Annulative π-Extension (APEX) of Heteroarenes with Dibenzosiloles

Letter pubs.acs.org/OrgLett

Annulative π‑Extension (APEX) of Heteroarenes with Dibenzosiloles and Dibenzogermoles by Palladium/o‑Chloranil Catalysis Kyohei Ozaki,† Wataru Matsuoka,† Hideto Ito,*,† and Kenichiro Itami*,†,‡,# †

Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan JST-ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464-8602, Japan # Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya 464-8602, Japan ‡

S Supporting Information *

ABSTRACT: Annulative π-extension (APEX) reactions of heteroarenes are described herein. A catalytic system comprising a cationic palladium species and o-chloranil using dimethyldibenzosiloles as π-extending agents enabled the extension of the π-system of benzo[b]thiophenes. π-Extended dibenzofurans and carbazoles could also be obtained from benzofuran and N-tosylindole, respectively, with dimethyldibenzogermole as a germanium-based π-extending agent. Mechanistic investigations indicated two possible reaction pathways involving carbopalladation-based double C−H arylation of benzothiophene or formal cycloaddition/oxidation cascades. uring the past few decades, fused π-conjugation systems containing heteroatoms have been recognized as quintessential structural motifs in the field of optoelectronics.1 The electronic structure of heteroarenes can be easily controlled by the replacement of heteroatoms with other ones, changing the substitution patterns, and the extension of fused π-conjugation, thereby manifesting unique and kaleidoscopic photophysical properties.2 As shown in Figure 1a, mainstream synthetic approaches toward heteroatom-containing fused π-systems include (i) intramolecular carbon−heteroatom bond formation of biaryl

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alcohols, amines, and sulfides,3 (ii) intramolecular carbon− carbon bond formation of diaryl heteroethers,4 (iii) stepwise functionalization and π-extension of heteroarenes,5 and (iv) single-step annulative π-extension (APEX)6 of unfunctionalized heteroarenes. Although synthetic methods (i), (ii), and (iii) reliably give π-extended fused heteroaromatics, stepwise reactions including the prefunctionalization of starting compounds always decrease the synthetic utility and total yields. In stark contrast, APEX reactions do not require the prefunctionalization of template heteroarenes, thereby providing considerable synthetic benefits from the viewpoint of convenience and step/atom economy. Thus, a variety of APEX reactions of unfunctionalized heteroarenes have recently garnered considerable attention.6−9 While a number of APEX reactions of pyrroles and indoles have been reported using Brønsted and Lewis acids as well as transition metal catalysts, APEX reactions of thiophenes and benzothiophenes are not well established.7 The development of thiophene-based APEX reactions would offer easy access to attractive π-extended fused thiophenes, which are promising compounds in materials science.2 Herein, we report a new APEX reaction of heteroarenes, especially benzothiophenes, with dibenzosiloles and dibenzogermole as π-extending agents (Figure 1b). During the course of our studies on APEX reactions of polycyclic aromatic hydrocarbons (PAHs)6a and alkynes6e with dibenzosiloles, we found that a palladium/o-chloranil catalytic system promoted APEX reactions at the most reactive, carbon− carbon multiple bond such as the K-region (most olefinic

Figure 1. (a) Classical synthetic methods for heteroatom-containing fused π-systems. (b) Pd-catalyzed annulative π-extension (APEX) of heteroarenes with dibenzosilole and dibenzogermole. © XXXX American Chemical Society

Received: March 14, 2017

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DOI: 10.1021/acs.orglett.7b00684 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters armchair convex region) on PAHs or triple bonds on alkynes. Based on this site selectivity, we envisioned that other aromatic templates with reactive C−C multiple bonds could be suitable candidates for novel APEX reactions. Optimal conditions for the APEX of benzo[b]thiophene (1a) were established using Pd(OAc)2 as a catalyst, dimethyldibenzosilole (2a) as a π-extending agent, a silver salt, and o-chloranil in 1,2-dichloroethane at 70 °C (Table 1). The use of 1.0 equiv of

With the optimized conditions in hand, the scope of benzo[b]thiophene derivatives 1 and dibenzosiloles 2 was investigated (Scheme 1). tert-Butyl and methyl substituted Scheme 1. Substrate Scope of APEX Reaction of Benzo[b]thiophenesa

