An Efficient and Practical Sequential One-Pot Synthesis of Suprofen
UPDATES
were charged with 4.510À2 mmol (4.5 mol%) monodentate
ligand or with 2.2510À2 mmol (2.25 mol%) bidentate
ligand and a magnetic stirring bar. The vials were closed via
septums containing an inlet needle and were flushed with
argon. When solid acids were used, 1 mmol p-TSA or
1 mmol oxalic acid were added to the vials. 2.17 mL of stock
we added 50 mL of 20% NaOH solution and 50 mL of
MeOH. The mixture was refluxed for 1 h and MeOH was
removed under vacuum. The solution was acidified to pH 2
by 2N HCl, extracted with diethyl ether three times and
washed with brine. After drying with NaSO4, the solvent
was removed and 37.4 g (73.5%) of a viscous yellow product
was obtained.
solution containing styrene (1.15 mL, 10 mmol), Pd(OAc)2
N
(16.8 mg, 0.075 mmol), hexadecane (590 mL, 2 mmol) and
20 mL of dioxane were added to each vial by syringe. Subse-
quently, in the case of liquid acids 1 mmol of 37% HCl or
1 mmol of 98% formic acid was added to the solution. Then,
the alloy plate was transferred into the autoclave. The
sealed autoclave was purged with CO several times and
pressurized with 5–50 bar CO at room temperature. After-
wards, it was heated to 1008C and the reaction was run for
20 h at this temperature. In order to determine the yield by
GC, a sample of 100 mL of each reaction solution was esteri-
fied with trimethylsilyldiazomethane in the presence of
100 mL MeOH. Since trimethylsilyldiazomethane reacts
sometimes with vinylarenes, a sample of the reaction solu-
tion with one aliquot of MeOH was taken without addition
of trimethylsilyldiazomethane to determine the conversion
by GC.
Methyl Ester of Ketoprofen: Yield: 60%; light yellow oil;
Rf (EE/heptane=1:10): 0.17; 1H NMR (300 MHz, CDCl3):
d=7.82–7.80 (m, 2H, 2CH), 7.75 (dd, J=1.6 Hz, 1H, CH),
7.68 (dpt, J=7.5, 1.6 Hz, 1H, CH), 7.63–7.56 (m, 1H, CH),
7.54 (dpt, J=7.7, 1.6 Hz, 1H, CH), 7.51–7.40 (m, 3H, 3CH),
3.81 (q, J=7.3 Hz, 1H, CHCH3), 3.68 (s, 3H, OCH3), 1.54
(d, J=7.3 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=
196.9 and 175.0 (2CO), 141.3, 138.4 and 137.9 (3C), 132.9,
131.9, 130.0, 130.0, 129.2, 129.0, 128.5, 128.3, 128.3 (9CH),
52.1 and 45.2 (CHCH3, OCH3), 18.5 (CH3); MS (70 eV):
m/z (%)=268 (42) [M+], 209 (100), 191 (23), 105 (51), 77
(36); IR (ATR): nmax =2950 (w), 1734 (s), 1657 (s), 1597 (w),
1580 (w), 1447 (m), 1434 (m), 1317 (m), 1281 (s), 1207 (s),
1165 (s), 1075 (m), 1024À(1w), 999 (w), 978 (w), 950 (m), 859
(w), 820 (w), 788 cm
(w); anal. calcd. for C17H16O3:
C 76.10, H 6.01; found: C 76.07, H 6.22.
Methyl Ester of Suprofen: Yield: 68%; light yellow solid,
1
mp 538C; Rf (EE/heptane=1:5): 0.19; H NMR (300 MHz,
Experimental Procedure for the Sequential Double
Carbonylation in One Pot
CDCl3): d=7.84 (d, J=8.5 Hz, 2H, CH), 7.42 (d, J=8.5 Hz,
2H, CH), 7.72 (dd, J=4.9, 1.2 Hz, 1H, CH), 7.65 (dd, J=
3.8, 1.2 Hz, 1H, CH), 7.16 (dd, J=4.9, 3.8 Hz, 1H, CH),
3.82 (q, J=7.2 Hz, 1H, CHCH3), 3.69 (s, 3H, OCH3), 1.55
(d, J=7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=
187.7 and 174.3 (2CO), 144.9, 143.6 and 137.0 (3C), 134.8,
134.2, 129.7, 129.7, 128.0, 127.7, 127.7 (7CH), 52.3 and 45.5
(CHCH3, OCH3), 18.5 (CH3); MS (70 eV): m/z (%)=274
A
100-mL Schlenk flask was charged with Pd
A
(16.8 mg, 0.075 mmol), (161.3 mg,
cataCXiumꢀ
A
0.45 mmol) and a stirring bar. The flask was evacuated,
filled with argon three times and 10 mL toluene were added.
