Study of synthesis of 2-(2-alkoxyphenyl)-1h-imidazoles. Comparison of oxidative aromatization reactions of imidazolines

Article abstract of DOI:10.1002/jhet.5570430404

The reaction of methyl salicylate with ethane-1,2-diamine has been used to prepare 2-(2-hydroxyphenyl)-1H-imidazoline. This compound was alkylated with alkyl halides to give five new 2-(2-alkoxyphenyl)-1H-imidazolines (alkyl = propyl, isopropyl, isobutyl,

Full text of DOI:10.1002/jhet.5570430404

Jul-Aug 2006
Study of Synthesis of 2-(2-Alkoxyphenyl)-1H-imidazoles.
835
Comparison of Oxidative Aromatization Reactions of Imidazolines.
Patrik Pa ík, Sylva ꢀenauerová, Vlasta Liꢁková, Karel Handlí , Miroslav Ludwig
Department of Organic Chemistry, Faculty of Chemical Technology, University of Pardubice,
nám. ꢂs. legií 565, 532 10 Pardubice, Czech Republic
Received July 5, 2005
N
NH
N
NH
A: Pd/C, toluene, reflux
B: MnO2, toluene, 60 °C
C: (KSO3)NO, r.t.
OR
OR
The reaction of methyl salicylate with ethane-1,2-diamine has been used to prepare 2-(2-hydroxy-
phenyl)-1H-imidazoline. This compound was alkylated with alkyl halides to give five new
2-(2-alkoxyphenyl)-1H-imidazolines (alkyl = propyl, isopropyl, isobutyl, sec-butyl, benzyl). Seven types
of transformation reactions of imidazolines into the respective imidazoles were tested. Out of them
successful were the dehydrogenation on palladium in toluene (several-day refluxing), oxidation with
activated manganese dioxide in toluene (several-hour heating at 60 °C), and the oxidation with potassium
nitrosodisulfonate (Fremy’s salt) at room temperature. Seven new 2-(2-alkoxyphenyl)-1H-imidazoles were
synthesized (alkyl = ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, benzyl) via mentioned methods.
Comparison of individual oxidative aromatization reactions is discussed from the point of view of
experimental arrangement, reaction time and conditions, purity of the products obtained, and yields.
J. Heterocyclic Chem., 43, 835 (2006).
Introduction.
The most frequently adopted method for transformation of
imidazolines into imidazoles consists in the oxidation of
imidazolines. 2-Substituted 1H-imidazolines can be
dehydrogenated in gas phase in the presence of noble metals
at a temperature of ca 300 °C or in the presence of
aluminium-zinc oxide at a temperature of 300-600 °C [11].
In some cases, this synthesis gives better yields than the
Radziszewski reaction (e.g. for 2-arylsubstituted
1H-imidazoles). Literature [12] describes dehydrogenation of
Oxazoline and bisoxazoline derivatives are known as
ligands for potential catalysts of asymmetric syntheses
[1,2]. Replacement of oxygen atom by nitrogen would
cause an increase in basic properties and nucleophilicity
of such heterocyclic ring, i.e. imidazoline and, still more,
imidazole. Recently, such derivatives have increasingly
been attracting interest, which is documented not only by
research activities in the field of synthesis, but also
investigation in the area of their catalytic behavior [3-5].
Therefore, we have chosen 2'-substituted 2-phenyl-1H-
imidazoline as a general model skeleton for potential
ligands. 2-(2-Alkoxyphenyl)-1H-imidazoles have proved
to be good models for the purposes of preparation of a
pilot non-chiral series of such derivatives and for testing
various synthetic ways leading to 2-phenylimidazole.
2-(2-Hydroxyphenyl)-1H-imidazoline can be prepared
by syntheses analogous to the synthesis of 2-phenyl-1H-
imidazoline. They include reactions starting from
derivatives of carboxylic acids, e.g. 2-hydroxybenzonitrile
[6], 2-hydroxybenzamide [7], methyl salicylate [8] or
2-hydroxybenzoic acid [9], which react with
ethane-1,2-diamine. The most reliable reaction producing
2-(2-alkoxyphenyl)-1H-imidazolines is the alkylation of
2-(2-hydroxyphenyl)-1H-imidazoline with the respective
alkyl bromides in ethanolic solutions without addition of
bases (NaOH, K2CO3) [10]. The authors expected
formation of N-substituted derivatives, but this
expectation failed to come true.
