The Methodological Value of TCFH: Advantages in Challenging Amidation and the Switching Logic of Carboxylic Acid Activation Pathways

Introduction

TCFH [N,N,N′,N,N′-tetramethylchloroformamidinium hexafluorophosphate] is often simply classified as a “powerful coupling reagent,” but a more accurate description is that it is a carboxylic acid activation reagent capable of directing carboxylic acids into different highly reactive activation pathways. A 2018 study showed that the combination of TCFH with NMI [N-methylimidazole] can generate a highly reactive N-acyl imidazolium intermediate in situ for challenging amidations between sterically hindered carboxylic acids and weakly nucleophilic amines, while in many cases preserving the stereocenter adjacent to the carboxyl component or at the α-position. Subsequent studies further extended this activation logic into esterification. A 2024 study showed that when the base is changed to pyridine, the system more closely follows an anhydride-dominated activation pathway, which in turn affects esterification yield, selectivity, and epimerization behavior.

1. The Place of TCFH in Challenging Amidation

Not every amide bond formation requires TCFH to be considered first. The situations in which it is most worth including in screening are usually not routine amidations in general, but rather cases in which common coupling conditions tend to lead to sluggish reactions, incomplete conversion, undesirably prolonged pre-activation times, or the need to consider switching to an acid chloride route. Typical examples include sterically hindered carboxylic acids, weakly nucleophilic amines, and substrates that are sensitive to configurational integrity. The 2018 paper addressed precisely this type of problem and clearly showed that difficult couplings between sterically hindered carboxylic acids and weakly nucleophilic amines can be accomplished efficiently under a TCFH/NMI [N-methylimidazole] system, while preserving adjacent stereocenters in many examples. The authors also demonstrated that this system can generate a highly reactive N-acyl imidazolium intermediate in situ.

A 2024 study on TCFH-mediated esterification pointed out that acid chlorides are among the most commonly used highly reactive acylating species and can be applied to multiple bond-forming reactions, including amidation, esterification, and thioesterification. However, commonly used chlorinating reagents such as oxalyl chloride and thionyl chloride are distinctly corrosive, and the associated safety and handling burdens often extend into the workup and product-isolation stages. For this reason, how to access highly reactive activated intermediates directly from stable carboxylic acids, while avoiding the separate preparation and handling of acid chlorides, has remained an important question in carboxylic acid activation methodology. This is precisely where the value of TCFH lies: it provides an alternative pathway that bypasses the isolation of acid chlorides and instead takes carboxylic acids directly to highly reactive acylating intermediates. Moreover, this activation logic is applicable not only to challenging amidation, but can also be further extended to esterification and thioesterification research.

1.1 Research Situations in Which TCFH Deserves Priority Consideration

Research scenario	Common problems with conventional systems	Why TCFH merits priority consideration
Sterically hindered carboxylic acid + weakly nucleophilic amine	Slow reaction and low conversion, often requiring heating or longer activation times	TCFH/NMI can form a highly reactive N-acyl imidazolium intermediate in situ, making it better suited to this type of difficult coupling
Adjacent stereocenters readily affected by base or activation time	The longer the pre-activation and the stronger the base, the higher the risk of epimerization	In the 2018 study on challenging amidation, multiple substrates gave high yields under relatively mild conditions while retaining adjacent stereocenters
A desire to avoid separate preparation of acid chlorides	Acid chloride routes are highly reactive, but chlorinating reagents are strongly corrosive and create a heavier operational and workup burden	TCFH provides an alternative route from carboxylic acids directly into a highly reactive activation pathway
A desire to extend the same carboxylic acid activation logic to esterification or thioesterification	Common amidation conditions are not necessarily suitable for oxygen or sulfur nucleophiles	Subsequent studies showed that TCFH systems can be extended to esterification and thioesterification, but the base and medium usually need to be re-optimized

2. Under Different Conditions, TCFH Follows Different Activation Pathways

One important feature of TCFH is that the same carboxylic acid activation system does not correspond to only one fixed intermediate. The 2018 study showed that under TCFH/NMI [N-methylimidazole] conditions, the reaction can generate a highly reactive N-acyl imidazolium intermediate in situ, which then enables challenging amidations between sterically hindered carboxylic acids and weakly nucleophilic amines. The authors summarized the value of this system as offering bond-forming capability close to that of highly reactive acylating species while retaining the operational convenience of starting directly from carboxylic acids.

