A convenient synthesis of new types of benzodiazepine derivatives: 2-Alkylsulfanyl-3 H-4,5-dihydro-1,3-benzodiazepin-4-ones and 2-Alkyl-sulfanyl-3 H-4,5-dihydro-1,3-benzodiazepine-4-thiones

Article abstract of DOI:10.1055/s-0029-1217100

An efficient method for preparing 2-alkylsulfanyl-3H-4,5-dihydro-1,3- benzodiazepin-4-ones and 2-alkylsulfanyl-3H-4,5-dihydro-1,3-benzodiazepine-4- thiones under mild conditions has been developed. Thus, 2-(2-isocyanophenyl) acetamides and 2-(2-isocyanophenyl)thioacetamides, easily available from respective 1-isocyano-2-methylbenzenes, were converted into the corresponding isothiocyanates on treatment with sulfur in the presence of a catalytic amount of selenium, which were then reacted with an equimolar amount to sodium hydride to give 2-(sodiosulfanyl)-3H-4,5-dihydro-1,3-benzodiazepin-4-one and 2-(sodiosulfanyl)-3H-4,5-dihydro-1,3-benzodiazepine-4-thione intermediates, respectively. These intermediates were allowed to react with various alkyl halides to afford the desired benzodiazepinone or benzodiazepinethione derivatives in a one-pot reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217100

288
PAPER
A Convenient Synthesis of New Types of Benzodiazepine Derivatives:
2-Alkylsulfanyl-3H-4,5-dihydro-1,3-benzodiazepin-4-ones and 2-Alkyl-
sulfanyl-3H-4,5-dihydro-1,3-benzodiazepine-4-thiones
Synthesis of
N
h
ew Types of
u
Benzodiazep
h
ine Derivati
eves i Fukamachi, Akihiro Kobayashi, Hisatoshi Konishi, Kazuhiro Kobayashi*
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University,
4-101 Koyama-minami, Tottori 680-8552, Japan
Fax +81(857)315263; E-mail: kkoba@chem.tottori-u.ac.jp
Received 26 August 2009; revised 16 September 2009
anophenyl)acetamides 1 were converted into the corre-
Abstract: An efficient method for preparing 2-alkylsulfanyl-3H-
sponding isothiocyanates 2 on treatment with sulfur in the
4,5-dihydro-1,3-benzodiazepin-4-ones and 2-alkylsulfanyl-3H-4,5-
presence of a catalytic amount of selenium and triethyl-
dihydro-1,3-benzodiazepine-4-thiones under mild conditions has
amine in tetrahydrofuran at reflux temperature,4 which
been developed. Thus, 2-(2-isocyanophenyl)acetamides and 2-(2-
isocyanophenyl)thioacetamides, easily available from respective 1- were then treated with an equimolar amounts of sodium
isocyano-2-methylbenzenes, were converted into the corresponding
isothiocyanates on treatment with sulfur in the presence of a catalyt-
ic amount of selenium, which were then reacted with an equimolar
mediates were allowed to react with an equimolar amount
amount to sodium hydride to give 2-(sodiosulfanyl)-3H-4,5-dihy-
dro-1,3-benzodiazepin-4-one and 2-(sodiosulfanyl)-3H-4,5-dihy-
hydride at room temperature to afford 2-sodiosulfanyl-
3H-4,5-dihydro-1,3-benzodiazepin-4-ones 3. These inter-
of alkyl halide, such as methyl iodide, benzyl bromide,
tert-butyl bromoacetate, 4-(bromomethyl)benzonitrile, 2-
bromoacetonitrile, (4-nitrophenyl)methyl bromide, at the
same temperature. The S-alkylation proceeded smoothly
and highly selectively. The progress of each step of the se-
quence could be monitored by TLC (silica gel) analyses.
The usual aqueous workup and subsequent purification by
column chromatography on silica gel afforded the desired
products 4. The results summarized in Table 1 indicate
that the yields are generally fair independent of the sub-
stituents on the benzene nuclei and N-substituents of the
starting materials 1 and alkyl halides used.
dro-1,3-benzodiazepine-4-thione intermediates, respectively. These
intermediates were allowed to react with various alkyl halides to af-
ford the desired benzodiazepinone or benzodiazepinethione deriva-
tives in a one-pot reaction.
