Letter Cite This: Org. Lett. 2018, 20, 6372−6375
pubs.acs.org/OrgLett
Oxazolium Salts as Organocatalysts for the Umpolung of Aldehydes Venkata Krishna Rao Garapati and Michel Gravel* Department of Chemistry, University of Saskatchewan, Saskatoon, SK Canada, S7N 5C9
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S Supporting Information *
ABSTRACT: Oxazolium salts were successfully employed for the first time as organocatalysts for benzoin, Stetter, and redox esterification reactions. An N-mesityl oxazolium salt catalyzed homobenzoin reaction of aromatic, heteroaromatic, and aliphatic aldehydes delivered α-hydroxy ketones in high yields. This new type of catalyst proved remarkably effective for the Stetter reaction of challenging substrates such as βalkyl-α,β-unsaturated ketones and electron-rich aromatic aldehydes in comparison to common thiazolium and triazolium salts.
T
Scheme 1. Synthesis of Oxazolium Salts Used in This Study
he catalytic activation of aldehydes through the formation of an acyl anion equivalent has a long history that is best exemplified by the benzoin and Stetter reactions.1 In the decades following a seminal paper by Ukai et al. on the benzoin reaction,2 the preferred catalysts were based on the thiazolium framework. Other carbene precursors have since been utilized, such as triazolium, imidazolium, and bis(dialkylamino)cyclopropenium salts.3 Each family of catalysts has its own advantages and drawbacks. Perhaps due to their unhindered nature, thiazolium salts can catalyze many Stetter reactions with great efficiency, whereas chiral triazolium salts have shown to be particularly effective at catalyzing a variety of reactions enantioselectively. Many challenges remain, however, such as the limited scope of cross-benzoin reactions and of enantioselective intermolecular Stetter reactions. Owing to the numerous ongoing challenges, we became interested in exploring other azolium salts with the aim of uncovering new or unexpected reactivity. We turned our attention to oxazolium salts, which have been left largely unexplored since early work by Ukai.4 In that work, 3-methyl benzoxazolium iodide and 2,3-dimethyl benzoxazolium iodide were used in an attempt to catalyze the homobenzoin reaction of benzaldehyde. The reported conditions employed NaOH in methanol, and no benzoin product was detected when the benzoxazolium salts were used as catalysts. We surmised that the salts’ heterocyclic framework underwent methanolysis under these conditions,5 thus thwarting their ability to act as catalysts. Based on this assumption, we decided to take another look at oxazolium salts using aprotic solvents. Four oxazolium salts were synthesized, each bearing a different N-substituent (Scheme 1). An N-alkyl oxazolium salt was prepared by simply refluxing oxazole and benzyl bromide in toluene for 16 h, affording N-benzyl oxazolium bromide (1).6 Oxazolium salts 2−4 bearing various N-aryl substituents were synthesized from the corresponding anilines and acetoin in three high-yielding steps. Acid-catalyzed condensation delivered the α-amino ketone, which was then N-formylated © 2018 American Chemical Society
before undergoing a dehydrative cyclization to provide the Naryl oxazolium salt.7,8 The oxazolium salts could be more conveniently purified and handled as borate salts following anion exchange (see Supporting Information).9 With these candidate catalysts (1−4) in hand, we first examined their catalytic activity in a benchmark homobenzoin reaction of benzaldehyde (Table 1). Using dichloromethane as solvent and DBU as base, a color change was immediately observed for all catalysts. However, only the reaction using the N-Mes oxazolium salt 3 provided the product in appreciable yield (entries 1−4). Changing the solvent to toluene again showed catalyst 3 to be far superior, with the reaction being clean and complete within an hour under those conditions (entries 5−8). The more polar solvents THF and Et2O were also screened with catalyst 3, but the transformation proved less efficient (entries 9−10). The conversion and yield proved very sensitive to the catalytic loading, as shown in entries 11− 12. Having established the optimized conditions, a sampling of representative aldehydes were subjected to the homobenzoin reaction (Scheme 2). The namesake benzoin (5) was obtained from the dimerization of benzaldehyde in 97% isolated yield. Excellent yields were also obtained in reactions using electronReceived: August 17, 2018 Published: October 1, 2018 6372
DOI: 10.1021/acs.orglett.8b02636 Org. Lett. 2018, 20, 6372−6375
Letter
Organic Letters Table 1. Optimization of the Homo-benzoin Reactiona
entry
catalyst
solvent
time (h)
yield (%)b
1 2 3 4 5 6 7 8 9 10 11c 12d
1 2 3 4 1 2 3 4 3 3 3 3
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 PhCH3 PhCH3 PhCH3 PhCH3 Et2O THF PhCH3 PhCH3
3 3 3 3 1 1 1 1 1 1 1 1
