Advances in Metal‐Free Transamidation: A Sustainable Approach to Amide Bond Formation

Abstract

The amide functionalities are a crucial functional group in organic synthesis, playing a vital role in many processes that are essential for the efficient synthesis of important pharmaceutical and industrial compounds. Despite being one of the most commonly conducted reactions by researchers in both academia and industry, the synthesis of amides remains a staple in chemical research and development. Transamidation reactions enable the one‐pot conversion of one type of amide into another. Additionally, this process is crucial in the complete synthesis of specific naturally‐occurring compounds. However, these methods have certain limitations such as using toxic and corrosive starting materials, usage of strong acid or base, and metal mediated reaction, which can lead to excessive hydrolysis of the desired amide product. To overcome these challenges, more practical and efficient approaches have been developed. Metal‐free transamidation reactions have emerged as a powerful and versatile synthetic methodology in organic chemistry, allowing for the direct conversion of amides into new amide products without relying on metal catalysts. In the review article, we have focused on various metal‐free transamidation protocols of unactivated amides.

This review highlights the recent developments of transamidation reactions under metal‐free reaction conditions. Various amines including weak nucleophilic amines such as aromatic amines have been used to achieve the transamidation reactions under mild and relatively green reaction conditions.

1. Introduction

The amide functionalities are an essential functional group in the fields of synthetic chemistry, biology, and the production of pharmaceuticals.^{[ 1} , ² , ^{3 ]} In the synthesis of active medicinal compounds, processes that create amide bonds are among the most routinely conducted due to the relevance of these bonds.^{[ 4} , ^{5 ]} Developing new methods for amide synthesis in the chemical industry is crucial due to the significant role that amides play in both biological and synthetic polymers, natural products, synthetic intermediates, and etc.^{[ 6} , ⁷ , ^{8 ]} Numerous synthetic ways have been discovered for amide bond production. The most common approach is the direct reaction of a carboxylic acid with an amine, referred to as direct amidation.^{[ 9 ]} The conventional approaches to amide synthesis encounter significant obstacles, mostly due to the need to use activating agents in stoichiometric quantities, resulting in waste generation. Additionally, using caustic and troublesome reagents such as acyl chlorides or anhydrides further complicates the process.^{[ 10 ]} In recent years, numerous methods for generating amide bonds have received significant interest.^{[ 11 ]} Transamidation reactions are particularly advantageous in this situation since they provide an opportunity to expand the variety of amide bonds, which are inherent in several biologically active compounds,^{[ 12 ]} and offer distinct methods for producing a broad spectrum of beneficial amides.^{[ 13 ]} The amide system is a significant and highly favored structural motif that is extensively found in nature. Wherever the amide derivatives prominently show various biological applications such as anticancer, antimicrobial, antihypertensive activities etc. synthetically obtained drug molecules with amides functionalities such as piperiline,^{[ 14 ]} moclobemide,^{[ 15 ]} piperlonguminine,^{[ 16 ]} avenanthramide‐A,^{[ 17 ]} ethenzamide, and lidocaine.^{[ 18 ]} Transamidation has been employed in several domains, including materials research,^{[ 19 ]} polymer synthesis,^{[ 20 ]} protein engineering,^{[ 21 ]} and enzyme transformations.^{[ 22 ]} The strong stability of the N─C(O) bond, due Figure 1 to nN → π*C═O conjugation, has greatly limited the effectiveness of amides in direct transamidation reactions.^{[ 23 ]}

Figure 1.

Amides present in natural products and drugs.

As an outcome, numerous metal‐based catalysts for such reactions have been described.^{[ 24 ]} These include heterobimetallic complexes^{[ 25 ]} and catalysts based on scandium,^{[ 26a ]} titanium,^{[ 26a ]} aluminium,^{[ 26b ]} hafnium,^{[ 27 ]} cerium,^{[ 28 ]} zirconium,^{[ 29 ]} niobium,^{[ 30 ]} nickel,^{[ 31 ]} copper,^{[ 32 ]} iron,^{[ 33 ]} and palladium.^{[ 34 ]} Nevertheless, several of these approaches have disadvantages, such the need for expensive work‐up processes, high temperatures, or catalysts composed of valuable metals. In recent years, there has been growing interest in developing metal‐free transamidation methods, which offer several advantages over metal‐mediated processes. A metal‐free approach is less expensive and less harmful to the environment. They also simplify reaction conditions, which increases their accessibility and safety for a wider variety of applications. In this detailed review, we have collaboratively examined the latest studies on metal‐free transamidation reactions.

2. Metal‐Free Catalyzed Transamidation Reactions

2.1. Base‐Mediated Transamidation Reactions

In 2017, Liu et al. introduced a metal‐free transamidation method for N‐activated secondary amides 1 under mild conditions (Scheme 1). This approach relies on selectively activating amides bearing N‐Boc or N‐Ts groups, which destabilize the amide both electronically and structurally. Subsequent nucleophilic addition of amines 2 leads to tetrahedral intermediates 4 that collapse thermodynamically to produce transamidation products 3. The efficiency of this process depends on the electronic properties of the Boc or Ts leaving groups. This adaptable method accommodates various amides and nucleophilic amines, enabling a one‐pot N‐activation/transamidation sequence, making it a practical and selective strategy for amide bond transformations.^{[ 35 ]}

Scheme 1.

Metal‐free transamidation of N‐activated secondary amides 1 under neat condition.

Later in 2018, the same group utilize the same conditions to transamidate N‐acyl‐glutarimides 5 with amines 6 (Scheme 2). When compared to conventional approaches, this novel strategy not only increases the transamidation process's efficiency but also greatly expands the range of various substrates, including electrophilic substituents which might be problematic in metal‐catalyzed procedures because of the possibility of side reactions or catalyst deactivation. According to their mechanistic studies, the amide bond's steric and electronic activation results in a lower strength of the amide resonance, which in turn causes the increased reactivity of N‐acyl‐glutarimides 5 and also the reactivity of this process is primarily controlled by the thermodynamic collapse of the tetrahedral intermediate 7 and the weakening of the amide bond.^{[ 36 ]}

Scheme 2.

N‐Acyl‐glutarimide 5 transamidation with amines 6 under mild reaction conditions.

In 2019, Dash and coworkers explored the potassium tert‐butoxide‐mediated transamidation of both primary 10 and tertiary amides 11 (Scheme 3).^{[ 37 ]} Various readily available inorganic bases were tried throughout the optimization process including KOH, K₂CO₃, Cs₂CO₃, KO ^t Bu, DBU, and NaOH. Among them, KO ^t Bu proved to be the most successful producing the maximum reaction yield of the desired transamidation product 12. The strategy was applicable to a variety of amines 9, including aryl, heteroaryl, and aliphatic amines, and transamidation processes were effectively carried out utilizing amides such as N,N‐dimethylformamide (DMF) and N,N‐dimethylacetamide (DMA). It was observed that the aniline derivatives with electron‐withdrawing substituents 12c and 12 d needed longer time for the reaction and resulted in lower yields than those with electron‐donating groups 12a and 12 b. Notably, an unusual reaction when cyclopropyl amine was employed in transamidation with tertiary amides. The reaction opened the cyclopropyl ring, resulting in the synthesis of enamide 12h, respectively.

Scheme 3.

Potassium tert‐butoxide promoted transamidation of amides 10 and 11.

Mechanistic investigations suggested that the reaction followed a free‐radical pathway, providing further insight into the reaction mechanism (Scheme 4).^{[ 37 ]} The reaction likely follows an electron‐transfer mechanism indicating a radical pathway for transamidation process. A Lewis basic amine coordinates with the potassium cation to form complex 13, which quickly generates anion 14 through proton abstraction. Anion 14 undergoes single electron transfer (SET) to form amine radical 15. This radical interacts with the amide 16 via another SET producing the radical anion intermediate 17. Finally, the radical 15 couples with intermediate 17 to yield 18. Finally, the intermediate 18 undergo an elimination of amino functionality to form the transamidation product 12.

Scheme 4.

Plausible mechanism for the transamidation of amides 10 and 11 in the presence of KO ^t Bu.

Similar to the recent protocol, A simple and successful approach for transamidating N,N‐disubstituted amides 20 with primary amines 9 was established, with potassium tert‐butoxide ( ^t BuOK) serving as the catalyst (Scheme 5). In the case of N,N‐dimethylformamide (DMF), the transamidation process occurs efficiently at room temperature (25 °C) when ^t BuOK is employed as base in 4.0 equivalents, with DMF serving as the solvent under an inert environment, the process takes around 2 h to complete. Under optimal conditions, the transamidation reaction worked well with various amines. Both electron‐rich and electron‐deficient anilines gave high yields (90%–98%). Halogen‐substituted anilines (ortho/para) also performed well, except for para‐trifluoromethyl. Aliphatic and heterocyclic amines remained unchanged, while secondary amines like N‐methylaniline were less efficient due to potential side reactions. Notably, α‐naphthylaniline and p‐cyanoaniline also reacted smoothly.^{[ 38 ]}

Scheme 5.