Key words: benzodiazepines, isocyanides, isothiocyanates, sulfur,
cyclization
The benzodiazepine skeletons, such as 3H-1,4-
benzodiazepine1 and 2,3-benzodiazepine,2 are found in
many biologically active compounds. Therefore, 3H-4,5-
dihydro-1,3-benzodiazepine derivatives are also of poten-
tial biological importance. However, few practical meth-
ods for the preparation of 3H-4,5-dihydro-1,3-
benzodiazepine derivatives are known, though Ito et al.
have reported the formation of two 3H-4,5-dihydro-1,3-
benzodiazepin-4-ones, as by-products in the preparation
of indole-3-carboxamides from 2-(2-isocyanophenyl)ace-
tamide derivatives.3 In this report, we wish to describe a
facile one-pot procedure for the synthesis of 2-alkyl-
sulfanyl-3H-4,5-dihydro-1,3-benzodiazepin-4-ones 4 and
2-alkylsulfanyl-3H-4,5-dihydro-1,3-benzodiazepine-4-
thiones 8 from secondary 2-(2-isocyanophenyl)acet-
amides 1 and 2-(2-isocyanophenyl)thioacetamides 5, re-
spectively. This is the first report on the synthesis of these
types of benzodiazepine derivatives.
R1
R2
NHR3
sulfur, selenium (cat.)
Et3N, THF, reflux
O
NC
1
O
R1
R2
NHR3
R1
NaH, r.t.
NR3
SNa
O
NCS
R2
N
2
3
O
R1
R2
1) R4X, r.t.
2) H3O+
NR3
N
SR4
The one-pot synthesis of 2-alkylsulfanyl-3H-4,5-dihydro-
1,3-benzodiazepin-4-one derivatives 4 was conducted by
the process illustrated in Scheme 1. The starting precur-
sors 2-(2-isocyanophenyl)acetamides 1 were prepared
from respective 1-isocyano-2-methylbenzenes according
to the procedure reported by Ito et al.3 The 2-(2-isocy-
4
Scheme 1 Preparation of 1,3-benzodiazepin-4-ones 4
We also found that 2-alkylsulfanyl-3H-4,5-dihydro-1,3-
benzodiazepine-4-thiones 8 could be similarly prepared in
one-pot from 2-(2-isocyanophenyl)thioacetamides 5, as
illustrated in Scheme 2. The starting precursors 2-(2-iso-
cyanophenyl)thioacetamides 5 were prepared from re-
spective 1-isocyano-2-methylbenzenes according to the
SYNTHESIS 2010, No. 2, pp 0288–0292
x
x
.
x
x
.2
0
0
9
Advanced online publication: 03.11.2009
DOI: 10.1055/s-0029-1217100; Art ID: F17609SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of New Types of Benzodiazepine Derivatives
289
on the substituents on the benzene nuclei and N-substitu-
ents of the starting materials 4 and alkyl halides used.
Table 1 Preparation of 3H-4,5-Dihydro-1,3-benzodiazepin-4-ones
4
Entry
1
1
R4X
MeI
4 (Yield, %)a
4a (69)
Table 2 Preparation of 3H-4,5-Dihydro-1,3-benzodiazepine-4-
thiones 8
1a (R1 = R2 = H,
R3 = Ph)
Entry
5
R4X
5a (R1 = R2 = H, R3 = Ph) MeI
8 (Yield, %)a
8a (69)
2
3
4
1a
1a
BnBr
4b (63)
4c (65)
4d (70)
1
2
3
4
t-BuO2CCH2Br
5a
5a
EtBr
BnBr
MeI
8b (59)
1b (R1 = R2 = H, R3 = MeI
3-Cl,4-MeC6H3)
8c (64)
5b (R1 = H, R2 = Me,
8d (67)
5
6
7
1c (R1 = H, R2 = Me,
R3 = n-Bu)
4-CNC6H4CH2Br 4e (70)
R3 = 2-ClC6H4)
5
5c (R1 = MeO, R2 = H,
MeI
8e (61)
1d (R1 = Cl, R2 = H,
R3 = t-Bu)
BrCH2CN
4f (68)
R3 = Et)
6
7
5c
5c
CH2=CHCH2Br 8f (68)
BrCH2CN 8g (60)
1e (R1 = MeO, R2 = H, 4-NO2C6H4CH2Br 4g (71)
R3 = 4-ClC6H4)
a Isolated yields.
a Isolated yields.
R1
NHR3
In conclusion, 2-(2-isocyanophenyl)acetamides 1 and 2-
(2-isocyanophenyl)thioacetamides 5 have been utilized
for the one-pot construction of new types of benzodiaz-
epine skeletons, 2-alkylsulfanyl-3H-4,5-dihydro-1,3-ben-
zodiazepin-4-ones 4 and 2-alkylsulfanyl-3H-4,5-dihydro-
1,3-benzodiazepine-4-thiones 8, respectively, via the cor-
responding isothiocyanates 2 and 6, respectively. The
present method may find value in organic synthesis be-
cause of its advantages: i) simplicity of the procedure, ii)
milder reaction conditions, and iii) ready availability of
the starting materials.
sulfur, selenium (cat.)
THF, reflux
S
R2
NC
5
S
R1
R2
NHR3
R1
NaH, r.t.
NR3
SNa
S
R2
NCS
N
6
7
S
R1
R2
1) R4X, r.t.
