Synthesis of 2′-aminoalkyl-1-benzylisoquinoline derivatives and medium sized ring analogues with mu opiod receptor binding activities

Article abstract of DOI:10.1016/j.tet.2010.03.110

Novel 2′-aminoalkyl-1-benzylisoquinoline compounds and medium size ring analogues have been prepared using reductive alkylation methods. Four of these analogues were tested for biological activity across 48 different CNS receptors and were showed to have

Full text of DOI:10.1016/j.tet.2010.03.110

Tetrahedron 66 (2010) 4133–4143
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 20-aminoalkyl-1-benzylisoquinoline derivatives and medium sized
ring analogues with mu opiod receptor binding activities
,
a,
*
Uta Mbere-Nguyen a, Alison T. Ung b , Stephen G. Pyne
*
a School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia
b Department of Chemistry and Forensic Science, University of Technology, Sydney, Broadway, NSW 2007, Australia
a r t i c l e i n f o
a b s t r a c t
Novel 20-aminoalkyl-1-benzylisoquinoline compounds and medium size ring analogues have been pre-
pared using reductive alkylation methods. Four of these analogues were tested for biological activity
across 48 different CNS receptors and were showed to have binding activities at the mu opiod receptor.
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Article history:
Received 8 February 2010
Received in revised form 12 March 2010
Accepted 29 March 2010
Available online 2 April 2010
1. Introduction
CNS active compounds are known, including the D1-antagonist LE
300 510 and the partial D1/D5 agonist SCH 39166 6.10–12
The 1-benzylisoquinolines alkaloids constitute a group of natural
products of diverse structure that arewidely present in many plants and
mammalian species.1,2 About 2500 1-benzylisoquinoline alkaloids have
been identified and shown to have a wide range of biological activities
including anticancer,2 antimalarial,3 anti-HIV,4 antiplatelet and vaso-
relaxant.5,6 Severalnatural andsynthetic benzylisoquinolinederivatives
have also displayed affinities for dopamine and seretonin receptors,
which are important neurotransmitters in the central nervous system
(CNS).7 Examples of some of these 1-benzylisoquinoline derivatives are
shown in Figure 1. Compounds with these biological activities have
potential application in the treatment of numerous physiological and
behavioural disorders such as schizophrenia, anxiety, Parkinson’s and
Huntington’s disease.7
In our continuing project concerned with the discovery of new
bioactive benzylisoquinoline derivatives,13–15 the 20-aminoalkyl-1-
benzylisoquinoline compound 7 and the medium side ring ana-
logues 8 were of interest. We report here our attempts to synthesise
these compounds and the biological activities of four of these an-
alogues on 48 different CNS receptors (Fig. 3).
O
S
H
N
O
O
N
O
3;
repinotan
H
N
F
O
CH3O
HO
HO
N
N
N
H
HO
HO
H
H
H
HO
HO
HO
N
O
O
N
CH3O
OH
O
1;
(S)-N-Norreticuline
2; SCH71450
4; SB-691673
Figure 1. 1-Benzylisoquinoline derivatives that were found to be dopaminergic ligands
in the micromolar range.7
Cl
CH3
N
CH3
N
HO
There are also an emerging class of CNS active compounds that
contain an amino group appended to a heterocyclic base structure
(Fig. 2), for example, the high affinity 5HT1A receptor agonist repino-
tan 38 and the 5HT7 active molecule SB-691673 4.9 Medium sized ring
N
H
5;
LE 300
6;
SCH 39166
* Corresponding authors. E-mail address: spyne@uow.edu.au (S.G. Pyne).
Figure 2. The structures of known CNS active compounds.8–12
0040-4020/$ – see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.110

4134
U. Mbere-Nguyen et al. / Tetrahedron 66 (2010) 4133–4143
CH3O
CH3O
CH3O
CH3O
CH3O
N
N
X
CH3O
CH3O
TFA
K2OsO4.2H2O, NMO,
acetone: H2O. rt, 18 h
N
CH3O
CH3O
CH3
N
CH3O
CH3O
TFA
N
CH3
1'
2'
1'
2'
OH
( )n
CH3O
()n
R1
OH
CH3O
CH3O
CH3O
( )n
N
CH3O
()n
R2
n = 0 or 1
X = O or H2
8
n = 0 or 1
9; n = 0
12; n = 1
13; n = 0, 82%
14; n = 1, 99%
7
Figure 3. The targeted 1-benzylisoquinoline derivatives containing 20-aminoalkyl
substituents (7) and the medium sized ring targets (8).
CH3O
2. Results and discussion
NaIO4, silica gel,
DCM, H2O, rt, 1 h
N
CH3O
CH3O
TFA
H
With the aim of preparing 20-aminoethyl-1-benzylisoquinoline
derivatives, we first examined the method reported by Seijas et al.
O
towards the preparation of b-phenylethylamines derivatives by ad-
CH3O
()n
dition of primary and secondary lithium amides to styrene.16 The ra-
cemic 20-vinyllaudanosine derivative 10 was prepared from the
known N-TFA derivative 914,15 in 75% overall yield. Morpholine was
treated with n-butyl lithium and the resulting solution of lithium
morpholinamide in THF was added to compound 10 at 0 ꢀC. The
mixture was left at 0 ꢀC for 18 h. 1H NMR analysis only showed
unreacted starting material 10 and no morpholine ethylene signals
were observed. This suggests that the vinyl group of 10 was too elec-
tron rich to react with the lithium morpholinamide nucleophile.
Therefore an alternative synthesis of the 20-aminoethyl-1-benzyliso-
quinoline and 20-aminomethyl-1-benzylisoquinoline derivatives was
examined using a reductive amination method (Schemes 1 and 2).
Here the racemic aldehydes 15 and 16 were prepared in good yields
from the known alkenes 9 and 12,14,15 respectively, using the two-step
sequence of dihydroxylation, followed by oxidative cleavage.17,18
15; n = 0, 92%
16; n = 1, 99%
Scheme 2. Preparation of the aldehydes 15 and 16 via oxidative cleavage of the diols
13 and 14, respectively.
R1
H
N
CH3O
R2
CH3O
N
O
N
NaCNBH3, CH3CN,
HOAc, rt, 18 h
CH3O
CH3O
TFA
H
CH3O
CH3O
TFA
R1
CH3O
( )n
CH3O
( )n N
R2
1) K2CO3, CH3OH/ H2O
rt,18 h
2) 38% formaldehyde
NaCNBH3,CH3CN,
pH ~ 6, rt, 18 h
CH3O
CH3O
N
CH3O
CH3O
TFA
N
15;
n = 0
n = 1
17-23
CH3O
CH3O
CH3
16;
CH3O
1) K2CO3, CH3OH/H2O,
rt, 18 h
2) 38% formaldehyde,NaCNBH3,
CH3CN, HOAc, rt, 16 h
75% over 2 steps
CH3O
CH3O
9
N
10
CH3O
CH3O
CH3
R1
1) n-butyl lithium,
morpholine, dry
THF, 00C, 18 h
2) CH3OH
CH3O
CH3O
CH3O
( )n N
N
R2
CH3
N
CH3O
CH3O
11; 24-29
O
11
Scheme 3.
Scheme 1. Attempted synthesis of 11 using lithium morpholinamide and the 20-
vinyllaudanosine derivative 10.
The synthesis of the medium sized ring 1-benzylisoquinoline
derivative 35 was attempted utilising an intramolecular reductive
amination reaction between the aldehyde and the amine group of
32 to provide the medium ring compound 35 (Scheme 4). The
synthesis started with the reductive amination reaction between
the aldehyde 15 and commercially available aminoacetaldehyde
diethylacetal, followed by basic hydrolysis of the N-TFA group to
afford the desired product 31 in 82% overall yield. Conversion of the
diethoxyl acetal group of the bis-amine 31 into the corresponding
aldehyde 32 was attempted using TsOH/CH3OH/H2O at rt to reflux
temperature, however no product was obtained. Alternatively, the
amine 31 was heated in a solution of 10% aqueous HCl/MeOH at
110 ꢀC to afford only the corresponding dimethoxyl acetal
The aldehydes 15 and 16 were subjected to reductive amination
reactions with several amines to give the corresponding aminated
products in moderate to good yields (Scheme 3, Table 1).
The final 20-aminoalkyl-1-benzylisoquinoline derivatives re-
quired for biological testing were obtained by basic hydrolysis of
the TFA group of 17–23, followed by reductive N-methylation using
a literature procedure.19 The final products 11 and 24–29 were
obtained in moderate to high yields (Table 1).
Overall, the above reductive amination procedure was an ef-
fective method used to synthesise a small library of seven 20-ami-
noalkyl-1-benzylisoquinoline derivatives, which represent a new
class of 1-benzylisoquinolines.

U. Mbere-Nguyen et al. / Tetrahedron 66 (2010) 4133–4143
4135
Table 1
Synthesis of 20-aminomethyl-1-benzylisoquinoline analogues by reductive amination, followed by N-TFA cleavage and N-methylation
Entry
Aldehyde
Amine
R1
Reductive amination
N-TFA cleavage and N-methylation
R2
Product
Yield (%)
Product
Yield (%)
1
2
3
4
5
6
7
15
15
15
15
16
16
16
–CH2CH2–O–CH2CH2–
–CH2CH2CH2CH2–
17
18
19
20
21
22
23
60
74
75
64
64
74
68
24
25
26
73
71
58
59
85
69
69
CH2CH3
H
CH2CH3
CH(CH3)2
27 (R1¼CH3)
-CH2CH2-O-CH2CH2-
–CH2CH2CH2CH2–
11
28
29
CH2CH3
CH2CH3
compound 33, which arose from exchange of the diethoxyl acetal
group with the solvent methanol. Further heating of compound 33
in 10% aqueous HCl/MeOH afforded a crude product, which when
1H NMR analysis was performed, showed that the dimethoxy signal
CH3O
CH3O
OEt
OEt
at
d 3.36 (s, 6H, CH(OCH3)2) had disappeared, however, the
N
1
N
H2N
CH3O
CH3O
TFA
CH3O
CH3O
TFA
expected aldehyde signal in the
d
9–10 region was not observed.
ESIMS analysis showed an MHþ signal at m/z 415.0, which would
correspond to the hemiacetal 34. The crude compound was sub-
jected to the reductive amination conditions with NaCNBH3,
however no identifiable products were obtained.
NaCNBH3, CH3CN,
HOAc, rt, 18 h
H
1''
CH3O
CH3O
OEt
2'''
OEt
O
1'''
HN
15
30
Alternatively (Scheme 5), the aldehydes 15 and 16 were reduc-
tively coupled with methylamine to afford the corresponding
benzylisoquinolines 36 and 37 in 71% and 79% yield, respectively.
The amines 36 and 37 subsequently underwent N-acylation with
CH3O
K2CO3, CH3OH/
H2O, rt, 18 h
1
NH
CH3O
CH3O
82% over 3 steps
from the diol 13
chloroacetyl chloride to give the corresponding
a-chloroacetamides
1''
CH3O
OEt
2'''
38 and 39 in good yields (72–80%). Hydrolysis of the N-TFA group of
1'''
HN
OEt
CH3O
CH3O
31
1
N
N
O
CH3NH2, NaCNBH3,
CH3O
CH3O
TFA
CH3O
CH3O
TFA
H
10% HCl
TsOH
CH3OH / H2O
rt - reflux, 18 h
CH3CN, HOAc, rt, 18 h
CH3OH, 110 0C, 4 h
41%
1''
CH3
n = 0, 71%
n = 1, 79%
CH3O
( )n
N
H
CH3O
( )n
36; n = 0
37; n = 1
15; n = 0
16; n = 1
CH3O
CH3O
1
NH
O
NH
CH3O
CH3O
CH3O
CH3O
CH3O
chloroacetyl chloride,
triethylamine,
1
N
1''
CH3O
CH3O
OCH3
1'''
CH3O
CH3O
TFA
O
0 οC-rt, 18 h.
2'''
HN
HN
33
H
OCH3
32
n = 0, 80%
n = 1, 72%
1''
Cl
CH3O
( )n
N
10% HCl, CH3OH,
110 0C, 23 h
38; n = 0
39; n = 1
CH3O
CH3O
CH3O
CH3O
OH
N
NH
O
1) K2CO3, CH3OH/H2O, rt, 2 h
2) triethylamine, CH2Cl2, rt, 18 h
CH3O
CH3O
4''
3''
1
N
O
CH3O
NH
N
CH3
2''
CH3O
CH3O
CH3O
n = 0, 57% over 2 steps
n = 1, 46% over 2 steps
( )n
HN
H
CH3O
CH3O
34
32
40; n = 0
41; n = 1
NaCNBH3, CH3CN
HOAc, rt, 18 h
CH3O
CH3O
CH3O
CH3O
n = 0
LiAlH4, THF,
0oC- rt, 18 h
N
N
3''
2''
N
NH
1''
CH3
81%
CH3O
CH3O
CH3O
CH3O
Scheme 5.
35
42
Scheme 4.

