Rapid assembly of α-ketoamides through a decarboxylative strategy of isocyanates with α-oxocarboxylic acids under mild conditions

Article abstract of DOI:10.1039/d1ob00562f

A simple and practical method for α-ketoamide synthesis via a decarboxylative strategy of isocyanates with α-oxocarboxylic acids is described. The reaction proceeds at room temperature under mild conditions without an oxidant or an additive, showing good substrate scope and functional compatibility. Moreover, the applicability of this method was further demonstrated by the synthesis of various bioactive molecules and different application examples through a two-step one-pot operation.

Full text of DOI:10.1039/d1ob00562f

Organic &
Biomolecular Chemistry
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Rapid assembly of α-ketoamides through a
decarboxylative strategy of isocyanates with
Cite this: Org. Biomol. Chem., 2021,
19, 4783
α-oxocarboxylic acids under mild conditions†
Junjie Huang,‡a Baihui Liang, ‡a Xiuwen Chen, *a Yifu Liu,a Yawen Li,a
Jingwen Liang,a Weidong Zhu,a Xiaodong Tang, *b Yibiao Li a and
a
Zhongzhi Zhu
*
A simple and practical method for α-ketoamide synthesis via a decarboxylative strategy of isocyanates
with α-oxocarboxylic acids is described. The reaction proceeds at room temperature under mild con-
ditions without an oxidant or an additive, showing good substrate scope and functional compatibility.
Moreover, the applicability of this method was further demonstrated by the synthesis of various bioactive
molecules and different application examples through a two-step one-pot operation.
Received 23rd March 2021,
Accepted 4th May 2021
DOI: 10.1039/d1ob00562f
rsc.li/obc
Metal- and solvent-free reaction systems are widely considered chemists have also developed a number of excellent works, for
as sustainable tools of green chemistry.1 Adopting such strat- example, Wang’s group and Patel’s group, respectively,
egies offers distinct advantages, such as reduced reaction costs reported Cu- and Pd(II)-catalyzed decarboxylative reactions of
through avoiding the use of precious metals and solvents, α-oxocarboxylic acids with different nitrogen sources in the
decreased by-product formation, and avoiding the waste from presence of oxidants (Scheme 1b).12a,b Recently, Wei and co-
the purification procedures.2 Hence, the development of new workers developed an efficient visible-light-promoted approach
environmentally friendly and metal- and solvent-free methods for preparing α-ketoamides from α-oxocarboxylic acids, isocya-
for organic transformations is of significant importance.
nides and water at room temperature (Scheme 1c).12c Despite
α-Ketoamides are key structural units and are frequently the above progress, development of practical, facile, mild and
found in natural products,3 which are considered as biologi- environmentally friendly strategies to access α-ketoamides
cally relevant molecules4 (with anti-HIV,4a,b anti-tumor,4c anti- from easily prepared or commercially available raw materials is
inflammatory4d and anti-bacterial4e activities). Furthermore, still highly desirable.
α-ketoamides are versatile intermediates in functional group
transformations and total synthesis.5 Therefore, a wealth of
interdependent research over the past few decades has culmi-
nated in the development of numerous synthetic methods to
access this scaffold.6 The adopted strategies are roughly classi-
fied into metal-catalyzed-transformations (Pd7 or Cu catalysts8)
and iodine-based catalysis.9 Among these processes, the ami-
dations of α-oxocarboxylic acids and amines are the most
common methods. However, equivalent carboxylic acid activat-
ing reagents such as thionyl chloride,10a–10c 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide hydrochloride (EDA·HCl)10e
or oxalyl chloride11 are necessary (Scheme 1a). In recent years,
aSchool of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020,
China. E-mail: chenxiuwen2010@126.com, zhongzhi_zhu@126.com
bGuangdong Provincial Key Laboratory of New Drug Screening, School of
Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
E-mail: tangxdong@smu.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00562f
‡These authors contributed equally to this work.
Scheme 1 Decarboxylative strategy for the formation of α-ketoamides.
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Isocyanates are an important class of commercially avail-
Organic & Biomolecular Chemistry
Table 2 Substrate scope of isocyanatesa
able bulk chemical raw materials, which can be obtained by a
two-step one-pot method using dimethyl carbonate and ani-
lines.13 Based on our previous work on decarboxylation
research,14 we here report a decarboxylative reaction of isocya-
nates and a-oxocarboxylic acids to construct α-ketoamides
(Scheme 1d). To the best of our knowledge, the decarboxylative
coupling of α-oxocarboxylic acids with isocyanates has not
been reported. In this synthetic design,
a series of
α-ketoamides were obtained in a single step with the gene-
ration of CO2 as a by-product at room temperature under mild
conditions.
Initially, 2-oxo-2-phenylacetic acid (1a) and phenyl isocya-
nate (2a) were used as model substrates to examine different
reaction conditions, and the results are summarized in
Table 1. When the reaction of 1a and 2a was undertaken in the
absence of any catalysts and additives in CH3CN, at room
temperature for 24 h under air, the desired product, 2-oxo-N,2-
diphenylacetamide (3aa), was detected in 80% NMR yield
(entry 1). Thereafter, CH2Cl2 was found to be the best solvent,
giving 3aa in 90% yield (entries 2–5). By further study of the
solvent amount, the optimal reaction conditions were observed
to be solvent-free conditions or those in the presence of a
small amount of solvent, providing 3aa in 97% NMR yield and
