Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Direct Acyloxylation of C(sp2)−H and C(sp2)−X (X = Cl, Br) Bonds in Aromatic Amides Using Copper Bromide and 2‑(4,5-Dihydro-oxazol2-yl)-phenylamine Gang-Jian Li, You-Lu Pan, Yan-Ling Liu, Hai-Feng Xu, and Jian-Zhong Chen* College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang, P. R. China
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S Supporting Information *
ABSTRACT: Here we reported a method for Cu2+-catalyzed ortho-acyloxylation of either the C(sp2)−H or C(sp2)−X (X = Cl, Br) bond of aromatic amides with carboxylic acid, especially olefine acids, to obtain corresponding products in good yields up to 91%. The catalyst CuBr2 is cheap and stable to conserve in comparison with other metals, like Rh, Pd, Ru, and Cu+. This simple procedure is applicable for wide substrate scope and various functional groups to produce carboxylic esters without any additives or ligands.
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directing group.8 Cu(II)-mediated C(sp2)−H acetoxylation and hydroxylation with the help of different directing groups was also reported.9 Lately, Zhang10 published the work about Cu+catalyzed ortho-acyloxylation of C(sp2)−H bonds of aromatic amides. However, when the reaction scope came to the cinnamic acid, products were obtained in moderate or low yields. Also, Cu+ is not easy to keep stable in air. Herein, we reported the Cu2+-catalyzed direct acyloxylation of C(sp2)−H bonds using 2(4,5-Dihydro-oxazol-2-yl)-phenylamine as the bidentate directing group which could be removed under the alkaline conditions.11 The reaction involved various substrate scopes to achieve high or moderate yields with diverse carboxylic acids. In the meantime, we found that Cu2+ was able to catalyze direct acyloxylation of C(sp2)−X (X = Cl, Br) bonds in our developed approach. Our initial research began with the reaction of 2-methyl-N(quinolin-8-yl) benzamide (1, 1 equiv) and croton acid (2a, 1.5 equiv) using catalyst CuBr (20 mol %) and oxidant Ag2CO3(2.0 equiv) in a component solvent of toluene and DMF (v/v, 3:1) at 130 °C in an air environment for 12 h. After many efforts involved to screen different catalysts, oxidants, and solvents, the yield of the reaction was up to 62% by changing CuBr with CuBr2 and the solvent DMF with DMA. Furthermore, no good consequence was observed by using other oxidants AgNO3, Ag2O, and Ag2SO4, respectively, to replace Ag2CO3 (results not shown here).
n the past decades, it has been widely studied to enable the direct conversion of C−H bonds of organic small molecules into various functional groups through one-step synthetic reaction by metal-promoted C−H bond activation.1 Owing to the C−O bond existing in numerous molecules, such as natural products, drugs, bioactive compounds, agricultural chemicals, and polymers, the method to form a C−O bond via metal catalysis is an important research subject, consuming lots of manpower and material resources.2 Traditionally, the C−O bond was formed by combining carboxylic acids and alcohols or two alcohols. However, this conventional method may have many disadvantages such as low efficiency and inevitable byproducts. Therefore, metal-catalyzed acyloxylation of C−H bonds with the help of directing group has been considered as a powerful means for the synthesis of esters.3 Stanford et al. first reported that Pd could catalyze the conversion from the C(sp2)−H bond to the C(sp2)−O bond with pyridine or other N-containing heteroarenes as directing groups.4 Subsequently, Cheng et al.5 described the transformation of the C(sp2)−H bond of 2-arylpyridines using [Rh(cod)Cl]2 to form the C−O bond without any oxidant. Zhong et al. published the outcomes of Pd-catalyzed direct acyloxylation of C(sp2)−H bonds.6 Ackermann7 demonstrated Ru-catalyzed C−H oxygenation reactions dependent on reusable sulfoximine benzamides. As we can see, these reactions need precious metal catalysts, which make reactions hard to exercise in industry. Due to abundance, cheap price, and low toxicity, copper salts have been the subject of extensive research. Kanai and Ge reported the copper-mediated direct acyloxylation of C(sp3)−H bonds, in which stoichiometric amounts of copper and silver salts were consumed, using 8-aminoquinoline as a bidentate © XXXX American Chemical Society
Received: January 24, 2019
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DOI: 10.1021/acs.orglett.9b00306 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Scheme 1. ortho-Acyloxylation Reaction of N-(2-(4,5Dihydrooxazol-2-yl)phenyl)-2-methylbenzamide with Olefine Acids
A couple of papers reported that the bidentate directing group, 2-(4, 5-dihydro-oxazol-2-yl)-phenylamine, could achieve Cu-mediated C−H thiolation, amination, hydroxylation, arylation, trifluoromethylation, and alkynylation.12 In order to further improve reaction achievement, 2-(4,5-dihydro-oxazol-2yl)-phenylamine was applied instead of 8-aminoquinoline, resulting in producing 3a in a yield of 87% (Table 1, entry 1). Table 1. Optimization of the Reaction Conditionsa
entry
catalyst (mol %)
oxidant
time (h)
yield (%)b
1 2 3 4c 5 6 7 8 9 10
CuBr2 (20) CuBr2 (20) CuBr2 (10) CuBr2 (20) CuI (20) CuCl2 (20) Cu(OAc)2 (20) CuBr (20) CuBr2 (20) -
Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3
12 15 12 12 12 12 12 12 12 12
87 87 64 62 77 81 72 78 NRd NRd
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), oxidant (2 equiv), and toluene/DMA (1.5 mL/0.5 mL) in air. bIsolated yield. c Reaction temperation, 120 °C. dNR means no reaction.
