Palladium-Catalyzed Synthesis of Diaryl Ketones from Aldehydes and

Heteroaryl ketones, as well as diaryl ketones, were synthesized in good to excellent yields, even in gram-scale, ... Journal of the American Chemical ...
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Letter Cite This: ACS Catal. 2018, 8, 3123−3128

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Palladium-Catalyzed Synthesis of Diaryl Ketones from Aldehydes and (Hetero)Aryl Halides via C−H Bond Activation Takayuki Wakaki,† Takaya Togo,† Daisuke Yoshidome,‡ Yoichiro Kuninobu,*,§,∥ and Motomu Kanai*,†,∥ †

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan Schrödinger K.K., 1-8-1 Marunouchi, Chiyoda-ku, Tokyo 100-0005, Japan § Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga-shi, Fukuoka 816-8580, Japan ∥ ERATO, Japan Science and Technology Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan ‡

S Supporting Information *

ABSTRACT: We developed a palladium-catalyzed C−H transformation that enabled the synthesis of ketones from aldehydes and (hetero)aryl halides. The use of picolinamide ligands was key to achieving the transformation. Heteroaryl ketones, as well as diaryl ketones, were synthesized in good to excellent yields, even in gram-scale, using this reaction. Results of density functional theory (DFT) calculations support the C−H bond activation pathway. KEYWORDS: C−H activation, palladium, aldehyde, ketone, heteroaryl ketone, ligand design

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INTRODUCTION Transition-metal-catalyzed C−H transformations are widely developed because of their promising features, such as step and atom economy. Directing groups are especially powerful for promoting the desired C−H transformations.1 Daugulis and coworkers developed a new bidentate directing group, as well as C−H transformations, using the bidentate directing group.2 Since then, many research groups have intensively studied bidentate directing group-assisted C−H transformations (Figure 1a).3 However, the use of bidentate directing groups requires additional steps to install and remove the directing groups before

and after the reactions. In addition, stoichiometric amounts of the directing groups are required. The two main roles of the directing groups are (i) to bring catalytically active transition-metal species close to the reaction sites and (ii) to work as ligands to the metal centers. By focusing on the latter role, we considered that C−H transformations could be achieved using a bidentate moiety of the directing group, such as a picolinamide group, as a catalyst ligand (Figure 1b). In this system, the use of only a catalytic amount of the bidentate moiety as a ligand is sufficient to promote the desired C−H transformations. To the best of our knowledge, C−H transformations using such a ligand have not been reported.4 Diaryl ketones are useful skeletons, but their efficient synthetic methods are limited. Generally, a method using the Weinreb amide, oxidation of the corresponding secondary alcohol, Friedel−Crafts acylation, and cross-coupling reaction of acyl chlorides using a palladium catalyst, are usually used.5 However, these methods have several problems, such as the requirement of multisteps to prepare substrates, which is dependent on the electronic properties of substrates, and the need to use excess amounts of oxidants. Although direct synthetic reactions of ketones from aldehydes have recently been developed, it is necessary to use stoichiometric amounts of oxidizing and reducing agents.6 Efficient synthetic reactions of heteroaryl ketones are also limited. Received: February 1, 2018 Revised: March 3, 2018 Published: March 8, 2018

Figure 1. C−H transformations using a picolinamide moiety: (a) as a bidentate directing group and (b) as a bidentate ligand. © XXXX American Chemical Society

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DOI: 10.1021/acscatal.8b00440 ACS Catal. 2018, 8, 3123−3128

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ACS Catalysis Scheme 3. Scope of Aldehydes 1a

Herein, we report the synthesis of diaryl ketones from aldehydes and aryl halides via C−H bond activation using a palladium/picolinamide catalyst. Because various aldehydes and aryl halides are readily available, a variety of aryl ketones can be synthesized using this reaction.

