Advances in nitroarene reductive amidations

The amide functional group is common in natural and synthetic products. Its prevalence in fine chemicals and pharmaceuticals has propelled a surge in the development of new synthesis procedures to access this amide bond. Nitroarenes are key building blocks in organic synthesis and are easily accessible via nitration of parent arenes. This review highlights the use of nitroarenes as alternatives to access the amide functional group. A broad range of reductive amidation reactions and their proposed mechanistic pathways are discussed


Introduction
The development of new synthetic strategies to access amide bonds has been a key area in chemistry research for the past decade.These research endeavors have been propelled by the extensive feature of amides in chemical structures of natural products, 1 peptides, 2 polymers 3,4 and small organic molecules with applications in the pharmaceutical, medical 5,6 as well as agricultural industries. 7Furthermore, the identification of amide bond formation as a key green-chemistry research area by a team of pharmaceutical industry role players provided impetus for the observed surge in recent efforts aimed at developing alternative amide coupling methods. 8,9Traditionally, amide bonds are synthesized by a condensation reaction between amines and carboxylic acids at elevated reaction temperatures or by using an equivalent amount or more of carboxylic acid activators such as hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) and N,N'dicyclohexylcarbodiimide (DCC). 10The disadvantage associated with these reactions is their poor atom economy.The recently reported, and potentially life-threatening, allergic reactions linked to uronium salts raises serious health and safety concerns regarding their continued use in amidation reactions. 11Thus, catalytic amidation protocols are a more viable and attractive option.Boronic-acid derivatives are some of the most successful and efficient catalysts for direct amidation of carboxylic acids and amines at low-catalyst loading and reaction temperatures (Scheme 1). 12,13Group IV transition metals such as titanium, 14 zirconium 15 and hafnium 16 have also shown impressive catalytic properties.Scheme 1. Promoter or heat-driven amidation of carboxylic acids.
The use of carboxylic acid and amine surrogates such as esters, 17 amides, 18 aldehydes, 19,20 alcohols, 21,22 and azides 23 has also gained momentum as alternative substrates for amide synthesis.These substrates present practical, and yet convenient, approaches to access amides.5][26][27][28][29][30][31][32][33] Nitroarenes can also be used as amine surrogates to provide a step economic approach to synthesize amides as well as carbamates via reductive amidation reactions, however, their use has not been extensively highlighted. 34,35Therefore, the main objective of the current review is to bring to the spotlight the application of nitroarenes as suitable substitutes for aryl amines in amide coupling reactions.As highlighted in Scheme 2, nitroarenes can be readily reduced to their nitroso i, hydroxylamine ii and amine iii derivatives.Intermediates i and ii can react to form azoxybenzene iv and azobenzene v which can be further reduced to amine iii. 36All these intermediates can react to a certain extent with carbonyl sources to form amide products, and these reactions as well as their mechanisms will be covered in this review.[39] Scheme 2. Proposed general mechanism for the reduction of nitroarenes to possible reactive intermediates.

