Copper-catalyzed amination of (bromophenyl)ethanolamine for a concise synthesis of aniline-containing analogues of NMDA NR2B antagonist ifenprodil

Article abstract of DOI:10.1039/b923255a

An operationally simple and concise synthesis of anilinoethanolamines, as NMDA NR2B receptor antagonist ifenprodil analogues, was developed via a copper-catalyzed amination of the corresponding bromoarene. Coupling was achieved with linear primary alkylamines, α,ω-diamines, hexanolamine and benzophenone imine, as well as with aqueous ammonia, in good yields using CuI and N,N-diethylsalicylamide, 2,4-pentadione or 2-acetylcyclohexanone as catalytic systems. Amination with ethylene diamine was efficient even in the absence of an additive ligand, whereas no reaction occurred with ethanolamine whatever the conditions used. The anilinoethanolamines were evaluated as NR2B receptor antagonists in a functional inhibition assay. Aminoethylanilines displayed inhibition effects close to that of ifenprodil. The Royal Society of Chemistry.

Full text of DOI:10.1039/b923255a

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Copper-catalyzed amination of (bromophenyl)ethanolamine for a concise
synthesis of aniline-containing analogues of NMDA NR2B antagonist
ifenprodil†
Ce´dric Bouteiller,a Javier Becerril-Ortega,b Patrice Marchand,a Olivier Nicole,b Louisa Barre´,a Alain Buissonb
and Ce´cile Perrio*a
Received 5th November 2009, Accepted 26th November 2009
First published as an Advance Article on the web 6th January 2010
DOI: 10.1039/b923255a
An operationally simple and concise synthesis of anilinoethanolamines, as NMDA NR2B receptor
antagonist ifenprodil analogues, was developed via a copper-catalyzed amination of the corresponding
bromoarene. Coupling was achieved with linear primary alkylamines, a,w-diamines, hexanolamine
and benzophenone imine, as well as with aqueous ammonia, in good yields using CuI and
N,N-diethylsalicylamide, 2,4-pentadione or 2-acetylcyclohexanone as catalytic systems. Amination
with ethylene diamine was efficient even in the absence of an additive ligand, whereas no reaction
occurred with ethanolamine whatever the conditions used. The anilinoethanolamines were evaluated as
NR2B receptor antagonists in a functional inhibition assay. Aminoethylanilines displayed inhibition
effects close to that of ifenprodil.
NR2 subunit (A–D) have been characterized. It is clear that the
pharmacological and functional properties of the NMDA receptor
are highly dependent on the NR2 isoforms (mainly NR2A or
Introduction
The N-methyl-D-aspartate (NMDA) receptor is a ligand-gated
cationic channel that plays a critical role in a wide range of
NR2B) that are present in the receptor. At present, the NR2B
physiological and pathological processes in the central nervous
sub-type NMDA receptor represents an essential molecular target
system, including memory, learning and cognition, as well as neu-
for the understanding of cerebral pathologies and the development
rotoxicity associated to stroke and neurodegenerative (Alzheimer’s
of new therapies.
and Parkinson’s) diseases.1 The structure of the NMDA receptor
Ifenprodil, from the phenylethanolamine class of compounds,
has been elucidated in great detail as a heterotetrameric complex
has remained the antagonist of reference of NR2B receptors
(Fig. 1).2 It was clearly demonstrated that ifenprodil potency
at NR2B was due to the key structural elements incorporating
a phenolic aromatic ring connected to a benzylamine moiety
via a linker of adequate length.3 The stereochemistry of the
ethanolamine linker was not found to be very crucial for the NR2B
subunit binding. Ifenprodil was usually used in the erythro (R*S*
or “unlike”) racemic form; the threo (R*R* or “like”) relative
configuration was suggested to be important for NR2B receptor
selectivity.2,4
made up of a combination of two major subunits, termed NR1
and NR2, based on the amino acid sequence identity. Eight splice
variants of the NR1 subunit (a–h) as well as four variants of the
aLaboratoire
de
De´veloppements
Me´thodologiques
en
TEP,
CEA/DSV/I2BM/CI-NAPS, UMR 6232, CNRS, Universite´ de Caen
- Basse Normandie, Cyceron, Bd Henri Becquerel, 14074 Caen Cedex,
France. E-mail: perrio@cyceron.fr; Fax: +33 (0)231470275; Tel: +33
(0)231470281
bEquipe Physiopathologie de la Synapse, CEA/DSV/I2BM/CI-NAPS,
UMR 6232, CNRS, Universite´ de Caen - Basse Normandie, Cyceron, Bd
Henri Becquerel, 14074 Caen Cedex, France
In recent years, extensive effort has been made to de-
velop ifenprodil-like molecules as pharmacotherapeutic agents
and molecular tools in the study of NMDA receptors’
† Electronic supplementary information (ESI) available: Further experi-
mental details and spectroscopic data. See DOI: 10.1039/b923255a
Fig. 1 Diastereoisomers of ifenprodil and anilines 1, and general structure of analogues A and target molecules B.
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physiopathology.5 From the structure–activity relationship stud-
ies, the replacement of phenol by a nitrogen-bearing aryl moiety
was identified as one of the structural requirements for improving
the pharmacological profile of this class of NR2B ligands. Anilines
1 were proposed as potential probes to investigate the NR2B
receptor active binding site,6 and several heterocyclic derivatives
of general formula A were found to display potent NR2B
antagonistic activity5 (Fig. 1). With the aim of developing selective
NR2B receptor imaging agents, we focused on ifenprodil-based
inhibitors possessing a functional group as an attachment point
for a contrastophore. In this context, we considered the aniline-
containing analogues B as valuable candidates (Fig. 1), and we
designed anilines 1–12 bearing a linear alkyl chain of varied length
(from two to twelve carbon atoms), eventually functionalized
with a reactive function (hydroxyl or amine) for bioconjugation
(Scheme 1). Therefore, we required an operationally simple and
general protocol to access to such products.
Scheme 2 Synthesis of aryl bromides 13a and 13b: (i) Br2, CCl4, rt, 1.5 h
(99%); (ii) 4-benzylpiperidine, Et3N, EtOH, 80 ◦C, 24 h (82%); (iii) NaBH4,
EtOH, rt, 24h (13a: 78%; 13b: 19%).
Coupling with primary monoamines
Amination of aryl bromide 13a, using n-propyl- and n-hexylamine
as model primary amines, was first attempted under palladium
catalysis9e (data not reported). Whatever the palladium source
[Pd2dba3, PdCl2(dppf), 1–5 mol%], the ligand (dppf, PPh3, 2–
10 mol%) or the base (tBuONa, 1–3 equiv.), the reactions carried
out in refluxing dioxane or toluene always led to numerous
unidentified degradation products. Although the formation of
the hydrogenated analogue 15a (Scheme 3) could be detected by
mass spectra analyses of the crude products, it was clear from
the 1H NMR spectra that the main transformations occurred on
the ethanolamine linker. These observations led us to examine
the stability of the phenylethanolamine 13a under palladium-
catalyzed amination conditions (Table 1). Bromoarene 13a was
found unchanged after refluxing in dioxane with tBuONa (en-
try 1), whereas it was converted into phenone 16 in 65% yield
when palladium catalyst [PdCl2(dppf), with or without extra dppf]
Scheme 1 Strategy for the synthesis of anilines 1–12 through transition
metal-catalyzed amination reaction from aryl bromides 13.
