A convenient synthesis of N-benzylpiperazine, 1-aralkyl-4-benzylpiperazines and an Isostere of Idebenone

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A Convenient Synthesis of N-
Benzylpiperazine, 1-Aralkyl-4-
benzylpiperazines and an Isostere of
Idebenone
Jin Wangabc, Shuo Lid, Xiao Hua & Jian Yanga
a Kunming University of Science and Technology Kunming, Yunnan
650224, P. R. China
b Université de Toulouse, Université Toulouse III - Paul Sabatier, 118
route de Narbonne 31062 Toulouse Cedex 9, France
c Institut de Pharmacologie et de Biologie Structurale, UMR 5089,
205 route de Narbonne, 31077 Toulouse Cedex 04, France
d The First Affiliated Hospital of Nanjing Medical University, 300
Guangzhou Road Nanjing, Jiangsu, 210029, P. R. China
Published online: 15 Sep 2014.
To cite this article: Jin Wang, Shuo Li, Xiao Hu & Jian Yang (2014) A Convenient Synthesis of N-
Benzylpiperazine, 1-Aralkyl-4-benzylpiperazines and an Isostere of Idebenone, Organic Preparations
and Procedures International: The New Journal for Organic Synthesis, 46:5, 469-474, DOI:
10.1080/00304948.2014.944409
To link to this article: http://dx.doi.org/10.1080/00304948.2014.944409
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Organic Preparations and Procedures International, 46:469–474, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.944409
OPPI BRIEF
A Convenient Synthesis of N-Benzylpiperazine,
1-Aralkyl-4-benzylpiperazines and an Isostere
of Idebenone
Jin Wang,1,2,3 Shuo Li,4 Xiao Hu,1 and Jian Yang1
1Kunming University of Science and Technology Kunming, Yunnan 650224,
P. R. China
2Universite´ de Toulouse, Universite´ Toulouse III - Paul Sabatier, 118 route de
Narbonne 31062 Toulouse Cedex 9, France
3Institut de Pharmacologie et de Biologie Structurale, UMR 5089, 205 route de
Narbonne, 31077 Toulouse Cedex 04, France
4The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou
Road Nanjing, Jiangsu, 210029, P. R. China
N-Benzylpiperazine (4) is a known central nervous system stimulant, with effects com-
parable to that of S(+)-amphetamine.1 It is also a key structural element of a variety of
biologically active compounds and especially of 1-aralkyl- 4-benzylpiperazine derivatives
(7) which exhibit remarkable affinities to σ receptors against dopamine D-2 and 5-HT1A
receptors.2 Pharmacological studies have shown that many of these derivatives are potent
ligands to the σ sites and some of them are of potential interest for the treatment of mental
disorders.3,4
Although several methods for the preparation of N-benzylpiperazine have been re-
ported, most of them employ the direct benzylation of piperazine or start from mono-
protected N-acyl- and N-aroylpiperazines under carefully controlled basic conditions; how-
ever, these methods always produce a mixture of products from which N-benzylpiperazine
(4) is difficult or impossible to isolate.2–6 Therefore, a convenient and practical method for
its synthesis is still a desirable goal and we now report a simple and efficient route for the
preparation of 4 and also of 1-aralkyl- 4-benzylpiperazine derivatives (7).
Monobenzylation was achieved cleanly and in high yield (95% after chromatogra-
phy) without the need of using a monoprotected piperazine by converting anhydrous
Submitted by April 11, 2014.
Address correspondence to Jin Wang, Universite´ de Toulouse, Universite´ Toulouse III - Paul
Sabatier, 118 route de Narbonne 31062 Toulouse Cedex 9, France. E-mail: woongching@gmail.com
or Jian Yang, Kunming University of Science and Technology Kunming, Yunnan 650224, P. R. China.
