Ultrasound-Assisted Solvent-Free Parallel Synthesis of 3-Arylcoumarins Using N-Acylbenzotriazoles

Article abstract of DOI:10.1021/acscombsci.6b00055

An ultrasound-assisted one-pot acylation/cyclization reaction between N-acylbenzotriazoles and 2-hydroxybenzaldehydes has been developed for the synthesis of substituted 3-arylcoumarins. Using ultrasound not only allows rapid and clean conversion but also simplifies experimental setup and parallel workup leading to rapid generation of 3-arylcoumarin libraries under mild, solvent-free, and chromatography-free conditions.

Full text of DOI:10.1021/acscombsci.6b00055

Technology Note
pubs.acs.org/acscombsci
Ultrasound-Assisted Solvent-Free Parallel Synthesis of
3‑Arylcoumarins Using N‑Acylbenzotriazoles
Sirawit Wet-osot, Chuthamat Duangkamol, Wong Phakhodee, and Mookda Pattarawarapan*
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Chiang Mai University, Chiang
Mai 50200, Thailand
S
* Supporting Information
ABSTRACT: An ultrasound-assisted one-pot acylation/cycli-
zation reaction between N-acylbenzotriazoles and 2-hydrox-
ybenzaldehydes has been developed for the synthesis of
substituted 3-arylcoumarins. Using ultrasound not only allows
rapid and clean conversion but also simplifies experimental
setup and parallel workup leading to rapid generation of 3-
arylcoumarin libraries under mild, solvent-free, and chroma-
tography-free conditions.
KEYWORDS: coumarins, N-acylbenzotriazoles, 2-hydroxybenzaldehydes, solvent-free, ultrasound
ver the past decades, solution-phase parallel synthesis has
acetoxy esters. Subsequent cyclization of the formed esters
Obeen increasingly applied as an efficient tool for the rapid then provides 3-arylcoumarins (Scheme 1). Since the released
generation of combinatorial chemical libraries.1,2 While the
method offers several benefits over solid-phase synthesis in
terms of the ease of reaction monitoring, flexible choices of
solvents, and a wide range of accessible reaction conditions,
time-consuming purification step is still a bottleneck that slows
down the synthetic process.3
Scheme 1. Synthesis of 3-Arylcoumarins Using N-
Acylbenzotriazoles
The use of ultrasound in promoting chemical trans-
formations is well-documented.4,5 Due to cavitation effect,
reactions carried out under ultrasonic irradiation have been
achieved with cleaner conversion, higher yields, improved
selectivity, and shorter reaction times as compared to the
conventional methods.6,7 Despite its effectiveness, the
application of ultrasound in the parallel synthesis of compound
libraries is rather limited since problems associated with the
conventional workup and purification procedures remain
unsolved.8,9
N-Acylbenzotriazoles are neutral acylating agents which have
been extensively used as a substitute for acid chlorides.10 Unlike
acid chlorides, N-acylbenzotriazoles are stable solids which can
be readily prepared and kept at room temperature without
decomposition. Additionally, the water-soluble benzotriazole
byproduct from the acylation reaction can be readily removed
by solvent extraction. Such property makes N-acylbenzotriazole
a good candidate as an acylating agent for a solution-phase
library synthesis.
In a continuation of our study toward the synthetic
applications of N-acylbenzotriazoles,11−14 we wish to report
herein a parallel synthesis of a small library of 3-arylcoumarins
from the reaction between N-acylbenzotriazoles and 2-
hydroxybenzaldehydes under ultrasound-assisted conditions. It
was envisaged that, in the presence of base, the reaction of
benzotriazole derivatives of aryl acetic acids with substituted 2-
hydroxybenzaldehydes should lead to the formation aryl
benzotriazole and the remaining reactants are soluble in
aqueous base, product isolation can be carried out in a parallel
format through ultrasound-assisted solvent extraction, followed
by filtration through a short silica plug.
It should be noted that although a number of methods have
been developed for the synthesis of 3-arylcoumarins, most of
the procedures involve thermal condensation between aryl
acetic acids and 2-hydroxybenzaldehydes in the presence of
activators such as 1,4-diazabicyclo[2.2.2]octane (DABCO),15
cyanuric chloride,16 dicyclohexylcarbodiimide (DCC),17−19
N,N-dimethyl(dichlorophosphoryloxymethylene)ammonium
chloride,20 POCl3,21 PhOP(O)Cl2,22 and the Mukaiyama
reagent.23 These procedures generally require high temper-
ature, long reaction times, and tedious work-ups and
purification steps. An alternative method that enables rapid
and clean conversion under mild conditions without require-
ment of column chromatography would be of great benefit,
especially for a parallel library synthesis.
