CTSOBt Benzotriazole–Sulfonate Coupling Reagent: Carboxylic Acid Activation and Synthetic Application Value

Overview

In 2026, Roy and Mandal published a study in RSC Advances titled “New benzotriazole–sulfonate coupling reagents and applications,” reporting a class of benzotriazole–sulfonate coupling reagents. Among them, CTSOBt, namely O-benzotriazolyl 5-chlorothiophene-2-sulfonate and recorded in the literature as the optimal reagent 1Xc, showed particularly strong performance. This reagent can be used for carboxylic acid activation and can further enable the synthesis of amides, esters, thioesters, peptides, ketones, and nitrile compounds.

The value of CTSOBt lies in its ability to establish reaction pathways from carboxylic acids to amides, esters, thioesters, peptides, and certain ketone structures, centered on the key step of “carboxylic acid activation.” For drug discovery, peptide synthesis, and fine chemical manufacturing, the significance of this type of reagent is mainly reflected in three aspects: improving the efficiency of carboxylic acid derivatization, reducing the risk of racemization of chiral substrates, and, in certain reaction scenarios, reducing the waste and workup burden associated with traditional coupling systems.

Structural Formula and Carboxylic Acid Activation Pathway of CTSOBt

Item	Description
Reagent name	CTSOBt, O-benzotriazolyl 5-chlorothiophene-2-sulfonate
Literature code	1Xc
Simplified structural formula	5-Cl-thiophene-2-SO₂-O-Bt
Molecular formula	C₁₀H₆ClN₃O₃S₂
Key structural feature	S–O–Bt bond; single-crystal results confirmed an O-substituted structure rather than an N-substituted structure
Reaction entry point	Carboxylic acid RCO₂H
Main intermediates	Mixed anhydride intermediate and active OBt ester
Main products	Amides, esters, thioesters, and peptides; under specific conditions, it can be used for the transformation of aromatic carboxylic acids into aryl ketones and can also mediate the dehydration of aromatic aldoximes to aryl nitriles

The simplified mechanism for carboxylic acid activation is shown below.

 

Here, DIPEA refers to N,N-diisopropylethylamine, HOBt refers to 1-hydroxybenzotriazole, and OBt refers to the benzotriazolyloxy leaving group.

1. Practical Value of Coupling Reagents in Drug and Peptide Synthesis

1.1 Amide and Ester Bonds Are High-Frequency Structural Units

Amide and ester bonds are widely present in drug molecules, peptides, natural product derivatives, and fine chemicals. Amide bonds are not only used to connect molecular fragments but also influence molecular conformation, polarity, hydrogen-bonding interactions, and metabolic stability. Ester bonds are commonly found in prodrug design, fragrances, material monomers, agrochemicals, and pharmaceutical intermediates. Amidation and esterification are high-frequency and critical bond-forming steps in drug discovery and fine chemical synthesis. The performance of a coupling reagent directly affects reaction yield, substrate scope, product purification difficulty, and route development efficiency.

1.2 Traditional Coupling Systems Still Leave Room for Improvement

Commonly used coupling reagents can already meet many synthetic needs. However, in drug and peptide synthesis, several practical issues remain:

Issue	Impact on Synthetic Work
Many by-products	Increases the difficulty of separation and purification and affects product purity
Reagents are not recoverable	Increases material consumption and waste-treatment pressure
Dependence on solvents such as DMF, DCM, and NMP	Increases environmental, safety, and scale-up pressure
Chiral substrates are prone to racemization	Affects the quality of peptides and chiral pharmaceutical intermediates
High compatibility requirements for complex substrates	Side reactions can easily occur during drug modification and peptide-fragment coupling

DMF refers to N,N-dimethylformamide, DCM refers to dichloromethane, and NMP refers to N-methyl-2-pyrrolidone. In peptide and drug synthesis, reducing the use of these solvents, lowering racemization risk, and improving workup convenience are important directions in the development of new coupling reagents.

The research value of CTSOBt is built precisely on this background. It is not intended to simply replace one traditional coupling reagent, but rather to achieve a better overall balance among carboxylic acid activation efficiency, compatibility with greener solvents, stereochemical retention, and reagent recovery.

