Studies on the chemistry of thienoannelated O,N- and S,N-containing heterocycles. 25 [1]. Synthesis of new imidazolyl and pyrazolyl derivatives of thiophene as inhibitors of nitric oxide synthase

Article abstract of DOI:10.1002/jhet.5570390501

Some novel imidazolyl and pyrazolyl thiophene derivatives were synthesized. Different substituted N-containing heterocycles were chosen with the aim of enhancing the activity or selectivity of the products towards inhibition of one of the three isoforms of nitric oxide synthase. One series of substances was prepared by substitution reactions of 3-bromo-2-nitrothiophene with various heterocycles. In the other series introduction of a second heterocyclic substituent to pyrazolylthiophene compounds was attempted.

Full text of DOI:10.1002/jhet.5570390501

Sep-Oct 2002
Studies on the Chemistry of Thienoannelated O,N- and S,N-Containing
Heterocycles. 25 [1]. Synthesis of New Imidazolyl and Pyrazolyl
Derivatives of Thiophene as Inhibitors of Nitric Oxide Synthase
857
1
1
2
Thomas Erker *, Maria E. Galanski and Markus Galanski
1
Institute of Pharmaceutical Chemistry, University of Vienna, A-1090 Vienna, Althanstraße 14, Austria
Institute of Inorganic Chemistry, University of Vienna, A-1090 Vienna, Währingerstraße 42, Austria
Received August 23, 2001
2
Some novel imidazolyl and pyrazolyl thiophene derivatives were synthesized. Different substituted N-
containing heterocycles were chosen with the aim of enhancing the activity or selectivity of the products
towards inhibition of one of the three isoforms of nitric oxide synthase. One series of substances was pre-
pared by substitution reactions of 3-bromo-2-nitrothiophene with various heterocycles. In the other series
introduction of a second heterocyclic substituent to pyrazolylthiophene compounds was attempted.
J. Heterocyclic Chem., 39, 857 (2002).
Phenylimidazole and other imidazole derivatives with
co-reactant. However, only a small amount of derivative
aromatic residues are known to have moderate to good
affinity towards hemoglobin containing enzymes. Nitric
oxide synthase (NOS) is one of the enzymes with a hemo-
globin group in its active center [2-4]. For example, some
imidazole derivatives of the general formula 1 show selec-
tive NOS inhibiting activity [5]. Additionally, it is known
that cytochrome P450, another Fe-containing enzyme is
inhibited by simple compounds as shown in formula 2 [6]
(Scheme 1).
Thus we planned to prepare a series of substituted
thienylimidazoles and other N-containing thienylhetero-
cycles of the general formula 3. We expected that variation
of the N-heterocycle may cause differentiated activity or
selectivity to the inhibition of one of the three NOS-iso-
forms. Furthermore we considered, in the course of our
studies on new substances with NOS-inhibiting activities,
to synthesize some thienylimidazole derivatives with a
second N-containing heterocycle attached to the thiophene
ring as shown in formula 4 (Scheme 1).
5c was obtained from heating compound 6 with 4,5-
dichloroimidazole and KHCO without solvent at 75°
3
while reaction of 6, KHCO and N-heterocycles in ethanol
3
at 75° or N,N-dimethylformamide at 60° failed. Finally,
compound 6 and various N-heterocycles were treated with
KHCO in N,N-dimethylformamide at 110° to afford the
3
target compounds 5a - 5g in low yields. Surprisingly, only
treatment with 1,2,4-triazole gave product 5b in relatively
good yield. Compounds 5c and 5e showed weak stability.
The formation of two isomeric products by treatment of 6
with 4-methylimidazole is possible. In analogy to com-
pound 10 only the preferred product 5f was formed. The
N-heterocyclic moieties, reaction conditions, melting
points and yields are summarized in Table 1.
The synthetic route to the target compounds 5a - 5g is
outlined in Scheme 2. As starting material, 3-bromothio-
phene was chosen. Treatment of 3-bromothiophene with
concentrated HNO and acetic anhydride gave 3-bromo-2-
nitrothiophene (6) [7] in good yield. Initial attempts to
The intermediates for synthesizing the target compounds
of general formula 4 were prepared as shown in Scheme 3.
Treatment of 5-acetyl-2-chloro-3-nitrothiophene 7 [8] with
an excess of pyrazole, imidazole or 4-methylimidazole
under heating gave compounds 8, 9, and 10 in good yields.
