pK -Based Electronic Switch for C−X Bond Activation
a
A R T I C L E S
under these general conditions (see text and reaction schemes for
specific temperatures and product ratios): Into a 10 mL round-bottom
flask (rbf) was added 3 mL of THF, CsF (57 mg, 0.57 mmol, 2.0 equiv),
(4-methoxyphenyl)boronic acid (52 mg, 0.35 mmol, 1.5 equiv), and 5
(50 mg, 0.23 mmol, 1.0 equiv). After 53 mg of (PPh3)4Pd (46 mmol,
0.2 equiv) was added, the reaction was heated to the desired temperature
and the reaction’s progress was monitored by TLC. When the reaction
was deemed complete, it was cooled and diluted with ether, and 5 mL
of H2O was added. The phases were separated and the organic layer
was dried over anhydrous MgSO4. Following filtration, the solvent was
removed in vacuo and the residue was purified by flash chromatography
(95:5 hexanes/ether).
be adopted by others and used reliably. We are broadening our
studies to probe these issues and to try to compartmentalize
steric and electronic effects. By doing so, we anticipate the
production of a series of broadly useful olefin templates whose
functional groups can be activated selectively by a single catalyst
in any order necessary to fulfill the synthetic requirement. We
propose to do this by matching the pKa value(s) for the allylic
leaving groups with the bond strengths of the oxidative addition
partners.
Experimental Section
1-(Phenoxy)-2-(4-methoxyphenyl)prop-2-ene (6). 1H NMR (CDCl3,
400 MHz) δ 7.46 (d, J ) 8.0 Hz, 2H), 7.30 (m, 2H), 6.98 (m, 3H),
6.90 (d, J ) 8.0 Hz, 2H), 5.55 (s, 1H), 5.40 (s, 1H), 4.89 (s, 2H), 3.84
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 159.5, 158.7, 142.4, 130.8,
129.5, 127.2, 121.0, 115.0, 113.9, 113.3, 70.0, 55.3.
1,2-Di(4-methoxyphenyl)prop-2-ene (7). 1H NMR (CDCl3, 400
MHz) δ 7.37 (d, J ) 8.5 Hz, 2H), 7.14 (d, J ) 8.5 Hz, 2H), 6.82 (d,
J ) 8.5 Hz, 2H), 6.81 (d, J ) 8.5 Hz, 2H), 5.40 (s, 1H), 4.94 (s, 1H),
3.85 (S, 2H), 3.79 (s, 3H), 3.78 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 159.1, 158.0, 146.5, 133.3, 131.7, 129.8, 127.3, 113.8, 113.6, 112.7,
55.2 (two coincident peaks), 40.9.
1,2-Diphenoxy-2-propene (8). 1H NMR (CDCl3, 300 MHz) δ 7.38-
7.25 (m, 4H), 7.17-7.04 (m, 3H), 7.02-6.93 (m, 3H) 4.63 (s, 2H),
4.59 (d, J ) 2.2 Hz, 1H), 4.24 (d, J ) 2.2 Hz, 1H); 13C NMR (CDCl3,
75 MHz) δ 158.43, 158.19, 155.02, 129.64, 129.43, 124.30, 121.23,
120.65, 115.01, 91.31, 67.46; HRMS calcd for C15H14O2 [M]+ 226.0994,
found 226.0995.
1,2-Diphenoxy-2-propene (8). Into a 10 mL test tube were added
THF (1 mL), NaH (60% dispersion in mineral oil, 3.0 equiv, 36.2 mg,
1.50 mmol), and 141 mg of phenol (3.0 equiv, 1.50 mmol), which was
added slowly to control H2 gas evolution. To this homogeneous solution
was added 29.0 mg of (PPh3)4Pd (0.05 equiv, 0.025 mmol) followed
by 1 (100 mg, 0.50 mmol), and the mixture was stirred for 16 h. The
suspension was then diluted with 40 mL of ether and 10 mL of water.
The organic layer was separated and dried over anhydrous MgSO4,
and the solvent was removed in vacuo. Purification by flash chroma-
tography (straight pentane) afforded 104 mg of 8 as a clear oil (78%
yield).
General Procedure. All reactions were carried out under a positive
atmosphere of dry nitrogen. Tetrahydrofuran (THF) was distilled from
sodium benzophenone immediately prior to use. Proton NMR spectra
were recorded either on a Bruker Avance spectrometer at 400 MHz or
on a GE spectrometer at 300 MHz. Carbon NMR spectra were recorded
either on a Bruker Avance spectrometer at 100 MHz or on a GE
spectrometer at 75 MHz.
Methyl 4-Bromo-2-(carboxymethyl)-2-methylpent-4-enoate (2).
To a suspension of NaH (60% in mineral oil, 290 mg, 7.2 mmol, 1.5
equiv) in THF (10 mL) was added dimethyl methylmalonate (905 mg,
6.2 mmol, 1.3 equiv). After 5 min, the resultant solution was added to
a mixture of (PPh3)4Pd (280 mg, 0.24 mmol, 0.05 equiv) and 1 (1.0 g,
4.8 mmol) in 2 mL of THF. This mixture was stirred at room
temperature for 19 h, after which it was quenched with H2O and diluted
with ether. The organic layer was separated, dried over anhydrous
MgSO4, and filtered, and the solvent was removed in vacuo. Purification
by flash chromatography (80:20 hexanes/ether) afforded 1.3 g of 2 as
a colorless liquid (98% yield). 1H NMR (CDCl3, 300 MHz) δ 5.66 (s,
1H), 5.58 (s, 1H), 3.74 (s, 6H), 3.16 (s, 2H), 1.50 (s, 3H); 13C NMR
[CDCl3, 75 MHz, APT pulse sequence, evens up (+), odds down (-)]
δ 171.7 (+), 127.2 (+), 121.9 (+), 53.1 (+), 52.8 (-), 46.1 (+), 19.4
(-).
