Selective hydrogenation of benzophenones to benzhydrols. Asymmetric synthesis of unsymmetrical diarylmethanols

Article abstract of DOI:10.1021/ol9904139

(Graph presented) trans-RuCl₂[P(C₆H₄-4-CH₃) ₃]₂(NH₂CH₂CH₂NH ₂) acts as a highly effective precatalyst for the hydrogenation of a variety of benzophenone derivatives to benzhydrols that proceeds smoothly at 8 atm and 23-35 °C in 2-propanol containing t-C₄H₉OK with a substrate/catalyst ratio of 2000-20000. Use of a BINAP/chiral diamine Ru complex effects asymmetric hydrogenation of various ortho-substituted benzophenones and benzoylferrocene to chiral diarylmethanols with consistently high ee.

Full text of DOI:10.1021/ol9904139

ORGANIC
LETTERS
2000
Vol. 2, No. 5
659-662
Selective Hydrogenation of
Benzophenones to Benzhydrols.
Asymmetric Synthesis of Unsymmetrical
Diarylmethanols
Takeshi Ohkuma,†,‡ Masatoshi Koizumi,† Hideyuki Ikehira,‡ Tohru Yokozawa,‡ and
,†,‡
Ryoji Noyori*
Department of Chemistry and Research Center for Materials Science,
Nagoya UniVersity, Chikusa, Nagoya 464-8602, Japan, and ERATO Molecular
Catalysis Project, Japan Science and Technology Corporation, 1247 Yachigusa,
Yakusa-cho, Toyota 470-0392, Japan
noyori@chem3.chem.nagoya-u.ac.jp
Received December 30, 1999
ABSTRACT
trans-RuCl2[P(C H -4-CH ) ] (NH CH CH NH ) acts as a highly effective precatalyst for the hydrogenation of a variety of benzophenone derivatives
6
4
3 3 2
2
2
2
2
to benzhydrols that proceeds smoothly at 8 atm and 23−35 °C in 2-propanol containing t-C H OK with a substrate/catalyst ratio of 2000−
4
9
20000. Use of a BINAP/chiral diamine Ru complex effects asymmetric hydrogenation of various ortho-substituted benzophenones and
benzoylferrocene to chiral diarylmethanols with consistently high ee.
Benzhydrols are widely used as intermediates for the
commercial synthesis of pharmaceuticals.1 Although the
catalytic hydrogenation of benzophenone derivatives is the
simplest way of synthesizing this important class of com-
pounds, the general method remains elusive. Hydrogenation
of benzophenone over Pd/C in hexane or a 1:1 mixture of
ethanol and acetic acid largely gives diphenylmethane, an
over-reduction product,2 although the catalyst modified with
ethylenediamine gives benzhydrols selectively.3 The Lindlar
or some other heterogeneous catalysts,4 phosphine-Ru
complexes,5 and t-C4H9OK as catalyst6 are known to show
high selectivity for carbinol formation, but their scope and
limitations are not clear.7 Therefore, the current industrial
processes of producing benzhydrols rely on stoichiomeric
(2) Hydrogenation of benzophenone (182 mg) on 10% Pd/C (20 mg) in
hexane (6 mL) at 8 atm H2 and 28 °C for 18 h gave a 35:65 mixture of
benzhydrol and diphenylmethane (total 100% yield), whereas reaction in a
2:1 mixture of C2H5OH and CH3COOH afforded diphenylmethane exclu-
sively.
(3) Sajiki, H.; Hattori, K.; Hirota, K. J. Chem. Soc., Perkin Trans. 1
1998, 4043-4044.
(4) (a) Werbel, L. M.; Elslager, E. F.; Pearlman, W. M. J. Org. Chem.
1964, 29, 967-968. (b) Gosser, L. W. U.S. Patent 4 302 435, 1981. (c)
Kumbhar, P. S.; Rajadhyaksha, R. A. Stud. Surf. Sci. Catal. 1993, 78, 251-
258.
†
Nagoya University.
ERATO Molecular Catalysis Project.
