Arylboronic acid-facilitated selective reduction of aldehydes by tributyltin hydride

Article abstract of DOI:10.1081/SCC-100105400

Aldehydes were selectively reduced in the presence of a ketone with tributyltin hydride (n-Bu₃SnH) and arylboronic acids. The double bond of an α-β-unsaturated system was not affected under the reaction conditions.

Full text of DOI:10.1081/SCC-100105400

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ARYLBORONIC ACID-FACILITATED SELECTIVE
REDUCTION OF ALDEHYDES BY TRIBUTYLTIN HYDRIDE
Hongwu Yu a & Binghe Wang b
a Department of Chemistry , North Carolina State University , Raleigh, North Carolina,
27695-8204, U.S.A.
b Department of Chemistry , North Carolina State University , Raleigh, North Carolina,
27695-8204, U.S.A.
Published online: 09 Nov 2006.
To cite this article: Hongwu Yu & Binghe Wang (2001) ARYLBORONIC ACID-FACILITATED SELECTIVE REDUCTION OF
ALDEHYDES BY TRIBUTYLTIN HYDRIDE, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:17, 2719-2725, DOI: 10.1081/SCC-100105400
To link to this article: http://dx.doi.org/10.1081/SCC-100105400
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SYNTHETIC COMMUNICATIONS, 31(17), 2719–2725 (2001)
ARYLBORONIC ACID-FACILITATED
SELECTIVE REDUCTION OF ALDEHYDES
BY TRIBUTYLTIN HYDRIDE
Hongwu Yu and Binghe Wang*
Department of Chemistry, North Carolina State University,
Raleigh, North Carolina 27695-8204, USA
ABSTRACT
Aldehydes were selectively reduced in the presence of a ketone
with tributyltin hydride (n-Bu3SnH) and arylboronic acids.
The double bond of an a,b-unsaturated system was not
affected under the reaction conditions.
Tributyltin hydride (n-Bu3SnH) is a commonly used source of radicals
for a variety of radical chain reactions. It has also been reported that
Bu3SnH can be used for the reduction of aldehydes and ketones in the
presence of HMPA,1 trimethylaluminum and tris(pentafluorophenyl)-
boron,2 triphenylphosphine oxide,3 AIBN,4 or SiO2 or in boiling metha-
5,6
nol.7 Arylboron compounds, such as tris(pentafluorophenyl)boron and
bis(3,4,5-trifluoro-phenyl)borinic acid were used as efficient, air stable and
water tolerant Lewis acid catalysts in aldol condensations.8–12
Tris(pentafluorophenyl)boron was also used as a chelating Lewis acid in
allylation and reduction with allyltributyltin8 and Bu3SnH.2 We have
found that the carbonyl reducing ability of Bu3SnH can be remarkably
*Corresponding author. E-mail: Binghe_Wang@ncsu.edu
2719
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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YU AND WANG
enhanced by arylboronic acids. Therefore, we have examined the reduction
of a series of 11 aldehydes and ketones by Bu3SnH in the presence
of arylboronic acids. Among the compounds that we have examined,
only aldehyde carbonyls were effectively reduced to primary alcohols.
Ketone carbonyls were found to be relatively stable under the same
conditions. Though there are many methods6,13–18 in the literature for
the selective reduction of aldehydes in the presence of ketones, arylboronic
acids have not been reported as a promoter for the selective reduction
of aldehydes by Bu3SnH. These arylboronic acids are readily available
commercially. Given the importance and the high frequency at which
we encounter the need of aldehyde reductions, a new method for the
selective reduction of an aldehyde will broaden the arsenal of tools avail-
able for such kind of conversions. Herein, we report our results in
using Bu3SnH for the selective reduction of aldehydes in the presence of
arylboronic acids.
For the initial examination of the reductions by Bu3SnH, we used
benzaldehyde as a model compound (Scheme 1). In the absence of a boronic
acid or boronate compound, the reduction of benzaldehyde with tributyltin
hydride gave an 18% isolated yield after 24 h of reaction at RT (Table,
Entry 1). In contrast, 88% of benzyl alcohol was obtained after 4 h of
reaction in the presence of 1 equivalent of phenylboronic acid (1) using
otherwise the same conditions (Table, Entry 2). The facilitation of the reduc-
tion by phenylboronic acid is most likely due to the activation of the car-
bonyl group through chelation of the carbonyl oxygen by phenylboronic
acid, which acts as a Lewis acid.
To study the generality of the arylboronic acid-facilitated reduction
of aldehydes, we also examined the effectiveness of three other aryl-
boronic acids (2–4) with different pKa’s (Scheme 1) in facilitating the
Scheme 1. Arylboronic acid-mediated reduction of aldehydes with Bu3SnH.

