Palladium-Catalyzed Synthesis of Diaryl Ketones from Aldehydes and

ketone, ligand design. Introduction. Transition .... Bromo- substituted ketone 3v was obtained using 4-bromoiodobenzene 4k under the optimized conditi...
4 downloads 17 Views 915KB Size
Download PDF
Subscriber access provided by - Access paid by the | UCSB Libraries

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 ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00440 • Publication Date (Web): 08 Mar 2018 Downloaded from http://pubs.acs.org on March 9, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

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,*§,‖ 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

E-mail: [email protected]; [email protected] Supporting Information Placeholder

ABSTRACT: We developed a palladium-catalyzed C-H transformation enabling 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 gramscale, using this reaction. Results of DFT calculations support the C-H bond activation pathway.

Keywords: C-H activation, palladium, aldehyde, ketone, heteroaryl ketone, ligand design 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 co-workers 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 groupassisted C-H transformations (Figure 1a).3 The use of bidentate directing groups, however, 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 to bring catalytically active transition metal species close to the reaction sites and 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

Figure 1. C-H transformations using a picolinamide moiety: (a) As a bidentate directing group; (b) as a bidentate ligand. Diaryl ketones are useful skeletons, but their efficient synthetic methods are limited. Generally, a method using 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 These methods, however, have several problems, such as the requirement of multi-steps to prepare substrates, dependent of 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. We report herein 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.

ACS Paragon Plus Environment

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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 (Scheme 1). The desired reaction 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.

Scheme 3. Scope of Aldehydes 1a

Scheme 1. Investigation of Several Ligands

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 p-bromoanisole 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 (Scheme 2).7 Because aryl bromides are more widely available organohalides than aryl iodides, we investigated the substrate scope using aryl bromides. Scheme 2. Reaction between Benzaldehyde (1a) and Aryl Bromide 4a

We then investigated the substrate scope of aldehydes (Scheme 3). The desired ketones 3b-3k were produced in good to excellent yields using benzaldehydes with an electron-donating or –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 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 withdrawing group produced the desired products 3s-3v in 78%90% yields. Fluorine, chlorine, and bromine atoms and functional groups, such as ketone, ester, amide, silyl, thiomethyl, and ether groups, tolerated the present reaction conditions, and afforded ketones 3x-3z and 3A-3F, respectively, in 56%-99% yields. Bromosubstituted ketone 3v was obtained using 4-bromoiodobenzene 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 2-bromonaphthalene (4t and 4u) also reacted with aldehyde 1a to give the corresponding ketones 3D and 3m in 84% and 98% yields, respectively. Heteroaryl ketones are common structures in drug lead molecules, but few effective methods are available to 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-3F).

ACS Paragon Plus Environment

Page 2 of 7

Page 3 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Scheme 4. Scope of Aryl Bromides 4a

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% (Scheme 5). We then investigated several heteroaromatic aldehydes and bromides to expand the scope of heteroaryl ketones (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. Scheme 6. Synthesis of Mono- and Di(heteroaryl)ketonea

The reaction proceeded in excellent yield, even on gram scale (Scheme 7). Treatment of 0.686 g of benzaldehyde 1a with 2-bromonaphthalene 4u gave 1.33 g of 2-benzoylnaphthalene 3m in 88% yield. Examples of the synthesis of bis(heteroaryl)ketone are still rare.9a 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 nitrogen atom of the amide moiety did not improve the yield of 3G (ligand L7-L11). Electron density of the pyridyl group gave high influence Scheme 5. Further Investigation of Several Ligands

Scheme 7. Gram-scale Reaction

This reaction was applied to the synthesis of a drug molecule (Scheme 8). Fenofibrate 6 is a commercial drug 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. Scheme 8. Application to the Synthesis of Fenofibrate

ACS Paragon Plus Environment

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

We considered four possible mechanisms: an insertion pathway and three formyl C-H activation pathways (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 -hydride elimination and the activation barrier for this step is predicted to be 16.6 kcal/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 hydrogen 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 palladium atom. The activation barrier for this step is estimated to be 2.8 kcal/mol. These three states have similar 3D structures (see the Supporting Information). The distances of C-H (formyl group)/O-H (between carbonate and hydrogen atom of 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 hydrogen 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 by 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) ISP5, through TS-P4. The activation barrier of this step is calculated to be 15.5 kcal/mol. The next step is the generation of aryl palladium(IV) species IS-P7, 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 P-P9. 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 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 (Scheme 9):12 (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; (3) formation of intermediate III (IS-P5 in Figure 2) from intermediate II and aldehyde 1 via C-H bond activation by 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

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 for the other atoms was 6-31G**++.

