Microwave-Assisted Aqueous Suzuki Cross-Coupling Reactions
J . Org. Chem., Vol. 64, No. 11, 1999 3889
with 1.0 g of 2 (approximately 0.31 mmol aryl halide) and 5
mL of water. 3-Methoxy phenyl boronic acid (57 mg, 0.37
Hz, 2H), 7.99 (d, J ) 8.15 Hz, 2H), 7.94 (d, J ) 8.20 Hz, 2H),
4.43 (t, J ) 4.65 Hz, 2H), 3.65-3.41 (m, PEG).
mmol), 7 mg (10 mol %) of Pd(OAc)
2
, and 107 mg of (0.78 mmol)
4-Na p h th a len e-1-ylben zoic Acid P EG Ester (4c, Table
1
K
2
CO were added. The reaction mixture was argon flushed
3
2, entry 6). White crystals; H NMR (500 MHz, DMSO-d ) δ
6
and stirred for 2 h at 70 °C. The solvent was coevaporated
8.13 (d, J ) 8.16 Hz, 2H), 8.03 (m, 2H), 7.78 (d, J ) 8.36 Hz,
1H), 7.66 (d, J ) 8.21 Hz, 2H), 7.64-7.48 (m, 4H), 4.46 (t, J )
4.65 Hz, 2H), 3.66-3.40 (m, PEG).
with 400 µL toluene at 60 °C under reduced pressure. toluene
(
15 mL) was added and the mixture centrifuged. The clear
supernatant was precipitated with 60 mL of cold (-18 °C) tert-
butyl methyl ether and centrifuged, and the precipitate was
3
′,5′-Bis(tr iflu or om eth yl)bip h en yl-4-ca r boxylic Acid
1
P EG Ester (4d , Table 2, entry 7). White crystals; H NMR
500 MHz, DMSO-d
.45 Hz, 2H), 8.06 (d, J ) 8.40 Hz, 2H), 4.44 (t, J ) 4.75 Hz,
H), 3.78-3.37 (m, PEG).
dissolved in CH
2 2
Cl . This procedure was repeated twice, and
(
8
2
6
) δ 8.42 (s, 2H), 8.17 (s, 1H), 8.09 (d, J )
the product was dried under vacuum until no signal of residual
3
2
solvent could be detected (m ) 921 mg, 92%).
Rep r esen ta tive Micr ow a ve-Assisted Cr oss-Cou p lin g
R ea ct ion on P E G 6000-Bou n d Ar yl Ha lid es a n d Ar yl
3′-Meth oxybip h en yl-4-ca r boxylic Acid P EG Ester (4e,
1
Table 2, entry 8). White crystals; H NMR (500 MHz, DMSO-
3
3
Su lfon a tes (Table 2, entry 7 [400 µL]). A 20-mL screw-cap
culture tube was charged with 0.2 g of PEG 6000-bound aryl
iodide (approximately 0.062 mmol end groups) and 400 µL
water. 3,5-Bis(trifluoromethyl) phenyl boronic acid (19 mg,
d ) δ 8.05 (d, J ) 8.19 Hz, 2H), 7.85 (d, J ) 8.21 Hz, 2H), 7.43
6
(t, J ) 7.93 Hz, 1H), 7.31 (d, J ) 7.62 Hz, 1H), 7.27 (s, 1H),
7.01 (d, 8.20 Hz, 1H), 4.42 (t, J ) 4.62 Hz, 2H), 3.84 (s, 3H),
3.60-3.41 (m, PEG).
0
.37 mmol), 1.4 mg (10 mol %) of Pd(OAc)
mmol) of K CO were added under argon. The reaction mixture
was vortexed (some samples were warmed to approximately
2
, and 21 mg (0.16
5
-P h en ylth iop h en e-2-ca r boxylic Acid P EG Ester (5a ,
2
3
Table 1, entry 2). White crystals; H NMR (500 MHz, DMSO-
) δ 7.81 (d, J ) 3.77 Hz, 1H), 7.77 (d, J ) 7.46 Hz, 2H), 7.63
d, J ) 3.74 Hz, 1H), 7.48 (t, J ) 7.42 Hz, 2H), 7.43 (d, J )
.16 Hz, 1H), 4.39 (t, J ) 4.55 Hz, 2H), 3.65-3.42 (m, PEG).