2. Carboxylic Acid Activation Is the Core Reaction Basis of CTSOBt

2.1 Carboxylic Acids Need to Be Converted into More Reactive Intermediates

Carboxylic acids are widely available and generally stable, and they are common functional groups in pharmaceutical intermediates, amino acid derivatives, and aromatic compounds. However, direct reactions of carboxylic acids with amines, alcohols, or thiols are usually limited in efficiency. In most cases, the carboxylic acid must first be activated in order to smoothly form amides, esters, or thioesters.

The core function of CTSOBt is to convert carboxylic acids into active intermediates that are more susceptible to nucleophilic substitution. According to the plausible mechanism proposed in the literature, the carboxylic acid forms a carboxylate under the action of DIPEA, which then attacks the sulfonyl center of CTSOBt to generate a mixed anhydride intermediate while releasing OBt⁻. Subsequently, OBt⁻ attacks the carbonyl carbon of the mixed anhydride to form an active OBt ester. Finally, an amine, alcohol, thiol, or amino acid attacks this active ester to afford the corresponding product.

2.2 The Active OBt Ester May Be the Key to Reaction Control

The key feature of CTSOBt is not merely that it “can activate carboxylic acids,” but that the OBt ester formed after activation provides good reaction control. OBt-related structures have long been used in peptide synthesis to reduce racemization risk, which is also one of the important reasons why CTSOBt performs well with amino acid and peptide substrates.

The role of CTSOBt can be understood as three consecutive steps:

① Improving carboxylic acid reactivity: converting stable carboxylic acids into more reactive acyl intermediates.

② Controlling the reaction pathway: using the active OBt ester to guide the introduction of nucleophiles such as amines, alcohols, and thiols.

③ Improving the synthetic outcome: increasing yields, reducing racemization, and lowering separation pressure under appropriate conditions.

3. Multi-Type Transformation Capability of CTSOBt

3.1 C–N Bond Formation: Amide and Peptide Synthesis

C–N bond formation is the most important application direction for CTSOBt. The study by Roy and Mandal showed that under optimized conditions, using acetone as the solvent, DIPEA as the base, and conducting the reaction at room temperature, CTSOBt could efficiently promote the reaction of carboxylic acids with amines to form amides. In the model reaction, benzoic acid and benzylamine afforded the product in 98% isolated yield within 30 min under acetone/DIPEA conditions.

This system is applicable to a variety of aromatic carboxylic acids, aliphatic carboxylic acids, heterocyclic carboxylic acids, and amino acid derivatives. More importantly, in the coupling of protected amino acids and peptide fragments, CTSOBt can maintain good chiral purity while delivering relatively high yields. Taking the synthesis of dipeptide 3a44 as an example, the literature compared CTSOBt with coupling systems such as BOP, HBTU, HATU, DCC, EDC·HCl/Oxyma, and COMU. CTSOBt provided 96% yield and >99% ee.

HBTU refers to O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate;

HATU refers to O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate;

DCC refers to N,N′-dicyclohexylcarbodiimide;

EDC refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;

COMU refers to an Oxyma-based uronium-type coupling reagent.

3.2 C–O and C–S Bond Formation: Ester and Thioester Synthesis

When the nucleophile is changed from an amine to an alcohol or thiol, the CTSOBt-activated carboxylic acid can be further converted into an ester or thioester. CTSOBt is not limited to amide-bond formation; rather, it can enable the introduction of different nucleophiles through the same active ester intermediate.

The literature shows that aromatic carboxylic acids, long-chain aliphatic carboxylic acids, heterocyclic carboxylic acids, and Fmoc-protected amino acids can react with aromatic or aliphatic alcohols to form esters. Certain carbohydrate acceptors can also participate in esterification. Boc-protected amino acids can further react with thiols to generate thioesters.

Fmoc refers to 9-fluorenylmethoxycarbonyl, and Boc refers to tert-butyloxycarbonyl. These protecting groups are commonly used in amino acid and peptide synthesis. The above results indicate that CTSOBt has a certain degree of applicability to protected amino acid substrates.

3.3 C–C Bond Formation: Transformation of Aromatic Carboxylic Acids into Aryl Ketones

CTSOBt can also be used for the coupling of aromatic carboxylic acids with arylboronic acids to generate aryl ketones. This reaction is not a conventional amidation or esterification. Instead, CTSOBt first converts the carboxylic acid into an activated acyl intermediate, which then undergoes Suzuki–Miyaura-type coupling with an arylboronic acid under palladium catalysis to form an aryl ketone.

