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. 2011 Jul 13;133(27):10402-5.
doi: 10.1021/ja203810b. Epub 2011 Jun 16.

Catalytic asymmetric intermolecular Stetter reaction of enals with nitroalkenes: enhancement of catalytic efficiency through bifunctional additives

Daniel A DiRocco  1 , Tomislav Rovis
Affiliations

Catalytic asymmetric intermolecular Stetter reaction of enals with nitroalkenes: enhancement of catalytic efficiency through bifunctional additives

Daniel A DiRocco et al. J Am Chem Soc. .

Abstract

An asymmetric intermolecular Stetter reaction of enals with nitroalkenes catalyzed by chiral N-heterocyclic carbenes has been developed. The reaction rate and efficiency are profoundly impacted by the presence of catechol. The reaction proceeds with high selectivities and affords good yields of the Stetter product. Internal redox products were not observed despite of the protic conditions. The impact of catechol has been found to be general, facilitating far lower catalyst loadings than were previously achievable.

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Figures

Figure 1
Figure 1
Proposed mode of activation.
Scheme 1
Scheme 1
Effect of catechol in the intramolecular Stetter Reaction.
Chart 1
Chart 1
Effect of Brønsted acid additives a,b,c aReactions conducted with 1 equiv of 1a and 1.5 equiv of 2a. b Enantiomeric excess determined by HPLC analysis on a chiral stationary phase. c Yield refers to isolated yields after chromatography.
Chart 2
Chart 2
Variation of the Catechol Additive a,b,c,d aReactions conducted with 1 equiv of 1a and 1.5 equiv of 2a. b Experiments quenched after 30 min. c Enantiomeric excess determined by HPLC analysis on a chiral stationary phase. d Yield refers to isolated yields after chromatography.
Chart 3
Chart 3
Examination of pre-catalysts a,b,c a,b See Chart 1. c Catalyst counterion (BF4) omitted for clarity.
Chart 4
Chart 4
Reaction Scope abc a Reactions conducted with 1 equiv of 1 and 1.5 equiv of 2. b Enantiomeric excess determined by HPLC analysis on a chiral stationary phase. c Absolute stereochemistry determined by X-ray analysis of 3e; see supporting information. d Product crystallized from reaction mixture. e 4-(ethoxycarbonyl)catechol (Chart 2, Entry 4) was used.
Chart 5
Chart 5
Influence of the N-aryl Substituent on Selectivity. a Opposite enantiomer obtained.
Chart 6
Chart 6
2H Kinetic Isotope Effect Studies.a a See supporting information for complete experimental details.
See this image and copyright information in PMC

References

    1. For reviews see: Marion N, Díez-González S, Nolan SP. Angew. Chem. Int. Ed. Engl. 2007;46:2988–3000. Enders D, Niemeier O, Henseler A. Chem. Rev. 2007;107:5606–5655. Moore JL, Rovis T. Top. Curr. Chem. 2009;290:77–144.

    1. Stetter H, Schrecke M. Angew. Chem., Int. Ed. Engl. 1973;12:81. Stetter H. Angew. Chem., Int. Ed. Engl. 1976;15:639–647. Stetter H, Kuhlmann H. Org. React. 1991;40:407–496. Christmann M. Angew. Chem., Int. Ed. 2005;44:2632–2634. Rovis T. Chem. Lett. 2008;37:2–7.. For a review of the asymmetric intramolecular Stetter reaction see: Read de Alaniz J, Rovis T. Synlett. 2009:1189–1207.. For a general review on Lewis base catalysis, see: Denmark SE, Beutner GL. Angew. Chem. Int. Ed. 2008;47:1560–1638.

    1. DiRocco DA, Oberg KM, Dalton DM, Rovis T. J. Am. Chem. Soc. 2009;131:10872–10874.. For review of fluorine’s effect on molecular conformation, see: Hunter L. Beilstein J. Org. Chem. 2010 doi:10.3762/bjoc.6.38.

    1. For other contributions to the asymmetric intermolecular Stetter reaction, see: Liu Q, Perreault S, Rovis T. J. Am. Chem. Soc. 2008;130:14066–14067. Liu Q, Rovis T. Org. Lett. 2009;11:2856–2859. Enders D, Han J, Henseler A. Chem. Commun. 2008:3989–3991. Enders D, Han J. Synthesis. 2008:3864–3868. Jousseaume T, Wurz NE, Glorius F. Angew. Chem. Int. Ed. 2011;50:1410–1414.. (f) For an enzyme-catalyzed asymmetric Stetter, see: Dresen C, Richter M, Pohl M, Lüdeke S, Müller M. Angew. Chem. Int. Ed. 2010;49:6600–6603.

    1. Evidence suggests that the role of the heteroatom is not simply that of a proximal Lewis base given that both pyridazine carboxaldehyde and furfural participate with equal facility in spite of their very low basicity. See reference .

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