Advances in amidation chemistry – a short overview

synthetic methods development using transition metal


Introduction
N,N-Dimethylformamide (DMF) is primarily used as a polar solvent in a variety of chemical processes. DMF is also a versatile reagent that is commonly used in chemistry. DMF, for example, can be used as an effective ligand in the production of metallic complexes. 1 In addition to acting as a source of various important intermediates, DMF can react as an electrophile or a nucleophile and can play a role in reactions as a dehydrating agent, a reducing agent, a catalyst, [2][3][4][5] or a stabilizer. [6][7][8][9] For the synthesis of metallic compounds DMF can be an effective ligand. N,N-dialkylamides could be considered as a combination of several functional groups such as alkyl, amide, carbonyl, dialkyl amine, formyl, N-formyl and highly polar C-N, C=O, and C-H bonds. Due to flexible reactivity of N,N-dialkylamides, during the past few years, chemists have succeeded in developing reactions, where DMF and DMA could be used to deliver different functional groups such as -CO, -NMe2,-CONMe2, -Me, -CHO, etc., a single atoms such as C, O, H etc. (Figure 1). Similarly, DMF could be used in the preparation of heterocyclic compound through formylation of active methylene groups, conversion of methyl groups to enamines, and formylation of amino groups to amidines. Further, it can also be utilized as an intermediate in the modification of heterocyclic compounds. 10 Muzart's 1 seminal review highlighted the role of DMF in organic synthesis until 2009; Ding and Jiao's comprehensive review in 2012 covered DMF as a multipurpose precursor for various reactions. 11 Additionally, Batra et al. 12 conducted a comprehensive review of DMF as a reagent for various applications and reviewed the triple function of DMF as a catalyst, reagent, and stabilizer. 13,14 Figure 1. Dimethylformamide as precursor/synthon for various functional groups [11].
In this review we summarize developments on applications of DMF in reactions such as amination (R-NMe2), formylation (R-CHO), 15,16 as a single carbon source (R-C), methylene group (R-CH2), 17 carbonylation (R-CO), as well as newer reactions such as amidoalkylation (-CH2N(CH3)-C(=O) CH3-R), 18 metal catalyzed aminocarbonylation (R-CONMe2), 19 cyanation (R-CN), 20,21 and, formation of heterocycles, which took place during the past few decades and up to October 2019. Heterocycles are essential compounds used in various applications, from materials to medicines. This unlike other reviews appeared on this subject, 1,22 we provided special emphasis on reactions involving DMF. Although DMF can serve as a reagent in organic reactions such as Friedel-Crafts 23 and Vilsmeier-Haack 24 reactions the actual reagent is derivative of DMF, hence we did not cover such subjects. We hope this review will stimulate further research interest on the application of DMF in organic synthesis.

