Convenient one-pot synthesis of N3-substituted pyrido[2,3-d]-, pyrido[3,4-d]-, pyrido[4,3-d]-pyrimidin-4(3H)-ones, and quinazolin-4(3H)-ones analogs

Article abstract of DOI:10.1016/j.tetlet.2013.04.096

A convenient microwave-assisted one-pot sequential synthesis provided access to novel pyridopyrimidin-4-(3H)-ones in good to excellent yields. Anthranilic acid, 2- and 4-aminonicotinic acids, and 3-aminoisonicotinic acid were quantitatively converted into

Full text of DOI:10.1016/j.tetlet.2013.04.096

Tetrahedron Letters 54 (2013) 3518–3521
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient one-pot synthesis of N3-substituted pyrido[2,3-d]-,
pyrido[3,4-d]-, pyrido[4,3-d]-pyrimidin-4(3H)-ones, and quinazolin-4(3H)-ones
analogs
⇑
Emmanuel Deau , Damien Hédou , Elizabeth Chosson, Vincent Levacher, Thierry Besson
Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesnière, 76821 Mont St Aignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient microwave-assisted one-pot sequential synthesis provided access to novel pyridopyrimi-
din-4-(3H)-ones in good to excellent yields. Anthranilic acid, 2- and 4-aminonicotinic acids, and 3-ami-
noisonicotinic acid were quantitatively converted into the analogous amidinoesters which undergo rapid
cyclization in the presence of an amine.
Received 23 March 2013
Revised 19 April 2013
Accepted 23 April 2013
Available online 30 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Microwave-assisted chemistry
Pyrido[2,3-d]-pyrimidin-4(3H)-ones
Pyrido[3,4-d]-pyrimidin-4(3H)-ones
Pyrido[4,3-d]-pyrimidin-4(3H)-ones
One-pot sequential synthesis
The main interests of our research group include the synthesis
of C,N,S-containing heterocyclic precursors of bioactive molecules
able to modulate the role of kinases in signal transduction.1 As part
of this work, the syntheses of various quinazoline derivatives were
described.2 Among all the studied compounds, N3-susbtituted
quinazolines were particularly studied and their synthesis has
been the focus of a large part of our efforts for 10 years. The biolog-
ical activity of such derivatives3 incited us to extend recent inves-
tigations to novel pyridopyrimidine analogs with the aim of
carrying out further structure-activity relationship studies. The
main part of the chemistry performed in this study was achieved
under microwave irradiation as a continuation of our global strat-
egy which consists to design adapted reactants and techniques
offering operational, economic, and environmental benefits over
conventional methods. This Letter describes the development of
a reliable and simple method that allows the preparation of a small
library of novel pyridopyrimidine derivatives for which interesting
biological properties can be expected.
The first part of this work was inspired by Foster and co-work-
ers who described a preliminary study dealing with the synthesis
of N3-susbstituted quinazolin-4-ones. The authors demonstrated
that the bicyclic compounds can be readily synthesized from
substituted anthranilic acids by treatment with dimethylformam-
ide-dimethylacetal (DMFDMA), followed with acid-catalyzed cycli-
zation of the intermediate formamidinoester by attack of an
aliphatic amine (Scheme 1).4
O
DMFDMA
R'NH2
APTS (cat.)
COOH
COOMe
R'
(2.6 eq.)
N
R
R
R
Dioxane
DMF, Δ
NH2
N
NMe2
N
Δ, 4h
R' = alkyl 43-84%
R = H, 3, 5 or 6-CH3
4 or 5-Cl, 4-NO2
72-99%
Scheme 1. Conditions described for the synthesis of N3-substituted quinazolines using DMFDMA.4
⇑
Corresponding author. Tel.: +33 (0) 2 3552 2904; fax: +33 (0) 2 3552 2962.
E-mail address: thierry.besson@univ-rouen.fr (T. Besson).