2) H3O+
NR3
All melting points were obtained on a Laboratory Devices MEL-
TEMP II melting apparatus and are uncorrected. IR spectra were de-
N
1
SR4
termined with a Shimadzu FTIR-8300 spectrophotometer. The H
NMR spectra were determined in CDCl3 using TMS as an internal
reference with a JEOL ECP500 FT NMR spectrometer operating at
500 or a JEOL LA400 FT NMR spectrometer operating at 400
MHz. The 13C NMR spectra were determined in CDCl3 using TMS
as an internal reference with a JEOL ECP500 FT NMR spectrome-
ter operating at 125 MHz. Low-resolution MS spectra (EI, 70 eV)
were measured by a JEOL JMS AX505 HA spectrometer. TLC was
carried out on a Merck Kieselgel 60 PF254. Column chromatography
was performed using Merck Kieselgel 60 (0.063–0.200 mm). All of
the organic solvents used in this study were dried over appropriate
drying agents and distilled prior to use. 1-Isocyano-2-methylben-
zenes were prepared according to the procedure reported previously
by Ito et al.5 All other chemicals used in this study were commer-
cially available.
8
Scheme 2 Preparation of 1,3-benzodiazepine-4-thiones 8
procedure reported by Ito et al.3 First, conversion of 2-(2-
isocyanophenyl)thioacetamides 5 into the corresponding
isothiocyanates 6 was attempted under the same condi-
tions as described for the conversion of 2-(2-isocyanophe-
nyl)acetamides 1 into the corresponding isothiocyanates
2. However, each of the reactions resulted in the forma-
tion of an intractable mixture of products. Presumably,
initially formed isothiocyanates were further converted
into other complicated products in the presence of the rel-
atively strong base, triethylamine. It was found that when
triethylamine was omitted, the desired isothiocyanates 6
were formed cleanly; here the thioamide function may
work as a weak base. These isothiocyanates were then
treated successively with sodium hydride and various
alkyl halides to give the desired benzodiazepine-4-thiones
8, via the 2-sodiosulfanyl-3H-4,5-dihydro-1,3-benzodiaz-
epine-4-thiones 7. The results summarized in Table 2 in-
dicate that the yields are also generally fair independent
2-(2-Isocyanophenyl)acetamides 1
These compounds were prepared by treating the respective 1-isocy-
ano-2-(lithiomethyl)benzenes, generated from 1-isocyano-2-meth-
ylbenzenes, with isocyanates according to the procedure reported
by Ito et al.3
2-(2-Isocyanophenyl)-N-phenylacetamide (1a)3
Yield: 50%; white solid; Rf = 0.23 (THF–hexane, 1:4); mp 137–138
°C (hexane–CH2Cl2).
IR (KBr): 3275, 2126, 1665 cm–1.
Synthesis 2010, No. 2, 288–292 © Thieme Stuttgart · New York

290
S. Fukamachi et al.
PAPER
1H NMR (500 MHz): d = 3.86 (s, 2 H), 7.12 (t, J = 7.3 Hz, 1 H),
7.30 (s, 1 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.32 (t, J = 7.8 Hz, 1 H), 7.36
(t, J = 7.8 Hz, 1 H), 7.43 (t, J = 7.3 Hz, 2 H), 7.50 (d, J = 7.8 Hz, 1
H), 7.51 (t, J = 7.3 Hz, 2 H).
was added. During the reaction, the progress of each step was mon-
itored by TLC (silica gel) analyses. The organic materials were ex-
tracted with EtOAc (3 × 10 mL), and the combined extracts were
washed with brine (15 mL), dried (Na2SO4), and concentrated by
evaporation. The residue was purified by column chromatography
on silica gel to afford a crude solid, which was recrystallized to give
pure 4a as colorless crystals; yield: 82 mg (69%); mp 112–113 °C
(hexane–Et2O); Rf = 0.43 (EtOAc–hexane, 1:4).
Anal. Calcd for C15H12N2O: C, 76.25; H, 5.12; N, 11.86. Found: C,
76.10; H, 5.15; N, 11.80.
N-(3-Chloro-4-methylphenyl)-2-(2-isocyanophenyl)acetamide
(1b)
IR (KBr): 1701, 1610 cm–1.
Yield: 47%; pale-yellow solid; Rf = 0.25 (THF–hexane, 1:3); mp
160–162 °C (hexane–CHCl3).
IR (KBr): 3269, 2124, 1663 cm–1.
1H NMR (500 MHz): d = 2.45 (s, 3 H), 3.66 (s, 2 H), 7.17 (dd,
J = 7.3, 1.4 Hz, 1 H), 7.23 (td, J = 7.3, 1.4 Hz, 1 H), 7.28 (t, J = 7.8
Hz, 2 H), 7.36–7.42 (m, 5 H).
