LETTER
Access to Original Polycyclic Pyrrolopiperazine Scaffolds
1325
b-ketoester 1 (200 mg, 1.0 equiv), freshly distilled acrolein
(2, 1.2 equiv), and amine 3 (1.0 equiv). The heterogeneous
mixture was stirred at reflux under Ar for 24 h. The solution
was filtered through a short pad of Celite®, which was
thoroughly washed with toluene. The solvent was
evaporated under reduced pressure to afford crude
compound 4 with good chemical purity. An analytical
sample was isolated by flash chromatography over silica gel.
Selected Physical Data for Compounds 4h
Yellow oil; Rf = 0.57 (PE–EtOAc, 3:1). IR (liquid film): n =
2924, 1735, 1654, 1156, 1094 cm–1. MS (ESI): m/z (rel.
intensity, %) = 392 [M + H]+ (13.0), 273 (100), 120 (10.7).
1H NMR (300.13 MHz, CDCl3): d = 7.23 (5 H, m), 6.50 (1
H, m), 6.16 (1 H, dd, J = 3.6, 2.7 Hz), 5.85 (1 H, t, J = 1.5
Hz), 4.90 (1 H, dd, J = 4.7, 2.1 Hz), 4.10 (2 H, m), 4.03 (1 H,
m), 3.94 (1 H, br dd, J = 11.6, 3.0 Hz), 3.68 (1 H, d, J = 13.3
Hz), 3.58 (1 H, dd, J = 11.6, 2.8 Hz), 3.54 (1 H, br dd,
J = 12.0, 3.5 Hz), 3.47 (1 H, br dd, J = 15.3, 4.7 Hz), 3.42 (1
H, d, J = 13.3 Hz), 3.10 (1 H, dd, J = 11.2, 1.2 Hz), 2.92 (1
H, td, J = 11.9, 4.1 Hz), 2.91 (1 H, dd, J = 15.3, 2.0 Hz), 2.30
(1 H, dt, J = 13.0, 3.1 Hz), 2.19 (1 H, d, J = 11.2 Hz), 2.12 (1
H, dq, J = 13.5, 3.1 Hz), 1.70 (1 H, tdd, J = 13.9, 11.3, 3.3
Hz), 1.48 (1 H, td, J = 13.5, 3.6 Hz), 1.13 (3 H, t, J = 7.2 Hz).
13C NMR (75.47 MHz, CDCl3): d = 173.9, 144.2, 138.5,
130.7, 128.5 (2 C), 128.0 (2 C), 126.8, 118.0, 108.1, 101.7,
101.4, 61.5, 60.6, 60.5, 57.9, 53.5, 48.8, 45.1, 44.4, 31.2,
28.9, 14.0.
References and Notes
(1) For a special issue in environmental chemistry, see: Chem.
Rev. 1995, 95, 3.
(2) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
(3) Weber, L.; Illgen, M.; Almstetter, M. Synlett 1999, 366.
(4) Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997,
19, 765.
(5) (a) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, 2005. (b) Ramon, D. J.; Yus, M.
Angew. Chem. Int. Ed. 2005, 44, 1602. (c) Dömling, A.
Chem. Rev. 2006, 106, 17.
(6) (a) Domino Reactions in Organic Synthesis; Tietze, L. F.;
Brasche, G.; Gericke, K. M., Eds.; Wiley-VCH: Weinheim,
2006. For some representative reviews, see: (b) Tietze, L.
F.; Lieb, M. E. Curr. Opin. Chem. Biol. 1998, 2, 363.
(c) Rodriguez, J. Synlett 1999, 505.
(7) (a) Schreiber, S. L. Science 2000, 287, 1964. (b)Wender, P.
A.; Gamber, G. G.; Hubbard, R. D.; Pham, S. M.; Zhang, L.
J. Am. Chem. Soc. 2005, 127, 2836. (c) Vugts, D. J.;
Koningstein, M. M.; Schmitz, R. F.; de Kanter, F. J. J.;
Groen, M. B.; Orru, R. V. A. Chem. Eur. J. 2006, 12, 7178.
