Selective oxidative β-C–H bond sulfenylation of tetrahydroisoquinolines with elemental sulfur

Abstract

In this article, a convenient and efficient KIO₃-promoted oxidative sulfenylation at the β-position of tetrahydroisoquinolines and subsequent aromatization in the presence of elemental S₈ is presented. The reaction proceeds with moderate to good yields via a double C–S formation process. A wide range of structurally diverse 4-sulfenylisoquinolines/3-sulfenylpiperidine were synthesized with excellent functional group tolerance and high efficiency.

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Introduction

Organosulfur compounds are prevalent in the areas of organic functional materials, natural products and pharmaceuticals. They often display versatile fluorescence, biological and medicinal properties.¹ As a result, continuous efforts have been applied to the synthesis of various organosulfur compounds, including thiophenes, thioamides, sulfides, disulfides and thiazoles using a variety of sulfenylating reagents.² In recent years, elemental sulfur (S₈) has gained more interest than other sulfur sources (such as RSSR, RSO₂Cl, RSO₂NHNH₂, RSO₂Na, SO₂) because it is economical, non-toxic and easily handled as a powder.^3,4 Generally, the metal-mediated S-arylation/heteroarylation of R–X/OH/OTf/B(OH)₂ with S₈ through direct C–H activation has emerged as a reliable and valuable method for the synthesis of organosulfur compounds (Scheme 1a).⁵ Nevertheless, the pre-functionalization steps required for the preparation of appropriate halo or boronic acid fragments limit the application of these methods. From an atom- and step-economy standpoint, direct oxidative dual C–H sulfenylation represents a sustainable and concise strategy for the synthesis of organosulfur compounds.⁶ For example, Tang and co-workers reported a DTBP-induced α-C–H S-heteroarylation of ethers/alkanes with imidazopiperidine in the presence of elemental S₈ (Scheme 1b).⁷ Subsequently, our group described a DMSO-promoted Ar–H/HetAr–H S-heteroarylation of arylamines/arenols/indoles using elemental sulfur (Scheme 1c).⁸ However, more efficient synthetic methods involving elemental sulfur are still required.

Scheme 1 Synthetic strategies for the synthesis of organosulfur compounds with S_8.

Because of their simplicity and commercial availability, 1,2,3,4-tetrahydroisoquinolines (THIQs) are commonly used in the synthesis of value-added compounds, often via their C(sp³)–H functionalization. Recently, various methods have been developed for the direct C–H functionalization at the C1(α) position of THIQs, such as N-arylation, α-sulfenylation, phosphonylation and annulation.⁹ Due to its lower activity, functionalization of the β-C–H bond of THIQs is more challenging, and therefore much less studied, than functionalization of the α-C–H bond.¹⁰ Organosulfur compounds that include an isoquinoline motif represent a diverse library of bioactivities and unique properties. These activities are critically dependent on the nature of the substituent at the 4-position;¹¹ thus, several advancements in the β-sulfenylation of isoquinolines have been made in recent years. However, most of these studies involve multiple steps or require pre-functionalization reactions.¹² Continuing our efforts in S₈-mediated C–H sulfenylation for the construction of organosulfur compounds in medicinal chemistry,^8,13 here we present a metal-free cascade method for the generation of 4-sulfenylisoquinolines and 3-sulfenylpyridines via the KIO₃-promoted oxidative β-C–H bond sulfenylation and aromatization of THIQs/piperidines (Scheme 1d). This strategy presents the following benefits: (i) the β-C–H bond of the N-heterocycles is directly functionalized, and the ring is further aromatized, without the introduction of directing or protecting groups; (ii) a thioether is synthesized, which links the two subunits, using stable and odorless S₈ as the sulfur source; (iii) the reaction is green and environmentally friendly through its use of a non-metallic oxidant.