^t BuOK initiated direct transamidation protocol of N,N‐dimethyl amides 20 with primary amines 9.

In 2019, Zhang and coworkers successfully developed the transamidation of N,N‐dimethyl amides 22 with a range of primary amines 9 using sodium tert‐butoxide (NaO ^t Bu) as a base (Scheme 6).^{[ 39 ]} They tested a number of bases throughout the reaction optimization phase and when the reaction was carried out in an inert atmosphere, NaO ^t Bu produced the maximum conversion of amides to transamidation products 23. It was observed that the course of reaction was influenced with stoichiometry of the base used. The versatility of the approach was highlighted by the high yields of amides that could be synthesized from aromatic, heteroaromatic, and aliphatic primary amines under optimal circumstances. Notwithstanding these benefits, there is a significant drawback to the methodology: substrates with aromatic substituents at the amide's α‐position are incompatible with NaO ^t Bu. Mechanistic investigations into the reaction showed that this transamidation does not proceed via a radical pathway, distinguishing it from other transamidation methods that employ bases like ^t BuOK, where radical mechanisms are typically involved.

Scheme 6.

Sodium tert‐butoxide‐mediated transamidation of amides 22 with a range of primary amines 9 to amides 23.

In 2018, Li et al. introduced a selective, metal‐free approach for transamidation of amides 26 with less‐nucleophilic amines 25 at room temperature using LiHMDS as a base and toluene as a solvent (Scheme 7). The method works well with both amides and esters as starting materials and accommodates a wide range of substrates including electron‐deficient and sterically hindered anilines along with functional groups like esters, halides, and heterocycle systems. It is also compatible with diverse amides such as N,N‐Boc_₂ amides, N‐Ts, N‐Ms amides, and N‐acyl‐pyrroles.^{[ 18 ]}

Scheme 7.

LiHMDS‐mediated transamidation of N‐Boc and N‐Ts amides 24 to amides 26.

In 2019, the same research group extended their protocol to a broader range of substrates including amides derived from anilines substituted with halo, alkoxy, carboxyl, and alkyl groups. Notably, the reaction demonstrated compatibility with aromatic, aliphatic, and cyclic amines and consistently producing the desired transamide products 26 in excellent yields. This method was particularly remarkable for achieving the high chemo‐selectivity and its applicability to a wide range of N,N‐substituted amides regardless the type of substitution including pyrrolidinyl, morpholinyl, piperidinyl, and various N,N‐dialkyl amides. Additionally, the researchers investigated the transamidation of a model twisted bridged lactam (τ = 30.7°, χN = 49.7°, RE = 8.7 kcal/mol) and observed a strong preference for selective acyl N─C(O)N─C(O) bond cleavage over σ∖sigma C─NC─N bond scission.^{[ 15 ]}

Recently, Sumerlin and coworkers developed another base‐mediated transamidation of unactivated tertiary amides 27 to diversify poly (N,N‐dimethylacrylamide) (PDMA) and related acrylamide polymers 29 using three equivalents of LiHMDS (Scheme 8).^{[ 40 ]} This approach enhances atom economy, overcomes hydrolysis susceptibility and eliminates the requirement for extra functional monomer synthesis. Tolerance for functionalized amines, quantitative to moderate conversions and wide substrate compatibility were all observed. The chemo‐selective transamidation of copolymers with different amide reactivities including ultra‐high‐molecular‐weight copolymers were made possible in UHMW polymer synthesis. By demonstrating the possibility of small molecule chemistry in macromolecular modifications, this work broadens the tools available for precision polymer synthesis.^{[ 40 ]}

Scheme 8.

LiHMDS‐mediated direct transamidation of poly(N,N‐dimethylacrylamide) 27.

Szostak and others developed a highly chemo‐selective approach for the transamidation of thioamides 30 via N─C(S) transacylation by employing weak nucleophilic anilines (Scheme 9).^{[ 41 ]} This approach allows site‐selective N‐Boc activation of primary and secondary thioamides by destabilizing the thioamide bond and enabling cleavage of the C(S)─N bond. The method works well with N‐thioacyl‐azoles and N‐Ar tertiary thioamides as selective N‐thioacyl transfer reagents. According to the DFT studies, thioamides highlight as “single‐atom substitution” isosteres of amides, with enhanced nN→π^∗ _{C = S} resonance due to increased polar form contributions. This resonance previously hindered direct transamidation. This approach effectively enables late‐stage derivatization of pharmaceuticals such as N‐mono‐Boc‐activated thioamides of probenecid, bexarotene, and ataluren reacted with functionalized anilines to yield transamidation products in good yields.^{[ 41 ]}

Scheme 9.

Base‐mediated transamidation of thioamides 30 using NaHMDS as a base.

In 2021, Kandasmy and coworkers developed base‐mediated approach for the transamidation of N‐Boc α‐ketoamides 33 with various alkyl amines 34 in the presence of relatively weak base Cs₂CO₃ (Scheme 10).^{[ 42 ]} The reactions proceeded at room temperature and reaction products were obtained in good to excellent yields under optimized conditions. The methodology displayed broad substrate scope, functional group tolerance, and rapid conversion rates. Heteroaromatic amines such as 2‐aminomethyl pyridine and 2‐aminoethyl pyridine acted as effective nucleophiles by yielding products 35a and 35b with 95% and 93% yields, respectively. Similarly, acyclic and cyclic secondary amines including diethylamine, pyrrolidine, piperidine, morpholine, and N‐benzhydryl piperazine participated efficiently producing desired products 35c–35f in high yields. However, no reaction occurred with less nucleophilic arylamines like aniline and its derivatives highlighting the critical role of amine nucleophilicity in the transamidation process.^{[ 42 ]}

Scheme 10.

Base‐mediated transamidation of α‐ketoamides 33 with alkylamines 34 using Cs₂CO₃ as a base.

2.2. Acid‐Mediated Transamidation Reactions

There are a few acid‐mediated transamidation reactions that have been developed using by Lewis acid species. In 2019, Lee and coworkers demonstrated a Lewis acid‐mediated transamidation reaction of primary amides 36 was developed using trimethylsilyl chloride (TMSCl) as an activator (Scheme 11).^{[ 43 ]} This corresponding activation likely involves the conversion of the amide 36 into a more reactive intermediate, facilitating the nucleophilic attack by an amine 37. This makes the primary amides more susceptible to undergo nucleophilic substitution. The reactions with primary amines produced the corresponding secondary amides 38 in moderate to excellent yields, when the transamidation was carried out in methylpyrrolidone (NMP) at 160 °C. The selection of solvent was found to play a crucial role in reactions involving secondary amines. Interestingly, the reaction facilitating the transamidation with secondary amines only in a mixture of NMP and chloroform, which is likely used to modulate the polarity and solvent effects.

Scheme 11.

Trimethylsilyl chloride‐assisted transamidation of primary amides 36 to amides 38 using amines 37.

Sakurai et al. utilized tert‐butyldimethylsilyl triflate as an activator for developing an effective synthetic tool for the formylation of amines 40 with DMF 39 (Scheme 12).^{[ 44 ]} According to their optimization research, in case of activators, silane‐based Lewis acid activators such as TMSCl, TMSOTf, and TBSOTf excelled well compared with other Lewis acids including BF₃, OEt₂, AlCl₃, TiCl₄, and SnCl₄. The amide products 41 exhibited a high tolerance toward aliphatic, aromatic, and heteroaromatic hydrazides along with the moderate‐to‐excellent yields. Furthermore, amines including heterocyclic, aromatic, and aliphatic amines performed well under the same circumstances. Nonetheless, the yield statistics showed that the yield of secondary amines was greater than that of primary amines. Importantly, imidazole and the supplementary equivalent of TBSOTf were also utilized in the reaction with amines/hydrazines that have a hydroxy group substituent.

Scheme 12.

Lewis acid‐mediated transamidation of N,N‐dimethyl formamide 39 to amides 41.

2.3. Salt‐Mediated Transamidation Reaction

In 2019, Zeng and others demonstrated a divergent transamidation of N‐acylisatins 42 with secondary amines 43 using cesium fluoride as an activator (Scheme 13).^{[ 45 ]} N‐Acylisatins are reactive twisted amides (τ = 22.0°, χN = 13.9°) which generated unique products under varies conditions. Using four equivalents of CsF in acetonitrile at 120 °C provides exo‐transamidation products via formation of acyl fluoride intermediates. Alternatively, typical circumstances acetonitrile–water at 100 °C with no additives resulted in endo N─C(O) bond cleavage to generate distinct compounds 44 and 45. Typically, the reaction between N‐acyl isatins and amines results in predictable transamination products through inner C─N bond cleavage. However, adding CsF unexpectedly promotes outer‐ring transamination favoring the cleavage of the outer C─N bond. This study introduces a novel strategy for achieving diverse chemical transformations from a single amide by selectively cleaving different C─N bonds.

