N-Arylimidazole synthesis by cross-cycloaddition of isocyanides using a novel catalytic system

Article abstract of DOI:10.1016/j.tet.2007.03.152

A direct catalytic synthesis of N-arylimidazoles starting from the corresponding N-arylformamides and N-formylglycine esters is?described. Application to different aryl substituted electron-withdrawing and -donating groups provided the analogous heterocyc

Full text of DOI:10.1016/j.tet.2007.03.152

Tetrahedron 63 (2007) 4912–4917
N-Arylimidazole synthesis by cross-cycloaddition
of isocyanides using a novel catalytic system
*
ꢀ
Marc-Andre Bonin, Denis Giguere and Rene Roy
ꢁ
ꢀ
´
´
ꢁ
´
´
Department of Chemistry, Universite du Quebec a Montreal, PO Box 8888, Suc. Centre-Ville, Montreal, QC H3C 3P8, Canada
Received 19 January 2007; revised 22 March 2007; accepted 23 March 2007
Available online 30 March 2007
Abstract—A direct catalytic synthesis of N-arylimidazoles starting from the corresponding N-arylformamides and N-formylglycine esters
is described. Application to different aryl substituted electron-withdrawing and -donating groups provided the analogous heterocyclic
compounds in very high yields. The use of copper(I) oxide/proline catalysts allowed the reactions to proceed at room temperature. The first
synthesis of N-arylimidazole bearing carbohydrate moieties is also described.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
and nucleophiles.7 Unfortunately this functional group is
unstable and unpleasant to work with. If crude isocyanides,
resulting from dehydration of formamides could be per-
formed straightforwardly, it would constitute a beneficial
improvement in isocyanide chemistry. This is, to the best
of our knowledge, the first report of a catalytic N-arylimid-
azole synthesis involving crude isocyanides prepared from
the corresponding formamides. Herein, a direct catalytic
synthesis of N-arylimidazoles is described that proceed
without the need for purification of unstable isocyanide in-
termediates. Moreover, a novel catalytic system that allows
this reaction to proceed at room temperature is exemplified
(Fig. 1). In addition, application of this new methodology
toward the first synthesis of carbohydrate-bearing N-aryl-
imidazole aglycones is depicted together with a plausible
reaction mechanism.
Imidazole derivatives are found in several natural products.1
They display widespread applications in organic synthesis
and constitute important pharmacophores.2 As such, wide
interests have been devoted at developing new and efficient
methodologies toward the synthesis of N-aryl-containing
imidazoles. Losartan3 (antihypertension), Etomidate4
(hypnotic agent), and Flumazenil5 (benzodiazepine antago-
nist) are a few examples of arylimidazole-containing drugs
widely used. Due to their extensive and useful relevance
and properties, several methodologies have been developed
for the synthesis of the core imidazole ring.2,6 This hetero-
cyclic system is usually prepared using Bredereck’s syn-
thesis or by cyclization between p-tosylmethyl isocyanides
and aldimines or imidoyl chlorides. However, only a few cat-
alytic methods exist toward their synthesis.6a–c For instance,
Abell’s group performed the synthesis of trisubstituted imid-
azoles using palladium-catalyzed cyclization of O-penta-
fluorobenzoyl-amidoximes,6b while the heterocoupling
between two different isocyanides using copper(I) oxide as
catalyst and 1,10-phenanthroline as ligand has been de-
scribed by Yamamoto and co-workers.6a Previously reported
procedures required the use of strong base,6d high tempera-
ture,6a,b,e and/or unstable isocyanides as starting mate-
rials.6a,e,g Thus, a new catalytic methodology that proceed
under smooth reaction conditions is required.
R
1) POCl3, Et3N
R
NHCHO
DCM
EWG
NHCHO
+
2) Cu2O, Proline
THF, rt
N
EWG
N
Figure 1. Synthesis of N-arylimidazoles by cross-cycloaddition of iso-
cyanides using copper(I) oxide and proline.
