Chiral triazolium salts

The triazole 76, which is more accurately portrayed as the nucleophilic carbene structure 76a, acts as a formyl anion equivalent by reaction with alkyl halides and subsequent reductive cleavage to give aldehydes as shown (75TL1889). The benzoin reaction may be considered as resulting in the net addition of a benzoyl anion to a benzaldehyde, and the chiral triazolium salt 77 has been reported to be an efficient asymmetric catalyst for this, giving the products (/ )-ArCH(OH)COAr, in up to 86% e.e. (96HCA1217). In the closely related intramolecular Stetter reaction e.e.s of up to 74% were obtained (96HCA1899). 

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>. 

NHC-catalysed homoenolate generation has been applied by Bode and Struble in the formal synthesis of the natural product salinosporamide A [77], The key step in the synthesis is a late-stage NHC-catalysed intramolecular lactonisation step of intermediate 186. When this reaction was attempted with an achiral triazolium-derived NHC, a 4 1 diastereomeric ratio of products was obtained in preference for the undesired product 189. In order to circumvent this, chiral triazolium salt 187 was employed, giving an approximately 1 1 mixture of desired undesired diastereoisomers (Scheme 12.41). 

Scheldt and co-workers have nsed their in situ hydroxyazolium oxidation strategy to allow the desymmetrisation of diol 249 using chiral triazolium salt 187, giving mono-ester 250 in 80% ee (Scheme 12.55) [99]. 

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>. 

Bicyclic chiral triazolium salt 382 <2002AG(E)1743> has been used in new catalytic enantioselective crossed aldehyde-ketone benzoin cyclizations <2006SL2431, 2006AG(E)3492>. 

In the context of our work in the area of chiral nucleophilic carbenes and their utility in organic synthesis, we have developed a conceptually distinct approach to catalyzed acylation using a-haloaldehydes as acylation precursors. The use of a chiral triazolium salt in the presence of base allows an enantioselective desymme-trization of meio-hydrobenzoin to proceed in 83% ee and good yield ... 

When 2,2-dichloro-3-phenylpropanal 203 is subjected to standard reaction conditions with chiral triazolium salt 75c, the desired amide is produced in 80% ee and 62% yield Eq. 20. This experiment suggests that the catalyst is involved in an enantioselec-tive protonation event. With this evidence in hand, the proposed mechanism begins with carbene addition to the a-reducible aldehyde followed by formation of activated car-boxylate XLII (Scheme 32). Acyl transfer occurs with HOAt, presumably due to its higher kinetic nucleophilicity under these conditions, thus regenerating the carbene. In turn, intermediate XLin then undergoes nucleophilic attack by the amine and releases the co-catalyst back into the catalytic cycle. 

The catalytic enantioselective crossed aldehyde-ketone benzoin cyclization has been reported.145 The reactions have been performed in the presence of Rovis aminoindanol- derived chiral triazolium salts (37) as catalysts with excellent enantioselectivities (up to 99% ee) (Scheme 19). 

It should, however, be pointed out that - where applicable - product composition can be significantly different. For example, whereas thiazolium catalysts afford exclusively dihydroxyacetone with formaldehyde as substrate, the triazolium systems afford glycolic aldehyde (plus glyceraldehyde and C4 and C5 sugars as secondary products) [246], Catalyst-dependent differences in the relative rates of the partial reactions within the catalytic cycle (Scheme 6.105) most probably account for this phenomenon. A subsequent study by Enders et al. on chiral triazolium salts identified the derivative 233 as a first catalyst for the asymmetric benzoin condensation that affords substantial enantiomeric excesses (up to 86%) with satisfactory chemical yields (Table 6.3) [247]. 

In addition to the stabilized carbanions, electron-rich aromatic compounds, for example indole derivatives have emerged as new Michael donors [25], In these reactions, aromatic sp2-C-H transformation is involved. These reactions are described in detail in Section 111.1.3.1.3. A highly enantioselective intramolecular Stetter reaction, in which umpolung reactivity of a formyl group was accomplished using a chiral triazolium salt, has also been reported by Rovis [26]. 

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%. 

