Reduction of ketones to corresponding alcohols with magnesium metal in absolute alcohols

Article abstract of DOI:10.1016/j.tetlet.2005.10.140

Various aliphatic and aromatic ketones are treated with 10 equiv of magnesium metal in absolute methanol or ethanol to afford corresponding alcohols in very high yields at room temperature within 12 h.

Full text of DOI:10.1016/j.tetlet.2005.10.140

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 9–12
Reduction of ketones to corresponding alcohols with
magnesium metal in absolute alcohols
Ji Young Kim,a Hak Do Kim,a Min Jung Seo,a Hyoung Rae Kim,a Zaesung No,a
Deok-Chan Hab and Ge Hyeong Leea,*
aKorea Research Institute of Chemical Technology, PO Box 107, Yusung, Taejeon 305-600, Republic of Korea
bKorea University, Department of Chemistry, Anam-dong Seongbuk-Gu, Seoul 136-701, Republic of Korea
Received 15 September 2005; revised 25 October 2005; accepted 27 October 2005
Available online 10 November 2005
Abstract—Various aliphatic and aromatic ketones are treated with 10 equiv of magnesium metal in absolute methanol or ethanol to
afford corresponding alcohols in very high yields at room temperature within 12 h.
Ó 2005 Published by Elsevier Ltd.
For the reduction of ketones (or aldehydes) to the corre-
sponding alcohols, all the Group I metals (Li, Na, K,
Rb, and Cs) and Group II metals (Ca, Sr, and Ba),1
Al(Hg),2 Yb,3 and low-valent transition metal com-
pounds (Ti, V, Ce, and Sm)4 have been used but the
alkali metals (Li, Na, and K) are employed most
frequently. Zn5 or Fe6 have been also used for aldehydes
and aromatic ketones. The common reaction solvents
were liquid NH3 (or low-molecular weight aliphatic
amines), NH3/alcohol, alcohol, aqueous alcohol, and
water. NaOH5b and acetic acid6 were used for Zn5 and
Fe6 as a proton source, respectively. Ether (THF,
DMF, and diethyl ether) are often used as co-solvent
to increase the solubility of the organic substrates in
the reaction mixture.
The reduction potentials of alkali metals are not suffi-
ciently high enough to add two electrons to aliphatic
carbonyl group.7a Thus, an alternative mechanism7
was suggested, which is now generally accepted to
account for the reaction in the absence or the presence
of added proton sources as shown in Scheme 1.
The reaction depends upon the reaction media and met-
als used. While the radical anion dimerized to give the
pinacol adduct without an added proton source, the
reaction in the presence of an added proton source
proceeded by the protonation of radical anion to give
carbon-centered radical followed by another one-
electron transfer to give anion from which alcohol was
obtained after abstracting proton from the proton
HO OH
dimerization
R
R (pinacol)
M
R R
R
R
R
e-
M
R
R
R
R
R
R
O-
O
O-
O-
disproportionation
M
R
O- + enolate
H
H+
R
H
R
R
H+
e-
R
R
R
OH
OH
OH
Scheme 1. Proposed mechanism for the electron transfer to carbonyl group.
*
Corresponding author. Tel.: +82 42 860 7173; fax: +82 42 860 7160; e-mail: ghlee@krict.re.kr
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.10.140

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J. Y. Kim et al. / Tetrahedron Letters 47 (2006) 9–12
Table 1. Reduction of ketones to corresponding alcohols with magnesium metal in absolute EtOH in the presence of a catalytic amount of HgCl2
R1
H
R1
R2
10 eq Mg/EtOH
O
R2
OH
cat. HgCl2, rt
< 12 h
Entry
1
Substrates 1
Reaction conditiona
Reaction time (h)
Products 2
Isolated yield (%)
99
Cis/transb
O
OH
1a
2a
A
12
O
OH
2
1b
A
12
2b
97
O
OH
3
4
1c
B
A
5
8
2c12
91
94
1/2.7
1/2.3
O
O
O
HO
1d10
A
A
12
12
2d13
1/3.5
1/2.6
O
OH
5
1e10
2e14
88
O
OH
6
7
1f11
A
A
12
12
2f15
80
74
1/9.3
1/4.7
OH
OH
O
OH
1g11
2g15
OH
OH
8
9
1h
A
A
12
12
2h16
97
92
1/3.3
1/4.9
O
HO
O
OH
1i
2i17
O
O
10
11
1j
A
A
12
12
2j18
93
92
1/10c
OH
OH
1k
2k19
1/11.3c
a A: EtOH/cat. HgCl2, rt; B: MeOH/cat. HgCl2, À23 °C.
b Ratios were determined by 1H NMR.
c exo/endo ratio.
donor. The stereochemical results of the reaction are rel-
atively insensitive to the nature of the metals used for
reduction.8 With less acidic proton donors, there is com-
petition between the reduction and the disproportion-

