Examination of the mechanism of the intramolecular amination of N-(3-bromopyridin-2-yl)azaheteroarylamines and N-(2-chloropyridin-3-yl)azaheteroarylamines: a Pd-catalyzed amination and/or a base-assisted nucleophilic aromatic substitution?

Article abstract of DOI:10.1016/j.tet.2007.02.041

The intramolecular amination of N-(3-bromopyridin-2-yl)azaheteroarylamines and N-(2-chloropyridin-3-yl)azaheteroarylamines was investigated. In this way we unraveled the mechanism of the ring closure reaction in the auto-tandem amination (inter- and intramolecular Pd-catalyzed amination) of 2,3-dibromopyridine with amino(benzo)(di)azines and 2-chloro-3-iodopyridine with amino(benzo)(di)azines, respectively. Depending on the substrate a Pd-catalyzed amination, a base-assisted nucleophilic aromatic substitution or?a combination of both is occurring. An explanation based on the aromaticity of the amidine, supported by theoretical calculations, is provided. In addition we gained evidence that the intramolecular metal-catalyzed amination of N-(3-bromopyridin-2-yl)azaheteroarylamines and N-(2-chloropyridin-3-yl)azaheteroarylamines indeed involves a nitrogen atom that is not substituted with a hydrogen atom.

Full text of DOI:10.1016/j.tet.2007.02.041

Tetrahedron 63 (2007) 3818–3825
Examination of the mechanism of the intramolecular amination of
N-(3-bromopyridin-2-yl)azaheteroarylamines and N-(2-
chloropyridin-3-yl)azaheteroarylamines: a Pd-catalyzed
amination and/or a base-assisted nucleophilic aromatic
substitution?
*
Kristof T. J. Loones, Bert U. W. Maes, Wouter A. Herrebout, Roger A. Dommisse,
ꢀ
Guy L. F. Lemiere and Benjamin J. Van der Veken
Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
Received 27 December 2006; accepted 9 February 2007
Available online 15 February 2007
ꢁ
This paper is dedicated to Professor G. Queguiner on the occasion of his 70th birthday
Abstract—The intramolecular amination of N-(3-bromopyridin-2-yl)azaheteroarylamines and N-(2-chloropyridin-3-yl)azaheteroarylamines
was investigated. In this way we unraveled the mechanism of the ring closure reaction in the auto-tandem amination (inter- and intramolecular
Pd-catalyzed amination) of 2,3-dibromopyridine with amino(benzo)(di)azines and 2-chloro-3-iodopyridine with amino(benzo)(di)azines,
respectively. Depending on the substrate a Pd-catalyzed amination, a base-assisted nucleophilic aromatic substitution or a combination of
both is occurring. An explanation based on the aromaticity of the amidine, supported by theoretical calculations, is provided. In addition
we gained evidence that the intramolecular metal-catalyzed amination of N-(3-bromopyridin-2-yl)azaheteroarylamines and N-(2-chloropyr-
idin-3-yl)azaheteroarylamines indeed involves a nitrogen atom that is not substituted with a hydrogen atom.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Glu-P’s in DNA via their tricyclic dipyrido[1,2-a:30,20-d]-
imidazole core (Scheme 1).9
During the heating of protein rich food mutagenic hetero-
cyclic amines (HCA’s) are formed. They are so called ‘food
borne carcinogens’ and hitherto more than 20 have already
been isolated.1 These HCA’s can be subdivided in two
main families, the first one consisting of IQ-type HCA’s,
also called thermic HCA’s. They are generated through the
reaction of free amino acids, creati(ni)ne and sugars at tem-
peratures below 300 ꢀC. The HCA’s of the second family,
called non-IQ type or pyrolytic HCA’s are formed through
the pyrolytic reaction of amino acids and proteins at temper-
atures above 300 ꢀC.2–4 Representatives of the latter group
are Glu-P-1 and Glu-P-2, which are pyrolysis products of
L-glutamic acid (Scheme 1).5 The Glu-P’s are transformed
into carcinogenic species by N-hydroxylation, catalyzed
by cytochrome P-450, followed by an enzymatic ester-
ification of the hydroxylamino group with acetyltrans-
ferases.2,4,6–8 The formation of a DNA adduct in position 8
of a guanine is preceded by the intercalation of the activated
N
N
N
N
N
N
H2N
N
H2N
N
N
Glu-P-2
dipyrido[1,2-a:3',2'-d]imidazole
Glu-P-1
Scheme 1. Structures of Glu-P’s and the dipyrido[1,2-a:30,20-d]imidazole
core skeleton.
An attractive new synthetic method to prepare heterocyclic
amines is the Pd-catalyzed amination reaction (Buchwald–
Hartwig reaction). Due to the pioneering diligence of the
research groups of Buchwald10 and Hartwig,11 tin-free Pd-
catalyzed amination has since the mid nineties emerged as
an extremely powerful tool for C(sp2)–N bond forma-
tion.12–15 In 2004 our group reported that the Buchwald–
Hartwig methodology can be used to synthesize
dipyrido[1,2-a:30,20-d]imidazole, the core skeleton of Glu-
P’s, via auto-tandem Pd-catalyzed amination of 2-chloro-
3-iodopyridine with 2-aminopyridine.16 Aza and benzo
analogues could also be obtained in a similar way using
the corresponding amino(benzo)(di)azines (Scheme 2b).