The asymmetric intramolecular benzoin condensation with model substrate 106 (R = Me) and the chiral triazolium salt 119 as precatalyst gave rise to the desired acyloin 107 in good yields by utilizing toluene as solvent and diazabicycloundecane (DBU) or KOt-Bu as the base (Scheme 33). Unfortunately only moderate enantiomeric excess (37% 18%) could be achieved, even at 5°C. The use of 10 mol% of the TBS-substituted catalyst 123 and stoichiometric amounts of DBU in toluene at room temperature enabled the methyl-substituted acyloin 106 to be obtained in high yield (92%) but with only moderate enantios-electivity (61%). Application of the TIPS substituted catalyst 123 under the same conditions resulted in an increased enantiomeric excess of 77%, which could be further improved to 84% with almost unchanged yields by performing the reaction at 5°C. The reactions with the tetracyclic catalyst 127 were conducted in tetrahydrofuran for better solubility. Furthermore, DBU was found to cause side-reactions that could be suppressed when KOf-Bu was used in substoichiometric amounts (9... 

With the enantioselective intramolecular benzoin reaction established as a synthetic tool, and in combination with our efforts in the synthesis of bioactive natural products bearing a quaternary a-hydroxy ketone unit (Davis and Weismiller 1990 Heller and Tamm 1981), such as the 4-chromanone derivative (S)-eucomol (Bohler and Tamm 1967 Crouch et al. 1999), a catalytic asymmetric synthesis of various 3-hydroxy-4-chromanones brought about by the chiral triazolium salts 127, 123b and 102 as pre-catalysts was investigated (Enders et al. 2006d). The sterically different pre-catalysts were chosen in order to adjust the catalyst system to the steric and electronic properties of the substrates 128. A screening of the reaction conditions indicated 10 mol% of the... 

Enders D, Breuer K, Teles JH (1996b) A novel asymmetric benzoin reaction catalyzed by a chiral triazolium salt. Preliminary communication. Helv Chim Acta 79 1217... 

The asymmetric intramolecular crossed benzoin reaction catalysed by a chiral triazolium salt has been used to synthesise 3-hydroxychroman-4-ones 34 in good to high yields and ee. The absolute configuration at the quaternary stereocentre C-3 has been shown to be S by X-ray analysis of the camphanyl ester <06SL2431>. Both enantiomers of 2-(2-phenylethyl)chroman-4-one, flindersiachromanone, have been obtained from racemic l-phenylhex-5-en-3-ol after resolution via lipase-catalysed acetylation <06H(68)483>. 

Isoflavonoids isolated from the subfamily Leguminosae have been reviewed <07NPR417>. Isoflavanones have been obtained with 100% atom efficiency by the Au-catalysed reaction between salicylaldehydes and arylalkynes (Scheme 37) <07AG(E)1117, 07TL8343>. The cyclisation of enolisable keto aldehydes to 3-substituted 3-hydroxychromanones by an enantioselective benzoin condensation is effected by chiral triazolium salts designed to minimise competing aldol reactions <07OL2713>. 

Note A chiral triazolium salt leads to higher yield and greater enantioselectivity than a chiral thiazole [20],... 

Accordingly, our research group [33] synthesized a variety of chiral triazolium salts and examined their ability to catalyze the benzoin reaction. However, the enantiomeric excesses and catalytic activities proved to vary strongly with slight structural changes in the substitution pattern of the triazolium system. 

A series of chiral triazolium salts have been reacted with a base to form the corresponding chiral carbenes, which was shown to catalyze the Stetter reaction efficiently and to provide 1,4-dicarbonyl products in high yields and enantioselectivities (eq 33). A survey of common bases identified KHMDS as providing an optimal balance between the yield and selectivity in this reaction. The reaction is sensitive to the nature of the Michael acceptor while electron deficient -alkenes provided the desired product in good yields and enantioselectivities, no reaction was observed in the case of Z-alkenes. ... 

You and co-workers successfully developed a series of novel chiral triazolium salts based on the readily available camphor scaffold in 2008. These catalysts are capable of rendering excellent enantioseleetivity in the intramolecular Stetter reaction (up to 97% yield, 97% ee). A later report from the same group delivered the synthesis of chiral NHCs from (lR,2R)-(+)-diphenyl ethylenediamine. With 10 mol% of the catalyst, the intramolecular Stetter reaction was realized in excellent yields with up to 97% ee. These newly developed catalysts from camphor and (lR,2R)-(+)-diphenyl ethylenediamine accumulate in the toolkit of NHCs. 

