Thiophene-Fused Heteroaromatic Systems Enabled by Internal

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Thiophene-Fused Heteroaromatic Systems Enabled by Internal Oxidant-Induced Cascade Bis-Heteroannulation Huawen Huang,* Zhenhua Xu, Xiaochen Ji, Bin Li, and Guo-Jun Deng* Key Laboratory for Green Organic Synthesis and Application of Hunan Province, Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China

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S Supporting Information *

ABSTRACT: A concise access to thiophene-fused polycyclic πconjugated systems is described. Methyl aromatic ketoxime acetates, aromatic aldehydes, and elemental sulfur are efficiently assembled in a facile copper-catalytic system through a novel cascade bis-heteroannulation to afford a fused thieno[3,2-d]thiazole motif. The robust nature of this reaction system is reflected by the remarkable simplicity-to-complexity transformation in a one-pot operation, high-yield gram-scale synthesis, and potential applications on the synthesis of high-performance optoelectronic materials. hiophene-fused polycyclic π-conjugated systems have found wide applications in materials science due to their high charge transport properties.1 Hence, thiophenecontaining polycyclic molecules have been intensively studied as basic materials in high-performance organic field-effect transistors (OFETs), organic light-emitting diodes (OLED), and organic photovoltaics (OPVs).2 Apparently, the development of facile thiophene-annulation reactions is of great significance and thereby has attracted much attention in molecular synthesis.3 Given the recent success in C−H functionalization chemistry for the rapid preparation and modification of organic materials,4 a straightforward route to thiophene-fused polycyclic π-conjugated systems via C−H functionalization from easily available chemicals would be highly desirable. The strategy involving an internal oxidant, especially Noxyenamines, has emerged to feature excellent levels of chemoselectivity for oxidative C−H functionalization.5 Therein, C(sp2)−H activation with the N-oxyenamine moiety as an oxidizing directing group was achieved by the catalysis of Pd,6 Rh,7 Ru,8 Co,9 etc,10 providing viable external-oxidant-free protocols for site-targeted C−H functionalization and heterocycle synthesis (Figure 1a). On the other hand, ketoximes bearing α-protons were generally employed as an internal oxidant as well as C−C−N building blocks to enable condensation-based N-heterocycle formation (Figure 1b).11 Despite tremendous advances in N-heterocycle synthesis by this viable strategy, the construction of highly functionalized molecules under facile reaction conditions is still underdeveloped. Herein, we report on the first 2-fold heteroannulation of oxime internal oxidants initiated by the coppercatalyzed activation of N−O and thereby cascade formation of multiple C−S bonds. Hence, our protocol provides rapid access to the thiophene-containing polycyclic systems from simple chemicals (Figure 1c). The advantages of the present

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© XXXX American Chemical Society

Figure 1. Heteroannulation by internal oxidant strategy.

method include the following: (i) simple and easily available starting materials; (ii) user-friendly elemental sulfur as the sulfur source;12 (iii) easy operational handling; (iv) excellent levels of chemo- and regioselectivities; and (v) gram-scalable synthesis with high yields. Based on our previously developed internal oxidant-induced aerobic oxygenation and recent annulation reactions involving elemental sulfur,13 we suspected that the acetophenone oxime acetate (1a) could be activated in situ by copper catalysis to form highly active imino-Cu(III) species and/or an iminoReceived: June 30, 2018

A

DOI: 10.1021/acs.orglett.8b02049 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters radical, which would trigger the activation and incorporation of elemental sulfur to assemble sulfur-containing molecules (Figure 2, A to B). Thus, initial attempts at this speculation

Figure 2. Copper-catalyzed heteroannulation of oxime acetate and elemental sulfur.

