Catalytic enantioselective borohydride reduction of Ortho-fluorinated benzophenones

Article abstract of DOI:10.1021/ol060927p

In the presence of the optically active ketoiminatocobalt(II) complexes, the enantioselective borohydride reduction of benzophenones was successfully completed. The fluorine atom on the ortho position of the benzophenone and aryl ketones proved effective for obtaining high enantioselectivities. The combined use of modified lithium borohydride afforded the corresponding benzhydrols and arylcarbinols in high yield and high enantioselectivity (88-96% ee).

Full text of DOI:10.1021/ol060927p

ORGANIC
LETTERS
2
006
Vol. 8, No. 14
025-3027
Catalytic Enantioselective Borohydride
Reduction of Ortho-Fluorinated
Benzophenones
3
Ai Kokura, Saiko Tanaka, Taketo Ikeno, and Tohru Yamada*
Department of Chemistry, Faculty of Science and Technology, Keio UniVersity,
Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
yamada@chem.keio.ac.jp
Received April 17, 2006
ABSTRACT
In the presence of the optically active ketoiminatocobalt(II) complexes, the enantioselective borohydride reduction of benzophenones was
successfully completed. The fluorine atom on the ortho position of the benzophenone and aryl ketones proved effective for obtaining high
enantioselectivities. The combined use of modified lithium borohydride afforded the corresponding benzhydrols and arylcarbinols in high
yield and high enantioselectivity (88−96% ee).
Although sodium borohydride is an inexpensive, safely
handled, and readily available reducing agent that provides
various reduction processes both in the laboratory and in
industry, a catalytic and enantioselective version has been
very limited, except for the catalytic enantioselective 1,4-
sponding reduced products with high to excellent enanti-
oselectivities. Optically active benzhydrols are some of the
most important frameworks of pharmaceutical compounds,
8
9
such as neobenodine, carbinoxamine, and orphenadrine. For
their synthesis, two strategies have been proposed: the
enantioselective reduction of precursory benzophenone de-
rivatives using enantioselective hydrogenation catalyzed by
1
reduction with semicorrin cobalt(II) complexes. The catalytic
enantioselective borohydride reduction catalyzed by the
optically active cobalt(II) complexes developed in our
10
BINAP/ruthenium complexes and the enantioselective CBS
2
11
laboratory has been a unique practical process that has been
reduction catalyzed by oxazaborolidine derivatives, though
3
applied to various substrates, such as ketones, imine
high pressure or high catalyst loading was sometimes
required for high enantioselectivity. An alternative method
4
5
derivatives, R,â-unsaturated carboxylates, 1,3-dicarbonyl
6
7
compounds, ferrocenyl ketones, etc., to afford the corre-
(
5) Ohtsuka, Y.; Ikeno, T.; Yamada, T. Tetrahedron: Asymmetry 2003,
(
1) (a) Leutengger, U.; Madin, A.; Pfaltz, A. Angew. Chem., Int. Ed.
Engl. 1989, 28, 60-61. (b) Matt, P. V.; Pfaltz, A. Tetrahedron: Asymmetry
991, 691-700.
2) (a) Nagata, T.; Yorozu, K.; Yamada, T.; Mukaiyama, T. Angew.
14, 967-970.
(6) (a) Ohtsuka, Y.; Kubota, T.; Ikeno, T.; Nagata, T.; Yamada, T. Synlett
2000, 535-537. (b) Ohtsuka, Y.; Koyasu, K.; Ikeno, T.; Yamada, T. Org.
Lett. 2001, 3, 2543-2546.
1
(
Chem., Int. Ed. Engl. 1995, 34, 2145-2147. (b) Sugi, K. D.; Nagata, N.;
Yamada, T.; Mukaiyama, T. Chem. Lett. 1997, 493-494. (c) Yamada, T.;
Nagata, T.; Sugi, K. D.; Yorozu, K.; Ikeno, T.; Ohtsuka, Y.; Miyazaki, D.;
Mukaiyama, T. Chem.-Eur. J. 2003, 9, 4485-4509.
(7) Sato, H.; Watanabe, H.; Ohtsuka, Y.; Ikeno, T.; Fukuzawa, S.;
Yamada, T. Org. Lett. 2002, 4, 3313-3316.
(8) Muller, P.; Nury, P.; Bernardinelli, G. Eur. J. Org. Chem. 2001, 21,
4137-4147.
(3) (a) Sugi, K. D.; Nagata, T.; Yamada, T.; Mukaiyama, T. Chem. Lett.
(9) (a) Casy, A. F.; Drake, A. F.; Ganellin , C. R.; Mercer , A. D.; Upton,
C. Chirality 1992, 4, 356-366. (b) Shafi’ee, A.; Hite, G. J. Med. Chem.
1969, 12, 266-270.
1
996, 737-738. (b) Sugi, K. D.; Nagata, T.; Yamada, T.; Mukaiyama, T.
Chem. Lett. 1996, 1081-1082. (c) Nagata, T.; Sugi, K. D.; Yamada, T.;
Mukaiyama, T. Synlett 1996, 1076-1078.
(10) Ohkuma, T.; Koizumi, M.; Ikehira, H.; Yokozawa, T.; Noyori, R.
Org. Lett. 2000, 2, 659-662.
(4) Sugi, K. D.; Nagata, T.; Yamada, T.; Mukaiyama, T. Chem. Lett.
1
997, 493-494.
(11) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995, 50, 9153-9156.
1
0.1021/ol060927p CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/08/2006

