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Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue Highly-chemoselective step-down reduction of carboxylic acids to aromatic hydrocarbons via Cite this: Chem. Sci.,2019,10,5736 † All publication charges for this article palladium catalysis have been paid for by the Royal Society b c c c ab of Chemistry Chengwei Liu, Zhi-Xin Qin, Chong-Lei Ji, Xin Hong * and Michal Szostak * Aryl carboxylic acids are among the most abundant substrates in chemical synthesis and represent a perfect example of a traceless directing group that is central to many processes in the preparation of pharmaceuticals, natural products and polymers. Herein, we describe a highly selective method for the direct step-down reduction of carboxylic acids to arenes, proceeding via well-defined Pd(0)/(II) catalytic cycle. The method shows a remarkably broad substrate scope, enabling to direct the classical acyl reduction towards selective decarbonylation by a redox-neutral mechanism. The utility of this reaction is highlighted in the direct defunctionalization of pharmaceuticals and natural products, and further Received 21st February 2019 emphasized in a range of traceless processes using removable carboxylic acids under mild, redox- Accepted 27th April 2019 Creative Commons Attribution 3.0 Unported Licence. neutral conditions orthogonal to protodecarboxylation. Extensive DFT computations were conducted to DOI: 10.1039/c9sc00892f demonstrate preferred selectivity for the reversible oxidative addition and indicated that a versatile rsc.li/chemical-science hydrogen atom transfer (HAT) pathway is operable. Introduction Herein, we report the rst highly selective method for the direct step-down reduction of ubiquitous carboxylic acids to The reduction of carboxylic acid derivatives represents one of arenes (decarbonylative pathway), proceeding via well-dened the most fundamental transformations in synthetic chemistry Pd(0)/(II) cycle (Fig. 1C). The method supersedes the two-step This article is licensed under a and catalysis.1 Reduction reactions of carboxylic acids and methods using less general substrates and shows much derivatives are traditionally performed using stoichiometric broader reaction scope owing to the versatility of Pd-catalysis.5 metal hydrides.2 However, these reagents suffer from major The use of preformed carboxylic acid derivatives has been of choice to effect the direct reduction to hydrocarbons (Fig. 1B).6,7 Open Access Article. Published on 29 April 2019. Downloaded 9/25/2021 10:40:27 PM. scope limitations and are inherently less safe than milder silane-based hydrides due to their pyrophoric nature.3 The Recognizing that these specically-designed and less general N- reduction of carboxylic acid chlorides to aldehydes (acyl and O-derivatives (pyrazoles, glutarimides, phenolic esters) are pathway) has been achieved by Rosenmund using Pd-catalysis4 via an oxidative insertion/transmetallation/reductive elimina- tion mechanism,5 thus establishing the classic cross-coupling tactics for the synthesis of aldehydes from carboxylic acids (Fig. 1A). More recently, a Ni-catalyzed step-down reduction of N-chelating amides directly to hydrocarbons has been achieved by Maiti and co-workers,6 while the Rueping group developed a selective methodology for the Ni-catalyzed step-down reduc- tion of phenolic esters and N-acyl-glutarimides (Fig. 1B),7 developed earlier by our group.8 aCollege of Chemistry and Chemical Engineering and Key Laboratory of Auxiliary Chemistry and Technology for Chemical Industry, Ministry of Education, Shaanxi University of Science and Technology, Xi'an 710021, China bDepartment of Chemistry, Rutgers University, 73 Warren Street, Newark, NJ 07102, USA. E-mail: [email protected] cDepartment of Chemistry, Zhejiang University, Hangzhou 310027, China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental details and characterization data. See DOI: 10.1039/c9sc00892f Fig. 1 Transition-metal-catalyzed reduction of carboxylic acids. 5736 | Chem. Sci.,2019,10,5736–5742 This journal is © The Royal Society of Chemistry 2019 View Article Online Edge Article Chemical Science prepared from carboxylic acids in a separate step, we recently exquisite selectivity for decarbonylation. Overall, the scope of questioned whether a more straightforward approach engaging the reaction shows a number of clear advantages over other directly simple aromatic carboxylic acids could be realized in methods.6,7,9–11,16 this important reaction class using versatile Pd-catalysis To demonstrate the generality and potential impact of this (Fig. 1C). new reduction method, we applied this protocol to late-stage Specically, we proposed that the direct reduction of derivatization of bioactive natural products and pharmaceuti- carboxylic