94% isolated yield (entries 6–9). In addition, raising or lower-
ing the temperature has little effect on the reaction (entries 10
and 11).
a Standard conditions: 1a (0.3 mmol) and 2 (0.33 mmol) at room temp-
erature for 24 h under air. Isolated yield. b 0.5 mL CH2Cl2 was added.
groups, such as ethyl, tert-butyl, and methoxy groups, and elec-
Having achieved the optimized reaction conditions, the tron-withdrawing groups, such as fluorine, chlorine, bromine,
scope of isocyanates was investigated by employing 2-oxo-2- iodine, acetyl, trifluoromethyl and cyano groups, were con-
phenylacetic acid (1a) as the coupling partner, and the results verted into the corresponding α-ketoamides (3ab–3az) in good
are summarized in Table 2. Generally, this decarboxylative yields (85%−94%). Furthermore, ortho- and meta-substituted
reaction proceeds efficiently to construct the desired products isocyanates resulted in moderate to good yields of the desired
3 in moderate to good yields (78%−94%, Table 2). A series of products (3am–3ap). Satisfactorily, poly-substituted substrates
para-substituted aroyl isocyanates, including electron-donating were able to give the desired products in good yields (3aq–3as).
2-Naphthoyl isocyanate was observed to undergo this decar-
boxylative process, affording 3at in 86% yield. Importantly, a
large number of alkyl isocyanates were compatible with this
Table 1 Optimization of the reaction conditionsa
transformation to generate the desired products in moderate
to good yields (3au–3bb). Additionally, alkyl isocyanates substi-
tuted with halogen and alkenyl groups were easily transformed
into the corresponding products in 82% and 78% yields,
respectively (3bc and 3bd).
Next, the substrate scope with respect to various α-oxocar-
Entry
T (°C)
Solvent
Yieldb (%)
boxylic acids was examined (Table 3). Typically, a variety of α-
oxocarboxylic acids bearing various substituents were observed
to be tolerable in this process. For example, α-oxocarboxylic
acids with electron-donating substituents (methyl and
methoxy moieties) led to the desired products in good yields
(3be and 3bf). In addition, electron-withdrawing substituents,
such as fluoro, chloro, bromo, iodo and trifluoromethyl
groups, at the para-position of the aromatic ring, did not show
obvious influence on the yields (3bg–3bk). Furthermore, diha-
logen-substituted and heteroarene α-oxocarboxylic acids with
1a were also converted to the corresponding products 3bl and
3bm in 87% and 83% yields, respectively. Additionally,
naphthalene α-oxocarboxylic acids reacted with 1a, providing
1
2
3
4
5
6
7
8
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
0
CH3CN (2 mL)
Acetone (2 mL)
CH2Cl2 (2 mL)
n-hexane (2 mL)
Ethyl acetate (2 mL)
CH2Cl2 (1 mL)
CH2Cl2 (0.5 mL)
CH2Cl2 (0.3 mL)
—
80
82
90
87
81
94
96
96
9
10
11
97(94)c
95
—
—
94
a Unless otherwise stated, the reaction was performed with 1a
(0.3 mmol) and 2a (0.33 mmol), under air, in 24 h. b Yields and conver-
sions analyzed by NMR with CH2ClBr as an internal standard are
based on 1a. c Isolated yield.
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Table 3 Substrate scope of α-oxocarboxylic acidsa
a Standard conditions: 1 (0.3 mmol) and 2a (0.33 mmol) at room temp-
erature for 24 h under air. Isolated yield. b 0.5 mL CH2Cl2 was added.
Scheme 3 The synthesis of bioactive molecules and application in
organic synthesis.
3bn in 88% yield. Finally, a series of aliphatic α-oxocarboxylic
acids were compatible affording the desired products in good
yields (85%–92%), which significantly broadened the scope of
this reaction (3bo–3bv).
A gram-scale reaction of 1a was undertaken on a 100 mmol
scale under the standard reaction conditions, providing
22.47 g of the desired product 3ab in 94% isolated yield
(Scheme 2). This experiment shows the practicability of this
method and reveals that it can be an advantageous alternative
to classic methods (see the ESI† for a detailed comparison of
the two methods).
To demonstrate the practical use of this decarboxylative
strategy, the epoxide hydrolase inhibitor 3bw and cytokine
inhibitor 3bx were synthesized in good yields (80% and 83%,
respectively) in a single step (Scheme 3a). Furthermore, the
orexin receptor antagonist 3by was prepared in 70% yield
through a two-step one-pot operation (Scheme 3b). In addition,
a Friedel–Crafts hydroxyalkylation of indoles from 1a and 2a
through a two-step one-pot reaction was realized, giving 4a in
80% yield (Scheme 3c).10c Besides, the formed α-ketoamide
3aa can be easily reduced to 5a in a dimethylformamide
/NaOH/H2O system (Scheme 3d).10d Furthermore, polycyclic
imidazolidinones 6a and 6b can be obtained by using 1a and
2a with cyclic secondary amines through a two-step one-pot
operation in good yields (Scheme 3e).11 These two-step one-pot
experiments further show an important advantage of this strat-
egy over the classic methods.
To elucidate the mechanistic reaction, numerous control
experiments were performed, as shown in Scheme 4. First, no
target product was detected when aniline was used to replace
2a (Scheme 4.1). Similarly, the use of benzoic acid 1a′ instead
Scheme 2 Gram-scale synthesis of 3ab.
Scheme 4 Control experiments.
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Acknowledgements
We thank the Guangdong Basic and Applied Basic Research
Foundation (2019A1515110866 and 2019A1515110522),
Department of Education of Guangdong Province
(2019KZDXM052), Science Foundation for Young Teachers of
Wuyi University (2019td06) and the “Climbing Program”
(pdjh2020a0596) Special Funds.
Notes and references
Scheme 5 NMR detection experiment.
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There are no conflicts of interest to declare.
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