Synthesis of 3-hydroxy-6-methyl- and 3-hydroxy-2-(2-phenylethyl)pyridines and their sulfur-containing amino and hydroxymethyl derivatives

Article abstract of DOI:10.1007/s10593-005-0270-9

The aminomethylation of 3-hydroxy-6-methyl- and 3-hydroxy-2-(2-phenylethyl) pyridines by secondary amines has been investigated. It was shown that like 2-alkyl-3-hydroxypyridine aminomethylation is directed primarily to position 6 and then 4 of the pyridi

Full text of DOI:10.1007/s10593-005-0270-9

Chemistry of Heterocyclic Compounds, Vol. 41, No. 8, 2005
SYNTHESIS OF 3-HYDROXY-6-METHYL- AND 3-HYDROXY-
2-(2-PHENYLETHYL)PYRIDINES AND THEIR SULFUR-CONTAINING
AMINO AND HYDROXYMETHYL DERIVATIVES
L. D. Smirnov, V. I. Kuz'min, and Yu. V. Kuznetsov
The aminomethylation of 3-hydroxy-6-methyl- and 3-hydroxy-2-(2-phenylethyl)pyridines by secondary
amines has been investigated. It was shown that like 2-alkyl-3-hydroxypyridine aminomethylation is
directed primarily to position 6 and then 4 of the pyridine ring. On heating the aminomethyl derivatives
of 3-hydroxy-6-methyl- and 3-hydroxy-2-(2-phenylethyl)pyridines with acetic anhydride the
corresponding acetoxy derivatives were obtained, which were converted on heating with hydrochloric or
hydrobromic acids into hydroxy and bromomethyl derivatives. Isothioureidomethyl and
benzimidazolylthiomethyl derivatives were synthesized by heating the bromomethyl-substituted
derivative with thiourea or with 2-mercaptobenzimidazole. The structures of compounds were confirmed
by data of 1H NMR spectra.
Keywords: isothioureido and thiobenzimidazolyl derivatives, 3-hydroxy-2-(2-phenylethyl)pyridine,
aminomethylation.
Among the known synthetic antioxidants significant interest is generated by derivatives of
3-hydroxypyridine (3-HP), close in structure to the vitamin B6 group [1]. They possess an inhibiting action on
free radical reactions, they change the structure–functional state of membranes, receptors, and membrane-bound
enzymes [2].
As a result of systematic investigations of the pharmacological properties of 3-HP derivatives a series of
effective medicinal preparations was revealed (emoxypine and mexidol), which opened broad possibilities in the
search for promising new medicinal agents in the 3-HP series [3].
Analysis of structure–activity links in a series of 3-HP derivatives indicated that their biological activity
is not determined by antiradical activity and lipophilic properties alone. A significant role in the development of
pharmacological properties in 3-HP derivatives is played by the entry of pharmacophoric groups into their
structure (aminomethyl, aralkyl, isothioureido, etc.) [2].
With the aim of searching for new bioantioxidants in this class of compounds we have therefore carried
out the synthesis of isothioureido, benzimidazolethio, amino, and hydroxymethyl derivatives of
2-(2-phenylethyl)-3-HP (1) and of 6-methyl-2-(2-phenylethyl)-3-HP (2).
__________________________________________________________________________________________
N. M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow 119991;
e-mail: ldsmirnov@polymer.chphp.ras.ru, ldsmirnov@mail.ru. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 8, pp. 1189-1194, August, 2005. Original article submitted September 10, 2002; revision
submitted January 14, 2005.
0009-3122/05/4108-1013©2005 Springer Science+Business Media, Inc.
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The synthesis of 4-isothioureidomethyl and benzimidazolylthiomethyl derivatives of 6-methyl- and
2-(2-phenylethyl)-3-HP was carried out by a scheme containing as initial step the aminomethylation of
compounds 1 and 2 with subsequent replacement of the aminomethyl group by acetoxy and then by hydroxy and
bromomethyl groups.
