The remarkable role of water during the chemoselective reduction of ketones mediated by metallic aluminium

Article abstract of DOI:10.1016/j.tetlet.2004.03.077

Diaryl ketones are reduced selectively to the corresponding benzhydrols in good yield by aluminium powder in the presence of sodium hydroxide in the solvent system MeOH:H₂O=2:1 whereas dialkyl ketones, α-tetralone, aryl alkyl ketones and cycloalkanones remain mostly unaffected. Interestingly, diaryl ketones remain totally unchanged by the present reagent combination in the absence of water, that is in anhydrous methanol.

Full text of DOI:10.1016/j.tetlet.2004.03.077

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3775–3777
The remarkable role of water during the chemoselective reduction
of ketones mediated by metallic aluminium
*
Sanjay Bhar and Sharmistha Guha
Department of Chemistry, Organic Chemistry Section, Jadavpur University, Kolkata 700032, India
Received 30 December 2003; revised 10 March 2004; accepted 15 March 2004
Abstract—Diaryl ketones are reduced selectively to the corresponding benzhydrols in good yield by aluminium powder in the
presence of sodium hydroxide in the solvent system MeOH:H
2
O ¼ 2:1 whereas dialkyl ketones, a-tetralone, aryl alkyl ketones and
cycloalkanones remain mostly unaffected. Interestingly, diaryl ketones remain totally unchanged by the present reagent combination
in the absence of water, that is in anhydrous methanol.
Ó 2004 Elsevier Ltd. All rights reserved.
The selective manipulation of one functional group in
the presence of other(s) using nontoxic chemicals in
economically viable and environmentally benign condi-
tions is a formidable task for synthetic organic chem-
O
Al (5 eq.)
OH
H
NaOH (2.5 eq.)
2
R1
R2
R1
R
MeOH : H O = 2 :1
2
1
ists. There is a growing interest in carrying out
2
Scheme 1.
important synthetic transformations in aqueous media.
3
There are reports of organic reactions where surpris-
ingly beneficial effects of stoichiometric and sub-stoi-
chiometric amounts of water have been elegantly
demonstrated. The chemoselective reduction of ketones
in the presence of other reducible functional groups is an
tween various types of carbonyl functionality has been
observed. The results are shown in Table 1.
As shown in Table 1, various diaryl ketones underwent
smooth reduction to the corresponding benzhydrols
4
4;5
important synthetic transformation. Many methods
have been developed for this purpose including catalytic
hydrogenation, hydride transfer, dissolving metal
reduction, reduction using low-valent cationic reagents,
Meerwein–Pondorff–Verley reduction and photochemi-
cal and electrochemical reductions. There are also
(Table 1, entries 1–4) in good yields and high purities
using this reagent system as depicted in Scheme 1. Diaryl
ketones, aryl alkyl ketones and aryl aldehydes have been
reported to undergo pinacol coupling with Al/Hg in
7a
dichloromethane albeit in poor yield accompanied by
6
reports on the reduction of diaryl ketones in preference
by-products. However, the same compounds along with
cycloalkanones are found to be reduced to the corre-
sponding alcohols with Al/Hg in aqueous THF
to other types of ketonic functionality. However, many
of these reactions involve the use of costly and toxic
substances, are difficult to carry out and the reaction
products are complicated by side reactions. We report
herein a simple and mild procedure for the reduction of
diaryl ketones (Scheme 1) using aluminium powder and
7b
(THF:H
2
O ¼ 9:1). Cycloalkanones and aliphatic acy-
clic ketones have been found to give complex mixtures
of unidentified products during aluminium-mediated
7c
reduction in dry methanol in the presence of excess
KOH
sodium
MeOH:H
hydroxide
in
aqueous
methanol
having
reagent
combination
substrate:
(
2
O ¼ 2:1), where excellent discrimination be-
Al:KOH ¼ 1:3:9. During dissolving metal reductions
of ketones to the corresponding alcohols it has been
frequently observed
5b;8
that diaryl ketones and a-
tetralone are converted to the corresponding hydrocar-
bons by over-reduction. In contrast, in the present
aluminium-mediated method in aqueous methanol
Keywords: Solvents and solvent effects; Reduction; Aluminium and
compounds.
*
Corresponding author. Tel.: +91-033-24146193; fax: +91-033-2414-
584; e-mail addresses: sanjaybharin@yahoo.com; sssbhar@
lycos.com
6
(MeOH:H
strate:Al:NaOH ¼ 1:5:2.5 (which involves less alkali
2
O ¼ 2:1) using the reagent combination sub-
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.077

