Chemoselective Reduction of α,βUnsaturated Aldehydes, Ketones, Carboxylic Acids, and Esters with Nickel Boride in Methanol-Water

Article abstract of DOI:10.1246/bcsj.77.549

A facile procedure for the conjugate reduction of α,β -unsaturated aldehydes, ketones, carboxylic acids, and esters is reported with nickel boride generated in situ from NiCl₂·6H ₂O/NaBH₄ in methanol-water at ambient temperature.

Full text of DOI:10.1246/bcsj.77.549

Ó 2004 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 77, 549–552 (2004)
549
Chemoselective Reduction of ꢀ,ꢁ-Unsaturated Aldehydes, Ketones,
Carboxylic Acids, and Esters with Nickel Boride in Methanol–Water#
ꢀ
Jitender Mohan Khurana and Purnima Sharma
Department of Chemistry, University of Delhi, Delhi-110007, India
Received August 15, 2003; E-mail: jmkhurana@chemistry.du.ac.in
A facile procedure for the conjugate reduction of ꢀ,ꢁ-unsaturated aldehydes, ketones, carboxylic acids, and esters is
reported with nickel boride generated in situ from NiCl2 6H2O/NaBH4 in methanol–water at ambient temperature.
ꢁ
The conjugate reduction of ꢀ,ꢁ-unsaturated carbonyl com-
pounds remains an active and widespread area of organic syn-
thesis. Different reagents are reported in the literature, each
having its characteristic advantages and disadvantages.1 Fac-
tors such as handling of reagents, strict reaction conditions,
temperature maintenance, cost and poor yields of the desired
product are some of the drawbacks associated with most of
the reagents. Therefore, the development of a mild and selec-
tive reducing agent for the conjugate reduction of a variety of
ꢀ,ꢁ-unsaturated carbonyl compounds still attracts a great deal
of attention of organic chemists. Nickel boride2 has been re-
ported as a facile reagent in many reductions. We have also re-
ported the selective deoxygenation of sulfoxides and selenoxi-
des,3a the chemoselective reduction of aldehydes and ketones to
alcohols3b and aromatic nitriles to primary amines,3c benzopyr-
ones to 2H-1-benzopyran-4-ols,3d and the reductive desulfuri-
zation of thioureas, benzimidazoline-2-thiones and thiobarbi-
turates.3e With our experience in handling nickel boride, we be-
lieved that it must be possible to selectively reduce the conju-
gate double bonds under appropriate conditions.
ing material. Thus, methanol appeared to be the solvent of
choice for further investigation to achieve the goal. Thereafter,
we investigated the role of water as a co-solvent to achieve se-
lective reduction. We observed that Ia was regioselectively re-
duced by nickel boride when the molar ratio of substrate to
nickel chloride hexahydrate to sodium borohydride was 1:5:2
in methanol–water to give the corresponding dihydrochalcone
(IIa) in high yield. Similarly chalcones Ib and Ic could also
be regioselectively reduced to dihydrochalcones IIb and IIc un-
der these conditions. Chalcones (Id–m) with poor solubility in
