Cross-double carbon-carbon cleavage coupling of ketones via oxidative SH2 homolytic substitution

Cross-double carbon-carbon cleavage coupling of ketones via oxidative SH2 homolytic substitution | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Cross-double carbon-carbon cleavage coupling of ketones via oxidative SH2 homolytic substitution Heng Jiang, Jian-Xiong Yang, Meng-Yao Zhang, Qi Wen, Jia-Run Wang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7421874/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Mar, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract The α-C-C cleavage coupling of ketones offers a highly challenging yet promising approach for C–C bond formation, particularly given the ubiquity and ready accessibility of ketones as fundamental synthons in organic synthesis. However, the deacylative cross-coupling between two distinct ketones via a single activation mode remains an unmet challenge, although this coupling paradigm could be leveraged to construct C(sp 3 )–C(sp 3 ) linkages with exceptional structural diversity. Herein, we describe a cross-ketone deacylative coupling via nickel-catalyzed bimolecular homolytic substitution (S H 2), in which the synergistic oxidative photocatalysis is combined to produce simultaneously two distinct open-shell carbons from ketone-derived dihydroquinazolinones. This heteroselective radical-radical coupling protocol enables the construction of quaternary carbon centers through a critical S H 2 displacement mechanism, providing an efficient approach to furnish β-quaternary aliphatic amines. Additionally, a wide array of biorelevant small molecules, including β-amino alcohol, β-diamine and β-aminothiol derivatives, could also be obtained via this cross-double deacylative C 1 -alkylation approach between distinct ketones. Physical sciences/Chemistry/Catalysis/Photocatalysis Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology Physical sciences/Chemistry/Photochemistry/Photocatalysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Among numerous native functional groups, ketones hold a privileged position owing to their unparalleled abundance, structural diversity and versatile synthetic accessibility. 1 It is well-known that ketones participate extensively in a wide array of fundamental transformations centered on the carbonyl group. 2 Given broad utility as native functional groups, the bimolecular reactions between ketones would serve as a practical strategy for C-C bond formation with both high modularity and diversity (Fig. 1 a). This perspective is well-substantiated by the aldol reactions between two ketones, a class of text-book transformations for the construction of β-hydroxy ketones. 3 Furthermore, metal-mediated reductive coupling of ketones, encompassing both the McMurry reaction and pinacol coupling, are also well-established coupling protocols for the production of alkenes and vicinal alcohols, respectively. 4 – 5 However, the necessity for stoichiometric amount of reducing metal reagents coupled with the inherent challenge for heteroselective control significantly limit their broad utility. Despite these notable achievements, the single-functional group cross-coupling of ketones to serve as a general synthetic platform for modular construction of C(sp 3 )-C(sp 3 ) bond linkages has remained elusive to date. With the advances of ketone C-C activation during recent years, 6 – 8 we envisioned that the transition metal-catalyzed cross-ketone deacylative coupling is an unknown yet viable approach to enable the heteroselective C(sp 3 )-C(sp 3 ) bond formation (Fig. 1 b). The critical challenge lies primarily in the difficulty to devise a catalytic system capable of simultaneously cleaving the α-C-C bonds of both ketones through a single activation mode and mediating fragment-recombination in a precise heteroselective control. 9 – 11 Moreover, the construction of all-carbon quaternary centers via this coupling paradigm is still challenging, 12 – 15 although it would be attractive due to the importance of this structural motif in medicinal chemistry. 16 – 17 We sought to achieve the cross-double deacylative coupling between distinct ketones through open-shell mechanism, 18 – 25 involving hetero-dimerization of short-lived alkyl radicals generated through homolytic C-C activation (Fig. 1 c, left). 26 Clearly, the frequently encountered competing pathways including radical homocoupling and H atom abstraction must be rigorously suppressed to ensure the heteroselective coupling outcome. 26 – 27 As such, the bimolecular homolytic substitution (S H 2) of transition-metal complexes, an outer-sphere coupling process operating through the open-shell displacement mechanism, was considered to serve as an ideal scenario for the cross-ketone deacylative coupling protocol (Fig. 1 c, left). 28 – 32 This speculation was inspired by the pioneering reports of MacMillan, 33 – 38 Shenvi 39 – 41 among others on transition metal-catalyzed S H 2 reactions, 42 – 50 including single-functional group cross-coupling of native functionalities such as carboxylic acids and alcohols. 33 – 34 , 50 Accordingly, in our proposed cross-ketone deacylative coupling protocol, two distinct open-shell carbons generated through homolytic α-C-C cleavage of ketones perform different functions. More specifically, the metal catalyst would preferentially capture the less sterically hindered open-shell primary carbon, forming a relatively stable alkyl-metal complex with higher bond dissociation energy (BDE). 51 Meanwhile, the sterically congested secondary or tertiary alkyl radical generated from another ketone features with favorable SOMO nucleophilicity, 52 thereby poised to undergo S H 2 displacement to forge the cross-coupling product. It is well-known that photo-induced Norrish Type I reaction of ketones would enable a direct access to produce alkyl radicals through homolytic α-cleavage of ketones. 53 However, the concomitant generation of acyl radicals is considered detrimental to the desired heteroselective fragment coupling process. As such, we sought to use the heterocyclic pre-aromatic intermediates (PAIs) to serve as alkyl radical precursors, 54 – 61 given prior demonstrations that they can be readily obtained from ketones through a simple condensation step and are competent to produce alkyl radicals through redox-triggered fragmentation, with concomitant formation of a sacrificial aromatic heterocycles. Among diverse PAIs, dihydroquinazolinone (DHQ) skeletons were identified as particularly feasible masked ketones in our S H 2 coupling protocol, owing to the advantages that they can be modularly synthesized, and the aromatic quinazolinone released as a byproduct during β-scission step poses no interfere with the metal catalyst (Fig. 1 c, left). 62 – 72 Taken these considerations into account, we endeavored to develop the first example of cross-dual C-C cleavage coupling between distinct ketones, enabling the molecular construction of C(sp 3 )-C(sp 3 ) linkages via transition metal-catalyzed S H 2 homolytic substitution (Fig. 1 c, left). The DHQs obtained from aminoacetone or acetol precursors could generate primary alkyl radicals, a kind of reactive intermediates that would bind to the nickel catalyst. Subsequent S H 2 displacement by sterically congested tertiary alkyl radicals stemming from α-quaternary ketones facilitates the modular assembly of primary amines, ethers and thioethers containing β-all-carbon quaternary centers, which are biologically relevant scaffolds for the medicinal chemistry research (Fig. 1 c, right). 73 – 74 Moreover, we also devoted to achieve the heteroselective coupling of distinct α-amino alkyl fragments with subtle steric disparities, enabling efficient synthesis of β-amino alcohol and β-diamine derivatives through the cross-ketone deacylative coupling protocol. (Fig. 1 c, right). Results Reaction condition optimization We focused our initial exploration on the cross-deacylative coupling of α-quaternary methyl ketone 1a with α-amino acetone derivative 1b , motivated by the prevalence of primary amines bearing β-quaternary center motifs in bioactive molecules (Table 1 ). Building upon our previous studies, 69 we first examined the DHQs 2a and 2b in this coupling protocol. Notably, these DHQ precursors are bench-stable and can be purified by operations of both column chromatography and recrystallization. After a systematically evaluation of photosensitizers, nickel catalysts and oxidants, we were pleased to discover that the reaction of DHQs 2a and 2b in the presence of 2,4,5,6-tetrakis(9 H -carbazol-9-yl)isophthalonitrile (4CzIPN), Ni(acac) 2 , dibenzoyl peroxide (Bz 2 O 2 ) and 2,4-pentanedione (Hacac) delivered desired cross-coupling product 3a in a satisfactory yield (92%) under blue LED irradiation (entry 1). Other ketone-derived PAIs that are capable of producing alkyl radicals through oxidative aromatizaiton, such as benzothiazoline 2c , benzoimidazoline 2d and methyl substituted DHQ 2e , proved ineffective for this coupling protocol (entries 2–4). Diminished reaction performance was observed with sterically encumbered nickel salts, such as Ni(THMD) 2 and the K[Tp*]-ligated nickel catalyst (entries 5 and 6). 