Reactions of furoxanyl and furazanyl diazonium salts with NaNO2 in weakly acidic medium, a new approach to the preparation of nitrofuroxans and nitrofurazans

Article abstract of DOI:10.1007/s11172-012-0068-8

A new approach to the preparation of nitrofuroxans and nitrofurazans is suggested based on the diazotization of aminofuroxans and aminofurazans in aqueous organic medium at pH = 4-5 in the presence of excess NaNO₂.

Full text of DOI:10.1007/s11172-012-0068-8

Russian Chemical Bulletin, International Edition, Vol. 61, No. 2, pp. 472—475, February, 2012
472
Reactions of furoxanyl and furazanyl diazonium salts with NaNO2
in weakly acidic medium, a new approach to the preparation
of nitrofuroxans and nitrofurazans
A. O. Finogenov, I. V. Ovchinnikov, A. S. Kulikov, and N. N. Makhova
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: mnn@ioc.ac.ru
A new approach to the preparation of nitrofuroxans and nitrofurazans is suggested based on
the diazotization of aminofuroxans and aminofurazans in aqueous organic medium at pH = 4—5
in the presence of excess NaNO2.
Key words: aminofuroxans, aminofurazans, diazotization, ionic liquids, triazenes, nitroꢀ
furoxans, nitrofurazans.
The tendency of amino compounds to diazotization is
verted to the known azo coupling products 4a,b upon treatꢀ
ment with a mixture of anisole with pyridine. However,
our attempts to carry out the Sandmeyer reaction under
both strongly and weakly acidic conditions by addition of
the reaction mixture to the aqueous solution of excess
NaNO2 in the presence of CuCl led to the entire decomꢀ
position of diazonium salt 3a,b without formation of any
detectable by TLC products (Scheme 1).
known to significantly depend on their basicity, and for
weakly basic amines the use of strongly acidic media are
preferable, and often the only possible, conditions for their
diazotization.1 4ꢀAminoꢀ1,2,5ꢀoxadiazole 2ꢀoxides (aminoꢀ
furoxans) 1 and their close analogs, 4ꢀaminoꢀ1,2,5ꢀoxaꢀ
diazoles (aminofurazans) 2, belong to weakly basic amines.
Thus, the pKa of 4ꢀaminoꢀ3ꢀmethylfuroxan (1a) is –3.01
and the pKa of 4ꢀaminoꢀ3ꢀmethylfurazan (2a) is –2.14.2
Earlier,3 diazotization of aminofuroxans 1 and aminoꢀ
furazans 2 was successfully accomplished with sodium
nitrite in a mixture of concentrated H2SO4 and H3PO4,
and it turned out that the formed diazonium salts 3 underꢀ
go further reactions maintaining the N—N group intact
(azo coupling, formation of triazenes and azides). Attemptꢀ
ed introduction of diazonium salts 3 into the Sandmeyer
reaction with neutral solutions of alkali metal halides or
nitrites in the presence of copper salts led to their entire
decomposition with the ring opening, that is apparently
resulted from the instability of 1,2,5ꢀoxadiazole radicals
formed after elimination of the nitrogen molecule. We
suggested that carrying out diazotization of aminofuroxꢀ
ans in strongly polar ionic liquids (IL) will facilitate proꢀ
ceeding of the Sandmeyer reaction due to the stabilization
of intermediates formed under the reactions conditions.
