1H, OH3 or OH2). 13C (chloroform-d) C 144.6 (C2), 142.1 (C3),
General procedure for demethylation to biphenyl catechols
139.6 (C1′), 135.1 (C5′ or C2′), 134.4 (C2′ or C5′), 134.0 (C6′),
133.3 (C3′), 131.8 (C4′), 126.9 (C1), 125.0 (C6), 122.4 (C5), 122.4
(C4). (EI-MS, 70 eV) 288 (M+,100%), 253 (10, M+ − Cl), 239 (10,
M+ − CH2Cl), 218 (7, M+ − Cl2). Exact mass: 287.9504. Required
for C12H735Cl3O2: 287.9512.
Demethylation was accomplished by treatment of the dimethoxy
biphenyls with boron tribromide as described by Bauer et al.11
To a stirred solution of boron tribromide in anhydrous CH2Cl2, a
CH2Cl2 solution of the dimethoxy biphenyl was added drop-wise
and the reaction continued for 1 h at −40 °C and an additional
2 h at 4 °C. Following the addition of ice cold water, the organic
layer was separated and the aqueous layer washed with ether. The
combined organic layers were dried over anhydrous sodium sulfate
and evaporated under reduced pressure. The catechols were further
purified by thin-layer chromatography on silica developed in 5:95
methanol/chloroform or by HPLC.
3,4-Dihydroxy-2′,5,5′-trichlorobiphenyl (14) (30%). 1H-NMR
(500 MHz, acetone-d6) H 7.42 (d, 1H, J3′,4′ = 7.8 Hz, H3′), 7.33 (d,
1H, J6′,4′ = 2.5 Hz, H6′), 7.30 (dd, 1H, J4′,3′ = 7.9 Hz, J4′,6′ = 2.5 Hz,
H4′), 6.94 (d, 1H, J5,2 = 2.0 Hz, H5), 6.93 (d, 1H, J5,2 = 2.0 Hz, H2).
13C (chloroform-d) C 115.5(C2), 119.5 (C5), 121.2 (C6), 128.8
(C4′), 130.9 (C3′ + C6′), 132.0 (C2′), 132.6 (C5′), 139.3 (C4), 139.8
(C1), 140.3 (C1′), 144.5 (C3). m/z (EI-MS, 70 eV) 186 (M+,30%),
118 (10, M+ − C4H12), 70 (100). Exact mass: 287.9535. Required
for C12H735Cl3O2: 287.9512. m/z (GC/EI-MS as di-HFB) 680 (M+,
75%), 645 (5, M+ − Cl), 483 (100, M+ − C4OF7), 455 (43, M+ −
C5O2F7), 427 (75, M+ − C6O3F7).
2,3-Dihydroxybiphenyl (9) (12%). 1H NMR (500 MHz,
acetone-d6) H 7.59 (d, 2H, J2′, 3′ (= J5′,6′) = 7.4 Hz, H 2′ and H 6′),
7.38 (t, 2H, J3′, 4′ (= J5′,4′) ≈ J2′, 3′ (= J5′,6′) = 7.6 Hz, H 3′ and H 5′),
7.25 (bt, 1H, J4′,3′ = 7.4 Hz, H 4′), 6.85 (dd, 1H, J4 or 6,5 = 7.8 Hz,
J4,6 = 1.5 Hz, H 4 or H 6), 6.81 (dd, 1H, J4 or 6,5 = 7.8 Hz, J4,6
=
1.5 Hz, H 4 or H 6), 6.75 (t, 1H, J 4,5 ≈ J 5,6 = 7.7 Hz, H5). m/z
(EI-MS, 70 eV) 186 (M+,100%), 168 (10, M+ − H2O), 157 (21,
M+ − CHO), 139 (33, M+ − CH3O2). Exact mass: m/z 186.0681.
C12H10O2 requires 186.0681. m/z (GC/EI-MS as di-HFB derivative)
578 (M+,68%), 409 (100, M+ − C3F7), 381 (13, M+ − C4OF7), 365
(20, M+ − C4O2F7).
