Highly diastereoselective multicomponent synthesis of unsymmetrical imidazolines.

Article abstract of DOI:10.1021/ol026703y

We report here a highly diastereoselective multicomponent synthesis of imidazolines. These low molecular weight scaffolds contain a four-point diversity applicable to alkyl, aryl, acyl, and hetereocyclic substitutions. [structure: see text]

Full text of DOI:10.1021/ol026703y

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3533-3535
Highly Diastereoselective
Multicomponent Synthesis of
Unsymmetrical Imidazolines
Satymaheshwar Peddibhotla, S. Jayakumar, and Jetze J. Tepe*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
tepe@cem.msu.edu
Received August 9, 2002
ABSTRACT
We report here a highly diastereoselective multicomponent synthesis of imidazolines. These low molecular weight scaffolds contain a four-
point diversity applicable to alkyl, aryl, acyl, and hetereocyclic substitutions.
The development of small molecular weight scaffolds
containing a high degree of diversity has become a leading
focus in modern drug discovery.1-5 As part of our program
to develop small molecule libraries containing antiinflam-
matory activity, we developed a highly diastereoselective
multicomponent one-pot synthesis of substituted imidazo-
lines. These low molecular weight scaffolds contain a four-
point diversity applicable to alkyl, aryl, acyl, and heterocyclic
substitutions.
interesting synthetic and pharmacological properties,9-15 we
examined the synthesis of imidazolines via the reaction of
oxazolones with a variety of imines in the presence of Lewis
acids. After screening a small number of Lewis acids, we
found that TMSCl promotes the reaction of oxazolones and
imines to afford the imidazoline scaffold in very good yields
as single diastereomers (Scheme 1).
1,3-Dipolar cycloaddition reactions utilizing N-methylated
mesoionic oxazolones (or munchnones) provide a general
route for the syntheses of pyrroles and imidazoles.6-8
Surprisingly, the utilization of oxazolones (or azlactones) has
not yet resulted in an efficient entry into a stereoselective
highly diverse class of imidazoline scaffolds. Because of their
Scheme 1. Multicomponent One-Pot Synthesis of
Imidazolines
(1) Schreiber, S. L. Science 2000, 287, 1964-1968.
(2) Ding, S.; Gray, N. S.; Wu, X.; Ding, Q.; Schultz, P. G. J. Am. Chem.
Soc. 2002, 124, 1594-1596.
(3) Spring, D. R.; Krishnan, S.; Blackwell, H. E.; Schreiber, S. L. J.
Am. Chem. Soc. 2002, 124, 1354-1363.
The oxazolones were prepared from different N-acyl-R-
amino acids by EDCI-mediated dehydration to provide the
pure oxazolones in high yields.16-18 The cycloaddition
(4) Spring, D. R.; Krishnam, S.; Schreiber, S. L. J. Am. Chem. Soc. 2000,
122, 5656-5657.
(5) Janvier, P.; Sun, X.; Bienayme, H.; Zhu, J. J. Am. Chem. Soc. 2002,
124, 2560-7.
(6) Hershenson, F. M.; Pavia, M. R. Synthesis 1988, 999-1001.
(7) Consonni, R.; Croce, P. D.; Ferraccioli, R.; La Rosa, C. J. Chem.
Res., Synop. 1991, 188-189.
(9) Puntener, K.; Hellman, M. D.; Kuester, E.; Hegedus, L. S. J. Org.
Chem. 2000, 65, 8301-6.
(10) Hsiao, Y.; Hegedus, L. S. J. Org. Chem. 1997, 62, 3586-3591.
(11) Gilbert, I. H.; Rees, D. C. Tetrahedron 1995, 51, 6315-6336.
(8) Bilodeau, M. T.; Cunningham, A. M. J. Org. Chem. 1998, 63, 2800-
2801.
10.1021/ol026703y CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/30/2002

