Highly efficient system for reduction of carboxylic acids and their derivatives to alcohols by HfCl4/KBH4

Article abstract of DOI:10.1080/00397910802573130

HfCl4/KBH4 was found to be a facile, efficient, convenient, and chemoselective system for the reduction of carboxylic acids and their derivatives to the corresponding alcohols under mild conditions. HfCl4/NaBH4 was also utilized to reduce the same carboxylic acids and their derivatives, and it was found that the reducing ability of HfCl4/NaBH4 was similar to that of HfCl4/KBH4. The action of HfCl4/KBH4 on other types of substrates, such as benzyl chloride, peracid, epoxide, ketone, amide, imine, pyridine-N-oxide, and nitrile, was investigated, too. In addition, some competitive reductions of styrene oxide in the presence of carboxylic acid, carboxylic ester, nitrile, and amide were achieved. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802573130

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Highly Efficient System for
Reduction of Carboxylic Acids
and Their Derivatives to
Alcohols by HfCl4/KBH4
Jianghua Zhang a , Xinqin Gao a , Chengyi Zhang a ,
Jianfei Ma a & Defeng Zhao a
a State Key Laboratory of Fine Chemicals, Dalian
University of Technology, Dalian, China
Published online: 02 Apr 2009.
To cite this article: Jianghua Zhang , Xinqin Gao , Chengyi Zhang , Jianfei Ma
& Defeng Zhao (2009) Highly Efficient System for Reduction of Carboxylic Acids
and Their Derivatives to Alcohols by HfCl4/KBH4 , Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:9,
1640-1654, DOI: 10.1080/00397910802573130
To link to this article: http://dx.doi.org/10.1080/00397910802573130
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Synthetic Communications1, 39: 1640–1654, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802573130
Highly Efficient System for Reduction of
Carboxylic Acids and Their Derivatives to
Alcohols by HfCl4/KBH4
Jianghua Zhang, Xinqin Gao, Chengyi Zhang,
Jianfei Ma, and Defeng Zhao
State Key Laboratory of Fine Chemicals,
Dalian University of Technology, Dalian, China
Abstract: HfCl4=KBH4 was found to be a facile, efficient, convenient, and
chemoselective system for the reduction of carboxylic acids and their derivatives
to the corresponding alcohols under mild conditions. HfCl4=NaBH4 was also
utilized to reduce the same carboxylic acids and their derivatives, and it was found
that the reducing ability of HfCl4=NaBH4 was similar to that of HfCl4=KBH4.
The action of HfCl4=KBH4 on other types of substrates, such as benzyl chloride,
peracid, epoxide, ketone, amide, imine, pyridine-N-oxide, and nitrile, was inves-
tigated, too. In addition, some competitive reductions of styrene oxide in the
presence of carboxylic acid, carboxylic ester, nitrile, and amide were achieved.
Keywords: Alcohols, carboxylic acid derivatives, carboxylic acids, HfCl4=KBH4,
reduction
INTRODUCTION
Reduction of carboxylic acids and their derivatives to the corresponding
alcohols is one of the most useful, versatile, and important functional-
group transformations in organic, medicinal, and multistep synthesis of
many natural products,[1] and it has been effected with a variety of
reagents.
Received July 2, 2008.
Address correspondence to Xinqin Gao, State Key Laboratory of Fine
Chemicals, Dalian University of Technology, 158 Zhongshan Road, Dalian
116012, China. E-mail: gaoxq@dlut.edu.cn
1640