33 Suprisingly, Fe(OEP)Cl as an analogue of porphine-Fe(III) is impotent to trigger the coupling process, even it has demonstrated an exceptional efficacy in several outer-sphere cross-coupling reactions (entry 7). 35 While dibenzoyl peroxide remains the optimal oxidant, other commercially available oxidants (e.g., LPO and TBPB) are also applicable, albeit with diminished yields (entries 8 and 9). Control experiments confirmed that the Ni(acac) 2 plays a critical role, enabling the fragment copling with exceptional heteroselectivity and surpressing side reactions such as homocoupling, hydrogen atom transfer or free radical oxidation (entry 11). The other reaction components–photocatalyst, oxidant, and light–were also demonstrated to be necessary to deliver the desired coupling product (entries 12–14). Notably, the addition of 2,4-pentanedione acetylacetone in this oxidative coupling protocol allows a reduced Ni catalyst loading, as previously demonstrated by Hartwig and co-workers (entry 15). 45 Substrate scope With optimal conditions in hand, we next sought to evaluate the scope of this cross-ketone deacylative coupling protocol, aiming to construct β-quaternary amines through cross-coupling of distinct DHQs derived from an α-quaternary methyl ketone and an α-aminoacetone (Fig. 2 ). It is important to recognize that the primary amines with β-all-carbon quaternary centers are highly desirable due to their particular biologically activities and thus have been frequently found in drug candidates. 75 However, the C 1 aminomethylation strategy to construct these privileged scaffolds remains elusive, especially started from abundant native functional handles. 76 – 78 To this end, a battery of DHQs derived from structurally diverse ketones were subjected to the standard reaction conditions. Remarkably, this coupling protocol enabled efficient cross-ketone deacylative coupling, affording β-quaternary amines with broad functional group tolerance. As illustrated in Fig. 2 , drug like structural motifs such as piperidine- and tetrahydropyran-fused amines were yielded in good yields ( 4 – 6 , 61–88% yield). In addition to tert -butyl group, a diverse array of functional groups including terminal alkenes, hydroxy groups, esters and chloro groups were also well-tolerated in this protocol ( 7 – 12 , 59–76% yield). We further examined that β-aryl ketones bearing electronically and sterically varied substituents in aryl groups proved compatible, furnishing phenylpropylamine derivatives in moderate to good yields ( 13–22 , 50–80% yield). Surprisingly, the reaction efficiency dramatically decreased using 1-adamantyl methyl ketone-derived DHQ as a coupling partner ( 23 , 26% yield). Expanding the scope further, ketones with heteroatom-containing α-quaternary centers delivered β-aminoalcohol derivatives in moderate yields ( 24 and 25 , 47 and 43% yield, respectively), further underscoring the diversity of quaternary centers that can be constructed via this cross-ketone deacylative coupling protocol. It should be noted that α-tertiary ketones are not applicable in this cross coupling protocol, likely due to the low β-scission efficiency of DHQ radical cations in generating open-shell secondary carbons. After extensive evaluations, we found that the α-amino secondary alkyl radicals coupled with the aminomethyl radical smoothly in excellent radical sorting results, providing an expedient access to construct valuable β-diamine ( 26 – 30 , 37–64% yield), β-aminoalcohol ( 31 and 32 , 42% and 57% yield, respectively) and β-aminothiol ( 33 , 50% yield) derivatives from native ketone functionalities. Intriguingly, this S H 2 protocol allows the construction of diamine derivatives via cross-coupling of dual α-amino primary alkyl radicals ( 34 – 38 , 45–58% yield). The heteroselective radical sorting result is unambiguously regulated by nickel catalyst, while the unsymmetric diamine product 35 was not formed in absence of Ni(acac) 2 . We speculated that the α-amino methylene radicals bearing sterically slightly congested tertiary amidyl groups poised to undergo S H 2 displacement rather than coordinating with the nickel catalyst. Notably, the radical sorting outcome is enhanced in this reaction system between benzylic and α-amino primary radicals ( 38 and 39 , 45 and 54% yield, respectively), whereas the homocoupling products of benzylic radicals are dominated in absenece of the nickel catalyst. Next, we sought to evaluate the scope of DHQs that derived from α-secondary methyl ketones as C 1 -alkylating coupling partners in this cross-ketone deacylative coupling protocol (Fig. 3 ). Both benzoxycarbonyl- (Cbz) and acetyl-protected α-amino ketones gave satisfactory yields comparable to that obtained with t -butyloxycarboryl (Boc) protecting group ( 40 and 41 , 78 and 72% yield, respectively). DHQs derived from ketones bearing α-tertiary amidyl groups also engaged in this coupling protocol, in which a diverse array of substituents on amino group were tolerated, including alkyl groups, amides and ethers ( 42 – 47 , 33–82% yield). Additionally, α-amino primary radicals bearing benzylamine and aniline motifs could also be cross-coupled with tertiary carbon radicals, delivering β-quaternary amine derivatives in good yields ( 48 – 54 , 46–69% yield). The β-quaternary-benzamides ( 56 – 58 , 45–65% yield), -alkylamides ( 59 , 40% yield) and -phthalimides ( 60 , 36% yield) were also achieved using corresponding DHQs for C 1 -aminomethylation. Finally, this coupling protocol also allows for deacylative C 1 -alkoxymethylation, producing a variety of β-quaternary ethers ( 61 – 64 , 52–58% yield), β-aminoalcohols ( 65 and 66 , 73 and 47% yield, respectively) and 1,2-dialcohols ( 67 , 45% yield) that are structurally useful for further medicinal and biological research. 79 Having evaluating the scope of ketones, we attempted to apply this single-functional group cross-coupling methodology to the late-stage modification (LSF) 80 of bioactive molecules bearing common functionalities that can be readily converted to ketones, such as carboxyl, halide and hydroxy groups (Fig. 4 ). To this end, ketone analogues derived from Gemfibrozil and Ciprofibrate underwent efficient deacylative aminomethylation, yielding structurally diversified drug analogues suitable for further medicinal exploration ( 68 and 69 , 72 and 74% yield, respectively). Similarly, 3-aminopropyl ester derivatives incorporating core structural motifs of drug molecules, including Sulbactam acid, Oxaprozin, Febuxostat, Indomethacin and Isoxepac, were successfully obtained via this cross-ketone deacylative coupling protocol ( 70 – 74 , 36–47% yield). The piperidine derivative with a Naproxen core was obtained in highly efficiency ( 75 , 59% yield). Further, this method also enables the preparation of diverse β-amino alcohol derivatives—longstanding as a privileged structural motif in medicinal chemistry—from phenol-containing drug molecules such as Tyramine and Acetaminophen ( 76 and 77 , 63 and 66% yield, respectively). The α-quaternary ketone derived from Melonal also engaged in this coupling protocol, providing β-quaternary amine product in a moderate yield ( 78 , 52% yield). Noteworthy, the late-stage functionalization of amino-containing pharmaceuticals such as Mexiletine was also accomplished via S H 2 coupling of distinct DHQs derived from amino ketones ( 79 , 63% yield). These LSF results evidently highlight the broad applicability of this strategy in rational drug design and diversification. Mechanistic studies and proposed reaction mechanism Preliminary mechanistic studies have been conducted to investigate the details of the deacylative cross-coupling reaction. The coupling process was completely suppressed upon addition of TEMPO, with trapping of both tertiary alkyl radical and primary α-amino alkyl radical as their corresponding TEMPO adducts ( 80 and 81 , 56 and 112% yield, respectively). These results unambiguously confirm the oxidative generation of two distinct alkyl radical species spontaneously from DHQs 2a and 2b (Fig. 5 , a). To elucidate the oxidation state of the nickel catalyst during the reaction process, 4-bromo- and 4-iodobenzonitrile were separately introduced into the model reaction as diagnostic reagents due to their known propensity to undergo oxidative addition with low-valent nickel species (Fig. 5 , b). 