Biaryl Analogues of Constrained Tricyclic Tropanes
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 10 2003
(45), 189 (42), 165 (37), 149 (100), 141 (46), 115 (30), 108 (47).
Anal. (C24H24ClNO2‚0.25HCl) C, H, N.
NMR (CDCl3): δ 31.8, 32.4, 36.4, 37.2, 40.6, 48.2, 52.0, 52.3,
53.9, 56.3, 112.7, 122.2, 126.1, 127.5, 128.8, 132.0, 132.1, 134.9,
139.1, 149.9, 174.0; MS m/z (%): 403 (M+ + 1, 49), 402 (M+,
21), 344 (20), 320 (72), 262 (27), 235 (46), 201 (85), 171 (100),
165 (52), 150 (47), 130 (89), 117 (75), 105 (56). Anal.
(C26H30N2O2‚0.6HCl) C, H, N.
(1S,3S,6R,10S)-(Z)-9-[4-(3-Ch lor op h en yl)ben zylid en e]-
7-a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl
Ester (11e). Procedure B was followed, giving the title
compound as an oil. [R]25 +47.2° (c 1.20, CHCl3); 1H NMR
D
(CDCl3): δ 1.46-1.54 (m, 3H), 2.05-2.28 (m, 3H), 2.43 (t, J )
3.0 Hz, 1H), 2.73 (dd, J ) 2.7 and 5.6 Hz, 1H), 3.28-3.34 (m,
1H), 3.66 (s, 3H), 3.78-3.82 (m, 1H), 3.96 and 4.10 (ABq, J )
19.2 Hz, both d with J ) 2.4 Hz, 2H), 6.17 (t, J ) 2.7 Hz, 1H),
7.27 (d, J ) 8.7 Hz, 2H), 7.31 (d, J ) 7.5 Hz, 1H), 7.36 (dd, J
) 7.5 and 7.8 Hz, 1H), 7.47 (d, J ) 7.8 Hz, 1H), 7.53 (d, J )
8.4 Hz, 2H), 7.58 (s, 1H); 13C NMR (CDCl3): δ 32.0, 32.6, 36.5,
37.4, 48.4, 51.9, 52.4, 53.7, 56.3, 121.5, 125.0, 127.0, 127.2,
127.5, 128.9, 130.0, 134.7, 137.1, 137.4, 141.5, 142.5, 174.3;
MS m/z (%): 393 (M+, 13), 334 (34), 215 (28), 202 (30), 189
(28), 167 (34), 149 (100), 141 (51), 115 (30), 108 (48). Anal.
(C24H24ClNO2‚0.33H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-9-[4-[4-(Tr iflu or om eth yl)ph en yl]ben -
zyliden e]-7-azatr icyclo[4.3.1.03,7]decan e-10-car boxylic Acid
Meth yl Ester (11j). Procedure B was followed, giving the title
1
compound as a white solid. [R]25 +55.9° (c 0.32, CHCl3); H
D
NMR (CDCl3): δ 1.44-1.60 (m, 3H), 2.06-2.26 (m, 3H), 2.45
(t, J ) 3.0 Hz, 1H), 2.75 (dd, J ) 3.0 and 5.8 Hz, 1H), 3.26-
3.36 (m, 1H), 3.67 (s, 3H), 3.80-3.84 (m, 1H), 3.96 and 4.10
(ABq, J ) 18.0 Hz, both d with J ) 2.4 and 2.7 Hz, respectively,
2H), 6.19 (t, J ) 3.0 Hz, 1H), 7.29 (d, J ) 8.4 Hz, 2H), 7.57 (d,
J ) 8.7 Hz, 2H), 7.69 (br s, 4H); 13C NMR (CDCl3): δ 32.0,
32.6, 36.5, 37.4, 48.4, 51.9, 52.3, 53.7, 56.2, 121.4, 125.6, 125.7,
127.1, 127.2, 128.9, 130.1, 137.4, 141.9, 174.3 (CF3 and the
adjacent aromatic C not observed); MS m/z (%): 427 (M+, 52),
368 (100), 299 (18), 285 (24), 259 (43), 215 (42), 202 (36), 189
(39), 174 (64), 164 (66), 152 (46), 141 (60), 115 (42), 106 (46).
