Bifunctional Mannich reaction

Bifunctional thiourea-catalysed enantioselective Michael reaction has been achieved. The thiourea moiety and an amino group of the catalyst activated a nitroolefin and a 1,3-dicarbonyl compound, respectively afford the Michael adduct with high enantioselectivity.177,178 Thioureas work as one of the most effective and general enantioselective nitro-Mannich reaction and carbonyl cyanation catalyst.179,180... 

Shortly thereafter, Terada demonstrated that the Mannich reaction between several N-Boc aryl imines and acetoacetone was effectively catalyzed by only 2 mol% of le (Scheme 5.2) [4]. In view of AMyama s work, this study is particularly significant because it suggested that le may act as a bifunctional catalyst [9] not only to form a chiral ion pair with the electrophile but also to activate the nucelo-phile through hydrogen bonding of the a-proton with Lewis basic phosphoryl oxygen. 

A highly enantioselective direct Mannich reaction of simple /V-Boc-aryl and alkyl- imines with malonates and /1-kclo esters has been reported.27 Catalysed by cinchona alkaloids with a pendant urea moiety, bifunctional catalysis is achieved, with the urea providing cooperative hydrogen bonding, and the alkaloid giving chiral induction. With yields and ees up to 99% in dichloromethane (DCM) solvent, the mild air- and moisture-tolerant method opens up a convenient route to jV-Boc-amino acids. 

The use of bifunctional thiourea-substituted cinchona alkaloid derivatives has continued to gamer interest, with the Deng laboratory reporting the use of a 6 -thiourea-substituted cinchona derivative for both the Mannich reactions of malo-nates with imines [136] and the Friedel-Crafts reactions of imines with indoles [137]. In both reports, a catalyst loading of 10-20 mol% provided the desired products in almost uniformly high yields and high enantioselectivities. Thiourea-substituted cinchona derivatives have also been used for the enantioselective aza-Henry reactions of aldimines [138] and the enantioselective Henry reactions of nitromethane with aromatic aldehydes [139]. 

The present chapter deals with the application of Mannich aminomethylation or Mannich bases to the synthesis and modification of macromolecular compounds. As summarized in Fig. 150, a remarkable number of different combinations exist, as the Mannich reaction enables us (a) to perform polymerizations by using bifunctional substrate and amine as well as (d) to functionalize polymeric derivatives behaving, alternatively, as substrate or amine components of Mannich synthesis. On the other hand, the manifold reactivity of Mannich bases makes it possible (b) to produce polymers by amino group replacement with bifunctional nucleophiles or to polymerize suitable moieties (e.g., double bonds) present in the base. Furthermore (e), macromolecular compounds can be subjected to amino group replacement as well as to various other reactions given by Mannich bases. Finally (c), crosslinked derivatives are obtained from oligomeric or polymeric products through any of the above mentioned methods. 

Kig. 162. The crosslinking of high polymers by Mannich reaction using bifunctional amines. 

Propose a transition state for the direct vinylogous Mannich reaction with the bifunctional thiourea catalyst 51 reported by Chen and his group that accounts for the observed relative and absolute configurations of the products (Scheme 5.11). 

The acyl-Mannich reaction [34], acyl-Pictet-Spengler reaction [35,36] and cyanosilyla-tion [37] catalysed with bifunctional thiourea catalysts have also been developed by fine tuning of the side chain. 

Some of the catalyst systems used in the asymmetric aldol reaction are also effective in related reactions. Thus, bifunctional catalysts and L-prohne-based organocatalysts have been used to good effect in the nitroaldol reaction and Mannich reaction. The latter process is also effectively catalysed by enantiomeri-cally pure Bronsted acids. Furthermore, much recent progress has been made in the development of a catalytic asymmetric Morita-Baylis-Hillman reaction using Lewis/Bronsted acid catalysts and bifunctional catalysts. 

Scheme 5.28 Bifunctional catalyst 56 facilitates the nitro-Mannich reaction in an enantioselective manner...