Scheme 13.

Selective exo/endo N─C bond cleavage in N‐acyl isatins 42.

2.4. Radical‐Initiated Transamidation Reactions

tert‐Butyl hydroperoxide (TBHP), a green and ecologically‐friendly radical initiator was used by Mishra et al. to achieve the transamidation of N‐Boc activated secondary amides (Scheme 14).^{[ 46 ]} In order to increase the electrophilicity amide's nitrogen and get it ready for later transamidation, this activation step was required. In the subsequent phase, TBHP facilitates the transamidation of the activated amide 47 with diverse amines 48. According to their studies based on various amines, reaction occurs more readily with less hindered amine 49a and 49 b than with α‐disubstituted hindered amine 49c and 49 d. It is also observed that TBHP undergoes cross‐coupling with a broad range of substrates, a significant improvement over the limitations observed in the Et₃N‐catalyzed transamidation reactions as well as with nickel catalysis.

Scheme 14.

Transamidation of secondary amides 46 via C─N bond activation initiated by TBHP.

In 2018, Hillmyer and colleagues developed a metal‐free transamidation process for poly‐N,N‐Boc₂‐acrylamides [poly(DBAm)] 51, which enabled rapid synthesis of poly(acrylamides) 53 (Scheme 15).^{[ 47 ]} The procedure started with site‐selective Boc protection of the primary amide 50, followed by radical polymerization with AIBN at 75 °C. Poly(DBAm) 51 was then treated with different amines 52 and catalytic DMAP in THF or DMF in order to generate poly(acrylamides) 53 in good to excellent yields. This approach has extensive substrate tolerance, including primary, α‐branched, sterically‐inhibited secondary amines and anilines. Its importance has been demonstrated in the synthesis of block copolymers and on‐demand gelation methods, indicating its ability to create a wide range of polymer structures. This method marks a substantial progress in polymer functionalization and material development.^{[ 47} , ^{48 ]}

Scheme 15.

Metal‐free transamidation of N‐Boc‐activated polyacryl amides 51.

2.5. Persulfate‐Mediated Transamidation Reaction

Sawant and coworkers developed a green and efficient protocol for the transamidation of amides 54 and 56 with amines 9 using potassium persulfate in water (Scheme 16).^{[ 49 ]} The reaction is compatible with both conventional thermal heating and microwave irradiation allowing for greater flexibility in implementation. This protocol enables the preparation of a wide range of amides, demonstrating excellent substrate scope and selectivity and offering excellent yields. Interestingly, using this protocol l‐phenylalanine methyl ester hydrochloride was trans amidated and generating the N‐formyl product with no change in configuration or optical purity. This indicates the method's potential in asymmetric synthesis. Similarly, many other amino acids can also be transamidated using this protocol and same reaction and conditions.^{[ 49 ]}

Scheme 16.

A metal‐free transamidation approach for amide–amine bond formation in aqueous medium.

From a mechanistic perspective, a time‐monitored experiment revealed the formation of various intermediates alongside the product within 30 min under conventional heating. Initially, the peroxy bond of K₂S₂O₈ cleaves upon mixing with an amide, forming intermediate 58 (Scheme 17). Subsequent addition of aniline 9 converts intermediate 58 to intermediate 59, which ultimately releases ammonia and yields KHSO₄, leading to the formation of the transamidated product.

Scheme 17.

Mechanistic perspective of K₂S₂O₈ mediated transamidation.

Govindan et al. developed an effective synthetic approach for producing secondary amides 62 utilizing readily available N‐(2‐aminophenyl)benzamide 60 and phenyl isocyanate 61 in the presence of an additive potassium persulfate (Scheme 18). This approach features atom economy, practicality, and a one‐pot, two‐step reaction involving sequential nucleophilic/intramolecular addition and transamidation. Notably, the leaving group is recovered as a carbonylated N‐heterocycle, 1,3‐dihydrobenzimidazole‐2‐one 63, which has pharmaceutical significance. Substrates with electron‐donating para‐substituents on the phenyl ring of N‐(2‐aminophenyl)benzamide yielded products 62a and 62b in 87% and 86% yields, respectively. Reactions with substituted N‐(2‐aminophenyl)benzamides and phenyl isocyanates produced double‐substituted amides 62c–f with yields of 45%–95%. However, no product was obtained with aliphatic isocyanates. The by‐product, 1,3‐dihydrobenzimidazole‐2‐one 63 was recoverable under refined conditions and showed potential as a hypoglycemic agent and a versatile pharmaceutical structural motif.^{[ 50 ]}

Scheme 18.

Mechano‐synthesis of secondary amides 62 from N‐(2‐aminophenyl) benzamides 60 via transamidation process.

2.6. Iodide‐Mediated Transamidation Reaction

Xie and coworkers developed a straightforward and efficient protocol for synthesizing amides 66 through the transamidation of amides 64 using amines 65 as nucleophile and NH₄I acting as a promoter (Scheme 19).^{[ 51 ]} Their procedure demonstrates a remarkable versatility in accommodating a wide range of aromatic, aliphatic, and heterocyclic amine substrates 65 which makes this approach highly adaptable for diverse synthetic needs. Notably, the reaction shows enhanced efficiency with anilines bearing electron‐donating substituents. These groups increase the nucleophilicity of the amine, facilitating smoother transamidation reactions and leading to higher yields of the desired amides 66a and 66b. However, when anilines contain electron‐withdrawing or deactivating groups, such as nitro (─NO₂) or halides (─Cl, ─Br), the nucleophilicity of the amine is significantly reduced. In the case of substrates like 4‐nitroaniline and 4‐methylaniline, the reaction went unsuccessful. These compounds are hindered either by steric factors or electronic effects, which compromise their ability to participate in the transamidation reaction efficiently. Furthermore, it was discovered that the presence of 2.0 equivalents of NH₄I was crucial for successful N‐acetylation when dimethylacetamide is employed as the acylating agent. Moreover, a noteworthy 29% yield of the antipyretic medication paracetamol was produced.^{[ 51 ]}

Scheme 19.

N‐acetylation of aromatic amines 65 by NH₄I in the presence of DMA and DMF amides 64.

2.7. Hypervalent Iodine‐Mediated Transamidation Reaction

Hypervalent iodine reagents have shown some promising results in transamidation reactions.^{[ 52 ]} In 2022, Dandela and coworkers have developed hypervalent iodine mediated transamidation of amides in good yields using phenyliodine(III) bis(trifluoroacetate) (PIFA) 69 as an activator (Scheme 20).^{[ 53 ]} This novel approach takes advantage of PIFA's distinct features to enable the transamidation of dimethyl amide 68 with different amines 67. One equivalent of PIFA was found sufficient to drive the reaction efficiently, making it a cost‐effective and practical alternative for amide synthesis. Under these conditions, an extensive range of aromatic amines, particularly those with fluoro substituents, reacted easily and afforded amide derivatives in excellent yields.

Scheme 20.

Hypervalent iodine‐mediated transamidation of carboxamides 68 with amines 67 using PIFA as an electrophile.

A probable mechanism for PIFA‐promoted transamidation has been proposed. Initially, formamide 68 coordinates with PIFA 69, facilitating a nucleophilic attack by amines 67 to form intermediate 71. Proton transfer then generates intermediate 72, followed by deamination to yield the desired amide product 70 (Scheme 21).^{[ 53 ]}

Scheme 21.

A plausible mechanism for PIFA‐induced transamidation of amides 68 with amine 67.

2.8. Nitrite‐Mediated Transamidation Reaction

In 2019, Kandasamy and coworkers developed an effective methodology for the transamidation reaction promoted by the use of tert‐butyl nitrite by reacting secondary amides 73 with a variety of amines 75 including primary, secondary, cyclic, and acyclic amines (Scheme 22).^{[ 54 ]} Where the secondary amide undergoes N‐nitrosation to form N‐nitrosamide intermediate 74 and it further undergoes nucleophilic addition with the respective amines 75, followed by elimination offered transamidated products 76 in good‐to‐excellent yields. N‐Methyl benzamides showed good involvement in the reaction with amines 75a–c. Interestingly, heteroaromatic amines like 2‐aminomethyl pyridine and 2‐aminoethyl pyridine proved to be effective nucleophiles in the transamidation process, yielding the desired products efficiently 76d and 76 e. However, nucleophilic amines like aniline could not work well under given reaction conditions. In case of N‐alkyl benzamides, reactions worked well regardless of the substituents on the aryl ring and desired products were obtained with good to excellent yields 76g and 76 h.

