Chemoselective reduction of aldehydes in the presence of ketones with NaBH4 in polyethylene glycol dimethyl ethers

Article abstract of DOI:10.1081/SCC-200051041

Aldehydes and ketones were treated with NaBH₄ in polyethylene glycol dimethyl ethers (PEGDME) to give the corresponding alcohols in good yields. Chemoselective reduction of aldehydes in the presence of ketones was described.

Full text of DOI:10.1081/SCC-200051041

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Chemoselective Reduction of Aldehydes
in the Presence of Ketones with NaBH4 in
Polyethylene Glycol Dimethyl Ethers
Kiyoshi Tanemura a , Tsuneo Suzuki a , Yoko Nishida a , Koko Satsumabayashi
a & Takaaki Horaguchi b
a School of Dentistry at Niigata , The Nippon Dental University ,
Hamaura‐cho, Niigata, Japan
b Department of Chemistry, Faculty of Science , Niigata University ,
Ikarashi, Niigata, Japan
Published online: 20 Aug 2006.
To cite this article: Kiyoshi Tanemura , Tsuneo Suzuki , Yoko Nishida , Koko Satsumabayashi & Takaaki
Horaguchi (2005) Chemoselective Reduction of Aldehydes in the Presence of Ketones with NaBH4 in
Polyethylene Glycol Dimethyl Ethers, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:6, 867-872, DOI: 10.1081/SCC-200051041
To link to this article: http://dx.doi.org/10.1081/SCC-200051041
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Synthetic Communicationsw, 35: 867–872, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200051041
Chemoselective Reduction of Aldehydes in
the Presence of Ketones with NaBH4 in
Polyethylene Glycol Dimethyl Ethers
Kiyoshi Tanemura, Tsuneo Suzuki, Yoko Nishida, and
Koko Satsumabayashi
School of Dentistry at Niigata, The Nippon Dental University, Hamaura-
cho, Niigata, Japan
Takaaki Horaguchi
Department of Chemistry, Faculty of Science, Niigata University,
Ikarashi, Niigata, Japan
Abstract: Aldehydes and ketones were treated with NaBH4 in polyethylene glycol
dimethyl ethers (PEGDME) to give the corresponding alcohols in good yields.
Chemoselective reduction of aldehydes in the presence of ketones was described.
Keywords: Reduction, aldehydes, sodium borohydrate, phase transfer catalysts
Reduction of aldehydes and ketones with NaBH4 is a process that is
widely used in organic synthesis.[1] NaBH4 is too reactive to reduce
aldehydes selectively in the presence of ketones under normal conditions.
Selective reduction of aldehydes with NaBH4 has been achieved at
2788C[2] or in the presence of thiol,[3] but these methods require cooling to
very low temperatures or the addition of the other reagents.
Polyethylene glycol dimethyl ethers (PEGDME) have been frequently
used for phase-transfer catalysts in a two-phase system of organic-aqueous
Received in Japan October 20, 2004
Address correspondence to Kiyoshi Tanemura, School of Dentistry at Niigata,
The Nippon Dental University, Hamaura-cho, Niigata 951-8580, Japan. E-mail:
tanemura@ngt.ndu.ac.jp

868
K. Tanemura et al.
phase or organic-solid phase using organic solvents such as benzene or
CH2Cl2,[4] however, there are few examples on the use of PEGDME as
solvents for this purpose as far as we know.[5–7] We supposed that interesting
reactivities might be expected in PEGDME.
In this article, we report that aldehydes and ketones react with NaBH4 in
PEGDME, which have an average molecular weight of 250 (PEG250DME),
to give the corresponding alcohols in good to excellent yields. Furthermore,
selective reduction of aldehydes in the presence of ketones at room tempera-
ture (rt) is described.
First, we examined the reactions of a variety of aldehydes with NaBH4 in
PEG250DME. The results are summarized in Table 1. In all cases, the reactions
proceeded at room temperature within 0.5 h to give the corresponding alcohols
in good yields (entries 1 and 3–6). On the other hand, reduction of ketones
required heating at 60 or 1008C to afford the corresponding alcohols in good
yields (entries 9–13). In the case of the reactive ketone, 4-tert-butylcyclohex-
anone (6), the longer reaction time (9 h) at room temperature was necessary
(entry 7). The difference of reactivities between aldehydes and ketones
makes chemoselective reduction of aldehydes possible. When this method
was applied to the reduction of a,b-unsaturated ketones, small amounts of
1,4-addition products as well as 1,2-addition products were yielded at room
temperature under high dilution conditions (entries 14, 16, and 17). When the
reactions were conducted at normal concentrations (conditions of footnote a
in Table 1), large amounts of polymeric materials were obtained together with
the desired products. The ratios of 1,2- and 1,4-addition products were almost
the same as those of the other reported methods.[8] When PEG500DME was
employed as a solvent, the reactions proceeded more slowly and gave the same
products in almost the same yields (entries 2, 8, and 15).
Next, we examined the chemoselective reduction of aldehydes in the
presence of ketones in PEG250DME under high dilution conditions. The
results are shown in Table 2. Indeed, aldehydes were reduced selectively in
the presence of ketones in each case. The concentration of the solution is an
important factor. When the reactions were conducted at normal concen-
trations, aldol-type dehydration products and small amounts of polymeric
materials were obtained together with the reduced alcohols. For example,
alcohols 18 (58%) and 25 (16%), a,b-unsaturated ketone 32 (14%), and
small amounts of polymeric materials were obtained from the reaction of
aldehyde 4 and ketone 11 with NaBH4 in PEG250DME.
When the reduction with NaBH4 was carried out in conventional protic
solvents such as MeOH, EtOH, and H2O, a large excess of the reducing