‡
(1) Examples include: antihistaminic and -serotonic homochlorcyclizine
(Pendse, V. K.; Madan, B. R. Indian J. Physiol. Pharmacol. 1969, 13, 29-
36), antihistaminic oxatomide (Awouters, F.; Niemegeers, C. J. E.; Van
den Berk, J.; Van Nueten, J. M.; Lenaerts, F. M.; Borgers, M.; Schellekens,
K. H. L.; Broeckaert, A.; De Cree, J.; Janssen, P. A. J. Experientia 1977,
33, 1657-1659), antihypertensive manidipine (Meguro, K.; Aizawa, M.;
Sohda, T.; Kawamatsu, Y.; Nagaoka, A. Chem. Pharm. Bull. 1985, 33,
3787-3797), antimycotic bifonazole (Regel, E.; Draber, W.; Bu¨chel, K.
H.; Plempel, M. Ger. Patent 2 461 406, 1976), and flunarizine, a calcium
antagonist (Janssen, P. A. J. Fr. Patent 2 014 487, 1970).
(5) (a) Blum, Y.; Czarkie, D.; Rahamim, Y.; Shvo, Y. Organometallics
1985, 4, 1459-1461. (b) Linn, D. E., Jr.; Halpern, J. J. Organomet. Chem.
1987, 330, 155-159. (c) Lau, C.-P.; Cheng, L. J. Mol. Catal. 1993, 84,
39-50.
(6) Walling, C.; Bollyky, L. J. Am. Chem. Soc. 1964, 86, 3750-3752.
10.1021/ol9904139 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/03/2000

reduction using NaBH4.8 We here disclose a practical
procedure for the hydrogenation of benzophenones using the
recently discovered RuCl2(phosphine)2(1,2-diamine) com-
plexes as precatalysts.9,10 Furthermore, the reaction using a
chiral Ru complex effects the enantioselective conversion
of appropriately substituted diaryl ketones to chiral diaryl-
methanols.
Benzophenone can be hydrogenated to benzhydrol in a
nearly quantative yield under 8 atm of hydrogen in 2-pro-
panol containing trans-RuCl2[P(C6H4-4-CH3)3]2 (NH2CH2-
CH2NH2) (3) and t-C4H9OK ([ketone] ) 1 M, ketone/Ru/
base ) 3000:1:12, 35 °C, 18 h). No diphenylmethane was
detected in the product. Table 1 exemplifies the hydrogena-
regardless of the substituents, while halogen atoms, CF3, and
methoxy groups in the aromatic ring were left intact.9 This
hydrogenation can be conducted with a substrate/catalyst
molar ratio (S/C) as high as 20000. The reaction does not
require a homogeneous 2-propanol solution of a ketonic
substrate, and sparingly soluble solid benzophenones can be
subjected to hydrogenation as a slurry (for example, 200 g
of benzophenone in 200 mL of 2-propanol with mechanical
strirring at 700 rpm), thereby maintaining a high rate and
also minimizing the quantity of solvent.
Separate experiments showed that p-trifluoromethylben-
zophenone was hydrogenated 11 times faster than the
p-methoxy derivative (5 atm, 28 °C). Thus, in this hydro-
genation, electron-withdrawing substituents are favored over
donor groups, but the difference is unimportant from a
synthetic point of view. The electronic effect of ring
substituents on the rate was also examined by competition
experiments using an equimolar mixture of benzophenone
and a series of para-substituted benzophenones and 3 as
catalyst. When the relative rates were plotted against the σp
constant,11 a linear relationship with a F value of +1.78 was
obtained (see the Supporting Information). The sensitivity
to the electronic influence in the hydrogenation of para-
substituted benzophenones is higher than in the reaction of
acetophenone derivatives with 3, which showed F ) +0.99.
This value is less than +3.1 observed in the NaBH4 reduction
of acetophenones.12,13
Table 1. Ruthenium(II)-Catalyzed Hydrogenation of
Benzophenonesa
ketone 1
R1
conditions
concnc (M)
alcohol 2
R2
S/Cb
yieldd (%)
He
o-CH3
o-Cl
m-Cl
p-C6H5
p-CH3O
p-F
p-F
p-Cl
p-CF3
H
H
H
H
H
H
H
p-F
H
20000
3000
2000
2000
2000
3000
2000
3000
3000
2000
2.7
1.5
0.8
0.4
0.4
1.5
0.4
1.4
1.3
0.4
99
99
97
98
99f
99
99
99
100
99g
(7) Transfer hydrogenation: (a) Kleinfelter, D. C. J. Org. Chem. 1967,
32, 840-842. (b) Mestroni, G.; Zassinovich, G.; Camus, A.; Martinelli, F.