In this connection, we studied diazotization of aminoꢀ
furoxans 1a,b in acidic IL, viz., (1ꢀbutylꢀ3ꢀmethylimidꢀ
azolium) hydrogen sulfate ([bmim][HSO4]) or (1ꢀbutylꢀ
Therefore, in the next step of our research we studied
a possibility of preparation of nitrofuroxans based on the
transformation of diazonium salts 3a,b under different
conditions. In the literature, there are examples of prepaꢀ
ration of nitroheterocycles (1,2,4ꢀtriazole, 1,3,4ꢀthiadiꢀ
azole, tetrazole, 1,3,4ꢀoxadiazole) by replacement of the
diazo group with a nitro group in the corresponding diazoꢀ
nium salt, pouring its solution in an acid into the dilute
aqueous solution of a large excess of NaNO2, but in abꢀ
sence of copper salts.4 The reaction was performed at the
temperatures from 0 to 60 C depending on the structure
of the starting aminoheterocycle. The authors of the work4
assumed that the mechanism of this reaction is heterolytꢀ
ic, in contrast to the radical mechanism, which is characꢀ
teristic of the Sandmeyer reaction. This mechanism has
been suggested based on the kinetic studies of a similar
reaction of aromatic compounds carried out in the work.5
This studies showed that the reaction has a total third
order, which seems very unlikely provided that the entroꢀ
py of activation is positive. In the authors´ opinion,5 this
reaction is most likely a twoꢀstep process, which includes
two bimolecular reactions: 1) addition of the NO2 anion
to the terminal nitrogen atom of the diazonium salt 5 to
form diazonitrite 6 and 2) nucleophilic substitution for the
N=N—NO2 fragment in compound 6 upon the action of
1ꢀmethylpyrrolidinium)
trifluoromethanesulfonate
([bmpyrr][CF3SO3]), using a 40% solution of nitrosylsulꢀ
furic acid in H2SO4 as a nitrosating agent. It was found
that under these conditions, amines 1a,b are successfully
diazotized to form diazonium salts 3a,b, which were conꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 769—472, February, 2012.
1066ꢀ5285/12/6102ꢀ472 © 2012 Springer Science+Business Media, Inc.

Nitrofuroxans(furazans) through diazotization
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
473
Scheme 1
R = Me (a), Ph (b)
i. [NO+][HSO4–]/H2SO4, 0—5 C, [bmim][HSO4] or [bmpyrr][CF3SO3]; ii. NaNO2/CuCl/H2O; iii. PhOMe/Py
the second NO2 anion with elimination of the nitrogen
molecule and the first NO2 anion to form the nitroaroꢀ
matic compound via the intermediate 7 (Scheme 2). The
mechanism suggested in the work5 quite agrees with the
modern concept of the nucleophilic substitution reactions
of the diazonium cation in arenediazonium salts: formaꢀ
tion in the first step of a covalent compound of the type 6
with subsequent substitution of the NO2 anion for the
diazonitrite fragment by the SNAr mechanism via the
Meisenheimer anionic ꢀcomplex 7.
If the mechanism of formation of nitroheterocycles is
similar to the mechanism given in Scheme 2, then, beꢀ
cause of the earlier found low stability of furoxanyl diazoꢀ
nium ions 3a,b in aqueous solutions, it was reasonable to
effect their transformation into nitrofuroxans in situ, right
in the moment of formation, moreover, the reaction should
not be carried out in strongly acidic medium in order to
have sufficient amount of the NO2 anions in the reaction
mixture. To achieve this goal, we studied diazotization of
aminofuroxans 1a,b in water in the presence of a large
excess of NaNO2, in which case DMSO was added to
increase solubility of the starting compounds in the reacꢀ
tion mixture. The reaction was performed at reduced temꢀ
perature (0—2 C) at pH = 4—5. To provide a desired pH
value, hydrochloric acid was slowly (1.5—2 h) added to
a mixture of aminofuroxans 1a,b and excess of NaNO2 in
a mixture of DMSO—water and the reaction mixture was
kept at room temperature for 16 h. Under these condiꢀ
tions, nitrofuroxans 8a,b were for the first time obtained
by nucleophilic substitution of the diazonium ion for an
NO2 anion (Scheme 3). Earlier,6,7 aminofuroxans were
successfully converted to nitrofuroxans only upon the acꢀ
tion of strong oxidants. Unfortunately, only aminofurꢀ
oxans 1a,b with Me and Ph substituent were involved into
this reaction. In the case of furoxan 1a, besides the desired
compound 8a, 1,3ꢀbis(3ꢀmethylfuroxanꢀ4ꢀyl)triazꢀ2ꢀene
(9a) was isolated as a side product. Formation of triazenes
is known to proceed through the reaction of the forming
diazonium salts with the unreacted amine. Therefore, the
isolation from the reaction mixture of compound 9a is yet
another evidence of the formation of diazonium salts 3
under weakly acidic conditions. 4ꢀAminofuroxans with
electronꢀwithdrawing substituents (CO2Et, CON3, CONH2)
decomposed under the reaction conditions.