In addition, extending the reaction time to 15 h (Table 1, entry 2) did not improve the reaction yield. If the amount of CuBr2 was reduced to 10 mol %, the reaction yield came down to 64% (Table 1, entry 3). In addition, the reaction temperature was demonstrated to have an influence on the yield. The reaction temperature at 120 °C made the yield decrease to 62% (Table 1, entry 4). With the optimal reaction conditions, it was further tested with some other copper sources, such as CuI (Table 1, entry 5), CuCl2 (Table 1, entry 6), Cu(OAc)2 (Table 1, entry 7), or CuBr (Table 1, entry 8), to have a yield decreased in comparison with CuBr2. In the meantime, it was noticed that both CuBr2 and Ag2CO3 were indispensable to produce the desired product in the reaction as shown in entries 9 and 10 in Table 1. However, when the acid was changed to acrylic acid, the yield of product 3b declined sharply to 51% (Scheme 1), and monomethyl fumarate provided the product 3c in a lower yield of 31% (Scheme 1). We also tested Boc-glycine, and as predicted, there was no reaction. We guessed that the ester group or amide group would be unsuitable for this reaction condition. As we further used acetylsalicylic acid and Nacetylanthranilic acid, respectively, as the acyloxylation reagent to react with 1a, there were also no reactions in these two systems. With the above optimal reaction conditions, on the basis of methyl olefin acid, the method was further applied for the C−H acyloxylation of compound 1a with diversely modified cinnamic acid (Scheme 1). At first, cinnamic acid reacted with 1a to produce 3d in a yield of 89% and 4-methylcinnamic acid for a 76% yield of product 3e under the same reaction conditions. Then, it was tested with 1a for its C(sp2)−H acyloxylation with other various cinnamic acids. As shown in Scheme 1, reactions were compatible with cinnamic acids with a large scope of
a
Reaction time was extended to 16 h.
substituents on the phenyl ring, and no substantial substitution effect was ascertained for cinnamic acids. Generally, cinnamic acids with either an electron-donating or electron-withdrawing substituent on the ortho-position of the phenyl ring obtained products (3f and 3i) in a higher yield than those with a substituent on the para-position (3g and 3j) or the metaposition (3h and 3k) of the phenyl ring. Typically, compound 3f was obtained in the yield of 91%. Furthermore, other cinnamic acids with an electron-withdrawing substituent on the paraposition of the phenyl ring were tested to produce corresponding products 3l, 3m, and 3n (reaction time, 16 h) in yields of 83%, 91%, and 75%, respectively. Next, various benzoic acids were also applied to check whether our method was universally applicable to aromatic acids. To our delight, the results were good, almost all of which were in a high or moderate yield as shown in Scheme 2. In detail, benzoic acid made compound 1a ortho-acyloxylated in a high yield of 90% (4a). Furthermore, if benzoic acid has an electrondonating substituent, like the methyl or methoxyl group on the phenyl ring, the C−H acyloxylation of 1a happened to get products, like 4b, 4c, 4d, 4e, 4f, and 4g, in a high yield of more than 87%, and typically the ortho- and para-electron-donating substituent made the reaction in a higher yield than the metagroup. On the other hand, electron-withdrawing substituents, B
DOI: 10.1021/acs.orglett.9b00306 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Reaction Scope with Respect to Aromatic Acids
Scheme 3. Scope of Benzamides
