Synthesis of new tetracyclic azaheteroaromatic cores via auto-tandem Pd-catalyzed and one-pot Pd- and Cu-catalyzed double C-N bond formation

Article abstract of DOI:10.1016/j.tet.2010.06.038

Inter- and intramolecular transition metal-catalyzed amination of 2-chloro-3-iodopyridine and 2,3-dibromopyridine, respectively, with benzodiazinamines yielded six hitherto unknown tetracyclic azaheteroaromatic cores. C-N bond formation was achieved via auto-tandem (Pd-catalyst) as well as one-pot (sequential use of a Pd- and Cu-catalyst) catalysis.

Full text of DOI:10.1016/j.tet.2010.06.038

Tetrahedron 66 (2010) 6958e6964
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of new tetracyclic azaheteroaromatic cores via auto-tandem
Pd-catalyzed and one-pot Pd- and Cu-catalyzed double CeN bond formation
*
Tom R.M. Rauws, Claudio Biancalani, Joris W. De Schutter, Bert U.W. Maes
Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Inter- and intramolecular transition metal-catalyzed amination of 2-chloro-3-iodopyridine and 2,3-di-
bromopyridine, respectively, with benzodiazinamines yielded six hitherto unknown tetracyclic azahe-
teroaromatic cores. CeN bond formation was achieved via auto-tandem (Pd-catalyst) as well as one-pot
(sequential use of a Pd- and Cu-catalyst) catalysis.
Received 18 March 2010
Received in revised form 11 June 2010
Accepted 14 June 2010
Available online 18 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Amination
Palladium
Copper
Rearrangement
Nitrogen heterocycles
One-pot catalysis
1. Introduction
construct nitrogen-containing heterocyclic skeletons.22e27 One of
the challenges in this research field is the development of tandem or
Aryl amines are important entities with several important ap-
plications (pharmaceuticals, agrochemicals, polymers and mate-
rials for the electronics and xerographic industry).1e6 The most
important method available to synthesize these aryl amines is the
Pd-catalyzed amination, autonomously discovered by the groups of
Buchwald and Hartwig in the mid 1990s.7,8 Over the years the
BuchwaldeHartwig reaction has made tremendous progress, es-
pecially by the refinement of the ligands.9e16 More recently a revival
of the Cu-catalyzed amination has occurred via the introduction of
ligands through which the harsh reaction conditions, required for
the Ullmann-type CeN bond formation, could be avoided.6,17e21
Meanwhile, Pd- and Cu-catalyzed aminations have been used to
one-pot metal-catalyzed protocols for scaffold design in which
several bonds can be formed in one reaction step.28,29 Using such
processes relatively complex heterocyclic structures can be
obtained starting from easily available building blocks. In 2004 our
group reported the first regioselective auto-tandem inter- and
intramolecular Pd-catalyzed double amination of 2-chloro-3-iodo-
pyridine (1) with a set of benzoazinamines and (di)azinamines
(Scheme 1).30e32 More recently, regioisomers (4) of dipyrido[1,2-
a:30,20-d]imidazole and its benzo and aza analogues (3) were
obtained via an orthogonal (Pd- and Cu-catalyst) regioselective
inter- and intramolecular double amination on 2,3-dibromopyr-
idine (2) (Scheme 1).31,33
R2
R1
N
R3
Pd(OAc)2
Pd2dba3
Xantphos
CuI
Xantphos
R3
R4
X
Y
R4
R2
R1
N
(N)
+
(N)
N
N
R4
R3
N
N
(N)
N
N
H2N
Cs2CO3
toluene
reflux
Cs2CO3
DME
160°C
R1
R2
3
4
1: X= I, Y= Cl
2: X=Y= Br
Scheme 1. Schematic overview of previously reported auto-(left) and orthogonal (right) tandem double aminations.
In this article we report a further exploration of the scope of the
transition metal-catalyzed double amination of dihalopyridines
* Corresponding author. Fax: þ32 32653233; e-mail address: bert.maes@ua.ac.be
(B.U.W. Maes).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.038

T.R.M. Rauws et al. / Tetrahedron 66 (2010) 6958e6964
6959
using hitherto unexplored benzodiazinamines (phtalazin-1-amine
(5a), quinazolin-4-amine (5b) and quinoxalin-2-amine (5c)) as
coupling partners.
In accordance with our previous work we then tried to use CuI in
combination with a higher reaction temperature to induce the ring
closure reaction of 7b.33 When successful an orthogonal tandem
process towards 6b could be attempted. Treating 7b with CuI and
base at high temperature gave indeed the expected pyrido
[30,20:4,5]imidazo[1,2-c]quinazoline (6b) in 55% yield. Surprisingly,
we also isolated 37% of regioisomeric pyrido[20,30:4,5]imidazo[2,1-
a]quinazoline (8b) (Scheme 4), which we actually envisioned
(Section 2.3) to make by double aminating of 2 with 5b.
A control experiment without the addition of CuI showed also
transformation to 6b and its regioisomer 8b, this time in 44% and
42%, respectively. This shows that no copper is necessary to obtain
8b. The formation of 8b can be rationalized by a Smiles type rear-
rangement where the negative charge of the N-(2-chloropyridin-3-
yl)quinazolin-4-amide is delocalized onto the pyrimidine N-3,
which subsequently performs an ipso-substitution on C-3 of the
pyridine ring.36,37 The hereby generated anion gives access to 8b via
a classical addition elimination mechanism on C-2 of the pyridine
ring (Scheme 5).
2. Results and discussion
2.1. Synthesis of the benzodiazinamines (5)
The required benzodiazinamines phtalazin-1-amine (5a), qui-
nazolin-4-amine (5b) and quinoxalin-2-amine (5c) were not com-
mercially available and thus had to be synthesized. Compound 5a
was obtained by dehalogenation of 4-chlorophtalazin-1-amine, 5b
via ONSH (oxidative nucleophilic substitution of hydrogen) on
quinazoline with liquid ammonia in the presence of KMnO4 as
oxidant34 and 5c via aminolysis of 2-chloroquinoxaline.