-(4-F or m ylp h en yl)th iop h en e-2-ca r boxylic Acid P EG
1
d
(
7
6
4
4
5 °C to give a homogeneous mixture) and then irradiated for
min at 75 W. After cooling to room temperature, the
remaining solvent was coevaporated with 400 µL toluene at
5
8
0 °C in a parallel evaporation system under reduced pressure
1
Ester (5b, Table 1, entry 3). White crystals; H NMR (500
MHz, DMSO-d ) δ 10.04 (s, 1H), 8.01 (d, J ) 8.35 Hz, 2H),
for 4 h. The residue was dissolved in 8 mL of toluene and
centrifuged. The clear supernatant was transferred into 80-
mL centrifugation vessels and precipitated with 60 mL of ice
cold tert-butyl methyl ether (-18 °C). The crystalline precipi-
6
7
.98 (d, J ) 8.35 Hz, 2H), 7.86 (d, J ) 4.00 Hz, 1H), 7.82 (d,
J ) 3.90 Hz, 1H), 4.41 (t, J ) 4.55 Hz, 2H), 3.65-3.41 (m,
PEG).
2 2
tate was centrifuged and dissolved in 2 mL of CH Cl . The
5
-Na p h th a len e-1-ylth iop h en e-2-ca r boxylic Acid P EG
precipitation process was repeated once and the purified PEG-
1
E st er (5c, Table 1, entry 4). White crystals; H NMR (500
MHz, DMSO-d ) δ 8.12 (d, J ) 3.35 Hz, 1H), 8.05 (d, 7.70 Hz,
H), 7.92 (d, J ) 3.7 Hz, 1H), 7.66 (d, J ) 6.7 Hz, 1H), 7.62
m, 3H), 7.44 (d, J ) 6.7 Hz, 1H), 4.55 (t, J ) 5.45 Hz, 2H),
.65-3.41 (m, PEG).
-(3,5-Bis(t r iflu or om et h yl)p h en yl)-t h iop h en e-2-ca r -
boxylic Acid P EG Ester (5d , Table 1, entry 5). White
bound product dried under vacuum (m ) 182 mg, 94%).32
6
Rep r esen ta tive Micr ow a ve-Assisted Cr oss-Cou p lin g
2
(
3
3
3
Rea ction of Ar yl Iod id es (Table 4, entry 3). A 20-mL screw-
cap culture tube was flushed with argon and charged with 87
mg (0.33 mmol) of 4-iodobenzoic acid methyl ester, 69 mg (0.4
mmol) of 1-naphthaleneboronic acid, 3.7 mg (5 mol %) of Pd-
5
(
OAc)
2
, 114 mg (0.825 mmol) of K
2
CO
3
, 1.0 g (0.17 mmol) of
1
crystals; H NMR (500 MHz, DMSO-d
H), 8.09 (d, J ) 3.91 Hz, 1H), 7.88 (d, J ) 3.90 Hz, 1H), 4.40
t, J ) 4.60 Hz, 2H), 3.65-3.41 (m, PEG).
-(3-Meth oxyp h en yl)th iop h en e-2-ca r boxylic Acid P EG
6
) δ 8.41 (s, 2H), 8.14 (s,
PEG 6000, and 1.5 mL of water. The reaction mixture was
vortexed (some samples were warmed to approximately 45 °C
to give a homogeneous mixture) and then irradiated for 4 min
at 70 W. After cooling to room temperature, 200 µL toluene
was added and the volume of the mixture was reduced in a
parallel evaporation system under vacuum for 1 h. The residue
was dissolved in 8 mL of toluene and centrifuged. The clear
supernatant was transferred into 80-mL centrifugation vessels
and precipitated with 70 mL of ice cold (-18 °C) tert-butyl
methyl ether. The crystalline precipitate was centrifuged and
1
(
5
1
E st er (5e, Table 1, entry 6). White crystals; H NMR (500
MHz, DMSO-d ) δ 7.80 (d, J ) 3.76 Hz, 1H), 7.65 (d, J ) 3.82
6
Hz, 1H), 7.38 (t, J ) 7.88 Hz, 1H), 7.32 (d, J ) 7.63 Hz, 1H),
7
3
.28 (s, 1H), 6.99 (d, J ) 6.70 Hz, 1H), 4.38 (s, 2H), 3.83 (s,
H), 3.65-3.41 (m, PEG).