ACS Paragon Plus Environment

Page 4 of 7

Page 5 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Scheme 9. Proposed Mechanism

REFERENCES

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.

ASSOCIATED CONTENT Supporting Information. Typical experimental procedure, characterization data for ketones, and results of DFT calculations. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: kyo.ac.jp

[email protected];

[email protected]

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

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT This work was supported in part by ERATO from JST and JSPS KAKENHI Grant Number JP 26288014. T. W. thanks JSPS for fellowships.

(1) For recent reviews on C−H transformations, see: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Palladium(II)-Catalyzed C-H Activation/CC Cross-Coupling Reactions: Versatility and Practicality Angew. Chem. Int. Ed. 2009, 48, 5094-5115. (b) Davies, H. M. L.; Morton, D. Guiding Principles for Site Selective and Stereoselective Intermolecular C–H Functionalization by Donor/Acceptor Rhodium Carbenes Chem. Soc. Rev. 2011, 40, 1857-1869. (c) Zhou, M.; Crabtree, R. H. C–H Oxidation by Platinum Group Metal Oxo or Peroxo Species Chem. Soc. Rev. 2011, 40, 1875-1884. (d) Kuninobu, Y.; Takai, K. Organic Reactions Catalyzed by Rhenium Carbonyl Complexes Chem. Rev. 2011, 111, 19381953. (e) Gutekunst, W. R.; Baran, P. S. C–H Functionalization Logic in Total Synthesis Chem. Soc. Rev. 2011, 40, 1976-1991. (f) Hartwig, J. F. Regioselectivity of the Borylation of Alkanes and Arenes Chem. Soc. Rev. 2011, 40, 1992-2002. (g) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Rhodium Catalyzed Chelation-Assisted C–H Bond Functionalization Reactions Acc. Chem. Res. 2012, 45, 814-825. (h) Neurfeldt, S. R.; Sanford, M. S. Controlling Site Selectivity in Palladium-Catalyzed C–H Bond Functionalization Acc. Chem. Res. 2012, 45, 936-946. (i) Rouquet, G.; Chatani, N. Catalytic Functionalization of C(sp2)-H and C(sp3)-H Bonds by Using Bidentate Directing Groups Angew. Chem. Int. Ed. 2013, 52, 11726-11743. (j) Gao, K.; Yoshikai, N. Low-Valent Cobalt Catalysis: New Opportunities for C–H Functionalization Acc. Chem. Res. 2014, 47, 1208-1219. (k) Song, G.; Li, X. Substrate Activation Strategies in Rhodium(III)-Catalyzed Selective Functionalization of Arenes Acc. Chem. Res. 2015, 48, 1007-1020. (l) Daugulis, O.; Roane, J; Tran, L. D. Bidentate, Monoanionic Auxiliary-Directed Functionalization of Carbon–Hydrogen Bonds Acc. Chem. Res. 2015, 48, 1053-1064. (m) Kuninobu, Y.; Sueki, S. C–H Bond Transformations Leading to the Synthesis of Organic Functional Materials Synthesis 2015, 47, 3823-3845. (n) Hartwig, J. F. Evolution of C–H Bond Functionalization from Methane to Methodology J. Am. Chem. Soc. 2016, 138, 2-24. (o) Moselage, M.; Li, J.; Ackermann, L. Cobalt-Catalyzed C–H Activation ACS Catal. 