Chiral amino-urea derivatives of (1R,2R)-1,2-diaminocyclohexane as ligands in the ruthenium catalysed asymmetric reduction of aromatic ketones by hydride transfer

Article abstract of DOI:10.1016/S0957-4166(01)00042-8

Several new chiral urea and thiourea ligands have been prepared by reaction of (1R,2R)-1,2-diaminocyclohexane with various organic isocyanates and isothiocyanates. These were used as ligands in the ruthenium catalysed enantioselective reduction of aromati

Full text of DOI:10.1016/S0957-4166(01)00042-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 329–336
Chiral amino-urea derivatives of (1R,2R)-1,2-diaminocyclohexane
as ligands in the ruthenium catalysed asymmetric reduction of
aromatic ketones by hydride transfer
Catherine Bied, Joe¨l J. E. Moreau* and Michel Wong Chi Man
Laboratoire He´te´rochimie Mole´culaire et Macromole´culaire, CNRS UMR 5076,
Ecole Nationale Supe´rieure de Chimie de Montpellier, 8, rue de l’Ecole Normale, 34296 Montpellier Cedex 05, France
Received 26 December 2000; accepted 23 January 2001
Abstract—Several new chiral urea and thiourea ligands have been prepared by reaction of (1R,2R)-1,2-diaminocyclohexane with
various organic isocyanates and isothiocyanates. These were used as ligands in the ruthenium catalysed enantioselective reduction
of aromatic ketones by isopropanol. The reduction proceeded at room temperature using 2 mol% of ruthenium catalyst to give
good yields of the (R)-alcohol with enantiomeric excesses of up to 83%. By contrast, the use of bis-urea ligands gave much lower
enantioselectivities. Amino-thiourea ligands led to the (S)-alcohol with low enantiomeric excess. © 2001 Elsevier Science Ltd. All
rights reserved.
1. Introduction
derived mainly from 1,2-diamino-1,2-diphenylethane
have been recently described by Lemaire et al.20 Also,
the catalytic activity of rhodium, ruthenium and irid-
ium complexes containing mono(thio)urea or
di(thio)urea ligands was studied in the enantioselective
reduction of acetophenone by hydride transfer.20–23
Hybrid materials, combining organic and inorganic
components, have attracted the attention of chemists
and material scientists due to interest in their applica-
tions.1 In this context, we are currently studying
poly(silsesquioxane)s2–4 networks containing chiral
organic sub-structures.5–8 These chiral hybrid solids are
prepared by sol-gel hydrolysis–condensation of opti-
cally active trialkoxysilylated organic molecules6–8 and
are of potential interest in the fields of molecular recog-
nition and asymmetric catalysis.9 We recently reported
the use of chiral hybrids derived from (R)-binol or
(1R,2R)-1,2-diaminocyclohexane as support for hetero-
geneous catalytic species. Chiral matrix effects leading
to enhanced enantioselectivity have been observed.6,7
As part of our studies of chiral hybrid catalytic materi-
als for asymmetric synthesis, we are interested in the
use of urea derivatives as a result of their capability of
auto-association via hydrogen bonds.8
We decided to explore the use of urea derivatives of the
readily available chiral (1R,2R)-1,2-diaminocyclohex-
ane, with the aim of incorporating them in chiral helical
hybrid materials.8 Herein, we report the synthesis of
new urea ligands derived from (1R,2R)-1,2-diaminocy-
clohexane and their use in the ruthenium catalysed
reduction of prochiral ketones by hydride transfer. We
found that amino-urea derived ligands containing the
rigid cyclohexane unit led to good conversions and
enantioselectivities, much higher than those observed
with 1,2-bis-ureido cyclohexane derivatives. The abso-
lute configuration of the product could be changed by
use of amino-thiourea ligands, but the latter led to both
lower conversions and selectivities.
The asymmetric reduction of prochiral aromatic
ketones in the presence of soluble transition metal
catalysts was developed several years ago.10–13 Nitrogen
containing chiral ligands were shown to be useful for
catalytic asymmetric reductions, giving high enantiose-
lectivities.11,14–19 Interestingly, chiral urea ligands
2. Results and discussion
2.1. Synthesis of mono-urea 2, bis-urea 3 and thio-urea
4 ligands
Mono-urea ligands 2 have been prepared by reaction of
(1R,2R)-1,2-diaminocyclohexane hydrochloride with a
variety of isocyanates RNCO, according to Eq. (1).
* Corresponding author. Tel.: 33 (0)4 67 14 72 11; fax: 33 (0)4 67 14
72 12; e-mail: jmoreau@cit.enscm.fr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00042-8

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C. Bied et al. / Tetrahedron: Asymmetry 12 (2001) 329–336
(1)
The formation of 2 was always accompanied by the
formation of bis-urea derivatives. It was minimised by
dropwise addition of the isocyanate at −30°C to an
excess of the diamine hydrochloride 1 (1.4 equivalents)
in CH2Cl2. Compounds 2a–2h were isolated with yields
ranging from 55 to 72%, and in all cases, the bis-urea
formed as a side product (20–35%). Mono-ureas 2 were
easily isolated by selective extraction, the bis-urea being
insoluble in CH2Cl2. The ligands 2 were analysed by
2.2. Catalytic reduction of acetophenone with chiral
urea/ruthenium complexes
Complexes of ruthenium were formed by reacting one
equivalent of [RuCl2(p-cymene)]2 with two equivalents
of ligand 2 in propan-2-ol (ligand to metal ratio: 2/
Ru=1) upon stirring for 30 minutes at 80°C. Evidence
for the formation of 2–ruthenium complexes was
obtained upon analysing the solution by UV spec-
troscopy; in all cases, the absorption bands characteris-
tic of [RuCl2(p-cymene)]2 at 341 and 436 nm shifted to
310–320 and 380–390 nm, respectively, in the presence
of the amino-urea ligands 2. The hydride transfer
reductions of acetophenone were performed at 20°C
according to Eq. (4), using 2 or 3 mol% of ruthenium,
a ratio KOH/Ru=5 and a 0.1 M concentration of
acetophenone in propan-2-ol. The results are sum-
marised in Table 1.
