Synthesis of 4-aminoquinazolines by palladium-catalyzed intramolecular imidoylation of N-(2-bromoaryl)amidines

Article abstract of DOI:10.1002/chem.201102468

Compared with the widespread use of carbonylative Pd-catalyzed cross-coupling reactions, similar reactions involving isocyanide insertion are almost virgin territory. We investigated the intramolecular imidoylative cross-coupling of N-(2-bromoaryl)amidines, leading to 4-aminoquinazolines. After thorough optimization of the reaction with respect to palladium source and loading, ligand, base, temperature, and solvent, a small library of 4-aminoquinazolines was prepared to determine the scope of this method. Various substituents are tolerated on the amidine and the isocyanide, providing efficient access to a broad range of diversely substituted 4-aminoquinazolines of significant pharmaceutical interest.

Full text of DOI:10.1002/chem.201102468

FULL PAPER
DOI: 10.1002/chem.201102468
Synthesis of 4-Aminoquinazolines by Palladium-Catalyzed Intramolecular
Imidoylation of N-(2-Bromoaryl)amidines
Gitte Van Baelen,[a] Sander Kuijer,[a] Lukꢀsˇ Rycˇek,[a] Sergey Sergeyev,[b] Elwin Janssen,[a]
´
Frans J. J. de Kanter,[a] Bert U. W. Maes,*[b] Eelco Ruijter,*[a] and Romano V. A. Orru*[a]
Dedicated to Professor Christian Bruneau on the occasion of his 60th birthday
Abstract: Compared with the wide-
spread use of carbonylative Pd-cata-
lyzed cross-coupling reactions, similar
reactions involving isocyanide insertion
are almost virgin territory. We investi-
gated the intramolecular imidoylative
cross-coupling of N-(2-bromoaryl)ami-
dines, leading to 4-aminoquinazolines.
After thorough optimization of the re-
action with respect to palladium source
and loading, ligand, base, temperature,
and solvent, a small library of 4-amino-
quinazolines was prepared to deter-
mine the scope of this method. Various
substituents are tolerated on the ami-
dine and the isocyanide, providing effi-
cient access to a broad range of di-
versely substituted 4-aminoquinazo-
lines of significant pharmaceutical in-
terest.
Keywords: homogeneous catalysis ·
isocyanides · insertion · nitrogen
heterocycles · palladium · synthetic
methods
Introduction
use of isocyanides in multicomponent reactions and our con-
tinuing interest in the efficient synthesis of nitrogen hetero-
cycles, we decided to investigate the potential of Pd-cata-
lyzed imidoylative cross-coupling reactions in the synthesis
of nitrogen heterocycles. The general mechanism of Pd-cata-
lyzed imidoylative cross-coupling reactions is depicted in
Scheme 1. We reasoned that intramolecular cross-coupling
reactions involving an isocyanide insertion that leads to the
formation of five- or six-membered rings would be most fa-
vorable because it would plausibly suppress multiple isocya-
nide insertion, which is the most likely side reaction. In ad-
dition, we assumed that reaction sequences that are termi-
Pd-catalyzed cross-coupling reactions have made an enor-
mous impact on organic synthesis over the past few decades,
as shown by the award of the 2010 Nobel Prize in Chemistry
to Heck, Suzuki, and Negishi. Moreover, the synthetic po-
tential of these reactions has been considerably expanded
by the development of carbonylative cross-coupling reac-
tions, in which carbon monoxide is inserted between the two
coupling partners.[1] Although isocyanides are isoelectronic
with carbon monoxide, synthetic applications of Pd-cata-
lyzed isocyanide insertion are extremely scarce.[2] These re-
actions would provide interesting opportunities for Pd-cata-
lyzed cascade reactions.[3] On the other hand, isocyanide in-
À
sertion into Pd C bonds is a well-known phenomenon in co-
ordination chemistry.[4] In light of our experience with the
´ ˇ
[a] Dr. G. Van Baelen, S. Kuijer, L. Rycek, E. Janssen,
Dr. F. J. J. de Kanter, Dr. E. Ruijter, Prof. Dr. R. V. A. Orru
Department of Chemistry & Pharmaceutical Sciences
Amsterdam Institute for Molecules, Medicines & Systems
VU University Amsterdam, De Boelelaan 1083
1081 HV Amsterdam (The Netherlands)
Fax : (+31)20-5987488
E-mail: e.ruijter@vu.nl
r.v.a.orru@vu.nl
[b] Dr. S. Sergeyev, Prof. Dr. B. U. W. Maes
Organic Synthesis, Department of Chemistry
University of Antwerp, Groenenborgerlaan 171
B-2020 Antwerp (Belgium)
Fax : (+32)32653233
E-mail: bert.maes@ua.ac.be
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102468.