However, when the synthetic target shifts from amidation to esterification, the activation pathway followed by the system is not exactly the same. The 2024 study showed that in the presence of NMI, the reaction can still be understood in terms of an N-acyl imidazolium intermediate. But when the base is changed to pyridine, IR and NMR data indicate that the dominant activated species in the system is not well explained by an N-acyl pyridinium intermediate; instead, the evidence is more consistent with the formation of an anhydride intermediate. The authors also noted that this pathway is consistent with the better selectivity and lower levels of epimerization observed in certain esterification reactions.

The experimental behavior of TCFH depends critically on what kind of activated intermediate it forms under the specific conditions being used. In amidation, the key species mainly involves an N-acyl imidazolium intermediate; in some esterifications, pyridine conditions more closely correspond to an anhydride pathway. Therefore, when optimizing TCFH conditions, one should not compare yields alone, but also consider the base, medium, nucleophile type, and whether the original configuration of the substrate can be maintained effectively throughout the reaction.

2.1 Representative Activation Pathways of TCFH under Different Conditions

System conditions	Main activated species	Suitable application scenarios	Issues requiring attention
TCFH + NMI	N-acyl imidazolium intermediate	Challenging amidation; can also be extended to some esterifications and thioesterifications	In thioesterification, the carboxylic acid usually needs to be pre-activated first, with the thiol added afterward; otherwise, TCFH can react competitively with the thiol
TCFH + pyridine	An anhydride pathway is better supported	In certain esterifications, this can provide good yields, good selectivity, and lower epimerization	Not all substrates are suitable for this pathway; sterically hindered or structurally complex substrates in particular still require individual optimization

3. Representative TCFH Studies and Its Current Practical Position

Time	Representative study	What this study mainly showed	What needs to be kept in mind
2008	Case study on prodrug esterification of a low-reactivity alcohol substrate	In thiocoraline prodrug development, conventional methods were unsatisfactory for esterifying the less reactive alcoholic hydroxyl group in the molecule, whereas TCFH enabled the corresponding ester prodrug to be constructed relatively smoothly, showing that it has practical value for certain difficult esterification substrates	This kind of work is better regarded as an early case-specific application showing that TCFH can be valuable for particular difficult substrates; it is not yet sufficient to generalize TCFH as a mature, broadly applicable amidation or esterification system
2018	Study on challenging amidation	The TCFH/NMI system can be used for challenging amidations between sterically hindered carboxylic acids and weakly nucleophilic amines, with an N-acyl imidazolium intermediate as the key activated species; this is currently the strongest core evidence representing the methodological value of TCFH	What this study most strongly supports is the role of TCFH in challenging amidation, not that it is superior in all amidations; for ordinary substrates, whether it outperforms HATU, HBTU, COMU, or carbodiimide systems still needs to be judged in light of substrate type and process goals
2024	Study on esterification	The carboxylic acid activation logic of TCFH can be further extended to esterification; under pyridine conditions, mechanistic evidence better supports an anhydride pathway, and some substrates show improved selectivity and lower levels of epimerization	This shows that TCFH can be further applied in esterification research, but the appropriate conditions are not the same for different nucleophiles; sterically hindered, structurally complex, or peptide-like substrates usually still require renewed optimization

4. The Place of TCFH in Process Scale-Up and Safety Assessment

4.1 TCFH has already begun to enter scale-up and low-solvent process exploration

Existing studies show that TCFH is no longer confined to small-scale methodological work. Mechanochemical studies have shown that TCFH/K₂HPO₄ and some TCFH/NMI conditions can be used for low-solvent or near-solvent-free amidation, while process chemistry literature indicates that TCFH has already entered the scope of practical scalable process development. Accordingly, the value of TCFH lies not only in laboratory condition screening, but also in route exploration where process efficiency, scalability, and solvent reduction are more heavily emphasized.

4.2 TCFH should not be simply regarded as a “safe reagent”

A 2022 occupational health study showed that this class of highly reactive amide-bond-forming reagents as a whole requires careful attention to occupational exposure risk. Under Local Lymph Node Assay (LLNA) conditions at ≤1%, TCFH was not classified as sensitization-positive, but the authors clearly stated that this does not mean it should be regarded as free of sensitization risk. Given its reactivity and structural similarity to related reagents, real-world use still requires serious exposure control and protective measures, as would be appropriate for a highly reactive coupling reagent.

