Decarboxylative Acylation of Carboxylic Acids: Reaction Investigation and Mechanistic Study

Open AccessCCS ChemistryRESEARCH ARTICLE14 Jul 2022Decarboxylative Acylation of Carboxylic Acids: Reaction Investigation and Mechanistic Study Xiaopeng Wu†, Jie Han†, Siyu Xia, Weipeng Li, Chengjian Zhu and Jin Xie Xiaopeng Wu† State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023 , Jie Han† State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023 , Siyu Xia State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023 , Weipeng Li *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023 , Chengjian Zhu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023 State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032 and Jin Xie *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023 Advanced Catalytic Engineering Research Center of the Ministry of Education, Hunan University, Changsha 410082 https://doi.org/10.31635/ccschem.021.202101197 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Ketones serve as one of the most critical building blocks in organic synthesis, involving numerous functional group transformations. Herein, we report an unprecedented photoredox–nickel metallaphotoredox-catalyzed decarboxylative acylation of common aliphatic acids with readily available aromatic and aliphatic thioesters. A wide range of structurally diverse asymmetrical aryl alkyl and dialkyl ketones have been constructed in yields of up to 98% with this strategy. The protocol has excellent reaction selectivity and functional group compatibility, representing a significant step forward in ketone synthesis. The one-pot decarboxylative acylation at the gram scale from two different carboxylic acids and the late-stage application for the synthesis of complex ketones shows its synthetic robustness. Both mechanistic experiments and density functional theory (DFT) calculations suggest that the decarboxylative acylation reaction operates via an underdeveloped Ni(I)–Ni(II)–Ni(I)–Ni(III)–Ni(I) catalytic cycle. Download figure Download PowerPoint Introduction The ketone moiety is involved in many versatile synthetic transformations in organic synthesis and regarded as a core linkage in retrosynthetic analysis.1 In view of the availability and structural diversity of carboxylic acids, the development of new methods of ketone synthesis from carboxylic acids attracts continuing interest. Examples of this type of reaction include Friedel–Crafts acylation,2,3 nucleophilic addition of organometallic compounds to amides,4 and transition-metal-catalyzed cross-coupling reactions.5–10 The combination of photoredox and nickel catalysis recently initiated by MacMillan et al.11 and Molander et al.12 has led to advances in redox-neutral chemical bond formation.13–20 In this context, several research groups21–24 have reported elegant examples of metallaphotoredox-catalyzed C(sp3)-H acylation with amides, anhydrides, or activated 2-pyridylthioesters as acyl surrogates. In these reactions, substrates such as compounds with an α-C(sp3)-H adjacent to a heteroatom or simple alkanes have been employed in a facile hydrogen atom transfer (HAT) process to control the regioselectivity. There is still, however, a great demand for the development of a practical protocol using a readily available chemical as an alkyl radical source,25–27 with the aim to construct complex ketones without redundant protection and deprotection processes. Carboxylic acids can realize a synthetase-catalyzed formal decarboxylative acylation by transfer of an acyl group from coenzyme A (CoA)-activated thioesters to deliver a chain-extended ketone (Scheme 1a).28 We questioned if it is possible to use metallaphotoredox catalysis with readily available thioesters to develop a decarboxylative acylation strategy of aliphatic carboxylic acids. In such a reaction, a transition-metal catalytic unit is responsible for the activation of thioesters (Scheme 1b). Additionally, in recent years, visible-light-mediated radical decarboxylation is a powerful strategy