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U. Mbere-Nguyen et al. / Tetrahedron 66 (2010) 4133–4143
38 and 39 exposed the free amino groups for an intramolecular SN2
displacement of the chloride under basic conditions with triethyl-
amine to provide the desired medium ring compounds 40 and 41 in
moderate yields (46–57% over two steps). The 9-membered ring
compound 40 was subjected to carbonyl reduction using lithium
aluminium hydride to afford the corresponding cyclic amino
compound 42 in 81% yield. Analysis of the 1H NMR spectrum of 42
revealed the newly formed methylene proton resonances for H200 at
In conclusion, seven novel 20-aminoalkyl-1-benzylisoquinoline
analogues and three medium sized ring 1-benzylisoquinoline an-
alogues were successfully synthesised. Four analogues 11, 25, 26
and 27 showed moderate to good inhibition of control specific
binding activities at 1–10 mM concentrations against the mu re-
ceptor. Unfortunately, compounds 24, 28, 29 and 40–42 were un-
able to be tested.
d
2.79 (m, 1H), 2.57 (m, 1H) and for H300 at
d 3.10 (m, 1H), 2.79 (m,
4. Experimental
4.1. General
1H). These newly observed methylene proton signals confirmed the
successful amide reduction to the amine 42. The benzylic protons of
42 were observed more prominently at
and 3.42 (d, 1H, J 12.5 Hz, H100).
d
4.49 (d, 1H, J 12.5 Hz, H100)
Petrol refers to the fraction of petroleum spirit with a boiling
point of 40–60 ꢀC. All 1H NMR spectra were performed at 300 MHz
and all 13C NMR and DEPT spectra at 75 MHz in CDCl3 solution,
unless otherwise noted. All spectra were referenced to CDCl3 (1H
3. In vitro CNS receptor binding studies
The in vitro testing was conducted at Cerep Corporation in
France. Four 20-aminoalkyl-1-benzylisoquinoline derivatives 11,
25, 26 and 27 were tested for biological activities on 48 different
CNS receptors.20 The activities were expressed as % inhibition of
control specific binding (Table 2), which is the measure of the
direct inhibition activity of the tested drug exerted on the con-
trolled ligand. Therefore the drug is considered active when the %
inhibition of control specific binding is high at the CNS receptor
type tested.
d d
7.26 ppm and 13C NMR 77.00 ppm). 1H NMR assignments were
achieved with the aid of gCOSY, and in some cases NOESY and
TOCSY experiments. 13C NMR assignments were based on DEPT,
gHSQC and gHMBC experiments. All compounds were homoge-
neous by TLC analysis and judged to be of >95% purity based upon
1H NMR analysis. Compound numbering of 1-benzylisoquinoline
derivatives is based on that of compounds 11 and 24. Compound
numbering of the medium ring benzylisoquinoline derivatives is
based on that of compounds 40 and 41.
Table 2
In vitro CNS receptor binding activities of compounds 11 and 25–27. Across the 48 CNS receptors, only the receptors with 25% or more of inhibition activities are illustrated
below
Assay
Reference compounds
Reference compound
% Inhibition of control specific binding at 1 mM
IC50 (nM)
Compound 11
Compound 25
Compound 26a
Compound 27
m
k
(h) (MOP)
(KOP)
DAMGO
U 50488
[d(CH2)51,Tyr(Me)2]-AVP
Prazosin
Veratridine
1.2
1.2
1.8
46
d
d
d
d
25
d
d
d
d
52
40
37
25
25
35
d
d
d
d
V1a (h)
a1 (non-selective)
Naþ channel
0.30
4650
The symbol ‘d’ indicates binding inhibition of less than 25%.
a
Testing was conducted at 10 mM concentration.
The CNS binding activities of the four derivatives 11, 25–27 are
shown in Table 2. All four compounds showed binding activities at
5
4
1
4
5
6
6
4a
CH3O
4a
8a
CH3O
3
2
3
2
7
the mu (
highest mu receptor activity with 46% inhibition of the control
(DAMGO) specific binding at 1 M concentration. Compound 26
was tested at 10 M concentration and was shown to have binding
m) opiod receptor (MOP), with compound 11 having the
7
1
N
N
8a
1'
CH3O
CH3O
CH3
2'''
CH3O
CH3O
CH3
8
8
6'
6'
7'
5'
4'
1'
2'
5'
4'
m
2''
2'
m
1''
3'''
CH3O
N
CH3O
3'
1''
4
activities against several receptors, most prominently at the mu
and kappa opiod (KOP) receptors, with inhibition activities of 52%
and 40%, respectively. The IC50 of these compounds are yet to be
determined, but that of compound 11 and 27 would be estimated
to be in the low micromolar range activities against the mu
receptor.
The mu opiod receptor is one major class of opiod receptors,
which has been targeted for its analgesic properties.21 Opiod ago-
nists such as morphine exert their activities mainly at the mu opiod
receptor and have been widely used in pain therapy.21 Chronic
morphine therapy, however, can produce unwanted side effects
such as tolerance, respiratory suppression and constipation.21 Mu
opiod antagonists are commonly used as a rescue medication to
reverse these side effects as well as combating alcohol and narcotic
addiction.22,23 Mu opiod antagonists also have potential applica-
tions in the treatment of obesity, psychosis and Parkinson’s dis-
ease.22 Therefore, depending on their agonist or antagonist
properties, compounds 11 and 25–27 and their analogues could be
used in pain treatment therapy, or for the treatment of narcotic
addictions as well as obesity, psychosis and Parkinson’s disease.
3'
O
N1'''
5'''
2'''
3'''
5'''
24
11
4'''
4'''
O
4
5
5
CH3O
6
CH3O
CH3O
6
4a
4a
3
2
3
7
N
3''
1
2
CH3O
CH3O
8a
1
7
N
8a
7'
8
O
8
4''
7'
1'
2''
O
N
1''
6'
3''
CH3
1'
2'
3'
6'
5'
N
5'
4'
CH3O
2'
CH3
2''
1''
3'
CH3O
4'
OCH3
40
41
4.2. (RS) 1-(20-Ethenyl-40,50-dimethoxyphenyl)methyl-1,2,3,4-
tetrahydro-6,7-dimethoxy-2-methylisoquinoline (10)
To a solution of the 20-vinyllaudanosine derivative 9 (227 mg,
0.487 mmol) in a mixture of CH3OH (20 mL) and H2O (3 mL) at rt

U. Mbere-Nguyen et al. / Tetrahedron 66 (2010) 4133–4143
4137
was added K2CO3 (339 mg, 2.44 mmol). The reaction mixture was
stirred for 18 h at rt. The CH3OH was evaporated and the residue
was dissolved in CH3CN (10 mL). Formaldehyde of 38% (8 mL) was
added to the solution, followed by NaCNBH3 (41 mg, 0.633 mmol).
The reaction mixture was stirred for 20 min at rt and the pH was
adjusted to w6 using glacial acetic acid. The reaction mixture was
stirred for 18 h at rt. The solvent was evaporated and the residue
was dissolved in CH2Cl2 and washed with 1 M aqueous NaOH, H2O
(2ꢁ) and dried (K2CO3) to give an oil. The oil was purified by col-
umn chromatography (CH3OH/EtOAc/NH3 (3:7:0.1)) to give 10
(140 mg, 75% overall) as a yellow oil. Rf 0.25 (CH3OH/EtOAc (1:1)).
36.1 Hz, COCF3), 148.1 (C50, C7), 147.6 (C40), 147.0 (C6), 131.8 (C10),
126.2 (C20), 125.9 (C4a), 124.6 (C8a), 118.2 (q, J 285.1, COCF3), 114.2
(CH-60), 111.4 (CH-8), 110.8 (CH-5), 109.6 (CH-30), 70.7 (CH-100), 67.3
(CH2-200), 55.7 (4ꢁOCH3), 55.5 (CH-1), 40.6 (CH2-3), 38.0 (CH2-70),
28.2 (CH2-4). 13C NMR of the minor diastereomer (in part):
d 132.1
(C10),126.1 (C20),124.4 (C8a), 114.4 (CHþ-60),110.2 (CH-þ50), 109.5 (CH-
30), 67.5 (CH2-200), 28.3 (CH2-4). MS (EI ): m/z 499 (M , 20%). HRMS
(ESIþ): calcd for C24H28F3NNaO7, 522.1716 (MþNaþ), found
522.1724.
4.4.2. (1RS,200RS) and (R,S) 2-Trifluoroacetyl-1,2,3,4-tetrahydro-1-[20-
(200,3%-dihydroxypropyl)-40,50-dimethoxyphenyl]methyl-6,7-dime-
thoxyisoquinoline (14). A solution of the olefin 12 (120 mg,
0.255 mmol) in acetone (7 mL) was treated as described above in
the general dihydroxylation reaction procedure using
K2OsO4$2H2O (6 mg, 0.015 mmol), followed by NMO (63 mg,
0.537 mmol) and H2O (1 mL) except the reaction mixture stirred for
5 h at rt. The crude oil was purified by column chromatography
(EtOAc) to give the diol 14 (130 mg, 99%) as clear oil. The diol 14 was
obtained as a 60:40 mixture of diastereomers. Rf 0.38 (EtOAc). 1H
1H NMR: 6.97 (s, 1H, H30), 6.73 (dd,1H, J 17.4, 10.8 Hz, H100), 6.54 (s,
d
1H, H5), 6.39 (s, 1H, H60), 5.72 (s, 1H, H8), 5.45 (dd, 1H, J 17.4, 1.2 Hz,
H200(E)), 5.11 (dd, 1H, J 10.8, 1.2 Hz, H200(Z)), 3.86 (s, 3H, OCH3-40),
3.80 (s, 3H, OCH3-6), 3.72 (s, 3H, OCH3-7), 3.68–3.62 (m, 1H, H1),
3.43 (s, 3H, OCH3-50), 3.28–3.25 (m, 1H, H3), 3.24 (dd, 1H, J 13.5,
4.8 Hz, H70), 2.94–2.78 (m, 2H, H3, H4), 2.76 (dd, 1H, J 13.5, 9.0 Hz,
H70), 2.64–2.57 (m, 1H, H4), 2.54 (s, 3H, NCH3). MS (ESIþ): m/z 384
(MHþ, 20%). HRMS (ESIþ): calcd for C23H30NO4, 384.2175 (MHþ),
found 384.2180.
NMR of the major diastereomer: d
6.71 (s, 1H, H30), 6.61 (s, 1H, H5),
4.3. Attempted synthesis of (RS) 1,2,3,4-tetrahydro-6,7-
dimethoxy-1-(40,50-dimethoxy-20-(200-morpholinoethyl)-
phenyl)methyl-2-methylisoquinoline (11)
6.39 (s, 1H, H60), 6.27 (s, 1H, H8), 5.47 (dd, 1H, J 5.4, 3.3 Hz, H1), 4.02
(dt, 1H, J 8.1, 3.0 Hz, H3), 3.97–3.91 (m, 1H, H200), 3.84 (s, 3H, OCH3-
7), 3.83 (s, 3H, OCH3-50), 3.81–3.78 (m, 1H, H300), 3.75–3.70 (m, 1H,
H3), 3.69 (s, 3H, OCH3-40), 3.58–3.54 (m,1H, H300), 3.52 (s, 3H, OCH3-
6), 3.13 (dd, 1H, J 8.1, 3.3 Hz, H70), 3.02 (dd, 1H, J 8.1, 5.4 Hz, H70),
2.94–2.89 (m, 1H, H100), 2.88–2.85 (m, 1H, H4), 2.83–2.79 (m, 1H,
H4), 2.68–2.62 (m, 1H, H100). 1H NMR of the minor diastereomer (in
To a solution of 10 (139.5 mg, 0.364 mmol) in dry THF (4 mL)
was added a solution of lithium morpholinamide, prepared by the
addition of 2.5 M nBuLi in hexane (0.2 mL, 0.5 mmol) to a solution
of morpholine (79.3 mg, 0.91 mmol, 0.1 mL) in dry THF (1 mL) at
0 ꢀC. The reaction mixture was kept at 0 ꢀC for 18 h. The reaction
mixture was quenched with CH3OH and the solvent was evapo-
rated. The residue was purified by column chromatography to re-
trieve only a quantitative amount of starting material 10.
part): d
6.70 (s, 1H, H30), 6.44 (s, 1H, H60), 6.01 (s, 1H, H8), 5.59 (dd,
1H, J 5.4, 3.3 Hz, H1), 3.88–3.84 (m, 1H, H200), 3.74 (s, 3H, OCH3-40),
3.66 (s, 3H, OCH3-6), 3.15 (dd, 1H, J 8.1, 3.3 Hz, H70), 3.03 (dd, 1H, J
8.1, 5.4 Hz, H70), 2.97–2.94 (m, 1H, H100), 2.75–2.71 (m, 1H, H100). 13C
NMR of the major diastereomer: (signals for COCF3 and COCF3 were
not observed)
d
148.3 (C7), 148.2 (C50), 147.5 (C6), 147.3 (C40), 129.3
4.4. General method for dihydroxylation17,18
(C10), 127.7 (C20), 126.2 (C4a), 124.6 (C8a), 114.5 (CH-60), 113.3 (CH-
30), 111.0 (CH-8, CH-5), 73.1 (CH-200), 66.2 (CH2-300), 55.0 (4ꢁOCH3),
55.7 (CH-1), 40.8 (CH2-3), 38.6 (CH2-70), 35.7 (CH2-100), 28.5 (CH2-
To a solution of the olefin in acetone was added potassium
osmate dihydrate (K2OsO4$2H2O), followed by N-methylmorpho-
line N-oxide (NMO). H2O was subsequently added and the mixture
was stirred at rt for 18 h. Sodium sulfite (Na2SO3) (ca. 10 equiv) was
added and stirred for 30 min before the acetone was evaporated.
