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    11 views7 pages

    Late-Stage Aromatic C-H Oxygenation - Enhanced Reader

    Uploaded by

    Ankit Maharshi

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    © All Rights Reserved
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    J/A\C|S=—= 0, 16025-16091 pubsacsorgIAcs, Late-Stage Aromatic C—-H Oxygenation Jonas Bérgel,® Lalita Tanwar, Plorian Berger, and Tobias Ritter™ Max Planck Institut fir Koblenforschung, Kaiser Wilhelm Platz 1, D-45470 Milheim an der Rue, Germany © Supporting Information 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 atestage 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 function- alization of arenes over other functional groups. lectrophiic aromatic substitution (S,Ar) reactions such as nitration or halogenation are among the most widely used ‘synthetic methods to install aromatic CN or C=X bonds in positions of innate reactivity, over a broad range of substrates, from electron poor to electron-rich arenes and heteroarenes.” For analogous C—O bond-forming reactions, only nature has developed methods that achieve a similar substrate scope Cytochrome P4S0 enzymes (CYPs) catalyze electrophilic hydroxylation of aromatic compounds fo their corresponding, phenols daring phase one metabolism.? The few known non- enzymatic arene oxygenation reactions have nat been shown to proceed generally on complex small molecules, possibly 2 consequence of competing hydrogen atom abstraction. by formed oxygen-based radicals.” Herein, we present a strategy for oxidative C—O bond formation for electron-deficient and rich arenes, heteroarenes, and highly functionalized com- ‘pounals with bis(methanesulfonyl) peroxide (1) asthe oxidant. ‘We provide a plausible rationale how our method may differ from previous arene hydroxylation reactions through the formation of charge-transfer (CT) complenes, 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 method the substrate scope was extended to electron- poor 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 asa direct precursor for aryl fluoride formation, Therefore, the product aryl mesylates give access to potential phenol metabolites and aryl urides, in which the metabolism is blocked exactly at the site that would have been most prone to metabolism in the original structure (Scheme 1). 5@ ACS Publications 620% Aran enon Sey Scheme 1. Conceptual Approach To Access Potential Metabolites and Their Fluorinated Analogues cytochrome Paso Ho {Late Stage Aromatic oh Oxygenation a \ 4 ee Eonotan current eectrtyia not spot ceed” Hydroxylation of xenobiotics is the most frequent trans- formation catalyzed by CYP enzymes during phase one metabolism.”** ‘Therefore, CYPs are commonly used as catalysts in the direct synthesis of oxygenated metabolites in sitro."° To obviate the need to express enzymes and faciitate ‘material throughput, catalyst systems that mimic active sits of| monooxygenases have been designed," For example, in 1954 the Udenfriend system was reported, which consists of a mixture of an iron(Il) 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%° "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.” In 1996, Crabtree and co-workers reported a C=H acetoxyation of simple arenes with Pa(OAc) as catalyst and Phl(OAc)> a the oxidant" The reaction protocol was mechanistically studied and improved by the addition of pyridine as a ligand to accelerate CH metalation by Sanford and co-workers; an excess of the arene substrate is stil needed for high yields based on oxidant.” 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.” Received: August 27, 2018 Published: November 13, 2018 Journal of the American Chemical Society ‘Table 1. Substrate Scope of C-O Bond Formation (uti, 23°, 12-28 (2s mena nabentPra aster se ye me 9 ons A eC" , Sn 7 7 smog yom j , wh. ¢ .Oe) wot Tone : ome oe OMe Mer eiy-ome say mow 1D oar Sy ous [ f Yous NS, Ae . 3 Ly fs stom ienuromise from hyeeoquline fom ate M50, fom pent newt neew wane sth sche hye cs ic 7 "CFs peamineme — wnsifcatlewe tenons ton te ant uw Pr snare sone cis WS oh SP BS L eee, 7 ms ghey : SO et x — ow A neg : a f so aye 7 ow MM Se Some cacao ve scons dott once seve! sew set tex swan “Performed ia HIP /phospate butler (pH added at 0°C. 2, LOM). SHOH (20 equiv) added. “TFA (1.1 equiv) added. “TYOH (11 equiv) added “Reagent In 2013, Siegel, Houk, and co-workers reported in a seminal ‘publication that phthaloyl peroxide reacts with electron ich carboarenes as limiting reagents through a radical reverse rebound mechanism.!" 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,-dichloro- phthaloyl peroxide.!” In addition, malonoyl peroxide has been reported by ‘Tomkinson et al. for CH oxygenation of simple arenes, which is suggested to proceed via an electrophilic pathway.'” Moreover, O-centered radical additions to arenes that are enabled by photoredox catalysis have been described by the ‘ata, Ngo, and Togni groups: ar benzoate esters! and aryl teluoromethyl ethers!® were prepared with the use of excess arene substrate. Until now, a general chemical approach for oxidative C=O bond formation with synthetically usefl yields spanning electron-rich arenes, eletron-poor arenes, small rolecule pharmaceuticals, and etezoarenes has not been reported. In this contest, itis especially noteworthy to point cut that for the synthesis of metabolites, C=O bona formation must proceed late stage on structurally complex small 16027 oatrasaviaasone Journal of the American Chemical Society 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,” 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 organi peroxides lies in the ‘convenient preparation of I: Peroxide Lis realy obtained by constant current electrolysis of a sodium mesylate solution in ‘methaneselfonie acid and therefore does not require a source ‘of peroxide for its synthesis. Reagent 1 is described as a stable, shock-insensitive colorless solid that shows no decomposition below $0 °C.'