acids9,10 to hydrocarbons via a heretofore unknown cals (Fig. 2B). We were delighted to nd that decarboxylation of redox-neutral, decarbonylative11–15 Pd(0)-catalyzed pathway probenecid (2af) as well as of carboxylic acids derived from could enable to use ubiquitous carboxylic acids as traceless a uorine-containing18 diufenican (2ag), estrone (2ah) and activating groups, offering high level of predictability5a,b and tocopherol (2ai)afforded the decarbonylation products in high functional group tolerance5e–g under redox-neutral conditions yields, underscoring the mild conditions and high potential orthogonal to protodecarboxylation.16 Furthermore, the method impact of the present protocol. would allow us for a more convenient approach to hydrocarbons As a further illustration of the synthetic utility we conducted that the reduction of designer N- and O-carboxylic acid deriva- a series of metal-catalyzed and metal-free reactions using tives, which are further limited by substrate scope.6,7 Finally, carboxylic acid as a traceless directing group (Fig. 3A–D). We since aromatic carboxylic acids are commercially synthesized were pleased to nd that Ru-catalyzed ortho-arylation directed from the corresponding and cheaper toluenes, the method by a carboxylic acid,19 electrophilic meta-iodination/Suzuki would establish Pd-promoted access to benzenes from feed- cross-coupling20 and electrophilic meta-iodination/Heck cross- stock toluenes, thus enabling to valorize crude oil as a mild coupling20 provide rapid access to a range of valuable products alternative to toluene hydrodealkylation.17 in high yields, thus signifying a clear appeal of this novel method to organic synthesis. Furthermore, the decarbonylative Results and discussion reduction of carboxylic acids establishes valuable access to Creative Commons Attribution 3.0 Unported Licence. benzenes from feedstock toluenes (Fig. 3D). New valorization We initiated our studies by probing the direct reduction of methods of oil processing products are of high interest from the electronically- and sterically-unbiased 4-phenyl benzoic acid as industrial and sustainability standpoints.17a,b a model substrate. Aer extensive optimization (see ESI†), we Altogether, the broad scope of reactivity, tolerance to various found that the reduction of 4-Ph-benzoic acid in the presence of sensitive functional groups and the potential to predictably use Pd(OAc)2 (1 mol%), dppb (2 mol%, dppb ¼ 1,4-bis(diphenyl- in functionalization of complex acids provide distinct advan- phosphino)butane), piv2O (1.5 equiv., piv ¼ 2,2-dimethylpro- tages from other processes for removing carboxylic acid 6,7,9–11,16 panoyl), Et3N (1.5 equiv.) and Et3SiH (1.5 equiv.) as a hydride group and Bode well for future applications. source afforded the desired reduction product in 97% yield on Although the scope of the reaction is very broad, several This article is licensed under a gram scale, attesting to the scalability of the method. Under the points should be noted: (1) typically, the yield can be improved optimized conditions reduction to the aldehyde or aldehyde by using small excess of Et3SiH (3.0 equiv.) and/or triethylamine derived products was not observed, consistent with high facility as a base. For example, the yield of 2l can be improved to 67% Open Access Article. Published on 29 April 2019. Downloaded 9/25/2021 10:40:27 PM. of catalytic system to trigger the reduction (cf. acyl pathway) under these conditions. (2) In general, the reduction of electron- under redox-neutral conditions. rich aromatics is less efficient than that of electron-decient With optimal conditions in hand, we next focused on counterparts (vide infra). (3) Direct reduction of electro-rich examining the scope of the decarbonylative reduction of ve-membered heterocycles is feasible; for example, the carboxylic acids (Fig. 2A). We were delighted to nd that the reduction of 5-chlorothiophene-2-carboxylic acid proceeds in scope of the reaction is very broad and compatible with a variety 91% yield. (4) Multiple reductions are feasible; for example, of functional groups. As shown, unbiased as well as sterically- reduction of [1,10-biphenyl]-3,30,4,40-tetracarboxylic acid (bis- hindered aryl (2a–a0, 2c–f) and alkenyl benzoic (2b–b0) acid phthalic acid) proceeds in 81% yield. (5) Halides on the underwent smooth reduction. Substitution with electron- carboxylic acid containing ring are possible. (6) We typically did donating (2c–d) or electron-withdrawing (2e–f) groups was not observe side reactions (e.g. aldehyde formation, reduction readily tolerated. Simple (2g–g0) and substituted naphthalenes to the alcohol, deoxygenation). Studies on further expansion of (2h–i) were found to be competent substrates.

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