1H NMR (500 MHz): d = 2.31 (s, 3 H), 3.84 (s, 2 H), 7.14 (d, J = 8.3
Hz, 1 H), 7.24 (dd, J = 8.3, 2.3 Hz, 1 H), 7.32 (s, 1 H), 7.36 (td,
J = 7.3, 1.4 Hz, 1 H), 7.42–7.44 (m, 2 H), 7.50 (dd, J = 7.3, 1.4 Hz,
1 H), 7.60 (d, J = 2.3 Hz, 1 H).
13C NMR: d = 15.81, 41.87, 123.99, 125.07, 126.33, 128.40,
128.57, 128.64, 128.67, 129.09, 138.02, 143.86, 153.16, 168.66.
MS: m/z (%) = 282 (100, [M+]).
Anal. Calcd for C16H14N2OS: C, 68.06; H, 5.00; N, 9.92. Found: C,
67.96; H, 5.19; N, 9.84.
Anal. Calcd for C16H13ClN2O: C, 67.49; H, 4.60; N, 9.84. Found: C,
67.28; H, 4.68; N, 9.79.
3-Phenyl-2-(phenylmethyl)sulfanyl-3H-4,5-dihydro-1,3-benzo-
diazepin-4-one (4b)
Pale-yellow solid; Rf = 0.50 (EtOAc–hexane, 1:3); mp 107–109 °C
(hexane–Et2O).
IR (KBr): 1703, 1611 cm–1.
1H NMR (500 MHz): d = 3.62 (s, 2 H), 4.28 (s, 2 H), 7.12 (dd,
J = 7.3, 2.3 Hz, 2 H), 7.23–7.40 (m, 12 H).
13C NMR: d = 37.19, 41.88, 123.90, 125.12, 126.43, 127.29, 128.40
(2 C), 128.56, 128.59, 128.64, 129.05, 129.10, 136.71, 137.72,
143.73, 151.81, 168.55.
N-Butyl-2-(2-isocyano-4-methylphenyl)acetamide (1c)
Yield: 70%; yellow solid; Rf = 0.47 (THF–hexane, 1:3); mp 63–64
°C (hexane–Et2O).
IR (KBr): 3295, 2118, 1645 cm–1.
1H NMR (400 MHz): d = 0.90 (t, J = 7.3 Hz, 3 H), 1.31 (sext,
J = 7.3 Hz, 2 H), 1.47 (quint, J = 7.3 Hz, 2 H), 2.34 (s, 3 H), 3.25 (q,
J = 7.3 Hz, 2 H), 3.61 (s, 2 H), 5.52 (s, 1 H), 7.19 (d, J = 7.8 Hz, 1
H), 7.20 (s, 1 H), 7.31 (d, J = 7.8 Hz, 1 H).
Anal. Calcd for C14H18N2O: C, 73.01; H, 7.88; N, 12.16. Found: C,
72.95; H, 7.98; N, 12.10.
MS: m/z (%) = 358 (100, [M+]).
2-(5-Chloro-2-isocyanophenyl)-N-(1,1-dimethylethyl)acet-
amide (1d)
Yield: 45%; white solid; Rf = 0.26 (THF–hexane, 1:5); mp 149–150
°C (hexane–Et2O).
Anal. Calcd for C22H18N2OS: C, 73.71; H, 4.57; N, 8.47. Found: C,
73.60; H, 4.78; N, 8.42.
1,1-Dimethylethyl 2-(4-Oxo-3-phenyl-3H-4,5-dihydro-1,3-ben-
zodiazepin-2-yl)sulfanylacetate (4c)
Pale-yellow needles; Rf = 0.42 (EtOAc–hexane, 1:3); mp 122–124
°C (hexane–CH2Cl2).
IR (KBr): 3298, 2126, 1643 cm–1.
1H NMR (500 MHz): d = 1.37 (s, 9 H), 3.54 (s, 2 H), 5.48 (br s, 1
H), 7.29 (dd, J = 8.7, 2.3 Hz, 1 H), 7.32 (d, J = 8.7 Hz, 1 H), 7.43
(d, J = 2.3 Hz, 1 H).
IR (KBr): 1709, 1614 cm–1.
1H NMR (500 MHz): d = 1.42 (s, 9 H), 3.65 (s, 2 H), 3.72 (s, 2 H),
7.20 (dd, J = 7.8, 1.4 Hz, 1 H), 7.21 (t, J = 7.8 Hz, 1 H), 7.24–7.27
(m, 2 H), 7.36 (t, J = 7.8 Hz, 1 H), 7.38–7.42 (m, 4 H).
Anal. Calcd for C13H15ClN2O: C, 62.28; H, 6.03; N, 11.17. Found:
C, 62.28; H, 6.09; N, 11.13.
13C NMR: d = 27.97, 36.17, 41.86, 81.97, 124.00, 124.99, 126.54,
128.37, 128.58, 128.70, 128.88, 129.17, 137.58, 143.46, 151.08,
167.58, 168.56.
N-(4-Chlorophenyl)-2-(2-isocyano-5-methoxyphenyl)acet-
amide (1e)
Yield: 41%; pale-yellow solid; Rf = 0.21 (THF–hexane, 1:3); mp
162–163 °C (hexane–CHCl3).
