Enantioselective hydrogenation and transfer hydrogenation of bulky ketones catalysed by a ruthenium complex of a chiral tridentate ligand

Article abstract of DOI:10.1002/chem.200801929

A study on the enantioselective hydrogenation of tertiary alkyl ketones catalysed by a novel class of tridentate-Ru complex is reported. In contrast to the extensively studied [RuCl₂(diphos)(di-primary amine)] complexes, this new class of hydro

Full text of DOI:10.1002/chem.200801929

FULL PAPER
DOI: 10.1002/chem.200801929
Enantioselective Hydrogenation and Transfer Hydrogenation of Bulky
Ketones Catalysed by a Ruthenium Complex of a Chiral Tridentate Ligand
M. Belꢀn Dꢁaz-Valenzuela,[a] Scott D. Phillips,[a] Marcia B. France,[b]
Mary E. Gunn,[a] and Matthew L. Clarke*[a]
Abstract: A study on the enantioselec-
tive hydrogenation of tertiary alkyl ke-
tones catalysed by a novel class of tri-
dentate–Ru complex is reported. In
contrast to the extensively studied
problematic substrates such as bulky
heterocyclic ketones. Unusually for a
pressure hydrogenation catalyst, similar
enantioselectivity can be obtained
under transfer hydrogenation condi-
tions. The transfer hydrogenations are
somewhat slower than the pressure hy-
drogenations, but this drawback is
readily overcome, since we have dis-
covered that a microwave accelerated
transfer hydrogenation of the above
ketones occurs within 20 min at about
908C with similar selectivity to that ob-
tained in the pressure hydrogenation
system.
[RuCl
G
amine)]
complexes, this new class of hydrogena-
tion catalyst smoothly reduces these
less reactive bulky ketones with up to
94% ee. The same catalyst system can
also selectively reduce other potentially
Keywords: asymmetric catalysis
·
heterocyclic ketones hydrogen
·
transfer · hydrogenation · N,P li-
gands
Introduction
bonds, show industrially relevant turnover numbers, and if
the catalyst shown in Scheme 1 is used, extremely high
enantioselectivity for a range of acetophenone derivatives.
Since Noyoriꢀs original publications, there has been intense
Reduction of C=O and C=N double bonds using molecular
hydrogen is a very important process in industrial organic
syntheses, due to its low cost and complete atom efficien-
cy.[1À4] There has consequently been a massive research
effort aimed at developing homogeneous catalysts that can
carry out this goal with high efficiency, chemoselectivity
and, in the case of prochiral ketones, enantioselectivity.
Asymmetric hydrogenation of b-keto esters and related sub-
strates has been an industrial process for some time.[3,4] Ho-
mogeneous hydrogenation of unfunctionalised ketones
could not be carried out with sufficient efficiency or chemo-
selectivity until Noyoriꢀs pioneering research on ruthenium
complexes containing both diphosphine and diamine li-
gands.[5,6] These catalysts are highly chemoselective for C=O
interest in [RuCl2ACTHUNRGTENN(UG diphos)AHCTUNGTRENN(UGN diamine)] systems, with several
structurally related catalysts also showing similarly excellent
selectivity and reactivity for reduction of acetophenone de-
rivatives.[7,8] The key to the massively enhanced reactivity
relative to simple Ru–phosphine catalysts is proposed to be
a unique mechanism in which the substrate hydrogen bonds
to the NH functionality in the diamine ligand.[9]
[a] Dr. M. B. Dꢁaz-Valenzuela, S. D. Phillips, M. E. Gunn,
Dr. M. L. Clarke
Scheme 1. General structure of Noyori catalysts and the most selective
catalyst known
School of Chemistry, University of St Andrews
EaStCHEM, St Andrews, Fife (UK)
Fax : (+44)1334-463808
E-mail: mc28@st-andrews.ac.uk
However, [RuCl
AHCTUNGTREG(NNUN diphenylphosphino)-1,1’-binaphthyl, DAIPEN=1,1-bis(4-
methoxyphenyl)-3-methyl-1,2-butanediamine) and related
catalysts do have some important limitations and are far less
effective for the hydrogenation of tetralones,[7j,k] dialkylke-
2ACHUTGTNREN(UNG BINAP)ACHTUNGTERN(NUGN DAIPEN)] (BINAP=2,2’-bis-
[b] Prof. M. B. France
Department of Chemistry, Washington and Lee University
Lexington, VA 24450 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800xxx.
