Preparation of N-arylpiperazines and other N-aryl compounds from aryl bromides as scaffolds of bioactive compounds

Article abstract of DOI:10.1016/j.tet.2006.07.011

Aryl bromides are coupled with N-compounds to give the corresponding arylamines in the presence of a palladium catalyst, a suitable ligand, and a weak base. The catalysts perform well for a large number of different starting material combinations at 100-150 °C with drops of toluene or without solvent, and with low catalyst levels (0.12 mol % Pd). The low catalyst amount makes the process environment friendly.

Full text of DOI:10.1016/j.tet.2006.07.011

Tetrahedron 62 (2006) 9010–9016
Preparation of N-arylpiperazines and other N-aryl compounds
from aryl bromides as scaffolds of bioactive compounds
*
M. Romero, Y. Harrak, J. Basset, L. Ginet, P. Constans and M. D. Pujol
Laboratori de Quı ´m ica Farmac eꢀ utica (Unitat associada al CSIC), Facultat de Farm aꢀ cia, Universitat de Barcelona,
Av. Diagonal 643, E-08028 Barcelona, Spain
Received 11 April 2006; revised 4 July 2006; accepted 5 July 2006
Available online 28 July 2006
Abstract—Aryl bromides are coupled with N-compounds to give the corresponding arylamines in the presence of a palladium catalyst, a suit-
ꢀ
able ligand, and a weak base. The catalysts perform well for a large number of different starting material combinations at 100–150 C with
drops of toluene or without solvent, and with low catalyst levels (0.12 mol % Pd). The low catalyst amount makes the process environment
friendly.
Ó 2006 Elsevier Ltd. All rights reserved.
In the course of our work aimed at obtaining new compounds
with biological activity, we required an easy source of N-aryl
derivatives to serve as precursors. N-arylpiperazines, N-aryl-
indoles, N-arylpyrroles, and substituted anilines are impor-
tant compounds, particularly in pharmaceutical research
and also as intermediates of synthesis. The N-arylpiperazine
subunitis embedded in severalpharmacologically interesting
N-derivatives have furnished interesting results but have
revealed the need to find more general conditions or the
optimization of each process is strongly recommended.
Moreover, efficient conditions for the arylation of pipera-
zines have not been reported up to now.
The synthesis of arylpiperazines by palladium-catalyzed
amination reaction from unprotected piperazine has been
1
targets such as compounds related to the serotonine ligands,
calcium blockers, antipsychotic drugs, antihypertensive,
and acetylcholinesterase inhibitory activity. For these rea-
sons significant efforts have gone into the development of
efficient methods for their preparation.
2
3
4
15,16
previously reported.
the piperazine arylation was successful only in low to moder-
The results clearly indicate that
5
1
7
ate yields. Fort and co-workers reported a nickel-catalyzed
method for the synthesis of N,N -diarylpiperazines from aryl
0
chlorides and Zhao et al. described first the use of Pd[P(o-
1
6
In the last decade, several research groups such as Buchwald
et al.
tolyl) ] Cl catalyst for the arylation of piperazines.
3 2 2
6
–10
11–14
and Hartwig et al.
reported the palladium-
catalyzed coupling of aryl halides with several amino-
derivatives. This important reaction opens a new way for
synthesizing several pharmaceutical molecules that are
otherwise difficult to prepare.
This work was initiated by searching efficient methods for
the preparation of scaffolds for potential bioactive com-
pounds, and intends to develop general reaction conditions
for the palladium-catalyzed formation of these anilines.
Herein we describe our results and details (Tables 1 and 2).
This direct N-arylation is an alternative to classical S Ar
N
reactions for the preparation of arylamines. Compared to
analogous C–C bond-forming such as Suzuki, Stille, and
Heck coupling reactions, the cross-coupling methodology
to form C–N bonds is more limited.
