Synthesis of piperazine derivatives by Cp (*)Ir complex-catalyzed N-alkylative reactions of ethanolamines

Article abstract of DOI:10.3987/COM-08-S(F)77

A new method for the synthesis of piperazine derivatives catalyzed by a Cp (*)Ir complex has been developed. Cp (*)Ir complex-catalyzed N-alkylative homocoupling reactions of N-benzylethanolamines give N,N'-dibenzylpiperazine derivatives. For example, the

Full text of DOI:10.3987/COM-08-S(F)77

HETEROCYCLES, Vol. 77, No. 2, 2009
1371
HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 1371 - 1377. © The Japan Institute of Heterocyclic Chemistry
Received, 30th July, 2008, Accepted, 24th September, 2008, Published online, 25th September, 2008
COM-08-S(F)77
SYNTHESIS
OF
PIPERAZINE
DERIVATIVES
BY
Cp*Ir
OF
COMPLEX-CATALYZED
ETHANOLAMINES
N-ALKYLATIVE
REACTIONS
Ken-ichi Fujita, Yasushi Kida, and Ryohei Yamaguchi*
Graduate School of Human and Environmental Studies, Kyoto University, Kyoto
606-8501, Japan. yama@kagaku.mbox.media.kyoto-u.ac.jp
Abstract – A new method for the synthesis of piperazine derivatives catalyzed by
a Cp*Ir complex has been developed. Cp*Ir complex-catalyzed N-alkylative
homocoupling reactions of N-benzylethanolamines give N,N’-dibenzylpiperazine
derivatives. For example, the reaction of N-benzylethanolamine in the presence
of [Cp*IrCl2]2 (2.5 mol%) and NaHCO3 (15 mol%) in toluene at 110 °C for 17 h
gives N,N’-dibenzylpiperazine in 66% yield.
Cp*Ir complex-catalyzed
N-alkylative cross coupling reactions of Boc-protected diethanolamines with
benzylamine also give N-benzyl-N’-Boc-piperazine derivatives in moderate to
good yields.
INTRODUCTION
Piperazine and its derivatives are synthetically important and valuable because of their roles as
indispensable structures of a variety of pharmaceutical compounds.1 For example, some of piperazine
derivatives having benzyl substituent on nitrogen are known to be promising as anticancer agents or
peptidomimetic drugs.1a,c Generally, synthesis of piperazines has been carried out by heterocyclization
using primary amines and bis(haloalkyl)amines,2 reductive coupling of diimines,3 and reduction of keto-
or diketopiperazines.4 In such reactions, formation of wasteful byproducts (hydrogen chloride or metal
salt) and/or use of strong reductant can not be avoided.
Recently, we and other groups have developed atom-economical catalytic systems for carbon-nitrogen
bond formation using amines and alcohols, which are based on the high catalytic performance of
iridium5,6 and ruthenium6,7 complexes in hydrogen transfer reactions. In such catalytic reactions, only
water is generated as a stoichiometric co-product. When this methodology is extended to the synthesis
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 2, 2009
of piperazine, two strategies can be considered.8 The first one is the double N-alkylation of primary
amines with diethanolamines (the left arrow in eq 1). This type of reaction was actually studied by
Watanabe et al.9 and van Koten et al.10 Several N-arylpiperazines were synthesized by the catalytic
system using ruthenium complexes. However, these reactions had to be conducted under harsh
conditions (180 °C), and the yields of the piperazines were relatively low (<44%).
OH
HO
HO
RHN
HO
cat. Ir
cat. Ru
(1)
+
RNH2
+
NR
RN
NR
180 oC
up to 44%
ref. 9 and 10
110 oC
NHR
this work
In this paper, we wish to report the synthesis of piperazines according to the second strategy (i.e. double
N-alkylative homocoupling of ethanolamines, the right arrow in eq 1). By using a Cp*Ir catalyst (Cp* =
pentamethylcyclopentadienyl), the reaction proceeds under relatively mild conditions (110 °C) to give a
series of benzylpiperazine derivatives. We also disclose an effective catalytic system according to the first
one (the left arrow in eq 1), in which use of Cp*Ir catalyst makes them possible to lower the reaction
temperature and to improve the yields.
RESULTS AND DISCUSSION
First, we investigated the homocoupling reaction of N-benzylethanolamine (1a) giving
N,N’-dibenzylpiperazine (2a) catalyzed by [Cp*IrCl2]2 under various conditions (Table 1). When the
reaction of 1a was carried out at 110 °C for 17 h in toluene in the presence of [Cp*IrCl2]2 (2.5 mol%) as a
catalyst, 2a was formed in 20% yield (entry 1). The reaction was considerably accelerated by the
addition of a weak base (entries 2-5). When the reaction was carried out in the presence of 15 mol% of
NaHCO3, the yield of 2a increased up to 66% (entry 2). Other weak bases, such as Na2CO3, NaOAc,
and K2CO3 were also effective (entries 3-5), while stronger bases Cs2CO3 and NaOtBu were not (entries 6
and 7). When the reaction was carried out using a smaller amount of catalyst (1.0 mol%), the yield of
2a was lowered (entry 8). The reaction could be conducted under the solvent-free conditions, resulting
in a slightly low yield (entry 9). The optimum reaction temperature was 110 °C: the reactions at higher
(130 °C) or lower (90 °C) gave inferior results (entries 10 and 11).
On the basis of the optimization of the catalytic conditions, the homocoupling reactions of a series of
N-benzylethanolamines having functional groups on aromatic ring were conducted. The results are
summarized in Table 2. Methyl, methoxy, chloro, bromo, and trifluoromethyl substituents were tolerant
in the present heterocyclization system to give the corresponding piperazine derivatives in moderate to
good yields.11

