Convenient and Rapid Synthesis of 3-Selenocyanato-4 H -chromen-4-ones

Article abstract of DOI:10.1055/s-0037-1609340

A sequential one-pot, simple and convenient method is described for the synthesis of 3-selenocyanato-4 H -chromen-4-ones by addition, first of DMF-DMA and then of triselenodicyanide as electrophile.

Full text of DOI:10.1055/s-0037-1609340

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
A. R. Kosso et al.
Letter
Synlett
Convenient and Rapid Synthesis of 3-Selenocyanato-4H-chromen-
4-ones
Anne Roly Obah Kosso
Julie Broggi
O
O
1. (MeO)2CHNMe2
2 h, 100 °C
SeCN
Sébastien Redon*
0
0
0
0
0-
0
0
1
8-
5
7
7
0-
8
4
5
Me
R
R
Patrice Vanelle*
CN
O
OH
2. SeO2
+
Aix Marseille Univ, CNRS, Institut de Chimie Radicalaire
(ICR), UMR 7273, Laboratoire de Pharmaco-Chimie
Radicalaire (LPCR), Faculté de Pharmacie, 27 Boulevard Jean
Moulin CS–30064, 13385 Marseille Cedex 05, France
sebastien.redon@univ-amu.fr
16 examples
56–81%
CN
DMSO, 30 min, 25 °C
chromatography-free
inexpensive reagents
patrice.vanelle@univ-amu.fr
Received: 29.01.2018
Accepted after revision: 19.02.2018
Published online: 19.03.2018
cycles6b). In continuation of our research centered on effi-
cient one-pot synthesis,6c we investigated the reactivity of
triselenodicyanide in a one-pot two-step procedure for the
selenocyanation of chromones from o-hydroxyacetophe-
nones. Chromone structures, widely found in many natural
products, are valued in pharmacology notably for their
antiallergic, anti-inflammatory, antidiabetic, antitumoral,
and antimicrobial properties.7 We hypothesized that com-
bining selenocyanates with chromones could enhance these
biological properties. Selenation for chromones has so far
only concerned the introduction of arylselanyl groups8 in
the C3-position; to our knowledge, no C3-selenocyanation
has been performed to date.
To validate the sequential one-pot procedure, we first
optimized the insertion of the dimethylamino group to ac-
tivate the enaminone 2a9 thus-formed for the subsequent
addition of the electrophilic selenocyanate. The o-hydroxy-
acetophenone (1a) was heated with different equivalents of
N,N-dimethylformamide dimethyl acetal (DMF-DMA) un-
der neat conditions at temperatures ranging from 80 °C to
120 °C; and the reaction was monitored by LC–MS. The best
result was obtained at 100 °C in two hours with 1 equiva-
lent of DMF-DMA. We then explored the electrophilic addi-
tion of triselenodicyanide without prior isolation of the
intermediate. Using a previously optimized solvent system
(DMSO, 1 mol.L–1),6b we tested different amounts of SeO2
and malononitrile at room temperature for one hour (Table
1, entries 1–4). With a SeO2/malononitrile proportion of
1:0.5, low conversion of 1a was obtained (31%). Moderate
conversion was obtained with a proportion of 2:1 (Table 1,
entry 2). Surprisingly, increasing the amount of malono-
nitrile decreased the conversion, probably due to the for-
mation of unreactive selenium-based intermediate. An ex-
cellent NMR conversion was obtained with SeO2/malononi-
trile proportion of 3:1 after only 30 minutes at room
temperature (Table 1, entry 4). Addition of three volumes of
DOI: 10.1055/s-0037-1609340; Art ID: st-2018-v0063-l
Abstract A sequential one-pot, simple and convenient method is de-
scribed for the synthesis of 3-selenocyanato-4H-chromen-4-ones by ad-
dition, first of DMF-DMA and then of triselenodicyanide as electrophile.
