New benzotriazole–sulfonate coupling reagents and applications

Abstract

Amide and ester bond formation is crucial in medicinal chemistry and relies heavily on coupling reagents in both academic and industry. We report the development of new cost-effective recyclable benzotriazole–sulfonate coupling reagents in a straightforward, rapid, and easy manner. The reagents efficiently activate carboxylic acids to form amides, esters, thioesters, and peptides, with excellent yields and high chirality retention. The reagent enables drug modifications and transformations, including aldoxime-to-nitrile and carboxylic acid-to-ketone conversions. The use of green solvents effectively minimizes the environmental impact.

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1 Introduction

Peptide therapeutics have garnered considerable interest, with many peptide-based drugs now approved for commercial use.¹ Amide and ester functionalities are also widespread in pharmaceuticals and fine chemicals.^2,3 Coupling reagents play a vital role in their synthesis, but their industrial production generates large amounts of toxic waste (Fig. 1A). One promising strategy to minimize waste generation involves the use of recyclable reagents. Recently, a novel recyclable NDTP-based coupling reagent was reported, enabling rapid and sustainable amide and peptide synthesis without epimerization.⁴ Chiba et al. developed an electrochemical peptide-coupling method in which oxidized triphenylphosphine cations activate carboxylic acids to form amides, allowing for efficient phosphine reagent recycling.⁵ Similarly, the Saito group introduced a greener peptide-coupling protocol that uses a recyclable bicyclic benziodazolone reagent, which also serves as a base and can be electrochemically regenerated from its iodine(I) form.⁶ Recently, we reported a new Oxyma-sulfonate-based recyclable coupling reagent for sustainable amidation and esterification.⁷ Recycling solvents and reagents significantly reduced the environmental impact. Replacing hazardous solvents with greener ones, another effective route to enhancing the sustainability of chemical synthesis. For instance, North et al. replaced hazardous DMF with the polar aprotic propylene carbonate solvent, yielding peptides with comparable purity and efficiency.⁸ Cebri et al. demonstrated green solvent mixtures of Cyrene, sulfolane, or anisole with dimethyl or diethyl carbonate can effectively replace DMF in Fmoc solid-phase peptide synthesis.⁹ Pawlas et al. reported green solid-phase peptide synthesis (SPPS) using a recyclable EtOAc/DMSO mixture solvent.¹⁰ In peptide synthesis, hydroxybenzotriazole (HOBt) is widely used as a racemization suppressor.¹¹ Many uronium and phosphonium reagents incorporate HOBt derivatives;¹² however, their non-recyclable nature and the reliance on hazardous solvents (DMF, DCM, NMP) increase environmental risks.¹³ Very few benzotriazole–sulfonate coupling reagents have been reported in the literature; these are either inefficient in peptide synthesis or insufficiently explored in other organic transformations.^14–20 We envisioned the development of a five-member heterocycle containing recyclable coupling reagents that operate efficiently in green solvents, eliminating hazardous DMF and enabling sustainable, diverse organic transformations. We also envisioned that the presence of a heteroatom in the five-membered ring may facilitate interaction with the acid group. This interaction could keep the acid in close proximity to the coupling reagent, thereby enabling facile and efficient activation of the acid group upon reaction and promoting efficient amidation, esterification, and other organic transformations.

Fig. 1 (A) Coupling reagents in organic transformations, (B) synthesized heterocyclic reagents.

