Synthesis and properties of 2-(2-furyl)benzothiazole

Article abstract of DOI:10.1007/s10593-008-0156-8

The electrophilic reactions (nitration, bromination, hydroxymethylation, formylation, acylation) and radical substitution reactions (nitration, arylation) of 2-(2-furyl)benzothiazole have been studied. It was found that all of the reactions occur at position 5 of the furan ring. Only nitration in PPA gave the 5′,6-dinitro derivative. Quantum-chemical calculation data for the electron density distribution in the neutral and protonated 2-(2-furyl)benzothiazole molecules are given.

Full text of DOI:10.1007/s10593-008-0156-8

Chemistry of Heterocyclic Compounds, Vol. 44, No. 9, 2008
SYNTHESIS AND PROPERTIES OF 2-(2-FURYL)BENZOTHIAZOLE*
E. B. Melnikova1, M. M. Elchaninov1, A. A. Milov2, and B. S. Lukyanov3
The electrophilic reactions (nitration, bromination, hydroxymethylation, formylation, acylation) and
radical substitution reactions (nitration, arylation) of 2-(2-furyl)benzothiazole have been studied. It was
found that all of the reactions occur at position 5 of the furan ring. Only nitration in PPA gave the
5',6-dinitro derivative. Quantum-chemical calculation data for the electron density distribution in the
neutral and protonated 2-(2-furyl)benzothiazole molecules are given.
Keywords: 2-(2-furyl)benzothiazole, quantum-chemical calculations, substituents orientation,
electrophilic and radical substitution reactions.
In continuing our search for novel biologically active compounds and organic luminophores amongst
2-hetaryl-substituted benzazoles we aimed to develop or select a convenient method for the synthesis and study
of the relative reactivity of the 2-(2-furyl)benzothiazole (1) compared with its benzimidazole analog 2.
N
N
N
S
O
O
Me
2
1
Only the results of bromination [1, 2] and formylation [3] of compound 1 were known at the beginning
of our work. Hence it was of interest to broaden the range of electrophilic substitution reactions by carrying out
some of these using radical and oxidative reagents.
It has previously been shown [4] that, in contrast to other methods [5, 6], the synthesis of 2-(2-furyl)-
benzothiazole (1) gives best results via condensation of furoyl chloride with o-aminothiophenol in DMF. The
work carried out by us has confirmed that this method permits the preparation of compound 1 in 85% yield.
Compound 1 was then treated with electrophilic reagents including a mixture of nitric acid in PPA, bromine in
dichloroethane, formalin in the presence of hydrochloric acid, hexamethylenetetramine in PPA, acetic anhydride
in the presence of perchloric acid, and carboxylic acids in PPA. Radical substitution reactions were also carried
out including nitration in dilute nitric acid and Meerwein arylation.
_______
* Dedicated to Boris Aleksandrovich Trofimov on his 70th jubilee.
__________________________________________________________________________________________
1South Russia State Technical University, Novocherkassk 346428; e-mail: katrin_novochek@mail.ru.
2South Scientific Centre, Russian Academy of Sciences, Rostov-on-Don 344006. 3Research Institute of Physical
and Organic Chemistry, South Federal University, Rostov-on-Don 344104, Russia; e-mail: bluk@ipoc.rsu.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1331-1338, September, 2008. Original
article submitted February 11, 2008.
1070
0009-3122/08/4409-1070©2008 Springer Science+Business Media, Inc.

