Reaction of phenyl glycidyl ether with some heterocycles

Article abstract of DOI:10.1007/s10593-008-0093-6

The respective hydroxypropyl phenyl ethers were obtained by the reaction of 5,5-dimethylhydantoin, morpholine, benzotriazole, benzimidazole, pyrrolidone, and phthalimide with phenyl glycidyl ether. 8-(2-Hydroxy-3-phenoxy) quinoline was synthesized by O-alkylation.

Full text of DOI:10.1007/s10593-008-0093-6

Chemistry of Heterocyclic Compounds, Vol. 44, No. 6, 2008
REACTION OF PHENYL GLYCIDYL
ETHER WITH SOME HETEROCYCLES
E. G. Mesropyan, G. B. Ambartsumyan, A. A. Avetisyan, and A. S. Galstyan
The respective hydroxypropyl phenyl ethers were obtained by the reaction of 5,5-dimethylhydantoin,
morpholine, benzotriazole, benzimidazole, pyrrolidone, and phthalimide with phenyl glycidyl ether.
8-(2-Hydroxy-3-phenoxy) quinoline was synthesized by O-alkylation.
Keywords: benzimidazole, benzotriazole, 8-hydroxyquinoline, 5,5-trimethylhydantoin, morpholine,
pyrrolidone, phenyl glycidyl ether, phthalimide, Krasuskii rule.
The development of methods for the synthesis of compounds with heterocyclic fragments is currently of
some importance due to the prospects of finding new biologically active substances containing widely known
highly active pharmacophoric fragments among them [1-3].
With this end in view a single-stage method was proposed for the synthesis of the N-(2-hydroxy-
3-phenoxypropyl)-5,5-dimethyl derivatives of hydantoin (1a), morpholine (1b), benzotriazole (1c),
benzimidazole (1d), pyrrolidone (1e), and phthalimide (1f), which can also be used in preparative chemistry.
PhO–CH2–CH–CH2–X
PhO–CH2–HC
CH2
HX
+
2a–f
OH
O
1a–f
1,2a X = 4,4-dimethyl-2,5-dioxoimidazolidin-1-yl, b X = morpholino,
c X = benzotriazol-1-yl, d X = benzimidazol-1-yl,
e X = 2-oxopyrrolidino, f X = phthalimido.
It should be noted that the opening of the oxide ring by the action of the heterocycles 2a-f takes place
according to the Krasuskii rule, i.e., the hydroxyl group is formed at the least hydrogenated carbon atom, which
is also favored by steric factors [4, 5].
For the synthesis of the quinoline derivative we prepared 2-hydroxy-1-phenoxy-3-chloropropane by the
reaction of phenyl glycidyl ether with hydrogen chloride. The product was converted into 8-(2-hydroxy-
3-phenoxypropoxy)quinoline (1g) by reaction with the potassium derivative of 8-hydroxyquinoline in isopropyl
alcohol.
__________________________________________________________________________________________
Erevan State University, Erevan 375049, Armenia; e-mail: mag_union@yahoo.com. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 817-820, June, 2008. Original article submitted February 5,
2006.
650
0009-3122/08/4406-0650©2008 Springer Science+Business Media, Inc.

