Study of the Reaction of Hydroxybenzoyl Chlorides and Their Derivatives with Imidazole

Article abstract of DOI:10.1134/S1070428019050026

The reaction of hydroxybenzoyl chlorides with imidazole was studied on an example of the Schotten-Baumann reaction of salicyloyl and acetylsalicyloyl chlorides with imidazole, which, according to soe published data, can take two different ways. It was sho

Full text of DOI:10.1134/S1070428019050026

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 5, pp. 592–597. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 5, pp. 683–689.
Study of the Reaction of Hydroxybenzoyl Chlorides
and Their Derivatives with Imidazole
a
a,
А. K. Brel’ and S. V. Lisina *
a
Volgograd State Medical University (VolgGMU), pl. Pavshikh Bortsov 1, Volgograd, 400131 Russia
*
e-mail: svlisina@gmail.com
Received May 25, 2018; revised June 10, 2018; accepted August 17, 2018
Abstract—The reaction of hydroxybenzoyl chlorides with imidazole was studied on an example of the
Schotten–Baumann reaction of salicyloyl and acetylsalicyloyl chlorides with imidazole, which, according to
soe published data, can take two different ways. It was shown that the Schotten–Baumann reaction with
imidazole involves imidazole ring opening (Bamberger cleavage) to form 1,2-bis(salicyloylamino)ethylene and
1,2-bis(acetylsalicyloylamino)ethylene rather than N-salicyloylimidazole and N-acetylsalicyloylimidazole. N-
Hydroxybenzoylimidazoles were synthesized by the reaction of hydroxybenzoyl chlorides (and derivatives)
with a double excess of imidazole in an aprotic solvent (chloroform, benzene, or diethyl ether) at room
temperature. The highest yields (about 80%) of N-hydroxybenzoylimidazoles were obtained in chloroform.
Some of the newly synthesized compounds were tested for psychotropic (open field and passive avoidance
response tests) and analgesic activities (vocalization threshold test). The best results were obtained with N-(2-
hydroxybenzoyl)imidazole, which showed an evident analgesic activity, and, therewith, the motor score and
oriented exploratory activity parameters were higher than in the control group.
Keywords: hydroxybenzamides, N-hydroxybenzoylimidazoles, Schotten–Baumann reaction, Bamberger
imidazole cleavage, biological activity
DOI: 10.1134/S1070428019050026
Amides of hydroxybenzoic acids exhibit diverse
pharmacological activity: antipyretic, sedative, anticon-
vulsant, choleretic, neuroleptic, etc. We previously showed
that the modification of hydroxybenzoic acids with
physicologically active amino acid residues produces
unexpected changes in the biological activity of such deri-
vatives N-Hydroxybenzoyl derivatives of γ-amino-
butyric acid (GABA) and glycine showed anti-depress-
sive (anxiolytic), antiamnestic, psychostimulant, and
cerebroprotective effects [1]. The role of such molecular
fragments can also be played by heterocyclic structures.
For example, N-acyl-imidazoles are not only acylating
agents and structural components of biomolecules, but also
compounds with a broad-spectrum biological activity [2–4].
chloride with imidazole. According to some sources,
this reaction forms N-benzoylimidazole [2], while accor-
ding to other, more numerous sources, the reaction
under the same conditions but a higher concentration
of alkali involves imidazole ring opening to form 1,2-
bis(benzoylamino)ethylene (Bamberger cleavage;
Scheme 1) [5–7]. The ring opening product has a cis-
configuration and is stabilized by intermolecular
hydrogen bonds [6].
The relative contribution of one or the other
reaction route, nucleophilic substitution (Scheme 1,
route b) or cleavage (Scheme 1, route b), depends on
different factors, specifically, the concentration and
strength of the attacking nucleophile (base), the nature
of the solvent, the reaction temperature, and the
structure of the substrate. For example, if the
concentration of the base is low, the product ratio will
depend on the structure of the cation. However, it was
found that Bamberger cleavage occurs with both in
unsubstituted and substituted imidazoles, as well as
benzimidazoles and adenines, and is insensitive to the
nature of the N-acylating agent [7].
