A simple one-pot method for the mercuric oxide mediated synthesis of piperazines via oxidative diamination of olefins

Article abstract of DOI:10.1016/j.tetlet.2012.11.110

Mercuric oxide mediated one-pot synthesis of substituted piperazines via oxidative diamination of olefins with N-protected ethylene diamine has been reported. Among the various conditions tried, mercuric(II)oxide/tetrafluoroboric acid gave good to excellent yields of the desired products. A series of piperazines have been synthesized and characterized by NMR and mass spectroscopy methods.

Full text of DOI:10.1016/j.tetlet.2012.11.110

Tetrahedron Letters 54 (2013) 761–764
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple one-pot method for the mercuric oxide mediated synthesis of
piperazines via oxidative diamination of olefins
Harpreet Kour a, Satya Paul a, , Parvinder Pal Singh b, Monika Gupta a, Rajive Gupta a
⇑
a Department of Chemistry, University of Jammu, Jammu 180006, India
b Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu 180001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2012
Revised 8 November 2012
Accepted 11 November 2012
Available online 1 December 2012
Mercuric oxide mediated one-pot synthesis of substituted piperazines via oxidative diamination of ole-
fins with N-protected ethylene diamine has been reported. Among the various conditions tried, mercu-
ric(II)oxide/tetrafluoroboric acid gave good to excellent yields of the desired products. A series of
piperazines have been synthesized and characterized by NMR and mass spectroscopy methods.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Piperazine derivatives
Mercuric oxide
Tetrafluoroboric acid
Oxidative diamination
Ethylene diamine
Olefins
The substituted piperazine scaffold is considered to be a privi-
leged structure in medicinal chemistry and is widely present in
the bio-active molecules of many therapeutic areas viz anti-
inflammatory, antibacterial, antimalarial, anticonvulsant, antipy-
retic, antitumor, anthelmintic, analgesic, antidepressant, anti-
fungal, antitubercular, anticancer, antidiabetic etc.1–12 Moreover,
in drug discovery hit to lead optimization programs, piperazine
moieties have been utilized for the pK optimization of many
leads.13–15 Piperazine ring gives inherent rigidity to two hydrogen
bond participants and lends itself well to binding within biological
systems.16 Additionally, this structural rigidity has led to the use of
piperazines as ligands in asymmetric catalysis.17 Since this privi-
leged scaffold occurs regularly in complex natural products, a
plethora of synthetic methods have been reported in the literature
for their synthesis.18–20 Moreover, in recent years, more than ten
different strategies based on multicomponent reactions (MCRs)
have also been published for their synthesis.21 In spite of many
synthetic strategies for the synthesis of piperazine and its deriva-
tives, there is a need for the development of an effective and simple
synthetic method for the synthesis of piperazines. An attractive
strategy for the synthesis of piperazines is the oxidative diamina-
tion of olefins. This strategy was first developed by Bäckvall in
1975 for the synthesis of small heterocyclic compounds.22 After-
ward, this strategy was highly exploited for the synthesis of many
heterocyclic compounds.23 Various metal catalysts based on palla-
dium, nickel, gold as well as stoichiometric copper reagents have
been successfully employed.24 As per our literature survey, this
strategy is still not exploited for the synthesis of piperazine and
its derivatives. One reason could be because most of the diamina-
tion reactions (catalyzed by above mentioned catalysts) required
tethered amine25 (amine having electron-withdrawing group).
Meantime in our literature survey, we found that mercuric salts
have also been utilized for the oxyamination as well as diamina-
tion reaction with simple amines for the generation of heterocyclic
moiety, but still not explored for the synthesis of piperazine and its
derivatives.26 In this direction, we hypothesized that mercuric salts
could be explored for the oxidative diamination addition of
suitable diamine to alkenes and subsequently we successfully
developed a mercuric oxide mediated one-pot synthetic method
for the generation of piperazines via oxidative diamination of
olefins with N-protected ethylene diamine.
Initially, we selected various mercuric salts such as Hg(OAc)2,
HgCl2, HgO, and HgI without or with acids such as perchloric acid,
boron trifluorideꢀetherate, and tetrafluoroboric acid to test the idea
and started this study by the reaction of styrene 1a with benzyl-
protected ethylenediamine 2a (all the results are summarized in
Table 1).
During our study, THF was used as a solvent. The reaction of
styrene 1a with N,N0-dibenzylethylenediamine 2a in the presence
of various mercury salts gave only a minor quantity of desired
product 3a (Table 1, entries a–d). Among these conditions, mercu-
ric acetate and mercuric oxide gave 10% and 11% of the desired
product 3a respectively. This indicates that mercuric salts could
⇑
Corresponding author. Fax: +91 191 2431365.
E-mail address: paul7@rediffmail.com (S. Paul).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.110

