Synthesis of 6-alkyl-2-dialkylaminomethyl-7-hydroxy-3-(4-methylthiazol-2- yl)-4h-chromen-4-ones

Article abstract of DOI:10.1007/s10593-012-1119-7

Amination of 6-alkyl-2-chloromethyl-7-hydroxy-3-(4-methylthiazol-2-yl)-4H- chromen-4-ones by secon-dary cyclic amines gives the corresponding 2-dialkylaminomethyl derivatives.

Full text of DOI:10.1007/s10593-012-1119-7

Chemistry of Heterocyclic Compounds, Vol. 48, No. 8, November, 2012 (Russian Original Vol. 48, No. 8, August, 2012)
SYNTHESIS OF 6-ALKYL-2-DIALKYLAMINOMETHYL-
7-HYDROXY-3-(4-METHYLTHIAZOL-2-YL)-4H-CHROMEN-
4-ONES
T. V. Shokol1*, N. V. Gorbulenko1, A. V. Turov1, and V. P. Khilya1
Amination of 6-alkyl-2-chloromethyl-7-hydroxy-3-(4-methylthiazol-2-yl)-4H-chromen-4-ones by secon-
dary cyclic amines gives the corresponding 2-dialkylaminomethyl derivatives.
Keywords: 2-dialkylaminomethyl-3-thiazolylchromones, 2-chloromethyl-3-thiazolylchromones.
The modification of flavonoid molecules by the introduction of aminomethyl groups is one of the
promising routes in the chemistry of this class of compounds. Mannich bases are readily formed by the direct
aminomethylation of chromones or via amination of a corresponding halomethyl group. They are generally
soluble in water after conversion to the quaternary ammonium salts, have high biological activity, and can serve
as starting materials in the preparation of other classes of heterocyclic compounds [1].
By direct aminomethylation (using aminals) of a series of 3-hetarylchromones, we have obtained
N-substituted aminomethyl derivatives at the positions 6 and 8 of the chromone system for isoxazole [2],
pyrazole [3], thiazole [4], benzothiazole [5], benzimidazole [6], or triazole [7] analogs. Several of these show
hypoglycemic, analeptic, antimicrobial, or anti-inflammatory activity.
2-Aminomethyl-3-hetaryl chromones were unknown to this time.
Analysis of literature data has shown that N-substituted 2-aminoalkylchromones prepared via amination
of 2-halomethylchromones are antiblastic and immunosuppressive agents [8], active CNS stimulants [9]. They
are -adrenoceptor blockers [10], selective -ligands, and can be used in the treatment of psychoses [11, 12].
Derivatives of isoflavone thiazole analogs also are promising medicinal substances with a set of useful
properties (analeptic, hypoglycemic, hypolipidemic, cytoprotective, anti-inflammatory, and diuretic activity) [4,
13-18].
The aim of this study was the synthesis of 2-dialkylaminomethyl-7-hydroxy-3-(4-methylthiazol-2-yl)-
chromones by the amination of the corresponding 2-chloromethyl derivatives with secondary cyclic amines.
In this work, 5-alkyl-2,4-dihydroxy--(4-methylthiazol-2-yl)acetophenones 1a,b [19] were treated at room
temperature or with heating with an excess of chloroacetic acid anhydride or chloroacetyl chloride in dioxane or
acetonitrile in the presence of an organic base (pyridine or triethylamine). In selecting optimal conditions for the
preparation of the 6-alkyl-7-chloroacetoxy-2-chloromethyl-3-(4-methylthiazol-2-yl)chromones 2a,b we were
guided by such criteria as product purity, yield, and simplicity of performing the synthesis. The choice of solvent
_______
*To whom correspondence should be addressed, e-mail: shokol_tv@mail.univ.kiev.ua.
1Kyiv Taras Shevchenko National University, 60 Volodymirska St., Kyiv 01601, Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1266-1271, August, 2012.
Original article submitted October 14, 2011.
0009-3122/12/4808-1181©2012 Springer Science+Business Media New York
1181

