Electrophotocatalytic Oxygenation of Multiple Adjacent C–H Bonds

Summary:

Oxygen-containing functional groups are nearly ubiquitous in complex small molecules. The installation of multiple C–O bonds by the concurrent oxygenation of contiguous C–H bonds in a selective fashion would be highly desirable but has largely been the purview of biosynthesis. Multiple, concurrent C–H bond oxygenation reactions by synthetic means presents a challenge,^{1–2,3,4,5,6} particularly because of the risk of overoxidation. Here, we report the selective oxygenation of two or three contiguous C–H bonds by dehydrogenation and oxygenation, enabling the conversion of simple alkylarenes or trifluoroacetamides to their corresponding di- or tri-acetoxylates. The method achieves such transformations by the repeated operation of a potent oxidative catalyst, but under conditions that are selective enough to avoid destructive overoxidation. The reactions are achieved using electrophotocatalysis,⁷ a process that harnesses the energy of both light and electricity to promote chemical reactions. Notably, judicious choice of acid allows for the selective synthesis of either di- or trioxygenated products.

Most complex molecules incorporate functional groups comprised of carbon-oxygen (C–O) bonds. A particularly attractive strategy to synthesize such molecules is to convert relatively inert carbon-hydrogen (C–H) bonds, which are ubiquitous in simple precursor molecules, into C–O bonds in a process known as C–H oxygenation.^{1–2,3,4,5,6} Nature follows this type of strategy for the synthesis of a plethora of secondary metabolites, such as the antimalarial drug artemisinin (Fig. 1A),⁸ by using enzymes to achieve selectivity between what can otherwise be difficult to distinguish C–H bonds. Chemists find it difficult to recapitulate this type of strategy because of the challenge of site selectivity and the risk of overoxidation, which can lead to undesired carbonyl products or carbon-carbon (C–C) bond cleavages (Fig. 1B). Nevertheless, tremendous progress has been made in achieving controlled, site-selective C–H oxygenation reactions in complex settings.^{1–6, 9–10,11,12,13} However, it remains very difficult to oxygenate multiple C–H bonds simultaneously, particularly if those bonds are adjacent to one another, where the risk of overoxidation is severe. The challenge then is to develop a chemical strategy that is strongly oxidizing enough to effect multiple C–H oxygenations yet selective enough to avoid overoxidation of the substrate.

Fig. 1. Oxygenation of Multiple C–H Bonds:

(A) Nature’s approach to multiple C–H bond oxygenations. (B) Synthetic approach to multiple C–H bond oxygenations. (C) Mechanistic rationale of electrophotocatalytic oxygenation of multiple C–H bonds. Ac, acetyl; Me, methyl; SET, single electron transfer; TAC, trisaminocyclopropenium.

Recently, a number of challenging oxidative reactions have been achieved in a selective fashion using electrophotocatalysis (EPC),^{14–15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30} a process that utilizes both electrochemical^{31–32,33,34,35} and photochemical energy to promote reactions. We have shown that a trisaminocyclopropenium ion¹⁸ (TAC⁺) can serve as a potent oxidative electrophotocatalyst (Fig. 1C), enabling a range of C–H bond functionalizations and other transformations.^{7,17,18,19,20–21} In these reactions, the TAC cation (TAC⁺) is oxidized in an electrochemical cell at a relatively low anodic potential (1.26 V vs. Standard Calomel Electrode, SCE) to produce the deep red TAC radical dication (TAC^•2+). While this species is not itself strong enough to oxidize the substrate, when photoexcited it becomes a powerful oxidant (TAC^•2+*, 3.33 V vs. SCE).¹⁸ Thus, irradiation of an electrochemical cell containing TAC⁺ can oxidize even poorly reactive substrates via single electron transfer (SET) to generate the corresponding radical cations, which are highly reactive intermediates that can lead to a number of advantageous reaction outcomes. Previously, we showed that TAC electrophotocatalysis could achieve the diamination of vicinal C–H bonds of alkylarenes to furnish dihydroimidazole products.²⁰ Given the ubiquity of polyoxygenated molecules, both in nature and in pharmaceutically active compounds, a method that achieved two or even three contiguous C–H oxygenations in one step would be of great interest.

