Synthesis of dinitro-substituted furans, thiophenes, and azoles

Article abstract of DOI:10.1055/s-2008-1032187

Direct nitration of the corresponding mononitro furans with fuming nitric acid, thiophenes with acetyl nitrate, and thiazoles with trifluoroacetyl nitrate, gave dinitro-substituted furans, thiophenes, and thiazoles. The nitrations of 2-alkylthiophenes wit

Full text of DOI:10.1055/s-2008-1032187

PAPER
699
Synthesis of Dinitro-Substituted Furans, Thiophenes, and Azoles
D
initrofurans,
Din
l
itrohiop
a
henes, and
n
D
initroazoles R. Katritzky,*a Anatoliy V. Vakulenko,a Jothilingam Sivapackiam,a Bogdan Draghici,a Reddy Damavarapub
a
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Fax +1(352)3929199; E-mail: katritzky@chem.ufl.edu.
US Army ARDEC, Picatinny Arsenal, NJ 07806-5000, USA
b
Received 27 September 2007; revised 19 November 2007
Abstract: Direct nitration of the corresponding mononitro furans
with fuming nitric acid, thiophenes with acetyl nitrate, and thiazoles
with trifluoroacetyl nitrate, gave dinitro-substituted furans,
thiophenes, and thiazoles. The nitrations of 2-alkylthiophenes with
3 and 5 molar equivalents of acetyl nitrate, generated in situ, are dis-
cussed. Reactions of the mononitro furans with fuming nitric acid
gave 1,1,5,5-tetrasubstituted dihydrofurans as by-products. Treat-
ment of 5-methyl-4-nitroisoxazole with hydrazine or its methyl or
phenyl derivative, followed by oxidation of the corresponding 4-
amino-5-nitro-1H-pyrazoles with hydrogen peroxide (50%) gave
4,5-dinitro-1H-pyrazoles. A safe one-pot synthesis of 1-alkyl-3,5-
dinitro-1H-[1,2,4]triazoles was developed from dicyandiamide.
NO2
COOH
O
HO3S
O
1
HNO3
2
HNO3
3%
67%
5%
O2N
i) HNO3, (Ac)2O
+
NO2
NO2
O2N
O
ii) HNO3
27%
O
O
5
3 87–89 °C
4 99–101 °C
Scheme 1
Key words: dinitrofurans, dinitrothiophenes, dinitroazoles, nitra-
tion, oxidation
(Ac)2O,
HNO3 (1.5 equiv)
–30 °C, 1 h
concd HNO3,
50–55 °C, 4 h
8a–c 7–8%
NO2
R
R
Dinitro derivatives of five-membered heterocycles have
diverse biological activities (e.g., 2,4-dinitroimidazole de-
rivatives increase the sensitivity of hypoxic cells toward
irradiation in cancer radiotherapy1), are useful intermedi-
ates (e.g., conversion of dinitrofuran into various polysub-
stituted phenols2), and are of potential interest as energetic
materials and blowing agents.
O
O
7a 39%
7b 43%
7c 36%
6a R = Me
6b R = Et
6c R = n-Bu
fuming HNO3, AcOH
70–75 °C, 8 h
O2N
R
NO2
NO2
O2N
+
O
NO2
R
O
8a 17%
8b 24%
9a 29%
9b 30%
Approaches to the preparation of dinitro-substituted five-
membered heterocycles comprise: (i) direct nitration,3 (ii)
ring construction,4 and (iii) functional group transforma-
tion.5 However, published methods usually suffer from
low yields, starting material availability, harsh conditions,
and/or difficult-to-separate isomer formation. This
prompted us to search for more general and milder routes.
Scheme 2
give 42 (Scheme 1). 2-Alkyl-3,5-dinitrofurans 8 are side
products (up to 4%) in the nitration of 2-alkylfurans or
ethyl 2-alkyl-5-furancarboxylates.13
We have previously6 reported facile access to poly-
nitroimidazoles,7 trinitroazetidine,8 nitropyridines,9 and
mononitro five-membered heterocycles.10 We now report
on the synthesis of dinitro-substituted furans, thiophenes,
thiazoles, pyrazoles and 1H-[1,2,4]triazoles.
2-Alkylfurans 6a–c with 1.5 molar equivalents of acetyl
nitrate (generated in situ by the reaction of nitric acid with
acetic anhydride) at –30 °C afforded 2-methyl-5-nitro-
furan (7a) (39%), 2-ethyl-5-nitrofuran (7b) (43%) and
2-butyl-5-nitrofuran (7c) (36%). Recently, Schuisky et al.
reported the preparation of 2-methyl-5-nitrofuran (7a) in
35% yield.13a Initial attempts to prepare 2-alkyl-3,5-dini-
trofurans 8a–c in situ by addition of 2-alkylfurans 6a–c to
1.5 molar equivalents of acetyl nitrate at –30 °C and fur-
ther treatment of the reaction mixture with concentrated
nitric acid at 50–55 °C gave the desired 8a–c in up to 8%
yield after four hours (Scheme 2).
Dinitrofurans
Published routes to dinitrofurans comprise: (i) nitration of
2-nitrofuran (1) to give 2,5- (4) (67%) and 2,4-dinitro-
furan (3) (5%),11 (ii) reaction of 5-sulfofuran-2-carboxylic
acid (2) with fuming nitric acid to give 2,5-dinitrofuran
(4) (3%),12 and (iii) two-step nitration of furan (5) with
acetyl nitrate/acetic anhydride/HNO3 (27% overall) to
Treatment of 2-alkyl-5-nitrofurans 7a,b with fuming ni-
tric acid in glacial acetic acid at 70–75 °C for eight hours
gave 2-alkyl-3,5-dinitrofurans 8a,b (17–24%) and tetra-
substituted dihydrofurans 9a,b (29–30%) (Scheme 2).
