Stereoselective hydrogenation of simple ketones catalyzed by ruthenium(II) complexes

Full text of DOI:10.1021/jo960997h

4872
J . Org. Chem. 1996, 61, 4872-4873
Ster eoselective Hyd r ogen a tion of Sim p le
Keton es Ca ta lyzed by Ru th en iu m (II)
Com p lexes
Takeshi Ohkuma, Hirohito Ooka,
Masashi Yamakawa,† Takao Ikariya, and
Ryoji Noyori*,‡
ERATO Molecular Catalysis Project, Research Development
Corporation of J apan, 1247 Yachigusa, Yakusa-cho,
Toyota 470-03, J apan
Received May 29, 1996
Diastereoselective reduction of ketones to secondary
alcohols is a major subject of organic synthesis.1 This
important transformation has mainly been accomplished
by stoichiometric metal hydride reagents.2 Although a
wide range of stereoselective reducing agents are avail-
able, each reagent has a limited scope due to the inherent
chemical property as well as the difficulty in structural
modification. Development of stereoselective hydrogena-
tion catalyzed by transition metal-based molecular com-
plexes is ardently desired because of the higher structural
permutability of the catalyst, in addition to a series of
practical benefits.3,4 Here, we present some examples of
highly diastereoselective hydrogenation of ketones cata-
lyzed by a Ru(II)-phosphine-1,2-diamine combined
system,5,6 which can easily be perturbed by electronic and
steric effects (bulkiness and chirality). The synthetic
utility is further enhanced by the application of dynamic
kinetic discrimination7 of configurationally labile dia-
stereomeric, epimeric, and enantiomeric ketones.
facile hydrogenation of various ketones in 2-propanol
with a high substrate/catalyst molar ratio (S/C) in 1-8
atm of H2 at room temperature to give the corresponding
alcohols in a near quantitative yield. We first tested
steric requirements of the standard P(C6H5)3-NH2(CH2)2-
NH2 combined system. Hydrogenation of 4-tert-butylcy-
clohexanone (1a ), a conformationally anchored substrate,
with S/C ) 500, or even 10 000 on a 30-g scale, occurred
preferentially from the less crowded equatorial direction
to give a 98.4:1.6 mixture of cis-4-tert-butylcyclohexanol
(cis-2a ) and its trans isomer (eq 1).8 As expected, the
stereoselectivity of the hydrogenation of other 4-substi-
tuted cyclohexanones is controlled basically by the popu-
lation of the equatorial and axial conformers,9 leading
to a predominance of the cis alcohols (Table 1). Hydro-
genation of 3-methylcyclohexanone (3c) afforded quan-
titatively trans-4c and the cis isomer with a 96:4 dias-
tereoselectivity (eq 2). In a similar manner, 2-alkyl-
cyclohexanones (5) were hydrogenated to afford predomi-
nantly cis-6 over the trans isomers (eq 3). The diaste-
reoselectivity, observed with 5, is higher than the equi-
librium ratio of the equatorial and axial conformers.
Perhaps this is due to the repulsive interaction between
the axial R-substituent and incoming Ru hydride species
which prevents trans alcohol formation. 2-Methylcyclo-
pentanone gave the cis alcohol with a diastereoselection
as high as 99:1 (100%). Bicyclo[2.2.1]heptan-2-one pro-
duced a 99:1 mixture of the endo and exo alcohols.
Reaction of the 1-phenylethyl ketones 7a and 7b,
conformationally flexible standards, showed a high Cram
selectivity10,11 to give syn-8a ,b and anti-8a ,b in a 98:2
and 93:7 ratio, respectively, in >96% isolated yield (eq
4). Overall, the degrees of the kinetic diastereoface
discrimination observed with the standard Ru catalyst
system are well compared with those accomplished by
stoichiometric reduction using Selectride reagents.2
This catalyst system is characterized by the high
tunability of the stereochemical and electronic properties
A Ru(II) catalyst in situ formed from RuCl2(phosphine)n,
a 1,2-diamine, and KOH in a 1:1:2 molar ratio5,6 effects
† Permanent address: Kinjo Gakuin University, Omori, Moriyama,
Nagoya 463, J apan.