2-substituted
1H-imidazolines
using
potassium
permanganate in dry dioxane as effective and competitive
with related procedures. Also dehydrogenations of
imidazoline system to imidazole on metal catalysts at various
conditions were described [13] (Zn-Al2O3, 300-600 °C, [14];
Ni, 300 °C, [15]); however, these methods employ rather
harsh conditions and cause some undesirable transformations
of functional groups on the imidazoline ring. The
dehydrogenation of 1H-imidazolines and 2,4-disubstituted
1H-imidazolines into 1H-imidazoles can also be carried out
on the catalyst Pd/C [8,16]. Barium manganate (BaMnO4) is
used for oxidations of 2-aryl-1H-imidazolines to 2-aryl-
1H-imidazoles [17]. The preparation of 2-aryl-1H-imidazoles
is also dealt with in a study that for this purpose recommends
the dehydrogenation by heating in dimethyl sulfoxide or by
means of 10 % Pd/C [18]. The preparation took 48 h at the
temperature of 120 °C. Imidazoles can be prepared by
oxidation of imidazolines with selenium [19], active
manganese dioxide [20], dibenzoyl peroxide [21], bromine in
pyridine/chloroform [21], and Fremy’s salt [22]. It would

836
P. Paꢀík, S. ꢁenauerová, V. Liꢂková, K. Handlíꢀ, M. Ludwig
Vol 43
General Procedures for Synthesis of 2-(2-Alkoxyphenyl)-1H-
imidazoles 2a – 2i.
also be possible to adopt synthetic routes leading to cognate
five-membered heterocycles, such as e.g. the oxidation with
active manganese dioxide giving pyrazoles [23] and oxazoles
[24], or the oxidation using nickel peroxide [25]
giving pyrazoles. The oxidation using trichloroisocyanuric
acid [26] and a similar method using oxalyl chloride [27]
have been published in very recent time.
Method A, Dehydrogenation of Imidazolines on Palladium [18].
Mixture of starting 2-(2-alkoxyphenyl)imidazoline (0.004
mol), dry toluene (70 mL), and of Pd/C (5%) (0.7 g) was stirred
and refluxed under argon atmosphere. Conversion was
monitored by tlc. The precipitate was removed by filtration and
toluene evaporated after the reaction termination. The crude
product was crystallized from toluene/hexane (1:1).
In the case of synthesis of 2g after refluxing even for 97 hour
the reaction mixture contains about 25% of starting imidazoline
1g. In spite of this the imidazole 2g was obtained after
crystallization from the same solvent.
EXPERIMENTAL
General Data: The purity of imidazolines and imidazoles
was checked by elemental analysis using an automatic
1
analyser EA 1108 (Fisons). H NMR spectra of the model
Method B, Oxidation of Imidazolines Using Activated
Manganese Dioxide [23].
compounds were measured at 25 °C using their 5% solutions
in DMSO-d6 or CDCl3 on a Bruker AMX 360 apparatus at
360.14 MHz, and on a Bruker Avance 500 apparatus at
500.13 MHz, the chemical shifts were referenced to the
solvent signal. Infra-red spectra were measured in KBr or in
Nujol (for only one liquid product 2-(2-sec-butoxyphenyl)-
1H-imidazoline) in the range of 4000-350 cm-1 on an Infrared
Spectrophotometer 684 (Perkin-Elmer) connecting to data
station DS 3600 (Perkin-Elmer).
Mixture of starting 2-(2-alkoxyphenyl)imidazoline (0.006
mol), dry toluene (80 mL), and activated manganese dioxide (10
g) was intensively stirred and heated at 60 °C. Conversion was
monitored by tlc. The precipitate was removed by filtration and
toluene evaporated after the reaction termination. Resulting
product was crystallized from hexane/toluene (1:1) if necessary.
Method C, Oxidation of Imidazolines Using Fremy's Salt
[22,28].
2-(2-Hydroxyphenyl)-1H-imidazoline (1a) [8].
Mixture of methyl salicylate (0.13 mol, 40 g) and ethane-1,2-
diamine (0.8 mol, 48 g) was intensively mixed for 11 h under
reflux. The excess of ethane-1,2-diamine was removed by
distillation leaving a crude product which was crystallized from
water/ethanol (2:1). Yellow crystals were obtained in 50.3 %
yield (20.1 g), mp 200-202 °C (200-203 °C [8]).
Ice-cold solution of sodium bisulfite (17.5 g) in water (50
mL) was added during 3 minutes to a stirred mixture of sodium
nitrite (17.3 g), water (50 mL), and crushed ice (100 g) at -5 °C
followed by addition of glacial acetic acid (10 mL) during 1
minute at 0 °C. After addition of cold concentrated aqueous
ammonia (14 mL) during 1 minute at 0 °C, ice cold potassium
permanganate solution (6.4 g) in water (200 mL) was added
dropwise during 40 minutes with continued cooling in an ice
bath. Precipitated manganese dioxide was removed by gravity
filtration and purple Fremy’s salt solution was allowed to warm
up to room temperature.
The mixture of starting 2-(2-alkoxyphenyl)imidazoline (0.01
mol), fresh Fremy’s salt solution (300 mL), methanol (100 mL),
and sodium carbonate (5 g) was stirred overnight at r.t.
Precipitated material was collected by filtration. Methanol was
evaporated while product doesn’t precipitate. Product was
crystallized from hexane/toluene (1:1).
General Procedure for Synthesis of 2-(2-Alkoxyphenyl)-1H-
imidazolines 1b – 1i [10].
Mixture of 2-(2-hydroxyphenyl)-1H-imidazoline, alkyl halide,
and absolute ethanol (100 mL) was refluxed. Ethanol was then
vacuum evaporated and the residue was treated with 15%
aqueous natrium hydroxide and chloroform. Chloroform layer
was then washed twice with 15% aqueous natrium hydroxide,
dried and chloroform was evaporated. The crude product was
crystallized from heptane. Amounts of starting materials,
reaction times, and yields are summarized in Table I.
