A novel and facile method to synthesize (R)- and (S)-2-methylpiperazine

Article abstract of DOI:10.1081/SCC-200036590

A concise and efficient synthesis of (R)- and (S)-2-methylpiperazine in only five steps from (D)- and (L)-alanine is described. The key step is reaction of benzylamine with a bifunctional molecule to build a six-membered ring.

Full text of DOI:10.1081/SCC-200036590

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A Novel and Facile Method
to Synthesize (R)‐ and
(S)‐2‐methylpiperazine
Bo Liu a b , Guang‐Yu Xu a , Chun‐Hao Yang a , Dr.
Xi‐Han Wu a & Yu‐Yuan Xie a
a State Key Laboratory of Drug Research , Shanghai
Institute of Materia Medica, SIBS , CAS 555
Zuchongzhi Road, Shanghai, 201203, China
b Graduate School of the Chinese Academy of
Sciences , Beijing, China
Published online: 10 Jan 2011.
To cite this article: Bo Liu , Guang‐Yu Xu , Chun‐Hao Yang , Dr. Xi‐Han Wu & Yu‐Yuan
Xie (2004) A Novel and Facile Method to Synthesize (R)‐ and (S)‐2‐methylpiperazine,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:22, 4111-4118, DOI: 10.1081/SCC-200036590
To link to this article: http://dx.doi.org/10.1081/SCC-200036590
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 22, pp. 4111–4118, 2004
A Novel and Facile Method to Synthesize
(R)- and (S)-2-methylpiperazine
Bo Liu,1,2 Guang-Yu Xu,1 Chun-Hao Yang,1 Xi-Han Wu,1,
and Yu-Yuan Xie1
*
1State Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, SIBS, CAS, Shanghai, China
2Graduate School of the Chinese Academy of Sciences, Beijing, China
ABSTRACT
A concise and efficient synthesis of (R)- and (S)-2-methylpiperazine in
only five steps from (D)- and (L)-alanine is described. The key step
is reaction of benzylamine with a bifunctional molecule to build a six-
membered ring.
Key Words: (R)- and (S)-2-methylpiperazine; Synthesis.
*
Correspondence: Dr. Xi-Han Wu, State Key Laboratory of Drug Research, Shanghai
Institute of Materia Medica, SIBS, CAS 555 Zuchongzhi Road, Shanghai 201203,
China; Fax: 86-21-50806770; E-mail: xhwu@mail.shcnc.ac.cn.
4111
DOI: 10.1081/SCC-200036590
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Liu et al.
INTRODUCTION
Piperazine derivatives are particularly important to medicinal chemist.
They were found to be used as base templates and substituents to impart the
desired pharmacological and pharmacokinetic properties to several pharma-
ceutical agents, such as in quinolone antibiotics,[1] HIV-protease inhibitors,[2]
5HT-anxiolytics,[3] anti-hypertensives,[4] and d-opioid receptor agonists.[5]
Recently piperazine functioning as bifunctional linking agent to couple
quinolone and oxazolidinone[6] through its six-membered heterocycle
was reported. As part of our research involving the study of quinolone and
oxazolidinone antibiotics we became interested in preparing enantiomerically
pure 2-methylpiperazines and their analogue synthons.
There are some reports on the synthesis of the enantiomerically pure
2-methylpiperazines. The procedure of Armarego suffers from low yield
(18%).[7] Enlightened by Armarego’s idea, J.S. Kiely[8] and E.J. Jacobsen[9]
made a modification and reported their methods in 1990 and 1995, respec-
tively. However, due to the restricted availability of chemical reagents, it’s
still valuable for us to develop a simple and practical method to synthesize
the enantiomerically pure 2-methylpiperazines, especially for preparation in
large quantities.
RESULTS AND DISCUSSION
The intermediates of enantiomerically pure 2-methylpiperazines and
their analogue synthons were prepared as shown in Scheme 1. Thus, the enan-
tiomerically pure alanine was converted to its methyl ester with SOCl2 in
Scheme 1.

