Efficient copper-catalyzed cross-coupling of 1-Boc-piperazine with aryl iodides and its application in the synthesis of trazodone

Article abstract of DOI:10.1016/j.tetlet.2013.07.104

A convenient and practical strategy is developed for the cross-coupling of N-Boc protected piperazines with aryl iodides using CuBr/1,1′-bi-2- naphthol as the catalyst and K₃PO₄ as the base. The protocol affords N-arylated piperazine products in moderate to good yields under the optimized conditions. The application of this catalytic system to the synthesis of trazodone is also successfully demonstrated using commercially available substrates.

Full text of DOI:10.1016/j.tetlet.2013.07.104

Tetrahedron Letters 54 (2013) 5332–5334
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient copper-catalyzed cross-coupling of 1-Boc-piperazine
with aryl iodides and its application in the synthesis of trazodone
⇑
Fui-Fong Yong, Yong-Chua Teo , Khee-Ngiap Tan
Natural Sciences and Science Education, National Institute of Education, Nanyang Technological University, 1 Nanyang Walk, Singapore 637616, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 April 2013
Revised 8 July 2013
Accepted 19 July 2013
Available online 26 July 2013
A convenient and practical strategy is developed for the cross-coupling of N-Boc protected piperazines
with aryl iodides using CuBr/1,10-bi-2-naphthol as the catalyst and K3PO4 as the base. The protocol
affords N-arylated piperazine products in moderate to good yields under the optimized conditions. The
application of this catalytic system to the synthesis of trazodone is also successfully demonstrated using
commercially available substrates.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cross-coupling
Copper-catalyzed
Piperazines
N-arylation
Trazodone
Transition metal catalyzed cross-coupling reactions are impor-
tant for the formation of carbon and heteroatom bonds in organic
synthesis.1 In particular, N-arylated aliphatic amines have found
widespread applications in the preparation of numerous interme-
diates that are prevalent in bioactive pharmaceuticals and con-
ducting materials.2 Among the various strategies developed to
date, the copper-catalyzed Ullmann-type cross-coupling repre-
sents a straightforward manner and convenient method for the
assembly of the required core structures. However, the classical
versions of this cross-coupling have limited synthetic applications
due to the harsh reaction conditions employed, such as high reac-
tion temperatures, stoichiometric amounts of a copper catalyst,
long reaction times, and low yields.3 Significant developments
made to the Ullmann-type cross-coupling reaction have been con-
cerned with the addition of assisting ligands to the protocols to en-
hance the reactivity of the copper catalysts and thereby increasing
the reaction rate.4 Wan reported the N-arylation of aliphatic
amines with aryl halides using copper powder or CuI in combina-
tion with racemic 1,10-bi-2-naphthol (rac-BINOL) as the catalyst.5
Fu has demonstrated an efficient CuBr/rac-BINOL-catalyzed
N-arylation of aliphatic amines with aryl iodides at room temper-
ature.6 However, the cross-coupling of piperazine-based secondary
amines with aryl iodides remains limited. Hence, there is still a
need to develop simple protocols for the cross-coupling of this
class of cyclic secondary amine.
In this Letter, we disclose our findings on the application of a
copper ligand assisted catalytic system for the N-arylation of
N-Boc-protected piperazines. Thereafter, we validated the protocol
by applying the catalytic system to the synthesis of tert-butyl
4-(3-chlorophenyl)piperazine-1-carboxylate (3a), an important
intermediate for the synthesis of trazodone.
In our initial studies, the reaction between 1-Boc-piperazine
(1.5 equiv) and 3-chloro-iodobenzene (1.0 mmol) was selected as
the model system for optimizing the reaction conditions (Table 1).
The reaction carried out using a combination of CuBr (20 mol %),
rac-BINOL (40 mol %), and K3PO4 (2 equiv) in DMF (0.5 mL) at
100 °C led to a significant formation of the desired product. How-
ever, the presence of a side product leads to difficulties in the puri-
fication step. Based on 1H NMR analysis of the crude material, it
was apparent that the side product was probably generated via
the N-arylation of the assisting ligand. In order to remove the side
product from an economical viewpoint, the catalyst:ligand loading
was reduced to 20:15 (mol %) and the catalyst was pre-formed for
10 min prior to the addition of the substrates. To our delight, this
modified procedure afforded a good isolated yield (71%) of the
product (Table 1, entry 1). Encouraged by this result, we investi-
gated the merits of various copper salts for the N-arylation process
(entries 1–4). Among these, CuBr was the best catalyst. Next, we
probed the ligand effect using a series of commercially available
ligands: N,N0-dimethylethylenediamine (DMEDA, L2, entry 5),
N,N,N0,N0-tetramethylethylenediamine (TMEDA, L3, entry 6),
trans-1,2-diaminocyclohexane (L4, entry 7), and 2,2,6,6,-tetra-
methylheptane-3,5-dione (TMHD, L5, entry 8). The use of rac-
BINOL was shown to be critical for the success of this protocol as
⇑
Corresponding author. Tel.: +65 6790 3846; fax: +65 6896 9414.
E-mail address: yongchua.teo@nie.edu.sg (Y.-C. Teo).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.104