2 Results and discussion

Herein, we designed and synthesized several heterocyclic coupling reagents by reacting various thiophene sulfonyl or carbonyl chloride derivatives with other heterocycles such as HOBt, N-hydroxyphthalimide, or N-hydroxysuccinimide (Fig. 1B). The reagents were synthesized in good yields in a rapid, straightforward procedure. We then evaluated their efficiency in amidation. The reaction of benzoic acid (0.5 mmol) and benzylamine (0.5 mmol) in the presence of 1Xa (0.5 mmol), DIPEA (0.6 mmol) in DCM (1 mL) offered amide 3a1 in 73% yield. Other reagents, except 1Xf and 1Xg, afforded the product in varying yields, with 1Xc providing the highest yield (83%, entry 3, Table S1). Therefore, 1Xc was used for subsequent reactions. HOBt can react at either O- or N-positions; the crystal structure of 1Xc (CCDC 2296562) confirmed an O-substituted structure. Its synthesis in other solvents also gave excellent yields (Table S2). The large-scale synthesis of 1Xc offered >99% yield (entry 7, Table S2). Amidation with 1Xc was optimized in other solvents (THF, EtOAc, ACN, DMSO, DMF, CHCl₃, acetone, and acetone/H₂O) and bases (DIPEA, Et₃N, DBU). The highest yield of 3a1 (98%) was achieved in acetone with DIPEA within 30 min (entry 8, Table 1), and these conditions were considered as optimized. Using the optimized conditions, we explored the scope of amides, esters, thioesters, and peptides in solution (Table 2). Under optimized conditions, aromatic acids with electron-donating or withdrawing groups reacted efficiently with various amines, including benzylic, electron-deficient aromatic, and aliphatic amines, to afford the corresponding amides (3a1–3a9) in excellent yields (91–98%). C- and N-terminal protected amino acids, even with rigid side chains, gave amides (3a10–3a15) in excellent yields. Heterocyclic and long-chain aliphatic acids afforded amides (3a16, 3a17) in good yields (96% and 89%). We further explored the synthesis of esters and thioesters. Aromatic acids with electron-donating and electron-withdrawing groups reacted efficiently with benzylic and poorly nucleophilic aromatic alcohols, affording the desired esters (3a18–3a22, 3a21 (CCDC 2307268)) in good yields. The slightly lower yields are likely due to the weaker nucleophilicity of alcohols compared to amines. Long-chain, heterocyclic, and Fmoc-amino acids gave esters (3a24–3a27) in good yields (84–96%) with aromatic/aliphatic alcohols. Acetonide-protected carbohydrate acceptors gave esters (3a28, 3a29) satisfactorily, and Boc-amino acids afforded thioesters (3a30, 3a31) in good yields. Interestingly, C- and N-protected amino acids under optimized conditions afforded excellent peptide formation. Boc-, Fmoc-, and Cbz-protected amino acids bearing aromatic, sterically hindered, or protected side chains offered excellent peptides (3a32–3a44) yields. We also successfully synthesized tripeptides (3a45, 3a46) and a tetrapeptide (3a47) with satisfactory yields. The protocol's practical applicability was demonstrated by modifying various drug molecules. Ciprofibrate and the NSAIDs reacted efficiently with amines, alcohols, and thiols to give amide, ester, and thioester derivatives (3a48–3a58) in good to excellent yields. Febuxostat and gemfibrozil reacted with aromatic alcohol and cyclic aliphatic amine to afford modified drugs (3a59, 3a60) satisfactorily. Paracetamol was also synthesised successfully (3a61), and benzocaine reacted smoothly with Fmoc amino acid, offering 3a62 in good yield. Upon synthesizing dipeptide 3a44 using several literature-reported coupling reagents, we compared the coupling efficiency and epimerization/racemization suppressing capacity with reagent 1Xc. Reagent 1Xc delivered the peptide yield superior to that obtained after the reaction with literature-reported reagents and provided excellent chiral retention (entry 7, Table 3). The same dipeptide system has previously been used in the literature to study racemization/epimerization.^21,22

