ORGANIC LETTERS
Synthesis of Highly Substituted Pyrroles via a Multimetal-Catalyzed Rearrangement−Condensation−Cyclization Domino Approach
2006 Vol. 8, No. 10 2151-2153
Jo1 rg T. Binder and Stefan F. Kirsch* Department Chemie, Technische UniVersita¨t Mu¨nchen, Lichtenbergstrasse 4, 85747 Garching, Germany
[email protected] Received March 17, 2006
ABSTRACT
In a convenient one-pot process, easily accessed propargyl vinyl ethers and aromatic amines are effectively converted into tetra- and pentasubstituted 5-methylpyrroles which can further be transformed into 5-formylpyrroles via IBX-mediated oxidation. The cascade reaction proceeds through a silver(I)-catalyzed propargyl−Claisen rearrangement, an amine condensation, and a gold(I)-catalyzed 5-exo-dig heterocyclization.
Highly substituted pyrroles are important structural elements of many natural products1 and pharmaceutically active substances (e.g., lipitor).2 Moreover, they are widely used in materials science.3 The construction of multiple substituted pyrrole rings typically relies on classical condensation methods such as the Paal-Knorr synthesis,4 although catalytic multicomponent coupling approaches5 are particularly attractive due to their rapid access to structural diversity. Despite numerous strategies for pyrrole synthesis through cyclization,6 access to pentasubstituted pyrroles5e,6b is somewhat limited. (1) (a) Sundberg, R. J. In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford, UK, 1996; Vol. 2, p 119. (b) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54. (c) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435. (d) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753. (e) Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582. (f) Agarwal, S.; Ca¨mmerer, S.; Filali, S.; Fro¨hner, W.; Kno¨ll, J.; Krahl, M. P.; Reddy, K. R.; Kno¨lker, H.-J. Curr. Org. Chem. 2005, 9, 1601. (2) (a) Huffman, J. W. Curr. Med. Chem. 1999, 6, 705. (b) Thompson, R. B. FASEB J. 2001, 15, 1671. (3) (a) Curran, D.; Grimshaw, J.; Perera, S. D. Chem. Soc. ReV. 1991, 20, 391. (b) Lee, C. F.; Yang, L. M.; Hwu, T. Y.; Feng, A. S.; Tseng, J. C.; Luh, T. Y. J. Am. Chem. Soc. 2000, 122, 4992. (c) Domingo, V. M.; Aleman, C.; Brillas, E.; Julia, L. J. Org. Chem. 2001, 66, 4058. (4) (a) Knorr, L. Ber. Dtsch. Chem. Ges. 1884, 17, 1635. (b) Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367. 10.1021/ol060664z CCC: $33.50 Published on Web 04/12/2006
© 2006 American Chemical Society
In the context of ongoing efforts to develop cascade reactions initiated by transition-metal-catalyzed π-activation, we recently reported that acceptor substituted propargyl vinyl ethers can be effectively transformed into furans by a gold(I)catalyzed cascade reaction.7 Herein, we report a conceptually new synthetic approach to tetra- and pentasubstituted pyrroles utilizing a transition-metal-catalyzed domino reaction of a formal [3,3]-sigmatropic rearrangement, an amine condensation, and a heterocyclization. In this simple one-pot assembly, (5) For a review, see: (a) Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238. For selected examples, see: (b) Braun, R.; Zeitler, K.; Mu¨ller, T. J. J. Org. Lett. 2001, 3, 3297. (c) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Milton, M. D.; Hidai, M.; Uemura, S. Angew. Chem., Int. Ed. 2003, 42, 2681. (d) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465. (e) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126, 468. (f) Tejedor, D.; Gonza´lez-Cruz, D.; Garcı´a-Tellado, F.; Marrero-Tellado, J. J.; Rodrı´guez, M. L. J. Am. Chem. Soc. 2004, 126, 8390. (g) Schro¨ter, S.; Bach, T. Synlett 2005, 1957. (h) Yamamoto, Y.; Hayashi, H.; Saigoku, T.; Nishiyama, H. J. Am. Chem. Soc. 2005, 127, 10804. (6) For recent examples, see: (a) Kim, J. T.; Kel’in, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2003, 42, 98. (b) Wang, Y. L.; Zhu, S. Z. Org. Lett. 2003, 5, 745. (c) Larionov, O. V.; de Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 5664. (d) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9260. (e) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. (f) Wurz, R. P.; Charette, A. B. Org. Lett. 2005, 7, 2313. (g) Lu, L.; Chen, G.; Ma, S. Org. Lett. 2006, 8, 835. (7) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925.
readily obtained acceptor substituted propargyl vinyl ethers 1 and aromatic amines 2 are used as starting materials to produce pyrrole products 3 with high diversity (Scheme 1).
Scheme 1.
Synthesis of Pyrrole 3 from Propargyl Vinyl Ether 1 and Amine 2
During the envisioned process, three independent reactions should occur sequentially: a catalytic version of a propargylClaisen rearrangement8,9 to generate allenic ketones, a condensation with a primary amine,10 and a transition-metalcatalyzed 5-exo-dig cyclization.7 To realize a single-step process by subsequent addition of reactants and catalysts,11 we first developed the silver(I)-catalyzed rearrangement route to the intermediary occurring allenylcarbonyl compounds. Treatment of propargyl vinyl ethers 1 with several silver(I) salts at room temperature produced an isomeric mixture of the corresponding allenes in a remarkably clean reaction. By far, the best catalyst was AgSbF6, which provided the rearrangement products rapidly in CH2Cl2. The reaction takes place at room temperature without the formation of significant amounts of any byproducts. Of primary importance, the corresponding furans7 were not seen by 1H NMR analysis of crude reaction mixtures. Low catalyst loadings (1-5 mol %) are sufficient to effect rearrangement in almost quantitative yield. As the next step, we attempted to combine the Ag(I)catalyzed propargyl-Claisen rearrangement with condensation and heterocyclization.12 After formation of the corresponding allenylcarbonyl compound from propargyl vinyl ether 1a (R1 ) Ph, R2 ) Me, R3 ) H, Y ) OEt), using 5 mol % of AgSbF6 in CH2Cl2, 1.5 equiv of aniline was added directly to the reaction mixture followed by 5 mol % of (PPh3)AuCl to provide pyrrole 3aa in 71% yield after 30 min at 38 °C (Table 1, entry 1).13,14 The Au(I)-catalyzed cyclization was (8) Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579. (9) For a single example of a Ag(I)-catalyzed rearrangement, see: (a) Grissom, J. W.; Klingberg, D.; Huang, D.; Slattery, B. J. J. Org. Chem. 1997, 62, 603. For a single example of a Au(I)-catalyzed rearrangement, see: (b) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978. (10) Arcadi, A.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. AdV. Synth. Catal. 2001, 343, 443. (11) By performing these steps simultaneously, treatment of a preformed mixture of 1 and 2 with a variety of transition-metal complexes gave only traces of the desired pyrroles 3 (