Chem. Eur. J. 2009, 15, 1227 – 1232
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1227

tones,[10] bulky ketones,[11] some heterocyclic ketones,[12] and
imines.[13] Given that so many drugs, agrochemicals, materi-
als, and natural products can be disconnected back to enan-
tiopure secondary alcohols, it is of significant importance to
extend asymmetric hydrogenation chemistry such that it is
effective for every major class of substrate. We therefore ini-
tiated a project aimed at successfully hydrogenating these
difficult substrates, with the general impression that a depar-
The X-ray crystal structure of this pre-catalyst has already
been discussed in our communication.[14]
One of our main goals when we initiated this research
was to hydrogenate unreactive ketones using the new cata-
lysts, ideally with some asymmetric induction. The enantio-
pure variant, (R, R)-2 was used for the experiments below.
Noyori and co-workers have reported that 1,1’,1’’-tri
acetophenone 3 gave only a 6% yield when hydrogenated
using [RuCl2A(BINAP)(DPEN)] (DPEN=1,2-Diphenylethyl-
enediamine). When this work was initiated, there were no
ACHTUNGTRENNUNGmethyl-
AHCTUNGTRENNUNG
ture from the [RuCl2(diphosphine)
N
C
R
ACHTUNGTRENNUNG
offer the best chance of some success in this challenging
goal. In our preliminary communication,[14] we reported that
a ruthenium complex of a chiral tridentate ligand is an
active hydrogenation catalyst for a very wide range of car-
bonyl substrates and provided two examples of highly enan-
tioselective hydrogenation of the highly challenging tertiary
alkyl ketones. Herein, we report a more extensive study into
the enantioselective hydrogenation and microwave-acceler-
ated transfer hydrogenation of two classes of poorly reactive
ketones using the new tridentate Ru system.
A
ACHTUNGTRENNUNG
effective ruthenium catalysts for asymmetric hydrogenation
of this substrate,[6,11] so it was therefore selected as a chal-
lenging example of a bulky ketone. We were therefore de-
lighted to find that the hydrogenation proceeds smoothly at
508C to give the (S)-alcohol in quantitative yield and up to
77% ee using (R,R)-2 as catalyst (Table 1). A series of ex-
periments with varied solvents and temperature show that
running reactions in iPrOH with a base/Ru ratio of 2 at tem-
peratures between 50 and 708C give the best results for this
substrate (Table 1).
Alternative tert-butyl ketones 5a–5d, readily available as
shown in Scheme 3, were also tested in this general protocol.
These gave very similar enantioselectivity showing that sub-
Results and Discussion
Given the absence of data on hydrogenation catalysis using
tridentate ligands,[15] ruthenium complexes of tridentate
P^N^NH2 type ligands seemed worthy of investigation. This
type of ligand could form octahedral ruthenium complexes
with a more open co-ordination environment, thus increas-
ing substrate scope or reactivity in hydrogenation. The use
of a single ligand to play the roles carried out by both di-
phosphine and diamine ligands in Noyori catalysts is also a
topic of considerable recent interest.[8f,g]
Table 1. Hydrogenation of tert-butyl ketones using catalyst 2.
After some optimisation, we found that heating readily
Entry[a] Ketone
G
E
T
Solvent Conversion
ee
available compound 1[16] with [RuCl
2ACHTNUGTRNEUNG(DMSO)4] in THF at
AHCTUNGTRENNUNG
1208C in a microwave gave a quantitative yield of rutheni-
um complex 2 in sufficient purity (ꢀ90–95%) for the appli-
cations described here (Scheme 2). On the other hand, com-
plexation reactions carried out using conventional heating
always gave a significant amount of side products. Com-
pletely pure samples of complex 2 can be obtained by
column chromatography or by recystallisation from acetoni-
trile to form the MeCN–solvate. (All samples gave similar
selectivity in catalysis.) Samples of complex 2 have remained
unchanged in air for extended periods of time, and in the
majority of the hydrogenations reported here, autoclaves
were loaded under a non-inert atmosphere, prior to flushing
with hydrogen, which is a desirable feature for a catalyst.
