Iridium-catalyzed reductive sulfonamidation of alkoxy aryl alkynes

Abstract

Sulfonamides are valuable structural building blocks, bioactives, and pharmaceuticals. While there have been great achievements in the sulfonamidation of alkyl and alkenyl carbon, the sulfonamidation of alkynyl carbon has not been studied. Herein, we report the synthesis of N-benzylated sulfonamides from alkoxy aryl alkynes and sulfonamides enabled by Ir-catalyzed reductive sulfonamidation using HCO₂H as a hydrogen donor. This process was performed under mild conditions, resulting in the transformation of a variety of substituted benzene, heteroaromatic, and aliphatic sulfonamides. Particularly, the structural diversification of valdecoxib and zonisamide showcased the utility of this protocol.

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Introduction

Sulfonamides are not only valuable structural building blocks in synthetic intermediates, but are also commonly found in biological and pharmaceutical fields.¹ For instance, sulfonamides of almotriptan,² sulfamethoxazol,³ hydrochlorothiazide,⁴ and naratriptan⁵ have found applications in the treatments of heavy migraine headache, urinary tract infections, and high blood pressure, respectively (Scheme 1). The latest statistics show that over 8% active pharmaceutical ingredients (APIs) contain sulfonamide skeletons, which have special physicochemical properties of metabolic stability.⁶ Therefore, the extensive application of sulphonamides in medicinal chemistry has attracted the attention of chemists in the synthesis and functionalization of sulfonamides in recent decades.⁷

Scheme 1 Drugs containing sulfonamide motifs.

Reactions of primary sulfonamides with aliphatic halides,⁸ alcohols,⁹ and carbonyls¹⁰ present classical strategies for the synthesis of sulfonamides, in which the organic,¹¹ inorganic,¹² Ir,¹³ Ru,¹⁴ Rh,¹⁵ and other metal¹⁶ catalysts are employed. Coupling of primary sulfonamides with aryl halides,¹⁷ boronic acids,¹⁸ and diaryliodonium triflate¹⁹ constitutes another efficient approach to sulphonamide synthesis, where Cu,²⁰ Pd,²¹ and Ni²² metals are commonly utilized as catalysts. Direct sulfonamidation of alkyl carbon provides an atom- and step economy strategy for sulfonamide synthesis, with commendable substrate scope and efficiency (Scheme 2a).²³ However, the inevitable use of hypervalent iodine reagents or strong oxidation,²⁴ excessive equivalents of oxidants,²⁵ and poor regioselectivity²⁶ limit the application of this strategy. Approaches to sulfonamide synthesis based on the sulfonamidation of alkenyl carbon via classical hydroamination or hydrogen atom transfer of alkenes are attractive alternatives (Scheme 2b).²⁷ Notably, asymmetric sulfonamidation of alkenyl carbon for the synthesis of enantioenriched sulfonamides via hydrogen atom transfer has also be established.²⁸ While there have been great achievements with regards to sulfonamidation of alkyl and alkenyl carbon, the sulfonamidation of alkynyl carbon has not been studied.

Scheme 2 Sulfonamidation of differential hybridized carbons.

With our continuous research on transfer hydrogenation with Cp*Ir complexes,²⁹ N-alkylation³⁰ or para-Friedel–Crafts alkylation³¹ were achieved from alkynes via hydration and transfer hydrogenation. In a previous work, a relatively stable benzyl carbocation was generated from alkynes via a hydration, transfer hydrogenation, and successive dehydroxylation process, which might be captured by primary or secondary sulfonamides to deliver a variety of N-benzylated sulfonamides. Using alkynes as substrates comes with various challenges: (a) although hydration of alkynes had been developed in our previous work,³¹ there is a risk of deactivation of hydration using primary or secondary sulfonamides as nucleophilic reagents; (b) a similar outcome of poisoning subsequent transfer hydrogenation is possible under these reaction conditions; (c) a weaker nucleophilic property is noted while using nitrogen atoms as a nucleophilic reagent under acidic conditions, and using sulfonamides as nucleophilic agents will likely have similar related issues, hindering the final cross nucleophilic coupling process. Despite these difficulties, through protracted and unremitting efforts, herein, we realized the reductive sulfonamidation of alkynes with primary and secondary sulfonamides using metal catalysis, which provides inspiration for the synthesis of diversified sulfonamides (Scheme 2c).