Key words selenocyanate, chromones, triselenodicyanide, selenium
dioxide, malononitrile, electrophile addition, oxidation, rearrangement
Organic selenocyanates (RSeCN) interest medicinal
chemists because of their remarkable activities as antileish-
manial1 and cancer chemopreventive agents.2 The chemical
field has known organoselenocyanates for almost a century,
but recent advances led to a revival of interest in these com-
pounds. Compared to the arylselanyl group, the SeCN func-
tional group offers the advantage of being an air- and
moisture-stable intermediate. They behave like pseudo-
halides, where the CN acts as a leaving group.3a–c They can
also be transformed by base- or NaBH4-mediated decyana-
tion.3d For the selenocyanation of electron-rich arenes, po-
tassium selenocyanate (KSeCN) is typically used as radical
source with an oxidant such as cerium ammonium nitrate4a
or K2S2O8,4b or as an electrophilic source with N-iodosuccin-
imide4c or N-chlorosuccinimide.4d The disadvantage with
most of these methods is that they require odorous, air-
sensitive and expensive potassium selenocyanate, along
with tedious product purification by column chromatography.
Developing a more attractive industry-compatible pro-
cess requires a straightforward, odorless, inexpensive and
scalable method. Triselenodicyanide [Se(SeCN)2] represents
an ideal electrophilic source,5 especially considering its
simple and cheap generation from malononitrile and odor-
less selenium dioxide. So far, this reagent has only been em-
ployed for the direct selenocyanation of activated nitrogen-
containing heterocycles (indoles6a and imidazohetero-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
A. R. Kosso et al.
Letter
Synlett
water precipitated the pure selenocyanated product to give
76% yield. Lower conversion was obtained when the reac-
tion was conducted with anhydrous DMSO under nitrogen
atmosphere, probably due to lower SeO2 solubility in the
absence of water (Table 1, entry 5).
to an iminium salt. Cyclization with phenol may occur,
leading to a new iminium salt. After elimination of the vola-
tile dimethylamine, the 3-selenocyanato-4H-chromen-4-
one (3a) is isolated.
Table 1 Optimization of the Reaction Conditionsa
MeO
MeO
Me
Me
1.
N
CN
O
O
O
O
O
O
SeO2
+
SeCN
H
SeCN
2 h, 100 °C
DMF-DMA
100 °C, 2 h
Me
Me
CN
R
R
Me
CN
DMSO,
25 °C
OH
OH
OH
N
O
2. SeO2
+
Me
2a
1a
3a
CN
3
1
DMSO, 30 min, 25 °C
Entry
SeO2 (equiv)
Malononitrile (equiv)
Yield (%)b
O
O
O
O
1
2
3
4
5
1
2
2
3
3
0.5
1
31
Br
SeCN
SeCN
X
SeCN
72
O
O
2
39
3b, X = F, 71%
3c, X = Cl, 75%
3a, 76%
3d, 69%
1
100 (76)c
78d
O
O
O
1
Me
SeCN MeO
SeCN
NC
SeCN
SeCN
a Reaction conditions: o-hydroxyacetophenone (1a; 0.5 mmol, 1 equiv),
DMF-DMA (1 equiv) at 100 °C for 2 h. Then a preprepared solution of SeO2
and malononitrile in DMSO (0.5 mL) at 25 °C for 20 min was added under
air atmosphere. The reaction mixture was stirred for a further 1 h.
b 1H NMR yield of 3a (isolated yield).
O
O
O
3g, 72%
3e, 75%
3f, 77%
c Reaction time was 30 minutes.
O
O
O
d The reaction was performed with anhydrous DMSO under nitrogen atmo-
sphere.
SeCN
SeCN
SeCN
SeCN
O
Cl
O
F
O
3i, 73%
3h, 81%
3j, 75%
Next, we examined the scope of our selenocyanation
method with variously decorated o-hydroxyacetophenones
(Scheme 1).10
O
O
O
SeCN
Me
SeCN
SeCN
The selenocyanation led to good yields and tolerated nu-
merous functional groups such as halogen (3b, 3c, 3d, 3i, 3j,
3k), methyl (3e, 3l), alkoxy (3f, 3m) or nitrile groups (3g).
Both electron-rich and electron-deficient substituents were
well tolerated. Only the o-hydroxyacetophenone bearing a
NO2 group at the para position of the phenol did not react.
The relative positioning of the substituent on the aromatic
ring (ortho, meta or para position) did not affect the effi-
ciency of the reaction. Replacing the phenyl moiety by a naph-
thalene led to a better yield of 3-cyanoselenatochromone (3h,
81%). In contrast, the yield in the presence of two hydrophilic
substituents (two methoxy) was moderate (3o, 56%).
