Copper-catalyzed coupling of anthranils and α-keto acids: Direct synthesis of α-ketoamides

Article abstract of DOI:10.1039/c9ob00822e

Copper-catalyzed coupling of α-keto acids with anthranils is reported for the synthesis of α-ketoamides. This process involves N-O/C-O bond cleavages and C-N bond formation. Furthermore, the decarboxylation of α-keto acids can be successfully suppressed under redox-neutral conditions.

Full text of DOI:10.1039/c9ob00822e

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Copper-Catalyzed Coupling of Anthranils and α-Keto Acids: Direct
Synthesis of α-Ketoamides
Received 00th January 20xx,
Accepted 00th January 20xx
Ping-Gui Li,a,b† Hao Zhu,a† Min Fan,a Cheng Yan,a Kai Shi,a Xi-Wen Chia and Liang-Hua Zou*a
DOI: 10.1039/x0xx00000x
with isonitrile.7 To date, considerable efforts have been made
A copper-catalyzed coupling of α-keto acids with anthranils is
reported for the synthesis of α-ketoamides. This process involves
to synthesize such compounds for the discovery of biological
N–O/C–O bond cleavages and C–N bond formation. Furthermore, scaffolds or anti-cancer medicines.8 Among these methods,
amidation of α-keto acids and α-keto acyl halides,9 oxidation of
the decarboxylation of α-keto acids can be successfully suppressed
under the redox-neutral conditions.
α-hydroxyamides and α-aminoamides,10 transition-metal
catalyzed double carbonylative amination of aryl halides,11
α-Ketoamides represent a class of important building blocks
oxidative coupling,12 and other methods13 have been widely
due to the fact that they provide the gateway to access a
used. Despite the numerous efforts toward the synthesis of α-
variety of other scaffolds through functional group
transformations,1 as well as their relevance in biological and
ketoamides, these methods are limited to simple amidations.
pharmacological activities (Figure 1).2 For example,
Ideally, the introduction of multiple functional groups (FGs)
Chloropeptin I can inhibit HIV replication, and thereby
considerable efforts have been made in the studies on the
total synthesis, modification, and activity of this compound.3
Bestatin analogue bearing the α-keto skeletons were proved to
be inhibitors of the serine proteinase elastase.[2a] Furthermore,
the α-ketoamide moiety widely exists in fungicide and
fungicide precursors,4 antibiotics,5 and various inhibitors.6
simultaneously allows the molecular synthetic versatility and
structure diversity. However, it still remains a formidable
challenge, possibly due to the limited FG compatibility and
possible product inhibition.
Recently, several research groups have introduced
anthranils as nitrogen nucleophiles for the amination of
various carbon sources (Scheme 1, a-c).14 Besides, Wu and co-
workers also reported Pd/C-catalyzed aminocarbonylation of
aryl iodides with anthranils using Mo(CO)6 as the CO source
(Scheme 1, d).15 It is noteworthy that such aminations can
deliver a nucleophilic amino group tethered to an electrophilic
formyl group, which is normally hard to introduce, and
compatibility issues may also exist in many coupling systems
regarding to the formyl group.16 Significantly, the resulting
skeleton with an amino and a carbonyl group represents a
class of useful synthetic building blocks.17
α-Keto acids and their derivatives are usually considered as
ideal substrates since they are less toxic, structurally diverse
and can be easily obtained from both natural and synthetic
source. However, normally α-keto acids underwent
decarboxylation under transition-metal catalyzed conditions in
most cases due to the fact that the C–C bond between the
ketone carbon atom and carboxyl carbon atom was weak,
which was resulted from the relatively strong electronegativity
of oxygen atom.18 Herein, we report a copper-catalyzed
protocol for the synthesis of novel α-ketoamides bearing an
aldehyde group under redox-neutral conditions, in which the
Figure 1. Biologically active molecules with α-ketoamide moiety.
