N-(iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines: Synthesis and adrenergic and dopaminergic activity studies

Article abstract of DOI:10.1021/jm980284m

A series of N-(iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines was synthesized and assayed in vitro for their dopaminergic and α-adrenergic activity. Structure-activity relationship (SAR) analysis revealed that the tested benzoquinolines exhibited activity at the D1 rather than the D2 receptor sites in contrast to the D2 receptor subfamily activity reported for their aminotetralin congeners. N-Iodopropenyl substitution was apparently a decisive factor for D1 activity independent of ring substitution pattern. Considering the structural factors influencing α-adrenergic activity, in a general trend, N-iodopropenyl analogues were α₁-active, with the ring- hydroxylated congeners exhibiting the highest affinity. Affinity to the α₂ receptor was even higher with no detectable trend of SAR. However, a combination of the linear arrangement of the [g]-ring system, combined with the ring hydroxyl and the N-iodopropenyl substitution in compound 5c, resulted in a significant enhancement of α₂ activity in this series as demonstrated by an IC₅₀ value of 0.5 nM. A new synthetic approach to the [g]benzoquinoline system is also described.

Full text of DOI:10.1021/jm980284m

J . Med. Chem. 1998, 41, 4165-4170
4165
N-(Iod op r op en yl)-octa h yd r oben zo[f]- a n d -[g]qu in olin es: Syn th esis a n d
Ad r en er gic a n d Dop a m in er gic Activity Stu d ies
Nikos Tagmatarchis, Kyriaki Thermos,† and Haralambos E. Katerinopoulos*
Division of Organic Chemistry, Department of Chemistry, and Laboratory of Pharmacology, School of Medicine, University of
Crete, Iraklion 71 409, Crete, Greece
Received May 5, 1998
A series of N-(iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines was synthesized and assayed
in vitro for their dopaminergic and R-adrenergic activity. Structure-activity relationship (SAR)
analysis revealed that the tested benzoquinolines exhibited activity at the D1 rather than the
D2 receptor sites in contrast to the D2 receptor subfamily activity reported for their
aminotetralin congeners. N-Iodopropenyl substitution was apparently a decisive factor for D1
activity independent of ring substitution pattern. Considering the structural factors influencing
R-adrenergic activity, in a general trend, N-iodopropenyl analogues were R1-active, with the
ring-hydroxylated congeners exhibiting the highest affinity. Affinity to the R2 receptor was
even higher with no detectable trend of SAR. However, a combination of the linear arrangement
of the [g]-ring system, combined with the ring hydroxyl and the N-iodopropenyl substitution
in compound 5c, resulted in a significant enhancement of R2 activity in this series as
demonstrated by an IC50 value of 0.5 nM. A new synthetic approach to the [g]benzoquinoline
system is also described.
Ch a r t 1
In tr od u ction
Dopaminergic system dysfunction in the central ner-
vous system has been related to brain diseases such as
Parkinson’s disease and schizophrenia. Pharmacologi-
cal and biochemical evidence suggests the existence of
the dopamine receptor subtypes, D1 and D2, in the
central nervous system as proposed by Kebabian and
Calne in 1979.1 The D1 site has been linked to the
activation of the adenylate cyclase, whereas the D2
receptor is negatively coupled with this enzyme. To
date, five different dopamine receptor subtypes, D1-D5,
have been cloned that belong to either D1-like (D1, D5)
or D2-like (D2, D3, D4) receptor subfamilies.2
To gain some insight into the topography of dopamine
receptors, it is very important to develop and study the
effects of subtype-selective dopaminergic drugs. During
the last 25 years, a number of different categories of
compounds such as phenethylamines, aminotetralins,
and isochromans, as well as octahydrobenzoquinolines,
which incorporate the basic dopamine skeleton in their
structure, have been synthesized and studied for bio-
logical activity. Octahydrobenzoquinolines are semi-
rigid molecules. They exist in isomeric forms such as
the octahydrobenzo[f]quinolines 1 (Chart 1), where the
piperidine ring shares the C-1 with the tetralin moiety,
and the octahydrobenzo[g]quinolines 2, where the pip-
eridine ring extends the tetralin molecule in a linear
form. Also, each class of these compounds can exist in
the cis and the trans forms depending on the junction
between the B and C rings. As has been shown, the
trans derivatives, maintaining the phenethylamine
moiety in the favored antiperiplanar position, are more
rigid molecules than the cis forms and generally exhibit
higher dopaminergic D2 activity.3 Thus the trans-N-
n-propyl-7-hydroxy analogue of 1 (G ) 7-OH, R ) N-n-
Pr) is more potent in stimulating both DA autoreceptors
and postsynaptic DA receptors than its cis isomer.4
Similarly the trans-N-n-propyl-6-hydroxy analogue of 2
(G ) 6-OH, R ) N-n-Pr) showed stimulatory effects in
the D1 and D2 dopamine models and DA-sensitive
adenylate cyclase and electrically evoked acetylcholine
release, respectively. The cis isomer showed no effect
in either assay.5
Recently a series of trans-monohydroxy-2-[N-propyl-
N-(3′-iodo-2′-propenyl)amino]tetralins was synthesized
and assayed for D2 subfamily dopaminergic activity.6
Among all derivatives, compound 3 shows the highest
binding affinity and receptor selectivity for the D3
receptor. Apparently, the structural features that give
rise to its activity are (a) the position (meta) of the
hydroxyl substituent and (b) the N-trans-iodopropenyl
group.
A combination of the structural elements of com-
pounds 1 and 2 or 3 leads to molecules such as 4a -c
and 5a -c which are expected to exhibit dopaminergic
activity (Chart 2). Prompted by the observation that
in a number of cases D1-active compounds exhibit R2-
adrenergic activity,7,8 we have tested the synthesized
compounds 4 and 5, as well as a number of N- and ring-
substituted derivatives, for both dopaminergic and
R-adrenergic activity.
Ch em istr y
In expanding the aminotetralin system of 3 to the
tricyclic structures of 4 and 5, an additional rigidity
† Laboratory of Pharmacology.
