A new approach to enantiomerically pure bis-imidazoles derived from trans-1,2-diaminocyclohexane

Article abstract of DOI:10.1016/j.tetasy.2008.06.015

Racemic as well as enantiomerically pure trans-1,1′-(cyclohexane-1,2-diyl)bis(imidazole N-oxides) were prepared from trans-cyclohexane-1,2-bis(methylidenamine) and 1,2-dione monooximes (α-hydroxyiminoketones). The enantiomeric purity of selected products was determined by means of ¹H NMR spectroscopy in the presence of (+)-(R)-(tert-butyl)(phenyl)phosphonothioic acid as a chiral solvating agent. Deoxygenation by treatment with Raney-nickel led to the corresponding chiral bis-imidazoles.

Full text of DOI:10.1016/j.tetasy.2008.06.015

Tetrahedron: Asymmetry 19 (2008) 1600–1607
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A new approach to enantiomerically pure bis-imidazoles derived from
trans-1,2-diaminocyclohexane
a,
Paulina Mucha a, , Grzegorz Mloston , Marcin Jasinski a,à, Anthony Linden b, Heinz Heimgartner b,
*
*
´
´
a
´
´
Department of Organic and Applied Chemistry, University of Łódz, Narutowicza 68, PL-90-136 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
Racemic as well as enantiomerically pure trans-1,10-(cyclohexane-1,2-diyl)bis(imidazole N-oxides) were
Article history:
Received 3 May 2008
Accepted 13 June 2008
Available online 14 July 2008
prepared from trans-cyclohexane-1,2-bis(methylidenamine) and 1,2-dione monooximes (a-hydroxy-
iminoketones). The enantiomeric purity of selected products was determined by means of 1H NMR
spectroscopy in the presence of (+)-(R)-(tert-butyl)(phenyl)phosphonothioic acid as a chiral solvating
agent. Deoxygenation by treatment with Raney-nickel led to the corresponding chiral bis-imidazoles.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
ment of the corresponding diimine with tosylmethylisocyanide
(TosMIC).11
It has been well documented that 2-unsubstituted imidazole
N-oxides can be prepared from readily available -hydroxyimino
a
O
N
O
N
N
N
N
N
ketones and N-alkyl methanimines (formaldehyde imines).3–5
Their structure shows a certain similarity with nitrones and,
therefore, diverse transformations leading to imidazol-2-ones,6
imidazole-2-thiones,7,8 imidazole-2-carbonitriles,6 and other
imidazole derivatives9 are accessible. Deoxygenation of imidazole
N-oxides with Raney-Ni yields the corresponding imidazoles,5
which can be prepared alternatively by using a 1,2-dicarbonyl
compound, a primary amine, ammonia and formaldehyde.10
In recent years, there has been a growing interest in the synthe-
sis and applications of bis-imidazole derivatives. Especially
attractive are their metal complexes as catalysts in organic synthe-
sis.11,12 Most of the reported compounds are achiral, and the lim-
ited availability of optically active bis-imidazoles results from the
fact that no general methods are known for their preparation. To
the best of our knowledge, there are only two published papers
aimed at the preparation of optically active bis-imidazoles. In
one case, the co-condensation of (R,R)- and (S,S)-1,2-diphenyleth-
ane-1,2-diamine with glyoxal, formaldehyde and ammonia gave
(R,R)- and (S,S)-bis-imidazoles 1, albeit the yields were rather poor
in both cases (ca. 20%). The authors claimed that the products were
enantiomerically pure, but no physical data were reported.13 The
second type of optically active bis-imidazoles 2, which contains
the trans-1,2-diaminocyclohexane scaffold, was prepared by treat-
R2
R2
N
N
N
N
R
R
N
N
*
* *
*
R1
R1
Ph
Ph
(CH2)n
2
3
1
Recently, we described an alternative method for the synthesis
of bis(imidazole N-oxides) 3 via condensation of in situ prepared
alkane-a,x-bis(methylidenamines) with a-hydroxyimino ket-
ones.14 In analogy to the previously described 2-unsubstituted
imidazole N-oxides, compounds 3 were transformed into imida-
zole derivatives.4–7
Herein, we report the synthesis of bis(imidazole N-oxides) de-
rived from racemic and enantiomerically pure trans-1,2-diamino-
cyclohexane, as well as some transformations of them.
2. Results and discussion
The first experiments were carried out with racemic trans-1,2-
diaminocyclohexane (rac-4), which reacted with formaldehyde in
methanolic solution at room temperature to yield the dimer rac-
6 of the initially formed di-imine rac-515 (Scheme 1). The crystal-
* Corresponding authors. Tel.: +48 42 635 5761; fax: +48 42 635 5380 (G.M.); tel.:
+41 44 635 4282; fax: +41 44 635 6812 (H.H.).
E-mail addresses: gmloston@uni.lodz.pl (G. Mloston´ ), heimgart@oci.uzh.ch
(H. Heimgartner).
line product rac-6 reacts with an excess of a-hydroxyimino ketone
7 (dione monooxime) in refluxing ethanol to give the correspond-
ing racemic bis-imidazole N-oxide rac-8 in ca. 30–40% yield.
Optimization of the procedure led to better yields by reacting
rac-6 and 7 in glacial acetic acid at room temperature. Using this
See Ref. 1.
à
See Ref. 2.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.06.015

P. Mucha et al. / Tetrahedron: Asymmetry 19 (2008) 1600–1607
1601
CH
N
CH
N
2
2
H
H
H
H N
2
NH
2
N
N
(CH O)
2
n
N
N
MeOH,
r.t.
H
4
5
rac
-
rac-
6
-
rac
O
O
N
OH
EtOH,
reflux, 3 h
2
2
N
R
R
2
1
R
N
6
rac
-
+
N
N
or
1
1
R
R
R
O
1. AcOH, 16 h, r.t.
2. HCl gas
3. NaHCO , MeOH, r.t.
3
1
2
1
2
7a
b
c
d
e
8a
R = R = Me
R = R = Me
rac
-
1
2
1
2
b
R = Me, R = Ph
R = Me, R = Ph
1
2
1
2
c
d
e
R = Ph, R = Me
R = Ph, R = Me
1
2
1
2
R = R = Ph
R = R = Ph
1
2
1
2
R = Me, R = H
R = Me, R = H
Scheme 1.
method, bis-imidazoles, rac-8, were obtained in 58–88% yield. The
spectroscopic data of the products 8 fit well with previously
described imidazole N-oxides.5,14 The most characteristic feature
of the 1H NMR spectra is the signal of H–C(2) at 8.7–8.0 ppm. In
the case of rac-8a, the structure was established by X-ray crystal-
lography (Fig. 1).
The compound in the crystal is racemic. The asymmetric unit
contains one zwitterionic molecule 8a and two water molecules.
Each symmetry-independent water molecule acts as a donor for
two hydrogen bonds. One water molecule interacts with the oxide
O-atom from two different molecules of 8a, while the second water
molecule interacts with an oxide O-atom from a third molecule of
8a and with the first water molecule. One of the oxide O-atoms
accepts one hydrogen bond from each of two different water mole-
cules, while the other oxide O-atom accepts just one hydrogen
bond. Only one of the water molecules acts as a hydrogen-bond
acceptor. One path generated by these interactions links the two
water molecules and a single oxide O-atom into extended chains,
which run parallel to the [001] direction and have a graph set
motif17 of C32ð6Þ. The interaction between a water molecule and
the second oxide O-atom cross-links these chains and thereby
forms new chains, which run parallel to the [010] direction and
have a graph set motif of C33ð15Þ. The interactions combine to link
the water and zwitterionic molecules into two-dimensional
networks, which lie parallel to the (100) plane.
