10-Ketomorphinan and 3-Substituted-3-desoxymorphinan Analogues as Mixed κ and μ Opioid Ligands: Synthesis and Biological Evaluation of Their Binding Affinity at Opioid Receptors

Article abstract of DOI:10.1021/jm0304156

A series of 10-ketomorphinan analogues were synthesized, and their binding affinity at all three opioid receptors was investigated. In most cases, high affinity μ and κ receptors, and lower affinity at δ receptor was observed, resulting in good selectivit

Full text of DOI:10.1021/jm0304156

J . Med. Chem. 2004, 47, 165-174
165
10-Ketom or p h in a n a n d 3-Su bstitu ted -3-d esoxym or p h in a n An a logu es a s Mixed K
a n d µ Op ioid Liga n d s: Syn th esis a n d Biologica l Eva lu a tion of Th eir Bin d in g
Affin ity a t Op ioid Recep tor s
Ao Zhang,† Wennan Xiong,† J ean M. Bidlack,‡ J ames E. Hilbert,‡ Brian I. Knapp,‡ Mark P. Wentland,§ and
J ohn L. Neumeyer*,†
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street,
Belmont, Massachusetts 02478, Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of
Rochester, Rochester, New York 14642, and Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180
Received August 28, 2003
A series of 10-ketomorphinan analogues were synthesized, and their binding affinity at all
three opioid receptors was investigated. In most cases, high affinity at µ and κ receptors, and
lower affinity at δ receptor was observed, resulting in good selectivity for µ and κ receptors. A
wide range of substituents can be accommodated on the nitrogen position. The N-(S)-
tetrahydrofurfuryl analogue 11 displayed the highest affinity at all three receptors. The
N-cyclobutylmethyl analogue 13 gave both high affinity and selectivity at κ receptor, and N-2-
phenylethyl analogue 18 exhibited good affinity and selectivity at µ receptor. Further
modifications of the 3-substituent indicated that one H-bond donor was an essential requirement
for good affinity at µ and κ receptors. Similar modifications were investigated at the 3-OH
group of morphinans: levorphanol (2a ), cyclorphan (2b), and MCL-101 (2c) lacking the 10-
keto group. The 3-amino bioisosteric analogues (40 and 41) displayed reasonably good affinity
at µ and κ receptors. The 3-carboxamido replacement (compounds 46-48) in the morphinan
subseries resulted in similar affinities comparable to their corresponding 3-OH congeners. The
high affinity of these carboxamido analogues, along with their greater lipophilicity and metabolic
stability, make them promising candidates for further pharmacological investigation.
In tr od u ction
contains high level of both κ opioid receptors and highly
potent κ opioid endogenous peptides, thus an interaction
between dopamine neurons and κ receptors may exist.5-9
It was suggested that agonists at κ opioid receptors may
modulate the activity of dopaminergic neurons and alter
the neurochemical and behavioral effects of cocaine.10-19
Recent studies on the effects of benzomorphan and
arylacetamide κ agonists on cocaine self-administration
in rhesus monkeys demonstrated that most of these κ
agonists with relatively higher efficacy at κ receptors
produced a dose-dependent decrease in cocaine self-
administration, while a low-efficacy κ agonist or κ
antagonist were ineffective.20,21 Further, nonselective κ
agonists such as ethylketocyclazocine 1 (EKC), which
produce µ receptor-mediated effects in addition to their
κ agonist properties, decreased cocaine self-administra-
tion more effectively and with fewer unwanted side
effects than highly selective κ agonists.20-22 All these
findings indicated that κ agonists with additional prop-
erties at µ receptors may provide a novel approach for
the treatment of cocaine abuse and dependence.
Opioid receptors (µ, κ, and δ) are distributed through-
out the central and peripheral nervous system and are
involved in a variety of physiological processes, espe-
cially analgesia.1 Mu (µ) opioid receptor agonists such
as morphine are used extensively for the treatment of
severe pain, but serious side effects, including respira-
tory depression, tolerance, withdrawal symptoms, de-
creased gastric motility, and emesis, are frequently
present.2 Studies with kappa (κ) receptor agonists and
antagonists demonstrated that κ receptor ligands can
also produce analgesia in animals and humans, but lack
respiratory depressant, constipating, and strong addic-
tive (euphoria and physical dependence) properties.2,3
Self-reward response investigations suggested that µ
agonists work upstream in the reward neuronal system
by exerting an inhibitory action on GABAergic neurons,
thus initiating the self-reward response and causing
euphoric stimuli, while κ agonists work at a site more
downstream in the system and cause an aversive and
dysphoric stimulus.2,4 These findings led to extensive
interests in compounds with combined µ and κ agonist/
antagonist properties, which may be effective analgesics
and have therapeutic potential for drug abuse and
dependence. In fact, the nucleus accumbens, a brain
region implicated in the dopaminergic actions of cocaine,
In our continuing studies on the development of
effective analgesics, and the development of pharma-
ceutical agents for cocaine abuse, we focused our
interests on the structural modification and pharma-
cological evaluation of analogues of benzomorphans and
morphinans (Chart 1), which were known to possess
mixed κ agonist and µ agonist/antagonist pharmacologi-
cal profiles.20-24 We have recently developed a series of
N-substituted benzomorphan and morphinan deriva-
tives, with varying N-alkyl substituents, a number of
* To whom correspondence should be addressed. Tel: 617-855-3388;
Fax: 617-855-2519; E-mail: Neumeyer@mclean.harvard.edu.
† Harvard Medical School.
‡ University of Rochester.
§ Rensselaer Polytechnic Institute.
10.1021/jm0304156 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/09/2003

166 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 1
Zhang et al.
Ch a r t 1
Sch em e 1a
a
Reagents and conditions: (i) CH2N2, Et2O; (ii) CrO3, H2SO4, 100 °C; (iii) CH3CHClOCOCl, Na2CO3, ClCH2CH2Cl; (iv) HBr (48%),
HOAc, 110 °C; (v) BBr3 (1 M in CH2Cl2); (vi) CH3CHClOCOCl, Na2CO3, ClCH2CH2Cl, then MeOH
Sch em e 2a
which were found to be highly potent at both µ/κ
receptors, and only moderate affinity at δ receptor.23,24
These compounds are potentially useful candidates as
chemotherapeutic agents for cocaine abuse and are
currently under further evaluation. In the present
report, we described the synthesis and preliminary
pharmacological examination of N-alkyl-3-hydroxy (or
3-desoxy-3-substituted)-10-ketomorphinan and morphi-
nan analogues. We speculated that the introduction of
a 10-keto group in morphinans would improve the
pharmacological properties at κ receptor, similar to 1.21
a
Reagents and conditions: (i) NaHCO3, DMF, 75-80°C; (ii)
Our previous study23,24 suggested that the activities of
Et3N, EtOH, reflux.
this class of compounds were sensitive to N-alkyl
substituents, thus a systematic examination of the
N-alkyl groups, as well as the bioisosteric replacement
of the phenolic hydroxyl moiety (with both morphinan
and ketomorphinan templates) will be reported. The
purpose of this study was to identify novel morphinan
ligands which have good binding affinity at both µ/κ
receptors but lower affinity at δ receptor.
