Features of the α-azolyl-2-hydroxy-acetophenones reaction with chloroacetyl chloride

Full text of DOI:10.1007/s10593-012-0906-5

Chemistry of Heterocyclic Compounds, Vol. 47, No. 10, January, 2012 (Russian Original Vol. 47, No. 10, October, 2011)
LETTERS TO THE EDITOR
FEATURES OF THE -AZOLYL-2-HYDROXY-
ACETOPHENONES REACTION WITH
CHLOROACETYL CHLORIDE
T. V. Shokol1*, N. V. Gorbulenko1, V. P. Khilya1
Keywords: -azahetaryl-2-hydroxyacetophenones, 3-azolyl-2-chloromethyl-7-hydroxychromones,
acylation.
The patent [1] reports the synthesis of 2-chloromethyl-7-hydroxyisoflavones by condensation of -aryl-
2-hydroxyacetophenones with chloroacetic acid anhydride and subsequent acid hydrolysis of the 7-acyloxy
group. In our study of the reactivity of -hetaryl-2-hydroxyacetophenones of type 1 we have shown that
chloroacetyl chloride acylation of the derivative with a 5-phenyl-1,3,4-thiadiazol-2-yl substituent gives a
2-chloromethylchromone of type 2 [2], while both the -(2-pyridyl)- and -(2-quinolyl) derivatives form the
products of subsequent intramolecular cyclization with annelation of indolizine or pyrroloquinoline ring to the
chromone ring [3, 4].
O
Cl
HO
R
OH
O
O
R
O
HO
R
O
O
ClCH2COCl
Py
HCl
Cl
Het
Cl
Het
EtOH
Het
O
1a–e
2a,b,e
1–3 а R = Et, Het = 4-methylthiazol-2-yl, b R = Hex, Het = benzothiazol-2-yl, с R = Pr,
3a,b,e
Het = 1-methylbenzimidazol-2-yl, d R = Et, Het = 3-isoxazolyl, e R = Et, Het = 1-phenylpyrazol-4-yl
In order to define the boundaries of use of this method for synthesis of 2-chloromethyl-3-hetaryl
chromones we have introduced acetophenones with 4-methylthiazol-2-yl (1a), 2-benzothiazolyl (1b), 1-methyl-
benzimidazol-2-yl (1c), 3-isoxazolyl (1d), or 1-phenylpyrazol-4-yl (1e) substituents into this reaction. It was
found that ketones 1a,b, treated with excess chloroacetyl chloride and pyridine in dioxane or acetonitrile, give
satisfactory yields of the corresponding chloroacetoxy products 2a,b (even at room temperature) and that these
hydrolyze in alcohol in the presence of HCl to the 7-hydroxychromones 3a,b. By comparison, carrying out the
cyclization of ketones 1c and 1d was unsuccessful either under mild conditions or upon heating but the ketone
1e gave the product 3e, even though in only low yield.
_______
*To whom correspondence should be addressed, e-mail: shokol_tv@mail.univ.kiev.ua.
1Taras Shevchenko Kyiv National University, 60 Volodymyrska St., Kyiv 01601, Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1568-1570, October, 2011.
Original article submitted February 15, 2011.
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0009-3122/12/4710-1298©2012 Springer Science+Business Media, Inc.