Reduction of the acetyl group in 8 - 10 with trifluoroacetic
acid and triethylsilane was expected to afford the ethyl
derivatives. It is known that compounds with an alkyl
group next to the sulfur atom of the thiophene ring can
show increased biological activity [9]. Compound 8 was
smoothly reduced to 11, while reduction of 9 failed. From
10 was obtained only the alcohol 12. A second attempt, to
reduce the ketones in 9 and 10 to alkanes with lithium alu-
3
introduce the pyrazole, imidazole or 4,5-dichloroimidazole
moiety into the 3-position of substance 6 by heating with
the corresponding heterocycle in N,N-dimethylformamide
for several hours failed. These results suggested that a
minium hydride and AlCl also failed.
3
Reduction of the nitro groups in 9, 10 and 11 to the amine
compounds 13, 14 and 15 was accomplished with iron
powder in glacial acetic acid and water. Treatment of the
weak base, such as KHCO , could be an appropriate
3

858
T. Erker, M. E. Galanski and M. Galanski
Vol. 39
Table 1
amines 13, 14 and 15 with acetyl chloride gave the
expected amides 16, 17 and 18. These amides were also
prepared in one step with higher yields by heating 9, 10 and
11 with iron powder in glacial acetic acid and water at 110°.
The reaction of 18 with potassium tert-butoxide and
diethyl chlorophosphate followed by ethyl isocyanoacetate
[10] gave compound 19 in an unsatisfactory low yield of
less than 1% and therefore will be not discussed here.
The exact position of the methyl group in compound 10
Compd.
R
React. React. melting
temp. time (h) point
Yield
(°C)
(°C)
5a
5b
5c
110
4
20
4
98
167 mg (17%)
744 mg (75%)
355 mg (36%)
110
110
146
92
13
1
could not undoubtedly be confirmed using C, H-COSY
13
1
and C, H-HMBC nmr spectroscopy because of the lack
13
1
2
of protons to obtain long-range C, H correlations via J
13
1
3
13
1
( C, H) and J ( C, H). Therefore, 10 was treated with
Raney-Ni to produce substance 20 via reductive desulfura-
5d
5e
110
110
16
16
168
175 mg (17%)
145 mg (13%)
tion of the thiophene ring forming a CH group at the imi-
2
13
dazole nitrogen. The structure elucidation with C,
102-104
5f
110
110
20
4
142-144
147-151
300 mg (29%)
349 mg (28%)
5g

Sep-Oct 2002
Studies on the Chemistry of Thienoannelated O,N- and S,N-Containing Heterocycles
859
13
1
7.46 (d, J = 5.8, 1H, thiophene H); C nmr (deuteriochloroform):
δ 152.4, 145.9, 132.6, 130.5, 126.5; ms: m/z 196 (22), 113 (23),
70 (26), 45 (100).
H-HMBC nmr spectroscopy was accomplished using the
shift correlation signals of the methylene protons and the
tertiary imidazole carbons. We observed that the CH -
N
zole carbons but not with the quaternary carbon that is
bound to the methyl group. The lack of the latter shift cor-
relation signal verifies the structure of compound 10.
2
Anal. Calcd. for C H N O S: C, 36.73; H, 2.06; N, 28.56.
Found: C, 36.86; H, 2.04; N, 28.26.
6
4 4 2
protons of 20 correlate with both tertiary imida-
imidazole
4,5-Dichloro-1-(2-nitro-3-thienyl)-1H-imidazole (5c).
The product was purified by recrystallisation from 50%
ethanol; H nmr (dimethyl-d sulfoxide): δ 7.70 (d, J = 5.6 Hz,
1
6
1H, thiophene H), 7.13 (d, J = 5.6 Hz, 1H, thiophene H), 7.58 (s,
13
1H, imidazole H); C nmr (dimethyl-d sulfoxide): δ 136.6,
6
133.0, 129.7, 128.2, 125.6, 113.4; ms: m/z 263 (2), 233 (2), 207
(32), 82 (71), 45 (100).
Anal. Calcd. for C H Cl N O S: C, 31.84; H, 1.15; N, 15.91.
7
3
2 3 2
Found: C, 31.68; H, 1.23; N, 15.58.
2-Methyl-1-(2-nitro-3-thienyl)-1H-imidazole (5d).
