Reactions of 2-unsubstituted 1H-imidazole 3-oxides with heterocumulenes and dimethyl acetylenedicarboxylate

Article abstract of DOI:10.1016/S0040-4020(00)00449-X

Reaction of 2-unsubstituted 1H-imidazole 3-oxides with isocyanates, isothiocyanates, and dimethyl acetylenedicarboxylate led to the formation of 2-functionalized imidazole derivatives. Stepwise reaction mechanisms via zwitterionic intermediates are propos

Full text of DOI:10.1016/S0040-4020(00)00449-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5405±5412
Reactions of 2-Unsubstituted 1H-Imidazole 3-Oxides with
Heterocumulenes and Dimethyl Acetylenedicarboxylate
a,² a,b
Grzegorz Mloston, Tomasz Gendek and Heinz Heimgartner
b,
*
Â
aSection of Heteroorganic Compounds, University of èodz, Narutowicza 68, PL-90-136 èodz, Poland
È È È
Organisch-chemisches Institut der Universitat Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
b
Dedicated to Professor Rolf Huisgen on the occasion of his 80th birthday
Received 26 April 2000; accepted 9 May 2000
AbstractÐReaction of 2-unsubstituted 1H-imidazole 3-oxides with isocyanates, isothiocyanates, and dimethyl acetylenedicarboxylate led
to the formation of 2-functionalized imidazole derivatives. Stepwise reaction mechanisms via zwitterionic intermediates are proposed. The
intermediate [312] cycloadducts stabilize via extrusion of COX or ring opening. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
additions with suitable dipolarophiles. In the case of other
aza-aromatic N-oxides, this type of reaction is well estab-
lished. E.g. pyridine N-oxides 1 react with phenyl iso-
cyanate at 1108C to give oxazolo[4,5-b]pyridines 2 which,
at 1508C, extrude CO2 to give 2-aminopyridines 3 (Scheme
1).9 The reaction of 1 with dibenzoylacetylene occurs
smoothly at room temperature leading to 2-substituted
pyridine derivatives 4.10 The structures of the isolated
products 2 and 4 show that the primarily formed [312]
cycloadducts undergo fast secondary reactions. Several
examples of similar transformations with pyridine, quino-
line, and isoquinoline N-oxides have been reviewed
recently.11 The isolation of the initial cycloadduct was
achieved in the case of the reaction of dimethyl acetylene-
dicarboxylate and a quinoxaline 4-oxide.12
In contrast to other azaheterocyclic N-oxides, imidazole
N-oxides cannot be prepared by oxidation of the parent
compound.1,2 However, syntheses based on condensation
reactions with a-hydroxyimino ketones and imines3 or
1,2-diimines and oximes4 were recently developed which
offered an easy access to differently substituted imidazole
N-oxides. In the case of unsubstituted C(2), they can con-
veniently be exploited for the preparation of C(2)-function-
alized derivatives. Thus, photolysis in methanolic solution
afforded imidazol-2-ones,5 cyanation using trimethylsilane-
carbonitrile (Me3SiCN) led to imidazole-2-carbonitriles,6,7
and chlorination with POCl3 yielded 2-chloroimidazoles.8
Formally, imidazole N-oxides contain the structural frag-
ment of a 1,3-dipole which is comparable with nitrones.
Therefore, they are expected to undergo [312] cyclo-
Reactions of N-oxides of ®ve-membered aromatic aza-
heterocycles including imidazole N-oxides are rarely
Scheme 1.
Keywords: imidazole N-oxides; isocyanates; isothiocyanates; acetylenedicarboxylate; [312] cycloadducts.
* Corresponding author. Tel.: 141-1-635-42-82; fax: 141-1-635-68-12; e-mail: heimgart@oci.unizh.ch
Tel.: 148-42-635-57-61; fax: 148-42-678-16-09; e-mail: gmloston@krysia.uni.lodz.pl
²
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00449-X

Â
G. Mloston et al. / Tetrahedron 56 (2000) 5405±5412
5406
Scheme 2.
reported. A study of the reaction of 2-unsubstituted imida-
zole N-oxides 5 with cycloaliphatic thioketones leading to
the corresponding imidazole-2-thiones 7 was published two
years ago (Scheme 2).3 The proposed reaction mechanism
involves the formation of the [312] cycloadduct 6 which
spontaneously eliminates 2,2,4,4-tetramethylcyclobuta-1,3-
dione. This reaction is clear-cut evidence for the `nitrone-
like' 1,3-dipolar reactivity of 5.
butyl isocyanate (8b); in this case, the smooth reaction led to
9b in 65% yield. Finally, we attempted to react 5a with (tert-
butyl) isocyanate. Although the reaction time was extended
to 3 days, no addition product could be detected.
Under the same reaction conditions (dichloromethane, room
temperature) cyclohexyl isothiocyanate (8c), butyl isothio-
cyanate (8d), and methyl isothiocyanate (8e) reacted simi-
larly as the corresponding isocyanates to give 9a±c (Scheme
3). The molecular structure of 9c was established by X-ray
crystallography (Fig. 1). The NH group forms an inter-
molecular H-bond with the unsubstituted N-atom of the
imidazole ring of a neighboring molecule. The H-bonds
link the molecules into in®nite one-dimensional chains
running parallel to the z-axis.
