Transition Metal and Inner Transition Metal Catalyzed Amide Derivatives Formation through Isocyanide Chemistry

Abstract The synthesis of amides is a substantial research area in organic chemistry because of their ubiquitous presence in natural products and bioactive molecules. The use of easily accessible isocyanides as amidoyl (carbamoyl) synthons in cross-coupling reactions using transition metal and inner transition metöal catalysts is a current trend in this area. Isocyanides, owing to their coordination ability as a ligand and inherent electronic properties for reactions with various partners, have expanded the potential application of these transformations for the preparation of novel synthetic molecules and pharmaceutical candidates. This review gives an overview of the achievements in isocyanide-based transition metal and inner transition metal catalyzed amide formation and discusses highlights of the proposed distinct mechanisms. 1 Introduction 2 Synthesis of Arenecarboxamides 3 Synthesis of Alkanamides 4 Synthesis of Cyclic Amides 5 Formation of Alkynamides 6 Formation of Acrylamide-like Molecules 7 Formation of Ureas and Carbamates 8 Conclusion


Introduction
Amides as a privileged carboxylic acid derivatives are ubiquitous both in nature and synthetic laboratories and they are an extremely important structural motif in natural products, pharmaceuticals, drug intermediates, agrochemicals, and polymers. 1 Amide groups are one of the most abundant functional groups in the medicinal chemistry database and more than a quarter of all marketed pharmaceutical drugs possess at least one amide bond. 2 The favorable features of amides, such as high polarity, stability, and conformational diversity, make them one of the most reliable reaction partners in a wide variety of transformations, for instance as directing groups in C-H activation and as electrophilic partners in coupling reactions (such as arylation, phosphorylation, olefination, cyanation, alkynylation, borylation, silylation, and alkylation, etc.). 3 Therefore, owing to this remarkable chemistry, the synthesis of amides is one of the most widespread processes in organic chemistry research laboratories. Common classical methods for the preparation of amides do not meet the standards of green chemistry due to the requirements for harsh conditions and the production of chemical wastes, therefore, activity in the search for reliable synthetic methods continues.
In 2020, Benaglia and co-workers reviewed amide synthesis from 2017, specially focusing on metal-free strategies. 4 In his review and much other literature in this field, the use of isocyanides as a reagent has been shown to be prominent. Actually, isocyanides are a very versatile reagent; they are simultaneously a one carbon building block and amine precursor which means that it is one of the best reagents for generating the amide functional group.
Although isocyanides have a long history in synthetic chemistry, their use flourished after the development of the Ugi reaction by Ivar Ugi in 1959. 5 Notably, the Ugi fourcomponent reaction (aldehyde/ketone, amine, isocyanide, and carboxylic acid) 5 is a successful reaction (Scheme 1a) that is an elegant modification of the Passerini three-component reaction (aldehyde/ketone, isocyanide, and carboxylic acid) which was reported in 1921 (Scheme 1b). 6 So far, different versions of these two original Passerini and Ugi reactions that mainly produced amide derivatives have been reported. 7 After the Ugi report, exhaustive efforts were devoted to utilizing isocyanides in many innovative reactions. 7d,8 In this regard, in 2014 Orru and co-workers re-viewed isocyanide-based multicomponent reactions (IMCRs) for the construction of cyclic amidic bond linkages and peptidomimetic compounds. 8a Transition-metal-catalyzed cross-coupling reactions are powerful tools for producing diverse arrays of compounds. 9 The nature of isocyanides in generating high structural diversity and molecular complexity and the application of transition-metal catalysts in their reactions expands this capability. 10 There are some excellent articles that have reviewed isocyanide-based transition-metal-catalyzed reactions, however, owing to the importance of amide synthesis, as a result of further developments a specific, comprehensive, and up-to-date review article is required to reveal the synergistic effects of the combination of these two proliferous fields. Herein, we summarize the most important achievements in this field with a focus on synthetic applications of the derived products as well as their mechanistic aspects.

Synthesis of Arenecarboxamides
In a pioneering study, in 2011 Jiang and co-workers disclosed the synthesis of arenecarboxamides 2 using a Pd-catalyzed reaction of aryl halides 1, isocyanides, and water (Scheme 2a). 11 In 2016, Perego, Ciofini, Grimaud, and coworkers detailed a mechanistic study of this imidoylative coupling reaction (Scheme 2b). 12 They found that isocyanide can act as an unprecedented ligand for Pd complexes as well as disclosing the formation of amides from the reaction of [(ArC=NR)Pd(CNR) 2 I] species with H 2 O. They also used ab initio calculations at the DFT level to rationalize the multiple roles of RNC in the different steps of the catalytic cycle.

Scheme 2 Pd-catalyzed C-C bond coupling reactions of aryl halides and isocyanides
Subsequently, the use of a polymer-supported Pd-NHC complex 13 and nanodomain cubic Cu 2 O 14 as heterogeneous catalysts for the reaction of aryl halides and isocyanides have been also reported. Yavari and co-workers developed a Cu-catalyzed version of this reaction. 15 Bazgir and co-workers reported a Co-catalyzed reaction of brimonidine with isocyanides to yield imidazol-2-ylamino-substituted quinoxaline-5-carboxamides. 16 Synthesis of 3-(oxazol-5-yl)quinoline-2-carboxamides using 5-(2-chloroquinolin-3-yl)oxazoles and isocyanides in the presence of Pd(OAc) 2 was reported. 17 Liu, Gao, and coworkers described a Pd/Cu-catalyzed oxidative cross-coupling of arylboronic acids with isocyanides for the selective synthesis of substituted benzamides. 18 Wang, Ji, and co-workers prepared imides 4 by a Mn(III)-mediated oxidative radical process from arylboronic acids 3 and aryl isocyanides (Scheme 3). 19 Arylboronic acids 3 on treatment with Mn(III) generate aryl radicals, which can be trapped by isocyanides en route to the final imides 4.

