Nickel-mediated amination chemistry. Part 2: Selective N-arylation or N,N'-diarylation of piperazine

Article abstract of DOI:10.1016/S0040-4039(00)00277-X

The 2,2'-bipyridine liganded Ni catalyst has revealed a good selectivity in the mono arylation of piperazine starting from aryl chlorides allowing a selective and efficient synthesis of N-arylpiperazines using stoichiometric amounts of reagents. The preparation of N,N'-diaryl substituted piperazines is also described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00277-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2881–2884
Nickel-mediated amination chemistry. Part 2:
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Selective N-arylation or N,N -diarylation of piperazine
∗
Eric Brenner, Raphaël Schneider and Yves Fort
Synthèse Organique et Réactivité, UMR CNRS-UHP 7565, Université Henri Poincaré, Nancy I, Faculté des Sciences, BP 239,
5
4506 Vandoeuvre les Nancy Cedex, France
Received 17 January 2000; accepted 11 February 2000
Abstract
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The 2,2 -bipyridine liganded Ni catalyst has revealed a good selectivity in the mono arylation of piperazine
starting from aryl chlorides allowing a selective and efficient synthesis of N-arylpiperazines using stoichiometric
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amounts of reagents. The preparation of N,N -diaryl substituted piperazines is also described. © 2000 Elsevier
Science Ltd. All rights reserved.
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Keywords: nickel; arylamination; N-arylpiperazine; N,N -diarylpiperazine.
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N-Aryl and N,N -diarylpiperazines are key structural elements of many compounds possessing broad
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biological activities such as ligands of serotonin (5-HT) receptors, antifungals, antivirals or cholesterol
ester transfer protein inhibitors. During the last decade, numerous procedures have been reported for the
preparation of these compounds including S Ar reactions in liquid phase or on solid support, S Ar re-
actions on tricarbonyl chromium complexes, displacement of a chlorine atom in arene–iron complexes,
reaction of aniline derivatives with bis(2-bromoethyl) N-substituted amines on basic alumina or, more
recently, palladium catalysed aminations of aryl halides (generally bromides). The latter reactions,
extensively developed during recent years, have only scarcely been used with piperazine itself due to
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N
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N
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the competitive bis-arylation reaction. Indeed, four equivalents of piperazine are needed to obtain N-
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arylpiperazines in moderate yields, ranging from 10 to 50%, using the Pd/P(o-tol) system. A large
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excess of amine (up to six equivalents) associated to the Pd/P(t-Bu) catalyst was used to improve the
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selectivity and the yields. Alternatively, the preparation of N-arylpiperazines in a multistep protocol
starting from N-protected piperazines had also been described and did not afford better results.
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Herein, we wish to report that our recently described 2,2 -bipyridine liganded nickel catalyst is
effective for the synthesis of N-arylpiperazines 1 using only 1.1 equivalents of the starting amine relative
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to the aryl chloride (Scheme 1).
All the results obtained using this methodology are reported in Table 1. For example, the amination
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of chlorobenzene using 1.1 equivalents of piperazine in the presence of 10 mol% 2,2 -bipyridine
∗
Corresponding author. E-mail: yves.fort@sor.uhp-nancy.fr (Y. Fort)
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040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00277-X
tetl 16557

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Scheme 1.
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liganded Ni in refluxing THF gave after workup and purification a mixture of N-phenyl 1a and N,N -
diphenylpiperazine 2a in, respectively, 61 and 16% isolated yields (Table 1, entry a, reaction conditions
A).
Table 1
Nickel-catalysed synthesis of N-arylpiperazines 1 from aryl chlorides
N-Arylpiperazines can be prepared from various aryl chlorides substituted either by electron-
withdrawing or electron-donating groups. For all reactions described in Table 1, side products arising
from reduction and homocoupling were obtained in less than 2% yield. Note that reduction was consider-
ably decreased by addition of a catalytic amount of styrene in the reaction medium.13a The amination
reaction was found to be sensitive to the steric hindrance of the aryl chloride. 2-Chlorotoluene gave
N-(2-methylphenyl)piperazine 1d in 29% yield. Electron-poor aryl chlorides gave the corresponding

