Hydrogen thiourea catalysts

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... 

As expected, the reaction is fastest in water due to its hydrogen-bonding ability and high dielectric constant. Addition of 1 mol% of the thiourea catalyst 10 increases the yields after 1 h in cyclohexane and chloroform by about 60% a 40 mol% catalyst doubles the yield. A sizeable catalytic effect of the m-trifluoromethyl-substi luted thiourea was also found in water. Explanations for the surprising fact that this hydrogen-bond donor is catalytically active even in a highly competitive solvent such as water will be given in Section III.D.3. 

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... 

Br0nsted acids such as thioureas 2 represent hydrogen-bonding catalysts. Phosphoric acids 3, AT-triflyl phosphoramides 4, and dicarboxyUc acids 5 are examples of stronger specific Brpnsted acids (Fig. 1). 

It was found that both the replacement of the secondary amide unit with a bulkier tertiary amide and the incorporation of a thiourea moiety instead of the urea unit resulted in a significant improvement in stereoinduction (from initial 80% ee obtained with 42 to 97% ee). This led to the identification of hydrogen-bonding Schiff base thiourea catalyst 47, while the urea derivatives 43-46 gave lower ee values (Figure 6.16). 

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-... 

Scheme 6.150 Proposed mechanistic picture for (S)-favored enantioselective Michael addition of O-benzylhydroxylamine to 2,4-dimethyl pyrazole substituted a,P-unsaturated substrates in the presence of hydrogen-bonding thiourea catalyst 139.

In 2008, Tang and co-workers reported the utilization of tertiary amine-functionalized saccharide-thiourea 211 as a bifunctional hydrogen-bonding catalyst for the enantioselective aza-Henry [224] (nitro-Mannich) addition [72] of... 

Scheme 6.178 Typical products provided from the asymmetric aza-Henry addition of nitromethane to N-Boc-protected aldimines in the presence of saccharide thiourea 211 as bifunctional hydrogen-bonding catalyst.

The small-molecule catalysts are covered in Chapters 5 and 6. In Chapter 5, Joshua Payette and Hisashi Yamamoto discuss the importance of polar Bronsted-acid-type catalysts as well as cooperative effects in hydrogen bonding catalysis. Chapter 6 by Mike Kotke and Peter Schreiner is then devoted to the single most popular small-molecule catalyst types, the thiourea catalysts. Chapter 6, the longest of all chapters, also provides an excellent overview of the history and development of the field of small-molecule hydrogen bond catalysis. 

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). 

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