Table 1. Screening of Reaction Conditions for Pd-Catalyzed APEX Reactions of Benzo[b]thiophene (1a) with 9,9Dimethyldibenzosilole (2a)a

entry

Ag salt

oxidant

yieldb

1 2c 3 4 5 6 7 8 9 10d 11 12e

AgPF6 AgPF6 AgPF6 (50 mol %) AgOTf AgBF4 AgSbF6 AgNTf2 none AgPF6 AgPF6 AgPF6 AgPF6

o-chloranil o-chloranil o-chloranil o-chloranil o-chloranil o-chloranil o-chloranil o-chloranil DDQ DTBQ BQ o-chloranil

63% 35% 46% 34% 27% 38% 40% 0% 18% 0% 0% 69% (68%)f

a

Reaction conditions: 1 (0.20 mmol), 2 (3.0 equiv), Pd(OAc)2 (5 mol %), AgPF6 (1.0 equiv), o-chloranil (2.0 equiv), 1,2-dichloroethane (1.5 mL), 70 °C, 16 h. bPd(OAc)2 (10 mol %).

benzo[b]thiophenes 1b and 1c provided desired APEX products 3ba and 3ca in moderate yields. The reaction of electrondeficient benzo[b]thiophenes, such as 5-bromo, 5-chloro, and 5fluorobenzo[b]thiophenes 1d, 1e, and 1f, provided the desired products 3da, 3ea, and 3fa without concomitant loss of the halogen atoms, which are useful for further functionalization by classical cross-coupling protocols. Additionally, the reaction of benzo[b]thiophene (1a) with 3,7-di-tert-butyldibenzosilole (2b) afforded the corresponding APEX product 3ab in 28% yield. When unsymmetrical dibenzosilole 3-chlorodimethyldibenzosilole (2c) was used as the π-extending agent, regioisomers 3ac and 3ac′ were obtained in 38% combined yield as a 78:22 mixture. Other heteroarene templates were also investigated (Scheme 2). Under the optimized conditions, 2,3-diphenylthiophene (1g) and 2-aryl-3-methoxythiophene 1h were transformed into phenanthro[9,10-b]thiophenes 3ga and 3ha in 50% and 36% yields, respectively. However, the standard conditions with dibenzosilole 2a were not applicable to the APEX of Ntosylindole (5). Further optimization revealed that the combination of dimethyldibenzogermole (2d) and 30 mol % of AgOTf provided dibenzocarbazole 6, albeit in a low yield (30% yield). When benzofuran (7) was used in the APEX reaction with 2.0 equiv of dibenzogermole 2d, desired benzonaphthofuran 8 was obtained in 19% yield, along with cis-dehydrogenated 8′ in 23% yield. Increasing the amount of o-chloranil afforded 8 as the only product. Notably, 8′ was readily oxidized to 8 in the presence of 2.0 equiv of o-chloranil in 1,2-dichloroethane at room temperature. Although these phenomena may only occur in the

a

Reaction conditions: benzo[b]thiophene (1a: 0.20 mmol), 9,9dimethyldibenzosilole (2a: 3.0 equiv), Pd(OAc)2 (5 mol %), AgPF6 (1.0 equiv), o-chloranil (2.0 equiv), 1,2-dichloroethane (2.0 mL), 70 °C, 16 h. bGC or NMR yield. GC yield was determined using ndecane as an internal standard. NMR yield was determined using CH2Br2 as an internal standard. c2.0 equiv of 2a was used. dβBiphenylbenzo[b]thiophene (4) was obtained in 7% GC yield. e1.5 mL of 1,2-dichloroethane was used. fIsolated yield.

AgPF6, 3.0 equiv of 2a, and 2.0 equiv of o-chloranil (relative to 1a) gave the best result affording APEX product 3aa in 63% yield (Table 1, entry 1). Decreasing the amount of 2a or AgPF6 resulted in lower yields (entries 2 and 3). While the reactions with other silver salts such as AgOTf, AgBF4, AgSbF6, and AgNTf2 also provided 3aa in 27−40% yields, the reactions did not exceed the yield obtained with AgPF6 (entries 4−7). The use of neutral palladium acetate without any silver salt did not afford 3aa at all (entry 8). Although 5,6-dichloro-2,3-dicyanobenzoquinone (DDQ) instead of o-chloranil afforded the APEX product in 18% GC yield (entry 9), 3,5-di-tert-butylbenzoquinone (DTBQ) only gave nonfused β-biphenylbenzo[b]thiophene (4) in 7% GC yield (entry 10). p-Benzoquinone (BQ) was not an effective oxidant (entry 11). Finally, the best result was obtained under a marginally higher concentration of 1a (0.13 M), which gave 3aa in 68% isolated yield (entry 12), along with a byproduct derived from the hydrofluorination of 2a (see SI for details).10 B