Scheme 22.

Transamidation of secondary amides 73 mediated by tert‐butyl nitrite.

Possible mechanism of the above transamidation reaction is shown in (Scheme 23). According to this, the reaction begins with the N‐nitrosation of the secondary amide 73 in the presence of tert‐butyl nitrite resulting in the formation of N‐nitrosamide 74. This intermediate subsequently interacts with an amine 75 via nucleophilic addition to yield transitory intermediate 77. Because of its instability, intermediate 77 undergoes an elimination process resulting in the desired transamidation product 76 along with the byproduct, alkyl N‐nitrosamine 78.^{[ 54 ]}

Scheme 23.

Plausible reaction mechanism for the tert‐butyl nitrite mediated transamidation of amides 73 to 76.

Nasiri et al. reported an innovative and unconventional method for the transamidation of primary amides 79 using dichloroimidazolidinedione (DCID) 81 as a C─N bond activator (Scheme 24).^{[ 55 ]} This method stands out for its simplicity and efficiency as DCID alone mediates the reaction without the need for additional metal catalysts making it a cleaner and more environmentally friendly alternative. The study demonstrated a broad substrate scope and successfully synthesized secondary and tertiary amides 82 in good yields. Under optimized reaction conditions, the method exhibited a high degree of amine tolerance allowing smooth reactions with a wide variety of amines including benzylic, aliphatic, heteroaromatic, and secondary amines. However, the reaction showed limitations with less nucleophilic aniline by producing only trace amounts of the product 82 h. This limitation was attributed to the delocalization of the nitrogen lone pair within the aromatic ring, reducing its nucleophilicity and reactivity in the transamidation process. This approach highlights the potential of DCID as a versatile and effective mediator for transamidation.

Scheme 24.

DCID‐mediated direct synthesis of amide 82 via transamidation of amides 79.

The proposed mechanism begins with the heterolytic cleavage of the C─Cl bond in DCID that facilitated by the electron donation from two nitrogen atoms adjacent to the quaternary carbon forming the 2‐chloro‐4,5‐dioxo‐imidazolinium chloride salt 85. Next, a benzamide sodium salt acts as a nucleophile attacking the C2 position of intermediate 85 to produce intermediate 86. This intermediate then undergoes a nucleophilic acyl substitution with amine functionality leading to the formation of a tetrahedral intermediate 87. Finally, the elimination of 1,3‐dicyclohexylimidazolidine‐2,4,5‐trione (DCIT) 83 results in the formation of the desired transamidation products 82. This stepwise process underscores the critical roles of nucleophilic attack and substitution in achieving the final product (Scheme 25).^{[ 55 ]}

Scheme 25.

Reaction pathway for DCID mediated direct synthesis of amide 82 via transamidation protocol.

2.9. Microwave‐Assisted Transamidation Reaction

Microwave irradiation (MWI) is an unconventional, environmentally friendly energy source that has enhanced organic synthesis by enabling faster, more efficient, and sustainable transformations. It has been extremely useful in transamidation processes, in which one amide group is replaced by another. Recent advances include using potassium persulfate (K₂S₂O₈) for unactivated amides, heteropoly anion‐based ionic liquids for improved selectivity, ammonium salts for tertiary amides, and a catalytic system of iodine and hydroxylamine hydrochloride for primary, secondary, and tertiary amides. These achievements emphasize MWI's significance in advancing efficient, selective, and environmentally friendly techniques in contemporary chemistry.

In 2015, Srinivas et al. developed a microwave‐assisted transamidation protocol for the synthesizing amides (Scheme 26). Utilizing various amines 9 and amides 54 and 56 mediated by K₂S₂O_8. This method works well in both traditional heating (Scheme 16) and MW assisted synthesis. This peroxy reagent facilitates N‐protection of diverse amines, serving as a versatile protection strategy in synthetic organic chemistry. It offers an economical route to phthalimide‐protected derivatives, including amino acid derivatives, and is compatible with branched amines, nitrogen‐containing, and hydroxyl‐bearing substrates. To broaden the scope of this reaction, its application was explored for synthesizing various drugs and natural products such as phenacetin, paracetamol, and lidocaine, as well as the natural product piperine. This method is also suitable for synthesizing other drug intermediates or natural products, demonstrating its versatility.^{[ 50 ]}

Scheme 26.

Microwave‐assisted synthesis of amides mediated by K₂S₂O₈.

Fu et al. introduced an innovative catalytic system for the transamidation of nonactivated carboxamides 88 with amines 89, employing catalytic quantities of heteropolyacid‐based ionic liquids (HPAILs) 90 under microwave‐assisted and solvent‐free conditions (Scheme 27). This method displayed a broad substrate scope, successfully facilitating reactions with a diverse range of amines, including primary, secondary, and tertiary amines. The versatility of the approach was further highlighted by its compatibility with various amine types, demonstrating its potential for efficient and environmentally friendly synthesis of amides 91.^{[ 56 ]}

Scheme 27.

Ionic liquid‐mediated transamidation of carboxamides 88 with amines 89.

A microwave‐assisted, chemoselective approach has been established to transamidate Boc‐activated secondary carboxamides 93 with amines 94 in the absence of solvents, catalysts, and additives. Singh et al. (2023) used microwave irradiation to accomplish quick, efficient, and selective amide synthesis 95 (Scheme 28).^{[ 57 ]} They showed extensive application with a variety of N‐Boc‐activated aliphatic and aromatic amides as well as amines. When optimized, both weakly nucleophilic aromatic and aliphatic amines interacted smoothly, with yields dependent on amine structure and electrical characteristics. Electron‐donating groups on aryl amines produced high yields, but electron‐withdrawing groups produced moderate to good yields. Sterically hindered amines demonstrated slower reaction speeds and slightly decreased yields. According to mechanistic study, electron‐withdrawing amides are more reactive than electron‐donating amides.^{[ 57 ]}

Scheme 28.

Chemoselective transamidation of secondary amides 93 with the utilization of microwave.

Tan et al. demonstrated the efficient protocol for the transamidation of N,N‐disubstituted amides 96 such as N,N‐dimethylacetamide (DMA), or dimethyl benzamide (DMB) with primary amines 9 was established, with ^t BuOK serving as the catalyst under microwave condition. Subsequently, the reaction also works with traditional method (Scheme 29). The reaction operates differently when DMA and DMB are employed as substrates, however. These changes need substantially higher temperatures, ranging from 110 °C–130 °C, and are carried out over 20–50 min utilizing microwave heating. The reaction also uses diglyme as a solvent in the presence of ^t BuOK to accomplish the required transamidation. During the substrate scope ortho‐substituted anilines are observed to provide a lower yield than all other anilines.^{[ 38 ]}

Scheme 29.

^t BuOK initiated direct transamidation of N,N‐dimethyl amides 96 with primary amines 9 under microwave irradiation.

3. Transamidation Reactions Involving Catalysis

3.1. Organocatalyzed Transamidation Reaction

Catalysis is one of the key tools of organic chemistry by which several organic transformations can be achieved with minimum negative on our environment.^{[ 52 ]} There are several catalytic approaches that have been developed to achieve the transamidation reaction in one decade. In this section, various transamidation reactions involving catalysis would be highlighted. In 2013, Adimurthy and coworkers developed a novel transamidation process catalyzed by l ‐proline 100, which allows for the selective and efficient transamidation of carboxamides 98 with various amine substrates 99 (Scheme 30).^{[ 58a ]} This method was designed to target specific amide groups enabling their transformation with high precision and effectiveness. During the screening of substrate scope, the reaction demonstrated significant functional group compatibility when acetamide was used and it works well for corresponding amine derivates bearing electron rich and electron deficient substituents 101a‐c. Additionally, the less nucleophilic anilines such as p‐methyl aniline 101e and m‐chloroaniline 101 g provides better yields due to the delocalization of the nitrogen lone pair on aromatic ring system. Moreover, the formamide performs exceptionally well under these reaction conditions and produces transamidated products in good yields. This is attributed to the strong electrophilic nature of formamide, which enhances the reaction. However, this method proves ineffective for acyclic secondary amines like dibenzylamine and diisopropylamine. It was determined that the presence of free N─H and COOH groups in l ‐proline is essential for the transamidation process to proceed efficiently.

Scheme 30.

l ‐roline‐mediated transamidation of carboxamides 98 with amines 99.

Depending upon the literature reports^{[ 58b ]} and experimental observations, the plausible reaction mechanism is given in (Scheme 31). According to that l ‐proline 100 interacts with an amide 98 to make intermediate 102, which then reacts with amine 99 to form tetrahedral intermediate 103. The elimination of ammonia from 103 produces intermediate 104, which when hydrolyze and generates the ultimate transamidation product 101 along with catalytic species. The process consists of three chemical steps‐ nucleophilic addition, elimination, and hydrolysis.

