Site‐Selective Late‐Stage Aromatic [18F]Fluorination via Aryl Sulfonium Salts

Abstract Site‐selective functionalization of C−H bonds in small complex molecules is a long‐standing challenge in organic chemistry. Herein, we report a broadly applicable and site‐selective aromatic C−H dibenzothiophenylation reaction. The conceptual advantage of this transformation is further demonstrated through the two‐step C−H [18F]fluorination of a series of marketed small‐molecule drugs.

Abstract: Site-selective functionalization of C À Hb onds in small complex molecules is al ong-standing challenge in organic chemistry.H erein, we report ab roadly applicable and site-selective aromatic CÀHdibenzothiophenylation reaction. The conceptual advantage of this transformation is further demonstrated through the two-step C À H [ 18 F]fluorination of aseries of marketed small-molecule drugs.
Over the past ten years,several promising new methods for the introduction of the 18 Fnucleus into small molecules have been disclosed, with the aim of improving clinical care and drug discovery through 18 Fp ositron-emission tomography (PET). [1,2] However,i mplementation and translation to hospital settings is challenging if the fluorination reactions are operationally complex. [3,4] Unfortunately,the introduction of conventional leaving groups that can directly provide aryl fluorides upon reaction with fluoride cannot currently be accomplished at al ate stage,s ot he requirement for de novo syntheses slows down the development of PET tracers (Scheme 1a). Direct C À Hf luorination in this regard is promising but selectivity becomes as ubstantial concern in every direct CÀHf unctionalization reaction, especially for PET tracer synthesis because even small quantities of constitutional isomers must be separated (Scheme 1b). [5] There are few highly regioselective arene C À Hfunctionalization reactions,a nd all of them either require suitable substitution patterns [6a,d] or directing groups, [6b,c] or afford functional groups that are not suitable for 18 Ffluorination. [6e] Herein, we report ah ighly selective and late-stage CÀH functionalization to afford aryl dibenzothiophenium salts, which can be converted into [ 18 F]Ar-F in as traightforward nucleophilic aromatic substitution reaction simply by adding fluoride (Scheme 1). TheC À Hd ibenzothiophenylation reaction developed herein proceeds in high selectivity for both small complex molecules and simple monosubstituted arenes to afford aryl dibenzothiophenium salts.G iven its high selectivity and the operational simplicity,t his two-step method to quickly access [ 18 F]Ar-F by arene C À Hf unctionalization holds promise for the acceleration of 18 FP ET development.
Some of the modern 18 Ffluorination reactions are starting to have an impact on the synthesis of structurally complex [ 18 F]labeled small molecules that cannot be made by conventional nucleophilic aromatic substitution. [7] Most notably, practical [ 18 F]fluorodemetallation reactions mediated by copper that proceed on al arge variety of small molecules have been developed by the groups of Gouverneur, [7c] Sanford and Scott,[7f,h] and Neumaier. [7d] Our group has reported deoxyfluorination reactions [7g,i] that in addition can also functionalize small peptides. [7l] Sanford, Scott, and co-workers have described aC u-mediated two-step [ 18 F]fluorination of electron-rich arenes using hypervalent iodine compounds. [7j] Nicewicz, Li, and co-workers have developed apromising CÀ Ht oC -18 Ff luorination reaction that does not require coordination directing groups and is enabled by laser-photoredox catalysis. [5d] None of the useful functional groups for F 18 introduction can currently be introduced selectively at al ate stage in ag eneral sense.D irect [ 18 F]fluorination is desirable, but control of regioselectivity is challenging.
Aryl sulfonium salts are good precursors for 18 Fl abeling of arenes. [8] rstad and co-workers have demonstrated that dibenzothiophene sulfonium salts can be efficiently converted into 18 F-labeled arenes for electron-poor and electron-neutral substrates,i ncluding several valuable PET tracers. [8d] However,reported methods for the preparation of aryl sulfonium salts often require aryl Grignard reagents,multistep syntheses from aryl halides,orstrong acids as co-solvents,none of which are suitable for site-selective late-stage incorporation. [8,9] Our previous approach through selective CÀHt hianthrenation [10] can also provide access to aryl fluorides but requires an iridium-catalyzed photoredox method, [11] which adds additional challenges for implementation at good manufacturing practice (GMP) production facilities in radiopharmacies. Herein, we report as econd highly selective arene CÀH functionalization reaction, which differs conceptually from thianthrenation in that it can provide aryl sulfonium salts that can engage directly in C À Fb ond formation, simply through the addition of fluoride.F urthermore,w es how how ag roup of three electronically different dibenzothiophenes designed for [ 18 F]fluorination show am arkedly expanded