We have prepared arylamines from interesting substrates
using Pd[P(o-tolyl) ] Cl as catalyst, chelating ligand such
as 2,2 -bis(diphenylphosphino)-1,1 -binaphthyl (BINAP) or
3
2
2
0
triphenylphosphine (PPh ), and cesium carbonate base with-
0
3
out solvent or few drops of toluene were added when the
starting material were solid compounds. The reagents can
be weighed and manipulated in contact with air facilitating
the industrial use. This is a fast and clean reaction and the
results showed that it is possible to replace the expensive
Recent reports from several research groups on the
palladium-catalyzed cross coupling of aryl halides with
Keywords: N-Arylpiperazines; N-Arylindoles; Substituted anilines; Palla-
dium catalyst; N-Arylation; Aryl halides.
BINAP by PPh more readily available than other classic
3
used ligands. This is a modified Buchwald–Hartwig amina-
tion of aryl bromides using different substrates and
*
Corresponding author. Tel.: +34 93 4024534; fax: +34 93 4035941;
e-mail: mdpujol@ub.edu
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.011

M. Romero et al. / Tetrahedron 62 (2006) 9010–9016
Table 1. Palladium-catalyzed formation of tertiary amines
9011
a
Entry
Ar-X
Br
R
1
R
2
NH
Product
Yield (%)
Conditions
R
N
NH
R
N
N
SO CH
2
3
3
3
3
3
3
3
3
1
92 (75)
Pd[P(o-tolyl)
3
3
3
3
]
]
]
]
2
2
2
2
Cl
Cl
Cl
Cl
2
2
2
2
/BINAP (ꢁ)/Cs
2
CO
3
R¼4-fluorophenyl
R¼4-fluorophenyl
SO CH3
2
Br
R
N
NH
R
N
N
SO CH
2
2
3
4
5
6
7
8
9
91
Pd[P(o-tolyl)
Pd[P(o-tolyl)
Pd[P(o-tolyl)
2 3
/BINAP (+)/Cs CO
R¼4-fluorophenyl
R¼4-fluorophenyl
SO CH3
2
Br
R
N
NH
R
N
N
SO CH
2
88
3 2 3
/PPh /Cs CO
R¼4-fluorophenyl
R¼4-fluorophenyl
SO CH3
2
Br
R
N
NH
R
N
N
SO CH
2
0
2 3
/Cs CO without ligand
R¼4-fluorophenyl
R¼4-fluorophenyl
SO CH3
2
Br
R
N
NH
R
N
N
SO CH
2
23
2 2 3
Pd(OAc) /BINAP (+)/Cs CO
R¼4-fluorophenyl
R¼4-fluorophenyl
SO CH3
2
Br
R
N
NH
R
N
N
SO CH
2
81 (78)
Pd[P(o-tolyl)
3
]
Cl
2 2
/BINAP (ꢁ)/KOt-Bu
R¼4-fluorophenyl
R¼4-fluorophenyl
SO CH3
2
Br
R
N
NH
R
N
N
SO CH
2
55
2 3
Cu/K CO
R¼4-fluorophenyl
R¼4-fluorophenyl
SO CH3
