Aminimides as potential CNS-acting agents. III. Design, synthesis, and receptor binding of aminimide analogues of dopamine, serotonin, morphine, and nicotine

Article abstract of DOI:10.1071/CH08060

A series of aminimide derivatives of centrally acting agents, namely dopamine, serotonin, morphine and nicotine, were designed on the basis of the physicochemical properties of the aminimide functional group and synthesized to investigate their central nervous system (CNS) receptor affinity. The target compounds were readily prepared from an appropriate tertiary amine by N-acylation of a hydrazinium salt intermediate using acetic anhydride or acetyl chloride. The aminimides were tested for in vitro affinity at the dopaminergic D₄, serotonergic 5-HT_2A, opiate (?, ?, and non-selective) and nicotinic acetylcholine receptors and were found to possess mixed affinities for the aforementioned receptor systems. CSIRO 2008.

Full text of DOI:10.1071/CH08060

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2008, 61, 422–431
www.publish.csiro.au/journals/ajc
Aminimides as Potential CNS-Acting Agents. III. Design,
Synthesis, and Receptor Binding of Aminimide Analogues
of Dopamine, Serotonin, Morphine, and Nicotine
Ben Capuano,A Ian T. Crosby,A,D Edward J. Lloyd,A Juliette E. Neve,A,B
and David A. TaylorC
ADepartment of Medicinal Chemistry, Victorian College of Pharmacy, Monash University,
381 Royal Parade, Parkville VIC 3052, Australia.
BPresent address: Eskitis Institute for Cell and Molecular Therapies, Griffith University,
Nathan QLD 4111, Australia.
CDepartment of Pharmaceutical Biology, Victorian College of Pharmacy, Monash University,
381 Royal Parade, Parkville VIC 3052, Australia.
DCorresponding author. Email: ian.crosby@vcp.monash.edu.au
A series of aminimide derivatives of centrally acting agents, namely dopamine, serotonin, morphine and nicotine, were
designed on the basis of the physicochemical properties of the aminimide functional group and synthesized to investigate
their central nervous system (CNS) receptor affinity. The target compounds were readily prepared from an appropriate
tertiary amine by N-acylation of a hydrazinium salt intermediate using acetic anhydride or acetyl chloride.The aminimides
were tested for in vitro affinity at the dopaminergic D4, serotonergic 5-HT2A, opiate (µ, κ, and non-selective) and nicotinic
acetylcholine receptors and were found to possess mixed affinities for the aforementioned receptor systems.
Manuscript received: 14 February 2008.
Final version: 23 April 2008.
Introduction
serotonin do not cross the BBB themselves but their zwit-
terionic amino acid precursors, l-dihydroxyphenylalanine (l-
DOPA) and l-tryptophan, respectively, demonstrate facile BBB
penetration.[3,4] Morphine and nicotine do cross the BBB with
nicotine more readily than morphine.[5] The incorporation of an
aminimide functional group into these compounds may provide
balanced hydrophilic and hydrophobic character for effective
passage across the BBB. Furthermore, the reported enzymatic
and proteolytic stability of this functional group[6,7] could render
these analogues superior to agents such as l-DOPA for the deliv-
ery of a dopaminergic agent to the CNS. Thus, the dual nature
of organic and aqueous solubility of simple aminimides and the
electrically neutral and zwitterionic nature of these compounds
make them attractive targets as novel CNS-acting agents. Here
we report the design, chemical synthesis and preliminary recep-
tor binding affinity of such aminimide-containing CNS active
compounds.
As an extension of our interest in the aminimide functional group
and its incorporation into potential antipsychotic agents,[1,2]
we embarked on the synthesis and preliminary pharmacologi-
cal evaluation of aminimide analogues of other centrally acting
agents (Fig. 1, shown as in their physiologically relevant ions)
to investigate the biochemical influence of this functionality.
The biogenic amines dopamine (1) and serotonin (2), and the
narcotic alkaloid morphine (3) were chosen as these compounds
exert their effects on the central nervous system (CNS) by action
at G-protein coupled receptors (GPCRs), namely the dopamin-
ergic, serotonergic, and µ-opiate (OP3) receptors, respectively.
Nicotine (4) was also investigated as a representative of com-
pounds that act at ligand-gated ion channels, specifically the
nicotinic acetylcholine receptor. These four parent amines were
also chosen on the basis that they varied significantly in their
ability to cross the blood–brain barrier (BBB). Dopamine and
H
H3C
H
H
ꢀ
N
ꢀ
H
H
N H
HO
H
R2
HO
HO
N
ꢀ
CH3
N
N
H
ꢀ
N
ꢀ
ꢁ
N
H
CH3
N
R1
CH3
O
Dopamine, 1
O
HO
OH
Nicotine, 4
Serotonin, 2
Aminimide
template
Morphine, 3
Fig. 1. The chemical structures of dopamine (1), serotonin (2), morphine (3), nicotine (4) and the aminimide template at physiological pH.
© CSIRO 2008 10.1071/CH08060 0004-9425/08/060422

Aminimides as Potential CNS-Acting Agents
423
OH
N(CH3)2
N(CH3)2
O
O
(i)
O
O
(ii)
O
O
O
O
7
6
5
(iii)
H3C
H3C
H3C
CH3
CH3
CH3
NH2
HO
HO
N
N
N
(v)
O
(iv)
O
O
ꢀ
ꢀ
ꢀ
ꢁ
ꢁ
N
N
ꢁ
SO3
O
O
O
CH3
CH3
9
H3C
CH3
10
8
CH3
CH3
H
N
HO
HO
N
HO
HO
CH3
H
1a
1
Scheme 1. Reagents and conditions: (i) (CH3)2NH·HCl, TBTU, NEt3, RT; (ii) BH3-THF, THF, reflux; (iii) O-mesitylene-
sulfonylhydroxylamine (MesSO3NH2), CH2Cl2, 0◦C; (iv) a. Ac2O, 120◦C; b. Amberlite IRA-400(OH), MeOH; (v) BBr3,
CH2Cl2, RT.
Chemistry
methylene group (H1) and an ion (M+, 209) observed in the pos-
itive ion electrospray mass spectrum indicated that N-amination
had occurred successfully. The 2,4,6-trimethylbenzenesulfonate
anion was also observed in the 1H and 13C NMR, spectrum
confirming the formation of 8. N-acylation of 8 using acetic
anhydride smoothly afforded the aminimide (9) in 92% yield.
Subsequent de-etherification on treatment with boron tribro-
mide gave the target dopamine aminimide analogue (10) in 42%
overall yield from 5.
The synthesis of acetyl aminimides from hydrazinium salts has
been described previously[8] using acetic anhydride or acetyl
chloride as the acylating species. Both of these methods were
examined for the synthesis of the desired acetyl aminimides of
the designated CNS-active agents.The tertiary amines morphine
(3) and nicotine (4) could be used directly for the generation of
the corresponding hydrazinium salts (16) and (19) respectively.
In the case of the primary amines, dopamine and serotonin, the
corresponding O-alkylidene or alkyl N,N-dimethyl derivatives
(7) and (11), respectively, were utilized as the tertiary amines
required for aminimide synthesis.
Serotonin
N,N-dimethyl-5-hydroxytryptamine(bufotenin, 2a)wasselected
as the parent amine for the synthesis of an acetyl aminimide ana-
logue of 5-hydroxytryptamine (serotonin, 14; Scheme 2). As in
the dopamine scenario, the O-protected tertiary amine (11) was
envisaged as an appropriate substitute for 2a owing to possi-
ble side-reactions in the aminimide synthesis arising from an
unprotected hydroxy group. By reason of the commercial avail-
ability of N,N-dimethyl-5-methoxytryptamine (11), we decided
to utilize this material as the aminimide precursor and complete
the desired synthesis of 14 by O-demethylation. N-Amination
of 11 proceeded smoothly to give the hydrazinium salt (12) in
98% yield. Unfortunately, attempts to N-acylate 12 using acetic
anhydride proved problematic in this case, because not only did
N-acylation occur at the hydrazinium nitrogen (13), but also at
the indole nitrogen to afford 13a (Scheme 2). Di-acetylation
was indicated by the presence of two singlet resonances (δ 1.90
and 2.57 ppm) in the 1H NMR spectrum of 13a (see Accessory
Publication). Further analysis revealed the doublet resonances
assigned to H7 and H2 had shifted downfield from δ 7.29 and
7.04 ppm for the desired aminimide (13) to δ 8.29 and 7.27 ppm
(s), respectively, for 13a.The absence of the characteristic indole
N–Hprotonresonanceobservedfor 13(H1, δ9.46 ppm)wasalso
supportive of the formation of 13a.
