Thiocyanation, halogenation, dehalogenation, transhalogenation, and nitration of 2-substituted 4-(2-furyl)thiazoles

Article abstract of DOI:10.1023/A:1020602308595

Bromination and thiocyanation of 2-amino- and 2-acetylamino-4-(2-furyl)thiazoles when 1 mol of reagent is used at 10°C are directed to the 5 position. Formation of 5′-bromo-substituted derivatives when the reaction temperature is raised is the result of a secondary, thermodynamically controlled process. Monohalogenation and mononitration of 4-(2-furyl)-2-methylthiazole are directed to the 5′ position. Nitration of 2-acetylamino-4-(5-nitro-2-furyl)thiazole by a nitrating mixture is accompanied by oxidative cleavage of the 5-nitrofuran moiety and leads to formation of 5,5′- and 3′,5′-dinitro derivatives.

Full text of DOI:10.1023/A:1020602308595

Chemistry of Heterocyclic Compounds, Vol. 38, No. 7, 2002
THIOCYANATION, HALOGENATION,
DEHALOGENATION, TRANSHALOGENATION,
AND NITRATION OF 2-SUBSTITUTED
4-(2-FURYL)THIAZOLES
N. O. Saldabol, J. Popelis, and V. Slavinska
Bromination and thiocyanation of 2-amino- and 2-acetylamino-4-(2-furyl)thiazoles when 1 mol of
reagent is used at 10°C are directed to the 5 position. Formation of 5'-bromo-substituted derivatives
when the reaction temperature is raised is the result of a secondary, thermodynamically controlled
process. Monohalogenation and mononitration of 4-(2-furyl)-2-methylthiazole are directed to the
5' position. Nitration of 2-acetylamino-4-(5-nitro-2-furyl)thiazole by a nitrating mixture is accompanied
by oxidative cleavage of the 5-nitrofuran moiety and leads to formation of 5,5'- and 3',5'-dinitro
derivatives.
Keywords: 2-R-4-(2-furyl)thiazoles (R = NH2, NHAc, Me), bromination, iodination, nitration, oxidative
cleavage of 5-nitro-2-furyl group, transbromination, thiocyanation.
It was shown earlier that 4-(2-furyl)thiazoles with electron-donor groups in the position 2 of the thiazole
ring form 5,5'-dibromo-substituted derivatives upon bromination [1]. Thiocyanation products of 2-amino- and
2-acetamino-4-(2-furyl)thiazoles were assigned the structure of the 5-thiocyano derivative substituted on the
thiazole ring [2]. However, as was demonstrated by 1H NMR spectra, treating the same compounds with 1 mol
of bromine in an acetic acid medium at 40-65°C and also holding the reaction mixture at room temperature for
many hours leads to the 5'-bromo derivative substituted on the furyl group [1]. Moreover, according to data in
[3], treatment of the thienyl analogs of the above-indicated heterocycles with 1 mol of bromine leads to
substitution at the thiazole ring.
The aim of this work was to refine the reactivity with respect to electrophilic substitution for furan and
thiazole rings in 2-amino- (1a), 2-acetylamino- (1b), and 2-methyl-4-(2-furyl)thiazoles (1c).
We found that thiocyanation of compounds 1a,b upon treatment with 1 mol of dithiocyanogen in fact
1
leads to the 5-thiocyano derivatives substituted on the thiazole ring 2a,b, which was confirmed by H NMR
spectra. Monosubstitution is highly selective; the yields of monothiocyano-substituted derivatives are almost
quantitative. When we use 2 mol of dithiocyanogen, subsequent substitution occurs at the position 5' of the furyl
group, but the reaction proceeds slowly, competing with polymerization of the dithiocyanogen. Complete
conversion of compounds 1a,b to the 5,5'-substituted 5a,b occurs only when we use 4-5 mol of dithiocyanogen.
The thiocyano group in compounds 2b, 5b is not exchanged for the nitro group upon heating with NaNO2 in
acetic acid but remains unchanged, in contrast to the 5,5'-dibromo analog [4].