3-Desoxy-3-substituted 10-ketomorphinans 21, 22,
24-27 were prepared as described in Scheme 3. N-Cy-
clobutylmethyl-10-ketomorphinan 13 was treated with
PhNTf2/ Et3N/CH2Cl2 to give triflate 20 in 78% yield.27a
The reaction of 20 with 2 equiv of Zn(CN)2 and a
catalytic amount of Pd(PPh3)4 in DMF at 120 °C for 2 h
afforded the corresponding nitrile 21 in moderate yield
(less than 60%), while carrying out the cyanation under
microwave irradiation (200 °C, 15 min) produced the
product in 89% yield.27a Amination of the triflate 13 with
benzophenone imine or benzylamine using the catalytic
system of Pd(OAc)2/BINAP/Cs2CO3 gave the corre-
sponding products 23 and 25 in 45-52% yields.28
Treatment of 23 with NH2OH‚HCl/NaOAc in MeOH
provided the primary amine 24.29 Hydrolysis of the
nitrile 21 in KOH/H2O2/tBuOH gave the acid 22 rather
than the expected amide 26 in 20% yield.30,31 Treatment
of 21 with NaN3/Bu3SnCl produced the tetrazole 27 in
46.9% yield, and a small amount of amide 26 was
isolated as the byproduct (10.6%).32
Syn th esis
The synthesis of the 10-ketomorphinans was initiated
from commercially available (-)-3-hydroxy-N-methyl-
morphinan (levorphanol, 2a ) as shown in Scheme 1.
Thus, 2a was treated with diazomethane (prepared in
situ from diazald) to yield the methyl ether 3. Oxidation
of 3 with CrO3/H2SO4 produced the 10-ketomorphinan
4 in 80% yield.25 Treatment of 4 with R-chloroethyl
chloroformate followed by reflux in HBr/HOAc yielded
the 3-hydroxy-normorphinan 5.23 O-Demethylation of 4
with BBr3/CH2Cl2 gave the N-methyl-10-ketomorphinan
6. 3-Methoxy normorphinan 7 was obtained by using
the standard procedure reported by Olfoson et al.26 The
alkylation of 5 was carried out initially by using
NaHCO3/DMF system (Scheme 2), which gave N-alky-
lated products 12 and 13, along with the N,O-bisalky-
lated morphinans 8 and 9 as the minor products.
N-alkyl 10-ketomorphinans 14-19 were obtained as the
only products by using Et3N/EtOH system.
Using similar procedures described above, 2a was
triflated and then converted to the nitrile 29 in 72%
yield. In this case, microwave heating failed to give an
improved yield over the previously reported procedure.27b
After removal of the N-methyl group, realkylation of
norlevorphanol 30 provided nitriles 31 and 32 (Scheme
4). Triflates 34 and 35 were prepared using similar

Mixed κ and µ Opioid Ligands
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 1 167
Sch em e 3a
a
t
Reagents and conditions: (i) PhNTf2, Et3N, CH2Cl2; (ii) Zn(CN)2, Pd(PPh3)4, DMF; (iii) 25% KOH, BuOH, H2O2; (iv) Ph2CdNH or
BzNH2, BINAP, Pd(OAc)2, Cs2CO3, THF; (v) NH2OH‚HCl, NaOAc; (vi) NaN3, Bu3SnCl, DMF.
Sch em e 4a
a
Reagents and conditions: (i) PhNTf2, Et3N, CH2Cl2; (ii) Zn(CN)2, Pd(PPh3)4, DMF; (iii) CH3CHClOCOCl, Na2CO3, ClCH2CH2Cl; (iv)
MeOH, 10% NaOH; (v) RBr, Na2CO3, DMF.
Sch em e 5a
a
Reagents and conditions: (ii) CH3CHClOCOCl, Na2CO3, ClCH2CH2Cl; then MeOH, 10% NaOH; (ii) RBr, Na2CO3, DMF.
Sch em e 6a
a
Reagents and conditions: (i) Ph2CdNH, BINAP, Pd(OAc)2, Cs2CO3, THF, reflux; (ii) NH2OH‚HCl, NaOAc.
methods in which triflate 28 was first demethylated and
then realkylated (Scheme 5). The Pd-catalyzed amina-
tion of the triflates 28, 34, and 35 was conducted under
the same condition used for the preparation of 24
producing the corresponding primary amines 39-41 in
57-68% yield (Scheme 6).
The tetrazoles 42 and 43 were prepared from the
corresponding nitriles using the same procedure as for
the preparation of 27. Reduction of nitriles 29, 32 with
LiAlH4 afforded 3-aminomethyl morphinans 44 and 45
(Scheme 7). Hydrolysis of the nitriles 29, 31, and 32
with 25% KOH and H2O2 in MeOH provided 3-carboxa-
mido analogues 46-48.
comparison purposes, opioid binding affinity data for
compounds 1, 2a -c, and the 10-ketomorphinans 10 and
11 were also included.23
Structurally, the phenol moiety, the basic nitrogen,
and the keto group are the functional sites in the 10-
ketomorphinan template that interact with opioid re-
ceptor peptides. They constitute an important pharma-
cophore of 10-ketomorphinan analogues. The conforma-
tional analysis of compound 10 revealed that in this
rigid structure (Figure 1), both the keto group and the
basic nitrogen moiety are above and much closer to the
center of the aromatic ring in the phenol moiety, which
results in extensive interaction (electrostatic) between
the three functional groups. This analysis33 can be
further supported by the distance map calculated from
the conformation which indicates that the distance
values (3-5 Å) between the three functional groups are
optimal for good activity (Figure 1). The strong electro-
Resu lts a n d Discu ssion
All new compounds were evaluated for their binding
affinity at all three opioid receptors (µ, κ, and δ) (Tables
1 and 2) using a previously reported procedure.23,24 For

168 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 1
Zhang et al.
Sch em e 7a
a
Reagents and conditions: (i) NaN3, Bu3SnCl, DMF; (ii) 25% KOH, MeOH, H2O2; (iii) LiAlH4, THF.
for both µ and κ receptors. Thus with the 3-hydroxy
group intact, we investigated a variety of N-substituents
in compounds 10-19. Compared to compound 5, cyclo-
propylmethyl at the nitrogen position (compound 10)
resulted in an appreciable increase in binding affinity
at the δ receptor, but a 12-fold decrease at µ receptor
and a retained affinity at κ receptor. As reported
previously,23 3-(S)-tetrahydrofurfuryl group in com-
pound 11 greatly improved the affinity at all three
opioid receptors (0.38 nM for µ, 1.0 nM for δ, and 0.18
nM for κ receptors). It was suggested that extensive
interactions between the tetrahydrofurfuryl group and
all three opioid receptors existed, but it was not clear
that the stereochemistry, the steric bulk, or both in the
(S)-tetrahydrofurfuryl moiety were responsible for this
significant improvement. Compound 12 with a propar-
gyl group as the N-substituent gave similar results at
µ and κ receptors as compound 10, but the affinity at δ
receptor fell into the micromolar range. It is noteworthy
that the cyclobutylmethyl group as the N-substituent
in compound 13 produced a pronounced improvement
in affinity with a Ki value of 3.3 nM for µ receptor, 260
nM for δ receptor, and 0.48 nM for κ receptor. The
selectivity for κ over δ is 540, and κ over µ is 7.
