Characteristics of the synthesis of substituted and condensed 2-methyl-1,3-diazoles

Article abstract of DOI:10.1007/s10593-005-0281-6

Condensation of aliphatic and carbocyclic α-bromo ketones with thioacetamide in ethanol usually leads to substituted or condensed 2-methyl-1,3-thiazoles. However in a number of cases the required compounds are only obtained in pyridine.

Full text of DOI:10.1007/s10593-005-0281-6

Chemistry of Heterocyclic Compounds, Vol. 41, No. 8, 2005
CHARACTERISTICS OF THE
SYNTHESIS OF SUBSTITUTED AND
CONDENSED 2-METHYL-1,3-DIAZOLES
A. Yu. Liakina, I. V. Mikhura, I. S. Popova, and A. A. Formanovsky
Condensation of aliphatic and carbocyclic α-bromo ketones with thioacetamide in ethanol usually leads
to substituted or condensed 2-methyl-1,3-thiazoles. However in a number of cases the required
compounds are only obtained in pyridine.
Keywords: α-bromo ketones, dioxane dibromide, 2-methyl-1,3-thiazoles, thioacetamide, Hantzsch
condensation.
Compounds of the thiazole series are of interest on account of their high pharmacological activity. The
thiazole ring is an important structural component in substances with diuretic, anthelminthic and antihistaminic
properties [1], mitodepressants and mitostatics [2], antiparasitic, antipyretic, and antiviral preparations [2,3].
Thiazoles are used as antioxidants and promoters of vulcanization [2], dyestuffs [3-5] and also in the polymer
industry [2-4].
2-Methylthiazoles are used as synthons for the preparation of aldehydes and alcohols [6], while
thiazolium salts may be used to obtain acyloins and benzoins [7].
The aim of the present work was to prepare 2,5-dimethyl-1,3-thiazoles containing substituents at
position 4, and also condensed 2-methyl-1,3-thiazoles for subsequent functionalization at the 2-CH3 group. All
compounds were prepared by the Hanztsch method from α-bromo ketones and thioacetamide:
R
R
O
Me
Br
MeCSNH2
EtOH
N
Me
Me
S
1a–f
2a–f
a R = p-FC6H4; b R = o-FC6H4; c R = m-ClC6H4; d R = p-MeC6H4;
e R = p-MeOC6H4; f R = 2-thienyl
O
R
Br
N
S
MeCSNH2
EtOH
R
Me
4a,b
3a,b
3 a R = 6-MeO; b R = 7-MeO;
4 a R = 7-MeO; b R = 8-MeO
__________________________________________________________________________________________
M. M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of
Sciences, Moscow 117997; e-mail: synorg@ibch.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 8, 1244-1249, August, 2005. Original article submitted April 28, 2004.
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0009-3122/05/4108-1066©2005 Springer Science+Business Media, Inc.

The described methods for the preparation of α-bromo ketones by radical bromination with molecular
bromine or N-bromosuccinimide did not always give the desired products in high yield. In all cases we used
bromination with dioxane dibromide in ether [8]. The yields of all the compounds 1a-f, 3a,b, 5, 7, and 9 were
quantitative and the α-bromo ketones prepared were used without further purification for condensation with
thioacetamide.
Several methods were tried to obtain 2-bromo-1-(6-methoxy-2-naphthyl)propanone (1g): treatment of
the corresponding ketone 1) with dioxane dibromide in CH2Cl2; 2) with dioxane dibromide in CH2Cl2 in the
presence of CaCO3; 3) with phenyltrimethylammonium perbromide in THF. In all cases 2-bromo-1-(5-bromo-6-
methoxy-2-naphthyl)propanone (5) was formed, despite the assertion of the authors of [9] that 2-bromo-1-(6-
methoxy-2-naphthyl)propanone (1g) should be formed by the interaction of 1-(6-methoxy-2-naphthyl)propanone
with phenyltrimethylammonium perbromide in THF.