Reductive Amidation of Carboxylic Acids
Carboxylic acids are the most commonly used coupling partners with amines which are themselves derived from nitro compounds through reduction reactions.Therefore, direct reductive coupling reactions between nitroarenes and carboxylic acids are an attractive and convenient way to access amides.Reports in 1977 by Owsley and Ho represent some of the earliest reactions that shed light on reductive amidation reactions between carboxylic acids and nitroarenes.Owsley reported the use of iron powder and acetic acid to reduce nitroarenes to their acetanilide derivatives. 40Ho then used molybdenum hexacarbonyl (Mo(CO)6) as a reducing agent in the presence of acetic acid to afford the desired acetanilide products in moderate yields. 41n 1984, Watanabe and co-workers reported a platinum (Pt) and tin (Sn) catalyzed reductive amidation of nitroarenes with carboxylic acids such as succinic acid, acetic acid and propionic acid at 150 or 180 o C under 60 atm carbon monoxide. 42Interestingly, and as shown in Scheme 3, reactions were successful with both nitroarenes as well as nitroalkanes; however, lower product yields were obtained for the later substrates.
Proposed reaction-mechanism studies suggest a Pt-catalyzed carbon monoxide deoxygenation of the nitro functional group to form a nitrene intermediate.Pt and Sn then catalyze a CO insertion to afford the isocyanate intermediate, which then reacts with carboxylic acid to afford the amide and CO2 byproduct.Kim and co-workers later explored Owsley's iron-promoted reductive-amidation reactions, and investigated the reactivity of more carboxylic-acid substrates such as formic acid, propionic acid, butyric acid, trifluoroacetic acid, and chloroacetic acid with various nitroarenes. 43Their reactions also required more than three mol equivalences of Fe as well as reflux temperatures as reported by Owsley, and products were obtained in good to excellent yields.Kumar and co-workers recently demonstrated a direct reductive amidation of nitroarenes with carboxylic acids using cobalt(II) phthalocyanine catalyst and polymethylhydrosiloxane as a reducing agent. 44Their methodology was compatible with a variety of substituted nitroarenes affording products in good to excellent yields.Unfortunately, the substrate scope with carboxylic acids (just like in the case of Owsley and Ho) was limited, as reaction yields were poor with solid or aromatic carboxylic acid substrates.
Yields determined by GC whilst isolated yields are in parentheses.a Reactions conducted at 150 o C. Scheme 3. Platinum and tin co-catalyzed reductive amidations.
In 2006, Xu and co-workers reported a red-phosphorus-mediated and iodine-or iodide-catalyzed reductive acylation of nitroarenes. 45Excellent conversions and selectivity towards amide products were obtained with alkyl carboxylic acids whilst aryl carboxylic acids had a lower selectivity.In addition to iodine, iodide sources such as sodium iodide, potassium iodide and potassium triiodide were found to be effective catalysts, suggesting an I -/I 0 redox cycle catalytic system.As shown in the proposed reaction mechanism in Scheme 4, phosphorus is oxidized to phosphorus(V) and iodine is reduced to I -which in turn reduces nitroarenes to their amine derivatives.Amidation is then promoted by the phosphorus pentaiodide intermediate.
Following earlier work on direct amidation of carboxylic acids and amines by Lakshman and co-workers, 46 Ma and co-workers reported a modified two-step triphenylphosphine and iodine promoted reductive amidation of nitroarenes with carboxylic acids using manganese (Mn) and trimethylsilyl chloride (TMSCl) as reducing agents. 47As highlighted in Scheme 5, a broad variety of amides were synthesized from a diverse range of functionalized alkyl, (hetero)aromatic α,β-unsaturated carboxylic acids, and nitroarenes.Amide containing drug molecules such as mepronil, human 11β-HSD1 enzyme inhibitor as well as a benzoxazole antibacterial agent were successfully synthesized to demonstrate the applicability of their protocol.Furthermore, several agrochemicals, and drug molecules possessing carboxylic acids such as ibuprofen, MCPA, naproxen, gemfibrozil and dehydrocholic acid were converted into their amide derivatives.Attempts to perform reactions in a onestep procedure afforded lower product yields.

AUTHOR(S)
Mechanistic studies (Scheme 6) suggest that TMSCl or TMSI (generated from halide exchange with KI) acts as a deoxygenating agent and together with Mn, reduce nitroarenes to the nitrosoarene derivative i.This can be further reduced to the N-aryl hydroxylamine derivative ii.Both intermediates i and ii can react with the acyloxyphosphonium salt iii, acyl chloride iv or iodide derivatives v (obtained from TMSCl or KI, respectively) to form a N-(trimethylsilyl)oxy vi or N-hydroxy amide intermediate vii.These undergo a further Mn-mediated reduction to afford the desired amides upon acid workup.Scheme 6. Proposed PPh3/I2, TMSCl and Mn-mediated reductive-amidation reaction mechanism.i) Nitroarene reduction.ii) COOH activation and subsequent amidation.

