Synthesis and selected transformations of 1H-imidazole 3-oxides derived from amino acid esters

Article abstract of DOI:10.1002/hlca.200890205

A series of new optically active 1H-imidazole 3-oxides 5 with a substituted acetate group at N(1) as the chiral unit were prepared by the reaction of α-(hydroxyimino) ketones, α-amino acid methyl esters, and formaldehyde. In an analogous reaction, ethyl 2

Full text of DOI:10.1002/hlca.200890205

1916
Helvetica Chimica Acta – Vol. 91 (2008)
Synthesis and Selected Transformations of 1H-Imidazole 3-Oxides Derived
from Amino Acid Esters
by Marcin Jasin´ski*1) and Grzegorz Mloston´
´
´
´
´
University of Łodz, Department of Organic and Applied Chemistry, Narutowicza 68, PL-90-136 Łodz
(phone: þ 48426355769; fax: þ 48426355380; e-mail: mjasinski@uni.lodz.pl)
and Anthony Linden and Heinz Heimgartner*
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
(phone: þ 41446354282; fax: þ 41446356812; e-mail: heimgart@oci.uzh.ch)
A series of new optically active 1H-imidazole 3-oxides 5 with a substituted acetate group at N(1) as
the chiral unit were prepared by the reaction of a-(hydroxyimino) ketones, a-amino acid methyl esters,
and formaldehyde. In an analogous reaction, ethyl 2-(hydroxyimino)-3-oxobutyrate and 1,3,5-trialkyl-
hexahydro-1,3,5-triazines gave 3-oxido-1H-imidazole-4-carboxylates 14, which easily rearranged into the
2-oxo derivatives 15. Selected examples of N-oxides 5 could be transformed into the corresponding 2,3-
dihydro-1H-imidazole-2-thione derivatives 10 via a ꢀsulfur-transfer reactionꢁ, and the reduction of the
histidine derivative 5i with Raney-Ni yielded the optically active 2,3-bis(imidazolyl)propanoate 12.
Furthermore, reaction of the (1H-imidazol-1-yl)acetates with primary amines yielded the corresponding
acetamides.
1. Introduction. – In a series of recent articles, a versatile method for the synthesis of
2-unsubstituted 1H-imidazole 3-oxides based on a three-component reaction of an a-
(hydroxyimino) ketone, formaldehyde, and a primary amine was described [1 – 3]. In
general, aliphatic primary amines are required, and diamines can also be applied
leading to bis[imidazole 3-oxides]. Starting with enantiomerically pure amines, e.g., 1-
phenylethylamine or trans-cyclohexane-1,2-diamine, optically active 1H-imidazole 3-
oxides 1 and 2, respectively, were obtained without racemization [4][5].
1
´
´
)
Part of the Ph.D. thesis of M. J., University of Łodz, 2008.
ꢂ 2008 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 91 (2008)
1917
1H-Imidazole 3-oxides without a substituent at C(2) undergo reactions similar to
nitrones according to the mechanism of 1,3-dipolar cycloadditions. The initially formed
[2 þ 3] cycloadducts spontaneously undergo conversion to 1H-imidazole derivatives
functionalized at C(2) [1][2][6 – 8]. These reactions show that 1H-imidazole 3-oxides
are versatile starting materials for the preparation of diverse imidazole derivatives,
which, in some instances, exhibit attractive biological activities [9][10].
With the aim of preparing further optically active 1H-imidazole 3-oxides, we turned
our attention to a-amino acid derivatives as the amino component containing the
stereogenic center. A few years ago, Lettau et al. reported the synthesis of some
optically active 1H-imidazole 3-oxides by treatment of diacetylmonooxime with
aldehydes and a-amino acids [11] (see also [12]). Whereas the reactions with
formaldehyde yielded optically active products, the experiments with acetaldehyde,
benzaldehyde, and isobutyraldehyde, respectively, led to completely racemized
products. The products obtained from formaldehyde and enantiomeric amino acids
showed the opposite optical rotation (Æ 30%), but the enantiomeric purity has not
been determined. The authors claimed that, in contrast to other representatives [13]
(see also [14]), these products do not isomerize to give the corresponding 1H-imidazol-
2-ones. The unusual stability was explained by ꢀthe association between the N-oxide
and the COOH groupꢁ. Furthermore, the products are insoluble in most organic
solvents, and, therefore, they could not be transformed into other imidazole
derivatives2).
Prompted by this observation, we elaborated a protocol for the preparation of
amino acid-derived 1H-imidazole 3-oxides by using a-amino acid esters as the amino
component. We expected that these products will display more advantageous proper-
ties, which allow further transformations of both the imidazole ring and the carboxylic
group. Such transformations are of interest with respect to further application of
imidazole derivatives, e.g., in organocatalysis.
2. Results and Discussion. – To optimize the reaction conditions, first experiments
were carried out with glycine methyl ester (4a), formaldehyde, and butane-2,3-dione
monooxime (3a) in boiling EtOH (Method A). After 3 h, the reaction was complete,
and the N-oxide 5a was obtained as viscous oil (Scheme 1 and Table 1). The structure of
the product was confirmed by the presence of the characteristic absorptions of HÀC(2)
of the imidazole ring at 8.09 ppm (s) and of the CH2 group of the glycine moiety at
4.64 ppm (s) in the 1H-NMR spectrum (CDCl3). The IR spectrum (film) shows a strong
absorption band for the ester group at 1741 cmÀ1.
For comparison, the same reaction was carried out in glacial AcOH at room
temperature overnight, followed by treatment with HCl gas (Method B). Subsequent
workup led to 5a in better yield and higher purity (Table 1). The analogous reaction
with 4a and a-(hydroxyimino) ketones 3b – 3d yielded the expected products 5b – 5d,
respectively, and, in all cases, Method B turned out to be more advantageous.
2
)
Attempts to convert the glycine derivative obtained with diacetylmonooxime and formaldehyde
[12] into the corresponding 1H-imidazole-2-thione or into the methyl ester by treatment with
CH2N2 or MeOH/H2SO4 were unsuccessful [15].

1918
Helvetica Chimica Acta – Vol. 91 (2008)
Scheme 1
a) EtOH, reflux, 3 h (Method A). b) AcOH, 16 h, HCl (g), NaHCO3 (Method B).
Table 1. Preparation of 2-(3-Oxido-1H-imidazol-1-yl)acetates 5
5
R1
R2
R3
[a]2D0 (c ¼ 0.2, CH2Cl2)
Yield [%]
Method A
Method B
a
b
c
d
Me
Ph
Me
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
H
H
H
H
65
71
49
55
50
88
90
58
71
67
72
90
Ph
e (S)
e (R)
f
g
h
i
Me
Me
Me
Me
Me
Me
Me
Me (S)
Me (R)
þ 47.1
À 48.5
þ 31.3
þ 10.6
0
Me2CH (S)
Me2CHCH2 (S)
Ph (rac)
(4-Im)CH2 (S)
4-HOC6H4CH2 (S)
44
43a), 22a)b)
63
81a)
70
À 26.0
j
À 99.5
81a)
a) Racemate. b) Modified Method A: MeOH, paraformaldehyde, reflux 6 h.
Based on the results obtained with 4a, reactions of 3a with the methyl esters of (S)-
alanine ((S)-4b), (R)-alanine ((R)-4b), (S)-valine (4c), (S)-leucine (4d), (R)-phenyl-
glycine (4e), (S)-histidine (4f), and (S)-tyrosine (4g) were performed according to
Method B. The spectroscopic data of the products, which were obtained in good yields,
were in agreement with the expected structures of 1H-imidazole 3-oxides of type 5
(Table 1). However, in the case of 5h and 5j (phenylglycine and tyrosine derivatives,
resp.) using Method B, the products showed no optical activity. Repetition of the
reactions according to Method A gave 5h again as racemate; however, in the case of 5j,
the product was optically active (Table 1).
To obtain more information about the racemization in the case of 5h, the optically
active hexahydro-1,3,5-triazine 6a [16] was prepared from (R)-phenylglycine methyl
ester and HCHO (Scheme 2). The optical activity of the crystalline 6a did not change in

Helvetica Chimica Acta – Vol. 91 (2008)
1919
boiling EtOH after 2 h. However, using the optically active 6a in the reaction with 3a
(Method A) resulted again in the formation of racemic 5h. Therefore, we propose that
the crucial intermediate 7 in the formation of 5h undergoes fast racemization. The
appearance of such an intermediate also allows racemization under acidic conditions in
the case of tyrosine 5j. Surprisingly, the formation of the histidine derivative 5i occurs
without racemization by using Method B.
Scheme 2
a) 1n NaOH, 37% CH2O, H2O/benzene. b) (CH2O)n, MeOH, NaHCO3, r.t., 14 h.
The enantiomeric purity of all optically active N-oxides 5 was determined by
1H-NMR spectroscopy using 1 equiv. of (þ)-(R)-(tert-butyl)(phenyl)phosphonothioic
acid as a chiral solvating agent [4][5][17]. The results obtained with 5e are shown in
Fig. 1. Whereas in the case of rac-5e, the 1H-NMR spectrum of the 1:1 mixture showed
clearly separated singlets for the diagnostic HÀC(2) (9.13 and 8.98 ppm), the
corresponding spectra of the optically active products (S)-5e and (R)-5e revealed in
each case only one signal. In addition, the other signals of the spectra confirmed the
presence of a single stereoisomer. To check the accuracy of the spectroscopic
determination, a mixture of 98% of (S)-5e and 2% of (R)-5e was analyzed, and, in this
case, the signal of the minor isomer could be detected clearly. Thus, the ee value of the
isolated products was higher than 96%.
The oily 1H-imidazole 3-oxides 5a – 5d easily undergo reactions with primary
aliphatic amines to give the corresponding amides of type 8 (Scheme 3 and Table 2). In
contrast to the starting materials, the amides were obtained as crystalline substances,
which are easy to handle and to purify. In the case of (R)-(1-phenylethyl)amine, the
reactions with 5a and 5b led to the optically active products 8h and 8i, respectively. The
structure of 8h was confirmed by X-ray crystallography (Fig. 2).
There are four symmetry-independent molecules of 8h and four molecules of H2O
in the asymmetric unit. The Ph ring in one of the molecules is disordered over two
orientations. The space group permits the compound to be enantiomerically pure, but
the absolute configuration of 8h has not been determined. The enantiomer used in the
refinement was based on the known (R)-configuration of the molecule. The NH group
in each molecule forms an intermolecular H-bond with the oxide O-atom of a
neighboring symmetry-independent molecule. These molecules, A and B, are thereby
linked alternatively into extended chains which run parallel to the [110] direction and
can be described by a binary graph set motif [19] of C22(8). Molecules C and D form
similar chains which run parallel to the [1À10] direction. From an analysis of O ··· O