2.2. Transition metal-catalyzed double amination of 2-
chloro-3-iodopyridine (1) with benzodiazinamines (5)
The previously developed reaction conditions for the auto-tan-
dem Pd-catalyzed double amination of 2-chloro-3-iodopyridine (1)
with (di)azinamines and benzoazinamines (4% Pd(OAc)2, 4.4%
Xantphos, 4 equiv Cs2CO3, toluene, reflux)30 were applied for
benzodiazinamine 5a. The desired pyrido[30,20:4,5]imidazo[2,1-a]
phthalazine (6a) scaffold could be obtained in 80% yield
(Scheme 2). Based on the reaction of 1 with isoquinolin-1-amine
previously reported by us, a ring closure mechanism involving
a SNAr rather than a transition metal-catalyzed CeN bond forma-
tion for the intramolecular amination cannot be excluded.35
H
N
N
N
N
N
N
N
N
N
N
Cl
N
Cl
N
Cl
7b
N
N
N
N
N
N
N
N
Cl N
N
N
N
Cl
8b
NH2
4% Pd(OAc)2
I
N
N
Scheme 5. Smiles rearrangement of N-(2-chloropyridin-3-yl)quinazolin-4-amine (7b)
followed by SNAr.
4.4% Xantphos
N
N
+
N
N
Cl
Cs2CO3
toluene
reflux
N
1
5a
Since the intramolecular amination reaction at high temper-
ature gave an undesired Smiles rearrangement we turned our
attention to the use of ligands for the copper catalyst in order to
achieve ring closure of 7b at a lower temperature. Unfortunately,
previous results of our laboratory indicated that a CuI/ligand
catalyst system at lower temperature hampered an orthogonal
tandem approach starting from 2 since the copper species partly
inhibits the Pd-catalyzed intermolecular amination reaction.33 In
order to circumvent this inhibitory action of copper catalyst on
the palladium catalyzed amination we attempted to develop
a one-pot approach consisting of a Pd-catalyzed intermolecular
amination step followed by the addition of the copper catalyst,
upon completion of the first amination, in order to allow the
intramolecular amination reaction. Interestingly, repeating the
Cu-catalyzed ring closure reaction on 7b with rac, trans-cyclo-
hexane-1,2-diamine as ligand, in a Cu/L ratio of 1:2, indeed
allowed a ring closure at lower temperature without rearrange-
ment as a full conversion to pyrido[30,20:4,5]imidazo[1,2-c]qui-
nazoline (6b) was achieved within 8 h at reflux. Gratifyingly, upon
combining the Pd-catalyzed intermolecular amination presented
in Scheme 3, with DME instead of toluene as solvent, with this
6a
17h
80%
Scheme 2. Auto-tandem Pd-catalyzed double amination on 2-chloro-3-iodopyridine
(1) using phtalazin-1-amine (5a).
However, applying the same reaction conditions for the cou-
pling of 1 with 5b, no pyrido[30,20:4,5]imidazo[1,2-c]quinazoline
(6b) was formed. Instead, 92% of N-(2-chloropyridin-3-yl)quina-
zolin-4-amine (7b) was isolated (Scheme 3). Neither an increase of
the loading of Pd from 4 to 6% nor the changing of the Pd/ligand
ratio to 1:2 did affect the outcome.
NH2
H
N
4% Pd(OAc)2
4.4% Xantphos
I
N
+
N
N
Cs2CO3
toluene
reflux
Cl
N
Cl
N
N
1
5b
7b
17h
92%
Scheme 3. Attempted auto-tandem Pd-catalyzed double amination on 2-chloro-3-
iodopyridine (1) using quinazolin-4-amine (5b).
N
H
N
N
10% CuI
N
N
N
+
Cs2CO3
N
N
N
N
N
Cl
DME
160°C
8h
N
7b
6b
8b
37%
55%
Scheme 4. Ring closure reaction of N-(2-chloropyridin-3-yl)quinazolin-4-amine (7b) using CuI at high temperature.

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T.R.M. Rauws et al. / Tetrahedron 66 (2010) 6958e6964
Cu-catalyzed intramolecular amination reaction pyrido[30,20:4,5]
imidazo[1,2-c]quinazoline (6b) was obtained as the sole reaction
product in 85% yield (Scheme 6).
Table 1
Intermolecular Pd-catalyzed amination on 2 with benzodiazinamines 5
4% Pd2dba3
Br
Br
8.8% Xantphos
NH2
+
Ar-NH2
Ar
4% Pd(OAc)2
4.4% Xantphos
10% CuI
20% ligand
Cs2CO3
DME
N
N
H
N
Br
I
N
N
N
+
reflux
17h
2
5
9
reflux
8h
Cs2CO3
DME
reflux
17h
N
N
Cl
N
N
1
5b
6b
85%
ligand: rac. trans -cyclohexane-1,2-diamine
Benzodiazinamine 5
Product 9
Yield
Br
N
NH2
Scheme 6. One-pot Pd-catalyzed intermolecular and Cu-catalyzed intramolecular
amination reaction of 2-chloro-3-iodopyridine (1) with quinazolin-4-amine (5b).
N
9a
76%
N
N
5a
N
N
N
H
For the reaction of 1 with quinoxalin-2-amine (5c) we initially
tested the auto-tandem double aminationprotocol, which allowed to
access 6a via coupling of 1 with 5a (Scheme 2). Only a partial con-
version to the desired pyrido[30,20:4,5]imidazo[1,2-a]quinoxaline 6c
(13% isolated yield) along with 86% of the intermediate
intermolecular amination reaction product 7c was obtained
(Scheme 7). Switching toluene to DME as solvent gave a full conver-
sion to pyrido[30,20:4,5]imidazo[1,2-a]quinoxaline (6c) in 17 h and an
isolated yield of 82% (Scheme 7). As SNAr reactions are promoted in
more polar solvents the ring closure reaction of 7c is therefore most
probably not Pd-catalyzed and a tandem reaction involving a Pd-
catalyzed aminationdSNAr reaction sequence rather than an auto-
tandem Pd-catalyzed double amination mechanistically occurs.35
NH2
Br
N
N
49% (24 h)
9b
N
5b
(30% 2)
N
H
N
Br
N
N
9c
5c
86%
N
N
H
N
H2N
N
Scheme 7. Auto-tandem Pd-catalyzed double amination on 2-chloro-3-iodopyridine (1) using quinoxalin-2-amine (5c).
