Highly enantioselective hydrogenation and transfer hydrogenation of cycloalkyl and heterocyclic ketones catalysed by an iridium complex of a tridentate phosphine-diamine ligand

Article abstract of DOI:10.1039/c3cc45545a

Ir complexes of chiral phosphine-diamine ligands catalyse the hydrogenation and transfer hydrogenation of aryl-piperidin-4-yl methanones, and ketones bearing both an aryl group and secondary alkyl substituent with up to 98% e.e., and with substrate to catalyst ratios of up to 4000.

Full text of DOI:10.1039/c3cc45545a

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Highly enantioselective hydrogenation and transfer
hydrogenation of cycloalkyl and heterocyclic ketones
catalysed by an iridium complex of a tridentate
phosphine-diamine ligand†
Cite this: Chem. Commun., 2013,
49, 10245
Received 22nd July 2013,
Accepted 20th September 2013
a
a
b
a
DOI: 10.1039/c3cc45545a
´
Jose A. Fuentes, Ian Carpenter, Nina Kann and Matthew L. Clarke*
www.rsc.org/chemcomm
Ir complexes of chiral phosphine-diamine ligands catalyse the hydro- effective for the hydrogenation of a-tertiary alkyl ketones,3a hetero-
genation and transfer hydrogenation of aryl-piperidin-4-yl methanones, cycle functionalised bulky ketones,3b,c esters3d,e and cyano-ketones.3f
and ketones bearing both an aryl group and secondary alkyl substituent
Unfortunately, we have only been partially successful in ration-
with up to 98% e.e., and with substrate to catalyst ratios of up to 4000. ally tuning the ligand structure to increase the ‘sweetspot’ in
substrate scope for asymmetric hydrogenations.3g Using the Ru
The enantioselective reduction of ketones using molecular hydro- catalysts, we were unable to get synthetically useful results for some
genation is one of the most important and scalable methods for of our target applications, including the enantioselective hydro-
preparing the ubiquitous chiral building blocks, secondary alcohols. genation of aryl(piperidin-4-yl)methanones. This was of interest to
The excellent results that are obtained in the reduction of a wide us, in part due to the steric bulk and free secondary amine
range of acetophenone derivatives using Noyori catalysts of type presenting challenges, but more importantly due to their repeated
[RuCl2(diphos)(diamine)] are well known, and these Ru complexes occurrence as a chiral building block in the pharmaceutical patent
are industrially viable catalysts (Fig. 1, 1).1 Most of these catalysts literature.6 Motivated by the renaissance in the hydrogenation of
give between 85–99% e.e. and high rates for acetophenone deriva- carbonyl derivatives using iridium complexes,5 we have studied Ir
tives. There has been considerable interest in examining both catalysed ketone hydrogenation using phosphine-diamine ligands
fundamentally different and slightly modified catalyst structures derived from cyclohexane-diamine. Here we show that changing
for ketone hydrogenation.2–5 This line of enquiry should, in principle from ruthenium to iridium, with the same very economic ligand
lead to increased substrate scope. A case in point is the development system, delivers a catalyst that is able to hydrogenate this class of
of a range of Ru complexes of phosphine diamine and phosphine ketone to give the industrially important enantioenriched alcohols
amino-alcohol ligands (Fig. 1, 2).3 These catalysts proved quite with high enantioselectivity. We also report an initial investigation
into substrate scope that reveals this catalyst is highly competent
for the reduction of a range of other substrates.
Due to the tendency of ligand 3 to give mixtures on reaction
with well-known Ir precursors, and the observation that the
best selectivity was observed with a ligand:iridium ratio of 0.5,
an equimolar combination of [IrCl(COD)]2/(R,R)-3 was used as
pre-catalyst in most of the reactions discussed below.