1920
Helvetica Chimica Acta – Vol. 91 (2008)
Fig. 1. 1H-NMR Spectra of (S)-5e, (R)-5e, and rac-5e in CDCl3 recorded in the presence of 1 equiv. of
(þ)-(R)-(tert-butyl)(phenyl)phosphonothioic acid
distances, each H2O molecule forms H-bonds with two O-atoms of just one molecule of
8h.
The transformation of 2-unsubstituted 1H-imidazole 3-oxides into 1H-imidazole-2-
thiones was reported earlier [1]. In the case of the glycine derivatives 5, treatment with
2,2,4,4-tetramethylcyclobutane-1,3-dithione (9) in CH2Cl2 at room temperature gave
the crystalline 1H-imidazole-2-thiones 10 in high yields (Scheme 3 and Table 3). The
analogous procedure applied to MeOH solutions of the amides of type 8 afforded the
corresponding 2-thioxo-1H-imidazol-1-yl acetamides 11. The characteristic absorption
of the C¼S group in the 13C-NMR spectrum appears at ca. 161 ppm, in accordance with
the data reported for 1H-imidazole-2-thiones [6]. The signals for the ester and amide

Helvetica Chimica Acta – Vol. 91 (2008)
1921
Scheme 3
Table 2. Preparation of 2-(3-Oxido-1H-imidazol-1-yl)acetamides 8
8
R1
R2
R3
Yield [%]
a
b
c
d
e
f
g
h
i
Me
Ph
Me
Ph
Me
Ph
Ph
Me
Me
Ph
Ph
Me
Ph
Ph
Me
Me
PhCH2
PhCH2
PhCH2
PhCH2
Cyclopropyl
Cyclopropyl
Cyclohexyl
PhCHMe (R)
PhCHMe (R)
68
59
51
84
81
61
44
91
77
Me
Ph
Table 3. Preparation of 1H-Imidazole-2-thiones 10 and 11
R1
R2
R4
Yield [%]
10a
10b
11a
11b
11c
Ph
Me
Me
Ph
Ph
Me
Ph
Me
Me
Ph
MeO
MeO
PhCH2N
PhCH2N
PhCH2N
86
76
H
H
H
96
57
60
C¼O groups of 10 and 11 are located at ca. 168 ppm. The IR absorptions of the esters
10 and the amides 11 were observed, as expected, at ca. 1740 and 1650 – 1695 cmÀ1,
respectively.
The enhanced acidity of HÀC(2) in 1H-imidazole 3-oxides is a characteristic
property [2][20]. Therefore, the H/D exchange can be achieved in D2O or CD3OD. In

1922
Helvetica Chimica Acta – Vol. 91 (2008)
Fig. 2. ORTEPPlot [18] of the molecular structure of one of the four symmetry-independent molecules of
8h (with 50% probability ellipsoids; arbitrary numbering of the atoms)
the case of 5c and 8c, heating a solution of these compounds in a mixture of D2O and
CD3OD for 5 h led to an almost complete exchange (1H-NMR).
The transformations 5 ! 8 and 5 ! 10 described for glycine derivatives (Scheme 3)
were also carried out with an optically active 1H-imidazole 3-oxide of type 5. Thus,
treatment of (S)-5e with PhCH2NH2 led to the racemic amide 8j with the preserved N-
oxide function (Scheme 4). The S-transfer reaction with (S)-5e by using 9 in the typical
manner afforded the optically active 1H-imidazole-2-thione 10c. These experiments
demonstrate that the optically active 1H-imidazole 3-oxides 5 can be converted into
other optically active imidazole derivatives only in selected cases.
In a recent publication, we described the preparation of symmetrical bis-imidazole
derivatives starting with a,w-diamino-alkanes, formaldehyde, and the corresponding a-
(hydroxyimino) ketones [3]. In an extension of these studies, the reaction of l-histidine
Scheme 4

Helvetica Chimica Acta – Vol. 91 (2008)
1923
with 3a was carried out according to Method B. The optically active product 5i was
isolated as a crystalline material in 70% yield (Scheme 5). The deoxygenation of 9 with
Raney-Ni led to the the bis-imidazole 12, which proved to be optically active.
Scheme 5
With the aim of preparing other functionalized 1H-imidazole 3-oxides, the reaction
of ethyl 2-(hydroxyimino)-3-oxobutanoate (13) with 1/3 equiv. of hexahydro-1,3,5-
triazine 6 was carried out in Et2O at room temperature. In solution, 6 is in equilibrium
with the corresponding methylidenamine, which reacts with 13 according to the known
mechanism [21] (Scheme 6). Under these conditions, the initially formed 1H-imidazole
3-oxides 14 easily undergo an isomerization to give the isomeric 1H-imidazol-2-ones 15.
In the case of 14a, the product could be isolated in pure form, whereas, in the cases of
14b and 14c, ca. 4 :1 mixtures of 14 and 15 were obtained. After attempted purification
by crystallization from CH2Cl2/Et2O, the corresponding 1H-imidazol-2-ones were
isolated exclusively3).
Scheme 6
The N-oxide 14a was transformed into the corresponding amide 16 by treatment
with an excess of cyclopropylamine at room temperature (Scheme 7). The structure of
this new amide was confirmed by the spectroscopic data. Finally, the structure was
confirmed by an X-ray crystal-structure determination (Fig. 3).
3
)
The reaction of 13 with 6 performed in MeOH at room temperature was significantly slower, and
heating resulted in the formation of a complex mixture of products containing 14 and 15, as well as
transesterificated analogues.

1924
Helvetica Chimica Acta – Vol. 91 (2008)
Scheme 7
Fig. 3. ORTEPPlot [18] of the molecular structure of one of the two symmetry-independent molecules of
16 (with 50% probability ellipsoids; arbitrary numbering of the atoms)
The asymmetric unit contains two molecules of 16 plus one molecule of MeOH. In
each molecule of 16, the amide group forms an intramolecular H-bond with the oxide
O-atom to give a six-membered loop, which can be described by a graph set motif [19]
of S(6). The MeOH molecule forms an intermolecular H-bond with the oxide O-atom
of one of the molecules of 16; graph set motif D.
Unexpectedly, the amide 16 was thermally stable and did not isomerize to give the
corresponding 1H-imidazol-2-one after heating in benzene for 4 h. For comparison,
under the same conditions, the ester 14a was completely converted into 15a after 2 h. It
is likely that the intramolecular H-bond stabilizes the N-oxide structure (see crystal
structure).
3. Conclusions. – The presented study shows that a-amino acid esters can be
conveniently applied as amino components in the synthesis of 1H-imidazole 3-oxides
containing an acetate group at N(1). Diverse conversions can be performed both at the
ester function and at the imidazole ring, e.g., formation of amides and 1H-imidazole-2-
thiones, respectively. 1H-Imidazole 3-oxides bearing the ester group at C(4) can be
obtained from 2-(hydroxyimino)-3-oxobutanoate by condensation with methyliden-

