One-step three-component coupling of aromatic organozinc reagents, secondary amines, and aromatic aldehydes into functionalized diarylmethylamines

Article abstract of DOI:10.1016/j.tet.2006.08.008

Numerous functionalized diarylmethylamines have been synthesized in high yield according to a one-step three-component coupling between an aromatic organozinc reagent, a secondary amine, and an aromatic aldehyde. Both organozinc species and aldehyde can bear a functional group and either aromatic or non-aromatic amines can be used in this versatile procedure.

Full text of DOI:10.1016/j.tet.2006.08.008

Tetrahedron 62 (2006) 9953–9965
One-step three-component coupling of aromatic organozinc
reagents, secondary amines, and aromatic aldehydes into
functionalized diarylmethylamines
*
ꢀ ꢀ
Erwan Le Gall, Michel Troupel and Jean-Yves Nedelec
´
Laboratoire d’Electrochimie, Catalyse et Syntheꢁse Organique (LECSO), CNRS-Universite Paris 12 Val de Marne,
UMR 7582, 2-8 rue Henri Dunant, 94320 Thiais, France
Received 15 June 2006; revised 12 July 2006; accepted 2 August 2006
Available online 23 August 2006
Abstract—Numerous functionalized diarylmethylamines have been synthesized in high yield according to a one-step three-component
coupling between an aromatic organozinc reagent, a secondary amine, and an aromatic aldehyde. Both organozinc species and aldehyde
can bear a functional group and either aromatic or non-aromatic amines can be used in this versatile procedure.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
processes leading to arylmethylamine derivatives, aromatic
Mannich reactions12 have been set as evident candidates
since they allow the potential synthesis of benzylamines,
mixed alkylarylmethylamines, or diarylmethylamines sim-
ply depending on starting compounds, which are involved
in the reaction. Thus, several years ago, Lubben and Feringa
described the aminomethylation of phenol derivatives
through a Mannich-type reaction among phenol derivatives,
amines and formaldehyde.13 Organoboronic acids were
employed in three-component couplings with salicylalde-
hydes14 or heteroaromatic aldehydes15 and amines to provide
arylmethylamine derivatives in moderate to good yield.
Recently, some diarylmethylamines were also efficiently
obtained using organotrifluoroborates instead of arylboronic
acids in a Petasis-related reaction.16 Despite their indubita-
ble interest, these methods suffer from some limitations.
Indeed, aromatic Mannich reactions require the use of elec-
tron-rich benzene derivatives to proceed and no control of
the regioselectivity of the carbon–carbon bond formation
can be envisaged. In the organoboronic Mannich reac-
tion,14–16 only aldehydes bearing an activating group (OH
or N atom) at the position a to the CHO function undergo
the three-component coupling.
Diarylmethylamines constitute important intermediates in
the synthesis of pharmacologically active compounds.1
Although chiral diarylmethylamine blocks are found in many
substances displaying a biological activity, their asymmetric
synthesis has not gained much attention until these last
years. Among several efficient procedures, which have
been developed,2–5 there is a particular emphasis on stereo-
selective additions of carbon nucleophiles to imines.3–5
Thus, it was shown that arylmethylamine derivatives can
be obtained in good yields and enantiomeric excesses either
starting from chiral imines4 or using chiral mediators.5 The
antihistamine agent cetirizine was obtained under its enan-
tiomerically-pure form via a resolution technique employing
tartaric acid.6 In the field of racemate synthesis, reductive
procedures involving carbonyl compounds were employed
for the synthesis of several diarylmethylamines7,8 and other
methods like arylation of iminium salts,9 displacement of
polymer-supported benzotriazole10 using aromatic organo-
magnesium reagents, or addition of phenyllithium to sele-
noamides11 have been also reported.
Multi-component reactions are known to be among the most
powerful building tools available in organic synthesis, since
they rapidly increase the complexity of final products start-
ing from simple precursors. In the field of multi-component
In a recent paper,17 we reported preliminary results about
the possible use of aromatic organozinc reagents18 as
nucleophiles in expedient three-component couplings with
aromatic aldehydes and secondary amines leading to diaryl-
methylamines. It was shown that organozinc reagents consti-
tute valuable nucleophiles in this process and that the
reaction is efficient even with non-activated benzaldehyde
derivatives. In order to clarify the scope of the procedure,
Keywords: Diarylmethylamines; Multi-component reaction; Aromatic orga-
nozinc reagents; Aromatic aldehydes; Secondary amines.
* Corresponding author. Tel.: +33 149781136; fax: +33 149781148; e-mail:
legall@glvt-cnrs.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.008

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E. Le Gall et al. / Tetrahedron 62 (2006) 9953–9965
several other experiments were realized and we report herein
our whole results concerning the possible use of aromatic
organozinc reagents in this multi-component reaction.
coupling occurred faster when CuI was added in catalytic
amount to the 4-methoxyphenylzinc bromide solution before
introduction of piperidine and benzaldehyde. Furthermore,
the reaction appeared to be more selective in the presence
of cuprous salts, fewer side products being detected.
2. Results and discussion
Consequently, we envisaged to extend the reaction to several
organozinc compounds. These reagents were prepared effi-
ciently (77–97% GC yield) starting from 30 mmol of various
aromatic bromides. Wemade the observation that in ageneral
manner, electron-rich organozinc species can be activated
with cuprous iodide (coupling method A) whereas elec-
tron-deficient organozinc fast produces dimeric biaryl com-
pounds upon addition of cuprous iodide. The redox-type
mechanism of this unwanted reaction could be clearly con-
firmed by the concomitant production of copper powder.
Starting from electron-poor organozinc compounds, best
conditions for an efficient coupling were found as Barbier-
like reaction conditions. It consisted in the dropwise addition
of the organozinc into a pre-heated mixture of piperidine and
benzaldehyde (coupling method B). We could also remark
that this coupling method B was more versatile than coupling
method A since it could be applied to any organozinc
reagent, independently from its reactivity and stability.
In a previous work, we had noticed the possibility of using
aromatic organozinc reagents as nucleophiles in Bruylants-
type reactions with a-aminonitriles derived from piperidine,
yielding diarylmethylamines.19 Considering that a-amino-
nitriles are stable iminium equivalents, we anticipated that
organozinc compounds would also react with iminium inter-
mediates, which could be for instance generated in situ from
an aromatic aldehyde and a secondary amine. Hence we
undertook to scan the possibilities provided by a Mannich-
type reaction in which an organozinc reagent would be
used as the carbon nucleophile. Indeed, such a method could
allow the synthesis of numerous diarylmethylamines simply
according to the starting compounds.
In a first time, we had envisaged to form a-aminonitriles in
situ using a Strecker-type reaction.20 Unfortunately, protic
conditions found in classical syntheses20,21 are incompati-
ble with the subsequent use of organozinc reagents, which
are very basic species. Thus, in a second time we envisaged
to synthesize diarylmethylamines following a two-steps
procedure: in a first step, a transient hemiaminal formed
by reaction between an aldehyde and an amine would be
O-methylated into an a-aminoether. In a second step, an
organozinc reagent would be used as nucleophile for the
displacement of the methoxy group. As outlined in Scheme 1,
experiments were achieved starting from piperidine, benz-
aldehyde, and 4-methoxyphenylzinc bromide, prepared
separately in acetonitrile according to a procedure inspired
from the cobalt-catalyzed process previously developed in
the laboratory.22
Results are presented in Table 1.
Diarylmethylamines are obtained in moderate to excellent
yields (40–95%). The reaction proceeds efficiently with
both electron-donating substituents (entries 2–7 of Table 1)
and electron-withdrawing groups (entries 8–11 of Table 1)
connected to the phenyl ring.
Considering the presence of a nitrogen atom on the final
diarylmethylamine structures, the simplest work-up was
found as an acid–base treatment, which ensured the removal
of most by-products. Indeed, these compounds (hydro-
dehalogenation products ArH, biaryl Ar–Ar, or alcohol
sometimes arise from the addition of the organozinc to the
aldehyde) were easily separated from the diarylmethylamine
using this method provided they do not contain nitrogen.
Curiously, it was shown that the corresponding diaryl-
methylamine was obtained only when the methoxylating
agent MeI was used in understoichiometric amount. We
then envisaged to add the arylzinc compound to a solution
containing only piperidine and benzaldehyde and remarked
that reaction products started appearing within a few minutes
when at least 1 equiv of the arylzinc compound was used.
Furthermore, the optimum value for an efficient coupling
was found to be at least 2 equiv of the arylzinc reagent, the
reaction being almost quantitative beyond this value. The
need for such quantities of the organozinc may account for
a base-assisted elimination on the intermediate hemiaminal
leading to a formal iminium ion, which is further attacked
by the remaining arylzinc compound.
Additional experiments were conducted using commercial
solutions of phenylzinc bromide and 4-methoxyphenylzinc
iodide in tetrahydrofuran24 following typical experimental
conditions of coupling method A as well as conditions of
coupling method B. Only traces of the expected product
were observed, even with a large excess of the starting orga-
nozinc (3 equiv). The addition of catalytic amounts of cobalt
and zinc bromide did not improve the production of diaryl-
methylamine. In order to confirm that cobalt salts were not
involved in the reaction mechanism, benzylzinc bromide
was synthesized in acetonitrile in the absence of a cobalt
catalyst. The organozinc thus obtained was allowed to react
with benzaldehyde and piperidine at room temperature for
We then attempted to enhance the reaction rate by adding
copper salts to the reaction medium.23 We observed that
MeO
ZnBr
t
1. BuOK
2. MeI
THF
N
N
+
CHO
N
H
OMe
OMe
Scheme 1.