To further explore the applicability of the procedure, we
performed a gram-scale synthesis of 3a with 10 mmol of o-
hydroxyacetophenone. This reaction was accomplished
with a slight increase in yield (79%) without changing the
reaction time (Scheme 2).
We suggest the following mechanism to explain our ex-
perimental results (Scheme 3). First, the o-hydroxyaceto-
phenone (1a) is converted into the enaminone 2a with
DMF-DMA. Meanwhile, the reaction between three equiva-
lents of selenium dioxide and one equivalent of malononi-
trile gives the triselenodicyanide 4.6a The enaminone 2a
reacts on the most electrophilic selenium of 4 atom, leading
Br
O
O
MeO
O
3k, 64%
3l, 76%
3m, 78%
O
O
O
Br
SeCN MeO
MeO
Cl
O
O
Me
O
Br
3p, 75%
3o, 56%
3n, 65%
Scheme 1 Scope of the synthesis of 3-selenocyanato-4H-chromen-4-
ones. Reagents and conditions: a mixture of o-hydroxyacetophenone
1a–p (1 mmol, 1 equiv) and DMF-DMA (1 equiv) was heated for 2 h at
100 °C; then a preprepared solution of SeO2 (3 equiv) and malononitrile
(1 equiv) in DMSO (1 mL) stirred at 25 °C for 20 min was added at 25 °C.
The reaction mixture was stirred for 30 min under air atmosphere.
Isolated yield is provided based on 1a–p.
O
O
1. DMF-DMA
SeCN
2 h, 100 °C
CN
OH
O
2. SeO2
+
1a (1.36 g, 10 mmol)
3a (1.97 g, 79%)
CN
DMSO, 30 min, 25 °C
Scheme 2 Gram synthesis
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
A. R. Kosso et al.
Letter
Synlett
ring could expulse the oxoacetic acid and the o-hydroxy-
benzoic acids in the presence of water. The requirement of
four equivalents of H2O2 for complete reaction is in agree-
ment with the mechanism described. These successive oxi-
dation steps demonstrate that these chromone-4-ones with
a selenium on position 3 could be compounds of interest
due to their antioxidant properties.
O
CN
O
OMe
Me
3 SeO2
+
Me
Me
+
N
CN
MeO
N
Me
ref. 6a
OH
OH
2a
Me
1a
Se CN
4
Se
Se CN
O
O
O
O
O
O
O
CN
Se
O
O
CN
Se
H
O
SeCN
SeCN
SeCN
Me
SeCN
H2O2
H2O2
O
Me
Me
N
O
Se2 CN
N
– (HNMe2, H+)
O
O
O
3a
Me
H
H
1a
H2O
2 H2O2
Scheme 3 Suggested mechanism of the reaction
HOO
SeCN
O
HOSeCN
+
O
O
O
O
O
O
To demonstrate the utility of the selenocyanated chro-
mones, two transformations of the SeCN functional group
were explored (Scheme 4). The 3-selenocyanato-4H-
chromen-4-one (3a) was converted into (5a) bearing a
seleno ester group in 80% yield via a reduction with NaBH4
into a selenolate followed by addition of an electrophile
(acetyl chloride). The chromen-4-one (3a) was then sub-
jected to H2O2 oxidation (1 equiv) in dichloromethane. To
our surprise, no selenoxide was isolated; instead only the
unexpected o-hydroxybenzoic acid appeared. The reaction
was not completed even after one day at room temperature.
Adding 3 equivalents of H2O2, allowed complete conversion
into o-hydroxybenzoic acid with a 76% yield.
O
O
H
Baeyer–Villiger oxidation
OH
O
CO2H
O
H2O
CO2H
O
O
+
OH
OH
O
6a
Scheme 5 Mechanism for the peroxidation of selenium
In summary, we have developed an efficient approach
for the preparation of 3-selenocyanato-4H-chromen-4-ones
using readily available selenium dioxide and 2-hydroxyaceto-
phenones. This one-pot two-step reaction leads to good
yields with easy purification by simple filtration. The meth-
od uses odorless and inexpensive starting materials. Oxida-
tion of the core of the chromones gives the o-hydroxy-
benzoic acid by rearrangement of the selenium. This result
indicates that insertion of SeCN in position 3 of chromones
could increase their antioxidant properties.