J. Y. Kim et al. / Tetrahedron Letters 47 (2006) 9–12
11
O-
R
OH
R
OH
R
e-
H+/e-
O
R
n
n
n
n
cis as minor
H+
OH
R
n
trans as major
Figure 1. Proposed reduction mechanism for ketones.
ation. When K1a is used, the yield of pinacol adduct is
lower than those from Li and Na regardless of the con-
ditions employed.
reduced at this reaction condition because carbonyl
group of cyclobutanone is more strained comparing to
five- and six-membered rings. Nonetheless, stereoselec-
tivity was not improved comparing to EtOH/cat.
HgCl2/rt condition. The relative stereochemistry of 2c
was determined unequivocally by 2-D COSY experi-
ments and 1-D NOE difference spectroscopy. Upon irra-
diation of the C1–H resonance at 3.88 ppm, a 0.3% NOE
at benzylic CH2 was observed in trans isomer. In case of
2-hydroxymethyl cycloketones (1f–g), electronic repul-
sion between two oxygen atoms reinforces trans stereo-
selectivity similar to intramolecular ketyl-olefin
cyclization. Substituted cyclohexanones (1h–i) gave the
expected trans alcohols as major products. Bicyclic
ketones (1j–k) were reduced to afford thermodynami-
cally more stable endo-products as major. Interestingly,
benzaldehyde was not reduced under above reaction
conditions. In basic alcohols, aldehydes are transformed
into hemiacetals which are inert intermediates against
reduction.
In our continuing efforts to expand the synthetic utility
and reaction mechanism of magnesium metal in protic
solvents such as absolute methanol and ethanol as a
convenient electron transfer agent,9b–e we have recently
reported that magnesium metal in absolute methanol
facilitates various reductive reactions.9a Here, we report
the results of reduction of various aliphatic and aro-
matic ketones to corresponding alcohols with magne-
sium metal under mild reaction conditions in high
yields (74–97%). Comparing to Na and K metals, hand-
ling of magnesium metal is very safe and easy.
Various substrates (1a–k) were treated with 10 equiv of
magnesium metal in absolute EtOH at room tempera-
ture and results are shown in Table 1. In all cases, trans
isomers were obtained as major products. These indicate
that electron transfer from magnesium give ketyl
radicals and additional electron transfer generate ketyl
anions to afford more sterically and electronically
favorable trans isomers after protonation by protic
solvent such as MeOH and EtOH as shown in
Figure 1.
In summary, magnesium metal can be used for the
reduction of ketones more safely, easily, and economi-
cally and complementary to Na- and K-mediated reduc-
tion of ketones.
A typical procedure is as follows. A mixture of substrate
(2.0 mmol), Mg (486 mg, 20.0 mmol, À50 mesh), and a
few crystals of HgCl2 in dry EtOH (50 mL) was stirred
for 12 h at room temperature. The reaction mixture
was poured into cold 0.5 N HCl solution and extracted
with ethyl acetate. The organic layer was washed with
saturated aqueous NaHCO3 solution, dried (MgSO4),
filtered, and then concentrated in vacuo to give crude
product which was purified by flash column chromato-
graphy (SiO2).
Except for cyclobutanone (1c), when magnesium metal
was used in absolute MeOH, reaction was not complete
because reaction of magnesium with MeOH solvent to
evolve hydrogen gas is faster than electron transfer to
carbonyl groups. Also, reaction did not proceed with
Mg/EtOH at room temperature after 12 h in the absence
of HgCl2. In the presence of the catalytic amount of
HgCl2, however, reduction products were obtained in
high yields within 12 h. The stereochemistry of alcohols
was determined with comparing to the reported proton
NMR data. Noncyclic aliphatic ketone (1a) was
smoothly reduced to afford corresponding alcohol quan-
titatively. In aromatic ketone (1b), however, reaction did
not proceed in absolute EtOH solvent. Alcohol was ob-
tained in high yield in absolute MeOH at 0 °C without
catalyst. It seems that more basic Mg(OEt)2 deprotonate
acetophenone to give inert enolate. 2-Substituted cyclo-
ketones (1c–g)1 were smoothly reduced to give cor-
responding trans alcohols as major adducts. Cyclobuta-
none (1c) was reduced in absolute MeOH at À23 °C but
cyclopentanone (1d) and cyclohexanone (1e) were not
Acknowledgements
We thank the Ministry of Science and Technology for
financial support.
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