HETEROCYCLES, Vol. 77, No. 2, 2009
1373
Table 1. N-Alkylative Homocoupling of N-Benzylethanolamine (1a)
Catalyzed by Cp*Ir Complex under Various Conditionsa
cat. [Cp*IrCl2]2
OH
N
N
H
base
N
toluene
110 oC, 17 h
1a
2a
yield (%)b
base
(mol%)
Ir catalyst
(mol%)
entry
1
2
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.0
2.5
2.5
2.5
none
20
66
56
54
36
7
NaHCO3 (15)
Na2CO3 (15)
NaOAc (15)
K2CO3 (15)
Cs2CO3 (15)
NaOtBu (15)
NaHCO3 (6)
NaHCO3 (15)
NaHCO3 (15)
NaHCO3 (15)
3
4
5
6
7
1
8
42
57
54
51
9c
10d
11e
aThe reaction was carried out with 1a (1.0 mmol), [Cp*IrCl2]2 (0.025 mmol), and base (0.15
mmol) in toluene (0.1 mL) at 110 oC for 17 h. bDetermined by GC. cWithout solvent. dAt 90
oC. eAt 130 oC.
Table 2. N-Alkylative Homocoupling of Several N-Benzylethanolamines
(1a-g) Catalyzed by [Cp*IrCl2]2 / NaHCO3 Systema
[Cp*IrCl2]2 2.5 mol%
NaHCO3 15 mol%
OH
N
Ar
Ar
N
H
toluene
Ar
N
110 oC, 17 h
1a-g
2a-g
yield (%)b
product
entry
substrate
OH
N
H
R
1
2
3
4
5
6
7
1a R = H
2a
2b
2c
2d
2e
2f
(66)
45
47
53
49
63
54
1b R = 4-Me
1c R = 2-Me
1d R = 4-OMe
1e R = 4-Cl
1f R = 4-Br
1g R = 4-CF3
2g
aThe reaction was carried out with 1 (1.0 mmol), [Cp*IrCl2]2 (0.025 mmol), and NaHCO3
(0.15 mmol) in toluene (0.1 mL) at 110 oC for 17 h. bIsolated yield. The value in
parentheses indicates GC yield.

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HETEROCYCLES, Vol. 77, No. 2, 2009
Furthermore, we examined the cross coupling reactions of Boc-protected diethanolamines (3a-c) with
benzylamine (4) on the basis of the strategy shown in the left side in eq 1. These reactions gave
N-benzyl-N’-Boc-piperazine derivatives (5a-c) under relatively mild conditions (110 °C) in moderate to
high yields (eq 2).
R2
[Cp*IrCl2]2 5.0 mol%
NaHCO3 30 mol%
R1
Boc R2
N
N
(2)
H2N
+
N
HO
OH
toluene
Boc
110 oC, 17 h
R1
5a (R1 = R2 = H):
82%
56%
67%
4
3a-c
5b (R1 = Me, R2 = H):
5c (R1 = H, R2 = Me):
In the previous papers, we have proposed mechanisms for intermolecular N-alkylation of primary amines
with alcohols,5b,g intramolecular N-alkylation of amino alcohols,5a and cycloalkylation of primary amines
with diols5c,e catalyzed by a Cp*Ir complex. On the basis of those, a possible mechanism for the present
N-alkylative homocoupling of ethanolamines is described in Scheme 1. The first stage of the reaction
would involve an intermolecular carbon-nitrogen bond formation through hydrogen transfer processes
and condensation to afford a diaminoethanol intermediate A.
Subsequent intramolecular
carbon-nitrogen bond formation would give a piperazine product.
R
N
R
OH
N
N
H
R
R
OH
[Cp*Ir]
R
N
N
H
O
R
H2O
N
N
R
H
, H+
[Cp*Ir] H
[Cp*Ir] H
H2O
OH
H
O
H
N
N
N
R
N
R
R
, H+
R
[Cp*Ir]
H
OH
N
N
R
R
A
Scheme 1
In summary, we have developed a new method for the synthesis of piperazine derivatives catalyzed by a
Cp*Ir complex using ethanolamines as starting materials. Furthermore, we have disclosed an effective

