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C2gc00006g 1372.1375 ++
Cite this: Green Chem., 2012, 14, 1372
Selective reduction of aldehydes and ketones to alcohols with ammoniaborane in neat water†
Lei Shi, Yingying Liu, Qingfeng Liu, Bin Wei and Guisheng Zhang*
Received 4th January 2012, Accepted 20th February 2012DOI: 10.1039/c2gc00006g
Chemoselective reduction of various carbonyl compounds to alcohols with ammonia borane (AB), anontoxic, environmentally benign, and easily handled reagent, in neat water was achieved in quantitativeconversions and high isolated yields. Interestingly, α- and β-keto esters were selectively reduced tocorresponding hydroxyl esters by AB, while diols were obtained when sodium borohydride was used as areducing agent. The procedure is also compatible with the presence of a variety of base-labile protectinggroups, such as tosyl, acetyl, benzoyl, ester groups, and acid-labile protecting groups such as trityl andTBDMS groups, and others, such as the unsaturated double bond, nitro and cyano groups. Finally, a kiloscale reaction of methyl benzoylformate with AB was conducted in water and gave methyl mandelate in94% yield.
thermal and hydrolytic stability. AB is not only a nontoxic,environmentally benign, and stable material that can be safely
The reduction of carbonyl compounds to alcohols is one of the
transported without hydrogen loss, but also equally important for
most widely used and fundamental reactions in organic chem-
various applications in synthetic organic chemistry.17 Recently
istry.1 Catalytic hydrogenation,2 transition metal catalyzed
S. G. Shore et al. and P. V. Ramachandran et al. have reported
hydrogenation,3 biocatalytic reductions with bakers' yeast
large-scale methods for the preparation of AB,18 which make it
reductase4 and chemical reductions by LiAlH4, nickel–aluminum
very readily available. Reactions in aqueous media have attracted
alloy,5 tri-n-butyltin hydride,6 sodium formate,7 alkyl phos-
much attention in synthetic organic chemistry, because water is
phines,8 poly(methylhydrosiloxane),9 or borane reagents such as
one of the most abundant, cheap, and environmentally friendly
zinc borohydride, 10 NaBH4,11 NaBH3CN,12 BH3-THF,13 and
solvents.19 Since AB is water-soluble, nontoxic and environmen-
amine boranes14 have been utilized to accomplish the reduction
tally benign, it is a good combination to conduct green organic
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of the carbonyl group. However, the reductive activity and selec-
reactions in water using AB as a reductant. Although the use of
tivity of catalytic hydrogenation greatly depend on the catalysts
AB for the reduction of carbonyls was reported three decades
and conditions used. Biocatalytic reductions usually require a
ago,14b,c to the best of our knowledge, its application in neat
specific temperature, pH value and reductase. The use of
water for reduction of various carbonyl compounds has not been
NaBH3CN may result in the contamination of products with
reported. Thus, we report herein a detailed investigation on the
toxic materials.15 The traditional methods for the reduction of a
reduction of carbonyl compounds using AB as a green reductant
carbonyl group often involve long reaction times,7 harsh con-
in neat water (Scheme 1).
ditions (under nitrogen; in acid or alkaline condition5), toxic sol-vents (such as toluene,6 benzene,14a ether,14b THF) andcomplicated operation. NaBH4 is the most common reductant in
Results and discussion
the chemical conversion due to its relatively cheap cost, ease ofhandling, and possibility of being used in aqueous alcohol
The reduction of various carbonyl compounds with AB to alco-
hols in neat water was shown in Scheme 1. In a typical reaction
Ammonia borane (AB), the simplest amine borane, has
protocol, AB (0.5 mmol) was added to the solution of carbonyl
recently received a lot of attention as one of the promising
compound (0.5 mmol) in neat water (2 mL), and the reaction
materials for alternate energy.16 AB is a solid with remarkable
mixture was stirred at room temperature until the completion of
Key Laboratory of Green Chemical Media and Reactions, Ministry ofEducation, College of Chemistry and Environmental Science, HenanNormal University, Xinxiang 453007, China. E-mail:
[email protected];Tel: +86 373 3325250†Electronic supplementary information (ESI) available. See DOI:10.1039/c2gc00006g
Reduction of carbonyl compounds with AB in neat water.
