One-pot synthesis of imidazole-4-carboxylates by microwave-assisted 1,5-electrocyclization of azavinyl azomethine ylides

Article abstract of DOI:10.1002/ejoc.201000434

Diversely functionalized imidazole-4-carboxylates were synthesized by microwave-assisted 1,5-eletrocyclization of 1,2diaza-l,3-diene-derived azavinyl azomethine ylides. 1,2-Diaza-1,3-dienes were treated with primary aliphatic or aromatic amines and subjected to microwave irradiation in the presence of aldehydes. 3-Alkyl- and 3-arylimidazole-4-carboxylates were prepared in good yields through a one-pot multicomponent procedure. Modulation of the substituents at C-2, N-3, and C-5 was possible, and 2-unsubstituted imidazoles were obtained when paraformaldehyde was used.

Full text of DOI:10.1002/ejoc.201000434

FULL PAPER
DOI: 10.1002/ejoc.201000434
One-Pot Synthesis of Imidazole-4-Carboxylates by Microwave-Assisted
1,5-Electrocyclization of Azavinyl Azomethine Ylides
Lisa Preti,[a] Orazio A. Attanasi,[b] Emilia Caselli,[a] Gianfranco Favi,[b] Claudia Ori,[a]
Paolo Davoli,[a] Fulvia Felluga,[c] and Fabio Prati*[a]
Keywords: Azomethine ylides / Electrocyclic reactions / Microwave chemistry / Multicomponent reactions / Nitrogen
heterocycles
Diversely functionalized imidazole-4-carboxylates were syn-
thesized by microwave-assisted 1,5-eletrocyclization of 1,2-
diaza-1,3-diene-derived azavinyl azomethine ylides. 1,2-Di-
presence of aldehydes. 3-Alkyl- and 3-arylimidazole-4-carb-
oxylates were prepared in good yields through a one-pot
multicomponent procedure. Modulation of the substituents
aza-1,3-dienes were treated with primary aliphatic or aro- at C-2, N-3, and C-5 was possible, and 2-unsubstituted imid-
matic amines and subjected to microwave irradiation in the
azoles were obtained when paraformaldehyde was used.
imidazole-4-carboxylates in a one-pot fashion without the
need of isolating reaction intermediates. Initial attempts
with α-aminohydrazones under the same reactions condi-
tions[5,6] did provide the desired imidazole-4-carboxylates in
very modest yields. Because charged chemical species or in-
termediates are well known to benefit from microwave irra-
diation, as in the case of 1,3-dipolar cycloadditions,[3] we
reasoned that our 1,5-electrocyclization of DD-derived aza-
vinyl azomethine ylides could be likewise enhanced by em-
ploying microwave heating.
Introduction
The field of organic synthesis has witnessed a dramatic
surge in the application of microwave irradiation as an al-
ternative to conventional heating. In most cases, microwave
heating has resulted in drastic reduction of reaction times,
improvement of workup procedures, and, ultimately, in-
creased product yields in comparison to classical heating.[1]
To date, microwave irradiation has been applied successfully
to a broad array of reaction types[1] and has become a stan-
dard tool in organic synthesis. Microwave-enhanced cyclo-
additions have also been reported,[2] including [3 + 2] cyclo-
additions of azomethine ylides.[3]
Results and Discussion
Recently, we reported the successful synthesis of α-imid-
azol-1-yl esters through 1,5-electrocyclization of azavinyl
DDs 1a and 1b were treated with the appropriate amine
azomethine ylides that were ultimately derived from 1,2-di- in acetonitrile at room temperature until complete decol-
aza-1,3-dienes (henceforth DDs)[4] and aziridines[5] or by se- oration of the solution occurred. In the case of DD 1a, the
quential reaction with α-aminoesters and aldehydes.[6] In compound was freshly prepared from the parent chloro-
particular, conjugated azavinyl azomethine ylides were gen- hydrazone by preliminary treatment with triethylamine in
erated by heating DD-derived α-aminoester hydrazones in acetonitrile at room temperature and then used as such
toluene at reflux in the presence of aldehydes, and they were without further purification for the following reaction. Sub-
found to undergo an original 1,5-electrocyclization into sequent treatment with paraformaldehyde in a sealed vessel
imidazoles.[5,6] To follow up our work, we envisioned replac- under microwave irradiation at 150 °C for 20 min afforded
ing α-aminoesters with primary aliphatic or aromatic 2-unsubstituted 3H-imidazole-4-carboxylates 2a–i generally
amines, which would allow more general access to simpler in good yields (Table 1), with the exception of 2f (Table 1,
Entries 11 and 12), most presumably due to partial loss of
[a] Dipartimento di Chimica, Università degli Studi di Modena e the tert-butyl substituent at the nitrogen atom under the
Reggio Emilia,
reaction conditions employed. Yields with DD 1b were gen-
Via Campi 183, 41100 Modena, Italy
erally comparable to those with in situ generated 1a. Ali-
phatic and aromatic amines (Table 1, Entries 1–14 and 15–
18, respectively) performed equally well. When (R)-α-phen-
ylethylamine was used (Table 1, Entries 7 and 8), enantio-
merically pure imidazole 2d was recovered (Ͼ95%ee).
Using microwave irradiation, the reaction resulted in higher
yields and shorter reaction times than with conventional
Fax: +39-059-373543
E-mail: fabio.prati@unimore.it
[b] Istituto di Chimica Organica, Università degli Studi di Urbino
“Carlo Bo”,
Via I Maggetti 24, 61029 Urbino, Italy
[c] Dipartimento di Scienze Chimiche, Università di Trieste,
Via L. Giorgieri 1, 34127 Trieste, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000434.
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One-Pot Synthesis of Imidazole-4-Carboxylates
heating, that is, heating at reflux in toluene. In particular, generated 1a with benzylamine in acetonitrile at room tem-
yields for imidazoles 2a and 2e were in the 51–55% range perature and subsequent microwave heating in the presence
under classical conditions, but rose to 71–77% when micro- of aliphatic or aromatic aldehydes under the same reaction
wave heating was employed.
conditions afforded 2-substituted 3-benzyl imidazole-4-carb-
oxylates 2j–o in moderate to good yields (Table 2). In the
Table 1. One-pot synthesis of 2-unsubstituted 3H-imidazole-4- case of butanal and phenylacetaldehyde, yields were excel-
carboxylates 2a–i.
lent with in situ prepared 1a (Table 2, Entries 1 and 4), but
dropped when DD 1b was used (Table 2, Entries 2 and 5).
When butanal was replaced with its dimethyl acetal, imid-
azole 2j was still obtained, albeit in lower yield (Table 2,
Entry 3). Yields were only moderate with benzaldehyde,
Table 2. One-pot synthesis of 2-substituted 3-benzyl-3H-imidazole-
4-carboxylates 2j–o.
[a] Isolated yield (after silica gel chromatography) based on starting
material, viz. DD 1b or the corresponding chlorohydrazone in the
case of 1a. [b] DD 1a was prepared in situ from the parent chloro-
hydrazone and used without further purification.
[a] Isolated yield (after silica gel chromatography) based on starting
Encouraged by the success with paraformaldehyde, we
material, viz. DD 1b or the corresponding chlorohydrazone in the
sought to extend the scope of this one-pot protocol by vary-
case of 1a. [b] DD 1a was prepared in situ from the parent chloro-
ing the aldehyde partner. Treatment of DD 1b and in situ hydrazone and used without further purification.
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F. Prati et al.
FULL PAPER
either by using 1a or 1b as the starting material (Table 2, ferent functionalities at C-2 and N-3, respectively, modula-
Entries 10 and 11). tion of the substituent at C-5 required the use of an appro-
When benzylamine and either paraformaldehyde or but- priate DD as the starting material. Therefore, additional
anal were added simultaneously, rather than sequentially, to DDs 1c–f were allowed to react with benzylamine or allyl-
freshly formed DD 1a, and the resulting solution was sub- amine in the presence of paraformaldehyde under the same
jected immediately to microwave irradiation, imidazoles 2a conditions. 5-Alkyl and 5-arylimidazole-4-carboxylates 2p–
or 2j were isolated in 71 and 70% yield, respectively. Strictly w were isolated in moderate to good yields (Table 3). In
speaking, therefore, the whole process displays multicompo- particular, yields were higher for imidazoles 2p–s having an
nent character, as all reagents can be mixed at the same ethyl or a propyl side chain (Table 3, Entries 1–4), whereas
time without affecting the reaction outcome and, import- DD 1f gave 5-phenylimidazoles 2v and 2w only in moderate
antly, with comparable overall yields.
yields (Table 3, Entries 7 and 8). Use of benzylamine or al-
Whilst simple variations of the aldehyde or amine part- lylamine always resulted in comparable yields, except for
ners allowed access to imidazole 4-carboxylates with dif- DD 1e, which afforded the corresponding 5-methoxy-
carbonylmethylimidazoles in good yield only for the latter
(Table 3, Entries 5 and 6).
