Fluorous derivatives of (1R,2R)-diaminocyclohexane as chiral ligands for metal-catalyzed asymmetric reactions

Article abstract of DOI:10.1016/j.tetasy.2005.05.040

Perfluoroalkyl-substituted, enantiopure diamines derived from (1R,2R)-diaminocyclohexane were conveniently prepared from readily available precursors. In situ generated metal complexes of these ligands were tested as chiral catalysts in three standard asymmetric reactions (cyclopropanation of styrene, hydrogen transfer reduction of acetophenone, and allylic alkylation of 1,3-diphenyl-2-propenyl acetate) affording enantioselectivities of up to 47% in the copper-catalyzed cyclopropanation of styrene.

Full text of DOI:10.1016/j.tetasy.2005.05.040

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2319–2327
Fluorous derivatives of (1R,2R)-diaminocyclohexane as
chiral ligands for metal-catalyzed asymmetric reactions
Jerome Bayardon,a Denis Sinou,a Orsolya Holczknecht,b
b
Laszlo Mercs and Gianluca Pozzi
b,
*
´
a
`
´
´
´
Laboratoire de Synthese Asymetrique, associe au CNRS, CPE Lyon, Universite Claude Bernard Lyon 1,
43, boulevard du 11 Novembre 1918, 69622 Villeurbanne cedex, France
bCNR, Istituto di Scienze e Tecnologie Molecolari, via Golgi 19, 20133 Milano, Italy
Received 17 May 2005; accepted 26 May 2005
Abstract—Perfluoroalkyl-substituted, enantiopure diamines derived from (1R,2R)-diaminocyclohexane were conveniently prepared
from readily available precursors. In situ generated metal complexes of these ligands were tested as chiral catalysts in three standard
asymmetric reactions (cyclopropanation of styrene, hydrogen transfer reduction of acetophenone, and allylic alkylation of 1,3-
diphenyl-2-propenyl acetate) affording enantioselectivities of up to 47% in the copper-catalyzed cyclopropanation of styrene.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ligands in two metal-catalyzed asymmetric reactions,
namely transfer hydrogenation of ketones and the cyclo-
propanation of styrene.13–15 Herein, we report practical
procedures for the functionalization of (1R,2R)-diami-
nocyclohexane with readily available fluorinated reac-
tants to give enantiopure fluorous secondary diamines.
Preliminary data concerning their use as ligands in
metal-catalyzed reactions are also reported.
Enantiomerically pure 1,2-diamines, in particular, those
possessing C2-symmetry, and their derivatives have
found wide application as chiral auxiliaries and ligands
in asymmetric synthesis.1,2 Moreover, they are valuable
building blocks for generating multicomponent organo-
metallic catalysts, such as ruthenium derivatives of dual
ligand systems composed of a chiral diamine and a
chiral bisphosphine,3 dendritic catalysts,4 or hybrid
organic–inorganic materials.5
2. Results and discussion
An intense research activity is currently devoted to the
synthesis of easily recoverable enantiopure 1,2-diamines.
As in the case of other families of chiral ligands and cat-
alysts,6,7 immobilization onto inorganic supports,5,8
attachment to soluble or insoluble organic polymers,9,10
and solubilization in water upon introduction of hydro-
philic substituents11 have been explored. Fluorous tech-
niques have recently been introduced in asymmetric
synthesis and are rapidly emerging as a convenient alter-
native for recovering chiral catalysts.12 In this context,
we had previously reported the synthesis of certain
enantiopure C2-symmetric 1,2-diamines bearing perflu-
oroalkyl substituents and demonstrated their use as
Most fluorous chiral diamines employed so far as
ligands in asymmetric organometallic catalysis are deriv-
atives of commercially available, enantiomerically pure
trans-1,2-diaminocyclohexane.12–14 These have been
prepared by the condensation of the chiral diamine with
two molar equivalents of an aryl aldehyde bearing per-
fluoroalkyl substituents, followed by reduction of the
imino functionalities (Scheme 1). We thus tried to ex-
tend this method towards the use of (F-alkyl)alkanals
(RF(CH2)mCHO, m = 1–4)16 in order to attach perfluori-
nated alkyl chains RF to the nitrogen atoms of trans-1,2-
diaminocyclohexane through methylene spacers of
various length. Unfortunately, attempted N,N0-dialkyla-
tion by stepwise or in situ reductive amination with
RF(CH2)mCHO resulted in the formation of complex
product mixtures, containing massive amounts of
unknown fluorous by-products which were hardly
*
Corresponding author. Tel.: +39 (0)2 50 31 41 63; fax: +39 (0)2 50 31
41 59; e-mail: gianluca.pozzi@istm.cnr.it
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.05.040

2320
J. Bayardon et al. / Tetrahedron: Asymmetry 16 (2005) 2319–2327
studied (Scheme 2). We were primarily interested in
RF
the effect of the molar ratio alkylating agent/primary
amine on the outcome of the reaction, so various
amounts of commercially available perfluoroalkyl iod-
ides 1 and 2 were reacted with cyclohexylamine in boil-
CHO
NH2
NH2
N
N
EtOH
+
2
∆
RF
1
ing CH3CN in the presence of K2CO3 as a base. H
RF
NMRanalysis of crude reaction mixtures showed that
in the case of 1 only mono N-alkylation occurs, even if
using a large excess of alkylating agent. This is possibly
due to the residual electron withdrawing effect of RF,
which is not completely shielded by two CH2 spacing
units, thus making the secondary amine 3 a poor nucleo-
phile with respect to cyclohexylamine. In the case of 2,
bis-N-alkylation of cyclohexylamine could be avoided
by using substoichiometric amounts of the iodide, but
this would be obviously unpractical if N,N0-functionali-
zation of a diamine was sought. Mixtures of mono- and
bis-N-alkylated products 4 and 5 were obtained for 2/
cyclohexylamine molar ratios up to 3, whereas in the
presence of a further excess of alkylating agent, the ter-
tiary amine 5 was the only product detected. The inser-
tion of a further CH2 spacing unit effectively reduces the
influence of RF on the electronic density of the nitrogen
atom, so that the secondary amine 4 is still prone to
attack by a second molecule of alkylating agent.
