Copper-TEMPO-catalyzed synthesis of α-ketoamides: Via tandem sp3C-H aerobic oxidation and amination of phenethyl alcohol derivatives

Article abstract of DOI:10.1039/c6ob01387b

An efficient copper-TEMPO-catalyzed one-pot synthesis of α-ketoamides from phenethyl alcohol derivatives was developed firstly. Moreover, molecular oxygen in open air was employed as the oxidant with a broad substrate scope, which makes this methodology more practical. Based on some control experiments, a plausible mechanism was proposed.

Full text of DOI:10.1039/c6ob01387b

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Copper-TEMPO-catalyzed synthesis of ɑ-ketoamides via
tandem sp3C-H aerobic oxidation and amination of
phenethyl alcohol derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Chengkou Liu,a Zhao Yang,b Shiyu Guo,a Yu Zeng,a Ning Zhu,a Xin Li,a Zheng Fanga,* and Kai Guoa, c,
*
DOI: 10.1039/x0xx00000x
An efficient copper-TEMPO-catalyzed one-pot synthesis of ɑ-ketoamides from phenethyl alcohol derivatives was
developed firstly. Moreover, molecular oxygen in the open air was employed as the oxidant with a broad substrate scope,
which makes this methodology more practical. Based on some control experiments, a plausible mechanism was proposed.
www.rsc.org/
Previous work
Ar
Introduction
O
O
Jiao's work
OH
Ar
Ar
ɑ-keto amide moiety is a prevalent structural unit in drug
O
R1
N
O
candidates and variety of biologically active natural
a
Ar
R2
Ar
Ar
Ar
products1 Moreover, they can serve as useful precursors for
further transformations, especially the synthesis of
heterocycles.2 Accordingly, developing practical and economic
O
O
O
Ar
OH
methodologies to synthetize
ɑ-ketoamides remains a hot
Ar
research topic and immense work has been done. A series of
traditional methods3 have been built as shown in scheme 1.
However, their application was limited by the use of hazardous
reagents, harsh reaction conditions or multi-step processes.
So, developing more practical and economic methodology
attracted considerable interest.
This work
Ar
O
R1
N
R1
N
R2
OH
CuBr-TEMPO
H
Ar
R2
O
Figure 1 one-pot preparation of ɑ- ketoamides from a series of starting materials
Over the past decade, direct functionalization of C−H bond has
become a field of intense interest.4 It offers substantial
benefits because it is atom-economy. However, it is also a
fundamental challenge in organic chemistry. With the
development of C-H activation, C−C and C−heteroatom bonds
were built successfully via tandem C-H/heteroatom-H
cleavages. In parallel, ɑ-ketoamides were generated effectively
via oxidative cross-dehydrogenative couplings between C−H
center and N-H center as shown in figure 1.5
Scheme1 Traditional methods for the synthesis of ɑ-ketoamides
eq1: the amidation of α-ketoacids
or α-keto acyl halides
O
O
OH
X
or
R
R
eq 2: the amidation of
the resulting α,β-diketone nitrile
O
O
eq 3: the oxidation of α-hydroxyamides
or α-aminoamides
O
O
R1
N
R1
N
O
R1
OH
O
O
CN
PPh3
CN
Firstly, Jiao reported a one-pot preparation of ɑ-ketoamides
from aryl acetaldehydes5a involving two Csp3-H, one Csp2-H, and
one N-H bond cleavages. About the same time, aryl methyl
ketones were proved to be the effective starting material
under the similar reaction system by Ji.5b Immediately, many
synthetic methods were built to prepare the ɑ-ketoamides
from different starting materials, such as acetophenone,
ethylbenzene, styrene, phenylacetylene, 1-arylethanol,
phenylglyoxal and 2-hydroxy-1-phenyl-ethanon. Among these
starting materials, acetophenone and phenylglyoxal have been
widely used. As for phenylglyoxal, one Csp2-H and one N-H
bond cleavages were involved, which was relatively easy
compared with Csp3-H cleavage. Similarly, the sequential C-O
and C-N bond formation to synthesis ɑ-ketoamides from
styrene or phenylacetylene was based on tandem Csp2-H or Csp-
H/ N-H bond cleavages. Although, Csp3-H cleavage was involved
N
R
R
or
R
R2
R2
R
R2
R
O
O
O
CN
R
X
eq 4: the double carbonylative
amidation of aryl halides
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when acetophenone was used, activated methyl compounds Delightedly, a good yield (88%) was produced when CuBr
(carbonyl compounds) were necessary. Herein, a copper- was involved (Table 1, entry 4). However, only a trace
catalyzed one-pot aerobic oxidative coupling of phenethyl amount of or almost no product was detected when other
alcohol derivatives with amines via four Csp3-H and one N-H metal complexes were used (Table 1, entries 1,2,5,6).