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RESULTS AND DISCUSSION We first investigated several picolinamide ligands in the reaction between benzaldehyde 1a and p-iodoanisole 2a in the presence of Pd(OAc)2 and KHCO3 (see Scheme 1). The desired reaction Scheme 1. Investigation of Several Ligands

proceeded with ligand L1 and afforded ketone 3a in 19% yield. The yield of 3a was improved to 66% and 83% using ligands L2 and L3, respectively. The positions of the pyridyl and amide moieties were important to promote the reaction efficiently. In fact, 3a was formed in only 3% yield, using ligand L4 with an amide moiety at the 3-position of the pyridine ring. We confirmed the importance of the picolinamide structure based on the following experiments: the yield of 3a was low when picolinate L5 or amide L6 was used, and iminopyridine L7, diimine L8, bipyridine, pyridine, BINAP, and triphenylphosphine were also ineffective in this reaction. In many reactions, aryl bromides are less reactive, compared with the corresponding aryl iodides. Interestingly, the yield of ketone 3a was slightly higher (89% yield) when using pbromoanisole 4a instead of p-iodoanisole 2a with ligand L3. Furthermore, the yield of 3a was improved by changing the ligand to L2 when using aryl bromide 4a (see Scheme 2).7 Because aryl bromides are more widely available organohalides than aryl iodides, we investigated the substrate scope using aryl bromides.

a Using 4b (3.0 equiv). bA decarbonylated product (anthracene) of aldehyde 1n was also formed in 64% yield.

with an ester group, 1k, proceeded because such substrates are generally difficult to use in ketone synthesis with Grignard reagents.8 Sterically hindered aldehyde 1m also reacted with bromobenzene 4b in 95% yield. The reaction of 2-naphthaldehyde 1m, anthracene-9-carbaldehyde 1n, and pyrene-1-carbaldehyde 1o gave the desired products 3m−3o in 36%−86% yields. The yield of 3n was moderate, because of the decarbonylation of aldehyde 1n to give anthracene. The desired reaction also proceeded using aliphatic aldehydes 1p and 1q, whereas the yields of ketones 3p and 3q were low. We then investigated the substrate scope of aryl bromides (Scheme 4). Aryl bromides 4c−4h with an electron-donating or electron-withdrawing group produced the desired products 3s− 3v in yields of 78%−90%. F, Cl, and Br atoms and functional groups, such as ketone, ester, amide, silyl, thiomethyl, and ether groups, tolerated the present reaction conditions and afforded ketones 3h, 3i, 3v−3z, and 3A−3C, respectively, in yields of 56%−99%. Bromo-substituted ketone 3v was obtained using 4bromoiodobenzene 4k under the optimized conditions, whereas the C−Br bond is also the reactive site. Although it is difficult to synthesize ketones containing a thiomethyl group by oxidizing the corresponding secondary alcohols, because the thiomethyl group is easily oxidized, product 3A was obtained in high yield, using the present method in a single step from commercially available coupling partners. Ketone 3l was produced in moderate yield using ortho-substituted bromobenzene 4s. 1-Bromo- and 2bromonaphthalene (4t and 4u) also reacted with aldehyde 1a to give the corresponding ketones 3D and 3m in yields of 84% and 98%, respectively. Heteroaryl ketones are common structures in drug lead molecules, but few effective methods are available to

Scheme 2. Reaction between Benzaldehyde 1a and Aryl Bromide 4a

We then investigated the substrate scope of aldehydes (Scheme 3). The desired ketones 3a−3k were produced in good to excellent yields, using benzaldehydes with an electrondonating or electron-withdrawing group. Fluorine and chlorine atoms and an ester group were tolerant to the reaction conditions, and the corresponding ketones 3h−3k were produced. It is noteworthy that the desired reaction of aldehyde 3124

DOI: 10.1021/acscatal.8b00440 ACS Catal. 2018, 8, 3123−3128

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ACS Catalysis Scheme 4. Scope of Aryl Bromides 4a