S0022-2623(98)00284-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/12/1998

4166 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Notes
Sch em e 1a
a
Reagents: (i) pyrrolidine, p-TsOH; (ii) acrylamide, then H2O, AcOH; (iii) Et3SiH, TFA; (iv) LiAlH4; (v) allyl bromide; (vi) Bu3SnH,
AIBN; (vii) I2; (viii) HBr, 48%.
Ch a r t 2
of the N-iodopropenyl group was verified by the large
coupling constant of the vinylic protons in the NMR
spectra. Finally demethylation of 10b and 4b by
overnight heating under reflux with 48% HBr yielded
the final compounds 10c and 4c.
The synthesis of the octahydrobenzo[g]quinoline de-
rivatives 5a ,c calls for a selective alkylation of the C-3
position of the â-tetralone systems. This known14,15
synthetic process afforded the desired C-3-allylated
products 12a ,b in overall 83% and 80% yields from the
corresponding â-tetralones (Scheme 2). The carbonyl
group was then protected as its ethylene glycol ketal,
and the intermediates 13a ,b were subjected to a hy-
droboration-oxidation reaction with disiamylborane
and hydrogen peroxide-sodium hydroxide, to furnish
primary alcohols 14a ,b, respectively. J ones’ oxidation
of the hydroxyl groups and esterification of the resulting
acids with methanol gave the unmasked keto esters
15a ,b. The C ring was formed in a three-step sequence
where the above keto esters were transformed to the
N-benzyl derivatives 18a ,b. Reaction of the keto esters
with excess benzylamine in the presence of acetic acid
yielded dark-brown residues, which NMR spectra showed
a singlet at 5.6 ppm for the vinylic protons with a
concurrent disappearance of the methyl ester peak
indicating their conversion to the corresponding enam-
ides. Reduction of the carbonyl group of 16a ,b with
lithium aluminum hydride followed by sodium borohy-
dride/acetic acid treatment yielded the trans compounds
18a ,b as the major products. The verification of the
trans fusion of the B/C rings was established by the
NMR spectra of the N-benzyl derivatives.9-12,16,17 At the
trans-fused rings the N-benzyl methylene protons ap-
pear as a pair of doublets which have a large chemical
shift difference, whereas at the cis compounds these
benzyl protons appear as a singlet. The IR spectra of
18a ,b again exhibited the typical for trans fusion
“Bohlman bands”. Hydrogenolysis over 10% Pd on
activated carbon afforded the N-debenzylated octahy-
drobenzo[g]quinolines which, under the same experi-
mental conditions followed for the octahydrobenzo[f]-
quinolines, yielded the desired derivatives.
factor was introduced in the target molecules: The
possibility of the cis or trans fusion of the B/C rings had
to be considered, and given the higher activity of the
latter as reported in the literature, an improved syn-
thetic path was followed for the synthesis of octahy-
drobenzo[f]quinolines. Considering a number of set-
backs of various procedures reported to date,9-12 a new
synthetic pathway was designed for the preparation of
the [g] analogues.
Compounds 4c and 5c were prepared in 7 and 10
steps in 11% and 7.7% overall yields, respectively.
Using an improved procedure to the 1,2,3,4,4a,5,6,10b-
octahydrobenzo[f]quinoline system,13 aza-annulation of
â-tetralone pyrrolidine enamines 6a ,b (easily isolated
and characterized by their NMR and IR spectra) with
neat acrylamide gave the corresponding enamides 7a ,b
(Scheme 1). These enamides, upon “ionic hydrogena-
tion” with triethylsilane-trifluoroacetic acid, furnished
exclusively the trans-hexahydrobenzo[f]quinolinones 8a,b.
The trans disposition of the 4a and 10b hydrogens in
these structures was verified by their NMR coupling
constants. Lithium aluminum hydride reduction of the
lactams gave the desired octahydrobenzo[f]quinolines
9a ,b. The presence of the strong “Bohlman bands” in
their respective IR spectra further verified the trans
fusion of the B and C rings.13 N-Alkylation with
propargyl bromide, in the absence of base (which could
isomerize the triple bond to the corresponding allene),
produced the N-propargyl derivatives 10a ,b which,
under free radical reaction conditions (tributyltin hy-
dride, AIBN), gave the syn addition products to the
triple bond. An iodo-demetalation reaction furnished
iodopropenyl compounds 4a ,b. The trans conformation

Notes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4167
Sch em e 2a
a
Reagents and conditions: (i) (CH3O)2CO, CH3ONa, reflux; (ii) LDA (2 equiv) allyl bromide, -78 °C; (iii) LiCl, DMSO, H2O, reflux; (iv)
HOCH2CH2OH, p-TsOH, reflux; (v) disiamylborane, H2O2, NaOH, 0 °C; (vi) J ones reagent, 0 °C, (vii) CH2OH, H2SO4 (conc), rt; (viii)
BnNH2, AcOH, reflux; (ix) LiAlH4, rt; (x) NaBH4, rt; (xi) H2, 10% Pd/C, EtOH, rt; (xii) allyl bromide; (xiii) Bu3SnH, AIBN, PhCH3, reflux;
(xiv) I2; HBr, 48%, reflux.
Ta ble 1. Inhibition of [3H]Spiroperidol and [3H]SCH-23390
Ta ble 2. Inhibition of [3H]Prazosin and [3H]Rauwolscine
Binding to Rat Striatal Membranesa
Binding to Rat Cortical Membranesa
IC50 (µM)
IC50 (nM)
drug
[3H]spiroperidol
[3H]SCH-23390
drug
[3H]prazosin
[3H]rauwolscine
9a
10a
4a
NAb
NA
NA
NA
NA
NA
1.90 ( 0.5
NA
9a
10a
4a
NAb
NA
253 ( 116
NA
154 ( 66
160 ( 81
128 ( 86
55d
9b
9b
10b
4b
4c
10c
19a
20a
5a
19b
20b
5b
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
0.49 ( 0.10
5.11 ( 0.91
0.70 ( 0.02
0.22 ( 0.05
NA
10b
4b
4c
10c
19a
20a
5a
19b
20b
5b
497 ( 51
508 ( 71
225 ( 77
NA
196 ( 134
18 ( 4.5
47 ( 28
49 ( 27
130 ( 61
142 ( 84
33 ( 2
67.5 ( 3.5
197 ( 8
226 ( 54
0.5 ( 0.2
251 ( 78
750c
0.27 ( 0.22
1.13 ( 0.13
NA
NA
NA
NA
1300 ( 295
274 ( 151
2200 ( 700
1850 ( 350
43 ( 16
54 ( 29
209 ( 173
1500c
0.22c
NA
NA
0.08 ( 0.04
0.12 ( 0.01
0.70 ( 0.31
5c
5c
20c
20c
(()-ADTN
(-)-APO
noradrenaline
0.43 ( 0.05
a
b
Experiments were performed three times in duplicate. Not
a
b
d
Experiments were performed three times in duplicate. Not
active up to a concentration of 5 µM. c Values from ref 18. Tested
only once due to limited amount of material.
