Design and novel synthesis of aryl-heteroaryl-imidazole MAP kinase inhibitors

Article abstract of DOI:10.1016/S0040-4039(03)01834-3

Inhibitors of the MAP kinase p38, potentially useful for the treatment of rheumatoid arthritis and inflammatory diseases, were found to exhibit antifungal activity. We have developed a new diversity-oriented strategy leading to concise and efficient syntheses of known and new members of this compound class. The strategy is based on carbon-carbon cross-coupling reactions using N-protected 4,5-diiodo-imidazoles as the starting templates.

Full text of DOI:10.1016/S0040-4039(03)01834-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7115–7117
Design and novel synthesis of aryl-heteroaryl-imidazole MAP
kinase inhibitors
Markus R. Dobler
Syngenta Crop Protection AG, Lead Finding Chemistry, 4002 Basel, Switzerland
Received 4 April 2003; revised 14 April 2003; accepted 30 July 2003
Abstract—Inhibitors of the MAP kinase p38, potentially useful for the treatment of rheumatoid arthritis and inflammatory
diseases, were found to exhibit antifungal activity. We have developed a new diversity-oriented strategy leading to concise and
efficient syntheses of known and new members of this compound class. The strategy is based on carbonꢀcarbon cross-coupling
reactions using N-protected 4,5-diiodo-imidazoles as the starting templates.
© 2003 Elsevier Ltd. All rights reserved.
Chronic inflammatory diseases such as rheumatoid
arthritis and psoriasis affect millions of people. It is
now clear that inflammatory cytokines, such as inter-
leukin-1 and tumor necrosis factor-a, play an important
role in these diseases. The inhibition of the cytokine
interactions have been recognized as rewarding targets
for the development of tailor-made anti-inflammatory
drugs.1 Among the most promising small-molecular
anti-cytokine agents are inhibitors of p38MAP kinase
like SB 203580 (1).2
metallation and cross-coupling behavior of polyhalo-
genated imidazole templates.5,6
A potentially versatile and attractive route for the
synthesis of polyfunctionalized imidazoles is via the
sequential formation of imidazole anions and their
reactions with electrophiles. However, this approach is
complicated by the tendency of imidazole-4-yl and -5-yl
anions to rapidly equilibrate to imidazole-2-yl anions.7
We planned to overcome this problem by applying a
combination of metallation and metal–halogen
exchange reactions in combination with metal-catalyzed
cross-coupling reactions. The use of different ortho-
directing or blocking N-protecting groups was investi-
gated in order to broaden the scope of the
methodology. Following the work of Lindell5 and
Benhida6 we chose N-protected 4,5-diiodoimidazoles as
the starting materials. Methyl, benzyl and dimethylsul-
famoyl served as N-protecting groups.
Recently it was found that these kinase inhibitors also
act as powerful antifungal agents against phyto-patho-
gens.3 In order to explore this interesting biological
activity and to confirm it as a valid mode of action, we
have established a novel diversity-oriented synthetic
approach to this compound class (Fig. 1).
While numerous syntheses of substituted imidazoles are
described in the literature, mostly based on a cycliza-
tion or condensation approaches,4 little is known on the
Figure 1. Lead structure 1 and retrosynthetic aspects.
E-mail: markus.dobler@syngenta.com
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01834-3