Scheme 3 Mn(OAc) 3 -catalyzed oxidative coupling reaction of arylboronic acids and aryl isocyanides
In this context, styrenes substituted with electronreleasing alkyl and alkoxy groups and also benzylamines acted as aryl sources and react with aryl isocyanides to form N-arylbenzamides. 20 The reaction was catalyzed by Cu(OAc) 2 in the presence of tert-butyl hydroperoxide (TBHP). A Cu-catalyzed cross-coupling reaction of arenediazonium salts and isocyanides gave arenecarboxamides in moderate to good yields. 21 Two synthetic methods for the preparation of amides derived from the Pd-catalyzed reaction of aryl isocyanides with carboxylic acids 22 and Cu-catalyzed reaction of isocyanides with aldehydes have also been described. 23 Interestingly, Zhu and co-workers reported a Pd(II)-catalyzed direct amidation of indoles 5 with isocyanides as a amide source, through a C-H bond activation process at C3, to give indole-3-carboxamides (Scheme 4). 24 The reaction starts with electrophilic palladation at C3 of the indole 5 followed by isocyanide incorporation to generate imidoyl-Pd(II) intermediate 8. Notably, when the C3 of indole is blocked, palladation takes place at C2. The existence of an acidic additive is crucial for the formation of N-alkyl(aryl)-1H-indole-3-carboxamides 6 inducing a rapid OAc -/OHexchange in Pd(II)-C species 8. Without acid and water, tertiary N-acetyl-N-alkyl(aryl)-1H-indole-3-carboxamides 7 are formed. Using Cu(OAc) 2 as an oxidant assists the regeneration of Pd(II) from Pd(0) species. Khalaj and co-workers extended this direct access to the formation of benzamide derivatives using the reaction of benzene and active aromatic compounds with isocyanides; 25 this reaction was catalyzed with Pd(OAc) 2 in the presence of (NH 4 ) 2 S 2 O 8 as oxidant and mixture of acidic additives PivOH and TFA in diglyme as solvent.

Scheme 4 Amidation of indoles by isocyanides through C-H activation
In another impressive strategy for the preparation of indole-3-carboxamides 10 and 11, 2-alkynyltrifluoroacetanilides 9 underwent sequence annulation and isocyanide insertion reactions (Scheme 5). 26 The cyclization proceeds via activation of the C≡C bond by Pd(II) followed by basemediated nucleophilic attack of the nitrogen of the trifluoroacetanilide moiety. Next, imidoylative coupling with isocyanide, hydroxyl replacement, and then tautomerization delivers the desired product 10. Notably, addition of KOAc rather than Cs 2 CO 3 furnished tertiary N-acetylindole-3-carboxamides 11.
Alternatively, Yao, Wu, and co-workers employed a tandem protocol to develop synthetic methods for the preparation of similar indole-3-carboxamides by use of 2-alkynylanilines. 27 Accordingly, the combination of N,N-dimethyl-2-alkynylanilines, isocyanides, and AgOAc as oxidant in the presence of Pd(II) catalyst gives indole-3-carboxamides in good to high yields. Replacing AgOAc with other oxidants led to inferior yields. Liu, Wu, and co-workers also used silver trifluoroacetate as an alternative oxidant in the same reaction in DCE solvent, but, surprisingly, indole-3-carbonitriles were obtained as major products. 28 However, in this strategy, the solvent has a determinative role in the selectivity for the products. When the solvent was switched to THF, the yield of indole-3-carboxamides improved further to 72% in the presence of Pd(OAc) 2 , which, according to the authors, was probably due to the amount of water present in THF.
Pal and co-workers developed an innovative Pd catalytic scenario for the straightforward synthesis of indoloquino-line-11-carboxamides 13 from the treatment of N-arylindole-2-amines 12 by isocyanides in DMSO/H 2 O as solvent and DBU as base (Scheme 6). 29 Inspired by the formation of 11-arylamino-substituted 6H-indolo[2,3-b]quinolines 14 in DMF as solvent and Cs 2 CO 3 as base 30 which included Pd-catalyzed imidoylative insertion of isocyanide between aryl and indolyl moieties in 12, the authors proposed four key steps for the formation of 13. These are include isocyanide insertion, intramolecular nucleophilic attack of indole C3, coupling of a second isocyanide, and desulfonylation (Scheme 6). Optimization of the reaction conditions demonstrated the necessity of using DBU as the base and the presence of water for accessing indolo[2,3-b]quinoline-11-carboxamides 13 preferentially over the C11-aminosubstituted products 14. Finally, the anticancer activities of products were evaluated by in vitro biological studies.
Sarkar, Sen, and co-workers designed a chemo-and regioselective intramolecular decarboxylative C-H arylation followed by carboxamidation of aryl halide 15 with isocyanides. The reaction was efficiently catalyzed by reusable nano-Cu 2 O under sonication to form benzofuran-1-carboxamides 16 (Scheme 7). 31 Zhu, Wang, and co-workers developed a successful protocol for the synthesis of 2-substituted 5-aminooxazole-4carboxamides 17 from carboxylic acids and isocyanides using ZnBr 2 as an efficient Lewis acid catalyst (Scheme 8). 32 This strategy is accomplished by co-trimerization of isocyanide with the carboxylic acid followed by the loss of an alkyl group. The best results were obtained when 1.5 equiv. of catalyst were used probably due to chelate formation of oxazole products with Zn 2+ leading to product inhibition.

Special Topic Synthesis
oxazole came from the carboxylic acid. They also presented an efficient synthetic method for the preparation of 5-aminothiazole-4-carboxamides from thiocarboxylic acids and isocyanides in which Y(OTf) 3 mediated the reaction. 33 Finally, the fluorescence activity of the synthesized compounds as novel fluorescent dyes was probed.
In 2020, Wang and co-workers extended this protocol to a one-pot, three-component reaction for the preparation of oxazole-linked 1,2,3-triazoles, involving a Ce-catalyzed triple isocyanide insertion reaction with alk-2-ynoic acids to yield 2-alkynyloxazoles and then [2+3]cycloaddition with organic azides. 34 The in vitro biological evaluation of the products displayed good results against HepG2 and MGC803 cells for some selected synthesized compounds.

Special Topic Synthesis
Pd(0) complex and propargyl carbonate 18 affording allenyl-Pd(II) species 22 with loss of CO 2 which is trapped by tert-butylamine to yield carbamate ion 21. Allenyl-Pd intermediate 22 undergo triple isocyanide insertion (see Scheme 9) resulting in intermediate 23, which reacts with carbamate 21 to give 24. Nucleophilic addition of an alcohol to 24 gives product 19 through intramolecular cyclization and the loss of a carbamate molecule. In the presence of water, the reaction advances in the same manner, but with an additional intramolecular acylation step to result in the formation of bicyclic furopyrrole products 20.

