10.1002/ejoc.201901001
European Journal of Organic Chemistry
FULL PAPER
J = 7.4, 2.2 Hz, 1H), 3.90 (q, J = 7.3 Hz, 1H), 3.79 (q, J = 7.3 Hz, 1H),
3.59 (s, 3H), 3.52 – 3.41 (m, 1H), 3.16 (qd, J = 7.2, 2.0 Hz, 1H), 3.12 –
3.03 (m, 2H), 2.40 (q, J = 9.9, 8.4 Hz, 2H), 2.15 (s, 3H), 2.07 (s, 3H), 2.04
– 1.96 (m, 1H), 1.92 (q, J = 9.6 Hz, 1H), 1.85 (q, J = 9.6 Hz, 1H), 1.77 –
1.71 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 163.9, 149.3, 144.4,
137.1, 136.7, 121.9, 121.6, 115.2, 79.3, 66.5, 62.2, 49.3, 38.7, 37.9,
35.9, 34.8, 34.2, 12.9, 9.9. LCMS (CI): m/z = 327 [M+H]+. Anal. Calcd. for
C19H26N4O: C 69.91; H 8.03; N 17.16. Found: C 70.21; H 8.38; N 16.76.
Calcd. for C19H23N5: C 71.00; H 7.21; N 21.79. Found: C 71.13; H 7.21; N
21.51.
(R)-N-((1-(Methylsulfonyl)pyrrolidin-2-yl)methyl)-3-(pyridin-2-
yl)cyclobutanamine (15{1,12}). The compound was obtained as ca. 2:1
1
mixture of diastereomers. Yield 62.2 mg (62%); yellow oil. H NMR (500
MHz, DMSO-d6) δ 8.51 (d, J = 2.5 Hz, 0.33H) and 8.48 (d, J = 2.5 Hz,
0.66H), 7.69 – 7.64 (m, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.17 (dd, J = 7.6,
4.7 Hz, 1H), 3.65 – 3.59 (m, 1H), 3.57 – 3.53 (m, 0.34H) and 3.43 – 3.38
(m, 0.66H), 3.26 – 3.20 (m, 2H), 3.20 – 3.09 (m, 2H), 2.88 (s, 2H) and
2.87 (s, 1H), 2.65 – 2.60 (m, 1H), 2.47 – 2.43 (m, 1H), 2.41 – 2.29 (m,
1H), 2.16 – 2.05 (m, 1H), 1.96 – 1.76 (m, 6H). 13C NMR (126 MHz,
DMSO-d6) δ 165.0 and 163.9, 149.5 and 149.3, 136.8 and 136.7, 121.9
and 121.9, 121.6 and 121.5, 60.1 and 60.0, 51.7 and 51.5, 51.4 and
50.2, 49.2, 37.6 and 35.6, 37.4 and 35.5, 36.3 and 34.7, 34.1 and 34.0,
29.6 and 29.6, 24.3 and 24.3. LCMS (CI): m/z = 310 [M+H]+. Anal. Calcd.
for C15H23N3O2S: C 58.22; H 7.49; N 13.58; S 10.36. Found: C 58.53; H
7.67; N 13.49; S 10.37.
(R)-8-Methyl-N-(3-(pyridin-4-yl)cyclobutyl)chroman-4-amine
(15{3,3}). Yield 39.4 mg (79%); yellow oil. 1H NMR (500 MHz, DMSO-d6)
δ 8.51 – 8.41 (d, J = 3.1 Hz, 2H), 7.28 (d, J = 3.1 Hz, 2H), 7.09 (d, J = 6.7
Hz, 1H), 6.97 (d, J = 6.7 Hz, 1H), 6.73 (t, J = 7.3 Hz, 1H), 4.31 – 4.25 (m,
1H), 4.21 – 4.15 (m, 1H), 3.70 (s, 1H), 3.06 (quint, J = 8.6 Hz, 1H), 2.63
(quint, J = 7.4 Hz, 2H), 2.42 – 2.13 (m, 2H), 2.08 (s, 3H), 1.97 – 1.78 (m,
4H). 13C NMR (126 MHz, DMSO-d6) δ 154.6, 152.9, 149.8, 129.5, 128.2,
125.0, 124.7, 122.7, 119.4, 62.7, 49.4, 47.8, 39.0, 32.2, 28.4, 16.4.