for forming C–C or C–X bonds,29–36 such as decarboxylative alkynylation, alkenylation, alkylation, arylation, fluorination, and borylation. However, the decarboxylative acylation of aliphatic carboxylic acids has not been reported to date.37 Given the structural diversity of carboxylic acids, the success of a metallaphotoredox-catalyzed decarboxylative acylation protocol could potentially enhance the synthesis of complex ketones. More significantly, decarboxylative acylation can be used to construct ketones from two different carboxylic acids in a one-pot operation, thus expanding the existing ketone synthetic routes. Scheme 1 | Synthesis of ketones from two carboxylic acids by decarboxylative acylation. Download figure Download PowerPoint Based on these assumptions, a plausible mechanism is proposed in Scheme 2. Initially, irradiation of the iridium(III) photocatalyst (PC) Ir[dF(CF3)ppy]2(dtbbpy)PF6 produces a photoexcited *IrIII species. A carboxylate anion could participate in a single electron transfer (SET) with the photoexcited PC [E1/2red [*IrIII/IrII] = + 1.21 V vs saturated calomel electrode (SCE)]38,39 to generate an alkyl radical (I) and CO2. In the presence of N-containing ligands, the nickel-based catalyst precursor can be reduced to an LNiX species (II),40 which undergoes radical recombination with generated alkyl radical (I) to produce alkyl-Ni(II) species (III). This can accept an additional electron from the Ir(II) species (E [IrII/IrIII] = −1.37 V vs SCE)38,39 to furnish a highly active R–Ni(I) species (IV).41 Subsequent oxidative addition of the thioester C–S bond to the R–Ni(I) species forms the Ni(III) species (V).42 Finally, reductive elimination would form the requisite C–C bond delivering the desired ketone product, completing the catalytic cycle. Scheme 2 | Proposed mechanism of decarboxylative acylation. Download figure Download PowerPoint Experimental Methods General procedure for ketone synthesis Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.2 mg, 2.0 mol %), NiCl2·1,2-dimethoxyethane (NiCl2·DME) (2.2 mg, 10 mol %), 4,7-dimethyl-1,10-phenanthroline (4.2 mg, 20 mol %), carboxylic acid (0.3 mmol, 3.0 equiv), and anhydrous powder Cs2CO3 (97.5 mg, 0.3 mmol, 3.0 equiv) were added to an oven-dried 10 mL Schlenk tube equipped with a poly(tetrafluoroethylene) (PTFE) stir bar. The tube was evacuated and backfilled with argon three times. Subsequently, the thioester (0.1 mmol, 1.0 equiv) and CH3CN (3.0 mL) were added into this Schlenk tube under argon. The tube was then sealed and placed approximately 5 cm from two 45-W blue light-emitting diodes (LEDs) (λmax = 455 nm). The reaction mixture was stirred for 21–48 h at room temperature (rt) (a fan and air-conditioners were used to keep the reaction temperature close to 25 °C). After completion, the reaction mixture was removed from the light, diluted with water, and the aqueous layer was extracted with EtOAc (3 × 2.0 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel to afford the corresponding ketone products. 1a, R = nBu; the other substrates, R = tBu, unless otherwise noted. Density functional theory calculation All the calculations were carried out using density functional theory (DFT) and an ultrafine grid as implemented in Gaussian16 program package. Gibbs free energies were calculated at PBE0-D3/def2-SVP/def2-TZVP/SMD(CH3CN) level of theory (see the detailed computational methods and reference in the Supporting Information). Results and Discussion Initially, the reaction of 3-(3,4-dimethoxyphenyl)propanoic acid ( 1a) and S-butyl benzothioate ( 2a) was selected for a model reaction and to optimize the standard reaction conditions. As shown in Table 1, the optimized reaction conditions include the use of 2 mol % of Ir[dF(CF3)ppy]2(dtbbpy)PF6 as the PC, 10 mol % of the nickel catalyst together with 20 mol % of 4,7-dimethyl-1,10-phenanthroline ( L4) as the ligand in CH3CN. These conditions deliver the desired ketone ( 3a) in 98% yield under the irradiation of blue LEDs at rt. The other PCs screened failed to