Synthesis of 2,2′-bipyrroles and 2,2′-thienylpyrroles from donor-acceptor cyclopropanes and 2-cyanoheteroles

Article abstract of DOI:10.1021/ol049857h

(Equation presented) Two new series of 2,2′-bipyrroles and 2,2′-thienylpyrroles have been prepared by trimethylsilyl trifluoromethanesulfonate (TMSOTf)-mediated reaction of donor-acceptor cyclopropanes with 2-cyanopyrroles and 2-cyanothiophene, respectively. This method opens the door toward a wide variety of unsymmetrical bipyrroles and thienylpyrroles.

Full text of DOI:10.1021/ol049857h

ORGANIC
LETTERS
2004
Vol. 6, No. 6
1057-1059
Synthesis of 2,2′-Bipyrroles and
2,2′-Thienylpyrroles from
Donor−Acceptor Cyclopropanes and
2-Cyanoheteroles
Ming Yu, G. Dan Pantos, Jonathan L. Sessler, and Brian L. Pagenkopf*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
pagenkopf@mail.utexas.edu
Received January 25, 2004
ABSTRACT
Two new series of 2,2′-bipyrroles and 2,2′-thienylpyrroles have been prepared by trimethylsilyl trifluoromethanesulfonate (TMSOTf)-mediated
reaction of donor−acceptor cyclopropanes with 2-cyanopyrroles and 2-cyanothiophene, respectively. This method opens the door toward a
wide variety of unsymmetrical bipyrroles and thienylpyrroles.
Pyrrole and its derivatives are ubiquitous in nature.1 Pyrrole-
containing compounds are spread throughout the phylogenic
tree;1 leaves (chlorophyll), red-blood cells (heme), and
seabird eggs2 (bipyrrole) are just a few well-known examples.
Thienylpyrrole and bipyrroles have been the focus of material
science and medicinal chemistry. In material science, they
have found applications in indigoid dyes,3 conducting
polymers,4 anion binding agents,5 and nuclear waste removal
agents,6 while in medicinal chemistry, they are important
building blocks for the synthesis of antitumor agents (pro-
digiosins,7 sapphyrins8) and therapeutic agents in photo-
dynamic therapy as radiation sensitizers.8
Classic bipyrrole syntheses mostly employ oxidative,9
Ullman-type10 homocouplings or couplings of pyrrolinones
(7) Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582-3603.
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Chem. 1985, 22, 281-285. (c) Boger, D. L.; Patel, M. Tetrahedron Lett.
1987, 28, 2499-2502. (d) Boger, D. L.; Patel, M. J. Org. Chem. 1988, 53,
1405-1415. (e) Falk, H.; Flo¨dl, H. Monatsh. Chem. 1988, 119, 247-252.
(f) Glaser, M.; Gruner, M.; Viola, H. J. Prakt. Chem. 1994, 336, 363-365.
(g) Wasserman, H. H.; Petersen, A. K.; Xia, M.; Wang, J. Tetrahedron
Lett. 1999, 40, 7587-7589. (h) Oda, K.; Sakai, M.; Ohno, K.; Machida,
M. Heterocycles 1999, 50, 277-282.
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O. Angew. Chem., Int. Ed. Engl. 1987, 26, 928-931. (b) Sessler, J. L.;
Cyr, M. J.; Lynch, V.; McGhee, E.; Ibers, J. A. J. Am. Chem. Soc. 1990,
112, 2810-2813. (c) Sessler, J. L.; Cyr, M.; Burrell, A. K. Tetrahedron
1992, 48, 9661-9672. (d) Guilard, R.; Aukauloo, M. A.; Tardieux, C.;
Vogel, E. Synthesis 1995, 1480-1482. (e) Nonell, S.; Bou, N.; Borrell, J.
I.; Teixido, J.; Villanueva, A.; Juarranz, J.; Can˜ete, M. Tetrahedron Lett.
1995, 36, 3405-3408. (f) Johnson, M. R.; Slebodnick, C.; Ibers, J. A. J.
Porphyrins Phthalocyanines 1997, 1, 87. (g) Merz, A.; Kronberger, J.;
Dunsch, L.; Neudeck, A.; Petr, A.; Parkenyi, L Angew. Chem., Int. Ed.
1999, 38, 1442-1446. (h) Shevchuk, S. V.; Davis, J. M.; Sessler, J. L.
Tetrahedron Lett. 2001, 42, 2447-2450. (i) Skowronek, P.; Lightner, D.
A. Monatsh. Chem. 2003, 134, 889-899. (j) Merz, A.; Anikin, S.; Lieser,
B.; Heinze, J.; John, H. Chem.sEur. J. 2003, 9, 449-455.
(1) (a) Battersby, A. R. Nat. Prod. Rep. 2000, 17, 507-526. (b) Milgrom,
L. R. The Colours of Life; Oxford University Press: Oxford, 1997. (c)
Chlorophylls; Scheer, H., Ed.; CRC Press: Boca Raton, 1991. (d) Falk, H.
The Chemistry of Linear Oligopyrroles and Bile Pigments; Springer-
Verlag: Wien, 1989.
(2) Tittlemier, S. A.; Simon, M.; Jarman, W. M.; Elliott, J. E.; Norstrom,
R. J. EnViron. Sci. Technol. 1999, 33, 26-33.
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Mater. 1998, 10, 1166-1175.
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26, 1107-1117. (b) Sessler, J. L.; Camiolo, S.; Gale, P. A. Coord. Chem.
Rew. 2003, 240, 17-55. (c) Sessler, J. L.; An, D.; Cho, W.-S.; Lynch, V.
M. J. Am. Chem. Soc. 2003, 125, 13646-13647. (d) Sessler, J. L.; An, D.;
Cho, W.-S.; Lynch, V. M. Angew. Chem., Int. Ed. 2003, 42, 2278-2281.
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Chim. Acta 2002, 341, 54-70.
10.1021/ol049857h CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/20/2004

