Palladium-Catalyzed Direct Annulation of Benzoic Acids with Phenols

Letter pubs.acs.org/OrgLett

Palladium-Catalyzed Direct Annulation of Benzoic Acids with Phenols to Synthesize Dibenzopyranones Yang Wang,† Jie-Yu Gu,† and Zhang-Jie Shi*,†,§ †

Beijing National Laboratory for Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China § State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China S Supporting Information *

ABSTRACT: Direct annulation of benzoic acids with phenols via palladiumcatalyzed oxidative coupling is reported. Readily available and inexpensive starting materials were used in this novel method to synthesize highly valuable and useful dibenzopyranone scaffolds. Broad substrate scope and simple operation make this method potentially practical. Preliminary mechanistic studies were conducted to understand this chemistry and inspire new designs of oxidative coupling of different functionalized arenes.

D

dehydrogenative coupling reactions (CDC) were rapidly developed and became more and more important methods for C−C bond formation.6 To produce the desired dibenzopyranone scaffold, the most efficient method may be the sequential direct coupling/lactonization with benzoic acids and phenols. Benzoic acids and phenols are inexpensive and readily available. Both carboxylic7 and hydroxyl8 groups were reported as good directing groups to assist ortho C−H activation. Although transition-metal-catalyzed ortho-functionalization of benzoic acids and phenols have been well developed, the combination of both C−H activations in a single catalytic cycle to construct C−C bonds remains challenging. First, when the first C−H activation occurs, the property of the transition-metal catalyst is changed by formation of metallacycle. The newly formed complexes may not be capable of activating the second C−H bond. Meanwhile, the desired coupling should be conducted under oxidative conditions, and the proper oxidant is essential. However, phenols are electron rich and easy to oxidize or decompose. The side processes will consume the starting material of phenols, and the byproducts may inhibit the desired reaction due to their coordination and/or redox ability. Until now, only one reaction was reported with a very low yield as a side reaction when the CDC reaction was conducted with benzoic acid and phenol.2g Herein, we first successfully reported a novel method for the synthesis of dibenzopyranones via Pdcatalyzed direct annulation of benzoic acids with phenols. We initiated our experiments with 4-tert-butylphenol (1a) and benzoic acid (2a) in the presence of Pd(OAc)2 as catalyst and NaOAc as base in PhMe at 140 °C (Table 1). Only Cu(OAc)2 gave the desired product 3aa in 13% yield, and other oxidants completely failed (entries 1−4). The yield sharply decreased when the reaction was conducted with a catalytic amount of Cu(OAc)2 (entry 5), and a stoichiometric amount of Cu(OAc)2 under N2 atmosphere maintained the efficiency (entry 6). These

ibenzopyranone broadly exists in natural products and pharmaceutical molecules, some of which show broad spectra of biological activities.1 Efficient synthetic methods toward this scaffold are highly desirable. In traditional methods to synthesize dibenzopyranones, aryl halides were commonly used as coupling partners to react with organometallic reagents or C−H bonds (Scheme 1, A)).2 Other methods to synthesize Scheme 1. Synthesis of Dibenzopyranone

dibenzopyranones were also developed to use starting materials with existing biaryl structures (Scheme1, B)).3 In 2015, the Xu group reported another example, using N-methoxybenzamides and hydroquinones as substrates via Rh-catalyzed C−H arylation with quinones as intermediates, while the substrate scope was limited to hydroquinones.4 Current strategies show their reliability, while tedious prefunctionalizations are required from readily available chemicals, thus resulting in complicated manipulations and high costs. Recently, much attention has been paid to transition-metalcatalyzed direct C−H functionalization due to its high atom- and step-economy.5 Taking advantage of these virtues, cross© XXXX American Chemical Society

Received: January 18, 2017

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DOI: 10.1021/acs.orglett.7b00177 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Optimization of Reaction Conditionsa

Scheme 2. Screening of Substrate Scopea

entry

oxidant

base

solvent

yieldb (%)

1 2 3 4 5c 6d 7 8 9 10 11 12 13 14e 15f 16g 17f,h

AgOAc Cu(OAc)2 Cu(OTf)2 CuCl2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2

NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc Li2CO3 Na2CO3 K2CO3 Li3PO4 Li3PO4 Li3PO4 Li3PO4 Li3PO4

PhMe PhMe PhMe PhMe PhMe PhMe DCE t BuPh dioxane t BuPh t BuPh t BuPh t BuPh t BuPh/dioxane t BuPh/dioxane t BuPh/dioxane t BuPh/dioxane

0 13 0 trace 3 11 3 12 6 13 10 trace 15 52 64 37 63

a

All reactions were carried out on a 0.2 mmol scale in 1 mL of solvent under air. bThe yield was determined based on 1H NMR with 1,3benzodioxole as internal standard. c0.2 equiv of Cu(OAc)2 was used. d N2 atmosphere. eVolume of cosolvent: 0.8/0.2 mL. fVolume of cosolvent: 0.7/0.3 mL. gVolume of cosolvent: 0.6/0.4 mL. hDry air was used.

a The volume of the cosolvents is shown in parentheses. bIsolated yield on a 1.0 mmol scale.

chemistry,9 and the yield was moderate (3ja). The acylsubstituted phenol showed high efficiency (3ka). Remarkably, the fluoro and chloro substituents also survived well, and moderate yields were obtained (3la and 3ma), which provided another chance to carry out orthogonal transformations.10 Considering the electronic nature of phenols, the electronpoor ones were better than the electron-rich ones. It is reasonable to assume that the latter were much easier to oxidize. Indeed, methoxy-substituted phenols gave much lower yields (less than 30%). Then, different benzoic acids were surveyed (Scheme 2). When o-, m-, and p-methyl-substituted benzoic acids were used, the desired products (3ib, 3ic, 3id) were isolated in significantly different yields, indicating that the less steric hindered one was favored. Notably, electronic properties of benzoic acids did not affect the efficiency. m-Phenyl-substituted benzoic acid was good, and only one regioisomer (3ie) at a less hindered position was observed. Different F-containing groups were well-tolerated, and o-CF3O-substituted substrate showed good reactivity (3if, 3ih, and 3ij). p-MeO- (3ig) and Cl- (3ii) substituents only gave moderate yields, probably arising from their coordinating ability, which affected the properties of both the catalyst and the oxidant. Disubstituted benzoic acids also showed good reactivity (3ik and 3il), further extending the substrate scope. Unfortunately, with this method, substrates containing heteroarenes such as pyridine, thiophene, furan, and indole showed low reactivity due to their coordination ability (see Table S2). To gain insight into the mechanism, we conducted a series of experiments. To verify whether this reaction was initiated by esterification, we conducted the experiment using phenyl benzoate (4) under the standard conditions. No product was observed, and 4 was recovered in quantity, indicating that the esterification did not occur before the oxidative coupling

results indicated that Cu(OAc)2 was a real oxidant and O2 was not involved. Solvents and bases were screened (entries 7−13). Arene solvent and Li3PO4 were the best choices, although the yields were not ideal. Compound 1a was totally consumed in arenes. While in dioxane, 1a remained with a good quality balance. These results indicated that solvents intensely affected the oxidation of 1a. To our delight, when tBuPh and dioxane were mixed as cosolvent in different ratios (entries 14−16), the yields increased, and the best yield was achieved at 64% (tBuPh/ dioxane = 0.7 mL/0.3 mL). Moisture was harmful, and dry air maintained the same efficiency and made the yield stable (entry 17). Control experiments indicated that both Pd(OAc)2 and Cu(OAc)2 were essential. Other tests, such as lowering the reaction temperature, tuning the ratio of two substrates, diluting the mixture, or using water as additive, lowered the yields (see Table S1, SI). The substrate scope was investigated (Scheme 2). Although simple phenol was much more easily oxidized compared to 1a, 3ba was still isolated in a good yield. The effect of steric hindrance of alkyl substituents was investigated. p-Methylsubstituted phenol gave a moderate yield (3ca). The o-methyl group was unfavorable, and the yield was lower (3da). When a tert-butyl group was at the meta-position, the reaction showed good efficiency and specific regioselectivity at less hindered positions (3ea). Many other functional groups on the phenol moiety were further tested. With a phenyl group, a good yield was obtained (3fa). It was very important to note that the protected hydroxyl group survived (3ga). Indeed, many pharmaceutical dibenzopyranone molecules were multihydroxyl substituted.1 Nitro (3ha) and ester (3ia) were well-tolerated and could be easily converted to amino and carboxylic groups. We tested the trifluoromethyl group, which is important in the pharmaceutical B

