Straightforward access to (imidazol-2-yl)acetates by reaction of 2-unsubstituted imidazole 3-oxides with dimethyl acetylenedicarboxylate

Article abstract of DOI:10.1002/ejoc.201001594

A new method for the preparation of 1,4,5-trisubstituted (imidazol-2-yl)acetates, based on the reaction of the corresponding imidazole 3-oxides with dimethyl acetylenedicarboxylate (DMAD) is described. Formation of the products is rationalized by a formal 1,3-dipolar cycloaddition and subsequent oxaloyl cleavage. 1,4,5-Trisubstituted imidazole 3-oxides bearing an electron-withdrawing substituent at C(4), easily react with dimethyl acetylenedicarboxylate (DMAD), yielding the corresponding oxobutanoates, which subsequently, in a one-pot procedure undergo hydrolysis through an "oxaloyl cleavage" mode. New (imidazol-2-yl)acetates were isolated in high yields. Copyright

Full text of DOI:10.1002/ejoc.201001594

FULL PAPER
DOI: 10.1002/ejoc.201001594
Straightforward Access to (Imidazol-2-yl)acetates by Reaction of
2-Unsubstituted Imidazole 3-Oxides with Dimethyl Acetylenedicarboxylate
Grzegorz Mloston´,[a] Marcin Jasin´ski,*[a] and Heinz Heimgartner[b]
Dedicated to Professor Józef Drabowicz on the occasion of his 65th birthday
Keywords: Nitrogen heterocycles / Alkynes / Cycloaddition
A new method for the preparation of 1,4,5-trisubstituted
(imidazol-2-yl)acetates, based on the reaction of the corre-
sponding imidazole 3-oxides with dimethyl acetylenedicar-
boxylate (DMAD) is described. Formation of the products is
rationalized by a formal 1,3-dipolar cycloaddition and subse-
quent oxaloyl cleavage.
droimidazole N-oxides and alkynoates.[1e] In a recent re-
port, an interesting rearrangement of the initially formed
[3+2] cycloadducts of imidazoline N-oxides and DMAD,
followed by aromatization of the heterocyclic ring was pre-
sented.[1f] In the described system, the corresponding imid-
azoles or ylides were isolated as the final products. The lat-
ter smoothly eliminated the oxaloyl moiety under acidic
conditions.
Introduction
In a series of recent papers we have demonstrated that 2-
unsubstituted imidazole 3-oxides are versatile building
blocks for the preparation of more complex imidazole de-
rivatives.[1a–d] The general methodology, which involves the
corresponding 3-oxides, was efficiently applied to the syn-
thesis of chiral ionic liquids,[2] bis-imidazoles,[3] some novel
organocatalysts of C2-symmetry,[3b,4] and other compounds
of potential biological importance bearing an imidazole
moiety.[5] The structure of 2-unsubstituted imidazole 3-ox-
ides resembles aldonitrones and, in the presence of appro-
priate dipolarophiles, they smoothly undergo cascade reac-
tions initiated by a [2+3] cycloaddition step. Reactions with
2,2,4,4-tetramethylcyclobutane-1,3-dithione,[1a]
isocyan-
ates,[1b] hexafluoropropene,[6] and 2,2-bis(trifluoromethyl)-
ethylene-1,1-dicarbonitrile[1d] generate the corresponding
Scheme 1. Reaction of 1,4,5-trialkyl/aryl-imidazole 3-oxides 1 with
imidazole-2-thiones, 2-aminoimidazoles, 2-(fluoroalkyl)- DMAD leading to butanedioates 2.
imidazoles, and 2-dicyanomethylidene imidazoles, respec-
Reactions of DMAD with both benzimidazole 3-oxides[7]
tively. After the 1,3-dipolar cycloaddition step and subse-
quent re-aromatization, C(2)-substituted imidazoles were
obtained. As shown in Scheme 1, an analogous reaction
pattern was observed in the reaction of dimethyl acetylene-
dicarboxylate (DMAD) with imidazole 3-oxides 1 bearing
alkyl or aryl moieties at N(1), C(4), and C(5).[1b] 2-Oxobut-
anoate derivatives of type 2 were isolated in good yields as
the only products. A regioselective course of the analogous
reaction was observed in the case of more reactive 4,5-dihy-
and imidazole 3-oxides[8] were extensively studied and, in
the case of 2-unsubstituted substrates, the products were
described as tautomeric forms of 2. On the other hand, the
reaction of DMAD with 2-substituted benzimidazole 3-ox-
ides resulted in the formation of a completely different
product with a betaine structure.[7b] It should be emphas-
ized that the reported reactions with DMAD led to prod-
ucts that are isomeric with the proposed initially formed
cycloadducts.
In a continuation of our ongoing interest in the synthesis
and transformations of 2-unsubstituted imidazole 3-oxides,
a new type of compound 1, bearing a carboxamide group
at C(4), was reported.[9] The reaction of 1 (R2 = CONHR)
with 2,2,4,4-tetramethylcyclobutane-1,3-dithione and acetic
anhydride-induced isomerization led to the expected imid-
azole-2-thiones and imidazol-2-ones, respectively, however,
[a] Department of Organic and Applied Chemistry, University of
Łódz´,
Tamka 12, 91-403 Łódz´, Poland
Fax: +48-42-635-5380
E-mail: mjasinski@uni.lodz.pl
[b] Institute of Organic Chemistry, University of Zürich,
Winterthurerstrasse 190, 8057 Zürich, Switzerland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001594.