To the best of our knowledge, the only other examples of
1,3-dipolar cycloadditions of 5 were reported by Ferguson
and Scho®eld.8 Their study was limited to one reaction with
phenyl isocyanate and dimethyl acetylenedicarboxylate,
respectively, and 1-benzyl-4,5-dimethyl-1H-imidazole
3-oxide (5, R1ˆPhCH2, R2ˆR3ˆMe). The isolated products
were described as 2-substituted imidazole derivatives
similar to those obtained with pyridine 1-oxide (i.e. 3 and 4).
Unexpectedly, 2-amino-imidazoles 9a±c were not
converted into thiourea derivatives under the reaction con-
ditions. Similarly, in the case of the reactions with iso-
cyanates 8a,b, urea derivatives were formed neither with
equimolar amounts of 5a and 8a,b nor with a twofold excess
of 8a.
The aim of the present study was to determine the scope and
limitations of [312] cycloadditions using imidazole N-
oxides 5. Attempted reactions with different dipolarophiles
showed that isocyanates, isothiocyanates, and acetylene-
dicarboxylates are the most promising reagents.
In contrast to reactions with 8a, phenylisocyanate and
1-methyl-4,5-diphenyl-1H-imidazole 3-oxide (5a) yielded
two different products depending on the ratio of the
reagents. Whereas in the experiment with equimolar
amounts the only product was 1-methyl-4,5-diphenyl-2-
(phenylamino)imidazole (9d), the reaction with excess
phenyl isocyanate led to urea derivative 10a (Scheme 4).
In an additional experiment, 9d was transformed into 10a by
treatment with phenyl isocyanate at room temperature.
Results and Discussion
In order to test the reactivity of aliphatic isocyanates
towards imidazole N-oxides, we selected cyclohexyl iso-
cyanate (8a) and 1-methyl-4,5-diphenyl-1H-imidazole
3-oxide (5a) as reaction partners. Equimolar amounts of
the components were dissolved in dichloromethane at 08C,
and the mixture was stirred at room temperature for 20 h.
The crude reaction mixture was examined by 1H NMR spec-
troscopy which indicated the presence of only one major
product. Crystallization from methanol afforded 2-(cyclo-
hexylamino)imidazole 9a in 68% yield, which was identi-
®ed by elemental analysis and spectroscopic data (Scheme
3). The analogous reaction course was observed with 5a and
With imidazole N-oxides 5b,c the reactions were carried out
using excess phenyl isocyanate (ratio 1:2), and the urea
derivatives 10b and 10c, respectively, were obtained as
the sole products. The formation of 10b deserves a comment
as Ferguson and Scho®eld8 reported on the same reaction. A
crystalline solid with a melting point of 237±2388C was
Scheme 3.

Â
G. Mloston et al. / Tetrahedron 56 (2000) 5405±5412
5407
Figure 1. ortep-Plot13 of the molecular structure of 9c (arbitrary numbering of atoms, 50% probability ellipsoids; H-atoms given arbitrary displacement
parameters for clarity).
believed to possess structure 10b. The substance in our hands,
fully characterized by elemental analysis and spectral data
corresponding thiourea derivative with an excess of phenyl
isothiocyanate at room temperature was in vain.
1
³
(MS, H and 13C NMR, IR), melted at 157±1588C.
Another dipolarophile, which easily enters reactions with
imidazole N-oxides 5, was dimethyl acetylenedicarboxylate
(DMAD).§ The reactions with 5b±e were carried out in
chloroform at 08C, and they were complete after 1 h. In
all cases, only one product was obtained and identi®ed as
butanedioate 11 (Scheme 5). The structures were con®rmed
by their spectral data; e.g. the IR spectrum (KBr) of 11a
shows three (CvO) absorptions at 1720, 1670, and
In analogy to the reactions of 5 with aliphatic isothio-
cyanates, treatment of 5a, b, and d, respectively, with phen-
yl isothiocyanate afforded imidazoles 9d, e, and f as the sole
products. An attempted conversion of the isolated 9d to the
³
Imidazole N-oxides are dif®cult to obtain free of water. Therefore, one
can expect that the reaction with phenyl isocyanate can lead to considerable
§
amounts of N,N0-diphenylurea (carbanilide, mp 238±2408C).
Phenylacetylene was shown to be unreactive under these conditions.
Scheme 4.
Scheme 5.

Â
G. Mloston et al. / Tetrahedron 56 (2000) 5405±5412
5408
Scheme 6.
1650 cm21 and in the 13C NMR spectrum (CDCl3) three
signals for (CvO) groups appeared at 208.7, 168.4 and
167.8 ppm. The signals of C(2) and the methylidene-C
atom were found at 143.7 and 80.9 ppm, respectively.
Experimental
Melting points were determined in a capillary using a Melt-
Temp (Aldrich) or BuÈchi-510 apparatus and are uncor-
rected. IR Spectra: Specord-71 IR and Perkin±Elmer FT-
1
The mechanistic interpretation of the reactions leading to 9
and 11 is based on the assumption that cycloadducts 13 and
15, respectively, are the precursors. The formation of 13 and
15, which formally are [312] cycloadducts of 5 and the
dipolarophiles, is expected to occur stepwise via the pri-
marily formed zwitterionic intermediates 12 and 14, respec-
tively. This proposal is supported by the fact that
isocyanates and isothiocyanates gave the same products
9.k In the case of isothiocyanates, zwitterion 12 should
form the ®ve-membered ring via attack of the more nucleo-
philic S-atom. As the elimination of COS to give 9 requires
1,2,4-oxadiazolidine-5-thione 13 (XˆS) as an appropriate
precursor, an equilibrium between the initially formed
1,4,2-oxathiazolidin-5-imine and 12 has to be postulated.
