Reactivity of hydroxy and amino derivatives of 2-phenyl-1H-imidazoline and 2-phenyl-1H-imidazole toward isocyanates: Synthesis of appropriate carbamates and ureas

Article abstract of DOI:10.1002/jhet.984

Reactivity of 2-(4-hydroxyphenyl)-1H-imidazoline and 2-(4-hydroxyphenyl)- 1H-imidazole toward substituted phenyl isocyanates was studied. When mentioned imidazoline was treated with 2.5 equiv of substituted phenyl isocyanate, three N,O-dicarboxamides were

Full text of DOI:10.1002/jhet.984

July 2013
Reactivity of Hydroxy and Amino Derivatives of 2‐Phenyl‐1H‐
imidazoline and 2‐Phenyl‐1H‐imidazole toward Isocyanates:
Synthesis of Appropriate Carbamates and Ureas
903
a
b
c
d
*
Patrik Pařík, Josef Jansa, Sylva Holešová, Aleš Marek,
and Věra Klimešováe
aFaculty of Chemical Technology, Institute of Organic Chemistry and Technology
University of Pardubice, Studentská 573532 10 Pardubice, Czech Republic
bResearch Institute for Organic Syntheses (VUOS), Rybitví 296533 54 Rybitví
Czech Republic
cNanotechnology Centre, VŠB‐TU Ostrava17. listopadu 15/2172, 708 33 Ostrava‐Poruba, Czech Republic
dInstitute of Organic Chemistry and Biochemistry AS CR, v.v.i.,, Flemingovo nám. 2,
166 10 Praha 6, Czech Republic
eDepartment of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University,
Heyrovského 1203500 05 Hradec Králové, Czech Republic
*
E-mail: patrik.parik@upce.cz
Received February 18, 2011
DOI 10.1002/jhet.984
Published online 2 July 2013 in Wiley Online Library (wileyonlinelibrary.com).
Reactivity of 2‐(4‐hydroxyphenyl)‐1H‐imidazoline and 2‐(4‐hydroxyphenyl)‐1H‐imidazole toward
substituted phenyl isocyanates was studied. When mentioned imidazoline was treated with 2.5 equiv of
substituted phenyl isocyanate, three N,O‐dicarboxamides were prepared (substituents are H, 4‐NO2, and
4‐CH3). Subsequently, N,O‐diacetylated 2‐(4‐hydroxyphenyl)‐1H‐imidazoline was prepared and selective
deprotection method was developed for preparation of 1‐acetyl‐2‐(4‐hydroxyphenyl)‐1H‐imidazoline
using diethylamine in acetone. Six carbamates derived from this imidazoline were then prepared using
1.1 equiv of substituted phenyl isocyanates (substituents are H, 4‐CH3, 4‐OCH3, 4‐NO2, 4‐CN, and
3‐CF3). Finally, two carbamates were prepared from 2‐(4‐hydroxyphenyl)‐1H‐imidazole (substituents
are 4‐NO2 and 4‐CN). No reactivity to imidazole ring was observed in this case. Eight derivatives were
subjected to antimycobacterial screening. Concurrently, reactivity of 2‐(2‐aminophenyl)‐ and 2‐(2‐
hydroxyphenyl)‐1H‐imidazole toward aliphatic and aromatic isocyanates was studied. Eight ureas were
prepared using equivalent mixture of 2‐(2‐aminophenyl)‐1H‐imidazole and isocyanate (Et, Pr, isoPr,
terc‐Bu, Cy, Ph, 4‐CH3C6H4, 4‐CNC6H4). Similar attempts to obtain related carbamates from 2‐(2‐
hydroxyphenyl)‐1H‐imidazole lead only to three substituted phenyl carbamates (substituents are 4‐CH3,
4‐NO2, and 4‐CN). In both cases, no reactivity to imidazole ring was observed again.
J. Heterocyclic Chem., 50, 903 (2013).
INTRODUCTION
hair colors. Modern trend in catalysis is searching and test-
ing of urea and thiourea‐based derivatives as
organocatalysts [8].
Imidazoline and imidazole derivatives play important
role in biological processes. They have substantial biolog-
ical activity and its structural motive makes a part of many
types of medical drugs [1, 2]. Nowadays, new compounds
are developed in which imidazole or imidazoline deriva-
tives acts as a chiral ligands for enantioselective catalysis
[3–6]. In addition, carbamates are fundamental fragments
of many polymers, pesticides, and drugs, and are tested
as acetylcholinesterase inhibitors [7]. Derivatives based
on ureas as the next derivatives of carbonic acid are usually
used as agrochemicals, pharmaceuticals, or in petrochemi-
cal industry. Such compounds are also utilized as additives
to fuels, detergents, polymers, inhibitors of corrosion, or as
Recently, we have studied some synthetic possibilities
leading to derivatives based on 2‐(2‐hydroxyphenyl)‐1
H‐imidazoline and 2‐(2‐hydroxyphenyl)‐1H‐imidazole skel-
eton [9]. Now, we have also focused on related 2‐amino and
4‐hydroxy analogs. 2‐(4‐Hydroxyphenyl)‐1H‐imidazoline
and 2‐(4‐hydroxyphenyl)‐1H‐imidazole have been prepared
by Roger and Bruice [10], for example, but their carbamates
have not been described in the literature yet. Also, carba-
mates derived from 2‐(2‐hydroxyphenyl)‐1H‐imidazole
have not been described yet. On the other hand, wide group
of ureas based on 2‐(4‐aminophenyl)‐1H‐imidazoline was
synthesized and tested as chemotherapeutics [11, 12]; however,
© 2013 HeteroCorporation

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P. Pařík, J. Jansa, S. Holešová, A. Marek, and V. Klimešová
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Scheme 1. Reaction of 2‐(4‐hydroxyphenyl)‐1H‐imidazoline 1 with 1.05
equiv of substituted phenyl isocyanates.
no ureas derived from 2‐(2‐aminophenyl)‐1H‐imidazole were
developed yet. Reactions of some 2‐substituted imidazolines
with phenyl isocyanate and isothiocyanate have been studied,
corresponding ureas and thioureas have been prepared [13].
Kinetic (reversible N‐substitution) and thermodynamic (irre-
versible C2‐substitution) control have been observed in the case
of reaction of imidazole with isocyanates [14]. Mentioned 2‐
(4‐hydroxyphenyl)‐1H‐imidazole motive also includes Hoechst
33258 entity, which exhibits antitumor activity. Carbamate
derivatives of Hoechst 33258 have been prepared as potential
anticancer agents [15].
Generally, N‐substitution of imidazoline ring was easily
recognized, because two triplets of imidazoline methylene
groups appeared due to blocking of imidazoline
tautomerism.
In this study, we have investigated reactivity of 2‐
(4‐hydroxyphenyl)‐1H‐imidazoline,
H‐imidazole, 2‐(2‐hydroxyphenyl)‐1H‐imidazole, and
2‐(4‐hydroxy‐phenyl)‐1
2‐(2‐
Respective amount of individual products estimated by
1H‐NMR is: when R = 4‐NO2C6H4 ratio of 3, 4, and 5 is
76, 12, and 12%; when R = 4‐CNC6H4 ratio is 72, 28,
0%; when R = 4‐CH3OC4H6 ratio is 85, 15, and 0%.
This result correspond with higher nucleofilicity of ni-
trogen, but it is interesting when compared to alkylation
of 2‐(2‐hydroxyphenyl)‐1H‐imidazoline in which no N‐al-
kylation was observed [9, 18]. Reaction of related 2‐phe-
nyl‐1H‐imidazoline with phenyl isocyanate was presented
in literature [13]. Finally, when 2.5 equiv of isocyanate in
refluxing acetone was used, pure N,O‐dicarboxamides
5a–c were obtained in 56–88% yield.