‡ Permanent address: Department of Chemistry, Nagoya Univer-
sity, Chikusa, Nagoya 464-01, J apan.
(1) Selected reviews: (a) Brown, H. C.; Krishnamurthy, S. Tetra-
hedron 1979, 35, 567-607. (b) El-Khawaga, A. M.; Hoffmann, H. M.
R. In Methods of Organic Chemistry (Houben-Weyl), 4th ed.; Helmchen,
G., Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.; Georg Thieme
Verlag: Stuttgart, 1995; Vol. E21d, pp 3967-3987. (c) Davis, A. P. In
Methods of Organic Chemistry (Houben-Weyl), 4th ed.; Helmchen, G.,
Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.; Georg Thieme
Verlag: Stuttgart, 1995; Vol. E21d, pp 3988-4048. (d) Krohn, K. In
Methods of Organic Chemistry (Houben-Weyl), 4th ed.; Helmchen, G.,
Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.; Georg Thieme
Verlag: Stuttgart, 1995; Vol. E21d, pp 4099-4142. See also: (e) Fisher,
G. B.; Fuller, J . C.; Harrison, J .; Alvarez, S. G.; Burkhardt, E. R.;
Goralski, C. T.; Singaram, B. J . Org. Chem. 1994, 59, 6378-6385. (f)
Barden, M. C.; Schwartz, J . J . Org. Chem. 1995, 60, 5963-5965.
(2) Selectride reagents: (a) Brown, H. C.; Krishnamurthy, S. J . Am.
Chem. Soc. 1972, 94, 7159-7161. (b) Krishnamurthy, S.; Brown, H.
C. J . Am. Chem. Soc. 1976, 98, 3383-3384.
(3) Reviews on stereoselective hydrogenation: (a) Rylander, P.
Catalytic Hydrogenation in Organic Syntheses; Academic Press: New
York, 1979; Chapter 6. (b) Harada, K.; Munegumi, T. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 8, pp 139-158.
(4) Examples of other catalytic stereoselective methods. Transfer
hydrogenation: (a) Henbest, H. B.; Mitchell, T. R. B. J . Chem. Soc. C
1970, 785-791. (b) Konishi, K.; Aida, T.; Inoue, S. J . Org. Chem. 1990,
55, 816-820. Hydrosilylation: (c) Ojima, I.; Nihonyanagi, M.; Nagai,
Y. Bull. Chem. Soc. J pn. 1972, 45, 3722. (d) Semmelhack, M. F.; Misra,
R. N. J . Org. Chem. 1982, 47, 2469-2471. (e) Fujita, M.; Hiyama, T.
J . Org. Chem. 1988, 53, 5405-5415. Hydrostannation: (f) Quintard,
J .-P.; Pereyre, M. Bull. Soc. Chim. Fr. 1972, 1950-1955.
(5) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J .
Am. Chem. Soc. 1995, 117, 2675-2676.
(8) (a) Eliel, E. L.; Senda, Y. Tetrahedron 1970, 26, 2411-2428. (b)
Boone, J . R.; Ashby, E. C. Top. Stereochem. 1979, 11, 53-95. (c)
Wigfield, D. C. Tetrahedron 1979, 35, 449-462. (d) Franck, R. W. In
Conformational Behavior of Six-Membered Rings; J uaristi, E., Ed.;
VCH: New York, 1995; Chapter 5.
(9) (a) Krohn, K. In Methoden der Organischen Chemie (Houben-
Weyl), 4th ed.; Bracht, J ., Friedrichsen, W., Krohn, K., Kropf, H.,
Maher-Detweiler, M., Margaretha, P., Messinger, P., Ohloff, G.,
Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1984; Vol. 6/1b,
pp 289-431. (b) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry
of Organic Compounds; Wiley: New York, 1994; pp 731-737.
