I2-DMSO mediated oxidative amidation of methyl ketones with anthranils for the synthesis of: α -ketoamides

Article abstract of DOI:10.1039/d1ob00468a

An I2-DMSO mediated oxidative amidation of methyl ketones using anthranils as masked N-nucleophiles has been developed for the direct synthesis of α-ketoamides with high atom-economy. This metal-free process involves reductive N-O bond cleavage of anthranils and oxidative C-N bond formation of methyl ketones under mild conditions. The iodo group and electrophilic formyl group provide multiple possibilities for further functionalization of α-ketoamides.

Full text of DOI:10.1039/d1ob00468a

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I2-DMSO mediated oxidative amidation of methyl
ketones with anthranils for the synthesis of
α-ketoamides†
Cite this: DOI: 10.1039/d1ob00468a
Received 10th March 2021,
Accepted 13th April 2021
Shi-Yi Zhuang, Yong-Xing Tang, Xiang-Long Chen, Yan-Dong Wu and
DOI: 10.1039/d1ob00468a
An-Xin Wu
*
rsc.li/obc
An I2-DMSO mediated oxidative amidation of methyl ketones using accompanied with the generation of electrophilic formyl group.
anthranils as masked N-nucleophiles has been developed for the However, the formyl group is difficult to introduce and its
direct synthesis of α-ketoamides with high atom-economy. This functional group compatibility remains a challenge. Recently,
metal-free process involves reductive N–O bond cleavage of Zou’s group has reported the copper-catalyzed amidation of
anthranils and oxidative C–N bond formation of methyl ketones α-keto acids with anthranils under Ar atmosphere (Scheme 1a).14
under mild conditions. The iodo group and electrophilic formyl On account of our continued interest in I2-DMSO mediated
group provide multiple possibilities for further functionalization of reactions,11b,d we proposed that methyl ketones might be oxi-
α-ketoamides.
dized to in situ-generated phenylglyoxals and captured by
anthranils (Scheme 1b). This approach involved N–O bond
cleavage and C–N bond formation, providing a novel strategy
for the oxidative amidation of acetophenones in the absence
of metal catalyst under air conditions. The iodo group might
provide more opportunities for further transition-metal cata-
lyzed coupling reactions.15
Introduction
α-Ketoamides and their derivatives represent a class of valu-
able structure motifs which display unique reactivity in bio-
logically natural products and the pharmaceutical industry.1
Besides, they are important synthetic intermediates and pre-
cursors for further functionalization.2 Consequently, the for-
mation of α-ketoamides has attracted general interest and
remained of vital practical significance. A number of tra-
ditional synthetic strategies have been applied for the for-
mation of α-ketoamides: (1) the direct amidation of α-ketoalde-
hydes3 and α-keto acids;4 (2) the oxidation of α-hydroxya-
mides;5 (3) the oxidative amidation of ethylbenzenes,6 sty-
renes,7 phenylacetylenes,8 benzylic alcohols,9 benzaldehydes10
and acetophenones;11 and (4) transition-metal catalyzed dicar-
bonylation of aryl halides.12
Results and discussion
At the beginning of this study, we used acetophenone (1a) and
anthranil (2a) as model substrates (Table 1). The corres-
ponding product was only obtained in 10% yield in the pres-
ence of I2 in DMSO (Table 1, entry 1). The introduction of
Lewis acid caused a slight increase in reaction productivity,
giving the best result when TfOH was used as an additive
(Table 1, entries 2–6). The reaction temperature was deemed to
play a crucial role in the outcome of the yields and the optimal
Compared to employing simple amination agent, the intro-
duction of amino source with multiple functional groups pro-
vides more possibilities for further transformation of α-ketoa-
mides. To date, numerous protocols have been established
using anthranil as a masked N-nucleophile.13 The N–O bond
of anthranil is unstable and undergoes bond cleavage facilely
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Wuhan 430079, P. R. China.
E-mail: chwuax@mail.ccnu.edu.cn
†Electronic supplementary information (ESI) available. CCDC 2026166. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1ob00468a
Scheme 1 Strategies for the synthesis of α-ketoamides.
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Table 1 Optimization of the standard conditions of 3aa
Entry
Acid (equiv.)
I2 (equiv.)
Temp. (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
None
TFA (1.0)
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
0.8
1.2
2.0
120
120
120
120
120
120
110
130
140
150
140
140
140
140
140
140
10
13
10
20
11
13
33
54
60
45
58
78
55
33
60
65
TsOH (1.0)
TfOH (1.0)
PhCOOH (1.0)
CuBr2 (1.0)
TfOH (1.0)
TfOH (1.0)
TfOH (1.0)
TfOH (1.0)
TfOH (0.3)
TfOH (0.5)
TfOH (1.5)
TfOH (0.5)
TfOH (0.5)
TfOH (0.5)
9
10
11
12
13
14
15
16
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), and I2 heated in
2 mL of DMSO. b Products were obtained in isolated yields.
temperature was 140 °C (Table 1, entries 7–10). We sub-
sequently investigated the amount of acid from 0.3 to 1.5
equiv. and found that the best result was obtained in the pres-
ence of 0.5 equiv. of acid (Table 1, entries 11–13). Further
experiments revealed that the optimal equivalent of I2 was 1.6
equiv. and 3a was obtained in 78% yield (Table 1, entries
14–16). No side product via the Friedel–Crafts reaction was
