Synthesis, characterization and use of a new tethered Rh(III) complex in asymmetric transfer hydrogenation of ketones

Article abstract of DOI:10.1016/j.catcom.2015.01.012

A new Rh(III) complex containing the TsDPEN ligand and an η⁶-arene connected through a carbon tether is reported. The asymmetric transfer hydrogenation of a series of ketones catalyzed by this complex using the formic acid/triethylamine system provided the corresponding alcohols with complete conversions and a high level of enantioselectivity.

Full text of DOI:10.1016/j.catcom.2015.01.012

Synthesis, characterization and use of a new tethered Rh(III) complex in
asymmetric transfer hydrogenation of ketones
Pierre-Georges Echeverria, Charle`ne Fe´rard, Phannarath Phansavath,
Virginie Ratovelomanana-Vidal
PII:
DOI:
Reference:
S1566-7367(15)00020-5
doi: 10.1016/j.catcom.2015.01.012
CATCOM 4194
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
22 December 2014
9 January 2015
10 January 2015
Please cite this article as: Pierre-Georges Echeverria, Charl`ene F´erard, Phannarath
Phansavath, Virginie Ratovelomanana-Vidal, Synthesis, characterization and use of a
new tethered Rh(III) complex in asymmetric transfer hydrogenation of ketones, Cataly-
sis Communications (2015), doi: 10.1016/j.catcom.2015.01.012
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ACCEPTED MANUSCRIPT
Synthesis, characterization and use of a new tethered Rh(III) complex in
asymmetric transfer hydrogenation of ketones
Pierre-Georges Echeverria, Charlène Férard, Phannarath Phansavath,* Virginie Ratovelomanana-
Vidal*
PSL Research University, Chimie ParisTech-CNRS, Institut de Recherche de Chimie Paris, 75005 Paris, France
Corresponding authors. Tel. +33(1)44276743. E-mail addresses: phannarath.phansavath@chimie-paristech.fr, virginie-
vidal@chimie-paristech.fr.
Abstract
A new Rh(III) complex containing the TsDPEN ligand and an 6-arene connected through a carbon
tether is reported. The asymmetric transfer hydrogenation of a series of ketones catalyzed by this
complex using the formic acid/triethylamine system provided the corresponding alcohols with
complete conversions and a high level of enantioselectivity.
Keywords: Rhodium, Asymmetric catalysis, Transfer hydrogenation, Ketone, Enantioselectivity,
Reduction
1. Introduction
The preparation of enantiomerically pure secondary alcohols is the subject of considerable interest
owing to their use as intermediates in the pharmaceutical industry and for the manufacture of
advanced materials. A particularly useful method to access these compounds involves the direct
reduction of prochiral ketones through asymmetric transfer hydrogenation (ATH).1-8 Most of the work
carried out in this area has used ruthenium(II) catalysts in combination with the N-(p-toluenesulfonyl)-
1,2-diphenylethylendiamine (TsDPEN) ligand following the initial report by Noyori of complex 1 (Fig.
1) which showed excellent catalytic performances in the ATH of aromatic ketones using either
isopropanol or formate salts as the hydrogen donor.9-12 The related Rh(III)-TsDPEN (2) and Ir(III)-
TsDPEN (3) catalysts have also been successfully employed for the ATH of ketones and imines.13-22 In
order to achieve more efficient catalytic activity, extensive efforts have been displayed toward the
synthesis of modified Ru(II) complexes and in this context Will’s tethered catalyst 4 is of particular
interest because it showed a greater stability than the original catalysts and a higher efficiency in the
ATH.23-24 Furthermore, the same group has developed Rh-tethered versions where complexes 5,25
6
and 726-27 were used effectively in the asymmetric reduction of imines and of complex functionalized
ketones. As part of our ongoing studies toward the development of efficient catalysts for the
asymmetric reduction of unsaturated compounds,28-31 we were interested in the preparation of the
rhodium(III)-TsDPEN complex 8, which is an analogue of 5 bearing a methoxy group on the tethering
phenyl ring. We report herein the synthesis of complex 8 and its use in the asymmetric transfer
hydrogenation of a series of ketones.
Fig. 1. Ru, Rh and Ir-TsDPEN-based ATH precatalysts.