methanol required a higher molar ratio of substrate to nickel
boride (1:10:4) for selective reduction of the carbon–carbon
double bond (Scheme 1, Table 1). The selective reduction of
ꢀ,ꢁ-unsaturated carbonyl compounds was undoubtedly due to
the in situ generation of nickel boride as a reducing species
since the reaction of Ia with sodium borohydride in a 1:2 molar
ratio resulted in the complete reduction of chalcone to tetrahy-
drochalcone, while Ia was recovered unchanged when treated
with nickel chloride hexahydrate in a 1:5 molar ratio. The
amount of water plays a crucial role in the selective reduction.
The use of a higher amount of water caused the reaction to be
sluggish and/or incomplete. With lower amount of water, the
competitive formation of the alcohol was also observed.
Results and Discussion
We report herein a convenient and facile procedure for the
selective reduction of the carbon–carbon double bond of ꢀ,ꢁ-
unsaturated carbonyl compounds with nickel boride in metha-
nol–water at ambient temperature. The nickel boride was gen-
erated in situ from nickel chloride hexahydrate and sodium bor-
ohydride. Chalcone (Ia) and 40-methylchalcone (Ib) were chos-
en as model substrates to investigate the appropriate conditions
for selective conjugate reduction. In order to achieve the selec-
tive carbon–carbon double bond reduction in chalcones, the
molar ratio of substrate to nickel chloride to sodium borohy-
dride was varied, and reactions were attempted in different sol-
vents such as THF, DMF, dichloromethane, ethanol, and meth-
anol. While the reactions of Ia and Ib in THF, dichlorometh-
ane, ethanol, and DMF were either incomplete and/or gave a
mixture of products, reactions in methanol showed the pre-
dominant formation of dihydrochalcones. Reaction of Ia with
NiCl2:NaBH4 in a 1:5:2 molar ratio in methanol yielded dihy-
drochalcone (48%), tetrahydrochalcone (14%), and unreacted
starting material (32%). Similarly, the reaction of Ib yielded
47% dihydrochalcone, 5% tetrahydrochalcone, and 34% start-
Further, we extended the scope of this reagent to achieve
chemoselective reduction of ꢀ,ꢁ-unsaturated aldehydes, ke-
tones, carboxylic acids, and esters under these conditions. Re-
markable chemoselective carbon–carbon double bond reduc-
tions were observed in all of these cases, and labile functional-
ities like aldehyde, ketone, acid, and ester were unaffected
R
R
R'
R'
R"
R"
NiCl2.6H2O, NaBH4
MeOH–H2O, r.t.
O
O
Ia-m
IIa-m
a
b
c
d
e
f
:
:
:
:
:
:
:
R = R' = R" = H
R = R' = H; R" = CH3
R = R' = H; R" = Cl
R = OCH3; R' = R" = H
R = R' = H; R" = OCH3
R = R" = H; R' = OCH3
R' = H; R = R" = OCH3
h
i
j
k
l
:
:
:
:
:
:
R = CH3; R' = R" = H
R1 = H; R = R" = CH3
R = R" = Cl; R' = H
R = –O–CH2–O–; R' = R" = H
R = –O–CH2–O–; R' = H; R" = OCH3
R = R' = H; R" = Br
m
g
Scheme 1.
Published on the web March 12, 2004; DOI 10.1246/bcsj.77.549