DOI: 10.1021/acs.orglett.7b00684 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 2. APEX of Thiophene Derivatives (1g and 1h), Benzofuran (5), and N-Tosylindole (7)

Figure 2. Two possible reaction pathways in the carbopalladationtriggered APEX reaction of benzoheteroles.

carbopalladation events in monoarylation product C to give the trans-fused precursor of APEX product D. Then, a second βH elimination/demetalation occurs to give APEX product 3aa. As an alternative mechanism for the reaction of benzofuran (7) with dibenzogermole 2d, path B involving formal cycloaddition/ oxidation cascades is also possible, where the intramolecular transmetalation of intermediate B is followed by reductive elimination from palladacycle E to give cis-dihydro adduct 8′, which would be oxidized by o-chloranil to provide APEX product 8. In summary, APEX reactions of heteroarene templates such as thiophenes, benzofuran, and N-tosylindole in the presence of a palladium catalyst, silver salts, and o-chloranil have been established. The combination of π-extending agents such as dimethyldibenzosilole and dimethyldibenzogermole with silver hexafluorophosphate or silver triflate enabled the synthesis of a variety of π-extended fused heteroarenes in one-step. The developed APEX methodology has obvious advantages over existing stepwise π-extension methods in terms of the step- and atom-economy.

reaction with benzofuran, these results provided mechanistic insights into the APEX reaction (vide inf ra). In light of previous studies on the APEX of PAHs6a and oxidative C−H arylation of thiophenes,11 we surmised that the current heterocycle APEX reaction of benzo[b]thiophene (1a) might be initiated by the oxidative β-arylation of benzo[b]thiophene via carbopalladation (vide inf ra). In fact, when trimethylsilylbenzene was used as a coupling partner under the influence of the Pd(OAc)2/AgOTf/o-chloranil system, C−H arylation of 1a gave α- and β-arylated products 9a and 9b in 27% combined yield with 93% β-selectivity (Scheme 3). Thus, β-

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Scheme 3. (a) β-Selective C−H Arylation of Benzo[b]thiophene (1a) with Trimethylsilylbenzene; (b) Intramolecular C−H Arylation of Silylated 3Biphenyllbenzothiophene 10

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00684. Experimental procedures and characterization data for all compounds, general procedures, and ORTEP drawings (PDF) X-ray crystallographic data for 3da (CIF) X-ray crystallographic data for 8′ (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (H.I.) *E-mail: [email protected] (K.I.)

arylation of 1a11g might be the first step in the current APEX with dibenzosilole. Furthermore, palladium-catalyzed intramolecular C−H arylation of quasi-intermediate 10 under the standard conditions gave 3aa in 51% NMR yield. Based on the aforementioned mechanistic insights, two possible reaction pathways can be assumed (Paths A and B, Figure 2). Both pathways are initiated from the formation of biphenyl palladium intermediate A by the transmetalation of a cationic palladium species with dibenzosilole or dibenzogermole. As described in the literature,11g regioselective carbopalladation can occur with benzoheteroles to form β-biphenyl-α-palladated adduct B. Path A involves β-H elimination/demetalation from intermediate B,10 followed by sequential transmetalation/

ORCID

Hideto Ito: 0000-0002-4034-6247 Kenichiro Itami: 0000-0001-5227-7894 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the ERATO program from JST (to K.I.), JSPS KAKENHI Grant Numbers JP26810057 and JP16H00907, and a grant from SHOWA DENKO Award in Synthetic Organic Chemistry, Japan (to H.I.). We thank Dr. C

DOI: 10.1021/acs.orglett.7b00684 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

