New data on heteroarene thiocyanation by anodic oxidation of NH 4SCN. the processes of electroinduced nucleophilic aromatic substitution of hydrogen

Article abstract of DOI:10.1016/j.tetlet.2014.06.028

Potentiostatic (galvanostatic) electrolysis of NH₄SCN in an undivided cell under mild conditions (25 °C, Pt anode, MeCN) was employed to perform the anodic thiocyanation of nitrogen-containing heterocycles with yields up to 95%. The regularitie

Full text of DOI:10.1016/j.tetlet.2014.06.028

Tetrahedron Letters 55 (2014) 4306–4309
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New data on heteroarene thiocyanation by anodic oxidation
of NH4SCN. The processes of electroinduced nucleophilic aromatic
substitution of hydrogen
⇑
Vladimir A. Kokorekin, Vera L. Sigacheva, Vladimir A. Petrosyan
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Potentiostatic (galvanostatic) electrolysis of NH4SCN in an undivided cell under mild conditions (25 °C, Pt
anode, MeCN) was employed to perform the anodic thiocyanation of nitrogen-containing heterocycles
with yields up to 95%. The regularities of the process are discussed, which show that it can be considered
as electroinduced nucleophilic aromatic substitution of hydrogen.
Received 7 March 2014
Revised 27 May 2014
Accepted 5 June 2014
Available online 12 June 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Anodic thiocyanation
Indole
Pyrrole
Azole
Cyclic voltammetry
Methodology for introducing CAC and CAX (X@O, N, S, etc.)
bonds on the basis of direct nucleophilic substitution of hydrogen
in arenes (SHNAr)1,2 has been developed extensively. The process
represents an attractive version of SNAr reactions and, in a number
of cases, a practical alternative to the well-known3 arene function-
alization based on metal complex catalysis.
eliminated as a proton. From an analysis of the characteristics of
SHN(An) reactions two basic pathways of such processes differing
in their mechanism, stood out:7 with the participation of Nuꢀ (I)
being harder to oxidize than arenes, and (II) being more readily
oxidizable than arenes.
According to Ingold’s classification,8 processes
I and II
The key intermediate of SNHAr reactions is the rꢀH adduct, the
aromatization of which formally corresponds to hydride ion elim-
ination. Among approaches to implementing such reactions
(Scheme 1) are addition–oxidation reactions, SHN(AO),2 where
organohalogen compounds were not used. However, they are char-
acterized by a few limitations. The most difficult here is the
empiric selection of an external oxidant that would selectively oxi-
dize rꢀH adducts rather than Nuꢀ, which is normally readily oxidiz-
able.1,4 An excellent alternative is an electrochemical version of
SHN(AO) reactions based on the selective electrooxidation of
chemically generated rꢀH adducts.5,6
On the other hand, a comparison of chemical and anodic
(electrochemical) substitution processes in arenes allowed the
conclusion7 that the latter should be considered as another versa-
tile type of SHN reaction denoted as SHN(An), where An is the anode.
These reactions (Scheme 2) proceed via the generation of r+H rather
than rꢀH adducts, therefore the substituted hydrogen was easily
(Scheme 2), irrespective of the mechanism, should be regarded as
nucleophilic substitution since, in the ongoing formation of a
new bond, the substituting reagent donating its electrons behaves
as
a nucleophile. Anodic substitution reactions have been
discussed from this standpoint.7,9
Previously (see Ref. 10 and literature cited therein), we per-
formed SHN(An) processes occurring via path I for the azolation of
arenes. This research examined the thiocyanation of arenes pro-
ceeding by path IIb, through the well-known11 electrogeneration
of thiocyanogen, (SCN)2. The electrochemical method where the
anode was used as a ‘green’ oxidizing agent was the most feasible
and expedient way to prepare thiocyanogen12 because chemical
methods typically employ toxic inorganic or organic oxidants in
excess amounts.13
[O]
ArH + Nu
ArHNu
H adduct
ArNu
[- H ]
σ
⇑
Corresponding author. Tel.: +7 4991377070.