2. Results and discussion
The first aim of this study was to synthesize imidazoles start-
ing from N-arylformamides8 and ethyl N-formylglycine
esters. Several efficient methods are known to convert
formyl groups into isocyanides.9 A general method that
could be used for both dehydration of aromatic and aliphatic
formamides is however required. After evaluating numerous
dehydrating conditions, phosphorus oxychloride/Et3N ap-
peared to be most appropriate for the above purpose. Only
The synthesis of imidazoles starting from stable formamides
would provide much simpler and efficient strategy toward
this goal. Although synthetically useful in organic syntheses,
isocyanides can undergo a-addition with both electrophiles
* Corresponding author. Tel.: +1 514 987 3000x2546; fax: +1 514 987
4054; e-mail: roy.rene@uqam.ca
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.152

M.-A. Bonin et al. / Tetrahedron 63 (2007) 4912–4917
4913
Table 1. Catalytic synthesis of N-arylimidazoles 3a–m from N-arylform-
amides 2a–m and ethyl N-formylglycine ester 1 using copper(I) oxide
and 1,10-phenanthrolinea
was selected because it is known that amino acids and cop-
per(I) salts can catalyze Ullmann-type reactions and C–N
bond formations between aryl halides and amines.10 To
our delight, substitution of 1,10-phenanthroline by proline
(Table 2) allowed N-arylimidazole synthesis, albeit in
slightly lower yields in refluxing THF but in 45 min rather
than 3 h (entry 2 compared to 1). Fortuitously, the reaction
proceeded even better at room temperature (entry 3). Addi-
tionally, lowering the amount of 1 decreased the yield only
marginally to 89% (entry 4) and lowering the amount of
copper(I) to 1 mol % and proline to 2 mol % (entry 5) did
not allow the reaction to proceed satisfactorily.
R
1) POCl3, Et3N
DCM
R
EtO
NHCHO
NHCHO
+
2) Cu2O, THF, Δ
1,10-phenanthroline
N
O
CO2Et
N
3a-m
1
2a-m
Entry
Aryl
R
Product (yield,b %)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
3a (95)
3b (92)
3c (96)
3d (65)
3e (76)
3f (20)
3g (10)
3h (92)
3i (93)
3j (95)
3k (91)
3l (92)
3m (97)
4-OMe
3-OMe
2-OMe
4-NO2
3-NO2
2-NO2
4-Me
3-Me
2-Me
4-Cl
With these optimized ligand and reaction conditions (Table
2, entry 3), the cycloaddition was attempted using 1 and
N-arylformamides 2b–m. Interestingly, similar yields were
obtained for almost all compounds. Table 3 shows compar-
ative yields between three methods for the synthesis of
various N-arylimidazoles. The reference method6a used pre-
formed isocyanides in refluxing THF, while both methods A
(1,10-phenanthroline, refluxing THF) and B (proline, rt)
started with crude isocyanides obtained from the corre-
sponding formamides. Both new methods provided similar
or better yields than the previous6a method for N-arylimid-
azoles 3a,d–f,h, and k. Proline was even more efficient than
1,10-phenanthroline for the synthesis of N-arylimidazoles
3d and f. Synthesis of imidazole 3d, starting with N-(2-
methoxyphenyl)formamide 2d, was accomplished in 76%
(Table 3, entry 2) instead of 65% yield (Table 1, entry 4)
and synthesis of 4-ethoxycarbonyl-1-(2-nitrophenyl)imid-
azole 3f was accomplished in 50% (Table 3, entry 4) instead
9
10
11
12
13
2j
2k
2l
3-Cl
2-Cl
2m
a
Reactions were conducted with 2.96 mmol of 1 and 1.97 mmol of 2a–m in
refluxing THF (<4 h).
Isolated yields.
b
silica gel filtration of the crude isocyanide mixtures was
necessary for their direct use in the cross-cycloadditions,
without affecting the overall yields. Table 1 shows the
synthesis of N-arylimidazoles 3a–m starting from ethyl
N-formylglycine ester 1 using a panel of N-arylformamides
2a–m. This direct synthesis of N-arylimidazoles tolerated
different functionalities at different positions. Thus, p-, m-,
and o-methoxyphenyl formamides 2b–d afforded the corre-
sponding N-methoxyarylimidazoles 3b–d in 92, 96, and
65% yields, respectively (entries 2–4). N-(Nitrophenyl)-
formamides 2e–g provided N-nitroaryl-imidazoles 3e–g in
lower yields ranging from 76 to 10% (entries 5–7). Finally,
methyl- and N-(chlorophenyl)-formamides (2h–m) gave im-
idazoles 3h–m in greater than 91% yields (entries 8–13).
Yields given in Table 1 refer to both isocyanide formation
and cycloaddition (three operations in total) and only one
silica gel chromatography.
Table 3. Comparative yield (%) using various methods for the synthesis of
N-arylimidazoles 3a,d–f,h, and ka
Entry N-Aryl-imidazoles Yamamotob Method A Method B
1
2
3
4
5
6
3a (H)
93
88
88
—
—
93
95
65
76
20
92
91
96
76
83
50
87
93
3d (2-OMe)
3e (4-NO2)
3f (3-NO2)
3h (4-Me)
3k (4-Cl)
a
See Section 5 for complete experimental details for method A (Cu2O,
1,10-phenanthroline, rt, and THF) and B (Cu2O, proline, rt, and THF).
Ref. 6a (Cu2O, 1,10-phenanthroline, and refluxing THF).