active up to a concentration of 5 µM. c Tested only once due to
limited amount of material.
octahydrobenzoquinolines were inactive at D2 receptor
sites. The only exception was 6-hydroxy-N-(iodoprope-
nyl)octahydrobenzo[g]quinoline (5c) which exhibited
higher D2 affinity as compared to the reference drugs.
Affinity to the D1 receptors, however, was exhibited by
Discu ssion of Resu lts
Binding assays revealed a number of unexpected
results, presented in Tables 1 and 2. In contrast to the
activity exhibited by their aminotetralin congeners,

4168 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Notes
added dried DMF (4 mL), 9a 13 (0.15 g, 0.8 mmol), and
propargyl bromide (0.1 g, 0.8 mmol). The mixture was heated
at 100 °C for 3 h. Ether (25 mL) was added to the system,
the organic layer was extracted with saturated NaCl (5 × 25
mL) and dried over Na2SO4, and the solvents were removed
in vacuo. The product was purified by flash chromatography
using 4% MeOH/CH2Cl2 as eluent, to give 0.1 g (60%) of an
oil: IR (neat) ν 2858, 2804; 1H NMR (CDCl3) δ 7.30-7.27 (m,
1H), 7.19-7.05 (m, 3H), 3.86 (dd, J 1 ) 2.3 Hz, J 2 ) 17.6 Hz,
1H), 3.39 (dd, J 1 ) 2.3 Hz, J 2 ) 17.6 Hz, 1H), 2.93-2.85 (m,
3H), 2.65-2.56 (m, 2H), 2.51 (dt, J 1 ) 3.3 Hz, J 2 ) 12.9 Hz,
1H), 2 37-2.27 (m, 1H), 2.18 (t, J ) 2.3 Hz, 1H), 1.89-1.77
(m, 2H), 1.64-1.47 (m, 1H), 1.35-1.18 (m, 1H), 0.94-0.84 (m,
1H); GC/MS (m/z) 225 (M+). Anal. (C16H19N) C, H, N.
tr a n s-1,2,3,4,4a ,5,6,10b-Octa h yd r o-N-(3′-tr ibu tylsta n yl-
2′-p r op en yl)ben zo[f]qu in olin e (11a ). A mixture of 10a
(0.22 g, 0.98 mmol), tributyltin hydride (0.85 g, 2.93 mmol),
and a trace of AIBN was heated at 90 °C for 4 h under nitrogen
atmosphere. The solvent was then evaporated, and the residue
was purified by flash chromatography using ethyl acetate/
petroleum ether (20/80) to give 0.2 g (40%) of the product.
a number of compounds including ring-unsubstituted
analogues 4a and 5a , methoxy ring-substituted com-
pounds 4b and 5b, and their phenolic analogues 4c and
5c. It appears therefore that ring substitution is not a
decisive factor for D1 activity. Compound 4c, among
the most active compounds in the [f]-series, is D1-
selective, whereas its [g]-series analogue 5c exhibits
similar activity for both D2 and D1 receptors as indi-
cated by the respective IC50 values of 0.49 and 0.12 µM.
Worth noting is that the linear arrangement of the
tricyclic system in the [g]-series, combined with the ring
hydroxylation, fulfills the requirements for D1 activity
regardless of the N-substitution: N-propargyl analogue
20c, a noniodinated compound, has an IC50 value of 0.70
µM as compared to 0.12 µM for 5c and a value of 0.43
µM for (-)-apomorphine. Selectivity between the R
receptor subtypes was not as distinctive as in the
dopaminergic receptors, although IC50 values are, in
general terms, lower for the R2 receptor.
Considering the structural factors influencing the
drugs’ affinity to the R adrenoceptors, in a general trend,
N-iodopropenyl-substituted compounds were R1-active,
with the ring-hydroxylated congeners exhibiting the
highest affinity. However a distinct preference for the
R2 receptor is demonstrated by the facts that (a) all
tested compounds, regardless of ring or nitrogen sub-
stitution pattern, were active at this receptor and (b)
statistically, respective IC50 values for the R2 receptor
were lower than those for the R1 receptor. Although
there is not a clear structure/R2 activity relationship
pattern in either series, the linear tricyclic arrangement
of the [g] isomers, combined with the ring-hydroxyl and
the N-iodopropenyl substitution, resulted in the signifi-
cantly R2-active compound 5c with an IC50 value of 0.5
nM as compared with the reported value of 750 nM for
noradrenaline, thus making this compound a potential
R2-acting drug.