We began our study by optimizing the reaction conditions
using phenylacetyl benzotriazole (1 equiv) and salicylaldehyde
Received: April 11, 2016
Revised: May 10, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acscombsci.6b00055
ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Technology Note
(1.1 equiv) as model substrates. Different set of reaction
conditions were screened under ultrasonic irradiation. Accord-
ing to Table 1, the reaction carried out using K2CO3 (3 equiv)
Scheme 2. Synthetic Route and Building Blocks for 3-
Arylcoumarins
a
Table 1. Optimization of the Reaction Conditions
entry
base
solvent
method
time (min)
yield (%)
1
2
3
4
5
K2CO3
K2CO3
K2CO3
Et3N
THF
sonication
sonication
sonication
sonication
stirring
20
20
20
5
81
74
68
96
57
DMF
CH3CN
Et3N
5
a
Reaction conditions: phenylacetyl benzotriazole (0.0498 g, 0.21
mmol), salicylaldehyde (0.0281 g, 0.23 mmol), base (0.63 mmol),
solvent (2 mL).
as base in THF was found to give 81% of the coumarin product
within 20 min (entry 1). However, changing the solvent to
DMF or acetonitrile lowered the yield of the reaction (entries 2
and 3), possibly due to partial decomposition of the starting
benzotriazole. When changing the base to triethyamine (entry
4), the reaction proceeded rapidly (within 5 min) to give the
desired product in 96% under neat conditions. In a control
experiment where a similar reaction was carried out under
stirring at room temperature (entry 5), a complex mixture was
observed and the desired product was isolated in lower yield.
These data indicate a significant improvement of the reaction
outcome through the effect of ultrasound.
With the established optimal conditions, a parallel synthesis
of a small library of substituted 3-arylcoumarins was then
carried out in a 10 mL glass vial using 1:1.1:3 molar ratio of N-
acylbenzotriazoles/2-hydroxybenzaldehydes/Et3N. N-acylben-
zotriazoles chemset 1{1−8} were first synthesized from the
corresponding aryl acetic acids using the previously reported
procedure.14 These benzotriazole derivatives then subjected to
the reactions with salicylaldehyde and its derivatives containing
electron-donating as well as electron-withdrawing groups
(Scheme 2).
As shown in Table 2, the reaction of N-acylbenzotriazoles
1{1−8} with salicylaldehyde, 2{1}, proceeded rapidly (within 5
min in most cases) to give the respective coumarins in good to
excellent yields. The reaction was slightly less effective when
the starting carboxylic acids are electron-deficient giving the
products in slightly lower yields in comparing with those using
the electron-rich acids. Notably, the protocol is compatible with
the substrate containing free hydroxyl group, (1{7}), as the
product 3{7,1} was obtained in 60% yield, compared with the
reported Perkin conditions: stirring at 180−190 °C for 5 h with
a 45% yield.24 The presence of sterically hindered groups in the
starting acids was also highly tolerated as exemplify in the
reaction of 1-naphylacetic acid derivative (1{8}), which
provided the corresponding product 3{8,1} in a satisfactory
yield (88%).
electron-deficient 5-bromo-2-hydroxybenzaldehyde giving the
coumarin products in higher yields. The presence of free
hydroxyl group on the starting compound 1{7} led to low
conversion to the products 3{7,2} and 3{7,3} with 64% and
52% yields, respectively. Nevertheless, these yields were greater
than those obtained using other reported methods where the
reactions were performed at high temperatures using
significantly longer times.24,25 Unfortunately, the reaction did
not proceed at all when using 2-hydroxy-5-nitrobenzaldehyde,
2{4}, as a substrate under the standard reaction conditions.
This is not surprising since the presence of the strong electron-
withdrawing nitro group at para position to the hydroxyl group
could make this substrate considerably less nucleophilic.
Attempts to perform the reaction with increasing reaction
times or temperatures only led to the decomposition of the
starting N-acylbenzotriazoles without product formation.
In summary, we have developed a facile method for parallel
synthesis of a small library of substituted 3-arylcoumarins using
N-acylbenzotriazoles as acylating agents obviates the need to
prepare unstable aryl acetic chlorides or the use of corrosive
condensing agents. Although the reaction with less reactive
substrate bearing the nitro group requires further investigation,
the method works well with other substrates including those
containing free hydroxyl group. The use of ultrasound was
found to greatly simplify both the experimental setup and the
parallel workup which enabled rapid synthesis of 3-arylcoumar-
in libraries in high yields under mild conditions.