2
Br
R
N
NH
R
N
N
SO CH
2
0
2 3
BINAP (+)/Cs CO without catalyst
R¼4-fluorophenyl
R¼4-fluorophenyl
SO CH3
2
Br
R
N
NH
R
N
N
OCH3
OCH3
43 (47)
Pd[P(o-tolyl)
3
]
Cl
2 2
2 3
/BINAP (ꢁ)/Cs CO
R¼4-fluorophenyl
R¼4-fluorophenyl
OCH3
Br
R
N
NH
R
N
N
1
1
0
1
32
Pd[P(o-tolyl)
3
]
]
2 2 3 2 3
Cl /PPh /Cs CO
R¼4-fluorophenyl
R¼4-fluorophenyl
OCH3
Br
R
N
NH
R
N
N
81 (68)
Pd[P(o-tolyl)
3
Cl
2 2
/BINAP (+)/Cs
2
CO
3
R¼4-fluorophenyl
R¼4-fluorophenyl
(
continued)

9
012
Table 1. (continued)
Entry Ar-X
M. Romero et al. / Tetrahedron 62 (2006) 9010–9016
a
R
1
R
2
NH
Product
Yield (%)
Conditions
Br
R
N
NH
12
R
N
N
78
Pd[P(o-tolyl)
3
]
2
Cl /PPh /Cs
2 3 2
CO
3
R¼4-fluorophenyl
R¼4-fluorophenyl
N
R
N
NH
R
N
N
1
1
3
4
41
Pd[P(o-tolyl)
3
3
]
2
2
Cl
2
/BINAP (ꢁ)/Cs
2 3
CO
N
Br
Br
R¼4-fluorophenyl
R¼4-fluorophenyl
N
R
N
NH
R
N
N
45 (48)
Pd[P(o-tolyl)
]
Cl
2
3 2 3
/PPh /Cs CO
N
R¼4-fluorophenyl
R¼4-fluorophenyl
Br
R
N
NH
R
N
N
Cl
1
1
5
6
79
90
Pd[P(o-tolyl)
3
]
2
Cl
2
/BINAP (ꢁ)/Cs
2 3
CO
R¼4-fluorophenyl
R¼4-fluorophenyl
Cl
Br
NHCH3
CH3
N
Pd[P(o-tolyl)
3
]
2
Cl
2
2 3
/BINAP (+)/Cs CO
SO CH
2
3
SO CH3
2
H C
3
N
CH3
NH(CH ) OCH
R
Br
O
R
2
2
17
R
85 (87)
Pd[P(o-tolyl)
3
]
2
2 2 3
Cl /BINAP (ꢁ)/Cs CO
R
R¼4-fluorophenyl
R¼4-fluorophenyl
H C
3
N
CH3
NH(CH ) OCH
R
Br
Br
O
R
2
2
1
1
8
9
R
87
86
Pd[P(o-tolyl)
3
]
2
Cl
2 2 3
/BINAP (+)/Cs CO
R
R¼4-fluorophenyl
R¼4-fluorophenyl
CH3
NH(CH ) OCH
R
H C
3
N
2
2
R
O
R
Pd[P(o-tolyl)
3
]
2
2 3 2 3
Cl /PPh /Cs CO
R¼4-fluorophenyl
R
Br
Br
Br
NHCH3
H C
3
N
N
N
2
2
2
0
1
2
78 (69)
Pd[P(o-tolyl)
Pd[P(o-tolyl)
Pd[P(o-tolyl)
3
3
3
]
2
]
2
]
2
Cl
2
Cl
2
Cl
2
/BINAP (ꢁ)/Cs
2 3
CO
NHCH3
NHCH3
H C
3
79
2 3
/BINAP (+)/Cs CO
H C
3
76
3 2 3
/PPh /Cs CO
Br
NHCH3
H C
3
N
23
5
Pd(OAc)
2
2 3
/BINAP (+)/Cs CO
a
ꢀ
Yields reported correspond to analytically pure isolated compounds (average of two or three runs). All the reactions were conducted at 120 C for 2 h except
for entries 7 (120 h) and 8 (24 h). Compounds of entries 1, 6, 9, 11, 14, 17, and 20 have been prepared on a 1-g scale and the yields are indicated in brackets.