Table I
Type of alkyl halide, amount of starting materials, reaction times, and yields of syntheses of
2-(2-alkoxyphenyl)-1H-imidazolines 1b – 1i (R is alkyl).
product
RX
n (1a) / mol
n (RX) / mol
time / h
yield / %
1b
1c
1d
1e
1f
1g
1h
1i
MeI
EtI
PrBr
isoPrBr
BuBr
isoBuBr
sec-BuBr
BnBr
0.123
0.031
0.068
0.100
0.050
0.100
0.100
0.100
0.240
0.037
0.134
0.200
0.050
0.150
0.100
0.100
26
22
25
23
20
24
20
24
51
29
50
75
20
14
30
40

Jul-Aug 2006
Study of Synthesis of 2-(2-Alkoxyphenyl)-1H-imidazoles
837
Scheme 1
6
6
5
HN
N
8
9
10 11
8
R is
CH3 (1b, 2b)
CH2CH2CH2CH3 (1f, 2f)
OR
4
3
1
8
9
8
9
10
2
(1c, 2c)
CH2CH3
(1g, 2g)
(1h, 2h)
1b - 1i
CH2CH(CH3)2
6
9
10
7
8
9
10
8
CH2CH3
11
CH3
CH2CH2CH3 (1d, 2d)
5
CH
HN
N
OR
4
3
1'
5'
2'
4'
8
9
8
CH2
CH(CH3)2 (1e, 2e)
1
3'
(1i, 2i)
2
2b - 2i
Proton numbering for assignment of 1H NMR shifts.
Tlc was succesfully used for conversion monitoring in the
2-(2-Propoxyphenyl)-1H-imidazoline (1d).
case of synthesis of 2-(2-alkoxyphenyl)-1H-imidazolines and of
Colourless crystals. Yield: 50%, m.p. 61-65 °C (heptane). IR
2-(2-alkoxyphenyl)-1H-imidazoles by methods
A and B.
(KBr): ꢁ 3442, 3206 (NH), 1600 (C=N), ꢀs 1392 (CH3), ꢁas 1242
Chromatography was accomplished using Silikagel 60 F254
(Merck) with methanol as mobile phase: for 2-(2-hydroxy-
phenyl)-1H-imidazoline, 2-(2-alkoxyphenyl)-1H-imidazolines,
and 2-(2-alkoxyfenyl)-1H-imidazoles are Rf 0.25 – 0.35, 0, and
0.55 – 0.65, respectively.
1
(C-O-C), ꢂ 755 cm-1 (CH arom); H NMR (DMSO-d6): ꢀ = 1.03
t, 3 H (H-10); 1.83 m, 2 H (H-9); 3.60 s, 4 H (H-6); 4.06 t, 2 H
(H-8); 7.00 m, 1 H (H-3); 7.14 d, 1 H (H-1); 7.43 m, 1 H (H-2);
7.90 dd, 1 H (H-4).
Anal. Calcd. for C12H16N2O (204.3): C, 70.56; H, 7.89; N,
13.71. Found: C, 70.41; H, 7.99; N, 13.73.
1
Yields, melting points, H NMR shifts, IR bands, and results
of elemental analyses of imidazolines 1a – 1i are given in the
text below.
2-(2-isoPropoxyphenyl)-1H-imidazoline (1e).
20
2-(2-Hydroxyphenyl)-1H-imidazoline (1a).
Colourless liquid. Yield: 23.5%, nD 1.5531. IR (KBr): ꢁ
3442, 3205 (NH), 1605 (C=N), ꢀs 1387, 1374 (CH3), ꢁas 1237
Colourless crystals. Yield: 50%, m.p. 200-202 °C
(water/ethanol 2:1) (200-203 °C [8]). H NMR (DMSO-d6): ꢀ =
3.74 s, 4 H (H-6); 6.72 m, 1 H (H-3); 6.81 dd, 1 H (H-1); 7.30
m, 1 H (H-2); 7.63 dd, 1 H (H-4); 11.01 br s, 2 H (H-5, OH).
Anal. Calcd. for C9H10N2O (162.2): C, 66.65; H, 6.21;
N,17.27. Found: C, 66.89; H, 6.46; N, 17.38.
1
(C-O-C), ꢂ 752 cm-1 (CH arom); H NMR (DMSO-d6): ꢀ = 1.36
1
d, 6 H (H-9); 3.60 s, 4 H (H-6); 4.74 m, 1 H (H-8); 6.99 t, 1 H
(H-3); 7.15 d, 1 H (H-1); 7.42 m, 1 H (H-2); 7.93 dd, 1 H (H-4).
Anal. Calcd. for C12H16N2O (204.3): C, 70.56; H, 7.89; N,
13.71. Found: C, 70.81; H, 7.66; N, 13.80.
2-(2-Butoxyphenyl)-1H-imidazoline (1f).
2-(2-Methoxyphenyl)-1H-imidazoline (1b).