Reduction of Carboxylic Acids
1641
Over the past decades, many reducing agents have been applied, such
as lithium aluminum hydride,[2] by which other functional groups in the
molecule, such as the nitro group and halogen group, can also be
reduced; borane,[3] which is incompatible with several functional groups,
most notably amides, nitriles, and so forth; various combinations of
certain additives and sodium borohydride, such as MeOH=NaBH4,[4]
CF3COOH=NaBH4,[5] H2SO4=NaBH4,[6] I2=NaBH4,[7] Br2=NaBH4,[8]
(CNCl)3=NaBH4,[9] LiCl=NaBH4,[10] ZnCl2=NaBH4,[11] CaCl2=NaBH4,[12]
AlCl3=NaBH4,[13] TiCl4=NaBH4,[14] and ZrCl4=NaBH4;[15] and potassium
borohydride in combination with some additives, such as LiCl=KBH4,[16]
ZnCl2=KBH4,[17] or MgCl2=KBH4.[18] However, most of the reported
reducing systems suffer from various drawbacks, such as toxic and hazar-
dous agents (e.g., borane agent,[3] I2=NaBH4,[7] Br2=NaBH4[8]), excessive
usage of reagent (e.g., MeOH=NaBH4[4]), weaker reducing ability [e.g.,
CF3COOH=NaBH4,[5] H2SO4=NaBH4,[6] (CNCl)3=NaBH4[9]], lower che-
moselectivity (e.g., AlCl3=NaBH4,[13] TiCl4=NaBH4[14]), longer reaction
time, higher reaction temperature (CaCl2=NaBH4,[12] ZrCl4=NaBH4[15]),
and poor yield (LiCl=KBH4,[16] ZnCl2=KBH4,[17] MgCl2=KBH4[18]). To
develop a more facile, efficient, or chemoselective reducing system, we
report that HfCl4=KBH4 reduces carboxylic acids and their derivatives
in good yields under mild conditions.
RESULTS AND DISCUSSION
HfCl4 has been extensively used as a catalyst in organic synthesis, including
intramolecular allylsilylation of alkynes,[19] esterification of carboxylic
acids,[20] and synthesis of benzimidazole derivatives.[21] In ongoing
research after the utility of HfCl4 as a catalyst for Friedel–Crafts alkyla-
tion, we observed that HfCl4=KBH4 could efficiently reduce ethyl 4-
nitrobenzoate 1 to 4-nitrobenzyl alcohol 2 in excellent yield (95%) without
any change to the nitro group under mild conditions (Scheme 1). Then the
effect of different molar ratios of 1=HfCl4=KBH4 on the reduction was
investigated to optimize the experimental conditions. The results are listed
in Table 1.
Scheme 1. Reduction of ethyl 4-nitrobenzoate to 4-nitrobenzyl alcohol by HfCl4=
KBH4.

1642
J. Zhang et al.
Table 1. Reduction of ethyl 4-nitrobenzoate 1 with different molar ratios of
1=HfCl4=KBH4
Entry
1=HfCl4=KBH4 (molar ratio)
Conditionsa
Yieldb (%)
1
2
3
4
5
6
7
0.8=0=4.0
0.8=0.1=4.0
0.8=0.2=4.0
0.8=0.5=5.0
0.8=0.8=4.0
0.8=1.0=4.0
0.8=1.0=4.0
67ꢀC, 30 h
67ꢀC, 30 h
67ꢀC, 30 h
67ꢀC, 10 h
67ꢀC, 10 h
40ꢀC, 10 h
40ꢀC, 25 h
Trace
15
42
81
87
95
82c
aDry THF was added to the mixture of HfCl4 and KBH4 under nitrogen and
stirred for 3 h at room temperature, and then a solution of 1 in dry THF was
added dropwise and heated to the reaction temperature (according to typical
experimental procedure 1).
bIsolated yield; all products were identified by 1H NMR and mass
spectrometry.
cThe preparation of reducing agent was not under nitrogen.
The optimum experimental conditions for the reduction of 1 to 2
were as follows: (1) the molar ratio of 1=HfCl4=KBH4 was 0.8=1.0=4.0,
(2) the optimal temperature was 40ꢀC, and (3) the reduction should be
carried out under nitrogen. Then a variety of structurally diverse
carboxylic acids and their derivatives were investigated according to these
experimental conditions to establish the generality of the present reducing
agent and to examine the tolerance of the other functional groups present
in the substrates. The process of the reaction was monitored by thin-layer
chromatography (TLC), and the results are shown in Table 2.
As listed in Table 2, functional groups, such as chloro group (entries
2, 10, and 12), bromo group (entries 3 and 4), iodo group (entries 5 and
13), and nitro group (entry 1), were tolerated in the reduction process.
Benzoic acids and their derivatives substituted by electron-withdrawing
groups, like the nitro group (entry 1), chloro group (entries 2, 10, and
12), bromo group (entries 3 and 4), and iodo group (entry 5), were
reduced much faster than those with electron-donating groups, such as
the methyl group (entries 7 and 17). Besides, the reduction of aliphatic
carboxylic acids by HfCl4=KBH4 (entries 8 and 9) was faster than that
of aromatic acids (entries 1–7). For the two aromatic esters (entries 15
and 21), methyl 2-hydroxy-3-naphthoate (entry 21) was reduced
much more smoothly than ethyl 2-hydroxybenzoate (entry 15). Sodium
benzoate (entry 23) could not be reduced because of its insolubility.
According to these results, HfCl4=KBH4 is a more facile, efficient, and

