Side-chain prototropic tautomerism of 4-hydroxyfuroxans in methylation reactions

Article abstract of DOI:10.1016/j.tetlet.2016.11.023

A general and simple method for the preparation of under explored 3-aryl-4-hydroxyfuroxans by nucleophilic substitution of the nitro group in 3-aryl-4-nitrofuroxans using NaOH in H₂O-THF has been developed. The methylation of 3-aryl-4-hydroxyfu

Full text of DOI:10.1016/j.tetlet.2016.11.023

Accepted Manuscript
Side-chain prototropic tautomerism of 4-hydroxyfuroxans in methylation reac-
tions
Leonid L. Fershtat, Margarita A. Epishina, Igor V. Ovchinnikov, Marina I.
Struchkova, Anna A. Romanova, Ivan V. Ananyev, Nina N. Makhova
PII:
S0040-4039(16)31479-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.023
TETL 48309
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 September 2016
24 October 2016
4 November 2016
Please cite this article as: Fershtat, L.L., Epishina, M.A., Ovchinnikov, I.V., Struchkova, M.I., Romanova, A.A.,
Ananyev, I.V., Makhova, N.N., Side-chain prototropic tautomerism of 4-hydroxyfuroxans in methylation reactions,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.023
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Side-chain prototropic tautomerism of 4-hydroxyfuroxans in methylation
reactions
Leonid L. Fershtat,a Margarita A. Epishina,a Igor V. Ovchinnikov,a Marina I. Struchkova,a
Anna A. Romanova,b,c Ivan V. Ananyev,b,c Nina N. Makhovaa*
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47, Leninsky prosp., 119991, Moscow,
Russian Federation. Tel: +7(499) 1355326; Fax: +7 (499) 1355328; E-mail: mnn@ioc.ac.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,28 Vavilova str., 119991
Moscow, Russian Federation. Fax: +7 (499) 135 5085. E-mail: i.ananyev@gmail.com
cHigher Chemical College, Russian Academy of Sciences, 125047 Moscow, Russian Federation
Abstract
A general and simple method for the preparation of under explored 3-aryl-4-
hydroxyfuroxans by nucleophilic substitution of the nitro group in 3-aryl-4-nitrofuroxans using
NaOH in H2O-THF has been developed. The methylation of 3-aryl-4-hydroxyfuroxans was
studied with various methylating reagents (CH2N2, MeI, (MeO)2SO2) which showed for the first
time that 3-aryl-4-hydroxyfuroxans are prone to side-chain prototropic tautomerism. Furoxan
derivatives of a novel type, N(5)-alkylation products (3-aryl-5-methyl-1,2,5-oxadiazol-4(2H)-one
2-oxides), were synthesized under mild conditions, along with regioselective formation of the O-
alkylation products (3-aryl-4-methoxyfuroxans).
Keywords: 3-aryl-4-hydroxyfuroxans; nucleophilic substitution; side-chain prototropic
tautomerism; O- and N-methylation; regioselectivity.
Tautomerism is a prevailing property of heterocyclic compounds and is defined as a
phenomenon in which two or more molecular structures exist in dynamic equilibrium with each
other. One of the most widely studied type of tautomerism is side-chain prototropic tautomerism,
involving migration of a proton between a ring and a side-chain atom.1 Our research interest is
concerned with the synthesis and reactivity of different azoles, primarily, 1,2,5-oxadiazoles
(furazans) and their 2-oxides (furoxans).2 Furazans are stable systems which are not prone to
tautomerism involving annular centers, and although side-chain tautomerism involving
functional groups (e.g. tautomerism of OH and NH forms) can be theoretically conceived,3 IR
and NMR spectral data for hydroxyfurazans shows only the presence of the hydroxy form.1c,4

