Monodentate Transient Directing Group Enabled Pd-Catalyzed Ortho

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Monodentate Transient Directing Group Enabled Pd-Catalyzed Ortho-C−H Methoxylation and Chlorination of Benzaldehydes Feng Li,†,§ Yirong Zhou,‡,§ Heng Yang,† Ziqi Wang,† Qinqin Yu,† and Fang-Lin Zhang*,† †

School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan 430070, China Key Laboratory of Functional Small Organic Molecules, Ministry of Education, College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China

‡

Org. Lett. Downloaded from pubs.acs.org by UNIV OF ROCHESTER on 05/08/19. For personal use only.

S Supporting Information *

ABSTRACT: We report Pd-catalyzed ortho-C−H methoxylation and chlorination of benzaldehydes by employing monodentate transient directing groups (TDGs) as an alternative strategy to bidentate TDGs. More importantly, a single crystal of benzaldehyde imine ortho-cyclopalladium intermediate was successfully obtained, and its structure was unambiguously determined by X-ray diffraction, which clearly showed that it was a binuclear palladium species bridged by a pyridone ligand. The utility of this approach was further demonstrated through the synthesis of key intermediates of natural products and drugs.

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Scheme 1. C(sp2)−H Functionalization of Benzaldehydes

ransition-metal-catalyzed C−H functionalizations proved to be a powerful strategy to access valuable complex molecules with high selectivity and efficiency. Omitting the covalent installation and removal of the stoichiometric directing groups, transient directing groups (TDGs), which form reversible linkages with the substrates in situ, constitute a promising alternative approach to direct metal-catalyzed C−H functionalizations.1 Since Yu’s breakthrough work employing amino acids as bidentate transient directing groups (BiTDGs) for Pd-catalyzed arylation of o-alkyl benzaldehydes and ketones,2 a set of small organic molecules, such as 3-aminopropanoic acid,3 acetohydrazide,4 2-amino-2-methyl-propionic acid,5 anthranilic acid,5,6 orthanilic acid,7 o-sulfinyl aniline,8 and 2-hydroxynicotinaldehyde,9 have been successfully utilized as suitable BiTDGs to enable Pd-catalyzed various C−H functionalizations by our and other groups. Generally, for the above BiTDG activation models, the imine provides the first neutral coordinating site, while the second coordinating site is required to form the stable 5- or 6-membered cyclopalladium intermediate, and most of the achievements for BiTDG-assisted Pd catalysis are restricted in C−H arylation (Scheme 1a).10 It is well-known that a multitude of nitrogen-based motifs, such as heterocycles, imines, and azo groups, have been widely employed as monodentate directing groups due to their strong coordination to various metals.11 However, Pd-catalyzed C−H functionalization using a structurally similar monodentate transient directing group (MonoTDG) remain rare and give generally low yields.8,11 Therefore, the investigation of a new MonoTDG strategy allowing flexible and diverse reactivities is of great importance and highly desirable. Our continuous focus on TDG-mediated C−H functionalizations5,12 prompted us to develop a new catalytic strategy for direct ortho-C−H functionalizations of benzaldehydes via Pd catalysis. Herein, we report a highly effective MonoTDG© XXXX American Chemical Society

enabled Pd-catalyzed ortho-C−H methoxylation13 and chlorination of benzaldehydes with or without the assistance of external ligands14 (Scheme 1b). Moreover, a pyridone ligand bridged binuclear cyclopalladium intermediate was successfully isolated and characterized by X-ray diffraction, which shed light on the plausible reaction mechanism of this new catalytic model.15 The investigation of the effect of TDGs on the bench reaction of ortho-methoxylation of 2-methylbenzaldehyde was initially carried out (Scheme 2). Unfortunately, all of the widely used Received: April 2, 2019

