Non-Nitrogen Inhibitors of Monoamine Transporters
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 17 2669
brown viscous oil was obtained (88%): Rf 0.19 (20% EtOAc/
hexanes); 1H-NMR (CDCl3, 100 MHz) δ 7.0-7.2 (m, 4H), 4.95-
5.05 (m, 1H), 4.55-4.75 (m, 1H), 3.52 (s, 3H), 2.95 (dd, 1H, J
) 5, 18 Hz), 1.7-2.3 (m, 5H). Anal. (C15H15O3F) C, H.
(1R,1S)-2-Ca r b om et h oxy-3-(4-ch lor op h en yl)-8-oxa b i-
cyclo[3.2.1]-2-octen e (5c). Compound 5c was prepared from
4 with 4-chlorophenylboronic acid as described for 5a . A light
brown viscous oil was obtained (92%): Rf 0.23 (20% EtOAc/
hexanes); 1H-NMR (CDCl3, 100 MHz) δ 7.0-7.4 (m, 4H), 4.95-
5.1 (m, 1H), 4.55-4.75 (m, 1H), 3.52 (s, 3H), 2.95 (dd, 1H, J )
5, 18 Hz), 1.7-2.2 (m, 5H). Anal. (C15H15O3Cl) C, H, Cl.
(1R,1S)-2-Ca r b om et h oxy-3-(4-b r om op h en yl)-8-oxa b i-
cyclo[3.2.1]-2-octen e (5d ). Compound 5d was prepared from
4 with 4-bromophenylboronic acid as described for 5a . A clear
viscous oil was obtained (41%): Rf 0.39 (20% EtOAc/hexanes);
1H-NMR (CDCl3, 100 MHz) δ 7.48 (d, 2H, J ) 9 Hz), 6.97 (d,
2H, J ) 9 Hz), 4.95-5.1 (m, 1H), 4.5-4.75 (m, 1H), 3.52 (s,
3H), 2.95 (dd, 1H, J ) 5, 18 Hz), 1.65-2.4 (m, 5H). Anal.
(C15H15O3Br) C, H, Br.
1H). Anal. (C15H17O3F) C, H. 7b: 1H-NMR (CDCl3, 400 MHz)
δ 7.1-7.2 (m, 2H), 6.9-7.0 (m, 2H), 4.5-4.8 (m, 2H), 3.55 (s,
3H), 3.20 (ddd, 1H, J ) 7, 11, 11 Hz), 2.44 (dd, 1H, J ) 2, 11
Hz), 2.38 (ddd, 1H, J ) 7, 9, 13 Hz), 1.9-2.2 (m, 2H), 1.76
(ddd, 1H, J ) 5, 9, 13 Hz), 1.6-1.7 (m, 1H), 1.32 (ddd, 1H, J
) 2, 11, 13 Hz). Anal. (C15H17O3F) C, H.
(1R,1S)-2â-Ca r b om et h oxy-3â-(4-ch lor op h en yl)-8-oxa -
bicyclo[3.2.1]octa n e (6c) a n d (1R,1S)-2â-Ca r bom eth oxy-
3r-(4-ch lor op h en yl)-8-oxa bicyclo[3.2.1]octa n e (7c). Com-
pounds 6c and 7c were prepared from 5c as described for
compounds 6a and 7a . Compound 6c was obtained (19%) as
a white solid (mp 116-117 °C; Rf 0.27 (30% EtOAc/hexanes))
and 7c (51%) as a white solid (mp 89-90 °C; Rf 0.32 (30%
EtOAc/hexanes)). 6c: 1H-NMR (CDCl3, 100 MHz) δ 7.1-7.4
(m, 4H), 4.55-4.8 (m, 2H), 3.55 (s, 3H), 3.20 (ddd, 1H, J ) 5,
5, 12 Hz), 2.55-2.95 (m, 2H), 1.5-2.3 (m, 5H). Anal. (C15H17O3-
Cl) C, H, Cl. 7c: 1H-NMR (CDCl3, 100 MHz) δ 7.1-7.4 (m,
4H), 4.4-4.65 (m, 2H), 3.58 (s, 3H), 3.05-3.45 (m, 1H), 1.2-
2.6 (m, 7H). Anal. (C15H17O3Cl) C, H, Cl.