We examined the hydrogenation of the unprotected aryl(piper-
idin-4-yl)methanones 5k to 8k; these were readily prepared from
the Weinreb amides of the piperidines.† While Rh catalysts have
been used on chelating unprotected amino-ketones,4d hydrogena-
tion of secondary amine-containing ketones generally requires
protecting groups;1b,g,h the very few studies that specifically
mention aryl(piperidin-4-yl)methanones use protected or tertiary
amines.1h,7 We were therefore delighted to find that good conver-
sions and high enantioselectivity can be obtained using this iridium
catalyst. The dimethoxyphenyl substituted secondary alcohol has
been the subject of large scale asymmetric synthesis studies
before, from the Boc protected ketone 6k; 18 kilos of DIP-chloride
chiral reducing agent were required to produce 6.45 Kg of product
Fig. 1 Schematic of the Noyori catalysts and the systems studied in St Andrews.
a School of Chemistry, University of St Andrews, EaStCHEM, St Andrews, Fife, UK.
E-mail: mc28@st-andrews.ac.uk; Fax: +(44) 1334 463808; Tel: +(44) 1334 463850
b Department of Chemical and Biological Engineering, Chalmers University of
Technology, SE-412 96, Gothenburg, Sweden
† Electronic supplementary information (ESI) available: Full experimental proce-
dures, analytical data, NMR and HPLC spectra. See DOI: 10.1039/c3cc45545a
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 10245--10247 10245

View Article Online
Communication
ChemComm
Table 1 Hydrogenation of piperidine functionalised substrates 5k–8ka
Table 2 Hydrogenation of substrates 9k–12ka
Catalyst (%)
Entry Substrate ligand [%]
Time Conversion
T (1C) (h) (%) [ yield] ee
1
2
9k
9k
9k
9k
9k
9k
9k
9k
0.05 [0.1]
0.1 [0.1]
0.05 [0.05]
0.025 [0.025] 60
0.1 [0.1]
0.1
0.1 [0.1]
0.1
0.1
0.5 [0.5]
0.05 [0.1]
0.05 [0.1]
0.1 [0.1]
0.05 [0.1]
50
50
80
17
17
2
46
0.33
499
499 [89]
89
89
78
85
98
97
98.5
499 [97]
99
98 [89]
96
77(S)
84(S)
90(S)
95(S)
98(S)
97(S)
93(S)
87(S)
64(S)
89(S)
18.5(S)
67(S)
32
3
4b
5
Entry Substrate T (1C) Time (h) Conversion (%) [ yield] ee
21
21
45
45
50
50
50
50
17
40
6c
7
0.33
1
2
3
4
5
6
7
8
9
5k
5k
6k
6k
6k
7k
7k
8k
8k
8k
35
50
17
50
50
35
15
22
50
50
71
25
48
17
17
71
65
42
14
2
70
80b
78
75
75
69c
94
93
96
93
96
1
1
3
1
499 [68]
499 [94]
499
499
499 [71]
75
499 [77]
499 [72]
499
8c
9c
10
11
12
13
14
9k
10k
11k
11kd
12k
12kd
22
22
48
22
99 [80]
71
a
10
Reactions carried out using 0.1 mol% [IrCl(COD)]2 and 0.1% ligand
(R,R)-3 using 2 mol% KOtBu co-catalyst in dry IPA at 50 bar initial
hydrogen pressure, unless indicated otherwise. See ESI for determina-
a
Reactions carried out using 0.1 mol% [IrCl(COD)]2 and 0.1% (R,R)-3
using 2 mol% KOtBu co-catalyst in dry IPA at 50 bar initial hydrogen
pressure, unless indicated otherwise. See ESI for determination of ee
b
tion of ee and configurations. 0.025% [IrCl(COD)]2, 0.25% KOtBu,
c
d
61% yield, 499% e.e. Complex 13 was used. Ligand 4 was used.
b
c
and configurations. (R,R)-3 gives S product. 0.05 mol% [IrCl(COD)]2
0.1% 3.
even using a magnetically stirred reaction vessel, high conversion for
the hydrogenation of 9k can be reached using 0.025 mol% catalyst
loading with 95% e.e.; a single unoptimised recrystallisation gave
enantiopure material in 61% yield. Isobutyrophenone, 10k was also
reduced with high enantioselectivity (Table 2, entry 10). The tertiary
alkyl substituted ketones gave significantly inferior results than
those obtained with Ru catalysts of ligand 3. However, rather more
encouraging results could be obtained when ligand 3 is substituted
with P-chiral ligand 4. For example, the successful and completely
chemoselective hydrogenation of the unsaturated ketone 12k at
0.1 mol% catalyst loading with significantly better e.e. than
with the parent system (Table 2: compare entries 13 and 14)
shows that this type of catalyst can be tuned and therefore
bodes well for other applications.