550 Bull. Chem. Soc. Jpn., 77, No. 3 (2004)
Chemoselective Reductions with Nickel Boride
Table 1. Reaction of Chalcones with Nickel Boride at Ambient Temperature in MeOH–H2Oa)
Run
Substrate(s)
S:NiCl2 6H2O:NaBH4
Productb)
Time/min
Yieldc)/%
ꢁ
1
2
3
4
5
6
7
8
9
10
11
12
13
Ia
Ib
Ic
Id
Ie
If
Ig
Ih
Ii
1:5:2
1:5:2
1:5:2
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
0.25
0.5
0.5
0.75
0.5
0.75
1.25
0.75
2.5
3
0.5
0.5
0.5
90
81
90
88
85
87
83
87
87
82
82
84
76
1:10:4
1:10:4
1:10:4
1:10:4
1:10:4
1:10:4
1:10:4
1:10:4
1:10:4
1:10:4
Ij
Ik
Il
IIj
IIk
IIl
Im
IIm
a) Reactions were performed with 12 mL MeOH and 2 mL water/1 mmol of substrate. b) Products were
characterized by IR, NMR, mp and by comparison with authentic compound (wherever applicable). c)
Yield refers to the yield of pure isolated product (>98% purity).
double bond has an olefinic character.6 Slower reductions in
the case of cholest-4-en-3-one, chromones, and flavones could
also be attributed to the steric bulk of the molecule.
R
R"
R
R"
NiCl2.6H2O, NaBH4
MeOH-H2O, r.t.
O
O
R'
R'
R = Alkyl, Aryl; R' = H, Alkyl; R" = H, Alkyl, Vinyl, OH, O alkyl
Experimental
Scheme 2.
All melting points were recorded on a tropical labquip appara-
tus. IR spectra were recorded on
a Perkin-Elmer FT-IR
under these conditions (Scheme 2). These results are summa-
rized in Table 2.
SPECTRUM-2000. NMR spectra were recorded on a FT–NMR
model R-600 Hitachi (60 MHz) and Bruker Advance-300 Spec-
trometer (300 MHz) with TMS as the internal standard. The prod-
ucts were identified by co-TLC (wherever applicable), mp, IR, and
NMR spectra.
It can be inferred from Table 2 that disubstituted ꢀ,ꢁ-unsat-
urated aldehydes are selectively reduced faster and also require
lower molar ratios than the di- and tri-substituted ꢀ,ꢁ-unsatu-
rated ketones (runs 15–22). In the case of dibenzylideneace-
tone, both conjugated bonds were reduced selectively to yield
1,5-diphenylpropan-3-one as the major product. Similarly, cin-
namylideneacetophenone underwent selective reduction of
both double bonds to yield 1,5-diphenylpropan-1-one. A keto
group locked in a transoid conformation, e.g. 2-cyclohexenone,
which otherwise requires longer duration for selective hydroge-
nation,4,5 underwent fast reduction to cyclohexanone in 1 h
with nickel boride. Also, 4-(2-furyl)-3-buten-2-one was re-
duced selectively to 4-(2-furyl)butan-2-one without any inter-
ference from the sensitive furan nucleus. Reduction of ꢀ,ꢁ-un-
saturated acids (runs 23–25) and esters (runs 26, 27) yielded the
saturated acids and esters chemoselectively in high yields. ꢀ,ꢁ-
Unsaturated carboxamide, namely cinnamide, and carbonitrile,
namely cinnamonitrile, could not be selectively reduced, as
their reactions were sluggish and showed the formation of a
mixture of compounds.
Starting Materials.
Methanol (S.D.Fine), nickel chloride
hexahydrate (Thomas Baker), and sodium borohydride (E. Merck)
were used in all the reactions. Washing with 5% sodium carbonate
solution, drying and distilling under vacuum purified the aldehydes
obtained from commercial sources. Distillation or recrystallization
purified the commercial ketones. Chalcones were prepared by con-
densation of corresponding acetophenones with corresponding
benzaldehydes by the general procedure of Kohler and Chadwell.7
Mesityl oxide,8a benzylideneacetone,8b dibenzylideneacetone,8b
furfurylideneacetone,8c cholest-4-en-3-one8d were prepared by
methods reported in the literature. Chromone, 6-methylchromone
and 7-methoxychromone were synthesized by acid catalyzed cyc-
lization of the appropriately substituted 1-(2-hydroxyphenyl)-1,3-
butanediones.9 Flavone and 6-methylflavone were prepared by
a modified Baker–Venkataraman synthesis.10
In a typical reaction, a 50 mL round-bottomed flask fitted with a
reflux condenser was mounted over a magnetic stirrer and chalcone
(Ia) (0.208 g, n mmol) dissolved in 12 mL of methanol was placed
Chromones could also be selectively reduced with nickel
boride in methanol–H2O to give the corresponding chroma-
nones, though these substrates required comparatively longer
reaction times and a higher molar ratio of reagents. On the other
hand, flavones seemed to be more difficult to reduce selectively
to give flavanones. Thus, flavone and 6-methylflavone were re-
duced selectively using a higher molar ratio of substrate to
nickel boride to the corresponding flavanones in low yield after
long reaction times. This could be due to the fact that the car-
bonyl group and pyrone double bond in flavones are in contin-
uous conjugation with two phenyls, whereas in chromone the
in it. To this was added NiCl2 6H2O (5n mmol) followed by 2 mL
ꢁ
of distilled water. Then NaBH4 (2n mmol) was added and the re-
action mixture was stirred vigorously at room temperature. The
progress of the reaction was monitored by TLC (thin layer chroma-
tography) using petroleum ether:ethyl acetate (90:10; v/v) as an
eluent. TLC of the reaction mixture showed the complete disap-
pearance of the starting material after 15 min. A new product hav-
ing a slightly higher Rf than the starting material was observed, and
was believed to be dihydrochalcone. The reaction was quenched
with ꢂ10 mL of methanol, and the reaction mixture was filtered
through a celite pad (one inch) using a pump and washed with

