 110.6, 111.9, 128.2, 129.8, 130.1, (d, J = 12 Hz, 1H, CH2), 7.29­7.38 (m, 4H, ArH), 7.40 (m, 2H,
131.7, 132.6, 138.1, 145.9, 149.6, 171.3 (C=O), 196.8 (C=O). ArH), 7.54 (d, J = 8 Hz, 1H, ArH), 7.57 (d, J = 8 Hz, 1H,
HRMS: Calcd for C18H16O5 m/z = 312.0998 (M+). Found ArH), 7.66 (s, 1H, ArH); 13C NMR (CDCl3): ¤ 23.3 (CH3), 39.0

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(CH2), 126.6, 127.4, 127.9, 129.7, 129.7, 129.8, 130.0, 130.4, 16 h at rt, the reaction mixture was evaporated to give brown
132.0, 134.5, 139.8, 140.8, 155.6 (C=N), 158.0 (C=N). oil, which was chromatographed over silica gel by elution with
HRMS: Calcd for C16H13ClN2 m/z = 268.0767 (M+). Found hexane dichloromethane (1:1) to afford Tofisopam 1g (34.4 mg,
m/z = 268.0765 (M+). 0.09 mmol) and diketone 8 (17 mg, 0.044 mmol).
1c: Yellow solid; mp 236­238 °C (ref 4, mp 238­240 °C). 1g: Pale yellow crystals; mp 155­157 °C (ref 4, mp 156­
1
H NMR (CDCl3): ¤ 2.18 (s, 3H, CH3), 2.99 (d, J = 12 Hz, 1H, 157 °C). 1H NMR (CDCl3): ¤ 0.55 (t, J = 8 Hz, 3H, CH3), 1.97
CH2), 3.34 (d, J = 12 Hz, 1H, CH2), 3.75 (s, 3H, OCH3), 3.99 (s, 3H, CH3), 2.30 (m, 2H, CH2), 3.74 (s, 3H, OCH3), 3.85
(s, 3H, OCH3), 6.70 (s, 1H, ArH), 6.76 (s, 1H, ArH), 7.89 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 6.35
(d, J = 8 Hz, 2H, ArH), 8.27 (d, J = 8 Hz, 2H, ArH); 13C NMR (s, 1H, ArH), 6.70 (d, J = 8 Hz, 1H, ArH), 6.87 (s, 1H, ArH),
(CD3CN): ¤ 23.0 (CH3), 38.5 (CH2), 56.2 (OMe), 56.2 (OMe), 6.94 (d, J = 8 Hz, 1H, ArH), 7.55 (s, 1H, ArH); 13C NMR
108.8, 111.8, 121.5, 123.4, 130.3, 133.2, 144.9, 148.3, 148.6, (CDCl3): ¤ 7.8 (CH3), 12.4 (CH3), 25.5, 55.5 (OCH3), 56.0
152.6, 154.6 (C=N), 156.6 (C=N). (OCH3), 56.0 (OCH3), 56.0 (OCH3), 72.3 (CH), 108.9, 110.1,
1d: Pale yellow crystal; mp 172­173 °C (ref 4, mp 167­ 110.6, 111.7, 117.9, 121.5, 122.7, 127.8, 149.0, 149.1, 149.8,
169 °C). 1H NMR (CDCl3): ¤ 2.16 (s, 3H, CH3), 2.99 (d, J = 151.6, 179.8. HRMS: Calcd for C22H26N2O4; m/z = 382.1893.
