Synthesis of azolylethyl benzhydryl ethers, analogs of diphenhydramine

Article abstract of DOI:10.1007/s11172-009-0118-z

Alternative approaches to the preparation of azolylethyl benzhydryl ethers have been studied. It was shown that the reaction of diphenylmethyl halide with 2-(azol-1-yl)ethanol in the presence of triethylamine is the optimum way. An efficient method for the synthesis of 2-(imidazol-1-yl)ethanol using phase-transfer catalysis has been developed.

Full text of DOI:10.1007/s11172-009-0118-z

Russian Chemical Bulletin, International Edition, Vol. 58, No. 5, pp. 936—939, May, 2009
936
Synthesis of azolylethyl benzhydryl ethers, analogs of diphenhydramine
M. L. Burdeinyi, S. V. Popkov, and M. V. Kharchevnikova
D. I. Mendeleev University of Chemical Technology of Russia,
9 Miusskaya pl., 125047 Moscow, Russian Federation.
Fax: +7 (499) 200 4204. Eꢀmail: popkovsv@rctu.ru
Alternative approaches to the preparation of azolylethyl benzhydryl ethers have been
studied. It was shown that the reaction of diphenylmethyl halide with 2ꢀ(azolꢀ1ꢀyl)ethanol
in the presence of triethylamine is the optimum way. An efficient method for the synthesis of
2ꢀ(imidazolꢀ1ꢀyl)ethanol using phaseꢀtransfer catalysis has been developed.
Key words: imidazole, 1,2,4ꢀtriazole, Nꢀalkylation of azoles, 2ꢀ(imidazolꢀ1ꢀyl)ethanol,
2ꢀ(1,2,4ꢀtriazolꢀ1ꢀyl)ethanol, azolylethyl benzhydryl ether.
Many nitrogenꢀcontaining benzhydryl ethyl ethers
The present work is aimed at the development of
efficient method for the preparation of 2ꢀ(imidazolꢀ
1ꢀyl)ethylꢀ and 2ꢀ(1,2,4ꢀtriazolꢀ1ꢀyl)ethyl benzhydryl
ethers, which, possibly, possess antihistamine activity.
Three alternative schemes have been chosen for
the synthesis of the target compounds. Alkylation of subꢀ
stituted diphenylmethanol 1a with βꢀchloroethylazole
hydrochlorides in acetonitrile in the presence of potasꢀ
sium carbonate (method 1, Scheme 1) afforded ethers 2a
and 3a in 15% and 10% yield, respectively. The starting
chloroethylazole hydrochlorides were synthesized by the
reaction of the corresponding azolylethanols with thionyl
chloride3 in quantitative yield.
possess biological activity: benzhydryl 2ꢀ(dimethylamino)ꢀ
ethyl ether (diphenhydramine) is one of the first antiꢀ
histamine drugs,1 benzhydryl 2ꢀ(nitroimidazolyl)ethyl
ethers exhibit antiviral activity and belong to the class
of nonnucleoside inhibitors of reverse transcriptase.2
Scheme 1
The necessary intermediate benzhydryl βꢀhaloethyl
ethers 4a were initially obtained by the reaction of sodium
diphenylmethoxide with 1,2ꢀdihaloethanes (Scheme 2,
method a). The alkylation in acetonitrile at room temꢀ
perature does not yield the target βꢀbromoethyl benzhydryl
ether, rather, only competing elimination reaction proꢀ
ceeds. Ether 4a can be successfully obtained in 40% yield
at reduced temperature (0 °C) as a result of nucleophilic
substitution. When 1,2ꢀdibromoethane is replaced by
1,2ꢀdichloroethane, the yield of ether 5a decreases to 25%.
Z = CH (2a), N (3a)
i.
, CH3CN, K2CO3, reflux
Scheme 2
X = Br (4a), Cl (5a)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 916—918, May, 2009.
1066ꢀ5285/09/5805ꢀ0936 © 2009 Springer Science+Business Media, Inc.

