Easy and efficient selenocyanation of imidazoheterocycles using triselenodicyanide

Article abstract of DOI:10.1016/j.tetlet.2017.06.003

The regioselective selenocyanation of imidazoheterocycles using triselenodicyanide at room temperature is reported. The electrophilic aromatic substitution of a broad range of substrates is promoted by the triselenodicyanide obtained by oxidative coupling

Full text of DOI:10.1016/j.tetlet.2017.06.003

Accepted Manuscript
Easy and efficient selenocyanation of imidazoheterocycles using triselenodi-
cyanide
Sébastien Redon, Anne Roly Obah Kosso, Julie Broggi, Patrice Vanelle
PII:
S0040-4039(17)30713-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.003
TETL 48995
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 May 2017
31 May 2017
1 June 2017
Please cite this article as: Redon, S., Kosso, A.R.O., Broggi, J., Vanelle, P., Easy and efficient selenocyanation of
imidazoheterocycles using triselenodicyanide, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.06.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Tetrahedron Letters
journal homepage: www.els evier.com
Easy and efficient selenocyanation of imidazoheterocycles using triselenodicyanide
Sébastien Redon,* Anne Roly Obah Kosso, Julie Broggi and Patrice Vanelle∗
Aix Marseille Univ, CNRS, ICR Institut de Chimie Radicalaire, UMR 7273, Equipe Pharmaco-Chimie Radicalaire (LPCR), Faculté de Pharmacie, 27 Bd Jean
Moulin CS–30064 13385 Marseille Cedex5, France
ARTICLE INFO
ABSTRACT
Article history:
Received
The regioselective selenocyanation of imidazoheterocycles using triselenodicyanide at room
temperature is reported. The electrophilic aromatic substitution of a broad range of substrates is
promoted by the triselenodicyanide obtained by oxidative coupling of malononitrile and
selenium dioxide, under an air atmosphere. The major advantages of the presented method are
an easy set-up, excellent yields, short reaction times, use of odorless and inexpensive reagents
and easy purification of the final products.
Received in revised form
Accepted
Available online
Keywords:
© 2017 Elsevier Ltd. All rights reserved
.
Selenocyanate
Imidazoheterocycles
Triselenodicyanide
Selenium dioxide
Malononitrile
Corresponding authors. E-mail address: patrice.vanelle@univ-amu.fr
sebastien.redon@univ-amu.fr

Interest in the fused bicyclic imidazo[1,2-a]pyridine moiety
has been demonstrated in medicinal chemistry, offering a wide
range of activities including antibacterial, antifungal,
antiinflammatory, antiviral, and antitumor properties.1 The
biological activities of some remarkable imidazo[1,2-a]-pyridines
(such as alpidem, necopidem, miroprofen, saripidem, zolpidem
or zolimidine) are chiefly dependent on the nature of the
substituents at the C-2 or C-3 positions. Therefore, substantial
efforts have been devoted to the development of new methods for
the efficient functionalization of this heterocyclic ring.2
with yields ranging from 10 to 60% (Table 1, entries 1-4). No
Table 1. Optimization of reaction conditions.
CN
Solvent,
SeO2
+
N
25 °C, 30 min
N
CN
Ph
Ph
N
N
Se CN
Se
SeCN
1a
2a
Moreover, selenocyanate substituted heterocycles have
shown interesting activities as antileishmanial agents3 and
cancer chemopreventive agents.4 The selenocyanate functional
group has also demonstrated its synthetic usefulness as an air-
and moisture-stable selenium halide analogue. This groups
reacts with a large panel of reagents leading upon decyanation
to the corresponding selenolate5 (with NaBH4 or base),
trifluoromethylselenide6 (with Ruppert–Prakash reagent) and
unsymmetrical selenide7 (by cross-coupling) derivatives. In this
sense, new synthetic strategies to insert the SeCN group will
indubitably be of high value.
Se CN
Entry
Solvent
Acetone
SeO2
(equiv.)
Malononitrile
(equiv.)
Yielda
2a (%)
1
3
3
3
3
3
3
3
3
1
2
3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.5
1
60
50
45
10
n.r.
n.r.
84
75
32
63
85
2
Propan-2-ol
Ethanol
3
4
1,4-Dioxane
Ethyl acetate
Dichloromethane
DMSO
Methodologies to introduce the selenocyanate functional
group are relatively recent and present the disadvantage of
using odorous and air sensitive potassium selenocyanate
(KSeCN). Reported procedures, applied to enriched arenes,
utilise this reagent as an electrophilic source with N-
iodosuccinimide as a catalyst and tert-butyl hydroperoxide as an
5
6
7
8
DMF
9
DMSO
oxidant,8 or as a radical SeCN source with cerium(IV) ammonium
10
11
DMSO
9b
nitrate9a (or K2S2O8
)
as an oxidant. Regarding the
DMSO
1
a Isolated yield. n.r.= no reaction (recovered starting material).
imidazoheterocycles,
selenocyanation has been performed with only one substrate
(1a) using KSeCN as a radical nucleophile10 via visible light
photoreduction with eosin Y in moderate yield (51%) or as an
electrophilic source with the oxidant N-chlorosuccinimide.11 In
addition to KSeCN, these methods require the use of blue LEDs
and tedious column chromatography.
Scheme 1. Scope of the selenocyanation of imidazo[1,2-
a]heterocycles.a, b
In order to develop a more attractive industrial process, it is of
high importance to offer a straightforward, odorless, inexpensive
and scalable method. Triselenodicyanide represents an ideal
electrophilic source,12 especially considering its simple and cheap
generation from malononitrile and odorless selenium dioxide.13
So far, this reagent has only been employed for the
selenocyanation of aniline derivatives.3 In a continuation of our
research program centered on the medicinal chemistry of
nitrogen-containing heterocycles,14 we investigated the reactivity
of triselenodicyanide in the selenocyanation of various
imidazoheterocycles.
We first undertook a detailed optimization study summarized
in Table 1. First, triselenodicyanide was prepared by mixing
selenium dioxide (3 equiv.) and malononitrile (1.5 equiv.) in
different solvents for 20 min. Performing these reactions under
diluted condition (1.0 mol.L-1) was necessary to circumvent the
problems encountered at higher concentrations, namely
insolubility of the substrates, high exothermicity of the reaction
and a gas release.15 Then, 2-phenylimidazo[1,2-a]pyridine (1a)
was added as a model substrate at room temperature. Solvent
evaluation revealed that organic solvents, such as acetone,
isopropanol, ethanol, and 1,4-dioxane, gave moderate results