Structures 9a,b were supported by NMR spectral data and
elemental analyses. The 15N NMR spectrum of 2-ethyl-
SYNTHESIS 2008, No. 5, pp 0699–0706
x
x
.
x
x
.2
0
0
8
Advanced online publication: 18.02.2008
DOI: 10.1055/s-2008-1032187; Art ID: M07107SS
© Georg Thieme Verlag Stuttgart · New York

700
A. R. Katritzky et al.
PAPER
(i) Ac2O (10.5 equiv),
HNO3 (1.3 equiv),
–30 °C, 3 h,
(i) Ac2O (1.1 equiv),
HNO3 (1.1 equiv),
–30 °C, 3 h,
25 °C, 12 h, 59%
25 °C, 12 h, 60%
11a
12a
R
R = Me
R = Me
S
10a
10b
R = Me
R = Et
(ii) Ac2O (8.9 equiv), HNO3 (3.0 equiv),
–40 °C to 45 °C, 6 h, 25 °C, 18 h
(iii) Ac2O (8.9 equiv), HNO3 (5.0 equiv),
–40 °C to 45 °C, 6 h, 25 °C, 18 h
O2N
+
R
+
R
NO2
NO2
R
NO2
S
S
S
O
(ii) 12b 24%
(iii) 12a 67%
(iii) 12b 70%
(ii) 13b 4%
(iii) 13a 10%
(iii) 13b 8%
(ii) 11b 40%
(iii) 11a 12%
(iii) 11b 11%
Figure 1 1H–15N gHMBC spectrum of 9b
Scheme 3
6.89
6.70
139.6
150.2
O
O
acid in the presence of sulfuric acid21 or trifluoroacetic ac-
id.22 Isomer proportions formed by nitration of 2- and 3-
nitrothiophenes in trifluoroacetic acid were determined
indirectly22 by a combination of NMR, GLC, and mass-
spectral analyses of products from nitration of mixtures of
the 2- and 3-nitrothiophenes with fuming nitric acid. Blatt
obtained 2,5-dinitrothiophene (15%) from a crude mix-
ture of dinitrothiophene isomers.3 Newcombe separated
dinitrothiophenes by column chromatography.23
(–10.9) N+
N+
(2.3)
–O
O–
124.5
127.1
(–12.2)
O
–O
N+
1.04
7.4
2.43, 2.59
28.8
O
Figure 2 Chemical shifts of 1H, 13C (underlined), and 15N (in paren-
theses) NMR spectra for 9b
A mixture of nitric acid and acetic anhydride is effective
for mononitration of 2-alkylthiophenes.24 An electron-de-
ficient substituent in addition to the 2-alkyl group requires
the application of HNO3–H2SO4.24a,25 3-Nitro-substituted
thiophene by-products were isolated in up to 19% yields
after direct nitration of 2-alkylthiophenes.26 2-Alkyl-3-ni-
trothiophenes were prepared in yields of 56–82% by
decarboxylation27 or desulfonation28 reactions.
2,5,5-trinitro-2,5-dihydrofuran (9b) showed signals in the
region of –12.2 to +2.3 ppm characteristic of a nitro group
(Figure 1).
The structure of compound 9b is also supported by corre-
lation between 1H and 13C over three bonds and by the 1H–
13C gHMBC spectrum. Total correlations for compound
9b based on 1H –15N and 1H–13C gHMBC experiments are
given in Figure 2.
Treatment of 2-methylthiophene (10a) with 1.3 molar
equivalents of acetyl nitrate (generated in situ by reaction
of 1.3 equivalents of nitric acid with 10.5 equiv of acetic
anhydride) at –30 °C for three hours followed by reaction
of 2-methyl-5-nitrothiophene (11a) with another 1.1 mo-
lar equivalents of acetyl nitrate at –30 °C for three hours,
gave 2-methyl-3,5-dinitrothiophene (12a) (method i) in
35% overall yield (Scheme 3). Attempts to use a single
batch (method ii) of acetyl nitrate (3.0 equiv) in acetic an-
hydride (8.9 equiv) with 2-ethylthiophene (10b) at –40 to
–45 °C for six hours and then at room temperature for 18
hours gave 2-ethyl-5-nitrothiophene (11b) (40%) as a ma-
jor product together with 2-ethyl-3,5-dinitrothiophene
(12b) (24%) and 2-methyl-5-nitrothiophene S-oxide
(13b) (4%). One-step dinitration (method iii) of 2-alkyl-
thiophenes 10a,b with 5 equivalents of acetyl nitrate gave
67–70% of 12a,b (Scheme 3). Products 13a,b were char-
Dinitrothiophenes
After ‘countless futile attempts’,14 thiophene was first
successfully nitrated by Meyer and Stadler when air satu-
rated with thiophene was passed through fuming nitric
acid to give mononitro- and dinitrothiophenes.15 Direct ni-
tration is still the most commonly used method for the
preparation of nitrothiophenes. Thus, for instance, ben-
zoyl nitrate,16 acetyl nitrate17 and various mixtures of ni-
tric acid and acetic anhydride18 are effective nitrating
agents for thiophene itself. Other routes such as cycliza-
tion are less convenient or general.19
Nitration is one of the least selective of electrophilic sub-
stitution processes in benzenoid systems;20 thus the
thiophene nucleus undergoes some b-nitration even when