81 The ketone deacylative cross-coupling results were unaffected, accompanied with almost full recovery of aryl halides, indicating that there has no low-valent nickel species (Ni 0 or Ni Ⅰ ) involved in the coupling process to trigger the oxidation addition with aryl halides. These findings also reflect, on the other hand, the coupling reaction proceeds via the S H 2-mediated outer-sphere mechanism. 33 , 82 To further elucidate the mechanistic details of the oxidative coupling system, we conducted the Stern-Volmer luminescence quenching studies on photoexcited 4CzIPN using key reaction components (Fig. 5 , c). Different quenching behaviors were observed, as both DHQs 1a and 2a exhibited strong quenching effects, while the quenching process by nickel catalyst was dramatically less efficient. Notably, the oxidant Bz 2 O 2 showed no measurable quenching capability, providing direct spectroscopic evidence that both primary and tertiary radical species are produced through single-electron oxidation of DHQs by photoexcited 4CzIPN, rather than through Bz 2 O 2 -mediated pathways. Additionally, the calculated fragmentation rates for generating alkyl radicals from DHQ radical cations revealed that both tertiary and α-amino primary radicals undergo exceptionally rapid β-scission steps, several orders of magnitude faster than secondary cyclohexyl and primary propyl radicals (Fig. 5 , d). These computational results align with experimental observations, wherein both radicals must be generated at comparable rates. Otherwise, competing side reactions such as homocoupling, HAT or radical oxidation will dominate, thereby intercepting the cross-coupling pathway. The heteroselective coupling outcome is rational because the calculated BDE of the Ni-tertiary alkyl complex is remarkably lower than that of the primary counterpart (Fig. 5 , e). 83 This energy difference indicates that the primary radical preferentially combines with the metal center, during which accumulating tertiary radicals in the reaction system and poised to undergo subsequent outer-sphere S H 2 displacement. Based on the mechanistic studies and previous reports, 34 , 63 , 82 a proposed reaction mechanism is depicted in Fig. 6 . Firstly, the DHQs 2a and 2b derived from α-quaternary ketone 1a and aminoacetone 1b would be oxidized by excited photocatalyst, leading to N-centered radical cation species A and B , respectively. The reduced photocatalyst (4CzIPN –• ) concurrent generated is likely to be oxidized by Bz 2 O 2 , thereby closing the photoredox cycle. The radical cation B is not a persistent species, tend to undergo rapid and thermodynamically favorable β-scission to generate primary radical species D , which can be rapidly captured by the nickel catalyst to form persistent Ni − alkyl intermediate E . Meanwhile, the tertiary radical species C , produced through β-scission of radical cation A , would interact with Ni − alkyl complex E , delivering the desired C(sp 3 )–C(sp 3 ) coupled product 3 via S H 2 mechanism and reconstitute the nickel catalyst. Noteworthy, a wide range of substrates containing alkyl and aryl halide moieties ( 12 – 14 , 48–50 , 56 , 57 ) work smoothly in this coupling protocol, further excludes the involvement of low-valent nickel species. This mechanistic paradigm stands in sharp contrast to previously reported deacylative cross-coupling reactions of ketones that proceed through inner-sphere mechanism involving Ni(0) or Ni(I) intermediates. Discussion In summary, we have established a synergistic nickel/photoredox-catalyzed cross-deacylative coupling of ketones through an open-shell mechanism, employing dihydroquinazolinones as ketone analogs to generate diverse open-shell carbon intermediates. This operationally simple protocol enables efficient and modular construction of sterically demanding C(sp 3 )–C(sp 3 ) bonds from readily accessible ketones under exceptionally mild conditions. Mechanistic studies reveal that the nickel(II) catalyst operates through selective radical interception, facilitating C(sp 3 )-C(sp 3 ) bond formation via an outer-sphere bimolecular homolytic substitution (S H 2) pathway. The transformation demonstrates remarkable functional group compatibility and offers an expedient access to sterically congested quaternary carbon centers, showcasing potential for late-stage functionalization of complex molecules including bioactive compounds and pharmaceutical intermediates. Methods General Procedure for Cross-Ketone Decaylative Coupling A flame-dried Schlenk-tube equipped with a magnetic stir bar was charged with 2a (71.9 mg, 0.2 mmol, 1.0 equiv.), 2b (87.3 mg, 0.3 mmol, 1.5 equiv.), 4CzIPN (3.2 mg, 2 mol%), Ni(acac) 2 (5.1 mg, 10 mol%) and Bz 2 O 2 (72.7 mg, 0.3 mmol, 1.5 equiv.). EtOAc (2.0 mL) and 2,4-pentanedione (10.0 µL, 0.1 mmol, 50 mol%) were added by syringe. The tube was then purged with nitrogen for 3 minutes. The tightly sealed tube was then irradiated by a Kessil™ PR160L 456 nm blue lamp (40 W, 100% intensity) for 2 hours under stirring at room temperature. After completion, the mixture was transferred into a 100 mL separating funnel which contained 30 mL sat. NaHCO 3 . The mixture was extracted three times by ethyl acetate (15 mL for each) and the combined organic layer was washed with sat. NaHCO 3 , brine and then dried over Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 8:1) to give the cross-ketone deacylative coupling product 3 (59.8 mg, 91%) as a white solid. Declarations Data availability Data relating to the materials and methods, optimization studies, experimental procedures, mechanistic studies, NMR spectra and mass spectrometry are available in the Supplementary Information. Acknowledgements We are grateful to the financial support from the National Natural Science Foundation of China (Grant No. 22101176 to H. Jiang, Grant No. 22137003 and 22225703 to Y. 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Nature 567:373–378 Zhou X, Xu Y, Dong G (2021) Deacylation-aided C-H alkylative annulation through C-C cleavage of unstrained ketones. Nat Catal 4:703–710 Zhou X, Xu Y, Dong G (2021) Olefination via Cu-mediated dehydroacylation of unstrained ketones. J Am Chem Soc 143:20042–20048 Zhou X, Yu T, Dong G (2022) Site-specific and degree-controlled alkyl deuteration via Cu-catalyzed redox-neutral deacylation. J Am Chem Soc 144:9570–9575 Zhang Z, Zhu Q, Pyle D, Zhou X, Dong G (2023) Methyl ketones as alkyl halide surrogates: a deacylative halogenation approach for strategic functional group conversions. J Am Chem Soc 145:21096–21103 Zhou X, Pyle D, Zhang Z, Dong G (2023) Deacylative thiolation by redox-neutral aromatization-driven C-C fragmentation of ketones. Angew Chem Int Ed 62:e202213691 Zhang B et al (2024) Deacylative arylation and alkynylation of unstrained ketones. Sci Adv 10:eado0225 Li L, Fang L, Wu W, Zhu J (2020) Visible-light-mediated intermolecular radical conjugate addition for the construction of vicinal quaternary carbon centers. Org Lett 22:5401–5406 Lv X, Abrams R, Martin R (2022) Dihydroquinazolinones as adaptative C(sp 3 ) handles in arylations and alkylations via dual catalytic C-C bond-functionalization. Nat Commun 13:2394 Lv X, Abrams R, Martin R (2023) Copper-catalyzed C(sp 3 )-amination of ketone-derived dihydroquinazolinones by aromatization-driven C-C bond scission. Angew Chem Int Ed 62:e202217386 Cong F, Mega RS, Chen JH, Day CS, Martin R (2023) Trifluoromethylation of carbonyl and unactivated olefin derivatives by C(sp 3 )-C bond cleavage. Angew Chem Int Ed 62:e202214633 Wu H et al (2024) Construction of C-S and C-Se bonds from unstrained ketone precursors under photoredox catalysis. Angew Chem Int Ed 63:e202314790 Li J, Zhang D, Tan L, Li C (2024) Direct excitation strategy for deacylative couplings of ketones. Angew Chem Int Ed 63:e202410363 Li Q et al (2024) Molecular editing of ketones through N-heterocyclic carbene and photo dual catalysis. J Am Chem Soc 146:22829–22839 Yang J et al (2024) Photoexcitation of dihydroquinazolinone anionic compounds: difluoroalkylarylation and difluoroalkylamination of alkenes. CCS Chem 6:2549–2559 Miao H et al (2024) Aromatization-driven deconstructive functionalization of spiro dihydroquinazolinones via dual photoredox/nickel catalysis. Chem Sci 15:8993–8999 Lee SC et al (2022) Aromatization as an impetus to harness ketones for metallaphotoredox-catalyzed benzoylation/benzylation of (hetero)arenes. Org Lett 24:85–89 Mondal PP et al (2023) Visible-light-photocatalyzed dicarbofunctionalization of conjugated alkenes with ketone-based dihydroquinazolinones. Org Lett 25:1441–1446 Huang C, Doyle A (2015) Electron-deficient