Journal of Medicinal Chemistry
ARTICLE
room temperature. The mixture was stirred at room temperature for
10 min. SiliaBond cyanoborohydride (1.1 g, 1.1 mmol, 1 g/mmol) was
added and stirred at room temperature for another 10 min. The mixture
was then heated via microwave irradiation at 150 ꢀC for 5 min, filtered,
and concentrated under vacuum. The crude product was purified via
flash column chromatography (EtOAc:hexanes, 10:90 to 100:0; MeOH:
DCM, 1:99 to 10:90) to provide product (100 mg, 38% yield). 1H NMR
(400 MHz, CDCl3) δ 7.70 (d, J = 15.9 Hz, 1 H), 7.50 (d, J = 8.1 Hz, 2 H),
7.42 (d, J = 8.2 Hz, 2 H), 6.44 (d, J = 16.0 Hz, 1 H), 4.55 (dt, J = 47.7,
5.0 Hz, 2 H), 3.83 (s, 3 H), 3.72 (s, 2 H), 2.82 (dt, J = 26.9, 5.1 Hz, 2 H).
MS m/z 238.2 (MH+).
8g (460 mg, 1.7 mmol) and (2-methyl-1H-indol-3-yl)-acetaldehyde
(200 mg, 1.2 mmol). H NMR (400 MHz, CDCl3) δ 7.90 (br, 1 H),
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7.74 (d, J = 16.0 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 2 H), 7.40 (d, J = 8.0 Hz,
2 H), 7.32 (d, J = 7.8Hz, 1 H), 7.24 (dt, J = 8.0, 0.9Hz, 1 H), 7.10 (ddd, J =
8.1, 7.0, 1.2 Hz, 1 H), 7.03 (ddd, J = 7.8, 7.0, 1.0 Hz, 1 H), 6.48 (d, J = 15.9
Hz, 1 H), 3.87 (s, 2 H), 3.85 (s, 3 H), 2.96 (t, J = 13.2 Hz, 2 H), 2.89ꢀ2.79
(m, 4 H), 2.29 (s, 3 H), 1.65 (t, J = 18.8 Hz, 3 H). MS m/z 427.2 (MH+).
(E)-3-(4-{[[2-(1H-Indol-3-yl)-ethyl]-(3,3,3-trifluoro-propyl)-amino]-
methyl}-phenyl)-acrylic Acid Methyl Ester (9h). Following method A,
the title compound (160 mg, 41% yield) was prepared from 8h (300 mg,
0.90 mmol) and 3,3,3-trifluoro-propionaldehyde (105 mg, 0.94 mmol).
1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1 H), 7.71 (d, J = 16.1 Hz, 1 H),
7.49ꢀ7.46 (m, 3 H), 7.39ꢀ7.35 (m, 2 H), 7.20 (ddd, J = 8.1, 6.9, 1.3 Hz,
1 H), 7.09 (ddd, J = 8.0, 7.2, 1.0 Hz, 1 H), 7.00 (d, J = 2.9 Hz, 1 H), 6.46
(d, J = 16.3 Hz, 1 H), 3.84 (s, 3 H), 3.73 (s, 2 H), 2.99ꢀ2.93 (m, 2 H),
2.90ꢀ2.81 (m, 4 H), 2.36 (m, 2 H). MS m/z 431.2 (MH+).
(E)-3-{4-[(2,2-Difluoro-ethylamino)-methyl]-phenyl}-acrylic Acid
Methyl Ester (8d). Starting from 2,2-difluoro-ethylamine (250 mg,
3.1 mmol) the title compound was prepared following the procedure
for 8c (550 mg, 70% yield). 1H NMR (400 MHz, CD3OD) δ 7.69 (d,
J = 16.3 Hz, 1 H), 7.58 (d, J = 8.3 Hz, 2 H), 7.40 (d, J = 8.3 Hz, 2 H), 6.52
(d, J = 15.6 Hz, 1 H), 5.90 (tt, J = 56.3, 4.3 Hz, 1 H), 3.84 (s, 2 H), 3.78
(s, 3 H), 2.90 (td, J = 15.6, 4.6 Hz, 2 H). MS m/z 256.1 (MH+).