Helvetica Chimica Acta – Vol. 91 (2008)
1925
amines. The presence of the ester group at C(4) enhances the ability of the N-oxide to
undergo the rearrangement into the corresponding 1H-imidazol-2-one.
Starting with enantiomerically pure a-amino acid esters, the three-component
reaction can be applied for the synthesis of optically active 1H-imidazole 3-oxides. An
especially interesting case of a bis-imidazole was obtained from l-histidine. In contrast
to the previously described symmetrical bis-imidazoles, this opens an access to novel
unsymmetrical bis-imidazoles. New optically active imidazole and bis-imidazole
derivatives are promising new ligands for asymmetric catalysis.
We thank the analytical sections of our institutes for spectra and analyses. G. M. acknowledges
financial support by the Ministry of Science and Higher Education (Grant No. PBZ-KBN-126/T09/12),
and H. H. thanks F. Hoffmann-La Roche AG, Basel, for financial support.
Experimental Part
1. General. M.p.: Melt-Temp. II (Aldrich); uncorrected. Optical rotation: automatic digital
polarimeter Krüss P3002RS. IR Spectra: NEXUS FT-IR spectrophotometer; in KBr; absorptions in
1
cmÀ1. H- and 13C-NMR Spectra: Tesla BS567A (80 and 20 MHz, resp.) or Bruker AC 300 instrument
(300 and 75.5 MHz, resp.); in CDCl3 or CD3OD; d in ppm (Me4Si ¼ 0 ppm), coupling constants J in Hz.
The multiplicity of the 13C signals was deduced from DEPT spectra. MS: Finnigan MAT-90 or Finnigan
SSQ-700 instruments. HR-MS: Finnigan MAT-95. Elemental analyses were performed in the Analytical
Laboratory of the University of Zürich or in the Laboratory of the Polish Academy of Sciences
´
´
(CBMiMM) in Łodz.
2. Starting Materials. All reagents and solvents are commercially available and used as received. a-
(Hydroxyimino) ketones 3 were obtained according to known protocols: butane-2,3-dione monooxime
(3a) [22a], 1-phenylpropane-1,2-dione 1-oxime (3b) [22b], and 1-phenylpropane-1,2-dione 2-oxime (3c)
[22c] by nitrosation of the corresponding ketones by using isoamyl nitrate, and 1,2-diphenylethane-1,2-
dione monooxime (3d; benzil monooxime) [22d] from dibenzoyl and hydroxylamine hydrochloride. 2-
(Hydroxyimino)-3-oxobutanoate (13) was prepared from ethyl acetoacetate by treatment with NaNO2 in
glacial AcOH according to [22e]. 1,3,5-Trisubstituted hexahydro-1,3,5-triazines 6 were prepared
according to known procedures: R2 ¼ (Ph)(MeCO2)CH [16], R2 ¼ Me [23a], R2 ¼ Bn [23b], R2 ¼ cy-
clohexyl(cHex) [23c]. Methyl esters of glycine, (S)-valine, (S)-leucine, and (S)-tyrosine, 4a, 4c, 4d, 4g,
resp. were obtained from the corresponding amino acids according to the general protocols and used
immediately without further purification [24]. (R)-Phenylglycine methyl ester (4e), (S)- and (R)-alanine
methyl esters ((S)-4b and (R)-4b, resp.), and histidine methyl ester (4f) are commercially available.
3. Synthesis of Imidazole N-Oxides 5. General Procedures. Method A. A soln. of the corresponding a-
(hydroxyimino) ketone 3 (10 mmol), amino acid methyl ester 4 (10 mmol), and HCHO (1.25 g,
15 mmol) in EtOH (30 ml) was heated under reflux for 3 h. Evaporation of the solvent under reduced
pressure yielded an oil, which was washed twice with Et2O (2 ꢀ 10 ml). The crude products 5 were
purified by flash chromatography (FC; SiO2; MeOH/AcOEt, 1:1), and the viscous oily substances were
used in the next steps without further purification.
Method B. A soln. of 3 (10 mmol), 4 (10 mmol), and paraformaldehyde (0.83 g, 10 mmol) in glacial
AcOH (10 ml) was stirred overnight at r.t. Then, gaseous HCl was bubbled through the soln. for 1 h at 08,
and Et2O (typically ca. 200 ml) was added. The crude hydrochloride was separated, washed with Et2O
(3 ꢀ 30 ml), and dissolved in CHCl3/MeOH (5 :1, 30 ml). The resulting soln. was treated with excess solid
NaHCO3, stirred for ca. 30 min, and filtered. The solvent was removed in vacuo to give crude product 5.
Methyl (4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)acetate (5a). Yield: 1.20 g (65%, Method A), 1.62 g
(88%, Method B). Pale yellow oil. IR (film): 3200 – 2800s (br.), 1748vs (C¼O), 1632m, 1438m, 1400m,
1388m, 1335m, 1227vs, 1185m. 1H-NMR (CDCl3): 8.02 (s, HÀC(2’)); 4.65 (s, CH2); 3.79 (s, MeO); 2.17,
2.10 (2s, 2 Me). 13C-NMR (CDCl3): 166.9 (s, C¼O); 126.7, 121.4 (2s, C(4’), C(5’)); 125.0 (d, C(2’)); 52.8
(q, MeO); 46.1 (t, CH2); 8.4, 7.1 (2q, 2 Me). EI-HR-MS: 184.08464 (Mþ, C8H12N2O3þ ; calc. 184.08479).

1926
Helvetica Chimica Acta – Vol. 91 (2008)
Methyl (5-Methyl-3-oxido-4-phenyl-1H-imidazol-1-yl)acetate (5b). Yield after FC (SiO2; AcOEt/
MeOH 1:1): 1.75 g (71%, Method A), 2.21 g (90%, Method B). Pale yellow oil. IR (film): 3100 – 2750s
(br.), 1741vs (C¼O), 1679m, 1443m, 1389m, 1347m, 1231s, 699m. 1H-NMR (CDCl3): 8.09 (s, HÀC(2’));
7.75 – 7.23 (m, 5 arom. H); 4.64 (s, CH2); 3.78 (s, MeO); 2.19 (s, Me). 13C-NMR (CDCl3): 167.1 (s, C¼O);
130.5, 126.8, 123.2 (3s, arom. Cq, C(4’), C(5’)); 129.9, 128.5, 128.4, 125.0 (4d, 5 arom. C, C(2’)); 53.1 (q,
MeO); 46.6 (t, CH2); 9.2 (q, Me). EI-MS: 246 (26, Mþ), 230 (100), 171 (42), 130 (21), 103 (38), 77 (26).
Anal. calc. for C13H14N2O3 (246.27): C 63.40, H 5.73, N11.38; found: C 62.92, H 5.69, N11.12.
Methyl (4-Methyl-3-oxido-5-phenyl-1H-imidazol-1-yl)acetate (5c). Yield: 1.20 g (49%, Method A),
1.43 g (58%, Method B). Colorless solid. M.p. (dec.) 158 – 1618 (CH2Cl2/Et2O). IR (KBr): 3100 – 2850s
1
(br.), 1747vs (C¼O), 1437m, 1402m, 1381s, 1335s, 1221vs, 1181m, 1165m, 1153s, 763s, 706m. H-NMR
(CDCl3): 8.08 (s, HÀC(2’)); 7.60 – 7.16 (m, 5 arom. H); 4.56 (s, CH2); 3.73 (s, MeO); 2.21 (s, Me).
13C-NMR (CDCl3): 167.2 (s, C¼O); 129.9, 129.5, 129.0, 125.9 (4d, 5 arom. C, C(2’)); 128.2, 126.65, 126.58
(3s, arom. Cq, C(4’), C(5’)); 52.6 (q, MeO); 46.4 (t, CH2); 7.4 (q, Me). EI-HR-MS: 246.10033 (Mþ,
C13H14N2Oþ3 ; calc. 246.10044).
Methyl (3-Oxido-4,5-diphenyl-1H-imidazol-1-yl)acetate (5d). Yield: 1.69 g (55%, Method A), 2.19 g
(71%, Method B). Pale yellow oil. IR (film): 3200 – 2800s (br.), 1751vs (C¼O), 1444m, 1398m, 1348m,
1225vs, 764s, 700s, 657m. 1H-NMR (CDCl3): 8.33 (s, HÀC(2’)); 7.68 – 7.09 (m, 10 arom. H); 4.58 (s, CH2);
3.70 (s, MeO). 13C-NMR (CDCl3): 167.2 (s, C¼O); 130.6, 129.7, 129.5, 129.1, 128.1, 127.9, 127.1 (7d, 10
arom. C, C(2’)); 130.5, 127.3, 126.7, 126.6 (4s, 2 arom. Cq, C(4’), C(5’)); 52.8 (q, MeO); 46.5 (t, CH2). EI-
HR-MS: 308.11566 (Mþ, C18H16N2O3þ ; calc. 308.11609).
Methyl (S)-2-(4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)propanoate ((S)-5e). Yield after CC (SiO2;
acetone, then AcOEt/MeOH 1:1): 0.99 g (50%, Method A), 1.33 g (67%, Method B). Colorless crystals.
M.p. 144 – 1468 (CH2Cl2/Et2O). [a]2D0 ¼ þ47.1 (c ¼ 0.20, CH2Cl2); þ 30.5 (c ¼ 0.2, MeOH). IR (KBr):
3100 – 2900s (br.), 1743vs (C¼O), 1636w, 1434w, 1381w, 1339m, 1265w, 1208m, 1195m, 1060w. 1H-NMR
(CDCl3): 7.92 (s, HÀC(2’)); 4.75 (q, J ¼ 6.9, 1 H); 3.77 (s, MeO); 2.18, 2.13 (2s, 2 Me); 1.73 (d, J ¼ 6.9,
Me). 13C-NMR (CDCl3): 169.5 (s, C¼O); 126.6, 120.9 (2s, C(4’), C(5’)); 122.6 (d, C(2’)); 52.8 (q, MeO);
52.7 (d, CHN); 17.2, 8.4, 7.0 (3q, 3 Me). EI-HR-MS: 198.10081 (Mþ, C9H14N2O3þ ; calc. 198.10044).
Methyl (R)-2-(4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)propanoate ((R)-5e). Yield after CC (SiO2;
acetone, then AcOEt/MeOH 1:1): 1.43 g (72%, Method B). Colorless crystals. M.p. 142 – 1458 (CH2Cl2/
Et2O). [a]2D0 ¼ À48.5 (c ¼ 0.20, CH2Cl2).
Methyl (S)-2-(4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)-3-methylbutanoate (5f). Yield after CC
(SiO2; acetone, then AcOEt/MeOH 1:1): 2.03 g (90%, Method B). Colorless oil. [a]2D0 ¼ þ31.3 (c ¼
0.24, CH2Cl2). IR (film): 3350 – 2850vs (br.), 1743vs (C¼O), 1633w, 1437m, 1380m, 1332m, 1307m,
1273m, 1196m, 1178m, 1012w. 1H-NMR (CDCl3): 8.11 (s, HÀC(2’)); 4.22 (d, J ¼ 9.6, 1 H); 3.37 (s, MeO);
2.61 – 2.27 (m, 1 H); 2.20, 2.17 (2s, 2 Me); 1.03, 0.86 (2d, J ¼ 8.0, 2 Me). 13C-NMR (CDCl3): 168.8 (s,
C¼O); 126.4, 122.5 (2s, C(4’), C(5’)); 126.2 (d, C(2’)); 64.9 (d, CHN); 53.3 (q, MeO); 19.3, 19.0, 9.2, 7.4
(4q, 4 Me). EI-HR-MS: 226.13189 (Mþ, C11H18N2O3þ ; calc. 226.13174).
Methyl (S)-2-(4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)-4-methylpentanoate (5g). Yield after two CC
(SiO2; AcOEt/MeOH 1:1): 1.06 g (44%, Method B). Pale orange oil. [a]2D0 ¼ þ10.6 (c ¼ 0.20, CH2Cl2).
IR (film): 3250 – 2800vs (br.), 1747vs (C¼O), 1632s (br.), 1436s, 1380s, 1335s, 1275s, 1243s, 1194s, 1131m,
1
1042m, 994m, 732m. H-NMR (CDCl3): 8.09 (s, HÀC(2’)); 4.62 – 4.35 (m, 1 H); 3.38 (s, MeO); 2.12 (s,
2 Me); 2.00 – 1.19 (m, 3 H); 1.92 (d, J ¼ 6.4, 2 Me). 13C-NMR (CDCl3): 169.2 (s, C¼O); 127.0 (d, C(2’));
126.2, 122.2 (2s, C(4’), C(5’)); 57.2 (d, CHN); 53.2 (q, MeO); 40.0 (t, CH2); 24.5 (d, CH); 22.4, 21.3, 9.0, 7.0
(4q, 4 Me). EI-HR-MS: 240.14782 (Mþ, C12H20N2O3þ ; calc. 240.14739).
Methyl (4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)phenylacetate (5h). Yield after CC (SiO2; acetone,
then AcOEt/MeOH 1:1): 0.57 g (22%, modified Method A; see Table 1), 2.11 g (81%, Method B). Pale
yellow oil. IR (film): 3250 – 2900vs (br.), 1747vs (C¼O), 1632w, 1455m, 1437m, 1402m, 1380m, 1336m,
1311m, 1226m, 1200s, 1006w, 714s. 1H-NMR (CDCl3): 7.74 (s, HÀC(2’)); 7.51 – 7.17 (m, 5 arom. H); 5.79
(s, 1 H); 3.83 (s, MeO); 2.17, 2.14 (2s, 2 Me). 13C-NMR (CDCl3 þ 2 drops of CD3OD): 170.2 (s, C¼O);
134.3 (s, arom. Cq); 129.3, 128.2 (2d, 5 arom. C, C(2’)); 125.1, 123.7 (2s, C(4’), C(5’)); 65.0 (d, CHN); 8.6,
6.6 (2q, 2 Me). EI-HR-MS: 260.11596 (Mþ, C14H16N2O3þ ; calc. 260.11609).
Methyl (S)-2-(4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)-3-(1H-imidazol-4-yl)propanoate (5i). The
oily substance (2.40 g) obtained after CC (SiO2; acetone, then AcOEt/MeOH 1:1) was heated to reflux