2542
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2542–2547

Straightforward Access to (Imidazol-2-yl)acetates
both transformations occurred remarkably slowly. The ob-
served decrease in reactivity was explained by intramolecu-
lar hydrogen bonding of the amide NH with the NǞO moi-
ety.
The goal of the study described in this paper was the
reaction of 3-oxido-1H-imidazole-4-carboxamides 1 (R2 =
CONH-Alkyl/Aryl) with DMAD. Unexpectedly, compared
with previously reported reactions of this type, the reactions
described here afforded completely different products.
Scheme 3. Synthesis of imidazole 3-oxide 1g.
ever, attempted purification by crystallization in CHCl3 re-
sulted in the formation of a yellowish oil, which, after col-
umn chromatography, delivered a crystalline material 6b as
Results and Discussion
The starting materials 1b–f were prepared according to a the major product in moderate yield.
1
literature protocol from commercially available ethyl aceto-
The H NMR spectrum of 6b showed only one singlet
acetate by using slightly modified methods as shown in for a MeO group at δ = 3.74 ppm along with another singlet
Scheme 2.[9a] In the case of N-alkyl amides 1b and 1c, the that was attributed to a CH2 group. The signal located at δ
required oxime 3 was smoothly prepared by nitrosation = 169.0 ppm in the 13C NMR spectrum confirmed the pres-
using NaNO2 in glacial acetic acid.[10] Compound 3 was ence of only one ester group. The second C=O signal at δ
subsequently reacted with 1,3,5-trimethylhexahydro-1,3,5- = 164.4 ppm revealed the unchanged amide function. Two
triazine under mild conditions (diethyl ether, room tem- strong absorption bands at 1728 and 1662 cm–1 supported
perature), and the crude ester 1a was used for aminolysis in the presence of these functional groups. Finally, the EI- and
the presence of excess alkylamine.
ESI-MS showed that the molecular ion corresponded to
The N-aryl analogues 1d–f were prepared following the m/z 225. These results, together with elemental analyses al-
three-step procedure (aminolysis, nitrosation, imidazole lowed the structure of 6b to be identified as the hitherto
ring formation) using aniline, 4-bromoaniline and anisidine, unknown (imidazol-2-yl)acetate (Scheme 4). This structure
respectively. All imidazole 3-oxides 1b–f were isolated as corresponds to the product of the oxaloyl cleavage[12,13] of
crystalline materials in fair overall yields. Finally, imidazole the expected product 2b.
3-oxide 1g, bearing an acetyl moiety at C(4), was prepared
In the case of 1b and 1d, the corresponding oxobut-
in high yield, starting with 3-hydroxyiminopentane-2,4-di- anoates 2b and 2d were isolated as colorless solids after
one by condensation with 1,3,5-trimethylhexahydro-1,3,5- evaporation of the solvents (water/ice bath) and treatment
triazine in diethyl ether, at room temperature (Scheme 3).[11] with a small amount of cold acetone. Their structures were
The first experiment was carried out using 1b as a hy- proved by means of spectroscopic methods; for example, in
1
drate and 1.2 equiv. of DMAD in CHCl3. After mixing the the case of 2d, two MeO absorptions were found in the H
reagents at 0 °C, the solution was stirred at room tempera- NMR spectrum at δ = 3.80 and 3.63 ppm, along with a
ture and the progress of the reaction was monitored by signal arising from an MeN group localized at δ =
TLC. The starting material 1b was completely consumed 3.56 ppm. The 13C NMR spectrum of the same compound
after approximately 1.5 h to form a colorless solid, which revealed the presence of four C=O groups absorbing at δ =
was expected to be the 2-oxobutanoate derivative 2b. How- 179.4 (ketone), 169.4, 167.3 (two ester groups), and 157.8
Scheme 2. Synthesis of imidazole 3-oxides 1a–f.
Eur. J. Org. Chem. 2011, 2542–2547
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2543

M. Jasin´ski et al.
FULL PAPER
Scheme 4. Synthesis of (imidazol-2-yl)acetates 6.
(amide) ppm. The data collected for 2b also fitted well with TLC. After flash-chromatography and crystallization from
the postulated structure. Without further purification, each ethyl acetate, crystalline 6a was obtained in satisfactory
of the products 2 were converted into 6b and 6d, respec- yield.
tively, by heating in wet chloroform solution.