Results and discussion

Because the imidazopyridine backbone is a core unit of many commercially available drugs, we surmised that imidazopyridine would be a good candidate for reaction development. Initially, THIQ (1a), 2-phenylimidazopyridine (2a) and elemental sulfur were selected as model substrates for optimization reactions with various oxidants, additives and solvents under air atmosphere (Table 1). In consideration of easy oxidation features¹⁴ and purity of THIQ (96%, Innochem), 4 equivalents of 1a was used. First, the role of the oxidant was examined through background experiments. No product was observed in the absence of oxidant (entry 1). The use of a metallic oxidant (Cu(OAc)₂, Ag₂CO₃) also did not lead to the desired product (entries 2 and 3). Instead, metal-free oxidative reagents (KIO₃) were found to promote the reaction; coupling product 3a was isolated in 27% yield (using DMF as a reaction solvent, entry 4). Only a trace amount of product was detected when a stronger oxidant was used (entry 5). Next, the investigation of different solvents (DMAc, xylene, NMP and DMSO), revealed that DMSO was the most favorable, affording 3a in 56% yield (entries 6–9). Increasing the reaction temperature to 110 °C (from 100 °C) resulted in an increased yield. However, when the reaction temperature was further increased (120 °C) or reduced (to 90 °C), lower yields were observed (entries 10–12). The amount of oxidant influenced the reaction efficiency; decreasing the amount of KIO₃ from 2 equiv. to 1 equiv. lowered the yield of the desired product to 39% (entries 13 and 14). Changing the concentartion of solvent did not improve the yield of the reaction. Several different additives (I₂, TBAI, FeCl₃) were trailed; however, none of them promoted the formation of desired product 3a (entries 15–17). Furthermore, a longer reaction time did not increase the yield (entry 18). Control experiments revealed that a nitrogen atmosphere decreased the yield of 3a (entry 19). However, reaction using an oxygen balloon did not increase the yield (affording 75% yield, compared to 78% with an air atmosphere), suggesting that the use of an oxygen atmosphere was not necessary (entry 20). Consequently, the conditions in entry 11 were selected as optimized conditions.

Table 1 Optimization of the reaction conditions^a

Entry^a	Oxidant (eq.)	Additive (eq.)	Solvent (0.1 M)	Temperature (°C)	Yield^b (%)
a Reaction conditions: 1a (0.8 mmol), S8 (0.6 mmol), 2a (0.2 mmol), oxidant, additive, and solvent in air reacted for 10 h. b Isolated yield. c Reaction time: 24 h. d Under N2. e Under O2.
1	––	––	DMF	100	ND
2	Cu(OAc)2 (2)	––	DMF	100	ND
3	Ag2CO3 (2)	––	DMF	100	ND
4	KIO3 (2)	––	DMF	100	27
5	KIO4 (2)	––	DMF	100	Trace
6	KIO3 (2)	––	DMAc	100	Trace
7	KIO3 (2)	––	Xylene	100	ND
8	KIO3 (2)	––	NMP	100	Trace
9	KIO3 (2)	––	DMSO	100	56
10	KIO3 (2)	––	DMSO	90	33
11	KIO 3 (2)	––	DMSO	110	78
12	KIO3 (2)	––	DMSO	120	62
13	KIO3 (1)	––	DMSO	110	39
14	KIO3 (3)	––	DMSO	110	73
15	KIO3 (2)	I2 (0.5)	DMSO	110	70
16	KIO3 (2)	TBAI (0.5)	DMSO	110	68
17	KIO3 (2)	FeCl3 (0.2)	DMSO	110	30
18^c	KIO3 (2)	––	DMSO	110	76
19^d	KIO3 (2)	––	DMSO	110	45
20^e	KIO3 (2)	––	DMSO	110	75

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To explore the substrate scope of the reaction, various substituted THIQs and imidazoheterocycles were tested (Table 2). Imidazoheterocycles containing electron-withdrawing (CN, CF₃, NO₂) or electron-donating (OMe, OH) substituents at various positions on the phenyl ring were tolerated; these compounds reacted with THIQ (1a) to afford the expected products 3b–3g in 34–80% yields. However, steric hindrance from the OH group at the ortho position negatively impacted the yield (3f). Furthermore, n-pentyl, naphthyl, and thienyl-substituted imidazopyridines worked well, indicating that a π–π interaction is not required for the transformation. Substrates with Br or Me substituents on the pyridine ring of the imidazopyridine were also applicable (3j–3k). A hetero-analog (3l) was obtained in 50% yield, by subjecting imidazo[2,1-b]thiazole to the optimized reaction conditions. The structure of 3l was further confirmed by X-ray crystallography (CCDC 2168420).†

Table 2 Substrate scope for β-C–H Bond sulfenylation of N-heterocycles with imidazoheterocycle^a,b

a Reaction conditions: 1 (0.8 mmol), S₈ (0.6 mmol), 2 (0.2 mmol), KIO₃ (2 equiv.), and DMSO (2 mL) in air reacted at 110 °C for 10 h. b Isolated yield. c 15 h. d 36 h.

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Next, several THIQs were subjected to the reaction with S₈ and 2a. THIQs functionalized with Me, OMe, Cl, NO₂ and NH₂ groups were tolerated. The electronic nature of the phenyl ring had a significant effect on the yield of the reaction; substrates bearing strong electron-donating groups (OMe, NH₂) afforded lower yields than those bearing electron-withdrawing groups (Cl, NO₂, CO₂Me) (3n–pversus3q–s). Additionally, 3-methylpiperidine delivered the desired coupling product 3t in 49% yield. Notably, 3u was generated using 4-methylpiperidine as a substrate, albeit with definite steric hindrance. Most importantly, elemental S₈ could be replaced with Se under similar conditions to afford 4-selanylisoquinoline 3v, highlighting the wide applicability of the method.

