8224 J. Am. Chem. Soc., Vol. 123, No. 34, 2001
Nilsson et al.
in General Procedure for Palladium-Catalyzed Double R,â-Arylation
of Vinyl Ethers. The R-arylated enol ethers gradually decompose11a
and were therefore not further purified except for 3a, 3h, and 3i.
N,N-Dimethyl-2-[(1-phenyl)ethenyloxy]ethanamine (3a). An alu-
mina column was used for purification of the enol ether 3a in 92%
yield (0.88 g, >95% by GC-MS, eluent: pentane/ethyl acetate (39/1)
1
with 2% (vol) triethylamine, clear yellow oil). H NMR (270 MHz,
CDCl3) δ 7.64-7.59 (m, 2H), 7.36-7.29 (m, 3H), 4.66 (d, J ) 2.7
Hz, 1H), 4.21 (d, J ) 2.8 Hz, 1H), 3.98 (t, J ) 5.9 Hz, 2H), 2.77 (t,
J ) 5.8 Hz, 2H), 2.35 (s, 6H); 13C NMR (67.8 MHz, CDCl3) δ 160.1,
136.6, 128.6, 128.3, 125.6, 82.6, 66.5, 58.3, 46.2; MS m/z (relative
intensity 70 eV) 191 (M+, 1), 103 (16), 77 (39), 58 (100). Anal. Calcd
for C12H17NO: C, 75.35; H, 8.96: N, 7.32. Found: C, 75.65: H,
8.95: N, 7.15.
Figure 3. X-ray structure of complex 16. Thermal ellipsoids are drawn
at the 50% probability level.
â,â-Diarylation of Crude 3. Synthesis of 4. A thick-walled tube
was charged under a nitrogen atmosphere with the crude R-product 3
(∼5 mmol), Pd(OAc)2 (0.300 mmol, 0.067 g), PPh3 (0.600 mmol, 0.157
g), aryl bromide (25.0 mmol), NaOAc (5.0 mmol, 0.41 g), K2CO3 (25
mmol, 3.5 g) and DMF (20 mL). An extra addition of Pd(OAc)2 (0.30
mmol, 0.067 g) after 18 h was routinely performed. After heating with
stirring at 100 °C for 48 h the tube was cooled, and a portion of diethyl
ether was added. The organic mixture was transferred to a separatory
funnel and washed twice with 0.1 M NaOH. Additional extraction of
the aqueous phases was performed with diethyl ether. The combined
organic portions were thereafter washed with brine, dried with K2CO3-
(s) and evaporated under reduced pressure. Finally, the residue (4) was
purified by chromatography as described for the individual compounds.
1,1,2-Triphenylethanone (5a, Table 1). An alumina column was
used for purification of the intermediate triphenylated enol ether 4a
(yellow oil, eluent: pentane/ethyl acetate (39/1) with 2% (vol)
triethylamine). In addition, a pre-fraction of enol ether 6a was isolated
(0.080 g, 6%). The ketone 5a was obtained after hydrolysis with 6 M
HCl/TBME (24 h) and preparative straight-phase HPLC in 65% yield
(0.86 g, >95% by GC-MS, eluent: hexane/ethyl acetate (99/1)).
Alternatively, the triphenylated enol ether 4a was further purified with
a second alumina column (pentane/ethyl acetate (39/1) with 2% (vol)
triethylamine) in 65% yield (1.12 g, >95% by GC-MS, white crystals).
1H NMR (270 MHz, CDCl3) δ 7.34-7.14 (m, 10H), 7.08-7.03 (m,
3H), 6.98-6.94 (m, 2H), 3.70 (t, J ) 6.1 Hz, 2H), 2.50 (t, J ) 6.1 Hz,
2H), 2.15 (s, 6H); 13C NMR 152.2, 141.3, 141.0, 135.5, 131.3, 130.2,
129.8, 129.7, 127.8, 127.7, 127.6, 126.3, 125.9, 125.8, 68.2, 58.5, 45.7;
MS m/z (relative intensity 70 eV) 343 (M+, 1), 165 (5), 72 (100). High-
Resolution MS calcd for C24H25NO: M+ 343.1936, Found: 343.1938.
