Highly Efficient Access to Original Polycyclic Pyrrolopiperazine Scaffolds by a Three-Component Reaction with 1,3-Dicarbonyls

Abstract

Molecular sieves have been found to promote a new fast, environmentally friendly and experimentally simple multicomponent domino reaction from 1,3-dicarbonyls for the synthesis of pyrrolopiperazine and azasteroid-like scaffolds, of potential synthetic and biological interests.

Key words

multicomponent reaction - atom economy - pyrrolopiperazine - 1,3-dicarbonyls - molecular sieves - heterogeneous catalysis

References and Notes

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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), β-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; R _f = 0.57 (PE-EtOAc, 3:1). IR (liquid film): ν = 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): δ = 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): δ = 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.

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: [phone]; e-mail: [e-mail]].

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.

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%.