Copper-Catalyzed Electrophilic Ortho C(sp²)–H Amination of Aryl Amines: Dramatic Reactivity of Bicyclic System

Abstract

A practical copper-catalyzed, 2-picolinamidedirected ortho C−H amination of anilines with benzoylprotected hydroxylamines has been disclosed that proceeds smoothly without any external stoichiometric oxidant or additives. Remarkably, besides anilines, bicyclic naphthyl or heterocyclic amines furnished amination products with fiveand six-membered cyclic and acyclic amines at the ortho position selectively. This electrophilic C−H amination also proceeds smoothly in water under slightly modified reaction conditions.E fficient construction of C−N bonds represents one of the mainstays of research in organic synthesis over the last decades, because of the exponential use of nitrogen-containing molecules in pharmaceutical, medicinal, and materials science. 1 Following the pioneer works of Buchwald and Hartwig regarding palladium-catalyzed C−N bond formation from aryl halides and amines, 2 an impressive array of Earthabundant, inexpensive copper-catalyzed C−N coupling reactions have been explored. 3 A mechanistically distinct coppercatalyzed/mediated oxidative C−N coupling using organometallic reagents has also been developed under mild conditions. 4 A paradigm shift from transition-metal-catalyzed cross-coupling with organometallic reagents to direct C−H amination strategy has been observed in the last decades. In this vein, the research groups of Yu and Chatani independently reported copper-mediated C−H amination of 2-arylpyridines. 5 Remarkably, the Daugulis group expanded the scope of C−H amination using removable, bidentate directing groups. 6 Recently, the Chang group also reported copper-mediated C−H amination with aqueous ammonia. 7 2-Aminoanilide moiety is ubiquitously found in drug candidates for the treatment of cancer, Alzheimer's disease, wet age-related macular degeneration (wet AMD), and infectious diseases. 8 In 2014, the research groups of Rodri ́guez and Chen independently reported copper-catalyzed, 2picolinamide-directed ortho C−H amination of aniline. 9 However, stoichiometric amount of expensive PhI(OAc) 2 was used as an oxidant, which generates PhI as a byproduct. More recently, an electrochemical synthesis of C−H amination of the same substrate was reported by the Mei group, using tetrabutylammonium iodide (TBAI) as a redox mediator. 10 However, all these protocols are limited to the six-membered cyclic amines only. Acyclic amines, pyrrolidine (<5% yield),

Preparation, Characterization, and Reactivity of Aliphatic Amino Iodane(III) Reagents

“…N ‐(4‐methoxy‐2‐morpholinophenyl)picolinamide (4 ae) [14c,15,17] . White crystalline solid, yield: 81 %; 1 H NMR (400 MHz, Chloroform‐d) δ 10.86 (s, 1H), 8.73–8.59 (m, 1H), 8.56–8.41 (m, 1H), 8.27 (d, J =7.6 Hz, 1H), 7.88 (d, J =1.8 Hz, 1H), 7.45 (t, J =3.8 Hz, 1H), 6.72 (q, J =3.3 Hz, 2H), 3.96 (dd, J =5.5, 3.4 Hz, 4H), 3.80 (d, J =3.3 Hz, 3H), 2.93 (dt, J =4.5, 3.1 Hz, 4H); 13 C NMR (101 MHz, Chloroform‐d) δ 156.41, 150.68, 148.26, 143.45, 137.64, 126.41, 126.25, 122.32, 120.65, 108.72, 107.34, 67.61, 55.61, 52.42.…”

“…N ‐(3‐morpholino‐[1, 1'‐buphenyl]‐4‐yl)picolinamide (4 af) [14c,17] . White solid, yield: 87 %; 1 H NMR (400 MHz, Chloroform‐d) δ 11.16 (s, 1H), 8.65 (d, J =8.2 Hz, 2H), 8.31 (d, J =7.8 Hz, 1H), 7.91 (s, 1H), 7.58 (d, J =7.7 Hz, 2H), 7.51–7.46 (m, 1H), 7.43 (t, J =7.4 Hz, 3H), 7.38 (s, 1H), 7.32 (s, 1H); 13 C NMR (101 MHz, Chloroform‐d) δ 161.95, 150.54, 148.34, 142.32, 140.87, 137.71, 137.20, 132.31, 128.90, 127.24, 126.97, 126.46, 124.02, 122.49, 119.93, 118.95, 67.72, 52.60.…”

“…N ‐(4‐fluoro‐2‐morpholinophenyl)picolinamide (4 ag) [14c,16] . White solid, yield: 56 %; 1 H NMR (400 MHz, Chloroform‐d) δ 10.90 (s, 1H), 8.64 (d, J =4.6 Hz, 1H), 8.53 (dd, J =8.5, 6.2 Hz, 1H), 8.28 (d, J =8.0 Hz, 1H), 7.90 (t, J =7.6 Hz, 1H), 7.47 (dd, J =7.6, 5.0 Hz, 1H), 6.87 (d, J =9.6 Hz, 2H), 3.97 (t, J =4.5 Hz, 4H), 2.93 (t, J =4.5 Hz, 4H); 13 C NMR (101 MHz, Chloroform‐d) δ 161.77, 160.57, 158.14, 150.37, 148.31, 143.52, 143.45, 137.74, 129.08, 126.49, 122.46, 120.84, 120.76, 111.51, 111.29, 107.82, 107.58, 67.48, 52.31.…”

“…N ‐(2‐morpholino‐4‐(trifluoromethoxy)phenyl)picolinamide (4 ak) [14c] . White solid, yield: 48 %; 1 H NMR (400 MHz, Chloroform‐d) δ 11.00 (s, 1H), 8.65 (d, J =4.8 Hz, 1H), 8.59 (d, J =9.0 Hz, 1H), 8.28 (d, J =7.8 Hz, 1H), 7.91 (td, J =7.8, 1.6 Hz, 1H), 7.49 (dd, J =7.5, 4.9 Hz, 1H), 7.05 (dd, J =8.6, 2.6 Hz, 1H), 6.99 (d, J =2.5 Hz, 1H), 4.12–3.86 (m, 4H), 3.07–2.77 (m, 4H); 13 C NMR (101 MHz, Chloroform‐d) δ 161.99, 150.18, 148.35, 145.23, 143.10, 137.78, 131.71, 126.64, 122.55, 120.36, 117.64, 113.57, 67.47, 52.30.…”

“…methy 3‐morpholino‐4‐(picolinamido)benzoate(4 al) [14c,16,17] . White solid, yield: 45 %; 1 H NMR (400 MHz, Chloroform‐d) δ 11.30 (s, 1H), 8.86–8.50 (m, 2H), 8.29 (d, J =8.1 Hz, 1H), 7.90 (t, J =6.7 Hz, 2H), 7.84 (s, 1H), 7.50 (s, 1H), 3.99 (dt, J =6.2, 3.0 Hz, 4H), 3.89 (d, J =2.3 Hz, 3H), 2.97 (dd, J =6.0, 2.9 Hz, 4H); 13 C NMR (101 MHz, Chloroform‐d) δ 166.81, 162.31, 150.12, 148.39, 141.62, 137.80, 137.32, 127.42, 126.75, 125.47, 122.64, 121.72, 118.81, 67.60, 52.47, 52.16.…”