E. Le Gall et al. / Tetrahedron 62 (2006) 9953–9965
Table 1. Coupling of functionalized organozinc reagents with piperidine and benzaldehyde
9955
1a-k
R
N
R
+
+
N
H
ZnBr
CHO
MeCN
Entry
1
Organozinc and GC yield (%)
Reaction time (h)
Product
Isolated yield (%)a
N
N
80
18b
1a
1b
1c
59
ZnBr
Me
Me
2
3
97
93
18b, 4c
71b, 77c
ZnBr
ZnBr
Me
N
18b
56
Me
N
t
4
82
18b
1d
75
Bu
ZnBr
t
Bu
OMe
ZnBr
N
OMe
5
6
95
92
18b
1e
1f
95
62
MeO
N
18b
OMe
ZnBr
N
7
8
9
89
93
92
3b
4c
4c
1g
1h
1i
88
40
70
MeO
ZnBr
OMe
EtO2C
N
CO2Et
ZnBr
N
EtO2C
ZnBr
CO2Et
(continued)

9956
E. Le Gall et al. / Tetrahedron 62 (2006) 9953–9965
Table 1. (continued)
Entry
10
Organozinc and GC yield (%)
Reaction time (h)
Product
Isolated yield (%)a
F3C
N
N
95
77
4c
1j
83
CF3
ZnBr
11
4c
1k
72
NC
ZnBr
CN
a
Yields based on initial amine and aldehyde amounts (10 mmol).
Coupling method A: CuI (ca. 0.3 equiv vs ArZnX) was added at room temperature into the organozinc (>20 mmol) solution before addition of the amine
(10 mmol) and the aldehyde (10 mmol).
Coupling method B: The organozinc-containing (>20 mmol) solution was added dropwise into the pre-heated mixture (70 ꢀC) of the amine (10 mmol) and
the aldehyde (10 mmol) in acetonitrile (15 mL).
b
c
3 h giving rise to the almost quantitative formation of the
Mannich reaction product (Scheme 2).
50 ꢀC for 1 h allowed the formation of compound 1g in
85% GC yield. This procedure might be efficient especially
with electron-rich organozinc compounds since they react
clearly faster than electron-deficient organozinc compounds
and do not have a so affirmed tendency to yield biaryls upon
heating. Nevertheless, additional tests might be necessary to
clarify the scope of this one-step reaction.
N
N
Zn
H
MeCN
ZnBr
Br
CHO
Another series of experiments, involving benzaldehyde as
the aldehyde and 4-methoxyphenylzinc bromide as the
model organozinc reagent, was realized in order to test the
effect of the secondary amine on the course of the reaction.
Scheme 2.
This result clearly shows that the very poor reactivity of
these commercial organozinc compounds cannot be linked
with the absence of cobalt salts in the reaction medium.
This may account for a possible role of the solvent in the
reaction course. Considering the experimental conditions
used in coupling method B, in which a limited amount of
tetrahydrofuran is added in the acetonitrile solution in order
to stabilize the organozinc reagent during the course of time,
one can imagine that important amounts of tetrahydrofuran
can also noticeably slow down the coupling reaction. Never-
theless, the absence of reactivity of commercial organozinc
reagents may not be solely explained by solvent effects.
Results are presented in Table 2.
Diarylmethylamines are again obtained in moderate to
excellent yields (50–96%). Both aromatic (entries 7 and 8
of Table 2) and non-aromatic amines (entries 1–6 of Table
2) are convenient substrates in this procedure, yields being
just a bit lower in the case of aromatic amines. This result
is consistent with their generally admitted lower reactivity
as nucleophiles. It is important to note that piperazine deriv-
atives, which are known to exhibit various biological activ-
ities, can be obtained using this procedure (entry 3 of Table
2). Yield is only moderate in that case but the coupling prod-
uct showed a lower stability during work-up and even after
purification, this compound fast darkened when exposed to
air and/or light. More accurate conditions for the reaction
and the isolation of products might certainly increase yields
for this class of compounds.
In order to test the reactivity of Grignard reagents in this
three-component procedure, an experiment involving phe-
nylmagnesium bromide was conducted. As it could be antic-
ipated, the use of phenylmagnesium bromide in a coupling
reaction with piperidine and benzaldehyde did not led to
the formation of the corresponding diarylmethylamine but
gave rise to an exclusive addition of phenylmagnesium
bromide to benzaldehyde producing diphenylmethanol.
In a third series of experiments, we employed substituted
benzaldehydes to ensure that functionalities can be present
on the related phenyl ring. Moreover, we investigated the
possible use of heteroaromatic aldehydes in the process.
It should also be mentioned that an attempt to synthesize
compound 1g in a one-step reaction was realized. Thus,
piperidine and benzaldehyde were placed along with 4-
methoxyphenyl bromide in the reaction mixture containing
cobalt salts and zinc dust. No cuprous iodide was added in
that case since the only result would have been the produc-
tion of copper(0) and zinc salts upon redox reaction of cop-
per(I) with zinc dust. An exothermic reaction occurred fast
and after 1 h at room temperature, the additional heating at
Results are presented in Table 3.
In most cases, yields are good to excellent (76–99%). It
appears that benzaldehyde derivatives react fairly well with
either electron-donating or -withdrawing groups connected
to the phenyl moiety. It should nevertheless be mentioned
that in some cases, electronic effects can play a role in the

E. Le Gall et al. / Tetrahedron 62 (2006) 9953–9965
9957
Table 2. Coupling of 4-methoxyphenylzinc bromide with secondary amines and benzaldehyde
'
R
R
2a-h
N
'
R
R
+
+
N
H
MeO
ZnBr
CHO
MeCN
OMe
Entry
Amine
Reaction time (h)a
Product
Isolated yield (%)b
O
N
O
1
3
2a
90
N
H
OMe
OMe
S
N
S
2
3
2b
96
N
H
Me
N
Me
N
N
3
4
5
4
3
3
2c
2d
2e
50
94
89
N
H
OMe
OMe
N
N
H
N
N
N
H
OMe
OMe
N
H
6
7
3
3
6
2f
94
80
53
N
2g
2h
N
H
OMe
OMe
Me
N
8
Me
N
H
a
Coupling method A: CuI (ca. 0.3 equiv vs ArZnX) was added at room temperature into the organozinc (>20 mmol) solution before addition of the amine
(10 mmol) and the aldehyde (10 mmol).
Yields based on initial amine and aldehyde amounts (10 mmol).
b

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E. Le Gall et al. / Tetrahedron 62 (2006) 9953–9965
Table 3. Coupling of 4-methoxyphenylzinc bromide with piperidine and aromatic aldehydes
3a-u
N
+
ZnBr
+
Ar CHO
MeO
MeCN
Ar
N
H
OMe
Entry
Aldehyde
Reaction time (h)
Product
Isolated yield (%)a
N
1
3b
3a
83
NC
CHO
NC
OMe
NO2
NO2
N
2
3
4
5
6
7
8
9
18c
3b
3c
3d
3e
3f
46
98
78
79
99
86
96
96
CHO
OMe
O2N
N
3c
O2N
CHO
OMe
OMe
N
3c
O2N
CHO
O2N
CF3
CHO
CF3
N
3b
OMe
N
3b
F3C
CHO
F3C
OMe
Cl
Cl
N
18b
3g
3h
3i
CHO
OMe
Cl
N
3b
Cl
Cl
CHO
OMe
OMe
N
18b
Cl
CHO
(continued)

