Evaluating a sodium dispersion reagent for the Bouveault-Blanc reduction of esters

Article abstract of DOI:10.1021/jo501093g

A new sodium dispersion reagent has been evaluated for the reduction of esters. Na-D15, a sodium dispersion with sodium particle size of 5-15 μm, is a nonpyrophoric reagent that can be handled in air. In this study, a broad range of aliphatic ester substrates were reduced to primary alcohols by Na-D15/i-PrOH with good yields. The method compares favorably with modern metal hydride reductions and is much safer and efficient than the traditional Bouveault-Blanc reduction.

Full text of DOI:10.1021/jo501093g

Note
pubs.acs.org/joc
Evaluating a Sodium Dispersion Reagent for the Bouveault−Blanc
Reduction of Esters
Jie An,† D. Neil Work,‡ Craig Kenyon,‡ and David J. Procter*,†
†School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
‡Pentagon Fine Chemicals Ltd., Lower Road, Halebank, Widnes, Cheshire WA8 8NS, United Kingdom
S
* Supporting Information
ABSTRACT: A new sodium dispersion reagent has been
evaluated for the reduction of esters. Na-D15, a sodium
dispersion with sodium particle size of 5−15 μm, is a
nonpyrophoric reagent that can be handled in air. In this study,
a broad range of aliphatic ester substrates were reduced to
primary alcohols by Na-D15/i-PrOH with good yields. The method compares favorably with modern metal hydride reductions
and is much safer and efficient than the traditional Bouveault−Blanc reduction.
he dissolving metal reduction of esters has found
widespread use in synthesis for access to important
no systematic study of the application of a pre-prepared sodium
dispersion for the electron transfer reductions of esters has
been reported.
T
alcohols.1 Compared with metal hydride reduction, this method
does not suffer from the formation of toxic metal residues and
has higher atom economy.2 The process was first achieved by
Bouveault and Blanc using sodium lump and absolute ethanol
(Scheme 1A).3 Since the reaction takes place on the metal
The sodium dispersion Na-D15 (Scheme 1B) is prepared by
a robust, reliable, and scalable sodium dispersion technology.6
It is a free-flowing suspension that has an optimized particle
size (5−15 μm). Na-D15 is transferable by syringe or pipette
and can easily be handled in the open atmosphere, thus its use
offers key advantages over that of alternative sodium
dispersions. The feasibility of using Na-D15 as a base in
large-scale industry synthesis has already been demonstrated.
The initial trial of the ester reduction using Na-D15 was
carried out under the same reaction conditions as those
employed for the classic Bouveault−Blanc reduction; however,
the reaction was carried out at 0 °C rather than at reflux.4d
When 5.0 equiv of Na-D15 was used in EtOH, only 10% of the
desired alcohol product 2a was detected (entry 1, Table 1) with
90% of the ester recovered. The low yield was due to the
competitive oxidation of sodium by EtOH. We found that the
yield could be increased to 80% by using 10 equiv of Na-D15
(entry 2, Table 1). Replacing EtOH with MeOH resulted in a
lower yield (entry 3, Table 1).
Scheme 1. Na-D15/i-PrOH-Promoted Electron Transfer
Reductions of Esters
Given the fast side reaction between Na-D15 and the protic
solvent and the poor miscibility of the suspending agent in Na-
D15 in alcohols, the application of other aprotic solvents was
explored. When hexane was used as the solvent, an excellent
93% yield was obtained (entry 4, Table 1). EtOH could be
replaced by other proton sources, and i-PrOH was found to be
the most effective alcohol whose use led to a quantitative yield
of 2a (entry 8, Table 1). When approximately quantitative7 Na-
D15 was used, an excellent 94% yield of 2a was also obtained
(entry 10, Table 1). No competitive Claisen condensation and/
or ester hydrolysis was observed under these conditions. When
H2O was used instead of an alcohol, intermolecular acyloin
surface, it is crucial that the metal is finely dispersed.1a,b To
form the dispersion in situ, external heating is required to melt
the alkali metal, and high-speed stirring is also important. To
facilitate this process, the sodium lump is normally precut into
small pieces.4 These procedures can result in reproducibility
problems and give rise to safety issues (e.g., excess foaming and
fire).4 Furthermore, the high temperature accelerates com-
petitive base-promoted Claisen condensation and ester
hydrolysis (Scheme 1A).1a Reactions at lower temperature
can be achieved by using the EtOH/NH3 solvent system
instead of EtOH1a or using NaK instead of the pure metal.5
These alternative protocols, however, are not general. Herein,
we present the use of a pre-prepared, nonpyrophoric, and high
surface area sodium dispersion, Na-D15, in place of sodium
lump for the Bouveault−Blanc reduction. To our knowledge,
Received: May 18, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo501093g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
the reaction (Scheme 2). Primary, secondary, and tertiary alkyl
esters were all reduced to the corresponding primary alcohols
Table 1. Optimization of the Ester Reductions Using Na-
D15
a
a b
,
Scheme 2. Reduction of Esters with Na-D15
ROH
(equiv)
Na-D15
(equiv)
yield of 2a
entry solvent
ROH
(%)
b
1
2
EtOH
EtOH
MeOH
hexane
hexane
hexane
hexane
hexane
hexane
hexane
THF
EtOH
51
5.0
10
10
10
8
10
80
b
EtOH
51
b
3
MeOH
EtOH
74
66
4
10
93
5
EtOH
10
90
6
EtOH
10
6
86
7
MeOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
10
10
10
6.0
4.5
4.5
4.5
4.5
4.5
71
8
10
>99
>99
94
9
6.0
4.5
4.5
4.5
4.5
4.5
10
11
12
13
14
86
Et2O
93
toluene
hexane
90
t-BuOH
87
a
1
Yield determined by H NMR spectroscopy using CH3NO2 as an
b
a
internal standard. ROH was used as the solvent.