Helvetica Chimica Acta – Vol. 91 (2008)
1927
in acetone. After cooling, solid impurities were filtered off to give 1.85 g (70%, Method B) of pure 5i as a
colorless, hygroscopic solid. [a]2D0 ¼ À26.0 (c ¼ 0.20, CH2Cl2). IR (KBr): 3350 – 3600vs (br.), 1747vs
1
(C¼O), 1438m, 1409m, 1383m, 1348m, 1320m, 1266m, 1203m, 1181m. H-NMR (CDCl3): 8.73 (br. s,
NH); 8.05 (s, HÀC(2’)); 7.39 (d, J ¼ 1.6, 1 H); 6.56 (s, 1 H); 5.22 (q, J ¼ 4.8, 1 H); 3.81 (s, MeO); 3.42 –
3.24 (m, 2 H); 2.07, 2.02 (2s, 2 Me). 13C-NMR (CDCl3): 169.0 (s, C¼O); 135.8, 125.53, 125.47 (3d,
3 CH(imidazole)); 131.7, 122.6, 116.5 (3s, 3 Cq(imidazole)); 57.9 (d, CH); 53.1 (q, MeO); 29.9 (t, CH2);
8.5, 6.9 (2q, 2 Me). EI-HR-MS: 264.12182 (Mþ, C12H16N4O3þ ; calc. 264.12224).
Methyl (S)-2-(4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)-3-(4-hydroxyphenyl)propanoate (5j). Yield
after two CC (SiO2; acetone, then AcOEt/MeOH 1:1): 2.17 g (63%, Method A), 2.35 g (81%, Method
B). Colorless solid. M.p. 164 – 1698 (CHCl3/Et2O). [a]2D0 ¼ À99.5 (c ¼ 0.20, CHCl3). IR (KBr): 3550 –
3300vs, 3200 – 2450vs (br.), 1744vs (C¼O), 1613m, 1518s, 1448m, 1260s, 1174m. 1H-NMR (CDCl3):
8.09 (s, HÀC(2’)); 6.72, 6.68 (2 br. s, 4 arom. H); 4.87 – 4.74 (m, 1 H); 3.78 (s, MeO); 3.53 – 2.98 (m, CH2);
2.08, 1.79 (2s, 2 Me). 13C-NMR (CDCl3): 168.6 (s, C¼O); 157.9, 125.8, 123.6, 122.1 (4s, 2 arom. Cq, C(4’),
C(5’)); 129.5, 124.0, 116.2 (3d, 5 arom. C); 59.8 (d, CH); 53.1 (q, MeO); 38.4 (t, CH2); 8.4, 6.9 (2q, 2 Me).
EI-HR-MS: 290.12646 (Mþ, C15H18N2O4þ ; calc. 290.12666).
4. Aminolysis of N-Oxides 5. To a sat. soln. of N-oxide 5 (3 mmol) in benzene (for 8b – 8d) or CHCl3
(for 8a and 8e – 8g) (ca. 1.0 ml), the corresponding amine (3.5 mmol, i.e., 375 mg of PhCH2NH2, 200 mg
of cyclopropylamine, 347 mg of cyclohexylamine, and 424 mg of (1-phenylethyl)amine, resp.) was added,
and the resulting mixture was occasionally shaken. The mixture was left for 48 h at r.t. (usually, after 2 h a
little precipitate was observed). The soln. was concentrated, the resulting solid was treated with Et2O,
triturated with a small portion of cold acetone, and left in the refrigerator for 30 min. The pure crystalline
product was filtered and dried under reduced pressure for 2 h. The synthesis of amides 8b, 8c, 8e, 8f, and
8h – 8i was also performed without solvent in very good yields: to the N-oxide 5 (1 mmol), an excess of
amine (2 – 2.5 mmol) was added, and the mixture left at r.t. for the required time (usually ca. 2 – 3 d) with
occasional stirring. The resulting suspension was treated with Et2O, washed with cold acetone, filtered,
and purified by crystallization from the appropriate solvent.
N-Benzyl-2-(4,5-dimethyl-3-oxido-1H-imidazol-1-yl)acetamide (8a). Yield: 528 mg (68%), 2 d.
Colorless crystals. M.p. 190 – 1918 (CH2Cl2/acetone). IR (KBr): 3450 – 2700vs (br.), 1683vs (C¼O),
1605s, 1453m, 1403s, 1378m, 1338m, 1275m, 1237m, 1193m, 1174m, 702m, 656m. 1H-NMR (CD3OD): 8.19
(s, HÀC(2’)); 7.28 (s, 5 arom. H); 4.72, 4.38 (2s, 2 CH2); 2.12, 2.10 (2s, 2 Me). 13C-NMR (CD3OD): 168.0
(s, C¼O); 139.8, 128.4, 127.2 (3s, arom. Cq, C(4’), C(5’)); 129.8, 128.9, 128.6, 124.8 (4d, 5 arom. C, C(2’));
48.8, 44.4 (2t, 2 CH2); 8.3, 7.0 (2q, 2 Me). EI-MS: 259 (3, Mþ), 241 (100, [M À H2O]þ), 150 (44), 109 (28),
91 (88). Anal. calc. for C14H17N3O2 (259.31): C 64.85, H 6.61, N16.20; found: C 64.69, H 6.59, N16.07.
N-Benzyl-2-(5-methyl-3-oxido-4-phenyl-1H-imidazol-1-yl)acetamide (8b). Yield: 570 mg (59%),
2 d. Colorless crystals. M.p. 205 – 2068 (MeOH/H2O). IR (KBr): 3450 – 2750vs (br.), 1689vs (C¼O),
1585m, 1497m, 1436m, 1401m, 1346m, 1263m, 1214m, 1016m, 764m, 738m, 698s, 608m. 1H-NMR
(CD3OD): 8.03 (s, HÀC(2’)); 7.57 – 7.21 (m, 5 arom. H); 7.28 (s, 5 arom. H); 4.58, 4.39 (2s, 2 CH2); 2.21 (s,
Me). 13C-NMR (CD3OD): 166.2 (s, C¼O); 138.3, 130.5, 127.0, 124.8 (4s, 2 arom. Cq, C(4’), C(5’)); 130.4,
129.4, 129.2, 129.0, 128.4, 128.1, 128.0 (7d, 10 arom. C, C(2’)); 48.8, 44.2 (2t, 2 CH2); 9.6 (q, Me). EI-MS:
321 (2, Mþ), 303 (100, [M À H2O]þ), 212 (36), 158 (13), 109 (27), 91 (54). Anal. calc. for C19H19N3O2
(321.38): C 71.01, H 5.96, N13.07; found: C 71.07, H 5.80, N13.03.
N-Benzyl-2-(4-methyl-3-oxido-5-phenyl-1H-imidazol-1-yl)acetamide (8c). Yield: 480 mg (51%),
2 d. Colorless crystals. M.p. 220 – 2228 (MeOH/H2O). IR (KBr): 3450 – 2600vs (br.), 1663vs (C¼O),
1
1608m, 1454m, 1395m, 1369m, 1336m, 1284m, 1227m, 1165m, 757m, 702m, 656m. H-NMR (CD3OD):
8.10 (s, HÀC(2’)); 7.52 – 7.17 (m, 10 arom. H); 4.51, 4.35 (2s, 2 CH2); 2.16 (s, Me). 13C-NMR (CD3OD):
166.2 (s, C¼O); 138.0, 135.7, 127.1, 126.5 (4s, 2 arom. Cq, C(4’), C(5’)); 130.5, 130.1, 129.4, 128.9, 128.1,
128.0, 127.8 (7d, 10 arom. C, C(2’)); 48.5, 43.8 (2t, 2 CH2); 7.6 (q, Me). EI-MS: 321 (2, Mþ), 303 (61, [M À
H2O]þ), 212 (28), 177 (33), 144 (20), 106 (18), 91 (100). Anal. calc. for C19H19N3O2 (321.38): C 71.01, H
5.96, N13.07; found: C 69.90, H 5.87, N12.99.
N-Benzyl-2-(3-oxido-4,5-diphenyl-1H-imidazol-1-yl)acetamide (8d). Yield: 970 mg (84%), 2 d.
Colorless crystals. M.p. 112 – 1168 (MeOH/H2O). IR (KBr): 3450 – 2800vs (br.), 1675vs (C¼O),
1603m, 1590m, 1577m, 1452m, 1404m, 1351m, 1272m, 1203m, 757s, 697vs, 657m. 1H-NMR (CD3OD): 8.43
(s, HÀC(2’)); 7.60 – 6.98 (m, 15 arom. H); 4.67, 4.29 (2s, 2 CH2). 13C-NMR (CD3OD): 165.8 (s, C¼O);