Synthesis of azolylethylbenzhydryl ethers
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
937
It is reasonable to obtain similar compounds by conꢀ
densation of ethylene chlorohydrin with benzhydrol in
the presence of sulfuric acid (see Ref. 4), in this case,
ether 5a was obtained in quantitative yield (see Scheme 2,
method b). Unfortunately, the alkylation of sodium
azolates with 1ꢀ(diphenylmethoxy)ꢀ2ꢀhaloethanes 4a and
5a in acetonitrile does not lead to the target products.
Substituted diphenylmethyl chlorides5 6a—e, obtained
in quantitative yields from benzhydrols 1a—e, were used
as alkylation agents. Their reaction with 2ꢀ(azolylꢀ
1ꢀyl)ethanols (Scheme 3) takes place in boiling xylene in
the presence of triethylamine, which allows us to obtain
ethers 2a—e and 3a—e in high yields, from 55 to 75%.
of imidazole (m/z 157.2) is also formed in the ratio 1 : 1.65.
Thus, the bisalkylation products are formed predominately
under these conditions. When temperature is decreased
from 75 to 35 °C, the fraction of quaternization products
significantly decreases and after 8 h, 2ꢀ(imidazolꢀ
1ꢀyl)ethanol was obtained in 82% yield.
In conclusion, it was found that the alkylation of
2ꢀ(azolꢀ1ꢀyl)ethanols with diphenylmethyl halides in the
presence of triethylamine is the optimum way from alterꢀ
native methods for obtaining diphenylmethoxyethylazoles.
The best method for the preparation of 2ꢀ(azolyl)ethanols
is alkylation of azoles with ethylene chlorohydrin under
conditions of phaseꢀtransfer catalysis, which allowed us
to obtain high yields of the target azolylethanols. A preꢀ
parative method developed for the synthesis of benzꢀ
hydroxyethylazoles can be used for the preparation of a
wide range of imidazoleꢀ and triazoleꢀcontaining biologiꢀ
cally active compounds.
Scheme 3
Experimental
IR spectra were recorded on a Specord Mꢀ80 spectrometer
in Nujol (for solids) and neat (for liquids). 1H NMR spectra
were recorded on a Bruker ACꢀ200 spectrometer (200 MHz
for 1H) in CDCl3 and (CD3)2SO, using Me4Si as an internal
standard. Mass spectroscopic analysis was performed on a
Surveoyr MSQ Thermo Finnigan instrument in the ESI mode
with registration of positive ions, the potential on the needle
point was 3 kV (the solvent, 0.1% aq. formic acid in 60% aq.
acetonitrile). The course of the reaction and purity of compounds
obtained were monitored by TLC on Silufol UVꢀ254 plates
(visualization, under the UV light and by a workꢀup with a
modified Dragendorf reagent).7
1
2
1
2
R
= H, R = Cl (a), R = R = H (b), F (c), Cl (d), Br (e)
i.
(7,8), Et N, xylene, Δ
3
1
2
2ꢀ(1ꢀImidazolꢀ1ꢀyl)ethanol (7). Ethylene chlorohydrin
(10 mL, 12.07 g, 0.15 mol) was added to a mixture of imidazole
(10.2 g, 0.15 mol), sodium hydroxide (6.0 g, 0.15 mol), triethylꢀ
benzylammonium chloride (1.13 g, 5 mmol), and dioxane
(50 mL) heated to 35 °C with vigorous stirring over 2 h, then, the
reaction mixture was kept under the same conditions for another
8 h, a precipitate formed was filtered off and washed with dioxane.
The filtrate was concentrated in vacuo of a waterꢀjet pump and
the residue was distilled in vacuo of an oil pump collecting
the fraction of 2ꢀ(imidazolꢀ1ꢀyl)ethanol 7 (11.13 g, 82%), with
b.p. 138—141 °C (0.5 Torr) (cf. Ref. 3: 134—136 °C (0.5 Torr)),
Comꢀ
pound
R
R
Yield (%)
2
3
a
b
c
d
e
H
H
Cl
H
79
75
62
61
56
64
67
75
72
70
F
F
Cl
Br
Cl
Br
The starting 2ꢀ(azolyl)ethanols 7 and 8 were obtained
by two methods. 2ꢀ(1ꢀImidazolꢀ1ꢀyl)ꢀ (7) and 2ꢀ(1,2,4ꢀtriꢀ
azolꢀ1ꢀyl)ethanol (8) were obtained by the reaction of the
corresponding azoles with ethylene carbonate in toluene
on heating3 (method A).