The two bis(imidazole N-oxides) rac-8b and rac-8d were deoxy-
genated by treatment with Raney-Ni in ethanol; after 30 min, the
reaction was complete (TLC). Products 9b and 9d were obtained
in 78% and 85% yields, respectively (Scheme 2). As expected, the
signal of H–C(2) is shifted to higher field compared with 8b and 8d.
In order to test if the synthesis of bis-imidazole of type 9 can be
performed by the co-condensation of rac-4 and diphenylethanedi-
one (benzil) in the presence of formaldehyde and ammonium
acetate, the mixture in methanol was heated at reflux for 7 h.
Figure 1. ORTEP plot16 of the molecular structure of rac-8a (arbitrary numbering of the atoms, 50% probability ellipsoids).

1602
P. Mucha et al. / Tetrahedron: Asymmetry 19 (2008) 1600–1607
The enantiomerical purity of (ꢀ)-(R,R)-8a was determined by
O
N
O
N
1H NMR spectroscopy after the addition of 2 equiv of (+)-(R)-
(tert-butyl)(phenyl)phosphonothioic acid ((+)-(R)-12).19 Of special
diagnostic value is the signal of the H–C(2) of the imidazole
rings, which, in the complex of rac-8a with (+)-(R)-12 appears
at 10.2 and 10.4 ppm (Fig. 2). In the corresponding spectrum
of (ꢀ)-(R,R)-8a, the presence of only one signal at 10.2 ppm con-
firms that this compound is enantiomerically pure. This result is
supported by the presence of only two Me signals between 2.1
and 1.6 ppm.
N
N
Ph
R1
Ph
R1
Ph
R1
Ph
R1
N
N
N
N
Raney-Ni
EtOH
rac-9b R1 = Me
d R1 = Ph
rac-8b R1 = Me
d R1 = Ph
Similarly, the enantiomeric purity of (ꢀ)-(R,R)-8b, (+)-(S,S)-8b,
and (+)-(R,R)-8d was determined by 1H NMR spectroscopy.
The treatment of the bis(imidazole N-oxides) (R,R)- and (S,S)-
8b–d with Raney-Ni in methanol led to the deoxygenated bis-imid-
azoles (R,R)-and (S,S)-9b–d, respectively.
Scheme 2.
The chromatographic separation gave the known hexahydroqui-
noxaline 10 and 4,5-diphenylimidazole 11 as the main products.
The desired bis-imidazole rac-9d was isolated in only 14% yield
(Scheme 3). This result shows that the condensation of rac-4 with
7 followed by deoxygenation offers a superior access to bis-imida-
zoles of type 9.
3. Conclusions
The present study shows that the previously described method
for the preparation of bis(imidazole N-oxides) from
a,x-di-
The successful synthesis of racemic bis(imidazole N-oxides) 8
prompted us to investigate the preparation of enantiomerically
pure compounds. For this reason, the enantiomerically pure
(R,R)- and (S,S)-trans-1,2-diaminocyclohexanes [(R,R)-and (S,S)-4,
resp.] were prepared by the resolution of rac-4. Fractional crystal-
aminoalkanes and -hydroxyiminoketones can be successfully
a
applied to the synthesis of optically active derivatives. In this case,
enantiomerically pure trans-1,2-diaminocyclohexane is used as
the chiral substrate. The mild deoxygenation with Raney-Ni offers
a convenient access to the corresponding optically active bis-imi-
dazoles, which are potentially attractive building blocks for the
preparation of chiral metal carbene complexes.
lization of its diastereoisomeric (R,R)- and (S,S)-L
-tartrates,18a–c
followed by treatment with HCl in methanol/diethyl ether, gave
the hydrochlorides, which after neutralization with NaOH solu-
tion18dafforded the free bases.
4. Experimental
4.1. General
The enantiomerically pure diamines (R,R)- and (S,S)-4 were
treated with 2.1 equiv of formaldehyde in methanol in order to
prepare the di-imines 5 (Scheme 1). In contrast to the racemic sub-
strate, no crystalline product of type 6 was formed and the crude
Melting points were determined on a Melt-Temp. II apparatus
(Aldrich) in capillary and are uncorrected. IR spectra were mea-
sured on a NEXUS FT-IR spectrophotometer in KBr. 1H and 13C
NMR spectra were recorded on a Tesla BS567A (80 and 20 MHz,
resp.) or Bruker AC 300 instrument (300 and 75.5 MHz, resp.) in
CDCl3, CD3OD, or DMSO-d6 as solvent and with TMS as an internal
standard. The multiplicity of the 13C signals was deduced from
the DEPT spectra. MS (EI, ESI or CI) were registered on Finnigan
MAT-90 or Finnigan SSQ-700 instruments. Elemental analyses
were performed in the Analytical Laboratory of the University of
Zürich.
materials were used for the reactions with
a-hydroxyimino
ketones 7 in glacial acetic acid. The workup and isolation of
(R,R)- and (S,S)-bis(imidazole N-oxides) of type 8 were carried
out analogously to the procedure applied in the case of rac-8.
O
N
O
N
O
N
O
N
R2
R1
R2
R1
R2
R1
R2
R1
N
N
N
N
*
*
*
*
4.2. Starting materials
(
S,S)-8a R1 = R2 = Me
b R1 = Me, R2 = Ph
c R1 = Ph, R2 = Me
d R1 = R2 = Ph
(
R,R)-8a R1 = R2 = Me
b R1 = Me, R2 = Ph
c R1 = Ph, R2 = Me
d R1 = R2 = Ph
a
-(Hydroxyimino)ketones 7 were obtained according to known
protocols: butane-2,3-dione monooxime 7a,20a 1-phenylpropane-
1,2-dione 1-oxime 7b,20b and 1-phenylpropane-1,2-dione 2-oxime
7c20c by nitrosation of the corresponding ketones using isoamyl
nitrite, 1,2-diphenylethane-1,2-dione monooxime 7d (benzil
monooxime)20d from dibenzoyl and hydroxylamine hydrochloride,
and hydroxyiminoacetone 7e by hydrolysis, nitrosation, and
Starting with (ꢀ)-(R,R)-4 and 7a, the isolated bis(imidazole N-
oxide) 8a showed an [
a
]D-value of ꢀ267.6 (c 1.00, MeOH). Based
on the reaction mechanism of the formation of 8a, we assume that
the configuration of the product is (R,R), that is, the stereochemical
integrity is preserved.
decarboxylation of ethyl acetoacetate by
a modified Beech
procedure.20e
H2N
NH2
CH2O
AcONH4
Ph
Ph
N
Ph
Ph
Ph
Ph
O
O
N
+
rac-9d
+
+
MeOH
reflux, 7 h
N
H
N
10
rac-4
11
Scheme 3.

P. Mucha et al. / Tetrahedron: Asymmetry 19 (2008) 1600–1607
1603
O
N
O
N
Me
Me
Me
S
P
.
2
N
N
OH
Me
Ph
(+)-(R)-12
rac-8a
O
O
N
N
Me
Me
Me
S
.
2
P
N
N
OH
Me
Ph
*
*
(+)-(R)-12
(R,R)-8a
Figure 2. Selected 1H NMR signals of rac-8a and (R,R)-8a in CDCl3 in the presence of 2 equiv of (+)-(R)-(tert-butyl)(phenyl)phosphonothioic acid (+)-(R)-12.
4.3. Synthesis of 1,3,5,7-tetraazapentacyclo[3.3.2.49,10411,12]-
eicosane rac-6
(340.44): C, 56.45; H, 8.29; N, 16.46. Found: C, 56.43; H, 8.31; N,
15.66. Suitable crystals for an X-ray crystal structure determina-
tion were obtained from a solution in chloroform/hexane.