Our next attention was directed at using ligands that could
allow the reaction to proceed at room temperature. Proline
b
Table 2. Improved procedure for the catalytic synthesis of N-arylimidazole using copper(I) oxide and prolinea
R
1) POCl3, Et3N
R
DCM
NHCHO
EtO
NHCHO
+
2) Cu2O, THF
Ligand
N
CO2Et
O
N
3a, d, f
1
2a, d, f
Entry
Ligand
Aryl (R)
Time (h)
Temperature (ꢀC)
Equiv of 1
Product (yield,b %)
1
2
3
1,10-Phenanthroline
Proline
Proline
Proline
Proline
2a (H)
2a
2a
2a
2a
3
0.75
1
1
3
79
79
25
25
25
1.5
1.5
1.5
1.0
1.5
3a (95)
3a (86)
3a (96)
3a (89)
3a (Trace)
4
5c
a
Reactions were conducted with 1.5 mmol of 1 and 1.0 mmol of 2a catalyzed by 10 mol % of Cu2O and 20 mol % of ligand unless otherwise noted.
Isolated yields.
Reaction was conducted with 1 mol % of Cu2O and 2 mol % of proline.
b
c

4914
M.-A. Bonin et al. / Tetrahedron 63 (2007) 4912–4917
of 20% yield (Table 1, entry 6). The yields obtained by
method B represent a direct synthesis that proceeded at
room temperature and without the need for purification of
unstable and noxious isocyanides. Therefore, this method
is more appropriate toward heat sensitive compounds. More-
over proline is less expensive than 1,10-phenanthroline and
stays in the aqueous layer during work-up.
formed isocyanides were treated under the copper-catalyzed
cross-cycloaddition to provide N-arylimidazole 8 in 80%
yield. Moreover, galactoside 7 reacted in the same way
with N-arylformamide 2a to provide N-arylimidazole galac-
toside 9 in a modest 46% yield. Under this consideration, we
envisaged a stepwise strategy and isolated isonitrile 10 in
58% yield, followed by the cycloaddition that produced
imidazole 9 in 76% yield.
In continuation of our interest toward the synthesis of hetero-
cyclic glycomimetics for biological applications,11 this new
methodology was used for the synthesis of carbohydrate-
containing imidazoles. Syntheses of both N-arylformamides
and N-formylglycine glycosides are described in Scheme 1.
Commercially available p-nitrophenyl 2,3,4,6-tetra-O-
acetyl-b-D-galactopyranoside 4 underwent reduction using
a catalytic amount of Pd/C (10 mol %) and the newly formed
aniline derivative was formylated under acidic conditions to
afford N-arylformamide 5 in yield comparable to those al-
ready published.12 Furthermore, galactosyl N-formylglycyl
ester 7 was synthesized in a one-step sequence using a
Mitsonubu reaction between 2-hydroxyethyl 2,3,4,6-tetra-
O-acetyl-b-D-galactopyranoside 613 and commercially
available N-formylglycine in 87% yield.14 Both N-formyl
galactoside 5 and 7 were able to provide imidazole glyco-
mimetics as described in Scheme 2.
Being also interested by the synthesis of glycoclusters11a,15
and glycodendrimers,16 the same strategy toward galactosyl
dimer 11 was accomplished next by coupling crude de-
hydrated galactoside 5 and 10. The reaction produced
N-arylimidazole di-galactoside 11 in 53% yield. Interest-
ingly, imidazole is part of the essential amino acid histidine
and this simple sequence is efficient to prepare optically
active glycopeptide mimetics containing a N-terminal imid-
azole (glycopeptide 8). Moreover, this first direct synthesis
of imidazole containing carbohydrates did not affect the
acid sensitive glycosidic bond or acetate protecting groups.
3. Plausible mechanism
The previously6a described mechanism cannot explain why
this powerful reaction was effective only with aromatic iso-
cyanides. As depicted in Scheme 3, copper(I) oxide/proline
complex could react with ethyl N-isocyanide glycine ester 1
through extrusion of water to form intermediate A.17 This
chelated copper(I) proline adduct might render the aromatic
ring of the p-complex B more electron-deficient, thereby
facilitating the nucleophilic attack onto the aryl isocyanide
at carbon center (C). As proline is a weaker chelator than
1,10-phenanthroline to copper(I) oxide, this might explain
why using proline as ligand, the reaction occurred at room
temperature. p-Complexes mechanism involving copper
were initially proposed by Paine18 for Ullmann-type cou-
pling involving copper(I) and proline.10a Intramolecular
attack of nitrogen on carbon atom of isocyanide allowed
formation of intermediate D, which is protonated by 1 to
produce N-arylimidazole 3.