delivered the dithiazole product (C) (Figure 2a), while the addition of benzaldehyde (2a) as the third component unexpectedly led to the formation of 2-phenyl-benzo[4,5]thieno[3,2-d]thiazole (3a) (Figure 2b). These observations indicated that the aldehyde component could conceal the nitrogen atom by condensation, and consequently ortho C−H sulfuration was prioritized to form the benzothiophene moiety followed by the thiazole-annulation. Systematic screening of reaction conditions including catalysts, bases, solvents, et al. indicated that the most effective transformation was derived from the catalytic system with CuBr and Li2CO3 in DMSO as the media at 120 °C (Table S1, Supporting Information (SI)). Comparably, the combination of acetophenone with ammonium acetate or benzylamine instead of oxime acetate 1a could not give the target bis-annulation product 3a. These results reflect the uniqueness of oxime acetate for this annulation and demonstrate indirectly that the formation of imino-radical (A) by copper(I) treatment of 1a would be the initial step. With the optimal reaction conditions established, the substrate scope of the novel four-component bis-heteroannulation was probed. Thus, a variety of polycyclic aromatic systems with the thieno[3,2-d]thiazole moiety were accessed by the facile copper-based catalytic system. Specifically, a broad application on aromatic aldehydes was first accomplished (3a− 3s), with a series of compatible functional groups such as synthetically useful halo (F, Cl, Br), decorated hydroxyl, etc. (Figure 3). Notably, the electronic and steric properties of the substituents influenced very few regarding the yield of the bisheteroannulation. The remarkable efficacy of our method was revealed by the effective gram-scale synthesis, by which an excellent yield of 3s was afforded when the reaction with 2naphthaldehyde was performed on a 5 mmol scale. It is particularly noteworthy that the heteroaromatic aldehydes bearing furanyl, thienyl, and pyridinyl moieties proved to be compatible with the present copper-based catalytic system, affording the corresponding heteroarene-substituted products with generally modest yields (3t−3x). Subsequently, we explored the scope of methylketoxime acetates 1 (Figure 4). In the case of oximes derived from substituted acetophenones, the robust catalytic system tolerated a variety of functional groups, including chloro,

Figure 3. Scope of aromatic aldehydes. a Yield on a 5 mmol scale.

bromo, and methoxy (4a−4l). The structure of 4e was confirmed by single-crystal X-ray diffraction analysis. Among them, intramolecular competition reactions proceeded preferably at the C2-position when meta-substituted reactants were used (4h−4j). The versatility of this copper-catalyzed system was further mirrored by the successfully used heteroaromatic ketoximes, which provided a rapid access to a range of novel triheterofused arenes (4m−4p). Specifically, pyridine-3-yl ketoxime afforded the most effective conversion (4o), albeit with moderate levels of regioselectivity, while thienyl and pyrazinyl motifs furnished the corresponding products in moderate yields. Furthermore, tetra- and pentacyclic aromatic systems 4q and 4r were also efficiently produced from the corresponding naphthyl and phenanthyl ketoximes, respectively. Thereafter, we subjected vinyl ketoximes to the robust copper-catalyzed system in a reaction complementary to aromatic ketoximes. To our delight, those reactants were accommodated with the present system, affording substituted thieno[3,2-d]thiazoles (4s−4u) in moderate to good yields. Since we noted that many of the thieno-fused poly heterocyclic products are fluorescent under ultraviolet light, the photophysical properties such as UV−vis absorption and photoluminescence spectra of some compounds were measured. All of these selected compounds show similar absorption profiles, indicating that these thiophene-based conjugated compounds may have an application on blue organic lightemitting diodes (OLEDs) (for details, see SI). At this stage, the exact mechanism of the present two bisheteroannulations is not clear. We still found some mechanistic B

DOI: 10.1021/acs.orglett.8b02049 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Figure 4. Scope of ketoxime acetates. a Yield of two isomers (major isomer was given, rr = 2:1 to 3:1; see SI).

Figure 5. Summary of key mechanistic studies.

