Synthesis of imidazole-4-carboxylic acids via solid-phase bound 3-N,N-(dimethylamino)-2-isocyanoacrylate

Article abstract of DOI:10.1016/j.tetlet.2003.12.158

The novel 3-N,N-(dimethylamino)isocyanoacrylate-Wang-resin is used for the synthesis of imidazole-4-carboxylic acids. The syntheses are performed in a microwave reactor with reaction times of only 15min at 220°C in the solvent dimethoxyethane.

Full text of DOI:10.1016/j.tetlet.2003.12.158

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2219–2221
Synthesis of imidazole-4-carboxylic acids via solid-phase bound
3-N,N-(dimethylamino)-2-isocyanoacrylate
Bernd Henkel*
Morphochem AG, Gmunder Str. 37-37A, D-81379 M€unchen, Germany
Received 4 December 2003; revised 17 December 2003; accepted 23 December 2003
Abstract—The novel 3-N,N-(dimethylamino)isocyanoacrylate-Wang-resin is used for the synthesis of imidazole-4-carboxylic acids.
The syntheses are performed in a microwave reactor with reaction times of only 15 min at 220 ꢀC in the solvent dimethoxyethane.
ꢁ 2004 Elsevier Ltd. All rights reserved.
The imidazole system can be found in numerous medi-
cally relevant compounds such as the fungicide Keto-
conazole1 and its relatives,the benzodiazepine
antagonist Flumazenil,2 the antineoplastic drug Dacar-
bazine,3 the antibiotic Metronidazole,4 the antiulcer-
ative agent Cimetidine,5 the antihyperthyroid drug
Methimazole,6 the prohormone Thyroliberin,7 the
muscarinic receptor agonist Pilocarpine8 and the hyp-
notic agent Etomidate9 (Scheme 1).
4-imidazole carboxylic acids represent a special case due
to the formation of regioisomeric mixtures upon alkyl-
ation of 4-imidazole carboxylate. A solution to this
synthetic problem was first reported by Allgeier11 and
later by Helal and Lucas12 who both used 3-N,N-
(dimethylamino)isocyanoacrylate as starting material,
which was reacted with different amines. This afforded
quite long reaction times especially when using aromatic
or sterically hindered amines. The applicability of 3-
N,N-(dimethylamino)isocyanoacrylate for the synthesis
of different heterocycles has been communicated else-
where.13
Different synthetic strategies for this nucleus are
described in the literature,10 whereby 1-substituted
Here,the use of resin-bound 3- N,N-(dimethylamino)-
isocyanoacrylate is described for the synthesis of
1-substituted 4-imidazolecarboxylates. HMBA-linker
bound 3-N,N-(dimethylamino)isocyanoacrylate (4-(hy-
droxymethyl)benzoic acid ¼ HMBA) has already been
used for the synthesis of thiazoles13 (Scheme 2).
O
N
O
N
O
N
NH2
N
H
N
N N N
O
Flumazenil
Dacarbazine
Wang-resin bound 3-N,N-(dimethylamino)isocyano-
acrylate was obtained simply by reacting a twofold
excess of the potassium salt14 of isocyanocarboxylic acid
with (4-bromomethylphenoxy)methyl polystyrene in
DMF.15 Thereafter the intermediate so obtained was
treated with dimethylformamide diethyl acetal in a
mixture of ethanol and THF (Scheme 3). The loading
could be determined as already cited in another article16
and was 0.36 mmol/g.
OH
H
N
CN
S
N
O2N
N
N
N
N
H
N
H
Metronidazole
Cimetidine
Scheme 1. Examples of imidazole-containing drugs.
Different protocols were tested for the reaction of resin-
bound 3-N,N-(dimethylamino)isocyanoacrylate with
amines. The best results were obtained with the following
process: The amine was added in an eightfold excess to
the resin,which was swollen in dimethoxyethane
* Tel.: +49-89-780050; fax: +49-89-78005555; e-mail: bernd.henkel@
morphochem.de
0040-4039/$ - see front matter ꢁ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.158

2220
B. Henkel /Tetrahedron Letters 45 (2004) 2219–2221
O
R1
O
O
R1 NH2
C
R1
O
N+
N
O
LiOH
N
N
S
O
N
O
N
S
R3
HO
R2 CHO
R3 COSH
R3
R2
R2
Scheme 2. Synthesis of thiazoles via HMBA-linker bound 3-N,N-(dimethylamino)isocyanoacrylate.
O
C
N+
O
O
C
O
N+
O
O
DMF
+
Br
KO
O
O
C
N+
N
N
O
O
Scheme 3. Preparation of Wang-resin-bound 3-N,N-(dimethylamino)isocyanoacrylate.
in a Smith Process glass vial. The reaction mixture was
heated in the sealed vial upon microwave irradiation to
220 ꢀC for 15 min. The resin was washed thoroughly and
afterwards treated with 50% TFA in dichloromethane
for 60 min. Crude products were purified via preparative
HPLC using a methanol/water gradient giving yields
from 20% to 90% (Scheme 4).17
The reaction proceeded well with different aromatic and
aliphatic amines. Hydroxy groups have no negative
O
O
C
O
N+
Microwave
N
N
TFA
OH
N
N
O
O
HO
H2N R
+
220°C
N
R
R
H2N
32%
45%
RNH2 =
H2N
H2N
47%
64%
N
H2N
20%
40%
H
Cl
H2N
H2N
H2N
F
H2N
35%
82%
N
37%
90%
O
H2N
N
H2N
OH
23%
H2N
Scheme 4. Examples of the 1-substituted 4-imidazole carboxylates prepared with their isolated yields.

