Dinitro-furans, -Thiophenes, and -Azoles - Ark.chem.ufl.edu ...

699
Dinitro-furans, -Thiophenes, and -Azoles
Alan R. Katritzky* § , Anatoliy V. Vakulenko § , Jothilingam Sivapackiam, § Bogdan Draghici, § and Reddy
Damavarapu #
§ Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200
# US Army ARDEC, Picatinny Arsenal, USA
Fax: (352) 392-9199.
E-mail: katritzky@chem.ufl.edu.
Abstract: Direct nitration of the corresponding mononitro furans
7a–c with fuming nitric acid, thiophenes 11a,b with acetyl nitrate
and thiazoles 15a,b with trifluoroacetyl nitrate, gave dinitrosubstituted
furans 8a–c thiophenes 12a,b and thiazoles 16a,b
respectively. The nitrations of 2-alkylthiophenes 10a,b with 3 and
5 molar equivalents of acetyl nitrate, generated in situ, are discussed.
Reactions of 7a,b with fuming nitric acid gave, as byproduct,
1,1,5,5-tetra-substituted dihydrofurans 9a,b. Treatment of 4nitro-5-methylisoxazole
18 with hydrazine or its methyl or phenyl
derivative, followed by oxidation of the corresponding 4-amino-5nitro-1H-pyrazoles
19a–c with hydrogen peroxide (50%) gave
4,5-dinitro-1H-pyrazoles 20a–c. A safe one-pot synthesis of 1alkyl-3,5-dinitro-1H-[1,2,4]triazoles
22a,b was developed from
dicyandiamide.
Key words: dinitrofurans, dinitrothiophenes, dinitroazoles, nitration
and oxidation reactions.
Introduction
Di-nitro derivatives of five-membered heterocycles have
diverse biological activity (2,4-dinitroimidazole derivatives
increase the sensitivity of hypoxic cells toward
irradiation in cancer radiotherapy 1 ), are useful intermediates
(e.g. convertion of di-nitrofuran into various polysubstituted
phenols 2 ) and are of potential interest as energetic
materials and blowing agents.
Approaches to the preparation of dinitro-substituted five
membered heterocycles comprise: (i) direct nitration 3 ,
(ii) ring construction 4 and (iii) functional group transformation.
5 However published methods usually suffer
from low yields, starting material availability, harsh
conditions, and/or difficult-to-separate isomer formation.
This prompted our search for more general and milder
routes.
We previously 6 reported facile access to polynitroimidazoles,
7 trinitroazetidine, 8 nitropyridines 9 and mononitro-
five-membered heterocycles. 10 We now report on dinitrosubstituted
furans, thiophenes, thiazoles, pyrazoles and
1H-[1,2,4]triazoles.
Results and Discussion
(i) Dinitrofurans
Published routes to dinitrofurans comprise: (i) nitration
of 2-nitrofuran 1 to give 2,5- (4) (67%) and 2,4dinitrofuran
3 (5%). 11 (ii) 5-Sulfo-furan-2-carboxylic
acid 2 and fuming nitric acid give 2,5-dinitrofuran 4
(3%), 12 or (iii) two-step nitration of furan 5 with acetyl
nitrate - acetic anhydride - HNO3 (27% overall) to give
4 2 (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-furancarboxylate. 13
O 2 N
5%
O
HNO 3
NO 2
O
+
O 2 N
NO 2
O
67%
NO 2
HNO 3
SO 3 H
3 87-89 o C 4 99-101 o C 5
Scheme 1
1
3%
i) HNO 3 , (Ac) 2 O
ii) HNO 3 , 27%
2
O
O
COOH
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 o C afforded 2-methyl-5nitrofuran
7a (39%), 2-ethyl-5-nitrofuran 7b (43%) and
2-n-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-3,5dinitrofurans
8a–c in situ by addition of 2-alkylfurans
6a–c to 1.5 molar equivalents of acetyl nitrate at –30 o C
and further treatment of the reaction mixture with concentrated
nitric acid at 50-55 o C gave the desired 8a–c in
up to 8% yield after 4 h (Scheme 2).
R R
O
O
6a R=Me
6b R=Et
6c R=n-Bu
Scheme 2
(Ac) O, 1.5 eq.HNO ,
2 3
-30 o C, 1 h
O 2 N
R
O
8a 17%
8b 24%
7a 39%
7b 43%
7c 36%
NO 2
+
O 2 N
c. HNO 3 ,
50-55 o C, 4 h
NO 2
f. HNO 3 , AcOH
70-75 o C, 8 h
R
O
9a 29%
9b 30%
NO 2
NO 2
8a-c 7-8%
Treatment of 2-alkyl-5-nitrofuran 7a,b with fuming nitric
acid in glacial acetic acid at 70–75 o C for 8 h gave 2alkyl-3,5-dinitrofuran
8a,b (17–24%) and tetrasubstituted
dihydrofuran 9a,b (29–30%) (Scheme 2).

700
Structures 9a,b were supported by NMR spectral data
and elemental analyses. The 15 N NMR spectrum of 2ethyl-2,5,5-trinitro-2,5-dihydrofuran
9b showed signals
in the region -12.1 – +2.3 ppm characteristic of a nitro
group (Fig.1).
