Generation of (2-oxoindolin-3-yl)methanesulfonohydrazides via a photo-induced reaction of N-(2-iodoaryl)acrylamide, DABSO, and hydrazine

Abstract

A photo-induced catalyst-free three-component reaction of N-(2-iodoaryl)acrylamide, sulfur dioxide, and hydrazine is reported. Under ultraviolet irradiation, diverse (2-oxoindolin-3-yl)methanesulfonohydrazides are generated in moderate to good yields. During the process, the sulfonyl group can be easily incorporated via insertion of sulfur dioxide in the absence of any metals or photo-redox catalysts under mild conditions. A plausible mechanism is proposed, which involves 5-exo radical cyclization and subsequent insertion of sulfur dioxide.

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Introduction

In the past decade, photo-induced organic transformations using photocatalysis have rapidly developed.^1,2 In most cases, reactive radical species as intermediates are involved during the process. The presence of photocatalysis usually assists electron transfer to promote the completion of the reaction. Recently, interesting results under catalyst-free conditions enabled by photoenergy were reported.³ Under ultraviolet irradiation, aryl/alkyl halides would afford the corresponding aryl/alkyl radicals in the absence of photocatalysis during the reaction process. For example, Li and co-workers described a metal-free coupling of aryl alkynes with alkyl iodides in water under ultraviolet irradiation.^3a They also developed a photo-induced halogen exchange in aryl or vinyl halides under metal-free conditions (Scheme 1).^3b It was found that these reactions proceeded through alkyl or aryl radicals, generated from the corresponding alkyl/aryl halides enabled by photoenergy. Thus, a new route to the coupling of aryl/alkyl halides would be expected, since these reactions promoted by ultraviolet irradiation could be performed under metal-free conditions. This approach is promising, especially in the drug discovery process. Consequently, it will avoid contamination of metal salts in the final products.

Scheme 1 A proposed three-component reaction of N-(2-bromoaryl)acrylamide 1, sulfur dioxide, and hydrazine 2.

Recently, continuous attention has been given to the fixation of sulfur dioxide into small molecules.^4–7 A sulfonyl group can be easily introduced by using sulfur dioxide as the starting material. The importance of the sulfonyl group is well recognized, due to its wide presence in pharmaceutical and agrochemical molecules.^8,9 So far, transition-metal-catalyzed or metal-free aminosulfonylation of aryl electrophiles, sulfur dioxide, and hydrazines has been developed.⁴ For instance, Willis and co-workers described a palladium-catalyzed aminosulfonylation of aryl iodides, sulfur dioxide, and hydrazines.^4a During the transformation, an innoxious and bench-stable DABCO·(SO₂)₂ (DABSO) was used as the SO₂ source.⁷ In the meantime, we reported an efficient route to aryl N-aminosulfonamides through a coupling of aryldiazonium tetrafluoroborates, sulfur dioxide, and hydrazines under metal-free conditions.^4j It was demonstrated that this transformation proceeded through a radical process. Additionally, the strategy via insertion of sulfur dioxide has been applied effectively in the generation of sulfones.^5,6

As part of a program in our laboratory for the construction of nitrogen-containing heterocycles in the studies of chemical genetics,¹⁰ we are interested in methodology development for the synthesis of sulfonyl-substituted 2-oxoindoline derivatives. As a privileged scaffold, the 2-oxoindoline core can be found in many natural products and pharmaceuticals with remarkable biological activities.¹¹ It would be attractive if the fixation of sulfur dioxide could be incorporated in the generation of sulfonyl-substituted 2-oxoindoline compounds. As mentioned above, aminosulfonylation of aryldiazonium tetrafluoroborates, sulfur dioxide, and hydrazines proceeded through a radical process.^4j We also discovered that aryl halides could be used in the insertion of sulfur dioxide with hydrazines enabled by photoenergy.⁴ⁿ Prompted by these results and the advancement of metal-free coupling of aryl/alkyl halides under ultraviolet irradiation,³ we envisioned that N-(2-haloaryl)acrylamide 1 could be utilized as the starting material in the reaction of sulfur dioxide and hydrazine for the synthesis of sulfonyl-substituted 2-oxoindolines (Scheme 1). During the transformation, tandem 5-exo radical cyclization and insertion of sulfur dioxide were designed for the final outcome although a competitive pathway involving the direct aminosulfonylation of aryl halides seemed to be inevitable. We reasoned that under ultraviolet irradiation, the C–X bond of N-(2-haloaryl)acrylamide 1 would be broken to produce radical A. Consequently, an intramolecular 5-exo cyclization would happen to afford an alkyl radical B, which was believed to be the key intermediate during the tandem process. We expected that the subsequent insertion of sulfur dioxide via the radical process would provide the desired (2-oxoindolin-3-yl)methanesulfonohydrazide 3. To verify the feasibility of this hypothesis as shown in Scheme 1, we therefore started to explore the three-component reaction of N-(2-haloaryl)acrylamide 1, sulfur dioxide, and hydrazine 2.

Results and discussion

At the outset, the reaction of N-(2-iodophenyl)-N-methylmethacrylamide 1a, DABCO·(SO₂)₂, and morpholin-4-amine 2a was selected as the model for method development (Table 1). The reaction was performed at 25 °C under ultraviolet irradiation by using a standard photo-reactor (see the ESI†). Initially, the reaction was performed in DMF (Table 1, entry 1). However, no reaction occurred under the conditions. We postulated that the solubility of DABSO in the solvent might retard the transformation. Thus, TBAI (tetrabutylammonium iodide) was added to make DABSO more soluble, and the reaction showed a trace amount of the product (Table 1, entry 2). A similar result was observed when the solvent was changed to 1,4-dioxane (Table 1, entry 3). No reaction took place when dichloromethane or 1,2-dichloroethane was employed as the solvent (Table 1, entries 4 and 5). To our delight, the reaction worked efficiently in acetonitrile, leading to the corresponding product 3a in 71% yield (Table 1, entry 6). A controlled experiment showed that the presence of TBAI was essential in the reaction, since the corresponding product 3a could not be isolated without the addition of TBAI (Table 1, entry 7). To our surprise, the reaction failed to provide the desired product 3a when TBAI was replaced by TBAB or TBAC (Table 1, entries 8 and 9). The yield was lower when the amount of TBAI was decreased (Table 1, entry 10).