Dopamine
The N,N-dimethyl analogue of dopamine, 1a, was selected as
the parent tertiary amine for the synthesis of the dopamine
aminimide (10; Scheme 1). The O-protected tertiary amine
(7) was envisaged as an appropriate substitute for 1a
because it was considered that problems might be encoun-
tered with the free hydroxy groups during aminimide synthesis.
Compound 7 was synthesized from commercially available
3,4-methylenedioxyphenylacetic acid (5) in two steps. The
activated hydroxybenzotriazolyl ester of 5 was prepared from
3,4-methylenedioxyphenylacetic acid (5) and 1-(bis(dimethyl-
amino)methylene)-1H-benzo[d][1,2,3]triazol-1-ium 3-oxide
tetrafluoroborate (TBTU) in N,N-dimethylformamide. Subse-
quent treatment with dimethylamine hydrochloride in the pres-
ence of triethylamine gave, after flash chromatography and
distillation, the amide (6) in 69% yield. Treatment of the amide
(6)withborane–tetrahydrofurancomplexgavethetertiaryamine
(7) in 83% distilled yield.The boiling points of compounds 6 and
7 were in good agreement with those reported in the literature.[9]
N-Aminationof 7by O-mesitylenesulfonylhydroxylamine[10]
gave the hydrazinium salt 8 as cream-coloured needles in
84% yield. A downfield shift observed for the 1H and 13C
NMR resonances of both the N,N-dimethyl group and adjacent
N-acylation of 12 to afford 13 using acetyl chloride
(Scheme 2) proved more successful with only a small amount of
the doubly acetylated product detected by TLC and in the mass

424
B. Capuano et al.
ꢁ
SO3
H3CO
H3CO
H3C
H3C
CH3
CH3
NH2
(i)
N(CH3)2
N
ꢀ
HN
HN
CH3
12
11
(ii)
HO
H3CO
H3CO
H3C
H3C
CH3
CH3
CH3
CH3
ꢀ
N
N
N
(iii)
ꢁ
N
ꢀ
ꢀ
ꢁ
ꢁ
N
N
HN
HN
N
CH3
O
O
O
14
13
CH3
CH3
O
13a
CH3
HO
HO
CH3
H
N
N
CH3
H
HN
HN
2a
2
Scheme 2. Reagents and conditions: (i) O-mesitylenesulfonylhydroxylamine, CH2Cl2, 0◦C; (ii) CH3COCl, NaH, DMF,
−15◦C–RT; (iii) BBr3, CH2Cl2, RT.
H3C
H3C
N
N
15
(i)
O
O
HO
OH
PhOCO
OCOPh
3
(ii)
N
ꢁ
H3C
H3C
N
NH2
ꢁ
N
ꢀ
CH3
SO3
ꢀ
O
H3C
CH3
(iii)
CH3
O
O
RO
OR
PhOCO
OCOPh
16
17: R ꢂ COPh
18: R ꢂ H
(iv)
Scheme 3. Reagents and conditions: (i) PhCOCl, pyridine, 0–50◦C; (ii) O-mesitylenesulfonylhydroxylamine,
CH2Cl2, 0◦C; (iii) a. Ac2O, 120◦C; b. Amberlite IRA-400(OH), MeOH; (iv) 1% aq. NaOH, MeOH.
spectrum of the crude reaction mixture. The compound was iso-
lated in 56% recrystallized yield as pale orange plates.Treatment
of 13 with boron tribromide under standard aromatic demethy-
lation conditions[11] proceeded smoothly to give the indolol, 14,
in 42% yield.
the dibenzoate ester (15) to avoid possible side reactions
during the N-amination step. Amination of 15 proceeded
smoothly at the tertiary nitrogen on treatment with O-
mesitylenesulfonylhydroxylamine[10] to afford the dibenzoate-
protected hydrazinium salt (16) in 75% yield. The method
described byTamura et al.[8] utilising acetic anhydride as the acy-
lating species was preferred, as the acid chloride gave a complex
mixture of products. Examination of the positive ion electrospray
mass spectrum of the reaction mixture resulting from treatment
Morphine
The chemical synthesis of the target morphine aminimide
is depicted in Scheme 3. Morphine (3) was protected as

Aminimides as Potential CNS-Acting Agents
425
CH3
C16
H
H
O
C17
N2
C15
N1
ꢁ
D
OH
D
A
OH
N
C1
C2
C4
E
E
ꢀ
C11
N
N
C10
H3C
H3C
B
B
O
O
C
C
C9
C12
C5
C6
C3
O2
O1
A
C18
O4
C13
O5
C19
OH
OH
C14
C8
18
3
C20
Fig. 3. The absolute structures of 3 and 18.
C7
O3
Fig. 2. An ORTEP view of 18. Displacement ellipsoids are drawn at the
50% probability level.
CH3
H
H
O
6
6
H2N
ꢁ
OH
OH
N
N
14
14
ꢀ
ꢀ
9
9
of 16 with acetyl chloride indicated that not only had the forma-
tion of the acetyl aminimide occurred, but also debenzoylation
and O-acetylation to varying degrees of both the aminimide and
the hydrazinium salt. Deamination to the tertiary amine was also
detected. This is in contrast to the treatment of 16 with acetic
anhydride, which proceeded smoothly to afford the dibenzoyl-
protected morphine aminimide (17) in 69% yield. Removal of
the benzoyl groups by treatment with aqueous sodium hydro-
xide (1%) in methanol gave the target morphine aminimide (18),
which afforded colourless needles from methanol in 78% yield
suitable for X-ray analysis.
N
H3C
H3C
15
15
12
O
O
12
17
17
10
10
3
3
1
1
OH
OH
18
16
Fig. 4. NOEs observed for 18 and 16 for the determination of stereochem-
istry about the quaternized nitrogen.
both slightly longer than expected for double bonds, thus indicat-
ing that there is significant charge delocalisation present about
the acyl aminimide moiety. This delocalization is also supported
by the characteristic aminimide infrared resonance (−OC=N) at
All dibenzoate morphine analogues were characterized by the
presence of two ester carbonyl stretching frequencies between
1735 and 1710 cm−1 in their infrared spectra. The two mor-
phine aminimides, 17 and 18, showed the characteristic amini-
mide infrared absorption bands (1587, 1563 cm−1) due to the
major contribution of the −OC=N resonance form observed for
aminimides.[12] Structural assignments of 15–18 were achieved
by one- and two-dimensional NMR techniques and compar-
1563 cm−1
.
The stereochemistry about the quaternary nitrogen is
assigned as the R configuration. This is supported by the crys-
tal structure of 18 and the correlations observed in the nuclear
Overhauser effect correlation spectroscopy (NOESY) spectrum
for both the aminimide, 18, and the hydrazinium salt, 16 (Fig. 4).
Nuclear Overhauser effects (NOEs) were observed for 18 from
the +N-methyl resonance, H17 (δ 3.45 ppm) to H9 (δ 4.95 ppm)
and the respective axial and equatorial proton resonances of
H10 (δ 2.77, 3.26 ppm) and H16 (δ 2.90, 3.85 ppm). This indi-
cates that the +N-methyl group is equatorial. Similarly, NOEs
were observed for 16 from the +N-methyl resonance, H17 (δ
3.95 ppm) to the equatorial resonance of H10 (δ 3.38 ppm),
the axial H16 resonance (δ 3.17 ppm), and H9 (δ 4.78 ppm).
NOEs were also observed from the hydrazinium amino reso-
nance (δ 6.64 ppm) to H17 (δ 3.95 ppm), H14 (δ 4.20 ppm), H9
(δ 4.78 ppm), and H5 (δ 5.33 ppm). This evidence indicates an
equatorial methyl group and an axial hydrazinium amino or ace-
timide group about the positively charged nitrogen, confirming
the R stereochemistry for 16–18, which was also observed in the
solid state (Fig. 2).