Reductive Amidation of Esters
9] Reactions of esters with nitroarenes are, therefore, also desirable, as this may offer alternative protocols to access amides under relatively mild reaction conditions.Reductive amidation of esters was initially explored by Wang and co-workers who, in 2004, reported a room-temperature reductive amidation using nitroarenes and samarium diiodide (SmI2). 50Electronic as well as steric effects around the nitro group did not reduce reactivity of the nitroarenes as reactions were complete within 30 minutes, forming the desired products in excellent yields.In addition, reactions were compatible with alky, aryl, and α,β-unsaturated esters as well as lactones (Scheme 7).In 2017, Hu and co-workers reported an efficient nickel (Ni)-catalyzed direct amidation of esters using nitroarenes. 51eactions were successful in the presence of Ni(glyme)Cl2 pre-catalyst, 1,10-phenanthroline ligand, TMSCl and zinc (Zn) as reducing agents as well as N-methyl-2-pyrrolidone (NMP) solvent (Scheme 8).Overall, the authors successfully synthesized a library of over 65 amides to establish the scope and limitations of their protocol.Highly functionalized alkyl and aromatic esters were transformed to amides using electronically diverse nitro(hetero)arenes.Amidations were successful with esters possessing O-alkyl or O-aryl groups bonded to the carbonyl carbon.
Stronger reducing agents such as Mn and TMSI as an additive as well as higher reaction temperatures, however, were required to achieve better reaction yields for sterically hindered esters.The reported protocol tolerated a broad range of base-and acid-sensitive functional groups such as carbonyls, amines, alkyl halides and alkenes.In addition, the authors demonstrated that reductive amidation with nitroarenes was efficient compared to the traditional two-step reduction of nitroarenes-to-amine derivatives followed by amidation.The reaction conditions were subsequently applied in the derivatization of valuable ester-possessing agrochemicals, and medicinal compounds such as Tazarotene and MCPA-methyl.Furthermore, application of the protocol in late-stage functionalization of nitroarenes provided alternative and more efficient routes to access amidecontaining medicinal compounds and natural products.
Although not conclusive, preliminary mechanistic studies reported by the authors propose the reaction to proceed via two possible mechanisms (Scheme 9).In the first case (A), Zn reduces Ni(II) to Ni(0), followed by ester insertion and subsequent reaction with azoarene (generated from Zn and TMSCl nitroarene reduction More detailed mechanistic studies involving gas-chromatography-supported reaction monitoring, reaction kinetics, as well as Hammett plots generated from these studies, identified azoarene as the final nitrogen source from nitroarene reduction. 52In addition, DFT-computational studies proposed the Ni catalytic cycle to proceed via a complex mechanism whereby azoarene coordinates to Ni(0) as proposed in mechanism B to form the Ni(II) nitrene intermediate species vi (Scheme 10).These intermediates further react with Zn salts to form the bridged Ni2(imide)2 intermediate vii.Monomers viii are then formed as the result of N-Ni bond cleavage, resulting in a ZnCl2-stabilized bimetallic complex which is believed to be the species that reacts with esters to form the amides.
In 2019, Ma and co-workers reported an alternative reductive-ester-amidation protocol using manganese (Mn) as both a promoter and reducing agent, thus, requiring no additional metal catalyst or ligand (Scheme 11). 53TMSCl was used as a co-reducing agent whilst the use of TMSI did not improve reaction yields.No product was observed when TMSOTf was used as an additive.Amide products were successfully obtained in good-toexcellent yields from the coupling of a broad substrate scope of esters and nitroarenes.The reaction conditions were compatible with substituted alkyl and (hetero)aromatic esters with a diverse range of alkoxy, benzyloxy or aryloxy groups.Scheme 11.Mn-mediated reductive amidation.
The methodology was also successfully applied in the gram-scale synthesis of amide drug intermediates as well as antimicrobial agents.Preliminary reaction-mechanism studies reveal nitrosoarene i as a possible nitrogen source involved in the amidation step.Reactions with other possible nitroarene reduction intermediates or products such as aniline, azoarene and N-phenylhydroxylamine did not afford any product, whilst trace amounts of product were observed for azoxyarene ii and 1,2-diarylhydrazine intermediate iii.
In 2019, Zeng and co-workers also demonstrated esters as suitable coupling partners for reductive amidation with nitroarenes, using chromium chloride (CrCl3) as a catalyst, magnesium (Mg) as a reducing agent and TMSCl as an additive (Scheme 12). 54Reactions were successful at 90 o C with aliphatic or aryl esters and substituted nitroarenes affording amides in good to excellent yields.The utility of this protocol was further demonstrated by synthesizing biologically relevant molecules as well as their derivatives.Activated esters were found to be more reactive than their inactivated counterparts, whilst electron-rich nitroarenes were more reactive than electron-poor counterparts.

