From 1,2,4-Triazolium Salts

Treatment of the phenacyliminium salt 114, derived from 5,7-dimethyl[l,2,4]-triazolo[l,5-fl]pyrimidine 113 and phenacyl bromide, with 2 equiv of triethylamine gives rise to the 2-iminooxazoline 118 by way of the in situ generated intermediary A -ylides 115. Acidic hydrolysis affords the 3-(2-pyrimidinyl)-2(3//)-oxazolone 

Similarly, the [l,2,4]triazolo[l,5-fl]pyridinium salt 121 affords 5-phenyl-3-(2-pyridinyl)-2(3//)-oxazolone 122 (Fig. 5.29).  

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Acyloin condensation. Carbene species (for promoting intramolecular acyloin condensation) are mote readily generated from 1,2,4-triazolium salts when one of the iV-substituents is highly electron-deficient (e.g., 1). The bicychc triazolium salt 2 derived... 

The first asymmetric intramolecular Stetter reactions were reported by Enders and co-workers utilising triazolium salt pre-catalyst 125. Treatment of substrate 123 generated 1,4-dicarbonyl compound 124 in good yield and enantioselectivity [56]. These salicylaldehyde-derived substrates 123 have since become the standard test substrates for the development of new catalysts for the asymmetric intramolecular Stetter reaction. Bach and co-workers have achieved moderate enantioselectivities using axially-chiral thiazolium pre-catalyst 126 [41], whilst Miller and co-workers have developed peptidic thiazolium pre-catalyst 127 [57]. In 2005, Rovis and coworkers showed that the NHCs derived from triazolium salts 128-130 were excellent catalysts for the asymmetric intramolecular Stetter reaction of a wide range of substrates, giving typically excellent yields and enantioselectivities [58]. The iV-pentafluorophenyl catalyst 129 currently represents the state of the art in asymmetric Stetter reactions (Scheme 12.24) [59]. 

This homoenolate methodology has been extended to the use of nitrones 170 as electrophiles [72]. Scheldt and co-workers have shown that enantiomerically enriched y-amino esters 172 can be prepared with excellent levels of stereocontrol from an enal 27 and a nitrone 170 using the NHC derived from triazolium salt 164 (Scheme 12.37). The oxazinone product 171, formally a result of a [3-1-3] cycloaddition, is cleaved to afford the y-amino ester product 172. The reaction shows broad substrate scope, as a range of substituted aryl nitrones containing electron donating and withdrawing substituents are tolerated, while the enal component is tolerant of both alkyl and aryl substituents. 

Displacement of bromide from triazolium salts by either hydroxide or sulhde takes place readily and leads to the formation of mesoionic triazolium oxides or sulfides (e.g. Scheme 44).2i . 217,229,230... 

The 1,2,4-triazolium salt 117 (Figure 1.10) was prepared by Bertrand and co-workers. Although all attempts to isolate the free dicarbene by deprotonation of the dication had failed thus far, it was possible to obtain the mono-and disilver complexes by deprotonation and metalation of the carbon atoms of the heterocycle. Several other homo- and heterodinuclear complexes have been prepared from triazolium salt 117. Peris and co-workers obtained the diiridium eomplex by reaetion of 117 (R = Me) with two equivalents of [IrCl(COD)]2 in the presenee of KOt-Bu. A heterobimetallie Ir-Rh complex was obtained by sueeessive reaetion of 117 with [IrCl(COD)]2 and [RhCl(COD)]2. ... 

Formylphenoxy)but-2-enoates, available from salicyclaldehydes and 4-bromo-crotonates, undergo an intramolecular Stetter reaction, which, in the presence of a chiral triazolium salt, affords chroman-4-ones with good enantiomeric excesses <96HCA1899>. 

Disubstituted triazolium salts are prepared from alkyl or aryl hydrazines via an oxadiazolium salt 28 (Scheme 16). Addition of a chiral amine on this salt resulted in a ring opening - ring closure reaction affording the triazolium salts 29. 

Catalytic enantioselective crossed aldehyde-ketone benzoin cyclizations of ketoaldehydes, such as 13, readily obtained from an aryl nitrile oxide and a 1,3-diketone, were studied in order to perform the synthesis of complex molecules. Significant asymmetric induction was observed with chiral triazolium salts such as 14, in the presence of DBU as base, leading to compound 15 in high yield and with 99% ee in favor of the R enantiomer <06AG(E)3492>. 

The synthesis of pyrazolo[4,3-rf]-l,2,3-triazine starting from a pyrazolo-3-carbaldehyde derivative has been reported <00JIC168>. Azolo-l,2,4-triazine derivatives have been prepared via the reaction of functionalized thiazole derivatives with several heterocyclic diazonium salts <00JCR(S)206>. The reaction of 1,2,4-triazolium salt 67 with alkene 68 gives the pyrrolo[2,l-/][l,2,4]triazine 69 <00H(53)213>. 

In order to vary the electronic situation at the carbene carbon atom a number of carbo- and heterocycle-annulated imidazolin-2-ylidenes like the benzobis(imida-zolin-2-ylidenes) [58-60] and the singly or doubly pyrido-annulated A -heterocyclic carbenes [61-63] have been prepared and studied. Additional carbenes derived from a five-membered heterocycle like triazolin-5-ylidenes 10 [36], which reveals properties similar to the imidazolin-2-ylidenes 5 and thiazolin-2-ylidene 11 [37] exhibiting characteristic properties comparable to the saturated imidazolidin-2ylidenes 7 have also been prepared. Bertrand reported the 1,2,4-triazolium dication 12 [64]. Although all attempts to isolate the free dicarbene species from this dication have failed so far, silver complexes [65] as well as homo- and heterobimetallic iridium and rhodium complexes of the triazolin-3,5-diylidene have been prepared [66]. The 1,2,4-triazolium salts and the thiazolium salts have been used successfully as precatalysts for inter- [67] and intramolecular benzoin condensations [68]. 