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DOI: 10.1021/acs.orglett.9b01158 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Transient Directing Groups Screening for OrthoMethoxylation of Benzaldehydesa

naphthaldehydes (1s,t). Moreover, a series of other alcohols, such as primary alcohols (ethanol, propanol, n-butanol) and secondary alcohols (2-propanol, cyclobutanol, cyclopentanol, and cyclohexanol), could also be coupled with 2-methylbenzaldehyde to access the corresponding products (the detailed information can be found in Table S7). o-Chlorobenzaldehydes are highly versatile building blocks for the synthesis of drugs and natural products as well as agrochemicals and materials. Encouraged by the above success in the methoxylation of benzaldehydes, we wanted to extend this new MonoTDG strategy for chlorination of benzaldehydes (Scheme 4). In contrast to our previous BiTDG methodology,5 Scheme 4. Transient Directing Groups and Ligand Screening for Ortho-Chlorination of Benzaldehydesa

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Reaction conditions: 2-methylbenzaldehyde (0.4 mmol, 1.0 equiv), MeOH (20.0 equiv), Pd(OAc)2 (10 mol %), T (40 mol %), K2S2O8 (2.0 equiv), DCM (4.0 mL) at 60 °C for 24 h. Isolated yields for all.

BiTDGs (T1−T5) failed to promote the reaction. The poor preliminary results promoted us to explore new MonoTDGs to facilitate the reaction. It was pleasing to observe that 4(trifluoromethyl)aniline (T6) afforded the desired product 1a in 50% isolated yield. Encouraged by these initial results, a series of anilines as MonoTDGs (T7−T12) were further evaluated, and the optimal result was obtained with 3-(trifluoromethyl)aniline (T7) to generate 67% yield 1a. With the optimized reaction conditions in hand, the generality of the substrate scope was investigated (Scheme 3). In general, a Scheme 3. Substrate Scope Investigation for OrthoMethoxylation of Benzaldehydesa a

Reaction conditions: 3-bromobenzaldehyde (0.4 mmol, 1.0 equiv), NCS (1.5 equiv), Pd(OAc)2 (5 mol %), T (10 mol %), L (30 mol %), TFA (10.0 equiv), DCE (4.0 mL) at 80 °C for 24 h. Isolated yields for all.

herein we reduced the loadings of Pd(OAc)2 (5 mol %) and TDG (10 mol %) in the absence of Ag(I) salt. It was disappointing to find that BiTDG anthranilic acid (T4), which was the optimal one in our previously reported conditions,5 only gave the chlorinated product 2a in 30% yield. Fortunately, when moved to MonoTDG T6, the expected product 2a was isolated with 74% yield. Either the other two isomers (T7 and T8) or introduction of one stronger electron-withdrawing CF3 group on the aniline (T9 and T10) did not improve the results. Inspired by Yu and other groups’ work on external ligands acceleration effect in various C−H activation process,14 next, external ligands (L1− L11) were evaluated to exploit ligand acceleration effectiveness. L10 turned out to be the optimal ligand to deliver the chlorinated product 2a in excellent yield of 94%. Finally, control experiments indicated that MonoTDG (T6) was necessary for the successful transformation. Since the optimized procedure was established, the reaction scope for this new catalytic system was explored with or without ligand L10. As demonstrated in Scheme 5, a broad scope of benzaldehydes as well as heterocyclic aldehydes was probed to achieve good to excellent efficiency. Not only simple substituents on the benzene ring (such as halogen atoms and methyl as well as methoxyl groups) but also some traditional directing groups proved to be amenable for this new chlorination process. For instance, this in situ transiently formed imine could override a wide range of functional moieties, including ester (2f and 2q),

a

Reaction conditions: substrate (0.4 mmol, 1.0 equiv), MeOH (20.0 equiv), Pd(OAc)2 (10 mol %), T7 (40 mol %), K2S2O8 (2.0 equiv), DCM (4.0 mL) at 60 °C for 24 h. Isolated yields for all.

broad substrate scope was explored with moderate to good yields. A variety of halogen atoms, including chloride and bromide (1b,c), could be well tolerated, which offers valuable opportunities for further late-stage derivatization. The steric hindrance exhibited significant influence on the transformations. In contrast to ortho-substituted benzaldehydes (1a−1d), the meta-substituted analogues afforded lower efficiencies (1e and 1f), while the para-substituted benzaldehydes delivered dimethoxylated products solely (1g and 1h). It is noteworthy that besides monosubstituted benzaldehydes, a large group of disubstituted benzaldehydes were compatible for this direct methoxylation (1i−1r), and this method was also amenable to B

