From “Reduction First, Then Acylation” to “Direct Amidation”: An Unconventional Route to Amide Bond Formation from Nitro and Nitroso Substrates with α-Keto Carboxylic Acids

1. Why This Unconventional Amide Bond-Forming Strategy Deserves Reconsideration

 

The most familiar route from nitro compounds to amides is usually to first reduce the nitro group to an amine, and then react that amine with a carboxylic acid derivative or an activated carboxylic acid system. This route is mature, reliable, and remains the most common choice in both laboratory practice and process chemistry. However, in recent studies on amide bond formation, one question has attracted increasing attention: must the nitrogen source always be introduced in the form of a pre-prepared, isolable amine? In 2016, Chemical Reviews classified such approaches as “nonclassical amide bond-forming routes,” including strategies in which nitrogen-containing precursors are used directly as amine surrogates rather than following the traditional framework of “first prepare the amine, then perform the coupling.”

 

Against this background, the truly noteworthy aspect of direct amide bond formation from nitro compounds is that it changes the starting point of route design. A 2021 thematic review pointed out that nitro compounds can enter amide synthesis directly as amine surrogates; under suitable conditions, they can often be converted in situ through intermediates such as nitroso compounds, hydroxylamines, diazo compounds, hydrazines, or aniline-type amines, and then participate in aminocarbonylation or amidation reactions. In other words, they are not merely precursors that must first be reduced and isolated as amines in the conventional sense; they can also serve as nitrogen-source precursors that are transformed in situ during the reaction and directly participate in bond formation.

 

2. What Methodological Change This 2020 Study Actually Introduced

 

The work reported by Barak and co-workers in Organic Letters in 2020 is a specific example developed within this conceptual framework. It is not a universally applicable “one-step amidation of ordinary nitroarenes with α-keto carboxylic acids,” but rather a decarboxylative oxidative amidation between aryl α-keto carboxylic acids and a more specific set of nitro/nitroso substrates. According to the original abstract, the substrate scope included 5-aryl-3-nitroisoxazole-4-carboxylates and substituted dinitrobenzenes, and the strategy was also extended to nitroso compounds; the reaction was carried out under oxidative aqueous conditions to afford N-aryl amides.

 

This distinction is important because it defines the range of applicability that is currently supported by experimental evidence. Here, “nitro compounds” does not refer broadly to all common nitroarenes, but rather to a specific set of substrates that were demonstrated to be viable in the original study. At the same time, the α-keto carboxylic acid is not merely a substitute for an ordinary carboxylic acid, but the key acyl precursor that undergoes decarboxylation and then enters the subsequent bond-forming process. The original paper also proposed that the reaction likely proceeds through a radical pathway, and on this basis extended the chemistry from nitroarenes to nitroso compounds. What this 2020 study truly changed was not simply the order of operations, but the attempt to allow a nitrogen-containing precursor and an acyl precursor to undergo synchronous transformation within the same reaction process and complete amide bond formation together. What it primarily represents is a methodological rewriting of route design, rather than a broadly validated general process.

 

Core Differences Between the Traditional Route and This Unconventional Route

 

Dimension	Traditional “Reduction First, Then Acylation”	One-Step Amidation of Nitro/Nitroso Substrates with α-Keto Carboxylic Acids
Mode of nitrogen source entry	The nitro group is first reduced to an amine, which then participates in amidation	The nitro/nitroso substrate is used directly as a nitrogen-source precursor
Acyl source	Activated carboxylic acids, acid chlorides, anhydrides, or coupling-based systems	Aryl α-keto carboxylic acids
Bond-forming process	Nitrogen-source preparation and amide bond formation are carried out in separate steps	Transformation of the nitrogen-containing precursor and amide bond formation occur within the same process
Current positioning	Mature and generally more broadly applicable	Methodologically inspiring, but its currently demonstrated substrate scope remains relatively specific

 

3. Research Progress in Amide Bond Formation Using Nitro and Nitroso Substrates as Nitrogen-Source Precursors

 

