Accelerating lead optimization of chromone carboxamide scaffold throughout microwave-assisted organic synthesis

Article abstract of DOI:10.1016/j.tetlet.2011.09.095

Microwave irradiation offers a considerable advantage over conventional synthesis with rate enhancements and cleaner reactions. Accordingly, a new microwave-assisted method for the synthesis of func-tionalized chromones was developed allowing the obtention of a library of chromone carboxamides. The method has been shown to present several advantages including operational simplicity, good performance, significant reduction in reaction time, less formation of by-products, and easier work-up.

Full text of DOI:10.1016/j.tetlet.2011.09.095

Tetrahedron Letters 52 (2011) 6446–6449
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Accelerating lead optimization of chromone carboxamide scaffold
throughout microwave-assisted organic synthesis
⇑
Fernando Cagide, Joana Reis, Alexandra Gaspar, Fernanda Borges
CIQUP, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave irradiation offers a considerable advantage over conventional synthesis with rate enhance-
ments and cleaner reactions. Accordingly, a new microwave-assisted method for the synthesis of func-
tionalized chromones was developed allowing the obtention of a library of chromone carboxamides.
The method has been shown to present several advantages including operational simplicity, good perfor-
mance, significant reduction in reaction time, less formation of by-products, and easier work-up.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 6 August 2011
Revised 15 September 2011
Accepted 20 September 2011
Available online 22 September 2011
Keywords:
Chromone carboxamide
Microwave-assisted organic synthesis
Lead optimization program
PyBOP
PCl3O
Microwave chemistry and microwave-assisted organic synthe-
sis (MAOs) are nowadays undeniably effective tools in medicinal
chemistry.1 The availability of safe, single-mode dedicated micro-
wave units has allowed the incorporation of this new technology
into accelerating drug-discovery, hit-to-lead, and lead optimiza-
tion programs. The development of more economical synthetic
routes can ameliorate the overall process since drug discovery is
a costly exercise with a high attrition rate.1
The use of MAOs has been shown to dramatically reduce process-
ing times, increase product yields, and enhance the purity of the
product when compared to the conventionally processed experi-
ments.1 Since there are several manufacturers of professional-grade
equipment and a plethora of adapted methods, one can conclude
that this interest continues to grow.2
Privileged structures, such as benzopyranes are currently de-
scribed as supportive approaches in drug discovery. In fact, different
natural heterocyclic families, such as xanthones and coumarinshave
been used as scaffolds in medicinal chemistry programs, namely for
the search of novel monoamine oxidase inhibitors.3,4 Chromones
(benzopyran-4-one) are a group of similar naturally occurring het-
erocyclic compounds. They occupy an important place in the realm
of natural products and in synthetic organic chemistry due to their
particular structural features. Chromone scaffold has been recog-
nized as a pharmacophore of a great number of bioactive molecules.
The remarkable biological properties discovered so far have stimu-
lated a continuous search in this field that leads at present to the
appearance of some drugs on the market.5,6 The functionalization
of the chromone nucleus originates interesting derivatives, namely
those possessing a reactive carbonyl group (aldehyde or carboxylic
acid), that are versatile synthons owing to its ability to participate
in a wide spectrum of reactions, for instance the reactivity toward
nucleophiles.7,8
Noteworthy data have been previously acquired to strengthen
the interest of chromone carboxamides as potent and selective
monoamine oxidase inhibitors (IMAO).9,10 The reported chromone
carboxamide synthesis9,10 correspond to a one-pot condensation
reaction that occurs between the corresponding chromone carbox-
ylic acid and aniline (phenylamine), or its ring-substituted deriva-
tives. The coupling reagent selected for carboxylic acid activation
was an organophosphoric compound designated as (benzotriazol-
1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (Py-
BOP).9,10 Although effective this reagent is very expensive and the
work-up of the reactions was very tedious and time-consuming.
Keeping in view these observations and in continuation of our
project on medium-throughput screenings of diverse chromone
carboxamides, toward a number of targets involved in neurode-
generative disorders, a larger number of synthetic analogues are
expected to be needed.
In an attempt to accelerate the synthetic process the application
of microwave-assisted methods was envisaged. Accordingly, a so-
lid evidence of the benefits of a microwave synthetic approach over
the conventional synthetic method (with PyBOP as the coupling
agent) has been acquired along this study.
The synthesis of chromone carboxamide (3) as a model sub-
strate, using the chromone carboxylic acid (1) and aniline (2),
⇑
Corresponding author. Tel.: +351 220402560.
E-mail address: fborges@fc.up.pt (F. Borges).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.095

