A facile and rapid synthesis of N-benzyl-2-substituted piperazines

Article abstract of DOI:10.1016/j.tetlet.2011.02.011

A facile and rapid synthetic approach of N-benzyl-2-substituted piperazine building-blocks via an Ugi strategy is described. This strategy is high yielding (80-92% overall yield), step-efficient and fast using microwave heating and tert-butylisocyanide as a convertible isocyanide. This method is useful for the obtention of key intermediates in medicinal chemistry.

Full text of DOI:10.1016/j.tetlet.2011.02.011

Tetrahedron Letters 52 (2011) 1705–1708
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile and rapid synthesis of N-benzyl-2-substituted piperazines
Mouhamad Jida a,b,c,d, Mohamad Soueidan d,e, Nicolas Willand a,b,c,d, Francine Agbossou-Niedercorn d,e
,
a,b,c,d,
Lydie Pelinski d,e, Guillaume Laconde a,b,c,d, Rebecca Deprez-Poulain a,b,c,d, , Benoit Deprez
⇑
⇑
a INSERM U761 Biostructures and Drug Discovery, Lille F-59000, France
b Faculté de Pharmacie, Université Lille Nord de France, Lille F-59000, France
c Institut Pasteur de Lille, IFR 142, Lille F-59021, France
d PRIM, Lille F-59000, France
e UMR CNRS 8181 Unité de Catalyse et de Chimie du Solide, Université Lille, Cité Scientifique Villeneuve d0Ascq F-59655, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and rapid synthetic approach of N-benzyl-2-substituted piperazine building-blocks via an Ugi
strategy is described. This strategy is high yielding (80–92% overall yield), step-efficient and fast using
microwave heating and tert-butylisocyanide as a convertible isocyanide. This method is useful for the
obtention of key intermediates in medicinal chemistry.
Received 17 November 2010
Revised 27 January 2011
Accepted 1 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
UGI
Piperazines
Microwave
The piperazine ring is a core structure present in many bioactive
molecules. First, it can serve either as a linker between the groups
responsible for activity or behave as a pharmacocophore like in the
well known first three generations of fluoroquinolone antibiotics
(i.e., levofloxacin, Fig. 1). In natural products this heterocycle is
rather present in fused or oxidized forms (i.e., ergotamine, safricin
B, Fig. 1). Recently published bioactive piperazines include
monoamine reuptake inhibitors,1 MAP kinase inhibitors,2 CCK1R
agonists,3 urotensin antagonists,4 GHSR antagonists,5 and HIV
integrase inhibitors.6 Also, the piperazines can be used by medici-
nal chemists as a basic pharmacophore whose pH can be modu-
lated by the N1 and N4 substituents,7 thus modulating the ability
to interact with the biological target. Secondly, this heterocycle is
a powerful tool for the fine-tuning of pharmacokinetics of bioactive
compounds. Indeed, it modulates in numerous examples the solu-
bility, permeability, and metabolism like for imatinib (Fig. 1) or
IGF-1R kinase inhibitors.8
pKa7 and lipophilicity. As a consequence, it influences permeation,
solubility, and bioavailability of the compounds. Some recent
examples include the enhancement of passive membrane perme-
ation for HIV protease inhibitors6 or the enhancement of brain per-
meation in
a
template hopping strategy.1 N-substituted
piperazines can be metabolized to Nor-derivatives or by hydroxyl-
ation in the 2-position and subsequent ring opening (i.e., prazosin
and sildenafil).11,12 Thus, the use of a 2-substituted piperazine pre-
cursors could protect against both the metabolic processes by
reducing N-dealkylation thanks to steric hindrance or by direct
prevention of hydroxylation.
In that context, a convenient and rapid synthesis of N-benzyl-2-
substituted piperazine building-blocks is of high interest for
medicinal chemists (Fig. 2).
The 2-substituted piperazines can be prepared by (1) intramolec-
ular acylation and reduction of diketopiperazines or ketopipera-
zines,13 (2) alkylation and reduction of substituted pyrazines14 or
(3) lithiation and alkylation of N-Boc piperazines.15 These methods
often require multiple steps and the chemical diversity is limited
by the commercial availability of starting materials and the harsh
conditions usually required. Recently, multicomponent reaction
approaches have emerged in the field of piperazine synthesis.16,17
We have already published the use of multicomponent reactions
to access biologically interesting molecules.18 We report, in this
paper, a facile and rapid method to access, in high yield and purity,
diverse N-protected-2-substituted piperazines ready-to-use
building-blocks.
The 2-substituted piperazines are of high interest for pharmaco-
modulation. Unfortunately, examples in the literature are limited
almost exclusively to 2-methyl and 2-phenylpiperazines, because
of the limited availability of suitably protected piperazines in com-
mercial databases.5,9,10 The 2-substituent is also a key feature of
pharmacokinetic properties of piperazines as it modulates its
⇑
Corresponding authors. Tel.: +33 3 20964947; fax: +33 3 20964709 (R.D.-P.).
E-mail addresses: rebecca.deprez@univ-lille2.fr (R. Deprez-Poulain), benoit.
deprez@univ-lille2.fr (B. Deprez).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.011