disubstituted product 5a in 45% yield. If we used orthoethylbenzamide as a substance, the yield of product 5b was up to 98%, and the product 5c of ortho-methoxybenzamide was obtained in only a 41% yield. When the electron-withdrawing CF3 and NO2 were at the ortho-position of benzamides, the result was different; that is, one was no reaction (5d), and the other was 78% (5e). We also tested compounds with a fluoro, chloro, or bromide, respectively, at the ortho-position of benzamide. There was an interesting phenomenon that the acyloxylation reaction happened at the site of C6 to replace Cl or Br (not F) to produce the disubstituted products as 5f and 5g shown in Scheme 3, indicating both C(sp2)−H and C(sp2)−X (X = Cl, Br) bonds acyloxylated in our developed approach. Furthermore, it was found that the yield of mono products was very low or zero whether trifluoromethyl, methoxy, or methyl at the meta-position or at the para-position. In some cases, like 5k and 5m, the disubstituted products were dominant, which may be the evidence that 2-(4,5-dihydro-oxazol-2-yl)-phenylamine had a stronger directing function in this condition. Also, we performed another two meaning reactions with the optimal method in hand, as shown in Scheme 4. However, we did not obtain the products we anticipated. Further studies are ongoing. Based on our observations and previous reports,9,13 a plausible mechanism was proposed as described in Scheme 5. First, the reaction could be ignited with Cu2+ inserting into the N,N-bidentate directing group to form the copper complex A. Then, copper in the complex A activates the C−H bond of the aromatic nucleus to produce intermediate B. Next, Br as the easy leaving group is introduced to afford intermediate C. Subsequently, with Br leaving and acyloxy coming, it can produce the targeted molecule. Last, the oxidant of Ag+ oxidizes Cu+ to bring Cu2+ back to result in a closed circulation.
a
Reaction time was extended to 16 h. bReaction time was extended to 20 h.
like halogen, −CF3, −NO2, and −CN, were tested to affect the reaction. Obviously, it was found that these electron-withdrawing substituents on the phenyl ring of benzoic acid did not have a positive effect on the C−H acyloxylation of 1a. Most products (4h−4o) were obtained in a relatively lower yield of around 70% than compound 4a, and compounds 4p and 4q were produced in a much lower yield of about 30%, although reaction time for these products was extended to 16 or 20 h. Another para-substituted benzoic acid, 4-phenyl benzoic acid, reacted with compound 1a to produce 4s in the yield of 80%. In addition, another two kinds of aromatic acids, naphthoic acid and furan-2-carboxylic acid, were provided to react with 1a, producing the products 4r and 4t in the yields of 83% and 58%, respectively. Besides, two aliphatic acids were also tested to achieve good yields for the products 4u (88%) and 4v (70%), indicating our developed method was suitable for either olefin acid, aromatic acid, or aliphatic acid. In addition, we tested different benzamides to enrich the structural variety of targeted products (Scheme 3). When benzamide was employed, it was rational that we got C2,6C
DOI: 10.1021/acs.orglett.9b00306 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
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ACKNOWLEDGMENTS Support for this project was provided by the National Natural Science Foundation of China (81773638, 81473135) and the Natural Science Foundation of Zhejiang Province (LZ18H300001). We thank Jianyang Pan (Research and Service Center, College of Pharmaceutical Sciences, Zhejiang University) for performing NMR spectrometry for structure elucidation.