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2.
Results and discussion
The synthesis of complex (R,R)8 followed the route established by Wills and co-workers for the
preparation of the parent Rh complex 5 (Scheme 1).25 Thus, after protection of commercially available
2-bromo-5-methoxybenzaldehyde 9 as its 1,3 dioxolane 10, halogen/metal exchange in the presence of
nbutyllithium and addition of 2,3,4,5-tetramethylcyclopent-2-enone afforded the corresponding
alcohol 11. Treatment of the latter with 3% hydrochloric acid allowed concomittant deprotection of
the aldehyde and dehydration of the tertiary alcohol delivering 12 in 65% yield.
Scheme 1. Synthesis of complex (R,R)8.
Subsequent reductive amination of 12 using (R,R)-TsDPEN furnished 13 which upon treatment with
RhCl3 in refluxing methanol led after flash chromatography to (R,R)8 as an orange solid and as a
single diastereomer, the structure of which was confirmed by an X-ray crystallographic analysis
(Figure 2).
Fig. 2. X-ray crystallographic structure of (R,R)8.
We then investigated the catalytic activity of this new complex in the ATH of acetophenone 14 using
various hydrogen donor systems (Table 1). The reduction of acetophenone with 0.5 mol% of (R,R)8
in an HCOOH/NEt3 (5:2) azeotropic mixture proceeded at room temperature with full conversion after
5 h of reaction time delivering the corresponding alcohol 15 with an enantiomeric excess of 98%
(entry 1). Variation of the azeotropic mixture ratio from (5:2) to (1:1) had no effect on the course of
the reaction (entry 2). A lower catalytic activity was observed with NaH2PO2.H2O in THF since the
conversion decreased dramatically to 7% even after a prolonged reaction time (entry 3) whereas using
the iPrOH/tBuOK system as the hydrogen source resulted in the formation of degradation products
(entry 4). Finally, using HCO2NH4 in dichloromethane afforded a moderate conversion of 53% (entry
5).

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Table 1
Optimization of the reaction conditions for the ATH of
acetophenone with (R,R)-8
Entry Hydrogen donor
Solvent
t
conv ee
(h) (%)a (%)b
1
2
3
4
5
HCO2H/Et3N (5:2)
HCO2H/Et3N (1:1)
NaH2PO2.H2O
iPrOH/tBuOK
HCO2NH4
5
5
29
29
100
100
7
98
99


98


THF


CH2Cl2 29 53
a Determined by 1H NMR of the crude product.
b Determined by HPLC analysis.
The ATH of acetophenone with (R,R)-8 in formic acid/triethylamine (5:2) using the previously defined
optimal conditions was followed by 1H NMR spectroscopy (400 MHz) at 25 °C and the reaction/time
profile is reported in Fig. 3. Full conversion was attained after 5 h of reaction time, demonstrating a
higher catalytic activity of complex (R,R)-8 over the parent compound (R,R)-5 which required 10 h to
reach full conversion.25
Fig. 3. Reaction/time profile for ATH of acetophenone
by (R,R)8 followed by 1H NMR (400 MHz).
In order to study the scope of the ATH catalyzed by the Rh complex (R,R)-8 using the formic
acid/triethylamine system, a range of variously functionalized ketones were subjected to the reduction
conditions. The corresponding alcohols 16-27 were obtained with complete conversions in 2-27 h with
high ee values up to 99% (Table 2). The reduction of para-substituted acetophenones possessing either
methyl, bromo or benzyloxy substituents proceeded with uniformly high yields and enantiomeric
excesses (96-99% ee, entries 1-3). Noteworthy, short reaction times (7 h and 3 h) were observed for
the synthesis of alcohols (R)-16 and (R)-17. 3,5-Dimethoxyacetophenone was reduced to (R)-19 with a
high level of enantiofacial discrimination (96% ee, entry 4). Furthermore, 2’-bromoacetophenone was
converted into (R)-20 in excellent 98% yield with 70% ee (entry 5). The asymmetric reduction of 1-
acetonaphtone proceeded with 94% yield after a reaction time of 27 h delivering (R)-21 in 82% ee
(entry 6) whereas ATH of -chloroacetophenone and tetralone afforded the corresponding alcohols
with excellent enantioselectivities (99% ee, entries 7 and 8). Pleasingly, complex (R,R)-8 was also
efficient for heteroaromatic compounds as well as for alkyl-substituted ketones since (R)-24 and (R)-
25 were obtained respectively in 94% and 95% ee (entries 9 and 10). Furthermore, a 1,4-
diaryldiketone such as 1,4-diphenyl-1,4-butanedione was successfully submitted to the ATH to afford
the corresponding diol (R,R)-26 with an excellent 96:4 dl/meso ratio and >99% ee (entry 11). An
access to enantiomerically pure 1,4-diphenyl-1,4-butanediol is of interest since this compound is a
precursor of (2R,5R)-diphenylpyrrolidine which has been efficiently used for asymmetric

