Rapid aqueous borohydride reduction of carbonyls under sealed-tube microwave conditions

Article abstract of DOI:10.1080/00397911.2010.551171

Ketones and aldehydes are conveniently and rapidly reduced to the corresponding alcohols in good yields using sodium borohydride under sealed-tube microwave conditions in either 95% ethanol or water. In purely aqueous systems, highly aliphatic substrates are sluggish, but this can be overcome by introducing sodium dodecyl sulfate (SDS) at the critical micelle concentration. With a 2:1 substrate/borohydride ratio and a reaction temperature of 100°C, reduction is typically complete within 1min in 95% ethanol and 5min in water/SDS. The methodology is well suited for parallel and combinatorial synthetic approaches.

Full text of DOI:10.1080/00397911.2010.551171

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Rapid Aqueous Borohydride Reduction of
Carbonyls Under Sealed-Tube Microwave
Conditions
a
a
a
S. Shaun Murphree , Jeremy D. Mason , Theodore G. Bean
&
a
Michelle C. Perry
a
Department of Chemistry, Allegheny College, Meadville,
Pennsylvania, USA
Accepted author version posted online: 27 Oct 2011.Published
online: 26 Mar 2012.
To cite this article: S. Shaun Murphree , Jeremy D. Mason , Theodore G. Bean & Michelle C. Perry
2012): Rapid Aqueous Borohydride Reduction of Carbonyls Under Sealed-Tube Microwave Conditions,
(
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
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1
Synthetic Communications , 42: 1979–1986, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.551171
RAPID AQUEOUS BOROHYDRIDE REDUCTION
OF CARBONYLS UNDER SEALED-TUBE
MICROWAVE CONDITIONS
S. Shaun Murphree, Jeremy D. Mason, Theodore G. Bean, and
Michelle C. Perry
Department of Chemistry, Allegheny College, Meadville, Pennsylvania, USA
GRAPHICAL ABSTRACT
Abstract Ketones and aldehydes are conveniently and rapidly reduced to the corresponding
alcohols in good yields using sodium borohydride under sealed-tube microwave conditions in
either 95% ethanol or water. In purely aqueous systems, highly aliphatic substrates are slug-
gish, but this can be overcome by introducing sodium dodecyl sulfate (SDS) at the critical
micelle concentration. With a 2:1 substrate/borohydride ratio and a reaction temperature
ꢀ
of 100 C, reduction is typically complete within 1 min in 95% ethanol and 5 min in water/
SDS. The methodology is well suited for parallel and combinatorial synthetic approaches.
Keywords Aldehydes; aqueous; ketones; microwave; sodium borohydride
INTRODUCTION
The discovery of synthetic methodology conforming to green principles
[
1]
continues to be the subject of intense investigation. Two innovations have shown
particular promise in this regard. First, microwave-assisted organic synthesis
(
MAOS) allows for rapid access to target compounds, often in greater yield and with
[2]
fewer by-products. Second, the emerging use of water as a solvent for organic reac-
tions promises both to reduce the environmental burden of waste solvent and to miti-
gate the energy consumption associated with solvent recovery. It has become
increasingly evident that these two innovations can be used to considerable synthetic
advantage. With this backdrop, the current study examines the scope and limi-
tations of aqueous microwave conditions for the microwave-mediated aqueous
borohydride reduction of carbonyl compounds.
[
3]
[
4]
Received December 21, 2010.
Address correspondence to S. Shaun Murphree, Department of Chemistry, 520 N. Main Street,
Allegheny College, Meadville, PA 16335, USA. E-mail: smurphre@allegheny.edu
1
979