DMF Mediated Aminocarbonylation Reactions
Hiyama et al. 25 (Figure 2) established an effective approach for obtaining benzamides 2 by aminocarbonylation of aryl and alkenyl iodides 1 using DMF as an amide source in the presence of a Pd/POCl3 catalytic system. Similarly, Indolese et al. demonstrated under pressure aminocarbonylation of aryl halides 1 using a Pd catalyst and a triphenylphosphine ligand in a CO environment. DMAP is utilized as the base in this reaction, and the yield is quite high. 26 It is an essential synthetic approach since it may also be used to synthesize pyridine and thiophene halides ( Figure 2). Furthermore, Lee and colleagues established the same reaction between aryl bromides/iodides 1 and DMF in dioxane solvent using phosphite ligand and sodium methoxide as base ( Figure 2). 27 Wang et al. demonstrated a metal-free radical amidation of thiazoles and oxazoles 3 using a series of formamides and tertbutyl perbenzoate (TBPB) as radical initiator. High yields of amidated azoles 4 were easily produced using this approach (Figure 3). 28 Wang et al., demonstrated direct amidation of alcohols 5 with formamides in the presence of an I2/TBHP with sodium hydroxide as a base and DMF as amide source (Figure 4). 29 The same author reported amidation of benzylamine 5a under the acidic condition. 30 Feng and co-workers proposed green protocol for the synthesis of α-ketoamides 6 through TBAI catalyzed sp 3 C-H oxidative radical/radical cross-coupling. This method is applicable for broad range of substrates. 31 The only by product is water and no CO or CO2 emission is observed ( Figure 5). Similarly, α-ketoamides 6a using aryl methyl ketones 7 were synthesized utilizing widely accessible N,Ndialkylformamides in the presence of nBu4NI and aq. TBHP as catalyst and oxidant for the radical oxidative coupling process ( Figure 5). Mai et al. devised this technique as a green and metal-free solution. 32  In 2016, Xiao and his colleagues discovered a simple and effective method for synthesizing amides 2 by cross coupling carboxylic acids 8 with N-substituted formamides in the presence of a Ru catalyst, and the appropriate amide was produced following CO2 release ( Figure 6). The carbonyl group in the amide product was formed by benzoic acid rather than N-substituted formamides. This synthetic approach is stable, low toxicity, and environmentally benign. This approach is effective with several carboxylic acid derivatives and N-substituted formamides. 33 Similarly, Tortoioli and colleagues showed metal-free one-pot synthesis of dialkyl amides using benzoic acid and DMF in the presence of propyl phosphonic anhydride (T3P) and acid additives. 34 This gentle approach was used to create triazinate, a dihydrofolate reductase inhibitor. (Figure 7). Bhat et al. 10 reported direct carbonylation of heterocycles 9 by direct dehydrogenative aminocarbonylation in the absence of transition metals ( Figure 8). Persulfate, which served as an effective oxidant, a good radical initiator, a moderate and environmentally favourable low-cost reagent, and formamides served as reagents in the formation of primary to tertiary carboxamides. 35 Bhisma et al. demonstrated an efficient copper catalyzed synthesis of phenol carbamates 11 from dialkylformamides as an aminocarbonyl surrogate and phenols with directing groups such as benzothiazoles, quinoline, and formyl at ortho-position ( Figure 9). It is a low-cost and environmentally benign reaction that tolerates a wide range of functional groups and provides a phosgene-free path to carbamates. 36 Phan and colleagues created organic carbamates 13 employing metal organic framework Cu2(BPDC)2(BPY) (BPDC = 4,40-biphenyldicarboxylative, BPY = 4,40-bipyridine) as heterogeneous catalyst for cross dehydrogenative coupling of DMF with 2-substituted phenols 12 under oxidative conditions ( Figure 10). This catalyst has a higher catalytic activity and is easily recovered and reused. 37   Figure 11). 38 This procedure is both efficient and environmentally friendly.
Kamal and colleagues devised a more efficient and environmentally friendly technique for synthesising selenocarbamates 17 by an oxidative coupling reaction between formamides and diselenides 16 in metal-free circumstances ( Figure 12). A metal-free approach to direct C-Se bond synthesis happened at carbonyl carbon employing TBHP and molecular sieves under simple reaction conditions. This reaction has the benefit of using a non-functionalized substrate. 39  Kantam et al. created unsymmetrical urea derivatives 19 by copper catalyzed C-H/N-H coupling of formamides (both mono and di) with various amines 18 (primary, secondary, and modified aromatic amines) and radicals. The significance of this green reaction is that it eliminates the usage of pre-functionalized substrates, which saves atoms. 40