E-mail: pharmacistkg101@126.com
469

470
Wang et al.
piperazine to its somewhat unstable monohydrochloride (3) in situ by reaction with piper-
azine dihydrochloride (2).in ethanol at reflux as shown in Scheme 1; piperazine dihy-
drochloride (2) was recovered quantitatively (100%) by filtration at the completion of the
reaction.
Scheme 1
As shown in Scheme 2, chloromethylation of 5a-c7 using paraformaldehyde and conc.
hydrochloric acid (Blanc reaction) under solvent-free conditions, gave excellent yields of
Scheme 2
5a-c which are key intermediates for the preparation of CoQ10 and its analogues.8,9 Treat-
ment of 6a-c with N-benzylpiperazine in the presence of K2CO3 under mild conditions
provided 1-aralkyl-4-benzylpiperazines (7a-c), which were subsequently converted into
their hydrochloride salts in good yields by addition of conc. hydrochloric acid in methanol.
In view of the difficulties associated with the preparation of previous CoQ analogues,8,
15–17
the availability of 6c prompted us to devise a practical route to 2,3-dimethoxy-
5-hydroxymethyl-6-methyl-1,4-benzoquinone (9), an isostere of idebenone, which is a
clinical drug used for the treatment of various cognitive diseases such as Alzheimer’s
and Parkinson’s and is also an efficient free radical scavenger for reactive oxygen species
(ROS).15 The addition of one equivalent tetra- (n-butyl)ammonium bromide facilitated the
hydrolysis of 6c to 8 in 91% yield; compound 8 was then oxidized to 9 with ceric ammonium
nitrate (CAN); the overall yield of 9 from 6c is 84% (Scheme 3).
In conclusion, an improved procedure for the preparation of N-benzylpiperazine (4)
has been developed. Furthermore, we have devised a convenient preparation of benzyl
chlorides (6a-c) via the Blanc reaction under solvent-free conditions cleanly without further
purifications. Furthermore, a novel and efficient direct amination of benzyl chlorides (6a-
c) with 4 for the synthesis of 1-aralkyl-4-benzylpiperazine hydrochlorides (7a-c) was
developed under metal-free conditions. Moreover, we developed a easy and efficient route
for the synthesis of isostere of idebenone 9, which could be useful for the synthesis of other
Coenzyme Q analogues. We believe that these experimentally simple approaches to be a
useful addition to reported methods.

N-Benzylpiperazine, 1-Aralkyl-4-benzylpiperazines and an Isostere of Idebenone 471
Scheme 3
Experimental Section
All reactions were monitored by TLC (SiO2, pet ether/EtOAc 3:1), Melting points were
1
measured on a YRT-3 temp apparatus and are uncorrected. H NMR and mass spectra
were recorded on a Bruker DRX NMR and a ZAB-2F Mass spectrometers, respectively.
Elemental analyses were performed on Perkin-Elmer PE2400 Elemental Analyzer. All
reagents (anhydrous piperazine, paraformaldehyde, benzyl chloride) were purchased from
Adamas-beta, P. R. China, and used without further purification. Compounds 5a-c were
prepared according to literature procedures.7,10–13
Synthesis of N-Benzylpiperazine (4)
A solution of anhydrous piperazine (1, 9.5 g, 0.11 mol) and piperazine dihydrochloride
(2, 31.8 g 0.2 mol) in ethanol (80 ml) were placed in a three-necked flask equipped with
a magnetic stir bar and reflux condenser was heated with vigorous stirring at 75◦C for
3 h. Then a solution benzyl chloride 13.9 (0.11 mol) was added dropwise over a period of
30 minutes to the hot solution. The reaction mixture was refluxed for another 2 h. or until
benzyl chloride had been completely consumed (the progress of the reaction was monitored
by TLC). The mixture was cooled and the precipitated piperazine dihydrochloride (2) was
collected and washed three times with ethanol. The filtrate combined with the washes was
concentrated in vacuo to give the N-benzylpiperazine hydrochloride which was then treated
with 6 M NaOH to pH >12. The aqueous layer of crude N-benzylpiperazine was extracted
into CH2Cl2 (3 × 50 ml). The combined organic extracts were dried over Na2SO4 and
concentrated in vacuo. The crude oily product was purified by flash column chromatography
on silica gel (1:3 MeOH-CH2Cl2) to give 18.4 g. (95%) of N-benzylpiperazine as a colorless
oil.14
1H NMR (500 MHz, CDCl3): δ 7.34-7.28 (m, 5H), 3.57 (s,2H), 3.23 (s,4H), 2.77
(s,4H). MS (ESI): m/z = 177 (M++H)

472
Wang et al.