LCMS (CI): m/z = 295 [M+H]+. Anal. Calcd. for C19H22N2O: C 77.52; H
7.53; N 9.52. Found: C 77.45; H 7.33; N 9.75.
1,1,1-Trifluoro-2-(1-methyl-1H-imidazol-2-yl)-4-((3-(pyridin-2-
1-(3-Chloropyridin-2-yl)-N-(3-(pyridin-3-yl)cyclobutyl)pyrrolidin-3-
amine (15{2,4}). The compound was obtained as ca. 2:1 mixture of
diastereomers. Yield 38.9 mg (78%); yellow oil. 1H NMR (500 MHz,
CDCl3) δ 8.53 (s, 0H), 8.46 (s, 0.33H) and 8.43 (d, J = 4.7Hz, 0.67H),
8.05 (d, J = 4.7 Hz, 1H), 7.59 (d, J = 7.9 Hz, 0.33H) and 7.55 (d, J = 7.9
Hz, 0.67H), 7.46 (d, J = 7.6 Hz, 1H), 7.26 – 7.20 (m, 1H), 6.58 (dd, J =
7.7, 4.7 Hz, 1H), 3.88 – 3.83 (m, 1H), 3.81 – 3.71 (m, 2H), 3.65 – 3.58
(m, 0.67H) and 3.48 – 3.38 (m, 1.67H) and 3.21 – 3.14 (m, 0.67H), 3.55
– 3.49 (m, 1H), 2.84 – 2.75 (m, 1.33H) and 2.48 – 2.43 (m, 0.67H), 2.34
(tt, J = 9.5, 5.3 Hz, 1H), 2.20 – 2.03 (m, 2H), 1.91 – 1.86 (m, 1H), 1.83 –
1.75 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 155.2, 148.7 and 148.5,
147.4 and 147.3, 145.4, 140.8 and 139.4, 138.9, 133.9, 123.3 and 123.2,
116.7, 114.1, 55.8 and 55.8, 55.8 and 55.7, 50.1 and 49.2, 48.1, 39.1
and 39.1, 36.7, 32.3 and 32.2, 32.0 and 30.6. LCMS (CI): m/z = 329
[M+H]+. Anal. Calcd. for C18H21ClN4: C 65.75; H 6.44; N 17.04; Cl 10.78.
Found: C 65.69; H 6.57; N 16.95; Cl 10.77.
yl)cyclobutyl)amino)butan-2-ol (15{1,13}). The compound existed as
ca. 2:1 mixture of diastereomers. Yield 64.6 mg (59%); yellowish oil. 1H
NMR (500 MHz, DMSO-d6) δ 8.53 – 8.47 (m, 1H), 7.67 (t, J = 7.2 Hz,
1H), 7.24 – 7.20 (m, 1H), 7.17 (dd, J = 7.5, 4.7 Hz, 1H), 7.13 (d, J = 6.4
Hz, 1H), 6.86 (d, J = 3.3 Hz, 1H), 3.83 (s, 1H), 3.80 (s, 2H), 3.58 – 3.53
(m, 0.33H), 3.49 – 3.40 (m, 0.67H), 3.23 – 3.05 (m, 2H), 2.85 – 2.78 (m,
1H), 2.63 – 2.54 (m, 2H), 2.48 – 2.38 (m, 1.67H), 2.38 – 2.32 (m, 0.33H),
2.31 – 2.25 (m, 0.33H), 2.17 – 1.97 (m, 1.67H), 1.99 – 1.74 (m, 2H). 13C
NMR (126 MHz, DMSO-d6) δ 164.4, 163.5, 149.5 and 149.3, 142.7,
136.8 and 136.8, 127.0 and 126.9, 125.0, 124.6, 121.8 (d, J = 13.7 Hz),
77.7 (q, J = 28.4 Hz), 50.4 and 48.8, 42.5 and 42.3, 36.5 and 36.4, 36.1
and 35.6, 34.6 and 34.3, 30.8 and 30.6. 19F NMR (470 MHz, dmso) δ -
79.1, -79.2. LCMS (CI): m/z = 355 [M+H]+. Anal. Calcd. for C17H21F3N4O:
C 57.62; H 5.97; N 15.81. Found: C 57.24; H 6.23; N 16.18.
