[4 + 2] Annulation Cascades of 2-Bromo-1-arylpropan-1-ones with

Letter Cite This: Org. Lett. 2018, 20, 4659−4662

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[4 + 2] Annulation Cascades of 2‑Bromo-1-arylpropan-1-ones with Terminal Alkynes Involving C−Br/C−H Functionalization Xuan-Hui Ouyang,†,§ Chao Hu,†,§ Ren-Jie Song,*,† and Jin-Heng Li*,†,‡ †

Key Laboratory of Jiangxi Province for Persistent Pollutants Control and Resources Recycle, Nanchang Hangkong University, Nanchang 330063, China ‡ State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China

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S Supporting Information *

ABSTRACT: Straightforward access to various substituted naphthalenones by copper-catalyzed [4 + 2] annulation cascades of 2-bromo-1-arylpropan-1-ones with terminal alkynes is presented. Employing a Cu(MeCN)4PF4 catalyst and 1,10phenanthroline (1,10-Phen) ligand enables the formation of three new C−C bonds in a single reaction via [4 + 2] annulation of a 2-bromo-1-arylpropan-1-one with an alkyne followed by α-alkylation with the other 2-bromo-1-arylpropan-1-one with excellent functional group tolerance and step efficiency.

N

bromo-1,3-dicarbonyl compounds in the presence of Ir(ppy)2(dtbbpy)PF6 catalysis (Scheme 1a).5 Recently, the

aphthalenones are an important class of structural motifs found in bioactive compounds and natural products.1 As an example, Perenniporide A (Figure 1) showed antifungal

Scheme 1. Tandem Annulation of 2-Bromo-1-arylpropan-1ones and Alkynes

application of α-bromo carbonyl compounds6,7 have long attracted attention from our group and other chemists. In light of the role of naphthalenones and our interest in the development of the annulation reactions of α-bromo carbonyl compounds, herein, we reported a copper-catalyzed cascade [4 + 2] annulation 8 of 2-bromo-1-arylpropan-1-ones with terminal alkynes leading to the construction of substituted naphthalenones (Scheme 1b). We commenced our studies using 2-bromo-1-phenylpropan1-one (1a) and ethynylbenzene (2a) as reaction components to give 2-methyl-2-(1-oxo-1-phenylpropan-2-yl)-4-phenylnaphthalen-1(2H)-one 3aa (Table 1). Treatment of substrate 1a with alkyne 2a, Cu(MeCN)4PF6, and K2CO3 in toluene under argon at 120 °C afforded the desired annulation product 3aa in a 61% yield (entry 1). A higher yield was achieved with

Figure 1. Representative bioactive examples of naphthalenones.

activity against five plant pathogens,1g including Fusarium moniliforme, Verticillium alboatrum, Gibberella zeae, Fusarium oxysporum, and Alternaria longipes. Classical protocols for the syntheses of naphthalenone derivatives mainly focus on the intramolecular tandem cyclization of α-alkynyl aryl ketones enabled by palladium, copper, manganese, or peroxide.2 However, the substituted groups in substrates limited these protocols for accessing the structural diversity of naphthalenones. Therefore, the development of new general strategies to selectively construct the polysubstituted naphthalenone skeletons from simple starting materials would be interesting.3 Carbocyclizations of alkynes with arenes and alkenes has unarguably become an importantly strategy for the synthesis of heterocyclic and carbocyclic compounds.4 In 2013, Zhang, Yu and co-workers reported the synthesis of naphthols via a visible-light promoted tandem coupling of alkynes with 2© 2018 American Chemical Society

Received: June 23, 2018 Published: July 19, 2018 4659

DOI: 10.1021/acs.orglett.8b01962 Org. Lett. 2018, 20, 4659−4662

Letter

Organic Letters Table 1. Screening of Optimal Conditionsa

Scheme 2. Variation of the Terminal Alkynes (2)a

entry

[Cu salt]

ligand

base

solvent

yield (%)b

1 2 3 4 5 6 7 8 9c 10d 11 12 13 14 15 16 17 18e 19f 19g

Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 CuI CuCl CuBr2 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6 Cu(MeCN)4PF6

 L1 L2 L3 L4 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1

K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 Na2CO3 Ag2CO3 Et3N  K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3

toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene PhCl MeCN dioxane toluene toluene toluene

