Nickel-catalysed selective N-arylation or N,N′-diarylation of secondary diamines

Article abstract of DOI:10.1016/S0040-4020(02)00750-0

The selective synthesis of N-aryl or N,N′-diaryl piperazines and trimethylene(bis)piperidines from the corresponding diamines and aryl chlorides using a catalyst combination of Ni(0) associated to 2,2′-bipyridine is described. The Ni/2,2′-bipyridine catalyst is also effective for the sequential arylation of piperazine. The preparation of novel and unsymmetrical 1,4-diaryl piperazines is reported.

Full text of DOI:10.1016/S0040-4020(02)00750-0

Tetrahedron 58 (2002) 6913–6924
Nickel-catalysed selective N-arylation or N,N0-diarylation of
secondary diamines
*
¨
Eric Brenner, Raphael Schneider and Yves Fort
´ ` ´ ´ ´ ´
Faculte des Sciences, Synthese Organique et Reactivite, UMR CNRS-UHP 7565, Universite Henri Poincare, Nancy I, BP 239,
54506 Vandoeuvre les Nancy Cedex, France
Received 14 May 2002; accepted 25 June 2002
Abstract—The selective synthesis of N-aryl or N,N0-diaryl piperazines and trimethylene(bis)piperidines from the corresponding diamines
and aryl chlorides using a catalyst combination of Ni(0) associated to 2,20-bipyridine is described. The Ni/2,20-bipyridine catalyst is also
effective for the sequential arylation of piperazine. The preparation of novel and unsymmetrical 1,4-diaryl piperazines is reported. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
of aniline derivatives with bis(2-bromoethyl) N-substituted
amines on basic alumina.10
N-arylated and N,N0-diarylated piperazines are building
blocks or intermediates widely used in the drug discovery
process. Unsymmetrically substituted piperazines are
present in several investigational and established bio-
logically active compounds such as ligands of serotonin
(5-HT) receptors,1 antifungals,2 antivirals,3 antibacterials4
or cholesterol ester transfer protein inhibitors.5 Examples
include the neurotransmitter TFMPP, the cardiotonic
agent Vesnarinone and the antifungal Itraconazole
(Chart 1).
By contrast, palladium-catalysed aminations of aryl halides,
extensively studied during recent years,11 have only
scarcely been used with piperazine itself due to the
competitive bis-arylation reaction. A proper choice of
catalyst seemed to be crucial for the success of the coupling.
Zhao reported first the use of the PdCl2[P(o-tolyl)3]2 catalyst
for the direct monoarylation of piperazine.12 Koie disclosed
a superior catalyst system which involved the Pd/P(t-Bu)3
combination for the coupling of aryl bromides with
piperazine.13 The Pd/BINAP catalyst system was also
successfully employed for the amination of 1,2,3-trihalo-
geno substituted benzenes, bromotriazolones and benzimi-
dazoles.14 While all these ‘one-pot’ methods are
noteworthy, they require an excess of piperazine (up to
6 equiv. relative to the aryl halide) to obtain 1-arylpiper-
During the last decade, numerous procedures have been
reported for the preparation of these compounds including
SNAr reactions in liquid phase6 or on solid support,7 SNAr
reactions on tricarbonyl chromium complexes,8 displace-
ment of a chlorine atom in arene–iron complexes,9 reaction
Chart 1.
Keywords: N-arylation; N,N0-diarylation; secondary diamines; nickel catalysis.
*
Corresponding author. Tel.: þ33-3-83-68-47-81; fax: þ33-3-83-68-47-85; e-mail: yves.fort@sor.uhp-nancy.fr
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00750-0

6914
E. Brenner et al. / Tetrahedron 58 (2002) 6913–6924
Scheme 1.
azines with good selectivity and yields. This excess can also
be a drawback if expensive piperazines derivatives have to
be coupled. Only Gala reported very recently the synthesis
of 1-arylpiperazines using almost equimolar amounts of aryl
bromides and piperazine in the presence of the Pd/BINAP
catalyst.15 Alternatively, the preparation of 1-arylpipera-
zines in a multistep protocol starting from Boc-protected
piperazine had also been described and afforded disappoint-
ing results.16
Nickel-catalysed amination reactions have received less
attention. Buchwald first reported the use of Ni(cod)2
(cod¼cyclooctadiene) associated with 1,10-bis(diphenyl-
phosphino)ferrocene (dppf) or 1,10-phenanthroline for the
synthesis of arylamines.17 A heterogeneous Ni(0)/C catalyst
liganded with dppf was also recently developed by
Lipshutz.18 For our part, we have reported the use of a
catalyst combination of in situ generated colloidal Ni(0)
associated with 2,20-bipyridine or N-heterocyclic carbenes
Table 1. Nickel-catalysed synthesis of 1-arylpiperazines 1 from aryl chlorides
Reaction conditions Aa
Reaction conditions Bb
Entry
Aryl chloride
Reaction time (h)c
Yield of 1 (%)d
Yield of 2 (%)d
Reaction time (h)c
Yield of 1 (%)d
Yield of 2 (%)d
a
8.5
61
16
6
86
8
b
8
65
23
5
87
7
c
9.5
9
56
57
15
15
6.5
6
81
82
8
9
d
e
12
29
2
8
42
0
f
8
62
52
10
11
6
6
87
87
4
5
g
9.5
h
i
12
9
23
84
1
3
8
5
41
90
0
0
j
9.5
8
58
63
28
12
7
7
85
78
6
4
k
a
Reactions were carried out with 25 mmol aryl chloride, 27.5 mmol piperazine, 2.5 mmol Ni(OAc)2, 7.5 mmol bipyridine, 5 mmol t-AmOH, 30 mmol NaH
and 5 mmol styrene in 40 ml THF.
b
Reactions were carried out with 25 mmol aryl chloride, 50.0 mmol piperazine, 2.5 mmol Ni(OAc)2, 7.5 mmol 2,20-bipyridine, 5 mmol t-AmOH, 30 mmol
NaH and 5 mmol styrene in 40 ml THF.
Determined by GC analysis.
c
d
Products were isolated by chromatography on silica gel. Yields are based on the aryl chloride. All yields reported are isolated yields of compounds estimated
to be .97% pure by NMR and GC analysis. All compounds were characterised by NMR (1H, 13C), IR, MS or combustion analysis.

E. Brenner et al. / Tetrahedron 58 (2002) 6913–6924
Table 2. Nickel-catalysed synthesis of substituted 1-arylpiperazines 3 from aryl chlorides
6915
Entry
a
Aryl chloride
Amine
Product 3
Reaction time (h)a
9
Yield (%)b
66
b
10
53
c
d
e
9
65
34
54
13
8.5
f
9
69
70
g
9.5
h
12
26
Reactions were performed on 20 mmol aryl chloride and 22 mmol amine.
a
Determined by GC analysis.
Products were isolated by chromatography on silica gel. Yields are based on the aryl chloride. All yields reported are isolated yields of compounds estimated
b
to be .97% pure by NMR and GC analysis. All compounds were characterised by NMR (1H, 13C), IR, MS or combustion analysis.
which provided efficient routes to substituted anilines.19,20
In addition, the Ni/2,20-bipyridine catalyst has also been
shown to be effective for polyamination or selective
monoamination of aryl di- and trichlorides.21 Since the
coupling of secondary amines with aryl chlorides was
efficient with this new catalyst system, we sought to develop
a simple, general and efficient method for the synthesis of
arylpiperazines, thereby expanding the substrate scope of
the nickel-catalysed amination methodology. A preliminary
account of these nickel-catalysed arylation reactions has
appeared.22 Herein, we disclose the results of a detaile0d
study of the use of Ni/2,20-bipyridine catalyst in N- or N,N -
diarylation reactions of secondary cyclic amines.
reaction of chlorobenzene with piperazine was initially
studied.
