Stereoselective synthesis of enantiopure N-protected-3-arylpiperazines from keto-esters

Article abstract of DOI:10.1016/j.tetlet.2012.07.031

An efficient method for a stereoselective synthesis of optically pure N-Boc-3-arylpiperazines has been developed. After optimization of the protecting group strategy and experimental conditions, compounds were obtained via a highly stereoselective synthesis in up to 45% overall yield. This is a practical route to optically pure piperazines for medicinal chemistry.

Full text of DOI:10.1016/j.tetlet.2012.07.031

Tetrahedron Letters 53 (2012) 5215–5218
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of enantiopure N-protected-3-arylpiperazines
from keto-esters
Mouhamad Jida a,d, Guillaume Laconde a,d, Olivier-Mohamad Soueidan b,d, Nicolas Lebegue c,d
,
Germain Revelant a,d, Lydie Pelinski b,d, Francine Agbossou-Niedercorn b,d, Benoit Deprez a,d,
,
⇑
Rebecca Deprez-Poulain a,d,
⇑
a INSERM U761 Biostructures and Drug Discovery, Univ Lille Nord de France, Institut Pasteur de Lille, Lille F-59000, France
b UMR CNRS 8181, Unité de Catalyse et de Chimie du Solide, ENSCL, Université de Lille1, Villeneuve d’Ascq, F-59655, France
c EA 4481, Laboratoire de Chimie Thérapeutique, Univ Lille Nord de France, Lille F-59000, France
d PRIM, Lille F-59000, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for a stereoselective synthesis of optically pure N-Boc-3-arylpiperazines has been
developed. After optimization of the protecting group strategy and experimental conditions, compounds
were obtained via a highly stereoselective synthesis in up to 45% overall yield. This is a practical route to
optically pure piperazines for medicinal chemistry.
Received 23 May 2012
Revised 3 July 2012
Accepted 9 July 2012
Available online 15 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Stereoselective ring opening
Cyclocondensation
Lactams
Piperazines
Nitrogen heterocycles
Chiral
The piperazine ring is present in many bioactive molecules and
acts as a linker,1 a pharmacophore,2 or a modulator of pharmacoki-
netics.3 Consequently, 2- or 3-substituted piperazines are interest-
ing target compounds. In these structures, the residue on the
As 2- or 3-monosubstituted piperazines are chiral, their highly
stereoselective synthesis is greatly desirable for medicinal
chemists.
Recent examples of chiral 2- or 3-aryl substituted piperazine-
based bioactive compounds were reported (Fig. 1).9 Enantiopure
2- or 3-substituted piperazines may be prepared following non-
stereoselective syntheses including an enantiomeric resolution
requiring most of the time functionalization of both nitrogen
atoms.10 In addition, the resolution step is carried out quite often
late in the synthesis. A dynamic kinetic resolution would increase
the overall yield significantly.11
Other methods include first the synthesis of chiral 2-oxopiper-
azines.12 As such, the preparation of enantio-enriched piperazines
using an asymmetric hydrogenation of tetrahydropyrazines has
been reported (up to 97% ee).13
Procedures via stereoselective opening of an optically pure
epoxide (synthesized using a chiral auxiliary) or aminolysis of
enantiomeric aziridines were also described.14 An interesting
method based on a stereoselective Grignard addition in the pres-
ence of (ꢀ)-sparteine constitutes one example of enantio-enriched
piperazine preparation through a one-pot procedure starting from
pyrazine N-oxide (20% yield, 83% ee).15 At last, a recent method
uses a three-step to access alkyl substituted piperazines proline
as a catalyst (21–50% yield, 55–96% ee).16
4
carbon adjacent to one nitrogen atom alters the piperazine pKa
and lipophilicity.5 It can also protect the ring from N-dealkylation
thanks to steric hindrance and from hydroxylation, which are both
key metabolic pathways of N-substituted piperazines.6
In that context, a convenient and rapid synthesis of N-pro-
tected-substituted piperazine building-blocks is of high interest
for medicinal chemists. Classical synthetic strategies to access
racemic 2- or 3-substituted-piperazines include reduction of keto-
or diketo-piperazines, alkylation and reduction of substituted
pyrazines, lithiation, and alkylation of N-Boc piperazines, and mul-
ticomponent reactions.7 We have recently published an efficient
synthesis of N-benzyl-2-substituted piperazines via Ugi’s reac-
tion.8 This methodology allowed the preparation of an array of
racemic piperazines which expanded the availability of the pro-
tected piperazines found currently in commercial databases.
