Synthesis of fused bicyclic imidazoles by sequential van Leusen/ring-closing metathesis reactions

Article abstract of DOI:10.1021/ol050852+

(Chemical Equation Presented) A new strategy employing the van Leusen three-component reaction and the ring-closing metathesis reaction in a sequential fashion to access fused bicyclic imidazole rings is reported. The two-step sequence generated compounds

Full text of DOI:10.1021/ol050852+

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3183-3186
Synthesis of Fused Bicyclic Imidazoles
by Sequential Van Leusen/Ring-Closing
Metathesis Reactions
Vijaya Gracias,* Alan F. Gasiecki, and Stevan W. Djuric
Scaffold-Oriented Synthesis, Medicinal Chemistry Technologies, Abbott Laboratories,
R4CP, AP10, 100 Abbott Park Road, Abbott Park, Illinois 60064-6099
Vijaya.gracias@abbott.com
Received April 18, 2005
ABSTRACT
A new strategy employing the van Leusen three-component reaction and the ring-closing metathesis reaction in a sequential fashion to
access fused bicyclic imidazole rings is reported. The two-step sequence generated compounds of significant molecular complexity from
simple starting materials in an expedient fashion with excellent yields.
Multicomponent reactions (MCRs) have been extensively
investigated in organic and diversity-oriented synthesis
mostly due to their ability to install complex molecular
functionality in simple one-step transformations.1 In recent
years, isocyanide-based MCRs such as the Passerini three-
component and the Ugi four-component reactions have been
combined with postcondensation modifications that allow
access to even more functionalized and specialized hetero-
cyclic molecules. Some examples of postcondensation reac-
tions include Diels-Alder reactions, amino cyclizations,
nucleophilic aromatic substitutions, lactonizations, and ring-
closing metathesis.2 As part of our efforts to develop new
routes to access novel heterocyclic structures, we have
recently reported sequential Ugi/Heck,3 Ugi/intramolecular
nitrile oxide cycloaddition,4 Ugi/intramolecular alkyne-azide
C.; Labaudiniere, R. Tetrahedron Lett. 2000, 41, 1509-1514. (e) Hulme,
C.; Peng, J.; Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R.
Tetrahedron Lett. 1998, 39, 7227-7230. (f) Strocker, A. M.; Keating, T.
A.; Tempest, P. A.; Armstrong, R. W. Tetrahedron Lett. 1996, 37, 1149-
1152. (g) Short, K. M.; Ching, B. W.; Mjalli, A. M. M. Tetrahedron Lett.
1996, 37, 7489-7492. Nucleophilic aromatic substitutions: (h) Cristau, P.;
Vors, J.-P.; Zhu, J. Tetrahedron Lett. 2003, 44, 5575-5578. (i) Tempest,
P.; Ma, V.; Kelly, M. G.; Jones, W.; Hulme, C. Tetrahedron Lett. 2001,
42, 4963-4968. Lactonizations: Park, S. J.; Keum, G.; Kang, S. B.; Koh,
H. Y.; Kim, Y. Tetrahedron Lett. 1998, 39, 7109-7112. Ring-closing
metathesis: (j) Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596-
597. (k) Beck, B.; Larbig, G.; Mejat, B.; Magnin-Lachaux, M.; Picard, A.;
Herdtweck, E.; Do¨mling, A. Org. Lett. 2003, 5, 1047-1050. (l) Banfi, L.;
Basso, A.; Guanti, G.; Riva, R. Tetrahedron Lett. 2003, 44, 7655-7658.
(m) Piscopio, A. D.; Miller, J. F.; Koch, K. Tetrahedron. 1999, 55, 8189-
8198. (n) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709-
712. (o) Krelaus, R.; Westermann, B. Tetrahedron Lett. 2004, 45, 5987-
5990. (p) Dietrich, S. A.; Banfi, L.; Basso, A.; Damonte, G.; Guanti, G.;
Riva, R. Org. Biomol. Chem. 2005, 3, 97-106. (q) Kazmaier, U.; Hebach,
C.; Watzke, A.; Maier, S.; Mues, H.; Huch, V. Org. Biomol. Chem. 2005,
3, 136-145. Wittig reaction: (r) Beck, B.; Picard, A.; Herdtweck, E.;
Do¨mling, A. Org. Lett. 2004, 6, 39-42.
(1) For reviews on Ugi 4-CC reaction and other MCRs with isocyanides,
see: (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-
3210. (b) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51-80. (c)
Do¨mling, A. Curr. Opin. Chem. Biol. 2002, 6, 306-313. (d) Zhu, J. Eur.
J. Org. Chem. 2003, 1133-1144. (e) Gokel, G.; Lu¨dke, G.; Ugi, I. In
Isonitrile Chemistry; Ugi, I., Ed.; Academic: New York, 1971; p145-
199.
(2) Examples of post-Ugi transformations include the following: Diels-
Alder reactions: (a) Paulvannan, K. Tetrahedron Lett. 1999, 40, 1851-
1854. (b) Wright, D. L.; Robotham, C. V.; Aboud, K. Tetrahedron Lett.
2002, 43, 943-946. Amino cyclizations: (c) Tempest, P.; Ma, V.; Thomas,
S.; Hua, Z.; Kelly, M. G.; Hulme, C. Tetrahedron Lett. 2001, 42, 4959-
4962. (d) Hulme, C.; Ma, L.; Kumar, N. V.; Krolikowski, P. H.; Allen, A.
(3) Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron Lett. 2004, 45,
417-420.
(4) Akritopoulou-Zanze, I.; Gracias, V.; Moore, J. D.; Djuric, S. W.
Tetrahedron Lett. 2004, 45, 3421-3423.
10.1021/ol050852+ CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/28/2005

