Highly Enantioselective Hydrogenation of Aromatic-Heteroaromatic Ketones

Article abstract of DOI:10.1021/ol0360795

(Equation presented) Asymmetric hydrogenation of ketone 1 using trans-RuCl₂[(R)-xylbinap][(R)-daipen] (3) as a catalyst afforded secondary alcohol 2 quantitatively and in 99.4% ee. Further exploration of the effect of the thiazole ring substitution revealed that the catalyst was highly effective for the enantioselective hydrogenation of 5-benzoyl thiazoles, which afforded corresponding alcohols in 92-99% ee. The same protocol was applicable to a variety of aromatic-heteroaromatic ketones to generate secondary alcohols in excellent enantioselectivities.

Full text of DOI:10.1021/ol0360795

ORGANIC
LETTERS
2003
Vol. 5, No. 26
5039-5042
Highly Enantioselective Hydrogenation
of Aromatic-Heteroaromatic Ketones
Cheng-yi Chen,* Robert A. Reamer, Jennifer R. Chilenski, and
Chris J. McWilliams
Department of Process Research, Merck & Co., Inc., P.O. Box 2000,
Rahway, New Jersey 07065-0900
cheng_chen@merck.com
Received October 24, 2003
ABSTRACT
Asymmetric hydrogenation of ketone 1 using trans-RuCl2[(R)-xylbinap][(R)-daipen] (3) as a catalyst afforded secondary alcohol 2 quantitatively
and in 99.4% ee. Further exploration of the effect of the thiazole ring substitution revealed that the catalyst was highly effective for the
enantioselective hydrogenation of 5-benzoyl thiazoles, which afforded corresponding alcohols in 92−99% ee. The same protocol was applicable
to a variety of aromatic-heteroaromatic ketones to generate secondary alcohols in excellent enantioselectivities.
Enantiomerically pure alcohols, especially those bearing
heterocycles, are important intermediates in the pharmaceuti-
cal industry and are usually available from the reduction of
ketones either by chemical means or biotransformation.1
Among the many protocols available for the transformation
of prochiral ketones to chiral alcohols, the catalytic, asym-
metric hydrogenation of ketones is one of the most efficient
and cost-effective methods.2 Chiral RuCl2(diphosphine)
(diamine) complexes pioneered by Noyori and co-workers,
catalyze rapid, highly efficient asymmetric hydrogenation of
a wide array of ketones in 2-propanol containing an alkaline
base to afford the corresponding alcohols.3 Recently, Burk
et al. has reported that the ruthenium complexes based upon
the novel PhanePhos ligands also serve as efficient catalyst
precursors for highly enantioselective hydrogenation of
ketones.4 Other ligands have also emerged that are useful
for the asymmetric hydrogenation of prochiral ketones.5
Although several methods for the asymmetric hydrogenation
of ketones exist, the enantioselective hydrogenation of
aromatic-heteroaromatic or bis heteroaromatic ketones re-
(2) (a) Noyori, R. AdV. Synth. Catal. 2003, 345, 15. (b) Wills, M.;
Hannedouche, J. Curr. Opin. Drug Dis. DeV. 2002, 5 (6), 881. (c) Chaplin,
D.; Harrison, P.; Henschke, J. P.; Lennon, I. C.; Meek, G.; Moran, P.;
Pilkington, C. J.; Ramsden, J. A.; Watkins, S.; Zanotti-Gerosa, A.. Org.
Process Res. DeV. 2003, 7 (1), 89. (d) Everaere, K.; Mortreux, A.;
Carpentier, J. AdV. Synth. Catal. 2003, 345, 67. (e) Blaser, H.; Malan, C.;
Pugin, B.; Spindler, F; Steiner, H.; Studer, M. AdV. Synth. Catal. 2003,
345, 103. (f) Noyori, R.; Okhuma, T. Angew. Chem., Int. Ed. 2001, 40, 40.
(3) (a) Doucet, H; Ohkuma, T.; Murata, K.; Yokozawa, M.; Katayama,
E.; England, a. F.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1998, 37,
1703. (b) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1995, 117, 2675. (c) Ohkuma, T.; Koizumi, M.; Ikehira,
H.; Yokozawa, T.; Noyori, R. Org. Lett. 2000, 2, 659. (d) Ohkuma, T.;
Koizumi, M.; Yoshida, M.; H.; Noyori, R. Org. Lett. 2000, 2, 1749.