(10) Reviews: (a) Eliel, E. L. In Asymmetric Synthesis; Morrison,
J . D., Ed.; Academic Press: New York, 1983; Vol. 2, Part A, Chapter
5. (b) J uaristi, E. Introduction to Stereochemistry and Conformational
Analysis; Wiley: New York, 1991; Chapter 11.
(6) Ohkuma, T.; Ooka, H.; Ikariya, T.; Noyori, R. J . Am. Chem. Soc.
1995, 117, 10417-10418.
(7) (a) Kitamura, M.; Tokunaga, M.; Noyori, R. J . Am. Chem. Soc.
1993, 115, 144-152. (b) Kitamura, M.; Tokunaga, M.; Noyori, R. J .
Am. Chem. Soc. 1995, 117, 2931-2932. (c) Noyori, R.; Tokunaga, M.;
Kitamura, M. Bull. Chem. Soc. J pn. 1995, 68, 36-55.
S0022-3263(96)00997-8 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 15, 1996 4873
Ta ble 1. Dia ster eoselective Hyd r ogen a tion of
Cycloh exa n on esa
ketone
alcohol
formula
-∆G°, kcal/mol (ratio)b
% yieldc
cis:transc
1a
1c
1d
3c
5b
5c
7.62 (100:0)
1.76 (95:5)
2.66 (99:1)
1.18 (88:12)
0.63 (74:26)
2.16 (97:3)
>99 (96)
97
98.4:1.6
92:8
96:4
4:96
>99.8:0.2
98:2
>99 (96)
100
>99 (95)d
95e
a
A 5 mmol-scale reaction in 2-propanol. [Ketone] ) 0.8-1.0
M, 4 atm of H2, 28 °C, 1 h. Substrate: RuCl2[P(C6H5)3]3:
NH2(CH2)2NH2:KOH ) 500:1:1:2. b Free energy difference between
the axial and equatorial conformation estimated by ab initio MO
calculation at the MP2/6-31G* level using the Gaussian 94
program.14 The equatorial:axial ratio is given in parentheses.
c Determined by GC. Isolated yield is given in parentheses.
fact, hydrogenation of 14 in the presence of a RuCl2-
[P(C6H5)3]3-NH2(CH2)2NH2 catalyst at 4 atm for 8 h15
gave cis,cis-15 with 98.7% selectivity together with the
cis,trans (0.2%, much less than the equilibrium popula-
tion of trans-14) and trans,trans (1.1%) isomers (100%
combined yield) (eq 6). When enantiomerically pure (-)-
menthone [(1R,4S)-16] equilibrating with isomenthone,
a 4R epimer of 16, was subjected to hydrogenation with
an achiral RuCl2[P(C6H5)3]3-NH2(CH2)2NH2 catalyst sys-
tem at 8 atm for 9 h,15 a 93.7:6.1:0.2 mixture of (+)-
neomenthol [(1R,3S,4S)-17] and the 1R,3R,4R and
1R,3R,4S stereoisomers was obtained (eq 7). However,
with a chiral (R)-11-(S)-12 combined system,15 (1R,3S,4S)-
17 was formed exclusively.
Finally, hydrogenation of racemic 2-isopropylcyclohex-
anone [(R,S)-18] in the presence of a RuCl2[(S)-11]-
(dmf)n-(R)-12 combined catalyst5,6 at 4 atm for 11 h15
afforded quantitatively a 99.8:0.2 mixture of the cis
alcohol, (1R,2R)-19 (93% ee), and the trans, 1R,2S isomer
(28% ee) (eq 8).16 Computer-aided analysis7c of the
reaction showing an inherent 1R,2R:1S,2S:1R,2S:1S,2R
selectivity of 97.26:2.57:0.10:0.07 indicates that, under
such conditions,15 (R)-18 is hydrogenated 36 times faster
than (S)-18. The slow-reacting S substrate undergoes
in situ stereochemical inversion 47 times faster than it
is hydrogenated. The extent of the substrate-based
asymmetric induction in favor of the cis isomer is
calculated to be 192 and the catalyst-controlled asym-
metric induction (R*/S*) to be 7.2.