Hence this method has proved effective in the synthesis of 2-chloromethylchromones only with a sulfur-
containing azole substituent in position 3.
1H NMR spectra were recorded on a Varian Mercury 400 spectrometer (400 MHz) using DMSO-d6 with
TMS as internal standard. Melting points were determined on a Boetius type mini observation stage with a VEB
Analytic PHMK 0.5 apparatus.
2-Chloromethyl-6-ethyl-3-(4-methyl-1,3-thiazol-2-yl)-4-oxo-4H-chromen-7-yl Chloroacetate (2a).
Pyridine (1.19 g, 15 mmol) and chloroacetyl chloride (1.69 g, 15 mmol) were added to a solution of compound
1a (1.38 g, 5 mmol) in acetonitrile (15 ml), held for 24 h at room temperature, and obtained precipitate was filtered
1
off. Yield 44%; mp 147-148ºC (MeCN). H NMR spectrum, , ppm (J, Hz): 1.26 (3H, t, J = 7.2, 6-CH3CH2);
2.55 (3H, s, 4'-CH3); 2.70 (2H, q, J = 7.2, 6-CH3CH2); 4.68 (2H, s, COCH2Cl); 5.56 (2H, s, 2-CH2Cl); 7.33 (1H,
s, H-5'); 7.64 (1H, s, H-8); 8.11 (1H, s, H-5). Found, %: N 3.67; S 7.59. C18H15Cl2NO4S. Calculated, %: N 3.40;
S 7.78.
3-(1,3-Benzothiazol-2-yl)-2-chloromethyl-6-(n-hexyl)-4-oxo-4H-chromen-7-yl Chloroacetate (2b).
1
Prepared similarly to product 2a from compound 1b. Yield 54%; mp 132ºC (MeCN). H NMR spectrum, ,
ppm (J, Hz): 0.89 (3H, t, J = 7.2, CH3); 1.30-1.36 (6H, m, (CH2)3); 1.58-1.62 (2H, m, CH2(CH2)3CH3); 2.68
(2H, t, J = 7.2, CH2(CH2)4CH3); 4.66 (2H, s, COCH2Cl); 5.58 (2H, s, 2-CH2Cl); 7.46 (1H, t, J = 8.0, H-6'); 7.53
(1H, t, J = 8.0, H-5'); 7.68 (1H, s, H-8); 8.06-8.11 (3H, m, H-5,4',7'). Found, %: N 2.60; S 6.33. C25H23Cl2NO4S.
Calculated, %: N 2.78; S 6.36.
2-Chloromethyl-6-ethyl-7-hydroxy-3-(4-methyl-1,3-thiazol-2-yl)-4H-chromen-4-one
(3a).
A
solution of compound 2a (1.23 g, 3 mmol) was refluxed in a mixture of EtOH (50 ml) and 37% HCl (1 ml) for
1
1.5 h, held for 24 h at room temperature, and filtered off. Yield 88%; mp 213ºC (decomp.) (EtOH). H NMR
spectrum, , ppm (J, Hz): 1.24 (3H, t, J = 7.2, 6-CH3CH2); 2.57 (3H, s, 4'-CH3); 2.67 (2H, q, J = 7.2,
6-CH3CH2); 5.51 (2H, s, 2-CH2Cl); 6.92 (1H, s, H-5'); 7.27 (1H, s, H-8); 7.83 (1H, s, H-5); 10.90 (1H, s, OH).
Found, %: N 3.99; S 9.47. C16H14ClNO3S. Calculated, %: N 4.17; S 9.55.
3-(1,3-Benzothiazol-2-yl)-2-chloromethyl-6-(n-hexyl)-7-hydroxy-4H-chromen-4-one (3b). Prepared
1
from compound 2b similarly to product 3a. Yield 94%; mp 188ºC (decomp.) (EtOH). H NMR spectrum, ,
ppm (J, Hz): 0.90 (3H, t, J = 7.2, CH3); 1.34 (6H, m, (CH2)3); 1.61 (2H, m, CH2(CH2)3CH3); 2.63 (2H, t, J = 7.2,
CH2(CH2)4CH3); 5.55 (2H, s, 2-CH2Cl); 6.94 (1H, s, H-8); 7.41 (1H, t, J = 8.0, H-6'); 7.50 (1H, t, J = 8.0, H-5');
7.84 (1H, s, H-5); 8.03 (1H, d, J = 8.0, H-4'); 8.06 (1H, d, J = 8.0, H-7'); 10.87 (1H, s, OH). Found, %: N 3.33;
S 7.33. C23H22ClNO3S. Calculated, %; N 3.27; S 7.49.
2-Chloromethyl-6-ethyl-7-hydroxy-3-(1-phenylpyrazol-4-yl)-4H-chromen-4-one (3e). Triethylamine
(0.5 g, 5 mmol) and chloroacetyl chloride (0.56 g, 5 mmol) were added to a solution of 5-ethyl-2,4-dihydroxy-
-(1-phenylpyrazol-4-yl)acetophenone (1e) (0.41 g, 1.2 mmol) in acetonitrile (5 ml), refluxed for 1.5 h, and
treated with water. The oil formed was separated, refluxed in ethanol, and the precipitate formed was filtered
off. Yield 6%; mp 273ºC (EtOH). 1H NMR spectrum, , ppm (J, Hz): 1.23 (3H, t, J = 7.2, 6-CH3CH2); 2.67 (2H,
q, J = 7.2, 6-CH3CH2); 4.73 (2H, s, 2-CH2Cl); 6.86 (1H, s, H-8); 7.30 (1H, t, J = 7.6, H-4''); 7.49 (2H, t, J = 7.6,
H-3'',5''); 7.75 (1H, s, H-5'); 7.84 (1H, s, H-5); 7.85 (2H, d, J = 7.6, H-2'',6''); 8.54 (1H, s, H-3'); 10.69 (1H, s,
OH). Found, %: N 7.20. C21H17ClN2O3. Calculated, %: N 7.36.
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