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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Late-Stage Aromatic C−H Oxygenation Jonas Börgel, Lalita Tanwar, Florian Berger, and Tobias Ritter* Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr, Germany
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S Supporting Information *
Scheme 1. Conceptual Approach To Access Potential Metabolites and Their Fluorinated Analogues
ABSTRACT: Synthetic methods for oxidative aromatic C−O bond formation are sparse, despite their demand in metabolite synthesis for drug discovery and development. We report a novel methodology for late-stage C−O bond formation of arenes. The reaction proceeds with excellent functional group tolerance even for highly functionalized substrates. The resulting aryl mesylates provide access to potential human metabolites of pharmaceuticals, and may be used directly to install a C−F bond to block metabolic hotspots. A charge-transfer interaction between the reagent bis(methanesulfonyl) peroxide and the substrate arenes may be relevant for the chemoselective functionalization of arenes over other functional groups.
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lectrophilic aromatic substitution (SEAr) reactions such as nitration or halogenation are among the most widely used synthetic methods to install aromatic C−N or C−X bonds in positions of innate reactivity, over a broad range of substrates, from electron-poor to electron-rich arenes and heteroarenes.1 For analogous C−O bond-forming reactions, only nature has developed methods that achieve a similar substrate scope. Cytochrome P450 enzymes (CYPs) catalyze electrophilic hydroxylation of aromatic compounds to their corresponding phenols during phase one metabolism.2 The few known nonenzymatic arene oxygenation reactions have not been shown to proceed generally on complex small molecules, possibly a consequence of competing hydrogen atom abstraction by formed oxygen-based radicals.3 Herein, we present a strategy for oxidative C−O bond formation for electron-deficient and -rich arenes, heteroarenes, and highly functionalized compounds with bis(methanesulfonyl) peroxide (1) as the oxidant. We provide a plausible rationale how our method may differ from previous arene hydroxylation reactions through the formation of charge-transfer (CT) complexes, which could account for the high functional group tolerance. The CT complex may favor chemoselective arene functionalization as compared to peroxide reactivity with other functional groups, such as hydrogen atom abstraction chemistry. Compared to known methods, the substrate scope was extended to electronpoor arenes and heteroarenes. The mesylate substituent bears three advantages: it deactivates the reaction product for subsequent oxidation, it is stable but can be readily cleaved under appropriate, mild conditions, and it can serve as a direct precursor for aryl fluoride formation. Therefore, the product aryl mesylates give access to potential phenol metabolites and aryl fluorides, in which the metabolism is blocked exactly at the site that would have been most prone to metabolism in the original structure (Scheme 1). © XXXX American Chemical Society
Hydroxylation of xenobiotics is the most frequent transformation catalyzed by CYP enzymes during phase one metabolism.2a,4 Therefore, CYPs are commonly used as catalysts in the direct synthesis of oxygenated metabolites in vitro.3a,5 To obviate the need to express enzymes and facilitate material throughput, catalyst systems that mimic active sites of monooxygenases have been designed.3a,b For example, in 1954 the Udenfriend system was reported, which consists of a mixture of an iron(II) salt, EDTA, and ascorbic acid under an atmosphere of oxygen. Under these conditions, aliphatic and aromatic drug metabolites were obtained, albeit in yields lower than 10%.6 An alternative strategy to access phenols is transition-metal-catalyzed borylation or silylation followed by oxidation with peroxide reagents, which was reported by Hartwig, Miyaura, and co-workers, and is complementary in selectivity to electrophilic hydroxylation.7 In 1996, Crabtree and co-workers reported a C−H acetoxylation of simple arenes with Pd(OAc)2 as catalyst and PhI(OAc)2 as the oxidant.8 The reaction protocol was mechanistically studied and improved by the addition of pyridine as a ligand to accelerate C−H metalation by Sanford and co-workers; an excess of the arene substrate is still needed for high yields based on oxidant.9 To obviate the need of excess arene, directing groups have been employed in the synthesis of oxygenated arenes, as demonstrated by Yu et al. and Gevorgyan and co-workers.10 Received: August 27, 2018
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DOI: 10.1021/jacs.8b09208 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
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Journal of the American Chemical Society Table 1. Substrate Scope of C−O Bond Formation
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Performed in HFIP/phosphate buffer (pH = 7.2, 1.0 M). bTfOH (2.0 equiv) added. cTFA (1.1 equiv) added. dTfOH (1.1 equiv) added. eReagent 1 added at 0 °C.