(E)-3-{4-[(3,3-Difluoro-propylamino)-methyl]-phenyl}-acrylic Acid
Methyl Ester (8g). Starting from 3,3-difluoro-propylamine hydrochlor-
ide (250 mg, 2.1 mmol) the title compound was prepared following the
procedure for 8c (460 mg, 81% yield). MS m/z 270.1 (MH+).
(E)-3-[4-({(2-Fluoro-ethyl)-[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino}-
methyl)-phenyl]-acrylic Acid Methyl Ester (9c). Following method A,
the title compound (100 mg, 60% yield) was prepared from 8c (100 mg,
0.42 mmol) and (2-methyl-1H-indol-3-yl)-acetaldehyde (80 mg,
(E)-3-[4-({(2-Fluoro-ethyl)-[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino}-
methyl)-phenyl]-N-hydroxy-acrylamide (11c). Following method B, the
title compound (8.9 mg, 9.3% yield) was prepared from 9c (100 mg,
0.24 mmol). 1H NMR (400 MHz, CD3OD) δ 7.56 (d, J = 15.6 Hz, 1 H),
7.54 (d, J = 7.6 Hz, 1 H), 7.41 (d, J = 7.9 Hz, 2 H), 7.29 (d, J = 8.1 Hz, 2 H),
7.25 (d, J = 8.3 Hz, 1 H), 7.02 (ddd, J = 8.1, 7.0, 1.1 Hz, 1 H), 6.93 (ddd, J =
8.1, 7.0, 1.1 Hz, 1 H), 6.56 (d, J = 16.0 Hz, 1 H), 4.63 (dt, J = 47.4, 5.4 Hz,
2 H), 3.86(s, 2H), 3.03(dt, J= 26.8, 5.2 Hz, 2 H), 2.95ꢀ2.78 (m, 4 H), 2.32
(s, 3 H). MS m/z 396.2 (MH+). HRMS calcd for C23H26N3O2F (MH+)
396.2087, found 396.2092.
(E)-3-[4-({(2,2-Difluoro-ethyl)-[2-(2-methyl-1H-indol-3-yl)-ethyl]-
amino}-methyl)-phenyl]-N-hydroxy-acrylamide (11d). Following
method B, the title compound (180 mg, 46% yield) was prepared
from 9d (400 mg, 0.92 mmol). 1H NMR (400 MHz, CD3OD) δ 7.58
(d, J = 15.5 Hz, 1 H), 7.43 (d, J = 7.8 Hz, 2 H), 7.27 (d, J = 7.8 Hz, 2 H),
7.22 (d, J = 5.3 Hz, 1 H), 7.20 (d, J = 4.7 Hz, 1 H), 6.97 (t, J = 7.3 Hz,
1 H), 6.88 (t, J = 7.5 Hz, 1 H), 6.48 (d, J = 15.8 Hz, 1 H), 5.78 (tt, J =
56.2, 4.4 Hz, 1 H), 3.67 (s, 2 H), 2.88 (td, J = 14.9, 4.2 Hz, 2 H),
2.79ꢀ2.64 (m, 4 H), 2.23 (s, 3 H). MS m/z 414.2 (M + 1). 13C NMR
(400 MHz, CD3OD) δ 166.50, 142.87, 141.54, 137.11, 135.14, 132.62,
130.52, 129.89, 128.79, 121.22, 119.3, 118.35, 117.98, 111.24, 109.32,
60.26, 57.37 (t), 56.29, 49.46, 23.23, 11.35. HRMS calcd for
C23H25N3O3F2 (Mꢀ) 412.1837, found 412.1854.