In 2013, Law and McErlean demonstrated the intramolecular vinylogous Stetter reaction as a new addition to the collection of NHC-catalyzed transformations. The products of this new transformation possess multiple sites for chemoselective functionalization, including (but not limited to) ketones, esters, and alkenes. Utilizing chiral triazolium salts as the NHC catalyst precursor, aromatic aldehydes or aliphatic aldehydes proceeded with various heteroatom tethered vinylogous Michael acceptors to give five- and sk-membered rings (up to 88% yield, 96% ee) (Scheme 7.20). 

In 2008, the Scheldt group reported a direct electrophilic amination via homoenolates catalyzed by N-heterocyclic carbenes using l-acyl-2-aryldiazenes as the electrophilic acceptors, which further increased the versatility of the homoenolate chemistry. It is worthwhile to note that only electron-rich substituents on the aryl component of the diazene could result in product formation (up to 84% yield), while electron-poor aryl substituents gave a lowyield (25%). An example of an asymmetric version of this new ami-nation reaction was achieved with the utilization of the chiral triazolium salt developed in their own group, providing the pyrazolidinone product in good yield (61%) and excellent enantioselectivity (90% ee) (Scheme 7.51). 

In 2008, the Bode group documented a highly enantioselective cis-cyclopentene-forming annulation of enals and -4-oxo-2-butenoate using a chiral triazolium salt. A cascade sequence involving a catalytic, asymmetric... 

Subsequently, with the newly developed sterically bulky chiral triazolium salt precatalyst, the Rovis group disclosed a homoenolate Michael addition reaction of enals to nitroalkenes that delivers complementary syw stereoselectivity and allows coupling with aliphatic nitroalkenes. Bulky substituents in the ortho ortho position of the Al-aryl ring of the NHC are crucial for the success of this reaction as it would shift product distribution toward the desired nitro ester by partially bloeking the aeyl anion position (Scheme 7.64). 

In 2011, You and co-workers developed a series of novel bicyclic triazolium salts from readily available (li ,2i )-DPEN. The NHC catalyst derived from the chiral triazolium salt and EtjN is also found to be efficient for enanti-oselective oxodiene Diels-Alder reactions, affording 3,4-dihydropyridinones and their derivatives in good yields, diastereo- and enantioselectivity (up to 97% ee) (Scheme 7.79). 

A great deal of the development of this reaction came from the labs of Tomislav Rovis who developed a range of novel chiral triazolium salts (Fig. 1.6) for this process [49]. 

To minimise the formation of possible isomers of the products, a highly active acceptor is generally required for the intermolecular crossbenzoin reaction. In 2010, Enders and coworkers reported the enantioselective crossbenzoin reactions of aromatic aldehydes with trifluoromethyl ketones, resulting in formation of a-hydrojyketones 13 in good yields and with good enantioselectivities using chiral triazolium salt D2 as catalyst. (Scheme 20.8). 

In 2005, Rovis et al. reported the synthesis of a-chloroesters from a,a-dichloroaldehydes using chiral triazolium salt F5 as the precatalyst. A variety of dichloroaldehydes worked well for the reaction and afforded the desired esters 134 in good yields and enantioselectivities. (Scheme 20.57). 

Recently, the group reported the synthesis of a-fluoroamides from a-fluoroenals using chiral triazolium salt F9 as the catalyst.Subjecting a... 

The development of efficient chiral NHC catalysts has proved to be a challenging task. For instance, following the first attempts at developing an asymmetric benzoin reaction, carried out by Sheehan and co-workers in 1966 using chiral thiazolium salt-derived NHCs [118], in 2002 Enders and Kallfass achieved enantiomeric excesses of 90% by means of a chiral triazolium salt-derived NHC [119]. These catalysts are usually generated in situ by treatment of chiral triazolium salts (see Figure 2.25) by a suitable base. 

EIGURE 2.25. Chiral triazolium salts used as precursors of NHCs. 

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