61 82 76 21 trace 74 57 46 83 73 57 54 trace 0 79 74 77 80 78 75

a Reaction conditions: 1a (0.2 mmol), 2 (0.1 mmol), K2CO3 (0.4 mmol), Cu(MeCN)4PF6 (10 mol %) and L1 (20 mol %), toluene (2 mL) at 120 °C under argon atmosphere for 16 h. The dr value is given in the parentheses determined by GC-MS analysis of the crude products.

a Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), [Cu] (0.01 mmol), ligand (0.02 mmol), base (0.4 mmol), solvent (2 mL) at 120 °C under argon atmosphere for 16 h. The dr value of 3aa is about 1.1:1 determined by GC-MS analysis of the crude products. bIsolated yield. cCu(MeCN)4PF6 (20 mol %) and L1 (40 mol %). d Cu(MeCN)4PF6 (5 mol %) and L1 (10 mol %). eAt 130 °C. fAt 110 °C. g1a (4 mmol), 2a (2 mmol), toluene (5 mL) for 48 h.

electron-withdrawing group 2e were compatible with the reaction conditions and provided products 3ab and 3ae in 78% and 54% yields, respectively. Moreover, the disubstituted alkyne 2i smoothly underwent the tandem reaction with 1a, affording the desired product 4-(3,5-dimethylphenyl)-2-methyl-2-(1-oxo-1-phenylpropan-2-yl)naphthalen-1(2H) -one 3ai in 80% yield. In particularly, the electron-rich heterocycle alkyne 3j was a suitable substrate for the reaction, affording the corresponding product 3aj in 74% yield. It was noteworthy that the reaction performed using 3-ethynylcyclohex-1-ene 2k resulted in the formation of the desired product 3ak in 58% yield with excellent diastereoselectivities. Interestingly, aliphatic alkynes 2l and 2m could convert to the corresponding products 3al and 3am in 49% and 53% yields, respectively, and also had excellent diastereoselectivity under the present reaction conditions. We next evaluated the scope of the tandem cyclization protocol with regard to 2-bromo-1-arylpropan-1-ones 1 in the presence of ethynylbenzene (2a) or 3-ethynylthiophene (2j), Cu(MeCN)4PF6, 1,10-Phen (L1), and K2CO3 (Scheme 3). In general, para-substituted α-bromo aryl ketones 1b−f were well tolerated under the optimal conditions. Various functional groups, such as methoxyl, methyl, bromo, chloro, and fluoro, were compatible with the standard reaction conditions and afforded the corresponding products 3ba−fa in 59−78% yields. Importantly, halogen groups, Br, Cl, and F, were welltolerated, thus providing opportunities for additional modification of the products (3da−fa). The annulation protocol was applicable to meta-substituted α-bromo aryl ketone 1g, giving 3ga in 63% yield. However, the benzo[b]thiophene 4ha, not the expected annulation product 3ha, was obtained from 2-

1,10-phenanthroline L1 (82%, entry 2). Other ligands, such as 2,2′-bipyridine L2, 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine L3, and triphenylphosphane L4, were tested, and the results show that they were less effective than ligand L1 in terms of yield (entries 3−5). We found that Cu(MeCN)4PF6 is superior to other copper salts, such as CuI, CuCl, and CuBr2 (entry 1 vs entries 6−8). Further optimization revealed that 10 mol % of copper salt gave the best result (entries 9−10). A series of other bases, such as Na2CO3, Ag2CO3, and Et3N, were subsequently examined (entries 11−13): Na2CO3 and Ag2CO3 displayed high catalytic activity, but they were less efficient than K2CO3, while only a trace yield of 3aa was detected in the presence of Et3N. However, only a trace yield of product 3aa was detected in the absence of a base (entry 14). Solvent screening showed that toluene was the best solvent compared to PhCl, MeCN, and dioxane (entry 1 vs entries 15−17). We also tested different reaction temperatures and observed that 120 °C was the most efficient (entry 1 vs entries 18−19). Gratifyingly, a reaction scale up to 2 mmol of 2a succeeded in accessing 3a in good yield (entry 20). Under the optimal conditions, the substrate scope of alkynes was explored in Scheme 2. Various electron-donating and electron-withdrawing functional groups, such as Me, Cl, Br, and COMe, on the aryl rings of alkynes were well tolerated.9 For example, substrates bearing electron-donating group 2b or 4660