As shown in previous sections, NHCs promote acyl transfer in transesterification reactions. In a similar manner, O C acyl transfer can be achieved with substrates such as 351 in the presence of 0.9 mol% of triazolium pre-catalyst 353 and KHMDS (Scheme 53). Moderate yields are obtained by varying substitution of the oxazole from R = Me, Ph, t-Bu, and t-Pr [171], Deprotonation of the triazolium salt followed by nucleophilic addition to the carbonate moiety of the oxazole results in enolate intermediate LXXXIII and activated carboxylate LXXXIV. Enolate addition and regeneration of the active catalyst provides quaternary stereocenters 352. 

Triazolium salts can be prepared from thiazolium salts by treatment with amines (Equation (69)) <74ZOR377>. Methylthiothiazolium salts react similarly (Scheme 36) <73IJC753>. 

Scheme 61, yielded thiazole 200 as the major product, along with minor amounts of carbinol 201 [152]. On the other hand, treatment of the imine formed from 199 and p-methoxyphenylamine with catalytic tetrabutylammonium cyanide, produced suc-cinimide derivative 202. In both cases, the process is initiated by nucleophilic attack to the carbaldehyde C=0 (or azomethine s C=N) group, which is followed up by an anionic rearrangement. A variation of the above process using as catalysts /V-heterocyclic carbenes (NHC) derived from base treatment of azolium, imidazo-lium, or triazolium salts, has also been developed to access gem-disubstituted succinimides [153, 154]. Unfortunately, an attempt of kinetic resolution of racemic 4-formyl (3-lactams by using chiral NHC resulted in moderate selectivities only [154]. 

Substituents at C4 and C5 influence the outcome of the reaction of the transient l-methoxy-2-substituted 1,2,3-triazolium salts 383 according to the following trends extracted from the checker board investigation in (1982JCS(P1)2749) (Scheme 118) ... 

In cooperation with Teles and colleagues, our research group has studied the triazole heterocycle as an alternative core structure of nucleophilic carbenes. First, the triazol-5-ylidene 12 (Fig. 9.3 see also Scheme 9.2) was synthesized and shown to be stable at temperatures up to 150 °C in the absence of air and moisture [22]. Compound 12 exhibited the typical behavior of a nucleophilic N-heterocyclic car-bene, and was found to be sufficiently stable to become the first commercially available carbene [23]. As shown in Scheme 9.2, the crystalline carbene was obtained from the corresponding triazolium salt precursor 13 by the addition of methanolate and subsequent thermal decomposition of the adduct 14 in vacuo via a-elimination of methanol [24]. 

Unfortunately, the chiral bicyclic triazolium salt that had been found to be an excellent catalyst for the enantioselective intermolecular benzoin condensation proved to be ineffective in the intramolecular reaction. In searching for alternative catalysts, we synthesized the novel triazolium salts 19 and 20, starting from easily accessible enantiopure polycyclic y-lactams (Schemes 9.4 and 9.5) that finally delivered good results in the enantioselective intramolecular cross-benzoin condensation [35]. 

Precatalyst 19 was built up from cheap L-pyroglutamic acid (21) in a short and easy synthesis sequence involving a one-pot variant developed by Rovis et al. to form the triazolium core (Scheme 9.4) [36]. The synthesis of 20 started from a-tetralone (22), which was stereo selectively converted to the polycyclic y-lactam 23 with inexpensive (R)-phenylglycinol as chiral source. After cleavage of the auxiliary, the one-pot-procedure that had already been used before yielded the triazolium salt 20 (Scheme 9.5). 

Fu et al. recently presented their results on carbene-catalyzed intramolecular Heck-type cyclizations [68]. The N-heterocyclic carbene generated in situ from the triazolium salt 83 catalyzed cyclization of the substrates 84 to form the cycloalkanes 85 (Scheme 9.25). The lowest yields were obtained when the reaction products were cyclobutanes. These authors assumed that the carbene initially reacted with the Michael acceptor site of the substrate to the intermediate 86, which subsequently cyclized via 86 to the final products 85. 

Enders and Kallfass reported the synthesis of unsymmetrical triazolium salt 78 [134]. This compound is obtained by a three-step procedure from the corresponding oxazolidinone 77. 

The promising results of triazolium salt catalysis inspired our research group to synthesize a variety of chiral triazolium salts for the asymmetric benzoin condensation (Enders et al. 1996b Enders and Breuer 1999 Teles et al. 1999). Extensive investigations have shown that the enantiomeric excesses and catalytic activities are highly dependent on the substitution pattern of the triazolium system. The most active catalyst (S, S)-97, which is readily available from an intermediate of the industrial chloramphenicol synthesis, provided benzoin (857) in its (R)-configuration with 75% ee and a good yield of 66%. Remarkably, only... 

Scheme 31. Preparation of triazolium salts 123 derived from pyroglutamic acid...

Apart from the higher reactivity over their thiazolium counterparts, these triazolium salts allow not only the introduction of a second group of greater steric demand at the former unfunctionalized position of sulfur, but also the integration of the triazolium core within further stabilized bi- or polycyclic scaffolds of enhanced rigidity. Only by application of these types of catalysts ee-values greater than 90% can be... 

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