Methyl 2-(Carboxymethyl)-4-(4-methoxyphenyl)-2-methylpent-
4-enoate (3). To a solution of 2 (285 mg, 1.07 mmol, 1.0 equiv),
4-methoxyphenylboronic acid (179 mg, 1.18 mmol, 1.1 equiv), and
(PPh3)4Pd (62 mg, 0.05 mmol, 0.05 equiv) in 7 mL of THF was added
1.34 mL of a 2 M KOH solution. After stirring at 60 °C for 3 h, ether
was added and the mixture was partitioned. The organic layer was dried
over anhydrous MgSO4 and filtered, and the solvent was removed in
vacuo. Flash chromatography (70:30 hexanes/ether) provided 172 mg
of 3 as a clear oil (55% yield). 1H NMR (CDCl3, 300 MHz) δ 7.24 (d,
J ) 8.5 Hz, 2H), 6.82 (d, J ) 8.5 Hz, 2H), 5.20 (s, 1H), 5.03 (s, 1H),
3.80 (s, 3H), 3.51 (s, 6H), 3.14 (s, 2H), 1.31 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 172.2, 159.1, 143.8, 134.0, 127.9, 117.0, 113.4, 55.3, 53.4,
52.3, 40.6, 19.9.
1-[(2-Bromoprop-2-enyl)oxy]benzene (5). To a suspension of NaH
(560 mg, 14 mmol, 1.4 equiv) and n-Bu4NI (4.35 g, 12 mmol, 1.2 equiv)
in THF (25 mL) was added dropwise a solution of phenol (1.13 g, 12
mmol, 1.2 equiv) in THF (25 mL). The resultant suspension was heated
at 65 °C until complete dissolution of the solids occurred. 2,3-
Dibromoprop-1-ene (1) (1.93 g, 10 mmol, 1 mL) was then added and
the reaction mixture was stirred for 17 h before being quenched with
H2O. The mixture was diluted with ether, 5 mL of a 2 M NaOH solution
was added, and the layers were separated. The organic phase was dried
over anhydrous MgSO4 and filtered, and the solvent was removed in
vacuo. Purification by flash chromatography (95:5 hexanes/ether)
afforded 1.51 g of 5 as a colorless liquid (98% yield). 1H NMR (CDCl3,
300 MHz) δ 7.35 (d, J ) 8.0 Hz, 2H), 7.04 (t, J ) 7.5 Hz, 1H), 6.97
(d, J ) 8.0 Hz, 2H), 6.05 (s, 1H), 5.72 (s, 1H), 4.68 (s, 2H); 13C NMR
(CDCl3, 100 MHz) δ 157.9, 129.6, 127.3, 121.7, 117.7, 115.0, 71.7;
HRMS calcd for C18H19O6N - 2H+ (M - 2H+) 211.9865, found
211.9837.
1-[(2-Bromoprop-2-enyl)oxy]-4-ethylbenzene (10). To a solution
of 4-ethylphenol (2.93 g, 24 mmol, 1.2 equiv) in THF (50 mL) was
added NaH (60% mineral oil suspension, 0.88 g, 22 mmol, 1.1 equiv)
in small portions. After gas evolution had ceased, 4.06 g of 1 (20 mmol,
1 equiv) was added. The reaction mixture was stirred at 60 °C for 16
h, quenched with brine, and diluted with ethyl acetate, and the phases
were separated. The organic phase was washed with 2 M aqueous
NaOH, dried over anhydrous MgSO4, and filtered, and the solvent was
removed in vacuo. Purification by flash chromatography (80:20 hexanes/
1
ether) afforded 4.8 g of 10 as a pale yellow liquid (99% yield). H
NMR (CDCl3, 400 MHz) δ 7.13 (d, J ) 8.0 Hz, 2H), 6.86 (d, J ) 8.0
Hz, 2H), 6.02 (s, 1H), 5.68 (s, 1H), 4.64 (s, 2H), 2.63 (q, J ) 7.5 Hz,
2H), 1.23 (t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 155.9,
137.0, 128.8, 127.5, 117.5, 114.9, 71.9, 28.0, 15.8.
1-[(4-Ethylphenyl)oxy]-2-(4-methoxyphenyl)prop-2-ene (11). To
a solution of 10 (0.48 g, 2.0 mmol) in THF (2 mL) was added bis-
[1,3-(diphenylphosphino)propane]palladium(0) (93.0 mg, 0.1 mmol,
0.05 equiv). The orange solution was heated to 45 °C for 1 h, after
which a 1 M solution of n-Bu4NF in THF (6 mL, 0.6 mmol, 3 equiv)
containing (4-methoxyphenyl)boronic acid (0.33 g, 2.2 mmol, 1.1 equiv)
was added dropwise via cannula. Upon addition, the reaction mixture
became clear and it was heated to 60 °C for 1.6 h, at which time it was
quenched with H2O. Ether and 2 M aqueous NaOH were added and
the layers were separated. The organic phase was dried over anhydrous
MgSO4 and filtered, and the solvent was removed in vacuo. Purification
by flash chromatography (90:10 hexanes/ether) afforded 271 mg of 11
Reaction of Compound 5 under Suzuki Conditions (Products 6,
7, and 8). This reaction was performed at a number of temperatures
9
J. AM. CHEM. SOC. VOL. 124, NO. 7, 2002 1293