1
isons of the H and 13C NMR spectra with those of morphine
and its O-acetyl derivatives in the literature (see Accessory
Publication).[13] Several key features such as the proton res-
onances associated with the benzoate groups of 15–17, the
+N-methyl proton resonances (δ 3.6–3.9 ppm) for 16–17, and
the acetimide methyl proton resonances (δ 1.8–1.9 ppm) for 17
and 18 were used for confirmation of structure. Also observed
were downfield shifts for the proton resonances in the vicin-
ity of the nitrogen, namely H9, H10, H15, H16 and H17, due
to the effect of the ionized nitrogen for analogues 16–18. The
crystal structure of 18 was also determined by X-ray crystal-
lography and an ORTEP view of the molecule together with the
atomic numbering is shown in Fig. 2. The atomic coordinates,
anisotropic displacement parameters, bond lengths, bond angles
and torsion angles of the derivative 18 are listed as Accessory
Publication.
The morphine moiety of 18 adopts a similar ‘T-shaped’ con-
formation to that observed for the parent compound, morphine
(3).[14] The ‘T-shaped’conformation ideally comprises two mean
planes that intersect in a near-normal fashion. Each mean plane
is defined by the rings of the morphine molecule such that the
first plane comprises rings A, B, and C, and the second rings
D and E. As was observed for morphine (3),[14] the piperidine
ring of 18 adopts a chair conformation with the methyl group
assuming an equatorial orientation and the acetimide group
axial (Fig. 3). Charge delocalisation is observed on the carbonyl
oxygen (O4) of the aminimide group for 18. The N(1)–N(2)
(1.482(2) Å) bond is similar to a single bond in length and the
N(2)–C(18)(1.324(3) Å)andC(18)–O(4)(1.250(3)Å)bondsare
Nicotine
Scheme 4 illustrates the chemical synthesis of the target nico-
tine aminimide. (S)-(−)-Nicotine (4) was mono-N-aminated at
the more basic nitrogen by the procedure described by Tamura
et al.[8] to give the hydrazinium salt 19 in 58% yield. The cation
of 19 appeared at m/z 178 in the positive ion electrospray mass
spectrum indicating that mono-N-amination had occurred. Con-
firmation that reaction had occurred only at the tertiary aliphatic
amine nitrogen was obtained on examination of the 1H and 13
C
NMR spectra of 19, which revealed a methyl group attached to
a positively charged nitrogen (δH 3.14 ppm, δC 51.9 ppm). The
methylene and methine carbons (C5 and C2) resonated at δ 67.8
and 76.6 ppm, respectively, in the 13C NMR spectrum, which

426
B. Capuano et al.
H3C
O3S
O
ꢀ
ꢀ
ꢁ
(i)
(ii)
N
N
N
CH3
N
ꢁ
CH3
NH2
CH3
H3C
20
H3C
N
N
N
H3C
4
19
Scheme 4. Reagents and conditions: (i) O-mesitylenesulfonylhydroxylamine, CH2Cl2, 0◦C; (ii) a. Ac2O, 120◦C; b. Amberlite IRA-400(OH), MeOH.
Table 1. Preliminary binding studies
is consistent with these carbons being attached to a positively
charged nitrogen. All other data collected in the experimental
section were consistent with those reported in the literature.[8]
As (S)-(−)-nicotine is a chiral molecule, N-amination could
potentially produce two diastereomers. Only one diastereomer,
19, was visible by 1H and 13C NMR spectroscopy and by TLC.
H3C
H3C
CH3
CH3
N
HO
HO
N
O
O
ꢀ
ꢀ
ꢁ
ꢁ
N
N
O
O
CH3
CH3
9
10
1
Examination of a H-1H NOESY spectrum (Accessory Publi-
cation) indicated that the stereochemistry about the quaternary
nitrogen is S. NOEs were observed for 19 from the methine
proton resonance, H2 (δ 4.93 ppm) to the +N-methyl resonance
(δ 3.14 ppm), thus indicating that the +N-methyl group is syn
to H2. NOEs were also observed from H2 (δ 4.93 ppm) to H3a
(δ 2.37 ppm), and H5a (δ 3.81 ppm), indicating that these two
protons are also syn to H2. Furthermore, NOEs were observed
from the hydrazinium amino proton resonance (δ 5.55 ppm) to
the +N-methyl resonance (δ 3.14 ppm), H5b (δ 3.88 ppm), and
H3b (δ 2.64 ppm), thus indicating that the amino group, H5b and
H3bareallanti toH2. Subsequentacetylationofthehydrazinium
salt (19) with acetic anhydride at 120◦C, followed by treatment
with Amberlite IRA-400(OH) ion-exchange resin gave, after
repeated chromatography, the desired nicotine acetyl aminimide
(20) in 37% yield.
Compound
Binding affinity percentage
inhibition (% I) at 10−6 M
D
4,4[3H]spiperoneA
Dopamine, 1
9
10
55
−5
−3
ADetermined in duplicate by MDS PANLABS (Taiwan).
Table 2. Preliminary binding studies
H3C
H3C
CH3
H
ꢀ
N
N
ꢁ
N
CH3
H3CO
RO
ꢀ
CH3
O
N
H
N
H
Receptor Binding Studies
13: R ꢂ CH3
14: R ꢂ H
11
Biological Results
Binding data were obtained from MDS Panlabs (Taiwan). Each
compound was tested at a concentration of 10−6 M at the recep-
tors indicated and compared with the affinity of the amine from
which the aminimide was obtained. In the case of the dopamine
and serotonin analogues, affinities were also compared with that
of the endogenous neurotransmitters dopamine and serotonin,
respectively.
The affinities of aminimide analogues of dopamine, 9 and
10, for the dopamine D4.4 receptor in human recombinant CHO
cells using [3H]spiperone as the competing radioligand were
−3 and −5% inhibition at 10−6 M (Table 1). These values were
well below that of the reference compound dopamine, which
displayed a 55% inhibition of radioligand.
Both the 5-methoxy (13) and the 5-hydroxy (14) aminimide
analogues of serotonin were tested at a concentration of 10−6
M for their binding affinities for the 5-HT2A receptor in rat
cerebral cortex (Table 2). Serotonin (2) and N,N-dimethyl-5-
methoxytryptamine (11) were also evaluated at this receptor
for comparative purposes. A significant reduction in binding
affinity for the 5-HT2A receptor was evident on replacement of
the tertiary amine group (11, 60% I) with an aminimide group
(13, 16% I). A comparable affinity for the 5-HT2A receptor was
observed on the removal of the 5-methoxy group of 13 to afford
the 5-hydroxy analogue (14, 26% I); however, these values were
significantly below that of the reference compound serotonin
(77% I).
Compound
Binding affinity percentage
inhibition (% I) at 10−6 M
5-HT2A[3H]ketanserinA
Serotonin
77
60
16
26
11
13
14
ADetermined in duplicate by MDS PANLABS (Taiwan).
along with the rat brain opiate (non-selective) receptor (Table 3).
As was observed for the aminimides of the biogenic amines
dopamine and serotonin, there was a pronounced decrease in
binding affinity on introduction of the aminimide functional
group.
Both nicotine (4) and the nicotine aminimide (20) were evalu-
ated at the central nicotinic acetylcholine receptor (Table 4). The
introduction of the aminimide group into nicotine to give 20 only
produced a modest reduction in receptor affinity compared with
nicotine. This result was quite pleasing when evaluated against
the relative drop in affinity associated with the dopamine, sero-
tonin, and morphine aminimides compared with their respective
parent compounds.
The nicotinic acetylcholine receptor is a ligand-gated ion
channel, not a GPCR like the dopamine, 5-HT, and opiate
receptors used in the present study. Consequently, the binding
interactions are somewhat different when comparing the two
Both morphine (3) and the morphine aminimide (18) were
evaluated at the human recombinant µ and κ opiate receptors

Aminimides as Potential CNS-Acting Agents
427
Table 3. Preliminary binding studies
A three-dimensional structure determined by electron
microscopy has described the structure of the nicotinic acetyl-
choline receptor in both the open and closed state.[16] These
structures and affinity labelling studies indicate that acetyl-
choline interacts predominantly with the α-subunit of the
receptor.[17] A model of the binding site[18] has described inter-
actions between the ionized amine of the ligand, in this case
acetylcholine, and the negatively charged region of the binding
site. Traditional ion pair-type interactions between the ionized
amine and aspartic acid and serine residues, and cation–π inter-
actions of the ionized amine with aromatic residues (tyrosine
and tryptophan) have been described. This cation–π interaction
is thought to stabilize the positive charge of the trimethyl-
ammonium group of acetylcholine, forming an anionic solvation
shell.[19] This cation–π interaction could stabilize the positive
charge of the aminimide group, which may not be available in
the models of the GPCRs.
