Asymmetric hydrogenation of tert-alkyl ketones

Article abstract of DOI:10.1021/ja052071+

A combined system of RuCl₂(tolbinap)(pica) and an alkaline or organic phosphazene base catalyzes asymmetric hydrogenation of sterically congested tert-alkyl ketones (TolBINAP = 2,2-bis(di-4-tolylphosphino)-1,1-binaphthyl, PICA = α-picolylamine). Hydrogenation with RuH(η1-BH4)(tolbinap)(pica) does not require any strong base. Alcoholic solvents strongly affect the catalytic efficiency. The reaction proceeds smoothly in ethanol under 1-20 atm of H₂ and at room temperature with a substrate to catalyst molar ratio of up to 100000. Various aliphatic, aromatic, heteroaromatic, and olefinic tert-alkyl ketones are convertible to the corresponding chiral carbinols in high enantiomeric purity. Olefinic and heteroaromatic functions are left intact. Certain cyclic ketones are also usable. The mode of enantioface selection is consistent and predictable. Copyright

Full text of DOI:10.1021/ja052071+

Published on Web 05/18/2005
Asymmetric Hydrogenation of tert-Alkyl Ketones
Takeshi Ohkuma,*,‡ Christian A. Sandoval,†,§ Rajagopal Srinivasan,§ Quinghong Lin,† Yinmao Wei,†
Kilian Mun˜iz,† and Ryoji Noyori*,†
Department of Chemistry and Research Center for Materials Science, Nagoya UniVersity, Chikusa,
Nagoya 464-8602, Japan, DiVision of Chemical Process Engineering, Graduate School of Engineering,
Hokkaido UniVersity, Sapporo 060-8628, Japan, and Nagoya Industrial Science Research Institute, Naka-ku,
Nagoya 460-0008, Japan
Received March 31, 2005; E-mail: noyori@chem3.chem.nagoya-u.ac.jp
No practical methods exist for asymmetric hydrogenation of tert-
alkyl ketones, despite tremendous efforts made to date.1 Chiral
RuX2(binap)(1,2-diamine)2 complexes (X ) anionic ligand) with3,4
or without5,6 a strong base allow rapid, enantioselective hydrogena-
tion of various simple, unfunctionalized ketones, where 2-propanol
is the solvent of choice. However, for an obvious steric reason,
tert-alkyl ketones are feebly reactive in this hydrogenation. For
example, trans-RuCl2[(S)-tolbinap][(S,S)-dpen]2 hydrogenated pi-
nacolone (1a) in 2-propanol at 9 atm to produce (S)-2a in only
20% yield and 14% ee ([1a] ) 1.04 M, [KOC(CH3)3] ) 21.2 mM,
1a:Ru:base ) 2000:1:20, 25 °C, 24 h). With trans-RuCl2[(S)-
tolbinap](bipy)2 under similar conditions, no hydrogenation took
place. We here report that this problem can be overcome by
replacement of the symmetrical 1,2-diamine or bipyridine ligand
by an unsymmetrical NH2/pyridine hybrid ligand, R-picolylamine
(PICA), and also by the use of ethanol rather than 2-propanol as
solvent.7 The new BINAP/PICA-based Ru catalyst system allows
for practical asymmetric hydrogenation of a wide range of tert-
alkyl ketones.
RuCl2[(S)-tolbinap](pica) [(S)-3a] was conveniently synthesized
8
by treatment of oligomeric RuCl2[(S)-tolbinap](dmf)n with 1.2
equiv of commercial PICA in CH2Cl2 at 25 °C for 2 h (see
Supporting Information). Five diastereomers are possible for this
pale orange octahedral Ru complex, and in fact, the 31P{1H} NMR
spectrum (benzene-d6, 22 °C) showed two major AB quartets at
42.2 and 45.9 ppm with JP-P ) 35.6 Hz (30%) and 44.7 and 48.2
ppm with JP-P ) 36.0 Hz (20%) together with three minor quartets
(total 50%). The content of the most dominant diastereomer was
increased to >90% by heating at 80 °C for 30 min in toluene.