Previously we established the possibility of aminomethylating 3-HP at positions 2 and 6 of the ring, and
in the case of a 2,6-dialkyl-3-HP at position 4 of the pyridine ring [4, 5]. We therefore investigated
the aminomethylation of 2-phenylethyl-3-HP 1 and 6-methyl-2-(2-phenylethyl)-3-HP 2. The initial
3-HP 1 and 2 were synthesized by the Leditschke reaction [6] by heating the appropriate furyl ketones with
ammonium acetate at 220-250°C. Aminomethylation of pyridine 1 was carried out under analogous
conditions to 2-alkyl-3-HP with the stoichiometric ratio of formaldehyde and secondary amine (dimethylamine).
As a result, 6-mono- and 4,6-bis-substituted Mannich bases of 2-phenylethyl-3-HP 3-5 were obtained
(Tables 1 and 2). The aminomethylation of compound 2 proceeded under analogous conditions leading to the
formation of the 4-substituted Mannich base 5. The structures of 3-HP 3-5 were confirmed by data of
1H NMR spectra.
The corresponding acetoxy derivatives of 6 and 7 were obtained by heating aminomethyl derivatives 4
and 5 with acetic anhydride. Then by heating the acetoxy derivatives with hydrochloric or hydrobromic acids the
hydroxymethyl-3-HP 8 and 9 and the bromomethyl derivative of 3-HP 10 were synthesized. The
isothioureidomethyl and the benzimidazolylthiomethyl-substituted 11 and 12 were synthesized by heating
bromomethyl derivative 10 with thiourea or with 2-mercaptobenzimidazole as in the Scheme. Their structures
were confirmed by data of 1H NMR spectra.
The synthesized sulfur-containing derivatives 11 and 12 displayed marked antihypoxic and
actoprotective properties [7].
TABLE 1. Physicochemical Characteristics of the Synthesized Compounds
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, ºС
Yield, %
С
Н
1
C13H13NO
C14H15NO
78.36
78.35
78.82
78.87
58.27
58.31
53.95
53.92
57.88
57.94
65.20
65.45
69.45
69.67
57.67
57.36
64.71
64.36
46.47
46.49
51.35
51.30
56.48
56.65
6.62
6.58
7.06
7.04
6.62
6.74
7.13
7.16
6.85
7.15
5.87
5.97
6.52
6.48
6.64
6.37
6.35
6.50
4.36
4.39
5.62
5.66
5.32
5.39
203.5-204.5
231-232
206-207
166-167
119-120
—*
52
72
90
85
89
75
80
58
70
85
72
85
2
3
C16H20N2O·2HCl
C19H27N3O·3HCl
C17H22N2O·2HCl·0.5H2O
C21H23NO6
4
5
6
7
C19H21NO4
—*2
8
C15H17NO3·HCl·H2O
C15H17NO2·HCl
C15H17Br2NO
196-197
221-222
169-171
190-192
190-192
9
10
11
12
C16H19N3OS·2HCl
C22H21N3OS·2HCl·H2O
_______
* Bp 170-172°C (2-3 mm Hg).
*2 Bp 175-178°C (1-3 mm Hg).
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1
TABLE 2. H NMR Spectra of Amino, Acetoxy, and Hydroxymethyl
Derivatives of 2-Phenylethyl-3-HP
Com-
pound
Chemical shifts, δ, ppm (J, Hz)*
1
2
2.85 (4H, m, СН2–СН2); 6.95-7.25 (5Н, m, H arom.); 7.70-8.30 (3Н, m, H pyrid.)
2.40 (3H, s, CH3); 3.30 (4H, m, СН2–СН2); 6.95-7.25 (5Н, m, H arom.);
7.70-8.30 (2Н, m, H pyrid.)