The optimized conditions for this reaction are as follows: the carboxylic acid is first treated with CTSOBt and DIPEA in acetone to form the intermediate, followed by reaction with the arylboronic acid under Pd(OAc)₂/PCy₃, K₂CO₃, DME, 80 °C, and nitrogen conditions. After optimization, the model reaction between benzoic acid and phenylboronic acid afforded the product in 71% yield. Different aromatic carboxylic acid and arylboronic acid substrates furnished ketone products in 58–75% yields.

Here, Pd(OAc)₂ refers to palladium acetate, PCy₃ refers to tricyclohexylphosphine, and DME refers to ethylene glycol dimethyl ether. This result indicates that the acyl intermediate formed after CTSOBt activation of the carboxylic acid can not only be attacked by amines, alcohols, and thiols, but can also enter transition-metal-catalyzed C–C bond-forming processes.

3.4 Dehydrative Transformation of Aromatic Aldoximes into Aryl Nitriles

In addition to carboxylic acid transformations, CTSOBt can also mediate the dehydration of aromatic aldoximes to generate aryl nitriles. The reaction conditions are as follows: aromatic aldoxime, CTSOBt, and DBU in DCM at room temperature under nitrogen for 2 h. The literature reports that aromatic aldoximes bearing electron-withdrawing or electron-donating substituents can afford aryl nitrile products in relatively high yields.

DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene. The nitrile group is a common functional group in drug molecules, agrochemicals, and functional materials, and it can also serve as a synthetic precursor for further transformations. This reaction demonstrates that CTSOBt also possesses dehydrative activation capability. However, from the perspective of its main application focus, carboxylic acid activation remains the most important reaction basis of this reagent.

3.5 CTSOBt-Related Reaction Types and Core Value

Reaction Type	Main Substrates	Product Type	Core Function
Amidation	Carboxylic acid + amine	Amide	Constructs C–N bonds in drugs and intermediates
Peptide coupling	Protected amino acids / peptide fragments	Peptides	Constructs peptide bonds and reduces racemization risk
Esterification	Carboxylic acid + alcohol	Ester	Expands the scope of carboxylic acid derivatization
Thioesterification	Carboxylic acid + thiol	Thioester	Generates carboxylic acid derivatives with greater potential for subsequent transformations
Suzuki–Miyaura-type coupling	Aromatic carboxylic acid + arylboronic acid	Ketone	Enables carboxylic acids to enter C–C bond construction
Aldoxime dehydration	Aromatic aldoxime	Aryl nitrile	Expands the dehydrative activation utility of CTSOBt

4. Practical Significance of CTSOBt for Peptide and Drug Synthesis

4.1 Peptide Synthesis Is Concerned with More Than Yield

Peptide synthesis places higher demands on coupling reagents than ordinary amidation reactions. This is because amino acids contain chiral centers. If racemization or epimerization occurs during coupling, product quality will be affected even if the target peptide bond is successfully formed. For therapeutic peptides and bioactive peptides, stereochemical configuration is directly related to activity, selectivity, and quality control.

CTSOBt demonstrated good stereochemical retention in a dipeptide model reaction. When compared with several commonly used coupling reagents, CTSOBt provided 96% yield and >99% ee, indicating that in a specific amino acid coupling model it combines coupling efficiency with racemization control.

4.2 Greener Solvent Replacement in Solid-Phase Peptide Synthesis

Solid-phase peptide synthesis, or SPPS, typically relies on polar solvents such as DMF. DMF is beneficial for resin swelling and coupling efficiency, but it creates significant pressure in terms of environmental impact, safety, and waste-liquid treatment. Therefore, identifying solvent systems that can replace DMF is an important direction in greener peptide synthesis.

In the CTSOBt study, the authors applied it to SPPS and used a DMSO/EtOAc = 1:9 mixed solvent as the optimized system. DMSO refers to dimethyl sulfoxide, and EtOAc refers to ethyl acetate. This system was used to synthesize linear peptides such as Fmoc-KLVFF-NH₂, LPFFD, and VYIHPF, as well as cyclic peptides such as Cy-NFGAILER-NH₂ and Cy-KLVFfAE. It should be noted that this part mainly demonstrates the feasibility of DMF replacement and method development. Some solid-phase peptide synthesis examples gave moderate yields, such as 53% for Fmoc-KLVFF-NH₂, 33% for LPFFD, 35% for VYIHPF, and 27% for Cy-NFGAILER-NH₂.