The product was purified by column chromatography (ethyl
1
acetate/methanol 9/1); H nmr (dimethyl-d sulfoxide): δ 7.63 (d,
Some of the compounds described herein have already
been tested with respect to their NOS-inhibiting activity
and show interesting pharmacological profiles. The results
of the tests will be published elsewhere.
6
J = 5.8 Hz, 1H, thiophene H), 7.10 (d, J = 1.5 Hz, 1 H, imidazole
H), 7.06 (d, J = 5.8 Hz, 1H, thiophene H), 6.95 (d, J = 1.5 Hz, 1H,
imidazole H), 2.30 (s, 3H, CH ); C nmr (dimethyl-d sulfox-
ide): δ 145.5, 144.1, 134,1, 129.7, 128.6, 127.5, 119.9, 13.3; ms:
13
3
6
m/z 209 (5), 153 (5), 137 (4), 69 (6), 43 (100).
EXPERIMENTAL
Anal. Calcd. for C H N O S: C, 45.93; H, 3.37; N, 20.08.
8
7 3 2
Found: C, 45.68; H, 3.11; N, 19.89.
Melting points were obtained on a Kofler hot-stage apparatus and
2-Ethyl-1-(2-nitro-3-thienyl)-1H-imidazole (5e).
1
13
are uncorrected. The H and C nmr spectra were recorded on a
Bruker Avance 200 (200 MHz), a Bruker Avance 400 DPX (400
MHz) or on a Varian UnityPlus-300 (300 MHz) spectrometer using
deuteriochloroform as solvent, if not otherwise stated, and tetra-
methylsilane as internal standard. Mass spectra were obtained by
using a Shimadzu GC/MS QP 1000 EX or a Hewlett Packard (GC:
5890; MS 5970) spectrometer. Column chromatography was per-
formed using silica gel 60, 70 - 230 mesh ASTM (Merck). Solutions
in organic solvents were dried over anhydrous sodium sulfate. All
materials were commercially available unless otherwise noted.
The product was purified by column chromatography (ethyl
1
acetate/methanol 9/1); H nmr (dimethyl-d sulfoxide): δ 8.22 (d,
6
J = 5.8 Hz, 1H, thiophene H), 7.47 (d, J = 5.8 Hz, 1H, thiophene
H), 7.35 (d, J = 1.3 Hz, 1H, imidazole H), 7.03 (d, J = 1.3 Hz, 1H,
imidazole H), 2.56 (q, J = 7.5 Hz, 2H, CH ), 1.17 (t, J = 7.5 Hz,
2
13
3H, CH ); C nmr (dimethyl-d sulfoxide): δ 148.8, 139.9,
3
6
134.3, 132.6, 128.2, 127.4, 120.8, 19.8, 11.8; ms: m/z 223 (3),
167 (6), 137 (6), 11 (4), 57 (100), 45 (45).
Anal. Calcd. for C H N O S: C, 48.42; H, 4.06; N, 18.82.
9
9 3 2
Found: C, 48.17; H, 3.76; N, 18.55.
1-(2-Nitro-3-thienyl)-1H-imidazole (5a).
4-Methyl-1-(2-nitro-3-thienyl)-1H-imidazole (5f).
A suspension of 1.03 g (5 mmoles) of 6, 0.34 g (5 mmoles) of
The product was purified by recrystallisation from 40%
imidazole and 0.5 g (5 mmoles) of KHCO in 12.5 ml of absolute
3
1
ethanol; H nmr (dimethyl-d sulfoxide): δ 8.17 (d, J = 5.8 Hz,
6
N,N-dimethylformamide was stirred at 110 °C for 4 hours. The
reaction mixture was concentrated and the residue diluted with
ethyl acetate and washed with water. The organic layer was dried
1H, thiophene H), 8.09-8.05 (m, 1H, imidazole H), 7.42 (d, J =
5.8 Hz, 1H, thiophene H), 7.35-7.29 (m, 1H, imidazole H), 2.22
13
(d, J = 8.7 Hz, 3H, CH ); C nmr (dimethyl-d sulfoxide): δ
3
6
and evaporated in vacuo. The product was purified by recrystallisa-
139.8, 137.4, 133.9, 132.9, 126.6 (2C), 116.4, 13.4; ms: m/z 209
(5), 179 (17), 139 (38), 111 (34), 42 (100).