(E)-N-Hydroxy-3-(4-{[[2-(1H-indol-3-yl)-ethyl]-(2,2,2-trifluoro-ethyl)-
amino]-methyl}-phenyl)-acrylamide (11e). Following method B, the
title compound (26 mg, 19% yield) was prepared from 9e (140 mg, 0.39
mmol). 1H NMR (400 MHz, CD3OD) δ 7.58 (d, J = 15.8 Hz, 1 H), 7.54
(d, J = 8.2 Hz, 2 H), 7.50 (d, J = 8.2 Hz, 1 H), 7.45 (d, J = 7.6 Hz, 2 H), 7.34
(d, J = 8.2 Hz, 1 H), 7.13 (t, J = 8.2 H2, 1 H), 7.03 (t, J = 7.6 Hz, 1 H), 6.47
(d, J = 15.8 Hz, 1 H), 4.28 (q, J = 7.6 Hz, 1 H), 4.00 (d, J = 13.9 Hz, 1 H),
3.86(d, J= 13.9 Hz, 1 H), 3.43 (m, 1 H), 3.15 (d, J= 13.2, 5.0 Hz, 1 H), 3.01
(m, 1H), 2.61 (dd, J= 17.0, 3.2 Hz, 1 H). MS m/z(M +1). 13CNMR(400
MHz, CD3OD) δ 142.09, 141.40, 138.40, 135.56, 130.56, 128.88, 127.78,
125.07, 123.23, 119.98, 119.19, 118.25, 112.20, 111.90, 79.04, 59.01, 46.65,
17.72. HRMS calcd for C22H22N3O2F3 (MH)+ 418.1742, found 416.1611.
(E)-3-[4-({(3,3-Difluoro-propyl)-[2-(2-methyl-1H-indol-3-yl)-ethyl]-
amino}-methyl)-phenyl]-N-hydroxy-acrylamide (11g). Following
method B, the title compound (200 mg, 53% yield) was prepared
from 9g (380 mg, 0.85 mmol). 1H NMR (400 MHz, CD3OD) δ 7.59
(d, J = 15.4 Hz, 1 H), 7.51 (d, J = 7.9 Hz, 2 H), 7.38 (d, J = 8.2 Hz, 2 H),
7.21 (d, J = 3.4 Hz, 1 H), 7.19 (d, J = 3.7 Hz, 1 H), 6.96 (td, J = 7.5, 1.2
Hz, 1 H), 6.86 (td, J = 7.5, 1.3 Hz, 1 H), 6.48 (d, J = 15.3 Hz, 1 H), 3.81
(s, 2 H), 2.93 (t, J = 13.2 Hz, 2 H), 2.86ꢀ2.82 (m, 2 H), 2.75ꢀ2.71 (m,
2 H), 2.26 (s, 3 H), 1.58 (t, J = 19.2 Hz, 3 H). MS m/z 428.3 (MH+).
HRMS calcd for C24H27N3O2F2 (MH+) 428.2150, found 428.2148.
(E)-N-Hydroxy-3-(4-{[[2-(1H-indol-3-yl)-ethyl]-(3,3,3-trifluoro-propyl)-
amino]-methyl}-phenyl)-acrylamide (11h). Following method B, the
title compound (33 mg, 21% yield) was prepared from 9h (160 mg,
1
0.46 mmol). H NMR (400 MHz, CDCl3) δ 7.80 (s, 1 H), 7.74 (d,
J = 15.9 Hz, 1 H), 7.49 (d, J = 8.9 Hz, 2 H), 7.40 (d, J = 8.0 Hz, 2 H), 7.38
(d, J = 7.3 Hz, 1 H), 7.26 (d, J = 8.1 Hz, 1 H), 7.13 (t, J = 7.5 Hz, 1 H),
7.06 (t, J = 7.5 Hz, 1 H), 6.48 (d, J = 15.7 Hz, 1 H), 4.58 (dt, J = 47.6, 5.3
Hz, 2 H), 3.86 (s, 3 H), 3.83 (s, 2 H), 3.01ꢀ2.78 (m, 6 H), 2.32 (s, 3 H).
