Copper diisobutyl-t-butoxyaluminum hydride: A novel reagent for chemoselective reduction of tertiary amides over esters

Article abstract of DOI:10.1016/j.tetlet.2018.04.082

We demonstrate that copper diisobutyl-t-butoxyaluminum hydride, readily prepared from lithium diisobutyl-t-butoxyaluminum hydride and CuI, effectively and chemoselectively reduces tertiary amides over esters at ambient temperature, affording the corresponding aldehydes in excellent yields.

Full text of DOI:10.1016/j.tetlet.2018.04.082

Accepted Manuscript
Copper Diisobutyl-t-butoxyaluminum Hydride: A Novel Reagent for Chemo-
selective Reduction of Tertiary Amides over Esters
So Hee Im, Won Kyu Shin, Ashok Kumar Jaladi, Duk Keun An
PII:
S0040-4039(18)30568-9
https://doi.org/10.1016/j.tetlet.2018.04.082
TETL 49945
DOI:
Reference:
Tetrahedron Letters
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29 January 2018
26 April 2018
29 April 2018
Please cite this article as: Im, S.H., Shin, W.K., Jaladi, A.K., An, D.K., Copper Diisobutyl-t-butoxyaluminum
Hydride: A Novel Reagent for Chemoselective Reduction of Tertiary Amides over Esters, Tetrahedron Letters
(2018), doi: https://doi.org/10.1016/j.tetlet.2018.04.082
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Tetrahedron Letters
Copper Diisobutyl-t-butoxyaluminum Hydride: A Novel Reagent for Chemoselective
Reduction of Tertiary Amides over Esters
So Hee Im, Won Kyu Shin, Ashok Kumar Jaladi and Duk Keun An
Department of Chemistry, Kangwon National University, and Institute for Molecular Science and Fusion Technology,
Chunchon 24341, Republic of Korea. *E-mail: dkan@kangwon.ac.kr
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We demonstrate that copper diisobutyl-t-butoxyaluminum hydride, readily prepared from
lithium diisobutyl-t-butoxyaluminum hydride and CuI, effectively and chemoselectively reduces
tertiary amides over esters at ambient temperature, affording the corresponding aldehydes in
excellent yields.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Chemoselective reduction
Tertiary Amide
Ester
Aldehyde
CDBBA
Chemoselective hydride reducing agents allowing quantitative
conversion into the desired product are highly sought after,1
ideally being affordable and thus suitable for general-purpose
use. In view of this demand, the past decades have witnessed the
development of a large number of such reagents (prepared by
modifying highly reactive metal hydrides), with their selectivities
mainly determined by the steric/electronic properties of
substituents and reagent mildness.2,3 For instance, lithium
aluminum hydride4 is an extremely powerful agent reducing most
organic functional groups and thus leaving almost no room for
selectivity. However, derivatives such as lithium tri-t-
butoxyaluminum hydride,5 bis(4-methyl-1-piperazinyl)aluminum
hydride,6 and lithium tris(diethylamino)aluminum hydride7 have
been reported as mild and efficient reducing agents with
reactivities similar to that of NaBH4.8 Likewise, other reducing
agents have also been successfully modified to achieve stereo-
and chemoselective reduction.9
aliphatic substrates. Consequently, efficient and readily available
amide to aldehyde reducing agents applicable to both aromatic
and aliphatic substrates are still in high demand.
As part of our ongoing search for highly efficient reducing
agents, we have identified several promising species such as
lithium diisobutylmorpholinoaluminum hydride (LDBMOA),15
lithium diisobutylpiperidinoaluminum hydride (LDBPA),16
lithium diisobutyl-t-butoxyaluminum hydride (LDBBA),17
sodium diisobutyl-t-butoxyaluminum hydride (SDBBA),18 and
potassium diisobutyl-t-butoxyaluminum hydride (PDBBA).19,20
Herein, we report the chemoselective reduction of tertiary amides
to aldehydes in the presence of esters using copper diisobutyl-t-
butoxyaluminum hydride (CDBBA) (Scheme 1).
The reduction of amides to aldehydes is an important and
well-studied chemical transformation.10 However, this
transformation is difficult to accomplish in the presence of the
more reactive ester moieties, with only few reagents reported to
be suitable for this purpose, e.g., the Schwartz reagent
(Cp2Zr(H)Cl),11 LiBH(CHMeEt)3,12 ClMg+(H3BNMe2)–,13 and
[Mo(CO)6]/TMDS.14 Despite the significant progress achieved
using these systems, such reagents are very expensive and highly
sensitive. Furthermore, some of the above systems require
Scheme 1. Chemoselective reduction of tertiary amides over
esters with CDBBA
additional synthetic steps or suitable for either aromatic or
———
 Corresponding author. Tel.: +82-33-250-8494; fax: +82-33-253-7582; e-mail: dkan@kangwon.ac.kr