The driving force of the COX elimination from 13 is the
stability of the extruded molecule and the aromatization of
the imidazole ring. Similarly, stabilization of 15 occurs via
cleavage of the weak N±O bond and formation of the conju-
gated, `push±pull-stabilized' product 11. Additionally, 11 is
stabilized by an intramolecular H-bond between NH and the
ketone O-atom indicated by the down-®eld shift of the NH
absorption (d(NH) in 11b: 12.35 ppm) (Scheme 6).
IR-1600 spectrometers; in KBr. H and 13C NMR Spectra:
Varian-Gemini-BB spectrometer (200 MHz for 1H and
50.4 MHz for 13C) or Bruker ARX-300 (300 MHz for H
1
and 75.5 MHz for 13C); CDCl3 solutions; other solvents are
given in parentheses; TMS was used as an internal standard
(d(TMS)ˆ0 ppm). EI-MS: Varian-MAT-112S spectro-
meter; at 70 eV; CI-MS with NH3.
Starting materials
The 1H-imidazole 3-oxides 5 were prepared by conden-
sation of the corresponding hexahydro-1,3,5-triazines and
a-hydroxyimino ketones following a known protocol.3
Phenyl isocyanate, phenyl isothiocyanate as well as iso-
cyanates 8a, b and isothiocyanates 8c±e were commercially
available reagents purchased from Aldrich or Fluka.
Reactions of 1-methyl-4,5-diphenyl-1H-imidazole
3-oxide (5a) with isocyanates 8a,b and phenyl isocyanate
(molar ratio 1:1)
General procedure: A solution of 767 mg (3 mmol) of 5a in
6 ml of abs. dichloromethane was cooled in a water/ice bath.
The solution was stirred magnetically and 3 mmol of freshly
distilled isocyanate dissolved in 6 ml of dichloromethane
were added dropwise at such a rate that the temperature
did not exceed 58C. When the addition was complete, the
bath was removed and the stirring was continued at room
temperature for 20 h. Then, the solvent was evaporated
under vacuum and the crude products were puri®ed by
recrystallization. Reported yields refer to recrystallized
products.
Considering the above interpretation, unsuccessful experi-
ments with other dipolarophiles, known to be good reaction
partners in cycloaddition reactions with nitrones,15 can be
plausibly explained.
In contrast to 5, non-aromatic imidazole N-oxides16 behave
like nitrones in reactions with DMAD and form stable
[312] cycloadducts 1716 (Scheme 7; cf. also Ref. 17).
k
Generally, 1,3-dipolar cycloadditions with isocyanates and isothiocya-
2-Cyclohexylamino-1-methyl-4,5-diphenylimidazole (9a).
With cyclohexyl isocyanate (8a; 375.3 mg, 3 mmol). Color-
less crystals with mp 135±1368C (hexane/dichloromethane);
nates lead to different products. Whereas in the case of isocyanates addition
onto the CvN bond is observed, isothiocyanates react preferably at the
CvS bond.14
Scheme 7.

Â
G. Mloston et al. / Tetrahedron 56 (2000) 5405±5412
5409
yield: 676 mg (68%). IR: 2925s, 2852s, 1574vs, 1526s,
1031s, 774s, 704s. H NMR: 7.47±7.05 (m, 10 arom. H);
N-(1-Methyl-4,5-diphenylimidazol-2-yl)-N,N0-diphenyl-
urea (10a). With 5a (750.9 mg, 3 mmol). Colorless crystals
with mp 157±1588C (hexane/ethyl acetate); yield: 920 mg
(69%). IR: 1702vs (CvO), 1600vs, 1526vs, 1496vs, 1442vs,
1401s, 1311s, 1274vs, 1234vs, 760s, 741s, 693vs. 1H NMR:
8.71 (s, NH); 7.56±7.39, 7.36±7.15, 7.09±7.04 (3m, 20
arom. H); 3.12 (s, CH3N). 13C NMR: 152.4 (s, CvO);
142.0, 139.7, 138.2, 135.3, 133.9, 130.2, 128.6 (7s, C(2),
C(4), C(5), 4 arom. C); 129.2, 129.0, 128.9, 128.2, 126.6,
126.5, 123.5, 119.7 (8d, 20 arom. CH); 31.2 (q, CH3N). EI-
MS: 325 (24), 324 (100, [(M11)2C6H5NHCO]1), 323 (30),
309 (7), 234 (5), 197 (7), 193 (12), 186 (5), 119 (32), 91 (8).
Anal. Calcd for C29H24N4O (444.54): C 78.35, H 5.44, N
12.60; found: C 78.14, H 5.63, N 12.60.
1
3.75±3.70 (m, CHN); 3.20 (s, CH3N); 2.21±2.16, 1.86±1.12
(2m, 5 CH2). 13C NMR: 148.9, 134.9, 133.0, 131.3, 124.5
(5s, C(2), C(4), C(5), 2 arom. C); 130.7, 128.7, 127.8, 127.7,
126.7, 125.6 (6d, 10 arom. CH); 52.6 (d, CHN); 34.0, 25.8,
24.9 (3t, 5 CH2); 29.6 (q, CH3N). CI-MS: 333 (22), 332
(100, [M11]1), 261 (17), 228 (16). Anal. Calcd for
C22H25N3 (331.46): C 79.72, H 7.60, N 12.68; found: C
79.64, H 7.50, N 12.64.
2-Butylamino-1-methyl-4,5-diphenylimidazole
(9b).