Colourless crystals. Yield: 20%, m.p. 47-52 °C (heptane) (55
°C [10]). IR (KBr): ꢁ 3435, 3280 (NH), 1602 (C=N), ꢀs 1395
(CH3), ꢁas 1243 (C-O-C), ꢂ 750 cm-1 (CH arom); 1H NMR
(DMSO-d6): ꢀ = 0.98 t, 3 H (H-11); 1.47 m, 2 H (H-10); 1.80 p,
2 H (H-9); 3.60 s, 4 H (H-6); 4.09 t, 2 H (H-8); 7.00 t, 1 H (H-
3); 7.13 d, 1 H (H-1); 7.43 m, 1 H (H-2); 7.91 dd, 1 H (H-4).
Anal. Calcd. for C13H18N2O (218.3): C, 71.53; H, 8.31; N,
12.83. Found: C, 71.52; H, 8.20; N, 12.65.
Colourless crystals. Yield: 39%, m.p. 60-64 °C (heptane) (60
°C [10]). IR (KBr): ꢁ 3441, 3224 (NH), 1600 (C=N), ꢀs 1440
(CH3), ꢁas 1245 (C-O-C), ꢂ 768 cm-1 (CH arom); 1H NMR
(DMSO-d6): ꢀ = 3.59 s, 4 H (H-6); 3.88 s, 3 H (H-8); 7.02 m, 1
H (H-3); 7.14 d, 1 H (H-1); 7.46 m, 1 H (H-2); 7.91 dd, 1 H (H-
4).
Anal. Calcd. for C10H12N2O (176.2): C, 68.16; H, 6.86; N,
15.90. Found: C, 68.55; H, 7.08; N, 16.07.
2-(2-isoButoxyphenyl)-1H-imidazoline (1g).
2-(2-Ethoxyphenyl)-1H-imidazoline (1c).
Colourless crystals. Yield: 14%, m.p. 70-75 °C (heptane). IR
(KBr): ꢁ 3442, 3249 (NH), 1600 (C=N), ꢀs 1390, 1360 (CH3),
ꢁas 1239 (C-O-C), ꢂ 770 cm-1 (CH arom); 1H NMR (CDCl3): ꢀ =
1.03 d, 6 H (H-10); 2.15 m, 1 H (H-9); 3.60 s, 4 H (H-6); 3.89 d,
2 H (H-8); 7.01 m, 1 H (H-3); 7.13 d, 1 H (H-1); 7.44 m, 1 H
(H-2); 7.87 dd, 1 H (H-4).
Colourless crystals. Yield: 29%, m.p. 72-76 °C (heptane) (76
°C [10]). IR (KBr): ꢁ 3436, 3194 (NH), 1600 (C=N), ꢀs 1391
(CH3), ꢁas 1243 (C-O-C), ꢂ 743 cm-1 (CH arom); 1H NMR
(CDCl3): ꢀ = 1.45 t, 3 H (H-9); 3.71 s, 4 H (H-6); 4.11 q, 2 H
(H-8); 6.90 d, 1 H (H-1); 6.97 t, 1 H (H-3); 7.34 m, 1 H (H-2);
8.09 m, 1 H (H-4).
Anal. Calcd. for C13H18N2O (218.3): C, 71.53; H, 8.31; N,
12.83. Found: C, 71.35; H, 8.19; N, 12.83.
Anal. Calcd. for C11H14N2O (190.2): C, 69.45; H, 7.42; N,
14.72. Found: C, 69.72; H, 7.30; N, 14.75.

838
P. Paꢀík, S. ꢁenauerová, V. Liꢂková, K. Handlíꢀ, M. Ludwig
Vol 43
2-(2-sec-Butoxyphenyl)-1H-imidazoline (1h).
Anal. Calcd. for C12H14N2O (202.3): C, 71.26; H, 6.98; N,
13.85. Found: C, 71.18; H, 7.22; N, 13.59.
20
Orange liquid. Yield: 30%, nD 1.5312. IR (nujol): ꢀ 3442
(NH), 1604 (C=N), ꢀas 1235 (C-O-C), ꢁ 749 cm-1 (CH arom); 1H
NMR (CDCl3): ꢂ = 0.98 t, 3 H (H-10); 1.31 d, 3 H (H-11); 1.67
m, 1 H (H-9); 1.77 m, 1 H (H-9); 3.62 s, 4 H (H-6); 4.52 m, 1 H
(H-8); 7.00 t, 1 H (H-3); 7.13 d, 1 H (H-1); 7.42, 1 H (H-2), 7.98
dd, 1 H (H-4).
Anal. Calcd. for C13H18N2O.HCl (254.8): C, 61.31; H, 7.47;
N, 11.00; Cl, 13.93. Found: C, 62.15; H, 7.33; N, 11.53; Cl,
13.90.
2-(2-isoPropoxyphenyl)-1H-imidazole (2e).
