Cyano-substituted 2-carboxyimidazoles: Synthesis of 4-cyano-1-{[2- (trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-carboxylate potassium salt

Article abstract of DOI:10.1055/s-0028-1083173

The first example of a monocyano-substituted 2-carboxyimidazole is reported. A synthesis of potassium 4-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}- 1H-imidazole-2-carboxylate (2) is demonstrated where the carboxylate group is introduced via bromine-magnesium exchange on a SEM-protected cyanoimidazole followed by reaction with ethyl cyanoformate. The synthesis includes the equilibration of a regioisomeric mixture of SEM-protected imidazoles to give a single product. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083173

SHORT PAPER
3377
Cyano-Substituted 2-Carboxyimidazoles: Synthesis of 4-Cyano-1-{[2-(tri-
methylsilyl)ethoxy]methyl}-1H-imidazole-2-carboxylate Potassium Salt
C
yano-Substituted 2-C
a
arboxyimid
r
a
zoles k J. Wall,* Carsten Schubert, Carl R. Illig
Johnson and Johnson Pharmaceutical Research and Development, LLC, 665 Stockton Drive, Exton, PA 19031, USA
Fax +1(610)4588249; E-mail: mwall2@prdus.jnj.com
Received 30 May 2008; revised 22 July 2008
H
O
N
N
O
N
Abstract: The first example of a monocyano-substituted 2-car-
boxyimidazole is reported. A synthesis of potassium 4-cyano-1-
{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-carboxylate (2)
is demonstrated where the carboxylate group is introduced via bro-
mine–magnesium exchange on a SEM-protected cyanoimidazole
followed by reaction with ethyl cyanoformate. The synthesis in-
cludes the equilibration of a regioisomeric mixture of SEM-protect-
ed imidazoles to give a single product.
NBS
SEMCl
OEt
N
OEt
SEM
3
4
Br
NC
O
N
N
O
OEt
N
N
see text
X
OEt
Key words: cyanoimidazole, bromine–magnesium exchange, car-
boxylation, protecting group migration
SEM
SEM
6
5
Scheme 1 Attempted route to 4(5)-cyanoimidazole-2-carboxylate
In a recent drug discovery program to evaluate kinase in-
hibitors 1 for the type III receptor tyrosine kinase FMS,
we needed to prepare the previously unknown 4(5)-cy-
anoimidazole-2-carboxylic acid derivative 2 (Figure 1)
for the synthesis of a potential drug substance. Herein we
describe the development of a scalable synthetic route for
the preparation of compound 2, which has now been pre-
pared in kilogram quantities utilizing the synthetic route
described here.
cyanoimidazole 6. However, while we could prepare the
bromide 5, the conversion of the bromide into the cy-
anoimidazole proved to be problematic. Copper cyanide
in refluxing N,N-dimethylformamide resulted in loss of
the SEM group; palladium-catalyzed methods using sodi-
um cyanide/copper(I) iodide1 or zinc cyanide2 failed to
give any product; attempts to produce the organomagne-
sium species with isopropylmagnesium chloride also
failed. Attempts to synthesize an iodoimidazole analogue
were also unsuccessful and led to loss of the protecting
group or decomposition of the starting material.
NC
NC
O
O
N
N
N
N
H
O–K+
HN
R
We then turned to an alternate route shown in Scheme 2
where the cyano was first installed in the imidazole core
followed by introduction of the carboxylate. We prepared
the cyanoimidazole 7 from commercially available imida-
zole-4(5)-carboxaldehyde using hydroxylamine and ace-
tic anhydride according to the procedure of Kawakami.3
Protection then with SEMCl4 gave 8a/8b as a mixture of
regioisomers with the 4-cyano regioisomer 8a being the
major product, assigned by 1D-NOESY NMR experi-
ments. For reactions run on a small scale, we found that
we could get greater than 80:20 ratios of regioisomers 8a/
8b and then remove the minor isomer by chromatography.
However, for larger scale reactions, the ratio was reduced
to 60:40 and the separation proved to be more difficult and
resulted in considerable loss of material and low yields.