⇑
Corresponding authors. Tel.: +33 320 964 947; fax: +33 320 964 709.
E-mail addresses: benoit.deprez@univ-lille2.fr (B. Deprez), rebecca.deprez@
univ-lille2.fr (R. Deprez-Poulain).
URLs: http://www.deprezlab.fr, http://www.drugdiscoverylille.org.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.031

5216
M. Jida et al. / Tetrahedron Letters 53 (2012) 5215–5218
O
O
a: Ar = Ph
Cl
N
Br
b: Ar = pMe-C6H4
c: Ar = pMeO-C6H4
N
H
Ar
F
1) methyl glycinate,
DIEA, DMF, rt
2) CbzCl, pyridine, DCM
3) LiOH 1M
N
Cl
Ph
Ph
NH2
O
HO
Ar
HO
Ar
N
N
N
N
*
*
O
Cbz OH
N
+
F
NH
Cl
DPPIV inhibitor
CXCR3 antagonist
N
LiAlH4, AlCl3
Ar
O
Cbz
3a
Me
THF, -78 °C
1a-c
CF3
4a
(R)-phenylglycinol
CSA cat.
60% de
HN
CN
toluene, reflux
N
CF3
Ph
Ph
Ph
N
O
OH
HO
Ar
N
Cl
O
N
N
N
O
1) LiAlH4, AlCl3
THF, -78 °C
O
N
O
*
H2, Pd/C
EtOH, rt
Ar
N
Ar
F
N
2) Boc2O,
NEt3,
DCM, rt
N
H
CB1 antagonist
O
NK1 antagonist
O
Boc
Cbz
N
6a-c
2a-c
5a-c
H
N
60% de
>99% de
>99% de
N
N
N
H
Ph
N
N
N
H
HO
Ar
Ar
N
O
N
diastereomers
separation
H2, Pd(OH)2/C
MeOH, rt
F
N
Boc
O
N
5HT2a antagonist
PDE 10a inhibitor
Boc
7a-c
8a-c
>99% ee
Figure 1. Examples of chiral bioactive compounds bearing 2- or 3-substituted
piperazines.
Scheme 1. Route A: Synthesis of piperazines from carbobenzyloxy-protected keto-
acids.
Following our ongoing interest in the use of chiral bicyclic lac-
tams,17 we sought to extend their use in the stereoselective syn-
thesis of aryl-substituted piperazines.18
Pd/C, to obtain compounds 5a–c in 70–92% yields. Then, treatment
with LiAlH4/AlCl3 gave the desired 2-phenyl-(piperazin-1-yl)-etha-
nol) intermediates as a mixture of diastereomers in 80/20 ratio.
These intermediates were reacted with Boc2O providing deriva-
tives 6a–c with preservation of the diastereomeric ratio. After
separation of diastereomers by column chromatography, (7a–c)
and subsequent hydrogenolysis of using Pearlman’s catalyst
(Pd(OH)2/C), the desired piperazines 8a–c were obtained (Scheme
1). The pMe- and pMeO- substituted phenyl derivatives were ob-
tained in similar yields (24–32% from the corresponding bromo-
acetophenones). Thus, piperazines 8 were obtained in five steps
from Cbz-protected keto-esters following route A.