Water was added and the mixture was extracted with CH2Cl2. The
combined CH2Cl2 extracts were washed with brine, dried (MgSO4)
and evaporated to give an oil. The oil was purified by column
chromatography (EtOAc) to afford the desired product.
4). 13C NMR of the minor diastereomer (in part):
d 148.3 (C7), 147.3
(C6), 148.0 (C50), 147.1 (C40), 129.0 (C10), 127.9 (C20), 126.6 (C4a),
124.8 (C8a), 114.0 (CH-60), 113.1 (CH-30), 110.9 (CH-5), 110.4 (CH-8),
72.9 (CH-200), 66.0 (CH2-300), 55.6 (CH-1), 40.4 (CH2-3), 38.5 (CH2-
70), 36.0 (CH2-100), 28.6 (CH2-4). MS (EIþ): m/z 513 (Mþ, 20%). HRMS
(ESIþ): calcd for C25H31F3NO7, 514.2053 (MHþ), found 514.2064.
4.5. General method for oxidative cleavage of diols
4.4.1. (1RS,100RS) and (1RS,100SR) 2-Trifluoroacetyl-1,2,3,4-tetrahydro-
1-[20-(100,200-dihydroxyethyl)-40,50-dimethoxypheny]methyl-6,7-dime-
To a warm solution (ca. 40 ꢀC) of NaIO4 in H2O was added silica
gel with vigorous stirring. The powder was cooled and a solution of
the diol in CH2Cl2 was added. The mixture was stirred vigorously
for 1 h at rt. The CH2Cl2 layer was collected by pipetting and the
silica was washed several times with CH2Cl2. The combined CH2Cl2
washings were evaporated to give pure aldehydes without the need
for further purification.
thoxyisoquinoline (13). A solution of the olefin
9 (135 mg,
0.290 mmol) in acetone (3 mL) was treated as described above in
the general dihydroxylation reaction procedure using
K2OsO4$2H2O (6 mg, 0.015 mmol), NMO (72 mg, 0.609 mmol) and
H2O (1 mL). Purification by column chromatography gave the diol
13 (119 mg, 82%) as a light yellow oil. The diol 13 was obtained as
a 4:1 mixture of diastereomers. Rf 0.39 (EtOAc). 1H NMR of the
4.5.1. (RS) 1-(20-Formyl-40,50-dimethoxyphenyl)methyl-2-trifluoroacetyl-
1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (15). Silica gel coated
with NaIO4 was prepared as above using NaIO4 (827 mg, 3.89 mmol),
H2O (2 mL) and silica gel (1.7 g). To this powder was added a solution
of the vicinal diol 14 (167 mg, 0.335 mmol) in CH2Cl2 (3 mL), which
was treated as described above in the general oxidative cleavage re-
action procedure to afford the pure aldehyde 15 (144 mg, 92%) as
major diastereomer: d
6.99 (s, 1H, H30), 6.61 (s, 1H, H5), 6.31 (s, 1H,
H60), 6.08 (s, 1H, H8), 5.48 (dd, 1H, J 8.2, 5.8 Hz, H1), 5.08 (dd, 1H, J
8.1, 4.2 Hz, H100), 3.94 (dt, 1H, J 13.5, 3.6 Hz, H3), 3.85 (s, 3H, OCH3-
7), 3.84 (s, 3H, OCH3-50), 3.78 (dt, 1H, J 12.6, 4.8 Hz, H3), 3.69 (s, 3H,
OCH3-40), 3.68–3.60 (m, 2H, 2ꢁH200), 3.57 (s, 3H, OCH3-6), 3.17 (dd,
1H, J 13.5, 5.8 Hz, H70), 3.03 (dd, 1H, J 13.5, 8.2 Hz, H70), 2.98–2.93
(m, 1H, H4), 2.84–2.76 (m, 1H, H4). 1H NMR of the minor di-
a white solid. Rf 0.80 (EtOAc). Mp 154–158 ꢀC. 1H NMR:
d 9.90 (br s, 1H,
astereomer (in part):
d
6.95 (s, 1H, H30), 6.49 (s, 1H, H5), 6.23 (s, 1H,
CHO), 7.28 (s, 1H, H30), 6.74 (s, 1H, H5), 6.59 (s, 2H, H60, H8), 5.64 (dd,
1H, J 8.7, 5.7 Hz, H1), 3.92 (s, 3H, OCH3-7), 3.88 (s, 3H, OCH3-50), 3.84 (s,
3H, OCH3-40), 3.79 (s, 3H, OCH3-6), 3.71–3.54 (m, 3H, 2ꢁH3, H70), 3.15
(dd, 1H, J 13.5, 8.1 Hz, H70), 2.94–2.88 (m, 1H, H4), 2.86–2.70 (m, 1H,
H60), 5.59 (t, 1H, J 7.5 Hz, H1), 4.94 (dd, 1H, J 8.1, 4.2 Hz, H100), 3.77 (s,
3H, OCH3-7), 3.73–3.71 (m, 2H, 2H200), 3.68 (s, 3H, OCH3-40), 3.28–
3.23 (m, 1H, H70). 13C NMR of the major diastereomer:
d 156.3 (q, J

4138
U. Mbere-Nguyen et al. / Tetrahedron 66 (2010) 4133–4143
H4). 13C NMR: (signals for COCF3 and COCF3 were not observed)
d
190.8
(CH2-100), 40.1 (CH2-3), 37.9 (CH2-70), 28.7 (CH2-4). MS (EIþ): m/z
538 (Mþ, 30%). HRMS (ESIþ): calcd for C27H34F3N2O6, 539.2369
(MHþ), found 539.2363.
(CHO), 153.0 (C40), 148.3 (C6), 148.0 (C50), 147.8 (C7), 134.1 (C20), 127.6
(C4a), 126.5 (C10), 124.7 (C8a), 114.6 (CH-60), 113.9 (CH-30), 110.9 (CH-8),
110.3 (CH-5), 56.0 (OCH3-7, OCH3-50), 55.9 (OCH3-40, OCH3-6), 55.1
(CH-1), 40.3 (CH2-3), 37.7 (CH2-70), 28.6 (CH2-4). MS (EIþ): m/z 467
(Mþ,10%). HRMS (ESIþ): calcd for C23H25F3NO6, 468.1634 (MHþ), found
468.1642.
4.6.2. (RS) 2-Trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-[40,50-
dimethoxy-20-(pyrrolidinyl)methylphenyl]methylisoquinoline (18). A
mixture of the aldehyde 15 (91 mg, 0.194 mmol), pyrrolidine
(0.10 mL, 1.13 mmol), CH3CN (3 mL) and NaCNBH3 (16 mg,
0.252 mmol) was treated as described above in the general reductive
amination reaction procedure to give an oil. The oil was purified by
column chromatography (CH3OH/EtOAc (4:6)) to afford 18 (77 mg,
74%) as a light yellow oil. Compound 18 was a 95:5 mixture of
rotamers. Rf 0.20 (CH3OH/EtOAc (4:6)). 1H NMR of the major rotamer:
4.5.2. (RS) 2-Trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-[40,50-
dimethoxy-20-(200-oxoethyl)phenyl]methylisoquinoline (16). Silica gel
coated with NaIO4 was prepared as above using NaIO4 (676 mg,
3.18 mmol), H2O (2 mL) and silica gel (1.7 g). To this solution was
added a solution of diol 14 (134 mg, 0.265 mmol) in CH2Cl2 (3 ml),
which was reacted as described above in the general oxidative
cleavage reaction procedure to give the pure aldehyde 16 (127 mg,
99%) as a clear oil. Compound 16 was a 95:5 mixture of rotamers. Rf
d
6.97 (s, 1H, H30), 6.59 (s, 1H, H5), 6.34 (s, 1H, H60), 6.04 (s, 1H, H8),
5.44 (dd, 1H, J 8.1, 6.1 Hz, H1), 3.93–3.87 (m, 1H, H3), 3.87 (s, 3H,
OCH3-7), 3.83 (s, 3H, OCH3-50), 3.80–3.75 (m, 1H, H3), 3.69 (s, 3H,
OCH3-40), 3.56 (s, 3H, OCH3-6), 3.42 (d, 1H, J 6.6 Hz, H100), 3.38 (d, 1H, J
6.6 Hz, H100), 3.16 (dd, 1H, 13.5, J 6.1 Hz, H70), 3.08 (dd, 1H, J 13.5,
8.1 Hz, H70), 2.97–2.87 (m, 1H, H4), 2.83–2.74 (m, 5H, H4, H2%,
2ꢁH5%), 1.92–1.84 (m, 4H, 2ꢁH3%, 2ꢁH4%). 1H NMR minor rotamer
0.88 (EtOAc). 1H NMR of the major rotamer:
d 9.61 (t, 1H, J 2.1 Hz,
CHO), 6.60 (s, 2H, H30, H5), 6.50 (s, 1H, H60), 6.02 (s, 1H, H8), 5.33 (dd,
1H, J 8.7, 5.4 Hz, H1), 3.90 (dt,1H, J 12.6, 4.5 Hz, H3), 3.86 (s, 6H, OCH3-
7, OCH3-50), 3.74 (s, 3H, OCH3-40), 3.67 (dd, 1H, J 8.4, 3.6 Hz, H3), 3.55
(s, 3H, OCH3-6), 3.55–3.47 (m, 2H, 2ꢁH100), 3.07 (dd,1H, J 13.5, 5.4 Hz,
H70), 2.91 (dd, 1H, J 13.5, 8.9 Hz, H70), 2.89–2.85 (m, 1H, H4), 2.83–
(in part):
1H, H8). 13C NMR of the major rotamer: (signals for COCF3 and COCF3
were not observed)
148.3 (C40, C6), 148.1 (C50), 147.2 (C7), 128.3
d
6.79 (s, 1H, H30), 6.56 (s, 1H, H5), 6.44 (s, 1H, H60), 6.04 (s,
2.78 (m, 1H, H4). 1H NMR of the minor rotamer (in part):
CHO), 5.87 (s, 1H, H8). 13C NMR of the major rotamer:
199.6 (CHO),
d
9.43 (br s,
d
d
(C20), 126.9 (C10), 126.2 (C4a), 125.1 (C8a), 114.4 (CH-60), 113.5 (CH-30),
111.0 (CH-5), 110.7 (CH-8), 56.5 (CH2-100), 56.2 (OCH3-7), 56.0 (OCH3-
50), 55.8 (OCH3-40, OCH3-6), 55.7 (CH-1), 53.6 (CH2-2%, CH2-5%), 40.8
(CH2-3), 38.4 (CH2-70), 28.5 (CH2-4), 23.3 (CH2-3%, CH2-4%). MS (EIþ):
m/z 522 (Mþ, 20%). HRMS (ESIþ): calcd for C27H34F3N2O5, 523.2420
(MHþ), found 523.2435.
156.1 (q, J 35.8 Hz, COCF3), 148.3 (C40), 148.2 (C6), 148.2 (C50), 147.2
(C7), 128.4 (C20), 125.9 (C4a), 124.9 (C10), 123.4 (C8a), 116.5 (q, J
286.4 Hz, COCF3), 114.5 (CH-60),113.9 (CH-30),110.9 (CH-8), 110.8 (CH-
5), 56.0 (OCH3-7), 55.9 (OCH3-50, OCH3-40), 55.7 (OCH3-6), 55.6 (CH-
1), 47.8 (CH2-100), 40.8 (CH2-3), 38.5 (CH2-70), 28.6 (CH2-4). 13C NMR of
the minor rotamer (in part): d 199.0 (CHO), 40.9 (CH2-3), 55.4 (CH-1),
47.9 (CH2-100). MS (EIþ): m/z 481 (Mþ, 10%). HRMS (ESIþ): calcd for
4.6.3. (R,S) 1-[20-(Diethylamino)methyl-40,50-dimethoxyphenyl]methyl-
C24H27F3NO6, 482.1790 (MHþ), found 482.1812.
2-trifluoroacetyl-1,2,3,4-dihydro.-6,7-dimethoxyisoquinoline
(19). A
mixture of aldehyde 15 (112 mg, 0.239 mmol), diethylamine (0.2 mL,
1.93 mmol), CH3CN (3 mL) and NaCNBH3 (16 mg, 0.252 mmol) was
treated as described above in the general reductive amination re-
action procedure to give an oil. The oil was purified by column
chromatography (CH3OH/EtOAc (4:6)) to afford 19 (83 mg, 75%) as
a light yellow oil. Compound 19 was a 95:5 mixture of rotamers. Rf
4.6. General method of reductive amination
To a solution of the aldehyde and the amine in CH3CN was added
NaCNBH3. The reaction was stirred at rt for 20 min before glacial
acetic acid was added to adjust the pH to w6. The resulting solution
was stirred for 18 h at rt. The CH3CN was evaporated and the res-
idue was dissolved in CH2Cl2. The solution was washed sub-
sequently with H2O (3ꢁ), satd Na2CO3, brine and dried (MgSO4) to
give an oil. The oil was purified by column chromatography to af-
ford the pure product.
