of 1,1′-di(o-bromobenzoyl)ferrocene was very slow at 0 °C
due to the steric hindrance. Therefore, the enantioselective
reduction was carried out at the diethyl ether reflux temper-
ature to afford the corresponding diols in 96% yield for 0.5
h with 87% dl-selectivity and 97% ee (Table 2, entry 8).
The present enantioselective reduction could be applied to
not only the 1,1′-dibenzoylferrocene analogues but also the
1,1′-dialkanoylferrocenes. Although the dl-selectivity from
1,1′-dihexanoylferrocene was not sufficient at 0 °C, the
reduction was tried at -40 °C to afford the corresponding
diol with 87% dl-selectivity and >99% enantioselectivity
(Table 2, entry 11). Also, the 1,1′-dipropanoyl-, dibutanoyl-,
and dioctanoylferrocenes were stereoselectively reduced to
the corresponding ferrocenyl diols with high dl-selectivity
and excellent enantioselectivity (Table 2, entries 9, 10, and
12).16 Most catalytic enantioselective reductions including
hydrogenation17 and hydride reduction18 are generally limited
to π-system conjugated carbonyl functions, e.g., aryl ketones,
vinyl ketones, and alkynyl ketones, etc. The enantioselective
sense was then determined for each reduction. Comparing
the optical rotation with the reported values10c revealed that
the enantioselective reduction of 1,1′-dibenzoylferrocene in
the presence of the (S,S)-cobalt complex afforded the (R,R)-
ferrocenyl diol, whereas the (S,S)-diol was obtained from
1,1′-dialkanoylferrocene (Figure 2). The enantioselective
sense in the reduction of 1,1′-dibenzoylferrocene was in
accord with that19 of acetophenone20 on the condition that
they both are regarded as phenyl ketones. As for the
enantioselective reduction of 1,1′-dialkanoylferrocene, it is
reasonable to consider that the cobalt complex catalyst should
recognize the ferrocenyl group as the π-system, similar to
the reduction of phenyl ketone, to achieve a high enantiose-
lection. Since both enantiomers of the cobalt complex
catalysts are available, both desired antipodes of the ferro-
cenyl diols with an aryl or alkyl substituent can be prepared
Table 1. Various Solvents for Enantioselective Reduction of
1,1′-Dibenzoyllferrocene 2a
entrya
solvent
reaction time/h yieldb/% eec/% (dl/meso)d
1
2
3
4
5
6
CHCl3
CH2Cl2
benzene
CH3CN
THF
12
18
12
72
18
99
86
81
68
87
92
>99 (88:12)
>99 (87:13)
>99 (87:13)
>99 (81:19)
>99 (89:11)
>99 (89:11)
Et2O
0.5
a Reactions were carried out using 0.125 mmol of 1,1′-dibenzoyllfer-
rocene 2a. b Isolated yield. c Determined by HPLC analysis (Chiralpak AD-
H). d Determined by 13C NMR analysis.
with high enantio- and dl-selectivities (Table 1, entry 6).
The enantioselective borohydride reduction was success-
fully applied to various 1,1′-diacylferrocenes for the prepara-
tion of the corresponding C2-symmetrical chiral diol using
5 mol % of a cobalt catalyst 1g in diethyl ether solvent (Table
2). Various 1,1′-dibenzoylferrocene derivatives, possessing
Table 2. Enantioselective Reduction of Various
Diacylferrocenes
(16) Preparation of the Modified Borohydride Solution. To the
suspension of NaBH4 (75.7 mg, 2 mmol) in CHCl3 (13.3 mL) were added
EtOH (0.11 mL, 2 mmol) and tetrahydrofurfuryl alcohol (THFA) (2.71 mL,
28 mmol) at 0 °C under a dry nitrogen atmosphere. The mixture was stirred
for 3 h at 0 °C and then cooled to -20 °C. Enantio- and Diastereoselective
Reduction of the 1,1′-Dibenzoylferrocene (2a). 1,1′-Dibenzoylferrocene
(2a) (0.125 mmol) and the (S,S)-cobalt complex catalyst 1g (3.6 mg, 0.00625
mmol, 5.0 mol % against 1, 1′-dibenzoylferrocene) were dissolved in Et2O
(10 mL) and cooled to 0 °C under a dry nitrogen atmosphere. The modified
borohydride solution (4 mL, 0.5 mmol) was added to the reaction mixture
and stirred for 0.5 h at 0 °C. The reaction was quenched by the dropwise
addition of ice-cold water (10 mL). The reaction mixture was extracted
with AcOEt. The combined organic layers were washed with brine and
dried over anhydrous sodium sulfate. After filtration and evaporation, the
residue was purified by silica gel column chromatography (hexane/AcOEt)
to afford the corresponding 1,1′-ferrocenyl diols 3a and 4a. The dl/meso
selectivity was determined by 13C NMR analysis, and the optical purity
was determined by HPLC analysis (Daicel Chiralpak AD-H, 2-propanol/
hexane).
(17) (a) Ohkuma, T.; Ooka, H.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1995, 117, 10417-10418. (b) Ohkuma, T.; Ikehira, H.; Ikariya, T.;
Noyori, R. Synlett 1997, 467-468. (c) Ohkuma, T.; Ooka, H.; Hashiguchi,
S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 2675-2676.
(18) Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am. Chem. Soc. 1996,
118, 10938-10939.
(19) In the presence of the (R,R)-cobalt complex catalyst, aryl ketones
were selectively converted to the corresponding (R)-alcohols in the previous
experiments with a few exceptions. See ref 13.
a To a solution of the substrate and the cobalt catalyst 1g was added a
solution of the modified borohydride, 0.125 mmol of substrate, 0.00625
mmol (5.0 mol%) of cobalt catalyst 1g, and 0.5 mmol of modified
borohydride at 0 °C in Et2O (10 mL), 0.5-3 h. b Et2O, reflux temperature,
0.5 h. c 0.0125 mmol (10 mol%) of cobalt catalyst 1g, 1.25 mmol of
modified borohydride at -40 °C, 48 h. d Isolated yield. e Determined by
HPLC analysis. f Determined by 1H NMR analysis and or 13C NMR analysis.
g Chiralpak AD-H (2-propanol/hexane). h Chiralcel OD-H (2-propanol/
hexane). i Chiralpak AD-H (EtOH/hexane).
p-fluorophenyl (Table 2, entry 2), p-chlorophenyl (Table 2,
entry 3), p-bromophenyl (Table 2, entry 4), p-methylphenyl
(Table 2, entry 5), o-fluorophenyl (Table 2, entry 6), and
o-chlorophenyl (Table 2, entry 7) were converted to the
corresponding optically active ferrocenyl diols with excellent
enantiomeric excesses and high dl-selectivity. The reaction
(20) Since the prior order of substituents around the asymmetric carbon
is hydroxyl > ferrocenyl > phenyl > alkyl > hydrogen, the descriptions
for the same enantioselective sense were reversed between the reduction
of 1,1′-dibenzoylferrocene and that of acetophenone.
Org. Lett., Vol. 4, No. 19, 2002
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