promote the decarboxylative acylation possibly because the strong oxidation potential of the photoexcited *Ir-species can facilitate the single electron oxidation of aliphatic acids (entries 2 and 3, Table 1). Phenanthrolines are better as ligands than substituted bipyridines, and among the ligands examined 4,7-dimethyl-1,10-phenanthroline ( L4) gave good yields (entries 4–7, Table 1). Control experiments (entries 8–10, Table 1) showed that PC, base, nickel catalyst, and ligand are indispensable for the decarboxylative acylation reaction. Table 1 | Optimization of Reaction Conditionsa Entry Variation of Standard Conditions Yield (%)b 1 None 98 (81) 2 PC2 instead of PC1 70 (53) 3 PC3, PC4 or PC5 instead of PC1 ND 4 L1 instead of L4 36 5 L2 instead of L4 Trace 6 L3 instead of L4 76 (55) 7 L5 instead of L4 ND 8 Without PC ND 9 Without nickel/ligand ND 10 Without base ND aStandard reaction conditions: Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol %), NiCl2·DME (10 mol %), 4,7-dimethyl-1,10-phenanthroline ( L4) (20 mol %), 1a (0.1 mmol), 2a (0.3 mmol), Cs2CO3 (3.0 equiv), CH3CN (3 mL), blue LEDs, 21 h, rt. ND, not detected. bGas chromatography (GC) yield using biphenyl as an internal standard and isolated yield is shown in parentheses. With the optimal reaction conditions in hand, we examined the scope of commercial carboxylic acids that can construct aryl alkyl ketones with this acylation reaction (Scheme 3). A variety of carboxylic acids bearing electron-rich and -poor functional groups on the phenyl ring undergo decarboxylative acylation smoothly, giving rise to the corresponding ketones in moderate to excellent yields of up to 98% ( 3a– 3y). The mild reaction conditions accommodate an array of useful functional groups including ethers ( 3c– 3f and 3h), an ester ( 3w), amides ( 3u and 3v), and an acetal ( 3g). Strongly electron-withdrawing groups like methylsulfonyl ( 3p) and ester ( 3w) are well tolerated. Halogen- (F, Cl, and Br) and trifluoromethyl (CF3)-substituted phenylacetic acids ( 3j– 3m, 47–61%) are compatible with the reaction process, which opens the possibility of further downstream conversion. Notably, carboxylic acid substrates containing aryl bromide ( 3k) and free N–H groups ( 3q and 3r), which are known to be sensitive in traditional metal-catalyzed cross-coupling reactions, appear to be tolerated, and heterocyclic carboxylic acids are also competent coupling starting materials ( 3r– 3t). Biologically important molecules such as actarit ( 3v, 73%), indomethacin ( 3x, 77%), repaglinide precursor ( 3w, 49%), and zolpidem precursor ( 3y, 82%) can also be used in this reaction. Additionally, α-ketocarboxylic acids ( 3z), piperidine formic acid ( 3aa), pyrrolidine formic acid ( 3bb), proline ( 3cc), and azacyclobutanoic acid ( 3dd) give the corresponding aryl alkyl ketones in 40–60% yields. Unfortunately, the employment of a tertiary carboxylic acid failed to give rise to the desired product ( 3mm). In general, direct decarboxylation generating an alkyl radical can ensure good regioselectivity and complement the reported C–H acylation protocols.21–24 Scheme 3 | Scope of aryl alkyl ketones. Standard reaction conditions: Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol %), NiCl2·DME (10 mol %), 4,7-dimethyl-1,10-phenanthroline (L4) (20 mol %), carboxylic acid (1) (0.3 mmol), thioesters (0.1 mmol), Cs2CO3 (0.3 mmol), CH3CN (3 mL), blue LEDs, 21 h, rt. Isolated yield is shown. aYield determined by GC-MS using biphenyl as an internal standard. b–StBu instead of –SnBu. Download figure Download PowerPoint We also evaluated the nature of thioesters in this photoredox–nickel mediated cross-coupling reaction. As shown in Scheme 3, both electron-rich and -deficient groups on the phenyl ring have little effect on the insertion of the C–S bond and produce the desired ketones ( 3ee– 3ll) in moderate to good yields. Thioesters containing heterocycles such as furan and thiophene can participate readily in this acylation, furnishing the desired products ( 3jj and 3kk). In view