Products of type 3, 4, and 5 depicted in Scheme 1 were
unstable in DMSO‐d6, probably due to known basicity/nu-
cleophilicity of imidazoline and/or presence of water in
DMSO‐d6. NMR spectra were recorded promptly after
mixing the sample. Decomposition was studied by 1H‐
NMR in case of 5c (Scheme 2).
amino‐phenyl)‐1H‐imidazole toward different isocyanates, lead-
ing to new group of species bearing imidazoline or imidazole
ring together with carbamate or urea group. Low selectivity of
carbamoylation was observed in the case of mentioned
imidazoline, so we have studied methods for selective
imidazoline N‐protection.
In addition to the synthetic study, compounds 9a–f and
starting imidazolines
1 and 8 were subjected to
antimycobacterial screening. Compounds were evaluated
in vitro against Mycobacterium tuberculosis and
nontuberculous mycobacterial strains (M. avium and M.
kansasii). The aim of this study was find out a new scaffold
of antimycobacterially active compunds.
RESULTS AND DISCUSSION
para-Analogs. 2‐(4‐Hydroxyphenyl)‐1H‐imidazoline 1
was prepared from methyl 4‐hydroxybenzoate and ethane‐
1,2‐diamine (three times excess) by modification of
literature procedure [10] in 78% yield. For transformation
of 1 to 2‐(4‐hydroxyphenyl)‐1H‐imidazole 2, we have
used dehydrogenation by means of Pd/C. Because of low
solubility of 1 in nonpolar solvents, we succesfully used
n‐BuOH for this dehydrogenation instead of toluene [9]
or DMSO [16], which were previously used. Oxidative
reagents we did not tested with regard to our previous
experience [9] concerned oxidative aromatization of 2‐
hydroxy analog in which use of oxidation agents caused
formation of quinones, for example, the use of Fremy’s
salt [17].
Decomposition products were starting imidazoline 1 and
corresponding aniline 6, eventually corresponding urea 3
as intermediate. Decomposition of carbamate group was
faster than urea (Table 1), carbamate 4 was not observed
during this experiment. After 24 h staying in DMSO‐d6,
only imidazoline 1 and corresponding aniline 6 was ob-
served in reaction mixture in case of decomposition of
5a–c.
As the reactivity of 1 toward isocyanates is in favor of
N‐carbamoylation, we have tried to realize selective N‐pro-
tection of 1. N‐Protective methods are summarized in
Table 1
We studied the reactivity of some aromatic isocyanates
toward 1. When 1.05 equiv of isocyanate in acetone was
used, products 3 of N‐ (72–85%), 4 of O‐ (12–28%), even-
tually 5 of N,O‐dicarbamoylation (0–12%) were detected
by 1H‐NMR (Scheme 1). Constitution of reaction mixture
depends on substitution of aromatic isocyanate. Products
were not separated. Scheme 1 summarizes respective
amount of individual products estimated by 1H‐NMR mea-
surements realized immediately after sample preparation.
Decomposition of 4‐{1‐[(4‐nitrophenyl)carbamoyl]‐1H‐imidazoline‐2‐yl}
phenyl N‐(4‐nitrophenyl)carbamate 5c: time‐dependent composition of its
DMSO‐d6 solution (detected by 1H‐NMR).
Timea (min)
5c (%)
3 (%)
1 (%)
6 (%)
3
10
180
90
80
0
5
10
46
0
0
13
5
10
41
aTime after mixing the sample.
Journal of Heterocyclic Chemistry
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Reactivity of Hydroxy and Amino Derivatives of 2-Phenyl-1H-imidazoline and
2-Phenyl-1H-imidazole toward Isocyanates: Synthesis of Appropriate Carbamates and Ureas
905
Scheme 2. Decomposition of 4‐{1‐[(4‐Nitrophenyl)carbamoyl]‐1H‐
imidazoline‐2‐yl}phenyl N‐(4‐nitrophenyl)carbamate 5c (R = 4‐NO2C6H4)
in DMSO‐d6 (1H‐NMR experiment).
reaction. Products obtained by reaction of 7 with ammonia
or ethylamine miscarried to be identified. When
methanolysis with basic reagents was tested (NaOH,
K2CO3, NaHCO3, Et3N, Et2NH), pure N,O‐deacetylation
product 1 was observed. Finally, when diacetyl derivate 7
was refluxed with the excess of diethylamine in acetone,
pure N‐acetylderivate 8 was obtained in 79% yield. This
reaction probably proceeds as aminolysis in comparison
with methanolysis reaction, when diethylamine was used
in methanol and both acetyl groups were cleaved.
Six carbamates 9a–f were obtained by reaction of 8 with
substituted phenyl isocyanates in 67–83% yield. These
products were soluble and fully stable in CDCl3. Stability
of 9f in DMSO was checked for the reason of its interesting
antimycobacterial activity. NMR measurements realized
immediately, 7 days, and 36 days after mixing the sample
in DMSO‐d6 confirmed its stability.
When the imidazole 2 reacted with substituted phenyl
isocyanates (Scheme 4), no N‐carbamoylation was ob-
served. Formation of urea from 2‐phenylimidazole was
reported as reversible reaction [14, 21]. Two carbamates
10a–b were obtained by reaction of 2 with 1.2 equiv of
4‐nitro or 4‐cyanophenyl isocyanate in dichloromethane
in very good yields. These products are also unstable in
DMSO‐d6, products of hydrolysis were detected. Presence
of strong electron‐withdrawing substituent is probably cru-
cial because differently substituted phenyl isocyanates
were also tested but without success. Heterogeneous reali-
zation of the reaction can be also limitative.
Scheme 3. First, the hydrochloride of 1 was synthesized
[19]. Unfortunately, the hydroxy group of this compound
was probably too deactivated to react with all isocyanates.
Only 4‐nitrophenyl and 4‐cyanophenyl isocyanate react
with this hydrochloride with 100% selectivity toward hy-
droxy group. Decomposition of these imidazoline hydro-
chloride carbamates in DMSO‐d6 was also observed,
failing the hypothesis of base induced decomposition. Un-
fortunately, these products were not obtained in quite pure
form.
Reductive methylation of 1 with formaldehyde [20] was
100% N‐selective (observed by 1H‐NMR) but not com-
plete. Attempts to isolate pure 1‐methyl‐2‐(4‐
hydroxyphenyl)‐1H‐imidazoline by recrystallization or
column chromatography failed.
Acetylation of 1 with acetanhydride in pyridine proceed
well and even when 1.5 equiv of acetanhydride was used,
only N,O‐diacetyl derivate 7 was isolated. Therefore, this
reaction was conducted to yield this product and try its se-
lective O‐deprotection. Many reagents were tested for this
Generally, tested reactions of 1 and 2 with aliphatic iso-
cyanates and sulfonylisocyanates afforded no carbamates.
Scheme 4. Synthesis of carbamates and ureas from 2‐(4‐hydroxyphenyl)‐1
H‐imidazole 2, 2‐(2‐hydroxyphenyl)‐1H‐imidazole 11 and 2‐(2‐aminophenyl)‐
1H‐imidazole 12.
Scheme 3. Synthesis of N‐protected carbamates derived from 2‐
(4‐hydroxyphenyl)‐1H‐imidazoline 1.
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Attempts to analyze all prepared carbamates 9a–f and
10a–b using GC‐MS technique failed because of decom-
position of derivatives during analyses.