EXPERIMENTAL PROCEDURES
■
Four different N-acylbenzotriazoles 1 (0.21 mmol) were placed
into different 10 mL glass vials, and treated sequentially with
substituted 2-hydroxybenzaldehydes 2 (0.23 mmol) and
triethylamine (0.63 mmol) before being capped and placed
inside a test tube rack submerged in an ultrasonic bath
containing water. After sonication at ambient temperature until
completion of the reaction (5−10 min), dichloromethane (1
mL) was added. The solution was washed briefly with a 2 M
aqueous sodium hydroxide solution (2 mL), followed by water
(2 mL) under sonication. The organic layer was isolated and
dried over anhydrous sodium sulfate before passing through a
short silica pad packed inside a SPE cartridge to afford
The reaction of N-acylbenzotriazoles 1{1−8} with other
substituted 2-hydroxybenzaldehydes 2{2−3} also led to the
formation of the corresponding 3-arylcoumarins in various
yields. The electron-rich 2-hydroxy-5-methoxybenzaldehyde
was found to be more effective substrate relative to the
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DOI: 10.1021/acscombsci.6b00055
ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Technology Note
a
Table 2. Parallel Synthesis of Library of Substituted 3-Arylcoumarins
a
Reaction conditions: N-acylbenzotriazole 1 (0.21 mmol), substituted 2-hydroxybenzaldehyde 2 (0.23 mmol), Et3N (0.63 mmol), 5 min sonication.
10 min sonication.
b
1
(5) Puri, S.; Kaur, B.; Parmar, A.; Kumar, H. Applications of
Ultrasound in Organic Synthesis - A Green Approach. Curr. Org.
Chem. 2013, 17, 1790−1828.
coumarin 3. Every member of chemset 3 was subjected to H
and 13C NMR analysis.
(6) Patil, R.; Bhoir, P.; Deshpande, P.; Wattamwar, T.; Shirude, M.;
Chaskar, P. Relevance of sonochemistry or ultrasound (US) as a
proficient means for the synthesis of fused heterocycles. Ultrason.
Sonochem. 2013, 20, 1327−1336.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscombs-
ci.6b00055.
■
S
(7) Peng, Y.; Song, G.; Xu, X. Ultrasound-promoted scavenging: A
rapid parallel purification for solution phase combinatorial synthesis. J.
Chem. Res. 2004, 2004, 261−263.
General experimental details, analytical data, and copies
of 1 H and 13C NMR spectra of representative coumarins
3 (PDF)
(8) Yu, S.-J.; Zhu, C.; Bian, Q.; Cui, C.; Du, X.-J.; Li, Z.-M.; Zhao,
W.-G. Novel Ultrasound-Promoted Parallel Synthesis of Trifluoroa-
trolactamide Library via a One-Pot Passerini/Hydrolysis Reaction
Sequence and Their Fungicidal Activities. ACS Comb. Sci. 2014, 16,
17−23.
(9) Chen, L.-H.; Chung, T.-W.; Narhe, B. D.; Sun, C.-M. A Novel
Mechanistic Study on Ultrasound-Assisted, One-Pot Synthesis of
Functionalized Benzimidazo[2,1-b]quinazolin-1(1H)-ones. ACS
Comb. Sci. 2016, 18, 162−169.
(10) Katritzky, A. R.; Suzuki, K.; Wang, Z. Acylbenzotriazoles as
advantageous N-, C-, S-, and O-acylating agents. Synlett 2005, 1656−
1665.
AUTHOR INFORMATION
Corresponding Author
*Tel.: +66 5394 3341. Fax: +66 5389 2277. E-mail:
mookdap55@gmail.com.
■
Notes
The authors declare no competing financial interest.
(11) Wet-osot, S.; Pattarawarapan, M.; Phakhodee, W. A convenient
one-pot synthesis of ketone cyanohydrin esters in aqueous media.
Tetrahedron Lett. 2015, 56, 7172−7175.
(12) Wet-osot, S.; Duangkamol, C.; Pattarawarapan, M.; Phakhodee,
W. Facile synthesis of N-acylbenzotriazoles from carboxylic acids
mediated by 2,4,6-trichloro-1,3,5-triazine and triethylamine. Monatsh.
Chem. 2015, 146, 959−963.
(13) Wet-osot, S.; Phakhodee, W.; Pattarawarapan, M. TCT-
mediated synthesis of N-acylbenzotriazoles in aqueous media.
Tetrahedron Lett. 2015, 56, 6998−7000.
(14) Duangkamol, C.; Wangngae, S.; Pattarawarapan, M.;
Phakhodee, W. Acyloxyphosphonium versus Aminophosphonium
Intermediates: Application to the Synthesis of N-Acylbenzotriazoles.
