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Decarboxylative oxidation-enabled consecutive C-C bond cleavage

The selective cleavage of C-C bonds is of fundamental interest because it provides an alternative approach to traditional chemical synthesis, which is focused primarily on building up molecular complexity. However, current C-C cleavage methods provide only limited opportunities. For example, selective C(sp3)-C(sp3) bond cleavage generally relies on the use of transition-metal to open strained ring systems or iminyl and alkoxy radicals to induce β-fragmentation. Here we show that by merging photoredox catalysis with copper catalysis, we are able to employ α-trisubstituted carboxylic acids as substrates and achieve consecutive C-C bond cleavage, resulting in the scission of the inert β-CH2 group. The key transformation relies on the decarboxylative oxidation process, which could selectively generate in-situ formed alkoxy radicals and trigger consecutive C-C bond cleavage. This complicated yet interesting reaction might help the development of other methods for inert C(sp3)-C(sp3) bond cleavage.

The art of making and breaking bonds has been the driving forces of innovation for chemists [1][2][3] . It is also the basis of metabolism, enzymology, and biochemistry as a whole 4 . In this context, the cleavage of C-C bonds is of fundamental interest for chemists because it provides an alternative approach to traditional chemical synthesis, which is focused primarily on building up molecular complexity 5,6 . The oxidative cleavage of alkyl aromatics could also lead to the selective degradation of polystyrene related plastics and generate high-value chemicals from abundant polystyrene wastes [7][8][9] . Despite many impressive advances in this field, the cleavage of inert C(sp 3 )-C(sp 3 ) bonds and their subsequent functionalization is still one of the most sought-after challenges in chemistry 10 . Generally, the known strategies for C(sp 3 )-C(sp 3 ) bond cleavage could be divided into two classes. One focuses on the strained ring systems employing transition-metal-catalyzed processes that are triggered by C-C bond activation and β-carbon elimination 11,12 . Another process exploits the chemistry of iminyl and alkoxy radicals because of their abilities to break into an alkyl radical species and an unsaturated fragment through β-fragmentation [13][14][15] . Recently, the group of Sarpong developed the first homolytic C-C bond cleavage method for the deconstructive diversification of cyclic amines mediated by a silver salt by breaking one C(sp 3 )-C(sp 3 ) bond through an in-situ installed hydroxyl group ( Fig. 1) 16,17 . Acids are inexpensive, highly stable, and readily available compounds. Decarboxylation enabled C(sp 2 )-C(sp 3 ) and C(sp 2 )-C(sp 2 ) bond cleavage has been employed for many useful transformations [18][19][20][21][22][23][24] . However, little studies have been performed using acids as potential substrates for C(sp 3 )-C(sp 3 ) bond cleavage.
We propose to generate peroxyl radicals through the decarboxylative oxidation process [25][26][27][28][29] . We anticipate the photoredox decarboxylation of α-trisubstituted acid I would produce tertiary radical II which could trap oxygen to create the in-situ formed peroxyl radical III. This peroxyl radical then collapses to deliver the radical species IV through fragmentation. A few more oxidative transformations from IV will provide the final product VI.
Here we show, by merging photoredox catalysis with copper catalysis, we are able to use α-trisubstituted acids as substrates and employ a decarboxylative oxidation process to achieve consecutive C-C bond cleavage, resulting in the complete scission of the inert β-CH 2 group.
We also evaluated this method with β-hydroxy acids (Fig. 5). Interestingly, the C-C cleavage tended to happen at the α-β position, probably because the radical intermediates were stabilized by the βhydroxy group. Thus, diketones were usually provided as the main products. For substrates which contain tertiary β-hydroxy groups (Fig. 5, substrates 38a-40a), the products were isolated in good yields. However, substrates with secondary β-hydroxy groups delivered the products only in moderate yields (Fig. 5, substrates 41a-42a). For substrate 43a, the C-C cleavage happened at both sides with about 3:1 ratio.      Based on our proposed mechanism (Fig. 1), radical intermediate IV was formed during the process. To capture this intermediate, we tried to add additives. Eventually, we found the addition of Selectfluor successfully delivered ketone-alcohol as the main product. Thus, under the optimized condition, cyclobutanecarboxylic acid substrates provided 4-hydroxybutyrophenones in good yields (Fig. 6, substrates 44a-46a).
This reaction provides a direct method to construct different diketones, which are versatile building blocks in the synthesis of natural products and bioactive compounds. Thus, we performed the synthesis of Primaperone, Melperone and Haloperidol (Fig. 7). These drugs could be accessed in one step from product 12b via reductive amination in good yields. We also did late-stage modification of commercial drug and complex natural products. For Sertraline derivative 54a, the reaction worked smoothly and the product was isolated in 83% yield. For steroids 55a and 56a, the regioselectivities were good and we only isolated one product. However, the reactions were sluggish and much of the starting materials were recovered.
To better understand the mechanism, we did control experiments (Fig. 8). First, when substrate 15a was evaluated under the reaction condition, compound 15c was isolated as a byproduct in 31% yield. However, when 15c was submitted to the reaction condition, no 15b was formed, which clearly indicates 15c is a by-product, not a reacting intermediate. We did Stern-Volmer experiments and found out the acid 1a could quench the photocatalyst under basic condition. We also found that no reaction happened when compound 57 was treated with the standard condition. These observations clearly demonstrated that photocatalytic decarboxylation was the initial step and the key to induce the consecutive C-C bond cleavage. We also synthesized aldehyde 58a and 59a. When aldehyde 58a was reacted under standard condition, product 58b was formed and we observed the formation of formaldehyde 33 . When 59a were treated with copper, base and O 2 , we were able to isolate one carbon shorter products 59b 30 .
Based on the above experiments and literatures [29][30][31][32][33][34] , especially the recent publication by Xia 31 , we propose a plausible mechanism as shown in Fig. 9. Photocatalyzed decarboxylation of substrate 15a provides radical A, which is captured by oxygen to generate peroxyl radicals B. Intermediate B might form the dioxetane intermediate C

Discussion
In conclusion, we have successfully developed consecutive C-C bond cleavage by taking the advantages of photoredox catalysis along with copper catalysis. This complicated process exploits the use of stable αtrisubstituted acids as substrates and efficiently breaks three C-C bonds at the same time. The key transformation features a   decarboxylative oxidation process to generate the in-situ formed alkoxy radical which could trigger fragmentation and the following oxidation process. We believe this finding might shed light on the development of other methods for inert C(sp 3 )-C(sp 3 ) bond cleavage.

Methods
General procedure for consecutive C-C bond cleavage products To a 50 ml round bottomed flask equipped with a magnetic stirrer bar were added acid (0.5 mmol, 1.0 equiv.), Ir-1 or Ir-2 (0.015 mmol, 0.03 equiv.), Cu(OAc) 2 (18.1 mg, 0.1 mmol, 0.2 equiv.), 2,2′-bipyridine (19.5 mg, 0.125 mmol, 0.25 equiv.), Cs 2 CO 3 (245 mg, 0.75 mmol, 1.5 equiv.) and DCM (10 mL). The flask was quickly degassed three times and flushed with oxygen through balloon, and then the mixture was heated to 30°C in an oil bath and irradiated with three 45 W blue LEDs (5 cm away) for 40 h or 72 h. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica with petroleum ether/ethyl acetate mixture as the eluent.

Data availability
Materials and methods, optimization studies, experimental procedures, mechanistic studies, 1 H NMR spectra, 13 C NMR spectra and mass spectrometry data generated in this study are provided in the Supplementary Information file.