Oxidative C–S bond cleavage reaction of DMSO for C–N and C–C bond formation: new Mannich-type reaction for β-amino ketones

Abstract

A novel oxidative C–S bond cleavage reaction of DMSO for N-methylation and subsequent C–C bond formation is described. A series of aryl ketones as well as acetone derivatives could be selectively converted into the corresponding β-amino ketones. Mechanistic studies suggested that N-methylation between imine and DMSO was involved in the reaction.

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β-Amino carbonyl compounds are important biological molecules as well as useful synthetic intermediates for various pharmaceuticals and natural products.¹ The most classic method for the preparation of β-amino carbonyl compounds is the three-component Mannich reaction with aldehydes, amines, and C–H acidic carbonyl compounds, which has been employed numerous times as a key step in natural product synthesis as well as in medicinal chemistry (eqn (1)).² In recent years, oxidative Mannich reactions, originating from readily available tertiary amines,³ have emerged as a powerful method for preparation of β-amino carbonyl compounds with the aid of a metal catalyst and oxidant (eqn (2)).⁴ However, some substrate limitations and side reactions limit its wide application. Alternative methods for preparation of β-amino carbonyl compounds suffer from multiple steps such as the Michael addition reaction between a ketene and an amine component, or the substitution reaction of β-halo/hydroxyl ketones with nucleophilic nitrogen sources.⁵

In past decades, the common polar solvents DMF and DMSO were widely used as multipurpose building blocks and have played an important role in organic synthesis.⁶ Recently, the Zhang group reported the first N-methylation reaction between N–H bonds of amidines and methyl C(sp³)–H bonds of DMSO and DMF.⁷ Subsequently, the Xiao group also reported the N-methylation of amines and nitro compounds with DMSO.⁸ It is well known that methylation of amines is a general transformation in organic synthesis⁹ and many methods for preparation of methylated amines have been developed.^10,11 However, N-methylation using DMF and DMSO as a methyl source is rare and to the best of our knowledge, using the common solvents DMF and DMSO in the Mannich reaction as a methyl source has never been reported. As part of our continuing interest in the construction of C–N bonds directly from C–H bonds,¹² we proposed that the indispensable formaldehyde analogues in Mannich reactions may be replaced with the cheap and low-toxicity solvents DMF/DMSO and give the key enamine or methyl amine intermediate through N-methylation.

Based on this assumption, our initial investigations focused on the effect of various solvents with selectfluor as an oxidant and Cu(OTf)₂ as the catalyst, which was an efficient combination for N-methylation reactions in previous reports.⁷ To our delight, DMF, N,N-dimethylacetamide (DMA), DMSO and N-methyl-2-pyrrolidone (NMP) were all effective amine methylation sources and gave the desired product 2a in moderate yields. However, no reaction occurred with N,N-diethylacetamide (DEA) as the corresponding methyl source (Scheme 1). After detailed screening it was revealed that RuCl₃ was the best catalyst and DMSO was the suitable choice as methyl source and solvent. In the presence of the additive Na₂CO₃, the yield of 2a could be increased to 91% (see ESI†). It is highlighted that this new type of Mannich reaction may be a breakthrough compared to the conventional Mannich reaction which uses toxic formaldehyde analogues as an indispensable methyl source.

Scheme 1 Diverse methyl sources in the Mannich reaction.

With the optimal conditions in hand, we continued to evaluate the substrate scope of this method for the synthesis of various β-amino ketones. Different aryl ketones were reacted with saccharin and the results are summarized in Table 1. Functional group compatibility was quite broad as demonstrated with both electron-rich Me, MeO, cyclohexyl, Ph and -deficient F, Cl, Br, CN, CF₃, NO₂ and ester groups being obtained in good to excellent yields (2a–2q). The results of this work are significant considering that the ester unit may be used as a readily manageable protecting group in organic synthesis, as well as F, Cl, Br and CN which can be converted into various functional groups under ambient conditions. Similarly, smooth coupling was observed for aromatic ketones bearing substituent groups at different positions such as 2-Cl, 3-Cl, 4-Cl and 2-Me, 3-Me, 4-Me, and no previous yield disparity was observed. (Table 1, 2b–2g). The multisubstituted substrates 1r, 1s and 1t can also provide the desired products 2r, 2s and 2t in high yields (91%, 81% and 96%). Furthermore, the fused bicyclic acetylnaphthalenes 1u, 1v and the heterocyclic ketone 1w were all effective substrates under these conditions. The yields of the corresponding products 2u, 2v and 2w were up to 91%, 87% and 81%, respectively.

