Synthesis of Thieno [2,3-d] imidazoles by copper-catalyzed amidine cyclization

Article abstract of DOI:10.1055/s-0033-1340959

A new synthetic approach to thieno[2,3-d]imidazoles is presented on the basis of the N′-(3-halothiophen-2-yl)amidine cyclization under copper-catalyzed cross-coupling. Using commercially available starting materials such as 2-aminothiophenes or their Boc-protected derivatives and copper catalysts, this method offers a convenient route to a wide range of thieno[2,3-d]imidazole derivatives, especially the 5-alkyl-subtituted thieno[2,3-d]imidazoles. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0033-1340959

LETTER
▌965
lSetyternthesis of Thieno[2,3-d]imidazoles by Copper-Catalyzed Amidine Cyclizati-
on
Approach to Thieno[2,3-d]imidazoles
Kostiantyn Liubchak,*a,c Andrey Tolmachev,b Kostiantyn Nazarenkoa
a
Institute of Organic Chemistry of NAS of Ukraine, Murmanska Street 5, Kyiv 02094, Ukraine
b
Kyiv National Taras Shevchenko University, Volodymyrska Street 64, Kyiv 01601, Ukraine
c
Enamine Ltd., Aleksandra Matrosova Street 23, Kyiv 01103, Ukraine
Fax +380(50)445373253; E-mail: kliubchak@gmail.com
Received: 05.11.2013; Accepted after revision: 19.02.2014
2-bromothiophen-3-isocyanides with primary amines.11
Abstract: A new synthetic approach to thieno[2,3-d]imidazoles is
However, none of these approaches affords 5-alkyl-
presented on the basis of the N′-(3-halothiophen-2-yl)amidine cycli-
substitued thieno[2,3-d]imidazoles. Furthermore, each
procedure includes several steps with resultant low over-
zation under copper-catalyzed cross-coupling. Using commercially
available starting materials such as 2-aminothiophenes or their Boc-
protected derivatives and copper catalysts, this method offers a con- all yields.
venient route to a wide range of thieno[2,3-d]imidazole derivatives,
especially the 5-alkyl-subtituted thieno[2,3-d]imidazoles.
A synthesis of imidazoles including N-arylation and het-
eroarylation under copper catalyst has been developed in
recent years.12 Using complexes of Cu(I/II) formed in situ
or under ligand-free conditions, the imidazole moiety
could be obtained from amidines by cyclization of 2-hal-
ogen-1-amidine III into imidazole IV (Scheme 1),13 C–H
functionalization/C–N bond formation14 or via diamina-
tion of terminal alkynes.15 Derivates III could be obtained
from the appropriate amines I and V and imidoyl chlo-
rides, amides or thioamides. Herein we report an approach
to thieno[2,3-d]imidazoles based on the cyclization of
thiophene amidines III using copper(I) as catalyst.