olefin ligands enable generation of quaternary carbons by Ni-catalyzed cross-coupling. J Am Chem Soc 137:5638–5641 Estrada JG, Williams WL, Ting SI, Doyle AG (2020) Role of electron-deficient olefin ligands in a Ni-catalyzed aziridine cross-coupling to generate quaternary carbons. J Am Chem Soc 142:8928–8937 Bryans JS et al (1998) Identification of novel ligands for the gabapentin binding site on the α 2 δ subunit of a calcium channel and their evaluation as anticonvulsant agents. J Med Chem 41:1838–1845 Wang K, Yu J, Shao Y, Tang S, Sun J (2020) Forming all-carbon quaternary stereocenters by organocatalytic aminomethylation: concise access to beta 2,2 -amino acids. Angew Chem Int Ed 59:23516–23520 El Khatib M, Serafim RAM, Molander GA (2016) α-Arylation/heteroarylation of chiral α-aminomethyltrifluoroborates by synergistic iridium photoredox/nickel cross-coupling catalysis. Angew Chem Int Ed 55:254–258 Zheng S, Wang W, Yuan W (2022) Remote and proximal hydroaminoalkylation of alkenes enabled by photoredox/nickel dual catalysis. J Am Chem Soc 144:17776–17782 Mayol-Llinas J, Nelson A, Farnaby W, Ayscough A (2017) Assessing molecular scaffolds for CNS drug discovery. Drug Discov Today 22:965–969 Liang Y et al (2023) Carbon-carbon bond cleavage for late-stage functionalization. Chem Rev 123:12313–12370 Diccianni JB, Diao T (2019) Mechanisms of nickel-catalyzed cross-coupling reactions. Trends Chem 1:830–844 Yuan M, Song Z, Badir SO, Molander GA, Gutierrez O (2020) On the nature of C(sp 3 )-C(sp 3 ) bond formation in nickel-catalyzed tertiary radical cross-couplings: a case study of Ni/photoredox catalytic cross-coupling of alkyl radicals and aryl halides. J Am Chem Soc 142:7225–7234 Gutierrez O, Tellis JC, Primer DN, Molander GA, Kozlowski MC (2015) Nickel-catalyzed cross-coupling of photoredox-generated radicals: uncovering a general manifold for stereoconvergence in nickel-catalyzed cross-couplings. J Am Chem Soc 137:4896–4899 Tables Table 1 is available in the Supplementary Files section. Additional Declarations There is NO Competing Interest. Supplementary Files KetKetcouplingSI.pdf Cross-double carbon-carbon cleavage coupling of ketones via oxidative SH2 homolytic substitution Table1.docx Cite Share Download PDF Status: Published Journal Publication published 19 Mar, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7421874","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":512332875,"identity":"5d10b78f-3d06-41a1-8ac3-29734f9d320c","order_by":0,"name":"Heng Jiang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYBACxmYQ0QAk2BsYDMBCB4jWwnOAweAAMVog+kBaJBKgqglpYW5nfvbw6w6bPPnI5w+KP7YxyPHdSGD8XIDXYWzmxrJn0ooNb+cYGBxsYzCWvJHALD0Dv1/MpCXbDidunJ3DANKSuOFGAhszD14t7N+AWv4nbpx5/AFISz0RWnjMJD+2HUicL8EAdliCARFayqQZ25ITN/AA/XLmnIThzDMPm6XxaTHsP75N8mebXeL89uPPDCrKbOT5jicf/IxXSwMwoEEKgNHIBox9CQZoNOEG8iAlP0CMBgbmB3iVjoJRMApGwYgFAPwWUBAkFmngAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0009-0009-1297-8106","institution":"Shanghai Jiao Tong University","correspondingAuthor":true,"prefix":"","firstName":"Heng","middleName":"","lastName":"Jiang","suffix":""},{"id":512332876,"identity":"a0310bf1-8b96-44f9-b461-7c1c6de88e4f","order_by":1,"name":"Jian-Xiong Yang","email":"","orcid":"","institution":"Nanjing University","correspondingAuthor":false,"prefix":"","firstName":"Jian-Xiong","middleName":"","lastName":"Yang","suffix":""},{"id":512332877,"identity":"c04f596f-3186-4d72-aa3c-83d8725347bc","order_by":2,"name":"Meng-Yao Zhang","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Meng-Yao","middleName":"","lastName":"Zhang","suffix":""},{"id":512332878,"identity":"2a6d7d93-f8ae-4d08-a256-95fc5204586c","order_by":3,"name":"Qi Wen","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Qi","middleName":"","lastName":"Wen","suffix":""},{"id":512332879,"identity":"be8ce16e-d8bb-4190-8b93-ded46d049328","order_by":4,"name":"Jia-Run Wang","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"prefix":"","firstName":"Jia-Run","middleName":"","lastName":"Wang","suffix":""},{"id":512332880,"identity":"e6fcc765-4dd1-470e-9e44-a773aad17aa1","order_by":5,"name":"Yan Zhang","email":"","orcid":"https://orcid.org/0000-0002-8858-8894","institution":"Nanjing University","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-08-21 03:40:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7421874/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7421874/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-026-70619-5","type":"published","date":"2026-03-19T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":91022541,"identity":"634038b3-2cad-486f-9981-070917d40a80","added_by":"auto","created_at":"2025-09-10 19:02:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":79487,"visible":true,"origin":"","legend":"\u003cp\u003e(\u003cstrong\u003ea\u003c/strong\u003e) Single functional group transformations of dual ketones: aldol reaction, pinacol coupling and McMurry reaction. (\u003cstrong\u003eb\u003c/strong\u003e) Cross-double α-C-C cleavage coupling of distinct ketones: a robust synthetic platform for (sp\u003csup\u003e3\u003c/sup\u003e)-C(sp\u003csup\u003e3\u003c/sup\u003e) bond formation but previously unknown. (\u003cstrong\u003ec\u003c/strong\u003e) This work: cross-double deacylative coupling of ketones via oxidative S\u003csub\u003eH\u003c/sub\u003e2 homolytic substitution.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7421874/v1/5f867ba06dbf4c119a3830cb.png"},{"id":91022540,"identity":"5ad64f7c-1185-4227-a20a-c99d7166fbce","added_by":"auto","created_at":"2025-09-10 19:02:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":54293,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScope of cross-ketone deacylative coupling with α-amino acetone-derived DHQ 2b.\u003c/strong\u003e The reactions were conducted at 0.2 mmol scale. Isolated yields were provided based on \u003cstrong\u003eDHQ 1\u003c/strong\u003e. \u003csup\u003ea\u003c/sup\u003eThe\u003csup\u003e \u003c/sup\u003eα-quaternary phenyl ketone instead of methyl ketone was used. \u003csup\u003eb\u003c/sup\u003eDMSO instead of EtOAc was used as a solvent. \u003csup\u003ec\u003c/sup\u003eThe yields were recorded according to \u003csup\u003e1\u003c/sup\u003eH NMR analysis.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7421874/v1/da4d22a4b7a811f281aed380.png"},{"id":91023193,"identity":"2f5f3b5d-8dd9-4b25-b881-4edcc7ba3927","added_by":"auto","created_at":"2025-09-10 19:10:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":57084,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScope of cross-ketone deacylative coupling with α-quaternary acetone-derived DHQ 2a. \u003c/strong\u003eThe reactions were carried out at 0.2 mmol. Isolated yields were provided based on \u003cstrong\u003eDHQ 1\u003c/strong\u003e. \u003csup\u003ea\u003c/sup\u003eDMSO instead of EtOAc has been used as a solvent. \u003csup\u003eb\u003c/sup\u003eIr(ppy)\u003csub\u003e2\u003c/sub\u003e(dtbbpy)PF\u003csub\u003e6\u003c/sub\u003e was used as a photocatalyst instead of 4CzIPN. \u003csup\u003ec\u003c/sup\u003eIr[dF(CF\u003csub\u003e3\u003c/sub\u003e)ppy]\u003csub\u003e2\u003c/sub\u003e(dtbbpy)PF\u003csub\u003e6\u003c/sub\u003e was used as a photocatalyst instead of 4CzIPN. \u003csup\u003ed\u003c/sup\u003eThe DHQs prepared from hydroxyacetophenone derivatives were used.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7421874/v1/1130f6cbcd2ddb6f6158e859.png"},{"id":91022545,"identity":"958056c3-4fb2-40d0-907e-802fbeba74f0","added_by":"auto","created_at":"2025-09-10 19:02:53","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":52893,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLate-stage modification of bioactive molecules.\u003c/strong\u003e The reactions were carried out at 0.2 mmol scale. Isolated yields were provided based on \u003cstrong\u003eDHQ 1\u003c/strong\u003e. \u003csup\u003ea\u003c/sup\u003eDMSO was used as a solvent and Ir[dF(CF\u003csub\u003e3\u003c/sub\u003e)ppy]\u003csub\u003e2\u003c/sub\u003e(dtbbpy)PF\u003csub\u003e6\u003c/sub\u003e was used as a photocatalyst.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7421874/v1/ce48fb648b6b856080d1774a.png"},{"id":91022547,"identity":"46e3dd5b-c3c2-4ad9-807d-78fae79cf085","added_by":"auto","created_at":"2025-09-10 19:02:53","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":65135,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMechanistic investigations.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7421874/v1/daaa83d1a2e63909f56127d1.png"},{"id":91022552,"identity":"db9fe536-53d0-4a12-8d8d-778ec85d0b9f","added_by":"auto","created_at":"2025-09-10 19:02:53","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":54104,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProposed mechanism for cross-ketone deacylative coupling.