bond cleavages was presented. As far as we know, there has Interestingly, the reaction gave a satisfactory yield (76%)
been no report on the synthesis of ɑ-ketoamides from aryl when CuBr and CuI were added together (Table 1, entry 3).
ethanols. β-phenylethylalcohol can be obtained by Friedel- This was likely because that CuBr and CuI promoted part of
Crafts reaction between benzene and ethylene oxide easily.6 the process separately. An obvious decrease of yield (52%)
Thus, the preparation of ɑ-ketoamides from phenethyl alcohol was observed in the absence of TEMPO (Table 1, entry 7). It
derivatives was meaningful.
was likely indispensable in the oxidation of alcohol. Then,
the reaction was performed under N2. As expected, the
reaction failed to produce desire product, which revealed
that O2 was the terminal oxidation (Table 1, entry 8). Only a
little desired product (5 %) was observed in the absence of
base, which indicated that it can promote this process
smoothly. The addition of pyridine, K2CO3, trimethylamine
or N,N-diisopropylethylamine could improve this
transformation obviously (Table 1, entries 4, 9-13).
Relatively, pyridine and K2CO3 were the better choice than
trimethylamine and N,N-diisopropylethylamine. However,
an obvious lower yield (34%) was obtained when Cs2CO3
was involved. The K2CO3 was chosen finally because of its
low toxicity. Afterwards, the solvents were examined.
Toluene was found to be the best choice among toluene,
dimethyl sulfoxide, N,N-dimethylformamide and 1,4-
dioxane (Table 1, entries 4, 14-16). DMSO showed a similar
reactivity as toluene. Considering the toxicity, DMSO was
chosen for the following research. The screening of
Results and discussion
Recently, two metal-free oxidation systems were reported on
the direct preparation ɑ-ketoamides from aryl methyl ketones
and 1-arylethanols by our group.5o, 5p During the works above,
some transition metals were involved and various substrates
were tested to extend starting materials. A new finding was
found that CuBr/TEMPO-promoted direct oxidation coupling of
phenethyl alcohol derivatives with many aliphatic amines and
aromatic amines.
The direct coupling between phenethyl alcohol and 1-oxa-4-
azacyclohexane was chosen as the model reaction shown in
table 1. Initially, various transition metal complexes,
especially the copper salts, were studied in the presence of
20 mmol% TEMPO and 2.0 equiv. of pyridine in toluene at
90℃ under an oxygen atmosphere (Table 1, entries 1-6).
Table 1 optimization of the reaction conditiona
temperature indicated that 70
℃ should be the proper
choice (Table 1, entries 4, 17-19). An obvious lower yield
was obtained when the temperature was decreased further.
To our delight, the decrease of the yield could be ignored
when the reaction was performed under air instead of O2
(Table 1, entry 20). Furthermore, the equiv. of TEMPO, CuBr,
K2CO3 and amine were screened shown in Table S2, S3, S4
and S5. Loading fewer TEMPO, CuBr or K2CO3 resulted in a
negligible decrease of the yield when the reaction time was
prolonged. And, 1.5 equivalent of amines were proved to be
effective (SI, Table S5). After screening of the reaction
parameters above, the optimized reaction conditions were
obtained: 1a (1 mmol), 2a (1.5 mmol), CuBr (8 mmol%),
Entry
1
Catalyst
CuBr2
CuI
Additive
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
T(℃) Yield (%)b
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
80
70
60
70
8
trace
76
88
NO
NO
52
NO
4
2
3
CuBr2/CuI
CuBr
CuO
4
5
6
NiBr2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
7c
8d
TEMPO (15 mmol%)
，K2CO3 (1 mmol) in DMSO (3 mL) at
9
70 under air for 12h.