1928
Helvetica Chimica Acta – Vol. 91 (2008)
138.3, 128.1, 128.0, 126.6, 126.5 (5s, 3 arom. Cq, C(4’), C(5’)); 130.7, 129.6, 129.5, 128.8, 128.3, 128.2, 127.9,
127.7, 127.0, 126.9 (10d, 15 arom. C, C(2’)); 48.0, 43.4 (2t, 2 CH2). Anal. calc. for C24H21N3O2 · 1.25 H2O
(405.97): C 71.01, H 5.83, N10.35; found: C 70.82, H 5.67, N10.11.
N-Cyclopropyl-2-(4,5-dimethyl-3-oxido-1H-imidazol-1-yl)acetamide (8e). Yield: 511 mg (81%),
24 h. Colorless crystals. M.p. 192 – 1948 (acetone). IR (KBr): 3450 – 2750vs (br.), 1679vs (C¼O),
1635m, 1589s, 1407s, 1357m, 1339s, 1284s, 1179m, 1151m, 1091m, 991m, 897m, 811m, 646s, 600m.
1H-NMR (CD3OD): 7.94 (s, HÀC(2’)); 4.47 (s, CH2); 2.77 – 2.63 (m, HÀC(cPr)); 2.15, 2.14 (2s, 2 Me);
0.79 – 0.75, 0.56 – 0.52 (2m, 2 CH2(cPr)). 13C-NMR (CD3OD): 166.9 (s, C¼O); 126.0, 122.5 (2s, C(4’),
C(5’)); 125.5 (d, C(2’)); 47.5 (t, CH2); 22.2 (d, CH(cPr)); 7.9, 6.5 (2q, 2 Me); 5.5 (t, 2 CH2(cPr)). EI-MS:
209 (81, Mþ), 192 (56), 164 (62), 109 (100), 68 (62). Anal. calc. for C10H15N3O2 · 2 H2O (245.29): C 48.97,
H 7.81, N17.13; found: C 48.75, H 7.70, N17.03.
N-Cyclopropyl-2-(3-oxido-4,5-diphenyl-1H-imidazol-1-yl)acetamide (8f). Yield: 610 mg (61%),
24 h. Colorless crystals. M.p. 176 – 1798 (acetone). IR (KBr): 3450 – 2950vs (br.), 1678vs (br., C¼O),
1557m, 1445m, 1393m, 1357m, 1277m, 1201m, 762m, 698s, 655m. 1H-NMR (CD3OD): 8.21 (s, HÀC(2’));
7.48 – 7.07 (m, 10 arom. H); 4.45 (s, CH2); 2.69 – 2.59 (m, HÀC(cPr)); 0.78 – 0.71, 0.54 – 0.44 (2m,
2 CH2(cPr)). 13C-NMR (CD3OD): 166 (s, C¼O); 134.1, 130.2, 126.1, 125.7 (4s, 2 arom. Cq, C(4’), C(5’));
130.5, 129.6, 129.5, 128.8, 128.4, 127.9, 126.5 (7d, 10 arom. C, C(2’)); 48.7 (t, CH2); 22.2 (d, CH(cPr)); 5.6
(t, 2 CH2(cPr)). EI-MS: 333 (36, Mþ), 315 (100, [M À H2O]þ), 286 (75), 249 (58), 178 (34), 104 (45).
Anal. calc. for C20H19N3O2 · H2O (351.41): C 68.36, H 6.02, N11.96; found: C 68.42, H 5.89, N11.94.
N-Cyclohexyl-2-(3-oxido-4,5-diphenyl-1H-imidazol-1-yl)acetamide (8g). Yield: 495 mg (44%), 2 d.
Colorless crystals. M.p. 192 – 1938 (acetone). IR (KBr): 3500 – 2600vs (br.), 1679s, 1635vs (C¼O),
1507m, 1487m, 1447m, 1382s, 1352m, 1304m, 1204m, 1185m, 769m, 740m, 698s, 666m. 1H-NMR
(CD3OD): 8.36 (s, HÀC(2’)); 7.45 – 7.26 (m, 10 arom. H); 4.42 (s, CH2); 2.95 – 2.77 (m, HÀC(cHex));
2.02 – 0.95 (m, 5 CH2(cHex)). 13C-NMR (CD3OD): 170.9 (s, C¼O); 130.4, 129.6, 129.0, 128.8, 128.3,
128.0, 125.7 (7d, 10 arom. C, C(2’)); 128.9, 128.4, 126.2, 125.8 (4s, 2 arom. Cq, C(4’), C(5’)); 50.2 (d,
CH(cHex)); 49.7 (t, CH2); 30.6, 24.4, 24.0 (3t, 5 CH2(cHex)). EI-HR-MS: 376.2021 (Mþ, C23H25N3O2þ ;
calc. 376.2025).
2-(4,5-Dimethyl-3-oxido-1H-imidazol-1-yl)-N-[(R)-1-phenylethyl]acetamide (8h). Yield: 745 mg
(91%), 3 d. Colorless crystals. M.p. (dec.) 205 – 2098 (MeOH/H2O). [a]2D0 ¼ þ137 (c ¼ 0.20, MeOH).
IR (KBr): 3300 – 2700vs (br.), 1671vs (C¼O), 1601m, 1565m, 1581m, 1450m, 1408m, 1381m, 1340m,
1281m, 1182w, 758w, 701m. 1H-NMR (CDCl3): 7.79 (s, HÀC(2’)); 7.27 (br. s, 5 arom. H); 5.04 (q, J ¼ 6.9,
1 H); 4.49 (s, 2 H); 2.13, 2.08 (2s, 2 Me); 1.49 (d, J ¼ 6.9, Me). 13C-NMR (CDCl3 þ 2 drops of CD3OD):
164.8 (s, C¼O); 142.9 (s, arom. Cq); 128.7, 127.5, 126.2, 125.6 (4d, 5 arom. C, C(2’)); 126.5, 122.8 (2s, C(4’),
C(5’)); 48.1 (d, PhCH); 49.2 (t, CH2); 21.4, 8.4, 7.0 (3q, 3 Me). EI-HR-MS: 273.14751 (Mþ, C15H19N3O2þ ;
calc. 273.14773).
Suitable crystals for a crystal-structure determination were obtained from acetone by slow
evaporation of the solvent.
2-(5-Methyl-3-oxido-4-phenyl-1H-imidazol-1-yl)-N-[(R)-1-phenylethyl]acetamide (8i). Yield:
775 mg (77%). Colorless crystals. M.p. (dec.) 226 – 2318 (MeOH/H2O). [a]2D0 ¼ þ139.6 (c ¼ 0.25,
MeOH). IR (KBr): 3250 – 2650vs (br.), 1686vs (C¼O), 1581m, 1402m, 1271m, 1219m, 774m, 758m, 702s.
1H-NMR (CD3OD): 8.07 (s, HÀC(2’)); 7.66 – 7.17 (m, 5 arom. H); 7.29 (s, 5 arom. H); 5.07 (q, J ¼ 7.2,
1 H); 4.62 (s, CH2); 2.20 (s, Me); 1.52 (d, J ¼ 7.2, Me). 13C-NMR (CD3OD): 164.6 (s, C¼O); 143.0, 129.9,
127.1, 124.6 (4s, 2 arom. Cq, C(4’), C(5’)); 129.8, 128.9, 128.8, 128.7, 127.4, 126.1, 126.0 (7d, 10 arom. C,
C(2’)); 48.2 (t, CH2); 30.8 (d, CH); 21.6, 9.0 (2q, 2 Me). EI-HR-MS: 335.1629 (Mþ, C20H21N3O2þ ; calc.
335.1634).
N-Benzyl-2-(4,5-dimethyl-3-oxido-1H-imidazol-1-yl)propanamide (8j). Yield: 696 mg (85%). Col-
orless solid. M.p. 127 – 1328. IR (KBr): 3300 – 2700vs (br.), 1671vs (C¼O), 1615m, 1454m, 1411m,
1389m, 1335s, 1225m, 1195m, 703m. 1H-NMR (CD3OD): 8.09 (s, HÀC(2’)); 7.30 (s, 5 arom. H); 4.76 (q,
J ¼ 6.9, 1 H); 4.38 (s, CH2); 2.14, 2.11 (2s, 2 Me); 1.72 (d, J ¼ 6.9, Me). 13C-NMR (CD3OD): 171.0 (s,
C¼O); 139.5 (s, arom. Cq); 129.7, 128.8, 128.5, 126.0 (4d, 5 arom. C, C(2’)); 127.1, 123.8 (2s, C(4’), C(5’));
56.2 (d, CHN); 44.5 (t, CH2); 18.4, 8.6, 7.0 (3q, 3 Me). EI-HR-MS: 273.14763 (Mþ, C15H19N3O2þ ; calc.
273.14773).