reactions proceeded well with a wide variety of imines at
slightly elevated temperatures (40 °C) to provide the highly
substituted imidazolines in very good yields. Only the trans
diastereomers (with respect to R2 and R3) of the imidazolines
were observed as determined by NOE experiments and X-ray
crystallography (Figure 1).
Figure 2. Structures of imidazolines 1-12 (% yield is listed in
Figure 2). Yield of compound 5 was based on the isolated trans
product.
Figure 1. X-ray crystal structure of compound 7. HCl salt.
This diastereoselective multicomponent one-pot synthesis
provides a wide range of aryl, acyl, alkyl, and heterocyclic-
substituted imidazolines in very good yields (Figure 2). Some
limitation of the cycloaddition reaction was noticed with
respect to the R4 moiety. Increasing the steric environment,
for example, by using 1-phenyl ethylamine, resulted in no
product formation (Figure 2, compound 6). In addition, only
compound 5 was isolated as a mixture of diastereomers (68%
yield, 3:1 trans:cis, with respect to R2:R3), whereas all other
compounds were isolated as single diastereomers.
While the complete mechanistic details of this process are
still under investigation, the reaction does not seem to
proceed via a ring-opened nitrilium ion intermediate as
anticipated (Scheme 2, pathway a).14 The possibility of a
Michael-type addition via the formation of the nitrilium ion
was investigated by first preparing the silyl enol ether with
TMSCl (1.0 equiv) and TEA (1.0 equiv) followed by the
addition of the imine and an additional 1 equiv of TMSCl.
This resulted merely in isolation of starting materials. Excess
of triethylamine also halted the reaction suggesting that acidic
conditions were required. However, Lewis acids such as
TiCl4 and BF3‚OEt2 or protic acids such as camphor sulfonic
acid and methyl sulfonic acid did not promote product
formation. The absence of trimethylsilyl chloride resulted
in the formation of â-lactams and N-acyl amino acid amides
presumably via the corresponding ketene intermediate (Scheme
2, path b).19,20
O-Silation with TMSOTf also did not result in any product
formation. This indicates the requirement of a nucleophilic
Scheme 2. Proposed Mechanisms of Oxazolone Reactions
(12) Zhou, X.-T.; Lin., Y.-R.; Dai, L.-X.; Sun, J.; Xia, L.-J.; Tang, M.-
H. J. Org. Chem. 1999, 64, 1331-1334.
(13) Derstine, C. W.; Smith, D. N.; Katzenellenbogen, J. A. J. Am. Chem.
Soc. 1996, 118, 8485-8486.
(14) Viso, A.; Fernandez De La Pradilla, R.; Guerrero-Strachan, C.;
Alonso, M.; Martinez-Ripoll, M.; Andre, I. I. J. Org. Chem. 1997, 62, 2316-
2317.
(15) Dghaym, R. D.; Dhawan, R.; Arndtsen, B. A. Angew. Chem., Int.
Ed. 2001, 40, 3228-3230.
(16) Chen, F. M. F.; Kuroda, K.; Benoiton, N. L. Synthesis 1979, 230-
232.
(17) Mukerjee, A. K. Heterocycles 1987, 26, 1077-1097.
(18) Ivanova, G. G. Tetrahedron 1992, 48, 177-186.
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Org. Lett., Vol. 4, No. 20, 2002

counterion to establish an equilibrium between O-silation and
N-silation of the azlactone (Scheme 3). In light of these
Other silyl chlorides such as triphenyl silyl chloride and
triethyl silyl chloride also provided the product as a single
diastereomer, in notably longer reaction times and lower
yields (compound 1, 45 and 70%, respectively). In sup-
port of the proposed mechanism shown in Scheme 3, we
found that 1 equiv of acetyl chloride provided the formation
of the imidazoline, in somewhat lower yields (compound 1,
55%).
Scheme 3. Proposed Mechanism of 1,3-Dipolar Cycloaddition
In conclusion, we have identified an efficient diastereo-
selective synthesis of imidazoline scaffolds with a high
degree of diversity. The potential clinical applications and
antiinflammatory activity of this new class of compounds
will be reported soon.
Acknowledgment. The authors gratefully acknowledge
the financial support provided by the Donors of the Petroleum
Research Fund, administered by the American Chemical
Society, and Michigan State University.
findings, we propose that the reaction proceeds via a 1,3-
dipolar cycloaddition. Steric repulsion of the R3 group during
the cycloaddition might explain the diastereoselectivity
obtained in this reaction (Scheme 3).
Supporting Information Available: Experimental pro-
1
cedures and IR, H and 13C NMR, and HRMS data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(19) Schunk, S.; Enders, D. Org. Lett. 2000, 2, 907-910.
(20) Sain, B.; Sandhu, J. S. Heterocycles 1985, 23, 1611-1614.
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