(S)-2-((3-(Pyridin-4-yl)cyclobutyl)amino)propan-1-ol (15{3,14}). The
compound was obtained as ca. 2:1 mixture of diastereomers. Yield 29.4
mg (59%); yellow oil. 1H NMR (500 MHz, DMSO-d6) δ 8.59 – 8.30 (m,
2H), 7.28 (d, J = 3.9 Hz, 1H), 7.26 – 7.13 (m, 1H), 4.38 (s, 1H), 3.51 –
3.39 (m, 1H), 3.31 – 3.13 (m, 4H), 3.11 – 2.99 (m, 1H), 2.67 – 2.61 (m,
0.67H) and 2.33 – 2.12 (m, 1.33H), 2.59 – 2.56 (m, 0.67H) and 1.83 –
1.65 (m, 1.33H), 1.09 – 0.68 (m, 3H). 13C NMR (126 MHz, DMSO-d6) δ
155.4 and 154.5, 150.0 and 149.8, 122.6, 66.2 and 66.0, 53.2 and 53.1,
49.2 and 48.0, 39.0 and 36.6, 38.9 and 36.9, 33.5 and 32.1, 18.1 and
18.0. LCMS (CI): m/z = 207 [M+H]+. Anal. Calcd. for C12H18N2O: C 69.87;
H 8.80; N 13.58. Found: C 70.27; H 8.74; N 13.70.
2-((3-(Pyridin-2-yl)cyclobutyl)amino)-2-(2-(trifluoromethoxy)phenyl)-
ethanol (15{1,8}). The compound was obtained as ca. 1:1 mixture of
diastereomers. Yield 69.8 mg (69%); yellowish solid. 1H NMR (500 MHz,
DMSO-d6) δ 8.49 (d, J = 4.8 Hz, 0.5H) and 8.44 (d, J = 4.8 Hz, 0.5H),
7.71 – 7.58 (m, 2H), 7.41 – 7.32 (m, 2H), 7.28 (t, J = 8.9 Hz, 1H), 7.21 –
7.10 (m, 2H), 5.02 (s, 1H), 4.06 (ddd, J = 13.8, 8.1, 4.2 Hz, 1H), 3.55 –
3.49 (m, 1H), 3.46 – 3.40 (m, 1H), 3.22 (quint, J = 7.1 Hz, 1H), 3.07
(quint, J = 9.1 Hz, 1H), 2.93 (quint, J = 8.1 Hz, 1H), 2.46 – 2.43 (m, 1H),
2.33 – 2.24 (m, 2H), 2.16 (q, J = 9.1 Hz, 1H), 2.08 (q, J = 9.1 Hz, 1H),
1.91 (q, J = 9.1 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 164.9, 163.7,
149.5 and 149.4, 147.4, 136.8 and 136.7, 135.1 and 135.0, 129.7 and
129.7, 128.9 and 128.9, 127.8, 121.9 and 121.9, 121.7 and 121.5, 120.7,
65.5, 55.4 and 55.4, 49.3 and 48.1, 38.0 and 37.5, 36.0 and 35.7, 35.7
and 34.6. 19F NMR (470 MHz, dmso) δ -55.8, -55.9. LCMS (CI): m/z =
353 [M+H]+. Anal. Calcd. for C18H19F3N2O2: C 61.36; H 5.44; N 7.95.
Found: C 61.51; H 5.35; N 7.69.
1-Methyl-N-(3-(pyridin-4-yl)cyclobutyl)piperidin-4-amine (15{3,16}).