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7421874/v1/f417b8583f9016e8576c2ede.png"},{"id":109158072,"identity":"294e695c-0b6f-4507-8ed2-683184905337","added_by":"auto","created_at":"2026-05-13 07:05:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":586370,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7421874/v1/431f3b4d-ed03-4423-b3d5-953e96db2bc8.pdf"},{"id":91023527,"identity":"0831bc65-8081-45be-b36f-6283f9ab88a0","added_by":"auto","created_at":"2025-09-10 19:18:53","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29292442,"visible":true,"origin":"","legend":"Cross-double carbon-carbon cleavage coupling of ketones via oxidative SH2 homolytic substitution","description":"","filename":"KetKetcouplingSI.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7421874/v1/3e3741c3abc6582aafb6772f.pdf"},{"id":91022542,"identity":"9563eea3-8422-46a3-a5dd-bb1b9b4fc955","added_by":"auto","created_at":"2025-09-10 19:02:53","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":72845,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7421874/v1/ee17bbc476b091c894020336.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Cross-double carbon-carbon cleavage coupling of ketones via oxidative SH2 homolytic substitution","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAmong numerous native functional groups, ketones hold a privileged position owing to their unparalleled abundance, structural diversity and versatile synthetic accessibility.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e It is well-known that ketones participate extensively in a wide array of fundamental transformations centered on the carbonyl group.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Given broad utility as native functional groups, the bimolecular reactions between ketones would serve as a practical strategy for C-C bond formation with both high modularity and diversity (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). This perspective is well-substantiated by the aldol reactions between two ketones, a class of text-book transformations for the construction of β-hydroxy ketones.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Furthermore, metal-mediated reductive coupling of ketones, encompassing both the McMurry reaction and pinacol coupling, are also well-established coupling protocols for the production of alkenes and vicinal alcohols, respectively.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e However, the necessity for stoichiometric amount of reducing metal reagents coupled with the inherent challenge for heteroselective control significantly limit their broad utility. Despite these notable achievements, the single-functional group cross-coupling of ketones to serve as a general synthetic platform for modular construction of C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)-C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e) bond linkages has remained elusive to date.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eWith the advances of ketone C-C activation during recent years,\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e we envisioned that the transition metal-catalyzed cross-ketone deacylative coupling is an unknown yet viable approach to enable the heteroselective C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)-C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e) bond formation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). The critical challenge lies primarily in the difficulty to devise a catalytic system capable of simultaneously cleaving the α-C-C bonds of both ketones through a single activation mode and mediating fragment-recombination in a precise heteroselective control.\u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Moreover, the construction of all-carbon quaternary centers via this coupling paradigm is still challenging,\u003csup\u003e\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e although it would be attractive due to the importance of this structural motif in medicinal chemistry.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eWe sought to achieve the cross-double deacylative coupling between distinct ketones through open-shell mechanism,\u003csup\u003e\u003cspan additionalcitationids=\"CR19 CR20 CR21 CR22 CR23 CR24\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e involving hetero-dimerization of short-lived alkyl radicals generated through homolytic C-C activation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, left).\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Clearly, the frequently encountered competing pathways including radical homocoupling and H atom abstraction must be rigorously suppressed to ensure the heteroselective coupling outcome.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e As such, the bimolecular homolytic substitution (S\u003csub\u003eH\u003c/sub\u003e2) of transition-metal complexes, an outer-sphere coupling process operating through the open-shell displacement mechanism, was considered to serve as an ideal scenario for the cross-ketone deacylative coupling protocol (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, left).\u003csup\u003e\u003cspan additionalcitationids=\"CR29 CR30 CR31\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e This speculation was inspired by the pioneering reports of MacMillan,\u003csup\u003e\u003cspan additionalcitationids=\"CR34 CR35 CR36 CR37\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e Shenvi\u003csup\u003e\u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e among others on transition metal-catalyzed S\u003csub\u003eH\u003c/sub\u003e2 reactions,\u003csup\u003e\u003cspan additionalcitationids=\"CR43 CR44 CR45 CR46 CR47 CR48 CR49\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e including single-functional group cross-coupling of native functionalities such as carboxylic acids and alcohols.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e Accordingly, in our proposed cross-ketone deacylative coupling protocol, two distinct open-shell carbons generated through homolytic α-C-C cleavage of ketones perform different functions. More specifically, the metal catalyst would preferentially capture the less sterically hindered open-shell primary carbon, forming a relatively stable alkyl-metal complex with higher bond dissociation energy (BDE).\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e Meanwhile, the sterically congested secondary or tertiary alkyl radical generated from another ketone features with favorable SOMO nucleophilicity,\u003csup\u003e\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e thereby poised to undergo S\u003csub\u003eH\u003c/sub\u003e2 displacement to forge the cross-coupling product.\u003c/p\u003e\u003cp\u003eIt is well-known that photo-induced Norrish Type I reaction of ketones would enable a direct access to produce alkyl radicals through homolytic α-cleavage of ketones.\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e However, the concomitant generation of acyl radicals is considered detrimental to the desired heteroselective fragment coupling process. As such, we sought to use the heterocyclic pre-aromatic intermediates (PAIs) to serve as alkyl radical precursors,\u003csup\u003e\u003cspan additionalcitationids=\"CR55 CR56 CR57 CR58 CR59 CR60\" citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e given prior demonstrations that they can be readily obtained from ketones through a simple condensation step and are competent to produce alkyl radicals through redox-triggered fragmentation, with concomitant formation of a sacrificial aromatic heterocycles. Among diverse PAIs, dihydroquinazolinone (DHQ) skeletons were identified as particularly feasible masked ketones in our S\u003csub\u003eH\u003c/sub\u003e2 coupling protocol, owing to the advantages that they can be modularly synthesized, and the aromatic quinazolinone released as a byproduct during β-scission step poses no interfere with the metal catalyst (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, left).\u003csup\u003e\u003cspan additionalcitationids=\"CR63 CR64 CR65 CR66 CR67 CR68 CR69 CR70 CR71\" citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eTaken these considerations into account, we endeavored to develop the first example of cross-dual C-C cleavage coupling between distinct ketones, enabling the molecular construction of C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)-C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e) linkages via transition metal-catalyzed S\u003csub\u003eH\u003c/sub\u003e2 homolytic substitution (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, left). The DHQs obtained from aminoacetone or acetol precursors could generate primary alkyl radicals, a kind of reactive intermediates that would bind to the nickel catalyst. Subsequent S\u003csub\u003eH\u003c/sub\u003e2 displacement by sterically congested tertiary alkyl radicals stemming from α-quaternary ketones facilitates the modular assembly of primary amines, ethers and thioethers containing β-all-carbon quaternary centers, which are biologically relevant scaffolds for the medicinal chemistry research (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, right).