Tandem Cross-Coupling of gem-Dihaloolefins
1358, 1340, 1226, 1066. 1H NMR (300 MHz, CDCl3) δ 8.37 (1H,
br), 7.65-7.61 (2H, m), 7.46-7.40 (2H, m), 7.33 (1H, dddd, J )
7.3, 7.3, 1.2, 1.2 Hz), 7.16 (1H, dd, J ) 8.2, 0.9 Hz), 7.09 (1H,
ddd, J ) 7.9, 7.9, 4.9 Hz), 6.88 (1H, dd, J ) 2.5, 0.8 Hz), 6.79
(1H, ddd, J ) 10.3, 7.7, 1.0 Hz). 13C NMR (75 MHz, CDCl3) δ
156.5 (JC-F ) 247 Hz), 139.4 (JC-F ) 11.2 Hz), 138.1, 132.0, 129.3,
128.3, 125.4, 122.9 (JC-F ) 7.4 Hz), 118.6 (JC-F ) 22.3 Hz), 107.2
(JC-F ) 3.7 Hz), 105.2 (JC-F ) 18.9 Hz), 96.0 (JC-F ) 0.6 Hz).
19F NMR (282 MHz, CDCl3) δ -122.1. Anal. Calcd for C14H10-
NF: C, 79.60; H, 4.77; N, 6.63. Found: C, 79.37; H, 5.13; N,
6.63.
3-(4-Fluorophenyl)-2-phenyl-1H-indole (19c). General proce-
dure A for the Pd-catalyzed tandem coupling was followed. A
mixture of 2-[2,2-dibromo-1-(4-fluorophenyl)vinyl]-phenylamine
(0.125 g, 0.337 mmol), PhB(OH)2 (0.062 g, 0.505 mmol), K3PO4‚
H2O (0.35 g, 1.5 mmol), and a catalyst solution (Pd(OAc)2 (2.2
mg, 3 mol %) and S-Phos (8.8 mg, 6 mol %) in PhMe (1.5 mL))
was heated at 100 °C for 2 h. After an aqueous workup, the crude
material was purified by flash chromatography (10% EtOAc in
hexanes) to afford an off-white crystalline solid (0.087 g, 90%). Rf
) 0.21 (10% EtOAc in hexanes). mp 143-145 °C. IR (neat, cm-1):
3411, 3055, 1601, 1553, 1510, 1452, 1327, 1221. 1H NMR (400
MHz, CDCl3) δ 8.19 (1H, br), 7.62 (1H, d, J ) 7.9 Hz), 7.42-
7.29 (8H, m), 7.24 (1H, t, J ) 7.3 Hz), 7.15 (1H, t, J ) 7.5 Hz),
7.06 (2H, t, J ) 8.7 Hz). 13C NMR (100 MHz, CDCl3) δ 161.8
(JCF ) 245 Hz), 136.0, 134.4, 132.7, 131.8 (JC-F ) 8.4 Hz), 131.2
(JC-F ) 3.1 Hz), 129.0, 128.9, 128.3, 128.0, 123.0, 120.7, 119.7,
115.7 (JC-F ) 21.5 Hz), 114.2, 111.1. 19F NMR (376 MHz, CDCl3)
δ -116.4. HRMS (EI) calcd for C20H14NF ([M]+) 287.1110.
Found: 287.1113.
%) and S-Phos (8.1 mg, 6 mol %) in PhMe (1.5 mL)) was heated
at 100 °C for 2 h. After an aqueous workup, the crude material
was purified by flash chromatography (2% EtOAc in hexanes) to
afford a white solid (0.076 g, 86%). Rf ) 0.25 (2.5% EtOAc in
hexanes). mp 121-122 °C (Lit: 123-124 °C).38 1H NMR (400
MHz, CDCl3) δ 7.69-7.65 (1H, m), 7.25-7.16 (10H, m), 7.09
(2H, t, J ) 8.5 Hz), 6.79 (1H, s). 19F NMR (376 MHz, CDCl3) δ
-114.2.