With butyl isocyanate (8b; 297.4 mg, 3 mmol). Colorless
crystals with mp 189±1918C (hexane/dichloromethane);
yield: 596 mg (65%). IR: 3325s, 2949s, 1567vs, 766s,
1
700vs. H NMR (DMSO-d6): 8.58±8.52 (m, NH); 7.52±
N-(1-Benzyl-4,5-dimethylimidazol-2-yl)-N,N0-diphenyl-
urea (10b). With 1-benzyl-4,5-dimethylimidazole 3-oxide
(5b; 606.8 mg, 3 mmol). Colorless crystals with mp 120±
1228C (hexane/tetrachloromethane); yield: 405 mg (34%).
IR: 1675vs (CvO), 1597vs, 1542vs, 1497vs, 1443vs,
7.22 (m, 10 arom. H); 3.58±3.52 (m, CH2N); 3.31 (s,
CH3N); 1.72±1.60, 1.49±1.37 (2m, 2 CH2); 0.95 (t, CH3).
13C NMR (DMSO-d6): 146.6, 127.4, 126.7, 124.6, 122.4 (5s,
C(2), C(4), C(5), 2 arom. C); 130.8, 130.5, 129.6, 129.1,
128.3, 127.6 (6d, 10 arom. CH); 42.7 (t, CH2N); 30.8,
19.2 (2t, 2 CH2); 30.7 (q, CH3N); 13.6 (q, CH3). CI-MS:
307 (19), 306 (100, [M11]1). Anal. Calcd for C20H23N3
(305.42): C 78.65, H 7.59, N 13.76; found: C 78.55, H
7.65, N 13.70.
1
1315vs, 1246vs, 754s, 692s. H NMR: 7.61 (s, NH); 7.47±
7.13, 7.05±7.00, 6.88±6.85 (3m, 15 arom. H); 4.85 (s,
CH2N); 2.24, 2.02 (2s, 2 CH3). 13C NMR: 152.8 (s,
CvO); 139.8, 139.4, 135.8, 132.0, 123.1 (5s, C(2), C(4),
C(5), 3 arom. C); 129.0, 128.7, 127.5, 126.3, 126.1, 123.5,
120.0 (7d, 15 arom. CH); 46.9 (t, CH2N); 12.7, 9.0 (2q, 2
CH3). CI-MS: 397 (15, [M11]1), 278 (100), 213 (15). Anal.
Calcd for C25H24N4O (396.49): C 75.73, H 6.10, N 14.13;
found: C 75.54, H 6.02, N 14.05.
1-Methyl-4,5-diphenyl-2-(phenylamino)imidazole (9d).
With phenyl isocyanate (357.4 mg, 3 mmol). Colorless
crystals with mp 222±2248C (hexane/dichloromethane);
yield: 508 mg (52%). IR: 3175s, 3056m, 2930m, 1603vs,
1526vs, 1496vs, 1457vs, 1440s, 1380vs, 1256s, 780vs,
N-(1-Cyclohexyl-4,5-dimethylimidazol-2-yl)-N,N0-diphenyl-
urea (10c). With 1-cyclohexyl-4,5-dimethylimidazole
3-oxide (5c; 582.8 mg, 3 mmol). Colorless crystals with
mp 168±1708C (after chromatography on a silica gel
column with dichloromethane/ethyl acetate 8:2 and recrys-
tallization from diethyl ether/dichloromethane); yield:
583 mg (50%). IR: 3340s, 2930vs, 1690vs (CvO),
1590vs, 1490vs, 1443vs, 1440vs, 1305s, 1260vs, 1210vs,
745s, 690s. 1H NMR: 7.49 (s, NH); 7.45±6.95 (m, 10
arom. H); 4.02±3.98 (m, CHN); 2.22, 2.19 (2s, 2 CH3);
1.80±1.00 (m, 5 CH2). 13C NMR: 153.1 (s, CvO); 141.0,
138.3, 133.1, 122.5, 118.1 (5s, C(2), C(4), C(5), 2 arom. C);
128.8, 125.9, 125.4, 123.5, 120.0 (5d, 10 arom. CH); 56.5
(d, CHN); 31.4, 26.2, 25.2 (3t, 5 CH2); 12.7, 10.8 (2q, 2
CH3). EI-MS: 388 (7, M1z), 270 (43), 269 (100), 268 (12),
188 (47), 187 (100), 186 (100), 171 (8), 119 (45), 111 (18).
Anal. Calcd for C24H28N4O (388.51): C 74.20, H 7.26, N
14.42; found: C 74.06, H 7.18, N 14.37.
1
749vs, 720vs, 698vs. H NMR (DMSO-d6): 8.50 (s, NH);
7.58±7.38, 7.29±7.06, 6.87±6.82 (3m, 15 arom. H); 3.30 (s,
CH3N). 13C NMR (DMSO-d6): 144.2, 142.6, 134.8, 132.0,
130.8, 124.8 (6s, C(2), C(4), C(5), 3 arom. C); 130.6, 128.9,
128.6, 128.2, 127.8, 125.8, 125.6, 119.5, 116.0 (9d, 15 arom.
CH); 30.6 (q, CH3N). CI-MS: 326 (100, [M11]1). Anal.
Calcd for C22H19N3 (325.41): C 81.20, H 5.89, N 12.91;
found: C 81.08, H 6.31, N 12.95.