Conditions: 1 (0.50 mmol, 1.0 equiv), Na-D15 (4.5 equiv), i-PrOH
b
c
(4.5 equiv), hexane, 0 °C, 5−10 min. Isolated yields. Conditions: 1
d
e
(5.0 mmol). Conditions: 1 (25.0 mmol). Conditions: Na-D15 (6.5
equiv), i-PrOH (6.5 equiv); 3-(4-methoxyphenyl)propan-1-ol formed
as the product.
condensation gave rise to the major product, most likely due to
the poor miscibility of H2O in hexane.1b Different solvents were
then screened: hexane, which is seldom used for Bouveault−
Blanc reductions, is superior to arene solvents8 (e.g., toluene),
and Lewis basic solvents (e.g., THF and Et2O), which are
commonly used in dissolving metal reductions (entries 10−13,
Table 1).
Following the optimization studies, the influence of the ester
group was investigated using a range of esters derived from
hydrocinnamic acid. Methyl, ethyl, isopropyl, n-butyl, phenyl,
and 2-methoxyethyl esters were all reduced in high yield (Table
2). More hindered ester 1c was reduced in a slightly lower yield
(entry 3, Table 2). Similarly, allyl and benzyl esters were also
reduced to the corresponding alcohols in high yields (entries 5
and 6, Table 2).
in excellent yields. Minimal impact on the yield was observed
with sterically hindered substituents (1l and 1o, Scheme 2). A
substrate with an acidic proton was also tolerated very well (1n,
Scheme 2). The substrates bearing both internal and terminal
olefins (1q and 1r, Scheme 2) were reduced smoothly to the
corresponding alcohols. The α,β-unsaturated ester underwent
full reduction with Na-D15/i-PrOH to give the saturated
alcohol (1i, Scheme 2). Furthermore, this protocol tolerates the
heterocyclic ring in ester 1j and is able to reduce lactone 1m to
the corresponding diol. Importantly, no significant change in
yields has been observed upon scale up of this reaction from
0.50 to 25 mmol (1a, Scheme 2).
The scope of this reduction was then investigated using a
range of aliphatic ester and lactone substrates. The results
demonstrate that a broad range of esters readily participate in
Table 3 shows further examples of functional group
tolerance. Functional groups such as −F, −OMe, −SMe, and
−NH2 (entries 1 and 3−5, Table 3) are tolerated well. It is
a
Table 2. Reduction of Hydrocinnamic Esters with Na-D15
Table 3. Functional Group Tolerance in the Reduction of
a b
,
Esters with Na-D15
b
entry
ester
R
product
yield of 2a (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Me
Et
2a
2a
2a
2a
2a
2a
2a
2a
94
97
88
93
80
88
97
98
entry
1
1
R1
2
R2
yield of 2a (%)
1s
F
2s
F
90
81
90
78
73
c
i-Pr
n-Bu
allyl
Bn
2
1t
Cl
2a
2u
2v
2w
H
3
4
5
1u
1v
1w
OMe
SMe
NH2
OMe
SMe
NH2
1g
1h
Ph
a
(CH2)2OMe
Conditions: 1 (0.50 mmol, 1.0 equiv), Na-D15 (4.5 equiv), i-PrOH
b
c
(4.5 equiv), hexane, 0 °C, 5−10 min. Isolated yields. Conditions:
Na-D15 (6.5 equiv), i-PrOH (6.5 equiv); 3-phenylpropan-1-ol formed
as the product.
a
Conditions: Na-D15 (4.5 equiv), i-PrOH (4.5 equiv), hexane, 0 °C,
5−10 min. Isolated yields.
b
B
dx.doi.org/10.1021/jo501093g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
noteworthy that aryl fluorides are not tolerated in the improved
Bouveault−Blanc reduction using Na-SG(I) (stage I sodium in
silica gel).1d Na-SG(I) is a stabilized sodium metal, which
eliminates the dangers of handling neat sodium while retaining
its reactivity. However, chloride on an aromatic ring was fully
reduced when 6.5 equiv of Na-D15 was used (entry 2, Table 3).