Galactoside 5 and ethyl N-formylglycine ester 1 were ini-
tially dehydrated (POCl3, Et3N, and DCM) then, the newly
AcO
AcO
AcO
AcO
OAc
O
OAc
O
a, b
O
O
AcO
AcO
NO2
c
NHCHO
NHCHO
4
5
AcO
AcO
AcO
AcO
OAc
O
OAc
O
O
OH
O
O
2
2
AcO
AcO
O
6
7
Scheme 1. Reagent and conditions: (a) H2, Pd/C (10 mol %), MeOH; (b)
formic acetic anhydride, acetic acid; and (c) DEAD, PPh3, N-formylglycine,
THF, 87%.
AcO
AcO
AcO
AcO
OAc
O
OAc
O
EtO
a, b
NHCHO
O
O
+
O
80%
AcO
AcO
O
NHCHO
O
N
5
1
8
OEt
N
AcO
AcO
AcO
AcO
OAc
O
OAc
O
O
NHCHO
a, b
46%
+
O
NHCHO
O
N
O
O
O
AcO
AcO
N
7
2a
9
a
a
58%
b, 76%
AcO
AcO
AcO
OAc
O
OAc
O
O
b
53%
OAc
NC
O
AcO
O
O
O
AcO
AcO
a
AcO
AcO
O
O
OAc
5
N
N
11
10
Scheme 2. Reagent and conditions: (a) POCl3, Et3N, DCM and (b) Cu2O, proline, THF, rt.

M.-A. Bonin et al. / Tetrahedron 63 (2007) 4912–4917
4915
Cu2O.Proline
CN
5.1.1. General procedure for N-arylimidazole synthesis
using copper(I) oxide and 1,10-phenanthroline as cata-
lyst (Method A). To a solution of N-arylformamide deri-
vative (1.0 mmol) and glycine formamide derivative
(1.5 mmol) in DCM (3.5 mL) were added Et3N (7.5 mmol)
and POCl3 (3.5 mmol) dropwise at 0ꢀ C. The reaction was
stirred at 0ꢀ C until disappearance of the starting materials
(usually less than 2 h). After the required amount of time,
the mixture was filtered over silica gel (to separate the phos-
phorus salts from the organic compounds using 4/1 DCM/
Et2O) and concentrated under reduced pressure. The crude
residue was dissolved in THF (3.5 mL), Cu2O (0.1 mmol)
and 1,10-phenanthroline (0.2 mmol) were added and stirred
under reflux until completion of the reaction (usually less
than 4 h). A solution of aq EDTA (5%) (3.5 mL) was added
to the reaction mixture, which was then extracted (5ꢁ) with
ethyl acetate. The crude residue was purified by flash column
chromatography using a mixture of ethyl acetate and DCM
as an eluent.
Ar
N
EWG
1
H2O
N
EWG
CN
O
Ar
3
CN
EWG
NH
O
1
2
Cu
O
CN
EWG
Ar
A
X
NH
O
O
Ar
Cu
O
CN
N
Cu
EWG
NH
N
N
C
EWG
N
B
C
N
D
O
Cu
O
HN
EWG
C
Scheme 3. Plausible mechanism for copper(I)-catalyzed cross-cycloaddi-
tion between isocyanides having a p-complex intermediate B.
5.1.2. General procedure for N-arylimidazole synthesis
using copper(I) oxide and proline as catalyst (Method
B). To a solution of N-aryl formamide derivatives
(1.0 mmol) and glycine formamide derivative (1.5 mmol)
in DCM (3.5 mL) were added Et3N (7.5 mmol) and POCl3
(3.5 mmol) dropwise at 0 ꢀC. The reaction was stirred at
0 ꢀC until disappearance of the starting materials (usually
less than 2 h). After the appropriate time, the mixture was
filtered over silica using DCM/Et2O (4/1) and concentrated
under reduced pressure. The crude residue was dissolved
in THF (3.5 mL) to which Cu2O (0.1 mmol) and proline
(0.2 mmol) were added and the resulting solution stirred at
room temperature until completion of the reaction (usually
less than 4 h). A solution of aq EDTA (5%) (3.5 mL) was
added to the reaction mixture, which was then extracted
(5ꢁ) with ethyl acetate. The crude residue was purified by
flash column chromatography using a mixture of ethyl
acetate and DCM as an eluent.
4. Conclusions
In conclusions, we completed a direct catalytic synthesis of
N-arylimidazoles through copper(I)-catalyzed cross-cyclo-
addition between two different isocyanides obtained from
their corresponding formamide derivatives. By using proline
as ligand it was possible to decrease the reaction temperature
without affecting the reaction yields. This new methodology
was applied for the first time toward the synthesis of imid-
azole-bearing glycomimetics and a plausible mechanism
was proposed. We believe that using the crude isocyanides
in organic synthesis for further transformation is a under
exploited strategy. Finally, current progresses are being
made toward the synthesis of new imidazole glycomimetics.
