Synthesis and characterization of substituted (benzo[b]thiophen-2-yl)-4- methyl-4,5-dihydro-1H-imidazol-5-ones

Article abstract of DOI:10.1002/jhet.5570450334

(Chemical Equation Presented) Reactions of 3-chlorobenzo[b]thiophene-2- carbonyl chloride with 2-alkyl-2-aminopropanamides have been used to prepare a series of carboxamides 1a-d (yields 61-85 %). The products were submitted to base-catalysed ring closure reactions to give the corresponding 4,5-dihydro-1H-imidazol-5-ones 2a-d (yields 69-97 %). By N-methylation and N-benzylation were prepared the corresponding 1-alkyl derivatives 3a (91 %) and 3b (85 %). These two alkyl derivatives were studied from the standpoint of potential replacement of 3-chlorine substituent by piperidine via the Buchwald-Hartwig reaction. It was found that the reaction gives besides except required products of C-N coupling 5a (14 %) and 5b (12 %) also products of reductive dechlorination 4a (max. 57 %) and 4b (max. 56 %). The reductive dechlorination product 4a is formed exclusively (42 %) if butyl-di-(1-adamantyl) phosphine (BDAP) is used.

Full text of DOI:10.1002/jhet.5570450334

May-Jun 2008
859
Synthesis and Characterization of Substituted (Benzo[b]thiophen-2-
yl)-4-methyl-4,5-dihydro-1H-imidazol-5-ones
Miloš Sedlák*a, Pavel Drabinaa, Václav Lánskýa and Jiří Svobodab
aDepartment of Organic Chemistry, Faculty of Chemical Technology, University of Pardubice, Čs. legií 565,
532 10 Pardubice, Czech Republic.
bDepartment of Organic Chemistry, Institute of Chemical Technology, Technická 5, 166 28 Prague 6,
Czech Republic.
Received November 15, 2007
R3
Cl
CH3
N
O
R1
S
N
S
Cl
O
R2
R1= C2H5; CH(CH3)2; CH2CH(CH3)2; C(CH3)3; R2 = H; CH3; PhCH2; R3= H; Cl; (CH2)5N
Reactions of 3-chlorobenzo[b]thiophene-2-carbonyl chloride with 2-alkyl-2-aminopropanamides have
been used to prepare a series of carboxamides 1a-d (yields 61-85 %). The products were submitted to base-
catalysed ring closure reactions to give the corresponding 4,5-dihydro-1H-imidazol-5-ones 2a-d (yields
69-97 %). By N-methylation and N-benzylation were prepared the corresponding 1-alkyl derivatives 3a
(91 %) and 3b (85 %). These two alkyl derivatives were studied from the standpoint of potential
replacement of 3-chlorine substituent by piperidine via the Buchwald–Hartwig reaction. It was found that
the reaction gives besides except required products of C-N coupling 5a (14 %) and 5b (12 %) also products
of reductive dechlorination 4a (max. 57 %) and 4b (max. 56 %). The reductive dechlorination product 4a
is formed exclusively (42 %) if butyl-di-(1-adamantyl)phosphine (BDAP) is used.
J. Heterocyclic Chem., 45, 859 (2008).
INTRODUCTION
PhH2C
N
CH2Ph
N
Our previous papers [1] dealt with synthesis and
characterisation of substituted (4,5-dihydro-1H-imidazol-
5-on-2-yl)pyridines. These heterocyclic systems were
originally developed as selective and virtually non-toxic
herbicides [2], which have been used up to now. Other
application possibilities involve their use as ligands
forming coordination compounds with selected metal ions
[1i-m]. The rhodium complex of 2,6-bis(1-benzyl-4-
isopropyl-4-methyl-4,5-dihydro-1H-imidazol-5-on-2-yl)-
pyridine (I) proved to be a considerably effective catalyst
of deallylation reactions of diallyl malonates [1j].