Scheme 1. Proposed general mechanism for Pd-catalyzed imidoylative
cross-coupling reactions.
Chem. Eur. J. 2011, 17, 15039 – 15044
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
15039

nated by an irreversible step, such as tautomerization/aro-
matization, would have a favorable effect on the reaction.
In light of these considerations, we envisioned the synthe-
sis of 4-aminoquinazolines 1 by Pd-catalyzed intramolecular
imidoylative cross-coupling of N-(2-bromoaryl)amidines 3,
which in turn can be derived from 2-bromoanilines 4 and ni-
triles 5. A plausible reaction mechanism is presented in
inhibition of kinases[7] and the modulation of cannabinoid
receptor 2,[8] glutamate receptors,[9] and ion channels.[10] Very
recently, 4-amino-2-phenylquinazolines were also identified
as potent topoisomerase I inhibitors.[11] Representative ex-
amples of pharmaceutically relevant 4-amino-2-arylquinazo-
lines are shown in Figure 1.
À
Scheme 2. First, palladium oxidatively inserts into the C Br
Figure 1. Examples of biologically active 4-amino-2-arylquinazolines.
Results and Discussion
We set out to investigate the potential of Pd-catalyzed isocy-
anide insertion in the synthesis of 4-aminoquinazolines by
using the reaction between the known amidine 3a (R1 =H,
R2 =Ph) and tert-butyl isocyanide (2a) as a benchmark. To
our delight, the use of [Pd
deneacetone), XPhos (10 mol%; XPhos=2-dicyclohexyl-
phosphino-2’,5’,6’-trisisopropylbiphenyl), isocyanide
ACHTUNGERTN(NUNG dba)2] (5 mol%; dba=dibenzyli-
(1.5 equiv), and KOAc (3.0 equiv) led to full conversion of
the amidine starting material and, moreover, furnished the
desired 4-aminoquinazoline 1a in 95% isolated yield
(Table 1, entry 1).[12] Nevertheless, we decided to optimize
this model reaction further in terms of catalyst loading,
ligand, solvent, and temperature to achieve an optimal pro-
cedure.
Scheme 2. Proposed mechanism for the Pd-catalyzed synthesis of 1, in-
volving an isocyanide insertion (A: oxidative addition, B: isocyanide in-
sertion, C: deprotonation, D: reductive elimination, E: tautomerization/
aromatization).
Reduction of the Pd loading to 3 mol% still led to full
conversion of 3a, but the isolated yield dropped to 75%
(Table 1, entry 2). Further reduction of the catalyst loading
to 2 mol% led to incomplete conversion (Table 1, entry 3).
Evaluation of various monodentate dialkylbiaryl phosphine
ligands[13] (Figure 2) showed that the use of DCPB and
JohnPhos led to incomplete conversion of 3a, whereas
SPhos performed similarly to XPhos (Table 1, entries 4–6).
bond in 3 (A) and then coordinates to the amidine moiety.
Alternatively, a directed oxidative addition involving pre-co-
ordination of amidine could occur.[5] Next, the isocyanide in-
serts into the oxidative addition complex (B). Subsequent
deprotonation of the amidine results in a seven-membered
palladacycle (C). Reductive elimination (D) followed by
tautomerization/aromatization (E) affords the desired 4-
aminoquinazoline 1. At the same time, this benchmark reac-
tion also poses a challenge, that is, to avoid the competing
direct intramolecular amination leading to 1H-benzimida-
zole formation.[6] For the selective formation of the desired
À
4-aminoquinazolines, isocyanide insertion into the aryl pal-
ladium bond must be fast with respect to the amination re-
action with the amidine. However, our comparison with the
corresponding carbonylative reactions suggests that this is a
realistic assumption.[1]
Figure 2. Structures of the biphenyl-based phosphine ligands used.