Fig. 1 1 H – 15 N gHMBC spectrum of 9b
The structure of compound 9b is also supported by correlation
between 1 H and 13 C over 3 bonds and by the 1 H
– 13 C gHMBC spectrum. Total correlations for compound
9b based on 1 H – 15 N and 1 H – 13 C gHMBC experiments
are given in Figure 2.
(−10.9)
-O
O
N +
-O
(−12.2)
N +
127.1
O
6.70 6.89
150.2 139.6
O
124.5
O
N +
2.43, 2.59
28.8
Fig. 2 Chemical shift of 1 H, 13 C and 15 N for 9b
(ii) Dinitrothiophenes
2.3
O
1.04
7.4
After “countless futile attempts 14 ” thiophene was first
successfully nitrated by Meyer and Stadler when air
saturated with thiophene was passed through fuming
nitric acid to give mononitro- and dinitro-thiophenes. 15
Direct nitration is still the most usual method for the
preparation of nitrothiophenes. Thus, for instance, benzoyl
nitrate, 16 acetyl nitrate 17 and various mixtures of
nitric acid and acetic anhydride 18 are effective nitrating
agents for thiophene itself. Other routes such as cyclization
are less convenient or general. 19
Nitration is one of the least selective of electrophilic
subtitution processes in benzenoid systems; 20 thus the
thiophene nucleus undergoes some β-nitration even
when α positions are unsubstituted. Nitration of 2- or 3nitrothiophene
is conveniently effected with fuming
nitric acid in the presence of sulfuric acid 21 or
trifluoroacetic acid. 22 Isomer proportions formed by
nitration of 2- and 3-nitrothiophenes in trifluoroacetic
acid were determined indirectly 22 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 mixture of dinitrothiophene isomers.
3 Newcombe separated dinitrothiophenes by column
chromatography. 23
A mixture of nitric acid and acetic anhydride is effective
for mononitration of 2-alkylthiophenes. 24 An electrondeficient
substituent in addition to the 2-alkyl group
requires the application of HNO3–H2SO4. 24a,25 3-Nitrosubstituted
thiophene byproducts were isolated in up to
19% yields after direct nitration of 2-alkylthiophenes. 26
2-Alkyl-3-nitrothiophenes were prepared in yields of
55.5–82.0% by decarboxylation 27 or desulfonation 28
reactions.
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 equivalents
of acetic anhydride) at -30 o C for 3 h followed by
reaction of 2-methyl-5-nitrothiophene 11a with another
1.1 molar equivalents of acetyl nitrate at –30 o C for 3 h,
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
anhydride (8.9 equiv) with 2-ethylthiophene 10b at -40 –
-45 o C for 6 h and then at room temperature for 18 h
gave 2-ethyl-5-nitrothiophene 11b (40%) as a major
product together with 2-ethyl-3,5-dinitrothiophene 12b
(24%) and 2-methyl-5-nitrothiophen-1-oxide 13b (4%).
One-step dinitration (method iii) of 2-alkylthiophene
10a,b with 5 equivalents of acetic nitrate gave 67–70%
of 12a,b (Scheme 3). Products 13a,b were characterized
by 1 H, 13 C NMR and IR spectra together with elemental
analyses and are consistent with previous data published
in the literature. 29

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R
O 2 N
S
10a R=CH 3
10b R=C 2 H 5
Scheme 3
(i)10.5 eq.(Ac) 2 O,
1.3 eq.HNO 3 , -30 o C, 3 h,
25 o C, 12 h, 59%
R NO
S 2
(ii) 12b 24%
(iii) 12a 67%
(iii) 12b 70%
11a,
R=CH 3
(i)1.1 eq.(Ac) 2 O,
1.1 eq.HNO 3 , -30 o C, 3 h,
25 o C, 12 h, 60%
(ii) 8.9 eq.(Ac) 2 O, 3.0 eq.HNO 3 ,
-40-45 o C, 6 h, 25 o C, 18 h
+
(iii) Dinitrothiazoles
(iii) 8.9 eq.(Ac) 2 O, 5.0 eq.HNO 3 ,
-40-45 o C, 6 h, 25 o C, 18 h
+
R
S
NO2 R
S
NO2 (ii) 11b 40%
(iii) 11a 12%
(iii) 11b 11%
O
(ii) 13b 4%
(iii) 13a 10%
(iii) 13b 8%
12a,
R=CH 3
Parent 30 obtained 2,4-dinitrothiazole 16a from 2nitrothiazole
15a with boron trifluoride−nitrogen tetroxide
complex; Prijs 31 dinitrated 5-acylaminothiazole 17c
to give 16c using potassium nitrate in fuming sulfuric
acid (Scheme 4).
