P. Comba et al.
1
5
8
10
ylamine solution (0.65 mL, 7.7 mmol), and dimethyl 1,3-acetonedicarbox-
ylate (0.92 mL, 6.4 mmol) in methanol (5 mL) gave the product in 34%
The bispidones L , L , L , and L were synthesized according to pub-
lished methods.
[
22,23]
1
yield. H NMR (200 MHz, CDCl
3
, keto form): d=1.73(s, 3H , CH
3
ꢀN),
General bispidone synthesis: To a suspension of 1 equivalent piperidone
in methanol or ethanol, 2.4 equivalents of a 37% aqueous formaldehyde
solution and 1.2 equivalents of the corresponding amine were added at
room temperature. The mixture was refluxed for 1 to 24 h. After the mix-
ture was allowed to cool down, a white/yellow precipitate was formed, fil-
tered, washed with methanol, and dried in vacuo.
3
2
1
.30 (s, 6H, CH
1.2 Hz, CH), 4.59 (d, 2H,
3
ꢀAr), 3.63 (s, 6H, ArꢀOCH
3
), 4.41 (d, 2H,
H,H
J =
3
J
H,H =11.2 Hz, CH), 7.30–7.55 (m, 4H, Arꢀ
1
3
H), 8.32–8.40 ppm (m, 2H, Ar-H); C NMR (CDCl
), 33.7 (1C, CH
8.2 (2C, ArꢀCH ꢀN), 52.0 (2C, OCH
N), 69.8 (2C, CHꢀCO), 123.9, 132.6, 137.3, 149.4, 154.5 (10C, CAr), 168.6
2C, COOCH ), 200.7 ppm (1C, C=O); MS-FAB (nibeol) m/z: 412.2 [M];
elemental analysis calcd (%): C 64.22, H 6.12, N 10.21; found: C 64.31, H
3
; keto form): d=
1
3
3
3
), 57.6 (2C, CHꢀ
(
3
3
,7-Dimethyl-2,4-bis(5-methylpyridin-2-yl)-9-oxo-3,7-diazabicyclo
nonane-1,5-dicarboxylic acid dimethyl ester L : Following the general bis-
pidine synthesis, piperidone pL (0.80 g, 1.9 mmol), formaldehyde solu-
tion (0.37 mL, 4.6 mmol), and 41% (0.18 mL, 2.3 mmol) aqueous methyl-
amine solution in methanol
A
C
H
T
R
E
U
N
G
[3.3.1]-
2
A
H
R
U
G
6
.10, N 10.27.
2
2
,6-Bis(5-methoxypyridin-2-yl)-1-methyl-4-oxopiperidine-3,5-dicarboxylic
3
acid dimethyl ester pL : Following the general piperidone synthesis, 5-
methoxy-2-pyridinecarbaldehyde (0.80 g, 5.8 mmol), 41% aqueous meth-
ylamine solution 0.30 mL, 3.5 mmol), and dimethyl 1,3-acetonedicarboxy-
ACHTREUNG
1
H NMR (CDCl
H, CH
3
3
3
2
6
(
2
(
3
2
ꢀAr), 2.49 (d, 2H, JH,H =12.0 Hz, H6/H8 equatorial, CH
2
late (0.42 mL, 2.9 mmol) in methanol (3mL) gave the product in 27%
d, 2H,
J
H,H =12.0 Hz, H6/H8 axial, CH
2
), 3.81 (s, 6H, OCH
3
1
yield. H NMR (200 MHz, CDCl3
3
, keto form): d=1.80 (s, 3H, CH
3
ꢀN),
3
4
H, H2/H4, CH), 7.56 (dd, 2H, JH,H =8.0 Hz, JH,H =2.0 Hz, ArꢀH), 7.93
3
3
.70 (s, 6H, ArꢀOCH
3
), 3.92 (s, 6H, OCH
3
), 4.48 (d, 2H, JH,H =11.3Hz,
3
13
d, 2H,
CDCl
), 60.7 (2C, CH
32.4, 137.0, 149.5, 155.9 (10C, CAr), 168.7 (2C, COOCH
1C, C=O); MS-FAB (nibeol) m/z: 467.0 [M+H]; elemental analysis
calcd (%): C 64.36, H 6.48, N 12.01; found: C 63.95, H 6.39, N 11.95.