1
2
3
3
3
3
3
3
3
5a
5b
5c
5d
1.0
1.0
1.0
1.0
0.5
1.0
1.0
0.5
0.5
0.5
0.5
2.0
2.0
2.0
2.0
1.0
2.0
2.0
1.0
1.0
1.0
1.0
50 iPrOH >99 (>99)
50 EtOH >99 (>99)
50 iPrOH >99 (>99)
50 iPrOH >99 (>99)
70 iPrOH >99
74 (S)
53 (S)
74 (S)
74 (S)
77 (S)
61 (S)
71 (S)
77 (S)
69 (S)[c]
76 (S)[c]
80 (S)[c]
3[d]
4[e]
5[f]
6[g]
7[h]
8
70 iPrOH 19
50 iPrOH >99 (>99)
50 iPrOH >99 (79)
50 iPrOH >99 (97)
50 iPrOH >99 (84)
50 iPrOH >99 (69)
9
10
11
[a] Unless otherwise indicated in these footnotes, reactions were carried
out using 0.33 mmolmLÀ1 ketone at 50 bar of hydrogen pressure with a
24 h reaction time using tBuOK as base. [b] Conversions were deter-
mined by 1H NMR analysis of the crude reaction mixtures (all peaks as-
signed). Yields are for pure alcohols after short-path silica gel chromatog-
raphy or filtration through alumina. [c] The ee value was determined by
chiral HPLC (see Supporting Information). Configuration for alcohols
from hydrogenation of ketones 3 and 5a were determined to be (S) by
comparison of optical rotation to those in the literature. The closely re-
lated alcohols derived from ketones 5b–d have the same negative sense
of rotation of polarised light, and are therefore tentatively also assigned
as S. [d] 0.033 mmol ketone per mL iPrOH. [e] 1.66 mmol ketone per mL
iPrOH and reaction time reduced to 5 h. [f] Reaction time reduced to
38 min (hydrogen uptake monitored at constant pressure). [g] Reaction
was run in the absence of hydrogen for 38 min. [h] Reaction was run in
the absence of hydrogen for 24 h.
Scheme 2. Synthesis of the ruthenium catalyst 2.
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ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 1227 – 1232

Hydrogenation of Bulky Ketones
FULL PAPER
(up to 94% ee) for a class of ketone hydrogenation that
were reported to be unreactive to reduction with standard
Noyori-type catalysts (or other Ru–phosphine hydrogena-
tion catalysts) are very promising. One ketone that was not
reduced was the extremely bulky 1,1,1-triphenylacetophe-
none. However, we note that with this substrate no reduc-
tion occurred with NaBH4 and incomplete reduction oc-
curred with LiAlH4. Using the first member of this new
class of catalyst, asymmetric hydrogenation of simple aceto-
phenones gives essentially racemic alcohols.
Scheme 3. Preparation of tert-butyl ketones.
strate electronic effects on the selectivity of these hydroge-
nations are minimal.
In considering what might be useful design features of
catalyst 2, the presence of a labile solvent molecule in one
of the co-ordination sites seemed potentially advantageous
for functionalised substrates that might otherwise inhibit the
catalyst. Certain heterocyclic ketones have been found to be
either completely unreactive[12a] or unreactive unless Lewis
acid additives are added to the hydrogenations.[12b] This is
presumably due to deactivation of the catalyst by the het-
erocycle, through hydrogen bonding, deprotonation, or co-
ordination to Ru. It seemed possible that co-ordination of a
heterocycle to Ru could occur to complex 2, but still allow
the ketone to reach a transition state where hydride transfer
could occur. A small selection of heterocyclic substrates was
therefore investigated in this reduction (Table 3). Imidazole-
functionalised aryl alcohols are intermediates to a group of
compounds known to exhibit anti-fungal activity, and a pre-
To explore the scope of the new catalyst, a range of other
ketones were hydrogenated using catalyst 2, including 6–11,
which are even more sterically demanding than the tertiary
alkyl ketones studied recently by the Noyori group. As can
be seen from Table 2, all ketones are essentially quantita-
tively reduced to alcohols, and as the steric bulk of the sub-
strate increases, so does enantioselectivity. The (R,R) cata-
lyst generally gives S alcohols in cases where the bulky
group is of lower Cahn–Ingold priority to phenyl, although
for this new catalyst, it is not known if the Noyori NH-bi-
functional mechanism is in operation or an inner sphere
mechanism. For the first member of a new class of ketone
hydrogenation catalysts, the enantioselectivities observed
Table 2. Enantioselective hydrogenation of other bulky-aryl ketones
using catalyst 2.