12 Hz, 1H, CH2), 3.28 (d, J = 12 Hz, 1H, CH2), 3.76 (s, 3H, Found: 382.1896 (M+).
OCH3), 3.98 (s, 3H, OCH3), 6.74 (s, 1H, ArH), 6.76 (s, 1H, 8: pale yellow oil; 1H NMR (CDCl3): ¤ 0.79 (t, 3H, J =
ArH), 7.34 (t, J = 8 Hz, 1H, ArH), 7.41 (d, J = 8 Hz, 1H, ArH), 7 Hz, Me), 2.11 (s, 3H, Me), 2.24 (q, 1H, J = 7 Hz, CHH), 2.67
7.58 (d, J = 8 Hz, 1H, ArH), 7.72 (s, 1H, ArH); 13C NMR (q, 1H, J = 7 Hz, CHH), 3.81 (s, 6H, OMe), 3.86 (s, 3H, OMe),
(CDCl3): ¤ 22.1 (CH3), 37.4 (CH2), 52.2 (OMe), 55.3 (OMe), 3.88 (s, 3H, OMe), 6.69 (d, 1H, J = 9 Hz, 1H, Ar), 6.79 (d, 1H,
107.9, 111.2, 120.9, 126.9, 128.4, 128.6, 128.8, 132.3, 133.3, J = 9 Hz, Ar), 6.95 (d, 1H, J = 9 Hz, Ar), 7.05 (s, 1H, Ar), 7.30
139.9, 147.2, 151.4, 154.1 (C=N), 156.3 (C=N). HRMS: (d, 1H, J = 8 Hz, Ar), 7.44 (s, 1H, Ar); 13C NMR (CDCl3): ¤
Calcd for C18H17ClN2O2 m/z (%) = 328.0979 (M+, 100), 9.6 (CH3), 28.3 (CH3), 29.6 (CH2), 56.0 (OCH3), 56.0 (OCH3),
330.0949 (M2+, 32). Found m/z = 328.0971 (M+, 100), 56.2 (OCH3), 56.2 (OCH3), 72.3 (CH), 110.0, 111.1, 111.9,
330.0948 (M2+, 32). 112.3, 121.5, 125.1, 128.7, 131.6, 148.4, 148.7, 148.9, 153.2,
1e: Colorless solid; mp 188­189 °C. 1H NMR (CDCl3): ¤ 197.6 (C=O), 205.4 (C=O). HRMS: Calcd for C22H26O6;
2.18 (s, 3H, CH3), 2.93 (d, J = 12 Hz, 1H, CH2), 3.30 (d, m/z = 386.1729. Found: 386.1731 (M+).
J = 12 Hz, 1H, CH2), 6.03 (s, 1H, CH2), 6.07 (s, 1H, CH2), Reaction of Ethyl 2-Aroylphenylacetate with Hydrazine
6.68 (s, 1H, ArH), 6.78 (s, 1H, ArH), 7.87 (d, J = 7.9 Hz, Hydrate. To a solution of 7a (34 mg, 0.20 mmol) in BuOH
2H, ArH), 8.26 (d, J = 8.9 Hz, 2H, ArH); 13C NMR (CDCl3): (4.0 mL) was added a solution of hydrazine hydrate (50 mg,
¤ 19.7 (CH3), 20.1 (CH3), 23.2 (CH3), 38.5 (CH2), 123.6, 1.0 mmol). After refluxing for 16 h, the mixture was poured
127.0, 127.8, 130.5, 130.7, 136.3, 137.4, 141.9, 145.0, 148.7, into water and extracted with dichloromethane (5 mL © 3). The
156.1 (C=N), 157.8 (C=N). HRMS: Calcd for C18H17N3O2; separated dichloromethane solution was dried over magnesium
m/z = 307.1321 (M+). Found: 307.1321 (M+). sulfate, filtered, and evaporated to give pale orange oil, which
1f: Yellow crystals; mp 199­202 °C (ref 15, mp 200­ was chromatographed over silica gel by elution with hexane­
203 °C). 1H NMR (CDCl3): ¤ 2.18 (s, 3H, CH3), 2.93 (d, J = dichloromethane (1:1) to give 2,3-benzodiazepin-3-one 9a (20
12 Hz, 1H, CH2), 3.30 (d, J = 12 Hz, 1H, CH2), 6.03 (s, 1H, mg, 0.06 mmol).
CH2), 6.08 (s, 1H, CH2), 6.67 (s, 1H, ArH), 6.78 (s, 1H, ArH), 9a: Colorless solid; mp 200­202 °C (ref 17, mp 202­
7.87 (d, J = 8.4 Hz, 2H, ArH), 8.26 (d, J = 8.4 Hz, 2H, ArH). 204 °C). 1H NMR (CDCl3): ¤ 3.51 (s, 2H, CH2), 3.72 (s, 3H,
Reduction of Nitrobenzodiazepine 1c. To a suspension of OMe), 3.97 (s, 3H, OMe), 6.67 (s, 1H, ArH), 6.85 (s, 1H, ArH),
1c (13 mg, 0.038 mmol) and iron powder (9 mg, 0.16 mmol) 7.41­7.49 (m, 3H, ArH), 7.63 (d, J = 7 Hz, 2H, ArH), 8.49 (br,
in ethanol­water (4:1, 5 mL) was added conc. HCl (0.02 mL, 1H, NH); GCMS: calcd for C17H16N2O3 m/z = 296 (M+).