New Method to Synthesize (R)- and (S)-2-methylpiperazine
4113
methanol, and without purification, the resulting ester was treated with
ClCH2COCl and NaHCO3 in a mixture of water and benzene, which can
give the product in high purity and yield than in homogeneous solution.
The crude 2a (or 2b) reacted with benzylamine in methanol and the key inter-
mediate diketopiperazine 3a (or 3b) was obtained in good yield (about 80%)
through [5 þ 1] cycling reaction.[10]
In general, the low concentration of reactant is beneficial for the intra-
molecular reaction. But to our surprise, the [5 þ 1] cycling reaction didn’t
run well at low concentration, but gave better result when the concentration
of 2a (2b) was at about 0.5 mol/L. We considered that the chloro-group of
2a (2b) reacted first with benzylamine through the intermolecular path
which depended on the concentration of 2a (or 2b) and then the ester group
in the molecule reacted with the secondary amine group in the same molecule
going through the intramolecular path. The result of the cycling reaction run at
different concentration is listed in Table 1.
3a (or 3b) was reduced to 4a (or 4b) by LiAlH4 at rt for 36 hr to avoid
possible racemization. Therefore, the target molecule 2-methylpiperazines
5a (or 5b) and the Boc-protected 2-methylpiperazines 7a (or 7b) were
readily prepared as usual from 4a (or 4b) as shown in Scheme 2 and
Scheme 3, respectively. 7a and 7b can be used as very useful synthon in the
synthesis of the pharmaceutical agents containing 2-methylpiperazines.
In summary, we report here a novel facile and practical method to
synthesize enantiomerically pure 2-methylpiperazines and their analogue
synthons starting from cheap reagents in fewer steps and high yield.
EXPERIMENTAL
The 1HNMR spectra were recorded on a Varian Mercury-400
High Performance Digital FT-NMR with TMS as internal standard, and the
mass spectra were determined by using Finnigan MAT 95, EI: 70 eV.
Melting points were obtained at a Bu¨chi 510 melting point apparatus and
are uncorrected. Microanalyses were carried out on a Leco CHN-2000
Table 1. The experimental data of [5 þ 1] cycling reaction.
1 mol/L–higher
concentration
Lower concentration–
0.1 mol/L
2a(2b)
0.2–0.8 mol/L
Side-product
3a(3b)
Moderate
Moderate
Low
High
High
Low

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Liu et al.
Scheme 2.
elemental analyzer. The optical rotation value [a]D was determined with
Perkin–Elmer-341 (589 nm).
(R)-1-benzyl-3-methylpiperazine-2,5-dione (3a)
To a suspension of D-alanine (26.70 g, 0.30 mol) in CH3OH (200 mL)
cooled in ice-salt bath, SOCl2 (87.5 mL, 1.2 mol) was added dropwise while
stirring. After the addition, the resulting mixture was stirred for an additional
6 hr at rt. The clear solution was concentrated to dryness, and without any puri-
fication, the solid was dissolved in water (120 mL) and cooled in ice-salt bath.
To the solution, NaHCO3 (60 g, 0.71 mol) was added in one portion, and then
the solution of chloroacetyl chloride (23.8 mL, 0.3 mol) in benzene (100 mL)
was added dropwise. After the addition, the reaction mixture was stirred for
an additional 3 hr at rt. The aqueous layer was extracted twice with benzene
(100 mL), and the combined organic phase was dried over anhydrous
MgSO4. Subsequent filtration and removal of organic solvent in vacuo gave
a crude product (47.95 g, 89% based on 1a), which was purified by chromato-
graphy on the silica gel (3 : 1, PE : EtOAC) to give 44.18 g (82% based on 1a)
of 2a as a colorless oil (solidified on standing). Mp 34–358C; [a]2D5 ¼ þ 50.58
(c ¼ 2, MeOH); 1HNMR(CDCl3): d 7.12 (br s, 1 H), 4.60 (m, 1 H), 4.06 (s, 2
H), 3.77 (s, 3 H), 1.45 (d, J ¼ 7.13 Hz, 3 H).
A solution of benzylamine (24.1 mL, 0.22 mol) in CH3OH (180 mL) was
added dropwise over 1.5 hr to a solution of 2a (32.8 g, 0.183 mol) and TEA
Scheme 3.