Table 1 Optimization of reaction conditions

Entry	Solvent	Base	Time^c	Yield^d (%)
a Reaction conditions: 1a1 (0.5 mmol), 2a1 (0.5 mmol), 1Xc (0.5 mmol), base (0.6 mmol), solvent (1 mL), 25 °C.b 50 °C.c Time after adding amine.d Isolated yields.
1^a	DCM	DIPEA	12 h	83
2^a	THF	DIPEA	2 h	64
3^a	EtOAc	DIPEA	1.3 h	91
4^a	ACN	DIPEA	35 min	88
5^a	DMSO	DIPEA	3 h	50
6^a	DMF	DIPEA	15 min	90
7^a	CHCl3	DIPEA	1.4 h	89
8^a	Acetone	DIPEA	30 min	98
9^b	Acetone/H2O (1 : 1)	DIPEA	1 h 30 min	85
10^b	Acetone/H2O (1 : 4)	DIPEA	5 h	85
11^a	Acetone	Et3N	45 min	85
12^a	Acetone	DBU	50 min	79

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Table 2 Scope of amides, esters, thioesters, and peptides^a

a Reaction conditions: 1a1 (0.5 mmol, 1 equiv.), 2a1 (0.5 mmol, 1 equiv.), 1Xc (0.5 mmol, 1 equiv.), DIPEA (0.6 mmol, 1.2 equiv.), acetone (1 mL), 25 °C, isolated yield.

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Table 3 Comparative yields and racemization/epimerization during peptide 3a44 synthesis^a

Entry^a	Coupling reagents (CR)	Yield^c	ee^d
a Reaction conditions: 1a44 (0.5 mmol, 1 equiv.), 2a44 (0.5 mmol, 1 equiv.), CR (0.5 mmol, 1 equiv.), DIPEA (0.6 mmol, 1.2 equiv.), acetone (1 mL), 25 °C.b DIPEA (1.1 mmol, 2.2 equiv.).c Isolated yield.d Determined by HPLC.
1	BOP	84%	95%
2	HBTU	69%	98%
3	HATU	68%	95%
4	DCC	63%	90%
5^b	EDC HCl/Oxyma	67%	79%
6	COMU	78%	96%
7	1Xc	96%	>99%

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The application of reagent 1Xc was extended in solid-phase peptide synthesis (Table 4). Although peptide synthesis is well-established, long-chain peptide synthesis remains challenging. Here, we aimed to replace the hazardous solvent DMF with a greener alternative. Initially, Fmoc-KLVFF-NH₂ (4a1),²³ an amyloid beta fragment peptide, was synthesized on Rink amide MBHA resin in acetone, affording peptide 4a1 in 41% yield. Binary solvent mixtures DMSO/EtOAc (1 : 9) and DMSO/acetone (1 : 19) were tested, yielding peptide 4a1 in 53% and 54%, respectively (Table S3). DMSO/acetone (1 : 19) was neglected due to poor resin swelling, and DMSO/EtOAc (1 : 9) was considered as the optimized solvent. We also synthesized eledoisin-related peptide 4a2 (31%) and the Soto peptide LPFFD 4a3 (33%), with satisfactory yields.^24,25 The hexapeptide VYIHPF (4a4), a fragment of the tissue hormone Angiotensin II,²⁶ was obtained in 35% yield. Cyclic peptide Cy-NFGAILER-NH₂ (4a5) was obtained via side-chain-to-tail cyclization in 27% yield.²⁷ Similarly, the head-to-tail cyclic peptide Cy-KLVFfAE (4a6), an inhibitor of Aβ₄₀ aggregation,²⁸ was synthesised successfully.

Table 4 Scope of solid phase synthesized peptides^a

a Reaction conditions: Rink amide resin (0.14 mmol, loading 0.7 mmol g⁻¹), amino acids (0.28 mmol, 2 equiv.), 1Xc (0.35 mmol, 2.5 equiv.), DIPEA (0.7 mmol, 5 equiv.), solvent (2 mL): DMSO/EtOAc (1 : 9), Fmoc cleave: 10% 4-methylpiperidine (4 MP), coupling time: 3 h.b Yield in DMSO/acetone (1 : 19). AA = amino acid. Isolated yield.