(1R,1S)-2â-Ca r b om et h oxy-3r-(4-b r om op h en yl)-8-oxa -
bicyclo[3.2.1]octa n e (6d ) a n d (1R,1S)-2â-Ca r bom eth oxy-
3â-(4-br om op h en yl)-8-oxa bicyclo[3.2.1]octa n e (7d ). Com-
pounds 6d and 7d were prepared from 5d as described for
compounds 6a and 7a except no TFA was used when quench-
ing. Compound 6d was obtained (47%) as a white solid (mp
113-115 °C; Rf 0.29 (30% EtOAc/hexanes)) and 7d (32%) as a
white solid (mp 96-98 °C; Rf 0.38 (30% EtOAc/hexanes)).
6d : 1H-NMR (CDCl3, 100 MHz) δ 7.45 (d, 2H, J ) 9 Hz), 7.15
(d, 2H, J ) 9 Hz), 4.6-4.8 (m, 2H), 3.5 (s, 3H), 3.0-3.4 (m,
1H), 2.55-2.9 (m, 2H), 1.5-2.4 (m, 5H). Anal. C15H17O3Br.
7d : 1H-NMR (CDCl3, 100 MHz) δ 7.45 (d, 2H, J ) 10 Hz), 7.1
(d, 2H, J ) 10 Hz), 4.4-4.6 (m, 2H), 3.53 (s, 3H), 3.20 (ddd,
1H, J ) 6, 11, 11 Hz), 1.6-2.6 (m, 6H), 1.35 (ddd, 1H, J ) 2,
11, 13 Hz). Anal. (C15H17O3Br) C, H, Br.
(1R ,1S )-2-Ca r b om e t h oxy-3-(3,4-d ich lor op h e n yl)-8-
oxa bicyclo[3.2.1]-2-octen e (5f). Compound 5f was prepared
from 4 with 3,4-chlorophenylboronic acid as described for 5a .
A light brown viscous oil was obtained (97%): Rf 0.45 (30%
EtOAc/hexanes); 1H-NMR (CDCl3, 100 MHz) δ 7.4 (d, 1H, J )
10 Hz), 7.23 (d, 1H, J ) 2 Hz), 6.95 (dd, 1H, J ) 2, 10 Hz),
4.95-5.1 (m, 1H), 4.55-4.75 (m, 1H), 3.52 (s, 3H), 2.95 (dd,
1H, J ) 5, 18 Hz), 1.6-2.3 (m, 5H). Anal. (C15H14O3Cl2) C,
H, Cl.
(1R)-2-Ca r bom eth oxy-3-(3,4-d ich lor op h en yl)-8-oxa bi-
cyclo[3.2.1]-2-octen e (5g). Compound 5g was prepared from
(1R)-4 with 3,4-chlorophenylboronic acid as described for 5a .
A light brown viscous oil was obtained (94%): Rf 0.45 (30%
EtOAc/hexanes); 1H-NMR (CDCl3, 100 MHz) identical to 5f
above.