Next, the reduction of esters using deuterated alcohols was
conducted (Scheme 3). The formation of 2-D,D compounds
base-promoted side reactions observed in traditional Bou-
veault−Blanc reductions were suppressed by using Na-D15,
and higher yields were obtained. The chemoselectivity of Na-
D15 has been demonstrated to be comparable with metal
hydrides. Given that Na-D15 is easy to handle and stable, this
protocol provides an attractive alternative to the use of
pyrophoric metal hydrides for ester reduction.
EXPERIMENTAL SECTION
■
Scheme 3. Deuterium Incorporation
Glassware was dried in an oven overnight before use. Thin layer
chromatography was carried out on SIL G/UV254 silica−aluminum
plates, and plates were visualized using ultraviolet light (254 nm) and
KMnO4 solution. For flash column chromatography, 35−70 μm silica
gel 60 was used. NMR data were collected at either 400 or 500 MHz.
All samples were analyzed in CDCl3 unless otherwise stated. Reference
1
values for residual solvent were taken as δ = 7.27 (CDCl3) for H
NMR; δ = 77.1 (CDCl3) for 13C NMR. Multiplicities for coupled
signals were designated using the following abbreviations: s = singlet, d
= doublet, t = triplet, q = quartet, quin = quintet, br = broad signal and
are given in hertz.
suggests that anions are generated and protonated by the
alcohol during a series of single electron transfers. The kinetic
isotope effect was determined as shown in Table 4. The results
All compounds used in this study have been described in the
literature1 or are commercially available. All solvents and reagents were
used as supplied. Esters were purchased from commercial suppliers or
prepared by standard methods.1d,m
Table 4. Determination of Primary Kinetic Isotope Effect
General Procedure for the Reduction of Esters with Na-D15.
To a solution of ester (0.500 mmol) in anhydrous hexane (2.5 mL)
was added anhydrous i-PrOH (2.25 mmol, 172 μL), followed by Na-
D15 (27.7 wt %, 2.25 mmol, 209 μL) under N2 at 0 °C, and the
resulting solution was stirred vigorously. After 5 min at 0 °C, the
temperature was increased to rt. After the specified time (typically 0−
10 min), the reaction was quenched by an aqueous solution of HCl
(1.0 mL, 3.0 M) and the reaction mixture was diluted with Et2O (10
mL) and brine (20 mL). The aqueous layer was extracted with Et2O (2
× 10 mL), and the organic layers were combined, dried over MgSO4,
filtered, and concentrated. The crude product was purified by flash
chromatography (silica, 0−30% EtOAc/hexane).
entry
ester
ROH/ROD
kH/kD
1
2
3
4
1a
1a
1o
1o
i-PrOH/i-PrOD
EtOH/EtOD
1.1
1.4
1.0
1.3
i-PrOH/i-PrOD
EtOH/EtOD
suggest that, when EtOH and i-PrOH were used as the proton
donor, the proton transfer is not involved in the rate-
determining step for the reduction of simple and sterically
demanding esters.1m,n,9
Finally, the performance of Na-D15 was compared with that
of Na-SG(I):1d,10 similar yields were obtained using Na-SG(I)
for the reduction of 1b and 1o; however, 15 equiv of Na-SG(I)
was required to achieve full conversion (entries 5 and 6, Table
5).
In summary, a new sodium dispersion has been evaluated for
the reduction of aliphatic esters to primary alcohols in i-PrOH/
hexane. Only 4.5 equiv of the reagent was required in this
method. A broad range of aliphatic esters was reduced in high
yields under mild conditions without external heating. The
3-Phenylpropan-1-ol 2a1m (entry 1, Table 2). According to the
general procedure, the reaction of methyl 3-phenylpropanoate (0.50
mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25 mmol) for 5 min at 0
°C, after chromatography (hexanes, 30% EtOAc/hexane), afforded 2a
(64.0 mg) in 94% yield as a colorless oil: 1H NMR (500 MHz, CDCl3)
δ 7.34−7.29 (m, 2H), 7.25−7.19 (m, 3H), 3.69 (t, J = 6.3, 2H), 2.73
(t, J = 7.8, 2H), 1.96−1.88 (m, 2H), 1.76 (br, 1H); 13C NMR (125
MHz, CDCl3) δ 141.9, 128.5, 128.4, 125.9, 62.3, 34.2, 32.1.
3-Phenylpropan-1-ol 2a1m (entry 2, Table 2). According to the
general procedure, the reaction of ethyl 3-phenylpropanoate (0.50
mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25 mmol) for 5 min at 0
°C afforded 2a (66.1 mg) in 97% yield. Spectroscopic properties
matched those previously described.
3-Phenylpropan-1-ol 2a1m (entry 3, Table 2). According to the
general procedure, the reaction of isopropyl 3-phenylpropanoate (0.50
mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25 mmol) for 5 min at 0
°C and 10 min at rt afforded 2a (60.1 mg) in 88% yield. Spectroscopic
properties matched those previously described.
