C–H Cross-Coupling of - ACS Publications - American

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

pubs.acs.org/OrgLett

Oxidative C−H/C−H Cross-Coupling of [1,2,4]Triazolo[1,5‑a]pyrimidines with Indoles and Pyrroles: Discovering Excited-State Intramolecular Proton Transfer (ESIPT) Fluorophores Mangang Zhang, Rui Cheng, Jingbo Lan,* Huaxing Zhang, Lipeng Yan, Xingwen Pu, Zhenmei Huang, Di Wu, and Jingsong You*

Downloaded by UNIV AUTONOMA DE COAHUILA at 16:29:19:155 on May 24, 2019 from https://pubs.acs.org/doi/10.1021/acs.orglett.9b01238.

Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China S Supporting Information *

ABSTRACT: A highly efficient Rh(III)-catalyzed oxidative C−H/C−H cross-coupling of [1,2,4]triazolo[1,5-a]pyrimidines (TAP) with indoles and pyrroles has been developed, which provides an opportunity to rapidly assemble a large library of novel excited-state intramolecular proton transfer (ESIPT) fluorophores. The resulting 7-(pyrrol-2-yl)TAPs only show the enol-form emission, while 7-(indol-2-yl)TAPs would undergo an ESIPT process and mainly exhibit the keto-form emission. In highly polar solvents, the enol-form emission of 7-(indol-2-yl)TAPs is enhanced significantly, thus showing the dual emission of enol and keto forms.

E

Triazolo[1,5-a]pyrimidine (TAP), as a isomorphic purine analog, has been found in many biologically and pharmaceutically active compounds.6 Recently, we established a highly efficient strategy to construct a variety of 2,7-diaryl-TAPs through the C−H/C−X cross-coupling of TAPs with halobenzenes.7 We have found that 2-aryl-TAP with a 6:5 system, which consists of a six-membered benzene ring linking to the five-membered triazole ring of TAP, adopts a planar conformation, and 7-aryl-TAP with a 6:6 system, which consists of a six-membered benzene ring linking to the sixmembered pyrimidine ring of TAP, takes a twisted structure (Scheme 1).7,8 We envision that introducing a five-membered pyrrole ring to the 7-position of TAP to form a 5:6 system would be favorable for an enhanced molecular planarity. Moreover, the N−H of pyrrole and the nitrogen atom of triazole would form an intramolecular hydrogen bond, which can be considered as a “conformational lock,” fixing the molecular plane. Furthermore, the formation of an intramolecular hydrogen bond may endow these compounds with ESIPT properties, which may be an important class of ESIPT materials (Scheme 1). 7-(Pyrrol-2-yl)TAPs and 7-(indol-2-yl)TAPs are not readily accessible by conventional synthetic methods. Although the

xcited-state intramolecular proton transfer (ESIPT) fluorophores have been extensively studied due to the remarkable properties, such as the dual emission of the excited enol and keto forms, large Stokes shifts of the keto-form emissioin, and spectral sensitivities to the surrounding medium.1 The formation of an intramolecular hydrogen bond between the proton donor (−OH and −NH−) and the proton acceptor (CO and CN−) in close proximity to each other within a molecule is a prerequisite for an efficient ESIPT process owing to the excited-state H-atom transfer reaction along the direction of hydrogen bond formation.1,2 Recently, a variety of ESIPT molecules have been developed through extending the π-conjugation of the classical ESIPT dyes as well as further introducing electron-donating and/or electron-withdrawing functional groups.3 However, the excited-state H-atom transfer reaction may be suppressed with the electronic property change of the proton donor and acceptor.1b,4 It remains an appealing yet significantly challenging task to design and synthesize new ESIPT chromophores with predetermined photophysical properties, such as the dual emission of enol and keto forms. Fluorescent purine analogs have attracted much attention in the fields of chemistry, biological science, clinical diagnosis, and drug discovery because of a remarkable resemblance between the mimics and the natural nucleobases, which can minimize the perturbation to biological systems.5 [1,2,4]© XXXX American Chemical Society

Received: April 9, 2019

A

DOI: 10.1021/acs.orglett.9b01238 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. Scope of Indoles and Pyrrolesa

