Amide catalysts with tetradentate ligands and the asymmetric transfer hydrogenation of carbonyl compounds

Article abstract of DOI:10.1016/S0040-4039(00)01621-X

Amidic tetradentate catalysts comprising two trans-1,2-cyclohexanediamine units linked via a dicarbonyl spacer are shown to provide useful enantiomeric excesses in the asymmetric transfer hydrogenation from propan-2-ol to aromatic ketones. N-Benzylation of the terminal amino groups results, in several cases, in reversal of the absolute configuration of the major product. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01621-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8999–9003
Amide catalysts with tetradentate ligands and the
asymmetric transfer hydrogenation of carbonyl compounds
Charles M. Marson* and Ido Schwarz
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street,
London WC1H OAJ, UK
Received 3 August 2000; revised 13 September 2000; accepted 20 September 2000
Abstract
Amidic tetradentate catalysts comprising two trans-1,2-cyclohexanediamine units linked via a dicar-
bonyl spacer are shown to provide useful enantiomeric excesses in the asymmetric transfer hydrogenation
from propan-2-ol to aromatic ketones. N-Benzylation of the terminal amino groups results, in several
cases, in reversal of the absolute configuration of the major product. © 2000 Elsevier Science Ltd. All
rights reserved.
The design of new ligands for catalytic asymmetric synthesis is a ceaseless quest. New features
regarding ligand acceleration and the mechanism of catalysis can be revealed by ligands, which
hitherto have been predominantly bidentate.1 One notable exception is the class of chiral salen
derivatives2 extensively used in the epoxidation of unfunctionalised alkenes. However, multiple
coordination of a metal to nitrogen is frequently observed in metalloproteins, e.g. Cu, Zn
superoxide dismutase in which Cu(II) is tetragonally bound to four histidine ligands.3 We sought
tetradentate coordination as part of an amide network that might possess some essential features
of metalloprotein catalysts.4 Since metalloproteins are commonly involved in redox processes,5
we selected the contemporary area of asymmetric transfer hydrogenation6 as a probe reaction
for catalyst design and optimisation. While a small-molecule mimic of metalloproteins has been
designed,7 tests on asymmetric induction were unsuccessful. The use of amides in catalytic
asymmetric synthesis has been described only recently.8 In the present work, the potentially
tetradentate ligands 1 containing amides are shown to act as catalysts for enantioselective
transfer hydrogenation (Scheme 1).9
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01621-X

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Scheme 1. Asymmetric transfer hydrogenation using (1R,2R)-N,N%-bis-[2-(aminocyclohexyl)]diamide catalysts
Catalysts of type 1 were synthesised according to Scheme 2. (1R,2R)-(−)-1,2-Diaminocyclo-
hexane 210 was monoprotected by vigorous stirring with (Boc)2O (ethanol, 20°C, 16 h) to give
3 (74%).11 Oxamide 4a was prepared in 77% yield by heating 3 (2 mmol) with diethyl oxalate (1
mmol) in ethanol at reflux (16 h). The malonamide 4b was prepared in 75% yield by treating 3
(9.6 mmol) with dimethylmalonyl dichloride (4.8 mmol) and triethylamine (10 mmol) in
dichloromethane at 0°C for 16 h. The succinamide 4c was obtained in 90% yield from 3 (9.8
mmol) with succinyl dichloride (4.8 mmol) and triethylamine (10 mmol) in dichloromethane at
0°C for 16 h. For the Boc derivative 4a, deprotection to give 5a (99%) was accomplished by
stirring in a 1:1 v/v mixture of dichloromethane and trifluoroacetic acid (13 mL per mmol of 4a)
at 20°C for 2 h; 4b and 4c were similarly deprotected.12 The diimine 6a was obtained in 95%
yield by heating 5a with benzaldehyde (4 mmol per mmol of 5a) in ethanol at reflux for 16 h.
The imine 6b was similarly obtained (98%). Reduction of 6a to 7a (82%) was achieved with
sodium borohydride (0.5 mmol per mmol of 6a) in anhydrous methanol (20°C, 16 h). The
diamine 7b was similarly prepared in 65% yield.
Scheme 2. Synthesis of (1R,2R)-N,N%-bis-[2-(aminocyclohexyl)]diamide catalysts: (a) X=-; (b) X=(CH3)2C; (c)
X=CH2CH2
Ruthenium catalysed asymmetric transfer hydrogenation takes advantage of low redox
potentials and the strong affinities of ruthenium for heteroatoms, and has emerged as an
efficient system for the asymmetric reduction of carbonyl groups.6 Consequently, it was used to
test the amide ligands 5–7 (Table 1) under standard conditions, in which the catalysts are
preformed by heating the amide (2 mol%) with RuCl2(PPh3)3 (1 mol%)13 in propan-2-ol at 80°C

