The Journal of Organic Chemistry
NOTE
partner to produce B. The intermediate B could undergo a one-
electron oxidation to give the Cu(III)-intermediate C, which can
undergo CꢀN reductive elimination to release the o-amidated
2-phenylpyridine. Aerobic oxidation of the Cu(I)OAc can re-
form the active catalyst to restart the catalytic cycle. It should be
pointed out that CꢀO reductive elimination from intermediate
C would produce the detected o-acetoxylated complex 3.
In summary, a simple and efficient copper-catalyzed amidation
of 2-phenylpyridine has been developed employing molecular
oxygen as the terminal oxidant. A variety of N-reagents including
sulfonamides, carboxamides, and anilines have been found to
participate in the reaction with varying efficiency. Use of anisole
as solvent and DMSO as an additive enables catalytic turnover, with
oxygen putatively involved in inducing elimination of the product
from the copper center and in regenerating the active catalyst.
128.8, 128.5, 124.7, 123.6, 122.3, 122.1, 114.1, 114.3, 114.7, 113.7, 55.5;
HRMS (ESI) calcd for C18H16N2O3S (M ꢀ H) requires m/z 339.0809,
found m/z 339.0791.
N-(2-Pyridylphenyl)-4-nitrobenzenesulfonamide (3ac).21
The product was obtained as a bright yellow solid (0.064 g, 26% yield).
Rf (3:2 ethyl ether/hexane) 0.40; 1H NMR (CDCl3, 300 MHz) δ 12.44
3
3
(br, 1H), 8.61 (d, JHH = 4.2 Hz, 1H), 7.98 (d, JHH = 8.1 Hz, 2H),
7.74ꢀ7.68 (m, 2H), 7.61 (d, 3JHH = 6.6 Hz, 2H), 7.55 (d, 3JHH = 8.4 Hz,
1H), 7.43ꢀ7.37 (m, 2H), 7.29 (t, 3JHH = 6.0 Hz, 1H), 7.23 (t, 3JHH = 7.8
Hz, 1H); 13C{1H} NMR (CDCl3, 75 MHz) δ 156.6, 147.4, 144.9, 137.8,
135.8, 130.5, 128.6, 127.9, 125.7, 124.2, 123.6, 122.4, 122.2; LRMS
(ESI) 356 [(M þ H)þ], 378 [(M þ Na)þ].
N-(2-Pyridylphenyl)methylsulfonamide (3ad). The product
was obtained as a pale yellow solid (0.099 g, 52% yield). Rf (3:2 ethyl
1
ether/hexane) 0.28; H NMR (CDCl3, 300 MHz) δ 12.33 (br, 1H),
8.63 (d, 3JHH = 4.2 Hz, 1H), 7.89ꢀ7.74 (m, 4H), 7.42 (t, 3JHH = 8.1 Hz,
1H), 7.31 (t, 3JHH = 5.4 Hz, 1H), 7.22 (t, 3JHH = 8.1 Hz, 1H), 2.88 (s,
3H); 13C{1H} NMR (CDCl3, 75 MHz) δ 157.4, 147.7, 138.2, 137.7,
130.8, 129.0, 125.6, 124.2, 122.5, 122.4, 121.1, 39.7; HRMS (ESI) calcd
for C12H12N2O2S (M ꢀ H) requires m/z 247.0547, found m/z
247.0540.
’ EXPERIMENTAL SECTION
General Procedures. All manipulations were carried out with
Schlenk tube techniques under oxygen atmosphere (balloon). The
copper salts, anisole, 2-phenylpyridine, and the N-reagents were ob-
tained from commercial sources and used without any further purifica-
N-(2-Pyridylphenyl)-2,2,2-trifluoroacetamide (3ae).6b The
product was obtained as a white solid (0.12 g, 66% yield). Rf (3:2 ethyl
ether/hexane) 0.55; 1H NMR (CDCl3, 300 MHz) δ 8.64 (d, 3JHH = 6.0 Hz,
1H), 8.58 (d, 3JHH = 8.1 Hz, 1H), 7.93ꢀ7.87 (m, 2H), 7.83 (d, 3JHH = 8.1
Hz, 1H), 7.50 (t, 3JHH = 8.1 Hz, 1H), 7.36 (t, 3JHH = 6.9 Hz, 1H), 7.33 (d,
3JHH = 7.5 Hz, 1H); 13C{1H} NMR (CDCl3, 75 MHz) δ 157.2, 155.2 (q,
J = 36.6 Hz), 147.2, 138.3, 136.1, 130.6, 128.5, 125.4, 125.2, 122.6, 122.4,
122.0, 116.3 (q, J = 287 Hz); LRMS (ESI) 267 [(M þ H)þ], 289 [(M þ
Na)þ].
