Reactivity of electrogenerated thiocyanogen in the thiocyanation of pyrazolo[1,5-a]pyrimidines

Article abstract of DOI:10.1016/j.mencom.2016.09.016

Selective thiocyanation (yield 70–90%) at the 3-position of pyrazolo[1,5-a]pyrimidines was performed with thiocyanogen electrochemically generated in situ from NH₄SCN in MeCN on a Pt anode. For substrates with higher oxidation potential addition of Lewis acids was necessary.

Full text of DOI:10.1016/j.mencom.2016.09.016

Mendeleev
Communications
Mendeleev Commun., 2016, 26, 413–414
Reactivity of electrogenerated thiocyanogen
in the thiocyanation of pyrazolo[1,5-a]pyrimidines
Vladimir A. Kokorekin, Rauza R. Yaubasarova, Sergei V. Neverov and Vladimir A. Petrosyan*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: petros@ioc.ac.ru
DOI: 10.1016/j.mencom.2016.09.016
SCN
Selective thiocyanation (yield 70–90%) at the 3-position of
pyrazolo[1,5-a]pyrimidines was performed with thiocyanogen
electrochemically generated in situ from NH4SCN in MeCN
on a Pt anode. For substrates with higher oxidation potential
addition of Lewis acids was necessary.
R2
R2
N
N
R1
R1
N
N
N
N
– 2e
2 SCN–
(SCN)2
R3
R3
R1 = Alk; R2, R3 = Alk, Ar, NH2, CF3
The concept of electro-induced processes of hydrogen nucleo-
philic substitution in arenes, the SHN(An) reaction (where An is
the anode), was formulated in reviews.1,2 Based on the ideas
developed by Ingold,3 electrothiocyanation was considered among
these processes.4 It occurs through generation of thiocyanogen,
(SCN)2, due to polarity inversion (‘umpolung’)5 in the original
thiocyanate ion according to Scheme 1.
metry (CV) data, this potential corresponded to the thiocyanate
ion ® thiocyanogen oxidation peak (0.70 V vs. SCE). Regardless
of the known15 liability of thiocyanogen to polymerization, which
requires the use of rather low temperatures (–20 to 5°C),16 it
has been shown4 that electrothiocyanation in MeCN can be
successfully performed even at room temperatures (20–25°C).
The present study confirmed this conclusion. The process carried
out in accordance with Scheme 1 occurred at 3-position of the
pyrazole ring with sufficiently high yield (79–87%) of the target
products 2a–e (see Table 1).
‘umpolung’
× 2
ArH
– H+, – SCN–
– e
SCN–
SCN
(SCN)2
ArSCN
It follows from the Epox values from Table 1 (the potentials of
irreversible oxidation peaks of pyrazolo[1,5-a]pyrimidine systems)
that bicycles 1a–c containing electron-donating groups in the
pyrimidine ring undergo oxidation more easily than bicycles 1d,e
with electron-withdrawing groups in the pyrimidine ring. Thus,
Scheme 1
The interest in the synthesis of thiocyanation products stems
from the broad spectrum of their pharmacological activity, e.g.
antitumor,6 antiparasitic,7 antifungal,8,9 etc. On the other hand,
the electrochemical method10 is the simplest and most convenient
one for synthesizing ‘dirhodane’(known as thiocyanogen11) where
the anode is used as a ‘green’oxidizing agent, since the chemical
methods of thiocyanogen synthesis usually involve the use of a
considerable excess of inorganic or organic oxidants that are
often toxic (see the review12). Each of these reasons stimulated
the search for new objects for electrothiocyanation. Furthermore,
identification of factors that affect the process efficiency was
obviously of interest.
SCN
R2
R2
N
N
R1
R1
N
N
N
N
R3
R3
1a–e
2a–e
a R1 = R2 = Me, R3 = NH2
b R1 = R2 = R3 = Me
d R1 = Me, R2 = 2-thienyl, R3 = CF3
e R1 = Me, R2 = Ph, R3 = CF3
c R1 = cyclopropyl, R2 = R3 = Me
In the previous study,4 we addressed the electrothiocyanation
ofderivativesofnitrogen-containingfive-membered heterocycles
(pyrazoles, pyrroles, etc.) to give target products with antifungal
activity.9 In continuation of these studies, we tried to perform the
electrothiocyanation of functionally-substituted pyrazolo[1,5-a]-
pyrimidine systems (condensation products of pyrazoles with
1,3-diketones), which by themselves may be pharmacologically
active,13,14 and to study the regularities of these processes.