Scheme 31.

Plausible mechanism for l ‐proline catalyzed transamidation of amides 98 with amines 99.

Another organocatalytic approach for transamidation of amides 105 has been developed by utilizing imidazolium chloride as a catalyst (Scheme 32).^{[ 59 ]} This approach has a wide range of flexibility in the terms of substituents in amides and amines and can potentially use with various primary amines 106 with tertiary amides 105 because it is compatible with an extensive spectrum of substrates. The aromatic primary amines bearing electron‐donating and withdrawing groups were tolerated well under the reaction conditions with efficient acetyl donor DMA. Whereas amines with electron‐donating groups shows better activity than withdrawing groups and anilines with nitro substituents shows less activity. It was noteworthy that the electronic properties of the substituent groups on the phenyl ring played an important role in the reaction.

Scheme 32.

Imidazolium chloride catalyzed transamidation of tertiary amides 105 with amines 106.

Hypervalent iodine catalysis has played a vital role in the progress of organic synthesis in the past two decades.^{[ 60 ]} In 2013, Singh and coworkers developed an effective route for the transamidation of carboxamides 112 with amines 113 using phenyliodine(III) diacetate (PIDA) 114 as catalyst under the microwave irradiations (Scheme 33).^{[ 61 ]} Substrates scope study suggests that the amide reactivity is affected by both steric and electronic functionalities. The higher electron‐donating capacity of alkyl groups over aryl groups accounts for the typical higher reactivity of aliphatic amides 115a‐c over aromatic amides 115d–g. Aliphatic amines are frequently more reactive than aromatic amines but both types of amines were employed successfully. The amide nitrogen atom's steric barrier might decrease reactivity. Steric hindrance causes aromatic amines with ortho substituents to have reduced yields 115c although cyclohexylamine is entirely unreactive because of its large cyclohexyl group 115f. Many different functional groups and substituents, such as Me, OMe, NO₂, Cl, OH, and Br were tolerated in this catalytic protocol.

Scheme 33.

Hypervalent iodine‐catalyzed transamidation of carboxamides 112 with various amines 113.

The catalytic cycle was initiated with the activation of carbonyl functionality of an amide 112 by PIDA 114 to form the intermediate 116, which reacts with amine 113 to form another intermediate 117. Intermediate 117 undergoes the cleavage to yield transamidation product 115 along with formation of PhIO. PhIO further reacts with another molecule of an amide 112 to form the species 118 which undergo the nucleophilic addition of amine 113 to give the tetrahedral intermediate 119. Finally, tetrahedral intermediate 119 undergoes the elimination step to yield transamidation product 115 with regeneration of catalytic species PhIO to continue the catalytic cycle (Scheme 34).^{[ 61 ]} Moreover, Hofmann rearrangement product was also observed in traces during this catalytic approach.

Scheme 34.

Catalytic cycle for the hypervalent iodine catalyzed transamidation of carboxamides 112 with various amines 113.

In 2009, an interesting approach for the transamidation of amides was developed by Vaidyanathan and coworkers using DBU as catalyst.^{[ 62 ]} In this approach, the starting acyl imidazoles 122 were synthesized in situ from corresponding acids which were transamidated with various secondary amines 123 in high yields (Scheme 35). Surprisingly, it significantly enhances reaction rates comparable to well‐established other catalysts. It was observed that the DBU catalysis was more effective for the anilines bearing electron‐withdrawing functionalities compared to the electron‐donating groups in the anilines. More likely, the DBU acts as the nucleophilic catalyst during this transformation.

Scheme 35.

DBU‐catalyzed amidation of acyl imidazoles 122 to the amides 124.

The catalytic cycle for DBU catalyzed transamination reaction of acyl imidazoles 122 to the amides 124 is depicted in (Scheme 36). The catalytic cycle was initiated by a nucleophilic attack of DBU 125 to the carbonyl functionality of amide 122 to form intermediate 126. Intermediate 126 further reacts with the secondary amines 123 and gave the final products 124 along with regeneration of catalytic species to continue the catalytic cycle.

Scheme 36.

Catalytic cycle for DBU catalyzed transamidation of acyl imidazoles 122 to the amides 124.

In 2016, a synthetic approach for the N‐formylation of amines 127 utilizing catalytic amounts of borinic acid 132 was investigated by Blanchet and coworkers (Scheme 37).^{[ 63 ]} Numerous primary and secondary amines as well as functionalized α‐amino esters were used to test the N‐formylation of amines. Based on their experimental study, they proposed that the reaction operates through cooperative catalysis, primarily driven by the increased Lewis acidity of the boron center rather than the enhanced Brønsted acidity of acetic acid. For chiral substrates, the observed racemization prompted a change in the formyl donor from dimethylformamide to formamide to minimize racemization and maintain it at a low level. Additionally, reaction scope was extended for the synthesis of isocyanides from primary amines. Interestingly, the methyl glutamate diester produced the macrolactam 133 in 91% yield rather than the predicted formamide 129a. This data suggests an unexpected activation of the side chain, most likely involving the ester functional group. This activation might have enhanced intramolecular cyclization, favoring macrolactam synthesis over anticipated amidation. This unexpected result demonstrates the ester moiety's potential reactivity and significance in affecting the reaction route under the given circumstances.

Scheme 37.

Borinic acid catalyzed transamidation of formamide 128 and 130 to amides 129 and 131.

Ma et al. (2018) demonstrated the application of graphene oxide (GO) as a catalyst for amine N‐formylation. They used tertiary amides 134 and a variety of substituted secondary amines 135 to perform reactions in their investigation (Scheme 38).^{[ 64 ]} To avoid oxidation or other unintended reactions, the processes were carried out at 150 °C in an argon environment. This configuration demonstrated the efficiency of graphene oxide as a catalyst in enabling the transformation of the corresponding amide derivatives. However, the presence of an electron‐withdrawing group on the benzene ring of amine derivative negatively impacts this transformation and making it less effect In contrast, when other secondary amines whether cyclic or linear were employed as substrates, the reaction generally proceeded successfully. Using this strategy, fluoxetine, an antidepressant, was hydroformylated with a moderate yield of 46%. Unexpectedly, in primary amines, this reaction is highly dependent on the distance between the amino and phenyl groups. A remarkable 97% yield of 136c is achieved when three methylene units separate these group. Due to the conjugation of nitrogen and benzene ring in the amines with hydroxyl substitution will decrease the nucleophilicity of nitrogen which makes the reaction unfavorable. They also concluded that the carboxyl groups on the graphene oxide surface are probably drive graphene oxide's catalytic activity, as opposed to the hydroxyl and epoxide groups.

Scheme 38.

Graphene oxide‐catalyzed N‐formylation of amines 135 using transamidation process.

Based on experimental findings and supporting literature, they suggest a viable mechanism for the N‐formylation process (Scheme 39). The carboxyl groups on the GO surface activate the amino and formyl groups resulting in the formation of an intermediate complex 137. The carboxyl group's carbonyl moiety operates as Brønsted base and increasing the nucleophilicity of the amino group. The hydroxyl group interacts with the formyl group via hydrogen bonding and acts as a Lewis acid to activate the carbonyl group in DMF. The activated amino group attacks the activated carbonyl as nucleophile resulting in the formation of a tetrahedral intermediate 138. Finally, the sterically congested intermediate 138 undergoes by proton transfer for releasing the target compound 136 and regenerating the active species.^{[ 64 ]}

Scheme 39.

Proposed catalytic mechanism of GO catalyzed N‐formylation reaction of amines 135.

In 2018, Bhattacharya et al. developed the novel synthetic route for the metal‐free transamidation using GO as a heterogeneous catalyst, they devised a method to change aliphatic amides 140 into aromatic amides 142 by reacting with various aromatic amines 141 (Scheme 40).^{[ 65 ]} For this transamidation process, graphene oxide function as an effective and recyclable catalyst because of its enormous surface area and many carboxylic acid groups on its edges which they stimulate the weakly electrophilic amide group, facilitating the following attack of the amine nucleophile via hydrogen bonding. Researchers used GO catalysts in reactions with both organic and inorganic solvents at different temperatures during process optimization, but the results fell short of what was anticipated. It was interesting to note that a high yield of the intended product was produced at 150 °C in solvent‐free circumstances with the same quantity of catalyst. By reacting aromatic anilines with various aliphatic carboxamides, this approach efficiently produced a range of formamide and acetamide compounds. However, the equivalent transamide product was not effectively produced by the reaction of carboxamides with an aliphatic amine.

Scheme 40.

Graphene oxide‐mediated N‐formylation and N‐acetylation reactions.