To a solution of racemic trans-1,2-diaminocyclohexane rac-4
(5.00 g, 44.0 mmol) in methanol (50 mL), solid formaldehyde
(2.78 g, 93.0 mmol) was added, and magnetic stirring was contin-
ued overnight. The solvent was removed in vacuo and diethyl ether
(30 mL) was added to the resulting solid. After cooling in a fridge,
filtration gave a portion of crude product. The filtrate was concen-
trated and cooled, and a second portion of rac-6 was isolated. The
combined crude product was purified by crystallization from a
mixture of acetone and dichloromethane to give rac-6 as colorless
crystals (3.85 g, 64%). Mp 234–238 °C (Ref. 15 238–239 °C). IR
4.4.2. trans-1,10-(Cyclohexane-1,2-diyl)bis(5-methyl-4-phenyl-
imidazole)-3,30-dioxide rac-8b
Yield: 210 mg (41%). Colorless crystals. Mp (dec.) 206–211 °C
(CHCl3/hexane). IR (KBr):
1444m, 1405m, 1342s, 1255m, 1227s, 768m, 715s, 697s, 609m
cmꢀ1 1H NMR (CD3OD): d 8.77 (s, 2H, HC(2), HC (20) imidazole),
m 3350–2850vs (br), 1618m, 1497m,
.
7.48–7.39 (m, 10H, 10 arom. H), 4.63–4.56 (m, 2H, 2CH cHex),
2.36–1.68 (m, 8H, 4CH2 cHex), 2.06 (s, 6H, 2CH3). 13C NMR
(CD3OD): d 131.2, 130.1, 129.5 (3d, 10 arom. CH), 130.4 (s, 2Cq
arom.), 129.6, 125.8 (2s, C(4), C(40), C(5), C(50) imidazole), 127.5
(d, C(2), C(20) imidazole), 61.2 (d, 2CH cHex), 33.7, 25.6 (2t, 4CH2
cHex), 9.3 (q, 2CH3). MS (EI): m/z 428 (3, M+.), 412 (11), 280
(100), 239 (29), 159 (23), 105 (25), 77 (26). Anal. Calcd for
(KBr):
m
2937vs (br), 2857m, 1364m, 1273m, 1258s, 1164m,
1071m, 1024s, 1013s, 911m, 661m cmꢀ1
.
1H NMR (CDCl3): d 4.07
(AB, J = 12.8 Hz, 4H), 3.76 (AB, J = 12.8 Hz, 4H), 2.45–2.55 (m, 4H,
4CH), 1.75 (m, 8H, 4CH2 cHex), 1.28 (m, 8H, 4CH2 cHex). MS (CI):
m/z 277 (5, [M+1]+), 139 (100, [M/2+1]+). The obtained rac-6 was
used as a starting material for the synthesis of racemic bis-imidaz-
ole-3-oxides, rac-8.
C
26H28N4O2 ꢁ H2O (446.56): C, 69.93; H, 6.77; N, 12.55. Found: C,
70.31; H, 6.62; N, 12.31.
Method B: A mixture of rac-6 (1.0 mmol) and 4.0 mmol of the
corresponding dione monooxime 7 in glacial acetic acid (15 mL)
was magnetically stirred overnight at rt. Then, HCl gas was bubbled
through the solution for 1 h. In some cases, the product solidified.
Then, diethyl ether (ca. 175 mL) was added and the colorless pre-
cipitated hydrochloride was filtered, washed with cooled ether
(3 ꢂ 20 mL), and dried under reduced pressure. The crude hydro-
chloride was dissolved (or suspended) in methanol (25 mL), solid
NaHCO3 (1.64 g) was added, and stirring was continued for 1 h. Evo-
lution of CO2 was observed. The inorganic salts were filtered off and
the solvent was removed (because of partial precipitation of rac-8d,
the solution was warmed before filtration). The crude solid product
obtained was recrystallized. Following this procedure, rac-8a and
rac-8b were prepared with 85% and 89% yields, respectively.
4.4. Synthesis of racemic bis(imidazole N-oxides)
Method A: An ethanolic solution of rac-6 (1.0 mmol) and
4.0 mmol of the corresponding dione monoxime 7 was heated at
reflux for 3 h. Then, the solvent was removed under reduced pres-
sure, and the resulting deep-orange or deep-yellow oil was washed
with acetone until the color disappeared. The obtained solid was
purified by crystallization from a mixture of chloroform and ace-
tone. Recrystallization from an appropriate solvent gave analyti-
cally pure product as colorless crystals.
4.4.1. trans-1,10-(Cyclohexane-1,2-diyl)bis(4,5-dimethyl-
imidazole)-3,30-dioxide rac-8a
Yield: 191 mg (29%). Colorless crystals. Mp (dec.) 188–194 °C
4.4.3. trans-1,10-(Cyclohexane-1,2-diyl)bis(4-methyl-5-phenyl-
imidazole)-3,30-dioxide rac-8c
(CHCl3/hexane). IR (KBr):
1431m, 1408m, 1382m, 1332s, 1219m, 1194s, 1147m, 1086m,
706s, 632m, 582s cmꢀ1 1H NMR (CD3OD): d 8.56 (s, 2H, HC(2),
m 3350–2859vs (br), 1626m, 1448m,
Yield: 372 mg (77%). Colorless crystals. Mp (dec.) 157–163 °C
.
(CH2Cl2/hexane). IR (KBr):
m
3150–2850vs (br), 1684m, 1632m,
HC(20) imidazole), 4.51–4.48 (m, 2H, 2CH cHex), 2.24–1.59 (m,
8H, 4CH2 cHex), 2.04, 2.00 (2s, 12H, 4CH3). 13C NMR (CD3OD): d
126.6, 125.1 (2s, C(4), C(40), C(5), C(50) imidazole), 124.1 (d, C(2),
C(20) imidazole), 60.4 (d, 2CH cHex), 34.5, 25.5 (2t, 4CH2 cHex),
8.3, 6.9 (2q, 4CH3). MS (CI): m/z 305 (5, [M+1]+), 289 (28), 273
1444m, 1381m, 1327s, 1170m, 1013m, 766s, 705s cmꢀ1
.
1H NMR
(CD3OD): d 8.30 (s, 2H, HC(2), HC(20) imidazole), 7.58–7.51 (m,
6H, 6 arom. H), 7.19–6.96 (m, 4H, 4 arom. H), 4.28–3.98 (m, 2H,
2CH cHex), 2.18–1.26 (m, 8H, 4CH2 cHex), 1.90 (s, 6H, 2CH3). 13C
NMR: d 129.8, 129.4, 129.1, 125.0 (4d, 10 arom. CH, C(2), C(20)
imidazole), 126.5, 126.0, 125.7 (3s, 2Cq arom. C(4), C(40), C(5),
(100), 271 (49), 261 (7). Anal. Calcd for
C
16H24N4O2 ꢁ 2H2O

1604
P. Mucha et al. / Tetrahedron: Asymmetry 19 (2008) 1600–1607
C(50) imidazole), 59.5 (d, 2CH cHex), 31.8, 23.8 (2t, 4CH2 cHex), 7.1
(q, 2CH3). HRMS (CI) C26H28N4O2Na, [M+Na]+: calcd 451.21204;
found 451.21045. Anal. Calcd for C26H28N4O2 ꢁ 3H2O (482.60): C,
64.71; H, 7.10; N, 11.61. Found: C, 64.75; H, 6.71; N, 11.28.
cHex), 50.6, 35.3 (2t, 4CH2 cHex). HRMS (CI) C36H32N4, [M+1]+:
calcd 521.27167; found 521.26997. Anal. Calcd for
C36H32N4 ꢁ 2CH3OH (584.76): C, 78.05; H, 6.89; N, 9.58. Found: C,
77.77; H, 6.81; N, 9.54.