cycloaddition,5 and Ugi/carbonylation intramolecular ami-
dation6 sequences.
substituted TosMIC reagents allows for the exploitation of
versatile building blocks in the van Leusen reaction.12
Herein, we report on our efforts on postmodifications of
the van Leusen reaction using a ring-closing metathesis as
the ultimate step in our reaction sequence (Figure 2). The
The imidazole nucleus is present in a variety of natural
products and biologically important compounds and occupies
an important position in medicinally relevant heterocyclic
systems.7 In particular, bicyclic imidazole nuclei are present
in a number of bioactive molecules, including antiviral and
antibacterial agents.8 While a number of synthetic routes have
been reported to access diversely substituted or bicyclic
imidazole nuclei, some of these are circuitous and low-
yielding and sometimes require preparation of synthetically
challenging intermediates.9 We became interested in the van
Leusen imidazole synthesis10 as part of a program to identify
and synthesize novel heterocyclic skeletons that were primed
to undergo further modification and derivatization to generate
medicinally relevant, fused heterocyclic, bicyclic systems.
The van Leusen imidazole synthesis is a three-component
reaction involving the cycloaddition of tosylmethyl isocya-
nides (TosMICs) with imines under mild reaction conditions
(Figure 1). A variety of 1,4- and 4,5-disubstituted imidazoles
Figure 2. General strategy.
use of bifunctional starting materials with terminal olefinic
bonds in the van Leusen reaction in combination with the
RCM would allow access to novel fused imidazole scaffolds.
We envisioned control of ring size and functional group
features in the products based on the choice of the bifunc-
tional starting materials. This concept has been previously
reported in the context of Ugi and Passerini-type MCRs
wherein alkene inputs were introduced into the reaction
components and followed by a postcondensation RCM
reaction to afford cyclic lactams.2 Additionally, there has
been one report of a facile synthesis of five- and six-
membered bicyclic imidazoles via RCM of the alkene
functionality on the imidazole core.13 In this case, the authors
generated the RCM precursor by a chemoselective metala-
tion-electrophilic capture sequence.
Figure 1. Van Leusen three-component reaction to imidazoles.
as well as 1,4,5-trisubstituted imidazoles can be readily
synthesized by varying the aldehyde, amine and the TosMIC
components. Furthermore, an efficient one-pot protocol to
access polysubstituted imidazoles from aryl-substituted
TosMIC reagents and imines generated in situ has been
reported.11 This report also demonstrated the functional
groups that are tolerated by the van Leusen reaction,
including chiral amines, aldehydes, and amino acids. Ad-
ditionally, the availability of efficient routes to synthesize
The general method to access the fused imidazoles is
outlined in Scheme 1. Phenyl TosMIC was chosen as the
Scheme 1. General Method
(5) Akritopoulou-Zanze, I.; Gracias, V.; Djuric, S. W. Tetrahedron Lett.
2004, 45, 8439-8441.
(6) Vasudevan, A.; Verzal, K. M. Tetrahedron Lett. 2005, 46, 1697-
1701.
(7) (a) Greenlee, W. J.; Siegel, P. K. S. Annu. Rep. Med. Chem. 1992,
27, 59-68. (b) Hodges, J. C.; Hamby, J. M.; Blankley, C. J. Drugs Future
1992, 17, 575-593. (c) Meanwell, N. A.; Romine, J. L.; Seiler, S. M. Drugs
Future 1994, 19, 361-385.
(8) (a) Frannowski, A.; Seliga, C.; Bur, D.; Streith, J. HelV. Chim. Acta
1991, 74, 934-940. (b) Nishi, T.; Higashi, K.; Soga, T.; Takemura, M.;
Sato, M. J. Antibiot. 1994, 47, 357-369. (c) Browne, L. J.; Gude, C.;
Rodriguez, H.; Steele, R. E. J. Med. Chem. 1991, 34, 725-736. (d)
Aldabbagh, F.; Bowman, W. R.; Mann, E. Tetrahedron Lett. 1997, 38,
7937-7940.
(9) For imidazole syntheses, see: (a) Ebel, K. In Methoden der
Organischen Chemie (Houben-Weyl); Schaumann, E., Ed.; Georg Thieme
Verlag: Stuttgart, 1994; Band E8c, Hetarene III/Teil 3, pp 1-215. (b)
Grimmett, M. R. In AdVances in Heterocyclic Chemistry; Katritzky, A. R.,
Boulton, A. J., Eds.; Academic: New York, 1980; Vol. 27, pp 241-326.
(c) Grimmett, M. R. In AdVances in Heterocyclic Chemistry; Katritzky, A.
R., Boulton, A. J., Eds.; Academic: New York, 1970; Vol. 12, pp 103-
183.
isocyanide component in the model van Leusen reaction
system, as it had been previously reported to work well in
this reaction.11 Also, the best solvent/base combination for
this reaction, DMF/K2CO3, was used. The reaction proceeded
smoothly with the condensation of 4-pentenal with allylamine
in DMF at room temperature to generate the imine in situ,
which was followed by the addition of the TosMIC reagent
(10) (a) van Leusen, A. M.; Wildeman, J.; Oldenzeil, O. H. J. Org. Chem.
1977, 42, 1153-1159. (b) van Leusen, A. M. Lect. Heterocycl. Chem. 1980,
5, S-111.
(11) Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen,
M. A. J. Org. Chem. 2000, 65, 1516-1524.
(12) (a) Sisko, J.; Mellinger, M.; Sheldrake, P. W.; Baine, N. H.
Tetrahedron Lett. 1996, 37, 8113-8116. (b) Sisko, J.; Mellinger, M.;
Sheldrake, P. W.; Baine, N. H. Org. Synth. 2000, 77, 198-205.
(13) Chen, Y.; Dias, H. V. R.; Lovely, C. J. Tetrahedron Lett. 2003, 44,
1379-1382.
3184
Org. Lett., Vol. 7, No. 15, 2005

