Reactions of a novel modified Red-Al reducing agent with selected organic compounds containing representative functional groups and chemoselective reduction

Article abstract of DOI:10.1016/j.tetlet.2016.05.100

A new modified Red-Al reagent prepared from commercially available 1,1,1,3,3,3-hexamethyldisilazane and sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al) is reported for the selective reduction of carbonyl compounds containing representative functional groups. Moreover, this novel reagent is superior for the chemoselective reduction of aldehydes and ketones to the corresponding alcohols in excellent yields under mild reaction conditions. Moreover, aldehydes can be reduced selectively in the presence of ketones with similar reactivity.

Full text of DOI:10.1016/j.tetlet.2016.05.100

Tetrahedron Letters 57 (2016) 3247–3251
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reactions of a novel modified Red-Al reducing agent with selected
organic compounds containing representative functional groups and
chemoselective reduction
⇑
Ji Yeon Park, Won Kyu Shin, Ashok Kumar Jaladi, Duk Keun An
Department of Chemistry, Kangwon National University, and Institute for Molecular Science and Fusion Technology, Chunchon 200-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A new modified Red-Al reagent prepared from commercially available 1,1,1,3,3,3-hexamethyldisilazane
and sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al) is reported for the selective reduction of
carbonyl compounds containing representative functional groups. Moreover, this novel reagent is supe-
rior for the chemoselective reduction of aldehydes and ketones to the corresponding alcohols in excellent
yields under mild reaction conditions. Moreover, aldehydes can be reduced selectively in the presence of
ketones with similar reactivity.
Received 29 April 2016
Revised 23 May 2016
Accepted 27 May 2016
Available online 8 June 2016
Keywords:
Red-Al
Ó 2016 Elsevier Ltd. All rights reserved.
1,1,1,3,3,3-Hexamethyldisilazane
Chemoselective reduction
Aldehyde
Ketone
Introduction
time, and reversible reactions.11,12 LiAlH4 is a powerful reducing
agent; it can reduce all organic functional groups. Hence, it is dif-
Preparation of alcohols by the reduction of carbonyl compounds
is one of the most important chemical transformations in organic
synthesis. For this purpose, diverse reagents have been developed
in the past decades; among them, LiAlH4 and NaBH4 are the com-
monly used reducing agents.1,2 The selective (chemo, region, and
stereo) reduction of functional groups in the presence of other
reducible groups is highly desired in modern synthetic
approaches.3 NaBH4 is a convenient, mild, and selective reducing
agent for aldehydes, ketones, and acyl chlorides.4 Reducing agents
derived from NaBH4 have been widely investigated and provide
quantitative yields and higher selectivities.5–8 However, the reac-
tions are limited to protic solvents such as methanol and ethanol.
Recently, a resin-based reduction system (NaBH4/DOWEX) was
developed for the convenient reduction of carbonyl compounds
in a nonprotic solvent such as THF, but the reaction was limited
to aldehydes and ketones only.9
ficult to use LiAlH4 for the selective reduction of multifunctional
groups. Unlike the NaBH4 series of reducing agents, the selective
reduction of functional groups using Al reducing agents in
nonalcoholic solvents such as THF and ether has not been well
studied. However, considerable efforts have been made for partial
reductions.13–15
1,1,1,3,3,3-Hexamethyldisilazane (HMDS) is a bulky organosi-
lane compound, usually used for the trimethylsilylation of alco-
hols, amines, and thiols. Further it is a precursor for well-known
non-nucleophilic bases such as LiHMDS, NaHMDS, and KHMDS.
In continuation of our research on the development of novel
reducing agents, derived from commercially available reducing
agents such as DIBALH16 or Red-Al15 and experience in the modifi-
cation of Red-Al with secondary amines for the partial reduction of
carbonyl compounds, herein, we wish to report the modification of
Red-Al with commercially available bulky secondary amine HMDS
(Scheme 1).
Further, the reduction of aldehydes and ketones by the
Meerwein–Ponndorf–Verley (MPV) reduction10 method using a
metal alkoxide catalyst is well known. However, practical MPV
reductions suffer from some drawbacks such as a longer reaction
Results and discussion
The reaction of Red-Al and HMDS was monitored by gas buret
experiment by measuring the hydrogen gas evolution using
(Fig. 1).
⇑
Corresponding author.
E-mail address: dkan@kangwon.ac.kr (D.K. An).
http://dx.doi.org/10.1016/j.tetlet.2016.05.100
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

