Ketones Brpnsted acid catalysts

In 2006, Yamamoto and Nakashima picked np on this and designed a chiral A -triflyl phosphoramide as a stronger Brpnsted acid catalyst than the phosphoric acids based on this concept. In their seminal report, they disclosed the preparation of new chiral BINOL-derived A -triflyl phosphoramides and their application to the asymmetric Diels-Alder (DA) reaction of a,p-unsaturated ketones with sily-loxydienes [83], As depicted in Scheme 59, chiral A-triflyl phosphoramides of the general type 4 are readily synthesized from the corresponding optically active 3,3 -substituted BINOL derivatives 142 through a phosphorylation/amidation route. 

Inspired by the recent observation that imines are reduced with Hantzsch esters in the presence of achiral Lewis or Brpnsted acid catalysts (Itoh et al. 2004), we envisioned a catalytic cycle for the reductive amination of ketones which is initiated by protonation of the in situ generated ketimine 10 from a chiral Brdnsted acid catalyst (Scheme 13). The resulting iminium ion pair, which may be stabilized by hydrogen bonding, is chiral and its reaction with the Hantzsch dihydropyridine 11 could give an enantiomerically enriched amine 12 and pyridine 13. 

Stronger Brpnsted acid catalysts such as N-triflyl phospho-ramides. N-Triflyl phosphoramides were first apphed to the asymmetric Diels-Alder (DA) reaction of unsaturated ketones with silyloxydienes. While the established phosphoric acids demonstrated no catalytic activity, 5 mol% of N-triflyl phosphoramide 46 proved highly effective for the DA reaction of ethyl vinyl ketone with a range of sily-loxydienes, allowing access to highly enantioenriched endo products in good yields (35 to >99%, 82-92% ee) via a presumed boat transition state such as 47 (Scheme 7). 

Luo S, Xu H, Li J, Zhang L, Cheng JP. A simple primary-tertiary diamine-Brpnsted acid catalyst for asymmetric direct aldol reactions of linear aliphatic ketones. J. Am. Chem. Soc. 2007 129 3074 3075. 

Asymmetric hydride reduction using Hantzsch ester has recently been extensively explored in organocatalysis using iminium-based catalysts or Brpnsted acid catalysts [72a-c], As an advance to their asymmetric conterion-directed catalysis (ACDC), List and coworkers found that the combination of simple primary amino acids such as L-valine with a chiral phosphoric acid led to an effective primary aminocatalyst for asymmetric transfer hydrogenation of a,P-unsaturated ketones (Scheme 5.43) [72d]. The catalysis could be applied to a range of substrates with good yields and excellent enantioselectivity. 

Two years later, Terada and coworkers described an asymmetric organocatalytic aza-ene-type reaction (Scheme 28) [50], BINOL phosphate (7 )-3m (0.1 mol%, R = 9-anthryl) bearing 9-anthryl substituents mediated the reaction of A-benzoylated aldimines 32 with enecarbamate 76 derived from acetophenone. Subsequent hydrolysis led to the formation of P-amino ketones 77 in good yields (53-97%) and excellent enantioselectivities (92-98% ee). A substrate/catalyst ratio of 1,000 1 has rarely been achieved in asymmetric Brpnsted acid catalysis before. 

D-Camphorsulfonic acid (d-CSA) was identified as catalyst for the enantioselec-tive Michael-type Friedel-Crafts reactions of indoles with aromatic enones ArCH= CHCOAr to afford the corresponding /i-indolyl ketones in excellent yields and moderate enantioselectivities. A surprising synergistic effect was discovered between [Bmim] Br and d-CSA, which may originate from the catalytic Lewis acid activation of the Brpnsted acid.162... 

The design for a direct catalytic asymmetric aldol reaction of aldehydes and unmodified ketones with bifunctional catalysts is shown in Figure 36. A Brpnsted basic functionality (OM) in the heterobimetallic asymmetric catalyst (I) could deprotonate the a-proton of a ketone to generate the metal enolate (II), while at the same time a Lewis acidic functionality (LA) could activate an aldehyde to give (III), which would then react with the metal enolate (in a chelation-controlled fashion) in an asymmetric environment to afford a P-keto metal alkoxide (IV). 

The most important side reaction in heterogeneously catalysed MPVO reactions is the acid-catalysed aldol condensation. Aldol products are usually observed during the Oppenauer oxidation of alcohols, when a surplus of ketone or aldehyde is used as the oxidizing agent and the solvent. The low amount of by-products formed when Ti-beta was used as the catalyst, demonstrates the advantage of the titanium system over Al-beta. This is probably caused by the much weaker Brpnsted acidity of the solvated titanium site [8] compared with the strong H -acidity of the aluminium site in Al-beta. As we have shown earlier Ti-beta has a high tolerance towards water, which further shows the catalytic potential of Ti-beta in MPVO reactions [9]. 

In the previons section, secondary chiral amines were employed that give rise to enamine formation npon reaction with ketones or aldehydes. Chiral tertiary amines, unable to form enamines, are nevertheless capable of inducing enantioselectivity in case substrates are used that contain sufficiently acidic protons such as aldehydes, ketones or active methylene compounds [33]. The cinchona alkaloids, by far the most versatile source of Brpnsted base catalysts, have played a prominent role in various types of asymmetric organocatalytic reactions [34], which is also true for the Mannich reaction. 

Further extent of asymmetric Sjvl a-alkylation methodology to ketone motifs was disclosed by Cheng and co-workers [129] in 2010. They described the first asymmetric catalytic direct a-alkylation of cyclic ketones catalyzed by functionalized chiral ionic liquids, namely proline-derived catalyst containing benzoimida-zolium moiety (LXI, Figure 8.1), and Brpnsted acid (TFA or phthalic acid). Moreover, described catalytic system enables asymmetric desymmetiization of 3-and 4-substituted cyclohexanones to afford 2,4-trans- and 2,5-cis-substituted products, respectively, with up to 99% yield, greater than 99 1 dr and good enantioselectivities (up to 87% ee). 

The mechanistic studies of a chiral Brpnsted acid-catalysed asymmetric reduction of ketones with catecholborane as the reducing agent to give highly enantioselective chiral secondary alcohols indicated that phosphoryl catechol borate, derived from reaction of the Brpnsted acid with catecholborane, acts as the active catalyst. ... 

An achiral iridium catalyst gives high yields in hydrogenation of imines derived from acetophenone, and also imines of aliphatic ketones. An enantioselective version has been developed, using a chiral phosphoric acid as Brpnsted acid. This gives ees up to 98%, but at the expense of the reaction rate, slowed by the bulk of the BINOL-type phosphoric acid. 

On an acidic oxide, the allylic species exist as carbocations giving an unsaturated ketone R-CO-CH= CH2 or aldehyde R-CH= CH-CHO. Another possibility is that, the hydrocarbon is attacked by a Brpnsted acid site and forms an alkoxide intermediate, which gives a saturated ketone R-CO-CH2-CH3. It is clear that controlling the acid-base properties of the catalyst surface will affect the first C-H activation and first reaction intermediate, and thus the overall reaction scheme. 

The scope of the Brpnsted acid-catalyzed asymmetric Mannich reaction was later extended by Gong and colleagues, which used instead of silyl ketene acetals or acetyl acetone simple ketones as nucleophiles [95]. The combination of various cycloketones, phenylamines, and aldehydes in the presence of the chiral phosphoric acid catalyst 134 or 135, respectively, afforded the corresponding anti-Mamich products in high yields with good enantioselectivities (75-98% ee)... 

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