1
tion from 15% ethanol; H nmr (dimethyl-d sulfoxide): δ 7.86 (s,
6
1H, imidazole H), 7.62 (d, J = 5.8 Hz, 1H, thiophene H), 7.09 (d, J
Anal. Calcd. for C H N O S: C, 45.93; H, 3.37; N, 20.08.
8
7 3 2
13
= 5.8 Hz, 1H, thiophene H), 7.23 (s, 2H, imidazole H); C nmr
Found: C, 45.74; H, 3.36; N, 19.76.
(dimethyl-d sulfoxide): δ 140.4, 133.7, 132.9, 128.9, 126.9, 120.6;
6
1-(2-Nitro-3-thienyl)-1H-1, 2, 3-benzotriazole (5g).
The product was purified by column chromatography
ms: m/z 195 (5), 165 (50), 139 (52), 111 (56), 84 (45), 45 (100).
Anal. Calcd. for C H N O S: C, 43.07; H, 2.58; N, 21.53.
7
5 3 2
1
Found: C, 42.81; H, 2.53; N, 21.29.
(toluene/ethyl acetate 8/2); H nmr (deuteriochloroform): δ 8.19 (d,
Compounds 5b - 5g were obtained by the same method to that
used for 5a. The N-heterocycle moieties, reaction temperatures
and times, melting points and yields are listed in Table 1.
J = 8.3 Hz, 1H, benzotriazole-H), 7.74 (d, J = 5.8 Hz, 1H, thiophene
H), 7.41 (d, J = 5.8 HZ, 1H, thiophene H), 7.61-7.56 (m, 1H, benzo-
triazole H), 7.51-7.46 (m, 1H, benzotriazole H), 7.31 (d, J = 8.3 Hz,
13
1H, benzotriazole H); C nmr (deuteriochloroform): δ 145.7,
1-(2-Nitro-3-thienyl)-1H-1,2,4-triazole (5b).
144.4, 132.9, 131.9, 130.9, 128.9, 127.0, 124.8, 120.6, 110.6; ms:
m/z 246 (18), 172 (49), 128 (31), 92 (100), 64 (86), 45 (92).
Anal. Calcd. for C H N O S: C, 48.78; H, 2.46; N, 22.75.
The product was purified by recrystallisation from 70%
1
ethanol; H nmr (deuteriochloroform): δ 8.93 (s, 1H, triazole H),
10
6 4 2
Found: C, 49.01; H, 2.51; N, 22.51.
8.14 (s, 1H, triazole H), 7.64 (d, J = 5.8 Hz, 1H, thiophene H),

860
T. Erker, M. E. Galanski and M. Galanski
Vol. 39
1-[4-Nitro-5-(1H-1-pyrazolyl)-2-thienyl]-1-ethanone (8).
zole H), 7.74 (d, J = 1.7 Hz, 1H, pyrazole H), 7.26-7.24 (m, 1H,
thiophene H), 6.51 (dd, J = 1.7 Hz, J = 2.8 Hz, 1H, pyrazole H),
A solution of 6.00 g (29.2 mmoles) of 7 and 10.40 g (150
mmoles) of pyrazole in 100 ml of absolute acetonitrile was
refluxed for 27 hours, followed by addition of 5.00 g (72.1
mmoles) of pyrazole. After refluxing for further 43 hours the sol-
vent was removed under vacuum and the residue crystallized
2.80 (dq, J = 1.1Hz, J = 7.5 Hz, 2H, CH ), 1.34 (t, J = 7.5 Hz, 3H,
2
13
CH ); C nmr (deuteriochloroform): δ 142.8, 141.7, 140.8,
3
134.8, 132.9, 119.1, 108.5, 23.4, 14.9; ms: m/z 223 (75), 208
(30), 91 (28), 69 (64), 45 (100).
Anal. Calcd. for C H N O S: C, 48.42; H, 4.06; N, 18.82.
1
9
9 3 2
from ethanol to yield 5.92 g of 8 (86%), mp 155°; H nmr (deu-
Found: C, 48.29; H, 4.16; N, 18.44.
teriochloroform): δ 8.38 (d, J = 2.8 Hz, 1H, pyrazole H), 8.06 (s,
1H, thiophene H), 7.80 (d, J = 1.8 Hz, 1H, pyrazole H), 6.58 (dd,
1-[5-(4-Methyl-1H-1-imidazolyl)-4-nitro-2-thienyl]-ethanol
(12).
