Controlled Oxygenation of Multiple Contiguous C–H Bonds via Electrophotocatalysis


 Chemical reactions that directly convert carbon-hydrogen (C–H) bonds to carbon-oxygen (C–O) bonds provide a powerful means to rapidly synthesize valuable organic compounds. However, achieving multiple C–H bond oxygenation reactions at the same time is challenging, particularly because of the risk of overoxidation. Here, we report the selective oxygenation of two or three contiguous C–H bonds, enabling the conversion of simple alkylarenes to diols, triols, or their corresponding acetates. The reactions are achieved using electrophotocatalysis—a process that utilizes both light and electricity to activate a single catalyst—to promote the oxidation reactions. The rapid increase in molecular complexity achieved by these multiple oxygenations enables the synthesis of some compounds of pharmaceutical interest by dramatically shorter sequences than previously achieved.

could outcompete the nitrile solvent, or the use of a different solvent altogether; however, the feasibility of such a process was not at all obvious. Here, we report that TAC electrophotocatalysis can in fact achieve the controlled oxygenation of multiple contiguous C-H bonds using simply a mixture of acetic acid and acetic anhydride as the oxygen source (Fig. 1D).
A mechanistic rationale for this process is shown in Fig. 1E. The TAC cation (TAC + ) can be 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 react with 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 an alkylarene substrate 1 via single electron transfer (SET) to generate radical cation 2, which under the conditions leads to loss of a proton and further oxidation to produce benzylic carbocation 3. Capture of 3 with a nucleophile such as acetic acid (AcOH) then furnishes the mono C-H-oxygenated intermediate 4. In the presence of a Brønsted acid, 4 can undergo a reversible E 1 -type elimination to generate the styrene 5 (5 could also be formed directly from 3). The styrene 5 is susceptible to further EPC-oxidation by TAC ·2+* , leading to radical cation 6 that can be again captured by acetic acid, 20 this time at the non-benzylic carbon. Subsequent oxidation of the resulting radical 7 with anchimeric trapping by the acetate group leads to cation 8, which is highly susceptible to destructive opening by acetic acid to produce 9. ( These conditions effected the vicinal C-H dioxygenation of substrates bearing a range of functionality (Fig. 2). For example, ethylbenzene was converted to diacetate 10 in 58% yield. For some substrates, a higher yield was obtained with a hydrolytic workup to furnish a 1,2-diol product such as 11. As with most substrates, the diastereomeric ratio (dr) favored the anti isomer, but in this case only by a 2.9:1 ratio. Similarly, the dihydroxylation of n-pentylbenzene furnished a 1,2-diol 12, a product that is a known precursor to a BACE2 inhibitor. 37 Interestingly, product 13 bearing a longer alkyl chain was generated in higher yield. Diol products 14 and 15 bearing bromo or chloro substituents on the arene were generated with good e ciency, with the former being isolated in higher yield but the latter with higher diastereoselectivity. Meanwhile, a tri uoroacetamide substituent was accommodated in the formation of 16 in good yield, but with a nearly completely eroded dr. When 4-ethyltoluene was subjected to the reaction conditions, adduct 17, in which the ethyl group was vicinally dioxygenated and the methyl group was geminally dioxygenated, was isolated in 44% yield. Products 18-24 demonstrate some of the breadth of functional group compatibility of this reaction, including alkyl halide (18), acetoxy (19), carbomethoxy (20), imide (21), alcohol (22), carboxylic acid (23), and amino (24) substituents. The carbomethoxy group resulted in the preferential formation of the syn diastereomer 20, whereas the presence of a free carboxylic acid resulted in lactone product 23. The dimethylamino group apparently slows the reaction rate considerably, since the diacetate 24 was isolated in only 22% yield while the monoacetate product, which we presume is a precursor to 24, was formed in 45% yield. The amino group would certainly be protonated under the reaction conditions, and it is likely that the strongly electron-withdrawing ammonium group destabilizes the putative cationic intermediates of the dioxygenation mechanism. Substrates in which both of the vicinal C-H bonds were benzylic also proved viable, including 1,2diphenylethane and dibenzosuberone which were converted to diol 25 and diacetate 26 respectively in modest yields. On the other hand, adducts 27 and 28 were generated in which only one of the two benzylic positions reacted. Although the biphenyl moiety can sometimes be problematic under strongly oxidizing conditions, diacetate 29 was generated in modest yield. In addition to substituted benzenes, we found that alkylated thiophenes were also viable substrates. As well as undergoing the vicinal dioxygenation reaction, under the standard conditions the 5-position of the thiophene was also acylated, leading to products 30 and 31.
Although acetic acid and acetic anhydride are the most readily available and convenient oxygen donors for this reaction, we found that alternative ester products 32 and 33 could also be generated through the use of propionic or formic acid/anhydride respectively. Interestingly, for 33 the major isomer was syn.
In addition to unbranched substrates, benzylic-branched substrates also worked well, often in high yields.