DMF Mediated Amination Reactions
The direct amination of C-H bonds has been investigated as a less harmful alternative to the Ullmann-Goldberg and Buchwald-Hartwig aminations, which use (hetero)aryl halides or their equivalents to react with amines. Significant research is being conducted to develop an optimal C-H amination system that combines inactivated hydrocarbons with easily accessible amino sources under moderate circumstances while creating minimum waste. 41,42 Chang et al. reported that after treating benzoxazoles 3 with optically active formamide, (R)-N-methyl-N-(1-phenylethyl)-formamide (>99% ee), in the presence of an acid additive and using Ag2CO3 as a catalyst, 2aminated benzoxazole 20 was produced as a single product in reasonable yield ( Figure 14). Surprisingly, this approach is also applicable to optically active formamide, since the target product was produced in higher yield without racemization. 43 Figure 14. Amination of benzoxazole using Ag2CO3 catalyst.
Li et al. developed a method for the synthesis of 2-aminoazole derivatives 20 in which the C-N bond of azoles 3 is formed either by decarboxylative coupling with formamides as a nitrogen source or by direct C-H amination with secondary amines as a nitrogen source using an inexpensive Cu catalyst, O2 or air as an oxidant, and benzoic acid plays a major role in the release of amine from amides. 44 Yu et al. also discovered a decarbonylative coupling between azoles and formamides. In the presence of formamides and amines as nitrogen sources, iron catalyzed direct C-H amination of azoles at C2 ( Figure 15). Under air, easily available iron (II) salts worked as Lewis's acids, activating the C2 position of benzoxazoles 3 and acting as an oxidant, while imidazole was utilized as an addition in the catalyst. Direct azole amination was catalyzed by cheap and environmentally friendly reagents. The reaction was also carried out in the presence of acetonitrile with amines. 45 (>99% ee) ee (>99% ee) ee Figure 15. Amination of benzoxazole using Cu or Fe catalyst.
Peng and colleagues devised a simple and effective one-pot synthesis of 2-acyl-4-(dimethylamino)quinazoline 22 by direct amination of 2-aryl quinazoline-4(3H) ones 21 with DMF, with 4-toluene sulfonyl chloride acting as a C-OH bond activator ( Figure 16). As a base, KOt-Bu was utilized, which results in the synthesis of tosylate, which attacks DMF, which then undergoes hydrolysis to provide aminated product. This process is cheap and employs simple reagents. 46 Eycken et al. established a simple microwave-assisted de-sulfitative dimethylamination of 5-chloro-3-(phenylsulfanyl)-2-pyrazinones 24 utilizing DMF as a dimethylamine source and sodium carbonate as a necessary cofactor ( Figure 17). The solvent solution for this reaction was DMF: H2O at a ratio of 1:1, and the corresponding de-sulfitative aminated product 25 was produced in excellent yield. Finally, under improved circumstances, the applicability of this technology was tested on oxazinone instead of pyrazinones, and the intended products were generated in good yield. 47 Hongting et al. discovered an efficient, atom-economic, and environmentally benign method for producing enamines 28 by intermolecular hydroamination of activated alkynes (Figure 18). At room temperature, the reaction was carried out in a solvent-free environment with a catalyst. Without producing any waste products, primary or secondary amines 27 were added to triple bonds 26. DMF pretreatment with metal Na was utilized to synthesize (E)-ethyl-3-(dimethylamino)acrylate, and a new method for quinoline synthesis was presented. 48 Liang and colleagues described a simple and effective one-pot multicomponent process using chalcones 30, malononitrile 31, and DMF in the presence of NaOH to produce functionalized 4-oxobutanamides 32 (γketoamides) from simple, α, β-unsaturated enones ( Figure 20). This reaction possesses a high atom economy, readily available starting materials, operational simplicity under mode rate circumstances, a broad substrate scope, and a high tolerance with various functional groups. 50 Figure 20. Synthesis of γ-ketoamide.
Xia and colleagues reported a facile and environmentally friendly method for synthesizing sulfonamides by t-BuOK-mediated direct S-N bond formation from sodium sulfonates 33 with formamides ( Figure 21). This reaction takes place in a metal-free environment, and formamides are employed as an amine source. It avoids using pre-functionalized starting materials and provides an alternate approach for producing sulfonamides 34. 51

DMF Mediated Methylenation Reactions
Several ways for employing DMF as a methylene source have recently been devised. Wang et al. created a novel technique for synthesizing vinyl quinolines 37 from methyl quinolines 36 ( Figure 23) by employing DMF as a methylene source. The synthesis was accomplished using an iron-catalyzed sp 3 C-H functionalization followed by a C-N cleavage utilizing TBHP as a radical initiator. This approach is straightforward and efficient for producing many vinyl substituted quinoline derivatives with high yield. It also does not use organometallic compounds as reagents. 53 Figure 23. Synthesis of vinyl quinolones using DMF with iron catalyst. Qian Xu and colleagues created an environmentally friendly iron-catalyzed benzylic vinylation that transfers the carbon atom in the N,N-dimethyl group from DMA or DMF to 2-methyl azaarenes 38 to make 2vinyl azaarenes 39. (Figure 24). The radical mechanism was used to carry out the reaction of N,N-dimethyl amides as one carbon source. 54

DMF Mediated Amidoalkylation Reactions
The α-amidoalkylation reaction has been extensively reviewed, and it involves the addition of carbon nucleophiles (primarily aromatic rings, alkenes, cyanides, isocyanides, alkynes, organometallic and active methylene-containing compounds) to substituted amides, where X is a leaving group (Figure 31). 60 The reactive intermediates in these reactions are N-acylimines 49 or N-acyliminium salts 50. The higher electrophilicity of amidoalkylating reagents in comparison to those engaged in aminoalkylation reactions is the most essential property of their chemistry.  This technology may also be used to produce several benzothiazole 54 and fipronil analogues ( Figure  33). 61 Stephenson et al. used thermolysis and oxidative photocatalysis to create Friedel-Craft (FC) amidoalkylation of alcohols and electron-rich arenes as a powerful nucleophile with alkyl amides 1b ( Figure 34). The FC amidoalkylated product 53 was synthesized by oxidizing N,N-dialkyl amides with persulfate and a photocatalyst. Persulfate at 55°C, on the other hand, provides amidoalkylated product. Persulfate was utilized as an affordable and efficient oxidant in this procedure for the formation of C-O and C-C bonds. When compared to thermolytic reaction conditions, light catalysis offered superior selectivity and yields for Friedel-Crafts reactions most of the time. 62   Chen and colleagues showed copper-catalyzed C-N bond synthesis of triazoles in 2017 via cross dehydrogenative coupling of NH-1,2,3-triazoles 57 with N,N-dialkylamides to create N-amidoalkylated triazoles 58 (Figure 36). When the reaction was carried out using 4-aryl-substituted NH-1,2,3-triazoles, the expected N2substituted 1,2,3-triazoles were produced, as well as a tiny quantity of N1. This approach is effective for the selective synthesis of N2-substituted 1,2,3-triazoles. 64