Scheme 1. Molecular Design of 7-(Pyrrol-2-yl)TAPs and 7(Indol-2-yl)TAPs

C−H/C−X cross-coupling is also a simple and highly efficient pathway to various bi(hetero)arenes,9 a more ideal approach from the perspective of atom and step economy is transitionmetal-catalyzed oxidative C−H/C−H cross-coupling between two (hetero)arenes.10 Our recent research has focused on developing various C−H/C−H cross-coupling reactions to construct bi(hetero)aryl structures.11 Following our continuing interest, we herein present a highly efficient synthetic protocol to 7-(pyrrol-2-yl)TAPs and 7-(indol-2-yl)TAPs via rhodium(III)-catalyzed oxidative C−H/C−H cross-coupling of TAPs with indoles and pyrroles (Scheme 1). Due to the inherent electronic bias, the C−H functionalization of indoles usually occurs preferentially at the more electron-rich C3 position.12 Therefore, pyrimidine was selected as the directing group to achieve the C2-selective C−H/C−H cross-coupling of indoles with TAPs.13 The optimal reaction conditions were explored by using 2-(p-tolyl)-TAP (1a) and 5methoxy-1-(pyrimidin-2-yl)-1H-indole (2a) as substrates (Tables S1−S4). To our delight, Pd(II), Rh(II), and Ir(III) could effectively promote this cross-coupling reaction, and [Cp*RhCl2]2 was superior to the other two (Table S1). Further optimization of solvents showed that N,N′-dimethylformamide (DMF) was still the best choice (Table S2). The reaction was performed with different copper salts, silver salts, and silver oxide as oxidants. Of these, anhydrous Cu(OAc)2 was found to be superior to the others (Table S3). Finally, the optimal conditions were determined when employing 1a (1.0 equiv) and 2a (1.5 equiv) in the catalysis of [Cp*RhCl2]2 in combination with AgSbF6, with Cu(OAc)2 as an oxidant, and pivalic acid (PivOH) as an additive in DMF at 140 °C for 24 h under an N2 atmosphere (Table S4). With the optimal reaction conditions in hand, the scope of indoles and pyrroles (2) was examined (Scheme 2). This protocol was amenable to indoles with a substituent at their 4-, 5-, and 7-position, affording the coupling products in good to excellent yields (3a−c). 3a was also obtained in a yield of 80% when employing 1 mmol of 1a and 1.5 mmol of 2a as substrates. The reaction of 3-substituted indole provided the corresponding product 3d in a low yield of 32% perhaps due to steric hindrance. To our delight, this catalytic system was also compatible with various pyrrole derivatives, affording pyrrole substituted TAPs in good yields (3f−h). The structure of 3g was confirmed by 1H and 13C NMR spectra, HRMS, and single-crystal X-ray analysis (CCDC 1897887; Figure S1). Noteworthily, when employing 3.0 equiv of pyrrole (2h) and prolonging the reaction time to 48 h, bis(TAP)-functionalized pyrrole 3i could be obtained in 50% yield.

a

Reaction conditions: 1a (0.2 mmol), 2 (1.5 equiv), [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (10 mol %), Cu(OAc)2 (2.0 equiv), PivOH (1.0 equiv) in DMF (1.0 mL) at 140 °C for 24 h under N2. Isolated yields. b The yield in parentheses was for 1 mmol scale reaction for 3a. c1a (0.2 mmol), 2h (3.0 equiv), 48 h.

To obtain 7-(pyrrol-2-yl)TAPs and 7-(indol-2-yl)TAPs with different structural features, the substrate scope of 2-aryl TAPs was further extended (Scheme 3). 2-Phenyl TAP and parasubstituted 2-phenyl TAPs smoothly reacted with Npyrimidinyl indoles affording the desired products in satisfactory yields (4a−e). The single-crystal X-ray data of 4c were also obtained (CCDC 1897888; Figure S2). orthoSubstituted 2-phenyl TAPs could also work, albeit at slightly lower yields (4f−g). The cross-coupling reaction of 3,4dimethoxy and 3,5-bis(trifluoromethyl) substituted 2-phenyl TAPs with 5-methoxy N-pyrimidinyl indole afforded the corresponding products in 73% and 66% yields (4h−i). Moreover, 7-substituted 2-(3,5-bis(trifluoromethyl)phenyl) TAPs with 5-cyano-1H-pyrrol-2-yl, 5-(diphenylamino)-1Hindol-2-yl, and 5-(bis(4-tert-butylphenyl)amino)-1H-indol-2yl groups were also prepared under these conditions with moderate to good yields (4j−l). To our delight, the pyrimidyl directing group was readily removed from indole and pyrrole. Upon treatment of the C− H/C−H cross-coupled products with sodium methoxide in DMSO at 120 °C for 24 h under a nitrogen atmosphere, the corresponding free (NH) products (5a−f) were obtained in moderate to good yields (Scheme 4).13,14 Subsequently, the photophysical properties of 5a−f were investigated (Figures 1 and S3). The absorption band of 7(pyrrol-2-yl)TAPs (5a and 5b) in CH2Cl2 is located at around 300 to 390 nm, while the absorption band of 7-(indol-2yl)TAPs (5c−f) appears in the range 320−430 nm, both of which are assignable to a typical π−π* transition (Figure 1a). An additional charge-transfer (CT) absorption band at around 450 nm is observed for 5e and 5f, due to the strong electrondonating property of diphenylamino groups (Figure 1a). B

DOI: 10.1021/acs.orglett.9b01238 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Scope of 2-Aryl TAPsa

Figure 1. (a) Absorption and (b) emission spectra of 5a−f in CH2Cl2 (1 × 10−5 mol/L).