The reaction has proved of general character and can
be extended to aminofurazans 2a,b, but also only with Me
and Ph substituents. Nitrofurazans 10a,b were obtained in
high yields. The reaction obviously follows the SNAr
mechanism through the intermediate 11 and the anionic
ꢀcomplex of the Meisenheimer type 12. For the furoxan
derivatives, formation of an intermediate mesoionic strucꢀ
ture of the type 13 is possible (see Scheme 3).
The synthesized azo derivatives 4a,b and nitro derivaꢀ
tives 8a,b and 10a,b had identical physicochemical and
spectral characteristics with those of compounds described
earlier in the literature. All the synthesized nitro derivaꢀ
Scheme 2

474
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
Finogenov et al.
Scheme 3
Compound
n
1
1
0
0
R
Product
8a
8b
10a
10b
Product yield (%)
1a
1b
2a
2b
Me
Ph
Me
Ph
31
67
88
61
1.8 mmol) and H2SO4 (0.342 g, 3.5 mmol)) was added to the
ionic liquid [bmpyrr][CF3SO3] (2 g) at 0—2 C. After 5 min, the
reaction mixture developed a pale blue color. Then, the mixture
was stirred for 15 min at 0—2 C, followed by the in portions
addition of 4ꢀaminoꢀ3ꢀmethylfuroxan (0.115 g, 1 mmol) or
4ꢀaminoꢀ3ꢀphenylfuroxan (0.177 g, 1 mmol). The reaction mixꢀ
ture was stirred for 1.5 h at 0—2 C, then a solution of anisole
(0.108 g, 1 mmol) in pyridine (0.55 mL, 7 mmol) was added
dropwise to the obtained diazonium salt with cooling. The reacꢀ
tion mixture was stirred for 1.5 h at ~20 C, extracted with diethꢀ
yl ether (6×10 mL), the organic layer was washed with water
(2×10 mL), dried with MgSO4, and the solvent was evaporated
on a rotary evaporator. The residue was reprecipitated from
acetone with water to obtain 4ꢀ(4ꢀmethoxyphenylazo)ꢀ3ꢀmethylꢀ
furoxan 4a (68%) with m.p. 141—142 C (Ref. 3: 142—143 C)
and 4ꢀ(4ꢀmethoxyphenylazo)ꢀ3ꢀphenylfuroxan 4b (67%) with
m.p. 148—149 C (Ref. 3: 151—152 C).
tives 8a,b and 10a,b contained a signal characteristic of
the nitro group in the region  –32÷–35 of the 14N NMR
spectrum. The structure of compound 9a was inferred from
the combination of elemental analysis, 1H, 13C NMR
spectroscopic, and mass spectrometric data.
In conclusion, for methylꢀ and phenylꢀsubstituted
aminofuroxans and aminofurazans taken as examples, we
for the first time successfully effected nucleophilic substiꢀ
tution of the diazonium fragment for the nitro group in
furoxanyl and furazanyl diazonium salts, which allowed
us to avoid the use of strong oxidants applied in the methꢀ
ods developed earlier for the transformation of aminoꢀ
furoxans and aminofurazans into the corresponding nitro
derivatives. The reaction proceeds under mild conditions
(0—20 C, aqueous organic medium, pH = 4—5).
The use of [bmim][HSO4] as the IL under similar conditions
gave 4a and 4b in 45 and 39% yields, respectively.
