Imines phosphoric acid catalysis

Chiral phosphoric acids mediate the enantioselective formation of C-C, C-H, C-0, C-N, and C-P bonds. A variety of 1,2-additions and cycloadditions to imines have been reported. Furthermore, the concept of the electrophilic activation of imines by means of phosphates has been extended to other compounds, though only a few examples are known. The scope of phosphoric acid catalysis is broad, but limited to reactive substrates. In contrast, chiral A-triflyl phosphoramides are more acidic and were designed to activate less reactive substrates. Asymmetric formations of C-C, C-H, C-0, as well as C-N bonds have been established. a,P-Unsaturated carbonyl compounds undergo 1,4-additions or cycloadditions in the presence of A-triflyl phosphoramides. Moreover, isolated examples of other substrates can be electrophil-ically activated for a nucleophilic attack. Chiral dicarboxylic acids have also found utility as specific acid catalysts of selected asymmetric transformations. 

Although phosphoric acids have found broad applicability for a wide range of asymmetric transformations, most reactions are limited to electrophilic activation of imines. Expanding the scope of phosphoric acid catalysis to other classes of electrophiles, Akiyama and Terada subsequently reported activation of nitroalkene [38] and carbonyl [39] electrophiles, respectively (Scheme 5.23). 

Prior to Yamamoto s entry into this field, the scope of chiral phosphoric acid catalysis was strictly limited to electrophiUc activation of imine substrates. By designing a catalyst with higher acidity it was suspected that activation of less Lewis basic substrates might be possible. To this end, Yamamoto reported incorporation of the strongly electron accepting N-triflyl group [57] into a phosphoric acid derivative to yield the highly acidic N-triflyl phosphoramide 13 (Scheme 5.32)... 

Soon after these initial reports, the groups of Antilla [92] and You [93] indepen dently applied the chiral phosphoric acid catalysis to the enantioselective hydro genation of a imino esters. The method provides an alternative route to the enantioselective synthesis of a amino esters. Antilla and coworkers employed a new type of axially chiral phosphoric acid (9) derived from VAPOL originally developed by his research group (Scheme 3.42), whereas lg was used in You s case. In both cases, excellent enantioselectivities were achieved. You and coworkers further applied the method to the enantioselective reduction of a imino esters having an alkynyl substituent at the a position (Scheme 3.43) [94]. Both alkyne and imine moieties were reduced under transfer hydrogenation conditions with an excess amount of... 

FIGURE 2.36. The Simon-Goodman transition state working models for the binol-derived phosphoric acid catalysis of nucleophilic additions to imines. 

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]). 

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. 

The actual catalyst in phosphoric acid-catalyzed Mannich-type reaction of imines with 1,3-dicarbonyl compounds is certainly phosphoric acid itself [74], but metal contaminants, such as alkali or alkaline-earth metals, have interesting effects on the reactivity and stereoselectivity. HCl-washed, metal-free chiral phosphoric acid 149a and chiral calcium phosphate 149b are able to catalyze the Mannich-type reactions. The absolute stereoselectivity of the phosphoric acid catalysis is opposite that of the calcium phosphate catalysis (Scheme 28.16) [75]. 

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. 

Polyquinolines (PQ) are obtained by the Friedlander reaction of a bis-o-aminoaromatic aldehyde (or ketone) with an aromatic hisketomethylene reactant [Concilio et al., 2001 Stille, 1981]. The quinoline ring is formed hy a combination of an aldol condensation and imine formation (Eq. 2-221). Polymerization is carried out at 135°C in m-cresol with poly (phosphoric acid) as the catalyst. The reaction also proceeds under base catalysis, but there... 

In Ught of the recent developments in thiourea, diol, and phosphoric-acid-mediated catalysis, far fewer studies have focused on the use of chiral carboxyhc acids as suitable hydrogen bond donors. To this end, Mamoka synthesized binaphthyl-derived dicarboxylic acid 49 which catalyzes the asymmetric Mannich reaction of N-Boc aryl imines and tert-diazoacetate (Scheme 5.65) [120]. The authors postulate that catalytic achvity is enhanced by the presence of an addihonal car-boxyhc acid moiety given that use of 2-napthoic acid as catalyst provided only trace amounts of product... 

The TBS group was chosen as silyl fragment within the dienolate to prevent a attack of the imines on the nucleophile. As chiral catalyst we employed a BINOL based phosphoric acid of the same type that Akiyama and Terada had established in asymmetric catalysis and found 3,3 mesityl groups optimal for the enantioselectivity of the reaction. The reactions were run at 30 °C in a solvent mixture of fBuOH, 2 methyl 2 butanol,andTHFin equal amounts containing anadditionallequivofwater. 

