Optically active imidazoles derived from enantiomerically pure trans-1,2-diaminocyclohexane

Article abstract of DOI:10.1016/j.tetasy.2011.04.005

A new exploration of monoprotected derivatives of trans-1,2- diaminocyclohexane as a platform for the synthesis of enantiomerically pure imidazole derivatives is described. The primary amino group (-NH₂), present in the mono-imine derivative of salicylic aldehyde (hemi-salen derivative) 5 was used for sequential reactions with formaldehyde and the corresponding α-(hydroxyimino)ketone. (S)-(-)-1-Phenylethylamine was also used as starting material for the preparation of new imidazole N-oxides 7c and 10a-c, bearing a chiral N-(1-phenylethyl)carboxamido function at C(4). Imidazole N-oxides 10a,b possessing either a Me or i-Pr group at N(1), respectively, follow the known sulfur-transfer pathway to afford the corresponding imidazole-2-thiones 13a,b. However, in the case of imidazole N-oxide 10c with a bulky adamantan-1-yl substituent at N(1), the attempted 'sulfur-transfer reaction' led to the deoxygenated imidazole derivative 14. Finally, the same reaction with 7c, which bears an electron-withdrawing N-(1-phenylethyl) carboxamide residue at C(4) of the imidazole ring, yielded a mixture of deoxygenated imidazole 16 and imidazole-2-thione 15c.

Full text of DOI:10.1016/j.tetasy.2011.04.005

Tetrahedron: Asymmetry 22 (2011) 669–674
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Optically active imidazoles derived from enantiomerically pure
trans-1,2-diaminocyclohexane1
a,
⇑
a
a,
⇑
Grzegorz Mloston , Dorota Rygielska , Marcin Jasinski , Heinz Heimgartner b
´
´
a
´
´
Department of Organic and Applied Chemistry, University of Łódz, Tamka 12, PL-91-403 Łódz, Poland
b Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
A new exploration of monoprotected derivatives of trans-1,2-diaminocyclohexane as a platform for the
synthesis of enantiomerically pure imidazole derivatives is described. The primary amino group
(–NH2), present in the mono-imine derivative of salicylic aldehyde (hemi-salen derivative) 5 was used
Received 17 February 2011
Accepted 4 April 2011
Available online 12 May 2011
for sequential reactions with formaldehyde and the corresponding
a
-(hydroxyimino)ketone. (S)-(ꢀ)-
1-Phenylethylamine was also used as starting material for the preparation of new imidazole N-oxides
7c and 10a–c, bearing a chiral N-(1-phenylethyl)carboxamido function at C(4). Imidazole N-oxides
10a,b possessing either a Me or i-Pr group at N(1), respectively, follow the known sulfur-transfer path-
way to afford the corresponding imidazole-2-thiones 13a,b. However, in the case of imidazole N-oxide
10c with a bulky adamantan-1-yl substituent at N(1), the attempted ‘sulfur-transfer reaction’ led to
the deoxygenated imidazole derivative 14. Finally, the same reaction with 7c, which bears an electron-
withdrawing N-(1-phenylethyl)carboxamide residue at C(4) of the imidazole ring, yielded a mixture of
deoxygenated imidazole 16 and imidazole-2-thione 15c.
Dedicated to Professor Janusz Jurczak
(Warsaw) on the occasion of his 70th
birthday
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Chiral 1,2-diamines are widely applied as easily available start-
ing materials for the preparation of optically active heterocycles.2
Of particular note is trans-1,2-diaminocyclohexane 1a, which can
be isolated as a pure enantiomer by resolution via diastereomeric
tartrates.3 In recent papers we reported the efficient synthesis of
bis-imidazoles starting with enantiomerically pure 1a.4,5 The ini-
tially obtained N,N0-dioxides 2 were deoxygenated to give the
bis-imidazoles 3, which were subsequently alkylated to yield the
corresponding bis-imidazolium salts 4 (Fig. 1).4b Some of the opti-
cally active N,N0-dioxides as well as the deoxygenated bis-imida-
zoles were successfully applied as organocatalysts for the
asymmetric allylation of aromatic aldehydes5 and for asymmetric
cyclopropanations.6
Herein our goal was the synthesis of a novel series of optically
active imidazole N-oxides using some monoprotected derivatives
of 1a. Furthermore, the obtained N-oxides should be converted into
the corresponding imidazole-2-thiones. Both imidazole N-oxides
and imidazole-2-thiones are potentially attractive as new ligands
for asymmetric synthesis or as organocatalysts. In numerous re-
H2N
NH2
1a
R1
R1
R1
R1
R1
R1
-
N
N
N
N
.
N
N
N
N
2X
R2
R2
R2
R2
R2
N
R3
N
R3
R2
N
N
O
O
(X = Br or BF4)
2
3
4
Figure 1. trans-1,2-Diaminocyclohexane 1a (DACH) as a substrate for preparation
of C2-symmetrical bis-imidazole derivatives 2,4a 34a and 4.4b
cent papers, some optically active aza-aromatic N-oxides were
demonstrated to be efficient ligands.7a Moreover, it is well estab-
lished that many thiourea derivatives, which can be considered
as structural analogs of imidazole-2-thiones, act efficiently as
organocatalysts and ligands for asymmetric synthesis.7b–e Never-
theless, to the best of our knowledge, no reports on the synthesis
of optically active imidazole-2-thiones, potentially useful in asym-
metric synthesis, have been published.
⇑
Corresponding authors. Tel.: +48 42 635 57 61 (G.M.); fax: +48 42 665 5162;
tel.:+48 42 635 5766 (M.J.).
E-mail addresses: gmloston@uni.lodz.pl (G. Mloston´ ), mjasinski@uni.lodz.pl (M.
Jasin´ ski).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.04.005

´
670
G. Mloston et al. / Tetrahedron: Asymmetry 22 (2011) 669–674
1. (CH2O)n
CHO
MeOH
R
CHCl3
(R,R)-1a
+
N
NH2
N
N
2.