ACCEPTED MANUSCRIPT
organocatalysis.32 Finally, the ATH associated to a dynamic kinetic resolution process has been
performed on an -amido -keto ester derivative delivering the corresponding 1,2-aminoalcohol
(2R,3S)-27 with 97% yield and good diastereoselectivity (dr = 82:18) in favor of the syn isomer, with
>99% enantiomeric excess (entry 12).
Table 2
Asymmetric transfer hydrogenation of ketones catalyzed by Rh catalyst (R,R)-8.a
Entry Reduction
productb
T (h) yield ee
Entry Reduction
productb
T (h) yield ee
(%)c
(%)d
(%)c
(%)d
1
7
98
98
7
1.5
99
99f
(R)-22
(R)-16
2
3
99
97
90
96
8
7
92
99
68
>99
(R)-23
(R)-17
3e
23
2
99
96
9
4.5
7
94
(R)-24
(R)-18
4
10
95g
(R)-25
(R)-19
5
27
27
98
94
70
82
11e
27
7
96
97
dl/meso:96/4
ee > 99
(R)-20
(R,R)-26
6
12e
dr:82/18
ee > 99 (syn)
(2R,3S)-27
(R)-21
a Reactions performed on a 0.8 mmol scale. Conversions were determined by 1H NMR of the crude product.
b Absolute configuration assigned by comparing optical rotation with literature data or on the basis of the general observed trend of
enantioselectivity.
c Isolated yields after filtration through a pad of silica gel.
d Determined by HPLC or SFC analysis.
e Dichloromethane was used as a cosolvent to allow solubilisation of the reaction mixture.
f Ethyl acetate was used as a cosolvent.
g Determined by HPLC on the related benzoyl ester.
3. Experimental
3.1.
Synthesis and characterization of (R,R)8
2.1.1. Synthesis of 2-(2-bromo-5-methoxyphenyl)-1,3-dioxolane 10
A mixture of 9 (5.0 g, 23.2 mmol), ethylene glycol (3.1 mL, 56.6 mmol) and p-toluenesulfonic acid
(56 mg, 0.32 mmol) in toluene (40 mL) was refluxed under a Dean-Stark water separator for 24 h. The