Table 5. Comparison of Na-D15 and Na-SG(I)
3-Phenylpropan-1-ol 2a1m (entry 4, Table 2). According to the
general procedure, the reaction of butyl 3-phenylpropanoate (0.50
mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25 mmol) for 5 min at 0
°C afforded 2a (63.3 mg) in 93% yield. Spectroscopic properties
matched those previously described.
Na reagent
(equiv)
yield of 2
(%)
entry
1
ROH (equiv)
solvent
a
1
1b
1o
1b
1o
1b
1o
Na-D15 (4.5)
Na-D15 (4.5)
Na-SG(I) (4.5)
Na-SG(I) (4.5)
Na-SG(I) (15)
Na-SG(I) (15)
i-PrOH (4.5)
i-PrOH (4.5)
hexane
hexane
97
99
36
21
99
97
a
2
3-Phenylpropan-1-ol 2a1m (entry 5, Table 2). According to the
general procedure, the reaction of allyl 3-phenylpropanoate (0.50
mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25 mmol) for 5 min at 0
°C afforded 2a (54.5 mg) in 80% yield. Spectroscopic properties
matched those previously described.
ab
,
3
4
5
6
MeOH (26.5) THF
MeOH (26.5) THF
MeOH (26.5) THF
MeOH (26.5) THF
ab
,
c
c
3-Phenylpropan-1-ol 2a1m (entry 6, Table 2). According to the
general procedure, the reaction of benzyl 3-phenylpropanoate (0.50
mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25 mmol) for 5 min at 0
°C afforded 2a (60.2 mg) in 88% yield. Spectroscopic properties
matched those previously described.
a
1
Yield determined by H NMR spectroscopy using CH3NO2 as an
internal standard. Conditions: 1 (0.5 mmol, 1 equiv), Na-SG(I) (35
wt %, 4.5 equiv), MeOH (26.5 equiv, added dropwise over 5 min at 0
°C), 0 °C to rt, 35 min. Results reported in ref 1d.
b
c
C
dx.doi.org/10.1021/jo501093g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3-Phenylpropan-1-ol 2a1m (entry 7, Table 2). According to the
general procedure, the reaction of phenyl 3-phenylpropanoate (0.50
mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25 mmol) for 5 min at 0
°C afforded 2a (66.2 mg) in 97% yield. Spectroscopic properties
matched those previously described.
2H), 2.79 (t, J = 6.8, 2H), 1.94−1.85 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 154.6, 130.7, 127.6, 127.3, 120.9, 116.1, 60.9, 32.3, 25.3.
3,3-Diphenylpropan-1-ol 2n12 (Scheme 2). According to the
general procedure, the reaction of methyl 3,3-diphenylpropanoate
(0.50 mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25 mmol) for 5
min at 0 °C and 10 min at rt, after chromatography (hexanes, 30%
EtOAc/hexane), afforded 2n (96.0 mg) in 90% yield as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 7.34−7.27 (m, 8H), 7.23−7.18 (m,
2H), 4.17 (t, J = 7.9, 1H), 3.64 (t, J = 6.4, 2H), 2.39−2.32 (m, 2H),
1.40 (br, 1H); 13C NMR (125 MHz, CDCl3) δ 144.6, 128.6, 127.9,
126.4, 61.2, 47.5, 38.1.
3-Phenylpropan-1-ol 2a1m (entry 8, Table 2). According to the
general procedure, the reaction of 2-methoxyethyl 3-phenylpropanoate
(0.50 mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25 mmol) for 5
min at 0 °C afforded 2a (66.9 mg) in 98% yield. Spectroscopic
properties matched those previously described.
3-Phenylpropan-1-ol 2a1m (25 mmol scale reaction, Scheme
2).11 Na-D15 (112.5 mmol) was transferred to a 250 mL round-
bottom flask under N2. Hexane (110 mL) was added, and the
suspension was cooled to 0 °C. A solution of methyl 3-phenyl-
propanoate (25.0 mmol) and i-PrOH (112.5 mmol) in hexane (15
mL) was then transferred into the flask in one portion. The reaction
mixture was stirred at 0 °C for 5 min, and the temperature was
increased to rt. After 5 min, the reaction was quenched by an aqueous
solution of HCl (50 mL, 3.0 M). The reaction mixture was diluted
with Et2O (100 mL) and brine (100 mL), and the aqueous layer was
extracted with Et2O (3 × 100 mL). The organic layers were combined,
dried over MgSO4, filtered, and concentrated. The crude product was
purified by flash chromatography (silica, 30% EtOAc/hexane),
affording 2a (3.23 g) in 95% yield as a colorless oil. Spectroscopic
properties matched those previously described
1-Adamantanemethanol 2o1m (Scheme 2). According to the
general procedure, the reaction of methyl adamantane-1-carboxylate
(0.50 mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25 mmol) for 5
min at 0 °C and 15 min at rt, after chromatography (hexanes, 10%
EtOAc/hexane), afforded 2o (81.6 mg) in 98% yield as white crystals:
mp 117−118 °C; 1H NMR (500 MHz, CDCl3) δ 3.21 (s, 2H), 2.03−
1.98 (m, 3H), 1.77−1.71 (m, 3H), 1.69−1.63 (m, 3H), 1.54−1.50 (m,
6H), 1.37 (br, 1H); 13C NMR (125 MHz, CDCl3) δ 74.0, 39.1, 37.3,
34.6, 28.3.