General Procedure for Palladium-Catalyzed Double R,â-Aryla-
tion of Vinyl Ether 1a (Table 2). R-Arylation of 1a Using Aryl
Triflates. Syntheses of 3a and 3c. The reactants were dissolved or
dispersed in DMF (20 mL) and added under nitrogen atmosphere to a
thick-walled tube in the following order: Pd(OAc)2 (0.150 mmol, 0.034
g), 1a (10.0 mmol, 1.15 g), DPPP (0.330 mmol, 0.136 g), aryl triflate
(5.0 mmol), and triethylamine (10.0 mmol). Nitrogen gas was bubbled
through the solution during 1 min, the tube was closed, and the contents
were magnetically stirred and heated at 60 °C for 18 h. After cooling,
the reaction mixture was diluted with diethyl ether and was washed
twice with 0.1 M NaOH. The combined aqueous phases were
additionally extracted twice with diethyl ether. The ethereal phases were
combined and dried with K2CO3 (s). After evaporation of the solvent,
the remaining oil was concentrated under reduced pressure until no
nonarylated vinyl ether remained (GC-MS), yielding crude monoary-
lated product 3.
ture 16 and showed that the phenyl rings in fact were locked in
a “propeller” conformation26 (Figure 3), strongly disfavoring
π-complex formation/insertion.
Conclusions
The principle of reactivity enhancement with Heck arylation
reactions for substrates containing a palladium-coordinating
group by a chelation effect has now been demonstrated. Heck
triarylation reactions proceeded for the first time, utilizing a
catalyst-presenting auxiliary. The investigated ethyldimethyl-
amino auxiliary has been found to (1) accelerate the reaction
of the double bond by chelation-controlled delivery of the
oxidative addition complex, (2) control the regioselectivity by
nitrogen-directed â-arylation, (3) function as a separation tag,
allowing the use of convenient purification protocols, and (4)
enable rapid and efficient two-phase microwave-assisted hy-
drolysis. Additional work will be required to ascertain if the
application of single-mode microwave irradiation also provides
a general method for the promotion of palladium-catalyzed
chelation-accelerated multiarylation reactions.
Experimental Section
General Procedure for Palladium-Catalyzed Triple Arylation of
Vinyl Ether 1a (Table 1). R-Arylation of 1a-c Using Aryl Bromides
in Syntheses of 3a-i. The reactants were dissolved or dispersed in
DMF (20 mL) and added under a nitrogen atmosphere to a thick-walled
tube in the following order: Pd(OAc)2 (3a-c, 3g, 3i, 0.150 mmol,
0.0334 g; 3d-f, 0.250 mmol, 0.056 g; and 3h, 0.075 mmol, 0.0170 g,
DPPP (3a-c, 3g, 3i, 0.330 mmol, 0.136 g; 3d-f, 0.550 mmol, 0.227
g; and 3h 0.170 mmol, 0.068 g), aryl halide (5.00 mmol), TlOAc (5.50
mmol, 1.45 g), water 1.1 mL, K2CO3 (6.0 mmol, 0.83 g), and vinyl
ether (10.0 mmol). The tube was then closed, and the contents were
magnetically stirred and heated at 80 °C for the appropriate time (3a-
b, 3g, 3i 5 h, 3c-e, 3h 16 h and 3f 48 h). After cooling, the reaction
mixture was diluted with diethyl ether and was washed with two
portions of 0.1 M NaOH. The combined aqueous phases were
additionally extracted with diethyl ether. The ethereal phases were
combined, washed with 10% K2CO3 (aq), dried with K2CO3 (s) and
concentrated under reduced pressure until no nonarylated vinyl ether
remained (GC-MS). Alternatively, products 3a and 3j were prepared
from the corresponding aryl triflates using the methodology described
â-Arylation of Crude 3. Syntheses of 6. A thick-walled tube was
charged under nitrogen with the crude R-product (∼0.5 mmol) prepared
from aryl triflates or aryl bromides; see: R-Arylation of 1a-c Using
Aryl Bromides in Syntheses of 3a-i. Aryl bromides: Pd(OAc)2 (0.030
mmol, 0.0067 g), P(o-tolyl)3 (0.060 mmol, 0.0183 g), aryl bromide
(1.50 mmol), NaOAc (0.500 mmol, 0.041 g), K2CO3 (1.50 mmol, 0.207
g) and DMF (3 mL). Electron-poor aryl triflates: Pd(OAc)2 (0.030
mmol, 0.0067 g), aryl triflate (1.50 mmol), triethylamine (0.603 mmol,
0.061 g) and DMF (5 mL). Aryl iodides: Pd(OAc)2 (0.015 mmol,
0.0034 g), aryl iodide (2.50 mmol), NaOAc (0.600 mmol, 0.049 g),
K2CO3 (0.600 mmol, 0.083 g), LiCl (1.00 mmol, 0.042 g), H2O (0.300
mL) and DMF (2.7 mL). The tube was closed and the contents were
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