Subsequent treatment of 2-bromo-1-(5-bromo-6-methoxy-2-naphthyl)propanone (5) with thioacetamide
in ethanol by the standard method gave 4-(5-bromo-6-methoxy-2-naphthyl)-2,5-dimethyl-1,3-thiazole (6). We
were unable to remove the bromine atom from the naphthalene ring in compound 6 – it did not react with
metallic magnesium (synthesis of the Grignard reagent was attempted analogously to the synthesis of
methoxynaphthylmagnesium bromide [10]).
O
O
Me
Me
Br
MeO
MeO
1g
Me
N
O
Me
MeCSNH2
EtOH
S
Br
Me
MeO
MeO
Br
Br
5
6
Reaction of 2-bromocyclooctanone (7) and 2-bromobenzosuberone (9) with thioacetamide led to the
formation of elemental sulfur and the initial ketones with bromine removed. According to GLC, the required
thiazoles were formed in trace quantities. Compounds 8 and 10 were successfully synthesized in satisfactory
yields by carrying out the Hanztsch synthesis in pyridine.
O
N
S
MeCSNH2
Py
Me
Br
8
7
O
Br
MeCSNH2
Py
N
S
Me
9
10
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1
The H NMR spectra of compounds 2a-f the signals of the protons of the 2-CH3 group occur at weak
field (2.60-2.65 ppm) while those of the 5-CH3 occur at 2.30-2.45 ppm. In some cases (for compounds 2b, e-f)
this signal is split (J = 3 Hz), probably as the result of interaction with a close proton of the benzene ring. The
positions and multiplicities of the signals of the benzene ring correspond to the nature of the substitution.
Intense molecular ions are present in the mass spectra of the compounds synthesized. Decomposition
apparently begins with loss of a molecule of acetonitrile (m/z 41), i.e., with immediate fission of the thiazole
ring. An alternative path for decomposition of the molecular ion is the loss of a particle with mass 15
(presumably the 2-methyl group) with retention of the thiazole nucleus.
Elimination of a molecule of acetonitrile from the molecular ion was not observed in the mass spectrum
of compound 10. The intense peak with m/z 141 presumably corresponds to the benzotropylium cation.
Hence it has been shown that bromination of substituted aliphatic and carbocyclic ketones at the
α-position proceeds quantitatively under mild conditions with dioxane dibromide in ether as the brominating
agent. Bromination of 1-(6-methoxy-2-naphthyl)propanone occurs with disubstitution – in the aliphatic chain
and at position 5 of the naphthalene ring – independent of the method of bromination. Subsequent condensation
of the synthesized α-bromo ketones with thioacetamide in ethanol normally gave the corresponding 2-methyl-
1,3-thiazoles. However in a number of cases it was necessary to use pyridine as the solvent for the condensation
in place of ethanol.
EXPERIMENTAL
1H NMR spectra of CDCl3 solutions were recorded with a Varian UNITY INOVA (400 MHz) relative to
the residual protons of the solvent. Mass spectra were obtained with a Finnegan GQ chromato-mass spectrometer
equipped with a J&W Scientific DB-5MS capillary column (30 m × 0.25 mm, phase 0.25 µ 5%
phenylpolysiloxane), with an ionization energy of 70 eV.
Solvents were purified and dried by known methods. Synthesis of α-bromo ketones 1a, d-f, 3a-b, 5, 7,
and 9 was by method [8]. Their characteristics corresponded to those cited in the literature [11-19].
Synthesis of the α-Bromo Ketones 1b-c (General Method). Dioxane dibromide (3g) was added to a
solution of the ketone (0.3 mol) in dry ether (150 ml) and the reaction mixture was heated until colorless. Then
dioxane dibromide (74.4 g, 0.3 mol) was added over 20 min at ~20°C, the mixture was stirred for 1 h until
evolution of HBr ceased, then washed with water (2 × 500 ml) and saturated NaCl solution, and dried over
anhydrous Na2SO4. The solvent was evaporated in vacuum and the product was used without further
purification.
1
2-Bromo-1-(2-fluorophenyl)-1-propanone (1b). Yield 100%. Oil. H NMR spectrum, δ, ppm (J, Hz):
8.26-7.06 (4H, m, C6H4); 5.47 (1H, q, J = 9.0, CH); 2.10 (3H, d, J = 9.0, CH3). Found, %: C 46.87; H 3.50.
