Iridium-catalyzed enantioselective hydrogenation of α,β- unsaturated carboxylic acids

Article abstract of DOI:10.1021/ja802399v

A highly efficient iridium-catalyzed hydrogenation of α,β-unsaturated carboxylic acids has been developed by using chiral spiro-phosphino-oxazoline ligands, affording α-substituted chiral carboxylic acids in exceptionally high enantioselectivities and reactivities. Copyright

Full text of DOI:10.1021/ja802399v

Published on Web 06/12/2008
Iridium-Catalyzed Enantioselective Hydrogenation of r,ꢀ-Unsaturated
Carboxylic Acids
Shen Li, Shou-Fei Zhu, Can-Ming Zhang, Song Song, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai UniVersity, Tianjin 300071, China
Received April 2, 2008; E-mail: qlzhou@nankai.edu.cn
Scheme 1
Transition-metal-catalyzed asymmetric hydrogenation of prochiral
double bonds represents one of the most efficient and atom-
economic methods for preparing chiral compounds and has drawn
increasing attention in both academic research and industrial
production.1 In this research field, the search for new catalysts with
high activity and enantioselectivity is the key issue and also an
enduring challenge. Catalytic enantioselective hydrogenation of R,ꢀ-
unsaturated carboxylic acids is a straightforward method for the
synthesis of chiral carboxylic acids, which are important intermedi-
ates for the construction of biologically active compounds.2 In the
past decades, various Ru catalysts with chiral diphosphine ligands3
and Rh catalysts with chiral phosphorus or nitrogen-containing
ligands4 have been developed for the hydrogenation of different
R,ꢀ-unsaturated carboxylic acids in high enantioselectivities. How-
ever, the efficiency of the Ru and Rh catalysts is highly substrate-
dependent. For most reported catalysts, a high catalyst loading,
drastic reaction conditions, or long reaction time are needed for
achieving satisfactory results. Thus, more efficient chiral catalysts
are highly desirable in this useful reaction.
The chiral Ir catalysts, which are very efficient in the hydrogena-
tions of unfunctionalized olefins, imines, and heteroaromatic
compounds,5 have long been neglected in the hydrogenation of
unsaturated carboxylic acids. To the best of our knowledge, only
one example of Ir-catalyzed asymmetric hydrogenation of unsatur-
ated carboxylic acids has been reported so far. By using Pfaltz’s
Ir-PHOX catalyst, Scrivanti and co-workers6 achieved the asym-
metric hydrogenation of 2-phenethylacrylic acid. However, the high
catalyst loading (4.0 mol %) and moderate enantioselectivity (<81%
ee) showed that this Ir catalyst competes poorly against Ru catalysts.
Recently, we developed a novel class of chiral spiro iridium/
phosphine-oxazoline complexes (Ir-SIPHOX, Scheme 1, 1a-c),
which proved to be efficient catalysts for the asymmetric hydro-
genation of N-arylketimines under ambient pressure.7 The high
stability, ease of handling, and ready tunability of the Ir-SIPHOX
catalysts prompted us to extend the scope of their reactions. Herein,
we report the application of Ir-SIPHOX catalysts in asymmetric
hydrogenation of R,ꢀ-unsaturated carboxylic acids to produce
R-substituted chiral carboxylic acids in exceptionally high enanti-
oselectivity (up to 99.4% ee) and reactivity (TON up to 10 000).