and base (K2CO3) to afford the van Leusen imidazole product
1 in 91% isolated yield. Substrate 1 had to be pretreated
with 1 equiv of p-TsOH before subjecting it to the RCM.14
The subsequent RCM reaction catalyzed by the second-
generation Grubbs catalyst in refluxing CH2Cl2 cleanly
afforded the fused bicyclic imidazole 2 in 90% yield.15
Scheme 2. General Synthetic Routes for the Preparation of
the Starting Materials
On the basis of the success of the model system, a series
of products that could serve as precursors for the RCM were
constructed in order to evaluate the scope of this reaction
sequence. The results are outlined in Table 1.
Table 1. Results on the Van Leusen Imidazole Synthesis
One of the key features of this set was the variation in the
chain length of substituents on the aldehyde and amine
functionality. The imidazoles thus produced would serve as
RCM substrates that provide products of varied ring size.
Additionally, the scope of the reaction was expanded to
secondary amino aldehydes and amino esters as building
Table 2. Results on the RCM Reaction Sequence
Org. Lett., Vol. 7, No. 15, 2005
3185

blocks alongside simple primary amines and aldehydes.
These building blocks were either purchased from com-
mercial vendors or prepared according to known procedures
as illustrated in Scheme 2.16
All the van Leusen reactions proceeded without event to
generate C1/C5-position RCM precursors in moderate to
excellent yields (Table 1, entries 1-7). The reaction was
then carried out in the context of generating RCM precursors
with the alkene inputs at the C4/C5-position. To this end,
allyl TosMIC17 was used instead of phenyl TosMIC, which
provided the desired compound, albeit in modest yields
(Table 1, entry 8).
tionalized imidazoles were generated via this sequence of
reactions. The initial example of a 5,8-fused bicyclic imi-
dazole gave product in low yields (Table 2, entry 5). This
was not entirely surprising, as the formation of eight-
membered rings via the RCM methodology is considered
significantly more difficult than the six- or seven-membered
systems.18 However, examples, which incorporated substit-
uents on the alkene side chains R to the imidazole ring, gave
RCM products in good to excellent yields (Table 2, entries
6 and 7). It is possible that the introduction of this R-group
elicits just enough conformational cooperation from the
uncyclized alkene side chains, predisposing them to ring
closure.
In conclusion, we have demonstrated that the van Leusen
imidazole reaction followed by the RCM reaction provides
easy access to a variety of fused bicyclic imidazoles, a group
of structures that represent useful scaffolds for lead genera-
tion. Other van Leusen postmodification reactions are
currently in progress and will be reported in due course.
These imidazole products were then subjected to the RCM
reaction using the optimized procedure outlined above (Table