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: dzsile@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 983-991, July, 2002. Original article submitted February 28, 2001.
0009-3122/02/3807-0873$27.00©2002 Plenum Publishing Corporation
873

O
O
A–D
N
N
R
R
X
S
S
2a,b 3a,b 4b
1a,b
Br2–AcOH
< 20oC
X = Br
8–12oC
E
A'–D'
R = NH2
X
Br
O
O
E'
N
N
R
X = Br
R = NH2
R
X
S
S
8a,b
5a,b; 6a,b; 7b
2a,b, 5a,b X = SCN; 3a,b, 6a,b X = Br; 4b, 7b X = I; 1–3, 5, 6, 8a R = NH2; 1–8 b R = NHAc
A (SCN)2–AcOH, B Br2–AcOH, ~10°C, C NBS–AcOH, D 2I2–DMSO,
E 1HBr–AcOH, 100°C; A' 4(SCN)2–AcOH, B' 2Br2–AcOH, C' 2NBS–AcOH,
D' 3I2–DMSO, E' 2HBr–AcOH, 100°C
Since 2-amino-5-bromo(iodo)-4-methylthiazoles are easily dehalogenated [5], the question arose about
whether monobromination products of compounds 1a,b substituted at the position 5' of the furan moiety (8a,b),
described in [1], are products of a secondary reaction.
We found that when compounds 1a,b are treated with 1 mol of bromine in acetic acid at a temperature
of 8-12°C, judging from the 1H NMR spectrum, the products formed are ~80% 5-bromo derivatives substituted
on the thiazole ring 3a,b and ~10% dibromo-substituted derivatives 6a,b. When the reaction temperature is
raised to 20°C, compounds 8a,b also appear.
From this it follows that the kinetically controlled process leads to substitution on the thiazole ring,
while transhalogenation is a thermodynamically more favorable secondary process. This is confirmed
experimentally. Thus when heated for 1 h on a steam bath with 1 mole of hydrobromic acid in glacial acetic acid
medium, 5-bromothiazole 3a is 90% converted to 5'-bromofurylthiazole 8a, while when treated with 2 mol of
hydrobromic acid, 5,5'-dibromofurylthiazole 6a is 70% converted to the same compound 8a.
The 5-bromofurylthiazoles 3a,b are obtained in purer form when compounds 1a,b are treated with 1 mol
N-bromosuccinimide (method C), since strong acids are not isolated in the reaction. But even in this case, the
products contain ~5% dibromo-substituted 6a,b.
Amine 1a, when reacted with 2 moles of iodine in DMSO, forms a stable liquid complex and only traces
1
of 5-iodofurylthiazole 4a (according to the H NMR spectrum). With 3 mol of iodine and a prolonged reaction
time (10 days) followed by treatment with Na2S2O3 and NaOH, from amine 1a we obtained a mixture of 5-iodo-
substituted 4a, 5,5'-diiodo-substituted 7a, and the sodium salt of 3-(2-amino-5-iodo-4-thiazoloyl)acrylic acid 9
in 6:1:4 ratio (according to the 1H NMR spectrum). The acid 9 is the product of oxidative cleavage by iodine of
the 5-iodo-2-furyl group in the 5,5'-diiodo derivative 7a. Although iodine is a weak oxidizing agent, in this case
the exposure time to it was prolonged. Such cleavage has already been observed for 2-(5-bromo-2-furyl)- and
2-(5-nitro-2-furyl)imidazo[1,2-a]pyridines [4, 6]. In the 1H NMR spectrum of acid 9, we observe 2 doublets
with chemical shifts δ 6.90 ppm and 8.0 ppm (J = 16 Hz), i.e., in regions characteristic for the resonance of
protons of the trans vinyl group in HetCOCH=CHCOOH [4, 6].
874

2I2–DMSO
Na2S2O3
.