The two first authors contribute equally to this work.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.096

E. Deau et al. / Tetrahedron Letters 54 (2013) 3518–3521
3519
DMFDMA
(2.5 eq.)
DMFDMA
(2.5 eq.)
Purification of the intermediate compounds revealed to be very
tricky (Kügelrohr distillation at reduced pressure) due to the high
instability of the intermediate amidinoesters which may possibly
undergo hydrolysis to give rise to the corresponding formylesters.
Considering on-going experiments using DMFDMA for the
microwave-assisted synthesis of 4-substituted quinazolines via
Dimroth rearrangement2 and pyrimidin-4-amines via formamide
degradation,5,6 we decided to focus our first efforts on an efficient
one-pot multi-component reactant (MCR) synthesis of quinazolin-
4-ones and extend to original pyridopyrimidin-4-one derivatives
themselves obtained from aminonicotinic acid analogs (1–4; see
Scheme 3). Both steps of this new sequential synthesis were car-
ried out in a microwave oven allowing a strict control of the reac-
tion conditions as described in previous works.2
COOH
N
DMF
100°C (µw)
5 min.
DMF
100°C (µw)
10 min.
X
NMe2
X= CH 1a
2a
X= N
DMFDMA
(2.5 eq.)
Silica
gel
COOH
NH2
COOMe
CHO
N
H
DMF
100°C (µw)
15 min.
X
X
N
NMe2
X= CH
X= N
X= CH
X= N
qt.a
qt.a
1
2
5
6
Scheme 2. Conversion of anthranilic acid 1 and 2-aminonicotinic acid 2 into their
amidinoester analogs 5 and 6. aDetermined by 1H NMR of the crude mixture.
Optimization of the reaction conditions proved that at least
15 min of irradiation are necessary for the concomitant formation
of both amidine and ester functions in DMF when anthranilic acid
1 and 2-aminonicotinic acid 2 were used. Carrying out this exper-
iment without DMF led to a complex mixture of carbonaceous
compounds. Various conditions of chromatographic purifications
were tested (silica and alumina gels) and demonstrated that the
intermediate amidinoesters 5 and 6, were in fact completely trans-
formed into unexpected N-formylated analogs (Scheme 2).
A kinetic study of this first step in the case of 1 and 2 showed
that the amino function of the starting material was formylated
in 5 min, prior to the esterification process and no starting acid re-
mained after 5 min (Table 1).
O
N
R-NH2
(1.1 eq)
DMFDMA
(2.5 eq)
COOH
NH2
COOMe
R
Z
Y
Z
Y
Z
Y
N
DMF
100°C (µw)
15 min
AcOH
100°C (µw)
15 min
X
X
N
N
X
1-4
5-8
9a-f - 12a-f
STEP 1
STEP 2
R= n-Pr, i-Pr, cycloPr,
sec-Bu, Bn, furfuryl
X, Y, Z = CH; 1 (anthranilic acid), 5, 9
2
X = N; Y, Z = CH; (2-aminonicotinic acid), 6, 10
X = CH; Y = N; Z = CH; 3 (3-aminoisonicotinic acid),7,11
X, Y = CH; Z = N; 4 (4-aminonicotinic acid chlorhydrate), 8, 12
Scheme 3. Optimized protocol for the one-pot synthesis of 3-substituted quinaz-
olin-4(3H)-ones (9), pyrido[2,3-d]-pyrimidin-4(3H)-ones (10), pyrido[3,4-d]-pyr-
imidin-4(3H)-ones (11), and pyrido[4,3-d]-pyrimidin-4(3H)-ones (12). 4-
Aminonicotinic acid chlorhydrate 4 required 3 equiv of DMFDMA for completion
of step 1; for yields see Table 2.