Scheme 5. Further Investigation of Several Ligands

Scheme 6. Synthesis of Mono(heteroaryl)ketone and Di(heteroaryl)ketonea

a

Using 4 (3.0 equiv). b4-Bromoiodobenzene, Pd(OAc)2 (10 mol %), K2CO3 (2.5 equiv), L2 (20 mol %), tAmylOH (0.50 M), 120 °C.

synthesize them.9 In the present reaction conditions, heteroaryl bromides, such as 4-bromo-1H-pyrazole 4v and 2-bromothiophene 4w were tolerant and transformed into the corresponding heteroaryl ketones (3E and 3F). Examples of the synthesis of bis(heteroaryl)ketone are still rare.9a The pyridyl group-containing ketone 3G was obtained in only 35% yield using ligand L2. Therefore, we investigated ligands to improve the yield of 3N. Screening of substituents on the N atom of the amide moiety did not improve the yield of 3G (ligand L7−L11). Electron density of the pyridyl group gave high influence for the yield of 3G (ligand L12−L18). The yield of 3G was dramatically improved when using ligands with an electron-donating group. Finally, ligand L18 was proved to be the best ligand, and the yield of 3G was improved to 62% (see Scheme 5). We then investigated several heteroaromatic aldehydes and bromides to expand the scope of heteroaryl ketones (see Scheme 6). Ketones with quinolinyl, isoquinolinyl, quinoxalinyl, dihydroindolyl, and carbazolyl group, 3H−3L, were obtained in moderate to good yields. By using ligand L18, di(heteroaryl)ketones 3M−3O were also afforded in good yields. The reaction proceeded in excellent yield, even on a gram scale (see Scheme 7). Treatment of 0.686 g of benzaldehyde 1a with 2bromonaphthalene 4u gave 1.33 g of 2-benzoylnaphthalene 3m in 88% yield.

a

Using 1 (3.0 equiv). b1 (1.0 equiv), 4 (3.0 equiv).

Scheme 7. Gram-Scale Reaction

This reaction was applied to the synthesis of a drug molecule (see Scheme 8). Fenofibrate 6 is a commercial drug that is used to reduce cholesterol levels in patients at risk for cardiovascular disease. Fenofibrate 6 was obtained in 75% yield by the reaction of 4-chlorobenzaldehyde 1i with aryl bromide 5. We considered four possible mechanisms: an insertion pathway and three formyl C−H activation pathways (shown in Figure 2; for details, see the Supporting Information). For the insertion pathway (pathway i, red), the first transition state TS-I2 involves a four-membered intermediate, which is generated by approaching an aldehyde to an aryl-palladium intermediate. The activation barrier for this step is estimated to be 51.3 kcal/mol. TS-I2 is successively converted to IS-I3 (a palladium alkoxide). Then, benzophenone is generated by β-hydride elimination, and the activation barrier for this step is predicted to be 16.6 kcal/ 3125

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ACS Catalysis

activation barrier of this step is calculated to be 15.5 kcal/mol. The next step is the generation of aryl palladium(IV) species ISP7, via oxidative addition of an aryl bromide to an acyl palladium(II) species with the activation barrier of 34.1 kcal/mol. Finally, reductive elimination (TS-P8) gives benzophenone PP9. This process is also highly exothermic and requires small activation energy (10.3 kcal/mol). Pathway iv (green line) is for the generation of ketones P-P11 from the reaction of palladium(II) species IS-P3 and aryl bromides after the proton transfer from the aldehyde to the carbonate group in the square planar complex of Pd(II). This step requires a large activation energy of 29.0 kcal/mol. According to the energy diagram shown in Figure 2, the transition state TS-P4 with the highest energy in pathway iii is lower than the TS-I2 in pathway i for the insertion mechanism, TS-O5 in pathway ii, and TS-P10 in pathway iv for the other C− H activation mechanisms. Therefore, the results of theoretical calculations show that the C−H activation mechanism in pathway iii is more preferable to the others. In addition, as described in Scheme 3, product 3n, which is a decarbonylated product (anthracene) of aldehyde 1n, was formed in 64% yield. This result supports that the reaction proceeded via C−H bond activation.10 Furthermore, the desired reaction did not proceed well, using a catalytic amount of Pd(0) species, such as Pd(dba)2 (3a: 5% yield) and Pd2(dba)3 (3a: 6% yield). These results show that the reaction did not proceed via Pd(0)/Pd(II) catalytic cycle.11 Therefore, we considered the proposed mechanism for the formation of ketones as follows (see Scheme 9):12