The aim of the present work was to synthesize N-
hydroxybenzoyl derivatives of imidazole using
hydroxybenzoyl chlorides as acylating agents. To this
end, we studied the reactions of salicyloyl chloride and
acetylsalicyloyl chlorides with imidazole in different
conditions. As known, N-acylimidazoles are unstable
in an alkaline medium. However, there is controversial
information in the literature on the reaction of benzoyl
5
92

STUDY OF THE REACTION OF HYDROXYBENZOYL CHLORIDES
593
Scheme 1.
N
N
a. 5-10% NaOH
PhCOCl
+
N
N
H
COPh
CH
NH
CH
HN
b. conc. >10 % NaOH
PhOC
COPh
The mechanism of the cleavage reaction was
studied on an example of the modification of a
protein containing a histidine fragment using diethyl
pyrocarbonate as an acylating agent at рН ≈6
final reaction products in yields higher than 70% (see
table).
To preserve the ring and obtain N-hydroxybenzoyl
imidazole derivatives, the acid chlorides were reacted
with a double excess of imidazole in apolar aprotic
solvents (chloroform, diethyl ether, benzene) at room
temperature (Scheme 4). The excess imidazole played
the role of an electron acceptor. Attempted
replacement of imidazole in this role by pyridine and
trimethylamine resulted in a radical decrease in the
yields of the substitution products.
(
Scheme 2) [7].
We suggested that the observation of different
routes of the N-acylation reaction (Scheme 1), reported
in the literature, is explained by that the transition state
of the cleavage reaction has a stronger charge
distribution (Scheme 2), taking into account the effect
of the solvent. In this connection, to prepare the target
compounds, we studied the reactions of salicyloyl
chloride and acetyl salicyloyl chloride with imidazole
in different solvents. Presumably, under the Schotten–
Baumann reaction conditions, these reactions follow
the mechanism shown in Scheme 3.
Aprotic nucleophilic solvents are polar to a greater
or smaller extent (see table), and the higher the
dielectric constant of the solvent, the more the solvent
favors charge separation in the starting molecules or
transition states, and, consequently, drives the
nucleophilic reaction.
The positive change on the ammonium nitrogen
atoms in transition state A has a strong –I effect of the
Considering the reaction in terms of acid–base
interactions, solvents with a higher donor number,
which strongly solvate the electron-deficient reagent,
slightly decelerate the substitution reaction, thereby
decreasing the yield of the target products. In this
connection, the most optimal solvent for the synthesis
of N-hydroxybenzoyl imidazole derivatives is
chloroform (see table), which has the lowest donor
+
electron-deficient СН carbon, and further on the ring
–
opens under the action of the ОН base to form
compound 2а or 2b. Thus, we found that the use of the
Schotten–Baumann reaction reactions (6 N NaOH) for
preparing N-salicyloylimidazole and N-acetyl-
salicyloyl-imidazole, too, leads to the Bamberger
cleavage of the imidazole ring (Scheme 3) to give the
Scheme 2.
O
N+
N
OEt
+
N
N
OEt
EtO
HN
N
EtO
OEt
O
O
O
HOH
HCOOH
EtO
NH HN
OEt
EtO
HN
OEt
EtO
N
N
OEt
N
-
CHO
O
O
O
O
O
HO
H
O
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 5 2019

5
94
BREL’, LISINA
Scheme 3.
RO
C
O
O
O
C
C
Ph(OR)
N:
N+
Ph(OR)
N+
Cl
.
.