M. Romero et al. / Tetrahedron 62 (2006) 9010–9016
Table 2. Palladium-catalyzed N-arylation of pyrrole and indole
9013
Entry
Ar-X
R
1
R
2
NH
Product
Yield (%)
Conditions
Br
N
1
75 (69)
3 2 2 2 3
Pd[P(o-tolyl) ] Cl /BINAP (+)/Cs CO
N
H
SO CH
2
3
SO CH
2
3
Br
N
2
3
72
3 2 2 3 2 3
Pd[P(o-tolyl) ] Cl /PPh /Cs CO
N
H
SO CH
2
3
SO CH
2
3
Br
N
a
1
2
N
H
N
N
N
Pd[P(o-tolyl)
3
]
2
2 2 3
Cl /BINAP (+)/Cs CO
a
46
N
H
7
1
2
8
4
N
N
N
N
H
N
Br
Pd[P(o-tolyl)
Pd[P(o-tolyl)
Pd[P(o-tolyl)
3
3
3
]
2
]
2
]
2
Cl
2
Cl
2
Cl
2
2 3
/BINAP (+)/Cs CO
N
H
Br
N
5
87 (82)
2 3
/BINAP (+)/Cs CO
N
H
SO CH
2
3
SO CH
2
3
Br
N
6
90
3 2 3
/PPh /Cs CO
N
H
SO CH
2
3
SO CH
2
3
Br
N
7
8
9
48
Pd[P(o-tolyl)
Pd[P(o-tolyl)
Pd[P(o-tolyl)
3
3
3
]
2
]
2
]
2
Cl
2
Cl
2
Cl
2
/BINAP (+)/Cs
2
CO
3
N
H
N
N
N
N
N
N
86 (81)
/BINAP (+)/Cs
2
CO
3
N
H
Br
Br
88
3 2 3
/PPh /Cs CO
N
H
N
N
(
continued)

9014
M. Romero et al. / Tetrahedron 62 (2006) 9010–9016
Table 2. (continued)
Entry
Ar-X
R
1
R
2
NH
Product
Yield (%)
Conditions
Br
Br
Br
Br
F
Br
N
b
10
11
12
13
0
Pd[P(o-tolyl)
3
3
3
]
]
]
2
2
2
Cl
Cl
Cl
2
2
2
/BINAP (+)/Cs
/BINAP (+)/Cs
/BINAP (+)/Cs
2
2
2
CO
CO
CO
3
3
3
N
H
NH2
H N
2
F
F
F
Br
Br
Br
N
N
N
c
30
Pd[P(o-tolyl)
Pd[P(o-tolyl)
N
H
NH2
NH2
NH2
H N
2
d
65
N
H
H N
2
e
0
2 3
BINAP (+)/Cs CO without catalyst
N
H
H N
2
Compounds of entries 1, 5, and 8 have been prepared on a 1-g scale and the yields are indicated in brackets.
Yields reported correspond to analytically pure isolated compounds (average of two or three runs). All the reactions were conducted at 120 C for 2 h. Except the
indicated cases.
ꢀ
a
b
c
d
e
ꢀ
4
2
6
2
h at 150 C.
ꢀ
4 h at 130 C.
ꢀ
h at 150 C.
ꢀ
4 h at 150 C.
ꢀ
2
4 h at 180 C without catalyst.
optimized conditions, which allows the synthesis of precur-
sors of bioactive compounds. Aryl bromides were chosen as
starting compounds because they are readily available and
is less expensive, resulted in non-significant modification of
yields (Table 1, compare entry 1 vs entry 3; entry 9 vs entry
10; entry 13 vs entry 14; entry 17 vs entry 19). In the same
1
8
0
more reactive than aryl chlorides and triflates. Further-
more, the preparation of functionalized aryl iodides was
more difficult.
way, both racemic and non-racemic BINAP ((R)-(+)-2,2 -
0
sults in all the tested transformations (Table 1, compare entry
bis(diphenylphosphino)-1,1 -binaphthyl) gave similar re-
1
9
1
vs entry 2; entry 17 vs entry 18; entry 20 vs entry 21).
8
According to Buchwald and co-workers and Ma and co-
Moreover addition of a large excess of BINAP did not mod-
ify the yields under our experimental conditions and also
was determined that the order of addition of reagents was
not important. The experiments carried out from 1 g of sub-
strate provide the desired compounds in acceptable yields
using a minimal amount of catalyst (see Tables 1 and 2,
the yields of 1-g scale reactions were indicated in brackets).