Table 3. Enantioselective hydrogenation of bulky heterocyclic ketones
using catalyst 2.
Entry[a]
Ketone
T
[8C]
Conversion
A
ee
[%][c]
1
2
6
7
8
9
10
11
50
50
70
70
70
50
N
48 (S)
90
84
Entry[a]
Ketone
T
[8C]
Conversion
(Yield)[%][b]
ee
G
[%][c]
3[d]
4[d]
5[e]
6
>99 (79)
>99 (62)
75
1[d]
2
3
4
5
12
13
14
15
16
17
50
70
70
70
100
70
>99
61 (R)
53
60 (S)
69
70
67
46 (S)
>99 (86)
>99 (55)[e]
>99 (61)[e]
(>99)
>99 (98)
>99 (98)
94[f]
[a] Unless otherwise indicated in these footnotes, reactions were carried
out using 0.5 mol% catalyst and 1 mol% tBuOK at 50 bar of hydrogen
pressure in propan-2-ol as solvent with a 24 h reaction time. [b] Conver-
sions were determined by 1H NMR analysis against an internal standard.
Yield refers to yield of isolated pure alcohols after chromatography (or
in the case of those quoted as >99 refer to a quantitative yield after re-
moval of catalyst by filtration through a pad of alumina). [c] The ee value
was determined by chiral HPLC (see Supporting Information), configura-
tion for alcohols of entries 1 and 5 was determined to be (S) by compari-
son of optical rotation to those in the literature. [d] Hydrogenation car-
ried out at 40 bar of hydrogen pressure. [e] Hydrogenation carried out at
70 bar of hydrogen pressure. [f] Estimated diastereomeric ratio of 83:17
((S,R)+(R,S):meso) based on uncorrected HPLC data assuming equal
absorbance for both diastereomers (in agreement with those determined
6
[a] Unless otherwise indicated in these footnotes, reactions were carried
out using 0.5 mol% catalyst and 1 mol% tBuOK at 40 bar of hydrogen
pressure in propan-2-ol as solvent with a 24 h reaction time. [b] Conver-
sions were determined by 1H NMR analysis against an internal standard,
with yields of isolated pure alcohols after chromatography. [c] The ee
value was determined by chiral HPLC (see Supporting Information),
configuration for alcohol of entry 1 was determined to be (R) and for al-
cohol of entry 4 was determined to be (S) by comparison of optical rota-
tion to those in the literature. [d] Hydrogenation carried out at 50 bar of
hydrogen pressure. [e] The alcohol products from ketones 14 and 15 do
not elute well on silica hence reducing yields significantly below the
quantitative conversions.
1
by H NMR integration).
Chem. Eur. J. 2009, 15, 1227 – 1232
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www.chemeurj.org
1229

M. L. Clarke et al.
Table 4. Enantioselective transfer hydrogenation of bulky ketones using
catalyst 2.
vious paper has reported these substrates to be unreactive
to pressure hydrogenation by [RuCl2A(diphos)(diamine)] cat-
N
ACHTUNGTRENNUNG
Entry[a]
Ketone
T
[8C]
t
Conversion
(Yield)[%][b]
ee
alysts.[12a] It was therefore gratifying to find that 12 and 13
are readily hydrogenated by catalyst 2, even if enantioselec-
tivities are only moderate. The pyridyl ketones 14, 15 and
16, which also contain a deactivating bulky alkyl group,
were none-the-less hydrogenated readily enough with mod-
erate enantioselectivity. The tolerance of the catalyst to
bulky isoxazole rings was evaluated using ketone 17[17]; no
sign of inhibition was caused by this heterocycle either, and
reasonably good ee was observed.