Compared to compound 5, 3,3-dimethylallyl and 3-fluo-
ropropyl groups on the N-position (compounds 14 and
15) retained the affinity at µ receptor, but a 3-7-fold
increase in affinity at κ receptor was observed. Interest-
ingly, replacement of 3-fluoropropyl group in compound
15 by 2-fluoroethyl group in compound 16 produced 100-
fold and 28-fold decrease in affinity at κ and µ receptors,
respectively. This would indicate that there is a remote
binding site for both κ and µ receptors approximately
three carbons extended from the nitrogen. Introduction
of 2-methoxyethyl group at the N-position in compound
17 gave a similar binding profile, compared to compound
5, but a 4.5-fold decrease of binding affinity at µ
receptor, 1.5-fold increase of affinity at κ receptor, and
a high selectivity of 590 for κ versus δ receptors were
observed. With a 2-phenylethyl group as the N-sub-
stituent, compound 18 displayed remarkable increase
in affinity at all three receptors (0.63 nM for µ, 9.7 nM
for δ, and 7.7 nM for κ receptors). This was the only
example in this series where the selectivity of κ over µ
was significantly reversed. Apparently, there is a bind-
F igu r e 1. Conformational analysis and distance map of
ligand 10.
philicity of the keto group may partly impact the
interaction between the pharmacophore and receptors,
which may explain our previous observation that intro-
duction of a 10-keto group decreased the affinity of
morphinans (e.g. 2bf10)23 at all three opioid receptors.
But, optimization of the N-substituent and modifications
at the phenolic hydroxyl group may compensate this
interaction and potentiate the effect of the 10-ketomor-
phinan pharmacophore with the binding sites at the
opioid receptors.
Our initial effort was focused on the elaboration of
the N-substituent. It is of note that the 10-keto-
normorphinan 5 exhibited the desired pharmacological
profile giving good binding affinity (Ki ) approximately
20 nM) at both κ and µ receptors and nearly no affinity
at δ receptor, the selectivity for κ and µ versus δ was
greater than 400. Masking of the 3-hydroxy with a
methyl group (compound 7) resulted in 5- and 15-fold
decrease of the affinity at µ and κ receptors, respectively,
but the affinity at δ receptor was increased at least 600-
fold (Ki ) 16 nM). A remarkable decrease of affinity at
all the three receptors was observed in compounds 8 and
9, where the 3-OH was protected by propargyl and
cyclobutylmethyl groups, respectively. It is apparent
that there is a binding pocket at the 3-hydroxy position

Mixed κ and µ Opioid Ligands
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 1 169
Ta ble 1. Ki Values Inhibition of µ, δ, and κ Opioid Binding to CHO Membranes by 10-Ketomorphinan Seriesa
a
Guinea pig brain membranes, 0.5 mg of protein/sample, were incubated with 12 different concentrations of the compounds in the
presence of receptor-specific radioligands at 25 °C, in a final volume of 1 mL of 50 mM Tris-HCl, pH 7.5. Nonspecific binding was determined
using 1 µM naloxone. Data are the mean values SEM from three experiments, performed in triplicate. The statistics and the standard
chemicals were the same as used in ref 23.
ing site for the aromatic ring approximately two carbons
beyond the N-atom for all the three opioid receptors.
The second series of compounds focused on the 3-des-
oxy-3-substituted 10-ketomorphinans in which the bind-
ing ability of the compounds to hydrogen bond at the
3-position was evaluated. Since compound 13 with a
cyclobutylmethyl group as the N-substituent displayed
high affinity at κ and µ receptors, but low affinity at δ
receptor, it was selected as the lead for the evaluation
of the effect of 3-substituent on the opioid receptor
binding affinity. Replacement of the 3-hydroxy group,
a strong H-bond donor, by a cyano group, a moderate
H-bond acceptor (compound 21), almost abolished the
affinity at all three opioid receptors. While a carboxyl
group which contains both H-bond donating and ac-
cepting properties (compound 22) retained good affinity
at and selectivity for both κ and µ receptors. This
extensive structure/activity relationship suggested that
a H-bond-donating function at the C-3 position was
essential for the κ and µ receptor-selective profile for
this class of 10-ketomorphinan ligands. Thus, an amino
group that can be considered as a bioisosteric replace-
ment of the 3-OH was introduced into this position.34
Compared to acid 22, the affinity at µ receptor for the
3-amino analogue 24 that possesses two H-bond donors
was similar, but a 12-fold increase at κ receptor was
observed. Compared to the primary amine 24, the amino
analogue 25 exhibited a 5-fold increase in binding
affinity at µ receptor but a slight decrease at κ receptor,
and the selectivity of κ over µ was reversed. These

170 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 1
Zhang et al.
Ta ble 2. Ki Values Inhibition of µ, δ, and κ Opioid Binding to CHO Membranes by 3-Substituted Morphinansa
a
Same methods were used as in Table 1.
findings indicated that only one N-H bond was required
for reasonable affinity at µ receptor, and the stronger
H-bond donating ability of the 3-OH than the 3-NHBz
was, at least partially, responsible for the high affinity
at κ receptor in compound 13. A pronounced increase
of affinity at all the three receptors was observed in the
carboxamido analogue 26 which gave similar affinity
at both κ and µ receptors (Ki ) approximately 2.5 nM).
The carboxamido moiety, containing one H-bonding
acceptor and two H-bonding donors, was more favorable
than the 3-amino replacement pattern for both µ and κ
receptors. The SAR observed for compounds 24-26
roughly paralleled that observed in the cyclazocine
series.29a,31a The tetrazolo moiety containing both weak
H-bonding donor and H-bonding acceptor in compound
27 displayed remarkably lower affinity at both κ and µ
receptors.
Replacement of the 3-OH in 2a and 2b with a 3-CN,
a moderate H-bond acceptor, gave compounds 29 and
32. Compared to the parent compounds 2a and 2b, a
loss of affinity at δ receptor, and a 76-160-fold decrease
of affinity at both µ and κ receptors were observed.
Interestingly, compound 29 was µ-selective, while 32
was κ-selective. The decrease of affinity was less than
that observed in 10-ketomorphinans. The affinity of the
3-amino analogues 39-41 was decreased 16-37-fold at
µ and 5-47-fold at κ receptor compared to their corre-
sponding 3-OH congeners. Replacement of the 3-OH by
a tetrazole moiety (compounds 42 and 43) gave a 2-3-
orders of magnitude decrease in the affinity at µ and κ
receptors. Extension of the amino group by one meth-
ylene unit further decreased the affinity at both κ and
µ receptors (compounds 44 and 45) compared to the
corresponding 3-amino substituted analogues 39 and 41.
However, high affinity was observed in the 3-carboxa-
mido morphinans 46-48. Compared to their parents
(2a -c), similar or slightly lower affinity was observed
at κ receptor (1-5-fold). The three analogues were
comparable to their corresponding 3-OH congeners. The
different H-bonding and electrostatic properties of the
3-carboxamido substitution pattern from the 3-OH
prototypes may provide novel pharmacological proper-
ties. These findings, combined with recently reported
observations in the benzomorphan series,31 suggested
that recognition sites at both κ and µ opioid receptors
in the carboxamido analogues differed from that in the
phenol prototypes.
Our recent findings21-23 indicated that the morphin-
ans (2b and 2c) (Chart 1) displayed high affinity at κ
and µ receptors and had longer durations of action than
compound 1. They act as full κ agonists and have
approximately 2-fold selectivity for κ/µ receptors. These
findings suggested that we focus on the synthesis of a
series of 3-desoxy-3-substituted morphinans 29, 32, 39-
48. We envisaged that the further functional transfor-
mation at the C-3 position may produce a series of
compounds with different pharmacological properties.
Thus, with 2a -c as the lead compounds, we investi-
gated the effect of a series of 3-desoxy-3-substituents
on the binding affinity at the three opioid receptors.

Mixed κ and µ Opioid Ligands
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 1 171
mL) and basified with NH4OH. The layers were separated, and
the aqueous phase was extracted with CHCl3 (3 × 50 mL).
