150 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1
McKew et al.
was added in DMF (5 mL). The reaction was stirred at 40 °C
overnight, diluted with EtOAc, washed with brine, dried, filtered,
and concentrated. Flash chromatogragphy (20% EtOAc/hexanes)
afforded 41 (0.62 g, 37% over two steps): 1H NMR (400 MHz,
DMSO-d6) δ 3.15 (t, J ) 6.7 Hz, 2H), 3.80 (s, 3H), 4.28 (t, J )
6.8 Hz, 2H), 7.03-7.11 (m, 3H), 7.34 (d, J ) 2.3 Hz, 1H), 7.36
(d, J ) 8.6 Hz, 1H), 7.66 (d, J ) 2.3 Hz, 1H), 7.90 (d, J ) 9.1 Hz,
2H).
Methyl 4-[2-[5-Chloro-1-(diphenylmethyl)-1H-indol-3-yl]-
ethoxy]benzoate (42): Compound 41 was N-alkylated according
to the general procedure to afford 42 as a colorless oil in 60%
yield: 1H NMR (400 MHz, CDCl3) δ 3.16 (t, J ) 6.9 Hz, 2H),
3.88 (s, 3 H), 4.19 (t, J ) 6.9 Hz, 2H), 6.72-6.76 (m, 2 H), 6.83
(d, J ) 8.8 Hz, 2H), 7.02-7.15 (m, 6H), 7.29-7.41 (m, 6H), 7.62
(s, 1H), 7.95 (d, J ) 8.8 Hz, 2H).
4-[2-[5-Chloro-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy]ben-
zoic Acid (43). Compound 42 was hydrolyzed according to the
general procedure to yield 43 in 79% yield: 1H NMR (400 MHz,
DMSO-d6) δ 3.13 (t, J ) 6.7 Hz, 2H), 4.23 (t, J ) 6.6 Hz, 2H),
6.94 (d, J ) 9.1 Hz, 2H), 7.03 (s, 1 H), 7.06-7.15 (m, 6H), 7.28-
7.40 (m, 6H), 7.43 (d, J ) 8.6 Hz, 1H), 7.72 (d, J ) 1.8 Hz, 1H),
7.85 (d, J ) 8.8 Hz, 2H).
CDCl3) δ 3.12 (s, 3H), 7.17 (m, 4H), 7.32 (m, 2H), 7.51 (d, J )
7.5 Hz, 1H), 8.25 (d, J ) 1.9 Hz, 1H), 8.38 (br s, 1H).
2-(5-Chloro-2-phenyl-1H-indol-3-yl)ethanol (49). Compound
48 was reduced using the procedure for 130 to yield 49 in 80%
yield: 1H NMR (300 MHz, CDCl3) δ 3.01 (t, J ) 6.6 Hz, 2H),
3.83 (q, J ) 6.5 Hz, 2H), 7.05 (dd, J ) 8.5, 1.9 Hz, 1H), 7.18 (d,
J ) 8.6 Hz, 1H), 7.33 (m, 3H), 7.50 (m, 3H), 7.19 (br s, 1H).
2-[5-Chloro-1-(diphenylmethyl)-2-phenyl-1H-indol-3-yl]etha-
nol (51). Compound 49 was N-alkylated as described in the general
procedure to yield 51 in 40% yield: 1H NMR (300 MHz, CDCl3)
δ 2.79 (t, J ) 6.6 Hz, 2H), 3.67 (m, 2H), 6.46 (s, 1H), 6.56 (d, J
) 8.8 Hz, 1H), 6.75 (dd, J ) 2.1 Hz, 8.9, 1H), 6.92 (m, 4H), 7.14
(m, 7H), 7.29 (m, 3H), 7.48 (d, J ) 2.1 Hz, 2H).
Methyl 4-[2-[5-Chloro-1-(diphenylmethyl)-2-phenyl-1H-indol-
3-yl]ethoxy]benzoate (54). Applying the Mitsunobu procedure used
to make 132, reaction of methyl 4-hydroxybenzoate and 51 afforded
54 in 67% yield: 1H NMR (300 MHz, CDCl3) δ 3.01 (t, J ) 7.1
Hz, 2H), 3.75 (s, 3H), 4.07 (t, J ) 7.2 Hz, 2H), 6.46 (s, 1H), 6.55
(d, J ) 8.8 Hz, 1H), 6.54 (d, J ) 8.9 Hz, 2H), 6.75 (dd, J ) 8.9,
2.2 Hz, 1H), 7.15 (m, 7H), 7.30 (m, 4H), 7.52 (d, J ) 2.1 Hz, 2H),
7.79 (d, J ) 8.9 Hz, 2H).