observed in this transformation.16 Besides, the structure of 3a
was confirmed by X-ray crystallography (see ESI†).
With the optimized reaction conditions in hand, we began
to examine the substrate scope for the synthesis of α-ketoa-
mide and its derivatives under the optimal conditions
(Scheme 2). Methyl ketones containing EDGs (Me, OMe, OEt,
3,4-OCH2O, 3,4-O(CH2)2O, SMe, and Ph) and halogen substitu-
ents showed relatively high reactivities and transformed to the
Scheme 2 Substrate scope of methyl ketones. Reaction conditions:
0.5 mmol scale. Isolated yields.
corresponding products in 55%–78% yields (3a–3l, 3p–3t). (1ac) under the I2-DMSO mediated reaction (Scheme 4a). By
Electron-withdrawing groups on the phenyl ring (CO2Me, NO2, replacing acetophenone (1a) with phenylglyoxal (1ab) to react
and SO2Me) led to slight decreases in the yields (3m–3o). with anthranil (2a), the corresponding product 3a was
Moreover, for naphthyl- and thienyl-substituted methyl obtained in 75% yield, indicating that phenylglyoxal (1ab)
ketones, the target compounds were afforded in moderate might be a possible intermediate (Scheme 4b). When using
yields (3u–3x). However, aliphatic ketones were not compatible 2-aminobenzaldehyde (5) to react with 1a and 1ab, 3a was
with this transformation (see ESI†).
obtained in 30% and 55% yields, respectively (Scheme 4c and d).
The reactions were further extended to investigate the scope This result revealed that 5 might be a possible intermediate,
of anthranil derivatives and various C4/C5-substituted benzoi- which was formed through N–O bond cleavage of anthranil.
soxazole substrates with electron donating groups or halogen We subsequently used anthranil to react under standard con-
groups proved to be feasible for constructing α-ketoamides ditions. However, 2-aminobenzaldehyde (5) and 2-amino-5-
(Scheme 3), giving the corresponding products (4a–4h) in iodobenzaldehyde (5a) were detected instead of 5-iodobenzoi-
55%–68% yields.
soxazole (2aa). With the addition of 1.6 equiv. HI, 5 was
To obtain a deep understanding of the mechanism for the obtained in a 25% yield which further verified that anthranil
synthesis of 3a, a series of control experiments were carried (2a) was reduced by HI and transformed to intermediate 5
out (Scheme 4). Acetophenone (1a) could be transformed to (Scheme 4e). Besides, we used 2-aminobenzaldehyde (5) as a
phenylglyoxal (1ab) and its corresponding hydrated species substrate to react under standard conditions, 2-amino-5-iodo-
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that the iodination reaction occurred after ring-opening of
anthranil (2a).
Further synthetic transformations of α-ketoamides were
also explored to investigate the applicability of this reaction
(Scheme 5). The iodo group of 3a could be substituted by the
cyano group in DMF, giving the corresponding product 7 in
60% yield (Scheme 5a). Besides, 3a was able to undergo a tran-
sition-metal catalyzed coupling reactions, such as Suzuki–
Miyaura coupling and Sonogashira coupling. These reactions
gave the desired products 9 and 11 in relatively high yields
(Scheme 5b and c). The formyl group of 3a could undergo
Seyferth–Gilbert Homologation and transform to the terminal
alkyne compound 13 (Scheme 5d).
Based on the control experiments and previous studies, we
disclose a possible mechanism for the synthesis of 3a
(Scheme 6).17 Initially, acetophenone (1a) reacts with I2 to
Scheme 3 Substrate scope of anthranils. Reaction conditions:
0.5 mmol scale. Isolated yields.
Scheme 5 Synthetic applications.
Scheme 4 Control experiments.
benzaldehyde (5a) was detected by GC-MS (Scheme 4f).
However, α-ketoamide (6) was recovered in a 95% yield under
the standard conditions (Scheme 4g). These results revealed Scheme 6 Proposed mechanism.
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afford α-iodo ketone (1aa). After Kornblum oxidation, 1aa can
be transformed into phenylglyoxal (1ab) with the release of HI.
At the same time, anthranil (2a) is reduced by HI to obtain
2-aminobenzaldehyde (5) which further reacts with I2 giving
intermediate 5a. The intermediate 1ab is attacked by 5a to get
intermediate A. Intermediate A is oxidized by I2 to form the
desired product 3a.
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Conclusions
In summary, we have developed a novel and efficient strategy
for enriching the synthesis of α-ketoamides using commer-
cially available anthranils as masked N-nucleophiles. This
metal-free process involves oxidative amidation of methyl
ketones and reductive N–O bond cleavage of anthranils under
air conditions. The synthetic approach has great tolerance for
functional groups and high atom-efficiency, which means it
has potential for practical applications. Further synthetic
applications of this process are currently underway in our
laboratory.
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Conflicts of interest
There are no conflicts to declare.
6 For selected reviews please see: (a) F. Liu, K. Zhang, Y. Liu,
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Grants 21971079, 21971080 and
21772051). This work was supported by “The Fundamental
Research Funds for the Central Universities”. This work was
supported by the 111 Project B17019. This work was also sup-
ported by “Laboratory Research Projects of Central China
Normal University” (No. 201984).
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