Anal. (C25H24F3NO2‚0.5H2O) C, H, N.
(1S ,3S ,6R ,10S )-(Z)-9-[4-(3,4-D ic h lo r o p h e n y l)b e n -
zyliden e]-7-azatr icyclo[4.3.1.03,7]decan e-10-car boxylic Acid
Meth yl Ester (11f). Procedure B was followed, giving the title
1
compound as a white solid. [R]25 +80.6° (c 0.74, CHCl3); H
D
NMR (CDCl3): δ 1.42-1.58 (m, 3H), 2.04-2.28 (m, 3H), 2.43
(t, J ) 3.0 Hz, 1H), 2.73 (dd, J ) 2.7 and 5.7 Hz, 1H), 3.24-
3.34 (m, 1H), 3.66 (s, 3H), 3.78-3.82 (m, 1H), 3.95 and 4.07
(ABq, J ) 18.3 Hz, both d with J ) 2.4 and 2.7 Hz, respectively,
2H), 6.16 (t, J ) 2.7 Hz, 1H), 7.28 (d, J ) 8.4 Hz, 2H), 7.42
(dd, J ) 2.1 and 8.4 Hz, 1H), 7.49 (d, J ) 8.4 Hz, 2H), 7.51 (d,
J ) 8.4 Hz, 1H), 7.67 (d, J ) 2.1 Hz, 1H); 13C NMR (CDCl3):
δ 31.9, 32.5, 36.4, 37.4, 48.3, 51.9, 52.3, 53.7, 56.2, 121.3, 126.0,
126.9, 128.6, 128.9, 130.6, 131.2, 132.8, 136.2, 137.3, 140.6,
141.7, 174.2; MS m/z (%): 427 (M+, 12), 368 (34), 215 (33),
202 (29), 189 (41), 184 (35), 166 (49), 148 (100), 141 (63), 120
(41), 106 (48). Anal. (C24H23Cl2NO2‚0.1H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-9-[4-(4-Cya n op h en yl)ben zylid en e]-
7-a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl
Ester (11k ). Procedure B was followed, giving the title
compound as an oil. [R]25 +73.6° (c 0.37, CHCl3); 1H NMR
D
(CDCl3): δ 1.44-1.60 (m, 3H), 2.06-2.26 (m, 3H), 2.45 (t, J )
3.3 Hz, 1H), 2.74 (dd, J ) 3.3 and 5.8 Hz, 1H), 3.24-3.34 (m,
1H), 3.66 (s, 3H), 3.78-3.82 (m, 1H), 3.95 and 4.08 (ABq, J )
18.9 Hz, both d with J ) 2.4 and 2.7 Hz, respectively, 2H),
6.18 (t, J ) 3.0 Hz, 1H), 7.30 (d, J ) 8.1 Hz, 2H), 7.56 (d, J )
8.4 Hz, 2H), 7.68 (d, J ) 8.7 Hz, 2H), 7.72 (d, J ) 8.7 Hz, 2H);
13C NMR (CDCl3): δ 32.0, 32.6, 36.4, 37.4, 48.4, 51.9, 52.3,
53.7, 56.3, 110.7, 119.0, 121.3, 127.1, 127.4, 129.0, 132.6, 136.6,
137.9, 142.4, 145.1, 174.3; MS m/z (%): 384 (M+, 60), 325 (100),
256 (21), 242 (29), 227 (29), 216 (54), 192 (50), 162 (76), 152
(36), 141 (66), 115 (47), 106 (43). Anal. (C25H24N2O2‚2/3HCl)
C, H, N.