RF
H
N
[H]
N
H
RF
Scheme 1. Synthesis of fluorous N,N0-dibenzyl derivatives of (1R,2R)-
diaminocyclohexane.
separable from the desired compounds. Alternative
routes to N,N0-dialkylation, which are consistent with
the use of readily available fluorinated starting materi-
als, were therefore examined.
Direct N,N0-dialkylation using perfluoroalkyl iodides
RF(CH2)mI appeared to be worth exploring. It is known
that such iodides behave in a different manner from their
non-fluorinated analogues when m = 0, 1, since the
strong electron-withdrawing effect of RF makes iodine
a very bad leaving group in nucleophilic substitutions.
For m P 2, the shielding effect of the methylene groups
is progressively enhanced and reactivity of iodides such
as 1 and 2 (Scheme 2) towards nucleophiles becomes clo-
ser to the usual one. Indeed, bis N-alkylation of certain
primary amines was observed upon reaction with 2.17,18
However, in other cases, the reaction stops after the first
alkylation step and a secondary amine is obtained as the
only product, even under strong conditions.14
With these results in mind, (1R,2R)-diaminocyclohexane
was reacted with four molar equivalents of commercially
available iodide 1 in boiling CH3CN in the presence of
K2CO3 as a base (Scheme 3). Diamine 6 was isolated
in a quite low yield (30%) from the reaction mixture
due to the rather awkward work-up required (see
Experimental).
NH2
NH2
NH
NH
K2CO3
C8F17
C8F17
C8F17
4
+
I
CH3CN, ∆
6
1
C8F17
NH2
HN
Scheme 3. N,N0-dialkylation of (1R,2R)-diaminocyclohexane with
fluorous iodide 1.
K2CO3
C8F17
+
I
CH3CN, ∆
1
(1-3 mol. equiv.)
3
Our attention next turned towards the synthesis of
disubstituted diamines by reduction of the correspond-
ing bis-amides, in order to overcome limitations of
direct N,N0-dialkylation.19 Indeed, (F-alkyl)alkanoic
acids RF(CH2)mCOOH and their derivatives are readily
available and are amongst the most useful building
blocks in the synthesis of more elaborated fluorous mole-
cules.20 Diacylation of (1R,2R)-diaminocyclohexane was
achieved using commercially available C7F15COCl 7 in
the presence of Et3N as a base (Scheme 4), affording
bis-amide 8 in 88% yield. This compound was then
reduced with LiAlH4 affording the corresponding
diamine 9 featuring a single CH2 spacing unit between
RF substituents and the nitrogen atoms in 57% yield.
Analogously, bis-diamides 11 and 14 were readily ob-
tained in 88% and 96% yield, respectively, using (F-
alkyl)alkanoyl chlorides 10 and 13 prepared following
slightly modified literature methods.21,22 Reduction of
bis-amides 11 and 14 with LiAlH4 went along with par-
tial cleavage of the final product. Better results were
NH2
HN
C8F17
K2CO3
C8F17
I
+
CH3CN, ∆
2
(5 mol. equiv.)
4
C8F17(CH2)3
(CH2)3C8F17
NH2
N
K2CO3
C8F17
I
+
4
+
CH3CN, ∆
2
5
(1-3 mol. equiv.)
Scheme 2. N-alkylation of cyclohexylamine with fluorous iodides.
To verify whether direct N,N0-dialkylation of (1R,2R)-
diaminocyclohexane was feasible, a simpler model reac-
tion, namely N-alkylation of cyclohexylamine was first

J. Bayardon et al. / Tetrahedron: Asymmetry 16 (2005) 2319–2327
2321
H
N
O
H
N
C7F15
C7F15
C7F15
C7F15
2 C7F15COCl 7
LAH
Et2O
Et3N, THF
N
H
N
H
O
9
8
H
N
H
O
NH2
NH2
,
C8F17
C8F17
N
C8F17
C8F17
2 C8F17(CH2)2COCl 10
BH3 THF
THF
Et3N, THF
N
H
N
H
O
12
11
H
N
H
O
O
N
,
2 C8F17(CH2)3COCl 13
BH3 THF
C8F17
C8F17
C8F17
C8F17
THF
Et3N, THF
N
H
N
H
O
O
15
14
Scheme 4. Synthesis of fluorous N,N0-diamines 9, 12, and 15 by acylation/reduction.
obtained using the milder reducing agent BH3ÆTHF with
diamines 12 and 15 recovered in 93% and 90% yield,
respectively.
(P = Cfluorous phase/Corganic phase) for 6, 9, 12, and 15
between perfluoro-1,3-dimethylcyclohexane (PDMC)
and standard organic solvents are reported in Table 1.
Moderate to good fluorous phase affinities were exhib-
ited by all the new compounds, as a result of the balance
between their high fluorine content and the presence of
two organophilic amino groups. Fluorophilicity was
also influenced by the number of CH2 spacing units
interposed between RF and the nitrogen atom, as evi-
denced by the higher P values consistently observed
for 12 (3CH2) with respect to 15 (4CH2) despite the si-
milar fluorine content of the two compounds (62% vs
61%). Even in the case of PDMC/MeOH biphasic sys-
tems, all these secondary diamines are preferentially dis-
solved in the fluorous phase, in contrast to what was
observed with primary fluorous diamines and b-amino
alcohols.23 Fortunately, they are also readily soluble in
Et2O, THF, and at low concentrations, in CH2Cl2. This
residual affinity for organic solvents greatly simplified
the use of these diamines as ligands in asymmetric orga-
nometallic catalysis.
Attempted diacylation of (1R,2R)-diaminocyclohexane
with C8F17CH2COCl 16 failed to give the desired bis-
amide because of concurrent HF elimination (Scheme
5). Dehydrofluorination of 16 by acid–base reaction
with Et3N or (1R,2R)-diaminocyclohexane and intramo-
lecular E2 elimination of HF from a monoacylated
intermediate are both possible, as pointed out by Selve
et al., for the reaction of (F-alkyl)ethanoyl chlorides
with polyfunctional amines.21 Since diamine 6 can be
obtained by direct N,N0-dialkylation, its preparation
via acylation/reduction was not further investigated.
