Efficient synthesis of chalcone-4′-sulfonyl chlorides and fluorides

Article abstract of DOI:10.1016/j.tetlet.2017.12.044

A library of 4′-chloro- and 4′-fluorosulfonyl-substituted chalcones was prepared via the aldol-type condensation reactions of 4-acetylbenzene-1-sulfonyl halides with various aromatic aldehydes, either in absolute ethanol or glacial acetic acid, in the pre

Full text of DOI:10.1016/j.tetlet.2017.12.044

Accepted Manuscript
Efficient synthesis of chalcone-4’-sulfonyl chlorides and fluorides
Dmitrii Semenok, Alexey Kletskov, Evgenij Dikusar, Vladimir Potkin, Oleg
Lukin
PII:
S0040-4039(17)31547-2
https://doi.org/10.1016/j.tetlet.2017.12.044
TETL 49546
DOI:
Reference:
Tetrahedron Letters
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26 September 2017
6 December 2017
12 December 2017
Please cite this article as: Semenok, D., Kletskov, A., Dikusar, E., Potkin, V., Lukin, O., Efficient synthesis of
chalcone-4’-sulfonyl chlorides and fluorides, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.
2017.12.044
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Efficient synthesis of chalcone-4’-sulfonyl
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chlorides and fluorides
Dmitrii Semenok, Alexey Kletskov, Evgenij Dikusar,
Vladimir Potkin, Oleg Lukin*

Tetrahedron Letters
1
Tetrahedron Letters
Efficient synthesis of chalcone-4’-sulfonyl chlorides and fluorides
Dmitrii Semenoka,b, Alexey Kletskovc, Evgenij Dikusarc, Vladimir Potkinc, and Oleg Lukina,*
a Skolkovo Institute of Science and Technology, 143026 Moscow, 3 Nobel St., Russia
b Moscow Institute of Physics and Technology, 141700 Dolgoprudny, Moscow Region, Russia
c Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, 13 Surganov St., 220072 Minsk, Belarus
*Corresponding author. Tel./fax: +7 495 270 41481; e-mail: o.lukin@skoltech.ru, oleg.lukin@gmail.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A library of 4’-chloro- and 4’-fluorosulfonyl-substituted chalcones was prepared via the aldol-
type condensation reactions of 4-acetylbenzene-1-sulfonyl halides with various aromatic
aldehydes, either in absolute ethanol or glacial acetic acid, in the presence of dry HCl. This
represents the first examples of chalcone sulfonyl halides in which the phenone ring bears one of
these functional groups. The reactivity of the chalcone sulfonyl halides were strongly dependent
on the styrene ring substituents; sulfonyl chlorides reacted with most nucleophiles (e.g. amines,
alcohols), while sulfonyl fluorides reacted only with charged nucleophiles (e.g. phenolates).
Available online
Keywords:
Chalcones
Sulfonyl chlorides
Sulfonyl fluorides
Aldol condensation
Nucleophilic displacement
2009 Elsevier Ltd. All rights reserved.
1. Introduction
direct sulfochlorination of the corresponding chalcones with
chlorosulfonic acid has been reported. However, there is only one
Compounds bearing a carbonyl group conjugated with a
carbon-carbon double bond are important subunits of biologically
active species1 and monomers for functional polymers.2,3 Recent
interest in these compounds is associated with the design of
covalent inhibitors,4 which represent promising drugs for the
treatment of thrombosis and various cancers. In this context,
benzylidene acetophenones (chalcones) are attractive building
blocks for introducing the conjugated motif into potential drugs
or monomers. Notably, the substituted chalcone structural unit
(Fig. 1) is found in many marketed and investigational drugs as
well as other biologically active compounds.5
report describing the preparation of a chalcone-4’-sulfonyl
fluoride via the condensation reaction of benzaldehyde with
SO2F-substituted acetophenone.9 To the best of our knowledge,
there are no reports describing chalcone-4’-sulfonyl chlorides in
which the chlorosulfo-group is attached to the phenone ring (Fig.
1). Given the potential of chalcone sulfonyl chlorides in drug
discovery and materials chemistry, it seems important to have
access to all isomeric forms. Herein, we describe the synthesis of
diverse chalcone-4’-sulfonyl chlorides and fluorides.
2. Results and Discussion
The synthetic route towards chalcone-4’-sulfonyl halides is
outlined in Scheme 1. Commercially available 4-
acetylbenzenesulfonyl chloride or 4-acetylbenzenesulfonyl
fluoride (prepared from the chloride via a Finkelstein-type
reaction with sodium fluoride) were reacted at room temperature
with various aldehydes in ethanol or glacial acetic acid in the
presence of dry HCl.
Figure 1. Structure and aromatic carbon atom numbering scheme
of the parent chalcone.
Therefore, the development of reliable methods for the
preparation of building blocks containing the chalcone scaffold is
of significance in drug discovery and materials chemistry.
Previously reported methods for incorporation of the chalcone
subunit include the use of chalcone acyl-3 or sulfonyl-6-8
chlorides. The latter are especially useful synthetic building
blocks since the biologically relevant sulfo-group is introduced
along with the valuable chalcone fragment. The preparation and
use of diverse chalcone-2-,8 3-,6,7 and 4-sulfonyl chlorides6,7 via