d
Reaction for 9 h. e Reaction for 2.5 h.
through structural modification of the phosphine and
diamine ligands. The reactive species generated in this
hydrogenation system behaves as a “bulky hydride” as
seen in eqs 1-4, but the extent of the diastereoselectivity
is also significantly affected by the electronic properties
of the phosphine ligands.12 Typically, the Cram selectiv-
ity in the hydrogenation of 3-phenyl-2-butanone (7c)
forming syn-8c and anti-8c varied from 96:4 to 95:5, 86:
14, and 78:22 with the Ru catalysts possessing P(C6H4-
p-OCH3)3, P(C6H4-p-CH3)3, P(C6H5)3, or P(C6H4-p-F)3
ligands in tandem with NH2(CH2)2NH2 (S/C ) 500, 4 atm,
28 °C). The phosphine and diamine ligands can be
chirally modified. Thus, hydrogenation of (R)-3-methyl-
cyclohexanone [(R)-9] with a Ru complex modified by (S)-
BINAP [(S)-11] and (S,S)-1,2-diphenylethylenediamine
[(S)-12]5,6 (S/C ) 500, 4 atm, 28 °C) formed a 97:3 mixture
of the trans and cis alcohols, (1R,3R)-10 and (1S,3R)-10,
respectively (eq 5). The replacement of the diphosphine
and diamine ligands to (R)-11 and (S)-1,1-bis(p-methoxy-
phenyl)-2-isopropylethylenediamine [(S)-13] in turn gave
a slightly cis-enriched mixture, (1R,3R)-10:(1S,3R)-10 )
44:56.
When a configurationally labile R-substituted ketone
is used, asymmetric transformation via in situ stereo-
mutation is possible.7 Thanks to the smooth reaction in
an alkali-containing 2-propanol, the dynamic kinetic
resolution method allows the diastereo- and enantiose-
lective synthesis of chiral alcohols having contiguous
stereogenic centers. 2,6-Dimethylcyclohexanone (14) is
in a rapid equilibrium between the cis and trans iso-
mers in 2-propanol containing KOH [diequatorial:equa-
torial,axial:diaxial ratio ) 92:8:0 (experiment)13 or 97:
3:0 (ab initio calculation)14 ], where trans-14 is expected
to be rather unreactive because of the presence of an
axially oriented methyl substituent at the R position. In
Su p p or tin g In for m a tion Ava ila ble: Hydrogention pro-
cedures and analytical data of the hydrogenation products (7
pages).
J O960997H
(11) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199-2204. (b) Anh, N. T. Fortschr. Chem. Forsch. 1980, 88, 145-
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Schlegel, H. B.; Gill, P. M. W.; J ohnson, B. G.; Robb, M. A.; Cheeseman,
J . R.; Keith, T.; Petersson, G. A.; Montgomery, J . A.; Raghavachari,
K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.;
Cioslowski, J .; Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.;
Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres, J . L.;
Replogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.;
Defrees, D. J .; Baker, J .; Stewart, J . P.; Head-Gordon, M.; Gonzalez,
C.; Pople, J . A. Gaussian, Inc., Pittsburgh, PA, 1995.
(15) A 5 mmol-scale reaction. [Ketone] ) 0.8 M, ketone:Ru:diamine:
KOH ) 500:1:1:20, 28 °C.
(16) Atomic coordinates for (1R,2R)- and (1S,2R)-2-isopropylcyclo-
hexyl (R)-N-[1′-(1-naphthyl)ethyl]carbamate have been deposited with
the Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.