Colourless crystals, m.p. 96.5-101 °C (hexane/toluene 1:1). IR
(KBr): ꢀ 3439 (NH), 1602, 1583 (C=N), ꢀas 1232, 1263 (C-O-
C), ꢁ 765, 749 (CH arom), 710 cm-1 (CH imidazole); H NMR
1
(DMSO-d6): ꢂ = 1.42 d, 6 H (H-9); 4.81 m, 1 H (H-8); 7.02-7.06
m, 2 H (H-3,6[7]); 7.20 d, 1 H (H-1); 7.23 s, 1 H (H-6 [7]); 7.32-
7.37 m, 1 H (H-2); 8.09 dd, 1 H, (H-4); 11.31 s, 1 H (H-5).
Anal. Calcd. for C12H14N2O (202.3): C, 71.26; H, 6.98; N,
13.85. Found: C, 71.16; H, 7.22; N, 13.84.
2-(2-Benzyloxyphenyl)-1H-imidazoline (1i).
2-(2-Butoxyphenyl)-1H-imidazole (2f).
Colourless crystals. Yield: 40%, m.p. 37-43 °C (heptane). IR
(KBr): ꢀ 3438 (NH), 1605 (C=N), ꢀas 1232 (C-O-C), ꢁ 749 cm-1
(CH arom); 1H NMR (DMSO-d6): ꢂ = 3.59 s, 4 H (H-6); 5.00 s,
2 H (H-8); 6.85-6.97 m, 2 H (H-1,3); 7.24-7.33 m, 6 H (H-2, H-
1’, H-2’, H-3’, H-4’, H-5’); 8.10 dd, 1 H (H-4).
Colourless crystals, m.p. 88-96 °C (hexane/toluene 1:1). IR
(KBr): ꢀ 3439 (NH), 1607, 1586 (C=N), ꢀas 1244, 1269 (C-O-
C), ꢁ 746 (CH arom), 715 cm-1 (CH imidazole); 1H NMR
(DMSO-d6): ꢂ = 0.97 t, 3 H (H-11); 1.45 m, 2 H (H-10); 1.86 m,
2 H (H-9); 4.22 t, 2 H (H-8); 7.04-7.07 m, 2 H (H-3,6 [7]); 7.18
d, 1 H (H-1); 7.23 s, 1 H (H-6 [7]); 7.33-7.37 m, 1 H (H-2); 8.08
dd, 1 H (H-4); 11.49 s, 1 H (H-5).
Anal. Calcd. for C16H16N2O (252.3): C, 76.17; H, 6.39; N,
11.10. Found: C, 75.88; H, 6.66; N, 11.34.
Melting points, 1H NMR shifts, IR bands, and results of
elemental analyses of imidazoles 2a – 2i are given in the
following text. Analyses of products obtained by all three
methods (A, B, and C) are comparable.
Anal. Calcd. for C13H16N2O (216.3): C, 72.19; H, 7.46; N,
12.95. Found: C, 72.04; H, 7.31; N, 13.11.
2-(2-isoButoxyphenyl)-1H-imidazole (2g).
2-(2-Hydroxyphenyl)-1H-imidazole (2a).
Colourless crystals, m.p. 114-123 °C (hexane/toluene 1:1). IR
Colourless crystals, m.p. 117-125 °C (133-134 °C [8]). IR
(KBr): ꢀ 3239 (NH), 1605, 1595 (C=N), ꢀas 1266 (C-O-C), ꢁ
765, 743 (CH arom), 700 cm-1 (CH imidazole); 1H NMR
(DMSO-d6): ꢂ = 6.95-7.00 m, 2 H (H-1,3); 7.25-7.30 m, 3 H (H-
2,6,7); 7.92 dd, 1 H, (H-4); 12.96 br s, 2 H (H-5, OH).
(KBr): ꢀ 3417 (NH), 1605, 1583 (C=N), ꢀas 1244, 1269 (C-O-
1
C), ꢁ 761, 749 (CH arom), 710 cm-1 (CH imidazole); H NMR
(DMSO-d6): ꢂ = 1.00 d, 6 H (H-10); 2.30 m, 1 H (H-9); 3.99 d, 2
H (H-8); 7.04-7.08 m, 2 H (H-3,6 [7]); 7.18 d, 1 H (H-1); 7.25 s,
1 H (H-6 [7]); 7.33-7.38 m, 1 H (H-2); 8.06 dd, 1 H (H-4); 11.45
s, 1 H (H-5).
Anal. Calcd. for C13H16N2O (216.3): C, 72.19; H, 7.46; N,
12.95. Found: C, 72.16; H, 7.69; N, 12.70.
Anal. Calcd. for C9H8N2O (160.2): C, 67.49; H, 5.03; N,
17.49. Found: C, 67.42; H, 5.05; N, 17.50.
2-(2-Methoxyphenyl)-1H-imidazole (2b).
2-(2-sec-Butoxyphenyl)-1H-imidazole (2h).