Though the desired compounds were obtained, we thought that
several aspects of the process should be changed to increase the
value of this methodology. First, diastereoisomeric excess should
be improved. Second, the number of steps could be reduced. Third,
manipulation of the protecting groups should be simplified.
The lactamization can be carried out with keto-esters as well as
with acids. As esters are intermediates in the synthesis of 1a–c, we
decided to spare the ester hydrolysis step. The protecting groups on
keto-aminoacid precursors are required for the lactamization step
avoiding thus by-products formation implying the secondary
amine. As described above, in the case of use of Cbz, a deprotection
step is required to prevent the reduction of the carbamate in the
presence of LiAlH4 into an undesirable N-methyl piperazine deriva-
tive. To avoid manipulation of protecting groups, carbamates were
In this paper, we report a facile and rapid method to access
ready-to-use N-protected substituted piperazines in good overall
yields, high purity, and ee, starting from easily accessible keto-acid
derivatives and the chiral auxiliary (R)-phenylglycinol (Fig. 2).
N-Cbz-3-aza-5-keto acids 1a–c were obtained by alkylation of
methyl glycinate with bromoacetophenones followed by protec-
tion using CbzCl and finally hydrolysis of the methyl esters.19 In-
spired by previous reports on the synthesis of chiral piperidines
like anabasine,20 we then prepared first the enantiopure bicyclic
lactams 2a–c by reaction of 1a–c with (R)-phenylglycinol in tolu-
ene in the presence of camphorsulfonic acid (Scheme 1).21 Under
these conditions, the absolute configuration of the ring-junction
carbons is well established.22
We next attempted a concomitant opening of the oxazoline ring
and reduction of lactam 2a with LiAlH4 in the presence of AlCl3.17
Simultaneous reduction of lactams and reductive opening of oxaz-
oline by LiAlH4 is known to be highly stereoselective in the case of
pyrrolidines.22 In the case of piperazines however, we show here
that the procedure leads to the desired compound 3a in 50% yield
but as a diastereomeric mixture (80/20) due to some partial inver-
sion of configuration. In addition, a reduction of the carbamate was
inevitable and provided compound 4a in 50% yield.
To avoid the undesired reduction of the carbamate, we removed
first the Cbz group from 2a–c via hydrogenolysis in the presence of
Ph
R
H
N
O
Ar
Ar
N
O
R-phenylglycinol
Ar
*
O
PG
N
O
*
CO2Me
Br
Ar
N
N
Boc
PG
Figure 2. Retrosynthetic analysis.

M. Jida et al. / Tetrahedron Letters 53 (2012) 5215–5218
5217
OTi(Cl)4
excluded and we considered the alternative use of benzyl and to-
syl23 residues (Table 1). In addition, their late deprotection would
also be beneficial to the purification steps along the synthesis.
As concomitant oxazoline opening and lactam reduction in the
presence of LiAlH4/AlCl3 induced some epimerization, we carried
out these two transformations in separate steps. Thus, we planned
O
Ph
Ph
H
H-
Figure 3. Retention of configuration during ring opening of oxazoline.
22
to use triethylsilane and TiCl4 to open the oxazoline before lac-
tam reduction. N-protected methyl esters 1d–e were first obtained
easily from the corresponding methyl glycine esters and bromo-
acetophenones in two-steps (Table 1). Conversion of the keto-es-
ters into bicyclic lactams 2d–e was efficient. Slightly better yields
were obtained for the benzyl derivative 2d.