3,4-Dihydroxy-2,2′,5′-trichlorobiphenyl (15) (46%). 1H-NMR
(500 MHz, chloroform-d) H 7.38 (d, 1H, J3,4 = 8.4 Hz, H3′), 7.28
(dd, 1H, J4′,3′ = 8.4 Hz, J4′,6′ = 2.1 Hz, H4′), 7.24 (d, 1H, J6′,4′
2.1 Hz, H6′), 6.91 (d, 1H, J6,5 = 8.4 Hz, H6), 6.73 (d, 1H, J5,6
=
=
8.4 Hz, H5), 5.81 (bs, 1H, OH3), 5.79 (bs, 1H, OH4). 13C (chloro-
form-d) C 147.4 (C4), 141.8 (C3), 141.6 (C1′), 135.1 (C1), 134.8
(C5′), 134.3 (C6′), 134.1 (C2′), 133.3 (C3′), 131.9 (C4′), 125.0 (C6),
122.0 (C2), 116.3 (C5). (EI-MS, 70 eV) 288 (M+,57%), 253 (22,
M+ − Cl), 239 (12, M+ − CH2Cl), 218 (10, [M+ − Cl2]). Exact mass:
287.9535. Required for C12H735Cl3O2: 287.9512. m/z (GC/EI-MS as
di-HFB) 680 (M+,100%), 645 (7, M+ − Cl), 483 (21, M+ − C4OF7),
455 (26, M+ − C5O2F7), 427 (50, M+ − C6O3F7).
3,4-Dihydroxybiphenyl (10) (61%). 1H NMR (500 MHz,
acetone-d6) H 7.98 (br s, 1H, OH), 7.96 (br s, 1H, OH), 7.54 (d, 2H,
J6′,5′ = J2′,3′ = 7.3 Hz, H2′ and H6′), 7.38 (t, 2H, J2′,3′ (= J6′,5′) ≈ J3′,4′
(= J5′,4′) = 7.6 Hz, H3′ and H5′), 7.25 (bt, 1H, J4′,3′ and 5′ = 7.4 Hz,
H4′), 7.12 (d, 1H, J2,6 = 2.0 Hz, H2), 6.99 (dd, 1H, J5,6 = 8.2, J5,1
=
2.0 Hz, H6), 6.89 (d, 1H, J5,6 = 8.2 Hz, H5). m/z (EI-MS,70 eV) 186
(M+,100%), 157 (10, M+ − CHO), 139 (35, M+ − CH3O2). Exact
mass: 186.0681. C12H10O2 requires186.0681. m/z (GC/EI/-MS as
di-HFB) 578 (M+,100%), 381 (43, M+ − C4OF7), 365 (11, M+ −
C4O2F7).
3,4-Dihydroxy-2,2′,5,5′-tetrachlorobiphenyl (16) (76%).
1H-NMR (500 MHz, acetone-d6) H 7.53 (d, 1H, J3′,4′ = 8.7 Hz,
H3′), 7.45 (dd, 1 H, J4′,3′ = 8.6 Hz, J4′,6′ = 2.8 Hz, H4′), 7.39 (d, 1H,
J6′,4′ = 2.8 Hz, H6′), 6.88 (s, 1H, H6). m/z (EI-MS, 70 eV) 322 (M+
of 35Cl4 isotopomer, 30), 287 (15, M+ − Cl), 252 (12, M+ − Cl2),
223 (13, M+ − CHOCl2). Exact mass major isotopomer: 323.9117.
Required for C12H435Cl337ClO2: 323.9092. m/z (GC/EI-MS as di-
HFB) 714 (M+, 67%), 517 (18, M+ − C4OF7), 505 (5, M+ − C5OF7),
489 (21, M+ − C5O2F7).
2,5-Dichloro-2′,3′-dihydroxybiphenyl (11) (37%). 1H-NMR
(500 MHz, chloroform-d) H 7.42 (d, 1H, J3,4 = 8.5 Hz, H3), 7.34
(d, 1H, J4,5 = 2.5 Hz, H6), 7.31 (dd, 1H, J4,3 = 8.5 Hz, J4,6 = 2.5 Hz,
H4), 6.94 (dd, 1H, J4′,5′ = 8.0 Hz, J4′,6′ = 1.4 Hz, H4′), 6.88 (t,
J5′,6′ ≈ J4′,5′ = 7.8 Hz, 1H, H5′), 6.71 (dd, 1H, J6′,5′ = 7.6 Hz, J4′,6′
=
1.4 Hz, H6′), 5.44 (bs, 1H, OH3), 4.98 (bs, 1H, OH2). 13C NMR
(chloroform-d): C 144.0 (C3′), 140.2 (C2′), 137.1 (C1), 132.8 (C2
and/or C5), 131.8 (C6), 130.9 (C3), 129.1 (C4), 125.2 (C1′), 122.1
(C6′), 120.9 (C5′), 115.4 (C4′). m/z (EI-MS, 70 eV) 254 (M+,100%),
219 (45, M+ − Cl), 184 (90, M+ − Cl2), 173 (22, M+ − CH2O2Cl).
Exact mass: 253.9881. Required for C12H835Cl2O2: 253.9901. m/z
(GC/EI-MS as di-HFB) (M+,100%), 477 (7, M+ − C3F7), 449 (23,
M+ − C4OF7), 414 (34, M+ − C4OClF7).