Attempts to analyze all prepared carbamates 13a–c and
ureas 14a–h using GC‐MS technique failed because of de-
composition of derivatives during analyses. Furthermore,
no carbamates 13a–c were analyzed applying NMR tech-
nique, because these carbamates are unstable in all tested
solvents (DMSO‐d6, CDCl3, CD3CN, CD3OD, and tolu-
ene‐d8) in which hydrolysis was observed. Proton number-
ortho‐Analogs.
Starting
2‐(2‐hydroxyphenyl)‐1
H‐imidazole 11 was already used as main substrate in our
previous article, this derivative was prepared using
procedure described in prior work [9]. Second starting
material for ortho‐analogs, 2‐(2‐aminophenyl)‐1H‐
imidazole 12, was synthesized using small modifications
of literature procedure. 2‐Nitrobenzaldehyde reacted with
glyoxal trimer dihydrate (instead of 30% aqueous
glyoxal solution used in [22]) in glacial acetic acid as
a solvent in the presence of ammonium acetate to afford
2‐(2‐nitrophenyl)‐1H‐imidazole. The yield of 19% is
quite low but better than previous reported (7.6%) [22].
This nitro derivative was hydrogenated overnight at
pressure 40 bar (instead of atmospheric pressure applied
in [22]) using Pd/C (10%) as catalyst, product 12 was
prepared in 91% yield.
Reactions of 2‐(2‐hydroxyphenyl)‐1H‐imidazole 11
with nine various aliphatic and aromatic isocyanates
(aliphatic are Et, Pr, isoPr, tert‐Bu, Cy; aromatic are Ph,
4‐CH3C6H4, 4‐NO2C6H4, 4‐CNC6H4) were tested (Scheme
4). Syntheses were realized using equimolar mixture of
starting compounds in toluene, which appeared as conve-
nient solvent. Only three target carbamates 13a–c were pre-
pared in moderate to good yields using substituted phenyl
isocyanates (substituents are 4‐CH3, 4‐NO2, and 4‐CN).
Miscarriages in the cases of using aliphatic isocyanates
can be caused by their lower reactivity coming from
electron‐donating inductive effect of aliphatic moiety.
Surprisingly, no carbamate was obtained using phenyl
isocyanate, and desired product was never detected in the
reaction mixture.
1
ing for assignment of H‐NMR shifts of ureas 14a–h is
stated in Scheme 5.
Antimycobacterial activity.
The newly prepared
derivatives 9a–f were tested for antimycobacterial activity
against four mycobacterial strains. The minimum inhibitory
concentrations (MICs) given in μmol/L are summarized in
Table 2. As reference the starting molecules 1 and 8, and
isoniazide (INH) were included in the assay.
As seen from the data of Table 2, 4‐(1‐Acetyl‐1
H‐imidazoline‐2‐yl)phenyl N‐(3‐trifluoro‐methylphenyl)
carbamate 9f exhibited very interesting activity, especially
against M. tuberculosis and M. kansasii. The derivative 9f
differs from the others carbamates 9 in phenylcarbamate
moiety, where phenyl is substituted in the position meta.
This steric change of molecule can play significant role in
the biological activity.
Because many low‐molecular weight drugs cross bio-
logical membranes through passive transport, which
strongly depends on their lipophilicity, we calculated the li-
pophilicity parameters values (log P) for evaluated com-
pounds. Log P of the compounds 1, 8, and 9 were
calculated using the commercially available program
ChemBioDraw. Compound 9f exhibited the highest
lipofilicity from all tested compounds.
CONCLUSIONS
Reactivity of 2‐(4‐hydroxyphenyl)‐1H‐imidazoline and
corresponding imidazole towards substituted phenyl isocya-
nates was studied. By using of 1.05 equiv of isocyanate the
mixture of three products of N‐, and O‐carbamoylation, and
N,O‐dicarbamoylation was obtained. When 2.5 equiv of
Reactions of 2‐(2‐aminophenyl)‐1H‐imidazole 12 with
eight same aliphatic and aromatic isocyanates (except
4‐NO2C6H4) were realized without problems (Scheme 4).
Acetonitrile was found as suitable solvent, equimolar mix-
ture of starting compounds was used and all new target
ureas 14a–h were obtained in poorer yields but very
good purity, which required no further purification.
4‐Nitrophenyl isocyanate and 3,5‐bis(trifluoromethyl)
phenyl isocyanate were also tested, appropriate ureas were
succesfully prepared and described in our previous article
concerned in their testing in homogeneous and heteroge-
neous catalysis [23].
Scheme 5. Proton numbering for assignment of 1H‐NMR shifts of 1‐alkyl‐
and 1‐substituted aryl‐3‐[2‐(1H‐imidazol‐2‐yl)phenyl]ureas 14a–h.
No N‐carbamoylated imidazole derivatives were isolated
or detected as products of reactions of hydroxy derivative
11 or amino derivative 12 with isocyanates analogously
to reactions of 2‐(4‐hydroxyphenyl)‐1H‐imidazole 2 with
isocyanates. It is in great contrast to reactivity of
imidazoline ring in 2‐(4‐hydroxyphenyl)‐1H‐imidazoline
1 in which isocyanate attacks imidazoline N atom together
with hydroxy O atom very readily.
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Reactivity of Hydroxy and Amino Derivatives of 2-Phenyl-1H-imidazoline and
2-Phenyl-1H-imidazole toward Isocyanates: Synthesis of Appropriate Carbamates and Ureas
907
Table 2
Antimycobacterial activities expressed as MIC (μmol/L).
Strains
Mycobacterium
Mycobacterium kansasii
Mycobacterium
Mycobacterium avium My
Compounds
tuberculosis My 331/88
My 235/80
kansasii 6509/96
330/88
logP
14 d/21 d
>1000/>1000
>1000/>1000
>1000/>1000
1000/n.d.
n.d./n.d.
>1000/>1000
250/500
7 d/14 d/21 d
500/>1000/>1000
500/>1000/>1000
1000/>1000/>1000
n.d./n.d./n.d.
7 d/14 d/21 d
125/500/1000
250/1000/1000
500/500/1000
500/n.d./n.d.
n.d./n.d./n.d.
500/500/>1000
125/500/1000
4/4/4
14 d/21 d
1000/>1000
1000/>1000
500/1000
n.d./n.d.
n.d./n.d.
>1000/>1000
500/1000
>250/>250
>250/>250
1
8
1.3
0.95
2.49
2.98
2.37
2.53
2.08
3.42
–
9a
9b
9c
9d
9e
9f
n.d./n.d./n.d.
1000/>1000/>1000
250/1000/1000
4/8/8
2/2
0.5/1.0
INH
>250/>250/>250
4/8/8
n.d., not determined (due to the limited solubility of the compounds in the test medium).
solutions in DMSO‐d6 or CDCl3. Chemical shifts are relative to
TMS, residual solvent signal was used as an internal standard.
MS spectra were recorded on GC/MS configuration Agilent
Technologies 6890N (HP‐5MS, 30 m × 0.25 mm × 0.25 μm)
with Network MS detector 5973 (EI = 70 eV, 33–550 Da). The
mid‐infrared spectra were obtained on Perkin Elmer 2000
Fourier transform infrared spectrometer in the 4000–400 cm−1
spectral range with a resolution of 4 cm−1 at room temperature
using the KBr pressed disc technique. Elemental analysis was
carried out using an automatic analyser EA 1108 (Fisons). Thin‐
layer chromatography was performed on SiO2 60 F254 (Merck)
with UV detection at 254 nm. Melting points were determined
on Büchi B‐540 apparatus.
isocyanate was used three pure N,O‐dicarboxamides were
prepared. Their decomposition in DMSO‐d6 solution
during NMR measurement was observed. Sequentially,
N,O‐diacetylated 2‐(4‐hydroxyphenyl)‐1H‐imidazoline was
prepared and its selective O‐deprotection was developed
for preparation of 1‐acetyl‐2‐(4‐hydroxyphenyl)‐1H‐
imidazoline using diethylamine in acetone. Six carbamates
derived from last imidazoline were then prepared using 1.1
equiv of substituted phenyl isocyanates as reactants. Finally,
two carbamates were prepared from 2‐(4‐hydroxyphenyl)‐
1H‐imidazole. No N‐carbamoylation was observed during
reaction of this imidazole with slight excess of isocyanate.