We then brominated both the 4-regioisomer 8a and the 5-
regioisomer 8b, using the radical conditions reported by
Rapoport5 for the bromination of methyl 1-methyl-1H-im-
idazole-5-carboxylate and, surprisingly, found that both
regioisomers gave the same product, assigned by 1D-
NOESY NMR experiments as the 4-regioisomer 9. Pre-
sumably, the SEM group can migrate during the reaction
to give the thermodynamic product, thus enabling us to
run the bromination on the mixture of regioisomers with-
SEM
1
2
Figure 1 Target structures
Although several syntheses of 2-carboxyimidazoles and
their derivatives exist in the literature, we were surprised
to find at the time we initiated these efforts, that no mono-
cyano-substituted derivatives of this sort, protected or un-
protected, had ever been reported. Initially, we envisioned
starting with the commercially available imidazole-2-car-
boxylate 3, where the carboxylate functionality is already
incorporated in the imidazole core, and synthesizing the
ester 6 of the desired target by installation of the nitrile ac-
cording to the route shown in Scheme 1. Protection with a
[2-(trimethylsilyl)ethoxy]methyl (SEM) group would
give only one possible isomer circumventing the need for
separation of regioisomers, followed by bromination and
then conversion of the bromoimidazole 5 into the desired
SYNTHESIS 2008, No. 21, pp 3377–3379
x
x.
x
x
.
2
0
0
8
Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083173; Art ID: M02408SS
© Georg Thieme Verlag Stuttgart · New York

3378
M. J. Wall et al.
SHORT PAPER
SEM
NC
NC
NC
NC
SEMCl
NBS
N
N
N
N
N
N
Br
+
K2CO3
acetone
90%
AIBN, CCl4
60 °C
N
H
N
SEM
SEM
8a
8b
77%
9
7
60:40 mixture
NC
i-PrMgCl
O
NC
O
N
N
O
O
KOH
N
EtOH
90%
O–K+
N
SEM
SEM
O
CN
2
6
74%
Scheme 2 Synthesis of potassium 4-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-carboxylate
2, a key intermediate in the synthesis of potent FMS ki-
nase inhibitors was produced by an efficient four-step
route from a known precursor. The synthesis includes a
thermodynamic equilibration of a SEM-protecting group
on a mixture of regioisomers to give a single product.
Crystals were obtained from overlaying a soln of 2 in EtOH with
Et2O. Diffraction data were collected on a Rigaku M007HF gener-
ator at 40 kV/10 mA (AFC11-goniometer, Saturn944 CCD) using
multilayered optics monochromated Cu-Ka radiation. Data were re-
duced and corrected in d*trek 97L (Rigaku) and the structure was
solved by direct methods using the SXTL-Shelx087 suite (Bruker-
AXS). NMR spectra were obtained on a Bruker Advance spectro-
meter at 400 MHz (1H NMR) and 100 MHz (13C NMR). MS data
were obtained with a Thermo Electron LCQ Classic or Thermo
Finnigan Trace spectrometer. HRMS data were obtained using Mi-
cromass Autospec E OA-TOF mass spectrometer. Elemental analy-
ses were performed at QTI (Whitehouse, NJ). Chemicals were
purchased from commercial suppliers and used without further pu-
rification.
Figure 2 X-ray crystal structure of 2
out the need for chromatographic purification of 8a/8b.
Similar equilibrations of regioisomeric mixtures of N-
protected imidazoles (SEM, MOM, BOM, N,N-dimethyl-
sulfamoyl, and benzyl) have been reported, where the
mixture of regioisomers is heated in the presence of a cat-
alytic amount of the alkyl halide of the respective protect-
1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-imidazole-4-carboni-
trile (8a) and 1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-imida-
zole-5-carbonitrile (8b)
ing group (i.e., SEMCl, for SEM-protected imidazoles).6 To a flask charged with 1H-imidazole-4-carbonitrile3 (7, 5.0 g, 52
mmol), K2CO3 (14.0 g, 104 mmol), and acetone (50 mL) was slowly
added SEMCl (9.5 mL, 53 mmol), and the mixture allowed to stir at
Presumably, in the synthesis of 9, N-bromosuccinimide
could generate a catalytic amount of SEMBr that would
r.t. for 10 h. The mixture was diluted with EtOAc (200 mL), washed
effect the equilibration. The bromide 9 was then treated
with H2O (200 mL) and brine (200 mL), and the organic layer dried
with isopropylmagnesium chloride to give the Grignard
(MgSO4). The crude product was purified by passing through a
short silica gel plug (30% EtOAc–hexane) to give 8a/8b (10.4 g,
reagent according to the procedure of Knochel,7 followed
by reaction with ethyl cyanoformate to give the desired
imidazolecarboxylate 6. The ester was then hydrolyzed
with potassium hydroxide and the final compound 2 was
conveniently isolated as the potassium salt, since the free
acid was prone to decarboxylation.