Replacement of an hydroxyl group in resorcinol, most probably through tautomerism and imine formation, has been effected by heating it in an autoclave with 1-aminobutane and a small amount of phosphoric acid at 200°C under pressure (13 bar) for 8 hours. Only the monobutylamino substitution product was obtained but by phase transfer catalysis on the reaction product, with a benzyttrimethylammonium salt, (formed in situ from a surfactant and potassium iodide), sodium hydroxide solution and 1-bromobutane for 20 hours at 60-80°C, 3-dibutylaminphenol was produced in 64% yield (ref. 106). 

The enamine catalysis detailed above proceeds via activation of the Mannich donor. An alternate strategy to the catalysis of the Mannich reaction is by the use of Brensted acids that activate the acceptor imine by protonation on nitrogen. Some of the most successful asymmetric variants of this process use BINOL-based phosphoric acids as catalysts. For instance Terada and coworkers used (7.144) to effect highly enantioselective addition of acetylacetone to a range of aryl aldimines ... 

Chiral phosphoric acids, such as 182, were also found to be suitable catalysts for this transformation [143], although with 182 the substrate scope was limited to N-tosyl and N-brosyl-substituted aryl imines 188. In contrast, catalysis by 183 considerably reduced the reaction time (<2 h to reach completion). Antilla reported the use of chiral phosphoric acid 184 in the enantioselective addition of indoles to... 

It worth to mention that despite the importance of the Kabachnik-Fields reaction, stereoselective versions for the synthesis of enantioenriched a-aminophosphonates are scarce [212, 213], and only few enantioselective examples have been published to date (for reviews on enantioselective catalytic direct hydrophosphonylations of imines, see Refs. [162a-c]). Organocatalytic examples use well-known chiral binol-derived phosphoric acid organocatalysts (Fig. 12.6,80 and 81) [214], and regarding metal catalysis, chiral scandium(III)-A,A -dioxide and... 

Scheme 26.14 Phosphoric acid effect in the activation of imines toward the addition of oxygen and nitrogen yUdes generated in diazo componnds by rhodimn(II) catalysis.

Chiral oxazaborolidine catalysts were applied in various enantioselective transformations including reduction of highly functionalized ketones/ oximes or imines/ Diels-Alder reactions/ cycloadditions/ Michael additions, and other reactions. These catalysts are surprisingly small molecules compared to the practically efficient chiral phosphoric acids, cinchona alkaloids, or (thio)ureas hence, their effectiveness in asymmetric catalysis demonstrates that huge substituents or extensive hydrogen bond networks are not absolutely essential for successful as5unmetric organocatalysis. 

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],... 

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-... 

Rueping et al. reported achiral Br0nsted acid assisted chiral Bronsted acid catalysis in the direct Marmich reaction of acyclic ketones. The reaction of N-aryl imines with acetophenone was conducted using a chiral phosphoric acid in the presence of acetic acid as the co-catalyst and the resulting products were obtained in moderate yields [11]. 

N-Boc-protected ethyl trifluoropyruvate imine was effectively used in a F-C reaction with indole derivatives for synthesizing, in high selectivities, quaternary a-amino acids via catalysis with chiral phosphoric acid 26e [64]. A binaphthyl-based chiral sulfonimide [42c] and a chiral squaramide-based hydrogen bond donor [42a] were used as effective catalysts for promoting F-C reaction of indoles with imines. Recently, the F-C alkylation of arenes with glyoxylate imine was described via a chiral phosphoric add (Scheme 35.11) [34]. 

The appHcation of chiral Bronsted acids in asymmetric catalysis has increased in recent years [6], In 2006, Rueping et al. reported a double Bronsted acid catalyzed reaction of imine 1 and cyclohexenone 2, in which the electrophile was achvated by a chiral phosphoric acid 4 and the nucleophile was activated by an achiral Bronsted acid 5 (Scheme 43.1) (10). Various aromahc and heteroaromatic substituted isoquinuclidines with electron-withdrawing and electron-donating substituents could be isolated in good yields and high enantiomeric ratios (82-88% ee), with exo/endo ratios between 1 3 and 1 9. The reachvity of a broad range of achiral Bronsted adds was examined and the effect on the enantiomeric induchon was obvious (52% ee to 86% ee for the product 3). 

Au(l)/Br0nsted Acid System Han et al. developed an unprecedented protocol to synthesize tetrahydroquinolines 332 directly from 2-(2-propynyl)aniline derivatives 365 in one pot under relay catalysis of an achiral Au complex 368 and a chiral phosphoric acid 5j [131]. The Au -catalyzed intramolecular hydroamination of 2-(2-propynyl)aniline provided the 1,4-dihydroquinolines 366, followed by isomerization into imine-like 3,4-dihydroquinoliniums 367 with 5j. This active intermediate then underwent asymmetric transfer hydrogenation with Hantzsch ester to produce enantioenriched tetrahydroquinoUne products (Scheme 2.97). 

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