tr a n s-1,2,3,4,4a ,5,6,10b-Octa h yd r o-N-(3′-iod o-2′-p r op e-
n yl)ben zo[f]qu in olin e (4a ). To a solution of 11a (0.2 g, 0.39
mmol) in dry chloroform (2 mL) was added a 0.1 M solution of
iodine in chloroform (2 mL) dropwise, and the system was
stirred at room temperature for 20 h. The solution was then
diluted with chloroform (15 mL), extracted with saturated
Na2S2O3 (6 × 25 mL) and saturated NaCl (3 × 5 mL), and
dried over Na2SO4, and the solvent was evaporated. The
residue was purified by flash chromatography using MeOH/
CH2Cl2, 2/98. The product yield was 0.12 g (87%): IR (neat)
1
ν 2855; H NMR(CDCl3) δ 7.27-7.24 (m, 1H), 7.17-7.04 (m,
3H), 6.64 (ddd, J 1 ) 6.5 Hz, J 2 ) 7.6 Hz, J 3 ) 14H.0 Hz, 1H),
6.23 (dd, J 1 ) 0.8 Hz, J 2 ) 14 Hz, 1H), 3.39 (ddd, J 1 ) 0.8 Hz,
J 2 ) 6.5 Hz, J 3 ) 14.7 Hz, 1H), 3.21 (dd, J 1 ) 7.6 Hz, J 2
14.7 Hz, 1H), 2.98-2.84 (m, 3H), 2.58 (dt, J 1 ) 3.2 Hz, J 2
)
)
9.8 Hz, 1H), 2.47 (ddd, J 1 ) 3.2 Hz, J 2 ) 8,0 Hz, J 3 ) 12.8 Hz,
1H), 2.32-2.10 (m, 3H), 1.84-1.73 (m, 1H), 1.68-1.52 (m, 2H),
1.32-1.16 (m, 1H); GC/MS (m/z) 353 (M+). Anal. (C16H20NI‚
1/3H2O) C, H, N.
tr a n s-7-Meth oxy-1,2,3,4,4a ,5,6,10b-octa h yd r o-N-(2′-p r o-
p yn yl)ben zo[f]qu in olin e (10b). Prepared from 9b13 in the
same manner as 10a in 73% yield: IR (neat) ν 2859, 2835; 1H
NMR (CDCl3) δ 7.14 (dd, J 1 ) J 2 ) 7.8 Hz, 1H), 6.93 (d, J )
7.8 Hz, 1H), 6.69 (d, J ) 7.8 Hz, 1H), 3.87 (dd, J 1 ) 2.1 Hz, J 2
) 17.6 Hz, 1H), 3.84 (s, 3H), 3.39 (dd, J 1 ) 2.1 Hz, J 2 ) 17.6
P h a r m a cology. The pharmacological behavior of
the synthesized octahydrobenzo[f]quinoline and octahy-
drobenzo[g]quinoline derivatives was examined with
radioligand binding assays as previously described.18
The dopaminergic activity of these compounds was
studied by examining their inhibition of the specific
binding of [3H]spiroperidol and [3H]SCH-23390 to D2
and D1 receptors, respectively, in rat striatal mem-
branes. The same compounds were tested also for R1-
and R2-adrenergic activity. [3H]prazosin and [3H]rau-
wolsine were used to label the R1- and R2-adrenergic
receptors in rat cortical membranes, respectively. Com-
pounds that displayed inhibitory constant (IC50) values
of more than 5 µM were characterized as inactive.
Hz, 1H), 3.01-2.84 (m, 2H), 2.67-2.54 (m, 5H), 2.46 (dt, J 1
)
2.6 Hz, J 2 ) 7.2 Hz, 1H), 2.30 (ddd, J 1 ) 2.6 Hz, J 2 ) 5.5 Hz,
J 3 ) 11.3 Hz, 1H), 2.19 (t, J ) 2.1 Hz, 1H), 1.89-1.77 (m, 2H),
1.44 (ddd, J 1 ) 5.5 Hz, J 2 ) 11.5 Hz, J 3 ) 17.8 Hz, 1H), 1.21
(ddd, J 1 ) 6.1 Hz, J 2 ) 12.4 Hz, J 3 ) 17.8 Hz, 1H); GC/MS
(m/z) 255 (M+). Anal. (C17H21NO‚6H2O) C, H, N.
tr a n s-7-Meth oxy-1,2,3,4,4a,5,6,10b-octah ydr o-N-(3′-tr ibu -
tylsta n yl-2′-p r op en yl)ben zo[f]qu in olin e (11b). Prepared
from 10b in the same manner as 11a in 70% yield.
tr a n s-7-Meth oxy-1,2,3,4,4a,5,6,10b-octah ydr o-N-(3′-iodo-
2′-p r op en yl)ben zo[f]qu in olin e (4b). Prepared from 11b in
the same manner as 4a in 74% yield: IR (neat) ν 2834; 1H
NMR (CDCl3) δ 7.14 (dd, J 1 ) 7.9 Hz, J 2 ) 8.0 Hz, 1H), 6.89
(d, J ) 8.0 Hz, 1H), 6.70-6.54 (m, 2H), 6.28 (d, J ) 14.4 Hz,
1H), 3.79 (s, 3H), 3.39 (dd, J 1 ) 6.5 Hz, J 2 ) 14.8 Hz, 1H),
3.29 (dd, J 1 ) 8.0 Hz, J 2 ) 14.8 Hz, 1H), 3.02-2.90 (m, 2H),
2.67-2.44 (m, 2H), 2.33-2.15 (m, 2H), 1.83 (ddd, J 1 ) 3.1 Hz,
Exp er im en ta l Section
Melting points were taken on a Thomas-Hoover apparatus
and are uncorrected. IR spectra were taken on a Perkin-Elmer
1760X FT IR spectrometer. NMR spectra were taken on a
Varian FT-80A, 80 MHz, and a AC 250 Bruker FT-NMR
spectrometer; proton chemical shifts are reported in ppm
relative to tetramethylsilane. Mass spectra were taken on a
Hewlett-Packard model 5890 gas chromatograph coupled with
a Hewlett-Packard 5971A mass selective detector. Elemental
analyses were taken by the Analytical Laboratory of the
Institute of Marine Biology, Crete, Greece, and are within 0.4%
of the theoretical values of the indicated elements unless
otherwise stated.