A synthetic scheme based on the reported preparations of
anilines 1, involving either a low yielding (17%) Friedel–Crafts re-
action from acetanilide6 or thiophenylation of a para-nitrophenyl-
propanaminodiol intermediate7 as key steps, could not be regarded
as an efficient and straightforward approach to N-substituted
anilines 2–12. For the last few years, transition metal-catalyzed
amination of aryl halides broke through in the field of aminoarene
synthesis.8–10 This approach, investigated mainly on model com-
pounds, has proven to be very efficacious and attractive due to the
mild reaction conditions and the broad functional group tolerance.
On the other hand, arylation of linear polyamines has remained
less explored,9d and extension to provide access to primary
anilines11 from ammonia sources may represent a real challenge.
Herein, we disclose our efforts towards the application of the
amination methodology to the synthesis of anilinoethanolamines
1–12, as well as our results for the evaluation of their NR2B
receptor inhibition activity (Scheme 1).
Scheme 3 Conversion of aryl bromide 13a into phenone 16: (i) tBuONa
(2 equiv.), PdCl2(dppf) (2 mol%), dppf (0 or 4 mol%), dioxane, 110 ◦C,
18 h (65% isolated yield).
Table 1 Stability of bromoarene 13aa
Bromoarene 13a
recovered (%)b
Results and discussion
Entry Base
Catalyst
Solvent
Synthesis of aryl bromide precursors 13a and 13b
1
2
3
4
5
6
7
tBuONa
—
Dioxane 98
tBuONa PdCl2(dppf)c
tBuONa PdCl2(dppf)c/dppfd
tBuONa CuIe
Dioxane <10f
The aryl halides we chose as precursors were the ( )-
(R*R*)- and ( )-(R*S*)-(bromophenyl)ethanolamines 13a and
13b, readily achieved starting from commercially available 4¢-
bromopropiophenone (Scheme 2).12 Preparation occurred accord-
ing to a three-step synthesis involving bromination, substitu-
tion with benzylpiperidine, then reduction. The use of sodium
borohydride2a as the reducing agent led to a mixture of the easily
separable (R*R*) and (R*S*) diastereoisomers in 80 : 20 ratio.
Bromoarenes 13a and 13b were obtained in 63 and 15% overall
yields respectively.
Dioxane <10f
DMF
DMF
DMF
97
98
97
K3PO4
K3PO4
K3PO4
—
CuIe
PdCl2(dppf)c
Dioxane <10g
a Bromoarene 13a (1 equiv.), base (2 equiv.), 110 ◦C in dioxane, or 90 ◦C in
DMF, 18 h reaction time. b Isolated yield. c 2 mol%. d 4 mol%. e 20 mol%.
f Formation of phenone 16 (65% isolated yield) and alcohol 15 (5% isolated
yield). g Formation of phenone 16 (55% isolated yield) and alcohol 15 (30%
isolated yield).
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was added (Table 1, entries 2 and 3). Both the oxidation of the
benzylic alcohol and the reduction of the bromophenyl moiety
occurred under these conditions (Scheme 3). Palladium-catalyzed
oxidation of the alcohol, which was proposed as resulting from
a deprotonation of palladium-coordinated alcohol followed by
a b-hydride elimination, usually needed a co-oxidant.13 In the
formation of phenone 16 under anaerobic conditions and in the
absence of an added oxidant reagent, we can suspect that the aryl
bromide moiety played such an oxidant role.13a,14 As a remark, the
palladium-induced oxidation of 13a to phenone 16 also occurred
using K3PO4 as the base, but to a lesser extent (entry 7). Attempts
to carry out palladium-catalyzed amination from bromophenone
14 and O-protected bromoarene 13a also failed (data not shown).
So, we turned to copper-mediated amination. As oxidation of
benzylic alcohol could also occur under copper catalysis,13c,15 we
examined as preliminary experiments the stability of the starting
ethanolamine 13a under usual coupling conditions involving
K3PO4 (2 equiv.) as base and CuI (20 mol%) as copper source
of 130 ◦C) and DMF as the solvent, formylation of the second
amine function also took place, leading to the corresponding
formamidoanilines 17a–19a as major compounds (entries 14,
18 and 21). The desired aminoanilines 9a–12a were obtained
as the sole coupling products by carrying out amination in
DMSO (entries 22, 28, 30 and 33). Using the CuI–L2 catalyst
that allowed reactions at a lower temperature (90 ◦C), coupling
in DMF proceeded without formylation, leading exclusively to
aminoanilines 7a–12a in high yields (entries 15, 19, 23, 29, 31 and
34). Amination was found to be strongly dependent on the nature
of the solvent, and the yields of aminoaniline 9a decreased by
changing the solvent according to the order DMF > dioxane >
DMSO ꢀ toluene (entry 23 compared to entries 26, 24 and 25
respectively). Extension of the reaction time from 24 to 48 h did
not allow an improvement in coupling efficiency (data not shown).
Contrary to ethanolamine, 1,2-ethylenediamine was found to be
very reactive, even when using a very low amount of CuI and
no additional ligand (entries 15–17 compared to entries 8–10).
Ethylenediamine probably acted both as nucleophile and as ligand.
None of the other a,w-diamines used, possessing a longer alkyl
chain, could display such a dual role (entries 20, 27 and 32).
◦
in DMF at 90 C (Table 1). Under nitrogen or air atmospheres,
no conversion of 13a was observed by reaction with K3PO4
alone (entry 5), or with CuI (entry 6). Ethanolamine 13a was
also found to be stable in tBuONa–CuI-containing medium
(entry 4). In the absence of an additional ligand, aryl bromide
13a was also inert in copper-catalyzed amination using n-propyl-
and n-hexylamine (data not shown). These data prompted us to
screen for appropriate ligands. Among the attractive, structurally
simple, commercially available ligands we tested,16 only N,N-
diethylsalicylamide10c, L1, and 2-acetylcyclohexanone,10a L2, were
found to be efficient (Table 2). For the CuI–L1 catalyst, coupling
Synthesis of aniline 1a
We extended the copper-catalyzed coupling approach to the
preparation of primary aniline 1a, using the optimal catalyst
CuI–L2 in DMF, and several ammonia surrogates or aqueous
ammonia (Scheme 4). First, coupling was achieved with sodium
azide,17 and was followed by reduction with lithium aluminium
hydride. Both the intermediate azide 20a and aniline 1a were
formed in very poor yields (10 and 30%, respectively). All attempts
to increase yields by changing the reaction conditions (reagent
amounts, reaction time, temperature, solvent and nature of the
ligand) failed (data not reported). Amination performed with
benzylamine10 led to the corresponding aniline 21a in yields that
did not exceed 26%, even by increasing the amounts of CuI and
L2 to 40 and 50 mol%, respectively, and by using benzylamine
in excess (5 equiv.). After catalytic hydrogenation, aniline 1a was
obtained in only 9% yield from bromoarene 13a. Coupling with
benzophenone imine18 afforded imine 22a in 80% yield using CuI–
L2 catalyst at 40/50 mol%. Imine 22a was then converted to
aniline 1a by treatment with hydroxylamine in 72% yield (58%
overall yield from bromoarene 13a). Finally, amination using
◦
was low at 90 C, whatever the amounts used (entries 1 and 4).
◦
At 130 C, anilines 2a and 3a were obtained in 50% yield using
at least 40 mol% of both CuI and L1 (entries 2 and 5). By using
the CuI–L2 catalyst, yields for anilines 2a and 3a reached 50–53%
under milder conditions, i.e. at 90 ◦C with 10 and 20 mol% of
CuI and ligand, respectively (entries 3 and 6). The replacement of
K3PO4 by Cs2CO3 led to yields that did not exceed 25%, and no
coupling occurred at rt (data not shown). In all assays, no trace of
oxidation product was detected. The only side products obtained,
besides anilines, were the starting aryl bromide 13a, recovered as
the major by-product, and the hydrogenated analogue 15a, formed
in less than 10% yields.