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cooled mixture was washed with H2O and brine. The organic layer was dried over MgSO4 and
concentrated. Purification of the residue by flash chromatography (SiO2, petroleum ether/EtOAc:
95/5) afforded 10 (6.01 g, quant.). 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J = 8.8 Hz, 1H), 7.15 (d, J =
13
3.1 Hz, 1H), 6.78 (dd, J = 8.8, 3.1 Hz, 1H), 6.04 (s, 1H), 4.18–4.03 (m, 4H), 3.79 (s, 3H). C NMR
(75 MHz, CDCl3) δ 158.9, 137.3, 133.6, 116.6, 113.1, 112.9, 102.4, 65.4, 55.5.
2.1.2. Synthesis of 5-methoxy-2-(2,3,4,5-tetramethylcyclopenta-1,3-dien-1-yl)benzaldehyde 12
To a solution of 10 (6.0 g, 23.2 mmol) in Et2O (42 mL) was added dropwise nBuLi (9.7 mL, 2.5 M in
hexane, 24.4 mmol) at −90 °C. After 1 h at this remperature, 2,3,4,5-tetramethylcyclopentenone (3.7
mL, 24.4 mmol) was added dropwise and the reaction was allowed to warm to rt and stirred for 3 h.
Toluene and water (30 mL/30 mL) were added and the aqueous layer was extracted with toluene. The
combined organic layers were washed with brine, dried over MgSO4 and concentrated to afford crude
11 upon which were added THF (140 mL), acetone (18 mL) and 3% aqueous HCl solution (60 mL).
The mixture was stirred overnight at rt and toluene was added. The organic layer was washed with
H2O then brine, dried over MgSO4 and concentrated. The crude residue was purified by flash
chromatography (SiO2, petroleum ether/EtOAc: 98/2) to give 12 (3.89 g, 65%) as a bright yellow oil.
1H NMR (300 MHz, CDCl3) δ 9.81 (br s, 1H), 7.44 (dd, J = 2.3, 0.8 Hz, 1H), 7.15–7.14 (m, 2H), 3.88
(s, 1H), 3.87 (s, 3H), 1.92 (s, 3H), 1.85 (t, J = 1.4 Hz, 3H), 1.71 (d, J = 1.8 Hz, 3H), 0.93 (d, J = 7.7
13
Hz, 3H). C NMR (75 MHz, CDCl3) δ 192.9, 158.3, 141.8, 138.2, 135.3, 134.5, 132.0, 121.8, 109.0,
55.5 (2C), 14.2, 12.3, 11.9, 11.0.
2.1.3. Synthesis of complex (R,R)8
To a solution of compound 12 (538 mg, 2.1 mmol) in dry MeOH (24 mL) was added (R,R)-TsDPEN
(900 mg, 2.5 mmol) followed by the addition of 700 mg of molecular sieves (4 Å) and 2 drops of
glacial acetic acid. The mixture was stirred at rt for 5 h then sodium cyanoborohydride (170 mg, 2.7
mmol) was added and the reaction was stirred overnight at rt. After removal of the molecular sieves
and evaporation of MeOH, the residue was redissolved in EtOAc (40 mL). The organic layer was
washed with saturated NaHCO3 then brine, dried over MgSO4 and concentrated. Purification of the
residue by flash chromatography (SiO2, pentane/EtOAc: 9/1 to 8/2) afforded 13 (786 mg, 60%) as a
white solid. To a solution of 13 (740 mg, 1.22 mmol) in MeOH (28 mL) was added rhodium(III)
chloride hydrate (255 mg, 1.22 mmol) and the reaction mixture was heated under reflux for 23 h.
Triethylamine (0.34 mL, 2.44 mmol) was then added, the mixture was refluxed for a further 20 h and
concentrated. The residue was triturated with water and the solid was filtered, washed with water and
dried under vacuum. Purification of the black solid by flash chromatography (SiO2,
EtOAc/cyclohexane: 1/1 to EtOAc/MeOH: 95/5) afforded (R,R)8 (455 mg, 50%) as an orange solid.
mp > 260 °C (decomposition). Rf 0.51 (CH2Cl2/MeOH:9/1, UV, KMnO4). [α]D −154.4 (c 0.12, CHCl3).
IR (neat) : 2360, 2339, 1608, 1513, 1489, 1455, 1397, 1372, 1277, 1239, 1131, 1098, 1086, 1040,
1023, 940, 895, 812, 796, 766, 700, 682, 661, 646, 635, 622, 606 cm–1. 1H NMR (400 MHz, CDCl3) δ
7.37 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.6 Hz, 2H), 7.19–7.16 (m, 3H), 7.02 (dd, J = 8.4, 2.5 Hz, 1H),
6.73 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 7.3 Hz, 2H), 6.59 (t, J = 7.8 Hz, 2H), 6.48 (d, J = 7.4 Hz, 2H),
6.42 (d, J = 2.4 Hz, 1H), 4.98 (d, J = 12.4 Hz, 1H), 4.32 (d, J = 11.0 Hz, 1H), 4.22 (dd, J = 14.0, 2.9
Hz, 1H), 3.73 (s, 3H), 3.60 (d, J = 14.0 Hz, 1H), 3.26 (t, J = 12.4 Hz, 1H), 2.17 (s, 3H), 2.09 (s, 3H),
1.97 (s, 3H), 1.83 (s, 3H), 1.54 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 160.2, 142.3, 139.0, 138.6,
137.5, 135.7, 131.2, 128.8, 128.7, 127.9, 127.7, 127.1, 126.2, 118.6, 117.0, 115.0, 106.4 (d, JRh-C = 6.6
Hz), 99.2 (d, JRh-C = 6.6 Hz), 97.0 (d, JRh-C = 8.8 Hz), 88.7 (d, JRh-C = 9.5 Hz), 80.6 (d, JRh-C = 8.0 Hz),
75.9, 69.8, 55.5, 52.5, 21.3, 10.8, 10.7, 10.4, 8.3. HRMS (ESI): m/z [M – Cl]+ calcd for
C38H40N2O3RhS: 707.1809, found : 707.1813.
3.2.
General procedure for asymmetric transfer hydrogenation
To a round bottomed tube containing (R,R)8 (3.0 mg, 0.5 mol%) was added at rt an HCOOH/NEt3
(5/2) azeotropic mixture (430 L, 7.2 mmol) followed by 3 vacuum/argon cycles. The orange mixture
was stirred for 15 min before the ketone (0.8 mmol) was added (CH2Cl2 was added to improve the
solubility whenever needed). The reaction mixture was stirred at rt until consumption of the starting

