The Direct α-Arylation of Ethers via the Merger of Photoredox Mediated C–H Functionalization and the Minisci Reaction

Abstract

The direct α-arylation of cyclic and acyclic ethers with heteroarenes has been accomplished via the design of a new photoredox mediated C–H functionalization pathway. Transiently generated α-oxyalkyl radicals, produced from a variety of widely available ethers via hydrogen atom transfer (HAT), were found to couple with a range of electron-deficient heteroarenes in a Minisci-type mechanism. This mild, visible light-driven protocol allows direct access to medicinal pharmacophores of broad utility using feedstock substrates and a commercial photocatalyst.

Visible light photoredox catalysis has recently emerged as a powerful platform for the functionalization of C–H and C–X bonds via numerous single electron transfer (SET) pathways, a rapidly growing area of research that played a part in a large-scale renaissance of radical-based methodologies.^[1] Recently, we sought to expand the types of organic molecules that can participate in photoredox mediated C–H functionalization^[2] via the exploitation of physical properties that are predictable across a wide range of structural classes (e.g., bond dissociation energies (BDEs),^[3] hydrogen atom transfer exchange constants^[4] and oxidation potentials) (Figure 1). In previous work, we developed a new photoredox–organocatalytic C–H functionalization protocol that allows benzylic ethers to undergo selective α-oxy arylation (via radical-radical coupling) in the presence of functional groups that contain similar C–H bonds (e.g., α̃C–H amines, α̃C–H alcohols, and α̃C–H ethers).^[5] In this manuscript, we report a new photocatalytic mechanism that allows for a complimentary class of organic molecules, namely dialkyl ethers, to formally undergo selective C–H bond functionalization and thereafter Minisci-type coupling^[6] with electron-deficient heteroarenes. This mild, visible light-driven protocol enables the rapid conversion of feedstock ethers into α-oxy heteroarenes, an important and broadly employed pharmacophore within the realm of drug development.

Figure 1.

Photoredox mediated C–H functionalization.

Heteroaromatic moieties are undoubtedly among the most widespread constituents of pharmaceutical compounds.^[7] Over the last decade, the direct C–H functionalization of heteroarenes has become a powerful and efficient transformation, with extensive applications in both medicinal and process chemistry.^[8] Notably, the open-shell addition of alkyl groups to heteroarenes,^[9] known as the Minisci reaction, has also enjoyed a broad scale re-adoption and application within drug discovery programs.^[10] Recently, we questioned whether photoredox catalysis might be mechanistically coupled with the venerable Minisci reaction to create a new and selective C–H functionalization–heteroarylation reaction, a protocol that would convert cyclic and acyclic ethers to high value pharmacophore adducts [Eq. (1)]. While the use of unfunctionalized ethers in the Minisci transform was previously demonstrated in 1971, these exploratory studies require the use of metal salts or stoichiometric peroxides at high temperatures, a necessity which generally results in moderate or low yields, and the production of a variety of radical addition byproducts.^[6] On this basis we sought to develop a broadly useful α-oxyalkylation reaction that employs photoredox catalysis in conjunction with low-boiling feedstock ethers and mild, room temperature conditions. Our hope was to develop a complementary Minisci-type mechanism that enables a general, selective and efficient C–H functionalization–heteroarylation reaction, and at the same time deliver a protocol that can convert a broad range of cyclic and acyclic ethers to high value pharmacophore adducts.