proved to be important. When the reaction of compounds 1a,b with chloroacetyl chloride occurred in
acetonitrile unlike in dioxane, the chromones 2a,b precipitated along with pyridine hydrochloride (which could
be readily removed by treating the precipitate with water). The compounds 2a,b thus obtained were
chromatographically pure. When compounds 1a,b were acylated using chloroacetic acid anhydride in
acetonitrile, or the reaction was performed in dioxane, the chromones 2a,b did not precipitate from the reaction
mixture. Preparation of these compounds in a pure state needed more prolonged isolation process (evaporation
of solvent and treatment with water) and recrystallization. Variation of the base and heating the reaction mixture
on a water bath for 2 h did not give an increased yield of compounds 2a,b. Hence the best results for the
synthesis of chromones 2a,b were obtained when carrying out the reaction in acetonitrile at room temperature
with an acetophenone–chloroacetyl chloride–pyridine ratio of 1:3:3.
O
Cl
HO
R
OH
O
R
O
ClCH2COCl
Cl
S
Py, MeCN
room temp.
S
O
N
O
N
2a,b
Me
Me
1a,b
X
N
HO
R
O
Cl
S
X
HN
HO
O
HCl, EtOH

Dioxane
S
R

O
N
O
N
Me
3a,b
Me
4–6 a,b, 7a, 8b, 9b
1–7 a R = Et, 1–9 b R = n-Pr
4a,b X = O, 5a,b X = CH2, 6a,b X = CHCH2Ph, 7a X = NMe,
N
O
N
8b X =
, 9b X =
O
F
1
The H NMR spectra of compounds 2a,b were characterized by two singlets for the methylene protons
of the 7-chloroacetoxy group at 4.64-4.68 ppm and the 2-CH2Cl group at 5.55-5.56 ppm. The IR spectra of
these compounds showed C=O stretching absorption bands for the chromone ring at 1639 cm-1 and for the
acyloxy group at 1778 (compound 2a) or 1749 cm-1 (compound 2b).
It should be noted that the 7-chloroacetoxy group in compounds 2a,b is quite labile. Washing the
1
precipitated chromones 2a,b with water results in partial hydrolysis (indicated by H NMR data for these
compounds). The 2-chloromethyl-7-hydroxychromones 3a,b were prepared by refluxing compounds 2a,b in
ethanol in the presence of hydrochloric acid. The 1H NMR spectra of compounds 3a,b show the absence of the
methylene group singlet at 4.64-4.68 ppm and the appearance of a singlet for the 7-OH proton at 10.72-10.90 ppm.
The reaction of the 2-chloromethylchromones 3a,b with a twofold excess of secondary cyclic amines
(morpholine, piperidine and its 4-benzyl derivative, and N-alkyl(aryl)piperazines) in dioxane gives the 2-di-
alkylaminomethyl-7-hydroxy-3-(4-methylthiazol-2-yl)chromones 4-9 in high yields. Compounds 4-9 are
colorless crystalline substances, insoluble in water and a 5% hydrochloric acid solution, but soluble in a 5%
alkali solution and polar solvents. The structure and composition of compounds 4-9 were proved using
spectroscopic methods and elemental analysis (Table 1). In their IR spectra, the C=O stretching vibrations for
1182