(8) For selected APEX reactions of unfunctionalized pyrroles and indoles see: (a) Fletcher, H. Tetrahedron 1966, 22, 2481. (b) Cranwell, P. A.; Saxton, J. E. J. Chem. Soc. 1962, 3482. (c) Abid, M.; Spaeth, A.; Török, B. Adv. Synth. Catal. 2006, 348, 2191. (d) Kulkarni, A.; Quang, P.; Török, B. Synthesis 2009, 2009, 4010. (e) Zheng, X.; Lv, L.; Lu, S.; Wang, W.; Li, Z. Org. Lett. 2014, 16, 5156. (f) Maftouh, M.; Besselievre, R.; Monsarrat, B.; Lesca, P.; Meunier, B.; Husson, H. P.; Paoletti, C. J. Med. Chem. 1985, 28, 708. (g) Zhao, J.; Li, P.; Xia, C.; Li, F. Chem. - Eur. J. 2015, 21, 16383. (h) Palmieri, A.; Gabrielli, S.; Lanari, D.; Vaccaro, L.; Ballini, R. Adv. Synth. Catal. 2011, 353, 1425. (i) Suárez, A.; GarcíaGarcía, P.; Fernández-Rodríguez, M. P.; Sanz, R. Adv. Synth. Catal. 2014, 356, 374. (j) Nagase, Y.; Miyamura, T.; Inoue, K.; Tsuchimoto, T. Chem. Lett. 2013, 42, 1170. (k) Tang, R.-Y.; Li, J.-H. Chem. - Eur. J. 2010, 16, 4733. (l) Prakash, K. S.; Nagarajan, R. Adv. Synth. Catal. 2012, 354, 1566. (m) Yamashita, M.; Horiguchi, H.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 7481. (n) Matsuda, Y.; Naoe, S.; Oishi, S.; Fujii, N.; Ohno, H. Chem. - Eur. J. 2015, 21, 1463. (o) Thies, N.; Hrib, C. G.; Haak, E. Chem. - Eur. J. 2012, 18, 6302. (p) Dawande, S. G.; Kanchupalli, V.; Kalepu, J.; Chennamsetti, H.; Lad, B. S.; Katukojvala, S. Angew. Chem., Int. Ed. 2014, 53, 4076. (q) Rathore, K. S.; Harode, M.; Katukojvala, S. Org. Biomol. Chem. 2014, 12, 8641. (r) Wu, J.-Q.; Yang, Z.; Zhang, S.-S.; Jiang, C.-Y.; Li, Q.; Huang, Z.-S.; Wang, H. ACS Catal. 2015, 5, 6453. (s) Paria, S.; Reiser, O. Adv. Synth. Catal. 2014, 356, 557. (t) Wu, Y.; Peng, X.; Luo, B.; Wu, F.; Liu, B.; Song, F.; Huang, P.; Wen, S. Org. Biomol. Chem. 2014, 12, 9777 For other examples see refs 6d and 7.. (9) For selected APEX reactions of unfunctionalized furans and benzofurans see: (a) Paria, S.; Reiser, O. Adv. Synth. Catal. 2014, 356, 557 For other examples see refs 7b, 7c, 7eg−h, and 8t.. (10) The reaction on a 1 mmol scale of 1a resulted in the decreased yield of 46%. (11) For selected examples of the direct β-arylation of thiophene derivatives see: (a) Wang, Z.; Li, Y.; Yan, B.; Huang, M.; Wu, Y. Synlett 2015, 26, 531. (b) Tang, D.-T.; Collins, K. D.; Ernst, J. B.; Glorius, F. Angew. Chem., Int. Ed. 2014, 53, 1809. (c) Tang, D.-T.; Collins, K. D.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 7450. (d) Yamaguchi, K.; Kondo, H.; Yamaguchi, J.; Itami, K. Chem. Sci. 2013, 4, 3753. (e) Yuan, K.; Doucet, H. Chem. Sci. 2014, 5, 392. (f) Yamaguchi, K.; Yamaguchi, J.; Studer, A.; Itami, K. Chem. Sci. 2012, 3, 2165. (g) Funaki, K.; Sato, T.; Oi, S. Org. Lett. 2012, 14, 6186. (h) Biajoli, A. F. P.; da Penha, E. T.; Correia, C. R. D. RSC Adv. 2012, 2, 11930. (i) Kirchberg, S.; Tani, S.; Ueda, K.; Yamaguchi, J.; Studer, A.; Itami, K. Angew. Chem., Int. Ed. 2011, 50, 2387. (j) Ueda, K.; Yanagisawa, S.; Yamaguchi, J.; Itami, K. Angew. Chem., Int. Ed. 2010, 49, 8946.

Yasutomo Segawa and Dr. Takao Fujikawa for X-ray diffraction analyses. ITbM is supported by the World Premier International Research Center (WPI) Initiative, Japan.

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DOI: 10.1021/acs.orglett.7b00684 Org. Lett. XXXX, XXX, XXX−XXX