Triazolium salts synthesis

Suzuki and co-workers recently applied the asymmetric intramolecular benzoin reaction to the synthesis of the homoisoflavonoid (-F)-sappanone B 122 [54]. The authors found that triazolium salt pre-catalyst 120 gave the best results for the... 

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). 

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 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 ... 

Suzuki and co-workers have relayed this methodology into the synthesis of (+)-sappanone B (Scheme 5) [52], The authors found that catalysts previously introduced by Rovis and co-workers led to inferior results iV-Ph catalyst 41 gave significant elimination while Al-C Fj gave low enantioselectivities. By tuning the electronics of the M-aryl substituent these workers identified 49 as providing the optimal mix of reactivity and enantioselectivity. Commercially available 2-hydroxy-4-methoxybenzaldehyde 47 was transformed into aldehyde 48, which upon treatment with triazolium salt 49 in the presence of base was cycUzed to afford (R)-50 in 92% yield and 95% ee and subsequently transformed into (-t-)-sappanone B. 

Two general methods have been described for the synthesis of this new class of meso-ionic compounds (196). The most convenient method is by the treatment of 4-bromo-l,2,3-triazolium salts (197, X = Br) with sodium sulfide in dimethylformamide. Alternatively, N-methylation of the isomeric 4- or 5-alkylmercapto-1,2,3-triazoles 198 or 199 with methyl tosylate gave intermediate triazolium salts (197, X = SR, Y = Tos), which yielded meso-ionic l,2,3-triazole-4-thiones (196) by 5-dealkylation by heating with piperidine. 

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%. 

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). 

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. 

Scheme 51 Synthesis of oxazoline-based triazolium salt...

Unfortunately the bicyclic triazolium salt that had successfully been used in our research group for the enantioselective intermolecular benzoin condensation (Enders and Kallfass 2002) did not show any catalytic activity in the intramolecular reaction. We thus searched for alternative, easily accessible enantiopure polycyclic y-lactams as precursors for the synthesis of novel triazolium salts (Enders et al. 2006c for a related study see Takikawa et al. 2006). The rigid polycyclic structure of the catalysts should allow high asymmetric inductions. A first tar-... 

For the structural optimization of the tricyclic triazolium salt 119 the cw-tricyclic lactam 126 was chosen as the precursor for the synthesis of the tetracyclic triazolium salt 127. The diastereo- and enantiopure y-lactam 126 was synthesized following a procedure reported by Ennis et al. (Scheme 32) (Ennis et al. 1996 Nieman and Ennis 2000). a-Tetralone (124) was a-alkylated with ethyl bromoacetate and subsequently hydrolyzed to the corresponding carboxylic acid. Condensation with (R)-phenylglycinol yielded the lactam 125 as a single stereoisomer. Stereoselective reduction, dehydration of the alcohol, and acid-catalyzed enamine hydrolysis provided the cis-tricyclic lactam 126. The one-pot procedure that had previously been successful in the synthe-... 

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... 

In 1996, our research group observed an activity of triazolium salts, for example (S,. S )-97 as precatalysts in this intramolecular reaction. The stereoselective synthesis of various 4-chromanones (f )-138 via the first asymmetric intramolecular Stetter reaction was performed with enantiomeric excesses of 41%-74% and yields of 22%-73% (Scheme 38) (Enders etal. 1996c). 

Kerr MS, Read de Alaniz J, Rovis T (2005) An efficient synthesis of achiral and chiral 1,2,4-triazolium salts bench stable precursors for N-heterocyclic carbenes. J Org Chem 70 5725-5728... 

Kantchev EAB, O Brien CJ, Organ MG (2007) Palladium complexes of A-heterocyclic carbenes as catalysts for cross-coupling reactions - a synthetic chemist s perspective. Angew Chem Int Ed 46 2768-2813 Kerr MS, Rovis T (2004) Enantio selective synthesis of quaternary stereocenters via a catalytic asymmetric Stetter reaction. J Am Chem Soc 126 8876-8877 Kerr MS, Read de Alaniz J, Rovis T (2002) A highly enantio selective catalytic intramolecular Stetter reaction. J Am Chem Soc 124 10298-1029 Kerr MS, Read de Alaniz J, Rovis T (2005) An efficient synthesis of achiral and chiral 1,2,4-triazolium salts bench stable precursors for A-heterocyclic carbenes. J Org Chem 70 5725-5728... 

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a receptor is a valuable synthetic tool leading to the synthesis of highly funtionalized products. Acyl anion receptors include Michael acceptor (Stetter reaction), aromatic aldehyde (benzoin reaction), ketone, nitroalkene, aziridine, activated imine. Recently, nucleophilic addition of acyl anions to unactivated imines has been explored <07CC852>. Treatment of aryl aldehydes with imines 146 in the presence of triazolium salt 147 (20 mol%) and triethylamine (20 mol%) provides the a-amino ketones 148 in good yields. However, this methodology does not work for 4-pyridylaldehyde and tert-buty laldehyde. 

Sodium hydride in DMF at room temperature induces rearrangement of some l,4-dialkyl-4 T-l,2,4-triazolium salts to 5-aminoimidazoles the reaction can be generalized to permit synthesis of 4-acyl-5-aminoimidazoles from readily accessible starting materials, but yields are only moderate (21-60%) [22]. 

Convenient methods have been developed for the synthesis of triazolium salts. The 3-methylthio-substituted triazolium compounds 138 are readily accessible by the reaction of 5-methyl-1,4-diphenylisothiosemi-carbazide with acid chlorides, or (in the presence of phosphorus oxychloride) with carboxylic acids (74TL2649). Deprotonation of 138 (R = H) yields the nucleophilic carbene 139, which is readily alkylated to yield... 

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