Selective reduction of aldehydes and ketones to alcohols with ammonia borane in neat water

Article abstract of DOI:10.1039/c2gc00006g

Chemoselective reduction of various carbonyl compounds to alcohols with ammonia borane (AB), a nontoxic, environmentally benign, and easily handled reagent, in neat water was achieved in quantitative conversions and high isolated yields. Interestingly, α- and β-keto esters were selectively reduced to corresponding hydroxyl esters by AB, while diols were obtained when sodium borohydride was used as a reducing agent. The procedure is also compatible with the presence of a variety of base-labile protecting groups, such as tosyl, acetyl, benzoyl, ester groups, and acid-labile protecting groups such as trityl and TBDMS groups, and others, such as the unsaturated double bond, nitro and cyano groups. Finally, a kilo scale reaction of methyl benzoylformate with AB was conducted in water and gave methyl mandelate in 94% yield.

Full text of DOI:10.1039/c2gc00006g

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PAPER
Selective reduction of aldehydes and ketones to alcohols with ammonia
borane in neat water†
Lei Shi, Yingying Liu, Qingfeng Liu, Bin Wei and Guisheng Zhang*
Received 4th January 2012, Accepted 20th February 2012
DOI: 10.1039/c2gc00006g
Chemoselective reduction of various carbonyl compounds to alcohols with ammonia borane (AB), a
nontoxic, environmentally benign, and easily handled reagent, in neat water was achieved in quantitative
conversions and high isolated yields. Interestingly, α- and β-keto esters were selectively reduced to
corresponding hydroxyl esters by AB, while diols were obtained when sodium borohydride was used as a
reducing agent. The procedure is also compatible with the presence of a variety of base-labile protecting
groups, such as tosyl, acetyl, benzoyl, ester groups, and acid-labile protecting groups such as trityl and
TBDMS groups, and others, such as the unsaturated double bond, nitro and cyano groups. Finally, a kilo
scale reaction of methyl benzoylformate with AB was conducted in water and gave methyl mandelate in
94% yield.
thermal and hydrolytic stability. AB is not only a nontoxic,
environmentally benign, and stable material that can be safely
Introduction
The reduction of carbonyl compounds to alcohols is one of the
most widely used and fundamental reactions in organic chem-
istry.1 Catalytic hydrogenation,2 transition metal catalyzed
hydrogenation,3 biocatalytic reductions with bakers’ yeast
reductase4 and chemical reductions by LiAlH4, nickel–aluminum
alloy,5 tri-n-butyltin hydride,6 sodium formate,7 alkyl phos-
transported without hydrogen loss, but also equally important for
various applications in synthetic organic chemistry.17 Recently
S. G. Shore et al. and P. V. Ramachandran et al. have reported
large-scale methods for the preparation of AB,18 which make it
very readily available. Reactions in aqueous media have attracted
much attention in synthetic organic chemistry, because water is
one of the most abundant, cheap, and environmentally friendly
solvents.19 Since AB is water-soluble, nontoxic and environmen-
tally benign, it is a good combination to conduct green organic
reactions in water using AB as a reductant. Although the use of
AB for the reduction of carbonyls was reported three decades
ago,14b,c to the best of our knowledge, its application in neat
water for reduction of various carbonyl compounds has not been
reported. Thus, we report herein a detailed investigation on the
reduction of carbonyl compounds using AB as a green reductant
in neat water (Scheme 1).
phines,8 poly(methylhydrosiloxane),9 or borane reagents such as
10
zinc borohydride,
NaBH4,11 NaBH3CN,12 BH3-THF,13 and
amine boranes14 have been utilized to accomplish the reduction
of the carbonyl group. However, the reductive activity and selec-
tivity of catalytic hydrogenation greatly depend on the catalysts
and conditions used. Biocatalytic reductions usually require a
specific temperature, pH value and reductase. The use of
NaBH3CN may result in the contamination of products with
toxic materials.15 The traditional methods for the reduction of a
carbonyl group often involve long reaction times,7 harsh con-
ditions (under nitrogen; in acid or alkaline condition5), toxic sol-
vents (such as toluene,6 benzene,14a ether,14b THF) and
complicated operation. NaBH4 is the most common reductant in
the chemical conversion due to its relatively cheap cost, ease of
handling, and possibility of being used in aqueous alcohol
solvent.14
Results and discussion
The reduction of various carbonyl compounds with AB to alco-
hols in neat water was shown in Scheme 1. In a typical reaction
protocol, AB (0.5 mmol) was added to the solution of carbonyl
compound (0.5 mmol) in neat water (2 mL), and the reaction
mixture was stirred at room temperature until the completion of
Ammonia borane (AB), the simplest amine borane, has
recently received a lot of attention as one of the promising
materials for alternate energy.16 AB is a solid with remarkable
Key Laboratory of Green Chemical Media and Reactions, Ministry of
Education, College of Chemistry and Environmental Science, Henan
Normal University, Xinxiang 453007, China. E-mail: zgs@htu.cn;
Tel: +86 373 3325250
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2gc00006g
Scheme 1 Reduction of carbonyl compounds with AB in neat water.
