Checked by Bryon A. Merrill and Larry E. Overman.
1. Procedure
A.
4-Nitrophenyl trifluoromethanesulfonate (1). A dry,
100-mL, three-necked, round-bottomed flask equipped with a
magnetic stirring bar,
nitrogen gas inlet, and
rubber septum (Note
1) is charged sequentially with
10.0 g (71.9 mmol) of 4-nitrophenol and
38 mL of pyridine (Note
2). The stirred solution is cooled to 0°C and
13.5 mL (80 mmol) of trifluoromethanesulfonic anhydride (Note
3) is added through the septum via a syringe. The rate of addition is such that the internal temperature of the flask never exceeds 25°C (Note
4). The solution is allowed to warm slowly to room temperature and is maintained at room temperature for 25 hr. The reaction is quenched by pouring it into a
250-mL separatory funnel that contains 100 mL of water and
50 mL of diethyl ether. The two phases are separated and the aqueous phase is extracted with four additional
50-mL portions of diethyl ether. The combined organic fractions are dried over
magnesium sulfate, filtered, and concentrated to provide
18.7 g of crude
1 as a yellow, crystalline, solid.
The crude product is dissolved in
50 mL of diethyl ether and adsorbed onto
20 g of Celite 521 by evaporation of the
diethyl ether under reduced pressure. The dry Celite 521 is then added to the top of a column containing
200 g of silica gel (32–63 micron) and the column is eluted with a mobile phase of 9:1
hexanes-
ethyl acetate. The fractions containing the product (R
f = 0.50, 9:1
hexanes-
ethyl acetate) are collected and concentrated under reduced pressure to yield
17.7 g (
91%) of
1 as a colorless, crystalline, solid (Note
5).
B.
Tributyl(4-methoxyphenyl)stannane (2). A dry,
250-mL, three-necked, round-bottomed flask, equipped with a
reflux condenser, magnetic stirring bar, and
nitrogen gas inlet, is charged with
2.91 g (120 mmol) of magnesium turnings (Note
1) and (Note
6). The flask is fitted with a rubber septum and charged sequentially via syringe with
85 mL of tetrahydrofuran (Note
7),
14.0 mL (112 mmol) of 4-bromoanisole (Note
8), and
0.05 mL of methyl iodide (Note
9). The rubber septum is immediately replaced with a
Teflon stopper. Within 5 min, the reaction spontaneously warms to reflux temperature and continues to boil for approximately 10 min. The reaction is stirred an additional 2 hr without external heating or cooling. The flask is fitted with a rubber septum and
30.5 mL (112 mmol) of tributyltin chloride is added to the green solution via a syringe (Note
10). The septum is again replaced with a Teflon stopper and the reaction is heated at reflux for 12 hr.
Upon cooling to room temperature, a gray precipitate forms and the reaction is quenched with
220 mL of saturated, aqueous ammonium chloride. The resulting mixture is poured into a
1-L separatory funnel and extracted with
220 mL of diethyl ether. The organic fraction is washed two times with 100 mL of water, and once with
100 mL of brine, dried over
magnesium sulfate, filtered, and concentrated under reduced pressure to provide
44.1 g of crude product as a pale yellow oil. Purification of this material by bulb-to-bulb distillation (140–145°C, 0.5 mm) (Note
11) into a chilled (−78°C) receiving flask yields
41.0 g (
92%) of
2 as a clear, colorless oil (Note
12).
C.
4-Methoxy-4'-nitrobiphenyl (3). A dry,
500-mL, three-necked, round-bottomed flask equipped with a reflux condenser, magnetic stirring bar,
nitrogen gas inlet, and rubber septum (Note
1) is charged sequentially with
300 mL of anhydrous N,N-dimethylformamide (Note
13),
15.0 g (55.4 mmol) of 4-nitrophenyl trifluoromethanesulfonate (1),
27.8 g (70.0 mmol) of tributyl(4-methoxyphenyl)stannane (2) (Note
14),
7.5 g of dry lithium chloride (Note
15), and
1.6 g (4 mol percent) of bis(triphenylphosphine)palladium(II) chloride (Note
16). The rubber septum is replaced with a Teflon stopper and the yellow mixture is heated at 100–105°C for 2.5 hr. After approximately 20 min, the reaction turns dark brown.
The reaction mixture is cooled to room temperature and then vacuum-filtered through a
350-mL, medium frit, sintered-glass Büchner funnel that is filled to a height of 4 cm with
ethyl acetate-impregnated Celite 521. Four
100-mL portions of ethyl acetate are used to wash the pad of Celite 521. The filtrate is partially concentrated by removal of
ethyl acetate under reduced pressure. The resulting brown liquid is slowly poured into 1.5 L of water. After standing for 8 hr, the precipitate is collected by vacuum filtration and air dried. The solid is dissolved in
500 mL of acetonitrile, the resulting solution is poured into a 1-L separatory funnel, and is washed with three
300-mL portions of hexanes. The
acetonitrile layer is concentrated to provide
24 g of crude product as a brown solid.
The crude product is dissolved in a minimum amount of
dichloromethane and adsorbed onto
25 g of silica gel (32–63 micron) by subsequent evaporation of the
dichloromethane under reduced pressure. The sample of dry, dark brown silica gel is added to the top of a column containing
500 g of silica gel (32–63 micron) with a mobile phase of hexanes. The polarity of the mobile phase is gradually increased from hexanes to 95:5
hexanes-
ethyl acetate. The fractions containing the desired product (R
f = 0.26, 95:5
hexanes-
ethyl acetate) are combined and concentrated under reduced pressure to yield
6.9 g of
3 as a yellow solid. Additional purification is required to remove traces of tin by-products. Compound
3 is dissolved in
70 mL of ethyl acetate and stirred over
70 mL of saturated, aqueous potassium fluoride for 24 hr. The two phases are separated and the organic phase is dried over
magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting yellow solid is recrystallized from
ethyl alcohol to provide
6.1 g (
48%, 2 crops) of
3 as yellow needles (Note
17), (Note
18), and (Note
19).