These substrates required the use of a less potent acid, TFA, than the unbranched substrates. Thus, the product 34 derived from cumene and the halogenated analogue 35 were generated in 72% and 92% yields respectively. The heterocyclic product 36 bearing a thiazole ring was isolated in 44% yield. The presence of benzylic tri uoroacetamide or alcohol functionality, which might have been oxidatively sensitive, nevertheless proved compatible with the formation of adducts 37 and 38 in good yields (the alcohol group was acylated under the reaction conditions). When p-cymene, with its competing isopropyl and methyl benzylic sites, was subjected to the reaction conditions, a nearly equal mixture of 40 and 41 were produced, with no product resulting from oxygenation of both sites identi ed. Furthermore, a substrate with two inequivalent sites for the non-benzylic C-H functionalization led to both 42 and 43 in nearly equal quantities. On the other hand, a b-branched substrate led to 39 exclusively, likely due to conformational considerations. A 1,1-diarylethane was dioxygenated in good yield to furnish 44. Finally, a cycloalkane substrate, cyclohexylbenzene, led to the formation of products 45 and 46 in 36% combined yield; the modest yield in this case may be due to the competing formation of biphenyl.
Because an E 1 -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 fact, we found that using the stronger TfOH acid with this class of substrates enabled a third C-H oxygenation, thus leading to a trioxygenation of three contiguous C-H bonds (Fig. 3). For example, cumene was converted to triacetate 47 in 61% yield under the modi ed conditions. As noted above, some reactions bene ted from a hydrolytic workup, such as for the production of m-bromocumene-derived triol 48, which was produced in 76% yield. Both p-iodoand pbromocumene also participated in this reaction to furnish triacetates 49 and 50 respectively. The latter was also amenable to a preparative scale reaction (1.86 g). Products with electron-donating acetoxy (51) or tri uoroacetamido (52) substituents or an electron-withdrawing acyl group (53) could also be accessed in modest yields. Interestingly, p-cymene, which led to a mixture of products (40 and 41) with TFA as the acid, produced a good yield of triacetate 54 (51%) with TfOH. Similarly, product 55 with electron-donating tert-butyl substituent was isolated in 37% yield. 1,1-Diphenylethane led to the formation of triacetate 56 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-(57), 3-pentyl-(58), and 4heptylbenzene (59) were produced in modest to good yields, as was the p-bromophenyl product 60. The presence of tethered carbomethoxy, alkyl bromide, and acetoxy groups leading to products 61-63 proved feasible. Finally, a cyclic substrate, phenylcycloheptane, was converted to adduct 64 in 44% yield.
Interestingly, for alkyl groups larger than isopropyl, the benzylic position was substituted with hydroxy group instead of OAc group, perhaps due to steric hindrance.
To further demonstrate the utility of this chemistry, we investigated its application to some more complicated structures (Fig. 4). For example, this procedure was employed to dioxygenate the avor and fragrance agent celestolide, furnishing analogue 65 in 82% yield on small scale or 69% yield on a larger scale (2.5 g, 10 mmol) with inexpensive Ni plate as cathode. Analogues of a s-receptor agonist 66 38 and a uorobiphenyl structure related to the nonsteroidal anti-in ammatory drug urbiprofen 67 were generated with this procedure. In addition, analogues of a retinoic acid receptor agonist 39 using either the dioxygenation (68) or the trioxygenation (69) procedures were generated in 58% and 41% yields respectively. When a modi ed version 70 of the antidepressant drug sertraline was subjected to these conditions, a 12-electron oxidation occurred, giving rise to the diacetate ketone 71 in 47% yield.
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 (76) was previously synthesized from 75, which was prepared from di uoroacetophenone 74 in 8 steps and 8% overall yield ( Fig. 4B) 40 . We have used the trioxygenation procedure to prepare 75 in only three steps from 74 in 44% overall yield. Similarly, an intermediate 78 on the way to vanilloid receptor ligands, which was previously prepared over 5 steps in 11% yield from p-nitrophenylacetic acid (77) 41 , has been synthesized from 4isopropylaniline (79) in only three steps and 42% overall yield using the trioxygenation procedure.
Additionally, cytosporanone and intermediate for inhibitors of HIV-1 protease were also e ciently produced using the current method (see supplementary materials). These sequences underscore the notion that installing several functional groups by the concurrent functionalization of multiple C-H bonds can lead to dramatic improvements in synthetic e ciency.
Oxygen-containing functional groups are nearly ubiquitous in complex small molecules. The direct installation of C-O bond functionality by the oxygenation of C-H bonds offers a powerful means to install these moieties, and it is no coincidence that this is a strategy employed by both Nature and chemists alike. Nevertheless, the installation of multiple C-O bonds at the same time in a selective fashion has been largely the purview of biosynthesis. The current method achieves such transformations by the repeated operation of a potent oxidative catalyst, but under conditions that are selective enough to avoid destructive overoxidation. This method thus further expands the power of direct C-H functionalization strategies for complex molecule synthesis.

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