Hydroacylation of Activated Ketones Catalyzed by N-Heterocyclic Carbenes Audrey Chan and Karl A. Scheidt* Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208 Received February 3, 2006; E-mail: scheidt@northwestern.edu Direct methods for the selective oxidation of σ bonds are powerful bond-forming strategies in organic synthesis. One establish- ed approach to selectively oxidize C-H bonds utilizes transition metals capable of undergoing oxidative addition pathways. 1 The rhodium(I)-catalyzed intramolecular hydroacylations of alkenes, reported from many laboratories including Bosnich, Larock, Jun, Brookhart, Shair, Fu, and Morehead, functionalize aldehydic C-H bonds for the synthesis of carbocycles. 2 Interestingly, the develop- ment of analogous catalytic hydroacylation processes involving aldehydes and carbonyl π systems has not received the same atten- tion. 3 We have been interested in developing approaches in which an organic molecule promotes multiple bond-forming steps in a single catalytic cycle. 4 Herein, we report the hydroacylation of R-keto esters (2) with aldehydes (1) catalyzed by N-heterocyclic carbenes (eq 1). In this process, the carbene facilitates selective catalytic oxidation of a C-H bond with concomitant reduction of a ketone. The interaction of N-heterocyclic carbenes 5 with aldehydes has been extensively employed in the development of carbonyl anions, mainly in the additions of these Umpolung species 6 to aldehydes (benzoin reaction) 7 and conjugate acceptors (Stetter reaction). 8 A common premise in these processes is that the tetrahedral inter- mediate (I) resulting from the addition of the NHC to an aldehyde usually generates a “Breslow intermediate” structure (II, path A, Scheme 1). 9 However, an alternative course potentially involves the collapse of this intermediate to afford an acyl heteroazolium species (III) with concomitant formation of a hydride equivalent (path B). We envisioned that this Cannizzaro-type 10 reducing equiv- alent could be harnessed to reduce ketones. 11 The resulting alcohol (4) produced after a reduction step can undergo an acylation event with the acyl iminium species formed in situ (III), thus promoting catalyst turnover and yielding an overall hydroacylation process catalyzed by an organic molecule. Importantly, the aldehdye and activated ketone are separate components, thereby providing for a metal-free reaction with broader potential reaction scope than the related Al(III)-promoted Tishchenko disproportionation reaction. 12 To explore this transformation, a protic solvent (MeOH) was employed to decouple the reduction and acylation events (Scheme 2). After examining various heteroazolium salts and potential ketone electrophiles, the combination of R-keto ester (2a) with benzalde- hyde (1a) in the presence of 15 mol % triazolium salt 5 and DBU produces methyl mandalate (6) in excellent yield (96%). 13 Gratify- ingly, the use of an aprotic solvent, such as dichloromethane, and 10 mol % 5 affords the hydroacylation product (78%, 7), which is the product expected from path B in Scheme 1. A survey of aldehydes for this process (Table 1, eq 3), indicates that aromatic substituents afford high yields of the corresponding products. The process is tolerant of electron rich aldehydes, while the yields are generally lower when electron-deficient systems are employed. To date, the use of enolizable aldehydes yields pre- dominantly benzoin products. We have also examined the scope of the reaction with regard to the activated ketone component (Table 2, eq 4). Substituted aromatic keto esters provide the desired esters resulting from overall hydro- acylation in good yield when dichloromethane is used as the solvent. By switching the media to ethanol, the corresponding alcohols are Scheme 1. Proposed Reaction Pathway Scheme 2. Protic and Aprotic Reaction Conditions with Keto Ester 1 Table 1. Examination of Aldehydes in Hydroacylation entry R compd yield (%) 1 Ph 7 78 2 4-MeO-Ph 8 77 3 4-F-Ph 9 71 4 4-Me-Ph 10 72 5 2-Naphthyl 11 70 6 2-Furyl 12 73 7 Ph(CH2)2 13 0 Published on Web 03/21/2006 4558 9 J. AM. CHEM. SOC. 2006, 128, 4558-4559 10.1021/ja060833a CCC: $33.50 © 2006 American Chemical Society