a positions are unsubstituted. Nitration of 2- or 3-ni-
trothiophene is conveniently effected with fuming nitric
1
acterized by H, 13C NMR and IR spectra together with
elemental analyses, which are consistent with previously
published data.29
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Dinitrofurans, Dinitrothiophenes, and Dinitroazoles
701
O2N
H2N
Me
N
N
H2O2,
H2SO4
O2N
O2N
Me
i)
O2N
Me
N
RNHNH2,
reflux
R
S
NH2
R
NO2
15a, R = H, 28%
N
N
S
H2O, 1 h
or
EtOH, 15 h
N
R
0–25 °C,
16 h
N
R
O
14a,b
15b, R = Me, 21%
18
ii) or iii)
19a, R = H, 75%,a 87%b
19b, R = Me, 30%,a 86%b
19c, R = Ph, 81%b
20a, R = K, 40%
20b, R = Me, 81%
20c, R = Ph, 52%
O2N
R
N
iv)
N
R
NO2
a yield of 19 given for preparation in H2O
b yield of 19 given for preparation in EtOH
S
S
16a, R = H
17c
16b, R = Me
Scheme 5
16c, R = NHCOMe
Scheme 4 Reagents and conditions: i) aq HBF4, NaNO2, 4 °C, 20
min; NaNO2, Cu, 100 °C, 30 min; ii) BF3N2O4, MeNO2, 101 °C, 1 h
(80% for 16a30); iii) NH4NO3, TFA, TFAA, 0–5 °C, 0.5 h; 15a,b, 0–
5 °C; 25 °C for 20 h and 70–80 °C for 4 h (34% for 16a) or 0.5 h (91%
for 16b); iv) KNO3, oleum, 0–5 °C (37% for 16c31).
ates 19a–c were easily prepared by a modification of the
treatment37 of 5-methyl-4-nitroisoxazole (18) with the
corresponding hydrazines in water for one hour or ethanol
for 15 hours under reflux in 30–87% yields (Scheme 5).
One-Pot Synthesis of 1-Alkyl-3,5-dinitro-1H-
[1,2,4]triazoles
Dinitrothiazoles
Nitrotriazoles are important in fields as diverse as
medicine38 and agrochemicals.39 They are also
photosensitive40 and energetic41 with high density, high
energy, low sensitivity and good heat resistance, and thus
ideally insensitive high explosives for the space program
and deep oil-well drilling.42
Parent30 obtained 2,4-dinitrothiazole (16a) from 2-ni-
trothiazole (15a) with boron trifluoride-nitrogen tetroxide
complex; Prijs31 dinitrated 5-acylaminothiazole (17c) to
give 16c using potassium nitrate in fuming sulfuric acid
(Scheme 4).
2-Aminothiazoles 14a,b on diazotization and treatment
with NaNO2 give 2-nitrothiazoles 15a,b, which can be
further nitrated by trifluoroacetyl nitrate. Nitration of 15a
by heating the reaction mixture at 70–80 °C for four
hours, forms the dinitro derivative 16a (34%). A 5-methyl
group facilitates the preparation of 16b (91%) using sim-
ilar conditions (Scheme 4).
Three ring-nitrogens significantly reduce reactivity to-
ward electrophilic substitution43 and the only known di-
rect nitration is that of 1,2,4-triazol-3-one.44 1-Alkyl-3,5-
dinitro-1H-[1,2,4]triazoles were previously synthesized
in two steps (overall 40%): (i) by oxidation5a or Sandmey-
er reaction45 of 3,5-diamino-1H-[1,2,4]triazole, followed
(ii) by alkylation of the intermediate 3,5-dinitro-1H-
[1,2,4]triazole with an alkyl halide or sulfate.46
Dinitropyrazoles
We now report a convenient one-pot synthesis of 1-alkyl-
4-Unsubstituted pyrazoles are usually nitrated at position 3,5-dinitro-1H-[1,2,4]triazoles 22a,b by conversion of 1-
4,32 facilitated by electron-donating and retarded by elec- alkyl-3,5-amino-1H-[1,2,4]triazoles, prepared in situ
tron-withdrawing substituents. Thus, 4-nitropyrazole and from dicyandiamide (21) and alkylhydrazines, to 22a,b in
1-methyl-4-nitropyrazole do not undergo nitration.33 23–43% yields. The procedure was optimized in terms of
However, on prolonged heating with mixed acid 1-meth- the ratio of methylhydrazine to dicyandiamide to sodium
ylpyrazole affords the 4-nitro and 3,4-dinitro derivatives nitrite, the reaction time, and the temperature. Equimolar
(51% and 13%, respectively).34 1,5-Dimethyl-4-nitropy- amounts of methylhydrazine and dicyandiamide (21) in
razole, on heating with nitric acid and oleum, similarly aqueous nitric acid at 50 °C for 5 hours for cyclization and
gives 1,5-dimethyl-3,4-dinitropyrazole.35 Rare simulta- 10 molar equivalents of sodium nitrite at 50 °C for 1.5
neous introduction of two nitro groups into the pyrazole hours for diazotization proved to be appropriate for the
ring occurs36 in low yield under vigorous conditions.
