Heterocycles LXXVIII. Electrophilic substitution of 2′-phenyl-4R-2,4′-bisthiazoles

Article abstract of DOI:10.1007/pl00013474

The behaviour of some 2′-phenyl-4R-2,4′-bisthiazoles with respect to electrophilic substitution reactions (halogenation and nitration) has been studied in order to establish relationships between structure and reactivity of the two thiazole rings. The entry of the electrophilic reactants in position 5 or 5′ of the 2,4′-bisthiazole system depends on the nature of the residue in position 4.

Full text of DOI:10.1007/pl00013474

Monatshefte fuÈr Chemie 129, 661±669 (1998)
Heterocycles LXXVIII. Electrophilic
Substitution of 20-Phenyl-4R-2,40-bisthiazoles
Ovidiu Oniga1, Ion Grosu2, Sorin Mager2, and Ioan Simiti1;Ã
1
Department of Organic Chemistry, University of Medicine and Pharmacy Iuliu Hatieganu, Faculty
of Pharmacy, RO-3400 Cluj-Napoca, Romania
2
Department of Organic Chemistry, Babes Bolyai University, RO-3400 Cluj-Napoca, Romania
Summary. The behaviour of some 20-phenyl-4R-2,40-bisthiazoles with respect to electrophilic
substitution reactions (halogenation and nitration) has been studied in order to establish relationships
between structure and reactivity of the two thiazole rings. The entry of the electrophilic reactants in
position 5 or 50 of the 2,40-bisthiazole system depends on the nature of the residue in position 4.
Keywords. Atropisomerism; 2,40-Bisthiazoles; Halogenation; Nitration.
Heterocyclen, 78. Mitt. Elektrophile Substitution von 20-Phenyl-4R-2,40-bisthiazol
È
È
Zusammenfassung. Zur Ermittlung von Zusammenhangen zwischen Struktur und Reaktivitat der
beiden Thiazolringe wurde das Verhalten einiger 20-Phenyl-4R-2,40-bisthiazole bezuÈglich elektro-
philer Substitution (Halogenierung und Nitrierung) untersucht. Der Eintritt der Substituenten in die
0
È
Positionen 5 bzw. 5 des Bisthiazolsystems hangt von der Natur des Substituenten in Position 4 ab.
Introduction
The presence of the 2,40-bisthiazole system in bleomicine, an anticancerous
antibiotic, prompted us to synthetize a series of 20-aryl-4R1-5R2-2,40-bisthiazoles
with different substituents in position 4 and 5 [1] in order to establish qualitative
relationships between chemical structure and biological activity [2].
In a previous paper, the applicability of the Sommelet and Krohnke reactions in
a series of 20-aryl-4-halomethyl-2,40 bisthiazoles was presented [3]. Herein, our
studies of halogenation and nitration in the series of 20-phenyl-4R-2,40-bisthiazoles,
with two electrophilic centres in position 5 and 50 are continued, taking into account
our earlier observations that the phenyl substituent shows a ‡E effect with respect
to the thiazole ring, thus increasing the electronic density in position 5 [4±6].
Results and Discussion
The reactions of 20-phenyl-4R-2,40-bisthiazoles 1a,b with equimolar amounts of
bromine in acetic acid lead to a mixture or 5- and 50- monobromo derivatives 2a,b
Ã
Corresponding author