A rationale mechanism for the formation of imidazole-
4-carboxylates 2a–w is depicted in Scheme 1. Michael-type
1,4-conjugate addition of DDs 1a–f (either as an isolated
compound or in situ generated from the corresponding
chlorohydrazone by treatment with TEA in the case of 1a,c)
with the primary amine gives α-aminohydrazone A,[4e]
which in turn condenses with the aldehyde partner to yield
iminium ion B. Microwave-assisted heating may result in
the formation of conjugated azavinyl azomethine ylide[7,8]
C, which undergoes 1,5-electrocyclization to 2,3-dehydro-
imidazole-4-carboxylate D and, eventually, aromatization
with loss of carbamate or urea, thus affording the desired
3H-imidazole-4-carboxylates 2a–w, by analogy to the for-
mation of DD-derived α-imidazol-1-yl esters we have re-
cently disclosed.[5,6]
Table 3. One-pot synthesis of 2-unsubstituted 3H-imidazole-4-
carboxylates 2p–w using benzylamine or allylamine.
[a] Isolated yield (after silica gel chromatography) based on starting
material, viz. DD 1d–f or the corresponding chlorohydrazone in
the case of 1c. [b] DD 1c was prepared in situ from the parent
chlorohydrazone and used without further purification.
Scheme 1. Postulated mechanism for the formation of imidazole-4-
carboxylates 2a–w from DDs 1a–f.
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One-Pot Synthesis of Imidazole-4-Carboxylates
to the procedure described below. Amines and aldehydes were pur-
chased from Sigma–Aldrich and used as received, except for thio-
phen-2-yl-acetaldehyde, phenoxyacetaldehyde, and 2-phenoxypro-
panal (used for the synthesis of imidazole-4-carboxylates 2l, 2m
and 2n, respectively), which were prepared by reduction of the par-
ent methyl ester with DIBALH by analogy to a literature pro-
cedure[13] (see the Supporting Information). Chromatographic puri-
fication of compounds was performed on silica gel (60–200 µm) by
using the appropriate eluant as specified; commercial-grade light
petroleum ether/ethyl acetate mixtures were used for such purpose.
Microwave irradiation has been already employed for the
preparation of aryl or alkyl 2,4,5-trisubstituted and 1,2,4,5-
tetrasubstituted imidazoles.[9,10] In particular, a three-com-
ponent reaction between 1,2-diketones and aldehydes in the
presence of ammonium acetate was used for the synthesis of
2,4,5-triaryl- and 2,4,5-trialkylimidazoles,[9] whereas a four-
component variant that also included aliphatic or aromatic
amines gave 1,2,4,5-tetrasubstituted imidazoles.[9b,9c,9i,10] In
most of these cases, however, the resulting imidazole prod-
ucts displayed a rather low degree of functionalization that Preloaded (0.25 mm) glass supported silica gel plates (Kieselgel 60,
Merck) were used for TLC analysis, and compounds were visual-
ized by exposure to UV light and by dipping the plates in 1%
Ce(SO4)·4H2O, 2.5% (NH4)6Mo7O24·4H2O in 10% sulfuric acid
followed by heating on a hot plate. Melting points were determined
in open capillary tubes. 1H and 13C NMR spectra were recorded in
CDCl3 solution at 25 °C with Bruker 200 or 400 MHz instruments.
Multiplicity is given as s = singlet, d = doublet, t = triplet, q =
quartet, sext. = sextet, m = multiplet, and br. = broad signal, and
chemical shifts (δ) are reported in ppm downfield from tetramethyl-
silane as internal standard. Coupling constants (3JH,H) are given in
Hz. COSY, HSQC, and HMBC experiments were performed to aid
in the assignment of 1H and 13C resonances. Mass spectra were
recorded in the EI mode (70 eV). For elemental analyses, a Carlo
Erba Elemental Analyzer (model 1110) was used. The enantiomeric
excess (ee) of imidazole 2d was determined by chiral HPLC analysis
precludes further chemistries. The present method, by con-
trast, allows the preparation of functionalized imidazoles
whose substituents are amenable to subsequent manipula-
tions, especially in the framework of target-driven multistep
syntheses.
Conclusions
We have reported a significant extension of the 1,5-elec-
trocyclization of conjugated azavinyl azomethine ylides[5,6]
to substituted imidazole-4-carboxylates by one-pot sequen-
tial reaction between DDs and primary amines, followed by
microwave-assisted heating in the presence of aldehydes.
The method is efficient and straightforward and does not
require isolation of intermediates. Moreover, appropriate
choice of the amine, aldehyde, and DD partners makes pos-
sible the modulation of substituents at the N-3, C-2, and
C-5 atoms of the final product, respectively. Noteworthy is
that the reaction can be also performed in a multicompo-
nent fashion by simply mixing the three partners at room
temperature and subjecting them to microwave irradiation.
Such a one-pot multicomponent approach is most flexible
and useful for the synthesis of functionalized imidazole-4-
carboxylates starting from readily available materials such
as aliphatic or aromatic primary amines and aldehydes and
nicely adds to the variety of available methods to access the
biologically important and pharmaceutically relevant imid-
azole skeleton.[11]
(Jasco PU-980) by using
a Lux Cellulose-1 column (5 µm;
250ϫ4.6 mm; Phenomenex, Torrance, CA, US). The mobile phase
consisted of n-hexane/2-propanol (9:1) under isocratic elution at a
flow rate of 0.7 mLmin–1 at 20 °C; samples were dissolved in n-
hexane/2-propanol (1:1) and the injection volume was 20 µL. De-
tection was performed at 254 nm by using a variable wavelength
detector (Jasco UV-1575). Accuracy was within Ϯ5%.
Procedure for the Synthesis of DDs 1c–e: Commercially available
methyl 2-chloro-3-oxopentanoate (5 mmol) or freshly prepared (see
below) ethyl 2-chloro-3-oxohexanoate (5 mmol), or dimethyl 2-
chloro-3-oxopentanedioate (5 mmol) was added to a magnetically
stirred solution of semicarbazide hydrochloride (5 mmol, pre-
treated with an equimolecular amount of sodium acetate) or methyl
carbazate (5 mmol) in tetrahydrofuran (50 mL, 1c) or methanol
(50 mL, 1d,e). The reaction was magnetically stirred at room tem-
perature until the disappearance of the reagents (TLC). The reac-
tion solvent was evaporated under reduced pressure, the crude α-
chlorohydrazone was dissolved in ethyl acetate and washed with an
aqueous saturated solution of sodium carbonate (2ϫ50 mL) and
with an aqueous solution of sodium hydroxide (1%, 1ϫ50 mL,
only for 1c,d). Ethyl acetate was removed under reduced pressure,
and the crude residue was purified by chromatography on silica gel
column to afford DDs 1c–e.
Experimental Section
General Methods: Microwave-assisted reactions were performed in
sealed glass vials by using a temperature- and pressure-controlled
single-mode microwave reactor (CEM, Discover LabMate)
equipped with a 300 W power source. Temperature and pressure
were set at 150 °C and 150 psi, respectively, power source at 150 W.