Nevertheless, the alkylation of trimethylsilyl derivatives of hydroxyfurazans with triethyl
orthoformate at high temperature (160-180 °C)5 was reported to give a mixture of O-alkylation
products and the first representatives of N-alkylation products, 2-ethyl-l,2,5-oxadiazol-3(2H)-
ones (Scheme 1). This provided evidence for possible side-chain prototropic tautomerism of
hydroxyfurazans. However, the alkylation of hydroxyfurazans with diazomethane6 and dimethyl
sulfate7 was found to yield only O-alkylation products.
Scheme 1. Alkylation of trimethylsiloxyfurazans with triethylorthoformate.
Only single examples of hydroxyfuroxans are described in the literature,8-10 and their
reactions with electrophilic reagents, in particular alkylation reactions, have not been studied;
therefore no data about the possibility of side-chain prototropic tautomerism are currently
available.
Meanwhile, furoxans represent a distinct group of heterocyclic compounds exhibiting
interesting biological activities,11 including neuroprotective and precognitive,12 cytotoxic,13
antihelmintic,14 antibacterial,15 and fungicidal16 properties, depending on the structure of the
furoxan ring substituents. Thereby we aimed to synthesize a series of under explored
hydroxyfuroxans and to study their propensity for side-chain prototropic tautomerism during
alkylation reactions. It could be expected that hydroxyfuroxans would be more prone to side-
chain prototropic tautomerism than hydroxyfurazans, because of the lower aromaticity of the
furoxan ring due to the positively charged N(2)-nitrogen atom in the N-oxide moiety, which
interrupts conjugation17 (Scheme 2).
Scheme 2. Possible tautomeric forms of hydroxyfuroxans.
Several hydroxyfuroxan derivatives are described in the literature.8-10 However, to the
best of our knowledge, there is no general method for their synthesis.
Herein, we present the development of a general method for the preparation of 3-aryl-4-
hydroxyfuroxans 1 by nucleophilic substitution of the nitro group in 3-aryl-4-nitrofuroxans 2
under the action of NaOH in H2O-THF and their methylation by different methylating reagents

(CH2N2, MeI, (MeO)2SO2). For the first time hydroxyfuroxans 1 were shown to be prone to side-
chain prototropic tautomerism and novel furoxan derivatives, N(5)-alkylation products (3-aryl-5-
methyl-1,2,5-oxadiazol-4(2H)-one 2-oxides) along with O-alkylation products (3-aryl-4-
methoxyfuroxans), were formed in different molar ratios, depending on the methylating reagent
used and the aromatic ring substituents of the starting 3-aryl-4-nitrofuroxans 2, with
regioselective formation of O-alkyl derivatives achieved under very mild conditions.
3-Aryl-4-hydroxyfuroxans 1 were selected as suitable substrates for this research and
were prepared using a modification of Wieland’s approach8 based on nucleophilic displacement
of the nitro groups in readily accessible 3-aryl-4-nitrofuroxans18 2 under the action of NaOH in
water-Et2O. Investigations began with screening the optimal conditions for the reaction of model
substrate 3-(4-ethoxyphenyl)-4-nitrofuroxan 2b with NaOH. The 2b:NaOH molar ratio and the
reaction medium were varied (Table 1). The conditions of Wieland’s method proved to be
unsuitable for the synthesis of hydroxyfuroxan 1b (Table 1, entry 1). Evidently, according to
literature data,19 the furoxan ring was substantially opened in the presence of a large excess of
NaOH. Decreasing the amount of NaOH (2 equiv.) and homogenization of the reaction medium
by replacing Et2O with dioxane resulted in an increased yield (50%, entry 2). Replacement of
dioxane by THF resulted in a further minor increase in yield (56%, entry 3). The optimal
conditions for the synthesis of 3-(4-ethoxyphenyl)-4-hydroxyfuroxan 1b proved to be: 2b:NaOH
(molar ratio 1:3) in H2O-THF (1:1 v/v) for 5 h at 20 °C (Entry 5). Use of a decreased 2b:NaOH
molar ratio (1:2.5) was less successful in terms of yield (Entry 4). The use of an increased
2b:NaOH molar ratio (1:4) resulted in a small decrease in yield (Entry 6), while further
increasing the 2b:NaOH molar ratio (1:5) significantly decreased the yield of 1b (Entry 7).
Hydroxyfuroxan 1b was isolated in all cases from the intermediate sodium salt 3 by acidification
of the reaction mixture to pH 1.
Table 1. Screening of reaction conditions for the preparation of 3-(4-ethoxyphenyl)-4-
hydroxyfuroxan 1ba
Entry
NaOH (equiv.)
Reaction medium
H2O/ether (1:1 v/v)
H2O/dioxane (1:1 v/v)
H2O/THF (1:1 v/v)
Yield 1bb (%)
1
2
3
8
2
2
10
50
56