(8) Tucker, J. L. Org. Process Res. Dev. 2006, 10, 315.
(9) For recent reviews on the utilization of 1,3-dicarbonyl
derivatives in MCRs, see: (a) Simon, C.; Constantieux, T.;
Rodriguez, J. Eur. J. Org. Chem. 2004, 4957. (b) Liéby-
Muller, F.; Simon, C.; Constantieux, T.; Rodriguez, J. QSAR
Comb. Sci. 2006, 25, 432.
(10) (a) Peresada, V. P.; Medvedev, O. S.; Likhosherstov, A. M.;
Skoldinov, A. P. Khim. Farm. Zh. 1987, 21, 1054.
(b) Katritzky, A. R.; Jain, R.; Xu, Y.-J.; Seel, P. J. J. Org.
Chem. 2002, 67, 8220.
(11) (a) For a recent review, see: Hoffmann, H.; Lindel, T.
Synthesis 2003, 1753. (b) See also: Davis, F. A.; Deng, J.
Org. Lett. 2005, 7, 621.
(12) (a) Seredenin, S. B.; Voronina, T. A.; Likhosherstov, A. M.;
Peresada, V. P.; Molodavkin, G. L.; Halikas, J. A. US Patent
5,378,846, 1995. (b) Negoro, T.; Murata, M.; Ueda, S.;
Fujitani, B.; Ono, Y.; Kuromiya, A.; Komiya, M.; Suzuki,
K.; Matsumoto, J. J. Med. Chem. 1998, 41, 4118.
(13) (a) Simon, C.; Peyronel, J. F.; Rodriguez, J. Org. Lett. 2001,
3, 2145. (b) Simon, C.; Liéby-Muller, F.; Peyronel, J.-F.;
Constantieux, T.; Rodriguez, J. Synlett 2003, 2301.
(c) Liéby-Muller, F.; Constantieux, T.; Rodriguez, J. J. Am.
Chem. Soc. 2005, 127, 17176. (d) Liéby-Muller, F.; Simon,
C.; Imhof, K.; Constantieux, T.; Rodriguez, J. Synlett 2006,
1671.
(14) (a) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44,
2030. (b) For a review, see: Cox, E. D.; Cook, J. M. Chem.
Rev. 1995, 95, 1797.
(15) Jirkovsky, I.; Baudy, R. Synthesis 1981, 481.
(16) Typical Procedure for the Synthesis of Compounds 4
To a 50 mL two-necked round-bottomed flask flushed with
Ar, equipped with a magnetic stirring bar and a reflux
condenser, were added toluene freshly distilled over CaH2
(25 mL), commercially available inactivated 4 Å MS (6 g),
(17) The stereochemistry of the products has been fully studied
by 2D NMR analysis which is part of F. Liéby-Muller’s PhD
Thesis, and details will be published in due course.
(18) Although fully reproducible, the origin of the total
diastereoselectivity observed in the case of 1h is not yet
clear, and further experimentations and calculations are in
progress and will be reported in due course.
(19) Crystallographic data for the structure reported in this paper
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication no. CCDC
264343. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ,
UK [fax: +44 (1223)336033; e-mail:
deposit@ccdc.cam.ac.uk].
(20) Michael adduct 5h has been prepared by reaction of 1h with
acrolein (2), in the presence of Dowex resins. When this 1,5-
dicarbonyl compound reacts with amine 3, the same product
(4h) is obtained as in the one-pot sequence.
(21) Matoba, K.; Shibata, M.; Yamazaki, T. Chem. Pharm. Bull.
1982, 30, 1718.
(22) The presence of MS is crucial since no reaction takes place
under simple azeotropic distillation or in the presence of
TMOF as dehydrating agent. Moreover, some other
heterogeneous catalysts such as basic or acidic alumina,
montmorillonite K10 or Dowex ion-exchange resin have
been tested in this sequence with very lower efficiency,
leading sometimes to decomposition or to the desired
product in yields not exceeding 20%.
Synlett 2007, No. 8, 1323–1325 © Thieme Stuttgart · New York