Special Topic Synthesis
range of aldehydes, amines, isocyanides, and N,N-disubstituted hydroxylamines were used to give products 31 in moderate to high yields.
Furthermore, O-protected hydroxylamines participated in the Ugi reaction to form the corresponding N-acyl-N-hydroxypeptides. 42 Despite creating diverse organic molecules using MCRs, a grand challenge that still remains in isocyanide-based MCR chemistry is the control of the configuration of the new stereogenic center. 43 Notably, Houk, Tan, and co-workers overcame this formidable challenge by an interesting method. 44 They employed a chiral phosphoric acid derivative which efficiently catalyzed the Ugi reaction to construct more than 80 -(acylamino)amides in good to excellent enantiomeric excess. Experimental and computational studies establish the reaction mechanism and origins of stereoselectivity.
Banfi and co-workers developed a Lewis acid promoted diastereoselective Ugi reaction by use of enantiomerically pure 1,3-amino alcohols 33 obtained from the L/D-prolinecatalyzed Mannich-type reaction of aldehydes and N-Bocprotected imines 32 (Scheme 12). 45 Ugi condensation of aldehydes, carboxylic acids, and isocyanides with chiral deprotected 1,3-amino alcohols 33 in the presence of ZnBr 2 gave amide products 34 with good to moderate diastereoselectivities. ZnBr 2 as Lewis acid catalyst promoted the reaction through a cyclic transition state.

Scheme 12 ZnBr 2 -catalyzed diastereoselective Ugi reaction of 1,3amino alcohols
Schreiber and co-workers applied a chiral Cu(II) indanefused pybox catalyst to the Passerini reaction to yield optically active -(acyloxy)amides in good yields. 46 A diastereoselective Ugi reaction using an amino acid as chiral molecule in the presence of TiCl 4 was described by Ciufolini and co-workers. 47 The Zn-catalyzed asymmetric Ugi synthesis of -amino acids using a carbohydrate as a chiral auxiliary has also been reported, 48 a strategy that Kunz directed to solid support synthesis. 49 Riva and co-workers explored the ZnBr 2 -promoted diastereoselective (up to 76:24) Passerini reaction of enantiopure azetidine-2-carbaldehyde. 50 A ZnCl 2 -catalyzed diastereoselective Joullié-Ugi threecomponent reaction of 2H-azirines, isocyanides, and carboxylic acids has been reported. 51 Using this method, functionalized N-acylaziridine-2-carboxamide derivatives were prepared in up to 82% isolated yields and up to 99% diastereoselectivity. Also, the Zn-catalyzed insertion of aryl isocyanides into the C-O bond of (1,1-dimethoxyethyl)benzene followed by hydrolysis afforded the corresponding amides. 52 Mahdavi and co-workers prepared superparamagnetic iron oxide on SiO 2 modified with copper via 2-aminobenzamide (Fe 3 O 4 @SiO 2 with amine/CuCl) 36 and utilized it as catalyst in the one-pot condensation reaction of azidoacetic acid (35), isocyanides, aldehydes, and propargylamine followed by the intramolecular [3+2] cycloaddition of the azido and alkyne moieties to form pyrazinotriazoles 37 (Scheme 13). 53 The antibacterial activity of the synthesized compounds 37 was evaluated.
Interestingly, the use of N-formylmethyl-substituted amides 38 in an Ugi-type reaction with aliphatic amines and isocyanides gave functionalized imidazoliniums 39 (Scheme 14). 54 This one-pot reaction, which was efficiently catalyzed by Zn(OTf) 2 , starts with imine formation and subsequently isocyanide addition to generate intermediate 40.

Special Topic Synthesis
amide 39 comes from starting amide 38, so a bridged intermediate of 41 is proposed that finally rearranges to imidazoliniums 39.

Scheme 14 Domino reaction of N-(formylmethyl)carboxamides with amines and isocyanides
Xie, Xie, and co-workers developed a direct procedure, the Cu(I)-catalyzed Ugi-type reaction of N,N-dialkylanilines 42, carboxylic acids, and isocyanides, for the preparation of -amino imide products 43 in which the -C(sp 3 )-H bond to the aniline nitrogen is functionalized by the imide (Scheme 15). 55 The reaction proceeds by Cu-catalyzed oxidation of tertiary amine 42 by TBHP to give Cu-iminium complex 44 and then tandem nucleophilic attack of the isocyanide and carboxylate.
The use of Fe(OAc) 2 as an alternative catalyst for oxidative Ugi-type reaction of N,N-dimethylanilines was reported by Correa and co-workers. 56 The results were improved by Fe(II) compared to copper, albeit in some cases, high yields of -amino amides were obtained by the addition of acetic acid. Moreover, using picolinic acid preferentially led to picolinamides. Chen and Feng used this strategy for the functionalization of N-aryl-1,2,3,4-tetrahydroisoquinolines under aerobic conditions by employing Ru(bpy) 3 Cl 2 as a photoredox catalyst and MeCN as solvent. 57 Aqueous versions of the direct Ugi-type condensation of N-alkylamines, isocyanides, and H 2 O using the Cu(I)-TBHP oxidative system 58 as well as photocatalytic systems (TiO 2 /11-W lamp, 59 [Ir(ppy) 2 bpy]PF 6 /blue LEDs, 60 and Rose Bengal/green LEDs) 61 were also investigated.
A three-component Passerini reaction of alcohols, isocyanides, and carboxylic acids in which aldehydes were prepared by in situ oxidation of alcohols using a catalytic amount of CuCl 2 , NaNO 2 , and TEMPO has been reported by Brioche, Masson, and Zhu. 62 This Passerini reaction was also catalyzed by Fe(III) anchored to zirconium-based metalorganic framework in a photo-oxidative pathway. 63 In another impressive direct oxidative Ugi-type reaction, a primary benzylic amine acted as both a source of aldehyde and amine in the presence of Fe(NO 3 ) 3 ·9H 2 O and TEMPO (Scheme 16). 64 Fe(III) and TEMPO with air oxidize the benzylic amine to the corresponding aldehyde which reacts with another benzylamine, carboxylic acid, and isocyanide to give the products of an Ugi-type reaction. The scope of the reaction was successfully extended to dibenzylamine and tetrahydroisoquinoline giving the corresponding products in satisfactory yields (88% and 83%, respectively).

Scheme 16 Fe-mediated oxidative three-component Ugi-type reaction with benzylamine
Xie and Dixon reported an elegant reverse approach involving Ir-catalyzed reductive Ugi-type MCR of tertiary amides 45 and then reaction with thioacetic acid or acetic acid and isocyanide to afford -amino (thio)amides 46 (Scheme 17). 65 Initially, the tertiary amides 45 are partially reduced with tetramethyldisiloxane (TMDS) in the presence of a cat-

Special Topic Synthesis
alytic amount of IrCl(CO)(PPh 3 ) 2 (Vaska's complex, 1 mol%) to give silylated hemiaminal intermediate 47, then addition of the thioacetic acid or acetic acid gives the iminium ion 48 which is subjected to nucleophilic addition of isocyanide. Finally, reaction of the thioacetate or acetate with nitrilium ion 49 followed by deacetylation affords -amino amide or thioamide 46.