Substituted benzo[b]thiophenes also represent the basic
skeleton found in the molecules of biologically active
substances, such as, e.g., antiphlogistics, analgetics or
antimicrobial substances [3a]. Even earlier published
papers are dealing with preparation of heterocyclic
systems formed by attaching another heterocyclic species
to 3-chlorobenzo[b]thiophenes (II) [3b-g]. Such syntheses
make use of the reactions of 3-chlorobenzo[b]thiophene-
2-carbonyl chloride [4] with other fragments and
subsequent ring closure reactions. Connecting of two or
more heterocyclic compounds by means of ring fusion or
single or double bond leads to new systems whose
original properties may be modified.
O
O
N
N
N
I
Cl
O
S
N
II
1H-imidazol-5-one. The aim was to use the reaction of 3-
chlorbenzo[b]thiophene-2-carbonyl chloride [4] with 2-
amino-2-alkylpropanamides [1a] for preparation of the
corresponding aminoamides, and to use their ring closure
reactions for preparation of a series of substituted 2-(3-
chlorobenzo[b]thiophene-2-yl)-4-alkyl-4-methyl-4,5-
dihydro-1H-imidazol-5-ones. Another aim of this work
was to test the possibility of application of the Buchwald–
Hartwig reaction [5] to the chlorine-bearing carbon atom
at 3-position of the benzo[b]thiophen skeleton, so that it
would be possible to attach another nitrogen-bearing
heterocyclic system.
RESULTS AND DISCUSSION
The aim of this work is to synthesise and characterise
new heterocyclic systems formed by combination of 3-
chlorobenzo[b]thiophene with substituted 4,5-dihydro-
The reactions of 3-chlorobenzo[b]thiophene-2-carbonyl
chloride [4] with substituted 2-amino-2-alkylpropan-
amides [1a] were adopted to prepare a series of

860
M. Sedlák, P. Drabina, V. Lánský, J. Svoboda
Vol 45
1
substituted N-(1-carbamoyl-1-alkylethyl)-3-chlorobenzo-
[b]thiophene-2-carboxamides 1a–d (a: R1= C2H5; b: R1 =
CH(CH3)2; c: R1 = CH2CH(CH3)2; d: R1 = C(CH3)3)
(Scheme 1). The acylation reactions were performed in
anhydrous dichloromethane in the presence of
triethylamine. The substituted carboxamides 3a–d were
obtained in the yields of 61-85 % after evaporation of the
1a–d, 2a–d, 3a-b, were verified by means of H and 13C
NMR spectroscopy, EI-MS, and elemental analysis.
Scheme 2
Cl
CH3
N
R1
1a-d
CH3ONa/CH3OH
dichloromethane,
recrystallization.
washing
with
water,
and
S
HN
2a-d
O
Scheme 1
Besides others, one of potential applications of
substituted 2-(benzo[b]thiophene-2-yl)-4-isopropyl-4-
CH3
R1
O
methyl-4,5-dihydro-1H-imidazol-5-ones could be based on
their ability to coordinate atoms of transition metals and
thus produce their coordination compounds. This was the
reason why we studied the possibility of replacement of
chlorine substituent at the 3-position by another, better
coordinating group. Such well-coordinating groups
include, e.g., the amino group with its free electron pair.
Therefore, we tried to substitute the chlorine atom in
ligands 3a-b by piperidine. Since the benzo[b]thiophen
skeleton belongs to systems with high electron density,
this nucleophilic substitution cannot be carried out in
usual classic way. One of the possibilities of activation of
the chlorine atom lied in the oxidation of the sulphur atom
in benzo[b]thiophene skeleton to the corresponding 1,1-
dioxide. In contrast to the earlier-described uniform
course of oxidation [3d], in our case the reaction always
gave a complex mixture of products. Another possibility
of replacement of the chlorine substituent at the 3-position
consisted in the application of the Buchwald–Hartwig
reaction [5]. This reaction requires application of a
suitable palladium catalyst combined with a non-
nucleophilic base. It is well-known that bromo derivatives
are the best alternative for the Buchwald–Hartwig
reaction [5a-c]. However, recent papers also describe
syntheses starting from chloro derivatives and report very
high yields, particularly with application of butyl-di-(1-
adamantyl)phosphine (BDAP) as the palladium
coordinating ligand [5d,e].