2-Butyloctan-1-ol 2p1n (Scheme 2). According to the general
procedure, the reaction of methyl 2-butyloctanoate (0.50 mmol), i-
PrOH (2.25 mmol), and Na-D15 (2.25 mmol) for 5 min at 0 °C and
30 min at rt, after chromatography (hexanes, 10% EtOAc/hexane),
1
afforded 2p (68.2 mg) in 73% yield as a colorless oil: H NMR (500
3-(4-Methoxyphenyl)propan-1-ol 2i1m (Scheme 2). According to
the general procedure, the reaction of (E)-methyl 3-(4-methoxy-
phenyl)acrylate (0.50 mmol), i-PrOH (3.25 mmol), and Na-D15 (3.25
mmol) for 5 min at 0 °C and 5 min at rt, after chromatography
(hexanes, 30% EtOAc/hexane), afforded 2i (71.6 mg) in 86% yield as
MHz, CDCl3) δ 3.55 (d, J = 5.4, 2H), 1.51−1.42 (m, 1H), 1.38−1.23
(m, 17H), 0.91 (t, J = 6.6, 3H), 0.89 (t, J = 7.2, 3H); 13C NMR (125
MHz, CDCl3) δ 65.8, 40.6, 32.0, 31.0, 30.7, 29.8, 29.2, 27.0, 23.2, 22.8,
14.2 × 2.
Undec-10-en-1-ol 2q1n (Scheme 2). According to the general
procedure, the reaction of methyl undec-10-enoate (0.50 mmol), i-
PrOH (2.25 mmol), and Na-D15 (2.25 mmol) for 5 min at 0 °C and
10 min at rt, after chromatography (hexanes, 20% EtOAc/hexane),
1
a colorless oil: H NMR (500 MHz, CDCl3) δ 7.15−7.11 (m, 2H),
6.87−6.82 (m, 2H), 3.80 (s, 3H), 3.68 (t, J = 6.3, 2H), 2.66 (t, J = 7.6,
2H), 1.91−1.84 (m, 2H), 1.56 (br, 1H); 13C NMR (125 MHz,
CDCl3) δ 157.8, 133.9, 129.4, 113.9, 62.3, 55.3, 34.5, 31.2.
1
afforded 2q (81.9 mg) in 96% yield as a colorless oil: H NMR (500
2-(1H-Indol-3-yl)ethanol 2j1m (Scheme 2). According to the
general procedure, the reaction of methyl 2-(1H-indol-3-yl)acetate
(0.50 mmol), i-PrOH (4.50 mmol), and Na-D15 (2.25 mmol) for 5
min at 0 °C and 30 min at rt, after preparative TLC (20% EtOAc/
MHz, CDCl3) δ 5.86−5.77 (m, 1H), 5.03−4.97 (m, 1H), 4.96−4.91
(m, 1H), 3.64 (t, J = 6.6, 2H), 2.08−2.01 (m, 2H), 1.61−1.53 (m,
2H), 1.46−1.24 (m, 13H); 13C NMR (125 MHz, CDCl3) δ 139.3,
114.2, 63.2, 33.9, 32.9, 29.6, 29.5 × 2, 29.2, 29.0, 25.8.
1
(Z)-Octadec-9-en-1-ol 2r1n (Scheme 2). According to the general
procedure, the reaction of methyl oleate (0.50 mmol), i-PrOH (2.25
mmol), and Na-D15 (2.25 mmol) for 5 min at 0 °C, after
chromatography (hexanes, 10% EtOAc/hexane), afforded 2r (131.7
hexane), afforded 2j (65.3 mg) in 81% yield as a brown oil: H NMR
(500 MHz, CDCl3) δ 8.08 (br, 1H), 7.66−7.63 (m, 1H), 7.41−7.38
(m, 1H), 7.25−7.21 (m, 1H), 7.17−7.13 (m, 1H), 7.11−7.09 (m, 1H),
3.93 (t, J = 6.3, 2H), 3.06 (m, 2H), 1.59 (br, 1H); 13C NMR (125
MHz, CDCl3) δ 136.5, 127.5, 122.6, 122.3, 119.6, 118.9, 112.4, 111.3,
62.7, 28.8.
1
mg) in 98% yield as a colorless oil: H NMR (500 MHz, CDCl3) δ
5.39−5.31 (m, 2H), 3.65 (t, J = 6.8, 2H), 2.05−1.99 (m, 4H), 1.61−
1.54 (m, 2H), 1.39−1.22 (m, 23H), 0.89 (t, J = 7.1, 3H); 13C NMR
(125 MHz, CDCl3) δ 130.1, 129.9, 63.2, 32.9, 32.0, 29.9, 29.8, 29.6 ×
2, 29.5, 29.4 × 2, 29.3, 27.3 × 2, 25.8, 22.8, 14.2.