2. Notes
1. All glassware is
oven-dried at 140°C overnight and assembled while hot under a
nitrogen atmosphere.
4. The reaction turns deep red upon addition of the anhydride.
5.
4-Nitrophenyl trifluoromethanesulfonate exhibits the following properties: mp
54–55°C (lit.
4 53°C); IR (KBr) cm
−1: 3125, 3094, 1625, 1590, 1537, 1487, 1423, 1352, 1253, 1214, 1137, 1012, 900, 862, 759, 744, 692, 613;
1H NMR (300 MHz, CDCl
3) δ: 7.50 (d, 2 H, J = 9.2), 8.37 (d, 2 H, J = 9.2); high resolution mass spectrum (isobutane CI): 271.9848 (271.9840 calcd for C
7H
5F
3NO
5S).
6.
Magnesium turnings (99.99%) are purchased from Johnson Matthey/Alfa Products and used as received.
8.
4-Bromoanisole is purchased from the Aldrich Chemical Company, Inc., and used as received.
9.
Methyl iodide is purchased from the Aldrich Chemical Company, Inc., and used as received.
Methyl iodide is used as a catalyst to initiate the Grignard reaction.
10.
Tributlytin chloride is purchased from the Aldrich Chemical Company, Inc., and used as received. The reaction warms upon the introduction of
tributyltin chloride, but it does not boil spontaneously .
12.
Tributyl(4-methoxyphenyl)stannane exhibits the following properties:
1H NMR (500 MHz, CDCl
3) δ: 0.88 (t, 9 H, J = 7.3), 1.02 (m, 6 H), 1.33 (m, 6 H), 1.53 (m, 6 H), 3.80 (s, 3 H), 6.90 (d, 2 H, J = 8.5), 7.37 (d, 2 H, J = 8.5). The peaks at 1.02 and 7.37 ppm show coupling with tin; mass spectrum (isobutane CI) 399, 397, 395, 291, 289, 287. The product is at least 97% pure by GC analysis (30 m, Supelco SPB-1 fused silica column).
13. Anhydrous
N,N-dimethylformamide (water <0.005%) is purchased from the Aldrich Chemical Company, Inc., and transferred via
cannula directly from the
Sure/Seal bottle into the reaction flask. The solvent is deoxygenated by bubbling
nitrogen through it for 45 min prior to the addition of compound
2.
15.
Lithium chloride is dried by heating at 130°C under reduced pressure (0.5 mm) for 24 hr.
17.
4-Methoxy-4'-nitrobiphenyl (3) has the following properties: mp
109–110°C (lit.
6 111°C); IR (KBr) cm
−1: 3062, 2968, 2838, 1600, 1509, 1487, 1345, 1253, 1034, 1017, 857, 845, 830, 817, 757, 724, 696;
1H NMR (500 MHz, CDCl
3) δ: 3.88 (s, 3 H), 7.01 (d, 2 H, J = 8.7), 7.58 (d, 2 H, J = 8.7), 7.68 (d, 2 H, J = 8.7) 8.26 (d, 2 H, J = 8.7);
13C NMR (125 MHz, CDCl
3) δ: 55.4, 114.5, 124.1, 127.0, 128.5, 131.0, 146.4, 147.1, 160.4; mass spectrum (isobutane CI): 230 (MH). Anal. Calcd for C
13H
11NO
3: C, 68.10; H, 4.84; N, 6.11. Found: C, 67.99; H, 4.87; N, 6.13.
4,4'-Dimethoxybiphenyl (4) has the following properties: mp
175–177°C (lit.
7 176–178°C); IR (KBr) cm
−1: 2958, 2914, 2840, 1608, 1503, 1277, 1251, 1184, 1042, 1012, 825, 810;
1H NMR (500 MHz, CDCl
3) δ: 3.85 (s, 6 H), 6.96 (d, 4 H, J = 8.7), 7.48 (d, 4 H, J = 8.7);
13C NMR (125 MHz, CDCl
3) δ: 55.3, 114.1, 127.7, 133.5, 158.7; high resolution mass spectrum (70 eV, EI): 214.0993 (214.0994 calcd for C
14H
14O
2).
4-Amino-4'-methoxybiphenyl (5) has the following properties: mp
143–144°C (lit.
8 144–145.5°C): IR (KBr) cm
−1: 3396, 3334, 3224, 3033, 2965, 2837, 1636, 1608, 1500, 1270, 1241, 1181, 1035, 1015, 817;
1H NMR (500 MHz, CDCl
3) δ: 3.69 (broad s, 2 H), 3.84 (s, 3 H), 6.75 (d, 2 H, J = 8.5), 6.95 (d, 2 H, J = 8.8), 7.37 (d, 2 H, J = 8.4); 7.46 (d, 2 H, J = 8.8);
13C NMR (125 MHz, CDCl
3) δ: 55.3, 114.1, 115.4, 127.4, 127.6, 131.3, 133.8, 145.2, 158.4; high resolution mass spectrum (70 eV, EI): 199.0990 (199.0997 calcd for C
13H
13NO).
19. The checkers found that using
tetrakis(triphenylphosphine)palladium(0) as the catalyst and
dioxane as the solvent resulted in significant reduction of the nitro-substituent in the coupled product.
9 Biphenyls
3 and
5 are obtained in ratios as high as one to one under these conditions.
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
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