Microwave synthesis of α-cyano chalcones

Article abstract of DOI:10.1016/j.tetlet.2012.01.109

A novel methodology for facile production of α-cyano chalcones under microwave irradiation is described. Utilizing a Knoevenagel condensation between benzoylacetonitriles and aromatic aldehydes, substituted chalcones are generated via a 15-min, one-pot synthesis. Diversification of aromatic groups, including electron-withdrawing, electron-donating, and heterocyclic substitutions, has led to the isolation of over twenty colored, solid chalcone products. Furthermore the methodology can be extended to the synthesis of benzylidenemalononitriles as well as methyl and ethyl α-cyano cinnamates.

Full text of DOI:10.1016/j.tetlet.2012.01.109

Tetrahedron Letters 53 (2012) 1772–1775
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Tetrahedron Letters
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Microwave synthesis of
a
-cyano chalcones
⇑
Shyam J. Deshpande, Paul R. Leger, Stephen R. Sieck
Department of Chemistry, Grinnell College, 1116 8th Ave., Grinnell, IA 50112, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel methodology for facile production of
a-cyano chalcones under microwave irradiation is
Received 4 January 2012
Revised 23 January 2012
Accepted 24 January 2012
Available online 2 February 2012
described. Utilizing a Knoevenagel condensation between benzoylacetonitriles and aromatic aldehydes,
substituted chalcones are generated via a 15-min, one-pot synthesis. Diversification of aromatic groups,
including electron-withdrawing, electron-donating, and heterocyclic substitutions, has led to the isola-
tion of over twenty colored, solid chalcone products. Furthermore the methodology can be extended to
the synthesis of benzylidenemalononitriles as well as methyl and ethyl
a-cyano cinnamates.
Keywords:
Chalcones
Ó 2012 Elsevier Ltd. All rights reserved.
Cyano cinnamates
Knoevenagel condensation
Microwave
Chalcones, or 1,3-diarylpropenones, are common moieties in
biologically active molecules, with considerable agricultural, phar-
maceutical, and synthetic applications, as they compose essential
building blocks of agrochemicals,1 anticancer agents,2 scavenging,
and chelating agents,3 and various medicinal agents, including
antiinflammatories,4 and PET scan imaging probes.5 A common
synthetic approach toward the synthesis of chalcones is via the
Knoevenagel condensation6 many of which utilize microwave
techniques7 (Scheme 1).
et al. conditions, which produced
albeit in a low yield (30–46%).
a-cyano chalcones in 15 min,
Herein we report a useful method for the synthesis of an array
of
a-substituted cyano chalcones utilizing a microwave reactor.
The reaction is versatile on a range of substrates and requires
minimal post-reaction purification. Furthermore we have con-
firmed the stereochemistry of the alkene in our chalcones and have
extended our methodology to generate benzylidenemalononitriles
as well as methyl and ethyl a-cyano cinnamates.
We were particularly interested in the synthesis of
a-substituted
We began our study by examining the condensation of benzoyl
cyano chalcones due to their ability to be further functionalized.
Cyano-substituted chalcones have been utilized for nitrocycloprop-
anation reactions,8 and for the synthesis of Krohnke pyridines,9
quinolones, chromenes,10 functionalized 2,3-dihidroixazoles,11
and pyrazolo pyridines.12 Upon surveying the literature a number
of methodologies exist for the generation of phenyl-substituted
acetonitrile (1) with N,N-dimethyl benzaldehyde (2) to form the
desired amino
started by modifying the protocol reported by Kolosov et al. that
produced desired -substituted chalcone 3 in a 30% yield, by
a-substituted cyano chalcone (3) (Scheme 2). We
a
utilizing a microwave reactor in place of the previously reported
conventional heating method. Originally we began by treating
benzoyl acetonitrile with 1.2 equiv of the aromatic aldehyde in
2-pentanol (1.66 M to the ketone), in the presence of 8 mol % of
piperidine base catalyst. Initially we allowed the reaction to run
for 15 min at 120 °C at which time an orange solid was observed.
The product was washed with a mixture of hexanes and 2-pentanol
and allowed to air dry producing chalcone 3 in an 88% yield as an
orange crystal.
chalcones, but few report the synthesis of a-substituted cyano chal-
cones. The examples that are reported have limited generality, and
report low yields and/or require long reaction times. For example,
Inokuma,8 Lawrence,2g and Ryabukhim13 report the synthesis of
a-substituted cyano chalcones in high yield (75–96%) but reaction
times of 24–48 h with conventional heating methods are needed
to achieve these yields. Blum,14 Gazit,15 Kolosov,12 report generat-
ing
a-substituted cyano chalcones in shorter reaction times
(15 min to 3 h) but with lower conversions (15–45%). Reports of
protocols utilizing microwave techniques are limited in overall
generality and scope.7b,7c We were most intrigued by Kolosov
⇑
Corresponding author.
E-mail address: sieckste@grinnell.edu (S.R. Sieck).
Scheme 1. Knoevenagel condensation towards chalcones.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.109

