Rapid synthesis of aurones under mild conditions using a combination of microwaves and deep eutectic solvents

Article abstract of DOI:10.1016/j.tetlet.2016.12.015

The combination of microwave heating and the deep eutectic solvent formed from choline chloride and urea has resulted in a new, essentially neutral, yet rapid method for the synthesis of a wide range of aurone derivatives. While isolated yields remain somewhat variable, in virtually every case, a significant increase in yield has been observed on going from conventional thermal heating to microwave heating. In addition, some compounds inaccessible using prior methods have become reproducibly available using this modification. Further application of the combination of DES and microwave heating is expected to be highly promising and of general utility.

Full text of DOI:10.1016/j.tetlet.2016.12.015

Accepted Manuscript
Rapid synthesis of aurones under mild conditions using a combination of mi-
crowaves and deep eutectic solvents
Kimberly M. Taylor, Zachary E. Taylor, Scott T. Handy
PII:
S0040-4039(16)31642-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.015
TETL 48427
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
21 November 2016
6 December 2016
Please cite this article as: Taylor, K.M., Taylor, Z.E., Handy, S.T., Rapid synthesis of aurones under mild conditions
using a combination of microwaves and deep eutectic solvents, Tetrahedron Letters (2016), doi: http://dx.doi.org/
10.1016/j.tetlet.2016.12.015
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Rapid synthesis of aurones under mild
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microwaves and deep eutectic solvents
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Kimberly M. Taylor, Zachary E. Taylor, and Scott T. Handy

1
Tetrahedron Letters
Rapid synthesis of aurones under mild conditions using a combination of microwaves
and deep eutectic solvents
Kimberly M. Taylora , Zachary E. Taylora , and Scott T. Handya *
aDepartment of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The combination of microwave heating and the deep eutectic solvent formed from choline
chloride and urea has resulted in a new, essentially neutral, yet rapid method for the synthesis of
a wide range of aurone derivatives. While isolated yields remain somewhat variable, in virtually
every case, a significant increase in yield has been observed on going from conventional thermal
heating to microwave heating. In addition, some compound inaccessible using prior methods
have become reproducibly available using this modification. Further application of the
combination of DES and microwave heating is expected to be highly promising and of general
utility.
Available online
Keywords:
Deep eutectic solvents
Microwave heating
Aurones
2009 Elsevier Ltd. All rights reserved.
rate enhancement
Condensation chemistry
1. Introduction
solvents due to their greater ability to absorb microwave
radiation from a typical microwave reactor. Deep Eutectic
Aurones are an interesting sub-family of the flavonoids
primarily found in plants that produce yellow flowers.1 As might
be expected, they exhibit a wide range of biological activities,
including anti-cancer, anti-fungal, anti-microbial, and anti-
inflammatory.2 This range of activity has further resulted in the
development of a number of routes that can be used for their
synthesis. By far the most common and simple of these
solvents (DES) are certainly polar solvents, and thus would be
expected to be readily applicable to microwave accelerated
reaction conditions. Despite this obvious potential, only a single
report exists in which deep eutectic solvents and microwave
heating have been combined. Nagarkar and co-workers reported
the synthesis of nitriles from aldehydes by reaction with
hydroxylamine hydrochloride in the choline chloride/urea
(CC/U) deep eutectic solvent.5 (Scheme 2) By application of
microwave heating, reaction times were reduced from hours to
minutes and yields were similar to slightly improved. Based
upon this previous study, the combined application of microwave
heating and DES to the synthesis of aurones was undertaken.
approaches is the condensation of an aldehyde with
a
benzofuranone (coumaranone). (Scheme 1) This can be
accomplished using a wide range of conditions, including the
nearly neutral conditions reported earlier by this group.3 While
exceedingly mild and thus compatible with a wide range of
aldehyde substrates, including very sensitive ones such as 2-
furaldehyde, these reactions tended to require extended reaction
times, often requiring >12 hours for completion. As efforts to
further probe biological applications have moved forward, these
long reaction times have proven to be a significant obstacle to
timely progress. Further the long reaction times can, in certain
cases, result in partial decomposition and/or the formation of E/Z
isomeric mixtures. As a result, a mild, yet quicker set of reaction
conditions are required.
Scheme 2. Nagarkar Nitrile Synthesis.
Scheme 1. Condensation Approach to Aurones.
Using a CEM Discover microwave reactor, we combined an
aldehyde with benzofuran-3(2H)-one in a 1:2 molar ratio of
choline chloride/urea as solvent.6 (Scheme 3) The reaction was
heated to 90 C for 30 minutes. After completion, the reaction
mixture was partitioned between water and methylene chloride.
Following concentration of the organic layer, the crude product
was purified by simple trituration with ether in a simplification
that we had earlier noted. As can be seen, the results were quite
significant. The first test case afforded complete conversion of
One option that seemed possible was the use of microwave
heating. Microwave heating has been used over the last several
years to dramatically increase the rate and often yield of
reactions.4 In general, this impact is greater in more polar

