2
,4,6-Trihydroxy-3-methylbenzoic acid
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 1, January, 2019
77
o-HPh, J = 7.6 Hz); 7.53 (t, 1 H, p-HPh, J = 7.6 Hz); 7.58 (t, 2 H,
44(100). Found (%): С, 49.27; Н, 3.85; N, 3.22; S, 7.31.
C H NO S. Calculated (%): C, 49.20; H, 3.90; N, 3.19; S, 7.30.
m-HPh, J = 7.6 Hz); 8.94, 10.42 (br.s, С(5)OH, С(7)OH). HRMS
18
17
10
+
(
ESI), found m/z: 326.1023 [М] ; C18H16NO ; calculated
5,7-Dihydroxy-3-(3,4-dimethoxyphenyl)-2-imino-8-methyl-
5
+
М = 326.1028. MS (EI, 70 eV), m/z (Irel (%)): 280 [М – СО2]
2Н-chromene-6-carboxylic acid hydrosulfate (6f). Yield 0.14 g
1
(
21); 254 (10); 64(73); 44(100). Found (%): С, 50.99; Н, 4.10;
(21%), yellow powder. M.p. 163 C (EtOH). R = 0.09 (B). H
f
N, 3.34; S, 7.48. C H NO S. Calculated (%): C, 51.06; H, 4.05;
NMR (DMSO-d ), : 2.15 (s, 3 H, C(8)Me); 3.79 (s, 3 H, OCH );
18
17
9
6
3
N, 3.31; S, 7.57.
3.83 (s, 3 H, OCH ); 6.96 (s, 1 H, HAr); 7.04 (d, 1 H, HAr
,
3
5
,7-Dihydroxy-4,8-dimethyl-2-imino-3-(4-methoxyphenyl)-
J = 8.0 Hz); 7.41 (d, 1 H, HAr, J = 8.0 Hz); 8.27 (s, 1 H, H(4));
Н-chromene-6-carboxylic acid hydrosulfate (6b). Yield 0.1 g
9.83 (s, 1 Н, C(7)ОН); 10.29 (s, 1 Н, C(5)ОН). MS (EI, 70 eV),
+
m/z (Irel (%)): 328 [М – СО2] (25); 300 (12); 44 (100).
f
1
Found (%): С 48.61; Н 4.13; N 2.94; S, 6.78. C H NO S.
19
19
11
Calculated (%): C, 48.62; H, 4.08; N, 2.98; S, 6.83.
6
Synthesis of 2-(hetaryl)ethyl 2,4,6-trihydroxy-3-methylben-
zoates (7a,b) (general procedure). 2,4,6-Trihydroxy-3-methyl-
benzoic acid (2) (1.0 g, 5,43 mmol) was dissolved at room tem-
perature in DMF (10 mL), then DCC (1.0 g, 4.85 mmol), the
corresponding alcohol (6.43 mmol), and catalytic amount of
DMAP were added. The mixture was stirred at ~20 C for 12 h.
The precipitate of N,N´-dicyclohexyl urea was filitered, the
filtrate was partially evaporated, and diethyl ether was added. The
resulting product was purified by column chromatography (silica
gel-60 Merck, eluent was dichloromethane—methanol (95 : 5)).
2-(5-Methyl-2-nitroimidazol-1-yl)ethyl 2,4,6-trihydroxy-3-
methylbenzoate (7а). Yield 0.73 g (40%), pale-yellow powder.
3
Ar
Ar
+
18
16
5
rel
+
19
19
10
5,7-Dihydroxy-3-(3,4-dimethoxyphenyl)-4,8-dimethyl-2-imino-
2
Н-chromene-6-carboxylic acid hydrosulfate (6c). Yield 0.16 g
(
(
(
23%), yellow powder. M.p. 290 C (EtOH). R = 0.15 (B). UV
f
1
ЕtОН), max/nm (lg): 227.69 (3.59); 370.92 (3.36). H NMR
DMSO-d ), : 2.12 (s, 3 H, C(8)Me); 2.39 (s, 3 H, C(4)Me);
6
+
3
.77 (s, 3 H, OCH ); 3.80 (s, 3 H, OCH ); 6.95 (s, 1 H, HAr);
M.p. 185 C. LC-MS (APCI), m/z: 337.99 [M] . MS (EI, 70 eV),
3
3
m/z (Irel (%)): 337 [М] (100), 211 (50), 167 (45). 1H NMR
+
7
.02 (d, 1 H, HAr, J = 8.0 Hz); 7.39 (d, 1 H, HAr, J = 8.0 Hz);
9
.81 (s, 1 Н, С(7)ОН); 10.31 (s, 1 Н, 5-ОН). HRMS (ESI),
(DMSO-d ), : 1,84 (s, 3 H, Ar—CH ); 2.43 (s, 3 H, Het—CH );
6 3 3
+
found m/z: 386,1228 [М] . C18H16NO . Calculated: М =
4.68 (t, 2 H, J = 6.64 Hz); 4.77 (t, 2 Н, J = 6.13 Hz); 5.96 (s, 1 Н,
Ar—3-Н); 8.06 (s, 1 H, Het—H).
5
+
3
86.1234. MS (EI, 70 eV), m/z (Irel (%)): 340 [М – СО2] (10);
16 (5); 44 (100). Found (%): С, 49.61; Н, 4.43; N, 2.93; S, 6.58.