Year	Representative work	Reaction combination	What this advance showed
2019	Wang, Cheung, Ma	Nitroarenes + carboxylic acids	Demonstrated that nitroarenes can enter the construction of N-aryl amides directly without isolation of an aniline intermediate, showing that nitro compounds can indeed serve directly as nitrogen-source precursors.
2020	Barak et al.	Aryl α-keto carboxylic acids + specific nitro/nitroso substrates	Coupled decarboxylative/oxidative processes with amidation, further showing that a nitrogen-containing precursor and an acyl precursor can undergo synchronous transformation and bond formation within the same reaction process.
2021	Ning et al.	Carboxylic acids + nitroarenes / nitroalkanes	Established an umpolung amidation system under triple synergistic catalysis, showing that this direction has developed from a “single method” into one that can be systematically designed within different catalytic frameworks.
2024	Liu et al.	Nitroarenes + α-oxo carboxylic acids	Extended the concept of using nitro compounds as nitrogen-source precursors to the construction of α-ketoamides, showing that this direction is expanding toward different product types.
2025	Liu et al.	Benzoylformic acid derivatives + nitroarenes	Advanced this strategy into a flavin photocatalytic system, showing that amidation using nitro compounds as nitrogen-source precursors is still expanding into new reaction platforms.
2025	Khamkar et al.	Acyl saccharins + nitroarenes / nitroalkenes / nitroalkyl substrates	Extended this direction to aqueous systems, scale-up, and life-cycle assessment, showing that it is beginning to enter a more clearly defined framework for sustainability comparison.

 

4. The Practical Significance of This Route for Experimental Design and Research Topic Selection

 

What makes this route worth attention is not the idea of replacing all conventional amidations with “one-step amidation from nitro substrates,” but rather that it offers an unconventional strategy worth including in screening. When the research focus involves step economy, in situ conversion of nitrogen-source precursors, nitroso-related intermediates, or decarboxylative bond formation involving α-keto carboxylic acids, such methods are often more valuable from a research perspective than the traditional “reduction first, then acylation” sequence. A series of studies since 2019 has already shown that nitro compounds can not only undergo direct amidation with carboxylic acids, but can also enter different reaction frameworks involving decarboxylative/oxidative processes, triple synergistic catalysis, α-ketoamide construction, and photocatalysis.

 

However, if the experimental goal is simply to prepare common N-aryl amides quickly and reliably, with greater emphasis on broad substrate generality, established process chemistry, and a clear scale-up pathway, then the traditional “reduction first, then acylation” route will usually remain the more straightforward choice.

 

Research Situations in Which This Route Deserves Priority Attention

 

Current objective	Suitability	Reason
To investigate whether nitro/nitroso substrates can enter amide bond formation directly	High	This is the central methodological value of this direction: the nitrogen-containing precursor does not need to be isolated first as an amine in order to enter the bond-forming process directly.
To compare the differences between “reduction first, then acylation” and “in situ bond formation” routes	High	This most clearly highlights differences in step economy, handling of intermediates, and route organization logic.
To study the decarboxylative bond-forming reactivity of α-keto carboxylic acids or α-oxo carboxylic acids	High	Such studies directly couple acyl-precursor design with amide bond formation and are well suited for examining the role of different acyl precursors in unconventional bond-forming pathways.
To investigate nitroso intermediates, N-hydroxyamide intermediates, or related mechanistic pathways	High	This direction is closely connected to mechanistic discussions involving expansion to nitroso compounds, N-hydroxyamide intermediates, and radical processes.
To develop a robust and broadly applicable synthetic process for common N-aryl amides	Medium–Low	Current public evidence better supports its use in methodological studies and route comparison, and is not yet sufficient to show that it should be prioritized as a general preparation strategy for common N-aryl amides.

