54
N. Drinkwater et al. / European Journal of Medicinal Chemistry 110 (2016) 43e64
J
CF ¼ 30.0 Hz), 127.7, 126.7, 126.2 (q, JCF ¼ 5.3 Hz), 124.2 (q,
4.2.26. Methyl 2-((tert-butoxycarbonyl)amino)-2-(4-(thiophen-3-
yl)phenyl)acetate (7k)
þ
J
C
CF ¼ 273.6 Hz), 80.4, 57.5, 52.9, 28.4; m/z MS (TOF ES )
H F
22 3
NNaO
4
[MþNa]þ calcd 432.1; found 432.2; LC-MS t
R
:
Thiophen-3-ylboronic acid (111 mg) underwent Suzuki coupling
21
4
.11 min.
according to General Procedure C, to give 135 mg (67%) of yellow
1
solid. H NMR
d 7.64e7.53 (m, 2H), 7.44 (s, 1H), 7.42e7.31 (m, 4H),
0
5.61 (d, J ¼ 6.6 Hz, 1H), 5.34 (d, J ¼ 7.2 Hz, 1H), 3.73 (s, 3H), 1.61e1.18
4
.2.21. Methyl 2-((tert-butoxycarbonyl)amino)-2-(3 -
13
0
(m, 9H); C NMR
d
171.7,154.9,141.7,136.2,135.8,127.7,127.1, 126.5,
(
trifluoromethyl)-[1,1 -biphenyl]-4-yl)acetate (7f)
þ
1
[
26.4, 120.8, 80.3, 57.4, 52.9, 28.4; m/z MS (TOF ES ) C18
H
21NNaO
4
S
3
-(Trifluoromethyl)phenylboronic acid (165 mg) underwent
Suzuki coupling according to General Procedure C, to give 181 mg
MþNa]þ calcd 370.1; found 370.2; LC-MS t
R
: 3.94 min.
1
(
76%) of colourless oil. H NMR
d
7.80 (s, 1H), 7.73 (d, J ¼ 7.6 Hz, 1H),
4.2.27. Methyl 2-((tert-butoxycarbonyl)amino)-2-(4-(1-methyl-
7
.65e7.51 (m, 4H), 7.47 (d, J ¼ 8.2 Hz, 2H), 5.91e5.09 (m, 2H), 3.75
19
13
1H-pyrazol-4-yl)phenyl)acetate (7l)
-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
pyrazole (181 mg) underwent Suzuki coupling according to General
(
s, 3H),1.57e1.12 (m, 9H); F NMR
d
ꢃ62.63; C NMR
d 171.6,155.0,
1
1
1
1
C
41.4, 140.0, 137.0, 131.3 (q, JCF ¼ 32.2 Hz), 130.5 (q, JCF ¼ 1.0 Hz),
29.4, 127.9, 127.9, 124.3 (q, JCF ¼ 3.6 Hz), 124.2 (q, JCF ¼ 272.4 Hz),
1
þ
Procedure C, to give 127 mg (64%) of off-white solid. H NMR
(s, 1H), 7.60 (s, 1H), 7.43 (d, J ¼ 8.3 Hz, 2H), 7.34 (d, J ¼ 8.2 Hz, 2H),
.83e5.49 (m, 1H), 5.47e5.22 (m, 1H), 3.94 (s, 3H), 3.71 (s, 3H),
d 7.74
24.0 (q, JCF ¼ 3.8 Hz), 80.5, 57.4, 53.0, 28.4; m/z MS (TOF ES )
[MþNa]þ calcd 432.1; found 432.2; LC-MS t
21
H F
22 3
NNaO
4
R
:
5
4
.15 min.
13
1.61e1.16 (m, 9H); C NMR
d
171.7, 154.9, 136.5, 135.1, 132.7, 127.8,
127.4, 126.1, 122.7, 80.3, 57.4, 52.8, 39.2, 28.4; m/z MS (TOF ES )
þ
0
4
.2.22. Methyl 2-((tert-butoxycarbonyl)amino)-2-(4 -
þ
0
C
18
24
H N
3
O
4
[MH] calcd 346.2; found 346.2; LC-MS t
R
: 3.62 min.