It has long been established that α-oxyalkyl radicals are relatively stable yet nucleophilic open-shell species that can readily react with electron-deficient substrates, such as olefins, imines, and heteroarenes.^[11] However, the vast majority of photoredox-mediated C–H functionalization processes have been limited to α-alkyl and aryl substituted amines, while ethers and alcohols remain outside the scope of these SET–deprotonation pathways due to their comparatively high oxidation potentials (for THF, THP, and Et₂O, E_1/2^ox > +2.4 V vs. SCE in 2:1 MeCN:H₂O).^[12] In an effort to expand the range of organic moieties that can participate in photocatalytic C–H functionalization (and to circumvent the limitations of an oxidation potential-gated electron-transfer mechanism) we sought to employ a hydrogen atom transfer (HAT) pathway, that would allow hydrogen abstraction via photoredox catalysis in lieu of direct substrate oxidation. Previous studies from our lab have shown that substrates which incorporate weak C–H BDEs, such as benzylic ethers, can be directly functionalized via the combination of an organocatalytic thiyl activation mode and photoredox catalysis.^[5] In this study, we hypothesized that the intervention of a sulfate radical anion^[13] should allow substrates that incorporate much stronger C–H BDEs, such as non-benzylic dialkyl ethers, to be directly activated and thereafter employed in Minisci-type chemistry. Moreover, the successful execution of these ideals would further demonstrate the utility of photoredox catalysis for medicinal chemistry.

The mechanistic details of our proposed α-arylation of ethers are outlined in Scheme 1. Irradiation of photoredox catalyst Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (1) using visible light from a household light bulb at room temperature will produce a long-lived (2.3 μs) photoexcited state, *Ir^III[dF(CF₃)ppy]₂(dtbbpy)PF₆ (2).^[14] Given that the resulting *Ir^III species is a strong reductant (E_1/2^IV/*III = −0.88 V vs. SCE in 2:1 MeCN:H₂O),^[12,15] we expected it to be capable of reducing the persulfate anion (3)^[16] to afford Ir^IV[dF(CF₃)ppy]₂(dtbbpy)PF₆ (4), sulfate dianion and the sulfate radical anion (5). We presumed that the desired α-oxyalkyl radical (7) could then be generated via a HAT event between the dialkyl ether (6) and sulfate radical anion.^[17] At this stage, we expected that the resulting α-oxyalkyl radical (7) would be sufficiently nucleophilic to add to a protonated electron-deficient heteroarene (8) in a Minisci-type pathway to afford the amine radical cation (9). The cation (9), upon loss of a proton, would give the α-amino radical (10), which would undergo a second SET event with the oxidized photo-system (4) (E_1/2^IV/III = +1.70 V vs. SCE in 2:1 MeCN:H₂O)^[12] to regenerate the photocatalyst ground-state (1) and furnish the desired α-aryl ether product.

Scheme 1.

Proposed mechanism for α–arylation of ethers.

We recognize that α-oxyalkyl radical 7 might be generated via two distinct mechanisms: (1) hydrogen atom abstraction or (2) direct single-electron oxidation followed by deprotonation. While we cannot definitively rule out the latter possibility, we favor the proposed HAT pathway based on mechanistic evidence from the literature. Studies of the reaction of SO₄^•− and ethers via transient absorption spectroscopy,^[18a] kinetic isotope effects,^[18b] and correlation between BDEs and reaction rates^[18c] are consistent with HAT as the operative mechanism. In the related case of alcohols, both ESR experiments^[18b] and Minisci-type trapping reactions^[13a] suggest that hydrogen abstraction, not SET–deprotonation, is the dominant pathway in the sulfate radical anion-mediated generation of α-oxyalkyl radicals.^[X]