 

5. Product Navigation Table for the Unconventional Amide Bond-Forming Route from Nitro and Nitroso Substrates with α-Keto Carboxylic Acids (Tables 1–3)

 

Current research or experimental objective	Which table to consult first	Why this table should be consulted first	Which table to consult next in combination	Navigation note
To first understand what kinds of nitrogen-source precursors are used in this route, and compare the differences among mononitroarenes, dinitroarenes, and nitrosoarenes	Table 1	Table 1 focuses on nitro/nitroso nitrogen-source substrates and mechanistic validation compounds, making it the best starting point for building an overall understanding of nitrogen-source types, electronic effects, and substrate-structure differences	Then Table 2	First use Table 1 to identify which class of nitrogen-source precursor you want to examine, then combine it with the α-keto carboxylic acids and basic reaction system in Table 2, which is more suitable for the first round of condition screening.
To compare the performance differences of different nitro/nitroso nitrogen-source precursors in amidation reactions using nitro substrates	Table 1	Table 1 already separates neutral, electron-donating, electron-withdrawing, and different dinitroarene models, making it convenient for parallel screening based on substrate structure	Then Table 2	The key to this task is first to build the matrix of nitrogen-source precursors, and then combine it with the fixed acyl precursor and oxidant/base system in Table 2 for side-by-side comparison.
To verify whether nitroso substrates or N-hydroxyamide intermediates are closer to the actual reaction pathway	Table 1	Table 1 includes nitrosobenzene and N-benzoyl-N-phenylhydroxylamine, which are especially suitable for mechanistic validation, pathway comparison, and intermediate-conversion testing	Then Table 2	To determine whether a given intermediate can further enter product formation, it is usually also necessary to test it together with the persulfate, base, and solvent system in Table 2.
To first reproduce or fine-tune the 2020 main-route conditions and establish the most basic one-step amidation reaction system	Table 2	Table 2 contains the aryl α-keto carboxylic acid substrates, ester-type precursors, and the most critical oxidant, base, and mixed-solvent system of the main route, making it the most direct starting-condition table	Then Table 1	After establishing the basic system, it is more suitable to move from “set up the conditions first” to “expand the substrate scope afterward” by selecting different nitro/nitroso substrates from Table 1 for testing.
To compare the performance of different α-keto carboxylic acid substrates in this route and evaluate how acyl-precursor structure affects bond-forming outcomes	Table 2	Table 2 includes benzoylformic acid, phenylpyruvic acid, pyruvic acid, and ester-type precursors, making it most suitable for substrate expansion and comparison of acyl sources centered on variation in α-keto carboxylic acid structure	Then Table 1	First complete screening at the acyl-precursor level in Table 2, then combine it with different nitrogen-source substrates from Table 1 to judge more clearly whether the outcome is being governed mainly by the nitrogen source or by the acyl precursor.
To optimize the oxidant, base, and medium ratio in order to improve conversion, selectivity, or reaction stability	Table 2	Table 2 provides the most critical condition variables, including potassium persulfate, potassium carbonate, acetonitrile, and water, making it most suitable for optimization centered on the reaction system itself	Then Table 1	Condition optimization should usually begin with one fixed set of representative substrates; once the main system becomes stable, different substrate types can then be expanded from Table 1.
To extend the study from the 2020 main route to catalytic or photocatalytic amidation systems that also use nitro substrates as nitrogen-source precursors	Table 3	Table 3 focuses on nitroalkanes, iron catalysis, photocatalysis, and hydrosilane reduction-system components, making it most suitable for extension toward the broader research direction of amidation using nitro substrates	Then Table 1 / Table 2	This type of task is best carried out after the main route in Tables 1 and 2 has already been understood; Table 3 is better suited as an advanced selection table for moving from the main route to extended systems.
To compare the differences between a “persulfate oxidation system” and an “iron/photocatalytic reductive coupling system”	Table 3	Table 3 directly corresponds to the core components of the catalytic extension route, making it convenient for system-level comparison with the oxidative main route in Table 2	Then Table 2	For system comparison, Table 2 is generally used as the reference for the main route, and Table 3 is then used to build the catalytic extension system, making it easier to compare differences between distinct bond-forming pathways.
To study whether nitroalkanes can also serve as nitrogen-source precursors in amidation, rather than being limited to nitroarenes	Table 3	The nitromethane and related catalytic-system components in Table 3 are better suited for this type of extension study	Then Table 1	If the goal is to compare the differences between nitroarenes and nitroalkanes as nitrogen-source precursors, the nitroalkane system in Table 3 can be designed in parallel with the nitroarene model substrates in Table 1.
To first build an overall understanding of the entire route and then gradually move into experimental design	First Table 1, then Table 2, and finally Table 3	Table 1 first addresses “where the nitrogen source comes from,” Table 2 then addresses “how to pair the acyl precursor and conditions,” and Table 3 finally adds “which catalytic systems this route can be extended into”	In the order Table 1 → Table 2 → Table 3	This sequence best matches the progressive logic of moving from conceptual understanding to condition establishment and then to directional expansion, and is also suitable for readers outside the field to enter the topic quickly.