C9H8BrFO. Calculated, %: C 46.78; H 3.49.
2-Bromo-1-(2-chlorophenyl)-1-propanone (1c). Yield 100%. Oil.1H NMR spectrum, δ, ppm (J, Hz):
7.53-7.35 (4H, m, C6H4); 5.65 (1H, q, J = 9.0, CH); 2.15 (3H, d, J = 9.0, CH3). Found, %: C 43.70; H 3.35;
Br 32.28; Cl 14.32. C9H8BrClO. Calculated, %: C 43.67; H 3.26; Br 32.28; Cl 14.32.
Preparation of Substituted 2-Methyl-1,3-thiazoles 2a-f, 6 (General Method). Thioacetamide
(0.33 mmol) in ethanol (100 ml) was added to the α-bromo ketone (0.3 mmol). The reaction was exothermic
after a brief heating. When the spontaneous boiling ceased the reaction mixture was boiled for a further 6-13 h,
diluted with water, the ethanol was evaporated, water (50 ml) was added and the pH was adjusted to 9 with
NaOH solution, the solution was extracted with ether (3 × 100 ml) or CH2Cl2, the extract was washed with
water, saturated aqueous NaCl, and dried over Na2SO4. The solvent was evaporated and the residue was distilled
in vacuum. Compounds 2f and 6 were purified chromatographically (SiO2, benzene).
1068

Compounds 4a,b. The reaction mixture was boiled for 1 h, after which conc. HCl (25 ml) was added.
The precipitate was separated, dried, suspended in water (50 ml), and solid NaOH added to pH 10. The solution
produced was extracted with ethyl acetate (3 × 100 ml), and dried over Na2SO4. The solvent was evaporated in
vacuum and the residue was chromatographed (SiO2, CHCl3) to give compounds 4a,b.
Compounds 8 and 10 were obtained analogously to compounds 4a,b but with pyridine as the solvent in
place of ethanol.
1
4-(4-Fluorophenyl)-2,5-dimethyl-1,3-thiazole (2a). Yield 82%; bp 132-133°C (5 mm Hg). H NMR
spectrum, δ, ppm (J, Hz): 7.56 (2H, dd, J = 8.6, J = 6.0, Harom-3,5); 7.07 (2H, dd, J = 8.6, J = 8.6, Harom-2,6);
2.63 (3H, s, 2-CH3); 2.44 (3H, s, CH3, 5-CH3). Mass spectrum, m/z (Irel, %): 208 [M+1]+ (13), 207 [M]+(100),
206 [M-1]+(23), 166 (63), 133 (23), 122 (27),107 (12). Found, %: C 63.79; H 4.87; N 6.70. C11H10FNS.
Calculated, %: C 63.74; H 4.86; N 6.76.
1
4-(2-Fluorophenyl)-2,5-dimethyl-1,3-thiazole (2a). Yield 83%; bp 101-102°C (0.5 mm Hg). H NMR
spectrum, δ, ppm (J, Hz): 7.45 (1H, t, J = 7.7, Harom-4); 7.25 (1H, m, Harom-6); 7.13 (1H, t, J = 7.7, Harom-3); 7.05
(1H, t, J = 9.3, Harom-5); 2.60 (3H, s, 2-CH3); 2.27 (3H, s, 5-CH3). Mass spectrum, m/z (Irel, %): 209 [M+2]+ (11),
208 [M+1]+ (28), 207 [M]+ (100), 206 [M-1]+ (27), 188 (10), 166 (80), 133 (50), 122 (54), 107 (23). Found, %:
C 63.90; H 4.90; N 6.74. C11H10FNS. Calculated, %: C 63.74; H 4.86; N 6.76.
1
4-(2-Chlorophenyl)-2,5-dimethyl-1,3-thiazole (2c). Yield 76%; bp 130-131°C (1 mm Hg). H NMR
spectrum, δ, ppm (J, Hz): 7.26 (1H, dd, J = 3.7, J = 3.7, Harom-2); 7.47 (1H, dd, J = 7.4, J = 3.7, Harom-4); 7.30
(1H, dd, J = 7.4, J = 7.4, Harom-6); 7.24-7.28 (1H, m, Harom-5); 2.63 (3H, s, 2-CH3); 2.46 (3H, s, 5-CH3). Mass
spectrum, m/z (Irel, %): 226 [M+3]+ (5), 225 [M+2]+ (39), 224 [M+1]+ (30), 223 [M]+ (100), 222 [M-1]+ (52), 182
(56), 147 (47),13 9 (19), 102 (16). Found, %: C 59.06; H 4.50; Cl 15.95; N 6.20; S 14.41. C11H10ClNS.