All our attempts at reacting ligand 3 with [IrCl(COD)]2 or
[Ir(COD)2]+ at various stoichiometries gave mixtures that could
not be characterised and also decomposed within hours, even in
degassed solvents. Many attempts at growing crystals suitable for
X-ray diffraction failed. A complex that was free of any obvious
impurities could be isolated from the reaction of [Ir(OMe)(COD)]2
and ligand 3. The spectroscopic data is quite strongly supportive
of an amido complex with a formula [Ir(L–H)(COD)] (13) in
which ligand 3 exhibits a tridentate anionic coordination
mode. Further discussion of this assignment is in the ESI.†
With this complex and the in situ system in hand, we have
carried our preliminary studies to understand the nature of this
reduction, which is carried out in IPA solvent. Complex 13 and
[IrCl(COD)]2/3 also catalyse transfer hydrogenation using IPA as
hydrogen source. These reactions give similarly high selectivity
and productivity as the hydrogenations, and isolated complex
13 behaves similarly to the in situ catalyst (Scheme 2 and
further examples in ESI,† Table S3).
with 72.9% e.e. (4.6 Kg of 93% e.e. product after recryst.).6a Using
either the Boc protected or the free NH compound and these new
unoptimised catalytic protocols delivers product with higher selectivity
with significantly better atom economy. The Boc protected ketone
seems to reduce somewhat faster, but with lower selectivity in the
hydrogenations (Table 1, entries 2 and 4). Aryl(piperidin-4-yl)metha-
nones with less bulky aryl groups gave yet higher selectivity (Table 1,
entries 6–10), reaching close to enantiopurity (Scheme 1).
In order to investigate if this high selectivity was a very specific
niche for piperidine functionalised ketones, a range of studies were
carried out on ketones 9k–12k. The results in Table 2 show that
using 0.1% of the new Ir system, the cyclohexyl substituted ketone,
9k can be reduced very selectively: 98% e.e. and high conversion are
obtained in 20 minutes at room temperature (Table 2, entry 5).
While we have not carried out a full scale up study, we note that,
The hydrogenation reactions do utilise molecular hydrogen
as reductant as confirmed by an experiment using a ballast vessel at
constant pressure, and enhanced conversion at room temperature
relative to transfer hydrogenation.† The stoichiometric reaction
of 13 with hydrogen in the absence of IPA gives cyclooctane
Scheme 1 Substrates (k) reduced to alcohols (al) in this study.
10246 Chem. Commun., 2013, 49, 10245--10247
c
This journal is The Royal Society of Chemistry 2013

View Article Online
ChemComm
Communication
an Industry Fellowship and Dr Reddys Laboratories (UK) for
their co-support of this.
Notes and references
1 (a) T. Ohkuma, S. Hashaguchi, T. Ikariya and R. Noyori, J. Am. Chem. Soc.,
1995, 117, 2675; (b) R. Noyori and T. Ohkuma, Angew. Chem., Int. Ed.,
2001, 40, 40; (c) p. Saji, in The handbook of homogeneous hydrogenation,
ed. C. J. Elsevier and J. G. De Vries, Wiley-VCH, Weinheim, 2007;
(d) T. Ohkuma, K. Tsutsumi, N. Utsumi, N. Arai, R. Noyori and
K. Murata, Org. Lett., 2007, 9, 255; (e) T. Ohkuma, C. A. Sandoval,
Scheme 2 Transfer hydrogenation using the Ir–phosphinediamine system is
rapid and highly selective.
˜
(from hydrogenation of COD), and several Ir-hydride species as
determined by the multitude of peaks in the hydride region of the
1H NMR. The amido complex also reduces ketones very slowly
but selectively without added base.† The gas uptake of two
complex-13-catalysed reductions of 9k at 24 and 10 bar show
that the reactions are zero order in substrate and positive order in
R. Srinivasan, Q. Lin, Y. Wei, K. Muniz and R. Noyori, J. Am. Chem.
Soc., 2005, 127, 8288; ( f ) T. Ohkuma, N. Utsumi, K. Tsutsumi, K. Murata,
C. Sandoval and R. Noyori, J. Am. Chem. Soc., 2006, 128, 8724;
(g) M. Akashi, N. Arai, T. Inoue and T. Ohkuma, Adv. Synth. Catal.,
2011, 353, 1955; (h) N. Arai, H. Ooka, K. Azuma, T. Yabuuchi, N. Kurono,
T. Inoue and T. Ohkuma, Org. Lett., 2007, 9, 939; (i) N. B. Johnson,
I. C. Lennon, P. H. Moran and J. A. Ramsden, Acc. Chem. Res., 2007,
40, 1291.