Eur. J. Org. Chem. 2014, 2014, 7109−7112.
(15) Rahmani-Nezhad, S.; Khosravani, L.; Saeedi, M.; Divsalar, K.;
Firoozpour, L.; Pourshojaei, Y.; Sarrafi, Y.; Nadri, H.; Moradi, A.;
Mahdavi, M.; Shafiee, A.; Foroumadi, A. Synthesis and Evaluation of
ACKNOWLEDGMENTS
■
Financial support from the Thailand Research Fund through
the Royal Golden Jubilee Ph.D. Program to C.D. (Grant No.
PHD/0086/2557) is gratefully acknowledged.
REFERENCES
■
(1) An, H.; Cook, P. D. Methodologies for Generating Solution-
Phase Combinatorial Libraries. Chem. Rev. 2000, 100, 3311−3340.
(2) Barot, K. P.; Nikolova, S.; Ivanov, I.; Ghate, M. D. Liquid-Phase
Combinatorial Library Synthesis: Recent Advances and Future
Perspectives. Comb. Chem. High Throughput Screening 2014, 17,
417−438.
(3) Cork, D.; Hird, N. Work-up strategies for high-throughput
solution synthesis. Drug Discovery Today 2002, 7, 56−63.
(4) Mason, T. J. Ultrasound in synthetic organic chemistry. Chem.
Soc. Rev. 1997, 26, 443−451.
C
DOI: 10.1021/acscombsci.6b00055
ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Technology Note
Coumarin-Resveratrol Hybrids as 15-Lipoxygenaze Inhibitors. Synth.
Commun. 2015, 45, 741−749.
(16) Sashidhara, K. V.; Palnati, G. R.; Avula, S. R.; Kumar, A. Efficient
and general synthesis of 3-aryl coumarins studies on novel synthetic
methodologies. VIII. Using cyanuric chloride. Synlett 2012, 23, 611−
621.
(17) Hans, N.; Singhi, M.; Sharma, V.; Grover, S. K. A novel one-step
synthesis of 3-phenyl-, 4-methyl-3-phenyl- and 3-phenyl-4-styrylcou-
marins using DCC-DMSO. Indian J. Chem., Sect. B Org. Chem. Incl.
Med. Chem. 1996, 35B, 1159−1162.
(18) Olmedo, D.; Sancho, R.; Bedoya, L. M.; Lopez-Perez, J. L.; del
Olmo, E.; Munoz, E.; Alcami, J.; Gupta, M. P.; San Feliciano, A. 3-
Phenylcoumarins as inhibitors of HIV-1 replication. Molecules 2012,
17, 9245−9257.
(19) Vina, D.; Matos, M. J.; Yanez, M.; Santana, L.; Uriarte, E. 3-
Substituted coumarins as dual inhibitors of AChE and MAO for the
treatment of Alzheimer’s disease. MedChemComm 2012, 3, 213−218.
(20) Awasthi, A. K.; Tewari, R. S. A novel and convenient synthesis
of substituted coumarins. Synthesis 1986, 1986, 1061−2.
(21) Taksande, K.; Borse, D. S.; Lokhande, P. Facile Metal-Free
Synthesis of 3-Aryl-4-Substituted Coumarins from O-Hydroxy
Carbonyl Compounds. Synth. Commun. 2010, 40, 2284−2290.
(22) Gallastegui, J.; Lago, J. M.; Palomo, C. Simple one-step route to
substituted coumarins. J. Chem. Res., Synop. 1984, 170−1.
(23) Mashraqui, S. H.; Vashi, D.; Mistry, H. D. Efficient synthesis of
3-substituted coumarins. Synth. Commun. 2004, 34, 3129−3134.
(24) Rizzo, S.; Cavalli, A.; Ceccarini, L.; Bartolini, M.; Belluti, F.; Bisi,
A.; Andrisano, V.; Recanatini, M.; Rampa, A. Structure-Activity
Relationships and Binding Mode in the Human Acetylcholinesterase
Active Site of Pseudo-Irreversible Inhibitors Related to Xanthostig-
mine. ChemMedChem 2009, 4, 670−679.
(25) Quezada, E.; Delogu, G.; Picciau, C.; Santana, L.; Podda, G.;
Borges, F.; Garcia-Morales, V.; Vina, D.; Orallo, F. Synthesis and
vasorelaxant and platelet antiaggregatory activities of a new series of 6-
halo-3-phenylcoumarins. Molecules 2010, 15, 270−279.
D
DOI: 10.1021/acscombsci.6b00055
ACS Comb. Sci. XXXX, XXX, XXX−XXX