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2721
Table.
Reduction with Tributyltin Hydridea
Time Yieldb
Entry Substrate
Additive
(h)
(%)
1
2
3
4
5
6
7
Benzaldehyde
Benzaldehyde
No
1
2
24
4
4
18
88
91
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
3
4
5
5
4
94
48
27
24
NRc
38
27
(0.2 eq)
1
1
(0.5 eq)
8
9
4-Methoxybenzaldehyde
4-Methoxybenzaldehyde
0 2010
38
73
103,4-dimethoxybenzaldehyde
1
1
1
1
1
1
1
1
1
1
1
21
16
5.5
1
100
100
90
99
10
11
12
13
14
15
16
17
18
19
2,4-dimethoxybenzaldehyde
Trans-Cinnamaldehyde
2-Furaldehyde
4-Nitrobenzaldehyde
Phenylacetaldehyde
3
0
23
39
48
72
16
21
62
Cyclohexanone
Trace
NR
NR
100d
63e
40-methoxyacetophenone
4-Oxo-pentanoic acid methyl ester
2,4-dimethoxybenzaldehyde + Cyclohexanone
20Phenylacetaldehyde + Cyclohexanone
aAll the reactions were carried out in the dark at room temperature and with 1 eq. of
arylboronic acid; bIsolated yields; cNo reaction; d2,4-Dimethoxybenzyl alcohol as the
e
only product; 2-Phenyl ethanol as the only product.
reduction of aldehydes by tributyltin hydride. These arylboronic acids are
4-fluoro-2-methylphenylboronic acid (2), 3,4,5-trifluorophenyl-boronic acid
(3), and pyridineboronic acid (4). All three arylboronic acids should have
lower pKa’s than that of phenylboronic acid (1) due to the electron-with-
drawing nature of fluorine and the pyridine ring. It was found that aryl-
boronic acids 2 and 3 afforded similar facilitation of the reduction reaction
(Table, Entries 3, 4) as compared with the unsubstituted phenylboronic acid
1 (Table, Entry 2). However, to our surprise, pyridineboronic acid (4) was
ineffective in facilitating this reduction (Table, Entry 5). It is known that
pyridineboronic acid has a much lower pKa than that of phenylboronic
acid.19 Normally a lower pKa should allow for the tighter chelation of the
boronic acid moiety to the carbonyl oxygen and, therefore, further activate

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YU AND WANG
the carbonyl group toward reduction. However, in the case of pyridineboro-
nic acid, chelation of the lone pair electrons of the pyridine nitrogen to the
boronic acid moiety could ‘‘tie up’’ the boronic acid moiety and prevent its
binding to the carbonyl oxygen. Consequently, the carbonyl group is not
activated by pyridineboronic acid for its reduction of tributyltin (Table,
Entry 5).
Since trifluorophenylboronic acid (3) was shown to be very effective
in facilitating the reduction of benzaldehyde by tributyltin hydride and
cyclic boronates are known to be more acidic than the free acid,20
we were also interested in examining the effect of boronate 5. The boronate
(Scheme 1, 5) was prepared by reaction of 3 with neopentyl glycol in reflux-
ing benzene to azeotropically remove the water formed. However, 1 equiva-
lent of the boronate 5 did not afford the same kind of reaction facilitation
as the free boronic acid (3) did (Table, Entries 4, 7), giving only 38% yield
after 27 h of reaction. Such results with a boronate as an additive to the
reaction were only marginally better than that of the control reactions in
the absence of any catalyst (Table, Entry 1). It is not readily clear why
the boronate is not as good a catalyst as its boronic acid counterpart. The
results with the boronate (5) and pyridineboronic acid (4) indicate that
a lower pKa of an arylboronic acid compound does not directly translate
into a better catalyst. Other structural features may also affect the reaction
outcome.
Since the role of the arylboronic acid is essentially as catalyst, we also
examined the reaction with less than one equivalent of the arylboronic acid.
However, lower yields were obtained when less than 1 equivalent of phe-
nylboronic acid was used. For example, in the reduction of 4-meth-
oxybenzaldehyde, quantitative yield was obtained in the presence of 1
equivalent of phenylboronic acid (1) (Table, Entry 8). In contrast, a 73%
yield was obtained when 0.5 equivalent of phenylboronic acid (1) was used
under otherwise the same conditions (Table, Entry 9). Similar results were
obtained when boronate 5 was used as the catalyst. The reduction of ben-
zaldehyde in the presence of less than one equivalent of boronate 5 gave
a 27% yield (Table, Entry 7) as compared to a 38% yield when 1 equivalent
of the catalyst was used (Table, Entry 6).
The need for 1 full equivalent of the catalyst could be due to the
formation of oxyanions after the reduction, which preferentially chelate to
the boronic acid and, therefore, ‘‘trap’’ the catalyst in an inactive form. The
‘‘trapped’’ arylboronic acid is liberated only after an aqueous work-up,
which neutralizes the oxyanion. 11B NMR studies were performed to deter-
mine the possible reaction mechanism. However, no significant differences
in the 11B NMR signals were observed in different experiments to allow for
the establishment of a reaction mechanism.