This methodology was also applicable to a gram-scale
synthesis (Scheme 2). The reaction of 2-(phenyl)-imidazo[1,2-
a]pyridine (1a,
8
mmol) afforded the 2-phenyl-3-
selenocyanatoimidazo[1,2-a]pyridine (2b) in 84% yield. This
result demonstrates the practicality of our protocol.
Scheme 2. Gram-scale reaction.
A one-pot sequence was then tested using commercially
available α-bromo acetophenone and 2-aminopyridine as
starting materials (Scheme 3). The first step involved the
formation of the 2-phenylimidazo[1,2-a]pyridine motif by
cyclization in the presence of K2CO3 to trap the released HBr.17
After reaction completion, followed by 1H NMR, the
selenocyanation step on the C-3 position was accomplished
using the previously determined conditions. Unfortunately, no
precipitation occurred upon the addition of water in this case, so
a
Reaction conditions: substrate 1a-r (0.5 mmol) was added to a prepared
solution of SeO2 (3 equiv.) and malononitrile (1 equiv.) in DMSO (0.5 mL) at
25 °C. The reaction mixture was stirred for 30 min under an air atmosphere.
b Isolated yield. n.r.= no reaction.
reaction occurred with ethyl acetate or dichloromethane
(Entries 5-6). DMSO and DMF proved to be the best solvents,
with 84% and 75% yield, respectively (Entries 7-8). After 30 min
stirring at r.t., 6 volumes of water were added to precipitate the
pure selenocyanated product (2a). The proportions of selenium
dioxide and malononitrile could be decreased to a 3:1 ratio
without a loss of efficiency (Entry 11). Lower amounts led to
decreased yields (Entries 9-10).
the advantage of the simple filtration process was lost.
Purification by column chromatography gave the expected
product (2a) in 63% yield.
Scheme 3. Sequential, one-pot reaction.
Next, we examined the scope of our selenocyanation method
with a large number of variously decorated imidazoheterocycles
(Scheme 1).16 The electrophilic aromatic substitution proceeded
in excellent yields and tolerated numerous functional groups
such as methyl (2b, 2m), halogen (2c, 2d, 2e, 2f, 2n, 2o), alkoxy
(2j) or nitrile groups (2g, 2h). Both electron-rich and -deficient
substituents on the 2-phenyl moiety were well tolerated. The
relative positioning of the substituent on the aromatic ring
(meta- or para-position) did not affect the efficiency of the
reaction. Only one example failed to give the expected
selenocyanated 2-(4-nitrophenyl)-imidazo[1,2-a]pyridine (2g’),
bearing a strongly deactivating NO2 group. Other heterocycles
such as 2-furan (2k) or 2-thiophene rings (2l) were compatible
with imidazopyridine 3-selenocyanation. Finally, our optimized
selenocyanation procedure was successfully extended to other
imidazoheterocyclic compounds such as imidazopyrimidine (2p,
85%), imidazothiazole (2q, 81%) and imidazobenzothiazole (2r,
99%).
To demonstrate the utility of the selenocyanated substrates,
various transformations of the SeCN functional group were
examined (Scheme 4). The imidazopyridine (2a) could be
reduced with NaBH4 then oxidized at air to form a diselenide
bridge in the dimeric form (3a) in 79% yield. The SeCN group
could also be easily converted into a Se-CH3 group (3b) by a one-
pot reduction and alkylation with methyliodide. A Se-aryl
derivative (3c) was obtained in 91% yield by addition of a
Grignard reagent. The SeCF3 counterpart (3d) was obtained in
44% yield by addition of the Ruppert–Prakash reagent. Finally,
the SeO2H group, an attractive bioisotere of carboxy groups, was
introduced in moderate yield (3e, 55%) by the addition of
sulfuryl chloride followed by hydrochloric acid.