S. J. Deshpande et al. / Tetrahedron Letters 53 (2012) 1772–1775
1773
Scheme 2. Initial synthesis of a-cyano chalcone via Knoevenagel condensation.
Table 1
Optimization of reaction conditions
Entry
Equiv of CHO
Base
Solvent
Time (m)
Wash solvent
Yield
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.1
Piperldine
Piperidine
Piperldine
Piperldine
NaOH
NaOH
Piperldine
Piperldine
2-Pentanol
2-Pentanol
2-Pentanol
2-Pentanol
EtOH
2-Pentanol
EtOH
2-Pentanol
1
5
Hex/pentane
Hex/pentane
Hex/pentane
Hex/pentane
Hex/pentane
Hex/pentane
Hex/pentane
Hexane
73
95
95
95
89
78
93
97
10
15
10
10
10
10
Table 2
Diversification of chalcones via substituted aldehydes
85%
97%
83%
90%
91%
95%
93%
86%
85%
Excited by the initial success of this reaction we began
exploring an array of reaction conditions to further optimize this
particular system. We examined a number of variables including
reaction time (entries 1–4), reaction solvent, and bases (Table 1).
Originally, we allowed the reaction to proceed for 15 min but la-
ter found the reaction to be complete after 10 min of microwave
heating. Next, the solvent system for the reaction was examined
(entries 5 and 7). Both EtOH and pentanol were examined with
no significant observed differences when using either solvent in
the actual reaction.7 Both piperidine and NaOH were utilized as
bases, with the piperidine being the preferred base.
After completion of the reaction the solid is isolated via vac-
uum filtration, washed with a minimal amount of a solvent and
allowed to dry. Initially a mixture of hexanes and 2-pentanol or
ethanol was utilized for washes.16 In many of our original trials
we noticed small amounts of residual aldehyde present in our
purified product even after washing, so to alleviate this problem
we decreased the amount of aldehyde we utilized in the reaction
to 1.1 equiv (entry 8). After decreasing the amount of aldehyde,
only a minimal amount of cold hexane was required to isolate
the desired solid product in a 97% yield for reactions run with
2-pentanol. For this particular system the reaction gave the best