PhO–CH2–HC
CH2
HCl
PhO–CH2–CH–CH2–Cl
OH
+
O
N
3
3
N
OK
O–CH2–CH–CH2–OPh
OH
1g
EXPERIMENTAL
1
The H NMR spectra were obtained in DMSO on a Varian Mercury-300 spectrometer (300 MHz) with
HMDS as internal standard (δ 0.05 ppm). The IR spectra were recorded in thin layers in vaseline oil on a
Specord IR-75 spectrophotometer. The individuality and the purity of the products were monitored by TLC on
Silufol UV-254 plates; the eluants were acetone–chloroform–hexane (for 1a,c,f), acetone–chloroform (for
1b,d,g), and acetone–hexane (for 1e) (Tables 1-3).
3-(2-Hydroxy-3-phenoxypropyl)-5,5-dimethylhydantoin (1a). 5,5-Dimethylhydantoin (5.12 g,
0.04 mol) we added in small portions a solution of phenyl glycidyl ether (6 g, 0.04 mol) in of DMF (5 ml). The
mixture was heated at 165-175°C for 4 h. The obtained crystals were recrystallized from water; mp 128°C, Rf
0.56 (3.6:0.3:0.1 acetone–chloroform–hexane).
TABLE 1. The Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
C
H
N
1a
1b
1c
1d
1e
1f
C14H18N2O4
60.60
60.43
65.66
65.82
67.04
66.91
71.49
71.64
66.23
66.38
68.49
68.69
74.08
74.27
6.52
6.47
8.15
8.02
5.39
5.58
5.86
5.97
7.34
7.23
5.60
5.05
5.72
5.54
9.92
68
86
63
58
69
85
88
10.07
C13H19NO3
C15H15N3O2
C16H16N2O2
C13H13NO3
C17H15NO4
C19H17NO3
6.02
5.91
15.30
15.61
10.53
10.45
6.04
5.96
4.65
4.71
4.41
4.56
1g
TABLE 2. The IR Spectra of Compounds 1a-g
ν, cm-1
Compound
C=O
C=C
1595
C–O–Ph
OH
1a
1b
1c
1d
1e
1f
1695-1745
1240
1235
1250
1245
1240
1250
1250
3340
3250
3500
3400
3440
3520
3400
—
—
1590
1600
—
1605
1680
1700, 1770
—
1600
1610
1g
1600, 1570
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TABLE 3. The 1H NMR Spectra of Compounds 1a-g
Com-
pound
Chemical shifts, δ, ppm. (J, Hz)
1a
1b
1.35 (6H, s, CH3); 3.51 (1H, dd, J = 14.3, J = 6.9, CH2O);
3.56 (1H, dd, J = 14.3, J = 3.6, CH2O); 3.78 (1H, br. s, OH); 3.81 (1H, dd,
J = 13.8, J = 7.5, CH2N); 3.87 (1H, dd, J = 13.8, J = 4.2, CH2N); 4.08 (1H, m, CH);
6.86 (1H, tt, J = 7.2, J = 1.1, C6H5); 6.88 (2H, m, C6H5); 7.21 (2H, m, C6H5);
8.06 (1H, s, NH)
2.4-2.6 (6H, m, CH2N); 3.60 (4H, t, J = 6.0, CH2O in cycle); 3.90 (1H, dd,
J = 14.3, J = 6.9, CH2O); 3.96 (1H, dd, J = 14.3, J = 3.6, CH2O); 4.00 (1H, m, CH);
4.30 (1H, br. s, OH); 6.86 (1H, tt, J = 7.2, J = 1.1, C6H5); 6.88 (2H, m, C6H5);
7.21 (2H, m, C6H5)
1c
1d
1e
3.80 (1H, br. s, OH); 3.98 (1H, dd, J = 14.3, J = 6.9, CH2O); 4.02 (1H, dd,
J = 14.3, J = 3.6, CH2O); 4.38 (1H, m, CH); 4.78 (1H, dd, J = 13.8, J = 7.5, CH2N);
4.83 (1H, dd, J = 13.8, J = 4.2, CH2N); 6.85-8.00 (9H, m, Ar)
3.88 (1H, dd, J = 13.8, J = 7.5, CH2N); 4.93 (1H, dd, J = 13.8, J = 4.2, CH2N);
4.29 (1H, dd, J = 14.3, J = 6.9, CH2O); 4.32 (1H, dd, J = 14.3, J = 3.6, CH2O);
4.48 (1H, m, CH); 4.2 (1H, br. s, OH); 6.85–7.6 (9H, m, Ar); 8.05 (1H, c, NH)
2.00 (2H, m, CH2 in cycle); 2.20 (2H, m, CH2CO in cycle); 3.22 (1H, dd,
J = 13.8, J = 7.5, CH2N); 3.27 (1H, dd, J = 13.8, J = 4.2, CH2N);
3.3 (2H, m, CH2N in cycle); 3.8 (1H, br. s, OH); 4.08 (1H, dd, J = 14.3, J = 6.9, CH2O);
4.13 (1H, dd, J = 14.3, J = 3.6, CH2O); 4.4 (1H, m, CH); 6.86 (1H, tt,
J = 7.2, J = 1.1, C6H5); 6.88 (2H, m, C6H5); 7.21 (2H, m, C6H5)
1f
3.64 (1H, br. s, OH); 3.75 (1H, dd, J = 14.3, J = 6.9, CH2O); 3.79 (1H, dd,