[min]
N
[%][c]
1
2
3
4
5
6
7
8
3
3
3
3
70
80
90
100
90
120
120
120
90
120
120
120
90
120
120
120
38
38
38
38
20
20
20
20
20
20
20
20
20
20
20
20
98
98
>99
>99
76 (S)
76 (S)
77 (S)
68 (S)
77 (S)
85 (S)
79
72
77
91
84
3
98
5a
5b
5c
5d
7
8
9
11
13
14
15
>99 (75)
62
>99 (89)
>99 (82)
87
>99 (82)
18
70
9[d]
10
11
12
13
14
15[d]
16[d]
In the course of these studies, we also tested whether cat-
alyst 2 could promote transfer hydrogenation.[18] It has been
reported by Morris and co-workers that some hydrogenation
catalysts can also promote transfer hydrogenation, but in
these examples, good hydrogenation catalysts were generally
poorly selective transfer hydrogenation catalysts and vice
versa.[19] Catalyst 2 does promote transfer hydrogenation of
the above substrates with very similar selectivity to the pres-
sure hydrogenation described above. Transfer and pressure
hydrogenations run side-by-side suggest that the rate of
transfer hydrogenation is significantly slower (Table 1 en-
tries 5 and 6), and a labelling experiment was consistent
with this. A hydrogenation carried out in [D8]isopropanol at
50 bar H2 presssure gave >99% conversion with 23% of
the alcohol product incorporating the deuterium in the C-
H(D) position. A general catalyst for both pressure hydro-
genation and transfer hydrogenation of ketones is a sought-
after goal, since hydrogenation is preferred at commercial
scale, and transfer hydrogenation is more convenient in a re-
search laboratory. The fact that catalyst 2 does seem to give
similar ee values in transfer hydrogenation is encouraging.
The transfer hydrogenations were clearly slower than the
pressure hydrogenations, and as such we investigated if
faster reactions could be achieved at higher temperatures
using microwave heating (Scheme 4). Other reports on mi-
crowave-accelerated transfer hydrogenation[20] generally
show some eroding of the enantioselectivity at higher tem-
peratures, but the high degree of control offered by modern
microwaves should allow an optimum temperature where
the fastest rates are observed with no losses of enantioselec-
tivity. This did indeed prove to be the case, and in optimisa-
tion using ketone, 3, it was found that temperatures of 908C
and below all gave similar enantioselectivity to the pressure
hydrogenation of this substrate. In addition, at 908C, the re-
action was complete in just 20 min (Table 4; entry 5),
making the procedure highly convenient. A selection of the
other ketones studied in Tables 1–3 was also investigated.
Enantioselectivity of the reduction is very similar to that ob-
83
92[f]
64
41
>99 (56)
>99 (57)
57 (S)
61
[a] Unless otherwise indicated in these footnotes, reactions were carried
out using 1.0 mol% catalyst and 2.0 mol% tBuOK in a microwave.
1
[b] Conversions were determined by H NMR analysis against an internal
standard, with yields of isolated pure alcohols after chromatography. [c]
The ee value was determined by chiral HPLC (see Supporting Informa-
tion). [d] Reactions carried out using 0.5 mol% catalyst and 1.0 mol%
tBuOK solution. [e] Estimated diastereomeric ratio of 87:13 ((S,S)+
(R,R):meso) based on uncorrected HPLC data assuming equal absorb-
ance for both diastereomers (in agreement with those determined by
1H NMR integration).
served in pressure hydrogenation, and, in most cases the ke-
tones could be reduced selectivity in short reaction times.
Surprisingly, the imidazole containing ketones seemed to be
more reluctant to transfer hydrogenation[18g] using our cata-
lyst (ketone 12 was not reduced, and ketone 13 give a mod-
erate yield as shown in entry 14 of Table 4).
The ability of complex 2 to catalyse pressure hydrogena-
tion and transfer hydrogenation with very similar enantiose-
lectivity suggests a common pathway for the enantioselectiv-
ity-determining step of these two processes. This is no sur-
prise, but there does not seem to be a common pathway for
[RuCl
by Morris and co-workers.[19] Future studies using new cata-
lysts of the [RuCl2A(P^N^N)(L)]-type could lead to a highly
2ACHUTGTNERNNUG(BINAP)ACHUTNGTRENN(NGU DPEN)] and related catalysts as discussed
CTHUNGTRENNUNG
selective and reactive catalyst for both types of reduction.
Conclusion
In summary, a study on the enantioselective pressure and
transfer hydrogenation of some poorly reactive ketones that
are not reduced with established ketone hydrogenation cata-
lysts is presented. The mechanism of the reduction with this
new type of catalyst is currently unknown. The lack of C2
symmetry and presence of both NH2 and NH functions in
the catalyst could mean that either of these are involved in
the hydrogenation or that a completely different inner-
sphere process takes place. A project aimed at unravelling
this mechanism to aid the design of new derivatives will be
Scheme 4. Enantioselective transfer hydrogenation of some bulky ke-
tones.