New Method to Synthesize (R)- and (S)-2-methylpiperazine
4115
(73.2 mL, 0.55 mol) in CH3OH (180 mL) and refluxed for 20 hr, the pale
yellow solution was cooled to rt and concentrated, and the residue was
dissolved in 150 mL CH2Cl2. The organic phase was washed by 100 mL 5%
aqueous citric acid, 100 mL saturated aqueous NaHCO3, and 100 mL brine,
and dried over anhydrous Na2SO4. Subsequent filtration and removal of
organic solvent in vacuo gave a pale yellow solid (38.9 g), which was recrys-
tallized from toluene (175 mL) to give 31.1 g (78%) of 3a as a white solid. Mp
1
137–1398C; [a]2D0 ¼ þ 8.568 (c¼1, CHCl3); HNMR (CDCl3): d 7.39–7.23
(m, 5H), 4.59 (s, 2H), 4.14 (m, 1H), 3.84 (s, 2H), 1.53(d, J ¼ 6.86 Hz, 3H);
MS (EI): m/e(%) 218 (Mþ, 76), 91 (100), 57 (44); Anal. Calcd. for
C12H14N2O2: C, 66.03; H, 6.46; N,12.84. Found: C, 66.09; H, 6.37; N, 12.68.
If crude 2a was used directly for the next reaction, 3a was obtained in
66% yield based on 1a.
(S)-1-benzyl-3-methylpiperazine-2,5-dione (3b)
Starting from L-alanine (1b), this compound was prepared in 67.5% yield
based on 1b according to the procedure described above. Mp 138–139.58C;
1
[a]2D0 ¼ 28.858 (c ¼ 2, CHCl3); HNMR (CDCl3): d 7.39–7.23 (m, 5H),
4.59 (s, 2H), 4.14 (m, 1H), 3.84 (s, 2H), 1.53 (d, J ¼ 7.04 Hz, 3H); MS (EI):
m/e(%) 218 (Mþ, 76), 91 (100), 57 (44); Anal. Calcd. for C12H14N2O2: C,
66.03; H, 6.46; N, 12.84. Found: C, 65.74; H, 6.40; N, 12.66.
(R)-1-benzyl-3-methylpiperazine (4a)
To dry THF (300 mL) cooled in ice-salt bath, lithium aluminum hydride
(12.91 g, 0.331 mol) and 3a (20 g, 0.092 mol) were added subsequently. Under
N2 atmosphere, the mixture was stirred for 36 hr at rt. The reaction mixture
was cooled again by ice/water bath and 12.3 mL of H2O was added cau-
tiously, followed by addition of 14.6 mL aqueous 2N NaOH. After stirring
for 1 hr, the pale solid was removed by filtration and washed with THF. The
combined filtrate was concentrated, and the residue was distilled in vacuo to
give 14.1 g (81%) of 4a as a pale yellow liquid (0.1 mm Hg, Bp 92–958C)
which solidified on standing. Mp 30–328C; [a]2D0 ¼ þ7.38 (c ¼ 0.68,
CHCl3) flit.[9] [a]D25 ¼ þ78 (C ¼ 0.65, CHCl3)g; 1HNMR (CDCl3): d
7.33–7.24 (m, 5H), 3.48 (s, 2H), 2.94–2.74 (m, 5H), 2.05–1.95 (m, 1H),
1.66 (apparent t, 1H), 1.00 (d, J ¼ 6.2 Hz, 3H); MS (EI), m/e(%) 190
(Mþ, 10), 134 (70), 91 (100), 65 (17); Anal. Calcd. for C12H18N2: C,
75.74; H, 9.35; N, 14.72. Found: C, 75.42; H, 9.46; N, 14.69.