Experimental
Reaction of diazonium salts 3a and 3b with NaNO2. A soluꢀ
tion of a diazonium salt obtained in the preceding procedure was
either poured into a cold solution of excess NaNO2 (280 mg,
4 mmol) and CuCl (200 mg, 2 mmol) in water (10 mL) and
stirred for 1 h at room temperature, or preliminary treated with
pyridine (0.55 mL, 7 mmol), then poured into a cold solution of
excess NaNO2 (280 mg, 4 mmol) and CuCl (200 mg, 2 mmol) in
water (10 mL), and stirred for 1 h at room temperature.
Ethereal extracts of the reaction mixtures obtained, accordꢀ
ing to the TLC data, did not contain any detectable products.
Preparation of nitrofuroxans 8a,b, nitrofurazans 10a,b, and
triazene 9a on diazotization of the corresponding amines 1a,b and
2a,b (general procedure). Sodium nitrite (0.52 g, 7.5 mmol) was
added to a solution or a suspension of aminofuroxan or aminoꢀ
furazan (1.15 mmol) in DMSO (1 mL), the reaction mixture was
IR spectra were recorded on a URꢀ20 spectrometer in KBr
pellets. NMR spectra were recorded on Bruker WMꢀ250 (1H,
250 MHz) and Bruker AMꢀ300 spectrometers (13C 75.5 MHz
and 14N 21.5 MHz) in the  scale. Chemical shifts in 1H and
13C NMR spectra were measured relative to the internal stanꢀ
dard Me4Si, in 14N NMR spectrum, relative to the external
standard MeNO2. Thinꢀlayer chromatography was performed
on Silufol UVꢀ254, visualizing under a UV lamp. Melting points
were determined on a Sanyo ALLENKAMP apparatus. Mass
spectra were recorded on a Varian MAT CH 6 instrument (70 eV ).
Diazotization of 4ꢀaminoꢀ3ꢀmethylfuroxan (1a) and 4ꢀaminoꢀ
3ꢀphenylfuroxan (1b) in ionic liquid (general procedure). A soluꢀ
tion of nitrosylsulfuric acid ([NO+][HSO4–]) (0.3 mL, 0.57 g) in
concentrated H2SO4 (containing nitrosylsulfuric acid (0.228 g,

Nitrofuroxans(furazans) through diazotization
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
475
stirred for 20 min and cooled to 0—2 C. Concentrated HCl
(0.45 mL, 4.3 mmol) was added dropwise over 2 h to the resultꢀ
ing mixture at the same temperature with stirring, which was
continued for another 30 min, then the mixture was left to stand
for 16 h at ~20 C. After that, the reaction mixture was diluted
with water (5 mL) and extracted with CH2Cl2 (3×2 mL). The
solvent was evaporated in vacuo, the residue was stirred with
water (3 mL) for 30 min for the separation of DMSO, and the
water was decanted. The product was dissolved in CH2Cl2
(4 mL), dried with MgSO4, and the solvent was evaporated on
a rotary evaporator at 20 C.
References
1. T. I. Godovikova, O. A. Rakitin, L. I. Khmel´nitskii,
Usp. Khim., 1983, 52, 777 [Russ. Chem. Rev. (Engl. Transl.),
1983, 52].
2. A. Defilippi, G. Sorba, R. Calvino, A. Garrone, A. Gasco,
M. Orsetti, Arch. Pharm., 1988, 321, 77.
3. O. A. Rakitin, O. A. Zalesova, A. S. Kulikov, N. N. Makhoꢀ
va, T. I. Godovikova, L. I. Khmel´nitskii, Izv. Akad. Nauk,
Ser. Khim., 1993, 1949 [Russ. Chem. Bull. (Engl. Transl.),
1993, 42, 1865].
4. L. I. Bagal, M. S. Pevzner, A. N. Frolov, N. I. Sheludyaꢀ
kova, Khim. Geterotsikl. Soedin., 1970, 259 [Chem. Heteroꢀ
cycl. Compd. (Engl. Transl.), 1970].
5. L. I. Bagal, M. S. Pevzner, A. N. Frolov, Zh. Org. Khim.,
1969, 5, 1820 [J. Org. Chem. USSR (Engl. Transl.), 1969, 5].