In an extension of the study performed with 1a–g, con-
In an additional experiment, the same product 6b was taining an electron-withdrawing group at C(4), the earlier
obtained when the reaction mixture of 1b and DMAD was described 2-oxobutanedioate derivative 2h[1b] was tested as
kept overnight in CHCl3 at room temperature. Moreover, a substrate for the oxaloyl cleavage. The attempted uncata-
heating the mixture of 1b and DMAD already gave this lyzed reaction in wet CHCl3 was unsuccessful and 2h was
product after approximately 2 h. However, the best result recovered after heating for two hours. A similar reaction
with respect to reaction time and yield of 6b was obtained performed in the presence of CeCl3·7H2O (1.5 equiv.)
when a small amount of water was added to the solution yielded a complex mixture of unidentified products. On the
of crude 2b before heating.
other hand, when the experiment was carried out in aque-
Analogous results were obtained with imidazole 3-oxides ous methanol containing three equivalents of NaOH at
1c–f, and products of type 6 were isolated as crystalline ma- room temperature for two hours, (imidazol-2-yl)acetic acid
terials (Table 1).
7 was obtained as a solid material after neutralization. Fi-
nally, the reaction of 2h in an approximate 1:2 mixture of
H2O and Et3N, yielded, after 10 h heating at reflux, a mix-
ture of 7 (35%), the corresponding ester 6h (16%), and 1-
cyclohexyl-2,4,5-trimethylimidazole (8; 27%, Scheme 5).
Apparently, in this case, the product of the oxaloyl cleavage
undergoes easily hydrolysis, yielding 7, which partially de-
composes through decarboxylation to give 8.
To prove the structure of the isolated compounds, acid
7 was quantitatively transformed into methyl ester 6h by
treatment with diazomethane in Et2O at room temperature.
On the other hand, decarboxylation of 7 at 115 °C yielded
Table 1. (Imidazol-2-yl)acetates 6.
6
R
Yield [%]
M.p. [°C]
a
b
c
d
e
f
EtO
MeNH
CyclopropylNH
PhNH
4-BrC6H4NH
4-MeOC6H4NH
Me
38
62
43
51
64
33
47
92–94
137–138
111–112
146–148
196–198
158–160
143–145
g
To check the scope of the described protocol, imidazole the expected imidazole derivative 8 nearly quantitatively.
3-oxides 1a and 1g, bearing an ester and acetyl group,
The results obtained with 2h showed that the presence of
respectively, instead of an amide group, were also reacted an electron-withdrawing group, such as an ester, amide or
with DMAD. In the case of 1g, the expected product 6g acetyl group, at C(4) in the starting imidazole 3-oxide is
was formed without isolation of 2g, whereas in the reaction decisive for smooth conversion of the initially formed ad-
with 1a, the initially formed adduct 2a, in analogy to 2b ducts of type 2 into the corresponding (imidazol-2-yl)acet-
and 2d, could be isolated and identified spectroscopically. ates through uncatalyzed oxaloyl cleavage.
For example, the 1H NMR spectrum evidenced the presence
The oxaloyl cleavage is a known reaction and, to the best
of two MeO groups (δ = 3.85 and 3.69 ppm) and a broad of our knowledge, the first report on an acid-catalyzed
absorption (δ ≈ 10.21 ppm) was attributed to the NH group cleavage appeared in 1913.[12a] Some time ago, a base-cata-
(imidazole ring). Subsequently, the isolated material was lyzed version was applied for the synthesis of 3-substituted
heated to reflux in CHCl3 containing traces of water and, pent-4-enoic acids 10 from α-oxodicarboxylates
9
after two hours, no starting material could be detected by (Scheme 6).[12b]
Scheme 5. The Et3N-catalyzed oxaloyl cleavage of 2h.
2544
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2542–2547

Straightforward Access to (Imidazol-2-yl)acetates
diamines,[15c] and the alkoxycarbonylation of 2-methylimid-
azoles.[14a,14c] The method described in this paper sup-
plements the known protocols and offers access to deriva-
tives with a new and variable substitution pattern.
Scheme 6. Base-catalyzed oxaloyl cleavage of α-oxodicarboxylates
9 (ref.[12b]).
Experimental Section
General Information: Melting points were determined in capillaries
with a MEL-TEMP II apparatus (Aldrich). IR spectra were re-
corded with an FTIR NEXUS spectrophotometer as KBr pellets;
In the light of our results, adducts 2 are suitable sub-
strates for the uncatalyzed oxaloyl cleavage. An important
feature of the structure is the presence of a suitably substi-
tuted imidazole moiety, which activates the oxobutanoate
fragment toward nucleophilic addition of water. The pres-
ence of the electron-withdrawing substituent at C(4) of the
imidazole ring is especially important for the reaction to
proceed. As mentioned above, adducts of type 2 can be pre-
sented in two tautomeric forms 2 and 2Ј (Scheme 7). Tauto-
mer 2Ј is believed to display higher electrophilicity at the
keto group and, therefore, addition of water may occur un-
der milder conditions, leading to the formation of inter-
mediate A. The latter is believed to undergo cleavage of the
C–C bond through elimination of monomethyl oxalate
(retro-ene reaction). It is worth mentioning that, under the
applied mild reaction conditions, (imidazol-2-yl)acetates 6
are formed as the final products. The course of the studied
reaction resembles, to some extent, a retro-aldol type con-
version of 4,5-dihydro-2-(β-hydroxyalkyl)imidazole deriva-
tives into 4,5-dihydro-2-methylimidazole and the respective
aldehyde or ketone, observed at 110 °C.[13]
1
absorptions (ν) are given in cm–1. H and 13C NMR spectra were
˜
measured with a Bruker Avance III (1H at 600 MHz and 13C at
150 MHz) instrument in CDCl3; chemical shifts (δ) are given
in ppm, coupling constants (J) in Hz. The multiplicity of the 13C
NMR signals was deduced from DEPT, and supported by H–13C
1
HMQC spectra. Data are presented as follows: chemical shift, mul-
tiplicity (br. broad, s singlet, d doublet, t triplet, q quartet, m mul-
tiplet), coupling constant, integration. Mass spectra were recorded
with a Finnigan MAT-95 instrument. Elemental analyses were per-
formed in the Laboratory of the Polish Academy of Sciences
(CBMiM) in Łódz´. Reactions under MW irradiation were per-
formed with a μ-CHEMIST MWS star T-Systeme microwave
(MLS GmbH). Applied reagents such as ethyl acetoacetate, alk-
ylamines, anilines, paraformaldehyde (or formalin), DMAD, inor-
ganic reagents, and solvents are commercially available (Aldrich)
and were used as received. β-Oxobutyramides, which were required
for the preparation of substrates 5, were synthesized from ethyl
acetoacetate and the corresponding anilines under MW irradiation
or by heating in boiling xylenes (see Scheme 2).