Reduction of Carboxylic Acids
1643
Table 2. Reduction of carboxylic acids and their derivatives with HfCl4=KBH4
Entry
1
Substrate
Conditionsa
40ꢀC, 14.0 h
Product
Yieldb (%)
98
2
3
4
40ꢀC, 15.2 h
40ꢀC, 15.5 h
40ꢀC, 16.0 h
82
84
89
5
40ꢀC, 16.4 h
90
6
7
40ꢀC, 17.0 h
40ꢀC, 18.8 h
61
75
8
9
CH3(CH2)10COOH
40ꢀC, 12.2 h CH3(CH2)10CH2OH
40ꢀC, 13.0 h
96
81
10
40ꢀC, 10.0 h
88
11
12
40ꢀC, 10.6 h
40ꢀC, 8.0 h
63
82
13
14
40ꢀC, 9.2 h
40ꢀC, 4.5 h
86
52
15
40ꢀC, 10.2 h
70
16
17
40ꢀC, 10.2 h
40ꢀC, 17.5 h
68
81
18
19
CH3(CH2)10COOCH2CH3 40ꢀC, 6.5 h CH3(CH2)10CH2OH
40ꢀC, 7.4 h
95
86
(Continued )

1644
J. Zhang et al.
Table 2. Continued
Entry
20
Substrate
Conditionsa
40ꢀC, 10.7 h
Product
Yieldb (%)
63
21
22
40ꢀC, 9.0 h
rt, 10.3 h
94
60
23
40ꢀC, 35.5 h
No reaction
aDry THF was added to the mixture of HfCl4 and KBH4 under nitrogen and
stirred for 3 h at room temperature, and then a solution of substrate in dry
THF was added dropwise and heated to the reaction temperature (according to
typical experimental procedure 1).
bIsolated yield; all products were characterized by 1H NMR and mass
spectrometry.
chemoselective reducing system than those earlier reported methods, and
the yields are quite high.
HfCl4=NaBH4 was also compared with HfCl4=KBH4 in reducing
ability for the reduction of carboxylic acids and their derivatives. The
results are tabulated in Table 3.
In Table 3, carboxylic acids and their derivatives were reduced to the
corresponding alcohols by HfCl4=NaBH4, without any change to halogen
group (entries 2–5, 10, 13, and 14) and nitro group (entries 1 and 12),
similar to those by HfCl4=KBH4. The data also showed HfCl4=NaBH4
had reducing ability similar to HfCl4=KBH4. In general, NaBH4 is more
active than KBH4, so we suppose that for the reduction of carboxylic
acids and their derivatives to the corresponding alcohols, HfCl4=KBH4
and HfCl4=NaBH4 undergo the formation of Hf(BH4)4 first, which is
an active species in the reduction process.
To enlarge the synthetic utility of HfCl4=KBH4, other substrates,
such as benzyl chloride, peracid, epoxide, ketone, amide, imine, pyri-
dine-N-oxide, and nitrile, were further tested. Some competitive reduc-
tions (entry 9 to 13) were investigated. The data are shown in Table 4.
As listed in Table 4, benzyl chloride was stable to HfCl4=KBH4
from room temperature to 67ꢀC (entry 1). m-Chloroperbenzoic acid
(m-CPBA) (entry 2) was reduced to 3-chlorobenzyl alcohol in a good yield.