R
R
S
N
14a,b
S
N
17c
NH 2
i)
iv)
N
R NO
S 2
ii) or iii)
O 2 N
15a, R=H, 28%
15b, R=CH 3 , 21%
N
R NO
S 2
16a, R=H
16b, R=CH 3
16c, R=NHCOCH 3
Scheme 4 i) aq. HBF4, NaNO2, 4 o C, 20 min; NaNO2,
Cu, 100 o C, 30 min; ii) BF3N2O4, CH3NO2, 101 o C, 1 h
(80% for 16a 30 ); iii) NH4NO3, TFA, TFAA, 0–5 o C, 0.5
h; 15a,b, 0–5 o C; 25 o C for 20 h and 70–80 o C for 4 h
(34% for 16a) or 0.5 h (91% for 16b); iv) KNO3, Oleum,
0–5 o C (37% for 16c 31 ).
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 o C for 4 h,
forms dinitro derivative 16a (34%). A 5-methyl group
facilitates the preparation of 16b (91%) using similar
conditions (Scheme 4).
(iv) Dinitropyrazoles
4-Unsubstituted pyrazoles are usually nitrated at position
4, 32 facilitated by electron-donating and retarded by
electron-withdrawing substituents. Thus, 4-nitropyrazole
and 1-methyl-4-nitropyrazole do not undergo nitration. 33
However, on prolonged heating with mixed acid 1methylpyrazole
affords the 4-nitro– and 3,4-dinitro–
derivatives (51 and 13%, respectively). 34 1,5-Dimethyl-
4-nitropyrazole, on heating with nitric acid and oleum,
similarly gives 1,5-dimethyl-3,4-dinitropyrazole. 35 Rare
simultaneous introduction of two nitro groups into the
pyrazole ring occurs 36 in low yield under vigorous conditions.
Pyrazoles containing two adjacent nitro groups were
previously prepared in three-steps (average 40% yield)
by thermal rearrangement of N-nitropyrazoles and further
nitration with mixed acid. 33 We now report a convenient
synthesis of 3-methyl-4,5-dinitropyrazoles 20a–c
by oxidation of 3-methyl-4-nitro-5-amino-1H-pyrazoles
19a−c with 50% hydrogen peroxide - sulfuric acid at 0
o
C for 16 h in 40–81% yields. By contrast, diazotization
of 19a with 5 equivalents of sodium nitrite in 2N sulfuric
o
acid at 50 C for 1h led to difficult-to-separate mixtures
of di- 20a, 33%) and mono- (4%) nitro derivatives. Intermediates
19a-c were easily prepared by a modifica-
37
tion of the treatment of 4-nitro-5-methylisoxazole 18
with the corresponding hydrazines in water for 1 h or
ethanol for 15 h under reflux in 30–87% yields (Scheme
5).
O 2 N
C
H 3
O N
18
O2N RNHNH2 , reflux
water, 1 h or
ethanol, 15 h
N
H 2
N N
R
CH 3
19a, R=H, 75% a , 87% b
19b, R=CH 3 , 30% a , 86% b
19c, R=Ph, 81% b
a yield of 19 given for preparation in water
b yield of 19 given for preparation in ethanol
Scheme 5
H 2 O 2 , H 2 SO 4
O 2 N
O2N 0 to 25 oC, 16 h
N N
R
CH 3
20a, R=K, 40%
20b, R=CH 3 , 81%
20c, R=Ph, 52%
(v) One-pot synthesis of 1-alkyl-3,5-dinitro-1H-
[1,2,4]triazoles
Nitrotriazoles are important in fields as diverse as medicine,
38 and agrochemicals. 39 They are also photosensitive
40 and energetic 41 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
Three ring-nitrogens significantly reduce reactivity toward
electrophilic substitution 43 and the only known
direct nitration is of 1,2,4-triazol-3-one. 44 1-Alkyl-3,5dinitro-1H-[1,2,4]triazoles
were previously synthesized
in two steps (overall 40%) (i) by oxidation 5a or Sandmeyer
reaction 45 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
We now report a convenient one-pot synthesis of 1alkyl-3,5-dinitro-1H-[1,2,4]triazoles
22a,b by conversion
of 1-alkyl-3,5-amino-1H-[1,2,4]triazoles, prepared
in situ from dicyandiamide 21 and alkylhydrazines, to
22a,b in 23–43% yields. The procedure was optimized in

702
terms of the ratio of methylhydrazine to dicyandiamide
to sodium nitrite, the reaction time and the temperature.