Reactions of 5a with a two-fold molar amount of 8a,b
A solution of 367 mg (3 mmol) of 5a in 6 ml of abs.
dichloromethane was treated with 6 mmol of 8a and 8b,
respectively, according to the previous protocol. After
3 days, the solvent was evaporated under vacuum and the
residues were analyzed by 1H NMR spectroscopy. The only
products were 2-aminoimidazoles 9a and 9b, respectively.
Reactions of 1H-imidazole 3-oxides 5a±c with a two-fold
molar amount of phenyl isocyanate
Reactions of 1H-imidazole 3-oxides 5a±c with phenyl
isothiocyanate
General procedure: A stirred solution of 3 mmol of respec-
tive 5 in 6 ml of abs. dichloromethane was cooled in a water/
ice bath and a solution of 715 mg (6 mmol) of freshly
distilled phenyl isocyanate in 6 ml of abs. dichloromethane
was added in portions, whereby the temperature of the
mixture was kept at 0±58C. After complete addition, the
cooling bath was removed and the solution was stirred at
room temperature for 3 days. Evaporation of the solvent
under vacuum afforded solid residues which were puri®ed
by recrystallization. The stated yields refer to pure
compounds 10.
General procedure: To a stirred, cooled solution (water/ice
bath) of 3 mmol of respective 5 in 6 ml of abs. dichloro-
methane were added in small portions 405 mg (3 mmol)
phenyl isothiocyanate dissolved in 6 ml of abs. dichloro-
methane. After 20 h at room temperature, the solvent was
evaporated under vacuum and crude products 9 were
puri®ed either by chromatography or recrystallization.
1-Methyl-4,5-diphenyl-2-(phenylamino)imidazole (9d).
With 5a (750.9 mg, 3 mmol). Crystallization from hexane/
dichloromethane; mp 222±223.58C. Yield: 839 mg (86%).

Â
G. Mloston et al. / Tetrahedron 56 (2000) 5405±5412
5410
All spectral data were identical with those of the sample of
9d obtained from the reaction with phenyl isocyanate.
2-Methylamino-1-methyl-4,5-diphenylimidazole
(9c).
With methyl isothiocyanate (8e; 438.7 mg, 6 mmol). Color-
less crystals with mp 231±2338C (methanol/acetone); yield:
600 mg (76%). IR: 3230s, 1615vs, 1600vs, 1590s, 705vs. 1H
NMR (DMSO-d6): 7.54±7.09 (m, 10 arom. H); 3.42, 2.93
(2s, 2 CH3N). 13C NMR (DMSO-d6): 150.7, 135.6, 131.8,
131.3, 123.9 (5s, C(2), C(4), C(5), 2 arom. C); 130.5, 128.8,
127.7, 125.7, 125.0, 123.7 (6d, 5 arom. CH); 29.6, 29.0 (2q,
2 CH3N). CI-MS: 265 (18), 264 (100, [M11]1). Anal. Calcd
for C17H17N3 (263.34): C 77.54, H 6.51, N 15.96; found: C
77.44, H 6.36, N 15.96.
1-Benzyl-4,5-dimethyl-2-(phenylamino)imidazole (9e).
With 5b (606.8 mg, 3 mmol). Chromatography on silica
gel with hexane/ethyl acetate 1:1 and recrystallization
from hexane/dichloromethane; colorless crystals with mp
111.5±1138C; yield: 483 mg (58%). IR: 3029s, 2935s,
2914s, 1599vs, 1561vs, 1526vs, 1497vs, 1474s, 1447s,
1
1398vs, 1348s, 1306s, 1252s, 750s, 730s, 717s, 696s. H
NMR: 7.33±7.14, 7.02±6.99, 6.86±6.81, 6.79±6.76 (4m,
10 arom. H); 5.41 (s, NH); 4.92 (s, CH2N); 2.17, 2.05 (2s,
2 CH3). 13C NMR: 144.3, 144.0, 141.3, 136.7, 130.5 (5s,
C(2), C(4), C(5), 2 arom. C); 129.1, 128.8, 127.5, 126.1,
120.1, 115.1 (6d, 10 arom. CH); 46.3 (t, CH2N); 12.6, 9.0
(2q, 2 CH3). EI-MS: 278 (13), 277 (68, M1z), 226 (6), 187
(12), 186 (100, [M2C6H5N]1), 183 (6). Anal. Calcd for
C18H19N3 (277.37): C 77.94, H 6.90, N 15.15; found: C
77.36, H 7.08, N 15.03.
Reaction of 2-aminoimidazole 9d with phenyl isocyanate
and phenyl isothiocyanate
A solution of 1 mmol of 9d in 4 ml of dichloromethane was
treated with 1.3 mmol of phenyl isocyanate. The solution
was stirred at room temperature for 3 days. Evaporation of
the solvent under vacuum afforded crude 10a which was
puri®ed by recrystallization. Yield: 351 mg (79%).¶
1-Cyclohexyl-4,5-diphenyl-2-(phenylamino)imidazole (9f).