662
O. Oniga et al.
Scheme 1
and 3a,b as well as to 5,50-dibromo derivatives 4a,b, respectively (Scheme 1).
Further bromination of 2a,b and 3a,b results in 4a,b.
In the case of 20-phenyl-4-chloromethyl-2,40-bisthiazole (1b), the 50-mono-
bromoderivative 3b exceeds the 5-monobromoderivative 2b as a result of the
preferential attack of the bromine in the thiazole ring A. The 1H NMR spectrum of
3b (DMSO-d6) lacks the signal of the thiazole proton H50 (at ꢀ ˆ 7.91 ppm),
whereas in that of the dibromoderivative 4b the signals of both H50 and H5
(ꢀ ˆ 7.15 ppm) disappear.
Bromination of 20-phenyl-4-methyl-2,40-bisthiazole (1a) leads to an attack at
position 5 of thiazole ring B and affords preferentially the 5-monobromoderivative
2a. The 1H NMR spectrum con®rms the disappearance of the signal at
ꢀ ˆ 6.97 ppm belonging to the proton of the B thiazole ring, whereas the signal
of the proton of the thiazole ring (ꢀ ˆ 7.9 ppm) remains visible in the spectrum. In
the IR spectra of dibromoderivatives 4a,b, the corresponding ꢁC5-H and ꢁC50-H
absorption bands in the region of 3080±3100 cmꢀ1 could not be detected. The
preferential location of bromine attack in the case of 20-phenyl-4-chloromethyl-
2,40-bisthiazole was also con®rmed by the direct synthesis of 20-phenyl-50-bromo-
4-chloromethyl-2,40-bisthiazole (3b) starting from the oxime of 2-phenyl-4-formyl-
thiazole (13) (Scheme 2).
3b obtained in this way is identical with the major compound resulting from
bromination of 20-phenyl-4-chloromethyl-2,40-bisthiazole (1b). The preferential
bromination of the thiazole ring B in the case of 20-phenyl-4-methyl-2,40-
bisthiazole (1a) was con®rmed by decarboxylative bromination of 20-phenyl-5-
carboxy-4-methyl-2,40-bisthiazole (5) in alkaline medium with an equimolar
quantity of bromine (Scheme 3) [7].

Electrophilic Substitution of Bisthiazoles
663
Scheme 2
Scheme 3
The 5-monobromo derivative 2a obtained in this way was identical with the
major product formed by direct bromination of 1a with an equimolar amount of
bromine in acetic acid.
Chlorination of 1b with a mixture of concentrated hydrochloric and nitric acid
(d ˆ 1.42) in equimolar amounts results in a selective electrophilic attack in
position 50 of thiazole ring A, giving 20-phenyl-50-chloro-4-chloromethyl-2,40-
bisthiazole (6). Hydrolysis of 1b leads to 20-phenyl-50-chloro-4-hydroxymethyl-
2,40-bisthiazole (7), whose reaction with thionyl chloride affords the same
compound 6 (Scheme 4).
By bubbling gaseous chlorine into an acetic solution of compound 1b or 6, 20-
phenyl-4-chloromethyl-5,50-dichloro-2,40-bisthiazole (8) was obtained. The 1H
NMR spectrum (CDCl3) of 6 con®rms the absence of the A thiazole proton
(ꢀ ˆ 8.01 ppm), whereas in the spectrum of 8 both signals of the thiazole rings A
and B (ꢀ ˆ 7.37 ppm) are absent. The 13C NMR and mass spectra also con®rm the
structure of the 5,50-dichloro derivative 8.
Chlorination of 20-phenyl-4-methyl-2,40-bisthiazole (1a) with concentrated
hydrochloric and nitric acid under the same conditions as used for 1b yields a
mixture of two isomeric monochloro derivatives (20-phenyl-5-chloro-4-methyl-
2,40-bisthiazole (9a) and 20-phenyl-50-chloro-4-methyl-2,40-bisthiazole (9b)) in a
relative ratio of about 60:40. This-albeit low-regioselectivity of the reaction
demonstrates again the higher reactivity of the position 5 of the thiazole ring B if
substituted with a methyl group in position 4. Further chlorination of compounds

664
O. Oniga et al.
Scheme 4
Scheme 5
9a and 9b with hydrochloric and nitric acid resulted in the formation of the
dichloroderivative 10 (Scheme 5).
Concerning the nitration reaction of 1b with nitric acid in acetic anhydride,
only mononitration in position 50 occured (Scheme 6). Further nitration of 20-
phenyl-4-chloromethyl-50-nitro-2,40-bisthiazole (11) was not successful, suggesting
a deactivation of position 5 of the thiazole nucleus B induced by the presence of a
nitro group in 50. A steric effect may also be involved. The absence of the signal at
ꢀ ˆ 8.01 in the 1H NMR spectrum (CDCl3) of 11 is a proof of the nitration in that
position.