TABLE 1. Physicochemical Characteristics of the Synthesized
Compounds 2b, 3b, 4a,b, 5a,b, 6a,b, 7a, 8b, 9b
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Mp, °С
Yield, %
Rf
С
Н
N
S
C19H17Cl2NO4S
C17H16ClNO3S
C20H22N2O4S
C21H24N2O4S
C21H24N2O3S
C22H26N2O3S
C28H30N2O3S
C29H32N2O3S
C21H25N3O3S
C29H31N3O5S
C27H28FN3O3S
53.67
53.53
58.03
58.37
61.90
62.16
62.76
62.98
65.37
65.60
66.46
66.31
70.66
70.86
71.42
71.28
4.32
4.02
4.90
4.61
5.45
5.74
6.16
6.04
6.53
6.29
6.85
6.58
6.33
6.37
6.89
6.60
3.27
3.29
4.27
4.00
7.02
7.25
7.22
6.99
7.51
7.29
6.82
7.03
6.09
5.90
5.71
5.73
7.52
7.52
9.00
9.17
8.08
8.30
8.02
8.01
8.21
8.34
7.96
8.05
6.78
6.76
6.48
6.56
141-142
209-210
140-141
149-150
174-175
162-163
219-220
207-208
132-133
191-192
179-180
55
79
81
65
84
63
79
82
84
58
64
0.94
0.87
0.68
0.63
0.46
0.44
0.76
0.78
0.32
0.71
0.75
2b
3b
4a
4b
5a
5b
6a
6b
7a
8b
9b
62.79
63.13
65.53
65.27
65.48
65.70
6.60
6.31
5.97
5.86
5.96
5.72
10.52
10.52
8.10
7.87
8.69
8.51
8.05
8.03
6.30
6.01
6.38
6.50
the chromone carbonyl are observed at 1639-1636 cm-1. A characteristic feature of the 1H NMR spectra of these
compounds is a marked upfield shift by 1.4 ppm of the position 2 aminomethyl group, and also the presence of
proton signals for the groups or fragments at the tertiary nitrogen atom. Signals for the chromone ring, thiazole
substituent, and 7-OH group protons (10.56-10.72 ppm) are observed in the same regions as in the starting
2-chloromethyl derivatives 3a,b (Table 2).
1
The H NMR spectra of compounds 6a,b proved less easy to interpret. For a reliable signal assignment
in the spectrum of compound 6b its COSY-90 spectrum was recorded. The correlations discovered and the
corresponding chemical shift values are given in Figure 1.
7.14
2.43 H
H
7.24
H
2.04
H
7.10
H
H
H 1.40
H 1.43
N
H 2.81
H
10.56
6.90
7.79
H
HO
CH2
O
O
1.12
4.11
1.59
H2
C
S
H3C
0.91
C
H2
2.60
7.35
2.41
N
CH3
Fig. 1. Correlations observed in the COSY spectrum (↔) of compound 6b. The NOE correlation (→) is also
shown for the piperidine fragment protons with additional irradiation at the frequency of the 2-methylene group
signal.
1183

