A convenient access to β-iodo sulfone by the iodine-mediated iodosulfonylation of alkenes

Abstract

A novel iodine-mediated intermolecular iodosulfonylation reaction of alkenes for dual C–S and C–I bond formation is described. A series of alkenes could be selectively converted into the corresponding β-iodo sulfones, which are versatile building blocks in organic synthesis and medicinal chemistry. Molecular iodine was the iodine source in this reaction.

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Difunctionalization of alkenes is a class of significant synthetic transformations that allow for the buildup of molecular complexity in a single procedure.¹ Recently, transition-metal-catalyzed difunctionalization of alkenes provided a powerful strategy for the synthesis of two new vicinal chemical bonds simultaneously, and diamination,² aminooxygenation,³ dioxygenation,⁴ cyanotrifluoromethylation,⁵ fluoroamination,⁶ phosphonofluorination,⁷ and oxysulfonylation⁸ have been elegantly demonstrated. Despite the overall efficiency and versatility of these transformations, significant limitations, such as being costly and using toxic metal catalysts, have led to the emergence of a metal-free approach for the difunctionalization of alkenes. Difunctionalization of unsaturated bonds via a radical pathway is an attractive alternative compared to the transition-metal-catalyzed difunctionalization of alkenes.⁹ Molecular-iodine catalyst, in combination with TBHP as an environmentally benign and inexpensive co-oxidant, has been increasingly explored to substitute of rare or toxic heavy metal oxidants in recent years.¹⁰ Simple iodine has a broad transformation ability of functional groups and is used widely in organic synthesis.¹¹ The advantages of iodine are operational simplicity, low cost, and less toxicity. However, research towards the development of iodine-catalyzed/mediated methods for the direct functionalization of C–H bonds is still in its infancy, and further exploration of this fascinating area is highly desirable in synthetic chemistry.¹²

The sulfonyl group is of great importance in medical chemistry, photovoltaic materials, nonlinear optics, and synthetic chemistry.¹³ Therefore, it is valuable to develop new strategies to introduce sulfonyl groups to designated molecular frameworks. Difunctionalization of alkenes to incorporate the sulfone group is also an attractive target to pursue. Recently, Lei and co-workers reported an elegant aerobic oxysulfonylation of alkenes using sulfinic acids as the sulfonyl group.^8a Similar results were achieved by the Itoh's group using sodium sulfinates as a sulfonyl group promoted by molecular iodine.^8b We noticed that β-iodo sulfone was eliminated as a possible intermediate in Itoh's work. β-Iodo sulfone is a versatile building block in organic synthesis and medicinal chemistry, as well as a valuable intermediate since the chemical structure can be further elaborated in the construction of a series of useful active molecules. However, a convenient and direct synthetic method for β-iodo sulfone is rare.^14,9b Sulfonyl hydrazides have been widely used as reductants and as a source of sulfonylation and arylation.¹⁵ With our continuing interest in radical oxidative cross-coupling reactions,¹⁶ we now disclose an iodine-mediated intermolecular iodosulfonylation reaction of alkenes using sulfonylhydrazides as the sulfonyl source.¹⁷

We started our investigations with styrene 1a and 4-methylbenzenesulfonohydrazide 2a as model substrates. Several parameters, such as iodine sources, solvents and temperature, were all analyzed to investigate the impact of the reaction outcome and the results are listed in Table 1. Initially, the reaction of 1a with 2a was performed in EtOAc at 80 °C utilizing molecular iodine and TBHP (70% in water) combinations, but we did not detect the iodosulfonylation product 3a. The unexpected oxysulfonylation product 4 was obtained in 79% yield instead (Table 1, entry 1). To our delight, the reaction gave a low yield of 3a when we decreased the temperature to 40 °C, although 4 was still the main product (Table 1, entry 2). The yield of 3a could be increased to 52% when the reaction was performed at room temperature, and 4 was not detected (Table 1, entry 3). Other iodine sources, such as NaI, KI and nBu₄NI, were tested but all of them completely did not work (Table 1, entries 4–6). A variety of solvents were subsequently tested (Table 1, entries 7–11). EtOH was clearly the best choice for this catalytic system and the yield of 3a was improved to 89% (Table 1, entry 9). Moreover, THF was also a good choice for this procedure and gave the desired 3a in 79% yield (Table 1, entry 10). Further screening revealed that the yield of 3a was decreased severely when TBHP was absent (Table 1, entries 12). Obviously, TBHP plays a pivotal role in the catalytic cycle, although the exact reason needs to be revealed.