IR (KBr): 3279, 2120, 1655 cm–1.
1H NMR (500 MHz): d = 3.79 (s, 2 H), 3.84 (s, 3 H), 6.84 (dd,
J = 8.7, 2.7 Hz, 1 H), 6.98 (d, J = 2.7 Hz, 1 H), 7.27 (d, J = 8.7 Hz,
2 H), 7.36 (d, J = 8.7 Hz, 1 H), 7.39 (s, 1 H), 7.45 (d, J = 8.7 Hz, 2
H).
MS: m/z (%) = 382 (16, [M+]), 326 (100).
Anal. Calcd for C21H22N2O3S: C, 65.95; H, 5.80; N, 7.32. Found: C,
65.90; H, 5.85; N, 7.23.
3-(3-Chloro-4-methylphenyl)-2-methylsulfanyl-3H-4,5-dihy-
dro-1,3-benzodiazepin-4-one (4d)
Pale-yellow oil; Rf = 0.43 (THF–hexane, 1:5).
IR (neat): 1705, 1614 cm–1.
Anal. Calcd for C16H13ClN2O2: C, 63.90; H, 4.36; N, 9.31. Found:
C, 63.85; H, 4.43; N, 9.27.
1H NMR (500 MHz): d = 2.38 (s, 3 H), 2.46 (s, 3 H), 3.64 (s, 2 H),
7.00 (dd, J = 8.2, 2.3 Hz, 1 H), 7.15 (d, J = 2.3 Hz, 1 H), 7.23 (ddd,
J = 8.2, 7.8, 1.4 Hz, 1 H), 7.24–7.28 (m, 2 H), 7.29 (d, J = 8.2 Hz, 1
H), 7.38 (ddd, J = 8.2, 7.8, 1.4 Hz, 1 H).
13C NMR: d = 15.81, 19.87, 41.79, 124.08, 124.89, 126.44, 126.95,
128.48, 128.59, 129.11, 131.12, 134.60, 136.54, 136.98, 143.75,
152.65, 168.68.
2-Methylsulfanyl-3-phenyl-3H-4,5-dihydro-1,3-benzodiazepin-
4-one (4a); Typical Procedure
A mixture of 1a (0.10 g, 0.42 mmol), Et3N (0.11 g, 1.1 mmol), sul-
fur (16 mg, 0.51 mmol), and selenium (1.0 mg, 13 mmol) in THF (3
mL) was stirred at reflux temperature for 10 min. After cooling to
r.t., NaH (60% in oil; 20 mg, 0.51 mmol) was added and the mixture
was stirred for 30 min at the same temperature. MeI (72 mg, 0.51
mmol) was then added using a microsyringe and the stirring was
continued for an additional 20 min before sat. aq NH4Cl (10 mL)
MS: m/z (%) = 330 (100, [M+]).
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PAPER
Synthesis of New Types of Benzodiazepine Derivatives
291
Anal. Calcd for C17H15ClN2OS: C, 61.72; H, 4.57; N, 8.47. Found:
C, 61.71; H, 4.79; N, 8.31.
1H NMR (500 MHz): d = 4.32 (s, 2 H), 7.28 (d, J = 7.8 Hz, 1 H),
7.36–7.47 (m, 5 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.67 (d, J = 8.2 Hz, 2
H), 8.82 (s, 1 H).
4-[(3-Butyl-8-methyl-4-oxo-3H-4,5-dihydro-1,3-benzodiazepin-
2-yl)sulfanylmethyl]benzonitrile (4e)
Pale-yellow oil; Rf = 0.29 (THF–hexane, 1:5).
Anal. Calcd for C15H12N2S: C, 71.40; H, 4.79; N, 11.10. Found: C,
71.34; H, 4.84; N, 11.06.
IR (neat): 2230, 1694, 1593 cm–1.
N-(2-Chlorophenyl)-2-(2-isocyano-4-methylphenyl)thioacet-
amide (5b)
Yield: 76%; yellow needle; Rf = 0.26 (THF–hexane, 1:4); mp 88–90
°C (hexane–Et2O).
1H NMR (500 MHz): d = 0.78 (t, J = 7.3 Hz, 3 H), 1.09 (sext,
J = 7.3 Hz, 2 H), 1.40 (quint, J = 7.3 Hz, 2 H), 2.36 (s, 3 H), 3.35
(br s, 2 H), 3.71 (br s, 2 H), 4.39 (s, 2 H), 6.92 (s, 1 H), 7.01 (dd,
J = 7.8, 1.4 Hz, 1 H), 7.10 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 8.7 Hz,
2 H), 7.63 (d, J = 8.7 Hz, 2 H).
13C NMR: d = 13.51, 19.55, 21.11, 30.69, 35.76, 41.20, 45.96,
111.18, 118.63, 122.45, 123.61, 127.41, 128.06, 129.85, 132.20,
138.16, 143.20 (2 C), 151.63, 168.59.
