A one-pot preparation of 5-oxo 2,4-disubstituted 2,5-dihydro-1 H -imidazol-2-carboxylates from α-bromo esters

Article abstract of DOI:10.1055/s-0030-1259299

Nucleophilic substitution of a bromine atom by the azide group in aryl- and heteroaryl -α- bromoacetates triggers cascade reactions leading to imidazolin-5-ones formation. The α-azidoacetate intermediates undergo a transformation into non-isolable 2-imino

Full text of DOI:10.1055/s-0030-1259299

LETTER
315
A One-Pot Preparation of 5-Oxo 2,4-Disubstituted 2,5-Dihydro-1H-imidazol-
2-carboxylates from a-Bromo Esters
O
ne-Pot Preparatio
a
nof
I
mida
r
zolin-5-o
i
nes usz Cież,*a Jan Svetlikb
a
Department of Organic Chemistry, Jagiellonian University, 30060 Kraków, Poland
Fax +48(12)6340515; E-mail: ciez@chemia.uj.edu.pl
b
Department of Pharmaceutical Analysis and Nuclear Pharmacy, Comenius University, 83232 Bratislava, Slovak Republic
Received 11 October 2010
went slow and spontaneous decomposition in DMF or
DMSO at the room temperature with evolution of nitrogen
indicating formation of the nitrene intermediate. Increase
of the reaction temperature made the decomposition of a-
Abstract: Nucleophilic substitution of a bromine atom by the azide
group in aryl- and heteroaryl-a-bromoacetates triggers cascade re-
actions leading to imidazolin-5-ones formation. The a-azidoacetate
intermediates undergo a transformation into non-isolable 2-imino
esters that dimerize giving the heterocyclic imidazoline system. The azido ester faster but the reaction remained controllable at
process described is strongly promoted by dipolar aprotic solvents
all times. Monitoring of the thermal decomposition of a-
azidophenylacetate 1a at 80 °C by GC gave evidence for
(DMF, DMSO) and could be realized under base- and metal-free
conditions.
conversion into a-imino ester 2a followed by dimeriza-
Key words: azides, cyclization, substitution, imidazolin-5-ones,
tion to ethyl 5-oxo-2,4-diphenyl-2,5-dihydro-1H-imida-
nitrenes
zol-2-carboxylate (3a; Scheme 1). The final heterocyclic
product was isolated in very good yield from the reaction
mixture and its structure was determined using 2D NMR
The chemistry of imidazoline derivatives plays an impor-
tant role in the field of biological and pharmacological
sciences. The therapeutic applications of imidazolines and
imidazoline-5-ones as anticonvulsant,1 CNS depressant,2
sedative and hypnotics,3 hypotensive4 and antiparkinso-
nian agents5 are well known and have been described in
the literature. The newest pharmaceutical investigations
of imidazoline-5-one derivatives come from their leish-
manicidal activity6 and strong inhibition of b-secretase7
(known as BACE1). Some imidazolin-5-ones substituted
with aromatic groups indicate the potential for optoelec-
tronic application and they are promising candidates for
organic light-emitting diodes (OLEDs), organic solar
cells8 and photosensitizers.9
experiments (COSY, HMBC, HSQC) to assign all NMR
signals and confirm the proposed structure.12 Transforma-
tions of a-azido esters into reactive a-iminocarboxylates
have been reported previously as decomposition of a-azi-
do ester enolates.13 The results of our research led us to the
conclusion that the conversion of ethyl a-azido(phe-
nyl)acetate (1a) into a-imino ester 2a can be realized not
only under basic conditions but also in the absence of any
base in dipolar aprotic solvents.
