An outstanding catalyst for asymmetric transfer hydrogenation in aqueous solution and formic acid/triethylamine

Article abstract of DOI:10.1039/b606288a

A Rh/tetramethylcyclopentadienyl complex containing a tethered functionality has been demonstrated to give excellent results in the asymmetric transfer hydrogenation of ketones in both aqueous and formic acid/triethylamine media. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b606288a

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An outstanding catalyst for asymmetric transfer hydrogenation in
aqueous solution and formic acid/triethylamine{
Daljit S. Matharu,a David J. Morris,a Guy J. Clarksonb and Martin Wills*a
Received (in Cambridge, UK) 3rd May 2006, Accepted 5th June 2006
First published as an Advance Article on the web 23rd June 2006
DOI: 10.1039/b606288a
In certain cases, however, the Rh(III) catalysts are superior,
notably in the case of reduction of a-chloro ketones.8,9 These
applications originate from 2001 when a binary system was
introduced.9a This system and the associated procedure was
significantly improved through the use of the preformed catalysts
in 2002.8d–8f The system has also been demonstrated to be active in
aqueous solution using either sodium formate or FA/TEA as the
hydrogen source. In 2005, we reported an improved catalyst 8
which contained a tether between the cyclopentadienyl and
TsDPEN components.10 The performance of 8 was similar to
that of the tethered Ru(II)TsDPEN catalyst 9 that we have
previously reported11 but represented a significant improvement
over our earlier Rh(III) tethered catalyst 10 containing an amino
alcohol ligand.12
A Rh/tetramethylcyclopentadienyl complex containing a teth-
ered functionality has been demonstrated to give excellent
results in the asymmetric transfer hydrogenation of ketones in
both aqueous and formic acid/triethylamine media.
The reduction of ketones to enantiomerically-pure secondary
alcohols is a fundamental chemical transformation which provides
one of the most convenient methods for establishing chirality
within target molecules and building blocks for complex target
structures. Asymmetric transfer hydrogenation (ATH) is a highly
efficient and practical method for this transformation.1 Of the
ATH catalysts reported within the last decade, the most widely
used ligand classes are those based on 1,2-aminoalcohols2–5 such as
cis-aminoindanol 1, and monosulfonylated diamines5–8 such as
N-tosyl-1,2-diphenylethane-1,2-diamine (TsDPEN) 2 and N-tosyl-
1,2-diaminocyclohexane (TsDAC) 3. The latter class is the more
versatile, as it may be used in formic acid/triethylamine (FA/TEA)
medium, resulting in an essentially irreversible reaction.
Upon examination of the publications in this area, we noted
that, in contrast to the Ru(II)/TsDPEN 2 system, several successful
catalysts based on Rh(III)/monotosylated diamines are derived
from TsDAC 3.8,9 We therefore sought to prepare the ‘tethered’
catalyst 11 from this diamine. Following our procedure for the
synthesis of 8, monotosylated diamine R,R-3 was reductively
alkylated with aldehyde 1210 to give intermediate 13. Upon
reaction of 13 with RhCl3 in methanol, catalyst 11 was formed and
isolated in pure form by column chromatography on silica gel and
recrystallisation. The 1H-NMR spectrum of 11 exhibited a distinct
pattern of four singlets from the methyl groups on the
cyclopentadienyl ring with a fifth from the methyl of the tosyl
group. An X-ray crystal structure of 11 was obtained which
confirmed the expected structure (Fig. 1).13
Aminoalcohols, by contrast, form less stable complexes and are
limited to use in isopropanol, where the dilutions must be high in
order to avoid troublesome reversible reactions. Of the metal
complexes which may be formed with these ligands, those of arene/
Ru(II) such as 4 and 5 have been studied most widely by
researchers in academia and industry.2,3,6,7 In general, Ru(II)
catalysts are more versatile and more economical than the
isoelectronic Cp9/Rh(III) or Ir(III) catalysts such as 6 and 7.4,5,8,9
Cp9/Rh(III) complexes have been commercialised by Avecia and
marketed as ‘CaTHy’ catalysts.4,5
aAsymmetric Catalysis Group, Coventry, UK CV4 7AL.
E-mail: m.wills@warwick.ac.uk; Fax: +44 24 7652 4112;
Tel: +44 24 7652 3260
Complex 11 proved to be an excellent catalyst for the reduction
of a wide range of ketones in FA/TEA media (Scheme 1, Table 1).
Reductions were generally complete within times as short as 30 min
(for S/C = 200), although some substrates took longer to be fully
reduced. In the majority of cases, the product e.e.s were over 90%,
bX-ray Crystallography Unit, Department of Chemistry, The University
of Warwick, Coventry, UK CV4 7AL
{ Electronic supplementary information (ESI) available: Experimental
procedures and characterisation data for catalyst intermediates and
reduction products. See DOI: 10.1039/b606288a
3232 | Chem. Commun., 2006, 3232–3234
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reduced in exceptionally high e.e. of 99.4%, a result comparable to
that obtained using 8. Heterocyclic ketones also proved to be
excellent substrates: 2-acetylfuran gave a product of 98% e.e,
2-acetylthiophene 97% e.e, 3-acetylthiophene 93% e.e and 4-acetyl
pyridine 95% e.e., respectively (entries 12–15).
a-Substituted ketones are highly compatible with Rh(III)
catalysts, as has been previously demonstrated. In this work, 11
reduced a-chloroacetophenone in 96% e.e. (catalyst loading
