BULLETIN OF THE
Article
Oxadiazole M Muscarinic Acetylcholine Receptor Agonists
KOREAN CHEMICAL SOCIETY
1
1
-((3-(2-(Pyrrolidin-1-yl)ethyl)-4,5-dihydro-1,2-oxazol-5-
161.3, 103.5, 61.4, 58.0, 47.8, 46.9, 38.5, 34.2, 32.8, 29.5,
25.4, 18.2.
1
yl)methyl)pyrrolidin-2-one (3c). H NMR (400 MHz,
CDCl ): δ 4.75–4.68 (m, 1H), 3.64–3.50 (m, 3H),
3
1-((5-((1-Methylpyrrolidin-2-yl)methyl)-1,2,4-oxadiazol-3-
3
2
1
1
2
.41–3.37 (m, 1H), 3.11–3.01 (m, 1H), 2.84–2.67 (m, 3H),
1
yl)methyl)pyrrolidin-2-one (6b). H NMR (400 MHz,
.58–2.53 (m, 6H), 2.41–2.35 (m, 2H), 2.05–2.01 (m, 2H),
CDCl ) δ 4.58 (s, 2H), 3.46 (t, J = 7.0 Hz, 2H), 3.17 (dd,
3
13
.81 (m, 4H). C NMR (100 MHz, CDCl ): δ 176.2,
3
J = 4.1 Hz, 14.8 Hz, 1H), 3.06–3.03 (ddd, J = 2.0 Hz,
58.4, 79.33, 54.3, 54.3, 53.0, 49.52, 46.5, 40.5, 31.1,
7.7, 23.9, 23.8, 18.7.
9
2
2
1
.0 Hz, 18.4 Hz, 1H), 2.85 (dd, J = 8.7 Hz, 14.8 Hz, 1H),
.62–2.65 (m, 1H), 2.45 (t, J = 8.1 Hz, 2H), 2.36 (s, 3H),
.26 (q, J = 8.8 Hz, 1H), 2.08 (quin, J = 7.6 Hz, 2H),
l-((3-(Pyridin-3-yl)-4,5-dihydro-1,2-oxazol-5-yl)methyl)-
13
1
.99–2.02 (m, 1H), 1.60–1.79 (m, 3H).
C NMR
pyrrolidin-2-one (3d). H NMR (400 MHz, CDCl ): δ 8.86
3
(
4
100 MHz, CDCl ) δ 179.2, 175.2, 166.8, 63.7, 57.3, 47.6,
(s, 1H), 8.74 (d, J = 1.7 Hz, 1H), 8.35 (d, J = 1.7 Hz, 1H),
3
0.8, 38.6, 31.8, 31.2, 30.8, 22.4, 18.2.
8.05 (dd, J = 2.3 Hz, 2.4 Hz, 1H), 5.01–4.96 (m, 1H),
3.68–3.50 (m, 4H), 3.48–3.19 (m, 2H), 2.41–2.34 (m, 2H),
2.03–1.95 (m, 2H).
1-(5-((1-Methylpyrrolidin-3-yl)-1,2,4-oxadiazol-3-yl)
1
methyl)pyrrolidin-2-one (6c). H NMR (400 MHz, CDCl )
3
δ 4.59 (s, 2H), 3.60–3.66 (m, 1H), 3.48 (t, J = 3.5 Hz,
2H), 2.97 (t, J = 8.7 Hz, 1H), 2.82 (dd, J = 6.4, 9.4 Hz,
1
-((3-(1-Methylpiperidin-3-yl)-1,2-isoxazol-5-yl)methyl)
1
pyrrolidin-2-one (4a). H NMR (400 MHz, CDCl ): δ 6.08
3
1
2
H), 2.68 (t, J = 7.0 Hz, 2H), 2.45 (t, J = 8.1 Hz, 2H),
.40 (s, 3H), 2.32–2.38 (m, 1H), 2.16–2.30 (m, 1H), 2.09
(
(
(
(
s, 1H), 4.54 (s, 2H), 3.47 (t, J = 7.00 Hz, 2H), 3.05–2.97
m, 2H), 2.86–2.83 (m, 1H), 2.42 (t, J = 7.9 Hz, 2H), 2.31
s, 3H), 2.11–1.95 (m, 4H), 1.82–1.71 (m, 2H), 1.47–1.42
13
(
quin, J = 7.6 Hz, 2H). C NMR (100 MHz, CDCl ) δ
3
13
183.0, 175.7, 166.8, 60.4, 56.1, 47.6, 42.6, 42.1, 38.7,
m, 2H). C NMR (100 MHz, CDCl ): δ 175.4, 167.7,
3
3
6.1, 30.8, 30.2, 18.2.
1
2
66.5, 101.7, 60.3, 56.1, 47.8, 46.9, 38.5, 35.2, 30.8, 29.5,
5.4, 18.2.