1
FTIR, H and 13C NMR and mass spectroscopy. The
FTIR spectra of 2a–2h exhibit the characteristic vibra-
tions of the urea function (3360, 3310, 1640 and 1560
cm−1).
Two bis-ureas 3a and 3b were also prepared by reaction
of two equivalents of the isocyanate RNCO (with R=
cyclohexyl or dodecyl) with one equivalent of the
(1R,2R)-1,2-diaminocyclohexane, according to Eq. (2).
(2)
(3)
Moreover, we prepared amino-thiourea ligands
4
For most ligands, after a reaction of 24 hours, a
conversion of between 60 and 90% was reached. Com-
plexes with aryl-substituted urea ligands appeared less
reactive (entries 5–10) than the alkyl-substituted urea
ligands (entries 1, 2 and 3). A lower reactivity was also
observed upon increasing the steric hindrance of the
urea substituents (entries 4 and 8). The (R)-enantiomer
of 1-phenylethanol was always the major product and
good to excellent enantiomeric excess (e.e.) up to 83%
(in the case of the cyclohexyl urea, entries 2 and 3) were
according to the procedure described above for amino-
ureas, using thioisocyanates instead of isocyanates. The
compounds 4a–4c were isolated in 59–68% yields (Eq.
(3)). The reaction of phenylisothiocyanate with
diaminocyclohexane did not give amino-thiourea. The
formation of a guanidine derivative occurred, it results
from the cyclisation of the mono-thiourea and elimina-
tion of H2S, as already described in the case of
diaminodiphenylethane.24

C. Bied et al. / Tetrahedron: Asymmetry 12 (2001) 329–336
331
O
NH C NHR
/ 0.5 [RuCl2(p-cymene)]2
Ph
Ph
NH2
2-3 mol %
(4)
C
OH
C
O
H3C
H
H3C
iPrOH (solvent)
(R)
Table 1. Catalytic activity of mono-urea 2/ruthenium complexes in the reduction of acetophenone by isopropanol (according
to Eq. (4))
Entry
Ra
Catalyst mol% (with 2/Ru=1) T (°C)
Reaction time (h)
Conversionb (%) E.e.c (%) (configuration)
1
2
3
4
n-Propyl
Cyclohexyl
Cyclohexyl
t-Butyl
3
2
3
2
20
20
20
22
4
23
4
22
4
24
18
36
72
4
28
4
32
3
22
4
29
4
75
83
57
85
73
90
54
70
84
17
45
27
71
35
68
8
23
35
55
26
68
73
80
100
90
63 (R)
59 (R)
83 (R)
81 (R)
83 (R)
82 (R)
66 (R)
57 (R)
57 (R)
73 (R)
57 (R)
74 (R)
52 (R)
72 (R)
72 (R)
43 (R)
38 (R)
38 (R)
33 (R)
68 (R)
59 (R)
59 (R)
82 (R)
82 (R)
82 (R)
5
Phenyl
2
3
2
2
2
2
20
20
20
20
20
20
6
Phenyl
7
p-MeO-phenyl
o-Tolyl
8
9
p-CF3-phenyl
1-Naphtyl
22
4
24
30
4
10
11
12
Cyclohexyl
Cyclohexyl
2d
2e
20
20
22
4
a R=alkyl or aryl substituent in amino-ureas 2a–h (cf. Eq. (2)).
b The reaction was monitored by capillary gas chromatography.
c The e.e. was determined by HPLC on a Chiralcel OD column.
d With 2/Ru=2.
e With 2/Ru=8.
obtained. The e.e. as a function of reaction time was
examined and did not significantly decrease with time
when using alkyl substituted urea ligands, indicating that
the active catalytic species was stable during the reduc-
tion reaction. With the exception of the urea ligand
having a p-methoxyphenyl substituent (entry 7), for
which no variation in e.e. was noted, a small decrease in
the e.e. values was observed in the case of aryl substituted
ureas (entries 5–10). The catalytic species seemed to be
more stable with electron donating substituents such as
alkyl or p-MeO-phenyl. The use of 3 mol% instead of 2
mol% of catalyst led to increased conversion but did not
change the e.e. (entries 2 and 3, 5 and 6).
slightly increased (100% conversion after 22 hours), but
the e.e.’s were identical to those obtained when 2/Ru=1
(entries 11 and 12).