Equimolar amounts of methylhydrazine and dicyandiamide
21 in aqueous nitric acid at 50 o C for 5 h for cyclization
and 10 molar equivalents of sodium nitrite at 50
o C for 1.5 h for diazotization proved to be appropriate
for the safe, large scale preparation of 1-alkyl-3,5dinitro-1H-[1,2,4]triazoles
22a,b (Scheme 6). Assigned
structures of 22a,b were supported by NMR spectral
data in agreement with the published data. 47
N
H 2
NH 2
Scheme 6
N CN
i) RNHNH 2 , HNO 3
ii) NaNO 2 , H 2 SO 4
O 2 N
N
N N
R
NO 2
21 22a, R=CH 3 43%
22b, R=C 2 H 5 23%
+
O 2 N
N
N N
R
23a
Use of 1.4 molar equivalents of methylhydrazine at
shorter (1 h) reaction time led to the formation of 1methyl-3-azido-5-nitro-1H-[1,2,4]triazole
23a (7%) as a
byproduct. Possible formation of isomeric 5-azido- derivative
(24) from 1-methyl-3,5-dinitro-1H-
[1,2,4]triazole 22a is reported in the literature and proceeds
by treatment with acetyl hydrazide or hydrazine
followed by reaction with HONO (Scheme 7). 48
N 3
N
N N
CH 3
NO 2
AcNHNH 2
O 2 N
N
N N
CH 3
NO 2
NH 2 NH 2
H 2 NHN
24 22a 25
HONO
Scheme 7
Conclusions
N
N N
CH 3
N 3
NO 2
Novel, advantageous approaches for the syntheses of
dinitro-furans, -thiophenes, and -thiazoles, have been
developed using fuming nitric acid, acetyl- and
trifluoroacetyl- nitrates. Convenient methods for dinitro-
pyrazoles 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 energetic importance. The present procedures
require only simple manipulations and low-priced
reagents and allow syntheses of dinitro-furans,
-thiophenes and azoles in yields which are comparable
and, in many cases, higher than those in previously reported
methods.
Experimental Section
General. Melting points were determined using a capillary
melting point apparatus equipped with a digital
thermometer and are uncorrected. The elemental analyses
were performed on a Carlo Erba EA-1108 instrument.
1 H (300 MHz), 13 C (75 MHz) NMR spectra were
recorded in CDCl3 (with TMS as the internal standard),
unless otherwise stated. Compound 9b was characterized
by indirect detection correlation experiment. 1 H – 15 N
gHMBC and 1 H – 13 C gHMBC spectra were recorded on
INOVA 500 in CDCl3 with nitromethane as internal
standard (0 ppm in 15 N spectrum for 1 H – 15 N 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-methylisoxazole 18 was synthesized
according to a published procedure. 50
2-Alkyl-5-nitrofuran 7a-c; General Procedure
To 5 mL of acetic anhydride at –30 o C was added 0.37
mL (8.4 mmol) of fuming nitric acid, while maintaining
the temperature below –20 o C. The acetyl nitrate solution
was cooled to –30 o C and a solution containing (5 mmol)
of redistilled 2-alkylfuran 6 in 2 mL of acetic anhydride
was added slowly, while maintaining the temperature
below –30 o C. When addition 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 a
saturated solution of sodium carbonate. The mixture was
extracted with ether, dried over MgSO4 and concentrated
under reduced pressure. The resulting residue was subjected
to silica gel chromatography to give 7a-c.
2-Methyl-5-nitrofuran (7a)
Yellowish prisms (39%); mp 45.0–46.0 o C (Lit. 13a mp
43.0–44.5 o C).
1 H NMR δ 7.26 (d, J = 3.7 Hz, 1H), 6.29 (br d, J = 3.6
Hz, 1H), 2.45 (s, 1H).
13 C NMR δ 156.8, 151.3, 113.2, 110.0, 14.1.
Anal Calcd for C5H5NO3: C, 47.25; H, 3.97; N, 11.02.
Found: C, 47.50; H, 3.88; N, 10.88.
2-Ethyl-5-nitrofuran (7b)
Yellow oil (43%) (Lit. 51 bp 77.0–78.0 o C/2.5–3.0 mm).
1 H NMR δ 7.27 (d, J = 3.6 Hz, 1H), 6.29 (d, J = 3.6 Hz,
1H), 2.78 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H).
13 C NMR δ 162.1, 151.2, 113.1, 108.5, 21.8, 11.4.
Anal Calcd for C6H7NO3:
C, 51.06; H, 5.00; N, 9.92.
Found: C, 50.70; H, 4.91; N, 9.83.
2-(n-Butyl)-5-nitrofuran (7c)
Yellow oil (36%).
1 H NMR δ 7.26 (d, J = 3.6 Hz, 1H), 6.27 (d, J = 3.7 Hz,
1H), 2.73 (t, J = 7.6 Hz, 2H), 1.70 (quintet, J = 7.6Hz,
2H), 1.40 (sextet, J = 7.6 Hz, 2H), 0.95 (t, J = 7.4 Hz,
3H).

703
13
C NMR δ 161.1, 151.3, 113.1, 109.1, 29.4, 28.1, 22.1,
13.6.
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; General procedure
Fuming nitric acid (1.0 mL, 21.7 mmol) was added to
solution of 2-alkyl-5-nitrofuran 7a,b (2.0 mmol) in acetic
acid (4 mL) and the whole was heated at 70-75 o C for
8 h. After cooling, the reaction mixture was poured onto
ice and neutralized to pH 7 by the slow addition of sodium
bicarbonate below 5 o C. The solid was filtered and
washed with ethyl acetate. The products were extracted
from the filtrate with ethyl acetate, the combined organic
phase was dried over MgSO4 and filtered. Solvent was
evaporated under reduced pressure and the residue was
chromatographed on silica gel using hexanes/ethyl acetate
(v/v=5:1) to elute the products in the order 2-alkyl-
3,5-dinitrofuran 8a,b and 2-alkyl-2,5,5-trinitro-2,5- dihydrofuran
9a,b.