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H. Kour et al. / Tetrahedron Letters 54 (2013) 761–764
Table 1
Table 2
Effect of various mercury salts on the synthesis of piperazines via oxidative
diamination of olefins
Effect of different solvents on the synthesis of piperazines via oxidative diamination
of olefins
Bn
Bn
N
Bn
Bn
N
NH
NH
HgO.2HBF4
Hg salts
+
70 oC, 12-15h
Solvent
N
+
N
THF
NH
NH
Bn
Bn
Bn
2a
Bn
2a
1a
3a
1a
3a
Yielda (%)
Entry
Solventsa
Conversion (%)
Entry
Catalyst
Temp
Time (h)
ab
bb
cb
db
ec
fc
Hg(OAc)2
HgCl2
HgI
rt-70
rt-70
rt-70
rt-70
rt-70
rt-70
rt-70
rt-70
rt-70
70
10
10
10
10
14
14
12
12
12
12
10
5
0
11
15
25
50
45
60
70
a
Dioxane
Et2O
t-BME
CH2Cl2
MeOH
DMF
67
10
65
Traces
0
bb
c
db
e
f
HgO
Hg(OAc)2/BF3ꢀEt2O
Hg(OAc)2/HClO4
Hg(OAc)2/HBF4
HgO/BF3ꢀEt2O
HgO/HBF4
20
10
gc
hc
ic
g
Toluene
a
Reaction conditions otherwise unless noted: Styrene 1a (1 mmol), N,N0-
dibenzylethylenediamine 2a (1.5 mmol), preformed HgOꢀ2HBF4 (1 mmol).
jd
HgOꢀ2HBF4
b
Reactions performed under reflux conditions.
a
Isolated yield.
b
Reaction conditions: Styrene 1a (1 mmol), N,N0-dibenzylethylenediamine 2a
mind, we tried the reaction of styrene 1a with 2a in the presence
of mercuric acetate and acids such as perchloric acid, boron tri-
fluorideꢀetherate, and tetrafluoroboric acid (Table 1, entries e–g)
and among these conditions, mercuric acetate and tetrafluoroboric
acid increases the yield of the desired product 3a from 10% to 50%.
Mercuric oxide in the presence of tetrafluoroboric acid further im-
proved the yield of the desired product 3a (Table 1, entry i). From
this finding, it could be visualized that the addition of tetrafluorob-
oric acid significantly increases the yield, which might have made
b-aminomercury(II) intermediate 3a more labile and thus, very
easily replaced by second nucleophile. Further, addition of pre-
formed HgOꢀ2HBF4 reagent (prepared by the known method)26
(1.5 mmol), Hg salt (1 mmol).
c
Reaction conditions: Styrene 1a (1 mmol), N,N0-dibenzylethylenediamine 2a
(1.5 mmol), Hg salt (1 mmol), rt followed by addition of acid (1 mmol).
d
Reaction conditions: Styrene 1a (1 mmol), N,N0-dibenzylethylenediamine 2a
(1.5 mmol), preformed HgOꢀ2HBF4 (1 mmol).
be utilized for oxidative diamination but needed further optimiza-
tion for this conversion to get quantitative yield of the desired
product. Barluenga et al. have reported that mercuric salt in the
presence of perchloric acid and tetrafluoroboric acid successfully
catalyzed the diamination of olefins.26 Keeping these findings in
Table 3
Mercuric oxide/tetrafluoroboric acid mediated reaction of alkene with protected ethylene diamine for the generation of piperazines
R3
R3
N
H
N
R2
HN
R1
R
R2
R1
H2/Pd or 20 % TFA
HgO.2HBF4
+
HN
N
H
N
R1
R3
R3
R3 = Bn, BoC, Me
4
3
1
2
Entry
a
1
2
Time (h)
Yieldsa (%)
3
4
Yieldsb (%)
R3HN
R3
N
H
N
R3HN
7
70
85
N
H
N
R3= Bn
R3
R3
N
R3HN
H
N
R3HN
b
c
6
6
80
75
85
90
N
H
N
R3= Boc
R3
R3HN
R3
H
N
N
O
R3HN
N
H
N
R3= Bn
R3
O
O