J = 14.3, J = 3.6, CH2O); 3.91 (1H, dd, J = 13.8, J = 7.5, CH2N);
3.97 (1H, dd, J = 13.8, J = 4.2, CH2N); 4.18 (1H, m, CH); 6.85-7.95 (9H, m, Ar)
1g
3.95 (1H, br. s, OH); 3.5-3.8 (4H, m, CH2O);
4.10 (1H, ddd, J = 7.5, J = 5.5, J = 4.2, CH); 6.9-8.0 (11H, m, Ar)
4-(2-Hydroxy-3-phenoxypropyl)morpholine (1b). Morpholine (10.44 g, 0.12 mol) we added of
phenyl glycidyl ether (6 g, 0.04 mol). The mixture was heated on a boiling water bath for 3 h. The excess of
morpholine was removed, and the residue was distilled under vacuum; mp 60°C; bp 176-178°C (4 mm Hg);
nD20 1.5358, Rf 0.52 (4:1.5 acetone–chloroform).
1-(2-Hydroxy-3-phenoxypropyl)benzotriazole (1c). An equimolar mixture of benzotriazole and
phenyl glycidyl ether (0.04 mmol) was heated on a boiling water bath for 4 h. The precipitate was washed with
diethyl ether; mp 101-103°C, Rf 0.46 (0.4:1:0.4 acetone–chloroform–hexane).
1-(2-Hydroxy-3-phenoxypropyl)benzimidazole (1d). An equimolar mixture of benzimidazole and
phenyl glycidyl ether (0.04 mmol) was heated on a water bath for 4 h. The mixture was then dissolved in hot
ethanol (25 ml). After cooling crystals of compound (1d) separated; mp 122°C, Rf 0.46 (1.2:1 acetone–
chloroform).
1-(2-Hydroxy-3-phenoxypropyl)pyrrolidin-2-one (1e). An equimolar mixture of 2-pyrrolidone and
phenyl glycidyl ether (0.04 mol of each) was heated at 160°C for 2 h. The product was then distilled under
vacuum and recrystallized from hexane; mp 80-82°C; bp 200-205°C (1 mm Hg); Rf 0.49 (1:1 acetone–hexane).
N-(2-Hydroxy-3-phenoxypropyl)phthalimide (1f). A mixture of phenyl glycidyl ether (6 g, 0.04 mol)
and of phthalimide (5.88 g, 0.04 mol) was heated at 170-175°C for 4 h. Ethanol, in which the initial substances
are soluble, was then added, and the product was precipitated. The obtained crystals were recrystallized from
aqueous ethanol (1:4); mp 112-113°C; Rf 0.51 (0.4:1:0.6 acetone–chloroform–hexane).
8-(2-Hydroxy-3-phenoxypropoxy)quinoline (1g). To a solution of dry KOH (3.36 g, 0.06 mol) in
isopropyl alcohol (30 ml) we added of 8-hydroxyquinoline (8.5 g, 0.06 mol), dissolved in isopropyl alcohol
(30 ml). The mixture was heated on a water bath for 30 min. A solution of the chloride (3) (11.19 g, 0.06 mol)
(obtained by the reaction of phenyl glycidyl ether with hydrogen chloride, bp 110°C (0.5 mm Hg),
nD20 = 1.5415, yield 98%) in isopropyl alcohol (20 ml) was then added drop by drop, and the mixture was
652

heated on a water bath. The product was filtered, the filtrate was chromatographed on a column of aluminum
oxide (35×2 cm) with isopropyl alcohol as eluant, the solvent was evaporated, and the quinoline 1g was
obtained; nD20 1.6182, Rf 0.6 (2.2:0.1 acetone–chloroform).
Compounds 1a-g are readily soluble in DMSO, alcohol, acetone, and chloroform, and some of them
(1b,d,e) are soluble in benzene. They are insoluble in ether, heptane, and water.
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1.
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3.
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5.
E. G. Mesropyan, G. B. Ambartsumyan, and A. A. Avetisyan, Zh. Org. Khim., 36, 462 (2000).
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