In 2013, Siegel, Houk, and co-workers reported in a seminal publication that phthaloyl peroxide reacts with electron-rich carboarenes as limiting reagents through a radical reverserebound mechanism.11 The resulting phthaloyl esters can subsequently be hydrolyzed to the phenols. Two years after their initial report, the scope was extended to more electron -neutral arenes by employing the more reactive 4,5-dichlorophthaloyl peroxide.12 In addition, malonoyl peroxide has been reported by Tomkinson et al. for C−H oxygenation of simple arenes, which is suggested to proceed via an electrophilic pathway.13
Moreover, O-centered radical additions to arenes that are enabled by photoredox catalysis have been described by the Akita, Ngai, and Togni groups: aryl benzoate esters14 and aryl trifluoromethyl ethers15 were prepared with the use of excess arene substrate. Until now, a general chemical approach for oxidative C−O bond formation with synthetically useful yields spanning electron-rich arenes, electron-poor arenes, smallmolecule pharmaceuticals, and heteroarenes has not been reported. In this context, it is especially noteworthy to point out that, for the synthesis of metabolites, C−O bond formation must proceed late stage on structurally complex small B
DOI: 10.1021/jacs.8b09208 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
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Journal of the American Chemical Society
knowledge, our method is the first arene C−H oxygenation with a scope that reaches from electron-rich to electron-poor arenes and includes heteroarenes. Under both reaction conditions, mixtures of isomeric products with substrate specific ratios are obtained. In general, highly selective reactions are preferable; however, access to constitutional isomers presents an opportunity to access several oxygenated products from one reaction that are otherwise difficult to synthesize, especially if more than one metabolite is formed in vivo as well. Mesyloxy-clopidogrel (10),21 mesyloxy-nirvanol (11),22 mesyloxy-nefiracetam (13),23 and mesyloxy-efavirenz (15)24 are selected examples for complex small molecules that can be oxygenated at positions in which in vivo phase one metabolism occurs. All constitutional isomers have been isolated as analytically pure samples. The aryl mesylates are readily converted to the corresponding phenols: Selective cleavage of aryl mesylates using lithium diisopropylamide (LDA) has been reported to provide access to phenols on complex molecules with a variety of functional groups at −78 °C.25 Furthermore, aryl mesylates that do not contain O−H or N−H bonds can be converted efficiently to the phenols by removal of the mesyl group using tetrabutylammonium fluoride (TBAF). Hydroxylated heteroarenes (22, 23) and the identified metabolite 8-hydroxyefavirenz (24) were successfully synthesized by employing these methods (Scheme 2A). Compound 24 is otherwise accessible only via a tedious synthesis procedure.24 The reactivity of fluoride to cleave methanesulfonate esters led us to investigate deoxyfluorination with PhenoFluorMix on aryl mesylates directly (Scheme 2B).26 For example, 4′-OMs-flurbiprofen methyl ester (14A) was converted to its fluorinated analogue 25. Flurbiprofen methyl ester is a prodrug of flurbiprofen, which gets metabolized in the 4′-position; fluorination in this position is expected to block this metabolism pathway.27 Furthermore, the synthesis of the ezetimibe derivative 26 demonstrates that the aryl fluoride can still be accessed in a useful yield, despite the facile elimination of the acetoxy group under basic reaction conditions. The selected examples highlight the versatility of the aromatic mesylate functionality to access relevant complex small molecules without the need for de novo syntheses. Bis(methanesulfonyl) peroxide 1 is a strong oxidant, yet the functional group tolerance for the reaction in HFIP is excellent, even though peroxides as a source of O-centered radicals are typically prone to hydrogen atom abstraction, which typically limits their substrate scope.3d We offer a plausible explanation for the unusual chemoselectivity of 1 for arene functionalization, which could be due to a CT interaction between 1 and the arene substrate. The CT interaction may prevent the competing reaction of 1 with other electron-rich functional groups. Characteristic CT bands are observed in the UV/vis spectra for different methyl-substituted arenes in the presence of bis(methanesulfonyl) peroxide 1 (Scheme 3A). The ionization potential decreases from toluene to durene while the π-electron donor strength increases; the bathochromic shifts observed in the UV/vis spectra from toluene to durene with 1 are consistent with the proposed CT complexes, relevant for electron donor−acceptor complexes in SEAr reactions.28 The π-complex may further react to the Wheland intermediate (σ-complex), which is a common intermediate for SEAr reactions in polar solvents.29 Formation of the σ-complex could proceed either via SET processes or via a conventional two-electron pathway, depending on experimental conditions