13
J = 1.8 Hz, J = 2.8 Hz,1H, pyrazole H), 2.59 (s, 3H, CH );
C
3
nmr (deuteriochloroform): δ 189.7, 149.2, 144.1, 135.8, 133.4,
132.9, 127.7, 110.1, 25.8; ms: m/z 237 (100), 222 (62), 148 (49),
105 (45), 69 (80), 52 (54).
The reagents used were: 251 mg (1 mmol) of 10 in 3 ml of triflu-
oroacetic acid and 0.8 ml of triethylsilane. Reaction time: 96 hours.
Purification: the precipitate was dried and crystallized from water.
Yield: 120 mg of 12 (47%), mp 126-128°; H nmr (deuteriochloro-
form): δ 7.62 (s, 1H, thiophene H), 7.35 (s, 1H, imidazole H), 6.86
Anal. Calcd. for C H N O S: C, 45.57; H, 2.97; N, 17.71.
9
7 3 3
1
Found: C, 45.67; H, 2.91; N, 17.58.
1-[5-(1H-1-Imidazolyl)-4-nitro-2-thienyl]-1-ethanone (9).
(s, 1H, imidazole H), 5.08 (q, J = 6.4 Hz, 1H, CH), 4.37 (broad s,
1H, COH), 2.24 (s, 3H, imidazole CH ), 1.60 (d, J = 6.4 Hz, 3H,
3
A solution of 6.00 g (29.2 mmoles) of 7, 3.97 g (58.4 mmoles)
of imidazole and 100 ml of absolute ethanol was refluxed for 22
hours. After concentrating the reaction mixture the residue was
13
COH-CH ); C nmr (deuteriochloroform): δ 147.6, 139.1, 138.3,
3
136.2, 118.1, 117.7, 65.3, 25.0, 13.2; ms: m/z 253 (25), 183 (100),
137 (78), 110 (46), 96 (54), 84 (50), 78 (74), 69 (48).
1
crystallized from ethanol to yield 4.93 g of 9 (71%), mp 176°; H
Anal. Calcd. for C H N O S: C, 47.42; H, 4.38; N, 16.60.
10 11
3 3
nmr (deuteriochloroform/dimethyl-d sulfoxide): δ 8.61 (s, 1H,
6
Found: C, 47.72; H, 4.30; N, 16.57.
thiophene H), 8.21 (s, 1H, imidazole H), 7.70 (s, 1H, imidazole
13
H), 7.20 (s, 1H, imidazole H), 2.68 (s, 3H, CH ); C nmr
3
General Procedure for the Preparation of 13, 14 and 15.
(dimethyl-d sulfoxide): δ 190.6, 143.4, 138.4, 137.1, 130.0,
6
To a solution of 9, 10 or 11 in a mixture of glacial acetic acid
and water, iron powder was added portion-wise. After heating at
50° or 70° the mixture was filtered, concentrated and the product
purified.
128.5, 121.9, 25.9; ms: m/z 237 (84), 209 (45), 179 (73), 94 (83),
84 (100), 69 (81), 52 (100).
Anal. Calcd. for C H N O S: C, 45.57; H, 2.97; N, 17.71.
9
7 3 3
Found: C, 45.79; H, 3.11; N, 17.61.
1-[4-Amino-5-(1H-1-imidazolyl)-2-thienyl]-1-ethanone (13).
1-[5-(4-Methyl-1H-1-imidazolyl)-4-nitro-2-thienyl]-1-ethanone (10).
The reagents used were: 3.31 g (14 mmoles) of 9, 5.12 g of
iron powder, 70 ml of glacial acetic acid and 7 ml of water.
Reaction temperature: 70°. Reaction time: 90 minutes.
