Reversible condensation of 4-arylidene-1,2-dimethyl-1H-imidazol-5(4H)-ones with aromatic acyl chlorides

Article abstract of DOI:10.1007/s10593-015-1802-6

(Z)-1,2-Dimethyl-4-(4-methoxybenzylidene)-1 H-imidazol-5(4H)-one underwent a condensation reaction with aromatic acyl chlorides, forming keto derivatives that were structurally similar to chromophores of red fluorescent proteins, as well as to the product

Full text of DOI:10.1007/s10593-015-1802-6

DOI 10.1007/s10593-015-1802-6
Chemistry of Heterocyclic Compounds 2015, 51(10), 944–947
Reversible condensation of 4-arylidene-1,2-dimethyl-
1H-imidazol-5(4H)-ones with aromatic acyl chlorides
Svetlana V. Golodukhina1, Nadezhda S. Baleeva1,2,
Konstantin S. Mineyev1, Mikhail S. Baranov1,2*
1 Institute of Bioorganic Chemistry named after Academicians M. M. Shemyakin and Yu. A. Ovchinnikov,
Russian Academy of Sciences, 16/10 Miklukho-Maklaya St., Moscow 117997, Russia;
е-mail: baranovmikes@gmail.com
2 Russian National Research Medical University named after N. I. Pirogov,
1 Ostrovityanova St., Moscow 117997, Russia.
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2015, 51(10), 944–947
Submitted September 26, 2015
Accepted October 16, 2015
(Z)-1,2-Dimethyl-4-(4-methoxybenzylidene)-1H-imidazol-5(4H)-one underwent a condensation reaction with aromatic acyl chlorides,
forming keto derivatives that were structurally similar to chromophores of red fluorescent proteins, as well as to the products of their
maturation and/or degradation. The reverse reaction of the obtained products was observed upon treatment with aqueous alkali.
Keywords: imidazolones, chromophores, fluorescent proteins, condensation.
Various 4-arylidene-1H-imidazol-5(4H)-ones, which are the
basis of chromophores in fluorescent proteins, have been
attracting the attention of researchers for a long time. On
one hand, the synthesis of their derivatives has allowed to
characterize the structure and properties of fluorescent
At the same time, based on the example of (Z)-1,2-di-
methyl-4-(4-methoxybenzylidene)-1H-imidazol-5(4H)-one
(1), we were able to demonstrate not only the high efficiency
of this process, but also the possibility of achieving the
reverse reaction (Scheme 1).
We established that the reaction of imidazolone 1 with
aromatic acyl chlorides was most effective upon heating
with excess acyl chloride in the presence of diisopropyl-
ethylamine (DIPEA).
The mechanism of such transformation most likely
included the initial acylation of the starting imidazolone at
the N-3 atom with the formation of quaternary salts 2a–e. It
has been already shown that a similar reaction with Lewis
acids enables, for example, the condensation of
imidazolones with aromatic aldehydes.10,11 A further
acylation likely results in the formation of amides 3a–e, which
could be isolated only as mixtures of Z- and E-isomers. The
isomerization of benzylidene moiety in compounds
analogous to imidazolone 1 has been previously observed
in basic media,1 but in this case the formation of isomers
occurred simultaneously at two multiple bonds, leading to a
mixture of two to four compounds (Scheme 1).
proteins, leading to
a
better understanding of the
maturation mechanisms.1 On the other hand, their various
intense colors, small size, and highly hydrophilic nature
has enabled a range of useful applications, including RNA
tagging,2 design of two-photon,3 solid phase,4 polymeric,5
and other6 fluorescent dyes.
During our work dedicated to studying the chemistry of
compounds derived from the chromophore of green
fluorescent protein, we found that acyl chlorides reacted
with derivatives of 4-arylidene-1H-imidazol-5(4H)-ones
containing a methyl group at position 2 of the imidazole
ring, leading to a condensation reaction that produced
ketones. A similar reaction giving enols was so far
demonstrated only for a few derivatives of 2-methyl-
imidazole, primarily nitro derivatives7 and benz-
imidazoles,8 as well as
compounds.9
a small number of other
0009-3122/15/5110-0944©2015 Springer Science+Business Media New York
944

Chemistry of Heterocyclic Compounds 2015, 51(10), 944–947
Scheme 1
OMe
OMe
OMe
OMe
Cl–
HCl, AcOH
H2O
ArCOCl
DIPEA
ArCOCl
DIPEA
O
O
N
O
Ar
Ar
H
N
Ar
, 10 min
–HCl
, 5 min
N
N+
Me
Me
Ar
N
Me
N
N
N
O
O
O
3a e
O
4a e
O
Me
Me
Me
a
Ar = 4-MeC6H4
Ar = 4-MeOC6H4
Ar = 4-FC6H4
Ar = Ph
1
2a e
–
–
–
b
c
d
e
(From4a–c)
NaOH, H2O, EtOH
Ar = 4-BrC6H4
, 5 min
Nevertheless, the subsequent treatment with hydrochloric
acid led to the removal of one aroyl group, as well as iso-
merization of multiple bonds with the formation of pure
(2E,5Z)-2-(2-aryl-2-oxoethylidene)-5-(4-methoxybenzylide-
ne)-3-methylimidazolidin-4-ones 4a–e.
