Syntheses and reactions of 2-cyclohexyl-1,3,4,5-tetrahydro-10H-pyrrolo[3,4-b][1,5]benzodiazepine-1,4-dione and 4-aryl-2-cyclohexyl-1,3,4,10-tetra-hydropyrrolo[4,3-c][1,5]benzothiazepin-1-ones

Article abstract of DOI:10.3987/COM-05-10514

2-Cyclohexyl-1,3,4,5-tetrahydro-10H-pyrrolo[3,4-b][1,5]benzodiaze-pine-1,4-dione was synthesized by heating a solution of ethyl 1-cyclohexyl-2,3-dioxopyrrolidine-4-carboxylate and o-phenylenediamine in acetic acid. Alkylation and acylation of the synthesi

Full text of DOI:10.3987/COM-05-10514

HETEROCYCLES, Vol. 65, No. 10, 2005
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HETEROCYCLES, Vol. 65, No. 10, 2005, pp. 2451 - 2459
Received, 15th July, 2005, Accepted, 10th August, 2005, Published online, 12th August, 2005
SYNTHESES AND REACTIONS OF 2-CYCLOHEXYL-1,3,4,5-
TETRAHYDRO-10H-PYRROLO[3,4-b][1,5]BENZODIAZEPINE-
1,4-DIONE AND 4-ARYL-2-CYCLOHEXYL-1,3,4,10-TETRA-
HYDROPYRROLO[4,3-c][1,5]BENZOTHIAZEPIN-1-ONES
Keizo Matsuo,* Junko Kawanishi, Mariko Kobayashi, and Sachiko Ueno
Faculty of Pharmaceutical sciences, Kinki University, 3-4-1 Kowakae,
Higashiosaka, Osaka 577-8502, Japan. e-mail: k-matsuo@phar.kindai.ac.jp
Abstract- 2-Cyclohexyl-1,3,4,5-tetrahydro-10H-pyrrolo[3,4-b][1,5]benzodiaze-
pine-1,4-dione was synthesized by heating a solution of ethyl 1-cyclohexyl-2,3-
dioxopyrrolidine-4-carboxylate and o-phenylenediamine in acetic acid.
Alkylation and acylation of the synthesized compound were examined. 4-Aryl-
2-cyclohexyl-1,3,4,10-tetrahydropyrrolo[4,3-c][1,5]benzothiazepin-1-ones were
synthesized by Michael addition of 2-aminothiophenol to 4-arylidene-1-cyclo-
hexyl-2,3-dioxopyrrolidines and concomitant dehydrative cyclization.
In the course of our synthetic studies on the biologically active heterocyclic compounds using tetronic
acids, tetramic acids and thiotetronic acid, we reported that the synthesis and biological activities, namely
antimicrobial and analgesic activities, of 10-aryl-3,3-dimethyl-3,4,9,10-tetrahydro-1H-pyrrolo[4,3-b]-
[1,5]benzodiazepin-1-ones (1),1 10-aryl-3,3-dimethyl-1,3,4,10-tetrahydropyrrolo[3,4-c][1,5]benzothiaze-
pin-1-ones (2),2 and 10-aryl-3,3-dimethyl-1,3,3a,9-tetrahydrofuro[4,3-b][1,5]benzothiazepin-1-ones (3).3
As a continuation of our work on the structure-activity relationships of benzodiazepinones and
benzothiazepinones, we plan to synthesize 2-cyclohexyl-1,3,4,5-tetrahydro-10H-pyrrolo[3,4-b][1,5]-
benzodiazepine-1,4-dione (4),4 4-aryl-2-cyclohexyl-1,3,4,10-tetrahydropyrrolo[4,3-c][1,5]benzothiaze-
pin-1-one (5),5 and their derivatives (Figure 1).
Ar
Ar
Ar
O
O
O
H
H
S
X
N
N
N
HN
O
N
N
N
S
N
H
H
H
O
O
3
5
4
1: X=NH
2: X=S
Figure 1
For the synthesis of 4 and 5, ethyl 1-cyclohexyl-2,3-dioxopyrrolidine-4-carboxylate (6)6 was used as the
starting material. Treatment of 6 with o-phenylenediamine in methanol at refluxing temperature for 8 h

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HETEROCYCLES, Vol. 65, No. 10, 2005
gave the desired compound (4) in only 7% yield, and the major product was the intermediate (7) (52%).
