Palladium-catalyzed preparation of N-alkylated tacrine and huprine compounds

Article abstract of DOI:10.1002/ejoc.201001158

An efficient preparation of N-alkylated tacrine and huprine compounds using palladium-catalyzed amination was developed. Cross-coupling reactions with chloroquinolines and primary amines were achieved in good to excellent yields (50-95%) following microwa

Full text of DOI:10.1002/ejoc.201001158

FULL PAPER
DOI: 10.1002/ejoc.201001158
Palladium-Catalyzed Preparation of N-Alkylated Tacrine and Huprine
Compounds
Cyril Ronco,[a,b] Ludovic Jean,[a,b] Hakim Outaabout,[a,b] and Pierre-Yves Renard*[a,b,c]
Keywords: Amination / Palladium / Microwave chemistry / Nitrogen heterocycles / Cross-coupling
An efficient preparation of N-alkylated tacrine and huprine
compounds using palladium-catalyzed amination was devel-
oped. Cross-coupling reactions with chloroquinolines and
primary amines were achieved in good to excellent yields
(50–95%) following microwave irradiation. This method was
found particularly useful for functionalized substrates which
undergo degradation under SNAr conditions and for the syn-
thesis of tacrine- and huprine-based heterodimeric inhibi-
tors, examples of which are described.
Introduction
Tacrine-[1] and huprine-like[2,3] aminoquinolines 3 and 4
have interesting pharmacological properties because they
efficiently inhibit acetylcholinesterase (AChE) in a revers-
ible fashion. Consequently they are promising candidates
for use in the palliative treatment of Alzheimer’s disease
(AD). One strategy is to design dimeric inhibitors that take
advantage of the structure of AChE with its two active sites;
such compounds might be more potent and more selective
than others lacking a dimeric structure. Prevention of AD
by decreasing β-amyloid peptide deposition might therefore
be viable.[4] These dimeric inhibitors are usually made up
of at least one aminoquinoline core and can be homo- or
heterodimers of tacrine or huprine, where the two active
units are linked by a suitable spacer (Figure 1).
The preparation of such molecules is currently based on
SNAr reactions between chloroquinoline 1 or 2 and a pri-
mary amine. Alternatively, N-alkylation reactions of tacrine
or huprine with appropriate halogenated linkers has also
been employed to produce AChE inhibitors.[5] SNAr reac-
tions proceed with radically different efficiencies, whereas
N-alkylation reactions often afford the desired products in
only modest yields. Furthermore these reactions, which re-
quire high temperatures (refluxing phenol or 1-pentanol for
SNAr reactions) and long reaction times or harsh basic con-
ditions (KOH in DMSO for multiple days for N-alkylation
Figure 1. Structures of tacrine- and huprine-like aminoquinolines
3 and 4, homo- and heterodimeric inhibitors.
reactions), do not permit the use of substrates containing
functional groups (e.g., esters).
Only one example of palladium-catalyzed amination[6]
with 9-chlorotetrahydroacridine 1b has been reported in the
literature with low yield (40%)[7] although many reactions
of 2- or 4-chloroquinoline with aliphatic amines or anilines
have been described previously.[8] The aim of the present
study was to develop an efficient, general, and structurally
tolerant reaction leading to N-alkylated aminoquinolines 3
and 4.
[a] Equipe de Chimie Bio-Organique, COBRA-CNRS UMR
6014 & FR 3038,
Rue Lucien Tesnière, 76131 Mont-Saint-Aignan, France
Fax: +33-2-35522971
E-mail: pierre-yves.renard@univ-rouen.fr
[b] Université de Rouen, Place Emile Blondel,
76821 Mont-Saint-Aignan, France
Results and Discussion
[c] Institut Universitaire de France,
103 boulevard Saint Michel, 75005 Paris, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001158.
Palladium-catalyzed amine couplings are highly sub-
strate-dependent. To optimize conditions for the prepara-
302
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Palladium-Catalyzed Synthesis of Tacrine and Huprine Congeners
tion of N-alkylated tacrine and huprine compounds, the
We next investigated the influence of solvent on the am-
amination of chloroquinoline 1a/2a or 1c/2c with n-hex- ination reaction. The three most commonly used solvents
ylamine was initially investigated to determine the effects of in Pd-catalyzed reactions (toluene, 1,4-dioxane, and 1,2-di-
various ligands, palladium sources, solvents, and bases.
methoxyethane) were tested. Significant solvent effects were
Catalyst effects, with a special emphasis on catalyst li- noted; the use of 1,4-dioxane correlated to the highest
gands, were the focus of initial efforts. In a preliminary yields, whereas yields as low as 6% were observed for reac-
study, the reaction conditions were arbitrarily set to chloro- tions run in toluene (Table 2).
quinoline 1a/2a (1 equiv.), n-hexylamine (1.5 equiv.),
Table 2. Solvent effects on the Pd-catalyzed reaction of chloroquin-
oline 1a/2a with n-hexylamine.
Cs2CO3 (2.5 equiv.), Pd2(dba)3 (4 mol-%), and mono- or di-
phosphane ligand (8 mol-%) heated at 100 °C for 24 h in
Entry[a]
Substrate
Solvent
Yield [%][b]
1,4-dioxane. Six different ligands were tested for the amin-
ation reaction (Table 1). The best result was obtained by
using the diphosphane (Ϯ)-BINAP, which gave 3a and 4a
in 45 and 57% yield, respectively. The use of other diphos-
phane ligands (Xantphos and DPEphos) gave lower yields.
Although efficient in a large number of Pd-catalyzed amin-
ation reactions,[9] the use of biphenyl ligands for this appli-
cation clearly impaired the production of 3a and 4a (only
22%) relative to other ligands.
1
2
3
4
5
1a
2a
1a
2a
1a
toluene
toluene
1,4-dioxane
1,4-dioxane
DME
6
14
45
57
12
[a] Reagents and conditions: 1a/2a (1 equiv.), n-hexylamine
(1.5 equiv.), Pd2(dba)3 (4 mol-%), (Ϯ)-BINAP (8 mol-%), Cs2CO3
(2.5 equiv.), 100 °C, 24 h. [b] Isolated yield.
The influence of base on the amination of chloroquin-
oline 1c/2c with n-hexylamine was then evaluated, and the
results are reported in Table 3. Among the bases evaluated,
Cs2CO3 proved to be ideal. Using Cs2CO3, the amination
was found to proceed efficiently, affording desired products
3c and 4c in 81 and 73% yield, respectively. A similar result
was obtained by using K3PO4 as base, whereas tBuONa
proved to be completely unsuitable leading to a yield of
only 10% for 1c.
Table 1. Ligand effect on Pd-catalyzed amination of chloroquin-
oline 1a/2a with n-hexylamine.
Table 3. Base effect on the Pd-catalyzed reaction of chloroquinoline
1c/2c with n-hexylamine.
Entry[a]
Substrate
Base
Yield [%][b]
1
2
3
4
1c
1c
1c
2c
tBuONa
K3PO4
Cs2CO3
Cs2CO3
10
73
81
73
Entry[a]
Substrate
Ligand[a]
Yield[b]
1
2
3
4
5
6
7
8
9
1a
2a
1a
2a
1a
2a
1a
1a
1a
(Ϯ)-BINAP
(Ϯ)-BINAP
Xantphos
Xantphos
Davephos
Davephos
Johnphos
45
57
31
14
22
19
21
17
16
[a] Reagents and conditions: 1c/2c (1 equiv.), n-hexylamine
(1.5 equiv.), Pd2(dba)3 (4 mol-%), (Ϯ)-BINAP (8 mol-%), base
(2.5 equiv.), 1.4-dioxane, 100 °C, 24 h. [b] Isolated yield.
Finally, to complete this reaction optimization process,
we investigated palladium source effects. As reported in
Table 4, two sources of palladium were tested and both af-
forded some amination product, although the highest yield
was obtained by using Pd2(dba)3 (4 mol-%). We noticed
that the use of a lower catalyst loading (2 mol-%) resulted
in a noticeable decrease in coupling efficiency.
CyJohnphos
DPEphos
Table 4. Pd source effect on the Pd-catalyzed reaction of chloro-
quinoline 1c with n-hexylamine.
Entry[a]
Pd Source
Yield [%][b]
1
2
Pd2(dba)3
Pd(OAc)2
81
61
[a] Reagents and conditions: 1c (1 equiv.), n-hexylamine
(1.5 equiv.), Pd source (8 mol-%), (Ϯ)-BINAP (8 mol-%), Cs2CO3
(2.5 equiv.), 1.4-dioxane, 100 °C, 24 h. [b] Isolated yield.
From the screening of reaction parameters we concluded
that the ideal reaction conditions involve chloroquinoline
(1 equiv.), amine (1.5 equiv.), BINAP (8 mol-%), Pd2(dba)3
[a] Reagents and conditions: 1a/2a (1 equiv.), n-hexylamine
(1.5 equiv.), Pd2(dba)3 (4 mol-%), ligand (8 mol-%), Cs2CO3
(2.5 equiv.), 1.4-dioxane, 100 °C, 24 h. [b] Isolated yield.
