Catalytic radical difluoromethoxylation of arenes and heteroarenes

The first visible light photocatalytic generation and utilization of the OCF2H radical for direct (hetero)aryl C–H difluoromethoxylation at room temperature.


Introduction
Modern drug discovery and development involves extensive ne-tuning of physicochemical properties of drug candidates. A common approach to control these properties involves incorporation of uorine-containing functional groups such as the diuoromethoxy (OCF 2 H) group into drug candidates. 1 The OCF 2 H moiety is a privileged functional group in medicinal chemistry because molecules bearing the OCF 2 H group have dynamic lipophilicity, where they can adjust their lipophilicity to adapt to the chemical environment via simple bond rotations. 2 In addition, OCF 2 H-containing aromatic compounds can have an orthogonal structural geometry that enriches molecular spatial complexity and provides additional binding affinity to active sites in a target. 3 Thus, incorporation of the OCF 2 H group into organic molecules oen enhances their therapeutic efficacy by increasing metabolic stability, improving cellular membrane permeability, and altering pharmacokinetic properties. 3 As a result, the OCF 2 H group is prevalent among pharmaceuticals and agrochemicals such as Pantoprazole® (a proton-pump inhibitor that is one of the top 100 selling drugs), 4 Roumilast®, Flucythrinate®, and Diumetorim® (Scheme 1a).
Even though numerous biologically active molecules have the OCF 2 H motif in an aromatic system, access to such Scheme 1 Applications and strategies for the synthesis of difluoromethoxylated (hetero)arenes.
analogues oen requires the installation of the OCF 2 H group at an early stage of a multi-step synthetic sequence. The most common approach relies on O-diuoromethylation of phenols using different diuorocarbene precursors under basic and/or evaluated temperature conditions (Scheme 1b). 5 This strategy has facilitated the site-selective synthesis of aryl diuoromethyl ethers, but identication of the ideal position of the OCF 2 H substitution in a drug candidate still requires parallel and laborious multi-step syntheses from aryl precursors bearing activating or directing groups at various positions in an aromatic ring. Hartwig et al. recently developed an elegant onepot, three-step aryl C-H diuoromethoxylation protocol involving (i) catalytic C-H borylation of arenes, (ii) oxidation of the boronate esters, and (iii) diuoromethylation of phenols (Scheme 1c). 5h Although this method has advanced the state-ofthe-art, a catalytic, direct intermolecular C-H diuoromethoxylation of (hetero)arenes remains elusive.
As a part of our ongoing program to access and harness the reactivity of heteroatom radicals, 6 we questioned whether a radical-mediated aromatic substitution using the OCF 2 H radical would allow direct introduction of the OCF 2 H group to a drug candidate generating multiple regioisomers in a single chemical operation. Such an approach is appealing because it obviates the need for laborious synthetic effort and the prefunctionalization of aromatic compounds. Moreover, the preparation and isolation of regioisomers would allow rapid assays of the biological activity of OCF 2 H analogues, a feature which would be particularly benecial to modern drug discovery programs. Herein, we report the development of redox-active diuoromethoxylating reagents for late-stage, direct diuoromethoxylation of unactivated arenes and heteroarenes through a radical-mediated mechanism under visible light photocatalytic conditions at room temperature (Scheme 1d). [7][8][9] Results and discussion A key to the success of the proposed transformation is the ability to generate and trap the OCF 2 H radical under mild reaction conditions. Although computational studies of the OCF 2 H radical have been reported, experimental access to such a radical intermediate remains rare. 10 We envision that the ability to generate the OCF 2 H radical in a controllable, catalytic, and selective manner under mild conditions will open a new reaction platform for the preparation of an important class of diuoromethoxylated molecules. Our recent success in the development of triuoromethoxylating reagents by taking advantage of the weak N-O bond (DG N-O z 57 kcal mol À1 ) 6,11 prompted us to question whether we could develop diuoromethoxylating reagents for the rst photocatalytic formation and utilization of the OCF 2 H radical in organic synthesis. Thus, we synthesized and examined a series of benzotriazole-based OCF 2 H reagents (1a, DR1-5, Table 1) for direct aryl C-H diuoromethoxylation of benzene. We found that cationic nature of the reagent is critical as it enhances the oxidizing power of the reagent and undergoes a photocatalytic single electron reduction to produce a neutral radical 1a 0 that liberates the OCF 2 H radical selectively. Incorporation of electron decient substituents on the benzotriazole ring prevents the addition of the OCF 2 H radical to the reagent byproducts and improves the reaction yields (entries 1, 3-6). Further reaction optimizations revealed that the reaction works with 1 equivalent of benzene albeit with diminished yield (40%) accompanied with additional 24% of bis(diuoromethoxylated) side products (entry 7). Control experiments showed that photoredox catalysts and light are essential, but the oxygen free environment is not required (entries 8-10). It is noteworthy that reagent 1a (mp ¼ 153-154 C) be prepared in a multi-gram scale and is thermally stable beyond 200 C. Also, it can be manipulated and stored under ambient conditions without noticeable decomposition (see ESI †).