4.4.4. trans-1,10-(Cyclohexane-1,2-diyl)bis(4,5-diphenyl-
imidazole)-3,30-dioxide rac-8d
4.6. Attempted synthesis of trans-1,10-(cyclohexane-1,2-
diyl)bis(4,5-diphenylimidazole) rac-9d from benzil, ammonia,
and formaldehyde
Yield: 504 mg (87%). Colorless crystals. Mp (dec.) 260–267 °C
(CH2Cl2/hexane). IR (KBr):
1445m, 1405m, 1341m, 1259m, 1221m, 767m, 712m, 695m
cmꢀ1 1H NMR (CD3OD): d 8.06 (s, 2H, HC(2), HC(20) imidazole),
7.51–7.08 (m, 20H, 20 arom. H), 4.11–4.02 (m, 2H, 2CH cHex),
2.22–1.28 (m, 8H, 4CH2 cHex). 13C-NMR (CD3OD): d 130.2, 129.4,
129.0, 128.9, 127.7, 127.6, 124.2 (7d, 20 arom. CH, C(2), C(20) imid-
azole), 128.0, 127.1, 126.9, 126.6 (4s, 4Cq arom., C(4), C(40), C(5),
C(50) imidazole), 59.3 (d, 2CH cHex), 31.6, 23.8 (2t, 4CH2 cHex).
HRMS (CI) C36H32N4O2Na, [M+Na]+: calcd 575.24175; found
m 3400–2850vs (br), 1636m, 1577m,
A
solution of racemic trans-1,2-diaminocyclohexane rac-4
.
(0.57 g, 5.0 mmol), benzil (4.20 g, 20.0 mmol), paraformaldehyde
(0.60 g, 20.0 mmol), and ammonium acetate (1.50 g, 20.0 mmol)
in methanol (100 mL) was heated at reflux for 7 h. Then, the sol-
vent was evaporated, the resulting mixture was dissolved in
CH2Cl2 (80 mL) and extracted with 2 M aqueous NaOH solution
(200 mL). The separated deep-green organic phase was dried with
anhydrous Na2SO4 and the solvent was removed. The trans-
4a,5,6,7,8,8a-hexahydro-2,3-diphenylquinoxaline 10 and 4,5-
diphenylimidazole 11 were isolated as the main products. Small
amounts of benzil were also detected in the mixture. In addition,
the bis-imidazole derivative rac-9d was isolated after chromato-
graphic workup in 14% yield (SiO2, MeOH/AcOEt 1:3, Rf = 0.87).
575.24384. Anal. Calcd for
74.59; H, 6.09; N, 9.66. Found: C, 74.50; H, 6.03; N, 9.45.
C
36H32N4O2 ꢁ 1.5H2O (579.71): C,
4.4.5. trans-1,10-(Cyclohexane-1,2-diyl)bis(5-methylimidazole)-
3,30-dioxide rac-8e
Yield: 160 mg (58%). Colorless solid. Mp (dec.) 220 °C. IR (KBr):
m
3150–2850vs (br), 1632m, 1588m, 1450m, 1407s, 1311s, 1297s,
4.7. Resolution of 1,2-diaminocyclohexane; (R,R)- and (S,S)-
trans-1,2-diaminocyclohexane
1230m, 1045m, 819m, 693s cmꢀ1 1H NMR (CD3OD): d 8.56 (s,
.
2H, HC(2), HC (20) imidazole), 6.71 (s, 2H, HC(4), HC(40) imidazole),
4.44–4.38 (m, 2H, 2CH cHex), 2.05–1.45 (m, 8H, 4CH2 cHex), 1.92
To a magnetically stirred solution of (+)-L-tartaric acid (6.0 g,
13
(s, 6H, 2CH3). C NMR (CD3OD): d 125.4 (s, C(5), C(50) imidazole),
40 mmol) in distilled water (17 mL) were added commercially
available 1,2-diaminocyclohexane (ca. 90% mixture of cis- and
trans-isomers, 10 mL, 72 mmol) and glacial acetic acid (4.6 mL,
80 mmol). The resulting suspension was magnetically stirred for
2 h at rt, and then in an ice bath for another 2 h. The colorless pre-
123.2, 118.5 (2d, C(2), C(20), C(4), C(40) imidazole), 57.6 (d, 2CH
cHex), 32.6, 24.0 (2t, 4CH2 cHex), 8.5 (q, 2CH3). HRMS (EI)
C
14H20N4O2, M+Å: calcd 276.1586; found 276.1586.
4.5. Deoxygenation of racemic bis(imidazole N-oxides)
cipitate of (ꢀ)-(R,R)-1,2-diaminocyclohexane
L-tartrate was fil-
tered, washed with distilled water (5 °C) and methanol, and dried
To a solution of the corresponding bis(imidazole N-oxide) 8
(1.0 mmol) in ethanol (2 mL), an ethanolic suspension of freshly
prepared Raney-Nickel was added in small portions, and the pro-
gress of the reaction was followed by TLC (MeOH/AcOEt 1:3).
When the starting N-oxide was completely reduced, the solution
was filtered and the filtrate was concentrated under reduced pres-
sure. The crude product was purified by crystallization.
in vacuo. The filtrate was magnetically stirred and heated to
80 °C. Then, (+)-L-tartaric acid (15.0 g, 100 mmol) was added. The
resulting solution was magnetically stirred overnight at rt, and
then cooled in an ice bath. The colorless precipitate of (+)-(S,S)-
1,2-diaminocyclohexaneꢁ2
L-tartrate was filtered, washed with dis-
tilled water (5 °C) and methanol, and dried in vacuo. Calculated
yields relate to the total amount of cis- and trans-1,2-diamino-
cyclohexane used in the form of a commercial material.
4.5.1. trans-1,10-(Cyclohexane-1,2-diyl)bis(5-methyl-4-
phenylimidazole) rac-9b
4.7.1. (ꢀ)-(R,R)-1,2-Diaminocyclohexane
L-tartrate
Yield: 309 mg (78%). Colorless crystals. Mp 245–246 °C (CH2Cl2/
Yield: 7.7 g (40%). Colorless crystals. Mp (dec.) 252–267 °C
hexane). IR (KBr):
m
3140–2850vs (br), 1605m, 1498s, 1444m,
([lit.18e]: mp (dec.) 247–267 °C). ½a 2D0
ꢃ
¼ þ12:0 (c 1, H2O) ([lit.18e]:
1365m, 1242m, 1216s, 932m, 771s, 700vs cmꢀ1
.
1H NMR (CDCl3):
½
a 2D0
ꢃ
¼ þ11:6 (c 1, H2O)).
d 7.72 (s, 2H, HC(2), HC(20) imidazole), 7.45–7.43, 7.31–7.28 (2m,
8H, 8 arom. H), 7.22–7.19 (m, 2H, 2 arom. H), 4.03–3.97 (m, 2H,
2CH cHex), 2.35–1.58 (m, 8H, 4CH2 cHex), 1.75 (s, 6H, 2CH3). 13C
NMR (CDCl3): d 137.8, 134.9, 124.6 (3s, 2Cq arom., C(4), C(40),
C(5), C(50) imidazole), 133.0, 128.2, 127.3, 126.3 (4d, 10 arom.
CH, C(2), C(20) imidazole), 60.0 (d, 2CH cHex), 33.0, 25.3 (2t, 4CH2
cHex), 8.9 (q, 2CH3). HRMS (EI) C26H28N4, M+Å: calcd 396.2314;
found 396.2313.