9. a) V. Nair, A. Augustine, T. G. George, Eur. J. Org. Chem. 2002,
2363–2366. b) Chen, J.; Wang, T.; Wang, T.; Lin, A.; Yao, H.;
Xu, J. Org. Chem. Front. 2017, 4, 130–134.
10. Mitra, S.; Ghosh, M., Mishra, S.; Hajra, A. J. Org. Chem. 2015,
80, 8275–8281.
11. Zhang, H.; Wei, Q.; Wei, S.; Qu, J.; Wang, B. Eur. J. Org. Chem.
2016, 20, 3373–3379.
12. Kachanov, A. V.; Slabko, O. Y.; Baranova, O. V.; Shilova, E. V.;
Kaminskii. V. A. Tetrahedron Lett. 2004, 45, 4461–4463.
13. First synthesis: a) Verneuil, A. Ann. Chim. Phys. 1886, 41, 328–
340; crystal data: b) Aksnes O., Foss. O. Acta Chem. Scand. 1954,
1787–1795; c) Hauge, S. Acta Chem. Scand. 1971, 25, 3081–
3093; d) Burchell, C. J.; Kilian, P.; Slawin, A. M. Z.; Woollins, J.
D.; Tersago, K.; Van Alsenoy, C.; Blockhuys F. Inorg. Chem.
2006, 45, 710–716.
Scheme 4. Transformations of the SeCN functional group in 2a.
14. a) Castera-Ducros, C.; Paloque, L.; Verhaeghe, P.; Casanova, M.;
Cantelli, C.; Hutter, S.; Tanguy, F.; Laget, M.; Remusat, V.;
Cohen, A.; Crozet, M. D.; Rathelot, P.; Azas, N.; Vanelle, P.
Bioorg. Med. Chem. 2013, 21, 7155–7164; b) Szabo, R.; Crozet,
M. D.; Vanelle, P. Heterocycles 2008, 75, 2263–2274; c) Szabo,
R.; Crozet, M. D.; Vanelle, P. Synthesis 2008 16, 127–135; d)
Crozet, M. D.; Castera-Ducros, C.; Vanelle, P. Tetrahedron Lett.
2006, 47, 7061–7065; e) Castera-Ducros, C.; Crozet, M. D.;
Vanelle, P. Heterocycles 2005, 65, 2979–2989. f) Vanelle, P.;
Madadi, N.; Roubaud, C.; Maldonado, J.; Crozet, M. D.
Tetrahedron 1991, 47, 5173–5184.
In summary, we have developed an efficient methodology for
the regioselective selenocyanation of imidazo[1,2-a]pyridine
derivatives at room temperature with
a high degree of
functional group tolerance. The method is characterized by the
use of odorless and inexpensive starting materials, an ease of
purification (filtration), and excellent yields. The scope was
15. Kachanov and co-workers have identified CO2 and N2 gas as by-
products from the preparation of triselenodicyanide, see reference
12.
extended
to
imidazo[2,1-b]thiazole
and
2-
16. General procedure for the direct selenocyanation of
imidazoheterocycles (2a-2r): To a solution of malononitrile (34
mg, 0.52 mmol, 1 equiv.) in DMSO (0.5 mL) was added SeO2
(174 mg, 1.57 mmol, 3 equiv.) at 25 °C. After 20 min stirring, 2-
phenylbenzo[b]imidazo[2,1-b]thiazole derivatives. This method
represents a robust protocol for the functionalization of a new
class of medicinally important heterocycles.
phenylimidazo[1,2-a]pyridine 1a (0.52 mmol,
1 equiv.) was
added. The reaction mixture was stirred for a further 30 min, then
water was added (3 mL). The resulting precipitate was filtered off
and washed with water (10 mL). The solid was dried under
reduced pressure at 50 °C to obtain the pure product.
Spectral data of selected compounds; compound 2a: orange solid,
mp 166 °C; 1H NMR (250 MHz, CDCl3) δ ppm 8.46 (d, J = 6.7
Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 9.0 Hz, 1H), 7.44-
7.55 (m, 4H), 7.14 (t, J = 6.7 Hz, 1H). 13C NMR (62.5 MHz,
DMSO-d6): δ ppm 149.7 (C), 146.6 (C), 132.9 (C), 128.8, 128.6,
128.5, 127.8, 126.3, 117.0 (CH), 114.2 (CH), 104.3 (C), 99.4 (C);
compound 2b: yellow solid, mp 176 °C, 1H NMR (400 MHz,
CDCl3) δ ppm 8.40 (d, J = 7 Hz, 1H), 7.86 (d, J = 7 Hz, 2H), 7.70