(
trifluoromethyl)-[1,1 -biphenyl]-4-yl)acetate (7g)
4
-(Trifluoromethyl)phenylboronic acid (165 mg) underwent
0
0
4
.2.28. Methyl 2-((tert-butoxycarbonyl)amino)-2-(3 -cyano-[1,1 -
Suzuki coupling according to General Procedure C, to give 196 mg
83%) of off-white solid. H NMR
1
biphenyl]-4-yl)acetate (7m)
-Cyanophenylboronic acid (128 mg) underwent Suzuki
coupling according to General Procedure C, to give 137 mg (64%) of
(
d
7.69 (d, J ¼ 8.6 Hz, 2H), 7.66 (d,
3
J ¼ 8.7 Hz, 2H), 7.58 (d, J ¼ 8.2 Hz, 2H), 7.48 (d, J ¼ 8.3 Hz, 2H),
19
5
d
.88e5.01 (m, 2H), 3.74 (s, 3H), 1.82e1.10 (m, 9H); F NMR
1
13
clear, colourless oil. H NMR
.62 (ddd, J ¼ 7.7/1.3/1.3 Hz, 1H), 7.57e7.50 (m, 3H), 7.47 (d,
J ¼ 8.3 Hz, 2H), 5.71 (d, J ¼ 6.8 Hz,1H), 5.38 (d, J ¼ 7.1 Hz,1H), 3.73 (s,
d
7.82 (s, 1H), 7.77 (d, J ¼ 7.9 Hz, 1H),
ꢃ62.43; C NMR
d 171.5, 154.9, 144.1, 140.0, 137.2, 129.6 (q,
7
J
J
C
4
CF ¼ 32.4 Hz), 127.9, 127.9, 127.5, 125.9 (q, JCF ¼ 3.7 Hz), 124.3 (q,
þ
CF ¼ 272.0 Hz), 80.4, 57.4, 52.9, 28.4; m/z MS (TOF ES )
13
[MþNa]þ calcd 432.1; found 432.2; LC-MS t
3H), 1.70e0.94 (m, 9H); C NMR d 171.4, 154.9, 141.8, 139.0, 137.4,
21
H
F
22 3
NNaO
4
R
:
1
2
3
31.5, 131.0, 130.7, 129.8, 128.0, 127.7, 118.8, 113.1, 80.4, 57.3, 53.0,
.15 min.
þ
[MþNa]þ calcd 389.1 found
8.4; m/z MS (TOF ES ) C21
89.2; LC-MS t : 3.87 min.
22 2 4
H N NaO
R
0
0
0
4
.2.23. Methyl 2-((tert-butoxycarbonyl)amino)-2-(3 ,4 ,5 -
trifluoro-[1,1 -biphenyl]-4-yl)acetate (7h)
0
0 0
.2.29. Methyl 2-((tert-butoxycarbonyl)amino)-2-(4 -cyano-[1,1 -
biphenyl]-4-yl)acetate (7n)
-Cyanophenylboronic acid (128 mg) underwent Suzuki
coupling according to General Procedure C, to give 158 mg (74%) of
4
3
,4,5-Trifluorophenylboronic acid (153 mg) underwent Suzuki
coupling according to General Procedure C, to give 158 mg (69%) of
white solid. H NMR
4
1
d
7.48 (d, J ¼ 8.6 Hz, 2H), 7.45 (d, J ¼ 8.6 Hz, 2H),
7
.16 (dd, J ¼ 8.1/6.8 Hz, 2H), 5.69 (d, J ¼ 4.2 Hz, 1H), 5.37 (d,
1
white solid. H NMR
d
7.71 (d, J ¼ 8.4 Hz, 2H), 7.65 (d, J ¼ 8.3 Hz, 2H),
1
9
J ¼ 7.0 Hz,1H), 3.74 (s, 3H),1.64e1.11 (m, 9H); F NMR
d
ꢃ133.95 (d,
7
1
d
.57 (d, J ¼ 8.3 Hz, 2H), 7.48 (d, J ¼ 8.3 Hz, 2H), 5.70 (d, J ¼ 6.7 Hz,
13
J ¼ 20.5 Hz), ꢃ162.26 (dd, J ¼ 20.4/20.4 Hz); C NMR
d
171.4, 154.9,
13
H), 5.38 (d, J ¼ 7.1 Hz, 1H), 3.73 (s, 3H), 1.57e1.20 (m, 9H); C NMR
1
1
5
4
51.5 (ddd, JCF ¼ 249.8/10.0, 4.2 Hz), 139.5 (ddd, JCF ¼ 251.4/16.1/
171.4, 154.8, 145.0, 139.3, 137.7, 132.7, 127.9, 127.82, 127.77, 118.9,
6.1 Hz), 137.5, 136.7, 127.9, 127.5, 111.2 (dd, JCF ¼ 15.9/6.0 Hz), 80.5,
þ
þ
1
23 2 4
11.2, 80.4, 57.3, 53.0, 28.4; m/z MS (TOF ES ) C21H N O [MH]
þ
[MþNa]þ calcd
20 3 4
7.3, 53.0, 28.4; m/z MS (TOF ES ) C20H F NNaO
R
calcd 367.2; found 367.2; LC-MS t : 3.85 min.