1a
1a
2I2
3I2–DMSO
10 days, 20°C
H
I
O
I2
HOOCC=CCO
O
N
N
N
[O]
H
I
NH2
I
NH2
S
NH2
I
S
S
4a
7a
9
O2N
O2N
O
O
1) 2I2–DMSO
2) Na2S2O3
N
N
NH2
I
NH2
S
S
11
10
Iodination of amide 1b using 2 mol of iodine in DMSO for 30 min goes to completion, and leads to
formation of 5-iodothiazole 4b and 10% 5,5'-diiodo derivative 7b. Since the HI isolated in the reaction is
oxidized by DMSO to I2, we do not see transiodination from the position 5 to the position 5' in the case of
compound 4b or deiodination in the case of the diiodo-substituted derivative 7b at the position 5. 2-Amino-4-(5-
nitro-2-furyl)thiazole (10) is easily iodized in the presence of 2 mol of iodine, forming the 5-iodo derivative 11.
2-Methyl-4-(2-furyl)thiazole (1c) is halogenated only in the position 5' of the furan moiety when treated
with 1 mol of reagent. Upon iodination of heterocycle 1c using 2 mol of iodine in DMSO, we note only further
partial iodination of the methyl group of the compound.
X
O
O
B–D, F
N
N
Me
Me
S
S
12–14
1c
B D (see Scheme 1), F – N-chlorosuccinimide AcOH
−
−
12 X = Br, 13 X = I, 14 X = Cl
In contrast to the reactions of thiocyanation and halogenation of compound 1b, occurring at 8-12°C on
the thiazole ring upon reaction with 1 mol of reagent, its nitration with 1 mol of 70% HNO3 in a mixture of
conc. H2SO4 and glacial acetic acid (or in just H2SO4) leads to the 5'-nitro derivative substituted on the furan
ring 15b in 85-90% yield, i.e., without involving the thiazole ring, since nitration of 2-acetylamino-4-
phenylthiazole is directed to the para position of the phenyl substituent [7].
875

TABLE 1. Characteristics of Synthesized Compounds
Found, %
——————
Com-
pound
Empirical
formula
Yield, %
(method)
Calculated, %
mp, °С
C
H
N
C8H5N3OS2
43.22
43.03
2.01
2.26
19.05
18.82
184-185
99 (A)
98 (A)
2а
C10H7N3O2S2
C7H5BrN2OS
45.03
2.40
15.63
219-220
140-142
2b
3a
45.27
34.14
34.31
2.66
2.18
2.06
15.84
11.56
11.43
75 (B)
80 (C)
80 (C)
C9H7BrN2O2S
C7H5IN2OS
C9H7IN2O2S
C9H4N4OS3
C11H6N4O2S3
37.41
2.38
9.50
218-220
167-170
227-230
183-185
3b
37.65
2.46
9.76
29.03
28.78
1.60
1.73
9.30
9.59
60
4a
32.34
1.81
8.22
87 (D)
4b
32.35
2.11
8.38
5a*
5b*
38.68
38.56
1.56
1.44
19.71
19.99
40.60
1.60
17.70
> 250
(dec.)
40.98
1.88
17.38
6a*
6b
C7H4Br2N2OS
C9H6Br2N2O2S
C9H6I2N2O2S
C7H5BrN2OS
25.71
25.95
1.11
1.24
8.42
8.65
138-139
225-226
228-231
88 (C')
95 (C')
98 (D')
29.37
1.61
7.47
29.53
1.65
7.65
24.00
23.50
1.59
1.32
6.03
6.09
7b
8a*
34.15
2.03
11.63
163-164
[1]
90 (E)
70 (E')
34.30
2.06
11.43
C7H4IN3O3S
C8H6BrNOS
25.35
24.94
1.03
1.19
12.80
12.46
280
90-95
11
12
(dec.)
39.02
2.20
5.63
74-75 [4]
91 (B)
90 (C)
39.36
2.48
5.74
C8H6INOS
C8H6ClNOS
C9H7N3O4S
32.73
33.01
1.90
2.08
4.48
4.81
84-87
65-68
92 (D)
88 (E)
85-90
13
14*
15b
47.81
3.27
7.15
48.13
42.42
42.69
3.03
2.80
2.79
7.02
16.53
16.59
295-296
(dec.) [8]
C8H6N2O3S
45.43
2.68
13.60
142-143
65
15c
45.71
2.88
13.32
[8]
C9H6N4O6S
C9H6N4O6S
35.98
36.25
2.14
2.03
18.48
18.79
287-288
40
13
16b
17b
36.13
2.02
18.53
220
36.25
2.03
18.79
(dec.)
