Fine-tuning catalytic activity and selectivity-[Rh(amino acid thioamide)] complexes for efficient ketone reduction

Article abstract of DOI:10.1016/j.tetlet.2009.08.116

Amino acid-derived thioamides are prepared and evaluated as ligands in the rhodium-catalyzed asymmetric transfer hydrogenation of ketones in 2-propanol. It is found that increasing the steric bulk at the C-terminus of the ligand had a positive impact on both activity and selectivity in the reduction reaction. In order to find the optimum catalyst, a study is performed on a series of thioamide ligands having substituents of varying size.

Full text of DOI:10.1016/j.tetlet.2009.08.116

Tetrahedron Letters 50 (2009) 6321–6324
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Fine-tuning catalytic activity and selectivity—[Rh(amino acid thioamide)]
complexes for efficient ketone reduction
*
Katrin Ahlford, Madeleine Livendahl, Hans Adolfsson
Department of Organic Chemistry, Stockholm University, The Arrhenius Laboratory, SE-106 91 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2009
Revised 17 August 2009
Accepted 28 August 2009
Available online 2 September 2009
Amino acid-derived thioamides are prepared and evaluated as ligands in the rhodium-catalyzed asym-
metric transfer hydrogenation of ketones in 2-propanol. It is found that increasing the steric bulk at
the C-terminus of the ligand had a positive impact on both activity and selectivity in the reduction reac-
tion. In order to find the optimum catalyst, a study is performed on a series of thioamide ligands having
substituents of varying size.
Ó 2009 Elsevier Ltd. All rights reserved.
Previous studies on thioamides as ligands in the rhodium-cata-
lyzed ATH, using different amino acid-derived thioamides, showed
that the ligand 4a prepared from valine gave the best results.5g Fur-
thermore, the stereochemical outcome of the reaction was primarily
correlatedwiththeconfigurationof theaminoacidpartof theligand.
In fact, when employing ligand 4a in the ATH reaction of acetophe-
none in 2-propanol, the resulting 1-phenylethanol was obtained in
88% conversion and 95% ee (R) after 30 min.5g When the correspond-
ing glycine-derived ligand 4b was employed, the catalytic activity
was significantly reduced, and the selectivity was almost completely
lost [31% conversion and 4% ee (R) after 120 min].7 Conversely, the
Rh-catalyst based on the valine-derived ligand 5 having a benzyl
substituent at the C-terminus, resulted in somewhat reduced cata-
lyst activity and selectivity [67% conversion and 86% ee (R) after
120 min], while the catalyst formed with 6 possessing a larger
1-naphthylmethylsubstituentat thesameposition, thatis, alsolack-
ing the stereocentre at the C-terminus, performed as equally well as
Rh-4a(videinfra). Thus, thestereocentre at thispartof theligandcan
conveniently be omitted. In order to find out whether the substitu-
ent at the C-terminus had additional impact on the catalyst perfor-
mance, further investigation was performed.
The enantioselective reduction of prochiral ketones has become a
reaction of increasing importance, since the resulting enantioen-
riched secondary alcohols are key intermediates for the preparation
of a large number of biologically active compounds.1 Asymmetric
transfer hydrogenation (ATH) has proven to be an efficient, mild
and versatile method for this particular transformation, where the
use of hazardous molecular hydrogen or highly reactive hydride re-
agents can be avoided.2 A number of transition metal complexes
have been found to efficiently catalyze the ATH reaction, where a
combination of [Ru(p-cymene)Cl2]2 together with the monotosylat-
ed diamine ligand 1,2-diphenyl-1,2-diaminoethane (TsDPEN)
developed by Noyori, is the most well-known catalyst to date.3,4
Previously, we have reported that amino acid-derived pseudo-
dipeptides 1, thioamides 2 and hydroxamic acids 3 in combination
with Ru or Rh half-sandwich complexes are excellent catalysts for
the ATH reaction.5,6 Studies on ligand structure 2 indicated that an
aromatic substituent at the C-terminus is most appropriate, and that
increased steric bulk of this substituent could further enhance the
catalyst performance, regarding both activity and selectivity. Herein
we present the preparation of several amino acid thioamides bearing
N-substituents of varying size as well as different electronic proper-
ties. These novel compounds were subsequently evaluated as ligands
in the rhodium-catalyzed ATH reaction of ketones in 2-propanol.
S
Ph
S
R
N
H
Ar
N
H
R3
O
S
O
NH
NH
∗
R2
O
R4
OH
R2
O
R3
R2
O
OH
Boc
Boc
∗
∗
∗
∗
N
H
N
H
N
H
4a R = CH(CH3)2
4b
5
Ar = Ph
6 Ar = 1-naphthyl
O
NH
O
NH
O
NH
R = H
R1
R1
R1
1
2
3
Ligands6–13 wereprepared andscreenedin thereductionof ace-
tophenone using the reaction conditions presented in Scheme 1.8
Catalysts based on all the ligands showed good activity and excellent
* Corresponding author.
E-mail address: hansa@organ.su.se (H. Adolfsson).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.116