J. M. Khurana et al.
Bull. Chem. Soc. Jpn., 77, No. 3 (2004)
551
Table 2. Reactions of ꢀ,ꢁ-Unsaturated Carbonyls, Carboxylic Acids, Esters, and Benzopyrones with
Nickel Boride in MeOH–H2Oa)
Run
14
Substrate(s)
S:NiCl2:6H2O:NaBH4
Time/h
0.25
Productb)
Yieldc)/%
Ph
Ph
1:5:2
1:5:2
70
75
CHO
CHO
CHO
CHO
CHO
15
0.25
16
1:10:4
1.5
91
CHO
O
O
O
17
18
19
20
1:10:4
1:10:4
1:10:4
1:10:4
0.25
0.5
82
86
65
88
O
Ph
Ph
O
O
0.5
Ph
Ph
Ph
Ph
Ph
Ph
O
O
0.5
Ph
Ph
O
O
21
22
1:10:4
1:5:2
1
75
71
1.5
O
O
O
O
COOH
COOH
COOH
COOH
23
24
25
26
1:10:4
1:5:2
0.5
0.25
0.25
0.5
86
90
87
86
Ph
Ph
HO2C
Ph
HO2C
Ph
1:10:4
1:5:2
COOH
COOH
COOMe
COOMe
COOEt
COOEt
COOEt
27
1:10:4
0.25
96
COOEt
C8H17
C8H17
28
1:25:25d,e)
8
61
O
O
O
O
O
O
29
30
31
1:15:15d,e)
1:15:15d,e)
1:20:20d,e)
4.5
4
74
68
68
O
O
O
O
H3C
H3C
H3CO
O
H3CO
O
4.5
O
O
O
O
32
33
1:30:30d,e)
1:30:30d,e)
10
10
32
34
O
O
O
O
H3C
H3C
O
O
a) All reactions were performed with 12 mL MeOH and 2 mL water/1 mmol of substrate, unless
mentioned otherwise. b), c) See Table 1. d) Reactions were performed with 12 mL MeOH and 0.25
mL water/1 mmol of substrate. e) Reaction was initially started with 1:5:5 molar ratio, then lots of
5:5 molar ratio of NiCl2 6H2O to NaBH4 were added at intervals of 2 h to get required molar ratio.
ꢁ
methanol. Water (50 mL) was added to the combined filtrate,
which was extracted with dichloromethane (3 ꢃ 15 mL). The com-
bined dichloromethane extract was dried over anhyd. MgSO4, dec-
anted through a cotton pad and concentrated on a rotary vacuum
evaporator. The product was characterized by mp, IR, and NMR
spectra after recrystallization. Reactions of ꢀ,ꢁ-unsaturated alde-
hydes, ketones, carboxylic acids, and esters were carried out simi-
larly, but the products were separated by column chromatography
using silica gel (100–200 mesh) and petroleum ether/ethyl acetate
as eluent.

552 Bull. Chem. Soc. Jpn., 77, No. 3 (2004)
Chemoselective Reductions with Nickel Boride
In case of cholest-4-en-3-one, chromones, and flavones (runs
28–33), the reaction was started with n mmol of substrate in 12
mL of methanol and 5n mmol of NiCl2 6H2O placed in a 50 mL
round-bottomed flask attached to a reflux condenser and mounted
over a magnetic stirrer. The contents of the flask were stirred mag-
netically and NaBH4 (5n mmol) was added to the flask. Thereafter,
2
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ꢁ
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(Table 2) as observed by TLC. The reactions were worked up as
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petroleum ether:ethyl acetate (75:25; v/v) as an eluent.
4
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