Modular Synthesis of Benzimidazole-Fused Phenanthridines from 2

Letter pubs.acs.org/OrgLett

Modular Synthesis of Benzimidazole-Fused Phenanthridines from 2‑Arylbenzimidazoles and o‑Dibromoarenes by a PalladiumCatalyzed Cascade Process Chunxia Chen,*,† Guoning Shang,† Jingjie Zhou,† Yanhan Yu,† Bin Li,†,‡ and Jinsong Peng*,†,‡ †

Department of Chemistry and Chemical Engineering, College of Science, and ‡Post-doctoral Mobile Research Station of Forestry Engineering, Northeast Forestry University, Harbin 150040, P. R. China S Supporting Information *

ABSTRACT: An efficient palladium-catalyzed route for the synthesis of benzimidazole-fused phenanthridines from odibromoarenes and 2-arylbenzimidazoles is described. The sequentially accomplished reaction comprises intermolecular C−H arylation of 2-arylbenzimidazoles followed by an intramolecular N-arylation reaction promoted by the same Pd catalyst. This Pdcatalyzed double arylation provides a useful tool for the discovery of fluorescent materials.

T

Scheme 1. Possible Pathways for Pd-Catalyzed Double Arylations of 2-Arylbenzimidazoles and 1,2-Dihaloarenes

he discovery of novel polycyclic or heteropolycyclic aromatic compounds as organic electronic and optical materials has been intensely studied during the past decade.1 In particular, 1,2-disubstituted (hetero)aryl-fused imidazoles or benzimidazoles, as electron-transporting and emission functional units, are prevalent in advanced organic materials.2 Hence, straightforward and modular synthetic approaches to structurally diverse (hetero)aryl-fused imidazoles are highly anticipated to assist rapid development of heteropolycyclic aromatic compound-based functional materials.3 Palladium-catalyzed coupling reactions collectively represent some of the most powerful and versatile tools available to synthetic organic chemists.4 Furthermore, using highly active and versatile palladium catalyst systems, fundamentally different cross-coupling reactions can be carried out consecutively under the same reaction conditions for the rapid buildup of molecular complexity and diversity. During the past decade, both C−H arylation5 and amination processes6 of aryl halides with arene or amine have become extraordinarily popular, as they provide a very efficient and economical method for the regio- and stereospecific formation of the C(sp2)−C(sp2) or C−N bond. As a result, by taking advantage of this versatility of some Pd catalysts, one-pot catalytic processes incorporating C−H arylation and amination reactions would provide a straightforward method for the synthesis of heterocycles. However, examples of such annulations for the synthesis of heterocycles are limited.7 In parallel with our continuing efforts to develop new synthetic methods of nitrogen heterocycles,8 herein we report a Pd-catalyzed C−H arylation/N-arylation tandem process of 2arylbenzimidazoles 1 with 1,2-dihaloarenes 2 as a new entry to (hetero)aryl-fused benzimidazoles.9 As illustrated in Scheme 1, due to the dual nature of 1H-imidazole group as a nucleophilic © XXXX American Chemical Society

reagent or o-directing group, at the outset of this work, we wondered whether 2-arylbenzimidazoles 1 might undergo the Buchwald−Hartwig amination10 reaction to provide Narylation intermediate I (path A)3h,9 or a C-arylation reaction via benzimidazole group-directed aromatic C−H activation,11 similar to other nitrogen-containing o-directing groups such as imine, pyridine, acetamine, and oxazoline,12 to give direct arylation intermediate II (path B). Whatever it was, odihaloarene13 as an ideal substrate might participate in two consecutive cross-coupling processes to give benzimidazolefused phenanthridine derivatives. Extensive experiments were conducted for a palladiumcatalyzed 2-fold arylation of 2-phenylbenzo[d]imidazole (1a) and o-dibromobenzene (2a) as the coupling partners (Table S1, Supporting Information). Xphos or DPE-phos for Pd(OAc)2 Received: January 27, 2014

A

dx.doi.org/10.1021/ol500248h | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