The Boc protected piperazine 8a was then synthesized in five
steps from the bicyclic lactam 2d as depicted in Scheme 2. First,
10a was obtained from 2d by treatment with TiCl4/Et3SiH, followed
by lactam reduction using LiAlH4. Applying these new conditions,
no epimerization occurred and 10a was obtained as a single diaste-
reomer in 72% yield for the two steps.24
This can be explained by the ability of TiCl4 to form a chelated
intermediate in favor of retention of configuration (Fig. 3).25
Selective deprotection of the benzyl group, followed by protec-
tion of the piperazine by a Boc residue delivered 7a as a single dia-
stereomer. Removal of the chiral auxiliary using Pearlman’s
catalyst gave 8a in 44% overall yield from bromoacetophenone
(eight steps) and in >99% ee. The same protocol was used to access
its enantiomer 80a (Table 2). Tosyl piperazine 11a (Table 2) was
also obtained from 1e in an overall lower yield albeit we did not
need to manipulate protecting groups during synthesis (see Sup-
plementary data).
Table 2
Enantiopure piperazines synthesized
H
N
H
N
H
N
Ar
Ar
Ar
a: Ar =Ph
b: Ar = pMe-C6H4
c: Ar = pMeO-C6H4
N
N
N
Tos
11a
Boc
8a-c
Boc
8'a
Entry
Route
Compd
Overall yielda (%)
1
2
3
4
5
6
A
A
A
B
B
—
8a (R)
8b (R)
8c (R)
8a (R)
80a (S)
28
32
24
44
45
22
11a (R)
a
From bromoacetophenones.
nificantly and provided the desired compounds in higher yields
and a smaller number of steps. In addition, as the synthesis was
highly diasteroselective, no separation of diastereomers was re-
quired and better yields were obtained consequently (i.e. 44% vs
28% for 8a, Table 2). Finally, the Boc-protected 3-arylpiperazines
prepared here are of versatile use in medicinal chemistry due to
ease of deprotection and application will be reported in due course.
In summary, we have shown that the use of chiral bicyclic lac-
tams constitutes a very efficient strategy to access optically pure
arylated piperazines.26 The initial strategy has been improved sig-
Table 1
Acknowledgements
Preparation of bicyclic lactams 2d–e
Ph
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.
1) methylgl ycinate,
O
DIEA, DMF, rt
O
PG
N
O
O
(R)-phenylglycinol
N
O
Br
Ph
2) PGX, base,
solvent
Dean-stark
OMe
Ph
Ph
N
toluene, reflux
PG
2d
2e
PG = Bn1d
Ts 1e
Supplementary data
PGX
BnBr K2CO3/CH3CN 1d
TsCl Na2CO3/THF 1e
Base/solvent
Compd Yielda (%) Compd Yielda (%) deb (%)
78
65
2d
2e
90
80
>99
>99
Supplementary data (Detailed synthesis and spectral data for all
compounds. Detailed library synthesis. This material is free of
charge via the Internet at http://www.sciencedirect.com.) asso-
ciated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.07.031.
a
Isolated yields.
Determined by 1H and 13C NMR spectroscopy.
b
References and notes
H2 or
ammonium
formate,
Pd/C
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Ph
Ph
Ph
HO
Ph
HO
Ph
1) TiCl4, Et3SiH
THF, -78°C to rt
O
N
N
N
O
N
Ph
2) LiAlH4, THF
0°C to rt
EtOH, rt
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Bn
N
H
Bn
2d
10a, >99% de
9a, >99% de
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DCM, rt
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Scheme 2. Route B: Optimized synthesis of 8a.

5218
M. Jida et al. / Tetrahedron Letters 53 (2012) 5215–5218
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Synthesis of piperazines 10a and 100a using stereoselective cleavage by TiCl4
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dissolved in CH2Cl2 (5 mL) and cooled to ꢀ78 °C. The nucleophile tri-ethyl
silane (1 mmol) was then added dropwise using a syringe. After stirring at
ꢀ78 °C for 15 min, the Lewis acid TiCl4 (2 mmol) was added using a syringe and
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quenched by the addition of NH4Cl (2 mL) and water (5 mL). The aqueous
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filtered, and concentrated to dryness under reduced pressure. The obtained
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A suspension of Lithium
aluminium hydride (0.4 mmol) in THF (1 ml) was slowly added to an ice-
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further 10 min, the reaction mixture was allowed to reach room temperature
over 18 h. The reaction mixture was then quenched by the addition of
saturated MgSO4 solution (0.5 mL) and ether (1 mL) at 0 °C. The resultant
solution was filtered through Celite and washed with ether (1 mL). The organic
layer was washed with water (1 mL), dried over anhydrous magnesium sulfate,
filtered and concentrated to dryness under vacuum to give piperazines 10 or
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Obtention of 8a–c and 80a. 20% Pd(OH)2 (0.052 mol) was added to a solution of
7a–c or 70a (0.26 mmol) in EtOH (10 ml). The reaction was stirred under a H2-
atmosphere at room temperature for 18 h and was then filtered through Celite.