Given these results, we examined amination with functionalized
aliphatic amines, using either CuI–L1 (40/50 mol%) at 130 ◦C or
CuI–L2 (10/20 mol%) at 90 ◦C as reaction conditions. Coupling
was achieved in 51% yield with hexanolamine according to the
CuI–L2-based method (entry 11). Surprisingly, it did not exceed
15% yield with ethanolamine, whatever the protocol used (entries
7–10). Starting from N-Boc monoprotected hexyldiamine, no
coupling product was formed under either conditions (entries 12
and 13).
Coupling with a,x-diamines
=
Scheme 4 Synthesis of aniline 1a: (i) NaN3, BnNH2 or HN CPh2
(5 equiv.), CuI (40 mol%), L2 (50 mol%), K3PO4 (2 equiv.), DMF, 90 ◦C,
48 h (20a: 10%, 21a: 26%, 22a: 80%); (ii) 28% aqueous NH3 (5 equiv.),
CuI (10 mol%), L2 (60 mol%), K3PO4 or Cs2CO3 (2 equiv.), DMF, 90 ◦C,
18 h (1a: 28% or 43%); (iii) 28% aqueous NH3 (5 equiv.), CuI (10 mol%),
2,4-pentadione (60 mol%), Cs2CO3 (2 equiv.), DMF, 90 ◦C, 18 h (1a: 65%);
(iv) LiAlH4, THF, rt, 24 h (30%); (v) H2 (50 bar), Pd/C, THF, 60 ◦C, 72 h
(35%); (vi) NH2OH·HCl, CH3CO2Na, MeOH, rt, 24 h (72%).
Coupling was studied starting from unprotected a,w-diamines
for the synthesis of aminoanilines 7a–12a. Whatever the length
of the alkyl chain of the diamine (from 2 to 12 carbon atoms),
the monoamination of bromoarene 13a occurred in about 52–
86% yields (Table 2). No traces of bis-coupling product were
detected. Using the CuI–L1 combination (requiring a temperature
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Table 2 Copper-catalyzed amination of bromoarene 13aa
H2N(CH2)nXH
Entry
X
n
equiv
CuI (mol%)
Ligand (mol%)
Solvent
T/◦C
Aniline
Yield (%)b
1
2
3
CH2
2
1.5
1.5
1.5
40
10
10
L1 (30)
L1 (50)
L2 (20)
DMF
DMF
DMF
90 or 130
130
90
2a
2a
2a
<5c
50
53
4
5
6
CH2
O
5
2
1.2
1.5
1.5
40
40
10
L1 (40)
L1 (40)
L2 (20)
DMF
DMF
DMF
90
130
90
3a
3a
3a
10
50
50
7
8
9
10
2
2
2
5
40
10
20
20
L1 (40)
L2 (20)
—
DMF
DMF
DMF
DMF
130
90
90
4a
4a
4a
4a
5d
5d
<5c
15c
—
90
11
O
6
6
2
40
L1 (40)
DMF
130
5a
51
e
12
13
NBoc
2
2
40
10
L1 (40)
L2 (20)
DMF
DMF
130
90
6a
6a
—
—
e
14
15
16
17
NH
2
5
5
5
5
40
10
40
10
L1 (50)
L2 (20)
—
DMF
DMF
DMF
DMF
130
90
90
7a
7a
7a
7a
35f
68
86
84
—
90
18
19
20
NH
NH
4
6
5
5
5
10
40
10
L1 (50)
L2 (20)
—
DMF
DMF
DMF
130
90
90
8a
8a
8a
15g
61
—
21
22
23
24
25
26
27
5
5
5
5
5
5
5
40
40
10
10
10
10
10
L1 (50)
L1 (50)
L2 (20)
L2 (20)
L2 (20)
L2 (20)
—
DMF
DMSO
DMF
DMSO
Toluene
Dioxane
DMF
130
130
90
90
90
90
90
9a
9a
9a
9a
9a
9a
9a
8h
42
62
45
10
56
—
28
29
NH
NH
8
5
5
40
10
L1 (50)
L2 (20)
DMSO
DMF
130
90
10a
10a
54
58
30
31
32
10
5
5
5
40
10
10
L1 (50)
L2 (20)
—
DMSO
DMF
DMF
130
90
90
11a
11a
11a
53
57
—
33
34
NH
12
5
5
40
10
L1 (50)
L2 (20)
DMSO
DMF
130
90
12a
12a
52
55
a Bromoarene (13a) (1 equiv.), K3PO4 (2 equiv.), 24 h reaction time. b Isolated yields. c ArBr (13a) recovered. d Low conversion and difficult purification.
e Unidentified products. f Isolation of the corresponding formamidoaniline 15a in 38% yield. g Isolation of the corresponding formamidoaniline 16a in
41% yield. h Isolation of the corresponding formamidoaniline 17a in 30% yield.
aqueous ammonia and CuI–L2 catalyst at 10/60 mol% succeeded
in 28% yield. The yield of aniline 1a increased to 43% by changing
K3PO4 for Cs2CO3, and reached 65% under the recently reported
conditions11g using 2,4-pentadione instead of L2.19 The latter
coupling was revealed as a very efficient synthesis of aniline 1a
compared to those reported.6,7 The sequence with benzophenone
imine could represent an attractive alternative in the case of
ammonia-sensitive substrates.
It is noteworthy that the amination reaction occurred, in all
cases, without any epimerization. The stereochemistry of the
anilines 1a–12a and 17a–19a was unchanged compared to that
of bromoarene 13a. The erythro (R*S* or “unlike”) aniline 7b
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could be obtained in the same manner, starting from the erythro
diastereoisomer of bromoarene 13b (Scheme 5).
Scheme 5 Synthesis of ( )-(R*S*)-aniline 7b: (i) H2N(CH2)2NH2 (5
equiv.), CuI (10 mol%), K3PO4 (2 equiv.), DMF, 90 ◦C, 24 h (82%).
NMDA NR2B receptor inhibition studies
The antagonistic efficiency for the NR2B subunit of ifen-
prodil (threo and erythro isomers taken separately as reference
compounds)2a and anilines 1a–5a, 7a–12a and 7b (used in their am-
monium hydrochloride form or as neutral anilines) was evaluated
through the monitoring of the intracellular calcium concentration
under videomicroscopy in HEK-293 cells transfected with the
cDNA encoding for NR1-1A and NR2B. As NMDA receptors
are calcium-permeable ion channels and critical for glutamatergic
synaptic transmission,20 we measured calcium influx induced by
the application of NMDA (at 100 mM for 30 s) in the presence
of increasing concentrations of potential antagonists. HEK cells,
successfully transfected with NR1/NR2B-GFP subunits, display
a green fluorescence. In these GFP positive HEK cells, the
application of NMDA induced a rapid and sustained increase
in [Ca2+]i (determined as 100% value). Following a 5 min rinse
with HBBSS, erythro-, threo-ifenprodil and its analogues 1a–5a,
7a–12a and 7b (used at 10 mM in HBBSS) were applied for 1 min
before and during NMDA application. The results are presented
in Fig. 2. Incubation with erythro-ifenprodil reduced with a dose–
response relationship the amplitude of NMDA-induced [Ca2+]i,
with a maximum effect corresponding to 11.16 1.87% (p <
0.0001) of NMDA-induced [Ca2+]i. Close values were obtained
with threo-ifenprodil (21.53 1.48%; p < 0.0001), showing that
the stereochemistry had no significant influence on the functional
NR2B subunit binding. We did not observe a significant difference
between the non-substituted aniline 1a (18.60 3.46%; p < 0.0001)
and each diastereoisomer of ifenprodil. These results confirmed
that the replacement of the phenol by the primary aniline ring had
not modified the NR2B receptor inhibition properties. Within
the N-substituted anilines, both the nature and the length of
the substituent were crucial to retain receptor binding properties.