DMF or DMSO, 80 °C
CO2Et
CO2Et
– N2
N3
NH
1a
2a
Interest in the practical exploitation of imidazoline-5-one
derivatives has resulted in the search for new and simple
methods for preparation of this heterocyclic system. Syn-
thesis of the imidazoline-5-one core is usually accom-
plished in three ways. The first method consists in
transformation of 2-oxazolin-5-ones into imidazoline-5-
ones in the presence of an amine or Schiff base.10 The sec-
ond route is based on intermolecular cyclization of N-sub-
stituted a,b-unsaturated amino acid hydrazides.11
Condensation of a,b-dicarbonyl compounds with guani-
dine derivatives represents the third procedure for prepa-
ration of these heterocyclic products.7
– EtOH
EtO2C
N
N
H
O
3a
Scheme 1 Transformation of ethyl a-azido(phenyl)acetate (1a) into
Efficient formation of the imidazolin-5-ones from a-azido
esters was observed only in DMF and DMSO. Analysis of
the solvent effects indicated that the highest reaction rate
for the conversion of ethyl a-azido(phenyl)acetate (1a)
into
5-oxo-2,4-diphenyl-2,5-dihydro-1H-imidazol-2-
During our investigations on thermal stability of organic
azides we noted that dipolar, aprotic solvents support
transformation of a-azidocarboxylic esters into a-imi-
nocarboxylates. Ethyl a-azido(phenyl)acetate (1a) under-
carboxylate 3a at 80 °C occurred in DMSO whereas n-
butanol gave only traces of the dimerization product.
MeCN and toluene did not promote this transformation at
all. The spectroscopic data and physical properties deter-
mined for 3a were in accordance with those reported ear-
lier for the same compound prepared by a multistep
procedure.14
SYNLETT 2011, No. 3, pp 0315–0318
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x.
x
x.
2
0
1
1
Advanced online publication: 05.01.2011
DOI: 10.1055/s-0030-1259299; Art ID: D27110ST
© Georg Thieme Verlag Stuttgart · New York

316
D. Cież, J. Svetlik
LETTER
Table 1 Reaction of Ethyl a-Bromoacetates 5a–g with NaN3 (1.5 equiv) in DMF at 80 °C Leading to 5-Oxo 2,4-Disubstituted 2,5-Dihydro-
1H-imidazol-2-carboxylates 3a–g
Entry
Substrate
Time (h)
Product
Mp (°C)
Isolated yield (%)
EtO2C
N
CO2Et
1
5
148–149
92
N
Br
H
O
5a
3a
Br
Br
EtO2C
N
CO2Et
2
3
4
5
6
30
18
24
30
8
129–130
130–131
132–133
94–95
85
81
95
34
67
N
N
Br
Br
H
O
5b
3b
EtO2C
CO2Et
N
Br
H
O
5c
3c
EtO
OEt
EtO2C
N
CO2Et
N
EtO
Br
Br
H
O
5d
3d
O2N
NO2
EtO2C
N
CO2Et
N
O2N
H
O
5e
3e
N
EtO2C
N
CO2Et
73–74
N
N
N
Br
Br
H
O
5f
3f
S
EtO2C
S
N
CO2Et
S
7
18
103–104
58
N
H
O
5g
3g
Esters of a-azidocarboxylic acids are not commercially ly available aryl- and heteroarylacetates, to novel
available. The standard procedure for synthesis of a-azi- imidazolin-5-one derivatives 3b–f16 (Scheme 2). We also
do(aryl)acetates consists in the reaction of the appropriate found that freshly prepared a-bromo esters 5 could be
a-bromo esters with sodium azide in DMF, DMSO or used without purification,17 particularly important in rela-
MeCN at the room temperature.15 We noted, that solvent tion to unstable a-bromo esters, which undergo decompo-
and reaction temperature play the crucial role in the nu- sition during chromatography or distillation.
cleophilic substitution of bromine with azide group in a-
bromo(aryl)acetates 5. Ethyl a-bromo(phenyl)acetate
EtO2C
N
R
CO2Et
R
(5a) treated with sodium azide in DMF at the room tem-
perature gave ethyl a-azido(phenyl)acetate (1a) as the
main product. However, the same reaction carried out at
80 °C led to imidazolin-5-one 3a. GC analysis of the reac-
tion mixture showed nearly complete transformation of a-
bromo(phenyl)acetate into imidazolidin-5-one 3a in four
hours and only traces of a-imino(phenyl)acetate 2a were
indicated. We applied the same method for transforma-
tions of various a-bromo esters derived from commercial-
i
ii
R
CO2Et
R
N
Br
5b–f
H
O
4b–f
3b–f
Scheme 2 Two-step procedure for synthesis of 5-oxo 2,4-disubsti-
tuted 2,5-dihydro-1H-imidazol-2-carboxylates from commercially
available ethyl aryl- and heteroarylacetates. The reactions were car-
ried out without isolation of the intermediate a-azido esters. Reagents
and conditions: (i) NBS, Luperox®, CCl4, 74 °C; (ii) NaN3, DMF, 80 °C.