Electrophilic Substitution of Bisthiazoles
665
Scheme 6
Scheme 7
Nitration of 20-phenyl-4-methyl-2,40-bisthiazole (1a) under the same conditions
as used for 1b leads to the 5-nitro isomer as a major product (Scheme 7). In its 1H
NMR spectrum (CDCl3), the disappearance of the signal originating from the
thiazole ring B (ꢀ ˆ 6.97 ppm) was observed. The experimental results demonstrate
the distinct in¯uence of the methyl respectively chloromethyl-substituents in
position 4, on the orientation of the electrophilic reagents in position 5 and 50 of the
2,40 bisthiazole system.
The electron donating methyl group increases the electronic density in position
5, promoting electrphilic attack at this position. In the case of the 4-chloromethyl
derivative, the electron withdrawing inductive effect associated with its shielding
steric effect for position 5 determines the preferential entry of electrophilic
reagents in position 50 of the thiazole ring A.
Compounds substituted in position 50 of thiazole ring A demonstrate the
existence of atropisomerism by a hindered rotation of the two thiazole rings about
C2-C4 (Fig. 1). Experimental evidence of this atropisomerism in the series of some
0
1
50-substituted 2,40-bisthiazole compounds was provided in the case of 3b by H
NMR spectroscopy. The steric hindrance caused by the bromine atom in position 50
results in an approximately perpendicular orientation of the two thiazole rings
Fig. 1

666
O. Oniga et al.
Fig. 2
Fig. 3. 1H NMR spectrum of 3b (detail)
0
(Fig. 2). The C2-C4 axis represents the chiral element of the molecule, leading to
the possible existence of two enantiomers for 3b. The chirality of the molecule
1
induces diastereotopicity for the two protons of the chloromethyl group. The H
NMR spectrum of compound 3b (Fig. 3) shows an overlapping AB system looking
like a triplet for these protons. The signal exhibits a large geminal coupling
constant (J ˆ 12.3 Hz) and at the same time a splitting corresponding to a coupling
with the proton in position 5.
Experimental
1H NMR spectra were recorded on a Bruker AM 400 NMR spectrometer (solvent: CDCl3 or DMSO-
d6); ꢀ values are given in ppm relative to internal TMS. The mass spectra were recorded at 70 eVon a
Trio MS 1000 spectrometer. IR spectra were measured as KBr disks on a FT-IR-Nicolet 205
spectrophotometer. Melting points were measured with an electrothermal melting point apparatus
and are uncorrected. All compounds gave satisfactory elemental analyses (C, H, N) The syntheses of
compounds 1a, b, 5, and 13 have already been reported [1].
General procedure for the bromination of compounds 1a,b, 2a,b, 3a,b.
0.001 mol of 1a,b, 2a,b, or 3a,b were dissolved in a minimum amount of glacial acetic acid or acetic
anhydride. To the ice cooled solution, 0.06 ml (0.0012 mol) bromine were added dropwise under
stirring. After one hour, the solution was poured into water; the obtained precipitate was ®ltered and
washed with water. Puri®cation of 2a,b and 3a,b by preparative thin layer chromatography was
carried out using silica gel and different proportions of hexan-ethyl acetate-chloroform.