These results indicate that CTSOBt can complete peptide coupling in a greener solvent combination. In peptide synthesis, solvent consumption is typically large. If a coupling system can reduce dependence on DMF, it may help decrease waste-liquid pressure and improve process safety.

4.3 Application Value in Drug-Molecule Modification

Drug discovery often requires structural modification of known drugs or active fragments in order to evaluate how substituent changes affect activity, solubility, metabolic stability, and selectivity. CTSOBt can be used for the reaction of carboxylic acid-containing drugs with amines, alcohols, or thiols to obtain the corresponding amide, ester, or thioester derivatives. The literature also presents related modification examples involving nonsteroidal anti-inflammatory drugs, febuxostat, gemfibrozil, acetaminophen, and benzocaine.

These applications show that CTSOBt is suitable for late-stage modification of drugs involving carboxylic acids or derivatizable functional groups. For medicinal chemists, its practical value is mainly reflected in two aspects: first, it facilitates the rapid construction of derivatives; second, when amino acids, phenolic hydroxyl groups, amino groups, and related structures are involved, it can provide relatively mild transformation conditions.

5. Improvements in Separation, Recovery, and Reuse with P-CTSOBt

5.1 Polymer-Supported Design Addresses Workup Issues

P-CTSOBt is the polymer-supported form of CTSOBt and is recorded in the literature as 1Xp. It is prepared by reacting commercially available P-HOBt resin with 5-chlorothiophene-2-sulfonyl chloride to obtain a polymer-supported benzotriazole–sulfonate reagent. P-HOBt refers to polymer-supported 1-hydroxybenzotriazole.

The main advantage of polymer-supported reagents is improved practicality. After reactions using homogeneous coupling reagents, soluble by-products are often generated and require additional purification. In contrast, after reactions using polymer-supported reagents, the solid phase can be removed by filtration and washing, thereby simplifying product separation.

5.2 Reaction Performance of P-CTSOBt

The literature reports that P-CTSOBt can be used for the synthesis of amides, esters, thioesters, and peptides under DMSO/acetone = 1:19 conditions, with yields of 84–98% in the reported examples. After the reaction, polymer-supported HOBt can be recovered by solvent washing and used to regenerate P-CTSOBt. The literature reports that no obvious decrease in reaction activity was observed upon reuse.

This is particularly important for process development. In small-scale exploration, column chromatography can solve many purification problems. However, in scale-up preparation, separation methods, waste volume, residue control, and reagent recycling become important criteria for route evaluation. The value of P-CTSOBt lies in extending the reaction capability of CTSOBt into an operational format that is more convenient for separation and recovery.

5.3 Recoverability and Reagent Regeneration

The recoverable/regenerable design of CTSOBt and P-CTSOBt is an important feature of this study. For CTSOBt, the mixed by-products 5-chlorothiophene-2-sulfonic acid and HOBt generated after the reaction can be converted back into the corresponding sulfonyl chloride under SOCl₂, toluene, and catalytic DMF conditions. The sulfonyl chloride can then react again with HOBt to reform CTSOBt. The literature reports that 51% CTSOBt was recovered, and this recovered reagent was used in the reaction of benzoic acid with benzylamine to afford the amide product in 95% yield.

SOCl₂ refers to thionyl chloride. For P-CTSOBt, the recovered P-HOBt can be directly reacted with 5-chlorothiophene-2-sulfonyl chloride in the presence of a base to regenerate P-CTSOBt. Compared with single-use coupling reagents, this type of design helps reduce reagent consumption and by-product treatment pressure.

6. Scope and Rational Evaluation of CTSOBt

6.1 Application Scenarios That Deserve Priority Attention

The most noteworthy applications of CTSOBt are amidation, esterification, thioesterification, and peptide coupling involving carboxylic acids. In particular, this reagent has clear reference value in the following scenarios:

Application Scenario	Significance of CTSOBt
Derivatization of carboxylic acid-containing drug fragments	Rapid preparation of amide, ester, and thioester derivatives
Coupling of amino acids and peptide fragments	Maintains good stereochemical purity while giving relatively high yields
Solid-phase peptide synthesis	Enables the use of greener solvent combinations such as DMSO/EtOAc
Syntheses requiring simplified separation	P-CTSOBt can improve workup through solid-phase support
Transformation of aromatic carboxylic acids into aryl ketones	Can serve as an activated acyl intermediate and enter palladium-catalyzed coupling with arylboronic acids