(1R,1S)-2â-Ca r b om et h oxy-3â-(3,4-d ich lor op h en yl)-8-
oxa b icyclo[3.2.1]oct a n e (6f) a n d (1R,1S)-2â-Ca r b om e-
t h oxy-3r-(3,4-d ich lor op h e n yl)-8-oxa b icyclo[3.2.1]oc-
ta n e (7f). Compounds 6f and 7f were prepared from 5f as
described for compounds 6a and 7a . Compound 6f was
obtained (14%) as a white solid (mp 132-133.5 °C; Rf 0.31 (30%
EtOAc/hexanes)) and 7f (55%) as a white solid (mp 88.5-90
°C; Rf 0.33 (30% EtOAc/hexanes)). 6f: 1H-NMR (CDCl3, 100
MHz) δ 7.0-7.5 (m, 3H), 4.55-4.85 (m, 2H), 3.55 (s, 3H), 3.20
(ddd, 1H, J ) 5, 5, 11 Hz), 2.55-2.95 (m, 2H), 1.45-2.35 (m,
5H). Anal. (C15H16O3Cl2) C, H, Cl. 7f: 1H-NMR (CDCl3, 100
MHz) δ 7.0-7.5 (m, 3H), 4.4-4.65 (m, 2H), 3.60 (s, 3H), 3.20
(ddd, 1H, J ) 7, 11, 11 Hz), 1.5-2.5 (m, 6H), 1.30 (ddd, 1H, J
) 2, 11, 13 Hz). Anal. (C15H16O3Cl2) C, H, Cl.
(1S)-2-Ca r bom eth oxy-3-(3,4-d ich lor op h en yl)-8-oxa bi-
cyclo[3.2.1]-2-octen e (5h ). Compound 5h was prepared from
(1S)-4 with 3,4-chlorophenylboronic acid as described for 5a .
A clear viscous oil was obtained (80%): Rf 0.45 (30% EtOAc/
1
hexanes); H-NMR (CDCl3, 100 MHz) identical to 5f above.
Gen er a l P r oced u r e for Syn t h esis of t h e Oct a n es:
(1R,1S)-2â-Ca r bom eth oxy-3â-p h en yl-8-oxa bicyclo[3.2.1]-
octa n e (6a ) a n d (1R,1S)-2â-Ca r bom eth oxy-3r-p h en yl-8-
oxa bicyclo[3.2.1]octa n e (7a ). To 2-carbomethoxy-3-phenyl-
8-oxabicyclo[3.2.1]-2-octene, 5a (1.17 g, 4.8 mmol), in THF (10
mL) at -70 °C under N2 was added SmI2 (0.1 M in THF, 215
mL, 21.5 mmol). After the mixture was stirred for 30 min,
MeOH (anhydrous, 25 mL) was added. The reaction was
stirred at -70 °C for a further 2 h. The mixture was quenched
with TFA (5 mL) and H2O (100 mL). After the mixture was
warmed to 0 °C, NH4OH was added to attain pH 11 and the
mixture was then stirred for 30 min. The mixture was filtered
through Celite, washed with ether (400 mL), and then satu-
rated with Na2S2O3. The ether layer was washed with brine.
The dried (MgSO4) ether layer was concentrated to dryness.
The isomers were separated by gravity column chromatogra-
phy (eluent 10% EtOAc/hexanes) to afford 270 mg (23%) of 6a
as a white solid (mp 102.5-104 °C; Rf 0.30 (30% EtOAc/
hexanes)) and 789 mg (67%) of 7a as a white solid (mp 96.5-
98 °C; Rf 0.37 (30% EtOAc/hexanes)). 6a : 1H-NMR (CDCl3,
100 MHz) δ 7.25 (br s, 5H), 4.55-4.8 (m, 2H), 3.48 (s, 3H),
3.25 (ddd, 1H, J ) 5, 5, 14 Hz), 2.6-3.0 (m, 2H), 1.5-2.3 (m,
5H). Anal. (C15H18O3) C, H. 7a : 1H-NMR (CDCl3, 100 MHz)
δ 7.25 (br s, 5H), 4.4-4.65 (m, 2H), 3.58 (s, 3H), 3.25 (ddd,
1H, J ) 7, 11, 11 Hz), 2.52 (dd, 1H, J ) 2, 11 Hz), 1.6-2.5 (m,
5H), 1.41 (ddd, 1H, J ) 2, 11, 14 Hz). Anal. (C15H18O3) C, H.