Reductive Aminocarbonylations
Aminocarbonylation reactions provide an alternative method to access amides from alkenes, alkenyl and aryl halides.In 2013, Beller and co-workers reported a Pd-catalyzed aminocarbonylation of olefins using amines or nitroarenes (Scheme 13). 55Syngas (CO/H2) was used to introduce the carbonyl functionality as well as nitroarene reduction, whilst p-toluene sulfonic acid (p-TsOH) was used as an additive at 100 o C.Although the substrate scope was limited for nitroarene reactions, aliphatic alkene substrates and nitroarenes with reducible functional groups such as ketones and nitriles were tolerated.Scheme 13.Pd-catalyzed reductive aminocarbonylation of olefins.
In 2017, Driver and co-workers reported a Pd-catalyzed intermolecular C-H aminocarbonylation of Nheteroaryl bicyclic molecules using nitroarenes and Mo(CO)6 as nitrogen and carbonyl sources, respectively (Scheme 14). 56Reactions were conducted for 12 hours in DCE at 120 o C and were successful with a variety of substituted 2-aryl pyridines.Nitroarenes with electron-withdrawing groups afforded higher product yields compared to those possessing electron-donating groups.In addition, increasing steric functionalities around the nitro group hindered the reaction.Remarkably, heteroarenes such as thiophenes, pyrroles and indoles could also undergo C-H activation to afford corresponding amides in acceptable yields.Furthermore, the pyridine ring could be replaced with pyrimidine or an indazole to achieve structural diversity of products.
As shown in Scheme 15, the reaction mechanism proposed a nitrogen-directed C-H activation which forms palladacycle i.This compound then reacts with Mo(CO)6 to form a Pd-carbonyl species, ii, which reduces nitroarene to form a nitrosoarene intermediate.Nitroarene reduction simultaneously regenerates the palladacycle i which can reversibly form dimer iii.Palladacycle i then activates the 2-aryl pyridine substrate to form complex iv.Insertion of CO from Mo(CO)6 affords the acyl palladium intermediate v which reacts with nitrosoarene to afford the hydroxy amide intermediate vi.Mo-promoted reduction then affords the desired amide product.

AUTHOR(S)
Scheme 14.A representation of amide products obtained by Pd-catalyzed reductive C-H aminocarbonylation.

Scheme 15. Pd-catalyzed C-H aminocarbonylation.
Aminocarbonylation is the most commonly used method to construct amide bonds from aryl halides and amines, however, the use of nitroarenes as a nitrogen source in these reactions has not been widely explored.Hu and co-workers reported the first protocol demonstrating the use of nitroarenes in aryl halide aminocarbonylation . 57In their protocol, Ni was used as the catalyst of choice as it is cheaper and readily available.Dicobalt octacarbonyl (Co2(CO)8) was used as a source of CO, and Zn powder was used as a reducing agent in the presence of TMSCl (Scheme 16).Reactions were successful at 120 o C using electronically-diverse (hetero)aryl iodides as well as bromides.Nitro(hetero)arenes possessing a variety of functional groups, such as free NH, silyl protecting groups, esters and alkenes, were also compatible with the protocol.Steric substituents around the nitro group did not diminish product yields.Mechanistic studies proposed a Ni(II) pre-catalyst reduction by Zn to Ni(0), which then undergoes an oxidative addition to form a Ni(II)-aryl halide intermediate i. CO insertion affords acyl complex ii which then reacts with either N-phenyl hydroxylamine or aniline to form the amide anion iii as well as regeneration of the Ni(0) active catalyst.Acidic work-up affords the desired amide product.