The early method for the synthesis of N-monosubstituted α-
ketoamides could date back to half century ago when Ugi and
co-workers developed the coupling reaction of acyl chloride
a.The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of
Education, School of Pharmaceutical Sciences, Jiangnan University, Lihu Avenue
1800, Wuxi 214122, P.R. China
b.State Key Laboratory of Coordination Chemistry, School of Chemistry and
Chemical Engineering, Nanjing University, Xianlin Avenue 163, Nanjing 210093,
China
† PGL and HZ contributed equally to this work.
Electronic Supplementary Information (ESI) available. CCDC 1879290. For ESI and
crystallographic data in CIF, see DOI: 10.1039/x0xx00000x
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cleavage of C–O bond is favored but the normal C–C bond improve the reaction (Table 1, entries 25 and 26). At last, the
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cleavage is remarkably suppressed.19
yield dropped to 25% when the reactionDwOaI:s10p.e10r3fo9/rCm9eOdB0u0n8d22eEr
dioxygen atmosphere (Table 1, entry 27).
Table 1. Optimization of reaction conditions for the synthesis of 3a
.
Yieldb
(3a, %)
59
57
59
Entry
Catalyst
Ligand
Solvent
1
2
3
4
5
6
7
8
Cu(OAc)2
CuCl
A
A
A
A
A
A
A
A
A
-
B
C
D
E
F
A
-
A
A
A
A
A
A
A
A
A
A
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CuBr
.
CuCl2 2H2O
30
58
22
53
Cu2O
Cu(OTf)2
CuI
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
-
65,66c,70d
80e
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
25d
52e
66e
0e
Scheme 1. Intermolecular C–N bond formaion using anthranils as
masked nitrogen nucleophiles.
23e
40e
Tracee
0
The initial screening and optimization of the reaction
conditions was conducted with anthranil 1a and α-keto acid 2a
as substrates and all the results are summarized in Table 1.
Using 1a and 2a at a 1:2 ratio (on a 0.3 mmol scale), with
Cu(OAc)2 (0.15 equiv) as catalyst, PPh3 (0.1 equiv) as ligand,
and DCE as solvent, product 3a was obtained in 59% yield at
110 oC (Table 1, entry 1). To our delight, the decarboxylation of
α-keto acid 2a was to a great extent suppressed and only small
amounts of byproduct 3a’ (5% yield) were obtained. Then
various copper salts were screened and CuBr2 was proved to
be the best catalyst for the reaction with 65% yield of product
3a (Table 1, entries 2-8). Decreasing the loading of catalyst led
-
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
DMSO
DMF
HFIP
0e
0e
0e
toluene
chlorobenzene
dioxane
MeCN
DCE
64e
57e
61e
50e
67e,f,65e,g
60e,h,29e,i
25e,j
DCE
DCE
to a higher yield when 0.05 equiv of CuBr2 was used in the aReaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), catalyst
(0.15 equiv), ligand (0.1 equiv), solvent (3 mL), 110 oC, Ar atmosphere,
reaction (Table 1, entriy 8). The yield was increased to 80%
b
c
d
12 h. After column chromatograph. With 0.1 equiv of catalyst. With
when the combination use of 0.2 equiv of PPh3 and 0.05 equiv
of CuBr2 (Table 1, entry 9). The yield dropped to 25% in the
absence of ligand (Table 1, entry 10). Subsequently, several
ligands were tested in the reaction. Other phosphorus-
e
0.05 equiv of catalyst. Combination use of 0.05 equiv of catalyst and
0.2 equiv of ligand. f24 h. g4 h. h130 oC. i90 oC. jUnder dioxygen
atmosphere.
containing ligands
albeit lower yields were obtained (Table 1, entries 11 and 12).
