Solid-Supported Synthesis of Imidazoles: A Strategy for Direct Resin-Attachment to the Imidazole Core

Full text of DOI:10.1021/jo980027p

2800
J . Org. Chem. 1998, 63, 2800-2801
Sch em e 1
Solid -Su p p or ted Syn th esis of Im id a zoles: A
Str a tegy for Dir ect Resin -Atta ch m en t to th e
Im id a zole Cor e
Mark T. Bilodeau* and April M. Cunningham
Department of Medicinal Chemistry, Merck Research
Laboratories, West Point, Pennsylvania 19486
Received J anuary 9, 1998
Within the field of combinatorial chemistry there is a
flourishing interest in the development of methods for the
solid-phase synthesis of heterocycles.1 In the most useful
examples, a wide range of chemical functionality is tolerated,
and independent variation of several substituents is possible.
In many cases, substituent-based functional group handles
are employed for resin attachment, and this inherently limits
library diversity. In contrast, linking directly to a hetero-
cyclic structure is a valuable approach since the substituents
around the pharmacophore can be freely varied.2 In this
paper, we describe new resin-based chemistry for the
straightforward construction of 2,4,5-triarylimidazoles where
the three substituents are independently varied on the solid
support. Our process relies on a new imidazole linking
method where attachment is achieved through an imidazole
core nitrogen.3 In addition, we have developed a strategy
for the purification of the imidazoles before cleavage from
the resin.
Ta ble 1. Resu lts fr om a Libr a r y of Tw elve
Tr ia r ylim id a zoles
Our route utilizes a mu¨nchnone 3 + 2 cycloaddition
reaction in the key bond-forming step.4 Mu¨nchnone cycload-
dition reactions with activated alkynes to form pyrroles
(after elimination of carbon dioxide) have been developed
for the solid phase.5 While the analogous reaction of a
mu¨nchnone with a nitrile to provide an imidazole is not
viable due to the low reactivity of nitriles, Ferraccioli et al.
have reported that in solution aryltosylimines will react with
mu¨nchnones to provide imidazoles.6 While the yields of
these reactions are generally low, this is at least partly due
to the potential for mu¨nchnones to self-condense.4,6 Self-
condensation is a side reaction that can be readily sup-
pressed in a solid-phase approach.
Our successful translation of this chemistry to the solid-
phase is shown in the generic reaction sequence in Scheme
1. The commercially available polystyrene-poly(ethylene
glycol) graft copolymer resin 17 was employed in a standard
reductive alkylation protocol with an amino acid methyl
ester (5 equiv) until such a time as the aldehyde functional-
ity was consumed (as judged by IR and a qualitative 2,4-
dinitrophenylhydrazine test8) to provide 2. The resulting
amino ester was efficiently acylated with a carboxylic acid
yield,a purity,b
entry
R1
R2
phenyl
phenyl
4-F-phenyl
4-F-phenyl
R3
%
%
1
2
3
4
5
6
7
8
9
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
3-pyridyl
4-pyridyl
3-pyridyl
4-pyridyl
72
99
63
73
82
76
53
90
49
65
66
89
94
96
94
96
96
98
95
97
96
95
95
97
4-MeO-phenyl 3-pyridyl
4-MeO-phenyl 4-pyridyl
4-F-phenyl phenyl
4-F-phenyl phenyl
4-F-phenyl 4-F-phenyl
4-F-phenyl 4-F-phenyl
4-F-phenyl 4-MeO-phenyl 3-pyridyl
4-F-phenyl 4-MeO-phenyl 4-pyridyl
3-pyridyl
4-pyridyl
3-pyridyl
4-pyridyl
10
11
12
a
b
Yield based on theoretical loading of 0.41 mmol/g. Purity of
unpurified material determined by HPLC at 215 nM.
chloride (10 equiv) employing diisopropylethylamine as the
base in CH2Cl2. Cleavage of representative samples at this
stage indicated that resin loading approximated the manu-
facturer’s specification (0.41 mmol/g). The resulting R-amido
ester was then subjected to KOH hydrolysis in 3:1 dioxane/
H2O to provide the carboxylic acid 3.9
(1) For a recent review see: Balkenhohl, F.; von dem Bussche-Hu¨nnefeld,
C.; Lansky, A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288-
2337.
(2) Backes, B. J .; Ellman, J . A. Curr. Opin. Chem. Biol. 1997, 1, 86-93.
(3) Unrelated polymer-based syntheses of imidazoles have been reported
that use standard imidazole substituent-based handles for resin attach-
ment: Sarshar, S.; Siev, D.; Mjalli, A. M. M. Tetrahedron Lett. 1996, 37,
835-838. Zhang, C.; Moran, E. J .; Woiwode, T. F.; Short, K. M.; Mjalli, A.
M. M. Tetrahedron Lett. 1996, 37, 751-754.
Treatment of the resin-bound acid 3 under modified
conditions of EDC (10 equiv) and tosylimine (10 equiv) in
CH2Cl2 at ambient temperature for 24-48 h led initially to
the intermediate mu¨nchnone 4. Subsequent cycloaddition
of this mu¨nchnone 4 with the tosylimine, followed by
elimination of toluenesulfinic acid and CO2, provided the
polymer-linked imidazole.
(4) Potts, K. T. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley-Interscience: New York, 1984; Vol. 2, pp 1-82.
(5) (a) Strocker, A. M.; Keating, T. A.; Tempest, P. A.; Armstrong, R. W.
Tetrahedron Lett. 1996, 37, 1149-1152. (b) Mjalli, A. M. M.; Srashar, S.;
Baiga, T. J . Tetrahedron Lett. 1996, 37, 2943-2946.
(6) Consonni, R.; Croce, P. D.; Ferraccioli, R.; La Rosa, C. J . Chem. Res.,
Synop. 1991, 188-189.
(7) ArgoGel-MB-CHO, Argonaut Technologies Inc.
(8) Shriner, R. L.; Fuson, R. C.; Curtin, D. Y.; Morrill, T. C. The
Systematic Identification of Organic Compounds; J ohn Wiley & Sons: New
York, 1980; pp 162-163.
(9) Hankins, M. G.; Hayashita, T.; Kasprzyk, S. P.; Bartsch, R. A. Anal.
Chem. 1996, 68, 2811-2817.
S0022-3263(98)00027-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/07/1998