%" Differential scanning calorimetry (DSC) experiments (see Supporting Information (S1)) indicate an exothermie decom- position when heated above 80 °C (more than 50 °C above the reaction temperature reported here) 38a neat solid with an ‘encegy release of 1601 J-g !. Ths value is comparable to the heat of decomposition of m-chloroperoxybenzoic aid (1827 J 15°)" and significantly lower than the value fr bseyclopropyl- ‘carbonyl peroxide (2123 J"), which has been found valuable inthe pharmaceutical industry a a reagent for late-stage C—H eyclopropanation of heteroarenes.” Moreover, peroxide 1 is curently used as a radical initiator for the synthesis of methanesulfonie acid from methane and sulfur tioxide—a process to produce methanesulfonic acid on 10.000 ton seale Per yea, which shows the potential of I to be used in process chemistry.” Our aromatic H oxygenation protacl is characterized by 4 simple reaction setup: Peroride 1 can be used as an O electrphile for selective aromatic C-H oxidation for electron ich to clectron-poor and neutral arenes, at wll as complex small molecules (Table 1). A vase of fonctional groups such as_clectromich amides, sulfonamides, alcohols, and_cven alkenes ar tolerated, IF nacleophilic amines are present in stu protonation with either trifluoroacetic acd (TFA) of tific acid (TIOH) is slcient protection toward undesired ‘oidation on the otherwise nicleophilic sitrogen_ atoms Moreover, if acidsenstive functional groups are present, such a8 the electromich alkyne in the antiretroviral drug cfavirens (see 18), addition of phosphate buifer (1.0 Mp 72) to neutralize the methaneslfonic acid byproduct sit results in productive mesyloxylation. Electron ach heterocycles such as the quinoline motif of hydroquinin (9), the thiophene moiety of clopidogrel (10), and the pyrazole CH bond ofthe celecoxib desirative 18 could alo be successfully oxygenated, Which has not been demonstrated by the use of other ‘oxygenation methods, Product 18 was isolated in S7% yield, and 369 of remaining starting material wos reisolated, which is representative for most compounds tht are not oxygenated in high yield. ‘The reaction solvent hexafuoroisopeopanol (HEIP) fas boca identified as important for obtaining high ics The scope of heterorenes can be extended by the use of [Ra(bpy),](PF.)s a a single clectron transfer (SET) catalyst in acetonitrile, Pyridine (3), pyrrole (4), quinoraline (8), and Pyrimidine (7) derivatives gave the ‘desired. products in synthetically useful yields. However, pyridines without substituents in the 2-postions that diminish basicity could not be converted to desited products. The use of catalytic [Ra(bpy),J(PE)> i the prefered method to functionalie ‘lectron-poor arenes such as methyl benzoate (12), nitzo benzene (17), and procymidane (19). To the best of or knowledge, our method is the fist arene C—H oxygenation with a scope that reaches from electrontich 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 dificult to synthesize, especially if more than one metabolite is formed in vivo as well, Mesylony clopidogrel (10),2"" mesyloxy-nirvanol (11),""mesyloxy-nefircetam (13), and mesyloxy-favienz (18) are selected examples for complex small molecules that can be oxygenated at positions in whieh in viv phase one metabolism occurs. All constitutional isomers have been isolated as analytically pare samples, The aryl mesylates are readily converted to the corresponding phenols: Selective cleavage of aryl mesylates using lithium disopropylamide (LDA) has been reported to provide access to phenols on complex molecules with a variety of functional groups at ~78 °C." 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 (TRAE). Hydroxylated hetero arenes (22, 23) and the identified metabolite §-hydroxy efavirenz (24) were successfully synthesized by employing these methods (Scheme 2A). Compound 24 is otherwise accessible only via a tedious synthesis procedure." The reactivity of fluoride to cleave methanesulfonate esters led us to investigate deoxyiluorination with PhenoFluorMix on aryl rmesylates directly (Scheme 2B). For example, 4-OMs-flurbiprofen methyl ester (14A) was converted to its fluorinated analogue 28. Flurbiprofen methyl ester i a prodrug of furbiprofen, which gets metabolized inthe 4-position;tuorination in this position is expected to block this metabolism pathway.”” Furthermore, the synthesis ofthe czotimibe derivative 26 demonstrates thatthe aryl fuoride can still be accessed in a usefl 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 i exellent, even though peroxides as a source of O-centered radicals ae typically prone to hydrogen atom abstraction, which typically limits their substrate scope."! We offer a plausible explanation for the unusual chemoselectvity of 1 for arene functional ization, 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 CTT bands are observed in the UV/vis spectra for diferent methyl-substituted arenes in the presence of bis(methanesulfonyl) peroxide 1 (Scheme 3A). The jonization potential decreases from toluene to durene while the s-clectron 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. S,Ar reactions." The s-complex may further react to the Wheland intermediate (o-complex), which jsa common intermediate for S,Ar reactions in polar solvents.” Formation of the o-complex could proceed either via SET processes of via a conventional two-electron pathway, depending on experimental conditions 16028 oatrasaviaasone Journal of the American Chemical Society Scheme 2. Syntheses of (A) Complex Phenols and (B) Aryl Fluorides from Aryl Mesylates ‘Synthesis of henle ote ote “ey ‘TBAF (3.0 eau) worn Ay Tar own os Tian 7 men cm re LDA 25 eau) ed) om — an ho ‘ SP woaaseaum 1< 7 Cry : “cr, sorters 1 mr 2 yet ty orien Bee yo 1008F

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