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C. Ronco, L. Jean, H. Outaabout, P.-Y. Renard
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(4 mol-%), and Cs2CO3 (2.5 equiv.) in 1,4-dioxane heated methanocycloocta[b]quinolines 2a–e to explore the reaction
to 100 °C for 24 h. However, the application of these condi- scope in term of substrate (Table 5). Using the optimized
tions proved to be far from ideal and increasing the reaction conditions, most chloroquinolines could be coupled ef-
time from 24 to 68 h for compound 3a led only to a modest ficiently with n-hexylamine (Table 5 , Entries 1, 3, 4, 8, and
yield improvement (62% instead of 45%) with residual 9). However, nonactivated 9-chlorotetrahydroacridine 1b
starting material remaining. To achieve total substrate con- and 12-chlorotetrahydro-7,11-methanocycloocta[b]quinol-
version while also reducing reaction times, we investigated
the use of microwave irradiation.[10]
In determining the correlation of temperature to irradia-
tion time we again focused on the amination of 1a with n-
hexylamine. This reaction was carried out at three tempera-
tures (100, 120, and 150 °C) using a CEM Discover appara-
tus (Figure 2) set to 300 W. At 100 °C (Figure 2, Graph A),
the yield of 3a was very low. After a 120 min irradiation,
60% of 1a remained, and only 35% of desired product 3a
was obtained.
Table 5. Cross-coupling of 1a–e and 2a–e with n-hexylamine under
microwave irradiation.
Notably, we observed the formation of compound 3b
arising from the reduction of the second chlorine atom and
product 5 arising from the reaction with a second equiva-
lent of n-hexylamine; the N,N-diarylated product was never
observed. All products of this reaction were isolated and
1
fully characterized by H and 13C NMR spectroscopy and
mass spectrometry. Increasing the reaction temperature
(Figure 2, Graph B) improved the yield of 3a to 60% after
a 2 h reaction time although 18% of the starting material
remained. Heating to 150 °C (Figure 2, Graph C) with a
30 min irradiation afforded complete conversion and 3a was
produced in 65% yield. However, the prolonged reaction
time dramatically increased the amount of 3b formed. In
light of these results, the irradiation conditions were fixed at
150 °C for 30 min. Because some direct amination reactions
using microwave activation without transition-metal cata-
lyst have been reported in the literature,[11] the reaction with
1a and n-hexylamine was carried out in the absence of a Pd
catalyst. Importantly, the absence of Pd precluded pro-
duction of 3a, thus confirming the necessity of the catalyst.
We subsequently applied the established microwave con-
ditions to differently substituted 9-chlorotetrahydroacri-
Entry
ArX
Yield [%][a]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
60
68[b]
77
83
38
50[c,d]
95[b]
94
59
10
31[e]
[a] Isolated yield after flash chromatography. [b] The reaction was
carried out for 2 h. [c] The reaction was carried out for 5 h at
120 °C (300 W). [d] Product 2a was obtained in 90% yield by using
conventional heating (100 °C, 48 h). [e] Isolated along with 2e
dines 1a–e and the corresponding 12-chlorotetrahydro-7,11- (30%).
Figure 2. Time and temperature optimization of microwave irradiation for the amination of 1a with n-hexylamine. Proportion of products
in reaction mixture was determined by HPLC every 10 min for 1 h with additional measurements being made at 90n and 120 min: 1a
(–––); 3a (·····); 3b (–·–·–) and 5 (-----). Reaction temperatures: Graph A: 100 °C, Graph B: 120 °C, Graph C: 150 °C.
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Palladium-Catalyzed Synthesis of Tacrine and Huprine Congeners
ine 2b required longer reaction times to furnish compounds
Finally, we explored the selectivity of arylation between
3b and 4b in 68 and 95% yield, respectively. Surprisingly, primary and secondary amines by using diamine 8 as the
low selectivity of amination was observed for the coupling substrate. It is known that Pd-catalyzed amination of di-
reactions of n-hexylamine with trihalogenated compounds amines[12] or acyclic polyamines[8a,13] takes place preferen-
1e and 2e. Under the optimized reaction conditions, desired tially on the primary amino group. Accordingly, we found
products 3e and 4e were obtained in 38 and 31% yield amination of 1b to proceed with the primary amino group
(along with 30% of 2e), respectively, along with significant of 8 but not the secondary amine. Coupled product 9 re-
amounts of 6 (24%) or 7 (29%), whose structures were un- sulting from primary amine arylation was obtained in 62%
ambiguously confirmed by 1D and 2D NMR spectroscopic yield (Scheme 1); no trace of 10 was evident.
analysis (Figure 3). These results show that a large variety
of N-alkylated tacrine and huprine compounds are attain-
able in good to excellent yields by using the reported cou-
pling conditions.
Figure 3. Side products arising from the nonselective reaction with
1e and 2e.
Scheme 1. Amination of 1b with N-methylpropanediamine 8.
With the goal to efficiently prepare heterodimeric AChE
inhibitors and their precursors, we were interested in ex-
As a validation example, the coupling reaction between
n-hexylamine and 12-chloroquinoline 2f – an interesting
compound for which we recently reported the synthe-
sis[3b,14] – was performed by using both SNAr and Pd-cata-
lyzed amination reactions (Scheme 2). Although the SNAr
reaction led, as expected, to only substrate degradation, our
microwave-assisted Pd-catalyzed amination conditions af-
forded 4f in 39% yield (not optimized).
ploring the scope of the amination reaction with various
amines, specifically with functionalizable primary amines
(Table 6). Towards this end, amination reactions were car-
ried out by using either microwave irradiation or conven-
tional heating, and the best results are shown below. For
any single combination of 1a and amine, one of the two
reaction conditions was found to lead selectively to the N-
alkylated tacrine in yields ranging from 55 to 71%.
Table 6. Substrate scope for the coupling with 1a under microwave
activation or conventional heating.
Scheme 2. Conditions and reagents for the SNAr reaction: 2f
(1 equiv.), n-hexylamine (1.2 equiv.), phenol, NaI (0.25 equiv.),
160 °C, 3 h. Conditions and reagents for the Pd-catalyzed amin-
ation reaction: 2f (1 equiv.), n-hexylamine (1.5 equiv.), Cs2CO3
(2.5 equiv.), Pd2(dba)3 (4 mol-%), (Ϯ)-BINAP (8 mol-%), 1,4-diox-
ane, 150 °C (300 W), 30 min.
Finally, in order to illustrate the efficiency of this new
method, two heterodimeric AChE inhibitors 13 [IC50 (hu-
man AChE) = 0.34 nm][5c] and 14 were prepared in two steps
as depicted in Scheme 3. Pd-catalyzed arylations of 1,7-di-
aminoheptane (11) were realized consecutively with 1b and
2a/2b to afford desired inhibitors 13 and 14 in an overall
yield of 20 (after preparative HPLC) and 52%, respectively.
[a] Isolated yield after flash chromatography. [b] Product 3g was
obtained in 56% yield under conditions B. [c] Product 3i was ob-
tained in 39% yield under conditions B.
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305

C. Ronco, L. Jean, H. Outaabout, P.-Y. Renard
FULL PAPER
waveTM Synthesis System apparatus, Model Discover. The machine
consists of a continuous focused microwave power delivery system
with operator selectable power output from 0 to 300 W. All the
reactions were performed in special glass vessels under an atmo-
sphere of argon. Reaction mixture temperatures were measured
during microwave heating with an IR surface sensor located in the
base of the Discover. The chromatographic system used for the
preparative HPLC purification step involved reverse-phase HPLC
(C18, Thermo Hypersil GOLD, 5μ, 21.2ϫ250 mm) with CH3CN
and 0.1% trifluoroacetic acid (TFA 0.1%, pH 2.0) as the eluents
[100% H2O (TFA 0.1%) (5 min), then linear gradient from 0 to
100% (50 min) of CH3CN] at a flow rate of 20.0 mL/min. UV/Vis
detection was achieved at 264 nm.
General Procedure for the Palladium-Catalyzed Amination Reaction
under Conventional Heating: A Schlenk tube containing a stir bar
was charged with chloroquinoline (125 μmol, 1 equiv.), Pd2-
(dba)3 (4.6 mg, 4 mol-%), (Ϯ)-BINAP (6.2 mg, 8 mol-%), and
Cs2CO3 (102 mg, 313 μmol, 2.5 equiv.). The vessel was sealed with
a septum and purged with argon. Degassed 1,4-dioxane (0.5 mL)
and distilled amine (188 μmol, 1.5 equiv.) were then introduced
through the septum and the resulting mixture was heated to 100 °C
for 24 h unless otherwise stated. After cooling, the reaction mixture
was concentrated and purified by flash chromatography.
Scheme 3. Synthesis of heterodimeric AChE inhibitors 13 and 14.