OH
N
OH
R
R
N
OH
OH
O
R
O
5 (90%)
7a R = Me (51%)
7b R = Ph (43%)
6a R = Me
6b R = Ph
Scheme 1.
2. Results and discussion
Several methods for the monoprotection of 1a are known; the
most frequently applied are N,N-dialkylation,8 N-acetylation,9 and
N-Boc-protection.10 In addition to these methods, the conversion
to a monoimine with aldehydes or ketones is also described, and
this type of monoprotection with salicylic aldehydes is of special
importance (hemi-salen-type ligands).11
N
N
MeOH, r.t.
O
5 + (CH2O)n
N
OH
+ 8
reflux
HN
Ph
O
Based on literature protocol, the desired monoimine 5 was pre-
pared in high yield and, without purification, it was reacted with
paraformaldehyde (Scheme 1). The crude product obtained was
7c (46%)
Scheme 3.
used for a condensation with
a-hydroxyimino ketones 6 to yield,
after heating for 8 h in ethanol, the desired imidazole 3-oxides 7
as crystalline materials. The enantiomeric purity of these products
was proven by recording the 1H NMR spectra with equimolar
amounts of (S)-(ꢀ)-(tert-butyl)(phenyl)phosphinothioic acid.4a In
both cases, there was only one set of the diagnostic signals for
H-C(2) and HC@N. For example, in the spectrum of 7a, these
signals appeared at 9.70 and 8.13 ppm, respectively, and were
significantly downfield shifted in comparison with the parent
structure (7.82 and 8.00 ppm, respectively).
Recently, we described an efficient method for the preparation
of 3-oxidoimidazole-4-carboxamides using 2-(hydroxyimino)-3-
oxoamides in the reaction with N-methylidene amines.12 For the
purposes of this study, (S)-(ꢀ)-N-(1-phenylethyl)-2-hydroxyimi-
no-3-oxobutyramide 8 was prepared by trapping the in situ gener-
ated acetylketene13 with (S)-(ꢀ)-1-phenylethylamine 1b and
subsequent nitrosation of the b-oxoamide 9 (Scheme 2). In order
to check the utility of 8 in the synthesis of enantiomerically pure
3-oxidoimidazole-4-carboxamides 10, compound 8 was success-
fully employed in the reaction with N-methylidene amines 11
(R = Me, i-Pr, Ad). Even in the case of the bulky N-(adamant-1-
yl)formaldimine 11c, the product 10c was obtained in fair yield.
As evidenced in a series of papers, 2-unsubstituted imidazole
3-oxides can be easily converted into the corresponding imidaz-
ole-2-thiones via a sulfur-transfer reaction by treatment with
2,2,4,4-tetramethyl-3-thioxocyclobutanone 12a or the correspond-
ing dithione 12b.14 The reaction mechanism involves a [2+3] cyclo-
addition reaction as an initiating step. Both thioketones 12a and
12b are easily available and in contrast to other representatives
of this class of sulfur-containing substances, can be stored for a
longer time without decomposition.14a Earlier studies indicated
that they act as efficient dipolarophiles and superior ‘sulfur trans-
ferring agents’ in reactions with 2-unsubstituted imidazole 3-oxi-
des. With these 1,3-dipoles, the reactions of 12a and 12b, used as
dipolarophiles are more efficient than those of other popular thiok-
etones, such as thiobenzophenone or adamantanethione.14b
According to the general ‘sulfur transfer’ protocol, the new imidaz-
ole 3-oxides were treated with 12b in chloroform at room temper-
ature. In the case of 10a,b, the reactions occurred smoothly to
yield, as expected, imidazole-2-thiones 13a,b as the sole products
(Scheme 4). However, in the case of 10c, bearing the bulky ada-
mantyl substituent at N(1), the deoxygenated imidazole 14 was
obtained as the only product.15 A stepwise mechanism of the
[2+3]-cycloaddition reaction leading to deoxygenation of the start-
ing imidazole N-oxide, reacting as a ‘nitrone-like’ 1,3-dipole, was
extensively discussed in a previous paper15 and an elusive oxathii-
rane, derived from 12b, was evidenced as an intermediate. In order
to confirm the structure of the isolated product, imidazole 3-oxide
10c was reacted with freshly prepared Raney-nickel and imidazole
14 was isolated as the sole product in 61% yield.
O
O
O
O
toluene
reflux
14h
NaNO2
AcOH
+
Ph
NH2
Ph
N
H
O
O
1b
9
O
The reaction of dithione 12b with ‘hemi-salen derived’ imidaz-
ole 3-oxides 7a,b led to the expected imidazole-2-thiones 15a,b in
good yields (Scheme 5). The presence of the electron-withdrawing
carboxamide group at C(4) in 7c slightly influenced the reaction
course,15 and along with imidazole-2-thione 15c, the deoxygen-
ated imidazole 16 was formed. Both products were separated by
column chromatograph and obtained in 71% and 8% yield,
respectively.
O
O
[R-N=CH2]
N
Ph
N
Ph
N
H
11a R = Me
11b R = i-Pr
11c R = Ad
H
N
N
OH
R
8 (51%; 2 steps)
10a R = Me (72%)
10b R = i-Pr (82%)
10c R = Ad (48%)
Scheme 2.
In the 1H NMR spectrum of 15c recorded in CDCl3, two sets of
diagnostic signals (in ca. 4:1 ratio) were observed. An analogous
doubled-signal pattern was observed in CD3OD (ca. 3:1 ratio) as
well as in DMSO-d6 (ca. 5:3 ratio). The dynamic nature of 15c
was proven by the registration of a series of 1H NMR spectra in
DMSO-d6 at increased temperatures (the diagnostic part is shown
The successful synthesis of N-oxides 10 prompted us to use 8
for the reaction with 5 in order to prepare the more complex
hemi-salen-like imidazole 3-oxide 7c, which possess three stereo-
genic centers (Scheme 3).

´
671
G. Mloston et al. / Tetrahedron: Asymmetry 22 (2011) 669–674
O
O
O
O
H
N
N
N
N
Ph
N
H
Ph
N
H
R = Ad
Ph
N
H
R = Me, i-Pr
S
X
+
S
N
N
R
Ad
R
13a
13b
10
12a
14
(56%)
R = Me (36%)
, X = O
12b
, X = S
R = i-Pr (56%)
Scheme 4.