Cl
H2N
Cl
NH2
O
O
Cl
S
S
NH
TEA/CH2Cl2
R1
CH3
1a-d
H2N
O
1a-d (a: R1= C2H5; b: R1 = CH(CH3)2; c: R1 = CH2CH(CH3)2; d: R1 = C(CH3)3)
The ring closure reactions of carboxamides 1a–d giving
substituted 2-(3-chlorobenzo[b]thiophen-2-yl)-4-alkyl-4-
methyl-4,5-dihydro-1H-imidazol-5-ones 2a–d (a: R1
C2H5; b: R1 = CH(CH3)2; c: R1 = CH2CH(CH3)2; d: R1 =
C(CH3)3) (Scheme 2) were carried out in 1 mol·L–1
methanolic sodium methoxide at room temperature.
=
Subsequent neutralization (HCl aq.;
5
mol·L–1),
evaporation, washing with water, and recrystallization
gave products 2a–d in the yields of 69-97 %. At the
conditions described, only the ring closure reaction took
place, and no nucleophilic substitution of chlorine
substituent in the 3-chlorobenzo[b]thiophene skeleton by
methoxide ion was observed. No nucleophilic substitution
took place even in boiling methoxide solution or on
heating with sodium hydroxide solution in an autoclave.
Further experiments concerned investigation of possible
chemical modifications of the basic skeleton of 2-(3-
chlorobenzo[b]thiophen-2-yl)-4-isopropyl-4-methyl-4,5-
dihydro-1H-imidazol-5-one (2b). This derivative was
chosen because the substance can easily be prepared in
both enantionerically pure forms R and S because of the
availability of (R)-2-amino-2,3-dimethylbutanamide and
(S)-2-amino-2,3-dimethylbutanamide [6]. First, a methyl
group was introduced into the molecule of compound 2b
to give 2-(3-chlorobenzo[b]thiophen-2-yl)-4-isopropyl-
1,4-dimethyl-4,5-dihydro-1H-imidazol-5-one (3a) (91 %),
and a benzyl group to give 2-(3-chlorobenzo[b]thiophene-
2-yl)-1-benzyl-4-isopropyl-4-methyl-4,5-dihydro-1H-
imidazol-5-one (3b) (85 %) (Scheme 3). The N-methyl-
ation and N-benzylation removed the easily separated
acidic hydrogen atom that could unfavourably affect the
subsequent reactions. Structures of the products prepared,
Several attempts were made to substitute the chlorine
atom in compounds 3a and 3b by piperidine. The course
of these Buchwald–Hartwig reactions carried out under
Scheme 3
Cl
CH3
O
CH3
CH3
N
t-BuOK,CH3I/DMF
2b
or Cs2CO3, PhCH2Br/DMF
S
N
R2
3a, b
3a, b (a: R2 = CH3, b: R2 = PhCH2)

May-Jun 2008
Substituted (Benzo[b]thiophen-2-yl)-4-methyl-4,5-dihydro-1H-imidazol-5-ones
861
various conditions was monitored by means of GC-MS.
(Table) (Scheme 4).
% (Table, Entry 2), but the only product was the product
of reductive dechlorination of molecule 3a, namely
2-(benzo[b]thiophene-2-yl)-4-isopropyl-1,4-dimethyl-4,5-
dihydro-1H-imidazol-5-on (4a), while the substitution
product (5a) was not detected (Table, Entry 2). The
experiments using BINAP (Table, Entries 3-6) gave the
desired 2-[3-(1-piperidyl)benzo[b]thiophene-2-yl]-4-iso-
propyl-1,4-dimethyl-4,5-dihydro-1H-imidazol-5-on (5a)
or 2-[3-(1-piperidyl)benzo[b]thiophene-2-yl]-1-benzyl-4-
isopropyl-4-methyl-4,5-dihydro-1H-imidazol-5-on (5b),
but these product were obtained as minor components: 5a
(14 %) 5b (12 %), while the major components were
products of reductive dechlorination: 4a (15-57 %) and 4b
(56 %), which appeared in relatively high proportions (15-
57 %) in all the experiments.