of our previous aryl alkyl ketone synthesis routes,43,44 the flexibility of the alkyl source is a useful addition. Construction of more complex asymmetrical dialkyl ketones was attempted. As shown in Scheme 4, the commercially available short-chain thioesters could be converted into the desired alkyl ketones ( 4a– 4c) in yields as high as 91%. The α-substituted thioesters ( 4d) also gave acceptable yields. Aliphatic thioesters containing a carbonyl group are compatible, providing the 1,5-dione ( 4g) or the 1,7-dione ( 4h) in 95% and 73% yield, respectively. This can enhance the classical Weinreb ketone synthesis, which entails reactive ketones being attacked by organometallics. Thioesters prepared from cyclic carboxylic acids such as indene carboxylic acid ( 4l), cyclohexane formic acid ( 4j) and small-ring carboxylic acids ( 4i, 85%; 4k, 84%) also work well. The use of other substituted thioesters in place of S-(tert-butyl)ethane thioate afford the desired product ( 4a) in moderate yields, indicating structural changes in the thioester are possible for metallaphotoredox decarboxylative acylation. Scheme 4 | Scope of asymmetrical alkyl ketones. Standard reaction conditions: Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol %), NiCl2·DME (10 mol %), 4,7-dimethyl-1,10-phenanthroline (L4) (20 mol %), carboxylic acid (0.3 mmol), thioesters (0.1 mmol), Cs2CO3 (0.3 mmol), CH3CN (3 mL), blue LEDs, 21 h, rt. Isolated yield is shown. a–SEt instead of –StBu in thioester. b–SMe instead of –StBu in thioester. Download figure Download PowerPoint The high efficiency and good functional group tolerance of this photoredox–nickel-catalyzed reaction encouraged us to explore its late-stage application in the synthesis of complex ketones (Scheme 5). Some drug molecules such as ketoprofen ( 5a), loxoprofen ( 5b), oxaprozin ( 5c), and indomethacin ( 5f and 5h) selectively produce the desired ketones in moderate yield under standard conditions. When complex aliphatic acids and the corresponding thioesters were subjected to this protocol, they successfully constructed the related dialkyl ketones ( 5f– 5i). Scheme 5 | Late-stage application of the reaction for the synthesis of complex ketones. Reaction conditions: Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol %), NiCl2·DME (10 mol %), 4,7-dimethyl-1,10-phenanthroline (L4) (20 mol %), carboxylic acid (0.3 mmol), thioesters (0.1 mmol), Cs2CO3 (0.3 mmol), CH3CN (3 mL), blue LEDs, 21 h, rt. Isolated yield is shown. The structure in black represents the thioesters, blue represents the carboxylic acids, and the bond in red represents the newly formed bond. Download figure Download PowerPoint To further demonstrate the practicality of this protocol, experiments on gram scale were carried out (Scheme 6). The corresponding thioesters were prepared in situ by treatment of carboxylic acids with oxalyl chloride and thiols, and were used directly without purification in the subsequent decarboxylative acylation procedure. The synthetic route provides satisfactory access to linkages in the form of ketones connecting two functional fragments from different carboxylic acids. Scheme 6 | Gram-scale ketone synthesis in one-pot operation. Reaction conditions: (1) RCOOH (1.0 equiv), oxalyl chloride (1.5 equiv), CH2Cl2, 0 °C to rt. (2) thiol (1.5 equiv), CH2Cl2, rt. (3) Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.5 mol %), NiCl2·DME (10 mol %), L4 (20 mol %), RCOOH (1.5 equiv), Cs2CO3 (3.0 equiv), CH3CN (0.133 M), blue LEDs, 48 h, rt. Download figure Download PowerPoint Cyclic voltammetry (CV) measurements of 2a showed that the high oxidation potential of carboxylic acids ( 2a) is greatly diminished after the formation in situ of cesium salts (E = +0.72 V vs SCE). Consequently, they can be oxidized by an excited-state *IrIII-complex as shown in Scheme 2 (E1/2red [*IrIII/IrII] = +1.21 V vs SCE). Our luminescence quenching experimental results further indicate that the photoexcited *IrIII-complex is quenched by carboxylate cesium salts (see Supporting Information