A Powerful New Strategy for Diversity-Oriented Synthesis of Pyrroles from Donor-Acceptor Cyclopropanes and Nitriles

Article abstract of DOI:10.1021/ol036180+

(Equation presented) Lewis acid activated donor-acceptor cyclopropanes react with aliphatic, aromatic, and α,β-unsaturated nitriles in a novel cascade [3 + 2] dipolar cycloaddition, dehydration, and tautomerization sequence to afford pyrroles in moderate

Full text of DOI:10.1021/ol036180+

ORGANIC
LETTERS
2003
Vol. 5, No. 26
5099-5101
A Powerful New Strategy for
Diversity-Oriented Synthesis of Pyrroles
from Donor−Acceptor Cyclopropanes
and Nitriles
Ming Yu and Brian L. Pagenkopf*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
pagenkopf@mail.utexas.edu
Received November 6, 2003
ABSTRACT
Lewis acid activated donor−acceptor cyclopropanes react with aliphatic, aromatic, and r,â-unsaturated nitriles in a novel cascade [3 + 2]
dipolar cycloaddition, dehydration, and tautomerization sequence to afford pyrroles in moderate to excellent overall yield. This cost-effective
and regiospecific method is ideally suited for the preparation of combinatorial libraries.
Pyrroles, important heterocycles that occur in porphyrins,1
pigments,2 and other natural products,3 have found applica-
tions in materials science4 and are common components in
molecular recognition and self-assembly ensembles.5-7 There
are dozens of reported pyrrole syntheses, some of the most
reliable of which date from the 19th century, such as the
Hantzsch8 and Paal-Knoor9 procedures.10,11 These classic
condensation reactions between activated methylenes and
amino ketones can be limited by their efficiency, functional
group compatibility, regiospecificity, or the variety of substit-
uents that can be introduced around the pyrrole. More recent
pyrrole syntheses typically showcase special methodology
or excel at accessing one substitution motif, but a universal
strategy for efficiently preparing all combinations of sub-
stituted pyrroles from easily handled materials is lacking.12
Recently, we reported the first formal [3 + 2] cycload-
dition between nitriles and donor-acceptor (DA) cyclopro-
panes to afford 3,4-dihydro-2H-pyrroles.13,14 Cycloaddition
reactions between DA-cyclopropanes and other kinds of
dipolarophiles are known,15,16 but the novelty and the clear
synthetic potential of the nitrile cycloaddition prompted us
to explore extending the strategy to include additional classes
of DA-cyclopropanes. However, all attempted nitrile cy-
cloaddition reactions with cyclopropanes other than those
prepared by intramolecular cyclopropanation failed to in-
corporate nitrile,17 and only the rearrangement products 3
were obtained (Scheme 1).
(1) For a recent review: Smith, K. M. J. Porphyrins and Phthalocyanines
2000, 4, 319-324.
(2) Battersby, A. R. Nat. Prod. Rep. 2000, 17, 507-526.
(3) Christophersen, C. In The Alkaloids; Brossei, A., Ed.; Academic
Press: Orlando, 1985; Vol. 24, Chapter 2.
(4) For reviews: (a) Baumgarten, M.; Tyutyulkov, N. Chem. Eur. J. 1998,
4, 987-989. (b) Deronzier, A.; Moutet, J.-C. Curr. Top. Electrochem. 1994,
3, 159-200.
(5) Gale, P. A.; Anzenbacher, P.; Sessler, J. L. Coord. Chem. ReV. 2001,
222, 57-102.
(6) Prins, L. J.; Reinhoudt, D. N.; Timmerman, P. Angew. Chem., Int.
Ed. 2001, 40, 2383-2426.
(7) Wemmer, D. E. Biopolymers 1999, 52, 197-211.
(8) Hantzsch, A. Ber. 1890, 23, 1474-1483.
(9) Paal, C. Ber. 1885, 18, 367-371. (b) Knorr, L. Ber. 1885, 18, 299-
311. (c) Elming, N.; Clauson-Kaas, N. Acta Chem. Scand. 1952, 5, 867-
874.