Recently, we also synthesized regioisomers of these
Keywords: SNAr; Buchwald–Hartwig reaction; Aromaticity; Tautomers.
* Corresponding author. Tel.: +3232653205; fax: +3232653233; e-mail:
bert.maes@ua.ac.be
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.041

K. T. J. Loones et al. / Tetrahedron 63 (2007) 3818–3825
3819
(a)
(b)
Br
Br
Br
(N)
N
H2N
Pd-catalyst
or
Pd-catalyst
N
+
(N)
(N)
N
base-assisted
N
N
N
N
N
H
SNAr
1
2
3
4
H
I
N
H2N
Pd-catalyst
or
N
Pd-catalyst
+
(N)
(N)
N
N
base-assisted
(N)
N
N
5
Cl
N
Cl
6
N
SNAr
2
7
N
N
N
N
N
N
2a
H2N
2b
2c
2d
2e
N
H2N
H2N
H2N
H2N
Scheme 2. Possible mechanistic pathways for the synthesis of dipyrido[1,2-a:20,30-d]imidazole, dipyrido[1,2-a:30,20]imidazole, and their benzo and aza
analogues.
Glu-P analogues via an auto-tandem Pd-catalyzed or an
orthogonal-tandem Pd-catalyzed inter and Cu-catalyzed
intramolecular amination on 2,3-dibromopyridine with ami-
no(benzo)(di)azines (Scheme 2a).17 When only a Pd-cata-
lyst is required for the amination reactions the mechanism
of the intramolecular amination remains undefined since it
can in principle proceed via a Pd-catalyzed mechanism as
well as via a nucleophilic aromatic substitution reaction.
In the former case the reaction is auto-tandem catalyzed,
while in the latter case no tandem catalysis but a tandem re-
action (involving an intermolecular Pd-catalyzed amination
and an intramolecular SNAr) is occurring. Full comprehen-
sion of the mechanism of the cyclization step is interesting
from a fundamental point of view and is moreover highly
valuable in order to be able to perform a further rational op-
timization of the tandem reaction conditions. In this paper
information on the mechanism of the intramolecular ami-
nation is gained by studying the cyclization of the inter-
mediates of the double amination on 2,3-dibromopyridine
(1) (N-(3-bromopyridin-2-yl)azaheteroarylamines 3) and
2-chloro-3-iodopyridine (5) (N-(2-chloropyridin-3-yl)aza-
heteroarylamines 6).
to pyrido[20,30:4,5]imidazo[1,2-a]quinoline (4b) (53%) and
pyrido[20,30:4,5]imidazo[1,2-b]pyridazine (4e) (87%), re-
spectively (Table 1).18 These results imply that during the
tandem process on 1 the ring closure not only proceeds via
a Buchwald–Hartwig intramolecular amination but also
partly through a base-assisted addition–elimination path-
way. Interestingly, the ring closure of 3c gave an isolated
yield of 97% of pyrido[20,30:4,5]imidazo[2,3-a]isoquinoline
(4c) (Table 1). Of course, this ring closure experiment on 3c
does not exclude that metal catalyst is additionally involved
in the second step of the tandem process on 1 with 1-amino-
isoquinoline (2c).
These remarkable results inspired us to investigate whether
these base-assisted addition–elimination cyclization reac-
tions also occur in the presumed auto-tandem Pd-catalyzed
inter- and intramolecular amination of 2-chloro-3-iodopyri-
dine (5) with amino(benzo)(di)azines (2) (Scheme 2b).16
Therefore the N-(2-chloropyridin-3-yl)azaheteroarylamines
(6)19 were heated under the same reaction conditions and
for the same reaction time as used for the presumed auto-
tandem protocol only the Pd-catalyst was omitted (Cs2CO3
and toluene at reflux for 17 h). The reaction with N-(2-chloro-
pyridin-3-yl)isoquinolin-1-amine (6c) gave full conversion
and pyrido[30,20:4,5]imidazo[2,3-a]isoquinoline (7c) was
isolated in 99% yield. Of course, this experiment does not
exclude that metal catalyst is additionally involved in the
second step of the tandem process on 5 with 1-aminoisoqui-
noline (2c). On the contrary, the intramolecular amination
with the other analogues of 6 only gave traces of ring-closed
product and for these amidines the corresponding tandem
processes surely involve only Pd-catalysis in the ring closure
reaction. At this stage of the project the question raised
whether the reactivity of the base-assisted ring closure was
either influenced by the halopyridine or by the amidine
moiety. General conclusions can of course only be made,
provided that the ring closure of 3 and 6 are performed
under exactly the same reaction conditions. Therefore the
cyclizations of 3 were first performed under the same
reaction conditions as used for 6 (Cs2CO3 and toluene at
reflux for 17 h). Only the intramolecular amination of
3c gave some conversion into 4c (11%) but the remaining
analogues of 3 were completely recovered after 17 h. Sec-
ondly, the cyclizations of 6 were also investigated under
the same reaction conditions of 3 (Cs2CO3 and DME at