The individual experiments differed in the base used, the
source of palladium, and the ligand adopted for
coordination with palladium. The aim of these
experiments was to optimize the substitution reaction and
maximize the yield of the desired 2-[3-(1-piperidyl)-
benzo[b]thiophene-2-yl]-4-isopropyl-1,4-dimethyl-4,5-di-
hydro-1H-imidazol-5-one (5a) or 2-[3-(1-piperidyl)
benzo[b]thiophene-2-yl]-1-benzyl-4-isopropyl-4-methyl-
4,5-dihydro-1H-imidazol-5-one(5b) (Scheme 4) (Table).
P
EXPERIMENTAL
The starting compounds were purchased from Sigma-Aldrich
Butyl-di-(1-adamantyl)phosphine
Comp.
(BDAP)
was
purchased from ABCR GmBH & Co. KG Germany. The given
melting temperatures were not corrected. Structures of the
BDAP
1
products prepared were verified by means of H and 13C NMR
1
using a Bruker Avance 500 apparatus (500.13 MHz for H and
Scheme 4
125.77 MHz for 13C). The samples were dissolved in
hexadeuteriodimethyl sulphoxide (DMSO-d6). The calibration
used the residual signal of solvent (2.55 ppm 1H, 39.51 ppm
13C). The mass spectra were measured with apparatus set of
Agilent Technologies Comp. (gas chromatograph 6890N with
mass detector 5973 Network) (the samples were dissolved in
ether or acetone). The elemental analyses were performed on an
apparatus of FISONS Instruments, EA 1108 CHN.
CH3
N
R1
S
N
O
HN
R2
4a, b
3a, b
Catalytic systems (Table)
CH3
R1
S
N
General method of preparation of acylated aminoamides
(1a–d). A solution of 3-chlorobenzo[b]thiophene-2-carbonyl
chloride (2.31 g; 10 mmol) in dichloromethane (30 mL) was
added drop by drop to a solution of the respective aminoamide
(10 mmol) and triethylamine (TEA) (0.73 mL; 10 mmol) in dry
dichloromethane (20 mL). After 24-hour stirring at room
temperature, the suspension obtained was evaporated, and the
dry evaporation residue was washed with distilled water (2 × 20
mL). The remaining solid was recrystallized from an
ethanol/water mixture.
N
O
N
R2
5a, b
4a, b; 5a, b ( a: R1 = CH(CH3)2,R2 = CH3; b: R1 = CH(CH3)2, R2 = PhCH2)
N-(2-Carbamoylbut-2-yl)-3-chlorobenzo[b]thiophen-2-
carboxamide (1a). Yield 2.54 g (82 %); mp 210-212 °C; 1H
NMR: δ 0.79 (t, J = 7.4 Hz, 3H, CH2CH3), 1.69 (s, 3H, CH3),
1.92 (q, J = 6.9 Hz, 1H, CH2CH3), 2.46 (q, J = 6.8 Hz, 1H,
The Table indicates that maximal conversion reached
being 68 % (Table, Entry 6). The application of butyl-di-
(1-adamantyl)phosphine (BDAP) gave conversion of 42
Table
Buchwald–Hartwig reaction of derivatives 3a,b and piperidinea
Entry
Compound
Base
Phosphine
Catalyst
Product 4b
Product 5b
1
2
3
4
5
6
3a
3a
3a
3a
3a
3b
t-BuOK
t-BuOK
t-BuOK
t-BuOK
Cs2CO3
Cs2CO3
BDAP
BDAP
BINAP
BINAP
BINAP
BINAP
Pd(CH3COO)2
Pd2(DBA)3
Pd2(DBA)3
Pd(CH3COO)2
Pd2(DBA)3
Pd2(DBA)3
0
0
0
9
14
11
12
42
57
15
42
56
a
Reaction conditions: 1.2 eq. piperidine, 1.4 eq. base, 0.1 eq. Pd-cat., 0.1 eq. phosphine, toluene (10 mL), 48 h
reflux under Ar atmosphere; b Yields determined by GC-MS.