DOI: 10.1021/acs.orglett.8b01962 Org. Lett. 2018, 20, 4659−4662

Letter

Organic Letters

Based on the above results and previous reports,4−7 the possible mechanism for the copper-catalyzed tandem cyclization is proposed in Scheme 5. A Cu(II) species A was formed

Scheme 3. Variation of the 2-Bromo-1-arylpropan-1-ones (1)a

Scheme 5. Possible Mechanisms

with the aid of the base, and then oxidative addition of Cu(II) species A to alkynes leading to intermediate B, followed by the cyclization of intermediate B to give intermediate C. Reductive elimination of intermediate C formed the intermediate D. Finally, intermediate D reacted with the α-bromo ketone to give the desired product 3aa in the presence of a base. Alternatively, we also proposed a radical mechanism. Cleavage of the C−Br bond of substrate 1a with the Cu(I) species under heating affords the alkyl radical A′ and the Cu(II) species. A radical addition of alkyl radical A′ with alkyne 2a produces the radical intermediate B′, which is then converted to radical intermediate C′, which upon intramolecular cyclization constructs intermediate D. The last step is the same. In summary, we have developed a new copper-catalyzed tandem annulation reaction of 2-bromo-1-arylpropan-1-ones with alkynes for the straightforward synthesis of naphthaleones, in which two-component α-bromo ketones participate in the reaction. Importantly, three new C−C bonds were formed in the reaction; this method is highly efficient and various functional groups are well-tolerated. Work on the detailed mechanistic study and application of the tandem annulation strategy is currently underway in our laboratory.

a

Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), K2CO3 (0.4 mmol), Cu(MeCN)4PF6 (10 mol %) and L1 (20 mol %), toluene (2 mL) at 120 °C under argon atmosphere for 16 h. The dr value is given in the parentheses determined by GC-MS analysis of the crude products. b2-((5-Methyl-7-phenylbenzo[b]thiophen-4-yl)oxy)-1(thiophen-3-yl)propan-1-one (4ha) was obtained in 77% yield.

bromo-1-(thiophen-3-yl)propan-1-one 1h in 77% yield, possibly because the aromaticity of thiophene is less than that of benzene. To gain insight into the mechanism, the standard reaction was performed in the presence of a stoichiometric amount of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), hydroquinone, 2,6-ditert-butyl-4-methylphenol (BHT), and ethene1,1-diyldibenzene which are well-known radical scavengers, and the results show that the formation of product was completely inhibited, implicating a radical process. Substrate 1a and substrate 2a were treated with ethene-1,1-diyldibenzene to form 2-methyl-1,4,4-triphenylbut-3-en-1-one (4aa) in 68% yield (eq 1 in Scheme 4). We can isolate the naphthol derivative 5aa in 48% yield when the excess alkyne 2a was used in this reaction. However, compound 5aa could not converted to the product 3aa, which showed this reaction not process a naphthol intermediate (eq 2 in Scheme 4).

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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.8b01962. Descriptions of experimental procedures for compounds and analytical characterization (PDF)

Scheme 4. Control Experiments

Accession Codes

CCDC 1851204 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 [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 Authors