safe, large-scale preparation of 1-alkyl-3,5-dinitro-1H-
[1,2,4]triazoles 22a,b (Scheme 6). Assigned structures of
22a,b were supported by NMR spectral data, which are in
agreement with the published data.47
Pyrazoles containing two adjacent nitro groups were pre-
viously prepared in three-steps (average 40% yield) by
thermal rearrangement of N-nitropyrazoles and further ni-
tration with mixed acid.33 We now report a convenient
synthesis of 3-methyl-4,5-dinitropyrazoles 20a–c by oxi-
dation of 3-methyl-4-nitro-5-amino-1H-pyrazoles 19a–c
with 50% hydrogen peroxide–sulfuric acid at 0 °C for 16
hours in 40–81% yields. In contrast, diazotization of 19a
with 5 equivalents of sodium nitrite in 2 N sulfuric acid at
50 °C for one hour led to difficult-to-separate mixtures of
di-20a (33%) and mononitro (4%) derivatives. Intermedi-
N3
NO2
i) RNHNH2, HNO3
ii) NaNO2, H2SO4
N
N
NH2
N
+
O2N
N
CN
N
R
O2N
H2N
N
N
R
22a, R = Me 43%
22b, R = Et 23%
23a
21
Scheme 6
Synthesis 2008, No. 5, 699–706 © Thieme Stuttgart · New York

702
A. R. Katritzky et al.
PAPER
resulting residue was subjected to silica gel chromatography to give
7a–c.
NO2
NO2
NO2
AcNHNH2
O2N
NH2NH2
N
N
N
N
N
N
H2NHN
N3
N
N
N
2-Methyl-5-nitrofuran (7a)
Yellowish prisms; yield: 39%; mp 45.0–46.0 °C (Lit.13a mp 43.0–
44.5 °C).
Me
Me
Me
24
25
22a
HONO
1H NMR: d = 7.26 (d, J = 3.7 Hz, 1 H), 6.29 (br d, J = 3.6 Hz, 1 H),
2.45 (s, 1 H).
Scheme 7
13C NMR: d = 156.8, 151.3, 113.2, 110.0, 14.1.
Use of 1.4 molar equivalents of methylhydrazine at short-
2-Ethyl-5-nitrofuran (7b)
er (1 h) reaction time led to the formation of 3-azido-1- Yellow oil; yield: 43% (Lit.51 bp 77.0–78.0 °C/2.5–3.0 mmHg).
1H NMR: d = 7.27 (d, J = 3.6 Hz, 1 H), 6.29 (d, J = 3.6 Hz, 1 H),
2.78 (q, J = 7.6 Hz, 2 H), 1.32 (t, J = 7.6 Hz, 3 H).
13C NMR: d = 162.1, 151.2, 113.1, 108.5, 21.8, 11.4.
methyl-5-nitro-1H-[1,2,4]triazole (23a) (7%) as a by-
product. Possible formation of isomeric 5-azido deriva-
tive 24 from 1-methyl-3,5-dinitro-1H-[1,2,4]triazole
(22a) is reported in the literature and proceeds by treat-
ment with acetyl hydrazide or hydrazine followed by re-
action with HONO (Scheme 7).48
2-(Butyl)-5-nitrofuran (7c)
Yellow oil; yield: 36%.
1H NMR: d = 7.26 (d, J = 3.6 Hz, 1 H), 6.27 (d, J = 3.7 Hz, 1 H),
2.73 (t, J = 7.6 Hz, 2 H), 1.70 (quint, J = 7.6 Hz, 2 H), 1.40 (sext,
J = 7.6 Hz, 2 H), 0.95 (t, J = 7.4 Hz, 3 H).
13C NMR: d = 161.1, 151.3, 113.1, 109.1, 29.4, 28.1, 22.1, 13.6.
Conclusions
Novel, advantageous approaches for the syntheses of dini-
tro-substituted furans, thiophenes, and thiazoles, have
been developed using fuming nitric acid, acetyl and tri-
fluoroacetyl nitrates. Convenient methods for dinitropyra-
zoles and 1H-[1,2,4]triazoles from the corresponding
amino derivatives by oxidation or diazotization are also
described. These routes broaden the range of availability
of dinitro derivatives of five-membered heterocycles,
which are compounds of major synthetic, biological, and
Anal Calcd for C8H11NO3: C, 56.80; H, 6.55; N, 8.28. Found: C,
56.58; H, 6.64; N, 8.45.
Nitration of 2-Alkyl-5-nitrofurans 7a,b with Excess of Fuming
Nitric Acid to Dinitro Compounds 8a,b; General Procedure
Fuming HNO3 (1.0 mL, 21.7 mmol) was added to solution of 2-
alkyl-5-nitrofuran 7a,b (2.0 mmol) in AcOH (4 mL) and the mix-
ture was heated at 70–75 °C for 8 h. After cooling, the mixture was
poured onto ice and neutralized to pH 7 below 5 °C by the slow ad-
dition of aq NaHCO3. The solid was filtered and washed with
energetic importance. The present procedures require EtOAc (10 mL). The products were extracted from the filtrate with
EtOAc (3 × 10 mL), the combined organic phases were dried
(MgSO4), and filtered. The solvent was evaporated under reduced
pressure and the residue was chromatographed on silica gel using
hexanes–EtOAc (5:1) to elute the products in the order 2-alkyl-3,5-
dinitrofurans 8a,b and 2-alkyl-2,5,5-trinitro-2,5-dihydrofurans
9a,b.
only simple manipulations and low-priced reagents and
allow syntheses of dinitrofurans, dinitrothiophenes and
dinitroazoles in yields which are comparable and, in many
cases, higher than those in previously reported methods.
Melting points were determined using a capillary melting point ap-
paratus equipped with a digital thermometer and are uncorrected.
The elemental analyses were performed on a Carlo Erba EA-1108
2-Methyl-3,5-dinitrofuran (8a)
Yellowish needles; yield: 17%; mp 73.0–74.0 °C (Lit.13a mp 71.0–
72.5 °C).
