New heterogenized C2-symmetric bis(sulfonamide)-cyclohexane-1,2-diamine-RhIIICp* complexes and their application in the asymmetric transfer hydrogenation (ATH) of ketones in water

Article abstract of DOI:10.1016/j.tetlet.2009.02.183

C₂-symmetric bis(sulfonamide) ligands derived from chiral trans-(1R,2R)-cyclohexane-1,2-diamine were immobilized on silica gel and on polystyrene resin, and complexed to Rh^IIICp*. The resulting complexes were used as catalysts in the

Full text of DOI:10.1016/j.tetlet.2009.02.183

Tetrahedron Letters 50 (2009) 2228–2231
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New heterogenized C2-symmetric bis(sulfonamide)-cyclohexane-
1,2-diamine-RhIIICp* complexes and their application in the asymmetric
transfer hydrogenation (ATH) of ketones in water
*
Norma A. Cortez, Gerardo Aguirre, Miguel Parra-Hake, Ratnasamy Somanathan
Centro de Graduados e Investigación, Instituto Tecnológico de Tijuana, Apartado Postal 1166, Tijuana, B.C. 22510, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
C2-symmetric bis(sulfonamide) ligands derived from chiral trans-(1R,2R)-cyclohexane-1,2-diamine were
immobilized on silica gel and on polystyrene resin, and complexed to RhIIICp*. The resulting complexes
were used as catalysts in the asymmetric transfer hydrogenation (ATH) of acetophenone. The chiral sec-
ondary alcohol was obtained in high yields (>99%) and enantioselectivities (92%) with aqueous sodium
formate as the hydride source. The immobilized catalysts were recycled with no loss in activity.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 12 February 2009
Accepted 23 February 2009
Available online 27 February 2009
Keywords:
Asymmetric transfer hydrogenation
Sulfonamide ligands
Rh(III) complex
Heterogenized ligands
Asymmetric reduction of ketones to chiral secondary alcohols is
an important chemical transformation providing chiral intermedi-
ates for the chemical manufacture of pharmaceuticals, animal
health products, agrochemicals, fungicides, pheromones, flavors,
and fragrances.1–3 Reduction using molecular hydrogen or asym-
metric transfer hydrogenation (ATH) using isopropanol/KOH,
HCOOH/Et3N has received much attention in recent years. The for-
mer requires molecular hydrogen under pressure leading to clean
products and has found a niche in the fine chemicals manufactur-
ing industry;4 the latter (ATH), although involves a simple method-
ology, has been lagging behind due to lower TON, TOF, and the use
of environmentally unfriendly solvents (Eq. (1)).5–8 However, a
number of recent reports have appeared which may reverse this,
specially with the use of water-soluble ligands and heterogenized
ligands in conjunction with Ru(II), Rh(III), and Ir(III) complexes as
catalysts in aqueous sodium formate as the hydride source.9
Related to this we have reported the synthesis of C2-sym-
metric bis(sulfonamide) ligand 1 and its use in the ATH of
aromatic ketones, complexed to RhIIICp* in the presence of
aqueous sodium formate as hydride source, giving the sec-
ondary alcohols in excellent enantioselectivities (>90%) and
yields (>99%).9a
In this Letter, we report the immobilization of C2-symmetric
bis(sulfonamides) 1 and new ligand 2 on solid supports and
their application as catalysts with Rh(III) in the ATH of aromatic
ketones. Immobilized catalysts have been of great interest due
to several advantages, such as simplification of product work-
up, separation, isolation, and reuse of the catalyst.10 However,
their use in organic synthesis has been rather limited because
in many cases, immobilized catalysts are less active than the
corresponding original homogeneous catalysts.10 More impor-
tantly, recent interest in environmentally benign chemical pro-
cesses reducing waste and high-throughput organic synthesis
has triggered renewed interest in the chemistry of immobiliza-
tion of homogeneous catalysts.
OH
H
R
isopropanol/KOH
R
O
HCOOH/NEt3
R1
R1
or aq NaOOCH
ð1Þ
Cl Ru
H2N
Cl Ru
H2N
Rh
H2N
N SO2Ar
O2S
NH
SO2
HN
Cl
N
Ts
O
O2S
NH
SO2
HN
Me
Ph
NH2
H2N
NH2
H2N
* Corresponding author.
E-mail address: somanatha@sundown.sdsu.edu (R. Somanathan).
1
2
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.183