2). A number of 5,6-, 5,7-, and 5,8-fused, bicyclic, func-
(14) This treatment results in the formation of the imidazolium ion,
preventing the lone pair of the imidazole nitrogen from inactivating the
Grubbs catalyst. See ref 13. Our reaction failed to yield the RCM product
in the absence of this pretreatment procedure.
(15) A representative procedure is demonstrated by the preparation of
1-phenyl-8,9-dihydro-5H-imidazo[1,5-a]azepine (2). To the 4-pentenal (252
mg, 3.0 mmol) in DMF (3 mL) was added allylamine (171 mg, 3.0 mmol),
and the reaction mixture was stirred at room temperature for 2.5 h. This
was followed by the addition of phenyl TosMIC (543 mg, 2.0 mmol) and
K2CO3 (276 mg, 2.0 mmol), and the reaction mixture was allowed to stir
for an additional 17 h at room temperature. The reaction was quenched by
the addition of water. The aqueous layer was extracted with EtOAc, dried
(anhydrous MgSO4), concentrated, and purified by flash chromatography
(97:2.5:0.5 CH2Cl2-CH3OH-NH3) to afford 433 mg (91%) of 1 as a clear
oil. 1H NMR (300 MHz, CDCl3): δ 2.07 (m, 2H), 2.47-2.59 (m, 2H),
4.53 (m, 2H), 4.90-4.98 (m, 3H), 5.17 (m, 1H), 5.74 (m, 1H), 5.96 (m,
1H), 7.11-7.24 (m, 5H), 7.42 (s, 1H). MS (ESI): m/z 239 (M + H). To a
solution of 1 (410 mg, 1.72 mmol) in CH2Cl2 (30 mL) was added p-TsOH
(342 mg, 1.8 mmol), and the reaction mixture was heated at reflux for 30
min. The reaction was cooled to room temperature; the Grubbs catalyst
(73 mg, 0.087 mmol) was added, and the reaction mixture was refluxed
for an additional 30 min (TLC indicated disappearance of the starting
material). The reaction was quenched by adding aqueous saturated K2CO3
and extracted with EtOAc. The organic layer was dried (anhydrous MgSO4),
concentrated, and purified by flash chromatography (97:2.5:0.5 CH2Cl2-
CH3OH-NH3) to afford 327 mg (90%) of 2 as a light brown oil. 1H NMR
(300 MHz, CDCl3): δ 2.19 (m, 2H), 2.88 (m, 2H), 4.58 (d, J ) 6.0 Hz,
2H), 5.68 (m, 2H), 7.10-7.24 (m, 5H), 7.42 (s, 1H). MS (ESI): m/z 225
(M + H).
Acknowledgment. The authors would like to thank Dr.
Xenia Searle for the synthesis of 3-buten-1-amine and the
Structural Chemistry staff for NMR and MS data.
Supporting Information Available: Copies of 1H NMR
and MS spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL050852+
(16) (a) Goel, O. P.; Krolls, U.; Stier, M.; Kesten, S. Org. Synth. 1988,
67, 69-72. (b) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999,
121, 5653-5660. (c) Sato, T.; Nakamura, N.; Ikeda, K.; Michiyo, O.;
Hiroyuki, I.; Masazumi, I. J. Chem. Soc., Perkin. Trans. 1 1992, 18, 2399-
2408.
(17) Almansa, C.; Alfo´n, J.; de Arriba, A. F.; Cavalcanti, F. L.; Escamilla,
I.; Go´mez, L. A.; Miralles, A.; Soliva, R.; Bartol´ı, J.; Carceller, E.; Merlos,
M.; Garcia´-Rafanell, J. J. Med. Chem. 2003, 46, 3463-3475.
(18) Miller, S. J.; Kim, S.; Chen, Z.; Grubbs, R. H. J. Am. Chem. Soc.
1995, 117, 2108-2109.
3186
Org. Lett., Vol. 7, No. 15, 2005