Microwave-assisted synthesis of diversely substituted quinoline-based dihydropyridopyrimidine and dihydropyrazolopyridine hybrids

Article abstract of DOI:10.1021/acscombsci.7b00091

An efficient, catalyst-free, and one-pot three-component procedure for the synthesis of novel and nitrogen rich dihydropyrido[2, 3-d]pyrimidines and dihydro-1H-pyrazolo[3, 4-b]pyridines bearing a quinoline pharmacophore fragment is provided. Reactions proceeded in DMF under microwave irradiation of three-component mixtures of formyl-quinoline derivatives, primary heterocyclic amines and cyclic 1, 3-diketones. Interestingly, when conventional heating at reflux was used for the starting 5-amino-1-phenylpyrazole, the corresponding aromatized pyrazolopyridines were obtained as the main products. Single crystal X-ray analysis confirmed unequivocally the structure of both the dihydro- and aromatized products.

Full text of DOI:10.1021/acscombsci.7b00091

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Article
Microwave-assisted synthesis of diversely substituted quinoline-
based dihydropyridopyrimidine and dihydropyrazolopyridine hybrids
Daniel Insuasty, Rodrigo Abonia, Braulio Insuasty, Jairo
Quiroga, Kenneth K Laali, Manuel Nogueras, and Justo Cobo
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.7b00091 • Publication Date (Web): 19 Jul 2017
Downloaded from http://pubs.acs.org on July 20, 2017
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Microwaveꢀassisted synthesis of diversely
substituted quinolineꢀbased
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dihydropyridopyrimidine and
dihydropyrazolopyridine hybrids
Daniel Insuasty,† Rodrigo Abonia,†* Braulio Insuasty,† Jairo Quiroga,† Kenneth K. Laali,‡
Manuel Nogueras, § and Justo Cobo§
†Research Group of Heterocyclic Compounds (GICH), Department of Chemistry, Universidad
del Valle, A. A. 25360, Cali, Colombia
‡Department of Chemistry, University of North Florida, 1 UNF Drive, Jacksonville, FL 32224,
USA
§Department of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
KEYWORDS: Three-component reaction, quinolines, primary heterocyclic amines, microwave
irradiation, dihydropyrido[2,3-d]pyrimidines, dihydro-1H-pyrazolo[3,4-b]pyridines
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ABSTRACT: An efficient, catalystꢀfree and oneꢀpot threeꢀcomponent procedure for the
synthesis of novel and nitrogen rich dihydropyrido[2,3ꢀd]pyrimidines and dihydroꢀ1Hꢀ
pyrazolo[3,4ꢀb]pyridines bearing a quinoline pharmacophore fragment is provided. Reactions
proceeded in DMF under microwave irradiation of threeꢀcomponent mixtures of formylꢀ
quinoline derivatives, primary heterocyclic amines and cyclic 1,3ꢀdiketones. Interestingly, when
conventional heating at reflux was used for the starting 5ꢀaminoꢀ1ꢀphenylpyrazole, the
corresponding aromatized pyrazolopyridines were obtained as the main products. Single crystal
Xꢀray analysis confirmed unequivocally the structure of both the dihydroꢀ and aromatized
products.
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INTRODUCTION
The pyrimidine core has been widely studied due to its presence in numerous natural products
and in structurally diverse synthetic derivatives.1 In particular, pyridopyrimidines and
pyrazolopyridines have received considerable attention over the past years, due to their wide
ranging biological activities, mainly as antifolates,2 showing related antiproliferative properties
such as anticancer,3 antiꢀinflammatory,4 antimicrobial5 or antihistaminic6 agents. Figure 1 shows
several examples of bioactive compound with these core structures. The BPIPP 1 was identified
as novel potent inhibitor of cyclic nucleotide biosynthesis and a promising lead compound for
treatment of diarrhea and other diseases.7 Other linear tricyclic derivatives like pyrimido[4,5ꢀ
b][1,6]naphthyridines 28 and pyrazolo[3,4ꢀb]pyridines 3,9 exhibited significant anticancer
activity, while the BPIPP analogues 4 were evaluated against fifteen Mycobacterium spp strains,
some of them displaying remarkable antimycobacterial activity.10
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Figure 1. Examples of bioactive pyrido[2,3ꢀd]pyrimidine and pyrazolo[3,4ꢀb]pyridine
derivatives.
