Manganese-Catalyzed Deoxygenative [3+2] Annulations of Ketones and Aldehydes via C–H Activation
Ting Liu, Yuanyuan Hu, Yunhui Yang, Congyang Wang
Abstract
Open AccessCCS ChemistryCOMMUNICATION1 Feb 2021Manganese-Catalyzed Deoxygenative [3+2] Annulations of Ketones and Aldehydes via C–H Activation Ting Liu, Yuanyuan Hu, Yunhui Yang and Congyang Wang Ting Liu Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100049 , Yuanyuan Hu Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100049 , Yunhui Yang Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100049 Physical Science Laboratory, Huairou National Comprehensive Science Center, Beijing 101400. and Congyang Wang *Corresponding author: E-mail Address: [email protected] Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100049 Physical Science Laboratory, Huairou National Comprehensive Science Center, Beijing 101400. https://doi.org/10.31635/ccschem.020.202000206 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail Conventional reactive sites of ketones with aldehydes lie on the carbonyl and α-carbon positions, which lead to a wide range of classic reactions such as pinacol-coupling and aldol-type condensations. Herein, an unprecedented reactive site of aromatic ketones toward aldehydes has been revealed by using earth-abundant manganese catalysis, which enabled the first deoxygenative [3+2] annulations of ketones and aldehydes through C–H activation affording isobenzofuran derivatives. Mechanistic studies give hints on the dual role of triphenylborane additive in the reaction, that is, promoting C–H activation as a transmetalation reagent and activating aldehydes as a Lewis acid. Download figure Download PowerPoint Introduction Carbonyl compounds such as ketones and aldehydes are among the most readily accessible and practically useful building blocks in organic synthesis. Conventionally, reactions between two different carbonyl compounds, such as ketones and aldehydes, take place at the carbonyl or α-carbon sites of ketones (Scheme 1a). An illustrative example of the former type of reactions is the pinacol-coupling reaction, which occurs mainly through a single-electron transfer process.1–6 The latter type of reactions, which occurs at the α-carbon position is represented by the classic aldol-type reaction.7–9 Recently, the strategic use of C–H bond activation has reshaped traditional ways to build functional molecules. We are intrigued by the potential yet unraveled reactive site at inert C(sp2)–H positions of aromatic ketones toward aldehydes, which might open a new avenue for the use of two different carbonyl compounds in organic synthesis. Since the pioneering of ruthenium (Ru)-catalyzed aromatic C−H alkylation of ketones with olefins,10 ketone-directed C−H activation reactions have been investigated with a number of coupling partners.11,12 However, these reactions with aldehydes have remained surprisingly untouched so far. We presumed that the underlying challenges might arise from the following: (1) The weak coordination ability of ketone as a directing group for C–H activation,11–14 compared with strong coordination groups such as N-containing heterocycles and imines. (2) The obstacles in aldehyde-insertion step such as low nucleophilicity of the C–H activation intermediate, metallacycles, toward aldehydes, the reversibility of aldehyde insertion, and the difficulty in releasing metals from metal alkoxides after aldehyde insertion.15,16 (3) The selectivity in C–H activation of aromatic ketones and aldehydes. (4) The competing side reactions such as aldol-type condensations. To circumvent these issues, Kuninobu, Takai and co-workers17 reported an indirect strategy, that is, using strong-coordination N-containing imines instead of ketones to react with aldehydes through the benefit of strong N-coordination that stabilizes the addition reaction intermediate and decrease aldol-type side reactions under precious rhenium (Re) catalysis.17–19 Meanwhile, manganese (Mn)-catalyzed C–H addition of strongly coordinated N-containing heterocycles to aldehyde was achieved.20–22 Though elegant, the challenges mentioned above remain for the direct inert C–H transformations of