The electrothiocyanation of bicycles 1a–e during NH4SCN
oxidation was carried out in MeCN with 0.1 m NaClO4 as a
supporting electrolyte in an undivided cell with Pt electrodes
(Scheme 2, Table 1). These processes were implemented under
controlled potential electrolysis (CPE).† Based on cyclic voltam-
Scheme 2
potentiostat (Elins, scan rate 0.1 V s–1). A Pt wire 1 mm in diameter in a
Teflon casing was used as the working electrode. SCE separated from the
solution by a salt bridge filled with the supporting electrolyte (0.1 m NaClO4
in MeCN) was used as the reference electrode. A Pt plate (S = 3 cm2) was
used as the counter electrode.
The following compounds were synthesized as described: 2-methyl-
pyrazolo[1,5-a]pyrimidin-7-amine18 1a, 2-methyl-5-(thiophen-2-yl)-7-(tri-
fluoromethyl)pyrazolo[1,5-a]pyrimidine19 1d, 2-methyl-5-phenyl-7-(trifluoro-
methyl)pyrazolo[1,5-a]pyrimidine19 1e. 2,5,7-Trimethylpyrazolo[1,5-a]-
pyrimidine 1b and 2-cyclopropyl-5,7-dimethylpyrazolo[1,5-a]pyrimidine
1c were prepared as follows. 3-Methyl- or 3-cyclopropyl-1H-pyrazol-
5-amine (0.012 mol) was dissolved in water (5 ml). Concentrated HCl
(3 ml) and a solution of pentane-2,4-dione (5 ml, 0.01 mol) in EtOH were
added (if the mixture became turbid, more EtOH was added to obtain a
clear solution). The solution was stirred for 24 h, then EtOH was distilled
off in vacuo and 0.1 m aq. NaOH was added. The crystals that precipitated
were washed with water to pH ~7 and dried in air. The yield of products 1b,c
amounted to 60%.
†
1H and 13C NMR spectra were recorded on a Bruker Avance 300
instrument (300.13 MHz for H and 75.47 MHz for 13C). HRMS spectra
1
were recorded on a Bruker micrOTOF II instrument. CV studies were carried
out in a temperature-controlled (25°C) cell (V = 10 ml) using a P30JM
© 2016 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2016, 26, 413–414
Table 1 The oxidation peaks (Epox) of compounds 1a–e and the yields of
to 87%) in case of bicycles 1a–c but decreased to zero in the case
of bicyclic structures 1d,e.The latter had Epox values more positive
than 1.8 V and did not undergo electrothiocyanation at all under
the conditions of the experiment.
their thiocyanation products 2a–e in electrooxidation of NH4SCN in the
presence of 1a–e (Pt anode, E = 0.7 V vs. SCE, 0.1 m NaClO4, MeCN).
Reactant 1
Epox/V
Product
Yield (%)
It is interesting4 that the yield of thiocyanation products of
indoles and pyrroles also decreased with an increase in their Epox
values, while attempts at thiocyanation of 2-methylfuran, furan,
and thiophene failed (Epox = 1.7, 2.0, and 2.15 V, respectively).
It can therefore be concluded that the efficiency of using electro-
generated thiocyanogen in the thiocyanation of arenes is limited
by the Epox value of an arene. We assumed, however,4 that this
limitation that reflects the reactivity of thiocyanogen itself can
be mitigated to some extent by addition of electrophilic catalysts.
In fact, the yield of products 2d and 2e rose from 0 to almost
70% on addition of ZnCl2 to the reaction system. In this case, the
process mechanism can be described by Scheme 3.
1a
1b
1c
1d
1e
1.20
1.50
1.50
1.85
1.88
2a
2b
2c
2d
2e
79
87
82
71a
69a
a In the presence of ZnCl2, in its absence the yield was 0%.
the nature of the substituent in the pyrimidine ring of the bicycle
determines to a considerable extent the increase in Epox values on
transition from bicycle 1a to bicycle 1e. Note (see Table 1) that
the yield of thiocyanation products of the pyrazolo[1,5-a]pyri-
midine systems changed in reverse order. It was rather high (up
– 2e
2 SCN
(SCN)2
ZnCl2
Electrosynthesis (general procedure). A 0.1 m solution of NaClO4 in
MeCN (50 ml) containing NH4SCN (0.003 mol) and reactant 1a–e
(0.001 mol) was placed in a glass temperature-controlled (25°C) cell
(V = 60 ml) equipped with coaxial cylindrical Pt-electrodes (Sanode = 26 cm2,
Scathode = 10 cm2). In the case of 1d,e (see Table 1), ZnCl2 (0.0015 mol)
was also added. The electrolysis was carried out by passing 2–4 F of
electricity (based on 1 F per 1 mol NH4SCN) with vigorous stirring in a
stream of nitrogen at a potential of 0.70 V vs. SCE until the starting 1 was
fully consumed (TLC and CV monitoring).After the reaction was completed,
the solvent was distilled off in vacuo, water (20 ml) was added, and the
mixture was extracted with EtOAc (4×25 ml). The extracts were combined,
dried with anhydrous MgSO4, filtered and concentrated in vacuo. Column
–
+
SCN
H
ArH
ZnCl2 NCS SCN
Ar
ArSCN
– H+
Scheme 3
Thus, our study has revealed the principal possibility of electro-
chemical thiocyanation of pyrazolo[1,5-a]pyrimidine systems. The
efficiency of the process is dependent on the oxidation potential
of the substrate and can be regulated by Lewis acid additives.
