Asymmetric hydrogenation of isobutyrophenone using a [(diphosphine) RuCl2 (1,4-diamine)] catalyst

Article abstract of DOI:10.1021/ol047355y

(Chemical Equation Presented) The use of three chiral 1,4-diamines in the [(diphosphine) RuCl₂ (diamine)] catalyst system is demonstrated in the hydrogenation of acetophenone. The use of a 1,4-diamine offers unique properties that allow tuning of the catalyst system. These include the first example of the use of a racemic diamine in combination with a chiral phosphine, which gives 95% ee in the hydrogenation of isobutyrophenone

Full text of DOI:10.1021/ol047355y

ORGANIC
LETTERS
2005
Vol. 7, No. 8
1449-1451
Asymmetric Hydrogenation of
Isobutyrophenone Using a
[(Diphosphine) RuCl2 (1,4-Diamine)]
Catalyst
Gabriela A. Grasa, Antonio Zanotti-Gerosa, Jonathan A. Medlock, and
William P. Hems*
Johnson Matthey Catalysis and Chiral Technologies, Unit 28,
Cambridge Science Park, Milton Road, Cambridge, UK
william.hems@matthey.com
Received December 23, 2004
ABSTRACT
The use of three chiral 1,4-diamines in the [(diphosphine) RuCl2 (diamine)] catalyst system is demonstrated in the hydrogenation of acetophenone.
The use of a 1,4-diamine offers unique properties that allow tuning of the catalyst system. These include the first example of the use of a
racemic diamine in combination with a chiral phosphine, which gives 95% ee in the hydrogenation of isobutyrophenone
The preparation of enantiomerically pure secondary alcohols
is among one of the most important reactions for the
manufacture of pharmaceutical intermediates. The asym-
metric reduction of ketones represents the simplest and most
powerful method for the production of these chiral alcohols.
The use of hydrogen, a clean and inexpensive gas, in the
presence of a small amount of a catalyst makes this approach
highly viable for industrial application. The most general and
efficient catalyst for this reaction was pioneered by Noyori,
who showed that ruthenium complexes of the type [(diphos-
phine)-RuCl2-(diamine)], used in the presence of a base in
2-propanol, are extremely efficient and selective catalysts
for the asymmetric reduction of unfunctionalized ketones.1
Since Noyori’s work using XylBinap,2 a number of other
groups have demonstrated the use of other diphosphines that
give rise to high activities and selectivities when used in
this catalyst system.3-7 Much less effort has been dedicated
to the modification of the diamine ligand. Most phosphines
have been exclusively used in conjunction with 1,2-diamines,
with DPEN and DAIPEN being favored.8 We sought to
investigate the effect of other diamines in this catalyst system
with the aim of ultimately tuning the selectivity of the catalyst
to extend even further the range of potential substrates. Our
(2) Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa, M.;
Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1998, 120, 13529. Ohkuma, T.; Ishii, D.; Takeno, H.; Noyori,
R. J. Am. Chem. Soc. 2000, 122, 6510. Ohkuma, T.; Koizumi, M.; Ikehira,
H.; Yokozawa, T.; Noyori, R. Org Lett. 2000, 2, 659.
(3) Wu, J.; Chen, H.; Kwok, W.; Guo, R.; Zhou, Z.; Yeung C.-H.; Chan,
A. C. S. J. Org. Chem. 2002, 67, 7908. Wu, J.; Ji, J.-X.; Guo, R.; Yeung,
C.-H.; Chan, A. C. S. Chem. Eur. J. 2003, 9, 2963.
(4) Scalone, M.; Waldmeier, P. Org. Process Res. DeV. 2003, 7, 418.
(5) Henschke, J. P.; Zanotti-Gerosa, A.; Moran, P.; Harrison, P.; Mullen,
B.; Casy G.; Lennon, I. C. Tetrahedron Lett. 2003, 44, 4379.
(6) Burk, M.; Hems, W.; Herzburg, D.; Malan C.; Zanotti-Gerosa, A.
Org. Lett. 2000, 2, 4173.