The amino-urea ligand 2e (R=p-MeO-phenyl) was
tested in the ruthenium catalysed reduction of three other
aromatic ketones: 1-acetonaphthone, 2-acetonaphthone
and 2-methoxyacetophenone. The results are sum-
marised in Table 2. The reactions were performed at 20°C
with 2 mol% of catalyst and 2e/Ru=1. In these cases, the
reactivities were lower owing to steric effects, but the
enantioselectivities were similar to those obtained with
acetophenone and did not decrease with time, indicating
a good stability of the catalytic species with the p-MeO-
phenyl substituted ligand.
We also examined the influence of the ligand/ruthenium
ratio (2/Ru) both on the yield and on the e.e. Using the
cyclohexyl urea ligand 2b, the reaction was performed
with a 2/Ru ratio=2 or 8, in both cases, the reaction rate
Bis-urea and thio-urea chiral ligands have been shown to
give higher selectivities than amino-ureas derivated

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C. Bied et al. / Tetrahedron: Asymmetry 12 (2001) 329–336
Table 2. Catalytic activity of the mono-urea 2e (R=p-MeO-
phenyl)/ruthenium complex in the reduction of aromatic
ketones by isopropanol (according to Eq. (4))
measured at high conversion. The ruthenium complexes
formed with the bis-ureas appeared much less stable
than those obtained with mono-ureas. In the case of
amino-thiourea ruthenium complexes (entries 3, 4 and
5), both reactivities and selectivities were lower than
those obtained with the mono-ureas (Table 1). Surpris-
ingly the (S)-enantiomer of 1-phenylethanol was
obtained as the major product (Table 3, entries 3, 4 and
5), in contrast to the amino-urea ruthenium complexes
which predominantly gave the (R)-enantiomer (Table
1).
Aromatic ketone
Reaction Conversionb (%) E.e.c (%)
timea (h)
(configuration)
1-Acetonaphthone
2-Acetonaphthone
2-MeO-acetophenone
22
40
120
4
22
72
4
51
72
92
15
28
78
18
35
85
74 (R)
74 (R)
74 (R)
75 (R)
72 (R)
71 (R)
78 (R)
76 (R)
76 (R)
Lemaire et al. underlined the effect of the structure of
the ligands in the metal catalysed hydride transfer
reduction of aromatic ketones.21 On the basis of theo-
retical and experimental studies,25 it was concluded that
the active complex in the catalytic asymmetric reduc-
tion of ketones is most likely a metal complex with one
diamine and differed from the use of phenanthroline
ligands for which it was proposed in that two ligands
were coordinated to the metal centre.11,26 Moreover,
Noyori et al.17,27 determined the structure of the com-
plex formed upon reaction of [RuCl2(mesitylene)]2 with
two equivalents of (1S,2S)-N-(p-toluenesulfonyl)-1,2-
diphenylethylenediamine. Only one amino-sulfonamide
ligand and the arene cycle were found to be coordi-
nated to ruthenium. This led us to assume that in our
case, 1:1 complexes of 2 and ruthenium formed, consis-
tent with the observed absence of effect of the 2/Ru
ratio on the conversion and selectivities.
22
72
a The reactions were performed at 20°C with 2 mol% of catalyst and
2e/Ru=1.
b The reactions were monitored by capillary gas chromatography.
c E.e. was measured by HPLC on a Chiralcel OD column.
ligands in the rhodium, iridium or ruthenium catalysed
reduction of acetophenone.20–23 We also studied the
catalytic activity of chiral ruthenium complexes pre-
pared with the bis-urea and the amino-thiourea ligands
derived from the (1R,2R)-1,2-diaminocyclohexane. The
reduction reactions of acetophenone were performed
using two different bis-ureas (3a with R=cyclohexyl
and 3b with R=dodecyl) and three amino-thioureas (4a
R=n-butyl, 4b R=t-butyl, 4c R=cyclohexyl) under
the same reaction conditions (0.1 M concentration in
acetophenone, 2 or 3 mol% of catalyst and 3/Ru or
4/Ru=1). The results are given in Table 3.
Our observations with urea ligands derived from
diaminocyclohexane are quite different from those
reported using other ligands, the structures of which
derived from 1,2-diamino-1,2-diphenylethane. In the
latter, bis-ureas were found to give higher selectivities
than amino-ureas,21 when using ligand to metal ratios
from 2 to 1021,22 (lower selectivities were sometimes
Using bis-urea ligands,
a much slower reaction
occurred (entries 1 and 2). Furthermore, it led to low
selectivities and the e.e. values obtained in this case
decreased markedly with time. Very low e.e.’s were
Table 3. Catalytic activity of bis-urea 3a–b and amino-thiourea 4a–c/ruthenium complexes in the reduction of acetophenone
by isopropanol (according to Eq. (4))
Entry
1
Liganda
Catalyst mol% (with
2/Ru=1)
T (°C)
Reaction time
(h)
Conversionb (%) E.e.c (%)
(configuration)
Bis-urea 3a (R=cyclohexyl)
Bis-urea 3b (R=n-dodecyl)
3
20
4
23
120
4
22
4
23
2
22
4
15
30
78
20
69
29
45
37
72
20
64
30 (R)
20 (R)
4 (R)
20 (R)
6 (R)
32 (S)
32 (S)
42 (S)
36 (S)
22 (S)
22 (S)
2
3
4
5
2
2
2
2
20
20
20
20
Amino-thiourea 4a
(R=n-butyl)
Amino-thiourea 4b
(R=t-butyl)
Amino-thiourea 4c
(R=cyclohexyl)
22
a Ligands derived from (1R,2R)-1,2-diaminocyclohexane (cf. Eqs. (3) and (4)).
b The reaction was monitored by capillary gas chromatography.
c The e.e. was determined by HPLC on a Chiralcel column.