Concurrently, reactivity of 2‐(2‐aminophenyl)‐ and
2‐(2‐hydroxyphenyl)‐1H‐imidazole toward aliphatic and
aromatic isocyanates was studied. In the case of amino
derivative, eight ureas were prepared using equivalent
amount of aliphatic or aromatic isocyanates. No
carbamoylations proceed on imidazole N atom were
observed. Accomplished attempts realized on reactions of
2‐(2‐hydroxyphenyl)‐1H‐imidazole with equivalent amount
of aliphatic or aromatic isocyanates show that only three
substituted phenyl isocyanates produce desired carbamates.
Repeatedly, no carbamoylation to imidazole ring was
observed in this case.
2‐(4‐Hydroxyphenyl)‐1H‐imidazoline (1). The mixture of 20
g (0.13 mol) of methyl 4‐hydroxybenzoate and 27 mL (0.40 mol) of
ethane‐1,2‐diamine was stirred under reflux for 24 h. Volatile matter
was removed under reduced pressure, the residue was heated for 30
min to maximum 150°C and then refluxed with 100 mL of water‐
ethanol (2:1) mixture for 10 min to remove unreacted N‐(2‐
aminoethyl)‐4‐hydroxybenzamide. After cooling the product was
filtered and washed with 50 mL of water‐ethanol (2:1) mixture to
yield white powder, 16.6 g (78 %), mp 281–285°C (290–292°C
1
[24]), Rf = 0.1 (MeOH). H‐NMR (360 MHz, DMSO‐d6): δ 3.61
(s, 4H, CH2CH2), 6.76 (d, J = 8.0 Hz, 2H, ArH), 7.66 (d, J = 8.0
Hz, 2H, ArH). Anal. Calcd. for C9H10N2O (162.19): C, 66.65; H,
6.21; N, 17.27. Found: C, 66.70; H 6.43; N, 17.03.
2‐(4‐Hydroxyphenyl)‐1H‐imidazole (2). The mixture of 1
g (6.17 mmol) of 1 and 0.5 g of 10 % Pd/C in 150 ml of n‐
BuOH was stirred at reflux under argon atmosphere for 3 days
(progress was monitored by TLC). After, the hot solution was
filtered and solvent was removed under reduced pressure.
Column chromatography on silicagel (Silicagel 60, 0.040–0.063
mm, Merck) with MeOH as eluent provided 0.44 g (45 %) of
yellow crystals, which were used for next step without further
purification. Analytical sample was crystallized from MeOH,
The preliminary antimycobacterial screening found out
the significant activity of 4‐(1‐acetyl‐1H‐imidazoline‐2‐
yl)phenyl N‐(3‐trifluoromethylphenyl)carbamate 9f (MIC
2–8 μmol/L). This structure can create a new scaffold of
antimycobacterially active compounds.
1
EXPERIMENTAL
mp 270–276°C (267–270°C [25], Rf = 0.58 (MeOH). H‐NMR
(360 MHz, DMSO‐d6): δ 6.87 (d, J = 8.4 Hz, 2H, ArH), 7.09
(s, 2H, CHCH), 7.80 (d, J = 8.4 Hz, 2H, ArH), 9.70–10.00
(br s, 1H, OH), 11.80‐12.50 (br s, 1H, NH). Anal. Calcd. for
C9H8N2O (160.17): C, 67.49; H, 5.03; N, 17.49. Found: C,
67.40; H, 5.09; N, 17.63.
General data.
NMR spectra of model compounds were
measured at 25°C on Bruker AMX 360 spectrometer at 360
MHz (1H) and 90 MHz (13C) or Bruker Avance 500
spectrometer at 500 MHz (1H) and 125 MHz (13C) using
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General procedure for synthesis of N,O‐dicarboxamides 5
stirred at reflux for 24 h. The mixture was concentrated under
reduced pressure to ∼50 mL and cooled to –15°C. Product was
filtered and washed twice with cold acetone to yield 3.29 g (79
%) of white crystals, mp 182–183.5°C, Rf = 0.26 (CHCl3/
MeOH 10:1). 1H‐NMR (500 MHz, DMSO‐d6): δ 1.95 (s, 3H,
NCOCH3), 3.82 (t, J = 8.5 Hz, 2H, CH2), 3.99 (t, J = 8.5 Hz,
2H, CH2), 6.81 (d, J = 8.5 Hz, 2H, ArH), 7.38 (d, J = 8.5 Hz,
2H, ArH), 9.70–10.20 (br s, 1H, OH); 13C‐NMR (125 MHz,
DMSO‐d6): δ 24.9, 48.0, 52.6, 114.6, 122.9, 130.0, 158.7,
159.0, 167,8. Anal. Calcd. for C11H12N2O2 (204.23): C, 64.69;
H, 5.92; N, 13.72. Found: C, 64.56; H, 6.15; N, 13.58.
derived from 1. The mixture of 0.20 g (1.25 mmol) of 1 and
0.34 mL (3.12 mmol) of phenyl isocyanate in 50 mL of dry
acetone was stirred at reflux under argon atmosphere for 24 h.
The mixture was concentrated to 10–20 mL and cooled to −15°
C. Product 5a was filtered and washed with diethylether
(diethylether in the case of 5b, acetone in case of 5c).
4‐[1‐(Phenylcarbamoyl)‐1H‐imidazoline‐2‐yl]phenyl N‐
phenylcarbamate (5a). White crystals, yield 0.44 g (88%), mp
167.5–171°C, Rf 0.31 (CHCl3/MeOH 10:1). 1H‐NMR (360 MHz,
DMSO‐d6): δ 4.00 (t, J = 8.0 Hz, 2H, CH2), 4.12 (t, J = 8.0 Hz,
2H, CH2), 7.07 (m, 2H, ArH), 7.30 (m, 4H, ArH), 7.38 (t, J = 7.8
Hz, 2H, ArH), 7.51 (d, J = 8.0 Hz, 2H, ArH), 7.57 (d, J = 7.5 Hz,
2H, ArH), 7.63 (d, J = 8.2 Hz, 2H, ArH), 9.23 (s, 1H, NCONH),
10.34 (s, 1H, OCONH); 13C‐NMR (90 MHz, DMSO‐d6): δ 48.8,
53.9, 118.5, 119.7, 121.1, 122.8, 123.1, 128.5, 128.9, 129.1,
129.6, 138.5, 139.2, 151.4, 151.4, 152.6, 159.5. Anal. Calcd. for
C23H20N4O3 (400.42): C, 68.99; H, 5.03; N, 13.99. Found: C,
69.29; H, 5.22; N, 13.92.
General procedure for synthesis of 4‐(1‐Acetyl‐1H‐
imidazoline‐2‐yl)phenyl N‐(substituted phenyl)carbamates
9. The mixture of 0.19 g (0.93 mmol) of 8 and 0.11 mL (1.02
mmol) of appropriate phenyl isocyanate in 20 mL of dry acetone
was stirred at room temperature under argon atmosphere for 24 h
(progress was monitored by TLC). After cooling to –15°C, the
product was filtered and washed with diethylether. In case of 9f,
the reaction mixture was concentrated to ∼5 mL, and this solution
was diluted with 50 mL of hexane. Precipitated product was
filtered, washed with 5 mL of ether and with 20 mL of hexane.