Purification: extraction with water/ethyl acetate, drying, evapo-
rating the organic layer and recrystallizing from toluene. Yield:
A solution of 206 mg (1 mmol) of 7 and 164 mg (2 mmoles) of
4-methylimidazole in 5 ml of absolute N,N-dimethylformamide
was stirred at 70° for 3 hours. The reaction mixture was poured
onto ice water and the precipitate was collected by filtration and
crystallized from ethanol to yield 189 mg of 10 (75%), mp 114-
1
1.21 g of 13 (41%), mp 145-148°. H nmr (deuteriochloroform):
1
115°; H nmr (deuteriochloroform): δ 8.11 (s, 1H, thiophene H),
δ 7.69 (s, 1H, aromatic H), 7.22 (s, 2H, aromatic H), 7.14 (s, 1H,
7.79 (s,1H, imidazole H), 6.95 (s, 1H, imidazole H), 2.61 (s, 3H,
13
aromatic H), 3.77 (s, 2H, NH ), 2.52 (s, 3H, CH ); C nmr (deu-
13
2
3
COCH ), 2.29 (s, 3H, imidazole H); C nmr (deuteriochloro-
3
teriochloroform): δ 190.1, 139.9, 138.5, 130.5, 123.9, 120.8,
119.1, 26.2; ms: m/z 207 (63), 188 (50), 164 (18), 137 (35), 110
(38), 84 (48), 43 (100).
form): δ 189.8, 144.7, 141.2, 138.2, 137.9, 137.5, 127.8, 118.1,
26.2, 13.9; ms: m/z 251 (38), 223 (16), 19 (59), 181 (100), 153
(53), 107 (36), 84 (67), 69 (41).
Anal. Calcd. for C H N OS: C, 52.16; H, 4.38; N, 20.28.
9
9 3
Anal. Calcd. for C H N O S: C, 47.80; H, 3.61; N, 16.72.
10
9 3 3
Found: C, 52.13; H, 4.22; N, 20.03.
Found: C, 47.46; H, 3.71; N, 16.39.
1-[4-Amino-5-(4-methyl-1H-1-imidazolyl)-2-thienyl]-1-
ethanone (14).
General Procedure for the Reduction of compounds 8 and 10
(Preparation of 11 and 12).
The reagents used were: 502 mg (2 mmoles) of 10, 784 mg of
iron powder, 20 ml of glacial acetic acid 1.5 ml of water and 1.5
ml of methanol. Reaction temperature: 50°. Reaction time: 2
hours. Purification: extraction with water/ethyl acetate, drying
and evaporating the organic layer and recrystallizing from
isobutyl methyl ketone. Yield: 370 mg of 14 (84%), mp 165-
To a solution of 8 or 10 in trifluoroacetic acid, triethylsilane
was added dropwise and the mixture was stirred at room temper-
ature or at 40°. The reaction mixture was cooled, poured onto ice
water and neutralized with solid sodium bicarbonate. The product
was either extracted with ethyl acetate or collected by filtration in
case of a precipitate and purified.
1
166°. H nmr (deuteriochloroform): δ 7.54 (s, 1H, thiophene H),
1-(5-Ethyl-3-nitro-2-thienyl)-1H-pyrazole (11).
7.18 (s, 1H, imidazole H), 6.81 (s, 1H, imidazole H), 3.79 (s, 2H,
13
NH ), 2.48 (s, 3H, CO-CH ), 2.25 (s, 3H, imidazole CH );
C
The reagents used were: 5.92 g (25 mmoles) of 8 in 25 ml of
trifluoroacetic acid and 37.5 ml of triethylsilane. Reaction time:
72 hours at 40°. Purification: after extraction with ethyl acetate
the organic layer was dried, concentrated and triethylsilane
removed by kugelrohr distillation. Yield: 4.96 g (89%) of 11 as an
2
3
3
nmr (deuteriochloroform): δ 190.1, 139.7, 139.6, 138.1, 137.3,
124.0, 119.7, 117.0, 26.1, 13.5; ms: m/z 221 (85), 181 (14), 179
(100), 153 (29), 137 (16), 120 (16), 110 (56), 84 (24).
Anal. Calcd. for C H N OS: C, 54.28; H, 5.01; N, 18.99.
10 11
3
1
oil; H nmr (deuteriochloroform): δ 8.17 (d, J = 2.8 Hz, 1H, pyra-
Found: C, 54.52; H, 4.78; N, 18.73.