E-mail address: petros@ioc.ac.ru (V.A. Petrosyan).
Scheme 1.
http://dx.doi.org/10.1016/j.tetlet.2014.06.028
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

V. A. Kokorekin et al. / Tetrahedron Letters 55 (2014) 4306–4309
4307
electrolysis
Nu
potential (CPE), which, as evidenced by cyclic voltammetry (CV)
data, corresponded to the oxidation peak of the thiocyanate ion
(0.70 V vs SCE).23,24
In accordance with Scheme 2, path IIb, the mechanism of the
electrochemical thiocyanation included the following steps
(Scheme 3): (i) thiocyanate ion electrooxidation, (ii) thiocyanogen
formation, and competing steps (iii) polymerization and (iv)
reaction with the arene.
- e
- e
, - e
ArH, - e
I
H
H
Ar
Ar
a
HNu
Ar
H adduct
Nu
Ar
II Nu
Nu
- H
σ
x2
H
Ar
Nu2
b
- Nu-
Scheme 2.
The mechanism (Scheme 3) was confirmed by CV studies. For
example, Figure 1a shows the CV curve A for NH4SCN. The one-
electron peak of the SCNꢀ anion oxidation—1 (Eopx = 0.70 V)—was
non-reversible owing to the formation of (SCN)2 fixed by its reduc-
tion peak 2 (Erped = 0.38 V). There was a one-electron peak 3
(Eopx = 1.30 V) on the CV curve B of indole oxidation and peak 4
(Eopx = 1.67 V) corresponds to further electrooxidation of indole.
The equimolar amount of indole added to the solution that con-
tained SCN- led to the disappearance of peak 2 (curve C), which
was indicative of the complete consumption of (SCN)2 in stage iv
of the mechanism shown in Scheme 3. Simultaneously, peaks 3
and 4 became lower and peak 40of the target product oxidation
(Eopx = 1.47 V) appeared. A similar peak was present in the CV curve
D for 3-thiocyanato-1H-indole, which was isolated after electroly-
sis of an NH4SCN/indole mixture (3:1). Figure 1b shows the CV
curve evolution during such electrolysis (after removing NH4SCN
for more precise representation of the indole and target product
peaks).
Generally, it follows from the CVA data that the rate of polymer-
ization of thiocyanogen under the experimental conditions (stage
iii, Scheme 3) was lower than the rate of its reaction with the are-
nes under study (stage iv). Qualitative evidence of this was evident
from the yellowish flakes of polythiocyanogen12,22 and the inten-
sity of their formation during the course of electrolysis increased
if the yield of the target products was low.
Preliminary tests showed that at CPE (T = 20–25 °C) the best
yield of arylthiocyanates was obtained when NH4SCN was used
as the starting reagent and NaClO4 as the supporting electrolyte.
Other salts (NaSCN, KSCN), the absence of NaClO4 or its replace-
ment with NH4ClO4 (Bu4NClO4) as well as an increase in the
electrolysis temperature led to a significant reduction in the yield.
Table 1 summarizes the CPE results under the optimized
conditions and, for comparison, the results of the galvanostatic
electrolysis (GE) at a current density of 2.50 mA/cm2, which was
regarded as being optimum based on preliminary test results.
Passing of 2.1 F per mol of arene in the course of CPE, and 2.5 F
during GE, provided full conversion of the starting arenes.
polythiocyanogen
(iii)
- e
(i)
x 2
(ii)
SCN
SCN
(SCN)2
ArH (- HSCN)
ArSCN
(iv)
Scheme 3.