1-(4-Fluorophenyl)-3-methyl-2-phenyl-1H-indole (27b). Gen-
eral procedure A for the Pd-catalyzed tandem coupling was
followed. A mixture of [2-(2,2-dichloro-1-methylvinyl)-phenyl]-
(4-fluorophenyl)-amine (0.088 g, 0.297 mmol), PhB(OH)2 (0.055
g, 0.45 mmol), K3PO4‚H2O (0.35 g, 1.5 mmol), and a catalyst
solution (Pd(OAc)2 (2.2 mg, 3 mol %) and S-Phos (8.1 mg, 6 mol
%) in PhMe (1.5 mL)) was heated at 100 °C for 1 h. After an
aqueous workup, the crude material was purified by flash chro-
matography (2.5% EtOAc in hexanes) to afford a white solid
(0.0838 g, 94%). Rf ) 0.28 (2.5% EtOAc in hexanes). mp 108-
110 °C. IR (neat, cm-1): 3053, 2916, 1603, 1510, 1457, 1364, 1217.
1H NMR (400 MHz, CDCl3) δ 7.68-7.64 (1H, m), 7.31-7.18 (8H,
m), 7.15-7.11 (2H, m), 7.02 (2H, t, J ) 7.5 Hz), 2.40 (3H, s). 13
C
NMR (100 MHz, CDCl3) δ 161.3 (JC-F ) 246 Hz), 137.9, 137.2,
134.9 (JC-F ) 3.2 Hz), 132.1, 130.8, 129.6 (JC-F ) 8.3 Hz), 129.2,
128.3, 127.5, 122.8, 120.4, 119.2, 116.2 (JC-F ) 22.7 Hz), 111.0,
110.3, 9.8. 19F NMR (376 MHz, CDCl3) δ -115.0. HRMS (EI)
calcd for C21H16NF ([M]+) 301.1267. Found: 301.1260. Anal.
Calcd for C21H16NF: C, 83.70; H, 5.35; N, 4.65. Found: C, 83.91;
H, 5.26; N, 4.64.
2-(4-Fluorophenyl)-3-methyl-1-phenyl-1H-indole (27a). Gen-
eral Procedure C for the Pd-Catalyzed Tandem Reaction. A
5-mL round-bottomed flask was charged with [2-(2,2-dichloro-1-
methylvinyl)-phenyl]-phenylamine (0.056 g, 0.2 mmol), 4-FPhB-
(OH)2 (0.042 g, 0.30 mmol), and a powdered mixture of K3PO4‚
H2O/KOH (mol/mol ) 1:2, 0.072 g, 0.6 mmol), and the mixture
was purged with argon for at least 10 min. To a separate 5-mL
round-bottomed flask was charged with Pd(OAc)2 (1.34 mg, 3 mol
%) and S-Phos (3.3 mg, 6 mol %) and purged with argon for at
least 10 min. Toluene (1 mL) was added to the catalyst flask, and
the mixture was stirred at rt for 3 min. The homogeneous catalyst
solution was then cannulated to the reactant flask, and the
heterogeneous mixture was stirred at rt for 2 min. After heating at
100 °C for 1 h, the mixture was cooled to rt and diluted with Et2O
(5 mL). After an aqueous workup, the crude material was purified
by flash chromatography (2.5% EtOAc in hexanes) to afford a white
crystalline solid (0.058 g, 96%). Rf ) 0.22 (2.5% EtOAc in
hexanes). mp 154-155 °C. IR (neat, cm-1): 3053, 1995, 1499,
1452, 1362, 1217. 1H NMR (400 MHz, CDCl3) δ 7.66-7.64 (1H,
m), 7.35-7.26 (4H, m), 7.23-7.13 (6H, m), 6.96 (2H, ddd, J )
7.7, 7.7, 2.0 Hz), 2.38 (3H, s). 13C NMR (100 MHz, CDCl3) δ
162.1 (JC-F ) 248 Hz), 138.7, 137.8, 136.1, 132.4 (JC-F ) 7.7
Hz), 129.3, 129.1, 128.4 (JC-F ) 3.1 Hz), 128.1, 127.0, 122.8,
120.4, 119.1, 115.3 (JC-F ) 21.5 Hz), 110.9, 110.5, 9.7. 19F NMR
(376 MHz, CDCl3) δ -114.4. HRMS (EI) calcd for C21H16NF
([M]+) 301.1267. Found: 301.1257.