5. Which Tasks Are Better Suited to Prioritizing TCFH

Current task	Whether TCFH should be prioritized	Basis for judgment
Amide bond formation between sterically hindered carboxylic acids and weakly nucleophilic amines	Worth prioritizing	This is the application scenario with the strongest current evidence and the clearest demonstration of TCFH’s value; the 2018 study directly supports its use in challenging amidation
A desire to avoid separate preparation of acid chlorides while maintaining high reactivity	Worth considering	TCFH can take carboxylic acids directly into a highly reactive activation pathway and can, in many cases, replace the strategy of first preparing an acid chloride and then forming the bond
A desire to extend the same carboxylic acid activation logic to esterification or thioesterification	Worth considering, but the conditions need to be re-optimized	The 2024 study shows that TCFH can be further applied to esterification; however, different nucleophiles behave differently, and the base and medium usually need to be re-adjusted
Highly hindered alcohols or peptide-like substrates prone to epimerization	Requires cautious comparison	In esterification studies, such substrates may still show low conversion, loss of enantiopurity, or substantial epimerization, so TCFH should not be treated as a default first choice
General, non-challenging routine amidation	Not necessarily a priority	Existing evidence supports an advantage for difficult substrates, not that TCFH is superior to common coupling reagents in all ordinary amidations
Choosing it mainly because it is presumed to be “greener” or “safer”	This should not be judged so directly	Mechanochemical studies show that TCFH can enter low-solvent workflows, but that does not mean the reagent itself can simply be described as green; occupational health studies also indicate that this class of highly reactive bond-forming reagents generally requires careful attention to exposure risk

6. Product Selection Guide for Research on TCFH Activation Pathways and Challenging Couplings (Choose Table 1–Table 3 by Research or Experimental Goal)

Research or experimental goal	Recommended table to consult first	Why this table should be consulted first	Suggested related table(s)	Guidance note
You want to first establish a basic selection framework for TCFH-related research and determine whether to begin with the activating reagent itself, the base, or the solvent	Table 1	Table 1 brings together TCFH, TFFH, 1-methylimidazole, pyridine, common bases, and key media, making it the most suitable starting point for clarifying what actually determines the activation pathway	Then see Table 2	First establish the core system and the key condition variables, then move to comparison with benchmark coupling reagents; this makes it easier to judge the true experimental position of TCFH
You are preparing to screen sterically hindered carboxylic acids, weakly nucleophilic amines, or other challenging amidations, and want to build the main TCFH conditions first	Table 1	Challenging amidation depends first on the TCFH/NMI system, tertiary amine bases, solvent choice, and reagent-equivalent window; Table 1 contains the core components needed to set up exactly these conditions	Then see Table 2	First use Table 1 to establish the main TCFH conditions, then use Table 2 to introduce systems such as HATU, COMU, and DIC for side-by-side comparison, making the screening more targeted
You want to compare the effects of different bases such as NMI, pyridine, DBU, TMG, and DIPEA on reaction outcome and judge which activation pathway the system is closer to	Table 1	Table 1 contains the key bases and media that govern pathway switching and is therefore the most suitable for building a “same carboxylic acid, different base” condition matrix	Can be linked with Table 3	If conventional base screening still cannot drive conversion effectively, you can then refer to the acid chloride-type strongly activating routes in Table 3 to judge whether a more aggressive activation mode is needed
You want to determine whether TCFH is truly better than conventional coupling reagents, rather than judging only from the yield of a single system	Table 2	Table 2 focuses on the most common uronium-type, carbodiimide-type, and imidazole-activation benchmark systems and additives, making it suitable for methodological comparison	Then see Table 1	First use Table 2 to establish the baseline of what conventional routes can achieve; then, when you return to Table 1, it becomes easier to see where the actual gain from TCFH comes from
You want to study where additives or alternative activation routes such as Oxyma, HOBt, HOAt, and CDI differ from TCFH	Table 2	Table 2 is best suited for comparing different activation logics: uronium-type, carbodiimide-type, imidazole-activation-type, or halogenated formamidinium high-activation pathways	Then see Table 1	First clarify the characteristics of the comparison systems, then return to the TCFH-centered route; this makes it easier to understand that TCFH is not simply “stronger,” but works through a different activation mode
You want to extend a TCFH system from amidation to esterification, thioesterification, or milder carboxylic acid derivatization conditions	Table 1	For esterification and thioesterification, the first question is whether conditions such as pyridine, dichloromethane, and NMI are appropriate; Table 1 provides the key components needed for pathway switching	Then see Table 2	When extending to new reaction types, it is best to compare simultaneously with systems such as CDI and DIC/Oxyma to judge whether it is really necessary to stay with the TCFH route
You want to test mechanochemistry, low-solvent, or rapid-screening conditions and see whether TCFH fits such routes	Table 1	K₂HPO₄, ACN, NMI, and TCFH in Table 1 are the key condition components for such routes and are most suitable for first establishing the process window	Then see Table 2	If you want to compare the compatibility of different coupling systems under greener conditions, introducing controls such as COMU and DIC/Oxyma will be more informative
Conventional coupling reagents give mediocre results, and you want to judge whether it is necessary to switch directly to an acid chloride route	Table 3	Table 3 focuses on oxalyl chloride and thionyl chloride and is suitable for assessing whether the “prepare the acid chloride first, then form the bond” route is more appropriate	First link with Table 1	It is usually advisable to check Table 1 first to confirm whether there is still room to optimize a direct carboxylic acid activation system such as TCFH; only when the direct activation route is insufficient is it more prudent to consider the stronger activation options in Table 3
You want to compare the differences between “direct carboxylic acid activation” and “conversion to the acid chloride first, followed by bond formation” in operation and substrate compatibility	Table 3	Table 3 is best suited for establishing a reference framework for acid chloride-type strong-activation routes, helping to judge when a higher-reactivity pretreatment pathway is necessary	See Table 1 at the same time	Comparing Table 3 and Table 1 side by side makes it easiest to see the practical value of TCFH: it aims to provide a highly reactive activation entry point without first isolating the acid chloride
You only want to quickly determine whether the current experiment is better suited to “TCFH-centered optimization” or “comparison with conventional coupling reagents”	Tables 1 and 2	Table 1 answers how to tune the TCFH system itself, while Table 2 answers whether TCFH is actually necessary; together, these two tables are the most suitable for initial decision-making	See Table 3 if needed	If Tables 1 and 2 still cannot solve problems of conversion or selectivity, then using Table 3 as a backup option representing a stronger activation route will better match the practical sequence of experimental development