Alkyl groups were detrimental (>90% NMDA response found
for N-propyl- and hexylanilines 2a and 3a), as well as hydroxy
and aminoalkyl long chains to a slightly lesser extent (>68%
NMDA response for hydroxy and aminoalkylanilines 5a, 9–12a
at 6, 8, 10 and 12 carbon atoms). Hydroxyethyl, aminoethyl and
aminobutylanilines 4a (44.46 3.44%; p < 0.001), 7a (39.03
3.97%; p < 0.001) and 8a (47.71 2.21%; p < 0.001), respectively,
reduced NMDA responses with high magnitude. Both the threo
and erythro aminoethylanilines, 7a (39.03 3.97%; p < 0.001)
and 7b (35.69 3.64%; p < 0.001), were found to be potent NR2B
receptor inhibitors, with NMDA responses close to those of aniline
1a and ifenprodil.
Fig. 2 Effect of ifenprodil analogues on NMDA-induced calcium influx.
Histograms represent quantification of the calcium influx during 2 min
from the beginning of 100 mM NMDA application (30 s) from three
independent experiments s.e.m. (n = 3). Responses to the compounds’
application were normalized to NMDA 100 mM mean value. * indicates
significantly different from the NMDA alone; # indicates significantly
different from erythro-ifenprodil and NMDA alone.
Conclusion
In summary, we have shown that the copper-mediated amination
with alkylamines, hexanolamine, alkyldiamines, benzophenone
imine and aqueous ammonia could be efficiently applied to
the easily prepared bromoarene 13 and constituted an efficient,
operationally simple route to anilinoethanolamines 1–12. We
found that this coupling reaction was very ligand-sensitive, except
with ethylene diamine, and some unexpected failures (notably with
ethanolamine) were encountered. This work complemented the
scope of the copper-catalyzed amination methodology and illus-
trated once more the beneficial impact of this approach compared
with the pallado-catalyzed version. The aminoethylanilines 7 were
found to be active in an NR2B receptor inhibition functional assay,
and could be exploited for imaging agents elaboration. Further
applications of the amination reaction for the synthesis of new
generations of aniline analogues as potent NR2B antagonists are
under way, and will be reported in due course.
Experimental
General synthesis methods
All reactions were performed under anhydrous conditions and an
atmosphere of nitrogen. All reagents were purchased from Acros
Organics, Fluka or Sigma-Aldrich and were used as commercially
supplied. Anhydrous N,N-dimethylformamide (DMF) was dis-
tilled from calcium hydride under nitrogen prior to use. Flash
column chromatography was carried out on silica gel (Merck
Kieselgel 60 F254, 40–63 mm). Analytical thin layer chromatography
(TLC) was performed on Merck aluminium-backed plates pre-
coated with silica (0.2 mm, 60 F254), which were visualized by
quenching of ultraviolet fluorescence (l = 254 and 366 nm).
Melting points were determined on a Barnstead Electrothermal
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IA 9100 Mp apparatus and are uncorrected. Infrared spectra were
recorded on a Thermo Nicolet 350 FT-IR ATR spectrometer.
3.09 (t, J = 7.2 Hz, 2H), 2.88-2.82 (m, 1H), 2.72-2.65 (m, 1H),
2.58 (d, J = 7.2 Hz, 2H), 2.60-2.48 (m, 2H), 2.11-2.05 (m, 1H),
1.73-1.69 (m, 2H), 1.67 (sext, J = 7.2 Hz, 2H), 1.61-1.53 (m, 1H),
1.48-1.38 (m, 1H), 1.32-1.26 (m, 3H), 1.01 (t, J = 7.2 Hz, 3H),
0.73 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3, 100.6 MHz) d 148.5,
141.1, 130.9, 129.5, 128.7, 128.6, 126.2, 112.9, 74.3, 67.0, 46.3, 44.8,
43.6, 38.7, 33.4, 33.0, 23.1, 12.0, 8.3. IR (cm-1) 3342, 2955, 2927,
2873, 1614, 1522, 1453, 1289, 1148, 1082, 1016, 815, 741, 697,
543. ESI+/MS/MS m/z (%) 367.4 ([M + H]+, 55), 349.4 (100).
ESI+/HRMS calcd for C24H35N2O 367.2749; found 367.2732.
The ammonium salt of piperidine 2a was obtained as a white
solid after stirring in diethyl ether (5 mL) with HCl in diethyl ether
(1 M, 2 mL) for 30 min. Anal. calcd for C24H34N2O·1.1HCl, C,
70.89, H, 8.70, N, 6.89; found C, 70.91, H, 9.08, N, 6.63.
1
Only selected absorbances are reported (n in cm-1). H NMR
spectra were recorded at either 250 or 400 MHz on Brucker
DPX 250 or DPX 400. Chemical shifts (d) are quoted in parts
per million (ppm) and referenced to tetramethylsilane (TMS).
Coupling constants (J) are given in Hz and reported to the
nearest 0.5 Hz. Coupling patterns are abbreviated as follows: s
(singlet), d (doublet), t (triplet), q (quadruplet), qt (quintuplet),
sex (sextuplet), m (multiplet). 13C NMR spectra were recorded at
62.9 or 100.6 MHz on Brucker DPX 250 or DPX 400. Chemical
shifts (d) are quoted in parts per million (ppm) and referenced
to tetramethylsilane (TMS). MS and high resolution mass spectra
(HRMS) were recorded using a Waters Q-TOF micro spectrometer
by electrospray ionisation (ESI). Relative intensities are given in
brackets. Elemental analyses were performed on a ThermoQuest
analyser CHNS and were given within 0.4% of the calculated
values. Syntheses of bromoarenes 13a and 13b, aniline 21a and
imine 22a, and biological experimental procedures are given in the
ESI.†
(1R*,2R*)-2-(4-Benzylpiperidin-1-yl)-1-(6-
hexylaminophenyl)propan-1-ol 3a
Obtained from aryl bromide 13a (113 mg, 290 mmol) and
hexylamine (41 mg, 406 mL) as an orange oil (60 mg, 50%)
according to method A or B. Rf 0.18 (ethyl acetate–heptanes
General procedure for copper-catalyzed amination reactions
1
50 : 50). H NMR (CDCl3, 400 MHz) d 7.33-7.28 (m, 2H), 7.22-
7.14 (m, 5H), 6.58 (d, J = 8.8 Hz, 2H), 4.14 (d, J = 9.6 Hz, 1H),
3.10 (t, J = 7.2 Hz, 2H), 2.88-2.82 (m, 1H), 2.72-2.65 (m, 1H), 2.58
(d, J = 7.2 Hz, 2H), 2.60-2.48 (m, 2H), 2.11-2.05 (m, 1H), 1.73-
1.69 (m, 2H), 1.68-1.50 (m, 3H), 1.49-1.25 (m, 10H), 0.91 (m, 3H),
0.73 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3, 100.6 MHz) d 148.6,
141.0, 132.6, 129.5, 128.7, 128.6, 126.2, 112.9, 74.4, 68.4, 44.8,
44.5, 43.6, 38.7, 33.4, 32.9, 32.0, 30.0, 27.3, 26.0, 23.1, 14.5, 8.3. IR
(cm-1) 2923, 1600, 1448, 1380, 1291, 1233, 1179, 1119, 1070, 1019,
747, 701, 591, 552. ESI+/MS/MS m/z (%) 409.5 ([M + H]+, 60),
391.5 (100). ESI+/HRMS calcd for C27H41N2O 409.3219; found
409.3199.