1980
S. S. MURPHREE ET AL.
The microwave-assisted reduction of carbonyls using aqueous borohydride has
been previously reported; however, the reactions were carried out in open-vessel con-
[
5]
ditions using a modified domestic microwave oven. To extend this methodology
for use in industry-standard instrumentation, it was thus necessary to explore the
scope of this protocol under sealed-tube conditions using dedicated synthetic reac-
tors with precise temperature control.
Sodium borohydride is thermally unstable in aqueous and alcoholic solu-
[
6]
tions; therefore, it seemed prudent first to examine the behavior of the reducing
agent in various solvent systems in order to define an acceptable reaction tempera-
ture range that avoids the maximum operating pressure of 20 bar. In 95% ethanol,
ꢀ
pressures remained comfortably below the limit at temperatures as high as 120 C
(Fig. 1). Introducing more water into the system accelerated the generation of hydro-
ꢀ
gen; however, the pressure was still manageable even in pure water at 100 C (Fig. 2).
Clearly, the pressure is dependent upon other experimental parameters. In this case,
1
.5 mmol of sodium borohydride was dissolved in a total volume of 5.0 mL (the
maximum recommended fill volume, leaving a headspace of 5.0 mL). Thus, the pres-
sure attained in pure water (10 bar) roughly corresponds to the hydrogen generated
from the hydrolysis of the first equivalent of hydride.
To examine the impact of the solvent on chemical conversion, acetophenone
ꢀ
was used as a test substrate (Fig. 3). In 95% ethanol at 100 C, quantitative conver-
sion was achieved within 30 s. The reduction was somewhat more sluggish in water,
requiring 5 min for 97% conversion, but the results were still very promising. These
conditions were then applied to a series of aldehydes and ketones to explore the
scope and limitations of the method (Scheme 1, Fig. 4, and Table 1).
Virtually all substrates provided excellent yields of the corresponding alcohols
in 95% ethanol. The sole exception was camphor (entry 7), which tended to sublime
Figure 1. Pressure generation of sodium borohydride in 95% ethanol. Conditions: 0.30 M sodium borohy-
dride in 95% ethanol with total fill volume of 5.0 mL.

BOROHYDRIDE REDUCTION OF CARBONYLS
1981
Figure 2. Pressure generation of sodium borohydride in aqueous ethanol systems. Conditions: 0.30 M
ꢀ
sodium borohydride with total fill volume of 5.0 mL at 100 C.
Figure 3. Reduction of acetophenone in ethanol and water. Conditions: 3.0 mmol acetophenone; 1.5 mmol
ꢀ
NaBH , 5.0 mL fill volume, 100 C. (Figure is provided in color online.)
4
Figure 4. Product yields.

1982
S. S. MURPHREE ET AL.
Scheme 1. Microwave-mediated borohydride reduction of ketones and aldehydes.
a
Table 1. Microwave-mediated borohydride reductions of ketones and aldehydes
ꢀ
Conversion % @ 100 C
9
5% EtOH
(1 min)
Water
(15 min)
8.1 mM SDS
(5 min)
Aqueous solubility
b
(mM)
Entry
1
Substrate
100
100
100
95
100
91
20
2
3
8.1
100
100
56
75
3.4
4
5
100
96
66
13
c
84
d
86
3.4
e
6
7
94
100
0
90
2
4.6
6.9
f
5
8
9
100
100
100
100
9
100
100
100
9.9
2.9
13
1
0
41
a
b
c
Molar ratios of substrate=borohydride are 2:1 for 95% ethanol and 3:2 for aqueous systems.
Calculated using ACD=Labs Software v11.02 via SciFinder.
94% after 5 min.
d
94% after 30 min.
e
9
8% after 5 min.
f
9
2% after 5 min in tetrahydrofuran.