We speculated that a solvent capable of sufficiently
stabilizing the intermediate oxocarbenium ion might funnel
the reaction pathway back into the cycloaddition manifold.
In this regard, we found that the use of nitromethane or
nitroethane as solvent at low temperature (-45 to -30 °C)
(10) Piloty, O. Ber. 1910, 43, 489-498.
(11) For reviews, see: (a) Patterson, J. M. Synthesis 1976, 281-304.
(b) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1999, 2849-2866. (c)
Ketcha, D. M. Prog. Heterocycl. Chem. 2002, 14, 114-138.
10.1021/ol036180+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/03/2003

Scheme 1
Table 1. Pyrroles from DA Cyclopropane Nitrile
Cycloadditions
was critical to suppress the elimination pathway. Herein we
report a new and efficient synthesis of di-, tri-, and tetra-
substituted pyrroles from DA-cyclopropanes by a domino
cycloaddition, dehydration, and tautomerization strategy
(Scheme 2).18
Scheme 2
For our initial studies on the pyrrole synthesis we chose
as a model substrate the unsubstituted donor-acceptor
cyclopropane 2a (Table 1). Trimethylsilyl trifluoromethane-
sulfonate emerged as an ideal Lewis acid for cyclopropane
activation, and addition of Me3SiOTf to a solution of 2a in
acetonitrile gave the pyrrole in 80% isolated yield (entry 1,
yields based on cyclopropane).19 The inclusion of other sol-
vents generally gave lower yields (e.g., 73% in nitrometh-
ane), but practical considerations required the use of solvent
when most other nitriles were employed. The standard
reaction conditions20 for other nitriles were to add 1 equiv
of Me3SiOTf to a solution of cyclopropane and 10 equiv of
nitrile in either nitromethane or nitroethane solvent. Buty-
ronitrile gave a yield similar to that obtained with acetonitrile
(entry 2, 77%), and both aromatic (entries 3 and 4) and R,â-
unsaturated nitriles (entries 5-7) participate in the reaction.
No products from reaction across the double bond of the
unsaturated nitriles were detected.
(12) For some contemporary examples, see: (a) Martinez, G. R.; Grieco,
P. A.; Srivivasan, C. V. J. Org. Chem. 1981, 46, 3760-3761. (b) Nicolaou,
K. C.; Claremon, D. A.; Papahatjis, D. P. Tetrahedron Lett. 1981, 22, 4647-
4650. (c) Baldwin, J. E.; Bottaro, J. C. J. Chem. Soc., Chem. Commun.
1982, 624-625. (d) Barton, D. H. R.; Zard, S. Z. Chem. Commun. 1985,
1098-100. (e) Hegedus, L. S.; Mulhern, T. A.; Mori, A. J. Org. Chem.
1985, 50, 4282-4288. (f) Katrizky, A. R.; Hitchings, G. J.; Zhao, X.
Synthesis 1991, 863-7. (g) Van Leusen, D.; Van Echten, E.; Van Leusen,
A. M. J. Org. Chem. 1992, 57, 2245-9. (h) Winkler, J. D.; Siegel, M. G.
Tetrahedron Lett. 1993, 34, 7697-700. (i) Trofimov, B. A.; Mikhaleva,
A. I. Heterocycles 1994, 37, 1193-232. (j) Chan, W. H.; Lee, A. W. M.;
Lee, K. M.; Lee, T. Y. J. Chem. Soc., Perkin Trans. 1 1994, 2355-2356.
(k) QuicletSire, B.; Thevenot, I.; Zard, S. Z. Tetrahedron Lett. 1995, 36,
9469-9470. (l) Curran, T. P.; Keaney, M. T. J. Org. Chem. 1996, 61, 9068-
9069. (m) Nagafuji, P.; Cushman, M. J. Org. Chem. 1996, 61, 4999-5003.