Such values were reached within 5 min and were maintained for
further 20 min by IR sensor thermal control and pressure feedback
control. Commercial-grade acetonitrile was used without further
purification as reaction solvent. 1,2-Diaza-1,3-dienes (DDs) 1a,b
were synthesized as already described and occur both as a mixture
of E/Z isomers.[12] Whereas DD 1b is a shelf-stable red crystalline
compound,[12b] DD 1a[12a] is a somewhat unstable red liquid that
tends to decompose upon prolonged storage. Therefore, 1a was al-
ways generated in situ by treatment of the parent chlorohydrazone
with triethylamine in acetonitrile at room temperature, and the re-
sulting red solution was used as such for the subsequent chemistry
without further purification. DDs 1c–f were synthesized according
Ethyl 2-Chloro-3-oxohexanoate or Dimethyl 2-Chloro-3-oxopentane-
dioate: As required for the synthesis of DDs 1d,e, the compound
was prepared from the parent ethyl 3-oxohexanoate (5 mmol) or
dimethyl 3-oxopentanedioate (5 mmol) by chlorination with sulfur-
yl chloride (SO2Cl2, 5.5 mmol.). The reaction was performed in
dichloromethane (10 mL) at room temperature under magnetic stir-
ring for 15–30 min (monitored by TLC and/or 1H NMR spec-
troscopy). Thereafter, the reaction mixture was washed with brine
(5ϫ30 mL), dried (MgSO4), filtered, and concentrated under re-
duced pressure to afford the desired α-chlorohydrazone as a color-
less oil.
Procedure for the Synthesis of DD 1f: Ethyl 3 oxo-3-phenylpropano-
ate (5 mmol) was treated with tert-butyl carbazate (5 mmol,
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F. Prati et al.
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1 equiv.) and a catalytic amount of p-toluenesulfonic acid in a mini-
mum amount of tetrahydrofuran (5 mL). The reaction mixture was
allowed to react at room temperature for 48 h. The desired hydraz-
one separated as a white solid, which was recovered by filtration
and washed with light petroleum ether. The hydrazone was then
dissolved in dichloromethane and sulfuryl chloride (1.1 equiv.) was
added at room temperature, and the resulting solution was allowed
to react for 30 min under magnetic stirring. Thereafter, the reaction
mixture was washed with brine (5ϫ30 mL), and the organic layer
was dried with magnesium sulfate, filtered, and concentrated under
reduced pressure to give α-chlorohydrazone as a pale-yellow oil.
Finally, addition of N,N-diisopropylethylamine (1.0 equiv.) to a
magnetically stirred solution of the α-chlorohydrazone in a mini-
mum amount of dichloromethane at room temperature for 5 min
assisted to the 1,2-diaza-1,3-diene formation. The resulting red-
orange solution was directly purified by column chromatography
(cyclohexane/ethyl acetate, 90:10) to give DD 1f as a somewhat
unstable red liquid that tends to decompose upon storage.
[C(CH3)3], 60.9 (OCH2CH3), 27.7 [(CH3)3], 13.8 (CH3) ppm. MS
(EI): m/z (%) = 176 (27), 21(16), 131 (100), 103 (64), 77 (30).
C16H20N2O4 (304.14): calcd. C 63.14, H 6.62, N 9.20; found C
63.01, H 6.85, N 9.04.
Typical Procedure for the Synthesis of Imidazole-4-carboxylates
from DDs 1a,c (Method A): Ethyl 2-chloro-3-(ethoxycarbonyl-
hydrazono)butanoate[12] (0.6 mmol) or methyl 2-chloro-3-(meth-
oxycarbonylhydrazono)pentanoate (0.6 mmol) was dissolved in
acetonitrile (2 mL) in a microwave glass vial and treated with TEA
(84 µL, 0.6 mmol) at room temperature under magnetic stirring to
give a red solution. The primary amine (0.63 mmol) was added,
and the resulting solution was stirred until complete decoloration
of the solution, whereupon the aldehyde (1.2 mmol) was added.
The vessel containing the pale-yellow mixture was then sealed and
heated under microwave irradiation at 150 °C for 20 min. After re-
moval of the solvent in vacuo, purification by column chromatog-
raphy afforded the desired imidazole.
Typical Procedure for the Synthesis of Imidazole-4-carboxylates
from DDs 1b,d–f (Method B): A solution of DD 1b,[12b]d–f
(0.54 mmol) in acetonitrile (2 mL) in a microwave glass vial
equipped with a stir bar was treated with the amine (0.57 mmol) at
room temperature until complete decoloration of the solution. The
aldehyde (1.08 mmol) was added, and the vessel with the resulting
light-yellow mixture was sealed and heated under microwave irradi-
ation at 150 °C for 20 min. The solvent was evaporated under re-
duced pressure, and the crude residue was purified by column
chromatography to yield the desired imidazole-4-carboxylate.
4-Methoxycarbonyl-3-ethyl-1-metoxycarbonyl-1,2-diaza-1,3-diene
(1c): DD 1c was isolated (540 mg, 54%) by column chromatog-
raphy (cyclohexane/ethyl acetate, 90:10). 1H NMR (400 MHz,
CDCl3): δ = 6.84 (s, 1 H, CH), 4.03 (s, 3 H, OCH3), 3.83 (s, 3 H,
OCH3), 2.83 (q, J = 7.6 Hz, 2 H, CH2CH3), 1.01 (t, J = 7.6 Hz, 3
H, CH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.4
(CO2CH3), 165.7 (NCO2CH3), 162.7 (C-3), 131.1 (C-4), 54.9
(OCH3), 52.0 (OCH3), 17.7 (CH2), 12.2 (CH3) ppm. MS (EI): m/z
(%) = 200 (1) [M]+, 167 (2), 149 (5), 125 (10), 111 (22), 97 (38), 83
(39), 69 (60), 57 (100). C8H12N2O4 (200.08): calcd. C 48.00, H 6.04,
N 13.99; found C 47.81, H 6.31, N 14.23.
Ethyl 3-Benzyl-5-methyl-3H-imidazole-4-carboxylate (2a): Imid-
azole 2a was isolated (method A: 114 mg, 78%; method B: 101 mg,
77%) by column chromatography (light petroleum ether/ethyl acet-
ate, 50:50) as a pale-yellow solid, m.p. 54–56 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.72 (s, 1 H, 2-H), 7.33 (m, 3 H, 3Ј-H, 4ЈH,
5Ј-H), 7.18 (m, 2 H, 2Ј-H, 6Ј-H), 5.52 (s, 2 H, CH2Ph), 4.30 (q, J
= 7.1 Hz, 2 H, CH3CH2O), 2.56 (s, 3 H, CH3C), 1.34 (t, J = 7.1 Hz,
3 H, CH3CH2O) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.7
(C=O), 147.6 (C-5), 140.0 (C-2), 136.3 (C-1Ј), 128. 9 (C-3Ј, C-5Ј),
128.1 (C-4Ј), 127.2 (C-2Ј, C-6Ј), 118.8 (C-4), 60.5 (CH3CH2O), 50.9
(CH2Ph), 15.6 (CH3), 14.2 (CH3CH2O) ppm. MS (EI): m/z (%) =
244 (14) [M]+, 198 (12), 109 (8), 91 (100), 65 (10). C14H16N2O2
(244.12): calcd. C 68.83, H 6.60, N 11.47; found C 70.12, H 6.92,
N 11.79.
4-Ethoxycarbonyl-3-propyl-1-aminocarbonyl-1,2-diaza-1,3-diene
(1d): DD 1d was isolated (499 mg, 47%) by column chromatog-
raphy (cyclohexane/ethyl acetate, 65:35). 1H NMR (400 MHz,
CDCl3): δ = 6.87 (s, 1 H, CH), 6.23 and 6.02 (br., 2 H, NH2),
4.29 (q, J = 7.2 Hz, 2 H, CH3CH2O), 2.85 (t, J = 7.6 Hz, 2 H,
CH2CH2CH3), 1.43 (sext., J = 7.6 Hz, 2 H, CH2CH2CH3), 1.37 (t,
J = 7.6 Hz, 3 H, CH2CH2CH3), 0.91 (t, J = 7.2 Hz, 3 H,
CH3CH2O) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.4
(CO2CH2CH3), 165.4 (NCO2NH2), 161.1 (C-3), 132.1 (C-4), 61.1
(OCH2CH3), 26.3 (CH2CH2CH3), 21.3 (CH2CH2CH3), 14.1 (2
CH3) ppm. MS (EI): m/z (%) = 170 (3), 141 (27), 125 (72), 113
(50), 99 (60), 85 (24), 67 (66), 55 (100). C9H15N3O3 (213.11): calcd.
C 50.69, H 7.09, N 19.71; found C 50.47, H 7.33, N 19.63.