4‐(1‐Acetyl‐1H‐imidazoline‐2‐yl)phenyl N‐phenylcarbamate
(9a). White crystals, yield 0.21 g (70%), mp 147–149°C, Rf =
4‐{1‐[(4‐Methylphenyl)carbamoyl]‐1H‐imidazoline‐2‐yl}phenyl
N‐(4‐methylphenyl)‐carbamate (5b). White crystals, yield 0.34 g
1
(68%), mp 174‐176°C, Rf = 0.34 (CHCl3/MeOH 10:1). H‐NMR
(360 MHz, DMSO‐d6): δ 2.28 (s, 3H, CH3), 2.30 (s, 3H, CH3),
3.99 (t, J = 8.0 Hz, 2H, CH2), 4.10 (t, J = 8.1 Hz, 2H, CH2), 7.11
(d, J = 8.1 Hz, 2H, ArH), 7.18 (d, J = 8.0 Hz, 2H, ArH), 7.26 (d, J
= 8.4 Hz, 2H, ArH), 7.39 (d, J = 8.2 Hz, 2H, ArH), 7.45 (d, J =
7.9 Hz, 2H, ArH), 7.61 (d, J = 8.4 Hz, 2H, ArH), 9.13 (s, 1H,
NCONH), 10.24 (s, 1H, OCONH); 13C‐NMR (90 MHz, DMSO‐
d6): δ 20.4, 48.7, 53.8, 118.5, 119.6, 119.8, 121.1, 128.9, 129.1,
129.3, 129.6, 131.7, 131.0, 136.0, 136.6, 151.4, 152.5, 159.5.
Anal. Calcd. for C25H24N4O3 (428.48): C, 70.08; H, 5.65; N,
13.08. Found: C, 69.90; H, 5.77; N, 12.93.
4‐{1‐[(4‐Nitrophenyl)carbamoyl]‐1H‐imidazoline‐2‐yl}phenyl
N‐(4‐nitrophenyl)car‐bamate (5c). Light yellow crystals, yield
0.28 g (56 %), mp 174‐176°C. 1H‐NMR (360 MHz, DMSO‐d6): δ
4.03 (t, J = 8.0 Hz, 2H, CH2), 4.14 (t, J = 8.1 Hz, 2H, CH2), 7.33 (d,
J = 8.3 Hz, 2H, ArH), 7.66 (d, J = 8.2 Hz, 2H, ArH), 7.79 (m, 4H,
ArH ), 8.21 (d, J = 8.8 Hz, 2H, ArH), 8.29 (d, J = 8.7 Hz, 2H, ArH),
9.85 (s, 1H, NCONH), 11.05, (s, 1H, OCONH). Anal. Calcd. for
C23H18N6O7 (490.42): C, 56.33; H, 3.70; N 17.14. Found: C,
56.45; H, 4.00; N, 17.29.
1
0.38 (CHCl3/MeOH 10:1). H‐NMR (360 MHz, CDCl3): δ 1.91
(s, 3H, NCOCH3), 3.96 (t, J = 8.2 Hz, 2H, CH2), 4.08 (t, J = 8.3
Hz, 2H, CH2), 7.09 (t, J = 7.3 Hz, 1H, ArH), 7.20 (d, J = 8.5 Hz,
2H, ArH), 7.31 (t, J = 7.7 Hz, 2H, ArH), 7.42 (d, J = 7.9 Hz, 2H,
ArH), 7.53 (d, J = 8.5 Hz, 2H, ArH), 7.70 (s, 1H, NH); 13C‐NMR
(90 MHz, CDCl3): δ 25.4, 48.5, 53.3, 119.1, 121.7, 124.2, 129.2,
129.3, 129.7, 137.5, 151.2, 152.4, 159.1, 168.6. Anal. Calcd. for
C18H17N3O3 (323.35): C, 66.86; H, 5.30; N, 13.00. Found: C,
66.61; H, 5.43; N, 13.25.
4‐(1‐Acetyl‐1H‐imidazoline‐2‐yl)phenyl N‐(4‐methylphenyl)
carbamate (9b).
White crystals, yield 0.20 g (67%), mp
152.5–154°C, Rf = 0.41 (CHCl3/MeOH 10:1). 1H‐NMR (360
MHz, CDCl3): δ 1.89 (s, 3H, NCOCH3), 2.30 (s, 3H, CH3),
3.95 (t, J = 8.3 Hz, 2H, CH2), 4.08 (t, J = 8.3 Hz, 2H, CH2),
7.11 (d, J = 8.2 Hz, 2H, ArH), 7.20 (d, J = 8.5 Hz, 2H, ArH),
7.30 (d, J = 7.9 Hz, 2H, ArH), 7.52 (d, J = 8.6 Hz, 2H, ArH),
7.60 (s, 1H, NH); 13C‐NMR (90 MHz, CDCl3): δ 21.0, 25.4,
48.5, 53.3, 119.2, 121.7, 129.1, 129.6, 129.8, 133.8, 134.9,
151.3, 152.5, 159.1, 168.6. Anal. Calcd. for C19H19N3O3
(337.37): C, 67.64; H, 5.68; N, 12.46. Found: C, 67.62; H,
5.70; N, 12.39.
4‐(1‐Acetyl‐1H‐imidazoline‐2‐yl)phenyl acetate (7).
To a
suspension of 5 g (30.83 mmol) of 1 in 30 mL of pyridine was
added 6.4 mL (67.83 mmol) of acetanhydride at 0–5°C. The
mixture was stirred for 3 h at 10°C, then diluted with 200 mL of
water and extracted three times with dichloromethane. Organic
phase was washed with water and brine, and the solvent was
evaporated to yield off‐white crystals of product, which was used
for the next synthetic step without purification.
4‐(1‐Acetyl‐1H‐imidazoline‐2‐yl)phenyl N‐(4‐methoxyphenyl)
carbamate (9c). White crystals, yield 0.25 g (83%), mp 164.5–
166°C, Rf = 0.38 (CHCl3/MeOH 10:1). 1H‐NMR (360 MHz,
CDCl3): δ 1.90 (s, 3H, N COCH3), 3.79 (s, 3H, OCH3), 3.95 (t, J
= 8.4 Hz, 2H, CH2), 4.09 (t, J = 8.3 Hz, 2H, CH2), 6.87 (d, J =
9.0 Hz, 2H, ArH), 7.05 (s, 1H, NH), 7.25 (d, J = 8.6 Hz, 2H,
ArH), 7.34 (d, J = 8.4 Hz, 2H, ArH), 7.54 (d, J = 8.6 Hz, 2H,
ArH). Anal. Calcd. for C19H19N3O4 (353.37): C, 64.58; H, 5.42;
N, 11.89. Found: C, 64.74; H, 5.56; N, 11.87.
Yield 6.8 g (90%), mp 139–142°C (ethanol‐water 1:1), Rf = 0.41
(CHCl3/MeOH 10:1), 1H‐NMR (360 MHz, DMSO‐d6): δ 2.03
(s, 3H, NCOCH3), 2.33 (s, 3H, OCOCH3), 3.91 (t, J = 8.2 Hz, 2H,
CH2), 4.05 (t, J = 8.2 Hz, 2H, CH2), 7.20 (d, J = 7.6 Hz, 2H, ArH),
7.58 (d, J = 7.6 Hz, 2H, ArH); 13C‐NMR (90 MHz, DMSO‐d6): δ
20.9, 24.8, 47.8, 53.16, 121.1, 129.6, 130.0, 151.4, 158.1, 167.7,
169.1; MS: m/z 246 (M+, 9), 204 (83), 162 (68), 161 (47), 133
(100), 43 (28). Anal. Calcd. for C13H14N2O3 (246.26): C, 63.40; H,
5.73; N, 11.38. Found: C, 63.69; H, 5.94; N, 11.55.