(4) Burk, M. J.; Hems, W.; Herzberg, D.; Malan, C.; Zanotti-Gerosa, A.
Org. Lett. 2000, 2 (26), 4173.
(1) (a) Roy, S.; Alexandre, V,; Neuwels, M,; Le Texier, L. AdV. Synth.
Catal. 2001, 343, 738. (b) Roszkowski, A. P.; Govier, W. M. Pharmacolo-
gist 1959, 1, 60. (c) Barouth, V.; Dall, H,; Petal, D.; Hite, G. J. Med. Chem.
1971, 14, 834. (d) Huang, W.; Pu, L. Tetrahedron Lett. 2000, 41 (2), 145.
(e) Salvi, N. A.; Chattopadhyay, S. Tetrahedron 2001, 57 (14), 2833. (f)
Masui, M.; Shioiri, T. Synlett. 1997, 3, 273. (g) Miyashita, A.; Matsuoka,
Y.; Suzuki, Y.; Iwamato, K.; Higashino, T. Chem. Pharm. Bull. 1997, 45,
1235. (h) Okano, K.; Murata, K.; Ikariya, T. Tetrahedron Lett. 2000, 41,
9277. (i) Takeshita, M.; Yoshida, S.; Sato, T.; Akutsu, N. Heterocycles
1993, 35, 879. (j) Vasse, J. L.; Charpentier, P.; Levacher, V.; Dupas, G.;
Queguiner, G.; Bourguignon, J. Synlett. 1998, 10, 1144. (k) Takemoto, M.;
Achiwa, K. Chem. Pharm. Bull. 1994, 42, 802. (l) Bolm, C.; Muniz, K.
Chem. Comm. 1999, 14, 1295. (m) Okano, K.; Murata, K.; Ikariya, T.
Tetrahedron Lett. 2000, 41, 9277.
(5) (a) Xie, J.-H.; Wang, L,-X.; Fu, Y.; zhu, S.-F.; Fan, B.-M.; Duan,
H.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2003, 125, 4404. (b) Wu, J.; Chen,
H.; Kwok, W.; Guo, R.; Zhou, Z.; Yeung, C.; Chan, A. S. C. J. Org. Chem.
2002, 67, 7908.
10.1021/ol0360795 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/27/2003

mains fairly unprecedented. Herein, we wish to disclose a
general method for the highly efficient, enantioselective
hydrogenation of these ketones.6
between ketone 1 and catalyst 3 prompted us to seek the
structural origin of the enantioselectivity.
We were amazed by the exceedingly high enantioselec-
tivity for the hydrogenation of ketone 1 since it is not obvious
to predict on the basis of the structural motif of this fully
substituted aromatic-heteroaromatic ketone. Ru-catalyzed
enantioselective hydrogenation of benzophenones was re-
ported to provide benzhydrols in high enantioselectivity
provided that one aromatic ring was ortho-substituted.3a The
fact that ketone 1 does not possess any substituents at the
ortho position made us wonder if the asymmetric induction
originated from the substitution pattern on the thiazole ring.
We speculated that the high asymmetric induction may
largely be controlled by the steric effect of the bistrifluoro-
methyl MOM ether group at the 2-position of the thiazole
ring.12 To study the steric effect of the 2-substituent on the
enantioselectivity of hydrogenation, a variety of thiazole
ketones were prepared either by direct condensation of
5-lithium thiazole species with aromatic nitriles or with
aldehydes followed by oxidations using MnO2.13 4-Benzo-
thiazole was prepared from the addition of phenylmagnesium
chloride to the thiazole Weinreb amide. The results of their
asymmetric hydrogenations using catalyst 3 are summarized
in Table 1.