The reversibility problem in 1,2-additions is alleviated when imines bearing an electron-poor protecting group at nitrogen (sulfonyl, aeyl, ear-bamoyl) are employed as aeceptor partners, rendering possible even the use of 1,3-dicarbonyl compounds as donors. For example, Sehaus and eoworkers reported the highly enantioselective Mannich reaction of acetoacetates and cyclic 1,3-dicarbonyl compounds with N-carbamoyl imines derived from benzaldehydes and cinnamaldehydes catalysed by the natural Cinchona alkaloid cinchonine (CN) (Scheme 14.15). On the basis of the obtained results they developed a model that accounts for the observed diastereo- and enantioselectivity based on the bifunctional nature of the catalyst, which acts simultaneously as a hydrogen-bond donor and acceptor. 

More recently, Pihko introduced bifunctional tertiary amine-thioureas 26 and 27 for the Mannich reaction of Boc-imines with malonates. ° Dimethylamino-tertiary amine thiourea 26 proved ideal for aliphatic imines, while the Cinchona derivative 27 provided the best results for aromatic substrates. Catalyst loadings as low as 1 mol% could be employed providing the products in high yields and excellent enantioselec-tivities (Scheme 19.34). Notably, both catalysts presented cooperative assistance via intermolecular hydrogen bonding, as first shown by Smith in 2009. ... 

On the other hand, Zhao s group achieved remarkable results with bifunctional cinchona alkaloid and thiourea catalysts [35], which, over the years, have been broadly employed as catalysts in Mannich reaction. Indeed, as Brpnsted bases, the preferred bifunctional catalyst 46 can lead to the Mannich three-component product 47 with extranely high diastereo- and... 

In addition, various chiral amine-thioureas have been successfully applied to promote asymmetric Mannich reactions. As an example, Takemoto and Miyabe have employed a chiral bifunctional organocatalyst possessing a thiourea moiety and a tertiary amino group as catalyst of the Mannich reaction between ethyl malonate and A-Boc arylimines, which provided the corresponding products in excellent yields and enantioselectivities (93-98% ee), as shown in Scheme S.lb. The degree of enantioselectivity was shown to be dependent on the reaction temperature, with the best results obtained at low temperature. 

The dual activation mode of the aforementioned cinchona alkaloid-derived thiourea catalysts proved to be highly effective in catalyzing the asynunetric Mannich reaction, among other transformations. These findings prompted the development of new, more simple bifunctional chiral catalysts that are predominately based on tra 5 -l,2-diaminocy-clohexane. For example, the application of the thiourea catalyst 120, which was developed by Takemoto and coworkers, afforded upon the reaction of Af-Boc-protected imines with diethyl malonate the desired chiral amines in good chemical yields (up to 91%) and enantioselectivities (98% ee) (Scheme 11.23) [81]. The catalytic mechanism presumably involves deprotonation and coordination of the active carbonyl compound by the chiral tertiary amine moiety. The formed enolate then attacks the si-face of the... 

SCHEME 11.21 Bifunctional cinchona aUcaloid/thiourea-catalyzed asymmetric Mannich reaction. 

SCHEME 11.22 Three-component direct asymmetric Mannich reaction catalyzed by a bifunctional quinidine thiourea catalyst. 

Jacobsen et al also synthesized bifunctional thiourea catalysts (Figure 2.17). Jacobsen et al. reported nitro-Mannich reaction catalyzed by a thiourea (10a) to give P-nitro amine in favor of the syn isomer with excellent enantioselectivity (Scheme 2.41) [94]. 

Finally, it has been shown that thiourea-type bifunctional catalysts are also useful for asymmetric aldol reactions [234, 235] and a-chlorination of aldehydes [236]. Furthermore, 4-substituted bifunctional analogs have been developed for use in onti-selective Mannich reactions [237]. 

Mannich Reactions in Br0nsted Base Catalysis including Bifunctional Catalysis... 

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