F.-F. Yong et al. / Tetrahedron Letters 54 (2013) 5332–5334
5333
Table 1
Table 2
Optimization studies on the copper-catalyzed cross-coupling of 1-Boc-piperazine
CuBr-catalyzed N-arylation of 1-Boc-piperazine with different aryl iodidesa
with 3-chloro-iodobenzenea
CuBr (20 mol%)
1, 1'-Bi-2-naphthol (15 mol%)
[Cu] (20 mol%)
Ligand (15 mol%)
Cl
R
R
Cl
Boc
N
N
Boc
N
NH
I
+
K3PO4 (2 equiv)
DMF (0.5 mL)
100°C, 24 h
Boc
N
N
Boc
N
NH
I
+
K3PO4 (2 equiv)
DMF (0.5 mL)
100°C, 24 h
3a-j
3a
1
2
Entry
ArX
Product
Yieldb (%)
Boc
Boc
Boc
Boc
Boc
I
N
N
N
N
N
N
N
1
2
3b
3c
57
36
OH
OH
MeHN
NHMe
Me2N
NMe2
Me
Me
I
L1
L2
L3
Cl
Cl
3
4
5
6
3d
3e
3a
3f
41
60
71
70
I
I
I
N
N
N
O
O
Me
Cl
Me
Cl
H2N
NH2
L4
L5
Entry
(Cu) source
Ligand
Yieldb (%)
1
2
3
4
5
6
7
8
CuBr
CuCl
CuI
Cu2O
CuBr
CuBr
CuBr
CuBr
L1
L1
L1
L1
L2
L3
L4
L5
71
55
68
58
CF3
CF3
I
I
I
I
I
Boc
Boc
Boc
Boc
Boc
N
N
N
N
N
N
N
N
N
N
0
Trace
0
Trace
OMe
OMe
7
8
3g
3h
3i
72
60
71
60
F
F
a
Unless otherwise shown, the reaction was carried out with 1-Boc-piperazine
(1.5 mmol), 3-chloro-iodobenzene (1.0 mmol), K3PO4 (2 equiv), (Cu) source
(0.2 mmol), ligand (0.15 mmol), DMF (0.5 mL), 100 °C, 24 h.
Cl
Cl
9
b
Isolated yield after column chromatography.
CF3
CF3
10
3j
a
Unless otherwise shown, the reaction was carried out with 1-Boc-piperazine
(1.5 mmol), aryl iodide (1.0 mmol), K3PO4 (2.0 mmol), CuBr (0.2 mmol), 1,10-bi-2-
naphthol (0.15 mmol), DMF (0.5 mL), 100 °C, 24 h.
the other ligands gave either traces of the product or no product
formation. The optimal condition for the cross-coupling of 1-Boc-
piperazine with the aryl iodide was achieved using a combination
of CuBr (20 mol %), 1,10-bi-2-naphthol (15 mol %), and K3PO4
(2 equiv) in DMF (0.5 mL) at 100 °C for 24 h.
The generality of the reaction was next examined under our
optimized conditions using different functionalized aryl halides.
The results are summarized in Table 2. In general, good yields were
obtained for the cross-coupling of sterically unhindered aryl
iodides. ortho-Substituted aryl iodides gave moderate yields
(Table 2, entries 2 and 3) due to steric effects. No significant elec-
tronic effects were observed for both meta- and para-substituted
aryl iodides (entries 4–10).
These results prompted us to attempt the synthesis of
1-(3-chlorophenyl)piperazine, a key intermediate in the synthesis
of trazodone,7 which has antidepressant, anxiolytic, and hypnotic
properties. It is a widely used antidepressant drug that has med-
ium to high affinity for several serotonin receptors such as 5HT2A
and the a1 adrenergic receptor.8 The synthesis of trazodone could
be addressed efficiently by employing an N-arylation and two