H
N
O
NH2
NH2
2 C8F17CH2COCl 16
C8F17
C8F17
Et3N, THF
N
H
O
Not obtained
B
Table 1. Partition coefficients P for fluorous diamines between
perfluoro-1,3-dimethylcyclohexane (PDMC) and standard organic
solventsa
H
H
O
H
C7F15
C7F15
Cl
Cl
F
O
O
F
F
Organic
solvent
P [X]PDMC/ [X]org. solv.
B
= Et3N, 1,2-diaminocyclohexane
9 (F = 65%) 6 (F = 64%) 12 (F = 62%) 15 (F = 61%)
Toluene
CH2Cl2
5.5
5.5
8.0
8.6
4.1
4.4
2.9
2.6
F
F
O
H
F
CH3CN >20
CH3OH 7.7
>20
4.3
>20
5.3
>20
4.4
NH
C7F15
NH
C7F15
H
H
a In a 50:50 (v:v) mixture of PDMC/organic solvent at 25 ꢁC. Deter-
mined gravimetrically (see Experimental).
NH2
NH2
Scheme 5. Attempted acylation of (1R,2R)-diaminocyclohexane with
16.
Fluorous diamines 6, 9, 12, and 15, in association with
[Ir(COD)Cl]2 or [Ru(p-cymene)Cl2]2, were tested in the
asymmetric reduction of acetophenone with isopropanol
as the hydride source in the presence of PDMC as the
fluorous solvent at 70 ꢁC (Table 2). The reduction was
Next, we studied the equilibrium distribution of the
new secondary diamines between two immiscible
fluorous/non-fluorous solvents. Partition coefficients P

2322
J. Bayardon et al. / Tetrahedron: Asymmetry 16 (2005) 2319–2327
Table 2. Catalytic hydrogen transfer reduction of acetophenone using fluorous chiral diaminesa
O
OH
CH3
Diamine/Complex
CH3
*
i-PrOH/PDMC/KOH/70 °C
Entry
Diamine
Complex
t (h)
Conversion (%)
ee (%) Config.
1
2
3
4
5
6
7
9
[Ru(p-cymene)Cl2]2
[Ir(COD)Cl]2
3
98
98
96
98
60
98
99
6 (R)
—
6
0.5
20
6
[Ru(p-cymene)Cl2]2
[Ir(COD)Cl]2
6 (R)
12 (S)
5 (R)
5 (S)
3 (R)
12
12
15
15
0.5
48
[Ru(p-cymene)Cl2]2
[Ir(COD)Cl]2
[Ru(p-cymene)Cl2]2
0.5
20
a Diamine = 10 mol %; complex = 5 mol %; PDMC/i-PrOH = 1:1 v/v; conversion and ee determined by GC (see Experimental for details).
almost quantitative with all the ligands used and what-
ever the catalyst precursor, except in the case of the
combination 12/[Ru(p-cymene)Cl2]2 (entry 5). Unfortu-
nately, enantioselectivities (ee max = 12%, entry 4) were
much lower than those obtained using enantiopure flu-
orous N,N0-dibenzylcyclohexane-1,2-diamines (Scheme
1) associated with the same catalyst precursor (ee up
to 69%).13
etate. Indeed, catalytic systems based on combinations
of bidentate chiral nitrogen ligands and Cu(I) salts oper-
ate efficiently in the asymmetric cyclopropanation of sty-
rene derivatives.27 Positive results were also obtained
using enantiopure C2-symmetric diimines and diamines
derived from trans-1,2-diphenylethanediamine or
related compounds featuring a 1,2-cyclohexanediamine-
like skeleton derived from sugars.28,29 Furthermore,
the scope and limitations of enantiopure fluorous
N,N0-dibenzylcyclohexane-1,2-diamines as ligands in
the cyclopropanation of styrene has recently been
disclosed.14 Reaction conditions were optimized using
diamine 12 (5 mol %) as a model ligand (Table 4).
Cyclopropanation of styrene (5 mol equiv) with ethyl
a-diazoacetate (1 mol equiv) was carried out at 20 ꢁC
in CH2Cl2 and the trans- and cis-cyclopropanes isolated
by flash column chromatography (see Experimental). As
found for N,N0-dibenzylcyclohexane-1,2-diamines, the
nature of the Cu(I) precursor strongly affected the out-
come of the reaction (entries 1–3) while the use of
Cu(CH3CN)4PF6 (entry 3) led to the highest reaction
yield (68%) and ee for both trans (47%) and cis (47%)
diastereoisomers. The ratio of the diamine to the copper
is also important, with a 2:1 ratio giving higher enantio-
selectivities than a 1 to 1 ratio (entry 3 vs 4), whereas
increasing the amounts of both ligand and
Cu(CH3CN)4PF6 with respect to styrene did not result
in any improvement (entry 5 vs 3). As often observed
with chiral fluorous ligands, lowering the reaction tem-
perature had negative effects on the activity and enantio-
selectivity of the catalytic system (entry 7). Conversely,
performing the reaction at 40 ꢁC instead of 20 ꢁC led
Slightly better results were obtained in the case of the
enantioselective allylic alkylation of 1,3-diphenyl-2-pro-
penyl acetate with diethyl malonate catalyzed by Pd(0)
(Tsuji–Trost alkylation, Table 3).24 This reaction was
carried out in THF at room temperature, using the flu-
orous ligand (6 mol %) and [Pd(C3H5)Cl]2 (2.5 mol %)
in the presence of NaH as a base. Catalytic systems
based on diamines 6, 12, and 15 afforded the alkylated
product in almost quantitative yields, with ees up to
15–20% (entries 3–6), whereas 9 proved to be inadequate
as a ligand for this reaction (entries 1 and 2). Efficient
enantiopure fluorous bis(oxazolines) had been recently
developed for Tsuji–Trost alkylation, affording ees up
to 95% in the case of the alkylation of 1,3-diphenyl-2-
propenyl acetate.25 The new fluorous diamines 6, 12,
and 15 are clearly inferior to those fluorous bidentate
nitrogen ligands in terms of enantioselectivity. On the
other hand, they compare well with a synthetically
demanding fluorous BINAP analogue recently reported
by us.26
The new ligands were finally assessed in the copper-cat-
alyzed cyclopropanation of styrene with ethyl a-diazoac-
Table 3. Enantioselective allylic alkylation of 1,3-diphenyl-2-propenyl acetate using fluorous diaminesa
OAc
Ph
CO2CH3
Ph
CH3O2C
Ph
CO2CH3
CO2CH3
[Pd(C3H5)Cl]2, diamine
+
Ph
NaH, THF, 25°C
( )
*
Entry
Diamine
t (h)
Conversion (%)
ee (%) Config.