Conclusions
General Procedure for the Palladium-Catalyzed Amination Reaction
under Microwave Irradiation: A 10-mL microwave tube containing
a stir bar was charged with chloroquinoline (125 μmol, 1 equiv.),
Pd2(dba)3 (4.6 mg, 4 mol-%), (Ϯ)-BINAP (6.2 mg, 8 mol-%), and
Cs2CO3 (102 mg, 313 μmol, 2.5 equiv.). The vessel was sealed with
a microwave septum and purged with argon. Degassed 1,4-dioxane
(0.5 mL) and distilled amine (188 μmol, 1.5 equiv.) were introduced
through the septum, and the resulting mixture was heated by using
In conclusion, we have developed an efficient method of
preparing N-alkylated tacrine and huprine compounds by
using palladium-catalyzed amination of chloroquinolines 1
and 2. A large variety of 9-chlorotetrahydroacridines 1a–e
and 12-chlorotetrahydro-7,11-methanocycloocta[b]quinol-
ines 2a–f can be coupled with primary amines in good to
excellent yields. Finally, this reaction represents an excellent
alternative method to rapidly access quinoline-based dual– a CEM Discover apparatus to 150 °C (300 W) for 30 min unless
otherwise stated. After cooling, the reaction mixture was concen-
trated and purified by flash chromatography.
site binding AChE inhibitors.
6-Chloro-N-hexyl-1,2,3,4-tetrahydroacridin-9-amine (3a): The gene-
ral procedure for the palladium-catalyzed amination reaction under
microwave irradiation was followed using 1a (63 mg, 0.25 mmol)
and hexylamine (50 μL, 375 μmol). The reaction mixture was
heated to 150 °C (300 W) for 30 min. Purification by flash
chromatography (cyclohexane/EtOAc/Et3N, 10:0:0 to 8:2:0.1) af-
Experimental Section
General: Column chromatography was performed on silica gel (40–
63 μm) from SdS. Thin-layer chromatography (TLC) was carried
out on Merck DC Kieselgel 60 F-254 aluminum sheets. Com-
pounds were visualized by one of the two following methods: (1) il-
lumination with a short-wavelength UV lamp (λ = 254 nm) or
(2) staining with a 3.5% (w/v) phosphomolybdic acid solution in
absolute ethanol. All solvents were dried following standard pro-
cedures (CH2Cl2, 1,2-dichloroethane, and CH3CN: distillation over
P2O5; DMF and DMSO: distillation over BaO under reduced pres-
sure; THF, toluene, and Et2O: distillation over Na/benzophenone).
Triethylamine (TEA) and pyridine were distilled from CaH2 and
stored over BaO or KOH. Melting points were recorded with a
LEICA VMHB Kofler system at atmospheric pressure. Micro-
analyses were carried out with a Carlo–Erba 1106. Infrared spectra
were recorded as KBr pellets using a Perkin–Elmer FTIR Paragon
500 spectrometer. 1H and 13C NMR spectra were recorded with
a Bruker DPX 300 spectrometer (Bruker, Wissembourg, France).
Chemical shifts are expressed in parts per million (ppm) using
1
forded 3a as a white solid (47.0 mg, 60%). Rf (EtOAc) = 0.33. H
NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H, 16-H),
1.24–1.38 (m, 6 H, 13-H, 14-H, 15-H), 1.59–1.69 (m, 2 H, 12-H),
1.87–1.93 (m, 4 H, 7-H, 8-H), 2.62–2.67 (m, 2 H, 9-H), 2.98–3.03
(m, 2 H, 6-H), 3.45 (t, J = 7.0 Hz, 2 H, 11-H), 3.80 (br. s, 1 H,
NH), 7.25 (dd, J = 8.9, 2.1 Hz, 1 H, 2-H), 7.88 (d, J = 2.1 Hz, 1
H, 1-H), 7.89 (d, J = 8.9 Hz, 1 H, 4-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.1 (C-16), 22.7 (2 C, C-7, C-8), 23.0 (C-15), 24.6 (C-
9), 26.7 (C-13), 31.6 (C-14), 31.9 (C-12), 34.0 (C-6), 49.7 (C-11),
115.6 (C-10a), 118.4 (C-9a), 124.3 (C-2), 124.8 (C-4), 127.4 (C-1),
134.2 (C-3), 148.0 (C-4a), 151.1 (C-10), 159.4 (C-5a) ppm. MS
(ESI+): m/z (%) = 319 (31), 317 (100) [M + H]+. HRMS (ESI+):
calcd. for C19H26N2Cl 317.1802; found 317.1795.
N-Hexyl-1,2,3,4-tetrahydroacridin-9-amine (3b): The general pro-
cedure for the palladium-catalyzed amination reaction under mi-
crowave irradiation was followed using 1b (63 mg, 0.25 mmol) and
hexylamine (50 μL, 375 μmol). The reaction mixture was heated
to 150 °C (300 W) for 2 h. Purification by flash chromatography
(cyclohexane/EtOAc/Et3N, 10:0:0 to 8:2:0.2) afforded 3b as a yel-
CDCl3 (δH = 7.26 ppm, δC = 77.16 ppm), [D6]DMSO (δH
2.50 ppm, δC = 39.52 ppm), or CD3OD (δH = 3.31 ppm, δC
=
=
49.00 ppm) as internal standards. H and 13C NMR spectra of all
compounds were assigned through 2D-NMR experiments (COSY,
HSQC, HMBC). Mass spectra were obtained with a Finnigan LCQ
Advantage MAX (ion trap) apparatus equipped with an electro-
1
1
low solid (48 mg, 68%). Rf (EtOAc/MeOH, 9:1) = 0.17. H NMR
spray source. All analyses were performed in the positive mode. (300 MHz, CDCl3): δ = 0.88 (t, J = 6.4 Hz, 3 H, 16-H), 1.24–1.42
Microwave reactions were performed using a CEM Focused Micro- (m, 6 H, 13-H, 14-H, 15-H), 1.59–1.69 (m, 2 H, 12-H), 1.87–1.93
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Palladium-Catalyzed Synthesis of Tacrine and Huprine Congeners
(m, 4 H, 7-H, 8-H), 2.65–2.71 (m, 2 H, 9-H), 3.05–3.11 (m, 2 H, 2 H, 9-H), 3.08–3.13 (m, 2 H, 6-H), 3.43 (t, J = 7.4 Hz, 2 H, 11-
6-H), 3.52 (t, J = 7.4 Hz, 2 H, 11-H), 4.49 (br. s, 1 H, NH), 7.34
H), 3.88 (br. s, 1 H, NH), 7.65 (d, J = 2.3 Hz, 1 H, 3-H), 7.87 (d,
(t, J = 8.1 Hz, 1 H, 2-H), 7.55 (t, J = 8.1 Hz, 1 H, 3-H), 7.96 (d, J J = 2.3 Hz, 1 H, 1-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1
= 8.1 Hz, 2 H, 1-H, 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
14.1 (C-16), 22.7 (2 C, C-7, C-8), 23.1 (C-15), 24.8 (C-9), 26.7 (C-
13), 31.7 (C-14), 31.9 (C-12), 33.4 (C-6), 49.6 (C-11), 115.3 (C-10a),
119.8 (C-9a), 123.1 (C-1), 123.8 (C-2), 127.9 (C-4), 128.8 (C-3),
146.6 (C-4a), 151.5 (C-10), 157.8 (C-5a) ppm. MS (ESI+): m/z (%)
= 284 (25), 283 (100) [M + H]+. HRMS (ESI+):calcd. for C19H27N2
283.2174; found 283.2183.
(C-16), 22.7 (2 C, C-7, C-8), 23.0 (C-15), 24.8 (C-9), 26.7 (C-13),
31.7 (C-14), 31.9 (C-12), 34.6 (C-6), 50.0 (C-11), 117.9 (C-10a),
121.7 (C-1), 121.9 (C-9a), 128.0 (C-4), 128.9 (C-3), 134.0 (C-2),
142.7 (C-4a), 150.6 (C-10), 160.0 (C-5a) ppm. MS (ESI+): m/z (%)
= 353 (66), 351 (100) [M + H]+. HRMS (ESI+): calcd. for
C19H25Cl2N2 351.1395; found 351.1387.
N-Benzyl-6-chloro-1,2,3,4-tetrahydroacridin-9-amine (3f): The gene-
ral procedure for the palladium-catalyzed amination reaction under
microwave irradiation was followed using 1a (32 mg, 125 μmol) and
benzylamine (20.5 μL, 188 μmol). The reaction mixture was heated
to 150 °C (300 W) for 30 min. Purification by flash chromatog-
raphy (cyclohexane/EtOAc/Et3N, 10:0:0 to 8:2:0.2) afforded 3f as
pale-yellow solid (22 mg, 55%). Rf (EtOAc) = 0.37. 1H NMR
(300 MHz, CDCl3): δ = 1.84–1.90 (m, 4 H, 7-H, 8-H), 2.58 (t, J =
6.2 Hz, 2 H, 9-H), 3.03 (t, J = 6.2 Hz, 2 H, 6-H), 4.06 (br. s, 1 H,
NH), 4.61 (s, 2 H, 11-H), 7.26 (dd, J = 8.9, 2.1 Hz, 1 H, 2-H),
7.28–7.37 (m, 5 H, 13-H, 14-H, 15-H, 16-H, 17-H), 7.90 (d, J =
8.9 Hz, 1 H, 1-H), 7.92 (d, J = 2.1 Hz, 1 H, 4-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 22.7 (C-7 or C-8), 22.9 (C-7 or C-8), 24.7
(C-9), 34.0 (C-6), 53.7 (C-11), 116.8 (C-10a), 118.6 (C-9a), 124.6
(C-1), 124.8 (C-2), 127.7 (3 C, C-13, C-15, C-17), 128.0 (C-4), 129.1
(2 C, C-14, C-16), 134.3 (C-3), 139.5 (C-12), 148.1 (C-10), 150.7
(C-4a), 159.8 (C-5a) ppm. MS (ESI+): m/z (%) = 325 (31), 323
(100) [M + H]+. HRMS (ESI+): calcd. for C20H20N2Cl 323.1318;
found 323.1315.