The products resulting from this approach are interesting
from a medicinal chemistry perspective. 4-Amino-2-arylqui-
nazolines display diverse biological activities, including the
Interestingly, when we changed the palladium source to
PdACTHNUGTRENNG(U OAc)2 (Ac=acetyl) in combination with the relatively
15040
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 15039 – 15044

Synthesis of 4-Aminoquinazolines
FULL PAPER
Table 1. Screening of the reaction conditions for the Pd-catalyzed synthesis of 1a from 3a and tert-butyl isocy-
anide (2, R3 =tBu).
to chromatography on silica.
However, the use of a slight
excess of a volatile aliphatic ni-
trile (acetonitrile) followed by
aqueous work-up without sub-
sequent chromatographic purifi-
cation led to the isolation of
the desired amidine 3l (Table 2,
entry 12).
With a highly diverse set of
N-(2-bromoaryl)amidines (3a–
l) in hand, we turned our atten-
tion to the investigation of the
scope of the Pd-catalyzed imi-
doylative cross-coupling reac-
tion. To our delight, we found
that all of the synthesized ami-
dines react with various aliphat-
ic isocyanides to afford the de-
sired 4-aminoquinazolines in
moderate to excellent yield
(Scheme 3). The optimized con-
ditions for the formation of 3a
Entry[a]
Base
Solvent
Pd source
Ligand
Pd
[mol%]
T
[8C]
t
Remaining
3a
Yield of
G
[h]
1a [%][b]
1
2
3
4
5
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
K2CO3
KOAc
K2CO3
KOAc
KOAc
KOAc
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
N
XPhos
XPhos
XPhos
DCPB
JohnPhos
SPhos
DCPB
DCPB
DCPB
DCPB
DCPB
DCPB
DCPB
SPhos
5
3
2
3
3
3
3
3
3
3
3
3
3
3
120
120
120
120
120
120
120
120
120
110
110
100
160
110
5
7
7
7
7
7
7
7
7
7
7
7
3
7
no
no
yes
yes
yes
no
95
75
50
67
77
87
89
76
59
79
9
6
7
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
G
no
8[c]
9
E
yes
yes
no
yes
yes
no
DMF
ACHTUNGTRENNUNG
10
11
12
13
14
1,4-dioxane
1,4-dioxane
DMF
DMF
1,4-dioxane
ACHTUNGTRENNUNG
E
T
54
87
74
ACHTUNGTRENNUNG
C
yes
[a] Reactions were performed in a preheated oil bath on a 1 mmol scale in the indicated solvent (5 mL).
1.5 equivalents of isocyanide and 3 equivalents of the base were used. [b] Isolated yield. [c] 1.5 equivalents of
KOAc were used.
(PdACHTNUTRGNENG(U OAc)2 (3 mol%), DCPB
inexpensive ligand DCPB, amidine 3a was fully converted
Table 2. Synthesis of N-(2-bromophenyl)imidamides (3).
and 1a was isolated in 89% yield (Table 1, entry 7). Since
these conditions led to a similarly high isolated yield to the
original conditions (Table 1, entry 1), but have the addition-
al advantages of easier handling of a PdII versus a Pd0
source and the lower cost of DCPB versus XPhos, we decid-
Entry[a]
R1
R2
Product
Yield
[%][b]
ed to continue the optimization with the PdACTHNURGTNEUNG(OAc)2/DCPB
system. Changes in solvent, temperature, and the amount
and type of base did not lead to further improvements in
the isolated yield (Table 1, entries 8–13). The use of the
more expensive ligand SPhos did not offer an advantage
1
2
3
4
5
6
7
8
9
H
H
4-Cl
5-CF3
H
H
H
H
H
Ph
4-MeC6H4
Ph
3a
3b
3c
3d
3e
3 f
3g
3h
3i
90
80
75
77
97
82
97
53
Ph
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-pyridyl
2-furyl
4-ClC6H4
4-ClC6H4
Me
with respect to DCPB in combination with Pd
pare Table 1, entries 10 and 14). Thus, we decided to contin-
ue our investigation by using Pd(OAc)2 (3 mol%) and
ACHTUNGRTENN(UNG OAc)2 (com-
AHCTUNGTRENNUNG
60
53
DCPB (6 mol%) as the catalyst system, with KOAc
(1.5 equiv) as the base and DMF as the solvent (Table 1,
entry 7).