information from the results of control experiments and previous reports. The formation of an imino-radical through the treatment of oxime acetate with a copper(I) catalyst should be the initial step, which was supported by previously reported EPR experiments.14 Moreover, oxime ether 5, which would split into an imino radical under light inducement, afforded 3a in good yield in the absence of a copper catalyst (Figure 5a). Then, no 3a was obtained when using 2,4-diphenylthiazole or 2,4-diphenyl-5-bromothiazole as the substrate (Figure 5b), while 3-aminobenzothiophene furnished the product in good yield with or without the assistance of a copper catalyst (Figure 5c). These results demonstrate that the formation of a thiazole ring would be the last process and the copper catalyst plays no role in the process of thiazole formation, consistent with the results of our previous metal-free thiazole annulation.13d,e Then, the values of the intermolecular kinetic isotope effect (KIE) were determined to be 1.2 with D5-1a, 1.3 with D8-1a, and 1.0 with D1-2a (Figure 5d−f), revealing that the cleavage of all C−H bonds was not the rate-determining step of the overall transformation. Finally, the results of intermolecular competition experiments did not suggest an ortho electrophilic sulfuration process of the ketoximes (Figure 5g). In summary, we have developed a facile copper-catalyzed system for the synthesis of thiophene-fused polycyclic πconjugated compounds through a novel bis-heteroannulation of methyl aromatic ketoximes with aromatic aldehydes and elemental sulfur. A diverse range of new thiophene-containing bis-heterocycle products were synthesized with generally moderate to excellent yields. Mechanistic studies revealed

that the copper catalyst enabled the activation of an oxime N− O bond to form a highly active imino radical, which induced the cascade bis-heteroannulation reaction. None of the C−H bond cleavages of this conversion proved to be the ratedetermining step of the transformation. This work has potential applications in the synthesis of thiophene-containing high-performance optoelectronic materials.

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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.8b02049. Experimental procedures, characterization data, and 1H NMR and 13C NMR spectra for all new products (PDF) Accession Codes