Patel et al. (2019) explored graphene oxide as a heterogeneous catalyst for transamidation reactions with systematically optimized the catalytic amounts, solvents and temperature (Scheme 41).^{[ 66 ]} Among tested carbon nanomaterials, graphene oxide (20%) at 130 °C yielded the best results and achieving 48%–97% efficiency with aryl‐substituted benzylamines and unsubstituted benzamides, though substituted benzamides showed lower yields. The method also worked well with branched‐chain, cyclic aliphatic amines, and formamides demonstrating compatibility with aryl, heteroaryl, and aliphatic substrates. The reaction tolerated phthalimides, thioamides, and selectively favored aliphatic amines, with urea yielding a dimeric transamide product. This approach highlighted graphene oxide's versatility and selectivity.

Scheme 41.

Graphene oxide‐assisted transamidation of unactivated amides 143.

In 2020, the same research group invented a new pathway for the incorporation of solar energy in the amidation reactions thereby using concentrated solar radiation and graphene oxide as a catalyst. This synthetic process was established for the energy‐efficient and ecologically friendly transamidation of carboxamides and phthalimides 146 with different amines 144 (Scheme 42).^{[ 67 ]} This method not only minimizes energy consumption but also aligns with green chemistry principles by reducing the use of harmful reagents and promoting more sustainable chemical processes. Heat is produced when the molecules vibrate and spin due to the presence of infrared photons in solar radiation. The effective conversion of radiation into heat by concentrated sun energy allows for superheating at standard pressure. Solar radiation causes fast vibration and rotations which speeds up the rate of reaction by boosting molecular collisions and improving reactant‐reactant contact.

Scheme 42.

Graphene oxide catalyzed transamidation of amides 146 under solar radiation.

3.2. Inorganic Catalysis Transamidation Reaction

In recent years, inorganic catalysis has played a significant role in the development of organic synthesis.^{[ 68 ]} An aqueous approach of metal‐free transamidation was disclosed by Lee and co‐workers in which tetra‐n‐butylammonium iodide (TBAI) was used as catalyst and DTBP as radical initiator to achieve the reaction between various aromatic and aliphatic amines 149 with N‐acylpyrrolidin‐2‐one 148. Reactions were working smoothly and transamidated products 150 were obtained in high yields (Scheme 43).^{[ 69 ]} The use of water as a solvent lowers the generation of hazardous waste and is a sustainable substitute for conventional organic solvents. Additionally, the reaction exhibits a broad substrate scope, and this flexibility allows for both aromatic and aliphatic amines to participate in the reaction to enable the formation of a diverse range of transamidated products. Interestingly, halide‐substituted aniline derivatives fared well in the process. Furthermore, in this typical reaction conditions, both benzoylpiperidin‐2‐one and benzoylazepan‐2‐one showed excellent reactivity. The N‐acyl lactam amides were utilized for the first time ever in the transamidation process so far. They also propose a radical reaction mechanism based on the control experiment data which includes the generation of intermediate acyl and aniline radicals during the process.

Scheme 43.

Aqueous promoted metal‐free transamidation of benzoylpyrrolidin‐2‐one 148 with amines 149.

Based on their findings, they suggest the following chemical pathway: Di‐tert‐butyl peroxide (DTBP) interacts with TBAI to produce tert‐butoxyl radical and tert‐butoxide. tert‐Butoxide interacts with DTBP to produce tert‐butyl peroxy radical via iodine. Both radicals undergo single electron transfer with aniline resulting in aniline cation radical species 151. This compound interacts with benzoylpyrrolidin‐2‐one 148 via a radical pathway to produce intermediate 152, which then undergoes radical dissociation and releasing the pyrrolidin‐2‐one as a leaving group to yield the transamidated cation 153. Finally, hydroxide or tert‐butoxide removes a proton from 153 resulting in the desired product 150.^{[ 69 ]}

A solvent‐free methodology for the transamidation carboxamides 154 with amines 155 has been devised utilizing a catalytic amount of H₂SO₄‐SiO₂ by Das and others (Scheme 44).^{[ 70 ]} This method works well with a wide range of aliphatic, aromatic, heteroaromatic and both cyclic and acyclic primary, or secondary amines. Based on the substrate scope, electron‐neutral, electron‐rich, electron‐deficient, aliphatic, and cyclic secondary amines produced the corresponding transamidation products 156 with high yields. Notably, sterically hindered arylamines interacted efficiently and produced transamidated product 156a. Less reactive heteroaromatic compounds, such as 2‐aminopyrimidine 156b formed the transamidation product in lower yields and with longer reaction times. It is worthnoting that amines with substitution such as bromo 156c and chloro 156d are well‐tolerated under these reaction conditions. Moreover, the catalytic reaction was expanded to include formylation and acetylation 156e and 156 f. Additionally, this method paved way for the formation of commercially available drug procainamide 156g.

Scheme 44.

Acid‐catalyzed transamidation of amides 154 under solvent‐free conditions.

Based on the experimental data and the known role of H₂SO₄/SiO₂ as a proton‐transfer agent from its solid surface, a viable mechanism for the transamidation process has been postulated (Scheme 45). The process starts with the protonation and activation of the amide bond in N,N‐dimethyl benzamide 154 by the sulfonic acid group (─SO₃H) on the surface of H₂SO₄/SiO₂. This protonation produces a cationic intermediate 157 that is extremely reactive due to the partial positive charge on the carbonyl carbon. The cationic intermediate 157 is then attacked by an amine nucleophile 155. This step includes the generation of a tetrahedral intermediate 158 in which the amine group binds to the carbonyl carbon. The intermediate then loses dimethylamine (NHMe₂) as a leaving group forming the transamidation product 156. The contribution of H₂SO₄/SiO₂ in this process is critical since it not only aids in the initial protonation and activation of the amide bond but it also stabilizes the cationic intermediate enabling nucleophilic attack and eventual elimination. This solid acid catalyst serves as an efficient and reusable platform for the transamidation process, allowing for transformation under moderate circumstances.^{[ 70 ]}

Scheme 45.

Plausible reaction mechanism for H₂SO₄‐SiO₂‐mediated transamidation amides 154.

In 2018, a significant one‐pot, transition‐metal‐free transamidation of primary amides 159 was developed by using cesium fluoride as catalyst by Zeng and others.^{[ 71 ]} This approach involves of two steps: selective N‐tert‐butoxycarbonylation (N‐Boc) of primary amides in order to generate reactive twisted N,N‐Boc₂‐amides, followed by CsF‐catalysed transamidation (Scheme 46). CsF facilitates the formation of an electrophilic acyl fluoride intermediate 162, which undergoes nucleophilic attack by amines 160 to yield amides 161 along with the regeneration of CsF species to continue the catalytic cycle. This protocol operates under mild conditions, tolerates diverse functional groups, and accommodates sterically hindered substrates, making it efficient and practical. The process emphasizes the function of CsF in producing acyl fluoride and enhancing nucleophilic addition, resulting in excellent selectivity and reactivity without the need for transition metals.^{[ 71 ]}

Scheme 46.

Transition‐metal‐free transamidation of primary amides 159 via tandem di‐Boc activation process.

Furthermore, Lee and coworkers invented an ammonia carbonate‐catalyzed catalytic approach for synthesis of primary amides 164 by the transamidation of tertiary amides 163 under moderate reaction conditions (Scheme 47).^{[ 72 ]} Utilizing (NH₄)₂CO₃ in DMSO at 25 °C, tertiary amides containing N‐electron‐drawing groups such as sulfonyl, diacyl effectively generate primary amides with strong functional group tolerance. Furthermore, N‐tosylated lactams undergo ring opening to produce N‐tosylamido alkyl amides. This strategy is straightforward, adaptable, and works with a wide range of functional groups.

Scheme 47.

Synthesis of primary amides 164 by the transamidation of tertiary amides 163 using ammonium carbonate as catalyst.

In 2012, Allen and coworkers introduced an innovative method for the transamidation of primary carboxamides 165 with primary or secondary amines 166 to efficiently synthesize secondary or tertiary amides 167 (Scheme 48).^{[ 73a ]} The key to this approach lies in the use of catalytic amounts of hydroxylamine hydrochloride which plays a crucial role in activating the typically inert and chemically stable primary amides. This activation allows the unreactive primary amide group to undergo nucleophilic substitution with the amine substrates leading to the formation of intermediate hydroxamic acid 168, which further convert into secondary or tertiary amides. Subsequently, at lower temperatures, the quantity of catalyst required may increase. Among all the substituents, aliphatic amides gave the maximum conversions with less catalytic loading. Furthermore, the substrate screening revealed important insights such as the retention of Boc protecting groups throughout the process which permits specific acylation of a single nitrogen atom in mono‐protected diamines or selective coupling of an amine and an amino amide. Kinetic studies revealed a first‐order dependence on the concentration of hydroxylamine hydrochloride and the initial reaction rate. This indicates that one equivalent of hydroxylamine is involved in the rate‐determining step. As a result, the slow step of the mechanism could involve either the initial activation of the primary amide or the nucleophilic attack of the resulting complex.^{[ 73b ]}

Scheme 48.