3776
S. Bhar, S. Guha / Tetrahedron Letters 45 (2004) 3775–3777
Table 1. Aluminium-mediated reduction of different types of carbonyl compounds in the presence of sodium hydroxide in aqueous methanol
(methanol–water ¼ 2:1)
a
Entry
Substrate
Product
OH
Time (h)
2
Yield (%)
85
O
1
H
O
OH
H
2
3
4
3
3
2
79
71
92
Me
MeO
Cl
Me
MeO
Cl
O
OH
H
O
OH
H
O
O
5
4
93
O
OH
6
7
4
5
19
92
O
O
O
OH
H
8
9
4
3
23
OH
O
b
36
MeO
MeO
O
H
OH
c
10
2
89 (1:1)
H
H
OH
a
b
c
Yields refer to those of isolated pure products, fully characterized chemically and spectroscopically.
1
%
dl:meso by H NMR.
of conversion as measured by H NMR, remainder being starting material.
1
compared to the analogous method in anhydrous
Al (10 eq.)
7c
methanol ), a-tetralone (Table 1, entry 5) and dialkyl
ketones (Table 1, entry 7) remain mostly unaffected;
cycloalkanones (Table 1, entry 6), phenyl ethyl ketone
NaOH (5 eq.)
_
_
A +
Red A
+
Red B
B
MeOH : H O = 2 :1
2
(
entry 9) respond sluggishly. Therefore, the present alu-
minium-mediated method in an aqueous medium offers
Table 1, entry 8) and 4-methoxyacetophenone (Table 1,
Scheme 2.
9
excellent chemoselectivity towards the reduction of
diaryl ketones in the presence of other types of ketonic
functionalities. This is supported by compatibility
studies where binary mixtures of different types of
ketones in equimolecular amounts have been subjected
to reduction in the presence of an excess of the reagents
Although the mechanism of these aluminium-mediated
chemoselective reductions is not clear it seems to be
dependent on the reduction potentials of the carbonyl
functionalities, where a functional group with a less
negative reduction potential (i.e., a diaryl ketone) is
reduced more readily. This transformation also depends
on the amount of water present in the medium. It has
been observed that benzophenone yields benzopinacol
as the major product when the reaction is carried out in
(
Scheme 2, Table 2).
Intramolecular chemoselectivity of the present alumin-
ium-mediated protocol is demonstrated in Scheme 3
where a diaryl ketone is reduced selectively to the cor-
responding 2° alcohol leaving the benzo-fused cyclic
ketone intact.
MeOH:H
major product in MeOH:H
O ¼ 1:1 a mixture of benzhydrol and benzopinacol
were obtained. It is interesting to observe that the sub-
2
O ¼ 1:2 whereas benzhydrol is obtained as the
O ¼ 2:1. In MeOH:
2
H
2

