I₂-Catalyzed benzylation of NH-sulfoximines with diarylmethanes and alkylarenes

Abstract

A practical transition metal-free approach for the selective benzylation of NH-sulfoximines has been disclosed by using simple elemental iodine as the catalyst and tert-butyl hydroperoxide (TBHP) as the terminal oxidant. Comparing with known methods for the construction of N-benzylated sulfoximines, our protocol shows broad substrate scope with respect to both diarylmethanes and alkylarenes, and can be conducted in air with good functional group tolerance.

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The wide applications of sulfoximines in the fields of pharmaceuticals, agrochemicals, drug discovery and organic synthesis (as chiral substrates, catalysts, ligands and directing groups for C–H bond activation, etc.) have stimulated the development of green and novel methods for their selective construction.¹ In all such areas, N-alkylated derivatives have received considerable attention as it has been identified that the nitrogen substituent often leads to significantly improved bioactivities.² To this end, the development of green and convenient methods for the synthesis of the sulfoximine scaffold with versatile alkyl substituents on the nitrogen atom is of current interest.³ While typical methods rely on Michael addition⁴ and nucleophilic substitution,⁵ Eschweiler–Clarke-type methylation,⁶ Petasis reaction,⁷ some elegant radical-involved approaches which include cross-dehydrogenative coupling (CDC),⁸ transition metal-catalyzed alkylation with alkyl (pseudo) halides or peroxides,⁹ hydroamination or difunctionalization of alkenes,¹⁰ and others,¹¹ have also been disclosed. Among them, the sulfoximines N–H/C–H CDC strategy¹² with benzylic Csp³–H bonds has received great attention for the synthesis of versatile N-benzyl sulfoximines since 2014⁸ because of the use of simple starting materials in an atom- and step-economical way. For example, Bolm and co-workers pioneered the strategy via Fe catalysis, although only diarylmethanes are suitable (Fig. 1A).^8a Inspired by this and by taking advantage of electrosynthesis, our group^8c and Wang and Li^8e also disclosed the electrochemically driven CDC coupling, although no external metal catalyst is necessary, the scope of alkanes was limited to diarylmethanes and alkylarenes, respectively. Mo and co-workers reported the visible light-induced CDC with toluene (Fig. 1B).^8d In these excellent examples, (expensive) metal catalysts or photosensitizer with narrow scope or electrochemical reaction equipment was often necessary. Therefore, the development of a suitable and cheap catalytic system which can make up the shortcomings of the above strategies is of great importance. Herein, continuing with our previous work,^8c we are delighted to note that the use of simple elemental iodine as the catalyst¹³ could promote the efficient CDC reactions of NH-sulfoximines with diarylmethanes and alkylarenes for the first time by using cheap tert-butyl hydroperoxide (TBHP) as the terminal oxidant (Fig. 1C). Our newly developed practical strategy does not need any transition metal and can be conducted in air, with good functional group tolerance as well.

Fig. 1 Methods for benzylation via CDC strategy.

To establish the optimal conditions, simple 1a and diphenylmethane 2a have been chosen as the model substrates. After extensive screening of a variety of reaction parameters which include the iodine source, base and the amounts of reactants (Table 1), we were delighted to find out that the desired N-alkylated sulfoximines 3a could be isolated in 87% yield with a catalytic amount of I₂ (0.2 equiv.), Na₂CO₃ (0.5 equiv.) and tert-butyl hydroperoxide (TBHP, 1 equiv.) under air (entry 1). However, when other iodine sources, such as KI, NaI or n-Bu₄NI, were used as the catalyst, the yield of product 3a was decreased (entry 2). The oxidant TBHP is essential as the use of other common oxidants such as (^tBuO)₂, K₂S₂O₈ or H₂O₂ delivered no product 3a at all (entry 3). Na₂CO₃ was the optimal additive for this transformation compared to NaOH, K₂CO₃, NaHCO₃ and CH₃CO₂Na (entry 4). Changing the amount of I₂, Na₂CO₃, TBHP and 2a only gave inferior yields (entries 5–8). The yield of 3a was dropped obviously by changing the reaction temperature (entry 9). Finally, both I₂ and TBHP are essential as the absence of either of them shut down the reactivity (entry 10). Furthermore, our model reaction can be scaled up to 8 mmol, and the desired 3a could be isolated with 78% yield (2.0 gram), demonstrating the practicability of the protocol.