In the course of our recent drug development program for
a potent PDE-IV inhibitor (Scheme 1), we sought to convert
Scheme 1
ketone 1 to alcohol 2 in a catalytic, enantioselective manner.7
The enantioselective reduction of ketone 1 was initially
carried out using super stoichiometric amounts of BINAL-H
to give the alcohol in 89-96% ee.8 Though the reaction
performed well on scale-up, it also introduced 3 equiv of
BINOL that need to be recycled, and a more efficient,
catalytic method was desired. To this end, we attempted the
reduction of ketone 1 under a standard set of reaction
conditions (40 psi H2, K2CO3/Ru ) 25/1, S/C ) 50/1, 20
mL/g solution of ketone in i-PrOH) using trans-RuCl2[(R)-
xylbinap][(R)-daipen] (3) as a catalyst.2f,3 The reduction of
ketone 1 performed exceptionally well on our very first
attempt, which gave 2 in 99.4% ee in quantitative yield.9,10
Scheme 2. Formation of 5-Thiazole Ketone from Either ArCN
or ArCHO
Our initial efforts were to optimize this reduction in terms
of catalyst loading since S/C at 50/1 was not practical for
scale-up. After considerable optimization, we found that the
reaction was best carried out under the following condi-
tions: 40 psi H2, K2CO3/Ru ) 25/1, S/C ) 1000/1, 4 mL/g
solution of ketone in 4:1 i-PrOH-THF at ambient temper-
ature to give alcohol 2 in >99% ee.11 We felt that at S/C
1000/1, the process became viable for the preparation of this
advanced pharmaceutical intermediate. The perfect match
Hydrogenation of MOM-protected benzoyl thiazole 4a
afforded the corresponding alcohol 5a in 97.5% ee and 96%
yield. This result suggests that both alkoxyl groups in the
phenyl ring have no effect on the enantioselectivity in the
reduction of ketone 1. The hydrogenation was equally
efficient for the TBS-substituted ketone, which afforded
aldohol 5b (R ) TBS) in 97.5% ee. Hydrogenation of ketone
6, containing bulky 2-dioxalanyl substituent, afforded alcohol
7 in 92% ee and 97% yield. The ee of this alcohol could be
easily upgraded to >99% by crystallization from EtOAc-
hexanes. Similarly, hydrogenation of ketone 8a afforded
alcohol 9a in excellent yield and enantioselectivity (99% ee).
(6) (a) Schmid, R.; Broger, E. A.; Cereghetti, M.; Crameri, Y.; Foricher,
J.; Lalonde, M; Mu¨ller, R.; Scalone, M.; Schoettel, G.; Zutter, U. Pure
Appl. Chem. 1996, 1, 131. (b) Broger, E.; Hofheinz, W.; Meili, A.
(Hoffmann-La Roche) Eur. Pat. 553778, 1993.
(7) Friesen, R. W.; Ducharme, Y.; Ball, R. G.; Blouin, M.; Boulet, L.;
Cote, B.; Frenette, R.; Girard, M.; Guay, D.; Huang, Z.; Jones, T. R.;
Laliberte, F.; Lynch, J. J.; Mancini, J.; Martins, E.; Masson, P.; Muise, E.;
Pon, D. J.; Siegl, P. K. S.; Styhler, A.; Tsou, N. N.; Turner, M. J.; Young,
R. N.; Girard, Y. J. Med. Chem. 2003, 46, 2413.
(8) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6 (22), 6709.
(9) Absolute configuration of alcohol 2 was assigned as (R)- on the basis
of NMR spectra of its methoxyphenyl acetic acid derivatives and its
conversion to compound 3 via inversion chemistry (to be published).
(10) Seto, J. M.; Quin˜oa´, E.; Riguera, R. Tetrahedron: Asymmetry 2001,
12, 2915.
(11) THF was used as a cosolvent to improve the solubility of ketone 1
in IPA. The reaction became sluggish when lowering the catalyst loading
to S/C 10 000/1. A typical hydrogenation follows. To ketone 1 (1 mmol)
in 2-3 mL of THF-IPA (1:4) was added powdered K2CO3 (0.25 mmol).
The mixture was degassed three times via vacuum/nitrogen purge, followed
by addition of catalyst 3 (0.01 mmol). The mixture was hydrogenated at
40-60 psi at ambient temperature for 24-48 h. Removal of solvents
followed by SiO2 chromatography afforded alcohol 2.
(12) Bioreduction of a bulky ketone, 1-phenyl-1-(2-phenylthiazol-5-yl)-
methanone, was reported to give alcohol in up to 96% ee, partially attributed
to the size discrimination between the phenyl group and 2-phenyl thiazole
group (ref 1a).