Method A. CuI (0.4 equiv.), N,N-diethylsalicylamide (L1,
0.4 equiv.), aryl bromide 13a or 13b (1 equiv.) and potassium
triphosphate (2 equiv.) were added to a screw-capped tube with a
Teflon-lined septum. The tube was then evacuated and backfilled
with nitrogen. Amine (1.4–2 equiv.), aminoalcohol (2–5 equiv.)
or diamine (5 equiv.) and dry DMF (0.5 mL for 1.0 mmol
of aryl bromide 13) were added by syringe at rt. The reaction
mixture was stirred at 130 ◦C for 24 h, then allowed to reach
rt. Dichloromethane, water and NH4OH (respectively 10, 10
and 1 mL for 0.5 mL of DMF) were added. After extraction
with dichloromethane, the combined organic layers were washed
with brine and dried over MgSO4. The solvent was removed
in vacuo, and the crude residue was purified by flash column
chromatography on silica gel to afford the desired product.
The ammonium salt of piperidine 3a was obtained as a white
solid after stirring in diethyl ether (5 mL) with HCl in diethyl ether
(1 M, 2 mL) for 30 min. Anal. calcd for C27H40N2O·1.8HCl, C,
68.12, H, 9.23; found, C, 68.53, H, 9.57.
Method B. CuI (0.1 equiv.), 2-acetylcyclohexanone (L2, 0.2
equiv.), aryl bromide 13a or 13b (1 equiv.) and potassium
triphosphate (2 equiv.) were added to a screw-capped tube with a
Teflon-lined septum. The tube was then evacuated and backfilled
with nitrogen. Amine (1.4 or 2 equiv.) or diamine (5 equiv.) and
dry DMF (0.5 mL for 1.0 mmol of aryl bromide 13) were added
by syringe at rt. The reaction mixture was stirred at 90 ◦C for 24 h,
then allowed to reach rt. Dichloromethane, water and NH4OH
(respectively 10, 10 and 1 mL for 0.5 mL of DMF) were added.
After extraction with dichloromethane, the combined organic
layers were washed with brine and dried over MgSO4. The solvent
was removed in vacuo and the residue was purified by flash column
chromatography on silica gel to afford the desired product.
(1R*,2R*)-6-{4-[2-(4-Benzylpiperidin-1-yl)-1-
hydroxypropyl]phenylamino}ethan-1-ol 4a
Obtained from aryl bromide 13a (195 mg, 502 mmol) and
ethanolamine (75 mg, 2.51 mmol) as a yellow oil (27 mg, yield
15%) according to method A. Rf 0.80 (dichloromethane–methanol
90 : 10). 1H NMR (CDCl3, 400 MHz) d 7.23-7.05 (m, 7H), 6.51 (d,
J = 8.4 Hz, 2H), 4.04 (d, J = 9.6 Hz, 1H), 3.70 (t, J = 5.2 Hz, 2H),
3.16 (t, J = 5.2 Hz, 2H), 2.75-2.70 (m, 1H), 2.62-2.59 (m, 1H),
2.51-2.40 (m, 4H), 1.64-1.61 (m, 2H), 1.48-1.45 (m, 1H), 1.35-1.31
(m, 1H), 1.22-1.21 (m, 1H), 0.64 (d, J = 6.4 Hz, 3H). 13C NMR
(CDCl3, 100.6 MHz) d 147.8, 140.4, 131.0, 129.1, 128.4, 128.2,
125.8, 113.0, 66.5, 61.2, 52.8, 46.2, 44.4, 43.2, 38.3, 32.9, 32.5, 29.7.
IR (cm-1) 3353, 2916, 1615, 1522, 1054, 734, 699. ESI+/MS/MS
m/z (%) 369.3 ([M + H]+, 75), 351.3 (100). ESI+/HRMS calcd for
C23H33N2O2 369.2542; found 369.2548.
(1R*,2R*)-2-(4-Benzylpiperidin-1-yl)-1-(4-
propylaminophenyl)propan-1-ol 2a
Obtained from aryl bromide 13a (106 mg, 273 mmol) and
propylamine (32 mg, 546 mmol) as a yellow solid (50 mg, 50%)
according to method A. Mp 80 ◦C. Rf 0.12 (ethyl acetate–heptanes
The ammonium salt of piperidine 4a was obtained as a yellow
solid after stirring in THF (2 mL) with HCl in diethyl ether (2M,
1 mL) for 1 h. Anal. calcd for C27H40N2O2·2HCl·2.5 H2O·0.5 Et2O,
C, 57.35, H, 8.47, N, 5.35; found, C, 56.91, H, 8.83, N, 5.79.
1
50 : 50). H NMR (CDCl3, 400 MHz) d 7.33-7.28 (m, 2H), 7.22-
7.14 (m, 5H), 6.59 (d, J = 8.8 Hz, 2H), 4.14 (d, J = 9.6 Hz, 1H),
1116 | Org. Biomol. Chem., 2010, 8, 1111–1120
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(1R*,2S*)-1-[4-(4-Aminoethylamino)phenyl]-2-(4-benzylpiperidin-
1-yl)propan-1-ol 7b
(1R*,2R*)-6-{4-[2-(4-Benzylpiperidin-1-yl)-1-
hydroxypropyl]phenylamino}hexan-1-ol 5a
Obtained from aryl bromide 13b (100 mg, 250 mmol) and 1,2-
ethylenediamine (75 mg, 1.25 mmol) as an orange oil (77 mg, 87%)
according to method B. Rf 0.34 (dichloromethane–methanol–
Obtained from aryl bromide 13a (125 mg, 320 mmol) and 6-
aminohexan-1-ol (75 mg, 640 mmol) as a brown oil (70 mg, yield
51%) according to method A. Rf 0.80 (dichloromethane–methanol
90 : 10). 1H NMR (CDCl3, 400 MHz) d 7.32-7.15 (m, 7H), 6.58 (d,
J = 8.8 Hz, 2H), 4.15 (d, J = 9.6 Hz, 1H), 3.66 (t, J = 7.0 Hz, 2H),
3.12 (t, J = 7.0 Hz, 2H), 2.88-2.83 (m, 1H), 2.81-2.62 (m, 2H),
2.58 (d, J = 6.8 Hz, 2H), 2.58-2.51 (m, 2H), 2.16-2.11 (m, 1H),
1.75-1.71 (m, 2H), 1.64-1.55 (m, 5H), 1.44-1.39 (m, 9H), 0.75 (d,
J = 6.4 Hz, 3H). 13C NMR (CDCl3, 100.6 MHz) d 152.2, 139.6,
129.7, 129.5, 128.7, 128.6, 126.3, 113.0, 74.3, 66.9, 63.3, 53.8, 46.5,
44.7, 44.4, 33.2, 33.1, 32.2, 29.9, 27.3, 26.0, 8.2. IR (cm-1) 2958,
2926, 2858, 1727, 1456, 1271, 1122, 1071, 744, 703. ESI+/MS/MS
m/z (%) 425.4 ([M + H]+, 53), 407.4 (100). ESI+/HRMS calcd for
C27H41N2O2 425.3168; found 425.3188.