The reaction of 2ꢀchloroethanol with 1,2,4ꢀtriazole in
the presence of sodium hydroxide under conditions of
phaseꢀtransfer catalysis with triethylbenzylammonium
chloride in dioxane at 70 °C for 3 h (method B)6 results in
2ꢀ(1,2,4ꢀtriazolꢀ1ꢀyl)ethanol (8) in 90% yield. According
to the mass spectrometric data, the reaction mixture,
obtained by alkylation of imidazole under analogous
conditions, in addition to the target product 7 (m/z 113.2,
the yield of which was ∼30%), a product of bisalkylation
nD 1.5144. IR, ν/cm–1: 3380 (O—H), 1232, 1084 (C—O).
18
1H NMR (CDCl3), δ: 3.85 (t, 2 H, CH2OH, J = 4.2 Hz); 4.02
(t, 2 H, CH2N, J = 5.2 Hz); 4.85 (s, 1 H, OH); 6.95, 7.35, 7.63
(all s, 1 H each, CH imidazole). MS (CI), m/z (Irel (%)): 113.1
[M + H+] (100).
2ꢀ(1,2,4ꢀTriazolꢀ1ꢀyl)ethanol (8). A. A mixture of 1,2,4ꢀtriꢀ
azole (13.80 g, 0.2 mol), ethylene carbonate (21.5 g, 0.24 mol),
and toluene (35 mL) was stirred for 3.5 h at 80 °C, followed
by cooling and separation of layers. The lower layer was distilled
in vacuo of an oil pump, collecting the fraction of 2ꢀ(1,2,4ꢀ
triazolꢀ1ꢀyl)ethanol (8) (14.23 g, 42%) with b.p. 132—140 °C
18
(0.5 Torr) (cf. Ref. 6: 140 °C (0.5 Torr)), nD 1.5144.
IR, ν/cm–1: 3356 (O—H), 1278, 1062 (C—O). 1H NMR

938
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
Burdeinyi et al.
(CDCl3), δ: 3.98 (t, 2 H, CH2OH, J = 4.1 Hz); 4.12 (t, 2 H,
CH2N, J = 5.2 Hz); 4.95 (s, 1 H, OH); 7.73, 8.06 (both s,
1 H each, CH triazole). MS (CI), m/z (Irel (%)): 114.2
[M + H+] (100).
C, 61.63; H, 4.88; N, 7.99. IR, ν/cm–1: 1070, 1275 (C—O).
1H NMR ((CD3)2SO), δ: 3.60 (t, 2 H, OCH2, J = 4.3 Hz); 4.32
(t, 2 H, NCH2, J = 4.2 Hz); 6.50 (s, 1 H, OCH); 7.20 (t, 4 H,
CH arom., J1 = 8.3 Hz, J2 = 8.6 Hz); 7.30 (d, 4 H, CH arom.,
J2 = 8.6 Hz); 7.45, 7.65, 7.81 (all s, 1 H each, CH imidazole).
1ꢀ{2ꢀ[Bis(4ꢀchlorophenyl)methoxy]ethyl}imidazole hydroꢀ
chloride (2d). The yield was 61%, m.p. 120—122 °C. Found (%):
C, 56.72; H, 4.31; N, 7.66. C18H17Cl3N2O. Calculated (%):
C, 56.34; H, 4.47; N, 7.30. IR, ν/cm–1: 1065, 1265 (C—O).
1H NMR ((CD3)2SO), δ: 3.67 (t, 2 H, OCH2, J = 4.4 Hz); 4.27
(t, 2 H, NCH2, J = 4.5 Hz); 6.56 (s, 1 H, OCH); 7.32 (d, 4 H,
CH arom., J = 6.5 Hz); 7.38 (d, 4 H, CH arom., J = 6.5 Hz);
7.65, 7.75, 7.80 (all s, 1 H each, CH imidazole).
