Organocatalyst thiourea

Substituted thioureas have been used as ligands for transition-metal catalysed reactions and as organocatalysts for organic synthesis. These points will be discussed in Sects. 4 and 5. We first present some aspects of the coordination modes of ureas and thioureas. 

New organocatalysts prepared by the Jacobsen group showed that alkylation of the final amide bond increased the enantioselection (Scheme 38, compare R2 = Me, 98% ee to R2 = H, 91% ee). Thus, the reaction performed with N-allyl benzaldimine and with the dimethylamide-ending thiourea (Scheme 38 with Ri = R2 = Me) gave up to 99% ee. This compound is a structural analogue of the urea depicted in Scheme 36 [148,152,154]. 

Both the ureas and thioureas are highly suitable organocatalysts for the asymmetric Strecker synthesis. For example, the thiourea function was replaced by an urea function (note the opposite configurations). The organocatalysts thus obtained showed similar activity and slightly higher enantioselec-tivities with N-allyl benzaldimine (Scheme 39,74% yield with 95% ee for Ri = Bn and R2 = H). Once again, better enantioselectivity (up to 99% ee) was at-... 

This bifunctionnal amino-thiourea organocatalyst led to high selectivity because it was activating both the nitrone and the malonate, in its enol form, due to the acidic hydrogen atoms of the thiourea. Thus, the amino-thiourea catalyst promoted the Michael reaction of malonates to various nitroolefins... 

Diels-Alder reactions [165] using thiourea as organocatalyst were recently examined [166]. Kinetic measurements showed that accelerations of the relative reaction rates were more dependent on the thiourea substituents than on the substrates or the solvent (even in highly coordinating polar solvents like wa-... 

Aromatic thioureas were more active than alkyl (octyl, cyclohexyl) derivatives. Thioureas with trilluoromethyl substituents were even more effective. The same group also showed that these organocatalysts can act as weak Lewis acids and are thus able to alter the stereochemistry of the Diels-Alder reaction between cyclopentadiene and chiral acrylamide derivatives (Scheme 49) [167]. 

The first step of the catalytic process is the hydrogen bond directed assembly and orientation of the reactants. In this example, the azlactone and methanol form a ternary starting complex with the organocatalyst (Fig. 1) [39]. The pseudo-Lewis acidic thiourea forms two bifurcated, nearly symmetric hydrogen bonds (2.147 A, < (0,H,N) = 155.5° and 2.146A, <(0,H,N) = 155.8°) to the carbonyl oxygen atom of the azlactone. 

On the Bifunctionality of Chiral Thiourea Tertiary-Amine Based Organocatalysts Competing Routes to C-C Bond Formation in a Michael-Addition... 

Takemoto et al. were the first to report that hifunctional organocatalysts of the thiourea - tert-amine type efficiently promote certain Michael-reactions, e.g., the addition of P-dicarhonyl compounds to nitro olefins (Scheme 6) [43 5],... 

Wang and co-workers reported a novel class of organocatalysts for the asymmetric Michael addition of 2,4-pentandiones to nitro-olefms [131]. A screen of catalyst types showed that the binaphthol-derived amine thiourea promoted the enantiose-lective addition in high yield and selectivity, unlike the cyclohexane-diamine catalysts and Cinchona alkaloids (Scheme 77, Table 5). 

On the Bijunctionalit / of Chiral Thiourea-Tert-Amine-Based Organocatalysts 25... 

Wittkopp and Schreiner introduced the simple electron-deficient N,N -bis [3,5-(trif-luoromethyl)phenyl]thiourea 9 (Figure 6.3) as an efficient double hydrogen-bonding organocatalyst in a series of Diels-Alder reactions and 1,3-dipolar cycloadditions of... 

Figure 6.3 Stereoselective, chiral thiourea derivatives of achiral benchmark thiourea organocatalyst N,N -bis [3,5-(trifluoromethyl)phenyl]thiourea 9 stereoselective hydrogen-bonding thiourea organocatalysts incorporating the privileged 3,5-bis(trifluoromethylphenyl)thiourea moiety. The (thio)urea catalyst structure is the leitmotif for the chapter organization.

As demonstrated in a series of kinetic experiments by Wittkopp and Schreiner, nitrone N-benzylideneanihne N-oxide can be activated for 1,3-dipolar cycloadditions through double hydrogen-bonding 9 [Ij. Takemoto and co-workers, in 2003, published the nucleophilic addition of TMSCN and ketene silyl acetals to nitrones and aldehydes proceeding in the presence of thiourea organocatalyst 9 (Figure 6.4) [147]. 

Scheme 6.55 Design principle of amine-functionalized bifunctional thiourea organocatalysts derived from privileged monofunctional thiourea 9 cooperating with an amine base additive (A) and basic bifunctional mode of action of chiral amine...

Thiourea catalyst 139 was also screened in the asymmetric Friedel-Crafts reaction between 2-naphthol trans-nitrostyrene (73% yield 0% ee 18 h in toluene at -20 °C and 10 mol%) [277], in the asymmetric aza-Michael reaction of O-benzyl-hydroxylamine to chalcone (72% conv. 19% ee 72 h in toluene at 20 °C and 20mol% catalyst loading) [293], and in the asymmetric Morita-BayUs-HiUman [176, 177] reaction between cyclohexenecarbaldehyde and 2-cyclohexene-l-one (20% yield 31% ee 46 h at rt and 20mol% DABCO and 139) [310]. In aU these transformations, thiourea 139 proved to be not competitive to the organocatalysts probed for these transformations under identical screening conditions and thus was not employed in the optimized protocols. 

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