Reduction of 1,2-diketones with titanium tetraiodide: A simple approach to α-hydroxy ketones

Article abstract of DOI:10.1016/S0040-4039(00)01385-X

1,2-Diketones are readily reduced with titanium tetraiodide to give α-hydroxy ketones in good to excellent yields. Regioselectivity on the reduction of unsymmetrical substrates is also discussed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01385-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7939–7942
Reduction of 1,2-diketones with titanium tetraiodide: a
simple approach to a-hydroxy ketones
Ryuuichirou Hayakawa, Tetsuya Sahara and Makoto Shimizu*
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
Received 17 July 2000; revised 9 August 2000; accepted 10 August 2000
Abstract
1,2-Diketones are readily reduced with titanium tetraiodide to give a-hydroxy ketones in good to
excellent yields. Regioselectivity on the reduction of unsymmetrical substrates is also discussed. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: 1,2-diketones; titanium tetraiodide; a-hydroxy ketones.
Although a-hydroxy ketones are useful synthones in organic synthesis,1 their preparations are
not always readily conducted.2 While oxidation of enolates or their equivalents offers convenient
methodologies,3 another useful approach to this class of compounds involves the reduction of
1,2-diketones.4 However, there appear to be difficult problems of over-reduction to diols and/or
mono-ketones. In order to circumvent these problems, several methods have been developed.
For example, the use of low valent TiCl3 in MeOH effects the reduction of 1,2-diketones to
1,2-diols,5a and heating 1,2-diketones in aqueous HI at reflux gives mono-ketones.5b,c The use of
low valent VCl2 or Zn also gives a-hydroxy ketones selectively.6 However, the search for a new
reduction method with easier experimental operation under mild conditions is still a worthwhile
goal. We have recently disclosed that TiI4 is an excellent reagent for the reductive coupling of
aldehyde, leading to the formation of pinacol coupling products in good to excellent yields.7 We
have now found that TiI4 effects the reduction of 1,2-diketones to give a-hydroxy ketones in
good yields and wish to report herein an efficient method for the preparation of a-hydroxy
ketones (Scheme 1).
Scheme 1.
* Corresponding author. Tel & fax: +81 59 231 9413; e-mail: mshimizu@chem.mie-u.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01385-X

7940
An initial examination into the reduction of benzil with 0.5 equivalents of TiI4 met with the
formation of the desired mono-reduction product 2a in 20% yield.8 Further examination into the
amount of TiI4 led to the formation of benzoin in good yield, and the results are summarized
in Table 1.
Table 1
a
Reduction of benzil 1a with TiI4
Entry
TiI4/equiv.
Time/h
Yield/%b
1
2
3
4
0.5
0.75
1.0
1.5
2.0
1.5
21.0
15.0
5.4
5.3
2.0
20
51
85
92
90
88
5
6c
18.0
a The reaction was carried out according to the typical procedure.
b Isolated yields.
c CH2Cl2 was used as a solvent.
Benzoin 2a was obtained in excellent yield, when more than 1.0 equivalent of titanium
tetraiodide was used. The best result was obtained using 1.5 equivalents of TiI4 in acetonitrile,
and benzoin 2a was obtained in 92% yield. Regarding the solvent, acetonitrile was proved to be
the solvent of choice in terms of the product yield and the reduction rate.
A typical procedure under the optimum conditions follows: Acetonitrile (1.0 ml) was added to
TiI4 (263.3 mg, 0.512 mmol) at room temperature under an argon atmosphere. After stirring for
10 min, to it was added a solution of benzil 1a (50.0 mg, 0.237 mmol) in acetonitrile (1.0 ml) at
0°C. After being stirred at 0°C to room temperature, the reaction was quenched with sat. aq.
NaHCO3 and then 10% aq. NaHSO3. The mixture was filtered through a Celite pad, and
extracted with ethyl acetate (10 ml×3). The combined organic extracts were dried over
anhydrous Na2SO4 and concentrated in vacuo. Purification on preparative silica gel TLC
(n-hexane:ethyl acetate=3:2 as an eluent) gave benzoin 2a (46.2 mg, 92%) as a colorless oil.
Under the optimum conditions, the reduction of various 1,2-diketones 1 proceeded to give the
mono-reduction products 2, and the results are summarized in Table 2. a-Hydroxy ketone 2 was
obtained in the reduction of 4,4%-dimethyl-, 4,4%-dimethoxy-, or 3,3%,5,5%-tetramethoxy benzil
possessing electron donating groups in excellent yield (entries 1, 2, and 5), whereas reduction of
the 1,2-diketone possessing 4,4%-dibromo or 2,2%-dimethoxy groups gave the product in slightly
lowered yield (entries 3 and 4). The latter lowered yield may be due to the steric hindrance
caused by the ortho substituent on the aromatic ring. Alicyclic diketone also underwent clean
reduction to give cyclic a-hydroxy ketone in moderate yield (entry 6).
Furthermore, the present reaction was applied to unsymmetrical 1,2-dicarbonyl compounds
bearing other functional groups such as ester and aldehyde. The results of the reduction of
unsymmetrical 1,2-dicarbonyl compounds are summarized in Table 3.

