Hydrogen-bonding activation nitroalkenes

Scheme 6.104 Key intermediates of the proposed catalytic cycle for the 100-catalyzed Michael addition of a,a-disubstituted aldehydes to aliphatic and aromatic nitroalkenes Formation of imine (A) and F-enamine (B), double hydrogen-bonding activation of the nitroalkene and nucleophilic enamine attack (C), zwitterionic structure (D), product-forming proton transfer, and hydrolysis.

A systematic study on enzymatic catalysis has revealed that isolated enzymes, from baker s yeast or old yellow enzyme (OYE) termed nitroalkene reductase, can efficiently catalyze the NADPH-linked reduction of nitroalkenes. Eor the OYE-catalyzed reduction of nitrocyclohexene, a catalytic mechanism was proposed in which the nitrocyclohexene is activated by nitro-oxygen hydrogen bonds to the enzymes His-191 and Asn-194 [167, 168]. Inspired by this study Schreiner et al. 

Chen and co-workers presented, in 2007, a Michael-type Friedel-Crafts reaction of 2-naphthols and trans-P-nitroalkenes utilizing the bifunctional activating mode of cinchonine-derived catalyst 117 [277]. The nitroalkene was activated and steri-cally orientated by double hydrogen bonding, while the tertiary amino group interacts with the naphthol hydroxy group to activate the naphthol for the nucleophilic P-attack at the Michael acceptor nitroalkene (Scheme 6.117). 

When, on the other hand, organocatalyst 133 (possessing a bulky 2,5-diaryl-pyrrole moiety) is applied, product 134 was selectively formed by a highly diastereo- and enantioselective 1,3-dipolar cycloaddition (11 examples, 56-90%, 60-91% ee). This reaction most likely involves activation of the nitroalkene by the thiourea, via the earlier mentioned doubly hydrogen-bonded interaction, followed by a concerted attack of the in situ formed azomethine ylide (this ylide is not activated by nor coordinated to the organocatalyst, because of the bulky, nonbasic pyrrole group, but is most likely formed via a 1,2-prototropic rearrangement [92]). 

The proposed reaction mechanism is shown in Scheme 6.75. The nitroalkene moiety of bifunctional ortAo-alkyne-substituted nitrostyrenes 159 is activated through hydrogen bonding with catalyst 160 to incorporate the stereoehemieal information in the first AFC reaction. Then the alkyne is activated under gold catalysis to affect the seeond AFC/ring expansion cascade. 

In 2010, Bernal, Fernandez, and Lassaletta [198] disclosed an unprecedented asymmetric cyanosilylation of nitroalkenes that was catalyzed enantioselectively by a quinine derivative with tetraalkylammonium cyanide and thiourea moieties. The activation of the nitroalkene takes place by hydrogen bonding to the thiourea, while the tetraalkylammonium cation moiety binds the cyanide anion, which is dehvered stereoselectively to the double bond. 

Ricci et al studied a series of thiourea catalysts for the Friedel-Crafts alkylation of aromatic and heteroaromatic compounds with nitroalkenes. They have succeeded in developing the Friedel-Crafts alkylation of indoles with nitroalkenes for the first time by means of a novel thiourea catalyst (13) (Scheme 2.48) [101]. The authors proposed the bifunctional nature of the thiourea catalyst, where thiourea activates the nitro group and at the same time the free alcoholic function interacts with the indole proton through a weak hydrogen bond, directing the attack of the incoming nucleophile on the Si face of the nitroalkene (Figure 2.18). 

Takenaka and coworkers used 2-aminopyridinium salts as dual hydrogen-bond donors for the activation of nitroalkenes. The 7-azaindolium salt 65 was found to be particularly effective for the Friedel-Crafts reaction of nitroalkenes with various electron-rich arenes as well as for intra- and intermolecular Diels-Alder reactions (Scheme 10.63) [163, 164]. The same concept was successfully applied to the enantioselective conjugate addition of 4,7-dihydroindoles to nitroalkenes using helical chiral 2-aminopyridinium salts (Scheme 10.64) [165]. The reaction was found to have a broad substrate scope, affording various 2-substituted indoles in good to high enantiomeric ratios. 

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