The use of nitrogen-containing ligands and decreased
B and C were also effective for this reaction,
With the optimized reaction conditions in hand (Table 1,
entry 9), the scope of the reaction of α-keto acid 2a with a
D
,
E
F
variety of anthranils
1 was investigated and the results are
the yields remarkably (Table 1, entries 13-15). It is noteworthy
that only trace amounts of product 3a was obtained in the
absence of catalyst and no product was formed when neither
catalyst nor ligand was used in the reaction (Table 1, entries 16
and 17). Besides, various solvents were screened in the
reaction, among which DMSO, DMF and HFIP were ineffective
for the reaction and toluene, chlorobenzene, dioxane and
MeCN gave lower yields (Table 1, entries 18-24). Further
optimization on reaction time and temperature did not
summarized in scheme 2. Many substrates with various
electron-donating or electron-withdrawing substituents were
applied to the reaction system to synthesize a series of N-(α-
ketoacyl)anthranilic aldehydes. The reaction of substrate with
the methoxy group afforded product 3b in 72% yields. Another
electron-donating
substrate
[1,3]dioxolo[4,5-f]-2,1-
benzisoxazole was also employed in the reaction, providing the
2 | J. Name., 2012, 00, 1-3
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desired product 3c in an acceptable yield. Besides, for
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In order to further explore the scope of the reaction, a
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DOI: 10.1039/C9OB00822E
2 bearing various substituents were
substrates with fluoro- and chloro- groups at the para- or series of α-keto acids
meta-position, the reaction proceeded well to give the investigated and the results are summarized in Scheme 3. The
corresponding products 3d in yields varying from 65% to 75%. reactions of the substrates bearing methyl and methoxy
-
g
With substrate bearing bromo- group at meta-position, groups with anthranil 1a exhibited good efficiency, providing
product 3h was obtained in 80% yield. For the substrate with products 3k and 3l in 83% and 80% yields, respectively. 2-
strong electron-withdrawing group -CF3, the reaction was also Naphthylglyoxylic acid and 1-naphthylglyoxylic acid were both
proved to be effective, affording product 3i in 61% yield. tested in the reaction, providing the corresponding products
Importantly, for the substrate with a phenyl group at anthranil, 3m and 3n in 81% and 73% yields, respectively. For the
a relatively low yield was obtained under the optimized substrates with electron-withdrawing groups, such as fluoro-,
conditions, albeit the yield of 3j was enhanced to 88% when chloro- and bromo-substituents, all the reactions proceeded
the reaction time was prolonged to 24 h.
very well with good yields. Furthermore, substrates containing
thienyl and furan groups were also tried in the reaction,
affording products 3u and 3v in 70% and 20% yields,
respectively. Interestingly, the reaction of the substrate
containing a pyridine group could only afford a decarboxylated
product 3w’ in 23% yield. Meanwhile, only trace amounts of
product 3x was observed when the reaction was performed
using a substrate containing two methoxy groups. As regarding
to the substrates bearing strong electron-withdrawing
substituents, such as –NO2 and –CN, the reaction didn’t work
under the optimized reaction conditions.
In order to elucidate the mechanism, several control
experiments using radical scavengers such as 2,6-bis(1,1-
dimethylethyl)-4-methyl-phenol
(BHT)
and
2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) were conducted
(Scheme 4, eq a and b). The former decreased the yield
significantly to 33%, and to our surprise, a byproduct
obtained in 14% yield through alkylation of α-keto acid 2a with
DCE. In addition, compounds and were detected by GC-MS
analysis. The latter did not give product 3a and the yield of
byproduct was increased to 40%. Subsequently, bases, such
as Cs2CO3 and NEt3, were added to the reaction and only
product was obtained in the both cases (Scheme 4, eq c). The
4 was
5
6
Scheme 2. aReaction conditions:
(0.05 equiv), PPh3 (0.2 equiv), DCE (3 mL), 110 C, Ar atmosphere, 12 h.
b24 h.
1 (0.3 mmol), 2a (0.6 mmol), CuBr2
o
4
4
base abstracted hydrogen from 2a to generate the α-
oxocarboxylate anion, which reacted with DCE to form the
ester
was an intermediate in the process, a control reaction using
α-keto acid 2a and compound was performed under the
4. In order to investigate whether 2-aminobenzaldehyde
7
7
optimized reaction conditions (Scheme 4, eq d). However,
product 3a was not obtained, demonstrating that the reaction
did not proceed via the intermediate 7. Finally, benzoic acid 8
was tested under the procedure and product 3a’ was not
formed, showing that this procedure was specifically effective
to α-keto acids but not for simple benzoic acids (Scheme 4, eq
e). Considering the possibility that CuBr(PPh3)3 might be
formed in situ and served as a catalyst in the reaction, a
control reaction was performed using CuBr(PPh3)3 instead of
the combination use of CuBr2 and PPh3 (Scheme 4, eq f).