We hypothesized that TAC EPC could offer a unique strategy to realize such challenging transformations using inexpensive acetic acid (AcOH) as the oxygen source. Specifically, we reasoned that, under appropriate EPC conditions in the presence of AcOH, a substrate (1) bearing a redox-active substituent, such as an arene or an amine derivative, could be converted to the monoxygenated intermediate 2. Under the acidic EPC conditions, 2 could undergo slow, reversible elimination to generate olefin 3. By virtue of its conjugation to the redox active substituent, this olefin would be prone to a second round of EPC oxidation to form the dioxygenated adduct 4. Moreover, we reasoned that iteration of these elimination / oxidation steps with another adjacent C–H bond could lead to elusive trioxygenation products, such as 6. Here, we report the realization of this proposal for the controlled oxygenation of two or three contiguous C–H bonds of alkylarenes and trifluoroacetamides.

Under our optimized conditions, alkylated arenes were electrophotocatalytically dioxygenated using catalytic TAC⁺ClO₄⁻ (8 mol%) in the presence of acetic acid (AcOH), acetic anhydride (Ac₂O), and a strong acid (trifluoroacetic acid [TFA] for branched substrates or trifluoromethanesulfonic acid [TfOH] for unbranched substrates) in methylene chloride (CH₂Cl₂) with tetraethylammonium tetrafluoroborate (Et₄NBF₄) as electrolyte (Fig. 2). The reaction was conducted in an undivided electrolytic cell (carbon cloth anode, platinum plate cathode) under constant current (5 mA) irradiated by two compact fluorescent lights [CFLs].

Fig. 2. Substrate scope of electrophotocatalytic vicinal C–H dioxygenation.

^a All yields are of isolated products. See supplementary materials for experimental details. For unbranched substrates, TfOH was used, while for branched substrates, TFA was used. Unless otherwise specified, the major isomer is anti. ^b Certain products were found to be more readily isolated and purified as free diols or triols rather than as diacetates or triacetates. In these instances, hydrolytic workup with Na₂CO₃ (aq.)/CH₃OH revealed the free alcohols, which were then isolated and purified; ^c syn product is major; ^d without acid anhydride. ^e TfOH was used instead of TFA.

These conditions effected the vicinal C–H dioxygenation of a diverse menu of branched and unbranched alkylarenes bearing a range of functionality (Fig. 2). In the simplest case, ethylbenzene was converted to diacetate 7 in 58% yield. For some substrates, a higher yield was obtained with a hydrolytic workup to furnish a 1,2-diol product, such as 8. The diastereomeric ratio (dr) typically favored the anti isomer to varying degrees. Dihydroxylation of n-pentylbenzene furnished 1,2-diol 9, a known precursor to a Beta-secretase 2 (BACE2) inhibitor, in 68% yield and 2.3:1 dr.³⁶ Interestingly, product 10, bearing a longer alkyl chain, was generated in higher yield (78%) and diastereoselectivity (4:1). Diol 11, bearing a bromo substituent on the arene, was generated with good efficiency. Meanwhile, a trifluoroacetamide substituent was accommodated in the formation of 12 in good yield, though with a nearly completely eroded dr. Interestingly, under the reaction conditions 4-ethyltoluene was oxidized to form adduct 13, in which the ethyl group was vicinally dioxygenated and the methyl group was geminally dioxygenated. Products 14–20 demonstrate the breadth of functional group compatibility of this reaction, which readily accommodates alkyl halide (14), acetoxy (15), carbomethoxy (16), imide (17), alcohol (18), carboxylic acid (19), and amino (20) substituents. The carbomethoxy group resulted in the preferential formation of the syn diastereomer 16, whereas the presence of a free carboxylic acid resulted in lactone product 19. The dimethylamino group apparently slows the reaction rate considerably, since the diacetate 20 was isolated in only 22% yield while the monoacetate product, which we presume is a precursor to 20, was formed in 45% yield. Products 21 and 22, in which both vicinal C–H bonds are benzylic, were also accessible. On the other hand, cyclic adducts 23 and 24 were generated, in which only one of the two benzylic positions reacted. The biphenyl diacetate 25 and several heteroaromatic products 26–28 could also be furnished. Although acetic acid is the most convenient oxygen donor, alternative esters 29 and 30 could also be accessed using formic or propionic acid and anhydride. Interestingly, for product, 29 the major isomer was syn.