However, we used the diastereomeric mixture as a precatalyst since
be used in place of KOC(CH3)3 (Table 1). Hydrogenation of 1a in
the variable diastereomeric ratio did not affect the catalytic
ethanol with the H/BH4 complex (S)-3b (S/C ) 2000, 4 atm, 25
°C, 5 h) proceeded without added base to afford (S)-2a in 97% ee
and 100% yield. Some other examples are given in Table 1.
Reaction of an analogous ketone 1b with (R)-3a gave (R)-2b in
97% ee. Hydrogenation of pivalophenone (1d) (the simplest
aromatic tert-butyl ketone) catalyzed by (S)-3a in ethanol (ketone:
3:base ) 2000:1:18, [KOC(CH3)3] ) 20 mM, 5 atm, 25 °C, 12 h)
gave (R)-2d in 100% yield and 97% ee. This method can be used
for reaction of heteroaromatic tert-butyl ketones. Hydrogenation
of 1e and 1f with (S)-3a gave (R)-2e and (R)-2f in high enantiomeric
excess, where the furan or thiophene ring remained unaffected.4d
This hydrogenation is carbonyl-selective. Reaction of the olefinic
tert-butyl ketone 1g with (S)-3a quantitatively afforded the allylic
alcohol (S)-2g in 97% ee without saturation of the olefinic
linkage.3-5,10 The aliphatic enone 1h was converted to (R)-2h in
98% ee by using (R)-3a. The alkenyl groups behaved similarly to
aromatic and heteroaromatic rings in enantioface selection.
In the presence of (S)- or (R)-3a and a base in ethanol,
1-adamantyl ketone 4, cyclic tert-alkyl ketone 5, and aromatic cyclic
efficiency and enantioselectivity. Reaction of (S)-3a with 16 equiv
of NaBH4 in a 1:1 ethanol/benzene mixture afforded RuH(η1-BH4)-
[(S)-tolbinap](pica) [(S)-3b] as a pale yellow powder showing
31P{1H} NMR signals (benzene-d6, 22 °C) at 71.6 and 74.2 ppm
with JP-P ) 41.4 Hz (AB) and a hydride resonance at δ -13.82
(dd, JH-P ) 23.9 Hz).9
The chiral Ru complex 3 effects asymmetric hydrogenation of
various tert-butyl ketones with a high substrate/catalyst (S/C) ratio
under mild conditions. Thus, when an ethanol solution of 1a (the
simplest aliphatic tert-butyl ketone) (21.1 g, 5 M) containing (S)-
3a (2.0 mg, S/C ) 100 000) and KOC(CH3)3 (83.0 mg in HOC-
(CH3)3, 20 mM) was stirred under 20 atm of H2 in a 100 mL glass
autoclave with a plastic cover at 25 °C for 24 h, (S)-2a was obtained
quantitatively in 98% ee. The reaction proceeded even under
atmospheric pressure of hydrogen with the same enantioselectivity.
Phosphazene bases (metal-free, strong organic bases)6 could also
† Nagoya University.
‡ Hokkaido University.
§ Nagoya Industrial Science Research Institute.
9
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J. AM. CHEM. SOC. 2005, 127, 8288-8289
10.1021/ja052071+ CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Asymmetric Hydrogenation of tert-Alkyl Ketonesa
structural characteristics of PICA. The bidentate ligand has a
functional NH2 group6 and an unfunctional flat, small-sized pyridine
ring that mitigates the nonbonded repulsion with the tert-butyl group
of an approaching ketone. Notably, the BINAP/PICA-Ru catalyst
is suitable only for reaction of tert-alkyl ketones. Hydrogenation
of acetophenone with (S)-3a gave (R)-1-phenylethanol in 100%
yield, but with only 54% ee (ethanol) or 14% ee (2-propanol).
In summary, the newly devised BINAP/PICA-Ru complex 3,
with or without a strong base, depending on the anionic ligand,
efficiently catalyzes asymmetric hydrogenation of sterically con-
gested tert-alkyl ketones to chiral tert-alkyl carbinols in high
enantiomeric purity. Aliphatic, aromatic, heteroaromatic, and ole-
finic ketones, as well as certain cyclic ketones, can be employed.
The reaction proceeded smoothly under mild conditions (1-20 atm,
room temperature) with an S/C ratio as high as 100 000.