Organic phases were combined, washed with water and brine,
and then dried over Na2SO4. After removal of the solvent, a
Con clu sion
This study demonstrated that introduction of a 10-
keto group into the morphinan template provided a
series of compounds with mixed µ and κ receptor
pharmacological profile. The binding affinity at all three
opioid receptors generally was somewhat lower than the
corresponding morphinans without the keto group.23,24
In most cases, high affinity at µ and κ receptors and
lower affinity at δ receptor were observed, which
produced higher selectivity for µ and κ versus δ recep-
tors. The affinity at µ and κ receptors could be ultimately
adjusted by introduction of different N-substituents
without impact of the receptor selectivity profile. It was
apparent that there was a large hydrophobic recognition
pocket around the nitrogen which could tolerate a
variety of hydrophobic groups with variant structural
features and sizes. N-(S)-tetrahydrofurfuryl analogue
11 displayed high affinity at all three receptors, with
improved binding properities over 1. The N-cyclobutyl-
methyl analogue 13 gave both high affinity and selectiv-
ity at κ receptor, and N-2-phenylethyl analogue 18
exhibited good affinity and selectivity at µ receptor.
Further elaboration of the 3-substituent indicated that
one H-bond donor contributed to the good affinity at µ
and κ receptors.
Similar modification was applied to the morphinans
(2a -c) without the 10-keto group, whose N-substituents
have been previously well-documented.23,24 The 3-amino
bioisosteric analogues (40 and 41) displayed reasonably
good affinity at µ and κ receptors, although it was much
lower than the 3-OH congeners. Differing from the
ketomorphan analogues, the 3-carboxamido replace-
ment (compounds 46-48) in the morphinan subseries
gave substantially identical affinity compared to the
corresponding 3-OH congeners. This suggested that
different recognition sites and binding modes existed at
both κ and µ opioid receptors in the carboxamido
substitution pattern. Combined with recent observations
in the benzomorphan series,31 the high affinity of the
carboxamide analogues along with their greater lipo-
philicity and metabolic stability, make them promising
candidates for further pharmacological investigation.
1
pale yellow solid was obtained (75.3%). H NMR (CDCl3, 300
MHz): δ 8.00 (d, J ) 6.9 Hz, 1H), 6.76 (m, 2H), 5.30 (s, 1H),
3.05 (s, 1H), 2.67 (d, J ) 9.9 Hz, 1H), 2.38 (s, 3H), 2.36 (m,
1H), 2.11 (t, J ) 11.1 Hz, 1H), 1.91 (m, 1H), 1.30 (m, 8H); 13
C
NMR (CDCl3, 75 MHz): δ 194.0, 163.3, 148.4, 129.0, 127.7,
114.4, 112.7, 68.4, 47.7, 46.9, 43.0, 40.7, 37.9, 36.3, 25.9, 21.8.
Anal. (C17H21NO2) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of 3-Hyd r oxy/3-
Alk oxy-10-k eto-N-a lk ylm or p h in a n s 8,9,12,13. A mixture
of 5 (300 mg, 1.16 mmol), propargyl bromide or cyclobutyl-
methyl bromide (1.2 equiv.), and NaHCO3 (117 mg, 1.4 mmol)
in dry DMF (15 mL) was heated under nitrogen at 75 °C for
24 h. Solvent was removed under reduced pressure. The
remaining material was taken up with CHCl3 (50 mL), washed
with water (2 × 25 mL), dried (Na2SO4), and concentrated.
The residue was purified by flash chromatography (hexane/
EtOAc: 4/1) to yield the products 8 and 12 or 9 and 13.
3-O-P r opar gyl-10-keto-N-pr opar gylm or ph in an 8 (MCL-
155). Pale-yellow solid (30%). Mp: 120-122 °C; MS: m/e 333
(M+); 1H NMR (CDCl3, 300 MHz): δ 8.06 (dd, J ) 3.0, 8.4 Hz,
1H), 6.92 (m, 2H), 4.77 (m, 2H), 3.41 (m, 1H), 3.16 (m, 2H),
2.92 (dd, J ) 2.4, 11.1 Hz, 1 H), 2.58 (dd, J ) 2.4, 4.8 Hz, 1H),
2.39 (d, J ) 13.5 Hz, 1H), 2.24 (m, 1H), 2.10 (m, 3H), 1.47 (m,
8H); 13C NMR (CDCl3, 75 MHz): δ 194.3, 162.7, 147.8, 129.3,
128.4, 112.5, 80.5, 77.8, 72.9, 72.4, 66.6, 55.7, 47.1, 45.3, 44.5,
41.0, 38.5, 36.4, 26.0, 25.8, 21.8. Anal. (C22H23NO2‚0.2H2O) C,
H, N.
3-Hyd r oxy-10-k eto-N-p r op a r gylm or p h in a n 12 (MCL-
156). Pale-yellow solid (43%). Mp: 221-223 °C (dec). MS: m/e
295 (M+); 1H NMR (CDCl3, 300 MHz): δ 7.98 (dd, J ) 1.8, 8.4
Hz, 1H), 6.79 (m, 2H), 3.42 (dt, J ) 2.4, 16.5 Hz, 1H), 3.24 (m,
2H), 3.15 (m, 1H), 2.93 (m, 1H), 2.35 (d, J ) 13.8 Hz, 1 H),
2.24 (m, 1H), 2.10 (m, 3H), 1.93 (m, 2H), 1.39 (m, 5H); 13C NMR
(CDCl3, 75 MHz): δ 194.5, 162.2, 148.5, 128.9, 128.4, 114.3,
112.6, 79.7, 72.9, 72.7, 66.7, 47.0, 45.3, 44.5, 40.9, 38.4, 36.3,
26.0, 25.9. Anal. (C19H21NO2‚0.5HCl) C, H, N.
3-O-Cyclobu tylm eth yl-10-keto-N-cyclobu tylm eth ylm or -
p h in a n 9 (MCL-157). Pale-yellow oil (18%). MS: m/e 393
(M+); 1H NMR (CDCl3, 300 MHz): δ 8.01 (d, J ) 8.7 Hz, 1H),
6.83 (dd, J ) 2.1, 8.7 Hz, 1H), 6.77 (d, J ) 2.1 Hz, 1H), 3.98
(d, J ) 6.6 Hz, 2H), 2.99 (d, J ) 2.7 Hz, 1H), 2.78 (m, 1H),
2.62 (m, 3H), 2.30 (m, 2H), 2.16 (m, 2H), 1.78 (m, 21H); 13C
NMR (CDCl3, 75 MHz): δ 195.1, 164.5, 147.9, 128.7, 128.3,
112.0, 111.9, 72.0, 67.3, 61.6, 47.2, 45.8, 41.3, 38.6, 36.4, 34.5,
34.1, 27.6, 26.9, 26.1, 26.0, 24.8, 24.7, 22.0, 18.7, 18.5. Anal.
(C26H35NO2‚1.0H2O) C, H, N.
Exp er im en ta l Section
3-Hyd r oxy-10-k eto-N-cyclobu tylm eth ylm or p h in a n 13
(MCL-158). Pale-yellow solid (47%). Mp: 194-195 °C (dec);
MS: m/e 325 (M+); 1H NMR (CDCl3, 300 MHz): δ 7.98 (d, J )
8.1 Hz, 1H), 6.77 (m, 2H), 3.99 (m, 1H), 3.05 (m, 1H), 2.59 (m,
3H), 2.30 (m, 2H), 2.05 (m, 4H), 1.62 (m, 12H); 13C NMR
(CDCl3, 75 MHz): δ 194.7, 162.4, 148.6, 128.8, 128.4, 114.2,
112.5, 67.3, 61.7, 46.9, 45.9, 41.0, 38.5, 36.4, 33.9, 27.9, 27.0,
26.0, 24.8, 21.9, 18.7. Anal. (C21H27NO2‚0.5H2O) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of 3-Hyd r oxy-10-
k eto-N-a lk ylm or p h in a n s 14-19. To a solution of 5 (300 mg,
1.16 mmol) in 10 mL of anhydrous EtOH was added a solution
of Et3N (1.2 equiv.), followed by alkyl bromide (1.2 equiv.). The
resulting mixture was heated under nitrogen at 75 °C for 48
h. Solvent was removed under reduced pressure and the
remaining material was taken up in CHCl3 (50 mL), washed
with brine (2 × 25 mL), dried (Na2SO4), and concentrated. The
residue was further purified by flash chromatography (hexane/
EtOAc: 4/1) to yield the corresponding 3-hydroxy-10-keto
N-alkylmorphinan (50-62% yield).