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for 1 h. After cooling to 20°C, KOH (10 mol%) was added, then acetophenone (0.1 M) or a
derivative. The major conclusions to be drawn are: first, that the oxamide ligand 5a, possessing
terminal NH2 groups, afforded e.e.’s (39–48%) that depended little on the p-substituent R of the
aryl ketone (Scheme 1). Secondly, compared with NH2 as the terminal group, an N-benzyl
group generally furnishes higher yields (e.g. entries 4 and 5, Table 1), although in only low e.e.’s.
Thirdly, an oxamide linker gave the best yields but poor e.e.’s (9–15%, S or R); in contrast, a
malonamide spacer gave poorer yields but substantially higher e.e.’s (e.g. entries 1 and 2
compared with entries 6 and 7); a succinamide linker was unsuccessful. Lastly, and most
significantly, N-benzylation leads in every case for the oxamide catalysts to a greatly increased
proportion of the (R)-enantiomer, and for the examples R=H and Cl, even results in a reversal of
the absolute configuration of the major product. Thus, for R=H, entries 1 and 4, and entries 2
and 5 show switching to enantiomeric excess in favour of the (R)-configuration, using the
N-benzyl catalysts, as do the runs for R=Cl (entries 10 and 11). For both R=F and OMe, a
shift in favour of the (R)-configuration is again observed, but to a lesser extent. These examples
of reversal14 of enantiomeric excess designation are apparently the first to be reported for
asymmetric transfer hydrogenation. Thus, although rhodium catalysed reduction of ketones
with diurea ligands containing four chiral centres exhibited matched and mismatched effects,
depending on the diastereoisomerism of the ligands, N-methylation did not lead to reversal of
enantioselectivity.15 The potential of the same ligand skeleton to provide both enantiomers, thus
obviating the need to prepare both enantiomeric ligands, is a major advantage of these new
tetra-aza catalysts that deserves further study.
Table 1
Reduction of acetophenone and derivatives with propan-2-ol catalysed by RuCl2(PPh3)3 at 20°Ca
Entry
Ketone
(R)
Ligand
Ligand
linker X
Terminal
group
Reaction
time (h)
Conversion
(%)b
e.e. (%)c
Configurationc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H
H
H
H
H
H
H
H
5a
5a
6a
7a
7a
5b
5b
7b
6c
5a
7a
5a
7a
5a
7a
–
–
–
–
NH2
NH2
NꢀCHPh
NHCH2Ph
NHCH2Ph
NH2
NH2
NHCH2Ph
NH2
NH2
NHCH2Ph
NH2
24
48
24
24
48
24
48
48
48
72
72
72
72
72
72
29
44
45
64
71
8
8
0
0
28
49
29
71
22
13
48
44
B2
16
15
62
61
–
(S)
(S)
–
(R)
(R)
(R)
(R)
–
–
(CH3)2C
(CH3)2C
(CH3)2C
CH2CH2
–
–
–
–
–
–
H
–
–
Cl
Cl
F
F
OMe
OMe
39
13
46
9
43
12
(S)
(R)
(S)
(S)
(S)
(S)
NHCH2Ph
NH2
NHCH2Ph
a Standard conditions of KOH (10 mol%), ligand (2 mol%) and RuCl2(PPh3)3 (1 mol%) were used.
1
b Conversions were determined by H NMR spectroscopy.
c The e.e.’s and absolute configurations of the alcohols were determined in accordance with literature methods.16
Although tetradentate ligation of these catalysts through four nitrogen atoms is possible, it
has yet to be investigated. Amide coordination to metals is known in both the neutral amide and

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the anionic amide forms.17,18 The possibility of coordination through either nitrogen or oxygen
atoms presents further options.17,18 Dianionic bis-amides are known to stabilise high oxidation
states of coordinated metal ions,19 an important factor for asymmetric transfer hydrogenation.
Amide ligands have been used in catalysts for asymmetric nucleophilic ring opening,17,20 in
asymmetric Michael additions,8b and in C–H oxidations.21 The present study shows that
significant enantiomeric excesses can also be obtained for asymmetric transfer hydrogenation
using catalysts containing amide groups in the ligand. Consequently, these results hold promise
for the design of new amidic catalysts that mimic redox processes carried out by enzyme
complexes.
Acknowledgements
Financial support from the Deutsche Forschungsgemeinschaft (to I.S.) is gratefully
acknowledged.
References
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