R
N
R
N
CHCl3
r.t.
N
N
S
+
S
S
R
N
O
R
N
OH
OH
H
7a R = Me
7b R = Ph
12b
15a R = Me (79%)
15b R = Ph (63%)
N
N
N
N
N
N
N
12b, CHCl3
+
O
O
r.t.
O
S
N
OH
OH
N
H
OH
HN
Ph
O
HN
Ph
HN
Ph
15c (71%)
Scheme 5.
16 (8%)
7c
(Scheme 6). The IR spectrum of 15c supports this assumption; in
contrast to the corresponding imidazole N-oxide 7c
(
(
mC@O
mC@O
1660 cmꢀ1
)
and the deoxygenated derivative 16
1653 cmꢀ1), in the case of 15c a significant shift of the amide
C@O to 1629 cmꢀ1 was observed.
In addition, the synthesis of imidazole derivatives of 1, analo-
gous to 7, was attempted, starting with mono-Boc and mono-acetyl
protected trans-1,2-diaminocyclohexane 1a and
a-(hydroxyimi-
no)ketone 6a. In both cases, none of the expected imidazole N-oxi-
des was obtained.
3. Conclusions
The results presented herein show that the mono-imine 5, de-
rived from trans-1,2-diaminocyclohexane and salicylaldehyde, is
a suitable substrate for the preparation of non-symmetrical,
enantiomerically pure imidazole N-oxides 7. On the other hand,
optically active imidazole N-oxides with a carboxamide function
at C(4) can be prepared using 2-hydroxyimino-3-oxobutyramide
8, easily accessible from (S)-(ꢀ)-1-phenylethylamine 1b and
in situ generated acetylketene. Examples of both classes of
N-oxides can be converted into the corresponding imidazole-2-
thiones 13 and 15. However, in the cases of 10c and 7c, bearing
an electron-withdrawing carboxamido group at C(4) and a bulky
substituent at N(1), the deoxygenation of the imidazole N-oxide
was observed. The enantiomerically pure imidazole derivatives
described are potentially attractive ligands for asymmetric
syntheses.
Figure 2. The diagnostic part of 1H NMR spectra (DMSO-d6, 600 MHz) of 15c at
variable temperatures.
N
N
N
N
Ph
H
S
S
N
N
N
N
OH
OH
Ph
H
H
H
O
O
s-(Z)-15c
s-(E)-15c
4. Experimental
4.1. General
Scheme 6.
in Figure 2). A likely explanation of the observed phenomena is the
formation of two rotamers [s-(Z)-15c and s-(E)-15c] stabilized by
strong intramolecular hydrogen bonding of the amide function
Melting points were determined in a capillary using a MEL-
TEMP II apparatus (Aldrich) and are uncorrected. IR Spectra were

´
G. Mloston et al. / Tetrahedron: Asymmetry 22 (2011) 669–674
672
recorded with a NEXUS FT-IR instrument as KBr pellets or as films;
absorptions (
) are given in cmꢀ1 1H NMR and 13C NMR Spectra
765 m, 712 m. 1H NMR (CDCl3): 12.33 (s, 1H, OH); 8.22 (s, 1H,
HC(2)); 8.21 (s, 1H, –N@CH–); 7.45–7.36 (m, 5 arom. H); 7.31–
7.28 (m, 1 arom. H); 7.23 (dd, J = 7.2, J = 1.2, 1 arom. H); 7.19–
7.16 (m, 3 arom. H); 7.11–7.09 (m, 2 arom. H); 6.93–6.89 (m, 1
arom. H); 6.86 (dt, J = 7.5, J = 1.2, 1 arom. H); 4.03–3.98 (m, 1H,
cHex); 3.40–3.36 (m, 1H, cHex); 2.20–2.16 (m, 1H, cHex); 1.96–
1.74 (m, 4H, cHex); 1.63–1.56 (m, 1H, cHex); 1.49–1.41 (m, 1H,
cHex); 1.37–1.30 (m, 1H, cHex). 13C NMR (CDCl3): 165.7 (s,
–N@CH–); 160.5 (s, (Ph)C–OH); 132.8, 132.0, 130.9 (2C), 129.6,
129.5 (2C), 129.1 (2C), 128.0, 127.9 (2C), 119.0, 116.7 (10d,
14CH(Ph)); 128.1, 127.1, 126.5, 125.6, 118.3 (5s, 3C(Ph), C(4),
C(5)); 123.2 (d, C(2)); 72.9, 59.9 (2d, CH(cHex)); 34.0, 33.3, 24.9,
23.6 (4t, 4CH2(cHex)). ESI-HRMS: 438.2174 (calcd 438.2176 for
m
.
were recorded on a BRUKER AVANCE III (1H at 600 and 13C at
150 MHz) instrument in CDCl3, CD3OD or DMSO-d6 solutions;
chemical shifts (d) in ppm; coupling constants (J) in Hz. The
multiplicity of the 13C signals was deduced from DEPT, supported
by 1H–13C HMQC spectra. Optical rotations were determined on a
PERKIN-ELMER 241 MC polarimeter. ESI mass spectra were mea-
sured on a Finnigan MAT-95 instrument.
4.2. Starting materials
Applied reagents such as racemic trans-1,2-diaminocyclohexane
C28H28N3O2, [M+1]+). ½a D25
¼ ꢀ81:0 (c 1.05, CHCl3).
ꢁ
(technical grade),
L
-(+)-tartaric acid, salicylaldehyde, (S)-(ꢀ)-
1-phenylethylamine, acetylacetone, 2,2,6-trimethyl-4H-1,3-diox-
in-4-one, other ketones, alkyl amines, paraformaldehyde, and
solvents are commercially available and were used as received.