Helvetica Chimica Acta – Vol. 91 (2008)
1929
5. Synthesis of 1H-Imidazole-2-thiones 10 (ester derivatives). To a magnetically stirred soln. of the
corresponding 1H-imidazole N-oxide (5b, 5c, and 5e; 1.0 mmol) in CH2Cl2 (1.0 ml), a soln. of 2,2,4,4-
tetramethylcyclobutane-1,3-dithione (9; 0.6 mmol) in CH2Cl2 (1.0 ml) was added dropwise at 08. The
addition was complete after ca. 10 min, and stirring was continued for 1 h while a little precipitate was
formed. Then, the solvent was removed under reduced pressure, the resulting solid was washed with
hexane (to remove remaining 9 and the by-product 2,2,4,4-tetramethylcyclobutane-1,3-dione), and
filtered (in the case of 10c, the by-products were sublimed off at 508/60 mm Hg). The crude product 10
was recrystallized from the appropriate solvent to give anal. pure samples.
Methyl (2,3-Dihydro-5-methyl-4-phenyl-2-thioxo-1H-imidazol-1-yl)acetate (10a). Yield: 226 mg
(86%). Colorless solid. M.p. 205 – 2078 (EtOH). IR (KBr): 3450 – 2750vs (br.), 1739vs (C¼O), 1497s,
1
1438m, 1410s, 1364m, 1224s (br.), 1182m, 768m, 700m. H-NMR (CDCl3): 11.22 (br. s, NH); 7.48 – 7.26
(m, 5 arom. H); 4.99 (s, CH2); 3.80 (s, MeO); 2.25 (s, Me). 13C-NMR (CDCl3): 167.8, 161.5 (2s, C¼O,
C¼S); 129.0, 128.2, 127.2 (3d, 5 arom. C); 128.3, 123.5, 122.3 (3s, arom. Cq, C(4’), C(5’)); 52.8 (q, MeO);
45.6 (t, CH2); 10.1 (q, Me). EI-MS: 262 (100, Mþ), 230 (7, [M À S]þ), 204 (37), 203 (30), 144 (9), 115
(13), 103 (9). Anal. calc. for C13H14N2O2S (262.33): C 59.52, H 5.38, N10.68; found: C 59.32, H 5.20, N
10.49.
Methyl (2,3-Dihydro-4-methyl-5-phenyl-2-thioxo-1H-imidazol-1-yl)acetate (10b). Yield: 199 mg
(76%). Colorless solid. M.p. 132 – 1348 (MeOH). IR (KBr): 3200 – 2750vs (br.), 1742vs (C¼O),
1601w, 1508s, 1441m, 1417s, 1375s, 1290w, 1227vs (br.), 1005w, 955w, 765m, 742m, 702s. 1H-NMR
(CDCl3): 12.15 (br. s, NH); 7.64 – 7.15 (m, 5 arom. H); 4.69 (s, CH2); 3.72 (s, MeO); 2.17 (s, Me).
13C-NMR (CDCl3): 168.5, 161.1 (2s, C¼O, C¼S); 130.5, 129.5, 129.4 (3d, 5 arom. C); 128.4, 127.7, 122.5
(3s, arom. Cq, C(4’), C(5’)); 52.6 (q, MeO); 46.4 (t, CH2); 9.4 (q, Me). EI-MS: 262 (100, Mþ), 230 (20,
[M À S]þ), 203 (38), 144 (9), 115 (18). Anal. calc. for C13H14N2O2S (262.33): C 59.52, H 5.38, N10.68;
found: C 59.49, H 5.30, N10.74.
Methyl (S)-2-(2,3-Dihydro-4,5-dimethyl-2-thioxo-1H-imidazol-1-yl)propanoate (10c). Yield: 180 mg
(84%). Colorless solid. M.p. 146 – 1478 (CH2Cl2/Et2O). [a]2D0 ¼ þ38.2 (c ¼ 0.20, CH2Cl2). IR (KBr):
3250 – 2800vs (br.), 1740vs (C¼O), 1660m, 1497s, 1436s, 1408s, 1331m, 1314s, 1240s, 1110s, 1069m, 959m.
1H-NMR (CDCl3): 11.50 (br. s, NH); 5.90 (q, J ¼ 7.3, 1 H); 3.76 (s, MeO); 2.08, 2.02 (2s, 2 Me); 1.65 (d,
J ¼ 7.3, 3 H). 13C-NMR (CDCl3): 170.8, 158.9 (2s, C¼O, C¼S); 120.9, 120.8 (2s, C(4’), C(5’)); 53.1 (q,
MeO); 52.6 (d, CH); 15.8, 9.3, 8.8 (3q, 3 Me). EI-HR-MS: 217.07758 (Mþ, C9H14N2O2Sþ; calc.
214.07760).
6. Synthesis of 1H-Imidazol-2-thiones 11 (amide derivatives). To a magnetically stirred MeOH soln.
of the corresponding N-oxide 8 (1.0 mmol), a soln. of 9 (0.6 mmol) in CHCl3 (ca. 1.0 ml) was added
dropwise. After 1 h, the solvents were removed, and the resulting solid was washed with Et2O and
recrystallized.
N-Benzyl-2-(2,3-dihydro-4,5-dimethyl-2-thioxo-1H-imidazol-1-yl)acetamide (11a). Yield: 264 mg
(96%). Colorless solid. M.p. 229 – 2328 (MeOH). IR (KBr): 3450 – 2750vs (br.), 1662vs (C¼O),
1
1570m, 1497m, 1480m, 1453m, 1429m, 1411m, 1249w, 1221w, 1188w, 737w, 698m. H-NMR (CD3OD):
7.36 (br. s, 5 arom. H); 4.81, 4.43 (2s, 2 CH2); 2.09, 2.07 (2s, 2 Me). 13C-NMR (CD3OD): 169.7, 162.0 (2s,
C¼O, C¼S); 141.1, 124.3, 121.3 (3s, arom. Cq, C(4’), C(5’)); 130.5, 129.5, 129.1 (3d, 5 arom. C); 48.6, 44.7
(2t, 2 CH2); 10.2, 10.1 (2q, 2 Me). EI-HR-MS: 275.1092 (Mþ, C14H17N3OSþ; calc. 275.1092). Anal. calc.
for C14H17N3OS (275.38): C 61.06, H 6.22, N15.26; found: C 60.67, H 6.13, N15.16.
N-Benzyl-2-(2,3-dihydro-5-methyl-4-phenyl-2-thioxo-1H-imidazol-1-yl)acetamide (11b). Yield:
192 mg (57%). Colorless solid. M.p. 248 – 2508 (MeOH). IR (KBr): 3450 – 2750vs (br.), 1652vs
(C¼O), 1602w, 1541m, 1496s, 1454m, 1410m, 1260w, 1216w, 1182w, 766m, 740m, 698s. 1H-NMR
(CD3OD): 7.60, 7.47 (2 br. s, 10 arom. H); 5.02, 4.50 (2s, 2 CH2); 2.39 (s, Me). 13C-NMR (CD3OD): 168.7,
159.6 (2s, C¼O, C¼S); 138.7, 130.9, 128.5, 125.2 (4s, 2 arom. Cq, C(4’), C(5’)); 130.8, 130.6, 130.2, 129.3,
129.1, 128.7 (6d, 10 arom. C); 49.3, 44.2 (2t, 2 CH2); 11.6 (q, Me). EI-MS: 337 (76, Mþ), 304 (100, [M À
SH]þ), 230 (12), 204 (25), 191 (32), 190 (25), 91 (18, C7Hþ7 ). Anal. calc. for C19H19N3OS (337.45): C 67.63,
H 5.67, N12.45; found: C 67.52, H 5.72, N12.17.
N-Benzyl-2-(2,3-dihydro-4,5-diphenyl-2-thioxo-1H-imidazol-1-yl)acetamide (11c). Yield: 240 mg
(60%). Colorless solid. M.p. 260 – 2618 (MeOH). IR (KBr): 3450 – 2750vs (br.), 1694vs (C¼O),
1529m, 1509m, 1493s, 1446w, 1422m, 1395m, 1242m, 1227m, 1203m, 770m, 756m, 700s. 1H-NMR