B. Henkel /Tetrahedron Letters 45 (2004) 2219–2221
2221
H
O
O
O
C
N+
N
H2N R
NHR
N
N
N
O
O
O
α-Addition
N
R
Scheme 5. Proposed mechanism for the synthesis of 1-substituted 4-imidazole carboxylates.
10. Ebel,K. In Houben-Weyl: Methoden der organischen
Chemie, Hetarene III, 1H-Imidazole; Schaumann,E.,
Ed.; Georg-Thieme: Stuttgart,NY,1994; pp 1–215.
11. Allgeier,H. Eur. Pat. Appl. EP 0248414A2,1987; Chem.
Abstr. 1987, 108,112460.
impact on the reaction. In the case of phenylhydrazine
and tert-butylamine only poor yields were obtained,in
the latter example due to steric hindrance.
For the reaction of resin-bound 3-N,N-(dimethylamino)-
isocyanoacrylate with amines a mechanism involving
a-addition of the amine to the isocyanide can be proposed
similar to that already described in the literature18 where
heavy metal salts were used as catalysts (Scheme 5).
12. Helal,C. J.; Lucas,J. C.
4134.
13. Henkel,B.; Westner,B.; D omling,A. Synlett 2003,2410–
Org. Lett. 2002, 4,4133–
€
2413.
14. Hoppe,I.; Sch ollkopf,U. Chem. Ber. 1976, 109,482–487.
€
15. (a) Henkel,B. PCT Int. Appl. WO 2003051795,2003;
Chem. Abstr. 2003, 139,68959; (b) Resin-bound 3- N,N-
(dimethylamino)-2-isocyanoacrylate is available from Pri-
aton,Bahnhofstrasse 9-15,D-82327 Tutzing,Germany
(www.priaton.de).
In conclusion,the resin-based synthesis of 1-substituted
4-imidazole carboxylates is reported. The majority of
these compounds could be obtained in viable yields in
extremely short reaction times due to execution of the
reactions under microwave conditions.
16. Henkel,B.; Weber,L. Synlett 2002,1877–1879.
17. Representative example: Synthesis of 1-pyridine-3-ylmethyl-
1H-imidazole-4-carboxylic acid: 500 mg of Wang-resin
bound 3-N,N-(dimethylamino)isocyanoacrylate (0.18 mmol)
was placed in a Smith Process glass vial together with
4 mL of dimethoxyethane and 0.146 mL of 3-(amino-
methyl)pyridine (1.44 mmol). The vial was sealed and
heated to 220 ꢀC for 15 min with a Smith Creator
Microwave System from Personal Chemistry. The vial
was allowed to cool and the lid was removed. Then the
resin was washed three times with dimethoxyethane and
three times with methanol. The resin was dried under high
vacuum and thereafter treated with 50% trifluoroacetic
acid in dichloromethane for 60 min. After the resin had
been filtered off,the resulting solution was evaporated to
dryness. The crude product was purified via preparative
HPLC (column Grom-Sil 120 ODS-5,50 · 20 mm,5 lm,
flow 30 mL/min,gradient 10–100% A in 15 min,solvent
A ¼ methanol + 0.5% acetic acid,solvent B ¼ water + 0.5%
References and notes
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1
acetic acid). Yield: 30 mg (82%). H NMR (400 MHz, d6-
DMSO): d 5.44 (s,2H,CH 2); 7.63 (m,1H,CH); 8.04 (d,
1H,CH, J ¼ 7:8 Hz); 8.17 (s,1H,CH); 8.51 (s,1H,CH);
8.69 (s,1H,CH); 8.78 (s,1H,CH).
13C NMR (100 MHz,
d6-DMSO): d 47.9; 125.0; 126.1; 130.8; 133.1; 138.9; 146.9;
147.1; 158.7; 161.7.
9. Godefroi,E. F.; Janssen,P. A. J.; van der Eycken,C. A.
M.; van Heertum,A. H. M. T.; Niemegeers,C. J. E. J.
Med. Chem. 1965, 8,220–223.
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Tetrahedron