With 1-cyclohexyl-4,5-diphenylimidazole 3-oxide (5d;
955.3 mg, 3 mmol). Crystallization from hexane/dichloro-
methane; colorless crystals with mp 139±1408C; yield:
956 mg (81%). IR: 2940vs, 1605vs, 1525vs, 1500vs,
1460vs, 1400m, 1380s, 1300s, 1270s, 770s, 700vs. 1H
NMR: 7.46±6.83 (m, 15 arom. H); 3.77±3.73 (m, CHN);
1.91±1.49, 1.15±0.93 (2m, 5 CH2). 13C NMR: 145.0, 142.7,
137.4, 134.8, 134.6, 131.9 (6s, C(2), C(4), C(5), 3 arom. C);
131.6, 128.9, 128.7, 127.9, 126.8, 126.0, 125.3, 120.1, 115.6
(9d, 15 arom. CH); 56.3 (d, CHN); 32.4, 26.1, 25.1 (3t, 5
CH2). CI-MS: 394 (8, [M11]1), 393 (24, M1z), 303 (21),
302 (93), 220 (52), 219 (55), 193 (7), 165 (17), 93 (100), 77
(14). Anal. Calcd for C27H27N3 (393.53): C 82.41, H 6.92, N
10.68; found: C 81.82, H 7.22, N 10.67.
The analogous reaction with phenyl isothiocyanate gave no
thiourea derivative. More than 90% of 9d were recovered
unchanged.
Reactions of 1H-imidazole 3-oxides 5b±e with dimethyl
acetylenedicarboxylate (DMAD)
General procedure: A solution of 284 mg (2 mmol) of
DMAD in 4 ml of chloroform was cooled in a water/ice
bath and stirred magnetically. Then, 2 mmol of respective
5 dissolved in 3 ml of chloroform were added in small
portions in order to keep the temperature of the mixture at
0±58C. When the addition was complete, the cooling bath
was removed and the mixture was stirred at room tempera-
ture for 1 h. Evaporation of the solvent under vacuum
afforded crude products 11 which were puri®ed by recrys-
tallization.
Reactions of 5a with two-fold molar amount of
isothiocyanates 8c±e
Dimethyl
3-(1-benzyl-2,3-dihydro-4,5-dimethyl-1H-
In analogy to the reactions with isocyanates, solutions of
367 mg (3 mmol) of 5a in 6 ml of abs. dichloromethane
were reacted with 2 equiv. of 8c±e. After stirring for 20 h
at room temperature, evaporation of the solvent afforded
crude 2-aminoimidazoles 9a±c. In the cases of 8c
(847.4 mg, 6 mmol) and 8d (691.2 mg, 6 mmol), 2-cyclo-
imidazol-2-ylidene)-2-oxobutanedioate (11a). With 5b
(404.5 mg, 2 mmol). Colorless crystals; mp 200±2028C
(diethyl ether/dichloromethane); yield: 410 mg (60%). IR:
2950s, 1720vs (CvO), 1670vs (CvO), 1650vs (CvO),
1560vs, 1540s, 1440vs, 1390s, 1310vs, 1240vs, 1220vs,
1
1200vs, 1140s, 1090vs, 1030s, 980s. H NMR: 7.31±7.06
hexylamino-1-methyl-4,5-diphenylimidazole
(9a)
and
2-butylamino-1-methyl-4,5-diphenylimidazole (9b), respec-
(m, 5 arom. H); 5.13 (s, CH2N); 3.82, 3.52 (2s, 2 CH3O);
2.17, 1.96 (2s, 2 CH3). 13C NMR: 208.7 (s, CvO ketone);
168.4, 167.8 (2s, 2 CvO ester); 143.7 (s, C(2)); 134.7 (s, 1
arom. C); 127.8, 127.2, 126.0 (3d, 5 arom. CH); 123.6,
123.2 (2s, C(4), C(5)); 80.9 (s, CvC); 52.2, 51.5 (2q, 2
CH3O); 49.2 (t, CH2N); 9.4, 8.9 (2q, 2 CH3). CI-MS: 345
(70, [M11]1), 318 (16), 317 (100, [(M11)2CO]1), 314 (5),
313 (31), 285 (12, [M2COOCH3]1), 257 (5), 91 (14). Anal.
Calcd for C18H20N2O5 (344.37): C 62.78, H 5.85, N 8.13;
found: C 62.60, H 5.51, N 8.24.
tively, were formed as the only products.
The products were isolated as hydrochlorides: a solution of
crude 9a and 9b, respectively, was treated with 3 M HCl
until pH 3±4 was obtained. After stirring for 1 h, the white
precipitate was ®ltered, washed with diethyl ether, and
dried. Yields of hydrochlorides: 80 and 70%, respectively.
Then, a concentrated solution of ammonium hydroxide was
added to a suspension of the hydrochloride in diethyl ether
under vigorous stirring until pH 8±9 was reached. After 1 h
at room temperature, the organic phase was separated
and the aqueous phase was extracted with diethyl ether
(3£). The combined organic phases were dried with
MgSO4 and the solvent was evaporated. Yields: 90% of
9a and 9b.
Dimethyl 3-(1-cyclohexyl-2,3-dihydro-4,5-dimethyl-1H-
imidazol-2-ylidene)-2-oxobutanedioate (11b). With 5c
(388.5 mg, 2 mmol). Colorless crystals; mp 206±2088C
¶
Treatment of 9d with cyclohexyl isocyanate under the same conditions
yielded no urea derivative; 9d was recovered in .90% yield.