1372 Green Chem., 2012, 14, 1372–1375
This journal is The Royal Society of Chemistry 2012
Reduction of aldehydes and ketones to alcohols with AB in
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.
the reaction. Aldehydes and ketones were reduced rapidly inquantitative conversions and excellent isolated yields (82–97%)
(Tables 1 and 2). The procedure is perfectly compatible with thepresence of a variety of base-labile protecting groups, such astosyl, acetyl, benzoyl, ester groups, and acid-labile protecting
groups such as trityl and TBDMS groups. Unsaturated doublebond, nitro and cyano groups also remain intact in the process.
As shown in Table 1, aliphatic aldehyde (entry 1),
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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 yieldsat 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 nodeacetylated product was obtained, while the use of NaBH4 gave10% 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 andlower reactivity of ketones are due to their steric hindrance and
poor water-solubility (entries 18–31). The solubility is importantto the reaction rate. The reductions of substrates 1t–w, which are
poorly soluble in water, needed over 10 h at rt, while highertemperatures improved the solubility and thus, accelerated the
reaction (entries 20–29).
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 observedwith most chemical reductants, such as LiAlH4 and NaBH4. Forexample, aromatic and aliphatic keto esters were reduced to diols
This journal is The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 1372–1375 1373
Reduction of keto-esters with AB or NaBH4 in neat watera
Time/product/yield (%)b
10 min/2A,3A/22,39c
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
substrates including aliphatic, aromatic, α,β-unsaturated, and
using ethanol and water as solvent, whereas hydroxyl ester was
heterocyclic aldehydes, and keto esters to give excellent yields in
the major product when using THF as solvent.11b To further
neat water. It is noteworthy that AB showed better selectivity
evaluate the generality and selectivity of our procedure using AB
than NaBH4 in the reduction of α- and β-keto esters to hydroxyl
as a green reductant, the reactions of aromatic keto esters (1A–
esters in water. The procedure is also compatible with the pres-
E) and aliphatic keto ester 1F with AB were conducted in water
ence of a variety of base-labile protecting groups, such as tosyl,
(Table 2). As shown in Table 2, these keto esters were selectively
acetyl, benzoyl, ester groups, and acid-labile protecting groups
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reduced to corresponding hydroxyl esters 2A–F in isolated
such as trityl and TBDMS groups, and the unsaturated double
yields of 86–92% and no diols were observed. In our parallel
bond, nitro and cyano groups are intact in the process. AB is a
experiments with NaBH4, we observed that diols are exclusive
convenient reagent with remarkable thermal and hydrolytic stab-
products (Table 2) or major product (Table 2, entry 33) if the
ility, and easily handled, especially in large-scale manufacturing
reaction was quenched in short time.
in neat water solvent. The advantages of the present method,
To demonstrate the easy use of the reductant, a kilo scale
including green and convenient reaction processes, excellent
reduction of methyl benzoylformate with AB was conducted in
yields, mild conditions and simple operation, readily available
water. After vigorously stirring the mixture containing methyl
and stable reagent, applicability to a wide range of substrates and
benzoylformate 1A (1.0 kg, 6.1 mol), AB (189.1 g, 6.1 mol) in
large-scale manufacturing, and the nontoxic and environmentally
water (3 L) for 2 h, the completion of the reaction was monitored
friendly nature of the reductant, make this new method a valu-
by TLC. Thereafter, the reaction mixture was thoroughly
able addition to existing options.
extracted with EtOAc, and the combined organic layers werethen 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 awhite solid.
General procedure for the reduction of carbonyl compounds toalcohols
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
In conclusion, the present work describes a selective and con-
reaction was monitored by TLC. Upon completion, the reaction
venient green procedure for the reduction of a variety of alde-
mixture was extracted with ethyl acetate (3 × 5 mL). The com-
hydes and ketones to corresponding alcohols using AB as
bined organic extracts were dried over anhydrous magnesium
reductant. This method is applicable to a broad range of carbonyl
sulfate and concentrated by rotary evaporation, the residue was
1374 Green Chem., 2012, 14, 1372–1375
This journal is The Royal Society of Chemistry 2012
purified by silica gel column chromatography to obtain the
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AB (189.1 g, 6.1 mol) was added to a 10 L flask containing a
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mixture of methyl benzoylformate 1A (1.0 kg, 6.1 mol) in water
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was completed. The reaction mixture was thoroughly extracted
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sulfate, and thereafter concentrated to recover EtOAc. The
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residue was distilled under reduced pressure (11 mmHg) to
collect the fraction at 133–135 °C. The pure product mandelate
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We are grateful for financial support from NSFC (21172056),
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This journal is The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 1372–1375 1375
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