3248
J. Y. Park et al. / Tetrahedron Letters 57 (2016) 3247–3251
Table 2
Si
Si
Reactions of representative organic compounds with new modified Red-Al
N
H
Si Si
N
Al
H
Red-Al
Na
O
O
Si Si
N
0 oC, 1 h
O
O
Na
O
Al
O
O
O
H
Product
Compound
0 oC , THF-Toluene
4 eq , 1 h
Scheme 1. Synthesis of a new modified Red-Al reagent.
Entry
Compound
Product
OH
Yielda (%)
O
O
O
O
1
2
3
4
5
6
7
92
76
89
>99
4
Cl
O
OH
OH
OH
Cl
O
O
O
OH
OH
O
O
O
N
O
O
7
O
No reaction
No reaction
No reaction
No reaction
8
N
O
Figure 1. Measurement of hydrogen gas evolution: solid line indicates the
evolution of hydrogen gas from 1 mmol of amine (HMDS) by reacting with 1 mmol
of Red-Al. Dotted line indicates the evolution of hydrogen gas from 2 mmol of
amine by reacting with 1 mmol of Red-Al.
O
9
N
N
10
N
11
12
No reaction
No reaction
X
X = Cl, Br, I
7
Table 1
O
Reaction of representative aldehydes and ketones with new modified Red-Al
13
No reaction
a
Yields were determined by GC.
Si
O
Si
O
N
Al
H
Na
O
O
Compound
Product
0 oC , THF-Toluene
2 eq , 1 h
As shown in Figure 1, the gas buret experiment shows that only
one hydrogen atom of Red-Al participated in that reaction with
HMDS. Therefore, 1 mmol of H2 gas was evolved in the reaction
of 1 mmol of amine (HMDS) with 1 mmol of Red-Al, whereas, the
reaction of 2 mmol of HMDS with 1 mmol of Red-Al resulted in
1 mmol of H2 gas evolution rather than 2 mmol. Therefore, this
indicates that no other byproducts were generated in the prepara-
tion of new modified Red-Al reagent.
After 5 min of hydrogen gas evolution, the reaction was termi-
nated. To evaluate the reactivity of novel Red-Al reagent, represen-
tative aldehydes and ketones were first treated with 2 equiv of
reducing agent in THF at 0 °C; quantitative conversion to the corre-
sponding alcohol was observed at 1 h (Table 1).
Entry
1
Compound
Product
Yielda (%)
O
H
OH
>99
>99
>99
O
OH
2
3
H
O
O
OH
OH
4
5
6
>99
>99
>99
The reactions of aldehydes such as aromatic and aliphatic alde-
hydes afforded the corresponding primary alcohols (entries 1 and 2
in Table 1). Similarly, irrespective of the nature of ketones, the
reaction of aromatic ketones such as acetophenone and benzophe-
none, aliphatic ketones such as 2-heptanone, and cyclic ketones
such as cyclohexanone produced the corresponding alcohols in
O
OH
O
O
OH
OH
quantitative yields (entries 3–6 in Table 1). The reaction of
a,b-
unsaturated compound cyclohexenone afforded 1,2-reduction
rather than 1,4-reduction (entry 7 in Table 1).
7
>99
Moreover, the reaction of acyl chlorides and anhydrides with
this new reagent smoothly afforded the corresponding alcohols.
a
Yields were determined by GC.