1
NH4OH 90 : 10 : 0.1). H NMR (CDCl3, 400 MHz) d 7.31-7.28
(m, 2H), 7.21-7.08 (m, 5H), 6.58 (d, J = 8.8 Hz, 2H), 4.70 (d,
J = 4.4 Hz, 1H), 3.21-3.06 (m, 2H), 3.05-2.94 (m, 1H), 2.92-2.83
(m, 2H), 2.76-2.69 (m, 1H), 2.65-2.58 (m, 1H), 2.56-2.43 (m, 2H),
2.29-2.15 (m, 1H), 2.07-1.93 (m, 1H), 1.71-1.35 (m, 3H), 1.33-1.01
(m, 2H), 0.69 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3, 100.6 MHz)
d 147.3, 140.7, 131.2, 129.2, 129.1, 128.2, 127.0, 125.8, 112.5, 72.3,
64.6, 52.6, 49.4, 46.6, 46.5, 43.7, 43.2, 41.1, 38.1, 32.6, 10.1. IR
(cm-1) 2961, 2926, 1727, 1443, 1274, 1139, 1076, 1058, 931, 745,
699. ESI+/MS/MS m/z (%) 368.3 ([M + H]+, 90), 350.3 (100).
ESI+/HRMS calcd for C23H34N3O 368.2702; found 368.2704.
The ammonium salt of piperidine 5a was obtained as a white
solid after stirring in diethyl ether (5 mL) with HCl in diethyl ether
(1M, 2 mL) for 30 min. Anal. calcd for C27H40N2O2·HCl, C, 70.33,
H, 8.96, N, 6.07; found, C, 70.83, H, 9.18, N, 6.61.
(1R*,2R*)-N-(4-{4-[2-(4-Benzylpiperidin-1-yl)-1-
hydroxypropyl]phenylamino}butyl) formamide 16a
Obtained from aryl bromide 13a (141 mg, 360 mmol) and 1,4-
butanediamine (190 mg, 2.16 mmol) as an orange oil (58 mg, 41%)
according to method A. Rf 0.38 (dichloromethane–methanol–
NH4OH 95 : 5 : 0.5). 1H NMR (CDCl3, 400 MHz) d 8.10 (s, 1H),
7.32-7.28 (m, 2H), 7.22-7.14 (m, 5H), 6.57 (d, J = 8.8 Hz, 2H), 6.05
(bs, 3H), 4.13 (d, J = 9.6 Hz, 1H), 3.40-3.22 (m, 2H), 3.14-3.11 (m,
2H), 2.88-2.82 (m, 1H), 2.73-2.68 (m, 1H), 2.62-2.54 (m, 4H), 2.14-
2.10 (m, 1H), 1.75-1.68 (m, 2H), 1.68-1.51 (m, 5H), 1.49-1.38 (m,
1H), 1.38-1.22 (m, 1H), 0.74 (d, J = 6.8Hz, 3H). 13C NMR (CDCl3,
100.6 MHz) d 161.8, 148.3, 141.0, 131.0, 129.5, 128.8, 128.6, 126.2,
113.1, 74.3, 66.9, 53.0, 50.0, 43.7, 43.6, 38.7, 38.3, 33.4, 32.9, 27.6,
27.1, 8.3. IR (cm-1) 3309, 2927, 2848, 1661, 1614, 1522, 1382,
1321, 1140, 1045, 822, 744, 699, 545. ESI+/MS/MS m/z (%) 424.4
([M + H]+, 35), 406.4 (100). ESI+/HRMS calcd for C26H38N3O2
424.2964; found 424.2944. Anal. calcd for C26H37N3O2·H2O, C,
70.71, H, 8.90, N, 9.52; found, C, 70.60, H, 9.01, N, 9.70.
(1R*,2R*)-N-(2-{4-[2-(4-Benzylpiperidin-1-yl)-1-
hydroxypropyl]phenylamino}ethyl) formamide 15a
Obtained from aryl bromide 13a (107 mg, 270 mmol) and 1,2-
ethylenediamine (97 mg, 1.62 mmol) as an orange oil (60 mg, 60%)
according to method A. Rf 0.60 (dichloromethane–methanol–
NH4OH 95 : 5 : 0.5). 1H NMR (CDCl3, 400 MHz) d 8.12 (s, 1H),
7.32-7.24 (m, 2H), 7.23-7.14 (m, 5H), 6.58 (d, J = 8.8 Hz, 2H),
6.40 (bs, 3H), 4.13 (d, J = 9.6 Hz, 1H), 3.52-3.48 (m, 2H), 3.27 (t,
J = 7.2 Hz, 2H), 2.88-2.82 (m, 1H), 2.75-2.71 (m, 1H), 2.62-2.54
(m, 4H), 2.14-2.10 (m, 1H), 1.75-1.71 (m, 2H), 1.71-1.51 (m, 1H),
1.49-1.38 (m, 1H), 1.38-1.22 (m, 1H), 0.74 (d, J = 6.8 Hz, 3H).
13C NMR (CDCl3, 100.6 MHz) d 162.4, 147.9, 141.0, 131.3, 129.5,
128.9, 128.6, 126.3, 113.1, 74.3, 66.8, 53.1, 44.9, 44.1, 43.6, 38.6,
38.1, 33.3, 32.8, 8.4. IR (cm-1) 3274, 2926, 2850, 1669, 1614, 1525,
1334, 1139, 1018, 817, 744, 695, 546. ESI+/MS/MS m/z (%) 396.4
([M + H]+, 25), 378.4 (100). ESI+/HRMS calcd for C24H34N3O2
396.2651; found 396.2641. Anal. calcd for C24H33N3O2·0.7H2O, C,
70.63, H, 8.50, N, 10.30; found, C, 70.21, H, 8.65, N, 10.85.
(1R*,2R*)-1-[4-(4-Aminobutylamino)phenyl]-2-(4-benzylpiperidin-
1-yl)propan-1-ol 8a
Obtained from aryl bromide 13a (141 mg, 360 mmol) and 1,4-
butanediamine (190 mg, 2.16 mmol) as an orange oil (86 mg, 61%)
according to method B. Rf 0.17 (dichloromethane–methanol–
NH4OH 95 : 5 : 0.5). 1H NMR (CDCl3, 400 MHz) d 7.32-7.28 (m,
2H), 7.22-7.10 (m, 5H), 6.58 (d, J = 8.8 Hz, 2H), 4.18 (bs, 4H),
4.13 (d, J = 9.6 Hz, 1H), 3.04 (t, J = 7.2 Hz, 2H), 2.92-2.80 (m,
2H), 2.72-2.65 (m, 1H), 2.64-2.48 (m, 2H), 2.56 (d, J = 7.2 Hz,
2H), 2.12-2.04 (m, 1H), 1.75-1.51 (m, 8H), 1.49-1.22 (m, 2H), 0.70
(d, J = 6.8 Hz, 3H). 13C NMR (CDCl3, 100.6 MHz) d 148.6, 140.9,
130.2, 129.5, 128.7, 128.6, 126.3, 113.1, 74.2, 66.8, 53.0, 45.0, 43.7,
43.5, 40.5, 38.4, 33.0, 32.6, 26.8, 26.7, 8.5. IR (cm-1) 2964, 2922,
1725, 1445, 1270, 1137, 1071, 1053, 939, 741, 697. ESI+/MS/MS
m/z (%) 396.4 ([M + H]+, 65), 378.3 (100). ESI+/HRMS calcd for
C25H38N3O 396.3015; found 396.3003.