(n) Meyers, A. I.; Warmus, J. S.; Dilley, G. Org. Synth. 1996, 73, 246-
252. (o) Grigg, R.; Savic, V. Chem. Commun. 2000, 873-874. (p) Katritzky,
A. R.; Huang, T.-B.; Voronkov, M. V.; Wang, M.; Kolb, H. J. Org. Chem.
2000, 65, 8819-8821. (q) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J.
Am. Chem. Soc. 2001, 123, 2074-2075. (r) Takaya, H.; Kojima, S.;
Murahashi, S. I. Org. Lett. 2001, 3, 421-424. (s) Braun, R. U.; Zeitler, K.;
Mu¨ller, T. J. J. Org. Lett. 2001, 3, 3297-3300. (t) Quiclet-Sire, B.;
Wendeborn, F.; Zard, S. Z. Chem. Commun. 2002, 2214-2215. (u) Hover,
J. A.; Bock, C. W.; Bhat, K. L. Heterocycles 2003, 60, 791-798.
(13) Yu, M.; Pagenkopf, B. L. J. Am. Chem. Soc. 2003, 125, 8122-
8123.
The next examples in Table 2 illustrate the power of the
method to install alkyl groups selectively at either or both
of the C(4) and C(5) positions without formation of con-
stitutional isomers, which can plague traditional condensation
(16) Dipolar cycloaddition reviews: (a) 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley: New York, 1984. (b) Wade, P. A. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 4, p 1111. (c) A. Padwa, In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I. Eds.; Pergamon Press: Oxford,
1991; Vol. 4, p 1069. (d) Synthetic Applications of 1,3-Dipolar Cycload-
dition Chemistry Toward Heterocycles and Natural Products; Padwa, A.,
Pearson, W. H., Eds.; Wiley: New York, 2002.
(14) Meyers, A. I.; Sircar, J. C. In The Chemistry of the Cyano Group;
Rapporport, Z., Ed.; John Wiley: Belfast, 1970; Chapter 8.
(15) Donor-acceptor cyclopropane reviews: (a) Danishefsky, S. Acc.
Chem. Res. 1979, 12, 66-72. (b) Wenkert, E. Acc. Chem. Res. 1980, 13,
27-31. (c) Paquette, L. A. Chem. ReV. 1986, 86, 733-750. (d) Reissig,
H.-U. In The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; John
Wiley & Sons: Chichester, 1987; Chapter 8, pp 375-443. (e) Reissig, H.
U. Top. Curr. Chem. 1988, 144, 73-135. (f) Wong, H. N. C.; Hon, M.-Y.;
Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. ReV. 1989, 89, 165-
198. (g) de Meijere, A.; Wessjohann, L. Synlett 1990, 20-32. (h)
Kulinkovich, O. G. Russ. Chem. ReV. 1993, 62, 839-850. (i) Carbocyclic
Three- and Four-Membered Ring Compounds. In Houben-Weyl, Methods
of Organic Chemistry, 4th ed.; de Meijere, A., Ed.; Thieme Verlag:
Stuttgart, 1997; Vol. E17a, E17b, E17c, E17d. (j) Salau¨n, J. Top. Curr.
Chem. 2000, 207, 1-67. (k) de Meijere, A.; Kozhushkov, S. I.; Khlebnikow,
A. F. Top. Curr. Chem. 2000, 207, 89-147. (l) de Meijere, A.; Kozhushkov,
S. I.; Hadjiarapoglou, L. P. Top. Curr. Chem. 2000, 207, 149-227. (m)
Reissig, H. Y.; Zimmer, R. Chem. ReV. 2003, 103, 1151-1196. (n) Gnad,
F.; Reiser O. Chem. ReV. 2003, 103, 1603-1624.
(17) Yu. M.; Lynch, V.; Pagenkopf, B. L. Org. Lett. 2001, 3, 2563-
2566.
(18) The vinyl ethers were readily prepared by the method of Gassman:
(a) Gassman, P. G.; Burns, S. J. J. Org. Chem. 1988, 53, 5574-5576. (b)
Gassman, P. G.; Burns, S. J.; Pfister, K. B. J. Org. Chem. 1993, 58, 1449-
1457.