When the above reaction was carried out in acetic acid at refluxing temperature for 1 h, 4 was obtained in
91% yield (Scheme 1).
For the chemical modifications of 4, alkylation of 4 was tried first. Reaction of 4 with methyl iodide in
DMF in the presence of NaH afforded an unexpected methylation product (8) in 72% yield as a sole
1
product.7 In the H-NMR spectrum, 3a-CH3 and N-CH3 signals appeared at δ 0.95 and 3.47 ppm,
respectively. When diethylaminoethylation was performed by treatment of 4 with 2-diethylaminoethyl
bromide hydrobromide in DMF in the presence of NaH at room temperature, the desired compound (9)
was obtained in 25% yield and the most of the starting material was recovered (Scheme 1).
CO2C2H5
H2N
reflux
4 (7%)
N
+
CO2C2H5
O
in CH3OH
H2N
H2N
N
H
N
+
O
7 (52%)
reflux
O
4 (91%)
6
in CH3COOH
O
O
CH3
N
H
N
CH3
NaH, CH3I
NaH
N
N
4
N(C2H )
5 2 ・HBr
in DMF
(72%)
N
N
Br
O
O
N(C2H5)2
in DMF
(25%)
8
9
Scheme 1
Next, we examined acylation of 4. Reaction of 4 with benzoyl chloride in dioxane in the presence of
triethylamine at refluxing temperature overnight gave the amide (10) in 79% yield. Similarly, when 4 was
treated with chloroacetyl chloride, the chloroacetamide derivative (11) was obtained in 69% yield.
The product (11) was further reacted with morpholine in acetonitrile in the presence of Na2CO3 at
refluxing temperature for 3 h to give 12 in 52% yield.8 In this reaction, the compound (4) was obtained in
15% as the byproduct. Treatment of 11 with N-methylpiperazine under the same condition as above
afforded 13 and 4 in 40 and 46% yields, respectively (Scheme 2).
For the preparation of 5, we thought that it might be obtained by Michael addition of 2-aminothiophenol
to 4-arylidene-1-cyclohexyl-2,3-dioxopyrrolidines (14). 4-Benzylidene-1-cyclohexyl-2,3-dioxopyrroli-
dine (14a)9 was synthesized by the reaction of 6 with benzaldehyde in the presence of 20% HCl in 73%
yield. The other derivatives (14b-e) were synthesized by the similar method.
The synthesis of 4-aryl-2-cyclohexyl-1,3,4,10-tetrahydropyrrolo[4,3-c][1,5]benzothiazepin-1-one (5) was
performed by a similar procedure used in the preparation of 10-aryl-3,3-dimethyl-1,3,4,10-tetrahydro-
pyrrolo[3,4-c][1,5]benzothiazepin-1-ones (2).2 Thus, a mixture of 14a, 2-aminothiophenol and conc. HCl
in ethanol was heated under reflux to give 5a in 86% yield. Similarly, the other derivatives (5b-e) were
prepared in good yields (Scheme 3). As a chemical modification of 5, methylation of 5b was examined.

HETEROCYCLES, Vol. 65, No. 10, 2005
2453
Treatment of 5b with methyl iodide in the presence of potassium carbonate in acetone at refluxing
temperature resulted in recovery of the starting material. When 5b was reacted with methyl iodide in the
O
H
N
C6H5COCl
N
4
(C2H5)3N
(79%)
O
O
N
H
O
N
O
C6H5
4 (15%)
+
N
10
N
O
HN
O
N
O
O
H
N
Na2CO3
12 (52%)
ClCH2COCl
N
(C2H5)3N
(69%)
N
O
H
O
Cl
N
O
4 (46%)
HN
NCH3
+
N
11
N
Na2CO3
O
O
N
NCH3
13 (40%)
Scheme 2
presence of NaH in DMF at room temperature, a complex mixture was obtained. Therefore, we thought to
use 2-methylaminothiophenol10 as a Michael donor. Thus, when an ethanol solution of 14b, 2-methyl-
aminothiophenol and conc. HCl was refluxed, the N-methyl derivative (15) was obtained in 50% yield.