(7) Dominguez, B.; Zanotti-Gerosa, A.; Hems, W. Org. Lett. 2004, 6,
1927.
(8) DPEN ) 1,2-Diphenylethylenediamine; DIAPEN ) 1,1-di(4-anisyl)-
2-isopropyl-1,2-ethylenediamine; see: Wey, S.; O’Conner, K. J.; Burrows,
C. J. Tetrahedron Lett. 1993, 34, 1905.
(1) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (b) Noyori, R.;
Ohkuma, T. Angew Chem., Int. Ed. 2001, 40, 40.
10.1021/ol047355y CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/15/2005

working hypothesis for this was that chiral 1,4-diamines
would change the orientation of the N-H group by forming
a seven-membered chelate with the metal center. Hence, the
hydrogen bond interaction with the ketone that is believed
to occur in the catalytic cycle will be altered, which may
open up the opportunity to tune the catalyst for the reduction
of a larger range of ketones.9 Our choice of 1,4-diamines
was analogous to the fact that many phosphine ligands exist
as a seven-membered chelate with the metal center and that
the aryl groups on the phosphorus atoms adopt axial and
equatorial positions. Three such phosphorus ligands used in
Rh hydrogenation have been DIOP,10 SK-PHOS,11 and
BPPM,12 and therefore we sought to prepare the structurally
analogous diamines. Noyori has very recently reported the
use of [(XylBinap) RuCl2 (1)], which gave excellent selec-
tivities in the hydrogenation of cyclic ketones.13
Diamines 1 and 3 were synthesized according to literature
methodology,14 and 2 was synthesized from azide displace-
ment of the known dimesylate. The diamines were reacted
with chiral Ru phosphine complexes from the Binap and
P-Phos families according to literature procedures. Single-
crystal X-ray analysis of [(S)-Binap RuCl2 (R)-1] is shown
in Figure 2. As expected, the diamine forms a seven-
Figure 2. (S)-Binap-RuCl2-(R,R)-1 complex. All hydrogen atoms,
except the hydrogens on the diamine, have been omitted for clarity.
Selected bond lengths (Å) and angles (deg): Ru-N1 2.239(3),
Ru-N2 2.220(3), Ru-P1 2.2996(8), Ru-P2 2.3005(9), Ru-Cl1
2.4216(8), Ru-Cl2 2.4076(8), Cl1-H1A (N1) 2.610, Cl2-H2B
(N2) 2.628; N1-Ru-N2 92.00(10), P1-Ru-P2 89.17(3),
Cl1-Ru-Cl2 161.97(3).
Preliminary results revealed that extremely rapid hydro-
genation of acetophenone was achieved using diamines 1
and 3. Results with catalysts containing diamine 2 were less
promising, with much lower conversions obtained. The
hydrogenation started rapidly using this diamine but then
appeared to stop, suggesting that although the active Ru
hydride species was formed initially, this decomposed during
the reaction. Although rapid hydrogenation of acetophenone
was observed with diamine 3, the enantioselectivities were
disappointing, the highest being achieved using the sterically
bulky phosphine 4b in accordance with results observed with
1,2-diamines. The results obtained with diamine 1, however,
were much more interesting, as they showed distinct differ-
Table 1. Hydrogenation of Acetophenone Using
[(Diphosphine) RuCl2 (1,4-Diamine)] Catalysts
Figure 1. Diphosphine and diamine structures.
entry
catalyst
conversion
ee
membered chelate with λ configuration. The Binap ligand
adopts a δ seven-membered chelate with Ru with the phenyl
moieties adopting axial and equatorial arrangements. The
catalytic behavior of the catalysts was first examined using
acetophenone as a substrate (Table 1).