*E-mail: [email protected]. *E-mail: [email protected]. 4661

DOI: 10.1021/acs.orglett.8b01962 Org. Lett. 2018, 20, 4659−4662

Letter

Organic Letters ORCID

M. Chem. - Eur. J. 2013, 19, 7691. (h) Zhang, X.; Yi, H.; Liao, Z.; Zhang, G.; Fan, C.; Qin, C.; Liu, J.; Lei, A. Org. Biomol. Chem. 2014, 12, 6790. (i) Xu, T.; Cheung, C. W.; Hu, X. Angew. Chem., Int. Ed. 2014, 53, 4910. (j) Fan, J. H.; Wei, W. T.; Zhou, M. B.; Song, R. J.; Li, J.-H. Angew. Chem., Int. Ed. 2014, 53, 6650. (k) Tang, S.; Liu, K.; Liu, C.; Lei, A. Chem. Soc. Rev. 2015, 44, 1070. (l) Fan, J.-H.; Yang, J.; Song, R.-J.; Li, J.-H. Org. Lett. 2015, 17, 836. (m) Cheung, C. W.; Zhurkin, F. E.; Hu, X. J. Am. Chem. Soc. 2015, 137, 4932. (n) Ouyang, X.-H.; Song, R.-J.; Hu, M.; Yang, Y.; Li, J.-H. Angew. Chem., Int. Ed. 2016, 55, 3187. (o) Peacock, D. M.; Roos, C. B.; Hartwig, J. F. ACS Cent. Sci. 2016, 2, 647. (p) Hu, M.; Song, R.-J.; Ouyang, X.-H.; Tan, F.-L.; Wei, W.-T.; Li, J.-H. Chem. Commun. 2016, 52, 3328. (7) (a) Andrews, R. S.; Becker, J. J.; Gagne, M. R. Angew. Chem., Int. Ed. 2010, 49, 7274. (b) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.; Stephenson, C. R. J. Am. Chem. Soc. 2011, 133, 4160. (c) Wallentin, C. J.; Nguyen, J. D.; Finkbeiner, P.; Stephenson, C. R. J. Am. Chem. Soc. 2012, 134, 8875. (d) Devery Iii, J. J.; Douglas, J. J.; Nguyen, J. D.; Cole, K. P.; Flowers Ii, R. A.; Stephenson, C. R. J. Chem. Sci. 2015, 6, 537. (e) Zhang, X.; MacMillan, D. W. J. Am. Chem. Soc. 2016, 138, 13862. (f) Zhang, P.; Le, C. C.; MacMillan, D. W. J. Am. Chem. Soc. 2016, 138, 8084. (g) Li, Y.; Liu, B.; Song, R.-J.; Wang, Q.-A.; Li, J.-H. Adv. Synth. Catal. 2016, 358, 1219. (h) Li, M.; Yang, J.; Ouyang, X.-H.; Yang, Y.; Hu, M.; Song, R.-J.; Li, J.-H. J. Org. Chem. 2016, 81, 7148. (i) Andrews, R. S.; Becker, J. J.; Gagne, M. R. Angew. Chem., Int. Ed. 2012, 51, 4140. (j) Jiang, H.; Cheng, Y.; Wang, R.; Zheng, M.; Zhang, Y.; Yu, S. Angew. Chem., Int. Ed. 2013, 52, 13289. (8) (a) Perrotta, D.; Racine, S.; Vuilleumier, J.; de Nanteuil, F.; Waser, J. Org. Lett. 2015, 17, 1030. (b) Jeon, B.-S.; Wang, S.-A.; Ruszczycky, M. W.; Liu, H.-W. Chem. Rev. 2017, 117, 5367. (c) Ji, D.; Wang, C.; Sun, J.-T. Org. Lett. 2018, 20, 3710. (9) The structure of the product 3ad (CCDC 1851204):

Ren-Jie Song: 0000-0001-8708-7433 Jin-Heng Li: 0000-0001-7215-7152 Author Contributions §

X.-H.O. and C.H. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Natural Science Foundation of China (Nos. 21402046, 21625203, and 21472039), the Jiangxi Province Science and Technology Project (Nos. 20171BCB23055, 20171ACB21032, 20171ACB20015, and 20165BCB18007), and the Jiangxi Educational Committee Foundation of China (No. GJJ160725) for financial support.