with pyrroles.11 These methods, although widely employed,
are generally limited to the preparation of symmetric
bipyrroles (oxidative and Ullman couplings) or to a limited
range of unsymmetrical products (pyrrolinone pathway). In
recent years, advances in Suzuki12 and Stille4 couplings,
mostly focused on prodigiosin synthesis, were developed for
preparing unsymmetric bypyrroles. A different approach to
R,R′-fused heterocycles is to assemble the heterocycles from
a single appropriate precursor rather than coupling two
preformed assemblies.13
dehydration reaction cascade ensued that gave the targeted
byprrole products in good isolated yields (78 and 82%).
Protection of the pyrrole nitrogen proved to be unnecessary.
Inspired by these results, the generality of the bipyrrole
synthesis was examined with variously substituted DA
cyclopropanes, and the results are summarized in Table 1.
Table 1. Synthesis of Bipyrroles from DA Cyclopropanes and
Pyrrole-2-carbonitriles
Recently, we reported a new strategy for diversity-oriented
synthesis of pyrroles14 that involves the reaction of donor-
acceptor (DA) cyclopropanes with aliphatic, aromatic, and
R,â-unsaturated nitriles.15 Advantages to this method include
the use of readily accessible starting materials, complete
regiochemical control over substituent placement, and ease
of product purification. Herein we present a useful application
of this methodology to the synthesis of unsymmetrical
bipyrroles and thienylpyrroles, which employs the classic
synthetic strategy for pyrrole construction of utilizing a
functional group extending from a preexisting heterocycle.13
For our initial studies, we directed our attention toward
the synthesis of R,R′-bipyrroles from two 2-cyanoprroles that
are commercially available (1H-pyrrole-2-carbonitrile) or
accessible by reported procedures (3,4-diethyl-1H-pyrrole-
2-carbonitrile) (Scheme 1).16 When a cold (-25 to 0 °C)
Scheme 1
MeNO2 or EtNO2 solution of DA cyclopropane and pyrrole-
2-carbonitrile was treated with a stoichiometric amount of
trimethylsilyl triflate, a cyclization, tautomerization, and
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Perkin Trans. 1 1986, 455-463. (c) D’Alessio, R.; Rossi, A. Synlett 1996,
513-514. (d) Wu, J.; Vetter, W.; Gribble, G. W.; Schneekloth, J. S., Jr.;
Blank, D. H.; Go¨rls Angew. Chem., Int. Ed. 2002, 41, 1740-1743.
(12) (a) D’Alession, R.; Rossi, A. Synlett 1996, 513-514. (b) Fu¨rstner,
A.; Grabowski, J.; Lehmann, C. W. J. Org. Chem. 1999, 64, 8275-8280.
(c) Fu¨rstner, A.; Grabowski, J.; Lehmann, C. W.; Kataoke, T.; Nagai, K.
Chem. Biol. Chem. 2001, 2, 60-68. (d) Melvin, M. S.; Calcutt, M. W.;
Noftle, R. E.; Manderville, R. A. Chem. Res. Toxicol. 2002, 15, 742-748.
(13) (a) Farnier, M.; Soth, S.; Fournari, P. Can. J. Chem. 1976, 54, 1074-
1082. (b) Hinz, W.; Jones, R. A.; Patel, S. U.; Karatza, M.-H. Tetrahedron
1986, 42, 3753-3758. (c) Wasseman, H. H.; Lombardo. L. J. Tetrahedron
Lett. 1989, 30, 1725-1728. (d) Buchwald, S. L.; Wannamaker, M. W.;
Watson, B. T. J. Am. Chem. Soc. 1989, 111, 776-777. (e) Musicki, B. J.
Org. Chem. 1990, 55, 910-918. (f) Gupton, J. T.; Petrich, S. A.; Hicks, F.
A.; Wilkinson, D. R.; Vargas, M.; Hosein, K.; Sikorski, J. A. Heterocycles
1998, 47, 689-702. (g) Korostova, S. E.; Mikhaleva, A. I.; Trofimov, B.
A. Russ. Chem. ReV. 1999, 68, 459-482. (h) Barluenga, J.; Tomas, M.;
Rubio, E.; Lopez-Pelegrin, J. A.; Garcia-Granda, S.; Perez Priede, M. J.
Am. Chem. Soc. 1999, 121, 3065-3071. (i) Araki, S.; Tanaka, T.; Toumatsu,
S.; Hirashita, T. Org. Biomol. Chem. 2003, 1, 4025-4029.
The first examples studied gave bipyrroles with a methyl
group installed at the R-position (Scheme 1, Table 1, entries
1 and 2), and the reactions in entries 3 and 4 show that the
R-position need not be substituted. The experiments in entries
5 and 6 provided bipyrroles with alkyl substitution at both
the R- and â-positions, and entry 7 completes the series by
providing a bipyrrole with only â-substitution. The remaining
(14) Yu, M.; Pagenkopf, B. L. Org. Lett. 2003, 5, 5099-5101.
(15) Yu, M.; Pagenkopf, B. L. J. Am. Chem. Soc. 2003, 125, 8122-
8123.
(16) (a) Barnett, G. H.; Anderson, H. J.; Loader, C. E. Can. J. Chem.
1980, 58, 409-411. (b) Loader, C. H.; Anderson, H. J. Can. J. Chem. 1981,
59, 2673-2676.
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Org. Lett., Vol. 6, No. 6, 2004