1
9
9
48
48
48
24
20
20
8
17
—
—
2b
3
6
100
99
20 (R)
20 (R)
15 (R)
20 (S)
4b
5
6
12
15
98
100
6
a Diamine = 6 mol %; [Pd(C3H5)Cl]2 = 2.5 mol %; PDMC/i-PrOH = 1:1 v/v; conversion and ee determined by HPLC (see Experimental for details).
b T = 50 ꢁC.

J. Bayardon et al. / Tetrahedron: Asymmetry 16 (2005) 2319–2327
Table 4. Asymmetric cyclopropanation of styrene under homogeneous conditionsa
2323
Diamine / CuXn
Ph
Ph
CO2Et
Ph
*
N2CHCO2Et
+
+
*
*
*
CO2Et
CH2Cl2
Entry
Diamine
CuXn
Cu(OTf)2
Yield (%)b
Trans/cisc
ee trans (%)d,e
ee cis (%)d,f
1
12
12
12
12
12
12
12
12
12
9
29
48
68
17
68
63
18
75
37
23
39
37
67/33
66/34
67/33
65/35
67/33
67/33
66/34
67/33
77/23
61/39
62/38
65/35
38
38
47
28
46
36
36
44
30m
16
39
32
42
35
47
27
46
36
31
45
n.d.
10
35
24
2
Cu(CH3CN)4BF4
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
3
4g
5h
6i
7j
8k
9l
10
11
12
6
15
a Diamine = 5 mol %; CuXn = 2.5 mol %; reaction time = 1 h + 1 h; T = 20 ꢁC (see Experimental for details).
b Overall isolated yield (cis + trans).
c Determined by GC analysis of the isolated mixture (cis + trans).
d Determined by HPLC analysis.
e Configuration (1R,2R) determined by comparison with an authentic sample.
f Configuration (1S,2R) determined by comparison with an authentic sample.
g Diamine 6 = 5 mol%; Cu(I)X = 5 mol %.
h Diamine 6 = 10 mol%; Cu(I)X = 5 mol %.
i Reaction time = 4 h + 1 h.
j T = 0 ꢁC.
k T = 40 ꢁC.
l Using tert-butyl a-diazoacetate instead of ethyl a-diazoacetate.
m Configuration of the major enantiomer not determined.
to a modest increase in the isolated yield (entry 8).
Attempts to improve the enantioselectivity of the reac-
tion by using more bulky diazoacetates, for example,
tert-butyl-a-diazoacetate, also proved unsuccessful (en-
try 9). The presence of the tert-butyl group increases
the trans/cis ratio as it makes the cis-transition state ste-
rically less favorable. However, the major trans-cyclo-
propane isomer was obtained with an ee of 30% only.
Under optimized conditions, results obtained with fluor-
ous diamines 6, 9, and 15 were not as good as in the case
of 12 (entries 10–12). Enantioselectivities and reaction
yields increased with the number m of CH2 spacing units
for m = 1–3, but dropped quite unexpectedly for m = 4.
Currently, we have no plausible explanation for this
behavior.
The recovery of fluorous diamine 12 was then studied
(Table 5). First, the ligand was released from the copper
cation by decomplexation with cyanide ions, carried out
on the crude reaction mixture obtained after evapora-
tion of CH2Cl2 and styrene in excess. Ligand 12 was
recovered in 77% yield by fluorous liquid-liquid extrac-
tion of the mixture using PDMC and could be reused
with moderate success in a second run (entries 1 and
2). Unlike to what we found using fluorous N,N0-di-
benz- ylcyclohexane-1,2-diamines, the performance of
di-amine 12 is better under homogeneous conditions
than in a Fluorous Biphasic System. In the latter
case, the catalyst derived from ligand 12 and
Cu(CH3CN)4PF6 was extracted into the organic layer
during the reaction and could not be recovered by phase
Table 5. Asymmetric cyclopropanation of styrene: attempted recycling using diamine 12a
Entry
Solvent
CuXn
Yield (%)b
Trans/cisc
ee trans (%)d,e
ee cis (%)d,f
1
CH2Cl2
CH2Cl2
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6
Cu(OTf)2
68
43
40
37
18
67/33
63/37
67/33
67/33
70/30
47
24
33
31
30
47
22
35
32
32
2g
3
CH2Cl2/PDMC
CH2Cl2/PDMC
CH2Cl2/PDMC
4
5h
Cu(OTf)2
a Diamine 12 = 5 mol %; CuXn = 2.5 mol %; reaction time = 1 h + 1 h; T = 20 ꢁC (see Experimental for details).
b Overall isolated yield (cis + trans).
c Determined by GC analysis of the isolated mixture (cis + trans).
d Determined by HPLC analysis.
e Configuration (1R,2R) determined by comparison with an authentic sample.
f Configuration (1S,2R) determined by comparison with an authentic sample.
g Using diamine 12 recovered from the previous run by decomplexation.
h Using the complex recovered from the previous run.

2324
J. Bayardon et al. / Tetrahedron: Asymmetry 16 (2005) 2319–2327
separation (entry 3). On the other hand, the catalytic
species obtained from ligand 12 and Cu(OTf)2 (entry
4) turned out to be preferentially soluble in the fluorous
layer, as shown by the color of the two phases, which
were easily separated at the end of the reaction. The
green-blue fluorous phase containing the catalyst was
used in a subsequent run (entry 5). Although enantiose-
lectivity remained unchanged, a drop in yield was unfor-
tunately observed in the second run consistent with a
loss of catalyst into the organic layer.
parison of GC and HPLC retention times with those of
authentic samples.