Scheme 4. Direction of Struggling
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To sum up, we have developed an effective method for the ortho-acyloxylation of benzamides with the olefinic acids by the aid of copper bromide, which is more stable and easier to conserve. Also, this reaction condition is applicable for aliphatic carboxylic acid and aromatic carboxylic acid; that is, it has a wide substrate scope and good functional group compatibility.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00306. Experimental procedures and spectroscopic data for all new compounds (PDF)
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REFERENCES
(1) Ackermann, L. Acc. Chem. Res. 2014, 47, 281−295. Ackermann, L. Org. Process Res. Dev. 2015, 19, 260−269. Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792−9826. Bergman, R. G. Nature 2007, 446, 391−393. Li, G.; Leow, D.; Wan, L.; Yu, J. Q. Angew. Chem. 2013, 125, 1283−1285. Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147−1169. Rao, W. H.; Zhan, B. B.; Chen, K.; Ling, P. X.; Zhang, Z. Z.; Shi, B. F. Org. Lett. 2015, 17, 3552−3555. Seki, M. Org. Process Res. Dev. 2016, 20, 867−877. Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173−1193. Tang, C.; Jiao, N. J. Am. Chem. Soc. 2012, 134, 18924−18927. Wang, D. H.; Engle, K. M.; Shi, B. F.; Yu, J. Q. Science 2010, 327, 315−319. Wencel-Delord, J.; et al. Chem. Soc. Rev. 2011, 40, 4740−4761. (2) Imramovský, A.; Jorda, R.; Pauk, K.; Rezníčková, E.; Dušek, J.; Hanusek, J.; Kryštof, V. Eur. J. Med. Chem. 2013, 68, 253−259. Wang, S.; Beck, R.; Blench, T.; Burd, A.; Buxton, S.; Malic, M.; Ayele, T.; Shaikh, S.; Chahwala, S.; Chander, C.; et al. J. Med. Chem. 2010, 53, 1465−1472. Fuerst, E. P.; Arntzen, C. J.; Pfister, K.; Penner, D. Weed Sci. 1986, 34, 344−353. May, J. A.; Heptinstall, S.; et al. Platelets 1998, 9, 227−232. Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451−3479. Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400−5449. Theil, F. Angew. Chem., Int. Ed. 1999, 38, 2345−2347. (3) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147−69. Gou, F. R.; Wang, X. C.; Huo, P. F.; Bi, H. P.; Guan, Z. H.; Liang, Y. M. Org. Lett. 2009, 11, 5726−5729. Moghimi, S.; Mahdavi, M.; Shafiee, A.; Foroumadi, A. Eur. J. Org. Chem. 2016, 2016, 3282−3299. (4) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542−9543. (5) Ye, Z.; Wang, W.; Luo, F.; Zhang, S.; Cheng, J. Org. Lett. 2009, 11, 3974−3977. (6) Santra, S. K.; Banerjee, A.; Khatun, N.; Patel, B. K. Eur. J. Org. Chem. 2015, 2015, 350−356. Wang, Z.; Kuang, C. Adv. Synth. Catal. 2014, 356, 1549−1554. Patpi, S.; Sridhar, B.; Tadikamalla, P.; Kantevari, S. RSC Adv. 2013, 3, 10251−10261. Hu, C. J.; Zhang, X. H.; Lv, T.; Ge, S. P.; Ping, Z. Tetrahedron Lett. 2012, 53, 2465−2468. (7) Raghuvanshi, K.; Zell, D.; Ackermann, L. Org. Lett. 2017, 19, 1278−1281. (8) Wang, Z.; Kuninobu, Y.; Kanai, M. Copper-mediated direct C (sp3)−H and C (sp2)−H acetoxylation. Org. Lett. 2014, 16, 4790− 4793. Wu, X.; Zhao, Y.; Ge, H. Chem. - Asian J. 2015, 10, 499−499. (9) Sun, S. Z.; Shang, M.; Wang, H. L.; et al. J. Org. Chem. 2015, 80, 8843−8848. Li, X.; Liu, Y. H.; Gu, W. J.; Li, B.; Chen, F. J.; Shi, B. F. Org. Lett. 2014, 16, 3904−3907. (10) Wang, F.; Hu, Q.; Shu, C.; Lin, Z.; Min, D.; Shi, T.; Zhang, W. Org. Lett. 2017, 19, 3636−3639. (11) Shang, M.; Sun, S. Z.; Dai, H. X.; Yu, J. Q. J. Am. Chem. Soc. 2014, 136, 3354−3357. (12) Shang, M.; Wang, H. L.; Sun, S. Z.; et al. J. Am. Chem. Soc. 2014, 136, 11590−11593. Shang, M.; Sun, S. Z.; Wang, H. L.; et al. Angew. Chem., Int. Ed. 2014, 53, 10439−10442. Shang, M.; Wang, M. M.; SaintDenis, T. G.; et al. Angew. Chem., Int. Ed. 2017, 56, 5317−5321. Kong, W. J.; Shao, Q.; Li, M. H.; et al. Organometallics 2018, 37, 2832−2836. Xu, L. L.; Wang, X.; Ma, B.; et al. Chem. Sci. 2018, 9, 5160−5164. (13) Shang, M.; Sun, S. Z.; Dai, H. X.; Yu, J. Q. Org. Lett. 2014, 16, 5666−9. Lin, C.; Chen, Z.; Liu, Z.; Zhang, Y. Adv. Synth. Catal. 2018, 360, 519−532.
Scheme 5. Plausible Mechanism
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Letter
AUTHOR INFORMATION
Corresponding Author
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[email protected]. ORCID
Jian-Zhong Chen: 0000-0001-7990-7876 Notes
The authors declare no competing financial interest. D
DOI: 10.1021/acs.orglett.9b00306 Org. Lett. XXXX, XXX, XXX−XXX