O
H3C
CH3
ꢀ
N
N
ꢁ
18
O
OH
HO
Compound
Binding affinity percentage inhibition (% I) at 10−6
M
µ Opiate[3H]
κ Opiate[3H]
Opiate, non-selective
[3H]naloxone
diprenorphineA diprenorphineA
Morphine, 3
18
99
17
72
−10
94
14
ADetermined in duplicate by MDS PANLABS (Taiwan).
Table 4. Preliminary binding studies
Conclusion
A marked reduction in affinity was observed for the dopamine,
morphine, and serotonin aminimide analogues that were evalu-
ated for their affinity at GPCRs. Conversely, the same marked
reduction in affinity was not observed for the nicotine aminimide
analogue and an explanation relating to the different binding
interactions proposed for the nicotinic acetylcholine receptor is
given. Clearly, more detailed information relating to the affin-
ity of these compounds at the targeted receptors is required to
support the explanations for the reduced affinity of these com-
pounds. Further studies are needed that investigate aminimide
analogues of other CNS-acting agents that exert their action at
a larger selection of G-protein coupled as well as other types of
receptors within the CNS.Also the introduction, at an alternative
site not thought to be involved in receptor binding, of the amini-
mide group to several CNS-acting agents could be investigated
in an effort to balance the lipophilic and hydrophilic charac-
teristics of these molecules. Other functional groups could also
be investigated in an effort to increase the binding affinity and
improve aqueous solubility of several CNS-acting agents.
O
ꢀ
N
CH3
N
ꢁ
H3C
N
20
Compound
Binding affinity percentage
inhibition (% I) at 10−6
M
Central nicotinic acetylcholine α4β2
(rat)[3H]cytisineA
Nicotine, 4
20
92
71
ADetermined in duplicate by MDS PANLABS (Taiwan).
(a)
(b)
HO
OH
O
HO
OH
O
Experimental
O
O
ꢁ
3
H
N
General
N
ꢀ
ꢀ
CH3
O
H3C
N
O
ꢁ
ꢁ
Melting points were determined using a Reichert Micromelting
point apparatus and are uncorrected. Microanalyses were car-
ried out by Chemical and Micro Analytical Services Pty Ltd,
Melbourne, Australia or the Chemistry Department, University
of Queensland. Infrared spectra were recorded using a Hitachi
270–30 infrared spectrometer as potassium bromide (KBr) discs
for solids, as thin films of liquids (neat) between sodium chloride
plates and as chloroform (CHCl3) solutions of gums. UV-Visible
spectra were recorded as ethanolic solutions using a Pharmacia
Biotech Ultraspec 2000 UV-VIS spectrometer utilizing Swift II
software. 1H and 13C NMR spectra were obtained on a Bruker
DPX-300 spectrometer. 1H and 13C NMR spectra were recorded
at 300.13 MHz and 75.47 MHz, respectively. Chemical shifts
are reported in δ units relative to internal tetramethylsilane for
1H NMR spectra and the deuterated solvent resonance for 13C
spectra. NOESY, homonuclear(1H/1H)correlationspectroscopy
(DQFCOSY and gradient correlation spectroscopy (COSY))
and inverse heteronuclear (1H/13C) correlation spectroscopy
(HMQC and gradient HMBC) were obtained using the standard
Bruker pulse sequences for structural assignment of some NMR
spectra. Mass spectra were recorded on a JEOL JMS-DX300
CH3
18
O
TMIII
TMIII
Fig. 5. Salt bridge formation at TMIII between the aspartate residue and
(a) morphine (3) and (b) morphine aminimide (18).
classes of receptor. The positively charged amine of the drug
and ligand is thought to interact electrostatically with an ionized
aspartic acid residue on the receptor in the GPCRs, for example,
Asp-311 on transmembrane unit III (TMIII) for the dopamine
receptor.[15] This binding interaction can occur between the con-
served aspartate residue on TMIII of the dopamine, serotonin,
and opiate receptors and can be stabilized in the case of the
tertiary amine compounds such as morphine for the µ-receptor
(Fig. 5). Although there is a quaternized nitrogen that could par-
ticipate in an electrostatic interaction on receptor binding, there
is no available hydrogen bonding group for stabilization. There
is also a possibility of electrostatic repulsion from the opposing
negative charges of the aspartate and the aminimide nitrogen.

428
B. Capuano et al.
or a Micromass Platform II mass spectrometer in positive ion
electrospray mode. High resolution mass spectra (HRMS) were
recorded using a Bruker Bio Apex II FTICR mass spectrometer.
Silica gel (Merck Kieselgel 60 silica gel 230–400 mesh) was
used for column chromatography. TLC was performed on sil-
ica gel plates (Merck, ART 5554 60 F254). Preparative TLC
was performed on glass plates (Merck ART 5717). Solvents
were purified by literature methods.[20,21] Hexane refers to the
hydrocarbon fraction boiling between 60◦C and 80◦C.
1-[2-(1,3-Benzodioxol-5-yl)ethyl]-1,1-dimethylhydrazinium
2,4,6-Trimethylbenzenesulfonate 8
A solution of O-mesitylenesulfonylhydroxylamine[10] (501 mg,
2.33 mmol) in dichloromethane (5 mL) was added, with ice cool-
ing, to a solution of 7 (375 mg, 1.94 mmol) in dichloromethane
(8 mL) and the mixture left to stir for 20 min. Hexane was
then added to precipitate the crude product (668 mg, 84%),
which recrystallized from ethyl acetate/methanol to give 8
(598 mg, 76%) as cream needles, mp 179–180◦C (Found: C 58.8,
H 7.0, N 6.8. C20H28N2O5S requires C 58.8, H 6.9, N 6.9%).
νmax (KBr)/cm−1 3292, 1635, 1608. λmax/nm (ε/M−1 cm−1
)
2-(1,3-Benzodioxol-5-yl)-N,N-dimethylacetamide 6
223 (12600), 284 (4370) nm. δH ([D4]methanol) 2.30 (3H, s,
ArCH3), 2.70 (6H, s, 2 ×ArCH3), 3.17 (2H, m, H2), 3.40 (6H,
s, (CH3)2N+), 3.70 (2H, m, H1), 6.00 (2H, s, H2ꢀ), 6.83–6.88
(3H, m, H4ꢀ, H6ꢀ, H7ꢀ), 6.94 (2H, s, ArH). δC ([D4]methanol)
21.0 (ArCH3), 23.0 (2 ×ArCH3), 30.1 (C2), 56.7 ((CH3)2N+),
71.1 (C1), 102.6 (C2ꢀ), 109.7 (C4ꢀ), 110.4 (C7ꢀ), 123.4 (C6ꢀ),
130.6 (C5ꢀ), 131.9 (C3ꢀꢀ, C5ꢀꢀ), 138.4 (C2ꢀꢀ, C6ꢀꢀ), 140.3 (C4ꢀꢀ),
141.1 (C1ꢀꢀ), 148.4 (C7aꢀ), 149.7 (C3aꢀ). m/z (+ESI, 30V) 209
(M+, 100%).