Key words: amidines, cyclization, copper, thiophenes, imidazoles
The imidazole unit is a common structural motif in bio-
logically active molecules (Figure 1), being derived from
the amino acid histidine.1 Its ring-fused analogues are
well known in clinical therapy under brand names such as
Sildenafil, Udenafil and Granisteron.2 Preclinical studies
of thieno[2,3-d]imidazole derivatives have shown activity
in the treatment of osteoarthritis,3 hepatitis C4 and gastric
acid regulation.5
X
O
H
N
S
NH2
S
NH2
N
Cl
O
O
I
V
Ph
OMe
N
highly selective aggrecanase inhibitor
R2
R1
X
N
R2
R1
R2
R1
HN
HN
N
Figure 1 Biologically active thieno[2,3-d]imidazoles
N
N
The range of synthetic approaches to thieno[2,3-d]imidaz-
oles is limited, especially for derivatives with 1,2-disub-
stitution on the imidazole core. Construction of the fused
imidazole moiety on the thiophene ring may start from 2-
nitro-3-aminothiophene derivatives. These can be con-
verted into substituted 2,3-diamines by standard reac-
tions. Subsequent treatment of the products with PPA,6
triethoxymethane7 or bromocyane8 leads to the formation
of thieno[2,3-d]imidazoles. Condensation of 5-bromo-
1H-imidazole-4-carbaldehyde derivatives with thio-
glycolic acid amide9 or methyl ester10 is the probably the
most general synthetic approach to thieno[2,3-d]imidaz-
oles. There is also an Ullmann-type protocol by which
thieno[2,3-d]imidazoles can be obtained by reaction of
II
III
IV
Scheme 1 General approach to the ring-fused imidazoles by copper-
catalyzed amidines cyclization
Commercially available ethyl 5-amino-3-methylthio-
phene-2-carboxylate (1) was used as starting material
(Scheme 2). Reaction of 1 with imidoyl chlorides at room
temperature led to amidines 2a,b in 60–69% yield. Fur-
ther reaction of 2a,b with NBS gave the corresponding
bromides 3a,b in 74–79% yield. Previously we have de-
veloped a synthetic protocol for cyclization of N-halo-
pyrazolylamidines into imidazo[4,5-c]pyrazoles.16 Here
we designed reaction conditions for the thiophene deriva-
tives with model compound 2a. We examined the influ-
ence of solvent, ligand, and base on the course of the
copper-catalyzed intramolecular arylation (Table 1). The
nature of the solvent proved to be the most significant pa-
SYNLETT 2014, 25, 0965–0968
Advanced online publication: 14.03.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340959; Art ID: ST-2013-D1031-L
© Georg Thieme Verlag Stuttgart · New York

966
K. Liubchak et al.
LETTER
Table 1 Condition Optimization for the Cyclization of 3a into 4aa
rameter controlling the reaction efficiency as was found
for the N-halopyrazolylamidines derivatives.16 In all cas-
es, using DMSO or DMF led to an increase in yield of the
target product. Another important factor was the appropri-
ate choice of ligand, as seen from entries 9, 10, 15–18 in
Table 1, DMEDA and L-Pro appeared most advantageous
among the compounds conventionally used in such syn-
theses (cf. with 1,10-phenanthroline and 8-hydroxyquino-
line). Although using cesium carbonate as a base afforded
the highest conversion, potassium carbonate gave only a
slightly reduced yield. Potassium phosphate turned out to
be inefficient (cf. entries 9, 10 vs. 11). Therefore, the in-
expensive and effective potassium carbonate was selected
as the preferred base for the cyclization. The synthesis of
4b was carried out under similar conditions in 93% yield.
Entry Solvent
Ligandb
Base
Conv. (%)
1
2
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
MeCN
DMF
DMEDA
DMEDA
8-Oxy
K2CO3
Cs2CO3
K2CO3
Cs2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
K2CO3
0
7
3
3
4
8-Oxy
0
5
Phen
21
18
6
6
Phen
7
DMEDA
Phen
8
12
87
91
56
8
To explore the scope and limitations of our approach we
examined a range of thiophene derivatives. 2-Amino-5-
methylthiophene (7) was selected as starting material as
the simplest example (Scheme 3). This was obtained from
5-methylthiophene-2-carboxylic acid (5) using a Curtius
rearrangement protocol.17 However, although 7 formed
9
DMEDA
DMEDA
DMEDA
8-Oxy
10
11
13
14
15
16
17
18
DMF
DMF
DMF
N-(5-methylthiophen-2-yl)acetamide
with
acetic
DMF
Phen
34
0
anhydride17 it was unreactive toward N-methylbenzimi-
doyl chloride in the presence of Et3N; only decomposition
products of 7 were observed by LCMS analysis in the re-
action mixture after 24 hours of stirring in 1,4-dioxane at
room temperature.