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arylpiperazines 1 in good yields (entries e, f and h) while lower yields were obtained with electron-
rich aryl chlorides (entry g). It must be underlined that amounts of bis-arylation products increased
with electron-poor aryl chlorides due to their higher reactivity. We have also examined the influence
of piperazine/aryl chloride ratio on the selectivity. Increasing the initial amount of piperazine to 2
equivalents (reaction conditions B) led to 1 as the sole reaction product. These results are similar to those
obtained in Pd-catalysed amination reactions using a large excess (4–6 equiv.) of piperazine. However,
reaction conditions A (1.1 equiv. of piperazine) allowed for easy access to N-arylpiperazines especially
when the starting materials are of high cost.
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In order to extend the scope of the 2,2 -bipyridine liganded Ni catalyst, we next studied bis-arylation
reactions of piperazine (Scheme 2).
Scheme 2.
GC analysis of the reaction mixture indicated that the initial coupling is more facile than the second
one. Conversion into the desired products may be effected by extending the reaction time or by the
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use of an excess aryl chloride (4 equiv.). Under these conditions, symmetrically N,N -biaryl substituted
piperazines 2 were obtained in good yields (Table 2). Note that compound 1 and biaryl were obtained as
by-products in, respectively, less than 5 and 10% isolated yields. Except 2-chloropyridine which afforded
2
in a moderate 55% yield (entry d), aryl chlorides bearing electron withdrawing substituents were more
reactive in bis-arylation reactions and gave higher yields of 2 (compare entries b and c with entry e).
Table 2
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a
Nickel-catalysed synthesis of N,N -diarylpiperazines 2
We consider the mechanism of these amination reactions to proceed as follows: (i) generation of
Ni(0) by reduction of Ni(OAc) with alkoxide activated NaH followed by amine coordination to Ni;
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(ii) oxidative addition of the aryl chloride; (iii) reductive elimination of the arylamine and regeneration
of the Ni catalyst.

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In conclusion, novel syntheses of N-aryl and N,N -diaryl substituted piperazines have been achieved
using nickel-catalysed amination reactions. The main advantage of our method lies in the fact that
monoarylations could be performed using stoichiometric amounts of the starting materials. Further
extensions of these reactions with aryl polychlorides are under investigation.
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1
2829.
14. Representative procedure for reaction conditions A: N-phenylpiperazine (1a): A solution of t-AmOH (5 mmol) in THF (5
mL) was added to a suspension of NaH (30 mmol) in THF (30 mL) and the mixture was heated to 63°C. Piperazine (27.5
0
mmol) was added followed by dried Ni(OAc)
2
(2.5 mmol) and 2,2 -bipyridine (7.5 mmol) and the reflux was maintained
0
for 2 h. To the dark suspension of 2,2 -bipyridine liganded Ni(0) thus obtained was added chlorobenzene (25 mmol) and
styrene (5 mmol) in THF (5 mL) and the mixture was heated for 6 h. After cooling to room temperature, hydrolysis with
water (1 mL) and dilution with CH
was purified by chromatography on silica gel using MeOH/AcOEt (40/60) to give N-phenylpiperazine 1a in 61% yield. H
2 2 4
Cl , the mixture was filtered, dried over MgSO and concentrated. The crude material
1
5
1
3
3
0
3
3
3
0
NMR (CDCl , 400 MHz): 7.23 (dd, J= J =8.0 Hz, 2H); 6.88 (d, J=8.0 Hz, 2H); 6.83 (dd, J= J =8.0 Hz, 1H); 3.12–3.04
3
m, 4H); 2.98–2.90 (m, 4H). 13C NMR (CDCl
, 100 MHz): 152.20, 129.48, 120.10, 116.48, 50.71, 46.48. IR (ν, cm ):
−1
(
3
3
292 (NH).
15. Pollard, C. B.; MacDowell, L. G. J. Am. Chem. Soc. 1934, 2199.