J
H,H =8.0 Hz, ArꢀH), 8.30–8.34 ppm (m, 2H, ArꢀH); C NMR
3
3
CH), 4.64 (d, 2H,
J
H,H =11.3Hz, CH), 7.27 (dd, 2H,
J
H,H =8.5 Hz,
H,H =8.5 Hz, ArꢀH), 8.31 ppm (d,
H,H =2.7 Hz, ArꢀH); C NMR (CDCl
; keto form): d=25.5 (1C,
ꢀN), 52.0 (2C, OCH ), 55.5 (2C, ArꢀOCH ), 57.7 (2C, CHꢀN), 67.9,
9.3(2C, CH ꢀCO), 121.3, 124.7, 136.2, 149.4, 155.0 (10C, CAr), 168.5 (2C,
COOCH ), 200.7 ppm (1C, C=O); MS-FAB (nibeol) m/z: 444.0 [M+H];
elemental analysis calcd (%): C 59.59, H 5.68, N 9.48; found: C 59.43, H
(
3
): d=18.2 (2C, ArꢀCH
3
), 43.0, 44.5 (2C, CH
3
ꢀN), 52.4 (2C,
4
3
J
H,H =2.7 Hz, ArꢀH), 7.49 (d, 2H,
J
OCH
3
2
ꢀN), 62.2, (2C, CꢀCO), 73.6 (2C, CHꢀN), 123.0,
4
13
2
H,
J
3
1
3
), 203.8 ppm
CH
3
3
3
(
6
3
2
,4-Bis(5-methoxypyridin-2-yl)-3,7-dimethyl-9-oxo-3,7-diazabicyclo
nonane-1,5-dicarboxylic acid dimethyl ester L : Following the general bis-
pidine synthesis, piperidone pL (0.75 g, 1.7 mmol), formaldehyde solu-
tion (0.31 mL, 4.1 mmol), and 41% aqueous methylamine solution
0.17 mL, 2.0 mmol) in methanol (6 mL) gave the product in 38% yield.
A
C
H
T
R
E
U
N
G
[3.3.1]-
3
A
H
R
U
G
5
.90, N 8.92.
3
2
,6-Bis(5-bromopyridin-2-yl)-1-methyl-4-oxopiperidine-3,5-dicarboxylic
4
acid dimethyl ester pL : Following the general piperidone synthesis, 5-
bromo-2-pyridinecarbaldehyde (1.20 g, 6.5 mmol), 41% aqueous methyl-
amine solution (0.33 mL, 3.9 mmol), and dimethyl 1,3-acetonedicarboxy-
(
1
H NMR (CDCl
3
): d=1.97 (s, 3H, CH
2
H, JH,H =12.5 Hz, H6/H8 equatorial, CH ), 3.04 (d, 2H, JH,H =12.5 Hz,
3
ꢀN), 2.26 (s, 3H, CH ꢀN), 2.53(d,
3
2
2
2
late (0.47 mL, 3.2 mmol) in methanol (8 mL) gave the product in 66%
ꢀ
OCH ), 3.86 (s, 6H, -OCH ), 4.64 (s,
1
H6/H8 axial, CH
2
2
), 3.80 (s, 6H, Ar
3
3
yield. H NMR (200 MHz, CDCl3
3
, keto form): d=2.26 (s, 3H, CH
3
ꢀN),
3
4
H, H2/H4, CH), 7.28 (dd, 2H, JH,H =8.7 Hz, JH,H =2.9 Hz, ArꢀH), 7.93
3
4
7
.63 (s, 3H, OCH
3
), 3.73 (s, 3H, OCH ), 4.10–4.30 (m, 1H, CH), 4.30–
3
3
4
(
d, 2H,
J
H,H =8.7 Hz, ArꢀH), 8.18 ppm (d, 2H,
C NMR (CDCl ): d=42.9, 44.5 (2C, CH
(2C, ArꢀOCH
36.0, 150.8, 155.0 (10C, CAr), 168.7 (2C, COOCH
O); MS-FAB (nibeol) m/z: 499.0 [M]; elemental analysis calcd (%): C
9.52, H 6.27, N 10.89; found: C 59.35, H 6.02, N 11.14.