Isolation of Oxobutanoates 2a, 2b, and 2d: The known 2-unsubsti-
tuted imidazole N-oxides 1a, 1b, and 1d[9a] were treated with
DMAD in chloroform solution (molar ratio 1/DMAD of ca. 1:1.2)
at room temperature according to a known method.[1b] The solvent
was removed at 0 °C and the crude products 2a, 2b, and 2d were
washed with cold acetone, filtered, and used for the hydrolysis as
a wet chloroform solution without further purification. (Imidazol-
2-yl)acetates 6a, 6b, and 6d were obtained in comparable yields to
those reported for the one-pot procedure (see below).
Synthesis of (Imidazol-2-yl)acetates 6. General Procedure: To a
magnetically stirred solution (or suspension) of imidazole 3-oxide
1[11] (1.0 mmol) in CHCl3 (5 mL), cooled in a water/ice bath, a
solution of DMAD (1.2 mmol, 0.17 g) in CHCl3 (5 mL) was added
dropwise. The resulting yellow mixture was allowed to reach room
temperature. After 1 was completely consumed (usually ca. 2 h;
TLC monitoring: SiO2, acetone), water (0.5 mL) was added and
the mixture was heated to reflux for 2 h. After cooling to room
temp., the organic phase was separated, the solvent removed, and
the obtained residue was purified by chromatography on silica
(CHCl3, then CHCl3/acetone, 3:1) to give 6. Analytically pure sam-
ples were obtained by recrystallization from appropriate solvents.
Scheme 7. Proposed mechanism of the formation of (imidazol-2-
yl)acetates 6 through oxaloyl cleavage.
Conclusions
Ethyl 2-Methoxycarbonylmethyl-1,5-dimethyl-1H-imidazole-4-carb-
oxylate (6a): Yield 90 mg (38%). Colorless crystals; m.p. 92–94 °C
The easily available adducts 2 of 2-unsubstituted imid-
azole 3-oxides with DMAD are attractive substrates for
conversion into (imidazol-2-yl)acetates 6. To the best of our
knowledge, this is a new method for the preparation of
these useful building blocks, which are especially important
for the syntheses of biologically active compounds.[14] There
are several methods described for the synthesis of (imid-
azol-2-yl)acetates.[14a–c,15] The most general procedures are
(EtOAc). IR (KBr): ν = 1730 (vs), 1698 (vs), 1576 (m), 1438 (m),
˜
1377 (m), 1350 (m), 1237 (m), 1221 (s), 1206 (s), 1184 (m), 1083
1
(m) cm–1. H NMR (600 MHz, CDCl3): δ = 4.36 (q, J = 7.0 Hz, 2
H, OCH2CH3), 3.89 (s, 2 H, CH2), 3.72 (s, 3 H, OCH3), 3.50 (s, 3
H, NCH3), 2.54 (s, 3 H, CH3), 1.39 (t, J = 7.0 Hz, 3 H,
OCH2CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 169.0, 163.6
(2ϫ s, 2 ϫ C=O), 140.7, 137.1, 127.8 [3ϫ s, 3 ϫ C(imidazole)], 60.2
(t, OCH2CH3), 52.4 (q, CO2CH3), 33.7 (t, CH2), 30.8 (q, NCH3),
the condensation of imidates with α-amino ketals[15f] or 1,2- 14.5 (q, OCH2CH3), 10.3 (q, CH3) ppm. HRMS (ESI): calcd. for
Eur. J. Org. Chem. 2011, 2542–2547
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2545

M. Jasin´ski et al.
FULL PAPER
C11H16N2NaO4 [M + Na]+ 263.1002; found 263.1001; calcd. for
2ArH), 6.88–6.85 (m, 2 H, 2ArH), 3.81 (s, 2 H, CH2), 3.79, 3.74
(2ϫ s, 6 H, 2ϫ OCH3), 3.49 (s, 3 H, NCH3), 2.60 (s, 3 H,
CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 169.0, 161.6 (2ϫ s,
2ϫ C=O), 155.9, 139.2, 134.1, 131.7, 130.2 [5ϫ s, 2 ϫ C(Ar), 3ϫ
C(imidazole)], 121.2, 114.1 [2ϫ d, 4ϫ CH(Ar)], 55.5 (q, ArOCH3),
52.6 (q, CO2CH3), 33.8 (t, CH2), 30.6 (q, NCH3), 10.0 (q,
CH3) ppm. HRMS (ESI): calcd. for C16H19N3NaO4 [M + Na]+
340.1268; found 340.1268; calcd. for C16H20N3O4 [M + 1]+
318.1448; found 318.1448.