In general the substitution reactions of 2-(2-furyl)benzothiazole (1) occur smoothly with quite high
yields. Nitration by refluxing in dilute nitric acid (d = 1.32) gives the 2-(5-nitro-2-furyl)benzothiazole (3a) in
40% yield. As is known, it occurs in this case via a radical mechanism. Nitration using fuming nitric acid
(d = 1.51) in PPA at 20ºC also gives compound 3a and at 95ºC the 5',6-dinitro derivative 3b. Both of the nitro
compounds were formed in quantitative yields under these conditions. Compound 3a was also prepared through
a counter synthesis via ipso substitution of the bromine for a nitro group in the 2-(5-bromo-
2-furyl)benzothiazole (4). Bromination using bromine in dichloroethane also gives substitution at position 5 of
the furan ring. However, in contrast to the benzimidazole 2, further substitution in the benzothiazole fragment
does not occur even upon prolonged refluxing with a threefold excess of bromine.
(d = 1.32)
HNO3
Bzt
NO2
(d = 1.51)
PPA, HNO3
20°C
O
3a
(d = 1.51)
PPA, HNO3
N
95°C
NO2
O2N
S
O
3b
Br2
Cl
Cl
Bzt
Bzt
Br
O
4
CH2O
HCl
+
1
Bzt
Bzt
O
O
O
5
OH
R
6
(CH2)6N4
PPA
Bzt
Bzt
Bzt
O
8a
O
Ac2O
R
O
HClO4
O
8b
O
Ac2O
PPA
Me
O
8с
O
RCO2H
PPA
R
Bzt
O
O
8d–f
p-O2NC6H4N2Cl
NO2
Bzt
O
CuCl2
9
2-benzothiazolyl
8 a R = H, b R = Me, d R = Ph, e R = p-FC6H4, f R = p-O2NC6H4; Bzt =
1071

By contrast with the 2-(2-furyl)-1-methylbenzimidazole (2) the benzothiazole 1 does not participate in a
chloromethylation using paraformaldehye in concentrated HCl hence we tried to bring about its
hydroxymethylation by refluxing in a 40% solution of formaldehyde in the presence of a catalytic amount of
hydrochloric acid (d = 1.19). The yield of the 5-hydroxymethyl derivative 5 was 42%. In addition to compound
5 a side product 2,2'-di(2-benzothiazolyl)-5,5'-difurylmethane (6) was formed in 18% yield. It should be noted
that the furylbenzimidazole 2 does not generally react under these conditions. Oxidation of the hydroxymethyl
derivative 5 using potassium permanganate gave the corresponding carboxylic acid 7 which seemed very stable
(in contrast to the benzimidazole analog). This is evidently connected with the lower basicity of compound 1
compared with benzimidazole 2 which lowers the likelihood of an intermediate formation of a readily
decarboxylating zwitterion.
H
+
N
KMnO4
1
5
CO2H
Bzt
–CO2
–
O
CO2
S
O
7
TABLE 1. Physico-Chemical Characteristics of the Compounds
Synthesized 1, 3-9
Found, %
——————
Calculated, %
IR spectrum,
Com-
pound
Empirical
formula
mp, °C
(EtOH)
Yield,
%
ν, cm-1
C
H
N
85
1
С11Н7NOS
65.32 3.53
65.67 3.48
6.70
6.96
106-107
227-228
—
3a
С11Н6N2O3S
1370 (NO2)
40*,
96*2
99
53.33 2.41 11.63
53.65 2.46 11.38
3b
4
С11Н5N3O5S
45.72 1.53 14.55 214-215
45.36 1.72 14.43
1370 (NO2)
—
С11Н6BrNOS 46.83
2.42
47.16 2.16
5.22
5.00
125-126
86
42
18
28
5
С12Н9NO2S
62.54 4.17
62.32 3.92
5.95
6.06
6.95
6.76
5.65
5.71
165-167 (dec.)
218-220 (dec.)
87-88 (dec.)
1130 (ОН)
—
6
С23Н14N2О2S2 67.02 3.17
66.67 3.38
59.02 3.04
58.78 2.86
7
С12Н7NO3S
1700 (C=O),
2630 (OH)
8a
8b
8c
С12Н7NO2S
С13Н9NO2S
С15Н11NO3S
65.15 2.97
62.87 3.08
63.97 4.02
64.18 3.73
63.44 4.17
63.14 3.89
6.03
6.11
5.54
5.76
5.03
4.91
175-176 (174 [3]) 1680 (C=O)
95
92
54
191-192
209-210
1670
1670 (С=О),
1610 (С=О)
8d
8e
8f
С18Н11NO2S
71.12 4.02
70.80 3.63
4.30
4.59
4.57
4.33
7.85
8.00
137-138
184-185
234-235
1680 (С=О)
47
77
37
С18Н10FNO2S 67.32 2.95
1680 (C=O)
66.87 3.10
С18Н10N2O4S 62.12 3.15
1370 (NO2),
1680 (C=O)
61.71 2.86
9
С17Н10N2O3S 62.97 3.27
8.56
8.70
212-213
1370 (NO2)
38
63.35 3.11
_______
* Synthesis carried out by method A
*2 Synthesis carried out by method B
1072

