Room temperature copper-catalyzed oxidative amidation of terminal alkynes for the synthesis of α-ketoamides using: O -benzoyl hydroxylamines as aminating reagent and oxidant

Article abstract of DOI:10.1039/c6ra15219h

A novel and convenient copper-catalyzed oxidative amidation for the synthesis of α-ketoamides has been successfully developed, which uses easily available O-benzoyl hydroxylamines as aminating reagent and oxidant. The reaction proceeds smoothly at room temperature and is compatible with a range of substrates to give the desired products in moderate to good yields.

Full text of DOI:10.1039/c6ra15219h

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Room temperature copper-catalyzed oxidative amidation of
terminal alkynes for synthesis of α-ketoamides using O-benzoyl
hydroxylamines as aminating reagent and oxidant
Received 00th January 20xx,
Accepted 00th January 20xx
Guodong Shen,* Lingyu zhao, Yichen Wang, Tongxin Zhang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Previous work
A novel and convenient copper-catalyzed oxidative amidation for
synthesis of α-ketoamides has been successfully developed, which
uses easily available O-benzoyl hydroxylamines as aminating
reagent and oxidant. The reaction proceeds smoothly at room
temperature and is compatible with a range of substrates to give
the desired products in moderate to good yields.
0.1 eq. CuBr2, 10 eq. H2O
0.1 eq. TEMPO
O
H
N
R
+
Ar-NH2
eq 1
R
Ar
4 eq. Pyridine, O2 (1 atm)
Toulene, 60oC, 18h
O
0.1 eq. Cu(OTf)2
0.15 eq. TEMPO
O
R1
N
R1
R2
Ar
+
H
N
eq 2
Ar
R2
DMSO, Air, 80oC
O
Our work
α-Ketoamides are important functional scaffolds in many
natural products, biological compounds, pharmaceuticals, and
synthetic intermediates.1 Significant efforts have been made
toward the development of efficient methods for their
preparation. Traditional approaches for accessing α-
ketoamides mainly involve the condensation of their
corresponding a-keto acids or a-keto acyl halides with amines.2
Some alternative methods, such as double carbonylation
reactions,3 oxidative reactions4 and other methods5 have also
been developed. Recently, the copper-catalyzed oxidative
reaction for the synthesis of α-ketoamides have attracted
much attention,4a-4d especially using commercially available
terminal alkynes as coupling partners.6 For example, Jiao etal.
and Shah etal. have successfully developed copper-catalyzed
methods for the preparation of α-ketoamides involving
terminal alkynes as coupling partners with amines (Scheme 1,
eq 1-2).6a, 6b While generally effective, the methods require
external oxidants, additives and heating conditions. Therefore,
developing new methods for the synthesis of α-ketoamides
using easily available starting materials under mild conditions
is still of promising interest. In the past decade, O-benzoyl
hydroxylamines (BzO-NR1R2) have received great attention
because of easy handling and preparation, and high reactivity
in amination reactions as a convenient nitrogen source under
O
R1
N
0.1 eq. Cu(OTf)2
2.0 eq. DBU
R1
R2
eq 3
R
R2
R
BzO
N
2
+
THF, N2, RT
O
Scheme 1. Synthesis of α-ketoamides.
mild conditions.7 Herein, we present a novel and convenient
copper-catalyzed oxidative amidation of terminal alkynes for
the synthesis of α-ketoamides employing easily available O-
benzoyl hydroxylamines (BzO-NR1R2) as dually a reactive
aminating reagent and oxidant at room temperature (Scheme
1, eq 3).
Table 1. Optimization of the reaction conditions.a
O
Copper Catalyst
Base, Solvent, T
N
2
N
O
OBz
1b
1c
1a
Ent
ry
1
2
3
4
5
6
Catalyst
Base
Solvent
T(oC)
1c(%)b
CuI
CuBr
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
THF
THF
THF
THF
THF
THF
THF
THF
THF
RT
RT
RT
RT
RT
RT
RT
RT
RT
52
68
62
CuCl2
Cu(OTf)2
Cu(OTf)2
/
84
82c
n.r.d
38e
46f
n.r.