1930
Helvetica Chimica Acta – Vol. 91 (2008)
(CD3OD): 7.71 – 7.33 (m, 5 arom. H); 7.46 (br. s, 10 arom. H); 4.75, 4.44 (2s, 2 CH2). 13C-NMR (CD3OD):
166.0, 162.1 (2s, C¼O, C¼S); 138.7, 128.4, 127.9, 126.9, 123.9 (5s, 3 arom. Cq, C(4’), C(5’)); 130.6, 129.2,
128.8, 128.2, 128.0, 127.3, 126.8, 126.5, 126.0 (9d, 15 arom. C); 46.4, 41.7 (2t, 2 CH2). EI-HR-MS: 399.1396
(Mþ, C24H21N3OSþ; calc. 399.1405). Anal. calc. for C24H21N3OS (399.52): C 72.15, H 5.30, N10.52; found:
C 71.90, H 5.29, N10.66.
7. Synthesis of Methyl (S)-2-(4,5-Dimethyl-1H-imidazol-1-yl)-3-(1H-imidazol-4-yl)propanoate (12):
To a soln. of 5i (1.0 mmol) in EtOH (2 ml), a suspension of freshly prepared Raney-Ni in EtOH was
added in small portions, and the progress of the reaction was followed by TLC (MeOH/AcOEt 1:3).
After the starting N-oxide was completely reduced, the mixture was filtered through a silica-gel plug (ca.
2 cm, EtOH), and the filtrate was concentrated and dried under reduced pressure. The highly pure
product obtained was analyzed without further purification. Yield: 159 mg (64%). Colorless solid. M.p.
51 – 538. [a]2D0 ¼ À13.9 (c ¼ 0.20, CH2Cl2). IR (KBr): 3250 – 2500vs (br.), 1747vs (C¼O), 1496m, 1440m,
1271m, 1235m, 1205s, 1163m, 733m, 627m. 1H-NMR (CDCl3): 7.48, 7.45, 6.53 (3s, 3 arom. H); 5.02 (dd,
J ¼ 9.6, 5.6, 1 H); 3.73 (s, MeO); 3.65 – 3.04 (m, 2 H); 2.07, 1.99 (2s, 2 Me). 13C-NMR (CDCl3): 171.5 (s,
C¼O); 136.6, 135.6, 124.3 (3d, 3 CH(imidazole)); 134.5, 133.3, 117.5 (3s, 3 Cq(imidazole)); 62.4 (d, CH);
53.4 (q, MeO); 31.3 (t, CH2); 12.4, 8.5 (2q, 2 Me). EI-HR-MS: 248.12733 (Mþ, C12H16N4O2þ ; calc.
248.12725).
8. Synthesis of Ethyl 1,5-Dimethyl-3-oxido-1H-imidazole-4-carboxylate (14a). To the soln. of 13
(1.0 g, 6.3 mmol) in Et2O (15 ml) cooled in an ice-bath, a soln. of hexahydro-1,3,5-triazine 6a (0.35 g,
8.0 mmol) in Et2O (10 ml) was added dropwise at 08. After 30 min, the ice-bath was removed, and the
mixture was stirred magnetically overnight. The colorless precipitate was filtered and recrystallized.
Yield: 0.80 g (69%). Colorless needles. M.p. 76 – 788 (CH2Cl2/Et2O). IR (KBr): 3150 – 2900vs (br.),
1735 – 1690vs (br., C¼O), 1374m, 1313m, 1279m, 1237m, 1165m, 1070m, 1039m. 1H-NMR (CDCl3): 8.45
(s, HÀC(2)); 4.37 (q, J ¼ 7.1, CH2O); 3.66 (s, MeN); 2.46 (s, Me); 1.38 (t, J ¼ 7.1, MeCH2O). 13C-NMR
(CDCl3): 158.7 (s, C¼O); 132.4, 120.9 (C(4), C(5)); 128.0 (d, C(2)); 60.6 (t, CH2O); 32.4, 14.0, 9.8 (3q,
3 Me). EI-HR-MS: 184.0839 (Mþ, C8H12N2Oþ3 ; calc. 184.0848).
9. Synthesis of Ethyl 2,3-Dihydro-1,5-dimethyl-2-oxo-1H-imidazole-4-carboxylate (15a). A soln. of
14a (0.15 g, 0.9 mmol) in benzene (3 ml) was heated at 808 for 2 h. Then, the solvent was removed under
reduced pressure, and the resulting solid was recrystallized. Yield: 0.13 g (87%). Colorless crystals. M.p.
193 – 1968 (CH2Cl2/Et2O). IR (KBr): 3200 – 2900vs (br.), 1690vs (br., C¼O), 1455m, 1368m, 1319s,
1213m, 1186m, 1163m, 1076m. 1H-NMR (CDCl3): 9.35 (br. s, NH); 4.29 (q, J ¼ 6.7, CH2O); 3.22 (s, MeN);
2.39 (s, Me); 1.35 (t, J ¼ 6.7, MeCH2O). 13C-NMR (CDCl3): 160.3, 153.0 (2s, 2 C¼O); 130.7, 109.2 (C(4),
C(5)); 60.4 (t, CH2O); 27.1, 14.2, 10.0 (3q, 3 Me). EI-HR-MS: 184.08444 (Mþ, C8H12N2O3þ ; calc.
184.08479).
10. Synthesis of Ethyl 1,5-Disubstituted 2,3-Dihydro-3-oxo-1H-imidazole-4-carboxylates 15b and 15c.
To the soln. of 13 (1.6 g, 10 mmol) in Et2O (25 ml), a cooled mixture of the corresponding hexahydro-
1,3,5-triazine (15 mmol; 1.8 g of 6b or 1.7 g of 6c) in Et2O (10 ml) was added dropwise at 08. After
30 min, the ice-bath was removed, and the mixture stirred magnetically for the required time (TLC
monitoring). The resulting oil was separated and washed with Et2O (3 ꢀ 15 ml). The crude mixture
contained the corresponding N-oxide 14 and 15 in a ratio of ca. 4 :1 (1H-NMR). Crystallization from the
appropriate solvent gave pure 1H-imidazol-2-ones 15. 1H-NMR (CDCl3) of 14b and 14c (from the
mixtures): Data of 14b: 7.99 (s, HÀC(2)); 7.46 – 7.06 (m, 5 arom. H); 5.08 (s, CH2); 4.33 (q, J ¼ 7.1,
CH2O); 2.26 (s, Me); 1.32 (t, J ¼ 7.1, MeCH2O). Data of 14c: 7.92 (s, HÀC(2)); 4.42 (q, J ¼ 7.2, CH2O);
4.07 – 3.62 (m, 1 H, cHex); 2.49 (s, Me); 2.22 – 1.20 (3m, cHex); 1.40 (t, J ¼ 7.1, MeCH2O).
Ethyl 1-Benzyl-2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate (15b). 48 h. Yield: 1.95 g
(75%). Colorless crystals. M.p. 194 – 1988 (CH2Cl2/Et2O). IR (KBr): 3250 – 2900vs (br.), 1690vs (br.,
1
C¼O), 1626w, 1455m, 1409m, 1363m, 1325m, 1180m, 1088m, 1075m, 745m, 733m. H-NMR (CDCl3):
9.70 (br. s, NH); 7.37 – 7.21 (m, 5 arom. H); 4.91 (s, CH2); 4.28 (q, J ¼ 7.1, CH2O); 2.29 (s, Me); 1.32 (t, J ¼
7.1, MeCH2O). 13C-NMR (CDCl3): 160.0, 152.9 (2s, 2 C¼O); 136.3, 130.6, 109.6 (3s, arom. Cq, C(4),
C(5)); 128.8, 127.7, 127.0 (3d, 5 arom. C); 60.5, 44.4 (2t, 2 CH2); 14.2, 10.2 (2q, 2 Me). EI-HR-MS:
260.1166 (Mþ, C14H16N2Oþ3 ; calc. 260.1161).
Ethyl 1-Cyclohexyl-2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate (15c). 72 h. Yield:
1.73 g (69%). Colorless crystals. M.p. 195 – 1988 (CH2Cl2/Et2O). IR (KBr): 2950 – 2850s (br.), 1686vs

Helvetica Chimica Acta – Vol. 91 (2008)
1931
(br., C¼O), 1627m, 1452m, 1370w, 1314m, 1188m, 1077m. 1H-NMR (CDCl3): 9.45 (br. s, NH); 4.28 (q,
J ¼ 7.1, CH2O); 3.88 – 3.80 (m, 1 H, cHex); 2.52 (s, Me); 2.27 – 2.17, 1.89 – 1.68, 1.39 – 1.20 (3m, 10 H,
cHex); 1.36 (t, J ¼ 7.1, MeCH2O). 13C-NMR (CDCl3): 160.1, 152.5 (2s, 2 C¼O); 130.7, 109.3 (C(4), C(5));
60.4 (t, CH2O); 54.3 (d, CH(cHex)); 30.3, 26.1, 25.1 (3t, 5 CH2(cHex)); 14.3, 10.5 (2q, 2 Me). EI-MS: 252
(20, Mþ), 170 (100, [M À cHex þ 1]þ), 142 (30), 125 (19), 124 (51). Anal. calc. for C13H20N2O3 (252.32): C
61.88, H 7.99, N11.10; found: C 61.92, H 8.00, N11.29.
11. Synthesis of N-Cyclopropyl-1,5-dimethyl-3-oxido-1H-imidazole-4-carboxamide (16). A mixture
of 14a (1.52 g, 8.3 mmol) and cyclopropylamine (1.3 g, 23 mmol) was stirred at r.t. for 3 d. The crude
mixture was diluted with Et2O (50 ml) and filtered to give a colorless solid containing mainly the target
molecule 16 contaminated with small amounts of 15a. Pure amide 16 was obtained after CC (SiO2;
MeOH/AcOEt 8 :1). Yield: 744 mg (46%). Colorless solid. M.p. 204 – 2068 (MeOH). IR (KBr): 3150 –
2900s (br.), 1656vs, 1604s, 1557m, 1448m, 1411m, 1290m, 1037m, 616m, 599m. 1H-NMR (CDCl3): 10.58
(br. s, N H); 7.76 (s, HÀC(2)); 3.58 (s, Me); 3.08 – 2.66 (m, 1 H, cPr); 2.61 (s, Me); 0.88 – 0.56 (m, 4 H,
cPr). 13C-NMR (CDCl3): 162.9 (s, C¼O); 133.8, 122.7 (C(4), C(5)); 128.8 (d, C(2)); 33.5 (d, CH(cPr);
23.0, 10.6 (2q, 2 Me); 7.7 (t, 2 CH2(cPr). EI-HR-MS: 195.10063 (Mþ, C9H14N3O2þ ; calc. 195.10078).
Suitable crystals for a crystal-structure determination were obtained from MeOH by slow
evaporation of the solvent.
12. X-Ray Crystal-Structure Determination of 8h and 16 (Table, and Figs. 2 and 3)4). All
measurements were performed on a Nonius KappaCCD diffractometer [25] using graphite-monochro-
mated MoKa radiation (l 0.71073 Š) and an Oxford Cryosystems Cryostream 700 cooler. The data
collection and refinement parameters are given in Table 4, and views of the molecules are shown in Figs. 2
and 3. Data reduction was performed with HKL Denzo and Scalepack [26]. The intensities were
corrected for Lorentz and polarization effects but not for absorption. Equivalent reflections were
merged. The structures were solved by direct methods using SHELXS97 [27], which revealed the
positions of all non-H-atoms. The asymmetric unit of 8h contains four symmetry-independent molecules
of 8h and four molecules of H2O. The atomic coordinates of the molecules were tested carefully for a
relationship from a higher symmetry space group using the program PLATON[28], but none could be
found. The Ph ring in one of the molecules is disordered over two orientations. Two sets of overlapping
positions were defined for the atoms of this Ph group, and the site occupation factor of the major
conformation of the ring was refined to 0.57(3). Similarity restraints were applied to the chemically
equivalent bond lengths and angles involving all disordered C-atoms, while neighboring atoms within and
between each conformation of the disordered Ph rings were restrained to have similar atomic
displacement parameters. The asymmetric unit of 16 contains two molecules of 16 plus one molecule of
MeOH. The non-H-atoms of 8h and 16 were refined anisotropically. In the case of 8h, the amide H-
atoms were placed in the positions indicated by a difference electron-density map, and their positions
were allowed to refine with individual isotropic displacement parameters. The H-atoms of the H2O
molecules could not be located reliably and were omitted from the model. All remaining H-atoms and all
H-atoms of 16 were placed in geometrically calculated positions and refined using a riding model where
each H-atom was assigned a fixed isotropic displacement parameter with a value equal to 1.2Ueq of its
parent C-atom (1.5 Ueq for the Me groups). The refinement of each structure was carried out on F2 using
full-matrix least-squares procedures, which minimized the function Sw(F2o À Fc2 )2. A correction for
secondary extinction was applied for 8h. In the cases of 8h and 16, two and one reflection, resp., whose
intensities were considered to be extreme outliers, were omitted from the final refinement. The available
crystals of 16 were of poor quality, and the crystal structure is correspondingly of diminished quality.
Nonetheless, the composition and connectivity of the molecule has been established unequivocally.
Neutral atom scattering factors for non-H-atoms were taken from [29a], and the scattering factors for H-
atoms were taken from [30]. Anomalous dispersion effects were included in Fc [31]; the values for f’ and
f’’ were those of [29b]. The values of the mass-attenuation coefficients are those of [29c]. All calculations
were performed using the SHELXL97 [32] program.
4
)
CCDC-688309 – 688310 contain the supplementary crystallographic data for this article. These data
can be obtained free of charge from the Cambridge Crystallographic Data Centre, via
www.ccdc.cam.ac.uk/data_request/cif.