Ethyl 3-Allyl-5-methyl-3H-imidazole-4-carboxylate (2b): Imidazole
2b was isolated (method A: 100 mg, 86%; method B: 65 mg, 62%)
by column chromatography (light petroleum/ethyl acetate, 50:50)
4-Methoxycarbonyl-3-(2-methoxy-2-oxoethyl)-1-aminocarbonyl-1,2-
diaza-1,3-diene (1e): DD 1e was isolated (492 mg, 43%) by column
chromatography (cyclohexane/ethyl acetate, 40:60). 1H NMR
(400 MHz, CDCl3): δ = 7.21 (s, 1 H, CH), 6.28 and 6.02 (br., 2 H,
NH2), 4.03 (s, 3 H, CH3O), 3.86 (s, 3 H, CH3O), 3.66 (s, 2 H,
CH2CO2Me) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.1
(CH2CO2CH3), 165.5 (CO2CH3), 161.2 (NCO2NH2), 158.9 (C-3),
135.2 (C-4), 52.3 (2 OCH3), 30.4 (CH2) ppm. MS (EI): m/z (%) =
155 (68), 126 (56), 98 (100), 85 (70), 68 (58), 59 (100). C8H11N3O5
(229.07): calcd. C 41.92, H 4.84, N 18.33; found C 42.07, H 4.67,
N 18.09.
1
as a yellow liquid. H NMR (400 MHz, CDCl3): δ = 7.48 (s, 1 H,
2-H), 5.93 (ddt, J = 17.1, 10.3, 5.5 Hz, 1 H, CH2CH), 5.14 (ddd, J
= 10.3, 2.6, 1.2 Hz, 1 H, Hcis), 5.01 (ddd, J = 17.1, 2.6, 1.6 Hz, 1
H, Htrans), 4.82 (dt, J = 5.5, 1.4 Hz, 2 H, NCH2), 4.26 (q, J =
7.1 Hz, 2 H, CH3CH2O), 2.44 (s, 3 H, CH3C), 1.31 (t, J = 7.1 Hz,
3 H, CH3CH2O) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.9
(C=O), 148.0 (C-5), 139.9 (C-2), 133.3 (NCH2CH), 118.5 (C-4),
117.7 (CHCH2), 60.3 (CH3CH2O), 49.4 (CH2N), 15.8 (CH3C), 14.3
(CH3CH2O) ppm. MS (EI): m/z (%) = 194 (68) [M]+, 165 (58), 149
(67), 121 (78), 109 (33), 94 (25), 80 (21), 67 (24), 54 (22), 41 (100).
C10H14N2O2 (194.11): calcd. C 61.84, H 7.27, N 14.42; found C
62.09, H 7.07, N 14.71.
4-Ethoxycarbonyl-3-phenyl-1-tert-butoxycarbonyl-1,2-diaza-1,3-
diene (1f): DD 1f was isolated (851 mg, 56 %) by column
chromatography (cyclohexane/ethyl acetate, 90:10). 1H NMR
(400 MHz, CDCl3): δ = 7.42–7.37 (m, 3 H, CHAr), 7.24–7.20 (m,
2 H, CHAr), 6.92 (s, 1 H, CH), 4.11 (q, J = 7.2 Hz, 2 H,
OCH2CH3), 1.59 [s, 9 H, (CH3)3], 1.12 (t, J = 7.2 Hz, 3 H,
OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.8
(CO2CH2CH3), 163.0 (NCO2tBu), 161.2 (C-3), 134.2 (CHAr),
130.4 (C-4), 129.4 (CHAr), 129.0 (CHAr), 127.8 (CHAr), 85.6
Ethyl 5-Methyl-3-prop-2-ynyl-3H-imidazole-4-carboxylate (2c):
Imidazole 2c was isolated (method A: 96 mg, 83 %; method B:
64 mg, 62%) by column chromatography (light petroleum ether/
ethyl acetate, 70:30) as a pale-yellow solid, m.p. 56–58 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.51 (s, 1 H, 2-H), 4.82 (d, J = 2.5 Hz, 2 H,
NCH2), 4.10 (q, J = 7.1 Hz, 2 H, CH3CH2O), 2.27 (t, J = 2.5 Hz, 1
4316
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4312–4320

One-Pot Synthesis of Imidazole-4-Carboxylates
H, CϵCH), 2.24 (s, 3 H, CH3C), 1.14 (t, J = 7.1 Hz, 3 H,
60.8 (CH3CH2O), 55.6 (CH3O), 53.3 (CH2CO), 14.9 (CH3C), 14.2
CH3CH2O) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.00 (C=O), (CH3CH2O) ppm. MS (EI): m/z (%) = 302 (3) [M]+, 135 (100), 92
148.6 (C-5), 139.6 (C-2), 118.4 (C-4), 76.8 (CϵCH), 74.9 (CϵCH), (7), 77 (11). C16H18N2O4 (302.13): calcd. C 63.56, H 6.00, N 9.27;
60.5 (CH3CH2O), 37.1 (NCH2), 15.8 (CH3C), 14.3 (CH3CH2O) found C 63.66, H 6.25, N 9.50.
ppm. MS (EI): m/z (%) = 192 (19) [M]+, 163 (100), 147 (28), 136
Ethyl 5-Methyl-3-phenyl-3H-imidazole-4-carboxylate (2h): Imid-
(20), 119 (11), 109 (29), 92 (13), 65 (17), 52 (16), 39 (55).
azole 2h was isolated (method A: 111 mg, 80%; method B: 39 mg,
C10H12N2O2 (192.09): calcd. C 62.49, H 6.29, N 14.57; found C
31%) by column chromatography (light petroleum ether/ethyl acet-
62.74, H 6.44, N 14.80.
ate, 50:50) as a pale-yellow solid, m.p. 47–49 °C. 1H NMR
Ethyl (3R)-5-Methyl-3-(1-phenylethyl)-3H-imidazole-4-carboxylate
(2d): Imidazole 2d was isolated (method A: 116 mg, 75 %;
method B: 112 mg, 80%) by column chromatography (light petro-
leum ether/ethyl acetate, 50:50) as a pale-yellow liquid, [α]D = +48.3
(c = 1.5, CH2Cl2), 98%ee (by chiral HPLC analysis). 1H NMR
(400 MHz, CDCl3): δ = 7.63 (s, 1 H, 2-H), 7.44 (m, 3 H, 3Ј-H, 4Ј-
H, 5Ј-H), 7.27 (m, 2 H, 2Ј-H, 6Ј-H), 4.15 (q, J = 7.1 Hz, 2 H,
CH3CH2O), 2.58 (s, 3 H, CH3C), 1.13 (t, J = 7.1 Hz, 3 H,
CH3CH2O) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.1 (C=O),
147.7 (C-5), 140.0 (C-2), 137.1 (C-1Ј), 128.89 (C-3Ј, C-5Ј), 128.86
(400 MHz, CDCl3): δ = 7.66 (s, 1 H, 2-H), 7.25 (m, 3 H, 3Ј-H, 4Ј- (C-4Ј), 126.3 (C-2Ј, C-6Ј), 120.3 (C-4), 60.4 (CH3CH2O), 15.2
H, 5Ј-H), 7.10 (d, J = 7.1 Hz, 2 H, 2Ј-H, 6Ј-H), 6.27 (q, J = 7.1 Hz, (CH3C), 14.0 (CH3CH2O) ppm. MS (EI): m/z (%) = 230 (59)
1 H, NCH), 4.22 (q, J = 7.1 Hz, 1 H, CH3CH), 4.20 (q, J = 7.1 Hz, [M]+, 201 (63), 185 (49), 158 (29), 130 (30), 104 (18), 77 (100), 51
1 H, CH3CH2O), 2.45 (s, 3 H, CH3C), 1.78 (d, J = 7.1 Hz, 3 H, (45). C13H14N2O2 (230.11): calcd. C 67.81, H 6.13, N 12.17; found
CH3CH), 1.26 (t, J = 7.1 Hz, 3 H, CH3CH2O) ppm. 13C NMR C 68.11, H 6.30, N 12.44.