Chemoselective Reduction of Aldehydes
869
Table 1. Reduction of carbonyl compounds by NaBH4 in PEGDMEa
Time
T (8C) (h)
Entry
1
Substrate
Products (yield, %b)
rt
0.5
15 (98)
15 (96)
1
2c
3
rt
rt
1.5
0.25
2
16 (88)
17 (99)
4
5
rt
rt
0.25
0.5
3
18 (98)
19 (89)
4
5
6
7
rt
rt
0.5
9
6
20 (97) (cis:trans ¼ 76:24)
20 (97) (cis:trans ¼ 76:26)
8c
9
rt
18
60
8
21 (98)
22 (95)
7
10
60
60
7
8
5
11
12
9
23 (96)
24 (90)
60
6
10
(continued)

870
K. Tanemura et al.
Table 1. Continued
Time
T (8C) (h)
Entry
13
Substrate
Products (yield, %b)
100
2
3
11
12
25 (93)
14d
rt
26 (71)
26 (67)
27 (18)
27 (21)
15d
16d
rt
rt
7
3
13
14
28 (86)
29 (8)
rt
2
17d
30 (88)
31 (8)
aReagents and conditions: substrate 4.0 mmol, NaBH4 1.2 mmol, PEG250DME
1 mL.
bIsolated yields.
cPEG500DME was used.
dSolvent 20 mL.
Table 2. Reduction of aldehydes in the presence of ketonesa
Time
(h)
Products
(yield/%b)
Entry
Aldehyde
Ketone
1
2
3
4
5
6
7
8
1
1
3
3
4
4
5
5
6
7
2
2
1
1
2
2
2
2
15 (94), 20 (6)
15 (99), 21 (1)
17 (88), 23 (4)
17 (82), 24 (7)
18 (77), 23 (10)
18 (93), 25 (1)
19 (89), 21 (2)
19 (88), 22 (1)
9
10
9
11
7
8
aReagents and conditions: aldehyde 4.0 mmol, ketone 4.0 mmol, NaBH4 1.2 mmol,
PEG250DME 20 mL.
bIsolated yields.

Chemoselective Reduction of Aldehydes
871
agent was required because NaBH4 gradually decomposes in these solvents.
Under our conditions, 1.2 equiv. of NaBH4 were sufficient to complete the
reactions.
PEG250DME and PEG500DME can be readily removed by washing with
water. If the products were solids, these can be isolated only by filtration
(Table 1, entries 4, 5, 7, 8, 10, and 11). These PEG ethers possess high
boiling points (.3008C), low chemical reactivities, high thermal stability at
higher temperature, low vapor pressure (,0.01 hPa at 208C), low toxicity
(.2000 mg/kg), and low viscosity (PEG250DME, 7; PEG500DME,
25 mm2/s at 208C), which is much more lower than that of polyethylene
glycol 400 (PEG400) (For some reactions including NaBH4 reduction in
PEG400 see[9]) (97–110 mm2/s at 208C).[10,11] PEGDME can dissolve most
of polar and nonpolar substrates, especially for many inorganic salts to a
large extent. Thus, PEGDME possesses many advantages as a solvent.
PEG250DME and PEG500DME can be recovered quantitatively from the
reaction mixture and used for the next experiment. Low vapor pressure and
easy recovery of PEGDME indicate that PEGDME is also highly suitable as
a solvent from an environmental point of view. In contrast, reactions using
crown ethers or quaternary ammonium salts were conducted in highly
volatile organic solvents such as benzene or CH2Cl2.[12]
In summary, we have demonstrated that PEG250DME was the efficient
solvent for the reduction of carbonyl compounds with NaBH4. Chemoselec-
tive reduction of aldehydes in the presence of ketones was achieved. Further-
more, PEGDME is inexpensive and possesses many attractive properties as a
reaction medium.
EXPERIMENTAL
General
To a solution of 1 (512 mg, 4.0 mmol) in PEG250DME (1 mL) was added
NaBH4 (46 mg, 1.2 mmol). After stirring at room temperature for 0.5 h, a
solution of 4 M NH4Cl (10 mL) was added and the mixture was extracted
with ether. The extracts were washed with water, dried over Na2SO4, and
evaporated. The residue was chromatographed (hexane : acetone ¼ 5 : 1) on
silica gel to give 15 (511 mg, 98%) (Table 1, entry 1).
The combined aqueous layer was concentrated under reduced pressure to
remove water. The residue was dissolved in ether and insoluble materials were
removed by filtration. The filtrate was dried over Na2SO4 and evaporated to
recover PEG250DME (97%), which was dried over MS4A before use.
Recovered PEG250DME was used for the next experiment without further
purification (15, 497 mg, 96%). It can be further purified by distillation
under reduced pressure (123–2158C at 2 mmHg).

872
K. Tanemura et al.
ACKNOWLEDGMENTS
We are grateful for the financial support from The Nippon Dental University,
Niigata, Japan.
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