Triazolium salts, catalysis

The triazol-5-ylidene 12 was found to be a powerful catalyst for the conversion of formaldehyde to glycolaldehyde in a formoin reaction [25.] The concept of triazolium salt catalysis appeared to show promise, and consequently our research group undertook the synthesis of a variety of chiral triazolium salts for the asymmetric benzoin reaction [26]. However, the ce-values and catalytic activities shifted widely with slight structural changes in the substitution pattern of the triazolium system. The most active catalyst 15 (Fig. 9.4) afforded benzoin (6, Ar = Ph) in its (R -configuration with 75% ee and a satisfactory yield of 66%. 

While enantioselective transition metal catalysis continues to be important, several useful all-organic catalysts have been developed over the past few years. Tomislav Rovis of Colorado Stale University has reported (J. Am. Chem. Soc. 2004, /26, 8876) that the triazolium salt 5 catalyzes the enantioselective Stetter-type cyclization of 4 to 6. The cyclization also works well for the enantioselective construction of azacyclic, thiacyclic and carbocyclic rings. 

First attempts of an asymmetric Stetter reaction were made 1989 in our research group with the investigation of chiral thiazolium salts such as 136 as precatalysts. The reaction of n-bu Lanai (133) with chalcone (134) in a two-phase system gave the 1,4-diketone 135 with an enanan-tiomeric excess of 39%, but a low yield of only 4% (Scheme 37) (Tiebes 1990 Enders 1993 Enders et al. 1993b). The catalytic activity of thiazolium as well as triazolium salts in the Stetter reaction persisted at a rather low level. Triazolium salts have been shown to possess a catalytic activity in the non-enantioselective Stetter reaction (Stetter and Kuhlmann 1991), but in some cases stable adducts with Michael acceptors have been observed (Enders et al. 1996a), which might be a possible reason for their failure in catalysis. 

However, iV-ammonium salts as well as the IV-imines possess further acidic hydrogen atoms. In 0.2 N NaOD, (V-aminopyridinium salts (14) exchanged their hydrogen atoms at the 2-, and 4-, and 6-positions for a D atom within the time the NMR spectra could be measured.17 For the 4-amino-s-triazolium salts (93) base catalysis is not needed for the hydrogen exchange.134 The ylid or nucleophilic carbene structures 94 and 95 are intermediates (see also Wanzlick135 and Quast and Hunig136) and can be intercepted by sulfur or ethyl acetoacetate.134... 

In 1966, Sheehan reported a remarkable asymmetric benzoin reaction catalyzed by chiral thiazolium salts with moderate levels of enantioselectivity [56-59]. In 2002, Enders and coworkers made an important breakthrough when they reported the first highly enantioselective intermolecular benzoin reaction catalyzed by a triazolium salt derived from ferf-leucine [Eq. (1)] [60]. Since then, catalyst development for NHC catalysis has seen exponential growth for new triazolium salts derived from chiral amino acids and amino alcohols. 

Extension of this work to the diastereoselective synthesis of y-lactams from N-sulfonyl aldimines [93] and ketimines [94] was subsequently reported. Scheldt and coworkers disclosed an enantioselective version (up to 98% ee) from reactive hydrazones in the initial demonstration of cooperative NHC/Lewis acid catalysis using a bulky, chiral triazolium salt and catalytic Mg(OBu )2 [95]. Rovis and coworkers synthesized y-lactams 109 enantioselectively using a chiral N-C Fs triazolium salt (Scheme 18.19). A weak carboxylate base was sufficient to partially deprotonate the precatalyst 108 in situ, and the carboxylic acid formed could activate the N-Ar imine acceptor 107 via protonation [lib]. In all these cases, a fine balance must exist between sufficient electrophilicity vis-a-vis the competing enal and reversible addition of the carbene to the imine/hydrazone/iminium or to the Lewis acid. 

Carbenes belong to the most investigated reactive species in the field of organic chemistry. Besides their role as excellent ligands in metal-based catalytic reactions, organic carbene catalysis has emerged as an exceptionally fruitful research area. In 2002, Rovis reported a highly enantioselective intramolecular Stetter reaction of unsaturated esters 50 derived from salicylaldehyde by the catalysis of chiral aminoindanol-derived triazolium salt 49 (Scheme 36.14) [20a]. 

In 2006, Enders reported an intramolecular cross benzoin reaction of bifunctional substrates 53 containing aldehyde and ketone groups to give various six-membered cyclic acyloins 54 in moderate to good yields. Up to 98% ee has been obtained upon catalysis by the tetracyclic triazolium salt 52 (Scheme 36.15) [21aj. Suzuki also developed a similar intramolecular asymmetric cross benzoin reaction [2lb]. 

As well as the traditional benzoin and Stetter reactions, some new synthetic transformations were disclosed via carbene catalysis. In 2007, the Scheldt group developed an intramolecular Michael-type reaction with unsaturated substrates 56 through catalysis with chiral triazolium salt 55. The intermediates 57 were generated via a domino Michael addition/lactonization sequence, and bicyclic products 58 were afforded in satisfactory yields and with excellent enantioselectivity after... 

Recently, Glorius reported an elegant asymmetric hydroacylation of unactivated alkenes via carbene catalysis [24], Chromanone derivatives 70 containing an allcarbon based quaternary stereocenter could be efEciently produced from simple 2-aUyloxybenzaldehydes 69. Good yields and excellent enantioselectivity were obtained in the presence of chiral triazolium salt 68 and DBU. In addition, quantum-chemical calculations support a concerted but very asynchronous transition state (Scheme 36.18). 

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