The palladium-catalyzed cross-coupling reaction of cyclopropanol-derived ketone homoenolates with benzyl chlorides is reported. This reaction proceeds in high yields with electron-neutral and electron-rich benzyl chlorides; however, yields are low with electron-poor benzyl chlorides. In addition, a range of cyclopropanols can be coupled in good yields. The reaction can be conducted with a low catalyst loading (1% Pd) and on a gram scale without reduction in yield.
Strained alcohols have featured prominently in a wide array of transition-metal-catalyzed cross-coupling reactions, but methods involving cyclopropanols have only been developed relatively recently. In this account, we describe our group's work in this area, and we provide a concise summary of other palladium-catalyzed methods for C-C bond-forming reactions using cyclopropanols. 1
The cross-coupling of unprotected ortho-bromoanilines with cyclopropanols yields quinolines in a single operation via an intramolecular condensation and palladium-catalyzed oxidation sequence. The reaction tolerates a variety of cyclopropanols and substituted bromoanilines. Deuterium-labeling experiments provide direct evidence of a second equivalent of bromoaniline serving as the terminal oxidant.Due to their high strain energy, cyclopropanols react readily in ring-opening reactions under the influence of a variety of transition metals. We 1 and others 2 have explored the palladium-catalyzed cross-coupling reactions of cyclopropanol-derived homoenolates 3 with a range of electrophiles. An important aspect of these reactions is that the cyclopropanol functional group is converted into a ketone group in the product that can be used in further transformations (Equation 1). Equation 1Given the importance of substituted quinolines in pharmaceutical discovery, there has been a continued interest in new methods for their synthesis. In 1991, Larock 4 demonstrated the synthesis of quinolines from ortho-iodoanilines and an allylic alcohol (Equation 2). This reaction is thought to proceed through a Heck reaction to yield a ketoaniline, followed by condensation and oxidation steps. Interestingly, mixtures of quinolines and tetrahydroquinolines were obtained when the reaction was conducted in common solvents such as DMSO, MeOH, MeCN, and DMF, suggesting that a disproportionation reaction, possibly palladium-catalyzed, was taking place. The quinoline product was obtained exclusively when the reaction was conducted in HMPA, and it was unclear what reagent behaved as the terminal oxidant in this process. Equation 2Since Larock's seminal report, a number of related palladium-catalyzed syntheses of quinolines have been developed, 5 and improvements to the initial Larock protocol have been made. In a recent report by Stone, allylic alcohols are coupled with bromoanilines to yield dihydroquinolines that were oxidized by DIAD in acetic acid in a second step 6 (Equation 3). Equation 3Our interest in expanding the palladium-catalyzed chemistry of cyclopropanols led us to consider their use in the synthesis of benzofused heterocycles. Cyclopropanols are readily accessed using the Furukawa modification of the Simmons-Smith 7 reaction of enol ethers or by the Kulinkovich 8 reaction between esters and Grignard reagents, thus transforming a readily available ketone or ester into a cross-coupling partner for palladium-catalyzed reactions. We surmised that the cross-coupling of an orthobromoaniline (i) with a cyclopropanol (ii) would yield an equilibrating mixture of the acyclic ketoaniline (iii) and cyclic imine (iv) and enamine (v) tautomers. Furthermore, we also supposed that it should be possible to selectively oxidize or reduce the latter intermediates to the corresponding quinolines (vi) or tetrahydroquinolines (vii), respectively (Scheme 1). Ideally, the transformation of the equilibrating enamine-imine intermediates to the correspond...
Homoenolates represent a useful class of umpolung synthons with the potential to greatly streamline complex molecule synthesis. Because the direct formation of homoenolates faces many limitations, a number of alternative approaches to this synthon have been developed. In this review we present the main strategies for the generation and application of palladium homoenolates. We highlight the merits and limitations of each approach, and comment on aspects of the mechanism of these reactions where appropriate.
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