A quick survey of reaction conditions revealed that a good
yield (61%) of 1-phenylpiperazine 1a could be obtained by
heating the aryl chloride0and the diamine (1.1 equiv.) with
Ni(0) (10 mol%), the 2,2 -bipyridine ligand (20 mol%) and
t-AmONa activated sodium hydride at 658C in THF. Several
details are worthy of comments. No reaction occurred in the
absence of catalyst. 2,20-Bipyridine was found to be the
most effective ligand. The Ni/phenanthroline or Ni/tri-
phenylphosphine complexes did not show any catalytic
activity under classical reaction conditions. THF or dioxane
were comparable as the solvent whereas reaction in toluene
resulted in low conversion of the arylated product 1a. As
previously reported with simple secondary amines,19,21 the
efficiency of our system was markedly increased by adding
a catalytic amount of styrene, simultaneously to the aryl
chloride in the reaction medium, to trap hydrogen evolved
and thus inhibit hydrogenolysis of the carbon–chlorine
2. Results and discussion
In order to investigate the conditions for the nickel-
catalysed synthesis of 1-arylpiperazines (Scheme 1), the

6916
E. Brenner et al. / Tetrahedron 58 (2002) 6913–6924
Scheme 2.
bond. Finally, in contrast with most palladium-catalysed
arylation reactions of piperazine, the reaction proceeded
with equimolar ratios of the coupling substrates and
resulted in the selective formation of 1a accompanied by
16% of 1,4-diphenylpiperazine (Table 1, entry a, reaction
conditions A).
were obtained with electron-neutral or electron-poor aryl
chlorides (entries a–c and e) while an electron-rich
substrate like 4-chloroanisole (entry d) afforded the desired
arylpiperazine 3d in a modest 34% yield.
Not surprisingly, couplings performed with cis-2,6-
dimethylpiperazine gave the anticipated cis-1-aryl-3,5-
dimethylpiperazines 3f and 3g in good yields (entries f
and g) while reaction performed with trans-2,5-dimethyl-
piperazine in which both nitrogen atoms are hindered
afforded only 26% of the arylpiperazine 3h. In the latter
case, attempts to increase the reaction yield by extending the
reaction time or by heating at higher temperatures were not
effective. Interestingly, whereas palladium-catalysed
couplings performed with trans-3,5-dimethylpiperazine
gave a mixture of trans- and cis-arylated-2,5-dimethyl-
piperazine in a 5/1 ratio,12 such an isomerisation caused by a
b-hydride elimination has not been observed under nickel-
catalysis.
Table 1 describes the results of coupling of piperazine with
structurally and electronically diverse aryl and heteroaryl
chlorides. Using the conditions described above (10 mol%
Ni and 1.1 equiv. piperazine relative to the aryl chloride),
the Ni-catalysed couplings provided a general route to the
corresponding 1-arylpiperazines. The only side products
observed were the 1,4-diarylpiperazine 2 and the arene
resulting from reduction of the starting aryl chloride.
The amination reaction was found to be sensitive to an
ortho-substitution of the aryl chloride. 2-Chlorotoluene
reacted with piperazine in 29% yield (entry e) while 4- and
3-chlorotoluene reacted with the amine to give the desired
arylpiperazines 1c and 1d in 56 and 57% yield, respectively
(entries c and d). Electron-poor aryl chlorides gave the
corresponding arylpiperazines 1 in good yields (entries f, g,
i and k) whereas lower yields were obtained with electron-
rich aryl chlorides (entry h). It must also be underlined that
yields of bis-arylation products increased with electron-poor
aryl chlorides due to their higher reactivity.
Encouraged by these promising results on selective
N-monoarylation of piperazine using the Ni/2,20-bipyridine
catalyst, we wished to expand the method to other diamines
like trimethylene(bis)piperidine used in the preparation of
poly(aryleneamine)s by palladium-catalysed coupling with
aryl dibromides (Scheme 2).23
The couplings were first carried out using the classical
conditions for the arylation of piperazine (1.1 equiv. of the
diamine relative to the aryl chloride, 10 mol% of the
Ni/2,20-bipyridine catalyst, THF, 658C). Results are sum-
marised in Table 3 (reaction conditions A). In all cases, the
selectivity mono/bis arylation was disappointing and
mixtures of N-mono and N,N0-bis-arylated trimethylene-
(bis)piperidines 4 and 5 were obtained. For example, the
amination of chlorobenzene gave after work up and
purification a mixture of 4a and 5a in 51 and 32% isolated
yields, respectively (Table 3, entry a, reaction conditions A).
Using 3-chloroanisole (entry d), the selectivity was even
inverted and 5d was the major product of the coupling.
The selectivity of the coupling was markedly improved by
increasing the initial amount of piperazine (Table 1, reaction
conditions B). The use of 2 equiv. of piperazine was found
to be more efficient at minimising, although not eliminating,
the formation of 1,4-diarylpiperazines 2. Yields of 1 were
similar to those obtained in palladium-catalysed amination
reactions using a larger excess (4–6 equiv.) of pipera-
zine.12–14 However, reaction conditions A (1.1 equiv. of
piperazine) should allow easy access to 1-arylpiperazines
especially when the starting materials are of high cost (see
below).
Given our success in the arylation of piperazine itself, we
turned our attention to substituted piperazines. Using
1.1 equiv. of 2-methylpiperazine and 10 mol% of the
Ni/2,20-bipyridine catalyst, satisfactory yields were
obtained for the synthesis of arylpiperazines 3 (Table 2).
The couplings occurred at the less-hindered nitrogen atom
of the starting diamine and neither the other possible
regioisomer nor the 1,4-diarylpiperazine were detected in
the crude reaction mixture. The substrate scope was similar
to that for reactions performed with piperazine. Good results
This problem has been solved to some degree by increasing
the initial amount of trimethylene(bis)piperidine to 2 equiv.
(reaction conditions B, Table 3). Under these conditions,
improved 4/5 product ratios were obtained. For example, the
isolated yield of 4b was 79% with 2 equiv. of diamine while
this substrate was produced in a modest 48% yield using
1.1 equiv. of trimethylene(bis)piperidine (entry b).
The scope of the above arylation method was further

E. Brenner et al. / Tetrahedron 58 (2002) 6913–6924
6917
Table 3. Nickel-catalysed synthesis of N-aryl trimethylene(bis)piperidine 4 from aryl chlorides
Reaction conditions Aa
Reaction conditions Bb
Entry
Aryl chloride
Reaction time
(h)c
Isolated yield of 4
(%)d
Isolated yield of 5
(%)d
Reaction time
(h)c
Isolated yield of 4
(%)d
Isolated yield of 5
(%)d
a
b
c
12
14
10
51
48
43
32
29
34
9
11
8
81
79
74
8
5
6
d
11
36
42
9
78
8
a
Reactions were carried out with 25 mmol aryl chloride, 27.5 mmol trimethylene(bis)piperidine, 2.5 mmol Ni(OAc)2, 7.5 mmol 2,20-bipyridine, 5 mmol t-
AmOH, 30 mmol NaH and 5 mmol styrene in 40 ml THF.
b
Reactions were carried out with 25 mmol aryl chloride, 50.0 mmol trimethylene(bis)piperidine, 2.5 mmol Ni(OAc)2, 7.5 mmol 2,20-bipyridine, 5 mmol t-
AmOH, 30 mmol NaH and 5 mmol styrene in 40 ml THF.