Enantiomerically pure (R,R)-trans-1,2-diaminocyclohexane was
prepared by the resolution of racemic DACH using natural tartaric
acid.3 Formaldimines derived from methylamine, isopropylamine,
and 1-adamantaneamine were prepared according to literature
4.3.3. Imidazole 3-oxide 7c
Yield after column chromatography (SiO2, AcOEt then AcOEt/
MeOH 6:1, Rf = 0.54): 2.05 g (46%). Yellow solid. Mp 99–102 °C. IR
(KBr): 3427s (br), 2935s (br), 2862 m, 1660s, 1629s, 1598s, 1546s
(br), 1495 m, 1449 m, 1416 m, 1279s, 758 m, 700 m. 1H NMR
(CDCl3): 12.45 (s, 1H, OH); 11.00 (d, J = 7.8, 1H, NH); 8.09 (s, 1H,
–N@CH–); 7.97 (s, 1H, HC(2)); 7.34–7.30 (m, 2 arom. H); 7.27–
7.25 (m, 3 arom. H); 7.19–7.17 (m, 1 arom. H); 7.10 (dd, J = 7.8,
J = 1.8, 1 arom. H); 6.89–6.85 (m, 1 arom. H); 6.80 (dt, J = 7.5,
J = 1.2, 1 arom. H); 5.20 (quint, J = 7.1, 1H); 4.22–4.18 (m, 1H,
cHex); 3.29 (dt, J = 10.5, J = 4.3, 1H, cHex); 2.58 (s, 3H, Me); 2.12–
1.91 (m, 4H, cHex); 1.80–1.72 (m, 3H, cHex); 1.56–1.46 (m, 1H,
cHex); 1.52 (d, J = 7.1, 3H, Me). 13C NMR (CDCl3): 166.0 (s,
–N@CH–); 160.6 (s, (Ph)C–OH); 158.6 (s, CONH); 143.7, 131.3,
121.4, 118.0 (4s, 2C(Ph), C(4), C(5)); 133.1, 131.9, 128.5 (2C),
126.9, 126.0 (2C), 119.0, 117.1 (7d, 9CH(Ph)); 122.5 (d, C(2));
72.9, 59.4, 48.1 (3d, 3CH); 34.4, 32.6, 25.0, 23.7 (4t, 4CH2(cHex));
22.9, 9.7 (2q, 2Me). ESI-HRMS: 447.2387 (calcd 447.2391 for
protocols.16
a-(Hydroxyimino)ketones were obtained according to
known procedures: butane-2,3-dione monooxime by nitrosation
of butanone using isoamyl nitrite;17a 1,2-diphenylethane-1,2-dione
monooxime (benzil monooxime) from dibenzoyl and hydroxyl-
amine.17b Monoimine 511a was obtained in 90% yield (95% purity)
and used in the next step without further purification.
4.3. Synthesis of imidazole 3-oxides 7a–c
To the magnetically stirred solution of monoimine
5
(10.0 mmol, 2.2 g) in dry ethanol (30 mL), containing freshly acti-
vated molecular sieves 4 Å, paraformaldehyde (11.0 mmol,
0.33 g) was added in one portion at 0 °C. The resulting mixture
was allowed to reach rt and stirred overnight. Next, the respective
C
26H31N4O3, [M+1]+). ½a D25
¼ ꢀ195:0 (c 1.00, CHCl3).
ꢁ
a
-(hydroxyimino)ketone (11.0 mmol; 1.11 g of 6a, 2.48 g of 6b, or
4.4. Synthesis of (S)-(ꢀ)-N-(1-phenylethyl)-2-hydroxyimino-3-
2.57 g of 8) was added and the mixture refluxed for 8 h. After the
solution was cooled and filtered, the solvent was removed in va-
cuo, the oily residue was purified by column chromatography to
give the product of type 7 as a yellow solid.
oxobutyramide 8
A
mixture of (S)-(ꢀ)-1-phenylethylamine 1b (6.61 g,
54.6 mmol) and 2,2,6-trimethyl-4H-1,3-dioxin-4-one (9.09 g,
64.1 mmol) in dry toluene (150 mL) was refluxed for 16 h. After
the solvent was removed under reduced pressure, the residue
was flash chromatographed (SiO2, AcOEt/CHCl3 1:2, Rf = 0.37) to
give crude b-oxoamide 9 (10.82 g, 96%) as a pale orange oil, which
was used in the next step without purification. The amide 9
(10.82 g, 52.8 mmol) was dissolved in glacial AcOH (25.0 mL), the
resulting mixture was magnetically stirred while cooling (water/
ice bath), and a solution of sodium nitrite (4.9 g, 71.0 mmol) in
H2O (7.0 mL) was added dropwise. After ca. 2.5 h, the mixture
was diluted with H2O (90 mL) and extracted with three portions
of CH2Cl2 (70 mL each). The combined organic phases were washed
with a saturated aqueous solution of NaHCO3, then with water,
dried over MgSO4, and the solvent removed. The crude product
was flash chromatographed (SiO2, CH2Cl2) and purified by column
chromatography (SiO2, petroleum ether/Et2O 9:1, Rf = 0.25) to give
8 (6.52 g) as a pale yellow oil in 51% overall yield. IR: 3281vs (br),
2980s, 1686vs, 1648vs, 1551vs, 1496 m, 1451 m, 1416 m, 1363 m,
1107 m, 1019 m, 700 m. 1H NMR (CDCl3): 9.39 (br s, 1H, NH); 7.38–
7.35 (m, 2 arom. H); 7.32–7.28 (m, 3 arom. H); 5.15 (quint, J = 7.2,
1H); 2.50 (s, 3H, Me); 1.57 (d, J = 7.2, Me). 13C NMR (CDCl3): 199.6
(s, C@O); 162.6 (s, CONH); 143.4 (s, C@N); 141.6 (s, C(Ph)); 128.9,
127.8, 126.0 (3d, 5CH(Ph)); 48.7 (d, CH); 26.2, 21.9 (2q, 2 Me). ESI-
HRMS: 257.0894 (calcd 257.0896 for C12H14N2NaO3, [M+Na]+).
4.3.1. Imidazole 3-oxide 7a
Yield after column chromatography (SiO2, AcOEt then AcOEt/
MeOH 1:1, Rf = 0.36): 1.60 g (51%). Yellow solid. Mp 139–141 °C.