Melting points were determined on a Thomas-Hoover capil-
lary tube apparatus and are reported uncorrected. 1H and 13C
NMR spectra were recorded on a Brucker AC300 spectrometer
using tetramethylsilane as an internal reference. Elemental
analyses, performed by Atlantic Microlabs, Atlanta, GA, were
within (0.4% of theoretical values. Analytical thin-layer chro-
matography (TLC) was carried out on,0.2-mm Kieselgel 60F
254 silica gel plastic sheets (EM Science, Newark). Flash
chromatography was used for the routine purification of
reaction products. The column output was monitored with
TLC. 3-Methoxy-N-methylmorphinan 3, 3-methoxy-10-keto-
N-methylmorphinan 4, 3-hydroxy-10-keto-normorphinan 5
(MCL-164), and 3-methoxy-10-keto-normorphinan 7 (MCL-
165) were prepared as before.23
3-Hyd r oxy-10-k eto-N-m eth ylm or p h in a n 6 (MCL-172).
The crude ether 4 (10 mmol) was dissolved in CH2Cl2 (50 mL)
and cooled to 0 °C, and a solution of boron tribromide (1M in
CH2Cl2, 50 mL) was added slowly. The resulting brown
solution was stirred at room temperature overnight. MeOH
(200 mL) was introduced cautiously to quench the reaction.
After completion of gas evolution, the mixture was heated to
reflux (77-80 °C) for 2 h. The solvent was evaporated under
reduced pressure, and the residue was taken up in CHCl3 (100
3-Hyd r oxy-10-k eto-N-(3,3-d im eth yla llyl)m or p h in a n 14
(MCL-159). Pale-yellow solid (50%). Mp: 214-215 °C; MS:
1
m/e 325 (M+); H NMR (CDCl3, 300 MHz): δ 8.00 (d, J ) 8.4
Hz, 1H), 6.75 (m, 2H), 5.23 (brs, 1H), 3.13 (m, 2H), 2.92 (m,
1H), 2.73 (m, 1H), 2.31 (d, J ) 12 Hz, 1 H), 2.02 (m, 3H), 1.69

172 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 1
Zhang et al.
(s, 3H), 1.60 (s, 3H), 1.33 (m, 8H); 13C NMR (CDCl3, 75 MHz):
δ 195.0, 162.1, 148.6, 135.8, 128.8, 120.8, 114.2, 112.5, 67.1,
53.1, 47.2, 45.4, 41.1, 38.6, 36.4, 26.0, 25.9, 21.9, 18.1, 7.4. Anal.
(C21H27NO2‚1/3H2O) C, H, N.
product was purified by column chromatograph (hexane:
EtOAc ) 10:1) to yield imine 23 as pale-yellow foam (200 mg,
37.3%), the triflate 20 (200 mg) was recovered at the same
time. The crude 23 was used for next step without further
purification.
3-H yd r oxy-10-k et o-N-(3-flu or op r op yl)m or p h in a n 15
(MCL-160). Pale-yellow solid (54.0%). Mp: 207-208 °C; MS:
3-Am in o-10-k et o-N-cyclob u t ylm et h ylm or p h in a n 24
(MCL-167). To a solution of the crude imine 23 (200 mg, 0.43
mmol) in MeOH (8 mL) at room temperature were added
NaOAc (85 mg, 1.03 mmol) and hydroxylamine hydrochloride
(54 mg, 0.774 mmol). The mixture was stirred at room
temperature for 2 days. The solution was partitioned between
0.1 M NaOH and CH2Cl2. The organic layer was separated
and dried over anhydrous Na2SO4 and then concentrated in
vacuo. The crude product was purified by column chromato-
graph (hexane:EtOAc ) 3:1) producing the amine 24 as a white
solid (120 mg, 90.4%). M.p.: 214-215°C; MS (EI): 324 (M+);
1H NMR (CDCl3, 300 MHz): δ 7.88 (d, J ) 8.4 Hz, 1H), 6.54
(d, J ) 8.4 Hz, 1H), 6.48 (s, 1H), 4.14 (s, 2H), 2.96 (s, 1H),
2.63 (m, 4H), 2.89 (m, 3H), 1.99 (m, 3H), 1.76 (m, 4H), 1.41
(m, 8H); 13C NMR (CDCl3, 75 MHz): δ 194.4, 152.3, 148.0,
128.4, 126.7, 112.7, 110.4, 67.4, 61.6, 47.3, 45.9, 41.4, 38.4, 36.5,
34.2, 27.7, 26.9, 26.2, 26.1, 22.0, 18.7. Anal. (C21H28N2O) C,
H, N.
1
m/e 317 (M+); H NMR (CDCl3, 300 MHz): δ 7.99 (d, J ) 8.4
Hz, 1H), 6.77 (m, 2H), 4.26 (m, 2H), 3.11 (s, 1H), 2.70 (m, 3H),
2.89 (m, 3H), 2.00 (m, 4H), 1.51 (m, 8H); 13C NMR (CDCl3, 75
MHz): δ 194.8, 161.9, 148.4, 128.6, 128.4, 113.9, 112.3, 82.1
(d, J ) 163.0 Hz), 65.9, 50.6, 46.8, 45.9, 40.9, 38.3, 36.1, 27.9,
27.7, 25.8, 21.6. Anal. (C19H24FNO2‚0.1H2O) C, H, N.
3-Hyd r oxy-10-k eto-N-(2-flu or oeth yl)m or p h in a n 16 (M-
CL-162). Pale-yellow viscous solid (28.6%). MS: m/e 303 (M+);
1H NMR (CDCl3, 300 MHz): δ 7.95 (d, J ) 8.4 Hz, 1H), 6.81
(m, 2H), 4.60 (m, 2H), 3.12 (m, 1H), 2.89 (m, 3H), 2.13 (m,
4H), 1.49 (m, 8H); 13C NMR (CDCl3, 75 MHz): δ 195.0, 163.2,
148.7, 128.8, 127.7, 114.4, 112.7, 81.3 (d, J ) 167.02 Hz), 66.8,
55.2, 54.9, 46.8, 46.3, 40.8, 38.2, 36.2, 26.0, 21.8. Anal. (C18H22
-
FNO2‚0.1H2O) C, H, N.
