Effects of Isosteric Modifications of 3-Cl-AHPC Carboxylate
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 11 2633
1H, OH), 9.69 (bs, 1H, N HOH), 10.81 ppm (bs, 1H, NHO H).
HRMS calcd C25H26ClNO3 [M + H]+ 424.1674, found 424.1669.
(E)-2-[3′-(1-Adamantyl)-2-chloro-4′-hydroxy-4-biphenyl] -
ethenylboronic Acid (57). 56 (56 mg, 0.097 mmol) yielded after
chromatography (50% EtOAc/hexane) 31 mg (67%) of 57 as a pale-
Hz, 1H, 6ArH), 8.11 (d, J ) 1.8 Hz, 1H, 2-ArH), 10.07 ppm (s,
1H, CHO). FTMS (HRMS) calcd C8H5ClF3O4S [M + H]+ expected
288.9544, found 288.9542.
2-Chloro-4-nitrophenyl Trifluoromethanesulfonate (50). 49 (1.58
g, 9.12 mmol) gave after chromatography (12.5% EtOAc/hexane)
2.73 g (97%) of 50 as a yellow oil, which was used to prepare 51.
1H NMR δ 7.59 (d, J ) 9 Hz, 1H, 6-ArH), 8.26 (dd, J ) 9, 2.7
Hz, 1H, 5-ArH), 8.45 ppm (d, J ) 2.7 Hz, 1H, 3-ArH).
General Procedure for the Coupling between Aryl Boronic Acid
16 and Aryl Triflates 21, 28, 34, 40, and 50. To a stirred
suspension of the aryl triflate (1.6 mmol), 16 (651 mg, 1.8 mmol),
Pd(PPh3)4 (115 mg, 0.1 mmol), and LiCl (242 mg, 2.8 mmol) in
DME (8 mL) was added under argon 1.3 mL of 2.0 M aq Na2CO3
(2.6 mmol). The mixture was heated at reflux for 24 h, cooled,
and extracted (EtOAc). The extract was washed (water and brine),
dried, and concentrated. Flash chromatography on silica gel (5%
EtOAc/hexane) yielded the diaryl-coupling product.
1
tan solid, mp 186-189 °C. IR 3350, 2901, 1621, 1217 cm-1; H
NMR δ 1.81 (bs, 6H, AdCH2), 2.11 (bs, 3H, AdCH), 2.18 (m, 6H,
AdCH2), 4.92 (s, 1H, OH), 6.38 (d, J ) 18 Hz, 1H, CHdCHB),
6.74 (d, J ) 8.1 Hz, 1H, 5′-ArH), 7.22 (dd, J ) 8.4, 2.1 Hz, 1H,
6′-ArH), 7.36 (d, J ) 2.1 Hz, 1H, 2′-ArH), 7.39 (d, J ) 8.1 Hz,
1H, 6-ArH), 7.55 (dd, J ) 8.1, 1.5 Hz, 1H, 5-ArH), 7.73 (d, J )
1.5 Hz, 1H, 3-ArH), 7.76 ppm (d, J ) 18 Hz, 1H, CHdCHB).
HRMS calcd C24H26BClO3 [M + H]+ 409.1736, found 409.1730.
(3E)-4-[3′-(1-Adamantyl)-2-chloro-4′-hydroxy-4-biphenyl]-2-ox-
obut-3-enal (60). 59 (35 mg, 0.068 mmol) yielded after chroma-
tography (25% to 33% EtOAc/hexane) 22 mg (77%) of 60 as a
yellow wax, mp 121-123 °C. IR 3383, 2902, 1695, 1678, 1603,
1251 cm-1; 1H NMR δ 1.80 (bs, 6H, AdCH2), 2.11 (bs, 3H, AdCH),
2.16 (bs, 6H, AdCH2), 5.10 (s, 1H, OH), 6.74 (d, J ) 8.1 Hz, 1H,
5′-ArH), 6.97 (d, J ) 16.2 Hz, 1H, CHdCHCO), 7.20 (dd, J )
8.4, 2.1 Hz, 1H, 6′-ArH), 7.34 (d, J ) 2.1 Hz, 1H, 2′-ArH), 7.41
(d, J ) 8.1 Hz, 1H, 6-ArH), 7.52 (dd, J ) 8.1, 2.1 Hz, 1H, 5-ArH),
7.71 (d, J ) 1.5 Hz, 1H, 3-ArH), 7.80 (d, J ) 16.2 Hz, 1H, CHd
CHCO), 9.47 ppm (s, 1H, CHO). HRMS calcd C26H25ClO3 [M +
H]+ 421.1565, found 421.1573.