Synlett 2011, No. 3, 315–318 © Thieme Stuttgart · New York

LETTER
One-Pot Preparation of Imidazolin-5-ones
317
The experimental observations suggest a ‘Type 1’ path-
way for the decomposition of ethyl a-azido(phe-
nyl)acetate18 that can be characterized by the initial
release of the molecular nitrogen and subsequent isomer-
ization of the nitrene to imine by 1,2-H shift.19 The mech-
anism for the conversion of a-imino esters into the
imidazolin-5-one heterocyclic system consists of two in-
dependent steps, nucleophilic attack and addition of the
imine group to the C=N double bond followed by conden-
sation reaction.20
Acknowledgment
This work was partially supported by the Polish Ministry of Science
and Higher Education (Grant No. N204 310037) and the Slovak Na-
tional Research and Development Program No. 2003SP200280203.
References and Notes
(1) Pandya, K. C.; Kurien, P. N.; Surange, V. R. J. Indian Chem.
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A. C. J. Med. Chem. 1966, 9, 852.
Our research shows that formation of the nitrene can be
realized in the absence of any base by simple thermal de-
composition of a-azidoarylacetates in dipolar aprotic sol-
vents such as DMF or DMSO. We note that simple
aliphatic a-azido esters are more stable than a-azidoaryl-
acetates and do not undergo any thermal transformation
into nitrene derivatives below 120 °C, so they do not give
any aliphatic a-imino esters. We presume that there is a
correlation between the thermal stability of a-azido esters
and their a-CH acidity. Indeed, diethyl a-bromomalonate,
ethyl a-bromonitroacetate and ethyl a-bromocyanoace-
tate reacted quickly with sodium azide in DMF with ac-
companying nitrogen evolution even at room temperature.
GC of the reaction mixtures showed the absence of a-bro-
mo esters but spectroscopic analysis gave no evidence for
formation of imidazolin-5-ones. NMR investigation of
crude products indicated the formation of a-imino esters
as main products. However, separation of pure a-imino
esters was not possible owing to their hydrolytic instabil-
ity. When we tried to isolate diethyl iminomalonate21 after
reaction of diethyl a-bromomalonate with sodium azide,
NMR analysis of the crude extract confirmed the presence
of diethyl iminomalonate but its purification using col-
umn chromatography failed. However, we noted that this
intermediate did not undergo any thermal cyclization and,
after one hour of heating to 50 °C, gave a mixture of un-
defined decomposition products. Intermolecular cycliza-
tion of a-imino esters seems to begin with nucleophilic
attack of the NH group on a carbon atom at the C=NH
double bond and reaction rate depends on the basicity of
the nitrogen atom. The presence of electron-withdrawing
substituents at a-C reduces the basicity of the imino group
and strongly inhibits nucleophilic addition of the NH
group onto the C=NH double bond. The low basicity of a-
imino esters derived from diethyl a-bromomalonate, ethyl
a-bromonitroacetate and ethyl -bromocyanoacetate
makes the formation of imidazolin-5-one system impossi-
ble.
(3) Goldberg, M. W.; Lehr, H. H. US Patent, US2602086, 1952.
(4) Karjalainen, A. J.; Kurkela, K.; Oiva, A. P. S.; Sulevi, L.
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Sakurai, T. Tetrahedron 2004, 60, 9517. (b) Topuzyan, V.
O.; Arutyunyan, L. G.; Oganesyan, A. A.; Panosyan, G. A.
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Arutyunyan, L. G.; Oganesyan, A. A.; Panosyan, G. A. Russ.