7
8
9
Cu(OTf)2/BPO
Cu(OTf)2/O2
Cu(OTf)2
Na2CO3
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10
11
12
13
14
15
16
17
18
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
K2CO3
t-BuOK
Et3N
/
DBU
DBU
DBU
DBU
DBU
THF
THF
THF
THF
toluene
dioxane
H2O
RT
RT
RT
RT
RT
RT
RT
35
15
n.r.
trace
n.r.
n.r.g
70
trace
n.r.
72
Ent
ry
Yield
(%)b
a
b
c
THF
THF
24
a General reaction conditions: copper catalyst (0.05 mmol, 10
mol%), phenylacetylene (2.0 mmol, 0.204g, 4.0 equiv.) and N-
(benzoyloxy)piperidine (0.5 mmol, 0.103g, 1.0 equiv. ), base
(1.0 mmol, 2.0 equiv.), solvent (3.0 mL), N2, 12 h.
1
84
1a
1b
1c
b Isolated yield based on 1b
.
2
3
1b
1b
82
c Cu(OTf)2 (0.1 mmol) was added as the catalyst.
d No copper catalyst was used, n.r.= no reaction.
e Benzoyl peroxide (BPO, 0.5 mmol) was added.
f The reaction was performed under oxygen balloon.
g No base was used.
2a
3a
2c
64
3c
Initially, the synthesis of α-ketoamides with phenylacetylene
1a and N-(benzoyloxy)piperidine 1b was investigated in the
presence of copper catalyst to identify and optimize the
reaction parameters (Table 1). To our delight, when the
reaction was carried out with CuI (10 mol%) and DBU (2 eq) in
THF (3.0 mL) at ambient temperature under nitrogen, the
desired product could be detected (Table 1, entry 1). It was
found that the copper catalysts such as CuCl2, CuI, CuBr,
Cu(OTf)2 affected the reaction yield significantly (Table 1,
entries 1-4). The best result was obtained in the presence of 10
mol% of Cu(OTf)2 (0.05 mmol, 0.018g), phenylacetylene (2.0
mmol, 0.204g) and N-(benzoyloxy)piperidine (0.5 mmol,
0.103g), DBU (1.0 mmol, 0.152g) in THF (3.0 mL) at room
temperature for 12 h, and 84% yield was got (Table 1, entry 4),
while increasing the catalyst loading did not improve the
product yield (Table 1, entry 5). No reaction occurred in the
absence of copper catalyst (Table 1, entry 6). Notably, the
copper-catalyzed oxidative amidation reaction did not have
external oxygen source (Table 1, entries 1-5). Meanwhile,
addition of other oxidants such as benzoyl peroxide (BPO, 1 eq)
or oxygen into the catalytic system decreased the yield
obviously (Table 1, entries 7 and 8). Therefore, we surmised
that N-(benzoyloxy)piperidine could serve as dually aminating
reagent and oxidant. During the study of bases, we noticed
that the addition of DBU to the reaction showed the best
efficiency (Table 1, entries 9-13). Then, the reaction was
investigated in other solvents and THF was found to be the
best choice (Table 1, entries 14-16). The reaction temperature
was also screened and the reaction yields decreased obviously
at lower or higher reaction temperatures (Table 1, entries 17
and 18). Thus, the optimized reaction conditions for the
oxidative amidation of terminal alkynes involved using O-
benzoyl hydroxylamines as dually aminating reagent and
oxidant, Cu(OTf)2 as the catalyst, DBU as the base, THF as the
solvent and conducting the reaction at room temperature
under nitrogen.
4
1b
72
4a
5a
4c
5
6
7
8
1b
1b
80
5c
78
6a
1a
6c
80
2b
3b
7c
1a
1a
1a
72
8c
9
62
4b
5b
9c
10
68
10c
11
12
13
1a
1a
2a
76
6b
11c
60
7b
5b
12c(isomer)
65
13c
Table 2. Scope of copper-catalyzed oxidative amidation for
the synthesis of α-ketoamides.a
2 | J. Name., 2012, 00, 1-3
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the desired compound 15c, presumably because of the weak
oxidative ability of 8b (Table 2, entry 15). Aliphatic alkynes 1-
14
6a
1a
7a
5b
61
hexyne
7a
also
could
not
reacted
with
N-
14c
(benzoyloxy)piperidine 1b under the optimized reaction
condition (Table 2, entry 16).