S. Bhar, S. Guha / Tetrahedron Letters 45 (2004) 3775–3777
3777
Table 2. Intermolecular competition during aluminium-mediated reduction between different ketones in aqueous methanol (methanol–water ¼ 2:1)
a
a
Entry
Substrate (A)
Substrate (B)
Time (h)
%-Reduction of A
%-Reduction of B
O
O
O
1
2
4
4
>95
>95
<5
<5
O
O
O
O
3
4
4
4
>95
>95
25
30
O
a
1
%
of reduction measured by H NMR.
Al (5 eq.)
O
O
OH
O
T.; Williamson, T. C. Green Chemistry-Frontiers in Benign
Syntheses and Processes; Oxford University Press, 1998; (c)
Rajappa, S. Emerging Eco-Friendly Alternatives for the Fine
Chemical Industries; Sevak: Mumbai, 2000.
. (a) Li, C. J.; Chan, T.-H. Organic Reactions in Aqueous
Media; Wiley: New York, 1997; (b) Grieco, P. A. Organic
Synthesis in Water; Kluwer Academic: Dordrecht, The
Netherlands, 1997.
NaOH (2.5 eq.)
MeOH : H O = 2 :1
2
2
(
Yield 76%)
Scheme 3.
3
. (a) Ribe, S.; Wipf, P. Chem. Commun. 2001, 299–307; (b)
Dahlen, A.; Hilmersson, G. Tetrahedron Lett. 2002, 43,
strate (benzophenone) is recovered unchanged when the
reaction is carried out in anhydrous methanol using the
present reagent combination (substrate:Al:NaOH ¼
7
197–7200.
4
5
. Greeves, N. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I. 1991; Vol. 3, pp 1–24.
. (a) Yamamura, S.; Nishiyama, S. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I. 1991; Vol.
1
:5:2.5). This indicates that the presence of water in the
reaction medium is essential to bring about this reduc-
tion. Water in the reaction medium also seems to
attenuate the reactivity of the present reagent system
and plays an important role in imparting selectivity.
This was not observed in the analogous aluminium-
3
, pp 307–325; (b) Huffman, J. W. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I. 1991; Vol. 8,
pp 107–128; (c) Mander, E. N. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I. 1991; Vol. 3, pp 489–
521.
. Robertson, G. M. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I. 1991; Vol. 3, pp 563–611.
. (a) Schreibmann, A. A. P. Tetrahedron Lett. 1970, 4271–
7
mediated processes reported earlier.
6
In conclusion, this aluminium-mediated reaction in
aqueous methanol can serve as an efficient procedure for
the chemoselective reduction of diaryl ketones in the
presence of other types of ketonic functionality in rela-
tively mild conditions and using less toxic and easily
available reagents. Further investigations on mechanis-
tic aspects and synthetic applications of this reaction are
currently underway.
7
4
2
772; (b) Hulce, M.; LaVante, T. Tetrahedron Lett. 1988,
9, 525–528; (c) Khurana, J. M.; Sehgal, A.; Gorgia, A.;
Manian, A.; Maikap, G. C. J. Chem. Soc., Perkin Trans. 1
996, 2213–2215.
1
8
. (a) Hall, S. S.; Lipsky, S. D.; McEuroe, F. J.; Bartels, A. P.
J. Org. Chem. 1971, 36, 2588–2591; (b) Marcinow, Z.;
Rabideau, P. W. J. Org. Chem. 1988, 53, 2117–2119.
. Typical experimental procedure: Aluminium powder
9
(
135 mg, 5 mmol) was added to a solution of benzophen-
Acknowledgements
one (182 mg, 1 mmol) in methanol (3 mL) followed by a
solution of sodium hydroxide (100 mg, 2.5 mmol) in water
(1.5 mL) with stirring. Stirring was continued until the
completion of the reaction as monitored by TLC. The
reaction mixture was diluted with water, dichloromethane
was added and the mixture was filtered. The residue was
repeatedly washed with dichloromethane and the aqueous
layer was extracted twice with dichloromethane. The
combined organic extracts were washed with water, dried
and solvent was evaporated to furnish practically pure
benzhydrol (156 mg, 85%).
Financial support from CSIR, New Delhi [Grant No
01(1673)/00/EMR-II dated 07-12-2000] is gratefully
acknowledged.
References and notes
1
. (a) Anastas, P. T.; Warner, J. C. Green Chemistry-Theory
and Practice; Oxford University Press, 1998; (b) Anastas, P.