18b*2 C9H8N2O4S
44.61
45.00
3.23
3.36
11.48
11.66
> 300
14
_______
* Compound 14 was purified by vacuum sublimation, 5a,b was purified by
crystallization from aqueous DMF, 6a and 8a from AcOH, the rest from
EtOH or dilute EtOH.
*2 IR spectrum (vaseline oil), ν, cm-1: 1695 (COOH), 1680 (C=O), 980
(trans-CH=CH).
4-(2-Furyl)-2-methylthiazole 1c is nitrated similarly. The yield of the 5'-nitro derivative is 65%, i.e., the
same as described earlier for nitration of this compound in acetic anhydride [8].
876

O2N
O
HNO3
N
1b,c
H2SO4–AcOH
5–10oC
R
S
15b,c
H2SO4, 3–4oC
2HNO3
NO2
N
O2N
O2N
O
H
HOOCC=CC
H
O
O
N
N
R
S
R
NHAc
O2N
S
S
16b,c
17b,c
18b
15–17 b R = NHAc, c R = Me
Nitration of phenylazoles, in particular 2-, 4-, and 5-phenylthiazoles [9] and phenylpyrazole [10], when
treated with 1 mol of HNO3 in conc. H2SO4 medium, which is directed to the para position of the phenyl
substituent and not to the heterocycle, is explained by the fact that the indicated compounds do not react in the
form of the base but rather as the "conjugate acid" (i.e., in the protonated form). However, in the case of
2-(2-furyl)imidazo[1,2-a]pyridine, it was established earlier that "dissolution" in conc. H2SO4 is accompanied by
formation of 3,5'-disulfonic acids. Further addition of HNO3 leads to the nitrodesulfonation product [6]. In our
case, the 1H NMR spectrum of the solution of compound 1b in conc. H2SO4 did not give a clear idea of the site
and degree of sulfonation.
Further introduction of a nitro group into the 5'-nitro compound 15b is hindered. Therefore the reaction
of compound 15b with 1 mol of HNO3 in conc. H2SO4 does not go to completion, but according to TLC and the
1H NMR spectrum, treatment with 2 mol HNO3 leads to three products (16b-18b) in 3:1:1 ratio. The same
products are obtained upon reaction of compound 1b with 3 mol of HNO3. The products were separated using
preparative chromatography. In addition to the expected 5,5'-dinitro-substituted 16b, prepared previously from
5,5'-dibromo-substituted 6b and NaNO2 in acetic acid [4], we obtained the 3',5'-dinitro derivative substituted at
the furyl group 17b and the product of oxidative cleavage of the nitrofuryl group in compound 15b: trans-3-(2-
acetylamino-4-thiazoloyl)acrylic acid 18b. Formation of the 3,5-dinitrofuryl-substituted derivatives was noted
earlier only upon nitration of some 2-(2-heterylvinyl)furans (Het = 2-amino-4-thiazolyl [11], 2-imidazo[1,2-a]-
pyridinyl [6]). Oxidative cleavage of the nitrofuryl group was accompanied by further nitration of 2-(5-nitro-2-
furyl)-substituted imidazo[1,2-a]pyridine [6] and imidazo[1,2-a]pyrimidine [12].
Further nitration of methylthiazole 15c with 1.1 mol of HNO3 led to 5,5'- and 3',5'-dinitro-substituted
16c, 17c (1:3) with total yield 9% (according to the 1H NMR spectrum). The major products were the products
of exhaustive oxidation, which could not be separated. Due to the small amounts of the dinitro derivatives, only
the 1H NMR spectra were determined.