6.2 Scope and Key Evaluation Criteria

The multi-type transformation capability of CTSOBt is mainly based on carboxylic acid activation, formation of an active OBt ester, and subsequent nucleophilic substitution. Its key applications are concentrated in reactions of carboxylic acids with amines, alcohols, thiols, amino acids, or peptide fragments, enabling the synthesis of amides, esters, thioesters, and peptides. Under specific reaction conditions, it can also be used for the coupling of aromatic carboxylic acids with arylboronic acids to generate aryl ketones, as well as for the dehydration of aromatic aldoximes to generate aryl nitriles.

In specific experiments or route development, the applicability of CTSOBt should be evaluated by considering the following factors:

① Whether the substrate contains functional groups that may affect carboxylic acid activation.

② Whether the reactivity of nucleophiles such as amines, alcohols, or thiols is sufficient for conversion of the active OBt ester.

③ Whether chiral substrates are at risk of racemization or epimerization during the reaction.

④ Whether the solvent system meets the requirements for substrate solubility, solid-phase resin swelling, and subsequent scale-up.

⑤ Whether the loading capacity, reaction efficiency, recovery efficiency, and reuse performance of P-CTSOBt meet the target experimental requirements.

⑥ Whether extended reactions such as carboxylic acid-to-ketone and aldoxime-to-nitrile transformations have been validated with the target substrate.

Overall, CTSOBt is a new benzotriazole–sulfonate coupling reagent centered on carboxylic acid activation. In certain reactions, it combines compatibility with greener solvents and a recoverable/regenerable design. It has application value in amidation, esterification, thioesterification, and peptide coupling, and it demonstrates extended reaction capability in carboxylic acid-to-ketone and aldoxime-to-nitrile transformations. CTSOBt provides a new reagent option for efficient derivatization of carboxylic acid substrates, peptide coupling, and recoverable synthetic workflows.

7. Classification Table of Chemicals Related to CTSOBt-Mediated Carboxylic Acid Activation and Greener Synthesis

Table 1. Products Related to CTSOBt Structural Construction, OBt Sources, and Recovery/Regeneration

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Direct precursor of CTSOBt	2766-74-7	C110274	5-Chlorothiophene-2-sulfonyl chloride	≥96%	Provides the 5-chlorothiophene-2-sulfonyl structural unit and is used for the preparation of CTSOBt and polymer-supported CTSOBt
OBt structural source	2592-95-2	H684271	1-Hydroxybenzotriazole (HOBt)	≥99%	Provides the OBt active ester structural source and is used in studies of carboxylic acid activation, amidation, and peptide coupling
OBt structural source	123333-53-9	H106176	1-Hydroxybenzotriazole monohydrate	≥97%	Hydrated form of HOBt, used in coupling reagent preparation, active ester formation, and peptide-bond construction experiments
Upstream raw material for thiophene sulfonyl chloride	96-43-5	C106575	2-Chlorothiophene	≥96%	Used for the synthesis of chlorothiophene-containing intermediates and related to precursor routes for 5-chlorothiophene-2-sulfonyl chloride
Chlorosulfonation reagent	7790-94-5	C684374	Chlorosulfonic acid	≥99%	Used for chlorosulfonation of thiophene substrates and supports the preparation of sulfonyl chloride intermediates
Sulfonyl chloride regeneration reagent	7719-09-7	T433841	Thionyl chloride	Reagent grade, high-purity grade, ≥99.5%, low iron	Used to convert sulfonic acid by-products into sulfonyl chlorides and is related to CTSOBt recovery and regeneration experiments
Solvent for regeneration reaction	108-88-3	T399633	Toluene (regulated precursor chemical)	Anhydrous grade, ≥99.8%	Used in sulfonyl chloride regeneration reactions under anhydrous conditions and supports CTSOBt recovery studies

Table 2. Products Supporting Carboxylic Acid Activation, Peptide Coupling Conditions, and Protecting Groups