A solution of 2-(1,3-benzodioxol-5-yl)acetic acid (5) (1.00 g,
5.55 mmol), dimethylamine hydrochloride (498 mg, 6.11 mmol)
and TBTU (2.16 g, 6.73 mmol) in anhydrous tetrahydrofuran
(50 mL) was stirred at room temperature under an atmosphere
of nitrogen for 1 h. Triethylamine (3.1 mL, 2.23 g, 22.0 mmol)
was then added and the reaction mixture allowed to stir at room
temperature for a further 14 h. The solvent was removed under
vacuum to afford a brown gum, which was partitioned between
sodium hydroxide (2 M, 50 mL) and ethyl acetate (80 mL) and
the aqueous phase extracted with ethyl acetate (2 × 100 mL).The
combined organic phases were washed with water (150 mL),
dried over anhydrous sodium sulfate, then evaporated under
vacuum.The resulting brown oil was purified by flash chromato-
graphy (7:3 ethyl acetate/hexane) to afford 6, after concentrating
the appropriate fraction, as a pale yellow oil. Vacuum distillation
afforded the title compound 6 (796 mg, 69%) as a colourless oil,
bp 164–166◦C/270 Pa (lit.[9] 145◦C/40 Pa). νmax (KBr)/cm−1
2902, 1632, 1500. λmax/nm (ε/M−1 cm−1) 238 (4070), 289
(3720). δH (CDCl3) 2.97 (3H, s, CH3N), 3.01 (3H, s, CH3N),
3.63 (2H, s, H2), 5.94 (2H, s, H2ꢀ), 6.69 (1H, dd, J 8, 2, H6ꢀ), 6.75
(1H, d, J 8, H7ꢀ), 6.78 (1H, d, J 2, H4ꢀ). δC (CDCl3) 35.8 (CH3N),
37.8 (CH3N), 40.7 (C2), 101.1 (C2ꢀ), 108.4 (C4ꢀ), 109.4 (C7ꢀ),
121.9 (C6ꢀ), 128.9 (C5ꢀ), 146.5 (C7aꢀ), 148.0 (C3aꢀ), 171.2 (C1).
m/z (+ESI, 30V) 208 (100%, MH+).
1-Acetyl-2-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2,2-
dimethylhydrazin-2-ium-1-ide 9
A solution of 8 (253 mg, 0.62 mmol) in acetic anhydride
(20 mL) was heated at 120◦C for 5 h. The reaction mixture
was concentrated under vacuum to afford a brown syrup,
which was dissolved in methanol and treated with Amberlite
IRA-400(OH) ion-exchange resin. The resin was removed by
filtration and the filtrate concentrated under vacuum. The result-
ing orange gum was purified by flash chromatography (100:8:1,
dichloromethane/ethanol/ammonia) to afford a colourless oil
(142 mg, 92%), which solidified on cooling. Recrystalliza-
tion from ether/hexane gave the title compound 9 (104 mg,
67%) as colourless plates, mp 32◦C (Found: C 57.9, H 7.7,
N 10.3, MH+ 251.1387. C13H18N2O3·H2O requires C 58.2, H
7.5, N 10.4%, MH+ 251.1390). νmax (KBr)/cm−1 2974, 1578.
λmax/nm (ε/M−1 cm−1) 237 (3240), 288 (3020). δH (CDCl3)
1.86(3H, s, CH3CO), 2.96(2H, m, H2ꢀ), 3.32(6H, s, (CH3)2N+),
3.87 (2H, m, H1ꢀ), 5.92 (2H, s, H2ꢀꢀ), 6.67 (1H, br d, J 8,
H6ꢀꢀ), 6.71 (1H, br s, H4ꢀꢀ), 6.74 (1H, d, J 8, H7ꢀꢀ). δC (CDCl3)
23.1 (CH3CO), 29.7 (C2ꢀ), 56.7 ((CH3)2N+), 66.1 (C1ꢀ), 100.9
(C2ꢀꢀ), 108.3(C4ꢀꢀ), 109.1(C7ꢀꢀ), 121.7(C6ꢀꢀ), 130.2(C5ꢀꢀ), 146.4
(C7aꢀꢀ), 147.8 (C3aꢀꢀ), 173.9 (CO). m/z (+ESI, 30 V) 251 (40%,
MH+), 149 (100).
2-(1,3-Benzodioxol-5-yl)-N,N-dimethylethanamine 7
To a solution of 6 (586 mg, 2.83 mmol) in dry, oxygen-free
tetrahydrofuran (40 mL), at 0◦C, was added dropwise a solution
of borane in tetrahydrofuran (1.0 M, 4.7 mL, 4.7 mmol). Once
the addition was complete, the reaction mixture was heated at
reflux for 1 h and then allowed to cool. Aqueous hydrochloric
acid (5 M, 10 mL) was added and the reaction mixture left to stir
for a further 20 min. The solvent was removed under vacuum,
water (30 mL) added and the resulting mixture adjusted to pH 12
by the addition of solid potassium hydroxide pellets. Following
extraction with ethyl acetate (3 × 50 mL), the organic fractions
were dried over anhydrous sodium sulfate and concentrated.
The resulting residue was purified by flash chromatography
(100:8:1, dichloromethane/ethanol/ammonia) to afford 7, after
concentrating the appropriate fraction, as a pale yellow oil. Vac-
uum distillation afforded the title compound 7 (449 mg, 83%)
as a colourless oil, bp 123–125◦C/65 Pa (lit.[9] 95◦C/15 Pa).
νmax (KBr)/cm−1 2950–2782, 1608. δH (CDCl3) 2.29 (6H, s,
(CH3)2N), 2.47–2.52 (2H, m, H2), 2.68–2.73 (2H, m, H1), 5.92
(2H, s, H2ꢀ), 6.65 (1H, dd, J 8, 1.5, H6ꢀ), 6.71 (1H, d, J 1.5, H4ꢀ),
6.73 (1H, d, J 8, H7ꢀ). δC (CDCl3) 33.9 (C2), 45.3 (CH3N), 61.6
(C1), 100.7 (C2ꢀ), 108.1 (C4ꢀ), 109.0 (C7ꢀ), 121.3 (C6ꢀ), 134.2
(C5ꢀ), 145.7 (C7aꢀ), 147.5 (C3aꢀ). m/z (+ESI, 30V) 194 (100%,
MH+).
1-Acetyl-2-(3,4-dihydroxyphenethyl)-2,2-
dimethylhydrazin-2-ium-1-ide 10
A solution of 9 (200 mg, 0.80 mmol) in anhydrous dichloro-
methane (10 mL) was treated with a solution of boron tribromide
in dichloromethane (1.0 M, 4.0 mL, 4.0 mmol) at room temper-
ature and the reaction mixture left to stir overnight. Methanol
(10 mL) was added and the reaction mixture was stirred for
a further 20 min. The methanol was removed under vacuum
and the brown residue resuspended in methanol (10 mL) and
reconcentrated to afford the title compound 10 (180 mg, 94%)
as a pale brown gum (Found: MH+ 239.1385. C12H18N2O3
requires MH+ 239.1390). νmax (KBr)/cm−1 3292, 3154, 1599,
1554. λmax/nm (ε/M−1 cm−1) 224 (5370), 284 (2750). δH
([D4]methanol) 2.06 (3H, s, CH3CO), 2.94 (2H, m, H2ꢀ), 3.68
(6H, s, (CH3)2N+), 4.16 (2H, m, H1ꢀ), 6.68 (1H, d, J 8, H6ꢀꢀ),
6.76 (1H, d, J 2, H3ꢀꢀ), 6.68 (1H, dd, J 8, 2, H5ꢀꢀ). δC (D2O) 20.6
(CH3CO), 27.8 (C2ꢀ), 54.8 (CH3N+), 66.4 (C1ꢀ), 115.8 (C6ꢀꢀ),

Aminimides as Potential CNS-Acting Agents
429
116.0(C3ꢀꢀ), 127.3(C4ꢀꢀ), 120.8(C5ꢀꢀ), 142.5(C1ꢀꢀ), 143.6(C2ꢀꢀ),
0.29 mmol) in anhydrous dichloromethane (10 mL) at room tem-
perature. After stirring overnight, methanol (10 mL) was added,
the reaction mixture stirred for a further 30 min and then evap-
orated to dryness. The residue was redissolved in methanol
(10 mL) and the methanol removed under vacuum. The result-
ing brown residue was purified by flash chromatography (50:8:1,
dichloromethane/ethanol/ammonia) to afford the title compound
14 (33 mg, 42%) as a brown gum (Found: MH+ 262.1549.