140 ꢀC for 24 h). N-(2-Chloropyridin-3-yl)pyridin-2-amine
2. Results and discussion
We previously found that for the intramolecular amination of
N-(3-bromopyridin-2-yl)pyridin-2-amine (3a) and N-(3-
bromopyridin-2-yl)pyrazin-2-amine (3d), the use of CuI
catalyst was essential.17 Only the simultaneous use of
Pd2(dba)3/XANTPHOS and CuI gave access to dipyrido-
[1,2-a:20,30-d]imidazole (4a) and pyrido[20,30:4,5]imidazo-
[1,2-a]pyrazine (4d) starting from 2,3-dibromopyridine,
2-aminopyridine, and aminopyrazine, respectively. For the
double amination of 2,3-dibromopyridine (1) with 2-amino-
quinoline (2b), 1-aminoisoquinoline (2c), and 3-aminopyri-
dazine (2e) the use of Pd2(dba)3/XANTPHOS was sufficient
to get double amination. To exclude a base-assisted
addition–elimination ring closure mechanism, N-(3-bromo-
pyridin-2-yl)quinolin-2-amine (3b), N-(3-bromopyridin-2-
yl)isoquinolin-1-amine (3c), and N-(3-bromopyridin-2-yl)-
pyridazin-3-amine (3e) were therefore subjected to the
same reaction conditions and heated for the same reaction
time as used for the presumed auto-tandem protocol, only
the Pd-catalyst was omitted (Cs2CO3 and DME at 140 ꢀC
for 24 h). Interestingly, 3b and 3e were partly converted

3820
K. T. J. Loones et al. / Tetrahedron 63 (2007) 3818–3825
Table 1. Attempted ring closure of N-(3-bromopyridin-2-yl)azaheteroarylamines 3, and N-(2-chloropyridin-3-yl)azaheteroarylamines 6 via SNAr
Compound 3
DME 140 ꢀCa (%)
Toluene refluxb (%)
Compound 6
DME 140 ꢀCa (%)
Toluene refluxb (%)
3
4
3
4
6
7
6
7
H
N
Br
N
100c
0c
99
98
0
0
94
52
3
95
88
5
2
N
N
N
H
N
Cl
3a
6a
H
N
Br
N
N
N
N
39
53
42
N
Cl
N
N
N
H
6b
3b
Br
H
N
N
H
0
93
83
11
0
96
0
99
N
Cl
3c
6c
H
N
Br
N
N
100c
0c
96
98
0
0
59
0
31
72
98
94
0
3
N
N
N
N
H
N
N
N
Cl
6d
3d
H
N
Br
N
N
12
87
N
H
N
Cl
N
3e
6e
a
b
c
Compound 3 or 6 (0.5 mmol), Cs2CO3 (2.0 mmol), DME (5 mL), 160 ꢀC (oil bath). Experiments were performed in a 10 mL microwave vial.
Compound 3 or 6 (0.5 mmol), Cs2CO3 (2.0 mmol), toluene (5 mL), 120 ꢀC (oil bath). Experiments were performed in a 25 mL flask.
Via an auto-tandem Pd-catalyzed amination protocol 4a and 4d could not be formed. These results imply that also via a nucleophilic aromatic substitution
reaction using the same base at the same reaction temperature 4a and 4d cannot be synthesized.
(6a) could almost fully be recovered. Merely 3% of
dipyrido[1,2-a:30,20-d]imidazole (7a) was formed. N-(2-
Chloropyridin-3-yl)quinolin-2-amine (6b) and N-(2-chloro-
pyridin-3-yl)pyrazin-2-amine (6d) gave partial conversion
since pyrido[30,20:4,5]imidazo[1,2-a]quinoline (7b) and pyr-
ido[30,20:4,5]imidazo[1,2-a]pyrazine (7d) were isolated in,
respectively, 42% and 31%. N-(2-Chloropyridin-3-yl)pyri-
dazin-3-amine (6e) and N-(2-chloropyridin-3-yl)isoquino-
lin-1-amine (6c) gave full conversion. All the obtained
results are summarized in Table 1.
of the negative charge toward the endocyclic nitrogen
(Scheme 3). Therefore one can expect that the ring with
the lowest aromaticity is the most reactive for SNAr. The
fact that in DME at 140 ꢀC 6d can undergo SNAr and 3d
cannot, can be explained on the basis of the reactivity of
the halopyridine part. After all, a bromine atom in the b-
position of a pyridine nucleus is less reactive for nucleo-
philic substitution than a chlorine atom in the a-position.
X
X
N
N
N
-H
N
N
N
H
Whenonelooksatthecyclizationdataof6a–e(DME,140 ꢀC)
in Table 1 the following amidine sequence (going from a low
to a high conversion in 24 h) can be deduced: 2-amino-
pyridine<aminopyrazine<2-aminoquinoline<3-aminopyr-
idazine<1-aminoisoquinoline. Interestingly, the reactivity
of the substrates 3a–e under the same reaction conditions
seems to follow the same sequence. The only difference is
that 6d still undergoes base-assisted nucleophilic aromatic
substitution and 3d does not give any conversion. Also in
toluene a trend can be seen but in this case only the most re-
active amidine (of the sequence observed in DME at 140 ꢀC)
namely the isoquinoline derivatives 3c and 6c give conver-
sion. Since the reaction conditions in toluene are less harsh
it is not surprising that only the most reactive amidine gives
cyclization. These observations can be rationalized in
view of the reaction mechanism. After deprotonation the
aromaticity of the ring that contains the amidine must be
broken in order to enable the mesomeric electron pair shift
mesomeric
shift
X
N
N
N
-X
N
N
N
Scheme 3. Reaction mechanism of the cyclization via SNAr.