(Table 1, entries 4−9 and 16); however, the presence of electron-withdrawing substituents (such as CN) led to inferior results (14% isolated yield, Table 1, entry 8) under similar reaction conditions. In addition, 2-heteroarylbenzimidazoles (1h and 1i) and 2-arylimidazole derivatives 1l can also be efficiently transformed into the corresponding products in good yields (Table 1, entries 10, 11, and 14). When the application of this methodology to the synthesis of heteropolycyclic aromatic compounds is considered, potential regioselectivity issues exist in either direct C−H arylation14 or N-arylation processes.8a Consequently, various asymmetrically substituted 2-arylbenzimidazole or o-dihaloarene substrates were used to investigate the regioselectivity of the process (Scheme 2). In general, substituents such as Me, MeO, and Cl

was found to be the best catalyst system to achieve 3aa with K2CO3 as a base in DMF at 160 °C. Having established the feasibility of the tandem double-arylation sequence, the scope and generality of the present annulation process was then explored by testing a set of structurally diverse 2-arylbenzimidazoles with 1,2-dihalobenzene. The nature of dihalides was very important to the reaction outcome, and both 1,2dibromobenzene and 1-bromo-2-iodobenzene underwent the cyclization to afford the desired product (Table 1, entries 1 and Table 1. Pd-Catalyzed Annulation of Benzimidazole Derivative with o-Dihalobenzenea

Scheme 2. Regioselectivity in Pd-Catalyzed Double Arylations of 2-Arylbenzimidazoles and 1,2-Dihaloarenesa

a

a

Reaction conditions (isolated yields): 2-arylbenzimidazole 1 (0.2 mmol), 1,2-dihalobenzene 2 (0.3 mmol), K2CO3 (0.6 mmol), Pd(OAc)2 (10 mol %), Xphos (20 mol %) or DPE-phos (10 mol %), DMF (2.0 mL), 160 °C, 24 h. bDPE-phos was used. c72 h. d Determined by NMR. e3-Bromo-4-iodotoluene was used as a odihaloarene.

2); however, the use of aryl chlorides such as 1-bromo-2chlorobenzene and 1,2-dichlorobenzene gave no products (Table 1, entry 3). Symmetrically substituted 1,2-dibromoarenes or benzimidazoles bearing the neutral, electron-donating, or electron-withdrawing substituents (Table 1, entries 12, 13, and 15) can be smoothly transformed into structurally diverse (hetero)aryl-fused benzimidazoles in moderate to good yields. A variety of substituents (such as Me, OMe, Cl, Me2N, CN, and carbazoyl) on the 2-arylbenzimidazole moiety were applicable

in the meta-positions of the 2-aryl moiety seemed not to hamper the reaction, and C−H arylation process regioselectively occurred at the most sterically accessible site to give single regioisomers 3na, 3oa, and 3pa in good yields. When αnaphthyl benzimidazole 1q was reacted with o-dibromobenzene, the smaller six-membered heterocycle 3qa as the only product was isolated in 52% yield; however, β-naphthyl substrate 1r provided a 1:3 (α/β) mixture of regioisomers 3ra. The turnover of site-selectivity in 1r implies that this is not a characteristic outcome of electrophilic aromatic substitutions.14 4- or 5-monosubstituted benzimidazoles were then used to investigate the influence of sterics on the

Reaction conditions: 2-arylbenzimidazole 1 (0.2 mmol), 1,2dihalobenzene 2 (0.3 mmol), K2CO3 (0.6 mmol), Pd(OAc)2 (10 mol %), Xphos (20 mol %) or DPE-phos (10 mol %), DMF (2.0 mL), 160 °C, 24−72 h. bIsolated yield. cDPE-phos (10 mol %) was used.