(13) (a) Frey, L. F; Marcantonio, K. M., Chen, C.-y, Wallace, D.; Murry,
J. A.; Dolling, U. H.; Grabowski, E. J. J.; Tan, L.; Chen, W. Tetrahedron
2003, 59, 6363. (b) Marcantonio, K. M.; Frey, L. F.; Chen, C.-y.; Murry,
J. A. Tetrahedron Lett. 2002, 43, 8845.
5040
Org. Lett., Vol. 5, No. 26, 2003

All these results supported our initial hypothesis of a strong
steric effect of the 2-position on enantioselectivity. However,
we were very surprised to find that hydrogenation of
sterically less demanding ketones such as 8b (R ) Me) and
8c (R ) H) worked equally well to give alcohols in 97 and
95% ee, respectively. These results clearly ruled out the steric
effect of the 2-substituents of thiazole ketones on the
asymmetric induction that we had initially speculated. On
the basis of the results summarized in Table 1, we conclude
that reduction of 5-thiazole aromatic ketone using catalyst 3
would lead to high enantioselectivity.
has mainly been reported for the alkylpyridyl ketones.3d,4,5
The asymmetric transfer hydrogenation using a chiral Ru(II)
complex of benzoyl 2-pyridine was also reported; however,
the process gives the alcohol in very poor selectivity (9%
ee).1m
Surprisingly, hydrogenation of ketones 14 and 16 using
conditions11 reported in Table 1 gave decent enantioselec-
tivity despite the isosteric nature of the Ar group and
pyridinyl ring. For example, enantioselective hydrogenation
of 4-benzopyridine (14a) and 3-benzopyridine (14b) afforded
the corresponding (R)-alcohols, 15a and 15b, in 57.2 and
73.3% ee, respectively. Interestingly, the sense for the
asymmetric induction of 2-benzopyridine (16a) was opposite
to that of 14a,b, as the (S)-alcohol (17a) was obtained in
74.8% ee. The enantioselectivity for the hydrogenation of
derivatives of 16 was greatly influenced by the para
substitution on the phenyl ring. Hydrogenation of 16b (X )
Cl) afforded alcohol 17b1b,c,15 in lower ee (60.6 vs 74.8%
for 16a), whereas the hydrogenation of 16c (X ) OMe)
afforded 17c16 in higher ee (89.5 vs 74.8% for 16a). The
sense of asymmetric induction of 16a-c is opposite to that
of 14a,b, suggesting that the asymmetric induction may be
controlled by the coordination of the 2-pyridine nitrogen to
the catalyst. The substitution effect on the enantioselectivity
for 2-benzopyridines is quite significant and merits further
investigation.
Table 1. Effect of Substitution on Enantioselectivity
Since the documented high enantioselectivity for the
hydrogenation of unsymmetrical diaryl ketones relies on the
presence of an ortho substituent in one of the aromatic rings,3c
we reasoned that the same steric effect may be applied to
the pyridinyl ketones to override the electronic effect. Indeed,
introduction of the methyl group ortho to the carbonyl moiety
improved the enantioselectivity dramatically, as reduction
of ketone 18 gave alcohol 19 in 98.7% ee.17 The sense of
asymmetric induction in the reduction for ketone 18 is the
same as that observed for the reduction of 2-methylbenzo-
phenone using catalyst 3.18 This indicates that the steric effect
dominates for the reduction. A similar result was obtained
for quinoline ketone, which gave alcohol in 91.4% ee. The
methyl group in 18 and the fused phenyl ring in ketone 20
apparently generate sufficient stereobias between the aro-
matic groups to effect good enantiodifferentiation for the
reduction.
a All reactions were carried out using the procedure described in ref 11.
However, we discovered a significant dependence of the
enantioselectivity on the thiazole substitution pattern. In
contrast to ketone 8c, hydrogenation of 2-benzothiazole 10
under the same reaction conditions afforded alcohol 11 in
modest ee (42.2%). Reduction of 4-thiazole ketone 12,
however, gave alcohol 13 in 83.4% ee and 89% yield in (S)-
configuration. Interestingly, the sense of asymmetric induc-
tion for 4-benzothiazole (12) is opposite to that of the
5-benzothiazole counterparts.
The remarkable enantioselectivity of the hydrogenation of
prochiral ketone 1 prompted us to extend the application of
the catalyst 3 to other aromatic-heteroaromatic ketones. We
next sought to apply this method to arylpyridyl ketones since
practical stereoselective syntheses of optically active pyridyl
aromatic alcohols are rarely reported.1d-m,14 To our knowl-
edge, the enantioselective hydrogenation of these ketones
We also demonstrated that this procedure can be extended
to several classes of bis-aromatic ketones. For example,
hydrogenation of pyridinyl-thiazole ketone 22 afforded (R)-
(14) Bioreduction of 2-,3-,4-pyridnyl phenyl ketones were reported to
give corresponding alcohols in a wide range of enantioselectivities (3 to
100% ee). Reduction of 4-pyridyl phenyl ketone using chiral amino alcohols
and trimethyl borate was reported to give the alcohol in 61-83% ee.