for the enantioselective addition12 of air-sensitive aryl
reagents to aryl aldehydes has been proposed. It was reported
that the cobalt(II)-catalyzed enantioselective borohydride
reduction operated with less than 1 mol % of catalyst loading
in ordinary glass vessels, and the cobalt(II) complexes are
stable even in air during handling. In this communication,
we report the enantioselective borohydride reduction of
ortho-fluorinated benzophenones to the corresponding ben-
zhydrols in the presence of a catalytic amount of an optically
active cobalt(II) complex (Scheme 1).
differentiation of the two aryl groups of the benzophenones
during their enantioselective reduction. Various coordinative
substituents were then screened (Table 1). Among the ortho-
Table 1. Enantioselective Reduction of Various Substituted
Benzophenonesa
Scheme 1. Asymmetric Borohydride Reduction
entry
benzophenone
X
yield/%
ee/%b
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
p-F
m-F
o-F
o-Cl
o-Br
o-I
o-OH
o-CH3
95
76
90
89
74
74
90
49
14
0
81
15
17
9
2g
2h
46
0
a
Reaction conditions: 0.50 mmol of substrate, 0.0050 mmol of Co
catalyst, and 0.75 mmol of modified NaBH4 (0.75 mmol of NaBH4, 0.75
mmol of EtOH, and 10.3 mmol of THFA) in CHCl3. Reaction time: 20 h
(
entries 1-3, 7-8), 4 days (entries 4-6). b Determined by HPLC.
The catalytic enantioselective reduction was performed as
4
follows: Powdered NaBH was activated with ethanol and
tetrahydrofurfuryl alcohol (THFA) to generate the modified
borohydride solution, which was added to a solution of the
halogenated benzophenones, in the order of F > Br > Cl >
I, the enantioselectivity decreased (entries 3-6). It was
postulated that the sodium cation of the borohydride should
coordinate both the fluorine atom and the carbonyl oxygen
to fix the conformation to accelerate the reaction and improve
the enantioselectivity. During the reaction of o-hydroxyben-
zophenone, the corresponding alcohol was obtained with
moderate enantioselectivity (entry 7), whereas the o-meth-
ylbenzophenone provided the racemic product (entry 8).
Because these results supported the fact that chelation by
the ortho-fluorine was critical for the highly enantioselective
induction in the borohydride reduction of the benzophenones,
(R,R)-cobalt(II) catalyst, 1a or 1b, and benzophenone deriva-
tives. In the cobalt(II) complex catalyzed borohydride
reduction, the si/re face selection of carbonyl compounds
could be regulated by the conjugated π-system. For example,
the enantioselective reduction of 1,1′-dibenzoylferrocene in
the presence of the (S,S)-cobalt complex catalyst afforded
the (R,R)-ferrocenyl diol, whereas the (S,S)-diol was obtained
7
from the 1,1′-dialkanoylferrocene. On the basis of this
hypothesis, 4-fluorobenzophenone was subjected to the
present reduction system to afford the corresponding ben-
zhydrol in 95% yield with 14% ee (entry 1), whereas
3
-fluorobenzophenone produced the racemic benzhydrol
Table 2. Effect of the Countercationa
(
entry 2). In contrast, it was found that the 2-fluorinated
benzophenone was converted to the corresponding benzhy-
drol with 81% enantioselectivity (entry 3).
The highly diastereoselective borohydride reduction of the
R-fluoro ketones was recently reported,13 and the addition
of a Lewis acid improved the diastereoselectivity by coor-
dination of both the fluorine on the R-position and the
carbonyl oxygen. The chelation between the fluorine atom
and the carbonyl oxygen was expected to enhance the
entry
1
2
3
4
5
6
7
M+ in MBH4
yield/%
ee/%b
+
K
41
78
90
93
20
37
14
63
62
81
84
71
37
63
c
+
K
+
Na
Li
(12) (a) Huang, W. S.; Pu, L. J. Org. Chem. 1999, 64, 4222-4223. (b)
+
Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62, 444-445. (c)
Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445-446. (d) Bolm,
C.; Muniz, K. Chem. Commun. 1999, 1295-1296. (e) Bolm, C.; Hermanns,
N.; Hildebrand, J. P.; Muniz, K. Angew. Chem., Int. Ed. 2000, 39, 3465-
+
+
Me4N
Et4N
Bu4N
+
3
467. (f) Bolm, C.; Hildebrand, J. P.; Muniz, K.; Hermanns, N. Angew.
Chem., Int. Ed. 2001, 40, 3284-3308.
13) Mohanta, P. K.; Davis, T. A.; Gooch, J. R.; Flowers, R. A. J. Am.
a
Reaction conditions: 0.50 mmol of substrate, 0.0050 mmol of Co
catalyst, and 0.75 mmol of modified MBH4 (0.75 mmol of MBH4, 0.75
(
Chem. Soc. 2005, 127, 11896-11897. A similar chelation effect of the
fluorine atom was effectively employed for the stereocontrol of several
reactions. Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. ReV. 2004, 104, 1-16.
mmol of EtOH, and 10.3 mmol of THFA) in CHCl3. Reaction time: 20 h.
b
Determined by HPLC. c Methanol was used instead of ethanol.
3026
Org. Lett., Vol. 8, No. 14, 2006