DOI: 10.1021/acs.orglett.9b01158 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 5. Substrate Scope Investigation for OrthoChlorination of Benzaldehydesa

Scheme 6. Isolation and Subsequent Functionalization of Cyclopalladium Intermediate 3

Scheme 7. Plausible Mechanism

a

Reaction conditions: substrate (0.4 mmol, 1.0 equiv), NCS (1.5 equiv), Pd(OAc)2 (5 mol %), T6 (10 mol %), L10 (30 mol %),TFA (10.0 equiv), DCE (4.0 mL), 80 °C, 24 h. The yields in parentheses (in blue) were obtained without L10. Isolated yields for all. bNCS (2.5 equiv), isolated yields.

carbamate (2p and 2r), sulfonamide (2g), and ketone (2s), etc. In addition, this method was successfully for the late-stage diversification of the pharmaceutical molecule, which contains multiple coordinating sites. In case of a celecoxib analogue, good yield and site-selectivity were achieved (2bb). On one hand, steric hindrance controlled the mono- and diselectivity of the reaction, whereas the para-substituted benzaldehydes furnished dichlorinated products in excellent yields (2m−2s). On the other hand, electronic properties exerted less influence for the reaction. Both the strong electron-donating groups (including methoxyl and benzyloxy groups) and electron-withdrawing moieties (including cyano, nitro, and ester groups) can be well tolerated. Finally, a series of heterocyclic aldehydes (2cc−2ff) were also compatible partners to generate the expected products with moderate yields. To shed light on mechanistic insights for this novel combination strategy, cyclopalladium intermediate 3 was successfully isolated and characterized by X-ray diffraction, which clearly showed that it was a binuclear palladium species bridged by a pyridone ligand (Scheme 6).15 This result suggests a direct crystallographic evidence for external ligand assisted, MonoTDG-directed Pd(II) ortho-C−H insertion into the benzaldehyde mechanistic pathway. Further elaboration of complex 3 could be readily converted into 1a and 2h under the respective standard conditions. The moderate yields are not surprising considering that T7 is not optimal for chlorination and the preformed dimer may not be as reactive as the monomer generated in situ.16 On the basis of the crystallographic analysis of the binuclear cyclopalladium intermediate 3 and as shown in Scheme 7, first, benzaldehyde condenses with T6 or T7 to yield imine A. Then the ortho-C(sp2)−H activation of imine A leads to the formation of the five-membered cyclopalladium intermediate B. There may exist a monomer−dimer equilibrium between B and C.17

Subsequent oxidation addition with NCS or MeOH/potassium persulfate gives tetravalent palladium complex D. The following reductive elimination furnishes the product E along with regeneration of the active catalyst for the next catalytic cycle. Considering that the ortho-substituted benzaldehyde is versatile bifunctional building block for a large number of natural products and drugs, further practical application of this new synthetic strategy was investigated (Scheme 8). Starting from the commercially available 4-methoxy-3-methylbenzaldehyde, a sequential C−H functionalization was successfully Scheme 8. Synthesis of Key Intermediates of Natural Products and Drugs and Gram-Scale Preparation of 2f

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DOI: 10.1021/acs.orglett.9b01158 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