1
2
3
4
5
6
7
8
9
(R)-P-Phos RuCl2 (R)-1
(S)-P-Phos RuCl2 (R)-1
>99
>99
>99
>99
>99
>99
>99
>99
47
75 (R)
81 (S)
55 (S)
51 (R)
70 (R)
85 (S)
34 (S)
64 (R)
37 (R)
26 (S)
42 (R)
76 (S)
(R)-Xyl-P-Phos RuCl2 (R)-1
(S)-Xyl-P-Phos RuCl2 (R)-1
(R)-TolBinap RuCl2 (R)-1
(S)-TolBinap RuCl2 (R)-1
(R)-XylBinap RuCl2 (R)-1
(S)-XylBinap RuCl2 (R)-1
(S)-TolBinap RuCl2 (R)-2
(R)-TolBinap RuCl2 (R)-2
(S)-Xyl-P-Phos RuCl2 (S)-3
(R)-Xyl-P-Phos RuCl2 (S)-3
(9) Sandoval, C. A.; Ohkuma, T.; Muniz, K.; Noyori, R. J. Am. Chem.
Soc. 2003, 125, 13490. Abdur-Rashid, K.; Faatz, M.; Lough, A. J.; Morris,
R. H. J. Am. Chem. Soc. 2001, 123, 7473.
(10) Kagan, H. B.; Dang, T.-P. J. Am. Chem. Soc. 1972, 94, 6429.
(11) Li, W.; Waldkirch, J. P.; Zhang, X. J. Org. Chem. 2003, 67, 7618.
(12) Achiwa, K. J. Am. Chem. Soc. 1976, 98, 8265.
(13) Ohkuma, T.; Hattori, T.; Ooka, H.; Inoue, T.; Noyori, R. Org. Lett.
2004, 6, 2681
(14) (a) For diamine 1: Kim, D.-K.; Kim, G.; Gam, J.; Cho, Y.-B.; Kim,
H.-T.; Tai, J.-H.; Kim, K. H.; Hong, W.-S.; Park, J.-G. J. Med. Chem. 1994,
37, 1471. (b) Diamine 3: Nagamani, D.; Ganesh, K. N. Org. Lett. 2001, 3,
103.
10
11
12
37
>99
>99
a Conversion and ee determined by chiral GC (Chrompack Chirasil
DEX-CB column). The absolute configuration was determined by com-
parison of retention time with literature data.
1450
Org. Lett., Vol. 7, No. 8, 2005

ences from the usual catalytic behavior observed with 1,2-
diamines. First, the use of the less sterically bulky phos-
phines, P-Phos 4a instead of Xyl-P-Phos 4b, gave the highest
enantioselectivity. Second, there appeared to be only a small
difference in the enantioselectivities obtained with either the
matching or mismatching phosphine/diamine combinations,
and third, the configuration of the alcohol produced was
reversed to the 1,2-diamine case, with (R)-P-Phos giving the
(R)-alcohol, albeit in moderate ee. These subtle differences
in the hydrogenation of acetophenone heartened us to screen
these catalysts against other ketone substrates. Increasing the
steric bulk on the aromatic ring or the alkyl substituent of
the ketone appeared to give enhanced results. For example,
93% ee was obtained in the hydrogenation of o-OMe
acetophenone using (S)-P-Phos RuCl2 (R)-1.15 Therefore, the
hydrogenation of isobutyrophenone was studied in more
detail. The results are shown in Table 2.
ee was obtained. Again the observation of no matching or
mismatching phosphine/diamine catalyst combination was
highlighted even more starkly with this substrate, as both
gave a very high ee. When a catalyst was prepared with (R)-
TolBinap and racemic diamine 1, very high enantioselectivity
was obtained in the isobutyrophenone hydrogenation. We
believe that this is the first example of a racemic diamine
used in conjunction with a chiral phosphine in this catalyst
system that gives extremely high enantioselectivity in the
hydrogenation of an aromatic ketone.17 The same trend was
observed with the P-Phos family of ligands. When (S)-P-
Phos was used in combination with racemic 1, a very high
ee was obtained. 31P NMR experiments confirmed that this
(S)-P-Phos RuCl2 rac-1 complex was a 1:1 mixture of the
two diastereoisomers. It was also observed that the reaction
rates of (S)-P-Phos RuCl2 rac-1 and (S)-P-Phos RuCl2 (S)-1
were identical, which would rule out a process of selective
activation of one diasteroisomer of the complex. When a
catalyst prepared using racemic P-Phos and chiral diamine
1 was tested, virtually no stereoinduction was observed.