for details). A free radical trapping experiment with 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) showed that a radical process was highly likely (Scheme 7a), and this was further verified by electron paramagnetic resonance (EPR) experiments with N-tert-butyl-α-phenylnitrone (Scheme 7b). Interestingly, the control experiments with a prepared nickel(II) acyl intermediate ( 6) and a carboxylic acid ( 2c) under standard conditions could not successfully produce the target product. Only the decarboxylation byproduct of the carboxylic acid ( 2c) could be detected (Scheme 7c), suggesting that the radical addition to a Ni(II) species42,45 in the decarboxylative acylation is less likely. Scheme 7 | (a–f) Control experiments. HRMS, high-resolution mass spectrometry. Download figure Download PowerPoint We wished to experimentally control the sequence of the two processes, oxidative addition and radical addition, by varying the order of how the reaction components are added. Combining the thioester ( 8) and stoichiometric amounts of Ni(cod)2 (Scheme 7d) forces thioester ( 8) to undergo the oxidative addition first, leading to a low yield of expected product (16%). Delaying addition of the thioester ( 8) after prestirring of the Ni(II) catalyst and carboxylic acid ( 2c) under irradiation pre-generates the alkyl nickel(I) species, driving the reaction to the radical addition pathway first (Scheme 7e). As a result, continuous irradiation (2–10 min) promotes the radical addition into the nickel center to ensure the equivalent conversion to product (85–92%), while prolonged irradiation (30 min) may lead to a large amount of byproduct 7. Interestingly, without light irradiation, the in situ generated alkyl nickel species also underwent oxidation addition with the thioester, but only generated the desired product in trace yield (Scheme 7f). Thus, the pathway of initial radical addition is more feasible than initial oxidation addition. With the strong experimental evidences of our proposed mechanism, we further explored various mechanistic possibilities through quantum chemical calculations performed on selected model reactions as shown in Figures 1 and 2. Formation of 3a and 3c have been considered for comparison. All the calculations were carried out using DFT and an ultrafine grid as implemented in Gaussian16 program package (see Supporting Information for the full reference and computational details). Figure 1 | Free energy profiles of paths 1 and 2 for the nickel catalytic cycle of Scheme 2. Gibbs free energies were calculated at PBE0-D3/def2-SVP/def2-TZVP/SMD(CH3CN) level of theory. For each pathway, only MEP is shown here. LE, ligand exchange; MEP, minimum energy path; OA, oxidative addition; RA, radical addition; RE, reductive elimination. Download figure Download PowerPoint Based on the previous mechanism, we considered a reductive quenching cycle for the photoredox catalytic cycle Ir(III)−*Ir(III)–Ir(II) sequence of iridium oxidation states (Scheme 2), as well as two possible reaction pathways for the nickel catalytic cycle with a Ni(I) species as the active catalyst (Figures 1 and 2), that is, Ni(I)−Ni(0)−Ni(II)−Ni(III) (paths 1 and 1′) and Ni(I)−Ni(II)−Ni(I)−Ni(III) (path 2 and 2′). Both Ni(I)–Cl and Ni(I)–SnBu might serve as the active catalysts in the nickel catalytic cycle. Ni(I)–SnBu is excluded since the activation energies of all its relevant SET steps in the photoredox cycle are ∼10 kcal/mol higher than that of Ni(I)–Cl (see Supporting Information Figure S18). Regarding the formations of radicals 10 (unreactive alkyl radical) and 9 (benzylic radical), the calculated free energy barriers for the corresponding SET steps are negligible (0.0 and 1.1 kcal/mol). However, the relative values of their free energy changes vs indicate that the of 9 is more Figure 2 | Free energy profiles of pathways paths and for the nickel catalytic cycle of Scheme 2. Gibbs free energies were calculated at PBE0-D3/def2-SVP/def2-TZVP/SMD(CH3CN) level of theory. For each pathway, only MEP is shown