\u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e Moreover, we also devoted to achieve the heteroselective coupling of distinct α-amino alkyl fragments with subtle steric disparities, enabling efficient synthesis of β-amino alcohol and β-diamine derivatives through the cross-ketone deacylative coupling protocol. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec, right).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eReaction condition optimization\u003c/h2\u003e\u003cp\u003eWe focused our initial exploration on the cross-deacylative coupling of α-quaternary methyl ketone \u003cb\u003e1a\u003c/b\u003e with α-amino acetone derivative \u003cb\u003e1b\u003c/b\u003e, motivated by the prevalence of primary amines bearing β-quaternary center motifs in bioactive molecules (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Building upon our previous studies,\u003csup\u003e\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e we first examined the DHQs \u003cb\u003e2a\u003c/b\u003e and \u003cb\u003e2b\u003c/b\u003e in this coupling protocol. Notably, these DHQ precursors are bench-stable and can be purified by operations of both column chromatography and recrystallization. After a systematically evaluation of photosensitizers, nickel catalysts and oxidants, we were pleased to discover that the reaction of DHQs \u003cb\u003e2a\u003c/b\u003e and \u003cb\u003e2b\u003c/b\u003e in the presence of 2,4,5,6-tetrakis(9\u003cem\u003eH\u003c/em\u003e-carbazol-9-yl)isophthalonitrile (4CzIPN), Ni(acac)\u003csub\u003e2\u003c/sub\u003e, dibenzoyl peroxide (Bz\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e) and 2,4-pentanedione (Hacac) delivered desired cross-coupling product \u003cb\u003e3a\u003c/b\u003e in a satisfactory yield (92%) under blue LED irradiation (entry 1). Other ketone-derived PAIs that are capable of producing alkyl radicals through oxidative aromatizaiton, such as benzothiazoline \u003cb\u003e2c\u003c/b\u003e, benzoimidazoline \u003cb\u003e2d\u003c/b\u003e and methyl substituted DHQ \u003cb\u003e2e\u003c/b\u003e, proved ineffective for this coupling protocol (entries 2\u0026ndash;4). Diminished reaction performance was observed with sterically encumbered nickel salts, such as Ni(THMD)\u003csub\u003e2\u003c/sub\u003e and the K[Tp*]-ligated nickel catalyst (entries 5 and 6).\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Suprisingly, Fe(OEP)Cl as an analogue of porphine-Fe(III) is impotent to trigger the coupling process, even it has demonstrated an exceptional efficacy in several outer-sphere cross-coupling reactions (entry 7).\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e While dibenzoyl peroxide remains the optimal oxidant, other commercially available oxidants (e.g., LPO and TBPB) are also applicable, albeit with diminished yields (entries 8 and 9). Control experiments confirmed that the Ni(acac)\u003csub\u003e2\u003c/sub\u003e plays a critical role, enabling the fragment copling with exceptional heteroselectivity and surpressing side reactions such as homocoupling, hydrogen atom transfer or free radical oxidation (entry 11). The other reaction components\u0026ndash;photocatalyst, oxidant, and light\u0026ndash;were also demonstrated to be necessary to deliver the desired coupling product (entries 12\u0026ndash;14). Notably, the addition of 2,4-pentanedione acetylacetone in this oxidative coupling protocol allows a reduced Ni catalyst loading, as previously demonstrated by Hartwig and co-workers (entry 15).\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eSubstrate scope\u003c/h3\u003e\n\u003cp\u003eWith optimal conditions in hand, we next sought to evaluate the scope of this cross-ketone deacylative coupling protocol, aiming to construct β-quaternary amines through cross-coupling of distinct DHQs derived from an α-quaternary methyl ketone and an α-aminoacetone (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). It is important to recognize that the primary amines with β-all-carbon quaternary centers are highly desirable due to their particular biologically activities and thus have been frequently found in drug candidates.\u003csup\u003e\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u003c/sup\u003e However, the C\u003csub\u003e1\u003c/sub\u003e aminomethylation strategy to construct these privileged scaffolds remains elusive, especially started from abundant native functional handles.\u003csup\u003e\u003cspan additionalcitationids=\"CR77\" citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e\u003c/sup\u003e To this end, a battery of DHQs derived from structurally diverse ketones were subjected to the standard reaction conditions. Remarkably, this coupling protocol enabled efficient cross-ketone deacylative coupling, affording β-quaternary amines with broad functional group tolerance. As illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, drug like structural motifs such as piperidine- and tetrahydropyran-fused amines were yielded in good yields (\u003cb\u003e4\u003c/b\u003e\u0026ndash;\u003cb\u003e6\u003c/b\u003e, 61\u0026ndash;88% yield). In addition to \u003cem\u003etert\u003c/em\u003e-butyl group, a diverse array of functional groups including terminal alkenes, hydroxy groups, esters and chloro groups were also well-tolerated in this protocol (\u003cb\u003e7\u003c/b\u003e\u0026ndash;\u003cb\u003e12\u003c/b\u003e, 59\u0026ndash;76% yield). We further examined that β-aryl ketones bearing electronically and sterically varied substituents in aryl groups proved compatible, furnishing phenylpropylamine derivatives in moderate to good yields (\u003cb\u003e13\u0026ndash;22\u003c/b\u003e, 50\u0026ndash;80% yield). Surprisingly, the reaction efficiency dramatically decreased using 1-adamantyl methyl ketone-derived DHQ as a coupling partner (\u003cb\u003e23\u003c/b\u003e, 26% yield). Expanding the scope further, ketones with heteroatom-containing α-quaternary centers delivered β-aminoalcohol derivatives in moderate yields (\u003cb\u003e24\u003c/b\u003e and \u003cb\u003e25\u003c/b\u003e, 47 and 43% yield, respectively), further underscoring the diversity of quaternary centers that can be constructed via this cross-ketone deacylative coupling protocol.\u003c/p\u003e\u003cp\u003eIt should be noted that α-tertiary ketones are not applicable in this cross coupling protocol, likely due to the low β-scission efficiency of DHQ radical cations in generating open-shell secondary carbons. After extensive evaluations, we found that the α-amino secondary alkyl radicals coupled with the aminomethyl radical smoothly in excellent radical sorting results, providing an expedient access to construct valuable β-diamine (\u003cb\u003e26\u003c/b\u003e\u0026ndash;\u003cb\u003e30\u003c/b\u003e, 37\u0026ndash;64% yield), β-aminoalcohol (\u003cb\u003e31\u003c/b\u003e and \u003cb\u003e32\u003c/b\u003e, 42% and 57% yield, respectively) and β-aminothiol (\u003cb\u003e33\u003c/b\u003e, 50% yield) derivatives from native ketone functionalities. Intriguingly, this S\u003csub\u003eH\u003c/sub\u003e2 protocol allows the construction of diamine derivatives via cross-coupling of dual α-amino primary alkyl radicals (\u003cb\u003e34\u003c/b\u003e\u0026ndash;\u003cb\u003e38\u003c/b\u003e, 45\u0026ndash;58% yield). The heteroselective radical sorting result is unambiguously regulated by nickel catalyst, while the unsymmetric diamine product \u003cb\u003e35\u003c/b\u003e was not formed in absence of Ni(acac)\u003csub\u003e2\u003c/sub\u003e. We speculated that the α-amino methylene radicals bearing sterically slightly congested tertiary amidyl groups poised to undergo S\u003csub\u003eH\u003c/sub\u003e2 displacement rather than coordinating with the nickel catalyst. Notably, the radical sorting outcome is enhanced in this reaction system between benzylic and α-amino primary radicals (\u003cb\u003e38\u003c/b\u003e and \u003cb\u003e39\u003c/b\u003e, 45 and 54% yield, respectively), whereas the homocoupling products of benzylic radicals are dominated in absenece of the nickel catalyst.