J 2 ) 9.0 Hz, J 3 ) 12.6 Hz, 1H), 1.58 (ddd, J 1 ) 6.1 Hz, J 2
)
12.0 Hz, J 3 ) 18.2 Hz), 1.29-1.13 (m, 4H); GC/MS (m/z) 383
(M+). Anal. (C17H22NOI‚1/2H2O) C, H, N.
tr a n s-7-Hydr oxy-1,2,3,4,4a,5,6,10b-octah ydr o-N-(3′-iodo-
2′-p r op en yl)ben zo[f]qu in olin e (4c). Deprotection of the
methoxy compound was achieved by heating 4c (0.07 g, 0.18
mmol) under reflux with 48% HBr for 20 h. The solution was
cooled and diluted with chloroforn (20 mL); the organic layer
was washed with 10% NaHCO3 and brine. The organic solvent
was evaporated, and the residue was purified by flash chro-
matography (MeOH:CH2Cl2 ) 2:98) to yield 0.06 g (90%) of
tr a n s-1,2,3,4,4a ,5,6,10b-Octa h yd r o-N-(2′-p r op yn yl)ben -
zo[f]qu in olin e (10a ). In a 25-mL round-bottomed flask were

Notes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4169
1
pure product: IR (neat) ν 2860; H NMR (CDCl3) δ 6.99 (dd,
J 1 ) 7.7 Hz, J 2 ) 8.1 Hz, 1H), 6.72-6.55 (m, 3H), 6.24 (dd, J 1
) 0.7 Hz, J 2 ) 14.4 Hz, 1H), 3.24 (ddd, J 1 ) 0.7 Hz, J 2 ) 7.1
Hz, J 3 ) 14.4 Hz 1H), 3.18 (dd, J 1 ) 4.8 Hz, J 2 ) 14.8 Hz,1H),
2.93-2.81 (m, 2H), 2.66-2.15 (m, 3H), 1.90-1.45 (m, 7H).
Anal. (C16H20NOI‚3H2O) C, H, N.
methanol (80 mL) was added 10% palladium in activated
carbon, and the mixture was stirred under hydrogen atmo-
sphere for 15 h. The catalyst was then removed by filtration,
the solvent was evaporated, and the residue was purified by
flash chromatography (MeOH:CH2Cl2 ) 5:95) to give 1 g (95%)
of the product: 1H NMR (CDCl3) δ 7.21-7.00 (m, 4H), 3.54
(dd, J 1 ) 3.7 Hz, J 2 ) 9.1 Hz 1H), 3.39-2.84 (m, 4H), 2.60-
2.44 (m, 2H), 2.31-2.12 (m, 3H), 2.03-1.90 (m, 2H), 1.38 (ddd,
J 1 ) 3.7 Hz, J 2 ) 13.0 Hz, J 3 ) 15.7 Hz, 1H); GC/MS (m/z)
187 (M+). Anal. (C16H19N) C, H, N.
tr a n s-1,2,3,4,4a ,5,10,10a -Oct a h yd r o-N-(2′-p r op yn yl)-
ben zo[g]qu in olin e (20a ). Prepared from 19a in the same
manner as 10a in 53% yield: IR (neat) ν 2877; 1H NMR
(CDCl3) δ 7.29-7.17 (m, 1H), 7.15-7.09 (m, 3H), 3.86 (dd, J 1
) 2.3 Hz, J 2 ) 17.6 Hz, 1H), 3.39 (dd, J 1 ) 2.3 Hz, J 2 ) 17.6
Hz, 1H), 2.91-2.85 (m, 2H), 2.65-2.45 (m, 3H), 2.38-2.22 (m,
1H), 2.18 (t, J ) 2.3 Hz, 1H), 1.87-1.79 (m, 2H), 1.72-1.52
(m, 3H), 1.34-1.23 (m, 1H); GC/MS (m/z) 255 (M+).
tr a n s-7-Hyd r oxy-1,2,3,4,4a ,5,6,10b-octa h yd r o-N-(2′-p r o-
p yn yl)ben zo[f]qu in olin e (10c). Prepared from 10b in the
same manner as 4c in 85% yield: IR (neat) ν 2853; H NMR
(CDCl3) δ 7.04 (dd, J 1 ) J 2 ) 7.9 Hz, 1H), 6.88 (d, J ) 7.9 Hz,
1H), 6.61 (d, J ) 7.9 Hz, 1H), 3.86 (dd, J 1 ) 2.1 Hz, J 2 ) 17.7
Hz, 1H), 3.40 (dd, J 1 ) 2.1 Hz, J 2 ) 17.7 Hz, 1H), 2.95-2.86
(m, 2H), 2.64-2.59 (m, 3H), 2.49-2.30 (m, 3H), 2.20 (t, J )
2.1 Hz, 1H), 1.87-1.79 (m, 2H), 1.55-1.48 (m, 1H), 1.31-1.24
(m, 2H). Anal. (C16H19NO) C, H, N.
1
3-(3′-Hyd r oxyp r op yl)-2-tetr a lon e Eth ylen e Keta l (14a ).
To a dry, 150-mL round-bottomed flask was added a solution
of 13a 7 (1.2 g, 5.2 mmol) in 50 mL of dry THF, and a solution
of disiamylborane (prepared by the addition of 2-methyl-2-
butene (2.86 mL, 27.0 mmol) to a solutiom of 10 M BMS (1.3
mL, 13.0 mmol)) was added dropwise at 0 °C. The system was
then stirred at 0 °C for 1 h, and then a 3 N NaOH solution
(4.33 mL, 13 mmol) was added, followed by dropwise addition
of 30% H2O2 (4.43 mL, 39.0 mmol). The solution was stirred
for 1 h at room temperature, diluted with ethyl acetate (50
mL), washed with saturated NaCl solution (3 × 20 mL), and
dried over Na2SO4, and the solvents were evaporated. The
residue was purified by flash chromatography (MeOH:CH2-
Cl2 ) 5:95) to give 1.1 g (86%) of pure product.
