Imine bonds, acid-catalyzed formation

While the early part of the acid-catalyzed path to form an imine (i.e., production of a protonated hemiaminal) appears the same for secondary amines (Table 9.4, 2b) and primary amines (Table 9.4,2a), the absence of a proton on nitrogen denies that intermediate the ability to lose water as shown in Scheme 9.65. Therefore, if there is a proton on the adjacent carbon, water is lost with the formation of a nitrogenbearing, carbon-carbon double bond species called an enamine (Scheme 9.66). Although it wiU be discussed later in this chapter when addition to the carbon a alpha) to the carbonyl (C=0) is separately considered it is worthwhile noting here... 

The in situ-generated iminium could also be exploited as hydride acceptor, via which inert C(sp )-H bond could be functionalized to C-N bond efficiently. Seidel et al. reported a trifluoroacetic acid-catalyzed cascade [1,6]-hydride transfer/cy-clization of 77 to synthesize 7,8,9-trisubstituted dihydropurine derivatives 78 (Scheme 27) [73]. TFA plays two roles in this process (1) promotion of imine formation and (2) protonation of imine for acceleration of the hydride shift process. Meth-Cohn and Volochnyuk et al. reported similar reactions in 1967 [71] and 2007, respectively [72]. 

Based on the x-ray crystal structure of the [2]catenane and the DFT-calculated structure of the trefoil knot, the formation of the knotted structures resulted from a strong zinc templated chelation combined with the formation of dynamic covalent imine bonds catalyzed by Zn(II) acting as a Lewis acid and templated by strong tt-tt stacking interactions between the bipyridine of one strand and the phenoxy rings of another—an organization that predisposes the amine functions close to the formyl groups. 

Following immediately the initial efforts on primary amino acids catalyzed aldol reactions, the application of primary amine acid in Mannich reaction has also been attempted. Cordova reported that simple primary amino acids and their derivatives could catalyze the asymmetric Mannich reactions of ketones with comparable results to those obtained in the catalysis of proline[28]. Later, Barbas [29] and Lu [30] independently reported that L-Trp or 0-protected L-Thr could catalyze anti-selective asymmetric Mannich reactions of a-hydroxyacetones with eiflier preformed or in-situ generated imines. The preference of anii-diastereoselectivity was ascribed to the formation of a Z-enamine, with the assistance of an intramolecular H-bond (Scheme 5.15). 

Addition reactions of organoboronic acids to electron-deficient alkenes were found to be catalyzed by rhodium(i)931 or dicationic palladium(n) complexes.932,933 The reaction proceeding through the transmetallation to a transition metal has been proved to be a general technique for a wide range of selective carbon-carbon bond formation via 1,4-addition to a,/ -unsaturated ketones, aldehydes, esters, and amides, and the 1,2-addition to aldehydes and imines (Equation (217)).934... 

Activation of C=N double bonds by copper Lewis acids for nucleophilic addition has also been reported (Sch. 37) [73]. The a-imino ester 157 undergoes alkylation at the imine carbon with a variety of nucleophiles when catalyzed by copper Lewis acids. The presence of the electron-withdrawing ester group increases the reactivity of the imine and also assists in the formation of a stable five-membered chelate with the Lewis acid. Evidence for Cu(I) Lewis-acid catalysis and a tetrahedral chelate was obtained by FTIR spectroscopy, from the crystal structure of the catalyst, and from several control experiments. The authors rule out the intermediacy of a copper enol-ate in these transformations. The asymmetric alkylation of A,0-acetals with enol silanes mediated by a copper Lewis acid proceeding with high selectivity has been reported [74],... 

This classification is illustrated in Scheme 365. The synthesis of imidazoles under this classification is rare mainly due to the difficulty of C-C bond formation. A palladium-catalyzed coupling of imines 1415, 1417 and acid chloride 1416 to synthesize substituted imidazoles 1418 belongs to this category of ring formation. AT-Alkyl and AT-aryl imines can be used, as can imines of aryl and even nonenolizable alkyl aldehydes. A plausible reaction mechanism involving 1,3-dipolar cycloaddition with miinchnones is illustrated in Scheme 366 <2006JA6050>. 

---