0.33 (CH3OH:EtOAc (4:6)). 1H NMR of the major rotamer:
d 6.85 (s,1H,
H30), 6.57 (s,1H, H5), 6.56 (s,1H, H60), 6.12 (s, 1H, H8), 5.55 (t, 1H, J 7.8,
6.0 Hz, H1), 3.92 (dt, 1H, J 7.8, 3.3 Hz, H3), 3.82 (s, 6H, OCH3-7, OCH3-
50), 3.76 (s, 3H, OCH3-40), 3.73–3.66 (m, 1H, H3), 3.57 (s, 3H, OCH3-6),
3.32 (dd,1H, J 13.5, 7.8 Hz, H70), 3.28 (d,1H, J 13.5 Hz, H100), 3.16 (d,1H,
J 13.5 Hz, H100), 3.04 (dd,1H, J 13.5, 6.0 Hz, H70), 2.98–2.85 (m,1H, H4),
2.77–2.69 (m,1H, H4), 2.43 (q, 4H, J 6.9 Hz, 2ꢁNCH2CH3), 0.93 (t, 6H, J
4.6.1. (RS)
2-Trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-
[40,50-dimethoxy-20-(morpholino)methylphenyl]methylisoquinoline
(17). A mixture of the aldehyde 22 (58 mg, 0.125 mmol), morpho-
line (0.10 mL, 1.16 mmol), CH3CN (15 mL) and NaCNBH3 (10 mg,
0.162 mmol) was treated as described above in the general re-
ductive amination reaction procedure to give an oil. The oil was
purified by column chromatography (EtOAc) to afford 28 (40 mg,
60%) as a clear oil. Compound 28 was a 95:5 mixture of rotamers. Rf
6.9 Hz, 2ꢁNCH2CH3). 1H NMR of the minor rotamer (in part):
d 6.79 (s,
1H, H30), 5.85 (s, 1H, H8), 3.79 (s, 6H, OCH3-7, OCH3-50), 3.48 (s, 3H,
OCH3-6). 13C NMR of the major rotamer: (signals for COCF3 and COCF3
were not observed)
d
148.4 (C40), 147.7 (C6), 147.7 (C50), 147.5 (C7),
128.5 (C20, C8a), 127.2 (C10), 125.0 (C4a), 114.0 (CH-30), 113.6 (CH-60),
111.2 (CH-5), 110.7 (CH-8), 55.2 (OCH3-7), 56.1 (OCH3-50), 55.1 (OCH3-
40), 55.9 (OCH3-6), 55.7 (CH-1), 55.5 (CH2-100), 46.5 (2ꢁNCH2CH3),
40.6 (CH2-3), 37.7 (CH2-70), 28.8 (CH2-4),11.5 (2ꢁNCH2CH3). MS (EIþ):
m/z 524 (Mþ, 10%). HRMS (ESIþ): calcd for C27H35F3N2O5, 525.2576
(MHþ), found 525.2563.
0.38 (EtOAc). 1H NMR of the major rotamer: 6.73 (s, 1H, H30), 6.59
d
(s, 1H, H5), 6.47 (s, 1H, H60), 6.24 (s, 1H, H8), 5.78 (t,1H, J 7.2 Hz, H1),
4.04–3.95 (m, 1H, H3), 3.83 (s, 6H, OCH3-7, OCH3-50), 3.75 (dt, 1H, J
7.8, 6.7 Hz, H3), 3.74 (s, 3H, OCH3-40), 3.65 (t, 4H, J 4.8 Hz, 2ꢁH3%,
2ꢁH4%), 3.61 (s, 3H, OCH3-6), 3.41 (d, 1H, J 12.9 Hz, H100), 3.22 (dd,
1H, J 13.5, 7.2 Hz, H70), 3.19 (d, 1H, J 12.9 Hz, H100), 3.08 (dd, 1H, J
13.5, 7.2 Hz, H70), 3.00–2.90 (m, 1H, H4), 2.81–2.73 (m, 1H, H4),
2.44–2.39 (m, 4H, 2ꢁH200, 2ꢁH5%). 1H NMR of the minor rotamer
4.6.4. (R,S)
2-Trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-
[40,50-dimethoxy-20-(isopropylamino)methylphenyl]methylisoquino-
line (20). A mixture of aldehyde 15 (112 mg, 0.239 mmol),
isopropylamine (0.2 mL, 2.33 mmol), CH3CN (3 mL) and NaCNBH3
(16 mg, 0.252 mmol) was reacted as described above in the general
reductive amination reaction procedure to give an oil. The oil was
purified by column chromatography (CH3OH/EtOAc (4:6)) to afford
20 (67 mg, 64%) as a light yellow oil. Compound 20 was a 95:5
mixture of rotamers. Rf 0.17 (CH3OH/EtOAc (4:6)). 1H NMR of the
(in part):
NMR of the major rotamer: (signals for COCF3 and COCF3 were not
d
6.71 (s, 1H, H30), 6.50 (s, 1H, H60), 5.96 (s, 1H, H8). 13C
observed) d
148.2 (C40), 147.9 (C6), 147.4 (C50, C7), 128.9 (C20), 128.7
(C8a), 127.2 (C10), 124.8 (C4a), 114.2 (CH-30), 114.1 (CH-60), 111.0 (CH-
5), 110.4 (CH-8), 67.0 (CH2-3%, CH2-400), 61.4 (CH2-2%, CH2-5%), 55.9
(OCH3-7, OCH3-50), 55.8 (OCH3-40), 55.7 (OCH3-6), 55.0 (CH-1), 53.7
major rotamer: d
6.80 (s, 1H, H30), 6.57 (s, 1H, H5), 6.54 (s, 1H, H60),

U. Mbere-Nguyen et al. / Tetrahedron 66 (2010) 4133–4143
4139
6.12 (s, 1H, H8), 5.58 (t, 1H, J 8.1, 6.6 Hz, H1), 3.95–3.85 (m, 1H, H3),
3.83 (s, 3H, OCH3-7), 3.81 (s, 3H, OCH3-50), 3.76 (s, 3H, OCH3-40),
3.71–3.65 (m, 1H, H3), 3.56 (s, 3H, OCH3-6), 3.48 (d, 1H, J 12.6 Hz,
H100), 3.43 (d, 1H, J 12.6 Hz, H100), 3.20 (dd, 1H, J 13.8, 8.1 Hz, H70),
3.05 (dd, 1H, J 13.8, 6.6 Hz, H70), 2.96–2.85 (m, 1H, H4), 2.82–2.70
(m, 2H, H200, H4), 1.04 (d, 3H, J 2.4 Hz, CH(CH3)CH3), 1.02 (d, 3H, J
124.8 (C8a), 113.6 (CH-5), 111.7 (CH-30), 110.9 (CH-60), 110.4 (CH-8),
57.7 (CH2-200), 55.9 (OCH3-7, OCH3-50), 55.6 (OCH3-40, OCH3-6, CH-1),
54.0 (CH2-2%, CH2-5%), 40.5 (CH2-3), 37.8 (CH2-70), 31.9 (CH2-100),
28.5 (CH2-4), 23.4 (CH2-3%, CH2-4%). MS (EIþ): m/z 536 (Mþ, 10%).
HRMS (ESIþ): calcd for C28H36F3N2O5, 537.2576 (MHþ), found
537.2581.
2.4 Hz, CH(CH3)CH3). 1H NMR of the minor rotamer (in part):
d 6.76
(s, 1H, H30), 5.92 (s, 1H, H8), 3.77 (s, 3H, OCH3-50), 3.49 (s, 3H, OCH3-
6). 13C NMR of the major rotamer: (signals for COCF3 and COCF3
4.6.7. (RS)1-[20-(200-(Diethylamino)ethyl)-40,50-dimethoxyphenyl]methyl-
2-trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline
(23). A
were not observed)
d
148.4 (C40), 148.0 (C6), 147.9 (C50), 147.5 (C7),
mixture of aldehyde 16 (132 mg, 0.274 mmol), diethylamine (0.2 mL,
1.93 mmol), CH3CN (3 mL) and NaCNBH3 (22 mg, 0.356 mmol) was
treated as described above in the general reductive amination reaction
procedure to give an oil. The oil was purified by column chromatog-
raphy (CH3OH/EtOAc (4:6)) to afford 23 (100 mg, 68%) as a light yellow
oil. Compound 23 was a 95:5 mixture of rotamers. Rf 0.21 (CH3OH/
131.9 (C20), 127.9 (C8a), 126.9 (C10), 125.1 (C4a), 114.1 (CH-30), 113.1
(CH-60), 111.2 (CH-5), 110.7 (CH-8), 56.0 (OCH3-7), 56.1 (OCH3-50),
55.1 (OCH3-40), 55.9 (OCH3-6), 55.8 (CH-1), 49.3 (CH2-100), 49.2 (CH-
200), 40.7 (CH2-3), 38.0 (CH2-70), 28.8 (CH2-4), 23.1 (CH(CH3)CH3),
22.1 (CH(CH3)CH3). MS (EIþ): m/z 510 (Mþ, 10%). HRMS (ESIþ): calcd
for C26H34F3N2O5, 511.2421 (MHþ), found 511.2395.
EtOAc (4:6)). 1H NMR of the major rotamer: 6.63 (s, 1H, H30), 6.57 (s,
d
2H, H5, H60), 6.03 (s, 1H, H8), 5.49 (dd, 1H, J 8.4, 6.0 Hz, H1), 3.93 (dt,
1H, J 13.5, 5.7 Hz, H3), 3.82 (s, 3H, OCH3-7), 3.82 (s, 3H, OCH3-50), 3.75
(s, 3H, OCH3-40), 3.71–3.64 (m, 1H, H3), 3.54 (s, 3H, OCH3-6), 3.10 (dd,
1H, J 13.5, 8.4 Hz, H70), 3.03 (dd, 1H, J 13.5, 6.0 Hz, H70), 2.94–2.86 (m,
1H, H4), 2.79–2.71 (m, 1H, H4), 2.55 (q, 4H, J 6.9 Hz, 2ꢁNCH2CH3),
2.59–2.42 (m, 4H, 2ꢁH100, 2ꢁH200), 1.01 (t, 6H, J 6.9 Hz, 2ꢁNCH2CH3).
4.6.5. (RS) 2-Trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-[40,50-
dimethoxy-20-(200-(morpholino)ethyl)phenyl]methylisoquinoline(21). A
mixture of aldehyde 16 (80 mg, 0.166 mmol), morpholine (0.1 mL,
1.16 mmol), CH3CN (6 mL) and NaCNBH3 (16 mg, 0.252 mmol) was
treated as described above in the general reductive amination re-
action procedure to give an oil. The oil was purified by column
chromatography (CH3OH/EtOAc (4:6)) to afford 21 (59 mg, 64%) as
a clear oil. Compound 21 was a 95:5 mixture of rotamers. Rf 0.25
1H NMR of the minor rotamer (in part):
d
6.60 (s, 1H, H30), 3.52 (s, 3H,
d 155.6 (q, J 36.2 Hz, COCF3),
OCH3-6). 13C NMR of the major rotamer:
148.2 (C40), 147.89 (C6), 147.2 (C50, C7), 131.5 (C20), 127.0 (C4a), 126.3
(C10), 124.9 (C8a), 116.0 (q, J 286.3 Hz, COCF3), 113.8 (CH-5), 112.8 (CH-
30), 110.9 (CH-60), 110.5 (CH-8), 55.9 (OCH3-7, OCH3-50, CH-1), 54.6
(OCH3-40, OCH3-6), 54.2 (CH2-200), 46.6 (2ꢁNCH2CH3), 40.7 (CH2-3),
38.0 (CH2-70), 29.6 (CH2-100), 28.5 (CH2-4), 11.5 (2ꢁNCH2CH3). MS (EIþ):
m/z 538 (Mþ, 10%). HRMS (ESIþ): calcd for C28H38N2O5F3, 539.2733
(MHþ), found 539.2734.
