Ni-Catalyzed Amination of Aryl and Heteroaryl Chlorides
SCHEME 3. Ni-Catalyzed Arylation of Piperazine
(w), 2859 (w), 1616 (s), 1534 (m), 1485 (w), 1317 (vs), 1186 (m),
1158 (m), 1103 (vs), 1062 (vs), 1006 (w), 939 (w), 822 (s) 640
(w).
This reaction demonstrated a useful selectivity: by using 2
equiv of piperazine (2m) the monoarylated amine 3u can be
obtained almost exclusively in 86% yield after 18 h at 130 °C
(Scheme 3). The bisarylated adduct could be prepared in
moderate yield (53%) and selectivity only if an excess (4 equiv)
of the aryl chloride 1k was used and the reaction time was
prolonged to 40 h. Such selectivity can be useful for the selective
preparation of monoarylated piperazines, avoiding protection-
deprotection steps.
Conclusion. In summary, we have developed a practical
protocol for the silane-promoted nickel-catalyzed amination of
aryl chlorides. The Ni(acac)2/3,5,6,8-tetrabromophenanthroline/
PMHS catalyst system is efficient in loadings of 0.1-0.5 mol
% and affords high yields in the arylation and heteroarylation
of secondary cyclic or acyclic amines or anilines. The reaction
has a broad scope and could be applied to a variety of electron-
poor aryl chlorides as well as heteroaryl chlorides. Electron-
rich and sterically hindered aryl chlorides could be coupled so
far only with cyclic secondary amines. Good to excellent yields
were obtained with the vast majority of substrates. The use of
the toluene/DME solvent system proved to be the most
beneficial. Further studies are underway to expand the reaction
scope to primary amines, and to understand the role of PMHS
in the formation of the catalytically active system.
3-(Pyrrolidin-1-yl)benzoic Acid tert-Butyl Ester (3n). The
general procedure was used to couple 3-chlorobenzoic acid tert-
butyl ester (1g) (213 mg, 1.0 mmol) and pyrrolidine (1a) (85 mg,
1.2 mmol). After column chromatography (pentane/ether 10:1) the
1
title compound was isolated as a colorless oil (234 mg, 95%). H
NMR (CDCl3, 300 MHz, 25 °C) δ 7.32-7.28 (m, 2 H), 7.24-
7.22 (m, 2 H), 6.75-6.71 (m, 1 H), 3.37-3.32 (m, 4 H), 2.04 (qn,
J ) 3.3 Hz, 4 H), 1.62 (s, 9 H). 13C NMR (CDCl3, 75 MHz, 25
°C) δ 166.6, 147.8, 132.7, 128.8, 116.3, 115.5, 112.3, 80.5, 47.7,
28.2, 25.5. MS (EI, 70 eV) m/z (%) 247 (19) [M+], 191 (100), 191
(92), 174 (13), 135 (12). HRMS m/z calcd for C15H21NO2 247.1572,
found 247.1572. IR (cm-1) 2932 (m), 1721 (s), 1597 (s), 1574 (w),
1498 (s), 1453 (m), 1341 (s), 1245 (s), 1172(s), 1134 (s), 949 (m),
853 (m), 736 (vs).
1-[4-(Pyrrolidine-1-sulfonyl)phenyl]piperidine (3t). The gen-
eral procedure was used to couple 1-(4-chlorobenzenesulfonyl)-
pyrrolidine (1j) (246 mg, 1.0 mmol) and piperidine (2f) (102 mg,
1.2 mmol). After column chromatography (pentane/ether 1:1) the
title compound was isolated as a colorless solid (291 mg, 96%).
1H NMR (CDCl3, 300 MHz, 25 °C) δ 7.64 (ddd, J ) 9.6, 2.9, 2.5
Hz, 2H), 6.88 (ddd, J ) 9.6, 2.9, 2.5 Hz, 2H), 3.33-3.39 (m, 4H),
3.21-3.17 (m, 4H), 1.75-1.58 (m, 10H). 13C NMR (CDCl3, 75
MHz, 25 °C) δ 154.0, 129.3, 124.1, 113.8, 48.7, 47.8, 25.4, 25.1,
24.2. MS (EI, 70 eV) m/z (%) 294 (90) [M+], 224 (18), 207 (44),
176 (79), 160 (100). HRMS m/z calcd for C15H22N2O2S 294.1402,
found 294.1409. IR (cm-1) 2937 (m), 2851 (m), 1587 (s), 1505
(m), 1449 (m), 1360 (m), 1327 (vs), 1247 (s), 1155 (vs), 1125 (vs),
1092 (vs), 1062 (s), 1004 (vs), 917 (s), 813 (s). Mp 142.7-
144.5 °C.