Table 1 Scope of the Mannich reaction^a,b

a Reaction conditions: 1 (0.5 mmol), saccharin (1.0 mmol), RuCl₃ (5 mol%), 1,10-phen (0.025 mmol), selectfluor (1.0 mmol), Na₂CO₃ (1.0 mmol) and DMSO (2 mL) at 120 °C for 3–10 h.b Yield of the isolated products.

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The substrate scope of this reaction can be extended to propiophenone derivatives such as propiophenone (4a), 1-(4-chlorophenyl)propan-1-one (4b) and 1-(p-tolyl)propan-1-one (4c). The desired products could be obtained in 96%, 93% and 91% yields. It is highlighted that the potential of this reaction for catalytic asymmetric Mannich-type reactions might promote more research interest in this area.¹³ In addition, the present catalytic system was amenable to the reaction of the alkyl ketone compounds 3d, 3e and 3f, and gave the corresponding products 4d, 4e and 4f in high yields (97%, 95, and 88%), respectively. To our delight, this reaction was also applicable to other acidic C–H compounds such as nitromethane and nitroethane, and the desired products were obtained in 84% and 79% yields. It is noteworthy that this new reaction has not only expanded the range of methyl sources for the Mannich reaction, but has also enriched the content of the Mannich synthetic methodology (Table 2).

Table 2 Scope of the Mannich reaction^a,b

a Reaction conditions: 3 (0.5 mmol), saccharin (1.0 mmol), RuCl₃ (5 mol%), 1,10-phen (0.025 mmol), selectfluor (1.0 mmol), Na₂CO₃ (1.0 mmol) and DMSO (2 mL) at 120 °C for 3 h.b Yield of the isolated products.

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The mechanism of this reaction was then studied. First, the radical inhibitor BHT (2,6-di-tert-butyl-4-methylphenol) was introduced into the reaction mixture, the reaction progress was completely suppressed and an unexpected methyl imidated product H derived from BHT was isolated in 73% yield [eqn (4)]. When TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl) was added, the reaction was suppressed severely and the yield of 2d decreased from 92% to 18%. These results suggested that a radical intermediate may be involved during the transformation. The intermolecular kinetic isotope effect (KIE, K_H/K_D) was then utilised, to gain more insight into the mechanism. Thus, equimolar amounts of DMSO and DMSO-d₆ were added as the solvent, and after 0.5 h, one proton of the methylene adjacent to the nitrogen atom was replaced by a deuterium atom [eqn (5)]. After a longer reaction time of 3 h, approximately 1 : 1 protons of both methylene groups were replaced by deuterium atoms [eqn (6)]. These results clearly show that the new methylene group adjacent to the nitrogen arises from DMSO and that the keto-enol tautomerism of ketone is involved during this reaction. To get further evidence about the mechanism, the C(sp³)–H imidate product 2-((methylsulfonyl)-methyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide C was isolated from the reaction of DMSO with saccharin [eqn (7)]. Its structure was confirmed by ¹H and ¹³C NMR spectra (see ESI†). A stoichiometric reaction between 1-(p-tolyl)ethanone 1d and the possible intermediate C was also performed. To our delight, after 2 h, we obtained the desired product 2d in 94% yield [eqn (8)]. This result signified that the C–N bond formation reaction between sulfonamide and the methyl C(sp³)–H bonds of DMSO was involved and that compound C is a temporary intermediate in this reaction.

Based on the above experimental results, a possible mechanism is proposed for the present catalytic cycle (Scheme 2): The first step is likely to be an oxidative amination process by RuCl₃ and F⁺ (selectfluor) combination, thus affording the intermediate C.¹⁴ Subsequently, C–S bond cleavage in the presence of H⁺ delivers the enamine intermediate II.¹⁵ Finally, carbon–carbon bond formation between II and the ketone tautomer delivers the desired products.

Scheme 2 Plausible mechanism of this reaction.

In summary, we have succeeded in developing a new-type Mannich reaction between the ketone methyl C(sp³)–H bonds and N–H bond of saccharin with the addition of DMSO as a one carbon bridging group for the first time. A detailed mechanistic study revealed that N-methylation between saccharin and DMSO was involved during this procedure, which is an important transformation in organic synthesis as well as in biological processes. Considering its excellent reaction efficiency and wide substrate scope, the strategy would be highly desirable for convenient synthesis of β-amino ketone derivatives, which widely exist in natural products. Further application of the reaction is currently underway in our lab.

Acknowledgements

Financial support of this research from the NSFC (no. U1304825, 201302004) are greatly acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra14249g

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