4
-Hyd r oxyben zoic Acid P EG Ester (6). White crystals;
H NMR (500 MHz, DMSO-d ) δ 7.97 (d, J ) 8.4 Hz, 2H), 7.76
d, J ) 8.0 Hz, 2H), 7.49 (d, J ) 8.2 Hz, 2H), 7.20 (d, J ) 8.4
Hz, 2H) 3.66-3.36 (m, PEG)
-(Tr iflu or om et h a n esu lfon yloxy)b en zoic Acid P E G
1
6
2 2
the residue dissolved in 5 mL of CH Cl . This procedure was
(
repeated three times, and the combined solvents were filtered
through 1 g of silica gel. The volume of the filtered solvent
was reduced under vacuum and the crude product purified by
HPLC (conversion 88%, isolated yield m ) 70 mg, 80%).
Rep r esen ta tive Tr a n sester ifica tion Rea ction , 5-(4-
F or m ylp h en yl)th iop h en e-2-ca r boxylic Acid Meth yl Es-
ter (Table 1, entry 3). To 0.5 g (approximately 0.155 mmol
end groups) of dry PEG 6000-bound biaryl was added 15 mL
of dry 20% TEA/MeOH and the mixture stirred in a 20-mL
screw-cap culture tube under argon at 85 °C for 3 d. The
4
1
Ester (7). White crystals; H NMR (500 MHz, DMSO-d
6
) δ
.14 (d, J ) 8.8 Hz, 2H), 7.68 (d, J ) 8.8 Hz, 2H), 4.42 (t, J )
.6 Hz, 3H), 3.66-3.36 (m, PEG).
-(1,1,2,2,3,3,4,4,4-Non a flu or ob u t a n e-1-su lfon yloxy)-
8
4
4
1
ben zoic Acid P EG ester (8). White crystals; H NMR (500
MHz, DMSO-d ) δ 8.14 (d, J ) 8.8 Hz, 2H), 7.69 (d, J ) 8.6
Hz, 2H), 4.42 (t, J ) 4.7 Hz, 2H), 3.66-3.33 (m, PEG).
-P h en ylt h iop h en e-2-ca r b oxylic Acid Met h yl E st er
6
5
progress of the transesterification was followed by TLC (CH
Cl /EtOH 95:5). The mixture was precipitated with 60 mL of
ice cold tert-butyl methyl ether (-18 °C) and centrifuged and
the residue dissolved in 4 mL of CH Cl . The precipitation
2
-
3
4
(
Table 1, entry 2). White crystals; mp 97 °C (lit. 98 °C).
2
5-(4-F or m ylp h en yl)th iop h en e-2-ca r boxylic Acid Meth -
yl Ester (Table 1, entry 3). White crystals; mp 125.5-127 °C;
2
2
1
procedure was repeated three times, and the volume of the
combined solvents was reduced under vacuum. The crude
product was purified by HPLC (m ) 36.8 mg, 96%).
H NMR (500 MHz, CDCl
3
) δ 10.21 (s, 1H), 7.93 (d, J ) 8.19
Hz, 2H), 7.80 (d, J ) 7.92, 2H), 7.80 (d, J ) 4.44 Hz, 1H), 7.43
(d, J ) 3.92 Hz, 1H), 3.93 (s, 3H); 13C NMR (126 MHz, CDCl
)
3
δ 191.66, 162.76, 149.48, 139.36, 136.48, 134.82, 134.38,
Bip h en yl-4-ca r boxylic Acid P EG Ester (4a , Table 2,
1
130.91, 126.94, 125.71, 52.76; MS (EI) 246 (100), 215 (91), 143
entry 4). White crystals; H NMR (500 MHz, DMSO-d
(
7
1
6
) δ 8.05
(
6
28). Anal. Calcd for C13
3.66; H, 4.28.
-Na p h th a len e-1-ylth iop h en e-2-ca r boxylic Acid Meth -
10 3
H O S: C, 63.39; H, 4.09. Found: C,
d, J ) 8.16 Hz, 2H), 7.84 (d, J ) 8.22 Hz, 2H), 7.74 (d, J )
.58 Hz, 2H), 7.51 (t, J ) 7.60 Hz, 2H), 7.44 (t, J ) 7.31 Hz,
H), 4.42 (t, J ) 4.47 Hz, 2H), 3.65-3.41 (m, PEG).
5
1
yl Ester (Table 1, entry 4). White crystals; H NMR (500 MHz,
4
′-F or m ylbip h en yl-4-ca r boxylic Acid P EG Ester (4b,
1
Table 2, entry 5). White crystals; H NMR (500 MHz, DMSO-
) δ 10.09 (s, 1H), 8.09 (d, J ) 8.20 Hz, 2H), 8.04 (d, J ) 8.15
d
6
(34) Liebscher, J .; Hartmann, H. DD 97205,3, 1973.