On the other hand, quinolines and their oxoꢀderivatives are another important class of
heterocyclic compounds in chemistry, biology, medicine and in applied pharmacy. Examples of
some bioactive quinolone based derivatives are displayed in Figure 2: thus, the 2ꢀ
alkoxyquinoline and Nꢀalkylated quinolinone derivatives 5 and 6 were evaluated as potent and
selective cannabinoidꢀ2 receptor ligands through a bioisosteric approach,11 while, the quinolineꢀ
2ꢀone hybrids 7-10 are considered as antitumor agents,12a,b including a series of chalcones 9 and
benzimidazoloquinolinꢀ2ꢀones 10 that we have recently reported.12c,d
N
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H
Figure 2. Examples of bioactive quinolineꢀhybrids.
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Focusing on the synthetic methodologies, the multicomponent reactions (MCRs) have become a
powerful tool for accessing a vast number of synthetic and pharmaceutically relevant
compounds. The main advantages of the MRCs are high reaction rates, selectivity and efficiency,
as well as, low costs, high variability, high bond forming efficiency, simplicity and
environmentally friendly properties.13 In the same way, microwave assisted organic synthesis
(MAOS) is also a powerful tool, because it can decrease reaction times, improve yields and
purity of the final compounds, through the control of parameters such as temperature, pressure
and power irradiation.14 Therefore, the combination of both MCR and (MAOS) strategies offers
a rapid and cost efficient synthetic strategy to prepare diverse natural occurring and synthetic
products of great interest to fine chemical and drug discovery endeavors.
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In connection with our continuing interest in the synthesis of bioactive nitrogenꢀcontaining
heterocyclic compounds bearing the quinoline pharmacophore fragment,12c,15 herein we report a
versatile and efficient method for the preparation of diversely substituted quinolineꢀhybrids, with
dihydropyrido[2,3ꢀd]pyrimidines and dihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridines, by means of
microwave irradiation (MWI) assisted, oneꢀpot, threeꢀcomponent reaction with various
heterocyclic primary amines, cyclic 1,3ꢀdiketones and diverse 3ꢀformyl Nꢀ / Oꢀalkylꢀquinolines.
RESULTS AND DISCUSSION
According to previous related reports on the dihydropyrido[2,3ꢀd]pyrimidine core
construction,7,8,16 we visualized that parent frameworks could be synthesized bearing the
outstanding quinoline pharmacophore in their structures. In order to obtain the desired products
via a threeꢀcomponent protocol, several synthetic approaches were tested involving diverse
solvents, along with conventional heating or microwave irradiation, in an effort to find optimal
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reaction conditions for our transformations. In all cases, reactions were carried out between
dimedone 11{1}, 2,4,6ꢀtriaminopyrimidine 12{1} and 3ꢀformylꢀ2ꢀoxoꢀquinoline 13{1} as a
model reaction (see Table 1). Initially, stirring of an equimolar mixture of the above threeꢀ
components in ethanol (5 mL) at reflux, did not afford the product after 20 h of heating (TLC
monitoring). The limitation was associated to the low solubility of both pyrimidine 12{1} and
aldehyde 13{1} in this solvent (Table 1, entry 1). The problem was resolved with the use of
DMF instead of ethanol, and heating the ternary mixture in DMF at reflux gave the expected
product 14{1,1,1} (linear isomer), albeit in only 38% isolated yield after 20 h of reflux (Table 1,
entry 2). In order to improve the reaction yield, our model reaction was carried out by applying
MWI in DMF (1 mL) as the solvent at different temperatures (Table 1, entries 3ꢀ5). From the
best result, the linear isomer dihydropyridopyrimidine 14{1,1,1} was isolated in 82% yield after
8 min of irradiation at 130 oC (Table 1, entry 5).
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Table 1. Optimization of the reaction conditions for the threeꢀcomponent synthesis of
dihydropyridopyrimidine 14{1,1,1}
NH2
NH2
1N
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H
and/or
C
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NH2
NH2
H2N
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Conditions
NH
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11{1}
(0.3g, 1.0 equiv)
12{1}
13{1}
(1.0 equiv)
14{1,1,1}
Linear isomer
14{1,1,1}
Angular isomer
(1.0 equiv)
Entry
Conditions
Time
Yield (%)
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5
ethanol, reflux
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20 h
ꢀ
DMF, reflux
DMF, MWI, 70 oC
DMF, MWI, 100 oC
DMF, MWI, 130 oC
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12 min
8 min
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DMF, MWI, 150 oC
aSome decomposition products accompanied this assay.