3-Hyd r oxy-10-k eto-N-(2-m eth oxyeth yl)m or p h in a n 17
(MCL-161). White solid (56.5%). Mp: 196-197 °C; MS: m/e
1
315 (M+); H NMR (CDCl3, 300 MHz): δ 7.97 (d, J ) 8.4 Hz,
3-Ben zyla m in o-10-k et o-N-cyclob u t ylm et h ylm or p h i-
n a n 25 (MCL-170). Prepared according to the similar proce-
dure used for the preparation of imine 23 using benzylamine
as the amination reagent. The crude product was purified by
column chromatograph (hexane:EtOAc ) 4:1) giving the amine
1H), 6.79 (m, 2H), 3.58 (m, 2H), 3.34 (s, 3H), 3.12 (s, 1H), 2.81
(m, 2H), 2.54 (m, 1H), 2.08 (m, 4H), 1.36 (m, 8H); 13C NMR
(CDCl3, 75 MHz): δ 195.2, 163.1, 148.6, 128.7, 127.8, 114.4,
112.6, 69.4, 66.4, 58.7, 54.4, 46.6, 46.3, 40.8, 38.3, 36.3, 26.0,
21.9. Anal. (C19H25NO3‚0.5H2O) C, H, N.
1
25 (26.0%) as a foam. H NMR (CDCl3, 300 MHz): δ 7.90 (d,
3-H yd r oxy-10-k et o-N-(2-p h en ylet h yl)m or p h in a n 18
(MCL-163). Pale-yellow solid (50.6%). Mp: 183-184 °C; MS:
J ) 8.7 Hz, 1H), 7.34 (m, 5H), 6.53 (d, J ) 8.7 Hz, 1H), 6.40
(s, 1H), 4.60 (s, 1H), 4.39 (s, 2H), 2.95 (s, 1H), 2.62 (m, 4H),
2.25 (m, 3H), 2.02 (m, 3H), 1.72 (m, 6H), 1.35 (m, 6H); 13C NMR
(CDCl3, 75 MHz): δ 194.2, 153.1, 147.8, 138.2, 128.7, 128.3,
127.6, 127.5, 125.9, 110.7, 108.4, 67.4, 61.6, 47.7, 47.4, 45.9,
41.5, 38.5, 36.6, 34.2, 27.7, 26.9, 26.1, 21.9, 18.7. Anal.
(C28H34N3O‚0.2H2O), C, H, N.
1
m/e 361 (M+); H NMR (CDCl3, 300 MHz): δ 7.92 (d, J ) 8.4
Hz, 1H), 7.23 (m, 5H), 6.76 (m, 2H), 3.17 (s, 1H), 3.00 (d, J )
14.7 Hz, 1H), 2.52 (m, 5H), 2.02 (m, 3H), 1.35 (m, 8H); 13C
NMR (CDCl3, 75 MHz): δ 195.0, 163.4, 148.3, 139.9, 128.5,
128.4, 128.3, 128.1, 127.8, 125.7, 113.8, 113.6, 112.3, 66.0, 57.1,
48.6, 46.8, 46.2, 40.8, 38.3, 36.2, 33.5, 25.9, 21.7. Anal. (C24H27
NO2) C, H, N.
-
3-Ca r b oxa m id o-10-k et o-N-cyclob u t ylm et h ylm or p h i-
n a n 26 (MCL-173) a n d 3-Tetr a zolo- 10-k eto-N-cyclobu -
tylm eth ylm or p h in a n 27 (MCL-174). A mixture of 21 (115
mg, 0.34 mmol), tributylstannyl chloride (370 uL, 1.37 mmol),
and sodium azide (90 mg, 1.37 mmol) in DMF (5 mL) was
heated under nitrogen at 120 °C for 24 h. Saturated Na2CO3
was added, and the mixture was extracted with EtOAc (3 ×
60 mL). The extracts were combined, washed with brine, dried
over Na2SO4, and concentrated. The residue was purified by
flash chromatography (hexane/EtOAc: 1/1) to give the amide
26 as pale yellow oil (13 mg, 10.6%), and further chromatog-
raphy with EtOAc/MeOH (20/1) gave the tetrazole 27 as a
yellow solid (61 mg, 46.9%).
3-Hydr oxy-10-keto-N-(2-n aph th ylm eth yl)m or ph in an 19
1
(MCL-166). Pale-yellow solid (64.2%). Mp: 224-225 °C; H
NMR (CDCl3, 300 MHz): δ 8.05 (m, 1H), 7.76 (m, 4H), 7.50
(d, J ) 7.5 Hz, 1H), 7.41 (m, 2H), 6.83 (d, J ) 7.5 Hz, 1H),
6.71 (s, 1H), 4.00 (d, J ) 13.5 Hz, 1H), 3.49 (d, J ) 13.5 Hz,
1H), 3.16 (s, 1H), 2.61 (d, J ) 10.8 Hz, 1H), 2.21 (d, J ) 12.6
Hz, 1H), 2.07 (m, 2H), 1.78 (m, 1H), 1.30 (m, 8H); 13C NMR
(CDCl3, 75 MHz): δ 195.5, 162.5, 148.8, 135.8, 133.2, 132.7,
128.9, 128.3, 127.9, 127.8, 127.7, 127.5, 127.4, 125.8, 125.5,
114.3, 112.6, 66.8, 59.6, 47.1, 45.4, 41.0, 38.5, 36.3, 26.0, 25.9,
21.9. Anal. (C27H27NO2‚0.25H2O) C, H, N.
3-Ca r boxyl-10-k eto-N-cyclobu tylm eth yl m or p h in a n 22
(MCL-171). The nitrile 21 (171 mg, 0.51 mmol) in MeOH (5
mL) was added 25% potassium hydroxide (3 mL) and 2 drops
30% hydrogen peroxide solution. The mixture was refluxed for
5 h. After cooling to room temperature, the reaction mixture
was extracted with EtOAc (3 × 20 mL). The organic layers
were combined, washed with brine, dried over anhydrous Na2-
SO4 and concentrated in vacuo. The crude product was purified
by column chromatograph (EtOAc) yielding the product 22 as
pale yellow foam (50 mg, 28%). MS (EI): 354 (M+ + 1);1H NMR
(CDCl3, 300 MHz): δ 8.10 (m, 3H), 3.4 (brs, 1H), 3.05 (d, J )
6.3 Hz, 1H), 2.79 (m, 3H), 2.57 (m, 3H), 2.35 (d, J ) 12.6 Hz,
1H), 2.12 (m, 6H), 1.58 (m, 8H); 13C NMR (CDCl3, 75 MHz):
δ 194.7, 169.9, 166.4, 145.1, 138.7, 137.0, 128.0, 126.2, 66.2,
61.1, 46.1, 45.6, 39.7, 38.1, 35.9, 32.6, 27.9, 27.1, 26.0, 25.7,
21.7, 18.6. Anal. (C22H27NO3) C, H, N.
3-(Ben zh yd r ylid en ea m in o)-10-k eto-N-cyclobu tylm eth -
ylm or p h in a n 23. The triflate 20 (500 mg, 1.09 mmol) in THF
(20 mL) were added palladium(II) acetate (5 mg, 0.022 mmol),
rac-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl (20 mg, 0.032
mmol), benzophenone imine (237 mg, 1.31 mmol), cesium
carbonate (497 mg, 1.5 mmol), and 4,7,13,16,21,24-hexaoxa-
1,10-diazabicyclo[8.8.8]hexacosane (20 mg) under nitrogen.
The mixture was heated to 65-70 °C with stirring overnight.
The solvent was removed. The residue was diluted with CH2-
Cl2, washed with brine, dried, and concentrated. The crude
1
26 (MCL-173): H NMR (CDCl3, 300 MHz): δ 8.09 (d, J )
8.4 Hz, 1H), 7.87 (s, 1H), 7.65 (d, J ) 8.4 Hz, 1H), 6.15 (s,
1H), 5.82 (s, 1H), 3.06 (s, 1H), 2.16 (m, 3H), 2.27 (dd, J ) 6.9,
6.9 Hz, 1H), 0.92-2.12 (m, 18H); 13C NMR (CDCl3, 75 MHz):
δ 196.4, 168.6, 146.2, 138.4, 137.6, 126.3, 126.0, 124.4, 67.1,
61.4, 46.8, 45.5, 41.0, 38.6, 36.1, 33.9, 27.5, 26.8, 26.2, 25.8,
21.9, 18.7. Anal. (C22H28N2O2) C, H, N.