DA cyclopropanes and thiophene-2-carbonitrile (Table 2).
These results again demonstrate the ability of this synthetic
method to control the installation of alkyl groups at the R-
and â-positions of the newly formed pyrrole.
Table 2. Synthesis of Thienylpyrroles from DA Cyclopropanes
and Thiophene-2-carbonitriles
Higher yields were obtained from reaction with DA
cyclopropanes wherein the alkoxy group is attached to a
quaternary carbon (e.g., Table 1, entries 1, 2, 5, 6, 8, 9, and
12; Table 2, entry 2 (but not 4)), results that generally parallel
the stability of the intermediate oxocarbenium ion generated
from cyclopropane ring opening.
In some prospective applications, electron-rich variants of
these bipyrroles and thienylpyrroles will be required. In this
regard, the â-ethyl carboxylate can be removed by decar-
boxylation in hot alkaline ethylene glycol (Scheme 2). High
reaction temperatures and short reaction times (e.g., 160 °C
oil bath, 5 min) give the best yields.
Scheme 2
entries in Table 1 explore reactivity with 6,3- and 5,3-fused
DA cyclopropanes. These substrates afforded bipyrroles with
different substitution patterns, and in entries 10-13, a
hydroxyl group terminates the chain at the â-position, thereby
providing a synthetically useful functional handle.
A quick inspection of the results summarized in Table 1
reveals that the yields for the formation of bipyrroles starting
from 3,4-diethyl-1H-pyrrole-2-carbonitrile were consistently
higher than those obtained from the unsubstituted pyrrole.
This outcome is consistent with the greater nucleophilicity
expected to be endowed to the nitrile by the electron-donating
ethyl groups at the pyrrole â-positions.
Acknowledgment. This work was supported in part by
The Robert A. Welch Foundation, the donors of the
Petroleum Research fund, administered by the American
Chemical Society, the DOD Prostate Cancer Research
Program DAMD 17-01-1-0109, the Texas Advanced Re-
search Program 003658-0455-2001, the National Science
Foundation, and the National Institutes of Health.
Supporting Information Available: Experimental pro-
cedures and characterization of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The identical reaction conditions were then applied to the
synthesis of thienylpyrroles by the combination of various
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