N-Hexyl-7-nitro-1,2,3,4-tetrahydroacridin-9-amine (3c): The general
procedure for the palladium-catalyzed amination reaction under
microwave irradiation was followed using 1c (65.7 mg, 0.25 mmol)
and hexylamine (50 μL, 375 μmol). The reaction mixture was
heated to 150 °C (300 W) for 30 min. Purification by flash
chromatography (cyclohexane/EtOAc/Et3N, 10:0:0 to 5:5:0.2) af-
1
forded 3c as a yellow solid (63 mg, 77%). Rf (EtOAc) = 0.53. H
NMR (300 MHz, CDCl3): δ = 0.86 (t, J = 7.0 Hz, 3 H, 16-H),
1.26–1.32 (m, 4 H, 13-H, 14-H), 1.38–1.44 (m, 2 H, 15-H), 1.70–
1.74 (m, 2 H, 12-H), 1.89–1.92 (m, 4 H, 7-H, 8-H), 2.58–2.61 (m,
2 H, 9-H), 2.98–3.03 (m, 2 H, 6-H), 3.63 (dt, J = 7.0, 5.8 Hz, 2 H,
11-H), 4.28 (br. s, 1 H, NH), 7.83 (d, J = 9.3 Hz, 1 H, 4-H), 8.21
(dd, J = 9.3, 2.5 Hz, 1 H, 3-H), 8.99 (d, J = 2.5 Hz, 1 H, 1-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.0 (C-16), 22.5 (C-7 or C-8 or
C-13), 22.6 (C-7 or C-8 or C-13), 22.7 (C-7 or C-8 or C-13), 24.4
(C-9), 26.5 (C-15), 31.5 (C-14), 31.8 (C-12), 34.4 (C-6), 49.7 (C-11),
115.4 (C-9a), 117.5 (C-10a), 121.7 (2 C, C-1, C-3), 130.1 (C-4),
142.4 (C-4a), 150.3 (C-2), 152.2 (C-10), 161.9 (C-5a) ppm. MS
(ESI+): m/z (%) = 328 (100) [M + H]+. HRMS (ESI+):calcd. for N-Allyl-6-chloro-1,2,3,4-tetrahydroacridin-9-amine (3g)
C19H-26N3O2 328.2028; found 328.2025.
Procedure 1: The general procedure for the palladium-catalyzed
amination reaction with conventional heating was followed using
1a (31 mg, 125 μmol) and allylamine (14 μL, 188 μmol). The reac-
tion mixture was heated to 100 °C for 24 h. Purification by flash
chromatography (cyclohexane/EtOAc/Et3N, 10:0:0 to 8:2:0.2%) af-
6,7-Difluoro-N-hexyl-1,2,3,4-tetrahydroacridin-9-amine (3d): The
general procedure for the palladium-catalyzed amination reaction
under microwave irradiation was followed using 1d (63.4 mg,
0.25 mmol) and hexylamine (50 μL, 375 μmol). The reaction mix-
forded 3g as a pale-yellow solid (22 mg, 71%).
ture was heated to 150 °C (300 W) for 30 min. Purification by flash
chromatography (cyclohexane/EtOAc, 10:0 to 8:2) afforded 3d as a
Procedure 2: The general procedure for the palladium-catalyzed
yellow solid (66 mg, 83%). Rf (EtOAc) = 0.59. 1H NMR (300 MHz, amination reaction under microwave irradiation was followed using
CDCl3): δ = 0.87 (t, J = 6.6 Hz, 3 H, 16-H), 1.24–1.30 (m, 4 H, 1a (31 mg, 125 μmol) and allylamine (14 μL, 188 μmol). The reac-
14-H, 15-H), 1.31–1.41 (m, 2 H, 13-H), 1.57–1.68 (m, 2 H, 12-H), tion mixture was heated to 150 °C (300 W) for 30 min. Purification
1.85–1.91 (m, 4 H, 7-H, 8-H), 2.61–2.66 (m, 2 H, 9-H), 2.95–3.01 by flash chromatography (cyclohexane/EtOAc/Et3N, 10:0:0 to
(m, 2 H, 6-H), 3.40 (t, J = 7.2 Hz, 2 H, 11-H), 3.75 (br. s, 1 H,
NH), 7.58 (dd, J = 11.9, 8.1 Hz, 1 H, 4-H), 7.65 (dd, J = 11.9,
8:2:0.1) afforded 3g as a pale-yellow solid (19 mg, 56%). Rf
1
(EtOAc) = 0.29. H NMR (300 MHz, CDCl3): δ = 1.87–1.92 (m,
8.1 Hz, 1 H, 1-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (C- 4 H, 7-H, 8-H), 2.65–2.70 (m, 2 H, 9-H), 3.00–3.05 (m, 2 H, 6-H),
16), 22.6 (C-7), 22.7 (C-8), 23.0 (C-15), 24.5 (C-9), 26.7 (C-13), 31.6
(C-14), 31.8 (C-12), 34.0 (C-6), 49.6 (C-11), 109.3 (dd, J = 18.5, = 45.9, 10.2 Hz, 2 H, 13-H), 5.92–6.05 (m, 1 H, 12-H), 7.26 (dd, J
1.6 Hz, C-1), 114.6 (d, J = 15.8 Hz, C-4), 116.1 (C-9a), 116.8 (d, J = 9.1, 2.1 Hz, 1 H, 2-H), 7.85 (d, J = 9.1 Hz, 1 H, 1-H), 7.88 (d, J
= 5.5 Hz, C-10a), 145.7 (dd, J = 97.6, 10.4 Hz, C-2), 149.8 (d, J = = 2.1 Hz, 1 H, 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.6
5.5 Hz, C-10), 150.5 (d, J = 3.3 Hz, C-4a), 151.4 (dd, J = 97.6, (C-7 or C-8), 22.9 (C-7 or C-8), 24.7 (C-9), 33.8 (C-6), 51.8 (C-11),
10.4 Hz, C-3), 159.1 (C-5a) ppm. 19F NMR (282 MHz, CDCl3): δ 116.4 (C-10a), 117.3 (C-13), 118.4 (C-9a), 124.6 (C-1 or C-2), 124.7
4.00 (br. s, 1 H, NH), 4.07 (d, J = 5.5 Hz, 2 H, 11-H), 5.29 (dd, J
= –139.3 (d, J = 21.7 Hz, 2-F), –134.7 (d, J = 21.7 Hz, 3-F) ppm.
MS (ESI+): m/z (%) = 320 (20), 319 (100) [M + H]+. HRMS
(ESI+): calcd. for C19H25N2F2 319.1974; found 319.1986.
(C-1 or C-2), 127.2 (C-4), 134.4 (C-3), 135.5 (C-12), 147.7 (C-10),
150.9 (C-4a), 159.4 (C-5a) ppm. MS (ESI+): m/z (%) = 275 (37),
273 (100) [M + H]+. HRMS (ESI+): calcd. for C16H18N2Cl
273.1167; found 273.1159.
5,7-Dichloro-N-hexyl-1,2,3,4-tetrahydroacridin-9-amine (3e): The
general procedure for the palladium-catalyzed amination reaction
under microwave irradiation was followed using 1e (72 mg,
0.25 mmol) and hexylamine (50 μL, 375 μmol). The reaction mix-
ture was heated to 150 °C (300 W) for 30 min. Purification by flash
chromatography (cyclohexane/EtOAc, 100:0 to 94:6) afforded 3e as
a yellow solid (33 mg, 38%). Rf (cyclohexane/EtOAc, 9:1) = 0.36.
1H NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 7.0 Hz, 3 H, 16-H),
N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-6-chloro-1,2,3,4-tetra-
hydroacridin-9-amine (3h)
Procedure 1: The general procedure for the palladium-catalyzed
amination reaction with conventional heating was followed using
1a (31.5 mg, 125 μmol) and 2-(tert-butyldimethylsilyloxy)ethan-
amine (33 mg, 188 μmol). The reaction mixture was heated to
100 °C for 24 h. Purification by flash chromatography (cyclo-
1.24–1.34 (m, 4 H, 14-H, 15-H), 1.35–1.44 (m, 2 H, 13-H), 1.59– hexane/EtOAc/Et3N, 10:0:0 to 8:2:0.2%) afforded 3h as a yellow
1.70 (m, 2 H, 12-H), 1.89–1.93 (m, 4 H, 7-H, 8-H), 2.65–2.71 (m, solid (26 mg, 53%).