4-[2-[5-Chloro-1-(diphenylmethyl)-2-phenyl-1H-indol-3-yl]-
ethoxy]benzoic Acid (55). Compound 54 was hydrolyzed according
to the general procedure to afford 55 in 89% yield: 1H NMR (300
MHz, DMSO-d6) δ 2.89 (t, J ) 6.9 Hz, 2H), 4.04 (t, J ) 7.0 Hz,
2H), 6.45 (s, 1H), 6.53 (d, J ) 8.8 Hz, 1H), 6.71 (d, J ) 8.8 Hz,
1H), 6.78 (dd, J ) 8.9, 2.2 Hz, 1H), 6.86 (m, 4H), 7.20 (m, 7H),
7.35 (m, 2H), 7.66 (m, 2H).
2-tert-Butyl-5-chloro-1H-indole106 (44). 4-Chlorophenylhydra-
zine hydrochloride and 3,3-dimethylbutan-2-one were reacted
following the Fischer indole general procedure to give 44 in 50%
yield after purification: 1H NMR (300 MHz, CDCl3) δ 1.27 (s,
9H), 6.09 (s, 1H), 6.95 (dd, J ) 8.7, 1.8 Hz, 1H), 7.13 (m, 1H),
7.38 (s, 1H), 7.92 (br. s, 1H).
Methyl 4-[4-(5-Chloro-2-methyl-1H-indol-3-yl)butoxy]ben-
zoate (56). 5-Chloro-2-methyl-1H-indole and methyl 4-(4-bromo-
butoxy)benzoate108 were treated under the general Zn salt alkyla-
tion conditions to yield 56 in 23% yield: 1H NMR (300 MHz,
CDCl3) δ 1.74-1.92 (m, 4H), 2.39 (s, 3H), 2.75 (t, J ) 6.9 Hz,
2H), 3.91 (s, 3H), 4.03 (t, J ) 6.1 Hz, 2H), 6.91 (d, J ) 9.1 Hz,
1H), 7.07 (dd, J ) 9.1, 1.8 Hz, 1H), 7.19 (d, J ) 8.7 Hz, 2H), 7.48
(d, J ) 1.7 Hz, 1H), 7.82 (s, 1 H), 8.00 (d, J ) 8.8 Hz, 2H).
Methyl 4-[4-[5-Chloro-1-(diphenylmethyl)-2-methyl-1H-indol-
3-yl]butoxy]benzoate (57). Compound 56 was N-alkylated ac-
cording to the general procedure to afford 57 in 29% yield: 1H
NMR (300 MHz, CDCl3) δ 1.77-1.95 (m, 4H), 2.30 (s, 3H), 2.80
(t, J ) 6.7 Hz, 2H), 3.92 (s, 3H), 4.04 (t, J ) 5.8 Hz, 2H), 6.56 (d,
J ) 8.8 Hz, 1H), 6.83 (dd, J ) 8.8, 2.2 Hz, 1H), 6.89-6.96 (m,
3H), 7.10-7.17 (m, 4H), 7.31-7.46 (m, 6H), 7.51 (d, J ) 1.9 Hz,
1H), 8.02 (d, J ) 9.1 Hz, 2H).
4-[4-[5-Chloro-1-(diphenylmethyl)-2-methyl-1H-indol-3-yl]-
butoxy]benzoic Acid (58). Compound 57 was hydrolyzed accord-
ing to the general procedure to afford 58 in 46% yield: 1H NMR
(300 MHz, CDCl3) δ 1.78-1.94 (m, 4H), 2.29 (s, 3H), 2.79 (t, J
) 7.0 Hz, 2H), 4.06 (t, J ) 5.9 Hz, 2H), 6.55 (d, J ) 8.8 Hz, 1H),
6.82 (dd, J ) 8.8, 2.2 Hz, 1H), 6.89 (s, 1H), 6.94 (d, J ) 8.8 Hz,
2H), 7.09-7.16 (m, 4H), 7.30-7.45 (m, 6H), 7.50 (d, J ) 1.9 Hz,
1H), 8.07 (d, J ) 8.8 Hz, 2H).
Methyl (5-Chloro-2-methyl-1H-indol-3-yl)acetate (59). 5-Chloro-
2-methyl-1H-indole and methyl bromoacetate were treated under
the general Zn salt alkylation conditions to yield 59 in 47% yield:
1H NMR (300 MHz, CD3OD) δ 2.39 (s, 3H), 3.68 (m, 3H), 4.93
(s, 2H), 6.99 (dd, J ) 8.5, 1.9 Hz, 1H), 7.21 (d, J ) 8.5 Hz, 1H),
7.39 (d, J ) 1.9 Hz, 1H).
Methyl [5-Chloro-1-(diphenylmethyl)-2-methyl-1H-indol-3-
yl]acetate (60). Compound 59 was N-alkylated according to the
general procedure to afford the title compound in 77% yield: 1H
NMR (300 MHz, CD3OD) δ 2.28 (s, 3H), 3.72 (s, 3H), 4.93 (s,
2H), 6.57 (d, J ) 9.1 Hz, 1H), 6.74 (dd, J ) 8.8, 2.2 Hz, 1H), 7.04
(s, 1H), 7.08-7.14 (m, J ) 6.7, 2.9 Hz, 4H), 7.28-7.34 (m, 6H),
7.46 (d, J ) 2.2 Hz, 1H).