Hydroxylamine hydrochloride catalyzed transamidation of primary amides 165.

Nguyen and coworkers developed a solvent‐free method for the transamidation of carbamides 169 with amines 170 using catalytic amounts of boric acid. Reactions were performed with 10 mol% of catalytic loading and reaction products were isolated in excellent yields (Scheme 49).^{[ 74 ]} This approach demonstrates broad applicability with various amines such as primary, secondary, tertiary, aliphatic, aromatic, cyclic, and acyclic and phthalimides. Its economic efficiency, simplicity, and functional group tolerance make it ideal for synthesizing valuable compounds like amides, lactams, peptides, ureas, and aza‐heterocycles, particularly for large‐scale applications. This method offers significant potential for advancing organic and pharmaceutical chemistry.

Scheme 49.

Boric acid catalyzed transamidation of carboxamides 169 with amines 170.

The experiment showed that boric acid catalyzes transamidation even for tertiary amides through a mechanism involving intermediate 173. Boric acid acts as both a Lewis acid and coordinates with the oxygen of amide functionality and a hydrogen‐bond donor activating the amide for nucleophilic attack by amine 170. The catalytic cycle begins with the formation of adduct 173 via proton transfer and B─O bond formation followed by amine attack to form intermediate 175. The rate‐determining step is the conversion of aminal carbon to a boron‐bound amide facilitated by water which also prevents inactive boric acid aggregates. The cycle ends with the release of amide 171 (Scheme 50).^{[ 74 ]}

Scheme 50.

Proposed catalytic cycle for the boric acid catalyzed transamidation of amides 169.

Chaturbhuj and coworkers describe catalytic study in which sulfated polyborate was used as a catalyst to achieve the transamidation of amides.^{[ 75 ]} Reaction was optimized, and 10 mol% of catalytic loading was found sufficient to catalyze the reaction and transamination products were isolated in high yields (Scheme 51). The reaction scope was studied with substrates having electron‐donating and withdrawing substituents on aniline, benzylamine, cyclohexylamine, and alicyclic secondary amines performed well with formamide proving slightly more effective than DMF. N‐acetylation using acetamide and DMA also succeeded with anilines, benzylic, and alicyclic amines, with acetamide yielding better results. The protocol was further extended to phthalimide transamidation with primary aromatic, benzylic, and alicyclic amines, producing N‐substituted phthalimides in high yields, offering a viable alternative for phthaloyl protection of primary amines.

Scheme 51.

Sulfated polyborate catalyst transamidation of carboxamides 178 with amines 179.

Eidi et al. developed an efficient protocol for transamidation of amides 181 with amines 182 using mesoporous silica nanoparticles (MSNs) as a green, recyclable, and heterogeneous catalyst under solvent‐free conditions (Scheme 52).^{[ 76 ]} This method enables the synthesis of a variety of aromatic, aliphatic, and cyclic/acyclic amides 183 with yields ranging from 65% to 96%. Optimization studies showed that increasing the catalytic loading upto10 mol% provides the products in maximum yields while higher loading had no additional effect on the yield. The method demonstrated broad applicability, with successful transamidation of carboxamides and amines yielding aromatic, aliphatic, and heterocyclic amides efficiently. However, sterically hindered amines produced lower yields compared to aliphatic and benzylic amines. Additionally, the protocol extended to the transamidation of urea and thiourea with primary amines. This approach offers high yields, simplicity, short reaction times, and easy workups, presenting a practical and environmentally friendly alternative for other metal‐catalyst transamidation reactions.

Scheme 52.

MSNs‐mediated transamidation of carboxamides and thiourea 181 under neat conditions.

4. Catalyst/Additive‐Free Transamidation Reaction

In 2019, Szostak and coworkers demonstrated a simple and highly chemo‐selective protocol for the transamidation of N‐tert‐butoxycarbonylated secondary amides 184 (Scheme 53).^{[ 77 ]} Herein, various substituted N‐Boc amides 184 were reacted with wide range of secondary amines 185 in acetonitrile. Remarkably, the circumstances under which this reaction takes place are quite moderate and there is no need for any additives. There is a possibility that the efficiency of the transamidation process might be improved by stabilizing the tetrahedral intermediate in a transition state that is more polar. The crucial issue here is balancing the enhanced rate of nucleophilic addition to the N‐Boc activated N─C(O) amide bond with the amide bond deprotection by N‐Boc cleavage, which deactivates the amide bond against mild nucleophilic addition. The effectiveness of this approach has been proved in the direct synthesis of marketed antiemetic drug, Tigan 186a.

Scheme 53.

Transamidation of N‐Boc amides 184 without using any additive.

In 2018, Verho and coworkers developed a two‐step, metal‐free transamidation protocol of 8‐aminoquinoline amides 187.^{[ 78 ]} After destabilizing the ground state with N‐Boc, the secondary amides 188 were treated with amines 189 in toluene or DMF at 60 °C and reaction products were isolated on average‐to‐good yields (Scheme 54). The approach works with sensitive functional groups, less nucleophilic amines, and a variety of alkylamines. By producing functionalized amide products in high to outstanding yields, this method greatly expands the use of 8‐aminoquinoline amides as C─H functionalization intermediates. This method offers a productive, metal‐free substitute for altering 8‐aminoquinoline amides.

Scheme 54.

Transamidation of 8‐aminoquinoline amides 187 through intermediate N‐AcylBoc‐Carbamates 188.

In 2019, Fiore and Maas reported a metal‐free transamidation of N‐Tf‐propynamides 191 (Tf = triflyl) with amines 192 in good‐to‐excellent yields under moderate conditions (Scheme 55).^{[ 79 ]} Reaction showed good functional group tolerance with both aliphatic and aromatic amines. N‐Tf‐propynamides serve as N‐acylation precursors which can be conveniently synthesized from terminal alkynes, isocyanates, and triflic anhydride in a single step. Mechanistically, the process is most likely to involve acyl substitution, however ketene‐type intermediates cannot be eliminated. The triflimide group highly activates the amides, making N‐Tf‐propynamides much more reactive than N‐Ts amides.^{[ 80 ]} This study demonstrates the usefulness of triflyl activation for efficient, selective amide bond production.

Scheme 55.

Metal‐free transamidation of N‐triflylpropynamides 191 via twisted N‐Tf‐amides.

Recently, Rajan and Rajendran described a novel one‐pot transamidation process for the N‐pivaloyl‐activated amides 194 utilizing weak nucleophilic anilines 195 which requires no catalysts, bases, or additives. Transamidation products 196 were obtained in moderate‐to‐excellent yields by activating amides in situ with the pivaloyl group and reacting them with anilines at toluene reflux temperature (Scheme 56).^{[ 81 ]} In this approach, transamidation of various substrates was achieved effectively with different electrically varied aryl amines. Additionally, it paved way for the synthesis of various bioactive drugs 196a and 196b in good yields. Competitive studies demonstrated that planar N‐pivaloyl‐activated secondary amides and nonplanar N‐pivaloyl‐activated tertiary amides have comparable reactivity. The approach converts planar, resonance‐stabilized N‐activated secondary amides into stable precursors for transamidation, providing a flexible and chemo‐selective tool for chemical synthesis.

Scheme 56.

One‐pot transamidation of N‐pivaloyl activated amides 194.

Later on, the same group achieved the transamidation of planar (twist angle τ = 4.54°) and resonance‐stabilized N‐pivaloyl‐activated amides 198 without using any catalyst, base or additives at room temperature with alkyl amines 199 in short reaction times (0.5–2 h) and yields of 60%–97% (Scheme 57).^{[ 14 ]} The amidic resonance evidenced by C─N (1.374 Å) and C═O (1.222 Å) bond lengths does not hinder reactivity and the method tolerates amines with protic groups like hydroxy and carboxylic acids. A one‐pot protocol enables the transamidation of these planar (τ = 4.54°, χN = 6.39) and resonance‐stabilized amides, accommodating a wide range of alkyl amines including those with protic functionalities. Competitive and control studies reveal that steric hindrance influences chemo‐ and regioselectivity, highlighting the feasibility of nucleophilic addition to such amides under mild and catalyst‐free conditions. This strategy was also applied for the synthesis of natural products and drug molecules. Moreover, it was extended to other nucleophiles offering an environmentally benign approach to functionalizing N‐pivaloyl‐activated amides.

Scheme 57.

Catalyst and additive‐free transamidation of N‐pivaloyl activated amides 198.