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We further explored the application of 1Xc by synthesizing ketones from aromatic carboxylic acids (Table 5) and nitriles from aromatic aldoximes (Table 6A). Ketones are widely found in natural products and pharmaceuticals.²⁹ Activated carboxylic esters offer carbonyl retention in Suzuki–Miyaura reactions.³⁰ Initially, benzoic acid was treated with reagent 1Xc in acetone to generate an intermediate, which was subsequently extracted with ethyl acetate (EtOAc) and concentrated. This intermediate then underwent a palladium-catalyzed reaction with phenylboronic acid using Pd(OAc)₂/PCy₃, K₂CO₃, dioxane at 80 °C, yielding desired ketone 6a1 in 33% isolated yield (entry 1, Table S4). The reaction was optimized by varying solvents, bases, ligands, and catalysts. With 5 mol% Pd(OAc)₂ and 10 mol% PCy₃, using K₂CO₃ (2 equiv.) in dimethoxyethane (DME) at 80 °C, the yield of ketone 6a1 increased to 71% (entry 5, Table S4), which was identified as the optimized conditions. Under optimized conditions, diverse aromatic acids and aryl boronic acids coupled smoothly to give the desired ketones (6a2–6a10) in good yields (58–75%).

Table 5 Scope of ketones^a

a Reaction conditions: Step-i. 5a (0.2 mmol), 1Xc (0.2 mmol, 1 equiv.), DIPEA (0.2 mmol, 1 equiv.), acetone (1 mL); Step-ii. R⁴B(OH)₂ (0.3 mmol, 1.5 equiv.), Pd(OAc)₂ (5 mol%), PCy₃ (10 mol%), K₂CO₃ (0.4 mmol, 2 equiv.), DME (1 mL), 80 °C, N₂, isolated yield.

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Table 6 Scope of nitriles and synthesis of polymeric coupling reagent, applications^a

a Reaction conditions: (A) 7a (0.4 mmol, 1 equiv.), 1Xc (0.4 mmol, 1 equiv.), DBU (0.8 mmol, 2 equiv.), DCM (1 mL), rt, N₂, 2 h, isolated yield. (B) Polymer-bound HOBt resin (200 mg, 0.2 mmol, 1 mmol g⁻¹), DIPEA (0.2 mmol) and 5-chlorothiophene-2-sulfonyl chloride (0.2 mmol), acetone (1.5 mL). FT-IR of (C) P-HOBt, (D) P-CTSOBt (1Xp); EDX of (E) P-HOBt, (F) P-CTSOBt (1Xp). (G) 1Xp: 0.2 mmol (loading: 1 mmol g⁻¹), 9a (0.2 mmol, 1 equiv.), 10a (0.2 mmol, 1 equiv.), DIPEA (0.24 mmol, 1.2 equiv.), solvent (1 mL): DMSO/acetone (1 : 19), 25 °C, 1–6 h (after adding R⁸-XH), isolated yield.

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Furthermore, we replaced the coupling reagent with our 1Xc reagent to test the conversion of aromatic aldoximes to nitriles under previously reported conditions.³¹ Remarkably, aromatic aldoximes bearing either electron-donating or electron-withdrawing groups furnished the desired nitriles (8a1–8a4) in excellent yields, demonstrating the broad applicability of our reagent.

Polymer-supported coupling reagents have attracted considerable attention owing to their ease of recovery, ability to minimize racemization/epimerization, and simplified isolation of final products.³² Here, we also synthesised a polymer-supported coupling reagent (1Xp, Table 6B) and characterised it using IR and EDX analysis (Table 6C–F). In IR analysis, the disappearance of the 3421 cm⁻¹ peak (O–H stretching) and the appearance of 1398 cm⁻¹ (SO₃-ester) peak suggested the successful synthesis of the coupling reagent. This result was further supported by EDX analysis. In EDX, the presence of both the S and Cl atom %, along with the C, N, and O atom %, confirmed the successful synthesis of the coupling reagent (1Xp), which was missing in the EDX of commercial polymeric HOBt (P-HOBt). The amidation of 4-methoxybenzoic acid with cyclohexylamine using 1Xp was examined in acetone in the presence of DIPEA and in binary solvent systems (DMSO/EtOAc 1 : 9 and DMSO/acetone 1 : 19). The DMSO/acetone (1 : 19) mixture afforded amide 11a1 in 98% yield (Table S5). Using this solvent system, examples of amides, esters, thioesters, and peptides (11a2–11a5) were synthesised from aromatic, aliphatic, and amino acids, providing excellent yields (84–98%, Table 6G). Upon completion of the reaction, the polymer-supported HOBt could be conveniently recovered by washing with solvent and reused multiple times without a decrease in reactivity.