3
2-(4-Methylthiazol-5-yl)ethyl 2,4,6-trihydroxy-3-methyl-
benzoate (7b). Yield 0.75 г (45%), reddish powder. M.p. 182 C.
C20H NO S. Calculated (%): C, 49.69; H, 4.38; N, 2.90;
21
11
+
S, 6.63.
LC-MS (APCI), m/z: 309.87 [M] . MS (EI, 70 eV), m/z
+
1
Synthesis of 3-aryl-5,7-dihydroxy-2-imino-8-methyl-2Н-
chromene-6-carboxylic acid hydrosulfates (6d—f) (general proce-
dure). 2,4,6-Trihydroxy-3-methylbenzoic acid 2 (0.33 g, 1,8 mmol)
(Irel (%)): 310 [М] (100), 166 (50), 144 (75). H NMR (DMSO-d ),
6
: 1.86 (s, 3 H, Ar—CH ); 2.33 (s, 3 H, Het—CH ); 3.25 (t, 2 Н,
3
3
OCH CH , J = 4.5 Hz); 4.49 (t, 2 Н, OCH , J = 4.5 Hz; 5.96
2
2
2
(s, 1 Н, Ar—3-Н); 7.95 (s, 1 H, Het—H).
2
4
1 mL), then the corresponding arylsubstituted -oxo nitrile 4d—f
Methyl 2,4,6-trihydroxy-3-methylbenzoate (8а). To a stirred
solution of 2,4,6-trihydroxy-3-methylbenzoic acid 2 (0.5 g,
was stirred until complete dissolution, the resulting solution was
allowed to stay for 1 day. Then the mixture was poured into EtOH
2.71 mmol) in acetone (10 mL), К СО (0.27 g, 2.93 mmol) and
2 3
dimethyl sulfate (0.26 mL, 2.74 mmol) were added. The mixture
was allowed to stay at ~20 C for 20—24 h. After the solvent was
evaporated, the solids were dissolved in ethyl acetate (30—40 mL)
(
10 mL); in a while the mixture crystallized. The formed yellow
precipitate was separated using the Schott filter (16 m), and
dried at 25 C for 1 day in a vacuum desiccator.
and rinsed stepwise with cooled 5% HCl, saturated NaHCO and
3
5
,7-Dihydroxy-2-imino-8-methyl-3-phenyl-2Н-chromene-6-
NaCl solutions in a separation funnel. The organic layer was dried
for 10—12 h over anhydrous sodium sulfate. Followed evaporation
of the solvent, the residue was purified by column chromato-
graphy (silica gel-60, Merck, eluent was dichloromethane—
methanol (95 : 5)). The product (0.32 g, 60%) was obtained as
carboxylic acid hydrosulfate (6d). Yield 0.12 g (22%), yellow
1
powder. M.p. 139 C (EtOH). R = 0.12 (B). H NMR (DMSO-d ),
f
6
: 2.14 (s, 3 H, C(8)Me); 7.50 (d, 2 H, o-HPh, J = 7.2 Hz); 7.63
(
t, 1 H, p-HPh, J = 7.2 Hz); 7.68 (t, 2 H, m-HPh, J = 7.2 Hz);
+
8
.36 (s, 1 H, H(4)); 9.93 (с, 1 Н, С(7)ОН); 10.99 (s, 1 Н, С(5)
a beige powder. M.p. 121 C. LC-MS (APCI), m/z: 199.17 [M] .
+
+
ОН). MS (EI, 70 eV), m/z (Irel (%)): 268 [М – СО2] (15); 240
MS (EI, 70 eV), m/z (I (%)): 199 [М] (100), 167 [M –
rel
+
1
(
10); 64 (60). 44(100). Found (%): С, 49.79; Н, 3.72; N, 3.40;
HOCH3] (15). H NMR (DMSO-d ), : 1.86 (s, 3 H, CH );
6
3
S 7.88. C H NO S. Calculated (%): C, 49.88; H, 3.69; N, 3.42;
3.88 (s, 3 H, OCH ); 5.96 (s, 1 Н, Н(3)).
17
15
9
3
S, 7.83.
2,4,6-Trihydroxy-3-methylbenzhydrazide (8b). To a boiling
solution of ester 8а (1.5 g, 7.53 mmol) in ethanol (25 mL) hydr-
azine hydrate (1.5 mL, 48.2 mmol) was added, and this was re-
fluxed for 4 h. After cooling, the precipitate was filtered, rinsed
with ethanol, and dried in air. The resulting material was purified
by column chromatography (silica gel-60, Merck, eluent was
ethyl acetate—hexane (1 : 3)). The product (1.04 g, 70%) was
obtained as a beige powder. M.p. 243 C. LC-MS (APCI), m/z:
5
,7-Dihydroxy-2-imino-3-(4-methoxyphenyl)-8-methyl-2Н-
chromene-6-carboxylic acid hydrosulfate (6e). Yield 0.12 g (19%),
1
yellow powder. M.p. 151 C (EtOH). R = 0.13 (B). H NMR
f
(
DMSO-d ), : 2.15 (s, 3 H C(8)Me); 3.84 (s, 3 H, OCH );
6
3
6
8
.97 (d, 2 H, HAr, J = 7.9 Hz); 7.32 (d, 2 H, HAr, J = 7.9 Hz);
.28 (s, 1 H, H(4)); 9.81 (s, 1 Н, С(7)ОН); 10.31 (s, 1 Н, С(5)ОН).
MS (EI, 70 eV), m/z (Irel (%)): 298 [М – СО2]+ (48); 270 (12);