A new generation of multifunctional synthetic tools capable of synthesizing amides, esters, ketones, and nitriles.

I. Background Introduction:

The construction of amide and ester bonds is one of the most fundamental and core reactions in medicinal chemistry and organic synthesis. Bhubaneswar Mandal's team previously developed sulfonate-type recyclable condensing reagents, CTSOAt, which can be used for the synthesis of amides, esters, and ketones. Inspired by this, they further expanded the design of heterocyclic condensing reagents, among which 2-chloro-thiophene-5-(N- hydroxybenzotriazole )sulfonate (CTSOBt) showed the best performance.

As an analogue of CTSOAt, CTSOBt can also efficiently promote amidation, esterification, and ketone conversion, but the reaction conditions are adjusted. In addition, CTSOBt has some unique properties; it can mediate the conversion of aromatic aldehyde oximes to nitriles and can also be formulated as a resin-type condensation reagent by being loaded onto polymer materials.

II. Introduction:

CTSOBt (structure shown in Figure 1 below) is a novel multifunctional condensation reagent that promotes the formation of CO, CN, and CC bonds. It is recyclable and compatible with green solvents. Single-crystal structure analysis confirms that the key linkages in the CTSOBt molecule are SO bonds, rather than SN bonds, and this structural feature directly affects its reactivity .

Figure 1. CTSOBt structure

III. Applications:

CTSOBt can not only efficiently drive amidation and esterification reactions, but also participate in Suzuki coupling to achieve the conversion of carboxylic acids to ketones, and mediate the dehydration of aromatic aldehyde oximes to nitriles .

1. Amides and (thio)esters

The Bhubaneswar Mandal team optimized the reaction conditions as follows: using acetone as solvent and DIPEA as base, CTSOBt was used to activate carboxylic acids at room temperature, followed by reactions with various amines, alcohols, and thiols, efficiently yielding structurally diverse amides, peptides, esters, and thioesters (1xc in Figure 2 represents CTSOBt). This system has a wide substrate applicability, good functional group compatibility, and can effectively inhibit racemization of chiral centers, and has been validated in drug modification.

synthesis of amides and esters .

2. Solid-phase synthesis

In solid-phase synthesis, multiple peptides, including amyloid-β fragments, were successfully synthesized by replacing DMF with the green solvent 10% DMSO/ethyl acetate. The synthesis of cyclic peptides was also successfully achieved (Figure 3).

Figure 3. CTSOBt used for solid-phase synthesis

3. Polymer-supported coupling agent: P-CTSOBt

Polymer-supported coupling agents have attracted much attention due to their ease of recovery, ability to minimize racemization, and simplified product separation. Our team prepared P-CTSOBt using commercially available P- HOBt and 5-chlorothiophene-2- sulfonyl chloride, and successfully applied it to the synthesis of amides and esters with yields of 84-98% (Figure 4). After the reaction, P- HOBt can be recovered by solvent washing, and its activity does not decrease with repeated use.

Figure 4. P-CTSOBt used in the synthesis of amides and esters.

Similar to CTSOAt, CTSOBt (and P-CTSOBt) can be treated with thionyl chloride to regenerate into the corresponding condensation reagents. The condensation reaction mechanism is as follows (Figure 5): Carboxylic acid attacks CTSOBt under the action of a base to form a mixed anhydride intermediate. Subsequently, the oxygen anion in the HOBt fragment (or the polymer-supported HOBt fragment) attacks the mixed anhydride to form an activated OBt ester. Finally, alcohol/ amine attacks to obtain the corresponding ester and amide.

Figure 5. Mechanism of action of (P-)CTSOBt

4. Other organic transformations:

(1) Synthesis of ketones

CTSOBt can participate in the Suzuki coupling reaction, directly converting carboxylic acids into ketones. Regardless of whether the substrate has an electron-withdrawing or electron-donating group, the target compound can be obtained in a moderate to high yield (Figure 6).

Figure 6. CTSOBt used for ketone conversion.

(2) Synthesis of nitriles

CTSO Bt can also dehydrate aromatic aldehyde oximes to aryl nitrile , and is applicable to both electron-withdrawing and electron-donating substrates, with yields of 83-99% (Figure 7), further demonstrating the wide applicability of this reagent.

Figure 7. CTSOBt used for nitrile conversion

IV. Conclusion:

CTSOBt is a novel, recyclable condensation reagent with broad applicability and strong practicality. It not only efficiently promotes the synthesis of amides and esters but also significantly inhibits racemization, showing promising applications in polymer-supported coupling reagents and solid-phase synthesis. Furthermore, this reagent can achieve two unconventional transformations: carboxylic acids to ketones and aromatic aldehyde oximes to aryl nitriles. In summary, the development of CTSOBt provides a new, multifunctional tool for synthetic chemistry and related fields.

Company Introduction:

After more than 20 years of unremitting efforts and accumulation, Haofan Biotech has become the company with the most comprehensive range of customized peptide synthesis reagents and the largest production volume in the world, capable of meeting the specific needs of various customers. We sincerely invite customers interested in this product to contact us to learn more about the product details and explore cooperation opportunities.

References:

[1] Roy, S.; Mandal, B. New benzotriazole-sulfonate coupling reagents and applications [J]. RSC Adv., 2026, 16, 24659-24666.