Our examination of the proposed α-arylation of ethers began with tetrahydropyran (THP), isoquinoline, and a series of photocatalysts and persulfates (Table 1). To our delight, the desired α-arylation product was obtained in 68% yield using the Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (1) photocatalyst in combination with (NH₄)₂S₂O₈ as the oxidant, in MeCN under the irradiation of a 26 W household fluorescent light bulb (entry 1). The regioselectivity of addition at the isoquinoline C(1) position was fully expected based on the previously described polar effect.^[19] Notably, the addition of water allowed an increase in yield (entry 2, 77%), presumably due in part to the dissolution of the persulfate salt to generate a transparent biphasic reaction mixture, a measure that allows enhanced photon penetration. Changing the oxidant to K₂S₂O₈ improved the efficiency slightly, whereas the use of the more economical salt Na₂S₂O₈ provided a superior 81% yield of the heteroarylation product (entries 3 and 4). An examination of several photocatalysts revealed that Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (1) was the most effective in this α-arylation protocol (entries 5–7). It is intriguing to consider that in comparison to Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ (1), the less successful Ir(ppy)₃ and Ir(ppy)₂(dtbppy)PF₆ catalysts are more reducing at the *Ir^III excited state yet less oxidizing in the Ir^IV species, while Ru(bpy)₃Cl₂ exhibits a less reducing *Ru^II species yet more oxidizing Ru^III species.^[20–22] As such, we speculate that matched redox potentials are essential for both SET events to be efficient, a scenario that requires a highly tuned photocatalyst with respect to its intrinsic redox window. As a second issue, we were aware that the product ether α-C–H bonds are weaker than those of the ether starting materials, which could lead to multiple arylation or product decomposition events.^[6b] Indeed, we did observe oxidative dimerization of the arylation products in a small number of cases, with isoquinoline substrates, however, the use of EtCN as the reaction medium alleviated this issue (providing the desired adduct in 88% yield, entry 8). Given that the reduction potential of the persulfate anion is low,^[16] we expected that this reagent would be unable to react with the substrate ethers without further activation. Indeed, the critical roles of the photocatalyst and light in this α-arylation method were demonstrated using control experiments, wherein minimal amounts of desired product were detected in the absence of visible light photo-excitation (entries 9 and 10).

Table 1.

Preliminary studies toward α-heteroarylation of ethers.

Entry	Photocatalyst	Persulfate salt	Solvents	% Yield[a]
1	Ir[dF(CF3)ppy]2(dtbbpy)PF6	(NH4)2S2O8	MeCN	68
2	Ir[dF(CF3)ppy]2(dtbbpy)PF6	(NH4)2S2O8	MeCN/H2O	77
3	Ir[dF(CF3)ppy]2(dtbbpy)PF6	K2S2O8	MeCN/H2O	79
4	Ir[dF(CF3)ppy]2(dtbbpy)PF6	Na2S2O8	MeCN/H2O	81
5	Ir(ppy)3	Na2S2O8	MeCN/H2O	7
6	Ir(ppy)2(dtbbpy)PF6	Na2S2O8	MeCN/H2O	28
7	Ru(bpy)3Cl2	Na2S2O8	MeCN/H2O	22
8	Ir[dF(CF3)ppy]2(dtbbpy)PF6	Na2S2O8	EtCN/H2O	88
9[b]	Ir[dF(CF3)ppy]2(dtbbpy)PF6	Na2S2O8	EtCN/H2O	<1
10	none	Na2S2O8	EtCN/H2O	4

^[a]Yield determined by ¹H NMR using 1,3-benzodioxole as the internal standard after work-up following the general procedure in Supporting Information.

^[b]Reaction performed in the absence of light.

TFA = trifluoroacetic acid. CFL = compact fluorescent light.

Having identified the optimal conditions for this α-ether arylation protocol, we next focused on defining the scope of the heteroarene component. As revealed in Table 2, a variety of electron-deficient heteroarenes will readily couple with THP in good to excellent yield at the most electrophilic site. Notably, bromo- or chloro-substituents at the C(4) and C(6) positions of isoquinoline are well tolerated, along with the C(2) positions of both quinoxaline and quinoline (products 11–14, 75–92% yields). Moreover, the use of 2-methyl or 2-phenylquinoline resulted in alkylation with THP selectively at the C(4) position while 4-methylquinoline underwent coupling exclusively at the C(2)-position (products 15–17, 83–87% yields). It is important to note that various pyridine derivatives with electron-withdrawing groups worked well in this ether-arylation protocol (products 18–22, 62–91% yields). Dimethylpyrimidine readily participated in this α-ethereal coupling with THP at the C(2) site in 91% yield (product 23). It should be noted that the use of free amine substituents on the aromatic ring resulted in diminished reactivity towards the addition of the nucleophilic α-oxyalkyl radical. More specifically, the coupling of 2-amino-4-methylpyrimidine with THP required 48 h to reach full conversion, albeit in a useful 73% yield (product 24). Again, high levels of regioselectivity were also obtained with pyridazine-based heteroarenes, providing the ortho-chloro alkylation adduct with almost complete site selectivity (product 25, 85% yield).