Scheme 17 Synthesis of -amino (thio)amides and mechanism of the reductive Ugi reactions
Acridinium derivatives, because of their extended conjugated -systems, are known as visible-light sensitive organophotocatalysts. 66 García Mancheño, Alemán, and coworkers presented a straightforward synthetic method for the C9-imidation of acridines 51 whereby the dibenzylic substrates 50 undergo an oxidative Ugi-type reaction (Scheme 18). 67 The reaction was carried out by a Cu(OTf) 2 /bipyridyl/benzoyl peroxide oxidative system in the presence of excess isocyanide. The Cu-catalytic system promotes a radical oxidative process towards a benzylic carbocation 52 to accomplish an Ugi-type reaction for the formation of the 9-(N-acylcarbamoyl)acridinium 51. Compounds 51 were oxidized with trityl perchlorate to give acridinium perchlorates and their photochemical properties were investigated, which showed notable photocatalytic activity enhancement.

Scheme 19 Pd-catalyzed reaction of isocyanides and allyl ethyl carbonates
Yadav and co-workers 71 described a cost-effective Fe(III)-catalyzed carboxamidation of glycals 58 by isonitriles via Ferrier 72 rearrangement to give C-pseudoglycals 59. Mechanistically, Fe(III)-mediated acetoxy elimination generates oxocarbenium ion intermediate 60 and then sub- -Keto amide 63 was formed from the Pd(OAc) 2 -catalyzed reaction of -bromo ketone 61 and tert-butyl isocyanide (Scheme 21). 73 The reaction proceeds via an imidoylpalladium process to generate intermediate 62 followed by addition of water to yield amide 63. This strategy for the synthesis of intermediate 62 was used for the generation of the various important synthetic compounds, such as 5-aminopyrazoles, an -cyano ketone, tetrazoles, and an enaminone. Similarly, aminocarbonylation of -phosphate benzyl halides was also developed. 74 Furthermore, Qu, Chen, and co-workers found that nickel catalyzes aminocarbonylations of unactivated alkyl iodides with isocyanides. 75 Zhu and co-workers described a switchable method for synthesis of indolinone derivatives 65 and 66 (Scheme 22). The reaction is initiated by insertion of Pd into the C-I bond of N-arylacrylamide 64 to give a C(sp 2 )-Pd intermediate that undergoes sequential Pd-catalyzed intramolecular cyclization to give a C(sp 3 )-Pd intermediate (Scheme 22). 76 Subsequently t-BuNC insertion, depending on the reaction conditions, gives amide 65 or ester 66. For example, the reaction of N-(2-iodophenyl)-N-methylmethacrylamide with t-BuNC in toluene/MeOH as solvent and in the presence of KOH affords the amide product 65, whereas changing the solvent and base to THF and NaOMe under the same catalytic system results in the methyl ester 66 (Scheme 22).
Subsequently, Chen, Chen, and co-workers reported the tandem reaction of allenes 67 with isocyanides to produce heteroarylacetamides 69 (Scheme 23). 77 The mechanism involves formation of a key intermediate, ketenimine 68, which is generated through oxidative addition of palladium, regioselective addition of the allene group, 1,1-insertion of isocyanide, and -H elimination.

Scheme 23 Synthesis of indol-3-ylacetamides, benzofuran-3-ylacetamides, and isoquinolin-4-ylacetamides via application of heterocyclic ketenimines
Considering the dual roles of tosylmethyl isocyanide (TosMIC) as allenylative reagent and sulfonyl source, 78 Bi, Li, and co-workers developed a Ag-catalyzed heteroaromatization reaction between secondary propargylic alcohols and TosMIC. Increasing the amount of TosMIC from 1.5 equiv. to 2.5 equiv. in the presence of AgOAc catalyst gave (E)-vinyl sulfones 70 as unexpected products (Scheme 24). 79 They proposed that the stereoselective sulfonylation of allenic amide with excess TosMIC forms the products 70; it is probable that excess TosMIC is decomposed to formaldehyde, Ts -, and a cyanide ion (see also Scheme 63).
A catalytic synthetic method for the synthesis of 2-substituted indolines and/or tetrahydroisoquinolines was reported by Jiang and co-workers that involved intramolecular alkene amidoamination of N-sulfonyl-2-allylanilines 71 (n = 0) and N-(2-allylbenzyl)methanesulfonamides 71 (n = 1) by isocyanides (Scheme 25). 80 The reaction can be tuned to proceed through aminoamidation or aminocyanation depending on the reaction conditions. In the presence of Pd(TFA) 2 and Cu(TFA) 2 with 2 equiv. DABCO, the amide

Special Topic Synthesis
product 72 was formed as the major product, but replacing DABCO by trifluoroacetic acid gave the cyanated indolines 73 as the major product (Scheme 25).
Another pioneering example of transition-metalcatalyzed amidation reactions was reported by Cai, Ding, and Zhou using a Pd-catalyzed reaction of N-tosylhydrazones 74 and isocyanides (Scheme 26). 81 Mechanistically, it is proposed that the reaction proceeds through the formation of an isocyanide-Pd complex from the isocyanide and Pd catalyst and the formation of a diazo compound from the N-tosylhydrazone and base and together they give in situ generation of the carbene species 76. Intermediate 76 forms the ketenimine 77 and subsequently amide 75 in the presence of base and water (see Scheme 61 for more example of transition-metal-catalyzed coupling of two carbenes).

Scheme 26 Pd-catalyzed amidation of N-tosylhydrazones by isocyanides
Zhao, Jia, Li, and co-workers developed the alkylation of aryl isocyanides with diverse cycloalkanes and non-cyclic alkanes in the presence of di-tert-butyl peroxide (DTBO) as the oxidant catalyzed by ferrocene. 82 Mechanistically, radical hydrogen abstraction from the alkane by an alkoxyl radical generates the alkyl radical, which is trapped by the isocyanide to deliver the amide. Unfortunately, aliphatic isocyanides were not successful in this coupling.
Interestingly, Jia, Li, and co-workers used tertiary alkyl peroxides 78 as an alkylation reagent in a coupling reaction with isocyanides mediated by ferrocene catalyst (Scheme 27). 83 Mechanistically, alkyl peroxides 78 dissociate into two alkoxy radicals in the presence of the ferrocene catalyst; elimination of acetone from the tertiary hydroxyl radical gives an alkyl radical, which is trapped by isocyanide and after a sequential series of alkylation, oxygenation, and H-abstraction reactions affords amide 79.