Indeed, using the copper complex as the catalyst, product 3a
was obtained in a comparable yield of 82%. To demonstrate
the practical utility of this novel method, compound 3a was
Scheme 3. aReaction conditions: 1a (0.3 mmol),
2 (0.6 mmol), CuBr2
used for the synthesis of heterocycle
9
(Scheme 5).20 To our
(0.05 equiv), PPh3 (0.2 equiv), DCE (3 mL), 110 oC, Ar atmosphere, 12 h.
delight, compound
9
was obtained in 60% yield without
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further optimization.21
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DOI: 10.1039/C9OB00822E
Scheme 4. Control reactions.
Scheme 6. Proposed reaction pathway.
Conclusions
In summary, we have developed an efficient protocol for the
direct construction of a class of novel α-ketoamides bearing an
aldehyde group under the redox-neutral conditions. Taking
into account that compounds bearing an aldehyde group are
normally sensitive and difficult to prepare and save, this
protocol has significantly demonstrated valuable utility and
potentiality in academic and in industry by using anthranils as
a nitrogen source for the synthesis of α-ketoamides. In the
process, the unexpected C–O bond cleavage happened instead
of the normal decarboxylation of α-keto acids via the cleavage
of C–C bond, which was rarely reported before. Furthermore,
this process avoided the need for any external oxidant, base
and radical initiator and thereby featured being more atom-
efficient with the use of low loading of a copper catalyst and a
cheap ligand.
Scheme 5. The application of 3a for the synthesis of heterocycle 9.
Based on these results in hand and previous reports,22
a
plausible reaction mechanism is proposed as outlined in
Scheme 6. Firstly, Cu(I) species CuBr(PPh3)3 is formed in situ
starting from copper(II) bromide and triphenylphosphine.23
Secondly, Cu(I) species are inserted into compound 1a,
affording intermediate I, which provides intermediate II
through the coordination with compound 2a. Intermediate III
is then produced in the process through reductive elimination.
Subsequently, product 3a is obtained through the oxidation of
intermediate III with the aid of Cu(II) species.12e It is
noteworthy that radicals 10 and 11 may be formed from
intermediate II, which has been detected by GC-MS (Scheme 4,
a). Furthermore, byproduct 3a', which is determined by crude
NMR and GC-MS analysis, is formed through the coupling of
radicals 10 and 11. Apparently, the formation of these radicals
is disfavored under the reaction conditions so that only small
amounts of 3a' is produced, which is consistent with the
results of control reactions. The addition of radical scavengers
might promote the production of radicals, in which BHT
significantly decreased the yield and TEMPO completely
inhibited the expected formation of product 3a (Scheme 4, a
and b).
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was financially supported by NSF of Jiangsu Province
(BK20150129), and the Top-notch Academic Programs Project
of Jiangsu Higher Education Institutions (No. PPZY2015B146).
Notes and references
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Organic & Biomolecular Chemistry
Page 6 of 6
View Article Online
DOI: 10.1039/C9OB00822E
A copper-catalyzed coupling of α-keto acids with anthranils is reported for the synthesis of α-ketoamides
bearing an aldehyde group via N–O/C–O bond cleavages and C–N bond formation.
O
O
O
CuBr2 (5 mol%)
PPh3 (20 mol%)
H
N
OH
N
+
O
R
Ar/ArHet
Ar/ArHet
DCE, 110 o
C
R
O
O
22 examples, up to 88% yield
Ar = Phenyl groups
ArHet = Thienyl and furan groups
Radical initiator-free
Base-free
Bearing an aldehyde group
No decarboxylation
Atom-economic process