A plausible mechanistic pathway for the synthesis of amides, esters, thioesters, and peptides using 1Xc or 1Xp is depicted in Scheme 1A. Initially, DIPEA facilitates the generation of the carboxylate nucleophile. The nucleophilic attack of the carboxylate nucleophile on the sulfonyl center of 1Xc or 1Xp forms the mixed anhydride (II) with elimination of OBt⁻ (2′). Subsequent nucleophilic attack of OBt⁻ (2′) on the carbonyl carbon of intermediate (II) affords the activated intermediate (III). Finally, nucleophiles (e.g., amines, alcohols, thiols, or amino acids) attack intermediate (III) to produce the desired amides, esters, thioesters, or peptides.

Scheme 1 (A) Plausible mechanism for amidation/esterification and recyclability of coupling reagents 1Xc or 1Xp; (B) Plausible mechanism for ketone synthesis.

The recovered mixture of byproducts (5-chlorothiophene-2-sulfonic acid (SA) and HOBt) can be treated with SOCl₂ at 70 °C in toluene, using a catalytic amount of DMF, to regenerate the corresponding sulfonyl chloride. Then, the addition of base can lead to the formation of coupling reagent 1Xc. We recycled 51% of the coupling reagent 1Xc, and using this recycled reagent, the reaction between benzoic acid and benzylamine afforded 95% of amide 3a1. In the case of 1Xp, the recovered P-HOBt can directly react with 5-chlorothiophene-2-sulfonyl chloride in the presence of a base to form 1Xp.

A plausible mechanism for the synthesis of ketones is also proposed in Scheme 1B. Initially, Pd(OAc)₂ and the ligand (PCy₃) react to generate an in situ Pd(0) complex. This complex undergoes oxidative addition with acyl-OBt (A), forming intermediate B. Base-assisted transmetalation with the boronic acid then produces intermediate C. Finally, reductive elimination affords the desired ketone product D, regenerating the Pd(0) catalyst.

3 Conclusion

In conclusion, we have designed and synthesized new benzotriazole–sulfonate coupling reagents that enable the sustainable synthesis of amides, esters, thioesters, nitriles, ketones, and peptides with excellent yields and chirality retention. The use of recyclable coupling reagents (1Xc and polymer-supported 1Xp), green solvents, and broad substrate scope in diverse organic transformations highlights the wide applicability and practicality of this protocol. We believe these new coupling reagents will find wider applications in many other organic transformations.

Author contributions

S. R.: conceptualization, methodology, investigation, data curation, formal analysis, visualization, writing – review and editing. B. M.: conceptualization, supervision, writing – review and editing, and funding acquisition.

Conflicts of interest

The authors declare no conflicts of interest.

Data availability

CCDC 2296562 (1Xc) and 2307268 (3a21) contain the supplementary crystallographic data for this article.^33a,b

Supplementary information (SI): detailed experimental procedures and complete characterization data for all new compounds. See DOI: https://doi.org/10.1039/d6ra03443h.

Acknowledgements

We thank CIF, and Department of Chemistry, IIT Guwahati, for NMR, SC-XRD, and other instrumental facilities; and SERB, Govt. of India, for financial support (Grant Number: CRG/2023/004467).

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