1073

Study [3] reported the formylation of the 2-(2-furyl)benzothiazole (1) using the Vilsmeier reagent in
72% yield. We have used another method previously successfully employed in the formylation of
benzimidazoles via the action of hexamethylenetetramine in PPA on the benzothiazole 1. In comparison with the
benzimidazole 2 which forms the 5-formyl derivative in less than 31% yield [7] the benzothiazole 1 gives the
corresponding aldehyde 8a in almost quantitative yield (95%).
Different variants of the acetylation of compound 1 tried by us proved unsuccessful. In searching for the
optimum conditions for carrying out the reaction and bearing in mind the successful experimental acylation of
the furylbenzimidazole 2 [7] we have used the method of acylation of phenols and phenyl esters proposed by
Gardner [8] through the action of acetic acid or its anhydride in PPA at 110-120ºC on compound 1. However,
the main acetylation product under these conditions was not the 5-acetyl derivative 8b but evidently the diketone
8c formed through acetylation of the COMe group in the monoketone 8b. Column chromatography gave the 2-
(5-acetoacetyl-2-furyl)benzothiazole (8c) in 54% yield and the acetyl derivative 8b in only 5% yield. The IR
spectrum of compound 8c showed two C=O group stretching bands at 1610 and 1670 cm-1. The 2-(5-acetyl-
2-furyl)benzothiazole (8b) was obtained in 92% yield by refluxing the benzothiazole 1 in acetic anhydride in the
presence of a catalytic amount of perchloric acid. Compound 2 does not react under these conditions.
Benzoylation of compound 1 using benzoic, p-fluorobenzoic, and p-nitrobenzoic acids was also carried
out using the Gardner method but at higher temperature (170ºC). Formation of the 5-benzoyl derivatives 8d-f
takes place smoothly in this case and in good yields.
Meerwein arylation was performed by treating the benzothiazole 1 with p-nitrophenyldiazonium
chloride in aqueous acetone solution in the presence of CuCl2 as catalyst. The yield of the 2-[5-(p-nitrophenyl)-
2-furyl]-benzothiazole (9) was 38%.
As evident from the experimental data the furan ring in compound 1 proved very stable to rigid reaction
conditions (as in the analog 2). However, in contrast to compound 2, in strongly acidic medium a sharp lowering
of its reactivity was observed. Hence we were unable to prepare a sulfo derivative of compound 1 despite many
attempts at sulfonation under varying conditions (mixture of PPA and H2SO4, concentrated H2SO4, H2SO4 in
acetic anhydride, and sodium benzenesulfonate in PPA). We were also unable to obtain a chloromethylation
product using paraformaldehyde in conc. HCl and the starting benzothiazole 1. This is evidently connected with
the protonation of the benzothiazole fragment of compound 1 at the nitrogen atom and hence to an increase in its
electron acceptor nature. This proposal is confirmed by quantum-chemical calculation data using the B3LYP/6-
31G method with the help of the Gaussian 03 program [9]. Hence the overall positive charge of the furan ring in
the protonated molecule of 1 is almost three times greater than the neutral form (0.32 and 0.11 relative to
hydrogen).
EXPERIMENTAL
The IR spectra of the compounds studied were recorded on a Specord IR-75 spectrometer using vaseline
oil. H NMR spectra were recorded on a Varian Unity-300 spectrometer (300 MHz) with the signals of the
1
residual protons of the deuterated solvent (CDCl3, 7.26 ppm) as standard. Monitoring of the reaction course and
purity of the synthesized compounds was carried out by TLC on Brockmann activity grade II alumina plates in
CH2Cl2 (revealed using iodine vapor) and on Silufol UV-254 plates in CH2Cl2. Yields, melting points, and
spectroscopic characteristics the compounds obtained are given in Tables 1 and 2.
2-(2-Furyl)benzothiazole (1). Furoyl chloride (1 ml, 10 mmol) was added to a solution of o-amino-
thiophenol (1.25 g, 10 mmol) in DMF (10 ml) and refluxed for 30 min. The cooled reaction product was poured
into cold water (50 ml). The precipitate was filtered off, thoroughly washed with cold water, and recrystallized
from alcohol, drying at room temperature. Yield 1.71 g.
1074