F. Cagide et al. / Tetrahedron Letters 52 (2011) 6446–6449
6447
Table 1
Microwave-assisted optimization conditions for the synthesis of chromone carboxamide (3)
O
O
O
O
H2N
N
H
OH
+
O
3
O
1
2
Entry
Solvent
T (°C)
Coupling agent (mmol)
2 (mmol)
Timea (min)
Yield (%)
1
2
3
4
5
6
7
8
DMF
DMF
DMF
Xylene
Dioxan
DMF
DMF
DMF
DMF
DMF
DMF
DMF
160
160
160
160
160
100
200
160
160
160
160
160
PCl3 (1)
1
1
1
1
1
1
1
1
1
4
1
1
5
5
5
5
5
5
5
2
10
5
5
5
55
b
PBr3O (1)
PCl3O (1)
PCl3O (1)
PCl3O (1)
PCl3O (1)
PCl3O (1)
PCl3O (1)
PCl3O (1)
PCl3O (1)
PCl3O (0.4)
PCl3O (1.5)
82
—
22
47
40
41
78
81
35
61
9
10
11
12
— No reaction.
a
Irradiation time.
Complex mixture.
b
Table 2
Data from the comparative study between conventional versus microwave method
O
O
R
O
O
O
O
H2N
N
H
OH
R
+
Entry
Compound
Aniline Derivative
Chromone carboxamide
Yield (%)
PyBop
MW
82
H2N
O
O
N
1
3
81
50
23
23
H
O
H2N
Cl
O
O
N
Cl
2
3
4
4
5
6
59
76
78
H
O
O
O
H2N
Cl
N
H
Cl
O
O
H2N
O
N
H
Cl
Cl
O
(continued on next page)

6448
F. Cagide et al. / Tetrahedron Letters 52 (2011) 6446–6449
Table 2 (continued)
Entry
Compound
Aniline Derivative
Chromone carboxamide
Yield (%)
PyBop
38
MW
65
H2N
O
O
N
H
5
6
7
7
O
O
H2N
O
N
8
9
56
72
65
65
H
O
O
H2N
H2N
O
N
H
O
O
O
O
N
O
8
9
10
11
12
85
45
—
67
71
18
H
O
H2N
H2N
O
O
O
O
O
O
N
H
O
NO2
O
O
N
NO2
10
H
O
—, No reaction.
was initially chosen for the optimization of the microwave reaction
conditions (see method A11). The simple structure of the com-
pound as well as the synthetic data obtained so far, with other cou-
pling agents such as SOCl2, BOP, EDC, was vital to this decision.
Accordingly, different experimental conditions were explored to
attain optimization: type of phosphorus coupling agent, solvent,
stoichiometry, time, and temperature (Table 1).12
the reaction whereas the variations on the PCl3O quantity resulted
in a yield decrease (Table 1, entry 11 vs 12).
After optimization of the experimental variables the versatil-
ity of the microwave-assisted amidation reaction was tested
using different phenylamines as the starting material, (with di-
verse aromatic substitution patterns) reflecting different effects
in the amine nucleophilicity (method A11). The results of the
reaction (yield corresponding to the pure chromone product)
were compared with the conventional synthetic method using
PyBOP as the coupling agent (method B11). The results obtained
with method B were remarkably inferior, except in the case of
compounds 9 and 10 (Table 2, entries 7 and 8). No difference be-
tween the methods was observed with compound 3 (Table 2, en-
try 1).
The introduction of substituents in the exocyclic aromatic ring
of the chromone carboxamide scaffold was recognized to be a
disadvantage for the reaction (Table 2, entry 1), in terms of yield
performance, either with anilines possessing electron withdrawing
(Table 2, entries 2–4 and 10) or donating substituents (Table 2, en-
tries 5–9). The position of the substituent in the aromatic ring
(ortho, meta or para), had no significant influence on the yield both
for a weak electron releasing group (Table 2, entries 5–7,) or for a
weak electron withdrawing group (Table 2, entries 2–4). The in-
crease of the number of electron donating substituents did not
generate a significant effect on the yield (Table 2, entries 9).
Concerning the phosphorus coupling agents used in the
experiments, one can say that the best results were obtained with
PCl3O (Table 1, entry 3). The results with PCl3 (Table 1, entry 1) can
be classified as the modest and the worst reagent was PBr3O
(Table 1, entry 2) which gave a complex mixture of by-products.
The reaction was also performed in three solvents with different
polarity index. The change of DMF by dioxane (Table 1, entry 3 vs
5) or xylene (Table 1, entry 4) revealed to be unproductive. In fact,
with dioxane (Table 1, entry 5) only a yield of 22% was obtained,
mainly due to the solubility problems with the starting chromone,
and with xylene no reaction was observed. As to the influence of tem-
perature, it was concluded that a decrease to 100 °C (Table 1, entry 6)
or an increase to 200 °C (Table 1, entry 7) originates lower yields.
The microwave-assisted reaction was also optimized in relation
to the time of irradiation and stoichiometry: (a) it was observed
that a decrease on the irradiation time to 2 min or an increase to
10 min produced a yield reduction (Table 1, entries 9 vs 10); (b)
the increase of the phenylamine equivalents had no influence on