J. Y. Park et al. / Tetrahedron Letters 57 (2016) 3247–3251
3249
Table 3
Chemoselective reduction of aldehydes in the presence of various organic compounds using new modified Red-Al
Si Si
N
Al
H
Na
O
O
O
O
O
Compound
Product
R
H
0 oC , THF-Toluene
1 h
A
B
C
Entry
1
Compound
Product C
Equiv
Yield of Ca (%)
Recovery of Aa (%)
A
B
O
O
H
1.1
1.5
51
68
46
33
OH
H
O
2
3
1.1
60
76
Cl
O
1.1
1.5
32
50
8
0
Cl
O
1.1
1.5
>99b
>99b
>99b
77b
4
5
6
O
1.1
1.5
1.1
1.5
2.0
90
90
99
>99
>99
90
99
98
>99
>99
O
O
O
O
1.1
1.5
>99
89
>99
>99
7
8
O
1.1
1.5
>99
97
99
91
N
O
1.1
1.5
96
>99
>99
90
9
N
N
N
1.1
1.5
>99
>99
>99
98
10
1.1
1.5
98
>99
>99c
90
>99
>99
96c
56
11
12
O
O
1.1
1.5
OH
H
a
b
c
Yields were determined by GC.
Yields were determined by NMR.
Reaction was carried out at À78 °C.
However, esters showed very poor reactivity (entries 5 and 6 in
Table 2), 50% conversion even after 6 h. Amides and nitriles did
not produce the corresponding alcohols (entries 7–11 in Table 2).
Similarly, the novel Red-Al reagent was not suitable for dehalo-
genation and epoxide ring opening (entries 12 and 13 in Table 2).
The bulky nature of the modified Red-Al did not allow the partial
reduction of esters to the corresponding aldehydes. Thus, the modi-
fied Red-Al is a functional group-selective reducing agent for aldehy-
des, ketones, acyl chlorides, and anhydrides. The chemoselectivity
was further investigated by the reaction of a mixture of reactants
using 1.1 equiv and 1.5 equiv of the modified Red-Al reagent.
As shown in Table 3, benzaldehyde was reduced in the presence
of other functional groups such as acyl chloride, ketone, ester,
amide, and nitrile. Similarly, an aldehyde was reduced almost
quantitatively in the presence of other functional groups except
acyl chloride which might be due to similar reactivity.
Finally, the chemoselectivity of the modified Red-Al reagent for
multifunctionalized compounds was investigated under the opti-
mized conditions. The results clearly showed that the aldehyde
group was reduced in the presence of a ketone in the same com-
pound, thus affording the corresponding primary alcohol in 83%
yield (entry 1 in Table 5). Moreover, the aldehyde or ketone was
reduced in the presence of an ester in the same compound, thus
affording the corresponding primary or secondary alcohol in excel-
lent yields, respectively (entries 2–4 in Table 5). In the case of a
compound containing an
because of the formation of an enolate through the deprotonation
of -hydrogen before the reduction (entry 5 in Table 5). The reduc-
tion of an ,b-unsaturated compound yielded a mixture of prod-
a-hydrogen, the reaction did not proceed
a
a
ucts (entry 6 in Table 5). In the case of 4-oxopentanoate, the
corresponding lactone was produced by reduction followed by
in situ cyclization in 86% yield (entry 7 in Table 5).
Next, the selective reduction of a ketone was carried out in the
presence of other functional groups such as acyl chloride, ester,
amide, and nitrile. The ketone was reduced quantitatively in the
presence of other functional groups. Acid chlorides produced the
corresponding carboxylic acids because of their unstable nature
under acidic workup conditions (entries 1 and 2 in Table 4). The
results are summarized in Table 4.
In summary a new modified Red-Al reagent was prepared by
the reaction of commercially HMDS with Red-Al. This novel
reagent provides selective functional group reduction in excel-
lent-to-quantitative yields under mild reaction conditions. The
experimental results show that the new modified Red-Al reagent
has the potential for the chemoselective reduction of aldehydes
and ketones to the corresponding alcohols in a rapid and efficient

