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Substitution of Alcohols by N-Nucleophiles Via Transition Metal-Catalyzed Dehydrogenation Cite This: DOI: 10.1039/X0xx00000x

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Substitution of Alcohols by N-Nucleophiles Via Transition Metal-Catalyzed Dehydrogenation Cite This: DOI: 10.1039/X0xx00000x Chemical Society Reviews Substitution of alcohols by N -nucleophiles via transition metal-catalyzed dehydrogenation Journal: Chemical Society Reviews Manuscript ID: CS-REV-12-2014-000496.R1 Article Type: Review Article Date Submitted by the Author: 18-Dec-2014 Complete List of Authors: Yang, Qin; Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Wang, Qingfu; Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Yu, Zhengkun; Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Page 1 of 24 Chemical Society Reviews Journal Name RSC Publishing ARTICLE Substitution of alcohols by N-nucleophiles via transition metal-catalyzed dehydrogenation Cite this: DOI: 10.1039/x0xx00000x Qin Yang, a Qingfu Wang a and Zhengkun Yu* ab Received 18th December 2014 Transition metal-catalyzed substitution of alcohols by N-nucleophiles (or N-alkylation of Accepted amines and related compounds with alcohols) avoids the use of alkylating agents by means of borrowing hydrogen (BH) activation of the alcohol substrates. Water is produced as the only DOI: 10.1039/x0xx00000x by-product, which makes the “BH” processes atom-economic and environmentally benign. www.rsc.org/ Diverse types of homogeneous organometallic and heterogeneous transition metal catalysts, and substrates such as N-nucleophiles including amines, amides, sulfonamides and ammonia, and various alcohols, can be used for this purpose, demonstrating the promising potential of “BH” processes to replace the procedures using traditional alkylating agents in pharmaceutical and chemical industries. Borrowing hydrogen activation of alcohols for C-N bond formation has recently been paid more and more attention, and a lot of new and novel procedures and examples have been documented. This critical review summarizes the recent advances in “BH” substitution of alcohols by N-nucleophiles since 2009. “Semi -BH” N-alkylation processes with or without an external hydrogen acceptor is also briefly presented. Suitable discussion of the “BH” strategy provides new principles for establishing green processes to replace the relevant traditional synthetic methods for C-N bond formation. 1. Introduction partners such as halides, tosylates, triflates, sulfonates, organo- boron, -tin, and -zinc reagents, are usually required, and in some Construction of a C-N bond is one of the most important tasks for cases dangerous peroxides and diethyl azodicarboxylate have to 1 synthetic chemists. Substitution, addition, cycloaddition, and be used as the coupling partners. Although a variety of cross-coupling reactions, etc. can be employed to form this alkylating compounds have been successfully explored, the need chemical bond. Transition metal-catalyzed cross-coupling to develop readily available alkylating agents as well as the reactions have recently been made great progress in C-N bond corresponding effective catalytic systems is still strongly desired formation. However, in the traditional cross-coupling alkylation in N-alkylation of amines and the related compounds. to form a C-N bond various organic or organometallic coupling Alcohols are readily available chemicals in bulks and are considered as potential alkylating agents. However, alcohols are a Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), rather unreactive as alkylating agents because the hydroxyl 457 Zhongshan Road, Dalian, Liaoning 116023, P. R. China. moiety in an alcohol molecule can not be easily replaced by a E-mail: [email protected] nucleophilic reagent. Alcohols are usually involved in reactions b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of in the forms of their corresponding halides, tosylates, triflates, Organic Chemistry, CAS, 354 Fenglin Road, Shanghai 200032, P. R. China and sulfonates, etc. by converting the OH functionality to a better Qin Yang studied chemistry at Central Qingfu Wang studied chemistry at Hua China Normal University, Wuhan, Zhong University of Science and China, and received her BSc degree in Technology, Wuhan, China, and received July 2007. In September 2008, She his BSc degree in July 2011. He then joined Prof. Zhengkun Yu’s group at joined Prof. Zhengkun Yu’s group at Dalian Institute of Chemical Physics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS) to Chinese Academy of Sciences (CAS) to pursue a PhD degree. Her current pursue a PhD degree. His current research interest is focused on iron- research interest is centered on transition catalyzed cyclization and related metal complex-promoted homogeneous homogeneous catalysis. catalysis and synthetic methodologies. Qin Yang Qingfu Wang This journal is © The Royal Society of Chemistry 2013 J. Name ., 2013, 00 , 1-3 | 1 Chemical Society Reviews Page 2 of 24 ARTICLE Journal Name leaving group. Based upon the principle of atom-economy in N-nucleophiles under homogeneous organome-tallic and chemical transformations, the above-mentioned alternative heterogeneous transition metal catalysis since 2009. methods to utilize alcohols lack of efficiency and produce a lot of undesired wastes. 