(E)-3-[3′-(1-Adamantyl)-4′-benzyloxyphenyl]-3-chlorocinnamoni-
trile (22). 21 (498 mg, 1.6 mmol) yielded 510 mg (64%) of 22 as
a white solid, Rf 0.55 (5% EtOAc/hexane); mp 72-74 °C. IR
1
(CHCl3) 2906, 2221 cm-1; H NMR δ 1.75 (s, 6H, AdCH2), 2.06
(s, 3H, AdCH), 2.20 (s, 6H, AdCH2), 5.18 (s, 2H, ArCH2), 5.91
(d, J ) 16.8 Hz, 1H, CHdCHCN), 7.02 (d, J ) 8.7 Hz, 1H, 5′-
ArH), 7.28 (dd, J ) 8.4, 2.1 Hz, 1H, 6′-ArH), 7.45-7.35 (m, 7H,
ArH, 5-ArH, 2′-ArH), 7.48 (d, J ) 16.8 Hz, 1H, CHdCHCN),
7.53 (d, J ) 8.4 Hz, 1H, 6-ArH), 7.56 ppm (d, J ) 1.5 Hz, 1H,
3-ArH). The crude product was used to prepare 23.
Diethyl
(E)-2-[3′-(1-Adamantyl)-2-chloro-4′-hydroxy-4-bi-
phenyl]ethenylphosphonate (62). 61 (0.14 mmol, 82 mg) yielded
after chromatography (50% to 67% EtOAc/hexane) 61 mg (87%)
of 62 as an off-white solid, mp 110-112 °C. IR 3414, 2932, 1028,
4-[3′-(1-Adamantyl)-4′-benzyloxyphenyl]-3-chlorobenzonitrile (29).
28 (428 mg, 1.5 mmol) yielded 390 mg (57%) of 29 as a white
solid, Rf 0.55 (5% EtOAc/hexane); mp 60-62 °C, which was used
1
989 cm-1; H NMR δ 1.38 (t, J ) 6.9 Hz, 6H, OCH2CH3), 1.79
1
(bs, 6H, AdCH2), 2.09 (bs, 3H, AdCH), 2.17 (bs, 6H, AdCH2),
4.18 (m, 4H, OCH2CH3), 6.29 (t, J ) 17.4 Hz, 1H, CHdCHP),
6.82 (d, J ) 8.4 Hz, 1H, 5′-ArH), 7.17 (dd, J ) 8.4, 2.1 Hz, 1H,
6′-ArH), 7.31 (d, J ) 2.1 Hz, 1H, 2′-ArH), 7.33-7.41 (m, 3H,
5-ArH, 6-ArH, OH), 7.48 (dd, J ) 17.4, 22.5 Hz, 1H, CHdCHP),
7.59 ppm (s, 1H, 3-ArH). HRMS calcd C28H34ClO4P [M + H]+
501.1956, found 501.1958.
to prepare 30. IR (CHCl3) 2906, 2232 cm-1; H NMR δ 1.74 (s,
6H, AdCH2), 2 (s, 3H, AdCH), 2.18 (s, 6H, AdCH2), 5.18 (s, 2H,
ArCH2), 7.02 (d, J ) 8.4 Hz, 1H, 5′-ArH), 7.27 (dd, J ) 8.4, 2.1
Hz, 1H, 6′-ArH), 7.35-7.47 (m, 6H, 2′-ArH, ArH), 7.51 (d, J )
7.8 Hz, 1H, 5-ArH), 7.58 (dd, J ) 8.1, 1.5 Hz, 1H, 6-ArH), 7.76
ppm (d, J ) 1.5 Hz, 1H, 2-ArH).