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNext, we sought to evaluate the scope of DHQs that derived from α-secondary methyl ketones as C\u003csub\u003e1\u003c/sub\u003e-alkylating coupling partners in this cross-ketone deacylative coupling protocol (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Both benzoxycarbonyl- (Cbz) and acetyl-protected α-amino ketones gave satisfactory yields comparable to that obtained with \u003cem\u003et\u003c/em\u003e-butyloxycarboryl (Boc) protecting group (\u003cb\u003e40\u003c/b\u003e and \u003cb\u003e41\u003c/b\u003e, 78 and 72% yield, respectively). DHQs derived from ketones bearing α-tertiary amidyl groups also engaged in this coupling protocol, in which a diverse array of substituents on amino group were tolerated, including alkyl groups, amides and ethers (\u003cb\u003e42\u003c/b\u003e\u0026ndash;\u003cb\u003e47\u003c/b\u003e, 33\u0026ndash;82% yield). Additionally, α-amino primary radicals bearing benzylamine and aniline motifs could also be cross-coupled with tertiary carbon radicals, delivering β-quaternary amine derivatives in good yields (\u003cb\u003e48\u003c/b\u003e\u0026ndash;\u003cb\u003e54\u003c/b\u003e, 46\u0026ndash;69% yield). The β-quaternary-benzamides (\u003cb\u003e56\u003c/b\u003e\u0026ndash;\u003cb\u003e58\u003c/b\u003e, 45\u0026ndash;65% yield), -alkylamides (\u003cb\u003e59\u003c/b\u003e, 40% yield) and -phthalimides (\u003cb\u003e60\u003c/b\u003e, 36% yield) were also achieved using corresponding DHQs for C\u003csub\u003e1\u003c/sub\u003e-aminomethylation. Finally, this coupling protocol also allows for deacylative C\u003csub\u003e1\u003c/sub\u003e-alkoxymethylation, producing a variety of β-quaternary ethers (\u003cb\u003e61\u003c/b\u003e\u0026ndash;\u003cb\u003e64\u003c/b\u003e, 52\u0026ndash;58% yield), β-aminoalcohols (\u003cb\u003e65\u003c/b\u003e and \u003cb\u003e66\u003c/b\u003e, 73 and 47% yield, respectively) and 1,2-dialcohols (\u003cb\u003e67\u003c/b\u003e, 45% yield) that are structurally useful for further medicinal and biological research.\u003csup\u003e\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eHaving evaluating the scope of ketones, we attempted to apply this single-functional group cross-coupling methodology to the late-stage modification (LSF)\u003csup\u003e\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e\u003c/sup\u003e of bioactive molecules bearing common functionalities that can be readily converted to ketones, such as carboxyl, halide and hydroxy groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). To this end, ketone analogues derived from Gemfibrozil and Ciprofibrate underwent efficient deacylative aminomethylation, yielding structurally diversified drug analogues suitable for further medicinal exploration (\u003cb\u003e68\u003c/b\u003e and \u003cb\u003e69\u003c/b\u003e, 72 and 74% yield, respectively). Similarly, 3-aminopropyl ester derivatives incorporating core structural motifs of drug molecules, including Sulbactam acid, Oxaprozin, Febuxostat, Indomethacin and Isoxepac, were successfully obtained via this cross-ketone deacylative coupling protocol (\u003cb\u003e70\u003c/b\u003e\u0026ndash;\u003cb\u003e74\u003c/b\u003e, 36\u0026ndash;47% yield). The piperidine derivative with a Naproxen core was obtained in highly efficiency (\u003cb\u003e75\u003c/b\u003e, 59% yield). Further, this method also enables the preparation of diverse β-amino alcohol derivatives\u0026mdash;longstanding as a privileged structural motif in medicinal chemistry\u0026mdash;from phenol-containing drug molecules such as Tyramine and Acetaminophen (\u003cb\u003e76\u003c/b\u003e and \u003cb\u003e77\u003c/b\u003e, 63 and 66% yield, respectively). The α-quaternary ketone derived from Melonal also engaged in this coupling protocol, providing β-quaternary amine product in a moderate yield (\u003cb\u003e78\u003c/b\u003e, 52% yield). Noteworthy, the late-stage functionalization of amino-containing pharmaceuticals such as Mexiletine was also accomplished via S\u003csub\u003eH\u003c/sub\u003e2 coupling of distinct DHQs derived from amino ketones (\u003cb\u003e79\u003c/b\u003e, 63% yield). These LSF results evidently highlight the broad applicability of this strategy in rational drug design and diversification.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eMechanistic studies and proposed reaction mechanism\u003c/h3\u003e\n\u003cp\u003ePreliminary mechanistic studies have been conducted to investigate the details of the deacylative cross-coupling reaction. The coupling process was completely suppressed upon addition of TEMPO, with trapping of both tertiary alkyl radical and primary α-amino alkyl radical as their corresponding TEMPO adducts (\u003cb\u003e80\u003c/b\u003e and \u003cb\u003e81\u003c/b\u003e, 56 and 112% yield, respectively). These results unambiguously confirm the oxidative generation of two distinct alkyl radical species spontaneously from DHQs \u003cb\u003e2a\u003c/b\u003e and \u003cb\u003e2b\u003c/b\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, a). To elucidate the oxidation state of the nickel catalyst during the reaction process, 4-bromo- and 4-iodobenzonitrile were separately introduced into the model reaction as diagnostic reagents due to their known propensity to undergo oxidative addition with low-valent nickel species (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, b).\u003csup\u003e\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e\u003c/sup\u003e The ketone deacylative cross-coupling results were unaffected, accompanied with almost full recovery of aryl halides, indicating that there has no low-valent nickel species (Ni\u003csup\u003e0\u003c/sup\u003e or Ni\u003csup\u003eⅠ\u003c/sup\u003e) involved in the coupling process to trigger the oxidation addition with aryl halides. These findings also reflect, on the other hand, the coupling reaction proceeds via the S\u003csub\u003eH\u003c/sub\u003e2-mediated outer-sphere mechanism.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e\u003c/sup\u003e To further elucidate the mechanistic details of the oxidative coupling system, we conducted the Stern-Volmer luminescence quenching studies on photoexcited 4CzIPN using key reaction components (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, c). Different quenching behaviors were observed, as both DHQs \u003cb\u003e1a\u003c/b\u003e and \u003cb\u003e2a\u003c/b\u003e exhibited strong quenching effects, while the quenching process by nickel catalyst was dramatically less efficient. Notably, the oxidant Bz\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e showed no measurable quenching capability, providing direct spectroscopic evidence that both primary and tertiary radical species are produced through single-electron oxidation of DHQs by photoexcited 4CzIPN, rather than through Bz\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e-mediated pathways. Additionally, the calculated fragmentation rates for generating alkyl radicals from DHQ radical cations revealed that both tertiary and α-amino primary radicals undergo exceptionally rapid β-scission steps, several orders of magnitude faster than secondary cyclohexyl and primary propyl radicals (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, d). These computational results align with experimental observations, wherein both radicals must be generated at comparable rates. Otherwise, competing side reactions such as homocoupling, HAT or radical oxidation will dominate, thereby intercepting the cross-coupling pathway. The heteroselective coupling outcome is rational because the calculated BDE of the Ni-tertiary alkyl complex is remarkably lower than that of the primary counterpart (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, e).\u003csup\u003e\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e\u003c/sup\u003e This energy difference indicates that the primary radical preferentially combines with the metal center, during which accumulating tertiary radicals in the reaction system and poised to undergo subsequent outer-sphere S\u003csub\u003eH\u003c/sub\u003e2 displacement.