Table 1 Screening of the reaction conditions^a

Entry	Iodine source	Oxidant	Solvent	Yield of 3a/4^b (%)
a Reaction conditions: 1a (0.5 mmol), 2a (0.55 mmol), iodine source (0.25 mmol) and TBHP (1.0 mmol) at 0–20 °C for 8 h.b Yield of isolated product.c Reaction performed at 80 °C.d Reaction performed at 40 °C.
1	I2	TBHP	EtOAc	0/79^c
2	I2	TBHP	EtOAc	23/57^d
3	I2	TBHP	EtOAc	52/0
4	NaI	TBHP	EtOAc	0/0
5	KI	TBHP	EtOAc	0/0
6	nBu4NI	TBHP	EtOAc	0/0
7	I2	TBHP	MeCN	20/0
8	I2	TBHP	DCE	0/0
9	I2	TBHP	EtOH	89/0
10	I2	TBHP	THF	79/0
11	I2	TBHP	H2O	0/0
12	I2		EtOH	42/0

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Using the optimized conditions, we next explored the scope and generality of the process. As shown in Table 2, various substitutents on the benzene ring of styrene were well tolerated such as electron-withdrawing groups (F, Cl, Br and CO₂Me) and electron-donating groups (Me and t-butyl). Some of these functional groups are useful for further synthetic diversification. Substitution of groups on the aromatic ring at different positions, such as 2-Cl, 3-Br, 4-F, 4-Cl and 4-Br, did not show obvious yield disparity during this iodine-mediated procedure, thus affording the corresponding iodosulfonylation products in good-to-high yields (72–92%). Notably, the sterically bulky 1,6-dichloro-2-vinylbenzene 1k also reacted smoothly, affording the corresponding β-iodo sulfone 3k in 92% yield. Moreover, 4-methylbenzenesulfonohydrazide, benzenesulfonohydrazide and 4-chlorobenzenesulfonohydrazide were suitable sulfonyl sources and provided the desired products 3l and 3m in high yields (89% and 88%). In addition, the reactivity of several allylbenzene derivatives (1n, 1o, 1p and 1q) was investigated, and the corresponding products 3n, 3o, 3p and 3q were obtained in good yields (88–95%).

Table 2 Scope of styrene and propylene^a,b

a Reaction conditions: 1 (0.5 mmol), 2 (0.55 mmol), molecular-iodine source (0.25 mmol) and TBHP (1.0 mmol) at 0–20 °C for 5–12 h.b Yield of isolated product.

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Iodosulfonylation of alkenes is an important chemical process because the corresponding products are useful for further transformation. Encouraged by these results, we further investigated the scope of other easily accessible chain and cyclic olefins. As shown in Table 3, pent-1-ene 5a was an effective substrate and gave the desired product 6a in 76% yield. Notably, substrates bearing sensitive substituents, such as 4-bromobut-1-ene 5b, 3-chloroprop-1-ene 5c, methyl acrylate 5d and prop-2-en-1-ol 5e, still provided the desired products in moderate to good yields (71–87%). 2,5-Dihydrofuran 5f was also subjected to the process, thus affording the corresponding 6f in 84% yield. Finally, this reaction could be scaled up to the gram level, which suggests that it can be potentially applied in the chemical industry (eqn (1)).

Table 3 Scope of chain and cyclic alkenes^a,b

a Reaction conditions: 5 (0.5 mmol), 2a (0.55 mmol), molecular-iodine source (0.25 mmol) and TBHP (1.0 mmol) at 0–20 °C for 8 h.b Yield of isolated product.

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Having established the scope of the method, a preliminary study on the reaction mechanism was performed. 2,2,6,6-Tetramethyl-1-piperidinyloxyl (TEMPO) and 2,4-di-tertbutyl-4-methylphenol (BHT), which are well-known radical scavengers, were introduced into the reaction mixture. The reaction progress was severely suppressed and only a trace amount of the desired product 3a can be detected even after longer times (eqn (2)). When the reaction was carried out in the dark, the system was chaotic and no main product was obtained. β-Iodo sulfone 3a, which was eliminated as a possible intermediate in Itoh's work, can convert to β-hydroxy sulfone and β-oxo-sulfone in 27% and 31% yields at 60 °C in our system, respectively (eqn (3)). At present, we assume a radical iodosulfonylation mechanism, although nucleophilic attack on an iodonium intermediate can not be excluded (Scheme 1).

Scheme 1 Proposed reaction mechanism.

In conclusion, we reported an iodosulfonylation reaction between alkenes and sulfonyl hydrazides using molecular iodine as the iodine source and sulfonyl hydrazides as the sulfonyl source. This reaction provides an important method for preparing β-iodo sulfones, which are versatile building blocks and valuable intermediates in organic synthesis and medicinal chemistry. The features of mild conditions, wide substrate scope and easily scalable operation make this reaction attractive in industrial production. Further mechanistic studies are underway and will be demonstrated in due course.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra07065a

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