Reduction of Carboxylic Acids
1645
Table 3. Reduction of carboxylic acids and their derivatives with HfCl4=NaBH4
Entry
1
Substrate
Conditionsa
40ꢀC, 5.5 h
Product
Yieldb(%)
95
2
3
4
40ꢀC, 6.5 h
40ꢀC, 7.0 h
40ꢀC, 6.0 h
77
81
83
5
40ꢀC, 7.5 h
79
6
7
40ꢀC, 8.0 h
40ꢀC, 10 h
54
92
8
9
CH3(CH2)10COOH
40ꢀC, 8.0 h CH3(CH2)10CH2OH
40ꢀC, 8.4 h
94
76
10
rt, 3.0 h
94
11
12
rt, 3.5 h
rt, 2.0 h
51
92
13
14
15
16
rt, 3.5 h
rt, 4.4 h
rt, 4.5 h
rt, 5.0 h
98
84
73
61
17
18
rt, 3.0 h
rt, 7.0 h
70
87
19
CH3(CH2)10COOCH2CH3 rt, 1.5 h CH3(CH2)10CH2OH
91
(Continued )

1646
J. Zhang et al.
Table 3. Continued
Entry
20
Substrate
Conditionsa
rt, 2.2 h
Product
Yieldb(%)
85
21
22
23
rt, 1.0 h
rt, 1.5 h
rt, 5.0 h
60
87
65
24
40ꢀC, 33 h
No reaction
aReaction was performed with a 0.8=1.0=4.0 molar ratio of substrate=HfCl4=
NaBH4 (according to typical experimental procedure 2).
bIsolated yield; all products were identified by 1H NMR and mass
spectrometry.
Benzophenone (entry 3) was reduced to 90% of diphenylmethanol at room
temperature in 1.5 h, whereas when the reaction was performed at 67ꢀC for
10.5 h, a mixture of diphenylmethanol and diphenylmethane (molar ratio
88:12) was obtained.
It was also shown that amide (entry 4), imine (entry 5), nitrile (entry
6), and pyridine-N-oxide (entry 7) were reduced in poor yields by this
reagent, and styrene oxide was regioselectively reduced to 78% of 2-
phenylethanol without the formation of 1-phenylethanol (entry 8). There-
fore, styrene oxide was reduced more rapidly and conveniently than the
other substrates (entries 4–7). Competitive reduction of styrene oxide in
the presence of carboxylic acid (entry 9), carboxylic ester (entry 10),
nitrile (entry 11), and amide (entry 12) was later achieved at room tem-
perature. Thus, HfCl4=KBH4 features chemo- and regioselective reduc-
tion of epoxide in the presence of other reducible groups such as
nitrogroup, nitrile, amide, carboxylic acid, and ester.
CONCLUSION
In summary, HfCl4=KBH4 is a more facile, efficient, convenient, and che-
moselective reducing agent for the reduction of carboxylic acids and their

1647

1648

Reduction of Carboxylic Acids
1649
derivatives to the corresponding alcohols, and it also features chemo- and
regioselective reduction of epoxide in good yields under mild conditions.
We believe this procedure using the HfCl4=KBH4 system will present a
useful and efficient alternative to the existing reducing methods. Further
investigation is currently under way to extend the scope of this methodol-
ogy into other reductions, the results of which will be reported in due
course.
EXPERIMENTAL
General Procedure for the Reduction by HfCl4/KBH4: Typical
Experimental Procedure 1
Freshly distilled tetrohydrofuran (THF; 3 mL) was syringed in a
Schlenk with a stirrer bar, HfCl4 (0.32 g, 1 mmol), and KBH4
(0.216 g, 4 mmol) under nitrogen in an ice-water bath, immediately
forming a yellowish suspension. This mixture was stirred for 0.1 h
and allowed to warm to room temperature for 3 h. A solution of sub-
strate (0.8 mmol) in dry THF (3 mL) then was added dropwise and stir-
red for a further time at the reaction temperature. After this time, the
reaction mixture was poured into water (3 mL) with ice-cooling and
extracted with ethyl acetate (3 ꢁ 5 mL). In the case of imines, nitriles,
and amides, the mixture was basified with 28% aqueous ammonia to
pH 9 and extracted with ethyl acetate (3 ꢁ 5 mL). The combined extract
was washed with saturated NaHCO3 solution and brine, dried over
anhydrous Na2SO4, and then evaporated. The crude product was
purified by column chromatography.
General Procedure for the Reduction by HfCl4/NaBH4: Typical
Experimental Procedure 2
Freshly distilled THF (3 ml) was syringed into a Schlenk with a stirrer
bar, HfCl4 (0.32 g, 1 mmol), and NaBH4 (0.151 g, 4 mmol) under nitro-
gen in an ice-water bath, immediately forming a cream-colored suspen-
sion. This mixture was stirred for 0.1 h and allowed to warm to room
temperature for 2 h. A solution of substrate (0.8 mmol) in dry THF
(3 mL) was then added dropwise and stirred for a further time at the
reaction temperature. The following workup steps were the same as
in procedure 1.