Synthesis of Compounds 6a-c. General Procedure
To a stirred mixture of 5a-c (0.01 mol) and paraformaldehyde (0.45 g, 0.015 mol) was added
3 ml of conc. hydrochloric acid (37%) at room temperature. Then, the mixture was stirred at
40◦C for 1 h, Water (10 ml) was then added and the mixture was extracted with petroleum
ether (4 × 10 ml), and the combined organic extracts were washed with brine. The solution
was dried over Na2SO4 and concentrated in vacuo to afford desired compounds which were
used in the next step without further purification.
Compound 6a,7 yellow oil, 90% yield.
1H NMR (500 MHz,CDCl3): δ 4.69 (s,2H), 3.89 (s,3H),3.86 (s,3H), 3.84 (s,3H), 2.26
(s,3H).
Compound 6b,10 yellow oil, 96% yield
1H NMR (300 MHz, CDCl3): δ 4.70 (s,2H), 3.90 (s, 3H), 3.88(s, 3H), 3.87 (s, 3H),
2.46 (s, 3H).
Compound 6c,7 yellow oil, 97% yield.
1H NMR (500 MHz, CDCl3): δ 4.68(s, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H),
3.78 (s, 3H), 2.28 (s, 3H).
Synthesis of Compounds 7a-c. General Procedure
A suspension of 6a-c (10 mmol), N-benzylpiperazine (1.76 g, 10 mmol) and K2CO3 (1.65 g,
12 mmol) in CH2Cl2 (10 ml) were heated at 40◦C for 2 h; the progress of the reaction was
monitored by TLC. Water was added and the mixture was extracted with CH2Cl2 (30 ml)
washed with brine, dried over Na2SO4 and concentrated in vacuo. Then the concentrated oil
was dissolved in methanol and conc. HCl was added dropwise until the pH of the solution
at 1∼2. The white precipitate that formed immediately was collected and recrystallized
from methanol to afford the hydrochloride salts 7a-c.
Compound 7a, white solid, mp. 226-228◦C, 89% yield.
1H NMR (300 MHz, MeOD): δ 7.65 (s, 2H), 7.54-7.53 (m, 3H), 6.76 (s, 1H), 4.52
(s,2H), 4.46 (s, 2H), 4.01 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.75 (br, s, 8H), 2.47 (s, 3H).
13C NMR (75 MHz, MeOD): δ 156.9, 154.2, 140.9, 136.8, 132.7 (2C), 131.6, 130.5
(2C), 129.3, 113.3, 111.1, 61.9, 61.3, 56.5, 20.2. TOF-MS: m/z 371 (M++H). Calcd for
C22H31O3N2: 371.2334. Found: 371.2329.
Anal. Calcd for C22H32Cl2N2O3: C, 59.59; H. 7.27; N. 6.32. Found: C, 59.64; H, 7.29;
N, 6.34.
Compound 7b, white solid, mp. 221-222◦C, 88% yield.
1H NMR (300 MHz, MeOD): δ 7.69-7.65(m,2H), 7.52-7.51(s,2H), 4.60(s,2H), 4.55
(s,2H), 4.03 (s,3H), 3.92(s,3H), 3.91(s,3H), 3.80(br,s,4H), 3.75(br,s,4H),2.57(s,3H).