Eur. J. Org. Chem. 2011, 302–310
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
307

C. Ronco, L. Jean, H. Outaabout, P.-Y. Renard
FULL PAPER
Procedure 2: The general procedure for the palladium-catalyzed
amination reaction under microwave irradiation was followed using
1.84 (d, J = 12.4 Hz, 1 H, 10-H), 1.93–2.00 (m, 1 H, 10-H), 2.45
(dd, J = 17.9, 5.6 Hz, 1 H, 13-H), 2.62–2.68 (m, 1 H, 7-H), 2.92
1a (31 mg, 125 μmol) and 2-(tert-butyldimethylsilyloxy)ethanamine (dt, J = 17.7, 1.9 Hz, 1 H, 6-H), 3.07 (dd, J = 17.7, 5.5 Hz, 1 H,
(33 mg, 188 μmol). The reaction mixture was heated to 150 °C
(300 W) for 50 min. Purification by flash chromatography (cyclo-
hexane/EtOAc/Et3N, 10:0:0 to 8:2:0.2) afforded 3h as a yellow solid
(37 mg, 60%). Rf (EtOAc) = 0.68. H NMR (300 MHz, CDCl3): δ
= 0.08 (s, 6 H, 13-H, 14-H), 0.93 (s, 9 H, 16-H, 17-H, 18-H), 1.87–
6-H), 3.18–3.24 (m, 1 H, 11-H), 3.33–3.49 (m, 2 H, 15-H), 3.99 (br.
s, 1 H, NH), 5.46 (d, J = 4.5 Hz, 1 H, 8-H), 7.19 (dd, J = 6.6,
2.1 Hz, 1 H, 2-H), 7.85 (d, J = 2.1 Hz, 1 H, 4-H), 7.88 (d, J =
2.1 Hz, 1 H, 1-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (C-
20), 22.7 (C-19), 23.5 (C-14), 26.8 (C-17), 27.7 (C-11), 28.3 (C-7),
1
1.94 (m, 4 H, 7-H, 8-H), 2.71–2.77 (m, 2 H, 9-H), 3.00–3.06 (m, 2 29.3 (C-10), 31.7 (C-18), 31.9 (C-16), 37.0 (C-13), 39.8 (C-6), 50.8
H, 6-H), 3.55 (t, J = 4.8 Hz, 2 H, 11-H), 3.72 (t, J = 4.8 Hz, 2 H, (C-15), 119.0 (C-11a or C-12a), 121.0 (C-11a or C-12a), 124.3 (C-
12-H), 4.64 (br. s, 1 H, NH), 7.18 (dd, J = 9.0, 2.1 Hz, 1 H, 2-H), 2), 125.6 (2 C, C-1, C-8), 127.5 (C-4), 131.8 (C-3), 134.2 (C-9),
7.80 (d, J = 2.1 Hz, 1 H, 4-H), 7.83 (d, J = 9.0 Hz, 1 H, 1-H) ppm.
148.5 (C-4a or C-12), 150.7 (C-4a or C-12), 158.5 (C-5a) ppm. MS
13C NMR (75 MHz, CDCl3):: δ = –5.4 (2 C, C-13, C-14), 18.2 (C- (ESI+): m/z (%) = 371 (42), 369 (100) [M + H]+. HRMS (ESI+):
5), 22.7 (C-7 or C-8), 22.9 (C-7 or C-8), 24.5 (C-9), 25.9 (3 C, C-
16, C-17, C-18), 34.1 (C-6), 51.3 (C-11), 62.4 (C-12), 117.2 (C-9a),
119.0 (C-10a), 124.4 (C-2), 124.6 (C-1), 127.7 (C-4), 133.9 (C-3),
148.09 (C-10), 150.8 (C-4a), 159.8 (C-5a) ppm. MS (ESI+): m/z
(%) = 393 (45), 391 (100) [M + H]+. HRMS (ESI+): calcd. for
C21H32N2OSiCl 391.1957; found 391.1972.
calcd. for C23H30N2Cl 369.2089; found 369.2098.
N-Hexyl-9-methyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]-
quinolin-12-amine (4b): The general procedure for the palladium-
catalyzed amination reaction under microwave irradiation was fol-
lowed using chloroquinoline 2b (34 mg, 125 μmol) and hexylamine
(25 μL, 188 μmol). The reaction mixture was heated to 150 °C
(300 W) for 2 h. Purification by flash chromatography (petroleum
ether/EtOAc, 10:0 to 7.5:2.5) afforded 4b as a pale-yellow solid
(40 mg, 95%). Rf (EtOAc/MeOH, 9:1) = 0.29. 1H NMR (300 MHz,
CDCl3): δ = 0.90 (t, J = 6.6 Hz, 3 H, 20-H), 1.29–1.36 (m, 4 H,
18-H, 19-H), 1.39–1.44 (m, 2 H, 17-H), 1.50 (s, 3 H, 14-H), 1.66–
1.76 (m, 2 H, 16-H, 13-H), 1.82 (d, J = 16.7 Hz, 1 H, 13-H), 1.93
(dd, J = 12.2, 1.5 Hz, 1 H, 10-H), 2.01–2.07 (m, 1 H, 10-H), 2.53
(dd, J = 16.7, 4.4 Hz, 1 H, 13-H), 2.71–2.75 (m, 1 H, 7-H), 3.03
(d, J = 17.3 Hz, 1 H, 6-H), 3.17 (dd, J = 17.3, 5.5 Hz, 1 H, 6-H),
3.30–3.34 (m, 1 H, 11-H), 3.40–3.56 (m, 2 H, 15-H), 4.04 (br. s, 1
H, NH), 5.53 (d, J = 4.5 Hz, 1 H, 8-H), 7.33 (t, J = 7.1 Hz, 1 H,
2-H), 7.53 (t, J = 7.1 Hz, 1 H, 3-H), 7.90 (d, J = 8.5 Hz, 1 H, 4-H),
8.00 (d, J = 8.5 Hz, 1 H, 1-H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 14.1 (C-20), 22.7 (C-19), 23.5 (C-14), 26.8 (C-17), 27.7 (C-11),
28.4 (C-7), 29.3 (C-10), 31.7 (C-18), 31.9 (C-16), 37.2 (C-13), 40.0
(C-6), 50.6 (C-15), 120.9 (C-11a or C-12a), 121.1 (C-11a or C-12a),
123.6 (C-2), 124.0 (C-1), 125.6 (C-8), 128.4 (C-3), 128.7 (C-4), 131.8
(C-9), 147.9 (C-4a or C-12), 150.5 (C-4a or C-12), 157.4 (C-5a)
ppm. MS (ESI+): m/z (%) = 335 (100) [M + H]+. HRMS (ESI+):
calcd. for C23H31N2 335.2477; found 335.2487.
N-Benzyl-6-chloro-N-methyl-1,2,3,4-tetrahydroacridin-9-amine (3i)
Procedure 1: The general procedure for the palladium-catalyzed
amination reaction with conventional heating was followed using
1a (31 mg, 125 μmol) and N-methylbenzylamine (24 μL, 188 μmol).
The reaction mixture was heated to 100 °C for 24 h. Purification
by flash chromatography (cyclohexane/EtOAc/Et3N, 10:0:0 to
8:2:0.2%) afforded 3i as a pale-yellow solid (24 mg, 60%).
Procedure 2: The general procedure for the palladium-catalyzed
amination reaction under microwave irradiation was followed using
1a (63 mg, 0.25 mmol) and N-methylbenzylamine (24 μL,
188 μmol). The reaction mixture was heated to 120 °C (300 W) for
2 h. Purification by flash chromatography (petroleum ether/EtOAc,
10:0 to 8:2) afforded 3i as a pale-yellow solid (16 mg, 39%). Rf
1
(EtOAc) = 0.92. H NMR (300 MHz, CDCl3): δ = 1.76–1.85 (m,
2 H, 8-H), 1.89–1.98 (m, 2 H, 7-H), 2.81 (t, J = 6.2 Hz, 2 H, 9-H),
2.90 (s, 3 H, 18-H), 3.11 (t, J = 6.6 Hz, 2 H, 6-H), 4.36 (s, 2 H, 11-
H), 7.26–7.38 (m, 6 H, 2-H, 13-H, 14-H, 15-H, 16-H, 17-H), 7.96
(d, J = 2.3 Hz, 1 H, 4-H), 7.98 (d, J = 8.9 Hz, 1 H, 1-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 22.9 (C-8), 23.0 (C-7), 27.0 (C-9),
34.1 (C-6), 40.4 (C-18), 60.4 (C-11), 124.5 (C-10a), 125.9 (C-2),
126.0 (C-4), 127.5 (C-15), 127.8 (C-1), 128.2 (C-9a), 128.6 (2 C, C-
13, C-17), 128.7 (2 C, C-14, C-16), 134.1 (C-3), 139.1 (C-12), 148.5
(C-10), 154.6 (C-4a), 161.9 (C-5a) ppm. MS (ESI+): m/z (%) = 339
(37), 337 (100) [M + H]+. HRMS (ESI+): calcd. for C21H22N2Cl
337.1455; found 337.1472.