Scheme 27 Alkylation of isocyanides with peroxides
The reaction of styrenes and aryl isocyanides utilizing Cu(OAc) 2 and TBHP has a unique chemoselectivity giving benzoyloxyacetanilides 80 (Scheme 28). 20 A surprising point is that unsubstituted styrene and those with electronwithdrawing substituents act as an arylcarboxymethylene surrogate and give benzoyloxyacetanilides 80, while styrenes substituted with electron-releasing alkyl and alkoxy groups yield N-arylbenzamides (Section 2). Mechanistically, it was shown that the reaction proceeds by a radical N-sulfonyl-2-allylanilines and N-(2-allylbenzyl)

Special Topic Synthesis
approach through an initial oxidative C-C bond cleavage of styrene. Also, control experiments demonstrated the necessity for the presence of both copper catalyst and TBHP for the reaction to proceed.
AgOTf-catalyzed reaction of homopropargylamines 81 and isocyanides afforded silver isocyanide complex 82 by a 5-endo-dig cyclization; flash column chromatography produced N-aryl-or N-alkylprolinamides 83 (Scheme 29). 84 This 1,1-difunctionalization of terminal alkynes reaction resulted in a Ugi-Joullie-type reaction under slightly modified conditions using a primary homopropargyl amines, isocyanides, and carboxylic acids to give N-acylprolinamides 84 in good to high yields and diastereoselectivities.

Special Topic Synthesis
Pd(0) followed by insertion of isocyanide into the C-Pd bond leading to 110, which undergoes addition of water and reductive elimination of Pd(0). The emerging 111 then isomerizes to the cyclic hemiaminol 109a. Running the reaction in the presence of excess isocyanide and water results in Pd-mediated formation of isocyanate 112, which reacts with alcohol 109a to afford the carbamate 109b.

Scheme 37 Pd-catalyzed C-S activation/isocyanide insertion/hydrogenation
In this context, Sawant, Khan, Pardasani, and co-workers developed a regio-and stereoselective method for the synthesis of 3-methyleneisoindolin-1-ones 116 by utilizing 1-aryl-2-(2-haloaryl)acetylenes 115 and tertiary isocyanides (Scheme 38). 94 This tandem reaction is greatly influenced by the electronic nature of the aryl substituents (Ar) at the distal end of the C≡C bond. Accordingly, electron-releasing aryl groups and/or alternating alkyl substituents rather than Ar sluggish the reaction at the carboxamidation stage. Mechanistically, Pd catalyzes the carboxamidation by the steps oxidative addition to the C-Br bond, isocyanide migratory insertion, and reduction/eliminationcarboxamidation step, whereas the hydroamidation step is solely mediated by base to form mainly the E-isomeric product 116 via 5-exo-dig cyclization manner.

Scheme 39 Synthesis of highly diverse isoquinolin-1(2H)-one derivatives
Huang, Zhu, and co-workers elegantly combined Pdcatalyzed double isocyanide insertion and Cu-catalyzed Ullmann C-N reactions to construct amide 122 containing both phenanthridine and carbazole cores from substituted 2-iodo-2′-isocyanobiphenyls 121 (Scheme 40). 97 Double insertion starts by Pd(0) activation of 121 towards intramolecular isocyanide insertion to generate 123. Self-coupling occurs during the second insertion of isocyanide to yield 124 which reacts with water to produce amide 125. Finally, a typical intramolecular Ullmann reaction in the presence of CuI gives 122. In this cascade process, two C-C, one C-O, and one C-N bonds are formed consecutively without isolating an intermediate.

Special Topic Synthesis
Scheme 40 Double isocyanide insertion using 2-iodo-2′-isocyanobiphenyl Chen, Wei, and co-workers developed the synthesis of dihydroquinolinones 128 using aryl isocyanides 126 and Obenzoylhydroxylamines 127 in the presence of CuOAc and dppe ligand as the catalytic system (Scheme 41). 98 Exploration of the reaction conditions found that the role of PhONa as base is crucial for the construction of the desired products. The reaction with five-or eight-membered cyclic hydroxylamines and acyclic amines failed to afford the desired cyclic amide. Pyrimidinediones are a valuable scaffold that is found in many biological and pharmaceutical molecules. Wei and co-workers reported an efficient strategy for the synthesis of these structures starting from cyclic oximes 132 and isocyanides mediated by Ag 2 O (Scheme 42). 99 Mechanistically, it is proposed that the reaction goes through isocyanide insertion into the N-O bond then Mumm-type rearrangement gives pyrimidinedione 133. The practicality of the method was shown by the functionalization of important medicinal compounds such as pregnenolone, cetirizine, and tolecintin.

Special Topic Synthesis
co-workers (Scheme 43). 100 The proposed mechanism is initiated by oxidative addition of Pd(0) into the C(sp 2 )-halide bond, and then isocyanide insertion to form intermediate 136. Then intermolecular nucleophilic addition of the nitrogen of aniline to CO 2 gives the benzoxazinone intermediate 137 which spontaneously rearranges to quinazolinedione product 135 because of its higher thermodynamic stability. Temperature is a critical factor in this reaction; increasing the temperature removes CO 2 from the reaction pathway and then double isocyanide insertion provides indole derivatives 138. Similar transformations were independently reported by Zhang and co-workers, 101 Wang, Ji, and co-workers 102 and Islam and co-workers. 103 Khan, Tyagi, and co-workers reported a temperaturecontrolled synthesis of N-acylanthranilamide 140 and quinazolin-4-one 141 (Table  1). 104 N-(2-Bromophenyl)benzamide (139) reacted with tert-butyl isocyanide in the presence of Pd(OAc) 2 under microwave (MW) conditions at 120 °C to yield 2-benzamido-N-tert-butylbenzamide (140) via carboxamidation. By elevating the temperature to 160 °C under the same conditions, 2phenylquinazolin-4(3H)-one (141) was formed as the sole product through a carboxamidation/de-tert-butylation/cyclodehydration cascade. A diverse library of N-acylanthranilamide and quinazolin-4-one derivatives were synthesized.
A catalytic synthetic method for cyclic and acyclic imide formation was disclosed by Yao and co-workers whereby aryl halides, isocyanides, and carboxylic acids were coupled using a Pd(0) catalyst. 105