As a result of this preliminary study, a reaction first involving
the formation of the amidinoester followed with the cyclization
would best suit our needs for a new process giving access to the
desired compounds. Thus, in the hope to implement a one-pot syn-
thesis of N3-substituted quinazolin-4(3H)-ones by means of a
formylation/esterification/cyclization sequence, a MCR procedure
was initiated with starting anthranilic acid, DMFDMA, and benzyl-
amine, but failed to give the cyclized product.
Pursuing our effort, it was decided to operate via a one-pot
sequential strategy which consisted in performing the first step
as described above, namely irradiation of the starting anthranilic
acid 1 and DMFDMA in DMF for 15 min at 100 °C. Once the solvent
(DMF) was eliminated, the amine and acetic acid were immedi-
ately added in the reaction flask and irradiated at 100 °C for further
15 min. As depicted in Table 2 various amines could be used afford-
ing N3-alkylated quinazolin-4-ones 9a–f in good to excellent yields
within a short period of time (Scheme 3).
Table 1
Evolution of the ratios of starting acids (1 and 2), amidinoacids (1a and 2a), and
amidinoesters (5 and 6)
Reaction timea (min)
1:1a:5 Ratiob
2:2a:6 Ratiob
5
10
15
0:0.86:0.14
0:0.36:0.64
0:0:1c
0:0.83:0.17
0:0.17:0.83
0:0:1c
a
b
c
Reaction time does not include temperature ramp of 2 min.
Determined by 1H NMR of the crude mixture.
Quantitative yield.
Table 2
Isolated yields for the one-pot synthesis of 3-substituted quinazolin-4(3H)-ones (9a–9f), pyrido[2,3-d]-pyrimidin-4(3H)-ones (10a–10f), pyrido[3,4-d]-pyrimidin-4(3H)-ones
(11a–11f), and pyrido[4,3-d]-pyrimidin-4(3H)-ones (12a–12f)
Product
Formula
Yielda (%)
Product
Formula
Yielda (%)
O
O
N
N
N
9a
87
9b
82
N
O
N
O
9c
70
9d
N
N
N
87
83
N
O
N
O
O
N
N
9e
98
88
9f
N
O
N
O
10a
10b
84
N
N
N
N
(continued on next page)

3520
E. Deau et al. / Tetrahedron Letters 54 (2013) 3518–3521
Table 2 (continued)
Product
Formula
Yielda (%)
82
Product
Formula
Yielda (%)
89
O
O
N
N
10c
10d
N
N
N
N
N
O
N
N
N
O
O
10e
11a
98
86
10f
97
83
N
N
O
O
N
N
11b
N
N
N
N
N
O
N
O
N
11c
77
11d
N
82
N
N
O
O
O
N
N
N
N
N
11e
12a
86
67
11f
63
41
N
N
N
N
N
O
N
O
12b
N
O
N
O
N
N
12c
12e
48
63
12d
12f
N
N
N
N
54
58
N
N
O
O
O
N
N
N
a
Isolated yield.
O
N
O
O
CO2H
NH2
CO2H
OMe
N
H
N
Z
Y
Z
Y
Z
Y
O
N
X
1 - 4
X
X
(-MeOH)
OMe
OMe
N
N
H
AcOH
+
CO2Me
NH2
N
(-MeOH)
RNH2
13
O
OMe
O
O
N
N
Z
Y
OMe
H
Z
O
R
Z
Y
OMe
Z
Y
X
N
Y
X
N
H
NMe2
X
N
NH
R
R
N
(-Me2NH)
X
(-MeOH)
N
H
H
9 - 12
5 - 8
Scheme 4. Proposed mechanism for the synthesis of 3-substituted quinazolin-4(3H)-ones (9), pyrido[2,3-d]-pyrimidin-4(3H)-ones (10), pyrido[3,4-d]-pyrimidin-4(3H)-ones
(11), and pyrido[4,3-d]-pyrimidin-4(3H)-ones (12).