2.3. Transition metal-catalyzed double amination of 2,3-
dibromopyridine (2) with benzodiazinamines (5)
dehalogenation of 9b. (Table 2) Fortunately, increasing the loading to
6% Pd allowed a full conversion of 2 into 9b in 17 h and a subsequent
addition of copper catalyst gave pyrido[20,30-4,5]imidazo[1,2-c]qui-
nazoline (8b) in an excellent isolated yield (Scheme 9).
For the coupling of 2,3-dibromopyridine (2) with (di)azinamines
and benzoazinamines we previously developed an orthogonal
Pd-catalyzed inter- and Cu-catalyzed intramolecular amination
protocol (2% Pd2(dba)3, 4.4% Xantphos, 10% CuI, DME) requiring
a high reaction temperature (oil bath temperature: 160 ꢀC).33 Tak-
ing into account the result obtained for substrate 1, we decided to
immediately investigate the possibility of the use of the lower
temperature one-pot protocol involving a Pd and Cu-catalyst in
a sequential manner (Section 2.2).
Table 2
Dehalogenation of N-(3-bromopyridin-2-yl)benzodiazinamines 9
Pd-catalyzed amination conditions previously used to regiose-
lectively functionalize 2 in C-2 yielded N-(3-bromopyridin-2-yl)
phthalazin-1-amine (9a) in good yield (Table 1). In order to check
that the amination reaction had indeed taken place at C-2 of the
pyridine ring, 9a was dehalogenated using Pd/C and H2. The 1H
NMR coupling pattern of this compound confirmed the C-2 regio-
selectivity (Table 2).
N-(3-bromopyridin-2-yl)
benzodiazinamine
Product 10
Yield
99%
Subsequently, we attempted to use this catalyst system in a one-
pot protocol. Therefore, after 17 h intermolecular amination CuI/rac,
trans-cyclohexane-1,2-diamine was added to the reaction mixture in
order to induce the intramolecular amination step. In this way pyrido
[20,30-4,5]imidazo[2,1-a]phthalazinewasobtained in65% (Scheme 8).
For the coupling of 2 with 5b we again first verified if the Pd-ca-
talyst allowed full conversion to N-(3-bromopyridin-2-yl)quinazo-
lin-4-amine (9b) within 17 h. Unfortunately, this was not the case
andan increase of thereactiontime to 24 h did not solve this problem
as a work-up gave only 49% 9b and a recovery of 30% of substrate 2.
(Table 1) Again, C-2 substitution could be confirmed via
50%
50%

T.R.M. Rauws et al. / Tetrahedron 66 (2010) 6958e6964
6961
NH2
N
N
4% Pd2dba3
10% CuI
Br
Br
8.8% Xantphos
20% ligand
N
N
+
N
Cs2CO3
DME
reflux
17h
reflux
8h
N
N
2
8a
5a
65%
ligand: rac. trans -cyclohexane-1,2-diamine
Scheme 8. One-pot Pd-catalyzed intermolecular and Cu-catalyzed intramolecular amination reaction of 2,3-dibromopyridine (2) with phthalazin-1-amine (5a).
N
NH2
N
6% Pd2dba3
10% CuI
Br
Br
13% Xantphos
N
N
20% ligand
N
+
Cs2CO3
DME
reflux
17h
reflux
8h
N
N
8b
93%
ligand: rac. trans -cyclohexane-1,2-diamine
2
5b
Scheme 9. One-pot Pd-catalyzed intermolecular and Cu-catalyzed intramolecular amination reaction of 2,3-dibromopyridine (2) with quinazolin-4-amine (5b).
For the coupling of 2 with 5c, the same procedure was fol-
lowed as for 5a and 5b. In this case there was no need to
increase the palladium loading for the intermolecular amination
and N-(3-bromopyridin-2-yl)quinoxalin-2-amine (9c) could be
isolated in 86%. (Table 1) Dehalogenation of 9c confirmed C-2
functionalization through analysis via 1H NMR. (Table 2) Finally,
one-pot Pd-catalyzed intermolecular and Cu-catalyzed intra-
molecular amination reaction of 2 with 5c yielded pyrido[30,20-
4,5]imidazo[1,2-a]quinoxaline (8c) in 99% yield (Scheme 10).
4. Experimental section
4.1. General information
All melting points were determined on a Büchi apparatus and
are uncorrected. The 1H NMR and 13C NMR spectra were recorded
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
4% Pd2dba3
10% CuI
N
N
Br
Br
N
N
8.8% Xantphos
20% ligand
+
H2N
Cs2CO3
DME
reflux
8h
N
N
N
8c
reflux
17h
2
5c
99%
ligand: rac. trans -cyclohexane-1,2-diamine
Scheme 10. One-pot Pd-catalyzed intermolecular and Cu-catalyzed intramolecular amination reaction of 2,3-dibromopyridine (2) with quinazolin-2-amine (5c).
3. Conclusions
the following abbreviations: br for broad, d for doublet, t for triplet,
m for 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
It appears that the previously developed auto-tandem double
amination protocol for the coupling of 1 with benzoazinamines and
(di)azinamines cannot be generally applied for benzodiazinamines.