TABLE 2. Spectroscopic Characteristics of Compounds 2b, 3b, 4a,b,
5a,b, 6a,b, 7a, 8b, 9b
Com- IR spectrum,
1Н NMR spectrum, , ppm (J, Hz)
cm-1
pound
1639*,
1749*2
0.98 (3H, t, J = 7.2, CH3CH2CH2); 1.65 (2H, sextet, J = 7.2, CH3CH2CH2);
2.52 (3H, s, 4'-CH3); 2.66 (2H, t, J = 7.2, CH3CH2CH2); 4.64 (2H, s, COCH2Cl);
5.55 (2H, s, 2-CH2Cl); 7.29 (1H, s, H-5'); 7.62 (1H, s, H-8); 8.09 (1H, s, H-5)
2b
3b
4a
4b
1611*3
1639*
1636*
0.97 (3H, t, J = 7.2, CH3CH2CH2); 1.65 (2H, sextet, J = 7.2, CH3CH2CH2);
2.53 (3H, s, 4'-CH3); 2.62 (2H, t, J = 7.2, CH3CH2CH2); 5.49 (2H, s, 2-CH2Cl);
6.89 (1H, s, H-8); 7.19 (1H, s, H-5'); 7.80 (1H, s, H-5); 10.72 (1H, s, 7-OH)
1.23 (3H, t, J = 7.2, CH3CH2); 2.46 (3H, s, 4'-CН3); 2.55 (4H, br. s, CH2NCH2);
2.66 (2H, q, J = 7.2, CH3CH2); 3.54 (4H, br. s, CH2OCH2); 4.22 (2H, s, 2-CH2N);
6.87 (1H, s, H-8); 7.19 (1H, s, H-5'); 7.80 (1H, s, H-5); 10.70 (1H, s, 7-OH)
0.97 (3H, t, J = 7.2, CH3CH2CH2); 1.65 (2H, sextet, J = 7.2, CH3CH2CH2);
2.46 (3H, s, 4'-CH3); 2.54 (4H, br. s, CH2NCH2);
2.63 (2H, t, J = 7.2, CH3CH2CH2); 3.54 (4H, br. s, CH2OCH2);
4.22 (2H, s, 2-CH2N); 6.86 (1H, s, H-8); 7.15 (1H, s, H-5');
7.78 (1H, s, H-5); 10.64 (1H, s, 7-OH)
1639*
1636*
1637*
1.23 (3H, t, J = 7.2, CH3CH2); 1.36 (2H, br. s, N(CH2CH2)2CH2);
1.47 (4H, br. s, N(CH2CH2)2CH2); 2.46 (3H, s, 4'-CН3);
2.49-2.53 (4H, m, CH2NCH2); 2.67 (2H, q, J = 7.2, CH3CH2);
4.13 (2H, s, 2-CH2N); 6.86 (1H, s, H-8); 7.19 (1H, s, H-5');
7.80 (1H, s, H-5); 10.66 (1H, s, 7-OH)
5a
5b
6a
0.97 (3H, t, J = 7.2, CH3CH2CH2); 1.37 (2H, br. s, N(CH2CH2)2CH2);
1.49 (4H, br. s, N(CH2CH2)2CH2); 1.65 (2H, sextet, J = 7.2, CH3CH2CH2);
2.47 (3H, s, 4'-CH3); 2.54 (4H, br. s, СН2NCH2);
2.63 (2H, t, J = 7.2, CH3CH2CH2); 4.14 (2H, s, 2-CH2N);
6.86 (1H, s, H-8); 7.13 (1H, s, H-5'); 7.77 (1H, s, H-5); 10.56 (1H, s, 7-OH)
1.17-1.24 (5H, m, CH3CH2, CHАCH(CH2Ph)CHА);
1.40-1.46 (1H, m, CHCH2Ph); 1.50 (2H, d, J = 12.4, CHВCH(CH2Ph)CHВ);
2.09 (2H, t, J = 10.8, CHАNCHА); 2.45-2.53 (5H, m, 4'-CН3, CH2Ph);
2.65 (2H, q, J = 7.2, CH3CH2); 2.84 (2H, d, J = 10.4, CHВNCHВ);
4.16 (2H, s, 2-CH2N); 6.84 (1H, s, H-8); 7.05 (2H, d, J = 7.6, H-2,6 Ph);
7.10 (1H, t, J = 7.6, H-4 Ph); 7.14 (1H, s, H-5');
7.19 (2H, d, J = 7.6, H-3,5 Ph); 7.79 (1H, s, H-5); 10.63 (1H, s, 7-OH)
1639*
0.91 (3H, t, J = 7.2, CH3CH2CH2); 1.12 (2H, m, CHАCH(CH2Ph)CHА);
1.40 (1H, m, CHCH2Ph); 1.43 (2H, d, J = 12.0, CHВCH(CH2Ph)CHВ);
1.59 (2H, sextet, J = 7.2, CH3CH2CH2); 2.04 (2H, t, J = 10.4, CHАNCHА);
2.41-2.43 (5H, m, 4'-CH3, CH2Ph); 2.60 (2H, t, J = 7.2, CH3CH2CH2);
2.81 (2H, d, J = 10.4, CHВNCHВ); 4.11 (2H, s, 2-CH2N); 6.90 (1H, s, H-8);
7.10 (2H, d, J = 7.2, H-2,6 Ph); 7.14 (1H, t, J = 7.2, H-4 Ph);
7.24 (2H, d, J = 7.2, H-3,5 Ph); 7.35 (1H, s, H-5'); 7.79 (1H, s, H-5);
10.56 (1H, s, 7-OH)
6b
1639*
1639*
1.23 (3H, t, J = 7.2, CH3CH2); 2.14 (3H, s, NCH3);
2.30 (4H, br. s, CH2N(CH3)CH2); 2.46 (3H, s, 4'-CH3);
2.49-2.53 (4H, m, CH2NCH2); 2.66 (2H, t, J = 7.2, CH3CH2);
4.19 (2H, s, 2-CH2N); 6.86 (1H, s, H-8); 7.19 (1H, s, H-5');
7.79 (1H, s, H-5); 10.72 (1H, s, 7-OH)
7a
8b
0.98 (3H, t, J = 7.2, CH3CH2CH2); 1.65 (2H, sextet, J = 7.2, CH3CH2CH2);
2.32 (4H, br. s, CH2N(СН2Ar)CH2); 2.46 (3H, s, 4'-CH3);
2.56 (4H, br. s, CH2NCH2); 2.62 (2H, t, J = 7.2, CH3CH2CH2);
3.31 (2H, s, NCH2Ar); 4.21 (2H, s, 2-CH2N); 5.92 (2H, s, OCH2O);
6.65-6.67 (2H, m, H-5,6 Ar); 6.75 (1H, s, H-2 Ar); 6.85 (1H, s, H-8);
7.13 (1H, s, H-5'); 7.78 (1H, s, H-5); 10.57 (1H, s, 7-OH)
1636*
0.98 (3H, t, J = 7.2, CH3CH2CH2); 1.67 (2H, sextet, J = 7.2, CH3CH2CH2);
2.48 (3H, s, 4'-CH3); 2.54 (4H, br. s, CH2NCH2);
9b
2.63 (2H, t, J = 7.2, CH3CH2CH2); 2.74 (4H, br. s, CH2N(Ar)CH2);
4.31 (2H, s, 2-CH2N); 6.81-6.93 (5H, m, H-8, H Ar); 7.16 (1H, s, H-5');
7.79 (1H, s, H-5); 10.61 (1H, s, 7-OH)
_______
* C(4)=O.
*2 7-ClCH2COO.
*3 Overlapping C=O and C=C Ar stretching bands.
1184