Pleasingly, the same reaction sequence could be successfully
conducted with 2-aminonicotinic acid 2, 3-isonicotinic acid chlor-
hydrate 3, and 4-aminonicotinic acid 4 in the presence of a range of
amines to afford, in good to excellent yields, the corresponding
pyrido[2,3-d]pyrimidin-4-ones (10a–f), pyrido[3,4-d]pyrimidin-4-
ones (11a–f), and pyrido[4,3-d]pyrimidin-4-ones (12a–f), respec-
tively (Table 2).
Results collected in Table 2 demonstrated that the yields
obtained with a given amine are mostly influenced by the position
of the pyridine nitrogen. It appears that those yields decreased
with the ortho, meta, and para position of the formamidine function
to the intracyclic nitrogen.
Considering the kinetic study of the first step, attack of the aro-
matic amine (1–4) on the most electrophilic site of the iminium
methoxide salt was completed in 5 min. Methoxide anion thus re-
leased then trapped the carboxylic acid proton, allowing the corre-
sponding carboxylate to attack the second electrophilic site of the
iminium salt, affording the formimidamidoesters (5–8) in quanti-
tative yields. The mechanism of cyclization occurred via a first at-
tack of the amine on the activated carbon of the amidine. The

E. Deau et al. / Tetrahedron Letters 54 (2013) 3518–3521
3521
intermediate triamine species released dimethylamine and cy-
Supplementary data
clized into the expected quinazolines (9a–f) and pyridopyrimi-
dines (10a–f to 12a–f). In the specific case of 4-aminonicotinic
acid 4, the low yields observed can be explained by a substantial
contribution of a zwitterionic resonance form which could involve
the instability of the intermediate triamine resulting from the con-
densation of the primary amine on the formimidamidoester 8. The
elimination process turned in favor of the unexpected aminoester
(see 13 Scheme 4) which was isolated in 15–20% yield. This deac-
tivation was not significant with 2-aminonicotinic acid 2 since the
contribution of the analogous zwitterionic resonance form was
considerably less important.7
Supplementary data (experimental procedures, 1H and 13C NMR
spectra of products 9a–f, 10a–f, 11a–f, 12a–f) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.04.096.
References and notes
1. For our recent work see: (a) Loidreau, Y.; Marchand, P.; Dubouilh-Benard, C.;
Nourrisson, M.-R.; Duflos, M.; Loaëc, N.; Meijer, L.; Besson, T. Eur. J. Med. Chem.
2013, 59, 283–295; (b) Loidreau, Y.; Marchand, P.; Dubouilh-Benard, C.;
Nourrisson, M.-R.; Duflos, M.; Lozach, O.; Loaëc, N.; Meijer, L.; Besson, T. Eur. J.
Med. Chem. 2012, 58, 171–183.
Some comments can be made concerning the microwave proce-
dure as well as the technical and practical aspects.8 In the case of
our microwave-assisted synthesis, DMF and acetic acid present
the advantage of having good dielectric properties, thus giving an
efficient heating of the reaction mixture.9 A reactor able to work
at atmospheric pressure had some advantages, such as the possi-
bility of easier work-up and the use of common laboratory glass-
ware. In the main steps of the synthetic pathway described in
this Letter, irradiation power at 900 W was enough to efficiently
reach the programmed temperature with a short time ramp
(2 min, not added to the reaction time indicated in schemes). Tem-
perature was monitored via a contactless-infrared pyrometer
which was calibrated by control experiments with a fiber-optic
contact thermometer.
In conclusion, the highlight of this work is the development of a
convenient one-pot sequential process which was perfectly con-
trolled using microwave technology at atmospheric pressure. Thus,
the syntheses of various N3-alkylated quinazolin-4-ones (9a–f),
and novel pyrido[2,3-d]pyrimidin-4-ones (10a–f),10 pyrido[3,4-
d]pyrimidin-4-ones (11a–f) and pyrido[4,3-d]pyrimidin-4-ones
(12a–f), were optimized in a reliable and simple method which
can be applied to various ring systems and amines in order to con-
stitute libraries of chemical scaffolds.