2,4-Bis(5-bromopyridin-2-yl)-3,7-dimethyl-9-oxo-3,7-diazabicyclo
J
H,H =2.9 Hz, ArꢀH);
.50 (m, 1H, CH), 4.79 (s, 1H, CHꢀN), 7.10–7.20 (m, 2H, ArꢀH), 7.60–
.80 (m, 2H, ArꢀH), 8.50–8.70 (m, 2H, ArꢀH), 12.46 ppm (s, 1H, OH);
1
3
ꢀN), 52.4 (2C, OCH
3
), 55.6
3
3
1
3
3
), 60.7, 62.4 (2C, CꢀCO), 73.3 (2C, CHꢀN), 121.4, 123.9,
C NMR (CDCl
2.2, 52.7 (2C, OCH
25.7, 138.9, 139.1, 139.5, 149.7, 150.1, 150,3 (10C, CAr), 155.8 (1C, C=
); MS-FAB (nibeol) m/z: 541.8
M]; elemental analysis calcd (%): C 44.39, H 3.54, N 7.76; found: C
3
; enol form): d=31.6 (1C, CH
3
ꢀN), 37.7 (1C, CHꢀN),
1
3
), 203.8 ppm (1C, C=
5
1
3
), 60.2 (C, CHꢀN), 97.7 (1C, C=COH), 124.1, 124.8,
5
COH), 167.2, 168.4 ppm (2C, COOCH
3
[
A
C
H
T
R
E
U
N
G
[3.3.1]-
4
4
4.11, H 3.52, N 7.66.
ACHTREUNG
nonane-1,5-dicarboxylic acid dimethyl ester L : Following the general bis-
pidine synthesis, piperidone pL 1.06 g (2.0 mmol), formaldehyde solution
(0.35 mL, 4.7 mmol), and 41% aqueous methylamine solution (0.20 mL,
.4 mmol) in methanol (4 mL) gave the product in 74% yield. H NMR
): d=2.00 (s, 3H, CH
H,H =12.8 Hz, H6/H8 equatorial, CH
H8 axial, CH ), 3.80 (s, 6H, OCH ), 4.70 (s, 2H, H2/H4, CH), 7.92 (d,
4
2
,6-Bis(7-chloroquinolin-2-yl)-1-methyl-4-oxopiperidine-3,5-dicarboxylic
6
acid dimethyl ester pL : Following the general piperidone synthesis, 7-
chloro-2-quinolinecarbaldehyde (5.40 g, 28.2 mmol), 41% aqueous meth-
ylamine solution 1.43mL, 16.9 mmol), and dimethyl 1, 3- acetonedicarbox-
ylate (2.04 mL, 14.1 mmol) in methanol (20 mL) gave the product in
1
2
(
J
CDCl
3
3
-N), 2.23(s, 3H , CH
3
2
ꢀN), 2.50 (d, 2H,
2
2
), 2.90 (d, 2H, JH,H =12.8 Hz, H6/
1
6
5% yield. H NMR (200 MHz, CDCl3
3
, keto form): d=1.78 (s, 3H,
2
3
4
3
3
2H, JH,H =0.9 Hz, ArꢀH), 7.94 (d, 2H, JH,H =2.1 Hz, ArꢀH), 8.56 ppm
CH ), 4.56 (d, 2H, JH,H =11.2 Hz, CH), 5.21
3
ꢀN), 3.61 (s, 6H, ArꢀOCH
3
3
4
13
3
13
(dd, 2H,
J
=2.1 Hz,
J
=0.9 Hz, ArꢀH); C NMR (CDCl ): d=
(
(
d, 2H,
CDCl
J
H,H =11.2 Hz, CH), 7.27–8.25 ppm (m, 10H, ArꢀH); C NMR
; keto form): d=30.7 (1C, CH ), 61.1 (2C,
ꢀN), 51.8 (2C, OCH
H,H
H,H
3
4
3.2, 44.5 (2C, CH
3
ꢀN), 52.6 (2C, OCH
3
), 60.6 (2C, CH
2
ꢀN), 61.8 (2C,
3
3
3
CꢀCO), 73.1 (2C, CHꢀN), 120.1, 124.7, 139.2, 150.3, 157.4 (10C, CAr),
68.2 (2C, COOCH ), 202.8 (1C, C=O); MS-FAB (nibeol) m/z: 596.6
M+H]; elemental analysis calcd (%): C 44.97, H 4.27, N 9.12; found: C
5.37, H 4.24, N 9.15.