7116
M. R. Dobler / Tetrahedron Letters 44 (2003) 7115–7117
First we reinvestigated5,6 the scope of the Grignard-type
cross-coupling with our starting template 2 (Scheme 1).
As expected the ortho-directing sulfamoyl N-protecting
group greatly enhanced the stability of the in situ
formed Mg-species. Sequential copper catalyzed cross-
coupling of the Grignard intermediate following
Knochel’s protocol,8 with a set of electrophiles, pro-
ceeded smoothly.
The diiodoimidazoles also served as versatile elec-
trophilic coupling partners for the Suzuki cross-coup-
ling reaction. The reactions with a wide range of
commercially available boronic acids were investigated
in close detail (Table 1).
The reactions proceeded with high initial regio-selectivi-
ty (C5ꢀC4) but in all cases subsequent bis-coupling
was observed. However,
a balance between the
Subsequent Sonogashira- or Heck-type coupling
worked equally well for a broad range of substrates and
coupling partners. Representative examples are given in
Scheme 2.
base and the base stability of the N-protecting group
was found to be crucial for high overall yields. Espe-
cially the use of the sulfamoyl group led to certain
limitations of the reaction conditions to choose from
Scheme 1. Reagents and conditions: (i) EtMgBr, THF, −20°C, 30 min; (ii) CuCN·2LiCl, 15 min; (iii) electrophile, 0°C, 2 h.
Scheme 2. Reagents and conditions: (i) Pd(OAc)2 (5%), CuI, K2CO3, PPh3 (10%), DMF, 80°C, 16 h (syringe pump addition); (ii)
Pd(OAc)2 (5%), Et3N, PPh3 (10%), DMF, 80°C, 16 h.
Table 1. Selected Suzuki reactions, conditions and isolated yields
Entry
R
P
Ar-B(OH)2
Conditions
11 (%)
12 (%)
13 (%)
1
2
3
I
I
I
Bn
Bn
Bn
4-F-Ph (2 equiv.) Na2CO3, EtOH, H2O, DME, Pd(PPh3)4, 95°C, 8 h 27
53
91
95
–
–
–
4-F-Ph (4 equiv.) Na2CO3, EtOH, H2O, DME, Pd(PPh3)4, 95°C, 16 h
3,4-(MeO)2-Ph (4 CsF, DMF, Pd(OAc)2, dioxane, 14, 80°C, 16 h
equiv.)
–
–
4
5
6
7
I
I
SO2NMe2
Me
Me
Ph (2 equiv.)
Ph (2 equiv.)
K2CO3, DMF, Pd(PPh3)4, 60°C, 12 h
CsF, DMF, Pd(OAc)2, dioxane, 14, 80°C, 12 h
16
24
–
24
48
–
–
–
79
65
4-MeO
Isoprenyl
4-F-Ph (2 equiv.) CsF, DMF, Pd(OAc)2, dioxane, 14, 80°C, 12 h
4-Pyridyl (2
equiv.)
3-MeO-Ph (2
equiv.)
Me
CsF, DMF, Pd(OAc)2, dioxane, 14, 80°C, 12 h
CsF, DMF, Pd(OAc)2, dioxane, 14, 80°C, 12 h
–
–
8
4-MeS
Bn
–
–
77