2016, 6, 498-525. (p) Jiao, J.; Murakami, K.; Itami, K. Catalytic Methods for Aromatic C–H Amination: An Ideal Strategy for Nitrogen-Based Functional Molecules ACS Catal. 2016, 6, 610-633. (q) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Mild metal-catalyzed C–H activation: examples and concepts Chem. Soc. Rev. 2016, 45, 2900-2936. (2) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. Highly Regioselective Arylation of sp3 C−H Bonds Catalyzed by Palladium Acetate J. Am. Chem. Soc. 2005, 127, 13154-13155. (3) (a) He, G.; Chen, G. A Practical Strategy for the Structural Diversification of Aliphatic Scaffolds through the Palladium-Catalyzed Picolinamide-Directed Remote Functionalization of Unactivated C(sp3)-H Bonds Angew. Chem. Int. Ed. 2011, 50, 5192-5196. (b) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. Highly Efficient Syntheses of Azetidines, Pyrrolidines, and Indolines via Palladium Catalyzed Intramolecular Amination of C(sp3)–H and C(sp2)–H Bonds at  and  Positions J. Am. Chem. Soc. 2012, 134, 3-6. (c) Xie, Y.; Yang, Y.; Huang, L.; Zhang, X.; Zhang, Y. Pd-Catalyzed Arylation/Oxidation of Benzylic C–H Bond Org. Lett. 2012, 14, 1238-1241. (d) Zhang, S.-Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G. Efficient Alkyl Ether Synthesis via Palladium-Catalyzed, Picolinamide-Directed Alkoxylation of Unactivated C(sp3)–H and C(sp2)–H Bonds at Remote Positions J. Am. Chem. Soc. 2012, 134, 7313-7316. (e) Zhang, S.-Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. Palladium-Catalyzed Picolinamide-Directed Alkylation of Unactivated C(sp3)–H Bonds with Alkyl Iodides J. Am. Chem. Soc. 2013, 135, 2124-2127. (f) Roman, D. S.; Charette, A. B. C–H Functionalization of Cyclopropanes: A Practical Approach Employing a Picolinamide Auxiliary Org. Lett. 2013, 15, 4394-4397. (g) Nadres, E. T.; Santos, G. I. F.; Shabashov, D.; Daugulis, O. Scope and Limitations of Auxiliary-Assisted, Palladium-Catalyzed Arylation and Alkylation of sp2 and sp3 C–H Bonds J. Org. Chem. 2013, 78, 9689-9714. (h) Ju, L.; Yao, J.; Wu, Z.; Liu, Z.; Zhang, Y. Palladium-Catalyzed Oxidative Acetoxylation of Benzylic C–H Bond Using Bidentate Auxiliary J. Org. Chem. 2013, 78, 10821-10831. (i) Tran, L. D.; Roane, J.; Daugulis, O. Directed Amination of Non-Acidic Arene C-H Bonds by a Copper–Silver Catalytic System Angew. Chem. Int. Ed. 2013, 52, 6043-6046. (j) Cheng, T.; Yin, W.; Zhang, Y.; Zhang, Y.; Huang, Y. Palladium Catalyzed Acetoxylation of Benzylic C–H Bonds using a Bidentate