2
Tetrahedron
the benzofuran-3(2H)-one in the 30 minute reaction time and
References and notes
resulted in an improved yield of 20% compared to 3% using our
previously reported conditions.
1.
2.
Nakayama, T. Enzymology of aurone biosynthesis. J. Biosci. &
Bioeng. 2002, 94, 487-491.
Scheme 3. Aurone Synthesis in Deep Eutectic Solvent using
Microwave Heating.
Haudecoeur, R.; Boumendjel, A. Recent Advances in the
Medicinal Chemistry of Aurones, Curr Med Chem, 19 (2012)
2861-2875. Zwergel, C.; Gaascht, F.; Valente, S.; Diederich, M.;
Bagrel, D.; Kirsch, G. Aurones: Interesting Natural and Synthetic
Compounds with Emerging Biological Potential. Nat. Prod.
Commun. 2012, 7, 389-394.
3.
Hawkins, I.; Handy, S.T. Synthesis of aurones under neutral
conditions using a deep eutectic solvent. Tetrahedron 2013, 55,
3440-3442.
4.
5.
C. Oliver Kappe and Alexander Stadler, Microwaves in Organic
and Medicinal Chemistry, Wiley-VCH: Weinheim, 2005.
Patil, U.B.; Shendage, S.S.; Nagarkar, J.M. Synthesis 2013, 3295-
3299.
Armed with this promising result, a number of examples were
studied to determine the scope of this improvement. (Table 1) In
most cases, the yield was increased dramatically and in every
case there was at least some improvement. Due to the much
more rapid rate at which these reactions could be performed, we
have been able to prepare an increasing number of new aurone
derivatives, including several that are completely new.7 Some,
such as terphthalaldehyde had failed during prior attempts to
synthesize these unusual compounds. (Table 1, entry 8) The one
clear limitation that has been identified so far is with nitro-
containing compounds. (Table 1, entry 13) In this case, a
6.
7.
Representative procedure:
All newly reported compounds have been fully characterized.
Spectroscopic data can be found in the supplementary material
accompanying this article. The Z stereochemistry of the exocyclic
alkene for all new compounds is assigned in keeping with the
generally observed preference of these reactions.
Baudelet, D.; Lipka, E.; Millet, R.; Ghinet, A. Involvement of the
P2X7 Purinergic Receptor in Imflammation: An Update of
Antagonists Series Since 2009 and their Promising Therapeutic
Potential. Curr. Med. Chem. 2015, 22, 713-729.
Liang, Z-Q.; Gao, Z-H.; Jia, W-Q.; Ye,S. Bifunctional N-
Heterocyclic Carbene Catalyzed [3+4] Annulation of Enals and
Aurones. Chem. Eur. J. 2015, 21, 1868-1872.
8.
9.
decreased yield was observed.
Nevertheless, this new
combination of generally increased reaction scope and improved
speed has served to expand the range of new aurones available
for study.
10. Giri, R.R.; Lad, H.B.; Bhila, V.G.; Patel, C.V.; Brahmbhatt, D.I.
Modified Pyridine-Substituted Coumarins: A New Class of
Antimicrobial and Antitubercular Agents. Synth. Commun. 2015,
45, 363-375.
11. Lin, C-F.; Lu, W-D.; Wang, I-W.; Wu, M-W. Synthesis of 2-
(Diarylmethylene)-3-benzofuranones Promoted via Palladium-
Catalyzed Reactions of Aryl Iodides with 3-Aryl-1-(2-tert-
butyldimethylsilyloxy)phenyl -2-propyn-1-ones. Synlett 2004,
2057-2061.
Table 1. Comparative Results for Aurone Synthesis –
Conventional versus Microwave Heating.
Entry Aldehyde
Yield
Yield
Conventional Microwave
Heating (2-
13 hours)
Heating
(30
Supplementary Material
minutes)
70%
45%
26%
80%
96%
13
4-cyanobenzaldehyde
3-chlorobenzaldehyde
o-tolualdehyde
p-tolualdehyde
4-
trifluoromethylbenzaldehyde
3-
trifluoromethylbenzaldehyde
2-
67%
15%
<5%
63%
<5%
28
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
39
410
511
6
7
<5%
<5%
81%
33%
trifluoromethylbenzaldehyde
Terphthalaldehyde
4-iodobenzaldehyde
5-hydroxymethyl-2-furfural
3-fluorobenzaldehyde
Thiophene-2-
8
9
10
11
12*
0%
13%
3%
36%
34%
33%
56%
20%
39%
36%
carboxaldehyde
4-nitrobenzaldehyde
133
59%
17%
* = 6-hydroxybenzofuranone used in this reaction.
In conclusion, the combination of a deep eutectic solvent and
microwave heating appears to have great potential for the
efficient and rapid synthesis of many interesting compounds.
The potential for further application is under investigation and
these results will be reported in due course.
Acknowledgments
The authors thank the URECA program at Middle Tennessee
State University for support of this research.

3
Highlights



The use of microwaves to accelerate the rate of reactions in deep eutectic solvents is reported.
In addition to rate enhancement, yields are generally improved.
The potential for this to be broadly applicable to synthesis in deep eutectic solvents is proposed.