0.18 mmol) at rt. After refluxing for 2 h, resulting mixture was Found m/z = 296 (M+).
extracted with dichloromethane (3 mL © 3). 9b: Pale yellow solid; mp 263.5­265 °C (ref 18, no mp).
Saturated sodium carbonate solution (1 mL) was added to 1
H NMR (CDCl3): ¤ 3.50 (s, 2H, CH2), 3.74 (s, 3H, OMe), 3.97
the water layer, which was extracted with dichloromethane (s, 3H, OMe), 6.63 (s, 1H, ArH), 6.85 (s, 1H, ArH), 7.36
(2 mL © 3), dried over sodium sulfate, filtered, and evaporated (t, J = 8 Hz, 1H, ArH), 7.44 (d, J = 8 Hz, 1H, ArH), 7.48 (d,
to give almost pure Nerisopam 1c¤ (9 mg, 0.025 mmol). 1H, J = 8 Hz, ArH), 7.67 (s, 1H, ArH), 8.73 (br, 1H, NH);
1c¤: Yellow crystals; mp 223­226 °C (ref 4, mp 225­ 13
C NMR (CDCl3): ¤ 41.7 (CH2), 56.1 (OCH3), 56.2 (OCH3),
227 °C). 1H NMR (CDCl3): ¤ 2.13 (s, 3H, CH3), 3.04 (d, J = 110.4, 111.6, 123.0, 127.5, 129.2, 129.6, 129.7, 130.0, 134.6,
12 Hz, 1H, CH2), 3.22 (d, J = 12 Hz, 1H, CH2), 3.76 (s, 3H, 139.7, 147.8, 152.5, 160.1 (C=N), 170.7 (C=O). HRMS:
MeO), 3.97 (s, 3H, MeO), 6.55­6.75 (m, 3H, ArH), 6.85 (s, 1H, Calcd for C17H15ClN2O3 m/z = 330.0771 (M+). Found m/z =
ArH), 7.52 (d, J = 8 Hz, 2H, ArH). 330.0766 (M+).
One-Pot Synthesis of Tofisopam 1g. To a solution of 9c: Colorless oil; 1H NMR (CDCl3): ¤ 3.58 (s, 2H, CH2),
2-ethyl-1-(3,4-dimethoxyphenyl)butan-1,3-dione (3d) (50 mg, 3.91 (s, 3H, OMe), 3.93 (s, 3H, OMe), 6.86 (d, J = 8 Hz, 1H,
0.20 mmol) and CsF (152 mg, 1.0 mmol) in acetonitrile (7 mL) ArH), 7.00 (d, J = 8 Hz, 1H, ArH), 7.28­7.41 (m, 4H, ArH),
was added triflate 2a (122 mg, 0.34 mmol). After being stirred 7.55 (t, J = 8 Hz, 1H), 8.34 (br, 1H, NH); 13C NMR (CD3CN):
for 10 h at 60 °C, the reaction mixture was evaporated to give ¤ 42.1, 56.0 (MeO © 2), 110.3, 111.2, 123.4, 126.7, 128.0,
pale yellow oil, which was added to a solution of hydrazine 129.8, 130.4, 131.2, 131.9, 136.2, 149.0, 150.9, 161.9, 171.2.
hydrate (50 mg, 1.0 mmol) in EtOH (7 mL). After standing for HRMS: Calcd for C17H16N2O3 m/z (%) = 296.1161 (M+).

Bull. Chem. Soc. Jpn. 2015, 88, 1064–1073 | doi:10.1246/bcsj.20150064 © 2015 The Chemical Society of Japan | 1071
Found m/z = 296.1158 (M+). C18H18ClNO2 m/z (%) = 313.0870 (M+), 315.0840 (M2+).
9d: Colorless solid; mp 222.5­223.5 °C. 1H NMR (CDCl3): Found m/z = 313.0882 (M+), 315.0845 (M2+).
¤ 2.22 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.51 (s, 2H, CH2), 6.94 10c: Yellow solid; mp 168.2­169 °C (ref 21, mp 167­
(s, 1H, ArH), 7.16 (s, 1H, ArH), 7.35 (t, J = 8 Hz, 1H, ArH), 168 °C). 1H NMR (CDCl3): ¤ 2.76 (s, 3H, CH3), 7.50 (t, J =
7.43 (d, J = 8 Hz, 1H, ArH), 7.46 (d, J = 8 Hz, 1H, ArH), 7.63 7 Hz, 1H, ArH), 7.57 (s, 1H, ArH), 7.68 (t, J = 8 Hz, 1H, ArH),
(s, 1H, ArH), 8.44 (br, 1H, NH); 13C NMR (CD3CN): ¤ 19.5, 7.83­7.91 (m, 4H, ArH), 8.39 (d, J = 8.8 Hz, 2H, ArH).