Methyl (2-tert-Butyl-5-chloro-1H-indol-3-yl)oxoacetate (46).
Following the general procedure to form indole oxoacetates, indole
44 was treated with oxalyl chloride and then quenched with MeOH
to afford 46 in 50% yield: 1H NMR (300 MHz, CDCl3) δ 1.42 (s,
9H), 3.89 (s, 3H), 7.04 (dd, J ) 8.5, 1.8 Hz, 1H), 7.19 (d, J ) 8.7
Hz, 1H), 7.24 (d, J ) 1.8 Hz, 1H), 9.18 (br s, 1H).
2-(2-tert-Butyl-5-chloro-1H-indol-3-yl)ethanol (47). Compound
46 was reduced with LiAlH4 following the procedure for 130 to
give 47 in 76% yield: 1H NMR (CDCl3) δ 1.35 (s, 9H), 3.01 (t, J
) 7.1 Hz, 2H), 3.75 (t, J ) 7.1 Hz, 2H), 6.95 (dd, J ) 8.5, 2.0 Hz,
1H), 7.08 (d, J ) 8.5 Hz, 1H), 7.38 (d, J ) 2.1 Hz, 1H), 7.86 (br
s, 1H).
2-[2-tert-Butyl-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]-
ethanol (50). Compound 49 was N-alkylated as described in the
general procedure to give 50 in 31% yield: 1H NMR (CDCl3) δ
1.45 (s, 9H), 3.18 (t, J ) 7.3 Hz, 2H), 3.76 (t, J ) 7.4 Hz, 2H),
6.34 (d, J ) 8.9 Hz, 1H), 6.58 (dd, J ) 2.2, 8.9 Hz, 1H), 6.90 (m,
5H), 7.19 (m, 6H), 7.39 (d, J ) 2.06 Hz, 2H).
Methyl 4-[2-[2-tert-Butyl-5-chloro-1-(diphenylmethyl)-1H-in-
dol-3-yl]ethoxy]benzoate (52). Following the Mitsunobu procedure
used to make 132, reaction of methyl 4-hydroxybenzoate and 50
afforded 52 in 30% yield: 1H NMR (300 MHz, CDCl3) δ 1.49 (s,
9H), 3.42 (t, J ) 7.7 Hz, 2H), 3.76 (s, 3H), 4.11 (t, J ) 7.4 Hz,
2H), 6.35 (d, J ) 8.8 Hz, 1H), 6.59 (dd, J ) 8.8, 1.9 Hz, 1H), 6.79
(d, J ) 8.8 Hz, 2H), 6.98 (m, 5H), 7.18 (m, 6H), 7.38 (d, J ) 1.9
Hz, 1H), 7.86 (d, J ) 8.9 Hz, 2H).
4-[2-[2-tert-Butyl-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]-
ethoxy]benzoic Acid (53). Compound 52 was hydrolyzed according
to the general procedure to afford 52 in 94% yield: 1H NMR (300
MHz, DMSO-d6) δ 1.41 (s, 9H), 3.30 (t, J ) 7.1 Hz, 2H), 4.12 (t,
J ) 7.0 Hz, 2H), 6.26 (d, J ) 8.8 Hz, 1H), 6.58 (m, 1H), 6.89 (m,
5H), 7.20 (m, 8H), 7.47 (d, J ) 1.9 Hz, 1H), 7.71 (d, J ) 8.8 Hz,
2H).
5-Chloro-2-phenyl-1H-indole107 (45). 4-Chlorophenylhydrazine
hydrochloride and 1-phenylethanone were treated as in the Fischer
indole general procedure to yield 45 in 45% yield: 1H NMR (300
MHz, CDCl3) δ 6.64 (s, 1H), 7.02 (dd, J ) 8.6, 1.9 Hz, 1H), 7.19
(m, 3H), 7.33 (t, J ) 7.14, 1.9 Hz, 1H), 7.50 (m, 3H), 8.27 (br s,
1H).
[5-Chloro-1-(diphenylmethyl)-2-methyl-1H-indol-3-yl]acetic
Acid (61). Compound 60 was hydrolyzed according to the general
procedure to afford 61 in 86% yield: 1H NMR (300 MHz, CD3-
OD) δ 2.29 (s, 3H), 3.39 (m, 2H), 6.57 (d, J ) 8.8 Hz, 1H), 6.74
(dd, J ) 8.8, 2.2 Hz, 1H), 7.05 (s, 1H), 7.09-7.16 (m, 4H), 7.30-
7.35 (m, J ) 4.3, 2.3 Hz, 6H), 7.48 (d, J ) 1.9 Hz, 1H).
Methyl (5-Chloro-2-phenyl-1H-indol-3-yl)oxoacetate (48). Fol-
lowing the general procedure to functionalize at C3 with oxalyl
chloride, 45 yielded 48 in 80% crude yield: 1H NMR (300 MHz,