(2) Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q. Science 2016, 351, 252. (3) Yang, K.; Li, Q.; Liu, Y.; Li, G.; Ge, H. J. Am. Chem. Soc. 2016, 138, 12775. (4) Ma, F.; Lei, M.; Hu, L. Org. Lett. 2016, 18, 2708. (5) (a) Liu, X.-H.; Park, H.; Hu, J.-H.; Hu, Y.; Zhang, Q.-L.; Wang, B.L.; Sun, B.; Yeung, K.-S.; Zhang, F.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2017, 139, 888. (b) Wang, D.-Y.; Guo, S.-H.; Pan, G.-F.; Zhu, X.-Q.; Gao, Y.R.; Wang, Y.-Q. Org. Lett. 2018, 20, 1794. (6) (a) Chen, X.; Ozturk, S.; Sorensen, E. J. Org. Lett. 2017, 19, 1140. (b) Chen, X.; Ozturk, S.; Sorensen, E. J. Org. Lett. 2017, 19, 6280. (7) Chen, X.; Sorensen, E. J. J. Am. Chem. Soc. 2018, 140, 2789. (8) Mu, D.; He, G.; Chen, G. Chem. - Asian J. 2018, 13, 2423. (9) Wu, Y.; Chen, Y.; Liu, T.; Eastgate, M. D.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138, 14554. (10) (a) Zhang, X.; Zheng, H.; Li, J.; Xu, F.; Zhao, J.; Yan, H. J. Am. Chem. Soc. 2017, 139, 14511. (b) Hong, K.; Park, H.; Yu, J.-Q. ACS Catal. 2017, 7, 6938. (c) Liu, Y.; Ge, H. Nat. Chem. 2017, 9, 26. (d) Xu, J.; Liu, Y.; Wang, Y.; Li, Y.; Xu, X.; Jin, Z. Org. Lett. 2017, 19, 1562. (e) Li, B.; Seth, K.; Niu, B.; Pan, L.; Yang, H.; Ge, H. Angew. Chem., Int. Ed. 2018, 57, 3401. (f) Wang, J.; Dong, C.; Wu, L.; Xu, M.; Lin, J.; Wei, K. Adv. Synth. Catal. 2018, 360, 3709. (g) Lin, H.; Wang, C.; Bannister, T. D.; Kamenecka, T. M. Chem. - Eur. J. 2018, 24, 9535. (h) St JohnCampbell, S.; Ou, A. K.; Bull, J. A. Chem. - Eur. J. 2018, 24, 17838. (11) (a) Zhang, M.; Zhang, Y.; Jie, X.; Zhao, H.; Li, G.; Su, W. Org. Chem. Front. 2014, 1, 843. (b) St John-Campbell, S.; White, A. J. P.; Bull, J. A. Chem. Sci. 2017, 8, 4840. (c) Xu, Y.; Young, M. C.; Wang, C.; Magness, D. M.; Dong, G. Angew. Chem., Int. Ed. 2016, 55, 9084. (12) (a) Hu, J.-H.; Xu, Y.-C.; Liu, D.-D.; Sun, B.; Yi, Y.; Zhang, F.-L. RSC Adv. 2017, 7, 38077. (b) Li, F.; Zhou, Y.; Yang, H.; Liu, D.; Sun, B.; Zhang, F.-L. Org. Lett. 2018, 20, 146. (c) Tang, M.; Yu, Q.; Wang, Z.; Zhang, C.; Sun, B.; Yi, Y.; Zhang, F.-L. Org. Lett. 2018, 20, 7620. (13) (a) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141. (b) Wang, G.-W.; Yuan, T.-T. J. Org. Chem. 2010, 75, 476. (c) Chen, F.-J.; Zhao, S.; Hu, F.; Chen, K.; Zhang, Q.; Zhang, S.-Q.; Shi, B.-F. Chem. Sci. 2013, 4, 4187. (d) Li, S.; Zhu, W.; Gao, F.; Li, C.; Wang, J.; Liu, H. J. Org. Chem. 2017, 82, 126. (14) (a) Engle, K. M.; Yu, J.-Q. J. Org. Chem. 2013, 78, 8927. For selected examples, see: (b) Chen, G.; Gong, W.; Zhuang, Z.; Andrä, M. S.; Chen, Y.-Q.; Hong, X.; Yang, Y.-F.; Liu, T.; Houk, K. N.; Yu, J.-Q. Science 2016, 353, 1023. (c) Wang, P.; Farmer, M. E.; Yu, J.-Q. Angew. Chem., Int. Ed. 2017, 56, 5125. (d) Chen, Y.-Q.; Wang, Z.; Wu, Y.; Wisniewski, S. R.; Qiao, J. X.; Ewing, W. R.; Eastgate, M. D.; Yu, J.-Q. J. Am. Chem. Soc. 2018, 140, 17884. (e) Cabrera, P. J.; Lee, M.; Sanford, M. S. J. Am. Chem. Soc. 2018, 140, 5599−5606. (15) (a) Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302. (b) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234. (16) Zhang, X.-G.; Dai, H.-X.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 11948−948. (17) (a) Ryabov, A. D. Inorg. Chem. 1987, 26, 1252. (b) Powers, D. C.; Geibel, M. A. L.; Klein, J. E. M. N.; Ritter, T. J. Am. Chem. Soc. 2009, 131, 17050. (18) (a) Zhu, J.; Germain, A. R.; Porco, J. A. Angew. Chem., Int. Ed. 2004, 43, 1239. (b) Williams, D. R.; Shamim, K. Org. Lett. 2005, 7, 4161. (c) Wei, W.-G.; Zhang, Y.-X.; Yao, Z.-J. Tetrahedron 2005, 61, 11882. (d) Clark, R. C.; Lee, S. Y.; Boger, D. L. J. Am. Chem. Soc. 2008, 130, 12355. (e) Lin, L.; Mulholland, N.; Wu, Q.-Y.; Beattie, D.; Huang, S.W.; Irwin, D.; Clough, J.; Gu, Y.-C.; Yang, G.-F. J. Agric. Food Chem. 2012, 60, 4480. (f) Mahajan, J. P.; Mhaske, S. B. Org. Lett. 2017, 19, 2774. (19) Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.; Pierce, M. E.; Price, W. A.; Santella, J. B., III; Wells, G. J.; Wexler, R. R.; Wong, P. C.; Yoo, S.-E.; Timmermans, P. B. M. W. M. J. Med. Chem. 1991, 34, 2525.