4
5
6
7
2.5
3.0
4.0
5.0
H2O/THF (1:1 v/v)
H2O/THF (1:1 v/v)
H2O/THF (1:1 v/v)
H2O/THF (1:1 v/v)
70
82
76
67
a Reaction conditions: 1M NaOH, 2b (1 mmol), solvent (5 mL), 5-10 °C, then r.t.
b Isolated yield.
With the optimized conditions in hand, we investigated the substrate scope for the
synthesis of 3-aryl-4-hydroxyfuroxans 1. It was found that target 4-hydroxyfuroxans 1a-j were
formed in high yields under very mild conditions, regardless of the presence of electron-donating
(AlkO, Alk) or electron-withdrawing (Hal, NO2, CF3) groups and their position on the aromatic
ring (Table 2).
Table 2. Substrate scope for the synthesis of 3-aryl-4-hydroxyfuroxans 1a-ja,b
a Reaction conditions: NaOH (0.96 g, 24 mmol), 4-nitrofuroxan 2 (8 mmol), H2O (24 mL), THF (24 mL), 5-10 °C,
then r.t., 3-5 h.
b Isolated yield.
The structures of the synthesized 3-aryl-4-hydroxyfuroxans 1a-j were determined by IR,
13
19
1
1H, C, and F NMR spectroscopy as well as high-resolution mass spectrometry. The H NMR
and IR spectra of synthesized hydroxyfuroxans only showed the presence of the OH forms.
The methylation reaction of hydroxyfuroxans 1a-j was studied using three different
methylating reagents: CH2N2, MeI, and (MeO)2SO2. The investigations began using CH2N2 and
were carried out in Et2O at room temperature with an excess of CH2N2 (molar ratio 1:CH2N2 =
1:3). In all cases, with the exception of hydroxyfuroxan 1j containing the 4-CF3C6H4 substituent,
alkylation occurred with moderate regioselectivity to give two regioisomers, namely, O-
methylation products, 3-aryl-4-methoxyfuroxans 4a-j, and previously unknown N-methylation

