Decarboxylative/Oxidative Amidation of Aryl α-Ketocarboxylic Acids with Nitroarenes and Nitroso Compounds in Aqueous Medium

Article abstract of DOI:10.1021/acs.orglett.0c03666

The decarboxylative/oxidative amidation of aryl α-ketocarboxylic acids with 5-aryl-3-nitroisoxazole-4-carboxylates and substituted dinitrobenzenes under oxidative aqueous conditions to afford N-aryl amides is described. The reaction is suggested to proceed via a radical pathway in which a benzoyl nitroxyl radical, the key intermediate formed from reaction between nitroarene and benzoyl radical from glyoxalic acid, couples with hydroxyl radical from water to produce amide. Mechanistic insight allowed the scope of the strategy to be expanded to the synthesis of amides via reaction between aryl α-ketocarboxylic acids and nitroso compounds.

Full text of DOI:10.1021/acs.orglett.0c03666

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Letter
Decarboxylative/Oxidative Amidation of Aryl α‑Ketocarboxylic Acids
with Nitroarenes and Nitroso Compounds in Aqueous Medium
Dinesh S. Barak, Dipak J. Dahatonde, Shashikant U. Dighe, Ruchir Kant, and Sanjay Batra*
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ABSTRACT: The decarboxylative/oxidative amidation of aryl α-ketocarboxylic acids with 5-aryl-3-nitroisoxazole-4-carboxylates
and substituted dinitrobenzenes under oxidative aqueous conditions to afford N-aryl amides is described. The reaction is suggested
to proceed via a radical pathway in which a benzoyl nitroxyl radical, the key intermediate formed from reaction between nitroarene
and benzoyl radical from glyoxalic acid, couples with hydroxyl radical from water to produce amide. Mechanistic insight allowed the
scope of the strategy to be expanded to the synthesis of amides via reaction between aryl α-ketocarboxylic acids and nitroso
compounds.
Strikingly, the reaction of benzyl alcohols with nitroarene can
he ubiquitous presence of N-aryl amides in pharmaceut-
Ticals, bioactive compounds, agrochemicals, and functional be performed under metal-free oxidative conditions and the
hydrogen liberated from the oxidation of benzyl alcohol is
suggested to be the internal reductant for reducing nitroarene to
aniline.8b A metal-free reduction of the nitro group using
trichlorosilane followed by addition of an anhydride to obtain
amide was recently reported.9 Among nonconventional
approaches, the acylation of aniline to produce an amide linkage
using an acyl synthon equivalent has also received considerable
attention.
Considering different acyl equivalents, α-keto carboxylic acids
that undergo rapid decarboxylation have been illustrated to be
extremely useful for the formation of N-aryl amides via metal-
mediated, metal-free, or photoredox approaches.10 The
advancement in the development of different nonclassical
routes to amides was comprehensively reviewed by Figueredo
et al.,11 and a complementary perspective by Sheppard et al.12
assimilated some of the greener approaches to amides recently.
In addition, because of the significance of amides, several
innovative routes are continuously cited.13
materials makes them one of the most important classes of
organic molecules.1 In addition, amides are viable synthetic
intermediates to many key organic compounds, including
diverse amines and heterocycles.2 Traditionally, the synthesis
of N-aryl amides is achieved via coupling of aniline with an acid
in the presence of coupling reagents, such as acid chlorides,
anhydrides, carbodiimides, or boron derivatives (Figure 1).3 As
has been widely stated, this approach is associated with
drawbacks, such as the use of a stoichiometric amount of
activating reagents that are generally toxic or expensive, and the
process may require an activation step that can result in the
formation of side products.4 Furthermore, anilines used in the
process are usually prepared by reducing the nitroarenes via
metal- or acid-mediated reactions;5 hence, any nitroarene
bearing other reducible groups proves to be problematic and
cannot be used in this approach. As a consequence, recently
there has been more focus on the direct use of nitroarenes in the
formation of N-aryl amides.6 Wang et al. summarized different
approaches for directly transforming nitroarenes into the N-aryl
amides.7 They disclosed a novel approach for activating an acid
with triphenylphosphine and iodine followed by treatment with
a nitroarene in the presence of Mn metal to obtain N-aryl amide.