hydrogen.† This was confirmed for both 13 and the in situ catalyst 2 Some chiral catalysts with different designs: (a) Y. J. Xu, N. W. Alcock,
G. J. Clarkson, G. Docherty, G. Woodward and M. Wills, Org. Lett.,
2004, 6, 4105; (b) Y. Xu, G. C. Clarkson, G. Docherty, C. L. North,
G. Woodward and M. Wills, J. Org. Chem., 2005, 70, 8079; (c) Q. Jing,
with separate experiments run at 0.25 and 0.5 M concentration at
50 bar pressure. The independence on substrate concentration,
implying that hydride transfer is faster than other steps in the
cycle (i.e. activation of hydrogen), is in contrast to the slower
reactions catalysed by Ru complexes of P, NH, NH2 ligands.3c This
shows that the Ir systems are more proficient at the transfer of
hydride to the ketone. Complex 13 gives significantly lower
selectivity than [IrCl(COD)]2/3 under pressure hydrogenation
reactions at higher temperatures (e.g. 64% e.e. 99% conv. after
3 hours at 50 1C, 0.1% 13), but gives similar results at room
temperature (e.g. 96% e.e. at 81% conv. after 20 minutes at 21 1C,
0.1% 13). For the [IrCl(COD)]2/3 system the e.e. does not degrade
too much from 98% maximum right up to 80 1C (Table 2). A full
table (20 expts) is provided in the ESI.† A hydrogenation carried
out in d8-IPA reveals that over 90% of the CD(OH/D) signal is
deuterated and hence the transfer hydrogenation is competitive
with pressure hydrogenation. While since it is possible that Ir
X. Zhang, H. Sun and K. L. Ding, Adv. Synth. Catal., 2005, 347, 1193;
(d) F. Naud, C. Malan, F. Spindler, C. Ruggeberg, A. T. Schmidt and
H. U. Blaser, Adv. Synth. Catal., 2006, 348, 47; (e) K. Abdur-Rashid,
R. W. Guo, A. J. Lough, R. H. Morris and D. T. Song, Adv. Synth. Catal.,
2005, 347, 571; ( f ) H. Huang, T. Okuno, K. Tsuda, M. Yoshimura and
M. Kitamura, J. Am. Chem. Soc., 2006, 128, 8716; (g) N. Arai, K. Suzuki,
S. Sugizaki, H. Sorimachi and T. Ohkuma, Angew. Chem., Int. Ed.,
2008, 47, 1770; (h) W. N. M. O, A. J. W. Lough and R. H. Morris, Chem.
Commun., 2010, 46, 8240.
3 (a) M. L. Clarke, M. B. Diaz-Valenzuela and A. M. Z. Slawin, Organo-
metallics, 2007, 26, 16; (b) M. B. Diaz-Valenzuela, S. D. Phillips,
M. B. France, M. E. Gunn and M. L. Clarke, Chem.–Eur. J., 2009,
15, 1227; (c) S. D. Phillips, J. A. Fuentes and M. L. Clarke, Chem.–Eur. J.,
2010, 16, 8002; (d) I. Carpenter, S. C. Eckelmann, M. T. Kuntz,
J. A. Fuentes, M. B. France and M. L. Clarke, Dalton Trans., 2012,
41, 10136; (e) M. L. Clarke, Catal. Sci. Technol., 2012, 2, 2418;
( f ) J. A. Fuentes, S. D. Phillips and M. L. Clarke, Chem. Cent. J.,
2012, 6, 151; (g) S. D. Phillips, K. H. O. Anderson, N. Kann, M. T. Kuntz,
M. B. France, P. Wawryzniak and M. L. Clarke, Catal. Sci. Technol.,
2011, 1, 1336.