1706
M. Jida et al. / Tetrahedron Letters 52 (2011) 1705–1708
O
OH
N
H
N
O
HO
N
O
O
O
N
O
O
H
O
F
O
OH
N
N
H
N
O
N
H
H
H
CN
N
O
NH
O
N
levofloxacin
ergotamine
safracin B
H
NH2
O
N
N
N
NH2
N
N
N
O
O
O
N
O
N
N
S
N
N
N
N
N
H
N
O
N
HN
O
O
O
sildenafil
imatinib
prazosin
Figure 1. Examples of bioactive compounds containing a piperazine ring.
N-substituants:
- modulate pKa
R
1
N
R
Piperazine:
2-substituant:
- linker
- pharmacophore
- pharmacophore
- modulates pharmacokinetics
N
- modulates pKa & lipophilicity
- modulates pharmacokinetics & metabolism
R
2
Figure 2. Roles of piperazine and 2-substituted piperazine in medicinal chemistry.
NH2
NH2
OH
OH
BocNH
O
BocNH
O
N
R
O
O
O
a.
R1
b.
N
O
BocNH
N
+
N
+
H
BocNH
N
NC
O
O
R
N
H
H
O
O
R
NC
R
H
2a-p
1a-p
R1
1
R
H
Ugi Product
Scheme 1. Reagents and conditions: (a) MeOH, 18 h, rt; (b) glacial AcOH,
microwave, 180 °C, 10 min.
ible isocyanide19 or n-butylisonitrile.20 In a strategy to minimize
the cost of the reagents, we used the cheaper t-BuNC as a convert-
ible isocyanide, as we have already used it for the synthesis of
piperidines.18,21,22 Moreover, the t-butyl amine group can be
removed by intramolecular substitution using pure AcOH while
n-butyl group requires a mixture of TFA in dichloroethane and
further silica gel purification of the crude product. On the opposite,
our strategy allows obtaining easily of the desired diketopiperazine
(DKP) by simple precipitation of the reaction mixture in water.
The reaction proceeds as described in Scheme 1. Boc-Gly-OH,
benzylamine, various aldehydes, and t-BuNC react in methanol at
room temperature for 18 h affording the classical Ugi products
(1a–p). For all the chosen aldehydes, either electron–withdrawing
groups or electron-donor groups, yields are excellent (92–100%).
Also an organometallic derivative or heteroaromatic aldehydes
give good results. Then, the Ugi products are irradiated by micro-
waves at 180 °C for 10 min in glacial acetic acid to form the desired
corresponding DKP (2a–p) in excellent yields (91–98%) and puri-
ties. The results are presented in the Table 1. 2-Keto-piperazines
are obtained in two steps in 82–97% overall yield as compared to
44–67% using n-butylisonitrile.20
O
N
R
O
N
R
N
H
N
H
3
N-benzyl
2-subtituted
piperazine
2
DKP
Figure 3. Synthetic strategy.
N-Protected-2-substituted piperazines of general formula 3
(Fig. 3) can be prepared by reducing the corresponding diketopi-
perazines 2 which are obtained via a multicomponent reaction
from four cheap and readily available building-blocks: N-Boc-gly-
cine, amines, aldehydes, and a convertible isocyanide (Fig. 3). In
our case the benzylamine was used as a precursor of the N-benzyl
protected piperazine. This protecting group can be selectively
removed via Pd-catalyzed reduction. Yet, its presence allows the
differentiation of the two nitrogen atoms in subsequent reactions.
Other benzylamines can be used in the replacement of benzyl-
amine to fine-tune the deprotection conditions.
Hulme and co-workers have reported an Ugi sequence to con-
struct heterocyclic cores and have applied it to the synthesis of 6
The DKPs (2a–p) are then reduced by using 8 equivalents of
LiAlH4 in THF (Scheme 2).23 After 4 h, the corresponding 2-substi-
tuted piperazines (3a–p) bearing a benzyl protecting group on N1
keto-piperazines from glycine, Aib (
a-aminoisobutyric acid), ala-
nine, or phenylalanine.19,20 They use either Armstrong0s convert-

M. Jida et al. / Tetrahedron Letters 52 (2011) 1705–1708
1707
Table 1
Synthesis of N-benzyl-2-substituted DKPs and N-benzyl-2-substituted piperazines
R-
Ugi product yield (%)
DKP yield (%)
Piperazine yield (%)
1a
100
93
2a
97
98
98
95
3a
90
86
81
77
1b
1c
1d
1e
2b
2c
2d
2e
3b
3c
3d
3e
F
F
96
98
F
94
94
84
Cl
Br
1f
1g
1h
1i
100
93
95
97
92
90
93
2f
2g
2h
2i
95
94
93
96
92
91
93
3f
3g
3h
3i
80
91
83
88
80
83
87
H3CO
1j
2j
3j
N
N
1k
1l
2k
2l
3k
3l
N
O
1m
92
2m
95
3m
82
O
1n
1o
93
2n
2o
92
93
3n
3o
78
82
F3C
100
1p
93
2p
93
3p
79
Fe
on nitrogen atom N1 in good yields by reducing the corresponding
diketopiperazines (DKPs). These latter compounds were generated
in excellent yields using an Ugi reaction with a convertible isocya-
nide, followed by a reduction. The reported methodology appears
very suitable for the synthesis of a large number of 2-substituted
piperazines by simple variation of aldehyde compounds. The ac-
cess to enantiomerically pure N-benzyl-2-substituted piperazines
is currently under investigation in our laboratory.
O
N
R
O
N
R
N
H
N
H
2a-p
3a-p
Scheme 2. Reagents and conditions: (a) LiAlH4, THF, 0 °C then rt, 4 h.
Acknowledgments
are formed in excellent yields (77–91%) (Table 1). Slightly below
average yields were observed for fluorine-containing compounds
(3c, 3d, and 3n) or ferrocenic and bromine derivatives.
In conclusion, we have described a rapid and robust method to
synthesize 2-substituted piperazines bearing a Bn protecting group
We are grateful to the institutions that support our laboratory
(Inserm, Université de Lille2, Institut Pasteur de Lille, USTL). This
project was supported by Conseil Régional Nord-Pas de Calais,
DRRT PRIM 2008-07 PRIM-SP.

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M. Jida et al. / Tetrahedron Letters 52 (2011) 1705–1708
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