To support the aromaticity theory, for the different ring struc-
tures containing the amidine moiety, theoretical information
on the resonance energy was obtained by applying the model
described by Bird.20 For all species under study, the equilib-
rium geometry was calculated at the B3LYP/6-31G(d,p)
level. Subsequently, the calculated values for the carbon–
carbon, the carbon–nitrogen, and the nitrogen–nitrogen
bond lengths were used to estimate the resonance energy.
The resulting values for the resonance energies, obtained
by weighting the values derived from the different resonance

K. T. J. Loones et al. / Tetrahedron 63 (2007) 3818–3825
3821
Table 2. Resonance energies, in kJ molꢁ1, for the amidine fragments in the
N-(3-bromopyridin-2-yl)azaheteroarylamines 3 and N-(2-chloropyridin-3-
yl)azaheteroarylamines 6
exocyclic nitrogen atom during the catalytic cycle or a tauto-
meric equilibrium has to be taken into account for the ami-
dines. Therefore the equilibrium constants between the
tautomers 3 and 30 and 6 and 60 were calculated (Scheme
4). Theoretical information on the differences in free energy
DG and the equilibrium constants for the tautomeric equilib-
ria 3/30 and 6/60 were obtained from density functional cal-
culations, at the B3LYP/6-31G(d,p) level. To this end, for
all species under interest, geometry optimizations and fre-
quency calculations were performed. For the chlorine con-
taining species, the effect of the solvent was modeled by
using the polarizable continuum (SCRF) model developed
by Barone and co-workers,21,22 and by using the internally
stored parameters for toluene. For the bromine containing
molecules, the SCRF model was used in combination with
the parameters for THF, which has solvent properties similar
to those of the DME used in the experimental study. The dif-
ferences in free energy DG and the equilibrium constants,
obtained by applying standard statistical thermodynamics,
are summarized in Table 3.23 The values clearly show that
the presence of the tautomers with the hydrogen atom on
the endocyclic nitrogen (30 and 60) can be neglected. These
data therefore clearly support our previous hypothesis that
the endocyclic nitrogen atom of the amidine, that is not
substituted with a hydrogen atom, can indeed be involved
in an intramolecular Pd- or Cu-catalyzed amination reaction
and deprotonation (of the exocyclic nitrogen atom) occurs
after metal coordination of the endocyclic nitrogen of the
amidine (Schemes 5 and 6).16,17
3
RE (kJ molꢁ1 a
)
6
RE (kJ molꢁ1 a
)
3a
3b
3c
3d
3e
42.1
6a
6b
6c
6d
6e
42.9
23.2 (69.2)b
23.0 (69.0)b
38.2
24.4 (70.4)b
24.1 (70.1)b
39.2
32.6
34.3
a
The resonance energies were obtained using a procedure similar to that
reported by Bird.20 The carbon–carbon, carbon–nitrogen and nitrogen–
nitrogen bond lengths used were derived from DFT geometry optimiza-
tions, at the B3LYP/6-31G(d,p) level.
The values for 3b, 6b, 3c, and 6c, given in brackets, refer to the resonance
energy of the complete bicyclic system; the other values refer to the
resonance energy of the ring structure involved in the reaction.
b
structures involved, are summarized in Table 2. For the
2-aminoquinoline (3b and 6b) and 1-aminoisoquinoline
(3c and 6c) derivatives, two different values are reported,
which correspond to the resonance energy of the whole sys-
tem and that of the ring structure (pyridine moiety) directly
involved in the reaction. The latter is calculated by subtract-
ing the value for benzene (46.0 kJ molꢁ1), obtained using the
same procedure, from the resonance energy of the complete
bicyclic system.
For our series of (di)azines the theoretical resonance energy
sequence matches perfectly with the experimental observa-
tions. The resonance energy of the aminobenzazines should,
however, be interpreted with carewhen one wants to incorpo-
rate them in the amino(di)azine list as the aromaticity of the
entire bicyclic system is calculated. Therefore the value ob-
tained by subtracting the resonance energy of benzene should
be used for the aminobenzazines. However, this still yields
a general sequence for the (di)azines and aminobenzazines,
which is not fully, but almost, in agreement with the observed
SNAr reactivity (sequence based on calculated resonance
energies: 1-aminoisoquinoline>2-aminoquinoline>3-ami-
nopyridazine>aminopyrazine>2-aminopyridine; sequence
based on the experimentally observedreactivity: 1-aminoiso-
quinoline>3-aminopyridazine>2-aminoquinoline>amino-
pyrazine>2-aminopyridine). In contrast with the small
difference in the calculated values obtained between the
1-aminoisoquinoline and 2-aminoquinoline derivatives
(Table 2) their difference in reactivity is significant. The var-
iation of the reactivity can easily be explained by taking into
account the geometric difference between these two ami-
dines, which is of course not incorporated in our calculated
resonance energy values. The peri-hydrogen of the benzene
moiety of 3b and 6b hampers the nucleophilic attack of the
endocyclic nitrogen of the amidine onto the halopyridine
part sterically, in comparison with 3c and 6c. Therefore the
reactivity of 3b and 6b is less than that expected on the basis
of the resonance energy and drops from the second to the
third place (taking the calculated resonance energies as refer-
ence list) yielding the experimentally observed sequence 1-
aminoisoquinoline>3-aminopyridazine>2-aminoquinoline>
aminopyrazine>2-aminopyridine.