Sep-Oct 2002
Studies on the Chemistry of Thienoannelated O,N- and S,N-Containing Heterocycles
861
5-Ethyl-2-(1H-1-pyrazolyl)-3-thienylamine (15).
hours. Purification: column chromatography (toluene/ethyl
acetate 6/4). Yield: 615 mg of 18 (25%), mp 87-91°. H nmr
(deuteriochloroform): δ 9.81 (s, 1H, NH), 7.71 (d, J = 1.9 Hz, 1H,
thiophene H), 7.64 (d, J = 2.3 Hz, 2H, pyrazole H), 6.43-6.40 (dd,
J = 4.3 Hz, J = 4.9 Hz, 1H, pyrazole H), 2.79 (dq, J = 1.9 Hz, J =
1
The reagents used were: 454 mg (2 mmoles) of 11, 784 mg of
iron powder, 10 ml of glacial acetic acid and 1 ml of water.
Reaction temperature: 70°. Reaction time: 45 minutes.
Purification: column chromatography (toluene/ethyl acetate 8/2).
7.5 Hz, 2H, CH ), 2.16 (s, 3H, CH CO), 1.31 (t, J = 7.5 Hz, 3H,
2
3
1
Yield: 281 mg (51%) of 15 as an oil; H nmr (deuteriochloro-
13
CH CH ); C nmr (deuteriochloroform): δ 167.3, 140.5, 139.3,
3
2
form): δ 7.67 (s, 1H, pyrazole H), 7.58 (d, J = 2.3 Hz, 1H, pyra-
zole H), 6.39-6.35 (m, 1H, pyrazole H), 6.32-6.29 (m, 1H, thio-
129.1, 126.6, 120.3, 119.3, 106.6, 24.4, 23.7, 15.5; ms: m/z 235
(67), 193 (42), 178 (50), 164 (38), 43 (100).
phene H), 4.11 (s, 2H, NH ), 2.72 (q, J = 7.7 Hz, 2H, CH ), 1.27
2
2
Anal. Calcd. for C H N OS: C, 56.15; H, 5.57; N, 17.86.
11 13
3
13
(t, J = 7.7 Hz, 3H, CH ); C nmr (deuteriochloroform): δ 141.3,
3
Found: C, 56.04; H, 5.82; N, 17.64.
140.4, 136.4, 130.0, 117.4, 112.7, 106.2, 23.6, 15.4; ms: m/z 193
(99), 178 (62), 164 (57), 59 (55), 53 (100).
5-Amino-6-(4-methyl-1H-1-imidazolyl)-2-hexanol (20).
Anal. Calcd. for C H N S: C, 55.93; H, 5.74; N, 21.74
Found: C, 56.21; H, 5.53; N, 21.37.
9
11 3
To a refluxing suspension of 1.004 g (4 mmoles) of 10 and 2 g
of Raney-Nickel (W2) in 50 ml of ethanol, a further 2 g of
Raney-Ni was added after 30 and again after 60 minutes. The
reaction was completed after 90 minutes (thin layer chromatogra-
phy control) at which time the catalyst was removed by filtration
and washed with ethanol three times. The solvent was removed
under vacuum and the residue diluted with methylene chloride
and washed with water. The organic layer was dried, evaporated
General Procedure for the Preparation of 16, 17 and 18.
To a solution of 9, 10 or 11 in glacial acetic acid, iron powder
was added portion-wise. After heating at 110° the mixture was
filtered, concentrated, diluted with water and neutralized with
sodium hydrogen carbonate or made alkaline with NaOH in case
of 17. After extraction with ethyl acetate, drying and evaporating
the organic layer the products were purified by column chro-
matography or by recrystallizing the residue.
-2
and purified by kugelrohr distillation (1.4x10 mbar, 100°) to
1
yield 39 mg (3.9%) of 12 as an oil; H nmr (deuteriochloroform):
δ 7.36 (s, 1H, imidazole H), 6.64 (s, 1H, imidazole H), 3.93-3.59
(m, 2H, CH ), 3.05-2.85 (m, 1H, CH), 2.85-2.81 (m, 3H, CH,
N-[5-Acetyl-2-(1H-1-imidazolyl)-3-thienyl]acetamide (16).
2
CH ), 2.19 (s, 3H, CH ), 1.83-1.60 (m, 2H, CH ), 1.10-0.97 (m,
2
3
2
The reagents used were: 4.93 g (21.8 mmoles) of 9, 8.66 g of
iron powder and 150 ml of glacial acetic acid. Reaction time: 21
13
3H, CH ); C nmr (deuteriochloroform): δ 137.7, 136.7, 116.2,
3
63.5, 59.5, 52.4, 46.2, 32.1, 27.7, 20.8, 13.6, 12.6. Exact mass
hours. Purification: crystallisation from ethanol. Yield: 1.42 g of
Calcd. for C H N O: 197.1528. Found 197.1541.