2
0
workers, the acyclic secondary amines are usually prob-
lematic substrates for the coupling reactions, probably due
to steric hindrance, high nucleophilicity, and basicity and
also the possibility of b-elimination hydrogen can be consid-
ered. The preparation of hindered N,N-dialkylarylamines
was successful in these conditions giving the corresponding
disubstituted anilines (Table 1). Acyclic secondary amine
substrates (Table 1, entry 18) gave a lower yield of coupled
product than those obtained with cyclic secondary amines
and electron poor aryl bromide (Table 1, entry 1), but better
than cyclic secondary amines and electron rich aryl bromide
No reaction occurred without addition of ligand BINAP or
triphenylphosphine to Pd[P(o-tolyl) ] Cl , substrate, and ce-
sium carbonate (Table 1, entry 4). The results showed that
P(o-tolyl) present in the catalyst system was ineffective,
3
2
2
3
(
Table 1, entry 9). Electron poor aryl bromides containing
even for the N-arylation of the activated substrates. The
use of Pd(OAc) as a precatalyst was found to be less effi-
a sulfone group afforded the expected products with excel-
lent yields within 2 h (Table 1, entry 1). The reaction was
shown to tolerate the naphthyl group with good yield of
2
cient than Pd[P(o-tolyl) ] Cl in the tested substrates (Table
2
3
2
1, entries 5 and 23). When strongly basic KOt-Bu was used
instead of Cs CO the expected piperazine was obtained in
a good yield (Table 1, entry 6).
7
6–87% (Table 1, entries 17–22). Another interesting obser-
2
3
vation was the regioselective reaction of 1-bromo-4-chloro-
benzene with the substituted piperazine under the same
reaction conditions (Table 1, entry 15). Changing the chelat-
On the other hand the Ullmann-type coupling using Cu/
K CO gave the desired product in 55% yield and starting
ing ligand from BINAP to triphenylphosphine (PPh ), which
3
2
3

M. Romero et al. / Tetrahedron 62 (2006) 9010–9016
9015
aryl bromide remained unreacted after 120 h of reaction
Table 1, entry 7). In this study the Pd catalyst revealed
superiority over the Cu system.
pyridine nucleus (Table 2, entries 3 and 4). So, it is know
that the 2-position of bromopyridines is most susceptible
to do oxidative addition to palladium than the 3-position.
Moreover, due to pyrrole electronic distribution, it might
be involved in two different arylation mechanisms, as sug-
gested by the ab initio computational data included in Sup-
plementary material. Pyrrole and indole react readily with
electron poor aryl bromide and give N-arylpyrrole (Table
2, entry 1) and N-arylindole (Table 2, entry 5) in good yield.
(
When Pd (dba) was used as catalyst under conditions pre-
3
2
sented by Verkade and Urgaonkar the aryl bromide reacted
very slowly and the reaction was not complete after 3 days.
2
1
In the same way, the synthesis of N-arylpyrrole or indole has
been achieved by using the same conditions. Hartwig et al.
have reported previously the preparation of N-arylazoles
The N-arylation of pyrrole and indole can be obtained at
ꢀ
using the combination of Pd(dba) and dppfin the presence of
2
100 C, but a significant amount of starting material re-
mained unreacted after a long reaction time at this tempera-
ture. Considering these results, the process was optimized at
11
NaOt-Bu or Cs CO . The Pd(dba) is a good catalyst but
2
3
2
difficult the purification of products. More late the same au-
thors have optimized the reaction conditions using Pd(dba) /
ꢀ
a higher temperature (130–150 C). In general, this coupling
2
2
2
P(t-Bu)3. When 5-bromoindole was treated with 3-fluoro-
aniline, both possessing two reactive positions, the arylation
took place exclusively at the 1-position over the N-atom, giv-
ing the corresponding N-arylindole as a single isomeric prod-
reaction was found to be temperature dependent, higher reac-
tion temperatures increases the yield, but by raising the tem-
ꢀ
perature to 180 C, the ratio of side products was increased.
ꢀ
uct at temperature near to 150 C (Table 2, entries 11 and 12),
In summary, we report new conditions for the palladium-
catalyzed amination of aryl bromides, which do not require
the use of solvent or few drops of toluene (exceptional
cases), and need low catalyst amounts. The direct N-aryla-
tion of substituted piperazines was an interesting aspect of
this strategy. This developed methodology was efficient on
a 1-g scale for coupling aryl and aliphatic amines. This
protocol will be applied to the preparation of more complex
and interesting nitrogen containing compounds and these
studies will be reported in due course.
and the expected 5-(3-fluorophenylamino)indole was not de-
tected under these conditions. In contrast, the reaction was
ꢀ
0). Thus, this method allowed the synthesis of N-(3-amino-
unsuccessful at 130 C after more than 24 h (Table 2, entry
1
phenyl)-5-bromoindole from 5-bromoindole and 3-fluoro-
aniline under severe reaction conditions (Table 2, entry 12).