Â
G. Mloston et al. / Tetrahedron 56 (2000) 5405±5412
5411
(diethyl ether/dichloromethane); yield: 439 mg (64%). IR:
2950vs, 2870s, 1740vs (CvO), 1680vs (CvO), 1635vs
(CvO), 1560vs, 1530s, 1450vs, 1370s, 1295vs, 1220vs,
F using full-matrix least-squares procedures, which mini-
mized the function Sw(uFou2uFcu).2 A correction for second-
ary extinction was not applied. Neutral atom scattering
factors for non-H atoms were taken from Ref. 20, and the
1
1095vs, 1040s. H NMR: 12.35 (s, NH); 4.15±4.10 (m,
CHN); 3.83, 3.57 (2s, 2 CH3O); 2.30, 2.13 (2s, 2 CH3);
1.94±1.12 (m, 5 CH2). 13C NMR: 209.0 (s, CvO ketone);
169.4, 168.3 (2s, 2 CvO ester); 142.7 (s, C(2)); 124.8,
123.2 (2s, C(4), C(5)); 81.3 (s, CvC); 59.1 (d, CHN);
51.8, 50.6 (2q, 2 CH3O); 31.1, 26.0, 25.3 (3t, 5 CH2);
10.6, 9.1 (2q, 2 CH3). EI-MS: 337 (5, [M11]1), 336 (12,
M1z), 278 (15), 277 (100, [M2COOCH3]1), 249 (5), 195
(36), 194 (13), 167 (12), 136 (11), 135 (37), 83 (13). Anal.
Calcd for C17H24N2O5 (336.39): C 60.70, H 7.19, N 8.33;
found: C 60.14, H 7.12, N 7.97.
scattering factors for H-atoms from Ref. 21. Anomalous
22
dispersion effects were included in Fcalc
;
the values for f0
and f00 were those of Ref. 23. All calculations were
performed using the texsan crystallographic software
package.24
Crystal data for 9c
A crystal of dimension 0.15£0.25£0.45 mm3 was grown
from methanol. C17H17N3, Mrˆ263.34, orthorhombic,
space group Pbca, aˆ12.485(2), bˆ26.134(3), cˆ
Dimethyl 3-(1-cyclohexyl-2,3-dihydro-4,5-diphenyl-1H-
imidazol-2-ylidene)-2-oxobutanedioate (11c). With 5d
(636.8 mg, 2 mmol). Colorless crystals; mp 219±2218C
(methanol); yield: 760 mg (83%). IR: 2940vs, 2855s,
1720vs (CvO), 1680vs (CvO), 1635vs (CvO), 1560vs,
1540s, 1430vs, 1390s, 1370s, 1300s, 1230s, 1160s, 1100s,
1070vs, 1000s, 780vs. 1H NMR: 7.49±7.01 (m, 10 arom. H);
4.06±4.02 (m, CHN); 3.79, 3.68 (2s, 2 CH3O); 1.89±1.47,
1.19±0.80 (2m, 5 CH2). 13C NMR: 202.5 (s, CvO ketone);
168.4, 167.9 (2s, 2 CvO ester); 144.4 (s, C(2)); 132.1,
130.1, 127.7, 127.3 (4s, 2 arom. C, C(4), C(5)); 128.8,
128.7, 128.2, 126.8 (4d, 10 arom. CH); 82.0 (s, CvC);
60.6 (d, CHN); 51.8, 50.9 (2q, 2 CH3O); 32.0, 26.2, 24.9
(3t, 5 CH2). EI-MS: 461 (19, [M11]1), 460 (69, M1z), 402
(19), 401 (77, [M2COOCH3]1), 400 (28), 373 (23), 319
(80), 317 (100), 292 (21), 291 (55), 260 (28), 259 (70),
233 (10), 193 (18), 165 (11), 128 (12), 103 (15). Anal.
Calcd for C27H28N2O5 (460.53): C 70.42, H 6.13, N 6.08;
found: C 70.36, H 6.07, N 6.20.
8.580(2) A, Vˆ2799.3(9) A , Zˆ8, Dcˆ1.250 g cm23
,
Ê
Ê 3
m(MoKa)ˆ0.0757 mm21
;
Tˆ173(1) K, lˆ0.71069 A.
Ê
Cell dimension from 25 re¯ections in the range 2uˆ26±
378, v scans, 2u(max)ˆ558, 4286 re¯ections measured,
3219 symmetry-independent re¯ections, 2183 re¯ections
with I.2s(I) used in the re®nement of 249 parameters.
Final Rˆ0.0393, wRˆ0.0346 (wˆ[s2(Fo)1(0.005Fo)2]21),
GoFˆ1.527,
D
max/sˆ0.0004, Dr(max; min)ˆ0.19;
Ê 23
20.18 e A
.
Acknowledgements
We thank our analytical units for elemental analyses and
spectra, Dr A. Linden (ZuÈrich) for the X-ray crystal-struc-
ture determination, and Mrs M. Celeda (èodz) for technical
assistance. Financial support of this work by The Polish
State Committee for Scienti®c Research (KBN grant No.
3 T09A 007 16), the Swiss National Science Foundation,
and F. Hoffmann-La Roche AG, Basel, is gratefully
acknowledged. T. G. thanks the Dr Helmut Legerlotz-
Dimethyl 3-(2,3-dihydro-1,4,5-trimethyl-1H-imidazol-2-
ylidene)-2-oxobutanedioate (11d). With 1,4,5-trimethyl-
1H-imidazole 3-oxide (5d; 252.32 mg, 2 mmol). Colorless
crystals; mp 189±1918C (diethyl ether/dichloromethane);
yield: 320 mg (60%). IR: 2955m, 1730vs (CvO), 1650vs
È
È
Stiftung, Universitat Zurich, for a scholarship.