Scheme 16. Ni-catalyzed Zn-mediated reductive aminocarbonylation of aryl halides with proposed mechanism.
In 2018, Wu and co-workers reported a Pd-catalyzed aminocarbonylation of styrenes to afford α,βunsaturated amides in good stereo-and regioselectivity.Reactions were conducted at 130 o C for 14 hours in the presence of benzenesulfonic acid and the bidentate ligand 1,3-Bis(diphenylphosphino)propane (DPPP) (Scheme 17).Mo(CO)6 was used as both a carbonyl source and reductant.Furthermore, nitroarene proposed to play a dual role of oxidant and nitrogen source as reactions with aniline only produced products in the presence of nitrobenzene.Nitroarenes possessing electron-withdrawing groups afforded lower product yields, whilst electronics did not have a significant impact on the reactivities of styrenes.Aryl alkene derivatives such as trans-β-methylstyrene, α-methylstyrene and allylbenzene did not undergo the anticipated aminocarbonylation.
Preliminary mechanistic studies suggest a Pd reduction by Mo followed by complexation with nitroarenes to form imide species i. Coordination to styrene forms intermediate ii which is followed by a migratory insertion to give intermediate iii.CO insertion affords carbonyl-Pd intermediates iv or v. Reductive elimination affords the amide product, whilst nitroarene oxidizes Pd(0) to Pd(II).
In 2019, the groups of Wu and Ma reported the aminocarbonylation of boronic acids with nitroarenes using Pd and Ni, respectively. 59,60In the case of Pd-catalyzed reactions, Mo(CO)6 was used as a reducing agent and CO source.Interestingly, reactions were successful under basic conditions, and the use of acidic additives such as PTSA resulted in diminished product yields.Furthermore, reaction yields improved with the addition of H2O which is proposed to be a hydrogen source, thus, aiding in the nitroarene reduction.Ni was used as catalyst and reducing agent in aminocarbonylation reactions reported by Ma.Sodium iodide was found to improve Nicatalyst activity whilst TMSCl aided in nitroarene reduction and in their case, CO gas was used as the carbonyl source.Both protocols afforded a broad range of aryl amides in good-to-excellent yields.In the same year, Mankad and Zhao also reported a synergistic copper-catalyzed reductive aminocarbonylation of alkyl iodides with nitroarenes (Scheme 18). 61According to the authors, this represented the first, and only, example demonstrating C(sp 3 )-hybridized electrophiles in reductive aminocarbonylation reactions.N-heterocyclic carbene (NHC) ligands played a crucial role in preventing alkyl halide reduction.Reactions were successful with primary, secondary and tertiary halides, however, substituting iodine for bromine resulted in trace reactant conversions.Alkanes possessing aryl halides and reducible groups such as esters and cyanides afforded products in satisfactory yields.Nitrobenzene and its para-substituted derivatives afforded products in excellent yields, however, meta-or ortho-substituted derivatives afforded either low or no products.Mechanistic studies proposed a copper-mediated radical aminocarbonylation reaction.Aniline was the proposed nitrogen nucleophile as other possible nitrobenzene reduction intermediates gave low-product yields.NHC copper catalyst and PhSiH3 were also shown to play a role in reducing nitrobenzene to aniline, thus, indicating the dual role of copper in the reaction.

AUTHOR(S)
a Cl IMesCuCl used instead of Cl OMeIMesCuCl.b Product isolated with 10% inseparable impurities Scheme 18.A representation of some products obtained from Cu-catalyzed reductive-aminocarbonylation reactions.

Reductive Amidation of Aldehydes and Alcohols
Aldehydes have been widely used as suitable substrates for oxidative amide coupling with amines. 19In 2014, Vishwakarma and co-workers reported a MnO2-catalyzed method for the synthesis of amides from aldehydes and nitroarenes (Scheme 19). 62MnO2 is reported to play a role in the absorption and thermal deoxygenation of nitroarenes to afford the respective nitrosoarene intermediates.These intermediates then react with aldehydes to afford the observed amides. 63Reactions were performed at 60 o C in the presence of acetic acid as an additive, and afforded the desired amides in CHCl3.The use of greener solvents such as methanol afforded lower product yields.A variety of amides were synthesized by varying substituents on aromatic aldehydes whilst ortho-halosubstituted nitroarenes afforded minor product yields.Reactions with aliphatic nitro compounds did not afford the desired products.The authors were able to obtain both amides and hydroxamic acids in a 3:7 ratio using solvent-free conditions and a base as an additive.
In 2015, Zhang and co-workers reported a green and efficient protocol for synthesis of aromatic amides from aldehydes and nitroarenes using Zn as a reducing agent and NaClO3 as an oxidizing additive (Scheme 20). 64mide products were obtained at low reaction temperatures, and in relatively short reaction times.The protocol was also tolerated by a variety of functional groups such as alcohols, alkenes, halides, ester, ketones, carboxylic acids and nitro heterocycles.Alcohols can also be oxidized into their aldehyde derivatives in situ and subsequently be converted to amides. 65,21In 2012, Deng and co-workers reported a transition-metal-free alcohol oxidative amidation protocol using nitroarenes as a nitrogen source (Scheme 21). 66Chlorobenzene was the solvent of choice as it afforded the highest product yields, whilst tert-butyl peroxide (TBP) was the most effective oxidizing agent.Changing base from KOH resulted in diminished product yields.A broad range of benzyl alcohols and nitroarenes were reacted to afford aromatic amides in moderate-to-good yields.Electron-donating or -withdrawing groups did not reduce the reactivity of the benzyl alcohols or nitroarenes.Aliphatic alcohols and aliphatic nitro compounds did not afford the desired products.Control experiments designed to establish the reaction mechanism suggest an in situ generated aldehyde (obtained from TBP oxidation of the respective benzyl alcohol) and azoxybenzene (obtained from basic reaction conditions in the presence of phenyl chloride) as the reactive intermediates that form the observed amide products.Scheme 21. tert-Butyl hydroperoxide (TBP)-mediated oxidative amidation of alcohols.

