Yanbin Hu

Direct Amidation of Alcohols with N-Substituted Formamides under Transition-Metal-Free Conditions

and C [9]H oxidative amidation, have alsoproven to be efficient methods for the construction of amidebonds.Although considerable progress has been made towardsmethods facilitating amide formation, efficient and low costsyntheses of N,N-dimethyl-substituted amides under metal-free conditions are still less explored. In general, the tradi-tional syntheses of N,N-dimethyl-substituted amides are lim-ited by the need for prior activation of carboxylic acids(Scheme 1a).

Catalyst-free thiolation of indoles with sulfonyl hydrazides for the synthesis of 3-sulfenylindoles in water

A catalyst-free thiolation of indoles with sulfonyl hydrazides was efficiently developed in water under mild conditions without any ligand or additive. The reaction provided a variety of 3-sulfenylindoles with good to excellent yields and the only by-products were nitrogen and water.

Asymmetric Michael Reaction Catalyzed by Proline Lithium Salt: Efficient Synthesis of L-Proline and Isoindoloisoquinolinone Derivatives

Enamine catalysis has emerged as a powerful method for the potential application of carbonyl activation in asymmetric catalysis. Since List, Lerner, and Barbas first reported the proline-catalyzed direct aldol reaction, many pyrrolidine-type and imidazolidinone-type chiral amine catalysts have been developed with highly effective stereoinduction. In most cases, these catalysts were designed by increasing the steric bulk on the pyrrolidine moiety, 5] such as in the Jorgensen–Hayashi catalyst. By contrast, when amino acid metal salts were employed as enamine catalysts, the stereoselectivity was hardly controlled through shielding one face of the enamine intermediate. The seminal work of the Yamaguchi group, who employed a proline rubidium catalyst, as well as the groups of Feng, Reiser, and others, have demonstrated that amino acid metal salts are attractive alternatives to organocatalysts and other metalbased catalysts. Lithium, the closest congener of hydrogen, can form lithium-bonding interactions that are analogous to hydrogen-bonding interactions but with stronger bonding ability. We believe that the suitable combination of proline and lithium would facilitate reactions that proline alone cannot. The asymmetric Michael addition of unmodified aldehydes to nitroalkenes has attracted much attention because the installation of the formyl and nitro groups in a single step allows subsequent versatile transformations. Moreover, the Michael reaction has also been widely used as one of the steps in cascade reactions that allows for the construction of molecular complexity in a single procedure. Since Barbas and co-workers reported the first example of the asymmetric addition of an unmodified aldehyde to a nitroalkene, the groups of Alexakis, Wang, Hayashi, Palomo, Jacobsen, Chen, and Loh, among many others, have developed a series of efficient secondary and thio ACHTUNGTRENNUNG(urea)-primary amines to improve the stereoselectivity and substrate scope of this reaction. Although these reported methods can afford good-to-excellent diastereoand enantioselectivities, the need for a large excess of Michael donors, as well as the use of expensive and not readily available catalysts, seriously limit the application of this reaction on a large scale, especially on an industrial scale. To overcome these limitations, the immobilization of organocatalysts has been pursued to facilitate product separation and catalyst reuse. However, this approach has always led to a decrease in the reaction activity and enantioselectivity. Very recently, the Wennemers group successfully lowed the catalyst loading to as little as 0.1 mol% following kinetic studies. Moreover, the groups of Ni and Wang described highly efficient reusable catalysts for the excellent diastereoand enantioselective Michael reaction. Although significant progress has been made, the development of lowmolecular-weight, inexpensive, and readily available catalysts for the highly stereoselective Michael reaction with various linear, a-branched, and unsaturated aldehydes as donors is still of significance. Herein, we report a highly stereoselective Michael addition of aldehydes to nitroalkenes catalyzed by proline lithium salt. Remarkably, the asymmetric Michael reaction could be scaled up to 50 mmol with 23:1 d.r. and 90% ee. Furthermore, the useful building blocks were successfully transformed into biologically important l-proline and isoindoloisoquinolinone derivatives on the gram scale. The asymmetric Michael addition of n-butylaldehyde (1a) to nitrostyrene (2a) was selected as a model reaction for our initial optimization studies (Table 1). Preliminary experiments identified l-proline lithium salt as a suitable catalyst (see the Supporting Information, Table S1, entry 1), whereas other secondary amino acid metal salts gave inferior results with respect to the yields and stereoselectivities (Table 1, entries 2–5). The primary acid lithium salts showed minimal catalytic activity under the same reaction conditions (Table 1, entries 6 and 7), which may be attributed to the unfavorable equilibrium between the imine and the secondary enamine. When l-proline was employed as the catalyst, no Michael adduct was obtained (Table 1, entry 8). Then, the effect of water on the reaction was studied (Table 1, entries 9–12). The results indicated that a small amount of water was essential to obtaining a high yield (Table 1, entry 1 versus entry 11); however, the diastereoand enantioselectivities decreased with an increased amount of water (Table 1, entry 1 versus entries 9 and 10). The presence of molecular sieves during the catalytic reaction de[a] K. Xu, S. Zhang, Y. Hu, Z. Zha, Prof. Z. Wang Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry University of Science and Technology of China Hefei, Anhui, 230026 (P. R. China) Fax: ACHTUNGTRENNUNG(+86)551-3631760 E-mail : zwang3@ustc.edu.cn Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201202409.