Besides acids or their activated analogues, aryl aldehydes and
benzyl alcohols are described to react with nitroarenes to deliver
N-aryl amides.8
Received: November 4, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03666
© XXXX American Chemical Society
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Scheme 1. Proposed Mechanism for the Formation of Amide
It is reported that persulfate decomposes to a sulfate anion
radical in the presence of a base at elevated temperatures, which
can then perform a hydrogen atom transfer with α-
ketocarboxylic acid followed by decarboxylation to form the
acyl radical.19 Simultaneously, the sulfate anion radical reacts
with water to afford the hydroxyl radical.20 In principle, the
proposed reaction would essentially require 3.0 equiv of
persulfate and 2.0 equiv of glyoxalic acid. Hence, we commenced
our investigations by treating 5-(4-chlorophenyl)-3-nitroisox-
azole-4-carboxylate 1ca (1.0 equiv) with glyoxalic acid 2a (2.1
equiv) in the presence of K2S2O8 (3.0 equiv) in a mixture of
acetonitrile and water (1:1) under heating at 80 °C. Aging the
reaction for 20 h followed by workup afforded amide 3caa in
45% yield together with unreacted starting material 1ca (52%).
We reasoned that addition of a base would facilitate the reaction
by assisting the formation of salt of glyoxalic acid to allow an easy
decarboxylation step and concomitantly neutralizing the
benzoic acid liberated in the process. We were delighted to
discover that the addition of K2CO3 (1.0 equiv) improved the
yield of 3caa to 66%, and therefore, we considered screening the
reaction mixture to obtain the optimal yield of amide (see the
Supporting Information). Increasing the amount of K2CO3 to
1.5 equiv gave 3caa in 80% yield within 12 h, but any further
increase proved to be detrimental. Alternative bases such as
Na2CO3 or Cs2CO3 offered 3caa in inferior yields. With respect
to the oxidant, 3.0 equiv of K2S2O8 was optimal and other
persulfates tested, Na2S2O8 or (NH4)2S2O8, produced 3caa but
in relatively lower yields and increased reaction times. When
different solvents were considered, in DMSO, DMF, or 1,4-
dioxane, 3caa was isolated in lower yields and toluene halted the
desired reactivity completely. Performing the reaction in the
absence of water was unsuccessful, thus confirming the
requirement of water for the protocol. Thus, the best condition
for the reaction was heating a mixture of 5-(4-chlorophenyl)-3-
nitroisoxazole-4-carboxylate 1ca (1.0 equiv), glyoxalic acid 2a
(2.1 equiv), K2CO3 (1.5 equiv), and K2S2O8 (3.0 equiv) in
acetonitrile and water [1:1 (v/v)] at 80 °C for 12 h.
Figure 1. Synthesis of N-aryl amides from nitroarenes.
We have reported the synthesis of 3-nitroisoxazole-4-
carboxylates from the MBH adduct and have been probing the
chemistry of these compounds.14 The presence of an electron-
withdrawing group at C-4 of the isoxazole renders the nitro
group at C-3 highly susceptible to the nucleophilic substitution
in these substrates. Moreover, the classical approaches for
reducing the aromatic nitro group in this substrate were
suboptimal, and therefore, the free amino group was installed
using liquid ammonia via a nucleophilic reaction.14b The N-
(isoxazol-3-yl)-carboxylic acid amides are reported to be
herbicidal agents,15 and in a medicinal chemistry program
related to infectious diseases,16 we were interested in preparing
such amides bearing an acid moiety at C-4 for further synthetic
manipulations. However, attempted synthesis of amides from 3-
aminoisoxazoles via treatment with benzoyl chlorides or acids
using different coupling agents was unsuccessful. Therefore, we
considered direct transformation of 3-nitroisoxazole to N-
(isoxazol-3-yl)-carboxylic acid amide.