Special Topic Synthesis
high coordination tendency of the isocyanide or catalyst poisoning were inhibited. Also, the use of an asymmetric carboxylic acid gave chiral imides with slight enantioselectivities.
A method for synthesis of cyclic maleimides 145 based on the three-component cycloaddition reaction of isocyanides, -diazo ketones 144, and anhydrides was developed by Zhao and co-workers (Scheme 45). 106 Mechanistically, diazo ketone 144, under thermal conditions undergo a Wolf rearrangement to generate ketene intermediate 146, which is activated with Zn(II) towards nucleophilic addition of isocyanide. There are two possibilities for the formation of in-termediate 148 which can be obtained from the reaction of 147 and anhydride (path 1) or from the nucleophilic attack of the carboxylate ion and Passerini-type rearrangement (path 2). Finally, the reaction is completed by an intramolecular aza-cyclization to deliver the corresponding cyclic maleimide 145.
Jiang and co-workers developed a regioselective Pd-catalyzed annulation reaction of bromoalkynes 149 and isocyanides affording 5-iminopyrrol-2-one derivatives 150 (Scheme 46). 107 It is proposed that reaction is initiated by CsF-promoted nucleophilic addition of the isocyanide to bromoalkyne 149 to generate bromoacrylamide 151. Subsequently, Pd(0) catalyzes insertion-cyclization of isocyanide into bromoacrylamide 151 to furnish 150. Notably, in the absence of palladium, CsF promotes nucleophilic addition reaction of isocyanides to bromoalkynes to construct bromoacrylamide 151.

Special Topic Synthesis
Liu, Jiang, and co-workers extended this strategy to the Pd-catalyzed intermolecular cyclization reaction of activated alkynes with isocyanides to yield polysubstituted maleimide derivatives 152 through the formation of 5-iminopyrrol-2-ones followed by hydrolysis (Scheme 47). 108 Wang, Yang, and co-workers prepared a variety of maleimides 154 and their carbazole derivatives 155 by the Zncatalyzed tandem oxidative cyclization of aryl isocyanides and allenic ester 153 (Scheme 48). 109 The mechanism progresses by nucleophilic addition of the isocyanide to the C(sp) of allenic substrate 153 activated by Zn(OTf) 2 as a Lewis acid. Intermediates 156 are involved in a sequence of intramolecular ring-closure and [1,5]-H shift resulting in furans 157. With the aid of air, furans 157 are converted into orthoformates 158, which undergo a re-cyclization process to give the final maleimides 154. This work was extended to the construction of carbazole derivatives 155 by the aminolysis of 154 in methanolic ammonia and subsequent photoinduced 6-electrocyclization of 159.
Blay, Pedro, and co-workers synthesized diverse asymmetric cyclic ureas such as imidazolinones 163 through a 1,3-dipolar cycloaddition of isocyanoacetate ester 160 and nitrones 161 (Scheme 49). 110 They used a combined strategy of bifunctional squaramide (SQ) as a chiral Brønsted base organocatalyst and Ag 2 O as a Lewis acid catalyst. According to the proposed mechanism, squaramide together with Ag + generates an enolate ion from the isocyanoacetate ester 160 that adds as a nucleophile to the nitrone 161 to deliver intermediate 162. Subsequently, intermediate 162 undergoes a series of contiguous reactions, such as intramolecular nucleophilic addition of oxygen ion to isocyanide, [1,3]-cycloaddition, and rearrangement, to produce chiral trans-imidazolidinones 163 in good to high enantioselectivities (67-99% ee). In 2020, Kan, Liu, Wang, and coworkers described a diastereoselective version of this reaction. 111 They applied a cooperative catalytic system of base and Ag 2 CO 3 to promote the reaction. The ratio of cis/trans cycloproducts showed a high dependence on the base and temperature. When inorganic bases were applied, e.g. Cs 2 CO 3 , the yields of trans-diastereomers increased: in contrast, using DBU as an organic base dramatically improved the yields of cis-products. A density functional theory (DFT) study has also been performed.
Kärkäs, Liu, and co-workers developed a [3+2] annulation of nitrones 161 and isocyanides to yield a variety of 2,3,4-trisubstituted 1,2,4-oxadiazolidin-5-one derivatives 164 (Scheme 50). 112 The reaction was carried out by using silver oxide as the catalyst and molecular oxygen as the terminal oxidant. Based on empirical results a mechanism was proposed that includes a nucleophilic addition/cyclization/protodeargentation/oxidation pathway.
Ruijter, Orru, and co-workers reported a diastereoselective intramolecular Passerini three-center, two-component reaction of cyclic keto acids 165 and isocyanides in the pres-ence of Zn(OTf) 2 leading to bicyclic lactones 166 (Scheme 51). 113 Passerini products 166 rearranged to -hydroxy imide derivatives 167 in the presence of MeSO 3 H. Enantioenriched Passerini products were obtained from an enantioenriched keto acid.

Formation of Alkynamides
During the synthesis of substituted 5-iminopyrrolones by utilizing the Pd(II)/CsF-catalyzed reaction of bromoalkynes and isocyanides, Jiang and co-workers observed propynamides as byproducts (Scheme 46). 107 This encouraged us to develop an alternative approach for the synthesis of propynamides 169 using the Pd-catalyzed reaction of isocyanides with 1,1-dibromoalk-1-enes 168 (Scheme 52). 114 The reaction starts with activation of a C-Br bond of the 1,1-dibromoalk-1-ene 168 to give 170, which sub-

Special Topic Synthesis
sequently undergoes isocyanide insertion, base-mediated OH -/Xexchange followed by reductive elimination yield intermediate 171 that can be easily converted into the desired product 169 by the elimination of HBr. The big advantage of using 1,1-dibromoalk-1-enes 168 related to terminal alkynes is that 1,1-dibromoalk-1-enes are converted into terminal alkynes in basic media via Corey-Fuchs reaction. 115 Scheme 52 Pd-catalyzed cross-coupling reaction of 1,1-dibromoalk-1enes with isocyanides Catalytic monoinsertion of isocyanides into terminal alkynes for the construction of 1-aza-1,3-enynes using organoactinide and rare-earth metal complex, 116 Sm complex, 117 and half-sandwich rare-earth metal complexes has been reported. 118 Inspired by these reactions, in 2018 Wang, Ji, and co-workers developed an innovative threecomponent reaction of isocyanides, terminal alkynes, and water catalyzed by the Co(II)/Ag(I) system for the synthesis of alkynamides 172 (Scheme 53). 119 Co(II)/Ag(I) synergistically catalyzes the insertion of monoisocyanide into the C-H bond of the terminal alkyne, followed by oxidation and replacement of water to afford alkynamides 172.