Interest in thiocyanation products is connected with their wide
range of biological activity such as antifungal,14–16 antitumor,17
antiparasitic,18 etc. Furthermore, they are useful precursors for
the synthesis of sulfur-containing organic compounds (thiols,
sulfides, thiazoles, oxathiolanes, etc.).11
Electrochemical thiocyanation of aromatic substrates is mostly
limited to phenol and aniline derivatives,12 and only in recent
years has the scope been extended to methoxybenzenes19,20 and
indoles.15,21 The electrolysis was typically performed in the
presence of Brønsted acids, which formed a complex with thiocya-
nogen having better electrophilic properties, and, as a rule, at
rather low temperatures20 (ꢀ20 to 5 °C), due to the propensity of
thiocyanogen to undergo polymerization.22 Hence the search for
milder conditions for the realization of SHN(An) thiocyanation pro-
cesses and elucidation of the factors influencing their efficiency
are of interest.
As we found earlier,15,19 this process appeared feasible in
acetonitrile as the medium, even at room temperature (a similar
conclusion was recently made for the electrothiocyanation of
nitrogen-containing arenes in MeOH21). In the present research,
we continued our investigations on the thiocyanation of some
pyrazole, pyrrole, and isoxazole derivatives, which have not been
studied in such processes before. For comparison, the range of sub-
strates under study was widened by using indole derivatives and
aniline, the anodic thiocyanation of which had been described
under other conditions.20,21 The electrolysis was carried out in an
undivided cell with Pt electrodes in acetonitrile at a controlled
Figure 1. (a) Cyclic voltammograms: NH4SCN (2 ꢁ 10ꢀ3 M)—A, indole (2 ꢁ 10ꢀ3 M)—B, mixture of NH4SCN/indole (1:1)—C, 3-thiocyanato-1H-indole (2 ꢁ 10ꢀ3 M)—D;
(b) Evolution of CV curves during electrolysis of a mixture of NH4SCN/indole (6 ꢁ 10ꢀ3 M/2 ꢁ 10ꢀ3 M) after removing NH4SCN. Before electrolysis—B0, after passing of 1 F—C0,
after passing of 2.1 F—D0. (Pt electrode, 0.1 M NaClO4 in MeCN. Scan rate 0.20 V/s, T = 25 1 °C).

4308
V. A. Kokorekin et al. / Tetrahedron Letters 55 (2014) 4306–4309
2-methylfuran, furan, and thiophene (Eopx = 1.7, 2.0 and 2.15 V,
respectively) failed. However this limitation, which reflects the
reactivity of thiocyanogen, can be eliminated, to a greater or lesser
extent, with the addition of electrophilic catalysts.19
Table 1
Electrochemical thiocyanation of arenes and heteroarenesa
Entry
Aromatic substrate
Eopxb (V)
Productc
Yieldd (%)
85 (82)
SCN
At the same time, the thiocyanation efficiency also diminished
in the cases of arenes 7a and 8a with Eopx <1.1 V (entries 7 and 8)
being close to Eopx of the thiocyanate ion (0.7 V). The reason for this
being that the process occurs via another mechanism (different
from that shown in Scheme 3), where thiocyanogen could act as
the oxidant of the arene. However, this issue requires further
investigation.
In conclusion, the examined thiocyanation of aromatic systems
of different structures occurs via the SHN (An) process that proceeds
regioselectively under mild conditions (T = 20–25 °C) affording
high yields of the products. The antifungal activity of target prod-
ucts 1b–9b (Table 1)15,16 made the synthesis of these structures
attractive.
N
H
1
1.31
N
1a
H
1b
SCN
N
2
3
1.24
1.21
90 (84)
95 (89)
Me
N
2a
Me
2b
MeO
SCN
MeO
N
H
N
3a
H
3b
Acknowledgments
SCN
N
N
4
5
1.52
1.33
53 (50)
75 (70)
This study was supported by the Russian Foundation for Basic
Research (Grant No. 12-03-00517a) and the Division of Chemistry
and Materials Sciences of the Russian Academy of Sciences (Pro-
gramme No. 01 for fundamental research).
