C-Alkylation of Secondary Alcohols by Primary Alcohols via Manganese Catalyzed Double Hydrogen Autotransfer

A new manganese catalyzed alkylation of secondary alcohols with non-activated alcohols is presented. The use of a stable and well-defined manganese PNN complex together with catalytic amount of base enables the conversion of renewable alcohol feedstocks to a broad range of higher value alcohols in good yields while water is the sole by-product. The strategy eliminates the need for exogenous and detrimental alkyl halides as well as the use of noble metal catalysts, making the C-alkylation via double hydrogen autotransfer a highly sustainable and environmentally benign process. Mechanistic investigations support a hydrogen autotransfer mechanism in which a non-innocent ligand plays a crucial role. β-Alkylation of alcohols is one of the most fundamental carboncarbon bond forming reactions. The conventional route requires three chemical steps (i.e., stoichiometric oxidation, alkylation with alkyl halides and stoichiometric reduction), making the overall process environmentally unfriendly. With aim to avoid the use of mutagenic and waste-forming reagents, modern processes have emerged which are based on the hydrogen autotransfer strategy utilizing biomass derived alcohols as alkylating agents. Hence a strategy which comprises the dehydrogenation of both of the primary and secondary alcohols, followed by base catalyzed aldol condensation to produce α,βunsaturated ketones and subsequent double hydrogenation can provide β-alkylated alcohols. Thus, the need of stoichiometric oxidation and reduction reagents as well as alkyl halides can be substituted by abundantly available alcohols. So far, the vast majority of these approaches rely on the use of more expensive noble metal catalysts, such as iridium, ruthenium, rhodium [7] and palladium. Replacement of the precious metal catalysis by earth abundant low-toxicity base metals is a topic of current interest. Processes relaying on the use of iron nickel and copper catalysts have been disclosed. More recently, cobalt catalysis has been successfully used. However, higher catalyst loading (5 mol%) along with super stoichiometric amounts of a more sensitive and expensive base (KHMDS) may be a drawback. Despite all these efforts, the alkylation of sec-alcohols with primary alcohols often leads to mixtures of the desired βalkylated alcohols along with the corresponding undesired ketones, presenting a crucial selectivity issue. Therefore, the development of a base-metal catalyst for the selective alkylation of sec-alcohols would be highly desirable. Scheme 1. Manganese catalysed double hydrogen autotransfer Based on our recent experience in manganese catalysis and its application in the reduction of carbonates, we questioned if highly reactive Mn-catalysts may be suitable for the efficient hydrogenation of the intermediate α,β-unsaturated ketone, resulting exclusively in the desired alkylated alcohol products. However at the outset of this work, the alkylation of secondary alcohols by primary alcohols was not known by manganese catalysis. During the preparation of this manuscript a related parallel study was reported by Yu et al. Herein, we demonstrate that the Mn-PNN complex Mn-1 is remarkably active and selective catalyst for the alcohol alkylation reaction (Scheme 1). The cross-coupling between 1-phenylethanol (1a) and the benzyl alcohol (2a) was selected as test reaction (Table 1). Initially, we screened the catalytic properties of different manganese complexes (Mn-1 to Mn-4) in combination with 10 mol% of Cs2CO3. To our delight, the use of 3 mol% of our PNN complex Mn-1 led to promising results providing the desired product 3a in 49% yield along with 8% of the corresponding ketone 3a’ (Table 1, entry 1). The application of the di-tert-butyl complex Mn-2 showed similar dehydrogenation activity and slightly lower hydrogenation activity (Table 1, entry 2). In the presence of PNP complexes, such as Mn-3 and Mn-4, excellent conversion was observed. However, the inefficient hydrogenation of the unsaturated intermediate provided considerable amount of the undesired ketone 3a (Table 1, entry 3, 4). Thus, we decided to further optimize the model reaction using Mn-1 in combination with different bases and solvents. 1,4-Dioxane and 2-Me-THF proved to be unsuitable for this reaction. However, performing the reaction in toluene resulted in better results (table 1, entries 5-7). Additionally, we tested various bases such as KHMDS, KH, KOH and KOtBu (Table 1, entries 8-11). From these experiments the reaction proceeds best when 25 mol% of KOtBu are applied and the desired product was obtained in 92% yield (Table 1, entries 12-13). [a] Dr. O. El-Sepelgy, E. Matador, A. Brzozowska, Prof. Dr. M. Rueping Institute of Organic Chemistry RWTH Aachen University Landoltweg 1, 52074 Aachen (Germany) E-mail: Osama.Elsepelgy@rwth-aachen.de E-mail: magnus.rueping@rwth-aachen.de [b] Prof. Dr. M. Rueping KAUST Catalysis Center (KCC) King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 (Saudi Arabia) [+] These authors contributed equally to this work. Supporting information for this article is given via a link at the end of the document.