13CNMR(75 MHz, MeOD): 154.9, 154.3, 145.9, 136.5, 132.7(2C), 131.6, 130.5(2C),
129.4, 118.2, 116.9, 62.1, 61.7, 61.3, 54.7,21.2. TOF-MS: m/z 449 (M++H). Calcd for
C22H31BrN2O3:449.1440. Found: 449.1443.
Anal. Calcd for C22H31BrCl2N2O3: C, 50.59; H, 5.98; N, 5.36. Found: C, 50.63; H,
6.00; N, 5.35.
Compound 7c, white solid, mp. 202–204◦C, yield 92%.
1H NMR (300 MHz,CDCl3):
δ
7.66-7.64(m,2H),7.53-7.51(m,3H),4.53(s,2H),
4.50(s,2H), 3.96(s,3H), 3.91(s,3H), 3.80(s,3H),3.79(br,s,4H),3.72(br,s,4H),2.36(s,3H).

N-Benzylpiperazine, 1-Aralkyl-4-benzylpiperazines and an Isostere of Idebenone 473
13C NMR (75 MHz, MeOD): 149.5, 148.2, 144.5, 131.3(2C), 130.2, 129.1(2C),
128.4, 128.0, 115.0, 60.6, 60.3, 60.2, 59.8, 11.7. TOF-MS: m/z 401 (M++H). Calcd for
C23H33O4N2:401.2440. Found: 401.2433.
Anal. Calcd for C23H34Cl2N2O4:, 58.35; H, 7.24; N, 5.92. Found: C.,58.44; H, 7.26;
N, 5.94.
2,3,4,5-Tetramethoxy-6-hydroxymethyltoluene (8) :19
A mixture of NaOH (0.20 g, 5 mmol), Compound 6c (1.30 g, 5 mmol), KI (0.16 g, 1 mmol)
and tetra(n-butyl)ammonium bromide (TBAB, 1.61 g, 5 mmol) in water (10 ml) were
heated at 95◦C for 8 h, then quenched with water 20 ml, the crude was extracted with three
portions of CH2Cl2 (10 ml). The orange extracts were washed with brine until neutrality,
then dried over anhydrous Na2SO4 and concentrated in vacuo. The crude products were
purified by a silica-gel column chromatography with petroleum ether and EtOAc (3:1) as
eluent to give a yellow oil 8 (1.1 g, 91% yield).
1H NMR(500 MHz,CDCl3): δ 4.68 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H),
3.78 (s, 3H), 2.27 (s, 3H). MS: m/z = 242 (M++H)
2,3-Dimethoxy-5-hydroxymethyl-6-methyl-1,4-benzoquinone (9):18
Excess solution of CAN (11 g, 20 mmol) in water (10 ml) was added dropwise to a solution
of compound 8 (1.6 g, 6.6 mmol) in acetonitrile (10 ml) at 0◦C. The mixture was stirred at
room temperature for 1 h. Water (10 ml) was added and the mixture was extracted with three
portions of CH2Cl2 (20 ml). The organic layers were washed with brine until neutrality,
dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by
chromatography on silica gel (petroleum ether and EtOAc 2:1) to give an orange oil 9
(1.29 g, 92% yield).
1H NMR(500 MHz, CDCl3): δ 4.45 (s,2H),3.92 (s, 6H),2.92 (s,1H), 2.02 (s, 3H).
13CNMR(100 MHz, CDCl3): δ 184.9, 184.5, 144.6, 144.1, 140.6, 138. 6, 61.1 (2C),
11.6. MS: m/z = 213(M++H)
Acknowledgments
The authors are grateful to the executive Editor, Prof. J.-P. Anselme for his help with the
English and in editing and revising the article. This investigation was supported by the
China Scholarship Council (CSC) (No. 201208530032) and the Science Foundation of
Department of Education of Yunnan Province (No. 2011J077).
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