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(12) 1H NMR (600 MHz, DMSO-d6): d = 11.25 (s, 1 H, NH), 8.38
(d, 2 H, JHH = 7.8 Hz, CHAr), 7.62 (m, 2 H, CHAr), 7.54 (t, 2
H, JHH = 7.8 Hz, CHAr), 7.44 (t, 2 H, JHH = 7.8 Hz, CHAr),
7.40 (t, 2 H, JHH = 7.2 Hz, CHAr), 4.17 (q, 2 H, JHH = 7.2 Hz,
CH3CH2O), 1.14 (t, 3 H, JHH = 7.2 Hz, CH3CH2O). 13C NMR
(150 MHz, DMSO-d6): d = 167.7, 164.8, 162.9, 137.3,
132.3, 129.6, 128.8, 128.7, 128.4, 128.3, 126.5, 86.5, 62.5,
13.8. All 2D NMR experiments for 3a were carried out using
DMSO-d6 as a solvent. COSY correlation list: d [ppm]–d
[ppm](assignment): 1.14–4.17 (CH3CH2O), 4.17–1.14
(CH3CH2O), 7.40–7.44 (p-CH), 7.44–7.40, 7.62 (m-CH),
7.54–7.62, 8.38 (m-CH), 7.62–7.54 (p-CH), 7.62–7.44 (o-
CH), 8.38–7.54 (o-CH). HSQC: correlation list: 13C shift
[ppm]–1H shift [ppm](assignment): 13.7–1.14 (CH3CH2O),
62.5–4.17 (CH3CH2O), 126.5–7.62 (o-CH), 128.3–8.38 (o-
CH), 128.4–7.44 (m-CH), 128.7–7.54 (m-CH), 128.8–7.40
(p-CH), 132.3–7.62 (p-CH). HMBC: correlation list: 1H shift
[ppm]–13C shifts [ppm] (atom connectivity): 1.14–62.5
(ester group CH3CH2O), 4.17–13.7 and 167.7 (ester group
CH3CH2OCO), 7.40–126.5 (p-CH and C-2, phenyl group
A), 7.44–126.5, 128.8 and 137.4 (m-CH and C-2, C-4, C-1,
phenyl group A), 7.54–128.3, 129.6 (m-CH and C-2, C-1,
phenyl group B), 7.62–86.9, 126.5 and 128.8 (o-CH and
quaternary C-2 of the imidazolidine ring, C-2, C-4, phenyl
group A), 7.62–128.3 (p-CH and C-2, phenyl group B),
8.38–128.7, 132.3 and 162.9 (o-CH and C-3, C-4 in phenyl
group B and C=N in the imidazolidine ring), 11.25–86.9,
162.9 and 164.8 (NH group and quaternary C-2, C=N and
C=O in the imidazolidine ring). According to HMBC data,
In summary, our method can be adapted for convenient
synthesis of 5-oxo-2,4-diaryl- and 5-oxo-2,4-diheteroaryl-
2,5-dihydro-1H-imidazol-2-carboxylates from readily
available a-bromo(aryl)- and a-bromo(heteroaryl)ace-
tates in a very simple manner. The optimized procedure
gives the substituted imidazolin-5-ones in moderate to
very good yields.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 3, 315–318 © Thieme Stuttgart · New York

318
D. Cież, J. Svetlik
LETTER
phenyl substituents A and B were attached to the
imidazolidine ring at C-2 and C-4, respectively.
(13) (a) Cież, D. Org. Lett. 2009, 11, 4282. (b) For more data on
instability of lithium enolates of a-azidocarboxylic esters,
see also: Manis, P. A.; Rathke, M. W. J. Org. Chem. 1980,
45, 4952.
(14) (a) Matsuda, Y.; Tanimoto, S.; Okamoto, T.; Ali, S. M.
J. Chem. Soc., Perkin Trans. 1 1989, 279. (b) Yasunobu,
A.; Shoko, T.; Tomomi, K.; Masanori, S. Chem. Pharm.
Bull. 1984, 32, 1800.
14.0 (Me). IR (neat): 3168, 3071, 2979, 2936, 1742, 1705,
1595, 1571, 1512, 1237, 1172 cm–1. Anal. Calcd for
C22H24N2O5: C, 66.65; H, 6.10; N, 7.06. Found: C, 66.45; H,
6.01; N, 7.10.
(17) Standard Procedure for Synthesis of a-Bromoacetates
from Commercial Ethyl Aryl- and Heteroarylacetates;
Representative Preparation of Ethyl Bromo(4-ethoxy-
phenyl) Acetate (4d): Ethyl 4-ethoxyphenylacetate (1.695
g, 8.14 mmol) was treated with NBS (1.449 g, 1 equiv) and
Luperox® A70S (0.176 g, 0.50 mmol) in CCl4 (30 mL). The
reaction mixture was stirred and heated for 30 h at 74 °C.
After cooling the solution was filtered through a Celite pad
and the solvent was evaporated. The crude product, ethyl
bromo(4-ethoxyphenyl) acetate (4d), was pure enough to be
used for the next step.
(18) (a) Bock, H.; Dammel, R.; Horner, L. Chem. Ber. 1981, 114,
220. (b) Bock, H.; Dammel, R. S.; Aygen, J. J. Am. Chem.