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Base for carboxylic acid activation	7087-68-5	D109322	N,N-Diisopropylethylamine	Distilled grade, ≥99.5%	Used for deprotonation of carboxylic acids in the CTSOBt system and promotes amidation, esterification, and peptide coupling reactions
Organic base for condition screening	121-44-8	T103289	Triethylamine	For amino acid analysis, ≥99.5% (GC)	Used for condition screening in carboxylic acid activation and coupling reactions, and can also be used in sulfonyl chloride derivatization reactions
Base for aldoxime dehydration	6674-22-2	D106478	1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)	≥99%	Used in CTSOBt-mediated aldoxime dehydration reactions to prepare aromatic nitrile compounds
Inorganic base for coupling reactions	584-08-7	P485463	Potassium carbonate	Anhydrous grade, reagent grade, high-purity grade, ≥99%	Used as the basic condition for the coupling of aromatic carboxylic acids with arylboronic acids to prepare ketone compounds
Deprotection reagent for solid-phase peptide synthesis	626-58-4	M433148	4-Methylpiperidine	Suitable for peptide synthesis, 20% (w/w) in DMF	Used in Fmoc solid-phase peptide synthesis deprotection steps and supports CTSOBt-mediated peptide coupling experiments
Fmoc protecting reagent	28920-43-6	F106533	Fmoc chloride	≥98%	Used to prepare Fmoc-protected amino acids and supports substrate preparation for peptide coupling and solid-phase peptide synthesis
Boc protecting reagent	24424-99-5	D106159	Di-tert-butyl dicarbonate	≥99%	Used to prepare Boc-protected amines and amino acids and is suitable for substrate design in amidation, thioesterification, and peptide coupling
Cbz protecting reagent	501-53-1	B105737	Benzyl chloroformate	≥96%, contains 0.1% sodium carbonate as stabilizer	Used to prepare Cbz-protected amines and amino acids and is suitable for studies of protected amino acid coupling reactions

Table 3. CTSOBt-Related Greener Solvents, Reaction Solvents, and Traditional Solvent Control Products

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Optimized solvent for amidation	67-64-1	A486158	Acetone (regulated precursor chemical)	Natural, ≥97%	Used in the acetone system for CTSOBt-mediated model amidation reactions and related to condition studies for carboxylic acid–amine coupling
Component of greener mixed solvent	141-78-6	E119698	Ethyl acetate	Anhydrous grade, ≥99.8%	Combined with DMSO to form a mixed solvent for solid-phase peptide synthesis and related to DMF-replacement peptide coupling systems
Component of greener mixed solvent	67-68-5	D433293	Dimethyl sulfoxide (DMSO)	Anhydrous grade, ≥99.9%	Used in the DMSO/ethyl acetate solid-phase peptide synthesis system and also in reactions involving polymer-supported coupling reagents
Coupling solvent for ketone synthesis	110-71-4	D431452	1,2-Dimethoxyethane	Anhydrous grade, ≥99.5%, inhibitor-free	Used in the reaction system for preparing aryl ketones by coupling aromatic carboxylic acids with arylboronic acids
Screening solvent for ketone synthesis	123-91-1	D431640	1,4-Dioxane	Anhydrous grade, ≥99.8%	Used for screening coupling conditions in carboxylic acid-to-ketone transformations and is suitable for anhydrous organic reaction systems
Solvent for aldoxime dehydration	75-09-2	D433567	Dichloromethane	Suitable for analysis, ACS	Used in CTSOBt-mediated aldoxime dehydration to prepare nitrile compounds and also in condition screening for coupling reactions
Solvent for coupling-condition screening	109-99-9	T431417	Tetrahydrofuran (THF)	For DNA and peptide synthesis, max. 0.005% H₂O	Used for solvent screening in carboxylic acid coupling reactions and suitable for peptide and organic synthesis experiments under anhydrous conditions
Solvent for coupling-condition screening	75-05-8	A119012	Anhydrous acetonitrile (ACN)	Anhydrous grade, ≥99.8%, H₂O ≤0.003%	Used for condition screening in CTSOBt-related amidation reactions and polar anhydrous reaction systems
Traditional coupling solvent control	68-12-2	D119450	N,N-Dimethylformamide (DMF)	Anhydrous grade, ≥99.8%	Used as a control solvent in traditional peptide synthesis and coupling reactions, and also related to the catalytic additive used in CTSOBt recovery and regeneration
Traditional peptide synthesis solvent control	872-50-4	M119668	N-Methyl-2-pyrrolidone (NMP)	Anhydrous grade, ≥99.5%	Used in peptide synthesis and coupling reaction systems and serves as a traditional solvent control in greener solvent replacement studies