862
M. Sedlák, P. Drabina, V. Lánský, J. Svoboda
Vol 45
CH2CH3), 7.54 (bs, 1H, CONH2), 7.62 (m, 2H, Ar), 7.73 (bs,
1H, CONH2), 7.93 (m, 1H, Ar), 8.13 (m, 1H, Ar), 8.73 (bs, 1H,
CONH); 13C NMR: δ 12.8, 27.4, 32.6, 65.7, 122.2, 127.1, 127.8,
130.3, 132.0, 138.6, 140.8, 141.3, 162.6, 179.5; EI-MS: m/z 310,
266, 195 (100 %), 167, 132, 123. Anal. Calcd. for
C14H15ClN2O2S (310.8): C, 54.10; H, 4.86; Cl, 11.41; N, 9.01; S,
10.32. Found: C, 54.28; H, 5.06; Cl, 11.65; N, 8.83; S, 10.12.
N-(2-Carbamoyl-3-methylbut-2-yl)-3-chlorobenzo[b]thio-
phene-2-carboxamide (1b). Yield 2.75 g (85 %); mp 186-
152-153 °C; 1H NMR: δ 0.78 (d, J = 6.8 Hz, 3H, iPrCH3), δ 0.95
(d, J = 6.8 Hz, 3H, iPrCH3), 1.24 (s, 3H, CH3), 1.91 (sp,
J = 6.8 Hz, 1H, iPrCH), 7.57 (m, 2H, Ar), 7.87 (m, 1H, Ar),
8.08 (m, 1H, Ar), 11.29 (bs, 1H, CONH); 13C NMR: δ 21.0,
66.0, 117.8, 122.1, 125.2, 129.8, 133.7, 141.8, 145.7, 150.5,
153.2, 169.3; EI-MS: m/z 306, 263 (100 %),194, 159, 132, 114.
Anal. Calcd. for C15H15ClN2OS (306.1): C, 58.72; H, 4.93; Cl,
11.56; N, 9.13; S, 10.45. Found: C, 58.86; H, 4.79; Cl, 11.41;
N, 9.12; S, 10.34.
2-(3-Chlorobenzo[b]thiophene-2-yl)-4-isobutyl-4-methyl-4,
5-dihydro-1H-imidazol-5-one (2c). Yield 1.52 g (97 %); mp
150-151 °C; 1H NMR: 0.86 (d, J = 6.5 Hz 3H, iBuCH3), 1.03 (d,
J = 6.5 Hz 3H, iBuCH3), 1.27 (s, 3H, CH3), 1.52 (sp, J = 6.5 Hz,
1H, iBuCH), 1.62 (m, 1H, iBuCH2), 1.76 (m, 1H, iBuCH2),
7.60 (m, 2H, Ar), 7.91 (m, 1H, Ar), 8.12 (m, 1H, Ar), 11.34 (bs,
1H, CONH); 13C NMR: δ 23.3, 24.1, 24.4, 24.6, 46.5, 70.0,
122.4, 123.4, 126.1, 128.0, 136.1, 137.2, 148.5, 153.7, 185.6;
EI-MS: m/z 320, 305, 277, 264, 249, 207, 194 (100 %), 159,
114, 84, 57. Anal. Calcd. for C16H17ClN2OS (320.1): C, 59.90;
H, 5.34; Cl, 11.05; N, 8.73; S, 9.99. Found: C, 59.93; H, 5.40;
Cl, 10.88; N, 9.12; S, 9.89.