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The linear structure of the obtained compound 14{1,1,1} was ascertained by IR, 1D and 2D
NMR and MS spectrometric analysis. The most relevant spectroscopic features in the IR
spectrum correspond to the presence of three NH and NH2 absorption broad bands at 3404, 3340
and 3170 cmꢀ1 and two C=O absorption bands at 1645 and 1614 cmꢀ1. In the 1H NMR spectrum,
among others, the presence of two singlets at 0.99 and 1.04 ppm (integrating for 3H each), two
doublets at 1.95 and 2.18 ppm (integrating for 1H each) and a singlet overlapped with the DMSO
at 2.5 ppm. These five signals are assigned to the dimedone residue. Presence of a singlet at 5.06
ppm integrating for 1H assigned to Hꢀ5 proton, along with a broad singlet at 9.36 ppm
corresponding to the 10ꢀNH functionality agree with the formation of the dihydropyrido[2,3ꢀ
d]pyrimidine framework 14{1,1,1}. Additionally, NOESY experiments confirmed the formation
of the linear isomer instead of its angular regioisomers. In this case spatial NOE correlations
between Hꢀ9 and 10ꢀNH protons, as well as, 4ꢀNH2 and Hꢀ5 protons were clearly observed,
among others. In the 13C NMR spectrum the presence, among others, of six aliphatic signals (i.e.
two CH3, one Cq, two CH2 and one CH) also agrees with the proposed structure for 14{1,1,1}. In
particular, the 5ꢀCH signal at 27.9 ppm confirms the formation of the hydropyridinic moiety in
such structure. A molecular ion peak with m/z 402, also confirmed in such a structure.
In order to evaluate the reproducibility and application scope of this approach, a diversely
substituted chemset of 3ꢀformylꢀ2ꢀoxoꢀquinolines 13{1-9} and 3ꢀformylꢀ2ꢀalkoxyꢀquinolines
13{10-14} was synthesized. Firstly, the 2ꢀchloroquinolineꢀ3ꢀcarbaldehydes 17{1-6} were
obtained from a MethꢀCohn type methodology mediated by the VilsmeierꢀHaack (DMF +
POCl3) reagent.17 Subsequent treatment of compounds 17 with AcOH at reflux led to isolation of
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3ꢀformylꢀ2ꢀoxoꢀquinolines 13{1-6}. The alkylation and benzylation of compounds 13{1-6} with
1ꢀbromobutane and benzyl bromide, respectively, afforded the remaining Nꢀ/Oꢀbutylꢀ and Nꢀ/Oꢀ
benzylꢀquinolines 13{7-9} and 13{10-14}, respectively, Scheme 1 and Figure 3.
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Scheme 1. General procedure for the synthesis of the starting formyl-quinolines 13.
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Figure 3. Diversely substituted 3ꢀformylꢀquinolines 13 employed as reagents for the synthesis of
the title compounds 14.
In addition to the above results, and in an effort to increase diversity in this threeꢀcomponent
strategy a chemset of cyclic 1,3ꢀdiketones 11{1-3} and primary heterocyclic amines 12{1-4} was
considered, Figure 4. It was also necessary to prepare aminopyrimidines 12{2-3} and
aminopyrazole 12{4} because these reagents are not commercially available.18,19
Figure 4. Diverse chemset of cyclic 1,3ꢀdiketones 11 and heterocyclic primary amines 12 to be
used in the MCR.
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It is noteworthy that reaction between diketones 11{1-3}, aminopyrimidines 12{1-3}, and 3ꢀ
formylꢀquinolines 13{1-14} under the MWI established reaction conditions, satisfactorily led the
expected products 14 in all cases. Reactions proceeded in similar way than that for 14{1,1,1}
with yields in the range of 68ꢀ86% (Table 2). Their structures were also confirmed by a complete
analytical and spectroscopic analysis.
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Table 2. Threeꢀcomponent MAOS of the dihydropyrido[2,3ꢀd]pyrimidines 14.
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Continued Table 2
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Additionally, single crystals of compound 14{3,3,10} suitable for Xꢀray diffraction were
grown from a solution of DMF at ambient temperature, Figure 5. (See also Supporting
Information). The Xꢀray molecular structure confirm the formation of the linear
dihydropyrido[2,3ꢀd]pyrimidine framework in 14 without ambiguity.