Attempts to use an orthogonal (Pd and Cu-catalyst) tandem double
amination protocol, as developed for the coupling of 2 with ben-
zoazinamines and (di)azinamines, revealed unexpected rear-
rangement problems due to the high temperature applied. The use
of rac, trans-cyclohexane-1,2-diamine as ligand for the copper
catalyst allowed to work at a lower reaction temperature, but
required the performance of the intermolecular and intramolecular
reaction in a sequential manner. Application of the two catalysts in
a one-pot fashion was tested on 1 and 2 with the benzodiazin-
amines phtalazin-1-amine, quinazolin-4-amine and quinoxalin-2-
amine (5) and allowed the synthesis of six new nitrogen-containing
heterocyclic scaffolds of significant complexity in a short, practical
and efficient way.
(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
(Waters-Micromass). Accurate mass data were acquired on a Q-TOF
2 mass spectrometer (Waters-Micromass) equipped with a stan-
dard electrospray ionisation (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 [MþH]þ, a solution of poly-
ethylene glycol 300 in CH3OH/H2O with 1 mmol ammonium ace-
tate, was added just before the mass spectrometer (at a rate of
1 mL/min) to the mobile phase. The calculated masses of PEG
[MþH]þ and [MþNH4]þ ions were used as internal calibrant (lock
mass). Xantphos (9,9-dimethyl-4,5-bis(diphenylphosphanyl)-9H-
xanthene) and Cs2CO3 (99%) were purchased from Aldrich, Pd

6962
T.R.M. Rauws et al. / Tetrahedron 66 (2010) 6958e6964
(OAc)2, Pd2(dba)3 and DME from Acros. 4-Chlorophthalazin-1-
amine was prepared following a literature procedure.38 2-Chloro-3-
iodopyridine is commercially available from Lancaster. It can also
be synthesized starting from 2-chloropyridin-3-amine (Acros) via
diazotization and subsequent reaction with KI.39 All commercial
reagents were used without extra purification. Column chroma-
5 min and heated at reflux under vigorous magnetic stirring for 17 h.
After cooling down to room temperature, the mixture was filtered,
rinsed well with 150 mL CH2Cl2 and evaporated to dryness. The crude
product was purified by column chromatography on silicagel.
4.3. General procedure B for the synthesis of N-(pyridin-2-yl)
tography was performed on Kieselgel 60 (ROCC SI 1721, 40e60
mm).
benzodiazinamines (10)
4.1.1. Phthalazin-1-amine (5a). In Parr-apparatus flask 4-
a
In a Parr-apparatus flask N-(3-bromopyridin-2-yl)benzodiazin-
amine (9) (0.5 mmol), Pd/C 10% (0.050 g) and Na2CO3 (1.1 mmol)
were brought. Ethanol (15 mL) was added and the mixture was
flushed with argon. Then the mixture was hydrogenated under a H2
pressure of 24 psi in a Parr apparatus for 3 h. The mixture was
subsequently filtered and rinsed with 20 mL of CH2Cl2, evaporated
to dryness and purified by column chromatography on silicagel
using CH2Cl2 as eluent.
chlorophthalazin-1-amine (1 mmol, 0.179 g), NaOH (2 mmol,
0.080 g) and Pd/C 10% w/w (0.020 g) were weighed off. MeOH
(30 mL) was added and the resulting mixture was shaken in the
Parr hydrogenation apparatus for 3 h under a H2 pressure of 23 psi.
The mixture was subsequently purified by filtration over a filter
paper, evaporated to dryness and purified via column chromatog-
raphy on silicagel using CH2Cl2/MeOH (85/15) as the eluent. Yield:
80%; 0.116 g as a white fluffy solid.
1H NMR (400 MHz, CDCl3): 8.89 (s, 1H, H4), 8.25 (br d, J¼6.4 Hz,
1H, H5 or H8), 7.88 (m, 3H, H5 or H8, H6, H7), 6.98 (br s, 2H, NH2).
4.3.1. N-(3-Bromopyridin-2-yl)phthalazin-1-amine (9a). The gen-
eral procedure A was followed using phthalazin-1-amine (5a)
(1.8 mmol, 0.264 g). Eluent: CH2Cl2 to CH2Cl2/MeOH (98/2). Yield:
76%, 0.343 g as a beige solid.
4.1.2. Quinazolin-4-amine (5b)34. To
a four-necked flame-dried
250 mL flask 2 glass tubes, each connected bya pieceofrubbertubing,
and an oil bubbler were connected. In the two glass tubes quinazoline
(2 mmol, 0.2602 g) and KMnO4 (7 mmol, 1.1062 g) were weighed off.
Ammonia was condensed in the 250 mL flask by cooling the flask in
an acetone/dry ice bath under magnetic stirring while passing
a stream of ammonia (generated by gently adding aqueous ammonia
on NaOH) through the apparatus built. When approximately 30 mL of
NH3 was condensed, quinazoline was added in one portion and stir-
ring was continued for 5 min, then the KMnO4 was added in small
portions over a 10 min period. Subsequently, the cooling bath was
taken away, the flask wrapped in aluminium foil and stirring was
continued until all of the NH3 had evaporated. Then silicagel (1 g) was
added along with 30 mL of MeOH. The resulting slurry is evaporated
in vacuo and brought on a silicagel column for chromatography using
CH2Cl2/MeOH (95/5) until all the undesired quinazolin-4(3H)-one
had come off and then the eluent composition was changed to
CH2Cl2/MeOH (85/15). Yield: 76%; 0.220 g as a white solid.
1H NMR (400 MHz, CDCl3):
d
15.11 (br s, 1H, NH), 8.87 (br d,
0
J¼7.2 Hz, 1H, H8), 8.29 (dd, J¼4.9, 1.6 Hz, 1H, H6 ), 8.21 (s, 1H, H4),
0
7.95 (dd, J¼7.7, 1.7 Hz, 1H, H4 ), 7.79 (m, 2H, H6 and H7), 7.64 (br d,
J¼6.9 Hz, 1H, H5), 6.78 (dd, J¼7.7, 4.9 Hz, 1H, H5 ); 13C NMR
0
(100 MHz, CDCl3):
d 158.3, 149.5, 144.6, 141.1, 140.2, 132.6, 132.2,
129.4, 127.9, 126.3, 126.0, 118.2, 117.5. [MþH]þ calcd: 301.0089,
found: 301.0098. Mp: 167e169.7 ꢀC.
