Chemoselective reduction of α-keto amides using nickel catalysts

Article abstract of DOI:10.1039/c4cc02744b

Ni-catalysts are used for the first time to synthesize highly important α-hydroxy amides and β-amino alcohols from α-keto amides by chemoselective and complete reduction using hydrosilanes. Chemoselective complete reduction of α-keto amides in the presenc

Full text of DOI:10.1039/c4cc02744b

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Chemoselective reduction of a-keto amides using
nickel catalysts†
Cite this:DOI: 10.1039/c4cc02744b
N. Chary Mamillapalli and Govidasamy Sekar*
Received 14th April 2014,
Accepted 22nd May 2014
DOI: 10.1039/c4cc02744b
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Ni-catalysts are used for the first time to synthesize highly important
a-hydroxy amides and b-amino alcohols from a-keto amides by
chemoselective and complete reduction using hydrosilanes. Chemo-
selective complete reduction of a-keto amides in the presence of a
simple amide group is a key benefit of these Ni-catalysts.
a-Hydroxy amides and b-amino alcohols are very important building
blocks in the pharmaceutical industry and show several biological
activities such as anticonvulsant action,1 bronchospasm, bradycardia
and peripheral vascular resistance.2 Both these compounds can be
easily obtained from a-keto amides by chemoselective reduction of a
keto group and complete reduction of both keto and amide groups
respectively. A challenging task arises for selective reduction of a-keto
amides as both the keto and amide groups are present there.
Although ketone reduction is well established by hydrosilane,3
reduction of readily available but less reactive carboxylic amides to
Scheme 1 Chemoselective reduction of a-keto amides using Ni catalysts.
amines is one of the simplest less explored methodologies in organic reduction of a-keto amides to a-hydroxy amides and complete
chemistry. The traditional reducing agents such as LiAlH4 and reduction to b-amino alcohols. The advantage of this Ni catalyst is
hydroboranes have limitations like less chemoselectivity, moisture that it can selectively reduce keto groups of a-keto amides in the
sensitive, expensive and tedious purification process.4 Catalytic presence of a simple keto functional group and it has the ability to
hydrogenation5 should be the appropriate alternative, but there is reduce both keto and amide groups of a-keto amides in the
no general method available for the selective amide reduction.
Recently, considerable progress has been made in the field of
presence of other amide functional groups (Scheme 1).
Initially, 2-oxo-N-2-diphenylacetamide 1a was taken as the
amide reduction using hydrosilanes in the presence of metal model substrate and the reduction was carried out using various
catalysts. Initial reports used metal catalysts like Rh,6 Ru,7 Pd,8 nickel salts with the tetramethylethylene diamine (TMEDA) ligand
Pt,9 Ir10 etc.11 Later, other metal catalysts such as Fe,12 Cu,13 and and (EtO)3SiH at room temperature. The reaction took place in the
Zn14 were brought into action. In addition, there are reports on case of Ni acetate and 32% of a-hydroxy amides 2a were obtained.
reduction of tertiary amides using a KOH15 and a TBAF16 catalyst Further optimization was carried out with Ni(OAc)2 after screening
but reduction of secondary amides are difficult.17 Even though NaOtBu and KOtBu bases as additives, 10 mol% of KOtBu was
there are reports available for ketone reduction using an economic found to be the appropriate additive as it yielded a mixture of 82%
and readily available Ni18 catalyst and hydrosilanes, reduction of of 2a and 8% of 3a (Table 1, entry 2). In order to increase the
carboxylic amides to amines is yet to be reported. Herein for the efficiency of the reaction towards 2a, the temperature was increased
first time we report an efficient Ni catalyst for the chemoselective to 60 1C. Although the reaction time was reduced, the selectivity
also reduced (entry 3). To increase the selectivity, mild hydrosilanes
such as polymethyl hydrosilane (PMHS) were used as we expected,
the selectivity was increased and only 2a was obtained with an
Department of Chemistry, Indian Institute of Technology Madras, Chennai,
600 036, India. E-mail: gsekar@iitm.ac.in; Fax: +91 44 2257 4202;
isolated yield of 98% (entry 4). The same reaction without base
Tel: +91 44 2257 4229
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc02744b worked equally well but the reaction time was 24 hours (entry 5).