In addition to unbranched substrates, benzylic-branched substrates readily participated in the transformation with the use of a weaker acid (TFA). Thus, product 31, derived from cumene, and its halogenated analogue, 32, were generated in 72% and 92% yields, respectively. The presence of oxidatively sensitive benzylic trifluoroacetamide or alcohol functionality proved compatible, leading to adducts 33 and 34 in good yields. Diarylethane substrates also reacted efficiently to furnish products 35 and 36. Interestingly, the reaction does not appear to favor tertiary over primary benzylic C–H bonds. When p-cymene was subjected to the reaction conditions, nearly equal quantities of 37 and 38 were produced. Furthermore, a substrate with two inequivalent sites for the β-C–H oxygenation led to both 39 and 40 in nearly equal quantities. On the other hand, a β-branched substrate led to 41 exclusively. Meanwhile, a cycloalkane substrate led to the formation of products 42 and 43 in 36% combined yield. We also observed that certain heteroaromatic substrates could also be generated by these reactions (44–49).

To our knowledge, there is no report of a contiguous C–H trioxygenation within a single reaction flask. Along these lines, we hypothesized that our proposed mechanism could be extended to provide the first example of this elusive transformation. Thus, because an E₁-type elimination is believed to be a key step in this chemistry, we speculated that branched substrates, which are more capable of ionization than unbranched substrates, might be prone to further oxidation after the initial dioxygenation reaction. In practice, we found that by using the stronger TfOH acid with this class of substrates, we were able to achieve a third C–H oxygenation, thus leading to a novel trioxygenation of three contiguous C–H bonds (Fig. 3).

Fig. 3. Electrophotocatalytic vicinal C–H trioxygenation.

^a See the supplementary materials for detailed reaction conditions for each substrate. Unless otherwise specified, the major isomer was anti. ^b worked up with Na₂CO₃(aq.) / CH₃OH; ^c syn product was major.

A range of substrates proved amenable to this transformation. For example, cumene was converted to triacetate 50 in 61% yield, and halogenated cumenes furnished triacetates 52–54. The latter proved amenable to a preparative scale reaction (1.86 g). Products with electron-donating (54-55) or electron-withdrawing (56) substituents could be accessed in modest yields. Interestingly, p-cymene, which led to a mixture of products with TFA as the acid (see Fig. 2), produced a good yield of triacetate 57 (51%) in the presence of TfOH. Similarly, product 58 bearing a potentially acid-labile tert-butyl substituent was isolated in 37% yield. Oxidation of 1,1-diphenylethane led to the formation of triacetate 59 resulting from double oxygenation of the methyl group. We also explored the reaction of alkyl groups beyond isopropyl. For example, trioxygenated products derived from 2-butyl- (60), 3-pentyl- (61), and 4-heptylbenzene (62) were produced in modest to good yields, as was the p-bromophenyl product, 63. The presence of tethered carbomethoxy, alkyl bromide, and acetoxy groups leading to products 64–66 proved feasible. In addition, a cyclic substrate was converted to adduct 67 in 44% yield. Meanwhile, we found that 1,4-diphenylbutane underwent a 1,2,3-triacetoxylation reaction to furnish 68 in 33% yield. We also examined reactions of heteroaromatic compounds, including pyridine (69), benzofuran (70), furan (71 and 72), thiophene (73-75), acridine (76) and coumarin (77). Such compounds could be trioxygenated—and in some cases even tetraoxygenated (72, 74, and 75).

