Synthesis of pyridopyrimidines by palladium-catalyzed isocyanide insertion

Article abstract of DOI:10.1021/cs400926z

A new synthetic approach to 4-aminopyrido[2,3-d]pyrimidines and 4-aminopyrido[3,2-d]pyrimidines based on palladium-catalyzed reaction of isocyanides with readily available N-(bromopyridyl)amidines is reported. The target heterocycles were obtained in generally good to excellent yield. For the two regioisomeric pyrimidopyrimidines, we compared our approach involving oxidative addition with the analogous C-H activation protocol because both methods have been reported for the synthesis of 4-aminoquinazolines. We found that the C-H activation protocol does not allow one to obtain the target pyridopyrimidines, but the imidoylative cross-coupling protocol provided a new entry to the synthesis of these medicinally important scaffolds.

Full text of DOI:10.1021/cs400926z

Research Article
pubs.acs.org/acscatalysis
Synthesis of Pyridopyrimidines by Palladium-Catalyzed Isocyanide
Insertion
Veronica Estevez,†,§ Gitte Van Baelen,†,§,⊥ Babette H. Lentferink,† Tjøstil Vlaar,† Elwin Janssen,†
́
́
Bert U. W. Maes,*,‡ Romano V. A. Orru,*,† and Eelco Ruijter*,†
†Department of Chemistry & Pharmaceutical Sciences and Amsterdam Institute for Molecules, Medicines & Systems, VU University
Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
‡Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020, Antwerp, Belgium
S
* Supporting Information
ABSTRACT: A new synthetic approach to 4-aminopyrido-
[2,3-d]pyrimidines and 4-aminopyrido[3,2-d]pyrimidines
based on palladium-catalyzed reaction of isocyanides with
readily available N-(bromopyridyl)amidines is reported. The
target heterocycles were obtained in generally good to
excellent yield. For the two regioisomeric pyrimidopyrimi-
dines, we compared our approach involving oxidative addition
with the analogous C−H activation protocol because both
methods have been reported for the synthesis of 4-amino-
quinazolines. We found that the C−H activation protocol does not allow one to obtain the target pyridopyrimidines, but the
imidoylative cross-coupling protocol provided a new entry to the synthesis of these medicinally important scaffolds.
KEYWORDS: palladium, isocyanides, heterocycles, insertion reactions, homogeneous catalysis, cross-coupling
followed by stepwise introduction of the substituents by cross-
coupling or SNAr reactions.
INTRODUCTION
■
Nitrogen-rich fused heterocycles are of paramount importance
in medicinal chemistry, not the least owing to their typical
affinity for ATP binding sites in kinases and other pharmaceuti-
cally relevant enzyme targets.1 5,6-Fused pyrimidines such as
pyrido[3,2-d]pyrimidines (1) and pyrido[2,3-d]pyrimidines (2)
are prime example of such N-heterocycles that inhibit an array
of disease-related kinases (Chart 1).2 The synthesis of these
compounds is typically achieved by construction of the
heterocyclic core by classical methods using harsh conditions,
Palladium-catalyzed cross-coupling reactions have become
commonplace in medicinal chemistry for the decoration of
preconstructed scaffold structures.3 However, their utilization in
an integral approach to the de novo synthesis of highly
functionalized heterocycles is currently still underdeveloped.
On the other hand, many palladium-catalyzed cascade reactions
toward complex cyclic molecular scaffolds continue to be
developed.4 Among these reactions, the palladium-catalyzed
migratory insertion of isocyanides is currently emerging as a
highly efficient strategy for the construction of densely and
diversely functionalized heterocycles.5
Chart 1. Pharmaceutically Relevant Pyrido[3,2-
Recently, we reported the Pd-catalyzed intramolecular
imidoylative cross-coupling of N-(2-bromoaryl)amidines to
give 4-amino-2-arylquinazolines (Scheme 1, pathway A).6
Independently, Zhu et al. developed a similar oxidative cross-
coupling involving C−H activation (pathway B).7 Although the
latter method provides some clear advantages with respect to
atom economy and synthetic accessibility of the starting
materials, it suffers from regioselectivity issues that can be
avoided using our approach. Moreover, we anticipated that our
method would be a more general approach to the synthesis of
4-aminopyrimidines fused with nonbenzenoid (e.g., pyridine)
rings (pathway C), since C−H activation is likely not easily
d]pyrimidines (I and II) and Pyrido[2,3-d]pyrimidines (III)
Received: October 15, 2013
Revised: November 13, 2013
Published: November 25, 2013
© 2013 American Chemical Society
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Research Article
Scheme 1. Pd-Catalyzed Synthesis of Fused 4-
Aminopyrimidines
Scheme 2. Synthesis of N-(Bromopyridyl)amidines
transferred from an arene to an azine system (pathway D). We
therefore set out to investigate the palladium-catalyzed
insertion of isocyanides into several N-(bromopyridyl)amidines
as a new entry to pharmaceutically relevant 5,6-fused 4-
aminopyrimidines and compare it to the oxidative approach
using N-(pyridyl)amidines.