N. A. Cortez et al. / Tetrahedron Letters 50 (2009) 2228–2231
2229
Results show that the catalytic activity (ee and yield) of heter-
ogeneous ligand 4–Rh(III) complex was comparable to that of
homogeneous ligand 1–Rh(III) complex, except for the total run
time and TOF. The immobilized catalyst was recycled three times
with no change in activity.
Commercially available (Sigma Aldrich) functionalized silica
gels 3a–d were stirred with ligand 1 or 2 (3 equiv) in dichloro-
methane using triethylamine as base at room temperature (Eq.
(2)) to give immobilized ligands 4a–d or 5a–d (Fig. 1).
+
R
Ligand 1 or 2
Immobilized Ligands 4a-d or 5a-d
CH2Cl2
Et3N
3a-d
a, R=
ð2Þ
d, R=
c, R=
b, R=
NCO
Cl
SO2Cl
Cl
Initially, in order to compare the catalytic activity of homoge-
neous systems versus that of heterogeneous systems, the immobi-
lized chiral ligand 4d was complexed in situ with [RhCl2(Cp*)]2 and
reacted with acetophenone in water at 40 °C for 1 h. The chiral
alcohol was obtained in >99% conversion and 91% enantioselectiv-
ity (Table 1, entry 2). The ligand 4d–Rh(III) complex also efficiently
reduced functionalized ketones (Table 1, entries 4 and 6) to alcohol
in >99% conversion and 89–99% enantioselectivities.
Attempting to improve the performance of the heterogenized-
metal complex 4d, we explored the possibility of moving the
catalytically active center away from solid surface with a spacer or
linker, hoping it will enhance the activity. To test this, applying this
technique to our ligand, we synthesized ligand
2
from
4,40-bis(biphenylsulfonyl) chloride and trans-(1R,2R)-cyclohexane-
1,2-diamine, and immobilized it using silica gel 3d to give ligand
Table 1
Catalytic activity of homogeneous systems versus that of heterogeneous systems
L*=
O2S
NH
SO2
HN
O
OH
H
[RhCl2(Cp*)]2
,L*
NH
SO2
H2N
4d
HCOONa, H2O, 40°C
Entry
Ketone
Ligand
Run
t (h)
eea,b (%)
Yield (%)
Conf. abs.c
1
2
1d
4d
1
3
0.25
16
92
91
>99
>99
R
R
O
3
4
1
4d
1
3
0.25
12
90
89
98
>99
R
R
O
Br
5
6
1
4d
1
3
6
12
90e
92
100
>99
S
S
O
Cl
a
The substrate to metal ratio (S/C) was 100:1 and all reactions were carried out at 40 °C.
TM
b
c
Measured by GC analysis of the acetylated alcohol with chiral capillary column b-DEX 120.
Absolute configurations were assigned by comparing optical rotations with literature values.9d,f
Homogeneous reactions, carried out at 25 °C.
d
e
The substrate to metal ratio (S/C) was 3000:1.