1
instrument. H (300 MHz), 13C (75 MHz) NMR spectra were re-
1H NMR: d = 7.73 (s, 1 H), 2.89 (s, 3 H).
13C NMR: d = 156.7, 148.2, 136.2, 106.7, 14.4.
corded in CDCl3 (with TMS as the internal standard), unless other-
wise stated. Compound 9b was characterized by indirect detection
correlation experiment. 1H–15N gHMBC and 1H–13C gHMBC spec-
tra were recorded on INOVA 500 in CDCl3 with nitromethane as in-
ternal standard (0 ppm in 15N spectrum for 1H–15N gHMBC
preliminary calibrations).49 All the reactions were carried out in
flame-dried glassware. Purification by column chromatography
was performed on silica gel 200–425 mesh. 4-Nitro-5-methylisox-
azole (18) was synthesized according to a published procedure.50
2-Ethyl-3,5-dinitrofuran (8b)
Yellowish oil, yield: 24%.
1H NMR: d = 7.72 (s, 1 H), 3.28 (q, J = 7.6 Hz, 2 H), 1.43 (t, J = 7.6
Hz, 3 H).
13C NMR: d = 161.2, 148.3, 135.3, 106.7, 21.7, 10.9.
Anal Calcd for C6H6N2O5: C, 38.72; H, 3.25; N, 15.05. Found: C,
39.01; H, 3.18; N, 15.05.
2-Alkyl-5-nitrofurans 7a–c; General Procedure
To Ac2O (5 mL) at –30 °C was added fuming HNO3 (0.37 mL, 8.4
mmol) while maintaining the temperature below –20 °C. The acetyl
nitrate solution was cooled to –30 °C and a solution containing re-
distilled 2-alkylfuran 6 (5 mmol) in Ac2O (2 mL) was added slowly
while maintaining the temperature below –30 °C. When the addi-
tion was complete, the reaction was allowed to stir for an additional
0.5 h, poured into ice, and neutralized to pH 6 by the slow addition
of aq sat. Na2CO3. The mixture was extracted with Et2O (3 × 15
mL), dried (MgSO4), and concentrated under reduced pressure. The
2-Butyl-3,5-dinitrofuran (8c)
This compound was obtained by nitration of 7c with concd HNO3.
Yellowish oil; yield: 7%.
1H NMR: d = 7.72 (s, 1 H), 3.24 (t, J = 7.8 Hz, 2 H), 1.81 (quint,
J = 7.7 Hz, 2 H), 1.46 (sext, J = 7.6 Hz, 2 H), 0.99 (t, J = 7.3 Hz, 3
H).
13C NMR: d = 160.7, 148.2, 135.6, 106.7, 29.0, 27.7, 22.3, 13.5.
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Dinitrofurans, Dinitrothiophenes, and Dinitroazoles
703
Anal Calcd for C8H10N2O5: C, 44.86; H, 4.71; N, 13.06. Found: C,
45.22; H, 4.83; N, 12.97.
2-Methyl-5-nitrothiophene (11a)
Obtained via method iii; brownish prisms; yield: 12%; mp 25.0–
27.0 °C (Lit.24a mp 25–27 °C).
2-Methyl-2,5,5-trinitro-2,5-dihydrofuran (9a)
Yellow oil; yield: 29%.
1H NMR: d = 6.93 (d, J = 5.6 Hz, 1 H), 6.79 (d, J = 5.8 Hz, 1 H),
2.25 (s, 3 H).
1H NMR: d = 7.76 (d, J = 4.1 Hz, 1 H), 6.76 (dd, J = 4.1, 0.9 Hz, 1
H) 2.55 (s, 3 H).
13C NMR: d = 149.4, 149.2, 129.1, 125.5, 16.2.
13C NMR: d = 139.9, 128.7, 127.0, 120.9, 21.6.
2-Ethyl-5-nitrothiophene (11b)
Obtained via method iii; yellow oil; yield: 11% (Lit.52 no NMR data
or bp were reported).
Anal. Calcd for C5H5N3O7: C, 27.41; H, 2.30; N, 19.18. Found: C,
27.80; H, 2.09; N, 18.65.
1H NMR: d = 7.78 (d, J = 4.1 Hz, 1 H), 6.78 (d, J = 4.1 Hz, 1 H),
2.89 (q, J = 7.6 Hz, 2 H), 1.36 (t, J = 7.6 Hz, 3 H).
2-Ethyl-2,5,5-trinitro-2,5-dihydrofuran (9b)
Yellowish oil; yield: 30%.
13C NMR: d = 156.8, 149.3, 129.0, 123.7, 24.2, 15.3.
1H NMR: d = 6.88 (d, J = 5.6 Hz, 1 H), 6.70 (d, J = 5.8 Hz, 1 H),
2.57 (dq, J = 16.2, 7.5 Hz, 1 H), 2.40 (dq, J = 16.2, 7.5 Hz, 1 H),
1.05 (t, J = 7.5 Hz, 3 H).
13C NMR: d = 139.4, 128.7, 126.9, 124.2, 28.5, 7.1.
2-Methyl-3,5-dinitrothiophene (12a)
Obtained via method iii; yellow microcrystals; yield: 67%; mp
97.0–99.0 °C (Lit.24a mp 99–100 °C).
1H NMR: d = 8.35 (s, 1 H), 2.91 (s, 3 H).
13C NMR: d = 149.4, 145.3, 142.2, 124.3, 16.2.