Br
HN
Br
N
(N)
(N)
N
N
N
H
N
N
N
3
3'
H
N
N
(N)
(N)
HN
Cl
6'
N
Cl
6
Scheme 4. Possible tautomers of 3 and 6.
Table 3. B3LYP/6-31G(d,p) free energy differences DG, in kJ molꢁ1, and
equilibrium constants for the tautomeric equilibria 3/30 and 6/60
Compound DG/kJ Keq
3
Compound DG/kJ Keq
6
molꢁ1
molꢁ1
3a
3b
3c
3d
3e
39.2
17.8
17.6
46.9
25.8
8.1ꢂ10ꢁ7 6a
7.9ꢂ10ꢁ4 6b
8.6ꢂ10ꢁ4 6c
6.8ꢂ10ꢁ9 6d
3.2ꢂ10ꢁ5 6e
47.5
31.2
21.9
52.0
22.2
5.4ꢂ10ꢁ9
3.7ꢂ10ꢁ6
1.5ꢂ10ꢁ4
8.8ꢂ10ꢁ10
1.4ꢂ10ꢁ4
The values for 3/30 were obtained for a solution in THF; while those for 6/60
were obtained for a solution in toluene.
3. Conclusion
In conclusion we examined the intramolecular amination of
N-(3-bromopyridin-2-yl)azaheteroarylamines 3 and N-(2-
chloropyridin-3-yl)azaheteroarylamines 6. Two possible
cyclization pathways are observed: Pd-catalyzed amination
and base-assisted nucleophilic aromatic substitution. We
found that the occurrence of the base-assisted nucleophilic
Since the intramolecular amination reaction of our auto- and
orthogonal-tandem catalysis seems to involve a nitrogen
atom that is not substituted with a hydrogen atom, we won-
dered whether the proton indeed is removed from the

3822
K. T. J. Loones et al. / Tetrahedron 63 (2007) 3818–3825
P
P
X
N
H
N
oxidative
addition
HN
N
coordination
N
N
X
P
P
N
N
P
P
P
P
X
NH
N
Pd
X
or
NH
Pd
Pd
N
N
N
P
P
deprotonation
exocyclic nitrogen
N
N
N
reductive
elimination
N
Scheme 5. Mechanistic proposal for the intramolecular Pd-catalyzed amination of 3 and 6.
multiplet, and s for singlet. For mass spectrometric analysis,
samples were dissolved in CH3OH containing 0.1% formic
acid and diluted to a concentration of approximately
10ꢁ5 mol/L. Injections (1 mL) were directed to the mass
spectrometer at a flow rate of 5 mL/min (CH3OH and 0.1%
formic acid), using a CapLC HPLC system. Accurate mass
data were acquired on a Q-TOF 2 (Micromass) mass spec-
trometer equipped with a standard electrospray ionization
(ESI) interface. Cone voltage (approx. 35 V) and capillary
voltage (approx. 3.3 kV) were optimized on one compound
and used for all others. For the determination of the accurate
mass of the molecular ion [M+H]+, a solution of polyethyl-
ene glycol 300 in CH3OH/H2O with 1 mmol ammonium
acetate was added just before the mass spectrometer (at
a rate of 1 mL/min) to the mobile phase. The calculated
masses of PEG [M+H]+and [M+NH4]+ions were used as
lock mass. For the product ion experiments (MS) the mass
of the [M+H]+was used as lock mass for the fragments. Frag-
mentation was induced by low energy collisional activation
using different collision energies of 20 eV. All signals with
a signal-to-noise ratio ꢃ5/1 were reported. Density Func-
tional theory (DFT) calculations were performed with the
use of Gaussian03/TCP Linda as implemented in the Cal-
cUA supercomputing cluster.24 For all calculations the
B3LYP methodology was used, while the effects of the sol-
vent were modeled using the polarizable continuum model
developed by Barone and co-workers.21,22 All reagents
(except 3-aminopyridazine) are obtained form commercial
sources and used without extra purification. XANTPHOS
(9,9-dimethyl-4,5-bis(diphenylphosphanyl)-9H-xanthene)
and Cs2CO3 (99%) were purchased from Aldrich, Pd(OAc)2,
Pd2(dba)3, and DME (ethylene glycol dimethyl ether) from
Acros and (ꢄ)-BINAP (2,20-bis(diphenylphosphino)-1,10-
binaphthyl) from Rhodia. 3-Aminopyridazine was prepared
from 3-amino-6-chloropyridazine via hydrogenolysis.25
Flash column chromatography was performed on Kieselgel
60 (ROCC SI 1721, 40–60 mm).
deprotonation
H
N
N
Cu
N
coordination
exocyclic nitrogen
N
NH
Br
X
N
Br
N
N
Cu
CuX
N
Br
oxidative
addition
N
N
N
Br
Cu
N
N
reductive
elimination
N
Scheme 6. Mechanistic proposal for the intramolecular Cu-catalyzed
amination of 3.
aromatic substitution depends on the aromaticity of the ring
that contains the amidine moiety. The experimental
reactivity sequence (2-aminopyridine<aminopyrazine<2-
aminoquinoline<3-aminopyridazine<1-aminoisoquinoline)
is in agreement with the calculated resonance energy of the
ring that contains the amidine in 3 and 6 (the lower its aro-
maticity the higher the SNAr reactivity), taking into account
the steric effect when a quinoline moiety is involved. For in-
tramolecular aminations that occur via the involvement of
a metal catalyst we gained evidence that nitrogen atoms
that are not substituted with a hydrogen atom can indeed
be involved in the catalytic cycle.