5. Solvent‐Free Transamidation Reactions

In 2019, Subramani and Rajendran identified N‐acyl‐2‐piperidones 201 as highly effective substrates for metal‐free transamidation under moderate, solvent‐free conditions at room temperature (Scheme 58). The X‐ray structure of a vinyl derivative showed a considerably twisted amide bond (τ = 20.4°, χ_N = 11.7°) indicating structural characteristics that increase reactivity. This methodology displayed a broad substrate scope accommodating a variety of imide and amine substitutions including functionalized amines with carboxylic acid, ester, and hydroxyl groups functionalities that are frequently incompatible with metal‐catalyzed procedures. Importantly, the approach worked well with physiologically relevant substrates including amino acids and amino alcohols. The flexibility of N‐acyl‐2‐piperidones was further demonstrated by the synthesis of bioactive natural compounds such as antiepilepsirine, piperlonguminine, piperyline, and fagaramide. This approach provides a versatile and environmentally benign alternative to amide bond production in organic synthesis.^{[ 16 ]}

Scheme 58.

Transamidation of N‐acyl‐2‐piperidones 201 under solvent‐free condition.

In 2022, the same research group reported another catalyst, additive, base, and solvent‐free protocol for the transamidation of N‐acyl‐2‐piperidinones 204 with weakly nucleophilic aromatic amines 205 under melt conditions (Scheme 59).^{[ 17 ]} This environmentally benign methodology offers the transamidation products in good‐to‐excellent yields and demonstrates chemo‐selectivity, tolerating well the protic groups like carboxylic acids and hydroxy functionalities. The process is displayed for the synthesis of the bioactive natural product Avenanthramide‐A and highlights atom economy by isolating and reusing the by‐product, 2‐piperidinones for resynthesizing starting material. The protocol eliminates the need for protection‐deprotection steps offering a streamlined and sustainable approach to synthesizing amides, peptides, and amide‐based drugs. Its operational simplicity, broad applicability, and eco‐friendly nature make it a versatile tool for organic synthesis.

Scheme 59.

Transamidation protocol for weakly nucleophilic aromatic amines 205.

A proposed mechanism involves N‐acyl‐2‐piperidinones 204, where amide bond twist aligns the imide's nitrogen lone pair and exo‐carbonyl in different planes, enhancing resonance with the ring carbonyl 208. It increases exo‐carbonyl electrophilicity, enabling nucleophilic attack by aniline forming a C─N bond 209. Proton exchange yields intermediate 210 followed by C─N (lactam) bond cleavage, producing the transamidation product 206 and 2‐piperidinone as a by‐product 207 (Scheme 60).^{[ 17 ]}

Scheme 60.

Plausible reaction mechanism for transamidation of N‐acyl‐2‐piperidinones 204 with aromatic amines 205.

A catalyst and solvent‐free transamidation of glycosyl carboxamides has been developed by Laclef and others resulting in a green and efficient way for synthesis glycosyl amides.^{[ 82 ]} The reaction tolerates a wide range of amines and unprotected carbohydrates producing the reaction products 213 with good‐to‐high yields while producing primarily ammonia as a byproduct (Scheme 61). Although epimerization at the α‐position of the amide group is limited but this hypothesized process includes intermolecular hydrogen bond activation. This approach shows potential for producing glycolipids, glycoconjugates, and bioactive molecules such the phosphoglycolipids GLP 1 and GLP 2. Furthermore, this methodology was applied to glycopeptide synthesis by incorporating glycosyl carboxamides with amino acids.^{[ 82 ]}

Scheme 61.

Catalyst‐free transamidation of unprotected glycosyl carboxamides 211 under neat reaction conditions.

In 2014, Legros and others introduced an approach for the transamidation that involved the reaction of formamide 214 with various amines 215 under heating condition without requiring any catalyst or solvent (Scheme 62).^{[ 83 ]} This approach offered an environmentally friendly and neutral pathway for the formylation of primary and secondary amines aligning with green chemistry principles. A notable feature of this method was its simplicity and efficiency, as the resulting amide product could be directly converted into monomethylamine through a one‐pot sequence further enhancing its utility in chemical synthesis.^{[ 83 ]} In 2018, a similar approach was reported to extend its application by Gong and coworkers.^{[ 84 ]} In this approach, authors demonstrated the transamidation of weak nucleophilic aromatic amines 217 with formamide derivatives 214 as well as the reaction of low‐reactive tertiary amides with aliphatic amines. These advancements highlighted the versatility and robustness of the catalyst‐ and solvent‐free transamidation process displaying its ability to accommodate a broader range of substrates and reaction conditions while maintaining efficiency and sustainability.^{[ 84 ]}

Scheme 62.

Transamidation of formamide 214 under neat reaction conditions.

Singh et al. developed a catalyst, base, and additive‐free method for the transamidation of N‐tosyl α‐ketoamides 33 with alkyl amines 34 at room temperature (Scheme 63).^{[ 42 ]} Transamidation reactions were working smoothly and reaction products 35 were achieved in good‐to‐excellent yields. During these transformations, various functional groups were successfully tolerated. The protocol also worked in the presence of a base offering a simple, efficient, and environmentally friendly approach for synthesizing α‐ketoamide derivatives.^{[ 42 ]}

Scheme 63.

Transamidation of α‐ketoamides 33 with alkylamines 34 under neat reaction condition.

6. Conclusion

In conclusion, both academic and industrial regions have expressed a strong interest in amide synthesis. Amides are fundamental building components for many proteins and useful materials. Transamidation reactions were explored in order to discover new synthetic procedures. This has made it feasible to convert readily available amide derivatives into a wide range of target amides. This technique offers a modern solution to the challenge of interconverting functional groups as well as a pathway for the successful synthesis of target molecules. Transamidation processes are especially intriguing and scalable strategies that provide new possibilities for chemical synthesis in a range of fields. Transamidation facilitates the formation of novel amide bonds.

Author Contributions

Niharan Sivaraj was responsible for identifying and selecting relevant literature and drafting the manuscript. Fateh V Singh and Toshifumi Dohi contributed to the conceptualization, review, and final editing of the manuscript.

Conflict of Interests

The authors declare no conflict of interest

Biographies

Niharan Sivaraj, was born in Thanjavur, Tamil Nadu, India, in year 2000. He completed his Bachelor of Science in General Chemistry at A. V. V. M. Sri Pushpam College, affiliated with Bharathidasan University, Trichy, Tamil Nadu, India, in 2021. Subsequently, he obtained a Master of Science in General Chemistry from VIT University, Chennai, Tamil Nadu, India, in 2023. Following his graduate studies, he commenced his doctoral research at VIT Chennai, Chennai, Tamil Nadu, India, under the supervision of Dr. Fateh Veer Singh, specializing in synthetic organic chemistry. His doctoral research focuses on ring transformation reactions of α‐pyranones.

Toshifumi Dohi, received his MS degree in year 2002 (Prof. S. Murai) from the Graduate School of Engineering of Osaka University, Japan, and PhD degree in year 2005 (Prof. Y. Kita) from the Graduate School of Pharmaceutical Sciences of Osaka University, where he studied new reactivities of transition metal catalysts and synthetic chemistry using hypervalent iodine reagents. After completing his PhD research, he subsequently became an Assistant Professor at Osaka University. In year 2008, he relocated to Ritsumeikan University, where he was promoted to an Associate Professor in 2014 and to a full Professor in 2019. His current research interests focus on reagent/catalyst design and the development of new reactions using hypervalent iodine reagents. He has received the IUPAC‐ICOS 15 Poster Award for excellence in presentation, the Pharmaceutical Society of Japan (PSJ) Award for Young Scientists (2009), the Banyu Chemist Award (2013), the Thieme Chemistry Journal Award (2014), the GSC Encouragement Award (2015), and the International Congress on Pure and Applied Chemistry (ICPAC) Lecture Award (2019).

Fateh V Singh has completed his Masters in Chemistry from SSV College, Hapur, UP, India, in 1998. He has received his PhD in year 2007 in the supervision Dr Atul Goel, CSIR‐CDRI, Lucknow, India. After the completion of his doctoral studies, he was in Prof. H A Stefani's research group at USP, São Paulo, Brazil, more than two years. In 2010, he joined as Marie Curie postdoctoral fellow with Prof. Thomas Wirth at Cardiff University, UK and learned various new reactions regarding organoselenium and hypervalent iodine chemistry. He received the position of Assistant professor at Chemistry Division at VIT, Chennai, in 2014. He was promoted to Associate professor in 2022 at VIT, Chennai. Mainly, his research group is involved in the synthesis of nitrogen and oxygen containing heterocycles using organoselenium and hypervalent iodine reagents. Moreover, his research group is also involved in the development of new organic fluorescent molecules for OLEDs and chemical sensors. Recently, his research interest has grown significantly in transamidation reactions. He has published more than 100 research papers and authored several book chapters. In 2024, his name was included in the list of top 2% scientist by Stanford University.

Sivaraj N., Dohi T., Singh F. V., Chemistry - An Asian Journal. 2025, 00. 10.1002/asia.202500327

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.