ketones with aldehydes. With these aspects in mind, and as our continuous efforts to develop more efficient Mn catalytic systems to meet these unsolved challenges,20–51 we herein describe the first deoxygenative [3+2] annulations of ketones and aldehydes to access isobenzofuran derivatives via C–H/C=O bond cleavage (Scheme 1b), which were enabled by Mn catalysis and unprecedented for other transition metal catalysis. Of note, the isobenzofuran and o-diacylbenzene skeletons are not only widely found in many natural products and bioactive molecules (Figure 1) but are also versatile building blocks in organic synthesis.52–57 Scheme 1 | Varied reaction patterns between ketones and aldehydes. Download figure Download PowerPoint Figure 1 | Representative natural products, containing isobenzofuran and o-diacylbenzene skeletons. Download figure Download PowerPoint Result and Discussion Initially, benzophenone ( 1a) and 2-naphthaldehyde ( 2l) were chosen as model substrates to vary the reaction parameters (Table 1). After the extensive screening (see Supporting Information Table S1 for more details), we found that the treatment of 1a with 2l gave isobenzofuran 3l in 87% yield, obtained from 1H NMR analysis in the presence of Manganese pentacarbonyl bromide [MnBr(CO)5] (10 mol%) and triphenylborane (BPh3)40 (1.0 equiv.) in 1,2-dimethoxyethane (Table 1, entry 1). Solvent variations indicated that ethers were generally better than others, with 1,2-dimethoxyethane being the best (entries 2–5). A control experiment showed that BPh3 was indispensable for the reaction (entry 6). The use of triethylborane (BEt3) instead of BPh3 resulted in limited success (entry 7). Triethylborate [B(OEt)3] was not effective at all (entry 8). Surprisingly, methyl ammonium tetraphenylborate (Me3NHBPh4) gave a comparable yield of 3l, while sodium tetraphenylborate (NaBPh4) showed minimal reactivity (entries 9–10). Interestingly, the change of solvent from dimethoxyethane (DME) to tetrahydrofuran (THF) and addition of a catalytic copper salt, together with NaBPh4 gave dramatically increased yields of the products (entries 11–12; for more details, see the Supporting Information). The use of Me2Zn/ZnBr2 instead of BPh3 led to an insignificant result (entry 13).22,34 No reaction occurred in the absence of MnBr(CO)5 (entry 14), and Mn2(CO)10 was less effective (entry 15). Noncarbonyl manganese precursors and other metal carbonyls failed in the reactions (entries 16–19). Table 1 | Screening of Reaction Parametersa Entry Catalyst (10 mol%) Additive (1.0 equiv.) Solvent Yieldb 1 MnBr(CO)5 BPh3 DME 87 2 MnBr(CO)5 BPh3 THF 67 3 MnBr(CO)5 BPh3 MTBE 61 4 MnBr(CO)5 BPh3 DCE –c 5 MnBr(CO)5 BPh3 pentane –c 6 MnBr(CO)5 –d DME –c 7 MnBr(CO)5 BEt3 DME 20 8 MnBr(CO)5 B(OEt)3 DME –c 9 MnBr(CO)5 Me3NHBPh4 DME 85 10 MnBr(CO)5 NaBPh4 DME trace 11 MnBr(CO)5 NaBPh4 THF 14 12 MnBr(CO)5 NaBPh4/CuBre THF 64 13 MnBr(CO)5 Me2Zn/ZnBr2f DME 63 14 –g BPh3 DME –c 15 Mn2(CO)10 BPh3 DME 76 16 Mn(acac)3 BPh3 DME –c 17 ReBr(CO)5 BPh3 DME –c 18 Fe2(CO)9 BPh3 DME –c 19 Ru3(CO)12 BPh3 DME –c aReaction conditions: 1a (0.4 mmol), 2l (0.2 mmol), catalyst (10 mol%), additive (0.2 mmol), solvent (0.5 mL), 120 °C, 12 h. bDetermined by 1H NMR analysis. cNot detected. dNo additive. e20 mol% CuBr. fMe2Zn (1.5 equiv.), ZnBr2 (1.0 equiv.). gNo catalyst. DME = 1,2-dimethoxyethane. Having the optimized reaction conditions in hand, we first explored the scope of aldehydes using benzophenone 1a as a model ketone substrate (Scheme 2). A plethora of electronically varied para-functionalized aromatic aldehydes was amenable to this protocol affording the corresponding isobenzofurans in good yields, ranging from 69% to 83% ( 3a– h). Halogen groups allowing for further synthetic transformations were well tolerated in the reaction. Substituents on the meta and ortho positions of benzaldehydes were also compatible, despite the enhanced steric hindrance of the latter one ( 3i, 3j). Both 1- and 2-naphthaldehydes with extended conjugation provided the expected products in high yields of 81% and 89%, respectively ( 3k, 3l). Furan-2-carbaldehyde delivered the expected product featuring 2,2'-bifuran moiety in 85% yield ( 