10
11
12
5-CF3
4-Cl
H
3j
3k
3l
49
n.d.[c]
Having optimized the reaction conditions, we focused our
attention on the determination of the scope of our method-
ology. To this end, we synthesized a range of N-(2-bromoar-
yl)amidines (3a–l, Table 2) by using a previously published
procedure.[14] We found that a range of electron-rich and
electron-deficient aromatic and heteroaromatic nitriles react
with 2-bromoanilines in the presence of sodium hydride to
afford the corresponding amidines 3 in reasonable to excel-
lent yield after chromatography (Table 2, entries 1–11). We
experienced some problems when applying the same proce-
dure to aliphatic nitriles because the expected amidines
were not isolated after chromatography. However, MS anal-
ysis of the reaction mixture indicated that the desired ami-
dines were formed quantitatively. It appears that the ami-
dines derived from aliphatic nitriles are generally not stable
[a] Reaction conditions: nitrile 4 (1 equiv), 2-bromoaniline 5 (1.2 equiv),
NaH (1.5 equiv), DMF, RT, overnight. [b] Isolated yield. [c] The reaction
was performed in THF with nitrile 4 (1.2 equiv) and 2-bromoaniline 5
(1 equiv). The yield was not determined (n.d.) because the reaction prod-
uct was not purified, but was taken straight on to the subsequent reac-
tion.
(6 mol%), KOAc (3 equiv), DMF, 1208C; method A in
Scheme 3) did not prove optimal for all combinations of
amidines 3 and isocyanides 2 and the target 4-aminoquina-
zolines 1 were sometimes isolated in disappointing yields.
Fortunately, simply increasing the catalyst loading to 5
mol% Pd (methods B and D in Scheme 3), optionally com-
bined with increasing the reaction temperature to 1608C
(method C) led to significant improvements in yield in many
Chem. Eur. J. 2011, 17, 15039 – 15044
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
15041

E. Ruijter, B. U. W. Maes, R. V. A. Orru et al.
the amidine starting material
combined with maintaining a
lower reaction temperature can
therefore completely suppress
the dehalogenation reaction.
Interestingly, 4-aminoquina-
zolines substituted on both the
quinazoline core and the C2
phenyl ring (1ja and 1ka) were
also obtained in good yield,
even under the standard reac-
tion conditions. Not only
phenyl, but also heteroaryl C2
substituents are tolerated in this
reaction, as exemplified by the
synthesis of 2-(4-pyridyl)- and
2-(2-furyl)-substituted 4-amino-
quinazolines 1ha, 1hb, 1ia, and
1ib (Scheme 3). These com-
pounds were isolated in reason-
able to good yield, although an
elevated temperature was re-
quired to achieve full conver-
sion in the case of substrate 3i.
Although the reactions with
aliphatic isocyanides proved
very efficient, we were thus far
unsuccessful in employing aro-
matic isocyanides (phenyl isocy-
anide and 2,6-dimethylphenyl
isocyanide) in our synthesis of
4-aminoquinazolines. This is
somewhat surprising in light of
a recent study by Chatani and
Scheme 3. Study of the scope of our Pd-catalyzed isocyanide insertion reaction: synthesis of 4-aminoquinazo-
lines 1aa–1la. All reactions were performed by using amidines 3 (1 equiv), the appropriate isocyanide
(1.5 equiv), and KOAc (3 equiv) in DMF. Method A: Pd
method B: Pd(OAc)2 (5 mol%), DCPB (10 mol%), 1208C, 3 h; method C: Pd
(10 mol%), 1608C, 7 h; method D: Pd(OAc)2 (5 mol%), DCPB (10 mol%), 1208C, 7 h; method E: PdACTHUNGTRENNNUG
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
co-workers, who reported
a
A
direct intramolecular arylation
reaction involving isonitrile in-
sertion.[2f] However, they could
only use 2,6-dimethylphenyl
(3 mol%), XPhos (6 mol%), 1208C, 7 h. A * indicates reactions for which the dehalogenated product was
formed. Cy=cyclohexyl.