J. Organomet. Chem. 1980, 198, 87-96. (c) Ram, S.; Spicer, L. D. Synth.
Commun. 1992, 22, 2673-2681. (d) Fujii, A.; Hashiguchi, S.; Uematsu,
N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521-2522. (e)
Mizushima, E.; Yamaguchi, M.; Yamagishi, T. Chem. Lett. 1997, 237-
238.
H
a Unless otherwise stated, reactions were conducted at 8 atm of H2 for
6-18 h at 28-35 °C using a 2.5-12.5 mmol of the substrate 1 (S) in
2-propanol containing the precatalyst 3 (C) and t-C4H9OK. b Substrate/
catalyst molar ratio. Base/3 ) 8. c Concentration of the substrate. d Deter-
mined by GC analysis. e Reaction using 200 g (1.1 mol) of benzophenone
for 48 h. Base/3 ) 40. f Isolated yield. g Yield after 1 h.
(8) Another standard method benzhydrol preparetion is via the addition
of arylmetals to benzaldehydes.
(9) (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.;
Pham, T.; Kozawa, M.; Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya,
T.; Noyori, R. J. Am. Chem. Soc. 1998, 120, 13529-13530.
(10) See also: (a) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1995, 117, 2675-2676. (b) Ohkuma, T.;
Ooka, H.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 10417-
10418. (c) Ohkuma, T.; Ooka, H.; Yamakawa, M.; Ikariya, T.; Noyori, R.
J. Org. Chem. 1996, 61, 4872-4873. (d) Ohkuma, T.; Ikehira, H.; Ikariya,
T.; Noyori, R. Synlett 1997, 467-468. (e) Ohkuma, T.; Doucet, H.; Pham,
T.; Mikami, K.; Korenaga, T.; Terada, M.; Noyori, R. J. Am. Chem. Soc.
1998, 120, 1086-1087. (f) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma,
T.; Pham, T.; Noyori, R. Angew. Chem., Int. Ed. 1999, 38, 495-497.
(11) Hammett, L. P. Physical Organic Chemistry, 2nd ed.; McGraw-
Hill: New York, 1970; Chapter 11.
tion of a range of substituted benzophenones 1 (Scheme 1).
Benzhydrol itself and the p-CH3, -phenyl, and -chloro and
p,p′-difluoro derivatives are useful intermediates for synthe-
ses of commercial drugs.1 The yield of ortho-, meta-, and
para-substituted benzhydrol products 2 was consistently high
Scheme 1
(12) For kinetics of NaBH4 reduction of ketones, see: Brown, H. C.;
Wheeler, O. H.; Ichikawa, K. Tetrahedron 1957, 1, 214-220.
(13) (a) Bowden, K.; Hardy, M. Tetrahedron 1966, 22, 1169-1174. (b)
Bruce, G. T.; Cooksey, A. R.; Morgan, K. J. J. Chem. Soc., Perkin Trans.
2 1975, 551-553.
(14) XylBINAP ) 2,2′-bis(di-3,5-xylylphosphino)-1,1′-binaphthyl. Tol-
BINAP ) 2,2′-bis(di-4-tolylyphosphino)-1,1′-binaphthyl. DAIPEN ) 1,1-
di(4-anisyl)-2-isopropyl-1,2-ethylenediamine.
(15) For asymmetric reduction of diaryl ketones using silicon- and boron-
based hydrides, see: (a) Peyronel, J.-F.; Fiaud, J.-C.; Kagan, H. B. J. Chem.
Res. Miniprint 1980, 4057-4080. (b) Brunner, H.; Ku¨rzinger, A. J.
Organomet. Chem. 1988, 346, 413-424. (c) Brown, E.; Penfornis, A.;
Bayma, J.; Touet J. Tetrahedron: Asymmetry 1991, 2, 339-342. (d) Brown
E, Le´ze´ A, Touet J. Tetrahedron: Asymmetry 1992, 3, 841-844. (e) Shieh,
W.-C.; Cantrell, W. R., Jr.; Carlson, J. A. Tetrahedron Lett. 1995, 36, 3797-
3800. (f) Ramachandran, P. V.; Chen, G.-M.; Brown, H. C. Tetrahedron
Lett. 1996, 37, 2205-2208. (g) Corey, E. J.; Helal, C. J. Angew. Chem.,
Int. Ed. 1998, 37, 1986-2012, and references therein.