Scheme 53 Monoinsertion reaction of isocyanide into terminal alkynes with H 2 O
Also in 2019, with slight modifications, Wang, Pan, and co-workers reported the Pd-catalyzed synthesis of N-acylpropynamides 173 using terminal alkynes, isonitriles, and sodium alkanoates (Scheme 54). 120 Based on some empirical results, a mechanism was proposed that involves complexation of Pd, sodium alkanoate, and alkynes together to generate intermediate 174. Subsequently, isocyanide inser-tion and reduction form O-acylamidate 175, which rearranges to N-acylamide 173. The advantages of this protocol are that it is a three-component reaction strategy, it uses sodium alkanoates as the oxygen and acyl source, the starting materials are easily available, and it is an experimentally convenient catalytic process.

Scheme 54
Proposed mechanism for the formation of N-acylpropynamides

Formation of Acrylamide-like Molecules
Interestingly, Xu and co-workers added Ag 2 O to the Pdcatalyzed reaction of terminal alkynes, isonitriles, and sodium alkanoates, previously used by Wang, Pan, and coworkers, 120 and obtained 2-(acyloxy)acrylamides 176 (Scheme 55). 121 It is proposed that the reaction undergoes 1,1-addition of Ag and carboxylate to the terminal alkyne to yield silver complex 177, which is a key intermediate.

Special Topic Synthesis
nishes imidoyl intermediate 178. Finally, addition of hydroxyl to palladium complex 178 followed by reductive elimination affords amide 176. The generated Pd(0) is reoxidized to Pd(II) in the presence of silver salt to complete the catalytic cycle.
The reaction of isocyanides and bromoalkynes in basic media via nucleophilic addition reaction afforded bromoacrylamide 151 (see Scheme 46). 107 Enaminones 179 in reaction with isocyanides with a Pd catalyst undergo isocyanide insertion through a C-H activation process (Scheme 56). 122 The formed imidolyl intermediates undergo a 1,3-palladium migration process under dry conditions to deliver 4aminoquinoline derivatives 180 or in the presence of base and water they can be hydrolyzed to amide 181. o-Disubstituted aryl isocyanides such as o-dimethyl-or o-diethylphenyl isocyanides only react by 1,3-palladium migration process to give 4-aminoquinoline derivatives 180 while sterically hindered aliphatic isocyanides, like tert-butyl isocyanide and 1-adamantyl isocyanide, only give amides 181. Li, Jia, and co-workers reported a nucleophilic addition of isocyanides to substituted benzylidenemalonates 184 in the presence of Ag + catalyst which led to (carbamoylben-zylidene)malonates 185 (Scheme 58). 124 The Ag + catalyst behaves as a Lewis acid to promote the C-C coupling reaction.

Scheme 58 Unprecedented reaction of isocyanide and benzylidenemalonates
Jiang and co-workers reported an isocyanide-based oxidative coupling reaction for the synthesis of the (E)--carbamoylenamine derivatives 188 and 190 that proceeded through Pd-catalyzed -C(sp 2 )-H activation of (Z)-enamine ketones or esters 186 and isocyanide insertion (Scheme 59). 125 The key imidoylpalladium intermediate 187 generated from isocyanide incorporation can be transformed into either of products 188 and 190 depending on the conditions. A combination of Pd(OAc) 2 and CuCl 2 in the presence of oxygen and water under basic conditions exhibited the most suitable environment for the preparation of 188. On the other hand, lowering the amount of water and replacing CuCl 2 by Cu(OAc) 2 resulted an intermediate 189 that underwent intramolecular rearrangement and further electrophilic palladation. Subsequently, insertion of the other isocyanide delivered product 190 after expulsion of carbon monoxide. The presence of Cu(II) as a Lewis acid is efficient to promote keto-enol tautomerism towards the preparation of (Z)-isomers.

Scheme 59
Pd-catalyzed coupling reaction of (Z)-enamine ketones or esters and isocyanides A remarkable coupling reaction between isocyanides and active methylene groups 191 (C(sp 3 )-H activation) was reported by Bi and co-workers in which the Ag catalyst implements the reaction through a radical pathway to afford two different products depending on the isocyanide (Scheme 60). 126   In 2017, He, Shang, and co-workers developed the Rh 2 (OAc) 4 -catalyzed direct carboxamidation of cyclic 2-diazo 1,3-diketones 198 with isocyanides to give 2-hydroxy-6-oxocyclohex-1-enecarboxamides 199 (Scheme 61). 127 The fascinating mechanism due to the cross-coupling reaction of two carbenes to each other, starts with activation of the diazo compound 198 with the Rh catalyst followed by in-sertion of isocyanide to form cyclic intermediate 200. The latter undergoes Rh elimination and then hydrolysis that promotes synthesis of acylamide derivatives 199. Undoubtedly, this reaction enriches the chemistry of diazo compounds.

Scheme 61 Rh 2 (OAc) 4 -catalyzed synthesis of acylamide derivatives
Jing, Liang, and co-workers developed the synthesis of imide derivatives, N-benzoylbut-1-enamides 202, utilizing a Pd-catalyzed isocyanide insertion into the C-O bond of allyl esters 201 (Scheme 62). 70 The reaction proceeds by the formation of a -allyl-Pd complex 203 followed by Pd-assisted insertion of isocyanide into acyl and allyl moieties to provide intermediate 204, which undergoes intramolecular acyl transfer to generate imide 202.

Scheme 62 Pd-catalyzed reaction of allyl esters and isocyanides
The Ag-catalyzed C-C coupling reaction of isocyanides and propargylic alcohols 205 with accompanying oxygen transposition yields diverse allenamides 206 in moderate to good yields (Scheme 63). 128 A plausible mechanism proceeds by generation of the Ag acetylide 207 followed by isocyanide insertion giving 208; addition of another molecule of propargylic alcohol 205 to 208 along with intramolecular H-migration and rearrangement delivers Ag acetylide 209. M. Shiri et al.