4.2. (1R,2R)-N,N0-Bis(1H,1H,2H,2H-perfluorodecyl)-
cyclohexane-1,2-diamine 6
A
mixture of (1R,2R)-diaminocyclohexane (0.23 g,
2 mmol), K2CO3 (1.11 g, 8 mmol), and C8F17CH2CH2I
1 (4.59 g, 8 mmol) in dry CH3CN (20 mL) was refluxed
with stirring under nitrogen for 48 h. The suspension
was cooled to rt, treated with H2O (10 mL) and
extracted three times with Et2O (40 mL). The combined
organic layers were washed with brine and dried over
Na2SO4. After filtration, gaseous HCl was bubbled
into the ice-cold solution. The white solid precipi-
tate was recovered and recrystallized from EtOH to
give pure 6Æ(HCl)2 (0.65 g, 30%). Mp 188–195 ꢁC;
3. Conclusion
Unsophisticated fluorous derivatives of (1R,2R)-diami-
nocyclohexane have conveniently been prepared from
readily available precursors and used as chiral ligands
in the hydrogen transfer reduction of acetophenone,
the allylic alkylation of 1,3-diphenyl-2-propenyl acetate,
and the cyclopropanation of styrene. Catalytic systems
based on these new ligands showed similar activities,
but lower enantioselectivities than those achieved using
more synthetically demanding fluorous chiral ligands
such as fluorous bis(oxazolines). Best results were ob-
tained in the copper-catalyzed cyclopropanation of sty-
rene in the presence of diamine 12 (yield = 68%, trans/
cis = 67:33, ee of the trans and cis isomers = 47%). The
application of these fluorous enantiopure compounds
in other catalytic reactions is currently under investiga-
tion in our laboratories, as well as their use as building
blocks in the synthesis of enantiomerically pure tetra-
substituted diamines and P,N-ligands.
20
1
½aŠ ¼ À18.7 (c 0.2, CH3OH); H NMR(CD OD): d
3
D
1.35–1.67 (4H, m), 1.84–1.99 (2H, m), 2.32–2.47 (2H,
m), 2.64–3.10 (4H, m), 3.36–3.47 (4H, m), 3.56–3.65
(2H, m); 13C NMR(CD 3OD): d 25.5, 29.9, 30.8 (t,
J = 21.6 Hz, RFCH2CH2), 40.7, 61.6, 106.0–121.0
(C8F17, m); 19F NMR(CD 3OD): d À125.3 (4F, m),
À122.4 (4F, m), À121.8 (4F, m), À120.9 (8F, m),
À120.7 (4F, m), À112.8 (4F, m), À80.4 (6F, À1t,
J = 10.3 Hz); IR(KBr): 2700–3000, 1100–1300 cm
.
Anal. Calcd for C26H22F34N2Cl2: C, 28.93; H, 2.05; N,
2.60. Found: C, 29.13; H, 2.15; N, 2.72.
The title compound 6 was quantitatively obtained as a
white solid by neutralization of a suspension of
6Æ(HCl)2 in Et2O with aqueous 2.5% NaOH. Mp 40.0–
20
41.5 ꢁC; ½aŠ ¼ À28.1 (c 0.2, CH3OH); 1H NMR
(CDCl3): d D0.90–1.15 (2H, m), 1.18–1.29 (2H, m),
1.68–1.81 (2H, m), 2.08–2.20 (6H, m), 2.20–2.39 (4H,
m), 2.70–2.83 (2H, m), 3.01–3.15 (2H, m); 13C NMR
(CDCl3): d 25.3, 31.9, 32.4 (t, J = 21.3 Hz, RFCH2CH2),
38.9, 62.0, 107.0–122.4 (C8F17, m); 19F NMR(CDCl 3): d
À126.6 (4F, m), À124.1 (4F, m), À123.2 (4F, m), À122.4
(8F, m), À122.2 (4F, m), À113.9 (4F, m), À81.3 (6F, t,
J = 10.3 Hz); IR(KBr): 3296.9, 1100–1300 cm À1. Anal.
Calcd for C26H20F34N2: C, 31.03; H, 2.00; N, 2.78.
Found: C, 31.46; H, 1.82; N, 3.01.
4. Experimental
4.1. General
Solvents were purified by standard methods and dried if
necessary, except for perfluoro-(1,3-dimethylcyclohex-
ane) (PDMC) (Apollo Scientific Ltd., UK), which was
used as received. 1-Iodo-1H,1H,2H,2H-perfluorodecane
1, 1-iodo-1H,1H,2H,2H,3H,3H-perfluoroundecane 2,
and pentadecafluorooctanoyl chloride 7 were purchased
from Fluka and used as received. 2H,2H-Perfluorodeca-
noyl chloride 16 was prepared as described in the litera-
ture.21 2H,2H,3H,3H-Perfluoroundecanoyl chloride
10,30 and 2H,2H,3H,3H,4H,4H-perfluorododecanoyl
chloride 13,22 are known compounds. The original syn-
thetic procedures have been conveniently modified as
described below. Column chromatography was per-
formed on silica gel 60 (230–240 mesh, Merck). Melting
points (uncorrected) were determined with a capillary
4.3. (1R,2R)-1,2-Bis(perfluorooctylamido)cyclohexane 8
(1R,2R)-Diaminocyclohexane (0.23 g, 2 mmol) and
Et3N (1.15 mL, 8 mmol) were dissolved in dry THF
(10 mL) and the solution cooled to 0 ꢁC under nitrogen.