Hence potential biologically active 2-dialkylamino derivatives of 2-chloromethyl-7-hydroxy-3-(4-methyl-
thiazol-2-yl)chromones have been synthesized.
EXPERIMENTAL
1
IR spectra were recorded on a Perkin Elmer BX instrument in KBr pellets. H NMR spectra were
recorded on a Varian Mercury 400 spectrometer (400 MHz) using DMSO-d6 with TMS as internal standard.
COSY-90 and homonuclear NOE experiments were carried out by the Varian Company standard methods.
Elemental analysis was performed on a Perkin Elmer CHN analyzer. Melting points were determined on a mini
Boetius hot stage apparatus with a VEB Analytic PHMK 0.5 visual system. The course of the reaction and
purity of the compounds obtained were determined by TLC using Silufol UV-254 plates with CHCl3–MeOH
(95:5) as eluent.
Compounds 2a and 3a were obtained by a literature method and their physicochemical and
spectroscopic parameters agreed with those given in the study [20].
2-Chloromethyl-3-(4-methyl-1,3-thiazol-2-yl)-4-oxo-6-n-propyl-4H-chromen-7-yl Chloroacetate (2b).
Pyridine (1.19 g, 15 mmol) and chloroacetyl chloride (1.69 g, 15 mmol) were added to a solution of compound
1b (1.46 g, 5 mmol) in MeCN (15 ml) and held for 1 day at room temperature. The precipitate formed was
filtered off, washed with MeCN and ice water, and recrystallized from MeCN.
2-Chloromethyl-7-hydroxy-3-(4-methyl-1,3-thiazol-2-yl)-6-n-propyl-4H-chromen-4-one (3b). 37%
HCl (1 ml) was added to a solution of compound 2b (1.24 g, 3 mmol) in EtOH (50 ml), refluxed for 1.5-2.0 h,
held for 1 day at room temperature, and the precipitate formed was filtered off and recrystallized from EtOH.
6-Alkyl-2-dialkylaminomethyl-7-hydroxy-3-(4-methyl-1,3-thiazol-2-yl)-4H-chromen-4-ones
4-9
(General Method). The secondary amine (2 mmol) was added to a solution of compound 3a,b (1 mmol) in
dioxane (7 ml), refluxed for 0.5-3.0 h, and held for 1 day at room temperature. Compounds 5b, 6a,b, 8b formed
precipitates which were filtered off, washed with dioxane and water, and recrystallized from dioxane. In the
other cases, the solvent was evaporated and compounds 4a, 5a, 7a were recrystallized from ethyl acetate, while
compounds 4b, 9b were recrystallized from dioxane.
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1186