H. Kour et al. / Tetrahedron Letters 54 (2013) 761–764
763
Table 3 (continued)
Entry
1
2
Time (h)
Yieldsa (%)
3
4
Yieldsb (%)
R3HN
R3
N
H
N
R3HN
d
7
73
87
45
N
H
N
R3= Bn
R3
R3HN
R3
N
H
N
O2N
R3HN
e
7
76
N
H
N
R3= Bn
R3
O2N
HO
HO
O2N
BnO
BnO
OBn
R3HN
R3HN
R3
N
H
N
f
12
16
72
60
75
80
N
H
N
BnO
R3= Bn
R3
R3HN
R3
H
N
N
R3HN
g
N
H
N
R3= Bn
R3
R3HN
R3
N
H
N
O
R3HN
h
14
62
70
72
82
89
82
N
H
N
R3= Bn
R3
O
O
R3HN
R3HN
R3
N
H
N
F
i
8
N
H
N
R3= Bn
R3
F
F
R3HN
R3HN
R3
H
N
N
Cl
O
j
7
N
H
N
R3= Bn
R3
Cl
O
Cl
O
R3HN
R3HN
R3
H
N
N
N
H
O
k
7
7
73
77
88
N
R3= Bn
R3
O
O
R3HN
R3HN
R3
N
O
l
N
R3= Me
R3
O
a
Isolated yields of 3.
b
Isolated yields of 4. Reaction condition: 1 (1 mmol), N,N0-disubstituted ethylenediamine 2 (1.5 mmol), HgOꢀ2HBF4 (1 mmol) in THF at 70 °C.30 Products were charac-
terized by NMR and Mass spectroscopy of their respective de-protected piperazine derivatives which are in agreement with the literature reported value.29
yielded comparatively better yield of desired product 3a (Table 1,
entry j). The optimization results suggested that 1 equiv of
HgOꢀ2HBF4 is the best condition for the oxidative diamination of
olefins with diamines. In addition to this, the effect of various sol-
vents on the oxidative diamination of olefins with diamines was
also studied and the results are summarized in Table 2. When
the reactions were performed in other etherate solvents such as
dioxane, diethyl ether, and ter-butylmethyl ether (t-BME), 2-phe-
nylpiperazine derivative was formed in 67%, 10%, and 65%, respec-
tively (Table 2, entries a–c). The use of dichloromethane gave
traces of the desired product 3a as observed on TLC (Table 2, entry
d). Replacement with other solvents such as methanol, DMF, and
toluene also affected the formation of the desired product 3a dras-
tically (Table 2, entries e–g). The present method works well in
etherate based solvents, whereas in other solvents, lower yield of
the desired piperazine product was obtained.