nucleophilic substitution reactions. Herein, we apply our newly
developed copper-catalyzed cross-coupling strategy to synthesize
the key intermediate for the preparation of trazodone.
b
Isolated yield after column chromatography.
2H-[1,2,4]triazolo[4,3-a]pyridin-3-one and purification gave trazo-
done (8) in 65% yield.9 The incorporation of the cross-coupling
strategy to the synthetic route provides a convenient and rapid
method for chemical modifications to access a large range of struc-
turally related analogues.
In summary, a straightforward and operationally simple route
for the synthesis of N-arylated piperazines promoted by a copper
salt in DMF at moderate temperature has been developed. In most
cases, the N-arylated piperazine derivatives were obtained in mod-
erate to good yields. The use of cheap and readily available CuBr,
and rac-BINOL and the practical protocol should render this ap-
proach an attractive alternative to access various N-arylated piper-
azines. In addition, the extension of this system to the synthesis of
trazodone increases the synthetic utility of the catalytic system.
Overall, we believe that this catalyst system could serve as an
important protocol for synthesizing biological and pharmaceutical
products that require the formation of N-arylated piperazines.
Acknowledgments
Our synthesis started with the C–N cross-coupling of commer-
cially available 1-Boc-piperazine and 3-chloro-iodobenzene
(Scheme 1). As previously discussed the application of our cop-
per-catalyzed system afforded tert-butyl 4-(3-chlorophenyl)piper-
azine-1-carboxylate in 71% yield. This intermediate 3a was then
treated with trifluoroacetic acid to remove the Boc protecting
group. Next, mono-alkylation was carried out between intermedi-
The authors would like to thank the National Institute of Educa-
tion and Nanyang Technological University for generous financial
support.
Supplementary data
Supplementary data (experimental procedures and compound
characterization data) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.104.
ate
sodium hydride to afford 6 in good yield. Subsequent nucleophilic
substitution of bromide with commercially available
4 and commercially available 1,3-dibromopropane using
6

5334
F.-F. Yong et al. / Tetrahedron Letters 54 (2013) 5332–5334
CuBr (20 mol%)
1, 1'-Bi-2-naphthol (15 mol%)
Cl
Cl
Cl
TFA : DCM
1:1 (20 equiv)
Boc
N
N
Boc
N
NH
I
HN
N
+
K3PO4(2 equiv)
DMF (0.5 mL)
100°C, 24 h
2 h at rt
80%
3a
4
1
2
71%
O
NH
N
N
O
Cl
7
N
N
N
1. NaH (1.2 equiv)
NaH (1.2 equiv)
N
N
N
N
Cl
Reflux for 21 h
Dioxane
2. Br
Br
Br
6
5
8
20 h at rt
65%
50%
Scheme 1. Synthesis of trazodone.
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