Anal. Calcd for C6H7N3O7: C, 30.91; H, 3.03; N, 18.02. Found: C,
31.31; H, 2.95; N, 17.48.
2-Methyl-3,5-dinitrothiophene 12a from 10a via Two Steps
(Method i)
2-Methyl-5-nitrothiophene (11a)
2-Ethyl-3,5-dinitrothiophene (12b)
Obtained via method iii; yellow oil; yield: 70% (Lit.53 163–165/9
mmHg).
A solution of 2-methylthiophene (10a; 0.982 g, 10 mmol) in Ac2O
(5 g, 49 mmol) was added to a mixture of Ac2O (5 g, 49 mmol) and
fuming HNO3 (0.82 g, 13 mmol) at –30 °C during 3 h. The mixture
was stirred for 12 h at r.t., poured onto ice and neutralized with aq
sat. NaHCO3. The product was extracted with CH2Cl2 (3 × 25 mL),
the combined organic phases were dried (Na2SO4) and the solvent
was removed under reduced pressure. The residue was purified by
silica gel column using 5% EtOAc in hexanes as an eluent to give
(0.839 g, 59%) 11a as brownish microcrystals. NMR data and mp
of 11a are in agreement with those for an authentic sample obtained
by method iii (see below).
1H NMR: d = 8.36 (s, 1 H), 3.39 (q, J = 7.5 Hz, 2 H), 1.48 (t, J = 7.5
Hz, 3 H).
13C NMR: d = 157.4, 145.4, 141.3, 124.5, 23.8, 13.8.
2-Methyl-5-nitrothiophene S-Oxide (13a)
Obtained via method iii; brownish oil; yield: 10%.
IR (film): 3081, 2934, 2872, 1706, 1556, 1443, 1383, 1340, 1051
cm–1 (S=O).
1H NMR: d = 7.56 (d, J = 6.2 Hz, 1 H), 6.42 (d, J = 6.2 Hz, 1 H),
2.29 (s, 1 H).
13C NMR: d = 193.7, 152.6, 133.0, 100.2, 26.0.
2-Methyl-3,5-dinitrothiophene (12a)
2-Methyl-5-nitrothiophene (11a; 0.5 g, 3.5 mmol) was added to a
mixture of Ac2O (0.39 g, 3.84 mmol) and fuming HNO3 (0.24 g,
3.84 mmol) at –30 °C and the mixture was stirred at r.t. for 15 h. The
mixture was poured onto ice. The solid was filtered, washed with aq
sat. NaHCO3 (10 mL) and H2O (30 mL) to give 12a (0.4 g, 60%) as
yellow microcrystals. NMR data and mp of 12a are in agreement
with those for an authentic sample obtained by method iii (see be-
low).
Anal Calcd for C5H5NO3S: C, 37.73; H, 3.17; N, 8.80. Found: C,
38.07; H, 3.18; N, 8.75.
2-Ethyl-5-nitrothiophene S-Oxide (13b)
Obtained via method iii; brownish oil; yield: 8%.
IR (film): 3083, 2941, 2882, 1714, 1555, 1458, 1351, 1326, 1058
cm–1 (S=O).
1H NMR: d = 7.59 (d, J = 6.2 Hz, 1 H), 6.40 (d, J = 6.2 Hz, 1 H),
2.58 (dq, J = 7.0, 14.3 Hz, 2 H), 1.12 (t, J = 7.3 Hz, 3 H).
Nitration of 2-Alkylthiophenes 10a,b with Excess of Acetyl
Nitrate; General Procedure (Methods ii and iii)
13C NMR: d = 193.7, 151.5, 133.2, 105.9, 32.5, 9.1.
Fuming HNO3 (1.25 mL, 27.2 mmol, method ii) or (2.05 mL, 44.6
mmol, method iii) was added to Ac2O (7.5 mL, 79.5 mmol) at tem-
perature below –10 °C. After 0.5 h, the acetyl nitrate was cooled be-
tween –40 and –45 °C and a solution of 2-alkylthiophene 10a,b (8.9
mmol) in Ac2O (7.5 mL) was slowly added, while maintaining the
temperature below –40 °C. When the addition was complete, the re-
action was allowed to stir at this temperature for an additional 5 h,
and at r.t. for 12 h. Then, the mixture was poured onto ice, and the
whole was neutralized to pH 7 below 5 °C by the slow addition of
aq NaHCO3. The solid was filtered and washed with EtOAc (30
mL). The products were extracted from the filtrate with EtOAc (3 ×
35 mL), the combined organic phases were dried (MgSO4), and fil-
tered. The solvent was evaporated under reduced pressure and the
residue was chromatographed on silica gel using hexanes–EtOAc
(8:1) to elute the products in the order 2-alkyl-5-nitrothiophene 11,
2-alkyl-3,5-dinitrothiophene 12, and 2-alkyl-5-nitrothiophene S-
oxide 13.
Anal Calcd for C6H7NO3S: C, 41.61; H, 4.07; N, 8.09. Found: C,
41.61; H, 3.91; N, 8.35.
2-Nitrothiazoles 15a,b; General Procedure
2-Aminothiazole 14a,b (33 mmol) was dissolved in a solution of
H2O (100 mL) and aq 42% HBF4 (20 g). This solution was cooled
to 4 °C and maintained at this temperature with an ice-water bath
during the addition of NaNO2 (2.3 g, 33 mmol) dissolved in H2O (10
mL). The NaNO2 solution was added to the amine solution with
moderate stirring. The diazotization required 20 min. At the end of
the diazotization, the mixture was added immediately to a boiling
solution of NaNO2 (25 g) in H2O (100 mL) containing Cu powder
(5 g) and the mixture was stirred for 0.5 h at this temperature. After
cooling, the product was extracted with Et2O (3 × 40 mL), the or-
ganic layer was dried (MgSO4), and the solvent was evaporated un-
der reduced pressure. The residue was recrystallized from hexanes
to give 2-nitrothiazoles 15a,b.