Ar
CO2C2H5
HCl
Ar-CHO
N
N
N
H2O
O
O
O
O
O
O
6
14a: Ar=C6H5 (73%)
b: Ar=2-Cl-C6H4 (57%)
c: Ar=2-NO2-C6H4 (31%)
d: Ar=2-CH3-C6H4 (61%)
e: Ar=2-Thienyl (53%)
HS
Ar
S
H2N
N
N
HCl
H
HS
O
Cl
N
5 a: Ar=C6H5 (86%)
CH3HN
HCl
S
b: Ar=2-Cl-C6H4 (92%)
c: Ar=2-NO2-C6H4 (89%)
d: Ar=2-CH3-C6H4 (99%)
e: Ar=2-Thienyl (91%)
14b
N
O
CH3
15 (50%)
Scheme 3

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HETEROCYCLES, Vol. 65, No. 10, 2005
Thus, we synthesized new heterocyclic compounds, 2-cyclohexyl-1,3,4,5-tetrahydro-10H-pyrrolo[3,4-b]-
[1,5]benzodiazepine-1,4-dione (4), 4-aryl-2-cyclohexyl-1,3,4,10-tetrahydropyrrolo[4,3-c][1,5]benzothia-
zepin-1-one (5), and their derivatives (Scheme 3).
EXPERIMENTAL
Melting points were determined using a Yanagimoto micro-melting point apparatus, model MP-S3, and
are uncorrected. IR spectra were measured with a Hitachi 260-30 infrared spectrophotometer. 1H-NMR
spectra were recorded on a JEOL JNM-GSX270 (270 MHz) spectrometer using tetramethylsilane as the
internal standard. High-resolution MS (HRMS) spectra were measured with a JEOL JMS-HX100
instrument at 70 eV.
2-Cyclohexyl-1,3,4,5-tetrahydro-10H-pyrrolo[3,4-b][1,5]benzodiazepine-1,4-dione (4) and ethyl 3-
(2-aminophenylamino)-1-cyclohexyl-2H,5H-2-oxopyrrol-4-ylcarboxylate (7)
A mixture of 6 (2.000 g, 7.90 mmol) and o-phenylenediamine (0.854 g, 7.90 mmol) in CH3OH (10 mL)
was heated under reflux for 6 h. After addition of more 6 (0.40 g, 1.58 mmol), the mixture was heated
under reflux for further 2 h. The crystals formed by cooling were collected by filtration to give 4 (0.195 g,
7%). The filtrate was concentrated under reduced pressure to give the residue, which was recrystallized
from 2-propanol-hexane to afford 7 (1.686 g, 52%). 4: mp 288-290 ℃. IR (Nujol): 3260, 1660 cm-1.
1H-NMR (DMSO-d6) δ: 1.05-1.80 (10H, m, cyclohexyl), 3.79 (1H, m, NCH), 3.92 (2H, s, NCH2),
6.70-7.10 (4H, m, ArH), 8.08 and 8.58 (each 1H, br s, 2 x NH). HRMS (m/z): Calcd for C17H19N3O2:
297.1477. Found: 297.1458. 7: mp 131-135 ℃. IR (Nujol): 3225, 1660, 1245, 1220, 1130 cm-1. 1H-NMR
(CDCl3) δ: 1.17 (3H, t, J=7.0 Hz, CH2CH3), 1.30-1.86 (10H, m, cyclohexyl), 4.01 (2H, s, NCH2C), 4.00
(1H, m, NCH), 4.00 (2H, br s, NH2), 4.12 (2H, q, J=7.0 Hz, OCH2CH3), 6.68-7.07 (4H, m, ArH), 7.45
(1H, br s, NH). Anal. Calcd for C19H25N3O3: C, 66.45; H, 7.34; N, 12.24. Found: C, 66.56; H, 7.30; N,
12.21.
2-Cyclohexyl-1,3,4,5-tetrahydro-10H-pyrrolo[3,4-b][1,5]benzodiazepine-1,4-dione (4)
A solution of 6 (5.000 g, 19.74 mmol) and o-phenylenediamine (2.134 g, 19.73 mmol) in acetic acid (25
mL) was heated under reflux for 1 h. After cooling and addition of water, the crystals formed were
collected by filtration to give 4 (5.368 g, 91%).
2-Cyclohexyl-3a,5-dimethyl-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-b][1,5]benzodiazepine-1,4-dione (8)
To a suspension of NaH (205 mg, 60%, 5.10 mmol) in dry DMF (10 mL) was added 4 (500 mg, 1.68
mmol) and the whole was stirred at rt for 30 min. Iodomethane (0.40 mL, 7.09 mmol) was added to the
above solution and then the reaction mixture was stirred at rt overnight. After addition of water, the
precipitates formed were collected by filtration. The crude products were purified by SiO2 column
chromatography (hexane-acetone=5:3) to give 8 (0.392 g, 72%). mp 199.5-201 ℃ (2-propanol-hexane).