1ꢀ{2ꢀ[Bis(4ꢀbromophenyl)methoxy]ethyl}imidazole hydroꢀ
chloride (2e). The yield was 56%, m.p. 112—114 °C. Found (%):
C, 45.70; H, 3.51; N, 6.16. C18H17Br2ClN2O. Calculated (%):
C, 45.75; H, 3.63; N, 5.93. IR, ν/cm–1: 1080, 1275 (C—O).
1H NMR ((CD3)2SO), δ: 3.65 (t, 2 H, OCH2, J = 4.5 Hz); 4.27
(t, 2 H, NCH2, J = 4.5 Hz); 6.55 (s, 1 H, OCH); 7.30 (d, 4 H,
CH arom., J = 7.9 Hz); 7.35 (d, 4 H, CH arom., J = 7.8 Hz);
7.65, 7.75, 7.80 (all s, 1 H each, CH imidazole).
B. Ethylene chlorohydrin (10 mL, 12.07 g, 0.15 mol) was
added to a mixture of 1,2,4ꢀtriazole (13.8 g, 0.2 mol), sodium
hydroxide (8.0 g, 0.2 mol), triethylbenzylammonium chloride
(1.13 g, 5 mmol), and dioxane (50 mL) heated to 70 °C under
vigorous stirring over 2 h and it was kept for another 3 h at
the same temperature. A precipitate was filtered off and
washed with dioxane, the filtrate was concentrated in vacuo of a
waterꢀjet pump, the residue was distilled in vacuo of an
oil pump, collecting the fraction of compound 8 (20.56 g,
90%) with b.p. 140—145 °C (0.6 Torr) (cf. Ref. 6: 140 °C
(0.5 Torr)).
1ꢀ[2ꢀ(4ꢀChlorophenylphenylmethoxy)ethyl]imidazole hydroꢀ
chloride (2a). A. A mixture of 4ꢀchlorophenylphenylmethanol
(1.8 g, 8 mmol) (see Ref. 8), acetonitrile (10 mL), potassium
carbonate (1.66 g, 17 mmol), and chloroethylimidazole hydroꢀ
chloride (1.7 g, 10.2 mmol) was refluxed for 8 h, cooled, and
filtered, the filtrate was concentrated in vacuo of a waterꢀjet
pump, the residue was dissolved in diethyl ether and washed
with water. The organic layer was dried with magnesium sulfate,
the solvent was evaporated in vacuo of a waterꢀjet pump, the
residue was dissolved in solution of hydrogen chloride in
methanol (10 M), the solvent was evaporated in vacuo of a
waterꢀjet pump, the residue was washed with diethyl ether
(10 mL). The yield of 1ꢀ[2ꢀ(4ꢀchlorophenylphenylmethoxy)ethyl]ꢀ
imidazole hydrochloride 2b was 0.50 g (15%), m.p. 126—128 °C.
Found (%): C, 61.86; H, 5.21; N, 8.08. C18H18Cl2N2O. Calcuꢀ
lated (%): C, 61.90; H, 5.19; N, 8.02. IR, ν/cm–1: 1270, 1070
(C—O). 1H NMR ((CD3)2SO), δ: 3.65 (t, 2 H, OCH2, J = 4.7 Hz);
4.25 (t, 2 H, NCH2, J = 4.8 Hz); 6.55 (s, 1 H, OCH); 7.20 (t,
4 H, CH arom., J = 7.9 Hz); 7.20—7.35 (m, 5 H, CH arom.);
7.67, 7.75, 7.79 (all s, 1 H each, CH imidazole).
1ꢀ[2ꢀ(Diphenylmethoxy)ethylꢀ1,2,4ꢀtriazole hydrochloride
(3a). The yield was 67%, m.p. 124—126 °C. Found (%):
C, 64.62; H, 5.79; N, 13.36. C17H18ClN3O. Calculated (%):
C, 64.66; H, 5.75; N, 13.31. IR, ν/cm–1: 1080, 1265 (C—O).