5.1.2.1. 4-Ethoxycarbonyl-1-(3-nitrophenyl)imidazole
1
(3f). Brown solid, mp 152–155 ꢀC; H NMR (300 MHz,
5. Experimental
CDCl3, d ppm): 8.33–8.29 (m, 2H), 8.04 (d, 1H, J¼
1.5 Hz), 7.98 (d, 1H, J¼1.5 Hz), 7.84–7.74 (m, 2H), 4.41
(q, 2H, J¼7.0 Hz), 2.25 (s, 3H), 1.42 (t, 3H, J¼7.0 Hz);
13C NMR (75.5 MHz, CDCl3, d ppm): 162.2, 149.1, 137.3,
136.4, 136.0, 131.3, 127.5, 123.4, 123.0, 116.6, 61.0, 14.3;
IR (neat NaCl) cmꢂ1: 3132, 2924, 1697, 1652, 1531,
1101; HRMS m/z calcd C12H12N3O4 [M+H]+: 262.0822;
found: 262.0826.
5.1. General methods
All reactions in organic medium were carried out under
nitrogen atmosphere using freshly distilled solvents. Evolu-
tion of reactions was monitored by analytical thin-layer
chromatography using silica gel 60-F254 precoated plates
(E. Merck). Purifications by flash column chromatography
were performed using silica gel Si 60 (40–63 mm) with the
indicated eluent. NMR spectra were recorded on a Varian
Gemini 300 spectrometer. Proton chemical shifts (d) are re-
ported in parts per million downfield from CHCl3. Coupling
constants (J) are reported in hertz (Hz). Melting points
(uncorrected) were measured on a Fisher Jones apparatus
and optical rotations were measured with a JASCO P-1010
polarimeter. Accurate mass measurements were performed
on a LC-MSD-TOF instrument from Agilent Technologies
in positive electrospray at the regional MS facility of the
University of Montreal by Dr. A. Furtos. Either protonated
molecular ions (M+H)+ or sodium adducts (M+Na)+ were
used for empirical formula confirmation.
5.1.2.2. 4-Ethoxycarbonyl-1-(2-nitrophenyl)imidazole
(3g). Orange solid, mp 89–92 ꢀC; 1H NMR (300 MHz,
CDCl3, d ppm): 8.11 (dd, 1H, J¼8.0, 1.5 Hz), 7.83–7.66
(m, 2H), 7.76 (d, 1H, J¼1.5 Hz), 7.66 (d, 1H, J¼1.5 Hz),
7.49 (dd, 1H, J¼8.0, 1.5 Hz), 4.40 (q, 2H, J¼7.0 Hz), 2.25
(s, 3H), 1.40 (t, 3H, J¼7.0 Hz); 13C NMR (75.5 MHz,
CDCl3, d ppm): 162.3, 145.0, 138.0, 135.1, 134.2, 130.6,
129.7, 128.9, 126.0, 125.8, 60.9, 14.3; IR (neat NaCl)
cmꢂ1: 2924, 1734, 1696, 1652, 1541, 1096; HRMS m/z calcd
C12H12N3O4 [M+H]+: 262.0822; found: 262.0822.
5.1.2.3. 4-Ethoxycarbonyl-1-(4-methylphenyl)imid-
azole (3h). White solid, mp 129–131 ꢀC; 1H NMR

4916
M.-A. Bonin et al. / Tetrahedron 63 (2007) 4912–4917
(300 MHz, CDCl3, d ppm): 7.92 (d, 1H, J¼1.5 Hz), 7.82 (d,
1H, J¼1.5 Hz), 7.34–7.26 (m, 4H), 4.41 (q, 2H, J¼7.0 Hz),
2.43 (s, 3H), 1.42 (t, 3H, J¼7.0 Hz); 13C NMR (75.5 MHz,
CDCl3, d ppm): 162.7, 146.3, 138.4, 136.2, 134.8, 134.0,
130.5, 124.0, 121.5, 60.6, 20.9, 14.3; IR (neat NaCl)
cmꢂ1: 3146, 3117, 2987, 1705, 1555, 1275; HRMS m/z calcd
C13H15N2O2 [M+H]+: 231.1128; found: 231.1128.
2.00 (s, 3H), 1.93 (s, 3H); 13C NMR (75.5 MHz, CDCl3,
d ppm): 170.3, 170.1, 170.0, 169.4, 169.2, 161.3, 100.9,
70.6, 70.5, 68.4, 66.9, 66.8, 63.9, 61.1, 39.6, 20.6, 20.5
(2C), 20.4; IR (neat NaCl) cmꢂ1: 2919, 2846, 1749, 1734,
1652, 1096; HRMS m/z calcd C19H28NO13 [M+H]+:
478.1555; found: 478.1555; [a]2D5 ꢂ6.9 (c 1.2 in CHCl3).
