ORGANIC
LETTERS
2006
Vol. 8, No. 25
5837-5840
Regioselective Synthesis of Substituted
Pyrroles: Efficient Palladium-Catalyzed
Cyclization of Internal Alkynes and
2-Amino-3-iodoacrylate Derivatives
Matthew L. Crawley,*,† Igor Goljer,‡ Douglas J. Jenkins,† John F. Mehlmann,†
Lisa Nogle,‡ Rebecca Dooley,‡ and Paige E. Mahaney†
DiscoVery Medicinal Chemistry and DiscoVery Analytical Chemistry, Wyeth Research,
500 Arcola Road, CollegeVille, PennsylVania 19426
Received October 2, 2006
ABSTRACT
The first efficient and regioselective palladium-catalyzed cyclization of internal alkynes and 2-amino-3-iodoacrylates to give moderate to excellent
yields of highly functionalized pyrroles has been developed. This approach is applicable to a range of alkynes and affords the deacylated
pyrrole under reaction conditions for most substrates.
Pyrroles are prevalent and important heterocycles in natural
products,1 modern pharmaceuticals,2 and material science.3
Despite a vast range of published classical4,5 and recent6
methods on their synthesis, there are very few general
approaches that convert commercially available or readily
accessible materials in one step to highly substituted pyrroles.
In contrast, the literature is replete with methods for the
synthesis of indoles from simple building blocks.5 In an effort
to develop a synthesis of pyrroles relevant to our drug
discovery efforts we examined the potential of adapting the
“Larock Indole Synthesis7” type approach to the synthesis
of pyrroles.
Dozens of pyrrole synthesis methods involve alkynes as
starting materials;8 however, despite the depth of prior work
on pyrrole synthesis we were surprised to find that, to the
best of our knowledge, intermolecular metal-catalyzed cy-
clizations of alkynes with stabilized iodo enamines have
† Discovery Medicinal Chemistry.
‡ Discovery Analytical Chemistry.
(1) For a review see: Jones, R. A., Ed. Pyrroles; Wiley: New York,
1992; , Part II, Vol. 48.
(2) (a) Thompson, R. B. FASEB J. 2001, 15, 1671. (b) Muchowski, J.
M. AdV. Med. Chem. 1992, 1, 109. (c) Cozzi, P.; Mongelli, N. Curr. Pharm.
Des. 1998, 4, 181. (d) Fuerstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J.
Am. Chem. Soc. 1998, 120, 8305.
(3) For a review see: Higgins, S. Chem. Soc. ReV. 1997, 26, 247.
(4) Widely utilized methods include: (a) “Paal-Knorr pyrrole synthe-
sis”: Knorr, L. Ber. 1884, 17, 1635. Paal, C. Ber. 1885, 18, 367. (b) “Knorr,
pyrrole synthesis”: Fischer, H. Org. Synth. Collect. 1943, 2, 202.
(5) For a review of practical syntheses of both indoles and pyrroles see:
Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1999, 2849.
(6) For recent representative examples, see: (a) Winkler, J. D.; Ragains,
J. R. Org. Lett. 2006, 8, 4437. (b) Dhawan, R.; Arndtsen, B. A. J. Am.
Chem. Soc. 2004, 126, 468. (c) Shimizu, M.; Takahashi, A.; Kawai, S. Org.
Lett. 2006, 8, 3585.
(7) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652.
(8) For recent representative examples see: (a) Ishikawa, T.; Aikawa,
T.; Watanabe, S.; Saito, S. Org. Lett. 2006, 8, 3881. (b) Kamijo, S.;
Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260. (c)
Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151. (d) Harrison, T. J.;
Kozak, J. A.; Corbella-Pane, M.; Dake, G. R. J. Org. Chem. 2006, 71,
4525. (e) Ohri, R. V.; Radosevich, A. T.; Hrovat, K. J.; Musich, C.; Huang,
D.; Holman, T. R.; Toste, F. D. Org. Lett. 2005, 7, 2501. (f) Gorin, D. J.;
Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. (g) Tejedor,
D.; Gonzalez-Cruz, D.; Garcia-Tellado, F.; Marrero-Tellado, J. J.; Rodriguez,
M. L. J. Am. Chem. Soc. 2004, 126, 8390. (h) Ramanathan, B.; Keith, A.
J.; Armstrong, D.; Odom, A. L. Org. Lett. 2004, 6, 2957. (i) Kel’in, A. V.;
Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074.
10.1021/ol062424p CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/10/2006