Determined by GC analysis.
c
d
Products were isolated by chromatography on silica gel. Yields are based on the aryl chloride. All yields reported are isolated yields of compounds estimated
to be .97% pure by NMR and GC analysis. All compounds were characterised by NMR (1H, 13C), IR, MS or combustion analysis.
expanded by the use of the Ni/2,20-bipyridine catalyst in
bis-arylation reactions of piperazine and trimethylene(bis)-
piperidine.
10% isolated yields, respectively. Except 2-chloropyridine
(entry d, Table 4), aryl chlorides bearing electron-with-
drawing substituents were more reactive in bis-arylation
reactions and gave higher yields of 2 and 5. The reaction of
2-chloropyridine is typically slower than reactions using
simple aromatic derivatives. A possible explanation is that
the pyridinic substrate may compete with the 2,20-bipyridine
ligand for coordination to nickel, thereby inhibiting the
coupling reaction.
GC monitoring of the reaction mixture indicated in all cases
that the initial coupling was more facile than the second one.
Conversion into the desired products may be effected by
extending the reaction time or by the use of an excess aryl
chloride (4 equiv.). Under these conditions, symmetrically
N,N0-biaryl substituted diamines 2 and 5 were obtained in
good yields (Tables 4 and 5). Note that compounds 1 (or 4)
and biaryls resulting from the homocoupling of the starting
aryl chloride were obtained as by-products in less than 5 and
To further probe the application of our methodology, the
sequential functionalisation of piperazine with two different
aryl chlorides was examined. Initially, we attempted to
Table 4. Nickel-catalysed synthesis of 1,4-diarylpiperazines 2
Entry
a
Aryl chloride
Product 2
Reaction time (h)a
8
Yield (%)b
78
b
c
7
7
79
82
d
e
12
12
69
76
Reactions were performed on 20 mmol piperazine and 80 mmol aryl chloride.
a
Determined by GC analysis.
Products were isolated by chromatography on silica gel. Yields are based on piperazine. All yields reported are isolated yields of compounds estimated to be
b
.97% pure by NMR and GC analysis. All compounds were characterised by NMR (1H, 13C), IR, MS or combustion analysis.

6918
E. Brenner et al. / Tetrahedron 58 (2002) 6913–6924
Table 5. Nickel-catalysed synthesis of N,N0-diaryl trimethylene(bis)piperidines 5
Entry
a
Aryl chloride
Product 5
Reaction time (h)a
Yield (%)b
73
12
b
c
d
10
10
15
78
75
71
Reactions were performed on 20 mmol trimethylene(bis)piperidine and 80 mmol aryl chloride.
a
Determined by GC analysis.
Products were isolated by chromatography on silica gel. Yields are based on trimethylene(bis)piperidine. All yields reported are isolated yields of
b
compounds estimated to be .97% pure by NMR and GC analysis. All compounds were characterised by NMR (1H, 13C), IR, MS or combustion analysis.
Scheme 3.
prepare unsymmetrical 1,4-diarylpiperazines by a one-pot
method wherein the second aryl chloride was added after
complete consumption of the first one. Unfortunately, both
steps were sluggish. Apparently, the use of a larger amount
of sodium hydride for both Ni(0)-catalysed aminations
caused an increase of reduction products during the first
coupling. In most cases, the homocoupling of the aryl
chloride competed with the aryl amination reaction during
the second step and unsymmetrical N,N0-diarylpiperazines 6
were obtained in poor yields, usually less than 20%.
We therefore developed a two-step procedure for the
synthesis of 6 from piperazine and two different aryl
chlorides (Scheme 3).
Table 6. Nickel-catalysed synthesis of unsymmetrical 1,4-diarylpiperazines 6
Entry
a
FG1
FG2
Product 6
Overall yielda (%)
71
H
m-OMe
b
c
H
m-CF3
66
73
p-Me
m-OMe
Reactions were performed on 27.5 mmol piperazine. Each step was carried out with 25 mmol aryl chloride, 2.5 mmol Ni(OAc)2, 7.5 mmol 2,20-bipyridine,
5 mmol t-AmOH, 30 mmol NaH and 5 mmol styrene in 40 ml THF.
a
Products were isolated by chromatography on silica gel. Yields are based on the aryl chloride. All yields reported are isolated yields of compounds estimated
to be .97% pure by NMR and GC analysis. All compounds were characterised by NMR (1H, 13C), IR, MS or combustion analysis.

E. Brenner et al. / Tetrahedron 58 (2002) 6913–6924
6919
Reactions conditions A (Table 1) were employed for the
first coupling. The catalyst and the ligand were removed
from the reaction mixture by filtration through silica gel
followed by concentration. The crude 1-arylpiperazine was
used for the second step without further purification. Table 6
provides the results of these double arylation reactions of
piperazine. Using this procedure, unsymmetrical 1,4-
diarylpiperazines 6 were obtained in yields ranging from
66 to 73%.
in THF (10 mL) followed by 2,20-bipyridine (7.5 mmol) and
the mixture was heated at 658C. Dried Ni(OAc)2 (2.5 mmol)
was then added and the mixture was further stirred at 658C
for 2 h. To the dark suspension of 2,20-bipyridine liganded
Ni(0) thus obtained was added the aryl chloride (25 mmol)
and styrene (5 mmol) in THF. The reaction was monitored
by GC and after complete consumption of the starting aryl
chloride (see Table 1), the mixture was cooled to room
temperature. Water (1 mL) and dichloromethane (50 mL)
were added sequentially and the reaction mixture was
filtered, dried over MgSO4 and evaporated. The residue was
purified by silica gel column chromatography using
MeOH–AcOEt as eluant.
3. Conclusion
In conclusion, we have developed nickel-catalysed methods
for the selective N-mono- or N,N0-di-arylation of piperazine
and trimethylene(bis)piperidine that proceed under mild
conditions using readily available and easily handled
reagents. A two step procedure for the synthesis of
unsymmetrical N,N0-diarylpiperazines is also described.
Representative procedure for reaction conditions B. NaH
(30 mmol), piperazine (50 mmol), t-AmOH (5 mmol), 2,20-
bipyridine (7.5 mmol), Ni(OAc)2 (2.5 mmol) and styrene
(5 mmol) were used for the amination of 25 mmol aryl
chloride using the standard procedure described above.
4.2.1. 1-Phenylpiperazine13 1a (Table 1). Purification was
performed by silica gel chromatography using MeOH–
AcOEt (40/60) as eluant. The title compound was isolated as
a light yellow oil. 61% yield (method A) and 86% yield
(method B). IR (NaCl, cm21): nNH 3353. 1H NMR
(400 MHz, CDCl3) d ppm: 7.23 (t, J¼7.6 Hz, 2H), 6.93–
6.80 (m, 3H), 3.13–3.03 (m, 4H), 2.99–2.89 (m, 4H), 2.18
(NH). 13C NMR (CDCl3, 100 MHz) d ppm: 152.20, 129.48,
120.09, 116.48, 50.71, 46.48.
These catalytic couplings display broad scope with respect
to the steric and electronic properties of the substrate
combinations and are compatible with many functional
groups. These methods should therefore find wide appli-
cations in medicinal chemistry and drug discovery
processes.
