Efficient synthesis of imidazoles from aldehydes and 1,2-diketones using microwave irradiation

Article abstract of DOI:10.1021/ol049682b

A simple, high-yielding synthesis of 2,4,5-trisubstituted imidazoles from 1,2-diketones and aldehydes in the presence of NH₄OAc is described. Under microwave irradiation, alkyl-, aryl-, and heteroaryl-substituted imidazoles are formed in yields ranging from 80 to 99%. Short syntheses of lepidiline B and trifenagrel illustrate the utility of this approach.

Full text of DOI:10.1021/ol049682b

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1453-1456
Efficient Synthesis of Imidazoles from
Aldehydes and 1,2-Diketones Using
Microwave Irradiation
Scott E. Wolkenberg,* David D. Wisnoski, William H. Leister, Yi Wang,
Zhijian Zhao, and Craig W. Lindsley
Department of Medicinal Chemistry, Technology Enabled Synthesis Group,
Merck Research Laboratories, P.O. Box 4, West Point, PennsylVania 19486
scott_wolkenberg@merck.com
Received February 23, 2004
ABSTRACT
A simple, high-yielding synthesis of 2,4,5-trisubstituted imidazoles from 1,2-diketones and aldehydes in the presence of NH OAc is described.
4
Under microwave irradiation, alkyl-, aryl-, and heteroaryl-substituted imidazoles are formed in yields ranging from 80 to 99%. Short syntheses
of lepidiline B and trifenagrel illustrate the utility of this approach.
Since the introduction of controlled, precise microwave
reactors, microwave-assisted organic synthesis (MAOS) has
had a significant impact on synthetic chemistry. Reductions
in reaction time, increases in yield, and suppression of side
product formation have all been described for microwave
conditions relative to conventional thermal heating.1 Al-
though the basis of these practical benefits remains specula-
tive,2 the preparative advantages are obvious and have
motivated a large and continuing survey of nearly all classes
of thermal reactions for improvement upon microwave
heating. This exploration has extended to cross-coupling
reactions, cycloadditions, condensations, and heterocycle-
forming reactions.1,3,4
high-yielding microwave conditions for the synthesis of
triazines,3 quinoxalines, and pyrazinones4 from 1,2-diketones
(Figure 1). These conditions (microwave, 5 min, 80-95%)
As part of an ongoing development of efficient protocols
for the preparation of substituted heterocycles from common
intermediates, we recently discovered technically simple,
Figure 1. Microwave-assisted reactions of 1,2-diketones which
furnish diverse substituted heterocycles.
(1) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001,
57, 9225.
(2) Garbacia, S.; Desai, B.; Lavastre, O.; Kappe, O. J. Org. Chem. 2003,
68, 9136. Kuhnert, N. Angew. Chem., Int. Ed. 2002, 41, 1863. Strauss, C.
R. Angew. Chem., Int. Ed. 2002, 41, 3589.
(3) Zhao, Z.; Leister, W. H.; Strauss, K.; Wisnoski, D. D.; Lindsley, C.
W. Tetrahedron Lett. 2003, 44, 1123.
represent a dramatic improvement over conventional thermal
heating (8-24 h, 30-65%)5 and enable the use of 1,2-
diketones as diversification points in routes to biologically
active heterocycles. Importantly, when employed in an
(4) Zhao, Z.; Wisnoski, D. D.; Wolkenberg, S. E.; Leister, W. H.; Wang,
Y.; Lindsley, C. W. Manuscript in preparation.
(5) Boger, D. L. Chem. ReV. 1986, 86, 781. Benson, S. C.; Li, J.-H.;
Snyder, J. K. J. Org. Chem. 1992, 57, 5285.
10.1021/ol049682b CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/27/2004