Electrophilic Substitution of Bisthiazoles
667
2a: M.p.: 182ꢁC; C13H9BrN2S2 (337.27); 1H NMR: 8.1 (s, 1H, H50), 2.25 (s, 3H, CH3), 8.01 (m,
2H, C6H5 (o)), 7.47 (m, 3H, C6H5 (m, p)).
2b: M.p.: 153±154ꢁC; C13H8BrClN2S2 (371.71); 1H NMR: 8.01 (s, 1H, H50), 4.82 (s, 2H,
CH2Cl), 8.03 (m, 2H, C6H5 (o)), 7.48 (m, 3H, C6H5 (m, p)).
3a: M.p.: 129ꢁC; C13H9BrN2S2 (337.27); 1H NMR: 6.97 (s, 1H, H5), 2.32 (s, 3H, CH3), 8.01 (m,
2H, C6H5 (o)), 7.47 (m, 3H, C6H5 (m, p)).
1
3b: M.p.: 135ꢁC; C13H8BrClN2S2 (371.71); H NMR: 7.37 (s, 1H, H5), 4.79 (s, 2H, CH2Cl),
8.03 (m, 2H, C6H5 (o)), 7.48 (m, 3H, C6H5 (m, p)).
4a: M.p.: 148±150ꢁC (ethanol-acetic acid); C13H8Br2N2S2 (416.17).
4b: M.p.: 178ꢁC (ethanol-acetic acid); C13H7Br2ClN2S2 (450.61).
20-Phenyl-5-bromo-4-methyl-2,40-bisthiazone (2a)
0.29 g (0.001 mol) of 5 were dissolved in 60 ml 5% NaOH at 60ꢁC, and 0.06 ml (0.0012 mol)
bromine were added. Immediately 15 ml conc. HCl were added and the obtained compound was
crystallized.
Yield 65%; m.p.: 182ꢁC (ethanol-acetic acid); C13H9BrN2S2 (337.27); 1H NMR: 8.1 (s, 1H, H50),
2.25 (s, 3H, CH3), 8.01 (m, 2H, C6H5 (o), 7.47 (m, 3H, C6H5 (m, p)).
Oxime of 2-phenyl-5-bromo-4-formyl-thiazole (14)
2.05 g (0.01 mol) of 13 were dissolved in 20 ml of acetic acid. To the ice cooled solution, 0.6 ml
(0.012 mol) bromine were added dropwise under stirring. After 30 minutes, the solution was poured
into water; the obtained precipitate was ®ltered, washed with water, and crystallized.
Yield: 80%; m.p.: 182ꢁC (ethanol); C10H7BrN2OS (283.16).
2-Phenyl-5-bromo-4-cyano-thiazole (15)
1 g (0.0036 mol) 14 was treated with 5 ml acetic anhydride and re¯uxed for one hour. After cooling,
the precipitate was ®ltered, washed with water, and crystallized.
Yield: 50%; m.p.: 129ꢁC (ethanol); C10H5BrN2S (265.2).
2-Phenyl-5-bromo-4-thiocarbamido-thiazole (16)
0.5 g (0.0019 mol) 15 were dissolved in 10 ml absolute ethanol saturated with NH3. H2S was bubbled
through the solution for 24 hours which then was boiled for 10 minutes. After cooling, the solution
was poured into water; the resulting precipitate was ®ltered and crystallized.
Yield: 70%; m.p.: 132ꢁC (ethanol); C10H7BrN2S2 (299.3).
20-Phenyl-50-bromo-4-chloromethyl-2,40-bisthiazole (3b)
0.3 g (0.001 mol) of 16 were dissolved in the minimal amount of absolute ethanol and boiled for 1
hour after addition of 0.127 g (0.001 mol) of 1,3-dichloroacetone. After cooling, the solution was
poured into water; the precipitate was ®ltered and crystallized.
1
Yield: 80%; m.p.: 135ꢁC (acetic acid); C13H8BrClN2S2 (371.71); H NMR: 7.37 (s, 1H, H5),
4.79 (s, 2H, CH2Cl), 8.03 (m, 2H, C6H5 (o)), 7.48 (m, 3H, C6H5 (m, p)).
20-Phenyl-50-chloro-4-chloromethyl-2,40-bisthiazole (6)
a) 0.29 g (0.001 mol) of 1b were dissolved in 20 ml glacial acetic acid, and a mixture of 0.2 ml conc.
HCl and 0.14 ml conc. HNO3 63% (d ˆ 1.42) was added. The solution was heated at 40ꢁC for 10