2-Methyl-3,5-dinitrofuran (8a)
Yellowish needles (17%); mp 73.0–74.0 o C (lit. 13a mp
71.0–72.5 o C).
1
H NMR δ 7.73 (s, 1H), 2.89 (s, 3H).
13
C NMR δ 156.7, 148.2, 136.2, 106.7, 14.4.
Anal Calcd for C5H4N2O5: C, 34.90; H, 2.34; N, 16.28.
Found: C, 35.20; H, 2.22; N, 15.97.
2-Ethyl-3,5-dinitrofuran (8b)
Yellowish oil (24%).
1
H NMR δ 7.72 (s, 1H), 3.28 (q, J = 7.6 Hz, 2H), 1.43 (t,
J = 7.6 Hz, 3H).
13
C NMR δ 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-(n-Butyl)-3,5-dinitrofuran (8c) obtained by nitration
of 7c with concentrated HNO3
Yellowish oil (7%).
1
H NMR δ 7.72 (s, 1H), 3.24 (t, J = 7.8 Hz, 2H), 1.81
(quintet, J = 7.7 Hz, 2H), 1.46 (sextet, J = 7.6 Hz, 2H),
0.99 (t, J = 7.3 Hz, 3H).
13
C NMR δ 160.7, 148.2, 135.6, 106.7, 29.0, 27.7, 22.3,
13.5.
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-2,5,5-trinitro-2,5-dihydrofuran (9a)
Yellow oil (29%).
1
H NMR δ 6.93 (d, J = 5.6 Hz, 1H), 6.79 (d, J = 5.8 Hz,
1H), 2.25 (s, 3H).
13
C NMR δ 139.9, 128.7, 127.0, 120.9, 21.6.
Anal. Calcd for C5H5N3O7: C, 27.41; H, 2.30; N, 19.18.
Found: C, 27.80; H, 2.09; N, 18.65.
2-Ethyl-2,5,5-trinitro-2,5-dihydrofuran (9b)
Yellowish oil (30%).
1
H NMR δ 6.88 (d, J = 5.6 Hz, 1H), 6.70 (d, J = 5.8 Hz,
1H), 2.57 (dq, J = 16.2, 7.5 Hz, 1H), 2.40 (dq, J = 16.2,
7.5 Hz, 1H), 1.05 (t, J = 7.5 Hz, 3H).
13
C NMR δ 139.4, 128.7, 126.9, 124.2, 28.5, 7.1.
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 twosteps
(method i)
2-Methyl-5-nitrothiophene 11a
2-Methylthiophene 10a (0.982 g, 10 mmol) in acetic
anhydride (5 g, 49 mmol) was added to a mixture of
acetic anhydride (5 g, 49 mmol) and fuming nitric acid
(0.82 g, 13 mmol) at -30 o C for 3 h. The reaction mixture
was stirred for 12 h at room temperature, poured onto ice
and neutralized with saturated sodium bicarbonate solution.
The product was extracted with methylene chloride,
the organic phase was dried over anhydrous sodium
sulfate and the solvent was removed under reduced pressure.
The residue was purified by silica gel column using
5% ethyl acetate in hexanes as an eluent to give (0.839 g,
59%) of 2-methyl-5-nitrothiophene 11a as brownish
microcrystals. NMR data and mp of 11a are in agreement
with those for authentic sample obtained by
method iii.
2-Methyl-3,5-dinitrothiophene 12a
2-Methyl-5-nitrothiophene 11a (0.5 g, 3.5 mmol) was
added to a mixture of acetic anhydride (0.39 g, 3.84
mmol) and fuming nitric acid (0.24 g, 3.84 mmol) at -30
o
C and the whole was stirred at room temperature for 15
h. The reaction mixture was poured onto ice. The solid
was filtered, washed with saturated solution of sodium
bicarbonate and water to give 2-methyl-3,5dinitrothiophene
12a (0.4 g, 60 %) as a yellow microcrystals.
NMR data and mp of 12a are in agreement with
those for authentic sample obtained by method iii.
Nitration of 2-alkylthiophenes 10a,b with excess of
acetyl nitrate; General procedure (method ii and iii)
Fuming nitric acid (1.25 mL, 27.2 mmol, method ii) or
(2.05 mL, 44.6 mmol, method iii) was added to acetic
anhydride (7.5 mL, 79.5 mmol) at temperature below -10
o
C. After 0.5 h the acetyl nitrate was cooled to -40÷-45
o
C and a solution of 2-alkylthiophene (8.9 mmol) in
acetic anhydride (7.5 mL) was slowly added, while
maintaining the temperature below -40 o C. When the
addition was complete, the reaction was allowed to stir at
this temperature for an additional 5 h and at room temperature
for 12 h. Then the reaction mixture was poured
onto ice, and the whole was neutralized to pH 7 by the
slow addition of a sodium bicarbonate below 5 o C. The
solid was filtered and washed with ethyl acetate. The
products were extracted from the filtrate with ethyl acetate,
the combined organic phase was dried over MgSO4
and filtered. Solvent was evaporated under reduced pressure
and the residue was chromatographed on silica gel
using hexanes/ethyl acetate (v/v=8:1) to elute the prod-

704
ucts in the order 2-alkyl-5-nitrothiophene 11, 2-alkyl-
3,5-dinitrothiophene 12 and 2-alkyl-5-nitrothiophene 1oxide
13.