(100 MHz, CDCl3): δ = 160.9 (C=O), 147.8 (C-5), 141.3 (C-1Ј),
Ethyl 3-(4-Dimethylaminophenyl)-5-methyl-3H-imidazole-4-carb-
137.7 (C-2), 128.8 (C-3Ј, C-5Ј), 127.9 (C-4Ј), 126.2 (C-2Ј, C-6Ј),
oxylate (2i): Imidazole 2i was isolated (method A: 125 mg, 76%;
118.8 (C-4), 60.4 (CH3CH2O), 55.9 (NCH), 22.3 (NCHCH3), 15.8
method B: 103 mg, 70%) by column chromatography (petroleum
(CH3C), 14.2 (CH3CH2O) ppm. MS (EI): m/z (%) = 258 (5) [M]+,
ether/ethyl acetate, 50:50) as a pale-brown solid, m.p. 96–98 °C. 1H
154 (8), 105 (100), 77 (15). C15H18N2O2 (258.14): calcd. C 69.74,
NMR (400 MHz, CDCl3): δ = 7.66 (s, 1 H, 2-H), 7.11 (d, J =
H 7.02, N 10.84; found C 70.02, H 7.30, N 11.04.
9.0 Hz, 2 H, 3Ј-H, 5Ј-H), 6.71 (d, J = 9.0 Hz, 2 H, 2Ј-H, 6Ј-H),
Ethyl 3-sec-Butyl-5-methyl-3H-imidazole-4-carboxylate (2e): Imid-
azole 2e was isolated (method A: 105 mg, 83%; method B: 81 mg,
71%) by column chromatography (light petroleum ether/ethyl acet-
ate, 50:50) as a pale-yellow liquid. H NMR (400 MHz, CDCl3): δ
= 7.67 (s, 1 H, 2-H), 5.05 (m, 1 H, CH), 4.30 (q, J = 7.1 Hz, 2 H,
4.19 (q, J = 7.1 Hz, 2 H, CH3CH2O), 3.00 [s, 6 H, N(CH3)2], 2.59
(s, 3 H, CH3C), 1.20 (t, J = 7.1 Hz, 3 H, CH3CH2O) ppm. 13C
NMR (100 MHz, CDCl3): δ = 160.0 (C=O), 150.7 (C-4Ј), 146.0 (C-
5), 139.7 (C-2), 126.9 (C-2Ј, C-6Ј), 125.4 (C-1Ј), 120.7 (C-4), 111.7
(C-3Ј, C-5Ј), 60.5 (CH3CH2O), 40.5 [N(CH3)2], 15.0 (CH3C), 14.1
1
CH3CH2O), 2.47 (s, 3 H, CH3C), 1.77 (m, 2 H, CH3CH2CH), 1.43 (CH3CH2O) ppm. MS (EI): m/z (%) = 273 (100) [M]+, 227 (15),
(d, J = 6.8 Hz, 3 H, CH3CH), 1.35 (t, J = 7.1 Hz, 3 H, CH3CH2O), 200 (29), 173 (17), 159 (38), 147 (70), 132 (31), 121 (40), 113 (17),
0.85 (t, J = 7.4 Hz, 3 H, CH3CH2CH) ppm. 13C NMR (100 MHz,
105 (21), 86 (19), 77 (28), 42 (19). C15H19N3O2 (273.15): calcd. C
CDCl3): δ = 161.2 (C=O), 147.4 (C-5), 136.9 (C-2), 118.6 (C-4), 65.91, H 7.01, N 15.37; found C 66.33, H 7.45, N 15.60.
60.3 (CH3CH2O), 54.0 (CH3CH2CH), 30.6 (CH3CH2CH), 21.2
Ethyl 3-Benzyl-5-methyl-2-propyl-3H-imidazole-4-carboxylate (2j):
(CH3CH), 15.9 (CH3C), 14.3 (CH3CH2O), 10.3 (CH3CH2CH)
Imidazole 2j was isolated (method A: 149 mg, 87% using butanal,
ppm. MS (EI): m/z (%) = 210 (39) [M]+, 181 (8), 165 (14), 154 (17),
84 mg, 49% using 1,1-dimethoxybutane; method B: 57 mg, 37%)
137 (25), 125 (95), 109 (100), 82 (17), 54 (17), 41 (27). C11H18N2O2
by column chromatography (light petroleum ether/ethyl acetate,
(210.14): calcd. C 62.83, H 8.63, N 13.32; found C 63.18, H 8.95,
N 13.56.
1
70:30) as a yellow oil. H NMR (400 MHz, CDCl3): δ = 7.05 (m,
3 H, 3Ј-H, 4Ј-H, 5Ј-H), 6.73 (d, J = 7.2 Hz, 2 H, 2Ј-H, 6Ј-H), 5.29
Ethyl 3-tert-Butyl-5-methyl-3H-imidazole-4-carboxylate (2f): Imid-
azole 2f was isolated (method A: 56 mg, 44%; method B: 57 mg,
50%) by column chromatography (light petroleum ether/ethyl acet-
(s, 2 H, NCH2Ph), 3.99 (q, J = 7.1 Hz, 2 H, CH3CH2O), 2.37 (t, J
= 7.9 Hz, 2 H, CH3CH2CH2), 2.28 (s, 3 H, CH3C), 1.46 (m, J =
7.7 Hz, 2 H, CH3CH2CH2), 1.04 (t, J = 7.1 Hz, 3 H, CH3CH2O),
0.69 (t, J = 7.3 Hz, 3 H, CH3CH2CH2) ppm. 13C NMR (100 MHz,
1
ate, 50:50) as a pale-yellow liquid. H NMR (400 MHz, CDCl3): δ
= 7.73 (s, 1 H, 2-H), 4.30 (q, J = 7.1 Hz, 2 H, CH3CH2O), 2.44 (s, CDCl3): δ = 161.1 (C=O), 152.4 (C-2), 147.1 (C-5), 137.2 (C-1Ј),
3 H, CH3C), 1.68 [s, 9 H, (CH3)3C], 1.36 (t, J = 7.1 Hz, 3 H,
128.7 (C-3Ј, C-5Ј), 127.4 (C-4Ј), 125.8 (C-2Ј, C-6Ј), 118.4 (C-4),
CH3CH2O) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.6 (C=O), 60.1 (CH3CH2O), 48.1 (NCH2), 29.0 (CH3CH2CH2), 21.3
149.1 (C-5), 137.4 (C-2), 120.0 (C-4), 60.6 (CH3CH2O), 58.7 ( CH3 CH2 CH2 ) , 1 5. 8 ( CH3 C ), 14 . 2 (CH3 CH2 O), 13. 9
[(CH3)3C], 30.1 [(CH3)3C], 16.5 (CH3C), 14.3 (CH3CH2O) ppm. (CH3CH2CH2) ppm. MS (EI): m/z (%) = 286 (9) [M]+, 257 (13),
MS (EI): m/z (%) = 210 (10) [M]+, 154 (89), 125 (100), 109 (81), 82
(22), 57 (55), 41 (47). C11H18N2O2 (210.14): calcd. C 62.83, H 8.63,
N 13.32; found C 63.04, H 8.88, N 13.65.
167 (11), 91 (100), 65 (12). C17H22N2O2 (286.17): calcd. C 71.30,
H 7.74, N 9.78; found C 71.67, H 7.90, N 10.02.
