Synthesis of Functionalized Biaryls and Poly(hetero)aryl Containing

Letter pubs.acs.org/OrgLett

Synthesis of Functionalized Biaryls and Poly(hetero)aryl Containing Medium-Sized Lactones with Cyclic Diaryliodonium Salts Hao Xie, Mingruo Ding, Min Liu, Tao Hu, and Fengzhi Zhang* College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou, 310014, P. R. China S Supporting Information *

ABSTRACT: A novel one-pot procedure is described for the transition-metal catalyzed sequential difunctionalization of diaryliodonium reagents. Reaction of commercially available anthranilic acid derivatives with readily available cyclic diaryliodonium salts followed by a Sonogashira coupling afforded various alkyne substituted biaryls in good to excellent yields. The functionalized biaryls were then utilized for the rapid and efficient one-pot synthesis of novel poly(hetero)aryl containing 10-membered lactones which are potential G-quadruplex binders and telomerase inhibitors.

F

benzyne intermediate. This method could be limited by the availability of benzyne precursors.12 Due to their excellent usability, stability, and readily availability, linear diaryliodonium salts have been extensively investigated as electrophilic arylation agents for the formation of C−C and C−heteroatom bonds.13−15 Compared to the linear diaryliodonium salts, although most cyclic diaryliodonium salts are poorly reactive, research areas involving these reagents have received increasing interest.16 One example includes double arylation with the same nucleophiles such as alkenes,17 alkynes,18 indoles,19 amines,20 a sulfur source,21 etc. to generate different polycycles respectively (such as methylidenefluorenes, phenanthrenes, carbazoles, and sulfur containing heterocycles). With the exception of these, there are few examples regarding the relay bis-end functionalization of cyclic iodonium salts.22 In 2015, Wen and co-workers reported a good example of relayed regioselective alkynylation/olefination of unsymmetrical cyclic diaryliodonium reagents, which was focused on 7-phenylbenzoxazole synthesis.22a Our interest in arylation chemistry23 led us to investigate whether we could achieve the rapid synthesis of diverse biaryls 3 by O-arylation/ alkynylation relay functionalization of commercially available anthranilic derivatives 1 with cyclic iodonium salts 2 (Scheme 1c), which allows the incorporation of both aryl groups into the products in an atom and step economical manner. More importantly, the valuable functionalized biaryls 3 generated from this novel one-pot process could be further utilized for the rapid construction of novel 10-membered poly(hetero)aryl lactones, a novel class of potential G-quadruplex ligands and telomerase inhibitors.24 We initiated the investigation by performing the copper catalyzed O-arylation of the commercially available 2-amino-3methylbenzoic acid 1a with cyclic diaryliodonium salt 2a

unctionalized biaryls are prevalent in the core structures of pharmaceuticals,1 agochemicals,2 functional materials,3 bioactive natural products,4 and ligands5 (Scheme 1a). Much Scheme 1. Functionalized Biaryls and Their Synthesis

excellent research has been reported for biaryl synthesis,6 with transition-metal catalyzed cross-coupling being especially prominent (Scheme 1b).7 Conventional biaryl syntheses involve the classic cross-coupling (Stille, Negishi, Suzuki, and Heck) between two preactivated partners,8 which could be a time-consuming and economically inefficient process. An attractive alternative to this approach is direct arylation9 or oxidative dehydrogenation arene cross-coupling,10 which could reduce the waste and synthetic steps by treating the aryl C−H bond as a functional group. While such an approach is alluring, the ubiquitous and diverse nature of C−H bonds makes regioselective coupling a formidable challenge.11 Another complementary strategy is aryne biaryl synthesis which entails the addition of a suitable aryl nucleophile to the electrophilic © 2017 American Chemical Society

Received: March 28, 2017 Published: May 8, 2017 2600

DOI: 10.1021/acs.orglett.7b00933 Org. Lett. 2017, 19, 2600−2603

Letter

Organic Letters

catalyst after the completion of step I under the optimum acid biphenylation conditions (entry 14). With optimum conditions in hand, we next examined the scope of this novel tandem process using a range of commercially available anthranilic acid derivatives (Table 2).