E. Le Gall et al. / Tetrahedron 62 (2006) 9953–9965
9959
Table 3. (continued)
Entry
Aldehyde
Reaction time (h)
Product
Isolated yield (%)a
Br
N
10
3b
3j
96
Br
F
CHO
OMe
F
N
11
3b
3k
98
76
84
84
98
83
76
97
91
CHO
CHO
OMe
OMe
OMe
N
12
18b
18b
18b
3b
3l
N
t
13
14
15
16
17
18
19
Bu
CHO
3m
3n
3o
3p
3q
3r
3s
t
Bu
Me
Me
N
CHO
OMe
N
MeS
CHO
MeS
MeO
OMe
OMe
MeO
N
18b
18b
18b
18b
CHO
N
N
N
S
CHO
CHO
S
OMe
S
S
OMe
OMe
O
CHO
O
(continued)

9960
E. Le Gall et al. / Tetrahedron 62 (2006) 9953–9965
Table 3. (continued)
Entry
Aldehyde
Reaction time (h)
Product
Isolated yield (%)a
N
N
N
20
18b
3t
92d
CHO
CHO
N
N
OMe
21
18b
3u
87d
N
OMe
a
Yields based on initial amine and aldehyde amounts (10 mmol).
b
Coupling method A: CuI (ca. 0.3 equiv vs ArZnX) was added at room temperature into the organozinc (>20 mmol) solution before addition of the amine
(10 mmol) and the aldehyde (10 mmol).
Coupling method B: Conditions used in coupling method A but without CuI.
c
d
An additional chromatographic purification was performed over silica gel using a diethyl ether–dichloromethane: 90/10 mixture as an eluent.
course of the reaction. Indeed, with nitrobenzaldehydes, the
coupling is achieved rapidly without using additional
cuprous iodide (entries 3 and 4 of Table 3). ortho-Substituted
benzaldehydes react slower than meta- and para-substituted
benzaldehydes and yields are generally lower. This behavior
can be particularly noticed in the case of nitrobenzaldehydes.
ortho-Nitrobenzaldehyde leads to only 46% yield (entry 2 of
Table 3) whereas couplings featuring meta- and para-benz-
aldehydes arevery efficient (78–98%, entries 3 and 4 of Table
3). A similar behavior can be observed with heteroaromatic
aldehydes derived from thiophene. Indeed, the reaction is
clearly less efficient with thiophene-2-carboxaldehyde (entry
17 of Table 3) than with thiophene-3-carboxaldehyde (entry
18 of Table 3).
What would be the behavior of primary amines or amides
in this reaction and furthermore would amino-acids deriva-
tives be efficient as amines? Additionally, could they induce
stereoselectivity in the reaction and in a general manner, can
enantioselective syntheses be realized toward the use of
chiral mediators?
4. Experimental
4.1. General
Solvents (acetonitrile and THF in analytical grades) and
starting materials were purchased from commercial sup-
pliers and used without further purification. All reactions
were monitored by gas chromatography (GC) using a Varian
3400 chromatograph equipped with a 5 m SGE BP1 column.
Melting points (mp) were determined on a Kofler apparatus
and were not corrected. Infrared spectra were recorded in
CHCl3 on a Perkin–Elmer Spectrum BX FTIR spectrometer.
NMR spectra were recorded in CDCl3 at 200 MHz (1H),
50 MHz (13C), and 188 MHz (19F) on a Bruker AC200 spec-
trometer. In the case of fluoride-containing compounds 1j,
3e, 3f, and 3k, in order to determine accurately C–F coupling
constants, 13C NMR spectra were recorded in CDCl3 at
100 MHz using a Bruker Avance II 400 spectrometer. Data
are presented as follows: chemical shift (multiplicity, cou-
pling constants, integration). Mass spectra were recorded
on a Finnigan GC–MS GCQ spectrometer. High-resolution
mass spectra were recorded at the ‘Service central d’analy-
ses’, Vernaison, France. The mode of ionization used was
electrospray (ES+). Compounds, which have been previ-
ously described in the literature are linked to relevant biblio-
graphic references whereas compounds labeled by asterisk
(*) are, to the best of our knowledge, new compounds.
In the case of heteroaromatic aldehydes derived from pyri-
dine (entries 20 and 21 of Table 3), we could also observe
along the major product, diarylmethylpiperidine, the pres-
ence of the alcohol resulting from the addition of the arylzinc
compound to the aldehyde function. In these limited cases,
owing to the presence of nitrogen on both products, the
acid–base treatment was not sufficient to separate the diaryl-
methylpiperidine from the alcohol. Thus, an additional chro-
matographic purification over silica gel was applied to the
crude product.
3. Conclusion
In conclusion, the results presented in this paper show that
a three-component Mannich-type reaction involving aro-
matic organozinc reagents as nucleophile constitute a very
versatile methodology for the synthesis of diarylmethyl-
amines. Indeed, diarylmethylamines are obtained in high
yields and various functionalities can be introduced through
both organozinc reagents and benzaldehyde derivatives.
Heteroaromatic aldehydes are also efficient and either sec-
ondary aromatic or non-aromatic amines can be used in
the process thus highlighting the important scope of the
reaction. Nevertheless, additional developments might be
envisaged: can enolizable aldehydes be used in the proce-
dure and do aliphatic organozinc undergo the reaction?
4.2. Typical experimental procedure for the synthesis of
organozinc reagents
A dried 100 mL tricol was flushed with argon and charged
with acetonitrile (40 mL). Dodecane (0.2 mL, used as
internal standard), cobalt bromide (0.66 g, 3 mmol), zinc