3m). Similarly, a conjugated isobenzofuran–benzothiophene skeleton could be constructed from the corresponding ketone and aldehyde smoothly ( 3n). Remarkably, when isophthalaldehyde and terephthalaldehyde were adopted in the reaction, double-annulation products, 3o and 3p, with two isobenzofuran cores linked through a benzene moiety could be synthesized in one step with synthetically useful yields (46% and 55%, respectively). Next, with the success of aromatic aldehydes, we carried out a further investigation with aliphatic aldehydes. To our delight, 2-phenylacetaldehyde ( 2q) worked equally well, giving the expected isobenzofuran product 3q smoothly, which was, however, unstable during the purification process (Scheme 3, i). Therefore, the reaction product was further trapped with dimethyl maleate through Diels–Alder reaction, followed by dehydration, affording a naphthalene derivative 4a in synthetically useful yield (45%). Besides the trapping strategy using Diels–Alder reactions, oxidation of the unstable isobenzofuran products was also applicable. For instance, decanal ( 2r) and cyclohexanecarbaldehyde ( 2s) reacted with ketone 1b smoothly to afford isobenzofurans 3r and 3s, respectively (Scheme 3, ii) and o-diacylbenzene products 5a, 5b were obtained successfully after an ensuing simple oxidation step with MnO2. Notably, the ketone-directed C–H acylation reaction with aldehydes was still unprecedented.11,12 Scheme 2 | Scope of aromatic aldehydes. Reaction conditions: 1a (1.0 mmol), 2 (0.5 mmol), MnBr(CO)5 (0.05 mmol), BPh3 (0.5 mmol), DME (1.0 mL), 120 °C, 12 h. Yields of the isolated products were given. (a) 1a (2.0 mmol), BPh3 (1.0 mmol), 24 h. Download figure Download PowerPoint Then the reaction scope with respect to ketones was tested using 2-naphthaldehyde 2l as a model substrate (Scheme 4). Benzophenones with both electron-donating and electron-withdrawing groups were amenable to the reaction, affording the corresponding products 3t–v smoothly. When a meta-substituted ketone was used with two adjacent C–H bonds available in the benzene moiety, the less sterically hindered C–H bond was preferred ( 3w). A naphtho[1,2-c]furan derivative with extended conjugation ( 3x) could be accessed in one step from the reaction of di(naphthalen-1-yl)methanone and 2-naphthaldehyde. The sole product ( 3y) was obtained when unsymmetrical benzophenone was utilized. Alkyl aryl ketones were also amenable to this protocol delivering the expected isobenzofuran products smoothly, which were stable enough to be isolated during the purification process when electron-withdrawing groups existed in the benzene moiety ( 3z- B). For electron-neutral and -rich aryl alkyl ketones, an ensuing oxidation step was adopted again because of the instability of the corresponding alkyl-substituted isobenzofurans. As a result, the o-diacylbenzene products were obtained eventually, and electronically varied substituents on the benzene moiety were tolerant ( 5c- i). Secondary-alkyl aryl ketones were also suitable for the reaction giving products 5j– l as expected. Moreover, primary-alkyl aryl ketones delivered the corresponding o-diacylbenzene products 5m and 5n successfully under the same reaction conditions. Scheme 4 | Scope of ketones. Reaction conditions: 1 (1.0 mmol), 2l (0.5 mmol), MnBr(CO)5 (0.05 mmol), BPh3 (0.5 mmol), DME (1.0 mL), 120 °C, 12 h. Yields of the isolated products were given. (a) Combined yield of two regioisomers (6.7∶1), major isomer 3w was shown. (b) MnO2 (2.0 mmol), DCM (6.0 mL), room temperature, 12 h. (c) Oxidation under air-condition without MnO2. Download figure Download PowerPoint Moreover, a series of experiments were conducted to shed light on the possible reaction mechanism. First, the stoichiometric reaction of MnBr(CO)5 and BPh3 was tested; surprisingly, benzaldehyde, benzophenone, and isobenzofuran 3a were detectable in small or trace amount (Scheme 5a; Supporting Information Figure S1). The addition of MeONa increased the formation of 3a a little bit ( Supporting Information Figure S2). Obviously, the benzene rings in benzaldehyde and benzophenone originated from BPh3, the carbonyl moiety was derived from MnBr(CO)5, and 3a was