 

Table 1 | Nitro/Nitroso Nitrogen-Source Precursors and Mechanistic Validation Chemicals

(for broader studies on amidation using nitro substrates)

 

Category	CAS No.	Aladdin Cat. No.	Name	Grade or Purity	Product Features and Applications
Common mononitroarene nitrogen-source substrate	98-95-3	N116217	Nitrobenzene	Guaranteed reagent, ≥99%	One of the most fundamental mononitroarene model substrates, suitable for establishing baseline reaction conditions for one-step amidation and for serving as an electronically neutral reference substrate when comparing the reactivity of differently substituted nitroarenes.
Halogenated mononitroarene nitrogen-source substrate	100-00-5	C108539	1-Chloro-4-nitrobenzene	Chemically pure (CP), ≥98%	A representative halogen-substituted nitroarene substrate, suitable for examining how electron-withdrawing substitution affects the efficiency of unconventional bond formation, and also useful for observing the compatibility of aryl halides under the reaction conditions.
Electron-donating substituted mononitroarene nitrogen-source substrate	100-17-4	N105584	4-Nitroanisole	≥98%	A representative electron-rich mononitroarene substrate, suitable for parallel comparison with neutral or electron-withdrawing substituted substrates to evaluate how the electronic properties of the aryl ring influence nitrogen-source precursor activation and amidation outcomes.
Mononitroarene model substrate / candidate nitrogen-source precursor for extension studies	99-99-0	N104645	4-Nitrotoluene	≥99%	A representative mononitroarene substrate that can be used in extension studies or comparative investigations within broader nitro-substrate amidation research, and is suitable for analyzing differences in reactivity and applicability among different nitro/nitroso precursors.
Para-dinitroarene nitrogen-source substrate	100-25-4	D100641	1,4-Dinitrobenzene	Analytical standard, for environmental analysis, ≥99.9%	A classic representative para-dinitroarene, suitable for examining the reactivity of dinitroarenes as nitrogen-source precursors and for comparing the effects of substrate-structure differences relative to mononitroarenes.
Ortho-dinitroarene nitrogen-source substrate	528-29-0	D111112	1,2-Dinitrobenzene	Analytical standard	An ortho-dinitroarene model substrate, suitable for comparing how ortho arrangement and steric factors affect the efficiency and selectivity of one-step amidation.
Meta-dinitroarene nitrogen-source substrate	99-65-0	D108543	m-Dinitrobenzene	≥99% (HPLC), for HPLC derivatization and steroid detection	A representative meta-dinitroarene substrate, suitable for parallel screening with ortho- and para-dinitroarenes to compare how different substitution patterns affect reaction performance.
Nitrosoarene expanded nitrogen-source substrate	586-96-9	N159156	Nitrosobenzene	≥98% (GC)	A direct nitrosoarene nitrogen-source precursor that can be used to verify the feasibility of bond formation after further conversion from the nitro starting point, and is also an important model substrate in mechanistic extension studies.
N-Hydroxyamide mechanistic validation compound	304-88-1	B108480	N-Benzoyl-N-phenylhydroxylamine	AR, ≥98%	A representative N-hydroxyamide intermediate model, suitable for validating possible pathways leading to the target amide product under oxidative conditions and for helping analyze intermediate stages of the reaction.

