Table 1. Reduction of Benzoylacetone 1a with Various Reducing Agents under Different Reaction Conditions
entry
Lewis acid
reducing agent
solvent
amine (equiv)
yields (%)a,b
syn/anti
1
BH3-py
CH2Cl2
no reaction
2
3
4
5
6
7
8
9
BH3-py
Na-Selectride
BH3-py
BH3-py
BH3-py
BH3-lutidine
BH3-lutidine
BH3-lutidine
BH3-DMAP
BH3-PhNEt2
CH2Cl2
toluene-THF
toluene
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
py (0.1)
py (0.1)
py (0.1)
no reaction
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
20
50
78
87
65
85
50
70
65
70/30
80/20
85/15
97/3
70/30
90/10
60/40
95/5
lutidine (0.1)
lutidine (1)
DMAP (0.1)
PhNEt2 (0.1)
10
11
75/25
a Yields refer to pure isolated products. b The decomposition of cyclic boronates was carried out with method A.
LiInH4,8 are employed since the reaction suffers from the
occurrence of extensive side processes such as enolization,
reductive elimination, and reduction to monoalcohol. Only
when two methyl groups are present at position 2 are high
yields of 1,3-diols obtained.
In the present Letter we report a general and simple
method for the reduction of 1,3-diketones to the correspond-
ing syn-1,3-diols based on the use of borane complexes as
reducing agents in the presence of TiCl4.
1.1 equiv of TiCl4 (solution 1 M in CH2Cl2) and 0.1 equiv
of pyridine at -30 °C. After 30 min an excess of BH3-py
(3-4 equiv) is added at -78 °C. After 2 h the reaction is
quenched with aqueous HCl (1 M). The usual workup gives
a mixture of syn-2 and the boron cyclic derivative syn-3.9,10
To convert syn-3 to syn-2 this mixture is submitted to
treatment with H2O2 in a basic medium (method A).
Alternatively, pure syn-2 can be obtained by quenching the
reaction with aqueous HCl (1 M) and stirring the mixture
overnight (method B) (Scheme 2).
A series of preliminary experiments was performed on
benzoyl acetone 1a in order to determine the best reaction
conditions (see Table 1).
Scheme 2
From the obtained data the following indications
emerged: (a) The presence of TiCl4 is essential for the
reaction; in fact the reaction carried out in absence of the
Lewis acid does not work (Table 1, entries 1 and 2). (b)
The use of a borane-amine complex in nonpolar solvent is
necessary to achieve high yields and high selectivity; in fact
the reduction carried out with N-Selectride in a toluene-
THF solvent mixture (Table 1, entry 3) gives moderate
selectivity (syn/anti ) 70/30) and very low yields (20%).
(c) Among nonpolar solvents, CH2Cl2 gives better results
than toluene. (d) We tested a variety of BH3-amine
complexes as reducing agents, and the best results were
obtained with the simple BH3-pyridine system. (e) Yields
and diastereoselectivity increase if, after mixing the substrate
with TiCl4, 0.1 equiv of the appropriate amine is added prior
to treatment with the borane-amine complex (see Table 1,
entries 5 and 6). Stoichiometric amounts of amine give worse
results (Table 1, entry 9).
As a consequence, the best reaction conditions follow: 1
equiv of 1,3-diketone 1, dissolved in CH2Cl2, is treated with
This methodology was applied to a series of 1,3-diketones.
While the reactions reported in Table 1 were carried out by
adopting exclusively decomposition method A, r the reactions
reported in Table 2 employed both methods A and B.
The obtained results (Table 2, entries 1, 4, and 5) showed
that both decomposition methods are practically equivalent,
giving very similar results.
(5) For example, see: (a) Chan, A. S. C.; et al. Tetrahedron: Asymmetry
1997, 8, 4041. (b) Brunner, H.; Terfort, A. Tetrahedron: Asymmetry 1995,
6, 919.
(6) (a) Ikeda, H.; Sato, E.; Sugai, T.; Ohta, H. Tetrahedron 1996, 52,
8113. (b) Takeshita, M.; Miura, M.; Unuma, Y. J. Chem. Soc., Perkin Trans.
1 1993, 2901. (c) Chenevert, R.; Thiboutot, S. Can. J. Chem. 1986, 64,
1599.
(7) For example, see: (a) Bonini, C.; Righi, G.; Rossi, L. Tetrahedron.
1992, 48, 9801. (b) Barluenga, J.; Resa, J.; Olano, B. J. Org. Chem. 1987,
52, 1425.
The reaction proceeds with excellent diastereoselectivities
in all examined examples, showing that this procedure works
(8) Araki, S.; et al. Tetrahedron 1997, 53, 15685.
46
Org. Lett., Vol. 2, No. 1, 2000