substrate scope compared to previous reported [ 18 F]fluorinations of arylsulfonium compounds. [8] Essential for the success of as ite-selective late-stage 18 F labeling method is the availability of ap ractical and general method to produce the precursors from readily available starting materials.W ef ound that in the presence of acid anhydrides as activators, [12] the reaction of bench-stable dibenzothiophene S-oxide with ethylbenzene afforded the corresponding dibenzothiophenium salt with high positional selectivity (p/o = 50:1; p/m = 100:1;Scheme 2). In contrast to previously reported arylthianthrenium salts,a ryl dibenzothiophenium salts can provide aryl fluoride directly.F or example,t reatment of ab iphenyl-derived dibenzothiophe-nium salt with fluoride afforded the aryl fluoride in 84 %yield of isolated product, yet the corresponding thianthrenium salt gave the desired product in only 7%yield with the wrong C À S cleavage product as the major side product (Scheme 2). The site-selective CÀHf unctionalization reaction developed herein exhibits broad substrate scope (Table 1). Both electron-poor (2, 21-23)a nd electron-rich (16, 24, 27)a renes proceed efficiently with high regioselectivity.V arious functional groups are well tolerated, including halides (2,(21)(22)(23)(24), nitriles (3), ethers (4)(5)20), esters (4, 10, 15), ketones (5), aldehydes (7), amides (5,8,25), and sulfonamides (9,14). Heterocycles such as quinolines (12), imidazoles (19), and pyridines (20)a re also compatible.A renes that are more electron-deficient than 1,2-dichlorobenzene are too electronpoor to react. Theutility of our method for site-selective latestage aromatic C À Hfunctionalization is further demonstrated with the reactions of small complex substrates,d rugs,a grochemicals,a nd natural products.F or example,t he dibenzothiophenium salt of fenofibrate (10)w as obtained in 89 % yield of isolated product on agram scale.For all the substrates shown in Table 1, analytically pure compounds can be obtained through simple chromatography on silica gel.
As depicted in Scheme 1, three differently substituted dibenzothiophene S-oxides display similar high site-selectivity under otherwise identical reaction conditions.F or unsymmetrical triaryl sulfonium salts,t he S N Ar reaction occurs preferentially at the most electron-deficient arene. [8,13] As such, an electron-rich dibenzothiophen such as M-DBT should provide high selectivity for the desired arene fluorination. However,M-DBT is less reactive than more electrondeficient dibenzothiophenes such as DBT,and cannot be used to efficiently CÀHf unctionalize less electron-rich arenes. Thus the dibenzothiophene S-oxide selected for each arene should be electron-deficient enough to functionalize the arene,and electron-rich enough to provide high selectivity in fluorination. Fore xample,b oth DBT and B-DBT salts of compound 25 could be synthesized in good yields.H owever, fluorination of the B-DBT salt affords 94 %y ield of desired fluorination product while DBT salt gives only 55 %yield of desired product with 42 %yield of the undesired side-product (see the Supporting Information). By use of electron-rich M-DBT,[ 18 F]fluorination with aryl sulfoniums can now proceed on otherwise challenging electron-rich complex substrates (36, 38;T able 2). [8] Moreover,arange of small-molecule drugs were successfully 18 F-labeled. Halides (30-32, 34, 35, 37), amides (28), sulfonamides (31), heterocycles (33, 38)w ere well tolerated. Substrates bearing ortho-substituents proceeded efficiently to afford the desired 18 F-labeled products (29,30,32,37).
Elution of the [ 18 F]fluoride from the anion exchange cartridge is commonly achieved with an aqueous solution of abase. [14] Aryldibenzothiophenium salts can be used directly for elution of [ 18 F]fluoride,which avoids the addition of bases or kryptofix. [7g,i,l] No special care is required to exclude air or moisture at any stage of the radio-synthesis,a nd the radiolabeled product can be readily separated from the starting material due to the pronounced polarity difference owing to the cationic sulfonium salt. No carrier-added [ 18 F]fluorination enabled the automated synthesis of 18 F-labeled compound 32 in high specific activity (1.4 Ci mmol À1 ). AH ammett analysis of the [ 19 F]fluorination with aryl dimethoxyldibenzothiophenium salts (Hammett-slope 1 =+ 3.4) is consistent with amechanism proceeding via CÀFbond reductive elimination from hypervalent sulfurane as previously suggested. [8d, 15] In conclusion, we developed as ite-selective late-stage aromatic [ 18 F]fluorination, enabled by as elective C À H dibenzothiophenylation reaction. We show for the first time how ac ollection of three electronically different dibenzothiophenes appropriately matched to the electronic requirements of the arene can expand the substrate scope compared to prior art. Beyond the immediate practicality of our method, this new procedure may inspire the development of diverse site-selective reactions for carbon-heteroatom bond formation.

Conflict of interest
Theauthors declare no conflict of interest.