Tunable Bromomagnesium Thiolate Tishchenko Reaction Catalysts: Intermolecular Aldehyde–Trifluoromethylketone Coupling

Abstract

The Tishchenko reaction [1] (discovered by Claisen [2] in 1887) is the disproportionation of two aldehyde molecules to furnish an ester product (Scheme 1).[3] Aluminum alkoxides [1,4] and boric acid, [5] were the first classes of synthetically relevant homogeneous catalysts [6] for this reaction, these were then followed by a range of transition-metal complexes of low to high catalytic activity but often limited practical utility. [7,8] More recently, lanthanide, [9] actinide, [10] and calcium [11] complexes capable of promoting aldehyde dimerization with excellent activity have been reported. A generalized mechanistic outline of the process is given in Scheme 1: reaction of the transition-metal complex 1 with the aldehyde generates the metal alkoxide 2, which acts as the hydride-transfer agent in a metal-mediated redox process (i.e. 3) leading to ester 4.[12]The Tishchenko reaction is an unusual process from a mechanistic standpoint with the potential to allow chemists to plan the synthesis of ester products through an unconventional disconnection. While recent advances in catalyst development have resulted in increased promise as a general synthetic methodology, the utility of the Tishchenko reaction is somewhat limited by two factors: a) Often the reported catalyst systems result in lower yields of isolated products from substituted benzaldehydes, and b) intermolecular crossed-Tishchenko reactions between equimolar amounts of two different carbonyl moieties are generally not possible. In particular no examples of intermolecular cross-coupling [13,14] between an aldehyde and a ketone are known, meaning that the intermolecular reaction cannot currently be utilized to generate new stereogenic centers. We were therefore encouraged to attempt the development of an alternative catalyst system for the intermolecular Tishchenko process. Our objective was to devise a simple, inexpensive, and easy to use small-molecule promoter, the steric and electronic characteristics of which could be readily tuned, with the eventual goal of broadening the scope of the Tishchenko reaction to include ketone substrates. We were inspired by the mode of action of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (G3PDHase), which promotes aldehyde oxidation through base-catalyzed addition of a cysteine residue to the aldehyde substrate to give the corresponding hemithioacetal conjugate base 5 (Scheme 2, A), which participates in an intermolecular hydride-transfer reaction with enzyme-bound NAD + . The resulting electrophilic thioester 6 then undergoes either hydrolysis or substitution by inorganic phosphate (depending on the enzyme variant). [15][16][17] We postulated the viability of an artificial process in which an analogous hemithioacetal anion 9 generated from benzaldehyde (8) and a bromomagnesium thiolate [18] could transfer hydride [19,20] to another carbonyl moiety to give magnesium alkoxide 10 and thioester 11, [21] which would subsequently couple to form the ester product 12 with regeneration of the thiolate catal...

Bicyclic guanidinate compounds of magnesium and their activity as pre-catalysts in the Tishchenko reaction

“…29 With hpp-derivative 3, production is maintained at an approximately constant rate for an additional 20 min, whereas pre-catalyst 4 is notably slower, with 60% yield produced after 100 min. These data compare favourably with the reported magnesium thiolate systems, 7 where 5-20 mol% is required to give greater than 70% yield, and reaction times of 24-72 h.…”

“…5 Exploiting parallels between the 4f-and heavier group 2 elements, Hill et al reported the catalytic activity of Ca, Sr, and Ba amides. 6 The only example of a homogeneous catalyst employing magnesium is a bio-inspired thiolate system, 7 in which bromomagnesium salts were prepared in situ from PhMgBr and thiols.…”

The Thiolate‐Catalyzed Intermolecular Crossed Tishchenko Reaction: Highly Chemoselective Coupling of Two Different Aromatic Aldehydes

“…Much later, Chan and Scheidt [8] disclosed the first carbene-catalyzed hydroacylation reactions between benzaldehydes and 1,2-dicarbonyl compounds such as 7 (Figure 1 B) to afford 8 in high yield. In 2010, our group [9] utilized a similar strategy in the first thiolate-catalyzed (crossed) Tishchenko reactions (e.g., product 11). Later, selenide ions were shown to promote this reaction with improved efficacy.…”

“…This inexpensive thiol (considerably less smelly than benzyl mercaptan) was previously found to serve as a convenient precatalyst for the promotion of the Tishchenko homodimerization of benzaldehydes. [9] All four possible benzyl ester products were formed in a relatively unselective process.…”

Microwave-assisted efficient thiolate-catalysed homo- and crossed intermolecular Tishchenko reactions

“…4 Recently-inspired by the mode of action of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase [11][12][13] -we developed the first thiol(ate) catalysed Tishchenko reactions. 14 The catalysts required are simple, inexpensive thiols, used in the presence of a Grignard reagent base. 15 Homo-Tishchenko reactions involving either benzaldehyde or (significantly) substituted analogues proceeded in good-excellent yields with 5-20 mol% catalyst loading (Fig.…”