1
IR (CHCl3): 1695, 1665, 1600, 1310, 1270, 1210, 1110 cm-1. H-NMR (CDCl3) δ: 0.95 (3H, s, CCH3),
1.10-1.90 (10H, m, cyclohexyl), 3.19 (1H, d, J=11.0 Hz, NCH2), 3.47 (3H, s, NCH3), 4.25 (1H, tt, J=12.0,
3.5 Hz, NCH), 4.83 (1H, d, J=11.0 Hz, NCH2), 7.25-7.39 (3H, m, ArH), 7.64 (1H, d, J=8.5 Hz, ArH).
Anal. Cacd for C19H23N3O2: C, 70.13; H, 7.12; N, 12.91. Found: C, 69.88; H, 7.18; N, 12.96.

HETEROCYCLES, Vol. 65, No. 10, 2005
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2-Cyclohexyl-10-(2-diethylaminoethyl)-1,3,4,5-tetrahydropyrrolo[3,4-b][1,5]benzodiazepine-1,4-
dione (9)
To a suspension of NaH (0.194 g, 60%, 5.05 mmol) in dry DMF (10 mL) was added 4 (0.500 g, 1.68
mmol) and the mixture was stirred at rt for 15 min. N,N-Diethylaminoethyl bromide hydrobromide (0.528
g, 2.02 mmol) was added to the above mixture and the whole was stirred at rt for 1.5 h. After addition of
water, the precipitates formed were collected by filtration (0.322 g). These were identical with the starting
4. The filtrate was extracted with CHCl3 and the combined extracts were washed with water and brine,
and then dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure gave the residue
which was purified by SiO2 column chromatography (CHCl3-CH3OH=9:1) to give 9 (59 mg, 25%). mp
1
192-195 ℃ (2-propanol-hexane). IR (Nujol): 3230, 1690, 1660, 1630, 1270 cm-1. H-NMR (CDCl3) δ:
0.97 (6H, t, J=7.0 Hz, 2 x NCH2CH3), 1.10-1.90 (10H, m, cyclohexyl), 2.51 (4H, q, J=7.0Hz, 2 x
CH2CH3), 2.63 (2H, t, J=7.0 Hz, NCH2CH2N(C2H5)2), 3.97 (2H, t, J=7.0 Hz, NCH2CH2N(C2H5)2), 4.00
(1H, m, NCH), 4.08 (2H, s, NCH2C), 6.49 (1H, br s, NH), 6.80-7.22 (4H, m, ArH). HRMS (m/z): Calcd
for C23H32N4O2: 396.2525. Found: 396.2542.
10-Benzoyl-2-cyclohexyl-1,3,4,5-tetrahydropyrrolo[3,4-b][1,5]benzodiazepine-1,4-dione (10)
A solution of 4 (0.500 g, 1.68 mmol), benzoyl chloride (0.24 mL, 2.02 mmol) and triethylamine (0.28 mL,
2.02 mmol) in dioxane (40 mL) was heated under reflux for 9 h. After addition of more benzoyl chloride
(0.12 mL, 1.03 mmol) and triethylamine (0.14 mL, 1.01 mmol), the mixture was heated again under
reflux for 4 h. The solution was concentrated under reduced pressure and the residue was dissolved in
CHCl3. The solution was washed with water and brine, and dried over anhydrous Na2SO4. Removal of the
solvent under reduced pressure gave the crude product which was recrystallized from 2-propanol to give
1
10 (0.532, 79%). mp 258-261 ℃. IR (Nujol): 1680, 1630, 1300, 1260, 1220 cm-1. H-NMR (CDCl3) δ:
1.10-1.90 (10H, m, cyclohexyl), 4.09 (3H, s, NCH2, NCH), 7.26-7.57 (9H, m, ArH), 8.29 (1H, s, NH).
Anal. Calcd for C24H23N3O3: C, 71.80; H, 5.77; N, 10.47. Found: C, 71.86; H, 5.93; N, 10.51.