Table 1 | Core Halogenated Formamidinium Activating Reagents, Pathway-Switching Bases, and Key Media

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product features and applications
Core halogenated formamidinium activating reagent	94790-35-9	T117933	N,N,N′,N′-Tetramethylchloroformamidinium hexafluorophosphate	≥98%	A core halogenated formamidinium-type carboxylic acid activating reagent. In combination with 1-methylimidazole, it can form a highly reactive acyl imidazolium intermediate in situ. It is suitable for challenging amidations involving sterically hindered carboxylic acids and weakly nucleophilic amines, and can also be extended to esterification, thioesterification, and solvent-free or low-solvent amidation.
Related halogenated formamidinium control activator	164298-23-1	F102846	Fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate	≥98%	Like TCFH, this is a halogenated formamidinium-type highly active carboxylic acid activating reagent. It is suitable for parallel comparison with TCFH in initial coupling-reagent screening to observe how different leaving groups affect the distribution of activated intermediates and coupling performance.
Key promoter for the N-acyl imidazolium pathway	616-47-7	M109227	1-Methylimidazole	≥99%	One of the most important promoters in TCFH systems. It can direct carboxylic acids toward highly reactive acyl imidazolium-type intermediates and is commonly used in challenging amidation, some esterification/thioesterification reactions, and rapid screening with sterically hindered substrates.
Key base for the anhydride pathway / esterification conditions	110-86-1	P111511	Pyridine	AR, ≥99.5%	Can serve both as a base and as a component of the reaction medium. It is suitable for condition-switching screens in TCFH systems, especially for evaluating esterification, thioesterification, and milder activation conditions in combination with dichloromethane.
Tertiary amine base control	109-02-4	M104644	N-Methyl morpholine	For protein sequencing, ≥99.8% (GC)	A common tertiary amine base with reference value across carbodiimide, uronium, and halogenated formamidinium systems. When included in TCFH condition screening, it is suitable for comparing the effects of different tertiary amine bases on conversion and side-reaction distribution.
Tertiary amine base control	121-44-8	T431607	Triethylamine	For protein sequencing, ≥99.5% (GC), ampule	A classic organic base suitable as a baseline control base in TCFH conditions for comparison with systems based on 1-methylimidazole, N-methylmorpholine, DIPEA, and others in terms of activation efficiency and selectivity.
Non-nucleophilic tertiary amine base	7087-68-5	N433364	N-Ethyldiisopropylamine solution	Suitable for peptide synthesis, ~2 M in 1-methyl-2-pyrrolidinone	A sterically hindered non-nucleophilic tertiary amine base commonly used as a routine base control in peptide synthesis and challenging amidation conditions. It is suitable for side-by-side comparison with 1-methylimidazole to distinguish between a purely deprotonating pathway and a pathway that also includes nucleophilic promotion.
Strong-base condition variable	80-70-6	T105968	1,1,3,3-Tetramethylguanidine(TMG)	≥99%	A strong-base condition variable that can significantly alter the distribution of activated species. It is suitable for base screening in TCFH systems to observe changes in active ester formation, side reactions, and bond-forming efficiency under highly basic conditions.
Strong-base condition variable	6674-22-2	D106478	1,8-Diazabicyclo[5.4.0]undec-7-ene（DBU）	≥99%	A strong-base condition variable suitable for comparison with 1-methylimidazole and tertiary amine bases to determine whether stronger basic conditions lead to reduced conversion, mismatch of activated intermediates, or increased side reactions.
Key solvent for challenging amidation	75-05-8	A104443	Acetonitrile(ACN)	AR, ≥99% (GC)	One of the key media in TCFH/1-methylimidazole challenging amidation and base screening. It is suitable as a standard solvent for high-activity halogenated formamidinium systems, base-effect comparisons, and screening of some esterification/thioesterification conditions.