 

Table 2 | α-Keto Carboxylic Acid Substrates, Precursors, and the Key Reaction System of the Main Route

 

Category	CAS No.	Aladdin Cat. No.	English Name	Grade or Purity	Product Features and Applications
Core acyl precursor: aryl α-keto carboxylic acid	611-73-4	P100867	Phenylglyoxylic acid	≥95%	One of the most typical aryl α-keto carboxylic acid acyl precursors, suitable for directly establishing model reactions for one-step decarboxylative/oxidative amidation, and also serving as a benchmark substrate for comparing the performance of substituted aryl α-keto carboxylic acids.
Ester-type precursor of aryl α-keto carboxylic acid	15206-55-0	M158124	Methyl Benzoylformate	≥97% (GC)	An ester-type precursor of phenylglyoxylic acid, suitable for the preparation, conversion, or comparative study of related α-keto carboxylic acid substrates, and also useful for building substrate pretreatment and derivatization routes.
Extended substrate: α-keto carboxylic acid with an aromatic side chain	156-06-9	P107007	Phenylpyruvic acid	Moligand™, ≥98%	A representative α-keto carboxylic acid bearing an aromatic side chain, suitable for examining the applicability of non-phenylglyoxylic-acid-type substrates in decarboxylative amidation and for extending understanding of structure effects in α-keto carboxylic acids.
Simple α-oxo carboxylic acid candidate substrate for extension studies	127-17-3	P104138	Pyruvic acid	≥98% (T)	One of the simplest α-keto carboxylic acid models, suitable for baseline comparison and helpful for comparing the bond-forming behavior of aryl α-keto carboxylic acids with that of small aliphatic α-keto carboxylic acids.
Persulfate oxidant / initiator	7727-21-1	P112191	Potassium persulfate	Guaranteed reagent, ≥99.5%	A commonly used radical oxidant/initiator for triggering decarboxylation of α-keto carboxylic acids and the subsequent oxidative process; it is a key component in establishing this type of one-step amidation condition.
Mild inorganic base / basic medium	584-08-7	P485463	Potassium carbonate	Anhydrous, superior pure, reagent grade, ≥99%	A mild inorganic base suitable for providing a basic environment for persulfate systems, and often one of the first-choice inorganic bases during condition optimization.
Reaction solvent	75-05-8	A119012	anhydrous Acetonitrile (ACN)	Anhydrous, ≥99.8%, H₂O ≤0.003%	A commonly used polar aprotic solvent that can form a mixed medium with water, balancing substrate solubility with stability under oxidative conditions, and suitable for constructing semi-aqueous radical amidation systems.
Aqueous reaction medium	7732-18-5	W433895	Water	Suitable for analysis, premium grade	Used as the aqueous component of the reaction medium; together with acetonitrile, it can construct aqueous or semi-aqueous reaction environments and is suitable for comparing how different medium ratios affect reaction efficiency and substrate compatibility.