1650
J. Zhang et al.
DATA
4-Nitrobenzyl Alcohol
1
Mp 88–89ꢀC (lit.[22a] 91–92). H NMR (400 MHz, CDCl3): d 1.78 (br s,
1H, ArCH2OH), 4.85 (s, 2H, ArCH2), 7.54 (d, 2H, J ¼ 8.4 Hz, ArH),
8.23 (d, 2H, J ¼ 8.4 Hz, ArH). HRMS (EI) m=z found: Mþ, 153.0431;
calcd. for C7H7NO3: 153.0426.
3-Chlorobenzyl Alcohol
1H NMR (400 MHz, DMSO-d6): d 4.52 (d, 2H, J ¼ 5.6 Hz, ArCH2), 5.36
(t, 1H, J ¼ 5.6 Hz, ArCH2OH), 7.27–7.38 (m, 4H, ArH). HRMS (EI) m=z
found: Mþ, 142.0188; calcd. for C7H7ClO: 142.0185.
4-Chlorobenzyl Alcohol
1H NMR (400 MHz, CDCl3): d 1.72 (s, 1H, ArCH2OH), 4.67 (s, 2H,
ArCH2), 7.31–7.34 (q, 4H, J ¼ 8.4 Hz, ArH). HRMS (EI) m=z found:
Mþ, 142.0190; calcd. for C7H7ClO: 142.0185.
2-Bromobenzyl Alcohol
1
Mp 74–75ꢀC (lit.[22b] 78–80). H NMR (400 MHz, DMSO-d6): d 4.52 (d,
2H, J ¼ 5.6 Hz, ArCH2), 5.44 (t, 1H, J ¼ 5.6 Hz, ArCH2OH), 7.20 (t, 1H,
J ¼ 7.2 Hz, ArH), 7.40 (t, 1H, J ¼ 7.2 Hz, ArH), 7.54–7.57 (m, 2H, ArH).
HRMS (EI) m=z found: Mþ, 185.9677; calcd. for C7H7BrO: 185.9680.
4-Bromobenzyl Alcohol
1H NMR (400 MHz, CDCl3): d 1.75 (s, 1H, ArCH2OH), 4.65 (s, 2H,
ArCH2), 7.24 (d, 2H, J ¼ 8.0 Hz, ArH), 7.48 (d, 2H, J ¼ 8.0 Hz, ArH).
HRMS (EI) m=z found: Mþ, 185.9673; calcd. for C7H7BrO: 185.9680.
4-Iodobenzyl Alcohol
1
Mp 63–65ꢀC (lit.[22c] 65–67). H NMR (400 MHz, DMSO-d6): d 4.45 (s,
2H, ArCH2), 5.06 (br s, 1H, ArCH2OH), 7.13 (d, 2H, J ¼ 8.0 Hz,