C11H17N2O4 [M + 1]+ 241.1183; found 241.1182.
Methyl (1,5-Dimethyl-4-methylcarbamoyl-1H-imidazol-2-yl)acetate
(6b): Yield 140 mg (62%). Colorless crystals; m.p. 137–138 °C
(EtOAc). IR (KBr): ν = 3446 (m), 1728 (vs), 1662 (s), 1655 (s),
˜
1595 (m), 1536 (m), 1338 (m), 1227 (s), 1207 (s) cm–1. 1H NMR
(600 MHz, CDCl3): δ = 7.04 (br. s, 1 H, NH), 3.78 (s, 2 H, CH2),
3.74 (s, 3 H, OCH3), 3.48 [s, 3 H, NCH3(imidazole)], 2.91 (d, J
= 4.8 Hz, 3 H, CONHCH3), 2.57 (s, 3 H, CH3) ppm. 13C NMR
(150 MHz, CDCl3): δ = 169.0, 164.4 (2ϫ s, 2 ϫ C=O), 139.2, 133.1, Methyl (4-Acetyl-1,5-dimethyl-1H-imidazol-2-yl)acetate (6g): Yield
130.2 [3ϫ s, 3 ϫ C(imidazole)], 52.6 (q, CO2CH3), 33.8 (t, CH2), 99 mg (47%). Colorless crystals; m.p. 143–145 °C (EtOAc). IR
30.5 (q, NCH3), 25.3 (q, CONHCH3), 9.8 (q, CH3) ppm. MS (EI): (KBr): ν = 1735 (vs), 1663 (vs), 1559 (s), 1425 (m), 1385 (m), 1342
˜
m/z (%) = 225 (100) [M]+, 195 (58), 168 (81), 166 (99), 114 (38), 56 (m), 1229 (m), 1206 (s), 1174 (m) cm–1. 1H NMR (600 MHz,
(42). C10H15N3O3 (225.11): calcd. C 53.31, H 6.71, N 18.66; found
C 53.05, H 6.64, N 18.65.
CDCl3): δ = 3.85 (s, 2 H, CH2), 3.75 (s, 3 H, OCH3), 3.49 (s, 3 H,
NCH3), 2.54 (s, 3 H, CH3), 2.52 (s, 3 H, COCH3) ppm. 13C NMR
(150 MHz, CDCl3): δ = 195.8, 169.1 (2ϫ s, 2 ϫ C=O), 139.8, 136.2,
135.6 [3ϫ s, 3 ϫ C(imidazole)], 52.5 (q, CO2CH3), 33.8 (t, CH2),
30.5 (q, NCH3), 27.4 (q, COCH3), 10.5 (q, CH3) ppm. HRMS
(ESI): calcd. for C10H14N2NaO3 [M + Na]+ 233.0897; found
233.0898; calcd. for C10H15N2O3 [M + 1]+ 211.1077; found
211.1076.
Methyl (4-Cyclopropylcarbamoyl-1,5-dimethyl-1H-imidazol-2-yl)-
acetate (6c): Yield 108 mg (43%). Colorless crystals; m.p. 111–
112 °C (EtOAc). IR (KBr): ν = 3418 (s), 1736 (vs), 1652 (vs), 1591
˜
(s), 1531 (m), 1508 (s), 1470 (m), 1266 (s), 1231 (m), 1006 (m) cm–1.
1H NMR (600 MHz, CDCl3): δ = 7.10 (br. s, 1 H, NH), 3.77 (s, 2
H, CH2), 3.73 (s, 3 H, OCH3), 3.47 [s, 3 H, NCH3(imidazole)],
2.83–2.78 [m, 1 H, CH(cProp)], 2.57 (s, 3 H, CH3), 0.80–0.77, 0.60–
Et3N-Catalyzed Oxaloyl Cleavage of 3-(1-Cyclohexyl-2,3-dihydro-
0.58 [2ϫ m, 4 H, 2ϫ CH2(cProp)] ppm. 13C NMR (150 MHz, 4,5-dimethyl-1H-imidazol-2-ylidene)-2-oxobutanedioate (2h): A sus-
CDCl3): δ = 169.0, 165.2 (2ϫ s, 2 ϫ C=O), 139.2, 133.5, 130.0
[3ϫ s, 3 ϫ C(imidazole)], 52.6 (q, CO2CH3), 33.8 (t, CH2), 30.5 (q,
NCH3), 21.9 [d, CH(cProp)], 9.9 (q, CH3), 6.4 [s, 2ϫ
CH2(cProp)] ppm. HRMS (ESI): calcd. for C12H17N3NaO3 [M +
pension of 2h (1.0 g, 3.0 mmol) in a mixture of Et3N (10 mL) and
H2O (4 mL) was heated to reflux for 10 h. The organic layer was
separated, the aqueous layer was extracted with EtOAc (5 mL), and
the combined organic phase was dried with anhydrous Na2SO4.