IR (KBr): 3420vs (br), 2935s, 2860 m, 1629vs, 1579 m, 1497 m,
1452 m, 1413 m, 1339 m, 1275 m, 1208 m, 1197 m, 759 m. 1H
NMR (CDCl3): 12.70 (s, 1H, OH); 8.00 (s, 1H, –N@CH–); 7.82 (s,
1H, HC(2)); 7.32–7.29 (m, 1 arom. H); 7.14 (dd, J = 7.8, J = 1.8, 1
arom. H); 6.90 (dd, J = 8.4, J = 1.2, 1 arom. H); 6.86 (dt, J = 7.8,
J = 1.2, 1 arom. H); 4.03–3.99 (m, 1H, cHex); 3.23–3.19 (m, 1H,
cHex); 2.19–2.12 (m, 2H, cHex); 2.07, 2.03 (2s, 6H, 2Me); 2.01–
1.47 (m, 6H, cHex). 13C NMR (CDCl3): 165.7 (s, –N@CH–); 160.5
(s, (Ph)C–OH); 132.8, 132.0, 119.0, 116.7 (4d, 4CH(Ph)); 125.8,
121.8, 118.2 (3s, C(Ph), C(4), C(5)); 121.4 (d, C(2)); 73.9, 59.3 (2d,
CH(cHex)); 34.1, 32.4, 25.1, 23.8 (4t, 4CH2(cHex)); 8.9, 7.0 (2q,
2Me). ESI-HRMS: 314.1862 (calcd 314.1863 for
C
18H24N3O2,
[M+1]+). ½a 2D5
ꢁ
¼ ꢀ387:3 (c 1.10, CHCl3), ½a D25
ꢁ
¼ ꢀ386:9 (c 0.50,
CHCl3), ½a 2D5
¼ ꢀ388:0 (c 0.25, CHCl3).
ꢁ
4.3.2. Imidazole 3-oxide 7b
Yield after column chromatography (SiO2, AcOEt then AcOEt/
MeOH 1:1, Rf = 0.74): 1.88 mg (43%). Yellow solid. Mp 117–
120 °C. IR (KBr): 3420vs (br), 3060 m, 2934s, 2858 m, 1671 m,
1628vs, 1578 m, 1497 m, 1446 m, 1406 m, 1340 m, 1279 m,
½
a 2D2
ꢁ
¼ ꢀ98:3 (c 1.05, MeOH).

´
673
G. Mloston et al. / Tetrahedron: Asymmetry 22 (2011) 669–674
4.5. Synthesis of imidazole 3-oxides 10a and 10b
4.7. Reactions of imidazole 3-oxides of type 7 and 10 with
2,2,4,4-tetramethylcyclobutane-1,3-dithione 12b
A solution of (S)-N-(1-phenylethyl)-2-hydroxyimino-3-oxobu-
tyramide 8 (2.34 g, 10.0 mmol) and the respective formaldimine
11 (12.0 mmol) in ethanol (30 mL) was refluxed for 5 h. After the
solvent was removed, the residue was washed with Et2O (three
portions of ca. 20 mL) and purified by recrystallization of 10a or
chromatography of 10b.
To the magnetically stirred solution of an imidazole N-oxide
7a–c or 10a–c (1.0 mmol) in CHCl3 (5 mL), excess 2,2,4,4-tetram-
ethylcyclobutane-1,3-dithione 12b (1.8 mmol, 309 mg) in CHCl3
(3 mL) was added dropwise at 0 °C, and stirring was continued
overnight at rt. Then, the solvent was removed under reduced
pressure, the resulting material was purified and identified as the
corresponding imidazole-2-thione (13 or 15) and/or as an imidaz-
ole (14 and 16).
4.5.1. (S)-N-(Phenylethyl)-1,5-dimethyl-3-oxido-1H-imidazole-
4-carboxamide 10a
Yield: 1.86 g (72%). Colorless solid. Mp 170–171 °C (CHCl3/
Et2O). IR (KBr): 3442vs, 3152 m, 1655vs, 1604s, 1558 m, 1448 m,
1290 m, 766 m, 704 m. 1H NMR (CDCl3): 11.15 (br d, J = 6.6, 1H,
CONH); 7.74 (s, 1H, HC(2)); 7.40–7.39 (m, 2 arom. H); 7.33–7.30
(m, 2 arom. H); 7.22–7.20 (m, 1 arom. H); 5.27 (quint, J = 7.2,
1H); 3.55 (s, 3H, MeN); 2.59 (s, 3H, Me); 1.57 (d, J = 7.2, 3H, Me).
13C NMR (CDCl3): 158.6 (s, C@O); 143.8, 130.6, 125.2 (3s, C(Ph),
C(4), C(5)); 128.3, 126.7, 125.8, 121.9 (4d, 5CH(Ph), C(2)); 48.0 (d,
CH); 31.7, 22.8, 9.2 (3q, 3 Me). ESI-HRMS: 282.1212 (calcd
282.1213 for C14H17N3NaO2, [M+Na]+), 260.1392 (calcd 260.1393
4.7.1. (S)-N-(1-Phenylethyl)-1,3-dihydro-1,5-dimethyl-2-
thioxoimidazole-4-carboxamide 13a
Yield: 98 mg (36%). Colorless crystals. Mp 221–223 °C (EtOH). IR
(KBr): 3312vs, 3166vs (br), 1661s, 1626 m, 1537 m, 1487 m,
1475 m, 1450 m, 1425 m, 1395 m, 1368 m, 763 m, 702 m. 1H
NMR (CDCl3): 12.83 (br s, 1H, NH); 7.48 (br d, J = 7.8, 1H, NH);
7.30–7.28 (m, 2 arom. H); 7.23–7.20 (m, 2 arom. H); 7.16–7.13
(m, 1 arom. H); 5.16 (quint, J = 7.2, 1H); 3.41 (s, 3H, NMe); 2.42
(s, 3H, Me); 1.51 (d, J = 6.6, 3H, Me). 13C NMR (CDCl3): 158.9,
157.5 (2s, C@O, C@S); 143.2, 134.1, 118.7 (3s, C(Ph), C(4), C(5));
128.5, 127.2, 126.4 (3d, 5CH(Ph)); 49.3 (d, CH); 31.0, 22.1, 10.2
for C14H18N3O2, [M+1]+). ½a D25
¼ ꢀ12:5 (c 1.03, CHCl3).
