Palladium-catalysed amination of halopyridines on a KF-alumina surface

Article abstract of DOI:10.1016/S0040-4039(02)01852-X

Palladium-catalysed C-N hetero cross-coupling reactions between bromopyridines and amines (both primary and secondary) can be efficiently performed on a KF-alumina (basic) surface, thus negating the use of strong bases such as sodium tert-butoxide. The reaction conditions are optimised with reference to catalytic systems, solvents and the surface.

Full text of DOI:10.1016/S0040-4039(02)01852-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7967–7969
Palladium-catalysed amination of halopyridines on a
KF-alumina surface
Basudeb Basu,* Satadru Jha, Niranjan K. Mridha and Md. Mosharef H. Bhuiyan
Department of Chemistry, University of North Bengal, Darjeeling 734 430, India
Received 19 February 2002; revised 22 August 2002; accepted 30 August 2002
Abstract—Palladium-catalysed C–N hetero cross-coupling reactions between bromopyridines and amines (both primary and
secondary) can be efficiently performed on a KF-alumina (basic) surface, thus negating the use of strong bases such as sodium
tert-butoxide. The reaction conditions are optimised with reference to catalytic systems, solvents and the surface. © 2002 Elsevier
Science Ltd. All rights reserved.
Aminopyridines are versatile intermediates for synthetic
transformations to biologically active compounds1 and
are known to act as central nervous system stimulants.2
Their derivatives are often used as ligands in coordina-
tion and organometallic chemistry,3 and have found
industrial applications as fluorescent dyes.4 Most of the
early preparative methods for aminopyridines involve
aromatic nucleophilic substitution by SNAr, benzyne or
The weaker base (Cs2CO3) has been employed for
haloaromatics9 and halothiophenes,10 but not in the
case of halopyridines and its use is limited due to high
solubility in organic solvents and its hygroscopic
nature. Since the use of a base is one of the keys to the
success of this coupling reaction, we investigated palla-
dium-catalysed cross coupling of bromopyridines and
amines on a KF-alumina (basic) surface. KF-alumina
has been successfully employed in many other cases so
as to exploit its basicity on the surface11 and very
recently Pd-catalysed C–C couplings (Suzuki, Heck,
Stille, Trost-Tsuji) have been reported using KF-alu-
mina under mono-mode microwave irradiation.12 This
report describes our results, which constitute a conve-
nient and efficient heterogeneous method for C–N cou-
pling by Pd-catalysed amination of halopyridines on
KF-alumina (basic) surface (Scheme 1).
S
RN1 reactions.5 These methods either suffer from a
nucleophilic regiocontrol problem, the need for very
high temperature or the presence of specific functional-
ity on the heterocyclic ring. None of these methods
show a combination of good yields and high selectivity.
Buchwald and others6 have recently developed chelat-
ing bis-phosphine-palladium catalysed cross-coupling
reactions that allow the preparation of aminopyridines
from their corresponding halopyridines.7 The method
involves Pd(0)/bis-phosphine complexes as the effective
catalyst for oxidative addition to the carbon–halogen
bond, followed by coupling with the amine. The amina-
tion is catalyst-specific (Pd–ligand complexes) and very
sensitive to the nature of the base.6a,d Although this
reaction efficiently produces aminopyridines in the pres-
ence of chelating bis-phosphine/Pd(0) complexes, the
use of strong bases such as sodium tert-butoxide is not
desirable and remains associated with problems such as
in the case of direct amination using NaNHR or
NaNR2.5,8 Furthermore, the use of strong bases greatly
limits the functional group tolerance of the process.9
As can be seen from the results presented in Table 1,
the amination on KF-alumina surface works with dif-
ferent bromopyridines. While 2-bromopyridine (entries
1 and 2) reacts with different amines smoothly, 3-bro-
mopyridine (entry 7) undergoes amination in relatively
poor yield. Amination of dibromopyridines affords
only monoamine derivatives in good to excellent yields.
In the case of 2,5-dibromopyridine (entries 8 and 9),
amination occurs selectively at the 2-position. Buch-
Keywords: aminopyridines; palladium catalyst; carbon–nitrogen cross
coupling; KF-alumina.
* Corresponding author. Tel.: +91-353-581425; fax: +91-353-581546;
e-mail: basu nbu@hotmail.com
Scheme 1.
–
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01852-X

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B. Basu et al. / Tetrahedron Letters 43 (2002) 7967–7969
Table 1.
wald observed complete bis-amination of 2,6-dibromo-
pyridine using Pd2(dba)3-dppe catalyst in the presence
of excess amine.7a Our conditions, however, yielded
monoamines as the major products even after pro-
longed reaction times and in the presence of excess
amine (entries 3–6). This selectivity offers an advantage
for further reaction with the other halogen substituents.
In the bicyclic systems, 4-bromoisoquinoline (entries 10
and 11) and 3-bromoquinoline (entries 12 and 13)
undergo amination efficiently.
A great deal of experimentation on the cross coupling
of bromopyridines with primary and secondary amines
was carried out in order to optimise the reaction condi-
tions. Palladium sources, ligand, solvent and the sup-
port (KF-Al2O3) were optimised and several details are
worthy of comment. Firstly, different palladium sources
like PdCl2, Pd(OAc)2, Pd2(dba)3, Pd(acac)2 and
Pd[PPh3]4 complexing with either mono-phosphine [(o-
tolyl)3P] or bis-phosphines (BINAP and DPPF) were
employed as the catalytic systems. The Pd[(o-

B. Basu et al. / Tetrahedron Letters 43 (2002) 7967–7969
7969
46.3, 104.5, 116.1, 127.3, 127.4, 128.7, 138.3, 139.5,
140.2, 158.7.
tolyl)3P]2Cl2 and Pd2(dba)3/BINAP complexes were
found to be most effective in this amination process
(Table 1). The formation of bis-(pyridyl) complexes
using monophosphine ligands, as proposed by Buch-
wald,7a might possibly be avoided under these condi-
tions. The reactions were carried out with or without a
solvent. Clean reactions and better yields of the
aminopyridines were obtained when the reactions were
carried out on KF-Al2O3 surface with a slight excess of
amine and without solvent. Toluene and xylene have
been used as solvents with almost similar effects, whilst
the presence of DMF as a co-solvent induces faster
debromination (entry 10). 2-Bromopyridine (entries 1
and 2) also yields 10–15% of 2,2%-bipyridyls by inter-
molecular coupling and such coupling is further
increased in the presence of a solvent. The major limita-
tions of this protocol are that 3-bromopyridine fails to
cross-couple with primary amines and partial dehalo-
genation (<5%) was observed in the case of 3-bromo-
pyridine, 3-bromoquinoline and 4-bromoisoquinoline.
Acknowledgements
We thank the Department of Science and Technology,
New Delhi for financial support (Grant No. SP/S1/
G13/97). S.J. is a Junior Research Fellow under this
project.
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In conclusion, we have shown that Pd(0) catalysed
amination of bromopyridines can be performed
smoothly on the surface of basic alumina admixed with
KF. The simplicity of the experimental conditions,
good to excellent yields and favourable safety aspects
represent a significant improvement and useful exten-
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1
90%); mp 85°C; H NMR (CDCl3, 300 MHz): l 4.46
(d, 2H, J=5.9 Hz), 5.18 (br.s, 1H), 6.24 (d, 1H, J=8.2
Hz), 6.73 (d, 1H, J=7.5 Hz), 7.20 (dd, 1H, J=8.2; 7.5
Hz), 7.27–7.36 (m, 5H); 13C NMR (CDCl3, 75 MHz): l
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