here. LE, ligand exchange; OA, oxidative addition; RA, radical addition; RE, reductive elimination. Download figure Download PowerPoint For the acylation involved with in 1, Ni(I)–Cl with SET and with 1a to form species the free energy of the process is kcal/mol the photoredox cycle Figure 1). to undergo the oxidative addition with 1a to generate Ni(II) species with an energy as low as to radical 9 via a and forms an intermediate The reaction with reductive elimination of in the target product ( 3a) and Finally, the active catalysis is by ligand and with a free energy of The step of 1 is from Ni(I)–Cl to with an kcal/mol As shown in Figure 1, 2 from a radical addition of with leading to an intermediate The anion is from by SET with in Ni(I) species with 1a and then undergoes oxidative addition via and leading to a Ni(III) intermediate species which is kcal/mol than in The Ni(III) intermediate is in energy than thus the reaction of 2 is determined by the SET step to with an energy of the energy of 1 is higher than that of 2 to be more For the acylation involved with both paths and of the reaction are under the reaction conditions. is more than kcal/mol). is that radical addition of and 10 in a more intermediate with a 2), the of and 9 in 2 forms a kcal/mol). the radical addition step ( of is more than that ( of 2. with 1a and then undergoes oxidative addition via and leading to a Ni(III) intermediate and reaction paths and the Ni(III) intermediate is higher in energy than which is to the of 2 Consequently, the reaction of is determined from to with an energy of As shown in Figures 1 and 2 and are more than 1 and and the more radical can undergo this reaction more than alkyl radical kcal/mol in 2 vs kcal/mol in 2′). We have the first photoredox–nickel metallaphotoredox-catalyzed decarboxylative acylation of aliphatic carboxylic acids with readily available aromatic and aliphatic thioesters. This protocol the of a wide range of structurally diverse aryl alkyl ketones and asymmetrical dialkyl delivering moderate to good yields. This and practical protocol has excellent and functional group compatibility, and represents significant in decarboxylative of carboxylic acids. The one-pot decarboxylative acylation on a gram scale from two different carboxylic acids and late-stage application for the synthesis of complex ketones further its synthetic Both experimental and that decarboxylative acylation to with radical addition to which an underdeveloped catalytic cycle in metallaphotoredox Supporting Information Supporting Information is available and computational Figures chromatography mass chromatography and of There is of to Information The are for the from the of and the of Jiangsu Research for the of Jiangsu and of Advanced Catalytic Engineering Research Center of the Ministry of of Hunan The to Li for the experimental for products ( and All calculations were performed at the Center of Nanjing and at Institute of and Chemistry is for on DFT via 2. Acylation Friedel–Crafts Acylation and Weinreb as in Synthesis of Ketones from the of with Carboxylic 7. of Synthesis of to Synthesis of and Formation via of with MacMillan with of with Molander in by Molander Formation by in Organic Zhu in under Conditions via Molander in Zhu Synthesis of via and of and C(sp3)-H of C(sp3)-H of via and Acylation of C(sp3)-H by and of and for Acylation by of and Acylation for the Synthesis of of the of to the Xie Zhu for the of Zhu for of by of Synthesis in Zhu and of by and of Aliphatic and in the of of Carboxylic and of Carboxylic by of Li MacMillan of via the of and by and in Catalytic Acylation via a MacMillan with in Organic for C–C from Zhu into the and of Molander the of Formation in A Study of Catalytic of and Molander of a General for in Zhu Xie Synthesis from Carboxylic and Xie Zhu General for Synthesis of Ketones from Carboxylic and and of Cyclic Information Chemical to Li for the experimental for products and All calculations were performed at the Center of Nanjing and at Institute of and Chemistry is for on DFT