ꢁ
4.5.2. (S)-N-(Phenylethyl)-1-isopropyl-5-methyl-3-oxido-1H-
imidazole-4-carboxamide 10b
(3q,
C
3
Me). ESI-HRMS: 298.0986 (calcd 298.0984 for
14H28N3NaOS, [M+Na]+). ½a D25
¼ þ326:3 (c 0.80, CHCl3).
ꢁ
Yield after column chromatography (SiO2, AcOEt/MeOH 1:1,
Rf = 0.51): 2.36 g (82%). Colorless solid. Mp 124–126 °C. IR (KBr):
3432s, 3100–2850s (br), 1659vs, 1603s, 1551s, 1495 m, 1452 m,
1284s, 705 m, 700 m. 1H NMR (CDCl3): 11.23 (br s, 1H, CONH);
7.87 (s, 1H, HC(2)); 7.41–7.40 (m, 2 arom. H); 7.32–7.30 (m, 2
arom. H); 7.23–7.20 (m, 1 arom. H); 5.27 (quint, J = 7.2, 1H);
4.40–4.33 (m, 1H, iPr); 2.63 (s, 3H, Me); 1.57 (d, J = 7.2, 3H, Me);
1.45 (dd, J = 10.8, J = 6.6, 6H, iPr). 13C NMR (CDCl3): 158.9 (s,
C@O); 143.9, 129.6, 121.8 (3s, C(Ph), C(4), C(5)); 128.4, 126.8,
126.0, 122.3 (4d, 5CH(Ph), C(2)); 48.1, 47.8 (2d, 2CH); 22.9, 22.7,
4.7.2. (S)-N-(1-Phenylethyl)-1,3-dihydro-1-isopropyl-5-methyl-
2-thioxoimidazole-4-carboxamide 13b
Yield after column chromatography (SiO2, AcOEt/CHCl3 1:2,
Rf = 0.65): 173 mg (56%). Colorless solid. Mp 107–110 °C. IR (KBr):
3304s (br), 3061 m, 2973 m, 2933 m, 1656 m, 1626s, 1540 m,
1494s, 1451 m, 1416 m, 1370 m, 1282 m, 1197 m, 763 m, 700 m.
1H NMR (CDCl3): 13.11 (br s, 1H, NH); 7.62 (br d, J = 7.2, 1H,
NH); 7.38–7.37 (m, 2 arom. H); 7.30–7.28 (m, 2 arom. H); 7.23–
7.20 (m, 1 arom. H); 5.30 (br s, 1H, iPr); 5.23 (quint, J = 7.2, 1H);
2.64 (s, 3H, Me); 1.57 (d, J = 7.2, 3H, Me); 1.52–1.49 (m, 6H, iPr).
13C NMR (CDCl3): 158.0 157.7 (2s, C@O, C@S); 143.4, 134.0, 119.3
(3s, C(Ph), C(4), C(5)); 128.5, 127.2, 126.3 (3d, 5CH(Ph)); 49.5,
49.2 (2d, 2CH); 22.1, 20.4, 11.1 (3q, 4 Me). ESI-HRMS: 326.1299
9.3 (3q,
4 Me). ESI-HRMS: 310.1527 (calcd 310.1526 for
C
C
16H21N3NaO2, [M+Na]+), 288.1706 (calcd 288.1706 for
16H22N3O2, [M+1]+). ½a D25
¼ ꢀ12:3 (c 10.0, CHCl3).
ꢁ
4.6. Synthesis of (S)-N-(phenylethyl)-1-adamantyl-5-methyl-3-
oxido-1H-imidazole-4-carboxamide 10c
(calcd 326.1297 for C16H21N3NaOS, [M+Na]+). ½a D25
¼ þ149:0 (c
ꢁ
1.00, CHCl3).
A
solution of 1-adamantaneformaldimine 11c (1.96 g,
4.7.3. (S)-N-(Phenylethyl)-1-adamantyl-5-methyl-1H-imidazole-4-
carboxamide 14
12.0 mmol) and -(hydroxyimino)ketone 8 (2.34 g, 10.0 mmol) in
a
glacial AcOH (30 mL) was stirred for two days at rt. Then, a stream
of dry HCl gas was bubbled through the mixture for 1.5 h, and the
solvents were removed under reduced pressure. The resulting yel-
low oil was triturated with Et2O, decanted, dried under vacuum,
and dissolved in a 4:1 mixture of CHCl3 and methanol. After excess
solid NaHCO3 was added, vigorous stirring was continued for 2 h.
Then, the mixture was filtered, the solvents were removed, and
the resulting solid was recrystallized from CH2Cl2/Et2O to give
1.81 g (48%) of 10c as colorless crystals. Mp 257–260 °C. IR (KBr):
3432vs (br), 3135 m, 1916vs, 1663vs, 1589vs, 1551s, 1495 m,
1452 m, 1409 m, 1388 m, 1374 m, 1278s, 1212 m, 1152 m,
1103 m, 763 m, 747 m, 698 m. 1H NMR (CDCl3): 11.24 (br s, 1H,
CONH); 7.93 (s, 1H, HC(2)); 7.41–7.39 (m, 2 arom. H); 7.32–7.30
(m, 2 arom. H); 7.23–7.20 (m, 1 arom. H); 5.25 (quint, J = 7.2,
1H); 2.88 (s, 3H, Me); 2.28 (br s, 3H, CH, Ad); 2.19 (d, J = 2.4, 6H,
CH2, Ad); 1.80–1.73 (m, 6H, CH2, Ad); 1.56 (d, J = 7.2, 3H, Me).