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Figure 5. Displacement ellipsoid plots (40% probability level) of (a) the asymmetric unit for
the racemic 14{3,3,10} DMF solvate. (b) Molecular structure of (S)ꢀsteroisomer (Mercury 3.8).
In order to expand the generality of this procedure toward primary heterocyclic amines, we
subjected the previously synthesized 5ꢀaminoꢀ3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazol 12{4}, Figure 4, as
well as selected diketones 11 and fomylꢀquinolines 13 to our established methodology. This
approach afforded the expected dihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridine frameworks 18 in the range
of 15ꢀ63% isolated yield, Table 3. It is worth mentioning that these yields are relatively lower
than those obtained from the aminopyrimidines 12{1-3}.
Table 3. Threeꢀcomponent MAOS of dihydroꢀ1Hꢀpyrazolo[3,4ꢀb]pyridines 18 and their aromatized
analogues 19.
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We assume that the modest yields of compounds 18 are associated with decomposition of the
starting amine 12{4} under the reaction conditions, detected during the course of the reaction
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and confirmed by controlled experiments. In an attempt to improve the reaction yields of the
pyrazoloꢀderivatives 18, we decided to return to the earlier reaction conditions in DMF at reflux
under conventional heating (i.e. entry 2, Table 1. Reflux by 8 h), specifically for the assays with
aminopyrazole 12{4}. Interestingly, the reaction proceeded with less decomposition of amine
12{4} and better yields (62ꢀ79%) were achieved by employing this approach although the
isolated products corresponded to the aromatized pyrazolo[3,4ꢀb]pyridine analogues 19 instead
of their expected dihydroꢀderivative ones 18, specifically, when R1 = H (see compounds
19{1,4,1} through 19{2,2,4} in Table 2 and compare with their analogues 18). We suggest that
in this case the reactions proceed through the initial formation of the dihydroꢀderivatives 18, and
under the reaction conditions undergo subsequent aromatization, leading to the isolated products
19. Spectroscopic analysis support the proposed structures for 19.
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In order to confirm the suggested aromatization process, we were able to obtain single crystals
of the corresponding isolated product 19{1,4,1} from DMF. The analysis by Xꢀray diffraction
showed the formation of the aromatized pyrazolo[3,4ꢀb]pyridine framework in products 19,
Figure 6. (See also Supporting Information).
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Figure 6. Displacement ellipsoid plot (40% probability level) corresponding to the dimeric
unit formed by a cyclic intermolecular hydrogen bonding of two asymmetric units of compound
19{1,4,1} (Mercury 3.8).
It should be noted that the aromatization process was exclusively observed for the
aminopyrazole 12{4} derivatives but not for those obtained from aminopyrimidines 12{1-3}.
Apparently the starting formylꢀquinolines 13{1-4} R1 = H (but not their Nꢀalkylated analogues
13{7,9}), under the refluxing reaction conditions (not MWI), are contributing factors for this
transformation.
A similar process toward aromatized pyridine rings has previously been reported in the
literature when aminopyrazoles were used instead of aminopyrimidines.20
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According to these results, it may be suggested that the synthesis of the linear
dihydroderivatives 14 and 18 starts with in situ formation of the α,βꢀinsaturated intermediate 20
via an aldol condensation between ketone 11 and formylꢀquinoline 13. Subsequently, a Michael
addition of the amine 12 to intermediate 20 furnishes the ketoꢀamine 21 (route a). Next, an
intramolecular attack of the amino group onto the carbonyl functionality on structure 21 leads the
isolated linear products 14 and 18 with elimination of a molecule of water, as can be depicted in
Scheme 2. It is noteworthy that the Michael addition of 12 towards 20 proceeds exclusively by
the βꢀcarbon atom of 12 (route a), but not by the amino group (route b). This latter addition
would have led to angular isomeric products instead of the obtained linear ones.
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Scheme 2. Proposed mechanistic sequence for the formation of the linear dihydroꢀderivatives 14
and 18.
Taking into account that our synthetized compounds are hybrids of biological interest,2,12,15 some
selected structures were subjected to preliminary antitumor assays. Initially, the structures of all
new compounds 14, 18 and 19 were submitted to the Developmental Therapeutics Program
(DTP) at National Cancer Institute (NCI), Bethesda, MD (USA), for evaluation of their viability
as anticancer agents against different human cell lines.