4. Experimental
4.2.2. 1-(1-Naphthyl)piperazine13 1b (Table 1). Purifi-
cation was performed by silica gel chromatography using
MeOH–AcOEt (40/60) as eluant. The title compound was
isolated as a yellow oil. 65% yield (method A) and 87%
4.1. General comments
All experiments were carried out under a nitrogen
atmosphere. THF was distilled from benzophenone–sodium
adduct and stored over sodium wire. tert-Amyl alcohol was
distilled from sodium. Crushed Ni(OAc)2·4H2O (Fluka) was
dried under vacuum (20 mmHg) at 1108C for 12 h. Sodium
hydride (65% in mineral oil, Fluka) was used after two
washings with THF under nitrogen. 2,20-Bipyridine was
recrystallised from hexane before use. All reagents were
purchased from commercial sources and were used without
purification. Melting points were taken on a Tottoli
apparatus and are uncorrected. GC analysis were conducted
on a Shimadzu GC-8A instrument equipped with a flame-
ionisation detector and using an Alltech EC5 column
(30 m£0.32 mm£2.65 mm). Flash chromatography was
performed using Kieselgel 60 (230–400 mesh, Merck).
NMR spectra were recorded with Brucker AM 400 (1H at
400 MHz, 13C at 100 MHz) or AC 250 (19F at 235 MHz).
Chemical shifts are expressed in d (ppm) values with
tetramethylsilane (TMS) as internal reference. IR spectra
were recorded on a Perkin–Elmer 841 spectrometer. Yields
refer to isolated yields of compounds estimated to be up to
95% pure as determined by 1H NMR and up to 98% pure as
determined by capillary GC. HRMS and combustion
analyses were performed by the Service central d’analyses
du CNRS (Vernaison, France).
1
yield (method B). IR (NaCl, cm21): nNH 3313. H NMR
(400 MHz, CDCl3) d ppm: 8.15 (d, J¼7.6 Hz, 1H), 7.72 (d,
J¼7.6 Hz, 1H), 7.44–7.30 (m, 3H), 7.26 (dd, J¼8.0, 7.6 Hz,
1H), 6.81 (d, J¼8.0 Hz, 1H), 2.91–2.68 (m, 8H), 2.03 (NH).
13C NMR (CDCl3, 100 MHz) d ppm: 148.73, 133.39,
127.48, 126.99, 124.54, 124.37, 123.86, 122.25, 121.90,
113.21, 52.83, 44.95.
4.2.3. 1-(4-Methylphenyl)piperazine24 1c (Table 1). Puri-
fication was performed by silica gel chromatography
using MeOH–AcOEt (40/60) as eluant. The title
compound was isolated as a yellow oil. 56% yield
(method A) and 81% yield (method B). IR (NaCl, cm21):
1
nNH 3402. H NMR (400 MHz, CDCl3) d ppm: 7.04 (d,
J¼8.6 Hz, 2H), 6.84 (d, J¼8.6 Hz, 2H), 3.20–3.12 (m, 4H),
2.61–2.53 (m, 4H), 2.32 (s, 3H), 2.26 (NH). 13C NMR
(CDCl3, 100 MHz) d ppm: 149.12, 129.26, 129.00, 116.18,
50.04, 45.31, 20.09.
4.2.4. 1-(3-Methylphenyl)piperazine13 1d (Table 1).
Purification was performed by silica gel chromatography
using MeOH–AcOEt (40/60) as eluant. The title compound
was isolated as a light yellow solid. 57% yield (method A)
and 82% yield (method B). Mp¼1018C (lit. mp¼1018C). IR
1
(KBr, cm21): nNH 3383. H NMR (400 MHz, CDCl3) d
4.2. Nickel-catalysed synthesis of 1-arylpiperazines 1
ppm: 7.10 (t, J¼7.6 Hz, 1H), 6.76–6.60 (m, 3H), 3.08–2.98
(m, 4H), 2.93–2.84 (m, 4H), 2.27 (s, 3H), 1.78 (NH). 13C
NMR (CDCl3, 100 MHz) d ppm: 151.28, 137.86, 128.25,
119.87, 116.18, 112.56, 49.75, 45.53, 21.19.
Representative procedure for reaction conditions A. To a
suspension of degreased NaH (30 mmol) in THF (20 mL)
were added piperazine (27.5 mmol) and t-AmOH (5 mmol)

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E. Brenner et al. / Tetrahedron 58 (2002) 6913–6924
4.2.5. 1-(2-Methylphenyl)piperazine13 1e (Table 1). Puri-
fication was performed by silica gel chromatography using
MeOH–AcOEt (40/60) as eluant. The title compound was
isolated as a yellow solid. 29% yield (method A) and 42%
yield (method B). Mp¼1778C (lit. mp¼1758C). IR (KBr,
was isolated as a white solid. 58% yield (method A) and
85% yield (method B). Mp¼858C (lit. mp¼858C). IR (KBr,
cm21): nNH 3347. 1H NMR (400 MHz, CDCl3) d ppm: 7.19
(d, J¼8.6 Hz, 2H), 6.81 (d, J¼8.6 Hz, 2H), 3.21–2.91 (m,
8H), 2.84 (NH). 13C NMR (CDCl3, 100 MHz) d ppm:
150.17, 128.86, 124.34, 117.12, 49.97, 45.66.
1
cm21): nNH 3391. H NMR (400 MHz, CDCl3) d ppm:
7.15–7.09 (m, 2H), 7.04–6.96 (m, 2H), 3.15–3.07 (m, 4H),
2.85–2.66 (m, 4H), 2.35 (s, 3H), 2.21 (NH). 13C NMR
(CDCl3, 100 MHz) d ppm: 151.61, 132.86, 131.52, 127.21,
122.95, 119.57, 51.73, 46.35, 18.54.
4.2.11. 1-(2-Pyridinyl)piperazine26 1k (Table 1). Purifi-
cation was performed by silica gel chromatography using
MeOH–AcOEt (45/55) as eluant. The title compound was
isolated as a yellow oil. 63% yield (method A) and 78%
4.2.6. 1-[4-(4-Trifluoromethyl)phenyl]piperazine25 1f
(Table 1). Purification was performed by silica gel
chromatography using MeOH–AcOEt (40/60) as eluant.
The title compound was isolated as a white solid. 62% yield
(method A) and 87% yield (method B). Mp¼1078C (lit.
mp¼1098C). IR (KBr, cm21): nNH 3321. 1H NMR
(400 MHz, CDCl3) d ppm: 7.49 (d, J¼8.8 Hz, 2H), 6.93
(d, J¼8.8 Hz, 2H), 3.27–3.20 (m, 4H), 3.07–2.98 (m, 4H),
1.84 (NH). 13C NMR (CDCl3, 100 MHz) d ppm: 153.66,
126.28, 124.86 (q, J¼269 Hz), 120.48 (q, J¼32 Hz),
114.41, 49.02, 45.82. 19F NMR (235 MHz, CDCl3) d
ppm: 261.79.
yield (method B). IR (NaCl, cm21): nNH 3321. H NMR
1
(400 MHz, CDCl3) d ppm: 8.17 (dd, J¼4.75, 1.25 Hz, 1H),
745 (ddd, J¼7.4, 1.25 Hz, 1H), 6.67–6.57 (m, 2H), 3.53–
3.45 (m, 4H), 3.01–2.92 (m, 4H). 13C NMR (CDCl3,
100 MHz) d ppm: 159.44, 147.60, 137.11, 112.96, 106.74,
45.98, 45.57.
4.3. Nickel-catalysed synthesis of substituted 1-
arylpiperazines 3
Compounds 3 were prepared according to the typical
procedure A described for piperazine.
4.2.7. 1-(3-Methoxyphenyl)piperazine13 1g (Table 1).