DMF
no ligand
DMF
no ligand and CuI K2CO3
0
DMSO
DMSO
L-Pro
L-Pro
K2CO3
76
81
Cs2CO3
We then decided to examine the Boc-protected precursor
6 to avoid the instability of the aminothiophene deriva-
tives (Scheme 3). Reaction of 6 with sodium hydride in
a Conditions: amidine (1 mol), base (2 mol), CuI (0.05 mol), ligand
(0.1 mol), solvent (5 mL), stirring for 6 h, and heating at reflux. The
THF followed by addition of N-methylbenzimidoyl chlo- conversion value is given as the average of three independent experi-
ments.
ride led to amidine 9 in 72% yield. We examined several
halogenation protocols (such as bromine–iodine in meth-
anol, bromine in AcOH with or without sodium acetate,
b DMEDA = N,N′-dimethylethylenediamine; Phen = 1,10-phenanth-
roline; 8-Oxy = 8-hydroxyquinoline.
NBS/NIS with or without KHCO3). However all of them
resulted in complex mixtures and did not lead to 11. To
circumvent this, we first halogenated 6 with bromine in
methanol to form 10 in 74% yield.18 Reaction of 10 with
sodium hydride in THF with N-methylbenzimidoyl chlo-
ride led to carbamate 11 in 62% yield. The Boc-protecting
group was then removed by HCl in 1,4-dioxane, and com-
pound 12 was obtained. After six hours of refluxing of the
thieno[2,3-d]imidazole with copper(I) catalyst the final
product 13 was obtained in 92% yield as the pure product.
In conclusion, a new synthetic route to thieno[2,3-d]imid-
azole derivatives based on the cyclization of N′-(3-halo-
thiophen-2-yl)amidines under copper-catalyzed cross-
coupling conditions has been developed.19 The facile and
inexpensive method using 2-aminothiophenes or their
Boc-protected derivatives and copper catalysts allows a
variety of substituents to be introduced at all positions of
the thieno[2,3-d]imidazole scaffold. This approach af-
fords a novel access to different 5-alkyl-subtituted thieno-
[2,3-d]imidazoles.
Me
HN
Me
Me
Br
HN
N
N
R
R
NH2
i
ii
iii
EtO2C
R
N
S
EtO2C
S
N
S
S
EtO2C
EtO2C
1
2a,b
3a,b
4a,b
Scheme 2 Reagents and conditions: (i) 1,4-dioxane, Et3N, RC(Cl)NMe; (ii) MeCN, NBS; (iii) DMF, CuI, DMEDA, K2CO3; a: R = Ph; b: R
= 3-ClC6H4.
Synlett 2014, 25, 965–968
© Georg Thieme Verlag Stuttgart · New York

LETTER
Approach to Thieno[2,3-d]imidazoles
967
Ph
NH
Me
N
CO2H
NH2
HCl
Boc
S
S
S
N
H
S
5
6
7
8
Me
Me
Me
Br
Br
Br
N
HN
N
iii, iv
v
N
i
ii
Ph
Ph
NH
Ph
NH
Boc
S
N
Boc
S
N
S
S
S
Boc
6
10
N
11
12
13
Me
ii
Ph
N
S
Boc
9
Scheme 3 Reagents and conditions: (i) MeOH, Br2, KHCO3; (ii) 1,4-dioxane, NaH, PhC(Cl)NMe; (iii) 1,4-dioxane, HCl; (iv) NaOH, MeOH;
(v) CuI (5% mol), DMEDA (10% mol), K2CO3 (2.0 mol), DMF, reflux.
(8) (a) Binder, D.; Noe, C. R.; Kollmann, H.; Rosenwirth, B.
Acknowledgment
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this article. This work was financially supported by Enamine Ltd.
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iotSrat
ungIifoop
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© Georg Thieme Verlag Stuttgart · New York
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K. Liubchak et al.
LETTER
(16) Liubchak, K.; Tolmachev, A.; Nazarenko, K. J. Org. Chem.