The 3-fluoroaniline was the choice thinking that the arylation
will take place at the amine group. The displacement of fluo-
ride (3-fluoroaniline) instead of bromine (5-bromoindole) is
not clear; aryl fluorides have long been considered inert to
2
2
Pd-catalyzed coupling reactions, and only aryl fluorides
with strong electron-withdrawing substituents give coupling
Amination of aryl halides (Tables 1 and 2). General proce-
dure. A flask was charged with aryl halide (1.0 mmol),
amine (1.2 mmol), cesium carbonate (1.0 mmol), Pd[P(o-
tolyl) ] Cl (0.12 mol % Pd), and BINAP (0.0075 mmol)
2
3
reactions. Only the high temperatures can explain this
behavior. Attempts at the same temperature in the absence
of Pd catalyst were unsuccessful (Table 2, entry 13), result
that corroborate the radical mechanism of this reaction.
3
2
2
under argon without addition of solvent (just drops of tolu-
ene was added only in exceptional cases when both starting
compounds were solids). The flask was hermetically closed
ꢀ
The pyridinylation of indole was also conducted in the same
manner as described above using 3-bromopyridine and in-
dole but the intended coupled product was obtained in low
yield (Table 2, entry 7). Nevertheless, the 2-bromopyridine
in the same conditions gives the N-arylpyrrole in excellent
yield (Table 2, entry 8). It is interesting the reactivity of pyr-
role with heteroaromatic substrates such as the 2- and 3-bro-
mopyridine. In all cases, mixtures of two isomers were
obtained. The reaction of 3-bromopyridine with pyrrole
gave the N-arylpyrrole (21%) and the nornicotyrine (46%)
and the mixture was heated at 100–130 C (after the sub-
strate and all reagents have been added without any period
of incubation) with stirring until the starting material has
been completely consumed as analyzed by TLC. The mix-
ture was then allowed to cool to room temperature and the
crude product was directly purified further by flash chroma-
tography on silica gel, eluting with mixtures of hexane/ethyl
acetate. All the commercially available reagents used were
purchased from Aldrich Chemical Co. and were used with-
out previous purification. The catalyst was acquired from
Strem (Chemicals for Research). Yields reported correspond
to analytically pure isolated compounds.
(
Table 2, entry 3). Whereas the treatment of pyrrole with
2
(
4
-bromopyridine afforded the 2-(1-pyrrolyl) pyridine
72%) and the 2,2 -pyrrolylpyridine (18%) (Table 2, entry
0
). The reaction of 2-bromopyridine with the pyrrole and in-
Acknowledgements
dole rings proceeded with more yield and selectivity than the
reaction of 3-bromopyridine. Our hypothesis is that the 2-
bromopyridine facilitates the complexation with the catalyst
system and N-arylation of the azole was preferable as
expected (Table 2, entries 4 and 8). Recently, Doucet et al.
reported the significant effect of the position and the nature
of the halide on the heteroaromatic nuclei on catalyzed
Financial support for this work was provided by the Minis-
terio de Ciencia y Tecnolog ´ı a (MCYT, BQU 2002-00148)
and the Departament d’Universitats, Recerca I Societat de
la Informaci ꢁo de la Generalitat de Catalunya, Spain (2005-
SGR-00180).
2
4
palladium reactions.
Supplementary data
The substitution of the two different positions of the pyrrole
by the reaction of the pyrrole with the bromopyridine is
dependent on the position of the bromine atom over the
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.07.011

9016
M. Romero et al. / Tetrahedron 62 (2006) 9010–9016
12. Hartwig, J. F. Synlett 1996, 329–340.
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