C. Bied et al. / Tetrahedron: Asymmetry 12 (2001) 329–336
333
O
O
H
N
H
N
R
R
N
N
H
N
H
N
H
NH2
R
H
O
2
3
Figure 1. Representation of amino-ureas 2 and bis-ureas 3.
observed for L/M=1). The highest enantioselectivities
were obtained in the case of N-methylated bis-thiourea
derivatives.22 Concerning our ligands derived from the
diaminocyclohexane structure, the highest selectivities
were observed for the amino-ureas. The bis-urea lig-
ands gave much lower selectivities and the ruthenium
complexes exhibited poor stability under the reaction
conditions, as shown by the observed decrease in e.e.
values as a function of time. With amino-urea ligands,
a stable catalytic species formed for 2/Ru=1 and gives
e.e.’s of up to 83%. These observations may be related
to the rigid structure of the urea ligands derived from
diaminocyclohexane. Bis-urea derivatives 3 have been
shown28 to adopt a conformation in which the two
ureido groups lay up and down in parallel plans, as
shown in Fig. 1. These rigid structures easily auto-asso-
ciate in solution by intermolecular hydrogen bonds.29
Complexation of ruthenium may therefore be more
difficult in this case than in the case of the more flexible
diaminodiphenylethane structure.21
important to the observed enantioselectivity. The
amino-urea ligands containing the cyclohexane sub-
structure formed chiral complexes with ruthenium
which catalyse the reduction of acetophenone by
hydride transfer in good yields and higher e.e. than
those obtained with other amino-urea ligands. Bis-urea
or thiourea based ligands led to lower selectivities. We
are currently investigating the heterogenisation of such
catalytic species by immobilisation in hybrid silica
matrices.
4. Experimental
All reactions were performed under a nitrogen atmo-
sphere using Schlenk tube techniques. The solvents
were distilled under nitrogen over P2O5 (CH2Cl2) or Mg
turnings (propan-2-ol) before use. Isocyanates were
purchased from Aldrich, [RuCl2(p-cymene)]2 from
Strem Chemicals and they were used as received with-
out further purification. Commercial acetophenone was
distilled before use and kept at −30°C under nitrogen.
Homochiral (1R,2R)-diaminocyclohexane was obtained
in enantiomerically pure form from the commercial
racemic cis/trans mixture according to the method of
Jacobsen.30 1H and 13C NMR spectra in solution were
recorded on a Bruker AC-200 spectrometer and CDCl3
or DMSO-d6 were used as solvents. Chemical shifts (l,
ppm) are relative to tetramethylsilane. IR spectra were
determined with a Perkin–Elmer 1000 FTIR spectrome-
ter. Mass spectra were measured on a JEOL MS-DX
300 mass spectrometer. Elemental analyses were carried
out by the Service Central de Microanalyse du CNRS
in Vernaison (France). The UV spectra of solutions
were recorded on a Hewlett Packard 8453 spectropho-
tometer. Optical rotations were measured on a Perkin–
Elmer polarimeter 241. Enantiomeric excesses were
determined by HPLC analysis using a chiral column
(Chiralcel OD), UV detector at 254 nm, hexane/
propan-2-ol: 90/10 as eluant, flow 0.5 mL min−1.
The amino-urea ligand 2 with one primary amine group
does not have the same structural properties and may
easily form a 1:1 complex with ruthenium. Complex
formation may occur by coordination of the 1,2 nitro-
gen atoms of the diaminocyclohexane unit in a struc-
ture similar to the one described by Noyori et al. in the
case of amino-sulfonamide derivatives.17,27 Complex
formation is probably more difficult with the more rigid
bis-urea structure 3. Also, amino-thiourea showed a
different behaviour. With these ligands, enantioselectiv-
ities lower than those observed with amino-urea were
found, moreover, the major configuration was the
opposite one. The coordination mode of the amino-
thiourea is probably different from that of amino-urea,
since the absolute configuration of the alcohol product
reversed by replacing amino-urea with amino-thiourea.
Coordination of the sulfur atom to ruthenium may be
responsible for the observed changes upon using the
thio ligand.
3. Conclusion
4.1. General procedure for the synthesis of mono-urea
ligands 2
We have synthesised and characterised several new
chiral urea-containing ligands from (1R,2R)-1,2-
diaminocyclohexane. Ligand structural effects are
(1R,2R)-1,2-Diaminocyclohexane hydrochloride (1.05
g, 7 mmol) in dry CH2Cl2 (100 mL) was placed in a

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C. Bied et al. / Tetrahedron: Asymmetry 12 (2001) 329–336
Schlenk tube under nitrogen at −30°C. A solution of
the isocyanate (5 mmol) in dry CH2Cl2 (50 mL) was
added dropwise under nitrogen. After stirring for one
night at −30°C, the solution was washed with an
aqueous Na2CO3 solution to remove the excess diamine
hydrochloride. The organic phase was dried over
MgSO4 and after filtration, the solvent was evaporated.