1932
Helvetica Chimica Acta – Vol. 91 (2008)
Table 4. Crystallographic Data for Compounds 8h and 16
8h
16
Crystallized from
Empirical formula
Formula weight
acetone
C15H19N3O2 · H2O
291.35
MeOH
C9H13N3O2 · 0.5 MeOH
211.24
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
colorless, prism
colorless, prism
0.17 ꢀ 0.22 ꢀ 0.25
160(1)
0.17 ꢀ 0.20 ꢀ 0.35
160(1)
Crystal system
Space group
triclinic
P1
triclinic
P1
¯
Z
4
4
Reflections for cell determination
8938
3483
2q range for cell determination [8]
4 – 60
4 – 50
Unit cell parameters a [Š]
9.0797(3)
13.1025(5)
14.0338(3)
74.340(2)
81.753(2)
87.957(2)
1590.95(9)
1.216
7.6510(7)
9.945(1)
14.746(2)
83.311(6)
85.927(7)
69.088(7)
1040.5(2)
1.348
b [Š]
c [Š]
a [8]
b [8]
g [8]
V [Š3]
Dx [g cmÀ3
]
m(MoKa) [mmÀ1
Scan type
]
0.0859
f and w
60
0.0994
w
2q(max) [8]
50
Total reflections measured
Symmetry independent reflections
Reflections with I > 2s(I)
Reflections used in refinement
Parameters refined; restraints
Final R(F) [I > 2d(I) reflections]
wR(F2) (all data)
43631
9195
6829
9193
841; 178
0.0622
0.1749
0.1084; 0.0792
1.034
14870
3572
2221
3571
277; 0
0.1184
0.3549
0.1860; 0.4617
1.105
Weighting parameters [a; b]a)
Goodness-of-fit
Secondary extinction coefficient
0.022(6)
0.003
0.54; À 0.26
–
Final Dmax/s
D1 (max; min) [e Š
0.001
0.77; À 0.47
À3
]
wÀ1 ¼ s2 (Fo2 ) þ (aP)2 þ bP where P ¼ (Fo2 ) þ 2Fc2 )/3.
REFERENCES
[1] G. Mloston, T. Gendek, H. Heimgartner, Tetrahedron 2000, 56, 5405.
´
´
´
[2] G. Mloston, M. Jasinski, A. Linden, H. Heimgartner, Helv. Chim. Acta 2006, 89, 1304.
´
´
[3] M. Jasinski, G. Mloston, P. Mucha, A. Linden, H. Heimgartner, Helv. Chim. Acta 2007, 90, 1765.
´
[4] G. Mloston, P. Mucha, K. Urbaniak, K. Broda, H. Heimgartner, Helv. Chim. Acta 2008, 91, 232.
´
´
[5] P. Mucha, G. Mloston, M. Jasinski, A. Linden, H. Heimgartner, Tetrahedron: Asymmetry 2008, 19,
1600.
´
[6] G. Mloston, T. Gendek, H. Heimgartner, Helv. Chim. Acta 1998, 81, 1585.
[7] R. Loska, M. Ma˛kosza, Mendeleev Commun. 2006, 161; R. Loska, M. Ma˛kosza, Chem.–Eur. J. 2008,
14, 2577.

Helvetica Chimica Acta – Vol. 91 (2008)
1933
[8] S. Laufer, G. Wagner, D. Kotschenreuther, Angew. Chem., Int. Ed. 2002, 41, 2290.
[9] M. Boiani, M. Gonzales, Mini-Rev. Med. Chem. 2005, 5, 409.
[10] S. A. Laufer, W. Zimmermann, K. J. Ruff, J. Med. Chem. 2004, 47, 6311.
[11] H. Lettau, P. Nuhn, R. Schneider, P. Stenger, Pharmazie 1990, 45, 830
[12] R. Hossbach, H. Lettau, P. Nuhn, R. Schneider, P. Stenger, B. Stiebitz, Pharmazie 1991, 46, 412.
[13] H. Lettau, Z. Chem. 1970, 10, 462.
´
[14] G. Mloston, M. Celeda, G. K. S. Prakash, G. A. Olah, H. Heimgartner, Helv. Chim. Acta 2000, 83,
728.
´
[15] G. Mloston, M. Celeda, unpublished results.
[16] O. Nakaguchi, T. Oku, H. Takeno, M. Hashimoto, T. Kamiya, Chem. Pharm. Bull. 1987, 35, 3985.
´
[17] J. Omelanczuk, M. Mikołajczyk, Tetrahedron: Asymmetry 1996, 7, 2687.
[18] C. K. Johnson, ꢀORTEP IIꢁ, Report ORNL-5138, Oak Ridge National Laboratory, Oak Ridge,
Tennessee, 1976.
[19] J. Bernstein, R. E. Davis, L. Shimoni, N.-L. Chang, Angew. Chem., Int. Ed. 1995, 34, 1555.
´
[20] H. Cerecetto, A. Gerpe, M. Gonzales, Y. Fernandez Sainz, O. E. Piro, Synthesis 2004, 2678.
´
[21] R. Bartnik, W. Hahn, G. Mloston, Roczniki Chem. 1977, 51, 49 (Chem. Abstr. 1977, 87, 53155).
[22] a) W. L. Semon, V. R. Damerell, Org. Synth. 1943, 2, 205; b) W. F. Beech, J. Chem. Soc. 1955, 3095;
c) G. B. Bennett, R. B. Mason, L. J. Alden, J. B. Roach Jr., J. Med.Chem. 1978, 21, 627; d) T. Watson,
ˆ
J. Taylor, M. S. Marks, J. Chem. Soc. 1930, 2302; e) I. R. Correa Jr., P. J. S. Moran, Tetrahedron 1999,
55, 14221.
[23] a) J. R. L. Smith, L. A. V. Mead, J. Chem. Soc., Perkin Trans. 2 1976, 1172; b) A. F. McDonagh, H. E.
´
Smith, J. Org. Chem. 1968, 33, 8; c) L. Stefaniak, T. Urbanski, M. Witanowski, H. Januszewski,
Roczniki Chem. 1969, 59, 1687 (Chem. Abstr. 1970, 72, 210726).
[24] J. F. Almeida, J. Anaya, N. Martin, M. Grande, J. R. Moran, M. C. Caballero, Tetrahedron:
Asymmetry 1992, 11, 1431; S. Eisenbarth, B. Steffan, Tetrahedron 2002, 56, 363; A. G. Al-Sehemi,
R. S. Atkinson, J. Fawcett, J. Chem. Soc., Perkin Trans. 1 2002, 257; F. Kenta, O. Hiroyuki, Angew.
Chem., Int. Ed. 2007, 46, 1852; S. Aime, E. Gianolio, D. Corpillo, C. Cavallotti, G. Palmisano, M.
Sisti, G. B. Giovenzana, R. Pagliarin, Helv. Chim. Acta 2003, 86, 615; D. Ma, W. Tang, A. P.
Kozikowski, N. E. Lewin, P. M. Blumberg, J. Org. Chem. 1999, 64, 6366.
[25] R. Hooft, KappaCCD Collect Software, Nonius BV, Delft, The Netherlands, 1999.
[26] Z. Otwinowski, W. Minor, in ꢀMethods in Enzymologyꢁ, Vol. 276, ꢀMacromolecular Crystallographyꢁ,
Part A, Eds. C. W. Carter Jr., R. M. Sweet, Academic Press, New York, 1997, p. 307.
[27] G. M. Sheldrick, ꢀSHELXS97ꢁ, Program for the Solution of Crystal Structures, University of
Gçttingen, Germany, 1997.
[28] A. L. Spek, ꢀPLATONꢁ, Program for the Analysis of Molecular Geometry, University of Utrecht,
The Netherlands, 2007.
[29] a) E. N. Maslen, A. G. Fox, M. A. OꢁKeefe, in ꢀInternational Tables for Crystallographyꢁ, Ed. A. J. C.
Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 6.1.1.1, p. 477; b) D. C. Creagh,
W. J. McAuley, in ꢀInternational Tables for Crystallographyꢁ, Ed. A. J. C. Wilson, Kluwer Academic
Publishers, Dordrecht, 1992, Vol. C, Table 4.2.6.8, p. 219; c) D. C. Creagh, J. H. Hubbell, in
ꢀInternational Tables for Crystallographyꢁ, Ed. A. J. C. Wilson, Kluwer Academic Publishers,
Dordrecht, 1992, Vol. C, Table 4.2.4.3, p. 200.
[30] R. F. Stewart, E. R. Davidson, W. T. Simpson, J. Chem. Phys. 1965, 42, 3175.
[31] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17, 781.
[32] G. M. Sheldrick, ꢀSHELXL97ꢁ, Program for the Refinement of Crystal Structures, University of
Gçttingen, Germany, 1997.
Received July 14, 2008