2-(5-Nitro-2-furyl)benzothiazole (3a). A. A solution of the benzothiazole 1 (2.01 g, 10 mmol) in nitric
acid (d = 1.32, 50 ml) was refluxed for 3 h. The reaction product was cooled and poured into cold water
(250 ml). The precipitated compound 3a was filtered off and washed 2-3 times with a small amount of cold
water. Yield 0.98 g.
B. Nitric acid (d = 1.51, 0.42 ml, 10 mmol) was added to a solution of the benzothiazole 1 (2.01 g,
10 mmol) in PPA (40 g) and heated for 30 min at 20ºC with constant stirring. It was then poured into water
(200 ml), neutralized with 25% ammonia solution, and the precipitate was filtered off. Yield 2.36 g.
6-Nitro-2-(5-nitro-2-furyl)benzothiazole (3b). Nitric acid (d = 1.51, 1.25 ml, 30 mmol) was added to a
solution of the benzothiazole 1 (2.10 g, 10 mmol) in PPA (40 g) and heated for 3 h at 90-95°C with constant
stirring. It was then poured into water (200 ml), neutralized with a 25% solution of ammonia, and the precipitate
was filtered off. Yield 2.89 g.
2-(5-Bromo-2-furyl)benzothiazole (4). Bromine (0.53 ml, 10 mmol) was added to a solution of
compound 1 (2.01 g, 10 mmol) in dichloroethane (50 ml) and refluxed for 4 h. The dichloroethane was
evaporated in air and compound 4 was crystallized from alcohol. Yield 2.41 g.
2-(5-Hydroxymethyl-2-furyl)benzothiazole (5) and 2,2'-di(2-benzothiazolyl)-5,5'-difurylmethane
(6). Hydrochloric acid (3-4 drops) was added to a mixture of the benzothiazole 1 (2.01 g, 10 mmol) in formalin
(70 ml) and refluxed for 2 h, poured into cold water (200 ml), and neutralized with 25% ammonia solution until
its odor remained in the mixture. The precipitate was filtered off and thoroughly washed with cold water. It was
then suspended in water and refluxed for 5 min, cooled, and again filtered. The mixture of two compounds
obtained was chromatographed on a 3 cm long aluminium oxide column using chloroform as eluent. Yield of
compound 5 0.97 g and of compound 6 0.38 g.
2-(5-Carboxy-2-furyl)benzothiazole (7). Compound 5 (2.31 g, 10 mmol) was added to a solution of
KMnO4 (6.32 g, 40 mmol) in water (150 ml) and heated at 50-60°C to the disappearance of the permanganate
color. The hot solution was filtered from MnO2, cooled, and acidified using HCl to pH 1-2. The precipitated
carboxylic acid was filtered off. Yield 0.69 g.
2-(5-Formyl-2-furyl)benzothiazole (8a). Hexamethylenetetramine (5.6 g, 40 mmol) was added to a
solution of compound 1 (2.01 g, 10 mmol) in PPA (40 g) and heated for 3 h at 80-90°C with stirring. It was then
poured into water (200 ml), neutralized with a 25% solution of ammonia, and the reaction product was filtered.
The aldehyde obtained was crystallized from alcohol. Yield 2.18 g.
2-(5-Acetyl-2-furyl)benzothiazole (8b). Perchloric acid (2-3 drops) was added to a solution of
compound 1 (2.01 g, 10 mmol) in acetic anhydride (30 ml) and refluxed for 1.5 h. It was then carefully poured
into cold water (100 ml) and neutralized with a 25% solution of ammonia. The precipitate was filtered off and
crystallized from alcohol. Yield 2.23 g.
2-(5-Acetoacetyl-2-furyl)benzothiazole (8c). Acetic anhydride (1.89 ml, 20 mmol) was added to a
solution of compound 1 (2.01 g, 10 mmol) in PPA (40 g) and heated for 16 h at 110-120°C with constant
stirring. It was then poured into water (200 ml), neutralized with a 25% ammonia solution, filtered off, and
dried. The dried material was dissolved in methylene chloride and chromatographed on an alumina column (15
cm) using methylene chloride as eluent. Yield 1.54 g.
2-(5-Benzoyl-2-furyl)benzothiazole (8d). Benzoic acid (4.88 g, 40 mmol) was added to a solution of
compound 1 (2.01 g, 10 mmol) in PPA (40 g) and heated for 3 h at 170-180°C with stirring. It was then poured
into water (200 ml), neutralized with a 25% ammonia solution, filtered off, and dried. The dried material was
dissolved in chloroform and chromatographed on an alumina column (5 cm) using chloroform as eluent.
Compound 8d was then crystallized from ethanol. Yield 1.43 g.
2-[5-(p-Fluorobenzoyl)-2-furyl]benzothiazole (8e). p-Fluorobenzoic acid (5.6 g, 40 mmol) was added
to a solution of compound 1 (2.01 g, 10 mmol) in PPA (40 g) and was heated for 4 h at 170-180°C with constant
stirring. It was then poured into water (200 ml), neutralized with a 25% solution of ammonia, filtered, and the
precipitate was crystallized from ethanol. Yield 2.49 g.
1075