4‐(1‐Acetyl‐1H‐imidazoline‐2‐yl)phenyl N‐(4‐cyanophenyl)
carbamate (9d).
White crystals, yield 0.25 g (83%), mp
174–175°C, Rf = 0.42 (CHCl3/MeOH 10:1). 1H‐NMR (500 MHz,
CDCl3): δ 1.96 (s, 3H, NCOCH3), 3.99 (t, J = 8.5 Hz, 2H, CH2),
4.10 (t, J = 8.5 Hz, 2H, CH2), 7.21 (d, J = 8.5 Hz, 2H, ArH), 7.55
(d, J = 8.5 Hz, 2H, ArH), 7.56 (d, J = 9.0 Hz, 2H, ArH), 7.62
(d, J = 9.0 Hz, 2H, ArH), 7.67 (s, 1H, NH). Anal. Calcd. for
C19H16N4O3 (348.36): C, 65.51; H, 4.63; N, 16.08. Found: C,
65.25; H, 4.90; N, 16.35.
1‐Acetyl‐2‐(4‐hydroxyphenyl)‐1H‐imidazoline (8).
To the
solution of 5 g (20.30 mmol) of 5 in 250 mL of acetone was
added 12.5 mL (0.121 mol) of diethylamine. The mixture was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2013
Reactivity of Hydroxy and Amino Derivatives of 2-Phenyl-1H-imidazoline and
2-Phenyl-1H-imidazole toward Isocyanates: Synthesis of Appropriate Carbamates and Ureas
909
4‐(1‐Acetyl‐1H‐imidazoline‐2‐yl)phenyl N‐(4‐nitrophenyl)
carbamate (9e). Light yellow crystals, yield 0.24 g (80%),
Products were obtained after vacuum evaporation of the solvent.
Only three products were obtained using substituted phenyl
isocyanate (substituents are 4‐CH3, 4‐NO2, and 4‐CN).
2‐(1H‐Imidazol‐2‐yl)phenyl N‐(4‐methylphenyl)carbamate (13a).
White crystals, yield 0.25 g (54%), mp 100–105° C; IR (potassium
bromide): ν 3305 (NH), ν 1776 (CO), δ 1567 (NH in CO NH), νas
1241, νs 1139 (COC), γ 746 (CH arom.) cm−1. Anal. Calcd. for
C17H15N3O2 (293.32): C, 69.61; H, 5.15; N, 14.33. Found: C,
69.81; H, 5.27; N, 14.37.
1
mp 176–177°C. Rf = 0.36 (CHCl3/MeOH 10:1). H‐NMR (360
MHz, CDCl3): δ 1.97 (s, 3H, NCOCH3), 3.99 (t, J = 8.8 Hz,
2H, CH2), 4.10 (t, J = 8.7 Hz, 2H, CH2), 7.24 (d + CDCl3, 2H,
ArH), 7.51 (s, 1H, NH), 7.58 (d, J = 8.5 Hz, 2H, ArH), 7.61 (d,
J = 9.2 Hz, 2H, ArH), 8.24 (d, J = 8.8 Hz, 2H, ArH). Anal.
Calcd. for C18H16N4O5 (368.34): C, 58.69; H, 4.38; N, 15.21.
Found: C, 58.81; H, 4.68; N, 15.08.
4‐(1‐Acetyl‐1H‐imidazoline‐2‐yl)phenyl N‐(3‐trifluoromethylphenyl)
carbamate (9f). White crystals, yield 0.26 g (87%), mp 136. 5–138°
C, Rf = 0.38 (CHCl3/MeOH 10:1). H‐NMR (500 MHz, CDCl3):
2‐(1H‐Imidazol‐2‐yl)phenyl
(13b). Yellow crystals, yield 0.45 g (88%), mp 114–118°C;
N‐(4‐nitrophenyl)carbamate
1
IR (potassium bromide): ν 3366, 3337 (NH), ν 1775, 1740
(CO), δ 1552 (NH in CO NH), ν 1497 (NO2), νas 1248, νs 1131
(COC), γ 750 (CH arom.) cm−1. Anal. Calcd. for C16H12N4O4
(324.29): C, 59.26; H, 3.73; N, 17.28. Found: C, 59.09; H,
3.99; N, 17.00.
δ 1.93 (s, 3H, NCOCH3), 3.98 (t, J = 8.5 Hz, 2H, CH2), 4.10 (t, J
= 8.5 Hz, 2H, CH2), 7.15 (d, J = 8.5 Hz, 2H, ArH), 7.33 (d, J =
7.5 Hz, 1H, ArH), 7.42 (t, J = 8.0 Hz, 1H, ArH), 7.53 (d, J = 8.5
Hz, 2H, ArH), 7.62 (d, J = 8.5 Hz, 1H, ArH), 7.74 (s, 1H, ArH),
8.21 (s, 1H, NH); 13C‐NMR (125 MHz, CDCl3): δ 25.3, 48.5,
53.2, 115.8, 120.4, 121.6, 122.1, 122.9, 125.1, 129.1, 129.6,
129.8, 131.3, 131.6, 138.5, 151.4, 152.2, 159.3, 168,7. Anal.
Calcd. for C19H16F3N3O3 (391.34): C, 58.31; H, 4.12; N, 10.74.
Found: C, 58.11; H, 4.38; N, 10.76.
General procedure for synthesis of carbamates 10 derived
from 2‐(4‐hydroxyphenyl)‐1H‐imidazole 2. The mixture of
0.147 g (0.92 mmol) of 2 and 1.11–1.18 mmol of 4‐substituted
phenyl isocyanate in 20 mL of dry dichloromethane was stirred
at room temperature under argon atmosphere for 24 h. Product
was filtered and washed with dichloromethane.
2‐(1H‐Imidazol‐2‐yl)phenyl
N‐(4‐cyanophenyl)carbamate
(13c). White crystals, yield 0.40 g (85%), mp 121–124°C; IR
(potassium bromide): ν 3377, 3309 (NH), ν 2220 (CN), 1776, ν
1732 (CO), δ 1532 (NH in CO NH), νas 1246, νs 1139 (COC),
γ 744 (CH arom.) cm−1. Anal. Calcd. for C17H12N4O2 (304.30):
C, 67.10; H, 3.97; N, 18.41. Found: C, 66.96; H, 4.22; N, 18.35.
General procedure for synthesis of ureas 14 derived from 2‐
(2‐aminophenyl)‐1H‐imidazole 12. The mixture of 1.57 mmol
of 2‐(2‐aminophenyl)‐1H‐imidazole, 1.57 mmol of aliphatic or
aromatic isocyanate and 8 mL of acetonitrile was refluxed for 5 h
and then stirred overnight at room temperature. Precipitated products
were filtered off. Products were obtained using all tested isocyanates.
4‐(1H‐imidazole‐2‐yl)phenyl
N‐(4‐nitrophenyl)carbamate
1‐Ethyl‐3‐[2‐(1H‐imidazol‐2‐yl)phenyl]urea (14a).
White
(10a). Yellow crystals, yield 0.26 g (87%), mp 219.5–222.5°C,
Rf = 0.24 (CHCl3/MeOH 10:1). 1H‐NMR (360 MHz, DMSO‐d6):
δ 7.00–7.35 (br d, 2H, CHCH), 7.40 (d, J = 8.7 Hz, 2H, ArH),
7.80 (d, J = 9.2 Hz, 2H, ArH), 8.05 (d, J = 8.7 Hz, 2H, ArH),
8.30 (d, J = 9.2 Hz, 2H, ArH), 11.04 (s, 1H, OCONH), 12.61 (s,
1H, imidazole NH). Anal. Calcd. for C16H12N4O4 (324.29): C,
59.26; H, 3.73; N, 17.28. Found: C, 59.10; H, 3.80; N, 17.31.