1
(CvO), 1510vs, 1445s, 1305m, 1200s, 1070s. H NMR:
References
11.19 (s, NH); 3.84, 3.63 (2s, 2 CH3O); 3.44 (s, CH3N);
2.19, 2.16 (2s, 2 CH3). 13C NMR: 208.6 (s, CvO ketone);
168.8, 167.3 (2s, 2 CvO ester); 143.5 (s, C(2)); 123.1,
121.9 (2s, C(4), C(5)); 81.2 (s, CvC); 51.7, 50.9 (2q, 2
CH3O); 32.7 (q, CH3N); 9.0, 8.4 (2q, 2 CH3). CI-MS: 269
(100, [M11]1), 209 (21). Anal. Calcd for C12H16N2O5
(268.27): C 53.73, H 6.01, N 10.44; found: C 53.72, H
5.83, N 10.09.
1. Grimmett, M. R. In Comprehensive Heterocyclic Chemistry,
Potts, K. T., Ed.; Pergamon: Oxford, 1984; Vol. 5, pp 373±498.
2. Kaiya, T.; Aoyama, S.; Kohda, K. Bioorg. Med. Chem. Lett.
1998, 8, 625±630.
Â
3. Mloston, G.; Gendek, T.; Heimgartner, H. Helv. Chim. Acta
1998, 81, 1585±1595.
Â
4. Alcazar, J.; Begtrup, M.; de la Hoz, A. J. Chem. Soc., Perkin
Â
Trans. 1 1995, 2467±2470; Alcazar, J.; Begtrup, M.; de la Hoz, A.
Heterocycles 1996, 43, 1465±1470.
Crystal structure determination of 9c
Â
5. Bartnik, R.; Mloston, G. Roczniki Chem. 1977, 51, 1747±1750;
Chem. Abstr. 1978, 88, 62332.
Â
6. Mloston, G.; Celeda, M.; Prakash, G. K. S.; Olah, G. A.;
Heimgartner, H. Helv. Chim. Acta 2000, 83, 728±738.
(See Fig. 1.18) The intensities were collected on a Rigaku
AFC5R diffractometer using graphite-monochromated
MoKa radiation and a 12 kW rotating anode generator.
The intensities were corrected for Lorentz and polarization
effects but not for absorption. The structure was solved by
direct methods using shelxs86,19 which revealed the
positions of all non-H atoms. The non-H atoms were re®ned
anisotropically. All of the H-atoms were located in a differ-
ence electron density map and their positions were allowed
to re®ne together with individual isotropic displacement
parameters. Re®nement of the structure was carried out on
Â
7. Alcazar, J.; Begtrup, M.; de la Hoz, A. J. Org. Chem. 1996, 61,
6971±6973.
8. Ferguson, I. J.; Scho®eld, K. J. Chem. Soc., Perkin Trans. 1
1975, 275±277.
9. Matsuoka, T.; Shinada, M.; Suematsu, F.; Harano, K.; Hisano,
T. Chem. Pharm. Bull. 1984, 32, 2077±2090.
10. Nour El-Din, A. M.; Tawik, A.-R. M.; Ramadan, M. Rev.
Roum. Chim. 1988, 33, 183±187; Chem. Abstr. 1989, 110, 95085.

Â
G. Mloston et al. / Tetrahedron 56 (2000) 5405±5412
5412
11. Ryzhakov, A. V.; Rodina, L. L. Khim. Geterotsikl. Soedin.
1992, 579±591; Chem. Abstr. 1993, 118, 168895.
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: 144-
(0)-1223-336033, or e-mail: deposit@ccdc.cam.ac.uk).
19. Sheldrick, G. M. Shelxs86. Acta Crystallogr., Sect. A 1990,
46, 467±473.
12. Kim, H. S.; Kurasawa, Y.; Takada, A. J. Heterocycl. Chem.
1989, 26, 871±873.
13. Johnson, C. K. ortep ii, Report ORNL-5138; Oak Ridge
National Laboratory, Oak Ridge, Tennessee, 1976.
20. Maslen, E. N.; Fox, A. G.; O'Keefe, M. A. In International
Tables for Crystallography, Wilson, A. J. C., Ed.; Kluwer
Academic: Dordrecht, 1992; Vol. C, pp 477±486 (Table 6.1.1.1).
21. Stewart, E. F.; Davidson, E. R.; Simpson, W. T. J. Chem. Phys.
1965, 42, 3175±3187.
14. 1,3-Dipolar Cycloaddition Chemistry, Padwa, A., Ed.; Wiley:
New York, 1984; vols. 1/2.
15. Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry,
Padwa, A., Ed.; Wiley: New York, 1984; Vol. 2, pp 83±168.
16. Clark, B. A. J.; Evans, T. J.; Sommonds, R. G. J. Chem. Soc.,
Perkin Trans. 1 1975, 1803±1806.
22. Ibers, J. A.; Hamilton, W. C. Acta Crystallogr. 1964, 17, 781±
782.
23. Creagh, D. C.; McAuley, W. J. In International Tables for
Crystallography, Wilson, A. J. C., Ed.; Kluwer Academic:
Dordrecht, 1992; Vol. C, pp 219±222 (Table 4.2.6.8).
24. texsan, Single Crystal Structure Analysis Software, Version
5.0; Molecular Structure Corporation, The Woodlands: Texas,
1989.
17. Latham, D. W. S.; Meth-Cohn, O.; Suschitzky, H.; Herbert,
J. A. L. J. Chem. Soc., Perkin Trans. 1 1977, 470±478.
18. Crystallographic data (excluding structure factors) for the
structure have been deposited with the Cambridge Crystallo-
graphic Data Center as deposition No. CCDC-142963. Copies of
the data can be obtained, free of charge, on application to the