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H. Kour et al. / Tetrahedron Letters 54 (2013) 761–764
6. (a) McNair, T. J.; Wibin, F. A.; Hoppe, E. T.; Schmidt, J. L.; DePeyster, F. A. J. Surg.
R3
N
R2
NHR3
Res. 1963, 3, 130; (b) Lee, Y. B.; Gong, Y.-D.; Yoon, H.; Ahn, C.-H.; Jeon, M.-K.;
Kong, J.-Y. Bioorg. Med. Chem. 2010, 18, 7966.
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F4BHg
R1
R2
R3HN
R2
R1
HgO.2HBF4
+
N
R3HN
N
R1
R3
R3
1a
3a
3
2a
Figure 1. Plausible mechanism for HgOꢀ2HBF4 mediated synthesis of piperazines.
10. Groll, A. H.; Piscitelli, S. C.; Walsh, T. J. Adv. Pharmacol. 1998, 44, 343.
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In order to see the diversity of this method, various symmetrical
and unsymmetrical alkenes as well as differently substituted ethyl-
ene diamines have been tried under the optimized conditions and
the results are summarized in Table 3. These results showed that
there is no influence of the group present on the aromatic ring of
alkene (substituted styrene) toward the formation of piperazines.
There is very little effect of protected group present on the N-atom
of ethylene diamine. Boc-protected amines gave comparatively
better yield as compared to benzyl protected ethylene diamines
along with a minor quantity of Boc-deprotected product. Both
electron-donating group (Table 3, entries c–d and k–l) and
electron-withdrawing group (Table 3, entries e, i–j) bearing styrene
underwent a coupling reaction smoothly and gave protected
piperazine derivatives in good to excellent yields. Further,
electron-withdrawing group bearing styrene gave comparatively
better yield. The disubstituted alkene such as benzyl protected
(E)-but-2-ene-1,4-diol also underwent the coupling reaction and
gave corresponding piperazine in good yield (Table 3, entry f).
Further, other di-substituted alkenes such as phenyl-2-propene
and anethole also underwent diamination and gave the desired
piperazine product in a good yield (Table 3, entries g and h).
All the benzyl substituted piperazines prepared under the pres-
ent method were subjected to hydrogenolysis in the presence of
H2/Pd/C, which gave corresponding piperazines 4 in quantitative
yield27 and Boc-protected piperazine was also subjected to de-
protection of Boc group with 20% TFA (Table 3).28 All the protected
3a–h as well as de-protected piperazine derivatives 4a–h were
characterized by NMR and mass spectroscopy and by comparison
with literature reported data.29 The plausible mechanism of this
reaction can be visualized as, the reaction of HgOꢀ2HBF4 with al-
kene 1a followed by the attack of amino group of 2a to generate
the intermediate b-aminomercury(II)tetrafluoroborate 3a, which
undergoes an intra-molecular cyclization by the attack of second
amino group of ethylenediamine to generate piperazine 3 (Fig. 1).
In conclusion, a simple one-pot high yielding method was
developed for the synthesis of substituted piperazines via oxida-
tive diamination of olefins with N-protected ethylene diamine.
Both monosubstituted and di-substituted alkenes were success-
fully employed for the coupling reaction. Further exploration of
the full scope of these reactions and its extension to oxyamination
is underway and will be reported in due course.
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30. General procedure for the synthesis of piperazines. Olefins 1 (1 mmol) were
dissolved in dry THF (15 mL) under N2 and HgOꢀ2HBF4 (1.1 mmol) was added
portionwise followed by the addition of N,N0-disubstitutedethylene diamine 2
(1.5 mmol). The reaction mixture was stirred at 70 °C for the appropriate time
as shown in Table 1. After completion of the reaction, as indicated by TLC, the
reaction mixture was diluted with water and extracted with CH2Cl2
(3 ꢁ 30 mL). The combined organic layers were dried over anhydrous
Na2SO4, concentrated in vacuo, and purified by flash column
chromatography on silica gel to afford corresponding protected piperazine
derivatives 3. The compound 3 was dissolved in MeOH (9 mL) containing acetic
acid (1 mL) and then added Pd/C.27 The reaction mixture was stirred for 4 h
Acknowledgments
Authors thank the Director IIIM, Jammu for spectral, library, and
other facilities. One of the authors (H.K.) thanks the University of
Jammu for awarding research fellowship.
under H2 on
a Parr hydrogenator and the progress of the reaction was
monitored on TLC. After completion of reaction, the catalyst was filtered off
and the organic mixture was evaporated in a rota-vapour. The crude mixture
was purified by column chromatography using chloroform:methanol (95:5–
80:20) as eluting mixture to get the corresponding product 4. The products
reported herein, were characterized by 1H NMR, 13C NMR, and mass
spectroscopy. The spectroscopic data of the compounds are in agreement
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