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Liu et al.
(S)-1-benzyl-3-methylpiperazine (4b)
This compound was prepared in 79% yield from 3b according to the
procedure described above. Mp 31–338C; [a]2D0 ¼ 25.48 (c ¼ 0.51, CHCl3)
flit.[9] [a]D25 ¼ 258 (C ¼ 0.51, CHCl3)g; 1HNMR (CDCl3): d 7.33–7.24
(m, 5H), 3.48 (s, 2H), 2.94–2.74 (m, 5H), 2.05–1.95 (m, 1H), 1.66 (apparent
t, 1H), 1.00 (d, J ¼ 6.2 Hz, 3H); MS (EI), m/e(%) 190 (Mþ, 10), 134 (70),
91 (100), 65 (17); Anal. Calcd. for C12H18N2: C, 75.74; H, 9.35; N, 14.72.
Found: C, 75.32; H, 9.61; N, 14.75.
(R)-2-methylpiperazine (5a)
A mixture of 4a (9.51 g, 0.05 mol), 10% palladium on carbon (1.2 g) and
CH3COOH (0.5 mL) in CH3OH (100 mL) was stirred under 1 atm of H2 at rt
for 24 hr.The catalyst was removed by filtration and washed with CH3OH. The
combined filtrate was concentrated to give a solid, which was recrystallized
from ether (100 mL) to give 5a as colorless needles (3.8 g, 76% yield). Mp
91–938C. [a]D20 ¼ 216.68 (c ¼ 4.6, C6H6) flit.[11] [a]2D0 ¼ 216.58 (C ¼ 5,
C6H6)g; 1HNMR (CDCl3): d 3.00–2.64 (m, 6H), 2.35 (dd, J ¼ 9.89,
11.81 Hz, 1H), 1.95 (s, 2H), 0.99 (d, J ¼ 6.26 Hz, 3H); MS(EI): m/e(%)
.
100 (Mþ, 27), 85 (100), 56 (54); Anal. Calcd. for C5H12N2 0.26H2O: C,
57.28; H, 12.04; N, 26.72. Found: C, 57.28; H, 11.95; N, 26.69.
(S)-2-methylpiperazine (5b)
This compound was prepared in 74% yield from 4b according to the
procedure described above. Mp 91–938C; [a]2D0 ¼ þ6.78 (c ¼ 0.97, EtOH)
flit.[11] [a]D20 ¼ þ6.88 (C ¼ 1, EtOH)g; 1HNMR (CDCl3): d 3.00–2.64
(m, 6H), 2.35 (dd, J ¼ 9.89, 11.81 Hz, 1H), 1.95 (s, 2H), 0.99
(d, J ¼ 6.26 Hz, 3H); MS (EI): m/e(%) 100 (Mþ, 27), 85 (100), 56 (54);
.
Anal. Calcd. for C5H12N2 0.23H2O: C, 57.57; H, 12.04; N, 26.86. Found: C,
57.57; H, 12.12; N, 26.78.
(R)-tert-butyl 4-benzyl-2-methylpiperazine-1-carboxylate (6a)
A solution of di-tert-butyl bicarbonate (5.81 g, 26.6 mmol) in CH2Cl2
(30 mL) was added dropwise over 15 min to a solution of 4a (4.6 g,
24.2 mmol) and TEA (3.96 mL, 26.6 mmol) in CH2Cl2 (30 mL) cooled in
ice-water bath. After stirring for 20 hr at rt, the reaction mixture was

