Thiourea catalyst functional groups

Using the addition of dimethyl malonate to nitro-olefms as the model reaction, Connon et al. [72] in 2(X)5 reported a highly functionahzed Cinchona alkaloid-derived chiral thiourea. Key functional groups were identified to enhance the catalyst s stereodirecting properties. Aside from the advantage of a bifunctional Cinchona alkaloid... 

Acetoiicetyliition Reactions. The best known and commercially most important reaction of diketene is the aceto acetylation of nucleophiles to give derivatives of acetoacetic acid (Fig. 2) (1,5,6). A wide variety of substances with acidic hydrogens can be acetoacetylated. This includes alcohols, amines, phenols, thiols, carboxyHc acids, amides, ureas, thioureas, urethanes, and sulfonamides. Where more than one functional group is present, ring closure often follows aceto acetylation, giving access to a variety of heterocycHc compounds. These reactions often require catalysts in the form of tertiary amines, acids, and mercury salts. Acetoacetate esters and acetoacetamides are the most important industrial intermediates prepared from diketene. 

Catalysts similar to 24 were also developed by the Tsogoeva group (Scheme 2.42) [28], with the best results being obtained with chiral naphthylamine-based thiourea catalysts having free NH2 functions in the side chains (e.g., 25). This led to syn products with cyclic ketones (Scheme 2.43), whereas acyclic ketones afforded the anti product (Scheme 2.42). 

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. 

The alcohol group also works as an alternative functionality in thiourea catalysts. Catalytic enantioselective Friedel-Crafts alkylation of indoles with nitroalkanes using alcohol-... 

In many examples of Brpnsted base catalysis, the combination of a chiral tertiary amine and a hydrogen-bonding donor, such as a urea or thiourea moiety, significantly enhances the selectivity of the formation of carbon-carbon bonds. Catalysts possessing this combination of functional groups have proven useful due to their ability to simultaneously stabilize and activate both electrophilic and nucleophilic components. 

The bifunctional thioureas represent a group of bifunctional catalysts based on an interplay of Br0nsted acid-base activation that have obtained a prominent position over the last few years. Using these, the second functionality of choice is most often a basic nitrogen, such as a tertiary amine, and a simultaneous activation of nucleophile and electrophile can be achieved (409). 

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). 

Nagasawa et d. designed a novel bifunctional catalyst bearing both guanidine and thiourea functional groups (19), which effectively promoted the Henry reactions with aliphatic cyclic aldehydes and branched aldehydes in the presence of K1 as an additive to provide -nitroamine with high enantioselectivity. Use of a-substituted aldehyde improved the enantioselectivity to 95-99% (Scheme 2.60) [115]. 

Finally, bifunctional thiourea catalysts bearing primary or secondary amine have been reported by Tsogoeva [116], Jacobsen [117], Tang [118], and Xiao [119] (Figure 2.22). They are employed for the conjugate addition of ketone to ni-troalkenes. In principle, they are enamine catalysts bearing acidic functional group. 

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