ACS Paragon Plus Environment

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Picolinamide Directing Group Org. Biomol. Chem. 2014, 12, 14051411. (k) Seki, A.; Takahashi, Y.; Miyake, T. Synthesis of cis-3-Arylated Cycloalkylamines through Palladium-Catalyzed Methylene sp3 Carbon–Hydrogen Bond Activation Tetrahedron Lett. 2014, 55, 28382841. (l) Li, Q.; Zhang, S.-Y.; He, G.; Nack, W. A.; Chen, G. PalladiumCatalyzed Picolinamide-Directed Acetoxylation of Unactivated C(sp3)-H Bonds of Alkylamines Adv. Synth. Catal. 2014, 356, 15441548. (m) Wang, Z.; Kuninobu, Y.; Kanai, M. Copper-Catalyzed Intramolecular C(sp3)-H and C(sp2)-H Amidation by Oxidative Cyclization Angew. Chem. Int. Ed. 2014, 53, 3496-3499. (n) Kanyiva, K. S.; Kuninobu, Y.; Kanai, M. Palladium-Catalyzed Direct C–H Silylation and Germanylation of Benzamides and Carboxamides Org. Lett. 2014, 16, 1968-1971. (o) Cui, W.; Chen, S.; Wu, J.-Q.; Zhao, X.; Hu, W.; Wang, H. Palladium-Catalyzed Remote C(sp3)–H Arylation of 3-Pinanamine Org. Lett. 2014, 16, 4288-4291. (p) Zhang, L.-S.; Chen, G.; Wang, X.; Guo, Q.-Y.; Zhang, X.-S.; Pan, F.; Chen, K.; Shi, Z.-J. Direct Borylation of Primary C-H Bonds in Functionalized Molecules by Palladium Catalysis Angew. Chem., Int. Ed. 2014, 53, 3899-3903. (q) Martinez, A. M.: Rodriguez, N.; Arrayas, R. G.; Carretero, J. C. Copper-Catalyzed ortho-C–H Amination of Protected Anilines with Secondary Amines Chem. Commun. 2014, 50, 2801-2803. (r) Wang, Z.; Kuninobu, Y.; Kanai, M. Copper-Mediated Direct C(sp3)–H and C(sp2)–H Acetoxylation Org. Lett. 2014, 16, 4790-4793. (4) For copper-catalyzed formation of aryl ethers using picolinamide ligands, see: Sambiagio, C.; Munday, R. H.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C. Picolinamides as Effective Ligands for CopperCatalysed Aryl Ether Formation: Structure–Activity Relationships, Substrate Scope and Mechanistic Investigations Chem. Eur. J. 2014, 20, 17606-17615. (5) (a) Dieter, R. K. Reaction of Acyl Chlorides with Organometallic Reagents: A Banquet Table of Metals for Ketone Synthesis Tetrahedron 1999, 55, 4177-4236. b) Sibi, M. P. Chemistry of N-Methoxy-N-Methylamides. Applications In Synthesis. A Reveiw Org. Prep. Proced. Int. 1993, 25, 15-40. (c) O’s Neill, B. T. In Comprehensive Organic Synthesis (Nucleophilic Addition to Carboxylic Acid Derivatives); Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, pp 397-458. (6) For several examples of the synthesis of ketones from aldehydes, see: (a) Ishiyama, T.; Hartwig, J. A Heck-Type Reaction Involving Carbon−Heteroatom Double Bonds. Rhodium(I)-Catalyzed Coupling of Aryl Halides with N-Pyrazyl Aldimines J. Am. Chem. Soc. 2000, 122, 12043. (a) Huang, Y.-C.; Majumdar, K. K.; Cheng, C.-H. Nickel-Catalyzed Coupling of Aryl Iodides with Aromatic Aldehydes:  Chemoselective Synthesis of Ketones J. Org. Chem. 2002, 67, 1682-1684. (b) Pucheault, M.; Darses, S.; Genet, J.-P. Direct Access to Ketones from Aldehydes via Rhodium-Catalyzed Cross-Coupling Reaction with Potassium Trifluoro(organo)borates J. Am. Chem. Soc. 2004, 126, 1535615357. (c) Ruan, J.; Saidi, O.; Iggo, J. A.; Xiao, J. Direct Acylation of Aryl Bromides with Aldehydes by Palladium Catalysis J. Am. Chem. Soc. 2008, 130, 10510-10511. (f) Tang, B.-X.; Song, R.-J.; Wu, C.-Y.; Liu, Y.; Zhou, M.-B.; Wei, W.-T.; Deng, G.-B.; Yin, D.-L.; Li, J.-H. Copper-Catalyzed Intramolecular C−H Oxidation/Acylation of FormylN-arylformamides Leading to Indoline-2,3-diones J. Am. Chem. Soc. 2010, 132, 8900. (g) Tripathi, S.; Singh, S. N.; Yadav, L. D. S. MetalFree Efficient Cross Coupling of Aromatic Aldehydes with Aryldiazonium tetrafluoroborates using DTBP as a Radical Initiator Tetrahedron Lett. 2015, 56, 4211. (d) Suchand, B.; Satyanarayana, G. PalladiumCatalyzed Environmentally Benign Acylation J. Org. Chem. 2016, 81, 6409-6423. (e) Zahng, X.; MacMillan, D. W. C. Direct Aldehyde C–H Arylation and Alkylation via the Combination of Nickel, Hydrogen Atom Transfer, and Photoredox Catalysis J. Am. Chem. Soc. 2017, 139,