HETEROCYCLES, Vol. 77, No. 2, 2009
1375
catalytic system using Cp*Ir complex for the double N-alkylation of primary amines with
diethanolamines to afford piperazines.
EXPERIMENTAL
General: All reactions and manipulations were carried out under an atmosphere of argon by means of
standard Schlenk techniques. 1H and C NMR spectra were recorded on JEOL A-500 and EX-270
13
spectrometers. Gas chromatography (GC) analyses were performed on a Shimadzu GC-14A gas
chromatograph and on a GL-Sciences GC353B gas chromatograph with a capillary column (Shimadzu
CBP1-M25-025 or GL-Science TC-17). Column chromatography was carried out by using Wako-gel
C-200. Solvents were dried by using standard procedures and distilled prior to use. The catalyst
[Cp*IrCl2]2 was prepared according to the literature method.12
General procedure for the N-alkylative homocoupling of N-benzylethanolamine (1a) giving
N,N’-dibenzylpiperazine (2a) catalyzed by Cp*Ir complex shown in Table 1: Under an atmosphere of
argon in a heavy-walled glass reactor, 1a (1.0 mmol), [Cp*IrCl2]2 (0.025 mmol, 2.5 mol%), base (0.15
mmol, 15 mol%), and toluene (0.1 mL) were placed. The reactor was sealed, and the mixture was
stirred at 110 °C for 17 h. The yield of 2a was determined by GC analysis using decane as an internal
standard.
General procedure for the N-alkylative homocoupling of N-benzylethanolamines (1a-g) giving
N,N’-dibenzylpiperazine derivatives (2a-g) catalyzed by Cp*Ir complex shown in Table 2: Under an
atmosphere of argon in a heavy-walled glass reactor, 1 (1.0 mmol), [Cp*IrCl2]2 (0.025 mmol, 2.5 mol%),
base (0.15 mmol, 15 mol%), and toluene (0.1 mL) were placed. The reactor was sealed, and the mixture
was stirred at 110 °C for 17 h. After analysis by GC, the products were isolated by silica-gel column
chromatography (eluent: hexane-EtOAc).
N,N’-Dibenzylpiperazine (2a):13 1H NMR (270 MHz, CDCl3): δ 7.35-7.20 (m, 10H), 3.51 (s, 4H), 2.48 (s,
8H); 13C NMR (67.8 MHz, CDCl3): δ 138.2, 129.2, 128.2, 127.0, 63.1, 53.1.
N,N’-Bis(p-methylbenzyl)piperazine (2b): 1H NMR (270 MHz, CDCl3): δ 7.19 (d, J = 8 Hz, 4H), 7.10 (d,
13
J = 8 Hz, 4H), 3.46 (s, 4H), 2.46 (s, 8H), 2.32 (s, 6H); C NMR (67.8 MHz, CDCl3): δ 136.5, 135.0,
129.2, 128.8, 62.7, 53.0, 21.0. Anal. Calcd for C20H26N2: C, 81.59; H, 8.90; N, 9.51. Found: C, 81.19; H,
8.71; N, 9.15.
N,N’-Bis(o-methylbenzyl)piperazine (2c): 1H NMR (270 MHz, CDCl3):δ 7.26-7.20 (m, 2H), 7.14-7.07 (m,
6H), 3.43 (s, 4H), 2.44 (s, 8H), 2.34 (s, 6H); 13C NMR (67.8 MHz, CDCl3): δ 137.4, 136.6, 130.1, 129.7,
126.9, 125.4, 60.8, 53.3, 19.2. Anal. Calcd for C20H26N2: C, 81.59; H, 8.90; N, 9.51. Found: C, 81.48; H,
9.01; N, 9.37.
1
N,N’-Bis(p-methoxybenzyl)piperazine (2d): H NMR (270 MHz, CDCl3): δ 7.21 (d, J = 9 Hz, 4H), 6.84