(CH3OH/EtOAc (4:6)). 1H NMR of the major rotamer:
d 6.66 (s, 1H,
H30), 6.57 (s, 1H, H5), 6.52 (s, 1H, H60), 6.01 (s, 1H, H8), 5.48 (t, 1H, J
6.9 Hz, H1), 3.92 (dt, 1H, J 13.5, 5.1 Hz, H3), 3.81 (s, 6H, OCH3-7, OCH3-
50), 3.72 (s, 3H, OCH3-40), 3.67 (t, 4H, J 4.7 Hz, 2ꢁH3%, 2ꢁH4%), 3.67–
3.62 (m, 1H, H3), 3.53 (s, 3H, OCH3-6), 3.05 (d, 2H, J 6.9 Hz, 2ꢁH70),
2.96–2.86 (m, 1H, H4), 2.78–2.70 (m, 1H, H4), 2.63–2.57 (m, 1H, H200),
2.56–2.49 (m, 1H, H200), 2.40 (t, 4H, J 4.7 Hz, 2ꢁH2%, 2ꢁH5%), 2.37–
2.25 (m, 2H, 2ꢁH100). 1H NMR of the minor rotamer (in part):
d 6.64 (s,
1H, H30), 6.56 (s, 1H, H5), 5.75 (s, 1H, H8), 3.81 (s, 6H, OCH3-7, OCH3-
50), 3.77 (s, 3H, OCH3-40), 3.45 (s, 3H, OCH3-6). 13C NMR of the major
4.7. General method for N-trifluoroacetyl deprotection and
reductive N-methylation
rotamer:
d
156.1 (q, J 35.3 Hz, COCF3), 148.5 (C40), 148.1 (C6), 147.5
(C50), 147.4 (C7), 131.5 (C10), 127.2 (C20), 126.6 (C4a), 125.2 (C8a), 116.7
(q, J 286.5 Hz, COCF3), 114.2 (CH-60), 113.1 (CH-30), 111.2 (CH-5), 110.9
(CH-8), 67.2 (CH2-3%, CH2-4%), 60.5 (CH2-200), 55.8 (4ꢁOCH3), 55.7
(CH-1), 53.9 (CH2-2%, CH2-5%), 40.9 (CH2-3), 38.2 (CH2-70), 29.7 (CH2-
The N-TFA protected amine was dissolved in a mixture of CH3OH
and H2O. To this was added K2CO3 and the resulting solution was
stirred at rt for 18 h. CH3OH was removed and the residue was
dissolved in CH3CN. Formaldehyde of 38% was added followed by
NaCNBH3. Glacial acetic acid was added after 20 min of stirring to
adjusted the pH to w6. The reaction mixture was stirred at rt for
18 h. CH3CN was evaporated and the residue was redissolved in
CH2Cl2. The CH2Cl2 layer was washed with satd K2CO3 and dried
(MgSO4). Evaporation of the CH2Cl2 extracts gave the crude prod-
uct, which was purified by column chromatography to afford the
pure N-methylated analogues.
100), 28.7 (CH2-4). 13C NMR of the minor rotamer (in part):
d 147.9
(C50), 147.1 (C7), 131.8 (C10), 127.0 (C20), 126.0 (C4a), 111.2 (CH-5), 110.4
(CH-8), 65.9 (CH2-3%, CH2-4%), 60.1 (CH2-200), 53.8 (CH2-2%, CH2-5%),
40.9 (CH2-3), 39.2 (CH2-70), 31.8 (CH2-100), 27.4 (CH2-4). MS (ESIþ):
m/z 552.81 (MHþ, 100%). HRMS (ESIþ): calcd for C28H36F3N2O6,
553.2525 (MHþ), found 553.2486.
4.6.6. (RS) 2-Trifluoroacetyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-[40,50-
dimethoxy-20-(200-(N-pyrrolidinyl)ethyl)phenyl]methylisoquinoline
(22). A mixture of aldehyde 16 (71 mg, 0.149 mmol), pyrrolidine
(0.2 mL, 2.26 mmol), CH3CN (3 mL) and NaCNBH3 (12 mg,
0.194 mmol) was treated as described above in the general reductive
amination reaction procedure to give an oil. The oil was purified by
column chromatography (CH3OH/EtOAc (4:6)) to afford 22 (61 mg,
74%) as a light yellow oil. Compound 22 was a 95:5 mixture of
rotamers. Rf 0.20 (CH3OH/EtOAc (4:6)). 1H NMR of the major rotamer:
4.7.1. (RS) 1,2,3,4-Tetrahydro-6,7-dimethoxy-1-[40,50-dimethoxy-20-
(morpholino)methyl phenyl]methyl-2-methylisoquinoline (24). The
N-TFA protected amine 17 (40 mg, 0.074 mmol) was treated as
described above in the general N-TFA deprotection and reductive
N-methylation reaction procedure by initially using K2CO3 (50 mg,
0.370 mmol), CH3OH (5 mL) and H2O (1 mL), except it was stirred at
80 ꢀC for 3 h, then using 38% formaldehyde (3 mL), CH3CN (3 mL)
and NaCNBH3 (6 mg, 0.096 mmol) to give an oil. The oil was puri-
fied by column chromatography (CH3OH/EtOAc/NH3 (4:6:0.1)) to
afford 24 (25 mg, 73%) as a clear oil. Rf 0.34 (CH3OH/EtOAc/NH3
d
6.64 (s, 1H, H30), 6.60 (s, 1H, H5), 6.56 (s, 1H, H60), 6.02 (s, 1H, H8),
5.50 (dd, 1H, J 8.4, 5.7 Hz, H1), 3.93 (dt, 1H, J 13.8, 5.4 Hz, H3), 3.89 (s,
6H, OCH3-7, OCH3-50), 3.76 (s, 3H, OCH3-40), 3.71–3.62 (m, 1H, H3),
3.53 (s, 3H, OCH3-6), 3.05 (dd, 1H, J 13.5, 8.4 Hz, H70), 3.02 (dd, 1H, J
13.5, 5.7 Hz, H70), 2.96–2.81 (m, 1H, H4), 2.78–2.69 (m, 1H, H4), 2.58–
2.35 (m, 8H, 2ꢁH2%, 2ꢁH5%, 2ꢁH100, 2ꢁH200), 1.80–1.76 (m, 4H,
2ꢁH3%, 2ꢁH4%). 1H NMR of the minor rotamer (in part): 6.61 (s, 1H,
H30), 5.75 (s, 1H, H8), 3.39 (s, 3H, OCH3-6). 13C NMR of the major
(4:6:0.1)). 1H NMR:
d
6.80 (s, 1H, H30), 6.58 (s, 1H, H5), 5.41 (s, 1H,
H60), 5.71 (s, 1H, H8), 3.85 (s, 3H, OCH3-7), 3.84 (s, 3H, OCH3-50),
3.81 (dd, 1H, J 9.0, 5.2 Hz, H1), 3.76 (s, 3H, OCH3-40), 3.66 (t, 4H, J
2.7 Hz, 2ꢁH3%, 2ꢁH4%), 3.44 (s, 3H, OCH3-6), 3.29–3.25 (m, 1H,
H3), 3.19 (d, 1H, J 12.9 Hz, H100), 3.17 (dd, 1H, J 13.5, 5.2 Hz, H70), 2.96
(dd, 1H, J 13.4, 9.0 Hz, H70), 3.07 (d, 1H, J 12.9 Hz, H100), 2.88–2.85
(m, 1H, H4), 2.81 (dt, 1H, J 9.3, 3.0 Hz, H3), 2.63 (dd, 1H, J 5.7, 3.0 Hz,
H4), 2.56 (s, 3H, NCH3), 2.36 (t, 4H, J 2.7 Hz, H2%, H5%). MS (ESIþ):
rotamer: (signals for COCF3 and COCF3 were not observed)
d 148.2
(C40), 148.8 (C6), 147.2 (C50, C7), 131.44 (C20), 127.0 (C4a), 126.3 (C10),

4140
U. Mbere-Nguyen et al. / Tetrahedron 66 (2010) 4133–4143
m/z 457.1 (MHþ, 40%). HRMS (ESIþ): calcd for C27H39N2O5, 471.2859
(d, 1H, J 12.9 Hz, H100), 2.96–2.77 (m, 5H, H4, 2ꢁH70, H3, H200), 2.61–
2.52 (m, 1H, H4), 2.54 (s, 3H, NCH3), 0.94 (t, 6H, J 2.1 Hz,
(MHþ), found 471.2865.
CH(CH3)CH3). 13C NMR:
d
147.6 (C40), 147.5 (C6), 147.2 (C50), 146.0
4.7.2. (RS) 1,2,3,4-Tetrahydro-6,7-dimethoxy 1-[40,50-dimethoxy-20-
(pyrrolidinyl)methyl phenyl]methyl-2-methylisoquinoline (25). The
N-TFA protected amine 18 (79 mg, 0.148 mmol) was treated as de-
scribed above in the general N-TFA deprotection and reductive
N-methylation reactions procedure by initially using K2CO3
(101 mg, 0.740 mmol), CH3OH (5 mL) and H2O (1 mL) and then 38%
formaldehyde (3 mL), CH3CN (3 mL) and NaCNBH3 (20 mg,
0.328 mmol) to give an oil. The oil was purified by column chro-
matography (CH3OH/EtOAc/NH3 (4:6:0.1)) to afford 25 (48 mg, 71%
yield) as a light yellow oil. Rf 0.34 (CH3OH/EtOAc/NH3 (4:6:0.1)). 1H
(C7), 130.5 (C20, C4a), 128.0 (C10), 125.1 (C8a), 114.3 (CH-5), 113.4
(CH-30), 111.3 (CH-60), 111.1 (CH-8), 64.2 (CH-1), 56.1 (OCH3-7), 55.9
(OCH3-50), 55.8 (OCH3-40), 55.3 (OCH3-6), 54.4 (CH2-100), 53.2 (CH-
2%), 45.9 (CH2-3), 36.7 (CH2-70), 35.8 (NCH3), 24.9 (CH2-4), 17.7
(CH(CH3)CH3), 17.2 (CH(CH3)CH3). MS (ESIþ): m/z 443.1 (MHþ,
100%). HRMS (ESIþ): calcd for C26H39N2O4, 443.2910 (MHþ), found
443.2910.
4.7.5. (RS) 1,2,3,4-Tetrahydro-6,7-dimethoxy-1-[40,50-dimethoxy-20-
(2%-(morpholino)ethyl)phenyl]methyl-2-methylisoquinoline (1). The
N-TFA protected amine 21 (50 mg, 0.092 mmol) was treated as
described above in the general N-TFA deprotection and reductive
N-methylation reaction procedure by initially using K2CO3 (91 mg,
0.68 mmol), CH3OH (3 mL) and H2O (1 mL), then 38% formaldehyde
(3 mL), CH3CN (3 mL) and NaCNBH3 (10 mg, 0.164 mmol) to give an
oil. The oil was purified by column chromatography (CH3OH/EtOAc/
NH3 (4:6:0.1)) to afford 11 (37 mg, 85%) as a light yellow oil. Rf 0.30
NMR: d
6.91(s, 1H, H30), 6.55 (s, 1H, H5), 5.44 (s, 1H, H60), 5.76 (s, 1H,
H8), 3.85 (s, 3H, OCH3-7), 3.81 (s, 3H, OCH3-50), 3.86–3.80 (m, 1H,
H1), 3.72 (s, 3H, OCH3-6), 3.49 (d, 1H, J 12.9 Hz, H100), 3.44 (s, 3H,
OCH3-40), 3.29 (d, 1H, J 12.9 Hz, H100), 3.23–3.11 (m, 2H, H3, H70),
2.94–2.78 (m, 3H, H70, H3, H4), 2.63–2.54 (m, 1H, H4), 2.52 (s, 3H,
NCH3), 2.41 (br s, 4H, 2ꢁH2%, 2ꢁH5%), 1.70 (br s, 4H, 2ꢁH3%,
2ꢁH4%). 13C NMR:
d
147.5 (C40, C6), 147.2 (C50), 147.2 (C7), 130.8
(C20, C4a), 129.4 (C10), 125.9 (C8a), 114.9 (CH-5), 113.4 (CH-30), 111.8
(CH-60), 111.5 (CH-8), 64.1 (CH-1), 57.8 (CH2-100), 56.3 (OCH3-7), 56.1
(OCH3-50, OCH3-40), 55.5 (OCH3-6), 54.3 (CH2-2%, CH2-5%), 46.3
(CH2-3), 42.7 (NCH3), 37.1 (CH2-70), 25.1 (CH2-4), 23.8 (CH2-3%,
CH2-4%). MS (ESIþ): m/z 441.1 (MHþ, 100%). HRMS (ESIþ): calcd for
C26H36N2O4, 441.2753 (MHþ), found 441.2777.