Purification was performed by silica gel chromatography
using MeOH–AcOEt (40/60) as eluant. The title compound
was isolated as a yellow oil. 52% yield (method A) and 87%
4.3.1. 3-Methyl-1-phenylpiperazine27 3a (Table 2). Puri-
fication was performed by silica gel chromatography using
MeOH–AcOEt (40/60) as eluant. The title compound was
isolated as a pale yellow oil. 66% yield. IR (NaCl, cm21):
1
1
yield (method B). IR (NaCl, cm21): nNH 3323. H NMR
nNH 3387. H NMR (400 MHz, CDCl3) d ppm: 7.21 (dd,
(400 MHz, CDCl3) d ppm: 7.15 (t, J¼8.4 Hz, 1H), 6.51 (dd,
J¼8.4, 1.6 Hz, 1H), 6.45 (dd, J¼1.6 Hz, 1H), 6.40 (dd,
J¼8.4, 1.6 Hz, 1H), 3.75 (s, 3H), 3.14–3.08 (m, 4H), 3.02–
2.95 (m, 4H), 2.18 (NH). 13C NMR (CDCl3, 100 MHz) d
ppm: 160.27, 152.90, 129.47, 108.58, 104.17, 102.17,
54.85, 49.94, 45.77.
J¼8.4, 7.6 Hz, 2H), 6.86 (d, J¼8.4 Hz, 2H), 3.38–3.29 (m,
2H), 2.99 (ddd, J¼11.6, 3.2, 2.8 Hz, 1H), 2.95–2.84 (m,
2H), 2.62 (ddd, J¼11.6, 11.6, 3.2, 1H), 2.52 (NH), 2.29 (dd,
J¼11.6, 11.6, 1H), 1.06 (d, J¼6.4 Hz, 3H). 13C NMR
(CDCl3, 100 MHz) d ppm: 150.94, 128.50, 119.01, 115.54,
56.23, 49.93, 48.69, 45.21, 19.14.
4.2.8. 1-(4-Methoxyphenyl)piperazine13 1h (Table 1).
Purification was performed by silica gel chromatography
using MeOH–AcOEt (40/60) as eluant. The title compound
was isolated as a brown solid. 52% yield (method A) and
87% yield (method B). Mp¼1678C (lit. mp¼1688C). IR
4.3.2. 3-Methyl-1-(4-methylphenyl)piperazine12 3b
(Table 2). Purification was performed by silica gel
chromatography using MeOH–AcOEt (40/60) as eluant.
The title compound was isolated as a pale yellow oil. 53%
1
yield. IR (NaCl, cm21): nNH 3425. H NMR (400 MHz,
1
(KBr, cm21): nNH 3323. H NMR (400 MHz, CDCl3) d
CDCl3) d ppm: 7.06 (d, J¼8.4 Hz, 2H), 6.83 (d, J¼8.4 Hz,
2H), 3.47–3.38 (m, 2H), 3.10 (ddd, J¼11.6, 3.2, 2.8 Hz,
1H), 3.05–2.95 (m, 2H), 2.66 (ddd, J¼11.6, 11.6, 3.2 Hz,
1H), 2.42 (NH), 2.31 (dd, J¼11.6, 11.6 Hz; 1H), 2.26 (s,
3H), 1.12 (d, J¼6.4 Hz, 3H). 13C NMR (CDCl3, 100 MHz)
d ppm: 149.22, 129.43, 129.03, 116.37, 57.26, 50.40, 49.69,
45.57, 20.23, 19.45.
ppm: 6.89 (d, J¼8.8 Hz, 2H), 6.81 (d, J¼8.8 Hz, 2H), 3.71
(s, 3H), 3.28–3.18 (m, 4H), 3.02 (NH). 13C NMR (CDCl3,
100 MHz) d ppm: 152.07, 142.78, 116.49, 112.47, 53.42,
46.02, 41.64.
4.2.9. Phenyl(4-piperazinophenyl)methanone 1i (Table
1). Purification was performed by silica gel chromatography
using MeOH–AcOEt (50/50) as eluant. The title compound
was isolated as a yellow solid. 84% yield (method A) and
90% yield (method B). Mp¼1858C. IR (KBr, cm21): nNH
3315, nCO 1633. 1H NMR (400 MHz, CDCl3) d ppm: 7.70–
7.63 (m, 4H), 7.62–7.56 (m, 1H), 7.54–7.48 (m, 2H), 7.03–
6.95 (m, 2H), 3.36–3.30 (m, 4H), 2.94–2.88 (m, 4H), 2.65
(NH). 13C NMR (CDCl3, 100 MHz) d ppm: 193.91, 153.14,
137.83, 131.43, 130.60, 128.44, 127.20, 125.97, 112.40,
46.59, 44.17. HREIMS Obsd m/z¼266.1423 (M),
C17H18N2O requires 266.1419.
4.3.3. 1-(3-Methoxyphenyl)-3-methylpiperazine 3c
(Table 2). Purification was performed by silica gel
chromatography using MeOH–AcOEt (40/60) as eluant.
The title compound was isolated as a yellow oil. 65% yield.
IR (NaCl, cm21): nNH 3364. 1H NMR (400 MHz, CDCl3) d
ppm: 7.14 (dd, J¼8.4, 8.4 Hz, 1H), 6.51 (dd, J¼8.4, 2.0 Hz,
1H), 6.45 (dd, J¼2.0, 2.0 Hz, 1H), 6.40 (dd, J¼8.4, 2.0 Hz,
1H), 3.74 (s, 3H), 3.48 (d, J¼12.0 Hz, 2H), 3.09 (ddd,
J¼12.0, 3.2, 2.8 Hz, 1H), 3.03–2.92 (m, 2H), 2.74 (ddd,
J¼12.0, 12.0, 3.2 Hz, 1H), 2.48 (NH), 2.41 (dd, J¼12.0,
12.0 Hz, 1H), 1.14 (d, J¼6.4 Hz, 3H). 13C NMR (CDCl3,
100 MHz) d ppm: 160.13, 152.19, 129.36, 108.58, 104.19,
102.21, 55.82, 54.67, 50.07, 48.33, 44.84, 18.68. HREIMS
Obsd m/z¼206.1426 (M), C12H18N2O requires 206.1419.
4.2.10. 1-(4-Chlorophenyl)piperazine24 1j (Table 1).
Purification was performed by silica gel chromatography
using MeOH–AcOEt (40/60) as eluant. The title compound

E. Brenner et al. / Tetrahedron 58 (2002) 6913–6924
6921
4.3.4. 1-(4-Methoxyphenyl)-3-methylpiperazine 3d
(Table 2). Purification was performed by silica gel
chromatography using MeOH–AcOEt (40/60) as eluant.
The title compound was isolated as a pale yellow oil. 34%
150.62, 128.84, 124.55, 60.50, 52.28, 51.51, 51.09, 17.44,
17.05.
4.4. Nickel-catalysed monoarylation of
trimethylene(bis)piperidine
1
yield. IR (NaCl, cm21): nNH 3431. H NMR (400 MHz,
CDCl3) d ppm: 6.89 (d, J¼9.2 Hz, 2H), 6.83 (d, J¼9.2 Hz,
2H), 3.75 (s, 3H), 3.42–3.33 (m, 2H), 3.13–2.99 (m, 3H),
2.67 (ddd, J¼11.6, 11.6, 3.2 Hz, 1H), 2.39 (NH), 2.33 (dd,
J¼11.6, 11.6 Hz, 1H), 1.13 (d, J¼6.4 Hz, 3H). 13C NMR
(CDCl3, 100 MHz) d ppm: 153.47, 145.53, 118.01, 114.05,
57.98, 55.12, 50.39, 50.35, 45.46, 19.22. HREIMS Obsd
m/z¼206.1424 (M), C12H18N2O requires 206.1419.
Compounds 4 were prepared according to the typical
procedures A and B described for piperazine.