Results and discussion

We initially examined the reductive sulfonamidation of alkynes by employing 4-ethynylanisole 1a and benzene sulfonamide 2a as model substrates, Cp*Ir complexes as catalyst,³² and HCO₂H as a hydrogen donor (Table 1). Interestingly, the desired product 3aa was produced at a 38% yield using H₂O as a solvent and TsOH as an additive (Table 1, entry 1). Screening of further reaction parameters indicated that the H₂O and Cp*Ir catalyst were essential for successful reductive sulfonamidation (Table 1, entries 2–11). Increasing the ratio of TFEA would decrease the yield of 3aa (Table 1, entries 7–10). For instance, the yield of 3aa was reduced to trace even though the ratio of TFEA and H₂O was loaded over 1 : 1 (Table 1, entry 10). Additionally, catalyst optimization (Table 1, entries 12–17) showed that the Cp*Ir complex C5 could slightly enhance the sulfonamidation process leading to a 45% yield of the product 3aa (Table 1, entry 16). Satisfyingly, increasing the loading of 2a would sharply improve the yield of 3aa (Table 1, entries 18–24). Of note, the control experiment demonstrated that a Lewis acid was crucial for this reductive sulfonamidation process (Table 1, entries 25–35) and decreasing the loading of TsOH to 0.2 equiv. resulted in the best yield of 3aa (Table 1, entry 30). However, decreasing or increasing the reaction temperature was harmful to the production of 3aa (Table 1, entries 36 and 37). Control experiment showed that HCO₂H was the essential hydrogen donor in this transformation, indicating that H₂O only act as a reaction media (Table 1, entry 38).

Table 1 Optimization of the synthesis of sulfonamide 3aa^a

Entry	Cat.	Additive (equiv.)	2a (x equiv.)	Solvent	Yield 3aa^b (%)
a Reaction conditions: 1a (0.5 mmol), Cat. (1.0 mol%), HCO2H (10.0 equiv.), and solvent (1.5 mL) for 12 hours at 80 °C (under air).b Yield was determined by NMR with dimethyl terephthalate as the internal standard.c The ratio of the mixed solvent was 1 : 8 (v/v).d The ratio of the mixed solvent was 1 : 4 (v/v).e The ratio of the mixed solvent was 1 : 2 (v/v).f The ratio of the mixed solvent was 1 : 1 (v/v).g R1 = 4-Cl-Ph; R2 = 2-naphthyl.h 60 °C.i 100 °C.j Without HCO2H.
1	C3	TsOH (0.6)	1.0	H2O	38
2	C3	TsOH (0.6)	1.0	DMF	N.D.
3	C3	TsOH (0.6)	1.0	TFEA	N.D.
4	C3	TsOH (0.6)	1.0	MeCN	N.D.
5	C3	TsOH (0.6)	1.0	p-Xylene	N.D.
6	C3	TsOH (0.6)	1.0	Dioxane	N.D.
7	C3	TsOH (0.6)	1.0	TFEA/H2O^c	36
8	C3	TsOH (0.6)	1.0	TFEA/H2O^d	42
9	C3	TsOH (0.6)	1.0	TFEA/H2O^e	22
10	C3	TsOH (0.6)	1.0	TFEA/H2O^f	Trace
11	C3	TsOH (0.6)	1.0	p-Xylene/H2O^d	30
12	—	TsOH (0.6)	1.0	TFEA/H2O^d	N.D.
13	C1	TsOH (0.6)	1.0	TFEA/H2O^d	40
14	C2	TsOH (0.6)	1.0	TFEA/H2O^d	37
15	C4	TsOH (0.6)	1.0	TFEA/H2O^d	37
16	C5	TsOH (0.6)	1.0	TFEA/H2O^d	45
17	C6	TsOH (0.6)	1.0	TFEA/H2O^d	41
18	C5	TsOH (0.6)	1.2	TFEA/H2O^d	45
19	C5	TsOH (0.6)	1.4	TFEA/H2O^d	46
20	C5	TsOH (0.6)	1.6	TFEA/H2O^d	46
21	C5	TsOH (0.6)	1.8	TFEA/H2O^d	48
22	C5	TsOH (0.6)	2.0	TFEA/H2O^d	77
23	C5	TsOH (0.6)	2.5	TFEA/H2O^d	70
24	C5	TsOH (0.6)	3.0	TFEA/H2O^d	76
25	C5	—	2.0	TFEA/H2O^d	N.D.
26	C5	PhSO3H (0.6)	2.0	TFEA/H2O^d	52
27	C5	R^1SO3H (0.6)^g	2.0	TFEA/H2O^d	44
28	C5	MSA (0.6)	2.0	TFEA/H2O^d	59
29	C5	R^2SO3H (0.6)^g	2.0	TFEA/H2O^d	35
30	C5	TsOH (0.2)	2.0	TFEA/H2O^d	81 (79)
31	C5	TsOH (0.4)	2.0	TFEA/H2O^d	80
32	C5	TsOH (0.8)	2.0	TFEA/H2O^d	46
33	C5	TsOH (1.0)	2.0	TFEA/H2O^d	43
34	C5	TsOH (1.5)	2.0	TFEA/H2O^d	29
35	C5	TsOH (2.0)	2.0	TFEA/H2O^d	18
36^h	C5	TsOH (0.2)	2.0	TFEA/H2O^d	63
37^i	C5	TsOH (0.2)	2.0	TFEA/H2O^d	42
38^j	C5	TsOH (0.2)	2.0	TFEA/H2O^d	N.D.