(19) For activation with Lewis acids, see: (a) Yu, M.; Lynch, V.;
Pagenkopf, B. L. Tetrahedron 2003, 59, 2765-2771. (b) Reference 17.
(20) A solution of cyclopropane (1 mmol) and nitrile (10 equiv) in
nitromethane (2 mL) cooled to ca. -35 °C, depending on reaction partners,
was treated with Me3SiOTf (1 mmol). After 2-12 h, the reaction was poured
into vigorously stirred saturated aqueous NaHCO3, extracted and purified
by chromatography.
5100
Org. Lett., Vol. 5, No. 26, 2003

Table 2. Nitrile Cycloadditions with DA Cyclopropanes
Table 3. Nitrile Cycloadditions with DA Cyclopropanes
a Acidic workup (1 M HCl). b ArCN ) p-MeOC6H4CN.
pyrrole synthesis that allows precise control over the instal-
lation of substituents at three positions around the pyrrole.
The method is characterized by operational simplicity,
substrate generality, and mild reaction conditions. The
material costs associated with this procedure are generally
less than other modern strategies, and the ease of product
purification simplifies large-scale reactions. Given the com-
patibility of this method with various nitrile classes and the
great number of nitriles that are commercially available (over
4000), it is likely that this work will find useful application
in diversity-oriented synthesis.
methods. In entries 1-9, various nitriles are shown to react
with pyran and furan derived cyclopropanes, affording pyr-
roles with functionalized side chains at C(4). Introduction
of an alkyl group at C(5) resulted in lower yields for entries
8 and 9, but fortunately reaction efficiency was restored when
unnecessary ring strain in the starting materials was avoided
(entries 10-14). In entries 15 and 16, C(5) methyl pyrroles
were obtained in 55-62% isolated yield without substitution
at C(4). Placing the alkoxy leaving group at the bridgehead
of the [3.1.0] bicyclic system permitted the synthesis of
4,5,6,7-tetrahydroindoles (entries 17 and 18). These are useful
synthetic intermediates in natural product and pharmaceutical
chemistry and can be readily oxidized to the indole.21,22 The
results in Table 2 reveal the diverse substitution permutations
that are possible with this methodology. Another advantage
is that the stereochemistry of the cyclopropane appears to
have no effect on reaction efficiency. For example, in entries
3, 10, and 13, identical yields were obtained whether
mixtures or single stereoisomers of cyclopropanes were used.
Table 3 summarizes the results from cycloaddition reac-
tions with more densely functionalized cyclopropanes that
were prepared from glycals or related structures. These
reactions illustrate that the pyrrole synthesis is compatible
with a variety of protective groups, including di-tert-butyl
silylenes (entries 1-4), benzyl ethers (entries 4 and 5), and
acetates (entry 6).23 The considerable substrate and functional
group compatibility will be an important asset when prepar-
ing pyrroles of increased complexity.
Acknowledgment. We thank the DOD Prostate Cancer
Research Program DAMD17-01-1-0109, the Texas Ad-
vanced Research Program 003658-0455-2001, and the Robert
A. Welch Foundation for partial financial support. M.Y.
thanks the Dorothy B. Banks Charitable Trust Fund for a
graduate scholarship. We are grateful to Professor Jonathan
Sessler for helpful discussions.
Supporting Information Available: Characterization of
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL036180+
(21) For a review: Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1998,
615-628.
(22) For a recent example: Hodges, L. M.; Spera, M. L.; Moody, M.
W.; Harman, W. D. J. Am. Chem. Soc. 1996, 118, 7117-7127.
(23) A notable difference in reactivity with those substrates prepared by
intramolecular cyclopropanation is that under the standard reaction condi-
tions the 3,4-dihydro-2H-pyrroles 4 can be isolated, but treating them during
workup or in a separate step with aqueous acid affords the pyrrole in high
yield.
In conclusion, the domino donor-acceptor cyclopropane
nitrile [3 + 2] cycloaddition, dehydration, and tautomeriza-
tion strategy is a powerful and efficient new method for
Org. Lett., Vol. 5, No. 26, 2003
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