C7F15COCl 7 (1.00 mL, 4 mmol) dissolved in dry THF
(10 mL) was added dropwise over 15 min. After being
stirred for 1.5 h at 0 ꢁC, the solution was allowed to
warm up and stirred overnight at rt. Saturated aqueous
NH4Cl (10 mL) was added and the mixture was ex-
tracted three times with Et2O. The combined organic
layers were washed with H2O, brine, and dried over
Na2SO4. The solvent was removed under vacuum
affording bis-amide 8 (1.61 g, 88%) as a white solid,
which was used for the next step without further purifi-
melting point apparatus Buchi SMP-20. Optical rota-
¨
tions were recorded using a Perkin–Elmer 241 polari-
meter. The NMRspectra
(
1H: 300 MHz, 13C:
75.4 MHz, 19F: 282 MHz) were recorded on a Bruker
AC 300 MHz instrument with Me4Si, CDCl3, and
CFCl3 as the internal standard, respectively. Reactions
involving organometallic catalysis were carried out in
Schlenk tube under an inert atmosphere. Absolute con-
figurations of the enantiomers were determined by com-
cation. Analytical samples were obtained by recrystalli-
20
D
zation from hexane. Mp 143–144 ꢁC; ½aŠ ¼ þ2.5 (c 0.2,
(CH3)2CO); 1H NMR((CD 3)2CO): d 1.30–1.44 (2H, m),
1.62–1.66 (2H, m), 1.79–1.85 (2H, m), 1.99–2.04 (2H,

J. Bayardon et al. / Tetrahedron: Asymmetry 16 (2005) 2319–2327
2325
m), 3.93–4.01 (2H, m), 8,57 (2H, br s); 13C NMR
((CD3)2CO): d 25.3, 32.2, 53.7, 105.0–118.0 (m, C8F17),
203.7; 19F NMR((CD 3)2CO): d À126.4 (4F, m),
À122.9 (4F, m), À122.6 (4F, m), À122.3 (4F, m),
À121.8 (4F, m), À119.7 (4F, m), À81.3 (6F, t,
J = 10.3 Hz); IR(KBr): 3319.3, 1692.5, 1545.8, 1100–
(2.10 g, 70%) as a colorless liquid (physical data in
agreement with those reported in the literature).30
4.6. (1R,2R)-1,2-Bis(2H,2H,3H,3H-perfluoroundecanoyl-
amido)cyclohexane 11
1300 cmÀ1
.
Anal. Calcd for C22H12F30N2O2: C,
(1R,2R)-Diaminocyclohexane (0.23 g, 2 mmol) and
Et3N (1.15 mL, 8 mmol) were dissolved in dry THF
(10 mL) and the solution was cooled to 0 ꢁC under
nitrogen. C8F17CH2CH2COCl 10 (2.04 g, 4 mmol) dis-
solved in dry THF (10 mL) was added dropwise over
15 min. The mixture was stirred at 0 ꢁC for 1.5 h, then
allowed to warm up to rt and left overnight under stir-
29.15; H, 1.33; N, 3.09. Found: C, 28.78; H, 1.15; N,
3.25.
4.4. (1R,2R)-N,N0-Bis(1H,1H-perfluorooctyl)-cyclo-
hexane-1,2-diamine 9
Bis-amide 8 (1.80 g, 2 mmol) was slowly added under
nitrogen to a stirred suspension of LAH (0.70 g,
18 mmol) in dry THF (30 mL). The reaction mixture
was refluxed under nitrogen for 8 h, and then stirred
at rt for a further 18 h. The suspension was cooled to
0 ꢁC and carefully hydrolyzed with H2O (3 mL), aque-
ous 10% NaOH (3 mL) and then H2O (3 mL). The grey
slurry was stirred for 1 h and then extracted three times
with Et2O. The combined organic layers were washed
with saturated aqueous NH4Cl, dried over Na2SO4,
and evaporated to leave a residue which was purified
by flash column chromatography (silica gel, (i-Pr)2O/
ring. After filtration on a Buchner funnel, the precipitate
¨
was washed with ice-cold hexane, H2O, and dried under
vacuum affording bis-amide 11 (1.95 g, 88%) as a white
solid, insoluble in organic and fluorous solvents, which
was used for the next step without further purification.
Mp 186–192 ꢁC; IR(KBr): 3299.5, 1645.5, 1551.1,
1100–1300 cmÀ1. Anal. Calcd for C28H20F34N2O2: C,
31.65; H, 1.90; N, 2.64. Found: C, 32.19; H, 2.24; N,
2.71.
4.7. (1R,2R)-N,N0-Bis(1H,1H,2H,2H,3H,3H-perfluo-
roundecyl)-cyclohexane-1,2-diamine 12
hexane 1:4) yielding 9 (1.00 g, 57%) as a white solid.
20
D
Mp 35.5–37.5 ꢁC; ½aŠ ¼ À27.1 (c 0.2, Et2O); 1H
To a suspension of bis-amide 11 (0.85 g, 0.8 mmol) in
dry THF (8 mL) cooled at 0 ꢁC, BH3ÆTHF 1M in
THF (4.00 mL, 4 mmol) was added dropwise over
30 min. The mixture was refluxed for 2 h under stirring
and complete disappearance of the solid was observed.
The solution was cooled to rt, carefully acidified with
aqueous 10% HCl (ꢀ1 mL) and refluxed for 1 h, then
cooled to rt and treated with aqueous 10% NaOH
(ꢀ1 mL) to adjust pH to 11. The solution was diluted
with Et2O, washed with H2O, brine, and dried over
NMR(CDCl 3): d 1.00–1.04 (2H, m), 1.19–1.26 (2H,
m), 1.68–1.82 (4H, m), 2.03–2.08 (2H, m), 2.25–2.28
(2H, m), 3.17 (2H, q J = 14.9 Hz), 3.36 (2H, q,
J = 14.9 Hz); 13C NMR((CD ) CO): d 25.5, 32.0, 47.7
3 2
(t, J = 22.9 Hz, RFCH2N), 62.6; 19F NMR((CD ) CO):
3 2
d À126.4 (4F, m), À122.9 (8F, m), À122.1 (8F, m),
À117.6 (4F, m), À81.4 (6F, t, J = 10.3 Hz); IR(KBr):
3320.6, 1100–1300 cmÀ1. Anal. Calcd for C22H16F30N2:
C, 30.08; H, 1.84; N, 3.19 Found: C, 30.46; H, 1.77;
N, 3.00.