(CH3OH/EtOAc/NH3 (4:6:0.1)). 1H NMR: 6.61 (s, 1H, H30), 6.55 (s,
d
1H, H5), 6.53 (s, 1H, H60), 5.68 (s, 1H, H8), 3.80 (s, 3H, OCH3-7), 3.78
(s, 3H, OCH3-50), 3.75 (s, 3H, OCH3-40), 3.67 (t, 4H, J 4.5 Hz, 2H2%,
2H5%), 3.65–3.62 (m, 1H, H1), 3.38 (s, 3H, OCH3-6), 3.28–3.20 (m,
1H, H3), 3.15 (dd, 1H, J 13.2, 4.2 Hz, H70), 2.94–2.87 (m, 1H, H4),
2.85–2.81 (m, 1H, H3), 2.74 (dd, 1H, J 13.2, 9.6 Hz, H70), 2.61–2.54
(m, 1H, H4), 2.53 (s, 3H, NCH3), 2.38 (t, 4H, J 5.1 Hz, 2ꢁH3%,
2ꢁH4%), 2.34–2.27 (m, 2H, H200), 2.24–2.17 (m, 2H, H100). 13C NMR:
4.7.3. (RS) 1-[20-(Diethylamino)methyl-40,50-dimethoxyphenyl]methyl-
1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinoline (26). The N-TFA
protected amine 19 (75 mg, 0.161 mmol) was treated as described
above in the general N-TFA deprotection and reductive N-methylation
reaction procedure by initially using K2CO3 (109 mg, 0.810 mmol),
CH3OH (2 mL) and H2O (1 mL), except it was stirred for 4 h and then
using 38% formaldehyde (3 mL), CH3CN (3 mL) and NaCNBH3 (20 mg,
0.328 mmol) to give an oil. The oil was purified by column chroma-
tography (CH3OH/EtOAc/NH3 (4:6:0.1)) to afford 26 (41 mg, 58%) as
d
147.4 (C40), 147.3 (C6), 147.1 (C50), 146.0 (C7), 131.0 (C20), 129.4
(C4a), 128.1 (C10), 125.2 (C8a), 114.0 (CH-5), 112.8 (CH-30), 111.2 (CH-
60, CH-8), 66.8 (CH2-3%, CH2-4%), 64.3 (CH-1), 59.9 (CH2-200), 55.9
(OCH3-7), 55.9 (OCH3-50), 55.7 (OCH3-40), 55.3 (OCH3-6), 53.5 (CH2-
2%, CH2-5%), 45.9 (CH2-3), 42.2 (NCH3), 37.1 (CH2-70), 29.5 (CH2-100),
24.7 (CH2-4). MS (ESIþ): m/z 471.1 (MHþ, 40%). HRMS (ESIþ): calcd
for C27H39N2O5, 471.2859 (MHþ), found 471.2865.
a light yellow oil. Rf 0.32 (CH3OH/EtOAc/NH3 (4:6:0.1)). 1H NMR:
d
6.88
4.7.6. (RS) 1,2,3,4-Tetrahydro-6,7-dimethoxy-1-[40,50-dimethoxy-20-
(2%-(pyrrolidino)ethyl) phenyl]methyl-2-methylisoquinoline
(28). The N-TFA protected amine 22 (38 mg, 0.076 mmol) was
treated as described above in the general N-TFA deprotection and
reductive N-methylation reaction procedure by using initially
K2CO3 (52 mg, 0.381 mmol), CH3OH (5 mL) and H2O (1 mL), then
38% formaldehyde (3 mL), CH3CN (3 mL) and NaCNBH3 (10 mg,
0.164 mmol) to give an oil. The oil purified by column chromato-
graphy (CH3OH/EtOAc/NH3 (4:6:0.1)) to afford 28 (25 mg, 69%) as
a light yellow oil. Rf 0.30 (CH3OH/EtOAc/NH3 (4:6:0.1)). 1H NMR:
(s, 1H, H30), 6.54 (s, 1H, H5), 5.51 (s, 1H, H60), 5.69 (s, 1H, H8), 3.83 (s, 3H,
OCH3-7), 3.80 (s, 3H, OCH3-50), 3.74 (s, 3H, OCH3-6), 3.70 (dd, 1H, J 9.0,
4.8 Hz, H1), 3.40 (s, 3H, OCH3-40), 3.31–3.24 (m, 1H, H3), 3.18 (d, 1H, J
13.5 Hz, H100), 3.08 (dd, 2H, J 13.5, 4.8 Hz, H70), 2.98 (d, 1H, J 13.5 Hz,
H100), 2.89 (dd, 1H, J 9.6, 3.0 Hz, H3), 2.84 (dd, 1H, J 13.5, 9.0 Hz, H70),
2.80–2.76 (m, 1H, H4), 2.60–2.56 (m, 1H, H4), 2.54 (s, 3H, NCH3), 2.49–
2.29 (m, 4H, 2ꢁNCH2CH3), 0.90 (t, 6H, J 6.9 Hz, 2ꢁNCH2CH3). 13C NMR:
d
147.3 (C40), 147.2 (C6), 146.9 (C50), 145.9 (C7), 131.1 (C20), 130.7 (C4a),
128.9 (C10), 125.6 (C8a), 114.8 (CH-5), 113.1 (CH-30), 111.3 (CH-60), 111.2
(CH-8), 64.1 (CH-1), 56.0 (CH2-100), 55.9 (OCH3-7), 55.8 (OCH3-50), 55.3
(OCH3-40), 55.0 (OCH3-6), 46.6 (2ꢁNCH2CH3), 46.0 (CH2-3), 42.5
(NCH3), 36.5 (CH2-70), 25.1 (CH2-4), 11.6 (2ꢁNCH2CH3). MS (ESIþ): m/z
443.2 (MHþ, 100%). HRMS (ESIþ) calcd for C26H39N2O4, 443.2910
(MHþ), found 443.2928.
d
6.63 (s, 1H, H30), 6.56 (s, 1H, H5), 6.54 (s, 1H, H60), 5.74 (s, 1H, H8),
3.81 (s, 3H, OCH3-7), 3.80 (s, 3H, OCH3-50), 3.76 (s, 3H, OCH3-40),
3.66 (dd,1H, J 9.0, 4.5 Hz, H1), 3.42 (s, 3H, OCH3-6), 3.24 (m,1H, H3),
3.09 (dd, 1H, J 13.5, 4.5 Hz, H70), 2.94–2.87 (m, 1H, H4), 2.82–2.74
(m, 1H, H3), 2.78 (dd, 1H, J 13.5, 9.0 Hz, H70), 2.61–2.58 (m, 1H, H4),
2.54 (s, 3H, NCH3), 2.52–2.30 (m, 8H, 2ꢁH100, 2ꢁH200, 2ꢁH2%,
4.7.4. (RS) 1,2,3,4-Tetrahydro-6,7-dimethoxy-1-[40,50-dimethoxy-20-
(200-(isopropylamino)methyl)phenyl]methyl-2-methylisoquinoline
(27). The N-TFA protected amine 20 (60 mg, 0.136 mmol) was
treated as described above in the general N-TFA deprotection and
reductive N-methylation reaction procedure by initially using
K2CO3 (91 mg, 0.680 mmol), CH3OH (3 mL) and H2O (1 mL), except
it was stirred for 4 h, and then using 38% formaldehyde (3 mL),
CH3CN (3 mL) and NaCNBH3 (20 mg, 0.328 mmol) to give an oil. The
oil was purified by column chromatography (CH3OH/EtOAc/NH3
(4:6:0.1)) to afford 27 (36 mg, 59%) as a light yellow oil. Rf 0.34
2ꢁH5%), 1.75 (t, 4H, J 3.9 Hz, 2ꢁH3%, 2ꢁH4%). 13C NMR:
d 149.4
(C40), 148.9 (C6), 148.4 (C50), 147.0 (C7), 128.4 (C20), 126.3 (C4a),
121.5 (C10), 120.2 (C8a), 115.0 (CH-5), 113.0 (CH-30), 111.7 (CH-60),
111.5 (CH-8), 65.2 (CH2-200), 56.4 (OCH3-7, OCH3-50), 56.2 (OCH3-40),
55.6 (OCH3-6), 53.3 (CH2-1), 47.1 (CH2-2%, CH2-5%), 45.3 (CH2-3),
44.3 (NCH3), 40.0 (CH2-70), 37.8 (CH2-100), 27.4 (CH2-4), 21.4 (CH2-
3%, CH2-4%). MS (ESIþ): m/z 454.92 (MHþ, 20%). HRMS (ESIþ): calcd
for C27H39N2O4, 455.2910 (MHþ), found 455.2907.
4.7.7. (RS) 1-[20-(2%-(Diethylamino)ethyl)-40,50-dimethoxyphenyl]-
methyl-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinoline
(29). The N-TFA protected amine 23 (80 mg, 0.149 mmol) was
treated as described above in the general N-TFA deprotection and
reductive N-methylation reaction procedure by initially using
(CH3OH/EtOAc/NH3 (4:6:0.1)). 1H NMR:
d
6.82 (s, 1H, H30), 6.54 (s,
1H, H5), 5.52 (s, 1H, H60), 5.67 (s, 1H, H8), 3.82 (s, 3H, OCH3-7), 3.80
(s, 3H, OCH3-50), 3.75 (s, 3H, OCH3-6), 3.76–3.70 (m, 1H, H1), 3.39 (s,
3H, OCH3-40), 3.32–3.20 (m,1H, H3), 3.12 (d,1H, J 12.9 Hz, H100), 2.95

U. Mbere-Nguyen et al. / Tetrahedron 66 (2010) 4133–4143
4141
K2CO3 (100 mg, 0.735 mmol), CH3OH (5 mL) and H2O (1 mL), then
38% formaldehyde (3 mL), CH3CN (3 mL) and NaCNBH3 (20 mg,
0.328 mmol) to give an oil. The oil was purified by column chro-
matography (CH3OH/EtOAc/NH3 (4:6:0.1)) to afford 29 (65 mg,
69%) as a light yellow oil. Rf 0.31 (CH3OH/EtOAc/NH3 (4:6:0.1)). 1H
heated at 80 ꢀC for 18 h, however only the precursor 31 was re-
covered and none of the desired aldehyde 32 was obtained.
4.10. (RS) 1,2,3,4-Tetrahydro-1[40,50-dimethoxy-20-
(2,2-dimethoxyethylamino)methyl phenyl]methyl-6,7-
dimethoxyisoquinoline (33)
NMR: d
6.61 (s, 1H, H30), 6.57 (s,1H, H5), 6.54 (s,1H, H60), 5.71 (s,1H,
H8), 3.81 (s, 3H, OCH3-7), 3.79 (s, 3H, OCH3-50), 3.76 (s, 3H, OCH3-
40), 3.66 (dd, 1H, J 9.0, 4.2 Hz, H1), 3.40 (s, 3H, OCH3-6), 3.27–3.21
(m, 1H, H3), 3.09 (dd, 1H, J 13.0, 4.2 Hz, H70), 2.92–2.86 (m, 1H, H4),
2.83–2.78 (m, 1H, H3), 2.78 (dd, 1H, J 13.0, 9.0 Hz, H70), 2.59–2.54
(m, 1H, H4), 2.55 (s, 3H, NCH3), 2.52 (q, 4H, J 4.2 Hz, 2ꢁNCH2CH3),
2.52–2.44 (m, 2H, 2ꢁH200), 2.35 (dt, 2H, J 12.3, 4.1 Hz, 2ꢁH100), 1.00
To a solution of the amine 31 (116 mg, 0.225 mmol) in CH3OH
(3 mL) was added 10% aqueous HCl (1 mL). The mixture was heated
at reflux for 4 h. The solution was basified with K2CO3 (excess) to
about pH w6. The CH3OH was evaporated and the residue was
dissolved in CH2Cl2. The solution was washed with H2O (3ꢁ), brine
and dried (K2CO3) to give 33 (37 mg, 41%) as a yellow oil. Rf 0.1
(t, 6H, J 4.2 Hz, 2ꢁNCH2CH3). 13C NMR:
d
148.2 (C40, C6), 148.0 (C50),
146.5 (C7), 129.0 (C20, C4a), 125.9 (C10), 124.8 (C8a), 114.0 (CH-5),
112.7 (CH-30), 111.2 (CH-60), 111.0 (CH-8), 64.5 (CH-1), 56.0 (OCH3-7,
OCH3-50), 55.7 (OCH3-40, OCH3-6), 55.2 (CH2-200), 45.9
(2ꢁNCH2CH3), 45.3 (CH2-3), 41.2 (NCH3), 36.8 (CH2-70), 27.3 (CH2-
100), 23.4 (CH2-4), 8.8 (2ꢁNCH2CH3). MS (ESIþ): m/z 456.94 (MHþ,
30%). HRMS (ESIþ): calcd for C27H41N2O4, 457.3066 (MHþ), found
457.3060.
(CH3OH/EtOAc/NH3 (5:5:0.1)). 1H NMR: 6.86 (s, 1H, H30), 6.75 (s,
d
1H, H5), 6.65 (s, 1H, H60), 6.60 (s, 1H, H8), 4.51 (t, 1H, J 5.3 Hz, H2%),
4.26 (dd, 1H, J 8.7, 3.9 Hz, H1), 3.86 (s, 3H, OCH3-7), 3.83 (s, 3H,
OCH3-50), 3.81 (s, 3H, OCH3-40), 3.84–3.78 (m, 2H, 2ꢁH3), 3.79 (s,
3H, OCH3-6), 3.37 (s, 6H, 2ꢁOCH3), 3.32–3.27 (m, 1H, H70), 3.11 (dd,
1H, J 12.6, 4.2 Hz, H100), 2.94–2.89 (m, 2H, H70, H100), 2.80 (dd, 2H, J
5.3, 2.1 Hz, 2ꢁH1%), 2.72–2.66 (m, 2H, 2ꢁH4). 13C NMR:
d 148.4
(C40), 148.3 (C6), 147.9 (C50), 147.7 (C7), 133.4 (C20), 129.4 (C8a),
128.6 (C10), 127.6 (C4a), 114.7 (CH-5), 113.6 (CH-30), 111.9 (CH-60),
109.8 (CH-8), 103.8 (CH-2%), 56.2 (OCH3-7, OCH3-50), 56.1 (OCH3-40,
OCH3-6), 54.6 (CH-1), 54.5 (2ꢁOCH3), 51.3 (CH2-1%), 53.9 (CH2-3),
40.9 (CH2-100), 39.1 (CH2-70), 29.0 (CH2-4). MS (ESIþ): m/z 461.1
(MHþ, 50%).