668
O. Oniga et al.
minutes. After cooling, the precipitate was ®ltered, washed with water, and crystallized. The
reaction may be also performed in acetic anhydride at room temperature.
1
Yield: 70%; m.p.: 153ꢁC (ethanol-acetic acid); C13H8Cl2N2S2 (327.25); H NMR; 7.3 (s, 1H,
H5), 4.9 (s, 2H, CH2Cl), 8.1 (m, 2H, C6H5 (o)), 7.5±7.7 (m, 3H, C6H5 (m, p)).
b) 0.31 g (0.001 mol) of 7 were dissolved in 5 ml chloroform, and 3 ml thionyl chloride were added.
After 30 minutes, the chloroform and the excess of thionyl chloride were removed by distillation;
the remaining compound was crystallized.
Yield: 67% ; m.p.: 153±155ꢁC (ethanol-acetic acid); C13H8Cl2N2S2 (327.25).
20-Phenyl-50-chloro-4-hydroxymethyl-2,40-bisthiazole (7)
0.29 g (0.001 mol) of 1b were dissolved in 10 ml glacial acetic acid and then treated with 5 ml water
and 5 ml HNO3 (d ˆ 1.42) and re¯uxed for 6 hours. After cooling, the precipitate was ®ltered,
washed with water, and crystallized.
Yield: 80%; m.p.: 160 ꢁC (ethanol); C13H9ClN2OS2 (308.80).
20-Phenyl-4-chloromethyl-5,50-dichloro-2,40-bisthiazole (8)
0.29 g (0.001 mol) of 1b or 0.327 g (0.001 mol) of 6 were dissolved in 10 ml acetic anhydride or
glacial acetic acid. Chlorine was bubbled through the solution for 10 minutes. After 24 hours, the
precipitate was ®ltered, washed with water, and crystallized.
1
Yield: 90% m.p.: 163ꢁC (ethanol); C13H7Cl3N2S2 (361.69); H NMR: 4.8 (s, 2H, CH2Cl), 7.9
(m, 2H, C6H5 (o)), 7.45±7.55 (m, 3H, C6H5 (m, p)); MS: m/z ˆ 360, 325, 289, 222, 105.
20-Phenyl-5-chloro-4-methyl-2,40-bisthiazole (9a) and 20-Phenyl-50-chloro-4-
methyl-2,40-bisthiazole (9b)
0.11 g (0.00042 mol) of 1a were dissolved in 15 ml acetic anhydride, and a mixture of 0.2 ml conc.
HCl and 0.15 ml HNO3 63% (d ˆ 1.42) was added. After about 10 minutes, a precipitate was formed.
It was ®ltered and washed with water. From the crude product, the isomers 9a and 9b were separated
by preparative thin layer chromatography using silicagel and a mixture of heptane-ethylacetate
ˆ 7:3.
1
9a: Yield: 50%; m.p.: 178ꢁC; C13H9ClN2S2 (292.81); H NMR: 7.88 (s, 1H, H50), 2.41 (s, 3H,
CH3), 7.98±8.02 (m, 2H, C6H5 (o)), 7.46±7.49 (m, 3H, C6H5 (m, p)).
9b: Yield: 30%; m.p.: 153ꢁC; C13H9ClN2S2 (292.81); 1H NMR: 2.18 (s, 3H, CH3), 7.88±7.92 (m,
2H, C6H5 (o)), 7.48 (m, 4H, C6H5 (m, p), H5).
20-Phenyl-5,50-dichloro-4-methyl-2,40-bisthiazole (10)
10 was obtained by the procedure described for 9a, b, starting from 9a.
1
Yield: 70%; m.p.: 190ꢁC (ethanol-acetic acid); C13H8Cl2N2S2 (327.25); H NMR: 2.49 (s, 3H,
CH3), 7.90 (m, 2H, C6H5 (o)), 7.47 (m, 3H, C6H5 (m, p)).
20-Phenyl-4-chloromethyl-50-nitro-2,40-bisthiazole (11)
0.292 g (0.001 mol) of 1b were dissolved in 6 ml acetic anhydride, and 0.15 ml HNO3 63% (d ˆ 1.42)
were added. After about 7 hours, a precipitate was formed. It was ®ltered, washed with water, and
crystallized.

Electrophilic Substitution of Bisthiazoles
669
Yield: 80%; m.p.: 144ꢁC (ethanol-acetic acid); C13H8ClN3O2S2 (337.81); 1H NMR: 7.70 (s, 1H,
H5), 4.85±4.9 (s, 2H, CH2Cl), 8±8.1 (m, 2H, C6H5 (o)), 7.5±7.6 (m, 3H, C6H5 (m, p)); MS: m/
z ˆ 337, 292, 189, 186, 154, 83, 77.
20-Phenyl-4-methyl-5-nitro-2,40-bisthiazole (12)
0.260 g (0.001 mol) of 1a were dissolved in 15 ml acetic anhydride, and 0.12 ml HNO3 63%
(d ˆ 1.42) were added. After 24 hours, a precipitate was formed. It was ®ltered, washed with water,
and crystallized.
1
Yield: 60%; m.p.: 105±107ꢁC (ethanol-acetic acid); C13H9N3O2S2 (303.37); H NMR: 7.30 (s,
1H, H50), 2.65 (s, 3H, CH3), 8±8.05 (m, 2H, C6H5 (o)), 7.5±7.6 (m, 3H, C6H5 (m, p)).
References
[1] Simiti I, Oniga O, Zaharia V, Horn M (1995) Pharmazie 50(12): 794
[2] Oniga O, Zaharia V, Matinca D, Simiti I (1997) Clujul Medical LXXI(2): 296
[3] Simiti I, Oniga O (1996) Monatsh Chem 127: 733
[4] Fintlay, J, Dangherty N (1946) J Am Chem Soc 68: 1666
[5] Schwartz I (1971) ``Studia''-Univ. Babes Bolyai Cluj 1: 51
[6] Simiti I, Maria Farkas (1965) Chem Ber 98(11): 3446
[7] Simiti I, Coman M, Muresan A (1976) Arch Pharmaz 309: 128
Received August 24, 1997. Accepted (revised) October 3, 1997