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eBased on the mechanistic studies and previous reports,\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e, \u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e\u003c/sup\u003e a proposed reaction mechanism is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e. Firstly, the DHQs \u003cb\u003e2a\u003c/b\u003e and \u003cb\u003e2b\u003c/b\u003e derived from α-quaternary ketone \u003cb\u003e1a\u003c/b\u003e and aminoacetone \u003cb\u003e1b\u003c/b\u003e would be oxidized by excited photocatalyst, leading to N-centered radical cation species \u003cb\u003eA\u003c/b\u003e and \u003cb\u003eB\u003c/b\u003e, respectively. The reduced photocatalyst (4CzIPN\u003csup\u003e\u0026ndash;\u0026bull;\u003c/sup\u003e) concurrent generated is likely to be oxidized by Bz\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e, thereby closing the photoredox cycle. The radical cation \u003cb\u003eB\u003c/b\u003e is not a persistent species, tend to undergo rapid and thermodynamically favorable β-scission to generate primary radical species \u003cb\u003eD\u003c/b\u003e, which can be rapidly captured by the nickel catalyst to form persistent Ni\u0026thinsp;\u0026minus;\u0026thinsp;alkyl intermediate \u003cb\u003eE\u003c/b\u003e. Meanwhile, the tertiary radical species \u003cb\u003eC\u003c/b\u003e, produced through β-scission of radical cation \u003cb\u003eA\u003c/b\u003e, would interact with Ni\u0026thinsp;\u0026minus;\u0026thinsp;alkyl complex \u003cb\u003eE\u003c/b\u003e, delivering the desired C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)\u0026ndash;C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e) coupled product \u003cb\u003e3\u003c/b\u003e via S\u003csub\u003eH\u003c/sub\u003e2 mechanism and reconstitute the nickel catalyst. Noteworthy, a wide range of substrates containing alkyl and aryl halide moieties (\u003cb\u003e12\u003c/b\u003e\u0026ndash;\u003cb\u003e14\u003c/b\u003e, \u003cb\u003e48\u0026ndash;50\u003c/b\u003e, \u003cb\u003e56\u003c/b\u003e, \u003cb\u003e57\u003c/b\u003e) work smoothly in this coupling protocol, further excludes the involvement of low-valent nickel species. This mechanistic paradigm stands in sharp contrast to previously reported deacylative cross-coupling reactions of ketones that proceed through inner-sphere mechanism involving Ni(0) or Ni(I) intermediates.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn summary, we have established a synergistic nickel/photoredox-catalyzed cross-deacylative coupling of ketones through an open-shell mechanism, employing dihydroquinazolinones as ketone analogs to generate diverse open-shell carbon intermediates. This operationally simple protocol enables efficient and modular construction of sterically demanding C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)\u0026ndash;C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e) bonds from readily accessible ketones under exceptionally mild conditions. Mechanistic studies reveal that the nickel(II) catalyst operates through selective radical interception, facilitating C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)-C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e) bond formation via an outer-sphere bimolecular homolytic substitution (S\u003csub\u003eH\u003c/sub\u003e2) pathway. The transformation demonstrates remarkable functional group compatibility and offers an expedient access to sterically congested quaternary carbon centers, showcasing potential for late-stage functionalization of complex molecules including bioactive compounds and pharmaceutical intermediates.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eGeneral Procedure for Cross-Ketone Decaylative Coupling\u003c/h2\u003e\u003cp\u003eA flame-dried Schlenk-tube equipped with a magnetic stir bar was charged with \u003cb\u003e2a\u003c/b\u003e (71.9 mg, 0.2 mmol, 1.0 equiv.), \u003cb\u003e2b\u003c/b\u003e (87.3 mg, 0.3 mmol, 1.5 equiv.), 4CzIPN (3.2 mg, 2 mol%), Ni(acac)\u003csub\u003e2\u003c/sub\u003e (5.1 mg, 10 mol%) and Bz\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e (72.7 mg, 0.3 mmol, 1.5 equiv.). EtOAc (2.0 mL) and 2,4-pentanedione (10.0 \u0026micro;L, 0.1 mmol, 50 mol%) were added by syringe. The tube was then purged with nitrogen for 3 minutes. The tightly sealed tube was then irradiated by a Kessil\u0026trade; PR160L 456 nm blue lamp (40 W, 100% intensity) for 2 hours under stirring at room temperature. After completion, the mixture was transferred into a 100 mL separating funnel which contained 30 mL sat. NaHCO\u003csub\u003e3\u003c/sub\u003e. The mixture was extracted three times by ethyl acetate (15 mL for each) and the combined organic layer was washed with sat. NaHCO\u003csub\u003e3\u003c/sub\u003e, brine and then dried over Na\u003csub\u003e2\u003c/sub\u003eSO\u003csub\u003e4\u003c/sub\u003e. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc\u0026thinsp;=\u0026thinsp;8:1) to give the cross-ketone deacylative coupling product \u003cb\u003e3\u003c/b\u003e (59.8 mg, 91%) as a white solid.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData relating to the materials and methods, optimization studies, experimental procedures, mechanistic studies, NMR spectra and mass spectrometry are available in the Supplementary Information.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe are grateful to the financial support from the National Natural Science Foundation of China (Grant No. 22101176 to H. Jiang, Grant No. 22137003 and 22225703 to Y. Zhang), and startup funding from Shanghai Jiao Tong University (SJTU).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH.J. conceived the project. H.J., J.X.Y., M.Y.Z., J.R.W. designed and performed the experiments. Q. W. conducted the DFT calculations. H.J. wrote the manuscript according to the feedback from all authors. H.J. and Y. Z. directed the project.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence and requests for materials\u003c/strong\u003e should be addressed to H.J.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReprints and permissions information\u0026nbsp;\u003c/strong\u003eis available at http://www.nature.com/reprints.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eErtl P, Schuhmann T (2019) A systematic cheminformatics analysis of functional groups occurring in natural products. J Nat Prod 82:1258\u0026ndash;1263\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOoi T, Maruoka K (2000) Modern Carbonyl Chemistry ch. 1. Wiley-VCH, Weinheim\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHeathcock CH (1991) Comprehensive Organic Synthesis vol. 1. 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J Am Chem Soc 137:4896\u0026ndash;4899\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7421874/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7421874/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe α-C-C cleavage coupling of ketones offers a highly challenging yet promising approach for C\u0026ndash;C bond formation, particularly given the ubiquity and ready accessibility of ketones as fundamental synthons in organic synthesis. However, the deacylative cross-coupling between two distinct ketones via a single activation mode remains an unmet challenge, although this coupling paradigm could be leveraged to construct C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)\u0026ndash;C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e) linkages with exceptional structural diversity. Herein, we describe a cross-ketone deacylative coupling via nickel-catalyzed bimolecular homolytic substitution (S\u003csub\u003eH\u003c/sub\u003e2), in which the synergistic oxidative photocatalysis is combined to produce simultaneously two distinct open-shell carbons from ketone-derived dihydroquinazolinones. This heteroselective radical-radical coupling protocol enables the construction of quaternary carbon centers through a critical S\u003csub\u003eH\u003c/sub\u003e2 displacement mechanism, providing an efficient approach to furnish β-quaternary aliphatic amines. Additionally, a wide array of biorelevant small molecules, including β-amino alcohol, β-diamine and β-aminothiol derivatives, could also be obtained via this cross-double deacylative C\u003csub\u003e1\u003c/sub\u003e-alkylation approach between distinct ketones.\u003c/p\u003e","manuscriptTitle":"Cross-double carbon-carbon cleavage coupling of ketones via oxidative SH2 homolytic substitution","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-10 19:02:48","doi":"10.21203/rs.3.rs-7421874/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d4b87dae-31ca-4847-be9b-c0703a31eaec","owner":[],"postedDate":"September 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":54415293,"name":"Physical sciences/Chemistry/Catalysis/Photocatalysis"},{"id":54415294,"name":"Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology"},{"id":54415295,"name":"Physical sciences/Chemistry/Photochemistry/Photocatalysis"}],"tags":[],"updatedAt":"2026-05-13T07:05:49+00:00","versionOfRecord":{"articleIdentity":"rs-7421874","link":"https://doi.org/10.1038/s41467-026-70619-5","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2026-03-19 04:00:00","publishedOnDateReadable":"March 19th, 2026"},"versionCreatedAt":"2025-09-10 19:02:48","video":"","vorDoi":"10.1038/s41467-026-70619-5","vorDoiUrl":"https://doi.org/10.1038/s41467-026-70619-5","workflowStages":[]},"version":"v1","identity":"rs-7421874","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7421874","identity":"rs-7421874","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}