18.1; found 418.2; LC-MS t
R
: 4.11 min.
0
4
.2.30. Methyl 3-([1,1 -biphenyl]-4-yl)-2-((tert-butoxycarbonyl)
4
.2.24. Methyl 2-((tert-butoxycarbonyl)amino)-2-(4-(pyridin-3-yl)
amino)propanoate (7o)
Phenylboronic acid (102 mg) underwent Suzuki coupling ac-
cording to General Procedure C, to give 135 mg (68%) of white solid.
phenyl)acetate (7i)
Pyridin-3-ylboronic acid (107 mg) underwent Suzuki coupling
according to General Procedure C, to give 120 mg (60%) of yellow
solid. H NMR
1
1
d
1
H NMR
.23e7.17 (m, 2H), 5.02 (br. d, J ¼ 8.0 Hz, 1H), 4.63 (dd, J ¼ 13.9/
.1 Hz, 1H), 3.74 (s, 3H), 3.17 (dd, J ¼ 13.8/5.7 Hz, 1H), 3.09 (dd,
d 7.60e7.50 (m, 4H), 7.47e7.40 (m, 2H), 7.37e7.31 (m, 1H),
1
d
8.82 (s, 1H), 8.60 (d, J ¼ 4.5 Hz, 1H), 8.02e7.82 (m,
7
6
H), 7.56 (d, J ¼ 8.3 Hz, 2H), 7.48 (d, J ¼ 8.2 Hz, 2H), 7.45e7.35 (m,
13
H), 5.93e5.03 (m, 2H), 3.74 (s, 3H), 1.75e0.96 (m, 9H); C NMR
13
J ¼ 13.8/6.1 Hz, 1H), 1.43 (s, 9H); C NMR
d 172.5, 155.3, 140.9, 140.1,
171.4, 154.9, 147.8, 147.4, 137.6, 137.4, 136.5, 135.3, 128.1, 127.8,
1
35.2, 129.9, 128.9, 127.4 (3 ꢂ CH), 127.2, 80.1, 54.5, 52.4, 38.1, 28.4;
þ
þ
124.0, 80.4, 57.4, 53.0, 28.4; m/z MS (TOF ES ) C19
H
23
N
2
O
4
[MH]
þ
[MþNa]þ calcd 378.2; found 378.2;
m/z MS (TOF ES ) C21
LC-MS t : 4.04 min.
H26NNaO
4
calcd 343.2; found 343.2; LC-MS t : 3.40 min.
R
R
4
.2.25. Methyl 2-((tert-butoxycarbonyl)amino)-2-(4-(pyridin-4-yl)
4.2.31. Methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(1-methyl-
1H-pyrazol-4-yl)phenyl)propanoate (7p)
phenyl)acetate (7j)
Pyridin-4-ylboronic acid (107 mg) underwent Suzuki coupling
according to General Procedure C, to give 170 mg (85%) of dark
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
pyrazole (174 mg) underwent Suzuki coupling according to General
brown oil. 1H NMR
d
8.66 (s, 2H), 7.89e7.30 (m, 6H), 5.75 (d,
Procedure C, to give 148 mg (74%) of white solid. H NMR
1
d
7.73 (d,
13
J ¼ 4.8 Hz, 1H), 5.39 (d, J ¼ 6.4 Hz, 1H), 3.73 (s, 3H), 1.43 (s, 9H);
NMR 171.3,154.9,149.7,148.5,138.5,138.0,128.0,127.7,121.9, 80.5,
7.4, 53.0, 28.4; m/z MS (TOF ES ) C19
found 343.2; LC-MS t : 3.28 min.
C
J ¼ 0.7 Hz,1H), 7.58 (s,1H), 7.41e7.36 (m, 2H), 7.11 (app. d, J ¼ 8.1 Hz,
2H), 5.00 (br. d, J ¼ 8.0 Hz, 1H), 4.58 (dd, J ¼ 13.8/6.0 Hz, 1H), 3.93 (s,
3H), 3.72 (s, 3H), 3.11 (dd, J ¼ 13.8/5.7 Hz, 1H), 3.04 (dd, J ¼ 13.8/
d
þ
þ
23 2 4
H N O [MH] calcd 343.2;
5
13
R
6.1 Hz, 1H), 1.41 (s, 9H); C NMR d 172.5, 155.2, 136.8, 134.1, 131.5,