10 19
3
1
16 (26%), mp 288-291°. H nmr (dimethyl-d sulfoxide): δ 9.93
6
Acknowledgement.
(s, 1H, NH), 8.14 (s 1H, thiophene H), 8.10-8.05 (m, 1H, imida-
zole H), 7.60-7.55 (m, 1H, imidazole H), 7.23-7.18 (m, 1H, imi-
For experimental assistance we are in debt to H. Hrovat, D.
Kröner and P. Saiko.
13
dazole H), 2.60 (s, 3H, CH CO), 2.07 (s, 3H, CH CO); C nmr
3
3
(dimethyl-d sulfoxide): δ 190.7, 168.9, 136.8, 132.6, 131.2,
6
129.8, 129.3, 121.0, 26.0, 22.8; ms: m/z 249 (19), 207 (46), 192
(17), 84 (19), 43 (100).
REFERENCES AND NOTES
Anal. Calcd. for C H N O S: C, 53.00; H, 4.45; N, 16.87.
11 11
3 2
Found: C, 52.92; H, 4.28; N, 16.58.
[1] Part 24: T. Erker and N. Handler, J. Heterocyclic Chem.,
39, 645 (2002).
[2] D. J. Wolff and B. J. Gribin, Archives of Biochemistry and
Biophys., 311, 393 (1994).
N-[5-Acetyl-2-(4-methyl-1H-1-imidazolyl)-3-thienyl]acetamide
(17).
[3] D. J. Wolff, G. A. Datto and R. A. Samatovicz, J. Biol.
Chem., 268, 9430 (1993).
The reagents used were: 502 mg (2 mmoles) of 10, 784 mg of
iron powder and 20 ml of glacial acetic acid. Reaction time: 48
hours. Purification: crystallisation from ethyl acetate/ethanol.
Yield: 401 mg of 17 (76%), mp 202-204°. H nmr (deuteriochlo-
roform): δ 10.41 (s, 1H, NH), 8.45 (s, 1H, thiophene H), 6.72 (s,
[4] R. L. C. Handy, P. Wallace, Z. A. Gaffen, K. J. Whitehead
and P. K. Moore, Br. J. Pharmacology, 116, 2349 (1995).
[5] P. Hölscher, H. Rehwinkel, G. Burton, M. Möwes and H.
Hillmann, DE, German patent, 196,27,310 A1 (C 07 D 409/14);
Chem. Abstr. 128, 114949 (1999).
[6] H. J. Böhm, G. Klebe and H. Kubinyi, Wirkstoffdesign,
Spektrum Akademischer Verlag (1996).
[7] V. S. Babasinian, J. Am. Chem. Soc., 50, 2748 (1928).
[8] C. D. Hurd and K. L. Kreuz, J. Am. Chem. Soc., 74, 2965
(1952).
[9] S. Gronowitz, Thiophene and its Derivatives, Part I, John
Wiley and Sons (1985).
[10] E. J. Jacobsen, R. E. TenBrink, L. S. Stelzer, K. L.
Belonga, D. B. Carter, H. K. Im, W. B. Im, V. H. Sethy, A. H. Tang, P.
F. vonVoigtlander and J. D. Petke, J. Med. Chem., 39, 158 (1996).
1
1H, imidazole H), 2.57 (s, 3H, NH-CO-CH ), 2.24 (s, 3H, CO-
3
13
CH ), 2.07 (s, 3H, imidazole H); C nmr (deuteriochloroform):
3
δ 190.9, 169.3, 139.7, 138.8, 137.1, 133.0, 128.0, 127.0, 117.6,
26.1, 23.5, 13.1; ms: m/z 263 (93), 248 (19), 221 (76), 206 (28),
179 (100), 153 (28), 110 (26), 84 (33).
Anal. Calcd. for C H N O S: C, 54.74; H, 4.98; N, 15.96.
12 13
3 2
Found: C, 54.77; H, 4,89; N, 15.67.
N-[5-Ethyl-2-(1H-1-pyrazolyl)-3-thienyl]acetamide (18).
The reagents used were: 2.37 g (10.63 mmoles) of 11, 4.15 g of
iron powder and 80 ml of glacial acetic acid. Reaction time: 14