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Then, the output from the single dose screening was analyzed by the COMPARE program21
(data not shown), and compounds 14{1,1,2}. (NSC: 783179/1), 14{1,1,3} (NSC: 783180/1),
14{1,2,1} (NSC: 784183/1), 14{1,2,3} (NSC: 784181/1), 14{1,2,12} (NSC: 784184/1), ),
14{3,3,10} (NSC: 784185/1), 18{1,4,1} (NSC: 784178/1), 18{1,4,2} (NSC: 784179/1),
18{1,4,4} (NSC: 784180/1), were selected by the Drug Evaluation Branch of the (NCI) for in
vitro antiproliferative screening against a panel of 60 cancer cell lines at a single dose of 10 µM.
The 60 cell panel is derived from nine different cancer types: Leukemia, Non-Small Cell Lung,
Melanoma, Colon, CNS, Ovary, Renal, Breast and Prostate cancers. Results for each compound
were reported as a mean graph of the growth percent (GP) of the treated cells and they are
illustrated in Table 4 for the more sensitive lines. The synthesized compounds displayed
moderate to low activity in the in vitro screening on all tested cancer cell lines, being compound
18{1,4,4} the most active of the series against NCIꢀH522 cell line (Non-Small Cell Lung panel)
with a GP = 40.23%, followed by Tꢀ47D (Breast panel) with a GP = 59.00%. Compounds
14{1,1,2}, 14{1,1,3} and 14{1,2,3} showed moderate activity against NCIꢀH522 (Non-Small
Cell Lung panel) with GP = 64.10%, 66.32 and 61.15, respectively. The remaining compounds in
Table 4 showed less activity with an average growth percent of 65.23 ꢀ 89.76.
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Table 4. Range and mean growth % of NCI human cancer cell lines treated with some selected
compounds 14 and 18 at oneꢀdose 10 µM.
Some selected cell lines of the 60 cell lines panel assayed by the NCI
NSC: number
Mean
GP
Most sensitive cell lines
GP of the most
sensitive cell lines
Compound
NCIꢀH522 (Non-Small Cell
Lung)
64.10
NSC:
783179/1
14{1,1,2}.
96.19
A498 (Renal)
71.02
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NCIꢀH522 (Non-Small Cell
66.32
NSC:
783180/1
Lung)
14{1,1,3}
14{1,2,1}
14{1,2,3}
14{1,2,12}
14{3,3,10}
95.84
99.08
99.55
102.78
97.05
UACCꢀ257 (Melanoma)
76.33
73.75
NCIꢀH522 (Non-Small Cell
Lung)
NSC:
784183/1
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TKꢀ10 (Renal)
76.57
61.15
NCIꢀH522 (Non-Small Cell
Lung)
NSC:
784181/1
TKꢀ10 (Colon)
80.05
77.32
NCIꢀH522 (Non-Small Cell
Lung)
NSC:
784184/1
SNBꢀ75 (CNS)
87.16
72.97
NCIꢀH226 (Non-Small Cell
Lung)
NSC:
784185/1
MALMEꢀ3M (Melanoma)
76.23
75.42
A549/ATCC (Non-Small Cell
Lung)
NSC:
784178/1
18{1,4,1}
99.17
NCIꢀH226 (Non-Small Cell
Lung)
74.85
PCꢀ3 (Prostate)
Tꢀ47D (Breast)
84.19
86.18
NSC:
784179/1
18{1,4,2}
18{1,4,4}
97.84
NCIꢀH522 (Non-Small Cell
Lung)
40.23
59.00
NSC:
186.07
784180/
Tꢀ47D (Breast)
In summary, we have developed an efficient, catalystꢀfree, three component approach for the
synthesis of novel and diversely substituted linear dihydropyridopyrimidines 14 and
dihydropyrazolopyridines 18 mediated by MWI. When conventional heating at reflux was used
in the case of the starting aminopyrazole 12{4}, aromatized pyrazolopyridines 19 were obtained
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as the main products, specifically, for formylꢀquinolones 13 having R1 = H. This process should
involve the previous formation of the corresponding hydroꢀderivatives 18. Subsequent
oxidation/aromatization is apparently influenced by the mode of heating and the structure of the
formylꢀquinoline used. Considering that overall three starting materials are stoichiometrically
consumed in the course of the reactions forming three new bonds (i.e. 2 x CꢀC and a CꢀN) in
only oneꢀstep, and with water as the only byꢀproducts, the present approach brings together
outstanding bondꢀforming efficiency and environmentally friendly quality. Preliminary in vitro
antitumor assays at a single dose of 10 µM showed that the evaluated compounds displayed
moderate to low activity against all tested cancer cell lines.