2-(3-Chlorobenzo[b]thiophene-2-yl)-4-tert-butyl-4-methyl-4,
5-dihydro-1H-imidazol-5-one (2d). Yield 1.18 g (74 %); mp
197-200 °C; 1H NMR: δ 1.04 (s, 9H, C(CH3)3), 1.31 (s, 3H,
CH3), 7.66 (m, 2H, Ar), 7.97 (m, 1H, Ar), 8.18 (m, 1H, Ar),
11.31 (bs, 1H, CONH); 13C NMR: δ 18.4, 24.6, 36.2, 74.5, 95.0,
105.2, 122.5, 123.4, 125.7, 126.1, 127.8, 136.1, 152.6, 186.6,
191.8, 197.3; EI-MS: m/z 320, 264 (100 %), 194, 159, 114, 57.
Anal. Calcd. for C16H17ClN2OS (320.1): C, 59.90; H, 5.34; Cl,
11.05; N, 8.73; S, 9.99. Found: C, 60.09; H, 5.44; Cl, 10.78; N,
8.67; S, 9.98.
1
187 °C; H NMR: δ 0.94 (d, J = 6.8 Hz, 3H, iPrCH3), δ 1.04 (d,
J = 6.8 Hz, 3H, iPrCH3), 1.57 (s, 3H, CH3), 2.27 (sp, J = 6.8 Hz,
1H, iPrCH), 7.23 (bs, 1H, CONH2), 7.40 (bs, 1H, CONH2),
7.63 (m, 2H, Ar), 7.94 (m, 1H, Ar), 8.12 (m, 1H, Ar), 8.18 (bs,
1H, CONH); 13C NMR: δ 17.6, 17.7, 34.8, 37.5. 64.1, 118.5,
123.1, 123.7, 126,4; 128.0, 134.3, 136.7, 137.1, 159.6, 174.9; EI-
MS: m/z 324, 280, 195 (100 %), 167, 132, 123. Anal. Calcd. for
C15H17ClN2O2S (324.8): C, 55.46; H, 5.28; Cl, 10.91; N, 8.62; S,
10.32. Found: C, 55.56; H, 5.13; Cl, 10.96; N, 8.59; S, 10.07.
N-(2-Carbamoyl-4-methylpent-2-yl)-3-chlorobenzo[b]thio-
phene-2-carboxamide (1c). Yield 2.21 g (65 %); mp 147-
149 °C; 1H NMR: 0.82 (d, J = 7.0 Hz 3H, iBuCH3), 0.84 (d,
J = 7.0 Hz 3H, iBuCH3), 1.56 (sp, 3J = 7.0 Hz, 1H, iBuCH),
1.62 (s, 3H, CH3), 1.79 (m, 1H, iBuCH2), 2.43 (m, 1H, iBuCH2),
7.55 (bs, 1H, CONH2), 7.58 (m, 2H, Ar), 7.74 (bs, 1H, CONH2),
7.89 (m, 1H, Ar), 8.09 (m, 1H, Ar), 8.88 (bs, 1H, CONH); 13C
NMR: δ 23.0, 23.3, 24.4, 24.7, 43.0, 60.4, 117.5, 122.7, 123.3,
125.9, 127.6, 134.2, 136.4, 136.8, 158.0, 175.7; EI-MS: m/z
338, 294, 264, 207, 195 (100 %), 167, 132, 123. Anal. Calcd. for
C16H19ClN2O2S (338.9): C, 56.71; H, 5.65; Cl, 10.46; N, 8.27; S,
9.46. Found: C, 56.98; H, 5.76; Cl, 10.66; N, 8.39; S, 9.52.
N-(2-Carbamoyl-3,3-dimethylbut-2-yl)-3-chlorobenzo[b]-
thiophene-2-carboxamide (1d). Yield 2.08 g (61 %); mp 209-
Synthesis of 2-(3-chlorobenzo[b]thiophene-2-yl)-4-iso-
propyl-1,4-dimethyl-4,5-dihydro-1H-imidazol-5-one (3a). The
reaction was performed on a vacuum-argon line. 2-(3-Chloro-
benzo[b]thiophen-2-yl)-4-isopropyl-4-methyl-4,5-dihydro-1H-
imidazol-5-one (2b) (1.53 g; 5 mmol) was suspended in
potassium tert-butyl alcoholate (20 mL; 0.50 mol·L–1). After
dissolution, the solvent tert-butyl alcohol was distilled off. The