3-(2′-(Meth oxyca r bon yl)eth yl)-2-tetr a lon e (15a ). In a
dry 250-mL round-bottomed flask was added a solution of 14a
(4.8 g, 19.4 mmol). The compound was oxidized by dropwise
addition of J ones’ reagent until the solution turned red. The
excess reagent was destroyed by the addition of 2-propanol,
the solids were removed by filtration, and the solvents were
evaporated. Methanol (40 mL) and a trace of H2SO4 were
added to the residue, and the solution was stirred at room
temperature for 16 h. The solvent was then evaporated, the
residue was dissolved in ethyl acetate (100 mL) and washed
with saturated NaHCO3 (5 × 20 mL) and brine (5 × 20 mL),
and the solvent was evaporated. The residue was purified by
flash chromatography (ethyl acetate:petroleum ether ) 20:80)
to give 3.0 g (67%) of pure product.
tr a n s-1,2,3,4,4a,5,10,10a-Octah ydr o-N-(3′-tr ibu tylstan yl-
2′-p r op en yl)ben zo[g]qu in olin e (21a ). Prepared from 20a
in the same manner as 11a in 41% yield.
tr a n s-1,2,3,4,4a ,5,10,10a -Oct a h yd r o-N-(3′-iod o-2′-p r o-
p en yl)ben zo[g]qu in olin e (5a ). Prepared from 21a in the
1
same manner as 4a in 77% yield: IR (neat) ν 2871, 2854; H
NMR (CDCl3) δ 7.28-7.25 (m, 1H), 7.18-7.04 (m, 3H), 6.64
(ddd, J 1 ) 6.2 Hz, J 2 ) 7.6 Hz, J 3 ) 14.3 Hz, 1H), 6.23 (dt, J 1
) 1.2 Hz, J 2 ) 14.3 Hz, 1H), 3.38 (ddd, J 1 ) 1.4 Hz, J 2 ) 6.2
Hz, J 3 ) 14.8 Hz, 1H), 3.20 (ddd, J 1 ) 0.8 Hz, J 2 ) 7.6 Hz, J 3
) 14.8 Hz, 1H), 2.97-2.84 (m, 3H), 2.57 (dt, J 1 ) 3.4 Hz, J 2
11.4 Hz, 1H), 2.46 (dd, J 1 ) 3.4 Hz, J 2 ) 12.6 Hz, 1H), 2.30-
2.10 (m, 3H), 1.87-1.78 (m, 2H), 1.45 (ddd, J 1 ) 5.5 Hz, J 2
)
)
11.9 Hz, J 3 ) 17.7 Hz, 1H), 1.21 (ddd, J 1 ) 6.1 Hz, J 2 ) 12.4
Hz, J 3 ) 17.7 Hz, 1H); GC/MS (m/z) 353 (M+). Anal. (C16H20N)
C, H, N.
6-Meth oxy-3-(3′-h yd r oxyp r op yl)-2-tetr a lon e Eth ylen e
Keta l (14b). Prepared from 13b15 in the same manner as 14a
in 85% yield.
6-Meth oxy-3-(2′-(m eth oxyca r bon yl)eth yl)-2-tetr a lon e
(15b). Prepared from 14b in the same manner as 15a in 68%
yield: IR (neat) ν 2840; 1H NMR (CDCl3) δ 7.15 (dd, J 1 ) J 2
)
7.6 Hz, 1H), 6.72 (d, J ) 7.6 Hz, 1H), 6.68 (d, J ) 7.6 Hz, 1H),
3.81 (s, 3H), 3.64 (s, 3H), 3.59 (s, 1H), 3.55 (s, 1H), 3.31 (dd,
J 1 ) 4.7 Hz, J 2 ) 15.1 Hz, 1H), 2.60 (dd, J 1 ) 10.4 Hz, J 2
)
15.1 Hz, 1H), 2.63-2.49 (m, 3H), 2.13 (dddd, J 1 ) 6.7 Hz, J 2
) 7.3 Hz, J 3 ) 13.6 Hz, J 4 ) 14.2 Hz, 1H), 1.80-1.69 (m, 1H).
cis- a n d tr a n s-6-Meth oxy-1,2,3,4,4a ,5,10,10a -octa h yd r o-
N-b en zylb en zo[g]q u in olin e (cis- a n d tr a n s-18b ). Pre-
pared from 15b in the same manner as 18a in 2.8% and 53%
yields, respectively. tr a n s-18b: IR (neat) ν 2836; 1H NMR
(CDCl3) δ 7.35-7.11 (m, 6H), 6.92 (d, J ) 8.0 Hz, 1H), 4.15 (d,
J ) 13.7 Hz, 1H) 3.80 (s, 3H), 3.43 (d, J ) 13.7 Hz, 1H), 2.99-
2.89 (m, 2H), 2.71-2.64 (m, 1H), 2.56-2.49 (m, 2H), 2.15 (dt,
J 1 ) 2.2 Hz, J 2 ) 11.0 Hz, 1H), 2.09-2.02 (m, 1H), 1.77-1.59
(m, 3H), 1.27-1.17 (m, 2H); GC/MS (m/z) 307 (M+). cis-18b:
1H NMR (CDCl3) δ 7.34-7.08 (m, 6H), 6.71 (d, J ) 7.6 Hz,
1H), 6.61 (d, J ) 8.1 Hz, 1H), 3.77 (s, 3H), 3.74 (s, 2H), 3.01-
2.94 (m, 3H), 2.52-2.37 (m, 3H), 2.00-1.63 (m, 6H).
tr a n s-6-Meth oxy-1,2,3,4,4a ,5,10,10a -octa h yd r oben zo[g]-
qu in olin e (19b). Prepared from tr a n s-18b in the same
manner as 19a in 92% yield: 1H NMR (CDCl3) δ 7.14 (dd, J 1
) J 2 ) 8.0 Hz, 1H), 6.83 (d, J ) 8.0 Hz, 1H), 6.68 (d, J ) 8.0
Hz, 1H), 3.78 (s, 3H), 3.54 (dd, J 1 ) 3.4 Hz, J 2 ) 11.4 Hz, 1H),
3.11-2.96 (m, 3H), 2.59 (dt, J 1 ) 3.4 Hz, J 2 ) 13.2 Hz, 1H),
2.65-2.51 (m, 2H), 2.42-1.97 (m, 4H), 1.38 (ddd, J 1 ) 2.8 Hz,
J 2 ) 12.2 Hz, J 3 ) 15.0 Hz, 1H); GC/MS (m/z) 217 (M+). Anal.