Notably, direct amidation of aryl α-ketocarboxylic acids with
nitroarenes remains elusive in the literature. Janzen and Oehler
had earlier reported that benzoyl radicals are capable of
abstracting oxygen atoms from the nitro group of nitroarenes,
leading to benzoylnitroxyl radical with liberation of benzoic
acid.17 Furthermore, Nakagawa et al. reported that N-benzoyl N-
phenylhydroxylamine in the presence of nickel peroxide
produces a benzoylnitroxyl radical that reacts with a hydroxyl
radical to yield benzanilide as the major product.18 Encouraged
by these reports, we proposed that treating 3-nitroisoxazoles 1
with a benzoyl radical would offer benzoylnitroxyl radical C (via
nitrosoarene B). Next, quenching benzoylnitroxyl radical C with
a hydroxyl radical would afford an intermediate D that would
undergo in situ deoxygenation to give amide 3 as outlined in
Scheme 1. Herein, we describe successful implementation of this
strategy leading to unprecedented direct decarboxylative/
oxidative amidation of aryl α-keto carboxylic acids with 3-
nitroisoxazoles, dinitrobenzenes, or nitroso compounds under
metal-free and reducing agent-free conditions.
With the optimal reaction conditions in hand, we examined
the scope of this reaction by testing the oxidative amidation of
glyoxalic acid 2a with a variety of methyl 5-(substituted phenyl)
3-nitroisoxazole-4-carboxylates (1aa−1ha) (Scheme 2). All
reactions smoothly afforded the methyl 3-benzamido-5-
(substituted phenyl)isoxazole-4-carboxylates (3aaa−3haa) in
61−81% yields. To expand the scope with respect to aryl α-
ketocarboxylic acids, next the reactions of 1aa−1da, 1fa and 1ha
with different glyoxalic acids (2b−2f) were carried out.
Pleasingly, all reactions successfully afforded the required
methyl 3-(substituted benzamido)-5-(substituted phenyl)-
isoxazole-4-carboxylates (3aab, 3aad, 3aaf, 3bab−3bag,
3cab−3caf, 3dab−3daf, 3fab, 3fad, and 3hab) in good yields.
B
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a
Scheme 2. Scope of the Protocol
Scheme 3. Amide Formation from 1,3-Dinitrobenzenes
dinitrobenzenes 4b−4d were subjected to the reaction under
the optimized conditions, and we were delighted to observe that
the corresponding amides 5b−5d were isolated in 42−52%
yields. However, several substituted nitrobenzenes were found
to be incompatible with the protocol (see the Supporting
Information).
To provide evidence for a radical mechanism, we treated
isoxazole 1ca with 2a in the presence of 3.0 equiv of TEMPO
(radical inhibitor) and found that product 3caa was not formed.
To detect the possible intermediates, GCMS experiments were
carried out. In line with the previous report,17 we could detect
the formation of the benzoloxyl radical. This radical could be
trapped as the TEMPO adduct via GCMS of the reaction that
was performed in the presence of TEMPO (see the Supporting
Information). Thus, as delineated in Scheme 1, the first step
involves the attack of benzoyl radical to transform 3-nitro-
isoxazole 1 into nitroso intermediate B via loss of benzoic acid.
Intermediate B then reacts with another benzoyl radical to offer
benzoyl nitroxyl radical C. Previously, Uematsu et al. had
reported that the reaction between nitrosoarene and aryl α-keto
carboxylic acid in the presence of water and acetic acid gave N-
arylhydroxamic acid.21 This report together with the suggested
formation of nitroso intermediate B presented in our study
prompted us to investigate the fate of a nitroso compound in the
developed strategy. Accordingly, nitrosobenzene 6a was treated
with glyoxalic acid 2a under the standard condition and
expectedly produced N-arylamide 7aa in 78% yield (Scheme
4). Perhaps the transformation of nitrosobenzene to amide
a
Reactions were performed with 0.2 g of 3-nitroisoxazoles (1), and
yields are isolated yields after column chromatography.