+
CHH
N
+
2
N+
H
N
H
H
O
OH
O
C
C
C
O
Cl
OR
Ph(OR)
Ph(OR)
A
O
O
C
O
C
N
C
Ph(OR)
N
Ph(OR)
N
Ph(OR)
H
H
-
C(O)H
OH , H-OH
H-C(O)OH
N
N
C
N+
OH
H
H
H
-
C
O
O
C
O
Ph(OR)
a_2b
Ph(OR)
Ph(OR)
2
RO: 2-hydroxy (2a); 2-acetyloxy (2b).
number and highest dielectric constant among the
solvents studied (benzene, chloroform, diethyl ether) [8].
preventive injection of the test compounds and
diclofenac as a reference drug. Compound 1а showed
an evident analgesic activity, statistically reliably
higher than the respective values for the control group
and comparing with those for diclofenac; therewith,
the motor score and oriented exploratory activity
parameters were reliably higher than in the control
group. Similar trends with insignificant variability
were observed in the other groups, but the differences
between the groups did not reach statistical
significance.
We tested the newly synthesized imidazole
derivatives for biological activity, and some of them
showed psychotropic and analgesic activity.
The study of behavioral disorders in animals
(
cognitive and mnestic) was performed using standard
psychotropic tests, specifically an open field and a
passive avoidance response test. The analgesic activity
was assessed using the vocalization threshold test with
Effect of the solvent on the yield of substitution and cleavage products
Yield, %
substitution
8 (1а)
Solvent
µ
Dielectric constant
Donor number
а
cleavage
5
Benzene
0
2.28
4.70
4.34
84.0
3.5
1.0
–
–
–
6
8
8
8
1 (1i)
5 (1а)
7 (1i)
0 (1а)
Chloroform
1.87
1.25
–
Diethyl ether
19.2
18.0
7
9 (1i)
8
7 (2а)
Water
–
7
4 (2b)
а
Under the Schotten–Baumann reaction conditions (6 N aqueous NaOH).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 5 2019

STUDY OF THE REACTION OF HYDROXYBENZOYL CHLORIDES
595
Scheme 4.
O
C
O
.
.
N
O
C
N
Ph(OR)
N
C
Ph(OR)
+
Ph(OR)
_
+
N
H
-Cl
N
Cl
N
1
a_1o
RO: 2-OH (1a), 3-OH (1b), 4-OH (1c), 2,3,4-OH (1d), 2-OMe (1e), 3-OMe (1f), 4-OMe (1g), 2,3,4-OMe (1h), 2-OAc (1i),
-OAc (1j), 4-OAc (1k), 2,3,4-OAc (1l), 2,4-OH (1m), 2,4-OAc (1n), 2,4-OMe (1o).
3
EXPERIMENTAL
%: C 63.84; H 4.30; N 14.87. C10
: C 63.82; H 4.28; N 14.89.
H O N . Calculated,
8 2 2
%
1
The Н NMR spectra (DMSO-d ) were recorded on
6
N-(4-Hydroxybenzoyl)imidazole (1c). Yield 11.04 g
a Bruker АМ300 spectrometer (300 MHz), internal
reference HMDS. The mass spectra were recorded on a
Finnigan Trace DCQ GCMS system using an SGE
BPX-5 column (30 m × 0.32 mm), ionizing energy 70 eV.
The melting points were determined on a Stuart SMP-30
melting point apparatus at a heating rate of 10 deg/min.
Elemental analysis was performed on a Perkin Elmer
Series II 2400 analyzer. Thin-layer chromatography
was performed on Silufol UV-254 plates, eluent
hexane–ethyl acetate, 1 : 3.
2
0
1
(
80%), viscous oil. R 0.54, n 1.645. Н NMR
f D
spectrum, δ, ppm: 8.33 s (1H, OH), 8.02 s (1H, CH,
imidazole), 7.77 d (1H, CH, imidazole), 7.57 d
(
2Harom), 7.38 d (1H, CH, imidazole), 6.87 s (2Harom).
+
Mass spectrum (ESI), m/z: 188 [М] . Found, %: C
6
6
3.82; H 4.30; N 14.87. C H O N . Calculated, %: C
10 8 2 2
3.82; H 4.28; N 14.89.
N-(3,4,5-Trihydroxybenzoyl)imidazole (1d).