4. Experimental section
4.1. General information
€
All melting points were determined on a Buchi apparatus
and are uncorrected. The H NMR and 13C NMR spectra
1
were obtained on a Bruker Avance II 400 spectrometer
with TMS as the internal standard. All coupling constants
are given in hertz and the chemical shifts are given in parts
per million. Multiplicity is indicated using the following ab-
breviations: br for broad, d for doublet, t for triplet, m for
4.1.1. General procedure for the preparation of N-(2-
chloropyridin-3-yl)azaheteroarylamines (6).26 A round-
bottomed flask of 50 mL was charged with Pd(OAc)2
(0.12 mmol, 0.027 g), (ꢄ)-BINAP (0.12 mmol, 0.0747 g)
or XANTPHOS (0.12 mmol, 0.069 g), and toluene

K. T. J. Loones et al. / Tetrahedron 63 (2007) 3818–3825
3823
(10 mL). The obtained mixture was flushed with N2 for
10 min under magnetic stirring. Meanwhile a round-bot-
tomed flask of 100 mL was charged with 2-chloro-3-iodo-
pyridine (3.0 mmol, 0.722 g), amidine (2) (3.6 mmol), and
cesium carbonate (12 mmol, 3.910 g). To this mixture, the
preformed Pd(II) precatalyst was added under a N2 flow.
The flask of 50 mL was subsequently rinsed with toluene
(2ꢂ10 mL). Then the resulting mixture was flushed with
N2 for 5 min and heated at reflux (oil bath temperature:
120 ꢀC) (N2 atmosphere) under vigorous magnetic stirring.
After cooling down the reaction mixture to room tempera-
ture, dichloromethane (20 mL) was added and the suspen-
sion was filtered over a glass filter. The filter was rinsed
well with dichloromethane (130 mL) and the filtrate evapo-
rated under reduced pressure. The residue was purified by
flash column chromatography on silica gel using dichloro-
methane/methanol (99/1) as the eluent.
(400 MHz, CDCl3): 8.81 (1H, dd, J¼8.1, 1.8 Hz), 8.29
(1H, d, J¼1.5 Hz), 8.18 (1H, dd, J¼2.6, 1.5 Hz), 8.12
(1H, d, J¼2.6 Hz), 8.04 (1H, dd, J¼4.6, 1.8 Hz), 7.26 (1H,
dd, J¼8.1, 4.6 Hz), 7.1 (1H, s, NH); 13C NMR (100 MHz,
CDCl3): 150.9, 141.9, 141.3, 139.7, 136.3, 135.0,
133.5, 126.7, 123.2; MS (ESI): 207, 189, 171; HRMS
(ESI) for C9H8N435Cl [M+H]+: calcd: 207.0954, found:
207.0430.
4.1.1.5. N-(2-Chloropyridin-3-yl)pyridazin-3-amine
(6e). The general procedure was followed using 3-aminopyr-
idazine 2e (3.6 mmol, 0.342 g) as amine and XANTPHOS as
ligand. Reaction time: 8 h; white solid; mp: 153 ꢀC; 1H NMR
(400 MHz, CDCl3): 8.88 (1H, dd, J¼8.2, 1.5 Hz), 8.81 (1H,
br d, J¼4.6 Hz), 8.08 (1H, dd, J¼4.6, 1.5 Hz), 7.40 (1H, dd,
J¼9.0, 4.6 Hz), 7.29 (1H, dd, J¼8.2, 4.6 Hz), 7.07 (1H, dd,
J¼9.0, 1.1 Hz); 13C NMR (100 MHz, CDCl3): 156.2, 145.8,
142.8, 140.7, 133.0, 128.7, 128.5, 123.4, 117.1; MS (ESI):
207, 171, 144; HRMS (ESI) for C9H8N435Cl [M+H]+: calcd:
207.0954, found: 207.0430.
4.1.1.1.
N-(2-Chloropyridin-3-yl)pyridin-2-amine
(6a). The general procedure was followed using 2-aminopyr-
idine 2a (3.6 mmol, 0.338 g) as amine and rac-BINAP as li-
gand. Reaction time: 8 h; white solid; mp: 117 ꢀC; 1H NMR
(400 MHz, CDCl3): 8.76 (1H, dd, J¼8.0, 1.7 Hz), 8.26 (1H,
dd, J¼5.0, 1.9 Hz), 7.97 (1H, dd, J¼4.6, 1.7 Hz), 7.58 (1H,
ddd, J¼8.8, 6.7, and 1.9 Hz), 7.21 (1H, dd, J¼8.0, 4.6 Hz),
6.92 (1H, s, NH), 6.87 (1H, dd, J¼6.7, 5.0 Hz), 6.82 (1H,
d, J¼8.8 Hz); 13C NMR (100 MHz, CDCl3): 154.4, 148.1,
141.0, 139.6, 138.0, 134.8, 126.3, 123.2, 116.9, 111.5; MS
(ESI): 206, 170, 143; HRMS (ESI) for C10H9N335Cl
[M+H]+: calcd: 206.0485, found: 206.0860.