CCDC 1584913 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]. C

DOI: 10.1021/acs.orglett.8b02049 Org. Lett. XXXX, XXX, XXX−XXX

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(7) For representative examples, see: (a) Parthasarathy, K.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2008, 10, 325. (b) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6908. (c) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350. (d) Hyster, T. K.; Knörr, L.; Ward, T. R.; Rovis, T. Science 2012, 338, 500. (e) Ye, B.; Cramer, N. Science 2012, 338, 504. (f) Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 66. (g) Davis, T. A.; Hyster, T. K.; Rovis, T. Angew. Chem., Int. Ed. 2013, 52, 14181. (h) Hyster, T. K.; Ruhl, K. E.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 5364. (i) Liu, G.; Shen, Y.; Zhou, Z.; Lu, X. Angew. Chem., Int. Ed. 2013, 52, 6033. (j) Hu, F.; Xia, Y.; Ye, F.; Liu, Z.; Ma, C.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2014, 53, 1364. (k) Zhang, H.; Wang, K.; Wang, B.; Yi, H.; Hu, F.; Li, C.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2014, 53, 13234. (l) Ye, B.; Cramer, N. Angew. Chem., Int. Ed. 2014, 53, 7896. (m) Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2014, 136, 2735. (n) Romanov-Michailidis, F.; Sedillo, K. F.; Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2015, 137, 8892. (8) (a) Li, B.; Feng, H.; Xu, S.; Wang, B. Chem. - Eur. J. 2011, 17, 12573. (b) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548. (c) Kornhaaß, C.; Li, J.; Ackermann, L. J. Org. Chem. 2012, 77, 9190. (d) Chinnagolla, R. K.; Pimparkar, S.; Jeganmohan, M. Org. Lett. 2012, 14, 3032. (e) Kornhaaß, C.; Kuper, C.; Ackermann, L. Adv. Synth. Catal. 2014, 356, 1619. (f) Yang, F.; Ackermann, L. J. Org. Chem. 2014, 79, 12070. (g) Huang, H.; Nakanowatari, S.; Ackermann, L. Org. Lett. 2017, 19, 4620. (9) (a) Sun, B.; Yoshino, T.; Kanai, M.; Matsunaga, S. Angew. Chem., Int. Ed. 2015, 54, 12968. (b) Wang, H.; Koeller, J.; Liu, W.; Ackermann, L. Chem. - Eur. J. 2015, 21, 15525. (c) Sen, M.; Kalsi, D.; Sundararaju, B. Chem. - Eur. J. 2015, 21, 15529. (10) (a) Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918. (b) Yoshida, Y.; Kurahashi, T.; Matsubara, S. Chem. Lett. 2012, 41, 1498. (c) Deb, I.; Yoshikai, N. Org. Lett. 2013, 15, 4254. (d) Jiang, H.; An, X.; Tong, K.; Zheng, T.; Zhang, Y.; Yu, S. Angew. Chem., Int. Ed. 2015, 54, 4055. (11) For representative examples, see: (a) Ren, Z.-H.; Zhang, Z.-Y.; Yang, B.-Q.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett. 2011, 13, 5394. (b) Tang, X.; Huang, L.; Qi, C.; Wu, W.; Jiang, H. Chem. Commun. 2013, 49, 9597. (c) Huang, H.; Ji, X.; Tang, X.; Zhang, M.; Li, X.; Jiang, H. Org. Lett. 2013, 15, 6254. (d) Wei, Y.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 3756. (e) Huang, H.; Cai, J.; Ji, X.; Xiao, F.; Chen, Y.; Deng, G.-J. Angew. Chem., Int. Ed. 2016, 55, 307. (f) Tan, W. W.; Ong, Y. J.; Yoshikai, N. Angew. Chem., Int. Ed. 2017, 56, 8240. (g) Zhu, C.; Zhu, R.; Zeng, H.; Chen, F.; Liu, C.; Wu, W.; Jiang, H. Angew. Chem., Int. Ed. 2017, 56, 13324. (12) (a) Liu, H.; Jiang, X. Chem. - Asian J. 2013, 8, 2546. (b) Nguyen, T. B. Adv. Synth. Catal. 2017, 359, 1066. (c) Wang, X.; Qiu, X.; Wei, J.; Liu, J.; Song, S.; Wang, W.; Jiao, N. Org. Lett. 2018, 20, 2632. (13) (a) Liao, Y.; Peng, Y.; Qi, H.; Gong, H.; Deng, G.-J.; Li, C.-J. Chem. Commun. 2015, 51, 1031. (b) Xie, H.; Cai, J.; Wang, Z.; Huang, H.; Deng, G.-J. Org. Lett. 2016, 18, 2196. (c) Wang, Z.; Xie, H.; Xiao, F.; Guo, Y.; Huang, H.; Deng, G.-J. Eur. J. Org. Chem. 2017, 2017, 1604. (d) Che, X.; Jiang, J.; Xiao, F.; Huang, H.; Deng, G.-J. Org. Lett. 2017, 19, 4576. (e) Li, G.; Xie, H.; Chen, J.; Guo, Y.; Deng, G.-J. Green Chem. 2017, 19, 4043. (f) Wang, Z.; Qu, Z.; Xiao, F.; Huang, H.; Deng, G.-J. Adv. Synth. Catal. 2018, 360, 796. (14) (a) Ke, J.; Tang, Y.; Yi, H.; Li, Y.; Cheng, Y.; Liu, C.; Lei, A. Angew. Chem., Int. Ed. 2015, 54, 307. (b) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41, 3464.

Huawen Huang: 0000-0001-7079-1299 Guo-Jun Deng: 0000-0003-2759-0314 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Support by the National Natural Science Foundation of China (21602187, 21572194), the Collaborative Innovation Center of New Chemical Technologies for Environmental Benignity and Efficient Resource Utilization, the Scientific Research Fund of Hunan Provincial Education Department (16B251), and the Hunan Provincial Natural Science Foundation of China (2017JJ3299) is gratefully acknowledged.