Na]+ 274.1162; found 274.1160; calcd. for C12H18N3O3 [M + 1]+ The solvent was removed under reduced pressure to give 620 mg
252.1343; found 252.1338.
of an oily mixture, which was triturated with EtOAc, cooled, and
the pure acid 7 was filtered. The solvent was removed from the
filtrate, and the crude products 6h and 8 were separated by column
chromatography (SiO2; CHCl3 then CHCl3/acetone, 3:1).
Methyl (1,5-Dimethyl-4-phenylcarbamoyl-1H-imidazol-2-yl)acetate
(6d): Yield 145 mg (51%). Colorless crystals; m.p. 146–148 °C
(CH Cl /Et O). IR (KBr): ν = 1728 (s), 1657 (s), 1594 (m), 1576
˜
2
2
2
(m), 1522 (s), 1494 (m), 1440 (m), 1266 (m), 1233 (m), 761 (m) cm–1. Methyl (1-Cyclohexyl-4,5-dimethyl-1H-imidazol-2-yl)acetate (6h):
1H NMR (600 MHz, CDCl3): δ = 8.97 (br. s, 1 H, NH), 7.68–7.66 Yield 122 mg (16%). Light-yellow oil. IR (KBr): ν = 3550–3100
˜
(m, 2 H, 2ϫ ArH), 7.33–7.30 (m, 2 H, 2ϫ ArH), 7.07–7.04 (m, 1
H, ArH), 3.80 (s, 2 H, CH2), 3.74 (s, 3 H, OCH3), 3.47 (s, 3 H,
NCH3), 2.59 (s, 3 H, CH3) ppm. 13C NMR (150 MHz, CDCl3): δ
169.0, 161.7 (2ϫ s, 2 ϫ C=O), 139.3, 138.5, 134.4, 130.1 [4ϫ s,
(vs, br.) , 2934 (vs), 2858 (s), 1740 (vs), 1596 (m), 1504 (m), 1436
(vs), 1326 (s), 1290 (m), 1266 (s), 1200 (s), 1167 (s), 1010 (m) cm–1.
1H NMR (600 MHz, CDCl3): δ = 3.86–3.80 (m, 1 H, cHex), 3.78
(s, 2 H, CH2), 3.68 (s, 3 H, OCH3), 2.20, 2.08 (2ϫ s, 6 H, 2 ϫ
C(Ph), 3ϫ C(imidazole)], 128.8, 123.4, 119.5 [3ϫ d, 5ϫ CH(Ph)], CH3), 1.89–1.81 (m, 6 H, cHex), 1.73–1.70 (m, 1 H, cHex), 1.38–
52.6 (q, CO2CH3), 33.7 (t, CH2), 30.6 (q, NCH3), 10.0 (q, 1.30 (m, 2 H, cHex), 1.24–1.21 (m, 1 H, cHex) ppm. 13C NMR
CH3) ppm. HRMS (ESI): calcd. for C15H17N3NaO3 [M + Na]+
310.1162; found 310.1166; calcd. for C15H18N3O3 [M + 1]+
288.1343; found 288.1344.
(150 MHz, CDCl3): δ = 170.4 (s, C=O), 138.7, 133.7, 122.9 [3ϫ s,
3ϫ C(imidazole)], 57.4 (d, CH, cHex), 52.6 (q, CO2CH3), 35.2 (t,
CH2), 32.3, 26.6, 25.7 (3ϫ t, 5ϫ CH2, cHex), 12.8, 11.3 (2ϫ q,
2ϫ CH3) ppm. HRMS (ESI): calcd. for C14H23N2O2 [M + 1]+
251.17540; found 251.17551.
Methyl [4-(4-Bromophenylcarbamoyl)-1,5-dimethyl-1H-imidazol-2-
yl]acetate (6e): Crude product was flash purified by chromatog-
raphy on silica (CHCl3/acetone, 4:1) to give pure 6e (233 mg, 64%).