B

dx.doi.org/10.1021/ol500248h | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

regioselectivity of the N-atoms in the Pd-catalyzed C−N formation step. In the case of 4-methyl-substituted benzimidazoles, N-arylation occurred specifically at the sterically accessible N-atom to give single regioisomers such as 3sa, 3ta, and 3ua. Diminished selectivity was obtained when using 5-methyloxy-substituted 1v as a substrate, providing a 1:1.2 mixture of regioisomers 3va. Finally, the use of unsymmetrical o-dihaloarene containing two different halogen atoms, such as 3-bromo-4-iodotoluene, could not ensure a regioselective transformation under high temperature conditions; low selectivity was observed in nearly 1:1 ratio. To gain insight into the mechanism of the reaction, some designed control experiments were conducted as shown in Scheme 3. When the reaction of 4 (benzimidazole or 2-

Scheme 4. Proposed Mechanism for Sequential PdCatalyzed 2-Fold Arylation

Scheme 3. Investigation of the Reaction Mechanism

elimination to afford the desired product 3 and regenerate the active catalytic species. The absorption and fluorescence spectra of (hetero)arylfused benzimidazoles 3 were measured in CH2Cl2, as shown in Table 2. A change of less than 4 nm for λmax was observed Table 2. Photophysical Properties of Benzimidazole-Fused Phenanthridines 3

methylbenzimidazole) and 5 (iodobenzene, bromobenzene, or o-dibromobenzene) was conducted under standard reaction conditions, no N-arylation product was detected even with large excesses of aryl halide and base (eqs 1a−c).10 However, when N-isopropyl-2-phenyl benzoimidazole 6a and iodobenzene 5 were carried out under the optimized reaction conditions, 43% of the desired product 7 was obtained (eq 2).11 In addition, when 2a and 2-phenylindole 6b without an odirecting nitrogen atom were treated, the reaction could not proceed under optimized conditions (eq 3). 9 Finally, compound 11 was treated with K2CO3 in DMF at 160 °C, and no desired product was obtained; however, the use of Pd(OAc)2/Xphos could efficiently promote this transformation to give 3aa in 75% yield (eq 4). These experimental results revealed that this reaction probably proceeded through Pdcatalyzed intermolecular aromatic C−H arylation and subsequent intramolecular amination (Scheme 1, path B). On the basis of the above results, a possible catalytic cycle involved in the present process is outlined in Scheme 4. Oxidative addition of o-dibromobenzene 2 to Pd(0) was followed by the coordination of 1 to form intermediate 9, which reacted with the tethered arene to afford a fivemembered palladacycle 10 through C−H activation. Complex 10 underwent C−C reductive elimination to give C−H arylation product 11, which was then transformed into a new seven-membered palladacycle 13 by oxidative addition and subsequent K2CO3-promoted N−Pd bond-forming reaction. Palladacycle intermediate 13 underwent C−N reductive

entry

compd

1 2 3 4 5 6 7 8 9 10

3la 3aa 3qa 3ca 3ea 3fa 3da 3ma 3ia 3ha

λmax (nm) [ε (M−1cm−1)]a 260 272 283 272 274 270 271 272 266 268

[42967] [48867] [67967] [76333] [50400] [36700] [35167] [33733] [50000] [43367]

λema (nm)

ΦFb

381 374 413 398 389 409 417 403 395 380

0.50 0.85 0.57 0.67 0.32 0.90 0.23 0.65 0.50 0.57

Concentration: 3.0× 10−6 M in CH2Cl2. bDetermined by p-terphenyl (ΦF = 0.87, excited at 265 nm) as a standard. a

among 3aa, 3ca, 3da, 3ea, 3fa, and 3ma by simply modifying the substituents at the 2-aryl moiety position (Table 2, entries 2 and 4−8). In comparison with 3la, a longer wavelength of the absorption maximum peak (λmax) was obtained upon the introduction of π-extended framework (Table 2, entries 1−3). All of these compounds showed blue fluorescent emissions in CH2Cl2 when the C2 position was occupied by the aromatic moiety with electron-donating groups (such as MeO, Me2N, and carbazoyl), and all exhibited stronger fluorescence (Table 2, entries 4, 7, and 8). Notably, the fluorophores 3 exhibited a large Stokes shift in the range 100−150 nm in CH2Cl2, and the fluorescence quantum yield (ΦF) remained in the range of 0.23−0.90. In general, the introduction of cyano group into benzimidazole-fused phenanthridines showed a good fluorescence quantum yield (ΦF = 0.90) (Table 2, entry 6); the fluorescence can be quenched efficiently through the introduction of an electron-donating substituent (Me2N) or halides (Table 2, entries 5 and 7). C

dx.doi.org/10.1021/ol500248h | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