followed by Sonogashira coupling with trimethylsilylacetylene (Table 1). Table 1. One-Pot Reaction Optimizationa

Table 2. Arylation/Alkynylation of Various Benzoic Acids

entrya d

1 2e 3 4 5 6 7 8 9 10 11 12 13 14

yield (%)c

step I

step II

solventb

solventb

4a

5a

1,4-dioxane 1,4-dioxane 1,4-dioxane i PrOH toluene PhCl CH3CN DCE THF CH3CN/THF (1:1) CH3CN/1,4-dioxane (1:1) THF/1,4-dioxane (1:1) 1,4-dioxane 1,4-dioxane

− − − − − − − − − − − − CH3CN THF

53 − − − − − − 12 25 − − − − −

8 58 70 35 45 58 58 51 52 59 61 57 76 81

a

Reaction conditions: (1) 0.5 mmol of 1a, 1.0 mmol of 2a, 10 mol % CuI, 10 mol % 1,10-phenanthroline (phen), 1.5 equiv of Na2CO3, 2.0 mL of solvent, 95 °C, 17 h; (2) 10 mol % Pd(PPh3)2Cl2, 10 mol % CuI, 11.4 equiv of Et3N, 2.0 equiv of trimethylsilylacetylene, 50 °C, 20 h. bAnhydrous solvent. cIsolated yields. dNo Et3N in step II. eEt2NH rather than Et3N was used in step II.

a

CH3CN was used as solvent and Et3N was used as base in step 1.

Yields were generally good for anthranilic acids with electronrich substituents (5a−c). Substrates with highly electronwithdrawing groups (such as NO2, CF3) were effective for the reaction (5d−f). Substrates displaying halogenated functionalities or a carbonyl group were tolerated under the reaction conditions to give the corresponding products in good yields (5g−j). Gratifyingly, a heterocyclic acid derivative reacted as well under the optimum conditions (5k). Importantly, we were also pleased to find that other alkynes such as phenyl acetylene and 1-butyne were equally effective as the trimethylsilylacetylene (5l and 5m). To fully establish the scope of this one-pot O-arylation/ alkynylation process, a range of substituted cyclic diaryliodonium salts were prepared according to Olofsson’s method and subjected to the optimized reaction protocol with anthranilic acid derivatives (Table 3).26 Good yields were obtained with the alkyl substituted symmetrical cyclic diaryliodonium salts (6a−e). For the electron-withdrawing halogenated cyclic diaryliodonium salts, we were pleased to find that both the fluoro and chloro groups were tolerated (6f−j). For the unsymmetrical cyclic diaryliodonium salts bearing one aryl ring with a tBu group meta to the iodine center, it was found that 6k/6k′ were obtained as a mixture of products with a ratio of ∼1:1. However, for the unsymmetrical cyclic diaryliodonium salts bearing one aryl ring with a methyl group ortho to the I (III) center and one aryl ring with an electron-withdrawing F group, the only product 6l was obtained with O-arylation taking place at the less hindered and electron-deficient aryl ring, which is consistent with the