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material was observed by TLC. The reaction was filtered through a pad of silica gel using
pentane/EtOAc (8/2). The filtrate was concentrated under vacuum to give the reduced product.
Conversion was determined by TLC and enantiomeric excess by SFC (Chiralcel OD-H and Chiralpak
AD-H, AS-H, IA, IC or ID) or HPLC (Chiralpak IB column) analysis.
4.
Conclusions
In conclusion, we have reported the synthesis and characterization of a novel tethered rhodium-arene
complex (R,R)-8 containing TsDPEN which exhibits excellent catalytic performance in terms of
reactivity and selectivity for the asymmetric transfer hydrogenation of ketones. Thus, the reduction of
a series of variously functionalized ketones using formic acid/triethylamine afforded the
corresponding secondary alcohols with a high level of enantioselectivity demonstrating the efficiency
of this pre-catalyst. Furthermore, we have shown that the ATH of 1,4-diphenyl-1,4-butanedione
catalyzed by the Rh(III) complex (R,R)-8 allowed an access to enantiomerically pure 1,4-diphenyl-1,4-
butanediol, a valuable intermediate in the preparation of the (2R,5R)-diphenylpyrrolidine
organocatalyst.
Acknowledgments
We thank the Agence Nationale de la Recherche for financial support (ANR STIMAS, 2011-2014,
P.G.E.)
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Graphical abstract:
(R,R)-8:
(R,R)-8, HCO2H/Et3N (5:2), rt
O
HO
H
Rh
N
R1 R2
R1 R2
[S] = 1.9 M, S/C = 200
100% conversion
Cl
MeO
TsN
H
13 examples
up to >99% ee
Ph
Ph

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Highlights



A new tethered Rh(III) complex containing the TsDPEN ligand was synthesized.
This complex proved efficient for asymmetric transfer hydrogenation of ketones.
High level of enantio- and diastereoselectivities were obtained for this reaction.