Yield 10.20 g (60%), yellow crystals. R 0.84, mp 70–
f
1
7
2
2°C. Н NMR spectrum, δ, ppm: 8.03–7.98 m (3H,
Acid chlorides were synthesized by the reactions of
corresponding acids with oxalyl chloride [9–10].
OH, CH, imidazole), 7.89 s (1H, OH), 7.76 d (1H,
CH, imidazole), 7.36 d (1H, CH, imidazole), 6.72 d
Synthesis of hydroxybenzoylimidazoles.
solution of 50 mmol of acid chloride in 10 mL of
chloroform was slowly added dropwise to a solution of
A
+
(
2Harom). Mass spectrum (ESI), m/z: 220 [М] . Found,
%
: C 54.56; H 3.68; N 12.82. C H O N . Calculated,
10 8 4 2
%
: C 54.55; H 3.66; N 12.72.
N-(2-Methoxybenzoyl)imidazole (2e). Yield 13.37 g
1
00 mmol of imidazole in 70 mL of anhydrous
chloroform. Imidazole hydrochloride precipitated
immediately. The mixture was stirred for 30 min at
room temperature. The precipitate was separated, and
the organic layer was washed with cold water (3 × 10 mL),
dried over sodium sulfate, and dried in air. The residue
was washed with cold water and dried in air.
2
0
1
(
88%), viscous oil. R 0.25, n 1.583. Н NMR
f D
spectrum, δ, ppm: 7.93 s (1H, CH, imidazole), 7.76 d
(
1H, CH, imidazole), 7.69 d (1Harom), 7.49 t (1Harom),
7
3
.37 d (1H, CH, imidazole), 7.12–7.08 m (2Harom),
+
.81 s (3H, CH ). Mass spectrum (ESI), m/z: 202 [М] .
3
Found, %: C 65.38; H 4.00; N 13.83. C H O N .
Calculated, %: C 65.34; H 4.98; N 13.85.
1
1
10
2
2
N-(2-Hydroxybenzoyl)imidazole (1a). Yield 11.73 g
2
0
1
(
85%), viscous oil. R 0.62, n 1.637. Н NMR
f D
spectrum, δ, ppm: 8.49 s (1H, OH), 7.97 s (1H, CH,
imidazole), 7.75 d (1H, CH, imidazole), 7.55 d (1H,
CH, imidazole), 7.37 d (1Harom), 7.06–7.01 m (2Harom+),
N-(3-Methoxybenzoyl)imidazole (1f). Yield 13.06 g
2
0
1
(86%), viscous oil. R
0.23, n
1.577. Н NMR
f
D
spectrum, δ, ppm: 8.03 s (1H, OH), 7.78 s (1H, CH,
6
.96 d (2Harom). Mass spectrum (ESI), m/z: 188 [М] .
imidazole), 7.37–7.32
m
(4H, 2CHarom
,
2CH,
Found, %: C 63.83; H 4.32; N 14.87. C H O N .
imidazole) 7.12 d (1Harom), 3.81 s (3H, CH
spectrum (ESI), m/z: 202 [М] . Found, %: C 65.35; H
3
). Mass
1
0
8
2
2
+
Calculated, %: C 63.82; H 4.28; N 14.89.
N-(3-Hydroxybenzoyl)imidazole (1b). Yield
4
4
.99; N 13.81. C H O N . Calculated, %: C 65.34; H
11 10 2 2
.98; N 13.85.
N-(4-Methoxybenzoyl)imidazole (1g). Yield 14.43 g
2
0
1
1
1.31 g (82%), viscous oil. R 0.57, n 1.618. Н
f D
NMR spectrum, δ, ppm: 8.33 s (1H, OH), 8.02 s (1H,
CH, imidazole), 7.81 d (1H, CH, imidazole), 7.36–7.31
1
(85%), yellow crystals. R 0.20, mp 96–98°C. Н NMR
f
m (4H, 2CHarom, 2CH, imidazole), 7.11–7.02 m
spectrum, δ, ppm: 8.05 s (1H, CH, imidazole), 7.72 d
(1H, CH, imidazole), 7.55 d (2Harom), 7.34 d (1H, CH,
+
(
1Harom). Mass spectrum (ESI), m/z: 188 [М] . Found,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 5 2019

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BREL’, LISINA
imidazole), 7.05 d (2Harom), 3.77 s (3H, CH ). Mass
spectrum (ESI), m/z: 202 [М] . Found, %: C 65.33; H
imidazole), 7.39–7.36 m (2H, CHarom, СН, imidazole),
6.52–6.47 m (2Harom). Mass spectrum (ESI), m/z: 204
[М] . Found, %: C 58.91; H 3.91; N 13.75.
