Synthesis of Tofisopam by Way of Photoinduced CO2 Fixation

Article abstract of DOI:10.1002/asia.201901431

Herein reported is a unique synthetic route of Tofisopam, an anxiolytic drug containing a 2,3-benzodiazepine core structure. 3,4-Dimethoxypropylbenzene and 3,4-dimethoxybenzoic acid, which are both of plant origin, and CO₂ constitute its carbon skeleton. These three renewable substances are united by two C?C bond forming reactions, i.e., a Friedel–Crafts acylation reaction and a photoinduced carboxylation reaction to construct the major carbon framework. Finally, a methyl group is introduced by a Kumada-type cross-coupling reaction to furnish Tofisopam. Various analogs of Tofisopam are readily synthesized by introducing other substituents than a methyl group at the last C?C bond forming step.

Full text of DOI:10.1002/asia.201901431

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Synthesis of Tofisopam by Way of Photoinduced CO2 Fixation
Authors: Yusuke Masuda, Katsuhiko Makita, Naoki Ishida, and
Masahiro Murakami
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Synthesis of Tofisopam by Way of Photoinduced CO2 Fixation
Yusuke Masuda, Katsuhiko Makita, Naoki Ishida, and Masahiro Murakami*[a]
Abstract: Herein reported is a unique synthetic route of Tofisopam,
an anxiolytic drug containing a 2,3-benzodiazepine core structure.
3,4-Dimethoxypropylbenzene and 3,4-dimethoxybenzoic acid, which
are both plant-origin, and CO2 constitute its carbon skeleton. These
three renewable substances are united by two C–C bond forming
C–C bond with CO2 require highly energetic nucleophiles such
as carboanionic species. We have developed carboxylation
reactions which fix CO2 onto readily available and less energetic
organic compounds with the aid of UV or solar light.[7] Herein,
we report the synthesis of Tofisopam wherein the photoinduced
carboxylation reaction fixes gaseous CO2 into a carbon skeleton
made from two plant-origin, renewable compounds (Figure 2b).
Various Tofisopam analogs are readily synthesized by
introducing an organyl group onto the imidoyl chloride
intermediate at the last step.
reactions, i.e.,
a
Friedel-Crafts acylation reaction and
a
photoinduced carboxylation reaction to construct the major carbon
framework. Finally, a methyl group is introduced by a Kumada-type
cross-coupling reaction to furnish Tofisopam. Various analogs of
Tofisopam are readily synthesized by introducing other substituents
than a methyl group at the last C–C bond forming step.
There are a number of benzodiazepines which are known to
act on a -aminobutyric acid (GABA) receptor to generally
enhance the effect of GABA, causing anxiolytic, sedative,
anticonvulsant, and muscle relaxant.[1] Among them, 2,3-
benzodiazepine analogs are specifically potent as the anxiolytic
drug since they have no sedative, anticonvulsant, and muscle
relaxant activities.[2] Tofisopam (1a, Figure 1) possesses a 2,3-
benzodiazepine ring, to which two methoxy groups, a 3,4-
dimethoxyphenyl ring, ethyl, and methyl groups are appended.
The 2,3-benzodiazepine core is possibly constructed by
cyclocondensation of the 1,5-dicarbonyl compound shown in
Figure 1 with hydrazine. There have been various methods
developed for the synthesis of the key dicarbonyl compound.[3,4]
In the conventional syntheses are used a toxic chromium
reagent[3] or highly energetic compounds such as aryl lithium[4]
(Figure 2a).
Figure 2. Syntheses of key 1,5-dicarbonyl intermediates.
We envisaged the key substrate ketone for the photoinduced
carboxylation reaction would be synthesized by a Friedel-Crafts
acylation reaction of propylbenzene 2, which is readily
accessible by hydrogenation of methyl eugenol,[8] with another
plant-origin compound 3.[9] Thus, a mixture of propylbenzene 2
and the carboxylic acid 3 was heated at 80 C for 4 h in
polyphosphoric acid.[10] A dehydrative Friedel-Crafts acylation
reaction took place selectively at the para position of a methoxy
substituent of 2 to produce ketone 4 in 78% yield.
Figure 1. Structures of Tofisopam and a key 1,5-dicarbonyl intermediate.