DOI: 10.1021/acs.orglett.7b00177 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

considerably helpful for the C−H activation of phenols and the stabilization of palladium catalyst. The similar function of Cu(OAc)2 was proposed by the recent report of metal-catalyzed transformations of simple phenols.12 We further conducted the experiments to identify which C−H bond activation process occurred at the initiating stage. First, we added olefins, which could react with both benzoic acids7a and phenols.8e No matter if activated or nonactivated olefin was added to our standard reaction, only the coupling product of them with the phenol was detected, proving that the C−H activation of phenols occurred before the activation of benzoic acid (Scheme 5, A)). According to the literature,7c we also

(Scheme 3, A)). When either the carboxylic or hydroxyl groups in the starting materials were blocked, the reaction was totally Scheme 3. Control Experiments

Scheme 5. Mechanistic Experiments Relating to C−H Activation

terminated, indicating that the directing groups in both substrates were essential and the method was different from the early reports on palladium catalyzed oxidative arylations (Scheme 3, B)).11 When TEMPO was added, we found that only 8% product was generated, and no TEMPO-radical adducts were detected by GC−MS, which indicated that radical process might not be involved although the efficiency was dramatically affected. The addition of BQ did not not produce the corresponding hydroxyl-substituted dibenzopyranone as well as our desired product, indicating that benzoquinone was not one intermediate (Scheme 3, C)). Cu(OAc) 2 was found to be essential. Even when a stoichiometric amount of Pd(OAc)2 was used, no product was obtained in the absence of Cu(OAc)2, indicating that Cu(OAc)2 played an important role not only as an oxidant. We tested CuOAc, 1,4-benzoquinone, and 2,2′-biphenol, which might exist in the reaction system, as additives instead of Cu(OAc)2, respectively. No observation of 3aa implied that Cu(OAc)2 itself participated in the catalytic cycle. To clarify other possible functions of Cu(OAc)2, we conducted the reactions with only one metal species in the presence of D2O. As for the background reaction without any metal catalyst, the deuterium content of the ortho position of phenol was 35%. The addition of Pd(OAc)2 did not increase the ratio, while Cu(OAc)2 did. Furthermore, when only Pd(OAc)2 was added, Pd black appeared in a few minutes, and no ortho C−H activation of benzoic acid was observed. However, this phenomenon did not occur under standard conditions (Scheme 4). Thus, we conceived that phenols could reduce Pd(II) to Pd(0) to shut down the reaction, while a large amount of Cu(OAc)2 competed with Pd(OAc)2 to form complexes to prevent this process. Therefore, Cu(OAc)2 was

synthesized the palladacycle 5. A stoichiometric amount of 5 was set up to react with 1i in the presence or absence of Pd(OAc)2, and the yields were no more than 5%. Later on, comparative experiments were conducted by using either 5 or 2c to compete with benzoic acid 2a. We found that presynthesized palladacycle inhibited the formation of the corresponding product 3ic (Scheme 5, B)). Based on these results, complex 5 was proven not to be an active intermediate, and the reaction was not initiated by the C−H activation of benzoic acids. We also conducted a series of experiments to measure the isotopic effects (see the SI). Individual reactions of the benzoic acids or phenols and the deuterated ones were conducted, and the rate constants of these reactions were measured. The relatively ratios, which were approximately equal to 1.50 and 1.45, indicated that the C− H cleavage of benzoic acids was probably involved in the ratedetermining step.13 The catalytic pathway was proposed (Scheme 6). With the assistance of base, phenolate coordinated with Cu(OAc)2 and copper 1,3-migration gave complex A. Transmetalation occurred to form palladium−phenol complex B. Following ligand exchange with benzoate, complex C was formed. Subsequently, C−H activation in benzoate moiety occurred, generating complex D. Reductive elimination of complex D gave out complex E with the formation of the new C−C bond. The subsequent oxidation process regenerated Pd(II) catalyst. Lactonization of compound E easily took place under the current conditions, and the product formed. Based on the reported literature,2b,h,14 Pd(II) was capable of the reductive elimination process with these two moieties; thus, the Pd(II)/ Pd(0) catalytic cycle was proposed. We could not exclude the possibility of the oxidation of complex D and a high valent palladium catalytic cycle at the current stage.