5.1.2.9. 4-Ethoxycarbonyl-1-[4-(2,3,4,6-tetra-O-ace-
tyl-b-D-galactopyranosyloxy)phenyl]imidazole (8). Com-
pound 8 was isolated as a clear oil; H NMR (300 MHz,
5.1.2.4. 4-Ethoxycarbonyl-1-(3-methylphenyl)imid-
azole (3i). White solid, mp 83–85 ꢀC; 1H NMR (300 MHz,
CDCl3, d ppm): 7.95 (d, 1H, J¼1.5 Hz), 7.85 (d, 1H, J¼
1.5 Hz), 7.40 (t, 1H, J¼8.0 Hz), 7.30–7.20 (m, 3H), 4.41
(q, 2H, J¼7.0 Hz), 2.44 (s, 3H), 1.42 (t, 3H, J¼7.0 Hz);
13C NMR (75.5 MHz, CDCl3, d ppm): 162.5, 140.2, 136.2,
136.1, 134.7, 129.7, 128.9, 123.8, 122.0, 118.5, 60.5, 21.2,
14.2; IR (neat NaCl) cmꢂ1: 3122, 2977, 1724, 1691, 1546,
1270; HRMS m/z calcd C13H15N2O2 [M+H]+: 231.1128;
found: 231.1125.
1
CDCl3, d ppm): 7.81 (d, 1H, J¼1.0 Hz), 7.72 (d, 1H,
J¼1.0 Hz), 7.26 (d, 2H, J¼9.0 Hz), 7.07 (d, 2H, J¼9.0 Hz),
5.46–5.39 (m, 2H), 5.09–5.02 (m, 2H), 4.30 (q, 2H, J¼7.0,
14.2 Hz), 4.19–4.05 (m, 4H), 2.11 (s, 3H), 2.01 (s, 3H),
1.99 (s, 3H), 1.94 (s, 3H), 1.32 (t, 3H, J¼7.0 Hz); 13C
NMR (75.5 MHz, CDCl3, d ppm): 170.2, 170.0, 169.9,
169.2, 162.6, 156.5, 136.4, 134.9, 131.7, 127.9, 124.1, 123.2,
118.1, 117.5, 99.3, 71.1, 70.6, 68.4, 66.7, 61.2, 60.6, 20.6,
20.5, 20.4, 14.3; IR (neat, NaCl) cmꢂ1: 3019, 1734, 1653,
1216; HRMS m/z calcd C26H31N2O12 [M+H]+: 563.1872;
found: 563.1873; [a]2D5 +2.3 (c 0.9 in CHCl3).
5.1.2.5. 4-Ethoxycarbonyl-1-(2-methylphenyl)imid-
azole (3j). Yellowish oil; 1H NMR (300 MHz, CDCl3,
d ppm): 7.79 (d, 1H, J¼1.5 Hz), 7.66 (d, 1H, J¼1.5 Hz),
7.51–7.22 (m, 4H), 4.43 (q, 2H, J¼7.0 Hz), 2.25 (s, 3H),
1.45 (t, 3H, J¼7.0 Hz); 13C NMR (75.5 MHz, CDCl3,
d ppm): 162.3, 137.8, 135.5, 133.8, 133.1, 131.0, 129.0,
126.7, 125.9, 125.8, 60.1, 17.1, 13.9; IR (neat NaCl)
cmꢂ1: 3116, 2978, 1727, 1536, 1498, 1254; HRMS m/z calcd
C13H15N2O2 [M+H]+: 231.1128; found: 231.1128.
5.1.2.10. 4-[2-(2,3,4,6-Tetra-O-acetyl-b-D-galactopyra-
nosiloxy)ethoxycarbonyl]-1-phenylimidazole (9). Colorless
oil; 1H NMR (300 MHz, CDCl3, d ppm): 7.92 (d, 1H,
J¼1.0 Hz), 7.82 (d, 1H, J¼1.0 Hz), 7.47–7.33 (m, 5H), 5.29
(d, 1H, J¼3.0 Hz), 5.14 (dd, 1H, J¼10.5, 8.0 Hz), 4.94 (dd,
1H, J¼10.5, 3.5 Hz), 4.57 (d, 1H, J¼8.0 Hz), 4.46–4.36 (m,
2H), 4.06–4.03 (m, 3H), 3.94–3.86 (m, 2H), 2.04 (s, 3H), 1.94
(s, 3H), 1.89 (s, 3H), 1.88 (s, 3H); 13C NMR (75.5 MHz,
CDCl3, d ppm): 170.1, 169.9, 169.8, 169.2, 162.0, 136.2,
136.1, 134.1, 129.9, 128.2, 124.0, 121.3, 101.0, 70.6, 70.4,
68.4, 67.2, 66.8, 63.0, 61.0, 20.4 (3C), 20.3; IR (neat NaCl)
cmꢂ1: 3132, 2929, 1748, 1734, 1696, 1652, 1556; HRMS
m/z calcd C26H31N2O12 [M+H]+: 563.1872; found: 563.1867;
[a]2D5 ꢂ10.4 (c 1.6 in CHCl3).