O
O
O
H2O2
(4 equiv)
NaBH4,
Me MeOH
SeCN
Se
OH
DCM
25 °C
AcCl
25 °C
O
OH
O
O
5a, 80%
6a, 76%
3a
Scheme 4 Transformations of the selenocyanated group in 5a and 6a
Assuming that the chromone first lost the double bond
and the SeCN group and that the ketone was secondly con-
verted into carboxylic acid, a cascade reaction of several ox-
idations and rearrangements could be involved. The pro-
posed mechanism is based on previous studies on the oxi-
dative rearrangement of selenium (Scheme 5).11 The
selenocyanate group could first be oxidized by H2O2into
selenoxide species. A polarizable double bond further oxi-
dized would be easily convertible into epoxide by H2O2.
Then addition of water on position 2 could open this acti-
vated epoxide, inducing the expulsion of ‘HOSeCN’. HOSeCN
could then be further oxidized by the excess of H2O2 into
CNSe(O)OOH (cyanoperseleninic acid). Perseleninic acid is
known as a selective oxidant able to perform Baeyer–
Villiger reactions.12 The Baeyer–Villiger oxidation of the
diketone could give the acid anhydride derivative. The
hemiacetal formed upon opening of the seven-membered
Funding Information
Aix-Marseille Université and the Centre National de la Recherche
Scientifique (CNRS) are gratefully acknowledged for financial sup-
port. A. R. Obah Kosso thanks OGES-Congo for her PhD grant.
)(
Acknowledgment
We warmly thank Vincent Remusat and the Spectropole
(http://www.spectropole.fr) for NMR and HRMS analysis.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609340.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

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A. R. Kosso et al.
Letter
Synlett
References and Notes
(7) (a) Reis, J.; Gaspar, A.; Milhazes, N.; Borges, F. J. Med. Chem.
2017, 60, 7941. (b) Gaspar, A.; Matos, M. J.; Garrido, J.; Uriarte,
E.; Borges, F. Chem. Rev. 2014, 114, 4960.
(8) (a) Zhong, S.; Liu, Y.; Cao, X.; Wan, J.-P. ChemCatChem 2017, 9,
465. (b) Joussot, J.; Schoenfelder, A.; Larquetoux, L.; Nicolas, M.;
Suffert, J.; Blond, G. Synthesis 2016, 48, 3364.
(1) (a) Baquedano, Y.; Moreno, E.; Espuelas, S.; Nguewa, P.; Font,
M.; Gutierrez, K. J.; Jiménez-Ruiz, A.; Palop, J. A.; Sanmartín, C.
Eur. J. Med. Chem. 2014, 74, 116. (b) Baquedano, Y.; Alcolea, V.;
Toro, M. A.; Gutierrez, K. J.; Nguewa, P.; Font, M.; Moreno, E.;
Espuelas, S.; Jimenez-Ruiz, A.; Palop, J. A.; Plano, D.; Sanmartín,
C. Antimicrob. Agents Chemother. 2016, 60, 3802.
(2) (a) Facompre, N. D.; El-Bayoumy, K.; Sun, Y.-W.; Pinto, J. T.;
Sinha, R. Cancer Prev. Res. 2010, 3, 975. (b) Sohn, O. S.; Fiala, E.
S.; Upadhyaya, P.; Chae, Y. H.; El-Bayoumy, K. Carcinogenesis
1999, 20, 615.
(3) (a) Nikolaienko, P.; Rueping, M. Chem. Eur. J. 2016, 22, 2620.
(b) Mukherjee, N.; Kundu, D.; Ranu, B. C. Adv. Synth. Catal. 2017,
359, 329. (c) Maity, P.; Paroi, B.; Ranu, B. C. Org. Lett. 2017, 19,
5748. (d) Krief, A.; Dumont, W.; Delmotte, C. Angew. Chem. Int.
Ed. 2000, 39, 1669.
(4) (a) Vijay, N.; Anu, A.; Tesmol, G. G. Eur. J. Org. Chem. 2002, 2363.