Ethyl (E)-4-[3′-(1-Adamantyl)-4′-benzyloxyphenyl]-3-chlorocin-
namate (35).8 34 (500 mg, 1.40 mmol) yielded 1.33 g (91%) of
35 as a white solid, which was reduced to 36. Rf 0.51 (10% EtOAc/
General Procedure for Converting Phenols 20, 27, 33, 17, and
49 to Their Triflates. To a stirred solution of the phenol (2.0 mmol)
in pyridine (5 mL) at 0 °C (ice-bath) under argon was slowly added
Tf2O (846 mg, 3.0 mmol) over a 0.5-h period. The reaction mixture
was stirred at room temperature overnight and then extracted
(EtOAc). The extract was washed (10% HCl, 5% NaHCO3, brine
and water), dried, and concentrated to afford an oil, which was
purified by chromatography (5% EtOAc/hexane) to give the triflate.
(E)-3-(3-Chloro-4-trifluoromethanesulfonyloxy)cinnamonitrile
(21). 20 (358 mg, 2.0 mmol) gave 565 mg (91%) of 21 as a white
1
hexane); mp 72-74 °C. IR (CHCl3) 2906, 1713, 1640 cm-1; H
NMR δ 1.35 (t, J ) 7.2 Hz, 3H, CH3), 1.72 (s, 6H, AdCH2), 2.04
(s, 3H, AdCH), 2.17 (s, 6H, AdCH2), 4.27 (q, J ) 6.9 Hz, 2H,
OCH2), 5.17 (s, 2H, ArCH2), 6.46 (d, J ) 15.2 Hz, 1H, HCd
CHCO), 7.00 (d, J ) 8.1 Hz, 1H, 5′-ArH), 7.29 (d, J ) 8.1 Hz,
1H, 6′-ArH), 7.35-7.42 (m, 5H, ArH), 7.43 (d J ) 6.9 Hz, 1H,
5-ArH), 7.50 (s, 1H, 2′-ArH), 7.52 (d, J ) 7.2 Hz, 1H, 6-ArH),
7.62 (s, 1H, 2-ArH), 7.64 ppm (d, J ) 15.3 Hz, 1H, CHdCHCO).
4-[3′-(1-Adamantyl)-4′-benzyloxyphenyl]-3-chlorobenzalde-
hyde (41). 40 (289 mg, 1.00 mmol) yielded after chromatography
(10% EtOAc/hexane) 215 mg (78%) of 41 as a white solid, mp
powder,
Rf
0.68
(10%
EtOAc/hexane);
mp
93-
99 °C. IR (CHCl3) 2966, 2226 cm-1; 1H NMR δ 5.93 (d, J ) 16.5
Hz, 1H, HCdCHCN), 7.34 (d, J ) 16.8 Hz, 1H, HCdCHCN),
7.42 (s, 2H, 5,6-ArH), 7.62 ppm (s, 1H, 2-ArH). The crude product
was used to prepare 22.
1
115-116 °C. IR 2902, 1699, 1596, 1262 cm-1; H NMR δ 1.75
(bs, 6H, AdCH2), 2.06 (bs, 3H, AdCH), 2.19 (bs, 6H, AdCH2),
5.19 (s, 2H, ArCH2), 7.04 (d, J ) 8.4 Hz, 1H, 5′-ArH), 7.31-7.56
(m, 8H, 6-ArH, 2′-ArH, 6′-ArH, ArH), 7.81 (dd, J ) 7.8, 1.5 Hz,
1H, 5-ArH), 7.99 (d, J ) 1.5 Hz, 1H, 2-ArH), 10.01 ppm (s, 1H,
CHO). HRMS calcd C30H29ClO2 [M + Na]+ 479.1748, found
479.1763.