The residue was dried under vacuum to afford a white
powder. The mono-urea was obtained together with
some bis-urea. The mono-urea was soluble in CH2Cl2
whereas the bis-urea precipitated and these two prod-
ucts were separated by extraction with CH2Cl2 to give
the mono-ureas 2a–2h as colourless solids.
4.1.5.
(1R,2R)-1,2-Diaminocyclohexane
para-
methoxyphenylurea 2e. Yield: 61% (802 mg); mp=
171°C; [h]D=−3.6 (CHCl3, c=5); 1H NMR (CDCl3, l):
1.21 (4H, m), 1.82 (4H, m), 2.38 (1H, m), 3.31 (1H, m),
3.78 (3H, s), 4.79 (1H, d), 6.85–7.25 (4H, m), 7.42 (1H,
s); 13C NMR (CDCl3, l): 24.91, 25.14, 32.97, 35.09,
35.51, 55.96, 57.16, 114.47, 123.32, 129.45, 139.62,
157.05; wmax (KBr, cm−1): 3359, 3306, 2951, 2865, 1640,
1623, 1562, 1157; mass spectrum: m/z [FAB+] (%): 264
(79, M+), 247 (4), 166 (8), 154 (100), 137 (78), 123 (25),
107 (25), 98 (18); anal. calcd for C14H21N3O2: C, 63.85;
H, 7.98; N, 15.96. Found: C, 63.55; H, 7.89; N, 15.64%.
4.1.6. (1R,2R)-1,2-Diaminocyclohexane ortho-tolylurea
2f. Yield: 68% (935 mg); mp=167°C; [h]D=−4.7
(CHCl3, c=5); 1H NMR (CDCl3, l): 1.18 (4H, m), 1.86
(4H, m), 2.28 (3H, s), 3.33 (1H, m), 3.34 (1H, m), 5.5
(1H, d), 7.05–7.58 (4H, m), 7.54 (1H, s); 13C NMR
(CDCl3, l): 18.29, 24.77, 25.05, 32.88, 34.49, 55.68,
56.47, 123.63, 124.58, 126.73, 130.74, 136.82, 157.05;
wmax (KBr, cm−1): 3360, 3307, 2951, 2866, 1643, 1625,
1563; mass spectrum: m/z [FAB+] (%): 248 (12, M+),
221 (12), 207 (18), 191 (8), 147 (46), 136 (20) 98 (13);
anal. calcd for C14H21N3O: C, 67.98; H, 8.56; N, 16.99.
Found: C, 67.75; H, 8.29; N, 16.79%.
4.1.1. (1R,2R)-1,2-Diaminocyclohexane propylurea 2a.
Yield: 61% (607 mg); mp=133°C; [h]D=−1.7 (CHCl3,
1
c=5); H NMR (CDCl3, l): 0.92 (3H, t), 1.19 (4H, m),
1.49 (2H, q), 1.8 (4H, m), 2.35 (1H, m), 3.15 (2H, m),
4.42 (1H, d), 5.18 (1H, d); 13C NMR (CDCl3, l): 11.42,
23.42, 25.03, 33.19, 42.29, 56.36, 57.69, 159.08; wmax
(KBr, cm−1): 3359, 3305, 2954, 2871, 1643, 1561; mass
spectrum: m/z [FAB+] (%): 200 (100, M+), 183 (7), 141
(10), 115 (20), 98 (32); anal. calcd for C10H21N3O: C,
60.30; H, 10.55; N, 21.1. Found: C, 59.88; H, 10.58; N,
21.0%.
4.1.2. (1R,2R)-1,2-Diaminocyclohexane cyclohexylurea
2b. Yield: 65% (776 mg); mp=189°C; [h]D=−2.4
4.1.7. (1R,2R)-1,2-Diaminocyclohexane para-(trifluoro-
methyl)phenylurea 2g. Yield: 55% (827 mg); mp=
155°C; [h]D=−5.2 (CHCl3, c=5); 1H NMR (CDCl3, l):
1.15 (4H, m), 1.9 (4H, m), 2.59 (1H, m), 3.47 (1H, m),
6.24 (1H, m), 7.38–7.54 (4H, m), 8.8 (1H, s); 13C NMR
(CDCl3, l): 24.26, 24.87, 32.69, 34.37, 55.58, 56.30,
118.35, 122.85, 126.06, 142.66, 156.31; wmax (KBr,
cm−1): 3362, 3308, 2949, 2865, 1641, 1624, 1562, 1256;
mass spectrum: m/z [FAB+] (%): 302 (15, M+), 281 (6),
221 (6), 207 (12), 193 (5), 147 (24), 98 (16); anal. calcd
for C14H18N3OF3: C, 55.81; H, 6.02; N, 13.95. Found:
C, 55.78; H, 6.29, N, 13.42%.
1
(CHCl3, c=5); H NMR (CDCl3, l): 1.1–1.9 (18H, m),
2.36 (1H, m), 3.12 (1H, m), 3.5 (1H, m), 4.41 (1H, d),
5.05 (1H, d); 13C NMR (CDCl3, l): 24.9, 25.03, 25.25,
25.65, 33.18, 33.91, 35.01, 49.01, 56.3, 57.43, 159.78;
wmax (KBr, cm−1): 3362, 3310, 2955, 2867, 1642, 1561;
mass spectrum: m/z [FAB+] (%): 240 (100, M+), 230
(12), 154 (68), 136 (52), 98 (52); anal. calcd for
C13H25N3O: C, 65.17; H, 10.46; N, 17.57. Found: C,
64.81; H, 10.39; N, 17.46%.