(1-Cyclohexyl-4,5-dimethyl-1H-imidazol-2-yl)acetic Acid (7): Yield
Colorless solid; m.p. 196–198 °C (acetone). IR (KBr): ν = 1743 (s),
247 mg (35%). Colorless crystals. Decarboxylates rapidly at 112–
˜
1675 (s), 1598 (m), 1588 (m), 1519 (vs), 1485 (s), 1469 (m), 1394 114 °C. IR (KBr): ν = 3530–3200 (vs, br.) , 2936 (vs), 2859 (s), 1662
˜
(s), 1332 (s), 1298 (m), 1234 (s), 1199 (m), 1062 (m), 835 (m), 803 (vs), 1624 (vs), 1449 (s), 1400 (m), 1355 (vs), 1262 (s), 1227 (m),
1
(m) cm–1. 1H NMR (600 MHz, CDCl3): δ = 8.99 (s, 1 H, NH), 1193 (m), 1058 (m), 920 (m), 896 (m), 874 (m), 835 (m) cm–1. H
7.59–7.57 (m, 2 H, 2ϫ ArH), 7.42–7.41 (m, 2 H, 2ϫArH), 3.81 (s,
NMR (600 MHz, CDCl3): δ = 10.69 (br. s, 1 H), 4.19–4.14 (m, 1
2 H, CH2), 3.76, 3.50 (2ϫ s, 6 H, OCH3, NCH3), 2.60 (s, 3 H, H, cHex), 3.89 (s, 2 H, CH2), 2.21, 2.15 (2ϫ s, 6 H, 2 ϫ CH3),
CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 169.9, 161.6 (2ϫ s,
2ϫ C=O), 139.4, 137.6, 134.6, 129.8, 115.8 [5ϫ s, 2 ϫ C(Ar), 3ϫ
2.00–1.97 (m, 2 H, cHex), 1.88–1.84 (m, 4 H, cHex), 1.73–1.71 (m,
1 H, cHex), 1.43–1.36 (m, 2 H, cHex), 1.25–1.22 (m, 1 H,
C(imidazole)], 131.8, 121.0 [2ϫ d, 4ϫ CH(Ar)], 52.6 (q, CO2CH3), cHex) ppm. 13C NMR (150 MHz, CDCl3): δ = 170.0 (s, C=O),
33.7 (t, CH2), 30.6 (q, NCH3), 9.9 (q, CH3) ppm. HRMS (EI): 142.3, 125.7, 123.3 [3ϫ s, 3 ϫ C(imidazole)], 58.2 (d, CH, cHex),
calcd. for C15H16BrN3O3 [M]+ 365.038; found 365.039.
35.4 (t, CH2), 31.4, 26.0, 25.1 (3ϫ d, 5ϫ CH2, cHex), 10.3, 9.5
(2ϫ q, 2ϫ CH3) ppm.
Methyl [4-(4-Methoxyphenylcarbamoyl)-1,5-dimethyl-1H-imidazol-
2-yl]acetate (6f): Yield 105 mg (33%). Colorless crystals; m.p. 158–
1-Cyclohexyl-2,4,5-trimethyl-1H-imidazole (8): Yield 141 mg (27%).
160 °C (EtOAc). IR (KBr): ν = 1730 (s), 1662 (s), 1596 (m), 1518
Light-yellow oil. IR (KBr): ν = 2931 (vs), 2857 (s), 1601 (m), 1509
˜
˜
(s), 1409 (m), 1267 (m), 1252 (s), 839 (m) cm–1. 1H NMR
(m), 1448 (s), 1402 (s), 1370 (s), 1323 (m), 1291 (m) cm–1. 1H NMR
(600 MHz, CDCl3): δ = 8.85 (br. s, 1 H, NH), 7.59–7.56 (m, 2 H, (600 MHz, CDCl3): δ = 3.82–3.78 (m, 1 H, cHex), 2.37, 2.14, 2.07
2546
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2542–2547

Straightforward Access to (Imidazol-2-yl)acetates
ies – presented at the 16th European Symposium on Organic
Chemistry, July 12–16, 2009, Prague, Czech Republic, P1.228.
[6] R. Loska, M. Ma˛kosza, Chem. Eur. J. 2008, 14, 2577–2589.
(3ϫ s, 9 H, 3ϫ CH3), 1.90–1.82 (m, 6 H, cHex), 1.74–1.72 (m, 1
H, cHex), 1.40–1.32 (m, 2 H, cHex), 1.24–1.15 (m, 1 H, cHex) ppm.
13C NMR (150 MHz, CDCl3): δ = 142.2, 132.0, 121.9 [3ϫ s, 3 ϫ
C(imidazole)], 56.7 (d, CH, cHex), 32.4, 26.7, 25.7 (3ϫ d, 5ϫ CH2,
cHex), 15.6, 10.3, 9.5 (3ϫ q, 3ϫ CH3) ppm. HRMS (ESI): calcd.
for C12H21N2 [M + 1]+ 193.16993; found 193.16988.
[7] a) S. Takahashi, H. Kano, Chem. Pharm. Bull. 1964, 12, 1290–
¯
1295; b) S. Takahashi, H. Kano, J. Org. Chem. 1965, 30, 1118–
¯
1122.
[8] I. J. Ferguson, K. Schofield, J. Chem. Soc. Perkin Trans. 1 1975,
275–277.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of all new imidazole-2-ylacetates 6.
[9] a) M. Jasin´ski, G. Mloston´, Collect. Czech. Chem. Commun.
2010, 75, 871–885; b) M. Jasin´ski, G. Mloston´, A. Linden, H.
Heimgartner, Helv. Chim. Acta 2008, 91, 1916–1933.
[10] I. R. Corrêa Jr., P. J. S. Moran, Tetrahedron 1999, 55, 14221–
14232.
[11] D. Rygielska, Diploma Thesis, University of Lodz, 2010; G.
Mloston´, M. Jasin´ski, D. Rygielska, H. Heimgartner, Heterocy-
cles 2011, 83, DOI: ϽdoiϾ10.3987/COM-10-12130Ͻ/doiϾ.