1372 | Green Chem., 2012, 14, 1372–1375
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Table 1 Reduction of aldehydes and ketones to alcohols with AB in
Table 1 (Contd.)
neat watera
Entry
Substrate
Product
Time
Yieldb (%)
Entry
1
Substrate
Product
Time
Yieldb (%)
88
21
22
23
2u
10 h
2 hc
1 hd
85
86
85
2a
5 min
24
25
26
2v
21 h
6 hc
2 hd
88
89
85
2
3
2b
2c
20 min
8 min
94
90
27
28
29
2w
2x
28 h
86
85
86
24 hc
12 hd
4
5
2d
2e
8 min
91
91
30
1 h
91
10 min
31
2y
2.5 h
87
a All reactions were carried out with AB (0.5 mmol), aldehyde or ketone
(0.5 mmol) in H2O (2 mL) at room temperature, unless otherwise
indicated. b Isolated yields. c Reactions were conducted at 50 °C.
d Reactions were conducted at 80 °C.
6
2f
2g
2h
2i
8 min
10 min
10 min
50 min
40 min
95
93
92
85
88
7
8
9
the reaction. Aldehydes and ketones were reduced rapidly in
quantitative conversions and excellent isolated yields (82–97%)
(Tables 1 and 2). The procedure is perfectly compatible with the
presence of a variety of base-labile protecting groups, such as
tosyl, acetyl, benzoyl, ester groups, and acid-labile protecting
groups such as trityl and TBDMS groups. Unsaturated double
bond, nitro and cyano groups also remain intact in the process.
As shown in Table 1, aliphatic aldehyde (entry 1), α,β-unsatu-
rated aldehyde (entry 2), heterocyclic aldehydes (entries 3–5),
benzaldehyde (entry 6), and aromatic aldehydes with electron
donating groups (EDG) or electron withdrawing groups (EWG)
(entries 7–17) were reduced to alcohols 2a–q in excellent yields
at rt in 1 h. Diverse substituents on the aryl, whether EDG or
EWG, did not show significant effect on the yield. It is note-
worthy that the heterocyclic aldehyde 1e, a nucleoside analogue,
was reduced with AB in 10 min in 91% yield (entry 5) and no
deacetylated product was obtained, while the use of NaBH4 gave
10% deacetylated product. Reductions of ketones also underwent
smoothly and gave corresponding secondary alcohols in excel-
lent yields, but required longer time. The slow reaction rate and
lower reactivity of ketones are due to their steric hindrance and
poor water-solubility (entries 18–31). The solubility is important
to the reaction rate. The reductions of substrates 1t–w, which are
poorly soluble in water, needed over 10 h at rt, while higher
temperatures improved the solubility and thus, accelerated the
reaction (entries 20–29).
10
2j
11
2k
50 min
87
12
13
14
15
16
2l
10 min
10 min
50 min
10 min
10 min
91
85
82
97
90
2m
2n
2o
2p
17
2q
50 min
93
18
19
20
2r
2s
2t
2.5 h
24 h
1 h
86
85
89
α-Hydroxyl or β-hydroxyl esters are important synthetic inter-
mediates which are commonly prepared by reducing correspond-
ing keto esters.20 Reduction of ketoesters to diols was observed
with most chemical reductants, such as LiAlH4 and NaBH4. For
example, aromatic and aliphatic keto esters were reduced to diols
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Table 2 Reduction of keto-esters with AB or NaBH4 in neat watera
Entry
Substrate
Reductant
Time/product/yield (%)b
32
33
34
AB
NaBH4
NaBH4
0.5 h/2A/91
10 min/2A,3A/22,39c
1.0 h/3A/92
35
36
AB
NaBH4
8 h/2B/86
15 h/3A/92
37
38
AB
NaBH4
1.5 h/2C/92
2.0 h/3C/85
39
40
AB
NaBH4
10 h/2D/90
17 h/3C/80
41
42
AB
NaBH4
1.0 h/2E/90
2.0 h/3E/88
43
44
AB
NaBH4
3.0 h/2F/89
3.0 h/3F/80
a All reactions were carried out with AB (0.5 mmol), aldehyde or ketone (0.5 mmol) in H2O (2 mL) at room temperature, unless otherwise indicated.