IR (KBr): 3219, 2120, 1591 cm–1.
1H NMR (500 MHz): d = 2.38 (s, 3 H), 4.36 (s, 2 H), 7.20 (td,
J = 7.8, 1.4 Hz, 1 H), 7.25–7.28 (m, 2 H), 7.31 (td, J = 8.2, 1.4 Hz,
1 H), 7.41 (d, J = 7.8 Hz, 1 H), 7.44 (d, J = 7.8 Hz, 1 H), 8.52 (d,
J = 8.2 Hz, 1 H), 8.81 (s, 1 H).
MS: m/z (%) = 377 (100, [M+]).
Anal. Calcd for C16H13ClN2S: C, 63.89; H, 4.36; N, 9.31. Found: C,
63.79; H, 4.56; N, 9.46.
Anal. Calcd for C22H23N3OS: C, 70.00; H, 6.14; N, 11.13. Found:
C, 69.85; H, 6.15; N, 11.35.
N-Ethyl-2-(2-isocyano-5-methoxyphenyl)thioacetamide (5c)
Yield: 80%; yellow solid; Rf = 0.28 (THF–hexane, 1:2); mp 59–62
°C (hexane–Et2O).
IR (KBr): 3217, 2114, 1610 cm–1.
1H NMR (500 MHz): d = 1.27 (t, J = 7.3 Hz, 3 H), 3.69 (q, J = 7.3
Hz, 1 H), 3.70 (q, J = 7.3 Hz, 1 H), 3.84 (s, 3 H), 4.10 (s, 2 H), 6.83
(dd, J = 8.7, 2.7 Hz, 1 H), 7.04 (d, J = 2.7 Hz, 1 H), 7.32 (d, J = 8.7
Hz, 1 H), 7.33 (br s, 1 H).
2-{[7-Chloro-4-oxo-3-(1,1-dimethylethyl)-3H-4,5-dihydro-1,3-
benzodiazepin-2-yl]sulfanyl}acetonitrile (4f)
Colorless crystals; Rf = 0.20 (THF–hexane, 1:5); mp 156–158 °C
(hexane–Et2O).
IR (KBr): 2249, 1690, 1603 cm–1.
1H NMR (500 MHz): d = 1.44 (s, 9 H), 3.32 (d, J = 14.2 Hz, 1 H),
3.36 (d, J = 14.2 Hz, 1 H), 3.77 (d, J = 16.5 Hz, 1 H), 4.01 (d,
J = 16.5 Hz, 1 H), 7.14 (d, J = 8.7 Hz, 1 H), 7.23 (d, J = 2.3 Hz, 1
H), 7.32 (dd, J = 8.7, 2.3 Hz, 1 H).
Anal. Calcd for C12H14N2OS: C, 61.51; H, 6.02; N, 11.96. Found:
C, 61.57; H, 6.11; N, 11.86.
13C NMR: d = 17.97, 28.90, 42.95, 59.79, 115.32, 123.67, 127.85,
2-Methylsulfanyl-3-phenyl-3H-4,5-dihydro-1,3-benzodiaz-
epine-4-thione (8a); Typical Procedure
128.21, 128.56, 131.58, 142.25, 153.23, 172.14.
MS: m/z (%) = 321 (78, [M+]), 265 (100).
A mixture of 5a (0.11 g, 0.42 mmol), sulfur (16 mg, 0.50 mmol),
and selenium (1.0 mg, 13 mmol) in THF (3 mL) was stirred at reflux
temperature for 10 min. After cooling to r.t., NaH (60% in oil; 20
mg, 0.50 mmol) was added and the mixture was stirred for 30 min
at the same temperature. MeI (72 mg, 0.50 mmol) was added using
a microsyringe and the stirring was continued for an additional 20
min before sat. aq NH4Cl (10 mL) was added. During the reaction,
the progress of each step was monitored by TLC (silica gel) analy-
ses. The organic materials were extracted with Et2O (3 × 10 mL),
and the combined extracts were washed with brine (15 mL), dried
(Na2SO4), and concentrated by evaporation. The residue was puri-
fied by column chromatography on silica gel to afford the crude
product, which was recrystallized to give pure 8a as yellow crystals;
yield: 87 mg (69%); Rf = 0.40 (CH2Cl2–hexane, 1:1); mp 195–196
°C (hexane–CH2Cl2).
Anal. Calcd for C15H16ClN2OS: C, 55.98; H, 5.01; N, 13.06. Found:
C, 55.90; H, 5.00; N, 13.02.
3-(4-Chlorophenyl)-7-methoxy-2-(4-nitrophenylmethyl)sulfa-
nyl-3H-4,5-dihydro-1,3-benzodiazepin-4-one (4g)
Yellow solid; Rf = 0.60 (THF–hexane, 1:1); mp 157–159 °C (hex-
ane–CH2Cl2).