[12] a) R. Scholl, W. Egerer, Justus Liebigs Ann. Chem. 1913, 397,
301–366; b) E. Vedejs, M. Gingras, J. Am. Chem. Soc. 1994,
116, 579–588.
Acknowledgments
The authors thank PD Dr. L. Bigler, University of Zürich, for ESI-
HRMS. The help by Dr. R. Zimmer (Freie Universität Berlin) in
the MW-assisted synthesis is acknowledged. Financial support by
the Rector of University of Lodz (grant number 505/712/R) is ac-
knowledged.
[13] R. C. F. Jones, M. W. Anderson, M. J. Smallridge, Tetrahedron
Lett. 1988, 39, 5001–5004.
[14] a) A. A. Macco, E. F. Godefroi, J. J. M. Drouen, J. Org. Chem.
1975, 40, 252–255; b) G. Marciniak, D. Decolin, G. Leclerc, N.
Decker, J. Schwartz, J. Med. Chem. 1988, 31, 2289–2296; c)
L. I. Kruse, C. Kaiser, W. E. DeWolf, J. A. Finkelstein, J. S.
Frazee, E. L. Hilbert, S. T. Ross, K. E. Flaim, J. L. Sawyer, J.
Med. Chem. 1990, 33, 781–789; d) J. Crawforth, J. R. Atack,
S. M. Cook, K. R. Gibson, A. Nadin, A. P. Owens, A. Pike,
M. Rowley, A. J. Smith, B. Sohal, F. Sternfeld, K. Wafford,
L. J. Street, Bioorg. Med. Chem. Lett. 2004, 14, 1679–1682; e)
A. S. Kiselyov, Tetrahedron Lett. 2006, 47, 2941–2944; f) P. C.
Chua, J. Y. Nagasawa, F. Pierre, M. K. Schwaebe, A. Vialettes,
J. P. Whitten, Tetrahedron Lett. 2008, 49, 4437–4442.
[1] a) G. Mloston´, T. Gendek, H. Heimgartner, Helv. Chim. Acta
1998, 81, 1585–1595; b) G. Mloston´, T. Gendek, H.
Heimgartner, Tetrahedron 2000, 56, 5405–5412; c) G. Mloston´,
M. Celeda, G. K. S. Prakash, G. A. Olah, H. Heimgartner,
Helv. Chim. Acta 2000, 83, 728–738; d) G. Mloston´, M. Jasin´-
ski, A. Linden, H. Heimgartner, Helv. Chim. Acta 2006, 89,
1304–1316; e) R. C. F. Jones, J. N. Martin, P. Smith, T. Gel-
brich, M. E. Light, M. B. Hursthouse, Chem. Commun. 2000,
1949–1950; f) N. Cos¸kun, M. Çetin, Tetrahedron 2010, 66,
2053–2060.
[2] G. Mloston´, J. Roman´ski, M. Jasin´ski, H. Heimgartner, Tetra- [15] a) G. Cerioni, M. T. Cocco, C. Congiu, A. Maccioni, J. Hetero-
hedron: Asymmetry 2009, 20, 1073–1080.
cycl. Chem. 1981, 18, 1379–1382; b) H.-H. Lau, U. Schöllkopf,
Liebigs Ann. Chem. 1982, 2093–2095; c) E. Toja, P. Ferrari, G.
Tarzia, Heterocycles 1987, 26, 2129–2138; d) A. M. Moezzi, A.
Ghanbarpour, A. Shafiee, J. Heterocycl. Chem. 1996, 33, 2041–
2042; e) C. A. Ramsden, B. J. Sargent, C. D. Wallett, Tetrahe-
dron Lett. 1996, 37, 1901–1904; f) J. D. Ha, S. J. Lee, S. Y. Nam,
S. K. Kang, S. Y. Cho, J. H. Ahn, J.-K. Choi, Tetrahedron Lett.
2006, 47, 6201–6204; g) T. Horneff, S. Chuprakov, N. Cher-
nyak, V. Gevorgyan, V. V. Fokin, J. Am. Chem. Soc. 2008, 130,
14972–14974.
[3] a) M. Jasin´ski, G. Mloston´, P. Mucha, A. Linden, H.
Heimgartner, Helv. Chim. Acta 2007, 90, 1765–1780; b) P. Mu-
cha, G. Mloston´, M. Jasin´ski, A. Linden, H. Heimgartner, Tet-
rahedron: Asymmetry 2008, 19, 1600–1607.
[4] P. Kwiatkowski, P. Mucha, G. Mloston´, J. Jurczak, Synlett
2009, 1757–1760.
[5] a) M. Jasin´ski, G. Mloston´, H. Heimgartner, J. Heterocycl.
Chem. 2010, 47, 1287–1293; b) M. Jasin´ski, G. Mloston´, W.
Strzelczyk, P. Sobieszczyk, M. Palusiak, A. Palusiak, Remark-
able stability of N-oxides derived from imidazole-4-carboxam-
ides; Synthesis, structural analysis and microbiological stud-
Received: November 25, 2010
Published Online: March 16, 2011
Eur. J. Org. Chem. 2011, 2542–2547
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2547