Method A: A solution of 3a (1.1 equiv) and the appropriate nitrile (1.0
equiv) in dry DMF was added at 0 °C to a suspension of NaH (1.5
equiv, washed with pentane) in dry DMF, then stirred overnight at
RT. Method B: 3a or 3b (1.1 equiv) was added at 0 °C to a suspension
of NaH (1.5 equiv, washed with pentane) in dry DMF and stirred at 0
°C for 10 min before the addition of a solution of the appropriate
nitrile (1.0 equiv) in dry DMF. The resulting mixture was stirred
overnight at RT.
RESULTS AND DISCUSSION
■
We started our investigations with the synthesis of a range of
amidines 4 and 5 starting from commercially available 3-amino-
2-bromopyridine (3a) and 2-amino-3-bromopyridine (3b),
respectively, using a literature procedure8 (method A) or a
slightly adapted protocol (method B, Scheme 2). Without
optimization, we readily prepared a set of diversely substituted
N-(bromopyridyl)amidines 4 and 5 (Scheme 2).
Scheme 3. Synthesis of Pyrido[3,2-d]pyrimidines (1)
These amidines were then subjected to our previously
optimized conditions for Pd-catalyzed intramolecular imidoy-
lation [3 mol % Pd(OAc)2, 6 mol % Cy JohnPhos, 1.5 equiv of
isocyanide, 3 equiv of KOAc, DMF, 120 °C, 7 h].6 To our
delight, all amidines were smoothly converted to the
corresponding 4-aminopyridopyrimidines 1 (Scheme 3) and 2
(Scheme 4). The pyrido[3,2-d]pyrimidines 1a−i were generally
obtained in fair to good yield, although we found that a higher
catalyst loading and temperature were required compared with
our previous study on aminoquinazolines (5 mol % Pd, 160
°C). The presence of chloro substituents was tolerated (1b−d,
1h), although the 2-chlorobenzamidine derivative 4b led to a
lower yield, possibly for steric reasons. Heterocyclic sub-
stituents such as 4-pyridyl (1e, 1i) and 2-furyl (1f) are also
allowed. tert-Butyl isocyanide, as the benchmark isocyanide, was
most efficiently inserted, although cyclohexyl isocyanide could
also be used with slightly diminished efficiency.
Gratifyingly, amidines 5 underwent Pd-catalyzed isocyanide
insertion much more efficiently than amidines 4. The
pyrido[2,3-d]pyrimidines 2a−d were obtained in good to
excellent yield, even with lower catalyst loading (3 mol % Pd)
and at substantially lower temperature (120 °C). Both tert-butyl
and cyclohexyl isocyanide were in this case inserted with high
efficiency, as exemplified by the combination with amidines
featuring heterocyclic substituents (4-pyridyl and 2-furyl).
We then set out to confirm our hypothesis that these
scaffolds are presumably not accessible via the C−H activation
protocol described by Zhu et al. for the synthesis of 4-
aminoquinazolines.7 As anticipated, the amidines 6 and 7 were
not converted to the corresponding pyridopyrimidines 1a and
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Research Article
Scheme 4. Synthesis of Pyrido[2,3-d]pyrimidines (2)
Scheme 5. Attempted Synthesis of Pyridopyrimidines by C−
H Activation and Unexpected Formation of 8
2e under the reaction conditions reported (5 mol % Pd(OAc)2,
1.5 equiv of Cs2CO3, 1 atm O2, toluene, reflux, 3 h). In the case
of 6, incomplete conversion of the starting amidine and a
complex mixture of unidentified products was observed. A trace
peak with m/z corresponding to the pyridopyrimidine 1a was
observed during ESI-MS analysis of the reaction mixture.