27 (MCL-174): 1H NMR (CDCl3, 300 MHz): δ 8.20 (m, 1H),
8.09 (m, 2H), 3.28 (m, 2H), 2.70 (m, 3H), 2.48 (m, 1H), 1.14-
2.17 (m, 17H); 13C NMR (CDCl3, 75 MHz): δ 195.7, 162.0,
147.2, 137.5, 135.9, 127.5, 125.9, 68.1, 62.5, 49.8, 47.5, 41.2,
39.4, 37.0, 34.3, 28.4, 27.8, 27.1, 27.0, 23.0, 19.4. Anal.
(C23H27N5O.0.7HCl) H, N; C: calcd, 64.40; found, 64.85.
3-Tr iflu or om et h yl(su lfon yl)oxy-N-m et h ylm or p h in a n
28 was prepared according to the literature procedure27a in
78% yield. 1H NMR (300 MHz) δ 7.15 (d, J ) 8.1 Hz, 1H), 7.08
(s, 1H), 6.99 (dd, J ) 2.1, 8.4 Hz, 1H), 3.01 (d, J ) 18.6 Hz,
1H), 2.81 (d, J ) 3.0 Hz, 1H), 2.61 (dd, J ) 5.4, 18.3 Hz, 1H),
2.37-1.17 (complex, 16H).
3-Cya n o-N-m eth ylm or p h in a n 29 (MCL-137) was pre-
pared according to Kubota’s procedure27b in 72.5% yield. Mp
1
98-100 °C. H NMR (CDCl3, 300 MHz): δ 7.50 (s, 1H), 7.34
(d, J ) 8.1 Hz, 1H), 7.17 (d, J ) 7.8 Hz, 1H), 3.03 (d, J ) 19.2
Hz, 1H), 2.80 (s, 1H), 2.65 (dd, J ) 4.5, 18.6 Hz, 1H), 2.43-
1.31 (complex, 16H); 13C NMR (CDCl3, 75 MHz): δ 144.0,

Mixed κ and µ Opioid Ligands
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 1 173
142.4, 129.8, 128.9, 128.8, 119.7, 110.2, 57.6, 46.9, 45.1, 42.9,
42.0, 37.4, 36.4, 26.8, 26.5, 24.8, 22.1. Anal. (C18H22N2‚1.5H2O)
C, H; N: calcd, 9.55; found, 9.03.
NMR (CDCl3, 75 MHz): δ 162.6, 139.3, 135.7, 130.5, 129.8,
126.1, 125.0, 59.9, 53.6, 37.5, 36.3, 32.4, 28.0, 27.0, 22.9, 19.4.
Anal. (C22H29N5‚1.25H2O) C, H, N.
3-Cya n o-n or m or p h in a n 30 was prepared from nitrile 29
according to the same procedure for the preparation of
compound 7 in 77.7% yield. MS (EI): 252 (M+), 253 (M+ + 1);
1H NMR (CDCl3, 300 MHz): δ 7.57 (s, 1H), 7.44 (d, J ) 8.1
Hz, 1H), 7.26 (d, J ) 9.9 Hz, 1H), 3.33-0.88 (complex, 16H);
13C NMR (CDCl3, 75 MHz): δ 142.8, 141.5, 130.1, 129.5, 129.1,
119.5, 110.9, 50.8, 44.1, 41.2, 38.3, 37.9, 36.3, 32.8, 26.3, 26.5,
21.9.
3-Am in om eth yl-N-m eth ylm or p h in a n 44 (MCL-154). A
solution of nitrile 29 (0.22 mmol) in THF was added LiAlH4
(76 mg, 2 mmol) at room temperature. The mixture was stirred
for 20 h, and then excess LiAlH4 was decomposed with 10 mL
of EtOAc. Saturated ammonium tartrate was added, and the
mixture was stirred for additional 1 h. The solution was
filtered, and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were dried and concentrated to yield
crude product which was purified by column chromatography
on silica gel (CHCl3:MeOH ) 1:1) giving the amine 44 (12 mg,
3-Cya n o-N-cyclobu tylm eth ylm or p h in a n 32 (MCL-150)
was prepared according to the same procedure used for the
1
14%) as pale yellow oil. MS (EI): 270 (M+); H NMR (CDCl3,
1
preparation of 12 in 78% yield. MS (EI): 320 (M+); H NMR
300 MHz): δ 7.10 (s, 1H), 6.89 (s, 2H), 3.76 (s, 2H), 3.03-1.07
(CDCl3, 300 MHz): δ 7.35 (s, 1H), 7.37 (d, J ) 8.1, 1H), 7.20
(d, J ) 7.8 Hz, 1H), 3.07-1.23 (complex, 25H); 13C NMR
(CDCl3, 75 MHz): δ 144.3, 142.6, 129.8, 128.8, 128.7, 119.7,
110.1, 61.6, 55.7, 45.5, 44.9, 42.0, 38.0, 36.4, 34.9, 27.8, 26.9,
26.6, 25.6, 22.2, 19.0. Anal. (C22H28N2‚0.1H2O) C, H, N.
3-Tr iflu or om eth yl(su lfon yl)oxy-N-cyclop r op ylm eth yl-
m or p h in a n 34. Triflate 28 was demethylated according to
the procedure used for the preparation of 5 giving the
intermediate 33. Alkylation of 33 was carried out using the
same procedure for the preparation of 12 in 72% yield.27a
3-Tr iflu or om et h yl(su lfon yl)oxy-N-cyclob u t ylm et h yl-
m or p h in a n 35 was prepared from triflate 28 according to the
same procedure used for the preparation of 34.
(complex, 21H). Anal. (C18H26N2) C, H, N.
3-Am in om eth yl-N-cyclobu tylm eth ylm or p h in a n 45 (M-
CL-175) was prepared using the same procedure for prepara-
tion of compound 44. Pale yellow oil (27%), MS (EI): 324 (M+);
1H NMR (CDCl3, 300 MHz): δ 7.06 (s, 1H), 6.81 (s, 2H), 3.66
(s, 2H), 3.03-1.07 (complex, 27H); 13C NMR (CDCl3, 75
MHz): δ 138.9, 135.4, 133.1, 128.89, 127.0, 126.2, 58.5, 57.3,
46.1, 45.8, 42.9, 41.4, 38.6, 36.4, 35.1, 31.5, 27.1, 27.0, 25.9,
22.8, 18.3. Anal. (C22H32N2) calcd. C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of Am id e 46-
48. The nitriles 29, 31, 32 (1.09 mmol) in MeOH (10 mL) were
added 25% potassium hydroxide (5 mL) and 2 drops of 30%
hydrogen peroxide solution. The mixture was refluxed for 3
h. After cooling to room temperature, the reaction mixture was
extracted with EtOAc. The organic layers were combined,
washed with brine, dried over anhydrous Na2SO4, and con-
centrated in vacuo. The crude product was purified by column
chromatograph (hexane:EtOAc:Et3N ) 100:100:1) affording the
corresponding amides.
Amine 39-41 were prepared according to the same proce-
dure used for the preparation of 24.
3-(Ben zh yd r ylid en ea m in o)-N-m et h ylm or p h in a n 36.