The reactions in question play an important role in organic trans-
formations and preparation of hybrid/molecular systems.17
chromatography on SiO2 (light petroleum–EtOAc, with increasing fraction of
the latter from 5 to 100 vol%, as the eluent) gave pure thiocyanates 2a–e.
2-Methyl-3-thiocyanatopyrazolo[1,5-a]pyrimidin-7-amine 2a: yellowish
solid, mp > 180°C (decomp.). 1H NMR (DMSO-d6) d: 2.52 (merge with
DMSO, s, 3H, 2-Me), 6.26 (d, 1H, C6H, J6,5 5.4 Hz), 8.11 (br.s, 2H,
7-NH2), 8.20 (d, 1H, C5H, J5,6 5.4 Hz). 13C NMR, d: 12.50 (2-Me), 80.96
(C3), 90.48 (C6H), 111.92 (3-SCN), 148.37 (C2), 150.17 (C5a), 151.32
(C5H), 156.17 (C7). HRMS (ESI), m/z: 206.0498 (calc. for C8H7N5S, m/z:
206.0495 [M+H]+).
This work was supported by the Russian Science Foundation
(grant no. 14-50-00126).
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2-Cyclopropyl-5,7-dimethyl-3-thiocyanatopyrazolo[1,5-a]pyrimidine
2c: yellowish solid, mp 143–146°C. 1H NMR (CDCl3) d: 1.18 (m, 4H,
2-cyclopropyl, C2'H2, C3'H2), 2.34 (m, 1H, 2-cyclopropyl, C1'H), 2.66 (s,
6H, 5-Me, 7-Me), 6.66 (s, 1H, C6H). 13C NMR, d: 8.32 (2-cyclopropyl,
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2-Methyl-3-thiocyanato-5-(thiophen-2-yl)-7-(trifluoromethyl)pyrazolo-
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2.69 (s, 3H, 2-Me), 7.21 (dd, 1H, 5-C4H3S, C4'H, J4',5' 5.1 Hz, J4',3' 3.7 Hz),
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7.85 (dd, 1H, 5-C4H3S, C3'H, J3',4' 3.7 Hz, J3',5' 1.1 Hz). 13C NMR, d: 13.23
(2-Me), 87.62 (C3), 110.36 (3-SCN), 104.05 (q, C6H, 3JC,F 4.1 Hz), 117.26
1
(q, 7-CF3, JC,F 275.1 Hz), 128.95 (5-C4H3S, C4'H), 129.86 (5-C4H3S,
2
C5'H), 132.98 (5-C4H3S, C3'H), 134.60 (q, C7H, JC,F 37.8 Hz), 141.21
(5-C4H3S, C2'), 150.16 (C5a), 153.38 (C5), 159.79 (C2). HRMS (ESI),
m/z: 341.0138 (calc. for C13H7F3N4S2, m/z: 341.0137 [M+H]+).
2-Methyl-5-phenyl-3-thiocyanato-7-(trifluoromethyl)pyrazolo[1,5-a]
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2.63 (s, 3H, 2-Me), 7.63 (m, 3H, 5-Ph, C2'H, C4'H, C6'H), 8.28 (s, 1H,
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3
(C3), 106.11 (q, C6H, JC,F 3.9 Hz), 111.18 (3-SCN), 117.38 (q, 7-CF3,
1JC,F 274.9 Hz), 127.87 (5-Ph, C2'H, C6'H), 129.17 (5-Ph, C3'H, C5'H),
132.00 (5-Ph, C4'H), 132.94 (q, C7H, 2JC,F 37.2 Hz), 134.94 (5-Ph, C1'),
149.53 (C5a), 157.98 (C5), 158.52 (C2). HRMS (ESI), m/z: 335.0568 (calc.
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Received: 14th April 2016; Com. 16/4910
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