Calculated, %: C 59.055; H 4.51; Cl 15.85; N 6.26; S 14.33.
1
2,5-Dimethyl-4-(4-methylphenyl)-1,3-thiazole (2d). Yield 58%; bp 118-119°C (1 mm Hg). H NMR
spectrum, δ, ppm (J, Hz): 7.52 (2H, m, Harom-2); 7.21 (2H, m, Harom-3); 2.65 (3H, s, 2-CH3); 2.47 (3H, d, J = 3.0,
5-CH3); 2.37 (3H, s, CH3-C6H5). Mass spectrum, m/z (Irel, %): 204 [M+1]+ (26), 203 [M]+ (100), 202 [M-1]+ (48),
162 (85), 147 (31), 128 (22), 115 (18), 91 (19). Found, %: C 70.92; H 6.55; N 6.91; S 15.60. C12H13NS.
Calculated, %: C 70.89; H 6.45; N 6.89; S 15.77.
1
4-(4-Methoxyphenyl)-2,5-dimethyl-1,3-thiazole (2e). Yield 63%; bp 141-142°C (1 mm Hg). H NMR
spectrum, δ, ppm (J, Hz): 7.53 (2H, dd, J = 7.7, J = 2.7, Harom-2); 6.92 (2H, dd, J = 7.7, J = 2.7, Harom-3); 3.80
(3H, s, CH3O); 2.62 (3H, s, 2-CH3); 2.43 (3H, d, J = 1.0, 5-CH3). Mass spectrum, m/z (Irel, %): 220 [M+1]+ (35),
219 [M]+ (100), 218 [M-1]+ (30), 204 (19), 178 (84), 163 (99), 135 (33), 102 (16), 91 (29). Found, %: C 65.75;
H 6.06; N 6.40; S 14.69. C12H13NOS. Calculated, %: C 65.72; H 5.975; N 6.39; S 14.62.
2,5-Dimethyl-4-(2-thienyl)-1,3-thiazole (2f). Yield 57%; oil, Rf 0.86 (Silufol UV-254, 10:1
1
benzene–acetone). H NMR spectrum, δ, ppm (J, Hz): 7.19 (1H, dd, J = 3.8, J = 1.3, Hth-5); 7.17 (1H, dd,
J = 5.0, J = 1.0, Hth-3); 6.96 (1H, dd, J = 5.0, J = 3.8, Hth-4); 2.53 (3H, s, 2-CH3); 2.43 (3H, s, 5-CH3). Mass
spectrum, m/z (Irel, %): 197 [M+2]+ ((15), 196 [M+1]+ (19), 195 [M]+ (100), 154 (89), 153 (49), 139 (9), 121
(14), 110 (32), 95 (9). Found, %: C 55.48; H 4.72; N 7.32; S 32.95. C9H9NS2. Calculated, %: C 55.35; H 4.64;
N 7.17; S 32.84.
7-Methoxy-2-methyl-4,5-dihydronaphtho[1,2-d][3,1]thiazole (4a). Yield 41%; oil, Rf 0.6 (Silufol UV-
1
254, 10:1 benzene–acetone). H NMR spectrum, δ, ppm (J , Hz): 7.80 (1H, d, J = 8.4, H-9); 6.78 (1H, dd, J =
8.2, J = 3.0, H-8); 6.74 (1H, d, J = 3.0, H-6); 3.70 (3H, s, CH3O); 2.94 (m, CH2–CH2); 2.70 (3H, s, 2-CH3). Mass
spectrum, m/z (Irel, %): 232 [M+1]+ (11), 231 [M]+ (100), 230 [M-1]+ (28), 216 (44), 189 (9), 175 (8), 158 (6),
147 (23), 145 (11), 115 (9), 103 (9). Found %: C 67.56; H 5.65; N 6.78; S 13.67. C13H13NOS. Calculated, %: C
67.50; H 5.66; N 6.055; S 13.86.