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Chem. Eur. J. 2009, 15, 1227 – 1232

Hydrogenation of Bulky Ketones
FULL PAPER
MeCN], 100%), 603 (58); HRMS (ES+): found: 644.1205 ([MÀCl+
MeCN]), C29H38N3OPS35ClRu requires 644.1212. The acetonitrile solvate
was also characterised by X-ray crystallography as discussed in reference
[14]. Elemental analysis calcd (%) for C27H35Cl2N2OPRuS + 1DMSO +
2CH3CN: C 49.6, H 5.9, N 7.0; found: C 49.3, H 5.5, N 6.7.
Example procedure for preparation of ketones using CuI-promoted alky-
lation of acid chlorides: 1-(4-Methoxyphenyl)-2,2-dimethylpropan-1-one
underway shortly. By using this first-generation catalyst, syn-
thetically useful selectivity has been obtained for hydrogena-
tion and transfer hydrogenation of some challenging ke-
tones. In addition, the catalyst used in this study forms a
new alternative class of catalyst for future development in
other types of reductions.
(5a):
A 1.7m solution of tert-butyllithium in pentane (4.33 mL,
6.49 mmol) was added to a suspension of copper bromide dimethyl sul-
fide complex (1.33 g, 6.49 mmol) in tetrahydrofuran (20 mL) at À788C.
After the mixture had been stirred for 30 min, a solution of 4-methoxy-
benzoyl chloride (1.00 g, 5.86 mmol) in tetrahydrofuran (5 mL) was
added slowly by cannula. After the mxiture had been stirred for 4 h, the
reaction was quenched by addition of saturated ammonium chloride solu-
tion and the organic layer separated. The aqueous layer was extracted
with diethyl ether, and the organic fractions combined, dried over mag-
nesium sulfate, filtered and concentrated in vacuo. The residue was puri-
fied by short-path distillation to yield the pure product as a colourless oil
(0.73 g, 65%). n˜max =2969 (s), 2907 (m), 2872 (w), 2840 (w), 1667 (s),
1602 (s), 1462 (s), 1477 (m), 1307 (m), 1258 (s), 1167 (s), 1029 (m), 960
Experimental Section
All research chemicals were obtained from commercial sources and used
as received unless otherwise stated. Dry, degassed solvents were used for
reactions that were carried out under an N2 atmosphere unless otherwise
indicated. Normal grade solvents were used for chromatography and
work-up procedures under aerobic conditions. Solvents were removed by
rotary evaporation on a Heidolph labrota 4000. All microwave syntheses
were carried out in a Biotage Initiator Microwave reactor using 5 mL
heavy-walled vials equipped with an air tight septum. Melting points
were determined with a Gallenkamp melting point apparatus N8 889339
(s), 842 (s), 769 (m) cmÀ1
(2H, m, CArH), 6.85–6.79 (2H, m, CArH), 3.78 (3H, s, OCH3), 1.30 (9H,
s, C
(CH3)3) ppm; 13C NMR (75.5 MHz CDCl3): dC =206.3 (C=O), 162.0
(COCipso), 131.0 (CArH), 130.1 (CipsoOMe), 113.2 (CArH), 55.4 (OCH3),
43.9 (C(CH3)3), 28.4 (C
(CH3)3) ppm; (CI+) m/z (%): 193.1 (([M+H])+,
;
1H NMR (300 MHz, CDCl3): dH =7.81–7.74
1
and are uncorrected. H NMR, 13C NMR, 31P NMR and 19F NMR spectra
were recorded on Bruker Avance 300 instruments (1H 300.1 MHz, 13C
75.5 MHz, 31P 121.4 MHz and 19F 282 MHz). Chemical shifts are reported
in ppm from tetramethyl silane (TMS) with the solvent resonance as the
internal standard. Chemical shift values for 31P spectra are reported
downfield of phosphoric acid, and chemical shifts values for 19F spectra
are relative to CFCl3. Proton resonance multiplicities are given as s (sin-
glet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad) or a
combination of these. When appropriate, coupling constants (J) are
quoted in Hz and are reported to the nearest 0.1 Hz. All spectra were re-
corded at room temperature, and the solvent for a particular spectrum is
given in parentheses. Infrared spectra were recorded on a Perkin Elmer
Paragon 1000 Spectrum GX FT-IR system. Mass spectra were recorded
on Waters Micromass GCT (Time of flight) fitted with lockspray for ac-
curate mass (ESI) or GCT (CI) instruments. Only major peaks are re-
ported, and intensities are quoted as percentages of the base peaks. Opti-
cal rotations were measured on an Optical Activity Ltd AA-1000 digital
polarimeter using a 5 mL cell with a 1 cm path length at room tempera-
ture using the sodium D-line and a suitable solvent, reported along with
the concentration (c: g per 100 mL). Microanalysis for carbon, hydrogen
and nitrogen were performed using an EA 1110 CHNS CE instruments
elemental analyser at the University the St Andrews. HPLC analysis has
been determined using a Varian Prostar operated by Galaxie workstation
PC software. Experimental procedures and spectroscopic details for
known compounds produced by the methods described here can be
found in the Supporting Information.