E. Le Gall et al. / Tetrahedron 62 (2006) 9953–9965
9961
bromide (0.68 g, 3 mmol), phenyl bromide (0.32 mL,
3 mmol), and zinc dust (6 g, 92 mmol) were added to the
solution. Trifluoromethanesulfonic acid (0.2 mL) was added
to the mixture under vigorous stirring. After ca. 15 min, the
aryl bromide (30 mmol) was added to the solution and as
soon as the exothermic reaction had began (ca. 5 min), a
water bath at room temperature was used to moderate the
temperature of the medium. The reaction time, which was
monitored using gas chromatography, did not exceed
30 min in most cases. Yield of organozinc compounds thus
obtained were estimated as follows: a sample of the reaction
medium was exposed to iodine crystals then sodium thiosul-
fate, and extracted with diethyl ether. The amount of iodin-
ated product was compared to the amount of the starting aryl
bromide via the internal standard using gas chromatography
(GC). After completion of the reaction, the acetonitrile
solution was taken up using a syringe whenever possible
or filtered over Celite at 0 ꢀC.
d (ppm): 24.84, 26.39, 53.29, 76.88, 126.78, 128.13,
128.43, 143.38; MS, m/z (relative intensity): 251 (19), 175
(14), 174 (100), 168 (12), 167 (60), 166 (12), 165 (38),
152 (19), 91 (10), 84 (20); HRMS calcd for C18H22N
[M+H]+: 252.1752, found: 252.1761.
4.6.2. 1-(Phenyl(2-tolyl)methyl)piperidine (1b).1c,17 Pale
1
yellow viscous oil; H NMR, d (ppm): 1.30–1.60 (m, 6H),
2.20–2.40 (m, 7H), 4.38 (s, 1H), 6.99–7.91 (m, 9H); 13C
NMR, d (ppm): 20.12, 25.03, 26.51, 53.66, 71.07, 126.37,
126.79, 127.37, 127.61, 128.38, 128.93, 130.62, 135.93,
141.82, 142.52; MS, m/z (relative intensity): 266 (7), 265
(17), 189 (6), 188 (35), 187 (27), 186 (11), 182 (12), 181
(72), 180 (100), 179 (61), 178 (17), 175 (6), 174 (45), 167
(14), 166 (65), 165 (65), 153 (7), 152 (6), 105 (7), 91 (10),
86 (30), 84 (7); HRMS calcd for C19H24N [M+H]+:
266.1909, found: 266.1927.
4.6.3. 1-(Phenyl(3-tolyl)methyl)piperidine (1c)*. Pale yel-
low viscous oil; 1H NMR, d (ppm): 1.40–1.80 (m, 6H), 2.20–
2.60 (m, 7H), 4.36 (s, 1H), 7.12–7.61 (m, 9H); 13C NMR,
d (ppm): 21.59, 24.82, 26.35, 53.31, 76.62, 125.16, 126.66,
127.53, 128.34, 128.70, 137.80, 143.27, 143.48; MS, m/z
(relative intensity): 266 (7), 265 (20), 189 (11), 188 (88),
182 (26), 181 (100), 179 (11), 178 (12), 175 (11), 174
(79), 167 (27), 166 (72), 165 (69), 153 (9), 152 (7), 105
(10), 91 (12), 84 (56); HRMS calcd for C19H24N [M+H]+:
266.1909, found: 266.1928.
4.3. Typical coupling method A
To the solution of the organozinc reagent was added under
stirring CuI (1.2 g, 6 mmol) and 5 min later, benzaldehyde
(1 mL, 10 mmol) and piperidine (1 mL, 10 mmol). Stirring
was continued for additional 3 h at room temperature.
4.4. Typical coupling method B
To the solution of the organozinc reagent was added 5 mL
THF. The resulting solution was added dropwise (2 h) under
stirring to a pre-heated mixture (ca. 70 ꢀC) of benzaldehyde
(1 mL, 10 mmol) and piperidine (1 mL, 10 mmol) in aceto-
nitrile (15 mL). Stirring was continued for additional 2 h at
70 ꢀC.
4.6.4. 1-((4-tert-Butylphenyl)(phenyl)methyl)piperidine
1
(1d)*. Pale yellow solid, mp: 89 ꢀC; H NMR, d (ppm):
1.32 (s, 9H), 1.38–1.70 (m, 6H), 2.30–2.45 (m, 4H), 4.26
(s, 1H), 7.16–7.50 (m, 9H); 13C NMR, d (ppm): 24.74,
26.28, 31.40, 53.16, 76.36, 125.12, 126.51, 127.50,
127.81, 128.13, 140.07, 143.50, 149.21; MS, m/z (relative
intensity): 308 (5), 307 (19), 231 (18), 230 (87), 224 (21),
223 (100), 208 (19), 193 (24), 181 (6), 179 (8), 178 (16),
174 (23), 167 (25), 166 (6), 165 (16), 91 (6), 84 (16);
HRMS calcd for C22H30N [M+H]+: 308.2378, found:
308.2384.
4.5. Typical acid–base work-up
The reaction mixture was poured in 150 mL of a 5% sodium
hydroxide aqueous solution and extracted with dichloro-
methane (2ꢁ100 mL). The combined organic fractions
were concentrated to dryness and diethyl ether (150 mL)
was added to the residue. After complete dissolution, con-
centrated sulfuric acid (0.5–0.75 mL) was added carefully
to the vigorously stirred solution and allowed to react
for 5 min. The resulting ammonium salt was filtered and
washed with diethyl ether (2ꢁ50 mL). The solid was then
poured, under stirring, into a mixture of a 5% sodium
hydroxide aqueous solution (100 mL) and dichloromethane
(100 mL). After complete dissolution, the aqueous phase
was extracted with additional 100 mL of dichloromethane.
The combined organic fractions were dried over sodium sul-
fate and concentrated to dryness yielding analytically pure
(>97% GC) diarylmethylamines. In the case of diaryl-
methylamines 3t and 3u derived from pyridine carbox-
aldehydes, an additional chromatographic purification was
performed over silica gel (SDS 70–200 mm) using a diethyl
ether–dichloromethane: 90/10 mixture as an eluent.
4.6.5. 1-((2-Methoxyphenyl)(phenyl)methyl)piperidine
1
(1e)*. Pale yellow solid, mp: 100 ꢀC; H NMR, d (ppm):
1.40–1.60 (m, 6H), 2.20–2.40 (m, 4H), 3.69 (s, 3H), 4.77
(s, 1H), 6.70–7.66 (m, 9H); 13C NMR, d (ppm): 24.90,
26.36, 53.23, 55.41, 67.32, 110.77, 120.72, 126.32,
127.26, 128.06, 128.26, 131.72, 143.46, 157.13; MS, m/z
(relative intensity): 282 (10), 281 (39), 280 (16), 238 (6),
205 (13), 204 (100), 198 (17), 197 (70), 196 (17), 195 (8),
188 (5), 181 (19), 179 (15), 175 (8), 174 (51), 169 (8), 167
(6), 166 (6), 165 (25), 153 (9), 152 (20), 121 (6), 92 (6),
91 (90), 86 (28), 84 (11); HRMS calcd for C19H24NO
[M+H]+: 282.1858, found: 282.1861.
4.6.6. 1-((3-Methoxyphenyl)(phenyl)methyl)piperidine
(1f)*. Pale yellow viscous oil; H NMR, d (ppm): 1.40–
1
1.60 (m, 6H), 2.20–2.40 (m, 4H), 3.76 (s, 3H), 4.30 (s,
1H), 6.75–7.54 (m, 9H); 13C NMR, d (ppm): 25.02, 26.56,
53.40, 55.10, 76.82, 112.00, 113.95, 120.60, 127.00,
128.10, 128.45, 129.58, 143.35, 145.26, 159.91; MS, m/z
(relative intensity): 282 (6), 281 (11), 280 (6), 205 (12),
204 (77), 199 (15), 198 (100), 197 (78), 183 (19), 182
(44), 181 (20), 179 (10), 175 (13), 174 (80), 169 (21), 168
4.6. Analytical data
4.6.1. 1-Benzhydrylpiperidine (1a).8,11 Pale yellow solid,
1
mp: 70 ꢀC; H NMR, d (ppm): 1.50–1.70 (m, 6H), 2.30–
2.50 (m, 4H), 4.36 (s, 1H), 7.20–7.61 (m, 10H); 13C NMR,