4.4.1. 1-Phenyl-4-[3-(4-piperidinyl)propyl]piperidine 4a
(Table 3). Purification was performed by silica gel
chromatography using MeOH–AcOEt (40/60) as eluant.
The title compound was isolated as a white solid. 51% yield
(method A) and 81% yield (method B). Mp¼1868C. IR
4.3.5. 3-Methyl-1-(2-pyridinyl)piperazine27 3e (Table 2).
Purification was performed by silica gel chromatography
using MeOH–AcOEt (45/55) as eluant. The title compound
was isolated as a yellow oil. 54% yield. IR (NaCl, cm21):
1
(KBr, cm21): nNH 3397. H NMR (400 MHz, CDCl3) d
ppm: 7.24 (dd, J¼8.4, 7.6 Hz, 2H), 6.93 (d, J¼8.4 Hz, 2H),
6.81 (dd, J¼7.6, 7.6 Hz, 1H), 3.65 (d, J¼12.0 Hz, 2H), 3.46
(d, J¼12.0 Hz, 2H), 2.84 (dd, J¼12.0, 12.0 Hz, 2H), 2.66
(dd, J¼12.0, 12.0 Hz, 2H), 1.86 (d, J¼12.0 Hz, 2H), 1.76 (d,
J¼12.0 Hz, 2H), 1.66–1.56 (m, 2H), 1.49 (NH), 1.38–1.22
(m, 10H). 13C NMR (CDCl3, 100 MHz) d ppm: 151.68,
128.80, 119.01, 116.29, 49.83, 43.97, 36.33, 35.76, 35.43,
33.96, 32.03, 28.67, 23.27. HREIMS Obsd m/z¼286.2422
(M), C19H30N2 requires 286.2408.
1
nNH 3356. H NMR (400 MHz, CDCl3) d ppm: 8.16 (dd,
J¼4.8, 2.0 Hz, 1H), 7.42 (ddd, J¼8.4, 8.4, 2.0 Hz, 1H),
6.63–6.55 (m, 2H), 4.13 (d, J¼11.6 Hz, 1H), 4.06 (d,
J¼11.6 Hz, 1H), 3.05 (ddd, J¼11.6, 3.2, 3.2 Hz, 1H), 2.88–
2.80 (m, 3H), 2.52 (NH), 2.45 (dd, J¼11.6, 11.6 Hz, 1H),
1.11 (d, J¼6.4 Hz, 3H). 13C NMR (CDCl3, 100 MHz) d
ppm: 158.67, 147.10, 136.68, 112.53, 106.30, 51.56, 49.59,
44.72, 44.46, 18.78.
4.4.2. 1-(4-Methylphenyl)-4-[3-(4-piperidinyl)propyl]-
piperidine 4b (Table 3). Purification was performed by
silica gel chromatography using MeOH–AcOEt (40/60) as
eluant. The title compound was isolated as a pale yellow
solid. 48% yield (method A) and 79% yield (method B).
Mp¼2158C. IR (KBr, cm21): nNH 3412. 1H NMR
(400 MHz, CDCl3) d ppm: 7.04 (d, J¼8.6 Hz, 2H), 6.89
(d, J¼8.6 Hz, 2H), 3.58 (d, J¼12.0 Hz, 2H), 3.48 (d,
J¼12.0 Hz, 2H), 2.79 (dd, J¼12.0, 10.4 Hz, 2H), 2.64 (dd,
J¼12.0, 10.4 Hz, 2H), 1.82 (d, J¼12.0 Hz, 2H), 1.74 (d,
J¼12.0 Hz, 2H), 1.63–1.48 (m, 3H), 1.40–1.28 (m, 10H).
13C NMR (CDCl3, 100 MHz) d ppm: 151.12, 129.92,
129.53, 117.65, 49.42, 43.30, 37.02, 35.84, 35.70, 34.36,
31.65, 27.47, 22.84, 20.06. HREIMS Obsd m/z¼300.2569
(M), C20H32N2 requires 300.2565.
4.3.6. 3,5-Dimethyl-1-phenylpiperazine 3f (Table 2).
Purification was performed by silica gel chromatography
using MeOH–AcOEt (40/60) as eluant. The title compound
was isolated as a pale yellow oil. 69% yield. IR (NaCl,
cm21): nNH 3392. 1H NMR (400 MHz, CDCl3) d ppm: 7.25
(dd, J¼7.6, 1.2 Hz, 2H), 6.92 (d, J¼7.6 Hz, 2H), 6.84 (dd,
J¼7.6, 7.6 Hz, 1H), 3.51 (dd, J¼11.6, 2.8 Hz, 2H), 3.04
(ddq, J¼3.6, 2.8, 0.8 Hz, 2.28 (dd, J¼11.6, 11.6 Hz, 2H),
1.99 (NH), 1.13 (d, J¼6.4 Hz, 6H). 13C NMR (CDCl3,
100 MHz) d ppm: 151.15, 128.97, 119.45, 116.07, 56.11,
50.51, 19.60. HREIMS Obsd m/z¼190.1475 (M), C12H18N2
requires 190.1469.
4.3.7. 1-(3-Methoxyphenyl)-3,5-dimethylpiperazine 3g
(Table 2). Purification was performed by silica gel
chromatography using MeOH–AcOEt (40/60) as eluant.
The title compound was isolated as a pale yellow oil. 70%
4.4.3. 4-[3-(4-Piperidinyl)propyl]1-[(3-trifluoromethyl)-
phenyl]piperidine 4c (Table 3). Purification was performed
by silica gel chromatography using MeOH–AcOEt (40/60)
as eluant. The title compound was isolated as a pale yellow
oil. 43% yield (method A) and 74% yield (method B). IR
1
yield. IR (NaCl, cm21): nNH 3385. H NMR (400 MHz,
CDCl3) d ppm: 7.14 (dd, J¼8.4, 8.0 Hz, 1H), 6.51
(dd, J¼8.4, 2.0 Hz, 1H), 6.44 (dd, J¼4.4, 2.0 Hz, 1H),
6.37 (dd, J¼8.0, 2.0 Hz, 1H), 3.75 (s, 3H), 3.48 (dd, J¼11.6,
2.8 Hz, 2H), 3.01 (ddq, J¼3.6, 2.8, 0.8 Hz, 2H), 2.29 (dd,
J¼11.6, 11.6 Hz, 2H), 2.24 (NH), 1.11 (d, J¼6.4 Hz, 6H).
13C NMR (CDCl3, 100 MHz) d ppm: 160.20, 152.23,
129.38, 108.54, 103.84, 102.13, 55.56, 54.73, 50.26, 19.22.
HREIMS Obsd m/z¼220.1580 (M), C13H20N2O requires
220.1575.
1
(NaCl, cm21): nNH 3405. H NMR (400 MHz, CDCl3) d
ppm: 7.11 (dd, J¼8.0, 8.0 Hz, 1H), 6.51 (dd, J¼8.0, 2.0 Hz,
1H), 6.47–6.38 (m, 2H), 3.63 (d, J¼12.4 Hz, 2H), 3.41 (d,
J¼12.4 Hz, 2H), 2.90 (dd, J¼12.6, 12.4 Hz, 2H), 2.72 (dd,
J¼12.6, 12.4 Hz, 2H), 1.88–1.80 (m, 3H), 1.76 (d,
J¼12.0 Hz, 2H), 1.56–1.46 (m, 2H), 1.36–1.23 (m, 10H).
13C NMR (CDCl3, 100 MHz) d ppm: 151.79, 131.63,
130.05, 124.63, 118.95, 115.13, 112.20, 49.18, 46.32, 36.86,
35.60, 35.48, 33.97, 32.28, 27.65, 24.03. 19F NMR
(235 MHz, CDCl3) d ppm: 257.65. Anal. Calcd for
C20H29N2F3: C, 67.80, H, 8.19, N, 7.91, F, 16.10. Found:
C, 67.65, H, 8.21, N, 7.84.