Obviously, the structure of compounds 4a–e suggests
the possible existence of different tautomers: ketone
(structure 4) and enol (structure 4'), the formation of which
was postulated earlier7–9 (Scheme 2).
UV spectra of compounds 4a–e contained two absorption
maxima in the regions of 300 nm and 430 nm, the position
of which shifted by no more than by 5 nm, depending on
the aroyl substituent.
Thus, we propose a method for the synthesis of 2-(2-aryl-
2-oxoethylidene)-5-(4-methoxybenzylidene)-3-methylimid-
azolidin-4-ones with unexpected structure, containing a
multiple exo bond at position 2 of the imidazolone ring.
These compounds serve as good models for the study of
physicochemical properties of fluorescent proteins and
their chromophores.
Scheme 2
Experimental
UV spectra were recorded on a Varian Cary 100 Bio
spectrophotometer in EtOH. 1H, 13C, and 15N NMR spectra
were acquired on a Bruker Avance III instrument (700,
175, and 70 MHz, respectively) in DMSO-d6. The internal
1
standard for Н and 13С nuclei was TMS, the external
standard for 15N nuclei was liquid ammonia (0.0 ppm).
High-resolution mass spectra were recorded on a Thermo
Scientific LTQ Orbitrap instrument (capillary voltage 2 kV,
nanospray, needle temperature 200°С). Melting points
were determined on an SMP 30 apparatus and were un-
corrected. Thin-layer chromatography was performed on
Merck Kieselgel 60 F254 plates.
Reagents from Acros Organics were used without
additional purification, and reactions were performed in
freshly prepared solvents. Compound 1 was obtained
according to a published procedure.12
(2E,5Z)-2-(2-Aryl-2-exoethylidene)-5-(4-methoxyben-
zylidene)-3-methylimidazolidin-4-ones 4a–e (General
method). A suspension of imidazolone 1 (1.15 g, 5 mmol) in
(i-Pr)2NEt (20 ml) was treated with the appropriate acyl
chloride (20 mmol). The obtained mixture was refluxed for
10 min at 130°С. The solvent was removed on a rotary
evaporator, the residue was diluted with EtOAc (250 ml),
and the solution was washed with 3% HCl solution
(3×50 ml). The organic phase was washed with water,
NaCl solution, dried over anhydrous Na2SO4, and
evaporated to dryness. The residue was purified by silica
gel flash chromatography (eluent 20:1 CHCl3–MeOH),
collecting the colored fractions with Rf ~ 0.3. The obtained
product was complex mixture of Z- and E-isomers of
compounds 3a–e (from two to four compounds according
Actually, it was found that compounds 4a–e existed in
DMSO solutions exclusively in the ketone form with a
double exo bond. Such a structure in the case of compound
4a was confirmed by two-dimensional 1H–1H COSY, 1H–13C
1
1
HSQC, 1H–13C HMBC, H–15N HSQC, and H–15N HMBC
NMR experiments, while the double bond configuration
1
was confirmed with two-dimensional H–13C HSQMBC
(the coupling constant of the 4-СO carbon atom and the
=CНAr proton was equal to 5.4 Hz) and ROESY
experiments (the =CHCOAr proton gave a cross peak with
the protons of 3-CH3 group, but no cross peak with the 1-NH
proton).
During the study of deprotonation in compounds 4a–с, it
was found that they were readily converted by the action of
base to the starting imidazolone 1 in 56% to 76% yields
(Scheme 1).