On the other hand, it is highly desired to develop a reaction
which fixes carbon dioxide (CO2) onto organic molecules.[5,6]
Since CO2 is extraordinarily stable, most reactions which form a
[a]
Dr. Y. Masuda, K. Makita, Dr. N. Ishida, Prof. Dr. M. Murakami
Department of Synthetic Chemistry and Biological Chemistry
Kyoto University, Katsura, Kyoto 615-8510 (Japan)
E-mail: murakami@sbchem.kyoto-u.ac.jp
Scheme 1. Dehydrative Friedel-Crafts acylation.
Supporting information and the ORCID identification numbers for the
authors of this article can be found under:
With the substrate ketone 4 in hand, we tried the key
photoinduced carboxylation reaction of 4; a dimethyl sulfoxide
(DMSO) solution of ketone 4 under an atmospheric pressure of
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COMMUNICATION
CO2 was irradiated with UV light. No carboxylated compound
was formed under the conditions we previously reported, i.e., in
the absence of
a
base,[7b] although
4
was gradually
consumed.[11] On the other hand, the desired carboxylic acid 5
was produced in 86% yield when the photoinduced
carboxylation reaction of 4 was carried out in the presence of
Cs2CO3 (Scheme 2).[12] A [4 + 2] cycloaddition step between o-
quinodimethane[13] generated from
4 and CO2 might be
accelerated under the basic conditions, although we have no
theoretical or experimental evidence to support this explanation.
The reaction was scalable; when 5 mmol (1.7 g) of 4 was used,
5 was produced in 67% yield (1.3 g).
Scheme 3. Synthesis of imidoyl chloride 7.
Table 1. Synthesis of Tofisopam (1a) and its analogs.
Scheme 2. Photoinduced carboxylation of ketone 4 with CO2.
Next, the carboxylic acid 5 was treated with hydrazine in
DMSO to form the corresponding hydrazone (Scheme 4). After
heating the mixture at 120 C for 12 h, an aq. HCl solution was
added directly to the reaction mixture at room temperature to
promote the subsequent seven-membered ring formation. [7b,14]
Benzodiazepine 6 was isolated in 91% yield by silica gel
chromatography. Next, the benzodiazepine 6 was converted to
imidoyl chloride
7 almost quantitatively by treatment with
phosphoryl chloride in the presence of N,N-dimethylaniline.[15]
The last manipulation was substitution of the chloro
substituent with a methyl substituent. No reaction occurred
when the imidoyl chloride 7 was treated with methylmagnesium
bromide at room temperature.
Next, the reaction with
methylmagnesium bromide was carried out in the presence of
bis(tricyclohexylphosphine)nickel(II) dichloride [NiCl2(PCy3)2, 10
mol%].[16] To our delight, a desired substitution reaction took
place to afford Tofisopam (1a) in 60% isolated yield (Table 1).
The structure of the obtained material was confirmed by
comparison of its spectral data (IR[3a] and NMR[17]) and melting-
point[17] with those reported in literatures (See Supporting
Information).
Finally, we synthesized analogs of Tofisopam simply by
varying the Grignard reagent for the last substitution reaction.
The use of ethylmagnesium bromide afforded the ethyl analog
1b in 66% yield. Functional groups such as alkenyl (1c) and
To summarize, we synthesized Tofisopam in 5 steps and 36%
overall yield starting from readily available plant-origin
renewable compounds. The key 1,5-dicarbonyl intermediate
was synthesized by a photoinduced carboxylation reaction, in
which CO2 was successfully incorporated at the benzylic C–H
bond in a site-selective manner. Furthermore, the present
strategy renders it possible to diversify the imidoyl chloride
intermediate into various analogs of Tofisopam through a cross-
coupling reaction with a range of Grignard reagents.
phenoxy (1d) groups were successfully introduced onto
a
benzodiazepine pharmacophore, albeit in lower yields. Such
late-stage diversification demonstrates the advantage of the
present route introducing a C–C bond at the last step, and is
promising for the pharmaceutical discoveries.[18]
Experimental Section
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Synthesis of ketone 4: A mixture of 2 (1.8 g, 10 mmol), 3 (1.8 g, 10
mmol), and poly phosphoric acid (15 mL) was stirred at 80 C for 4 h.
After the reaction mixture was cooled to room temperature, water was
added. The resulting aqueous solution was extracted with EtOAc (3
times). The combined organic layer was washed with water, a sat. aq.
NaCl solution, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by flash column chromatography
(hexane/EtOAc = 3:1) to afford ketone 4 as white solids (2.7 g, 7.8 mmol,
78%).