Ph
4a
Ph
4b
SCN
N
N
Me
Me
5a
5b
Supplementary data
SCN
NH2
Supplementary data (containing spectral data of 1b–9b) associ-
ated with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.06.028. These data include MOL
files and InChiKeys of the most important compounds described
in this article.
N
6
7
1.12
1.04
N
75 (68)
65 (57)
NH2
N
N
Me
6a
Me
6b
Me
Me
SCN
NH2
N
N
References and notes
NH2
N
N
1. Chupakhin, O. N.; Charushin, V. N.; van der Plas, H. C. Nucleophilic Aromatic
Substitution of Hydrogen; Academic Press: New York, 1994.
2. Charushin, V. N.; Chupakhin, O. N. Mendeleev Commun. 2007, 17, 249.
3. Metal-Catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: Weinheim, 2004. 2nd ed..
Ph
Ph
7a
7b
O
NH2
O
NH2
N
N
4. Shchepochkin, A. V.; Chupakhin, O. N.; Charushin, V. N.; Petrosyan, V. A. Russ.
Chem. Rev. 2013, 82, 747.
5. Gallardo, I.; Guirado, G.; Marquet, J. Eur. J. Org. Chem. 2002, 261.
6. Cruz, H.; Gallardo, I.; Guirado, G. Eur. J. Org. Chem. 2011, 7378.
7. Petrosyan, V. A. Mendeleev Commun. 2011, 21, 115.
8. Ingold, C. K. Structure and Mechanism in Organic Chemistry, 2nd ed.; Cornell
University Press: Ithaca, New York, 1969. Chapter 5.
9. Lyalin, B. V.; Petrosyan, V. A. Russ. J. Electrochem. 2013, 49, 497.
10. Sigacheva, V. L.; Kokorekin, V. A.; Strelenko, Y. A.; Neverov, S. V.; Petrosyan, V.
A. Mendeleev Commun. 2012, 22, 270.
SCN
8
9
1.01
1.04
60 (52)
Me
NH2
Me
8a
8b
NH2
75 (55)
11. Guy, R. G. In Cyanates and Their Thio Derivatives; Patai, S., Ed.; ; John Wiley &
Sons Ltd: New York, 1977; Vol. 2, pp 819–886.
12. Wood, J. L. In Organic Reactions In ; John Wiley & Sons: New York, 1946; Vol. 3,
pp 240–266.
9a
SCN
9b
a
13. Nikoofar, K. Chem. Sci. Trans. 2013, 3, 691. and references cited therein.
14. Yagodinets, P. I.; Skripskaya, O. V.; Prodanchuk, N. G.; Chernyuk, I. N.;
Sinchenko, V. G.; Dozirtsiv, G. M.; Pityk, M. Y. Pharm. Chem. J. 1995, 29, 54.
15. Kokorekin, V. A.; Ramenskaya, G. V.; Rodionova, G. M.; Petrosyan, V. A. In
Materials of the 4th International Scientific-Practical Conference ‘High
Technologies, Basic and Applied Researches in Physiology and Medicine’, St.
Petersburg, Russia, 2012; Vol. 1. pp 40–42.
16. Kokorekin, V. A.; Terent’ev, A. O.; Ramenskaya, G. V.; Grammatikova, N. É.;
Rodionova, G. M.; Ilovaiskii, A. I. Pharm. Chem. J. 2013, 47, 422.
17. Nagamachi, T.; Fourrey, J. L.; Torrence, P. F.; Waters, J. A.; Witkop, B. J. Med.
Chem. 1974, 17, 403.
Pt anode, 0.1 M NaClO4 in MeCN (50 ml), NH4SCN (6 mmol), arene 1a–9a
(2 mmol). Ean = 0.70 V versus SCE, Q = 2.1 F/mol (CPE) or j = 2.50 mA/cm2, Q = 2.5 F/
mol (GE).
b
The first oxidation peak based on CVA.23
c
Isolated products. Identified by 1H and 13C NMR spectroscopy and elemental
analysis.
d
Yield based on the amount of initial arene under CPE (GE) conditions.