2
Tetrahedron Letters
quantities along with the corresponding chalcones (Entries 13-
15). In the case of p-nitrobenzaldehyde, aldol product 6e (Entry
14) was the major component of the condensation reaction. This
compound was transformed into chalcone 6a by heating at 155
°C in the presence of SiO2 to facilitate dehydration (Scheme 2).
Bulky aldehydes (e.g. 11) did not affect the reaction and the
corresponding chalcone was isolated in 30% yield (Entry 18).
Similarly, sulfonyl chloride 10а bearing a branched isoxazole
derivative was obtained in 45% yield. The reaction by-product
aldol 10e which was isolated in 27% yield, was transformed into
10a using solid phase thermolysis (Scheme 2).
Table 1. Isolated yields of sulfonyl halides and side-products as
shown in Scheme 1.
Products (Yield)
Y = Cl (a), F (b), OH (c),
OEt (d);
Entry
X
Ar
Solvent
aldol (Y = Cl (e), F (f))
1a (39%), 1d (11%)
2a (45%), 2d (20%)
5d (34%)
6d (15%)
10a (45%), 10e (27%)
2b (77%)
5b (58%)
6b (14%)
11b (46%), 11f (14%)
2a (16%), 2e (32%)
3a (30%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Cl
Cl
Cl
Cl
Cl
F
F
F
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
1
2
5
6
10
2
5
6
11
2
3
4
5
6
7
8
9
11
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
4a (46%)
5a (33%), 5e (11%)
6c (7%), 6e (43%)
7a (34%), 7e (10%)
8а (50%)
9a (21%)
11a (30%)
The synthesis of chalcone-4’-sulfonyl fluorides (Entries 6-9)
proceeded with better yields (up to 77%) compared the
corresponding sulfonyl chlorides. However, as in the case of
sulfonyl chlorides, aldehydes bearing electron withdrawing
groups and bulky groups gave low yields (e.g. 14% for 6b) and
aldol products (11f). Unlike the preparation of chalcone-4’-
sulfonyl chlorides, the synthesis of the corresponding sulfonyl
fluorides is much less sensitive to the reaction media on account
of their moderate reactivity. For example, ethanol was the most
suitable solvent for the synthesis of chalcone-4’-sulfonyl
fluorides and alcoholysis, as observed with sulfonyl chlorides,
was not detected.
Scheme 1. Chalcone-4’-sulfonyl halides and their derivatives
obtained as by-products.
The products typically crystallized from the reaction mixture
upon standing for 24 hours at 5 °C. A number of reaction
conditions were investigated; all details are given in the ESI
(Table S1), while the most important results are presented in
Table 1. The reaction outcomes and yields were substantially
dependent on the aldehyde structure. Thus, the presence of
electron donating groups (2-4, 8), electron withdrawing groups
(5-7), bulky substituents (11), and branched elements (8, 10) on
the aldehyde component required individual adjustments to the
reaction conditions. In the case of electron donating substituents
(Table 1, entries 5, 9, and 18), chalcone-4’-sulfonyl chlorides
were obtained in 30-46% yield. In some cases (e.g. entry 10) the
aldol product 2e was the major component of the reaction; this
could be easily dehydrated by heating in the solid phase to give
chalcone 2a. The limitations of the reaction include the
unsuccessful use of 2-furancarbaldehyde, which polymerized
under the acidic conditions, and the attempted synthesis of (E)-4-
(3-(phenanthren-9-yl)acryloyl)benzene-1-sulfonyl
chloride,
which rapidly hydrolyzed to the corresponding sulfonic acid.
The reactions of 4-acetylbenzenesulfonyl chloride with aldehydes
bearing electron withdrawing groups in ethanol gave the
corresponding ethyl sulfonates as the sole products (Entries 3-4).
In comparison, the use of glacial acetic acid as the solvent led to
chalcone-4’-sulfonyl chlorides as the major products (Entries 10-
18). However, aldol adducts 5e-7e were formed in considerable
Scheme 2. Formation of aldol products and their solid-state
dehydration.