5.1.2.6.
4-Ethoxycarbonyl-1-(3-chlorophenyl)imid-
azole (3l). White solid, mp 105–108 ꢀC; 1H NMR (300 MHz,
CDCl3, d ppm): 7.95 (d, 1H, J¼1.0 Hz), 7.86 (d, 1H,
J¼1.0 Hz), 7.47–7.26 (m, 4H), 4.41 (q, 2H, J¼7.0 Hz),
1.41 (t, 3H, J¼7.0 Hz); 13C NMR (75.5 MHz, CDCl3,
d ppm): 162.3, 137.3, 136.0, 135.7, 135.3, 131.1, 128.4,
123.5, 121.8, 119.6, 60.6, 14.2; IR (neat NaCl) cmꢂ1
:
3131, 3069, 2991, 1701, 1652, 1541, 1275; HRMS m/z calcd
C12H13ClN2O2 [M+H]+: 251.0582; found: 251.0581.
5.1.2.11. (2,3,4,6-Tetra-O-acetyl-b-D-galactopyrano-
syloxy)-2-hydroxyethyl isocyanoacetate (10). To a solution
of 7 (0.38 mmol, 180 mg) in DCM (2.0 mL) were added
Et3N (1.14 mmol) and POCl3 (0.38 mmol) dropwise at
0 ꢀC. The reaction was stirred at 0 ꢀC for 2 h and saturated
NaHCO3 was added. The mixture was extracted three times
with ethyl acetate, dried over Na2SO4, filtered, and concen-
trated under reduced pressure. The crude residue was puri-
fied by flash chromatography using 20% ether in DCM as
5.1.2.7.
4-Ethoxycarbonyl-1-(2-chlorophenyl)imid-
azole (3m). Yellowish oil; 1H NMR (300 MHz, CDCl3,
d ppm): 7.83 (d, 1H, J¼1.5 Hz), 7.70 (d, 1H, J¼1.5 Hz),
7.60–7.57 (m, 1H), 7.47–7.35 (m, 3H), 4.40 (q, 2H,
J¼7.0 Hz), 2.25 (s, 3H), 1.41 (t, 3H, J¼7.0 Hz); 13C NMR
(75.5 MHz, CDCl3, d ppm): 162.2, 137.9, 133.9, 133.7,
130.6, 130.1, 129.3, 127.8, 127.2, 125.9, 60.2, 14.0; IR (neat
NaCl) cmꢂ1: 3112, 2981, 1729, 1657, 1541; HRMS m/z
calcd C12H13ClN2O2 [M+H]+: 251.0582; found: 251.0580.
1
an eluent affording 101 mg (58%) of 10. Colorless oil; H
NMR (300 MHz, CDCl3, d ppm): 5.34 (dd, 1H, J¼3.5,
1.0 Hz), 5.15 (dd, 1H, J¼10.5, 8.0 Hz), 4.97 (dd, 1H,
J¼10.5, 3.5 Hz), 4.50 (d, 1H, J¼8.0 Hz), 4.34 (t, 2H,
J¼5.0 Hz), 4.25 (s, 2H), 4.16–3.75 (m, 5H), 3.77–3.70 (m,
1H), 2.11 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.93 (s, 3H);
13C NMR (75.5 MHz, CDCl3, d ppm): 170.2, 170.0, 169.9,
169.3, 163.8, 161.2, 100.9, 70.6, 70.5, 68.4, 66.8, 66.4,
65.0, 61.1, 43.2, 20.6, 20.5 (2C), 20.4; IR (neat NaCl)
cmꢂ1: 2923, 2165, 1749, 1734, 1652, 1556; HRMS m/z calcd
C19H26N2O12 [M+H]+: 460.1450; found: 460.1444; [a]2D5
ꢂ6.1 (c 1.5 in CHCl3).
5.1.2.8. (2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl-
oxy)-2-hydroxyethyl N-formylglycine ester (7). To a solu-
tion of 6 (1.15 mmol, 450 mg), PPh3 (3.45 mmol, 905 mg),
and N-formylglycine (4.03 mmol, 415 mg) in THF (5 mL)
was added dropwise DEAD (3.45 mmol, 0.68 mL) at 0 ꢀC.