Page 6 of 7

11353-11356. (f) Vandavasi, J. K.; Hua, X.; Halima, H. B.; Newman, S. G. A Nickel-Catalyzed Carbonyl-Heck Reaction Angew. Chem. Int. Ed. 2017, 56, 15441-15445. For several examples of the synthesis of ketones from aldehydes via C-H bond activation with a directing group, see: (g) Satoh, T.; Itaya, T.; Miura, M.; Nomura, M. Palladium-Catalyzed Coupling Reaction of Salicylaldehydes with Aryl Iodides via Cleavage of the Aldehyde C-H Bond Chem. Lett. 1996, 25, 823-824. (h) Ko, S.; Kang, B.; Chang, S. Cooperative Catalysis by Ru and Pd for the Direct Coupling of a Chelating Aldehyde with Iodoarenes or Organostannanes Angew. Chem. Int. Ed. 2005, 44, 455-457. (i) Whittaker, A. M.; Dong, V. M. Nickel-Catalyzed Dehydrogenative Cross-Coupling: Direct Transformation of Aldehydes into Esters and Amides Angew. Chem. Int. Ed. 2015, 54, 1312-1315. (j) Nowrouzi, N.; Motevalli, S.; Tarokh, D. J. Mol. Catal. A 2015, 396, 224-230. (k) Rao, M. L. N.; Ramakrishna, B.S. Rhodium-Catalyzed Directing-Group-Assisted Aldehydic C-H Arylations with Aryl Halides Eur. J. Org. Chem. 2017, 34, 5080-5093. (7) The reaction with 1.2 equiv amount of 4a gave the product in 88% yield. However some aryl bromides gave the corresponding ketones in moderate yields. We decided to investigate the scope of aldehydes and aryl bromides using 3 equiv amount of aryl bromides. (8) Crawford, J. J.; Henderson, K.W.; Kerr, W. J. Direct and Efficient OnePot Preparation of Ketones from Aldehydes Using N-tert-Butylphenylsulfinimidoyl Chloride Org. Lett. 2006, 8, 5073-5076. (9) (a) Toh, Q. Y.; Mcnally, A.; Vera, S.; Erdmann, N.; Gaunt, M. J. Organocatalytic C–H Bond Arylation of Aldehydes to Bis-heteroaryl Ketones J. Am. Chem. Soc. 2013, 135, 3772-3775. (b) Demkiw, K.; Araki, H.; Elliott, E.; Frankline, C.; Fukuzumi, Y.; Hicks, F.; Hosoi, K.; Hukui, T.; Ishimaru, Y.; O’Brien, E.; Omori, Y.; Mineno, M.; Mizufune, H.; Sawada, N.; Sawai, Y.; Zhu, L. A Nitrogen-Assisted One-Pot Heteroaryl Ketone Synthesis from Carboxylic Acids and Heteroaryl Halides J. Org. Chem. 2016, 81, 3447-3456. (10) (a) Whittaker, A. M.; Dong, V. M. Nickel-Catalyzed Dehydrogenative Cross-Couling: Direct Transformation of Aldehydes into Esters and Amides Angew. Chem. Int. Ed. 2015, 54, 1312-1315. (b) Modak, A.; Rana, S.; Phukan, A. K.; Maiti, D. Palladium-Catalyzed Deformylation Reactions with Detailed Experimental and in Silico Mechanistic Studies Eur. J. Org. Chem. 2017, 4168-4174. (11) Almost all Pd(II)-catalyzed C-H activation reactions using a bidentate directing group proceeded via the formation of Pd(IV) intermediate: (a) Tremont, S. J.; Rahman, H. U. Ortho-alkylation of acetanilides using alkyl halides and palladium acetate J. Am. Chem. Soc. 1984, 106, 57595760. (b) Catellani, M.; Motti, E.; Ca’, N. D.; Ferraccioli, R. Recent Developments in Catalytic Aryl Coupling Reactions Eur. J. Org. Chem. 2007, 4153-4165. (c) Topczewski, J. J.; Sanford, M. S. Carbon–hydrogen (C–H) bond activation at Pd(IV): a Frontier in C–H functionalization catalysis Chem. Sci. 2015, 6, 70-76. See also, ref. 3. (12) For the results of DFT calculations, see the Supporting information. (13) (a) Gou, Q.; Deng, Bin.; Qin J. Palladium-Catalyzed Arylation of (Di)azinyl Aldoxime Ethers by Aryl Iodides: Stereoselective Synthesis of Unsymmetrical (E)-(Di)azinylaryl Ketoxime Ethers Chem. Eur. J. 2015, 21, 12586-12591. (b) Yu, Y.; Lu, Q.; Chen. G.; Li, C.; Huang, X. Palladium-Catalyzed Intermolecular Acylation of Aryl Diazoesters with ortho-Bromobenzaldehydes Angew. Chem. Int. Ed. 2018, 57, 319-323. (14) Tatamidani, H.; Kakiuchi, F.; Chatani, N. A New Ketone Synthesis by Palladium-Catalyzed Cross-Coupling Reactions of Esters with Organoboron Compounds Org. Lett. 2004, 6, 3597-3599.

ACS Paragon Plus Environment

Page 7 of 7 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis We developed a palladium-catalyzed C-H transformation enabling 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 DFT calculations indicated the C-H bond activation pathway.

ACS Paragon Plus Environment

7