2
Tetrahedron
The CDBBA was readily prepared by the reaction of
aromatic and poly-aromatic moieties were also amenable to the
above reduction, affording the corresponding aldehydes in 68%
and 99% yields, respectively (entries 7 and 8).
LDBBA with CuI at room temperature,21,22 and its reactivity was
determined by reducing various carboxylic acid derivatives.
Surprisingly, treatment of tertiary amides and esters with
CDBBA at room temperature resulted in the reduction of the
relatively less reactive tertiary amides to aldehydes in reasonable
yield, leaving esters unreacted. In view of this interesting
observation, we systematically studied the chemoselective
reduction of tertiary amides in the presence of esters using
variable conditions like temperature, reagent:substrate mole
ratios, and solvents to optimize the yields of the desired
aldehydes (Table 1).
Table 2. Chemoselective reduction of aromatic tertiary amides
over esters with CDBBA23
Table 1. Optimization of the chemoselective tertiary amide
reduction
Table 1 shows that moderate tertiary amide conversion and
high selectivity over ester reduction were observed at 0 °C with a
10:1.0 (mol/mol) reagent:substrate ratio in THF (entry 1). Better
aldehyde yields were achieved at room temperature; however,
decreased selectivity and over-reduction (i.e., alcohol formation)
were observed (entry 2). To overcome this issue, the
reagent:substrate mole ratio was changed to 8.0:1.0, affording an
increased aldehyde yield and higher selectivity (entry 3). The use
of other solvents such as hexane, ether, dichloromethane, and
toluene resulted in moderate reduction yields and greater
Importantly, various aliphatic tertiary amides including
Weinreb amides were also well tolerated (Table 3),
chemoselectively affording the corresponding aldehydes in good
yields. However, some reported systems have failed to produce
aldehydes from aliphatic tertiary amides containing α-
hydrogens.14
Table 3. Chemoselective reduction of aliphatic tertiary amides
over esters with CDBBA
selectivity (entries 4–7).
A
further decrease of the
reagent:substrate molar ratio from 8.0:1.0 to 4.0:1.0 (THF)
decreased the amide to aldehyde conversion, whereas the ester
remained unreacted (entry 8). Finally, we investigated the effect
of the CuI:LDBBA ratio, revealing that deviations from the
1.1:1.0 value resulted in either simultaneous ester and tertiary
amide reduction or decreased yield of aldehyde from tertiary
amide (entries 9 and 10).
Based on the above data, it was concluded that the 8.0:1.0
reagent:substrate ratio was optimal, resulting in excellent tertiary
amide to aldehyde conversions in the presence of an ester group.
In the next step, the efficiency of CDBBA was tested by
screening a series of aromatic and aliphatic tertiary amides and
Weinreb amides under optimal conditions
As shown in Table 2, most of the tested tertiary amides could
be converted into the corresponding aldehydes in good to
excellent yields, with the electron donating/withdrawing nature
of tertiary amide substituents have shown similar effect on
selectivity and conversion. Tertiary amides containing hetero-

Subsequently, under optimized conditions, we reduced a
number of tertiary amides in the presence of esters bearing
electron rich and electron poor substituents (Table 4), showing
that amides smoothly underwent reduction with CDBBA to
afford the corresponding aldehydes in good yields and with
excellent chemoselectivity.
Next, the chemoselectivity of CDBBA was compared to those
of commercially available and modified DIBALH based reducing
agents. As shown in Table 5, although DIBALH has capable of
chemoselective reduction, its use resulted in decreased yield of
aldehyde from tertiary amide with over-reduction (entry 1).
Conversely, Red-Al did not exhibit any amide/ester group
selectivity (entry 2), whereas LDBBA reduced both functional
groups to aldehydes (entry 3), in agreement with the excellent
aldehyde yield observed for the corresponding tertiary amide
reduction at 12 h.19 Finally, SDBBA and PDBBA showed inverse
selectivity, reducing esters in preference to tertiary amides
(entries 4 and 5).
Table 4. Chemoselective reduction of tertiary amides with
CDBBA in the presence of different esters
Additionally, other modified DIBALH based reductants were
utilized to prepare CDBBA and evaluate its performance. Table 6
reveals that the chemoselective reduction of tertiary amides over
esters was only observed for LDBBA-derived CDBBA under
optimized conditions
Table 6. Chemoselective reduction of tertiary amide over ester
with CDBBA prepared by reacting CuI with several modified
DIBALH-based reagents
These results encouraged us to carry out the chemoselective
reduction of methyl 4-(dimethylcarbamoyl)benzoate (Scheme 2).
We easily obtained the desired product in 77% yield, suggesting
that CDBBA can be an alternative chemoselective reducing agent
of tertiary amides over esters.24
Finally, we evaluated the effects of the copper precursor, to
generate CDBBA in situ from CuCl, CuBr, and CuCl2. However,
only CuI-derived CDBBA exhibited acceptable selectivity, even
though it was given moderate yield under in situ condition.
Scheme 2. Chemoselective reduction of methyl 4-
(dimethylcarbamoyl)benzoate with CDBBA
In summary, the newly prepared CDBBA reagent enabled the
efficient and mild chemoselective reduction of tertiary amides in
the presence of the relatively more reactive esters. In addition,
the above reagent could be prepared from readily available
precursors and allowed the selective reduction of both aliphatic
and (hetero) aromatic tertiary amides to aldehydes in excellent
yields, being superior to other metal hydrides. Thus, the
developed approach allows amides to be used as convenient
alternative protecting groups for the ambient temperature
preparation of aldehydes in complex syntheses. The
corresponding mechanistic study is currently under way and will
be reported in due course.
Table 5. Chemoselective tertiary amide reduction with various
metal hydrides
Acknowledgments
This study was supported by the National Research Foundation
of Korea Grant funded by the Korean Government
(2017R1D1A1B03035412), and the 2017 Research Grant from
Kangwon National University (No. 520170524).