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
100), 135.1, 109.1, 85.1; HRMS (CI+): found: 193.1229 (Æ0.9 ppm),
C12H16O2 requires 193.1230.
General procedures for hydrogenation: A glass-lined stainless steel auto-
clave equipped with a magnetic stirring bead was charged with the cata-
lytic solution, prepared previously in a dried and degassed Schlenk tube,
containing the catalyst (0.5 mol%, 3.2 mg) dissolved in dry iPrOH
(3 mL). The substrate (1.0 mmol) was added in air, and tBuOK (1 mol%,
0.01 mL of 1m solution in tBuOH) was added prior to sealing the auto-
clave. The autoclave was flushed three times with hydrogen and finally
charged with hydrogen to the specific reaction pressure. The reactions
were stirred at the same speed for the desired times at the required tem-
perature using a stainless steel heating jacket connected to a thermocou-
ple and heater. After the desired time passed, the autoclave was cooled,
opened and the solvent removed. The conversion of the reaction was cal-
culated by NMR spectroscopy, generally using mesitylene as internal
standard. The products were isolated in pure form by column chromatog-
raphy (hexane/Et2O) and characterised by comparison of NMR, IR, MS,
HPLC/GCMS, optical rotation and, where appropriate, melting point
data with authentic samples (see the Supporting Information). The enan-
tiomeric excess was calculated by HPLC or using a chiral shift reagent as
indicated. Racemic authentic samples of all the products from ketone
and imine hydrogenation were first prepared by NaBH4 or LiAlH4 reduc-
tion. HPLC retention times and NMR data from hydrogenation experi-
ments matched the authentic samples exactly.
Complex 2 [RuCl2ACHTUNGTRENNUNG
(DMSO)4] (29 mg, 5.92ꢃ10À2 mmol) was added to a
solution of (1R,2R)-N-(2-dphenylphosphanylbenzyl)cyclohexane-1,2-dia-
mine (23 mg, 5.92ꢃ10À2 mmol) in dry THF prepared in a microwave
tube. The solution was then heated in the microwave at 1208C for
15 min. The solvent was removed under vacuum and the product was ob-
tained as a brown solid in quantitative yield and >95% purity. Recrystal-
lisation by slow evaporation of MeCN gave crystals of the bis-acetonitrile
adduct (25 mg, 65%). The complex can also be purified by chromatogra-
phy on silica gel (75:25 to 100:0 ethyl acetate/hexane) and isolated as a
brown powder. Crystals, powder and crude material gave similar results
The above method was used to prepare, for, example, 1-(4-methoxyphen-
yl)-2,2-dimethylpropan-1-ol (from ketone 5a): [a]2D0 À16.3 (c=4.24, tolu-
ene) (lit[21] (S, 99% ee): [a]2D0 À21.6 (c=4.24, benzene)); 1H NMR
(400 MHz, CDCl3): dH =7.14–7.09 (2H, m, CArH), 6.77–6.72 (2H, m,
CArH), 4.23 (1H, s, CHOH), 3.70 (s, 3H, OCH3), 1.92 (1H, br s, CHOH),
0.81 ppm (9H, s,
(Cipso), 134.5 (Cipso), 128.7 (CArH), 112.9 (CArH), 82.0 (CHOH), 55.2
CACTHNGUTERNNUG
(CH3)3); 31C NMR (75 MHz, CDCl3): dC =158.8
(OCH3), 35.7 (CACHTNUGTRENNG(U CH3)3), 25.9 ppm (CAHCTUNGTRENN(UNG CH3)3); (CI+) m/z (%): 195.1
in hydrogenation experiments. m.p. 169–1718C; [a]D20
+ 60 (c=0.5,
([MÀH2O], 100) and 177.1 ([M+H]+, 33). Enantioselectivity determined
by chiral HPLC. Chiralpak AD, 1.0 mL/min, 98:2 hexane:2-propanol.