3
+
+
4
4
.99; N 13.87. C H O N . Calculated, %: C 65.34; H
1
1
10
2
2
.98; N 13.85.
N-(3,4,5-Trimethoxybenzoyl)imidazole (1h).
Yield 18.33 g (77%), yellow crystals. R 0.18, mp 54–
C H O N . Calculated, %: C 58.82; H 3.95; N
10 8 3 2
1
3.72.
f
N-(2,4-Diacetoxybenzoyl)imidazole (1m). Yield
1
5
6°C. Н NMR spectrum, δ, ppm: 8.01 s (1H, CH,
1
6.18 g (68%), yellow crystals. R 0.38, mp 51–53°C.
f
1
imidazole), 7.76 d (1H, CH, imidazole), 7.36 d (1H,
Н NMR spectrum, δ, ppm: 8.01 s (1H, CH,
imidazole), 7.78–7.75 d (2H, CHarom, CH, imidazole),
7.35 d (1H, CH, imidazole), 7.19 d (1Harom), 7.09 s
CH, imidazole), 7.12–7.09 m (2Harom), 3.81 s (9H,
+
3
CH ). Mass spectrum (ESI), m/z: 262 [М] . Found,
3
%
: C 59.56; H 5.40; N 10.69. C H O N . Calculated,
(1Harom), 2.26 s (3H, CH
spectrum (ESI), m/z: 288 [М] . Found, %: C 58.29; H
1
3
14
4
2
3 3
), 2.16 s (3H, CH ). Mass
+
%
: C 59.54; H 5.38; N 10.68.
N-(2-Acetoxybenzoyl)imidazole (1i). Yield 15.66 g
4
.22; N 27.74. C H O N . Calculated, %: C 58.33; H
14 12 5 2
2
0
1
4.20; N 27.75.
(
87%), viscous oil. R 0.31, n 1.596. Н NMR
f D
spectrum, δ, ppm: 7.99 s (1H, CH, imidazole), 7.76–
N-(2,4-Dimethoxybenzoyl)imidazole (1n). Yield
7
7
.72 m (2H, CH, imidazole, CHarom), 7.49 t (1Harom),
13.16 g (71%), yellow crystals. R 0.20, mp 46–48°C.
f
1
.35 m (2Harom, CH, imidazole), 7.21 d (1Harom), 2.25
Н NMR spectrum, δ, ppm: 7.98 s (1H, CH,
imidazole), 7.77 d (1H, CH, imidazole), 7.36 d
+
(
3H, CH ). Mass spectrum (ESI), m/z: 230 [М] .
3
Found, %: C 62.61; H 4.40; N 12.11. C H O N .
12
10
3
2
(1Harom), 6.72 d (2Harom), 3.82 s (3H, CH ), 3.78 s (3H,
3
+
Calculated, %: C 62.60; H 4.38; N 12.17.
N-(3-Acetoxybenzoyl)imidazole (1j). Yield 14.58 g
CH ). Mass spectrum (ESI), m/z: 232 [М] . Found, %:
3
C 62.07; H 5.21; N 12.08. C H O N . Calculated, %:
12 12
3
2
2
0
1
C 62.06; H 5.21; N 12.06.
