CeCl3-catalyzed reduction of methyl esters of carboxylic acids to corresponding alcohols with sodium borohydride

Article abstract of DOI:10.1080/00397910903457233

A wide range of methyl esters, including esters of aromatic carboxylic acids, alkenyl carboxylic acids, aliphatic carboxylic acids, and protected amino acids, were reduced to the corresponding alcohols with NaBH₄ in ethanol in the presence of a catalytic amount of CeCl₃. The reaction was completed within 24h at ambient temperature and showed high functional group compatibility and chemoselectivity. With esters containing nitro, methoxyl, halogen, alkenyl, and protected amino functionalities, only the ester group was reduced. The alcohols were isolated after evaporation of the solvent and routine aqueous workup in good yields (75-95%). Copyright

Full text of DOI:10.1080/00397910903457233

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CeCl3-Catalyzed Reduction of
Methyl Esters of Carboxylic Acids to
Corresponding Alcohols with Sodium
Borohydride
Yinan Xu a & Yunyang Wei a
a School of Chemical Engineering, Nanjing University of Science and
Technology, Nanjing, China
Version of record first published: 15 Oct 2010.
To cite this article: Yinan Xu & Yunyang Wei (2010): CeCl3-Catalyzed Reduction of Methyl Esters of
Carboxylic Acids to Corresponding Alcohols with Sodium Borohydride, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:22, 3423-3429
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Synthetic Communications1, 40: 3423–3429, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903457233
CeCl3-CATALYZED REDUCTION OF METHYL ESTERS
OF CARBOXYLIC ACIDS TO CORRESPONDING
ALCOHOLS WITH SODIUM BOROHYDRIDE
Yinan Xu and Yunyang Wei
School of Chemical Engineering, Nanjing University of Science and
Technology, Nanjing, China
A wide range of methyl esters, including esters of aromatic carboxylic acids, alkenyl
carboxylic acids, aliphatic carboxylic acids, and protected amino acids, were reduced to
the corresponding alcohols with NaBH4 in ethanol in the presence of a catalytic amount
of CeCl3. The reaction was completed within 24 h at ambient temperature and showed
high functional group compatibility and chemoselectivity. With esters containing nitro,
methoxyl, halogen, alkenyl, and protected amino functionalities, only the ester group was
reduced. The alcohols were isolated after evaporation of the solvent and routine aqueous
workup in good yields (75–95%).
Keywords: Catalytic reduction; CeCl3; NaBH4
INTRODUCTION
Reduction is a fundamental transformation in synthetic and industrial
organic chemistry. Sodium borohydride has received considerable attention as a
selective, mild, yet effective reducing reagent since its discovery by Schlesinger
and coworkers,[1] especially in the reduction of aldehydes and ketones to corre-
sponding alcohols. The reduction of carboxylic acids or esters using sodium boro-
hydride is relatively difficult because of the low reactivity of sodium borohydride.
The NaBH4–MeOH system was reported to reduce methyl esters of aromatic
carboxylic acids to corresponding alcohols.[2] The reaction needs 6 equivalents of
NaBH4 for the reduction of 1 equivalent of the methyl ester. The reactivity of
sodium borohydride can be enhanced by carrying out the reaction in the presence
of certain additives, such as iodine,[3] lithium,[4] aluminum,[5] calcium,[6] cobalt,[7]
copper,[8] nickel,[9] and magnesium chloride.[10] Addition of iodine to NaBH4 in
tetrahydrofuran (THF) provides H3B–THF, which is useful for hydroborations,
reduction of esters, and various others functional groups.[11] The ZnCl2–NaBH4
reagent system also exhibits powerful reducing properties toward esters.[12]
Received April 21, 2009.
Address correspondence to Yunyang Wei, School of Chemical Engineering, Nanjing University of
Science and Technology, Nanjing 210094, China. E-mail: ywei@mail.njust.edu.cn
3423