C14H19N3O2 requires MH+ 262.1550). νmax (KBr)/cm−1 3600–
3200, 1629, 1605, 1572. λmax/nm (ε/M−1 cm−1) 223 (23400),
278 (5890), 298 (4680), 310 (3390). δH ([D4]methanol) 1.83
(3H, s, CH3CO), 3.03(2H, m, H2ꢀ), 3.30(6H, s, (CH3)2N+), 3.93
(2H, m, H1ꢀ), 6.63 (1H, dd, J 9, 2, H6ꢀꢀ), 6.94 (1H, d, J 2, H4ꢀꢀ),
7.01 (1H, br s, H2ꢀꢀ), 7.12 (1H, d, J 9, H7ꢀꢀ). δC ([D4]methanol)
20.9 (C2ꢀ), 54.6 ((CH3)2N+), 66.2 (C1ꢀ), 103.5 (C4ꢀꢀ), 110.0
(C3ꢀꢀ), 112.9 (C7ꢀꢀ), 113.0 (C6ꢀꢀ), 124.9 (C2ꢀꢀ), 129.2 (C3aꢀꢀ),
133.2 (C7aꢀꢀ), 151.6 (C5ꢀꢀ), 175.3 (CO). m/z (+ESI, 30V) 262
(20%, MH+), 173 (100).
169.6 (CO). m/z (+ESI, 30 V) 239 (100, MH+), 103 (90).
1-[2-(5-Methoxy-1H-indol-3-yl)ethyl]-1,1-
dimethylhydrazinium 2,4,6-
Trimethylbenzenesulfonate 12
A solution of O-mesitylenesulfonylhydroxylamine[10] (592 mg,
2.8 mmol) in dichloromethane (5 mL) was added over
5 min, with ice cooling, to a solution of N,N-dimethyl-5-
methoxytryptamine(11)(500 mg, 2.3 mmol)indichloromethane
(8 mL). The reaction mixture was left to stir for a fur-
ther 10 min after which hexane was added to precipitate the
crude product (976 mg, 98%). Recrystallization from ethyl
acetate/methanol gave the title compound 12 (814 mg, 82%) as
cream-coloured needles, mp 161–162◦C (Found: C 61.0, H 7.2,
N 9.6. C22H31N3O4S requires C 61.0, H 7.2, N 9.7%). νmax
(KBr)/cm−1 3272, 1650, 1623, 1602. λmax/nm (ε/M−1 cm−1
)
222 (41700), 276 (34700), 298 (22400), 310 (13200). δH
([D4]methanol) 2.24 (3H, s, ArCH3), 2.65 (6H, s, 2 ×ArCH3),
3.31 (2H, m, H2ꢀ), 3.40 (6H, s, CH3N+), 3.72 (2H, m, H1ꢀ),
3.86 (3H, s, CH3O), 6.83 (1H, dd, J 9, 2.5, H6ꢀꢀ), 6.88 (2H, s,
H3ꢀꢀꢀ, H5ꢀꢀꢀ), 7.10 (1H, d, J 2.5, H4ꢀꢀ), 7.18 (1H, br s, H2ꢀꢀ), 7.29
(1H, d, J 9, H7ꢀꢀ). δC ([D4]methanol) 20.4 (C2ꢀ), 21.0 (CH3Ar),
23.5 (2 × CH3Ar), 56.5 ((CH3)2N+, CH3O), 70.4 (C1ꢀ), 101.3
(C4ꢀꢀ), 109.2(C3ꢀꢀ), 113.1(C6ꢀꢀ), 113.4(C7ꢀꢀ), 125.1(C2ꢀꢀ), 128.6
(C3aꢀꢀ), 131.9 (C3ꢀꢀꢀ, C5ꢀꢀꢀ), 133.5 (C7aꢀꢀ), 138.4 (C2ꢀꢀꢀ, C6ꢀꢀꢀ),
140.3 (C4ꢀꢀꢀ), 141.1 (C1ꢀꢀꢀ), 155.5 (C5ꢀꢀ). m/z (+ESI, 30 V) 234
(M+, 100%), 174 (80).
(5α,6α)-7,8-Didehydro-4,5-epoxy-17-methylmorphinan-
3,6-dibenzoate (Dibenzoylmorphine) 15
Benzoyl chloride (620 µL, 742 mg, 5.3 mmol) was added, at 0◦C,
to a stirred solution of morphine (3) (300 mg, 1.1 mmol) in anhy-
drous pyridine (20 mL). The solution was heated to 50◦C for
2.5 h, cooledandthepyridineremovedundervacuum.Theresult-
ing brown oily residue was purified using flash chromatography
(200:8:1, dichloromethane/ethanol/ammonia) to afford a colour-
less solid (487 mg, 93%), which recrystallized from chloroform
to give the title compound 15 as −w1hite needles (391 mg, 75%),
mp 197–198◦C. νmax (KBr)/cm 1730, 1713 (lit.[22] 1732,
1715 cm−1). λmax/nm (ε/M−1 cm−1) 231 (33100), 276 (4680),
282 (4570). δH (CDCl3) 2.00 (1H, br dd, J 12.5, 1.5, H15eq), 2.17
(1H, ddd, J 13, 12.5, 5, H15ax), 2.42 (1H, dd, J 19, 5.5, H10ax),
2.47 (1H, app. td, 12.5, 3.5, H16ax), 2.52 (3H, s, H17), 2.72 (1H,
br dd, J 12.5, 3.5, H16eq), 2.84 (1H, app. p, J 2.5, H14), 3.14
(1H, d, J 19, H10eq), 3.50 (1H, dd, J 5.5, 3.5, H9), 5.27 (1H, d, J
7, H5), 5.42–5.47 (1H, m, H6), 5.54 (1H, app. dt, J 10, 2.5, H8),
5.82 (1H, br app. dt, J 10, 2, H7), 6.68 (1H, d, Jꢀꢀ8, H1), 6.95
(1H, d, J 8, H2), 7.25 (2H, app. t, J 7.5, H3ꢀꢀ, H5 ), 7.35 (2H,
app. t, J 8, H3ꢀ, H5ꢀ), 7.45 (1H, td, J 7.5, 1.5, H4ꢀꢀ), 7.54 (1H,
td, J 8, 1.5, H4ꢀ), 7.93 (2H, dd, J 8, 1.5, H2ꢀ, H6ꢀ), 8.01 (2H, dd,
J 7.5, 1.5, H2ꢀꢀ, H6ꢀꢀ). δC (CDCl3) 21.0 (C10), 35.3 (C15), 40.8
(C14), 43.0 (C13), 43.2 (C17), 46.8 (C16), 59.3 (C9), 68.3 (C6),
89.0 (C5), 119.6 (C1), 122.3 (C2), 128.3 (C3ꢀ, C5ꢀ), 128.5 (C3ꢀꢀ,
C5ꢀꢀ), 128.9 (C7), 129.4 (C4), 129.7 (C8), 130.0 (C2ꢀꢀ, C6ꢀꢀ),
130.2 (C2ꢀ, C6ꢀ), 131.8 (C12), 132.5 (C11, C1ꢀ, C1ꢀꢀ), 133.0
(C4ꢀꢀ), 133.3 (C4ꢀ), 149.8 (C3), 164.4 (COꢀ), 166.1 (COꢀꢀ). m/z
(+ESI, 30 V) 494 (100%, MH+).
1-Acetyl-2-(2-(5-methoxy-1H-indol-3-yl)ethyl)-2,2-
dimethylhydrazin-2-ium-1-ide 13
Sodium hydride (74 mg, 1.85 mmol, 60% dispersion in oil) was
washedwithanhydroushexane, driedunderastreamofdrynitro-
gen and cooled to −15◦C (dry ice–benzyl alcohol).A solution of
12 (200 mg, 0.46 mmol) and acetyl chloride (50 µL, 0.70 mmol)
in anhydrous N,N-dimethylformamide (8 mL, −15◦C) was then
added dropwise with stirring over 5 min, the mixture maintained
at −15◦C for a further 6 h, then allowed to warm to room tem-
perature overnight. The solvent was removed under vacuum to
afford a brown residue, which was resuspended in ethyl acetate,
and a white solid removed by filtration. The filtrate was evapo-
rated under vacuum and the resulting residue purified by flash
chromatography (50:5:2, dichloromethane/ethanol/ammonia) to
give a pale yellow solid (83 mg, 65%). The crude product was
recrystallized from dichloromethane/hexane to afford the title
compound 13 (71 mg, 56%) as pale orange plates, mp 182–
184◦C (Found: MH+ 276.1701. C15H21N3O2·H2O requires
MH+ 276.1706). νmax (KBr)/cm−1 3488, 1626, 1572. λmax/nm
(ε/M−1 cm−1) 222 (22900), 277 (6030), 298 (4680), 309 (3470).