4‐(1H‐imidazole‐2‐yl)phenyl N‐(4‐cyanophenyl)carbamate (10b).
White crystals, yield 0.29 g (97%), mp 234–240°C, Rf = 0.26
(CHCl3/MeOH 10:1). 1H‐NMR (360 MHz, DMSO‐d6): δ 7.08 (br
s, 1H, CH), 7.30 (br s, 1H, CH), 7.38 (d, J = 8.6 Hz, 2H, ArH),
7.75 (d, J = 8.7 Hz, 2H, ArH), 7.90 (d, J = 8.7 Hz, 2H, ArH),
8.04 (d, J = 8.6 Hz, 2H, ArH), 10.85 (s, 1H, OCONH), 12.59
(s, 1H, imidazole NH). Anal. Calcd. for C17H12N4O2 (304.30): C,
67.10; H, 3.97; N, 18.41. Found: C, 67.02; H, 4.24; N, 18.60.
crystals, yield 0.42 g (42%), mp 146–146.5°C; 1H‐NMR (360
MHz, DMSO‐d6): δ 1.12 (t, 3H, H‐11), 3.17 (m, 2H, H‐10) ,
6.99–7.07 (m, 2H, H‐2, 9), 7.28 (t, 3H, H‐3, 6, 7), 7.84 (d, 1H,
H‐4), 8.40 (d, 1H, H‐1), 11.59 (s, 1H, H‐5), 12.68 (s, 1H, H‐8);
IR (potassium bromide): ν 3311, 3262, and 3176 (NH), ν 1665
(CO), δ 1569 (NH in CO NH),γ 742 (CH arom.) cm−1. Anal.
Calcd. for C12H14N4O (230.27): C, 62.59; H, 6.13; N, 24.33.
Found: C, 62.79; H, 6.16; N, 24.10.
1‐[2‐(1H‐imidazol‐2‐yl)phenyl]‐3‐propylurea (14b).
White
crystals, yield 0.10 g (26%), mp 143–144°C; 1H‐NMR (360
MHz, DMSO‐d6): δ 0.92 (t, 3H, H‐12), 1.52 (m, 2H, H‐11), 3.10
(q, 2H, H‐10), 7.02 (t, 1H, H‐2), 7.18 (s, 1H, H‐6[7]), 7.28 (t, 1H,
H‐3), 7.36 (s, 1H, H‐6[7]), 7.83 (d, 1H, H‐4), 8.39 (d, 1H, H‐1),
7.10 (s, 1H, H‐9), 11.57 (s, 1H, H‐5), 12.68 (s, 1H, H‐8); IR
(potassium bromide): ν 3272, 3176 (NH), ν 1663 (CO), δ 1553
(NH in CO NH), γ 745 (CH arom.) cm−1. Anal. Calcd. for
C13H16N4O (244.29): C, 63.91; H, 6.60; N, 22.93. Found: C,
63.97; H, 6.66; N, 22.72.
2‐(2‐Hydroxyphenyl)‐1H‐imidazole (11).
This starting
derivative was prepared using procedure described in our
previous work [9].
2‐(2‐Aminophenyl)‐1H‐imidazole (12).
2‐(2‐Aminophenyl)‐1
1‐[2‐(1H‐imidazol‐2‐yl)phenyl]‐3‐isopropylurea (14c). White
crystals, yield 0.20 g (53%), mp 192–196°C; 1H‐NMR (360
MHz, DMSO‐d6): δ 1.16 (d, 6H, H‐11), 3.87 (m, 1H, H‐10),
6.96–7.03 (m, 2H, H‐2, 9), 7.19 (s, 1H, H‐6[7]), 7.27 (t, 1H, H‐3),
7.36 (s, 1H, H‐6[7]), 7.83 (d, 1H, H‐4), 8.40 (d, 1H, H‐1), 11.46
(s, 1H, H‐5), 12.66 (s, 1H, H‐8); IR (potassium bromide): ν 3261,
3151 (NH), ν 1661 (CO), δ 1555 (NH in CO NH), γ 746 (CH
arom.) cm−1. Anal. Calcd. for C13H16N4O (244.29): C, 63.91; H,
6.60; N, 22.93. Found: C, 64.11; H, 6.69; N, 23.10.
1‐Tert‐butyl‐3‐[2‐(1H‐imidazol‐2‐yl)phenyl]urea (14d).White
crystals, yield 0.15 g (37%), mp 195–202°C; 1H‐NMR (360
MHz, DMSO‐d6): δ 1.35 (s, 9H, H‐10), 7.00 (t, 1H, H‐2), 7.20
(s, 1H, H‐6[7]), 7.26 (t, 1H, H‐3), 7.35 (s, 1H, H‐6[7]), 7.80 (d,
1H, H‐4), 8.29 (d, 1H, H‐1), 6.81 (s, 1H, H‐9), 11.17 (s, 1H, H‐
5), 12.63 (s, 1H, H‐8); IR (potassium bromide): ν 3357, 3163
H‐imidazole (12) was synthesized with according the procedure
reported in literature. Reaction of 2‐nitrobenzaldehyde with
glyoxal trimer dihydrate in glacial acetic acid in the presence of
ammonium acetate afforded 2‐(2‐nitrophenyl)‐1H‐imidazole in the
low yield of 19% but more than two times better than in the
literature (7.6%) [22], mp 180–184°C (184°C [22]). This nitro
derivative was dissolved in ethanol and hydrogenated overnight at
room temperature at pressure 40 bar using Pd/C (10%) as catalyst.
2‐(2‐Aminophenyl)‐1H‐imidazole 12 was prepared in 91% yield,
mp 128–131°C (132–134°C [22]).
General procedure for synthesis of carbamates 13 derived
from 2‐(2‐hydroxyphenyl)‐1H‐imidazole 11. The mixture of
1.56 mmol of 2‐(2‐hydroxyphenyl)‐1H‐imidazole, 1.56 mmol of
aliphatic or aromatic isocyanate and 10 mL of dry toluene was
refluxed for 3 h and then stirred overnight at room temperature.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

910
P. Pařík, J. Jansa, S. Holešová, A. Marek, and V. Klimešová
Vol 50
(NH), ν 1659 (CO), δ 1538 (NH in CO NH), γ 734 (CH arom.)
cm−1. Anal. Calcd. for C14H18N4O (258.32): C, 65.09; H, 7.02;
N, 21.69. Found: C, 65.05; H, 7.08; N, 21.72.
days. MIC was the lowest concentration of a substance at which
the inhibition of the growth of mycobacteria occurred. INH was
used as a standard.
1‐Cyclohexyl‐3‐[2‐(1H‐imidazol‐2‐yl)phenyl]urea (14e).