lowered to 0.1 mol%), a-hydroxyacetophenone in 99.5% e.e. and
a-phenoxy acetophenone in 92% e.e. A final significant result was
the reduction of cyclohexylmethyl ketone in 87% e.e., representing
one of the highest selectivities observed for this class of ketone. Of
note was the observation that 32 was formed as the S-enantiomer.
This represents a reverse in selectivity relative to the aryl/alkyl
examples and mirrors our previous observation with catalyst 9.11a
These results again suggest that the reduction of alkyl/alkyl
ketones by tethered catalysts operates through a predominantly
sterically controlled mechanism. In our examples, we employed a
typical catalyst loading of 0.5 mol%, however, this could be
reduced to 0.1 mol% without loss of enantioselectivity.
Fig. 1 X-Ray crystallographic structure of R,R-11 (pTol replaced with
Me, and hydrogen atoms removed, for clarity).
Scheme 1 Asymmetric reduction of ketones using R,R-11.
and in many cases higher than those we had previously observed
with 8. In the case of substrates not containing an ortho-
substituent, e.e.s were consistently high (entries 1–4). ortho-
Chloro acetophenone was reduced in 85% e.e., compared to 77%
using 8, whilst 2-(methoxy)acetophenone was reduced in 94% e.e.
compared to 90% with 8.
Although still moderate, the 62% e.e. for 2-(trifluoromethyl)-
acetophenone represented a sharp improvement on that of 17%
using 8. The e.e.s of 96% and 75% for propiophenone and
isobutyrophenone (entries 9 and 10), respectively, compare well to
results obtained using other catalysts, including 8. Tetralone was
Table 1 Ketone reductions in formic acid/triethylamine
Encouraged by these results, we extended our studies to the
reduction of ketones in water.14,15 In our tests, we employed
sodium formate as the reducing agent. Again, the reactions were
generally rapid and highly enantioselective (Scheme 1, Table 2).
Again, consistently high enantiomeric excesses were obtained in
reductions of relatively unhindered aryl/alkyl ketones (entries 1–7),
with full conversions in reaction times of 3–6 h at a S/C of 200.
The reduction of ortho-substituted ketones was typically less
selective (entry 8) although the challenging cyclohexyl/methyl
ketone was reduced in 84% e.e., which again compares well with
other methods for this substrate (entry 9). Again, the absolute
configuration of the reduction product was reversed relative to the
aryl/alkyl ketones. The most remarkable feature of the catalyst is,
however, its longevity, since in all cases the catalyst loading could
be lowered significantly without suffering deterioration of the e.e.
This is illustrated for 2-acetylthiophene and -furan, respectively, in
entries 10 through 14. In all cases, increasing the S/C from 200
(already twice that typically used for ATH catalysts in aqueous
systems) to 1,000 and even as high as 10,000 necessitated longer
reaction times but without any decrease in enantioselectivity.
Entrya
Product
Timeb
Conversion
e.e. (R/S)
1
2
3
4
5
6
7
8
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
2 h
1 h
30 min
4 h
8 h
22 h
48 h
48 h
6 h
48 h
4 h
3.5 h
4.5 h
8 h
1.5 h
45 min
2 h
100%
100%
100%
99%
100%
100%
47%
99%
99%
27%
100%
100%
100%
99%
100%
100%
100%
100%
96%
96% R
95% R
96% R
94% R
85% R
94% R
62% R
84% R
96% R
75% R
99.4% R
98% R
97% R
93% R
95% R
96% S
99.5% S
92% S
87% S
9
10
11
12
13
14
15
16c
17
18
19
a
1 h
26 h
b
Catalyst R,R-11, S/C
=
200, 28 uC. Time taken to reach
c
conversion indicated. S/C = 1000.
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Table 2 Ketone reductions using sodium formate in water
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Entrya
Product
Timeb
Conversion
e.e. (R/S)
1
2
3
4
5
6
7
8
14
16
33
34
17
22
35
20
32
26
26
25
25
25
16
3 h
3 h
3 h
3 h
3 h
4 h
6 h
8 h
24 h
1.5 h
5 h
1 h
4 h
100%
100%
100%
100%
98%
100%
98%
96%
100%
100%
100%
100%
100%
100%
100%
b
96% R
96% R
94% R
93% R
97% R
96% R
91% R
51% R
84% S
97% R
97% R
98% R
98% R
98% R
97% R
9
10
11c
12
13c
14d
15c
a
7 days
16 h
Catalyst R,R-11, S/C
= 200, 28 uC. Time taken to reach
c
conversion indicated. S/C = 1,000. =S/C = 10 000.
d
These results highlight the high stability of tethered catalyst 11,
which can continue to turnover a reaction at exceptionally low
loading in the face of virtually zero background reaction. We
believe that this is one of the first examples of a Rh(III) transfer
hydrogenation system in which the catalyst loadings can be
decreased to levels typically associated with the best of pressure
hydrogenation catalysts.
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We thank the EPSRC for generous support of this work
through postdoctoral funding (to DJM) and Doctoral Training
Funds (to DSM). Dr B. Stein of the EPSRC MS service at
Swansea is thanked for HRMS analysis of certain compounds.
The use of the EPSRC Chemical Database Service at Daresbury is
acknowledged.16 We thank Arran Chemicals for donation of
homochiral diamines.
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˚
10.0963(12), b = 13.7861(16), c = 19.923(2) A, T = 180 K , m(Mo-Ka) =
0.077 mm21, U = 2773.1(6) A , Z 4, Dcal = 1.473 g cm23, 27747
3
˚
reflections measured, 6969 unique [Rint = 0.0312]. Final residuals for
327 parameters were R1 [I . 2s(I)] = 0.0294, wR2 [I . 2s(I)] = 0.0712
and R1 = 0.0309, wR2 = 0.0718 for all 6969 data. CCDC 603515. For
crystallographic data in CIF format or other electronic format see DOI:
10.1039/b606288a.
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