19
20
tion. Cu(PhCO2)2 and Cu(OTs)2 were synthesized by literature
methods. 1H and 13C{1H} NMR spectra were recorded on a 300 MHz
NMR spectrometer. 1H NMR peaks are labeled as singlet (s), doublet
(d), triplet (t), and multiplet (m). Mass spectra were acquired on a quadrupole
MS instrument in the ESI(þ) mode for low resolution spectra and in the
ESI(ꢀ) mode for high resolution analysis respectively. The 1H NMR yields
were determined with 1,3,5-trimethoxybenzene as an internal standard.
General Procedure for the Cu(OAc)2-Catalyzed Amidation
of 2-Phenylpyridine. To an oven-dried Schlenk tube under an O2
atmosphere was sequentially added Cu(OAc)2 (0.014 mmol) and the N-
reagent (1.39 mmol), followed by a solution of 2-phenylpyridine (0.70
mmol) and DMSO (0.05 mL) in anisole (ca. 2 mL). The reaction vessel
was immersed in an oil bath preheated to 160 °C and allowed to stir for the
stipulated period of time. After this the reaction mixture was allowed to
cool to room temperature, diluted with ethyl acetate (ca. 5 mL), and
filtered through a pad of silica. The silica pad was washed with ethyl acetate
(ca. 3 ꢁ 5 mL) and then finally with dichloromethane (ca. 10 mL). The
combined organic washings were concentrated under vacuum to yield the
crude product, which was purified by silica gel column chromatography
[diethyl ether/hexane (4:6)] to obtain the spectroscopically pure com-
pounds. The 1H NMR yields were determined with 1,3,5-trimethoxyben-
zene as the internal standard. NMR and MS spectral properties determined
for known products were identical with those reported (referenced below).
New compounds were also characterized by HR-MS and their purity
assessed by 1H NMR (see the SI).
N-(2-Pyridylphenyl)benzamide (3af).22 The product was
obtained as a pale yellow solid (0.088 g, 46% yield). Rf (3:2 ethyl
1
ether/hexane) 0.64; H NMR (CDCl3, 300 MHz) δ 13.33 (br, 1H),
8.81 (d, 3JHH = 8.4 Hz, 1H), 8.69 (d, 3JHH = 4.2 Hz, 1H), 8.05 (d, 3JHH
=
3
7.8 Hz, 2H), 7.89ꢀ7.79 (m, 2H), 7.74 (d, JHH = 7.5 Hz, 1H),
3
3
7.55ꢀ7.46 (m, 4H), 7.30 (t, JHH = 6.9 Hz, 1H), 7.22 (t, JHH = 8.7
Hz, 1H); 13C{1H} NMR (CDCl3, 75 MHz) δ 165.7, 158.4, 147.4, 138.2,
138.0, 135.9, 131.7, 130.4, 128.9, 128.7, 127.5, 125.7, 123.7, 123.2, 122.2,
122.1; LRMS (ESI) 275 [(M þ H)þ], 297 [(M þ Na)þ].