Scheme 8. Application to the Synthesis of Fenofibrate

mol. This pathway is totally found to be endergonic, based on these calculations. On the other hand, three possible pathways for the C−H activation mechanism are shown as pathway ii (black line), iii (blue line), and iv (green line). In pathway ii (black line), the abstraction of a H atom of the aldehyde occurs in the octahedral complex (IS-O2, TS-O3, and IS-O4) formed by the coordination of the carbonyl group of an aldehyde to the Pd atom. The activation barrier for this step is estimated to be 2.8 kcal/mol. These three states have similar three-dimensional (3D) structures (see the Supporting Information). The distances of C−H (formyl group)/O−H (between carbonate and the H atom of the formyl group) are 1.10/1.80 Å (for IS-O2), 1.36/ 1.22 Å (for TS-O3), and 1.76/1.02 Å (for IS-O4). The distances clearly showed that the H atom of the formyl group is transferred to the carbonate group. IS-O4 is continuously converted to acyl palladium(IV) species IS-O6, via TS-O5, through the release of HCO3− and the formation of a Pd−C bond. This step is a highly exothermic process and the activation barrier for this step is calculated to be 3.4 kcal/mol. In pathway iii (blue line), the similar proton transfer from the aldehyde to the carbonate group occurs and gives acyl palladium(II) IS-P5, through TS-P4. The

(1) formation of palladium intermediate I from Pd(OAc)2 and ligand L2; (2) formation of intermediate II (R0 in Figure 2) from intermediate I and KHCO3;

Figure 2. Energy diagrams of insertion (pathway i, red) and C−H activation (pathways ii, iii, and iv, black, blue, and green) pathways for the reaction between 1a and 4b. All data were computed using the M06-2X functional. The basis set for Pd atom was LACVP**++, and the basis set for the other atoms was 6-31G**++. 3126

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ACS Catalysis Notes

Scheme 9. Proposed Mechanism

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported in part by ERATO from JST and JSPS KAKENHI Grant No. JP 26288014. T.W. thanks JSPS for fellowships.

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(3) formation of intermediate III (IS-P5 in Figure 2) from intermediate II and aldehyde 1 via C−H bond activation via a concerted metalation-deprotonation (CMD) pathway;13 (4) oxidative addition of aryl bromide 4 to give intermediate IV (IS-P7 in Figure 2); and (5) reductive elimination to give ketone 3 and regenerate intermediate I.14

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CONCLUSION In summary, we successfully synthesized ketones from aldehydes and aryl halides via C−H activation under palladium catalysis. The picolinamide ligand played an important role in promoting the reaction. The desired ketones were obtained in good to excellent yields, even in gram-scale, with high functional group tolerance. Heteroaryl ketones could also be synthesized using the reaction. A bioactive compound was synthesized in a few reaction steps. Three possible reaction pathways were considered, but the results of DFT calculations indicated that the reaction proceeded via C−H bond activation of aldehydes and successive oxidative addition of aryl bromides to a palladium-amide intermediate. We hope that the reaction will provide useful insight into C−H transformations and become a useful method for synthesizing ketones with high functional group tolerance.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.8b00440. Typical experimental procedure, characterization data for ketones, and results of DFT calculations (PDF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (Y. Kuninobu). *E-mail: [email protected] (M. Kanai). ORCID

Yoichiro Kuninobu: 0000-0002-8679-9487 Motomu Kanai: 0000-0003-1977-7648 3127

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ACS Catalysis

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DOI: 10.1021/acscatal.8b00440 ACS Catal. 2018, 8, 3123−3128