Although arene rings are commonplace in organic molecules and thus provide a useful handle to initiate this oxygenation chemistry, we sought to expand the utility of this strategy by exploring alternative redox-active substituents. Toward this end, we found that trifluoroacetamides could also undergo multiple vicinal C–H oxygenations (Fig. 4A).³⁷ For example, piperidine trifluoroacetamide 78 was converted to triacetate 79 in 56% yield as a 10:1:0.6 mixture of diastereomers. The major stereoisomer was cis, trans as confirmed by single crystal X-ray analysis. Moreover, 4-alkylated piperidine derivatives 80–83 could be generated with good diastereoselectivity, preferentially as the trans, trans isomers. Meanwhile, triacetates 84 and 85 were formed in which the more substituted α-carbon remained untouched. Remarkably, X-ray analysis revealed an all cis stereochemistry for the major isomer of 84. These compounds are examples of azasugars, analogues of monosaccharides in which the ring oxygen has been replaced with a nitrogen atom. Many azasugars occur naturally and are of therapeutic interest in part because they operate as glycosidase inhibitors.³⁸ A bicyclic trifluoroacetamide was trioxygenated on the less-substituted positions of the nitrogen ring, leading to adduct 86 in 44% yield and 16:1 diastereoselectivity. Substrates without a γ-C–H bond led to the formation of diacetates 87 and 88, with little stereochemical preference. On the other hand, pyrrolidine trifluoroacetamide, which has γ-C–H bonds, led only to diacetate 89. Finally, reaction of an acyclic substrate furnished diacetate 90 in 43% yield.

Fig. 4. Vicinal C–H di- and trioxygenation of trifluoroacetamides and synthetic applications of electrophotocatalytic multiple adjacent C–H oxygenations.

(A) Di- and trioxygenation of trifluoroacetamides. (B) Di- and trioxygenation of bioactive compound analogues. See the supplementary materials for detailed reaction conditions. tBu, tert-butyl; Ac, acetyl.

To further demonstrate the utility of this novel peroxygenation chemistry, we applied it to the derivatization of a series of more complicated biologically-relevant structures (Fig. 4B). Under our standard conditions, we achieved facile dioxygenation of the flavor and fragrance agent celestolide, furnishing analogue 91 in 82% yield on small scale, or 69% yield on a larger scale (2.5 g, 10 mmol). Moreover, analogues of the sigma (σ)-receptor agonist 92³⁹ and a fluorobiphenyl structure related to the nonsteroidal anti-inflammatory drug flurbiprofen 93 were generated with this procedure. In addition, compounds 94 and 95, representing di- and tri-oxygenated analogues of a retinoic acid receptor agonist⁴⁰ were obtained in synthetically useful 58% and 41% yields, respectively. Interestingly, when substrate 96, a modified version of the antidepressant drug sertraline underwent a 12-electron oxidation, giving rise to the diacetate ketone 97 in 47% yield. Additionally, 8-, 10-, and 12-electron oxidations were realized, with the formation of tetra-, penta-, and hexa-acetate products 98–100 respectively.

Achieving multiple contiguous C–H oxygenations in a single operation can help to streamline the synthesis of complex molecules. For example, the antifungal agent genaconazole (103) is known to be accessible from 102, which was itself prepared from difluoroacetophenone 101 in 8 steps and 8% overall yield (see supplementary materials).⁴¹ Under our trioxygenation procedure, we were able to prepare 102 from 101 in just 3 steps with 44% overall yield. In addition, we have demonstrated that the azasugar derivative 105, a late-stage intermediate en route to glycosidase inhibitor 106, can be synthesized in a single electrophotocatalytic step from piperidine 104 (R = COCF₃). The previous route from 104 to 105 (R = CO₂Me) required five separate steps.⁴² Similarly, an intermediate in the synthesis of vanilloid receptor ligands, which was previously prepared over 5 steps in 11% yield from p-nitrophenylacetic acid,⁴³ has been synthesized from 4-isopropylaniline in only three steps and 42% overall yield using the trioxygenation procedure. Additional examples and mechanistic studies are included in the supplementary materials. These sequences highlight the dramatic improvements in synthetic efficiency that can be realized through installation of several functional groups via concurrent functionalization of multiple C–H bonds.

Data Availability.

The data supporting the findings of this study are available within the paper and its Supplementary Information.