Ethyl 2,3-Dibenzyl-5-methyl-3H-imidazole-4-carboxylate (2k):
Ethyl 3-[2-(4-Methoxyphenyl)-2-oxoethyl]-5-methyl-3H-imidazole-4- Imidazole 2k was isolated (method A: 159 mg, 79 %; method B:
carboxylate (2g): Imidazole 2g was isolated (method A: 136 mg, 86 mg, 48%) by column chromatography (light petroleum ether/
75%; method B: 113 mg, 69%) by column chromatography (light ethyl acetate, 70:30) as a yellow oil. H NMR (400 MHz, CDCl3):
petroleum ether/ethyl acetate, 50:50) as a pale-yellow solid, m.p. δ = 7.30–7.19 (m, 6 H, 3Ј-H, 4Ј-H, 5Ј-H, 3ЈЈ-H, 4ЈЈ-H, 5ЈЈ-H), 7.13
116–118 °C. H NMR (400 MHz, CDCl3): δ = 8.11 (s, 1 H, 2-H), (m, 2 H, 2Ј-H, 6Ј-H), 6.89 (m, 2 H, 2ЈЈ-H, 6ЈЈ-H), 5.41 (s, 2 H,
1
1
7.97 (d, J = 8.9 Hz, 3 H, 3Ј-H, 4Ј-H, 5Ј-H), 6.98 (d, J = 8.9 Hz, 2
H, 2Ј-H, 6Ј-H), 5.79 (s, 2 H, CH2CO), 4.22 (q, J = 7.1 Hz, 2 H,
CH3CH2O), 3.88 (s, 3 H, CH3O), 2.57 (s, 3 H, CH3C), 1.25 (t, J =
7.1 Hz, 3 H, CH3CH2O) ppm. 13C NMR (100 MHz, CDCl3): δ =
NCH2Ph), 4.23 (q, J = 7.1 Hz, 2 H, CH3CH2O), 4.06 (s, 2 H,
CCH2Ph), 2.57 (s, 3 H, CH3C), 1.27 (t, J = 7.1 Hz, 3 H, CH3CH2O)
ppm. 13C NMR (400 MHz, CDCl3): δ = 160.8 (C=O), 150.2 (C-2),
146.3 (C-5), 136.6 (C-1ЈЈ), 135.7 (C-1Ј), 128.9 (C-3Ј, C-5Ј), 128.8
189.9 (COCH2), 164.4 (C-4Ј), 160.6 (C=O), 145.4 (C-5), 140.4 (C- (C-3ЈЈ, C-5ЈЈ), 128.4 (C-2Ј, C-6Ј), 127.5 (C-4ЈЈ), 127.1 (C-4Ј), 125.8
2), 130.4 (C-3Ј, C-5Ј), 127.3 (C-1Ј), 119.3 (C-4), 114.2 (C-2Ј, C-6Ј), (C-2ЈЈ, C-6ЈЈ), 119.2 (C-4), 60.4 (CH3CH2O), 48.4 (NCH2Ph), 33.4
Eur. J. Org. Chem. 2010, 4312–4320
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4317

F. Prati et al.
FULL PAPER
(CCH2Ph), 15.6 (CH3C), 14.2 (CH3CH2O) ppm. MS (EI): m/z (%)
= 334 (14) [M]+, 243 (12), 215 (9), 167 (13), 91 (100), 65 (13).
C21H22N2O2 (334.17): calcd. C 75.42, H 6.63, N 8.38; found C
75.60, H 6.77, N 8.61.
7.2 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H), 5.58 (s, 2 H, NCH2Ph), 4.22 (q, J =
7.1 Hz, 2 H, CH3CH2O), 2.61 (s, 3 H, CH3C), 1.24 (t, J = 7.1 Hz,
3 H, CH3CH2O) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.1
(C=O), 151.5 (C-2), 148.2 (C-5), 138.1 (C-1ЈЈ), 134.0 (C-1Ј), 129.9
(C-4Ј), 129.4 (C-2Ј, C-6Ј), 128.82 (C-3Ј, C-5Ј), 128.78 (C-3ЈЈ, C-
5ЈЈ), 127.4 (C-4ЈЈ), 125.8 (C-2ЈЈ, C-6ЈЈ), 119.7 (C-4), 60.4
(CH3CH2O), 49.8 (NCH2), 16.0 (CH3C), 14.3 (CH3CH2O) ppm.
MS (EI): m/z (%) = 320 (12) [M]+, 274 (3), 115 (4), 104 (6), 91
(100), 65 (8). C20H20N2O2 (320.15): calcd. C 74.98, H 6.29, N 8.74;
found C 75.18, H 6.33, N 8.92.
Ethyl 3-Benzyl-5-methyl-2-thiophen-2-ylmethyl-3H-imidazole-4-
carboxylate (2l): Imidazole 2l was isolated (method A: 102 mg,
50%; method B: 74 mg, 40%) by column chromatography (light
petroleum ether/ethyl acetate, 70:30) as a pale-yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.31–7.21 (m, 3 H, 3Ј-H, 4Ј-H, 5Ј-H), 7.14
(dd, J = 5.1, 1.1 Hz, 1 H, 5Ј-H), 6.93 (d, J = 7.0 Hz, 2 H, 2ЈЈ-H,
6ЈЈ-H), 6.88 (dd, J = 5.1, 3.6 Hz, 1 H, 4Ј-H), 6.75 (dd, J = 3.6, Methyl 3-Benzyl-5-ethyl-3H-imidazole-4-carboxylate (2p): Imid-
1.1 Hz, 1 H, 3Ј-H), 5.49 (s, 2 H, NCH2Ph), 4.23 (q, J = 7.1 Hz, 2 azole 2p was isolated (method A: 101 mg, 69 %) by column
H, CH3CH2O), 4.17 (s, 2 H, CCH2-C-2Ј), 2.54 (s, 3 H, CH3C), 1.28 chromatography (light petroleum ether/ethyl acetate, 50:50 to
1
(t, J = 7.1 Hz, 3 H, CH3CH2O) ppm. 13C NMR (100 MHz, 40:60) as a pale-yellow oil. H NMR (200 MHz, CDCl3): δ = 7.53
CDCl3): δ = 161.1 (C=O), 149.6 (C-2), 147.2 (C-5), 138.2 (C-2Ј),
(s, 1 H, 2-H), 7.39–7.23 (m, 3 H, 3Ј-H, 4Ј-H, 5Ј-H), 7.20–7.08 (m,
136.8 (C-1Ј), 128.8 (C-3ЈЈ, C-5ЈЈ), 127.4 (C-4Ј), 127.0 (C-4ЈЈ), 125.9 2 H, 2Ј-H, 6Ј-H), 5.46 (s, 2 H, CH2Ph), 3.80 (s, 3 H, OCH3), 2.90
(C-3Ј), 125.8 (C-2ЈЈ, C-6ЈЈ), 124.7 (C-5Ј), 119.2 (C-4), 60.2 (q, J = 7.5 Hz, 2 H, CH3CH2C), 1.25 (t, J = 7.5 Hz, 3 H,
(CH3CH2O), 48.4 (NCH2), 28.4 (CCH2-C-2Ј), 16.0 (CH3C), 14.2 CH3CH2C) ppm. 13C NMR (50 MHz, CDCl3): δ = 161.3 (C=O),
(CH3CH2O) ppm. MS (EI): m/z (%) = 340 (13) [M]+, 249 (11), 173 154.2 (C-5), 140.7 (C-2), 136.6 (C-1Ј), 128.8 (C-3Ј, C-5Ј), 127.9 (C-
(15), 91 (100), 65 (13). C19H20N2O2S (340.12): calcd. C 67.03, H
5.92, N 8.23, S 9.42; found C 66.72, H 6.25, N 8.39, S 9.18.
4Ј), 127.1 (C-2Ј, C-6Ј), 117.8 (C-4), 51.2 (CH2Ph), 50.6 (OCH3),
22.8 (CH3CH2C), 13.5 (CH3CH2C) ppm. MS (EI): m/z (%) = 244
(51) [M]+, 229 (9), 197 (12), 153 (13), 121 (43), 91 (100), 65 (43).
C14H16N2O2 (244.12): calcd. C 68.83, H 6.60, N 11.47; found C
69.06, H 6.68, N 11.58.