(b) Chen, J.; Wang, T.; Wang, T.; Lin, A.; Yao, H.; Xu, J. Org. Chem.
Front. 2017, 4, 130. (c) Muniraj, N.; Dhineshkumar, J.; Prabhu, K.
R. Chemistry Select 2016, 1, 1033. (d) Zhang, H.; Wei, Q.; Wei, S.;
Qu, J.; Wang, B. Eur. J. Org. Chem. 2016, 20, 3373.
(9) For a similar one-pot procedure from o-hydroxyacetophenone
via enaminone species, see: Zhang, X.-Z.; Ge, D.-L.; Chen, S.-Y.;
Yu, X.-Q. RSC Adv. 2016, 6, 66320. For one-pot procedure from
enaminone species, see: Rafique J., Saba S., Schneider A. R.,
Franco M. S., Silva S. M., Braga A. L. ACS Omega; 2017, 2: 2280.
(10) 3-Selenocyanato-4H-chromen-4-ones 3; General Procedure:
A mixture of o-hydroxyacetophenone (1a; 136 mg, 1 mmol,
1 equiv) and dimethylformamide dimethylacetal (120 mg,
1 mmol, 1 equiv) was heated for 2 h at 100 °C. After cooling to
25 °C, a preprepared solution of malononitrile (66 mg, 1 mmol,
1 equiv) and SeO2 (332 mg, 3 mmol, 3 equiv) in DMSO (1 mL),
stirred at 25 °C for 20 min, was added at 25 °C. The reaction
mixture was stirred for a further 30 min, then H2O was added
(3 mL). The resulting precipitate was filtered off, washed with
H2O (3 × 10 mL) and dried under a fume hood overnight at 25 °C
to give the pure product 3a.
(5) For the first synthesis, see: (a) Verneuil, A. Ann. Chim. Phys.
1886, 41, 328. For crystal data, see: (b) Aksnes, O.; Foss, O. Acta
Chem. Scand. 1954, 1787. (c) Hauge, S. Acta Chem. Scand. 1971,
25, 3081. (d) Burchell, C. J.; Kilian, P.; Slawin, A. M. Z.; Woollins,
J. D.; Tersago, K.; Van Alsenoy, C.; Blockhuys, F. Inorg. Chem.
2006, 45, 710.
(6) (a) Kachanov, A. V.; Slabko, O. Y.; Baranova, O. V.; Shilova, E. V.;
Kaminskii, V. A. Tetrahedron Lett. 2004, 45, 4461. (b) Redon, S.;
Obah Kosso, A. R.; Broggi, J.; Vanelle, P. Tetrahedron Lett. 2017,
58, 2771. (c) Redon, S.; Kabri, Y.; Crozet, M. D.; Vanelle, P. Tetra-
hedron Lett. 2014, 55, 5052.
3-Selenocyanato-4H-chromen-4-one (3a): brown solid; yield:
76%; mp 136–137 °C. 1H NMR (250 MHz, CDCl3): δ = 8.26 (s,
1 H), 8.20 (dd, J = 8.0, 1.6 Hz, 1 H), 7.79 (dt, J = 8.4, 1.7 Hz, 1 H),
7.56 (dt, J = 8.4 Hz, 1 H), 7.51 (dt, J = 7.1, 1.1 Hz, 1 H). 13C NMR
(62.5 MHz, CDCl3): δ = 174.3 (CO), 156.7 (C), 153.1 (CH), 135.1
(CH), 126.5 (CH), 125.9 (CH), 122.0 (C), 118.6 (CH), 112.7 (C),
100.0 (CN). HRMS (ESI): m/z [M + H]+ calcd for C10H5NO2Se:
251.9559; found: 251.9557.
(11) Redon, S.; Pannecoucke, X.; Franck, X.; Outurquin, F. Org.
Biomol. Chem. 2008, 6, 1260.
(12) (a) ten Brink, G.-J.; Vis, J.-M.; Arends, I. W. C. E.; Sheldon, R. A.
J. Org. Chem. 2001, 66, 2429. (b) Zhang, X.; Ye, J.; Yu, L.; Shi, X.;
Zhang, M.; Xu, Q.; Lautens, M. Adv. Synth. Catal. 2015, 357, 955.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D