molecules to have an impact, which has hitherto not been accomplished. Although reagent 1 has been known since 1952 and its reactivity in solution with aromatic solvents has been described,16 the potential of 1 as a reagent to form aromatic sulfonate esters of small molecules has not been explored. One major advantage over many other organic peroxides lies in the convenient preparation of 1: Peroxide 1 is readily obtained by constant current electrolysis of a sodium mesylate solution in methanesulfonic acid and therefore does not require a source of peroxide for its synthesis.16c,17 Reagent 1 is described as a stable, shock-insensitive colorless solid that shows no decomposition below 50 °C.16a,b Differential scanning calorimetry (DSC) experiments (see Supporting Information (SI)) indicate an exothermic decomposition when heated above 80 °C (more than 50 °C above the reaction temperature reported here) as a neat solid with an energy release of 1601 J·g−1. This value is comparable to the heat of decomposition of m-chloroperoxybenzoic acid (1827 J· g−1)18 and significantly lower than the value for biscyclopropylcarbonyl peroxide (2123 J·g−1), which has been found valuable in the pharmaceutical industry as a reagent for late-stage C−H cyclopropanation of heteroarenes.19 Moreover, peroxide 1 is currently used as a radical initiator for the synthesis of methanesulfonic acid from methane and sulfur trioxidea process to produce methanesulfonic acid on 10 000 ton scale per year, which shows the potential of 1 to be used in process chemistry.20 Our aromatic C−H oxygenation protocol is characterized by a simple reaction setup: Peroxide 1 can be used as an Oelectrophile for selective aromatic C−H oxidation for electronrich to electron-poor and neutral arenes, as well as complex small molecules (Table 1). A variety of functional groups such as electron-rich amides, sulfonamides, alcohols, and even alkenes are tolerated. If nucleophilic amines are present, in situ protonation with either trifluoroacetic acid (TFA) or triflic acid (TfOH) is sufficient protection toward undesired oxidation on the otherwise nucleophilic nitrogen atoms. Moreover, if acid-sensitive functional groups are present, such as the electron-rich alkyne in the anti-retroviral drug efavirenz (see 15), addition of phosphate buffer (1.0 M, pH = 7.2) to neutralize the methanesulfonic acid byproduct in situ results in productive mesyloxylation. Electron-rich heterocycles such as the quinoline motif of hydroquinine (9), the thiophene moiety of clopidogrel (10), and the pyrazole C−H bond of the celecoxib derivative 18 could also be successfully oxygenated, which has not been demonstrated by the use of other oxygenation methods. Product 18 was isolated in 57% yield, and 36% of remaining starting material was re-isolated, which is representative for most compounds that are not oxygenated in high yield. The reaction solvent hexafluoroisopropanol (HFIP) has been identified as important for obtaining high yields. The scope of heteroarenes can be extended by the use of [Ru(bpy)3](PF6)2 as a single-electron-transfer (SET) catalyst in acetonitrile. Pyridine (3), pyrrole (4), quinoxaline (5), and pyrimidine (7) derivatives gave the desired products in synthetically useful yields. However, pyridines without substituents in the 2-positions that diminish basicity could not be converted to desired products. The use of catalytic [Ru(bpy)3](PF6)2 is the preferred method to functionalize electron-poor arenes such as methyl benzoate (12), nitrobenzene (17), and procymidone (19). To the best of our C
DOI: 10.1021/jacs.8b09208 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
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Journal of the American Chemical Society Scheme 2. Syntheses of (A) Complex Phenols and (B) Aryl Fluorides from Aryl Mesylates
Scheme 3. (A) Characteristic Charge-Transfer (CT) UV/Vis Bands of Arene−Peroxide Complexes in HFIP and (B) Proposed Electrophilic Mechanism in HFIP
relevance of CT complexes cannot be excluded for the oxygenation of arenes in MeCN with [Ru(bpy)3](PF6)2; we observed reactivity that is distinct from that of other Ocentered radicals; for example, even in the presence of a tertiary aliphatic C−H bond prone to undergo hydrogen atom abstraction with other O-centered radicals,31 arene functionalization is favored (see SI). The inherent reactivity of Ocentered radicals to abstract C(sp3)−H atoms typically renders C−H oxidation reactions employing peroxides as terminal oxidants unsuitable for selective, late-stage C(sp2)−H functionalization.3d In conclusion, we have presented a practical method for latestage C−O bond formation enabled by readily accessible reagent 1. Two different reaction conditions give rise to the broad substrate scope. High functional group tolerance may be explained through charge-transfer complex formation between 1 and the arene. We anticipate that our C(sp2)−O bond formation will be a valuable addition to the set of aromatic latestage C−H functionalization reactions with imminent relevance to drug discovery and development.
and on the oxidation potential of the substrate.30 The Wheland intermediate would then re-aromatize to provide the product upon deprotonation (Scheme 3B). In contrast to the electrophilic reaction mechanism in HFIP, the reaction in acetonitrile with [Ru(bpy)3](PF6)2 as SET catalyst may generate reactive O-centered mesyloxyl radicals that add to electron-poor arenes and heterocycles. Involvement of radical addition is supported by the regioselectivity observed for nitrobenzene functionalization (p/o/m = 8:3:1) and further by the different selectivity observed for radical substitution of methyl benzoate (p/o/m = 2:1:1) compared to the electrophilic reaction in HFIP (p/o/m = 1:2:5) (see SI). The
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b09208. Experimental procedures and characterization data (PDF) X-ray crystallographic data for 1 (CIF) D
DOI: 10.1021/jacs.8b09208 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
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Journal of the American Chemical Society
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AUTHOR INFORMATION
Corresponding Author
*
[email protected] ORCID
Jonas Börgel: 0000-0001-5301-8579 Tobias Ritter: 0000-0002-6957-450X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Dr. Fabien Serpier and Constantin Jäschke for initial experimental support, Dr. Matthew Plutschack for help with large-scale synthesis of bis(methanesulfonyl) peroxide, and Pascal Unkel and Andre Pommerin for assistance with DSC measurements. We are grateful for the help of all analytical departments of the MPI für Kohlenforschung, and we thank the MPI für Kohlenforschung for funding. J.B. acknowledges the Fond der Chemischen Industrie for a Kekulé Fellowship.
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