90%, 60:40 mixture) as a colorless oil that was used as a mixture in
the next step. For characterization, a sample of the isomers were
separated on silica gel; 8a: Rf = 0.50 (hexane–EtOAc, 1:1); 8b:
Rf = 0.35 (hexane–EtOAc, 1:1).
1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-imidazole-4-carboni-
In order to assign unambiguously the structure of 2, an X- trile (8a)
1H NMR (400 MHz, CDCl3): d = 7.68 (d, J = 1.3 Hz, 1 H), 7.65 (d,
J = 1.3 Hz, 1 H), 5.35 (s, 2 H), 3.54 (t, J = 8.1 Hz, 2 H), 0.94 (t,
J = 8.1 Hz, 2 H), –0.03 (s, 9 H).
13C NMR (101 MHz, CDCl3): d = 140.1, 128.9, 116.4, 116.1, 78.1,
68.7, 19.2, 0.0.
ray crystal structure was obtained, shown in Figure 2.8
The structure is in agreement with the spectral assign-
ments demonstrating synthesis of the 4-cyano regioiso-
mer.
In conclusion, we have provided a first synthesis of the
previously unknown monocyano-substituted 2-carboxy-
imidazole. SEM-protected 4-cyano-2-carboxyimidazole
MS (ESI+): m/z = 223.9 [M + H].
HRMS (FAB): m/z [M + H] calcd for C10H18N3OSi: 224.1222;
found: 224.1219.
Synthesis 2008, No. 21, 3377–3379 © Thieme Stuttgart · New York

SHORT PAPER
Cyano-Substituted 2-Carboxyimidazoles
3379
1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-imidazole-5-carboni-
trile (8b)
Potassium 4-Cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-
imidazole-2-carboxylate (2)
To a soln of 6 (4.0 g, 13 mmol) in EtOH (30 mL) was added 6 M
KOH (2.0 mL) and the reaction was stirred for 30 min and then con-
centrated. The solid thus obtained was triturated (MTBE) to give 2
(3.7 g, 90%) as a white solid; mp 215–217 °C.
1H NMR (400 MHz, CD3OD): d = 7.98 (s, 1 H), 5.92 (s, 2 H), 3.62
(t, J = 8.3 Hz, 2 H), 0.94 (t, J = 8.3 Hz, 2 H), 0.00 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): d = 159.6, 148.8, 130.1, 116.1,
109.8, 75.9, 65.6, 17.3, –1.3.
1H NMR (400 MHz, CDCl3): d = 7.79 (d, J = 0.8 Hz, 1 H), 7.00 (d,
J = 0.8 Hz, 1 H), 5.42 (s, 2 H), 3.62 (t, J = 8.1 Hz, 2 H), 0.95 (t,
J = 8.1 Hz, 2 H), –0.02 (s, 9 H).
13C NMR (101 MHz, CDCl3): d = 142.2, 141.5, 112.1, 106.7, 76.7,
69.0, 19.1, 0.0.
MS (ESI+): m/z = 223.9 [M + H].
HRMS (FAB): m/z [M + H] calcd for C10H18N3OSi: 224.1222;
found: 224.1220.
MS (ESI–): m/z = 266.0 [M – H].
2-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-4-
carbonitrile (9)
HRMS (FAB): m/z [M + K] calcd for C11H16K2N3O3Si: 344.0235;
found: 344.0249.
To a soln of 8a/8b (7.0 g, 31 mmol)(60:40 mixture of regioisomers)
in CCl4 (50 mL) was added NBS (6.1 g, 34 mmol) and AIBN (cat.),
and the mixture was heated at 60 °C for 4 h. The reaction was cooled
to r.t. and filtered and the filtrate was washed with sat. NaHCO3 soln
and then concentrated. The crude product was passed through a
short plug of silica gel (30% EtOAc–hexane) to give 9 (7.3 g, 77%)
as a white solid; Rf = 0.30 (hexane–EtOAc, 10:2).
1H NMR (400 MHz, CDCl3): d = 7.64 (s, 1 H), 5.32 (s, 2 H), 3.56
(t, J = 8.3 Hz, 2 H), 0.94 (t, J = 8.3 Hz, 2 H), –0.02 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): d = 133.4, 122.5, 114.3, 112.9,
76.5, 66.3, 17.1, –1.4.
Anal. Calcd for C11H16KN3O3Si: C, 43.25; H, 5.28; N, 13.76.