4
Tetrahedron
23. The following experimental procedure for the chemoselective
partial reduction of ethyl benzoate and N,N-dimethyl 3-toluamide
is representative. A dry and argon-flushed flask, equipped with a
magnetic stirring bar and a septum, was charged with ethyl
benzoate (0.07 mL, 0.5 mmol), N,N-dimethyl 3-toluamide (0.08
mL, 0.5 mmol)and 5 mL THF. After CDBBA (9.01 mL, 0.44 M
soln. 4.0 mmol) was slowly added and stirred for 12 h at room
temperature. The reaction was quenched by aqueous 1 N HCl (10
mL) and extracted with diethyl ether (2 x 10 mL). The combined
organic layers were dried over MgSO4. GC analysis showed a
97% recovery yield of ethyl benzoate and 95% yield of 3-
methylbenzaldehyde. All products in Table 2 were confirmed
through comparison with GC data of authentic sample.
References and notes
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24. Chemoselective
partial
reduction
of
A
methyl
dry and argon-
4-
(dimethylcarbamoyl)benzoate (Scheme 2).
flushed flask, equipped with a magnetic stirring bar and a septum,
was charged with methyl 4-(dimethylcarbamoyl)benzoate (207 mg,
1.0 mmol) and 5 mL THF. After CDBBA (18.2 mL, 0.44 M soln.
8.0 mmol) was slowly added and stirred for 12 h at room
temperature. 1 N HCl (20 mL) and extracted with diethyl ether (2
x 10 mL). The combined organic layers were dried over MgSO4,
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1
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21. Preparation of LDBBA. To a solution of t-butyl alcohol (5.26 mL,
55 mmol) in THF (10.34 mL) was added n-butyllithium (34.4 mL,
0
1.6 M in hexane, 55 mmol) at 0 C. After stirring for 1 h at room
temperature, DIBALH (50 mL, 1.0 M in hexane, 50 mmol) was
added dropwise to the reaction mixture at 0 0C and the mixture
was stirred for a further 2 h at room temperature to obtain a
colorless homogeneous solution. The concentration of LDBBA
solution in THF-hexane was measured gasometrically by the
hydrolysis of an aliquot of the solution with a hydrolyzing mixture
of t-butyl alcohol-THF (1:1) at 0 0C.
22. Preparation of copper diisobutyl-t-butoxyaluminum hydride
(CDBBA). A dry and argon-flushed flask, equipped with a little bit
small magnetic stirring bar and a septum, was charged CuI (9.22 g,
48.4 mmol). After cooling to 0 0C and gentle stirred for 5 min
using stirring bar, LDBBA (100.0 mL, 0.44 M soln. in THF-
hexane, 44.0 mmol) was added dropwise and gentle stirred for 8 h
at room temperature to give a mixture solution. The mixture
solution was allowed to settle for 1 h at room temperature and then
clear reagent was used.

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Copper Diisobutyl-t-butoxyaluminum Hydride:
A Novel Reagent for Chemoselective Reduction of
Tertiary Amides over Esters
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So Hee Im, Won Kyu Shin, Ashok Kumar Jaladi, Duk Keun An*
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Tetrahedron
Highlights:
 Designing of chemoselective reagent for amide
reduction over ester is challenging.
 New reducing agent CDBBA was developed.
 The CDBBA exhibited good selectivity for tertiary
amide reduction in the presence of ester.
 This method provides reduction of both aromatic
and aliphatic substrates in excellent yields.