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A. R. Katritzky et al.
PAPER
2-Nitrothiazole (15a)
3-Methyl-4,5-dinitro-1H-pyrazoles 20a–c; General Procedure
H2O2 (50%, 0.5 mL) was added dropwise to a solution of 5-amino-
3-methyl-4-nitropyrazole 19a–c (0.6 mmol) in concd H2SO4 (1.0
mL) at 0 °C and stirred for 15 min. Additional H2O2 (1.50 mL) was
slowly added to the mixture at 0 °C and then stirred at r.t. for 15 h.
The mixture was poured onto ice and extracted with EtOAc (3 × 20
mL). The combined organic phases were washed with H2O (25 mL),
then brine (10 mL), and dried (MgSO4). The solvent was removed
under reduced pressure and the crude products from 19b and c were
purified by column chromatography on silica to give corresponding
3-methyl-4,5-dinitro-1H-pyrazoles 20b and 20c as yellow microc-
rystals. The crude product from 19a was dissolved in acetone (5
mL), K2CO3 (0.35 g) was added and the mixture was stirred at r.t.
for 8 h. The solid was filtered, washed with acetone (10 mL) and the
filtrate was concentrated under reduced pressure. The residue was
purified by recrystallization from EtOH to give the 3-methyl-4,5-
dinitro-1H-pyrazole potassium salt 20a as yellow microcrystals.
Brown needles from hexanes; yield: 28%; mp 77–78 °C (Lit.54 mp
77–78 °C).
1H NMR: d = 7.92 (d, J = 3.2 Hz, 1 H), 7.72 (d, J = 3.2 Hz, 1 H).
13C NMR: d = 166.6, 142.5, 127.1.
5-Methyl-2-nitrothiazole (15b)
Yellow needles; yield: 21%; mp 60–61 °C (Lit.55 mp 60–61 °C).
1H NMR: d = 7.58 (d, J = 1.0 Hz, 1 H), 2.61 (d, J = 1.0 Hz, 3 H).
13C NMR: d = 163.7, 145.0, 140.7, 12.4.
2,4-Dinitrothiazoles 16a,b; General Procedure
Trifluoroacetic anhydride (2.5 g, 12 mmol) was added to a solution
of NH4NO3 (0.67 g, 12 mmol) in trifluoroacetic acid (2.8 mL) at 0–
5 °C. The mixture was stirred for 0.5 h and then 2-nitrothiazole
15a,b (3.5 mmol) was added in small portions to the suspension at
0 to 5 °C. After addition, the temperature was kept at 25 °C for 20
h, and then at 70–80 °C for 1–4 h. The cooled mixture was poured
into ice water (20 mL) and the precipitated solid was filtered and
washed with H2O (10 mL) to give 2,4-dinitrothiazole 16a,b. An
analytical sample was recrystallized from benzene.
3-Methyl-4,5-dinitro-1H-pyrazole Potassium Salt (20a)
Yield: 40%; mp 187.0–189.0 °C.
1H NMR (DMSO-d6): d = 2.34 (s).
13C NMR (DMSO-d6): d = 152.0, 146.6, 123.0, 14.0.
Anal Calcd for C4H3KN4O4·0.5H2O: C, 21.92; H, 1.84; N, 25.56.
Found: C, 21.90; H, 1.62; N, 25.16.
2,4-Dinitrothiazole (16a)
Yellow needles; yield: 34%; mp 144–146 °C (Lit.30 mp 145.5–
146.5 °C).
1,3-Dimethyl-4,5-dinitro-1H-pyrazole (20b)
Yield: 81%; mp 34–36 °C.
1H NMR (DMSO-d6): d = 4.12 (s, 3 H), 2.48 (s, 3 H).
13C NMR (DMSO-d6): d = 145.0, 141.5, 126.9, 39.9, 13.1.
1H NMR (acetone-d6): d = 9.14 (s, 1 H).
13C NMR: d = 164.5, 152.3, 129.8.
5-Methyl-2,4-dinitrothiazole (16b)
Yellowish prisms; yield: 91%; mp 130–131 °C.
1H NMR: d = 3.00 (s, 3 H).
Anal Calcd for C5H6N4O4: C, 32.27; H, 3.25; N, 30.10. Found: C,
32.46; H, 3.09; N, 29.82.
13C NMR: d = 158.2, 148.7, 145.7, 14.3.
3-Methyl-4,5-dinitro-1-phenyl-1H-pyrazole (20c)
Yield: 52%; mp 80–82 °C.
1H NMR (acetone-d6): d = 7.64 (br s, 5 H), 2.61 (s, 3 H).
Anal Calcd for C4H3N3O4S: C, 25.40; H, 1.60; N, 22.22. Found: C,
25.72; H, 1.27; N, 21.82.
13C NMR (acetone-d6): d = 146.6, 141.8, 137.1, 131.8, 131.0, 126.8,
125.4, 13.7.
5-Amino-3-methyl-4-nitro-1H-pyrazoles 19a–c; General Proce-
dure
Hydrazine (7.81 mmol) was added to a solution of 5-methyl-4-ni-
troisoxazole (18; 1.0 g, 7.81 mmol) in EtOH (20 mL) at –5 °C and
the mixture was stirred for 1 h, heated under reflux for 15 h, and
concentrated to 5 mL under reduced pressure. The solid was filtered
and dried to give 19a–c as yellow microcrystals.