However, the reaction did not afford an isolable amount of 1a
or an isomer. Surprisingly, amidine 7 was completely and
selectively converted to a single new product under these
conditions. MS and NMR analysis revealed that this product
was not pyridopyrimidine 2e, but an isomer. After extensive 1D
and 2D NMR studies, we were able to assign structure 8 to this
unexpected reaction product. Remarkably, this product was
formed very fast (within 1 h) and in very high yield compared
with the formation of 4-aminoquinazolines reported by Zhu et
al.7 The mechanism we propose for the formation of this
species is analogous to the oxidative isocyanide insertion of o-
phenylenediamines and related compounds we recently
reported.9 Amidine 7 can be regarded as an excellent bidentate
ligand for Pd(II). After coordination and insertion of the
isocyanide to the Pd(II) complex 11, reductive elimination of
Pd(0) affords the observed product 8. Reoxidation of Pd(0) by
O2 completes the catalytic cycle (Scheme 5).
and heated at 160 °C for 7 h. After cooling to room
temperature, the resulting mixture was filtered over a pad of
Celite and rinsed with ethyl acetate. The solvent was removed
under reduced pressure, and the obtained residue was purified
by flash column chromatography on silica gel using the
appropriate solvent mixture as the eluent.
General Procedure for the Synthesis of Pyrido[2,3-
d]pyrimidines 2. A round-bottomed flask was charged with
Pd (OAc)2 (3 mol %) and Cy JohnPhos (6 mol %), followed
by 5 mL of dry DMF. The mixture was flushed with N2 for 10
min. In another round-bottomed flask, KOAc (3 equiv), the
appropriate amidine (1 equiv), and isocyanide (1.5 equiv) were
weighed. To this mixture, the Pd catalyst solution was added,
and the flask was flushed with N2. Then, the mixture was stirred
and heated at 120 °C for 7 h. After cooling to room
temperature, the resulting mixture was filtered over a pad of
Celite and rinsed with ethyl acetate. The solvent was removed
under reduced pressure, and the obtained residue was purified
by flash column chromatography on silica gel using the
appropriate solvent mixture as the eluent.
CONCLUSIONS
■
We report the use of Pd-catalyzed intramolecular imidoylative
cross-coupling reactions to efficiently access nitrogen-rich,
fused, bicyclic heteroaromatics that are of significant interest
in medicinal chemistry. The reaction proceeds with a range of
N-(bromopyridyl)amidines in combination with secondary and
tertiary aliphatic isocyanides under mild conditions, allowing
straightforward incorporation of (acid-)labile functional groups,
which are incompatible with the majority of currently used
methods for the preparation of these classes of compounds.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures and characterization data for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of Pyrido[3,2-
d]pyrimidines 1. A round-bottomed flask was charged with
Pd (OAc)2 (5 mol %) and Cy JohnPhos (10 mol %), followed
by 5 mL of dry DMF. The mixture was flushed with N2 for 10
min. In another round-bottomed flask, KOAc (3 equiv), the
appropriate amidine (1 equiv), and isocyanide (1.5 equiv) were
weighed. To this mixture, the Pd catalyst solution was added,
and the flask was flushed with N2. Then, the mixture was stirred
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: bert.maes@ua.ac.be.
*E-mail: r.v.a.orru@vu.nl.
*E-mail: e.ruijter@vu.nl.
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Research Article
Present Address
⊥(G.V.B.) Agfa-Gevaert N.V., Septestraat 27, B-2640 Mortsel,
Belgium.
Author Contributions
§V.E. and G.V.B. contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
■
This work was supported by The Netherlands Organization for
Scientific Research and by the Hercules Foundation. We thank
Dr. M. T. Smoluch for (HR)MS measurements.
ABBREVIATIONS
■
ATP, adenosine triphosphate; Cy Johnphos, 2-
(dicyclohexylphosphino)biphenyl; PI3K,phosphoinositide-3-
kinase; TGF,transforming growth factor (tumor growth factor);
XPhos,2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl
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