(C17H21NO‚1.5H2O) C, H, N.
cis- a n d tr a n s-1,2,3,4,4a ,5,10,10a -Octa h yd r o-N-ben zyl-
ben zo[g]qu in olin e (cis- a n d tr a n s-18a ). A solution of 15a
(3.0 g, 12.9 mmol), benzylamine (6.9 g, 64.6 mmol), and glacial
acetic acid (0.78 g, 12.9 mmol) in benzene (100 mL) was heated
under reflux for 5 h. The volatiles were evaporated to give a
brownish residue that was dissolved in ether (150 mL). LiAlH4
(1.96 g, 51.7 mmol) was added; the mixture was stirred at room
temperature for 15 h, then treated with water (2 mL), 15%
NaOH (2 mL), and water (6 mL), and filtered. The solution
was washed with brine (5 × 20 mL) and dried over Na2SO4,
and the solvent was evaporated. To the resulting residue were
added 2-propanol and NaBH4 (0.98 g, 25.9 mmol), and the
mixture was stirred at room temperature for 15 h. The solvent
was then evaporated, and the residue was purified by flash
chromatography (MeOH:CH2Cl2 ) 3:97) to give 0.3 g (8.5%)
of the cis isomer and 1.7 g (48%) of the trans isomer. tr a n s-
18a : IR (neat) ν 2855; 1H NMR (CDCl3) δ 7.36-7.19 (m, 6H),
7.17-7.07 (m, 3H), 4.16 (d, J ) 13.6 Hz, 1H), 3.38 (d, J ) 13.6
Hz, 1H), 2.95-2.90 (m, 3H), 2.71 (dt, J 1 ) 3.5 Hz, J 2 ) 10.3
Hz, 1H), 2.49-2.39 (m, 2H), 2.17 (dt, J 1 ) 3.2 Hz, J 2 ) 10.3
Hz, 1H), 2.10-1.99 (m, 1H), 1.83-1.69 (m, 3H), 1.33-1.17 (m,
1H); GC/MS (m/z) 277 (M+). cis-18a : IR ν (cm-1) 3398, 3060,
3024, 2933, 2796; 1H NMR (CDCl3) δ 7.41-7.26 (m, 5H), 7.23-
7.06 (m, 4H), 3.77 (s, 2H), 3.13 (ddd, J 1 ) 2.9 Hz, J 2 ) 4.6 Hz,
J 3 ) 7.6 Hz, 1H), 3.04-2.96 (m, 1H), 2.95 (ddd, J 1 ) 3.1 Hz,
tr a n s-6-Met h oxy-1,2,3,4,4a ,5,10,10a -oct a h yd r o-N-(2′-
p r op yn yl)ben zo[g]qu in olin e (20b). Prepared from 19b in
the same manner as 10a in 53% yield: IR (neat) ν 2873, 2835;
1H NMR (CDCl3) δ 7.14 (dd, J 1 ) J 2 ) 8.0 Hz, 1H), 6.92 (d, J
) 8.0 Hz, 1H), 6.68 (d, J ) 8.0 Hz, 1H), 3.87 (dd, J 1 ) 2.2 Hz,
J 2 ) 5.5 Hz, J 3 ) 8.6 Hz, 1H), 2.73 (ddd, J 1 ) 6.2 Hz, J 2
)
11.6 Hz, J 3 ) 17.1 Hz, 1H), 2.56-2.53 (m, 2H), 2.08 (ddd, J 1
) 5.5 Hz, J 2 ) 11.6 Hz, J 3 ) 17.1 Hz, 1H), 1.94-1.75 (m, 5H).
t r a n s-1,2,3,4,4a ,5,10,10a -Oct a h yd r ob e n zo[g]q u in o-
lin e (19a ). To a solution of trans-18a (1.7 g, 6.2 mmol) in
J 2 ) 17.6 Hz, 1H), 3.79 (s, 3H), 3.38 (dd, J 1 ) 2.2 Hz, J 2
)
17.6 Hz, 1H), 3.15 (ddd, J 1 ) 3.8 Hz, J 2 ) 7.9 Hz, J 3 ) 11.1
Hz, 1H), 3.05-2.90 (m, 2H), 2.80-2.48 (m, 4H), 2.24 (t, J )

4170 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Notes
and 1,2,3,4,4a,5,6,10b-octahydrobenzoquinolines: Structural and
stereochemical considerations for centrally acting pre- and
postsynaptic dopamine-receptor agonists. J . Med. Chem. 1985,
28, 215-225.
2.2 Hz, 1H), 2.08-1.68 (m, 4H), 1.66-1.58 (m, 1H); GC/MS
(m/z) 255 (M+).
tr a n s-6-Met h oxy-1,2,3,4,4a ,5,10,10a -oct a h yd r o-N-(3′-
tr ibu tylsta n yl-2′-p r op en yl)ben zo[g]qu in olin e (21b). Pre-
pared from 21b in the same manner as 11a in 41% yield.
tr a n s-6-Met h oxy-1,2,3,4,4a ,5,10,10a -oct a h yd r o-N-(3′-
iod o-2′-p r op en yl)ben zo[g]qu in olin e (5b). Prepared from
21b in the same manner as 4a in 90% yield: IR (neat) ν 2869,
(5) Seiler, P M.; Markstein, R.; Walkinshaw, M. D.; Boelsterli, J . J .
Characterization of dopamine receptor subtypes by comparative
structure-activity relationships: Dopaminomimetic activities
and solid state conformation of monohydroxy-1,2,3,4,4a,5,10,-
10a-octahydrobenzo[g]quinolines and its implications for a rota-
mer-based dopamine receptor model. Mol. Pharmacol. 1989, 35,
643-651.
(6) Chumpradit, S.; Kung, M.-P.; Vessotskie, J .; Foulon, C.; Mu, M.;
Kung, H. F. Iodinated 2-Aminotetralins and 3-Amino-1-ben-
zopyrans: Ligands for Dopamine D2 and D3 Receptors. J . Med.
Chem. 1994, 37, 4245-4250.
(7) Katerinopoulos, H. E.; Tagmatarchis, N.; Zaponakis, G.; Ke-
falakjis, N.; Kordatos, K.; Spyrakis, M.; Thermos, K. â-Alkoxy-
substituted phenethylamines: a family of compounds potentially
active at the dopamine and R-adrenergic receptors. Eur. J . Med.