iterative analogue library approach this strategy permits
access to libraries containing diverse skeletons, thus distin-
guishing itself from the more limited approach in which a
central scaffold is “decorated” with various substituents.
Herein, we report the extension of this methodology to the
synthesis of trisubstituted imidazoles and demonstrate its
utility in expedient preparations of the imidazolium alkaloid
lepidiline B6 and the platelet aggregation inhibitor trifenagrel.7
The original synthesis of imidazole utilized glyoxal,
formaldehyde, and ammonia and established that the forma-
tion of four N-C bonds was a viable route.8,9 Although
classical methods were derived from this early success, the
reaction suffered low yields, mixtures of products (including
reversed aldol condensations and oxazole formation), and
lack of generality. Synthetic methodology alternatives are
many and varied10 and have resorted to harsh conditions (e.g.,
the formamide synthesis, which requires excess reagents,
H2SO4 as a condensing agent, 150-200 °C, 4-6 h, 40-
90%).9,11 Additionally, reagents for these procedures are not
readily or commercially available, a key deficiency when
developing conditions for library synthesis.
provided optimal yields (entries 7-9). Impressively, and akin
to observations made previously,2 conversions for short
reaction times are quite high (entries 7 and 8). Isolation of
the product from this and subsequent reactions required
neutralization of the reaction mixture (typically performed
with concentrated NH4OH) and filtration to provide solid
substituted imidazoles of analytical purity.
These conditions proved to be general for the reacting
aldehyde, as shown in Table 2. Aldehydes bearing either
Table 2. Representative 2,4,5-Trisubstituted Imidazoles
In light of the improvements MAOS has bestowed upon
similar thermal reactions, reinvestigation of the classical
conditions seemed warranted. Initial efforts focused on
optimizing microwave conditions for the formation of 2,4,5-
triphenylimidazole using NH4OAc in acetic acid, based on
prior investigations of conventional thermal conditions (Table
1).7 In 5 min reactions, yields increased with higher reaction
Table 1. Optimization of Imidazole Formation under
Microwave Irradiation
entry
T (°C)
time (min)
conversiona (%)
1
2
3
4
5
6
7
8
9
60
80
5
5
5
5
5
5
0.5
1
3
24
51
61
68
87
98
71
82
95
a Isolated yields for analytically pure compounds obtained after neutral-
ization of the reaction mixture followed by filtration. For details, see the
Supporting Information.
100
120
140
160
160
160
160
electron-withdrawing (Table 2, entry 2) or electron-donating
groups (entry 3) perform equally well in the reaction.
Additionally, aliphatic (see entry 4 and Scheme 1 below)
and heterocyclic aldehydes (entry 5) deliver the correspond-
ing imidazoles in high yield.
a Reactions run in HOAc with 0.2 mmol each of benzil and benzaldehyde
and 10 equiv of NH4OAc. Conversion determined by LCMS; isolated yield
for entry 6, 88%.
Importantly for the ultimate goal of applying this reaction
in a diversity-generating strategy, this broad generality
extends to the 1,2-diketone substrate as well (Table 3).
Heteroaromatic, aryl, and aliphatic 1,2-diketones uniformly
provide excellent yields of the corresponding imidazoles.
This includes both electron-deficient (entry 2) and electron-
temperatures up to 160 °C with complete conversions
observed in all cases at 180 °C (Table 1, entries 1-6).
Likewise, in 160 °C trials, only reactions times >3 min
(6) Cui, B.; Zheng, B. L.; He, K.; Zheng, Q. Y. J. Nat. Prod. 2003, 66,
1101.
(7) Abrahams, S. L.; Hazen, R. J.; Batson, A. G.; Phillips, A. P. J.
Pharmacol. Exp. Ther. 1989, 249, 359. Phillips, A. P.; White, H. L.; Rosen,
S. Eur. Patent 58890(A1), 1982.
(8) Japp, F. R.; Robinson, H. H. Ber. 1882, 15, 1268. Radziszewski, B.
Ber. 1882, 15, 1493.
(9) Grimmett, M. R. In ComprehensiVe Heterocyclic Chemistry; Ka-
tritzky, A. R., Rees, C. W., Eds.; Pergamon: New York, 1984; Vol. 5, p
457. Grimmett, M. R. In ComprehensiVe Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: New
York, 1996; Vol. 3, p 77.
1454
Org. Lett., Vol. 6, No. 9, 2004