℃
10
11
12
13
14
15
16
17
18
19
20e
TEA
70
73
86
34
85
72
62
85
86
72
84
Following the optimized conditions, the investigation into
scope of various substituents was carried out shown in
scheme 2, 3. Firstly, a range of phenethyl alcohol derivatives
were tested with 1-oxa-4-azacyclohexane (Scheme 2). To
our delight, a moderate to good yield (72%-84%, Scheme 2,
3a-3d, 3f-3h, 3l) was obtained when phenethyl alcohol with
substitution at the phenyl ring of electron donating as well
as electron withdrawing groups such as methyl, fluorine,
chlorine, bromine was involved. Furthermore, no obvious
effect on the reaction efficiency was observed by the
DIPEA
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
Dioxane
DMSO
DMSO
DMSO
DMSO
aReaction condition: 1a (1 mmol), 2a (3 mmol), catalyst (0.1 mmol), additive (2
mmol), TEMPO (0.2 mmol) and solvent (3 mL) were heated under O2 (O2 balloon)
for 12h. bYields of the isolated product. cIn the absence of TEMPO. dUnder N2.
eUnder air.
substituents as different positions (p-, m- and o- positions,
Scheme 2, 3b-3d, 3i-3k). Delightedly, both benzene fused
ring and aryl heterocyclic substituents could be
transformed into the desired products with acceptable
2 | J. Name., 2012, 00, 1-3
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Then, a range of amines were examined. To our delight, both
aliphatic amines and substituted anilines could be transformed
into the corresponding products (Scheme 3, 3a, 3p-3ae). As for
the aliphatic amines, good yield was obtained when secondary
was involved (Scheme 3, 3a, 3p-3s). Unfortunately, primary
amines reacted with 1a to produce an obvious lower yield
(Scheme 3, 3t, 3u). Interestingly, cyclic secondary amines gave
a better yield than acyclic secondary amine (Scheme 3, 3a, 3p-
3s). The substituted anilines with a range of functional groups
were examined. The oxidative coupling of phenethyl alcohol
and anilines with electron-withdrawing groups proceeded
smoothly to afford the desired products with moderate to
good yields (Scheme 3, 3v-3ae). Moreover, the effect of
substituents at different positions could be ignored (Scheme 3,
3v-3x). Notably, this methodology has a broad functional
group tolerance, including cyano, fluorine, chlorine, bromine,
ester, amide, nitro and methyl. So, it provides a potential
method to prepare pharmaceuticals and natural products. It is
noteworthy that an obvious lower yield was obtained when
anilines bearing electron-donating substituents were involved
(scheme 3, 3ag). Two possibly reasons are supplied. On the
one hand, electron-rich amines could be smoothly
transformed into the azo compounds,7 which were confirmed
by NMR. On the other hand, the instability of Schiff bases
(intermediate) bearing electron-rich amines resulted in the
decrease of the yield. In general, electron-poor amines could
be converted into the corresponding products with good yields.
However, 2,4-dinitroaniline was failed to give the desired
product. It is likely that the weak nucleophiles and instability of
the amine radical cation resulted in the few conversion.
yields (Scheme 2, 3m-3o). However, phenethyl alcohol with
strong electron withdrawing group such as nitro-group was
failed to give full conversion and a lower yield (36%-42%,
Scheme 2, 3i-3k) was observed. The unstable of the radical
intermediate discussed in the mechanism may be the main
reason. Unfortunately, only a trace amount of desired
product was detected when 4-methoxyphenethyl alcohol
was involved. The methoxy group was likely to be unstable
under the optimized conditions. The desired product was
not obtained when hexyl alcohol, trans-2-hexen-1-ol or 2-
hexyn-1-ol was employed (Scheme 2, 3ah). Actually, the
oxidation of aliphatic alcohols was successful under the
optimized conditions. The failure of the oxidation of the α-
position of alcohol might be the main nodus.