Soc. 1983, 105, 7681. (c) Bock, H.; Dammel, R. Angew.
Chem., Int. Ed. Engl. 1987, 26, 504; Angew. Chem. 1987, 99,
518. (d) Bock, H.; Dammel, R. J. Am. Chem. Soc. 1988, 110,
5261.
(19) For more details, see: (a) Dyke, J. M.; Levita, G.; Morris, A.
J.; Ogden, S.; Dias, A. A.; Algarra, M.; Santos, J. P.; Costa,
M. L.; Rodrigues, P.; Andrade, M. M.; Barros, M. T. Chem.
Eur. J. 2005, 11, 1665. (b) Shirtcliff, L. D.; McClintock, S.
P.; Haley, M. M. Chem. Soc. Rev. 2008, 37, 343. (c) Trost,
B. M.; Fleming, I.; Ley, S. V. Oxidation; In Comprehensive
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Modern Organic Chemistry, Vol. 7: 5th ed.; Elsevier Ltd.:
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(20) (a) Poisel, H. Chem. Ber. 1977, 110, 942. (b) Shin, C.;
Masaki, M.; Ohta, M. Bull. Chem. Soc. Jpn. 1971, 44, 1657.
(21) Partial NMR data for diethyl iminomalonate were
determined from the crude reaction mixture. 1H NMR (300
(15) Paul, A.; Bittermann, H.; Gmeiner, P. Tetrahedron 2006, 62,
8919.
(16) General Method for Preparation of Imidazolin-5-ones 3
from a-Bromoacetates; Representative One-Pot
Synthesis of Ethyl 2,4-Bis(4-ethoxyphenyl)-5-oxo-2,5-
dihydro-1H-imidazole-2-carboxylate (3d): Ethyl a-
bromo-2-(4-ethoxyphenylacetate) (4d; 1.254 g, 4.4 mmol)
and sodium azide (0.428 g, 6.6 mmol, 1.5 equiv) were added
to DMF (20 mL). The suspension was stirred and heated for
24 h at 80 °C. After cooling, the reaction mixture was poured
into H2O (100 mL) and extracted with EtOAc (3 × 30 mL).
The combined extracts were washed with H2O (2 × 50 mL)
and dried over anhyd Na2SO4. The mixture was filtered and
the solvent was removed under reduced pressure. The crude
product was purified by column chromatography using silica
gel (230–400 mesh; CHCl3–MeOH, 30:1) to give 3d as
colorless crystals (TLC silica gel; Fluka 60778; CHCl3–
MeOH, 30:1; Rf 0.55); mp 132 °C. 1H NMR (300 MHz,
CDCl3): d = 8.48 (d, 2 H, JHH = 9.1 Hz, CHAr), 8.40 (br s, 1
H, NH), 7.50 (d, 2 H, JHH = 9.0 Hz, CHAr), 6.95 (d, 2 H, JHH
= 9.1 Hz, CHAr), 6.89 (d, 2 H, JHH = 9.0 Hz, CHAr), 4.25 (2 ×
dq, 2 H, JHH = 7.11, 7.14, 10.7 Hz, OCH2), 4.10 (q, 2 H, JHH
= 7.0 Hz, OCH2), 4.02 (q, 2 H, JHH = 7.0 Hz, OCH2), 1.44 (t,
3 H, JHH = 7.0 Hz, Me), 1.40 (t, 3 H, JHH = 7.0 Hz, Me), 1.26
(t, 3 H, JHH = 7.1 Hz, Me). 13C NMR (75 MHz, CDCl3): d =
168.3 (COOEt), 165.7 (CONH), 162.3 (C=N), 161.6 (C4),
159.5 (C4), 130.8 (C3), 129.0 (C1), 127.4 (C3), 122.3 (C1),
114.6 (C2), 114.4 (C2), 86.0 (C2-imidazolidine), 63.6
(OCH2), 63.5 (OCH2), 62.9 (OCH2), 14.7 (Me), 14.7 (Me),
MHz, CDCl3): d = 11.76 (br s, 1 H, NH), 4.29 (q, 2 H, JHH
=
7.1 Hz, OCH2), 1.30 (t, 3 H, JHH = 7.1 Hz, Me). 13C NMR (75
MHz, CDCl3): d = 161.0 (COOEt), 152.3 (C=NH), 61.6
(OCH2), 14.3 (Me).
Synlett 2011, No. 3, 315–318 © Thieme Stuttgart · New York

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