4.1.3. (1R,2R)-1,2-Diaminocyclohexane tertiobutylurea
2c. Yield: 63% (670 mg); mp=149°C; [h]D=−5.8
(CHCl3, c=5); 1H NMR (CDCl3, l): 1.19 (4H, m), 1.28
(9H, s), 1.85 (4H, m), 2.35 (1H, m), 3.30 (1H, m), 4.42
(1H, d), 5.18 (1H, d); 13C NMR (CDCl3, l): 24.27,
25.20, 29.43, 31.44, 32.53, 49.79, 57.13, 66.63, 159.32;
wmax (KBr, cm−1): 3349, 3311, 2947, 2861, 1642, 1562;
mass spectrum: m/z [FAB+] (%): 214 (72, M+), 181 (4),
155 (5), 141 (8), 116 (35), 98 (38); anal. calcd for
C11H23N3O: C, 61.97; H, 10.79; N, 19.7. Found: C,
61.63; H, 10.55; N, 19.87%.
4.1.8. (1R,2R)-1,2-Diaminocyclohexane 1-naphthylurea
2h. Yield: 72% (1.02 g); mp=287°C; [h]D=−2.9
1
(CHCl3, c=2); H NMR (DMSO-d6, l): 1.21 (4H, m),
1.85 (4H, m), 2.4 (1H, m), 3.3 (1H, m), 6.58 (1H, d),
7.4–8.08 (7H, m), 8.52 (1H, s); 13C NMR (DMSO-d6,
l): 24.83, 25.11, 32.85, 34.90, 55.70, 56.45, 119.50,
124.65, 125.73, 129.44, 130.61, 132.77, 138.88, 139.75,
157.25; wmax (KBr, cm−1): 3311, 3290, 2928, 2851, 1623,
1561, 1395, 1342; mass spectrum: m/z [FAB+] (%): 284
(100, M+), 283 (14), 267 (8), 207 (12), 176 (6), 169 (23),
154 (93), 136 (95), 113 (32), 98 (47); anal. calcd for
C17H21N3O: C, 72.08; H, 7.42; N, 14.80. Found: C,
72.08; H, 7.35; N, 14.56%.
4.1.4. (1R,2R)-1,2-Diaminocyclohexane phenylurea 2d.
Yield: 58% (675 mg); mp=142°C; [h]D=−19.5 (CHCl3,
1
c=5); H NMR (CDCl3, l): 1.15 (4H, m), 1.85 (4H,
m), 2.38 (1H, m), 3.3 (1H, m), 5.25 (1H, d), 7.05–7.35
(5H, m), 8.15 (1H, s); 13C NMR (CDCl3, l): 24.73,
25.05, 32.85, 34.82, 55.65, 56.39, 119.62, 122.74, 129,
139.37, 156.81; wmax (KBr, cm−1): 3358, 3302, 2948,
2862, 1640, 1625, 1563; mass spectrum: m/z [FAB+]
(%): 234 (100, M+), 217 (6), 176 (4), 154 (58), 136 (45),
107 (16), 98 (27); anal. calcd for C13H19N3O: C, 66.9;
H, 8.15; N, 18.00. Found: C, 66.46; H, 8.43; N, 17.33%.
4.2. General procedure for the synthesis of bis-urea
ligands 3
The bis-ureas 3a and 3b were prepared according to the
general procedure described by Kellogg et al.29 starting
from (1R,2R)-1,2-diaminocyclohexane (5 mmol) and
isocyanate (11 mmol).

C. Bied et al. / Tetrahedron: Asymmetry 12 (2001) 329–336
335
4.2.1. (1R,2R)-1,2-Diaminocyclohexane cyclohexylbis-
urea 3a. Yield: 92% (1.68 g); mp=286°C; [h]D=+0.28
176 (6), 154 (100), 136 (75), 77 (38); anal. calcd for
C13H25N3S: C, 61.13; H, 9.87; N, 16.45; S, 12.55.
Found: C, 61.15; H, 10.14; N, 16.26; S, 12.15%.
1
(CHCl3/EtOH 1/1 v/v, c=1); H NMR (DMSO-d6, l):
1.2–1.9 (28H, m), 3.15 (1H, m), 3.55 (2H, m), 4.46 (2H,
d), 5.26 (2H, d); 13C NMR (DMSO-d6, l): 25.05, 25.62,
33.22, 33.95, 35.17, 49.01, 56.85, 159.35; wmax (KBr,
cm−1); 3320, 2919, 2887, 1633, 1585; mass spectrum:
m/z [FAB+] (%): 365 (25, M+), 363 (5), 307 (18), 289
(12), 266 (18), 240 (22), 222 (10), 154 (100), 136 (75),
107 (25), 98 (40); anal. calcd for C20H36N4O2: C, 65.90;
H, 9.95; N, 15.37. Found: C, 66.25; H, 10.22; N,
15.10%.