(1S ,3S ,6R ,10S )-(Z)-9-[4-(3,5-D ic h lo r o p h e n y l)b e n -
zyliden e]-7-azatr icyclo[4.3.1.03,7]decan e-10-car boxylic Acid
Meth yl Ester (11g). Procedure B was followed, giving the title
compound as an oil. [R]25 +76.9° (c 0.38, CHCl3); 1H NMR
D
(CDCl3): δ 1.43-1.58 (m, 3H), 2.04-2.28 (m, 3H), 2.44 (t, J )
3.0 Hz, 1H), 2.73 (dd, J ) 2.7 and 5.6 Hz, 1H), 3.26-3.34 (m,
1H), 3.66 (s, 3H), 3.78-3.81 (m, 1H), 3.94 and 4.08 (ABq, J )
19.2 Hz, both d with J ) 2.4 Hz, 2H), 6.17 (t, J ) 2.7 Hz, 1H),
7.27 (d, J ) 8.4 Hz, 2H), 7.32 (dd, J ) 1.8 and 2.1 Hz, 1H),
7.45 (d, J ) 2.1 Hz, 2H), 7.51 (d, J ) 8.7 Hz, 2H); 13C NMR
(CDCl3): δ 32.0, 32.6, 36.5, 37.4, 48.4, 51.9, 52.3, 53.7, 56.3,
121.3, 125.3, 126.9, 127.0, 129.0, 135.3, 136.0, 137.7, 142.1,
143.7, 174.3; MS m/z (%): 427 (M+, 27), 368 (53), 215 (43),
202 (38), 189 (53), 184 (35), 166 (46), 148 (100), 141 (61), 120
(40), 108 (53), 106 (46). Anal. (C24H23Cl2NO2‚0.4HCl) C, H, N.
(1S ,3S ,6R ,10S )-(Z)-9-[4-(2,4-D ic h lo r o p h e n y l)b e n -
zyliden e]-7-azatr icyclo[4.3.1.03,7]decan e-10-car boxylic Acid
Meth yl Ester (11h ). Procedure B was followed, giving the
title compound as an oil. [R]25D +79.4° (c 0.80, CHCl3); 1H NMR
(CDCl3): δ 1.42-1.59 (m, 3H), 2.04-2.26 (m, 3H), 2.43 (t, J )
3.3 Hz, 1H), 2.73 (dd, J ) 2.7 and 5.6 Hz, 1H), 3.26-3.34 (m,
1H), 3.67 (s, 3H), 3.78-3.82 (m, 1H), 3.94 and 4.08 (ABq, J )
18.9 Hz, both d with J ) 2.4 Hz, 2H), 6.18 (t, J ) 2.7 Hz, 1H),
7.24-7.29 (m, 4H), 7.37 (d, J ) 8.7 Hz, 2H), 7.48 (d, J ) 1.8
Hz, 1H); 13C NMR (CDCl3): δ 32.0, 32.6, 36.6, 37.4, 48.4, 51.9,
52.3, 53.7, 56.3, 121.5, 127.2, 128.1, 129.4, 129.7, 132.0, 133.2,
133.6, 136.0, 137.0, 138.7, 141.7, 174.3; MS m/z (%): 427 (M+,
7), 368 (11), 215 (31), 202 (24), 189 (36), 179 (12), 166 (26),
(1S ,3S ,6R ,10S )-(Z)-9-[4-(1-P yr r olyl)b e n zylid e n e ]-7-
a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl
Ester (15). Procedure A was followed, giving the title com-
pound as an oil. [R]25D +68.3° (c 0.21, CHCl3); 1H NMR (CDCl3):
δ 1.45-1.58 (m, 3H), 2.02-2.28 (m, 3H), 2.43 (t, J ) 3.0 Hz,
1H), 2.72 (dd, J ) 3.0 and 5.7 Hz, 1H), 3.24-3.34 (m, 1H),
3.66 (s, 3H), 3.78-3.82 (m, 1H), 3.92 and 4.06 (ABq, J ) 19.5
Hz, both d with J ) 2.4 Hz, 2H), 6.14 (t, J ) 3.0 Hz, 1H), 6.34
(dd, J ) 2.1 and 2.4 Hz, 2H), 7.09 (dd, J ) 2.1 and 2.4 Hz,
2H), 7.24 (d, J ) 8.4 Hz, 2H), 7.35 (d, J ) 8.4 Hz, 2H); 13C
NMR (CDCl3): δ 32.0, 32.6, 36.5, 37.3, 48.3, 51.9, 52.3, 53.7,
56.3, 110.4, 119.2, 120.3, 121.1, 129.5, 135.6, 137.0, 157.6,
174.2; MS m/z (%): 348 (M+, 50), 289 (47), 220 (11), 206 (9),
180 (19), 152 (13), 144 (28), 115 (16), 83 (100), 68 (50), 41 (50).