N-Hexyl-9-methyl-2-nitro-6,7,10,11-tetrahydro-7,11-methanocyclo-
octa[b]quinolin-12-amine (4c): The general procedure for the palla-
dium-catalyzed amination reaction under microwave irradiation
was followed using chloroquinoline 2c (79 mg, 0.25 mmol) and hex-
ylamine (25 μL, 188 μmol). The reaction mixture was heated to
150 °C (300 W) for 30 min. Purification by flash chromatography
(cyclohexane/EtOAc, 10:0 to 7.5:2.5) afforded 4c as an orange solid
(90 mg, 94%). Rf (EtOAc) = 0.79. M.p. 63–65 °C (decomp.). 1H
NMR (300 MHz, CDCl3): δ = 0.90 (t, J = 6.8 Hz, 3 H, 20-H),
1.31–1.37 (m, 4 H, 18-H, 19-H), 1.43–1.49 (m, 2 H, 17-H), 1.52 (s,
3 H, 14-H), 1.72–1.87 (m, 3 H, 16-H, 13-H), 1.92 (dd, J = 12.2,
1.7 Hz, 1 H, 10-H), 2.02–2.10 (m, 1 H, 10-H), 2.54 (dd, J = 16.9,
4.4 Hz, 1 H, 13-H), 2.72–2.77 (m, 1 H, 7-H), 2.96–3.05 (m, 1 H, 6-
H), 3.16 (dd, J = 17.7, 5.5 Hz, 1 H, 6-H), 3.72–3.77 (m, 1 H, 11-
H), 3.58–3.72 (m, 2 H, 15-H), 4.33 (br. s, 1 H, NH), 5.54 (d, J =
4.7 Hz, 1 H, 8-H), 7.88 (d, J = 9.2 Hz, 1 H, 4-H), 8.26 (dd, J =
9.2, 2.5 Hz, 1 H, 3-H), 9.08 (d, J = 2.5 Hz, 1 H, 1-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.1 (C-20), 22.7 (C-19), 23.5 (C-14),
26.7 (C-17), 27.6 (C-11), 28.2 (C-7), 29.1 (C-10), 31.6 (C-18), 31.9
N-Hexyl-9-methyl-3-chloro-6,7,10,11-tetrahydro-7,11-ethanocyclo-
octa[b]quinolin-12-amine (4a)
Procedure 1: The general procedure for the palladium-catalyzed
amination reaction with conventional heating was followed using
2a (38.0 mg, 125 μmol) and hexylamine (25 μL, 188 μmol). The re-
action mixture was heated to 100 °C for 48 h. Purification by flash
chromatography (petroleum ether/EtOAc, 10:0 to 7.5:2.5) afforded
4a as a pale-yellow solid (41 mg, 90%).
Procedure 2: The general procedure for the palladium-catalyzed
amination reaction under microwave irradiation was followed using
2a (38.0 mg, 125 μmol) and hexylamine (25 μL, 188 μmol). The re-
action mixture was heated to 120 °C (300 W) for 5 h. Purification
by flash chromatography (petroleum ether/EtOAc, 10:0 to 7.5:2.5)
afforded 4a as a pale-yellow solid (22 mg, 50%). Rf (EtOAc/MeOH, (C-16), 36.5 (C-13), 40.4 (C-6), 50.6 (C-15), 118.4 (C-11a or C-12a),
1
9:1) = 0.70. H NMR (300 MHz, CDCl3): δ = 0.83 (t, J = 7.0 Hz, 120.9 (C-11a or C-12a), 121.9 (C-3), 122.5 (C-1), 125.5 (C-8), 130.2
3 H, 20-H), 1.21–1.38 (m, 6 H, 18-H, 19-H, 17-H), 1.44 (s, 3 H,
(C-4), 131.9 (C-3), 142.6 (C-2), 133.1 (C-9), 150.6 (C-4a or C-12),
14-H), 1.58–1.68 (m, 2 H, 16-H), 1.74 (d, J = 17.2 Hz, 1 H, 13-H),
151.9 (C-4a or C-12), 161.1 (C-5a) ppm. MS (ESI+): m/z (%) =
308
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 302–310

Palladium-Catalyzed Synthesis of Tacrine and Huprine Congeners
380 (100) [M + H]+. HRMS (ESI+): calcd. for C23H30N3O2
380.2354; found 380.2338.
H), 2.61–2.70 (m, 4 H, 9-H, 13-H), 2.90–2.94 (m, 2 H, 6-H), 3.57
(t, J = 7.0 Hz, 2 H, 11-H), 7.34 (t, J = 7.1 Hz, 1 H, 2-H), 7.53 (t,
J = 7.1 Hz, 1 H, 3-H), 7.74 (d, J = 8.3 Hz, 1 H, 4-H), 8.08 (d, J =
8.3 Hz, 1 H, 1-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.1 (C-
7 or C-8), 23.4 (C-7 or C-8), 25.4 (C-9), 30.9 (C-12), 34.2 (C-6),
36.8 (C-14), 48.9 (C-11), 50.8 (C-13), 115.9 (C-10a), 120.4 (C-9a),
123.2 (C-1), 123.6 (C-2), 128.4 (C-4), 128.8 (C-3), 147.7 (C-4a),
151.3 (C-10), 158.6 (C-5a) ppm. MS (ESI+): m/z (%) = 271 (26),
270 (100) [M + H]+. HRMS (ESI+): calcd. for C17H24N3 270.1969;
found 270.1970.
2,3-Difluoro-N-hexyl-9-methyl-6,7,10,11-tetrahydro-7,11-methano-
cycloocta[b]quinolin-12-amine (4d): The general procedure for the
palladium-catalyzed amination reaction under microwave irradia-
tion was followed using 2d (76 mg, 0.25 mmol) and hexylamine
(25 μL, 188 μmol). The reaction mixture was heated to 150 °C
(300 W) for 30 min. Purification by flash chromatography (petro-
leum ether/EtOAc, 10:0 to 8:2) afforded 4d as an orange solid
(55 mg, 59 %). Rf (cyclohexane/EtOAc, 5:5) = 0.64. 1H NMR
(300 MHz, CDCl3): δ = 0.84 (t, J = 7.0 Hz, 3 H, 20-H), 1.24–1.31
9-(7-Aminoheptyl)-1,2,3,4-tetrahydroacridine (12): The general pro-
(m, 4 H, 18-H, 19-H), 1.32–1.38 (m, 2 H, 17-H), 1.45 (s, 3 H, 14- cedure for the palladium-catalyzed amination reaction under mi-
H), 1.58–1.67 (m, 2 H, 16-H), 1.73 (d, J = 17.3 Hz, 2 H, 13-H), crowave irradiation was followed using 1b (63 mg, 0.29 mmol) and
1.85 (d, J = 12.2 Hz, 1 H, 10-H), 1.94–2.02 (m, 1 H, 10-H), 2.47 1,7-diaminoheptane 15 (45 mg, 0.34 mmol). The reaction mixture
(dd, J = 16.9, 4.3 Hz, 1 H, 13-H), 2.63–2.71 (m, 1 H, 7-H), 2.90 was heated to 150 °C (300 W) for 2 h. Purification by flash
(d, J = 17.5 Hz, 1 H, 6-H), 3.06 (dd, J = 17.5, 5.5 Hz, 1 H, 6-H),
3.19–3.25 (m, 1 H, 11-H), 3.28–3.90 (m, 2 H, 15-H), 3.89 (br. s, 1 brown oil (64 mg, 71%). H NMR (300 MHz, CDCl3): δ = 1.28–
H, NH), 5.53 (d, J = 4.5 Hz, 1 H, 8-H), 7.60 (dd, J = 11.7, 7.9 Hz, 1.35 (m, 6 H, 13-H, 14-H, 15-H), 1.50–1.57 (m, 2 H, 16-H), 1.58–
chromatography (CH2Cl2/MeOH/Et3N, 9:1:1) afforded 12 as a
1
1 H, 4-H), 7.72 (dd, J = 11.7, 7.9 Hz, 1 H, 1-H) ppm. 13C NMR 1.64 (m, 2 H, 12-H), 1.85–1.92 (m, 4 H, 7-H, 8-H), 2.62–2.68 (m,
(75 MHz, CDCl3): δ = 14.1 (C-20), 22.7 (C-19), 23.5 (C-14), 26.7 2 H, 9-H), 2.73 (t, J = 7.2 Hz, 2 H, 17-H), 3.00–3.06 (m, 2 H, 6-
(C-17), 27.6 (C-11), 28.3 (C-7), 29.2 (C-10), 31.7 (C-18), 31.8 (C- H), 3.48 (t, J = 7.2 Hz, 2 H, 11-H), 5.60 (br. s, 3 H, NH, NH2),
16), 37.2 (C-13), 39.9 (C-6), 50.5 (C-15), 110.1 (d, J = 19.1 Hz, C- 7.31 (t, J = 8.1 Hz, 1 H, 2-H), 7.51 (t, J = 8.1 Hz, 1 H, 3-H), 7.87–
1), 114.7 (d, J = 19.1 Hz, C-4), 117.6 (d, J = 6.0 Hz, C-12a), 121.6 7.98 (m, 2 H, 1-H, 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
(C-11a), 125.6 (C-8), 131.8 (C-9), 145.9 (dd, J = 75.8, 15.8 Hz, C-
2), 149.7 (C-12), 150.1 (C-4a), 150.8 (d, J = 75.8 Hz, C-3), 158.1
(C-5a) ppm. 19F NMR (282 MHz, CDCl3): δ = –139.1 (d, J =
21.6 Hz, 2-F), –134.5 (d, J = 21.6 Hz, 3-F) ppm. MS (ESI+): m/z
14.8 (C-16), 22.5 (C-7 or C-8), 22.6 (C-7 or C-8), 24.79 (C-9), 26.6
(C-13 or C-15), 26.7 (C-13 or C-15), 28.9 (C-14), 30.9 (C-16), 31.4
(C-12), 33.1 (C-6), 41.1 (C-17), 49.2 (C-11), 115.1 (C-10a), 119.5
(C-9a), 123.1 (C-1), 123.8 (C-2), 127.4 (C-4), 128.8 (C-3), 146.1 (C-
(%) = 372 (25), 371 (100) [M + H]+. HRMS (ESI+): calcd. for 4a), 151.5 (C-10), 157.3 (C-5a) ppm. MS (ESI+): m/z (%) = 313
C23H29N2F2 371.2305; found 371.2299.