[2-(2,2-Dibromovinyl)phenyl]phenylamine (24a). General pro-
cedure for Cu(OAc)2-mediated coupling: A tube (24 × 150 mm)
of Carousel reaction station was charged with 1a (0.277 g, 1 mmol),
PhB(OH)2 (0.244 g, 2 mmol), Cu(OAc)2 (0.182 g, 1 mmol), myristic
acid (0.092 g, 0.4 mmol), 2,6-lutidine (125 µL, 1.07 mmol), and
toluene (3 mL). The mixture was stirred at 40 °C under an O2
atmosphere for 21 h. The mixture was diluted with Et2O (10 mL)
and Et3N (1.5 mL), stirred at rt for 15 min, filtered through a short
silica gel column, and eluted with a copious amount of Et2O (∼30
mL). The crude material was further purified by flash chromatog-
raphy (2.5% EtOAc in hexanes) to afford the desired product as a
solid (0.3134 g, 89%). Rf ) 0.28 (5% EtOAc in hexanes). mp 75-
77 °C. IR (neat, cm-1): 3407, 3035, 1597, 1577, 1506, 1455, 1311,
1
1214. H NMR (400 MHz, CDCl3) δ 7.59 (1H, d, J ) 7.7 Hz),
7.39 (1H, s), 7.30-7.23 (4H, m), 7.03-6.94 (4H, 4 m), 5.47 (1H,
s). 13C NMR (100 MHz, CDCl3) δ 143.0, 141.0, 134.3, 129.9, 129.7,
129.6, 126.4, 121.8, 121.4, 118.7, 118.2, 93.1. HRMS (EI) calcd
for C14H11NBr2 ([M]+) 350.9258. Found: 350.9253.
[2-(2,2-Dichloro-1-methylvinyl)phenyl]phenylamine (25a). The
general procedure for Cu(OAc)2-mediated coupling was followed
using 13b (0.105 g, 0.52 mmol), phenylboronic acid (0.122 g, 1
mmol), Cu(OAc)2 (0.091 g, 0.5 mmol), myristic acid (0.046 g, 0.2
mmol), and 2,6-lutidine (62.5 µL, 0.54 mmol) in toluene (1.5 mL).
The mixture was stirred at 40 °C for 6.5 h under an O2 atmosphere.
The crude material was further purified by flash chromatography
(2.5% EtOAc in hexanes) to afford the desired product as an oil
(0.1415 g, 98%). Rf ) 0.20 (2.5% EtOAc in hexanes). IR (neat,
cm-1): 3411, 3046, 1593, 1505, 1451, 1308. 1H NMR (400 MHz,
CDCl3) δ 7.30-7.25 (3H, m), 7.21 (1H, ddd, J ) 7.6, 7.6, 1.7
Hz), 7.10 (1H, dd, J ) 7.6, 1.6), 7.07-7.04 (2H, m), 6.98-6.93
(2H, m), 5.45 (1H, s), 2.14 (3H, s). 13C NMR (75 MHz, CDCl3) δ
143.2, 139.9, 134.2, 130.2, 129.6, 129.1, 129.0, 121.7, 121.4, 118.9,
118.8, 118.0, 22.2. HRMS (EI) calcd for C15H13NCl2 ([M]+)
277.0425. Found: 277.0426.
Acknowledgment. This work is supported by NSERC
(Canada), Merck Frosst Canada and the University of Toronto.
Y.-Q. F thanks the Ontario Government and the University of
Toronto for financial support in the form of postgraduate
scholarships (OGS, OGSST). We thank Degussa for donating
Pt catalysts.
Supporting Information Available: Experimental procedure
and characterization data for rest of substrates and products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
2-(4-Fluorophenyl)-1-phenyl-1H-indole (26d). General proce-
dure A for the Pd-catalyzed tandem coupling was followed. A
mixture of [2-(2,2-dibromovinyl)-phenyl]-phenylamine (0.109 g,
0.31 mmol), 4-FPhB(OH)2 (0.065 g, 0.45 mmol), K3PO4‚H2O (0.35
g, 1.5 mmol), and a catalyst solution (Pd(OAc)2 (2.2 mg, 3 mol
JO701987R
(38) Hay, A. S.; Paventi, M. PCT Int. Appl. WO 9309079, 1993.
J. Org. Chem, Vol. 73, No. 2, 2008 549