IR (KBr): 1703, 1614, 1520, 1346 cm–1.
1H NMR (500 MHz): d = 3.53 (s, 2 H), 3.82 (s, 3 H), 4.31 (s, 2 H),
6.77 (d, J = 3.2 Hz, 1 H), 6.94 (dd, J = 8.7, 3.2 Hz, 1 H), 7.04 (d,
J = 8.7 Hz, 2 H), 7.14 (d, J = 8.7 Hz, 1 H), 7.35 (d, J = 8.7 Hz, 2 H),
7.51 (d, J = 8.7 Hz, 2 H), 8.15 (d, J = 8.7 Hz, 2 H).
13C NMR: d = 36.23, 42.16, 55.70, 112.81, 115.20, 123.69, 125.31,
125.77, 129.53, 129.98, 130.00, 134.94, 136.12, 137.11, 145.15,
147.23, 148.48, 158.81, 168.11.
IR (KBr): 1605, 1582, 1144 cm–1.
1H NMR (500 MHz): d = 2.45 (s, 3 H), 4.21 (br s, 2 H), 7.17 (s, 2
H), 7.24–7.30 (m, 2 H), 7.38-7.45 (m, 5 H).
MS: m/z (%) = 467 (100, [M+]).
13C NMR: d = 16.05, 51.35, 124.00, 126.89, 127.21, 128.12 (2 C),
128.80, 129.25, 129.41, 142.04, 143.31, 153.98, 203.77.
Anal. Calcd for C23H18ClN3O4S: C, 59.04; H, 3.88; N, 8.98. Found:
C, 59.04; H, 4.15; N, 8.95.
MS: m/z (%) = 298 (79, [M+]), 251 (100).
2-(2-Isocyanophenyl)thioacetamides 5
Anal. Calcd for C16H14N2S2: C, 64.39; H, 4.73; N, 9.39. Found: C,
64.30; H, 4.78; N, 9.58.
These compounds were prepared by treating the respective 1-isocy-
ano-2-(lithiomethyl)benzenes with isothiocyanates according to the
procedure reported by Ito et al.3
2-Ethylsulfanyl-3-phenyl-3H-4,5-dihydro-1,3-benzodiazepine-
4-thione (8b)
Yellow crystal; Rf = 0.65 (THF–hexane, 1:4); mp 185–188 °C
(hexane–THF).
2-(2-Isocyanophenyl)-N-phenylthioacetamide (5a)3
Yield: 82%; pale-yellow solid; Rf = 0.25 (THF–hexane, 1:7); mp
93–95 °C (hexane–Et2O).
IR (KBr): 1605, 1578, 1142 cm–1.
IR (KBr): 3242, 2120, 1597 cm–1.
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S. Fukamachi et al.
PAPER
1H NMR (500 MHz): d = 1.31 (t, J = 7.3 Hz, 3 H), 3.04 (q, J = 7.3
Hz, 2 H), 4.20 (br s, 2 H), 7.16 (s, 2H), 7.24–7.31 (m, 3 H), 7.38–
7.45 (m, 4 H).
13C NMR: d = 13.56, 27.30, 51.32, 123.89, 126.94, 127.14, 128.09,
128.56, 128.74, 129.19, 129.35, 141.95, 143.32, 153.20, 203.68.
IR (KBr): 1611, 1578, 1153 cm–1.
1H NMR (500 MHz): d = 1.18 (t, J = 7.3 Hz, 3 H), 3.62–3.75 (m, 2
H), 3.81 (s, 3 H), 3.84–3.88 (m, 1 H), 4.10–4.13 (m, 2 H), 4.47–4.54
(m, 1 H), 5.19 (d, J = 10.1 Hz, 1 H), 5.36 (dd, J = 16.9, 1.4 Hz, 1 H),
5.94–6.02 (m, 1 H), 6.76 (d, J = 2.7 Hz, 1 H), 6.88 (dd, J = 8.7, 2.7
Hz, 1 H), 7.10 (d, J = 8.7 Hz, 1 H).
13C NMR: d = 12.19, 34.92, 48.24, 51.28, 55.56, 111.61, 115.14,
118.72, 124.84, 127.78, 132.44, 136.87, 151.66, 158.92, 200.24.
MS: m/z (%) = 312 (79, [M+]), 283 (100).
Anal. Calcd for C17H16N2S2: C, 65.35; H, 5.16; N, 8.97. Found: C,
65.35; H, 5.15; N, 8.95.
MS: m/z (%) = 306 (32, [M+]), 265 (100).
3-Phenyl-2-phenylmethylsulfanyl-3H-4,5-dihydro-1,3-benzodi-
azepine-4-thione (8c)
Yellow oil; Rf = 0.60 (THF–hexane, 1:3).
Anal. Calcd for C15H18N2OS2: C, 58.79; H, 5.92; N, 9.14. Found:
C, 58.73; H, 6.02; N, 9.11.