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REFERENCES

(1) (a) Ichihara, A.; Miki, S.; Kawagishi, H.; Sakamura, S. Tetrahedron Lett. 1989, 30, 4551. (b) Ingkaninan, K.; Ijzerman, A. P.; Verpoorte, R. J. Nat. Prod. 2000, 63, 315. (c) Petros, R. A.; Ropp, P. A.; DeSimone, J. M. J. Am. Chem. Soc. 2008, 130, 5008. (d) Shushni, M. A.; Mentel, R.; Lindequist, U.; Jansen, R. Chem. Biodiversity 2009, 6, 127. (e) Cimmino, A.; Villegas-Fernandez, A. M.; Andolfi, A.; Melck, D.; Rubiales, D.; Evidente, A. J. Agric. Food Chem. 2011, 59, 9201. (f) Gulder, T.; Hong, H.; Correa, J.; Egereva, E.; Wiese, J.; Imhoff, J.; Gross, H. Mar. Drugs 2012, 10, 2912. (g) Feng, Y.; Wang, L.; Niu, S.; Li, L.; Si, Y.; Liu, X.; Che, Y. J. Nat. Prod. 2012, 75, 1339. (h) Andolfi, A.; Maddau, L.; Cimmino, A.; Linaldeddu, B. T.; Franceschini, A.; Serra, S.; Basso, S.; Melck, D.; Evidente, A. J. Nat. Prod. 2012, 75, 1785. (i) Luo, J. G.; Wang, X. B.; Xu, Y. M.; U’Ren, J. M.; Arnold, A. E.; Kong, L. Y.; Gunatilaka, A. A. Org. Lett. 2014, 16, 5944. (j) Chen, G.; Pi, X. M.; Yu, C. Y. Nat. Prod. Res. 2015, 29, 174. (k) Guo, L.-N.; Zhang, R.; Guo, X.-Y.; Cui, T.; Dong, W.; Huo, J.-H.; Wang, W.-M. Chin. J. Nat. Med. 2015, 13, 707. (l) Zhao, D. L.; Shao, C. L.; Wang, C. Y.; Wang, M.; Yang, L. J.; Wang, C. Y. Molecules 2016, 21, 160. (2) (a) Wong, Y.-C.; Tseng, C.-T.; Kao, T.-T.; Yeh, Y.-C.; Shia, K.-S. Org. Lett. 2012, 14, 6024. (b) Wong, Y.-C.; Kao, T.-T.; Yeh, Y.-C.; Hsieh, B.-S.; Shia, K.-S. Adv. Synth. Catal. 2013, 355, 1323. (c) Wong, Y.-C.; Kao, T.-T.; Huang, J.-K.; Jhang, Y.-W.; Chou, M.-C.; Shia, K.-S. Adv. Synth. Catal. 2014, 356, 3025. (3) (a) Liu, C.; Tang, S.; Liu, D.; Yuan, J.; Zheng, L.; Meng, L.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 3638. (b) Nakatani, A.; Hirano, K.; Satoh, T.; Miura, M. Chem. - Eur. J. 2013, 19, 7691. (c) Nishikata, T.; Noda, Y.; Fujimoto, R.; Sakashita, T. J. Am. Chem. Soc. 2013, 135, 16372. (d) Xu, T.; Hu, X. Angew. Chem., Int. Ed. 2015, 54, 1307. (4) (a) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 10204. (b) Shaw, S.; White, J. D. J. Am. Chem. Soc. 2014, 136, 13578. (c) Zhou, T.; Wang, Y.; Li, B.; Wang, B. Org. Lett. 2016, 18, 5066. (d) Zhang, D.; Liu, J.; Córdova, A.; Liao, W.-W. ACS Catal. 2017, 7, 7051. (e) Xia, Y.; Wang, L.-J.; Wang, J.; Chen, S.; Shen, Y.; Guo, C.H.; Liang, Y.-M. J. Org. Chem. 2017, 82, 12386. (f) Xing, Y.-Y.; Liu, J.B.; Sun, C.-Z.; Huang, F.; Chen, D.-Z. J. Org. Chem. 2018, 83, 4545. (g) Posevins, D.; Qiu, Y.; Bäckvall, J.-E. J. Am. Chem. Soc. 2018, 140, 3210. (5) Jiang, H.; Cheng, Y.; Zhang, Y. Org. Lett. 2013, 15, 4884. (6) (a) Ikeda, Y.; Nakamura, T.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2002, 124, 6514. (b) Affo, W.; Ohmiya, H.; Fujioka, T.; Ikeda, Y.; Nakamura, T.; Yorimitsu, H.; Oshima, K.; Imamura, Y.; Mizuta, T.; Miyoshi, K. J. Am. Chem. Soc. 2006, 128, 8068. (c) Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 11340. (d) Weiss, M. E.; Kreis, L. M.; Lauber, A.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 11125. (e) Liu, C.; Tang, S.; Liu, D.; Yuan, J.; Zheng, L.; Meng, L.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 3638. (f) Nishikata, T.; Noda, Y.; Fujimoto, R.; Sakashita, T. J. Am. Chem. Soc. 2013, 135, 16372. (g) Nakatani, A.; Hirano, K.; Satoh, T.; Miura, 4662

DOI: 10.1021/acs.orglett.8b01962 Org. Lett. 2018, 20, 4659−4662