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EXPERIMENTAL PROCEDURES
General: Melting points were measured using a Stuart SMP3 melting point apparatus and are
uncorrected. IR spectra were recorded on a Shimadzu IRAffinityꢀ1 Spectrophotometer in KBr
1
disks. H and 13C NMR spectra were recorded on a Bruker Avance 400 spectrophotometer
operating at 400 MHz and 100 MHz respectively, using DMSOꢀd6 as solvent and
tetramethylsilane as internal standard. Mass spectra were run on a SHIMADZUꢀGCMS 2010ꢀDIꢀ
2010 spectrometer (equipped with a direct inlet probe) operating at 70 eV. High resolution Mass
spectra were run on a Waters Micromass AutoSpecꢀUltima spectrometer (equipped with a direct
inlet probe) operating at 70 eV. Microanalyses were performed on an Agilent CHNS elemental
analyzer and the values are within ± 0.4% of the theoretical values. Singleꢀcrystal Xꢀray data for
compounds 14{3,3,10} and 19{1,4,1} were collected at room temperature (298 K) on a Bruker
D8 Venture (APEX 3) diffractometer and deposited at Cambridge Crystallographic Data Center.
Microwave experiments were carried out using a focused microwave reactor (CEM Discover
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TM), with dynamic method. TLC analyses were performed on silica gel aluminum plates (Merck
60 F254) and spots visualized with ultraꢀviolet irradiation. The starting cyclic diketones 11{1-3},
triamine 12{1}, precursors and reagents for the synthesis of amines 12{2-4} and formylꢀ
quinolines 13{1-14}, and the required solvents were purchased from SigmaꢀAldrich, Fluka and
Merck (analytical grade reagent), and were used without further purification.
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General procedure for the synthesis of the dihydropyrido[2,3-d]pyrimidines 14 and
dihydro-1H-pyrazolo[3,4-b]pyridines 18 under MWI. A mixture of equimolar amounts of the
aminopyrimidine 12{1-3} or 5ꢀaminopyrazol 12{4} (0.05 mmol), cyclic diketone 11{1-3} (0.05
mmol) and the formylꢀquinoline 13{1-14} (0.05 mmol) in DMF (1.0 mL), was subjected to MWI
for 8ꢀ20 min at 125ꢀ135 °C, 250 W of power and 30 PSI of pressure. After finish (TLC
monitoring), the reaction mixture was allowed to cool to room temperature, the solids formed
were collected by filtration, washed with ethanol (2 x 3 mL) and dried in air. No further
purification was required.
General procedure for the synthesis of the pyrazolo[3,4-b]pyridines 19 under
conventional heating at reflux. A dry 25 mL oneꢀneck flask was charged with 5ꢀaminopyrazole
12{4} (0.05 mmol), cyclic diketones 11{1,2} (0.05 mmol), formylꢀquinolines 13{1,4} (0.05
mmol) and DMF (5 mL). The reaction mixture was stirred at reflux for 8 h (TLC monitoring),
and the solid formed was filtered under reduced pressure and washed repeatedly with warm
ethanol. No further purification was required.
ASSOCIATED CONTENT
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Supporting Information. Detailed experimental procedures, compound characterization data,
1H, 13C NMR spectra for all products and Xꢀray diffraction data. This material is available free of
charge via the Internet at http://pubs.acs.org
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: rodrigo.abonia@correounivalle.edu.co
ACKNOWLEDGMENT
Authors thank COLCIENCIAS, Universidad del ValleꢀProject Number 110665842661, the
Spanish “Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía” and “Centro de
Instrumentación CientíficoꢀTécnico de la Universidad de Jaén” for financial support. The
Developmental Therapeutics Program (DTP) of the National Cancer Institute of the United
States (U.S.) is also acknowledged by performing the preliminary in vitro anticancer screening to
the selected compounds.
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potential antiꢀtumor activity. Eur. J. Med. Chem. 2012, 57, 29–40; (d) Abonia, R.; Cortés, E.;
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benzimidazoles as potential antitumor agents. Eur. J. Med. Chem. 2011, 46, 4062–4070.