δH (CDCl3) 1.90 (3H, s, CH3CO), 3.21 (2H, m, H2ꢀ), 3.54 (6H,
s, (CH3)2N+), 3.86 (3H, s, CH3O), 4.10 (2H, m, H1ꢀ), 6.87 (1H,
dd, J 9, 2.5, H6ꢀꢀ), 7.04 (1H, d, J 2, H2ꢀꢀ), 7.08 (1H, d, J 2.5, H4ꢀꢀ),
7.29 (1H, d, J 9, H7ꢀꢀ), 9.46 (1H, br s, H1ꢀꢀ). δC (CDCl3) 20.0
(C2ꢀ), 56.2 ((CH3)2N+, CH3O), 65.3 (C1ꢀ), 100.7 (C4ꢀꢀ), 109.8
(C3ꢀꢀ), 112.2 (C7ꢀꢀ), 112.4 (C6ꢀꢀ), 123.5 (C2ꢀꢀ), 127.6 (C3aꢀꢀ),
132.0 (C7aꢀꢀ), 154.2 (C5ꢀꢀ), 174.2 (CO). m/z (+ESI, 30V) 276
(20%, MH+), 173 (100).
(5α,6α)-7,8-Didehydro-4,5-epoxy-17(R)-
aminomethylmorphinan-3,6-dibenzoyl
2,4,6-Trimethylbenzenesulfonate 16
To an ice-cooled solution of 15 (350 mg, 0.71 mmol) in
dichloromethane (5 mL) was added dropwise a solution of
O-mesitylenesulfonylhydroxylamine[10] (183 mg, 0.85 mmol)in
dichloromethane (5 mL). Once the addition was complete, the
reaction mixture was allowed to stir for a further 10 min and the
solvent removed under vacuum to afford an oily residue, which
was redissolved in ethanol. Diethyl ether was then added to pre-
cipitate the product as a white powder (482 mg, 96%), which
was recrystallized from chloroform to give the title compound
16 (397 mg, 79%) as colourless rhomboids, mp 166–168◦C
1-Acetyl-2-(2-(5-hydroxy-1H-indol-3-yl)ethyl)-2,2-
dimethylhydrazin-2-ium-1-ide 14
A solution of boron tribromide in dichloromethane (1 M, 1.5 mL,
1.5 mmol) was added to a stirred solution of 13 (81 mg,

430
B. Capuano et al.
(Found: C 66.2, H 5.6, N 3.8, M+ 509.2071. C40H40N2O8S·H2O
requires C 66.1, H 5.8, N 3.9%, M+ 509.2071). νmax (KBr)/cm−1
3286, 3154, 1737, 1712, 1623, 1602. λmax/nm(ε/M−1 cm−1)230
(38000), 278 (4790), 282 (4570). δH (CDCl3) 1.91 (1H, br d, J
12, H15eq), 2.24 (3H, s, ArCH3), 2.70 (6H, s, 2 ×ArCH3), 2.77
(1H, app. td, J 13, 4, H15ax), 2.94 (1H, dd, J 20.5, 6, H10ax), 3.17
(1H, app. td, J 12.5, 2.5, H16ax), 3.38 (1H, d, J 20.5, H10eq), 3.95
(3H, s, H17), 3.96 (1H, br d, J 18, H16eq), 4.20 (1H, br s, H14),
4.78 (1H, br s, H9), 5.33 (1H, d, J 7, H5), 5.36 (1H, d, J 10, H8),
5.42 (1H, dd, J 7, 2.5, H6), 5.86 (1H, br app. dt, J 10, 3, H7), 6.64
(2H, s, NH2), 6.70 (1H, d, J 8.5, H1), 6.87 (2H, s, H3ꢀꢀꢀ, H5ꢀꢀꢀ),
7.00 (1H, d, J 8.5, H2), 7.28 (2H, app. t, J 7, H3ꢀꢀ, H5ꢀꢀ), 7.31
(2H, app. t, J 7.5, H3ꢀ, H5ꢀ), 7.46 (1H, t, J 7, H4ꢀꢀ), 7.53 (1H,
t, J 7.5, H4ꢀ), 7.80 (2H, d, J 7.5, H2ꢀ, H6ꢀ), 7.98 (2H, d, J 7.0,
H2ꢀꢀ, H6ꢀꢀ). δC NMR (CDCl3) 21.0 (ArCH3), 23.4 (2 ×ArCH3),
25.1 (C10), 29.8 (C15), 32.9 (C14), 41.0 (C13), 57.5 (C17), 58.4
(C16), 67.1 (C6), 71.5 (C9), 87.7 (C5), 120.1 (C1), 124.0 (C2),
126.3 (C8), 127.2 (C4), 128.4, 128.5 (C3ꢀ, C3ꢀꢀ, C5ꢀ, C5ꢀꢀ), 129.0
(C12), 129.7, 129.8 (C1ꢀ, C1ꢀꢀ), 130.0 (C2ꢀꢀ, C6ꢀꢀ), 130.3 (C7,
C2ꢀ, C6ꢀ), 131.1 (C3ꢀꢀꢀ, C5ꢀꢀꢀ), 133.1 (C4ꢀꢀ), 133.4 (C11), 133.6
(C4ꢀ), 137.0 (C2ꢀꢀꢀ, C6ꢀꢀꢀ), 139.1 (C4ꢀꢀꢀ), 140.1 (C1ꢀꢀꢀ), 149.6 (C3),
164.1 (COꢀ), 165.8 (COꢀꢀ). m/z (+ESI, 30 V) 509 (100%, M+),
85 (90).
was allowed to stir for a further 30 min at room temperature
after which time TLC showed complete consumption of starting
material. Removal of the solvent under vacuum and purifi-
cation of the brown solid by flash chromatography (50:8:1,
dichloromethane/ethanol/ammonia) afforded 18 (106 mg, 90%)
as a colourless powder. Recrystallization from methanol gave
the title compound 18 (93 mg, 78%) as colourless needles, mp
272–275◦C (dec.) (Found: C 66.4, H 6.5, N 8.1. C19H22N2O4
requires C 66.7, H 6.5, N 8.2%). νmax (KBr)/cm−1 3550, 3406,
1641, 1563. λmax/nm (ε/M−1 cm−1) 245 (3890), 288 (1820). δH
([D6]DMSO) 1.61 (1H, br d, J 11, H15eq), 1.61 (3H, s, COCH3),
2.48 (1H, app. td, J 13, 4, H15ax), 2.77 (1H, dd, J 20.5, 7, H10ax),
2.90 (1H, app. td, J 13, 3.5, H16ax), 3.26 (1H, d, J 20.5, H10eq),
3.45 (3H, s, H17), 3.60 (1H, app. p, J 2.5, H14), 3.85 (1H, br d,
J 11.5, H16eq), 4.10 (1H, br s, J 5.5, 3, H6), 4.78 (1H, br d, J 6,
H5), 4.94–4.96 (1H, m, H9), 5.21 (1H, app. dt, J 10, 2.5, H8),
5.57 (1H, br d, J 9.5, H7), 6.50 (1H, d, J 8, H1), 6.52 (1H, d, J
8, H2). δC ([D6]DMSO) 23.8 (CH3CO), 23.8 (C10), 30.7 (C15),
33.5 (C14), 41.3 (C13), 50.1 (C17), 55.5 (C16), 66.0 (C9), 67.1
(C6), 90.5 (C5), 118.9 (C1), 117.0 (C2), 122.2 (C11), 126.5 (C8),
129.8 (C12), 135.1 (C7), 139.0 (C3), 146.0 (C4), 170.9 (CO).
m/z (+ESI, 30V) 343 (100%, MH+).
