Ketimine/activated hydrogen

In 2007, Feng et al. reported an efficient self-assembled catalytic system for the addition of trimethylsilyl cyanide to imines. The combined use of cinchonine (27), achiral 3,3 -(2-naphthyl)-2,2 -biphenol (28), and titanium tetra-isopropoxide gave an efficient catalyst for aldimines and ketimines (Scheme 7.19). Cinchonine induces a chiral environment around the titanium atom by fixing a stable chiral configuration to the biphenol ligand, and also activates hydrogen cyanide, generated in situ. In addition to trimethylsilyl cyanide, safer ethyl cyanoformate can be used with similar results. 

For the reduction of ketimines with trichlorosylane via a possible hydrogen-bonding activation, see Maikov, A. V. Mariani, A. MacDougall, K. N. Kocovsky, P. Org. Lett. 2004, 6, 2253-2256. 

The presence of a heteroatom directly connected to the nitrogen atom of the imine activates it toward hydrogenation, while creating a second coordination site for the catalyst. Indeed, some successful results have been achieved for the hydrogenation of N-acylhydrazone, sulfonimide, and N-diphenylphosphinyl ketimines. The Et-DuPhos-Rh complex is an efficient catalyst for the asymmetric hydrogenation of a variety of N-acyl- ... 

The Br0nsted acid catalyzed enantioselective reduction of several methyl-aryl ketimines affords the corresponding amines in good yields and enantioselectivities (Table 4.1). The mild reaction conditions and generally good chemoselectivity of this transfer hydrogenation render this transformation an attractive and metal-free approach to optically active amines. 

As shown in Scheme 1.95, the chiral titanocene catalyst 34 (see Scheme 1.10) prepared from 33, n-C4HgLi, andC6H5SiH3 shows a moderate-to-good enantioselectivity in the hydrogenation of /V-benzyl i mines of aryl methyl ketones, whereas the catalytic activity is rather low even at 137 atm [346]. The ketimine with R1 = 4-CH3OC6H4 is hydrogenated with (/ )-34 to give the R amine with 86% ee. The E Z of the imine substrate affects the enantioselection. The optical... 

Imines may be activated by complexation with Lewis acids, but this also increases the acidity of a-hydrogen atoms. A combination of copper(i) halide and boron trifluoride etherate is a possible solution to the problem [6, 7]. Activation by trimethylsilyl triflate is also effective with aldimines (though not with ketimines) [7, 8]. 

Based on the above activation mechanism we wondered whether it would be possible to develop a biomimetic, organocatalytic reductive amination or transfer hydrogenation of ketimines. We reasoned that the activation of the imine by catalytic protonation through the Brpnsted acid should enable the hydrogen transfer from a suitable NADH mimic to yield the corresponding amine (Fig. 2). Hence, initial experiments focused on the examination of various Brpnsted acids in combination with different hydride sources (Rueping et al. 2005a). 

With regard to the mechanism we assume that, similar to the dehydrogenase (Fig. 1), the ketimine 1 will be activated by protonation through Brpnsted acid 5 which results in the formation of a chiral ion-pair, an iminium ion A. Subsequent hydrogen transfer from the dihy-... 

The absolute configuration of the amine 7 may be explained by a stereochemical model based on the X-ray crystal structure of the chiral BINOL-phosphate (Fig. 4). In the transition state the ketimine is activated by the Brpnsted acid in such a way, that the nucleophile has to approach from the less hindered si face as the re face is effectively shielded by the large aryl substituent of the catalyst (Fig. 4, left). Furthermore, a bifunctional activation seems to be plausible, where next to the ketimine protonation, the dihydropyridine is activated through a hydrogen bond from the Lewis basic oxygen of the phosphoryl group. 

Nitriles with an activated methylene group in the a-position (39) react with sulfur and carbon disulfide.77 Ketimines (42) also give l,2-dithiole-3-thiones (7) with sulfur and carbon disulfide.78 A/-Aryl-3,3-bis(methylthio)-2-aryl propenimines (43) react with hydrogen sulfide79 to give aryl product 15. 

In 2005, Rueping et al. reported that chiral phosphoric acids function as an efficient catalyst for the enantioselective reduction of ketimines (Scheme 3.40a 1) [87]. A variety of aryl methyl ketimines were reduced to the corresponding amines in optically active forms using Hantzsch ester as the hydrogenation transfer reagent (HEH) [88]. Subsequently, List and coworkers improved the catalytic efficiency and enantioselectivity by thorough optimization of the substituents (G) that were introduced to the phosphoric acid catalyst (Scheme 3.40a 2) [89]. Almost simulta neously, MacMillan and coworkers successfully developed the enantioselective... 

Recognizing that FLP activation of H2 requires a bulky base and acid combination, we probed the question of whether a bulky imine could act both as the base component of an FLP and as the substrate for catalytic reduction. Indeed, a number of aldimines and ketimines could be hydrogenated with a catalytic amount of B(QF5)3 under H2 in a facile manner (Table 11.2, Scheme 11.13) [47]. As with the phosphino-borane catalyst, dx-triphenylaziridine is also reduced under these conditions to N-(l,2-diphenylethyl)aniline (Table 11.2) [47]. 

Taking imine activation as an example, the relative roles of proton transfer/ ion-pairing versus hydrogen bonding have been probed for Brpnsted acid catalysis. Taking simple diaryl ketimines and aldimines as model substrates and... 

Akiyama et al. reported a Brpnsted acid-catalyzed synthesis of 3-aryl-1-trifluoromethyltetrahydroisoquinolines 230 and 230 by a benzylic [l,5]-hydride shift-mediated C-H bond functionalization (Scheme 87) [142], which features the diastereo-divergent synthesis of 3-aryl-l-trifluoromethyltetrahydroisoquinolines 230 and 230 by tuning the substiments on nitrogen atom. The trifluoromethylketimine derived from para-anisidine and activated by Tf2NH served as hydride acceptor and the substituents on ketimines had dramatic impacts on the diastereoselectivities cis-product 230 could be furnished as major product when R was PMP group, whereas the diastereoselectivity was reversed with R as hydrogen. 

However, the lone-pair electrons activate the a-hydrogens of aliphatic amines, and hydrogen is therefore removed by some reagents as easily from this site as from nitrogen. This leads to the formation of unsaturated compounds such as aldimines, nitriles, ketimines and enamines. The actual products depend on the amine structure (equations 68 to 71) and others may arise from subsequent hydrolysis, oxidation. 

Primary amines can be used as substrates for C-C bond activation reactions that consist of four independent transformations [29]. This process is exemplified by reaction of 3-phenylpropan-l-amine (49) with 3,3-dimethylbut-l-ene (47) in the presence of 16 and 21, which produces both the symmetric dialkyl ketone 51 and tmsymmetric ketone 50 (Scheme 10a). The route followed in this reaction (Scheme 10b) begins with rhodium mediated transfer hydrogenation between amine 49 and alkene 47 to generate phenethylimine 52, which then undergoes transimination with 21 to yield the aminopicoline derived imine 53. Chelation-assisted hydroimination of 53 with the olefin then forms ketimine 54, which upon acid promoted hydrolysis produces ketone 50. In a competing pathway, Rh(I)-catalyzed C-C bond activation of ketimine 54, followed by subsequent addition of 47, affords the symmetric dialkyl ketimine 55, which is converted to symmetric dialkyl ketone 51 upon hydrolysis. 

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