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DOI: 10.1055/s-0029-1216885
Pyrrolidine-Based Organocatalysts for Enantioselective Michael Addition of Cyclohexanone to trans-β-Nitrostyrene
Publication History
Publication Date:
07 July 2009 (online)
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Abstract
A series of readily prepared bifunctional catalysts promote the Michael addition of cyclohexanone to trans-β-nitrostyrene with excellent asymmetric induction. The enantioselection (up to 97%) and diastereoselection (up to 95:5) is comparable to other pyrrolidine-thiourea organocatalysts recently reported, however, reaction times are often shorter.
Key words
addition reactions - asymmetric catalysis - Michael additions - bifunctional catalysis - nitroolefin
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References
We also prepared pyrrolidines with 2-carboxamide- or 2-methylacetamide-tethered thiourea and thiouronium functionality. Attempted catalysis of the conjugate addition of cyclohexanone to trans-β-nitrostyrene typically resulted in a syn/anti diastereomeric product ratio of >91:9 with carboxamide-tethered catalysts, comparable to that seen with monofunctional catalysis by (2S)-N-benzylpyrrolidine-2-carboxamide. However, poor syn enantioselectivity (<30% ee) resulted and all methylacetamide-tethered examples demonstrated little or no catalytic activity. Similar amide-linked, amine-thiourea catalysts were also reported to give only the racemic product of ketone addition to nitro-olefins during the course of our study (ref. 7e), presumably as a result of intramolecular hydrogen bonding between thiourea/uronium functionality and the tethering amide.
18To our knowledge, comparable rates of catalysis for the Michael addition of ketones to nitroalkenes only by diamines have been reported; see references 4e, 6a, and 6b.
20A 3:1 ratio of syn/anti with catalyst 13 was the best result obtained. The reaction was conducted with 0.5 mmol trans-β-nitrostyrene in 0.75 mL toluene, 15 mol% 13, 0.15 equiv AcOH and 1 equiv H2O at r.t. Typically syn/anti diastereo-meric ratios of 1:1 or 2:1 resulted with catalysts 4, 6, 7, 10, 12, or 14; major diastereoisomer ee (%) ranged between 8-77%.
21Configuration of (S)-2-[(R)-2-nitro-1-phenylethyl]cyclo-hexanone (16) was determined by literature comparison of HPLC elution order, see ref. 7e; and optical rotation; [α]D -26.7 (c = 1.0, CHCl3, 24 ˚C), see ref. 22.