A General Catalytic Enantioselective Transfer Hydrogenation Reaction of β,β-Disubstituted Nitroalkenes Promoted by a Simple Organocatalyst

Abstract

Given its synthetic relevance, the catalytic enantioselective reduction of β,β-disubstituted nitroalkenes has received a great deal of attention. Several bio-, metal-, and organo-catalytic methods have been developed, which however are usually applicable to single classes of nitroalkene substrates. In this paper, we present an account of our previous work on this transformation, which implemented with new disclosures and mechanistic insights results in a very general protocol for nitroalkene reductions. The proposed methodology is characterized by (i) a remarkably broad scope encompassing various nitroalkene classes; (ii) Hantzsch esters as convenient (on a preparative scale) hydrogen surrogates; (iii) a simple and commercially available thiourea as catalyst; (iv) user-friendly procedures. Overall, the proposed protocol gives a practical dimension to the catalytic enantioselective reduction of β,β-disubstituted nitroalkenes, offering a useful and general platform for the preparation of nitroalkanes bearing a stereogenic center at the β-position in a highly enantioenriched form. A transition state model derived from control kinetic experiments combined with literature data is proposed and discussed. This model accounts and justifies the observed experimental results.

Catalytic Asymmetric Conjugate Reduction

“…Nitro groups are readily coordinated through H‐bonding by ureas, thioureas, and other structurally related H‐bond donors that are summarized in Figure 32. Such coordination activates the olefin towards the attack of a suitable hydride source, Hantzsch esters serving this purpose [149] …”

“…Such coordination activates the olefin towards the attack of a suitable hydride source, Hantzsch esters serving this purpose. [149] The first example concerning H-bond catalyzed ACR was reported by List and co-workers in 2007. The reduction of β-methyl nitrostyrene was accomplished employing 65 as the reductant and thiourea OC11 as the best performing catalyst (Figure 33).…”

Synthesis of Tetrasubstituted Nitroalkenes and Preliminary Studies of Their Enantioselective Organocatalytic Reduction

“…The use of Hantzsch esters as biomimetic reducing agents [ 17 ] has been reported in different organocatalytic reductions of nitroalkenes, but also ketoimines and ketoesters [ 18 , 19 , 20 ]. In addition, Hantzsch esters are easily synthetized, and their structure readily tuned in order to maximize the efficiency of enantioselective reactions [ 21 ].…”

Asymmetric Michael Addition of 2-Acetyl Azaarenes to β-CF3-β-(3-indolyl)nitroalkenes Catalyzed by a Cobalt(II)/(imidazoline-oxazoline) Complex

“…Besides Friedel–Crafts reactions, an alternative direct and convenient approach to the chiral target molecules involves the reactions of prochiral CF 3 -containing 3-indoles. Surprisingly, reports on such reactions − are rather limited despite the fact that the availability of prochiral CF 3 -containing indoles such as β-CF 3 -β-indole enones and β-CF 3 -β-indole nitroalkenes is not a problem. Among the few examples, Yan and Wang reported a sulfa-Michael-aldol reaction between 2-mercaptobenzaldehydes and β-CF 3 -β-indole enones catalyzed by a squaramide, which produced 2-CF 3 -2-indole-substituted thiochromanes featuring a CF 3 -containing heteroquaternary stereocenter in high yields with excellent stereoselectivities (>20:1 dr, up to 99% ee ) .…”