(1R*,2R*)-1-[4-(4-Aminoethylamino)phenyl]-2-(4-benzylpiperidin-
1-yl)propan-1-ol 7a
Obtained from aryl bromide 13a (141 mg, 360 mmol) and 1,2-
ethylenediamine (159 mg, 1.80 mmol) as an orange oil (99 mg,
70%) according method B. Rf 0.17 (dichloromethane–methanol–
NH4OH 95 : 5 : 0.5). 1H NMR (CDCl3, 400 MHz) d 7.33-7.28 (m,
2H), 7.23-7.10 (m, 5H), 6.59 (d, J = 8.8 Hz, 2H), 4.10 (d, J =
9.6 Hz, 1H), 3.13-3.09 (m, 2H), 2.92-2.80 (m, 2H), 2.76-2.71 (m,
1H), 2.66-2.49 (m, 1H), 2.56-2.43 (m, 4H), 2.12-1.98 (m, 1H), 1.73-
1.63 (m, 2H), 1.58-1.46 (m, 1H), 1.39-1.23 (m, 1H), 0.69 (d, J =
6.8 Hz, 3H). 13C NMR (CDCl3, 100.6 MHz) d 148.0, 140.7, 130.8,
129.1, 128.6, 128.4, 128.2, 125.8, 112.8, 73.9, 66.6, 52.8, 46.6, 44.4,
43.6, 43.2, 41.2, 38.3, 33.1, 32.7, 32.6, 7.9. IR (cm-1) 2961, 2926,
1727, 1443, 1274, 1139, 1076, 1058, 931, 745, 699. ESI+/MS/MS
m/z (%) 368.3 ([M + H]+, 92), 350.3 (100). ESI+/HRMS calcd for
C23H34N3O 368.2702; found 368.2704.
The ammonium salt of piperidine 8a was obtained as a white
solid after stirring in diethyl ether (5 mL) with HCl in diethyl ether
(1M, 2 mL) for 30 min. Anal. calcd for C25H38N3O·2.8HCl, C,
60.21, H, 8.25, N, 8.43; found, C, 60.55, H, 8.64, N, 8.81.
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Ammonium salt of piperidine 10a was obtained as a white solid
after stirring in diethyl ether (5 mL) with HCl in diethyl ether (1 M,
2 mL) for 30 min. Anal. calcd for C29H45N3O·2.9HCl, C, 62.49, H,
8.66; found, C, 62.77, H, 8.79.
(1R*,2R*)-N-(6-{4-[2-(4-Benzylpiperidin-1-yl)-1-
hydroxypropyl]phenylamino}hexyl) formamide 17a
Obtained from aryl bromide 13a (110 mg, 280 mmol) and 1,6-
hexanediamine (195 mg, 1.68 mmol) as an orange oil (35 mg, 30%)
according to method A. Rf 0.23 (dichloromethane–methanol–
NH4OH 95 : 5 : 0.5). 1H NMR (CDCl3, 400 MHz) d 8.16 (s, 1H),
7.32-7.28 (m, 2H), 7.21-7.14 (m, 5H), 6.58 (d, J = 8.8 Hz, 2H),
5.70 (bs, 3H), 4.13 (d, J = 9.6 Hz, 1H), 3.35-3.27 (m, 2H), 3.11 (t,
J = 7.2 Hz, 2H), 2.88-2.82 (m, 1H), 2.72-2.66 (m, 1H), 2.61-2.48
(m, 2H), 2.57 (d, J = 7.2 Hz, 2H), 2.12-2.06 (m, 1H), 1.75-1.48
(m, 7H), 1.47-1.27 (m, 6H), 0.72 (d, J = 6.8 Hz, 3H). 13C NMR
(CDCl3, 100.6 MHz) d 161.6, 148.5, 141.1, 130.9, 129.5, 128.8,
128.6, 126.2, 113.0, 74.3, 66.9, 53.0, 48.0, 44.8, 44.3, 38.7, 38.4,
33.4, 33.0, 29.9, 29.8, 27.1, 27.0, 8.31. IR (cm-1) 3309, 2927, 2854,
1663, 1614, 1522, 1382, 1320, 1142, 1045, 1020, 822, 699, 545.
ESI+/MS/MS m/z (%) = 340.3 ([M + H]+, 32), 322.2 (100).
ESI+/HRMS calcd for C28H42N3O2 452.3277; found 452.3264.
Anal. calcd for C28H41N3O2·0.4H2O, C, 73.29, H, 9.18, N, 9.16;
found, C, 73.18, H, 9.58, N, 9.63.
(1R*,2R*)-1-[4-(10-Aminodecylamino)phenyl]-2-(4-
benzylpiperidin-1-yl)propan-1-ol 11a
Obtained from aryl bromide 13a (100 mg, 257 mmol) and 1,10-
decanediamine (266 mg, 1.54 mmol) as a yellow oil (70 mg,
yield 57%) according to method B. Rf 0.04 (dichloromethane–
1
methanol–NH4OH 95 : 5 : 0.5). H NMR (CDCl3, 400 MHz) d
7.30-7.12 (m, 7H), 6.56 (d, J = 8.8 Hz, 2H), 4.11 (d, J = 9.6 Hz,
1H), 3.08 (t, J = 7.0 Hz, 2H), 3.06 (bs, 4H), 2.83-2.80 (m, 1H), 2.68
(t, J = 7.0 Hz, 2H), 2.58-2.50 (m, 5H), 2.12-2.06 (m, 1H), 1.71-
1.68 (m, 2H), 1.61-1.18 (m, 19H), 0.71 (d, J = 6.4 Hz, 3H). 13C
NMR (CDCl3, 100.6 MHz) d 148.6, 141.1, 130.7, 129.5, 128.7,
128.6, 126.2, 112.9, 74.3, 66.9, 50.6, 44.8, 44.5, 43.6, 42.3, 38.7,
33.5, 33.4, 33.0, 30.0, 29.9, 29.8, 27.5, 27.2, 8.3. IR (cm-1) 2925,
2854, 1598, 1495, 1454, 1392, 1271, 1050, 1020, 746, 702, 592,
556. ESI+/MS/MS m/z (%) 480.8 ([M + H]+, 25), 462.8 (100).
ESI+/HRMS calcd for C31H50N3O 480.3954; found 480.3974.
The ammonium salt of piperidine 11a was obtained as a white
solid after stirring in diethyl ether (5 mL) with HCl in diethyl ether
(1 M, 2 mL) for 30 min. Anal. calcd for C31H49N3O·3HCl·1.8H2O,
C, 60.28, H, 9.42, N, 6.59; found, C, 60.12, H, 9.39, N, 6.49.
(1R*,2R*)-1-[4-(6-Aminohexylamino)phenyl]-2-(4-
benzylpiperidin-1-yl)propan-1-ol 9a
Obtained from aryl bromide 13a (110 mg, 280 mmol) and 1,6-
hexanediamine (195 mg, 1.68 mmol) as an orange oil (80 mg, 62%)
according to method B. Rf 0.05 (dichloromethane–methanol–
NH4OH 95 : 5 : 0.5). 1H NMR (CDCl3, 400 MHz) d 7.30-7.14 (m,
7H), 6.58 (d, J = 8.8 Hz, 2H), 4.13 (d, J = 9.6 Hz, 1H), 3.10 (t,
J = 7.0 Hz, 2H), 3.00 (bs, 4H), 2.88-2.82 (m, 1H), 2.73 (t, J =
7.0 Hz, 2H), 2.72-2.65 (m, 1H), 2.57 (d, J = 6.8 Hz, 2H), 2.60-
2.51 (m, 2H), 2.12-2.06 (m, 1H), 1.75-1.22 (m, 13H), 0.73 (d, J =
6.4 Hz, 3H). 13C NMR (CDCl3, 100.6 MHz) d 148.5, 141.0, 130.8,
129.5, 128.7, 128.6, 126.2, 112.9, 74.3, 66.9, 53.2, 44.8, 44.3, 43.6,
41.9, 38.7, 33.4, 32.9, 32.5, 29.8, 27.2, 26.9, 8.3. IR (cm-1) 2963,
2921, 1724, 1444, 1269, 1070, 1052, 939, 741, 697. ESI+/MS/MS
m/z (%) 424.4 ([M + H]+, 68), 406.4 (100). ESI+/HRMS calcd for
C27H42N3O 424.3328; found 424.3315.