3
4
5
6
2.87 (6H, s, N(CH3)2); 3.30 (4H, m, (CH2)2); 4.60 (2H, s, N–CH2);
7.2-7.5 (5H, m, H arom.); 7.88 (1H, d, J = 9.0, H-5); 8.05 (1H, d, J = 9.0, H-4)
2.75 (6H, s, N(CH3)2); 2.88 (6H, s, N(CH3)2); 3.20 (4H, m, (CH2)2);
4.35 (2H, s, N–CH2); 4.41 (2H, s, N–CH2); 6.95-7.20 (5Н, m, H arom.); 7.45 (1H, s, H-5)
2.48 (3H, s, CH3); 2.80 (6H, s, N(CH3)2); 3.5 (4H, m, (CH)2); 4.40 (2H, s, N–CH2);
6.80-7.20 (5Н, m, H arom.); 7.45 (1H, s, H-5)
1.98 (3H, s, COCH3); 2.03 (3H, s, COCH3); 2.20 (3H, s, COCH3);
2.90 (4H, m, (CH2)2); 4.90 (2H, s, OCH3); 5.15 (2H, s, OCH3);
7.00-7.20 (5H, m, H arom.); 7.10 (1H, s, H-5)
7
1.83 (3H, s, COCH3); 2.09 (3H, s, COCH3); 2.38 (3H, s, CH3);
2.81 (4H, m, (CH2)2); 4.90 (2H, s, OCH2); 6.85 (1H, s, H-5); 7.10 (5H, m, H arom.)
8
3.26 (4H, m, (CH2)2); 4.81 (2H, s, CH2OH); 4.83 (2H, s, CH2OH);
7.15-7.30 (5H, m, H arom.); 7.88 (1H, s, H-5)
9
2.65 (3H, s, CH3); 3.22 (4H, m, (CH2)2); 4.85 (2H, s, CH2OH);
7.10-7.30 (5H, m, H arom.); 7.62 (1H, s, H-5)
10
11
12
2.59 (3H, s, CH3); 3.22 (4H, m, (CH2)2); 4.86 (2H, s, CH2Br);
7.0-7.5 (5H, m, H arom.); 7.60 (1H, s, H-5)
2.39 (3H, s, CH3); 3.0 (4H, m, (CH2)2); 4.66 (2H, s, CH2S);
6.70-7.20 (5H, m, H arom.); 7.30 (1H, s, H-5)
2.50 (3H, s, CH3); 3.05 (4H, m, (CH2)2); 4.71 (2H, s, CH2S);
6.70-7.30 (5H, m, H arom.); 7.65 (1H, s, H-5)
_______
* Spectra were recorded in CD3OD (compound 1), D2O (compounds 2-7, 10-
12), and CDCl3 (compounds 8 and 9).
EXPERIMENTAL
The 1H NMR spectra were obtained on a Bruker AC-250 (250 MHz) spectrometer, internal standard was
HMDS (δ 0.05 ppm). The physicochemical and spectral characteristics are given in Tables 1 and 2.
3-Hydroxy-2-(2-phenylethyl)pyridine (1). A mixture of 1-(2-furyl)-3-phenylpropan-1-one (6.0 g,
0.03 mol) and ammonium acetate (6.9 g, 0.09 mol) was heated in an autoclave at 220-225°C for 14 h, cooled to
room temperature, H2O (100 ml) was added, the solid residue was filtered off, and dissolved with heating on a
water bath in 2 N NaOH (1000 ml). The solution was cooled to 20°C, filtered, and neutralized by passing in
gaseous CO2 or diluting with 10% H2SO4 to pH 7. The precipitated solid was separated, dried, sublimed at high
vacuum, and 3-HP 1 was obtained.
3-Hydroxy-6-methyl-2-(2-phenylethyl)pyridine (2) was obtained analogously to compound 1 from
1-(5-methylfur-2-yl)-3-phenylpropan-1-one (6.9 g, 0.03 mol) and ammonium acetate (6.9 g, 0.09 mol).
Dihydrochloride of 6-Dimethylaminomethyl-3-hydroxy-2-(2-phenylethyl)pyridine (3). Aqueous
33% dimethylamine (3 ml, 0.022 mol) and aqueous 30% formaldehyde solution (2.2 ml, 0.022 mol) were added
to a solution of compound 1 (4.2 g, 0.02 mol) in alcohol (20 ml) with constant stirring. The mixture was heated
for 28 h on a water bath, the solvent was removed in vacuum, the residue, a viscous oil, was dissolved in
anhydrous alcohol, and the solution saturated with gaseous HCl. Compound 3 was obtained.
