Scaffolds thiourea catalysts

The scope of Michael additions with catalysts containing cyclohexane-diamine scaffolds was broadened by Li and co-workers [95]. When screening for a catalyst for the addition of phenylthiol to a,p-nnsatnrated imides, the anthors fonnd that thiourea catalyst 170 provided optimal enantioselectivities when compared to Cinchon alkaloids derivatives (Scheme 41). Electrophile scope inclnded both cyclic and acyclic substrates. Li attributed the enantioselectivity to activation of the diketone electrophiles via hydrogen-bonding to the thiourea, with simultaneous deprotonation of the thiol by the tertiary amine moiety of the diamine (170a and 170b). Based on the observed selectivity, the anthors hypothesized that the snbstrate-catalyst... 

In 2003, Takemoto and co-workers introduced the first tertiary amrne-function-ahzed thiourea catalyst [129]. This new type of stereoselective thiourea catalyst incorporating both (R,R)-l,2-diaminocyclohexane as the chiral scaffold and the privileged 3,5-bis(trifluoromethyl)phenyl thiourea motif for strong hydrogen-bonding substrate binding, marked the introduction of the concept of bifunctional-... 

Nagasawa and co-workers reported the use of a chiral bis-thiourea catalyst (108) for the asymmetric MBH reactions of cyclohexenone with aldehydes [95]. Since others had already shown that thioureas form hydrogen bonds with both aldehydes and enones, it was hypothesized that the inclusion of two thiourea moieties in close proximity on a chiral scaffold would organize the two partners of the MBH reaction and lead to enantiofacial selectivity. Initial studies showed that the achiral 3,5-bis-(trifluoromethyl)phenyl-substituted urea increased the rate of MBH reaction between benzaldehyde and cyclohexenone. These authors then showed that chiral 1,2-cyclohexyldiamine-linked bis-thiourea catalyst 108, used at 40 mol% loading in the presence of 40 mol% DMAP, promoted the MBH reactions of cyclohexenone with various aliphatic and aromatic aldehydes (40) to produce allylic alcohols in moderate to high yields (33-99%) and variable enantio-selectivities (19-90% ee Table 6.33). 

The greater scope of this reaction was attributed to the dual cyclic Bronsted acid/H-Bond donar cocatalysis mechanism. The catalytic cycle initially involves imine protonation by the chiral thiourea catalyst 170 associated via H-bonding to the conjugate base (X ) of a weak Bronsted acid (H-X, benzoic acid in this case) additive. Intramolecular cyclization of the protonated iminium ion 146, followed by rearomatization regenerates the Bronsted acid cocatlayst (benzoic acid). Note for brevity, the plausible rearrangement (RR) step of the inital CCij-spiroalkylated adduct to the final tetrahydrohydroisoquinoline scaffold 147 is not shown. 

In addition, Wulff et al. have reported the first aza-Henry reaction catalysed by a bis-thiourea catalyst, which was based on the 2,2 -diaminobinaphthalene (BINAM) chiral scaffold.The aza-Henry adducts derived from A -Boc imines and nitromethane were isolated in moderate to good yields and good to high enantioselectivities of up to 91% ee (Scheme 3.25). 

The first report on the development and use of chiral squaramide derivatives as hydrogen-bond donor catalysts appeared in 2008 by Rawal and coworkers [78]. The authors showcased the usefulness of this new scaffold by evaluating the Michael addihon of 1,3-dicarbonyl compounds to nitroalkenes, the same reaction that was used to illustrate the capabilily of a thiourea catalyst by Takemoto [45]. Of the catalysts examined, the cinchonine-derived squaramide 13 functioned well as a bifunctional catalyst and provided the conjugate addition product in high yield and excellent enanhoselectivity (Scheme 10.12). Less reactive substrates such as a-substituted 1,3-dicarbonyl compounds also participate in the desired reaction. 

Figure 13,6 Basic scaffold of chiral Bronsted base derived thiourea catalysts.

Chiral phosphoric acid analogs as catalysts in the F-C alkylation reaction of indoles with a,(l-unsaturated aromatic enones were also devised [53]. p,y-Unsaturated a-ketoesters were also used as electrophiles in organocatalyzed F-C alkylations of indoles and 2-naphthols. With indoles, chiral acidic N-triflylphos-phoramide was successfully employed (Scheme 35.4) [28], whereas in the presence of 2-naphthols a thiourea-based catalyst showed better capacity to mediate a sequential F-C/cycUzation process, giving naphthopyran scaffolds in moderate yields and selectivities (up to 90% ee) [54]. Recently, a,P-unsaturated acyl phos-phonates were effectively used as hydrogen bond acceptors for F-C alkylations of indole derivatives in the presence of thiourea catalyst ent-19 [55]. 

For similar reactions, Takemoto et al. developed a novel organocatalyst 40, which was designed to place both acidic and basic moieties appropriately on the same catalyst scaffold (Scheme 20) [23]. It was proposed the thiourea activated nitroolefins by hydrogen bonding. 

The higher activity of primary amines in the reaction involving enones as Michael acceptors has also been extended to the use of different bifunctional catalysts (Scheme 3.19), which usually contain a primary amine functionality connected to a basic site by means of a chiral scaffold, as is the case in the use of 280 and 55. These diamine catalysts have been found to be excellent promoters of the Michael reaction of enones with cyclic 1,3-dicarbonyl compounds and malonates respectively, the tertiary amine basic site present at the catalyst structure being responsible for assisting in the deprotonation of the Michael donor in order to increase the concentration of the nucleophile species. In a different approach, bifunctional thiourea-primary amine catalyst 56a has also... 

In the next few years, the use of isobutyraldehyde as the nucleophile in conjugate additions to aromatic nitroalkenes received a lot of attention. He and coworkers reported a chiral thiourea that could efficiently catalyse this transformation, while Chen and coworkers employed a catalyst combining the 1,2-diaminocyclohexane moiety with the privileged Cinchona alkaloid scaffold. A more sustainable protocol was provided by Ma and coworkers, where catalyst 40, based on a beyerane skeleton, was found to promote the same transformation both in organic solvents (up to 92% yield and 98%... 

In addition, Chen et al. developed the aldolisation of cyclohexanone with benzaldehydes in water by using a chiral bifunctional thiourea-secondary amine catalyst bearing a hydrophobic camphor scaffold. In the presence of DBSA as an additive, these reactions afforded the anti- do products in moderate to high yields, and high to excellent diastereo- and enantioselectivities, as shown in Scheme 2.42. 

Takemoto and coworkers [32] elaborated bifunchonal catalyst 27, which was found, after this initial report, to be highly versahle in promohng a large variety of trans-formahons. The combinahon of a thiourea and a terhary amine separated by a chiral scaffold, (l ,l )-l,2-cyclohexyldiamine, was studied to build a new type of organocatalyst. Aminothiourea 27 was first examined as catalyst for the enanhose-lective addition of malonate to nitroaUcenes (Scheme 34.5). The thiourea moiety of catalyst 27 guides and activates the nitroolefin while the terhary amine part deprotonates the malonate. 

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