cases. Interestingly, a catalyst loading of 3 mol% Pd proved
sufficient for reactions involving primary isocyanides, but
the use of XPhos instead of DCPB as the ligand proved es-
sential to achieve a satisfactory isolated yield (1ac and 1ad,
Scheme 3). Another remarkable observation is that halogen-
substituted amidines 3c, 3e–g, 3j, and 3k are also converted
into the corresponding 4-aminoquinazolines 4. In some
cases, dehalogenation was observed (by MS analysis) as a
side reaction. Two interesting observations were made con-
cerning this side reaction. First, dehalogenation proved
more pronounced at elevated temperature (i.e., method C)
and could typically be fully suppressed by limiting the reac-
tion temperature to 1208C (method D). Second, although
dehalogenated 4-aminoquinazolines were observed during
MS analysis, the corresponding dehalogenated amidines
were not observed. This implies that the dehalogenation
side reaction only takes place after the desired reaction has
been completed. Careful monitoring of the conversion of
isocyanide (and similar sterically hindered aromatic isocya-
nides), whereas phenyl isocyanide and aliphatic isocyanides
were unreactive.[15] A possible rationalization for this obser-
vation is catalyst deactivation by multiple coordination of
the isonitrile to Pd[16] and/or decomposition of the reactants,
for example, through polymerization of the aromatic isoni-
triles under our catalytic conditions.[17] On the other hand,
the Pd-catalyzed isocyanide-insertion reactions recently re-
ported by the groups of Jiang[2g] and Murakami[2h] proceed
with both aromatic and aliphatic isocyanides. It appears that
a very subtle combination of steric and electronic effects of
the isocyanide, substrate, and catalyst used determine the
final outcome of the reaction.
Several of the products shown in Scheme 3 display phar-
maceutically important biological activities. For example,
compound 1ad inhibits phosphodiesterase V (PDE 5) with
an IC50 of 320 nm.[18] Furthermore, compound 1ab was re-
cently reported to display topoisomerase I inhibitory activity
15042
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 15039 – 15044

Synthesis of 4-Aminoquinazolines
FULL PAPER
equal to camptothecin.[11] All of the compounds reported in
Scheme 3 can therefore be considered to be potential topoi-
somerase I inhibitors. In addition, these compounds have
potential as, for example, kinase inhibitors.[7] Therefore, the
constructed library of 4-aminoquinazolines could serve as a
valuable source of new leads in various fields of medicinal
chemistry. Biological activities of compounds 1 will be re-
ported in due course.
[1] For recent reviews of palladium-catalyzed carbonylation reactions,
see: a) C. F. J. Barnard, Organometallics 2008, 27, 5402–5422; b) A.
Brennfꢁhrer, H. Neumann, M. Beller, Angew. Chem. 2009, 121,
4176–4196; Angew. Chem. Int. Ed. 2009, 48, 4114–4133.
[2] For examples of transition metal-catalyzed cyclization reactions in-
corporating isocyanides, see: a) M. Zhang, S. L. Buchwald, J. Org.
Chem. 1996, 61, 4498–4499; b) S. Kamijo, Y. Yamamoto, J. Am.
Chem. Soc. 2002, 124, 11940–11945; c) T. Shibata, K. Yamashita, E.
Katayama, K. Takagi, Tetrahedron 2002, 58, 8661–8667; d) K. Onit-
suka, S. Suzuki, S. Takahashi, Tetrahedron Lett. 2002, 43, 6197–
6199; e) S. Park, R. Shintani, T. Hayashi, Chem. Lett. 2009, 38, 204–
205; f) M. Tobisu, S. Imoto, S. Ito, N. Chatani, J. Org. Chem. 2010,
75, 4835–4840; g) H. Jiang, B. Liu, Y. Li, A. Wang, H. Huang, Org
Lett. 2011, 13, 1028–1031; h) T. Miura, Y. Nishida, M. Morimoto, M.
