Brpnsted acidity, catalyst activity

This review will concentrate on metal-free Lewis acids, which incorporate a Lewis acidic cation or a hypervalent center. Lewis acids are considered to be species with a vacant orbital [6,7]. Nevertheless, there are two successful classes of organocatalysts, which may be referred to as Lewis acids and are presented in other chapter. The first type is the proton of a Brpnsted acid catalyst, which is the simplest Lewis acid. The enantioselectivities obtained are due to the formation of a chiral ion pair. The other type are hydrogen bond activating organocatalysts, which can be considered to be Lewis acids or pseudo-Lewis acids. 

Recently, several research gronps reported on the use of chiral BINOL phosphates as Brpnsted acid catalysts in MCRs involving imine activation. 

In 2008, the Ackennann group reported on the use of phosphoric acid 3r (10 mol%, R = SiPhj) as a Brpnsted acid catalyst in the unprecedented intramolecular hydroaminations of unfunctionaUzed alkenes alike 144 (Scheme 58) [82], BINOL-derived phosphoric acids with bulky substituents at the 3,3 -positions showed improved catalytic activity compared to less sterically hindered representatives. Remarkably, this is the first example of the activation of simple alkenes by a Brpnsted acid. However, the reaction is limited to geminally disubstituted precursors 144. Their cyclization might be favored due to a Thorpe-Ingold effect. An asymmetric version was attempted by means of chiral BINOL phosphate (R)-3( (20 mol%, R = 3,5-(CF3)2-CgH3), albeit with low enantioselectivity (17% ee). 

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. 

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. 

The key feature of Br0nsted acid catalysis is often the choice of a catalyst with the appropriate acidity for particular substrate classes. Whereas less reactive substrates require stronger Brpnsted acids than the widely used phosphoric acids for activation, acid-sensitive substrates tend to decompose under strongly acidic conditions. Thus, weaker Brpnsted acid catalysts may prove beneficial. 

New Soluble Catalysts. Trifluoromethansulfonic acid (triflic acid, TfOH)42 and acyl triflates, that is mixed anhydrides of carboxylic acids and triflic acid,43 44 were first reported to be effective for Friedel-Crafts acylation in 1972. Significantly lower yields (<30%) were obtained with other Brpnsted acids. High activities were also observed for perfluorobutanesulfonic acid.37... 

Referring to a mechanistic classification of organocatalysts (Seayad and List 2005), currently the two most prominent classes are Brpnsted acid catalysts and Lewis base catalysts. Within the latter class chiral secondary amines (enamine, iminium, dienamine activation for a short review please refer to List 2006) play an important role and can be considered as—by now—already widely extended mimetics of type I aldolases, whereas acylation catalysts, for example, refer to hydrolases or peptidases (Spivey and McDaid 2007). Thiamine-dependent enzymes, a versatile class of C-C bond forming and destructing biocatalysts (Pohl et al. 2002) with their common catalytically active coenzyme thiamine (vitamin Bi), are understood to be the biomimetic roots ofcar-bene catalysis, a further class of nucleophilic, Lewis base catalysis with increasing importance in the last 5 years. 

Dumesic and co-workers studied the activity of isopropanol dehydration (247) on a series of silica-supported oxide catalysts as well as the acidic properties of these materials using IR spectroscopy and TGA of adsorbed pyridine (59) and adsorption microcalorimetry of pyridine at 473 K (18,104). Samples that showed only Lewis acidity were at least one to two orders of magnitude less active than the samples that displayed Brpnsted acidity. The activity of the latter samples increased in the order Sc < Ga < Al + This is the same order found for differential heats of pyridine adsorption on the Brpnsted acid sites, and a good correlation between the heats and the activity was found. No correlation was found with the initial heats or for the samples that had only Lewis acidity. 

Instead of using Br0nsted bases, chiral Br0nsted acids can also be utilized to enanti-oselectively acquire Mannich products. The acidic catalyst assists in the Mannich reaction by protonating the imine, thereby forming an iminium ion to which the deprotonated Brpnsted acid catalyst coordinates. This chiral counterion directs the incoming nucleophile and leads to an optically active Mannich product. 

In 2009, Klausen and Jacobsen disclosed another activation pathway, in which the thiourea catalyst enhances the acidity of a relatively weak Brpnsted acid catalyst, and applied this to an enantioselective version of the Pictet-Spengler cyclization [149]. This increase on the acidity of the Br0nsted acid allows the protonation of the imine substrate and to the formation of an iminium ion with a chiral counterion, which is stereoselectively attacked by a nucleophile (Scheme 2.28). 

Complementary method to organocatalytic enantioselective BH reaction would be the use of chiral Brpnsted acid to activate Michael acceptors or electrophiles. However, their incompatibility between the acid and base catalysts is important issue to be addressed since any possible acid-base quench would lead to inactive catalysts. Recent results have revealed that effective chiral Brpnsted acid catalysts are hydrogen-bond-donating organic molecules. 

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). 

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]). 

During our synthetic study on a Robinson annulation approach toward platensi-mycin, we used a carbon based Brpnsted acid to activate the valine derived oxazaborolidine catalyst to prepare a key chiral building block [46]. This new... 

In general, most chiral Br0nsted base catalysts are equipped with an additional hydrogen bond donor (Brpnsted acid), which activates the electrophile. Moreover, coordination of both the nucleophile and electrophile to the rigid chiral backbone of the bifunctional catalyst via hydrogen bonding and a basic tertiary amine anchors the electrophile and nucleophile in an optimal transition state, which seems essential for the highly stereoselective and predictable formation of a... 

During the past decade, Brpnsted acid catalysis has been employed successfully to promote versatile cascade processes, efficiently constructing a huge number of structurally diverse chiral architectures with high optical purity. Based on the deep insights in the active modes and reaction mechanisms, new Brpnsted acid catalysts and... 

The water-soluble palladium complex prepared from [Pd(MeCN)4](Bp4)2 and tetrasulfonated DPPP (34, n=3, m=0) catalyzed the copolymerization of CO and ethene in neutral aqueous solutions with much lower activity [21 g copolymer (g Pd) h ] [53] than the organosoluble analogue in methanol. Addition of strong Brpnsted acids with weakly coordinating anions substantially accelerated the reaction, and with a catalyst obtained from the same ligand and from [Pd(OTs)2(MeCN)2] but in the presence of p-toluenesulfonic acid (TsOH) 4 kg copolymer was produced per g Pd in one hour [54-56] (Scheme 7.16). Other tetrasulfonated diphosphines (34, n=2, 4 or 5, m=0) were also tried in place of the DPPP derivative, but only the sulfonated DPPB (n=4) gave a catalyst with considerably higher activity [56], Albeit with lower productivity, these Pd-complexes also catalyze the CO/ethene/propene terpolymerization. 

Bifunctional catalysts have proven to be very powerful in asymmetric organic transformations [3], It is proposed that these chiral catalysts possess both Brpnsted base and acid character allowing for activation of both electrophile and nucleophile for enantioselective carbon-carbon bond formation [89], Pioneers Jacobsen, Takemoto, Johnston, Li, Wang and Tsogoeva have illustrated the synthetic utility of the bifunctional catalysts in various organic transformations with a class of cyclohexane-diamine derived catalysts (Fig. 6). In general, these catalysts contain a Brpnsted basic tertiary nitrogen, which activates the substrate for asymmetric catalysis, in conjunction with a Brpnsted acid moiety, such as urea or pyridinium proton. 

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