catalysed H–D exchange can occur, but this is only possible 4 Other metals used in asymmetric ketone hydrogenation include:
(a) Os catalysts: W. Barratta, M. Ballico, G. Chelucci, K. Siega and
P. Rigo, Angew. Chem., Int. Ed., 2008, 47, 4362; (b) Fe catalysts:
R. H. Morris, Chem. Soc. Rev., 2009, 38, 2282; (c) Cu catalysts:
when the fundamental steps of transfer hydrogenation are
competitive with those of pressure hydrogenation. In the Ru
catalysed reductions, less than 20% of deuterium incorporation
is observed3a in accordance with those catalysts being much
slower at transfer hydrogenation.
K. Junge, B. Wendt, D. Addis, S. L. Zhou, S. Das, S. Fleischer and
M. Beller, Chem.–Eur. J., 2011, 17, 101 and ref’s therein; (d) Rh
catalysis: T. Hayashi and M. Kumada, Acc. Chem. Res., 1982, 15, 395.
5 (a) J.-B. Xie, J.-H. Xie, X.-Y. Liu, W.-L. Kong, S. Li and Q.-L. Zhou,
J. Am. Chem. Soc., 2010, 132, 4538; (b) J. E. D. Martins, D. J. Morris and
M. Wills, Tetrahedron Lett., 2009, 50, 688; (c) T. Irrgang, D. Friedrich
and R. Kempe, Angew. Chem., Int. Ed., 2011, 50, 2183; (d) C. Li,
B. Villa-Marcos and J. Xiao, J. Am. Chem. Soc., 2009, 131, 6967;
(e) transfer hydrogenation using Ir is more common, see R. J.
Lundgren and M. Stradiotto, Chem.–Eur. J., 2008, 14, 10388 and ref’s
therein; ( f ) R. Malacea, R. Poli and E. Manoury, Coord. Chem. Rev.,
2010, 254, 729; (g) J. K. Liu, X. F. Wu, J. A. Iggo and J. L. Xiao, Coord.
Chem. Rev., 2008, 252, 782; (h) W. W. N. O, A. J. Lough and
R. H. Morris, Organometallics, 2012, 31, 2152; (i) J.-B. Xie, J.-H. Xie,
X.-Y. Liu, Q. Q. Zhang and Q.-L. Zhou, Chem.–Asian J., 2011, 6, 899.
6 (a) E. D. Daugs, J. C. Evans, H.-W. Freming, T. H. E. Hilpert,
J. N. Koek, F. M. Laskovics, S. K. Stolz-Dunn and I. A. Tomlinson,
US20020151717, Aventis, 2002; (b) S. K. Stolz-Dunn, J. Evans and
I. A. Tomlinson, US7332607, Aventis, 2008; (c) R. B. Diebold,
G. Thomas, P. Grover, S. Huang, S. Ionndis, C. A. Ogoe, J. C. Saeh
and J. Varnes, WO2012/017252A1, Astra Zeneca, 2011; (d) G. J.
Bridger, Y. Zhou and R. Skerlj, WO2005/059107, Anormed Inc.,
2004; (e) F. Ledo-Gomez, A. Munoz Munoz and C. Pumar Duran,
WO2011/147780A1, Faes Farma S. A., 2011.
In conclusion, the combination of [IrCl(COD)]2 and chiral P,
N, N ligands derived from cyclohexane diamine gives a catalyst
that exhibits high selectivity and activity in the hydrogenation
and transfer hydrogenation of ketones bearing an aryl substitu-
ent and some form of secondary alkyl group. The selectivity and
activity observed is significantly higher than that obtained with a
Ru catalyst derived from the same ligand (or in fact the use of
[RhCl(COD)]2/ligand 3.†). The ability to deliver 490% e.e. at low
catalyst loading and near ambient temperature for these more
challenging substrates means this catalyst is already of synthetic
use, but this type of iridium catalyst is also a worthwhile lead
structure for further research.
The authors thank the EPSRC National Mass Spectrometry
Service, the St Andrews technical staff for their assistance, the
EPSRC, the Swedish Research Council, and the University of
St Andrews, for funding. MLC also thanks the Royal Society for 7 D. J. Morris, A. M. Hayes and M. Wills, J. Org. Chem., 2006, 71, 7035.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 10245--10247 10247