The study of optical properties of derivatives 4 showed
very low quantum yields of fluorescence (less that 5%) in
all cases, which was in a good agreement with the data
previously obtained for other free chromophores of
fluorescent proteins.1 At the same time, it was also found
that the nature of aroyl moiety had a very slight effect on
the position of absorption maxima of compounds 4. Thus,
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Chemistry of Heterocyclic Compounds 2015, 51(10), 944–947
1
to Н NMR data), dissolved in AcOH (10 ml) and diluted
with 10% HCl (10 ml). The mixture was refluxed for 5 min,
dissolved in EtOAc (250 ml), washed with saturated
NaHCO3 solution (3×50 ml), water, and NaCl solution. The
organic phase was dried over Na2SO4 and evaporated to
dryness. The residue was purified by silica gel column
chromatography (eluent 50:1 CHCl3–MeOH), collecting
the colored fractions with Rf ~ 0.4.
(35%), yellow powder, mp 188–190°С. UV spectrum, λmax,
1
nm (log ε): 300 (4.25), 431 (4.39). H NMR spectrum, δ,
ppm (J, Hz): 3.24 (3H, s, NCH3); 3.85 (3H, s, OCH3); 6.18
(1H, s, =СHCOAr); 6.67 (1H, s, =СHAr); 7.15 (2H, d,
3
3J = 8.8, H-3,5 CHAr); 7.51 (2H, t, J = 7.5, H-3,5 COPh);
3
3
7.55 (1H, t, J = 7.5, H-4 COPh); 7.59 (2H, d, J = 8.8,
3
H-2,6 CHAr); 8.05 (2H, d, J = 7.5, H-2,6 COPh); 12.31
(1Н, br. s, NH). 13C NMR spectrum, δ, ppm: 25.8; 55.2;
77.3; 110.6; 114.9; 124.3; 125.9; 126.9; 128.2; 130.2;
131.4; 138.7; 154.7; 159.8; 163.0; 187.2. Found, m/z:
335.1385 [М+H]+. C20H19N2O3. Calculated, m/z: 335.1396.
(2E,5Z)-2-[2-(4-Bromophenyl)-2-oxoethylidene]-5-(4-meth-
oxybenzylidene)3-methylimidazolidin-4-one (4e). Yield
660 mg (32%), yellow powder, mp 175–178°С. UV
spectrum, λmax, nm (log ε): 307 (4.31), 433 (4.42). 1H NMR
spectrum, δ, ppm (J, Hz): 3.22 (3H, s, NCH3); 3.84 (3H, s,
OCH3); 6.19 (1H, s, =СHCOAr); 6.67 (1H, s, =СHAr);
(2E,5Z)-5-(4-Methoxybenzylidene)-3-methyl-2-[2-(4-me-
thylphenyl)-2-oxoethylidene]imidazolidin-4-one
(4a).
Yield 750 mg (43%),* yellow powder, mp 191–193°С. UV
spectrum, λmax, nm (log ε): 301 (4.26), 431 (4.43). 1H NMR
spectrum, δ, ppm (J, Hz): 2.38 (3H, s, ArCH3); 3.23 (3H, s,
NCH3); 3.84 (3H, s, OCH3); 6.19 (1H, s, =СHCOAr); 6.66
3
(1H, s, =СHAr); 7.15 (2H, d, J = 8.7, H-3,5 CHAr); 7.32
(2H, d, 3J = 7.9, H-3,5 COAr); 7.59 (2H, d, 3J = 8.6, H-2,6
3
CHAr); 7.97 (2H, d, J = 7.9, H-2,6 COAr); 12.35 (1Н,
br. s, NH). 13C NMR spectrum, δ, ppm: 21.0 (ArCH3); 25.9
(NCH3); 55.3 (OCH3); 77.3 (=СHCOAr); 110.3 (=СHAr);
114.9 (C-3,5 CHAr); 124.4 (C-5); 126.0 (C-1 CHAr);
127.2 (C-2,6 COAr); 129.0 (C-3,5 COAr); 130.3 (C-2,6
CHAr); 136.1 (C-1 COAr); 141.7 (C-4 COAr); 154.6
(C-2); 159.8 (C-4 CHAr); 163.1 (4-CO); 187.1
(=CHCOAr). 15N NMR spectrum, δ, ppm: 109.0 (N-1);
135.5 (N-3). Found, m/z: 349.1547 [М+H]+. C21H21N2O3.
Calculated, m/z: 349.1552.
7.13 (2H, d, J = 8.8, H-3,5 CHAr); 7.57 (2H, d, J = 8.8,
3
3
3
H-2,6 CHAr); 7.69 (2H, d, J = 8.3, H-3,5 COAr); 8.00
3
(2H, d, J = 8.3, H-2,6 COAr); 12.26 (1Н, br. s, NH).