The R-methylcinnamic acid (2a) was chosen as a model substrate
to estimate the catalytic activity of catalysts 1. The hydrogenation
reaction was performed with 0.25 mol % of catalyst (S/C ) 400)
in MeOH under 6 atm of H2 at room temperature for 24 h. With
catalyst (Sa,S)-1a, the hydrogenation product R-methylhydrocin-
namic acid (3a) was obtained in 82% ee, but with only 15%
conversion (Table 1, entry 1). Notably, the reaction can not occur
with catalyst (Ra,S)-1a, demonstrating that the chiralities on the
spirobiindane backbone and oxazoline ring in this catalyst are
mismatched (entry 2). The catalysts (Sa,S)-1b and (Sa,S)-1c gave
almost the same results as those with catalyst (Sa,S)-1a (entries 3
and 4). We then synthesized the catalysts 1d-h bearing bulky 3,5-
di-tert-butylphenyl groups on the P atom and tested them in the
Table 1. Asymmetric Hydrogenation of R-Methylcinnamic Acida
entry
catalyst
additive
time (h) conv (%)b yield (%)c ee (%)d
1
2
3
4
5
6
7
8
9
(Sa,S)-1a none
(Ra,S)-1a none
(Sa,S)-1b none
(Sa,S)-1c none
(Sa,S)-1d none
(Sa,S)-1d 0.5 equiv of NEt3
(Sa,S)-1e 0.5 equiv of NEt3
(Sa,S)-1f 0.5 equiv of NEt3
(Sa,S)-1g 0.5 equiv of NEt3
24
24
24
24
24
15
NRe
16
29
58
100
100
100
100
100
100
-
-
82
-
-
85
-
-
76
>99
>99
96
>99
>99
>99
>99
0.5
99
99
98
99
97
98
1
2
3
8
4
10 (Sa)-1h
0.5 equiv of NEt3
11f (Sa,S)-1d 0.5 equiv of NEt3
a Reaction conditions: 0.5 mmol scale, [substrate] ) 0.25 mol L-1 in
MeOH, S/C ) 400, PH ) 6 atm, room temperature. b Determined by 1H
2
NMR. c Isolated yield. d Determined by chiral HPLC analysis of the
corresponding anilide. e No reaction. f PH ) 1 atm.
2
hydrogenation of 2a. Gratifyingly, the catalyst (Sa,S)-1d remarkably
increased both conversion (58%) and enantioselectivity (99% ee)
of the reaction (entry 5).8
To improve the reaction rate and conversion, we then examined
the effect of adding NEt3, which was often used to increase both
reaction rate and enantioselectivity in asymmetric hydrogenation
reactions.9 Satisfyingly, the addition of 0.5 equiv NEt3 significantly
improved the reaction rate, giving quantitative conversion within
30 min without losing enantioselectivity (Table 1, entry 6).10 Under
the conditions with NEt3, the catalysts (Sa,S)-1e-h gave results
similar to those of (Sa,S)-1d, showing that the substituent on the
oxazoline ring of the catalyst had a negligible influence on the
conversion and enantioselectivity of the reaction, albeit a slightly
longer reaction time was needed in the reaction with catalyst (Sa,S)-
1h (entry 10). In the presence of NEt3, the catalyst (Sa,S)-1d was
even able to hydrogenate R-methylcinnamic acid under ambient
hydrogen pressure (entry 11).
A variety of R-methylcinnamic acid derivatives 2 could be
hydrogenated by catalyst (Sa,S)-1d with excellent enantioselectivities
(>96% ee) regardless of the electronic properties of the substituents
on the phenyl ring of the substrates (Table 2). The hydrogenations
were very fast and gave full conversions within 1 h with few
exceptions. This result represents the highest enantioselectivity and
9
8584 J. AM. CHEM. SOC. 2008, 130, 8584–8585
10.1021/ja802399v CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Hydrogenation of Cinnamic Acid Derivativesa
the optimal conditions, different tiglic acid derivatives were
hydrogenated to produce the corresponding saturated acids in
excellent enantioselectivities (Table 3). A higher catalyst loading
was needed when a bulky group was introduced into either the
R-position or ꢀ-position of tiglic acid.
In summary, the first highly enantioselective Ir-catalyzed hy-
drogenation of R,ꢀ-unsaturated carboxylic acids was developed by
using SIPHOX ligands. The extremely high activity, enantioselec-
tivity, broad substrate scope, and mild reaction conditions demon-
strated that the Ir-SIPHOX were excellent catalysts for the synthesis
of enantiopure carboxylic acids.