1H NMR ((CD3)2SO), δ: 3.82 (t, 2 H, OCH2, J = 4.9 Hz); 4.45
(t, 2 H, NCH2, J = 4.9 Hz); 5.3 (s, 1 H, OCH); 7.20 (m, 6 H,
CH arom.); 7.20—7.35 (m, 4 H, CH arom.); 9.21, 10.32 (both s,
1 H each, CH triazole).
1ꢀ[2ꢀ(4ꢀChlorophenylphenylmethoxy)ethyl]ꢀ1,2,4ꢀtriazole
hydrochloride (3b). The yield was 64%, m.p. 135—137 °C.
Found (%): C, 58.59; H, 5.03; N, 11.79. C17H17Cl2N3O.
Calculated (%): C, 58.30; H, 4.89; N, 12.00. IR, ν/cm–1: 1075,
1280 (C—O). 1H NMR ((CD3)2SO), δ: 3.70 (t, 2 H, OCH2,
J = 4.8 Hz); 4.50 (t, 2 H, NOCH2, J = 4.8 Hz); 5.50 (s, 1 H,
OCH); 7.20 (d, 4 H, CH arom., J = 5.9 Hz); 7.25—7.35 (m,
5 H, CH arom.); 9.20, 10.33 (both s, 1 H each, CH triazole).
1ꢀ[2ꢀ(Bis(4ꢀfluorophenyl)methoxy)ethyl]ꢀ1,2,4ꢀtriazole hydroꢀ
chloride (3c). The yield was 75%, m.p. 132—134 °C. Found (%):
C, 58.09; H, 4.54; N, 11.90. C17H16F2ClN3O. Calculated (%):
C, 58.04; H, 4.58; N, 11.94. IR, ν/cm–1: 1065, 1275 (C—O).
1H NMR ((CD3)2SO), δ: 3.60 (t, 2 H, OCH2, J = 4.3 Hz); 4.40
(t, 2 H, NCH2, J = 4.3 Hz); 5.5 (s, 1 H, OCH); 7.15 (t, 4 H,
CH arom., J1 = 8.4 Hz, J2 = 8.6 Hz); 7.30 (m, 4 H, CH arom.,
J = 8.6 Hz); 9.19, 10.31 (both s, 1 H each, CH triazole).
1ꢀ[2ꢀ(Bis(4ꢀchlorophenyl)methoxy)ethyl]ꢀ1,2,4ꢀtriazole hydroꢀ
chloride (3d). The yield was 70%, m.p. 131—132 °C. Found (%):
C, 53.39; H, 4.44; N, 10.60. C17H16Cl3N3O. Calculated (%):
C, 53.08; H, 4.19; N, 10.92. IR, ν/cm–1: 1080, 1280 (C—O).
1H NMR ((CD3)2SO), δ: 3.84 (t, 2 H, OCH2, J = 4.5 Hz); 4.44
(t, 2 H, NCH2, J = 4.4 Hz); 5.5 (s, 1 H, CHO); 7.30 (d, 4 H, CH
arom., J = 6.4 Hz); 7.50 (m, 4 H, CH arom., J = 6.5 Hz); 9.21,
10.32 (both s, 1 H each, CH triazole).
B. A mixture of 4´ꢀchloroꢀ1ꢀphenylbenzyl chloride5 (1.0 g,
4.2 mmol), 2ꢀ(imidazolꢀ1ꢀyl)ethanol (0.47 g, 4.2 mmol),
triethylamine (0.58 mL, 0.42 g, 4.2 mmol) in a mixture of xylenes
(10 mL) was refluxed for 24 h. The upper layer was separated,
dissolved in diethyl ether, and washed with water, the organic
layer was dried with magnesium sulfate, the solvent was evaporated
in vacuo of a waterꢀjet pump, the residue was dissolved in solution
of hydrogen chloride in methanol (10 M). The solvent was
concentrated in vacuo of a waterꢀjet pump, the residue was washed
with diethyl ether (10 mL) to obtain 1ꢀ[2ꢀ(4ꢀchlorophenylꢀ
phenylmethoxy)ethyl]imidazole hydrochloride 2b. The yield was
0.83 g (79%), m.p. 126—127 °C.
Other diphenylmethoxyethylazoles were obtained similarly
to 1ꢀ[2ꢀ(4ꢀchlorophenylphenylmethoxy)ethyl]imidazole hydroꢀ
chloride 2b by method B.