Initially we conducted the reaction optimization and established the optimum conditions (10 mol % CuI, 10 mol % 1,10-phenanthroline, 1.5 equiv of Na2CO3, 1,4-dioxane; see the Supporting Information) for acid biphenylation step I. It is worth noting that Albright and Olofsson’s metal-free conditions are not effective for our biphenylation reaction.25 After the first biphenylation step was completed, 10 mol % Pd(PPh3)2Cl2, 10 mol % CuI, and 2.0 equiv of trimethylsilylacetylene were added to the reaction without an additional organic base (Table 1, entry 1). To our disappointment, we only obtained the desired alkyne substituted product 5a in 8% yield along with a 53% yield of the iodo-substituted product 4a when we combined these two reactions. We then undertook some optimization mainly by changing the base or solvent. When Et2NH was added during step II along with the catalyst and alkyne, to our delight the desired alkyne 5a was obtained as the only product in 58% yield (entry 2). By switching the organic base from Et2NH to Et3N, the yield was improved to 70% (entry 3). By using iPrOH, toluene, PhCl, or CH3CN as the solvent, the yield was decreased significantly (entries 4−7). The reactions with either DCE or THF as solvent gave a mixture of compounds 4a and 5a (entries 8−9). The employment of a mixture of solvents in step I still did not result in any improvement in yield (entries 10−12). However, the yield could be improved to 76% by adding CH3CN to the reaction mixture after the reaction of Step I was completed in 1,4-dioxane (entry 13). Finally, we found the desired product 5a could be obtained in optimum 81% yield by adding Et3N and THF along with the Pd/Cu 2601

DOI: 10.1021/acs.orglett.7b00933 Org. Lett. 2017, 19, 2600−2603

Letter

Organic Letters Table 3. Arylation/Alkynylation of Anthrianilic Acid Derivatives with Various Cyclic Diaryliodonium Salts

Table 4. Rapid Synthesis of 10-Membered Poly(hetero)aryl Containing Lactones

findings by Wen and co-workers.18b Overall, with readily available anthranilic acids and cyclic iodonium salts as substrates, various valuable biaryls with both alkyne and amine functionalities were made quickly and efficiently. Finally we are interested in applying the functionalized biaryls for the rapid synthesis of novel poly(hetero)aryl containing cyclic lactones with the Click reaction as the cyclization step, which to date had not been achieved for the synthesis of a poly(hetero)aryl containing medium-sized ring. After reaction conditions optimization, we are pleased to find that the desired lactones could be prepared successfully through a one-pot azidation/cyclization protocol (Table 4). Interestingly, the Click reaction could be carried out under the metalfree heating conditions and only the 10-membered 1,5-isomer was obtained without the detection of the 1,4-isomer. In the presence of a copper catalyst, the Click cyclization reaction still gave the same product in slightly poorer yields shown in parentheses (7a, 7b, and 7e). The structure of the 10membered poly(hetero)aryl lactone 7a was further confirmed by X-ray analysis. Various challenging medium-sized lactones were prepared via this simple one-pot reaction in good yields except the substrates with a meta-nitro group or an orthohalogen close to the carboxylic functionality (7g and 7h), and different functional groups (halogen, nitro, and carbonyl) were tolerated under the optimum conditions. In summary, we have developed a simple one-pot procedure for transition-metal catalyzed sequential difunctionalization of diaryliodonium reagents. Reaction of commercially available anthranilic acid derivatives with readily available cyclic diaryliodonium salts followed by a Sonogashira coupling afforded various alkyne substituted biphenyl esters in good to excellent yields, which were then applied in the fast and

a

With the addition of 5% CuSO4 in step 2. bReaction time: 72 h.

efficient synthesis of novel medium-sized poly(hetero)aryl containing lactones by a one-pot tandem copper-free Click reaction. A wide range of functional groups (such as halogens, nitro, carbonyl, etc.) were tolerated under the reaction conditions. Current efforts in our laboratory are focused on screening the biological activities of these valuable poly(hetero)aryl containing lactones. These results will be reported in due course.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00933. General experimental procedures, characterization details, and 1H and 13C NMR spectra of compounds (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. 2602