4.3.8. 2,5-Dimethyl-1-phenylpiperazine28 3h (Table 2).
Purification was performed by silica gel chromatography
using MeOH–AcOEt (40/60) as eluant. The title compound
was isolated as a colourless oil. 26% yield. IR (NaCl,
cm21): nNH 3388. 1H NMR (400 MHz, CDCl3) d ppm: 7.30
(dd, J¼7.6, 7.6 Hz, 2H), 7.13–7.09 (m, 3H), 3.33–3.25 (m,
3H), 3.11 (dd, J¼12.0, 3.2 Hz, 1H), 2.81 (dd, J¼12.0,
12.0 Hz, 2H), 2.09 (NH), 1.28 (d, J¼6.4 Hz, 3H), 0.92 (d,
J¼6.0 Hz, 3H). 13C NMR (CDCl3, 100 MHz) d ppm:
4.4.4. 1-(3-Methoxyphenyl)-4-[3-(4-piperidinyl)propyl]-
piperidine 4d (Table 3). Purification was performed by
silica gel chromatography using MeOH–AcOEt (40/60) as
eluant. The title compound was isolated as a pink solid. 36%

6922
E. Brenner et al. / Tetrahedron 58 (2002) 6913–6924
yield (method A) and 78% yield (method B). Mp¼2658C.
IR (KBr, cm21): nNH 3395. 1H NMR (400 MHz, CDCl3) d
ppm: 7.07 (dd, J¼8.4, 8.4 Hz, 1H), 6.48 (dd, J¼8.4, 2.0 Hz,
1H), 6.38 (dd, J¼4.0, 2.0 Hz, 1H), 6.30 (dd, J¼8.4, 2.0 Hz,
1H), 3.63 (d, J¼12.4 Hz, 2H), 3.26 (d, J¼12.4 Hz, 2H), 2.81
(dd, J¼12.4, 12.4 Hz, 2H), 2.63 (dd, J¼12.4, 12.4 Hz, 2H),
2.63 (dd, J¼12.4, 12.4 Hz, 2H), 1.89 (NH), 1.84–1.73 (m,
4H), 1.41–1.38 (m, 2H), 1.32–1.18 (m, 10H). 13C NMR
(CDCl3, 100 MHz) d ppm: 158.52, 151.12, 127.74, 106.97,
101.90, 100.30, 53.08, 47.56, 41.87, 34.52, 34.18, 33.56,
31.79, 30.12, 26.95, 21.38. Anal. Calcd for C20H32N2O: C,
75.95, H, 10.13, N, 8.86. Found: C, 75.80, H, 10.03, N, 8.60.
using hexane–AcOEt (15/85) as eluant. The title compound
was isolated as a white solid. 69% yield. Mp¼1218C (lit.
mp¼1218C). 1H NMR (400 MHz, CDCl3) d ppm: 8.21 (dd,
J¼8.0, 2.0 Hz, 2H), 7.48 (ddd, J¼8.0, 8.0, 2.0 Hz, 2H),
6.68–6.60 (m, 4H), 3.67 (s, 8H). 13C NMR (CDCl3,
100 MHz) d ppm: 159.21, 147.82, 137.36, 113.31, 106.98,
44.74.
4.5.5. 1,4-Bis(4-methylphenyl)piperazine29 2b (Table 4).
Purification was performed by silica gel chromatography
using hexane–AcOEt (4/96) as eluant. The title compound
was isolated as a white solid. 76% yield. Mp¼1278C (lit.
1
mp¼1288C). H NMR (400 MHz, CDCl3) d ppm: 7.09 (d,
4.5. Nickel-catalysed synthesis of symmetrical 1,4-
diarylpiperazines 2
J¼8.0 Hz, 4H), 6.89 (d, J¼8.0 Hz, 4H), 3.27 (s, 8H), 2.28
(s, 6H). 13C NMR (CDCl3, 100 MHz) d ppm: 149.14,
129.63, 129.49, 116.62, 49.96, 20.41.
Representative procedure. To a suspension of degreased
NaH (32.5 mmol) in THF (20 mL) were added piperazine
(12.5 mmol) and t-AmOH (5 mmol) in THF (10 mL)
followed by 2,20-bipyridine (7.5 mmol) and the mixture
was heated at 658C. Dried Ni(OAc)2 (2.5 mmol) was then
added and the mixture was further stirred at 658C for 2 h. To
the dark suspension of 2,20-bipyridine liganded Ni(0) thus
obtained was added the aryl chloride (50 mmol) and styrene
(5 mmol) in THF. The reaction was monitored by GC and
after complete consumption of the starting material, the
mixture was cooled to room temperature. Water (1 mL) and
dichloromethane (50 mL) were added sequentially and the
reaction mixture was filtered, dried over MgSO4 and
evaporated. The residue was purified by silica gel column
chromatography.
4.6. Nickel-catalysed synthesis of N,N0-diaryl
trimethylene(bis)piperidines 5
Compounds 5 were prepared according to the typical
procedure described for N,N0-diaryl piperazine 2.
4.6.1. 1-Phenyl-4-[3-(1-phenyl-4-piperidinyl)propyl]-
piperidine 5a (Table 5). Purification was performed by
silica gel chromatography using hexane–AcOEt (4/96) as
eluant. The title compound was isolated as a white solid.
73% yield. Mp¼1058C. 1H NMR (400 MHz, CDCl3) d
ppm: 7.22 (dd, J¼8.4, 7.6 Hz, 4H), 6.92 (d, J¼8.4 Hz, 4H),
6.81 (dd, J¼7.6, 7.6 Hz, 2H), 3.65 (d, J¼12.0 Hz, 4H), 2.65
(dd, J¼12.0, 12.0 Hz, 4H), 1.77 (d, J¼12.0 Hz, 4H), 1.40–
1.22 (m, 12H). 13C NMR (CDCl3, 100 MHz) d ppm: 151.88,
128.93, 119.10, 116.41, 50.01, 36.71, 35.64, 32.25, 23.74.
Anal. Calcd for C25H34N2: C, 82.82, H, 9.45, N, 7.73.
Found: C, 82.59, H, 9.23, N, 7.61.
4.5.1. 1,4-Diphenylpiperazine13 2a (Table 4). Purification
was performed by silica gel chromatography using hexane–
AcOEt (4/96) as eluant. The title compound was isolated as
1
a white solid. 78% yield. Mp¼1648C (lit. mp¼1648C). H
NMR (400 MHz, CDCl3) d ppm: 7.29 (dd, J¼8.4, 7.2 Hz,
4H), 6.98 (d, J¼8.4 Hz, 4H), 6.89 (dd, J¼7.2, 7.2 Hz, 2H),
3.33 (s, 8H). 13C NMR (CDCl3, 100 MHz) d ppm: 151.67,
129.61, 120.48, 116.76, 49.85.