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Table 1 Optimization of chemoselective reduction of a-keto amides
electron donating groups (2d and 2e), electron withdrawing groups
(2f, 2j and 2g) in the amide nitrogen attached aromatic ring and
aliphatic amide attached ketones (2i and 2h) were well tolerated. It
is important to note that other functional groups sensitive to
reduction reaction such as nitrile and halo groups are unaffected.
We were curious to know the reactivity of the keto group of
1a in the presence of externally added ketone like benzo-
phenone and in this reaction we have isolated a quantitative
amount of unreacted benzophenone along with 95% of
a-hydroxy amide. When a substrate such as 4, having an
isolated keto group and a-keto amide, was treated with a Ni
catalyst, the a-keto amide chemoselectively yielded 5 without
affecting the isolated ketone (Table 3). Few more substrates
were examined similar to 4 and the results are summarized in
Table 3. In this chemoselective reduction, the a-keto amide’s
keto group should be more electrophilic than isolated ketone
due to the presence of electron withdrawing a-amide. In addi-
tion to this, the nitrogen atom of a-keto amide should play a
vital role in co-ordinating with nickel hydride as a directing
group for a-keto group reduction.
using Ni catalystsa
Yieldb (%)
Silane
(equiv.)
Additive
(10 mol%)
Temp
(1C)
Time
(h)
Entry
2a
3a
1
2
3
4
(EtO)3SiH (2)
(EtO)3SiH (2)
(EtO)3SiH (2)
PMHS (4)
PMHS (4)
PMHS (4)
NaOtBu
KOtBu
KOtBu
KOtBu
—
NaOAc
NaOAc
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOAc
KOtBu
NaOAc
—
rt
rt
48
48
10
12
24
8
24
24
24
24
12
12
24
24
24
24
24
78
82
58
98
95
98
—
10
81
21
—
38
30
11
36
—
90
6
8
60
60
60
60
60
60
rt
rt
rt
rt
rt
18
—
—
—
—
78
16
74
97
8
10
—
13
—
—
5
6
7c
8
PMHS (4)
(EtO)3SiH (4)
Ph3SiH (4)
TMDSO (4)
Ph2SiH2 (4)
Ph2SiH2 (4)
Ph2SiH2 (4)
PMHS (4)
Ph2SiH2 (4)
PMHS (4)
Ph2SiH2 (4)
9
10
11
12c
13d
14d
15e
16e
17
60
rt
60
60
After achieving appropriate optimized reaction conditions
for chemoselective reduction of a-keto amide 1a to get 2a, we
shifted our focus to complete reduction of 1a to yield b-amino
alcohol 3a. Initially, we have increased the quantity of
(EtO)3SiH to 4 equivalents. As expected, this reaction gave
complete reduction 3a as the major product (Table 1, entry 3
vs. 8). In the case of Ph3SiH, the reaction gave very poor yield of
3a (16%) as the minor product (entry 9), whereas in the case of
tetramethyldisiloxane (TMDSO) the reaction gave 74% of 3a as
a major product (entry 10). Usage of stronger reducing agent
Ph2SiH2 yielded only complete reduction product 3a with an
isolated yield of 97% (entry 11). The same reaction without
Ni(OAc)2 and a ligand gave a series of spots in the TLC and we
isolated 38% of 2a and 8% of 3a along with 15% of aniline and
10% of benzoyl formic acid as by-products (entry 12). To know
the role of the ligand, two reactions were carried out without
the ligand, only in the presence of Ni(OAc)2 along with KOtBu.
The reaction yielded 30% of 2a and 10% of 3a. In the case of
NaOAc, the reaction yielded only 11% of 2a (entries 13 and 14).
Similarly, to know the role of metal salt in the reduction, blank
reactions were carried out only with TMEDA and additives.
a
b
c
Reaction condition: 0.5 mmol of 1a in THF. Isolated yield. Without
d
e
Ni(OAc)2 and ligand. Without TMEDA. Without Ni(OAc)2.
The rate of the reaction increased upon adding 10 mol% of NaOAc
as an additive (entry 6). The additive (acetate ion) may help to
release the hydride ion from the PMHS which may be the reason
for the fast reaction rate. The same reaction without a catalyst
(Ni(OAc)2–TMEDA complex) did not give any reaction (entry 7).