15
16
0
0
To gain some understanding of the mechanism for this
reaction, some control experiments were tentatively examined
under the optimized reaction conditions (for mechanism
details, see Supporting Information). We have concluded that
oxygen source of the product 1c come from N-
(benzoyloxy)piperidine 1b (Table 1, entries 1-8), and the
detected phenyl(piperidin-1-yl)methanone 1d also confirmed
our speculation (Scheme 2, eq 1). We used O-benzoyl-N,N-
dibutylhydroxylamine 6b to repeat the reaction, N,N-
dibutylbenzamide 11d was also detected from the reaction
(Scheme 2, eq 2). When the reaction was carried out with two
equivalents of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), it
could proceed smoothly and the reaction may not undergo a
radical mechanism (Scheme 2, eq 3). When 2.0mL THF and
1.0mL H218O used as the solvent to repeat the reaction, no
product was detected, and the Oxygen of the products did not
come from the H2O in THF (Scheme 2, eq 4).
15c
16c
8b
1b
a
Reaction conditions: copper(II) trifluoromethanesulfonate
(0.05 mmol, 0.018g, 10 mol%), terminal alkyne (2.0 mmol,
4.0 equiv.) and O-benzoyl hydroxylamine (0.5 mmol, 1.0
a
b
equiv.), DBU (1.0 mmol, 0.152g, 2.0 equiv.), THF (3.0 mL), N2,
RT, 12 h.
b Isolated yield based on
b.
With the optimized reaction conditions in hand, we
evaluated the scope of the copper-catalyzed oxidative
amidation for the synthesis of α-ketoamides. As shown in
Table 2, the reaction yields were slightly influenced by the
electronic effect of substituents of terminal alkynes. Terminal
alkynes with electron-donating methyl, tertiary butyl and
pentyl groups (Table 2, entries 2-4) and electron-withdrawing
fluoro and chloro groups (Table 2, entries 5-6) generated the
desired products in moderate to good yields. Various O-
benzoyl hydroxylamines with acyclic and cyclic N-alkyl
substituents were explored by reacting with phenylacetylene
In summary, we have developed a novel and convenient
copper-catalyzed oxidative amidation of terminal alkynes for
synthesis of α-ketoamides. This protocol displays attractive
features including using easily available O-benzoyl
hydroxylamines (BzO-NR1R2) as aminating reagent and oxidant,
and conducting the reaction at room temperature. The
reaction also exhibits some functional group tolerance and
allows for the preparation of a number of α-ketoamides in
moderate to good yields. The importance of the α-ketoamides
scaffold would render this protocol attractive for both
synthetic and medicinal chemistry.
(
1a) under the optimum reaction conditions (Table 2, entries
7-12). The five-membered cyclic amines 2b bearing
a
pyrrolidine moiety, the six-membered cyclic amines 1b and 3b
bearing a piperidine and morpholine moiety, and the seven-
membered cyclic amines 4b bearing a azepane moiety are
compatible to the reaction conditions (Table 2, entries 7-9). O-
benzoyl hydroxylamines which were derived from N,N-diethyl
5b, N,N-di-n- butyl 6b, and N-n-butyl-N-ethyl 7b amines were
smoothly converted to α-ketoamides 10c−14c in 60-76 %
yields (Table 2, entries 10-14). An O-benzoyl-N-
phenylhydroxylamine 8b, which is prepared from primary
phenylamine, could not be utilized in this protocol to furnish
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (No. 21402079) and the Shandong
Provincial Natural Science Foundation of China (ZR2015PB004).
Notes and references
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Room temperature copper-catalyzed oxidative amidation of
terminal alkynes for synthesis of α-ketoamides using O-benzoyl
hydroxylamines as aminating reagent and oxidant
Guodong Shen,* Lingyu zhao, Yichen Wang, Tongxin Zhang*
School of Chemistry and Chemical Engineering, School of Pharmacy, Liaocheng
University, Liaocheng 252000, Shandong, PR China
Tel & Fax: (+86)-635-8239680; e-mail: shenguodong33@163.com
TOC Graphic
Abstract
A novel and convenient copper-catalyzed oxidative amidation for synthesis of
α-ketoamides has been successfully developed, which uses easily available O-benzoyl
hydroxylamines as aminating reagent and oxidant. The reaction proceeds smoothly at
room temperature and is compatible with a range of substrates to give the desired
products in moderate to good yields.