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With the successfully optimized conditions, the substrate scope with respect to aryl alkynes and aryl sulfonamides was investigated (Table 2). As anticipated, aryl sulfonamides with electron-donating groups at differential positions were well tolerated, including methyl, ethyl, tert-butyl, hydroxyl, and methoxy, delivering the corresponding products (3ab–3ag) in good to excellent yields. Additionally, di-substituted aryl sulfonamide (2h) also performed well in this system. Aryl sulfonamides with electron-withdrawing groups, such as fluorine (2i), chlorine (2j, 2n), nitrile (2k, 2l), and trifluoromethyl (2m), were also efficient substrates to afford similar yields of the desired products (3ai–3an). However, significantly different yields were achieved with heteroaromatic sulfonamides (2o–2s) as substrates. For instance, low yield (15–26%) of corresponding products 3ao, 3ap were obtained using pyridine sulfonamides as substrates, while 2-thiophene-sulfonamides delivered the desired products 3aq–3as in good yields (69–77%). This difference could be attributed to the difference in the density of π electrons. Interestingly, switching the primary aryl sulfonamides to secondary aryl sulfonamides also allowed the formation of the desired products (3at–3av) in moderate yields. Furthermore, other alkoxy-substituted aryl alkynes (2b–2d) were also good substrates in the iridium catalyzed reductive sulfonamidation process.

Table 2 Substrate scope of aromatic sulfonamides and alkoxy aryl alkynes^a

a Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), C5 (1.0 mol%), HCO₂H (10.0 equiv.), and TFEA (0.3 mL), H₂O (1.2 mL) for 12 hours at 80 °C, and isolated yield.

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Having established the conversion of aromatic sulfonamides into diversified sulfonamides, this method was extended to employ alkyl sulfonamides as substrates (Table 3). In comparison with aryl sulfonamides, the corresponding products (5aa–5ah, 5aj) were delivered in relatively lower yields using differential primary alkyl sulfonamides as substrates. Surprisingly, a better yield (66%) of sulfonamide 5ai was delivered by using secondary cyclic aliphatic sulfonamide of 1,3-propanesultam as a substrate.

Table 3 Substrate scope of alkyl sulfonamides^a

a Reaction conditions: 1a (0.5 mmol), 4 (1.0 mmol), C5 (1.0 mol%), HCO₂H (10.0 equiv.), and TFEA (0.3 mL), H₂O (1.2 mL) for 12 hours at 80 °C, and isolated yield.

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Following success in developing a broad range of sulfonamides, we then explored the synthetic applications of this method. First, we investigated the derivatization of drugs containing the sulfonamide scaffold, which are of interest in medicinal chemistry. As shown in Scheme 3a, valdecoxib (COX-2 inhibitor)³³ and zonisamide (used as an adjunctive therapy in adults with partial-onset of seizures)³⁴ could be easily converted into N-benzyl sulfonamides. Moreover, the model reaction was scaled to a 10.0 mmol reaction and it delivered 2.5 g of the sulfonamide 3aa in 86% yield, which exhibited potential synthetic application in the organic chemistry industry (Scheme 3b).

Scheme 3 Derivatization of drugs and gram-scale experiment.

To gain more insights into the reaction mechanism, control experiments were performed. According to our previous work,³⁵ hydration of alkynes proceeded smoothly under acidic conditions to generate ketone and alcohol intermediates. Therefore, the ketone 6a and sulfonamide 2a were employed as substrates under standard conditions, resulting in a 70% yield of 3aa (Scheme 4a). Moreover, subjecting alcohol 7a and sulfonamide 2a to the standard conditions in the absence of C5 resulted in a 73% yield of 3aa (Scheme 4b).

Scheme 4 Control experiments.

Based on the reaction result and control experiments (Scheme 4), a possible mechanism was proposed (Scheme 5). The mechanism is characterized by a catalytic cycle that includes hydration and a transfer hydrogenation process that was completed to generate the intermediate alcohol 7a. Subsequently, carbocation occurred by dehydroxylation of 7a under acidic conditions, which was followed by cross-nucleophile coupling with sulfonamide to produce the desired product 3aa.

Scheme 5 Proposed mechanism.

Conclusions

In conclusion, we have shown the sulfonamidation of alkoxy aryl alkynes with viable sulfonamides for the synthesis of diverse N-benzylated sulfonamides. This modular Cp*Ir complex-catalyzed reductive sulfonamidation synthesis was achieved under mild conditions. The reaction can be conducted at gram scale in air. Sulfonamide drugs of valdecoxib and zonisamide could also be employed as substrates and converted into N-benzyl sulfonamides. The good substrate suitability, wide range of functional group tolerance, scale-up performance, and mild reaction conditions provide evidence of the potential for the application of this reductive sulfonamidation transformation in rapid structural diversification of bioactive molecules.

Data availability

The data supporting this article have been included as part of the ESI.†

Author contributions

Yuqiu Liang, Chengxiu Liu, and Penghao Wei: investigation, data curation, validation, visualization, manuscript, and ESI† writing and editing. Youchun Li and Lu Ouyang: conceptualization, funding acquisition, project administration, resources, supervision, visualization, revising the manuscript and the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Ganzhou Bureau of Science and Technology (2022-YB1402), the Fundamental Research Funds for Gannan Medical University (QD201810, QD202106, TD2021YX05, TD202310) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4ra07579j

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