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E. Le Gall et al. / Tetrahedron 62 (2006) 9953–9965
(8), 167 (29), 166 (29), 165 (55), 164 (8), 155 (8), 154 (20),
153 (26), 152 (19), 121 (9), 91 (18), 84 (100); HRMS calcd
for C19H24NO [M+H]+: 282.1858, found: 282.1869.
116 (7), 91 (10), 84 (38); HRMS calcd for C19H21N2
[M+H]+: 277.1705, found: 277.1720.
4.6.12. 4-((4-Methoxyphenyl)(phenyl)methyl)morpho-
line (2a).10 Pale yellow solid, mp: 66 ꢀC; 1H NMR,
d (ppm): 2.25–2.40 (m, 4H), 3.60–3.75 (m, 7H), 4.12 (s,
1H), 6.77 (d, J¼8.7 Hz, 2H), 7.08–7.42 (m, 7H); 13C
NMR, d (ppm): 52.55, 54.96, 67.06, 75.85, 113.81,
126.83, 127.70, 128.46, 128.85, 134.29, 142.65, 158.50;
MS, m/z (relative intensity): 283 (7), 198 (17), 197 (100),
182 (10), 166 (7), 165 (15), 154 (6), 153 (11), 152 (6);
HRMS calcd for C18H22NO2 [M+H]+: 284.1651, found:
284.1648.
4.6.7. 1-((4-Methoxyphenyl)(phenyl)methyl)piperidine
1
(1g).17 Pale yellow solid, mp: 60 ꢀC; H NMR, d (ppm):
1.30–1.60 (m, 6H), 2.20–2.40 (m, 4H), 3.65 (s, 3H), 4.17
(s, 1H), 6.77 (d, J¼8.7 Hz, 2H), 7.06–7.40 (m, 9H); 13C
NMR, d (ppm): 24.81, 26.36, 53.17, 55.17, 75.95, 113.74,
126.61, 128.37, 129.021, 135.40, 143.69, 158.41; MS, m/z
(relative intensity): 281 (15), 204 (20), 198 (17), 197
(100), 182 (11), 167 (5), 166 (7), 165 (16), 154 (7), 153
(11), 152 (6); HRMS calcd for C19H24NO [M+H]+:
282.1858, found: 282.1874.
4.6.13. 4-((4-Methoxyphenyl)(phenyl)methyl)thiomor-
1
4.6.8. Ethyl 3-(phenyl(piperidin-1-yl)methyl)benzoate
(1h)*. Pale yellow viscous oil; IR, n (cmꢂ1): 1710; 1H
NMR, d (ppm): 1.20–1.60 (m, 9H), 2.20–2.40 (m, 4H),
4.20–4.40 (m, 3H), 7.09–8.07 (m, 9H); 13C NMR,
d (ppm): 14.44, 24.76, 26.31, 53.22, 60.94, 76.41, 126.99,
128.09, 128.57, 129.19, 129.43, 130.69, 132.37, 142.77,
143.95, 166.70; MS, m/z (relative intensity): 324 (8), 323
(33), 322 (9), 294 (5), 247 (20), 246 (100), 240 (9), 239
(32), 218 (21), 211 (8), 195 (12), 194 (8), 193 (35), 175
(15), 174 (100), 168 (8), 167 (59), 166 (32), 165 (71), 164
(9), 152 (11), 91 (11), 84 (45); HRMS calcd for
C21H26NO2 [M+H]+: 324.1964, found: 324.1964.
pholine (2b).17 Pale brown solid, mp: 78 ꢀC; H NMR,
d (ppm): 2.62 (s, 8H), 3.67 (s, 3H), 4.31 (s, 1H), 6.78 (d,
J¼8.7 Hz, 2H), 7.08–7.36 (m, 7H); 13C NMR, d (ppm):
28.12, 53.50, 55.06, 75.11, 113.82, 126.80, 127.85,
128.38, 129.02, 134.09, 142.54, 158.51; MS, m/z (relative
intensity): 299 (9), 271 (6), 198 (16), 197 (100), 182 (8),
166 (7), 165 (13), 153 (9), 152 (6); HRMS calcd for
C18H22NOS [M+H]+: 300.1422, found: 300.1432.
4.6.14. 1-((4-Methoxyphenyl)(phenyl)methyl)-4-methyl-
1
piperazine (2c).1b Pale yellow solid, mp: 78 ꢀC; H NMR,
d (ppm): 2.24 (s, 3H), 2.41 (br s, 8H), 3.65 (s, 3H), 4.16 (s,
1H), 6.76 (d, J¼8.7 Hz, 2H), 7.10–7.42 (m, 7H); 13C
NMR, d (ppm): 46.05, 51.97, 55.11, 55.51, 75.58, 113.89,
126.79, 127.82, 128.52, 128.95, 134.97, 143.27, 158.56;
MS, m/z (relative intensity): 296 (20), 239 (7), 238 (41),
237 (100), 236 (32), 225 (11), 224 (42), 210 (7), 198 (11),
197 (60), 182 (12), 181 (8), 167 (5), 166 (10), 165 (25),
154 (10), 153 (22), 152 (10), 121 (5), 99 (17), 70 (8), 56
(13); HRMS calcd for C19H25N2O [M+H]+: 297.1967,
found: 297.1950.
4.6.9. Ethyl 4-(phenyl(piperidin-1-yl)methyl)benzoate
(1i).17 Pale yellow solid, mp: 98 ꢀC; IR, n (cmꢂ1): 1710;
1H NMR, d (ppm): 1.20–1.60 (m, 9H), 2.20–2.40 (m, 4H),
4.20–4.40 (m, 3H), 7.10–7.97 (m, 9H); 13C NMR,
d (ppm): 14.20, 24.53, 26.08, 52.97, 60.59, 76.24, 126.88,
127.70, 128.32, 128.85, 129.59, 142.16, 145.58, 166.29;
MS, m/z (relative intensity): 324 (8), 323 (33), 322 (8),
278 (5), 247 (17), 246 (100), 240 (9), 239 (45), 218 (19),
193 (6), 175 (9), 174 (79), 168 (8), 167 (55), 166 (38), 165
(62), 164 (5), 152 (14), 91 (10), 84 (41); HRMS calcd for
C21H26NO2 [M+H]+: 324.1964, found: 324.1940.
4.6.15. 1-((4-Methoxyphenyl)(phenyl)methyl)pyrrolidine
(2d).9 Pale yellow solid, mp: 54 ꢀC; H NMR, d (ppm):
1
1.80–2.00 (m, 4H), 2.50–2.70 (m, 4H), 3.76 (s, 3H), 4.28
(s, 1H), 6.93 (d, J¼8.7 Hz, 2H), 7.22–7.64 (m, 7H); 13C
NMR, d (ppm): 23.66, 53.66, 54.94, 75.80, 113.77,
126.74, 127.38, 128.50, 136.70, 144.79, 158.49; MS, m/z
(relative intensity): 267 (8), 198 (17), 197 (100), 190 (27),
182 (10), 165 (11), 154 (6), 153 (8), 152 (5); HRMS calcd
for C18H22NO [M+H]+: 268.1701, found: 268.1713.
4.6.10. 1-(Phenyl(3-(trifluoromethyl)phenyl)methyl)-
piperidine (1j).17 Pale yellow viscous oil; 1H NMR,
d (ppm): 1.30–1.60 (m, 6H), 2.20–2.40 (m, 4H), 4.28 (s,
1H), 7.10–7.71 (m, 9H); 13C NMR, d (ppm): 24.61, 26.20,
53.05, 76.38, 123.72 (q, J¼4 Hz), 124.50 (q, J¼271 Hz),
124.78 (q, J¼4 Hz), 127.25, 128.19, 128.68, 128.92,
130.85 (q, J¼31 Hz), 131.47, 142.30, 144.73; 19F NMR,
d (ppm): ꢂ62.18; MS, m/z (relative intensity): 320 (11),
319 (40), 318 (12), 243 (13), 242 (85), 236 (11), 235 (45),
233 (6), 217 (11), 216 (8), 215 (49), 214 (9), 195 (13), 175
(16), 174 (100), 167 (13), 166 (39), 165 (61), 164 (6), 159
(10), 91 (11), 84 (45); HRMS calcd for C19H21F3N
[M+H]+: 320.1626, found: 320.1634.
4.6.16. 2-((4-Methoxyphenyl)(phenyl)methyl)-1,2,3,4-tet-
rahydro isoquinoline (2e)*. Pale yellow solid, mp: 96 ꢀC;
1H NMR, d (ppm): 2.75–2.92 (m, 2H), 2.93–3.08 (m, 2H),
3.74 (s, 2H), 3.78 (s, 3H), 4.52 (s, 1H), 6.94–7.66 (m,
13H); 13C NMR, d (ppm): 29.63, 49.42, 55.34, 75.27,
75.56, 114.21, 125.80, 126.26, 127.09, 127.82, 128.11,
128.94, 129.26, 134.34, 135.27, 135.60, 143.63, 158.87;
MS, m/z (relative intensity): 329 (5), 252 (7), 198 (22),
197 (100), 182 (10), 167 (5), 166 (8), 165 (14), 154 (6),
153 (10), 133 (7), 132 (36); HRMS calcd for C23H24NO
[M+H]+: 330.1858, found: 330.1878.
4.6.11. 4-(Phenyl(piperidin-1-yl)methyl)benzonitrile
(1k)*. Pale yellow viscous oil; IR, n (cmꢂ1): 2230; 1H
NMR, d (ppm): 1.30–1.60 (m, 6H), 2.20–2.40 (m, 4H),
4.27 (s, 1H), 7.14–7.35 (m, 5H), 7.52 (s, 4H); 13C NMR,
d (ppm): 24.55, 26.16, 53.02, 76.18, 110.42, 118.95,
127.29, 128.05, 128.53, 132.23, 141.54, 149.13; MS, m/z
(relative intensity): 276 (20), 275 (6), 200 (11), 199 (97),
193 (23), 192 (78), 191 (32), 190 (47), 177 (8), 175 (14),
174 (100), 166 (10), 165 (66), 164 (10), 163 (7), 152 (6),
4.6.17. N,N-Diethyl-N-((4-methoxyphenyl)(phenyl)-
methyl)amine (2f)*. Pale yellow viscous oil; H NMR,
1
d (ppm): 1.11 (t, J¼7.1 Hz, 6H), 2.71 (q, J¼7.1 Hz, 4H),
3.73 (s, 3H), 4.83 (s, 1H), 6.91 (d, J¼8.7 Hz, 2H), 7.20–7.60