4.6.2. 3-(4-{3-[3-Methoxyphenyl)-4-piperidinyl]propyl}-
piperidino)phenylmethyl ether 5b (Table 5). Purification
was performed by silica gel chromatography using hexane–
AcOEt (4/96) as eluant. The title compound was isolated as
a white solid. 78% yield. Mp¼1038C. 1H NMR (400 MHz,
CDCl3) d ppm: 7.13 (dd, J¼8.4, 8.0 Hz, 2H), 6.54 (dd,
J¼8.4, 2.0 Hz, 2H), 6.47 (dd, J¼4.4, 2.4 Hz, 2H), 6.36 (dd,
J¼8.0, 2.0 Hz, 2H), 3.76 (s, 6H), 3.65 (d, J¼12.4 Hz, 4H),
2.66 (dd, J¼12.4, 12.0 Hz, 4H), 1.75 (d, J¼12.0 Hz, 4H),
1.32–1.22 (m, 12H). 13C NMR (CDCl3, 100 MHz) d ppm:
160.41, 153.16, 129.52, 109.17, 103.76, 102.64, 54.99,
49.84, 36.66, 35.64, 32.13, 23.67. Anal. Calcd for
C27H38N2O2: C, 76.74, H, 9.06, N, 6.63, O, 7.57. Found:
C, 76.67, H, 8.87, N, 6.44.
4.5.2. 1,4-Bis(3-methoxyphenyl)piperazine12 2b (Table
4). Purification was performed by silica gel chromatography
using hexane–AcOEt (10/90) as eluant. The title compound
was isolated as a white solid. 79% yield. Mp¼1418C (lit.
mp¼1428C). 1H NMR (400 MHz, CDCl3) d ppm: 7.17 (dd,
J¼8.4, 8.4 Hz, 2H), 6.53 (dd, J¼8.4, 2.0 Hz, 2H), 6.49 (dd,
J¼4.0, 2.0 Hz, 2H), 6.42 (dd, J¼8.4, 2.0 Hz, 2H), 3.77 (s,
6H), 3.29 (s, 8H). 13C NMR (CDCl3, 100 MHz) d ppm:
161.07, 153.05, 130.31, 109.51, 105.16, 103.19, 55.64, 49.67.
4.5.3. 1,4-Bis[(3-trifluoromethyl)phenyl)piperazine13 2c
(Table 4). Purification was performed by silica gel
chromatography using hexane–AcOEt (4/96) as eluant.
The title compound was isolated as a pale yellow oil. 82%
yield. 1H NMR (400 MHz, CDCl3) d ppm: 7.37 (dd, J¼8.0,
8.0 Hz, 2H), 7.18–7.16 (m, 2H), 7.14–7.09 (m, 4H), 3.38
(s, 8H). 13C NMR (CDCl3, 100 MHz) d ppm: 151.12,
131.21, 129.67, 124.27, 119.08, 116.39, 112.49, 48.73. 19F
NMR (235 MHz, CDCl3) d ppm: 263.02.
4.6.3. 1-[3-(Trifluoromethyl)phenyl]-4-(3-{1-[(trifluoro-
methyl)phenyl]-4-piperidinyl}propyl) piperidine 5c
(Table 5). Purification was performed by silica gel
chromatography using hexane–AcOEt (4/96) as eluant.
The title compound was isolated as a white solid. 75% yield.
1
Mp¼878C. H NMR (400 MHz, CDCl3) d ppm: 7.31 (dd,
J¼8.0, 8.0 Hz, 2H), 7.14–7.10 (m, 2H), 7.09–7.01 (m, 4H),
3.70 (d, J¼12.4 Hz, 4H), 2.74 (dd, J¼12.4, 12.0 Hz, 4H),
1.80 (d, J¼12.0 Hz, 4H), 1.45–1.24 (m, 12H). 13C NMR
(CDCl3, 100 MHz) d ppm: 151.87, 131.50, 129.40, 124.42,
119.06, 115.17, 112.40, 49.51, 36.66, 35.60, 32.04. 19F
NMR (235 MHz, CDCl3) d ppm: 263.11. Anal. Calcd for
4.5.4. 1,4-Bis(2-pyridinyl)piperazine26 2d (Table 4).
Purification was performed by silica gel chromatography

E. Brenner et al. / Tetrahedron 58 (2002) 6913–6924
6923
C27H32N2F6: C, 65.05, H, 6.47, N, 5.62, F, 22.86. Found: C,
64.96, H, 6.36, N, 5.54.
References
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4.6.4. 1-(4-Methylphenyl)-4-{3-[1-(4-methylphenyl)-4-
piperidinyl]propyl}piperidine 5d (Table 5). Purification
was performed by silica gel chromatography using hexane–
AcOEt (4/96) as eluant. The title compound was
isolated as a white solid. 71% yield. Mp¼998C. 1H
NMR (400 MHz, CDCl3) d ppm: 7.04 (d, J¼8.6 Hz, 4H),
6.85 (d, J¼8.6 Hz, 4H), 3.57 (d, J¼11.6 Hz, 4H), 2.61
(dd, J¼11.6, 11.6 Hz, 4H), 2.25 (s, 6H), 1.77 (d,
J¼11.6 Hz, 4H), 1.39–1.26 (m, 12H). 13C NMR
(CDCl3, 100 MHz) d ppm: 149.85, 129.45, 128.64,
116.84, 50.67, 36.72, 35.58, 32.31, 23.76, 20.37. Anal.
Calcd for C27H38N2: C, 83.02, H, 9.81, N, 7.17. Found:
C, 82.85, H, 9.71, N, 7.12.
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¨
¨
4.7. Nickel-catalysed synthesis of unsymmetrical 1,4-
diarylpiperazines 6
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Compounds 6 were prepared using general reaction
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chromatography using hexane–AcOEt (4/96) as eluant.
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1
overall yield. Mp¼118–1198C (lit. mp¼1188C). H NMR
(400 MHz, CDCl3) d ppm: 7.26 (dd, J¼7.6, 7.6 Hz, 2H),
7.17 (dd, J¼8.4, 8.4 Hz, 1H), 6.94 (d, J¼8.0 Hz, 2H),
6.86 (dd, J¼7.6, 7.6 Hz, 1H), 6.57 (dd, J¼8.4, 1.6 Hz,
1H), 6.50 (dd, J¼2.4, 2.0 Hz, 1H), 6.43 (dd, J¼8.4,
1.6 Hz, 1H), 3.76 (s, 3H), 3.32–3.36 (m, 8H). 13C NMR
(CDCl3, 100 MHz) d ppm: 152.45, 151.05, 129.72,
129.03, 119.89, 116.16, 108.91, 104.54, 102.61, 55.02,
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title compound was isolated as a white solid. 66% overall
yield. Mp¼1628C. 1H NMR (400 MHz, CDCl3) d ppm: 7.45
(d, J¼8.8 Hz, 2H), 7.29 (dd, J¼7.6, 7.6 Hz, 2H), 6.97 (d,
J¼8.8 Hz, 2H), 6.92–6.85 (m, 3H), 3.33–3.27 (m, 8H). 13C
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126.45, 124.91, 120.48, 120.27, 116.76, 114.53, 49.35,
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HREIMS Obsd m/z¼306.1350 (M), C17H17N2F3 requires
306.1343.
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zine 6c (Table 6). Purification was performed by silica gel
chromatography using hexane–AcOEt (4/96) as eluant. The
title compound was isolated as a yellow oil. 73% overall
yield. 1H NMR (400 MHz, CDCl3) d ppm: 7.18 (dd, J¼8.4,
8.4 Hz, 1H), 7.10 (d, J¼8.0 Hz, 2H), 6.92 (d, J¼8.0 Hz,
2H), 6.56 (dd, J¼8.4, 2.0 Hz, 1H), 6.50 (dd, J¼2.4, 2.0 Hz,
1H), 6.42 (dd, J¼8.4, 2.0 Hz, 1H), 3.75 (s, 3H), 3.29–3.27
(m, 4H), 3.27–3.25 (m, 4H), 2.29 (s, 3H). 13C NMR
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129.72, 116.82, 109.63, 105.23, 103.44, 55.62, 49.86, 49.51,
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requires 282.1732.
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