10-Chloroacetyl-2-cyclohexyl-1,3,4,5-tetrahydropyrrolo[3,4-b][1,5]benzodiazepine-1,4-dione (11)
A solution of 4 (3.445 g, 11.59 mmol), chloroacetyl chloride (1.11 mL, 13.91 mmol) and triethylamine
(2.52 mL, 18.08 mmol) in dry dioxane (240 mL) was heated under reflux for 5 h. After addition of more
chloroacetyl chloride (1.11 mL, 13.91 mmol) and triethylamine (2.52 mL, 18.08 mmol), the solution was
heated under reflux for further 5 h. After cooling, the reaction mixture was concentrated under reduced
pressure to give the residue, which was dissolved in CHCl3. The solution was washed with water and
brine, and dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure gave the residue,
which was recrystallized from 2-propanol to give 11 (2.989 g, 69%). mp 250.5-252 ℃. IR ( Nujol): 3200,
1690, 1665, 1630, 1595, 1260, 1230 cm-1. 1H-NMR (CDCl3) δ: 1.10-1.92 (10H, m, cyclohexyl), 4.08 (1H,
m, NCH), 4.17 (2H, s, NCH2C), 4.48 (2H, s, COCH2Cl), 7.30-7.42 (4H, m, ArH), 8.54 (1H, br s, NH).
Anal. Calcd for C19H20N3O3Cl: C, 61.04; H, 5.39; N, 11.24. Found: C, 60.87; H, 5.45; N, 10.99.
2-Cyclohexyl-10-(morpholin-4-ylethanoyl)-1,3,4,5-tetrahydropyrrolo[3,4-b][1,5]benzodiazepine-1,4-
dione (12)
A mixture of 11 (0.500 g, 1.34 mmol), morpholine (0.116 g, 1.33 mmol) and Na2CO3 (0.142 g, 1.34

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HETEROCYCLES, Vol. 65, No. 10, 2005
mmol) in dry acetonitrile (10 mL) was heated under reflux for 1 h. After cooling, the insoluble materials
were filtered off and washed with acetonitrile. The insoluble materials were dissolved in water and the
solution was extracted with CHCl3. The extract was washed with water and brine, and then dried over
anhydrous Na2SO4. Removal of the solvent under reduced pressure gave the residue which was
recrystallized from 2-propanol to give 4 (61 mg, 15%). The original filtrate and washings were combined
and the whole was concentrated under reduced pressure. The residue was dissolved in CHCl3 and the
solution was washed with water and brine, and then dried over anhydrous Na2SO4. Removal of the
solvent under reduced pressure gave the residue which was recrystallized from 2-propanol to give 12
1
(0.295 g, 52%). 12: mp 213-215 ℃. IR (Nujol): 3230, 1675 cm-1. H-NMR (CDCl3) δ: 1.18-1.92 (10H,
m, cyclohexyl), 2.39 (4H, t, J=5.0 Hz, 2 x NCH2CH2O), 3.47 ( 4H, t, J=5.0 Hz, 2 x NCH2CH2O), 3.49
(2H, s, COCH2N), 4.12 (1H, m, NCH), 4.19 (2H, s, NCH2C), 7.14-7.42 (4H, m, ArH), 7.73 (1H, s, NH).
Anal. Calcd for C23H28N4O4: C, 65.08; H, 6.65; N, 13.20. Found: C, 64.69; H, 6.60; N, 13.14. HRMS
(m/z): Calcd for C23H28N4O4: 424.2111. Found: 424.2121.
2-Cyclohexyl-10-(4-methylpiperazin-1-ylethanoyl)-1,3,4,5-tetrahydropyrrolo[3,4-b][1,5]benzodiaze-
pine-1,4-dione (13)
A mixture of 11 (0.500 g, 1.34 mmol), N-methylpiperazine (0.134 g, 1.34 mmol) and Na2CO3 (0.142 g,
1.34 mmol) in dry acetonitrile (10 mL) was heated under reflux for 6 h. After addition of more
N-methylpiperazine (0.134 g, 1.34 mmol) and Na2CO3 (0.142 g, 1.34 mmol), refluxing was continued for
1 h. After cooling, the insoluble materials were filtered off and washed with acetonitrile. The filtrate and
washings were combined and the whole was concentrated under reduced pressure. The residue was
purified by SiO2 column chromatography (CHCl3-CH3OH=9:1) to give 13 (0.236 g, 40%) and 4 (0.184 g,
1
46%). 13: mp 240-243 ℃ (2-propanol). IR (Nujol): 3250, 1680, 1650 cm-1. H-NMR (CDCl3) δ:
1.10-2.00 (10H, m, cyclohexyl), 2.17 (3H, s, NCH3), 2.41 (8H, br s, 2 x NCH2CH2N), 3.47 (2H, br s,
COCH2N), 4.14 (1H, m, NCH), 4.19 (2H, s, NCH2C), 7.20-7.42 (4H, m, ArH), 8.02 (1H, br s, NH). Anal.