3-Chloro-4-(trifluoromethanesulfonyloxy)benzonitrile (28). Crude
27 (306 mg, 2.0 mmol) gave 530 mg (93%) of 28 as a white
powder, Rf 0.80 (20% EtOAc/hexane); mp 55-56 °C, which was
used directly for coupling to produce 29. IR (CHCl3) 2961, 2243
cm-1; 1H NMR δ 7.50 (d, J ) 8.7 Hz, 1H, 5-ArH), 7.69 (dd, J )
8.1, 1.8 Hz, 1H, 6-ArH), 7.86 ppm (s, 1H, 2-ArH).
Ethyl (E)-3-Chloro-4-(trifluoromethanesulfonyloxy)cinnamate
(34).8 33 (800 mg, 3.54 mmol) gave 1.13 g (93%) of 34 as a white
solid, Rf 0.62 (10% EtOAc/hexane); mp 78-80 °C. IR (CHCl3)
2961, 1706, 1651, 1432 cm-1; 1H NMR δ 1.35 (t, J ) 6.9 Hz, 3H,
CH3), 4.29 (q, J ) 7.2 Hz, 2H, OCH2), 6.44 (d, J ) 15.9 Hz, 1H,
HCdCHCO), 7.39 (d, J ) 8.4 Hz, 1H, 5ArH), 7.48 (dd, J ) 8.4,
1.8 Hz, 1H, 6-ArH), 7.60 (d, J ) 16.2 Hz, 1H, CHdCHCO), 7.68
ppm (s, 1H, 2-ArH). HRMS calcd C12H10ClF3O5S [M + H]+
358.9962, found 358.9951.
3′-(1-Adamantyl)-4′-benzyloxy-2-chloro-4-nitrobiphenyl (51). 50
(721 mg, 2.36 mmol) yielded after chromatography (7% EtOAc/
hexane) 908 mg (81%) of 51 as a yellow solid, mp 52-54 °C,
1
which was reduced to 52. H NMR δ 1.77 (bs, 6H, AdCH2), 2.09
(bs, 3H, AdCH), 2.21 (m, 6H, AdCH2), 5.21 (s, 2H, ArCH2), 7.06
(d, J ) 8.7 Hz, 1H, 5′-ArH), 7.32 (dd, J ) 8.7, 2.1 Hz, 1H, 6′-
ArH), 7.35-7.56 (m, 7H, 2′-ArH, 6-ArH, ArH), 8.16 (dd, J ) 8.7,
2.4 Hz, 1H, 5-ArH), 8.37 ppm (d, J ) 2.4 Hz, 1H, 3-ArH).
(E)-5-{2-[3′-(1-Adamantyl)-2-chloro-4′-hydroxy-4-biphenyl]ethe-
nyl}-1H-tetrazole (24). A reported procedure73 was applied. To
23 (78 mg, 0.2 mmol) in toluene (2 mL) were added (n-Bu)2SnO
(5.0 mg, 0.02 mmol) and azidotrimethylsilane (58 mg, 1.0 mmol).
The mixture was stirred at 90-95 °C for 48 h. Additional
azidotrimethylsilane (34 mg, 0.3 mmol) was added, and stirring
3-Chloro-4-(trifluoromethanesulfonyloxy)benzaldehyde (40). 17
(1.56 g, 10.0 mmol) gave 2.30 g (79%) of 40 as a pale-yellow oil,
Rf 0.65 (20% EtOAc/hexane). IR (CHCl3) 2961, 1717, 1223 cm-1
;
1H NMR δ 7.61 (d, J ) 8.4 Hz, 1H, 5-ArH), 7.94 (dd, J ) 8.6, 1.8