660
Org. Lett., Vol. 2, No. 5, 2000

Use of chiral diphosphine/diamine Ru complexes such as
trans-RuCl2[(S)-xylbinap][(S)-daipen] [(S,S)-4a]9b,14 allows
for asymmetric hydrogenation of unsymmetrical diaryl
ketones with an S/C ratio of up to 20000.15,16 Table 2 lists
isomer expresses higher activity than its enantiomer;19b
however, to our knowledge, its absolute configuration has
not been determined. The stereochemistry was determined
by transforming (S)-(+)-2a (93% ee) to (S)-(+)-7 hydro-
chloride, [R]25D +12.5° (c 0.542, CH3OH), according to the
literature.19a The hydrogenation of other o-methoxy and -halo
ketones 1b, 1c, and 1e also displayed a high degree of
enantioselection. The sense of asymmetric induction in the
reactions of these heteroatom-substituted ketones is identical
to that observed with the methyl derivative 1a, indicating
that the possible interaction of the heteroatom to the Ru
catalyst is not the origin of enantioselection.7d,15g Asymmetric
hydrogenation of benzoylferrocene (5) with (S,S)-4b gave
(S)-6 in 95% ee in 100% yield, which is a useful intermediate
for chiral ferrocenyl ligands.20 The XylBINAP complex (S,S)-
4a gave (S)-6 in only 45% ee.
Table 2. Asymmetric Hydrogenation of Diaryl Ketonesa
ketone
R1
alcohol
yieldb (%)
no.
R2
catalyst
eec (%)
1a
1b
1c
1d d
1d e
1e
1f
1g
1h
1i
o-CH3
o-CH3O
o-F
o-Cl
o-Cl
o-Br
o-Br
m-CH3
p-CH3
p-CH3O
p-Cl
H
H
H
H
H
H
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4a
(S,S)-4b
99
100
99
99
99
99
99
98
98
95
97
99
100
93 (S)
99 (S)
97 (S)
97 (S)
97 (S)
96 (S)
98 (S)
33 (-)
8 (R)
35 (R)
9 (S)
47 (S)
95 (S)
p-CH3
As expected, simple meta- and para-substituted benzophe-
nones were hydrogenated with a moderate enantioselectivity.
In the presence of (S,S)-4a, p-trifluoromethylbenzophenone
(1k) gave the S alcohol in 47% ee, whereas the p-methoxy
derivative (1i) afforded the R-enriched product with 35%
ee. Thus, electronic influences of the para substituents and
steric effects of the ortho substituents appear to affect the
extent of the coplanarity of the benzene rings with CdO
function21 in the transition state, thereby generating an
asymmetric bias.
H
H
H
H
H
1j
1k
5f
p-CF3
benzoylferrocene
a Reactions were conducted at 8 atm of H2 using a 2.5 mmol of 1 (0.4-
0.8 M) in 2-propanol containing 4 and t-C4H9OK for 11-15 h at 28 °C.
Substrate/catalyst/base ) 2000:1:8. b Determined by GC or NMR analysis.
c Determined by chiral HPLC analysis. Absolute configuration is stated in
parentheses. d Reaction using 10.8 g of 1d for 47 h at 35 °C. Substrate/
catalyst/base ) 20000:1:80. e Reaction using 101.8 g of 1d for 55 h at 30
°C. Substrate/catalyst/base ) 20000:1:200. f Reaction in a 1:4 toluene/2-
propanol mixture.
Antihistaminic (R)-neobenodine [(R)-8]19,22 was synthe-
sized by utilizing asymmetric hydrogenation of o-bromo-p′-
methylbenzophenone (1f) as a key step where in the bromine
atom acts as an enantiodirective functional substituent (Table
2). Thus, the hydrogenation of a 0.8 M solution of 1f in
2-propanol containing the Ru complex (S,S)-4a and t-C4H9-
OK (ketone/Ru/base ) 2000:1:8, 8 atm, 28 °C, 16 h)
afforded (S)-9 in 98% ee in 99% yield. Lithiation of the
bromo alcohol with 3 equiv of n-C4H9Li in THF at -78 °C
for 3 h followed by hydrolysis and recrystallization from a
20:1 mixture of hexane and ethyl acetate gave (R)-10 in
some examples. A range of ortho-substituted substrates was
converted to the corresponding benzhydrols with high ee.