The yellow solution was stirred for 10 min. Then, hexade-
cane (590 mL, 2 mmol), aryl bromide (10 mmol), and
TMEDA (1.12 mL, 7.5 mmol) were added. Meanwhile, a
100-mL autoclave was charged with vinylboronic acid
(15 mmol, 2.22 g), evacuated and filled with argon three
times. Subsequently, the yellow solution was transferred to
the autoclave via syringe. After the autoclave had been
purged with CO several times, the reaction was run at
2.5 bar CO and at 80–1008C. After 24 h the reaction was fin-
ished. The autoclave was cooled to ambient temperature
and a sample was taken to determine the yield of the first
step by GC. Without opening the autoclave, a solution of di-
oxane (15 mL) and 37% HCl (832 mL, 10 mmol) was trans-
ferred by syringe into the autoclave. The second reaction
was carried out at 40 bar CO and 1008C for 20 h. After
cooling to room temperature, the reaction solution was
transferred to a 250-mL round-bottom flask containing
50 mL MeOH. From this solution, 200 mL were reacted with
trimethylsilyldiazomethane to give the corresponding ester.
Subsequently, the reaction solution was filtered, 98% H2SO4
(110 mL) was added and the solution was refluxed for 5 h.
Finally, the solvent was evaporated and the formed ester
was further purified by chromatography or crystallization.
(56) [M+], 215 (100), 111 (53), 103 (10); IR (ATR): nmax
=
3099 (w), 2947 (w), 1727 (s), 1630 (s), 1604 (m), 1514 (w),
1431 (w), 1414 (s), 1326 (w), 1284 (s), 1261 (s), 1232 (m),
1203 (s), 1161 (s), 1128 (w), 1085 (w), 1060 (m), 1012 (w),
964 (w), 886 (w), 866 (m), 845 (m), 807 (w), 774 (w), 737 (s),
À1
695 cm (w); anal. calcd. for C15H14O3S: C 65.67, H 5.14, S
11.69; found: C 65.89, H 5.11, S 11.73.
Methyl
2-[4-(4-methoxybenzoyl)phenyl]propionate:
Yield: 45%; light yellow oil; Rf (EE/heptane=1:10): 0.15;
1H NMR (300 MHz, CDCl3): d=7.82 (d, J=8.9 Hz, 2H,
Ph), 7.72 (d, J=8.4 Hz, 2H, Ph), 7.40 (d, J=8.4 Hz, 2H,
Ph), 6.96 (d, J=8.9 Hz, 2H, Ph), 3.88 (s, 1H, OCH3), 3.81
(q, J=7.2 Hz, 1H, CHCH3), 3.69 (s, 1H, OCH3), 1.54 (d, J=
7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=195.1 and
174.5 (2CO), 163.3, 144.6, 137.2 and 130.1 (4C), 132.6, 130.2,
127.4 and 113.6 (4CH), 55.5, 52.3 and 45.5 (2 OCH3,
CHCH3), 18.5 (CH3); MS (70 eV): m/z (%)=298 (95) [M+],
239 (81), 211 (32), 191 (17), 135 (100), 103 (10), 77 (16); IR
(ATR): nmax =2979 (w), 2951 (w), 1734 (s), 1649 (m), 1598
(s), 1508 (w), 1456 (w), 1416 (w), 1305 (m), 1281 (m), 1252
(s), 1208 (m), 1169 (s), 1147 (s), 1116 (w), 1068 (w), 1026
(m), 965 (w), 928 (s), 840 (m), 773 (m), 753 (m), 687 cmÀ1
(m); anal. calcd. for C18H18O4: C 72.47, H 6.08; found: C
72.66, H 6.01.
Experimental Procedure for the 51-g Scale Synthesis
of Ketoprofen
Methyl 2-[4-(4-trifluoromethylbenzoyl)phenyl]propionate:
Yield: 70%; light yellow oil; Rf (EE/heptane=1:10): 0.10;
1H NMR (300 MHz, CDCl3): d=7.89 (d, J=8.3 Hz, 2H,
Ph), 7.80–7.72 (m, 4H, Ph), 7.44 (d, J=8.3 Hz, 2H, Ph), 3.83
(q, J=7.2 Hz, 1H, CHCH3), 3.69 (s, 1H, OCH3), 1.55 (d, J=
According to our synthetic protocol for 2-(diarylcarbonyl)-
methyl propionate, we charged a 2-L autoclave with bromo-
benzene (21.02 mL, 200 mmol). We obtained 39.8 g (74%)
of the methyl ester of Ketoprofen. To isolate the free acid,
Adv. Synth. Catal. 2008, 350, 2437 – 2442
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2441