Found: C, 42.90; H, 5.17; N, 13.51.
References
(1) (a) Anderson, B. A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.;
Pagh, L. M.; Wepsiec, J. P. J. Org. Chem. 1998, 63, 8224.
(b) Takagi, K.; Okamoto, T.; Sakakibara, Y.; Oka, S. Chem.
Lett. 1973, 471.
(2) Selnick, H. G.; Smith, G. R.; Tebben, A. J. Synth. Commun.
1995, 25, 3255.
MS (CI, CH4): m/z = 302.1/304.1 [M + H].
(3) Kawakami, J.-I.; Kimura, K.; Yamaoka, M. Synthesis 2003,
677.
HRMS (FAB): m/z [M + H] calcd for C10H17BrN3OSi: 302.0324;
(4) Lipshutz, B. H.; Vaccaro, W.; Huff, B. Tetrahedron Lett.
1986, 27, 4095.
found: 302.0315.
(5) O’Connell, J. F.; Parquette, J.; Yelle, W. E.; Wang, W.;
Rapoport, H. Synthesis 1988, 767.
Ethyl 4-Cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imida-
zole-2-carboxylate (6)
(6) (a) He, Y.; Chen, Y.; Du, H.; Schmid, L. A.; Lovely, C. J.
Tetrahedron Lett. 2004, 45, 5529. (b) Sun, C.; Lin, X.;
Weinreb, S. M. J. Org. Chem. 2006, 71, 3159.
(c) Bhagavatula, L.; Premchandran, R. H.; Plata, D. J.; King,
S. A.; Morton, H. E. Heterocycles 2000, 53, 729.
(7) (a) Abarbri, M.; Thibonnet, J.; Berillon, L.; Dehmel, F.;
Rottlander, M.; Knochel, P. J. Org. Chem. 2000, 65, 4618.
(b) Dehmel, F.; Abarbri, M.; Knochel, P. Synlett 2000, 345.
(8) Accession number CCDC 694823. Crystal data of 2:
C11H16KN3O3Si, M = 305.46 g mol–1, colorless plates.
Monoclinic space group P21/c, a = 20.8(4), b = 26.29(5),
c = 11.52(2) Å, b = 96.24(3) °, V = 6263(2) Å3, T = –180 °C,
Z = 16, rcalcd = 1.296 g cm–3, m (Cu-Ka) = 3.781, multiscan,
F(000) = 2560, 40580 reflections in h(–20/20), k(–13/26),
l(–9/8) measured in the range 2.72° £ q £ 50.95°,
completeness 88%, 5979 unique reflections, Rint = 0.0987,
4703 reflections with Fo > 4s, 693 parameters, 0 restraints,
R1obs = 0.1365, wR2obs = 0.3996, R1all = 0.1595,
wR2all = 0.3996, GOOF = 1.544, largest difference peak and
hole 2.41/–0.97 eÅ–3.
To a soln of 9 (5.5 g, 18 mmol) in THF (60 mL) at –40 °C was added
dropwise 2 M i-PrMgCl in THF (10 mL). The mixture was allowed
to stir at –40 °C for 10 min and then cooled to –78 °C, and ethyl cy-
anoformate (3.0 g, 30 mmol) was added. The mixture was allowed
to attain r.t. and stirred for 1 h. The reaction was quenched with sat.
aq NH4Cl, diluted with EtOAc (200 mL), and washed with brine
(2 × 200 mL). The organic layer was dried (Na2SO4) and then con-
centrated. The product was purified by chromatography (silica gel,
30% EtOAc–hexane) to give 6 (4.0 g, 74%) as a colorless oil;
Rf = 0.25 (hexane–EtOAc, 10:2).
1H NMR (400 MHz, CDCl3): d = 7.79 (s, 1 H), 5.80 (s, 2 H), 4.46
(q, J = 7.1 Hz, 2 H), 3.61 (t, J = 8.3 Hz, 2 H), 1.45 (t, J = 7.1 Hz, 3
H), 0.96 (t, J = 8.3 Hz, 2 H), 0.00 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 158.1, 137.5, 130.8, 114.8, 113.5,
77.9, 68.0, 62.6, 17.8, 14.1, –1.5.
MS (ESI+): m/z = 296.1 [M + H].
HRMS (FAB): m/z [M + H] calcd for C13H22N3O3Si: 296.1430;
found: 296.1431.
Synthesis 2008, No. 21, 3377–3379 © Thieme Stuttgart · New York