Tetrahedron Letters
3
(14-77%). The prepared sulfonyl halides are promising building
The use of other solvents for the synthesis of sulfonyl fluorides,
such as methanol and glacial acetic acid, resulted in incomplete
conversion and by-product formation (see Table 1, Scheme 2,
and ESI).
blocks for medicinal and materials chemistry.
Acknowledgments
In order to investigate the reactivity of the obtained chalcone-4’-
sulfonyl halides, the reactions of selected sulfonyl halides were
carried out with 4-aminophenol, 6-aminohexan-1-ol, and 3-
methoxypropylamine. Thus, the reaction of sulfonyl fluoride 5b
with 4-aminophenol in the presence of triethylamine gave
sulfonate 5B in 58% yield; the amino-group remained unaffected.
However, 5b did not react with 6-aminohexan-1-ol or 3-
methoxypropylamine under these conditions. At the same time,
sulfonyl fluoride 2b showed moderate reactivity in the reaction
with 3-methoxypropylamine yielding sulfonamide 2B (40%
conversion after 72 h, yield 81%). Compared with 2b, sulfonyl
chloride 8a exhibited greater reactivity in the reaction with 3-
methoxypropylamine, giving sulfonamide 8A in 94% yield.
Unlike compound 5b, different chalcone sulfonyl chlorides
reacted unselectively with 4-aminophenol, leading to mixtures of
O- and N-sulfonylated products. Reactions of chalcone-4’-
sulfonyl chlorides with aliphatic aminoalcohols proceed
selectively to give the corresponding sulfonamides. For example,
the reaction of sulfonyl chloride 7a with 6-aminohexan-1-ol gave
sulfonamide 7A in 84% yield.
The authors would like to thank Dr. Peter V. Kurman
(Laboratory of Physical and Chemical Research Methods,
Institute Of Bioorganic Chemistry NAS Belarus) for measuring
mass spectra. D.S. thanks "Foundation for Assistance to Small
Innovative Enterprises in Science and Technology" (grant “Start”
No 1074GC1/21867) for financial support.
References and Notes
1.
Serafimova, I. M.; Pufall, M. A.; Krishnan, S.; Duda, K.; Cohen,
M. S.; Maglathlin, R. L.; McFarland, J. M.; Miller, R. M.; Frödin,
M.; Taunton, J. Nature Chem. Biol. 2012, 8, 471.
2.
3.
4.
Schmidt G. M. J. Pure Appl. Chem. 1971, 27, 647.
van Heijst, J.; Corda, M.; Lukin, O. Polymer 2015, 70, 1.
(a) Ostrem, J. M.; Peters, U.; Sos, M. L.; Wells, J. A.; Shokat, K.
M. Nature 2013, 503, 548. (b) Lewis, H. D.; Liddle, J.; Coote, J.
E.; Atkinson, S. J.; Barker, M. D.; Bax, B. D.; Bicker, K. L.;
Bingham, R. P.; Campbell, M.; Chen, Y. H.; Chung, C.; Craggs,
P. D.; Davis, R. P.; Eberhard, D.; Joberty, G.; Lind, K. E.; Locke,
K.; Maller, C.; Martinod, K.; Patten, C.; Polyakova, O.; Rise, C.
E.; Rüdiger, M.; Sheppard, R. J.; Slade, D. J.; Thomas, P.; Thorpe,
J.; Yao, G.; Drewes, G.; Wagner, D. D.; Thompson, P. R.; Prinjha,
R. K.; Wilson D. M. Nature Chem. Biol. 2015, 11, 189.
According to www.drugbank.ca (accessed in September 2017)
there are 13 marketed and over 20 investigational drugs bearing
the chalcone substructure.
5.
6.
7.
8.
9.
Cremlyn, R. J.; Swinbourne, F. J.; Shode, O. O. J. Chin. Chem.
Soc. 1984, 31, 383.
Cremlyn, R. J.; Swinbourne, F. J.; Bassin, P.; Dane, D.; Higgins,
K.; Mitchell, P. Phosphorus, Sulfur, and Silicon 1991, 63, 385.
Patel, C.; Bassin, J. P.; Scott, M.; Flye, J.; Hunter, A. P.; Martin,
L.; Goyal, M. Molecules 2016, 21, 861.
Orlov, V. D.; Vorob’eva, N. P.; Tishchenko, A. A.; Pikalev, O.
M.; Popov, V. I.; Yagupol’skii, L. M. Chem. Heterocycl. Comp.
1991, 27, 942.
Figure 2. Products of selected reactions of chalcone-4’-sulfonyl
halides with different nucleophiles
Supplementary Material
3. Conclusion
Supplementary material (experimental procedures and spectral
data) associated with this article can be found, in the online
version, at
The described approach allows the preparation of hitherto
unavailable chalcone-4’-sulfonyl halides bearing different
substituents on the styrene ring. Despite the apparent ease of the
aldol reaction, the condensation is highly sensitive to the
aldehyde nature, solvent, temperature, and reaction time. The
reactivity of the sulfonyl halides was dependent on the styrene
ring substituent and the halide, resulting in highly variable yields
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
The halogen type and substituents impact the
reactivity of the sulfonyl halides
Graphical Abstract


Synthesis of hitherto unavailable chalcone
sulfonyl halides was achieved
For every condensation case the optimal
reaction conditions were developed
To create your abstract, type over the instructions in the
template box below.
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Efficient synthesis of chalcone-4’-sulfonyl
Leave this area blank for abstract info.
chlorides and fluorides
Dmitrii Semenok, Alexey Kletskov, Evgenij Dikusar,
Vladimir Potkin, Oleg Lukin*

4
Tetrahedron Letters