evaporation residue was dissolved in dry N,N-dimethyl-
formamide (10 mL). After cooling to 0 °C, methyl iodide
(0.63 ml; 10 mmol) was added and the temperature of the
reaction mixture spontaneously increased up to 25 °C. After 24
hours, N,N-dimethylformamide was distilled off and the
evaporation residue was mixed with distilled water and extracted
with dimethyl ether (3 × 20 mL). The product was obtained by
evaporating the combined dried diethyl ether extracts. Yield
1
210 °C; H NMR: δ 1.13 (s, 9H, C(CH3)3), 1.68 (s, 3H, CH3),
7.25 (s, 1H, CONH2), 7.36 (bs, 1H, CONH2), 7.63 (m, 2H, Ar),
7.90 (bs, 1H, CONH), 7.94 (m, 1H, Ar), 8.14 (m, 1H, Ar),
8.36 (bs, 1H, CONH); 13C NMR: δ 17.4, 26.2, 36.8, 66.2, 79.4,
117.8, 122.9, 123.6, 126.1, 127.8, 134.9, 136.6, 137.0, 159.3,
173.0; EI-MS: m/z 264 (100 %), 207, 194, 159, 114, 57. Anal.
Calcd. for C16H19ClN2O2S (338.9): C, 56.71; H, 5.65; Cl, 10.46;
N, 8.27; S, 9.46. Found: C, 56.52; H, 5.62; Cl, 10.38; N, 8.30;
S, 9.43.
General method of preparation of substituted 4,5-dihydro-
1H-imidazol-5-ones (2a-d). The respective substituted
aminoamide 1a–d (5 mmol) was added to sodium methoxide
solution (25 mL; 1 mol·L–1). After 72-hour stirring at room
temperature, the pH value of reaction mixture was adjusted at
pH ~ 5-6 (HCl aq., 5 mol·L–1). The suspension formed was
evaporated, and the dry evaporation residue was washed with
1
1.45 g (91 %); mp 57-59 °C; H NMR: δ 0.86 (d, J = 6.5 Hz 3H,
iPrCH3), 1.03 (d, J = 6.5 Hz 3H, iPrCH3), 1.34 (s, 3H, CH3),
1.96 (sp, J = 6.6 Hz, 1H, iPrCH), 3.03 (s, 3H, NCH3), 7.68 (m,
2H, Ar), 7.98 (m, 1H, Ar), 8.24 (m, 1H, Ar); 13C NMR: δ 16.6;
16.8, 20.9, 27.5, 34.2, 74.1, 121.4, 122.4, 123.6, 124.5, 126.2,
127.5, 135.3, 137.5, 154.7, 185.0; EI-MS: m/z 320, 277
(100 %), 208, 193, 158, 114. Anal. Calcd. for C16H17ClN2OS
(320.1): C, 59.90; H, 5.34; Cl, 11.05; N, 8.73; S, 9.99. Found: C,
60.13; H, 5.43; Cl, 11.00; N, 8.74; S, 9.93.
Synthesis of 1-benzyl-2-(3-chlorobenzo[b]thiophene-2-yl)-4-
isopropyl-4-methyl-4,5-dihydro-1H-imidazol-5-one (3b). The
reaction was performed on a vacuum-argon line. Benzyl
bromide (1.2 ml; 10 mmol) was added to a mixture of 2-(3-
chlorbenzo[b]thiophen-2-yl)-4-isopropyl-4-methyl-4,5-dihydro-
1H-imidazol-5-one (2b) (1.85 g; 6 mmol) and cesium carbonate
(1.38 g; 10 mmol) in dry N,N-dimethylformamide (15 mL).
distilled water (2
× 10 mL). The remaining solid was
recrystallized from ethanol or an ethanol/water mixture.