19.8, 41.6, 127.5, 128.4, 129.2, 129.2, 129.6, 129.9, 130.0, 10d: Yellow solid; mp 198­199 °C (ref 15, mp 178­181 °C).
133.6, 134.5, 135.7, 139.9, 141.7, 160.7, 171.1; HRMS: Calcd 1
H NMR (CDCl3): ¤ 2.69 (s, 3H, CH3), 6.09 (s, 2H, ­OCH2O­),
for C17H15ClN2O m/z (%) = 298.0873 (M+). Found m/z = 7.08 (s, 1H, ArH), 7.12 (s, 1H, ArH), 7.41 (s, 1H, ArH), 7.82
298.0843 (M+). (d, J = 9 Hz, 2H, ArH), 8.38 (d, J = 9 Hz, 2H, ArH).
9e: Colorless solid; mp 180­181 °C (ref 19, mp 181.5­
182.5 °C). 1H NMR (CDCl3): ¤ 3.46 (s, 2H, CH2), 6.02 (s, 2H, References
­OCH2O­), 6.62 (s, 1H, ArH), 6.83 (s, 1H, ArH), 7.40­7.48 1 For recent reviews, see: S. Saito, Y. Yamamoto, Chem. Rev.
(m, 3H, ArH), 7.59 (d, J = 8 Hz, 2H, ArH), 8.86 (br, 1H, NH); 2000, 100, 2901; H. Pellissier, M. Santelli, Tetrahedron 2003, 59,
HRMS: calcd for C16H12N2O3 m/z = 280.0848 (M+). Found 701; H. H. Wenk, M. Winkler, W. Sander, Angew. Chem., Int. Ed.
m/z = 280.0841 (M+). 2003, 42, 502; D. Peña, D. Pérez, E. Guitián, Angew. Chem., Int.
9f: Colorless oil; 1H NMR (CDCl3): ¤ 3.45 (s, 2H, CH2), Ed. 2006, 45, 3579; H. Yoshida, J. Ohshita, A. Kunai, Bull. Chem.
6.05 (s, 2H, ­OCH2O­), 6.60 (s, 1H, ArH), 6.83 (s, 1H, ArH), Soc. Jpn. 2010, 83, 199; K. Okuma, Heterocycles 2012, 85, 515;
7.35 (t, J = 8 Hz, 1H, ArH), 7.43 (d, J = 8 Hz, 1H, ArH), 7.47 A. V. Dubrovskiy, N. A. Markina, R. C. Larock, Org. Biomol.
(d, J = 8 Hz, 1H, ArH), 7.61 (s, 1H, ArH), 8.63 (br, 1H, NH); Chem. 2013, 11, 191; P. M. Tadross, B. M. Stoltz, Chem. Rev.
13
C NMR (CDCl3): ¤ 42.1 (CH2), 102.3, 108.3, 108.9, 124.6, 2012, 112, 3550; A. Bhunia, S. R. Yetra, A. T. Biju, Chem. Soc.
127.7, 129.4, 129.9, 130.3, 131.2, 134.7, 139.8, 147.0, 151.2, Rev. 2012, 41, 3140.
160.1, 170.7 (C=O). HRMS: calcd for C16H11ClN2O3 m/z = 2 U. K. Tambar, B. M. Stoltz, J. Am. Chem. Soc. 2005, 127,
314.0458 (M+). Found m/z = 314.0445 (M+). 5340; H. Yoshida, M. Watanabe, J. Ohshita, A. Kunai, Chem.
9g: Colorless oil; 1H NMR (CDCl3): ¤ 3.55 (s, 2H, CH2), Commun. 2005, 3292.
7.07 (dd, 3JHF = 10 Hz, 4JHF = 8 Hz, 1H, ArH), 7.22 (dd, 3 For a review, see: E. J. Horváth, K. Horváth, T. Hámori,
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JHF = 10 Hz, 4JHF = 8 Hz, 1H, ArH), 7.43­7.49 (m, 3H, ArH), M. I. K. Fekete, S. Sólyom, M. Palkovits, Prog. Neurobiol. 2000,
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7.57 (d, J = 7 Hz, 2H, ArH), 8.50 (br, 1H, NH); 13C NMR
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