(d, J = 7.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.3 (d, J = 7.9 Hz,
2H), 7.08 (t, J = 7 Hz 1H), 2.42 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ ppm 153.2 (C), 148.1 (C), 139.6 (CH), 129.5 (CH),
129.1 (CH), 128.2 (CH), 125.6 (CH), 117.8 (CH), 114.5 (CH),
99.1 (C), 93.8 (C), 21.5 (CH3) ppm. HRMS (ESI): m/z calcd for
[C15H11N3Se+H]+: 314.0192, found: 314.0191.
Acknowledgments
Aix-Marseille Université and the Centre National de la Recherche
Scientifique (CNRS) are gratefully acknowledged for financial
support. A. R. Obah Kosso thanks the OGES-Congo for her PhD
grant. We warmly thank Vincent Remusat and the Spectropole
(http://www.spectropole.fr) for NMR and HRMS analysis.
Supplementary Material
17. Procedure for the one-pot sequential selenocyanation of 2-
phenylimidazo[1,2-a]pyridine: To a solution of 2-aminopyridine
(47 mg, 0.5 mmol) in DMSO (0.25 mL) was added 2-bromo-
Supplementary data associated with this article can be found in
the online version
acetophenone (100 mg, 0.5 mmol,
1 equiv.) and potassium
carbonate (76 mg, 1.1 equiv.). The reaction mixture was stirred at
room temperature for 2 h then a prepared solution of malononitrile
(33 mg, 0.50 mmol, 1 equiv.) and SeO2 (166 mg, 1.49 mmol, 3
equiv.) in DMSO (0.25 mL) was added. The reaction mixture was
stirred for a further 30 min, then water was added (13 mL). The
aqueous phase was extracted with dichloromethane (3 x 10 mL).
The combined organic layers were dried on sodium sulfate,
filtered and concentrated under reduced pressure. The crude
residue was purified by column chromatography on silica gel
using dichloromethane:ethyl acetate = 95:5 as eluent to afford the
pure product 2a (orange solid, 95 mg, 63% yield).
References and notes
1. Enguehard-Gueiffier, C.; Gueiffier, A. Mini-Rev. Med. Chem.
2007, 7, 888–899.
2. Bagdi, A. K.; Santra, S.; Monir, K.; Alakananda, H. Chem.
Commun., 2015, 51, 1555–1575.
3. 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, 116–123. b) Y. Baquedano, V.
Alcolea, M. A. Toro, K. J., Gutierrez, P. Nguewa, M. Font, E.
Moreno, S. Espuelas, A. Jimenez-Ruiz, J. A. Palop, D. Plano, S.
Sanmartín Antimicrob. Agents Chemother. 2016, 60, 3802–3812.
4. a) phenyleneselenocyanate p-XSC : Facompre, N. D.; El-
Bayoumy, K.; Sun, Y.-W.; Pinto, J. T.; Sinha, R. Cancer Prev.
Res. 2010, 3, 975–984. b) For comparison thio/selenocyanate:
Sohn, O. S.; Fiala, E. S.; Upadhyaya, P.; Chae, Y. H.; El-
Bayoumy, K. Carcinogenesis 1999, 20, 615–621.
5. Krief, A.; Dumont, W.; Delmotte, C. Angew. Chem. Int. Ed. 2000,
39, 1669–1672.
6. Nikolaienko, P.; Rueping, M. Chem. Eur. J. 2016, 22, 2620–2623.
7. Mukherjee, N.; Kundu, D.; Ranu, B. C. Adv. Synth. Catal. 2017,
359, 329–338.
8. Muniraj, N.; Dhineshkumar, J.; Prabhu K. R. ChemistrySelect
2016, 5, 1033–1038.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered
Leave this area blank for abstract info.
Easy and efficient selenocyanation of
imidazoheterocycles using triselenodicyanide
Sébastien Redon,* Anne Roly Obah-Kosso, Julie Broggi and Patrice Vanelle*

Highlights
•
•
•
•
The regioselective selenocyanation of imidazoheterocycles is reported.
The electrophilic aromatic substitution is promoted by the triselenodicyanide.
The triselenodicyanide is obtained from of malononitrile and selenium dioxide.
Odorless reagents and easy purification of products are the major advantages.