Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Arene Ruthenium Catalyst MCAT-53 for the Synthesis of Heterobiaryl Compounds in Water through Aromatic C−H Bond Activation Anita Mehta,* Biswajit Saha, Ali Aiden Koohang, and Mukund S. Chorghade Chicago Discovery Solutions LLC, 23561 West Main St., Plainfield, Illinois 60544, United States
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ABSTRACT: A new water friendly MCAT-53 [Ru2Cl2 (HCOO)3(p-cymene)] Na (sodium η-6-p-cymene dichloro diruthenium triformato complex) has been developed as a catalyst to effect aromatic C−H bond activation and C−C coupling reactions in water. Cross-coupling reactions were performed in DI/distilled water under air- and ligand-free conditions without further activation of the catalyst. Synthesis of an advanced intermediate of CETP inhibitor, Anacetrapib, in water has been demonstrated to give a single regioisomer using the MCAT-53 catalyst. KEYWORDS: C−H activation, C−C coupling, ruthenium catalyst, MCAT-53
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INTRODUCTION Functionalized biaryl containing motifs are among the most valuable synthetic scaffolds in organic chemistry due to their prevalence in natural products, advanced materials, and pharmaceuticals.1a−d Biphenyl moieties constitute pharmacophores in Active Pharmaceutical Ingredients (API) such as losartan, valsartan, and azilsartan.1e Biaryl compounds are commonly prepared using well-known aryl−aryl coupling reactions such as the Suzuki and Stille couplings.1a,b Typically, conventional coupling reactions involve C−C bond formation between an aryl halide and an organometallic agent (Scheme 1) and require a stoichiometric amount of transition metal derivatives.
proximity induced C−H ortho functionalization, is through transition metal catalyzed C−H activated C−C coupling with the help of DGs (ortho directing groups). DGs are strong coordinating or chelating groups that direct transition metal insertion at the ortho position, thereby allowing the bond formation between the site of metal insertion and a carbon atom on a reaction partner substituted with a suitable leaving group (e.g., halide). The use of ortho directing groups in C−H bond functionalization offers several advantages with respect to substrate scope and application to total synthesis. Complementary strategies for directed C(sp3)-H functionalization include 1,n-hydrogen atom transfer and transition metal catalyzed carbene/nitrene transfer.1f Significant progress has been reported in the past two decades on transition metal catalyzed ortho-directed C−H bond activation and functionalization reactions.1f−i,2 Nitrogen containing substrates such as 2-phenylpyridine, 2-phenyl-2oxazoline, benzo[h]quinoline, and N-phenyl pyrazole have been exploited to act as ortho-DG groups for aromatic C−H activation in the presence of transition metal complexes for the synthesis of heterobiaryl compounds.2 This strategy was first developed for palladium catalyzed reactions.2a,b More recently, relatively cheaper ruthenium2c−i and rhodium2j−m based catalysts have provided good results. There are reports of the utility of simple ruthenium compounds such as RuCl3·H2O and RuCl2(p-cymene) dimer in organic solvents.2n,o Ruthenium alkylidines as precatalysts were used by Ackerman et al.2p (in DMA under anhydrous conditions in an inert atmosphere). A ruthenium(II) carboxylate catalyst, generated in situ from [RuCl2 (pcymene)] 2 and 1-phenyl-1-cyclopentanecarboxylic acid (PCCA) in the presence of K2CO3, allowed activation of the C−H bond in phenyl-substituted pyrimidines and their direct functionalization with aryl halides in organic solvents.2q
Scheme 1. Common C−C Bond Forming Reaction Strategies
Within our sustainable chemistry programs, we have been interested in C−H bond activation and direct arylation as inherently green approaches to synthesize industrially useful biaryls.1f−i This approach is highly desirable, because of readily available starting materials and clean reaction conditions, as corresponding salts of Sn, B, and Zn are not produced; HX is the only side product. Direct arylation strategies have been formulated for step and cost economical syntheses of industrially useful biaryls and polyaryls.1i However, direct C−H bond functionalization reactions are limited by the inert nature of most carbon− hydrogen bonds and the requirement to control site selectivity in molecules that contain diverse C−H groups.1f−i A practical way to achieve direct arylation (Scheme 1), also known as © XXXX American Chemical Society
Received: May 8, 2018 Published: August 14, 2018 A
DOI: 10.1021/acs.oprd.8b00141 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
inert atmosphere using either pressure reactors or Schlenk tubes, as shown by Dixneuf et al.,4a Kuzman et al.,3k and Ackermann et al.2n−p For improved ease in handling and manipulation, air stable catalysts that avoid the use of sealed tubes/pressure reactors will be valuable. Ackermann3j reported examples of C−H arylation under a dry and inert gas atmosphere using phosphine oxides as preligands and a Ru2Cl2 (p-cymene)2 complex. The catalyst system was promising as, unlike previous reactions,2l,s it was tolerant of the use of reagent grade potassium carbonate as a stoichiometric base that need not be dried. Subsequently, the same group reported insight into the mechanism and identification of a well-defined ruthenium(II) dicarboxylate catalyst, [Ru((COOMes)2(p-cymene)].4b,c Direct arylation of C−H bonds was done using a ruthenium(II) dicarboxylate catalyst with phenols for the reaction of pyrazole derivatives with 4-methyl phenol in water under a nitrogen atmosphere.4d Two protocols for ligand free ruthenium- or palladiumcatalyzed direct arylations in user-friendly solvent polyethylene glycol (PEG) were reported by Ackermann and Vicente.4e This catalyst is air stable and is now commercially available and has been known to promote meta-selective C−H activation in dioxane and other organic solvents requiring anhydrous conditions for aklylation reactions with halides as well as the synthesis of angeotensin-II receptor blockers by C−H functionalization with organic halides in an organic solvent such as toluene.4f However, a sequential meta-ortho-C−H functionalization can be achieved with alkyl halides in organic solvents such as dioxane, dichloroethane, and toluene under extremely anhydrous conditions.2f Palladium catalyzed C−H activated coupling of aryl iodides with anilides and ureas in the presence of oxidants such as Ag(OAc) in 2 wt % surfactant water solution has been described by Lipshutz et al.4g,h Surfactants such as Brij 35 or TPGS-750 M in water were considered necessary for the success of the reaction. An oxidant was also required. Ruthenium catalytic complex RuCl2(PPh3)(p-cymene) was successfully used by Dixneuf et al. for arylation of functional arenes with aryl chloride and heteroaryl halides in water without using surfactants.4i Various phosphines were used for the [RuCl2(p-cymene)]2/KOAc system for the alkenylation of phenyl oxazolines in ethanol.4j Our investigation has been focused on conducting aryl−aryl coupling reactions in water with aryl halides under ambient pressure and in air without necessity to use ligands such as phosphines. C−H bond functionalization in water by various ruthenium(II) catalysts and potassium acetate and potassium pivalate was reported by Dixneuf et al.4a,k Diethyl carbonate as a more eco-friendly solvent was also used for C−H activated functionalization instead of NMP.4l All reactions were carried out under an inert atmosphere of argon in a closed Schlenck tube (pressure