4.7.2. (+)-(S,S)-1,2-Diaminocyclohexaneꢁ2
L-tartrate
Yield: 11.3 g (38%). Colorless crystals. Mp (dec.) 140–150 °C
([lit.18e]: mp (dec.) 130–144 °C). ½a 2D0
ꢃ
¼ þ25:4 (c 1, H2O) ([lit.18e]:
½
a 2D0
ꢃ
¼ þ25:8 (c 1, H2O)).
(ꢀ)-(R,R)-1,2-Diaminocyclohexane
L-tartrate (5.0 g, 19 mmol)
was dissolved in a minimum amount of 10% HCl in methanol. To
this solution was added diethyl ether dropwise until a white pre-
cipitate formed. The precipitate was filtered and dried in vacuo,
and then dissolved in a minimum amount of saturated NaOH solu-
tion. KOH pellets were added to remove water, and the mixture
was extracted with diethyl ether (3 ꢂ 50 mL). The organic layer
was separated, dried over MgSO4, and filtered. The solvent was
evaporated under reduced pressure (water/ice bath) to give a
colorless precipitate.
4.5.2. trans-1,10-(Cyclohexane-1,2-diyl)bis(4,5-diphenyl-
imidazole) rac-9d
Yield: 496 mg (85%). Colorless crystals. Mp 277–280 °C (MeOH).
IR (KBr):
m
3100–2800vs (br), 1603m, 1506s, 1490m, 1443m,
1361w, 1247m, 1040m, 775s, 721m, 698s, 661m cmꢀ1
.
1H NMR
(CDCl3): d 7.61–6.96 (m, 22H, 20 arom. H, HC(2), HC(20) imidazole),
4.14–3.88 (m, 2H, 2CH cHex), 2.24–1.28 (m, 8H, 4CH2 cHex). 13C-
NMR (CDCl3): d 137.4, 134.2, 130.0, 128.4 (4s, 4Cq arom., C(4),
C(40), C(5), C(50) imidazole), 133.5, 131.2, 129.3, 129.1, 128.0,
126.5, 126.3 (7d, 20 arom. CH, C(2), C(20) imidazole), 58.1 (d, 2CH
(+)-(S,S)-1,2-Diamiocyclohexane L-tartrate (5.0 g, 12 mol) was
dissolved in a minimum amount of saturated NaOH solution.
KOH pellets were added to remove water, and the mixture was
extracted with diethyl ether (3 ꢂ 50 mL). The organic layer was

P. Mucha et al. / Tetrahedron: Asymmetry 19 (2008) 1600–1607
1605
separated, dried over MgSO4, and filtered. The solvent was evapo-
rated under reduced pressure (water/ice bath) to give a colorless
precipitate.
2.35–1.65 (m, 8H, 4CH2 cHex), 2.05 (s, 6H, 2CH3). 13C NMR
(CD3OD): d 131.2, 130.1, 129.5 (3d, 10 arom. CH), 130.6 (s, 2Cq
arom.), 127.5, 125.8 (2s, C(4), C(40), C(5), C(50) imidazole), 126.4
(d, C(2), C(20) imidazole), 61.2 (d, 2CH cHex), 33.7, 25.6 (2t, 4CH2
cHex), 9.3 (q, 2CH3). MS (ESI): m/z 451 (100, [M+Na]+). HRMS
(ESI) C26H28N4O2Na, [M+Na]+: calcd 451.2110; found 451.2111.
4.7.3. (ꢀ)-(R,R)-trans-1,2-Diaminocyclohexane
Yield: 2.0 g (95%). Colorless crystals. ½a D20
¼ ꢀ20:0 (c 1, 1 M HCl)
ꢃ
([lit.18e]: ½a 2D0
ꢃ
¼ ꢀ29:7 (c 5, 1 M HCl)).
½
a 2D0
ꢃ
¼ ꢀ136:3 (c 0.82, MeOH).
4.7.4. (+)-(S,S)-trans-1,2-Diaminocyclohexane
4.8.4. (S,S)-trans-1,10-(Cyclohexane-1,2-diyl)bis(5-methyl-4-
phenylimidazole)-3,30-dioxide (S,S)-8b
Yield 0.9 g (67%). Colorless crystals. ½a D20
¼ þ17:0 (c 1, 1 M HCl)
ꢃ
([lit.18e]: ½a 2D0
¼ þ29:7 (c 5, HCl)).
ꢃ
Yield: 351 mg (82%). Colorless crystals. Mp (dec.) 230 °C. IR
(KBr):
m 3423–2867vs (br), 1612m, 1576m, 1497m, 1444m,
4.8. Synthesis of enantiomerically pure bis(imidazole N-oxides)
(R,R)- and (S,S)-8
1407m, 1343s, 1256m, 1226s, 1047m, 1031m, 847m, 769m,
715s, 698s, 611m cmꢀ1. MS (ESI): m/z 451 (100, [M+Na]+). HRMS
(ESI) C26H28N4O2Na, [M+Na]+: calcd 451.2110; found 451.2109.
a 2D0
ꢃ
¼ þ134:6 (c 0.82, MeOH).
To a stirred solution of (R,R)- or (S,S)-trans-1,2-diaminocyclo-
hexane (R,R)- or (S,S)-4 (114.0 mg, 1.0 mmol) in methanol (3 mL),
solid formaldehyde (63.0 g, 2.1 mmol) was added, the mixture
was stirred overnight, and the solvent was removed in vacuo.
The resulting oil and 2.1 mmol of the corresponding dione mono-
oxime 7a–d in glacial acetic acid (7 mL) were magnetically stirred
overnight at rt. Then, HCl gas was bubbled through the solution for
1.5 h. In some cases, a precipitate was formed. Then, diethyl ether
(ca. 50 mL) was added, and the colorless hydrochloride was filtered
and dried in vacuo. The crude hydrochloride was dissolved (or sus-
pended) in methanol (25 mL), after which solid NaHCO3 (1.0 g) was
added, and stirring was continued for 1.5 h, whereby evolution of
CO2 was observed. Sodium hydrocarbonate was filtered off, and
the filtrate was evaporated. The solid obtained was treated with
a CHCl3/MeOH mixture (2:1). The undissolved inorganic material
was filtered off and the solvent was removed in vacuo. Crude
products were triturated with small amounts of acetone to give
analytically pure samples. According to this procedure, (R,R)- and
(S,S)-8a–d were obtained in 62–85% yield.
½
4.8.5. (R,R)-trans-1,10-(Cyclohexane-1,2-diyl)bis(4-methyl-5-
phenylimidazole)-3,30-dioxide (R,R)-8c
Yield: 291 mg (68%). Colorless crystals. Mp (dec.) 231 °C. IR
(KBr):
m 3424–2869vs (br), 1698m, 1636m, 1596m, 1443m,
1380m, 1328s, 1177m, 1168m, 1015m, 759m, 708m, 639m. 1H
NMR (CD3OD): d 7.90 (s, 2H, HC(2), HC(20) imidazole), 7.70–7.51
(m, 6H, 6 arom. H), 7.18–7.05 (m, 4H, 4 arom. H), 4.28–4.13 (m,
2H, 2CH cHex), 2.30–1.37 (m, 8H, 4CH2 cHex), 2.04 (s, 6H, 2CH3).
13C NMR (CD3OD): d 131.4, 131.2, 130.7 (3d, 10 arom. CH), 128.8,
127.9, 127.4 (3s, 2Cq arom., C(4), C(40), C(5), C(50) imidazole),
125.8 (d, 2H, C(2), C(20) imidazole), 61.3 (d, 2CH cHex), 34.1, 25.3
(2t, 4CH2 cHex), 7.5 (q, 2CH3). MS (ESI): m/z 451 (100, [M+Na]+).
HRMS (ESI)
C
26H28N4O2Na, [M+Na]+: calcd 451.2110; found
451.2111. ½a 2D0
ꢃ
¼ ꢀ127:0 (c 0.84, MeOH).