Na2SO4. The solvent was evaporated to yield 12 as a
20
D
white solid (0.77 g, 93%). Mp 44–45 ꢁC; ½aŠ ¼ À29.5
1
4.5. 2H,2H,3H,3H-Perfluoro undecanoyl chloride 10
(c 0.2, Et2O); H NMR(CDCl ): d 0.90–1.11 (2H, m),
3
1.15–1.29 (2H, m), 1.50 (2H, br s), 1.65–1.81 (6H, m),
2.05–2.26 (8H, m), 2.51 (2H, dt, J = 11.7 Hz, 6.7 Hz),
A solution of KMnO4 (1.77 g, 11.3 mmol) in H2O
(30 mL) was added dropwise to a warm solution of
1H,1H,2H,2H,3H,3H-perfluoro undecan-1-ol31 (3.57 g,
7.5 mmol) and Bu4NHSO4 (0.35 g, 0.13 mmol) in tolu-
ene (23 mL). The biphasic mixture was vigorously stir-
red for 4 h at 70 ꢁC, then cooled to rt and acidified
with aqueous 10% HCl. Saturated aqueous Na2S2O3
was added until the mixture became colorless. The aque-
ous layer was extracted three times with (i-Pr)2O. The
combined organic layers were washed with brine, dried
over Na2SO4 and evaporated to dryness. The residue
was recrystallized from CHCl3 yielding 2H,2H,3H,3H-
perfluoroundecanoic acid (3.01 g, 82%) as a white crys-
talline solid (physical data in agreement with those
reported in the literature).30
2.82 (2H, dt, J = 11.7 Hz, 6.7 Hz); 13C NMR(CDCl ):
3
d 21.7, 25.4. 29.2 (t, J = 22.1 Hz, RFCH2CH2CH2),
32.2, 46.2, 62.0, 106.0–120.0 (C8F17, m); 19F NMR
(CDCl3): d À126.7 (4F, m), À124.0 (4F, m), À123.3
(4F, m), À122.5 (8F, m), À122.3 (4F, m), À114.9 (4F,
m), À81.3 (6F, t, J = 10.3 Hz); IR(KBr): 3296.9,
1100–1300 cmÀ1. Anal. Calcd for C28H24F34N2: C,
32.51; H, 2.34; N, 2.71. Found: C, 32.51; H, 2.36; N,
2.76.
4.8. 2H,2H,3H,3H,4H,4H-Perfluorododecanoyl chloride
13
To 2H,2H,3H,3H,4H,4H-perfluorododecanoic acid
C8F17CH2CH2CH2COOH (3.04 g, 6 mmol)22 placed in
a flame dried round-bottomed flask equipped with a
condenser, SOCl2 (1.75 mL, 24 mmol) was added. The
mixture was stirred for 2 h at 100 ꢁC, the condenser
was replaced with a Vigreux distilling column and the
excess SOCl2 distilled off at 80 ꢁC, at ambient pressure.
Distillation was continued under reduced pressure to
recover acyl chloride 13 (2.12 g, 67%) as a colorless
To the acid placed in a flame dried round-bottomed
flask equipped with a condenser SOCl2 (1.75 mL,
24 mmol) was added. The mixture was stirred for 2 h
at 100 ꢁC, the condenser was replaced with a Vigreux
distilling column and the excess SOCl2 was distilled off
at 80 ꢁC, ambient pressure. Distillation was continued
under reduced pressure to recover the acyl chloride 10

2326
J. Bayardon et al. / Tetrahedron: Asymmetry 16 (2005) 2319–2327
liquid (physical data in agreement with those reported in
the literature).22
4.12. Hydrogen transfer reduction of acetophenone
The catalyst was prepared in a Schlenk tube by stirring
[Ir(COD)Cl]2 (10.3 mg, 20 lmol), or Ru (p-cymene)Cl2]2
(12.2 mg, 20 lmol) and the fluorinated diamine
(40 lmol) in degassed PDMC (5 mL) at 70 ꢁC for 3 h.
To this solution cooled to rt was added a solution of
acetophenone (48 mg, 0.4 mmol) and KOH (5.6 mg,
0.1 mmol) in i-PrOH (5 mL). The mixture was stirred
at 70 ꢁC. The conversion and enantiomeric excess were
determined by GC analysis using a capillary Quadrex
OV1 column (30 m · 0.25 mm) and a capillary Cyclo-
dex-b column (30 m · 0.25 mm), respectively.
4.9. (1R,2R)-N,N0-Bis(2H,2H,3H,3H,4H,4H-
perfluorododecanoylamido)cyclohexane 14
(1R,2R)-Diaminocyclohexane (0.23 g, 2 mmol) and
Et3N (1.15 mL, 8 mmol) were dissolved in dry THF
(15 mL) and the solution was cooled to 0 ꢁC under
nitrogen. C8F17CH2CH2CH2COCl 13 (2.10 g, 4 mmol)
dissolved in dry THF (15 mL) was added dropwise over
15 min. The mixture was stirred at 0 ꢁC for 1.5 h then
allowed to warm up to rt and left overnight under stir-
ring. After filtration on a Buchner funnel, the precipitate
¨
4.13. Alkylation of 1,3-diphenyl-2-propenyl acetate
was washed with ice-cold hexane, H2O, and dried under
vacuum affording bis-amide 14 (2.00 g, 96%) as a white
solid, insoluble in organic and fluorous solvents, which
was used for the next step without further purification.
Mp 189–192 ꢁC; IR(KBr): 3296.9, 1643.2, 1548.0,
1100–1300 cmÀ1. Anal. Calcd for C30H24F34N2O2: C,
33.04; H, 2.22; N, 2.57. Found: C, 33.27; H, 2.29; N,
2.80.