Reduction of Carboxylic Acids
1651
ArH), 7.68 (d, 2H, J ¼ 8.0 Hz, ArH). HRMS (EI) m=z found: Mþ,
233.9553; calcd. for C7H7IO: 233.9542.
4-Methylbenzyl Alcohol
1H NMR (400 MHz, CDCl3): d 1.62 (s, 1H, ArCH2OH), 2.35 (s, 3H, Me),
4.65 (s, 2H, ArCH2), 7.16–7.27 (m, 4H, ArH). HRMS (EI) m=z found:
Mþ, 122.0734; calcd. for C8H10O: 122.0732.
4-Methoxybenzyl Alcohol
1H NMR (400 MHz, DMSO-d6): d 3.73 (s, 3H, ArOMe), 4.41 (d, 2H,
J ¼ 5.6 Hz, ArCH2), 5.06 (t, 1H, J ¼ 5.6 Hz, ArCH2OH), 6.88 (d,
2H, J ¼ 8.4 Hz, ArH), 7.23 (d, 2H, J ¼ 8.4 Hz, ArH). ESI-MS m=z:
[MþNa]þ 161.
2-Hydroxybenzyl Alcohol
1
Mp 85–86ꢀC (lit.[22d] 86–87). H NMR (400 MHz, CDCl3): d 2.13 (br s,
1H, ArCH2OH), 4.89 (s, 2H, ArCH2), 6.84–6.91 (m, 2H, ArH), 7.05 (d,
1H, J ¼ 7.6 Hz, ArOH), 7.22 (t, 2H, J ¼ 7.6 Hz, ArH). HRMS (EI) m=z
found: Mþ, 124.0530; calcd. for C7H8O2: 124.0524.
1,2-Benzenedimethanol
Mp 56–58ꢀC (lit.[22e] 63–65). 1H NMR (400 MHz, CDCl3): d 2.84 (s, 2H,
2ArCH2OH), 4.74 (s, 4H, 2ArCH2), 7.31–7.37 (m, 4H, ArH). ESI-MS
m=z: [MþNa]þ 161.
3-(Hydroxymethyl)-2-naphthol
Mp 178–180ꢀC (lit.[22f] 186–188). 1H NMR (400 MHz, DMSO-d6): d 4.66
(s, 2H, ArCH2), 5.21 (br s, 1H, ArCH2OH), 7.12 (s, 1H, ArH), 7.24 (t,
1H, J ¼ 7.6 Hz, ArH), 7.34 (t, 1H, J ¼ 7.6 Hz, ArH), 7.65 (d, 1H,
J ¼ 8.0 Hz, ArH), 7.77 (d, 1H, J ¼ 8.0 Hz, ArH), 7.83 (s, 1H, ArH),
9.85 (br s, 1H, ArOH). HRMS (EI) m=z found: Mþ, 174.0689; calcd.
for C11H10O2: 174.0681.

1652
J. Zhang et al.
2-Phenylethanol
1H NMR (400 MHz, CDCl3): d 2.38 (br s, 1H, ArCH2CH2OH), 2.71 (t,
2H, J ¼ 6.8 Hz, ArCH2), 3.66 (t, 2H, J ¼ 6.8 Hz, ArCH2CH2), 7.08–7.23
(m, 5H, ArH). HRMS (EI) m=z found: Mþ, 122.0733; calcd. for
C8H10O: 122.0729.
1-Dodecanol
1H NMR (400 MHz, CDCl3): d 0.84 (t, 3H, J ¼ 7.2 Hz, Me), 1.22–1.32 (br
s, 20H, CH2), 1.65 (s, 1H, OH), 3.60 (t, 2H, J ¼ 7.8 Hz, CH2OH). ESI-MS
m=z: [MþNa]þ 209.
Cyclohexylmethanol
1H NMR (400 MHz, CDCl3): d 0.80–1.69 (m, 11H, CH2, CH), 1.99 (br s,
1H, CHCH2OH), 3.35 (d, 2H, J ¼ 6.4 Hz, CHCH2). ESI-MS m=z:
[MþNa]þ 137.
Diphenylmethanol
1H NMR (400 MHz, CDCl3): d 2.11 (s, 1H, Ar2CHOH), 5.84 (s, 1H,
Ar2CH), 7.18–7.39 (m, 10H, ArH). ESI-MS m=z: [MþNa]þ 207.
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