6. N. N. Makhova, I. V. Ovchinnikov, B. N. Khasapov, L. I.
Khmel´nitskii, Izv. Akad. Nauk SSSR, Ser. Khim., 1982, 646
[Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.), 1982,
31, 573].
7. O. A. Rakitin, O. G. Vlasova, L. F. Chertanova, L. I.
Khmel´nitskii, Izv. Akad. Nauk SSSR, Ser. Khim., 1990, 1625
[Russ. Chem. Bull. (Engl. Transl.), 1990, 39, 1474].
8. O. A. Rakitin, V. A. Ogurtsov, Yu. A. Strelenko, T. I. Godoꢀ
vikova, L. I. Khmel´nitskii, Izv. Akad. Nauk SSSR, Ser.
Khim., 1990, 1020 [Russ. Chem. Bull. (Engl. Transl.), 1990,
39, 909].
9. D. E. Dmitriev, Yu. A. Strelenko, A. B. Sheremetev, Izv.
Akad. Nauk, Ser. Khim., 2002, 277 [Ryss. Chem. Bull., Int.
Ed., 2002, 51, 290].
10. A. A. Gakh, V. I. Ugrak, V. V. Kiseleva, Izv. Akad. Nauk
SSSR, Ser. Khim., 1990, 2069 [Russ. Chem. Bull.
(Engl. Transl.), 1990, 39, 1883].
The yield of 8b was 160 mg (67%), m.p. 95—96 C (CCl4)
(Ref. 6: 97—97.5 C); 14N NMR (CDCl3), : –34.46 (Ref. 8:
 –34.78, CDCl3).
The yield of 10a was 130 mg (88%), b.p. 52 C (14 Torr)
20
20
(Ref. 3: 58.8 C, 18 Torr); nD 1.4555 (Ref. 3: nD 1.4549);
14N NMR (CDCl3), : –33.69 (Ref. 9:  –32.4, acetoneꢀd6).
The yield of 10b was 134 mg (61%), m.p. 40—41 C (C6H14
(Ref. 6: 39 C); 14N NMR (CDCl3), : –33.92.
)
In the trial with 4ꢀaminoꢀ3ꢀmethylfuroxan 1a, evaporation
of CH2Cl2 gave a suspension of crystals in an oil. It was stirred
for 30 min with CH2Cl2 (0.3 mL), the crystals were filtered off,
washed on the filter twice with small amount of CH2Cl2, and
dried. The yield of triazene 9a was 22 mg (16%). The filtrate was
concentrated and the residue was recrystallized from MeOH to
obtain 8a 52 mg (31%), m.p. 66—67 C (MeOH), (Ref. 7: 67 C);
14N NMR (CDCl3), : –34.03 (Ref. 10: –31.84, acetoneꢀd6).
1,3ꢀBis(4ꢀmethylfuroxanꢀ3ꢀyl)triazꢀ2ꢀene (9a), m.p.
185—187 C. IR, /cm–1: 3839, 3291, 3228, 3068, 1688, 1556,
1305, 1182, 1016, 856, 587. 1H NMR (DMSOꢀd6), : 2.12 (s, 6 H,
2 Me); 10.11 (s, 1 H, NH). 13C NMR (DMSOꢀd6), : 8.32 (Me),
110.52 (C(3) in furox. rings); 150.50, 152.35 (C(4) in furox. rings).
MS, m/z (Irel (%)): 241 [M]+ (7), 225 [M – O]+ (3), 224
[M – O – 1]+ (10), 210 [M – NO – 1]+ (13), 196 [M – NO2 + 1]+
(9), 180 [M – 2 NO + 1]+ (15), 173 (22), 165 [M – NO – NO2]+
(33), 150 (30), 142 (methylfuroxanyltriazene) (58), 127 (methylꢀ
furoxanyldiazene) (30), 85 (72), 69 (100). Found (%): C, 29.61;
H, 2.80; N, 40.22. C6H7N7O4. Calculated (%): C, 29.88; H, 2.93;
N, 40.66.
Received July 11, 2011;
in revised form November 14, 2011