1
White crystals, yield 0.25 g (56%), mp 205–207°C; H‐NMR
(360 MHz, DMSO‐d6): δ 1.14–1.37 (m, 6H, Cy), 1.63 (d, 1H,
Cy), 1.76 (d, 2H, Cy), 1.88 (d, 2H, Cy), 6.95 (s, 1H, H‐9),
7.01 (t, 1H, H‐2), 7.19 (s, 1H, H‐6 [7]), 7.27 (t, 1H, H‐3),
7.36 (s, 1H, H‐6 [7]), 7.83 (d, 1H, H‐4), 8.41 (d, 1H, H‐1),
11.47 (s, 1H, H‐5), 12.67 (s, 1H, H‐8); IR (potassium
bromide): ν 3306, 3199 (NH), ν 1663 (CO), δ 1547 (NH in
Acknowledgments. The authors thank the Ministry of Education,
Youth ans Sports of the Czech Republic (projects MSM
0021627501, MSM 6198910016, and MSM 0021620822) and
Czech Grant Agency (project GACR No. 205/08/0869) for
financial support. This work was also performed as part of a
research project of the Institute of Organic Chemistry and
Biochemistry (Z40550506). The authors are indebted to Dr. Jiřina
Stolaříková (Regional Institute of Public Health, Ostrava) for
antimycobacterial evaluation.
CO NH),
γ . Anal. Calcd. for
745 (CH arom.) cm−1
C16H20N4O (284.36): C, 67.58; H, 7.09; N, 19.07. Found: C,
67.45; H, 7.15; N, 19.65.
1‐[2‐(1H‐Imidazol‐2‐yl)phenyl]‐3‐phenylurea (14f). White
crystals, yield 0.20 g (46%), mp 170–171°C; 1H‐NMR (360
MHz, DMSO‐d6): δ 7.02 (t, 1H, H‐2), 7.11 (t, 1H, H‐12), 7.
30–7.37 (m, 5H, H‐3, 6, 7, 11), 7.59 (d, 2H, H‐10), 7.89 (d, 1H,
H‐4), 8.30 (d, 1H, H‐1), 9.60 (s, 1H, H‐9), 11.80 (s, 1H, H‐5),
12.73 (s, 1H, H‐8); IR (potassium bromide): ν 3352, 3191
(NH), ν 1675 (CO), δ 1540 (NH in CO NH), γ 744 (CH arom.)
cm−1. Anal. Calcd. for C16H14N4O (278.31): C, 69.05; H, 5.07;
N, 20.13. Found: C, 69.03; H, 5.18; N, 20.12.
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[4] Kaukoranta, P.; Engman, M.; Hedberg, C.; Bergquist, J.;
Andersson, P. G. Adv Synth Catal 2008, 350, 1168.
[5] Jiang, H.‐Y.; Zhou, C.‐H.; Luo, K.; Chen, H.; Lan, J.‐B.; Xie,
R.‐G. J Mol Catal A Chem 2006, 260, 288.
[6] Seacome, R. J.; Coles, M. P.; Glover, J. E.; Hitchcock, P. B.;
Rowlands, G. J. Dalton Trans 2010, 39, 3687.
[7] Zhao, Q.; Yang, G.; Mei, X.; Yuan, H.; Ning, J. J Pestic Sci
2008, 33, 371.
[8] Connon, S. J. Synlett 2009, 354.
[9] Pařík, P.; Šenauerová, S.; Lišková, V.; Handlíř, K.; Ludwig,
M. J Heterocyclic Chem 2006, 43, 835.
1‐[2‐(1H‐Imidazol‐2‐yl)phenyl]‐3‐(4‐methylphenyl)urea (14g).
1
White crystals, yield 0.20 g (43%), mp 196–198.5°C; H‐NMR
(360 MHz, DMSO‐d6): δ 2.30 (s, 3H, H‐12), 7.07–7.14
(m, 3H, H‐2, 11), 7.21 (s, 1H, H‐6[7]], 7.31–7.39 (m, 2H, H‐3,
6[7]), 7.46 (d, 2H, H‐10), 7.88 (d, 1H, H‐4), 8.31 (s, 1H, H‐1),
9.47 (s, 1H, H‐9), 11.75 (s, 1H, H‐5), 12.72 (s, 1H, H‐8); IR
(potassium bromide): ν 3300, 3216 (NH), ν 1676 (CO), δ 1538
(NH in CO NH), γ 734 (CH arom.) cm−1. Anal. Calcd. for
C17H16N4O (292.34): C, 69.85; H, 5.52; N, 19.17. Found: C,
69.68; H, 5.38; N, 19.26.
1‐(4‐Cyanophenyl)‐3‐[2‐(1H‐imidazol‐2‐yl)phenyl]urea (14h).
1
[10] Rogers, G. A.; Bruice, T. C. J Am Chem Soc 1974, 96, 2463.
[11] Hirt, R.; Fischer, R. CH Pat. 525,898, 1972; Chem Abstr 1972,
77, 164694v.
White crystals, yield 0.15 g (32%), mp 217–219°C; H‐NMR
(360 MHz, DMSO‐d6): δ 7.15 (t, 1H, H‐2), 7.26 (s, 1H, H‐6[7]),
7.35–7.42 (m, 2H, H‐3, 6[7]), 7.78 (s, 4H, H‐10, 11), 7.92 (d, 1H,
H‐4), 8.29 (d, 1H, H‐1) 10.17 (s, 1H, H‐9), 12.04 (s, 1H, H‐5),
12.80 (s, 1H, H‐8); IR (potassium bromide): ν 3317, 3270 (NH), ν
2226 (CN), ν 1692 (CO), δ 1530 (NH in CO NH), γ 741 (CH
arom.) cm−1. Anal. Calcd. for C17H13N5O (303.32): C, 67.32; H,
4.32; N, 23.09. Found: C, 67.54; H, 4.57; N, 23.23.
[12] Hirt, R. GB Pat. 1,046,045, 1966.
[13] Hill, A. J.; Aspinall, S. R. J Am Chem Soc 1939, 61, 822.
[14] Papadopoulos, E. P. J Org Chem 1977, 42, 3925.
[15] Bielawski, K.; Bielawska, A.; Wołczyński, S. Biol Pharm Bull
2002, 25, 916.
[16] Anastassiadou, M.; Baziard‐Mouysset, G.; Payard, M. Synthe-
sis 2000, 13, 1814.
[17] Burke, S. D.; Danheiser, R. L. Handbook of Reagents for Or-
ganic Synthesis. Oxidizing and Reducing Agents; Wiley: Chichester
1999; pp 308–311.
[18] Beger, J.; Wagner, G. Z Chem 1981, 21, 184.
[19] Oxley, P.; Short, W. F. J Chem Soc 1947, 497.
[20] Marxer, A. J Am Chem Soc 1957, 79, 467.
[21] Papadopoulos, E. P.; Schupbach, Ch. M. J Org Chem 1979,
44, 99.
Antimycobacterial activity.
In vitro antimycobacterial
activity was evaluated against M. tuberculosis CNCTC My 331/
88, M. kansasii CNCTC My 235/80, M. kansasii 6509/96, and M.
avium CNCTC My 330/88 using the micromethod for the
determination of the MIC. All strains were obtained from the
Czech National Collection of Type Cultures (CNCTC), with the
exception of M. kansasii 6509/96, which was a clinical isolate.
The activities of the compounds were determined in the Šula
semisynthetic medium (SEVAC, Prague). The compounds were
added to the medium in dimethylsulfoxide solutions. The
following concentrations were used: 1000, 500, 250, 125, 62, 32,
16, 8, 4, 2, and 1 μmol/L. MICs were determined after incubation
at 37°C for 14 and 21 days, for M. kansasii for 7, 14, and 21
[22] Domány, G.; Gizur, T.; Gere, A.; Takács‐Novák, K.; Farsang, G.;
Ferenczy, G. G.; Tárkányi, G.; Demeter, M. Eur J Med Chem 1998, 33, 181.
[23] Holešová, S.; Pařík, P.; Ludwig, M. J Heterocyclic Chem, to
2011, 48, 907.
[24] Spychala, J. Synth Commun 2011, 48, 907.
[25] Krieg, B.; Schlegel, R.; Manecke, G. Chem Ber 1974, 107, 168.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet