Synthesis of imidazole derivatives using 2-unsubstituted 1H-imidazole 3- oxides

Article abstract of DOI:10.1002/(SICI)1522-2675(20000412)83:4<728::AID-HLCA728>3.0.CO;2-B

The reaction of 1,4,5-trisubstituted 1H-imidazole 3-oxides 1 with Ac₂O in CH₂Cl₂ at 0-5°leads to the corresponding 1,3-dihydro-2H-imidazol-2-ones 4 in good yields. In refluxing Ac₂O, the N-oxides 1 are transformed to N- acetylated 1,3-dihydro-2H-imidazol-2-ones 5. The proposed mechanisms for these reactions are analogous to those for N-oxides of 6-membered heterocycles (Scheme2). A smooth synthesis of 1H-imidazole-2-carbonitriles 2 starting with 1 is achieved by treatment with trimethylsilanecarbonitrile (Me₃SiCN) in CH₂Cl₂ at 0-5°(Scheme 3).

Full text of DOI:10.1002/(SICI)1522-2675(20000412)83:4<728::AID-HLCA728>3.0.CO;2-B

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Helvetica Chimica Acta ± Vol. 83 (2000)
Synthesis of Imidazole Derivatives Using 2-Unsubstituted 1H-Imidazole
3-Oxides
by Grzegorz MlostonÂ*1) and Maøgorzata Celeda
Â
Â
Â
Â
Department of Organic & Applied Chemistry, University of èodz, Narutowicza 68, PL-90-136 èodz
and G. K. Surya Prakash* and George A. Olah
Loker Hydrocarbon Institute, University of Southern California, Los Angeles, CA 90089
and Heinz Heimgartner*
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
The reaction of 1,4,5-trisubstituted 1H-imidazole 3-oxides 1 with Ac2O in CH2Cl2 at 0 ± 58 leads to the
corresponding 1,3-dihydro-2H-imidazol-2-ones 4 in good yields. In refluxing Ac2O, the N-oxides 1 are
transformed to N-acetylated 1,3-dihydro-2H-imidazol-2-ones 5. The proposed mechanisms for these reactions
are analogous to those for N-oxides of 6-membered heterocycles (Scheme 2). A smooth synthesis of 1H-
imidazole-2-carbonitriles 2 starting with 1 is achieved by treatment with trimethylsilanecarbonitrile (Me3SiCN)
in CH2Cl2 at 0 ± 58 (Scheme 3).
Introduction. ± The relevance of imidazole chemistry is clearly shown by the
presence of this heterocycle in biologically important systems and by numerous
applications of imidazole derivatives in pharmaceutical and agricultural chemistry
[1][2]. For this reason, the elaboration of new syntheses of imidazole derivatives is of
current interest. Among other important imidazole derivatives are 2H-imidazol-2-ones
[3] and imidazole-2-carbonitriles (ꢀ2-cyanoimidazolesꢁ) [4][5]. Although it is well-
known that heterocyclic N-oxides are versatile starting materials for the functionaliza-
tion of the parent heterocycles [6][7], the application of imidazole N-oxides for this
purpose is only rarely described.
In contrast to 6-membered N-heterocycles, the oxidation of imidazoles does not
lead to the expected N-oxides (cf. [1b][8])2). Therefore, imidazole N-oxides are only
available by cyclization of suitable open-chain precursors [2]. In a recent paper, we
described the preparation of a series of 2-unsubstituted imidazole N-oxides by
condensation of a-(hydroxyimino)ketones with methylidene alkylamines in EtOH
solution [10]. A related procedure, which is based on the condensation of 1,4-
diazabuta-1,3-dienes (1,2-diimines) or 2-iminopropanal dimethyl acetal with oximes in
solution or under solvent-free conditions (SiO2, alumina as solid support), was also
reported [11].
1
)
)
Sabbatical at the Loker Hydrocarbon Institute, USC, Los Angeles, CA 90089, 09.96 ± 03.97.
Attempted oxidations of 1-methyl-1H-benzimidazole derivatives with 3-chloroperbenzoic acid led to the
formation of 2-[(3-chlorobenzoyl)oxy]-1H-benzimidazoles or 1,3-dihydro-2H-benzimidazol-2-ones in
rather low yields [9].
2

Helvetica Chimica Acta ± Vol. 83 (2000)
729
Several years ago, Ferguson and Schofield described first synthetic applications of
2-unsubstituted imidazole N-oxides 1 for the functionalization of the ring system [12].
Treatment of 1 with Me2SO4 and KCN yielded 1H-imidazole-2-carbonitriles 2, and the
reaction with POCl3 led to the chlorinated 1H-imidazoles 3 (Scheme 1). Deoxygena-
tion of 1 was achieved either with PCl3 [12] or with Zn/AcOH [13].
Scheme 1
Another type of conversion of 1, in which the O-atom remains in the molecule, is
the photochemical isomerization to the corresponding 1,3-dihydro-2H-imidazol-2-one
4 [14]3). On the other hand, matrix photolysis at 70 K of imidazole N-oxides of type 1
afforded products containing an NˆCˆO group, and this result is explained in terms of
the formation of an oxaziridine intermediate and subsequent ring opening [16]. A
further synthetic potential for compounds of type 1 is their reactivity as 1,3-dipoles. The
first conversions of this type using phenyl isocyanate and dimethyl acetylenedicarbox-
ylate as dipolarophiles were also described in [12]. Recently, we reported on reactions
of 1 with thioketones, resulting in the formation of 1,3-dihydro-2H-imidazole-2-thiones
[10]. The mechanism of this S-transfer reaction involved a [2 ‡ 3] cycloaddition as the
initial step.
In the present paper, we describe the thermal transformation of 1H-imidazole 3-
oxides of type 1 into 1,3-dihydro-2H-imidazol-2-ones 4 and 5, as well as a convenient
route to 1H-imidazole-2-carbonitriles 2. As already pointed out, both types of
imidazole derivatives are of interest as building blocks in organic syntheses.
Results and Discussion. ± The heating of solutions of 1H-imidazole 3-oxides 1a ± h,
prepared according to [10], in Ac2O for 10 ± 60 min led to crystalline products 5a ± h in
high yields (Scheme 2, Table 1). Their mass spectra and elemental analyses indicated
that acetylated imidazolone derivatives were formed. Based on the IR and NMR data,
an unambiguous differentiation between an N- and an O-acylated product was
not possible. For example, the product 5a of the reaction with 1,4,5-trimethyl-1H-
imidazole 3-oxide (1a) showed 4s in the 13C-NMR spectrum (CDCl3) at 170.9, 152.6,
3
)
The photolysis of 2-phenyl-1H-imidazole 3-oxides led to ring opening and formation of N-benzoyl-1,4-
diazabuta-1,3-dienes as the only product [15].

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Helvetica Chimica Acta ± Vol. 83 (2000)
Scheme 2a)
a) For R1,R2, and R3, see Table 1.
Table 1. 1H-Imidazol-2(3H)-ones 4 and 5 Prepared by Treatment of 1a ± i with Ac2O
1a
1b
1c
1d
1e
1f
1g
1h
1i
R1
Me
Me
Me
±
Et
Me
Me
±
PhCH2 cHex
Me
Ph
Me
cHex
Ph
Ph
PhCH2CH2 cHex
Me
Ph
Ph
R2
Me
Me
Me
±
Ph
Ph
Ph
Me
R3
Me
4 (yield [%])a)
4c (34)
4e (68) 4f (66) 4g (72)
4h (53) 4i (84)
5h (63)
5 (yield [%])b) 5a (67) 5b (72) 5c (61) 5d (62) 5e (66) 5f (73) 5g (69)
±
a) Reaction of 1 in CH2Cl2 with Ac2O at 0 ± 58. b) Reaction of 1 in refluxing Ac2O.
117.8, and 113.3 ppm. The signal at 152.6 ppm could be attributed to C(2) of either a
1,3-dihydro-2H-imidazol-2-one or a 2-acetoxy-1H-imidazole. Moreover, the IR spec-
1
trum (KBr) showed only one strong absorption band at 1730 cm accompanied by a
1
rather weak one at 1690 cm . Therefore, an X-ray crystal-structure determination of the
product 5e obtained from 1e (Scheme 2, Table 1) was performed. The structure was
established as 1-acetyl-1,3-dihydro-3,4-dimethyl-5-phenyl-2H-imidazol-2-one (5e, Fig.).
Comparison of the spectral data of 5e with those of the other compounds 5
obtained in an analogous manner led us to the conclusion that N-acetylated derivatives
were obtained in all cases. There are only a few compounds of this type reported so far.
All of them were obtained by acylation of the corresponding 1,3-dihydro-2H-imidazol-
2-ones [3][18]. In comparison with our reaction conditions, longer reaction times were
required to complete the reactions in both protocols4). A comparable transformation
4
)
The structure of 1-acetyl-3-cyclohexyl-1,3-dihydro-5-methyl-4-phenyl-2H-imidazol-2-one prepared by
DeKimpe et al. was also established by X-ray crystallography [3].

Helvetica Chimica Acta ± Vol. 83 (2000)
731
Figure. ORTEP Plot [17] of the molecular structure of 5e (arbitrary numbering of the atoms; 50% probability
ellipsoids)
has been reported by Takahashi and Kano: the reaction of 1-methyl-1H-benzimidazole
3-oxide in Ac2O afforded 1-acetyl-1,3-dihydro-3-methyl-2H-benzimidazol-2-one [19].
In contrast, the treatment of 1c,e ± i in diluted CH2Cl2 solution with a slight excess of
Ac2O, while keeping the temperature at 0 ± 58, led to 1,3-dihydro-2H-imidazol-2-ones
4c,e ± i as the only products (Scheme 2, Table 1).
In analogy to the mechanistic interpretation of the reaction of pyridine 1-oxide with
Ac2O leading to 2-acetoxypyridine [20], we propose the formation of intermediate A as
the initial step followed by elimination of AcOH to give 2-acetoxy-1H-imidazole B
(Scheme 2). In refluxing Ac2O, a second acetylation to yield imidazolium species C is
conceivable; deacetylation of the latter by cleavage of the AcO group leads to 5. In
dilute solution at room temperature, no N-acetylation takes place. The activation for
the cleavage of the AcO group is achieved rather by protonation, and the deacetylation
occurs again via nucleophilic attack of AcO . There are some formal similarities of
these transformations with the Polonovski reaction [21], in which aliphatic N-oxides
are treated with acid anhydrides to give an acid amide and an aldehyde via cleavage of
one of the alkyl N bonds. As in the case of 1, the first step is the acylation of the N-
oxide. Whereas in the Polonovski reaction an elimination of the carboxylic acid leads to
an iminium ion, which subsequently adds a carboxylate ion, in the case of 1 an addition
of the carboxylate ion to the primarily formed imidazolium salt leads to intermediate
A, which, in turn, eliminates a carboxylic acid to give B.

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Helvetica Chimica Acta ± Vol. 83 (2000)
In recent years, synthetic methods for the formation of C C bonds by using silanes
have been studied extensively [22]. Two frequently applied reagents are trimethyl(tri-
fluoromethyl)silane (Me3SiCF3) [23] and trimethylsilanecarbonitrile (Me3SiCN) [24].
In this paper, we report on the cyanation of imidazoles at C(2) starting with the
corresponding 3-oxides 15). Fundamental work by Vorbrüggen on the cyanation of N-
oxides of 6-membered heterocycles using Me3SiCN opened new perspectives for the
synthesis of cyano derivatives [28]. Using this method for the cyanation of 1-substituted
1H-imidazole 3-oxides led to mixtures of 2-, 4-, and 5-cyano-substituted imidazoles
[29]. The ratio of the isomers depended on the solvent and the temperature of the
reaction.
Following the methodology of cyanation of pyridine 1-oxides (cf. [28]), solutions of
1,4,5-trisubstituted 1H-imidazole 3-oxides 1 in dry CH2Cl2 in the presence of Et3N and
molecular sieves (4Š)6) were treated with Me3SiCN. The temperature of the mixture
was kept at 0 ± 58, and the progress of the reaction was followed by TLC. After 1 h, the
starting material had been consumed, in contrast to the procedure described in [29]7).
After chromatographic workup, imidazole-2-carbonitriles 2 were obtained in good
yields (Scheme 3, Table 2). Careful drying of the substrate and the solvent, and addition
of activated molecular sieves was essential to reach the reported yields of 2 and to limit
the reaction time. For example, in the case of 1i, which forms stable hydrates, the
reaction carried out without activated molecular sieves led to a black mixture and tarry
by-products, and the yield of 2i dropped below 20%.
Scheme 3a)
TMS ˆ Me3Si
a) For R1,R2, and R3, see Table 2.
The reaction mechanism for the formation of 2 is analogous to that proposed for
the cyanation of azine N-oxides [28]: silylation of the N-oxide leads to the imidazolium
ion D, which adds a CN ion to give E (Scheme 3). Smooth elimination of Me3SiOH
yields 2.
5
)
Along with already cited methods for the cyanation of imidazole at C(2) [4][5][12], an electrophilic
cyanation of lithiated 1-methyl-1H-imidazole with TsCN has been reported recently [25]. Nucleophilic
substitution of 2,4-dibromo-1-methyl-5-nitro-1H-imidazole with NaCN gave the corresponding imidazole-
carbonitrile [26]. Anodic cyanation of 1-methyl-1H-imidazoles yielded mixtures of 2-, 4-, and 5-cyano-
substituted derivatives [27].
6
7
)
The molecular sieves were activated prior to their use by heating commercial 4-Š sieves with a gas flame for
15 min at 0.1 Torr.
Cyanation of 1-cyclohexyl-1H-imidazole 3-oxide was performed at 20, 40, and 608 with reaction times of 96,
24, and 17 h, respectively [29].
)

Helvetica Chimica Acta ± Vol. 83 (2000)
733
Table 2. 1H-Imidazole-2-carbonitriles 2 Prepared from 1 and Me3SiCN
1a
1c
1d
1f
1h
1j
R1
Me
Me
Me
PhCH2
Me
Me
cHex
Me
Me
cHex
Ph
Ph
Me
Ph
Ph
PhCH2
Ph
Ph
R2
R3
2 (yield [%])
2a (78)
2c (59)
2d (86)
2f (83)
2h (73)
2j (64)
In summary, smooth conversions of 2-unsubstituted 1H-imidazole 3-oxides 1 into
1,3-dihydro-2H-imidazol-2-ones 4, 1-acetyl-1,3-dihydro-2H-imidazol-2-ones 5, and 1H-
imidazole-2-carbonitriles 2 were achieved. As the starting compounds 1 with various
substituents are easily accessible, and as the procedures used led very efficiently to the
products in high yields, the described methods are highly recommendable for the
preparation of imidazole derivatives of type 2, 4 and 5.
G. M. thanks the Loker Hydrocarbon Institute, USC, for a scholarship, and the Rector of the University of
Â
Â
èodz for the permission to take a sabbatical leave (09.96 ± 03.97). We thank Dr. Anthony Linden, University of
Zürich, for performing the X-ray crystal-structure determination and F. Hoffmann-La Roche AG for financial
support.
Experimental Part
1. General. M.p.: Melt-Temp-II apparatus (Aldrich); in capillary; uncorrected. IR Spectra: Specord-75 IR
1
spectrometer; in KBr; cm 1. H- and 13C-NMR Spectra: Varian-Gemini-200 or Varian-VX-200 spectrometers;
CDCl3 solns.; chemical shifts d in ppm rel. to SiMe4 (ˆ0 ppm). MS: VG-7070 or Finnigan-MAT-90 instruments;
EI at 70 eV; CI with NH3; m/z (rel. %). Elemental analyses were performed in the Galbraith Laboratory
(Knoxville, Tennessee) and microanalytical laboratory of the University of Zürich.
2. Starting Materials. Syntheses and properties of 1H-imidazole 3-oxides 1a ± g were described in [10].
1-Cyclohexyl-5-methyl-4-phenyl-1H-imidazole 3-Oxide (1h) was prepared according to [10] from 3-(hydroxy-
imino)-3-phenylpropan-2-one [30] and 1,3,5-tri(cyclohexyl)hexahydro-1,3,5-triazine [31]. Colorless crystals.
M.p. 197 ± 1998 (Et2O/CH2Cl2). IR (KBr): 3090s, 2950vs, 2880s, 1620m, 1450s, 1420s, 1340vs (br.), 1315s, 1230vs,
1200s, 1025m, 890m, 790s, 760s, 710s, 700vs. 1H-NMR: 7.92 (s, CH); 7.65 ± 7.35 (m, 5 arom. H); 3.90 ± 3.85
(m, 1 H, cHex); 2.35 ± 1.20 (m, 10 H, cHex). 13C-NMR: 129.8, 127.4, 121.5 (3s, 1 arom. C, C(4), C(5)); 128.4,
.
‡
128.2, 122.5 (3d, 5 arom. C); 55.6 (d, CH); 33.8, 25.5, 24.9 (3t, 5 CH2). EI-MS: 256 (31, M ), 240 (59), 174 (51),
157 (100), 130 (26), 104 (29), 89 (20), 77 (22). Anal. calc. for C16H20N2O (256.35): C 74.97, H 7.86, N 10.93;
found: C 74.73, H 7.92, N 10.84.
Trimethylsilanecarbonitrile (Me3SiCN) was a commercial reagent (Aldrich) distilled prior to use and stored
in the refrigerator.
3. Isomerization of 1H-Imidazole 3-Oxides 1 to 1,3-Dihydro-2H-imidazol-2-ones 4: General Procedure. To a
stirred soln. of 1H-imidazole 3-oxide 1 (1 mmol) in abs. CH2Cl2 (1 ml) in a H2O/ice cooling bath, a soln. of
freshly distilled Ac2O (0.5 ml (5.3 mmol)) in 1.5 ml of CH2Cl2 was added portionwise within ca. 10 min. The
clear soln. was stirred until 1 was completely consumed (TLC monitoring; for reaction times, see data below).
Then, the mixture was diluted with MeOH (2 ml) and stirring continued for another 5 min. The solvents were
evaporated, and the solid residue was triturated with 80% EtOH (ca. 5 ml) and filtered under vacuum. Anal.
pure products were obtained by recrystallization from an appropriate solvent.
1-Benzyl-1,3-dihydro-4,5-dimethyl-2H-imidazol-2-one (4c): After 1.5 h, 68.8 mg (34%). Colorless crystals.
M.p. 195 ± 1978 (EtOH) ([32]: 197 ± 2018). IR: 3300 ± 2800s (br., NH), 1680vs (br., CˆO), 1460m, 1430m,
1410s, 1365m, 815m (br.), 730s. 1H-NMR: 10.25 (br. s, NH); 7.10 (br. s, 5 arom. H); 4.70 (s, CH2); 1.79, 1.42 (2s,
2 Me). 13C-NMR: 155.3 (s, CˆO); 138.4 (s, 1 arom. C); 129.2, 128.9, 127.5 (3d, 5 arom. C); 114.1, 113.0 (2s,
C(4), C(5)); 44.3 (t, CH2); 9.4, 8.5 (2q, 2 Me).
1,3-Dihydro-1,5-dimethyl-4-phenyl-2H-imidazol-2-one (4e): After 15 min, 128.0 mg (68%). Colorless
crystals. M.p. 246 ± 2518 (dec.) (EtOH) ([33]: 251 ± 2528). IR: 3200 ± 2800s (br., NH), 1680vs (br., CˆO),
1600m, 1505m, 1465m, 1440m, 1400m, 1395m, 990m, 845m (br.), 760m, 740s. 1H-NMR: 9.80 (br. s, NH); 7.40 ±
7.20 (m, 5 arom. H); 3.21 (s, MeN); 2.21 (s, Me). 13C-NMR: 154.5 (s, CˆO); 130.9 (s, 1 arom. C); 129.2, 127.0,
126.5 (3d, 5 arom. C); 117.7, 116.4 (2s, C(4), C(5)); 27.2 (q, MeN); 9.8 (q, Me).

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Helvetica Chimica Acta ± Vol. 83 (2000)
1-Cyclohexyl-1,3-dihydro-4,5-diphenyl-2H-imidazol-2-one (4f): After 15 min, 210.2 mg (66%). Colorless
crystals. M.p. 286 ± 2908 (EtOH) ([34]: 297 ± 2988). IR: 3200 ± 2800vs (br., NH), 1685vs (br., CˆO), 1600m,
1510m, 1450m (br.), 1375s, 840m, 765m, 760m, 755m, 695s. 1H-NMR: 10.50 (br. s, NH); 7.50 ± 7.20 (m,
5 arom. H); 7.10 (br. s, 5 arom. H); 3.60 ± 3.40 (m, 1 H, cHex); 2.55 ± 1.00 (m, 10 H, cHex). 13C-NMR: 154.5
(s, CˆO); 130.9, 130.3 (2s, 2 arom. C); 131.8, 129.5, 129.3, 128.8, 126.8, 125.8 (6d, 10 arom. C); 121.6, 118.6 (2s,
C(4), C(5)); 54.6 (d, CH); 30.5, 26.2, 25.0 (3t, 5 CH2).
1,3-Dihydro-4,5-diphenyl-1-(2-phenylethyl)-2H-imidazol-2-one (4g): After 25 min, 245.1 mg (72%). Color-
less crystals. M.p. 244 ± 2478 ([13]: 236 ± 2388). IR: 3300 ± 2800s (br., NH), 1690vs (br., CˆO), 1500s, 1450s,
1400s, 1360s, 1125m, 1030m, 960m, 760s, 700s. 1H-NMR: 10.50 (br. s, NH); 7.40 ± 6.80 (m, 15 arom. H); 3.78, 2.81
(2t, J ˆ 6.7, 2 CH2). 13C-NMR: 154.4 (s, CˆO); 138.9, 130.3, 127.0 (3s, 3 arom. C); 131.4, 129.4, 129.2, 128.8,
126.7, 125.9 (6d, 15 arom. C); 122.3, 118.9 (2s, C(4), C(5)); 43.0, 35.6 (2t, 2 CH2).
1-Cyclohexyl-1,3-dihydro-5-methyl-4-phenyl-2H-imidazol-2-one (4h): After 15 min, 135.0 mg (53%).
Colorless crystals. M.p. 244 ± 2468 (dec.) (hexane/CH2Cl2). IR: 3200 ± 2750s (br., NH), 1680vs (CˆO),
1500w, 1395m, 1370m, 1295w, 1265w, 1140w, 1000w, 890w, 835m, 800m, 770m, 750s, 695s. 1H-NMR: 10.40 (br. s,
NH); 7.45 ± 7.20 (m, 5 arom. H); 3.80 ± 3.60 (m, 1 H, cHex); 2.25 (s, Me); 2.15 ± 1.10 (m, 10 H, cHex). 13C-NMR:
153.4 (s, CˆO); 129.7 (s, 1 arom. C); 127.5, 125.4, 125.3 (3d, 5 arom. C); 116.9, 114.5 (2s, C(4), C(5)); 52.5
.
‡
(d, CH); 29.5, 25.0, 24.0 (3d, 5 CH2); 9.2 (q, Me). EI-MS: 256 (23, M ), 175 (12), 174 (100), 173 (15), 105 (15),
104 (18), 103 (11), 77 (18). Anal. calc. for C16H20N2O (256.35): C 74.97, H 7.86, N 10.93; found: C 74.54, H 7.90,
N 10.82.
1,3-Dihydro-1-methyl-4,5-diphenyl-2H-imidazol-2-one (4i): After 15 min, 210.5 mg (84%). Colorless
crystals. M.p. 286 ± 2908 (dec.) (EtOH) ([35]: 285 ± 2878). IR: 3200 ± 2600s (br., NH), 1680vs (br., CˆO),
1
1600m, 1505m, 1460s, 1440m, 1395s, 1020m, 955m, 865m, 830m, 770s, 740m, 715m, 700s. H-NMR: 9.90 (br. s,
NH); 7.50 ± 7.20 (m, 5 arom. H); 7.10 (br. s, 5 arom. H); 3.10 (s, MeN). 13C-NMR: 154.7 (s, CˆO); 130.2, 129.2
(2s, 2 arom. C); 131.1, 129.4, 129.0, 127.2, 126.1 (5d, 10 arom. C); 121.8, 118.5 (2s, C(4), C(5)); 28.3 (q, MeN).
4. 1-Acetyl-1,3-dihydro-2H-imidazol-2-ones 5 from 1H-Imidazole 3-Oxides 1: General Procedure. A soln. of
1 (1 mmol) in freshly distilled Ac2O (2 ml) was heated under reflux. After 2 h, the mixture was cooled to r.t., and
excess Ac2O was distilled off (bulb-to-bulb). After trituration with EtOH (5 ml), the colorless residue afforded
a crystalline product which was purified by recrystallization.
1-Acetyl-1,3-dihydro-3,4,5-trimethyl-2H-imidazol-2-one (5a): 112.7 mg (67%). Colorless crystals. M.p. 61 ±
638. IR: 1730vs (br., CˆO), 1690m, 1430m, 1400m, 1375s, 1320s. 1H-NMR: 3.15 (s, MeN); 2.64 (s, MeCO); 2.25,
1.97 (2s, 2 Me). 13C-NMR: 170.9 (s, MeCO); 152.6 (s, CˆO); 117.8, 113.3 (2s, C(4), C(5)); 27.1, 26.0, 11.8, 8.1
.
‡
(4q, 4 Me). EI-MS: 168 (24, M ), 127 (11), 126 (100), 125 (79), 111 (38), 97 (10), 56 (28). Anal. calc. for
C8H12N2O2 (168.19): C 57.13, H 7.19, N 16.65; found: C 57.01, H 7.00, N 16.52.
1-Acetyl-3-ethyl-1,3-dihydro-4,5-dimethyl-2H-imidazol-2-one (5b): 132.0 mg (72%). Colorless crystals.
M.p. 79 ± 818. IR: 1720vs (br., CˆO), 1680m (CˆO), 1460m, 1395s, 1370vs, 1310vs, 1040w, 955m. 1H-NMR: 3.13
(q, J ˆ 7.3, CH2); 2.65 (s, MeCO); 2.25, 1.99 (2s, 2 Me); 1.23 (t, J ˆ 7.3, Me). 13C-NMR: 171.0 (s, MeCO); 152.0
(s, CˆO); 117.3, 113.5 (2s, C(4), C(5)); 35.7 (t, CH2); 26.1 (q, MeCˆO), 14.6 (q, MeCH2); 11.7, 8.0 (2q, 2 Me).
.
‡
EI-MS: 182 (20, M ), 140 (100), 125 (19), 112 (32), 111 (22). Anal. calc. for C9H14N2O2 (182.22): C 59.32,
H 7.74, N 15.37; found: C 59.07, H 7.71, N 14.98.
1-Acetyl-3-benzyl-1,3-dihydro-4,5-dimethyl-2H-imidazol-2-one (5c): 149.0 mg (61%). Colorless crystals.
M.p. 51 ± 538 (hexane/CH2Cl2). IR: 1720vs (br., CˆO), 1680m (CˆO), 1400s, 1380s, 1310vs, 1190w, 1130w,
730w, 710w. 1H-NMR: 7.35 ± 7.20 (m, 5 arom. H); 4.80 (s, CH2); 2.68 (s, MeCO); 2.24, 1.87 (2s, 2 Me). 13C-NMR:
170.9 (s, MeCO); 152.7 (s, CO); 136.8 (s, 1 arom. C); 128.7, 127.5, 126.8 (3d, 5 arom. C); 118.0, 113.7 (2s, C(4),
.
‡
C(5)); 44.3 (t, CH2); 26.0 (q, MeCO); 11.7, 8.3 (2q, 2 Me). EI-MS: 244 (6, M ), 202 (62), 167 (16), 149 (13), 135
‡
(30), 121 (15), 111 (36), 105 (8), 104 (22), 92 (18), 91 (100, C7H7 ), 65 (15). Anal. calc. for C14H16N2O2 (244.29):
C 68.83, H 6.60, N 11.47; found: C 68.54, H 6.61, N 11.17.
1-Acetyl-3-cyclohexyl-1,3-dihydro-4,5-dimethyl-2H-imidazol-2-one (5d): 146.5 mg (62%). Colorless crys-
tals. M.p. 184 ± 1858 (hexane/CH2Cl2). IR: 1715vs (CˆO), 1680s (CˆO), 1410w, 1395s, 1390s, 1340s, 1195w,
980w, 770w, 600w. 1H-NMR: 3.75 ± 3.65 (m, 1 H, cHex); 2.61 (s, MeCO); 2.21, 1.98 (2s, 2 Me); 2.13 ± 1.21
(m, 10 H, cHex). 13C-NMR: 171.1 (s, MeCO); 152.0 (s, CˆO); 117.7, 113.6 (2s, C(4), C(5)); 54.0 (d, CH); 30.4,
‡
26.2, 25.2 (3t, q, 5 CH2, MeCO); 11.8, 9.0 (2q, 2 Me). CI-MS: 237 (100, [M ‡ 1] ), 209 (20). Anal. calc. for
C13H20N2O2 (236.31): C 66.07, H 8.53, N 11.85; found: C 66.11, H 8.48, N 11.70.
1-Acetyl-1,3-dihydro-3,4-dimethyl-5-phenyl-2H-imidazol-2-one (5e): 152.0 mg (66%). Colorless crystals.
M.p. 141 ± 1438 (hexane/CH2Cl2). IR: 1720vs (br., CˆO), 1430w, 1370s, 1310m, 1275s, 765m, 740w, 710w.
1H-NMR: 7.45 ± 7.00 (m, 5 arom. H); 3.20 (s, MeCO); 2.60, 1.93 (2s, 2 Me). 13C-NMR: 169.5 (s, MeCO); 152.8
(s, CˆO); 131.2 (s, 1 arom. C); 129.8, 128.1, 127.7 (3d, 5 arom. C); 121.6, 117.5 (2s, C(4), C(5)); 27.4 (q, MeCO);

Helvetica Chimica Acta ± Vol. 83 (2000)
735
.
‡
25.8 (q, MeN); 8.9 (q, Me). EI-MS: 230 (100, M ), 189 (11), 188 (100), 187 (20). Anal. calc. for C13H14N2O2
(230.27): C 67.81, H 6.13, N 12.17; found: C 67.61, H 6.15, N 12.15.
1-Acetyl-3-cyclohexyl-1,3-dihydro-4,5-diphenyl-2H-imidazol-2-one (5f): 263.1 mg (73%). Colorless crys-
tals. M.p. 151 ± 1538 (MeOH). IR: 1720vs (br., CˆO), 1455w, 1380m, 1320m, 1285m, 1180w, 660w, 620w, 605w.
1H-NMR: 7.35 ± 7.02 (m, 10 arom. H); 3.46 (m, 1 H, cHex); 2.69 (s, MeCO); 2.30 ± 1.07 (m, 10 H, cHex).
13C-NMR: 169.8 (s, MeCO); 151.6 (s, CˆO); 130.4, 128.3 (2s, 2 arom. C); 130.9, 129.6, 128.9, 128.5, 127.4, 127.2
(6d, 10 arom. C); 126.1, 118.7 (2s, C(4), C(5)); 55.1 (d, CH); 29.7, 26.1 (2t, 4 CH2); 25.9 (q, MeCO); 24.9 (t,
.
‡
1 CH2). EI-MS: 360 (11, M ), 319 (17), 318 (73), 236 (100), 193 (6), 105 (12), 104 (22). Anal. calc. for
C23H24N2O2 (360.46): C 76.64, H 6.71, N 7.77; found: C 76.86, H 6.68, N 7.80.
1-Acetyl-1,3-dihydro-4,5-diphenyl-3-(2-phenylethyl)-2H-imidazol-2-one (5g): 263.9 mg (69%). Colorless
crystals. M.p. 124 ± 1268 (EtOH). IR: 1720vs (br., CˆO), 1445w, 1360m, 1305m, 1205w, 1120w, 795w, 740w,
700m. 1H-NMR: 7.33 ± 6.80 (m, 15 arom. H); 3.80, 2.81 (2t, J ˆ 7.5, 2 CH2); 2.65 (s, MeCO). 13C-NMR: 169.9
(s, MeCO); 152.6 (s, CˆO); 138.2, 130.6, 128.1 (3s, 3 arom. C); 130.9, 130.1, 129.2, 129.1, 127.9, 127.7, 127.0 (7d,
15 arom. C); 126.0, 119.3 (2s, C(4), C(5)); 43.5, 35.0 (2t, 2 CH2); 26.1 (q, MeCO). CI-MS: 384 (25), 383 (100,
‡
[M ‡ 1] ), 340 (4). Anal. calc. for C25H22N2O2 (382.46): C 78.51, H 5.80, N 7.32; found: C 78.88, H 5.79, N 7.29.
1-Acetyl-3-cyclohexyl-1,3-dihydro-4-methyl-5-phenyl-2H-imidazol-2-one (5h): 188 mg (63%). Colorless
crystals. M.p. 112 ± 1138 (hexane). IR: 1725vs (br., CˆO), 1370s, 1300s, 1280m, 765w, 750w, 710w. 1H-NMR:
7.40 ± 7.15 (m, 5 arom. H); 3.85 ± 3.70 (m, 1 H, cHex); 2.62 (s, MeCO); 2.25 ± 1.20 (m, 10 H, cHex); 1.98 (s, Me).
13C-NMR: 169.3 (s, MeCO); 152.1 (s, CˆO); 130.9 (s, 1 arom. C); 129.4, 127.7, 127.3 (3d, 5 arom. C); 120.9, 117.4
.
‡
(2s, C(4), C(5)); 54.3 (d, CH); 30.2, 26.1 (2t, 4 CH2); 25.8 (q, MeCO); 25.1 (t, 1 CH2). EI-MS: 298 (5, M ), 257
(7), 256 (41), 175 (12), 174 (100), 173 (15), 130 (7), 104 (11), 103 (8), 77 (6). Anal. calc. for C18H22N2O2
(298.38): C 72.46, H 7.43, N 9.39; found: C 72.00, H 7.41, N 9.16.
5. Cyanation of 1H-Imidazole 3-Oxides 1. General Procedure. To a soln. of 1 (5 mmol, referring to the anh.
form of 1) in dry CH2Cl2 (4 ml), ca. 500 mg of freshly activated molecular sieves were added6). The mixture was
stirred in a septum-closed 25-ml flask at r.t. for 1 h and then placed in a water/ice cooling bath. Subsequently, a
soln. of trimethylsilanecarbonitrile (992.0 mg, 1.3 ml, 10 mmol) and Et3N (759.0 mg, 1.05 ml, 7.5 mmol) in
CH2Cl2 (3 ml) was slowly added through the septum using a syringe. The magnetic stirring was continued for 1 h
at 0 ± 58. Then the yellow mixture was diluted with CH2Cl2 (20 ml) and extracted with H2O (4 Â 40 ml), the org.
layer dried (MgSO4) and evaporated and the yellow residue purified by prep. TLC (CH2Cl2). The 1H-imidazole-
2-carbonitriles 2 were isolated as a fraction with Rf ca. 0.4 ± 0.5, and additional crystallization afforded anal. pure
samples.
1,4,5-Trimethyl-1H-imidazole-2-carbonitrile (2a): 527 mg (78%). M.p. 100 ± 1018 (Et2O). IR: 2870s, 2205s
(CꢀN), 1560vs, 1470vs, 1440vs, 1390s, 1300m, 1220m, 1000w, 830m, 735s, 695m. 1H-NMR: 3.68 (s, MeN); 2.22,
2.18 (2s, 2 Me). 13C-NMR: 137.1 (s, C(2)); 128.5, 119.0 (2s, C(4), C(5)); 111.8 (s, CꢀN); 31.9 (q, MeN); 12.8, 8.9
.
‡
‡
(2q, 2 Me). EI-MS: 136 (20, [M ‡ 1] ), 135 (100, M ), 134 (95), 120 (67), 93 (19), 79 (11), 68 (14), 67 (20).
Anal. calc. for C7H9N3 (135.17): C 62.20, H 6.71, N 31.09; found: C 62.19, H 6.81, N 30.99.
1-Benzyl-4,5-dimethyl-1H-imidazole-2-carbonitrile (2c): 623 mg (59%). M.p. 125 ± 1268 (hexane/CH2Cl2).
IR: 2210m (CꢀN), 1570s, 1450vs, 1430vs, 1390m, 1360m, 1310m, 1220m, 1140w, 1045m, 850w, 765s, 730vs, 700s.
1H-NMR: 7.32 (br. s, 3 arom. H); 7.09 (br. s, 2 arom. H); 5.21 (s, CH2); 2.20, 2.10 (2s, 2 Me). 13C-NMR: 137.8
(s, C(2)); 134.3 (s, 1 arom. C); 128.8, 128.0, 126.6 (3d, 5 arom. C); 128.3, 119.1 (2s, C(4), C(5)); 111.6 (s, CꢀN);
.
‡
‡
‡
48.7 (t, CH2); 12.6, 8.9 (2q, 2 Me). EI-MS: 212 (10, [M ‡ 1] ), 211 (46, M ), 92 (29), 91 (100, C7H7 ), 65 (32).
Anal. calc. for C13H13N (211.27): C 73.91, H 6.20, N 19.89; found: C 73.74, H 6.27, N 19.88.
1-Cyclohexyl-4,5-dimethyl-1H-imidazole-2-carbonitrile (2d): 874 mg (86%). M.p. 102 ± 1038 (hexane/
Et2O). IR: 2880vs, 2810s, 2205s (CꢀN), 1565s, 1455s, 1430vs, 1390s, 1370s, 1350m, 1290w, 1220w, 1140w,
1000w, 905m, 845w, 785m. 1H-NMR: 4.15 ± 4.10 (m, 1 H, cHex); 2.35 ± 1.15 (m, 10 H, cHex); 2.24, 2.17 (2s,
2 Me). 13C-NMR: 136.9 (s, C(2)); 127.3, 116.6 (2s, C(4), C(5)); 112.7 (s, CꢀN); 57.2 (d, CH), 32.0, 25.6, 24.5 (3t,
.
‡
‡
5 CH2); 12.5, 9.3 (2q, 2 Me). EI-MS: 204 (10, [M ‡ 1] ), 203 (39, M ), 122 (77), 121 (100), 120 (31), 106 (12),
‡
83 (48, C6H11 ), 80 (11). Anal. calc. for C12H17N3 (203.39): C 70.90, H 8.43, N 20.67; found: C 71.11, H 8.59,
N 20.64.
1-Cyclohexyl-4,5-diphenyl-1H-imidazole-2-carbonitrile (2f): 1.36 g (83%). M.p. 159 ± 1608 (MeOH). IR:
2880vs, 2800m, 2210m (CꢀN), 1600m, 1500m, 1450vs, 1430s, 1405m, 1370s, 1340s, 1285w, 1170w, 1085w, 980m,
900w, 800vs, 740s, 705vs. 1H-NMR: 7.53 ± 7.17 (m, 10 arom. H); 3.85 (m, 1 H, cHex); 2.24 ± 1.21 (m, 10 H, cHex).
13C-NMR: 140.2 (s, C(2)); 132.9 (s, 2 arom. C); 132.5, 118.8 (2s, C(4), C(5)); 130.7, 129.9, 129.5, 128.3, 127.5,
‡
126.9 (6d, 10 arom. C); 112.8 (s, CꢀN); 57.4 (d, CH); 32.6, 25.9, 24.6 (3t, 5 CH2). EI-MS: 328 (13, [M ‡ 1] ), 327
.
‡
(45, M ), 246 (20), 245 (100), 244 (31). Anal. calc. for C22H21N3 (327.40): C 62.20, H 6.71, N 31.09; found:
C 62.19, H 6.81, N 30.99.

736
Helvetica Chimica Acta ± Vol. 83 (2000)
Table 3. Crystallographic Data of Compound 5e
Crystallized from
MeOH
Empirical formula
Formula weight [g mol
Crystal color, habit
Crystal dimensions [mm]
Temperature [K]
Crystal system
Space group
C13H14N2O2
230.26
colorless, tablet
0.18 Â 0.28 Â 0.50
173(1)
1
]
monoclinic
P21/n
Z
4
Reflections for cell determination
25
2q Range for cell determination [8]
Unit-cell parameters a [Š]
38 ± 40
10.5031(8)
7.209(2)
16.2383(8)
103.481(5)
1195.6(3)
1.279
b [Š]
c [Š]
b [8]
V [Š3]
3
Dx [g cm
]
1
m(MoKa) [mm
2q(max) [8]
]
0.0877
60
Total reflections measured
Symmetry-independent reflections
Reflections used [I > 2s(I)]
Parameters refined
3918
3476
2571
211
Final R
0.0456
0.0409
1.774
1
wR (w ˆ [s2(Fo) ‡ (0.005Fo)2]
)
Goodness of fit
6
Secondary extinction coefficient
1.8(2) ´ 10
0.0002
Final Dmax/s
D1 (max; min) [e Š
3
]
0.27; 0.20
1-Methyl-4,5-diphenyl-1H-imidazol-2-carbonitrile (2h): 945 mg (73%). M.p. 142 ± 1438 (MeOH) ([36]:
144.5 ± 1478). IR: 2990w, 2205s (CꢀN), 1600w, 1470s, 1450vs, 1400w, 1310w, 1230w, 1140w, 1035w, 975m, 805m,
1
795m, 770s, 700vs. H-NMR: 7.50 ± 7.20 (m, 10 arom. H); 3.58 (s, MeN).13C-NMR: 140.3 (s, C(2)); 132.7, 130.1
(2s, 2 arom. C); 132.5, 121.3 (2s, C(4), C(5)); 129.5, 128.8, 128.1, 127.7, 126.6 (5d, 6 arom. C); 111.2 (s, CꢀN);
.
‡
‡
32.4 (q, Me). EI-MS: 260 (21, [M ‡ 1] ), 259 (100, M ), 258 (61), 244 (11), 243 (31). Anal. calc. for C17H13N3
(259.31): C 78.74, H 5.05, N 16.20; found: C 78.86, H 5.15, N 16.10.
1-Benzyl-4,5-diphenyl-1H-imidazole-2-carbonitrile (2j): 1.07 g (64%). M.p. 116 ± 1178 (EtOH). IR: 2210m
(CꢀN), 1600m, 1500s, 1450vs, 1425s, 1335s, 1090m, 1040m, 985m, 825m, 780vs, 710vs (br.). 1H-NMR: 7.50 ± 7.40
(m, 5 arom. H); 7.30 ± 7.15 (m, 8 arom. H); 6.95 ± 6.75 (m, 2 arom. H); 5.20 (s, CH2). 13C-NMR: 140.9 (s, C(2));
134.7, 132.6, 128.6 (3s, 3 arom. C); 132.5, 121.4 (2s, C(4), C(5)); 130.5, 129.7, 129.2, 128.8, 128.5, 127.5, 126.9 (7d,
.
‡
‡
‡
15 arom. C); 111.5 (s, CꢀN); 49.8 (t, CH2). EI-MS: 336 (11, [M ‡ 1] ), 335 (41, M ), 91 (100, C7H7 ). Anal.
calc. for C23H17N3 (335.41): C 82.36, H 5.11, N 12.53; found: C 82.40, H 5.19, N 12.45.
6. Crystal-Structure Determination of 5e8). All measurements were made on
a Rigaku-AFC5R
diffractometer using graphite-monochromated MoKa radiation (l 0.71069 Š) and a 12-kW rotating anode
generator. The w/2q scan mode was employed for data collection. The intensities were corrected for Lorentz and
polarization effects, but not for absorption. Data collection and refinement parameters are given in Table 3, a
view of the molecule is shown in the Figure. The structure was solved by direct methods using SHELXS97 [37].
8
)
Crystallographic data (excluding structure factors) for structure 5e reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication No. CCDC-
136002. Copies of the data can be obtained, free of charge, on application to the CCDC, 12 Union Road,
Cambridge CB21EZ, U.K. (fax: ‡44-(0)1223-336033; e-mail: deposit@ccdc.cam.ac.uk).

Helvetica Chimica Acta ± Vol. 83 (2000)
737
The non-H-atoms were refined anisotropically. All of the H-atoms were located in a difference electron-density
map, and their positions were allowed to refine together with individual isotropic displacement parameters.
Refinement of the structure was carried out on F using full-matrix least-squares procedures, which minimized
the function Sw(j Fo j j Fc j )2. A correction for secondary extinction was applied. Neutral-atom scattering
factors for non-H-atoms were taken from [38a] and the scattering factors for H-atoms from [39]. Anomalous
dispersion effects were included in Fc [40]; the values for f ' and f '' were those of [38b], and the values of the
mass-attenuation coefficients were those of [38c]. All calculations were performed using the ꢀteXsanꢁ
crystallographic software package [41].
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Helvetica Chimica Acta ± Vol. 83 (2000)
[34] V. B. Kalcheva, L. I. Tsvetanska, Khim. Geterotsikl. Soedin 1981, 1028; Chem. Heterocycl. Compd. (Engl.
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Received November 18, 1999