Calcd for C24H31N5O3: C, 65.88; H, 7.14; N, 16.01. Found: C, 65.81; H, 7.15; N, 15.83.
4-Benzylidene-1-cyclohexyl-2,3-dioxopyrrolidine (14a)9
The diketo ester (6) (5.000 g, 19.74 mmol) was dissolved in C2H5OH (38 mL) by warming. To this
solution were added 20% HCl (125 mL) and benzaldehyde (2.750g, 25.91 mmol) and the whole was
heated under reflux for 2 h. After cooling, the crystals formed were collected by filtration and
recrystallized from 2-propanol- hexane to give 14a (3.87 g, 73%). mp 208-209 ℃ (lit.,9 204-205.5 ℃).
1
IR (Nujol): 1710, 1670, 1610, 1580, 11270, 1140 cm-1. H-NMR (CDCl3) δ: 1.12-1.68 (6H, m,
cyclohexyl), 1.82-1.96 (4H, m, cyclohexyl), 4.32 (1H, m, NCH), 4.52 (2H, d, J=2.0 Hz, NCH2C), 7.50
(5H, br s, ArH), 7.70 (1H, t, J=2.0 Hz, =CH).
The other derivatives (14b-14e) were synthesized by the similar method
4-(2-Chlorobenzylidene)-1-cyclohexyl-2,3-dioxopyrrolidine (14b)
Yield: 57%. mp 200-202 ℃ (C2H5OH). IR (Nujol): 1720, 1680, 1620, 1580, 1285, 1160, 1120, 1030,
1000, 920 cm-1. 1H-NMR (CDCl3) δ: 1.10-1.90 (10H, m, cyclohexyl), 4.31 (1H, tt, J=12.0, 4.0 Hz, NCH),
4.44 (2H, d, J=2.0 Hz, NCH2C), 7.33-7.55 (5H, m, ArH), 8.11 (1H, t, J=2.0 Hz, =CH). Anal. Calcd for

HETEROCYCLES, Vol. 65, No. 10, 2005
2457
C17H18NO2Cl: C, 67.21; H, 5.97; N, 4.61. Found: C, 67.27; H, 6.00; N, 4.67.
1-Cyclohexyl-4-(2-nitrobenzylidene)-2,3-dioxopyrrolidine (14c)
Yield: 31%. mp 169.5-170.5 ℃ (2-propanol). IR (Nujol): 1725,1690, 1630, 1575, 1525, 1290, 1210,
1
1165, 1145, 1005 cm-1. H-NMR (CDCl3) δ: 1.14-1.92 (10H, m, cyclohexyl), 4.27 (2H, d, J=2.0 Hz,
NCH2C), 4.28 (1H, m, NCH), 7.51 (1H, dd, J=7.5, 1.0 Hz, ArH), 7.66 (1H, dt, J=7.5, 1.0 Hz, ArH), 7.77
(1H, dt, J=7.5, 1.0 Hz, ArH), 8.04 (1H, br t, J=2.0 Hz, =CH), 8.21 (1H, dd, J=7.5, 1.0 Hz, ArH). Anal.
Calcd for C17H18N2O4: C, 64.96; H, 5.77; N, 8.91. Found: C, 64.97; H, 5.67; N, 8.95.
1-Cyclohexyl-4-(2-methylbenzylidene)-2,3-dioxopyrrolidine (14d)
Yield: 61%. mp 200-201 ℃ (CH3OH). IR (Nujol): 1725, 1690, 1620, 1600, 1290, 1220, 1170, 1005 cm-1.
1H-NMR (CDCl3) δ: 1.10-1.90 (10H, m, cyclohexyl), 2.46 (3H, s, ArCH3), 4.30 (1H, tt, J=12.0, 4.0 Hz,
NCH), 4.45 (2H, d, J=2.0 Hz, NCH2C), 7.27-7.43 (4H, m, ArH), 7.99 (1H, t, J=2.0 Hz, =CH). Anal.
Calcd for C18H21NO2: C, 76.30; H, 7.47; N, 4.94. Found: C, 76.18; H, 7.42; N, 5.07.