For example, the hydrogenation of o-methylbenzophenone
(1a) in the presence of (S,S)-4a (ketone/Ru/t-C4H9OK )
2000:1:8, 8 atm, 28 °C, 14 h) afforded (S)-o-methylbenzhy-
drol [(S)-2a] in 93% ee in 99% yield.17,18 In a like manner,
the benzophenone 1d with a chloro substituent, sterically
similar but electonically different from methyl, gave the S
alcohol in 97% ee. Orphenadrine (7) is known as an
anticholinergic and antihistaminic agent.19 The dextrorotatory
99.7% ee, [R]25 +8.65° (c 0.780, CHCl3), in 96% yield.17
D
This chiral alcohol can readily be converted to (R)-8.19
(16) For catalytic asymmetric addition of Ti(C6H5)(OCH(CH3)2)3 or Zn-
(C6H5)2 to benzaldehydes, see: (a) Weber, B.; Seebach, D. Tetrahedron
1994, 50, 7473-7484. (b) Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem.
1997, 62, 444-445. (c) Bolm, C.; Mun˜iz, K. Chem. Commun. 1999, 1295-
1296. (d) Huang, W.-S.; Pu, L. J. Org. Chem. 1999, 64, 4222-4223.
(17) (a) Watanabe, M.; Kuwahara, S.; Harada, N.; Koizumi, M.; Ohkuma,
T. Tetrahedron: Asymmetry 1999, 10, 2075-2078. (b) Kuwahara, S.;
Watanabe, M.; Harada, N.; Koizumi, M.; Ohkuma, T. Enantiomer, in press.
See also: Harada, N.; Fujita, K.; Watanabe, M. Enantiomer 1997, 2, 359-
366. Harada, N.; Fujita, K.; Watanabe, M. Enantiomer 1998, 3, 64-70.
(18) A typical procedure of the 100-g scale reaction of o-chloroben-
zophenone (1d) with an S/C ratio of 20000 follows (see also the Supporting
Information): The ketone 1d (101.8 g, 0.47 mol), 2-propanol (150 mL),
1.0 M t-C4H9OK in tert-butyl alcohol (4.7 mL, 4.7 mmol), and solid (S,S)-
4a (28.7 mg, 0.0235 mmol) were placed in a 1.5-L stainless steel autoclave.
The mixture was degassed, and hydrogen was introduced to a pressure of
8 atm. This mixture was then stirred vigorously at 30 °C for 55 h. The
yield and ee of (S)-2d determined by GC and chiral HPLC analysis were
99 and 97%, respectively. After the solvent was removed under reduced
pressure, the residue was distilled to give pure (S)-2d (97.5 g, 95% yield):
(20) Ireland, T.; Perea, J. J. A.; Knochel, P. Angew. Chem., Int. Ed. 1999,
38, 1457-1460.
bp 138-139 °C/0.3 mmHg; [R]20 -21.51° (c 1.13, CHCl3).17
(21) Zuccarello, F.; Millefiori, S.; Trovato, S. Can. J. Chem. 1976, 54,
226-230.
D
(19) (a) van der Stelt, C.; Heus, W. J.; Nauta, W. T. Arzneim.-Forsch.
1969, 19, 2010-2012. (b) Rekker, R. F.; Timmerman, H.; Harms, A. F.;
Nauta, W. T. Arzneim.-Forsch. 1971, 21, 688-691.
(22) Casy, A. F.; Drake, A. F.; Ganellin, C. R.; Mercer, A. D.; Upton,
C. Chirality 1992, 4, 356-366.
Org. Lett., Vol. 2, No. 5, 2000
661

Overall, this hydrogenation method allows for a clean,
technically simple, and economical synthesis of achiral and
chiral benzhydrols from benzophenones.
the Ministry of Education, Science, Sports, and Culture of
Japan (Nos. 07CE2004 and 11440188).
Supporting Information Available: Procedures for the
hydrogenation of diaryl ketones, GC and HPLC behavior of
products, and [R]D values and an absolute-configuration
determination procedure for chiral alcohols. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank Dr. Chizuko Kabuto, To-
hoku University, for the X-ray determination of the structures
of the (R)-N-[1′-(1-naphthyl)ethyl]carbamate of (S)-2c and
the (2R,3R)-3-phenyl-2,3-epoxypropyl ether of (S)-6. This
work was financially supported in part by grants-in-aid from
OL9904139
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Org. Lett., Vol. 2, No. 5, 2000