CHꢀN), 69.3(2C, CH ꢀCO), 125.7, 125.9, 127.5, 128.3, 128.6, 135.1, 136.1,
47.2, 158.4 (18C, CAr), 169.2 (2C, COOCH ), 201.6 ppm (1C, C=O); MS-
FAB (nibeol) m/z: 551.8 [M]; elemental analysis calcd (%): C 60.22, H
1
3
1
3
[
4
4
.43, N 7.39; found: C 60.23, H 4.16, N 7.49.
2
,6-Bis(6-bromopyridin-2-yl)-1-methyl-4-oxopiperidine-3,5-dicarboxylic
2,4-Bis(7-chloroquinolin-2-yl)-3,7-dimethyl-9-oxo-3,7-diazabicyclo
A
C
H
T
R
E
U
N
G
[3.3.1]-
7
6
acid dimethyl ester pL : Following the general piperidone synthesis, 6-
bromo-2-pyridinecarbaldehyde (10.00 g, 53.8 mmol), 41% aqueous meth-
ylamine solution (2.73 mL, 32.3 mmol) and dimethyl 1,3-acetonedicarbox-
ylate (3.88 mL, 26.9 mmol) in methanol (25 mL) gave the product in
A
H
R
U
G
6
pidine synthesis, piperidone pL (2.00 g, 3.6 mmol), formaldehyde solu-
tion (0.64 mL, 8.6 mmol), and 41% aqueous methylamine solution
(0.37 mL, 4.3 mmol) in ethanol (15 mL) gave the product in 78% yield.
1
1
8
2% yield. H NMR (200 MHz, CDCl
3
, enol form): d=2.26 (s, 3H, CH
3
ꢀ
): d=2.11 (s, 3H, CH
2H, JH,H =12.2 Hz, H6/H8 equatorial, CH
H6/H8 axial, CH ), 3.92 (s, 6H, OCH ), 4.96 (s, 2H, H2/H4, CH), 7.51
3
N), 3.63 (s, 3H, OCH ), 3.83 (s, 3H, OCH
3
3
), 4.04 (d, 1H,
J
H,H =9.6 Hz,
3
CH), 4.50 (d, 1H, JH,H =9.6 Hz, CH), 4.80 (s, 1H, CHꢀN), 7.26–7.62 (m,
1
3
6
3
H, ArꢀH), 12.46 ppm (s, 1H, OH); C NMR (CDCl
1.6 (1C, CH
ꢀN), 37.7 (1C, CHꢀN), 52.2, 52.7 (2C, OCH
3
; enol form): d=
), 60.2 (C,
(dd, 2H, JH,H =8.6 Hz, JH,H =2.1 Hz, ArꢀH), 7.79 (d, 2H, JH,H =8.6 Hz,
ArꢀH), 7.96 (d, 2H,
ArꢀH), 8.35 ppm (d, 2H,
43.6, 44.4 (2C, CH
ꢀN), 52.6 (2C, OCH
CꢀCO), 74.0 (2C, CHꢀN), 120.9, 126.1, 127.8, 128.3, 128.7, 135.5, 136.3,
147.9, 160.8 (18C, CAr), 168.3(2C, COOCH ), 203.0 ppm (1C, C=O); MS-
3
3
3
13
CHꢀN), 97.7 (1C, C=COH), 121.8, 123.0, 127.4, 138.6, 138.8, 139.1, 140.7,
J
3
1
40.8, 141.6, (10C, CAr), 158.4 (1C, C=COH), 168.8 ppm (2C, COOCH );
3
3
3
2
MS-FAB (nibeol) m/z: 541.8 [M], elemental analysis calcd (%): C 44.39,
H 3.54, N 7.76; found: C 44.39, H 3.53, N 7.77.
3
5324
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 5313 – 5328