Alcohol
ketone
catalyst
S/Cb
H2,atm
time, h
% yieldc
% eed
config.e
1a
1a
1a
1ag
1a
1b
1c
1d
1ek
1f
(S)-3a
(R)-3a
(S)-3a
(S)-3a
(S)-3b
(R)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(S)-3a
(R)-3a
(S)-3a
(S)-3a
(R)-3a
(R)-3a
(S)-3a
(S)-3a
2000
2000
2000f
100000
2000h
2300
2020
2000
2400
2100
2050
2040
2000
2250
2050
2400
2000
2000
5
1
4
20
4
5
8
5
8
8
5
8
5
8
8
8
5
5
5
9
5
24
5
5
24
12
5
5
5
5
5
5
20
5
100
100
100
100
100
100
<5
97
98
97
98
97
97
ndj
97
97
98
97
98m
98
84
90
98
97
82
S
R
S
S
S
Ri
ndj
R
100
99
Ri
Ri
Si
Ri,m
Sn
Sp
S
100
100
99.6l
100
95
99.6
100
100
100
1g
1hl
4
5o
6a
6b
8a
8b
Acknowledgment. This work was supported by Grants-in-Aid
from the Japan Society for the Promotion of Science (JSPS) (Nos.
14GS0214 and 15350079), the New Energy and Industrial Technol-
ogy Development Organization (NEDO), and the Nagase Science
and Technology Foundation.
S
S
S
5
5
a Unless otherwise stated, reactions were conducted at 25-27 °C using
a 0.26-0.93 M ketone solution in ethanol containing 3 (0.10-0.53 mM)
and KOC(CH3)3 (20-28 mM). b Substrate/catalyst molar ratio. c GC or 1H
NMR analysis. d Chiral GC or HPLC analysis. e Determined by the sign of
rotation. f A phosphazene base, 1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-
bis[tris(dimethylamino)phosphoranylidenamino]-2′,4′-catenadi(phosphazene),
was used in place of KOC(CH3)3. g Reaction using 21.1 g of 1a (5 M) with
3a (0.05 mM) in 15 mL of ethanol. h No additional base. i See Supporting
Information. j Not determined. k Purity was 93%. l A 5:1 E/Z mixture. m Data
of the E allylic alcohol. n (S)-1-(1-Adamantyl)ethanol. o Purity was 92%.
p (S)-2,2-Dimethylcyclohexanol.
Supporting Information Available: Preparative methods and
properties of chiral Ru complexes 3, synthesis and procedures for
asymmetric hydrogenation of the tert-alkyl ketones, NMR, GC, and
HPLC behavior of products, together with [R]D values and absolute-
configuration determination (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
tert-alkyl ketones 6 were hydrogenated to the corresponding chiral
alcohols in good to excellent enantiomeric excess. The reaction
exhibited a consistent and predictable asymmetric induction. The
chiral alcohol obtained from 7a is an intermediate for the synthesis
of a herbicide.11 Highly hindered â-keto esters 8 behave as simple
tert-alkyl ketones. The BINAP/PICA-Ru complex is much more
reactive than the PICA-free BINAP-Ru complex, which hydro-
genates â-keto esters via a chelate mechanism.12,13 Thus, reaction
of the methyl and phenyl ketones 8a and 8b catalyzed by (S)-3a
gave the expected chiral hydroxy esters (S)-9a and (S)-9b in 97
and 82% ee, respectively.
Under optimum conditions, aliphatic, olefinic, and aromatic tert-
alkyl ketones are hydrogenated with equally high enantioselectivity
and the same mode of face selection.14 Thus, the asymmetric bias
results primarily from the difference in steric bulk of the two
substituents flanking the carbonyl function. Reaction parameters,
together with catalyst structures, must be carefully selected.
Alcoholic solvents influence both catalytic activity and enantiose-
lectivity.3,4,6 In fact, ethanol was found to be the best solvent for
this asymmetric hydrogenation. Hydrogenation of 1a in conven-
tional 2-propanol containing (S)-3a (S/C ) 2000, [KOC(CH3)3] )
20 mM, 9 atm, 12 h) gave (S)-2a quantitatively but in only 36%
ee (cf. 98% ee in ethanol). Use of tert-butyl alcohol even reversed
the asymmetric sense to give (R)-2a in 68% ee and 100% yield.