E. Le Gall et al. / Tetrahedron 62 (2006) 9953–9965
9963
(m, 7H); 13C NMR, d (ppm): 11.60, 43.24, 55.15, 70.89,
113.94, 126.79, 128.15, 128.44, 129.43, 135.72, 144.18,
158.72; MS, m/z (relative intensity): 269 (5), 198 (17), 197
(100), 192 (10), 182 (10), 167 (5), 166 (7), 165 (11), 154
(5), 153 (8); HRMS calcd for C18H24NO [M+H]+:
270.1858, found: 270.1865.
(36), 196 (18), 195 (13), 181 (5), 165 (6), 153 (18), 152 (14),
84 (8); HRMS calcd for C19H23N2O3 [M+H]+: 327.1709,
found: 327.1712.
4.6.23. 1-((4-Methoxyphenyl)(4-nitrophenyl)methyl)-
piperidine (3d)*. Pale orange viscous oil; IR, n (cmꢂ1):
1516, 1345; H NMR, d (ppm): 1.30–1.60 (m, 6H), 2.20–
1
4.6.18. 1-((4-Methoxyphenyl)(phenyl)methyl)indoline
2.40 (m, 4H), 3.72 (s, 3H), 4.29 (s, 1H), 6.81 (AB,
J¼8.7 Hz, 2H), 7.24 (AB, J¼8.7 Hz, 2H), 7.57 (AB,
J¼8.8 Hz, 2H), 8.09 (AB, J¼8.8 Hz, 2H); 13C NMR,
d (ppm): 24.64, 26.25, 53.06, 55.21, 75.39, 114.10, 123.75,
128.45, 129.20, 133.40, 146.68, 151.82, 158.92; MS, m/z
(relative intensity): 326 (9), 243 (16), 242 (100), 219 (5),
212 (8), 204 (19), 196 (20), 153 (8), 152 (7); HRMS calcd
for C19H23N2O3 [M+H]+: 327.1709, found: 327.1716.
1
(2g).17 Pale brown viscous oil; H NMR, d (ppm): 3.23 (t,
J¼8.1 Hz, 2H), 3.55 (t, J¼8.1 Hz, 2H), 4.01 (s, 3H), 5.89
(s, 1H), 6.60 (d, J¼7.8 Hz, 1H), 6.95–7.74 (m, 12H); 13C
NMR, d (ppm): 28.69, 51.75, 55.30, 66.30, 108.56,
114.13, 117.91, 124.62, 127.55, 128.80, 130.07, 130.64,
133.67, 142.05, 152.30, 159.11; MS, m/z (relative intensity):
315 (14), 198 (16), 197 (100), 182 (11), 166 (7), 165 (15),
154 (7), 153 (10), 152 (6); HRMS calcd for C22H22NO
[M+H]+: 315.1701, found: 316.1705.
4.6.24. 1-((4-Methoxyphenyl)(2-(trifluoromethyl)-
phenyl)methyl)piperidine (3e)*. Pale yellow viscous oil;
1H NMR, d (ppm): 1.44–1.52 (m, 6H), 2.16–2.37 (m, 4H),
3.68 (s, 3H), 4.60 (s, 1H), 6.78 (d, J¼8.8 Hz, 2H), 7.17 (t,
J¼7.6 Hz, 1H), 7.38–7.54 (m, 4H), 8.08 (d, J¼7.9 Hz,
1H); 13C NMR, d (ppm): 24.76, 26.40, 53.25, 55.11,
69.70, 113.75, 124.71 (q, J¼272 Hz), 125.57 (q, J¼6 Hz),
126.51, 128.05 (q, J¼29 Hz), 129.51, 129.63, 132.09,
134.47, 143.45, 158.60; 19F NMR, d (ppm): ꢂ56.14; MS,
m/z (relative intensity): 349 (20), 266 (17), 265 (100), 250
(7), 245 (10), 205 (6), 204 (30), 181 (6), 153 (6); HRMS
calcd for C20H23F3NO [M+H]+: 350.1732, found: 350.1711.
4.6.19. N-((4-Methoxyphenyl)(phenyl)methyl)-N-methyl-
1
aniline (2h)*. Pale brown solid, mp: 110 ꢀC; H NMR,
d (ppm): 2.67 (s, 3H), 3.69 (s, 3H), 6.09 (s, 1H), 6.62–6.80
(m, 5H), 7.01–7.30 (m, 9H); 13C NMR, d (ppm): 34.33,
55.11, 66.48, 112.37, 112.97, 113.75, 116.76, 127.06,
128.49, 129.15, 129.97, 132.73, 141.05, 150.18, 158.75; MS,
m/z (relative intensity): 303 (9), 198 (16), 197 (100), 182
(13), 166 (8), 165 (17), 154 (6), 153 (11), 152 (6); HRMS calcd
for C21H22NO [M+H]+: 304.1701, found: 304.1702.
4.6.20. 4-((4-Methoxyphenyl(piperidin-1-yl)methyl)ben-
zonitrile (3a).17 Pale yellow viscous oil; IR, n (cmꢂ1):
2230; H NMR, d (ppm): 1.30–1.60 (m, 6H), 2.20–2.40
(m, 4H), 3.74 (s, 3H), 4.23 (s, 1H), 6.81 (AB, J¼8.7 Hz,
2H), 7.22 (AB, J¼8.7 Hz, 2H), 7.52 (s, 4H); 13C NMR,
d (ppm): 24.64, 26.24, 53.04, 55.23, 75.60, 110.34, 114.05,
119.07, 128.49, 129.19, 132.28, 133.60, 149.63, 158.86;
MS, m/z (relative intensity): 306 (9), 223 (18), 222 (100),
204 (20), 190 (9), 178 (7); HRMS calcd for C20H23N2O
[M+H]+: 307.1810, found: 307.1816.
4.6.25. 1-((4-Methoxyphenyl)(4-(trifluoromethyl)-
phenyl)methyl) piperidine (3f)*. Pale yellow solid, mp:
1
1
59 ꢀC; H NMR, d (ppm): 1.40–1.55 (m, 6H), 2.26–2.29
(m, 4H), 3.71 (s, 3H), 4.23 (s, 1H), 6.80 (AB, J¼8.7 Hz,
2H), 7.26 (AB, J¼8.7 Hz, 2H), 7.51 (s, 4H); 13C NMR,
d (ppm): 24.69, 26.29, 53.28, 55.27, 75.66, 113.97, 124.39
(q, J¼270 Hz), 125.37 (q, J¼4 Hz), 128.10, 128.83 (q,
J¼32 Hz), 129.15, 134.26, 148.11, 158.78; 19F NMR,
d (ppm): ꢂ62.18; MS, m/z (relative intensity): 349 (21),
330 (6), 266 (21), 265 (100), 250 (6), 233 (6), 204 (27),
196 (5), 181 (6), 165 (5), 153 (8); HRMS calcd for
C20H23F3NO [M+H]+: 350.1732, found: 350.1741.
4.6.21. 1-((4-Methoxyphenyl)(2-nitrophenyl)methyl)-
piperidine (3b)*. Pale orange viscous oil; IR, n (cmꢂ1):
1527, 1247; H NMR, d (ppm): 1.39–1.51 (m, 6H), 2.27
1
(br s, 4H), 3.70 (s, 3H), 4.82 (s, 1H), 6.79 (d, J¼8.7 Hz,
2H), 7.19–7.33 (m, 3H), 7.46–7.62 (m, 2H), 8.02 (d,
J¼8.9 Hz, 1H); 13C NMR, d (ppm): 24.44, 26.03, 52.78,
54.92, 68.45, 113.60, 123.80, 127.15, 129.49, 129.67,
132.29, 137.66, 149.98, 158.61; MS, m/z (relative intensity):
326 (6), 310 (20), 309 (100), 279 (16), 278 (69), 242 (6), 227
(7), 226 (35), 225 (7), 211 (11), 196 (13), 195 (7), 183 (10),
181 (8), 165 (8), 154 (6), 153 (9), 152 (12), 135 (13), 123
(10), 84 (39); HRMS calcd for C19H23N2O3 [M+H]+:
327.1709, found: 327.1700.
4.6.26. 1-((2-Chlorophenyl)(4-methoxyphenyl)methyl)-
piperidine (3g)*. Pale yellow viscous oil; 1H NMR,
d (ppm): 1.41–1.54 (m, 6H), 2.28–2.30 (m, 4H), 3.67
(s, 3H), 4.70 (s, 1H), 6.76 (d, J¼8.7 Hz, 2H), 6.98–7.37
(m, 5H), 7.82 (d, J¼7.9 Hz, 1H); 13C NMR, d (ppm):
24.67, 26.16, 53.07, 54.96, 70.40, 113.52, 126.92, 127.26,
128.59, 128.90, 129.35, 129.58, 133.63, 141.15, 158.38;
MS, m/z (relative intensity): 317 (8), 316 (6), 315 (25),
234 (6), 233 (29), 232 (17), 231 (100), 204 (31), 197 (12),
196 (22), 195 (15), 181 (15), 165 (9), 153 (15), 152 (18),
84 (6); HRMS calcd for C19H23ClNO [M+H]+: 316.1468,
found: 316.1459.
4.6.22. 1-((4-Methoxyphenyl)(3-nitrophenyl)methyl)-
piperidine (3c)*. Pale orange viscous oil; IR, n (cmꢂ1):
1530, 1353; H NMR, d (ppm): 1.42–1.62 (m, 6H), 2.31
1
4.6.27. 1-((3-Chlorophenyl)(4-methoxyphenyl)methyl)-
piperidine (3h).17 Pale yellow viscous oil; 1H NMR,
d (ppm): 1.30–1.60 (m, 6H), 2.20–2.40 (m, 4H), 3.71 (s,
3H), 4.14 (s, 1H), 6.79 (d, J¼8.6 Hz, 2H), 7.05–7.40 (m,
6H); 13C NMR, d (ppm): 24.79, 26.35, 53.13, 55.23, 75.53,
113.93, 126.02, 126.76, 127.92, 129.17, 129.77, 134.37,
146.09, 158.69; MS, m/z (relative intensity): 315 (12), 234
(7), 233 (33), 232 (17), 231 (100), 204 (26), 197 (7), 196
(br s, 4H), 3.74 (s, 3H), 4.31 (s, 1H), 6.82 (AB, J¼8.7 Hz,
2H), 7.26 (AB, J¼8.7 Hz, 2H), 7.40 (t, J¼7.9 Hz, 1H),
7.75 (d, J¼7.8 Hz, 1H), 8.01 (d, J¼7.8 Hz, 1H), 8.29 (br s,
1H); 13C NMR, d (ppm): 24.61, 26.22, 52.98, 55.21,
75.16, 114.06, 121.74, 122.69, 129.18, 133.57, 133.84,
134.17, 146.34, 148.48, 158.86; MS, m/z (relative intensity):
327 (9), 326 (30), 243 (18), 242 (100), 226 (6), 225 (30), 204