Next, we turned our attention to the variation of the coupling partners, the result shown in Table 3. Other heteroarene/arene substrates 4, such as imidazo[1,5-a]pyridines, indoles and 2-naphthols, were employed instead of 2 in the reaction. Imidazo[1,5-a]pyridine and imidazo[1,5-a]quinolone were first treated with THIQ and S₈ under the standard conditions, giving 5a–5b in 73% and 64% yields, respectively. The reaction of indoles with Me, phenyl, or Br substituents at different positions afforded the corresponding products 5c–5h in 48–71% yields (a slight decrement in yield was observed in the case of 3-methylindole). The Br group, which may facilitate further synthetic transformations, was well-tolerated in the reaction. Gratifyingly, N-Me indole also reacted smoothly with THIQ and S₈, affording the corresponding product 5i in 62% yield. Furthermore, 2-naphthol derivatives were suitable as substrates, affording 4-sulfenylisoquinolines 5j–5l in 60–71% yields. Expectedly, the reaction of 2-naphthylamine gave the desired product 5m in 67% yield. Similarly, replacing the imidazoheterocycle core with a different arene core (1,3,5-trimethoxybenzene or N,N-dimethylaniline) also proved possible, resulting in the formation of 5n and 5o in 76% and 78% yields, respectively.

Table 3 Substrate scope for β-C–H Bond sulfenylation of THIQ with other (hetero)arenes^a,b

a Reaction conditions: 1 (0.8 mmol), S₈ (0.6 mmol), 4 (0.2 mmol), KIO₃ (2 equiv.), and DMSO (2 mL) in air reacted at 110 °C for 10 h. b Isolated yield. c 15 h.

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To probe the mechanism of the reaction, several control experiments were conducted (Scheme 2). First, treatment of 2a with S₈ without THIQ afforded 3-iodo-2-phenylimidazopyridine (6, 63%) and 7 (22%). Next, with the addition of the radical inhibitor TEMPO (2,2,6,6-tetramethylpiperidine, 2.0 equiv.) or the radical scavenger BHT (butylated hydroxytoluene, 2.0 equiv.), 3a was isolated in 42% and 70% yields, respectively, indicating that the reaction probably did not proceed via a radical intermediate. Furthermore, sulfide 7, disulfide 8, and isoquinoline 9 were detected by mass spectrometry in the standard reaction (see ESI P97–99 for details†). Next, potential intermediates were examined. No desired product was obtained from the reaction of 9 with 2a, excluding the possibility of isoquinoline as the intermediate. Treatment of THIQ 1a with 6, 7, and 8 afforded the desired product in 61%, 69%, and 54% yields, respectively, suggesting that all of 6–8 may be intermediates. Notably, the crucial intermediate 10 was confirmed by HRMS.

Scheme 2 Control experiments.

In light of these experimental observations and reports in the literature,¹⁵ a feasible reaction mechanism is presented in Scheme 3. Initially, 6 is generated by the oxidation of 2a. This is followed by sulfenylation and dimerization to yield disulfide 8,^15a–c which can be attacked by 2a to form sulfide 7.^15d Next, the nitrogen atom of THIQ can attack 7 and 8 to form the symmetrical thioether species 10.^15e,f Finally, 10 can undergo rearrangement^11c and further proton abstraction to yield 4-sulfenylisoquinoline 3a.

Scheme 3 Proposed reaction mechanism.

Conclusions

In summary, a novel KIO₃-promoted oxidative sulfenylation reaction of tetrahydroisoquinolines using elemental sulfur and air conditions has been developed. A variety of 4-sulfenylisoquinolines and 3-sulfenylpyridines were prepared from the double C–H sulfenylation of 1,2,3,4-tetrahydroisoquinolines/piperidines with (hetero)arenes with excellent functional group compatibility and wide substrate scope. Importantly, this research paves the way for applications of elemental sulfur in the β-C–H bond sulfenylation and aromatization of N-heterocycles in organic chemistry without the need for directing or protecting groups. The exploration of applications of the methods developed in this paper and the antitumor activities of the compounds is currently underway.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This research was supported by the National Natural Science Foundation of China (22202060), the Science and Technology Foundation of Henan Province (No. 212102210202), the Project of Youth Backbone Teachers of Henan University of Technology (21420072), the Science and Technology Cooperation Foundation of Zhengzhou City (21ZZXTCX16), the Innovative Funds Plan of Henan University of Technology (2021ZKCJ08), the Funding plan of key scientific research projects in colleges and universities of Henan Province (23A150029), the Ph.D. Foundation of Henan University of Technology (2021BS080), and Natural Science Foundation of Hunan Provincial (No. 2020JJ4028). The authors are also thankful to Xiaodi Yang, Shanghai University of Traditional Chinese Medicine, for her assistance with X-ray crystallography.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d2ob01976k

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