Michael reaction of malonates to nitroolefins with chiral bifunctional organocatalysts, bearing both a thiourea and tertiary amino group, afforded Michael adducts with high yields and enantioselectivities (up to 95%, up to 93% ee).

[reaction: see text] The aza-Henry reaction of imines with nitroalkanes was promoted by chiral thiourea with an N,N-dimethylamino group to give beta-nitroamines with good enantioselectivity. Various N-protected imines were examined as substrates. N-Phosphinoylimine gave the best result in terms of chemical yield and enantioselectivity (up to 91% yield, up to 76% ee).

The catalytic asymmetric formation of a carbon-carbon bond represents one of the most challenging fields in organic chemistry. A number of asymmetric Michael additions to a,bunsaturated carbonyl acceptors catalyzed by chiral catalysts have been reported.[1] However, the acceptors employed in the asymmetric Michael additions of 1,3-dicarbonyl compounds generally have been restricted to enones [2][3][4] and nitroalkenes.[5] Similarly, although organocatalysts that bear chiral secondary amine groups have been shown to be efficient catalysts for the Michael reaction with such acceptors, [6] their applications to a,b-unsaturated acid derivatives seems to be difficult. Therefore, the development of general and highly enantioselective versions of the reactions of a,bunsaturated acid derivatives still remains a challenging goal. Quite recently, two groups achieved the initial breakthroughs on these problems. The Jacobsen and Kanemasa groups independently reported the highly enantioselective metalcatalyzed Michael additions of malononitrile, which is equivalent to a 1,3-dicarbonyl compound, to a,b-unsaturated imides. [7,8] However, there have been no reports of such asymmetric Michael addition without any metal catalysts. Herein, we report the first enantioselective Michael reactions of malononitrile to acyclic a,b-unsaturated imides in the presence of a chiral organocatalyst.Although we recently reported that the bifunctionalthiourea-catalyzed Michael reaction of 1,3-dicarbonyl compounds to nitroalkenes proceeded with high enantioselectivity (up to 93 % ee), [9] the same reaction of other nucleophiles such as malononitrile to nitroalkenes gave the corresponding product with low enantioselectivity. To extend the synthetic utility of the bifunctional thiourea 1 a in the asymmetric reaction, we undertook the screening of proper Michael acceptors other than nitroalkenes to react with malononitrile. For the purpose, a,b-unsaturated imides seem to have an ideal structure to form hydrogen bonds with the thiourea catalyst 1 a as shown in Scheme 1.

Bifunctional thiourea 1a catalyzes aza-Henry reaction of nitroalkanes with N-Boc-imines to give syn-beta-nitroamines with good to high diastereo- and enantioselectivity. Apart from the catalyst, the reaction requires no additional reagents such as a Lewis acid or a Lewis base. The N-protecting groups of the imines have a determining effect on the chirality of the products, that is, the reaction of N-Boc-imines gives R adducts as major products, whereas the same reaction of N-phosphonoylimines furnishes the corresponding S adducts. Various types of nitroalkanes bearing aryl, alcohol, ether, and ester groups can be used as nucleophiles, providing access to a wide range of useful chiral building blocks in good yield and high enantiomeric excess. Synthetic versatility of the addition products is demonstrated by the transformation to chiral piperidine derivatives such as CP-99,994.

[reaction: see text]. A chiral phase-transfer catalyst has been applied to the asymmetric allylation of the tert-butyl glycinate-benzophenone Schiff base with various allylic acetates for the first time to give the allylated products in good yields and with comparable to higher enantioselectivity than for asymmetric alkylation at the same temperature (91-96% ee) without any chiral ligands for coordinating to the palladium.