(29), 312 (100) [M + H]+. HRMS (ESI+): calcd. for C20H30N3
312.2453; found 312.2440.
Ethyl (3-Chloro-N-hexyl-6,7,10,11-tetrahydro-7,11-methanocyclo-
octa[b]quinolin-9-yl)acetate (4f): The general procedure for the pal-
ladium-catalyzed amination reaction under microwave irradiation
was followed using 2f[14] (47 mg, 125 μmol) and hexylamine (25 μL,
188 μmol). The reaction mixture was heated to 150 °C (300 W) for
30 min. Purification by flash chromatography (cyclohexane/EtOAc,
3-Chloro-6,7,10,11-tetrahydro-9-methyl-12-({7-[(1,2,3,4-tetrahydro-
acridin-9-yl)amino]heptyl}amino)-7,11-methanocycloocta[b]quinoline
Ditrifluoroacetic Acid (13): The general procedure for the palla-
dium-catalyzed amination reaction under microwave irradiation
was followed using chloroquinoline 2a (27 mg, 0.09 mmol) and
amine 12 (33 mg, 0.105 mmol). The reaction mixture was heated to
8:2 to 6:4) afforded 4f as a yellow solid (21 mg, 39%). Rf (EtOAc)
1
= 0.42. H NMR (300 MHz, CDCl3): δ = 0.87–0.92 (m, 3 H, 23- 150 °C (300 W) for 2 h. Purification by preparative HPLC afforded
H), 1.01 (t, J = 7.2 Hz, 3 H, 17-H), 1.24–1.42 (m, 6 H, 21-H, 22- 13 as a yellow solid (20 mg, 28%). 1H and 13C NMR spectroscopic
H, 20-H), 1.64–1.76 (m, 2 H, 19-H), 1.90–2.13 (m, 3 H, 10-H, 10-
H, 13-H), 2.69 (d, J = 20.5 Hz, 1 H, 13-H), 2.75–2.80 (m, 1 H, 7-
H), 2.84–2.89 (m, 2 H, 14-H), 3.03 (d, J = 17.9 Hz, 1 H, 6-H), 3.18
(dd, J = 17.9, 5.5 Hz, 1 H, 6-H), 3.29–3.33 (m, 1 H, 11-H), 3.43–
3.57 (m, 2 H, 18-H), 3.94 (q, J = 7.2 Hz, 2 H, 16-H), 5.71 (d, J =
4.3 Hz, 1 H, 8-H), 7.27 (d, J = 9.0, 2.0 Hz, 1 H, 2-H), 7.89 (d, J =
2.0 Hz, 1 H, 4-H), 7.93 (d, J = 9.0 Hz, 1 H, 1-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.1 (C-23), 14.2 (C-17), 22.7 (C-22), 26.7
(C-20), 27.3 (C-11), 28.2 (C-7), 28.9 (C-10), 29.8 (C-21), 31.6 (C-
19), 35.1 (C-13), 39.2 (C-6), 43.3 (C-14), 50.5 (C-18), 60.6 (C-16),
105.5 (C-11a), 118.3 (C-12a), 123.6 (C-1), 124.7 (C-2), 125.7 (C-4),
129.4 (C-8), 131.5 (C-3), 138.9 (C-9), 149.6 (C-4a or C-12), 149.7
(C-4a or C-12), 164.9 (C-5a), 171.4 (C-15) ppm. MS (ESI+): m/z
(%) = 429 (37), 427 (100) [M + H]+. HRMS (ESI+): calcd. for
C26H34N2O2Cl 441.2337; found 441.2319.
data are in agreement with those given in the literature.[5c] MS
(ESI+): m/z (%) = 579 (50) [M + H]+, 290 (100) [M + 2H]2+
.
HRMS (ESI+): calcd. for C37H44N4Cl 579.3255; found 579.3244.
9-Methyl-6,7,10,11-tetrahydro-12-({8-[(1,2,3,4-tetrahydroacridin-9-
yl)amino]heptyl}amino)-7,11-methanocycloocta[b]quinoline (14): The
general procedure for the palladium-catalyzed amination reaction
under microwave irradiation was followed using chloroquinoline 2b
(16 mg, 0.06 mmol) and amine 12 (28 mg, 0.09 mmol). The reaction
mixture was heated to 150 °C (300 W) for 2 h. Purification by flash
chromatography (CH2Cl2/MeOH/Et3N, 9:1:1) afforded 14 as a
1
brown oil (24 mg, 73%). H NMR (300 MHz, CDCl3): δ = 1.20–
1.45 (m, 6 H, 17-H, 18-H, 19-H), 1.49 (s, 3 H, 14-H), 1.50–1.75 (m,
4 H, 16-H, 20-H), 1.75–1.85 (m, 1 H, 13-H), 1.85–1.95 (m, 5 H,
10-H, 29-H, 30-H), 2.02 (br. d, J ≈ 11 Hz, 1 H, 10-H), 2.51 (dd, J
= 17.3, 4.7 Hz, 1 H, 13-H), 2.60–2.80 (m, 3 H, 7-H, 31-H), 2.95–
N-1-Methyl-N-3-(5,6,7,8-tetrahydroacridin-9-yl)propane-1,3-di- 3.10 (m, 3 H, 6-H, 28-H), 3.16 (dd, J = 17.5, 5.4 Hz, 1 H, 6-H),
amine (9): The general procedure for the palladium-catalyzed amin-
ation reaction under microwave irradiation was followed using 1b
(63.0 mg, 0.28 mmol) and N-methyl-1,3-propanediamine (39 μL,
188 μmol). The reaction mixture was heated to 150 °C (300 W) for
45 min. Purification by flash chromatography (EtOAc then ace-
tone/Et3N, 100:0 to 93:7) afforded 9 as a yellow solid (46 mg, 62%).
Rf (DCM/MeOH/Et3N, 9:1:1) = 0.61. 1H NMR (300 MHz,
3.25–3.35 (m, 1 H, 11-H), 3.40–3.60 (m, 4 H, 15-H, 21-H), 4.00
(br. s, 2 H, NH), 5.52 (d, J = 4.5 Hz, 1 H, 8-H), 7.32 (br. t, 2 H,
2-H, 24-H), 7.53 (br. t, 2 H, 3-H, 25-H), 7.85–8.05 (m, 4 H, 1-H,
4-H, 23-H, 26-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 22.8 (C-
29 or C-30), 23.1 (C-29 or C-30), 23.5 (C-14), 24.8 (C-31), 26.9
(CH2), 27.0 (CH2), 27.7 (C-11), 28.3 (C-7), 29.2 (CH2), 29.3 (CH2),
31.8 (C-16 and C-20), 33.8 (C-28), 37.2 (C-13), 39.9 (C-6), 49.5 (C-
MeOD): δ = 1.78–1.91 (m, 6 H, 7-H, 8-H, 12-H), 2.35 (s, 3 H, 16- 15 or C-21), 50.5 (C-15 or C-21), 115.7 (C-22a), 120.0 (C-31a),
Eur. J. Org. Chem. 2011, 302–310
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
309

C. Ronco, L. Jean, H. Outaabout, P.-Y. Renard
FULL PAPER
Catalanotti, L. Savini, V. Nacci, E. Novellino, H. W. Holloway,
N. H. Greig, T. Belinskaya, J. M. Fedorko, A. Saxena, J. Med.
Chem. 2005, 48, 1919–1929; c) P. Camps, X. Formosa, D.
Muñoz-Torrero, J. Petrignet, A. Badia, M. V. Clos, J. Med.
Chem. 2005, 48, 1701–1704; d) D. Alonso, I. Dorronsoro, L.
Rubio, P. Muñoz, E. García-Palomero, M. Del Monte, A. Bi-
don-Chanal, M. Orozco, F. J. Luque, A. Castro, M. Medina,
A. Martínez, Bioorg. Med. Chem. 2005, 13, 6588–6597; e) M.-
K. Hu, C.-F. Lu, Tetrahedron Lett. 2000, 41, 1815–1818; f)
P. R. Carlier, E. S.-H. Chow, Y. Han, J. Liu, J. El Yazal, Y.-P.
Pang, J. Med. Chem. 1999, 42, 4225–4231.