(6) (a) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609. (b) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem. 1995, 107, 1456; Angew. Chem., Int. Ed. 1995, 34, 1348. (7) Selected examples, see: (a) Bedford, R. B.; Cazin, C. S. J. Chem. Commun. 2002, 2310. (b) Carril, M.; SanMartin, R.; Churruca, F.; Tellitu, I.; Domínguez, E. Org. Lett. 2005, 7, 4787. (c) Barluenga, J.; Jiménez-Aquino, A.; Valdés, C.; Aznar, F. Angew. Chem., Int. Ed. 2007, 46, 1529. (d) Bryan, C. S.; Lautens, M. Org. Lett. 2008, 10, 4633. (e) Barluenga, J.; Jiménez-Aquino, A.; Aznar, F.; Valdés, C. J. Am. Chem. Soc. 2009, 131, 4031. (f) Barluenga, J.; Jiménez-Aquino, A.; Aznar, F.; Valdés, C. Chem.Eur. J. 2010, 16, 11707. (g) Yadav, A. K.; Verbeeck, S.; Hostyn, S.; Franck, P.; Sergeyev, S.; Maes, B. U. W. Org. Lett. 2013, 15, 1060. (8) (a) Peng, J.; Shang, G.; Chen, C.; Miao, Z.; Li, B. J. Org. Chem. 2013, 78, 1242. (b) Peng, J.; Chen, T.; Chen, C.; Li, B. J. Org. Chem. 2011, 76, 9507. (9) A similar synthetic method of phenanthridine derivatives has been reported previously by Miura and colleagues through Pdcatalyzed intermolecular amination followed by intramolecular C−H arylation; see: Takeda, D.; Hirano, K.; Satoh, T.; Miura, M. Heterocycles 2012, 86, 487. (10) (a) Ueda, S.; Ali, S.; Fors, B. P.; Buchwald, S. L. J. Org. Chem. 2012, 77, 2543. (b) Ueda, S.; Su, M.; Buchwald, S. L. J. Am. Chem. Soc. 2012, 134, 700. (11) Chen, L.-H.; Wu, T.-Y.; Paike, V.; Sun, C.-M. Mol. Diversity 2013, 17, 641. (12) (a) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. Rev. 2005, 105, 2527. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (13) For selected examples of Pd-catalyzed double cross-coupling reactions using o-dihaloarenes, gem-dihaloolefins, or 1,n-dihaloalkenes as substrates for cyclic compounds, see: (a) Edmondson, S. D.; Mastracchio, A.; Parmee, E. R. Org. Lett. 2000, 2, 1109. (b) Churruca, F.; SanMartin, R.; Tellitu, I.; Domínguez, E. Eur. J. Org. Chem. 2005, 2481. (c) Dong, C.-G.; Hu, Q.-S. Angew. Chem. 2006, 118, 2347; Angew. Chem., Int. Ed. 2006, 45, 2289. (d) Jensen, T.; Pedersen, H.; Bang-Andersen, B.; Madsen, R.; Jørgensen, M. Angew. Chem. 2008, 120, 902; Angew. Chem., Int. Ed. 2008, 47, 888. (e) Dahl, T.; Tornøe, C. W.; Bang-Andersen, B.; Nielsen, P.; Jørgensen, M. Angew. Chem. 2008, 120, 1750; Angew. Chem., Int. Ed. 2008, 47, 1726. (f) Nagao, I.; Shimizu, M.; Hiyama, T. Angew. Chem. 2009, 121, 7709; Angew. Chem., Int. Ed. 2009, 48, 7573. (g) Liu, T.-P.; Xing, C.-H.; Hu, Q.-S. Angew. Chem. 2010, 122, 2971; Angew. Chem., Int. Ed. 2010, 49, 2909. (h) Cao, H.; Alper, H. Org. Lett. 2010, 12, 4126. (i) Knapp, J. M.; Zhu, J. S.; Tantillo, D. J.; Kurth, M. J. Angew. Chem., Int. Ed. 2012, 51, 10588. (j) Huang, R. Y.; Franke, P. T.; Nicolaus, N.; Lautens, M. Tetrahedron 2013, 69, 4395. (k) Chelucci, G. Chem. Rev. 2012, 112, 1344. (l) Ball, C. J.; Willis, M. C. Eur. J. Org. Chem. 2013, 425. (14) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 581.