Colourless crystals, m.p. 126-133 °C (hexane/toluene 1:1)
(129-131 °C [29]). IR (KBr): ꢀ 3434 (NH), 1607, 1588 (C=N),
ꢀas 1242, 1268 (C-O-C), ꢁ 763, 749 (CH arom), 712 cm-1 (CH
Colourless crystals, m.p. 78-81 °C (hexane/toluene 1:1). IR
(KBr): ꢀ 3438 (NH), 1604, 1580 (C=N), ꢀas 1239, 1266 (C-O-
C), ꢁ 761, 747 (CH arom), 721 cm-1 (CH imidazole); H NMR
1
1
imidazole); H NMR (DMSO-d6): ꢂ = 3.93 s, 3 H (H-8); 7.05-
(DMSO-d6): ꢂ = 0.95 t, 3 H (H-10); 1.37 d, 3 H (H-11); 1.71 m,
1 H (H-9); 1.93 m, 1 H (H-9); 4.59 m, 1 H (H-8); 7.02-7.06 m, 2
H (H-3,6 [7]); 7.19 d, 1 H (H-1); 7.24 s, 1 H (H-6 [7]); 7.32-7.36
m, 1 H (H-2); 8.11 dd, 1 H (H-4); 11.28 s, 1 H (H-5).
7.09 m, 2 H, (H-3,6 [7]); 7.17-7.20 m, 2 H (H-1,6[7]); 7.35-7.39
m, 1 H (H-2); 8.14 dd, 1 H (H-4); 11.82 s, 1 H (H-5).
Anal. Calcd. for C10H10N2O (174.2): C, 68.95; H, 5.79; N,
16.08. Found: C, 68.73; H, 5.96; N, 16.11.
Anal. Calcd. For C13H16N2O (216.3): C, 72.19; H, 7.46; N,
12.95. Found: C, 71.91; H, 7.63; N, 12.86.
2-(2-Ethoxyphenyl)-1H-imidazole (2c).
Colourless crystals, m.p. 130-133 °C. IR (KBr): ꢀ 3454 (NH),
1604, 1583 (C=N), ꢀas 1244, 1269 (C-O-C), ꢁ 749 (CH arom),
2-(2-Benzyloxyphenyl)-1H-imidazole (2i).
1
712 cm-1 (CH imidazole); H NMR (DMSO-d6): ꢂ = 1.46 t, 3 H
Colourless crystals, m.p. 113-115 °C (hexane/toluene 1:1). IR
(KBr): ꢀ 3435 (NH), 1602, 1583 (C=N), ꢀas 1223, 1273 (C-O-
(H-9); 4.29 q, 2 H (H-8); 7.04-7.08 m, 2 H (H-3,6[7]); 7.18 d, 1
H (H-1); 7.23 s, 1 H (H-6 [7]); 7.33-7.38 m, 1 H (H-2); 8.11 dd,
1 H (H-4); 11.53 s, 1 H (H-5).
Anal. Calcd. for C11H12N2O (188.2): C, 70.19; H, 6.43; N,
14.88. Found: C, 70.18; H 6.57; N, 14.66.
C), ꢁ 771, 740 (CH arom), 697 cm-1 (CH imidazole); H NMR
1
(DMSO-d6): ꢂ = 5.46 s, 2 H (H-8); 7.01-7.05 m, 1 H (H-3); 7.09
s, 1 H (H-6 [7]); 7.16 d, 1 H (H-1); 7.25-7.30 m, 2 H (H-2,6 [7]);
7.31-7.35 m, 1 H (H-3’); 7.38-7.43 m, 2 H (H-2’,4’); 7.51-7.53
m, 2 H (H-1’,5’); 8.11 dd, 1 H (H-4); 11.87 s, 1 H (H-5).
Anal. Calcd. for C16H14N2O (250.3): C, 76.78; H, 5.64; N,
11.19. Found: C, 76.72; H, 5.92; N, 11.01.
2-(2-Propoxyphenyl)-1H-imidazole (2d).
Colourless crystals, m.p. 101-102 °C. IR (KBr): ꢀ 3438 (NH),
1604, 1582 (C=N), ꢀas 1239, 1268 (C-O-C), ꢁ 769, 740 (CH
arom), 712 cm-1 (CH imidazole); 1H NMR (DMSO-d6): ꢂ = 1.42
d, 6 H (H-9); 4.81 m, 1 H (H-8); 7.04-7.08 m, 2 H (H-3,6[7]);
7.18 d, 1 H (H-1); 7.24 s, 1 H (H-6 [7]); 7.33-7.38 m, 1 H (H-2);
8.08 dd, 1 H (H-4); 11.49 s, 1 H (H-5).
Results and Discussion.
Imidazolines.
The most reliable synthesis of 2-(2-alkoxyphenyl)-1H-
imidazolines was the alkylation of 2-(2-hydroxyphenyl)-1H-

Jul-Aug 2006
Study of Synthesis of 2-(2-Alkoxyphenyl)-1H-imidazoles
839
imidazolines. Hence, the 2-(2-alkoxyphenyl)-1H-imidazolines
were prepared by a two-step synthesis starting from methyl
salicylate. In the first step, methyl salicylate reacted with
atmospheric pressure results in its decomposition, whereas the
compound is relatively stable during heating in vacuum.