4.4. Typical procedure for ruthenium-catalysed
reduction of aromatic ketones
A mixture of [RuCl2(p-cymene)]2 (18.4 mg, 0.03 mmol)
and the chiral urea ligand (0.06 mmol) was placed in
freshly distilled propan-2-ol (10 mL) and this solution
was stirred at 80°C for 30 min. After cooling to 20°C,
additional propan-2-ol (20 mL) was added followed by
the addition of solid KOH (16.8 mg) and the aromatic
ketone (3 mmol). The orange solution became brown.
The reaction was monitored by capillary gas chro-
matography and the e.e. was measured by HPLC on a
Chiralcel OD column. The results are summarised in
Table 1.
4.2.2. (1R,2R)-1,2-Diaminocyclohexane dodecylbis-urea
3b. Yield: 95%. This compound was obtained as
described in Ref. 29, and exhibited identical analytical
characteristics to those reported.
4.3. General procedure for the synthesis of amino-
thiourea ligands 4
References
The amino-thioureas 4 were synthesised according to
the same procedure as described for the synthesis of the
mono-ureas 2 using the corresponding commercial
isothiocyanates. The amino-thioureas, which formed
together with some bis-thioureas, were isolated by
recrystallisation from acetone.
1. (a) Sanchez, C.; Ribot, F. New J. Chem. 1994, 18, 989–
1007; (b) Laine, R. M.; Sanchez, C.; Brinker, C. J.;
Giannelis, E., Eds. Organic/Inorganic Hybrid Materials,
MRS Symp. Vol. 519, 1998; (c) Klein, L.; DeGuire, M.;
Lorraine, F.; Mark, J., Eds. Organic/Inorganic Hybrid
Materials II, MRS Symp. Vol. 576, 1999; (d) Laine, R.
M.; Sanchez, C.; Brinker, C. J., Eds. Organic/Inorganic
Hybrid Materials III, MRS Symp. Vol. 628, 2000.
2. (a) Shea, K. J.; Loy, D. A.; Webster, O. W. J. Am. Chem.
Soc. 1992, 114, 6700–6710; (b) Loy, D. A.; Shea, K. J.
Chem. Rev. 1995, 95, 1431–1442 and references therein.
3. (a) Corriu, R. J. P.; Moreau, J. J. E.; The´pot, P.; Wong
Chi Man, M. Chem. Mater. 1992, 4, 1217–1224; (b)
Corriu, R. J. P.; Moreau, J. J. E.; The´pot, P.; Wong Chi
Man, M. Chem. Mater. 1996, 8, 100–106.
4. Corriu, R. J. P.; Leclercq, D. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1420–1436 and references cited therein.
5. (a) Shvo, Y.; Becker, Y.; Gal, M. Chem. Commun. 1994,
2719–2720; (b) Shabat, D.; Grynszpan, F.; Saphier, F.;
Turniansky, A.; Avnir, D.; Keinan, E. Chem. Mater.
1997, 9, 2258–2260; (c) Gelman, F.; Avnir, D.; Schu-
mann, H. J. Mol. Catal., A. Chem. 1999, 146, 123–128.
6. (a) Adima, A.; Moreau, J. J. E.; Wong Chi Man, M. J.
Mater. Chem. 1997, 7, 2331–2333; (b) Adima, A.;
Moreau, J. J. E.; Wong Chi Man, M. Chirality 2000, 5–6,
411–420.
4.3.1. (1R,2R)-1,2-Diaminocyclohexane n-butylthiourea
4a. Yield: 65% (745 mg); mp=77°C; [h]D=+5.3
1
(CHCl3, c=5); H NMR (CHCl3, l): 0.91 (3H, t), 1.22
(4H, m), 1.49 (4H, m), 1.8 (4H, m), 2.35 (1H, m), 2.56
(1H, m), 3.18 (2H, m), 4.12 (1H, d), 5.78 (1H, d); 13C
NMR (CHCl3, l): 13.80, 20.04, 20.17, 24.71, 24.88,
31.19, 32.21, 34.97, 56.03, 61.33, 182.15; wmax (KBr,
cm−1): 3425, 3302, 2929, 1547, 1442; mass spectrum:
m/z [FAB+] (%): 230 (100, M+), 228 (22), 157 (19), 133
(45), 97 (96), 57 (86); anal. calcd for C11H23N3S: C,
57.60; H, 10.11; N, 18.32, S, 13.98. Found: C, 57.97; H,
10.22; N, 18.12; S, 13.69%.
4.3.2. (1R,2R)-1,2-Diaminocyclohexane tertiobutylth-
iourea 4b. Yield: 59% (675 mg); mp=98°C; [h]D=+6.5
(CHCl3, c=5); 1H NMR (CHCl3, l): 1.22 (4H, m), 1.47
(9H, s), 1.8 (4H, m), 2.32 (1H, m), 2.54 (1H, m), 4.52
(1H, d), 5.81 (1H, d); 13C NMR (CHCl3, l): 24.79,
24.83, 29.35, 32.26, 35.04, 53.08, 56.24, 62.04, 181.58;
wmax (KBr, cm−1): 3425, 3301, 2928, 1547, 1452; mass
spectrum: m/z [FAB+] (%): 230 (100, M+), 228 (18), 157
(18), 133 (40), 97 (98), 57 (82); anal. calcd for
C11H23N3S: C, 57.60; H, 10.11; N, 18.32; S, 13.98.
Found: C, 57.94; H, 10.25; N, 18.15; S, 13.76%.