MS m/z 395.2 (MH+).
(E)-3-[4-({(2,2-Difluoro-ethyl)-[2-(2-methyl-1H-indol-3-yl)-ethyl]-
amino}-methyl)-phenyl]-acrylic Acid Methyl Ester (9d). Following
method A, the title compound (400 mg, 81% yield) was prepared from
8d (550 mg, 2.1 mmol) and (2-methyl-1H-indol-3-yl)-acetaldehyde
(200 mg, 1.2 mmol). 1H NMR (400 MHz, CDCl3) δ 7.75 (br, 1 H), 7.72
(d, J = 15.8 Hz, 1 H), 7.49 (d, J = 7.9 Hz, 2 H), 7.41ꢀ7.37 (m, 2 H), 7.34
(d, J = 7.8 Hz, 1 H), 7.27 (d, J = 8.2 Hz, 1 H), 7.11 (td, J = 7.5, 1.3 Hz,
1 H), 7.04 (td, J = 7.5, 0.9 Hz, 1 H), 6.46 (d, J = 15.6 Hz, 1 H), 5.81 (t, J =
56.2 Hz, 1 H), 3.85 (s, 2 H), 3.84 (s, 3 H), 3.00 (td, J = 14.4, 3.8 Hz, 2 H),
2.89ꢀ2.83 (m, 4 H), 2.32 (s, 3 H). MS m/z 413.2 (MH+).
(E)-3-(4-{[[2-(1H-Indol-3-yl)-ethyl]-(2,2,2-trifluoro-ethyl)-amino]-
methyl}-phenyl)-acrylic Acid Methyl Ester (9e). 2,2,2-Trifluoro-ethane-
1,1-diol (100 mg, 0.90 mmol) and p-toluenesulfonic acid (6 mg,
0.03 mmol) were added to a solution of (E)-3-(4-{[2-(1H-indol-3-yl)-
ethylamino]-methyl}-phenyl)-acrylic acid methyl ester (200 mg,
0.60 mmol) in toluene (2 mL). The mixture was stirred at reflux
temperature under DeanꢀStark trap. Upon the completion of reaction,
THF (2 mL) and sodium triacetoxyborohydride (150 mg, 0.72 mmol)
were added. The resulting mixture was stirred at room temperature, and
then sodium bicarbonate solution was added. The aqueous layer was
extracted several times with EtOAc. The combined organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated. The
resulting crude product was purified via flash column chromatography to
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afford a white powder (215 mg, 86% yield). H NMR (CDCl3) δ
ppm 8.0 (br s, 1H), 7.72 (d, J = 16.0 Hz, 1 H), 7.61 (d, J = 8.6 Hz, 1 H),
7.54 (m, 4 H), 7.41 (d, J = 8.2 Hz, 1 H), 7.29 (m, 2 H), 7.20 (d, J = 7.7 Hz,
1 H), 6.48 (d, J = 16.0 Hz, 1 H), 4.29 (br s, 1 H), 4.14 (m, 5 H), 3.91 (s,
1 H), 3.84 (s, 4 H), 3.56 (m, 1 H), 3.35 (m, 1 H), 3.07 (br s, 1 H), 2.78
(m, 1 H), 2.07 (m, 2 H), 1.8 (m, 1 H).
(E)-3-[4-({(3,3-Difluoro-propyl)-[2-(2-methyl-1H-indol-3-yl)-ethyl]-
amino}-methyl)-phenyl]-acrylic Acid Methyl Ester (9g). Following
method A, the title compound (380 mg, 74% yield) was prepared from
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dx.doi.org/10.1021/jm200388e |J. Med. Chem. 2011, 54, 4752–4772