Imidazoles.
ethane-1,2-diamine
to
give
2-(2-hydroxyphenyl)-1H-
imidazoline, which was subsequently submitted the alkylation
with alkyl halides to give the respective 2-(2-alkoxyphenyl)-1H-
imidazoline. Beger & Wagner [10] used the starting substances
for the alkylation in the molar ratio of 1:1 and obtained the
required 2-(2-alkoxyphenyl)-1H-imidazolines in the yields
ranging about 40 %. In our alkylation reactions, an
approximately double amount of alkyl halide was adopted,
because the application of equimolar ratio of the reactants led to
alkoxyimidazolines that were contaminated with unreacted
2-(2-hydroxyphenyl)-1H-imidazoline that was difficult to
remove. In this way, eight 2-(2-alkoxyphenyl)-1H-imidazolines
were prepared with the substituents alkyl = Me, Et, Pr, isoPr,
Bu, isoBu, sec-Bu, Bn, in the yields about 30 %. The propyl,
isopropyl, isobutyl, sec-butyl, and benzyl derivatives have not
been described in literature yet. No formation of N-alkylated
products was observed. The measured melting points as well as
Our first successful transformation of imidazoline ring into
imidazole was achieved by dehydrogenation of 2-(2-
propoxyphenyl)-1H-imidazoline by means of Pd/C (5 %) with
refluxing in dry toluene under the inert atmosphere of argon.
The reaction was also successful in the cases of the hydroxy
derivative and the other alkoxy derivatives, except for the
synthesis of 2-(2-benzyloxyphenyl)-1H-imidazole, in which case
the reaction mixture contained the non-reacted imidazoline and
the dealkylation product (2-(2-hydroxyphenyl)-1H-imidazoline)
besides the desired product even after 146 h refluxing; the
resulting mixture could be separated neither chromatographi-
cally nor in any other way.
In the case of method A, 5% Pd/C was safely replaced by
10% Pd/C. In the case of some alkoxyphenylimidazoles
synthesized, it even was not necessary to carry out further
purification of the product obtained.
1
the H NMR chemical shifts of the known imidazolines 1a, 1b,
Imidazolines can also be oxidized by activated MnO2
in toluene [20]. In the case of oxidation of the 2-(2-propoxy-
phenyl)-1H-imidazoline, the reaction mixture was stirred at
room temperature for 24 h (in accordance with [23]), but no
product was formed. Therefore, the reaction temperature was
increased to 60 °C, and the reaction mixture was stirred at this
temperature for another 24 h to give 2-(2-propoxyphenyl)-1H-
imidazole in the yield of 65 %. For that reason the oxidation
reactions of another imidazolines were carried out at the
temperature of 60 °C; the degree of conversion during the
reaction course was monitored by means of tlc, and the reaction
was finished always after the starting imidazoline had
disappeared. The individual reaction times are given in Table II.
Moreover, we tested a modification of this reaction, in which
dry toluene was mixed with activated MnO2, and the water
present in the reagent was removed by azeotropic distillation
[24]. Then the starting 2-(2-propoxyphenyl)-1H-imidazoline was
introduced and the reaction was carried out by refluxing and
concomitant removal of the reaction water. After 1 h, the
starting imidazoline disappeared (tlc), and the product was
formed in the yield of 78 %. Hence, removing the reaction water
by azeotropic distillation can increase the reaction yields. For
successful results of this oxidation method to be achieved, it is
necessary to adopt the activated MnO2 (<5 micron, activated,
85%, Aldrich). The reaction was unsuccessfully tested with the
use of MnO2 (99+%, Aldrich).
1c, 1f agree with the literature data [8,10].
In order to increase the yields, we carried out the alkylation
reactions in several modifications. The synthesis of 2-(2-
propoxyphenyl)-1H-imidazoline was realized with addition of
an equimolar amount of sodium hydrogencarbonate. However,
the resulting reaction mixture contained besides the required
product also the starting substance and two other compounds.
Apart from this, the alkylation of 2-(2-hydroxyphenyl)-
1H-imidazoline was carried out in the presence of potassium
carbonate in N,N-dimethylformamide as the solvent. This
reaction failed to give the required product. Finally, we also
tested the methylation of 2-(2-hydroxyphenyl)-1H-imidazoline
with dimethyl sulfate in aqueous sodium hydroxide, which did
not give the expected 2-(2-methoxyphenyl)-1H-imidazoline
either. Hence, none of the modifications used resulted in
optimization of the alkylation reaction.
The preparation of 2-(2-alkoxyphenyl)-1H-imidazolines by
the reaction of methyl 2-alkoxybenzoates with ethane-1,2-
diamine (starting from the analogy with the reaction of methyl
salicylate and ethane-1,2-diamine giving 2-(2-hydroxyphenyl)-
1H-imidazoline) turned out to be entirely unsuitable. The
reactions tested by us were carried out with methyl
2-methoxybenzoate, methyl 2-ethoxybenzoate and methyl 2-
propoxybenzoate [30] as the starting substances, our aim being
to
synthesize
2-(2-methoxyphenyl)-1H-imidazoline,
2-(2-ethoxyphenyl)-1H-imidazoline, and 2-(2-propoxyphenyl)-
1H-imidazoline, respectively. If the final reaction mixture was
rid of ethane-1,2-diamine by atmospheric distillation, then the
isolated product of all the three preparations was 2-(2-
hydroxyphenyl)-1H-imidazoline. If the ethane-1,2-diamine was
removed by distillation under reduced pressure, then the
resulting mixture could not be separated and identified. The
decomposition of 2-(2-alkoxyphenyl)-1H-imidazolines by
dealkylation, giving 2-(2-hydroxyphenyl)-1H-imidazoline, could
be caused by thermal instability of the alkoxy derivatives at the
high temperature of removal of ethane-1,2-diamine by
distillation at atmospheric pressure. A similar problem is
discussed in literature [31], describing a decomposition of
2-methoxybenzoic acid giving salicylic acid on heating at
atmospheric pressure. Also the heating of methyl salicylate at
Potassium nitrosodisulphonate (KSO3)NO (Fremy’s salt) is
used most frequently for oxidation of phenols and aromatic
amines to the corresponding quinones; it is also used in
oxidative aromatization [32]. We prepared Fremy’s salt
according to [28] and used it in the form of a solution, because it
is somewhat unstable in solid form. The reagent was
successfully used in the transformations of all the 2-(2-
alkoxyphenyl)-1H-imidazolines to the respective imidazoles.