4.8.6. (S,S)-trans-1,10-(Cyclohexane-1,2-diyl)bis(4-methyl-5-
phenylimidazole)-3,30-dioxide (S,S)-8c
Yield: 364 mg (85%). Colorless crystals. Mp (dec.) 228 °C. IR
4.8.1. (R,R)-trans-1,10-(Cyclohexane-1,2-diyl)bis(4,5-
dimethylimidazole)-3,30-dioxide (R,R)-8a
(KBr):
m 3424–2870vs (br), 1684m, 1578vs, 1443s, 1380m, 1329s,
1178m, 1015m, 759m, 708m, 639m cmꢀ1. MS (ESI): m/z 451
Yield: 240 mg (79%). Colorless crystals. Mp (dec.) 210 °C. IR
(100, [M+Na]+). HRMS (ESI) C26H28N4O2Na, [M+Na]+: calcd
(KBr):
m 3420–2865vs (br), 1626m, 1450m, 1429m, 1408m,
451.2110; found 451.2106. ½a D20
¼ þ126:2 (c 0.84; MeOH).
ꢃ
1380m, 1332s, 1192s, 1146m, 1084m, 705s, 634m, 583s cmꢀ1 1H
.
NMR (CD3OD): d 8.53 (s, 2H, HC(2), HC(20) imidazole), 4.53–4.43
(m, 2H, 2CH cHex), 2.25–1.57 (m, 8H, 4CH2 cHex), 2.06, 1.91 (2s,
4.8.7. (R,R)-trans-1,10-(Cyclohexane-1,2-diyl)bis(4,5-
diphenylimidazole)-3,30-dioxide (R,R)-8d
13
12H, 4CH3). C NMR (CD3OD): d 126.7, 124.2 (2s, C(4), C(40),
C(5), C(50) imidazole), 125.2 (d, C(2), C(20) imidazole), 60.4 (d,
2CH cHex), 34.5, 25.6 (2t, 4CH2 cHex), 8.4, 6.9 (2q, 4CH3). MS
(ESI): m/z 327 (39, [M+Na]+), 305 (100, [M+1]+). HRMS (ESI)
Yield: 342 mg (62%). Colorless crystals. Mp (dec.) 209 °C. IR
(KBr):
1446m, 1405m, 1339s, 1259m, 1222m, 1193m, 767s, 711s,
658m, 636m cmꢀ1 1H NMR (CD3OD): d 8.08 (s, 2H, HC(2), HC(20)
m 3424–2867vs (br), 1635m, 1570m, 1506m, 1484m,
C
½
16H24N4O2Na, [M+Na]+: calcd 327.1797; found 327.1798.
.
a 2D0
ꢃ
¼ ꢀ267:6 (c 1.00, MeOH).
imidazole), 7.65–7.50 (m, 4H, 4 arom. H), 7.38–7.23 (m, 10H, 10
arom. H), 7.18–7.07 (m, 4H, 4 arom. H), 4.37–4.26 (m, 2H, 2CH
cHex), 2.38–1.40 (m, 8H, 4CH2 cHex). 13C NMR (CD3OD): d 131.8,
131.4, 131.2, 130.8, 129.9, 129.7 (6d, 20 arom. CH, C(2), C(20) imid-
azole), 131.0, 129.6, 127.3 (3s, 4Cq arom., C(4), C(40), C(5), C(50)
imidazole), 61.4 (d, 2CH cHex), 34.0, 25.3 (2t, 4CH2 cHex). MS
(ESI): m/z 575 (100, [M+Na]+). HRMS (ESI) C36H32N4O2Na,
4.8.2. (S,S)-trans-1,10-(Cyclohexane-1,2-diyl)bis(4,5-
dimethylimidazole)-3,30-dioxide (S,S)-8a
Yield: 253 mg (83%). Colorless crystals. Mp (dec.) 210 °C. IR
(KBr):
m 3416–2864vs (br), 1627m, 1449m, 1429m, 1408m,
1380m, 1332s, 1192s, 1146m, 1084m, 705s, 634m, 583s cmꢀ1
.
[M+Na]+: calcd 575.2423; found 575.2422. ½a 2D0
¼ þ6:0 (c 1.02,
ꢃ
MS (ESI): m/z 327 (100, [M+Na]+). HRMS (ESI) C16H24N4O2Na,
[M+Na]+: calcd 327.1797; found 327.1798. ½a 2D0
ꢃ
¼ þ241:7 (c 0.90,
MeOH).
MeOH).
4.8.8. (S,S)-trans-1,10-(Cyclohexane-1,2-diyl)bis(4,5-
diphenylimidazole)-3,30-dioxide (S,S)-8d
4.8.3. (R,R)-trans-1,10-(Cyclohexane-1,2-diyl)bis(5-methyl-4-
phenylimidazole)-3,30-dioxide (R,R)-8b
Yield: 364 mg (66%). Colorless crystals. Mp (dec.) 206 °C. IR
(KBr):
m 3420–2865vs (br), 1603m, 1577m, 1505m, 1484m,
Yield: 351 mg (82%). Colorless crystals. Mp (dec.) 230°C. IR
1445m, 1404m, 1340s, 1258m, 1222m, 1192m, 1077m, 1056m,
(KBr):
1343s, 1257m, 1226s, 1047m, 1031m, 847m, 768m, 715s, 697s,
612m cmꢀ1 1H NMR (CD3OD): d 8.77 (s, 2H, HC(2), HC(20) imidaz-
ole), 7.52–7.37 (m, 10H, 10 arom. H), 4.64–4.54 (m, 2H, 2CH cHex),
m 3420–2866vs (br), 1618m, 1497m, 1444m, 1407m,
766s, 711s, 658m, 636m cmꢀ1. MS (ESI): m/z 575 (100, [M+Na]+).
HRMS (ESI)
C
36H32N4O2Na, [M+Na]+: calcd 575.2423; found
.
575.2418. ½a 2D0
ꢃ
¼ ꢀ6:0 (c 1.00, MeOH).

1606
P. Mucha et al. / Tetrahedron: Asymmetry 19 (2008) 1600–1607
4.9. Deoxygenation of enantiomerically pure bis(imidazole
N-oxides) (R,R)- and (S,S)-9
7.02 (m, 12H, 12 arom. H), 4.08–3.98 (m, 2H, 2CH cHex), 2.38–
1.20 (m, 8H, 4CH2 cHex). 13C NMR (CDCl3): d 137.3, 134.1, 130.0,
128.5 (4s, 4Cq arom., C(4), C(40), C(5), C(50) imidazole), 133.5,
131.1, 129.2, 129.1, 128.0, 126.4, 126.3 (7d, 20 arom. CH, C(2),
C(20) imidazole), 58.0 (d, 2CH cHex), 35.2, 24.8 (2t, 4CH2 cHex).
MS ESI m/z 543 (100, [M+Na]+). HRMS (ESI) C36H32N4Na, [M+Na]+:
To a solution of the corresponding (R,R)- or (S,S)-bis(imidazole
N-oxide) (1.0 mmol) in methanol (2 mL), a methanolic suspension
of freshly prepared Raney-Nickel was added in small portions. The
progress of the reaction was followed by TLC (MeOH/CH3Cl 1:9).
When the starting material was completely reduced, the solution
was filtered through silica gel and the filtrate was concentrated un-
der reduced pressure.
calcd 543.2525; found 543.2531. ½a D20
¼ þ72:3 (c 0.94, MeOH).