8-Methoxy-2-methyl-4,5-dihydronaphtho[1,2-d][3,1]thiazole (4b). Yield 55%; oil, Rf 0.63 (Silufol
1
UV-254, 10:1 benzene–acetone). H NMR spectrum, δ, ppm (J , Hz): 7.47 (1H, d, J = 3.0, H-9); 7.07 (1H, d,
J = 8.2, H-6); 6.72 (1H, dd, J = 8.2, J = 3.0, H-7); 3.65 (3H, s, CH3O); 2.92 (m, CH2–CH2); 2.70 (3H, s, 2-CH3).
1069

Mass spectrum, m/z (Irel, %): 232 [M+1]+ (19), 231 [M]+ (100), 230 [M-1]+ (47), 216 (16), 200 (11),189 (13),
175 (8), 147 (14), 145 (16), 115 (11), 102 (8). Found %: C 67.51; H 5.67; N 6.00; S 13.77. C13H13NOS.
Calculated, %: C 67.50; H 5.66; N 6.055; S 13.86.
4-(5-Bromo–6-methoxy-2-naphthyl)-2,5-dimethyl-1,3-thiazole (6). Yield 65%; mp 135-137°C.
1H NMR spectrum, δ, ppm (J, Hz): 8.24 (1H, d, J = 8.7, Harom-1); 8.02 (1H, d, J = 3.0, Harom-4); 7.86 (1H, d,
J = 3.0, Harom-8); 7.84 (1H, d, J = 3.0, Harom-2); 7.25 (1H, m, Harom-7); 4.02 (3H, s, CH3O); 2.65 (3H, s, 2-CH3);
2.55 (3H, s, 5-CH3). Mass spectrum, m/z (Irel, %): 349 (100), 347 (100), 334 (39), 332 (39), 306 (29), 293 (34),
291 (34), 265 (17), 263 (27), 212 (10), 184 (31), 152 (25), 134 (21), 113 (17). Found, %: C 57.42; H 4.42;
N 4.12. C16H14BrNOS. Calculated, %: C 57.84; H 4.25; N 4.22.
2-Methylcycloocta[d][1,3]thiazole (8). Yield 53%; oil, Rf 0.44 (Silufol UV-254, 10:1
1
benzene–acetone). H NMR spectrum, δ, ppm (J, Hz): 2.70 (4H, dd, J = 13.2, J = 7.0, 4-,9-CH2); 2.50 (3H, s,
2-CH3); 1.58 (4H, m, 5-, 8-CH2); 1.30 (4H, m, 6-, 7-CH2). Mass spectrum, m/z (Irel, %): 182 [M+1]+ (13), 181
[M]+ (100), 180 [M-1]+ (3), 166 (14), 153 (95), 140 (55), 125 (54), 113 (42), 107 (55), 97 (4), 79 (41). Found, %:
C 66.13; H 8.30; N 7.89; S 17.24. C10H15NS. Calculated, %: C 66.25; H 8.34; N 7.73; S 17.69.
2-Methyl-5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-d]3,1]thiazole (10). Yield 56%; oil, Rf 0.71
1
(Silufol UV-254, 10:1 benzene–acetone). H NMR spectrum, δ, ppm (J, Hz): 8.00 (1H, d, J = 8, Harom-7); 7.29
(1H, m, Harom-10); 7.18 (2H, m, Harom-8,9); 2.90 (2H, t, J = 7.0, 4-CH2); 2.76 (2H, m, 6-CH2); 2.68 (2H, s,
2-CH2); 2.60 (2H, m, 6-CH2). Mass spectrum, m/z (Irel, %): 216 [M+1]+ (28), 215 [M]+ (100), 214 [M -1]+ (37),
200 (30), 182 (25), 173 (49), 141 (59), 128 (30), 115 (36). Found, %: C 72/57; H 6.12; N 6.35; S 14.45.
C13H13NS. Calculated, %: C 72.52; H 6.09; N 6.51; S 14.90.
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