1-Cyclohexyl-4-(2-thienylmethylene)-2,3-dioxopyrrolidine (14e)
Yield: 53%. mp 199-201 ℃ (C2H5OH). IR (Nujol): 3070, 1710, 1680, 1605, 1280, 1150, 1000 cm-1.
1H-NMR (CDCl3) δ: 1.10-1.95 (10H, m, cyclohexyl), 4.30 (1H, tt, J=12.0 3.0 Hz, NCH), 4.37 (2H, d,
J=2.0 Hz, NCH2C), 7.24 (1H, dd, J=5.0, 4.0 Hz, ArH), 7.49 (1H, br d, J=4.0 Hz, ArH), 7.73 (1H, d, J=5.0
Hz, ArH), 7.92 (1H, br t, J=2.0 Hz, =CH). Anal. Calcd for C15H17NO2S: C, 65.43; H, 6.22; N, 5.09.
Found: 65.29; H, 6.22; N, 5.13.
2-Cyclohexyl-4-phenyl-1,3,4,10-tetrahydropyrrolo[4,3-c][1,5]benzothiazepin-1-one (5a)
A solution of 14a (0.500 g, 1.86 mmol), o-aminothiophenol (0.230 g, 1.86 mmol) and conc. HCl (1 drop)
in C2H5OH (15 mL) was heated under reflux for 2 h. After cooling, the precipitates formed were collected
by filtration and recrystallized from benzene-hexane to give 5a (0.600 g, 86%). mp 230-235 ℃. IR
1
(Nujol): 3250, 1660, 1530, 1260, 1210 cm-1. H-NMR (CDCl3) δ: 1.02-1.44 (6H, m, cyclohexyl),
1.74-1.84 (4H, m, cyclohexyl), 3.64 (2H, s, NCH2C), 4.02 (1H, m, NCH), 4.96 (1H, s, ArCH), 6.95 (1H,
br s, NH), 7.08-7.24 (9H, m, ArH). Anal. Calcd for C23H24N2OS: C, 73.42; H, 6.42; N, 7.44. Found: C,
73.38; H, 6.52; N, 7.37.
The other derivatives (5b-5e and 15) were synthesized by the similar method.
4-(2-Chlorophenyl)-2-cyclohexyl-4-phenyl-1,3,4,10-tetrahydropyrrolo[4,3-c][1,5]benzothiazepin-1-
one (5b)
Yield: 92%. mp 211-212 ℃ (C2H5OH). IR (Nujol): 3340, 1670, 1580, 1510, 1250, 1210, 1160, 1120,
1
1040 cm-1. H-NMR (CDCl3) δ: 1.00-1.95 (10H, m, cyclohexyl), 3.60 (1H, d, J=18.0 Hz, NCH2C), 3.74
(1H, d, J=18.0 Hz, NCH2C), 4.03 (1H, tt, J=11.5, 3.0 Hz, NCH), 6.67 (1H, dd, J=8.0, 2.0 Hz, ArH), 6.75
(1H, dt, J=8.0, 1.0 Hz, ArH), 6.90-7.08 (2H, m, ArH, NH), 7.12 (1H, dt, J=8.0, 2.0 Hz, ArH), 7.22 (1H, dt,
J=8.0, 2.0 Hz, ArH), 7.39 (1H, dt, J=8.0, 1.0 Hz, ArH). HRMS (m/z): Calcd for C23H23N2OClS: 410.1219.
Found: 410.1245. Anal. Calcd for C23H23N2OClS・1/5H2O: C, 66.64; H, 5.69; N, 6.76. Found: C, 66.62; H,
5.58; N, 6.76.

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2-Cyclohexyl-4-(2-nitrophenyl)-1,3,4,10-tetrahydropyrrolo[4,3-c][1,5]benzothiazepin-1-one (5c)
Yield: 89%. mp: 209-210.5 ℃ (C2H5OH). IR (Nujol): 3250, 1670, 1580, 1525, 1250, 1220 cm-1.