(
81%), viscous oil. R 0.28, n 1.588. Н NMR
f D
spectrum, δ, ppm: 8.07 s (1H, CH, imidazole), 7.78 d
1H, CH, imidazole), 7.68–7.57 m (2Harom), 7.42–7.28
1
,2-Bis[(2-hydroxybenzoyl)amino]ethylene 2а and
(
1
,2-bis[(2-acetyloxybenzoyl)amino]ethylene 2b were
prepared by the procedure in [11].
m (4H, 2CHarom, 2CH, imidazole), 2.35 s (3H, CH ).
3
+
Mass spectrum (ESI), m/z: 230 [М] . Found, %: C
6
6
2.65; H 4.33; N 12.19. C H O N . Calculated, %: C
1,2-Bis[(2-hydroxybenzoyl)amino]ethylene (2a).
12
10
3
2
2.60; H 4.38; N 12.17.
N-(4-Acetoxybenzoyl)imidazole (1k). Yield 14.76 g
Yield 4.72 g (87%), white crystals. R
52°С. Н NMR spectrum, δ, ppm: 9.48–9.42 m (2H,
f
0.74, mp 151–
1
1
2
7
OH), 8.15–8.09 m (2H, 2NH), 7.79–7.55 m (2Harom),
2
0
1
(
82%), viscous oil. R 0.25, n 1.599. Н NMR
f D
.06–6.98 m (2Harom), 6.98–6.81 m (2Harom), 3.61–3.58
spectrum, δ, ppm: 8.03 s (1H, CH, imidazole), 7.84–
.66 d (2Harom), 7.36 d (1H, CH, imidazole), 7.25–7.21
d (2Harom), 2.21 s (3H, CH ). Mass spectrum (ESI), m/z:
+
m (2H, 2CH). Mass spectrum (ESI), m/z: 298 [М] .
7
Found, %: C 64.45; H 4.71; N 9.35. C H O N .
1
6
14
4
2
3
Calculated, %: C 64.42; H 4.73; N 9.39.
+
2
30 [М] . Found, %: C 62.62; H 4.35; N 12.12.
C H O N . Calculated, %: C 62.60; H 4.38; N
1,2-Bis[(2-acetyloxybenzoyl)amino]ethylene (2b).
1
2
10
3
2
1
2.17.
Yield 3.94 g (74%), white crystals. R 0.43, mp 156–
f
1
1
57°С. Н NMR spectrum, δ, ppm: 8.03–7.79 m
N-(3,4,5-Triacetoxybenzoyl)imidazole (1l). Yield
8.34 g (62%), yellow crystals. R 0.49, mp 63–64°C.
(
2Harom), 7.75–7.68 m (2H, 2NH), 7.54–6.48 m
(2Harom), 7.44 m (2Harom), 7.48–3.19 m (2Harom), 6.59–
.57 m (4H, 2CH), 2.23–2.17 (6H, 2CH ). Mass
1
f
1
Н NMR spectrum, δ, ppm: 8.23 s (1H, CH,
6
3
imidazole), 7.76 d (1H, CH, imidazole), 7.55 d
+
spectrum (ESI), m/z: 382 [М] . Found, %: C 62.80; H
(
2Harom), 7.36 d (1H, CH, imidazole), 2.25 s (6H,
4
.75; N 7.32. C H O N . Calculated, %: C 62.82; H
16 14 4 2
2
3
CH ), 2.19 s (3H, CH ). Mass spectrum (ESI), m/z:
3 3
+
4.74; N 7.33.
46 [М] . Found, %: C 55.50; H 4.10; N 8.01.
C H O N . Calculated, %: C 55.49; H 4.07; N 8.07.
1
6
14
7
2
FUNDING
N-(2,4-Dihydroxybenzoyl)imidazole (1m). Yield
.69 g (63%), yellow crystals. R 0.72, mp 64–66°C.
Н NMR spectrum, δ, ppm: 8.52 s (1H, OH), 8.33 s
9
The work was financially supported by the Russian
Foundation for Basic Research (project no. 15-43-
02445).
f
1
(
1H, OH), 7.97 s (1H, CH, imidazole), 7.77 d (1H, CH,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 5 2019

STUDY OF THE REACTION OF HYDROXYBENZOYL CHLORIDES
597
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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