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CDCl3): δ = 163.4, 147.2, 137.8, 129.8, 129.3, 129.2, 128.8,
123.3, 60.7, 33.4, 14.3, 13.0. Anal. Calcd for C16H16N2O2S:
C, 63.98; H, 5.37; N, 9.33. Found: C, 64.03; H, 5.15; N, 9.22.
Ethyl 2-(3-Chlorophenyl)-1,6-dimethyl-1H-thieno[2,3-
d]imidazole-5-carboxylate (4b): yield: 93%; mp 167–168
°C; Rf 0.40 (25% EtOAc–hexane). 1H NMR (500 MHz,
CDCl3): δ = 1.38 (t, J = 7.1 Hz, 3 H, Et), 2.82 (s, 3 H, Me),
3.97 (s, 3 H, Me), 4.33 (q, J = 7.1 Hz, 2 H, Et), 7.40–7.49 (m,
2 H, 2 × CH), 7.49–7.60 (m, 1 H, CH), 7.63–7.71 (m, 1 H,
CH). 13C NMR (125 MHz, CDCl3): δ = 12.3, 14.4, 30.5,
60.4, 123.9, 127.3, 129.0, 129.4, 129.8, 130.0, 131.5, 134.6,
137.8, 147.1, 154.3, 163.8. Anal. Calcd for C16H15ClN2O2S:
C, 57.40; H, 4.52; N, 8.37. Found: C, 57.02; H, 4.75; N, 8.50.
1,5-Dimethyl-2-phenyl-1H-thieno[2,3-d]imidazole (13):
yield: 92%; mp 110–115 °C; Rf 0.20 (25% EtOAc–hexane).
1H NMR (500 MHz, CDCl3): δ = 2.56 (s, 3 H, Me), 3.82 (s,
3 H, NMe), 6.62 (s, 1 H, CH), 7.34–7.45 (m, 1 H, CH), 7.48
(t, J = 7.8 Hz, 2 H, 2 × CH), 7.67 (d, J = 7.1 Hz, 2 H, 2 × CH).
13C NMR (125 MHz, CDCl3): δ = 17.0, 33.7, 106.8, 128.6,
128.7, 130.7, 137.9, 138.2, 141.8, 150.7. Anal. Calcd for
C13H12N2S: C, 68.38; H, 5.30; N, 12.27. Found: C, 68.12; H,
5.50; N, 12.45.
(17) Binder, D.; Habison, G.; Noe, C. R. Synthesis 1977, 255.
(18) Bonafoux, D.; Abibi, A.; Bettencourt, B.; Burchat, A.;
Ericsson, A.; Harris, C. M.; Kebede, T.; Morytko, M.;
Mcpherson, M.; Wallace, G.; Wu, X. Bioorg. Med. Chem.
Lett. 2011, 21, 1861.
(19) General Procedure for Amidines Cyclization: A round-
bottom flask was charged with N′-halothiophenylamidine
(0.84 mmol), K2CO3 (1.68 mmol), DMEDA (0.084 mmol)
and anhyd DMF (3 mL). To the stirred mixture was then
added powdered CuI (0.042 mmol) under Ar. The stirred
mixture was heated under Ar and monitored by TLC,
evaporated, diluted with CH2Cl2 (100 mL), and filtered. The
organic layer was washed with H2O (2 × 50 mL), dried over
Na2SO4, filtered and concentrated to give the pure product.
Ethyl 1,6-Dimethyl-2-phenyl-1H-thieno[2,3-d]imidazole-
5-carboxylate (4a): yield: 91%; mp 118–120 °C; Rf 0.38
(25% EtOAc–hexane). 1H NMR (500 MHz, CDCl3): δ =
1.37 (t, J = 9.0 Hz, 3 H, Et), 2.82 (s, 3 H, Me), 3.95 (s, 3 H,
Me), 4.33 (q, J = 9.0 Hz, 2 H, Et), 7.45–7.55 (m, 3 H, 3 ×
CH), 7.55–7.75 (m, 2 H, 2 × CH). 13C NMR (125 MHz,
Synlett 2014, 25, 965–968
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