As shown in Figure 1b and Table 1, 5a and 5b only exhibit the enol-form emission in CH2Cl2 solution with small Stokes Table 1. Photophysical Properties of 5a−f dye 5a 5b 5c 5d 5e 5f

λabsa (nm) 353, 348, 377, 382, 383, 381,

367 364 397 399 397, 450 399, 458

λemb (nm)

ΦFc

ΦFd

Stokes shift (cm−1)

386 393 481 486 448, 628 450, 660

0.82 0.78 0.37 0.37 0.20 0.01

0.55 0.76 0.37 0.42 0.68 0.50

1341 2027 4399 4486 9265 9911

Absorption maxima in CH2Cl2 (1 × 10−5 mol/L). bEmission maxima in CH2Cl2 (1 × 10−5 mol/L). cAbsolute quantum yields in CH2Cl2 (1 × 10−5 mol/L). dAbsolute quantum yields in PMMA film (c = 1 wt %). Absolute quantum yields determined with an integrating sphere system. a

shifts of 1341 and 2027 cm−1, respectively. Moreover, their emission spectra only show a slight change as the solvent polarity increases (Figures 2a and S4a). Surprisingly, the

a Reaction conditions: 1 (0.2 mmol), 2 (1.5 equiv), [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (10 mol %), Cu(OAc)2 (2.0 equiv), PivOH (1.0 equiv) in DMF (1.0 mL) at 140 °C for 24 h under N2. Isolated yields.

Scheme 4. Removal of Pyrimidyl Directing Groupa

Figure 2. Normalized emission spectra of (a) 5b and (b) 5e in different solvents (1 × 10−5 mol/L).

emission speak of 5b in DMF significantly red-shift to 466 nm, perhaps because the presence of a small amount of dimethylamine in DMF leads to the deprotonation of pyrrole nitrogen. Upon addition of 1.0 equiv of tetrabutylammonium hydroxide [(n-Bu)4NOH] into the acetonitrile solution of 5b, a similar spectroscopic red shift is also observed with that in DMF, indicating that the deprotonation of 5b does result in a red-shifted emission spectrum (Figure 2a). The results of fluorescence titration experiments (Figure S5) and NMR titration experiments (Figure S6) provide further evidence for the deprotonation process. The emission spectra of 5c and 5d in CH2Cl2 are located at around 480 nm, which are almost identical with each other, which indicates that the substituents on the 2-phenyl group of TAP, whether they are electron-donating methoxys (5c) or electron-withdrawing trifluoromethyls (5d), have a negligible effect on fluorescence emission (Figure 1b and Table 1). The

a

Reaction conditions: 3 or 4 (0.2 mmol) and NaOMe (3.0 equiv) in DMSO (1.0 mL) at 120 °C for 24 h under N2. Isolated yields.

C

DOI: 10.1021/acs.orglett.9b01238 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

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.