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2723
After the examination of the effect of different arylboronic acids
and the amount of the arylboronic acid needed, subsequent studies were
conducted with 1 equivalent of the free arylboronic acid 1.
To examine the general applicability of this boronic acid-facilitated
reduction reaction, we studied the reaction using a series of 11 aldehydes
and ketones with different structural features. The first series of reactions
examined were reductions of benzaldehyde with different substituents
by tributyltin hydride. Such aldehydes include those with one (Table,
Entries 8) or two (Table, Entries 10, 11) strong electron-donating methoxy
groups and one that has a strong electron-withdrawing group (Table,
Entry 14). In all cases, the facilitation by 1 equivalent of phenylboronic
acid resulted in the complete reduction of the aldehydes by tributyltin
hydride. However, the reaction time varied depending on the phenyl ring
substituent with the shortest reaction time being for the reduction of the
compound having an electron-withdrawing group, as expected (Table,
Entry 14). The reduction of another aromatic aldehyde, furan-2-carboxal-
dehyde, was also examined in a similar fashion and it was found that furan-
2-carboxaldehyde was completely reduced to the corresponding alcohol by
tributyltin hydride in the presence of 1 equivalent of phenylboronic acid
(Table, Entry 13). We have also examined the reduction of an a,b-unsatu-
rated aldehyde (Table, Entry 12) and found that the reaction gave exclu-
sively 1,2-reduction product in 90% isolated yield. Overall, excellent yields
were obtained with the reduction of aromatic aldehydes or a,b-unsaturated
aldehyde using tributyltin hydride in the presence of phenylboronic acid.
However, the reduction of an aliphatic aldehyde, phenylacetaldehyde, under
the same conditions gave a somewhat lower isolated yield (62%, Table,
Entry 15).
We have also examined the reduction of ketones under the same con-
ditions. However, such reactions failed to give any reduced product or were
very sluggish, starting with either an aromatic (Table, Entry 17) or aliphatic
ketone (Table, Entries 16, 18). The selective reduction of aldehydes could be
explored for synthetic applications. To test the selective reduction of an
aldehyde in the presence of a ketone, we studied two reactions using a
1 : 1 mixture of an aldehyde and a ketone. In both cases, only the aldehyde
was reduced to the corresponding alcohol (Table, Entries 19 and 20).
In a typical procedure, to a solution of the aldehyde (1 mmol) in dry
dichloromethane (2 mL) was added phenylboronic acid (1 mmol). This mix-
ture was stirred at RT until phenylboronic acid was dissolved (about
20min). Then Bu 3SnH (1 mmol) was added in 1 portion. The resulting sol-
ution was stirred at RT until the aldehyde disappeared as monitored with
TLC. Then 2-aminoethanol or 1,3-propanediol (1.1 mmol) was added and
the reaction mixture was stirred for an additional 10min to trap the boronic

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YU AND WANG
acid. The reaction mixture was then loaded on to a silica gel column. Pure
product was obtained using a mixture of hexanes and ethyl acetate in vari-
ous ratios as the eluent.
In conclusion, tributyltin hydride can be used as an effective reducing
agent for the reduction of aldehydes in the presence of an arylboronic acid.
The reagent is also applicable for the reduction of the aldehyde carbonyl
group in an a,b-unsaturated system without the side reaction of 1,4-reduc-
tion. It can be used for the preferential and effective reduction of aldehydes
in the presence of a ketone functional group.
ACKNOWLEDGMENT
We gratefully acknowledge the National Institutes of Health
(CA88343, GM52515, and DK55062) and the American Heart
Association (#9740117N) for their financial support of this work.
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Received in the USA November 21, 2000

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