Yamauchi, M. Murakami, Org Lett. 2011, 13, 1429; i) S. Zhang, W.-
X. Zhang, Z. Xi, Chem. Eur. J. 2010, 16, 8419–8426.
Conclusion
We have developed an efficient Pd-catalyzed intramolecular
imidoylative cross-coupling reaction of readily available N-
(2-bromoaryl)amidines, yielding 4-aminoquinazolines that
are of considerable interest in medicinal and agricultural
chemistry. We have optimized the reaction with respect to
the ligand, catalyst loading, base, temperature, and solvent.
[3] For a recent review of palladium-catalyzed cascade cyclizations, see:
T. Vlaar, E. Ruijter, R. V. A. Orru, Adv. Synth. Catal. 2011, 353,
809–841.
[4] a) B. Crociani, F. Dibianca, R. Bertani, C. B. Castellani, Inorg.
Chim. Acta 1985, 101, 161–169; b) R. Bertani, A. Berton, F. Di
Bianca, B. Crociani, J. Organomet. Chem. 1986, 303, 283–299; c) O.
Schuster, L. Yang, H. G. Raubenheimer, M. Albrecht, Chem. Rev.
2009, 109, 3445–3478; d) J. G. P. Delis, P. G. Aubel, K. Vrieze,
P. W. N. M. van Leeuwen, N. Veldman, A. L. Spek, F. J. R. van Neer,
Organometallics 1997, 16, 2948–2957; e) J. Vicente, M. T. Chicote,
A. J. Martꢂnez-Martꢂnez, P. G. Jones, D. Bautista, Organometallics
2008, 27, 3254–3271; f) J. Dupont, C. S. Consorti, J. Spencer, Chem.
Rev. 2005, 105, 2527–2572; g) V. K. Jain, L. Jain, Coord. Chem. Rev.
2005, 249, 3075–3197.
[5] K. S. Masters, T. R. M. Rauws, A. K. Yadav, W. A. Herrebout, B.
Van der Veken, B. U. W. Maes, Chem. Eur. J. 2011, 17, 6315–6320.
[6] For 1H-benzimidazole synthesis involving Pd-catalyzed intramolecu-
lar N-arylation, see: a) C. T. Brain, S. A. Brunton, Tetrahedron Lett.
2002, 43, 1893–1895; b) C. T. Brain, J. T. Steer, J. Org. Chem. 2003,
68, 6814–6816; c) J. M. Travins, R. C. Bernotas, D. H. Kaufman, E.
Quinet, P. Nambi, I. Feingold, C. Huselton, A. Wilhelmsson, A.
Goos-Nilsson, J. Wrobel, Bioorg. Med. Chem. Lett. 2010, 20, 526–
530.
[7] Rho kinase inhibitors: a) P. Sweetnam, A. Bartolozzi, A. Campbell,
B. Cole, H. Foudoulakis, B. Kirk, H. Seshadri, S. Ram (Surfacelogix,
Brighton, MA, USA), WO2010/104851A1, 2010. CHK2 kinase in-
hibitors: b) I. Collins, A. W. Oliver, T. M. Raynham, C. A. J. Matijs-
sen, E. J. Welsh, J. J. Caldwell, (Cancer Research Technology,
London, UK), WO2009/53694A1, 2009; c) J. J. Caldwell, E. J. Welsh,
C. Matijssen, V. E. Anderson, L. Antoni, K. Boxall, F. Urban, A.
Hayes, F. I. Raynaud, L. J. M. Rigoreau, T. Raynham, G. W. Aherne,
L. H. Pearl, A. W. Oliver, M. D. Garrett, I. Collins, J. Med. Chem.
2011, 54, 580–590.
Easier to handle PdACTHNUTRGNEN(UG OAc)2, in comparison with [PdCAHTUNGTNER(NUGN dba)2],
proved to be equally suited as the Pd source and generally
allowed the use of the relatively inexpensive (compared
with XPhos) ligand DCPB. An array of diversely substituted
amidines can be combined with various aliphatic isocyanides
to afford the target 4-aminoquinazolines in good to excel-
lent yield, although fine-tuning of the reaction conditions
was required for the more challenging substrates. The syn-
thesized 4-aminoquinazolines include known potent topoiso-
merase I inhibitors, as well as phosphodiesterase inhibitors.
The high modularity and mild reaction conditions make this
methodology very attractive for future applications in me-
dicinal chemistry.