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substituted 2ꢀpyrazoline with antiproliferative and antifungal activity. Molecules 2016, 21, 969.
doi:10.3390/molecules21080969; (b) Montoya, A.; Quiroga, J.; Abonia, R.; Nogueras, M.; Cobo,
J.; Insuasty, B. Synthesis and in vitro antitumor activity of a novel series of 2ꢀpyrazoline
derivatives bearing the 4ꢀaryloxyꢀ7ꢀchloroquinoline fragment. Molecules 2014, 19, 18656–
18675; (c) Laali, K. K.; Insuasty, D.; Abonia, R.; Insuasty, B.; Bunge, S. D. Novel quinolineꢀ
imidazolium adducts via the reaction of 2ꢀoxoquinolineꢀ3ꢀcarbaldehyde and quinolineꢀ3ꢀ
carbaldehydes with 1ꢀbutylꢀ3ꢀmethylimidazolium chloride [BMIM][Cl]. Tetrahedron Lett. 2014,
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Abonia, R.; Montoya, A.; Svetaz, L.; Zacchino, S.; Insuasty, B. Synthesis of novel quinoline–
based 4,5–dihydro–1H–pyrazoles as potential anticancer, antifungal, antibacterial and
antiprotozoal agents. Eur. J. Med. Chem. 2014, 131, 237–254.
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component reaction of 2ꢀchloroquinolineꢀ3ꢀcarbaldehydes, 6ꢀaminouracils, and cyclic methylene
active compounds. Tetrahedron Lett. 2016, 57, 5435–5438.
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and related fused pyridines. Tetrahedron Lett. 1978, 19, 2045–2048; (b) MethꢀCohn, O.; Narine,
B.; Tarnowski, B. A versatile new synthesis of quinolines and related fused pyridines, Part 5.
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(18) Aminopyrimidones 13{2-3} were prepared by an adaptation of the original procedure
described in (a) Engelmann, M. Üeber eine Synthese des 1ꢀMethylxanthins. Chem. Ber. 1909,
42, 177; (b) Pfleiderer, W. Untersuchungen in der Pyrimidinreihe, III. Über die Darstellung von
4.5‐Diamino‐Pyrimidinen. Chem. Ber. 1957, 90, 2272–2275.
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(19) Aminopyrazole 12{4} was prepared according to the procedure described by us in (a)
Abonia, R.; Albornoz, A.; Larrahondo, H.; Quiroga, J.; Insuasty, B.; Insuasty, H.; Hormaza, A.;
Sánchez, A.; Nogueras, M. Synthesis of pyrazole and pyrimidine Tröger´sꢀbase analogues. J.
Chem. Soc., Perkin Trans. 1 2002, 1588–1591; (b) Quiroga, J.; Portilla, J.; Abonia, R.; Insuasty,
B.; Nogueras, M.; Cobo, J. Synthesis of novel 5ꢀaminoꢀ1ꢀaroylpyrazoles. Tetrahedron Lett.
2008, 49, 5943–5945.
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pyrimido[4,5ꢀb][1,6]naphthyridine and its derivatives under microwave irradiation. J. Comb.
Chem. 2009, 11, 809–812.
(21) For information about the COMPARE program, please visit the web
site:http://dtp.nci.nih.gov/compare/.
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Microwave-assisted synthesis of diversely substituted quinoline-based
dihydropyridopyrimidine and dihydropyrazolopyridine hybrids
9
Daniel Insuasty,† Rodrigo Abonia,†* Braulio Insuasty,† Jairo Quiroga,† Kenneth K. Laali,‡ Manuel
Nogueras, § and Justo Cobo§
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†Research Group of Heterocyclic Compounds (GICH), Department of Chemistry, Universidad del Valle,
A. A. 25360, Cali, Colombia
‡Department of Chemistry, University of North Florida, 1 UNF Drive, Jacksonville, FL 32224, USA
§Department of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
NH2
N
O
H
N
N
N
N
NH2
H2N
+
NH2
X
N
NH2
R1
HN
O
N
O
O
O
O
O
H
+
R1
-
2 H2O
NH2
RO
N
R
RO
R
O
O
O
O
examples
O
26
H
R1
15-86%
yield
H
Microwave
irradiation
R1
O
N
R
RO
N
O
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