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REFERENCES

(1) (a) Perepichka, I. F.; Perepichka, D. F. Handbook of Thiophenebased Materials: Applications in Organic Electronics and Photonics; Wiley-VCH: Weinheim, 2009. (b) Takimiya, K.; Shinamura, S.; Osaka, I.; Miyazaki, E. Adv. Mater. 2011, 23, 4347. (c) Jiang, W.; Li, Y.; Wang, Z. Chem. Soc. Rev. 2013, 42, 6113. (d) Osaka, I.; Shinamura, S.; Abe, T.; Takimiya, K. J. Mater. Chem. C 2013, 1, 1297. (e) Cinar, M. E.; Ozturk, T. Chem. Rev. 2015, 115, 3036. (f) Boyd, D. A. Angew. Chem., Int. Ed. 2016, 55, 15486. (2) For examples, see: (a) Chen, H.; Cui, Q.; Yu, G.; Guo, Y.; Huang, J.; Zhu, M.; Guo, X.; Liu, Y. J. Phys. Chem. C 2011, 115, 23984. (b) Amin, A. Y.; Khassanov, A.; Reuter, K.; MeyerFriedrichsen, T.; Halik, M. J. Am. Chem. Soc. 2012, 134, 16548. (c) Xiao, Q.; Sakurai, T.; Fukino, T.; Akaike, K.; Honsho, Y.; Saeki, A.; Seki, S.; Kato, K.; Takata, M.; Aida, T. J. Am. Chem. Soc. 2013, 135, 18268. (d) Gbabode, G.; Dohr, M.; Niebel, C.; Balandier, J.-Y.; Ruziè, C.; Negrier, P.; Mondieig, D.; Geerts, Y. H.; Resel, R.; Sferrazza, M. ACS Appl. Mater. Interfaces 2014, 6, 13413. (e) Yue, W.; Ashraf, R. S.; Nielsen, C. B.; Collado-Fregoso, E.; Niazi, M. R.; Yousaf, S. A.; Kirkus, M.; Chen, H.-Y.; Amassian, A.; Durrant, J. R.; McCulloch, L. Adv. Mater. 2015, 27, 4702. (f) Tsutsui, Y.; Schweicher, G.; Chattopadhyay, B.; Sakurai, T.; Arlin, J.-B.; Ruzié, C.; Aliev, A.; Ciesielski, A.; Colella, S.; Kennedy, A. R.; Lemaur, V.; Olivier, Y.; Hadji, R.; Sanguinet, L.; Castet, F.; Osella, S.; Dudenko, D.; Beljonne, D.; Cornil, J.; Samorì, P.; Seki, S.; Geerts, Y. H. Adv. Mater. 2016, 28, 7106. (g) Higashino, T.; Imahori, H. Chem. - Eur. J. 2015, 21, 13375. (3) (a) Iwao, M.; Lee, M. L.; Castle, R. N. J. Heterocycl. Chem. 1980, 17, 1259. (b) Fukutomi, Y.; Nakano, M.; Hu, J.-Y.; Osaka, I.; Takimiya, K. J. Am. Chem. Soc. 2013, 135, 11445. (c) Baranov, D. S.; Gold, B.; Vasilevsky, S. F.; Alabugin, I. V. J. Org. Chem. 2013, 78, 2074. (d) Mori, T.; Nishimura, T.; Yamamoto, T.; Doi, I.; Miyazaki, E.; Osaka, I.; Takimiya, K. J. Am. Chem. Soc. 2013, 135, 13900. (e) Takimiya, K.; Nakano, M.; Kang, M. J.; Miyazaki, E.; Osaka, I. Eur. J. Org. Chem. 2013, 2013, 217. (f) Meng, L.; Fujikawa, T.; Kuwayama, M.; Segawa, Y.; Itami, K. J. Am. Chem. Soc. 2016, 138, 10351. (4) (a) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369. (b) Segawa, Y.; Maekawa, T.; Itami, K. Angew. Chem., Int. Ed. 2015, 54, 66. (5) (a) Tabolin, A. A.; Ioffe, S. L. Chem. Rev. 2014, 114, 5426. (b) Huang, H.; Ji, X.; Wu, W.; Jiang, H. Chem. Soc. Rev. 2015, 44, 1155. (c) Huang, H.; Cai, J.; Deng, G.-J. Org. Biomol. Chem. 2016, 14, 1519. (d) Bolotin, D. S.; Bokach, N. A.; Demakova, M. Y.; Kukushkin, V. Y. Chem. Rev. 2017, 117, 13039. (e) Tang, X.; Wu, W.; Zeng, W.; Jiang, H. Acc. Chem. Res. 2018, 51, 1092. (6) (a) Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 572. (b) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676. (c) Xu, Y.; Hu, W.; Tang, X.; Zhao, J.; Wu, W.; Jiang, H. Chem. Commun. 2015, 51, 6843. D

DOI: 10.1021/acs.orglett.8b02049 Org. Lett. XXXX, XXX, XXX−XXX