(1R*,2R*)-1-[4-(12-Aminododecylamino)phenyl]-2-(4-
benzylpiperidin-1-yl)propan-1-ol 12a
Obtained from aryl bromide 13a (100 mg, 257 mmol) and 1,12-
dodecanediamine (309 mg, 1.54 mmol) as a yellow oil (69 mg, 55%)
according to method B. Rf 0.04 (dichloromethane–methanol–
NH4OH 95 : 5 : 0.5). 1H NMR (CDCl3, 400 MHz) d 7.32-7.13
(m, 7H), 6.57 (d, J = 8.8 Hz, 2H), 4.12 (d, J = 9.6 Hz, 1H),
3.70 (bs, 4H), 3.08 (t, J = 7.0 Hz, 2H), 2.83-2.80 (m, 1H), 2.73
(t, J = 7.0 Hz, 2H), 2.72-2.67 (m, 1H), 2.58-2.50 (m, 4H), 2.12-
2.06 (m, 1H), 1.72-1.28 (m, 25H), 0.72 (d, J = 6.4 Hz, 3H). 13C
NMR (CDCl3, 100.6 MHz) d 148.6, 141.1, 130.8, 129.5, 128.7,
128.6, 126.2, 112.9, 74.3, 66.9, 53.2, 44.8, 44.5, 43.6, 42.2, 38.7,
36.2, 33.5, 33.0, 32.9, 30.0, 29.8, 29.7, 27.6, 27.2, 26.5, 24.5, 8.3.
IR (cm-1) 2923, 2852, 1725, 1598, 1455, 1384, 1272, 1071, 743,
701. ESI+/MS/MS m/z (%) 508.9 ([M + H]+, 36), 490.9 (100).
ESI+/HRMS calcd for C33H54N3O 508.4267; found 508.4265.
The ammonium salt of piperidine 12a was obtained as a white
solid after stirring in diethyl ether (5 mL) with HCl in diethyl ether
(1 M, 2 mL) for 30 min. Anal. calcd for C33H53N3O·3HCl·H2O C,
62.40, H, 9.20; found, C, 62.55, H, 9.77.
The ammonium salt of piperidine 9a was obtained as a white
solid after stirring in diethyl ether (5 mL) with HCl in diethyl ether
(1 M, 2 mL) for 30 min. Anal. calcd for C27H41N3O·3HCl, C, 70.18,
H, 9.60, N, 9.09; found, C, 70.63, H, 10.11, N, 9.78.
(1R*,2R*)-1-[4-(8-Aminooctylamino)phenyl]-2-(4-
benzylpiperidin-1-yl)propan-1-ol 10a
Obtained from aryl bromide 13a (103 mg, 264 mmol) and 1,8-
octanediamine (228 mg, 1.58 mmol) as an orange oil (70 mg, 58%)
according to method B. Rf 0.04 (dichloromethane–methanol–
NH4OH 95 : 5 : 0.5). 1H NMR (CDCl3, 400 MHz) d 7.32-7.14 (m,
7H), 6.57 (d, J = 8.8 Hz, 2H), 4.13 (d, J = 9.6 Hz, 1H), 3.50
(bs, 4H), 3.10 (t, J = 7.0 Hz, 2H), 2.88-2.82 (m, 1H), 2.71-2.67
(m, 3H), 2.60-2.48 (m, 4H), 2.12-2.06 (m, 1H), 1.73-1.71 (m, 2H),
1.71-1.27 (m, 15H), 0.72 (d, J = 6.4 Hz, 3H). 13C NMR (CDCl3,
100.6 MHz) d 148.6, 141.1, 130.8, 129.5, 128.7, 128.6, 126.2, 112.9,
74.3, 66.9, 53.2, 44.8, 44.5, 43.6, 42.1, 38.7, 33.4, 33.0, 29.9, 29.8,
29.7, 27.5, 27.2, 8.3. IR (cm-1) 2958, 2926, 2857, 1724, 1462, 1271,
1123, 1073, 743. ESI+/MS/MS m/z (%) 452.8 ([M + H]+, 32),
434.8 (100). ESI+/HRMS calcd for C29H46N3O 452.3641; found
452.3652.
(1R*,2R*)-1-(4-Aminophenyl)-2-(4-benzylpiperidin-1-yl)propan-
1-ol 1a
Obtained as a clear yellow solid (65 mg, yield 65%) from aryl
bromide 13a (120 mg, 0.31 mmol), CuI (5.8 mg, 31 mmol), 2,4-
pentadione (18 mg, 0.186 mmol), aqueous ammonia (28%, 95 mL,
1.55 mmol) and Cs2CO3 (202 mg, 0.62 mmol) in DMF (600 mL)
at 90 ◦C for 18 h according to method B. Mp 128 ◦C. Rf 0.2
(ethyl acetate). 1H NMR (CDCl3, 250 MHz) d 7.90-7.13 (m, 7H),
6.62 (d, J = 8.3 Hz, 2H), 4.09 (d, J = 9.8 Hz, 1H), 2.83-2.79
(m, 1H), 2.63-2.53 (m, 1H), 2.51-2.43 (m, 4H), 2.06-2.00 (m, 1H),
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1.70-1.65 (m, 2H), 1.63-1.23 (m, 3H), 0.69 (d, J = 6.7 Hz, 3H).
13C NMR (CDCl3, 62.9 MHz) d 145.9, 140.6, 132.0, 129.1, 128.8,
128.4, 125.8, 114.9, 73.9, 66.6, 53.5, 44.4, 43.2, 38.3, 33.0, 32.5,
7.9. IR (cm-1) 3332, 2958, 2922, 2890, 1610, 1518, 1443, 1238,
1148, 1094, 1069, 840, 740, 697, 538. ESI+/MS/MS m/z (%) 325.5
([M + H]+, 43), 307.5 (100). ESI+/HRMS calcd for C21H29N2O
325.2280; found 325.2289.
The ammonium salt of aniline 1a was obtained as a white solid
after stirring in diethyl ether (5 mL) with HCl in diethyl ether (1 M,
2 mL) for 30 min. Anal. calcd for C21H28N2O·2.5HCl, C, 60.69, H,
7.40, N, 6.74; found, C, 60.77, H, 7.72, N, 6.99.
J. Org. Chem., 2008, 73, 3047; (j) S. Doherty, J. G. Knight, C. H. Smyth,
R. W. Harrington and W. Clegg, Organometallics, 2008, 27, 1679.
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128, 8742; (b) T. Yang, C. X. Lin, H. Fu, Y. Y. Jiang and Y. F. Zhao,
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Lett., 2003, 5, 793; (d) F. Y. Kwong, A. Klapars and S. L. Buchwald,
Org. Lett., 2002, 4, 581; (e) L. Zhu, P. Guo, G. Li, J. Lan, R. Xie and
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Acknowledgements
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(b) D. S. Surry and S. L. Buchwald, J. Am. Chem. Soc., 2007, 129,
10354 and ref. cited therein; (c) J. Kim and S. Chang, Chem. Commun.,
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The authors thank the MENRT, CEA, CNRS, CRUNCH
Network, Re´gion Basse-Normandie and FEDER funding for
financial support.
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19 This result was in agreement with ref. 11g reporting that 2,4-pentadione
was more efficient than L2 for amination of aryl bromides with aqueous
ammonia. It is noteworthy that 2,4-pentadione and Cs2CO3 were
beneficial for coupling with aqueous ammonia, but detrimental for
coupling with primary amines.
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