The catalyst was prepared in a Schlenk tube by stirring
[Pd(C3H5)Cl]2 (45.6 mg, 12.5 lmol) and the fluorinated
diamine (30 lmol) in degassed THF (1.5 mL) at 50 ꢁC
for 1 h. 1,3-Diphenyl-2-propenyl acetate (126 mg,
0.5 mmol) dissolved in THF (1.5 mL) was added and
the solution stirred for a further 20 min after which it
was transferred under nitrogen into another Schlenk
tube containing a solution of NaH (36 mg, 1.5 mmol)
and dimethyl malonate (198 mg, 1.5 mmol) in THF
(2 mL). The solution was stirred at the desired tempera-
ture for the time indicated in Table 3. The conversion
was determined by GC using a Quadrex OV1 column
(30 m · 0.25 mm) and the enantioselectivity by HPLC
on a chiral stationary phase (column: Chiralpak AD;
eluent hexane/i-PrOH 60:40).
4.10. (1R,2R)-N,N0-Bis(1H,1H,2H,2H,3H,3H,4H,4H-
perfluorododecyl)-cyclohexane-1,2-diamine 15
To a suspension of bis-amide 14 (0.87 g, 0.8 mmol) in
dry THF (8 mL) cooled at 0 ꢁC, BH3ÆTHF 1M in
THF (4 mL, 4 mmol) was added dropwise over
30 min. The mixture was refluxed for 2 h under stirring
and complete disappearance of the solid observed. The
solution was cooled to rt, carefully acidified with aque-
ous 10% HCl (ꢀ1 mL) and refluxed for 1 h, then cooled
to rt and treated with aqueous 10% NaOH (ꢀ1 mL) to
adjust the pH to 11. The solution was diluted with
Et2O, washed with H2O, brine, and dried over Na2SO4.
4.14. Cyclopropanation of styrene
4.14.1. Homogeneous conditions. Fluorous diamine
(25 lmol) and CuXn (12.5 lmol) were stirred together
in degassed CH2Cl2 (3 mL) for 1 h at rt. When Cu(OTf)2
was used, phenylhydrazine (1.5 lL) was also added in
order to reduce Cu(II) to Cu(I). Styrene (260 mg,
2.5 mmol.) was added to the reaction mixture which
was allowed to stir for a further 10 min. Ethyl a-di-
azoacetate (57 mg, 0.5 mmol) dissolved in CH2Cl2
(2 mL) was added dropwise over 1 h using a syringe
pump and the mixture was stirred for a further hour.
The volatiles were then evaporated under vacuum to
leave a thick oil, an aliquot of which was analyzed by
GC (HP-1 100% dimethylpolysiloxane 30 m · 320 lm ·
0.25 lm column) to determine the trans/cis ratio. The
residue was purified by flash column chromatography
(silica gel, hexane/EtOAc 95:5) to give a mixture of the
two diastereoisomers. The enantiomeric excesses of
trans- and cis-cyclopropane were determined by HPLC
analysis on a chiral stationary phase (column: Chiralcel
OJ-H; eluent: hexane/i-PrOH 99.5:0.5).
The solvent was evaporated to yield 15 as a white
20
solid (0.76 g, 90%). Mp 51.0–52.5 ꢁC; ½aŠ ¼ À27.1 (c
D
0.2, Et2O); 1H NMR(CDCl 3): d 0.92–1.11 (2H, m),
1.18–1.29 (2H, m), 1.46–1.71 (10H, m), 1.85 (2H, br
s), 1.96–2.14 (8H, m), 2.46 (2H, dt, J = 11.5 Hz,
6.9 Hz), 2.79 (2H, dt, J = 11.5 Hz, 6.9 Hz); 13C NMR
(CDCl3): d 18.4, 25.5, 30.3, 31.2 (t, J = 22.6 Hz,
RFCH2CH2CH2CH2), 32.1, 46.7, 62.1, 106.0–120.0
(C8F17, m); 19F NMR(CDCl 3): d À126.7 (4F, m),
À124.0 (4F, m), À123.3 (4F, m), À122.5 (12F, m),
À115.1 (4F, m), À81.3 (6F, t, J = 10.3 Hz); IR(KBr):
3283.2, 1100–1300 cmÀ1. Anal. Calcd for C30H28F34N2:
C, 33.91; H, 2.66; N, 2.64. Found: C, 34.57; H, 2.60;
N, 2.75.
4.11. Determination of partition coefficients P
A 10 mL vial equipped with a magnetic stirrer was
charged with the fluorous diamine (50 mg), PDMC
(2 mL) and the organic solvent (2 mL). The mixture
was thermostatted at 25 ꢁC and vigorously stirred for
4 h. A 1 mL sample was taken out of each phase, evap-
orated to dryness, and weighed on an analytical balance.
The partition coefficient P was determined as the ratio
between the weight of the fluorous phase residue and
the weight of the organic phase residue.
4.14.2. Fluorous biphasic conditions. Diamine 12
(25 lmol) and CuXn (12.5 lmol) were stirred together
in a mixture of degassed CH2Cl2 (3 mL) and degassed
PDMC (4 mL) for 1 h at rt. When Cu(OTf)2 was used,
phenylhydrazine (1.5 lL) was also added to reduce
Cu(II) to Cu(I). Styrene (260 mg, 2.5 mmol) was added
to the reaction mixture that was allowed to stir for a fur-
ther 10 min. Ethyl a-diazoacetate (57 mg, 0.5 mmol) dis-

J. Bayardon et al. / Tetrahedron: Asymmetry 16 (2005) 2319–2327
2327
Maillet, C.; Praveen, T.; Janvier, P.; Minguet, S.; Evain,
M.; Saluzzo, C.; Tommasino, M. L.; Bujoli, B. J. Org.
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was allowed to stir for a further hour, then the CH2Cl2
layer removed and the fluorous phase extracted with
CH2Cl2 (2 mL). The combined organic layers were evap-
orated under vacuum to leave the crude products, which
were separated and analyzed as described above.
´
Chemistry; Gladysz, J. A., Curran, D., Horvath, I. T.,
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Acknowledgements
´
Chemistry; Gladysz, J. A., Curran, D., Horvath, I. T.,
The support of the COST Action D29 ꢀNew Fluorous
Media and Processes for Cleaner and Safer Chemistryꢁ
is gratefully acknowledged. L.M. and O.H. thank
ISTM-CNRfor a studentship. J.B. thanks the French
Ministry of Education for a fellowship.
Eds.; Wiley-VCH: Weinheim, 2004, pp 316–322; (d)
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