In summary, we have shown that it is possible to tune the
catalyst by the use of a structurally different diamine in this
catalyst system. We, in parallel with others, have discovered
a distinctly useful 1,4-diamine that in combination with Ru
and a phosphine exhibits wide scope in the hydrogenation
of two classes of aromatic ketones. For example, comple-
mentary to Noyori’s paper describing the use of diamine 1,
we found that the use of (S)-Xyl-P-Phos RuCl2 (R)-1 gave
96% ee in the hydrogenation of tetralone.18 Herein, we have
modified the catalyst further to show that in combination
with Ru P-Phos, high enantioselectivities can be obtained
for other aromatic ketones such as acetophenone derivatives.
The unique tuning of the complex allows for very high
selectivities to be obtained in the hydrogenation of isobu-
tyrophenone even with the use of a racemic diamine in the
presence of a chiral phosphine.
Table 2. Hydrogenation of Isobutyrophenone Using
[(Diphosphine) RuCl2 (1,4-Diamine)] Catalysts
entry
catalyst
conversion (%) ee (%)
1
2
3
4
5
6
7
8
9
(R)-XylBinap RuCl2 (R)-DAIPEN
(R)-XylBinap RuCl2 (R)-1
(S)-XylBinap RuCl2 (R)-1
(S)-TolBinap RuCl2 (S)-1
(S)-TolBinap RuCl2 (R)-1
(R)-TolBinap RuCl2 rac-1
(S)-P-Phos RuCl2 (R)-1
(S)-P-Phos RuCl2 (S)-1
(S)-P-Phos RuCl2 rac-1
(rac)-P-Phos RuCl2 (S)-1
(R)-Xyl-P-Phos RuCl2 (R)-1
(S)-Xyl-P-Phos RuCl2 (R)-1
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
99 (S)
68 (R)
58 (S)
94 (S)
97 (S)
95 (R)
97 (S)
95 (S)
96 (S)
9
10
11
12
Acknowledgment. We thank Fred Hancock for much
encouragement in this venture and Dr. John E. Davies of
the University of Cambridge for the X-ray structure analysis.
46 (R)
75 (S)
a Conversion and ee determined by chiral GC (Chrompack Chirasil
DEX-CB column). The absolute configuration was determined by com-
parison of retention time with literature data.
Supporting Information Available: Experimental pro-
cedures and NMR characterization data for all new [(diphos-
phine) RuCl2 (diamine)] catalysts described in the text, a
representative example of the hydrogenation procedure, and
also further examples of the hydrogenation of aromatic
ketones such as tetralone derivatives. This material is
available free of charge via the Internet at http://pubs.acs.org.
The direct hydrogenation of isobutyrophenone has been
reported using an Ir-Binap catalyst under relatively harsh
conditions.16 Highly enantioselective hydrogenation of isobu-
tyropheone using the Ru Noyori 1,2-diamine catalyst system
can be obtained using XylBinap as phosphine in combination
with the relatively expensive 1,2-DAIPEN diamine. The use
of diamine 1 in combination with XylBinap only gave a
modest ee. However, when TolBinap was used, an excellent
OL047355Y
(17) For an example of a conformationally flexible phosphine and chiral
diamine, see: Mikami, K.; Korrenaga, T.; Terada, M.; Ohkuma, T.; Pham,
T.; Noyori, R. Angew. Chem., Int. Ed. 1999, 38, 495. Mikami, K.,
Matsukawa, S. Nature 1997, 285, 613. Aikawa, K.; Mikami. K. Angew
Chem., Int. Ed. 2003, 42, 5455. Mikami, K.; Korenaga, T.; Yusu, Y.;
Yamanaka, M. AdV. Synth. Catal. 2003, 345, 246.
(15) See Supporting Information for a full table of results.
(16) Zhang, Z.; Kumobayashi, H.; Takaka, H. Tetrahedron: Asymmetry
1994, 1179.
(18) See Supporting Information for a full table of the hydrogenation of
cyclic aromatic ketones such as tetralone.
Org. Lett., Vol. 7, No. 8, 2005
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