Chem. 1995, 30, 949-954.
(8) DeNinno, M. P.; Schoenleber, R.; Perner, R. J .; Lijewski, L.; Asin,
K. E.; Britton, D. R.; MacKenzie, R.; Kebabian, J . W. Synthesis
and dopaminergic activity of 3-substituted 1-(aminomethyl)-3,4-
dihydro-5.6-dihydroxy-1H-benzopyrans: Characterization of an
auxiliary binding region in the D1 receptor. J . Med. Chem. 1991,
34, 2561-2569.
(9) Smissman, E. E.; El-Antably, S.; Hedrich, L. W.; Walaszek, E.
J .; Tseng, L.-F. Synthesis of cisoid and transoid analogues of
phenethylamine. J . Med. Chem. 1973, 16, 109-113.
(10) Cannon, J . G.; Lee, T.; Beres, J . A.; Goldman, H. D. N-Alkyl
derivatives of trans-6,7-dihydroxy1,2,3,4,4a,5,10,10b-octahy-
drobenzo[g]quinoline. A congener of apomorphine lacking the
non-oxygenated aromatic ring. J . Heterocycl. Chem. 1980, 17,
1633-1636.
(11) Cannon, J . G.; Amoo, V. E.; Long, J . P.; Bhatnagar, R. K.; Flynn,
J . R. p-Dimethoxy substituted trans-octahydrobenzo[f]- and -[g]-
quinolines: Synthesis and assessment of dopaminergic agonist
effects. J . Med. Chem. 1986, 29, 2529-2534.
1
2854; H NMR (CDCl3) δ 7.13 (d, J 1 ) J 2 ) 7.9 Hz, 1H), 6.90
(d, J ) 7.9 Hz, 1H), 6.71-6.61 (m, 2H), 6.24 (d, J ) 14.4 Hz,
1H), 3.79 (s, 3H), 3,40 (dd, J 1 ) 6.9 Hz, J 2 ) 14.8 Hz, 1H),
3.24 (dd, J 1 ) 7.6 Hz, J 2 ) 14.8 Hz, 1H), 2.97-2.89 (m, 2H),
2.64-2.44 (m, 3H), 2.35-2.11 (m, 3H), 1.88-1.77 (m, 3H),
1.53-1.42 (m, 1H); GC/MS (m/z) 383 (M+). Anal. (C17H22NOI‚
1.5H2O) C, H, N.
tr a n s-6-H yd r oxy-1,2,3,4,4a ,5,10,10a -oct a h yd r o-N-(3′-
iod o-2′-p r op en yl)ben zo[g]qu in olin e (5c). Prepared from
5b in the same manner as 4c in 90% yield: 1H NMR (CDCl3)
δ 6.92 (dd, J 1 ) 7.9 Hz, J 2 ) 8.1 Hz, 1H), 6.70-6.57 (m, 3H),
6.22 (d, J ) 14.3 Hz, 1H), 3.67-3.50 (m, 1H), 3.60 (dd, J 1
)
8.4 Hz, J 2 ) 15.0 Hz, 1H), 3.47 (dd, J 1 ) 5.6 Hz, J 2 ) 15.0 Hz,
1H), 3.06-2.88 (m, 2H), 2.66-2.60 (m, 2H), 2.52-2.15 (m, 2H),
1.84-1.54 (m, 3H), 1.26-1.20 (m, 2H). Anal. (C16H20NOI‚
2H2O) C, H, N.
tr a n s-6-H yd r oxy-1,2,3,4,4a ,5,10,10a -oct a h yd r o-N-(2′-
p r op yn yl)ben zo[g]qu in olin e (20c). Prepared from 21b in
1
the same manner as 10c in 85% yield: IR (neat) ν 2878; H
NMR (CDCl3) δ 7.02 (d, J 1 ) J 2 ) 8.0 Hz, 1H), 6.87 (d, J ) 8.0
Hz, 1H), 6.61 (d, J ) 8.0 Hz, 1H), 3.88 (dd, J 1 ) 2.1 Hz, J 2
)
17.6 Hz, 1H), 3.41 (dd, J 1 ) 2.1 Hz, J 2 ) 17.6 Hz, 1H), 2.92-
2.85 (m, 2H), 2.67-2.57 (m, 4H), 2.49-2.34 (m, 4H), 2.20 (t, J
) 2.1 Hz, 1H), 2.07-1.70 (m, 2H). Anal. (C16H19NO) C, H,
N.
(12) Hacksell, U.; Mellin, C. Stereoselective synthesis of methoxy
substituted 1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolines. Tet-
rahedron 1987, 43, 5443-5450.
(13) Tagmatarchis, N.; Katerinopoulos, H. E. Synthetic Studies to
the octahydrobenzo[f]quinoline system. J . Heterocycl. Chem.
1996, 983-985.
(14) Aristoff, P. A.; J ohnson, P. D.; Harrison, A. W. Total Synthesis
of a Novel Antinuclear Agent via a Modification of the Intramo-
lecular Wadsworth-Emmons-Wittig Reaction. J . Am. Chem. Soc.
1985, 107, 7967.
(15) Kouvarakis, A. N.; Katerinopoulos, H. E. A Diastereoselective
Synthesis of trans/ cis octahydronaphthoquinolizine. Synth.
Commun. 1995, 25, 3035-3044.
Ack n ow led gm en t. We would like to thank Ms.
Despina Papasava for excellent technical support. This
research was partly supported by a grant from the
Greek Ministry of Research and Development (PENED
94) to K.T.
Su p p or tin g In for m a tion Ava ila ble: IR and 1H NMR
spectra of 11a ,b, 14a ,b, 15a , and 21a ,b (2 pages). Ordering
information is given on any current masthead page.
Refer en ces
(16) Walsh, D. A.; Smissman, E. E. Observable magnetic nonequiva-
lence of diastereotopic protons as a stereochemical probe. J . Org.
Chem. 1974, 39, 3705-3708.
(17) Ripa, L.; Hallberg, A. Aryl Radical endo cyclization of enamides.
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H. E. Synthesis of oxygen bridged, ridgid catecholamine ana-
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