2-(4-Isobutylphenyl)propan-1-ol 2k1m (Scheme 2). According to
the general procedure, the reaction of methyl 2-(4-isobutylphenyl)-
propanoate (0.50 mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25
mmol) for 5 min at 0 °C and 10 min at rt, after chromatography
(hexanes, 20% EtOAc/hexane), afforded 2k (91.6 mg) in 95% yield as
3-(4-Fluorophenyl)propan-1-ol 2s1n (entry 1, Table 3). According
to the general procedure, the reaction of methyl 3-(4-fluorophenyl)-
propanoate (0.50 mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25
mmol) for 5 min at 0 °C and 10 min at rt, after chromatography
(hexanes, 50% EtOAc/hexane), afforded 2s (69.6 mg) in 90% yield as
1
a colorless oil: H NMR (500 MHz, CDCl3) δ 7.17−7.10 (m, 4H),
3.69 (d, J = 6.9, 2H), 2.98−2.90 (m, 1H), 2.46 (d, J = 7.3, 2H), 1.92−
1.81 (m, 1H), 1.48 (br, 1H), 1.28 (d, J = 6.9, 3H), 0.92 (d, J = 6.6,
6H); 13C NMR (125 MHz, CDCl3) δ 140.8, 140.1, 129.4, 127.2, 68.8,
45.1, 42.1, 30.3, 22.5, 17.7.
1
a colorless oil: H NMR (500 MHz, CDCl3) δ 7.19−7.13 (m, 2H),
7.00−6.95 (m, 2H), 3.67 (t, J = 6.5, 2H), 2.69 (t, J = 7.7, 2H), 1.91−
1.84 (m, 2H), 1.54 (br, 1H); 13C NMR (125 MHz, CDCl3) δ 161.3
(d, J = 242.9), 137.4 (d, J = 2.7), 129.2 (d, J = 7.3), 115.2 (d, J = 21.0),
62.1, 34.4, 31.3.
(1-Phenylcyclopentyl)methanol 2l1d (Scheme 2). According to the
general procedure, the reaction of methyl 1-phenylcyclopentane-
carboxylate (0.50 mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25
mmol) for 5 min at 0 °C and 30 min at rt, after chromatography
(hexanes, 20% EtOAc/hexane), afforded 2l (82.0 mg) in 93% yield as
3-Phenylpropan-1-ol 2a1m (entry 2, Table 3). According to the
general procedure, the reaction of methyl 3-(4-chlorophenyl)-
propanoate (0.50 mmol), i-PrOH (3.25 mmol), and Na-D15 (3.25
mmol) for 5 min at 0 °C and 20 min at rt, after chromatography
(hexanes, 20% EtOAc/hexane), afforded 2a (55.4 mg) in 81% yield as
a colorless oil. Spectroscopic properties matched those previously
described.
1
a yellow oil: H NMR (500 MHz, CDCl3) δ 7.37−7.32 (m, 4H),
7.25−7.21 (m, 1H), 3.54 (s, 2H), 2.08−2.00 (m, 2H), 1.94−1.86 (m,
2H), 1.80−1.68 (m, 4H), 1.30 (br, 1H); 13C NMR (125 MHz,
CDCl3) δ 146.9, 128.4, 127.4, 126.3, 70.4, 53.4, 34.4, 23.9.
2-(3-Hydroxypropyl)phenol 2m1m (Scheme 2). According to the
general procedure, the reaction of chroman-2-one (0.50 mmol), i-
PrOH (4.50 mmol), and Na-D15 (2.25 mmol) for 30 min at rt, after
chromatography (hexanes, 30% EtOAc/hexane), afforded 2m (68.5
3-(4-Methoxyphenyl)propan-1-ol 2u1n (entry 3, Table 3).
According to the general procedure, the reaction of methyl 3-(4-
methoxyphenyl)propanoate (0.50 mmol), i-PrOH (2.25 mmol), and
Na-D15 (2.25 mmol) for 5 min at 0 °C and 10 min at rt, after
chromatography (hexanes, 50% EtOAc/hexane), afforded 2u (74.9
1
mg) in 90% yield as a colorless oil: H NMR (500 MHz, CDCl3) δ
7.14−7.09 (m, 2H), 6.91−6.83 (m, 2H), 4.46 (br, 2H), 3.65 (t, J = 5.8,
D
dx.doi.org/10.1021/jo501093g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
mg) in 90% yield as a colorless oil. Spectroscopic properties matched
those previously described.
Amsterdam, 1991; pp 235−257. (b) Brettle, R. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Elsevier Science Ltd.:
Amsterdam, 1991; pp 613−632. (c) Huffman, J. W. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Elsevier Science Ltd.:
Amsterdam, 1991; pp 107−127. For an improved Bouveault−Blanc
reduction with sodium on silica gel, see: (d) Bodnar, B. S.; Vogt, P. F.