Bifunctional Amino Sulfonohydrazide Catalyzed Direct Asymmetric Mannich Reaction of Cyclic Ketimines with Ketones: Highly Diastereo- and Enantioselective Construction of Quaternary Carbon Stereocenters

A bifunctional amino sulfonohydrazide which contains multiple sites for hydrogen bonding with substrates was found to enhance reactivity and enantioselectivity in the direct asymmetric Mannich reaction of N-sulfonyl cyclic ketimines with ketones. In this efficient transformation, not only methyl ketones but also cyclic ketones can be employed to provide a general methodology to construct tetrasubstituted α-amino ester in a stereoselective manner. The synthetic utility of a substituted amino ester product is demonstrated by the synthesis of biologically active spirotetrahydrofuran.

Copper-catalyzed enantioselective Friedel-Crafts alkylation of pyrrole with isatins.

The highly enantioselective Friedel-Crafts alkylation of pyrrole with isatins catalyzed by the tridentate Schiff base/Cu catalyst was developed. Hexafluoroisopropanol (HFIP) was used as a crucial additive to improve the enantioselectivity. In the case of N-unprotected isatins, an innovative substrate slow-releasing strategy was applied by virtue of a Henry/retro-Henry reaction.

Highly Enantioselective Construction of Fluoroalkylated Quaternary Stereocenters via Organocatalytic Dehydrated Mannich Reaction of Unprotected Hemiaminals with Ketones.

A general organocatalytic asymmetric dehydrated Mannich reaction of fluoroalkyl hemiaminals with ketones is reported. In this Mannich reaction, previously less explored aryl ketones showed great reactivity. By virtue of this efficient method, a wide range of biologically active β-amino ketones were directly obtained. More importantly, two different intermediates involved in the reaction were detected and identified by (19)F NMR and HRMS analysis. Furthermore, the synthetic utility of the products was demonstrated by the synthesis of the biologically active fluoroalkyl β-amino alcohols.

Copper-catalyzed enantioselective hetero-Diels-Alder reaction of Danishefsky's diene with β,γ-unsaturated α-ketoesters.

A highly enantioselective hetero-Diels-Alder reaction of Danishefskys diene with β,γ-unsaturated α-ketoesters was developed for the first time by virtue of chiral copper complexes. This protocol provided a facile access to optically active dihydropyranones bearing a quaternary center with high enantioselectivities and good yields. Furthermore, on the basis of the isolated intermediate analysis, the reaction pathway was substrate-dependent.

Enantioselective Copper(I/II)‐Catalyzed Conjugate Addition of Nitro Esters to β,γ‐Unsaturated α‐Ketoesters

A highly enantioselective Michael addition of nitroacetates to β,γ-unsaturated α-ketoesters was developed by using chiral copper catalysts. The Michael addition products can be obtained in high yields with up to 99 % ee. With these densely functionalized products, the chiral cyclic nitrones, which are important synthetic intermediates, can be obtained in one step.

Copper Catalyzed Enantioselective Alkylation of Pyrrole with β,γ-Unsaturated α-Ketoesters: Application to One-Pot Construction of the Seven-Membered Ring by Merging a Gold Catalysis

A highly enantioselective Friedel-Crafts alkylation of pyrrole to β,γ-unsaturated α-ketoesters was developed by virtue of a chiral copper complex, affording the alkylated derivatives of pyrrole with good yields and excellent enantioselectivities. Moreover, merging copper catalysis with gold catalysis realized a one-pot construction of the seven-membered ring to give annulated pyrroles with moderate to good yields and high enantiomeric excesses.

Copper-Catalyzed Enantioselective Hetero-Diels–Alder Reaction of Danishefsky’s Diene with Glyoxals

The highly enantioselective hetero-Diels-Alder reaction of Danishefskys diene with glyoxals was developed by virtue of a readily accessible chiral copper catalyst. This efficient transformation provided a facile and scalable access to a wide range of biologically active dihydropyrones with a high level of enantioselectivities. Moreover, the substrate scope of this reaction could be extended to isatins with this catalytic system. More importantly, the mechanism involved in this reaction was proposed on the basis of the unambiguous structures of intermediates.