biologically active compounds. The well-known microtubule
stabilizing agents eleutherobin and sarcodictyin,12 among
numerous other marine- and plant-derived natural products,13
contain imidazole. Furthermore, a recent report indicates that
synthetic imidazoles can exhibit potent inhibition of protein-
protein interactions.14 As an exercise aimed at determining
the utility of the conditions described here, an example from
each of these two classes was prepared.
Table 3. Representative 2,4,5-Trisubstituted Imidazoles
Lepidilines A and B were recently isolated from the root
extract of Lepidium meyenii (“Peruvian ginseng”) collected
from the Andes Mountains of Peru during a search for
bioactive natural products.6 Characterized by their sym-
metrical imidazolium structures (Scheme 1), these simple
Scheme 1
alkaloids exhibit micromolar cytotoxicity against several
human cancer cell lines. Lepidiline B was prepared in an
expedient two-step procedure from 2,3-butanedione and
acetaldehyde (Scheme 1). Since both steps are microwave-
assisted, evaluation of the route and, in fact, completion of
the synthesis was possible in <2 h. Notably, preparation of
the intermediate 2,4,5-trimethylimidazole was technically
simpler, faster, and higher yielding than previous routes.15
Based on the MAOS of imidazoles described here, lepidiline
B was synthesized for the first time in 43% overall yield.
This preparation, which delivered 25 mg of the natural
product in 1 day, compares favorably with the reported
isolation, which yielded 10 mg of lepidiline B from 10 kg
of L. meyenii roots after multiple chromatographic separa-
tions.6
a Isolated yields for analytically pure compounds obtained after neutral-
ization of the reaction mixture followed by filtration. For details, see the
Supporting Information.
rich (entry 3) 1,2-diketones, as well as sterically hindered
systems (entry 4).
Part of the motivation for pursuing libraries of imidazoles
is their prevalence among naturally occurring and synthetic
Trifenagrel7 (Scheme 2) is a potent 2,4,5-triarylimidazole
arachidonate cyclooxygenase inhibitor that reduces platelet
aggregation in several animal species and humans. Indeed,
it inhibits both arachidonate and collagen-induced aggrega-
tion with equal or greater potency (5-21-fold) than in-
(10) Earlier reports described microwave assisted conditions for the
synthesis of imidazoles on solid support (Al2O3, SiO2, and zeolite HY),
and these procedures were limited to triarylimidazoles. See: Balalaie, S.;
Arabanian, A.; Hashtroudi, M. S. Monatsh. Chem. 2000, 131, 945.
Usyatinsky, A. Y.; Khmelnitsky, Y. L. Tetrahedron Lett. 2000, 41, 5031.
In general, although solvent-free conditions were commonly used with
multimode commercial microwaves (“kitchen” microwave ovens), they are
incompatible with currently employed, temperature- and pressure-controlled,
single-mode scientific reactors.
Scheme 2
(11) Wasserman, H. H.; Long, Y. O.; Zhang, R.; Parr, J. Tetrahedron
Lett. 2002, 43, 3351. Kamitori, Y. J. Heterocycl. Chem. 2001, 38, 773.
Deprez, P.; Guillaume, J.; Becker, R.; Corbier, A.; Didierlaurent, S.; Fortin,
M.; Frechet, D.; Hamon, G.; Heckmann, B.; Heitsch, H.; Kleemann, H.-
W.; Vevert, J.-P.; Vincent, J.-C.; Wagner, A.; Zhang, J. J. Med. Chem.
1995, 38, 2357.
Org. Lett., Vol. 6, No. 9, 2004
1455

domethacin and aspirin without exhibiting the gastric damage
associated with these typical cyclooxygenase inhibitors.
Preparation of the drug7 (Scheme 2) using the microwave-
assisted aldehyde-1,2-diketone condensation reaction pro-
ceeded smoothly and in high yield. This example highlights
the speed of the method: whereas the existing optimized
procedure for its preparation furnishes product after 2 h at
reflux, the MAOS protocol delivers pure trifenagrel in 99%
yield after 5 min.
In summary, we have developed a general microwave-
assisted synthesis of 2,4,5-trisubstituted imidazoles. In ad-
dition to its speed and simple setup, the reaction is high
yielding for a variety of substrates indicating its utility in a
parallel synthesis format. Further, the value of this transfor-
mation in target-oriented synthesis was demonstrated in the
first total synthesis of lepidiline B and a rapid, high-yielding
synthesis of trifenagrel.
(12) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza, A.
M.; Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997, 119, 8744.
D’Ambrosio, M.; Guerriero, A.; Pietra, F. HelV. Chim. Acta 1987, 70, 2019.
D’Ambrosio, M.; Guerriero, A.; Pietra, R. HelV. Chim. Acta 1988, 71, 964.
(13) Jin, Z.; Li, Z.; Huang, R. Nat. Prod. Rep. 2002, 19, 454.
(14) Vassilev, L. T.; Vu, B. T.; Graves, B.; Carvajal, D.; Podlaski, F.;
Filipovic, Z.; Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; Fotouhi, N.;
Liu, E. A. Science 2004, 303, 844.
Acknowledgment. We thank Joan Murphy for obtaining
HRMS measurements on all compounds.
Supporting Information Available: Full experimental
details and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) Kuhn, N.; Henkel, G.; Kreutzberg, J. Z. Naturforsch. B 1991, 46,
1706. Harper, J. L.; Smith, R. A. J.; Bedford, J. J.; Leader, J. P. Tetrahedron
1997, 53, 8211.
OL049682B
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Org. Lett., Vol. 6, No. 9, 2004