ꢃ
4.9.6. (S,S)-trans-1,10-(Cyclohexane-1,2-diyl)bis(4,5-
diphenylimidazole) (S,S)-9d
Yield: 499 mg (96%). Colorless crystals. Mp (dec.) 228 °C
(MeOH). IR (KBr): m 3424–2813vs (br), 1602s, 1576s, 1505s,
4.9.1. (R,R)-trans-1,10-(Cyclohexane-1,2-diyl)bis(5-methyl-4-
phenylimidazole) (R,R)-9b
1490m, 1443m, 1410m, 1361w, 1247m, 1072m, 1043m, 774s,
721m, 698s, 661s cmꢀ1. MS (ESI): m/z 543 (100, [M+Na]+), 521
(30, [M+1]+). HRMS (ESI) C36H32N4Na, [M+Na]+: calcd 543.2525;
Yield: 317 mg (80%). Colorless crystals. Mp (dec.) 221 °C. IR
(KBr):
m 3432–2862vs (br), 1632m, 1606s, 1497s, 1448m, 1363m,
1242m, 1216m, 1071m, 1013m, 936m, 773s, 702vs, 645m cmꢀ1
.
found 543.2529. ½a D20
¼ ꢀ70:2 (c 0.94; MeOH).
ꢃ
1H NMR (CDCl3): d 7.78 (s, 2H, HC(2), HC(20) imidazole), 7.45–
7.20 (m, 10H, 10 arom. H), 4.08–3.98 (m, 2H, 2CH cHex), 2.40–
1.55 (m, 8H, 4CH2 cHex), 1.74 (s, 6H, 2CH3). 13C NMR (CDCl3): d
137.7, 134.8, 124.6 (3s, 2Cq arom., C(4), C(40), C(5), C(50) imidazole),
133.0, 128.2, 127.3, 126.3 (4d, 10 arom. CH, C(2), C(20) imidazole),
60.0 (d, 2CH cHex), 32.9, 25.2 (2t, 4CH2 cHex), 8.8 (q, 2CH3). MS
(ESI): m/z 419 (100, [M+Na]+), 397 (15, [M+1]+). HRMS (ESI)
4.10. X-ray crystal-structure determination of rac-8a
All measurements were performed on a Nonius KappaCCD area-
diffractometer21 using graphite-monochromated MoK radiation
a
(k 0.71073 Å) and an Oxford Cryosystems Cryostream 700 cooler.
The data collection and refinement parameters are given below22
C
½
26H28N4Na, [M+Na]+: calcd 419.2212; found 419.2216.
¼ þ71 (c 1.00, MeOH).
and a view of the molecule is shown in Figure 1. Data reduction
a 2D0
ꢃ
was performed with HKL DENZO and SCALEPACK
.
The intensities were
23
corrected for Lorentz and polarization effects, but not for absorp-
tion. Equivalent reflections were merged. The structure was solved
by direct methods using SIR92,24 which revealed the positions of all
non-H-atoms. The asymmetric unit contains one molecule of rac-
8a and two water molecules. The non-H-atoms were refined aniso-
tropically. The H-atoms of the water molecules were placed in the
positions indicated by a difference electron density map and their
positions were allowed to refine together with individual isotropic
displacement parameters. All remaining H-atoms 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
(1.5Ueq for the methyl groups). The refinement of the structure
4.9.2. (S,S)-trans-1,10-(Cyclohexane-1,2-diyl)bis(5-methyl-4-
phenylimidazole) (S,S)-9b
Yield: 285 mg (72%). Colorless crystals. Mp (dec.) 220 °C. IR
(KBr):
m 3416–2817vs (br), 1606s, 1578s, 1497s, 1444m, 1414m,
1363m, 1242m, 1216m, 1034m, 936m, 773s, 702vs, 645m cmꢀ1
.
MS (ESI): m/z 419 (100, [M+Na]+). HRMS (ESI) C26H28N4Na,
[M+Na]+: calcd 419.2212; found 419.2218. ½a 2D0
¼ ꢀ60:0 (c 1.00,
ꢃ
MeOH).
4.9.3. (R,R)-trans-1,10-(Cyclohexane-1,2-diyl)bis(4-methyl-5-
phenylimidazole) (R,R)-9c
Yield: 293 mg (74%). Colorless crystals. Mp (dec.) 241 °C. IR
(KBr):
1492s, 1451m, 1385m, 1227m, 1218m, 1016m, 970m, 785s,
704s, 655m cmꢀ1 1H NMR (CDCl3): d 7.48–7.38 (m, 6H, 4 arom.
m
3416–2863vs (br), 1639m, 1607m, 1578m, 1569m,
was carried out on F2 using full-matrix least-squares procedures,
2
which minimized the function
R
wðF2o ꢀ F2c Þ . A correction for sec-
.
ondary extinction was applied. Three reflections, whose intensities
were considered to be extreme outliers, were omitted from the fi-
nal refinement. Neutral atom-scattering factors for non-H-atoms
were taken from Ref. 25 and the scattering factors for H-atoms
were taken from Ref. 26. Anomalous dispersion effects were in-
cluded in Fc;27 the values for f0 and f00 were those of Ref. 28. The val-
ues of the mass attenuation coefficients are those of Ref. 29. All
H, HC(2), HC(20) imidazole), 7.10–6.92 (m, 6H, 6 arom. H), 4.04–
3.96 (m, 2H, 2CH cHex), 2.25–1.22 (m, 8H, 4CH2 cHex), 2.06 (s,
6H, 2CH3). 13C NMR (CDCl3): d 134.7, 129.8, 128.3 (3s, 2Cq arom.,
C(4), C(40), C(5), C(50) imidazole), 132.6, 130.4, 128.7, 128.1 (4d,
10 arom. CH, C(2), C(20) imidazole), 58.6 (d, 2CH cHex), 35.1, 24.9
(2t, 4CH2 cHex), 12.8 (q, 2CH3). MS (ESI): m/z 419 (100, [M+Na]+).
30
HRMS (ESI)
C
26H28N4Na, [M+Na]+: calcd 419.2212; found
¼ ꢀ29:8 (c 1.02, MeOH).
calculations were performed using the SHELXL97 program.
419.2214. ½a 2D0
ꢃ
Crystal data for rac-8a: C16H24N4O2 ꢁ 2H2O, M = 340.42, color-
less, prism, crystal dimensions 0.12 ꢂ 0.17 ꢂ 0.22 mm, monoclinic,
space group P21/c, Z = 4, a = 13.5001(4) Å, b = 9.6212(3) Å,
c = 13.8420(3) Å, b = 91.625(2)°, V = 1797.17(9) Å3, T = 160 K,
4.9.4. (S,S)-trans-1,10-(Cyclohexane-1,2-diyl)bis(4-methyl-5-
phenylimidazole) (S,S)-9c
Yield: 293 mg (74%). Colorless crystals. Mp (dec.) 243 °C
DX = 1.258 g cmꢀ3 (MoK ) = 0.0911 mmꢀ1, scan type / and
, l x,
a
(MeOH). IR (KBr):
m
3420–2863vs (br), 1640m, 1606m, 1578m,
2h(max) = 60°, total reflections measured 44007, symmetry inde-
pendent reflections 5271, reflections with I > 2 (I) 3302, reflec-
tions used in refinement 5268, parameters refined 238, R(F)
1492s, 1484m, 1450m, 1443m, 1385m, 1227m, 1218m, 1016m,
970m, 785s, 704s, 655m cmꢀ1. MS (ESI): m/z 419 (91, [M+Na]+),
397 (100, [M+1]+). HRMS (ESI) C26H28N4Na, [M+Na]+: calcd
r
[I > 2
r
(I)
reflections] = 0.0521,
wR(F2)
,
[all
data] = 0.1442
2
419.2212; found 419.2214. ½a D20
ꢃ
¼ þ28:2 (c 1.02, MeOH).