The process proceeded regioselectively and with good product
yields in all experiments. In the cases of indole derivatives 1a,
2a, and aniline 9a, the obtained yield was comparable20 or higher19
than the thiocyanation product yields under other conditions. In
addition, the efficiency of thiocyanogen participation in such reac-
tions was limited by the potential of the first peak arene oxidation
(Eopx). The product yields of the thiocyanation of indoles 1a, 2a, and
3a, and those of pyrroles 4a and 5a, dropped as their Eopx increased
(Table 1, entries 1–3, 4, and 5), and attempts to thiocyanate
18. Elhalem, E.; Bailey, B. N.; Docampo, R.; Ujváry, I.; Szajnman, S. H.; Rodriguez, J.
B. J. Med. Chem. 2002, 45, 3984.
19. Burasov, A. V.; Petrosyan, V. A. Russ. Chem. Bull. 2008, 57, 1321.
20. Gitkis, A.; Becker, J. Y. Electrochim. Acta 2010, 55, 5854.
21. Fotouhi, L.; Nikoofar, K. Tetrahedron Lett. 2013, 54, 2903.
22. Cauquis, G.; Pierre, G. C. R. Acad. Sc. Paris, Serie C 1968, 294, 883.
23. The voltammetry studies were performed at a potential scan rate of 0.20 V/s in
a thermostated (25 °C) cell (V = 10 ml). A potentiostat (PI-50-1.1) controlled by
LabView software was used. A working electrode—Pt wire Ø 1 mm with a
Teflon insulating holder, reference electrode—SCE separated from the working

V. A. Kokorekin et al. / Tetrahedron Letters 55 (2014) 4306–4309
4309
solution by a salt bridge with the supporting electrolyte (0.1 M NaClO4 in
MeCN), counter electrode—Pt wire, was employed. The evolution of CV curves
during electrolysis of the NH4SCN/indole mixture were recorded after
removing the NH4SCN by the extraction procedure (see Ref.24), before
electrolysis, after passing 1 and 2.1 F of electricity.
electrolysis was terminated and the MeCN was distilled off. H2O (10 ml) was
added and the residue was extracted with CH2Cl2 (4 ꢁ 25 ml). The extracts
were combined, dried over anhydrous Na2SO4, filtered and the solvent was
distilled off. The residue was purified by column chromatography on silica gel
(eluent—a mix of light petroleum and EtOAc with a buildup of the volume
fraction of the latter from 5% to 20%) to afford pure 3-thiocyanato-1H-indole
(1b) [0.295 g (0.285 g), 85% (82%)]: Mp 74–76 °C.16 1H NMR (300.13 MHz,
CDCl3): d 8.90 (br s, 1H, NH), 7.80 (d, 1H, CH, J = 8.8 Hz), 7.56–7.15 (m, 4H,
C6H4). 13C NMR (75.48 MHz, CDCl3): d 136.09, 131.11, 127.69, 123.89, 121.92,
112.20, 118.71, 112.17, 92.02. Anal. calcd for C9H6N2S C, 62.05; H, 3.47; N,
16.08. Found: C, 62.32; H, 3.54; N, 15.82.
24. Typical procedure as an example of the electrosynthesis of 1a: A 0.1 M NaClO4
solution (50 ml) in MeCN containing NH4SCN (6 mmol, 0.46 g) and indole (1a)
(2 mmol, 0.24 g) was placed in
a glass cell with coaxally positioned Pt
electrodes (San. = 26 cm2, Scat. = 10 cm2). The electrolysis was performed at
E = 0.70 V vs SCE (CPE) or at j = 2.5 mA/cm2 (GE). After passing of 2.1 F of
electricity in CPE (or 2.5 F in GE) calculated on the basis of 1 F/NH4SCN mol, the