DOI: 10.1021/acs.orglett.7b00933 Org. Lett. 2017, 19, 2600−2603

Letter

Organic Letters ORCID

(16) (a) Grushin, V. V. Chem. Soc. Rev. 2000, 29, 315. (b) Chatterjee, N.; Goswami, A. Eur. J. Org. Chem. 2017, DOI: 10.1002/ ejoc.201601651. (17) Kina, A.; Miki, H.; Cho, Y. H.; Hayashi, H. Adv. Synth. Catal. 2004, 346, 1728. (18) (a) Zhu, D.; Wu, Y.; Wu, B.; Luo, B.; Ganesan, A.; Wu, F.; Pi, R.; Huang, P.; Wen, S. Org. Lett. 2014, 16, 2350. (b) Liu, Z.; Zhu, D.; Luo, B.; Zhang, N.; Liu, Q.; Hu, Y.; Pi, R.; Huang, P.; Wen, S. Org. Lett. 2014, 16, 5600. (19) Wu, Y.; Peng, X.; Luo, B.; Wu, F.; Liu, B.; Song, F.; Huang, P.; Wen, S. Org. Biomol. Chem. 2014, 12, 9777. (20) (a) Riedmüller, S.; Nachtsheim, R. J. Beilstein J. Org. Chem. 2013, 9, 1202. (b) Zhu, D.; Chen, M.; Li, M.; Luo, B.; Zhao, Y.; Huang, P.; Xue, F.; Rapposelli, S.; Pi, R.; Wen, S. Eur. J. Med. Chem. 2013, 68, 81. (c) Zhu, D.; Liu, Q.; Luo, B.; Chen, M.; Huang, P.; Pi, R.; Wen, S. Adv. Synth. Catal. 2013, 355, 2172. (21) (a) Wang, M.; Wei, J.; Fan, Q.; Jiang, X. Chem. Commun. 2017, 53, 2918. (b) Wang, M.; Fan, Q.; Jiang, X. Org. Lett. 2016, 18, 5756. (c) Shimizu, M.; Ogawa, M.; Tamagawa, T.; Shigitani, R.; Nakatani, M.; Nakano, Y. Eur. J. Org. Chem. 2016, 2016, 2785. (d) Luo, B.; Cui, Q.; Luo, H.; Hu, Y.; Huang, P.; Wen, S. Adv. Synth. Catal. 2016, 358, 2733. (22) (a) Zhu, D.; Liu, P.; Lu, W.; Wang, H.; Luo, B.; Hu, Y.; Pi, R.; Huang, P.; Wen, S. Chem. - Eur. J. 2015, 21, 18915. (b) Zhang, Y.; Han, J.; Liu, Z.-J. J. Org. Chem. 2016, 81, 1317. (23) (a) Zhang, F.; Greaney, M. F. Angew. Chem., Int. Ed. 2010, 49, 2768. (b) Zhang, F.; Das, S.; Walkinshaw, A. J.; Casitas, A.; Taylor, M.; Suero, M. G.; Gaunt, M. J. J. Am. Chem. Soc. 2014, 136, 8851. (24) (a) Zhang, S.; Wu, Y.; Zhang, W. ChemMedChem 2014, 9, 899. (b) Murat, P.; Singh, Y.; Defrancq, E. Chem. Soc. Rev. 2011, 40, 5293. (25) (a) Fuson, R. C.; Albright, R. L. J. Am. Chem. Soc. 1959, 81, 487. (b) Petersen, T. B.; Khan, R.; Olofsson, B. Org. Lett. 2011, 13, 3462. (c) Xie, H.; Yang, S.; Zhang, C.; Ding, M.; Liu, M.; Guo, J.; Zhang, F. J. Org. Chem. 2017, DOI: 10.1021/acs.joc.7b00513. (26) Bielawski, M.; Olofsson, B. Chem. Commun. 2007, 24, 2521.

Fengzhi Zhang: 0000-0001-9542-6634 Notes

The authors declare no competing financial interest. CCDC 1539512 (7a) contains the supplementary crystallographic data for this paper.

■

ACKNOWLEDGMENTS We thank the Natural Science Foundation for Distinguished Young Scholars of Zhejiang Province (LR15H300001), Thousand-Talent Program of Zhejiang Province, and Zhejiang University of Technology for financial support. We thank Prof. Guilin Zhuang at Zhejiang University of Technology for help with crystal structure determination.

