NickelButadiene Catalytic System for the Cross‐Coupling of Bromoalkanoic Acids with Alkyl Grignard Reagents: A Practical and Versatile Method for Preparing Fatty Acids

Abstract

Fatty acids are essential to natural life because they act as key components in biological membranes and glycerides, as well as in various biologically active agents, such as prostaglandins and endocannabinoids. For the construction of structurally diverse carbon frameworks of fatty acids, transition-metal-catalyzed cross-coupling reactions appear to be the most straightforward and efficient methods for carbon carbon bond formation and they have been employed in the synthesis of a wide variety of fatty acids with unsaturated bonds. However, these methods are limited to reactions at sp or sp carbon atoms, in which the stereochemistry of the olefinic moieties that are being introduced must be controlled. In contrast to these reactions, cross-coupling reactions between sp-hybridized carbon centers appear to be a useful and, potentially, more-promising tool, because they are applicable to the synthesis of both saturated and unsaturated fatty acids and they are free from the problems associated with double-bond stereochemistry. However, owing to the lower tolerance of the carboxylic group toward organometallic reagents, including transition-metal complexes, protected carboxy groups or their synthetic equivalents are often employed. Herein, we report a convenient and efficient one-pot procedure for the construction of carbon frameworks of fatty acids by using the nickelcatalyzed cross-coupling of alkyl halides that contain a carboxy functionality with Grignard reagents in the presence of 1,3-butadiene as an additive, in combination with an in situ protection procedure. As an example of a synthetic application of this method, the regioisomers of elaidic acid were synthesized through an iterative cross-coupling procedure. In our previous studies, we reported that the Ni-catalyzed cross-coupling reactions of alkyl halides with alkyl Grignard reagents in the presence of butadienes were effective for the construction of hydrocarbon skeletons that contained aprotic polar functionalities, such as ketones, esters, and nitriles. When alkyl halides that contained a carboxylic acid group are subjected to this cross-coupling reaction, without employing tedious protection-deprotection processes, the deprotonation of the carboxylic acid group is unavoidable. Thus, to develop a simple and straightforward route to fatty acids with various carbon chains, we examined the Ni-catalyzed cross-coupling reactions of 6-bromohexanoic acid (1a) with excess amounts of nBuMgCl under various conditions and we found that the expected decanoic acid was obtained in quantitative yield as the sole product, with no evidence of any undesirable side reactions, when the reaction was conducted at 0 8C for 1 h in the presence of 2.4 equivalents of nBuMgCl (Scheme 1). In this reaction, a