Imines Brpnsted acid catalysis

Until 2006, a severe limitation in the field of chiral Brpnsted acid catalysis was the restriction to reactive substrates. The acidity of BINOL-derived chiral phosphoric acids is appropriate to activate various imine compounds through protonation and a broad range of efficient and highly enantioselective, phosphoric acid-catalyzed transformations involving imines have been developed. However, the activation of simple carbonyl compounds by means of Brpnsted acid catalysis proved to be rather challenging since the acid ity of the known BINOL-derived phosphoric acids is mostly insufficient. Carbonyl compounds and other less reactive substrates often require a stronger Brpnsted acid catalyst. 

A different organocatalytic approach to isoquinuclidine molecules has been described based on a cooperative double Brpnsted acid catalysis (Scheme 11.46) [127]. Thus, a proton transfer from the chiral Brpnsted acid to the aromatic imine would occur forming the chiral ion pair A ready to react with the dienol derived from... 

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... 

Making acetals that contain A-atoms has been a fairly straightforward effort, following the advent of asymmetric phosphoric acid catalysis [9, 10]. Since the reports of Akiyama and Terada, asymmetric additions of nucleophiles to imines became a well-developed area of asymmetric Brpnsted acid catalysis [11, 12]. Consequently, heteroatom nucleophiles were shown to be viable nucleophiles and various N,N-, N,0-, and A,S -acetals could be prepared for the first time in a catalytic asymmetric fashion. These reactions are briefly summarized in the next section. 

Despite the massive advancements in asymmetric catalysis over the last several decades, the catalytic enantioselective generation of N,N-, N,0-, N.S-, and N,Se-acetals only recently became a possibility with the advent of asymmetric Brpnsted acid catalysis [16-22], Asymmetric syntheses of acyclic NJ -, N,0-, N,S-, and N, Se-acetals catalyzed by chiral phosphoric acids were developed in the Antilla group utilizing the addition of heteroatom nucleophiles to iV-protected imines (Scheme 4) [16-18, 22],... 

Within the field of chiral ion pair catalysis only aldimines and keto-imines had been activated so far. However, we have recently been successful in the activation of both the electrophile, as well as the nucleophile in a new double Brpnsted acid catalyzed reaction. 

An elaboration of this work involves the 3CR between primary a-isocyanoa-mides 67, carbonyl components 6 and primary amines 146, which could be directed towards either 2//-2-imidazolines 153 or M-(cyanomethyl)amides 156 by Ag -catalysis vs. Brpnsted acid mediated reaction, respectively (Scheme 14) [60]. The selective formation of M-(cyanomethyl)amides 156 (also earlier mentioned in the SRR approach. Scheme 7) can be rationalized by the same criteria as the formation of trisubstituted oxazoles 152 (Scheme 13), since the use of a Brpnsted acid, prevents the formation of 2-imidazolines 153 by the decreased pH. By applying a Brpnsted acid, the reaction initially proceeds via the same mechanism as for the oxazole MCR. However, when intermediate 155 is formed, it does not tautomerize to form the 5-aminooxazole 157. Instead, proton abstraction at the exocyclic imine nitrogen and subsequent ring opening gave the corresponding M-(cyanomethyl)amides 156. 

Based on previous studies where the imines were reduced with Hantzsch dihydropyridines in the presence of achiral Lewis [43] or Brpnsted acid catalysts, [44] joined to the capacity of phosphoric acids to activate imines (for reviews about chiral phosphoric acid catalysis, see [45-58]), the authors proposed a reasonable catalytic cycle to explain the course of the reaction (Scheme 3) [41]. A first protonation of the ketimine with the chiral Brpnsted acid catalyst would initiate the cycle. The resulting chiral iminium ion pair A would react with the Hantzsch ester lb giving an enantiomerically enriched amine product and the protonated pyridine salt B (Scheme 3). The catalyst is finally recovered and the byproduct 11 is obtained in the last step. Later, other research groups also supported this mechanism (for mechanistic studies of this reaction, see [59-61]). 

In general, bulky substituents at the 3,3 -position of the BINOL backbone are required to achieve good selectivities in asymmetric catalysis. This laborious catalyst fine-tuning can be simplified when chiral l,r-binaphthyI-2,2 -disulfonic acid (BINSA, 141) is used instead of the aforementioned BINOL-derived chiral phosphoric acids. Complexation with a suitable achiral amine enables to tune the bulkiness and Brpnsted acidity in situ [98]. Based on this approach, Ishihara and coworkers combined various A-Boc- or A-Cbz-protected imines and acetyl acetone in the presence of BINS A (1 mol%) and 2,6-diphenylpyridine (142, 2mol%) to afford the corresponding Mannich products in excellent yields and enantioselectivities (Scheme 11.31) [98]. However, the cata-... 

Ruthenium/Br0nsted Acid System The tandem isomerization/Friedel-Crafts reaction of aUylamides reported by Sorimachi and Terada was another early example of a cascade catalysis procedure using Brpnsted acid and metal salts as catalysts (Scheme 2.93) [127]. With the promotion of the ruthenium catalyst 342, the aUylamides isomerized to enamide X32, which was then tautomerized by a Brpnsted acid (343 or 344) to form imine X33 then the electron-enriched aromatic substrates 341 attacked the Brpnsted acid-activated imine intermediates to afford Friedel-Crafts products 345 in up to 91% yield. 

In 2008, Sorimachi and Terada reported a relay catalysis using a rhodium hydride complex/Brpnsted acid (129) binary system (Scheme 5.88) [89]. The sequential transformation involves a three-step relayed catalysis, where (1) isomerization of allylamide 130 to enamide A is catalyzed by RhClH(CO)(PPh3)j (2) subsequent isomerization of A to imine B is relayed by 129 and (3) the catalytic sequence is terminated by a carbon-carbon bond forming the reaction of B with a nucleophilic component 131 under 129. This approach enables the generation of reactive imines B from readily available allylamides 130 in a one-pot reaction via tandem isomerization. 

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