To establish the scope of the Ni catalyzed chemoselective
reduction of a-keto amides, several a-keto amides were examined
and the results are summarized in Table 2. Substitution like
Table 2 Chemoselective reduction of keto groups of a-keto amides
using the Ni(OAc)2–TMEDA catalysta
Table 3 Chemoselective reduction of keto groups of a-keto amides
using Ni catalysts in the presence of other keto functional groupsa
a
a
Reaction condition: 0.5 mmol of 1 in THF. Isolated yield.
Reaction condition: 0.5 mmol of 4 in THF. Isolated yield.
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Table 4 Complete reduction of both keto and amide groups of a-keto
Table 5 Selective reduction of a-keto amides in the presence of isolated
amides using Ni catalystsa
amide functional groups using Ni catalystsa
Entry
6
7
Time (h)
Yieldb (%)
1
20
92
a
Reaction condition: 0.5 mmol of 1a in THF. Isolated yield.
In the case of KOtBu, the reaction yielded 36% of 2a and 13% of
3a along with aniline and benzoylformic acid as side products.
But in the case of NaOAc, there is no reaction (entries 15 and 16).
To understand the role of base in complete reduction, a blank
reaction was carried out without KOtBu and the reaction did not
give complete reduction product 3a (entry 17). To establish the
substrate scope of complete reduction of a-keto amide, several
a-keto amides were reduced with Ph2SiH2 and 10 mol% of KOtBu
at room temperature using 5 mol% of Ni catalyst and the results
are summarized in Table 4. Electron donating groups on a-keto
amides (3c, 3d and 3e) and aliphatic ketone attached amide (3b)
were well tolerated. Only aromatic amide attached ketones get
reduced under the optimized reaction conditions.
When N-phenylbenzamide and phenyl(piperidin-1-yl)methanone
were added to a-keto amide 1a under complete reduction condi-
tions, only 1a reduced to yield 95% of b-amino alcohol 3a. Then we
synthesised diamide such as 6a containing simple carboxylic amide
and a-keto amide. Then 6a was treated under Ni catalyzed complete
reduction conditions, and the a-ketoamide functional group
got reduced without affecting the isolated amide to yield 7a. To
establish the substrate scope of this chemoselective reduction of
amide–ketoamide, a series of amide–ketoamides were synthesized
(Table 5, 6a–6e). In all the reactions, only the a-keto amide
functional group got reduced without affecting the isolated amide
(7a–7e) with quantitative yields. Highly reactive tertiary amides and
benzyl amide were well tolerated under the same reduction condi-
tions (7b, 7c and 7d).
2
3
4
18
12
90
95
20
18
90
92
5
a
b
Reaction condition: 0.5 mmol of 6 in THF. Isolated yield.
Generally, a keto group is more reactive than carboxylic
amide for the reduction reaction. In the case of amido-
ketoamide 6a, we assume that first the keto group chemoselec-
tively reduced to a-hydroxy amide 2a as an intermediate. The
resulting 2a co-ordinated with nickel hydride to reduce the
a-keto amide’s amide functional group which will not be
possible in the case of isolated amides.
To check this hypothesis, we used a-hydroxy amide 2a,
triphenylsilane protected hydroxy amide 8 and a-methoxy
amide 9 for the complete reduction conditions. 2a and 8
yielded amide reduced products in 83% and 89% yield respec-
Scheme 2 Reduction of a-hydroxy amides and their ether derivatives.
tively. As expected, a-methoxy amide 9 did not yield even a trace group of a-keto amide plays a crucial role in the amide
amount of reduced product which shows that the a-hydroxy reduction of a-keto amide (Scheme 2). However the detailed
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applications are in progress.
In conclusion, for the first time we have developed an
efficient Ni-TMEDA catalyst for the chemoselective reduction of
ketones of a-keto amides to yield a-hydroxy amide and complete
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appropriate silanes. Although metal catalysts such as Rh, Zn, Cu,
Fe, Co, Ti, Ru, etc. are known to reduce the keto group and metal
catalysts such as Rh, Ru, Pd, Pt, Ir, Fe, Cu, Zn, etc. are known to
reduce amide groups, Ni is the first metal salt used for the
chemoselective reduction of keto groups of a-keto amides in the
presence of other ketone functional groups and chemoselective
complete reduction of a-keto amides in the presence of other
amide functional groups.
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