7941
Table 2
a
Reduction of 1,2-diketones 1 with TiI4
Entry
R1
R2
Solvent
Yield/%b
1
2
3
4
5
6
4-MeC6H4
4-MeOC6H4
4-BrC6H4
2-MeOC6H4
3,5-(MeO)2C6H3
4-MeC6H4
4-MeOC6H4
4-BrC6H4
CH3CN
CH3CN
PhCH3
CH3CN
CH3CN
CH3CN
94
88
73
69
86
67
2-MeOC6H4
3,5-(MeO)2C6H3
ꢀ(CH2)6ꢀ
a The reaction was carried out according to the typical procedure.
b Isolated yields.
Table 3
a
Reduction of unsymmetrical 1,2-dicarbonyl compounds 1 with TiI4
Entry
R1
R2
Solvent
Yield of 2/%b
Yield of 3/%b
1
2
3
4
Ph
n-Pr
Ph
Me
Me
H
C2H5CN
CH3CN
CH3CN
CH3CN
54c
25c
40
–
13c
17c
–
Ph
OMe
33
a The reaction was carried out according to the typical procedure.
b Isolated yields.
1
c Determined by H NMR.
Complete discriminations were observed in the reductions of phenylglyoxal and methyl
phenylglyoxylate where one of the two carbonyls was selectively reduced, although the product
yields were low (entries 3 and 4). In contrast, the discrimination between two identical ketones
was not trivial (entry 2). However, the selective reduction was observed to some extent by
carrying out the reduction with due care (entry 1). The low yields in the above cases were mainly
due to the formation of by-products, which decomposed despite attempted purifications.
There are several arguments on the reaction mechanism, and one of them involves a
single-electron transfer mechanism, which has many precedents in dissolving metal reduction.9
Another concerns the iodination of the carbonyl group of 1,2-diketone 1, followed by the attack
with iodide anion from TiI4 to form an enolate species, which in turn quenched with a proton
source to give the reduction product 2 (Scheme 2). From the results in Table 3 where the
formation of benzyl radicals was not favorable (Table 3, entries 1 and 3), the mechanism shown

7942
in Scheme 2 appears to be likely. We are currently investigating the true reactive species in
detail, and the results will be reported shortly.
Scheme 2.
In conclusion, the reduction of 1,2-dicarbonyl compounds with TiI4 gave a-hydroxy carbonyl
compounds in good to excellent yields. Since titanium tetraiodide is commercially available and
inexpensive, and that the experimental procedure is quite simple, the present procedure offers a
convenient and practical method for a-hydroxy ketones. Furthermore, this is a useful example
of the reduction of 1,2-dicarbonyl compounds without the use of low valent metal species.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports, and Culture, of the Japanese Government.
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