With the redox-active cationic diuoromethoxylating reagent 1a 12 and optimized photoredox-catalysed aryl C-H diuoromethoxylation reaction conditions in hand, we then test the generality of the reaction against a wide array of arenes and heteroarenes. As shown in Table 2, a broad array of arenes and heteroarenes with diverse electronic properties and substitution patterns underwent photocatalytic (hetero)aryl C-H diuoromethoxylation under optimized reaction conditions using reagent 1a at room temperature. The reaction tolerated halide substituents such as uoride (3r), chloride (3b-3d), and bromide (3e, 3f, 3ab-3ad), which is important Table 1 Difluoromethoxylating reagent and reaction optimization a a Reactions were performed using 1 equivalent of reagent and 10 equivalents of benzene. b Yields were determined by 19 F NMR spectroscopy using triuorotoluene as an internal standard. c 1 equivalent of benzene. d Without Ru(bpy) 3 (PF 6 ) 2 . e Without light. f The reaction was set-up under air atomsphere. from a synthetic perspective since these substituents provide useful handles for further structural elaboration through metal-catalysed coupling reactions. The weak benzylic C-H bond (BDE z 88 kcal mol À1 , 3f-3i), 13 which is oen a site for undesired reactivity in radical processes, proved compatible. More remarkably, unprotected alcohols (3i) and phenols (3k-3n) remained intact during the reaction. Carbonyl derivatives such as aldehydes (3n), ketones with or without enolizable protons (3o, 3p), carboxylic acids (3r, 3s, 3ad), esters (3q), amides (3x), and carbonates (3z) reacted smoothly to afford the desired products in good yields. Other functional groups such as triuoromethyl (3d), methoxy (3q), triuoromethoxy (3x), cyano (3j, 3k, 3ac), nitro (3l, 3m), sulfonyl (3y), and pyridinium (3v) were all well tolerated under the reaction conditions. Moreover, no competing radical addition to electron decient olen (3m) or alkyne (3t) was observed during the aryl diuoromethoxylation reaction. Heteroarenes such as pyridine (3aa) and thiophene (3ab-3ad) derivatives were also viable substrates. The reaction proceeded with one equivalent of arenes, but higher yields were obtained using ten equivalents of arenes. 12 In such cases, we could recover 8.3-9.1 equivalents (see ESI †) of the aromatic substrates at the end of the reaction, which is critical for valuable aromatic compounds.
Late-stage modications of biologically active molecules are oen a key to identication of medicinal agents. 14 To demonstrate the amenability of the photocatalytic diuoromethoxylation processes to late-stage synthetic applications, biorelevant molecules were subjected to our standard reaction conditions using arenes as limiting reactants (Table 3). Approved drug molecules such as Baclofen® (muscle relaxant), Febuxostat® (anti-hyperuricemic), Mexiletine® (antiarrhythmic), Efavirenz® (antiretroviral drug for treating HIV), as well as Metronidazole® (antiparasitic) and L-menthol (decongestants and analgesics) analogues were successfully diuoromethoxylated using reagent 1a to afford the desired products (5a-5f) in synthetically useful 42-76% yields, based on the recovery of the starting materials (BRSM). Our diuoromethoxylation strategy is applicable to a range of drug molecules and tolerates a number of sensitive functionalities, and this shows its potential utility in modern drug discovery programs. Table 2 Selected examples of difluoromethoxylation of (hetero)arenes a a Reactions were performed using 1.0 equivalent of reagent 1a and 10.0 equivalents of (hetero)arene. The asterisk (*) and number sign (#) denote functionalization of minor regioisomeric products. Overall yields and the ratio of the constitutional isomers were determined by 19 F NMR spectroscopy using triuorotoluene as an internal standard. b Reaction performed with MeCN and CH 2 Cl 2 (1 : 1, 0.2 M). c Reaction performed with 10.0 equiv. of TfOH. See ESI for experimental details.