4
of ethanol, the modified KBH solution clearly improved the
yield to 78%, but the enantioselectivity did not change (62%
ee). Compared to sodium borohydride, using ammonium
borohydride, the reaction rate drastically decreased when
producing the corresponding alcohol with moderate enanti-
oselectivity and low yield (entries 5-7). In contrast, lithium
borohydride provided o-fluorobenzhydrol with the highest
yield and enantioselectivity (entry 4). Thus, the optimized
Table 3. Asymmetric Borohydride Reduction of Various
o-Fluoroaryl Ketonesa
4
reaction conditions, using LiBH as the reducing agent in
the presence of 1 mol % of the catalyst, 1a or 1b, were
successfully applied to the enantioselective reduction of
various o-fluorobenzophenones and o-fluorinated phenyl
ketones (Table 3). Pentafluoro- and 2,6-difluoro-substituted
benzhydrols were converted to the corresponding benzhy-
drols with excellent enantioselectivities, 96% ee and 95%
ee, respectively (entries 1 and 2). Various o-fluorophenyl
aryl ketones and 2-naphthyl, p-methoxyphenyl, p-fluorophe-
nyl, and o-methoxyphenyl ketones were converted into the
corresponding products, all with high enantioselectivities
(entries 3-6). These results indicated that only the substitu-
tion of a fluorine atom on the ortho position of the
benzophenones effectively afforded the corresponding ben-
zhydrols with high enantioselectivities. The present ortho-
fluorine effect could also be expected for the enantioselective
reduction of aryl alkyl ketones. Actually, the o-fluoroac-
etophenone was reduced with 91% ee in 8 h at -20 °C (entry
8
), whereas the acetophenone was reduced with 86% ee
under the same conditions (entry 7). The enantioselectivity
for the reduction of aryl alkyl ketones with ortho-fluoro
substitution was similarly improved.
In summary, various benzophenones and aryl alkyl ketones
substituted with a fluorine atom on the ortho position were
effectively converted into the corresponding alcohols with
high to excellent enantioselectivities. Further application of
the effect of the fluorine atom on the enantioselective
borohydride reduction is ongoing as well as the mechanistic
study of this remarkable effect.
a
Reaction conditions: 0.50 mmol of substrate, 0.005 mmol of Co
catalyst, and 0.75 mmol of modified LiBH4 (0.75 mmol of LiBH4, 0.75
mmol of EtOH, and 10.3 mmol of THFA) in CHCl3. Reaction time: 8 h
b
(
entries 1, 2, 6-9), 2 days (entries 3-5). Determined by HPLC. c Reaction
carried out in 0.05 M solution.
Supporting Information Available: Experimental details
and spectroscopic data for new compounds (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
the countercation of the borohydride was then examined
(
Table 2). As potassium borohydride was not completely
dissolved by adding ethanol and THFA, the reaction did not
go to completion providing o-fluorobenzhydrol in only 41%
yield with 63% ee (entry 1). When methanol was used instead
OL060927P
Org. Lett., Vol. 8, No. 14, 2006
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