After concentration under reduced pressure, the crude product was diluted
with H2O (10 mL) and extracted with EtOAc (3 ꢁ 10 mL). The combined organic
fractions were washed with 1 N HCl (3 ꢁ 5 mL). The aqueous acid fractions
were basified to pH 8–9 by the addition of NaHCO3 sat. while maintaining
vigorous stirring. The aqueous mixture was extracted with EtOAc (3 ꢁ 10 mL).
The combined organic fractions were washed with brine (10 mL), dried over
anhydrous magnesium sulfate, filtered and concentrated under vacuum to give
the enantiomerically pure N-Boc-piperazines.
(R)-tert-butyl 3-phenylpiperazine-1-carboxylate (8a): Yield (68 mg; 98%);
colorless oil; ½a D = +11.8 ° (c 0.3, CH2Cl2); Purity: 100%; 1H NMR (300 MHz,
ꢂ
CDCl3) d 7.45–7.27 (m, 5H), 5.04 (br s, 1H, NH), 4.11–3.97 (m, 2H), 3.75 (dd,
J = 10.8, 3.0 Hz, 1H), 3.06–2.79 (m, 4H), 1.46 (s, 9H). 13C NMR (75 MHz, CDCl3) d
154.54 (Cq), 139.50 (Cq), 128.69, 128.24, 127.22, 80.09 (Cq), 59.90, 45.27,
28.41; rt(LCMS) = 2.55 min (5 min, pH = 3.8); HRMS-ESI (m/z): [M+H]+
(C15H23N2O2) calcd 263.17540; found 263.17540.
15. Andersson, H.; Banchelin, T. S.-L.; Das, S.; Gustafsson, M.; Olsson, R.; Almqvist,
F. Org. Lett. 2010, 12, 284–286.
16. O’Reilly, M. C.; Lindsley, C. W. Tetrahedron Lett. 2012, 53, 1539–1542.
17. (a) Deprez-Poulain, R.; Willand, N.; Boutillon, C.; Nowogrocki, G.; Azaroual, N.;
Deprez, B. Tetrahedron Lett. 2004, 45, 5287–5290; (b) Beghyn, T.; Deprez-
Poulain, R.; Willand, N.; Folleas, B.; Deprez, B. Chem. Biol. Drug. Des. 2008, 72, 3–
15; (c) Jida, M.; Deprez-Poulain, R.; Malaquin, S.; Roussel, P.; Agbossou-
Niedercorn, F.; Deprez, B.; Laconde, G. Green Chem. 2010, 12, 961–964; (d) Jida,
M.; Malaquin, S.; Deprez-Poulain, R.; Laconde, G.; Deprez, B. Tetrahedron Lett.
2010, 51, 5109–5111.
18. For a review of the use of chiral bicyclic lactams from piperidines see (a) Amat,
M.; Pérez, M.; Bosch, J. Chem. -Eur. J. 2011, 17, 7724–7732. or pyrrolidines see;
(b) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843–9873.
19. (a) Gallicchio, S. N.; Bell, I. M. Tetrahedron Lett. 2009, 50, 3817–3819; (b)
Bencsik, J. R.; Kercher, T.; O’Sulliva, M.; Josey, J. A. Org. Lett. 2003, 5, 2727–2730.