Ethyl 3-Benzyl-5-methyl-2-phenoxymethyl-3H-imidazole-4-carb-
oxylate (2m): Imidazole 2m was isolated (method A: 156 mg, 74%)
by column chromatography (light petroleum ether/ethyl acetate,
70:30) as a brown solid, m.p. 51–53 °C. 1H NMR (400 MHz,
Methyl 3-Allyl-5-ethyl-3H-imidazole-4-carboxylate (2q): Imidazole
CDCl3): δ = 7.28–7.22 (m, 5 H, 3Ј-H, 5Ј-H, 3ЈЈ-H, 4ЈЈ-H, 5ЈЈ-H), 2q was isolated (method A: 91 mg, 78%) by column chromatog-
7.01–6.93 (m, 3 H, 4Ј-H, 2ЈЈ-H, 6ЈЈ-H), 6.90 (d, J = 8.0 Hz, 2 H, raphy (light petroleum ether/ethyl acetate, 50:50 to 40:60) as a pale-
2Ј-H, 6Ј-H), 5.69 (s, 1 H, NCH2Ph), 5.05 (s, 2 H, CCH2O), 4.25 yellow oil. 1H NMR (200 MHz, CDCl3): δ = 7.48 (s, 1 H, 2-H),
(q, J = 7.1 Hz, 2 H, CH3CH2O), 2.54 (s, 3 H, CH3C), 1.27 (t, J = 5.96 (ddt, J = 17.0, 10.3, 5.5 Hz, 1 H, NCH2CH), 5.18 (ddd, J =
7.1 Hz, 3 H, CH3CH2O) ppm. 13C NMR (100 MHz, CDCl3): δ =
10.3, 2.4, 1.3 Hz, 1 H, Hcis), 5.04 (ddd, J = 17.0, 2.6, 1.6 Hz, 1 H,
160.9 (C=O), 157.8 (C-1Ј), 147.0 (C-2), 146.6 (C-5), 137.0 (C-1ЈЈ), Htrans), 4.85 (dt, J = 5.5, 1.3 Hz, 2 H, NCH2), 3.84 (s, 3 H, CH3O),
129.6 (C-3Ј, C-5Ј), 128.7 (C-3ЈЈ, C-5ЈЈ), 127.4 (C-4ЈЈ), 126.1 (C-2ЈЈ, 2.87 (q, J = 7.5 Hz, 2 H, CH3CH2C), 1.22 (t, J = 7.5 Hz, 3 H,
C-6ЈЈ), 121.6 (C-4Ј), 120.3 (C-4), 114.8 (C-2Ј, C-6Ј), 62.5 (CCH2O), CH3CH2C) ppm. 13C NMR (100 MHz, CDCl3): δ = 161.3 (C=O),
60.4 (CH3CH2O), 48.8 (NCH2Ph), 15.9 (CH3C), 14.2 (CH3CH2O) 154.0 (C-5), 140.3 (C-2), 133.3 (NCH2CH), 117.7 (NCHCH2),
ppm. MS (EI): m/z (%) = 305 (1) [M – EtO]+, 257 (18), 211 (19), 117.6 (C-4), 51.2 (NCH2), 49.4 (OCH3), 22.7 (CH3CH2C), 13.6
183 (2), 115 (3), 91 (100), 77 (3), 65 (12), 39 (4). C21H22N2O3 (CH3CH2C) ppm. MS (EI): m/z (%) = 194 (64) [M]+, 179 (82), 163
(350.16): calcd. C 71.98, H 6.33, N 7.99; found C 72.30, H 6.55, N
8.28.
(20), 149 (11), 135 (22), 121 (100), 41 (33). C10H14N2O2 (194.11):
calcd. C 61.84, H 7.27, N 14.42; found C 61.95, H 7.40, N 14.70.
Ethyl 3-Benzyl-5-methyl-2-(1-phenoxyethyl)-3H-imidazole-4-
carboxylate (2n): Imidazole 2n was isolated (Method A: 133 mg,
61%) by column chromatography (light petroleum ether/ethyl acet-
ate, 70:30) as a yellow oil. H NMR (400 MHz, CDCl3): δ = 7.25–
7.16 (m, 5 H, 3Ј-H, 5Ј-H, 3ЈЈ-H, 4ЈЈ-H, 5ЈЈ-H), 6.95–6.85 (m, 3 H,
4Ј-H, 2ЈЈ-H, 6ЈЈ-H), 6.81 (d, J = 8.0 Hz, 2 H, 2Ј-H, 6Ј-H), 5.78 (d,
Ethyl 3-Benzyl-5-propyl-3H-imidazole-4-carboxylate (2r): Imidazole
2r was isolated (method B: 134 mg, 87%) by column chromatog-
raphy (light petroleum ether/ethyl acetate, 50:50 to 40:60) as a col-
orless oil. 1H NMR (200 MHz, CDCl3): δ = 7.50 (s, 1 H, 2-H),
7.37–7.20 (m, 3 H, 3Ј-H, 4Ј-H, 5Ј-H), 7.16–7.04 (m, 2 H, 2Ј-H, 6Ј-
H), 5.44 (s, 2 H, CH2Ph), 4.24 (q, J = 7.1 Hz, 2 H, CH3CH2O),
1
J = 16.3 Hz, 1 H, CH2Ph), 5.58 (d, J = 16.3 Hz, 1 H, CH2Ph), 5.50 2.86 (t, J = 7.4 Hz, 2 H, CH3CH2CH2C), 1.70 (sext., J = 7.4 Hz, 2
(q, J = 6.6 Hz, 1 H, CH3CH), 4.19 (q, J = 7.1 Hz, 2 H, CH3CH2O), H, CH3CH2CH2C), 1.28 (t, J = 7.1 Hz, 3 H, CH3CH2O), 0.95 (t,
2.55 (s, 3 H, CH3C), 1.65 (d, J = 6.6 Hz, 3 H, CH3CH), 1.23 (t, J J = 7.4 Hz, 3 H, CH3CH2CH2C) ppm. 13C NMR (50 MHz,
= 7.1 Hz, 3 H, CH3CH2O) ppm. 13C NMR (100 MHz, CDCl3): δ
= 160.8 (C=O), 157.1 (C-1Ј), 150.3 (C-2), 146.9 (C-5), 137.4 (C-
CDCl3): δ = 161.9 (C=O), 152.8 (C-5), 140.6 (C-2), 136.7 (C-1Ј),
128.7 (C-3Ј, C-5Ј), 127.8 (C-4Ј), 127.0 (C-2Ј, C-6Ј), 118.4 (C-4),
1ЈЈ), 129.6 (C-3Ј, C-5Ј), 128.6 (C-3ЈЈ, C-5ЈЈ), 127.2 (C-4ЈЈ), 125.7 60.2 (CH3CH2O), 50.5 (CH2Ph), 31.5 (CH3CH2CH2C), 22.8
(C-2ЈЈ, C-6ЈЈ), 121.6 (C-4Ј), 120.0 (C-4), 115.6 (C-2Ј, C-6Ј), 69.7 (CH3CH2CH2C), 14.1 (CH3CH2O), 13.9 (CH3CH2CH2C) ppm.
(CH3CH), 60.3 (CH3CH2O), 48.6 (CH2Ph), 19.3 (CH3CH), 15.9 MS (EI): m/z (%) = 272 (4) [M]+, 244 (22), 197 (6), 153 (5), 91
(CH3C), 14.2 (CH3CH2O) ppm. MS (EI): m/z (%) = 364 (1) [M]+, (100), 65 (6). C16H20N2O2 (272.15): calcd. C 70.56, H 7.40, N 10.29;
319 (1), 271 (26), 225 (5), 135 (4), 91 (100), 65 (11), 39 (5).
C22H24N2O3 (364.18): calcd. C 72.50, H 6.64, N 7.69; found C
72.33, H 6.90, N 7.88.
found C 70.79, H 7.49, N 10.46.
Ethyl 3-Allyl-5-propyl-3H-imidazole-4-carboxylate (2s): Imidazole
2s was isolated (method B: 102 mg, 81%) by column chromatog-
Ethyl 3-Benzyl-5-methyl-2-phenyl-3H-imidazole-4-carboxylate (2o): raphy (light petroleum ether/ethyl acetate, 50:50 to 40:60) as a pale-
Imidazole 2o was isolated (method A: 96 mg, 50 %; method B:
76 mg, 44%) by column chromatography (light petroleum ether/
ethyl acetate, 70:30) as a pale-yellow oil. 1H NMR (400 MHz,
yellow oil. 1H NMR (200 MHz, CDCl3): δ = 7.46 (s, 1 H, 2-H),
5.96 (ddt, J = 17.0, 10.3, 5.5 Hz, 1 H, NCH2CH), 5.17 (dd, J =
10.3, 1.1 Hz, 1 H, Hcis), 5.02 (dd, J = 17.0, 1.1 Hz, 1 H, Htrans),
CDCl3): δ = 7.52 (m, 2 H, 2Ј-H, 6Ј-H), 7.42–7.33 (m, 3 H, 3Ј-H, 4.85 (d, J = 5.5 Hz, 2 H, NCH2), 4.29 (q, J = 7.1 Hz, 2 H,
4Ј-H, 5Ј-H), 7.31–7.20 (m, 3 H, 3ЈЈ-H, 4ЈЈ-H, 5ЈЈ-H), 6.95 (d, J = CH3CH2O), 2.83 (t, J = 7.4 Hz, 2 H, CH3CH2CH2C), 1.67 (sext.,
4318
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4312–4320

One-Pot Synthesis of Imidazole-4-Carboxylates
J = 7.4 Hz, 2 H, CH3CH2CH2C), 1.34 (t, J = 7.1 Hz, 3 H,
(50 MHz, CDCl3): δ = 160.7 (C=O), 149.4 (C-5), 140.5 (C-2), 134.4
CH3CH2O), 0.93 (t, J = 7.4 Hz, 3 H, CH3CH2CH2C) ppm. 13C (C-1Ј), 133.2 (NCH2CH), 129.5 (C-3Ј, C-5Ј), 128.0 (C-4Ј), 127.5
NMR (50 MHz, CDCl3): δ = 160.9 (C=O), 152.5 (C-5), 140.1 (C- (C-2Ј, C-6Ј), 118.4 (C-4), 118.1 (CHCH2), 60.6 (CH3CH2O), 49.6
2), 133.4 (NCH2 CH), 117.6 (2 C: C-4, NCHCH2 ), 60.1
(CH2Ph), 13.8 (CH3CH2O) ppm. MS (EI): m/z (%) = 256 (100)
(CH3 CH2 O), 49.3 (NCH2 ), 31.4 (CH3 CH2 CH2 C), 22.7 [M]+, 209 (43), 183 (86), 171 (27), 89 (43), 41 (44). C15H16N2O2
(CH3CH2CH2C), 14.2 (CH3CH2O), 13.9 (CH3CH2CH2C) ppm.