products, 3-aryl-5-methyl-1,2,5-oxadiazol-4(2H)-one 2-oxides 5a-i, in ratios of 1.4:1 to 3:1 and
good total yields. The alkylation of hydroxyfuroxan 1j resulted in only O-methylation product
1
4j. The molar ratio of the regioisomers 4:5 was determined on the basis of H NMR data by
comparison of the integral intensity of the methyl group proton signals, because the proton
chemical shifts of the OMe (4.3-4.5 ppm) and NMe (3.3-3.5 ppm) groups were significantly
different.
The methylation of hydroxyfuroxans 1 using MeI and (MeO)2SO2 were carried out under
conditions commonly used for similar reactions (aprotic solvent in the presence of base).20 The
reactions were performed in different solvents (Et2O, THF, MeCN, DMF) in the presence of
organic and inorganic bases (TEA, DBU, K2CO3, Cs2CO3). Utilization of THF as the solvent and
Cs2CO3 as the base proved to be most appropriate for the reaction with MeI, whereas the reaction
with (MeO)2SO2 proceeded more successfully in DMF in the presence of K2CO3. Using organic
bases in these reactions resulted in decomposition of the initial hydroxyfuroxans. The
methylation of hydroxyfuroxans by MeI and (MeO)2SO2 proceeded with higher
regioselectivities. The molar ratios of regioisomers 4:5 was ~3:1 to 5:1 in the reactions with MeI
and 10:1 to 19:1 in the reactions with (MeO)2SO2. Only the O-methylation product was isolated
upon the methylation of hydroxyfuroxan 1j. After the reaction with diazomethane, compounds 4
and 5 were separated by column chromatography on SiO2 and all yields are summarized in Table
3.
Table 3. Hydroxyfuroxans 1a-j methylation with various methylating reagents
Total
Methylating
reagent
Molar ratio
Entry
1
Ar
yield
Compound 4e
Compound 5e
4:5c
(%)d
CH2N2
MeIa
2:1
2:1
98
74
Ph (a)
b
(MeO)2SO2
11:1
80
CH2N2
MeIa
1.4:1
4:1
90
81
97
94
69
4-EtOC6H4
2
(b)
b
(MeO)2SO2
19:1
1.5:1
3.5:1
CH2N2
MeIa
4-MeOC6H4
3
4
(c)
b
(MeO)2SO2
18:1
2:1
84
82
4-ClC6H4 (d)
CH2N2

MeIa
5:1
11:1
2.5:1
3.3:1
12:1
2.5:1
4:1
73
91
90
76
90
91
71
b
(MeO)2SO2
CH2N2
MeIa
5
6
7
8
4-BrC6H4 (e)
2-FC6H4 (f)
b
(MeO)2SO2
CH2N2
MeIa
b
(MeO)2SO2
12:1
81
CH2N2
MeIa
3:1
3:1
94
77
3-NO2C6H4
(g)
b
(MeO)2SO2
10:1
1.5:1
5:1
92
87
65
CH2N2
MeIa
4-MeC6H4
(h)
b
(MeO)2SO2
20:1
1.5:1
4:1
79
86
77
CH2N2
MeIa
9
4-iPrC6H4 (i)
b
(MeO)2SO2
12:1
90
f
CH2N2
MeIa
-
85
69
78
f
-
4-CF3C6H4
f
-
10
(j)
b
f
-
(MeO)2SO2
a Cs2CO3 used as base.
b K2CO3 used as base.
c Determined by 1H NMR spectroscopy.
d Isolated yield of a mixture of regioisomers.
e Isolated yield after methylation with CH2N2 and subsequent column chromatography.
f Only isomer 4j was isolated.
4-Methoxy-3-phenylfuroxan 4a is a known compound.21 The structures of compounds
1
4b-j and 5a-i were determined by spectral (IR, H, 13C, and 19F NMR spectroscopy and mass
spectrometry) and analytical methods. An important difference between the structures of the O-
1
and N-methylation products, apart from the H NMR chemical shifts of the Me groups, was the
appearance of a C=O absorption band (~ 1700 cm-1) in the IR spectra of N-methylation products
5a-i. Also, the fragmentation patterns of the molecular ions in the EI mass spectra of compounds
4 and 5 were substantially different. The major fragment ion in compounds 4 was (M+ – 2NO),
while for compounds 5, this was (M+ – ONMe – CO). Finally, the structure of 3-aryl-5-methyl-
1,2,5-oxadiazol-4(2H)-one 2-oxides 5 was unambiguously confirmed by the single-crystal X-ray
diffraction of compound 5a (Fig. 1). Notably, lengths of the N(2)-O(2), N(1)-O(1), N(2)-C(2)
and N(1)-C(1) bonds in the furoxan ring of 5a fall within the expected range according to CSD,22
with the only exception being the С(1)-С(2) bond, which was markedly elongated in comparison