3. Experimental Section
General Procedure for the Amination Reaction. A 25 mL
sealed tube, equipped with a Teflon screw cap, was loaded with
NaOtBu (135 mg, 1.4 mmol), Ni(acac)2 (1.3 mg, 0.005 mmol),
3,5,6,8-tetrabromophenanthroline 4b (5.0 mg, 0.01 mmol), 1,2-
dimethoxyethane (2 µL, 0.02 mmol), and toluene (1.5 mL). PMHS
(0.05 mL, 0.8 mmol) was added and the mixture was stirred for 15
min at 25 °C. The amine (1.2 mmol) and the aryl chloride (1.0
mmol) were added. The tube was sealed with a Teflon screw cap
and the mixture heated to 130 °C for the specified time. The reaction
mixture was cooled to room temperature, diluted with ether (15
mL), filtered through a short pad of Celite, and concentrated in
vacuo. The crude product was purified by column chromatography.
N-Hexyl-N-methyl-4-trifluoromethylaniline (3c). The general
procedure was used to couple 4-chlorotrifluoromethylbenzene (1a)
(181 mg, 1.0 mmol) and N-hexyl-N-methylamine (2b) (138 mg,
1.2 mmol). After column chromatography (pentane/ether 40:1) the
3-(N-Butyl-N-methylamino)pyridine (7f). The general proce-
dure was used to couple 3-chloropyridine (6b) (114 mg, 1.0 mmol)
and N-butyl-N-methylamine (2j) (105 mg, 1.2 mmol). After column
chromatography (CH2Cl2/ether 1:1) the title compound was isolated
1
as a colorless oil (132 mg, 80%). H NMR (CDCl3, 300 MHz, 25
°C) δ 8.09 (d, J ) 3.1 Hz, 1H), 7.90 (dd, J ) 4.6, 1.1 Hz, 1H),
7.07 (dd, J ) 8.6, 4.6 Hz, 1H), 6.90 (ddd, J ) 8.6, 3.1, 1.1 Hz,
1H), 3.29 (t, J ) 7.5 Hz, 2H), 2.91 (s, 3H), 1.59-1.49 (m, 2H),
1.39-1.26 (m, 2H), 0.92 (t, J ) 7.3 Hz, 3H). 13C NMR (CDCl3,
75 MHz, 25 °C) δ 145.0, 137.1, 134.7, 123.4, 118.0, 52.0, 37.9,
28.6, 20.2, 13.9, 14.1. MS (EI, 70 eV) m/z (%) 164 (11) [M+], 121
(100), 106 (3), 93 (4), 78 (7). HRMS m/z calcd.for C10H16N2
164.1313, found 164.1319. IR (cm-1) 3040 (w), 2956 (m), 2930
(m), 2871 (m), 1582 (vs), 1493 (vs), 1425 (m), 1364 (s), 1243 (s),
1185 (m), 1112 (m), 1087 (m), 1050 (m), 1004 (m), 928 (m), 789
(vs), 706 (vs).
1-(3-Trifluoromethylphenyl)piperazine (3u).23 The general
procedure was used to couple 3-chlorotrifluoromethylbenzene (1k)
(181 mg, 1.0 mmol), piperazine (2m) (172 mg, 2.0 mmol), and
NaOtBu (270 mg, 2.4 mmol). After column chromatography (CH2-
Cl2/ether 1:1) the title compound was isolated as a yellow oil (198
mg, 86%). 1H NMR (CDCl3, 300 MHz, 25 °C) δ 7.34 (t, J ) 7.94
Hz, 1H), 7.10-7.04 (m, 3H), 3.25-3.18 (m, 4H), 3.04 (dd, J )
9.5, 5.1 Hz, 4 H), 1.95 (s, 1H). 13C NMR (CDCl3, 75 MHz, 25 °C)
δ 151.8, 129.5, 119.2 (q, J ) 32.2 Hz), 117.4 (q, J ) 270.4 Hz),
1
title compound was isolated as a colorless oil (250 mg, 96%). H
NMR (CDCl3, 600 MHz, 25 °C) δ 7.44 (d, J ) 8.8 Hz, 2 H), 6.67
(d, J ) 8.8 Hz, 2 H), 3.35 (t, J ) 7.6 Hz, 2 H), 2.98 (s, 3 H),
1.61-1.57 (m, 2 H), 1.36-1.31 (m, 6 H), 0.91 (t, J ) 6.7 Hz, 3
H). 13C NMR (CDCl3, 150 MHz, 25 °C) δ 151.0, 126.2 (q, J )
7.5 Hz), 125.1 (q, J ) 270.0 Hz), 116.7 (q, J ) 32.6 Hz), 110.6,
52.3, 38.1, 31.5, 26.6, 26.5, 22.5, 13.8. MS (EI, 70 eV) m/z (%)
259 (11) [M+], 240 (3), 189 (11), 188 (100), 172 (4). HRMS m/z
calcd for C14H20NF3 259.1548, found 259.1549. IR (cm-1) 2930
(26) Molyneaux, C.-A.; Krugliak, M.; Ginsburg, H.; Chibale, K. Biochem.
Pharmacol. 2005, 71, 61.
J. Org. Chem, Vol. 73, No. 4, 2008 1433