4.3.2. N-(Pyridin-2-yl)phthalazin-1-amine (10a). The general pro-
cedure B was followed using N-(3-bromopyridin-2-yl)phthalazin-
1-amine (9a). Yield: 99%, 0.110 g as white plates.
1H NMR (400 MHz, CDCl3):
d
15.45 (br s, 1H, NH), 8.72 (d,
0
J¼6.1 Hz, 1H, H5 or H8), 8.36 (d, J¼5.0 Hz, 1H, H6 ), 8.15 (s, 1H, H4),
0
0
7.70 (m, 4H, H4 , H5 or H8, H6 and H7), 7.32 (d, J¼8.0 Hz,1H, H3 ), 6.92
(t, J¼5.8 Hz, 1H, H5 ); 13C NMR (100 MHz, CDCl3):
d 162.0, 149.2,
0
145.6, 139.5, 137.5, 132.2, 131.9, 129.1, 127.8, 126.0, 125.6, 122.2, 117.1.
Mp: >300 ꢀC. [MþH]þ calcd: 223.0984, found: 223.0984.
1H NMR (400 MHz, DMSO-d6): 8.38 (s, 1H, H2), 8.20 (d, J¼8.3 Hz,
1H, H5 or H8), 7.75 (ddd, J¼8.3, 6.9, 1.3 Hz, 1H, H6 or H7), 7.71 (br s,
2H, NH2), 7.65 (d, J¼7.6 Hz, 1H, H5 or H8), 7.48 (ddd, J¼8.2, 6.9,
1.2 Hz, 1H, H6 or H7).
4.3.3. N-(3-Bromopyridin-2-yl)quinazolin-4-amine (9b). The gen-
eral procedure A was followed using 4-aminoquinazoline (5b)
(1.8 mmol, 0.2636 g). Catalyst loading was increased to Pd2dba3
(0.06 mmol, 0.0550 g, 6 mol %) and Xantphos (0.132 mmol,
0.0762 g,13.2 mol %). Reaction time was 24 h. Eluent: CH2Cl2/MeOH
(98/2). Yield: 49%, 0.221 as white needles.
4.1.3. Quinoxalin-2-amine (5c)34. 2-Chloroquinoxaline (9 mmol,
1.481 g) was brought in a pressure tube. NH3 (aq 25%, 25 mL) was
added and the mixture was heated at 120 ꢀC for 4 h under magnetic
stirring. After the mixture was cooled to room temperature the
quinoxalin-2-amine was filtered off, rinsed well with 25 mL of
water and dried in vacuo. Yield: 54%; 0.705 g as an off-white solid.
1H NMR (400 MHz, DMSO-d6): 8.28 (s, 1H, H3), 7.75 (br d,
J¼8.0 Hz, 1H, H5 or H8), 7.52 (ddd, J¼8.3, 6.8, 1.4 Hz, 1H, H6 or H7),
7.51 (dd, J¼8.2, 1.6 Hz, 1H, H5 or H8), 7.32 (ddd, J¼8.5, 6.6, 1.6 Hz, 1H,
H6 or H7), 6.95 (br s, 2H, NH2).
1H NMR (400 MHz, CDCl3):
d
14.80 (br s, 1H, NH), 8.72 (dd, J¼8.0,
0
1.1 Hz, 1H, H5 or H8), 8.28 (dd, J¼4.9, 1.7 Hz, 1H, H6 ), 8.09 (s, 1H, H2),
0
8.00 (dd, J¼7.8, 1.7 Hz, 1H, H4 ), 7.73 (m, 1H, H6 or H7), 7.67 (dd,
J¼8.1, 1.1 Hz, 1H, H5 or H8), 7.54 (m, 1H, H6 or H7), 6.85 (dd, J¼7.8,
4.9 Hz, 1H, H5 ); 13C NMR (100 MHz, CDCl3):
d 158.4, 150.2, 146.9,
0
144.3, 142.0, 141.7, 133.5, 127.6, 127.4, 126.2, 123.5, 119.0, 118.5. Mp:
154.1e156.4 ꢀC. [MþH]þ calcd: 301.0089, found: 301.0089.
4.3.4. N-(Pyridin-2-yl)quinazolin-4-amine (10b). The general pro-
cedure B was followed using N-(3-bromopyridin-2-yl)quinazolin-
4-amine (9b). Yield: 50%, 0.056 g as a yellow solid.
4.2. General procedure A for the synthesis of N-
(3-bromopyridin-2-yl)benzodiazinamines (9)
1H NMR (400 MHz, CDCl3):
d
8.87 (s,1H, NH), 8.76 (br d, J¼7.0 Hz,
0
A round-bottomed flask of 50 mL was charged with Pd2dba3
(0.06 mmol, 0.0549 g, 4 mol %), Xantphos (0.132 mmol, 0.0763 g,
8.8 mol %) and DME (5 mL). The obtained mixture was flushed with
N2 for 10 min under magnetic stirring. Meanwhile a round-bottomed
flask of 100 mL was charged with 2,3-dibromopyridine (2) (1.5 mmol,
0.355 g), benzodiazinamine (5) (1.8 mmol) and caesium carbonate
(6.0 mmol, 1.955 g). To this mixture, the preformed Pd-catalyst was
added undera N2-flow. The 50 mL flask was subsequently rinsed with
2ꢂ5 mL DME. Then the resulting mixture was flushed with N2 for
1H, H5 or H8), 8.53 (br s,1H, H2), 8.33 (dd, J¼4.7,1.5 Hz,1H, H6 ), 8.03
0
(d, J¼6.4 Hz, 1H, H3 ), 7.95 (br d, J¼7.0 Hz, 1H, H5 or H8), 7.80 (m, 2H,
0
H6 or H7 and H4 ), 7.56 (m, J¼6.9 Hz, 1H, H6 or H7), 7.04 (dd, J¼7.4,
4.9 Hz, 1H, H5 ); 13C NMR (100 MHz, CDCl3):
d 156.6, 154.4, 152.0,
0
150.1, 147.9, 138.2, 133.1, 129.0, 127.0, 120.6, 119.2, 115.2, 115.0 Mp:
104.9e105.4 ꢀC. [MþH]þ calcd: 223.0978, found: 223.0984.