Only in the case of synthesis of 2-(2-hydroxyphenyl)-1H-
imidazole the reaction failed both when carrying it at room
temperature overnight and after subsequent heating of the
reaction mixture to 65 °C for 5 h.
The methods A, B and C were used to synthesize all the 2-(2-
alkoxyphenyl)-1H-imidazoles 2b – 2i (except for 2i, where
method A failed). In this way, seven 2-(2-alkoxyphenyl)-

840
P. Paꢀík, S. ꢁenauerová, V. Liꢂková, K. Handlíꢀ, M. Ludwig
Vol 43
1H-imidazoles were prepared (alkyl = Et, Pr, isoPr, Bu, isoBu,
sec-Bu, Bn), which have not been described in literature so far.
Both the melting points and H NMR chemical shifts of the
known imidazoles 2a and 2b agree with the literature data
[8,29].
good or satisfactory, in some cases very low: 66 %, 37 % and
33 % are average yields calculated from individual yields
obtained from methods A, B, and C, respectively. Methods A
and B are convenient in that easy monitoring of reaction process
using tlc is possible.
1
The long lasting refluxing during dehydrogenation (method
A) can be taken as a handicap. The application of method B or C
is more favorable from this point of view. The reaction time is
shorter and reaction temperature lower in the case of method B.
The oxidation reactions using Fremy’s salt (method C) were
even performed overnight only at room temperature.
Furthermore, mild conditions of method C can be safe for
various functional groups. A certain disadvantage of method B
can be seen in the necessity of using large excess of the reagent.
The highest yields were reached using method A.
Table II
Reaction times and yields of syntheses of imidazoles 2a – 2i by methods
A, B, and C.
method A
method B
method C
product
2a
2b
2c
2d
2e
2f
2g
2h
time / h yield / % time / h
yield / %
yield / %
-
52.5
16
61
14
58
15
18.5
25
23
73
49
66 [a]
95
67
48
18
30
43
4
21
14
5
-
50.5
26.5
67
Nevertheless, very recently it was reported [26,27] that 2-
imidazoles can be oxidized by another way. So far, we have not
tested these syntheses.
45
62 [a]
60
81
46.5
50
25
11.5
38.5
46
97
38
Conclusions.
117
146
60
2-(2-Alkoxyphenyl)-1H-imidazolines have been prepared by
alkylation of 2-(2-hydroxyphenyl)-1H-imidazoline using the
corresponding alkyl halides in ethanol without any addition of
bases. The yields were rather low, about 30 %. N-Alkylation was
not observed.
Several oxidative aromatization reactions were tested and
three successful methods were used for oxidation of
imidazolines to imidazoles, namely dehydrogenation on Pd/C,
oxidation by activated manganese dioxide, and oxidation by
potassium nitrosodisulphonate. The general results of the
methods used were comparable from the point of view of
experimental arrangement, purity and yields of the products, so
we can recommend all of them.
2i
-
8
29
[a] yield of product without crystallization.
We also tested other oxidation reactions usually adopted for
aromatization of imidazolines and cognate derivatives using
selected 2-(2-alkoxyphenyl)-1H-imidazolines. An unsuccessful
attempt at transformation of imidazoline to imidazole was the
oxidation of 2-(2-methoxyphenyl)-1H-imidazoline performed by
its reaction with bromine in a mixture of chloroform and
pyridine [21]. The introduced synthesis did not provide the
expected 2-(2-methoxyphenyl)-1H-imidazole, the non-reacted
starting
imidazoline
being
isolated
instead.
2-(2-Methoxyphenyl)-1H-imidazoline was also oxidized with
dibenzoyl peroxide in toluene [21]. Also this reaction gave only
the non-reacted imidazoline. Moreover, 2-(2-hydroxyphenyl)-
1H-imidazoline was oxidized with potassium permanganate in
dioxane in the presence of 18-crown-6-ether [12]; the reaction
gave a mixture of substances that could be neither separated nor
Acknowledgement.
The authors thank the Ministry of Education, Youth ans
Sports of the Czech Republic for financial support (project
MSM 0021627501).
identified.
The
oxidation
process
of
heating
of
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