13C NMR (CDCl3): 159.2 (s, C@O); 144.1, 130.8, 123.4 (3s, C(Ph),
C(4), C(5)); 128.5, 126.8, 126.1, 1228 (4d, 5CH(Ph), C(2)); 60.6 (s,
N–C(Ad)); 48.3 (d, CH); 41.9, 29.6 (2t, 6CH2, Ad); 35.5 (d, 3CH,
Ad); 23.0, 13.2 (2q, 2Me). ESI-HRMS: 402.2152 (calcd 402.2152
Yield after column chromatography (SiO2, AcOEt/CHCl3 1:2,
Rf = 0.70): 203 mg (56%). Colorless solid. Mp 132–134 °C. IR (KBr):
3407 m, 2910s, 2856 m, 1660vs, 1578s, 1494vs, 1452 m, 1235 m,
697 m. 1H NMR (CDCl3): 7.59 (br s, 1H, NH); 7.51 (s, 1H, HC(2));
7.40–7.38 (m, 2 arom. H); 7.33–7.29 (m, 2 arom. H); 7.23–7.20
(m, 1 arom. H); 5.25 (quint, J = 7.2, 1H); 2.86 (s, 3H, Me); 2.25 (br
s, 3H, 3CH, Ad); 2.21 (d, J = 2.4, 6H, 3CH2, Ad); 1.80–1.74 (m, 6H,
3CH2, Ad); 1.56 (d, J = 7.2, 3H, Me). 13C NMR (DMSO-d6): 162.9 (s,
C@O); 145.1, 132.2, 131.5 (3s, C(Ph), C(4), C(5)); 133.6 (d, C(2));
128.4 (2C), 126.7, 126.2 (2C) (3d, 5CH(Ph)); 57.9 (s, N–C(Ad));
47.4 (d, CH); 41.5, 29.2 (2t, 6CH2, Ad); 35.4 (d, 3CH, Ad); 22.4,
12.8 (2q, 2Me). ESI-HRMS: 386.2200 (calcd 386.2203 for
C
23H29N3NaO, [M+Na]+), 364.2384 (calcd 364.2383 for C23H30N3O,
[M+1]+). ½a 2D5
¼ ꢀ33:0 (c 1.00, CHCl3).
ꢁ
4.7.4. Imidazole-2-thione 15a
Yield after column chromatography (SiO2, AcOEt/CHCl3 1:1,
Rf = 0.74): 259 mg (79%). Yellow solid. Mp 89–92 °C. IR (KBr):
3423s (br), 3166 m, 3069s, 2929vs, 2857s, 1629vs, 1497 m,
1450 m, 1388 m, 1370 m, 1353 m, 1278 m, 756 m. 1H NMR
(CDCl3): 13.30 (s, 1H, OH); 10.30 (br s, 1H, NH); 8.34 (s, 1H, –
N@CH–); 7.18–7.15 (m, 1 arom. H); 7.12 (d, J = 7.2, 1 arom. H);
for
C
23H29N3NaO2, [M+Na]+), 380.2331 (calcd 380.2332 for
C
23H30N3O2, [M+1]+). ½a D25
¼ ꢀ6:4 (c 5.00, CHCl3).
ꢁ

´
G. Mloston et al. / Tetrahedron: Asymmetry 22 (2011) 669–674
674
6.81 (d, J = 8.4, 1 arom. H); 6.75 (t, J = 7.2, 1 arom. H); 5.19–5.16 (m,
1H, cHex); 3.86–3.81 (m, 1H, cHex); 3.31–3.24 (m, 1H, cHex); 1.91,
1.85 (2s, 6H, 2Me); 1.76–1.51 (m, 6H, cHex); 1.36–1.28 (m, 1H,
cHex). 13C NMR (CDCl3): 165.7 (s, –N@CH–); 161.1 (s, (Ph)C–OH);
157.2 (s, C@S); 132.1, 131.7, 118.5, 116.7 (4d, 4CH(Ph)); 122.8,
119.4, 118.8 (3s, C(Ph), C(4), C(5)); 64.9, 61.6 (2d, 2CH(cHex));
34.5, 27.2, 25.6, 23.7 (4t, 4CH2(cHex)); 9.2, 9.0 (2q, 2Me). ESI-
131.5, 128.4 (2C), 126.9, 126.1 (2C), 118.7, 117.0 (7d, 9CH(Ph));
132.1 (d, C(2)); 73.4, 58.7, 47.9 (3d, 3CH); 34.2, 32.8, 25.2, 23.9
(4t, 4CH2(cHex)); 22.2, 9.6 (2q, 2Me). ESI-HRMS: 453.2260 (calcd
453.2261 for C26H30N4NaO2, [M+Na]+), 431.2439 (calcd 431.2442
for C26H31N4O2, [M+1]+). ½a D25
¼ ꢀ174:8 (c 0.48, CHCl3).
ꢁ
4.8. Deoxygenation of 10c with Raney-nickel
HRMS: 330.1632 (calcd 330.1635 for
¼ ꢀ294:0 (c 1.00, CHCl3).
C
18H24N3OS, [M+1]+).
½
a 2D5
ꢁ
To the solution of 10c (101 mg, 0.26 mmol) in methanol
(8.0 mL) a suspension of freshly prepared Raney-Ni in methanol
was added in small portions at rt, until the starting material was
fully consumed (TLC monitoring). The crude mixture was filtered
through a CeliteÒ pad, washed with MeOH, and the solvent was re-
moved from the filtrate. The resulting residue was purified on pre-
parative TLC plates (SiO2) using CHCl3/AcOEt mixture (2:1) to give
58 mg (61%) of 14 as a colorless solid.