M. R. Dobler / Tetrahedron Letters 44 (2003) 7115–7117
7117
R. F.; Garigipati, R. S.; Bender, P. E.; Erhard, K. F.;
Krog, A. J.; Hofmann, G. A.; Sheldrake, P. L.;
McDonnell, P. C.; Kumar, S.; Young, P. R.; Adams, J.
L. Bioorg. Med. Chem. 1997, 5, 49–64.
2. Badger, A. M.; Bradbeer, J. N.; Votta, B.; Lee, J. C.;
Adams, J. L.; Griswold, D. E. J. Pharmacol. Exp.
Ther. 1996, 279, 1453–1461.
3. (a) Pillonel, C.; Meyer, T. Pestic. Sci. 1997, 49, 229–
236; (b) Mitani, A.; Ichinari, D.; Saiga, M.; Hama-
mura, H.; Sugiura, T. Jpn. Kokai Tokkyo Koho, 2000,
JP, JP 2000273088 A2, 28 pp.
Scheme 3. Reagents and conditions: (i) EtMgBr, THF, −20°C;
(ii) ZnCl2, −20°C to rt, 1 h; (iii) Pd(OAc)2, 14, reflux, 6 h.
4. For examples, see: (a) Gordon, T. D.; Singh, J.;
Hansen, P. E.; Morgan, B. A. Tetrahedron Lett. 1993,
34, 1901–1904; (b) Bilodeau, M. T.; Cunnigham, A. M.
J. Org. Chem. 1998, 63, 2800–2801; (c) Jetter, M. C.;
Reitz, A. B. Synthesis 1998, 829–831; (d) Njar, V. C.
O. Synthesis 2000, 2019–2028; (e); Bleicher, K. H.; Ger-
ber, F.; Wuthrich, Y.; Alanine, A.; Capretta, A. Tetra-
hedron Lett. 2002, 43, 7687–7690.
and often resulted in moderate to low reaction yields
(entry 4).
Both electron deficient and electron rich boronic acids
were found to react with the diiodoimidazole under the
highlighted conditions.
5. Carver, D. S.; Lindell, S. D.; Saville-Stones, E. A. Tet-
Exploration of Negishi-type cross-couplings completed
our investigation. The imidazol-4-yl-zinc reagent was
generated by treating 15 with Grignard reagent fol-
lowed by the addition of ZnCl2.8 The Negishi reaction
with 2-iodopyridine led to the desired arylpyridylimida-
zole (Scheme 3).
rahedron 1997, 53, 14481–14496.
6. Benhida, R.; Lezama, R.; Fourrey, J.-L. Tetrahedron
Lett. 1998, 39, 5963–5964.
7. (a) Groziak, M. P.; Wei, L. J. Org. Chem. 1991, 56,
4296–4300, ibid. 1992, 57, 3776–3780; (b) Takeuchi, Y.;
Kirk, K. L.; Cohen, L. A. J. Org. Chem. 1978, 43,
3570–3580; (c) Takeuchi, Y.; Yeh, H. J. C.; Kirk, K.
L.; Cohen, L. A. J. Org. Chem. 1978, 43, 3565–3570.
8. Rottlander, M.; Boymond, L.; Berillon, L.; Lepretre,
A.; Varchi, G.; Avolio, S.; Laaziri, H.; Queguiner, G.;
Ricci, A.; Cahiez, G.; Knochel, P. Chem. Eur. J. 2000,
6, 767–770.
Metallation followed by ZnCl2 addition was suitable
for preparing the imidazoyl-2-zinc coupling partners in
situ.9 An example is given in Scheme 4. The organozinc
reagent was cross-coupled with 2-iodopyridine to give
the desired bisarylpyridylimidazole. The use of 2-
iodopyridine gave a higher coupling yield than 2-bro-
mopyridine. Final deprotection was achieved by
hydrogenation.
9. Bell, A. S.; Roberts, D. A.; Ruddock, K. S. Tetra-
hedron Lett. 1988, 29, 5013–5016.
10. All new compounds were completely characterized and
gave satisfactory spectral and analytical data. Selected
data: Compound 10 (P=Bn, R=I) 1H NMR l: 7.53
(s, 1H); 7.24–7.19 (m, 3H); 7.08–7.02 (m, 2H); 5.02 (s,
2H); ES-MS m/z 411 (M+1); mp: 87–89°C (diethyl
ether). Compound 19 1H NMR l: 7.60 (s, 1H); 7.31–
7.28 (m, 3H); 7.06 (dd, 1H); 7.03–6.95 (m, 3H); 6.81 (d,
1H); 6.71–6.61 (m, 3H); 6.05 (s, 2H); 5.92 (s, 2H); 4.94
(s, 2H); ES-MS m/z 399 (M+1). Compound 20 1H
NMR l: 8.29 (d, 1H); 8.12 (d, 1H); 7.54 (dd, 1H);
7.02–6.88 (m, 6H); 6.68–6.59 (m, 3H); 6.57–6.42 (m,
3H); 5.80 (s, 2H); 5.82 (s, 2H); 5.53 (s, 2H); ES-MS
m/z 476 (M+1). Compound 21 1H NMR l: 8.43 (t,
1H); 7.81 (t, 1H); 7.22 (dd, 1H); 7.05–6.98 (m, 4H);
6.70 (d, 2H); 5.89 (s, 4H); ES-MS m/z 386 (M+1).
In summary, we have developed a concise and efficient
synthesis methodology leading to a structurally diverse
array of aryl-heteroaryl-imidazoles.10
References
1. (a) Brennan, F. M.; Feldmann, M. Curr. Opin.
Immunol. 1996, 8, 872–877; (b) Camussi, G.; Lupia, E.
Drugs 1998, 55, 613–620; (c) Gallagher, T. F.; Seibel,
G. L.; Kassis, S.; Laydon, J. T.; Blumenthal, M. J.;
Lee, J. C.; Lee, D.; Boehm, J. C.; Fier-Thompson, S.
M.; Abt, J. W.; Soreson, M. E.; Smietana, J. M.; Hall,
Scheme 4. Reagents and conditions: (i) tBuLi, THF, −78°C; (ii) ZnCl2, −78°C to rt, 1 h; (iii) Pd(OAc)2, 14, reflux, 4 h; (iv)
cyclohexadiene, Pd/C, reflux, 72 h.