Trihydrochloride of 4,6-Bis(dimethylaminomethyl)-3-hydroxy-2-(2-phenylethyl)pyridine (4).
Aqueous 33% dimethylamine (6 ml, 0.042 mol) and aqueous 30% formaldehyde solution (4 ml, 0.042 mol) were
added to a solution of compound 1 (4.2 g, 0.02 mol) in alcohol (20 ml) with constant stirring. The mixture
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was heated on a boiling water bath for 28 h. At the end of the reaction the solvent was removed in vacuum, the
residue, a viscous oil, was dissolved in anhydrous alcohol, and the solution was saturated with gaseous HCl.
Compound 4 was obtained.
Dihydrochloride of 4-Dimethylaminomethyl-3-hydroxy-6-methyl-2-(2-phenylethyl)pyridine (5).
Aqueous 33% dimethylamine solution (4.5 ml, 0.032 mol) and aqueous 30% formaldehyde solution (3 ml, 0.032
mol) were added with constant stirring to a solution of compound 2 (4.44 g, 0.02 mol) in alcohol (30 ml). The
mixture was heated on a boiling water bath for 28 h. At the end of the reaction the solvent was removed in
vacuum, the residual viscous oil was dissolved in anhydrous alcohol, and the solution saturated with gaseous
HCl. Compound 5 was obtained.
3-Acetoxy-4,6-bis(acetoxymethyl)-2-(2-phenylethyl)pyridine (6). A solution of compound 4
(0.05 mol) in freshly distilled (MeCO)2O was boiled for 6 h. The solvent was removed in vacuum and the
residue fractionated at high vacuum. Compound 6 was obtained.
3-Acetoxy-4-acetoxymethyl-6-methyl-2-(2-phenylethyl)pyridine (7) was obtained analogously to
compound 6.
Hydrochloride of 3-Hydroxy-4,6-bishydroxymethyl-2-(2-phenylethyl)pyridine (8). A solution of
compound 6 (0.026 mol) in 2 N HCl (100 ml) was boiled on a water bath for 7 h. The solvent was removed, the
residue was washed with dry acetone, and recrystallized from alcohol. Compound 8 was obtained.
Hydrochloride of 3-Hydroxy-4-hydroxymethyl-6-methyl-2-(2-phenylethyl)pyridine (9) was
obtained analogously to compound 8 from acetoxy derivative 7.
Hydrobromide of 4-Bromomethyl-3-hydroxy-6-methyl-2-(2-phenylethyl)pyridine (10). A solution
of compound 7 (3.27 g, 0.01 mol) in 48% HBr (50 ml) was boiled for 3-4 h, and the solvent distilled off in
vacuum. The residue was triturated with a mixture of i-PrOH and ether, and the solid separated. Compound 10
was obtained.
Dihydrochloride of 3-Hydroxy-4-isothioureidomethyl-6-methyl-2-(2-phenylethyl)pyridine (11). A
mixture of hydrobromide 10 (3.87 g, 0.01 mol), thiourea (0.76 g, 0.01 mol), and absolute ethanol (50 ml) was
boiled under reflux for 7 h . The solvent was distilled off to dryness, the residue was dissolved in water (20 ml),
the solution neutralized with aqueous 10% KOH solution to pH 7, the solvent removed, the residue washed with
water, dried, and an alcohol solution of HCl was added. Compound 11 was obtained.
Dihydrochloride of 4-(2-Benzimidazolylthiomethyl)-3-hydroxy-6-methyl-2-(2-phenylethyl)pyridine
(12). Sodium hydroxide (0.4 g, 0.02 mol) in ethanol (50 ml) and 2-mercaptobenzimidazole (1.5 g, 0.01 mol)
were mixed and heated on a water bath until solution was complete. Hydrobromide 10 (3.87 g, 0.01 mol) in
ethanol (50 ml) was added dropwise with stirring and heating, and the mixture was heated for 1-2 h. The solvent
was evaporated to dryness, the residue was washed with water, dried, and an alcohol solution of HCl was added.
Compound 12 was obtained.
The authors are grateful to V. P. Lezina for taking the NMR spectra of the synthesized compounds.
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