2-(3-Chlorobenzo[b]thiophene-2-yl)-4-ethyl-4-methyl-4,5-
dihydro-1H-imidazol-5-one (2a). Yield 1 g (69 %); mp 144-
1
147 °C; H NMR: δ 0.78 (t, J = 7.3 Hz, 3H, CH2CH3), 1.35 (s,
3H, CH3), 1.78 (m, 2H, CH2CH3), 7.65 (m, 2H, Ar), 7.97 (m,
1H, Ar), 8.18 (m, 1H, Ar), 11.32 (bs, 1H, CONH); 13C NMR: δ
7.9, 22.6, 30.3, 61.3, 117.8, 122.5, 123.3, 126.1, 127.6, 128.0,
136.0, 136.8, 158.2. 175.1; EI-MS: m/z 292, 277, 263, 229, 214,
194 (100 %), 159, 132, 114. Anal. Calcd. for C14H13ClN2OS
(292.0): C, 57.43; H, 4.48; Cl, 12.11; N, 9.57; S, 10.95. Found:
C, 57.66; H, 4.59; Cl, 12.23; N, 9.62; S, 10.74.
2-(3-Chlorobenzo[b]thiophene-2-yl)-4-isopropyl-4-methyl-4,
5-dihydro-1H-imidazol-5-one (2b). Yield 1.18 g (77 %); mp

May-Jun 2008
Substituted (Benzo[b]thiophen-2-yl)-4-methyl-4,5-dihydro-1H-imidazol-5-ones
863
REFERENCES AND NOTES
After 48-hour heating at 150 °C, the content of the flask was
cooled and filtered. The separated solid was washed with N,N-
dimethylformamide (50 mL), and the filtrate was evaporated in
vacuum. The evaporation residue was dissolved in ethyl acetate
(20 mL) and filtered through a silica gel layer (2 cm). The
product was obtained by evaporating the ethyl acetate. Yield
1.56 g (85 %), mp 80-82 °C; 1H NMR: δ 0.89 (d, J = 6.8 Hz 3H,
iPrCH3), 0.98 (d, J = 6.8 Hz 3H, iPrCH3), 1.39 (s, 3H, CH3),
2.09 (sp, J = 6.8 Hz, 1H, iPrCH), 4.7 (s, 2H, CH2Ph), 6.94 (m,
2H, CH2Ph), 7.21 (m, 3H, CH2Ph), 7.65 (m, 2H, Ar), 7.93 (m,
1H, Ar) 8.15 (m, 1H, Ar); 13C NMR: 16.9, 17.1, 21.4, 34.4, 37.4,
44.1, 74.4, 122.0, 122.6, 123.7, 126.5, 127.0, 127.7, 127.8,
128.7, 135.1, 136.2, 137.6, 154.2, 185.0; EI-MS: m/z 396, 353,
263, 194, 91 (100 %). Anal. Calcd. for C16H17ClN2OS (396.9):
C, 66.57; H, 5.33; Cl, 8.93; N, 7.06; S, 8.08. Found: C, 66.32;
H, 5.40; Cl, 8.86; N, 7.17; S, 7.99.
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2-(Benzo[b]thiophene-2-yl)-4-isopropyl-1,4-dimethyl-4,5-
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243 (100%), 174, 159, 133, 115, 102, 89.
2-[3-(1-Piperidyl)benzo[b]thiophene-2-yl]-4-isopropyl-1,4-
dimethyl-4,5-dihydro-1H-imidazol-5-one (5a) EI-MS m/z:
369, 326 (100 %), 285, 267, 257, 243, 226, 215, 201, 186, 173,
159, 147, 84.
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2-(Benzo[b]thiophene-2-yl)-l-benzyl-4-isopropyl-4-methyl-
4,5-dihydro-1H-imidazol-5-one (4b) EI-MS : m/z 362, 347,
319 (100 %), 281, 249, 229, 207, 187, 173, 159, 132, 115, 91.
2-[3-(1-Piperidyl)benzo[b]thiophene-2-yl]-1-benzyl-4-iso-
propyl-4-methyl-4,5-dihydro-1H-imidazol-5-one (5b) EI-MS
m/z: 445, 402, 354 (100 %), 319, 267, 249, 226, 186, 159, 91.
Acknowledgments The authors acknowledge the financial
support from the MSM 002 162 7501.