Polar medium for comparison	68-12-2	N433313	N,N-Dimethylformamide（DMF）	Suitable for peptide synthesis	A classic polar aprotic solvent commonly used in peptide synthesis and routine amidation systems. In TCFH conditions, it is suitable as a comparison medium to acetonitrile for evaluating the effects of different solvents on activated intermediates and coupling outcomes.
Common medium for esterification pathways	75-09-2	D433555	Dichloromethane	For biosynthesis, suitable for inorganic trace analysis	Commonly used in relatively mild organic acylation systems. It is suitable for evaluating TCFH in esterification, thioesterification, and alternative carboxylic acid activation conditions in combination with pyridine.
Key base for mechanochemistry / solvent-free amidation	7758-11-4	P112220	Potassium phosphate dibasic anhydrous	Molecular biology grade, ≥99% (T)	Suitable for TCFH-mediated amidation under mechanochemical or low-solvent conditions. It can serve as a base and may also help generate more reactive acyl phosphate-type intermediates, making it suitable for rapid screening with sterically hindered substrates and weakly nucleophilic amines.

Table 2 | Classical Benchmark Coupling Systems and Activation Additives

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product features and applications
Classical highly active uronium coupling reagent	148893-10-1	H109327	HATU	≥99%	A highly active uronium-type coupling reagent suitable for parallel comparison with TCFH in challenging amidation, coupling of sterically hindered substrates, and activation performance with stereochemically sensitive substrates.
Classical uronium coupling reagent	94790-37-1	H106174	HBTU	≥99%	A commonly used uronium coupling reagent suitable as a classical control system alongside TCFH for comparing reaction efficiency and applicability limits in routine amidation and more difficult substrate couplings.
Oxyma-type uronium coupling reagent	1075198-30-9	C340003	COMU	≥98%	An Oxyma-type uronium coupling reagent commonly used in relatively mild and clean amidation screening, and also suitable as a direct control against TCFH routes in mechanochemical amidation.
Imidazole-activation-type coupling reagent	530-62-1	C109315	N,N'-Carbonyldiimidazole (CDI)	≥99%	Activates carboxylic acids through imidazole-type activated intermediates. It is suitable for comparison with the TCFH/1-methylimidazole system to distinguish between “pre-formation of an imidazole-type activated species” and the halogenated formamidinium activation pathway.
Carbodiimide coupling reagent	538-75-0	D106074	N,N′-Dicyclohexylcarbodiimide	≥99%	A classic carbodiimide coupling reagent suitable for inclusion in methodological comparisons of carboxylic acid activation, allowing comparison between established carbodiimide routes and the highly active TCFH activation pathway.
Carbodiimide coupling reagent	693-13-0	N420184	N,N'-Diisopropylcarbodiimide	≥98.5%	A common liquid carbodiimide coupling reagent suitable for use with additives such as HOBt, HOAt, and Oxyma, and serves as a classical amidation control system outside the TCFH route.
Water-soluble carbodiimide coupling reagent	25952-53-8	E106172	N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride	≥98%	A water-soluble carbodiimide suitable for carboxylic acid activation in aqueous systems or with hydrophilic substrates, and also useful as a contrasting route to TCFH’s non-aqueous highly active systems.
Classical highly active additive	39968-33-7	H109328	1-Hydroxy-7-azabenzotriazole	≥99%	Commonly used together with uronium or carbodiimide systems to improve activation efficiency and difficult-coupling performance. It is suitable for comparison with TCFH systems in terms of how different activation strategies handle challenging substrates.
Classical additive	2592-95-2	H684271	1-Hydroxybenzotriazole(HOBT)	≥99%	A classic coupling additive commonly used in DCC, DIC, EDC, and related systems. It is suitable as a representative component of traditional carboxylic acid activation routes for methodological comparison with the TCFH route.
Oxyma-core additive	3849-21-6	E138773	Ethyl (hydroxyimino)cyanoacetate	≥98%	Commonly used as an additive in carbodiimide systems and also a key structural core of Oxyma-type coupling reagents. It is suitable for inclusion in parallel control screening against TCFH to compare activation behavior under different additive-dominated conditions.