Table 2.

Scope of heteroarenes in the Minisci ether addition.^[a,^b]

^[a]Yield of material isolated by column chromatography.

^[b]See Supporting Information for experimental details.

Next, we explored the scope of the ether component in this new α-heteroarylation protocol. As shown in Table 3, a range of cyclic and acyclic ethers were found to be suitable coupling partners. Besides tetrahydropyran (product 26, 88% yield), a series of tetrahydrofurans were found to be amenable to direct addition with isoquinoline (entries 27–29, 77–86% yields). It should be noted, however, for 2-methyltetrahydrofuran, that both the α-oxy methylene and α-oxy methine sites underwent arylation with a ~4:1 regioselectivity for the less hindered position (products 28, 81% yield). With this in mind it is intriguing to consider that the use of tetrahydrofurfuryl acetate led to α-methylene arylation with complete regioselectivity, a remarkable finding given the three available α-oxygen C–H containing positions (product 29, 77% yield). Moreover, the use of 3-oxotetrahydrofuran selectively gave the C(5)-arylation product in the presence of a β-carbonyl group, effectively leaving the α-position of the carbonyl untouched (product 30, 83% yield). A similar level of regiocontrol and efficiency was achieved with 4-oxotetrahydropyran (product 31, 86% yield). Recently oxetanyl moieties have emerged as a valuable new structural element in drug discovery.^[23] However, at the present time, there are few synthetic methods that allow for the facile introduction of oxetane in a direct and routine fashion into medicinal agents.^[23,24] We initially found that the use of this strained ring system led to an oxetanyl radical that underwent ring-opening polymerization under our optimal aqueous/acid conditions. Gratifyingly, when the coupling of oxetane and isoquinoline was carried out in MeCN (0.05 M) with the addition of (nBu)₄NCl to help solubilize the persulfate anion, a useful 42% yield of the desired product was obtained (product 32). It should be noted that 1,4-dioxane is also amenable to this arylation protocol (product 33, 90% yield), while 1,3-dioxolane provided the masked formyl equivalent in 62% yield (product 34, 83% yield, r.r. 3:1). The use of acyclic dialkyl ethers was also demonstrated via the application of the diethyl and dibutyl variants, both providing the heteroarylation adducts in excellent yield (product 35 and 36, 93% and 88% yields, respectively). The coupling of diethyl ether is of particular interest, as its volatility (b.p. 35 °C) renders it incompatible with the temperatures required for thermal radical generation (80–90 °C).^[6b,c] Moreover, dimethoxyethane underwent arylation at both the methylene and methyl sites (r.r. 2.3:1) with high levels of efficiency (product 37, 93% yield).

Table 3.

Scope of ethers in the photoredox ether addition.^[a,^b]

^[a]Yield of material isolated by column chromatography.

^[b]See Supporting Information for experimental details.

^[c]Regiomeric ratio (r.r.) determined by ¹H NMR. 28: 3.5:1 r.r.; 34: 3:1 r.r.; 37: 2.3:1 r.r.

^[d]Diastereomeric ratio (d.r.) determined by ¹H NMR. 28: 1.3:1 d.r.; 29: 2:1 d.r.

^[e]MeCN used as the only solvent; 2 equiv. of (nBu)₄NCl added; no TFA added.

In summary, we have developed a photoredox catalytic approach to the direct α-arylation of ethers with electron-deficient heteroarenes. This visible light-promoted method shows a broad scope with regard to both the dialkyl ether and heteroarene substrates, providing consistently high yields of α-oxyalkylated arenes. Remarkably, this C(sp³)–C(sp²) bond construction was achieved efficiently via C–H functionalization of both the coupling partners at room temperature, thereby allowing the coupling of even highly volatile ether substrates. We anticipate this new photoredox-mediated C–H functionalization–Minisci addition will find broad application in both the academic and pharmaceutical sciences.