4.1.2. General procedure I for the attempted ring closure
of N-(3-bromopyridin-2-yl)azaheteroarylamines (3) or
N-(2-chloropyridin-3-yl)azaheteroarylamines (6) via
SNAr. In a 10 mL microwave vial (Discover system) 3
(0.5 mmol) or
6 (0.5 mmol) and cesium carbonate
(2.0 mmol, 0.652 g) (Aldrich, 99%) were weighed. DME
(5 mL) was added and the resulting mixture was heated (oil
bath temperature: 160 ꢀC) with vigorous stirring for 24 h.
After cooling down to room temperature the reaction mixture
was filtered over a glass filter and (a) rinsed with dichlorome-
thane (150 mL) for compounds 4b, 4c, 7a, 7b, and 7c or (b)
rinsed with 7 N NH3 in MeOH (75 mL) and dichloromethane
(50 mL) for compounds 4e, 7d, and 7e. The solvent was re-
moved under reduced pressure and the residue was purified
by column chromatography on silica gel using dichloro-
methane/methanol (99:1) as the eluent to recover 3 and 6
and dichloromethane/methanol (97:3) to isolate 4 and 7.
4.1.1.2.
N-(2-Chloropyridin-3-yl)quinolin-2-amine
(6b). The general procedure was followed using 2-aminoqui-
noline 2b (3.6 mmol, 0.520 g) as amine and rac-BINAP as li-
gand. Reaction time: 4 h; white solid; mp: 136 ꢀC; 1H NMR
(400 MHz, CDCl3): 9.36 (1H, dd, J¼8.2, 1.7 Hz), 8.02 (1H,
dd, J¼4.7, 1.7 Hz), 8.01 (1H, d, J¼8.7 Hz), 7.86 (1H, d,
J¼8.3 Hz), 7.69 (1H, d, J¼8.0 Hz), 7.64 (1H, dd, J¼8.3,
7.0 Hz), 7.38 (1H, dd, J¼8.0, 7.0 Hz), 7.31 (1H, dd, J¼8.2,
4.7 Hz), 7.18 (1H, s, NH), 6.95 (1H, d, J¼8.7 Hz); 13C
NMR (100 MHz, CDCl3): 152.5, 146.8, 141.2, 139.3,
138.1, 134.3, 130.1, 127.5, 127.2, 127.0, 124.4, 124.2,
123.2, 113.5; MS (ESI): 256, 220; HRMS (ESI) for
C14H11N335Cl [M+H]+: calcd: 256.0642, found: 256.0363.
4.1.2.1. Pyrido[20,30:4,5]imidazo[1,2-a]quinoline (4b).
General procedure I was followed using 3b (0.50 mmol,
0.150 g). Yield: 0.058 g (53%); the characterization data
obtained for 4b are identical to those previously reported.17
4.1.2.2.
(4c). General procedure
Pyrido[20,30:4,5]imidazo[2,3-a]isoquinoline
was followed using 3c
4.1.1.3. N-(2-Chloropyridin-3-yl)isoquinolin-1-amine
(6c). The general procedure was followed using 1-aminoiso-
quinoline 2c (3.6 mmol, 0.520 g) as amine and rac-BINAP
I
(0.50 mmol, 0.150 g). Yield: 0.101 g (92%); the character-
ization data obtained for 4c are identical to those previously
reported.17
1
as ligand. Reaction time: 4 h; white solid; mp: 108 ꢀC; H
NMR (400 MHz, CDCl3): 9.12 (1H, br d, J¼8.1 Hz), 8.11
(1H, d, J¼5.7 Hz), 8.05 (1H, dd, J¼4.7, 1.6 Hz), 8.02 (1H,
d, J¼8.4 Hz), 7.81 (1H, d, J¼8.0 Hz), 7.72 (1H, dd,
J¼8.0, 7.0 Hz), 7.64 (1H, dd, J¼8.4, 7.0 Hz), 7.29 (1H,
dd, J¼8.1, 4.7 Hz), 7.25 (1H, br d, J¼6.3 Hz, not resolved);
13C NMR (100 MHz, CDCl3): 151.0, 141.2, 140.2, 139.6,
137.4, 134.3, 120.3, 127.7, 127.3 (2*C), 123.2, 121.1,
119.2, 114.9; MS (ESI): 256, 220, 128; HRMS (ESI) for
C14H11N335Cl [M+H]+: calcd: 256.0642, found: 256.0639.
4.1.2.3.
(4e). General procedure
(0.50 mmol, 0.125 g). Yield: 0.109 g (87%); the character-
ization data obtained for 4e are identical to those previously
reported.17
Pyrido[20,30:4,5]imidazo[1,2-b]pyridazine
was followed using 3e
I
4.1.2.4. Pyrido[30,20:4,5]imidazo[1,2-a]pyridine (7a).
General procedure I was followed using 6a (0.50 mmol,
0.103 g). Yield: 0.003 g (3%); the characterization data
obtained for 7a are identical to those previously reported.16
4.1.1.4.