Table 3 | Acid Chloride-Type Strong Activation Control Routes

Category	CAS No.	Aladdin Catalog No.	Name	Specification or Purity	Product features and applications
Acid chloride route reagent	79-37-8	O434200	Oxalyl chloride	Reagent grade, extra pure, ≥99%	A classic acid-chloride-forming reagent suitable for first converting carboxylic acids into acid chlorides and then carrying out highly reactive acylation. In TCFH research, it can serve as a strong-activation control for the “prepare the acid chloride first” route.
Acid chloride route reagent	7719-09-7	T433841	Thionyl chloride	Extra pure, reagent grade, ≥99.5%, low iron	A classic acid-chloride-forming reagent suitable for control screening of highly reactive acid chloride routes. It can be compared with direct carboxylic acid activation systems such as TCFH in terms of operation mode, substrate compatibility, and downstream bond-forming strategy.

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

References

[1] Beutner GL, Young IS, Davies ML, Hickey MR, Park H, Stevens JM, et al. TCFH–NMI: Direct Access to N-Acyl Imidazoliums for Challenging Amide Bond Formations. Organic Letters. 2018;20(14):4218-4222. doi:10.1021/acs.orglett.8b01591.

[2] Luis NR, Chung KK, Hickey MR, Lin Z, Beutner GL, Vosburg DA. Beyond Amide Bond Formation: TCFH as a Reagent for Esterification. Organic Letters. 2024;26(14):2745-2750. doi:10.1021/acs.orglett.3c01611.

[3] Tulla-Puche J, Torres A, Calvo P, Royo M, Albericio F. N,N,N′,N′-Tetramethylchloroformamidinium Hexafluorophosphate (TCFH), a Powerful Coupling Reagent for Bioconjugation. Bioconjugate Chemistry. 2008;19(10):1968-1971. doi:10.1021/bc8002327.

[4] Zell D, Dalziel ME, Carrera DE, Stumpf A, Bachmann S, Mercado-Marin E, et al. An Efficient Second-Generation Manufacturing Process for the pan-RAF Inhibitor Belvarafenib. Organic Process Research & Development. 2021;25(10):2338-2350. doi:10.1021/acs.oprd.1c00277.

[5] Dalidovich T, Mishra KA, Shalima T, Kudrjašova M, Kananovich D, Aav R. Mechanochemical Synthesis of Amides with Uronium-Based Coupling Reagents: A Method for Hexa-amidation of Biotin[6]uril. ACS Sustainable Chemistry & Engineering. 2020;8(41):15703-15715. doi:10.1021/acssuschemeng.0c05558.

[6] Graham JC, Trejo-Martin A, Chilton ML, Kostal J, Bercu J, Beutner GL, et al. An Evaluation of the Occupational Health Hazards of Peptide Couplers. Chemical Research in Toxicology. 2022;35(6):1011-1022. doi:10.1021/acs.chemrestox.2c00031.

For more related articles, please see below:

The Methodological Value of HATU in Difficult Couplings: Reactivity Advantages, Stereochemical Retention, and Condition Management

Understanding ATD-DMAP: From Reagent Design to Esterification, Amidation, and Stereochemical Integrity

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

β-Acyloxy Alkenyl Amides (AAAs): A New Approach to Amide Bond and Peptide Bond Construction Worth Attention

Greener Methods: Catalytic Amide Bond Formation