Scheme 2 Scope of phenethyl alcohol derivativesa
Scheme 4 the synthesis of cytokine inhibitor Pa
aReaction condition: 1 (1 mmol), 2a (1.5 mmol), CuBr (0.08 mmol), TEMPO (0.15
mmol), K2CO3 (1 mmol) and DMSO (3 mL) were heated under air for 12h. Yields
given were isolated products.
Scheme 3 Scope of aminea
aReaction condition: 2-naphthaleneethanol (1 mmol), 2-amino-6-
chlorobenzotrifluoride (1.5 mmol), CuBr (0.08 mmol), TEMPO (0.15 mmol),
pyridine (2 mmol) and toluene (3 mL) were heated under air for 12h. Yields
given were isolated products.
Now, a variety of simple structures of
preparation. Many bioactive natural products contain
structural of -keto amine discussed before. P, a cytokine
ɑ-keto amine were
ɑ
inhibitor8 was produced in 55% isolated yield from readily
available starting materials of 2-naphthaleneethanol and 2-
amino-6-chlorobenzotrifluoride shown in scheme 4. It
indicated that present method provides another choice of
starting materials to prepare ɑ-ketoamide.
Compared with the two oxidation systems5o,
5p
discussed
before, phenethyl alcohol derivatives, the simpler and readily
available substrates, were employed firstly instead of
acetophenone or 1-arylethanol. And, two-step processes were
necessary when 1-arylethanol was employed.5j, 5p Moreover,
this reaction is applicable to a wider variety of amine, such as
aliphatic amines and substituted anilines. It is noteworthy that
O2 in the open air is employed as the oxidant instead of I2 or
H2O2.
aReaction condition:
aliphatic amines used as the substrates: 1a (1 mmol), 2 (1.5 mmol), CuBr (0.08
mmol), TEMPO (0.15 mmol), K2CO3 (1 mmol) and DMSO (3 mL) were heated
under air for 12h.
substituted anilines used as the substrates: 1a (1 mmol), 2 (1.5 mmol), CuBr
(0.08 mmol), TEMPO (0.15 mmol), pyridine (2 mmol) and toluene (3 mL) were
heated under air for 12h.
Yields given were isolated products.
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phenomenon was observed. On the one hand, the
Journal Name
A
substituted anilines were found to be failed to afford the
desired products under the optimized condition of
CuBr/DMSO/K2CO3/TEMPO/O2 throughout the preparation of
various
ɑ-ketoamides. Comparatively, good yields could be
obtained under CuBr/ toluene/ pyridine /TEMPO/O2.
Moreover, phenylacetaldehyde was obtained and detected
under CuBr/ toluene/ pyridine /TEMPO/O2, which indicated
that the reaction process was similar to Jiao’s report5a (aryl
acetaldehydes was used as the starting material, Angew. Chem.
Int. Ed. 2011, 50, 11088
was shown in SI. On the other hand, aliphatic amines could be
transformed into the corresponding -ketoamides with good
–11092). The detailed mechanism
ɑ
yields under CuBr/DMSO/K2CO3/TEMPO/O2. Furthermore,
phenylacetaldehyde was not detected obviously. Besides, low
yields were obtained when DMSO was used as the solvent or
K2CO3 was used as the base under Jiao’s reaction condition. On
the basis of the results above, we believed that another
reaction process different from Jiao’s report was existent
under CuBr/DMSO/K2CO3/TEMPO/O2. In order to catch some
clues of this process, a series of control experiments were
performed shown in figure 2. Excellent yield was obtained
when 2-hydroxyacetophenone or phenylglyoxal was involved,
Figure 3 proposed mechanism
Based on the results above, a plausible mechanism was
provided. Initially, particularly active intermediate was
H
generated through step a and step b. Step a and step b were
the oxidation of alcohol and the oxidation of benzyl,
respectively. The plausible mechanism of step a and b was
shown in figure 3. Which occurred first between step a and
step b is not certain. It is likely that the two processes occurred
almost at the same time.