4.3.5. N-(3-Bromopyridin-2-yl)quinoxalin-2-amine (9c). The gen-
eral procedure
A was followed using 2-aminoquinoxaline

T.R.M. Rauws et al. / Tetrahedron 66 (2010) 6958e6964
6963
(1.8 mmol, 0.2613 g). Eluent: CH2Cl2/MeOH (98/2). Yield: 86%,
0.388 g as a brown solid.
1H NMR (400 MHz, CDCl3):
d
8.84 (d, J¼8.9 Hz, 1H, H1 or H4),
8.83 (s, 1H, H5), 8.67 (d, J¼4.6 Hz, 1H, H9), 8.33 (d, J¼8.1 Hz, 1H, H11),
8.00 (m, 2H, H1 and H3 or H2 and H4), 7.90 (br t, J¼7.3 Hz, 1H, H2 or
H3); 7.54 (dd, J¼8.1, 4.6 Hz, 1H, H10); 13C NMR (100 MHz, CDCl3):
1H NMR (400 MHz, CDCl3):
d
9.99 (s, 1H, H3), 8.26 (dd, J¼4.8,
0
1.5 Hz, 1H, H5 ), 8.04 (dd, J¼8.2, 1.0 Hz, 1H, H5 or H8), 7.97 (br s, 1H,
0
NH), 7.85 (dd, J¼7.8,1.5 Hz,1H, H4 ), 7.83 (dd, J¼8.2, 0.9 Hz,1H, H5 or
d
144.6, 144.6, 143.4, 142.1, 134.6, 133.1, 131.2, þ127.8, 127.8, 125.1,
H8) 7.67 (ddd, J¼8.4, 7.0, 1.4 Hz, 1H, H6 or H7), 7.58 (ddd, J¼8.4, 7.0,
124.9, 123.7, 120.9. Mp: 181.3e182 ꢀC. [MþH] calcd: 221.0827,
1.3 Hz, 1H, H6 or H7), 6.83 (dd, J¼7.8, 4.8 Hz, 1H, H6 ); 13C NMR
found: 221.0828.
0
(100 MHz, CDCl3):
d 150.1, 148.0, 146.5, 141.2, 141.1, 139.7, 139.5,
130.2, 129.0, 1127.0, 127.0, 118.2,107.0. Mp: 166.7e166.9 ꢀC. [MþH]þ
4.5.2. Pyrido[20,30:4,5]imidazo[2,1-a]phthalazine (8a). The general
procedure D was followed using phthalazin-1-amine (1.2 mmol, 0.
1742 g).
calcd: 301.0098, found: 301.0091.
4.3.6. N-(Pyridin-2-yl)quinoxalin-2-amine (10c). The general pro-
cedure B was followed using N-(3-bromopyridin-2-yl)quinoxalin-
2-amine (9c). Yield: 50%, 0.056 g as a grey solid.
The residue on the filter wasrinsedwith anextra portion ofCH2Cl2
and NH3 (ca. 7 N in MeOH) (3ꢂ50 mL each). Eluent: gradient CH2Cl2/
MeOH (98/2 to 96/4). Yield: 65%, 0.143 g as an off-white solid.
1H NMR (400 MHz, CDCl3):
d
8.80 (br s, 1H, NH), 8.72 (s, 1H, H3),
1H NMR (400 MHz, CDCl3):
d
8.85 (d, J¼7.8, 1H, H1 or H4), 8.81
0
0
8,49 (d, J¼8.6 Hz, 1H, H3 ), 8.33 (dd, J¼5.0, 0.6 Hz, 1H, H6 ), 7.94 (dd,
(dd, J¼4.6, 1.2 Hz, 1H, H10), 8.71 (s, 1H, H5), 8.39 (dd, J¼8.1, 1.2 Hz,
1H, H8), 7.97 (dd, J¼8.0, 7.4 Hz, 1H, H2 or H3), 7.95 (d, J¼8.0 Hz, 1H,
H1 or H4), 7.86 (dd, J¼7.8, 7.4 Hz, 1H, H2 or H3), 7.41 (dd, J¼8.1,
J¼8.2,1.1 Hz,1H, H5 or H8), 7.82 (dd, J¼8.3, 0.9 Hz,1H, H5 or H8), 7.74
0
(ddd, J¼8.7, 7.2, 1.8 Hz, 1H, H4 ), 7.63 (ddd, J¼8.3, 7.0, 1.3 Hz, 1H, H6
or H7), 7.49 (ddd, J¼8.2, 7.3, 1.3 Hz, 1H, H6 or H7), 6.99 (ddd, J¼7.2,
4.6 Hz, 1H, H9); 13C NMR (100 MHz, CDCl3):
d 154.1, 147.8, 144.3,
5.0, 0.7 Hz, 1H, H5 ); 13C NMR (100 MHz, CDCl3):
d
153.0, 148.2,
142.9, 133.2, 131.3, 127.7, 125.1, 124.8, 124.6, 123.9, 119.2, 118.0. Mp:
0
140.7,139.7,138.9,138.5,130.5, 129.2, 129.2,127.1,126.5,118.3,113.4.
183.9e184.5 ꢀC. [MþH]þ calcd: 221.0827, found: 221.0836.
Mp: 151.4e152.1 ꢀC. [MþH]þ calcd: 223.0984, found: 223.0979.