3424
Y. XU AND Y. WEI
Scheme 1. Reduction of methyl esters catalyzed by CeCl3 with NaBH4.
However, these methods suffer from limitations such as lack of generality, incom-
patibility with other functionalities in the substrates, and high equivalents of
sodium borohydride and additives.
To achieve functional group compatibility and efficient reduction, an alterna-
tive approach is to transform the carboxylic acid into an activated derivative such as
hydroxybenzotriazoly (HOBt) esters,[13] phenyl esters,[14,15] cyclic acyloxyboron
intermediate,[16] and cyanurates[17] followed by reduction with NaBH4. Although
these procedures give satisfactory results, use of expensive and hazardous reagents
limits their applications.
In this article, we report a simple procedure for the chemoselective reduction of
methyl esters of carboxylic acids to corresponding alcohols in good yields with 2
equivalents of NaBH4 in the presence of a catalytic amount of CeCl3 ꢀ 7H2O
(1 mol%) in ethanol within 24 h at ambient temperature (Scheme 1).
EXPERIMENTAL
All chemicals were obtained from commercial sources with more than 99%
purity and used without prior purification. Purity of products was analyzed
by high-performance liquid chromatography (HPLC). Products are all known
compounds and were identified by comparing of their physical and spectral data with
those reported in the literature.
General Experimental Procedure for Reduction of Esters
NaBH4 (40 mg, 2 mmol) was added to a stirred solution of methyl 4-
nitrobenzoate (181 mg, 1 mmol) and CeCl3 ꢀ 7H2O (4 mg, 0.01 mmol) in 5 mL of
EtOH at room temperature. The resulting suspension was stirred for 24 h. The
solvent was evaporated, and the residue was treated with 1 N HCl (20 mL).
The aqueous solution was extracted with ethyl acetate (3 ꢁ 20 mL). The organic layer
was separated and subsequently washed with saturated NaHCO3 and brine. After
drying over anhydrous Na2SO4, ethyl acetate was evaporated to give 4-nitrobenzyl
alcohol (137 mg, 90%).
RESULTS AND DISCUSSION
Effects of Different Metal Salts
In our recent work on metal-catalyzed reduction of methyl esters with NaBH4,
we use methyl 4-nitrobenzoate as a probe substrate and various metal salts as

REDUCTION OF METHYL ESTERS WITH NaBH4–CeCl3
3425
Table 1. Reduction of methyl 4-nitrobenzoate with NaBH4 in the presence of metallic saltsa
Salt
Solvent
Time (h)
Yieldb (%)
—
EtOH
Ether
THF
24
24
24
24
24
15
15
24
15
24
63
54
12
—
25
—
—
41
50
90
LiCl
CaCl2
ZnCl2
AlCl3
BiCl3
THF
THF
EtOH
EtOH
EtOH
EtOH
EtOH
NiCl2 ꢀ 6H2O
CoCl2 ꢀ 6H2O
CuSO4 ꢀ 5H2O
CeCl3 ꢀ 7H2O
aReaction conditions: methyl p-nitrobenzoate (1 mmol), NaBH4 (2 mmol), metallic salts
(1 mol%), solvent (5 mL), at room temperature (20–30 ꢂC).
bBased on HPLC analysis with cinnamyl alcohol as an internal standard.
coreducing agents to form reducing systems with NaBH4. It was found that
among the metal salts we used, CeCl3 catalyzed the reduction of the probe
substrate to the corresponding alcohol effectively. Reduction of methyl 4-
nitrobenzoate with 2 equivalents of NaBH4 in the presence of 1 mol% of
CeCl3 ꢀ 7H2O in ethanol within 24 h at ambient temperature gave (4-nitrophenyl)-
methanol in 90% yield (Table 1).
Reduction of Esters Catalyzed by CeCl3
We then studied the scope of the reaction and found that a wide range of
substrates, including esters of aromatic carboxylic acids, alkenyl carboxylic
acids, aliphatic carboxylic acids, and protected amino acids, can be reduced to
the corresponding alcohols in good yield with a NaBH4–CeCl3 system (Table 2).
The reactions proceeded smoothly at room temperature. Evaporation of the
solvent and routine aqueous workup gave the alcohol without further
purification.
As shown in Table 2, methyl esters bearing functionalities such as halogen,
nitro, methoxyl, and hydroxyl groups (Table 2, entries b, c, d, and h), underwent
clean reduction of the ester functionality. In the case of methyl cinnamate
(Table 2, entry e), the product was the expected allylic alcohol and no 3-phenylpro-
panol was detected. An N-protected methyl ester of amino acid (Table 2, entry i) was
also successfully transformed into the corresponding N-protected amino alcohol.
Electron-deficient methyl benzoate was more reactive than electron-rich esters.
Methyl benzoates substituted by Cl and NO2 groups in meta and para positions were
totally converted. Electron-donating methoxyl group inhibit the reduction when in
para position (Table 2, entry d), while hydroxyl groups in meta and para positions
gave a considerably good yield without detection of ester (Table 2, entry h). It was
evident that both the substitution pattern and positon of the aromatic ring affected
the reaction.