 

Table 3 | Common Substrates and Catalytic-System Components in Extension Studies of Amidation Using Nitro Substrates

 

Category	CAS No.	Aladdin Cat. No.	Name	Grade or Purity	Product Features and Applications
Nitroalkane expanded nitrogen-source substrate	75-52-5	N119666	Nitromethane	Anhydrous, ≥98.5% (GC)	A common nitroalkane model substrate, suitable for examining the amidation capability of nitroalkanes as nitrogen-source precursors and for pathway comparison with nitroarene systems.
Buffer base / phosphate-base system component	7758-11-4	D433945	di-Potassium hydrogen phosphate	Anhydrous, guaranteed reagent, suitable for analysis	Commonly used to construct a relatively mild phosphate basic environment, suitable for regulating acid-base balance and reaction stability in metal-catalyzed or photocatalytic amidation extension systems.
Iron catalyst	7783-86-0	I284056	Iron diiodide	PrimorTrace™, super dry grade, ≥99.99% metals basis	A representative iron catalytic component, suitable for catalytic extension studies of amidation involving nitro substrates, and also useful for comparing radical/reductive-coupling systems with metal-free oxidative systems.
Photoredox catalyst	870987-63-6	D396487	(4,4'-Di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-κN]phenyl-κC]iridium(III) Hexafluorophosphate	≥99%	A representative Ir photoredox catalyst, suitable for constructing extended nitro-based amidation systems involving photoredox catalysis, and for comparing differences between thermal and photocatalytic reaction platforms.
Hydrosilane reductant / additive	694-53-1	P160608	Phenylsilane	≥97% (GC)	A common hydrosilane reductant, suitable for catalytic amidation extension systems that require a mild reductive activation step, and helpful for exploring reductive-stage behavior during the conversion of nitro substrates to amides.

 

Note: The above are representative Aladdin products. For more product specifications, please refer to the product list at the end of the article, or search by “product name / CAS / catalog number” on the Aladdin official website.

 

References

 

[1] de Figueiredo RM, Suppo J-S, Campagne J-M. Nonclassical Routes for Amide Bond Formation. Chemical Reviews. 2016;116(19):12029-12122. doi:10.1021/acs.chemrev.6b00237.

 

[2] Wang S-P, Cheung CW, Ma J-A. Direct Amidation of Carboxylic Acids with Nitroarenes. The Journal of Organic Chemistry. 2019;84(21):13922-13934. doi:10.1021/acs.joc.9b02068.

 

[3] Barak DS, Dahatonde DJ, Dighe SU, Kant R, Batra S. Decarboxylative/Oxidative Amidation of Aryl α-Ketocarboxylic Acids with Nitroarenes and Nitroso Compounds in Aqueous Medium. Organic Letters. 2020;22(23):9381-9385. doi:10.1021/acs.orglett.0c03666.

 

[4] Barak DS, Batra S. Direct Access to Amides from Nitro-Compounds via Aminocarbonylation and Amidation Reactions: A Minireview. The Chemical Record. 2021;21(12):4059-4087. doi:10.1002/tcr.202100224.

 

[5] Ning Y, Wang S, Li M, Han J, Zhu C, Xie J. Site-specific Umpolung Amidation of Carboxylic Acids via Triplet Synergistic Catalysis. Nature Communications. 2021;12(1):4637. doi:10.1038/s41467-021-24908-w.

 

[6] Liu J, Yao J, Du J, Yu L, Duan W, Xiao Y, Lei Z. Direct Synthesis of α-Ketoamides via Copper-Catalyzed Reductive Amidation of Nitroarenes with α-Oxocarboxylic Acids. The Journal of Organic Chemistry. 2024;89(9):6575-6583. doi:10.1021/acs.joc.4c00237.

 

[7] Liu C, Qin X, Yuan W, Li H, Sun S, Li H, Xu T, Yin Z. Direct Photocatalytic Reductive Amidation of Nitroarenes: A Tandem Reduction-Decarboxylation Approach to Amide Bond Construction. Organic Letters. 2025;27(21):5417-5422. doi:10.1021/acs.orglett.5c01371.

 

[8] Khamkar SL, Mohan R, Santhosh J, Shinde HM, Handore KL, Mohan SV, Reddy DS, et al. Scalable and Sustainable Reductive Amidation of Nitroarenes, Nitroalkenes, and Nitroalkyls with Acyl Saccharins in Aqueous Media. Communications Chemistry. 2025;8(1):184. doi:10.1038/s42004-025-01464-8.

 

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