Although no hydrogenation took place in pure methanol, the
reaction in a methanol (>30%)/tert-butyl alcohol (>3:7) mixture
gave (S)-2a quantitatively in 97-99% ee. Reaction of 1a with (S)-
3a in (R)-1-phenylethanol (S/C ) 2000, [KOC(CH3)3] ) 22 mM,
4 atm, 6 h) formed (S)-2a in 76% ee, but, notably, the hydrogenation
in the S alcohol was 1.5 times slower and less stereoselective to
give (S)-2a in 39% ee.15 The stereochemical outcome is interpreted
in terms of a metal-ligand bifunctional mechanism6 involving an
18e cis-RuH(OR)[(S)-tolbinap](pica) complex(es) as dominant
reactive species. The higher activity in comparison to the conven-
tional BINAP/1,2-diamine complexes is ascribed to the functional/
(1) For earlier efforts, see: (hydrogenation) (a) Nagel, U.; Roller, C. Z.
Naturforsch. 1998, 53B, 267-270. (b) Jiang, Q.; Jiang, Y.; Xiao, D.; Cao,
P.; Zhang, X. Angew. Chem., Int. Ed. 1998, 37, 1100-1103. (c) Ito, M.;
Hirakawa, M.; Murata, K.; Ikariya, T. Organometallics 2001, 20, 379-
381. (Transfer hydrogenation with 2-propanol) (d) Nishibayashi, Y.; Takei,
I.; Uemura, S.; Hidai, M. Organometallics 1999, 18, 2291-2293.
(2) BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. TolBINAP ) 2,2′-
bis(di-4-tolylphosphino)-1,1′-binaphthyl. DPEN ) 1,2-diphenylethylene-
diamine. Bipy ) 2,2′-bipyridine.
(3) (a) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2005-2022. (b) Noyori,
R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40-73.
(4) (a) Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa, M.;
Katayama, E.; England, A. F.; Ikariya, T.; Noyori, R. Angew. Chem., Int.
Ed. 1998, 37, 1703-1707. (b) Ohkuma, T.; Koizumi, M.; Doucet, H.;
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T.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 13529-13530.
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(6) Sandoval, C. A.; Ohkuma, T.; Mun˜iz, K.; Noyori, R. J. Am. Chem. Soc.
2003, 125, 13490-13503.
(7) Hydrogenation of 1-tetralones is better effected by use of 1,4-diamine
ligands in place of 1,2-diamines. See: Ohkuma, T.; Hattori, T.; Ooka,
H.; Inoue, T.; Noyori, R. Org. Lett. 2004, 6, 2681-2683.
(8) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Org. Synth. 1993,
71, 1-13.
(9) On occasion, minor uncharacterized species could be detected (<5%).
(10) Ohkuma, T.; Ooka, H.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995,
117, 10417-10418.
(11) Tombo, G. M. R.; Bellus, D. Angew. Chem., Int. Ed. Engl. 1991, 30,
1193-1215.
(12) Noyori, R.; Kitamura, M.; Ohkuma, T. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5356-5362.
(13) Hydrogenation of methyl 2,2-dimethyl-3-oxobutanoate in methanol with
RuBr2[(S)-binap] under hard conditions (S/C ) 200, 100 atm, 50 °C, 68
h) gave the S hydroxy ester in 96% ee and 100% yield. See: Noyori, R.
Asymmetric Catalysis in Organic Synthesis; Wiley: New York, 1994;
Chapter 2.
(14) Due to the group priority in nomenclature, (S)-2a,b,g,h and (R)-2d-f have
the same â configuration.
(15) In hydrogenation of acetophenone with trans-RuH(η1-BH4)[(R)-tolbinap]-
[(R)-dpen], the nature of alcoholic solvents affects the reaction rate but
not the extent of enantioselection.6 trans-RuH2(tolbinap)(dpen) among
other coexisting RuH species has been considered to be the reacting
species. Enantioselectivity in hydrogenation of 1a and 1d catalyzed by
trans-RuCl2[(S)-tolbinap][(S,S)-dpen] was considerably enhanced by use
of ethanol in place of 2-propanol [(S)-2a in 14-82% ee and (R)-2d in
61-97% ee, respectively], albeit with moderate rate enhancement.
JA052071+
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