Table 4. Control Coupling Reagents and Coupling Additive Products

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Carbodiimide coupling reagent	538-75-0	D106074	N,N′-Dicyclohexylcarbodiimide (DCC)	≥99%	A classical carboxylic acid coupling reagent used to compare amidation efficiency and peptide-coupling performance with CTSOBt
Water-soluble carbodiimide coupling reagent	25952-53-8	E106172	1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride	≥98%	Used for carboxylic acid–amine coupling reactions and suitable as a control for comparing EDC systems with CTSOBt systems
Oxyma-type coupling additive	3849-21-6	E138773	Ethyl 2-cyano-2-(hydroxyimino)acetate	≥98%	Used in EDC/Oxyma coupling systems and related to control experiments on racemization suppression in peptide coupling
Phosphonium salt coupling reagent	56602-33-6	B106161	Castro’s reagent (BOP)	≥98%	Used in peptide-coupling control experiments to evaluate peptide-bond formation efficiency and stereochemical retention
Benzotriazole-type uronium salt coupling reagent	94790-37-1	H106174	Benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU)	≥99%	A commonly used peptide coupling reagent for comparison with CTSOBt in amino acid coupling and peptide synthesis
Azabenzotriazole-type uronium salt coupling reagent	148893-10-1	H109327	O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU)	≥99%	A highly active peptide coupling reagent used as a control in amino acid and peptide fragment coupling studies
Oxyma-type uronium salt coupling reagent	1075198-30-9	C340003	COMU	≥98%	Used in peptide coupling and racemization-control studies and suitable for comparison of coupling performance with CTSOBt

Table 5. Products Related to Model Substrates, Catalysts, and Extended Reactions

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Model carboxylic acid substrate	65-85-0	B433248	Benzoic acid	Suitable for synthesis	A representative carboxylic acid substrate used in CTSOBt-mediated amidation, esterification, and carboxylic acid-to-ketone transformations
Model amine substrate	100-46-9	B108477	Benzylamine	AR, ≥99%	Used in the model amidation reaction with benzoic acid to evaluate CTSOBt-mediated carboxylic acid activation and amide formation
Aliphatic amine substrate	108-91-8	C105034	Cyclohexylamine	Moligand™, chemically pure (CP), ≥98%	Used in aliphatic amine amidation reactions to evaluate the applicability of CTSOBt and polymer-supported coupling reagents to amine substrates
Arylboronic acid substrate	98-80-6	P396095	Phenylboronic acid (PBA) (contains variable amounts of anhydride)	≥99.5%	Used in Suzuki–Miyaura-type coupling reactions for the transformation of aromatic carboxylic acids into aryl ketones
Palladium catalyst	3375-31-3	P432639	Palladium(II) acetate (47% Pd)	Suitable for synthesis	Used for the coupling of CTSOBt-activated carboxylic acids with arylboronic acids to prepare aryl ketones
Phosphine ligand	2622-14-2	T399458	Tricyclohexylphosphine (PCy₃)	≥98%	Used in the palladium-catalyzed acylative coupling system of carboxylic acids and promotes aryl ketone formation
Aldoxime dehydration substrate	932-90-1	B768539	Benzaldoxime	≥95%, mainly E-isomer	Used in CTSOBt-mediated aldoxime dehydration reactions to prepare aromatic nitrile compounds

Note: The above are representative Aladdin products related to scientific research and formulation studies. Information on specifications, grades, COA, SDS, and inventory can be further searched on the Aladdin website. The products listed in the tables are mainly used for CTSOBt structural construction, carboxylic acid activation, peptide coupling, solvent screening, control coupling systems, and extended reaction studies. Specific product selection should be comprehensively evaluated based on the target substrate, reaction conditions, solubility, scale-up requirements, and safety considerations.

Safety and Use Notice: HOBt and its hydrates, sulfonyl chlorides, SOCl₂, DBU, DCM, DME, palladium catalysts, and phosphine ligands should all be handled in accordance with SDS information and laboratory safety protocols. When anhydrous systems, sulfonyl chloride regeneration, transition-metal catalysis, or scale-up experiments are involved, special attention should be paid to thermal stability, corrosiveness, volatility, waste-liquid treatment, and residue control. HOBt-type compounds have certain risks associated with thermal decomposition and impact/friction sensitivity; high temperature, strong impact, friction, and improper drying should be avoided during experimentation and storage.

References

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