BOROHYDRIDE REDUCTION OF CARBONYLS
1983
under microwave irradiation and condense along the top of the vial (this phenom-
enon can be suppressed by using tetrahydrofuran, in which camphor is soluble).
Changing the solvent to pure water led to much more uneven results. While the
smaller ketones and aldehydes still provided alcohols in excellent yield (albeit with
longer reaction times), the highly aliphatic substrates, such as citronellal and heptal-
dehyde (entries 9 and 10), were oddly recalcitrant.
The use of surfactants in aqueous systems involving sparingly soluble organic
[7]
components is well documented, so it was reasoned that such an approach might
prove advantageous for these sluggish examples. Indeed, adding sodium dodecyl
sulfate (SDS) at the critical micelle concentration (CMC) had the desired effect.
All reactions were accelerated, allowing for a reaction time of only 5 min across
the board. Moreover, the yields for the aliphatic aldehydes were brought in line with
the other substrates.
The nature of this effect is somewhat curious. As Table 1 demonstrates, the
yields in water do not correlate well with the aqueous solubilities of the starting
materials. One reasonable explanation for the anomalous behavior of citronellal
and heptanal is that hydrophobic interactions induce a globular conformation,
which obscures the electrophilic center. Thus, the surfactant may simply serve to
stabilize the extended conformers of the aldehydes, as opposed to frank micellar
catalysis.
In summary, aldehydes and ketones are cleanly and rapidly reduced using
aqueous sodium borohydride under sealed-tube microwave conditions in good to
excellent yields. As the aliphatic nature of the substrate increases, the facility of
reaction decreases in pure water. However, the addition of SDS at the CMC can
compensate for this effect. The present methodology should prove particularly useful
for parallel and combinatorial synthesis.
EXPERIMENTAL
All reactions were carried out under sealed-tube conditions in a Biotage
Initiator microwave reactor with the following settings: prestir ¼ 5 s; absorbance
level ¼ high; fixed hold time ¼ on. Sodium borohydride was obtained from Acros
Organics (New Jersey, USA); all other chemicals were purchased from Sigma-
Aldrich (Missouri, USA). Materials were used without further purification.
3-Phenylpropanol (Method A)
Sodium borohydride (56.7 mg, 1.5 mmol), 95% ethanol (4.6 mL), and 3-phenyl-
propionaldehyde (395 mL, 3.0 mmol) were charged to a 10-mL microwave vial
equipped with a magnetic stir bar. The vial was capped and heated in the microwave
ꢀ
ꢀ
reactor for 1 min at 100 C. After cooling to 40 C, the vial was opened and the con-
tents were transferred to a separatory funnel containing deionized water (ca. 100 mL)
and extracted with dichloromethane (2 ꢁ 25 mL). The organic extracts were com-
bined, dried over sodium sulfate, and concentrated in vacuo to give 3-phenylpropa-
nol as a clear oil in quantitative yield.

1984
S. S. MURPHREE ET AL.
3
-Phenylpropanol (Method B)
Sodium borohydride (56.7 mg, 1.5 mmol), deionized water (4.0 mL), and
-phenylpropionaldehyde (395 mL, 3.0 mmol) were charged to a 10-mL microwave
vial equipped with a magnetic stir bar. The vial was capped and heated in the
3
ꢀ
ꢀ
microwave reactor for 15 min at 100 C. After cooling to 40 C, the vial was opened
and the contents were transferred to a separatory funnel containing deionized water
(
ca. 100 mL) and extracted with dichloromethane (2 ꢁ 25 mL). The organic extracts
were combined, dried over sodium sulfate, and concentrated in vacuo to give
3
-phenylpropanol as a clear oil in quantitative yield.
Preparation of 0.67 M Aqueous Sodium Borohydride Solution with
8.2 mM SDS
Sodium dodecyl sulfate (117 mg, 0.41 mmol), sodium borohydride (1,261 g,
3.3 mmol), and deionized water (30 mL) were charged to a 50-mL beaker. After
3
carefully stirring with a spatula to dissolve the solids, the solution was transferred
to a 50-mL volumetric flask and diluted to the mark with deionized water. The final
ꢀ
solution was stored at 5 C and used within 12 h.
3-Phenylpropanol (Method C)
3-Phenylpropionaldehyde (395 mL, 3.0 mmol) and aqueous sodium
borohydride=SDS solution (3.0 mL, 2.0 mmol) were charged to a 10-mL microwave
vial equipped with a magnetic stir bar. The vial was capped and heated in the micro-
ꢀ
ꢀ
wave reactor for 5 min at 100 C. After cooling to 40 C, the vial was opened, and the
contents were transferred to a separatory funnel containing deionized water (ca.
1
00 mL) and extracted with dichloromethane (2 ꢁ 25 mL). The organic extracts were
combined, dried over sodium sulfate, and concentrated in vacuo to give 3-phenylpro-
panol (405 mg, 99%) as a clear oil.
Spectral Data
[
8]
1
1
-Phenylpropanol (Entry 1) . H NMR (400 MHz, CDCl ): d 7.24–7.40 (m,
3
5
H), 4.90 (q, J ¼ 6.34 Hz, 1H), 1.73 (br s, 1H), 1.50 (d, J ¼ 6.59 Hz, 3H).
[
9]
1
1
-Phenylpropan-1-ol (Entry 2) . H NMR (400 MHz, CDCl ): d 7.24–7.38
3
(
m, 5H), 4.58 (t, J ¼ 6.78 Hz, 1 Hz), 1.96 (br s, 1H), 1.68–1.88 (m, 2H), 0.91 (t,
J ¼ 7.50 Hz, 3H).
[
10]
1
1
-Phenylbutane-1-ol (Entry 3) . H NMR (400 MHz, CDCl ): d 7.23–7.37
3
(
1
m, 5H), 4.67 (dd, J ¼ 5.86, 5.79 Hz, 1H), 1.81 (br s, 1H), 1.74–1.84 (m, 2H),
.63–1.72 (m, 2H), 0.93 (t, J ¼ 7.50, 3H).
[
10]
1
4
-Phenylbutan-2-ol (Entry 4) . H NMR (400 MHz, CDCl ): d 7.15–7.32
3
(
m, 5H), 3.83 (sext, J ¼ 6.22 Hz, 1H), 2.62–2.82 (m, 2H), 1.70–1.85 (m, 2H), 1.58 (br
s, 1H), 1.23 (d, J ¼ 5.86, 3H).