(w ¼ ½r2ðF2oÞ þ ð0:0644PÞ þ 0:253Pꢃꢀ1
where P ¼ ðF2o þ 2F2c Þ=3),
goodness of fit 1.023, secondary extinction coefficient 0.006(2), fi-
nal Dmax
4.9.5. (R,R)-trans-1,10-(Cyclohexane-1,2-diyl)bis(4,5-
diphenylimidazole) (R,R)-9d
/r
0.001,
D
q
(max; min) = 0.26; ꢀ0.28 e Åꢀ3
.
Yield: 416 mg (80%). Colorless crystals. Mp (dec.) 224 °C
Acknowledgements
(MeOH). IR (KBr):
m 3416–2814vs (br), 1602s, 1578s, 1505s,
1490s, 1443m, 1410m, 1361w, 1247m, 1072m, 1043m, 774s,
721m, 698s, 661s. 1H NMR (CDCl3): d 7.56–7.48 (m, 6H, 4 arom.
H, HC(2), HC(20) imidazole), 7.38–7.30 (m, 4H, 4 arom. H), 7.18–
The authors thank the Polish Ministry for Science and Higher Edu-
cation (M.G.) for the Grant (PBZ KBN 126/T09/2004) and F. Hoff-
mann-La Roche AG (H.H.), Basel, for financial support.

P. Mucha et al. / Tetrahedron: Asymmetry 19 (2008) 1600–1607
1607
Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J. Org. Chem. 1994, 59,
1939–1942; (d) Guo, C.; Qiu, J.; Zhang, X. Tetrahedron 1997, 53, 4145–4158; (e)
Gawron´ ski, J.; Gawron´ ska, K.; Kacprzak, K.; Kwit, M. Współczesna Synteza
Organiczna, PWN, Warszawa 2004, pp 346–347.
References
1. Part of the planned PhD thesis of P.M., University of Łódz´.
2. Part of the planned PhD thesis of M.J., University of Łódz´.
3. (a) Ferguson, I. J.; Schofield, K.. J. Chem. Soc., Perkin Trans. 1 1975, 275–277; (b)
Bartnik, R.; Hahn, W. E.; Mloston´ , G. Roczniki Chem. 1977, 51, 49–57.
19. (a) Szawkało, J.; Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.; Drabowicz, J.;
Czarnocki, Z. Tetrahedron: Asymmetry 2005, 16, 3619–3621; (b) Szawkało, J.;
Czarnocki, S. J.; Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.; Maurin, J. K.;
Czarnocki, Z.; Drabowicz, J. Tetrahedron: Asymmetry 2007, 18, 406–413.
20. (a) Semon, W. L.; Damerell, V. R. Org. Synth. 1943, Coll. Vol. 2, 205–207; (b)
Beech, W. F. J. Chem. Soc. 1955, 3094–3098; (c) Bennett, G. B.; Mason, R. B.;
Alden, L. J.; Roach, J. B., Jr. J. Med. Chem. 1978, 21, 623–628; (d) Taylor, T. W. J.;
Marks, M. S. J. Chem. Soc. 1930, 2302–2307; (e) Zhang, C. Y.; Tour, J. M. J. Am.
Chem. Soc. 1999, 121, 8783–8790.
21. Hooft, R. KAPPACCD Collect Software, Nonius BV, Delft, The Netherlands, 1999.
22. CCDC-667057 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge Crystallographic
Data Centre, via www.ccdc.cam.ac.uk/data_request/cif.
23. Otwinowski, Z.; Minor, W. In Methods in Enzymology; Carter, C. W., Jr., Sweet, R.
M., Eds.; Macromolecular Crystallography, Part A; Academic Press: New York,
1997; Vol. 276, pp 307–326.
24. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.;
Polidori, G.; Camalli, M. SIR92, J. Appl. Crystallogr. 1994, 27, 435.
25. Maslen, E. N.; Fox, A. G.; O’Keefe, M. A. In International Tables for
Crystallography; Wilson, A. J. C., Ed.; Kluwer Academic: Dordrecht, 1992; Vol.
C, pp 477–486. Table 6.1.1.1.
26. Stewart, R. F.; Davidson, E. R.; Simpson, W. T. J. Chem. Phys. 1965, 42, 3175–
3187.
27. Ibers, J. A.; Hamilton, W. C. Acta Crystallogr. 1964, 17, 781–782.
28. Creagh, D. C.; McAuley, W. J. In International Tables for Crystallography; Wilson,
A. J. C., Ed.; Kluwer Academic: Dordrecht, 1992; Vol. C, pp 219–222. Table
4.2.6.8.
29. Creagh, D. C.; Hubbell, J. H. In International Tables for Crystallography; Wilson, A.
J. C., Ed.; Kluwer Academic: Dordrecht, 1992; Vol. C, pp 200–206. Table 4.2.4.3.
30. Sheldrick, G. M. SHELXL97, Program for the Refinement of Crystal Structures;
University of Göttingen: Germany, 1997.
´
4. Mloston, G.; Gendek, T.; Heimgartner, H. Tetrahedron 2000, 56, 5405–5412.
5. Mloston´ , G.; Jasin´ ski, M.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2006, 89,
1304–1316.
6. Mloston´ , G.; Celeda, M.; Prakash, G. K. S.; Olah, G. A.; Heimgartner, H. Helv.
Chim. Acta 2000, 83, 728–738.
´
7. Mloston, G.; Gendek, T.; Heimgartner, H. Helv. Chim. Acta 1998, 81, 1585–1595.
8. Laufer, S.; Wagner, G.; Kotschenreuther, D. Angew. Chem., Int. Ed. 2002, 41,
2290–2293.
9. Loska, R.; Ma˛kosza, M. Mendeelev Commun. 2006, 161–163.
10. (a) Grimmett, M. Imidazole and Benzimidazole Synthesis. In Best Synthetic
Methods; Meth-Cohn, O., Katritzky, A. R., Eds.; Academic Press: New York,
1997; (b) Grimmett, M. R. In Science of Synthesis; Neier, R., Ed.; Thieme:
Stuttgart, 2002; Vol. 12, pp 332–335; (c) Ebel, K. In Methoden der Organischen
Chemie (Houben-Weyl), Band E8c; Schaumann, E., Ed.; Thieme: Stuttgart, 1994;
pp 4–9; (d) Grimmett, M. R. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 5, pp 482–487.
11. Bonnet, L. G.; Douthwaite, R. E.; Hodgson, R. Organometallics 2003, 22, 4384–
4386.
12. Liu, I. J. B.; Vasam, C. S. Coord. Chem. Rev. 2007, 251, 642–670; Mata, J. A.;
Poyatos, M.; Peris, E. Coord. Chem. Rev. 2007, 251, 841–859.
13. Liu, J.; Chen, J.; Zhao, J.; Zhao, Y.; Li, L.; Zhang, H. Synthesis 2003, 2661–2666.
14. Jasin´ ski, M.; Mloston´ , G.; Mucha, P.; Linden, A.; Heimgartner, H. Helv. Chim. Acta
2007, 90, 1765–1780.
15. Edward, J. T.; Chubb, F. L.; Gilson, D. F. R.; Hynes, R. C.; Sauriol, F.; Wiesenthal,
A. Can. J. Chem. 1999, 77, 1057–1065.
16. Johnson, C. ‘ORTEP’, Report ORNL-5138, Oak Ridge National Laboratory, Oak
Ridge, Tennessee, 1976.
17. Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew. Chem., Int. Ed. Engl.
1995, 34, 1555–1573.
18. (a) Galsbøl, F.; Steenbøl, P.; Sørensen, B. S. Acta Chem. Scand. 1972, 26, 3605–
3611; (b) Whitney, T. A. J. Org. Chem. 1980, 45, 4214–4216; (c) Larrow, J. F.;