In summary, we have developed a palladium-catalyzed C−H arylation/N-arylation tandem process, and diverse heteropolycyclic aromatic compounds can be synthesized in good yields from 2-arylbenzimidazoles and 1,2-dihaloarenes. The results presented here should be of considerable interest for medicinal and material science. Further studies on the elucidation of the mechanism and the development of organic functional materials using the present 2-fold arylation are in progress.

■

ASSOCIATED CONTENT

S Supporting Information *

General experimental methods and 1H and 13C NMR spectra of the products. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Authors

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

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We are grateful for financial support from the Fundamental Research Funds for the Central Universities (DL12DB03), National Natural Science Foundation of China (31300286), China Postdoctoral Science Foundation (20110491013, 2012T50319), and Heilongjiang Postdoctoral Grant (LBHZ11251).

■

REFERENCES

(1) (a) Forrest, S. R., Thompson, M. E., Eds. Chem. Rev. 2007, 107, 923−1386 (Special issue on Organic Electronics and Optoelectronics). (b) Mishra, A.; Bäuerle, P. Angew. Chem., Int. Ed. 2012, 51, 2020. (c) Itoh, T. Chem. Rev. 2012, 112, 4541. (2) (a) Lai, M.-Y.; Chen, C.-H.; Huang, W.-S.; Lin, J. T.; Ke, T.-H.; Chen, L.-Y.; Tsai, M.-H.; Wu, C.-C. Angew. Chem., Int. Ed. 2008, 47, 581. (b) Ge, Z.; Hayakawa, T.; Ando, S.; Ueda, M.; Akiike, T.; Miyamoto, H.; Kajita, T.; Kakimoto, M. Adv. Funct. Mater. 2008, 18, 584. (c) Benelhadj, K.; Massue, J.; Retailleau, P.; Ulrich, G.; Ziessel, R. Org. Lett. 2013, 15, 2918. (d) Zhuang, S.; Shangguan, R.; Huang, H.; Tu, G.; Wang, L.; Zhu, X. Dyes Pigments 2014, 101, 93. (3) For the selected examples, see: (a) Sun, M.; Wu, H.; Zheng, J.; Bao, W. Adv. Synth. Catal. 2004, 354, 835. (b) Cerňa, I.; Pohl, R.; Klepetárovǎ, B.; Hocek, M. J. Org. Chem. 2010, 75, 2302. (c) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am. Chem. Soc. 2010, 132, 13217. (d) Masters, K.-S.; Rauws, T. R. M.; Yadav, A. K.; Herreb-out, W. A.; Van der Veken, B.; Maes, B. U. W. Chem.Eur. J. 2011, 17, 6315. (e) Qu, G.-R.; Liang, L.; Niu, H.-Y.; Rao, W.-H.; Guo, H.-M.; Fossey, J. S. Org. Lett. 2012, 14, 4494. (f) Huang, J.-R.; Dong, L.; Han, B.; Peng, C.; Chen, Y.-C. Chem.Eur. J. 2012, 18, 8896. (g) Reddy, V. P.; Iwasaki, T.; Kambe, N. Org. Biomol. Chem. 2013, 11, 2249. (h) Yan, L.; Zhao, D.; Lan, J.; Cheng, Y.; Guo, Q.; Li, X.; Wu, N.; You, J. Org. Biomol. Chem. 2013, 11, 7966. (i) Huang, J.-R.; Zhang, Q.-R.; Qu, C.H.; Sun, X.-H.; Dong, L.; Chen, Y.-C. Org. Lett. 2013, 15, 1878. (j) Maes, J.; Rauws, T. R. M.; Maes, B. U. W. Chem.Eur. J. 2013, 19, 9137. (4) (a) Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley: Hoboken, 2002. (b) Palladium Reagents and Catalysts; Tsuji, J., Ed.; Wiley: Chichester, 2004. (5) (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. D

dx.doi.org/10.1021/ol500248h | Org. Lett. XXXX, XXX, XXX−XXX