6322
K. Ahlford et al. / Tetrahedron Letters 50 (2009) 6321–6324
S
S
S
N
N
H
N
H
H
NH
NH
NH
Boc
Boc
Boc
Boc
Boc
7
8
6
S
S
N
H
N
H
NH
NH
9
10
S
S
S
N
H
N
H
N
H
NH
NH
NH
N
Boc
OMe
Boc
Boc
F
11
12
13
[RhCp*Cl2]2 (0.25 mol%)
L (0.55 mol%)
O
OH
(R)
LiCl (5 mol%)
2-PrONa (5 mol%)
2-PrOH, rt
Scheme 1. Reaction conditions employed in the ATH of acetophenone.
selectivity, as canbeseen inTable 1;ligand 7 appearedtobethemost
promising (Table 1, entry 2). Apparently, theincrease of steric bulkat
the C-terminus improved the catalyst performance but only to a cer-
tain extent. When employing the sterically demanding ligand 8, de-
rived from 9-(aminomethyl)anthracene, the selectivity was
somewhat reduced (Table 1, entry 3), whereas using the more bulk-
ier ligand 10 led to substantially lower activity even though the
selectivity was retained (Table 1, entry 5). The use of ligands 11–
13, containing substituents with different electronic properties re-
sulted in slightly poorer catalyst performance (Table 1, entries 6–8).
Traditionally, ligands or catalysts are screened with one bench-
mark substrate, of which the best-performing ligand/catalyst is
further tested in a substrate-screen to evaluate the scope of the
catalyst performance. In this manner, valuable information can
be lost, since a certain catalyst can be the most suitable for a par-
ticular substrate, whereas it can be out-performed by other cata-
lysts for different substrates. By performing a multiple screen
containing ligands and substrates, it is possible to fine-tune the
catalyst depending on the nature of the substrate.
electron-poor substrates. In addition, substrates having different
degrees of potential steric hindrance on the aryl or the
were evaluated (Scheme 2 and Fig. 1).
a-position
From the catalyst/substrate screen it was apparent that acetoph-
enones substituted with electron-withdrawing groups (14 and 15)
were readily reduced to the corresponding alcohols, whereas the
electron-rich substrates reacted more slowly and with slightly lower
selectivity (16 and 17). The catalytic reduction of 2,5-dimethoxyace-
tophenone (17)resultedinlowactivityusingligand7 (8%conversion
and 38% ee); however, when ligand 9 was used for the same sub-
strate, the catalyst performance was considerably higher (49% con-
version and 91% ee). As can be seen in Figure 1, substrate 18 was
reduced by catalysts based on ligands 7 and 9, in equally good results
(91% conversion and 94% ee). In the reduction of 1-propiophenone
(19), the best selectivity was obtained using ligand 7 (97% ee).
The overall best-performing ligand 7 was further evaluated in the
reduction of more challenging substrates, including two dialkyl
ketones (Scheme 3 and Table 2). The highest turnover frequency
(TOF), 704 hÀ1 after 15 min (1152 hÀ1 after 5 min), was observed for
4-nitroacetophenone(20),(Table2, entry7).10 2-Fluoroacetophenone
(21) reacted rather poorly, probably due to electronic effects (Table 2,
entry 8). As previously observed for most ATH protocols, this catalyst
system is evidently not appropriate for asymmetric reduction of dial-
kyl ketones, thus geranylacetone (24) is readily reduced, but with no
selectivity (Table 2, entry 11).
Rh-catalysts based on ligands 6–9 and 13 were used in the
reduction of various ketones, representing both electron-rich and
Table 1
ATH of acetophenone using ligands 6–13a
Entry
Ligand
t (min)
Conversionb (%)
eeb (%)
[RhCp*Cl2]2 (0.25 mol%)
L (0.55 mol%)
1
2
3
4
5
6
7
8
6
7
8
30
30
120
30
120
30
30
85
81
88
84
47
71
80
63
93
96
89
91
92
94
94
92
O
OH
R2
R1
R1
R2
LiCl (5 mol%)
2-PrONa (5 mol%)
2-PrOH, rt
9
10
11
12
13
R1= 4-Br-C6H4, R2= Me
R1= 4-CF3-C6H4, R2= Me
14
15
17 R1= 2,5-diMeO-C6H3, R2= Me
18
120
R1= 1-naphthyl, R2= Me
19 R1= Ph, R2= Et
a
16 R1= 4-MeO-C6H4, R2= Me
Reaction conditions according to Scheme 1.
Conversions and enantioselectivities were determined by GLC analysis (CP
b
Girasil DEX CB).
Scheme 2. Reaction conditions employed in the ATH of substrates 14–19.