Scheme 4. Mechanistic Experiments Relating to Cu(OAc)2.

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Y. J. Am. Chem. Soc. 2007, 129, 9304. (f) Carlson, E. J.; Riel, A. M. S.; Dahl, B. J. Tetrahedron Lett. 2012, 53, 6245. (g) Wu, Z.; Luo, F.; Chen, S.; Li, Z.; Xiang, H.; Zhou, X. Chem. Commun. 2013, 49, 7653. (h) Suarez-Meneses, J. V.; Oukhrib, A.; Gouygou, M.; Urrutigoity, M.; Daran, J. C.; Cordero-Vargas, A.; Ortega-Alfaro, M. C.; Lopez-Cortes, J. G. Dalton Trans. 2016, 45, 9621. (3) (a) Mehta, G.; Pandey, P. N. Synthesis 1975, 1975, 404. (b) Thasana, N.; Worayuthakarn, R.; Kradanrat, P.; Hohn, E.; Young, L.; Ruchirawat, S. J. Org. Chem. 2007, 72, 9379. (c) Li, Y.; Ding, Y.-J.; Wang, J.-Y.; Su, Y.-M.; Wang, X.-S. Org. Lett. 2013, 15, 2574. (d) Luo, S.; Luo, F.-X.; Zhang, X.-S.; Shi, Z.-J. Angew. Chem., Int. Ed. 2013, 52, 10598. (4) Yang, W.; Wang, S.; Zhang, Q.; Liu, Q.; Xu, X. Chem. Commun. 2015, 51, 661. (5) (a) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (c) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293. (d) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (e) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 10236. (f) Gandeepan, P.; Cheng, C.-H. Chem. Asian J. 2015, 10, 824. (6) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (c) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53, 74. (d) Wu, X.; Zhao, Y.; Ge, H. Chem. Sci. 2015, 6, 5978. (e) Zhang, X.-S.; Zhang, Y.-F.; Li, Z.-W.; Luo, F.-X.; Shi, Z.-J. Angew. Chem., Int. Ed. 2015, 54, 5478. (f) Liu, Y.; Yang, K.; Ge, H. Chem. Sci. 2016, 7, 2804. (7) (a) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org. Chem. 1998, 63, 5211. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.Q. Acc. Chem. Res. 2012, 45, 788. (c) Cheng, G.; Li, T.-J.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 10950. (8) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1996, 118, 6305. (b) Guo, X.; Yu, R.; Li, H.; Li, Z. J. Am. Chem. Soc. 2009, 131, 17387. (c) Huang, Z.; Jin, L.; Feng, Y.; Peng, P.; Yi, H.; Lei, A. Angew. Chem., Int. Ed. 2013, 52, 7151. (d) Kuram, M. R.; Bhanuchandra, M.; Sahoo, A. K. Angew. Chem., Int. Ed. 2013, 52, 4607. (e) Sharma, U.; Naveen, T.; Maji, A.; Manna, S.; Maiti, D. Angew. Chem., Int. Ed. 2013, 52, 12669. (f) Zhu, R.; Wei, J.; Shi, Z. Chem. Sci. 2013, 4, 3706. (g) Zhang, X.-S.; Li, Z.-W.; Shi, Z.-J. Org. Chem. Front. 2014, 1, 44. (h) Ochiai, M.; Fukui, K.; Iwatsuki, S.; Ishihara, K.; Matsumoto, K. Organometallics 2005, 24, 5528. (i) Patra, T.; Bag, S.; Kancherla, R.; Mondal, A.; Dey, A.; Pimparkar, S.; Agasti, S.; Modak, A.; Maiti, D. Angew. Chem., Int. Ed. 2016, 55, 7751. (j) Agasti, S.; Sharma, U.; Naveen, T.; Maiti, D. Chem. Commun. 2015, 51, 5375. (9) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (10) (a) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119. (b) Wang, Z.-X.; Guo, W.-J.; Shi, Z.-J., Catalysis In C−Cl Activation. In Homogeneous Catalysis for Unreactive Bond Activation; John Wiley & Sons2014; p 1. (11) (a) Yoshimoto, H.; Itatani, H. J. Catal. 1973, 31, 8. (b) Shiotani, A.; Itatani, H. Angew. Chem., Int. Ed. Engl. 1974, 13, 471. (c) Iataaki, H.; Yoshimoto, H. J. Org. Chem. 1973, 38, 76. (d) Akermark, B.; Eberson, L.; Jonsson, E.; Pettersson, E. J. Org. Chem. 1975, 40, 1365. (12) Zhu, F.; Li, Y.; Wang, Z.; Wu, X.-F. Angew. Chem., Int. Ed. 2016, 55, 14151. (13) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 3066. (14) (a) Hong, L. P. T.; White, J. M.; Donner, C. D. Aust. J. Chem. 2012, 65, 58. (b) Bringmann, G.; Manchala, N.; Büttner, T.; HertleinAmslinger, B.; Seupel, R. Chem. - Eur. J. 2016, 22, 9792.