4.7.5. Imidazole-2-thione 15b
Yield after column chromatography (SiO2, AcOEt/CHCl3 1:8,
Rf = 0.54): 285 mg (63%). Yellow solid. Mp 278–281 °C. IR (KBr):
3427vs (br), 3058vs (br), 2936vs, 2853 m, 1627s, 1579 m, 1495s,
1446 m, 1384 m, 1355 m, 1274 m, 1261 m, 1237 m, 754 m,
695 m. 1H NMR (CDCl3): 13.08 (s, 1H, OH); 9.86 (br s, 1H, NH);
8.56 (s, 1H, –N@CH–); 7.53–7.50 (m, 3 arom. H); 7.27–7.24 (m, 3
arom. H); 7.20 (d, J = 7.8, 1 arom. H); 7.16–7.15 (m, 3 arom. H);
7.03–6.99 (m, 2 arom. H); 6.91 (d, J = 8.4, 1 arom. H); 6.18 (t,
J = 7.5, 1 arom. H); 5.47–5.43 (m, 1H, cHex); 3.79–3.75 (m, 1H,
cHex); 3.23–3.17 (m, 1H, cHex); 1.87–1.63 (m, 4H, cHex); 1.54–
1.38 (m, 2H, cHex); 1.28–1.25 (m, 1H, cHex). 13C NMR (CDCl3):
166.0 (s, –N@CH–); 161.0 (s, (Ph)C–OH); 159.7 (s, C@S); 137.0,
133.7, 124.6, 119.8, 118.8 (5s, 3C(Ph), C(4), C(5)); 132.2, 131.8,
129.8, 129.4, 129.3, 128.7 (2C), 128.1, 128.0, 127.7, 125.9 (2C),
118.6, 116.8 (12d, 14CH(Ph)); 64.8, 62.1 (2d, CH(cHex)); 34.4,
27.7, 25.3, 23.7 (4t, 4CH2(cHex)). ESI-HRMS: 454.1949 (calcd
Acknowledgments
The authors thank PD Dr. L. Bigler, University of Zürich, for ESI-
HRMS. Financial support by the Rector of the University of Lodz
(Grant # 505/712/R) is gratefully acknowledged.
References
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454.1948 for C28H28N3OS, [M+1]+). ½a D25
¼ ꢀ69:0 (c 1.00, CHCl3).
ꢁ
4.7.6. Imidazole-2-thione 15c
Yield after column chromatography (SiO2, AcOEt/CHCl3 1:1, iso-
lated as a less polar fraction, Rf = 0.79): 328 mg (71%). Pale yellow
solid. Mp 138–140 °C. IR (KBr): 3432vs (br), 2931s, 1629vs (br),
1533 m, 1494s, 1452 m, 1384 m, 1348 m, 1278s, 1135 m, 759 m,
699 m. 1H NMR for major isomer (CDCl3): 13.03, 12.77 (2br s, 2H,
OH, NH); 8.27 (s, 1H, –N@CH–); 7.34–7.20 (m, 6 arom. H); 7.12
(d, J = 7.8, 1 arom. H); 6.85 (d, J = 8.4, 1 arom. H); 6.81–6.79 (m, 1
arom. H); 5.20 (quint, J = 7.2, 1H); 5.14–5.10 (m, 1H, cHex); 4.14–
4.09 (m, 1H, cHex); 3.26–3.19 (m, 1H, cHex); 2.51 (s, 3H, Me);
1.98–1.41 (m, 7H, cHex); 1.54 (d, J = 7.2, 3H, Me). 13C NMR for ma-
jor isomer (CDCl3): 165.9 (s, –N@CH–); 161.0 (s, (Ph)C–OH); 157.5,
157.4 (2s, CONH, C@S); 143.0, 134.7, 118.9, 118.6 (4s, 2C(Ph), C(4),
C(5)); 132.4, 131.7, 128.6 (2C), 127.2, 126.3 (2C), 118.4, 117.0 (7d,
9CH(Ph)); 65.1, 61.6, 49.1 (3d, 3CH); 34.6, 27.3, 25.3, 23.7 (4t,
4CH2(cHex)); 21.9, 9.9 (2q, 2Me). ESI-HRMS: 485.1985 (calcd
4. (a) Mucha, P.; Mloston´ , G.; Jasin´ ski, M.; Linden, A.; Heimgartner, H. Tetrahedron:
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6. Mucha, P. PhD thesis, University of Łódz, 2010.
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485.1982 for
C
26H30N4NaO2S, [M+Na]+), 463.2166 (calcd
463.2162 for C26H31N4O2S, [M+1]+). ½a D25
¼ ꢀ305:0 (c 1.00, CHCl3).
ꢁ
´
14. (a) Heimgartner, H.; Mloston, G. 2,2,4,4-Tetramethylcyclobutan-1-one-3-
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4.7.7. Imidazole 16
Yield after column chromatography (SiO2, AcOEt/CHCl3 1:1, iso-
lated as more polar fraction, Rf = 0.44): 34 mg (8%). Yellow semi-so-
lid. IR (KBr): 3400 m (br), 2932s (br), 2860 m, 1653s, 1630s, 1582s,
1494s, 1449 m, 1278 m, 1229 m, 758 m, 700 m. 1H NMR (CDCl3):
12.65 (s, 1H, OH); 7.91 (s, 1H, –N@CH–); 7.40 (s, 1H, HC(2));
7.33–7.28 (m, 2 arom. H); 7.26–7.24 (m, 3 arom. H); 7.21–7.18
(m, 1 arom. H); 7.01 (dd, J = 7.6, J = 1.6, 1 arom. H); 6.87 (d,
J = 8.1, 1 arom. H); 6.76 (dt, J = 7.4, J = 1.1, 1 arom. H); 5.19 (quint,
J = 7.1, 1H); 4.06–4.01 (m, 1H, cHex); 3.36 (dt, J = 10.5, J = 4.4, 1H,
cHex); 2.51 (s, 3H, Me); 2.14–2.11 (m, 1H, cHex); 2.02–1.75 (m,
6H, cHex); 1.54–1.49 (m, 1H, cHex); 1.51 (d, J = 7.1, 3H, Me). 13C
NMR (CDCl3): 165.1 (s, –N@CH–); 162.8 (s, (Ph)C–OH); 160.6 (s,
CONH); 143.8, 132.6, 130.7, 118.1 (4s, 2C(Ph), C(4), C(5)); 132.7,
´
´
Acta 2008, 91, 232–238; (e) Jasinski, M.; Mloston, G.; Linden, A.; Heimgartner,
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765–776.
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