120.7 (C-11a or C-12a), 121.1 (C-11a or C-12a), 123.0 (C-23), 123.7
(C-2), 123.8 (C-24), 124.0 (C-1), 125.6 (C-8), 128.4 (C-3 or C-4 or
C-25 or C-26), 128.5 (C-3 or C-4 or C-25 or C-26), 128.6 (C-3 or
C-4 or C-25 or C-26), 128.7 (C-3 or C-4 or C-25 or C-26), 131.8
(C-9), 147.0 (C-26a), 147.6 (C-4a or C-12), 150.5 (C-4a or C-12),
151.1 (C-10), 157.2 (C-5a or C-25a), 158.1 (C-5a or C-25a) ppm.
MS (ESI+): m/z (%) = 545 (10) [M + H]+, 273 (100) [M + 2H]2+
.
HRMS (ESI+): calcd. for C37H45N4 545.3652; found 545.3644.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures, preparation and characteri-
[6] a) L. Jiang, S. L. Buchwald in Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed. (Eds.: A. de Meijere, F. Diederich), Wiley-
VCH, Weinheim, 2004, pp. 699–760; b) J. F. Hartwig in Hand-
book of Organopalladium Chemistry for Organic Synthesis (Ed.:
E. I. Negishi), Wiley, New York, 2002, pp. 1051–1096.
[7] S. Butini, G. Campiani, M. Borriello, S. Gemma, A. Panico,
M. Persico, B. Catalanotti, S. Ros, M. Brindisi, M. Agnusdei,
I. Fiorini, V. Nacci, E. Novellino, T. Belinskaya, A. Saxena, C.
Fattorusso, J. Med. Chem. 2008, 51, 3154–3170.
[8] a) A. D. Averin, A. N. Uglov, E. R. Ranyuk, N. V. Lukashev,
I. P. Beletskaya, Russ. J. Org. Chem. 2009, 45, 273–284; b) J. A.
Smith, R. K. Jones, G. W. Booker, S. M. Pyke, J. Org. Chem.
2008, 73, 8880–8892; c) K. T. J. Loones, B. U. W. Maes, R. A.
Dommisse, Tetrahedron 2007, 63, 8954–8961; d) B. J. Margolis,
K. A. Long, D. L. T. Laird, J. C. Ruble, S. R. Pulley, J. Org.
Chem. 2007, 72, 2232–2235; e) I. P. Beletskaya, A. V. Tsvetkov,
P. V. Tsvetkov, G. V. Latyshev, N. V. Lukashev, Russ. Chem.
Bull. Int. Ed. 2005, 54, 215–219; f) Q. Shen, S. Shekhar, J. P.
Stambuli, J. F. Hartwig, Angew. Chem. Int. Ed. 2005, 44, 1371–
1375; g) B. U. W. Maes, K. T. J. Loones, G. L. F. Lemière, R. A.
Dommisse, Synlett 2003, 1822–1825; h) T. H. M. Jonckers,
B. U. W. Maes, G. L. F. Lemière, G. Rombouts, L. Pieters, A.
Haemers, R. A. Dommisse, Synlett 2003, 615–618; i) C. Wolf,
R. Lerebours, J. Org. Chem. 2003, 68, 7077–7084; j) J. Yin,
M. M. Zhao, M. A. Huffman, J. M. McNamara, Org. Lett.
2002, 4, 3481–3484; k) S. Jaime-Figueroa, Y. Liu, J. M. Mu-
chowski, D. G. Putman, Tetrahedron Lett. 1998, 39, 1313–1316.
[9] D. S. Surry, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47,
6338–6361 and references cited therein.
[10] a) C. O. Kappe, A. Stadler in Microwaves in Organic and Me-
dicinal Chemistry (Eds.: R. Mannhold, H. Kubinyi, G. Folkers),
Wiley-VCH, Weinheim, 2005, pp. 148–153; b) P. Nilsson, K.
Olofsson, M. Larhed, Top. Curr. Chem. 2006, 266, 103–144; c)
B. U. W. Maes, Top. Heterocycl. Chem. 2006, 1, 155–211; d)
B. U. W. Maes, K. T. J. Loones, S. Hostyn, G. Diels, G. Rom-
bouts, Tetrahedron 2004, 60, 11559–11564.
[11] a) L. Shi, M. Wang, C.-A. Fan, F.-M. Zhang, Y.-Q. Tu, Org.
Lett. 2003, 5, 3515–3517; b) G. R. Brown, A. J. Foubister, C. A.
Roberts, S. L. Wells, R. Wood, Tetrahedron Lett. 2001, 42,
3917–3919; c) G. Xu, Y.-G. Wang, Org. Lett. 2004, 6, 985–987.
[12] Y. Hong, C. H. Senanayake, T. Xiang, C. P. Vandenbossche,
G. J. Tanoury, R. P. Bakale, S. A. Wald, Tetrahedron Lett. 1998,
39, 3121–3124.
1
zation of compounds 1a–e, 2a–e, and 5–7, and H and 13C NMR
spectra of all compounds.
Acknowledgments
The French MRES (“Ministère de l’Enseignement Supérieur et de
la Recherche”) is acknowledged for a PhD Fellowship to C. R.;
FRM (“Fondation pour la Recherche Médicale”) through
INE20040300375, IUF (“Institut Universitaire de France“), ANR
(“Agence Nationale pour la Recherche”) through ANR_06_
BLAN_0163 DETOXNEURO program, and the Région Haute
Normandie (Crunch program) are gratefully acknowledged for
their financial support. We thank Dr. Geoffroy Sorin for prepara-
tion of selected chloroquinolines, Pr. Thierry Besson (Université
de Rouen) for helpful discussions on microwave technology, Dr.
Anthony Romieu (Université de Rouen) for HPLC analyses, Elisa-
beth Roger (INSA de Rouen) for IR measurements, and Annick
Leboisselier (INSA de Rouen) for the determination of elemental
analyses.
[1] a) J. L. Marco, M. C. Carreiras, Mini-Rev. Med. Chem. 2003,
3, 518–624; b) G. R. Proctor, A. L. Harvey, Curr. Med. Chem.
2000, 7, 295–302.
[2] a) P. Camps, R. El Achab, J. Morral, D. Muñoz-Torrero, A.
Badia, J. E. Baños, N. M. Vivas, X. Barril, M. Orozco, F. J.
Luque, J. Med. Chem. 2000, 43, 4657–4666; b) P. Camps, R.
El Achab, D. M. Görbig, J. Morral, D. Munõz-Torrero, A. Ba-
dia, J. E. Banõs, N. M. Vivas, X. Barril, M. Orozco, F. J. Luque,
J. Med. Chem. 1999, 42, 3227–3242.
[3] a) C. Ronco, G. Sorin, F. Nachon, R. Foucault, L. Jean, A.
Romieu, P.-Y. Renard, Bioorg. Med. Chem. 2009, 17, 4523–
4536; b) C. Ronco, P.-Y. Renard, L. Jean, F. Nachon, A. Rom-
ieu, A. EP10305366.6.
[4] a) P. Camps, X. Formosa, C. Galdeano, D. Muñoz-Torrero, L.
Ramírez, E. Gómez, N. Isambert, R. Lavilla, A. Badia, M. V.
Clos, M. Bartolini, F. Mancini, V. Andrisano, M. P. Arce, M. I.
Rodríguez-Franco, O. Huertas, T. Dafni, F. J. Luque, J. Med.
Chem. 2009, 52, 5365–5379; b) P. Camps, X. Formosa, C. Gal-
deano, T. Gómez, D. Muñoz-Torrero, M. Scarpellini, E.
Viayna, A. Badia, M. V. Clos, A. Camins, M. Pallàs, M. Bartol-
ini, F. Mancini, V. Andrisano, J. Estelrich, M. Lizondo, A. Bi-
don-Chanal, F. J. Luque, J. Med. Chem. 2008, 51, 3588–3598.
[5] Examples of homo- or heterodimeric AChE inhibitors: a)
M. L. Bolognesi, A. Cavalli, L. Valgimigli, M. Bartolini, M.
Rosini, V. Andrisano, M. Recanatini, C. Melchiorre, J. Med.
Chem. 2007, 50, 6446–6449; b) G. Campiani, C. Fattorusso,
S. Butini, A. Gaeta, M. Agnusdei, S. Gemma, M. Persico, B.
[13] a) I. P. Beletskaya, A. G. Bessmertnykh, R. Guilard, Tetrahe-
dron Lett. 1997, 38, 2287–2290; b) I. P. Beletskaya, A. G. Bes-
smertnykh, R. Guilard, Synlett 1999, 1459–1461; c) I. P. Belets-
kaya, A. D. Averin, A. G. Bessmertnykh, F. Denat, R. Guilard,
Tetrahedron Lett. 2002, 43, 1193–1196.
[14] C. Ronco, L. Jean, P.-Y. Renard, Tetrahedron 2010, 66, 7399–
7404.
Received: August 17, 2010
Published Online: November 12, 2010
310
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Eur. J. Org. Chem. 2011, 302–310