Anal. (C22H24N2O2‚0.75HCl) C, H, N.
(1S ,3S ,6R ,10S )-(Z)-9-[4-(2-Th ie n yl)b e n zylid e n e ]-7-
a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl
Ester (16a ). Procedure B was followed, giving the title
compound as a white solid. [R]25 +78.1° (c 0.80, CHCl3); H
1
D
NMR (CDCl3): δ 1.42-1.60 (m, 3H), 2.02-2.08 (m, 1H), 2.08-
2.30 (m, 2H), 2.45 (t, J ) 3.3 Hz, 1H), 2.74 (dd, J ) 2.7 and
5.6 Hz, 1H), 3.28-3.36 (m, 1H), 3.68 (s, 3H), 3.78-3.84 (m,
1H), 3.90 and 4.01 (ABq, J ) 18.9 Hz, both d with J ) 2.4 and
2.7 Hz, respectively, 2H), 6.16 (t, J ) 2.7 Hz, 1H), 7.10 (dd, J
) 3.6 and 3.3 Hz, 1H), 7.23 (d, J ) 8.1 Hz, 2H), 7.29 (d, J )
3.3 Hz, 1H), 7.33 (d, J ) 3.6 Hz, 1H), 7.59 (d, J ) 8.1 Hz, 2H);
13C NMR (CDCl3): δ 32.0, 32.6, 36.5, 37.4, 48.4, 51.9, 52.4,
53.7, 56.2, 121.5, 122.9, 124.7, 125.8, 126.8, 128.0, 128.8, 132.1,
136.6, 141.1, 174.3; MS m/z (%): 365 (M+, 28), 306 (29), 277
(6), 197 (9), 152 (21), 83 (100), 68 (36). Anal. (C22H23NO2S‚
0.2H2O) C, H, N.
148 (100), 141 (54), 120 (35), 108 (48), 106 (37). Anal. (C24H23
-
Cl2NO2‚0.5H2O) C, H, N.
(1S,3S,6R,10S)-(Z)-9-[4-[4-(Dim eth yla m in o)p h en yl]ben -
zyliden e]-7-azatr icyclo[4.3.1.03,7]decan e-10-car boxylic Acid
Meth yl Ester (11i). Procedure B was followed, giving the title
compound as an oil. [R]25 +97.1° (c 0.18, CHCl3); 1H NMR
D
(CDCl3): δ 1.42-1.58 (m, 3H), 2.04-2.26 (m, 3H), 2.42 (t, J )
3.0 Hz, 1H), 2.72 (dd, J ) 2.7 and 5.6 Hz, 1H), 2.99 (s, 6H),
3.26-3.34 (m, 1H), 3.65 (s, 3H), 3.76-3.82 (m, 1H), 3.96 and
4.08 (ABq, J ) 18.0 Hz, both d with J ) 2.4 Hz, 2H), 6.15 (t,
J ) 3.0 Hz, 1H), 6.79 (d, J ) 8.7 Hz, 2H), 7.22 (d, J ) 8.4 Hz,
2H), 7.50 (d, J ) 8.4 Hz, 2H), 7.53 (d, J ) 8.7 Hz, 2H); 13C
(1S,3S,6R,10S)-(Z)-9-[4-(5-Meth yl-2-th ien yl)ben zyliden e]-
7-a za tr icyclo[4.3.1.03,7]d eca n e-10-ca r boxylic Acid Meth yl
Ester (16b). Procedure B was followed, giving the title
1
compound as a white solid. [R]25 +71.8° (c 0.55, CHCl3); H
D
NMR (CDCl3): δ 1.42-1.60 (m, 3H), 2.04-2.30 (m, 3H), 2.42