(1R,1S)-2â-Ca r b om et h oxy-3â-(4-flu or op h en yl)-8-oxa -
bicyclo[3.2.1]octa n e (6b) a n d (1R,1S)-2â-Ca r bom eth oxy-
3r-(4-flu or op h en yl)-8-oxa bicyclo [3.2.1]octa n e (7b). Com-
pounds 6b and 7b were prepared from 5b as described for
compounds 6a and 7a . Compound 6b was obtained (22%) as
a white solid (mp 118-120.5 °C; Rf 0.27 (30% EtOAc/hexanes))
and 7b (62%) as a white solid (mp 58-60 °C; Rf 0.36 (30%
EtOAc/hexanes)). 6b : 1H-NMR (CDCl3, 400 MHz) δ 7.15-
7.25 (m, 2H), 6.9-7.0 (m, 2H), 4.6-4.7 (m, 2H), 3.48 (s, 3H),
3.17 (ddd, 1H, J ) 5, 5, 13 Hz), 2.78 (d, 1H, J ) 5 Hz), 2.73
(ddd, 1H, J ) 4, 13, 13 Hz), 1.7-2.2 (m, 4H), 1.5-1.65 (m,
(1R )-2â-C a r b o m e t h o x y -3â-(3,4-d ic h lo r o p h e n y l)-8-
oxa bicyclo[3.2.1]octa n e (6g) a n d (1R)-2â-Ca r bom eth oxy-
3r-(3,4-d ich lor op h en yl)-8-oxa bicyclo[3.2.1]octa n e (7g).
Compounds 6g and 7g were prepared from (1R)-5f as de-
scribed for compounds 6a and 7a . Compound 6g was obtained
(13%) as a white solid (mp 121-122 °C; Rf 0.31 (30% EtOAc/
hexanes)) and 7g (45%) as a white solid (mp 103.5-104.5 °C;
[R]21 ) -79° (c ) 1, MeOH); Rf 0.33 (30% EtOAc/hexanes)).
D
6g and 7g: 1H-NMR (CDCl3, 100 MHz) identical to 6f and 7f
above. Anal. (C15H16O3Cl2) C, H, Cl.
(1S )-2â-C a r b o m e t h o x y -3â-(3,4-d ic h lo r o p h e n y l)-8-
oxa bicyclo[3.2.1]octa n e (6h ) a n d (1S)-2â-Ca r bom eth oxy-
3r-(3,4-d ich lor op h en yl)-8-oxa bicyclo[3.2.1]octa n e (7h ).
Compounds 6h and 7h were prepared from (1S)-5f as de-
scribed for compounds 6a and 7a . Compound 6h was ob-
tained(11%) as a white solid (mp 121-122 °C; Rf 0.31 (30%
EtOAc/hexanes)) and 7h (45%) as a white solid (mp 103-104
°C; [R]21D ) +76° (c ) 1, MeOH); Rf 0.33 (30% EtOAc/hexanes)).
6h and 7h : 1H-NMR (CDCl3, 100 MHz) identical to 6f and 7f
above. Anal. (C15H16O3Cl2) C, H, Cl.
Syn th esis of (1R,1S)-2-Car bom eth oxy-3-(4-iodoph en yl)-
8-oxabicyclo[3.2.1]-2-octen e (5e): (1R,1S)-2-Car bom eth oxy-
3-[4-(t r ib u t ylst a n n yl)p h e n y l]-8-ox a b ic yc lo [3.2.1.]-2-
octen e. 2-Carbomethoxy-3-(4-bromophenyl)-8-oxabicyclo[3.2.1]-
2-octene, 5d (200 mg, 0.62 mmol), tetrakis(triphenylphos-
phine)palladium(0) (13 mg, 0.011 mmol), and bis(tributyltin)
(0.74 mL, 1.46 mmol) in toluene (4 mL) were degassed by
bubbling N2 through the solution for 10 min. The mixture was