J. Org. Chem. 2009, 74, 2598. For a detailed discussion of alkali metal
anions stabilized by crown ethers for potential applications in
functional group reductions, see: (e) Dye, J. L. Angew. Chem., Int.
Ed. Engl. 1979, 18, 587. For alkali-metal-promoted cyclization
reactions, see: (f) Cossy, J.; Gille, B.; Bellosta, V. J. Org. Chem. 1998,
63, 3141. (g) Srikrishna, A.; Ramasastry, S. S. V. Tetrahedron Lett.
2004, 45, 379. For other recent methods for the reduction of
carboxylic acid derivatives, see: (h) Kim, J.; Suri, J. T.; Cordes, D. B.;
Singaram, B. Org. Process Res. Dev. 2006, 10, 949. (i) Pasumansky, L.;
Goralski, C. T.; Singaram, B. Org. Process Res. Dev. 2006, 10, 959.
(j) Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 18.
(k) Pelletier, G.; Bechara, W. S.; Charette, A. B. J. Am. Chem. Soc.
2010, 132, 12817. (l) Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M.
J. Am. Chem. Soc. 2010, 132, 1770. (m) Szostak, M.; Spain, M.;
Procter, D. J. Chem. Commun. 2011, 47, 10254. (n) Szostak, M.; Spain,
M.; Procter, D. J. Org. Lett. 2012, 14, 840. (o) Szostak, M.; Spain, M.;
Procter, D. J. Chem.Eur. J. 2014, 20, 4222. (p) Szostak, M.; Spain,
M.; Eberhart, A. J.; Procter, D. J. J. Am. Chem. Soc. 2014, 136, 2268.
(q) Magano, J.; Dunetz, J. R. Org. Process Res. Dev. 2012, 16, 1156.
(2) (a) Nystrom, R. F.; Brown, W. G. J. Am. Chem. Soc. 1947, 69,
2548. (b) Bajwa, N.; Jennings, M. P. J. Org. Chem. 2008, 73, 3638.
(c) Kudo, T.; Higashide, T.; Ikedate, S.; Yamataka, H. J. Org. Chem.
2005, 70, 5157. (d) W. Gribble, G. Chem. Soc. Rev. 1998, 27, 395. It is
noteworthy that most commonly used metal hydrides are directly or
indirectly made from sodium metal: (e) Rittmeyer, P.; Wietelmann, U.
Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, Germany, 2000; pp 103−132.
(3) (a) Bouveault, L.; Blanc, G. Bull. Soc. Chim. Fr. 1904, 31, 666.
(b) Bouveault, L.; Blanc, G. Compt. Rend. 1903, 137, 60. (c) Bouveault,
L.; Blanc, G. Bull. Soc. Chim. Fr. 1904, 31, 1206. (d) Bouveault, L.;
Blanc, G. Bull. Soc. Chim. Fr. 1904, 31, 1213. (e) Bouveault, L.; Blanc,
G. Bull. Soc. Chim. Fr. 1903, 137, 328. (f) Gault, H. Compt. Rend. 1907,
145, 126.
3-(4-(Methylthio)phenyl)propan-1-ol 2v1n (entry 4, Table 3).
According to the general procedure, the reaction of methyl 3-(4-
(methylthio)phenyl)propanoate (0.50 mmol), i-PrOH (2.25 mmol),
and Na-D15 (2.25 mmol) for 5 min at 0 °C and 10 min at rt, after
chromatography (hexanes, 30% EtOAc/hexane), afforded 2v (71.0
mg) in 78% yield as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ
7.23−7.20 (m, 2H), 7.16−7.12 (m, 2H), 3.67 (t, J = 6.5, 2H), 2.68 (t, J
= 7.8, 2H), 2.48 (s, 3H), 1.92−1.84 (m, 2H), 1.63 (br, 1H); 13C NMR
(125 MHz, CDCl3) δ 139.0, 135.4, 129.0, 127.3, 62.2, 34.2, 31.6, 16.4.
3-(4-Aminophenyl)propan-1-ol 2w1n (entry 5, Table 3). According
to the general procedure, the reaction of methyl 3-(4-aminophenyl)-
propanoate (0.50 mmol), i-PrOH (2.25 mmol), and Na-D15 (2.25
mmol) for 5 min at 0 °C and 45 min at rt, after chromatography
(hexanes, 50% EtOAc/hexane), afforded 2w (55.3 mg) in 73% yield as
1
a colorless oil: H NMR (500 MHz, CDCl3) δ 7.02−6.98 (m, 2H),
6.66−6.62 (m, 2H), 3.66 (t, J = 6.5, 2H), 2.61 (t, J = 7.6, 2H), 1.88−
1.81 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 144.3, 131.9, 129.3,
115.4, 62.4, 34.6, 31.3.
3-Phenylpropan-1-ol 2a1m (entry 3, Table 5). According to the
reported procedure,1d the reaction of ethyl 3-phenylpropanoate (0.50
mmol), MeOH (13.3 mmol), and stage I sodium silica gel (35 wt %,
2.25 mmol) in anhydrous THF (8.0 mL) afforded 2a (24.7 mg) in
36% yield (1H NMR vs internal standard). Spectroscopic properties
matched those previously described.