3426
Y. XU AND Y. WEI
a
Table 2. CeCl3-catalyzed chemoselective reduction of methyl esters with NaBH4
Entry
Ester 1a–j
Product 2a–j
Yieldb (%)
a
90
86
b
c
d
e
f
90
75
95
88
91
g
h
i
92
85
j
CH3(CH2)16COOMe
CH3(CH2)10COOMe
MeOOC(CH2)8COOMe
CH3(CH2)17OH
CH3(CH2)11OH
HO(CH2)10OH
85
91
93
k
l
aReaction conditions: ester (1 mmol), NaBH4 (2 mmol), CeCl3 ꢀ 7H2O (1 mol%),
EtOH (5 mL), 20–30 ꢂC, 24 h.
bIsolated yields.
To probe the applicability of the same reaction conditions to other alkyl esters,
we tried the reduction of ethyl benzoate and ethyl 1H-imidazole-5-carboxylate:
the latter is a key intermediate in the synthesis of cimetidine. It was found that
reduction of ethyl benzoate under the same conditions for 48 h gave 30% yield

REDUCTION OF METHYL ESTERS WITH NaBH4–CeCl3
3427
of phenyl methanol with 36% conversion of ethyl benzoate. Reduction of
1H-imidazole-5-carboxylate under the same conditions for 24 h led to quantitative
recovery of the starting material. These results suggest that the present procedure
is best applied to the reduction of methyl esters.
Mechanistic Aspects
NaBH4–CeCl3 has been used in the selective reduction of a,b-unsaturated
ketones to the corresponding allylic alcohols.[18] The authors attributed the
1,2-selectivity in the reduction of a, b-unsaturated ketones to the in situ formation
of alkoxyborohydrides because of the lanthanoid-catalyzed decomposition of BH4ꢃ
in hydroxylic solvents. CeCl3-catalyzed reduction of esters with NaBH4 in ethanol
has seldom or never been reported, according to our knowledge.
The reducing reactivity of NaBH4 can be increased by either the catalysts
or protic solvents. Brown and coworkers concluded that LiBH4 in ethyl ether is
the preferred system for the reduction of esters.[19] Alcoholic solvents are less useful
for this application because of the competitive solvolysis. NaBH4 appears always to
be the least reactive. In the presence of metal salts, the reducing agent could be the
metal borohydride formed in situ. The reduction of esters in alcoholic solvent
involves loss of hydride, forming sodium alkoxyborohydrides, which are capable
of reducing esters.
In our procedure, 2 molar equivalents of NaBH4 were required for complete
reduction of the esters. An obvious hydrogen evolution occurred upon mixing
NaBH4 with the ethanol solution of CeCl3 ꢀ 7H2O. Obviously, Ce3þ can catalyze
the decomposition of BHꢃ4 in hydroxylic solvent to afford alkoxyborohydrides.
Therefore, it is highly probable that the actual reducing species is not BHꢃ4 but the
in situ–derived alkoxyborohydrides (Scheme 2). As shown in Table 1, without the
presence of any catalyst, yield of the reduction product decreased from 90% to
63%. The nature of the metallic ion was found to be an important factor for the
chemoselectivity. When Ce3þ was replaced by Cu2þ, Bi3þ, or Ni2þ, reduction of
Scheme 2. Possible mechanism for reduction of esters catalyzed by CeCl3.

3428
Y. XU AND Y. WEI
methyl 4-nitrobenzoate gave (4-nitrophenyl)methanol in a rather poor yield because
of the competitive reduction of the nitro group.
CONCLUSION
In conclusion, we have developed an efficient, chemoselective, and general pro-
tocol for the reduction of esters of aromatic carboxylic acids, alkenyl carboxylic
acids, aliphatic carboxylic acids, and protected amino acids to the corresponding
alcohols with good potential for industrial process.
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