2-[5-(p-Nitrobenzoyl)-2-furyl]benzothiazole (8f). p-Nitrobenzoic acid (0.67 g, 40 mmol) was added to
a solution of compound 1 (2.01 g, 10 mmol) in PPA (40 g) and heated for 5 h at 170-180ºC with constant
stirring. It was then poured into water (200 ml), neutralized with a 25% ammonia solution, filtered, and the
precipitate was dried. The dried material was dissolved in chloroform and chromatographed on an alumina
column (5 cm) using chloroform as eluent. Yield 1.29 g.
2-[5-(p-Nitrophenyl)-2-furyl]benzothiazole (9). p-Nitroaniline hydrochloride obtained from p-nitro-
aniline (1.38 g, 10 mmol), water (20 ml), and conc. HCl (8 ml) was diazotized using a solution of NaNO2
(0.69 g, 10 mmol) in water (3 ml). The reaction product was stirred for 30 min at 5°C and the 2-(2-furyl)-
benzothiazole (2.01 g, 10 mmol) in acetone (10 ml) and a solution of CuCl2 (0.2 g) in water (1 ml) were added.
The reaction product was stirred for 1 day at 20°C. The precipitated compound 9 was filtered and washed with a
50% aqueous solution of acetone. Yield 1.22 g.
This work was carried out with the financial support of the Russian fund for basic research (grant
07-03-0234).
REFERENCES
1.
2.
3.
V. Fǎrcǎsan, Studii si Cercetǎri Chim., 13, 103 (1962).
V. Fǎrcǎsan and J. Mester, Studia Univ. Babes-Bolyai, 12, 68 (1967).
M. Yu. Kornilov, E. M. Ruban, V. N. Fedchuk, E. V. Starinskaya, and M. V. Buznik, Zh. Org. Khim., 9,
2577 (1973).
4.
5.
6.
7.
A. I. Kiprianov and A. A. Shulezhko, Zh. Obshch. Khim., 34, 3932 (1964).
M. T. Bogert and A. Stull, J. Am. Chem. Soc., 48, 243 (1926).
V. Fǎrcǎsan and C. Makkay, Studii si Cercetǎri Chim., 10, 145 (1959).
M. M. El'chaninov, A. M. Simonov, and L. Ya. Oleinikova, Khim. Geterotsikl. Soedin., 1311 (1983).
[Chem. Heterocycl. Comp., 19, 1041 (1983)].
8.
9.
P. D. Gardner, J. Am. Chem. Soc., 76, 4550 (1951).
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman,
J. A. Montgomery Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi,
V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nacatsuji, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts,
R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala,
K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich,
A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J.
V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko,
P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez, and
J. A. Pople, Gaussian 03, Gaussian Inc., Pittsburgh PA (2003).
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