Bis-thiourea catalysts

The C2-symmetric chiral bis-thiourea catalyst 78 mediated the addition of cyclohexanone to a range of activated aldehydes in the presence of DMAP, or imida-... 

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). 

At almost the same time, Nagasawa s group developed the C2-symmetric chiral bis-thiourea-catalyzed asymmetric MBH reaction of cychc enones with aldehydes (Scheme 2.196). They found that the bis-thiourea catalyst 363 promoted the reaction of cyclohexenone with benzaldehyde in the presence of an additive (0.4 equiv) such as DMAP or imidazole to afford the allyhc alcohol (DMAP — 5 °C, 88%, 33% ee imidazole room temperature, 40%, 57% ee). Higher enantioselectivities were obtained in the reaction with aliphatic aldehydes (up to 90% ee). A transition state 364, in which both the aldehyde and the enone coordinate to the thiourea groups of 363 through hydrogen bonding interactions, was proposed to explain the stereochemistry of the product. 

Later, Berkessel et al. developed a new and improved bis(thio)urea catalysts 365, which was derived in one step from readily available isophorone-diamine (IPDA). Good yields and excellent enantiomeric excesses were obtained in the MBH reaction of cyclohexanecarbaldehyde with 2-cyclohexen-l-one by using bis-thiourea catalyst 365, in combination with a novel base (A,A,A, A -tetra-methylisophorone-diamine, TMIPDA) in toluene (Scheme 2.197). However, with the exception of cyclohexanecarbaldehyde as substrate, DABCO provides superior yields and ee values than TMIPDA. Furthermore, it was shown for the first time that bis-(thio)ureas can activate Michael-acceptors besides 2-cyclohexen-l-one. " °... 

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). 

Kitagaki, S. Ueda, T. Mukai, C. Planar Chiral [2.2]Paracyclophane-Based Bis(thiourea) Catalyst Application to Asymmetric Henry Reaction. Chem. Commun. 2013, 49, 4030-4032. 

Bis-thiourea catalysts have been developed by several research groups. Nagasawa et al. synthesized chiral bis-thiourea derivatives and demonstrated their catalytic activity in the Michael reaction of pyrrolidone, giving rise to a,p-unsaturated y-lactones with moderate enantioselectivity [80]. trans-l,2-Diaminocyclohexane-derived bis-thiourea (5) promoted the DMAP mediated Baylis-Hillman reaction to give the adducts with high enantioselectivity (Scheme 2.30) [81]. 

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-worker, in 2004, introduced the first bis-thiourea-type catalyst... 

P-Amino carbonyl compounds containing an a-atkyUdene group are densely functionalized materials, which are widely applied in the synthesis of medicinal reagents and natural products [265]. These products are usually prepared through the classic aza-Morita-Baylis-Hillman reaction [176, 177] of activated imines and electron-deficient alkenes catalyzed by tertiary amines or phosphines. Chen and co-workers, in 2008, identified bis-thiourea 106 as a suitable catalyst for the... 

Schreiner et al. developed thiourea catalyst as a promising hydrogen donor, which has more benefit in solubility, synthesis and catalytic mrn over number compared with urea catalyst, in the Diels-Alder reaction of A-crotonyloxazolidinone and cyclopentadiene [22,23] (Table 9.7). A,A -Di[3,5-bis(trifluoromethyl)phenyl]thiourea accelerates the reaction and improves stereoselectivity (run 4) similar to a metal catalyst such as aluminium chloride (AICI3) (mn 2) or titanium chloride (TiCls) (run 3). 

A more simple thiourea catalyst with amino functionality catalyses the asymmetric Michael addition of 1,3-dicarbonyl compound to nitroolefin [29,30]. In the reaction of malonate to nitrostyrene (Table 9.11) the adduct is satisfactorily obtained when A-[3,5-bis(trifluor-omethyl)phenyl]-A -(2-dimethylaminocyclohexyl)thiourea is used as a catalyst (ran 1), whereas the reaction proceeds slowly when the 2-amino group is lacking (ran2). In addition, chiral amine without a thiourea moiety gives a poor yield and enantioselectivity of the product (run 3). These facts clearly show that both thiourea and amino functionalities are necessary for rate acceleration and asymmetric induction, suggesting that the catalyst simultaneously activates substrate and nucleophile as a bifunctional catalyst. 

Bifunctional alkaloid-derived thiourea catalyst 79 promotes the conjugate addition of nitroalkanes to l,l-bis(benzenesulfonyl)ethylene in toluene to afford the corresponding enantiomerically enriched y-sulfonyl derivatives at-10°C [183]. Although... 

Bis(thiourea) (197) has been developed as an efficient catalyst for the MBH reaction of 2-cyclohexen-l-one with aromatic aldehydes (<84% ee) and aliphatic aldehydes (<96% ee) ... 

A novel bis-thiourea-type catalyst (7) was synthesized by Berkessel et al. [83]. The catalyst turned out to be effective in the Morita-Baylis-Hillman reaction (Scheme 2.32). 

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