1
2
-((5-(Pyridin-3-yl)-1,2,4-oxadiazol-3-yl)methyl)pyrrolidin-
1
-one (6d). H NMR (400 MHz, CDCl ) δ 9.29 (d,
3
l-((3-(Pyridin-3-yl)-1,2-oxazol-5-yl)methyl)-pyrrolidin-2-
one (4d). H NMR (400 MHz, CDCl ): δ 9.01 (d,
J = 1.90 Hz, 1H), 8.67 (dd, J = 1.80 Hz, 1.70 Hz, 1H),
J = 1.60 Hz, 1H), 8.78 (dd, J = 1.6 Hz, 4.9 Hz, 1H), 8.35
1
3
(tt, J = 1.90 Hz, 8.00 Hz, 1H), 7.46 (ddd, J = 0.6 Hz,
4
2
.9 Hz, 7.9 Hz, 1H), 4.69 (s, 2H), 3.53 (t, J = 7.0 Hz, 2H),
.47 (t, J = 8.1 Hz, 2H), 2.06–2.18 (m, 2H). C NMR
8.05 (tt, J = 2.3 Hz, 2.1 Hz, 1H), 7.35–7.39 (m, 1H), 6.59
13
(s, 1H), 4.66 (s, 2H), 3.52 (t, J = 7.0 Hz, 2H), 2.4 (t,
(
1
100 MHz, CDCl ) δ 175.8, 175.6, 167.8, 153.9, 149.5,
3
1
3
J = 7.9 Hz, 2H), 2.15–2.05 (m, 2H). C NMR (100 MHz,
35.7, 124.2, 120.7, 47.6, 38.6, 30.7, 18.2.
CDCl ): δ 175.2, 169.0, 160.2, 151.2, 147.9, 134.0, 124.9,
3
1
-((5-(1-Azabicyclo[2.2.2]octan-3-yl)-1,2,4-oxadiazol-3-yl)
123.8, 100.7, 47.4, 38.2, 30.4, 17.9.
1
methyl)pyrrolidin-2-one (6e). H NMR (400 MHz, CDCl )
3
General procedure for the preparation of 6a–6f: 1-(2-
δ 4.62 (s, 2H), 3.51 (t, J = 7.1 Hz, 2H), 3.28–3.34 (m,
Oxopyrrolidin-1-yl)acetamidoxime (2.40 equiv) was stirred
in dry THF with 4 Å MS for 1 h, and NaH (60% in oil, 3.0
equiv) was added and stirred for 50 min and then heated at
2
H), 3.16–3.19 (m, 1H), 2.84–2.97 (m, 4H), 2.46 (t,
J = 10.8 Hz, 2H), 2.22 (td, J = 3.0 Hz, 5.9 Hz, 1H), 2.10
(
q, J = 7.6 Hz, 2H), 1.68–1.74 (m, 2H), 1.55–1.59 (m,
ꢀ
50 C for 30 min. A solution of an ester 5a–5f (1.0 equiv)
13
1
1
3
H), 1.42–1.47 (m, 1H). C NMR (100 MHz, CDCl ) δ
3
in THF was added dropwise and the reaction mixture
was heated under reflux for 1.5 h. After cooling, solvent
was removed from the reaction mixture and the residue was
extracted with CH Cl . The organic extract was concen-
82.9, 175.7, 166.8, 51.5, 47.7, 47.6, 47.2, 38.7, 35.4,
0.8, 26.7, 26.0, 22.0, 18.3.
1
-(5-((1-Azabicyclo[2.2.1]heptan-3-yl)-1,2,4-oxadiazol-3-
2
2
yl)methyl)pyrrolidin-2-one (exo-6f)
trated in vacuo, and the residue was purified by column
chromatography on silica gel using chloroform/methanol
(approximately 30:1–10:1) as eluent to obtain the corre-
sponding compound 6a–6f. The isomeric mixtures obtained
from exo-5f and endo-5f were separated by using ethylace-
tate/methanol–chloroform/methanol (10:1–10:1) as eluent
to give compounds exo-6f and endo-6f (60% and 9% from
exo-5f; 48% and 13% from endo-5f), respectively.
1
H NMR (400 MHz, CDCl ) δ 4.56 (s, 2H ), 3.45 (t,
3
7
J = 7.1 Hz, 2H ), 3.08 (ddd, J = 2.3, 5.2, 12.3 Hz, 1H1a/b),
2
8
.95 (ddd, J = 2.6 Hz, 8.2 Hz, 14.8 Hz, 1H1a/b), 2.84–2.92
1
-((5-(1-Methylpiperidin-3-yl)-1,2,4-oxadiazol-3-yl)methyl)
(m, 2H3a/b, 6), 2.78–2.81 (m, 1H ), 2.71–2.74 (m, 1H2a/b),
4
1
pyrrolidin-2-one (6a). H NMR (400 MHz, CDCl ) δ 4.62
2.49–2.52 (m, 1H3a/b), 2.41 (t, J = 8.1 Hz, 3H2a/b, 9), 2.05
(quin, J = 7.6 Hz, 2H ), 1.64–1.70 (m, 1H5a/b), 1.22–1.27
3
(s, 2H), 3.46 (t, J = 7.0 Hz, 2H), 3.13–3.21 (m, 1H),
10
13
3
2
1
.05–3.09 (m, 1H), 2.75–2.79 (m, 1H), 2.44 (t, J = 8.1 Hz,
(m, 1H5a/b). C NMR (100 MHz, CDCl ) δ 182.1, 175.4,
3
H), 2.32 (s, 3H), 2.26–2.32 (m, 1H), 2.01–2.29 (m, 4H),
166.5, 60.4, 58.8, 53.7, 47.3, 42.7, 40.4, 38.3, 30.4,
30.1, 17.9.
13
.60–1.82 (m, 3H). C NMR (100 MHz, CDCl ): δ 177.5,
3
Bull. Korean Chem. Soc. 2016, Vol. 37, 1020–1028
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de 1022