with previously reported phenylfuroxans (1.467(5) Å vs 1.404 – 1.444 Å according to CSD),
probably due to disruption of π-conjugation in the 1,2,5-oxadiazolone ring (see the ESI for a
detailed discussion of 5a).
Figure 1. General view of 5a. Non-hydrogen atoms are represented by probability ellipsoids of
atomic vibrations (p = 50%).
A plausible mechanism for the methylation of 3-aryl-4-hydroxyfuroxans 1 is outlined in
Scheme 3. Firstly, diazomethane acts as a base, deprotonating hydroxyfuroxan to give anionic
intermediate 6 and MeN2 cation 7. The negative charge in intermediate 6 is delocalized between
the O and N atoms and subsequent nucleophilic substitution in MeN2 results in a mixture of O-
Me and N-Me regioisomers 4 and 5 with predominance for compounds 4 in a 1.4:1 to 3:1 molar
ratio. The amount of regioisomer 4 grows with an increase in the electron-withdrawing character
of the aromatic ring substituent.
The two other alkylation reagents can only be used in the presence of inorganic bases. In
these cases, the reaction begins with the formation of contact ion pair 8ʹ, and hence,
delocalization of the negative charge between the O and N atoms and ion pair 8ʹʹ is rather
complicated (Scheme 3). As expected, in these cases O-alkylation predominates over N-
alkylation and 4:5 molar ratio increases to 10:1-19:1 for (MeO)2SO2 (hard alkylating reagent),
while for MeI (a softer alkylating reagent) the 4:5 molar ratio was 4:1-5:1. An alternative
mechanism for formation of N-Me products 5 could be O- to N-methyl migration, which is
known to occur at high temperature in the presence of catalysts (e.g. NaI or LiI).23,24 However,
attempts to perform this process by prolonged heating of compound 4a in different solvents or
under solvent-free conditions at 100 °C in the presence of NaI or LiI were not successful.

Scheme 3. Plausible mechanism for the formation of O-Me and N-Me regioisomers 4 and 5.
Conclusion
In summary, a facile and highly efficient method for the synthesis of practically unknown
3-aryl-4-hydroxyfuroxans by nucleophilic substitution of the nitro group in readily available 3-
aryl-4-nitrofuroxans under the action of NaOH in H2O-THF has been developed. The
methylation of these products using different methylating reagents (CH2N2,25 MeI, (MeO)2SO2)
under very mild conditions, demonstrated for the first time that hydroxyfuroxans are prone to
side-chain prototropic tautomerism, resulting in the formation of the first representatives of a
new type of furoxan derivatives containing substituents on the N(5) nitrogen atom, N(5)-
alkylfuroxan-4-ones, as well as O-alkylation products. In all cases, the latter were formed
regioselectively and the molar ratio of O-Me and N-Me regioisomers were dependent on the
aromatic ring substituents and the nature of the methylating reagents. To the best of our
knowledge, this study represents the first experimental evidence for side-chain prototropic
tautomerism in the furoxan ring.
Acknowledgements
This work was supported by the Russian Science Foundation (Project No 14-50-00126).
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
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1240.

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25. A solution of CH2N2 (1.67M in Et2O, 2.6 mL) was added dropwise to a stirred mixture of
the corresponding hydroxyfuroxan 1 (1.4 mmol) in Et2O (7 mL). The resulting solution
was stirred for 24 h at room temperature, then the solvent evaporated and the residue
purified by column chromatography on SiO2 (eluent – CHCl3:CCl4, 1:1). The OMe
derivative 4 eluted first, and the NMe derivative 5 eluted second.

26.

Highlights
•
A method for the synthesis of hardly accessible hydroxyfuroxans has been developed.
•
Ring-chain prototropic tautomerism for the furoxan ring was found for the first time.
•
Furoxan derivatives of the novel type — N(5)-alkylation products were synthesized.
27.