Reductive Transamidations
Amides form part of a wide range of natural and synthetic products, and their transformation into new amide products is attractive.These reactions may be challenging, however, due to possible competition between the reacting amine and the ensuing amine byproduct.In 2017, Hu and co-workers reported a Ni-catalyzed and Zn-TMSI-mediated reductive transamidation of Boc-activated secondary amides with nitroarenes (Scheme 22). 67AUTHOR(S)

Reductive Amidation of Acid Chlorides and Acid Anhydrides
Acyl chlorides as well as acid anhydrides readily react with amines under mild reaction conditions to form amides. Thus, their reactions with nitroarenes are also desirable as these offer a step-economical amide synthesis option.Most of the early reductive acylation protocols were conducted in acetic acid or acetic anhydride affording the corresponding N-arylacetamides.Examples of these have been reported by Baruah in 2000, where an AcO2-Zn-Al2O3 system was used for acetamidation of nitroarenes at room temperature. 69In 2003, Kim and co-workers reported a room-temperature indium-mediated reductive acetamidation of nitroarenes using a combination of acetic acid and acetic anhydride in methanol. 70Products were obtained in relatively short reaction times and excellent yields (Scheme 24).Scheme 24.Indium mediated reductive acylation of nitroarenes.a Trace N,O-diacetylated product was observed.b 3 -5% of azobenzene was observed.
Furthermore, Bhattacharya and co-workers reported a thioacetate-mediated reductive acetamidation of nitroarenes to afford the desired amides in or under solvent-free conditions. 71The authors then applied their protocol to synthesize an analgesic p-hydroxyacetamide (Acetaminophen TM ) from p-nitrophenol in a single step.
In 2006, Maleczka Jr and Rahaim Jr reported a Pd-catalyzed silane-or siloxane-reductive amidation, amination, sulfonamidation, carbamation and hydroxylamination of nitroarenes. 72The amidation reactions were successfully achieved in a one-pot, two-step protocol using anhydrides as carbonyl donors (Scheme 25).In 2009, Hamann and co-workers reported a Zn and acetic acid promoted reductive amidation of nitroarenes with acyl chlorides and triethylamine (Scheme 26). 73Products were obtained in moderate yields under mild conditions and relatively short reaction times.The protocol was further used to successfully functionalize nitro derivatives of alkaloids, such as harmane as well as manzamine A.

Scheme 26.
A representation of the products obtained by Zn and acetic acid promoted nitroarene acylation with acyl chlorides.
In 2020, Benaglia and co-workers reported a metal-free, one-pot, two-step trichlorosilane-promoted reductive amidation of nitroarenes with anhydrides in the presence of methanol as an additive (Scheme 27). 74itroarenes with electron-withdrawing groups afforded higher product yields compared with those possessing electron-donating substituents.Reducible substituents such as nitriles and carbonyls were compatible with the protocol.Furthermore, acyl chlorides, pyridyl thioesters and lactones were also suitable acylating agents, with the latter affording functionalized amide products which could be utilized as intermediates for further synthetic manipulations.

Conclusions
Amides are found in a plethora of molecules with a broad range of beneficial applications.As a result, new methods are constantly being researched and developed to provide alternative and more sustainable ways to access amide bonds. 29Reductive amidation using nitroarenes as a direct source of nitrogen is a growing area of research and has gained momentum in recent years.This review has summarized some of the advances made thus far.Significant progress has been achieved in this research area with most of the reactions furnishing products from a comprehensive substrate scope.These reactions have proved to be step-economic, tolerant to different functional groups, and convenient for constructing amide bonds.Validation of the preliminary reaction mechanisms for some of the reported protocols will aid in understanding and improving the reaction conditions.Furthermore,the successful application of nitroarenes in direct reductive amidation reactions sets the stage for investigation of alkyl nitro compounds as suitable substrates for similar reactions.This creates a golden opportunity for further development and establishment of methodologies that can be applied in the synthesis of alkyl amides such as peptides.

Scheme 4 .
Scheme 4. Phosphorus-mediated and iodine-catalyzed reductive amidation of nitroarenes with carboxylic acids and the proposed reaction mechanism.

Scheme 12 .
Scheme 12. Reaction scheme and mechanism of Cr-catalyzed and Mg-mediated reductive amidation of esters.