MS (EI): m/z (%) = 222 (11) [M]+, 207 (10), 194 (100), 177 (9), 165
(29), 149 (29), 135 (33) 125 (35) 109 (40) 41 (44). C12H18N2O2
(222.14): calcd. C 64.84, H 8.16, N 12.60; found C 65.02, H 8.37,
N 12.67.
(256.12): calcd. C 70.29, H 6.29, N 10.93; found C 70.65, H 6.02,
N 10.83.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedure for the preparation of noncommerci-
ally available aldehydes (and spectroscopic data thereof) used for
the synthesis of imidazole-4-carboxylates 2l–n and 1H and 13C
NMR spectra for DDs 1c–f and imidazoles 2a–w.
Methyl 3-Benzyl-5-methoxycarbonylmethyl-3H-imidazole-4-carb-
oxylate (2t): Imidazole 2t was isolated (method B: 97 mg, 59%) by
column chromatography (light petroleum ether/ethyl acetate, 50:50
to 70:30) as a whitish solid, m.p. 68–71 °C. 1H NMR (200 MHz,
CDCl3): δ = 7.55 (s, 1 H, 2-H), 7.42–7.23 (m, 3 H, 3Ј-H, 4Ј-H, 5Ј-
H), 7.21–7.10 (m, 2 H, 2Ј-H, 6Ј-H), 5.48 (s, 2 H, CH2Ph), 3.96 (s,
2 H, CH2CO2CH3), 3.79 (s, 3 H, CH3O), 3.71 (s, 3 H, CH3O) ppm.
13C NMR (50 MHz, CDCl3): δ = 170.9 (CH2C=O), 160.6 (C=O),
144.5 (C-5), 140.8 (C-2), 136.1 (C-1Ј), 128.9 (C-3Ј, C-5Ј), 128.1 (C-
4Ј), 127.3 (C-2Ј, C-6Ј), 119.8 (C-4), 52.0 (CH2Ph), 51.4 (OCH3),
50.7 (OCH3), 35.7 (CH2CO2CH3) ppm. MS (EI): m/z (%) = 288
(22) [M]+, 228 (8), 197 (5), 121 (35), 91 (100), 65 (13). C15H16N2O4
(288.11): calcd. C 62.49, H 5.59, N 9.72; found C 62.80, H 5.40, N
9.96.
Acknowledgments
Financial support from the Ministero dell’Università, dell’Istru-
zione e della Ricerca (PRIN 2007) and by the US National Insti-
tutes of Health (grant GM63815 to B. K. Shoichet and F. P.) is
gratefully acknowledged. We are indebted to Prof. Livio Brasili (Di-
partimento di Scienze Farmaceutiche, Università di Modena e
Reggio Emilia) for kindly allowing use of the microwave reactor
and to Fondazione Cassa di Risparmio di Modena for refurbishing
the NMR and MS facilities.
Methyl 3-Allyl-5-methoxycarbonylmethyl-3H-imidazole-4-carboxyl-
ate (2u): Imidazole 2u was isolated (method B: 92 mg, 68%) by
column chromatography (light petroleum ether/ethyl acetate, 50:50
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1
to 40:60) as a colorless oil. H NMR (200 MHz, CDCl3): δ = 7.55
(s, 1 H, 2-H), 6.00 (ddt, J = 17.0, 10.3, 5.6 Hz, 1 H, NCH2CH),
5.24 (ddd, J = 10.3, 2.3, 1.3 Hz, 1 H, Hcis), 5.11 (ddd, J = 17.0,
2.5, 1.5 Hz, 1 H, Htrans), 3.96 (s, 2 H, CH2CO2CH3), 3.84 (s, 3 H,
CH3O), 3.71 (s, 3 H, CH3O) ppm. 13C NMR (100 MHz, CDCl3):
δ = 171.0 (CH2C=O), 160.6 (C=O), 144.3 (C-5), 140.4 (C-2), 132.9
(NCH2CH), 119.6 (C-4), 118.2 (NCHCH2), 52.1 (NCH2), 51.5
(OCH3), 49.6 (OCH3), 35.8 (CH2CO2CH3) ppm. MS (EI): m/z (%)
= 238 (19) [M]+, 206 (7), 179 (100), 147 (20), 119 (35), 41 (67).
C11H14N2O4 (238.10): calcd. C 55.46, H 5.92, N 11.76; found C
55.87, H 5.68, N 12.09.
Methyl 3-Benzyl-5-phenyl-3H-imidazole-4-carboxylate (2v): Imid-
azole 2v was isolated (method B: 99 mg, 57 %) by column
chromatography (light petroleum ether/ethyl acetate, 50:50 to
40:60) as a whitish solid, m.p. 99–101 °C. 1H NMR (200 MHz,
CDCl3): δ = 7.75–7.60 (m, 2 H, 2ЈЈ-H, 6ЈЈ-H), 7.66 (s, 1 H, 2-H),
7.48–7.27 (m, 6 H, 3Ј-H, 4Ј-H, 5Ј-H, 3ЈЈ-H, 4ЈЈ-H, 5ЈЈ-H), 7.22 (d,
J = 7.8 Hz, 2 H, 2Ј-H, 6Ј-H), 5.54 (s, 2 H, CH2Ph), 4.18 (q, J =
7.1 Hz, 2 H, CH3CH2O), 1.12 (t, J = 7.1 Hz, 3 H, CH3CH2O) ppm.
13C NMR (50 MHz, CDCl3): δ = 160.7 (C=O), 149.6 (C-5), 141.0
(C-2), 136.4 (C-1Ј), 134.3 (C-1ЈЈ), 129.5 (C-2ЈЈ, C-6ЈЈ), 128.9 (2 C),
128.09, 128.06, 127.6 (C-2Ј, C-6Ј), 127.2 (2 C), 118.6 (C-4), 60.7
(CH3CH2O), 50.8 (CH2Ph), 13.8 (CH3CH2O) ppm. MS (EI): m/z
(%) = 306 (44) [M]+, 260 (7), 233 (11), 171 (6), 91 (100), 65 (14).
C19H18N2O2 (306.14): calcd. C 74.49, H 5.92, N 9.14; found C
74.77, H 5.77, N 9.33.
Methyl 3-Allyl-5-phenyl-3H-imidazole-4-carboxylate (2w): Imid-
azole 2w was isolated (method B: 90 mg, 62 %) by column
chromatography (light petroleum ether/ethyl acetate, 70:30 to
40:60) as a pale-yellow oil. 1H NMR (200 MHz, CDCl3): δ = 7.78–
7.59 (m, 3 H, 2Ј-H, 6Ј-H, 2-H), 7.50–7.30 (m, 3 H, 3Ј-H, 4Ј-H, 5Ј-
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CH3CH2O), 1.20 (t, J = 7.1 Hz, 3 H, CH3CH2O) ppm. 13C NMR
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Received: March 31, 2010
Published Online: June 8, 2010
4320
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Eur. J. Org. Chem. 2010, 4312–4320