(1S,2S)-1-Amino-1-methyl-2-(pyridin-3-yl)pyrrolidinium
2,4,6-Trimethylbenzenesulfonate 19
(5α,6α)-7,8-Didehydro-4,5-epoxy-17(R)-
acetimidemethylmorphinan-3,6-dibenzoate 17
A solution of O-mesitylenesulfonylhydroxylamine[10] (1.88 g,
8.7 mmol) in dichloromethane (10 mL) was added over 10 min,
with ice cooling, to a stirred solution of (S)-(−)-nicotine (4)
(1.18 g, 7.3 mmol) in dichloromethane (10 mL). The reaction
mixture was allowed to stir for a further 10 min and the sol-
vent removed under vacuum to afford a yellow oil, which was
redissolved in ethanol. Diethyl ether was added to precipitate
the crude product as a white powder (1.59 g, 58%), which was
recrystallized from acetone to give the title compound 19 (1.36 g,
49%) as fine colourless needles, mp 183–185◦C (lit.[8] 184–
185◦C). νmax (KBr)/cm−1 3256, 3142. δH ([D6]DMSO) 2.13
(6H, s, 2 ×ArCH3), 2.16–2.23 (2H, m, H4), 2.32–2.42 (1H, m,
H3a), 2.49 (3H, s, ArCH3), 2.57–2.70 (1H, m, H3b), 3.14 (3H,
s, CH3N+), 3.77–3.91 (2H, m, H5), 4.93 (1H, dd, J 11.5, 8, H2),
5.55 (2H, s, NH2), 6.70 (2H, s, ArH), 7.55 (1H, dd, J 8, 5, H5ꢀ),
8.03 (1H, br d, J 8, H4ꢀ), 8.72 (1H, d, J 5, H6ꢀ), 8.75 (1H, d,
J 2, H2ꢀ). δC ([D6]DMSO) 19.0 (C4), 20.3 (2 ×ArCH3), 22.7
(ArCH3), 26.1 (C3), 51.9 (CH3N+), 67.8 (C5), 76.6 (C2), 123.8
(C5ꢀ), 125.3 (C3ꢀ), 129.9 (C3ꢀꢀ, C5ꢀꢀ), 135.9 (C1ꢀꢀ), 136.5 (C2ꢀꢀ,
C6ꢀꢀ), 138.9 (C4ꢀ), 142.5 (C4ꢀꢀ), 151.4 (C2ꢀ), 152.1 (C6ꢀ). m/z
(+ESI, 30V) 178 (60%, M+).
A solution of 16 (253 mg, 0.36 mmol) in acetic anhydride
(20 mL) was heated at 120◦C for 6 h. The reaction mixture
was concentrated under vacuum to give a brown syrup, which
was redissolved in methanol and treated with Amberlite IRA-
400(OH) ion-exchange resin. The resin was filtered off and
the methanol removed under vacuum to give a colourless
gum, which was purified by flash chromatography (100:8:1,
dichloromethane/ethanol/ammonia) to afford a colourless oil
(159 mg, 80%), which solidified on standing. Recrystallization
from diethyl ether gave the title compound 17 (137 mg, 69%) as
colourless prisms, mp 188–191◦C (Found: C 72.1, H 5.6, N 4.9.
C33H30N2O6 requires C 72.0, H 5.5, N 5.1%). νmax (KBr)/cm−1
1731, 1716, 1630, 1587. λmax/nm (ε/M−1 cm−1) 231 (34700),
2.77 (4900), 282 (4790). δH (CDCl3) 1.91 (1H, br d, J 11.5,
H15eq), 1.92 (3H, s, COCH3), 2.76 (1H, app. td, J 13, 4, H15ax),
2.90 (1H, dd, J 20.5, 6.5, H10ax), 2.92 (1H, app. td, J 12, 3,
H16ax), 3.21 (1H, d, J 20.5, H10eq), 3.57 (3H, s, H17), 3.80 (1H,
br d, J 12, H16eq), 3.91 (1H, app. p, J 2.5, H14), 5.29 (1H, br
d, J 7, H5), 5.45–5.49 (3H, m, H6, H8, H9), 5.80 (1H, br app.
dt, J 9.5, 3, H7), 6.66 (1H, d, J 8, H1), 6.94 (1H, d, J 8, H2),
7.21 (2H, app. t, J 7.5, H3ꢀ, H5ꢀ), 7.26 (2H, app. t, J 8, H3ꢀꢀ,
H5ꢀꢀ), 7.40 (1H, t, J 7.5, H4ꢀ), 7.47 (1H, t, J 8, H4ꢀꢀ), 7.76 (2H,
d, J 8, H2ꢀꢀ, H6ꢀꢀ), 7.92 (2H, d, J 7.5, H2ꢀ, H6ꢀ). δC (CDCl3) 23.9
(CH3CO), 25.2 (C10), 30.8 (C15), 33.8 (C14), 41.2 (C13), 51.3
(C17), 58.3 (C16), 67.4 (C9), 67.5 (C6), 88.1 (C5), 119.8 (C1),
123.6 (C2), 127.7 (C8), 128.2 (C4), 128.4, 128.6 (C3ꢀ, C3ꢀꢀ, C5ꢀ,
C5ꢀꢀ), 129.1 (C12), 129.6 (C1ꢀ, C1ꢀꢀ), 129.8 (C7), 129.9 (C2ꢀꢀ,
C6ꢀꢀ), 130.2 (C2ꢀ, C6ꢀ), 133.1 (C4ꢀꢀ), 133.3 (C11), 133.5 (C4ꢀ),
149.8 (C3), 164.2 (COꢀ), 165.9 (COꢀꢀ), 174.1 (NCO). m/z (+ESI,
30 V) 551 (100%, MH+).
Acetyl((1S,2S)-1-methyl-2-(pyridin-3-yl)pyrrolidinium-
1-yl)amide 20
A solution of 19 (503 mg, 1.33 mmol) in acetic anhydride
(30 mL) was heated at 120◦C for 4 h. The solvent was removed
under vacuum to afford a brown syrup, which was taken up
in methanol and treated with Amberlite IRA-400(OH) ion-
exchange resin. The resin was filtered off and the filtrate
concentrated to afford a brown gum, which was purified
by flash chromatography on neutral alumina (85:15, chloro-
form/methanol) to give the crude aminimide. Further purifi-
cation using flash chromatography on neutral alumina (95/5,
chloroform/methanol) afforded the title compound 20 (108 mg,
37%) as a yellow gum which rapidly discoloured in air (Found:
MH+ 220.1440. C12H17N3O requires MH+ 220.1444). νmax
(KBr)/cm−1 1572. λmax/nm (ε/M−1 cm−1) 255 (12000), 260
(5α,6α)-7,8-Didehydro-4,5-epoxy-17(R)-
acetimidemethylmorphinan-3,6-diol 18
An aqueous solution of sodium hydroxide (1% w/v, 5 mL)
was added dropwise over 5 min to a stirred solution of 17
(190 mg, 0.35 mmol) in methanol (5 mL). The reaction mixture

Aminimides as Potential CNS-Acting Agents
431
(2630), 266 (2880), 295 (2340). δH (CDCl3) 1.67 (3H, s,
CH3CO), 1.87–2.02 (1H, m, H4a), 2.09–2.15 (1H, m, H4b),
2.19–2.28 (1H, m, H3a), 2.52–2.66 (1H, m, H3b), 3.09–3.24
(1H, m, H5a), 3.23 (3H, s, CH3N+), 4.07 (1H, dd, J 11, 7, H2),
5.13 (1H, ddd, J 11.5, 9, 3, H5b), 7.28 (1H, dd, J 8, 5, H5ꢀ), 8.12
(1H, app dt, J 8, 2, H4ꢀ), 8.56 (1H, dd, J 5, 2, H6ꢀ), 8.64 (1H, br
d, J 2, H2ꢀ). δC (CDCl3) 20.0 (C4), 23.9 (CH3CO), 29.0 (C3),
48.2 (CH3N+), 62.3 (C5), 79.2 (C2), 123.1 (C5ꢀ), 128.2 (C3ꢀ),
139.9 (C4ꢀ), 151.1 (C6ꢀ), 152.2 (C2ꢀ), 174.1 (CO). m/z (+ESI,
30V) 220 (100%, MH+), 132 (20). Compound 20 was con-
verted to the pale yellow dihydrochloride salt for microanalysis
and testing by treatment with ethereal hydrogen chloride fol-
lowed by evaporation to dryness (Found: C 46.5, H 6.7, N 13.5%.
C12H17N3O·2HCl·H2O requires C 46.5, H 6.8, N 13.6%).
available from the authors, or, until June 2013, the Australian
Journal of Chemistry.
Acknowledgement
The receipt of a Monash Graduate Scholarship (J.E.N.) for support of the
present research is acknowledged.
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CHO-K1 cells), [3H]diprenorphine (0.6 × 10−9 M) as radio-
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Accessory Publication
The Accessory Publication showing 1H NMR spectra for 13
and 13a, crystal data, bond angles, and bond lengths for 18 is