Scheme 6. Proposed Mechanism

In summary, we developed a novel method to synthesize dibenzopyranones via direct oxidative annulation of benzoic acids and phenols. This process avoids prefunctionalization of both starting materials and significantly shortens synthetic procedures. The broad substrate scope and good functional group compatibility provides the potential for applications. Mechanistic studies indicate that C−H activation occurs before lactonization and Cu(OAc)2 plays dual important roles. Further developments are underway.

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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.7b00177. Experimental procedures, characterization data, and NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zhang-Jie Shi: 0000-0002-0919-752X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the “973” Project from the MOST of China (2013CB228102, 2015CB856600) and NSFC (No. 21431008).

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REFERENCES

(1) (a) Garazd, Y. L.; Garazd, M. M. Chem. Nat. Compd. 2016, 52, 1. (b) Koch, K.; Podlech, J.; Pfeiffer, E.; Metzler, M. J. Org. Chem. 2005, 70, 3275. (c) Sun, W.; Cama, L. D.; Birzin, E. T.; Warrier, S.; Locco, L.; Mosley, R.; Hammond, M. L.; Rohrer, S. P. Bioorg. Med. Chem. Lett. 2006, 16, 1468. (d) Abe, H.; Nishioka, K.; Takeda, S.; Arai, M.; Takeuchi, Y.; Harayama, T. Tetrahedron Lett. 2005, 46, 3197. (2) (a) Harayama, T.; Yasuda, H. Heterocycles 1997, 46, 61. (b) Molander, G. A.; George, K. M.; Monovich, L. G. J. Org. Chem. 2003, 68, 9533. (c) Kemperman, G. J.; Ter Horst, B.; Van de Goor, D.; Roeters, T.; Bergwerff, J.; Van der Eem, R.; Basten, J. Eur. J. Org. Chem. 2006, 2006, 3169. (d) Hussain, I.; Nguyen, V. T. H.; Yawer, M. A.; Dang, T. T.; Fischer, C.; Reinke, H.; Langer, P. J. Org. Chem. 2007, 72, 6255. (e) Zhang, W.; Wilke, B. I.; Zhan, J.; Watanabe, K.; Boddy, C. N.; Tang, D

DOI: 10.1021/acs.orglett.7b00177 Org. Lett. XXXX, XXX, XXX−XXX