Table 1 Optimization of conditions^a

Entry	Variation from standard conditions	Yield^b (%)
a Reaction conditions: 1a (0.5 mmol), 2a (10 mmol, 20 equiv.), I2 (0.1 mmol, 0.2 equiv.), Na2CO3 (0.25 mmol, 0.5 equiv.), TBHP (1 equiv.), 60 °C, under air. b Isolated yield.
1	None	87
2	KI, NaI or n-Bu4NI instead of I2	31, 55, 32
3	(^tBuO)2, K2S2O8 or H2O2 instead of TBHP	0, 0, 0
4	NaOH, K2CO3, NaHCO3 or CH3CO2Na instead of Na2CO3	34, 46, 29, 35
5	0.3 or 0.5 equiv. instead of 0.2 equiv. I2	79, 70
6	1.5 or 0.5 equiv. instead of 1 equiv. TBHP	42, 53
7	0 or 0.4 equiv. instead of 0.5 equiv. Na2CO3	32, 72
8	15 or 25 equiv. instead of 20 equiv. 2a	58, 41
9	50 °C or 70 °C instead of 60 °C	42, 50
10	No I2 or TBHP	0, 0
11	8 mmol of 1a scale	78%

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Under the optimized conditions, the scope with respect to various sulfoximines 1 was investigated at first (Table 2). To our delight, the introduction of either electron-donating methyl (1b), methoxy (1c) or electron-withdrawing halogen (1d–1f), nitro (1g), trifluoromethoxy (1h), cyano (1i) and carbonyl (1j) groups at the para position of the phenyl ring of 1 has marginal effect on the yield, and products 3a–3j could be facilely isolated in 73–90% yield. Then, substrates 1 with electron-donating or electron-withdrawing groups at meta- or ortho-positions were also checked, affording the products 3k–3o with good yields too (82–88%). In addition, the reactions between diaryl and heterocyclic sulfoximines 1p–1t and 2a gave 3p–3t in 64–91% yield. More interestingly, besides diarylmethanes, sulfoximines 1u–1v with one phenyl and one alkyl group also proceeded well, delivering products 3u–3v with 82% yield in both cases. Also, substituted diarylmethanes 2b and 2c were applied to this reaction, giving the corresponding products 3w and 3x in 70% and 79% yield.

Table 2 Scope with respect to sulfoximines and diarylmethanes^a

a For details, please see the ESI.†

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To our delight, compared with previous works that are only suitable for a narrow scope of diarylmethanes or alkylarenes,⁸ our current catalytic system is compatible with various alkylarenes. As shown in Table 3, ethyl-, propyl-, ester- or long carbon chain-substituted alkylarenes 4a–4d produced 5a–5d in 50–70% yield in our hands. No desired product was detected when using ethylbenzene as the substrate.

Table 3 Scope with respect to alkylarenes^a

a For details, please see the ESI.†

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To study the reaction mechanism, a series of control experiments have been conducted (Scheme 1). (1) First of all, the reaction was completely suppressed when the radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) was added under the standard conditions (Scheme 1A). (2) Furthermore, it was noticed that the dimer 6 could be formed in the presence of TBHP and I₂ (Scheme 1B), and such species could also be detected in the reaction mixture by GC-MS analysis. These indicate the diphenyl methyl radical might serve as the key intermediate for the transformation. Furthermore, although Patel and Rajbongshi¹⁴ have disclosed that N-iodosulfoximine could be obtained by mixing I₂, TBHP with 1a, an attempt to detect such intermediate failed in our system, ruling out the possibility of the reaction working through such a species. (3) To test whether the reaction might work through (iodomethylene)dibenzene 7, it has been mixed with 1a and Na₂CO₃, and no 3a was detected (Scheme 1C).

Scheme 1 Control experiments.

According to the above mechanistic studies and related literature,^8a,c,d a plausible mechanism has been proposed (with 1a and 2a as the model substrates). First of all, in the presence of Na₂CO₃, the I⁻/I₂ redox cycle promotes TBHP to deliver ^tBuO˙ and ^tBuOO˙ (Fig. 2).¹⁵ After this, either ^tBuO˙ or ^tBuOO˙ could abstract hydrogen from 2a, giving rise to diphenyl methyl radical I. Intermediate I could be further oxidized by TBHP to deliver benzylic cation II, which reacts with the anion formed by deprotonation of 1a by base, giving rise to the desired 3a.

Fig. 2 Plausible pathways.

Conclusions

In summary, we have developed an efficient method to generate N-alkylated sulfoximines by coupling diarylmethanes or alkylarenes with sulfoximines under transition metal-free and mild conditions. This reaction shows broad tolerance for both sulfoximine and alkylarene substrates. The development of other novel methods for the selective construction of N-substituted sulfoximines is ongoing in our laboratories.

Data availability

The data underlying this study are available in the published article and its supplementary information.†

Conflicts of interest

The authors declare no competing financial interests.

Acknowledgements

Financial support from NSFC (22102012, 22202021, 22272011, 22201062, and 22372015) is gratefully acknowledged. This project is also funded by China Postdoctoral Science Foundation (2024T170222), Postdoctoral Research Grant in Henan Province (HN2024001) and the Opening Funding of Hubei Key Laboratory of Natural Products Research and Development, China Three Gorges University (2022NPRD02), and this support is gratefully acknowledged. Prof. Xianqiang Kong thanks sponsorship by the Qinglan Project of Jiangsu Province of China, and the Changzhou Science and TechnologyPlan Applied Basic Research Project (CJ20235076).

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, methods; NMR, and MS data including ¹H, ¹³C NMR spectra. See DOI: https://doi.org/10.1039/d4ob01709a

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