Pale-yellow oil (63.3%). 1H NMR (CDCl3, 300 MHz): δ 7.74
(m, 2H), 7.41 (m, 3H), 7.22 (m, 3H), 7.09 (m, 2H), 6.93 (d, J )
8.1 Hz, 1H), 6.66 (dd, J ) 2.1, 7.8 Hz, 1H), 6.46 (d, J ) 2.1 Hz,
1H), 2.91 (d, J ) 18.3 Hz, 1H), 2.76-0.97 (complex, 18H); 13
C
3-Car boxam ido-N-m eth ylm or ph in an 46 (MCL-138). Pale
yellow solid (68%), Mp 245-247 °C. 1H NMR (CDCl3, 300
MHz): δ 7.77 (d, J ) 1.8 Hz, 1H), 7.50 (dd, J ) 2.1, 7.8 Hz,
1H), 7.18 (d, J ) 7.8 Hz, 1H), 6.02 (brs, 1H), 5.98 (brs, 1H),
3.08 (d, J ) 19.2 Hz, 1H), 2.86-1.23 (complex, 18H); 13C NMR
(CDCl3, 75 MHz): δ 169.6, 142.5, 141.2, 131.4, 127.9, 125.0,
123.9, 57.6, 46.9, 45.1, 42.7, 41.8, 37.2, 36.3, 26.7, 26.4, 24.4,
22.1. Anal. (C18H24N2O‚0.6H2O) C, H; N: calcd, 9.44; found,
9.03.
3-Ca r b oxa m id o-N-cyclop r op ylm et h ylm or p h in a n 47
(MCL-180). Pale yellow foam (57%), 1H NMR (CDCl3, 300
MHz): δ 7.79 (d, J ) 1.8 Hz, 1H), 7.51 (dd, J ) 2.1, 7.8 Hz,
1H), 7.17 (d, J ) 7.8 Hz, 1H), 6.05 (brs, 1H), 5.93 (brs, 1H),
3.24-0.14 (complex, 23H); 13C NMR (CDCl3, 75 MHz): δ 169.8,
141.2, 137.8, 131.8, 128.2, 125.3, 124.3, 59.8, 55.8, 45.7, 44.5,
41.3, 37.9, 36.3, 26.9, 26.6, 25.3, 22.3, 9.0, 4.3, 4.1. Anal.
(C21H28N2O‚2/3H2O) C, H, N.
3-Ca r boxa m id o-N-cyclobu tylm eth ylm or p h in a n 48 (M-
CL-148). Colorless foam (66%), 1H NMR (CDCl3, 300 MHz):
δ 7.76 (s, 1H), 7.50 (d, J ) 8.1 Hz, 1H), 7.17 (d, J ) 7.8 Hz,
1H), 6.08 (brs, 1H), 5.95 (brs, 1H), 3.07-1.01 (complex, 25H);
13C NMR (CDCl3, 75 MHz): δ 170.0, 143.1, 141.7, 131.4, 128.1,
125.2, 124.1, 61.7, 55.9, 45.7, 45.2, 42.0, 38.0, 36.5, 35.1, 28.0,
27.0, 26.7, 25.4, 22.4, 19.0. MS (EI): 338 (M+). Anal. (C22H30N2O‚
0.2H2O) calcd. C, H, N.
NMR (CDCl3, 75 MHz): δ 149.7, 140.6, 140.0, 136.8, 132.9,
130.8, 129.7, 129.4, 128.5, 128.4, 128.0, 119.3, 118.0, 58.1, 47.3,
45.5, 42.9, 42.2, 37.1, 36.6, 27.0, 26.7, 23.8, 22.4.
3-Am in o-N-m eth ylm or p h in a n 39 (MCL-181). Pale-yel-
1
low oil (57%). H NMR (CDCl3, 300 MHz): δ 6.89 (d, J ) 8.1
Hz, 1H), 6.61 (d, J ) 2.4 Hz, 1H), 6.50 (dd, J ) 2.4, 8.4 Hz,
1H), 3.51 (s, 2H), 2.93 (d, J ) 18 Hz, 1H), 2.79-1.17 (complex,
18H); 13C NMR (CDCl3, 75 MHz): δ 144.6, 141.5, 128.6, 128.2,
113.4, 112.1, 58.2, 47.5, 45.8, 43.0, 42.3, 37.2, 36.8, 27.0, 26.8,
23.5, 22.5. Anal. (C17H24N2‚0.4H2O) C, H, N.
3-Am in o-N-cyclop r op ylm et h ylm or p h in a n 40 (MCL-
149). Pale-yellow oil (70%). MS(EI): 296 (M+); 1H NMR
(CDCl3, 300 MHz): δ 6.86 (d, J ) 8.4 Hz, 1H), 6.61 (d, J ) 2.4
Hz, 1H), 6.48 (dd, J ) 2.7, 8.4 Hz, 1H), 3.50 (s, 2H), 3.06-
0.47 (complex, 23H); 13C NMR (CDCl3, 75 MHz): δ 140.8,
137.9, 124.7, 124.5, 109.5, 108.3, 56.4, 52.3, 42.2, 41.8, 38.4,
34.1, 33.1, 23.3, 23.1, 20.3, 18.7, 5.9. Anal. (C20H28N2‚0.1H2O)
C, H, N.
3-Am in o-N-cyclobu tylm eth ylm or p h in a n 41 (MCL-182).
Pale yellow oil (78%),1H NMR (CDCl3, 300 MHz): δ 6.88 (d,
J ) 7.8 Hz, 1H), 6.59 (d, J ) 2.4 Hz, 1H), 6.48 (dd, J ) 2.4,
8.1 Hz, 1H), 3.50 (s, 2H), 2.89 (d, J ) 18 Hz, 1H), 2.78-1.09
(complex, 24H); 13C NMR (CDCl3, 75 MHz): δ 144.6, 141.6,
128.6, 128.3, 113.3, 112.1, 61.7, 56.2, 46.2, 45.4, 42.1, 37.7, 36.8,
35.2, 28.1, 27.1, 26.8, 24.2, 22.5, 19.0. Anal. (C21H30N2) C,
H, N.
3-(1′H-Tetr a zol-5′-yl)-N-m eth ylm or p h in a n 42 (MCL-
151) was prepared using the same procedure for the prepara-
tion of 27. White solid (68%), Mp: 295-297 °C; 1H NMR
(CDCl3, 300 MHz): δ 7.88 (s, 1H), 7.70 (d, J ) 7.8 Hz, 1H),
Ack n ow led gm en t. This work was supported, in
part, by NIDA Grants K05-DA 00360, U-19-DA 11007,
K05-DA00101, and R01-DA14251. Levorphanol tartrate
was generously donated by Mallinckrodt Inc.. We grate-
fully acknowledge the calculation of the interatomic
distances and conformational analysis of compound 10
by Dr. Suobao Rong.
7.12
(d,
J ) 7.8 Hz, 1H), 3.05-0.68 (complex, 19H); 13C NMR (CDCl3,
75 MHz): δ 161.7, 138.2, 134.8, 129.3, 128.7, 124.9, 123.8, 60.2,
43.4, 41.3, 40.1, 37.1, 36.2, 29.2, 27.9, 26.9, 25.6, 22.9, 20.0,
14.0, 9.2. Anal. (C18H23N5‚2H2O) C, H, N.
3-(1′H-Tetr azol-5′-yl)-N-cyclobu tylm eth ylm or ph in an 43
(MCL-152) was prepared according to the procedure for the
preparation 42. White solid (63.7%), Mp: 200-202 °C; 1H
NMR (CDCl3, 300 MHz): δ 7.93 (s, 1H), 7.72 (d, J ) 7.8 Hz,
1H), 7.17 (d, J ) 8.1 Hz, 1H), 3.21-1.05 (complex, 25H); 13C
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