4.5.3. N-(2-Chloropyridin-3-yl)quinazolin-4-amine (7b). The gen-
eral procedure C was followed using quinazolin-4-amine (5b)
(1.8 mmol, 0.2613 g). Eluent: CH2Cl2/MeOH (98/2). Yield: 92%,
0.352 g as a pale yellow solid.
4.4. General procedure C for the synthesis of pyrido[30,20:4,5]
imidazobenzodiazines (6)
1H NMR (400 MHz, CDCl3):
d
9.25 (d, J¼8.0 Hz,1H, H4 ), 8.85 (s,1H,
0
A round bottomed flask of 50 mL was charged with Pd(OAc)2
(0.06 mmol, 0.013 g, 4 mol %), Xantphos (0.066 mmol, 0.0385 g,
4.4 mol %) and toluene (5 mL). The obtained mixture was flushed
with N2 for 10 min under magnetic stirring. Meanwhile a round-
bottomed flask of 100 mL was charged with 2-chloro-3-iodopyr-
idine (1) (1.5 mmol, 0.359 g), benzodiazinamine 5 (1.8 mmol) and
Cs2CO3 (6.0 mmol, 1.955 g). To this mixture, the preformed Pd-
0
H2), 8.21 (br s, 1H, NH), 8.14 (br d, J¼4.6 Hz, 1H, H6 ), 7.97 (m, 2H, H6
and H7), 7.88 (br t, J¼7.5 Hz, 1H, H5 or H8), 7.66 (br t, J¼7.5 Hz, 1H, H5 or
H8), 7.37 (dd, J¼8.0, 4.6 Hz,1H, H5 ); 13C NMR (100 MHz, CDCl3): 156.7,
0
154.2, 150.1, 143.1, 140.6, 133.4, 132.6, 129.5, 129.3, 127.4, 123.3, 120.0,
115.4. Mp: 149.6e151 ꢀC. [MþH]þ calcd: 257.0594, found: 257.0582.
catalyst was added under
a
N2-flow. The 50 mL flask was
4.5.4. Pyrido[30,20:4,5]imidazo[1,2-c]quinazoline (6b). The general
procedure C was followed using quinazolin-4-amine (1.8 mmol,
0.2613 g). Toluene was substituted for DME. After 17 h reflux, CuI
(0.15 mmol, 0.0285 g, 10 mol %) and rac, trans-cyclohexane-1,2-di-
amine (0.30 mmol, as a solution in 1 mL of DME, 20 mol %)were added
and heating was continued for an additional 8 h. Eluent: gradient
CH2Cl2/MeOH (98/2 to 96/4). Yield: 85%, 0.281 g as a pale yellow solid.
subsequently rinsed with 2ꢂ5 mL toluene. Then the resulting
mixture was flushed with N2 for 5 min and heated for 17 h at reflux.
After cooling down to room temperature, the reaction mixture was
filtered and rinsed well with CH2Cl2 (150 mL). The filtrate was
evaporated and the crude product was purified by column chro-
matography on silicagel.
1H NMR (400 MHz, CDCl3):
d
9.46 (s, 1H, H6), 8.68 (dd, J¼7.9,
4.5. General procedure D for the synthesis of pyrido[20,30:4,5]
imidazobenzodiazines (8)
1.4 Hz, 1H, H1 or H4), 8.56 (dd, J¼4.7, 1.4 Hz, 1H, H9), 8.29 (dd, J¼8.1,
1.4 Hz, 1H, H11), 8.03 (br d, J¼8.1 Hz, 1H, H1 or H4), 7.85 (ddd, J¼8.1,
7.3, 1.4 Hz, 1H, H2 or H3), 7.74 (br t, J¼7.3 Hz, 1H, H2 or H3), 7.56 (dd,
A round bottomed flask of 50 mL was charged with Pd2dba3
(0.04 mmol, 0.0366 g, 4 mol %), Xantphos (0.088 mmol, 0.0501 g,
8.8 mol %) and DME (5 mL). The obtained mixture was flushed with
N2 for 10 min under magnetic stirring. Meanwhile a round-bottomed
flask of 100 mL was charged with 2,3-dibromopyridine (2) (1 mmol,
0.237 g), benzodiazinamine 5 (1.2 mmol) and Cs2CO3 (4.0 mmol,
1.303 g). To this mixture, the preformed Pd-catalyst was added under
a N2-flow. The 50 mL flask was subsequently rinsed with 2ꢂ2.5 mL
DME. Then the resulting mixture was flushed with N2 for 5 min and
heated at reflux. After 17 h, CuI (0.10 mmol, 0.0190 g, 10 mol %) and
rac, trans-cyclohexane-1,2-diamine (0.20 mmol, 1 mL of a 0.2 M
stock solution in DME, 20 mol %) were added and the mixture was
refluxed for an additional 8 h. After cooling down to room temper-
ature, the reaction mixture was filtered and rinsed well with CH2Cl2
(150 mL) and 3 times 10 mL of a mixture of CH2Cl2/NH3 in MeOH (ca.
7 N) (1/1). The filtrate was evaporated to dryness and the crude
product was purified by column chromatography on silicagel.
J¼8.1, 4.7 Hz, 1H, H10); 13C NMR (100 MHz, CDCl3):
d 146.7, 144.0,
143.3, 142.2, 136.3, 135.5, 132.5, 128.9, 128.9, 127.9, 124.1, 122.0,
119.1. Mp: 214.5 ꢀC. [MþH]þ calcd: 221.0827, found: 221.0825.
4.5.5. Pyrido[20,30:4,5]imidazo[1,2-c]quinazoline (8b). The general
procedure D was followed using Pd2dba3 (0.06 mmol, 0.0550 g,
6 mol %) Xantphos (0.132 mmol, 0.0762 g, 13.2 mol %) and quina-
zolin-1-amine (5b) (1.2 mmol, 0. 174 g). Eluent: gradient CH2Cl2/
MeOH (98/2 to 96/4). Yield: 93%, 0.205 g as a white solid.
