Iodination of Remote Ortho-C–H Bonds of Arenes via Directed SEAr: A

ORGANIC LETTERS

Iodination of Remote Ortho-C
H Bonds of Arenes via Directed SEAr: A Streamlined Synthesis of Tetrahydroquinolines

XXXX Vol. XX, No. XX 000–000

William A. Nack, Gang He, Shu-Yu Zhang, Chengxi Lu, and Gong Chen* Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States [email protected] Received May 29, 2013

ABSTRACT

A new strategy for the synthesis of tetrahydroquinolines (THQs) via the sequential functionalizations of remote C
H bonds is reported. This method uses a single picolinamide directing/protecting group to effect Pd-catalyzed γ-C(sp3)
H arylation, metal-free ε-C(sp2)
H iodination, and Cu-catalyzed intramolecular C
N cross-coupling. The overall sequence is efficient and versatile, and offers a streamlined synthesis of THQs with complex substitution patterns from readily available aryl iodide and aliphatic amine precursors.

Tetrahydroquinoline (THQ) is a privileged N-heterocyclic scaffold found in many natural products and pharmaceutical agents.1 In contrast to most conventional synthesis strategies, which typically begin from prefunctionalized arene or arylamine precursors, we envisioned that THQs could be quickly assembled by connection at the C2
Cγ and C1
N positions through directed C
H functionalization reactions from simple aryl halide and alkyl (1) (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 48, 15031. (b) Sridharan, V.; Suryavanshi, P. A.; Men
endez, J. C. Chem. Rev. 2011, 111, 7157. (2) For selected recent syntheses of THQs, see: (a) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128, 13070. (b) Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am. Chem. Soc. 2008, 131, 4598. (c) Han, Z.-Y.; Xiao, H.; Chen, X.-H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 9182. (d) Rousseaux, S.; Li
egault, B.; Fagnou, K. Chem. Sci. 2012, 3, 244. For an elegant recent study on enantioselective THQ synthesis via Pd-catalyzed C
H functionalization approach, see: (e) Saget, T.; Cramer, N. Angew. Chem., Int. Ed. 2012, 51, 12842. (3) For an excellent review on C
H functionalization in the synthesis of N-heterocycles, see: Thansandote, P.; Lautens, M. Chem.;Eur. J. 2009, 15, 5874. (4) For selected recent reviews on C(sp3)
H functionalization, see: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (c) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem.;Eur. J. 2010, 16, 2654. (d) Newhouse, T. R.; Baran, P. S. Angew. Chem., Int. Ed. 2011, 50, 3362.

amine precursors (Scheme 1A).2
4 The picolinamide (PA) group has been shown to effect the palladium-catalyzed arylation of γ-C(sp3)
H bonds of N-alkylpicolinamides (e.g., 1) with aryl iodides, providing γ-arylpropylamine products (e.g., 2, Scheme 1B).5
7 We postulated that the installation of a halogen group at the ortho position of 2, followed by intramolecular C
N cross coupling could afford the desired THQ product in two discrete steps.8
10 Herein, we report a highly efficient and readily applicable (5) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154. (b) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012, 133, 7. (c) Tran, L. D.; Popov, I.; Daugulis, O. J. Am. Chem. Soc. 2012, 134, 18237. (6) (a) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192. (b) Zhao, Y.; Chen, G. Org. Lett. 2011, 13, 4850. (c) He, G.; Zhao, Y.; Zhang, S.-Y.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3. (d) Zhang, S.-Y.; He, G.; Zhao, Y.-S.; Wright, K.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2012, 134, 7313. (e) He, G.; Lu, C.; Zhao, Y.-S.; Nack, W. A.; Chen, G. Org. Lett. 2012, 14, 2944. (f) Zhao, Y.; He, G.; Nack, W. A.; Chen, G. Org. Lett. 2012, 14, 2948. (g) Zhang, S.-Y.; He, G.; Nack, W. A.; Zhao, Y.-S.; Qiong, L.; Chen, G. J. Am. Chem. Soc. 2013, 135, 2124. (7) Recently, we found that PA-directed Pd-catalyzed γ-C(sp3)
H arylation could be notably improved with the application of catalytic amount of (BnO)2PO2H. Detailed studies will be reported in a separate account. (8) Direct formation of THQs from γ-arylpropylpicolinamides via Pd-catalyzed intramolecular dehydrogenative ε-C(sp2)
H amination is under current investigation. 10.1021/ol4015078

r XXXX American Chemical Society

method for the selective iodination of the ε-C(sp2)
H bonds of these γ-arylpropyl picolinamides under metalfree conditions. The ortho-iodinated products can be cyclized under copper catalysis to give tetrahydroquinolines (THQs) in high yields. Neighboring group-directed halogenation of the orthoC(sp2)
H bonds of arenes has been achieved under a variety of metal-catalyzed or directed lithiation conditions.11,12 However, generally applicable methods for the selective halogenation of ortho-C
H bonds at the more remote ε position are very rare.13,14 In our initial attempts, C
H iodination of substrate 2 under an extensively optimized Pd-catalyzed condition gave a mixture of monoortho-iodinated product 3 and di-ortho-iodinated product 5 (entry 1, Table 1).15

Scheme 1. New Synthetic Strategy for THQs

Table 1. Iodination of ε-o-C
H Bonds of 2 via SEAr

yield (%)a

entry

reagents (equiv)

1

Pd(OAc)2 (10%), PhI(OAc)2 (2), I2 (2) KHCO3 (1) IPy2 3 BF4 (1.5), HBF4 3 OEt2 (3) IPy2 3 BF4 (1.1), HBF4 3 OEt 2 (2.2) NIS (1.1), HBF4 3 OEt2 (4) NIS (1.1), TfOH (4) NIS (1.1), BF3 3 OEt2 (4) NIS (1.5), HBF4 3 OEt2 (4) NIS (1.1)

2 3 4 5 6 7 8

solvents DMF

temp (°C)/h

3

130/24 44

4/5