New Method to Synthesize (R)- and (S)-2-methylpiperazine
4117
washed with brine and dried over NaSO4. Subsequent filtration and removal
of organic solvent in vacuo gave a residue that was purified by chromato-
graphy on silica gel (PE : EtOAC ¼ 20 : 1) to give 7.0 g (99%) of 6a as an
oil. [a]2D0 ¼ 262.68 (c ¼ 0.87, EtOH) flit.[9] [a]2D5 ¼ 2628 (C ¼ 0.84,
1
EtOH)g; HNMR (CDCl3): d 7.39–7.21 (m, 5H), 4.21–4.12 (m, 1H), 3.80
(d, J ¼ 13.04 Hz, 1H), 3.46 (ABq, JAB ¼ 13.32 Hz, Dg ¼ 41.23 Hz, 2H),
3.18–3.02 (m, 1H), 2.75 (d, J ¼ 11.12 Hz, 1H), 2.58 (d, J ¼ 11.13 Hz, 1H),
2.12 (dd, J ¼ 11.13, 3.85 Hz, 1H), 2.02–1.95 (m, 1H), 1.45 (s, 9H), 1.24
(d, J ¼ 6.73 Hz, 3H); MS(EI) m/e(%) 290 (M þ , 18), 233 (64), 160 (22),
146 (29), 134 (59), 91 (100); Anal. Calcd. for C17H26N2O2: C, 70.31; H,
9.02; N, 9.65. Found: C, 70.19; H, 9.21; N, 9.59.
(S)-tert-butyl 4-benzyl-2-methylpiperazine-1-carboxylate (6b)
This compound was prepared in 99% yield from 4b according to
the procedure described above. [a]2D0 ¼ þ59.58 (c ¼ 1.29, EtOH)
flit.[9] [a]D25 ¼ þ568 (C ¼ 0.44, EtOH)g; 1HNMR (CDCl3): d 7.39–7.21
(m, 5H), 4.21–4.12 (m, 1H), 3.80 (d, J ¼ 12.78 Hz, 1H), 3.46
(ABq, JAB ¼ 13.32 Hz, Dg ¼ 41.23 Hz, 2H), 3.18–3.02 (m, 1H), 2.75
(d, J ¼ 11.12 Hz, 1H), 2.58 (d, J ¼ 11.13 Hz, 1H), 2.12 (dd, J ¼ 11.13,
3.85 Hz, 1H), 2.02–1.95 (m, 1H), 1.45 (s, 9H), 1.24 (d, J ¼ 6.73 Hz, 3H);
MS(EI) m/e(%) 290 (Mþ, 18), 233 (64), 160 (22), 146 (29), 134 (59), 91
(100); Anal. Calcd. for C17H26N2O2: C, 70.31; H, 9.02; N, 9.65. Found: C,
70.25; H, 9.01; N, 9.51.
(R)-tert-butyl 2-methylpiperazine-1-carboxylate (7a)
A mixture of 6a (5.81 g, 20 mmol), 10% palladium on carbon (1.2 g) and
CH3COOH (8 drops) in CH3OH (50 mL) was stirred under 1 atm of hydrogen
at rt for 24 hr, and the catalyst was removed by filtration and washed with
CH3OH. The combined filtrate was concentrated, the residue was diluted
with CH2Cl2 (50 mL) and filtered. The filtrate was concentrated again
to give 3.68 g (92%) of 7a as a colorless oil that solidified on standing:
m.p. 34–368C; [a]D20 ¼ 260.48 (C ¼ 0.92, CHCl3) flit.[9] [a]2D5 ¼ 2598
(C ¼ 0.92, CHCl3)g; 1HNMR (CDCl3): d 4.10–4.30 (m, 1H), 3.75–3.80
(m, 1H), 2.60–3.00 (m, 5H), 1.84 (s, 1H), 1.46 (s, 9H), 1.22 (d, J ¼ 6.88 Hz,
3H); MS(EI): m/e(%) 200 (Mþ, 20), 144 (42), 127 (30), 99 (32), 70 (31), 57
(100); Anal. Calcd. for C10H20N2O2: C, 59.97; H, 10.07; N, 13.99. Found: C,
59.86; H, 9.95; N, 13.92.

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Liu et al.
(S)-tert-butyl 2-methylpiperazine-1-carboxylate (7b)
This compound was prepared in 90% yield from 6b according to the
procedure described above. Yield. Mp 34–368C; [a]2D0 ¼ þ68.58 (C ¼ 0.65,
CHCl3) flit.[9] [a]D25 ¼ þ678 (C ¼ 0.65, CHCl3)g; 1HNMR (CDCl3): d
4.10–4.30 (m, 1H), 3.75–3.80 (m, 1H), 2.60–3.00 (m, 5H), 1.84 (s, 1H),
1.46 (s, 9H), 1.22 (d, J ¼ 6.88 Hz, 3H); MS(EI): m/e(%) 200 (Mþ, 29),
144 (54), 127 (40), 99 (33), 70 (36), 57 (100); Anal. Calcd. for
C10H20N2O2: C, 59.97; H, 10.07; N, 13.99. Found: C, 59.92; H, 10.13; N,
13.78.
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