Bifunctional activation, nitroalkenes

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). 

Scheme 38 Proposed bifunctional activation in ALB-catalyzed hydrophosphonylation of nitroalkenes...

Finally, diarylprolinol 48c has also been employed as catalyst in the enantioselective p-peroxydation of nitroalkenes with tert-butyl hydroperoxide (Scheme 4.65). The catalyst is proposed to engage in a bifunctional activation mode, which on one hand assists the deprotonation of the hydroperoxide and on the other activates the nitroalkene by the formation of one H-bond with the nitro group. Under the optimized conditions, moderate yields and enan-tioselectivities around 85% ee were achieved for a variety of nitrostyrene derivatives. 

The Michael reactions [149-152] between cyclohexanone and trons-nitroalkenes were also explored by Xiao and co-workers utilizing bifunctional pyrrolidine-thiourea 213 and the pyrrolidine-thioureas 214-217 (Figure 6.61) [344]. The model Michael reaction between cyclohexanone and trons-nitrostyrene identified water as the best solvent and 217 to be the most efficient catalysts concerning the activity and asymmetric induction (90% yield 96% ee dr 98 2 in 12 h at 35 °C) in the presence of benzoic acid (10mol%) as additive. The optimized catalytic system allowed the formation of a broad spectrum of Michael adducts such as 1-6 resulting from... 

Zhang et al. investigated the asymmetric 1,3-dipolar cycloaddition of tert-butyl 2-(diphenylmethyleneamino)acetate and nitroalkenes promoted by bifunctional thiourea compounds derived from cinchona alkaloids, affording chiral pyrrolidine derivatives 13 with multisubstitutions. Catalyst lm delivered the best results in terms of catalytic activity, diastereoselectivity and enantioselectivity. Nevertheless, only moderate ee values could be obtained while the diastereoselectivities were generally good (Scheme 10.18) [22]. 

The single-crystal X-ray structure of the optimum catalyst (Figure 6.6) was obtained to get an insight into the reaction mechanism and a better understanding of the role of the achiral N ligands. The tridentate Schiff base ligand coordinates in a bidentate mode and the OH of the amino alcohol does not coordinate to the Zn center. Two piperidine molecules occupy two of the coordination sites of Zn, generating a distorted tetrahedral structure. A bifunctional catalyst mode is proposed in which the nitroalkene is activated... 

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. 

Depending of the catalyst structure, a dual catalyst activation mode may be involved in the process. For instance, in catalyst 42 (Fig. 2.4) [62] the presence of the trans-OH group in the 4-position of the pyrroUdine ring helps to activate the electrophile and also directs its approach from the less hindered face of the -enamine (B, Fig. 2.5). The bifunctional catalyst activation behavior is also suggested for other catalysts such as Jacobsen s thiourea 41 (Fig. 2.4) [61], where binding of the nitroalkene by the thioureamoiety allows the thermodynamically favorable E enamine to attain in close proximity for a highly diastereo- and enantioselective C-C bond-formation (C, Fig. 2.5). 

Proline derivatives possess a prominent position among the aminocatalysts utilised for carbonyl activation. In combination with the readily tunable properties of the (thio)urea functionality for electrophile activation, the development of bifunctional chiral pyrrolidine-based (thio)ureas was a rational extension. In 2006, Tang and coworkers reported thiourea 55 that can catalyse the conjugate addition reaction between cyclohexanone and nitroalkenes (Scheme 19.63). In the presence of 20 mol% of chiral thiourea 55 and butyric acid as the cocatalyst, the q -products were delivered in high yields (up to 98%) and in excellent diastereo- (up to >99 1 dr) and enan-tioselectivities (up to 98% enantiomeric excess). In addition to aromatic nitroalkenes, aliphatic nitroalkenes were also tolerated, but required a long reaction time (6 days). 

Akiyama et al. [33] were the first to introduce chiral phosphoric acids to the FCA reaction of nitroalkenes, and they found that the addition of 3-A molecular sieves dramatically improved both the reactivity and selectivity of the reaction between (3-nitrostryrene and indole (Scheme 9.13). A catalytic working model was proposed that phosphoric acid performed as a bifunctional catalyst to activate both indole and nitroalkene. This methodology was further extended to the reactions with pyrroles as nucleophiles [34] and fluoroalkylated nitroalkenes as electrophiles [35]. 

FIGURE 14.5. Bifunctional mode of activation in the sulfa-Michael additions to a,(3-unsaturated imides and nitroalkenes catalyzed by aminothioureas. 

The employment of bifunctional urea-tertiary amine 104 or monothiourea 105 catalysts selectively promotes either the Michael addition or cycloaddition process, respectively, [60]. As depicted in Scheme 2.30, the tertiary amine group would activate the in situ formed a-amino esters to produce azomethine ylides A (or enolates), whereas the nitroalkene counterparts would be activated by the thiourea (urea) moiety through a double H bonding interaction (B). 

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). 

An elegant 19-steps synthesis of (-)-nakadomarin A has been reported by Dixon and coworkers (Scheme 44.7) [84]. It is a marine hexacychc alkaloid that exhibits impressive biological activities [85], and a challenging complex stmcture for its total synthesis. A key step in this synthetic route is the diastereoselective organo-catalyzed Michael addition between P-keto ester 43 and nitroalkene 42. For a high diastereoselectivity (dr 18 1 0 0) and short reaction time, bifunctional urea 38 was required, affording intermediate 44 as a single diastereomer in 81% yield after isolation. 

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