F. Cagide et al. / Tetrahedron Letters 52 (2011) 6446–6449
6449
2. Kappe, C. O.; Dallinger, D.; Murphree, S. S. Practical Microwave Synthesis for
Organic Chemists; Weinheim: Wiley-VCH, 2009.
3. Thull, U.; Kneubühler, S.; Testa, B.; Borges, M. F.; Pinto, M. M. Pharm. Res. 1993,
10, 1187–1190.
4. Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Curr. Med. Chem.
2005, 12, 887–916.
5. Borges, M. F. M.; Gaspar, A. M. N.; Garrido, J. M. P. J.; Milhazes, N. J. S. P.;
Batoreu, M. C. C., PT 103665, WO 2008/104925 A1,2008; Chem. Abstr. 2008, 149,
332206.
Moreover with the microwave-assisted method, even consider-
ing the low yield of the reaction, amide 12 (Table 2, entry 10) was
obtained. The procedure was not successful with method B (with
PyBOP) due to the presence of a strong electron withdrawing group
(–NO2) in the phenylamine. In fact, the coupling between such
weakly nucleophilic amines was not trifling with standard cou-
pling reagents.13
In conclusion, a convenient procedure for preparing functional-
ized chromones was developed. Microwave heating enables the
formation of aromatic amides from chromone-2-carboxylic acid
with very acceptable results. The method is environmentally
friendly and allows the formation of the amide bond with a low-
price reagent. In addition, the microwave process, when compared
with the conventional one has several advantages: reduction of the
reaction time, less formation of by-products, and easier work-up.
Further, the method does not require dry solvents and/or inert
atmosphere and is applicable to scale-up the production.
The very first encouraging result will be the starting point of the
development of an automated process suitable for the synthesis of
a larger library of new functionalized chromones that can be used
in the discovery of new monoamino oxidase inhibitors.
6. Edwards, M.; Howell, J. B. L. Clin. Exp. Allergy 2000, 30, 756–774.
7. Sabitha, G. Aldrichimica Acta 1996, 29, 15–25.
8. Ellis, G. P.; Barker, G. Prog. Med. Chem. 1972, 9, 65–1162.
9. (a) Gaspar, A.; Reis, J.; Fonseca, A.; Milhazes, N.; Viña, D.; Uriarte, E.; Borges, F.
Bioorg. Med. Chem. Lett. 2011, 21, 707–709; (b) Gaspar, A.; Teixeira, F.; Uriarte,
E.; Milhazes, N.; Melo, A.; Cordeiro, M. N.; Ortuso, F.; Alcaro, S.; Borges, F.
ChemMedChem 2011, 6, 628–632.
10. Gaspar, A.; Silva, T.; Ya´n~ez, M.; Vina, D.; Orallo, F.; Ortuso, F.; Uriarte, E.;
Alcaro, S.; Borges, F. J. Med. Chem. 2011, 54, 5165–5173.
11. General methods used for the synthesis of chromone carboxamides:
METHOD A–To a solution of chromone-2-carboxylic acid (1, 1 mmol) in DMF
(1.5 mL), PCl3O (1 mmol), was added. The mixture was stirred at room
temperature for 30 min, with the formation of the corresponding acyl
chloride. Then the appropriate aniline was added. The system was heated
160 °C for 5 min in a microwave apparatus. After, the mixture was poured into
a beaker and water was added. The formed solid was filtered and purified by
recrystallization.
Microwave-assisted synthesis was performed in
Microwave Synthesizer.
a
BiotageÒ Initiator
METHOD B–To
a solution of chromone-2-carboxylic (1, 1 mmol) in DMF
(2.3 mL), DIPEA was added (1 mmol). After cooling the solution in an ice-water
bath PyBOP (1 mmol), previously dissolved in 1.5 mL of CH2Cl2, and the amine
(1 mmol) were added. The mixture was stirred in ice for 30 min and then, at
room temperature for 4 h. CH2Cl2 was removed under reduced pressure and
the solution was diluted with water (10 mL). After extraction with ethyl
acetate the combined organic phases were washed successively with HCl
(0.5%), NaHCO3 1 M and water and dried over anhydrous sodium sulfate. After
filtration and solvent evaporation the residue was purified by column
chromatography followed by recrystallization.
Acknowledgments
The authors thank the Foundation for Science and Technology
(FCT), Portugal (PTDC/QUI-QUI/113687/2009). A.G. (SFRH/BD/
43531/2008) and F.C. (SFRH/BPD/74491/2010) thank FCT grants.
References and notes
12. Lu, C.; Zhao, B.; Jiang, Y.; Ding, H.; Yang, S. Synth. Commun. 2011, 41, 1257–1266.
13. Han, S. Y.; Kim, Y. A. Tetrahedron 2004, 60, 2447–2467.
1. Kappe, C. O.; Stadler, A. Microwaves in Organic and Medicinal Chemistry;
Weinheim: Wiley-VCH, 2005.