N-(2-Chloropyridin-3-yl)pyrazin-2-amine
(6d). The general procedure was followed using aminopyr-
azine 2d (3.6 mmol, 0.342 g) as amine and rac-BINAP as li-
gand. Reaction time: 8 h; white solid; mp: 108 ꢀC; 1H NMR
4.1.2.5. Pyrido[30,20:4,5]imidazo[1,2-a]quinoline (7b).
General procedure I was followed using 6b (0.50 mmol,

3824
K. T. J. Loones et al. / Tetrahedron 63 (2007) 3818–3825
0.128 g). Yield: 0.046 g (42%); the characterization data
obtained for 7b are identical to those previously reported.16
4.1.3.8.
Pyrido[20,30:4,5]imidazo[2,3-a]isoquinoline
(4c). General procedure II was followed using 3c
(0.50 mmol, 0.150 g). Yield: 0.012 g (11%).
4.1.2.6.
(7c). General procedure
Pyrido[30,20:4,5]imidazo[2,1-a]isoquinoline
was followed using 6c
I
4.1.3.9. Pyrido[20,30:4,5]imidazo[1,2-b]pyrazine (4d).
General procedure II was followed using 3d (0.50 mmol,
0.125 g). Yield: 0 g (0%).
(0.50 mmol, 0.128 g). Yield: 0.106 g (96%); the character-
ization data obtained for 7c are identical to those previously
reported.16
4.1.3.10.
Pyrido[20,30:4,5]imidazo[1,2-b]pyridazine
(4e). General procedure II was followed using 3e
(0.50 mmol, 0.125 g). Yield: 0 g (0%).
4.1.2.7. Pyrido[30,20:4,5]imidazo[1,2-a]pyrazine (7d).
General procedure I was followed using 6d (0.50 mmol,
0.103 g). Yield: 0.026 g (31%); the characterization data
obtained for 7d are identical to those previously reported.16
Acknowledgements
4.1.2.8. Pyrido[30,20:4,5]imidazo[1,2-b]pyridazine (7e).
General procedure I was followed using 6a (0.50 mmol,
0.103 g). Yield: 0.061 g (72%); the characterization data
obtained for 7e are identical to those previously reported.16
The authors acknowledge financial support from the Univer-
sity of Antwerp (NOI BOF UA 2005) and the Flemish Gov-
ernment enabling the purchase of NMR and supercomputing
facilities (Impulsfinanciering van de Vlaamse Overheid voor
Strategisch Basisonderzoek PFEU 2003) as well as the tech-
nical assistance of G. Rombouts and P. Franck. We would
like to thank Prof. C. Stevens and Prof. P. Bultinck for help-
ful discussions, Dr. G. Mignani of Rhodia for the donation of
4.1.3. General procedure II for the attempted ring closure
of N-(2-chloropyridin-3-yl)azaheteroarylamines (6) or N-
(3-bromopyridin-2-yl)azaheteroarylamines (3) via SNAr.
In a 25 mL flask 6 (0.5 mmol) or 3 (0.5 mmol) and cesium
carbonate (2.0 mmol, 0.652 g) (Aldrich, 99%) were weighed.
Toluene (5 mL) was added and the resulting mixture was
heated (oil bath temperature: 120 ꢀC) with vigorous stirring
for 17 h. After cooling down to room temperature the reaction
mixture was filtered over a glass filter and (a) rinsed with di-
chloromethane (150 mL) for compounds 4b, 4c, 7a, 7b, and
7c or (b) rinsed with 7 N NH3 in MeOH (75 mL) and di-
chloromethane (50 mL) for compounds 4e, 7d, and 7e. The
solvent was removed under reduced pressure and the residue
was purified by column chromatography on silica gel using
dichloromethane/methanol (99:1) as the eluent to recover 3
and 6 and dichloromethane/methanol (97:3) to isolate 4 and 7.
ꢀ
rac-BINAP and CEPROMA (Prof. F. Lemiere, W. Van
Dongen) for HRMS.
References and notes
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General procedure II was followed using 6b (0.50 mmol,
0.128 g). Yield: 0.002 g (2%).
4.1.3.3.
Pyrido[30,20:4,5]imidazo[2,1-a]isoquinoline
(7c). General procedure II was followed using 6c
(0.50 mmol, 0.128 g). Yield: 0.109 g (99%).
4.1.3.4. Pyrido[30,20:4,5]imidazo[1,2-a]pyrazine (7d).
General procedure II was followed using 6d (0.50 mmol,
0.103 g). Yield: 0 g (0%).
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4.1.3.5.
Pyrido[30,20:4,5]imidazo[1,2-b]pyridazine
(7e). General procedure II was followed using 6e
(0.50 mmol, 0.103 g). Yield: 0.003 g (3%).
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1626.
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125–146.
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General procedure II was followed using 3a (0.50 mmol,
0.125 g). Yield: 0 g (0%).
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G. L. F. Chem. Commun. 2004, 2466–2467.
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4.1.3.7. Pyrido[20,30:4,5]imidazo[1,2-a]quinoline (4b).
General procedure II was followed using 3b (0.50 mmol,
0.150 g). Yield: 0 g (0%).
18. In our previous publication (Ref. 17) an incorrect yield for
the attempted ring closure of 3e via SNAr was published. The
correct yield is 87%.

K. T. J. Loones et al. / Tetrahedron 63 (2007) 3818–3825
3825
19. The N-(2-chloropyridin-3-yl)azaheteroarylamines are synthe-
sized using the conditions for the synthesis of dipyrido[1,2-
a:30,20-d]imidazole and its benzo and aza analogues (see
Ref. 16), only the reaction time was shortened.
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