Notably, the nature of the substitution on the phenyl ring of
glyoxalic acid did not have any impact on the reaction. Next the
scope of the protocol was evaluated by introducing changes at C-
4 of isoxazoles. The reactions of 3ab and 3db bearing an
ethoxycarbonyl group at C-4 with 2a under optimized
conditions furnished amides 3aba and 3dba, respectively, in
75−76% yields, but the reaction between 2a and 3cc having an
acid group at C-4 in place of ester afforded product 3cca in only
52% yield. Reactions of 2a with 3cd−3cf bearing an amide
group, or no substituent or iodo group at C-4, were unsuccessful
to afford the corresponding products 3cda, 3cea, and 3cfa,
respectively. This result indicated the requirement of an
electron-withdrawing moiety at C-4 of isoxazole. Finally, the
reaction between 2a and isoxazoles 3ia and 3ja containing a
hetaryl group and an aliphatic group, respectively, was
attempted, but in both cases, the TLC analysis revealed
formation of a complex mixture of products. The scalability of
the protocol was verified by performing the reaction of 1.0 g of
1ca with 2a to smoothly afford 3caa in 78% yield.
Scheme 4. Scope of the Synthesis of Amides 7 from Nitroso
Derivatives 6
a
a
All reactions were performed using 0.2 g of 3-nitroso compound 6,
and yields are isolated yields.
As 1,4-dintrobenzene and 1,3,5-trinitrobenzene were de-
scribed to offer stable benzoyloxy aminoxyl radicals and 1,3-
dinitrobenzene with only benzoyl nitroxyl radical was
detected,17 we considered studying the fate of different
nitrobenzenes in this strategy. Therefore, in a pilot reaction,
1,3-dinitrobenzene 4a was treated with 2a under the optimized
condition, and it was gratifying to discover that it produced
amide 5a, albeit in only 17% yield (Scheme 3). Next, different
would stoichiometrically require 1.0 equiv of glyoxalic acid, and
to validate it, the reaction of 6a with 1.0 equiv of 2a was
conducted to afford 7aa in identical yield. Next to test the
general applicability of this transformation, nitrobenzene 6a was
subjected to reaction with several aryl α-keto carboxylic acids
(2b−2f) to furnish the corresponding N-aryl amides 7aa−7af in
C
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76−82% yields. In addition, to evaluate the compatibility of
nitrosoarenes, 2a was treated with different substituted nitro-
sobenzenes 6b−6g to smoothly furnish amides 7ba−7ga,
respectively, in 63−79% yields. We next explored the substrate
scope of heterocyclic nitrosoarenes (6h and 6i) and aliphatic
nitroso compounds (6k−6m). All substrates underwent the
reaction with acid 2a to successfully afford the corresponding
amides 7ha−7ma in 41−74% yields.
The success of the protocol with nitrosoarenes provided
impetus to investigate the outcome of reaction with N-
arylhydroxamic acid (8). Hence, 8 was treated with 2a under
the optimized conditions, and gratifyingly, the reaction afforded
the desired benzanilide 7aa in 78% yield (Scheme 5). In
for accessing new isoxazole derivatives for our medicinal
chemistry program is underway.
ASSOCIATED CONTENT
* Supporting Information
■
sı
X-ray crystallographic analysis of 3daf is included. The
Supporting Information is available free of charge on the ACS
Publications Web site. SB-SI-amide (PDF) The Supporting
Information is available free of charge at https://pubs.acs.org/
doi/10.1021/acs.orglett.0c03666.