DMF Mediated Cyanation Reactions
The cyanation of Csp 3 -H bonds next to N atoms in tertiary amines is an essential technique for producing -amino nitriles, which are flexible precursors of amino acids with a wide range of applications in biochemistry and medicine. It is worth noting that dialkylamides can undergo reaction to form cyano groups. Ding et al. (2011) reported a novel and different type of pathway to produce aryl nitriles via Pd-catalyzed cyanation of indoles 46 and benzofurans via functionalization of the C-H bond using DMF as a source of CN, and control experiments revealed that N and C of the cyano group are generated from DMF. 66 Similarly, in 2015, Chen and co-workers developed a selective copper-catalyzed C3-cyanation of indole under an oxygen atmosphere with DMF as a safe CN source and as a solvent (Figure 38). 67  Figure  39). Aryl nitriles can be synthesized from electron-rich arenes and aryl aldehydes. The main intermediary in this reaction is acyl aldehydes. This reaction's process required C-H activation with the assistance of a copper catalyst, followed by carbonylation. Because of its usefulness in the medical area, particularly in the creation of therapeutic oestrogen receptor ligands, 3-cyanoindoles have drawn a lot of attention. 68  Chang et al. proposed a novel method for synthesizing Aryl nitriles 62. Cyanation of aryl halides 1 catalyzed by copper acetate and Ag as oxidants, using ammonium bicarbonate as a N supply and DMF as a C source for the cyanide functional group (Figure 40). Regarding the critical roles of Cu (II) species in the in-situ production of CN units and subsequent cyanation of aryl halides, Ag2CO3 re-oxidizes the resulting Cu(I) species under copper-catalyzed oxidative conditions. This process is feasible and safe, and it produces nitriles in moderate to excellent yields. 69 Ushijima et al. synthesized aromatic nitriles 62 from electron-rich aromatics in a metal-free one-pot process. When molecular iodine in aqueous ammonia is combined with POCl3 and DMF ( Figure 41). Figure 41 depicts a probable mechanism for this process. The aromatic imine can be produced by treating the iminium salt with ammonia. The aromatic imine is next oxidized by molecular iodine, which produces the aromatic Niodoimine, which is then eliminated in aqueous ammonia to produce the aromatic nitrile. 70 Figure 41. Conversion of electron-rich aromatics into aromatic nitriles.
The requirement for extremely electron-rich aromatics in the production of aromatic N, N-dimethyl iminium salts, on the other hand, limits the breadth of this transition. As a result, the writers should devise more user-friendly approaches for this change. Following this, they developed a unique one-pot approach for preparing aromatic nitriles from aryl bromides and arenes by forming aryl lithium and their DMF adducts ( Figure  42). 71 The treatment with molecular iodine in aqueous ammonia was then performed. Similarly, in the presence of Mg, the same author reported the synthesis of aryl nitriles from aryl bromides. 72 Figure 42. Conversion of electron-rich aromatics into aromatic nitriles and plausible mechanism.

DMF Mediated Formylation Reactions
DMF is used as a reagent in a variety of significant chemical processes, including the Vilsmeier-Haack reaction, which results in the formylation of aromatic, non-aromatic, and heteroaromatic compounds. Dialkylamides were also employed as a source of formylation. Wang et al. transformylated various amines, primary or secondary, aromatic or alkyl cyclic or linear, mono-or di-amine with DMF as a formylation reagent to obtain corresponding formamides with CeO2 catalyst. The reaction does not require any homogeneous acidic or basic additives and is water tolerant. The CeO2 catalyst's high basicity and medium water-tolerant acidity ( Figure 43) are its finest features. 73  (Figure 44). 74 It has a wide substrate range that includes aliphatic, aromatic, and heterocyclic molecules. The significance of these reactions is their low cost, readily available starting material, strong reactivity, and inertness to air and water [86]. Larsen et al. discovered a simple process for synthesizing, α, β-acetylenic aldehydes 66, acetylides, which are then converted to lithium acetylides using n-BuLi ( Figure 58). Formylation of lithium acetylides was completed in the presence of DMF, followed by α-aminoalkoxide with 10% aqueous KH2PO4 to obtain the desired product. 75 (Figure 45) Under microwave irradiation, Jeon and colleagues observed that methyl benzoate 67 enhanced Nformylation of several primary and secondary amines 69 using DMF as a formylating agent ( Figure 46). The primary benefit of this approach is selective N-formylation in the presence of a hydroxyl group. 76 Figure 46. N-formylation of various 1° and 2° amines.