1-Adamantanemethanol 2o1m (entry 4, Table 5). According to
the reported procedure,1d the reaction of methyl adamantane-1-
carboxylate (0.50 mmol), MeOH (13.3 mmol), and stage I sodium
silica gel (35 wt %, 2.25 mmol) in anhydrous THF (8.0 mL) afforded
2o (17.5 mg) in 21% yield (1H NMR vs internal standard).
Spectroscopic properties matched those previously described.
Deuterium Incorporation. (Adamantan-1-yl)methan-d2-ol 2o-
D,D. According to the general procedure, the reaction of methyl
adamantane-1-carboxylate (0.50 mmol), i-PrOD (2.25 mmol), and
Na-D15 (2.25 mmol) for 5 min at 0 °C afforded 2o-D,D with 99%
deuterium incorporation, yield >99% (1H NMR vs internal standard):
1H NMR (500 MHz, CDCl3) δ 2.03−1.98 (m, 3H), 1.77−1.71 (m,
3H), 1.69−1.63 (m, 3H), 1.54−1.50 (m, 6H), 1.36 (br, 1H); 13C
NMR (125 MHz, CDCl3) δ 73.2 (m), 39.1, 37.3, 34.4, 28.3.
(4) (a) Ford, S. G.; Marvel, C. S. Org. Synth. 1930, 10, 62. (b) Reid,
S. E. E.; Cockerille, F. O.; Meyer, J. D.; Cox, W. M., Jr.; Ruhoff, J. R.
Org. Synth. 1935, 15, 51. (c) Shriner, R. L.; Ruby, P. R. Org. Synth.
1953, 33, 76. (d) Manske, R. H. Org. Synth. 1934, 14, 20. (e) Adkins,
H.; Gillespie, R. H. Org. Synth. 1949, 29, 80.
Determination of Primary Kinetic Isotope Effect.1m,n
According to the general procedure, the reaction of methyl
adamantane-1-carboxylate (0.17 mmol), i-PrOD/i-PrOH (1:1, 18.4
mmol), and Na-D15 (0.77 mmol) for 5 min at 0 °C and 5 min at rt
afforded 2o and 2o-D,D. The amount of each species was determined
(5) Gol’dfarb, Y. L.; Taits, S. Z.; Belen’kii, L. I. Tetrahedron 1963, 19,
1851.
1
by H NMR. Kinetic isotope effect, kH/kD = 1.0.
(6) Sodium dispersion Na-D15 is commercially available. Please see
the Supporting Information for the details of the commercial supplier.
(7) The reduction of esters using Na-D15 is a four-electron process.
(8) When toluene was used as solvent, it is possible that the
reduction of esters was promoted by the arene radical formed by
electron transfer from sodium to toluene. See: Ohsawa, T.; Hatano, K.;
Kayoh, K.; Kotabe, J.; Oishi, T. Tetrahedron Lett. 1992, 33, 5555.
(9) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066.
(10) (a) Dye, J. L.; Cram, K. D.; Urbin, S. A.; Redko, M. Y.; Jackson,
J. E.; Lefenfeld, M. J. Am. Chem. Soc. 2005, 127, 9338. (b) Shatnawi,
M.; Paglia, G.; Dye, J. L.; Cram, K. C.; Lefenfeld, M.; Billinge, S. J. L. J.
Am. Chem. Soc. 2007, 129, 1386. (c) Dye, J. L.; Nandi, P.; Jackson, J.
E.; Lefenfeld, M.; Bentley, P. A.; Dunyak, B. M.; Kwarcinski, F. E.;
Spencer, C. M.; Lindman, T. N.; Lambert, P.; Jacobson, P. K.; Redko,
M. Y. Chem. Mater. 2011, 23, 2388. (d) Nandi, P.; Dye, J. L.; Jackson,
J. E. J. Org. Chem. 2009, 74, 5790. (e) Nandi, P.; Redko, M. Y.;
Petersen, K.; Dye, J. L.; Lefenfeld, M.; Vogt, P. F.; Jackson, J. E. Org.
Lett. 2008, 10, 5441. (f) Costanzo, M. J.; Patel, M. N.; Petersen, K. A.;
Vogt, P. F. Tetrahedron Lett. 2009, 50, 5463.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: david.j.procter@manchester.ac.uk.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC and Pentagon Fine Chemicals Ltd for
support. We thank Pentagon Fine Chemicals Ltd. for the
supply of sodium dispersion Na-D15.
REFERENCES
■
(11) For large-scale reactions, it is more convenient to transfer a
solution of ester substrate and i-PrOH in hexane to Na-D15.
(12) Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1982, 47, 3008.
(1) For reviews on the dissolving metal reductions of carbonyl
compounds, see: (a) Barrett, A. G. M. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Elsevier Science Ltd.:
E
dx.doi.org/10.1021/jo501093g | J. Org. Chem. XXXX, XXX, XXX−XXX