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E. Le Gall et al. / Tetrahedron 62 (2006) 9953–9965
(29), 195 (7), 181 (10), 165 (6), 153 (7), 152 (6); HRMS calcd
for C19H23ClNO [M+H]+: 316.1468, found: 316.1470.
4.6.33. 1-((2-Methylphenyl)(4-methoxyphenyl)methyl)-
piperidine (3n)*. Pale yellow viscous oil; 1H NMR,
d (ppm): 1.40–1.54 (m, 6H), 2.08–2.38 (m, 7H), 3.67 (s,
3H), 4.31 (s, 1H), 6.76 (d, J¼8.7 Hz, 2H), 6.99–7.29 (m,
5H), 7.79 (d, J¼7.6 Hz, 1H); 13C NMR, d (ppm): 20.04,
25.03, 26.50, 53.64, 55.23, 71.37, 113.76, 126.31, 127.16,
129.92, 130.61, 134.43, 135.80, 142.17, 158.48; MS, m/z
(relative intensity): 296 (5), 295 (20), 212 (14), 211 (100),
210 (74), 209 (17), 204 (16), 196 (21), 195 (6), 188 (5),
187 (7), 181 (11), 180 (13), 179 (47), 166 (5), 165 (13),
153 (8), 152 (7), 105 (13); HRMS calcd for C20H26NO
[M+H]+: 296.2014, found: 296.2012.
4.6.28. 1-((4-Chlorophenyl)(4-methoxyphenyl)methyl)-
1
piperidine (3i)*. Pale yellow solid, mp: 94 ꢀC; H NMR,
d (ppm): 1.40–1.54 (m, 6H), 2.25–2.28 (m, 4H), 3.74
(s, 3H), 4.15 (s, 1H), 6.80 (d, J¼8.7 Hz, 2H), 7.19–7.51
(m, 6H); 13C NMR, d (ppm): 24.80, 26.17, 52.93, 55.10,
75.11, 113.72, 128.40, 128.99, 132.04, 134.61, 142.19,
145.63, 158.43; MS, m/z (relative intensity): 317 (7), 315
(16), 233 (29), 232 (15), 231 (100), 204 (9), 196 (21), 195
(6), 181 (15), 165 (8), 153 (14), 152 (10); HRMS calcd for
C19H23ClNO [M+H]+: 316.1468, found: 316.1481.
4.6.34. 1-((4-Methoxyphenyl)(4-(methylthio)phenyl)-
methyl)piperidine (3o)*. Pale yellow solid, mp: 72 ꢀC;
1H NMR, d (ppm): 1.30–1.60 (m, 6H), 2.20–2.35 (m, 4H),
2.37 (s, 3H), 3.69 (s, 3H), 4.14 (s, 1H), 6.78 (d, J¼8.7 Hz,
2H), 7.10–7.32 (m, 6H); 13C NMR, d (ppm): 15.82, 24.67,
26.21, 52.96, 55.03, 75.31, 113.64, 126.71, 128.27,
128.86, 135.05, 136.14, 140.63, 158.32; MS, m/z (relative
intensity): 327 (7), 245 (6), 244 (17), 243 (100), 196 (11),
195 (6), 181 (6), 153 (7), 152 (6); HRMS calcd for
C20H26NOS [M+H]+: 328.1735, found: 328.1749.
4.6.29. 1-((3-Bromophenyl)(4-methoxyphenyl)methyl)-
piperidine (3j)*. Pale yellow viscous oil; 1H NMR,
d (ppm): 1.39–1.60 (m, 6H), 2.25–2.27 (m, 4H), 3.71
(s, 3H), 4.13 (s, 1H), 6.79 (d, J¼8.7 Hz, 2H), 7.05–7.33
(m, 5H), 7.56 (t, J¼1.7 Hz, 1H); 13C NMR, d (ppm): 24.49,
26.06, 52.87, 54.97, 75.27, 113.67, 122.34, 126.19, 128.92,
129.69, 130.42, 130.71, 134.19, 146.10, 158.42; MS, m/z
(relative intensity): 361 (16), 359 (20), 278 (17), 277 (97),
276 (24), 275 (100), 205 (10), 204 (56), 197 (14), 196 (53),
195 (16), 182 (7), 181 (35), 165 (15), 153 (24), 152 (23),
84 (12); HRMS calcd for C19H23BrNO [M+H]+: 360.0963,
found: 360.0950.
4.6.35. 1-((3-Methoxyphenyl)(4-(methoxy)phenyl)-
methyl)piperidine (3p)*. Pale yellow viscous oil;
1H NMR, d (ppm): 1.39–1.53 (m, 6H), 2.27–2.30 (m, 4H),
3.67 (s, 3H), 3.71 (s, 3H), 4.13 (s, 1H), 6.64–6.69 (m, 1H),
6.77 (AB, J¼8.7 Hz, 2H), 6.94–6.98 (m, 2H), 7.14 (t,
J¼7.8 Hz, 1H), 7.28 (AB, J¼8.7 Hz, 2H); 13C NMR,
d (ppm): 24.76, 26.30, 49.86, 53.10, 55.00, 75.93, 111.61,
113.47, 113.64, 120.25, 128.91, 129.11, 135.17, 145.56,
158.40, 159.62; MS, m/z (relative intensity): 311 (9), 229 (5),
228 (38), 227 (100), 212 (12), 204 (22), 197 (10), 196 (15),
195 (11), 181 (6), 169 (7), 141 (5), 121 (5), 84 (16); HRMS
calcd for C20H26NO2 [M+H]+: 312.1964, found: 312.1957.
4.6.30. 1-((3-Fluorophenyl)(4-methoxyphenyl)methyl)-
piperidine (3k).25 Pale yellow viscous oil; 1H NMR,
d (ppm): 1.39–1.59 (m, 6H), 2.26–2.29 (m, 4H), 3.70
(s, 3H), 4.17 (s, 1H), 6.79 (d, J¼8.7 Hz, 2H), 7.13–7.29
(m, 6H); 13C NMR, d (ppm): 24.72, 26.29, 53.07, 55.17,
75.49, 113.46 (d, J¼22 Hz), 113.84, 114.52 (d, J¼21 Hz),
123.52 (d, J¼2 Hz), 129.14, 129.74 (d, J¼8 Hz), 134.54,
146.66 (d, J¼6 Hz), 158.63, 163.05 (d, J¼243 Hz); 19F
NMR, d (ppm): ꢂ112.80; MS, m/z (relative intensity): 299
(18), 216 (16), 215 (100), 204 (26), 200 (8), 184 (8), 183
(14), 172 (7), 171 (12), 170 (5), 165 (6), 84 (6); HRMS calcd
for C19H23FNO [M+H]+: 300.1764, found: 300.1771.
4.6.36. 1-((4-Methoxyphenyl)(thiophen-2-yl)methyl)-
1
piperidine (3q)*. Pale yellow solid, mp: 60 ꢀC; H NMR,
d (ppm): 1.36–1.60 (m, 6H), 2.33–2.38 (m, 4H), 3.71 (s, 3H),
4.60 (s, 1H), 6.80–6.86 (m, 4H), 7.12–7.15 (m, 1H), 7.28–
7.33 (m, 2H); 13C NMR, d (ppm): 24.66, 26.28, 52.40, 55.17,
70.65, 113.54, 124.65, 124.92, 126.19, 129.55, 133.12,
148.19, 158.72; MS, m/z (relative intensity): 287 (7), 205 (6),
204 (21), 203 (100), 172 (5), 171 (6), 160 (7); HRMS calcd
for C17H22NOS [M+H]+: 288.1422 found: 288.1435.
4.6.31. 1-((4-Methoxyphenyl)(naphthalen-1-yl)methyl)-
piperidine (3l)*. Pale yellow viscous oil; 1H NMR,
d (ppm): 1.43–1.61 (m, 6H), 2.37–2.46 (m, 4H), 3.60 (s,
3H), 4.98 (s, 1H), 6.74 (d, J¼8.7 Hz, 2H), 7.34–7.53 (m,
5H), 7.68–7.81 (m, 2H), 8.02 (d, J¼7.2 Hz, 1H), 8.44 (d,
J¼8.2 Hz, 1H); 13C NMR, d (ppm): 24.70, 26.47, 53.71,
55.00, 71.53, 113.58, 123.78, 124.90, 125.78, 127.33,
128.87, 129.62, 131.64, 134.13, 134.56, 139.50, 145.56,
158.32; MS, m/z (relative intensity): 331 (13), 248 (27),
247 (100), 233 (5), 232 (16), 231 (7), 217 (9), 216 (15),
215 (26), 204 (15), 203 (13), 202 (14), 84 (21); HRMS calcd
for C23H26NO [M+H]+: 332.2014, found: 332.2018.
4.6.37. 1-((4-Methoxyphenyl)(thiophen-3-yl)methyl)-
1
piperidine (3r)*. Pale brown solid, mp: 67 ꢀC; H NMR,
d (ppm): 1.38–1.54 (m, 6H), 2.30 (br s, 4H), 3.73 (s, 3H),
4.38 (s, 1H), 6.81 (d, J¼8.4 Hz, 2H), 7.02–7.29 (m, 5H);
13C NMR, d (ppm): 24.59, 26.21, 52.51, 55.02, 70.84,
113.43, 121.35, 125.24, 127.44, 129.17, 134.07, 144.26,
158.32; MS, m/z (relative intensity): 287 (11), 205 (7), 204
(24), 203 (100), 172 (6), 171 (6), 160 (5), 159 (6), 84 (5);
HRMS calcd for C17H22NOS [M+H]+: 288.1422, found:
288.1433.
4.6.32. 1-((4-tert-Butylphenyl)(4-methoxyphenyl)-
methyl)piperidine (3m)*. Pale yellow solid, mp: 110 ꢀC;
1H NMR, d (ppm): 1.25 (s, 9H), 1.30–1.60 (m, 6H), 2.20–
2.40 (m, 4H), 3.68 (s, 3H), 4.14 (s, 1H), 6.77 (d, J¼
8.6 Hz, 2H), 7.20–7.40 (m, 6H); 13C NMR, d (ppm):
24.91, 26.43, 31.55, 34.47, 53.28, 55.18, 75.87, 113.75,
125.27, 127.56, 129.13, 135.76, 140.61, 149.28, 158.41;
MS, m/z (relative intensity): 337 (9), 253 (100), 238 (14),
223 (15), 204 (6); HRMS calcd for C23H32NO [M+H]+:
338.2484, found: 338.2503.
4.6.38. 1-(Furan-3-yl(4-methoxyphenyl)methyl)piperi-
dine (3s)*. Pale yellow solid, mp: 60 ꢀC; 1H NMR,
d (ppm): 1.36–1.59 (m, 6H), 2.29–2.34 (m, 4H), 3.74 (s,
3H), 4.30 (s, 1H), 6.34 (s, 1H), 6.82 (d, J¼8.7 Hz, 2H),
7.24–7.31 (m, 4H); 13C NMR, d (ppm): 24.65, 26.28,