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HETEROCYCLES, Vol. 77, No. 2, 2009
(d, J = 9 Hz, 4H), 3.79 (s, 6H), 3.44 (s, 4H), 2.45 (s, 8H); 13C NMR (67.8 MHz, CDCl3): δ 158.9, 130.6,
128.5, 113.6, 61.9, 55.1, 52.1. Anal. Calcd for C20H26N2O2: C, 73.59; H, 8.03; N, 8.58. Found: C, 73.37;
H, 7.99; N, 8.40.
N,N’-Bis(p-chlorobenzyl)piperazine (2e): 1H NMR (270 MHz, CDCl3): δ 7.28-7.21 (m, 8H), 3.45 (s, 4H),
13
2.44 (s, 8H); C NMR (67.8 MHz, CDCl3): δ 136.7, 132.6, 130.3, 128.3, 62.1, 52.9. Anal. Calcd for
C18H20Cl2N2: C, 64.48; H, 6.01; N, 8.36. Found: C, 64.18; H, 6.04; N, 8.21.
N,N’-Bis(p-bromobenzyl)piperazine (2f): 1H NMR (270 MHz, CDCl3): δ 7.42 (d, J = 9 Hz, 4H), 7.18 (d,
13
J = 9 Hz, 4H), 3.44 (s, 4H), 2.44 (s, 8H); C NMR (67.8 MHz, CDCl3): δ 137.2, 131.2, 130.7, 120.7,
62.2, 52.9. Anal. Calcd for C18H20Br2N2: C, 50.97; H, 4.75; N, 6.60. Found: C, 50.94; H, 4.67; N, 6.45.
N,N’-Bis(p-trifluoromethylbenzyl)piperazine (2g): 1H NMR (270 MHz, CDCl3):δ 7.56 (d, J = 8 Hz, 4H),
7.44 (d, J = 8 Hz, 4H), 3.56 (s, 4H), 2.48 (s, 8H); 13C NMR (67.8 MHz, CDCl3): δ 142.5, 129.3 (q, J = 32
Hz), 129.2, 125.5 (q, J = 4 Hz), 124.2 (q, J = 270 Hz), 62.4, 53.1. Anal. Calcd for C20H20F6N2: C, 59.70;
H, 5.01; N, 6.96. Found: C, 59.63; H, 5.00; N, 7.02.
General procedure for the N-alkylative cross coupling of Boc-protected diethanolamines (3a-c) with
benzylamine (4) giving N-benzyl-N’-Boc-piperazine derivatives (5a-c) catalyzed by Cp*Ir complex
shown in Eq 2: Under an atmosphere of argon in a heavy-walled glass reactor, 3 (0.50 mmol), 4 (1.5
mmol), [Cp*IrCl2]2 (0.025 mmol, 5.0 mol%), base (0.15 mmol, 30 mol%), and toluene (0.1 mL) were
placed. The reactor was sealed, and the mixture was stirred at 110 °C for 17 h. After analysis by GC,
the products were isolated by silica-gel column chromatography (eluent: hexane-EtOAc).
tert-Butyl 4-benzyl-1-piperazinecarboxylate (5a):14 1H NMR (270 MHz, CDCl3): δ 7.35-7.25 (m, 5H),
3.51 (s, 2H), 3.42 (t, J = 5 Hz, 4H), 2.38 (t, J = 5 Hz, 4H), 1.45 (s, 9H); 13C NMR (67.8 MHz, CDCl3): δ
154.8, 137.8, 129.1, 128.2, 127.1, 79.5, 63.0, 52.8, 28.4.
tert-Butyl 2-methyl-4-benzyl-1-piperazinecarboxylate (5b):15 1H NMR (270 MHz, CDCl3): δ 7.33-7.24
(m, 5H), 4.18 (m, 1H), 3.80 (d, J = 13 Hz, 1H), 3.46 (m, 1H), 3.11 (m, 1H), 2.75 (d, J = 11 Hz, 1H), 2.58
13
(d, J = 11 Hz, 1H), 2.11 (dd, J = 11, 4 Hz, 1H), 2.00 (m, 1H), 1.47 (s, 9H), 1.24 (d, J = 7 Hz, 3H); C
NMR (67.8 MHz, CDCl3): δ 154.8, 138.4, 128.7, 128.2, 127.0, 79.3, 62.8, 57.4, 53.2, 28.4, 15.9.
tert-Butyl 3-methyl-4-benzyl-1-piperazinecarboxylate (5c):16 1H NMR (270 MHz, CDCl3): δ 7.34-7.23
(m, 5H), 4.00 (d, J = 14 Hz, 1H), 3.67-3.62 (m, 2H), 3.18 (d, J = 14 Hz, 1H), 3.10-3.02 (m, 1H), 2.88 (br,
13
1H), 2.66-2.61 (m, 1H), 2.48-2.37 (m, 1H), 2.10-2.04 (m, 1H), 1.45 (s, 9H), 1.12 (d, J = 6 Hz, 3H); C
NMR (67.8 MHz, CDCl3): δ 154.7, 138.7, 128.9, 128.2, 126.9, 79.4, 58.0, 53.1, 50.0, 28.4, 15.3.
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