N-(2-Pyridylphenyl)-4-nitroaniline (3ag). The product was
obtained as a yellow solid (0.076 g, 38% yield). Rf (3:2 ethyl ether/
hexane) 0.45; 1H NMR (CDCl3, 300 MHz) δ 10.89 (br, 1H), 8.66 (d,
3JHH = 4.5 Hz, 1H), 8.11 (d, 3JHH = 9.0 Hz, 2H), 7.82 (dt, 7.5 and 1.8 Hz,
1H), 7.74ꢀ7.66 (m, 2H), 7.60 (dd, 8.4 and 1.2 Hz, 1H), 7.39 (dt, 8.1 and
1.8 Hz, 1H), 7.31ꢀ7.25 (m, 1H), 7.15 (dt, 8.7 and 1.2 Hz, 1H), 7.11 (d,
3JHH = 9.0 Hz, 2H); 13C{1H} NMR (CDCl3, 75 MHz) δ 158.3, 149.6,
147.8, 139.9, 139.5, 137.8, 130.4, 129.9, 126.3, 123.2, 123.0, 122.1, 120.2,
115.2, 110.2; HRMS (ESI) calcd for C17H13N3O2 (M ꢀ H) requires
m/z 290.0935, found m/z 290.0924.
N-(2-Pyridylphenyl)-4-methylbenzenesulfonamide (3aa).11
The product was obtained as a pale yellow solid (0.15 g, 65% yield). Rf
(3:2 ethyl ether/hexane) 0.39; 1H NMR (CDCl3, 300 MHz) δ 12.06 (br,
Isolation of [N-(2-Pyridylphenyl)-4-methylbenzenesulfo-
namido]2Cu(II)18 (1). To an ovenꢀdried Schlenk tube was added
2-phenylpyridine (0.155 g, 1.00 mmol), p-toluenesulfonamide (0.17 g,
1.00 mmol), and Cu(OAc)2 (0.091 g, 0.50 mmol) in xylenes (ca. 5 mL)
and the reaction mixture was stirred at 140 °C for 12 h under an oxygen
atmosphere. The reaction mixture was cooled to room temperature
and filtered. The copper 1 complex was collected as a red precipitate,
washed with diethyl ether (ca. 2 ꢁ 5 mL), and dried under vacuum
(0.18 g, 50%). LRMS (ESI) 710 [(63Cu ꢀ M þ H)þ], 732 [(63Cu ꢀ M
þ Na)þ].
1H), 8.53 (d, 3JHH = 4.8 Hz, 1H), 7.61 (d, 3JHH = 8 Hz, 2H), 7.44 (d, 3JHH
8 Hz, 1H), 7.33ꢀ7.23 (m, 4H), 7.16 (t, 3JHH = 4.8 Hz, 1H), 7.07 (t, 3JHH
=
=
7.8 Hz, 1H), 6.88 (d, 3JHH = 8.1 Hz, 1H), 2.19 (s, 3H); 13C{1H} NMR
(CDCl3, 75 MHz) δ 157.2, 147.5, 143.1, 137.6, 137.0, 136.6, 130.3, 129.3,
128.7, 127.4, 126.9, 124.8, 123.6, 122.4, 122.2, 21.6; LRMS (ESI) 325 [(M þ
H)þ], 347 [(M þ Na)þ].
N-(2-Pyridylphenyl)-4-methoxybenzenesulfonamide (3ab).
The product was obtained as an off-white solid (0.12 g, 49% yield). Rf
(3:2 ethyl ether/hexane) 0.26; 1H NMR (CDCl3, 300 MHz) δ 12.05 (br,
1H), 8.60 (d, 3JHH = 4.2 Hz, 1H), 7.72ꢀ7.68 (m, 1H), 7.76ꢀ7.69 (m, 2H),
7.52 (dd, 6.3 and 1.8 Hz, 1H), 7.42ꢀ7.31 (m, 4H), 7.25 (t, 3JHH = 6.2 Hz,
1H), 7.16 (t, 3JHH = 6.6 Hz, 1H), 6.63 (d, 3JHH = 9.0 Hz, 1H), 3.74 (s, 3H);
13C{1H} NMR (CDCl3, 75MHz) δ162.5, 147.3, 137.6, 130.2, 129.3, 129.3,
’ ASSOCIATED CONTENT
S
Supporting Information. Characterization data for all
b
the new compounds reported (1H and 13C NMR spectra, HR
4161
dx.doi.org/10.1021/jo200409h |J. Org. Chem. 2011, 76, 4158–4162