Retention times: 16.8 min (R enantiomer) and 18.0 min (S enantiomer).
CHCl3); n˜max =432 (w), 3282 (s), 3214 (s), 3136 (s), 3053 (s), 2929 (w),
2856 (s), 1648 (s), 1587 (s), 1483 (s), 1434 (w), 1092 (w, R2S=O), 1047
(w), 1018 (w) cmÀ1 1H NMR (400 MHz, CDCl3): dH =7.59–7.09 (14H,
;
General procedures for microwave accelerated transfer hydrogenation:
A solution of substrate (ca. 1 mmol), catalyst, tBuOK (1m solution) and
mesitylene (ca. 1 mmol) in degassed iPrOH (3 mL) was prepared in a mi-
crowave vial under an atmosphere of nitrogen. The vial was then placed
inside the heating cavity of the microwave and heated for the required
period at the desired temperature. After the desired time passed, the mi-
crowave vial was opened and the reaction mixture passed through a plug
of silica and concentrated in vacuo. The conversion of substrate to prod-
m, CArH), 4.41–3.91 (2H, m, ArCH2NH), 3.64–3.74 (1H, m, NH), 3.47–
3.26 (2H, m, CHNH, CHNH2), 2.99 (6H, s, SO(CH3)2), 2.72–2.52 (1H,
m, cyclohexyl-H), 1.55 (2H, br, NH2), 1.29–0.91 (4H, m, cyclohexyl-H);
13C NMR (75.5 MHz, CDCl3): dC =135.0–126.0 (12 ArCH + 4 ArCipso),
62.7 (CH-NH), 56.1 (CH-NH2), 51.5 (d, 3JC,P =7.7 Hz, NHCH2Ar,), 45.8
AHCTUNGTRENNUNG
(SOACHTUNGTRENNUNG(CH3)2), 44.2 (SOACHTUNGTRENNUNG(CH3)2), 35.1 (cyclohexyl-CH2), 29.5 (cyclohexyl-
CH2), 23.8 (cyclohexyl-CH2), 23.4 (cyclohexyl-CH2); 31P NMR
(121.4 MHz, CDCl3): dP = +43.6 ppm; (ES+): m/z (%): 644 ([MÀCl+
Chem. Eur. J. 2009, 15, 1227 – 1232
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1231

M. L. Clarke et al.
uct was calculated by 1H NMR spectroscopy using mesitylene as internal
standard. The products were isolated by column chromatography or
short-path distillation and characterised by comparison of NMR, IR, MS,
HPLC, optical rotation and, where appropriate, melting point data, with
authentic samples.
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Am. Chem. Soc. 2003, 125, 13490–13503.
[10] There are still no pressure hydrogenation catalysts capable of this
task with any generality. However, a promising transfer hydrogena-
tion system recently emerged: M. T. Reetz, X. Li, J. Am. Chem. Soc.
2006, 128, 1044–1045.
[11] While our work was in progress, the Noyori group reported the first
Ru catalyst to show promise in hydrogenation of a few tertiary alkyl
Acknowledgement
ketones. The catalyst is of the type [RuCl2ACTHNUTRGENNG(U BINAP)ACHTUNTGERN(NUGN picoline)]. T.
Ohkuma, C. A. Sandoval, R. Srinivasan, Q. Lin, Y. Wei, K. Muniz,
R. Noyori, J. Am. Chem. Soc. 2005, 127, 8288–8289.
The authors would like to thank the EPSRC for funding this project and
for an equipment grant, the Donors of the American Chemical Society
Petroleum Research Fund, and Washington and Lee University (Glenn
Grant) for partial support of this work (M.B.F.). Mrs M. Smith and Mrs
C. Horsburgh are also thanked for technical assistance.
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Received: September 18, 2008
Published online: December 15, 2008
1232
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Chem. Eur. J. 2009, 15, 1227 – 1232