2-Methyl-5-nitrothiophene (11a), method iii
Brownish prisms (12%), mp 25.0–27.0 o C (Lit. 24a mp
25.0–27.0 o C).
1 H NMR δ 7.76 (d, J = 4.1 Hz, 1H), 6.76 (dd, J = 4.1,
0.9 Hz, 1H) 2.55 (s, 3H).
13 C NMR δ 149.4, 149.2, 129.1, 125.5, 16.2.
2-Ethyl-5-nitrothiophene (11b), method iii
Yellow oil (11%), (Lit. 52 no NMR data or bp were reported).
1 H NMR δ 7.78 (d, J = 4.1 Hz, 1H), 6.78 (d, J = 4.1 Hz,
1H), 2.89 (q, J = 7.6 Hz, 2H), 1.36 (t, J = 7.6 Hz, 3H).
13 C NMR δ 156.8, 149.3, 129.0, 123.7, 24.2, 15.3.
Anal. Calcd for C6H7NO2S: C, 45.85; H, 4.49; N, 8.91.
Found: C, 45.88; H, 4.45; N, 9.11.
2-Methyl-3,5-dinitrothiophene (12a), method iii
Yellow microcrystals (67%), mp 97.0–99.0 o C (Lit. 24a
mp 99.0–100.0 o C).
1 H NMR δ 8.35 (s, 1H), 2.91 (s, 3H).
13 C NMR δ 149.4, 145.3, 142.2, 124.3, 16.2.
2-Ethyl-3,5-dinitrothiophene (12b), method iii
Yellow oil (70%), (Lit. 53 163–165/9 mm).
1
H NMR δ 8.36 (s, 1H), 3.39 (q, J = 7.5 Hz, 2H), 1.48 (t,
J = 7.5 Hz, 3H).
13
C NMR δ 157.4, 145.4, 141.3, 124.5, 23.8, 13.8.
Anal. Calcd for C6H6N2O4S: C, 35.64; H, 2.99; N, 13.86.
Found: C, 35.82; H, 2.83; N, 13.57.
2-Methyl-5-nitrothiophene 1-oxide (13a), method iii
Brownish oil (10%).
1
H NMR δ 7.56 (d, J = 6.2 Hz, 1H), 6.42 (d, J = 6.2 Hz,
1H), 2.29 (s, 1H).
13
C NMR δ 193.7, 152.6, 133.0, 100.2, 26.0.
Anal Calcd for C5H5NO3S: C, 37.73; H, 3.17; N, 8.80.
Found: C, 38.07; H, 3.18; N, 8.75.
IR (Firm, cm -1 ): 3081, 2934, 2872, 1706, 1556, 1443,
1383, 1340, 1051 (S=O).
2-Ethyl-5-nitrothiophene 1-oxide (13b), method iii
Brownish oil (8%).
1 H NMR δ 7.59 (d, J = 6.2 Hz, 1H), 6.40 (d, J = 6.2 Hz,
1H), 2.58 (dq, J = 7.0, 14.3 Hz, 2H), 1.12 (t, J = 7.3 Hz,
3H).
13 C NMR δ 193. 7, 151.5, 133.2, 105.9, 32.5, 9.1.
Anal Calcd for C6H7NO3S: C, 41.61; H, 4.07; N, 8.09.
Found: C, 41.61; H, 3.91; N, 8.35.
IR (Firm, cm -1 ): 3083, 2941, 2882, 1714, 1555, 1458,
1351, 1326, 1058 (S=O).
2-Nitrothiazoles 15a,b; General Procedure
2-Aminothiazole 14a,b (33 mmol) was dissolved in a
solution of 100 mL of water and 20 g of fluoroboric acid
solution (42%). This solution was cooled to 4 o C and
maintained at this temperature with an ice-water bath
during the addition of 2.3 g (33 mmol) of sodium nitrite
dissolved in 10 mL of water. The sodium nitrite solution
was added to the amine solution, using moderate stirring.
The diazotization required 20 min. At the end of diazotization,
the reaction mixture was added immediately to a
boiling solution of 25 g of sodium nitrite in 100 mL of
water containing 5 g of copper powder and the whole
was stirred for 0.5 h at this temperature. After cooling,
the product was extracted with ether, the organic layer
was dried over MgSO4, and the solvent was evaporated
under reduced pressure. Residue was recrystallized from
hexanes to give 2-nitrothiazoles 15a,b.
2-Nitrothiazole (15a)
Brown needles from hexanes (28%); mp 77–78 o C (lit. 54
mp 77–78 o C).
1
H NMR δ 7.92 (d, J = 3.2 Hz, 1H), 7.72 (d, J = 3.2 Hz,
1H).
13
C NMR δ 166.6, 142.5, 127.1.
2-Nitro-5-methylthiazole (15b)
Yellow needles (21%) mp 60–61 o C (lit. 55 mp 60–61 o C).