1H-NMR (CDCl3) δ: 1.00-1.90 (10H, m, cyclohexyl), 3.69 (1H, d, J=18.0 Hz, NCH2C), 3.85 (1H, d,
J=18.0 Hz, NCH2C), 4.05 (1H, tt, J=12.0, 4.0 Hz, NCH), 5.92 (1H, s, ArCH), 6.71 (1H, dt, J=8.0, 1.0 Hz,
ArH), 6.80 (1H, dd, J=8.0, 1.0 Hz, ArH), 6.95 (1H, dd, J=8.0, 1.0 Hz, ArH), 7.00 (1H, dd, J=8.0, 1.0 Hz,
ArH), 7.04 (1H, br s, NH), 7.17-7.24 (2H, m, ArH), 7.29 (1H, dt, J=8.0, 1.0 Hz, ArH), 7.92 (1H, dd, J=8.0,
1.0 Hz, ArH). Anal. Calcd for C23H23N3O3S: C, 65.54; H, 5.50; N, 9.97. Found: C, 65.27; H, 5.58; N,
9.73.
2-Cyclohexyl-4-(2-methylphenyl)-1,3,4,10-tetrahydropyrrolo[4,3-c][1,5]benzothiazepin-1-one (5d)
Yield: 99%. mp 202.5-203 ℃ (C2H5OH). IR (Nujol): 3270, 1665, 1585, 1530, 1255, 1220, 1200, 1170,
1
1140, 1090, 1040 cm-1. H-NMR (CDCl3) δ: 1.00-1.85 (10H, m, cyclohexyl), 2.50 (3H, s, ArCH3), 3.63
(2H, s, NCH2C), 4.03 (1H, tt, J=12.0, 3.5 Hz, NCH), 5.09 (1H, s, ArCH), 6.68 (1H, dd, J=8.0, 1.0 Hz,
ArH), 6.75 (1H, dt, J=8.0, 1.5 Hz, ArH), 6.93 (2H, m, ArH, NH), 7.01 (1H, dd, J=8.0, 1.0 Hz, ArH),
7.04-7.24 (4H, m, ArH). Anal. Calcd for C24H26N2OS: C, 73.81; H, 6.71; N, 7.17. Found: C, 73.51; H,
6.69; N, 7.10.
2-Cyclohexyl-4-(2-thienyl)-1,3,4,10-tetrahydropyrrolo[4,3-c][1,5]benzothiazepin-1-one (5e)
Yield: 91%. mp 212-213 ℃ (C2H5OH). IR (Nujol): 3250, 1665, 1585, 1530, 1255, 1215, 1190, 1160,
1075, 1040 cm-1. 1H-NMR (CDCl3) δ: 1.00-1.90 (10H, m, cyclohexyl), 3.73 (1H, d, J=18.0 Hz, NCH2C),
3.82 (1H, d, J=18.0 Hz, NCH2C), 4.03 (1H, tt, J=11.5, 3.5 Hz, NCH), 5.25 (1H, s, ArCH), 6.65 (1H, dt,
J=3.5, 1.0 Hz, ArH), 6.76-6.85 (2H, m, ArH), 6.95 (1H, br s, NH), 6.97-7.02 (1H, m, ArH), 7.11 (1H, dd,
J=5.5, 1.0 Hz, ArH), 7.20 (2H, d, J=7.5 Hz, ArH). Anal. Calcd for C21H22N2OS2: C, 65.94; H, 5.80; N,
7.32. Found: C, 65.66; H, 5.80; N, 7.18.
4-(2-Chlorophenyl)-2-cyclohexyl-10-methyl-1,3,4,10-tetrahydropyrrolo[4,3-c][1,5]benzothiazepin-
1-one (15)
1
Yield: 50%. mp 143-143.5 ℃ (2-propanol-hexane). IR (Nujol): 1690, 1580, 1260, 1120 cm-1. H-NMR
(DMSO-d6) δ: 1.00-1.80 (10H, m, cyclohexyl), 2.71 (3H, s, NCH3), 3.76 (1H, m, NCH), 4.09 (1H, dd,
J=15.0, 2.0 Hz, NCH2C), 4.40 (1H, dd, J=15.0, 3.0 Hz, NCH2C), 6.49 (1H, d, J=8.0 Hz, ArH), 6.65 (1H, t,
J=7.5 Hz, ArH), 6.99 (2H, d, J=7.5 Hz, ArH), 7.18 (1H, br t, J=2.0 Hz, ArCH), 7.33-7.54 (4H, m, ArH).
Anal. Calcd for C24H25NOClS・1/5H2O: C, 67.26; H, 5.97; N, 6.54. Found: 67.25; H, 6.01; N, 6.45.
HRMS (m/z): Calcd for C24H25NOClS: 424.1376. Found: 424.1354.
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