2 For modern synthetic chemistry in both the OH academic laboratories and industry, green chemistry-featured OH [X-MLn] cat. R2 R2 + R1 environmentally benign processes are always expected. R1 In the pioneering work by Grigg,3 and Watanabe, 4 alcohols Me were directly used as the alkylating agents for the N-alkylation of 2 amines under transition metal catalysis, which presents the first O LnMR examples of alcohol substitution by N-nucleophiles. Since then, R1 Me continuous efforts have been contributed to N-alkylation of HX HX amines as well as the related reactions by activating alcohols 5-10 Scheme 2 C-H functionalization of alcohols by through the so-called borrowing hydrogen (BH) or hydrogen 18 autotransfer (HA) 2,11,12 strategy. Diverse catalytic systems have redox-triggered carbonyl addition. been established for the catalytic N-alkylation reactions with alcohols as the alkylating agents. 13-17 A borrowing hydrogen (or 2. Homogeneous transition metal-catalyzed substitu- hydrogen autotransfer) process can be generally depicted by the tion of alcohols by N-nucleophiles substitution of an alcohol with an amine (or N-alkylation of an amine with an alcohol) (Scheme 1). In the BH (or HA) process, 2.1 Substitution of alcohols by amines an alcohol is temporarily removed hydrogen to form the corresponding aldehyde or ketone intermediate by a transition Amine synthesis may have received much more attention than the metal catalyst, rendering the alcohol as an alkylating agent. Such preparation of many other functional compounds in organic an intermediate is transformed to an imine by condensation with chemistry because amines are widely used as the organic inter- an amine in situ . Subsequent hydrogen return to the imine mediates in academic laboratories, chemical and pharmaceutical intermediate from the transition metal catalyst affords the amine industries, and they can also be employed for the synthesis of product with a newly formed C-N bond, producing water as the various biologically active materials. 23 Substitution of alcohols only by-product. Such a “BH” strategy avoids use of organic by amines or ammonia (or N-alkylation of amines or ammonia halides or other derivatives of alcohols as the alkylating agents, with alcohols) is considered as a promising alternative route to featuring an atom-economic and green chemical process. access new higher-order amines. In general, substitution of alcohols by amines through a BH strategy is catalyzed by [M] organometallic ruthenium, iridium, copper, iron, and palladium R OH R NHR' catalysts, etc. Relatively unreactive amides, sulfonamides, and [M] ammonia can also be used as the N-nucleophiles. Starting from primary amines higher-order amines such as secondary and tertiary amines, cyclic tertiary amines by means of diols, and N- heterocyclic compounds by employing functionalized amine [MH ] 2 substrates, were obtained. In a similar manner, secondary amines H2NR' and ammonia were applied for the same purpose. R O R NR' H2O 2.1.1 Ruthenium catalysts Scheme 1 Borrowing hydrogen (BH) strategy for the Ruthenium complexes are typically effective catalysts for substitution of alcohols by N-nucleophiles. substitution of alcohols by amines through a borrowing hydrogen mechanism. By using [Ru( p-cymene)Cl 2]2 with bidentate phos- Since 2009, transition metal-catalyzed N-alkylation of amines phine dppf or DPEphos as the catalyst the alkylation of amines and related compounds with alcohols through borrowing hydrogen activation of the alcohol substrates has been paid more Prof. Zhengkun Yu obtained his PhD degree and more attention. 8-10 Various homogeneous organometallic and at Dalian Institute of Chemical Physics heterogeneous transition metal catalysts, challenging substrates such as amides, ammonia, and polyols, related transformations in (DICP), CAS in July of 1995. During October aqueous phase, and asymmetric BH processes as well as scale-up 1995-January 2003 he worked as a post- preparation of industrially useful amines have been successfully doctoral fellow or research associate in the applied in this prosperous area. A lot of potentially useful new labs of Prof. Rudolf Aumann (University of and novel N-alkylation examples have been documented. It is Münster, Germany), Prof. John G. Verkade noted that an alternative strategy for alcohol activation by (Iowa State University, USA) and Prof. Chuck temporary oxidation to an aldehyde has been
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