877

TABLE 2. 1H NMR Spectra of Substituted 4-(2-Furyl)thiazoles
δ
Chemical shifts, , ppm*
Com-
Furyl group
pound
H-5
Other protons
H-3'
H-4'
H-5'
—
—
6.89
7.00
6.77
6.85
6.85
6.95
7.11
7.19
6.89
6.93
6.85
6.85
6.62
6.69
6.81
6.77
6.88
7.05
7.16
7.85
7.71
—
6.60
6.68
6.57
6.57
6.63
6.64
7.33
7.38
6.71
6.74
6.63
7.03
6.65
6.70
6.69
6.72
6.60
7.78
7.85
7.84
7.87
7.82
7.90
7.83
7.76
7.76
7.81
—
—
—
—
—
—
—
—
—
—
7.8 (2Н, br. s, NH2)
2.17 (3H, s, Me); 12.75 (1H, s, NH)
7.3 (2Н, br. s, NH2)
2.10 (3H, s, Me); 12.50 (1H, s, NH)
4.5 (2Н, br. s, NH2)
2.13 (3H, s, Me); 12.56 (1H, s, NH)
7.18 (2Н, br. s, NH2)
2.07 (3H, s, Me); 12.93 (1H, s, NH)
7.10 (2Н, br. s, NH2)
2.16 (3H, s, Me); 12.66 (1H, s, NH)
7.1 (2Н, br. s, NH2)
2.13 (3H, s, Me); 12.60 (1H, s, NH)
7.16 (2Н, br. s, NH2)
2.15 (3H, s, Me); 12.36 (1H, s, NH)
2.69 (3Н, s, Me)
2.69 (3Н, s, Me)
2.70 (3Н, s, Me)
2.03 (3H, s, Me); 12.55 (1H, s, NH)
2.77 (3Н, s, Me)
2.26 (3H, s, Me); 13.22 (1H, s, NH)
2.77 (3Н, s, Me)
2a
2b
3a
3b
4a
4b
5a
5b
6a
6b
7a
7b
8a
8b
12
13
14
15b
15c
16b
16c
17b
—
—
—
—
—
—
—
—
—
—
6.78
7.36
7.68
7.65
7.68
7.82
8.13
—
—
—
—
—
—
—
8.46 s
8.56 s
2.18 (3H, s, Me); 12.74 (1H, s, NH)
(8.56)
(8.46)
8.46 s
(8.79)
8.79 s
(8.46)
2.75 (3Н, s, Me)
17c
18b
8.29
—
—
—
2.17 (3H, s, Me); 6.76 and 7.93 (each 1H, 2d,
trans-CH=CH)*2; 12.50 (1H, s, NH)
_______
* Signals for 2-substituted furan: H-3, dd; H-4, q; H-5, dd; J(3-4) = 3.6-3.8,
J(3-5) = 0.9, J(4-5) = 1.7-1.8 Hz; 2,5-disubstituted furan – 2d, J(3-4) =
3.6-4.0 Hz.
*2 J = 16. Hz.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker WH-90/DS (90 MHz) in DMSO-d6, internal standard
TMS; the IR spectra were recorded on a Perkin-Elmer 580 B in vaseline oil. TLC was performed on Silufol
UV-254 (visualization in UV light) in the system benzene–ethylacetate, 3:1; the Rf values increase in the order:
starting compound < 5'-substituted derivative < 5-substituted derivative < 5,5'-disubstituted derivative. The
melting points were determined on a Boetius apparatus.
The starting compounds 1a,b were prepared based on 2-bromoacetylfuran according to the procedure in
[2], and 1c was prepared according to the procedure in [13]. N-Bromosuccinimide was purified by
crystallization from water, dried over P2O5.
2-Amino- and 2-Acetylamino-4-(2-furyl)-5-thiocyanothiazoles (2a,b). A. NH4SCN (3 g) were added
to a solution of compounds 1a,b (10 mmol) in AcOH (40 ml), and a solution of bromine (0.51 ml, 10 mmol) in
AcOH (10 ml) was added with vigorous stirring at a temperature of 8-12°C over a 20 min period; this was
878

stirred for an additional 30 min, poured over ice, and neutralized with an aqueous solution of NH4OH. The
precipitate of compounds 2a,b was filtered out and washed with water.