1
H NMR δ 7.58 (d, J = 1.0 Hz, 1H), 2.61 (d, J = 1.0 Hz,
3H).
13
C NMR δ 163.7, 145.0, 140.7, 12.4.
Anal Calcd for C4H4N2O2S: C, 33.33; H, 2.80; N, 19.43.
Found: C, 33.68; H, 2.64; N, 19.27.
2,4-Dinitrothiazoles 16a,b; General Procedure
Trifluoroacetic anhydride (2.5 g, 12 mmol) was added to
solution of ammonium nitrate (0.67 g, 12 mmol) in
trifluoroacetic acid (2.8 mL) at 0-5 o C. The reaction
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 ÷ +5 o C. After addition, the reaction
temperature was kept at 25 o C for 20 h, and then at 70–
80 o C for 1–4 h. The cooled reaction mixture was poured
into ice water and the precipitated solid was filtered and
washed with water to give 2,4-dinitrothiazole 16a,b. An
analytical sample was recrystallized from benzene.
2,4-Dinitrothiazole (16a)
Yellow needles (34%); mp 144–146 o C (lit. 30 mp 145.5–
146.5 o C).
1
H NMR (acetone-d6) δ 9.14 (s, 1H).
13
C NMR δ 164.5, 152.3, 129.8.
5-Methyl-2,4-dinitrothiazole (16b)
Yellowish prisms (91%); mp 130–131 o C.
1
H NMR δ 3.00 (s, 3H).
13
C NMR δ 158.2, 148.7, 145.7, 14.3.
Anal Calcd for C4H3N3O4S: C, 25.40; H, 1.60; N, 22.22.
Found: C, 25.72; H, 1.27; N, 21.82.

705
5-Amino-3-methyl-4-nitro-1H-pyrazoles (19a−c);
General Procedure
Hydrazine (7.81 mmol) was added to a solution of 5methyl-4-nitroisoxazole
18 (1.0 g, 7.81 mmol) in ethanol
(20 mL) at -5 o C and the mixture was stirred for 1.0 h,
heated under reflux for 15 h and concentrated to 5.0 mL
under reduced pressure. The solid was filtered and dried
to give 5-amino-3-methyl-4-nitro-1H-pyrazole 19a−c as
yellow microcrystals.
5-Amino-3-methyl-4-nitro-1H-pyrazole (19a)
Yellow microcrystals (87%); mp 206–208 o C (lit. 37 mp
206–207 o C).
1
H NMR (DMSO-d6) δ 11.96 (br s, 1H), 7.18 (br s, 2H),
2.31 (s, 3H).
13
C NMR (DMSO-d6) δ 148.0, 143.8, 116.3, 14.5.
5-Amino-1,3-dimethyl-4-nitro-1H-pyrazole (19b)
Yellow microcrystals (86%); mp 134–136 o C (lit. 37 mp
135–136 o C).
1
H NMR (DMSO-d6) δ 7.33 (s, 2H), 3.51 (s, 3H), 2.29
(s, 3H).
13
C NMR (DMSO-d6) δ 146.6, 143.0, 116.0, 34.3, 14.1.
5-Amino-3-methyl-4-nitro-1-phenyl-1H-pyrazole
(19c)
Yellow microcrystals (81%); mp 170–172 o C (lit. 37 mp
170–172 o C).
1
H NMR (DMSO-d6) δ 7.56–7.45 (m, 5H), 7.43 (br s,
2H), 2.40 (s, 3H).
13
C NMR (DMSO-d6) δ 146.2, 144.9, 136.8, 129.5,
128.2, 124.4, 116.6, 14.4.
Anal Calcd for C10H10N4O2: C, 55.04; H, 4.62; N, 25.67.
Found: C, 55.38; H, 4.51; N, 25.62.
3-Methyl-4,5-dinitro-1H-pyrazoles (20); General Procedure
Hydrogen peroxide (50%, 0.5 mL) was added dropwise
to a solution of 5-amino-3-methyl-4-nitropyrazole 19a−c
(0.6 mmol) in concentrated sulfuric acid (1.0 mL) at 0 o C
and stirred for 15 min. Additional hydrogen peroxide
(1.50 mL) was slowly added to the reaction mixture at 0
o
C and then stirred at room temperature for 15 h. The
reaction mixture was poured onto ice and extracted with
ethyl acetate. The combined organic phases were washed
with water, then saturated sodium chloride solution and
dried over anhydrous magnesium sulfate. 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 c as yellow microcrystals.
The crude product from 19a was dissolved in acetone
(5 mL), potassium carbonate (0.35 g) was added to
the solution and the mixture was stirred at room temperature
for 8 h. The solid was filtered, washed with
acetone and the filtrate concentrated under reduced pressure.
The residue was purified by recrystallization from
ethanol to give 3-methyl-4,5-dinitro-1H-pyrazole potassium
salt 20a.
3-Methyl-4,5-dinitro-1H-pyrazole potassium salt
(20a)
Yellow microcrystals (40%); mp 187.0–189.0 o C.
1
H NMR (DMSO-d6) δ 2.34 (s, 3H).