7. Hesemann, P.; Moreau, J. J. E. Tetrahedron: Asymmetry
2000, 11, 2183–2194.
8. Moreau, J. J. E.; Vellutini, L.; Wong Chi Man, M.; Bied,
C. J. Am. Chem. Soc. 2001, in press.
9. Moreau, J. J. E.; Wong Chi Man, M. Coord. Chem. Rev.
1998, 178–180, 1073–1084.
4.3.3. (1R,2R)-1,2-Diaminocyclohexane cyclohexylth-
iourea 4c. Yield: 68% (867 mg); mp=85°C; [h]D=+7.5
10. (a) Noyori, R. Asymmetric Catalysis in Organic Synthe-
sis; John Wiley & Sons: New York, 1994 and references
cited therein; (b) Noyori, R.; Hashiguchi, S. Acc. Chem.
Res. 1997, 30, 97–102 and references cited therein; (c)
Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999,
10, 2045–2061.
1
(CHCl3, c=5); H NMR (CHCl3, l): 1.05–1.85 (18H,
m), 2.37 (1H, m), 3.16 (1H, m), 3.61 (1H, m), 4.58 (1H,
d), 5.72 (1H, d); 13C NMR (CDCl3, l): 24.67, 24.82,
25.35, 25.48, 32.75, 34.62, 35.26, 53.12, 55.61, 57.18,
181.14; wmax (KBr, cm−1): 3425, 3263, 2928, 1547, 1447;
mass spectrum: m/z [FAB+] (%): 256 (35, M+), 222 (8),
11. Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. Rev.
1992, 92, 1051–1069 and references cited therein.

336
C. Bied et al. / Tetrahedron: Asymmetry 12 (2001) 329–336
12. (a) Chowdhury, R. L.; Ba¨ckvall, J. E. J. Chem. Soc.,
Chem. Commun. 1991, 1063–1064; (b) Wang, G. Z.;
Ba¨ckvall, J. E. J. Chem. Soc., Chem. Commun. 1992,
337–339; (c) Wang, G. Z.; Ba¨ckvall, J. E. J. Chem. Soc.,
Chem. Commun. 1992, 980–982.
21. Touchard, F.; Bernard, M.; Fache, F.; Lemaire, M. J.
Mol. Catal., A: Chem. 1999, 140, 1–11.
22. Touchard, F.; Bernard, M.; Fache, F.; Delbecq, F.;
Guiral, V.; Sautet, P.; Lemaire, M. J. Organomet. Chem.
1998, 567, 133–136.
13. Geneˆt, J.-P.; Ratovelomanana-Vidal, V.; Pinel, C. Synlett
23. Touchard, F.; Gamez, P.; Fache, F.; Lemaire, M. Tetra-
1993, 478–480.
hedron Lett. 1997, 38, 2275–2278.
14. Krasik, P.; Alper, H. Tetrahedron 1994, 50, 4347–4354.
15. (a) Von Hatt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl.
1993, 32, 566–568; (b) Zhon, Q. L.; Pfaltz, A. Tetra-
hedron 1994, 50, 4467.
16. (a) Gamez, P.; Fache, F.; Mangeney, P.; Lemaire, M.
Tetrahedron Lett. 1993, 34, 6897–6898; (b) Gamez, P.;
Fache, F.; Lemaire, M. Tetrahedron: Asymmetry 1995, 6,
705–718.
17. Hashiguchi, H.; Fujii, A.; Takehara, J.; Ikariya, T.; Noy-
ori, R. J. Am. Chem. Soc. 1995, 117, 7562–7563.
18. Pu¨ntener, P.; Schwink, L.; Knochel, P. Tetrahedron Lett.
1996, 37, 8165–8168.
19. Nayata, T.; Yorozu, K.; Yamada, T.; Mukaiyama, T.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2145–2147.
20. (a) Gamez, P.; Dunjic, B.; Fache, F.; Lemaire, M. J.
Chem. Soc., Chem. Commun. 1994, 1443–1444; (b)
Gamez, P.; Dunjic, B.; Lemaire, M. J. Org. Chem. 1996,
61, 5196–5197.
24. Touchard, F.; Fache, F.; Lemaire, M. Tetrahedron:
Asymmetry 1997, 8, 3319–3326.
25. Bernard, M.; Fache, F.; Delbecq, F.; Guiral, V.; Sautet,
P.; Lemaire, M. J. Am. Chem. Soc. 1998, 120, 1441–1446.
26. Gladiali, S.; Pinna, L.; Delogu, G.; De Martin, S.; Zassi-
novich, G.; Mestroni, G. Tetrahedron: Asymmetry 1990,
1, 635–648.
27. Haack, K.-J.; Hashiguchi, H.; Fujii, A.; Takehara, J.;
Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl.
1997, 36, 285–288.
28. De Loos, M.; Van Esch, J. H.; Strokroos, I.; Kellogg, R.
M.; Feringa, B. L. J. Am. Chem. Soc. 1997, 119, 12675–
12676.
29. Van Esch, J. H.; Schoonbeek, F. S.; De Loos, M.;
Kooijman, H.; Spek, A. L.; Kellogg, R. M.; Feringa, B.
L. Chem. Eur. J. 1999, 5, 937–950.
30. Jacobsen, E. N.; Larrow, J. F. J. Org. Chem. 1994, 59,
1939–1942.
.