■

REFERENCES

(1) Turrado, C.; Puig, T.; Garcia-Carceles, J.; Artola, M.; Benhamu, B.; Ortega-Gutierrez, S.; Relat, J.; Oliveras, G.; Blancafort, A.; Haro, D.; Marrero, P. F.; Colomer, R.; Lopez-Rodriguez, M. J. J. Med. Chem. 2012, 55, 5013. (2) Walter, H.; Tobler, H.; Gribkov, D.; Corsi, C. Chimia 2015, 69, 425. (3) (a) Klare, J. E.; Tulevski, G. S.; Sugo, K.; de Picciotto, A.; White, K. A.; Nuckolls, C. J. Am. Chem. Soc. 2003, 125, 6030. (b) Shinji, O.; Yoshinori, I.; Mika, Y.; Yasuhiro, K.; Koichi, E.; Kazuaki, H. WO 2015129672A1 20150903, 2015; PCT. Int. Appl. (c) Diehl, D. R.; Montbach, E. N. US 20140054498A1 20140227, 2014; U.S. Pat. Appl. Publ. (4) (a) Fujiwara, K.; Sato, T.; Sano, Y.; Norikura, T.; Katoono, R.; Suzuki, T.; Matsue, H. J. Org. Chem. 2012, 77, 5161. (b) Ye, Y. Q.; Negishi, C.; Hongo, Y.; Koshino, H.; Onose, J.-I.; Abe, N.; Takahashi, S. Bioorg. Med. Chem. 2014, 22, 2442. (5) (a) Reetz, M. T.; Guo, H.; Ma, J.-A.; Goddard, R.; Mynott, R. J. J. Am. Chem. Soc. 2009, 131, 4136. (b) Bruno, N. C.; Buchwald, S. L. Org. Lett. 2013, 15, 2876. (6) Stanforth, S. P. Tetrahedron 1998, 54, 263. (7) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. (8) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062. (9) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (10) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (11) Zhang, F.; Spring, D. R. Chem. Soc. Rev. 2014, 43, 6906. (12) (a) García-López, J.-A.; Greaney, M. F. Chem. Soc. Rev. 2016, 45, 6766. (b) Mathew, B. P.; Yang, H. J.; Kim, J.; Lee, J. B.; Kim, Y.-T.; Lee, S.; Lee, C. Y.; Choe, W.; Myung, K.; Park, J.-U.; Hong, S. Y. Angew. Chem., Int. Ed. 2017, 56, 5007 and references therein. (13) For selected reviews: (a) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052. (b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299. (14) Selected examples: (a) Beaud, R.; Phipps, R. J.; Gaunt, M. J. J. Am. Chem. Soc. 2016, 138, 13183. (b) Reitti, M.; Villo, P.; Olofsson, B. Angew. Chem., Int. Ed. 2016, 55, 8928. (c) Guo, J.; Lin, L.; Liu, Y.; Li, X.; Liu, X.; Feng, X. Org. Lett. 2016, 18, 5540. (d) Xu, Y.; Young, M. C.; Wang, C.; Magness, D. M.; Dong, G. Angew. Chem., Int. Ed. 2016, 55, 9084. (e) Sundalam, S. K.; Nilova, A.; Seidl, T. L.; Stuart, D. R. Angew. Chem., Int. Ed. 2016, 55, 8431. (f) Yang, Y.; Li, R.; Zhao, Y.; Zhao, D.; Shi, Z. J. Am. Chem. Soc. 2016, 138, 8734. (g) Liu, C.; Yi, J.C.; Zheng, Z.-B.; Tang, Y.; Dai, L.-X.; You, S.-L. Angew. Chem., Int. Ed. 2016, 55, 751. (15) (a) Modha, S. G.; Greaney, M. F. J. Am. Chem. Soc. 2015, 137, 1416. (b) Teskey, C. J.; Sohel, S. M. A.; Bunting, D. L.; Modha, S. G.; Greaney, M. F. Angew. Chem., Int. Ed. 2017, 56, 1. 2603

DOI: 10.1021/acs.orglett.7b00933 Org. Lett. 2017, 19, 2600−2603