2230
N. A. Cortez et al. / Tetrahedron Letters 50 (2009) 2228–2231
5d, where the active center is moved away from any silica surface
interaction. Results indicate that moving the active center by a
linker did not produce any dramatic difference in the
enantioselectivity and yield (Table 2, entries 9 and 10). However,
the ligand–5d-catalyst was recycled seven times with no change
in activity.
Having demonstrated that the catalytic activity of heteroge-
nized ligand–metal complexes is comparable to that of the homo-
geneous ligand–metal complexes, we turned to explore other
derivatized silica gels as sources of solid support. Derivatized silica
gels with benzyl chloride 3a, propyl chloride 3b and isocyantes 3c
were coupled to the ligands 1 and 2 using standard procedures to
give heterogenized ligands 4a–c and 5a–c. The application of these
immobilized ligand–Rh(III) complexes in the reduction of aceto-
phenone under ATH conditions was studied. Results are shown in
Table 2. The results clearly indicate that the ligands immobilized
O2S
NH
SO2
HN
O2S
NH
SO2
HN
NH
R
H2N
NH
R
H2N
5a-d
4a-d
a, R=
b, R=
d, R=
O
c, R=
N
SO2
H
Figure 1. Supported ligands derived from ligands 1 and 2.
Table 2
Heterogeneous asymmetric transfer hydrogenation of acetophenone in aqueous sodium formate
O2S
NH
SO2
HN
O2S
SO2
HN
L*=
NH
O
OH
H
NH
R
H2N
NH
R
H2N
4a-d
[RhCl2(Cp*)]2
,L*
5a-d
HCOONa, H2O, 40°C
Entry
Ligand
t (h)
0.25
0.3
16
16
16
16
16
16
16
16
Run
eea,b (%)
Yield (%)
Conf. abs.c
1
2
3
4
5
6
7
8
9
1d
1
1
1
1
1
1
1
1
3
7
92
94
75
71
70
35
26
22
91
90
>99
>99
89
44
53
29
43
22
99
R
R
R
R
R
R
R
R
R
R
2d
4a
5a
4b
5b
4c
5c
4d
5d
10
>99
a
The substrate to metal ratio was 100:1 and all reactions were carried out at 40 °C.
TM
b
c
Measured by GC analysis of the acetylated alcohol with chiral capillary column b-DEX 120.
Absolute configurations were assigned by comparing optical rotations with literature values.9d,f
Homogeneous reactions, carried out at 25 °C.
d
HO
O
NH2
(Boc2)O
0°C
SO2Cl
O
O
O2
S
O2
S
NH NHBoc
NH NHBoc
H2N
NH2
H2N
NHBoc
CH2Cl2
Et3N
HO
HN
DIC, DMAP
CH2Cl2
(1R,2R)
TFA 95%
= PS-DVB 1%
1.22 mmol/g
O
O2
S
NH NH2
HN
6
Scheme 1. Synthesis of the immobilized ligand 6.

N. A. Cortez et al. / Tetrahedron Letters 50 (2009) 2228–2231
2231
Wiley-VCH: Weinheim, Germany, 2004; (b)Chirality in Industry: The
Commercial Manufacture and Applications of Optically Active Compounds;
via benzenesulfonyl chloride bound to silica gel give the best re-
sults (entries 9 and 10). Binding through isocyanate led to lower
enantioselectivities and yields, probably due to the urea fuctional
group inhibiting the diamine–metal binding.
Collins, A. N., Sheldrake, G. N., Crosby, J., Eds.; John Wiley
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Once our ligands were successfully immobilized on silica gel,
we turned our attention to immobilization on polystyrene, since
catalysts show improved stability in polymer matrix. Ligand 1
was immobilized on commercially available polystyrene sulfonyl
chloride (PS–DVB 8.5%, mesh 70–90, loading 2.5–3.0 mmol/g) and
was complexed to RhIIICp* and used as a catalyst in the reduction
of acetophenone under ATH conditions (aqueous sodium formate
as hydride source) to give the alcohol in 17% ee and 24% conver-
sion. However, when the chiral (1R,2R)-diamine was tethered to
aminomethylated polystyrene (1.22 mmol gꢀ1, DVB 1%) through a
linker, ligand 6 (Scheme 1), the chiral secondary alcohol was ob-
tained in 90% enantioselectivity and >99% conversion. The catalyst
was recycled four times with a slight drop in the activity, indicat-
ing the amount of cross linking is critical in obtaining a good poly-
styrene tethered ligand.
In conclusion we have immobilized C2-symmetric ligand–Rh(III)
complexes to silica gel and polystyrene and showed that they are
excellent catalysts in reducing aromatic ketones to chiral alcohols
in good enantioselectivities and yields, using aqueous sodium for-
mate as hydride source. The catalysts were recycled several times
with only a slight loss in activity, showing potential practical
application.
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We gratefully acknowledge Consejo Nacional de Ciencia y Tec-
nología (CONACyT Grant 60475) and Dirección General de Educa-
ción Superior Tecnológica (DGEST Grant 944.08-P) for the
support given to this project , and CONACyT for graduate scholar-
ship for N.A. Cortez.
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Supplementary data
Supplementary data (Experimental procedures and spectro-
scopic and analytical data of compounds) associated with this Let-
ter can be found, in the online version, at doi:10.1016/
j.tetlet.2009.02.183.
References and notes
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