DMF Assisted Hydrogenation Reactions
Dialkylamides can operate as a hydrogen source and have been employed in a variety of functional group transformations. It is preferable to employ hydrogen gas produced in situ from dialkylamides rather than handling easily combustible hydrogen gas. Hua et al. described a triruthenium dodecacarbonyl [Ru3(CO)12] catalyzed stereo divergent semihydrogenation of diaryl alkynes 70 using N,N-dimethylformamide/water as the hydrogen source to produce cis-71 and trans 72-stilbenes ( Figure 47). When HOAc was employed, excellent stereoselectivity in favour of cisproduct production was found. Surprisingly, the stereochemical preference shifted to the trans-isomer, with TFA acting as an additive. This method is excellent for synthesizing natural product analogues such as ciscombretastatin A-4 and trans-resveratrol. 77  Figure 48). The C-C sigma bond of PCP is attacked by metallo radical Co (II) porphyrins, and the resulting benzyl radical removes a hydrogen atom from DMF to provide the hydrogenated product 74. The presence of benzyl radical intermediates in undergoing hydrogen atom transfer from DMF was indicated by the results of several control experiments. 78 Figure 48. DMF as hydrogenating reagent for benzylic positions.
In 2017, Liu and co-workers used a copper oxide and iodine-mediated direct redox method to synthesize α-arylketothioamides 76 from acetophenones, elemental sulphur 75, and DMF in a nitrogen environment ( Figure 49). Sulphur acts as a nucleophilic building block, while DMF acts as a solvent and an amino group supply (dimethylamine). This redox-efficient reaction tolerated a wide range of functional groups. 79 Figure 49. Synthesis of α-arylketothioamides.

DMF Mediated Carbonylation Reactions
Carbonylation is another important process that, in the presence of adequate catalysts, creates the lethal "CO" gas from dialkylamides. As a result, carbonylation with dialkylamides is quite advantageous. Gunanathan and colleagues developed a unique bond activation approach for the efficient synthesis of simple and functionalized symmetrical and unsymmetrical urea derivatives from amines with DMF as the CO source ( Figure 50). Ruthenium pincer complex stimulates amine N-H bonds, which results in CO insertion from DMF and hydrogen release. Amine nucleophilicity is essential for urea synthesis. This reaction is noteworthy because it occurs in an open state, produces no side products, and requires no pressure adjustment. 80 Furthermore, Chen and colleagues discovered a unique and highly effective method for synthesizing imidazolinones 78 from carbene complexes 77 using an oxygen atom insertion procedure of NHC copper complexes in the presence of DMF as an oxygen source ( Figure 51). 81

Conclusions
DMF/DMA can be particularly used in synthesizing functionalized carbo-and heterocyclic compounds to design novel, highly effective fine-chemicals, and broad-spectrum pharmaceuticals. With the introduction of novel reagents and catalytic systems, as well as the need to design efficient synthesis methods, dialkylamide is expected to find new uses in organic synthesis. Diakyl amides have mostly been employed as a synthetic agents by monomerizing one of the groups. Furthermore, it is more likely to be used as a difunctionalizing agent, as an alkyl group connected to the carbonyl and nitrogen in DMA can be functionalized at both ends at the same time. Dialkyl amides will continue to attract the interest of synthetic chemists as a synthon, ligand, dehydrating agent, and solvent due to their low cost, accessible availability, and versatility in reactivity. We thank all the writers cited here for their significant contributions to the advancement of this discipline. We hope that it is sufficiently impressive and thorough that it will enhance the interest of organic chemists, and spark further research into the applications of DMF/DMA beyond being just a polar solvent, because it can be used as a substrate in a variety of reactions such as formylation, amination, amidoalkylation, aminocarbonylation, amidation, and cyanation under both metal-catalyzed and metal-free conditions. We believe this review will make it easy for the synthetic chemists and invoke an idea about utility of dialkyl amides.

Conflict of interest
The authors declare no conflict of interest or any funding/support that could have affected the results presented in the work. On behalf of all authors, the corresponding author states that there is no conflict of interest.