K. Ahlford et al. / Tetrahedron Letters 50 (2009) 6321–6324
6323
95
91
a
b
99
85
96
91
91
99
89
77
97
89
90
99
94
85
60
97
87
85
Conversion (%)
100
95
89
49
ee (%)
100
34
99
94
91
84
86
38
97
77
78
80
60
80
60
40
20
0
14
46
97
81
87
36
93
84
88
8
91
54
40
96
88
24
20
0
14
94
6
6
91
49
53
93
7
7
84
91
17
15
15
27
61
92
8
8
Ligand
16
16
5
Ligand
17
Substrate
17
9
9
26
18
18
Substrate
13
13
19
19
Figure 1. ATH of substrates 14–19 using rhodium catalysts derived from ligands 6–9 and 13.9 (a) Conversion; (b) enantioselectivity.
[RhCp*Cl2]2 (0.25 mol%)
7 (0.55 mol%)
catalysts can be obtained using structurally simpler ligands contain-
ing only one stereogenic centre. From the multiple ligand- and sub-
strate-screen performed, it was possible to find the optimum
catalyst for a particular substrate.
O
OH
Me
R1
R1 Me
LiCl (5 mol%)
2-PrONa (5 mol%)
2-PrOH, rt
20 R1= 4-NO2-C6H4
21 R1= 2-F-C6H4
22 R1= 3-pyridyl
Acknowledgements
R1= c-hexyl
24 R1=
23
The Swedish Research Council, The Knut and Alice Wallenberg
Foundation and The Carl Trygger Foundation are gratefully
acknowledged for financial support.
Scheme 3. Reaction conditions employed in the ATH of substrates 14–24.
Table 2
ATH of substrates 14–24 using ligand 7a
Supplementary data
Supplementary data (experimental procedures for ligand prep-
aration, catalytic experiments along with ligand characterization
data) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2009.08.116.
Entry
Substrate
t (min)
Conversionb (%)
eeb (%)
1
2
14
15
16
17
18
19
20
21
22
23
24
30
30
30
120
30
120
15
120
120
120
120
96
>99
49
49
91
87
88
73
6
91
89
90
3
4c
5
91
94
97
78
59
n.d.
n.d.
rac
References and notes
6
7d
8
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Reaction conditions according to Scheme 3.
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8. See Supplementary data for detailed information on ligand formation.
9. Reaction conditions according to Scheme 2. Conversions and enanti-
oselectivities were determined by GLC analysis (CP Girasil DEX CB). A table
for Figure 1 is available in the Supplementary data.
10. 2-Propanol (1 mL) was exchanged for THF in order to dissolve the
substrate.