BOROHYDRIDE REDUCTION OF CARBONYLS
1985
[
9]
1
a-Tetralol (Entry 5) . H NMR (400 MHz, CDCl ): d 7.06–7.46 (m, 4H),
3
4
5
.78 (t, J ¼ 4.76 Hz, 1H), 2.68–2.88 (m, 2H), 1.73–2.03 (m, 4H), 1.71 (br s, 1H).
[
11]
1
1
-Indanol (Entry 6) . H NMR (400 MHz, CDCl ): d 7.20–7.44 (m, 4H),
3
.24 (t, J ¼ 6.04 Hz, 1H), 3.06 (ddd, J ¼ 15.84, 8.51, 4.76 Hz, 1H), 2.82 (app quint,
J ¼ 7.78 Hz, 1H), 2.43–2.54 (m, 1H), 1.89–1.99 (m, 1H), 1.79 (br s, 1H).
[
12]
1
Isoborneol (Entry 7) . H NMR (400 MHz, CDCl ): d 3.70 (t, J ¼ 6.25 Hz,
3
1
3
H), 1.70–1.80 (m, 6H), 1.64 (td, J ¼ 12.18, 3.29 Hz, 1H), 1.25–1.40 (m, 1H), 0.91 (s,
H), 0.87 (s, 3H), 0.79 (s, 3H).
[
13]
1
3
-Phenylpropan-1-ol (Entry 8) . H NMR (400 MHz, CDCl ): d 7.16–7.32
3
(
(
m, 5H), 3.68 (t, J ¼ 6.40 Hz, 2H), 2.71 (t, J ¼ 7.70 Hz, 2H), 1.85–1.94 (m, 2H), 1.48
br s, 1H).
[
14]
1
Citronellol (Entry 9) . H NMR (400 MHz, CDCl ): d 5.05–5.12 (m, 1H),
3
3
1
.61–3.74 (m, 2H), 1.87–2.07 (m, 2H), 1.67 (d, J ¼ 1.10 Hz, 3H), 1.59 (s, 3H),
.50–1.70 (m, 2H), 1.27–1.43 (m, 3H), 1.11–1.25 (m, 1H), 0.90 (d, J ¼ 6.59 Hz, 3H).
[
15]
1
1
-Heptanol (Entry 10) . H NMR (400 MHz, CDCl ): d 3.63 (t,
3
J ¼ 6.78 Hz, 2H), 1.56 (t, J ¼ 6.96 Hz, 2H), 1.46 (br s, 1H), 1.21–1.39 (m, 8H), 0.87
(t, J ¼ 6.96 Hz, 3H).
ACKNOWLEDGMENTS
The authors gratefully acknowledge Allegheny College and the National
Science Foundation (CCLI 0837640) for generous support of this project.
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