2-Amino- and 2-Acetylamino-5-thiocyano-4-(5-thiocyano-2-furyl)thiazoles (5a,b). A'. Obtained
similarly to method A, from compounds 1a,b (10 mmol) in AcOH (150 ml), NH4SCN (12 g), adding bromine
(2.1 ml, 40 mmol) in AcOH (30 ml) over a 1 h period.
2-Amino- and 2-Acetylamino-5-bromo-4-(2-furyl)thiazoles (3a,b). B. A solution of bromine
(0.51 ml, 10 mmol) in AcOH (20 ml) was added to a solution of compounds 1a,b (10 mmol) in AcOH (25 ml) at
8-12°C over a 40 min period. This was stirred for an additional 1 h at the same temperature, poured over ice,
alkalinized with an aqueous solution of NH4OH; the precipitate was filtered out. According to TLC and the
1H NMR spectrum, the crude products contain as an impurity the starting materials and the 5,5'-dibromo-
substituted derivatives.
C. NBS (1.78 g, 10 mmol) was added in very small portions to a solution of compounds 1a,b (10 mmol)
in AcOH (20 ml) at room temperature with vigorous stirring over a 30 min period. This was stirred for an
additional 30 min, diluted with ice water (100 ml), and neutralized with an aqueous solution of NaOH. The
precipitate of bromides 3a,b was filtered out, with 5% impurity of the dibromides 6a,b.
2-Amino- and 2-Acetylamino-5-bromo-4-(5-bromo-2-furyl)thiazoles (6a,b). B'. Obtained from
compounds 1a,b (10 mmol) as in method B, but using 20 mmol of bromine.
C'. Obtained from compounds 1a,b (10 mmol) as described in method C, using 20 mmol of NBS.
2-Amino-4-(2-furyl)-5-iodothiazole (4a). A solution of iodine (7.62 g, 30 mmol) in DMSO (20 ml)
was added to a solution of furylthiazole 1a (1.66 g, 10 mmol) in DMSO (20 ml), the reaction mixture was held
at room temperature for 10 days, diluted with a concentrated solution of Na2S2O3, and slightly alkalinized with
an NaOH solution. The precipitate was filtered out, washed with water, and dried. We obtained 1.9 g of a
mixture consisting of amine 4a, diiodo-substituted 7a, and compound 9. Compound 4a was separated using TLC
on a Kieselgel 60 UV-254 plate (eluent was benzene–ethylacetate, 3:1; middle fraction).
2-Acetylamino-4-(2-furyl)-5-iodothiazole (4b). D. Obtained from compound 1b and iodine (2 mol), as
described for amine 4a, holding the reaction mixture for 30 min and treating it with an Na2S2O3 solution.
2-Acetylamino-5-iodo-4-(5-iodo-2-furyl)thiazole (7b). D'. Obtained from compound 1b (10 mmol)
and iodine (30 mmol) in DMSO (50 ml), holding the reaction mixture for 20 h at room temperature. Then the
mixture was poured into water; the precipitating diiodo-substituted derivative, which precipitated as the base
and not as an iodine complex, was filtered out and washed with an Na2S2O3 solution and water.
2-Amino-4-(5-bromo-2-furyl)thiazole (8a). E. Compound 3a (0.54 g, 2.2 mmol) was heated with a
solution of 40% HBr (0.36 ml, 2.2 mmol) in AcOH (10 ml) for 1 h on a steam bath and then neutralized with an
aqueous ammonia solution; the precipitate was filtered out, washed with water, and dried. Yield of compound
1
8a 0.47 g. According to the H NMR spectrum, the reaction product contains 95% of substance 8a and
impurities of substances 1a and 6a.
E'. Obtained from dibromide 6a (0.75 g, 2.3 mmol), as described above, using 40% HBr (0.73 ml,
4.6 mmol). We obtained 0.42 g of crude aminobromothiazole 8a.