13
C NMR (DMSO-d6) δ 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.
1,3-Dimethyl-4,5-dinitro-1H-pyrazole (20b)
Yellow microcrystals (81%); mp 34–36 o C.
1
H NMR (DMSO-d6) δ 4.12 (s, 3H), 2.48 (s, 3H).
13
C NMR (DMSO-d6) δ 145.0, 141.5, 126.9, 39.9, 13.1.
Anal Calcd for C5H6N4O4: C, 32.27; H, 3.25; N, 30.10.
Found: C, 32.46; H, 3.09; N, 29.82.
3-Methyl-4,5-dinitro-1-phenyl-1H-pyrazole (20c)
Yellow microcrystals (52%); mp 80–82 o C.
1 H NMR (acetone-d6) δ 7.64 (br, s, 5H), 2.61 (s, 3H).
13 C NMR (acetone-d6) δ 146.6, 141.8, 137.1, 131.8,
131.0, 126.8, 125.4, 13.7.
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); General
Procedure
The appropriate alkylhydrazine (59.5 mmol) was added
dropwise to water (50 mL) at 10-20 °C, followed by
concentrated nitric acid (7. 65 mL, 10.86 g, 119 mmol)
also added dropwise over 15 min at temperature below
20 o C. The mixture was stirred at 20 o C for 15 min. Dicyandiamide
21 (5 g, 59.5 mmol) was added to the reaction
mixture at 20 o C and the whole stirred at 50–55 °C
for 5 h. Then 35 mL of 2.5 M sulfuric acid (prepared by
the addition of 4.75 mL concentrated sulfuric acid to
30.25 mL of water) was added at 20 o C. The resulting
solution was added dropwise (within 1.15 to 1.30 h) to a
solution of sodium nitrite (41.0 g, 595 mmol) in water
(100 mL) with rigorous stirring at 50 °C, followed by
80% sulfuric acid (10 mL), dropwise at 50 o C. The mixture
was heated under reflux for 15 min and cooled to
10–15 o C. The product was extracted immediately with
ethyl acetate (5 x 100 mL). The combined extracts were
washed with saturated sodium bicarbonate solution (1 x
20 mL), then with saturated sodium chloride solution (2
x 50 mL) and dried over magnesium sulfate (10 g). Solvent
was removed at 20–30 mm, 40–50 o C to give 6.0 g
of a brown oil. Chloroform (70 mL) was added to this oil
and evaporated at 20–30 mm again to eliminate ethyl
acetate. The residue was stirred in chloroform (100 mL)
for 0.5 h at 20 o C, the mixture was filtered, and the solvent
was evaporated at 20–30 mm, 40–50 o C. The solid
was recrystallized from chloroform or chromatographed
on silica gel chromatography to give pure 1-alkyl-3,5dinitro-1H-[1,2,4]triazole
22a,b.
1-Methyl-3,5-dinitro-1H-[1,2,4]triazole (22a)
Yellow prisms (43%); mp 97–99 o C (lit. 46a,47 mp 97–98.5
o C).

706
1 H NMR (DMSO-d6) δ 4.30 (s, 3H).
13 C NMR (DMSO-d6) δ 156.4, 151.0, 41.4.
Anal Calcd for C3H3N5O4: C, 20.82; H, 1.75; N, 40.46.
Found: C, 21.15; H, 1.60; N, 40.29.
1-Ethyl-3,5-dinitro-1H-[1,2,4]triazole (22b)
Yellow microcrystals (23%); mp 77.0–78.0 o C (lit. 46a mp
78.0 o C).
1
H NMR δ 4.85 (q, J = 7.3 Hz, 2H), 1.70 (t, J = 7.3 Hz,
3H).
13
C NMR δ 157.8, 150.2, 14.6.
1-Methyl-3-azido-5-nitro-1H-[1,2,4]triazole (23a)
Yellowish microcrystals (7%); mp 21.0–23.0 o C.
1 H NMR δ 4.25 (s, 3H).
13 C NMR δ 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
manuscript. We also wish to thank Dr. James W. Rogers (University
of Florida) for help in development of method for synthesis of
dinitrothiophenes.
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1947, 30, 1200.

708
O 2 N
O
S
R 1
R 1
X=S, Y=Z=C,
R 1 =Me, Et; R 2 =H
f. HNO 3 , AcOH
70-75 o C, 8 h
Graphical Abstract
O 2 N
O 2 N
R 2
N
NH 4 NO 3 , TFAA,
0-5 o C
AcNO2 ,
-40-45 oC X=O, Y=Z=C,
R 1 =Me, Et; R 2 =H
z
S
X
R
Y
R 1
X=S, Y=C, Z=N,
R 1 =H, CH 3
NO 2 (CH 3 )
R 1
H 2 O 2 , H 2 SO 4 ,
0-25 o C, 16h
X=Y=Z=N,
R=Me, Et
N
H 2
N
H 2
O 2 N
X=Y=N, Z=C,
R=Me, Ph; R 2 =NO 2
i) RNHNH 2 , HNO 3
ii) NaNO 2 , H 2 SO 4
NH 2
N N
R
N CN
CH 3