Special Topic Synthesis
The latter undergoes another isocyanide insertion and the addition of the third molecule of propargylic alcohol 205 resulting in an intermediate that goes through a series of rearrangements to give 210 which tautomerizes to give the amide products 206. The reaction was performed using tosylmethyl (TsCH 2 -), benzyl, and 1-tosylethyl isocyanides, that is more hindered isocyanides, and these failed to yield the desired products. The evaluation of the catalysts showed that AgOAc gave the best results for tertiary propargyl alcohols, while secondary propargylic alcohols gave better yields with Ag 2 CO 3 .
Chattopadhyay and co-workers utilized a cerium(IV) ammonium nitrate (CAN) catalyzed reaction in a Lewis acid accelerated multicomponent condensation of salicylaldehydes 221, anilines, and sterically hindered alkyl isocyanides to obtain N-alkyl-2-aryl-2-(arylimino)acetamides 222 or benzofuran-2,3-diamines 223 (Scheme 66). 131 Mechanistically, it is proposed that the reaction proceeds by CAN-promoted reaction of salicylaldehyde 221 and aniline to give 2-(arylimino)phenol 224 which activated by Ce for nucleophilic attack of isocyanide to give 225. The intramolecular hydrogen bonding strength in 225 has a determinant role on the preferred products and is affected by the aniline substituents. Using halo-substituted anilines and unsubstituted aniline gave preferentially N-alkyl-2-aryl-2-

Special Topic Synthesis
withdrawing substituents weaken the hydrogen bond, thus facilitating C-C bond rotation and subsequent intra-annulation to generate the benzofuran products 223. The reaction with 4-methoxy-and 4-methylaniline did not proceed satisfactorily.

Formation of Ureas and Carbamates
The synthesis of di-or trisubstituted ureas on gold nanoparticles by utilizing isocyanides and primary or secondary amines was reported by Angelici and co-workers. 132 Xu and co-workers developed a synthesis of unsymmetrical tetrasubstituted ureas 227 using secondary 2-aminopyrimidines 226 and isocyanides with Cu(O 2 CR) 2 ·H 2 O as the catalyst and acyl source (Scheme 67). 133 Mechanistically, the reaction begins by the formation of a carboxylate-isocyanide complex [R 4 COOCu(I)·(CNR 3 )] and then coordination occurs between one of the nitrogen atoms of the pyrimidine ring and Cu(I). Urea formation is completed by nucleophilic attack of amine to isocyanide and then reductive elimination/[1,3]-acyl transfer. Accordingly, anilines were not good substrates in this transformation, however a strong nucleophile such as morpholine was used successfully. M. Shiri et al.

Special Topic Synthesis
Scheme 67 Cu-catalyzed isocyanide insertion into N-H bonds of amines Wang, Ji, and co-workers used cobalt(II) acetylacetonate catalyzed isocyanide insertion reactions with amines utilizing tert-butyl hydroperoxide in an ultrasound irradiation protocol that gave ureas and thioureas. 134 Mechanistically, the isocyanide inserts into the N-H bond of the amine, activated by Co(acac) 2 , to give an amino methylidyneaminium that undergoes nucleophilic attack by water or sulfur; TBHP oxidized the Co complex to the required oxidation state to promote the reaction. The exploration of this strategy with a range of primary and secondary aliphatic amines and also anilines showed that electron-withdrawing substituents on the aniline suppressed the formation of the desired products. In similar approach, Pd(OAc) 2 -catalyzed condensation of amines and isonitriles in the presence of iodine provides N,N′-dialkylcarbodiimides at 100 °C under an oxygen atmosphere, while in the absence of iodine the corresponding ureas were obtained. 135 A Rh-catalyzed oxidative coupling reaction of isocyanides and amines or alcohols was performed by Zhao and co-workers in the presence of ethyl diazoacetate as a ligand leading to ureas and N-arylcarbamates, respectively. 136 Rh(PPh 3 ) 3 Cl and ethyl diazoacetate both have a crucial role in the reaction progress and the formation of the desired products. The reaction failed using tertiary alcohols, primary amines, and aliphatic isocyanides as substrates. A proposed pathway for the reaction involves a Rh-carbene complex generated from Rh catalyst and ethyl diazoacetate that reacts with isocyanide and then O 2 to produce the isocyanate. Finally, ureas and carbamates are readily are obtained by the nucleophilic addition of amines or alcohols, respectively.
Bi and co-workers developed a Ag-catalyzed reaction of isocyanides with alcohols and phenols which proceeds by a novel sequential radical approach of isocyanide hydration and coupling reaction with alcohol radicals, instead of 1,1addition, to give carbamates. 137 The proposed mechanism was evidenced by combining experimental and theoretical studies. This coupling showed a high compatibility with a broad range of substrates. This strategy was utilized for the post-functionalization of some pharmaceutically active molecules.
In the presence of CuBr, di-tert-butyl or di-tert-amyl peroxides 78 (R 1 = Me or Et) dissociate into two alkoxyl radicals. 83 These alkoxyl radicals were trapped with isocyanide and then oxidized to intermediate 230 (Scheme 68). Aryl isocyanides bearing electron-withdrawing groups directed the reaction to form carbamate 228, while electron-donating group substituted aryl isocyanides resulted in the formation of 229 by double isocyanide incorporation (Scheme 68). Aliphatic isocyanides are not compatible with this reaction. M. Shiri et al.

Special Topic Synthesis 8 Conclusion
Extraordinary progress has been made in the past decade towards the formation of amides through transitionmetal-catalyzed reactions of isocyanides.
As summarized in this review, utilizing isocyanides as amidoyl synthons for the preparation of amides using transition metal and inner transition metal catalysis is well established, and shows great potential for its use in the synthesis and/or post-synthesis of heterocycles and pharmaceutical precursors. Indeed, catalytic oxidative couplings of isocyanides, considering their high coordination tendency towards metal complexes and carbene-like reactivity of divalent carbon, open promising ways for chemists to further develop the reaction participants for the synthesis of a wide diversity of targeted amides. Generally, the given numerous examples, including a remarkable range of transition metals (Pd, Cu, Rh, Ag, Zn, Co, etc.), shows the synthetic efficiency and high atom economy that distinguish these reactions from traditional methods based on carboxylic acid derivatives. However, multiple coordination to the metal center and poly-insertion of isocyanides and intramolecular cyclization with a tethered nucleophile are substantial issues, which may induce some practical complexities and limitations in the reaction systems. We believe that further experimental and theoretical studies in this field will provide insights for a clearer understanding leading to ready prediction and control of these catalytic processes. In addition, the design of new knowledgeable catalytic systems based on choosing flexible starting materials will reveal the different aspects of insights in the field. Undoubtedly, progress in this area of chemistry will be an effective step towards expanding cheaper, greener, and more efficient strategies in accessing complex molecules especially in the pharmaceutical industry.

Special Topic Synthesis
M. Shiri et al.