2-Amino-5-iodo-4-(5-nitro-2-furyl)thiazole (11). A solution of iodine (5.08 g, 20 mmol) in DMSO
(15 ml) was added to a solution of compound 10 (2.11 g, 10 mmol) in DMSO (30 ml). The reaction mixture was
held at room temperature in the dark for 7 days, then it was diluted with a concentrated aqueous solution of
Na2S2O3; the precipitate was filtered out, washed with water, and dried in the dark. We obtained 3.22 g of the
5-iodo-substituted derivative with traces of the starting compound.
2-Methyl-4-(5-bromo-2-furyl)thiazole (12) was obtained from compound 1c (3.3 g, 20 mmol), treating
it with brominating agent (Br2, NBS) (20 mmol) by methods B and C described above.
2-Methyl-4-(5-iodo-2-furyl)thiazole (13) was obtained from compound 1c (1.65 g, 10 mmol) and
iodine (5.08 g, 20 mmol), as described in method D. The product was extracted with ether.
879

2-Methyl-4-(5-chloro-2-furyl)thiazole (14) was obtained from compound 1c (1.65 g, 10 mmol) and
N-chlorosuccinimide (1.33 g, 10 mmol) that had been stored for a long time, similarly to bromide 3a according
to method C. The reaction product 14 was extracted with ether and purified to remove unreacted starting 1c by
vacuum distillation.
2-Acetylamino-4-(5-nitro-2-furyl)thiazole (15b). Substance 1b (2.08 g, 10 mmol) was dissolved in a
mixture of conc. H2SO4 (50 ml) and glacial acetic acid (20 ml) at 15-20°C. A mixture of 70% HNO3 (0.70 ml,
11 mmol) with conc. H2SO4 (5 ml) was added to the solution obtained over a period of 15 min at a temperature
of 5-10°C, after which stirring was continued for 30 min at 0-5°C. The reaction mixture was poured over ice
(500 g); the precipitate was filtered out and washed with water. Yield of nitro compound 15b 2.16 g. The filtrate
was alkalinized with a 40% aqueous NaOH solution until the yellow color changed to red-brown; it was held for
24 hours at room temperature, and another 0.1 g of nitro compound 15b was filtered out.
The same reaction product was obtained by adding a solution of 70% HNO3 (0.63 ml, 10 mmol) in conc.
H2SO4 (3 ml) at 2-5°C over a 10 min period to a solution of compound 1b (1.92 g, 9.2 mmol) in conc. H2SO4
(50 ml). The reaction mixture was additionally stirred for 1 h and then poured over ice (200 g); 2.06 g of nitro
compound 15b was filtered out.
2-Methyl-4-(5-nitro-2-furyl)thiazole (15c) was obtained from compound 1c (20 mmol) in a mixture of
conc. H2SO4 and glacial acetic acid, as described above. The reaction mixture was poured over ice (200 g) and
the reaction product was separated by extraction with ether.
2-Acetylamino-5-nitro-4-(5-nitro-2-furyl)thiazole (16b), 2-Acetylamino-4-(3,5-dinitro-2-furyl)-
trans
thiazole (17b) and
-3-(2-Acetylamino-4-thiazoloyl)acrylic Acid (18b).
A solution of 70% HNO (2.5 ml,
3
40 mmol) in conc. H2SO4 (10 ml) was added with vigorous stirring at a temperature of 3-4°C over a 40 min
period to a solution of compound 15b (5.06 g, 20 mmol) in conc. H2SO4 (100 ml). The reaction mixture was
stirred for an additional 2 h at the same temperature and then poured over ice (800 g); the precipitate was
filtered out, and a mixture of dinitro compound 16b and 17b (3.09 g) was obtained, with traces of acid 18b. The
mixture was separated on a Kieselgel 60 UV-254 plate in the system benzene–ethylacetate, 3:1. The compounds
were extracted with acetone from the sorbent. The upper fraction was compound 17b, the middle fraction was
16b, and acid 18b was at the starting line.
After removal of the dinitro compounds, acid 18b (0.7 g) was precipitated from the filtrate by
neutralization with a 40% NaOH solution to pH 6. In order to remove traces of the dinitro compounds,
compound 18b was recrystallized from DMF–ether.
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