The reaction was allowed to warm slowly and stirred for
48 h at room temperature. The mixture was concentrated un-
der reduced pressure and purified by flash chromatography
using 100% ethyl acetate affording 478 mg (87%) of pure
1
7. Colorless oil; H NMR (300 MHz, CDCl3, d ppm): 8.2
(s, 1H), 6.69 (br t, 1H), 5.32 (dd, 1H, J¼3.5, 0.5 Hz), 5.12
(dd, 1H, J¼10.5, 8.0 Hz), 4.97 (dd, 1H, J¼10.5, 3.5 Hz),
4.48 (d, 1H, J¼8.0 Hz), 4.27 (t, 2H, J¼5.0 Hz), 4.12–3.87
(m, 7H), 3.77–3.70 (m, 1H), 2.10 (s, 3H), 2.01 (s, 3H),
5.1.2.12. 4-[2-(2,3,4,6-Tetra-O-acetyl-b-D-galactopyra-
nosyloxy)ethoxycarbonyl]-1-[4-(2,3,4,6-tetra-O-acetyl-b-
D-galactopyranosyloxy)phenyl]imidazole (11). To a solu-
tion of 5 (0.18 mmol) in DCM (2.0 mL) was added Et3N

M.-A. Bonin et al. / Tetrahedron 63 (2007) 4912–4917
4917
(0.54 mmol) and POCl3 (0.18 mmol) dropwise at 0 ꢀC. The
reaction was stirred at 0 ꢀC until disappearance of the start-
ing material. After this time, the mixture was filtered over
silica gel using DCM/Et2O (4/1) and concentrated under re-
duced pressure. The crude residue was dissolved in THF
(2.0 mL) and isocyanide 10 (0.18 mmol) was added fol-
lowed by Cu2O (0.02 mmol) and proline (0.04 mmol). The
resulting solution was stirred at room temperature until com-
pletion of the reaction. The crude residue was purified by
flash column chromatography using pure ethyl acetate as
an eluent. Compound 11 was obtained as a colorless oil
4. Godefroi, E. F.; Jansen, P. A. J.; van der Erychen, C. A. M.; van
Heertum, A. H. M. T.; Niemegeers, C. J. E. J. Med. Chem.
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5. Hunkeler, W.; Mohler, H.; Pieri, L.; Polc, P.; Bonetti, E. P.;
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2006, 128, 10662; (b) Zaman, S.; Mitsuru, K.; Abell, A. D.
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NY, 1971.
8. All none available arylformamides were synthesized using zinc
oxide with yield up to 97%, as described: Hosseini-Sarvari, M.;
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1
(86 mg, 53%); H NMR (300 MHz, CDCl3, d ppm): 7.91
(d, 1H, J¼1.0 Hz), 7.79 (d, 1H, J¼1.0 Hz), 7.36 (d, 2H,
J¼9.0 Hz), 7.14 (d, 2H, J¼9.0 Hz), 5.50 (dd, 1H, J¼10.5,
8.0 Hz), 5.47 (d, 1H, J¼3.0 Hz), 5.37 (d, 1H, J¼3.0 Hz),
5.21 (dd, 1H, J¼10.5, 8.0 Hz), 5.13 (dd, 1H, J¼10.5,
3.5 Hz), 5.09 (d, 1H, J¼7.5 Hz), 4.99 (dd, 1H, J¼10.5,
3.5 Hz), 4.62 (dd, 1H, J¼8.0 Hz), 4.54–4.42 (m, 2H),
4.26–4.09 (m, 6H), 4.00–3.91 (m, 2H), 2.19 (s, 3H), 2.13
(s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H), 2.02 (s,
3H), 1.97 (s, 3H), 1.96 (s, 3H); 13C NMR (75.5 MHz,
CDCl3, d ppm): 170.4, 170.2 (2C), 170.1 (2C), 170.0,
169.5, 169.3, 162.2, 156.6, 136.6, 134.4, 131.7, 124.6,
123.3, 118.2, 101.2, 99.4, 71.1, 70.8, 70.6 (2C), 68.6, 68.4,
67.4, 67.0, 66.7, 63.3, 61.2 (2C), 20.7, 20.6 (6C), 20.5; IR
(neat NaCl) cmꢂ1: 3021, 2924, 1744, 1739, 1652, 1556,
1222; HRMS m/z calcd C40H49N2O22 [M+H]+: 909.2772;
found: 909.2764; [a]2D5 ꢂ3.6 (c 1.4 in CHCl3).
€
€
Schollkopf, U.; Schroder, R.; Stafforst, S. Liebigs Ann.
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Acknowledgements
This work was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC) for a
Canadian Research Chair in Therapeutic Chemistry to R.R.
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M. Chem. Rev. 2002, 102, 1359; (e) Alcalde, E.; Dinares, I.;
Rodriguez, S.; Garcia de Miguel, C. Eur. J. Org. Chem.
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