b Isolated yields. c Recovered 20% methyl mandelate.
in methanol by NaBH4,11b and the diol was also obtained when
using ethanol and water as solvent, whereas hydroxyl ester was
the major product when using THF as solvent.11b To further
evaluate the generality and selectivity of our procedure using AB
as a green reductant, the reactions of aromatic keto esters (1A–
E) and aliphatic keto ester 1F with AB were conducted in water
(Table 2). As shown in Table 2, these keto esters were selectively
reduced to corresponding hydroxyl esters 2A–F in isolated
yields of 86–92% and no diols were observed. In our parallel
experiments with NaBH4, we observed that diols are exclusive
products (Table 2) or major product (Table 2, entry 33) if the
reaction was quenched in short time.
To demonstrate the easy use of the reductant, a kilo scale
reduction of methyl benzoylformate with AB was conducted in
water. After vigorously stirring the mixture containing methyl
benzoylformate 1A (1.0 kg, 6.1 mol), AB (189.1 g, 6.1 mol) in
water (3 L) for 2 h, the completion of the reaction was monitored
by TLC. Thereafter, the reaction mixture was thoroughly
extracted with EtOAc, and the combined organic layers were
then washed with saturated brine, dried over anhydrous mag-
nesium sulfate, and concentrated. The residue was distilled under
reduced pressure to give mandelate 2A (951 g, 94% yield) as a
white solid.
substrates including aliphatic, aromatic, α,β-unsaturated, and
heterocyclic aldehydes, and keto esters to give excellent yields in
neat water. It is noteworthy that AB showed better selectivity
than NaBH4 in the reduction of α- and β-keto esters to hydroxyl
esters in water. The procedure is also compatible with the pres-
ence of a variety of base-labile protecting groups, such as tosyl,
acetyl, benzoyl, ester groups, and acid-labile protecting groups
such as trityl and TBDMS groups, and the unsaturated double
bond, nitro and cyano groups are intact in the process. AB is a
convenient reagent with remarkable thermal and hydrolytic stab-
ility, and easily handled, especially in large-scale manufacturing
in neat water solvent. The advantages of the present method,
including green and convenient reaction processes, excellent
yields, mild conditions and simple operation, readily available
and stable reagent, applicability to a wide range of substrates and
large-scale manufacturing, and the nontoxic and environmentally
friendly nature of the reductant, make this new method a valu-
able addition to existing options.
Experimental
General procedure for the reduction of carbonyl compounds to
alcohols
A mixture of carbonyl compound 1 (0.5 mmol), AB (0.5 mmol)
in neat water (2 mL) was stirred at rt for an appropriate time. The
reaction was monitored by TLC. Upon completion, the reaction
mixture was extracted with ethyl acetate (3 × 5 mL). The com-
bined organic extracts were dried over anhydrous magnesium
sulfate and concentrated by rotary evaporation, the residue was
Conclusions
In conclusion, the present work describes a selective and con-
venient green procedure for the reduction of a variety of alde-
hydes and ketones to corresponding alcohols using AB as
reductant. This method is applicable to a broad range of carbonyl
1374 | Green Chem., 2012, 14, 1372–1375
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AB (189.1 g, 6.1 mol) was added to a 10 L flask containing a
mixture of methyl benzoylformate 1A (1.0 kg, 6.1 mol) in water
(3 L) and vigorously stirred for 2 h. TLC showed the reaction
was completed. The reaction mixture was thoroughly extracted
with EtOAc. The combined organic extracts were then washed
with saturated brine and dried over anhydrous magnesium
sulfate, and thereafter concentrated to recover EtOAc. The
residue was distilled under reduced pressure (11 mmHg) to
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Acknowledgements
We are grateful for financial support from NSFC (21172056),
PCSIRT (IRT1061) and Major Project of Henan Science and
Technology Agency (092102310115, 112300410313).
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