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9965
D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127,
1092–1093; (d) Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc.
2000, 122, 976–977; (e) Hermanns, N.; Dahmen, S.; Bolm, C.;
52.15, 55.05, 66.23, 110.42, 113.45, 126.74, 129.15, 133.72,
140.09, 142.75, 158.48; MS, m/z (relative intensity): 271
(17), 242 (7), 188 (18), 187 (100), 159 (9), 144 (19), 115
(8); HRMS calcd for C17H22NO2 [M+H]+: 272.1651, found:
272.1656.
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6. Opalka, C. J.; D’Ambra, T. E.; Faccone, J. J.; Bodson, S.;
Cossement, E. Synthesis 1995, 766–768.
4.6.39. 3-((4-Methoxyphenyl)(piperidin-1-yl)methyl)pyr-
idine (3t)*. Pale yellow solid, mp: 60 ꢀC; 1H NMR, d (ppm):
1.40–1.60 (m, 6H), 2.30 (br s, 4H), 3.71 (s, 3H), 4.25 (s, 1H),
6.81 (AB, J¼8.7 Hz, 2H), 7.15 (dd, J¼7.9, 4.8 Hz, 1H), 7.26
(AB, J¼8.7 Hz, 2H), 7.69 (dt, J¼7.9, 1.8 Hz, 1H), 8.40 (dd,
J¼4.8, 1.5 Hz, 1H), 8.63 (d, J¼1.9 Hz, 1H); 13C NMR,
d (ppm): 24.33, 25.90, 52.68, 54.89, 73.15, 113.68, 123.13,
128.82, 133.65, 135.06, 138.63, 147.90, 149.40, 158.43;
MS, m/z (relative intensity): 282 (13), 204 (32), 199 (21),
198 (100), 183 (17), 167 (15), 155 (17), 154 (17); HRMS
calcd for C18H23N2O [M+H]+: 283.1810, found: 283.1815.
7. Plobeck, N.; Delorme, D.; Wei, Z. Y.; Yang, H.; Zhou, F.;
Schwarz, P.; Gawell, L.; Gagnon, H.; Pelcman, B.; Schmidt,
R.; Yue, S. Y.; Walpole, C.; Brown, W.; Zhou, E.; Labarre,
M.; Payza, K.; St-Onge, S.; Kamassah, A.; Morin, P. E.;
Projean, D.; Ducharme, J.; Roberts, E. J. Med. Chem. 2000,
43, 3878–3894.
8. Chandrasekhar, S.; Raji Reddy, C.; Ahmed, M. Synlett 2000,
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Sonoda, N. Chem. Lett. 1990, 2053–2056.
4.6.40. 4-((4-Methoxyphenyl)(piperidin-1-yl)methyl)pyr-
idine (3u)*. Pale yellow solid, mp: 70 ꢀC; 1H NMR,
d (ppm): 1.39–1.54 (m, 6H), 2.09–2.28 (m, 4H), 3.70 (s,
3H), 4.18 (s, 1H), 6.80 (AB, J¼8.6 Hz, 2H), 7.23 (AB,
J¼8.6 Hz, 2H), 7.33 (d, J¼6.0 Hz, 2H), 8.47 (d, J¼6.0 Hz,
2H); 13C NMR, d (ppm): 24.36, 25.96, 52.64, 54.88,
74.69, 113.67, 122.72, 129.03, 132.84, 149.59, 152.52,
158.61; MS, m/z (relative intensity): 282 (23), 205 (14),
204 (100), 199 (29), 198 (85), 184 (5), 183 (19), 175 (5),
167 (24), 155 (16), 154 (15), 121 (8); HRMS calcd for
C18H23N2O [M+H]+: 283.1810, found: 283.1804.
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