2. Foucourt, A.; Dubouilh-Benard, C.; Chosson, E.; Corbière, C.; Buquet, C.; Iannelli,
M.; Leblond, B.; Marsais, F.; Besson, T. Tetrahedron 2010, 66, 4495–4502.
3. (a) Logé, C.; Testard, A.; Thiéry, V.; Lozach, O.; Blairvacq, M.; Robert, J.-M.;
Meijer, L.; Besson, T. Eur. J. Med. Chem. 2008, 43, 1469–1477; (b) Testard, A.;
Logé, C.; Léger, B.; Robert, J.-M.; Lozach, O.; Blairvacq, M.; Meijer, L.; Thiéry, V.;
Besson, T. Bioorg. Med. Chem. Lett. 2006, 16, 3419–3423.
4. Gupton, J. T.; Miller, J. F.; Bryant, R. D.; Maloney, P. R.; Foster, B. S. Tetrahedron
1987, 43, 1747–1752.
5. For recent selected articles on the reactivity of DMFDMA and related
alkylacetals see: (a) Loidreau, Y.; Melissen, S.; Levacher, V.; Logé, C.; Graton,
J.; Le Questel, J.-Y.; Besson, T. Org. Biomol. Chem. 2012, 10, 4916–4925; (b)
Nathubhai, A.; Patterson, R.; Woodman, T. J.; Sharp, H. E. C.; Chui, M. T. Y.;
Chung, H. H. K.; Lau, S. W. S.; Zheng, J.; Lloyd, M. D.; Thompson, A. S.; Threadgill,
M. D. Org. Biomol. Chem. 2011, 9, 6089–6099.
6. Loidreau, Y.; Besson, T. Tetrahedron 2011, 67, 4852–4857.
7. Stewart, R.; Harris, M. G. J. Org. Chem. 1978, 43, 3123–3126.
8. Microwave experiments were conducted in a commercial microwave reactor
especially designed for synthetic chemistry. RotoSYNTHTM (Milestone S.r.l.
Italy) is a multi-mode cavity with a microwave power delivery system ranging
from 0 to 1200 W. Open vessel experiments were carried out in 50 or 100 mL
round bottom flasks fitted with
monitored via contactless-infrared pyrometer which was calibrated by
control experiments with fiber-optic contact thermometer. The vessel
a reflux condenser. Temperature was
a
a
contents were stirred by means of an adjustable rotating magnetic plate
located below the floor of the microwave cavity and a Teflon-coated magnetic
stir bar inside the vessel. Temperature, pressure, and power profiles were
monitored in both cases through the EASY-Control software provided by the
manufacturer.
9. Lost dissipation factor (tan d) expresses the capacity of a molecule or a material
to transform electromagnetic energy into thermal energy.
A very high
susceptibility to microwaves is characterized by a high value (>0.5) of tan d.
Tan d (acetic acid) = 0.174 at 2.45 GHz. For more details see: Gabriel, C.;
Gabriel, S.; Grant, E. H.; Halstead, B. S. J.; Mingos, D. M. P. Chem. Soc. Rev. 1998,
27, 213–224.
Acknowledgments
Financial support from the MESR (Ministere de l’Enseignement
Superieur et de la Recherche) is gratefully acknowledged for the
doctoral fellowships to D.H. We thank the LABEX SynOrg (ANR-
11-LABX-0029) and AI-Chem Channel program for financial sup-
port. We also acknowledge Milestone S.r.l. (Italy) for provision of
the microwave reactors and technical support.
10. Except for compounds 10e and 10f (previously described in: Hou, G.; Gravier,
D.; Casadebaig, F.; Dupin, J.-P.; Bernard, H.; Boisseau, M. Pharmazie 1995, 50,
719–722) all the pyridopyrimidin-4-ones 10a–d, 11a–f and 12a–f described in
this paper can be considered as new products.