1H NMR (400 MHz, CDCl3):
d
9.15 (s, 1H, H6), 8.85 (dd, J¼4.8,
1.5 Hz, 1H, H10), 8.81 (ddd, J¼8.0, 1.5, 0.5 Hz, 1H, H1 or H4), 8.30 (dd,
J¼8.1, 1.5 Hz, 1H, H8), 8.02 (dd, J¼8.1 Hz, 1H, H1 or H4), 7.85 (m, 1H,
H2 or H3), 7.75 (br t, J¼7.3 Hz, 1H, H2 or H3), 7.56 (dd, J¼8.1, 4.7 Hz,
1H, H9); 13C NMR (100 MHz, CDCl3):
d 146.7, 144.03, 143.3, 142.2,
136.3, 135.5, 132.5, 128.9 (2), 127.9, 124.1, 122.0, 119.1. Mp: >300 ꢀC.
[MþH]þ calcd: 221.0827, found: 221.0832.
4.5.6. N-(2-Chloropyridin-3-yl)quinoxalin-2-amine (7c). The gen-
eral procedure C was followed using quinoxalin-2-amine (5c)
(1.8 mmol, 0.2613 g). No copper catalyst was added after 17 h but
the mixture was directly worked up. Eluent: CH2Cl2/MeOH (98/2).
Yield: 86%, 0.331 g as a yellow solid.
4.5.1. Pyrido[30,20:4,5]imidazo[2,1-a]phthalazine (6a). The general
procedure C was followed using 1-aminophthalazine (1.8 mmol,
0.2613 g). Eluent: EtOAc/MeOH (98/2). Yield: 80%, 0.264 g of
a white solid.

6964
T.R.M. Rauws et al. / Tetrahedron 66 (2010) 6958e6964
1H NMR (400 MHz, CDCl3):
d
9.33 (dd, J¼8.2,1.6 Hz,1H, H4 ), 8.50
References and notes
0
0
(s, 1H, H3), 8.09 (d, J¼4.6, 1.6 Hz, 1H, H6 ), 7.98 (d, J¼8.2 Hz, 1H, H5 or
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3. Torborg, C.; Beller, M. Adv. Synth. Catal. 2009, 351, 3027.
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348, 23.
6. Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651.
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34, 1348.
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H8), 7.85 (d, J¼8.4 Hz, 1H, H5 or H8), 7.68 (m, 1H, H6 or H7), 7.55 (m,
1H, H6 or H7), 7.39 (s, 1H, NH), 7.34 (dd, J¼8.2, 4.6 Hz, 1H, H5 ); 13C
0
NMR (100 MHz, CDCl3):
d
148.0, 142.1, 140.3, 139.5, 139.0, 138.3,
133.4, 130.6, 129.1, 127.2, 127.1, 126.6, 123.3. Mp: 149.6e151 ꢀC.
[MþH]þ calcd: 257.0589, found: 257.0594.
4.5.7. Pyrido[30,20:4,5]imidazo[1,2-a]quinoxaline (6c). The general
procedure C was followed using quinoxalin-2-amine (1.8 mmol,
0.2613 g). Toluene was substituted for DME. Eluent: CH2Cl2/MeOH
(98/2). Yield: 86%, 0.284 g as a beige solid.
1H NMR (400 MHz, CDCl3):
d
9.61 (dd, J¼8.3, 1.1 Hz, 1H, H1 or H4),
9.23 (s,1H, H6), 8.73 (dd, J¼4.6,1.5 Hz,1H, H10), 8.38 (dd, J¼8.3,1.5 Hz,
1H, H8), 8.14 (dd, J¼8.1, 1.3 Hz, 1H, H1 or H4), 7.78 (m,1H, H9), 7.61 (m,
1H, H2 or H3), 7.59 (m, 1H, H2 or H3); 13C NMR (100 MHz, CDCl3):
d
145.9,145.7,144.3,136.6,135.4,130.4,130.3,129.5,128.6,126.2,121.3,
117.3. Mp: 281.2 ꢀC. [MþH]þ calcd: 221.0827, found: 221.0824.
4.5.8. Pyrido[20,30:4,5]imidazo[1,2-a]quinoxaline (8c). The general
D was followed using quinoxalin-2-amine (5c)
(1.2 mmol, 0.1742 g). Eluent: CH2Cl2/MeOH 95/5. Yield: 99%, 0.218 g
as a brown solid.
procedure
1H NMR (400 MHz,CDCl3):
d
9.37 (s,1H, H6), 8.95(dd, J¼4.6,1.4 Hz,
1H, H9), 8.71 (dd, J¼8.4,1.4 Hz,1H, H11), 8.37 (dd, J¼8.4, 0.9 Hz,1H, H1
orH4), 8.22(dd, J¼8.0,1.4 Hz,1H, H1 orH4), 7.81 (ddd, J¼8.1, 7.3, 1.4 Hz,
1H, H2 orH3), 7.66 (ddd, J¼7.9, 7.5, 1.3 Hz, 1H, H2 orH3), 7.55 (dd, J¼8.4,
25. Hachiya, S.; Hashizume, D.; Maki, S.; Niwa, H.; Hirano, T. Tetrahedron Lett. 2010,
51, 1401.
4.6 Hz,1H, H10);13CNMR(100 MHz,CDCl3):
d155.6, 149.0,146.1, 141.9,
26. Melkonyan, F.; Topolyan, A.; Yurovskaya, M.; Karchava, A. Eur. J. Org. Chem.
2008, 5952.
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135.8, 131.8, 130.4, 129.2, 126.3, 122.6, 122.5, 119.3, 114.6. Mp:
193e195.1 ꢀC. [MþH]þ calcd: 221.0827, found: 221.0828.
Acknowledgements
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We would like to thank the University of Antwerp (NOI BOF UA
2005), the Flemish Government, the Hercules Foundation, the
University of Florence (scholarship to C.B.) and the IWT (scholar-
ship to T.R.M.R.) for financial support.
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Supplementary data
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found in the online version at doi:10.1016/j.tet.2010.06.038