13C NMR spectrum, δ, ppm: 25.8; 55.2; 77.2; 110.9; 114.9;
124.1; 125.2; 125.8; 129.0; 130.3; 131.2; 137.8; 154.9;
159.8; 162.9; 185.9. Found, m/z: 413.0498 [М(79Br)+H]+,
415.0476 [М(81Br)+H]+. C20H18BrN2O3. Calculated, m/z:
413.0501, 415.0480.
Preparation of (Z)-4-(4-methoxybenzylidene)-1,2-
dimethyl-1H-imidazol-5(4H)-one (1) by hydrolysis of
imidazolidinones 4a–c. An aqueous 1 N solution of
sodium hydroxide (10 ml, 10 mmol) was added to a
solution of imidazolidinone 4a–c (1 mmol) in EtOH (20 ml).
The obtained mixture was refluxed for 5 min, cooled to
room temperature, and the product was extracted with
CHCl3 (3×30 ml). The organic phase was dried over
anhydrous Na2SO4 and evaporated to dryness. The residue
was separated by silica gel column chromatography (eluent
10:1 CHCl3–MeOH), collecting the fraction with Rf 0.40.
Yield 155 mg (67%, from compound 4a), 130 mg (56%,
from compound 4b), 175 mg (76%, from compound 4c),
yellow powder, mp 126–128°С (mp 128–129°С12). 1H NMR
spectrum, δ, ppm (J, Hz): 2.34 (3H, s, 2-CH3); 3.09 (3H, s,
1-CH3); 3.81 (3H, s, OCH3); 6.93 (1H, s, =СHAr); 7.01 (2H,
d, 3J = 8.8, H Ar); 8.19 (2H, d, 3J = 8.8, H Ar).
(2E,5Z)-5-(4-Methoxybenzylidene)-2-[2-(4-methoxy-
phenyl)-2-oxoethylidene]-3-methylimidazolidin-4-one (4b).
Yield 580 mg (32%), yellow powder, mp 176–179°С. UV
spectrum, λmax, nm (log ε): 299 (4.29), 434 (4.41). 1H NMR
spectrum, δ, ppm (J, Hz): 3.23 (3H, s, NCH3); 3.84 (6H, s,
2OCH3); 6.16 (1H, s, =СHCOAr); 6.63 (1H, s, =СHAr);
3
3
7.04 (2H, d, J = 8.9, H-3,5 CHAr); 7.15 (2H, d, J = 8.8,
3
H-3,5 COAr); 7.57 (2H, d, J = 8.8, H-2,6 CHAr); 8.05
3
(2H, d, J = 8.8, H-2,6 COAr); 12.25 (1Н, br. s, NH).
13C NMR spectrum, δ, ppm: 25.9; 55.3; 55.4; 77.1; 109.9;
113.6; 115.0; 124.5; 126.1; 129.3; 130.3; 131.4; 154.3;
159.8; 162.1; 163.1; 186.6. Found, m/z: 365.1495 [М+H]+.
C21H21N2O4. Calculated, m/z: 365.1501.
(2E,5Z)-5-(4-Methoxybenzylidene)-2-[2-(4-fluorophe-
nyl)-2-oxoethylidene]-3-methylimidazolidin-4-one (4c).
Yield 650 mg (37%), yellow powder, mp 184–186°С. UV
spectrum, λmax, nm (log ε): 302 (4.27), 427 (4.42). 1H NMR
spectrum, δ, ppm (J, Hz): 3.23 (3H, s, NCH3); 3.84 (3H, s,
OCH3); 6.20 (1H, s, =СHCOAr); 6.67 (1H, s, =СHAr);
The study was performed with financial support from the
Russian Foundation for Basic Research in the framework
of the project No. 14-50-00131. The equipment of
Collective Use Center of the Institute of Bioorganic
Chemistry was used for part of this research.
3
7.14 (2H, d, J = 8.7, H-3,5 CHAr); 7.32 (2H, br. t,
3J = 8.7, H-3,5 COAr); 7.58 (2H, d, 3J = 8.8, H-2,6 CHAr);
8.13 (2H, dd, 3J = 8.6, 4JHF = 5.7, H-2,6 COAr); 12.25 (1Н,
br. s, NH). 13C NMR spectrum, δ, ppm (J, Hz): 26.0; 55.4;
2
77.3; 110.7; 115.0; 115.3 (d, JCF = 21.6, C-3,5 COAr);
References
3
124.2; 125.9; 129.9 (d, JCF = 8.8, C-2,6 COAr); 130.4;
1
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based on the starting imidazolone 1 is shown.
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