emission spectra of 5c present a remarkable red shift with the increase of the solvent polarity: from 433 nm in nonpolar cyclohexane to 528 nm in polar methanol, indicating typical CT character in the excited state (Figure S4b). In common solvents including cyclohexane, toluene, dichloromethane, tetrahydrofuran (THF), chloroform, acetonitrile, and DMF, 5d shows similar emission spectra with 5c. However, an additional emission peak appears at around 399 nm when 5d is dissolved in methanol, which may be attributed to its enolform emission (Figure S4c). In other words, 5c and 5d mainly exhibit keto-form emissions in most common solvents, while the dual emission of excited enol and keto forms can be observed for 5d in methanol. Notably, 5e and 5f exhibit the dual emission of both enol and keto forms in common solvents (Figures 1b, 2b, and S4d). They show a strong emission of keto form and a weak emission of enol form in nonpolar and low polar solvents. In highly polar solvents, such as acetonitrile and DMF, the enol-form emission of 5e and 5f is enhanced significantly, because the presence of an intermolecular hydrogen bond between the phenolic hydroxyl group and solvent inhibits the formation of an intramolecular hydrogen bond and the ESIPT process, thus favoring the normal enolform emission. In addition, the fluorescence quantum yields and emission spectra of 5a−f in PMMA film were investigated (Table 1, Table S5, and Figure S9). The fluorescence quantum yields of 5e and 5f doped in PMMA film (c = 1.0 wt %) are obviously higher than those in solution, which may be due to the inhibition of intramolecular rotation and nonradiative relaxation in PMMA film. Moreover, effective dispersion can also avoid aggregation-caused quenching. In conclusion, we have developed a highly efficient synthetic protocol to 7-(pyrrol-2-yl)TAPs and 7-(indol-2-yl)TAPs via rhodium(III)-catalyzed oxidative C−H/C−H cross-coupling of TAPs with indoles and pyrroles, which provides an opportunity to rapidly assemble a large library of ESIPT fluorophores. The ESIPT process of 7-(pyrrol-2-yl)TAPs may be hard to occur, and thus, only the enol-form emission is observed in common solvents. 7-(Indol-2-yl)TAPs would undergo an ESIPT process upon photoexcitation and mainly exhibit the keto-form emission in nonpolar and low polar solvents. In highly polar solvents, the enol-form emissions of 7(indol-2-yl)TAPs are enhanced significantly, because the presence of an intermolecular hydrogen bond inhibits the formation of an intramolecular hydrogen bond and the ESIPT process, thus showing the dual emission of enol and keto forms. We expect that these findings would provide important enlightenment to the development of single molecular whitelight emitting materials.

■

■

AUTHOR INFORMATION

Corresponding Authors

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

Jingbo Lan: 0000-0001-5937-0987 Jingsong You: 0000-0002-0493-2388 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (Nos. 21871193, 21772133, 21672154, and 21432005) for financial support. We also thank the Open Fund of the Key Laboratory of Functional Molecular Engineering of Guangdong Province (2016kf05, South China University of Technology) and the Comprehensive Training Platform Specialized Laboratory, College of Chemistry, Sichuan University.

■

REFERENCES

(1) (a) Hsieh, C.-C.; Jiang, C.-M.; Chou, P.-T. Acc. Chem. Res. 2010, 43, 1364. (b) Zhao, J.; Ji, S.; Chen, Y.; Guo, H.; Yang, P. Phys. Chem. Chem. Phys. 2012, 14, 8803. (c) Demchenko, A. P.; Tang, K.-C.; Chou, P.-T. Chem. Soc. Rev. 2013, 42, 1379. (d) Padalkar, V. S.; Seki, S. Chem. Soc. Rev. 2016, 45, 169. (e) Sedgwick, A. C.; Wu, L.; Han, H.-H.; Bull, S. D.; He, X.-P.; James, T. D.; Sessler, J. L.; Tang, B. Z.; Tian, H.; Yoon, J. Chem. Soc. Rev. 2018, 47, 8842. (f) Zhou, P.; Han, K. Acc. Chem. Res. 2018, 51, 1681. (g) Massue, J.; Jacquemin, D.; Ulrich, G. Chem. Lett. 2018, 47, 1083. (h) Chen, C.-L.; Chen, Y.-T.; Demchenko, A. P.; Chou, P.-T. Nat. Rev. Chem. 2018, 2, 131. (2) Kwon, J. E.; Park, S. Y. Adv. Mater. 2011, 23, 3615. (3) (a) Park, S.; Kwon, J. E.; Kim, S. H.; Seo, J.; Chung, K.; Park, S.Y.; Jang, D.-J.; Medina, B. M.; Gierschner, J.; Park, S. Y. J. Am. Chem. Soc. 2009, 131, 14043. (b) Tang, K.-C.; Chang, M.-J.; Lin, T.-Y.; Pan, H.-A.; Fang, T.-C.; Chen, K.-Y.; Hung, W.-Y.; Hsu, Y.-H.; Chou, P.-T. J. Am. Chem. Soc. 2011, 133, 17738. (c) Yang, X. F.; Huang, Q.; Zhong, Y. G.; Li, Z.; Li, H.; Lowry, M.; Escobedo, J. O.; Strongin, R. M. Chem. Sci. 2014, 5, 2177. (d) Mamada, M.; Inada, K.; Komino, T.; Potscavage, W. J., Jr.; Nakanotani, H.; Adachi, C. ACS Cent. Sci. 2017, 3, 769. (e) He, T.; Niu, N.; Chen, Z. J.; Li, S. J.; Liu, S.; Li, J. Adv. Funct. Mater. 2018, 28, 1706196. (f) Li, B.; Zhou, L.; Cheng, H.; Huang, Q.; Lan, J.; Zhou, L.; You, J. Chem. Sci. 2018, 9, 1213. (4) (a) Chung, M.-W.; Lin, T.-Y.; Hsieh, C.-C.; Tang, K.-C.; Fu, H.; Chou, P.-T.; Yang, S.-H.; Chi, Y. J. Phys. Chem. A 2010, 114, 7886. (b) Li, B.; Tang, G.; Zhou, L.; Wu, D.; Lan, J.; Zhou, L.; Lu, Z.; You, J. Adv. Funct. Mater. 2017, 27, 1605245. (5) Sinkeldam, R. W.; Greco, N. J.; Tor, Y. Chem. Rev. 2010, 110, 2579. (6) (a) Massari, S.; Nannetti, G.; Desantis, J.; Muratore, G.; Sabatini, S.; Manfroni, G.; Mercorelli, B.; Cecchetti, V.; Palù, G.; Cruciani, G.; Loregian, A.; Goracci, L.; Tabarrini, O. J. Med. Chem. 2015, 58, 3830. (b) Khare, S.; Nagle, A. S.; Biggart, A.; Lai, Y. H.; Liang, F.; Davis, L. C.; Barnes, S. W.; Mathison, C. J. N.; Myburgh, E.; Gao, M.-Y.; Gillespie, J. R.; Liu, X.; Tan, J. L.; Stinson, M.; Rivera, I. C.; Ballard, J.; Yeh, V.; Groessl, T.; Federe, G.; Koh, H. X.; Venable, J. D.; Bursulaya, B.; Shapiro, M.; Mishra, P. K.; Spraggon, G.; Brock, A.; Mottram, J. C.; Buckner, F. S.; Rao, S. P. S.; Wen, B. G.; Walker, J. R.; Tuntland, T.; Molteni, V.; Glynne, R. J.; Supek, F. Nature 2016, 537, 229.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01238. Detailed experimental procedures, characterization data, copies of 1H and 13C NMR spectra of products, and Xray crystal structures of 3g (CCDC 1897887) and 4c (CCDC 1897888) (PDF) Accession Codes

CCDC 1897887−1897888 contain the supplementary crystallographic data for this paper. These data can be obtained D

DOI: 10.1021/acs.orglett.9b01238 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters (7) Wu, J.; Cheng, Y.; Lan, J.; Wu, D.; Qian, S.; Yan, L.; He, Z.; Li, X.; Wang, K.; Zou, B.; You, J. J. Am. Chem. Soc. 2016, 138, 12803. (8) Dahlgren, M. K.; Schyman, P.; Tirado-Rives, J.; Jorgensen, W. L. J. Chem. Inf. Model. 2013, 53, 1191. (9) (a) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (b) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (c) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447. (d) Sun, C.-L.; Li, B.J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677. (e) Zhao, D.; You, J.; Hu, C. Chem. - Eur. J. 2011, 17, 5466. (f) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369. (g) Segawa, Y.; Maekawa, T.; Itami, K. Angew. Chem., Int. Ed. 2015, 54, 66. (10) (a) Ashenhurst, J. A. Chem. Soc. Rev. 2010, 39, 540. (b) Bugaut, X.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 7479. (c) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (d) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (e) Wu, Y.; Wang, J.; Mao, F.; Kwong, F. Y. Chem. - Asian J. 2014, 9, 26. (f) Liu, C.; Yuan, J.; Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei, A. Chem. Rev. 2015, 115, 12138. (g) Yang, Y.; Lan, J.; You, J. Chem. Rev. 2017, 117, 8787. (11) (a) Qin, X.; Li, X.; Huang, Q.; Liu, H.; Wu, D.; Guo, Q.; Lan, J.; Wang, R.; You, J. Angew. Chem., Int. Ed. 2015, 54, 7167. (b) Li, B.; Lan, J.; Wu, D.; You, J. Angew. Chem., Int. Ed. 2015, 54, 14008. (c) Shi, Y.; Zhang, L.; Lan, J.; Zhang, M.; Zhou, F.; Wei, W.; You, J. Angew. Chem., Int. Ed. 2018, 57, 9108. (12) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (13) Qin, X.; Liu, H.; Qin, D.; Wu, Q.; You, J.; Zhao, D.; Guo, Q.; Huang, X.; Lan, J. Chem. Sci. 2013, 4, 1964. (14) (a) Nishino, M.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2012, 51, 6993. (b) Wang, Y.; Lan, J. Sci. China: Chem. 2018, 61, 200.

E

DOI: 10.1021/acs.orglett.9b01238 Org. Lett. XXXX, XXX, XXX−XXX