Communications
J . Org. Chem., Vol. 63, No. 9, 1998 2801
F igu r e 1. 1H NMR of compound 7 after cleavage from the resin.
The 4-alkoxy-2-methoxybenzylic group is a very robust
linker for imidazoles, but we were able to take advantage
of this to obtain products of high purity. We followed the
cycloaddition step with a washing step employing 90% TFA/
H2O for 1 h. Importantly, the imidazole (5) was not removed
from the resin; rather, unreacted starting materials and
non-imidazole byproducts were removed during this washing.
This effectively served as a purification step of the resin-
bound imidazole. The imidazole was then found to be
efficiently and cleanly liberated from the resin by treatment
with glacial acetic acid at 100 °C for 2 h to provide 6.
A triarylimidazole library of 12 compounds was con-
structed to demonstrate the viability and generality of this
chemistry. The substituent variations that were employed
are shown in Table 1. Two arylglycines, three acid chlorides,
and two pyridyltosylimines10 were employed in the library
for a 2 × 3 × 2 matrix. All product combinations were
obtained in good to excellent yields after cleavage from the
resin. The average yield was 73% over the six-step sequence
(based on a theoretical loading of 0.41 mmol/g). More
importantly, the products were obtained in uniformly high
purity without purification. The average HPLC purity (UV
detection at 215 nM) for the 12 imidazoles in the library was
96%. All products were characterized by 1H NMR and by
mass spectrometry. The 1H NMR spectra also indicated the
products were formed in high purity, and a representative
example is shown for compound 7 in MeOH-d4 (Table 1,
entry 12) in Figure 1.
moieties.11 In traditional peg-grafted polystyrene resins the
attachment is a more labile benzylic ether bond. We had
previously followed a similar synthetic route employing a
resin of this latter type and observed very large quantities
of poly(ethylene glycol) contaminants in our cleaved prod-
ucts.
Comparison of the products also demonstrated that the
reactions were completely regioselective as they have been
reported to be in solution.6 In a nonregioselective reaction,
entries 3 and 7 (as well as 4 and 8) would be expected to
produce products in common. However, the products pro-
duced were unique, and neither product showed any level
of contamination by the other (by HPLC or NMR).
Our linking strategy, while requiring fairly harsh cleavage
conditions, was dependent on the use of the 4-alkoxy-2-
methoxybenzylic linking group. The attempted use of more
electron-rich potential imidazole linking groups (such as
Rink or PAL-type linkers) failed in the mu¨nchnone forma-
tion/cycloaddition step.12 It appears in these cases that the
mu¨nchnone is cleaved from the resin during the reaction as
no material can be recovered from the resin after this step.
However, as described above, the robustness of the current
linker proved to be an advantage to obtaining pure products.
In summary, we have developed a very efficient sequence
for the solid-phase synthesis of imidazoles employing a new
linking strategy involving direct linkage to the imidazole
core. The process utilizes a mu¨nchnone cycloaddition in the
key bond-forming step and allows for the independent
variation of three substituents on the resin. The method
also includes a strategy for the purification of the imidazoles
on the resin before cleavage. While we anticipate that this
chemistry will be compatible with a large range of chemical
functionality, the true test of this assertion will come with
future efforts to create large libraries employing this method.
It is particularly notable that under the cleavage condi-
tions very little, if any, poly(ethylene glycol) impurities were
observed in the 1H NMR spectra (generally a broad signal
at ∼3.6 ppm). This is a clear indication of the stability of
resins such as 1. Resin 1 contains an inert bis-homobenzylic
ether bond between the poly(ethylene glycol) and polystyrene
(10) Tosylimines were formed by azeotropic removal of water from a
refluxing toluene mixture of the appropriate aldehyde, toluenesulfonamide,
and catalytic toluenesulfonic acid. See the Supporting Information for
details.
Ack n ow led gm en t. We appreciate the helpful sugges-
tions of Professor David A. Evans (Harvard University).
Dr. Charles W. Ross III is acknowledged for obtaining mass
spectral data.
(11) Labadie, J . W.; Deegan, T. L.; Gooding, O. W.; Heisler, K.; Newcomb,
W. S.; Porco, J . A., J r., Tran, T. H.; van Eikeren, P. Proc. Am. Chem. Soc,
Div. of Polym. Matls: Sci. Eng. 1996, 7, 389-90. Porco, J . A., J r.; Deegan,
T.; Devonport, W.; Gooding, O. W.; Heisler, K. H.; Labadie, J . W.; Newcomb,
B.; Nguyen, C.; van Eikeren, P.; Wong, J .; Wright, P. Mol. Diversity 1996,
2, 197-206.
Su p p or tin g In for m a tion Ava ila ble: Experimental details for
synthesis of the tosylimines and the library and 1H NMR, mass
spectral, and HPLC data for all compounds (15 pages).
(12) The same observation has been reported for the Rink linker; see ref
5a, footnote 11.
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