generated from benzaldehyde and benzophenone. While the reaction between MnBr(CO)5 and Me3NHBPh4 only gave benzaldehyde and benzophenone in low yields ( Supporting Information Figure S3), to our delight, PhMn(CO)5 was indeed formed, despite its low yield (38%) when NaBPh4 was used in the reaction with MnBr(CO)5 ( Supporting Information Figure S4). These results undoubtedly indicated the transmetalation of the phenyl group from borane to manganese. Scheme 5 | Mechanistic studies. (a) Yields determined by 1H NMR analysis. (b) Isolated yields. Download figure Download PowerPoint Further, the C–H activation step of benzophenone 1a with PhMn(CO)5 was probed, and the five-membered manganacycle Mn-I was isolated in 53% yield (Scheme 5b), which revealed that PhMn(CO)5 was an efficient promoter of the C–H activation step. Then the reaction of Mn-I and aldehyde 2l was investigated, and isobenzofuran 3l was obtained in 23% 1H NMR yield (Scheme 5c) ( Supporting Information Scheme S2). Interestingly, the addition of a catalytic amount of BPh3 increased the yield of 3l dramatically (56%), which suggested a second role of BPh3 as a Lewis acid for activation of an aldehyde. Afterward, PhMn(CO)5 and Mn-I were tested as catalysts for the annulation of ketone 1a with aldehyde 2l, and isobenzofuran 3l was achieved in comparable yields (Scheme 5d). Finally, the kinetic isotope effect (KIE) value of this reaction was measured to be 3.3 by two parallel experiments (Scheme 5e; Supporting Information Table S2, Figures S5 and S6), which indicated the turnover limiting C–H activation step or the steps before it.58 In addition, the phenyl deuterated by-product, PhD, was detected by 2H NMR in the latter experiment with deuterated ketone 1a- d 10. Scheme 3 | Reactions of ketones with aliphatic aldehydes. Reaction conditions: 1 (1.0 mmol), 2 (0.5 mmol), MnBr(CO)5 (0.05 mmol), DME (1.0 mL), 120 °C, 12 h. i) BPh3 (0.5 mmol). ii) Me2Zn (0.75 mmol), ZnBr2 (0.5 mmol). PMP = p-methoxyphenyl. Download figure Download PowerPoint Finally, based on the above results, a plausible reaction mechanism was depicted in Scheme 6. The reaction started with the formation of PhMn(CO)5 from MnBr(CO)5 and BPh3 through transmetalation. Cyclomanganation of ketone 1a with PhMn(CO)5 afforded the five-membered manganacycle Mn-I. Insertion of aldehyde 2a activated by BPh2X (X = Ph, Br, or OH) gave the seven-membered manganacycle Mn-II, which underwent an intramolecular O-nucleophilic attack on the carbonyl generating Mn-III. Transmetalation of the phenyl group from borane to the manganese center in Mn-III was followed by ligand exchange with ketone 1a, releasing compound 6 with concomitant formation of phenylmanganese species Mn-IV. Cyclomanganation of Mn-IV via C–H activation regenerates Mn-I and eliminates benzene, thus closing the catalytic cycle. Aromatization of 6 provided the final product 3a. Of note, BPh3 played a dual role in the reaction, namely, promoting the C–H activation step as a transmetalation reagent and activating aldehydes as a Lewis acid. Scheme 6 | A proposed reaction mechanism for the manganese-catalyzed deoxygenative [3+2] annulations of Ketones and Aldehydes via C–H/C=O bond cleavage. Download figure Download PowerPoint Conclusion We have developed the first deoxygenative [3+2] annulations of ketones and aldehydes via inert C–H activation, enabled by manganese catalysis, which also opened new reaction space for the coupling of two carbonyls beyond the traditional carbonyl and α-carbon reactive sites of ketones toward aldehydes. The reaction featured basic starting materials, simple reaction conditions, good functional group tolerance, and broad substrate scopes. A series of isobenzofurans and/or o-diacylbenzenes have been synthesized from readily available ketones and aldehydes. Mechanistic studies revealed the dual roles of BPh3 in the reaction, facilitating C–H activation as a transmetalation reagent and activating aldehydes as a Lewis acid. Further explorations on manganese-catalyzed reactions of two carbonyls from our laboratory are underway. Supporting Information Supporting Information is available. 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