20. Amat, M.; Canto, M.; Llor, N.; Bosch, J. Chem. Commun. 2002, 526–527.
21. Attempts to use the solvent-free microwave procedure reported in reference
14c were unsuccessful with these keto-acids.
(S)-tert-butyl 3-phenylpiperazine-1-carboxylate (80a): Yield (66 mg; 97%);
colorless oil; ½a D
ꢂ
= ꢀ11.5 ° (c 0.3, CH2Cl2); Purity: 100%; 1H NMR (300 MHz,
CDCl3) d 7.43–7.25 (m, 5H), 4.60 (br s, 1H, NH), 4.18–3.91 (m, 2H), 3.74 (dd,
J = 10.8, 3.0 Hz, 1H), 3.06–2.81 (m, 4H), 1.46 (s, 9H). 13C NMR (75 MHz, CDCl3) d
154.57 (Cq), 139.85 (Cq), 128.66, 128.16, 127.18, 80.01 (Cq), 59.95, 45.40,
28.42; rt(LCMS) = 2.59 min (5 min, pH = 3.8); [M+H]+ (C15H23N2O2) calcd
263.1760; found 263.1760.
(R)-tert-butyl 3-p-tolypiperazine-1-carboxylate (8b): Yield (64 mg; 90%);
colorless oil; 1 enantiomer, ee = 100% ½aꢂD = ꢀ11.9 ° (c 0.3, CH2Cl2); Purity:
100%; 1H NMR (300 MHz, CDCl3) d 7.35 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.1 Hz,
2H), 4.09 (br s, 1H, NH), 4.04–3.96 (m, 2H), 3.85–3.80 (m, 2H), 3.21–2.85 (m,
3H), 2.35 (s, 3H), 1.48 (s, 9H). 13C NMR (75 MHz, CDCl3) d 154.38 (Cq), 138.38
(Cq), 135.23 (Cq), 129.67, 127.28, 80.30 (Cq), 59.70, 45.01, 29.97, 28.40, 21.21;
rt(LCMS)
=
2.72 min (5 min, pH = 3.8); HRMS-ESI (m/z): [M+H]+ calcd
22. Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57, 1656–1662.
23. Tosyl can be kept during all steps to give N-Tosyl protected piperazines 11.
24. Direct treatment of 2d–e with LiAlH4/AlCl3 gave a mixture 80/20 of the two
diastereomers.
25. Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z. Tetrahedron Lett. 1999,
40, 143–146.
26. General procedure for the preparation of bicyclic lactams: N-protected
oxazolo[3,2-a]pyrazin-5-ones (2a–e). To a solution of ketoacid or keto ester 1
(6 mmol, 1 equiv) in toluene was added (R)-2-phenylglycinol (or (S)-2-
277.19105; found 277.19069.
(R)-tert-butyl 3-(4-methoxyphenyl)piperazine-1-carboxylate (8c): Yield (63 mg;
83%); colorless oil; 1 enantiomer, ee = 100% ½a D = ꢀ24.1 ° (c 0.3, CH2Cl2);
ꢂ
Purity: 100%; 1H NMR (300 MHz, CDCl3) d 7.33 (d, J = 8.7 Hz, 2H), 6.89 (d,
J = 8.7 Hz, 2H), 4.16–3.96 (m, 2H), 3.81 (s, 3H), 3.67 (dd, J = 9.6, 2.4 Hz, 1H),
3.09–2.54 (m, 4H), 1.84 (br s, 1H, NH), 1.51 (s, 9H). 13C NMR (75 MHz, CDCl3) d
159.12 (Cq), 154.66 (Cq), 133.53 (Cq), 128.99, 128.02, 113.81, 79.64 (Cq), 59.58,
55.19, 46.02, 29.97, 28.38; rt(LCMS) = 2.65 min (5 min, pH = 3.8); HRMS-ESI
(m/z): [M+H]+ calcd 293.18597; found 293.18518.