[3,4,6-2H3]-2,5-Dichloronitrobenzene (18). To [2,3,5,6-2H4]-
1,4-dichlorobenzene (17), 1.02 g (0.68 mmol), 3.33 mL fuming
nitric acid was added drop-wise with cooling in a water bath. After
stirring for 15 min at ambient temperature, the reaction mixture
was added to 50 mL water cooled to 0 °C in an ice bath, and the
precipitate collected by filtration to give [3,4,6-2H3]-2,5-dichloro-
nitrobenzene (18), 1.31 g (99%).
[3,4,6-2H3]-2,5-Dichloroaniline (19). A solution of 18 (50 mg,
0.26 mmol) in methanol (10 mL) and 10 N HCl (0.2 mL) contain-
ing 5%Pd/C (5 mg) was hydrogenated at atmospheric pressure
and ambient temperature until the theoretical amount of hydrogen
(6.4 mL) was absorbed. Filtration followed by evaporation of
methanol yielded [3,4,6-2H3]-2,5-dichloroaniline as the hydro-
chloride. The salt was dissolved in water (20 mL), neutralized with
K2CO3 and extracted into diethyl ether. Drying over anhydrous
Na2SO4 followed by evaporation of ether yielded [3,4,6-2H3]-
2,5-dichloroaniline (19) 36 mg, (84%). m/z (EI-MS, 70 eV) 164
(M+, 100%), 129 (35, M+ − Cl), 102 (25, M+ − HCNCl), 93 (17,
M+ − HCl2).
2,5-Dichloro-3′,4′-dihydroxybiphenyl (12) (58%). 1H-NMR
(500 MHz, acetone-d6): H 7.49 (d, 1H, J3,4 = 8.6 Hz, H3), 7.38 (d,
1H, J4,6 = 2.6 Hz H2), 7.36 (dd, 1H, J4,3 = 8.6, J4,6 = 2.6 Hz), 6.96
(d, 1 H, J2′,6′ = 2.1 Hz, H2′), 6.92 (d, 1H, J5′,6′ = 8.2 Hz, H5′), 6.80
(dd, 1H, J6′,5′ = 8.2 Hz, J6′,2′ = 2.1 Hz, H6′). 13C NMR (acetone-d6)
C 149.3 (C4′), 148.6 (C3′), 146.2 (C1), 136.0 (C2 or C5), 135.2
(C3), 134.9 (C6), 134.5 (C5 or C2), 133.6 (C1′), 131.9 (C4), 124.9
(C5′), 120.3 (C2′), 118.9 (C6′). m/z (EI-MS, 70 eV) 254 (M+,100%),
225 (10, M+ − CHO), 184 (15, M+ − Cl2), 173 (52, M+ − CH2O2Cl).
Exact mass: 253.9869. Required for C12H835Cl2O2: 253.9901. m/z
(GC/EI-MS as di-HFB) 646 (M+,100%), 449 (33, M+ − C4OF7), 433
(20, M+ − C4O2F7), 393 (55, M+ − C4O2F7).
[3,4,6-2H3]-3′,4′-Dimethoxy-2,2′5,5′-tetrachlorobiphenyl
(20). Coupling of 19 (36 mg, 0.219 mmol) and 3,6-dichloro-1,2-
dimethoxybenzene (300 mg, 1.4 mmol) yielded 20, 10 mg (27%).
1H-NMR (400 MHZ, acetone-d6) H 7.23 (s, 1H), 3.85 (s, 3H),
3.78 (s, 3H). m/z (EI-MS, 70 eV) 353(M+, 100), 338 (12, M+ −
CH3), 310 (8, M+ − C2H3O), 297 (20, M+ − C3H6O), 275 (10, M+ −
C2H3OCl).
2,3-Dihydroxy-2′,4,5′-trichlorobiphenyl (13). A solution of 5
(5 mg, 0.016 mmol) in CH2Cl2 (25 mL) was treated with 1 M of
BBr3 (0.1 mL) to yield 3,4-dihydroxy-2′,5,5′-trichlorobiphenyl (13)
1
4 mg, (88%). H-NMR (500 MHz, chloroform-d) H 7.42 (d, 1H,
J3′,4′ = 8.4 Hz, H3′), 7.40 (d, 1H, J4′,6′ = 2.5 Hz, H6′), 7.33 (dd, 1H,
J3′,4′ = 8.4 Hz, J4′,6′ = 2.5 Hz, H4′), 6.97 (d, J5,6 = 8.4 Hz, 1H, H5),
6.74 (d, 1H, J5,6 = 8.4 Hz, H6), 5.63 (bs, 1H, OH2 or OH3), 5.45 (bs,
2 6 2 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 6 2 4 – 2 6 2 9