accomplished to provide pentasubstituted benzaldehyde 5, which is not easy to access by other means. Compound 5 represents a key synthetic intermediate to construct diverse important natural products and drug molecules, such as fungal metabolite terreinol, polyketide kendomycin, chlorizidine, chlorofusin, and sclerotiorin.18 On the other hand, orthochlorination of imidazolecarbaldehyde 6 provided 7, which can be readily converted to angiotensin II receptor antagonist losartan.19 Finally, an enlarged 10 mmol scale reaction was performed to demonstrate the practicality of the current methodology, generating the desired product 2f without any evident erosion of efficiency. Furthermore, a series of bioactive heterocycles were synthesized through diverse late-stage transformations (see section 2.9 in the Supporting Information). In summary, an unprecedented MonoTDG strategy was successfully developed for Pd-catalyzed direct ortho-C(sp2)−H methoxylation and chlorination of benzaldehydes. Moderate to excellent yields were obtained for a broad substrate scope under mild conditions. On the basis of the X-ray structure of binuclear cyclopalladium intermediate, a plausible mechanism was proposed. This new MonoTDG strategy provided an alternative approach for C−H activation and opened the door for discovering of new reactivities and activation modes. Detailed mechanistic studies and new applications of this TDG strategy are underway in our laboratory.

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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/acs.orglett.9b01158. Experimental details and spectra including fluorescence profiles and NMR spectra (PDF) Accession Codes

CCDC 1886914 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yirong Zhou: 0000-0002-3470-4562 Fang-Lin Zhang: 0000-0002-7472-9713 Author Contributions §

F.L. and Y.Z. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the National Natural Science Foundation of China (No. 21602089). REFERENCES

(1) (a) Zhao, Q.; Poisson, T.; Pannecoucke, X.; Besset, T. Synthesis 2017, 49, 4808. (b) Gandeepan, P.; Ackermann, L. Chem. 2018, 4, 199. (c) St John-Campbell, S.; Bull, J. Org. Biomol. Chem. 2018, 16, 4582. D

DOI: 10.1021/acs.orglett.9b01158 Org. Lett. XXXX, XXX, XXX−XXX