The compound was obtained as ca. 3:2 mixture of diastereomers. Yield
28.0 mg (56%); yellow oil. 1H NMR (500 MHz, DMSO-d6) δ 8.48 – 8.42
(m, 2H), 7.27 (d, J = 5.1 Hz, 0.8H) and 7.24 (d, J = 5.1 Hz, 1.2H), 3.46 –
3.42 (m, 1H), 3.20 (quint, J = 7.6 Hz, 1H), 3.14 (s, 1H), 3.07 – 2.96 (m,
1H), 2.65 (d, J = 10.7 Hz, 2H), 2.55 (qd, J = 7.6, 2.8 Hz, 2H), 2.37 – 2.31
(m, 1H), 2.29 – 2.22 (m, 1H), 2.21 – 2.14 (m, 1H), 1.82 (t, J = 11.6 Hz,
2H), 1.75 (q, J = 10.7 Hz, 2H), 1.68 (d, J = 11.6 Hz, 2H), 1.28 – 1.17 (m,
2H). 13C NMR (126 MHz, DMSO-d6) δ 155.4 and 154.6, 150.0 and 149.8,
122.6 and 122.6, 54.7 and 54.6, 52.8, 49.0 and 47.9, 46.5, 39.3, 36.9,
33.6 and 33.1, 33.1 and 32.3. LCMS (CI): m/z = 246 [M+H]+. Anal. Calcd.
for C15H23N3: C 73.43; H 9.45; N 17.13. Found: C 73.05; H 9.57; N 17.37.
N-(1-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-2-methylpropyl)-3-(pyridin-4-
yl)cyclobutanamine (15{3,11}). The compound was obtained as ca. 2:1
1
mixture of diastereomers. Yield 31.5 mg (63%); yellow oil. H NMR (500
MHz, DMSO-d6) δ 8.74 – 8.68 (m, 1H), 8.40 (d, J = 4.3 Hz, 2H), 7.72 (d,
J = 9.3 Hz, 1H), 7.32 (dd, J = 9.3, 6.6 Hz, 1H), 7.15 (d, J = 4.3 Hz, 2H),
6.94 (t, J = 6.6 Hz, 1H), 4.10 – 4.01 (m, 1H), 3.13 – 3.04 (m, 0.33H) and
2.87 (quint, J = 7.6 Hz, 1.67H), 2.69 (s, 1H), 2.47 – 2.36 (m, 1H), 2.23 –
2.18 (m, 1H), 2.14 – 2.09 (m, 0.33H) and 1.74 (q, J = 9.9 Hz, 0.67H),
2.00 – 1.90 (m, 1H), 1.87 – 1.82 (m, 0.33H) and 1.57 (q, J = 9.9 Hz,
0.67H), 1.05 (d, J = 6.5 Hz, 3H), 0.72 (d, J = 6.9 Hz, 1H) and 0.69 (d, J =
6.9 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 154.2, 149.9 and 149.8,
149.0, 148.0, 127.7, 125.1 and 125.0, 122.5 and 122.4, 115.9, 113.5,
59.5 and 59.1, 50.0 and 48.8, 38.1 and 35.7, 38.0 and 35.9 33.5, 31.9
and 31.8, 20.4 and 20.3, 19.8. LCMS (CI): m/z = 322 [M+H]+. Anal.
N-(3-(Pyridin-4-yl)cyclobutyl)-1-((tetrahydrofuran-3-yl)methyl)-
piperidin-4-amine (15{3,18}). The compound was obtained as ca. 3:2
1
mixture of diastereomers. Yield 27.8 mg (56%); yellow oil. H NMR (500
MHz, DMSO-d6) δ 8.44 (s, 2H), 7.28 (d, J = 3.2 Hz, 0.8H), 7.24 (d, J =
3.2 Hz, 1.2H), 3.71 – 3.65 (m, 2H), 3.58 (q, J = 6.8 Hz, 1H), 3.47 – 3.42
(m, 1H), 3.26 – 3.15 (m, 2H), 3.03 (quint, J = 9.1 Hz, 1H), 2.79 (d, J =
11.0 Hz, 1H), 2.73 (d, J = 11.2 Hz, 1H), 2.55 (q, J = 8.2 Hz, 1H), 2.40 –
2.33 (m, 2H), 2.30 – 2.23 (m, 1.2H), 2.21 – 2.12 (m, 2.8H), 1.91 – 1.82
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