1
Experimental details and copies of H NMR, 13C NMR,
and HRMS spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 3aaa−3haa, 3aab, 3aad, 3aaf, 3bab−3bag,
3cab−3caf, 3dab−3daf, 3fab, 3fad, 3hab, 3aba, 3dba,
3cca, 5a−5d, 7aa−7af, 7ba−7ma, 9, and 10a−10c (ZIP)
Scheme 5. Transformation of N-Benzoyl Hydroxamic Acid 8
to Benzanilide 7aa under Oxidative Conditions and a Control
Experiment
Accession Codes
CCDC 1940609 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
principle, under oxidative conditions, compound 8 should
directly give the benzoyl nitroxyl radical without requiring
glyoxalic acid, which subsequently furnishes the amide. Indeed,
reaction of 8 with persulfate, in the absence of glyoxalic acid, in
acetonitrile and water (1:1) afforded 7aa in 76% yield.
Removing the base from the reaction did not result in
attenuation of the yield of 7aa, but in the absence of either an
oxidant or water, the reaction was unsuccessful.
Finally, to demonstrate the usefulness of these amides for
preparing diverse isoxazoles, 3caa was subjected to reduction
with LiAlH4 to afford the corresponding alcohol 9 (Scheme 6).
Conversely, the reaction of 3caa with different Grignard
reagents gave adducts 10a−10c.
AUTHOR INFORMATION
Corresponding Author
■
Sanjay Batra − Medicinal and Process Chemistry Division,
CSIR-Central Drug Research Institute, Lucknow 226031,
India; Academy of Scientific and Innovative Research, CSIR-
Human Resource Development Centre (CSIR-HRDC),
Ghaziabad, Uttar Pradesh 201002, India; orcid.org/
0000-0002-8980-3592; Phone: +91-522-2772450, ext.
4727; Email: batra_san@yahoo.co.uk, s_batra@cdri.res.in
Authors
Dinesh S. Barak − Medicinal and Process Chemistry Division,
CSIR-Central Drug Research Institute, Lucknow 226031,
India
Scheme 6. Representative Transformations of Amide 3caa
Dipak J. Dahatonde − Medicinal and Process Chemistry
Division, CSIR-Central Drug Research Institute, Lucknow
226031, India
Shashikant U. Dighe − Medicinal and Process Chemistry
Division, CSIR-Central Drug Research Institute, Lucknow
226031, India
Ruchir Kant − Molecular and Structural Biology Division,
CSIR-Central Drug Research Institute, Lucknow 226031,
India
In conclusion, we have developed a direct transformation of 3-
nitroisoxazoles to N-(isoxazol-3-yl)-carboxylic acid amides by
reacting them with aryl α-ketocarboxylic acids under oxidative
aqueous conditions. The strategy was responsive to trans-
forming dinitrobenzenes to nitrobenzamides. This metal-free
and reducing agent-free operationally simple protocol has a
good substrate scope but essentially requires the presence of an
electron-withdrawing group in the nitroarene. The reaction
follows a radical pathway with benzoyl nitroxyl radical as the key
intermediate. The mechanistic insight led to the expansion of
the strategy for direct amidation of aryl α-ketocarboxylic acids
with aromatic, heterocyclic, and aliphatic nitroso derivatives to
yield amides. In addition, we could also demonstrate the direct
transformation of N-benzoyl hydroxamic acid to amide under
oxidative aqueous conditions. Further work to use these amides
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03666
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
D.S.B., D.J.D., and S.U.D. gratefully acknowledge the financial
support from CSIR, New Delhi, in the form of fellowships. The
authors acknowledge the SAIF, CDRI, for providing the
spectroscopic data. The authors acknowledge the Director,
Centre for Biomedical Research, Lucknow, for allowing to
perform the GCMS experiments at their facility. The work was
D
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(9) Massolo, E.; Pirola, M.; Puglisi, A.; Rossi, S.; Benaglia, M. A one
pot protocol to convert nitro-arenes into N-arylamides. RSC Adv. 2020,
10, 4040−4044.
supported by funds under Grant EMR/2016/002162 from
SERB, New Delhi. This is CDRI communication 10149.
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