Synthesis of carboxylic acid 5: A DMSO (5 mL) solution of 4 (68.9 mg,
0.20 mmol) and Cs2CO3 (130 mg, 0.40 mmol) was irradiated by UV light
(365 nm) under an atmospheric pressure of CO2 for 1 h. An aq. HCl
solution (1 M) was added to the reaction mixture. The resulting mixture
was extracted with Et2O (3 times). The combined organic layer was
washed with water (3 times) and extracted with an aq. NaOH solution (2
M) (3 times). The combined aqueous layer was acidified with an aq. HCl
solution (2 M), and extracted with Et2O (3 times). The organic layer was
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washed with
a sat. aq. NaCl solution, dried over Na2SO4, and
concentrated under reduced pressure to afford the carboxylic acid 5 as
white solids (67.0 mg, 0.17 mmol, 86% yield).
Synthesis of amide 6: A DMSO (1 mL) solution of 5 (77.7 mg, 0.20
mmol) and hydrazine monohydrate (100 mg, 1.0 mmol) was stirred at
120 C for 12 h. After the reaction mixture was cooled to room
temperature, an aq. HCl solution (2 M, 4 mL) was added. After stirring at
room temperature for 5 h, a sat. aq. NaHCO3 solution was added to the
reaction mixture, which was subjected to extraction with dichloromethane
(3 times). The combined organic layer was washed with water, a sat. aq.
NaCl solution, dried over Na2SO4, and concentrated under reduced
[6]
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Soc. 2015, 137, 14063-14066; c) N. Ishida, Y. Masuda, S. Uemoto, M.
Murakami, Chem. Eur. J. 2016, 22, 6524-6527.
pressure.
The residue was purified by preparative thin-layer
chromatography (dichloromethane/EtOAc = 2:1) to afford amide 6 as
white solids (70.2 mg, 0.18 mmol, 91%).
Synthesis of imidoyl chloride 7: A CHCl3 (2 mL) solution of amide 6
(115 mg, 0.30 mmol), N,N’-dimethylaniline (123 mg, 1.20 mmol), and
phosphoryl chloride (123 mg, 1.20 mmol) was stirred at 120 C for 4 h.
After the reaction mixture was cooled to room temperature, volatiles were
[8]
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K. Okamoto, R. Akiyama, S. Kobayashi, J. Org. Chem. 2004, 69, 2871-
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The compounds 2 and 3 are commercially available with surprisingly
inexpensive prices.
removed under reduced pressure.
The residue was purified by
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Arch. Pharm. 2013, 346, 447-454.
preparative thin-layer chromatography (dichloromethane/EtOAc = 20:1)
to afford imidoyl chloride 7 as pale yellow solids (117 mg, 0.28 mmol,
97%).
[11] Significantly different reactivities were previously observed between
ortho methyl-substituted and ethyl-substituted benzophenones.[7b] This
Typical procedure for synthesis of Tofisopam 1a: A THF (2 mL)
solution of 7 (40.6 mg, 0.10 mmol), NiCl2(PCy3)2 (13.8 mg, 0.02 mmol),
and methylmagnesium bromide (3.0 M in THF, 0.10 mL, 0.30 mmol) was
stirred at 80 C for 12 h. After cooling to room temperature, a sat. aq.
NH4Cl solution was carefully added to the reaction mixture, which was
subjected to extraction with EtOAc (3 times). The combined organic
layer was washed with water, a sat. aq. NaCl solution, dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified by
preparative thin-layer chromatography (hexane/EtOAc = 1:2) to afford
Tofisopam 1a as yellow solids (22.8 mg, 0.060 mmol, 60%).
is explained by assuming
a steric factor operating at the [4+2]
cycloaddition step of the intermediate quinodimethane with CO2.
A
similar steric retardation would explain the low reactivity of the ortho
propyl-substituted benzophenone derivative 4.
[12] Although the carboxylation reaction was also promoted by other
inorganic bases, Cs2CO3 gave the best result, probably because of its
high basicity and solubility in DMSO. See Supporting Information for
the effect of bases.
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Acknowledgements
[16] Y. Kiso, K. Yamamoto, K. Tamao, M. Kumada, J. Am. Chem. Soc. 1972,
94, 4374-4376.
This work was supported by JSPS KAKENHI Grant Numbers
15H05756 (M.M.), 18H04648 (N.I.) (Hybrid Catalysis), and
19K15562 (Y.M.).
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Keywords: tofisopam • photoreaction • carbon dioxide • C–H
carboxylation • 2,3-benzodiazepine
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