4.8. (RS) 1,2,3,4-Tetrahydro-6,7-dimethoxy-
1[20-((2%,2%-diethoxyethylamino)methy)-
40,50-dimethoxyphenyl]methylisoquinoline (31)
The aldehyde 15 was freshly generated from the diol 13 (139 mg,
0.278 mmol) as described in the general oxidative cleavage reaction
procedure using a suspension of silica gel coated with NaIO4, using
NaIO4 (827 mg, 3.89 mmol), H2O (2 mL), silica gel (1.7 g) and CH2Cl2
(5 mL). To the solution of the aldehyde 15 in CH3CN (4 mL) was
added aminoacetaldehyde diethylacetal (487 mg, 3.67 mmol,
0.5 mL) and NaCNBH3 (12 mg, 0.475 mmol). The reaction mixture
was stirred at rt for 20 min and the pH was adjusted to w6 using
glacial acetic acid. The reaction mixture was stirred for 18 h at rt.
The CH3CN was evaporated and the residue was dissolved in
a mixture of CH3OH (10 mL) and H2O (3 mL). K2CO3 (100 mg,
0.737 mmol) was added and the mixture was stirred at rt for 18 h.
CH3OH was evaporated and the residue was dissolved in CH2Cl2.
The solution was washed with H2O (3ꢁ), brine and dried (K2CO3) to
give an oil, which was purified by column chromatography (EtOAc
increase to CH3OH/EtOAc/NH3 (3:7:0.1)) to give 31 (118 mg, 82%
over three steps) as a yellow oil. Rf 0.07 (CH3OH/EtOAc (5:5)). 1H
4.11. (RS) 2-Trifluoroacetyl-1,2,3,4-tetrahydro-
1[40,50-dimethoxy-20-(methylamino)methylphenyl]methyl-
6,7-dimethoxyisoquinoline (36)
To a solution of the aldehyde 15 (136 mg, 0.290 mmol) and 33%
aqueous methylamine (0.05 mL) in CH3CN (3 mL) was added
NaCNBH3 (24 mg, 0.377 mmol). The reaction mixture was stirred at
rt for 20 min before the pH was adjusted to w6 using glacial acetic
acid. The resulting solution was stirred for 18 h at rt. The CH3CN was
evaporated and the residue was dissolved in CH2Cl2. The solution
was washed with H2O (3ꢁ), satd Na2CO3, brine and dried (MgSO4)
to give an oil. The oil was purified by column chromatography
(CH3OH/EtOAc/NH3 (5:5:0.1)) to afford 36 as a clear oil (100 mg,
71%). Compound 36 was a 95:5 mixture of rotamers. Rf 0.35
(CH3OH/EtOAc/NH3 (5:5:0.1)). 1H NMR of the major rotamer
(500 MHz): d
6.83 (s, 1H, H30), 6.57 (s, 1H, H5), 6.48 (s, 1H, H60), 6.08
NMR: (500 MHz) d
6.84 (s,1H, H30), 6.61 (s,1H, H5), 6.60 (s,1H, H60),
(s, 1H, H8), 5.53 (t, 1H, J 7.0 Hz, H1), 3.89 (dt, 1H, J 13.5, 4.5 Hz, H3),
3.82 (s, 3H, OCH3-7), 3.80 (s, 3H, OCH3-50), 3.72 (s, 3H, OCH3-40),
3.69 (dt, 1H, J 13.5, 3.5 Hz, H3), 3.54 (s, 3H, OCH3-6), 3.50 (br s, 2H,
2ꢁH100), 3.11 (d, 2H, J 7.0 Hz, 2ꢁH70), 2.96–2.85 (m, 1H, H4), 2.80–
2.72 (m, 1H, H4), 2.37 (s, 3H, NCH3). 1H NMR of the minor rotamer
6.54 (s, 1H, H8), 4.61 (t, 1H, J 5.0 Hz, H2%), 4.19 (dd, 1H, J 8.0, 4.5 Hz,
H1), 3.83 (s, 3H, OCH3-7), 3.81 (s, 3H, OCH3-50), 3.83–3.70 (m, 2H,
2H3), 3.78 (s, 3H, OCH3-40), 3.75 (s, 3H, OCH3-6), 3.65 (dq, 2H, J 14.5,
6.5, OCHHCH3), 3.50 (dq, 2H, J 14.5, 6.5, OCHHCH3), 3.22 (dd, 1H, J
13.5, 4.5 Hz, H70), 3.07 (dd, 1H, J 12.5, 6.5 Hz, H100), 2.89–2.84 (m,
2H, H70, H100), 2.76 (d, 2H, J 5.0 Hz, 2ꢁH1%), 2.64–2.62 (m, 2H,
(in part):
1H, H8), 5.09 (t, 1H, J 6.0 Hz, H1), 4.56 (dd, 1H, J 6.5 Hz, H3), 3.75 (s,
3H, OCH3-50). 13C NMR of the major rotamer:
156.0 (q, J 36.5 Hz,
d
6.77 (s, 1H, H30), 6.53 (s, 1H, H5), 6.52 (s, 1H, H60), 5.95 (s,
2ꢁH4), 1.14 (t, 6H, J 6.5 Hz, 2ꢁOCH2CH3). 13C NMR:
d
147.7 (C40),
d
147.3 (C6), 147.1 (C50), 146.9 (C7), 130.1 (C20), 129.5 (C8a), 129.1 (C10),
127.1 (C4a), 113.1 (CH-5), 112.8 (CH-30), 111.4 (CH-60), 109.3 (CH-8),
101.6 (CH-2%), 62.1 (2ꢁOCH2CH3), 55.8 (CH-1), 55.9 (OCH3-7), 55.6
(OCH3-50, OCH3-40), 55.5 (OCH3-6), 51.4 (CH2-1%), 50.7 (CH2-3),
40.4 (CH2-100), 38.6 (CH2-70), 28.8 (CH2-4), 15.0 (2ꢁOCH2CH3). MS
(ESIþ): m/z 488.6 (MHþ, 100%).
COCF3), 148.1 (C40), 147.7 (C6), 147.7 (C50), 147.2 (C7), 130.4 (C20),
127.7 (C8a), 126.5 (C10), 124.8 (C4a), 116.4 (q, J 287.5 Hz, COCF3),
114.0 (CH-5), 112.7 (CH-30), 110.9 (CH-60), 110.6 (CH-8), 58.9 (OCH3-
7), 55.8 (OCH3-50), 55.8 (OCH3-40), 55.6 (CH-1), 55.5 (OCH3-6), 52.8
(CH2-100), 40.6 (CH2-3), 37.8 (CH2-70), 36.0 (NCH3), 28.4 (CH2-4). MS
(ESIþ): m/z 483 (MHþ, 30%). HRMS (ESIþ): calcd for C24H30N2O5F3,
483.2107 (MHþ), found 483.2135.
4.9. Attempted synthesis of (RS) 1,2,3,4-tetrahydro-
1[40,50-dimethoxy-20-(2-oxoethylamino)methyphenyl]methyl-
6,7-dimethoxyisoquinoline (32)
4.12. (RS) 2-Trifluoroacetyl-1,2,3,4-tetrahydro-
1[40,50-dimethoxy-20-(methylamino)ethyl phenyl]methyl-
6,7-dimethoxyisoquinoline (37)
To a solution of 31 (71.3 mg, 0.146 mmol) in a mixture of CH3OH
(2 mL) and H2O (1 mL) was added TsOH (75.3 mg, 0.438 mmol) to
bring the pH to w3. The reaction mixture was stirred at rt for 18 h.
ESMS indicated only the unreacted 31. The reaction mixture was
A mixture of aldehyde 16 (131 mg, 0.272 mmol) and 33% aque-
ous methylamine (0.05 mL) in CH3CN (3 mL) was added NaCNBH3
(22 mg, 0.354 mmol). The mixture was treated as described above

4142
U. Mbere-Nguyen et al. / Tetrahedron 66 (2010) 4133–4143
for the synthesis of 36 to give an oil. The oil was purified by column
chromatography (CH3OH/EtOAc/NH3 (5:5:0.1)) to afford 37 as
a yellow oil (82 mg, 62% yield). Compound 37 was a 95:5 mixture of
rotamers. Rf 0.25 (CH3OH/EtOAc/NH3 (5:5:0.1)). 1H NMR of the
1H, H30), 6.58 (s, 1H, H60), 6.55 (s, 1H, H5), 6.13 (s, 1H, H8), 5.46 (dd,
1H, J 8.4, 6.3 Hz, H1), 4.01 (s, 2H, 2ꢁH2%), 3.90 (dt, 1H, J 5.4, 2.1 Hz,
H3), 3.81 (s, 6H, OCH3-7, OCH3-50), 3.82–3.78 (m, 1H, H3), 3.75 (s,
3H, OCH3-40), 3.57 (s, 3H, OCH3-6), 3.45 (dt, 1H, J 9.6, 3.6 Hz, H200),
3.29–3.19 (m, 2H, H200, H70), 3.06–2.99 (m, 1H, H70), 2.97 (s, 3H,
NCH3), 2.89–2.84 (m, 2H, 2ꢁH4), 2.61–2.53 (m, 2H, 2ꢁH100). 1H
major rotamer: d
6.65 (s, 1H, H30), 6.58 (s, 1H, H5), 6.53 (s, 1H, H60),
5.98 (s, 1H, H8), 5.48 (t, 1H, J 6.0 Hz, H1), 3.93 (dt, 1H, J 13.5, 5.0 Hz,
H3), 3.82 (s, 6H, OCH3-7, OCH3-50), 3.73 (s, 3H, OCH3-40), 3.69 (td,
1H, J 12.5, 3.0 Hz, H3), 3.52 (s, 3H, OCH3-6), 3.08 (d, 2H, J 6.0 Hz,
2ꢁH70), 2.95–2.88 (m, 1H, H4), 2.81–2.76 (m, 1H, H4), 2.64 (t, 2H, J
6.5 Hz, 2ꢁH200), 2.63–2.58 (m, 1H, H100), 2.55 (dd, 1H, J 13.5, 6.5 Hz,
H100), 2.37 (s, 3H, NCH3). 1H NMR of the minor rotamer (in part):
NMR of the minor rotamer (in part):
d
6.59 (s, 1H, H30), 6.40 (s, 1H,
H5), 5.90 (s, 1H, H8), 5.36 (dd, 1H, J 9.3, 4.8 Hz, H1), 3.67 (s, 6H,
OCH3-7, OCH3-50), 3.63 (s, 3H, OCH3-40), 3.50 (s, 3H, OCH3-6). 13C
NMR of the major rotamer: (signals for COCF3 and COCF3 were not
observed) d
116.1 (COCH2Cl), 148.1 (C40), 147.9 (C7), 147.4 (C50), 147.1
d
6.62 (s, 1H, H30), 3.78 (s, 3H, OCH3-40), 3.45 (s, 3H, OCH3-6). 13C
NMR of the major rotamer:
156.0 (q, J 36.9 Hz, COCF3), 148.5 (C40),
(C6), 129.8 (C20), 127.6 (C10), 126.3 (C4a), 124.8 (C8a), 114.0 (CH-30),
112.8 (CH-6), 110.8 (CH-5), 110.6 (CH-8), 56.9 (OCH3-7), 56.8 (OCH3-
50), 55.8 (OCH3-40), 55.7 (OCH3-6), 55.6 (CH-1), 50.4 (CH2-2%), 41.3
(CH2-200), 40.5 (CH2-3), 37.8 (CH2-70), 36.3 (NCH3), 29.7 (CH2-100),
d
147.2 (C6), 147.5 (C50), 147.4 (C7), 131.2 (C20), 127.5 (C4a), 126.0 (C10),
125.1 (C8a), 114.3 (CH-5), 116.9 (q, J 287.5 Hz, COCF3), 112.9 (CH-30),
111.2 (CH-60), 110.9 (CH-8), 56.2 (OCH3-7), 556.1 (OCH3-50), 56.1
(OCH3-40), 55.9 (CH-1), 55.8 (OCH3-6), 53.1 (CH2-200), 40.9 (CH2-3),
38.2 (CH2-70), 36.3 (NCH3), 32.4 (CH2-100), 28.7 (CH2-4). MS (ESIþ):
m/z 497.1 (MHþ, 100%). HRMS (ESIþ): calcd for C25H32F3N2O5,
497.2263 (MHþ), found 497.2237.
28.4 (CH2-4). 13C NMR of the minor rotamer (in part): 129.2 (C20),
d
127.2 (C10), 125.1 (C8a), 114.4 (CH-3), 112.6 (CH-60), 110.9 (CH-5). MS
(ESIþ): m/z 573.0 (M (35Cl)Hþ, 100%), 575.0 (M (37Cl)Hþ, 40%). HRMS
(ESIþ): calcd for C27H33N2O6F335Cl, 573.1979 (M (35Cl)Hþ), found
573.1985.
4.13. (RS) 2-Trifluoroacetyl-1,2,3,4-tetrahydro-
1[4050-dimethoxy-20-(N-(2-chloromethylcarbonyl)-N-methyl-
aminomethyl)phenyl]methyl-6,7-dimethoxyisoquinoline (38)
4.15. (RS) 3-(1,2)-Benzena-5-(1,2)-isoquinolinacyclo-1-aza-
7-oxo-heptaphane (40)
To a solution of 38 (92 mg, 0.165 mmol) in CH3OH (4 mL) and
H2O (1 mL) was added K2CO3 (112 mg, 0.825 mmol), and the mix-
ture was stirred at rt for 3 h. The CH3OH was gently removed under
pressure (without warming the water bath) to give an aqueous
residue. To the mixture was added CH2Cl2 (10 mL), followed by the
addition of triethylamine (0.3 mL). The reaction mixture was stirred
for 18 h at rt. The CH2Cl2 layer was washed with H2O (3ꢁ), brine
and then dried (K2CO3). The solvent was removed to give an oil,
which was purified by column chromatography (EtOAc) to give 40
To a solution of 36 (99 mg, 0.206 mmol) in dry CH2Cl2 (5 mL)
was added triethylamine (42 mg, 0.412 mmol, 0.06 mL) at 0 ꢀC
followed by chloroacetyl chloride (30 mg, 0.268 mmol, 0.02 mL).