which
indicated
that
2-hydroxyacetophenone
and
phenylglyoxal might be the intermediate in the process (Figure
2, eq 1 and 2). Interestingly, ethylenzene could be smoothly
transformed into the product in the moderate yield (Figure 2,
eq 3). In addition, acetophenone was detected among this
process. These results revealed that the oxidation of benzyl
was likely to be existent. Furthermore, good yield was
obtained in the absence of TEMPO (Figure 2, eq 4). However,
only trace amount of product was detected when O2 or CuBr
was removed (Figure 2, eq 5 and 6). It indicated that O2 and
CuBr were necessary in the oxidation of benzyl. Then an
isotope labeling experiment was performed (16O2, anhydrous
DMSO, H2O18 (2 equiv.)). An obvious 16O/18O-labeled product
(53%) was detected (HRMS spectrum, Figure 2, eq 7), which
Ⅰ
Ⅱ
As for the oxidation of alcohol, LCu was oxidized to LCu salt
firstly. And, copper ( ) alkoxide complex was produced in
the presence of base, which contributed to the deprotonation
of alcohols. Connecting of to TEMPO produced an six-
membered radical intermediate by Cu-N coordination bond
and O-H hydrogen bond, followed by an abstraction of
hydrogen with TEMPO to give radical intermediate . at the
same time, the hydroxylamine was produced, which could
Ⅱ
A
A
B
C
D
be oxidized to TEMPO to catalyst this process. Finally, the
intramolecular electron transfer (O to Cu) and O-Cu bond
Ⅰ
Ⅰ
cleavage led to the carbonyl compounds and Cu . Thus, Cu
was continuously regenerated to promote this reaction. As for
the oxidation of benzyl, radical intermediate was performed
indicated intermediate
H and the transformation between H
E
and L might be existent (Figure 3).
Ⅱ
in the presence of more-active Cu salt, which was obtained
Ⅰ
from the oxidation of Cu by O2. Subsequently, a four-
membered intermediate
product was produced from as intramolecular ring opening.
Afterwards, two processes existed probably as shown in path
and . On the one hand, amines reacted with quickly to form
imine I in path 1.5i, 9 So it is too hard to detect
. Two possible
F was formed. Then, the oxidation
G
1
2
H
H
paths were supplied for the following steps. In path
ɑ,
superoxide radical (O2•
¯
) was generated in the presence of O2
to give intermediate . The
intramolecular ring opened to give the desired product. In
path , nucleophilic attack of DMSO on gave intermediate K.
Ⅰ
and Cu , which reacted with
I
J
β
I
The corresponding product was produced through elimination
of DMS and H2O. On the other hand, hemiaminal intermediate
M
could be obtained from the addition of amine to aryl glyoxal
5b, 5j
in path
2.
The desired product was got from the oxidation
of M by O2 catalysed by copper salt.
Figure 2 control experiments
4 | J. Name., 2012, 00, 1-3
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McArdle and D. Cunningham, Org. Biomol. Chem., 2003, 1,
Conclusions
1122; (f) R. Wang, C. Chen, E. Duesler, P. S. Mariano and U. C.
Yoon, J. Org. Chem., 2004, 69, 1215; (g) A. Bacchi, M. Costa,
N. Della Ca, B. Gabriele, G. Salerno and S. Cassoni, J. Org.
Chem., 2005, 70, 4971.
In conclusion, a convenient and efficient copper-catalyzed
methodology for the one-pot preparation of
ɑ-ketoamide
was demonstrated. It is noteworthy that phenethyl alcohol
derivatives, the simple and readily substrates, were used as
the starting materials firstly. Four Csp3-H and one N-H bond
cleavages were involved. Moreover, O2 in the open air was
employed as the oxygen source. On the one hand, both
phenethyl alcohol derivatives containing electron-
withdrawing and electron-donating substituents and aryl
heterocyclic substituents could be transformed into the
desired products. On the other hand, both aliphatic amines
and substituted anilines could be transformed into the
3
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corresponding
broad substrate scope and holds great potential in
constructing -keto amide moiety. Furthermore, some
ɑ-ketoamides. So, this methodology has a
ɑ
control experiments were performed. And, a plausible
mechanism was proposed.
Acknowledgements
4
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The research has been supported by National Key Basic
Research Program of China (973 Program) 2012CB721104 and
2012CB725204; the National Natural Science Foundation of
China (Grant No.U1463201 and 21402240); Jiangsu Province
Natural Science Fund (Grant No.BK20150031 and
BK20130913).
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