Our approach capable of forming multiple regioisomers in a single synthetic operation is complementary to the conventional site-selective protocols using phenols as substrates and could be useful in discovery chemistry. The regioselectivity of the reaction resembles that of radical-mediated aromatic substitution processes and is guided by the electronics of the substituent except in the case of a bulky substituent such as 3j, in which case the OCF 2 H radical adds preferably to the position distal from the tert-butyl group. If an aromatic substrate has multiple reaction sites, the OCF 2 H radical will add to these sites to form regioisomeric products, which could be separated to provide pure isomers (see ESI †). Such reactivity is particularly attractive from a drug discovery point of view because it allows rapid access to various OCF 2 H derivatives without labourintensive, parallel multi-step analogue synthesis. 14,15 More importantly, it will increase the efficiency of structure-activity relationship (SAR) studies of OCF 2 H analogues and can conveniently produce promising new candidates that might have never been evaluated otherwise.
We then performed a series of experiments and DFT calculations to better understand the reactivity of the OCF 2 H radical and the reaction mechanism (Scheme 2). The quantum yield of the reaction is 0.52, which supports that an extended radical chain mechanism is unlikely. This observation corroborates DFT calculations (see Fig. S24 †). A series of Stern-Volmer quenching studies showed that only 1a quenched the excited *Ru(bpy) 3 2+ efficiently (k q ¼ 2.08 Â 10 9 M À1 s À1 ) (Fig. S8 †). To further probe the reaction mechanism, kinetic isotope effect (KIE) experiments were conducted using a 1 : 1 mixture of benzene and d 6 -benzene in the presence of reagent 1a, affording the desired products Ph-OCF 2 H and d 5 -Ph-OCF 2 H in a 1 : 1 ratio (Scheme 2b). This result excludes the possibility of H-atom abstraction/deprotonation as the rate-determining step. Moreover, intermolecular competition experiments using two electronically diverse arenes revealed that the OCF 2 H radical reacts more favourably with electron-rich arenes, and this conrms its electrophilic character (Scheme 2c). The formation of the OCF 2 H radical is the key for the success of the (hetero)aryl C-H diuoromethoxylation and is supported by (i) the regioselectivity of the reaction, and (ii) radical trap experiments using butylated hydroxytoluene (BHT) and 1,4cyclohexadiene (Scheme 2d). Addition of 1 equivalent of BHT to Table 3 Selected examples of difluoromethoxylation of biorelevant molecules a a Yields were determined based on the recovered starting material. The yield in parentheses is the isolated yield. The asterisk (*) denotes functionalization of a minor regioisomeric product. b Reaction performed with 1.00 equivalent of TfOH. c 1.00 equivalent of K 2 CO 3 . See ESI for experimental details.
Scheme 2 Experimental mechanism studies: a reactions were performed using 5.00 equivalents of arenes each. See ESI † for experimental details.
the reaction mixture lowered the product yield from 70% to 29%. When 1,4-cyclohexadiene was used as a substrate, we observed the formation of the desired product 3a in 7% yield. Presumably, once the OCF 2 H radical is formed, it undergoes two consecutive H-atom abstraction from 1,4-cyclohexadiene, generating benzene as the product. Subsequently, this benzene can react with the OCF 2 H radical under photocatalytic conditions, furnishing the diuoromethoxylated product. A key feature of our cationic redox-active reagent 1a is its susceptibility to single electron reduction to form a neutral radical (1a 0 ) that undergoes b-scission liberating the OCF 2 H radical exclusively (Scheme 3a). DFT calculations showed that both steps are energetically favourable in the presence of an excited photoredox catalyst, *Ru(bpy) 3 2+ . Once the OCF 2 H radical is formed, the subsequent steps (i.e., the addition of the OCF 2 H radical to an arene, oxidation of the resulting cyclohexadienyl radical by Ru(bpy) 3

Conclusions
In summary, we have developed a redox-active cationic reagent 1a and identied photocatalytic conditions that allow facile diuoromethoxylation of arenes and heteroarenes without the need for aryl ring pre-functionalization or pre-activation. This radical-based aromatic substitution process provides rapid access to multiple regioisomers in a single synthetic operation, which will facilitate molecular screening and SAR studies of OCF 2 H analogues. The synthetic utility of our strategy has been highlighted by the late-stage diuoromethoxylation of biorelevant molecules at ambient temperature and pressure. Notably, this report not only provides the rst experimental access to and utilization of the OCF 2 H radical but also establishes the rst photocatalytic and selective formation of the OCF 2 H radical. We expect that this reagent and protocol will create a new avenue for the design and development of diuoromethoxylation reactions of hydrocarbons to aid the discovery and synthesis of new pharmaceuticals.

Conflicts of interest
The authors declare no conict of interest.