Table 1 Initial studies of the photo-induced catalyst-free reaction of N-(2-iodophenyl)-N-methylmethacrylamide 1a, DABCO·(SO₂)₂ and morpholin-4-amine 2a ^a

Entry	Solvent	Additive	Yield^b (%)
a Reaction conditions: N-(2-iodophenyl)-N-methylmethacrylamide 1a (0.2 mmol), DABCO·(SO2)2 (0.16 mmol), morpholin-4-amine 2a (0.3 mmol), additive (0.3 mmol), solvent (4.0 mL), rt, 10 h. b Isolated yield based on N-(2-iodophenyl)-N-methylmethacrylamide 1a. c The reaction was performed in the presence of TBAI (1.0 equiv.).
1	DMF	TBAI	nr
2	DMF	TBAI	Trace
3	1,4-Dioxane	TBAI	Trace
4	CH2Cl2	TBAI	nr
5	ClCH2CH2Cl	TBAI	nr
6	MeCN	TBAI	71
7	MeCN	—	Trace
8	MeCN	TBAB	Trace
9	MeCN	TBAC	Trace
10^c	MeCN	TBAI	68

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We next explored the scope of the photo-induced catalyst-free three-component reaction of N-(2-iodoaryl)acrylamides 1, sulfur dioxide, and hydrazines 2 under the above optimized reaction conditions. The result is shown in Table 2. Various N-(2-iodoaryl)acrylamides 1 reacted with DABCO·(SO₂)₂ and hydrazines 2 efficiently, leading to the corresponding (2-oxoindolin-3-yl)methanesulfonohydrazides 3 in moderate to good yields. At the beginning, a range of N-(2-iodoaryl)acrylamides 1 were examined in the reaction of sulfur dioxide and morpholin-4-amine 2a. It seemed that the reactions of N-(2-iodoaryl)acrylamides 1 with electron-donating groups on the aromatic ring gave rise to better results. For instance, methyl-substituted (2-oxoindolin-3-yl)methanesulfonohydrazide 3b was obtained in 75% yield under the standard conditions, while nitro-substituted (2-oxoindolin-3-yl)methanesulfonohydrazide 3d was produced in 40% yield. The structure of compound 3b was identified via X-ray crystallography analysis (Fig. 1, also see the ESI†). Other hydrazines were examined subsequently, which were proven to be compatible under the standard conditions. Aryl bromide was applicable in the reaction as well. For instance, compound 3q was obtained in 39% yield when the corresponding N-(2-bromo-4-(trifluoromethoxy)phenyl)-N-methylmethacrylamide was employed under the standard conditions.

Fig. 1 ORTEP illustration of compound 3b (30% probability ellipsoids).

Table 2 Scope investigation of the photo-induced catalyst-free three-component reaction of N-(2-iodoaryl)acrylamide 1, sulfur dioxide, and hydrazine 2 ^a

a Isolated yield based on 2-alkynylbenzenesulfonamide 1.

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We postulated that the reaction proceeded through a radical process. Thus, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added to the reaction of N-(2-iodophenyl)-N-methylmethacrylamide 1a, DABCO·(SO₂)₂, and morpholin-4-amine 2a. As expected, the desired product 3a was not detected. According to this experimental observation and our previous reports,^4j,n we proposed a plausible mechanism as shown in Scheme 2. We reasoned that aryl radical A and an iodo radical would be afforded when N-(2-iodoaryl)acrylamide 1 was treated under ultraviolet irradiation. Then intramolecular 5-exo radical cyclization would occur to provide alkyl radical B. In the meantime, an exchange of hydrazine 2 with DABCO·(SO₂)₂ would happen to produce intermediate C, which would react with alkyl radical B to generate intermediate D. The subsequent electron transfer would lead to the formation of sulfone radical E and hydrazine 2. The presence of the iodo radical would promote the generation of radical G, which would be trapped by sulfone radical E to afford the final product 3.

Scheme 2 A proposed mechanism for the photo-induced three-component reaction of N-(2-iodoaryl)acrylamide 1, sulfur dioxide, and hydrazine 2.

Conclusions

In conclusion, we have described a catalyst-free photo-induced three-component reaction of N-(2-iodoaryl)acrylamide, sulfur dioxide, and hydrazine. Under ultraviolet irradiation, diverse (2-oxoindolin-3-yl)methanesulfonohydrazides are generated in moderate to good yields. During the process, the sulfonyl group can be easily incorporated via insertion of sulfur dioxide in the absence of any metals or photo-redox catalysts under mild conditions. A plausible mechanism is proposed, which involves 5-exo radical cyclization and the subsequent insertion of sulfur dioxide. The reaction scope with broad functional group tolerance is demonstrated. We believe that the photo-induced catalyst-free conditions would broaden the reaction types of insertion of sulfur dioxide, thus providing a new route for the fixation of sulfur dioxide.

Acknowledgements

Financial support from the National Natural Science Foundation of China (No. 21372046 and 21532001) is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure and related data. CCDC 1443052. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00163g

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