Acknowledgment. This work was supported by National
Natural Science Foundation of China (20702025, 20532010,
20721062), the Major Basic Research Development Program
(2006CB806106), and “111” Project of the Ministry of Education
of China (B06005). Dedicated to Prof. Xiyan Lu on the occasion
of his 80th birthday.
entry
Ar
R
time
yield (%)
ee (%)
TOF (h-1
)
1
2
3
4
5
6
7
8
Ph (2a)
Me 30 min
Me 40 min
Me 40 min
Me 40 min
99
97
98
98
98
99
97
97
98
97
97
97
98
96
98
97
95
99.2 (S)
99
99
99
99
98
99
96
99
98 (S)
99
98 (S)
97
99
98
800
600
600
600
686
686
686
40
800
800
800
800
400
50
2-MeC6H4 (2b)
3-MeC6H4 (2c)
4-MeC6H4 (2d)
2-OMeC6H4 (2e) Me 35 min
3-OMeC6H4 (2f) Me 35 min
4-OMeC6H4 (2g) Me 35 min
2-ClC6H4 (2h)
3-ClC6H4 (2i)
4-ClC6H4 (2j)
3-BrC6H4 (2k)
4-BrC6H4 (2l)
Me 10 h
9
Me 30 min
Me 30 min
Me 30 min
Me 30 min
10
11
12
13
14
15
16
4-CF3C6H4 (2m) Me 1 h
2-naphthyl (2n)
furan-2-yl (2o)
Ph (2p)
Me 8 h
Me 18 h
iPr 3 h
Ph 5 h
22
133
20
Supporting Information Available: Details of experimental pro-
cedures, the synthesis and analysis data of catalysts, and the analysis
data of ee values of products. This material is available free of charge
via the Internet at http://pubs.acs.org.
99
94
17b Ph (2q)
a Reaction conditions and analysis are the same as those of Table 1,
entry 6. Full conversions were obtained for all cases. b S/C ) 100.
References
Scheme 2
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entry
R1
R2
S/C
time (h)
yield (%)
ee (%)
1
2
3
4
5
6
Me
Et
Me (6a)
Me (6b)
Me (6c)
Me (6d)
Et (6e)
400
200
200
100
100
200
0.5
18
18
18
18
92
93
89
97
89
92
99.1 (S)
98 (S)
99 (S)
90
99.4 (S)
98 (R)
nPr
iBu
nPr
Me
nPr (6f)
18
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a Reaction conditions are the same as those of Table 1, entry 6,
unless otherwise indicated. Full conversions were obtained for all cases.
efficiency in the asymmetric hydrogenation of R-methylcinnamic
acid derivatives.3,4
To demonstrate the potential of this highly efficient catalytic
asymmetric reaction, we carried out the hydrogenation of R-iso-
propylcinnamic acid derivative 4 to prepare the acid (R)-5, which
is the key intermediate for the synthesis of the new blood-pressure-
lowering drug Aliskiren.11 The compound 4 was successfully
hydrogenated by catalyst (Sa)-1h, which had no substituent on the
oxazoline ring and gave the best performance in this reaction. The
carboxylic acid (R)-5 was attained in high yield with 98% and 95%
ee at catalyst loadings of 0.017 mol % (S/C ) 6000) and 0.01 mol
% (S/C ) 10 000), respectively (Scheme 2). This primary result
was superior to those reported previously.4e,11c,d
Further studies revealed that the iridium complexes 1 were also
suitable catalysts for the hydrogenation of tiglic acid and its
derivatives 6. In this reaction, the (Sa,S)-1f with an isopropyl group
on the oxazoline ring was the most efficent catalyst and Cs2CO3
was the most suitable additive for achieving the best result.12 Under
(8) For comparison of anions of catalysts, see Supporting Information.
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332. (b) Sun, X.; Zhou, L.; Wang, C.-J.; Zhang, X. Angew. Chem., Int. Ed.
2007, 46, 2623. (c) Fox, M. E.; Jackson, M.; Lennon, I. C.; Klosin, J.;
Abboud, K. A. J. Org. Chem. 2008, 73, 784.
(10) For experiment of amount of triethylamine, see Supporting Information.
(11) (a) Herold, P.; Stutz, S.; Spindler, F. WO 02/02508, 2002. (b) Herold, P.;
Stutz, S. WO 02/08172, 2002. (c) Sturm, T.; Weissensteiner, W.; Spindler,
F. AdV. Synth. Catal. 2003, 345, 160–164. (d) Boogers, J. A. F.; Felfer,
U.; Kotthaus, M.; Lefort, L.; Steinbauer, G.; de Vries, A. H. M.; de Vries,
J. G. Org. Process Res. DeV. 2007, 11, 585–591.
(12) For comparison of catalysts and additives, see Supporting Information.
JA802399V
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J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008 8585