The reaction mixture was brought to rt and was stirred for 18 h. The
CH2Cl2 layer was diluted and extracted with 10% aqueous NaOH,
washed with H2O (2ꢁ) and brine. The CH2Cl2 layer was dried
(K2CO3) and evaporated to give an oil. The oil was purified by col-
umn chromatography (EtOAc) to give 38 (92 mg, 80% yield) as
a clear oil. Compound 38 was a 95:5 mixture of rotamers. Rf 0.67
(41 mg, 57% yield) as a yellow oil. Rf 0.35 (EtOAc). 1H NMR
d 6.69 (s,
(EtOAc). 1H NMR of the major rotamer:
d
6.63 (s, 2H, H30, H60), 6.58
1H, H30), 6.61 (s, 1H, H5), 6.41 (s, 1H, H60), 5.96 (s, 1H, H8), 4.22 (br s,
1H, H100), 3.99 (t, 1H, J 7.0 Hz, H1), 3.88 (s, 3H, OCH3-7), 3.82 (s, 3H,
OCH3-50), 3.79 (s, 3H, OCH3-40), 3.52 (s, 3H, OCH3-6), 3.52 (br s, 6H,
OCH3-6, 2ꢁH300, H100), 3.38–3.32 (m, 1H, H70), 3.09 (s, 3H, NCH3),
2.86 (dt, 1H, J 10.5, 3.6 Hz, H3), 2.77 (dd, 1H, J 14.0, 3.0 Hz, H70), 2.56
(ddd, 1H, J 14.0, 10.5, 2.5 Hz, H3), 2.27 (br s, 2H, 2ꢁH4). 13C NMR
(s, 1H, H5), 6.25 (s, 1H, H8), 5.45 (t, J 7.3 Hz, H1), 4.48 (d, 1H, J
14.7 Hz, H100), 4.26 (d, 1H, J 14.7 Hz, H100), 4.01 (ABq, 2H, 6.6 Hz,
2ꢁH2%), 3.66 (dd, 1H, J 4.5, 1.8 Hz, H3), 3.81 (s, 6H, OCH3-7, OCH3-
50), 3.79 (s, 3H, OCH3-40), 3.78–3.74 (m, 1H, H3), 3.62 (s, 3H, OCH3-
6), 3.18 (dd, 1H, J 13.5, 8.1 Hz, H70), 2.95 (dd, 1H, J 13.5, 6.9 Hz, H70),
2.87–2.83 (m, 2H, 2ꢁH4), 2.83 (s, 3H, NCH3). 1H NMR of the minor
d
172.1 (CO), 147.6 (C40), 147.5 (C7), 147.4 (C50, C6), 130.0 (C20), 129.8
rotamer (in part):
major rotamer: (signals for COCF3 and COCF3 were not observed)
166.5 (COCH2Cl), 148.7 (C40), 147.4 (C7), 148.1 (C50), 147.5 (C6),
d
6.50 (s, 1H, H5), 6.20 (s, 1H, H8). 13C NMR of the
(C10), 129.2 (C4a), 129.0 (C8a), 115.0 (CH-8), 112.0 (CH-5), 111.0 (CH-
60), 110.4 (CH-30), 64.0 (CH-1), 62.1 (CH2-300), 56.6 (OCH3-7), 56.1
(OCH3-50, OCH3-40), 55.8 (OCH3-6), 54.5 (CH2-100), 49.7 (CH2-3), 40.7
(CH2-70), 36.2 (NCH3), 30.0 (CH2-4). MS (ESIþ): m/z 427.1 (MHþ,
100%). HRMS (ESIþ): calcd for C24H31N2O5, 427.2233 (MHþ), found
427.2227.
d
128.8 (C20), 127.4 (C10), 126.5 (C4a), 125.1 (C8a), 114.4 (CH-30), 113.4
(CH-60), 111.1 (CH-5), 110.9 (CH-8), 56.3 (OCH3-7), 56.1 (OCH3-50,
OCH3-40), 56.0 (OCH3-6), 55.4 (CH-1), 48.3 (CH2-100), 41.9 (CH2-2%),
40.8 (CH2-3), 37.7 (CH2-70), 34.6 (NCH3), 28.8 (CH2-4). 13C NMR of
the minor rotamer (in part):
d
114.9 (CH-3), 113.6 (CH-60), 111.3 (CH-
4.16. (RS) 4-(1,2)-Benzena-6-(1,2)-isoquinolinacyclo-1-aza-
8-oxo-octaphane (41)
5), 50.6 (CH2-100), 42.7 (CH2-2%), 41.1 (CH2-3), 38.0 (CH2-70), 28.5
(CH2-4). MS (ESIþ): m/z 581.0 (M (35Cl)þNaþ, 10%), 583.0 (M
(
37Cl)þNaþ, 4%). HRMS (ESIþ): calcd for C26H30F3N2NaO365Cl,
The synthesis of the title compound 41 was carried out using the
conditions described above for the synthesis of 40 starting with
compound 39 (63 mg, 0.108 mmol), CH3OH (3 mL), H2O (1 mL) and
K2CO3 (112 mg, 0.825 mmol). This was followed by intramolecular
cyclisation using CH2Cl2 (10 mL) and triethylamine (0.3 mL) to give
an oil, which was purified by column chromatography (EtOAc) to
give 41 (31 mg, 46% yield) as a yellow oil. Rf 0.48 (EtOAc). 1H NMR:
581.1642 (M (35Cl)þNaþ), found 581.1641.
4.14. (RS) 2-Trifluoroacetyl-1,2,3,4-tetrahydro-1[40,50-
dimethoxy-20-(N-(2-chloromethyl carbonyl)-N-ethyl-
aminomethyl)phenyl]methyl-6,7-dimethoxyisoquinoline (39)
To a solution of 38 (73 mg, 0.152 mmol) in dry CH2Cl2 (5 mL) was
added triethylamine (31 mg, 0.304 mmol, 0.041 mL) at 0 ꢀC, fol-
lowed by chloroacetyl chloride (22 mg, 0.198 mmol, 0.013 mL). The
reaction mixture was brought to rt and stirred for 18 h. The mixture
was worked up as described above in the synthesis of 38 to give an
oil. The oil was purified by column chromatography (EtOAc) to give
39 (63 mg, 72%) as a clear oil. Compound 39 was a 95:5 mixture of
d
6.71 (s, 1H, H30), 6.60 (s, 1H, H60), 6.53 (s, 1H, H5), 6.36 (s, 1H, H8),
4.06–4.01 (m, 1H, H1), 3.90 (s, 3H, OCH3-7), 3.86 (s, 3H, OCH3-50),
3.85 (s, 3H, OCH3-40), 3.70 (s, 3H, OCH3-6), 3.47 (br s, 2H, 2ꢁH400),
3.29–3.27 (m, 1H, H70), 3.12–3.08 (m, 2H, 2ꢁH200), 3.05 (s, 3H,
NCH3), 3.00–2.93 (m, 1H, H3), 2.89–2.81 (m, 1H, H70), 2.77–2.64 (m,
3H, 2ꢁH100, H3), 2.22–2.16 (m, 2H, 2ꢁH4). 13C NMR:
d 171.4 (CO),
148.5 (C40), 147.9 (C7), 147.5 (C50), 147.1 (C6), 131.7 (C20), 131.6 (C10),
128.6 (C4a), 127.9 (C8a), 114.7 (CH-8), 113.4 (CH-60), 111.4 (CH-5),
rotamers. Rf 0.60 (EtOAc). 1H NMR of the major rotamer:
d 6.61 (s,

U. Mbere-Nguyen et al. / Tetrahedron 66 (2010) 4133–4143
4143
110.6 (CH-30), 65.1 (CH-1), 60.8 (CH2-400), 56.4 (OCH3-7), 56.3
References and notes
(OCH3-50), 56.2 (OCH3-40), 56.1 (OCH3-6), 53.0 (CH2-200), 52.7 (CH2-
3, CH2-70), 35.3 (NCH3), 33.8 (CH2-100, CH2-4). MS (ESIþ): m/z 441.1
(MHþ, 100%). HRMS (ESIþ): calcd for C25H33N2O5, 441.2389 (MHþ),
found 441.2380.
1. Pienky, S.; Brandt, W.; Schmidt, J.; Kramell, R.; Ziegler, J. Plant J. 2009, 60, 56–67.
2. Cui, W.; Iwasa, K.; Tokuda, H.; Kashihara, A.; Mitani, Y.; Hasegawa, T.; Nish-
iyama, Y.; Moriyasu, M.; Nishino, H.; Hanaoka, M.; Mukai, C.; Takeda, K. Phy-
tochemistry 2006, 67, 70–79.
3. Buchana, M.; Davis, R.; Duffy, S.; Avery, V.; Quinn, R. J. Nat. Prod. 2009, 72, 1541–
1543.
4. Kashiwada, Y.; Aoshima, A.; Ikeshiro, Y.; Chen, Y.; Furukawa, H.; Itoigawa, M.;
Fujioka, T.; Mihashi, K.; Cosentino, L. M.; Morris-Natschke, S. L.; Lee, K. Bioorg.
Med. Chem. 2005, 13, 443–448.
4.17. (RS)-3-(1,2)-Benzena-5-(1,2)-isoquinolinacyclo-1-aza-
heptaphane (42)
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2441–2467.
To a slurry of LiAlH4 (38 mg, 1.02 mmol) in dry THF (1 mL) was
added a solution of the amide 41 (21 mg, 0.048 mmol) in dry THF
(1 mL) under a N2 atmosphere at 0 ꢀC. The resulting mixture as
brought to rt and stirred for 18 h. H2O (0.2 mL), 1 M aqueous NaOH
(0.2 mL) and H2O (0.5 mL) were added subsequently and the re-
action mixture was stirred for 1 h. The solid was filtered and
washed with EtOAc. The solution was dried (K2CO3) and evaporated
to give 42 (16 mg, 81%) as a clear oil without the need for further
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purification. Rf 0.15 (CH3OH/EtOAc/NH3 (5:5:0.1)). 1H NMR
d 6.84 (s,
1H, H30), 6.64 (s, 1H, H60), 6.58 (s, 2H, H5, H8), 4.50 (d, 1H, J 12.5 Hz,
H100), 4.22 (br s, 1H, H1), 3.89 (s, 3H, OCH3-7), 3.86 (s, 6H, OCH3-50,
OCH3-40), 3.83 (s, 3H, OCH3-6), 3.42 (d, 1H, J 12.5 Hz, H100), 3.40 (dd,
1H, J 14.0, 7.0 Hz, H70), 3.15–3.09 (m, 2H, 2ꢁH300), 2.81–2.72 (m, 3H,
H3, 2ꢁH200), 2.68 (dd, 1H, J 14.0, 2.0 Hz, H70), 2.59–2.51 (m, 3H, H3,
12. McQuade, R. D.; Duffy, R. A.; Coffin, V. L.; Chipkin, R. E.; Barnett, A. J. Pharmacol.
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2ꢁH4), 2.52 (s, 3H, NCH3). 13C NMR
d
147.6 (C40), 147.4 (C7), 147.3
(C50), 147.1 (C6), 134.0 (C20), 132.2 (C10), 131.5 (C4a), 127.5 (C8a),
114.4 (CH-30), 113.8 (CH-6), 111.2 (CH-5), 110.7 (CH-8), 61.5 (CH-1),
58.1 (CH2-100), 56.2 (OCH3-7), 56.0 (OCH3-50), 56.0 (OCH3-40), 55.8
(OCH3-6), 52.0 (CH2-200), 51.9 (CH2-3), 48.0 (CH2-70), 42.6 (NCH3),
29.7 (CH2-300), 27.1 (CH2-4). MS (ESIþ): m/z 413.2 (MHþ, 100%).
20. CNS receptors tested:
m (h) (MOP); A1 (h); A2A (h); A3; a1; a2; b1; AT1 (h); BZD
(central); B2 (h); CCKA (h); D1 (h); D2S (h); ETA (h); GABA (non-selective); GAL2
(h); CXCR2 (h); CCR1; H1 (h); H2 (h); MC4 (h); ML1; M1 (h); M2 (h); M3 (h); NK2
(h); NK3 (h); NT1 (h); d2 (h); k(KOP); ORL1 (h) (NOP); 5-HT1A (h); 5-HT1B; 5-
HT2A (h); 5-HT3 (h); 5-HT5A (h); 5-HT6 (h); 5-HT7 (h); sst (non-selective); VIP1
(h); V1a (h); Ca2þ channel; Kþ channel; Naþ channel; SKþ Ca channel; Clꢂ
channel; NE transporter; DA transporter.
Acknowledgements
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We thank Johnson and Johnson Research Pty. Limited, Sydney
and the University of Wollongong for supporting this research and
Dr. Wayne Gerlach for encouragement and support.