3250
J. Y. Park et al. / Tetrahedron Letters 57 (2016) 3247–3251
Table 4
Chemoselective reduction of ketones in the presence of various organic compounds using new modified Red-Al
Si Si
N
Al
H
Na
O
O
O
O
O
Compound
Product
0 oC , THF-Toluene
1 h
R
A
B
C
Entry
Compound
Product C
Equiv
Yield of Ca (%)
Recovery of Aa (%)
A
B
O
O
O
O
OH
1.1
1.5
50
66
37
0
1
2
3
4
5
Cl
O
O
O
O
1.1
1.5
>99
99
0
0
Cl
O
1.1
1.5
2.0
>99
90
91
99
99
98
1.1
1.5
>99
>99
>99
>99
1.1
1.5
>99
>99
91
90
N
N
1.1
1.5
>99
>99
>99
>99
6
7
N
1.1
1.5
>99
>99
89
93
N
O
1.1
1.5
>99
>99
>99
>99
8
9
O
O
O
OH
1.1
1.5
98
96
93
>99
1.1
1.5
95
>99
98
>99
10
11
N
N
1.1
1.5
92
>99
>99
>99
a
Yields were determined by GC.
manner. Moreover, aldehydes can be reduced selectively in the
presence of ketones with similar reactivity.
Preparation of new modified Red-Al
A dry and argon-flushed flask was equipped with a magnetic
stirring bar and a septum; then HMDS (5.4 mL, 55 mmol) and
80 mL THF were added. After cooling to 0 °C, Red-Al (14.3 mL,
3.5 M in toluene, 50 mmol) was added dropwise and stirred for
1 h at the same temperature, generating a colorless homogeneous
solution. The concentration of the modified Red-Al solution in
THF/toluene was measured gasometrically by the hydrolysis of
an aliquot of the solution with aqueous 1 N HCl at 0 °C.
Experimental
General
All the glassware was dried thoroughly in an oven, assembled
hot, and cooled under a stream of dry nitrogen prior to use. All
the reactions and manipulation of air- and moisture-sensitive
materials were carried out using the standard techniques for han-
dling air-sensitive materials. All the chemicals were commercial
reagents of the highest purity and further purified by standard
methods before use. THF was dried over sodium-benzophenone
and distilled before use. GC analyses were performed using a
Yonglin (Anyang-si, South Korea), Acme 6000 M FID chro-
matograph using an HP-5 (5%-diphenyl-95%-dimethylsiloxane
copolymer, 30 m) capillary column. All the GC yields were deter-
mined using a mixture of naphthalene as the internal standard
and an authentic sample of the product.
Representative procedure for the chemoselective reduction of
multifunctionalized compounds with new modified Red-Al
A dry and argon-flushed flask, equipped with a magnetic stir-
ring bar and septum, was charged with 4-acetylbenzaldehyde
(1.0 mmol) and THF (10 mL). After cooling to 0 °C, the modified
Red-Al (0.5 M, 2.2 mL in THF) was added dropwise and the mixture
was stirred for 1 h at 0 °C. The reaction was quenched with 1 N
aqueous HCl (10 mL) and the product was extracted with diethyl
ether (10 mL). The organic layer was dried over anhydrous

J. Y. Park et al. / Tetrahedron Letters 57 (2016) 3247–3251
3251
Table 5
magnesium sulfate, the solvent was removed under reduced pres-
sure and the crude residue was purified by column chromatogra-
phy (SiO2, ethyl acetate/hexane, 1:5 v/v) to affording the desired
alcohol (123 mg, 83% yield).
Chemoselective reduction of multifunctionalized compounds with new modified Red-
Al
Si Si
N
Al
H
Na
O
O
Acknowledgments
O
O
Product
Compound
This study was supported by the National Research Foundation
of Korea Grant funded by the Korean Government
(2014R1A1A2059124), and the 2014 Research Grant from
Kangwon National University (No. 520150434).
0 oC, THF-Toluene (1.1 eq)
Entry
1
Compound
Product
Yielda (%)
O
O
O
O
References and notes
83
98
99
H
O
HO
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O
O
2
3
H
O
HO
O
O
O
O
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O
O
OH
OH
O
O
O
4
5
6
7
93
O
O
9. Behzad, Z. J.; Farhad, S. Chem. Res. (S) 2003, 335.
O
O
O
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No reaction
Mixtures
86
O
O
O
O
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O
O
O
OH
O
O
H3C
O
O
O
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a
Isolated yields.