1ꢀ[2ꢀ(Diphenylmethoxy)ethyl]imidazole hydrochloride (2b).
The yield was 75%, m.p. 113—115 °C. Found (%): C, 68.72;
H, 6.01; N, 8.96. C18H19ClN2O. Calculated (%): C, 68.67;
H, 6.08; N, 8.90. IR, ν/cm–1: 1075, 1265 (C—O). 1H NMR
((CD3)2SO), δ: 3.58 (t, 2 H, OCH2, J = 4.7 Hz); 4.35 (t, 2 H,
NCH2, J = 4.6 Hz); 6.50 (s, 1 H OCH); 7.25 (t, 6 H, CH arom.,
J = 7.3 Hz); 7.26—7.40 (m, 4 H, CH arom.); 7.68, 7.77, 7.80
(all s, 1 H each, CH imidazole).
1ꢀ{2ꢀ[Bis(4ꢀbromophenyl)methoxy]ethyl}ꢀ1,2,4ꢀtriazole
hydrochloride (3e). The yield was 70%, m.p. 121—123 °C.
Found (%): C, 43.36; H, 3.64; N, 9.10. C17H16Br2ClN3O.
Calculated (%): C, 43.11; H, 3.41; N, 8.87. IR, ν/cm–1: 1070,
1265 (C—O). 1H NMR ((CD3)2SO), δ: 3.85 (t, 2 H, OCH2,
J = 4.3 Hz); 4.45 (t, 2 H, NCH2, J = 4.3 Hz); 5.5 (s, 1 H, CHO);
7.28 (d, 4 H, CH arom., J = 7.8 Hz); 7.51 (d, 4 H, CH arom.,
J = 7.9 Hz); 9.20, 10.30 (both s, 1 H each, CH triazole).
1ꢀ{2ꢀ[Bis(4ꢀfluorophenyl)methoxy]ethyl}imidazole hydroꢀ
chloride (2c). The yield was 62%, m.p. 102—104 °C. Found (%):
C, 61.33; H, 5.01; N, 7.59. C18H17ClF2N2O. Calculated (%):

Synthesis of azolylethylbenzhydryl ethers
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
939
7. M. Sharshunova, V. Shvarts, Ch. Mikhalets, Tonkosloinaya
khromatografiya v farmatsii i klinicheskoi biokhimii [Thinꢀlayer
Chromatography in Pharmacy and Clinic Biochemistry], Mir,
Moscow, 1980, 583 [M. Šašúnová, V. Schwarz. È. Michalec,
Chromatografia na tenkych vrstách vo farmácii a v klinickej
biochémii, Vydatel´stvo Osteva, 1977].
8. S. T. Ioffe, A. N. Nesmeyanov, Metody elementoorganicheskoi
khimii. Magnii, berillii, kalґtsii, strontsii, barii [Methods of
Organoelement Chemistry. Magnesium, Berylium, Calcium,
Strontium, Barium], Akad. Nauk SSSR Publ, Moscow, 1963,
101 (in Russian).
References
1. M. D. Mashkovskii, Lekarstvennye sredstva. Posobie dlya
vrachei [Medicines. Aids for Physicians], 15th ed., Novaya
Volna, Moscow, 2007, 286 (in Russian).
2. R. Silvestri, M. Artico, S. Massa, T. Marceddu, F. De Montus,
P. La Colla, Bioorg. Med. Chem. Lett., 2000, 10, 253.
3. EP Pat. 0118875; Chem. Abstrs, 1985, 102, 95466t.
4. Organic Syntheses. An annual publication of satisfactory methods
for the preparation of organic chemicals, Vol. 33, Wiley and
Sons, New York—London, 1953, 11.
5. A. Okamoto, M. S. Snow, D. R. Arnold, Tetrahedron, 1986,
42, 6175.
6. G. V. Asratyan, O. S. Attaryan, A. S. Pogosyan, G. A. Eliozyan,
E. G. Darbinyan, S. G. Matsonyan, Zh. Prikl. Khim., 1984,
59, 1296 [Russ. J. Appl. Chem. (Engl. Transl.), 1984, 57].
Received August 6, 2008;
in revised form November 20, 2008