IR (neat): 1607, 1582, 1144 cm–1.
1H NMR (500 MHz): d = 4.01 (br s, 2 H), 4.27 (s, 2 H), 7.13 (s, 2
H), 7.24–7.32 (m, 7 H), 7.38–7.41 (m, 5 H).
13C NMR: d = 37.53, 51.32, 123.94, 126.97, 127.31, 127.42,
128.11, 128.46, 128.55, 128.79, 129.12, 129.28, 129.37, 136.35,
141.69, 143.19, 152.65, 203.67.
2-Cyanomethylsulfanyl-3-ethyl-7-methoxy-3H-4,5-dihydro-
1,3-benzodiazepine-4-thione (8g)
Pale-yellow needles; Rf = 0.50 (THF–hexane, 1:3); mp 140–141 °C
(hexane–THF).
IR (KBr): 2245, 1614, 1593, 1123 cm–1.
1H NMR (500 MHz): d = 1.22 (t, J = 6.9 Hz, 3 H), 3.65 (br s, 1 H),
3.82 (s, 5 H), 4.12–4.18 (m, 2 H), 4.52 (br s, 1 H), 6.76 (d, J = 2.7
Hz, 1 H), 6.91 (dd, J = 8.7, 2.7 Hz, 1 H), 7.21 (d, J = 8.7 Hz, 1 H).
13C NMR: d = 12.28, 17.87, 48.18, 51.37, 55.60, 111.72, 115.29,
115.78, 125.33, 127.56, 136.11, 147.99, 159.66, 200.65.
MS: m/z (%) = 374 (62, [M+]), 283 (100).
Anal. Calcd for C22H18N2S2: C, 70.56; H, 4.84; N, 7.48. Found: C,
70.59; H, 4.80; N, 7.47.
3-(2-Chlorophenyl)-8-methyl-2-methylsulfanyl-3H-4,5-dihy-
dro-1,3-benzodiazepine-4-thione (8d)
Pale-yellow solid; Rf = 0.32 (Et2O–hexane, 1:20); 48–50 °C
(hexane).
MS: m/z (%) = 305 (75, [M+]), 265 (100).
Anal. Calcd for C14H15N3OS2: C, 55.06; H, 4.95; N, 13.76. Found:
C, 55.04; H, 4.85; N, 13.75.
IR (KBr): 1620, 1593, 1146 cm–1.
References
1H NMR (500 MHz): d = 2.39 (s, 3 H), 2.46 (s, 3 H), 4.21 (br s, 2
H), 7.08 (d, J = 7.8 Hz, 1 H), 7.09 (s, 1 H), 7.17 (d, J = 7.8 Hz, 1 H),
7.32–7.39 (m, 3 H), 7.45 (d, J = 8.2 Hz, 1 H).
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13C NMR: d = 16.00, 21.17, 50.62, 124.31, 126.72, 127.32, 127.35,
127.71, 128.19, 130.49, 130.57, 138.07, 138.48, 138.77, 153.47,
160.42, 198.75.
MS: m/z (%) = 346 (82, [M+]), 309 (100).
Anal. Calcd for C17H15N2S2: C, 58.86; H, 4.36; N, 8.08. Found: C,
58.75; H, 4.52; N, 7.91.
3-Ethyl-7-methoxy-2-methylsulfanyl-3H-4,5-dihydro-1,3-ben-
zodiazepine-4-thione (8e)
Pale-yellow needles; Rf = 0.60 (THF–hexane, 1:4); mp 85–88 °C
(hexane).
IR (KBr): 1614, 1593, 1121 cm–1.
1H NMR (500 MHz): d = 1.20 (t, J = 6.9 Hz, 3 H), 2.55 (s, 3 H),
3.63–3.65 (m, 1 H), 3.81 (s, 3 H), 4.10–4.15 (m, 2 H), 4.47–4.53 (m,
1 H), 6.76 (d, J = 2.7 Hz, 1 H), 6.88 (dd, J = 8.7, 2.7 Hz, 1 H), 7.11
(d, J = 8.7 Hz, 1 H).
13C NMR: d = 12.16, 15.12, 48.38, 51.31, 55.55, 111.62, 115.12,
124.87, 127.74, 136.98, 153.26, 158.83, 200.25.
MS: m/z (%) = 280 (80, [M+]), 243 (100).
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Anal. Calcd for C13H16N2OS2: C, 55.68; H, 5.75; N, 9.99. Found: C,
55.42; H, 5.93; N, 10.15.
2-Allylsulfanyl-3-ethyl-7-methoxy-3H-4,5-dihydro-1,3-benzo-
diazepine-4-thione (8f)
Pale-yellow solid; Rf = 0.46 (THF–hexane, 1:9); mp 57–59 °C
(hexane–Et2O).
Synthesis 2010, No. 2, 288–292 © Thieme Stuttgart · New York