(15) Alcohol 17b is a precursor to a medicinally useful histamine H1
antagonist (S)-carbinoxamine. Direct reduction of 2-benzopyridine using
oxazborolidine led to racemic alcohol and thus required for the protection
of nitrogen by forming N-alkylpyridinium salt to achieve high selectivity,
see: Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 5675.
(16) Absolute configuration of 17c was assigned as (S)- on the basis of
its optical rotation; see: Bojadziev, S. E.; Tsankov, D. T.; Ivanov, P. M.;
Berova, N. D. Bull. Chem. Soc. Jpn. 1987, 60, 2651.
(17) Absolute configuration of 19 was unambiguously established on
the basis of X-ray analysis on its (R)-methoxy phenyl acetate.
(18) Absolute configuration of 19 was unambiguously established on
the basis of X-ray analysis on its (R)-methoxy phenyl acetate.
Org. Lett., Vol. 5, No. 26, 2003
5041

mediate to Roche’s antimalarial drug, (R,S)-mefloquine.20
Asymmetric hydrogenation of ketone 28 under conditions
similar to those cited in Table 1 proceeded uneventfully to
give (R)-29 in 88% ee and 92% isolated yield. This
unoptimized result is comparable to the best example (29 in
92% ee and 86% conversion) obtained from the Rh(I)-
catalyzed hydrogenation using a variety of C-2 diphosphine
ligands.6
Table 2. Hydrogenation of Bis-aromatic Ketonesa,b
Scheme 3. Asymmetric Synthesis of (R,S)-Mefloquinea
a Conditions: (a) 1 mol% (S,S)-3, 25 mol% K2CO3, IPA-THF,
4:1, 25 °C, 25 psi of H2; (b) Pt, H2, HCl, ref 6.
In summary, we have identified a highly efficient and cost-
effective protocol for the catalytic, enantioselective hydro-
genation of ketone 1 to alcohol 2 using catalyst 3. This
catalyst proved to be exceptionally effective toward the
enatioselective hydrogenation of 5-benzoyl thiazoles regard-
less of the size of 2-substituents. The reaction was extended
to a variety of aromatic-heteroaromatic ketones, as well as
to bis-heterocyclic ketones. Many structurally interesting
heterocyclic benzylhydrols were readily prepared in a
catalytic manner in high enantioselectivity. We believe that
the broad scope of this catalyst toward the hydrogenation of
bis-aromatic ketones will lead to more applications of the
system to structurally diverse substrates.
a Same conditions as described in ref 11. b Absolute configurations of
15 and 17 were assigned on the basis of optical rotations. c Ketone 24 was
recovered (30%).
Supporting Information Available: All the new com-
pounds were fully characterized by 1H and 13C NMR spectra.
Absolute configurations for compounds 7, 9b, 13, 19 (as its
MPA ester), and 23 were unambiguously assigned based on
the X-ray analysis (ORTEP drawings attached). The enan-
tiomeric excess for the alcohols was assayed by chiral HPLC
methods. This material is available free of charge via the
Internet at http://pubs.acs.org.
alcohol 23 quantitatively in 94.4% ee. The asymmetric
induction for the hydrogenation of 22 is the same as that for
5-benzoyl thiazole ketones, as confirmed by the X-ray
analysis. Hydrogenation of imidazole-ketone 2419 gave
alcohol 25 in 93.6% ee (67% yield). Finally, hydrogenation
of TIP-substituted oxazole-phenyl ketone 26 afforded alcohol
27 in 94% yield in nearly perfect enantioselectivity (>99.5%
ee).
OL0360795
(19) Ketone 24 was prepared quantitatively by methylation of the
corresponding phenol using MeI in acetone in the presence of K2CO3.
(20) Ohnmacht, C. J.; Patel, A. R.; Lutz, R. E. J. Med. Chem. 1971, 14,
926.
With an efficient method for the asymmetric hydrogenation
in hand, we sought to apply this procedure to the synthesis
of chiral alcohol 29, which serves as the penultimate inter-
5042
Org. Lett., Vol. 5, No. 26, 2003