1774
S. J. Deshpande et al. / Tetrahedron Letters 53 (2012) 1772–1775
Table 3
on 1 mmol scale at 120 °C for 15 min in 2-pentanol. An extra
5 min of reaction time were added for some substrates, particularly
with benzaldehyde and 4-hydroxy benzaldehyde, due to the pres-
ence of small amounts of unreacted ketone after 10 min of reaction
time. A variety of substituted products generated a variety of
colored chalcones in high yield with minimal purification.
We next looked to further expand the reaction to even more
substituted chalcones by introducing substitution at the benzophe-
nones and aldehydes (Table 3). We were pleased that the addi-
tional diversity could be expanded using our methodology with
all products being isolated with the same simple purification
method previously described. All chalcones generated were iso-
lated as varying colored solids in high yield.
Diversification of chalcones via substituted ketones and aldehydes
Entry
Ar1
Ar2
Yield
1
2
3
4
5
–C6H4NMe2
–C4H3S
4-MeC6H4
4-CIC6H4
93
87
87
88
95
8a
8b
8c
8d
8e
4-NO2C6H4
6
7
8
9
–C6H4NMe2
–C4H3S
4-MeC6H4
4-CIC6H4
95
80
92
86
98
8f
8g
8h
8i
8j
The Knovenagel reaction is known to primarily give the acyl and
aryl group trans to one another but we wanted to confirm this under
the current conditions. We were able to confirm the configuration
10
4-NO2C6H4
of the double bond of the
a-substituted cyano chalcones by con-
11
12
13
14
15
–C6H4NMe2
–C4H3S
4-MeC6H4
4-CIC6H4
92
81
86
82
98
8k
81
8m
8n
8o
ducting a number of HMBC experiments measuring carbon–proton
couplings of the olefin to confirm its geometry. Figure 1 shows the
result of one of these experiments. The 1H d/13C d crosspeak at 8.03/
116.7 (ppm) corresponds to H,CN coupling (J = 14.0 Hz).This is con-
sistent with the trans 3JCH couplings reported in the literature.17 The
3JCH for a cis relationship is approximately 8.5. Furthermore the
4-NO2C6H4
16
–C6H4NMe2
–C6H4NMe2
98
8p
H,CO coupling at 1H d/13
C d crosspeak 8.03/187.1 (ppm) is
J = 6.3 Hz, which is consistent with the literature values predicted
for this particular alkene geometry.17 If this relationship was trans
rather than cis we would expect J values greater than 20. All these
values are consistent with the coupling constants indicative of a
trans-H,CN relationship, and cis-H,CO relationship. We conducted
a HMBC experiment for each compound and all the coupling
constants are included in the Supplementary data.
17
98
8q
Finally, we explored the possibility of utilizing these reaction
conditions to react cyanoacetates and malonitrile with various
substituted aldehydes. We are happy to report that we can also
utilize these species for the microwave assisted Knoevenagel con-
densation to produce an array of cyano-substituted alkenes,
typically in a high yield (Table 4). This is a useful extension of this
particular methodology to form an array of CN substituted alkenes
beyond substituted chalcones.
results with piperidine and 2-pentanol for 10 min. Furthermore,
we found the reaction scalable giving the product in the same
high yield on a multitude of scales (mg to multi-gram).
After optimizing the initial reaction in detail we explored utiliz-
ing these conditions to form other
a-cyano substituted chalcones
by looking at the reaction of benzoyl acetonitrile with an array of
substituted aldehydes (Table 2). All reactions in Table 2 were run
Figure 1. HMBC determination of stereochemistry: (E)-chalcone (8d).

S. J. Deshpande et al. / Tetrahedron Letters 53 (2012) 1772–1775
1775
References and notes
Table 4
Application of cyanoacetates and malonitriles
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–C4H3S
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–C6H4CI
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Conclusion
In conclusion we report a new method for the synthesis of
substituted -cyano chalcones and -substituted acrylates. This
method produces these products efficiently in short reaction times
with high yields and needs minimal purification. We continue to
study the utilization of these reaction conditions to explore other
types of substituted chalcones.
a
a
Acknowledgments
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The authors would like to thank Grinnell College for funding and
support. Additionally the authors would like to thank T. Andrew
Mobley for assistance with the 2D NMR experiments.
16. 2-Pentanol was utilized as a reaction solvent because it was on hand when we
first began exploring the reaction. If 2-pentanol is not available 1-pentanol can
also be utilized in its place to obtain similar results.
Supplementary data
17. Marshal, J. L. Carbon–Proton Couplings. In Carbon–Carbon and Carbon–Proton
NMR Couplings: Applications to Organic Stereochemistry and Conformational
Analysis; VerlagChemie International: Deerfield Beech, FL, 1983.
Supplementary data (all experimentals, 1H, and 13C NMR spec-
tra of various compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2012.01.109.