Experimental Section
General procedure for the synthesis of 4-aminoquinazolines (1) by Pd-
catalyzed intramolecular imidoylation of N-(2-bromoaryl)amidines (3): A
round-bottomed flask was charged with PdACTHNUTRGENUN(G OAc)2 (7 mg, 0.03 mmol) and
DCPB (21 mg, 0.06 mmol), followed by dry DMF (3 mL). The mixture
was flushed with N2 for 10 min. Meanwhile, amidine 3 (1.0 mmol), KOAc
(3.0 mmol, 3 equiv), and isocyanide 2 (1.5 mmol, 1.5 equiv) were added
to another round-bottomed flask. The Pd catalyst solution was then
added to this mixture, and the flask was subsequently flushed with N2 for
5 min. The resulting mixture was heated at the indicated temperature in
a pre-heated oil bath for 7 h under magnetic stirring. After cooling to
room temperature, EtOAc was added and the suspension was filtered
over a pad of Celite and rinsed with EtOAc (125 mL). The solvent was
removed under reduced pressure and the residue was purified by flash
column chromatography on silica gel to afford 4-aminoquinazolines 1 in
high purity.
[8] T. C. Gahman, D. J. Thomas, M. E. Massari, H. Lang (Kalypsis, San
Diego, CA, USA), WO2008/157500A1, 2008.
[9] M. Reich, S. Kuehnert, S. Oberboersch, M. Haurand, K. Schiene
(Gruenenthal, Aachen, DE), US2009/69320A1, 2009.
[10] D. Wilson, L. T. D. Fanning, P. Krenitsky, A. Termin, P. Joshi, U.
Sheth (Vertex Pharmaceuticals Incorporated, Cambridge, MA,
USA), US2008/167305A1, 2008.
[11] T. N. Le, S. H. Yang, D. B. Khadka, H. T. M. Van, S. H. Cho, Y.
Kwon, E.-S. Lee, K.-T. Lee, W.-J. Cho, Bioorg. Med. Chem. 2011, 19,
4399–4404.
[12] These conditions proved to be successful for domino condensation/
Heck cyclization reactions on 3-amino-4-bromoquinoline and 3-
amino-4-bromoisoquinoline with acetaldehyde, see: G. Van Baelen,
G. L. F. Lemiꢃre, R. A. Dommisse, B. U. W. Maes, ARKIVOC 2009,
vi, 174–182.
Acknowledgements
This work was financially supported by the Netherlands Organization for
Scientific Research (NWO) by means of a Rubicon grant to Dr. Gitte
van Baelen and by the Hercules Foundation. We thank Dr. M. T. Smo-
luch (VU University) for (HR)MS measurements.
[13] For a recent review of the use of dialkylbiaryl phosphines in Pd-cat-
alyzed aminations, see: D. S. Surry, S. L. Buchwald, Chem. Sci. 2011,
2, 27–50.
Chem. Eur. J. 2011, 17, 15039 – 15044
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
15043

E. Ruijter, B. U. W. Maes, R. V. A. Orru et al.
[14] G. Brasche, S. L. Buchwald, Angew. Chem. 2008, 120, 1958–1960;
Angew. Chem. Int. Ed. 2008, 47, 1932–1934.
[18] S. J. Lee, Y. Konishi, D. T. Yu, T. A. Miskowski, C. M. Riviello, O. T.
Macina, M. R. Frierson, K. Kondo, M. Sugitani, J. C. Sircar, K. M.
Blazejewski, J. Med. Chem. 1995, 38, 3547–3557.
[15] We performed the reactions with aromatic isocyanides not only
under the optimized conditions from Table 1, but also under the re-
action conditions used by Chatani and co-workers in ref. [2f].
[16] Y. Yamamoto, Coord. Chem. Rev. 1980, 32, 193–233.
[17] a) F. Millich, Chem. Rev. 1972, 72, 101–113; b) F. Millich, J. Polym.
Sci., Macromol. Rev. 1980, 15, 207–253; c) M. Suginome, Y. Ito,
Adv. Polym. Sci. 2004, 171, 77–136.
Received: August 9, 2011
Published online: November 28, 2011
15044
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 15039 – 15044