Anal Calcd for C10H8N4O2: C, 48.39; H, 3.25; N, 22.57. Found: C,
48.50; H, 2.91; N, 22.34.
1-Alkyl-3,5-dinitro-1H-[1,2,4]triazoles 22a,b and 3-Azido-1-
methyl-5-nitro-1H-[1,2,4]triazole (23a); General Procedure
The appropriate alkylhydrazine (59.5 mmol) was added dropwise to
H2O (50 mL) at 10–20 °C, followed by dropwise addition of concd
HNO3 (7. 65 mL, 10.86 g, 119 mmol) over 15 min at temperature
below 20 °C. The mixture was stirred at 20 °C for 15 min. Dicyan-
diamide (21; 5 g, 59.5 mmol) was added to the mixture at 20 °C and
the mixture stirred at 50–55 °C for 5 h. Then, 2.5 M H2SO4 [35 mL,
prepared by the addition of concd H2SO4 (4.75 mL) to H2O (30.25
mL)] was added at 20 °C. The resulting solution was added drop-
wise (within 1.15 to 1.30 h) to a solution of NaNO2 (41.0 g, 595
mmol) in H2O (100 mL) with rigorous stirring at 50 °C, followed by
dropwise addition of 80% H2SO4 (10 mL) at 50 °C. The mixture
was heated under reflux for 15 min and cooled to 10–15 °C. The
product was extracted immediately with EtOAc (5 × 100 mL). The
combined extracts were washed with aq sat. NaHCO3 (1 × 20 mL),
then with brine (2 × 50 mL) and dried (MgSO4, 10 g). The solvent
was removed at 40–50 °C/20–30 mmHg to give 6 g of a brown oil.
CHCl3 (70 mL) was added to this oil and evaporated at 20–30
mmHg again to eliminate EtOAc. The residue was stirred in CHCl3
(100 mL) for 0.5 h at 20 °C, the mixture was filtered, and the solvent
evaporated at 40–50 °C/20–30 mmHg. The solid was recrystallized
from CHCl3 or chromatographed on silica gel to give pure 22a,b.
5-Amino-3-methyl-4-nitro-1H-pyrazole (19a)
Yield: 87%; mp 206–208 °C (Lit.37 mp 206–207 °C).
1H NMR (DMSO-d6): d = 11.96 (br s, 1 H), 7.18 (br s, 2 H), 2.31 (s,
3 H).
13C NMR (DMSO-d6): d = 148.0, 143.8, 116.3, 14.5.
5-Amino-1,3-dimethyl-4-nitro-1H-pyrazole (19b)
Yield: 86%; mp 134–136 °C (Lit.37 mp 135–136 °C).
1H NMR (DMSO-d6): d = 7.33 (s, 2 H), 3.51 (s, 3 H), 2.29 (s, 3 H).
13C NMR (DMSO-d6): d = 146.6, 143.0, 116.0, 34.3, 14.1.
5-Amino-3-methyl-4-nitro-1-phenyl-1H-pyrazole (19c)
Yield: 81%; mp 170–172 °C (Lit.37 mp 170–172 °C).
1H NMR (DMSO-d6): d = 7.56–7.45 (m, 5 H), 7.43 (br s, 2 H), 2.40
(s, 3 H).
13C NMR (DMSO-d6): d = 146.2, 144.9, 136.8, 129.5, 128.2, 124.4,
116.6, 14.4.
Synthesis 2008, No. 5, 699–706 © Thieme Stuttgart · New York

PAPER
Dinitrofurans, Dinitrothiophenes, and Dinitroazoles
705
1-Methyl-3,5-dinitro-1H-[1,2,4]triazole (22a)
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Simpkin, D. S. A.; Follenfant, R. L.; Shankley, C.; Smith, T.
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Yellow prisms; yield: 43%; mp 97–99 °C (Lit.46a,47 mp 97–98.5 °C).
1H NMR (DMSO-d6): d = 4.30 (s, 3 H).
13C NMR (DMSO-d6): d = 156.4, 151.0, 41.4.
1-Ethyl-3,5-dinitro-1H-[1,2,4]triazole (22b)
Yellow microcrystals; yield: 23%; mp 77–78 °C (Lit.46a mp 78 °C).
1H NMR: d = 4.85 (q, J = 7.3 Hz, 2 H), 1.70 (t, J = 7.3 Hz, 3 H).
13C NMR: d = 157.8, 150.2, 14.6.
3-Azido-1-methyl-5-nitro-1H-[1,2,4]triazole (23a)
Yellowish microcrystals; yield: 7%; mp 21–23 °C.
1H NMR: d = 4.25 (s, 3 H).
(25) Khalaf, A. I.; Ebrahimabadi, A. H.; Drummond, A. J.;
Anthony, N. G.; Mackay, S. P.; Suckling, C. J.; Waigh, R. D.
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13C NMR: d = 155.9, 150.4, 40.1.
Anal Calcd for C3H3N7O2: C, 21.31; H, 1.79; N, 57.98. Found: C,
21.69; H, 1.69; N, 57.92.
Acknowledgment
The authors are indebted to Dr. Dennis Hall (University of Florida)
for help and useful discussions during the preparation of this ma-
nuscript. We also wish to thank Dr. James W. Rogers (University of
Florida) for his help in the development of a method for the synthe-
sis of dinitrothiophenes.
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