Ruthenium catalyzed α-methylation of sulfones with methanol as a sustainable C1 source

Abstract

Methylation of sulfones, which have an α-CH bond, can be easily achieved via a one-step, Ru(II) catalyzed redox neutral reaction using methanol as a sustainable C1 building block. The reaction requires a stoichiometric amount of base and generates only water as a byproduct. A series of value-added methylated sulfones with various functional groups are produced under the reaction conditions from readily available substrates. Mechanism studies shows that a sulfone carbanion addition to an in situ generated aldehyde formed via catalytic dehydrogenation and subsequent catalyst mediated reduction of the alkene by hydrogen may be involved.

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Introduction

The methyl group, as a very important chemical motif, is widely utilized in the discovery and development of new drugs, which can significantly increase the binding affinity,¹ improve the binding selectivity² and half-life.³ Njarđarson's poster entitled “Top 200 Brand Name Drugs by Prescription in 2016” reveals that over 77% of small-molecule drugs have at least one methyl group, emphasizing the great importance of this scaffold.⁴ Typically, α-methylated sulfones are often encountered in various biologically active molecules, pharmaceuticals, and natural products, as shown in Fig. 1.⁵ For example, ceritinib⁶ is a tyrosine kinase inhibitor for cure of non-small-cell lung cancer, while dorzolamide⁷ is used to treat elevated intraocular pressure. In addition, benzothiophenes A⁸ can be employed as insecticide. Furthermore, compound B⁹ exhibits highly potent inhibition of inflammatory cytokines production and compound C¹⁰ was regarded as a γ-secretase inhibitor.

Fig. 1 α-Methylated sulfones in various biologically active molecules, pharmaceuticals, and natural products.

Due to its widespread occurrence in nature as well as their remarkable biological activities, various synthetic methods have been developed for the construction of methyl-containing compounds via direct α-methylation. Conventionally, toxic and/or hazardous agents such as iodomethane, diazomethane, dimethyl sulfate, and dimethyl carbonate have been used for the formation of methylated products.¹¹ In order to develop more sustainable strategies, the borrowing hydrogen (BH) strategy or hydrogen autotransfer processes using primary alcohol as green and sustainable starting materials has emerged as a powerful tool for alkylation over the past decades.¹² In comparison with benzyl and long-chain n-alkyl alcohols, it is challenging to use methanol as the alkylating agent in BH processes, due partly to the increased energy of dehydrogenation to form the required transient reactive formaldehyde intermediate.¹³ Recently, exciting results have been achieved for the direct α-methylation of ketones through the borrowing hydrogen methodology employing methanol as a methyl source. Contributions from the groups of Donohoe,¹⁴ Obora,¹⁵ Andersson,¹⁶ Beller,¹⁷ Cai,¹⁸ Shimizu,¹⁹ Morrill,²⁰ and others,²¹ have illustrated that varieties of transition metals (Ru, Ir, Pd, Mn,…) were able to intrigue such methylation reactions, leading to versatile α-methylated ketones (Scheme 1A). In addition, the methylation of esters has also been developed by Obora,²² then Sortais²³ using iridium or manganese-based catalysts, respectively. In the meanwhile, nitriles were proved to be successful substrates in the borrowing hydrogen process to produce α-methyl arylacetonitriles (Scheme 1B).²⁴ However, the methylation of sulfones via BH strategy remains an unsolved task, owing to the high reactivity of the Julia-like intermediate.²⁵ Under previous reported conditions, the cyclopropanation²⁶ (path a) or sulfone elimination to form the olefin²⁷ (path b) was preferred to occur as a major reaction, whereas the direct reduction of Julia-like intermediate (path c) and the catalytic olefin hydrogenation of sulfonylated olefin (path d) to generate the methylated sulfones was suppressed. Very recently, Khaskin group achieved a α-C–H alkylation of sulfones and sulfonamides with long-chain n-alkyl alcohols via a commercial available MACHO ruthenium catalyst.²⁸ Nevertheless, methanol was not compatible in Khashkin's reaction. Encouraged by our previous work,²⁹ we reported here an efficient and straightforward methylation of sulfones using methanol as a sustainable C1 building block via a simple ruthenium catalysis (Scheme 1C).

Scheme 1 Transition metal catalyzed borrowing hydrogen (BH) reactions using MeOH as a C1 source.

Results and discussion

Initially, the methylation of (benzylsulfonyl)benzene (1a) with methanol was selected as a model reaction to optimize the reaction conditions. As shown in Table 1, the reaction of 1a (0.5 mmol) with methanol (1.5 mL) was performed in the presence of [Rh(cod)Cl]₂ (0.05 mmol, 5 mol%) and ^tBuOK (0.5 mmol, 100 mol%) at 120 °C for 24 h, giving the α-methylated product 2a in 25% isolated yield albeit in low efficiency (Table 1, entry 1). In order to improve the reaction yield, Ir and Ru complexes were used as catalysts, and the yield of the targeting product 2a was significantly increased to 88% (entries 2 and 3). The phosphine ligand played a significant role to enhance catalytic activity, switching dppe to other biphosphine ligand like dppb, dppp and dppf lead to a lower yield (entries 4–6). It was noteworthy that the enantioselective methylation was not observed when using chiral biphosphines (entries 7–9). Next, a set of bases were investigated, and KOH was most suitable for this transformation to offer the best yield of 91% (entries 11–13). In addition, a dramatically decreasement in yield was obtained when lowing the reaction temperature or reducing the amount of KOH (entries 14 and 15). Delightfully, no obvious influence was found when the reaction performed with 2.5 mol% of [Ru(cod)Cl₂] (entry 16). Further decreasing the catalyst loading to 1 mol% delivered a relatively lower yield (entry 17). In contrast, 13% yield of ((1-phenylethyl)sulfonyl)benzene (2a) was formed when a blank experiment was performed without the use of ligand, while the reaction failed to yield 2a in the absence of Ru catalyst (entries 18 and 19).

Table 1 Ru-Catalyzed α-methylated sulfones (1a) with MeOH^a

Entry	Catalyst	Ligand	Base	Yield^b (%)
a Reaction conditions: 1a (0.5 mmol), catalyst (5.0 mol%), ligand (7.0 mol%), base (0.5 mmol), MeOH (2.0 mL), oil bath 120 °C, 24 h. b All yields are isolated yields. c 100 °C. d KOH (0.25 mmol). e 2.5 mol% of [Ru(cod)Cl2] and 3.5 mol% of dppe were used. f 1 mol% of [Ru(cod)Cl2] and 1.4 mol% of dppe were used.
1	[Rh(cod)Cl]2	dppe	^tBuOK	25
2	[Ir(cod)Cl]2	dppe	^tBuOK	80
3	[Ru(cod)Cl2]	dppe	^tBuOK	88
4	[Ru(cod)Cl2]	dppb	^tBuOK	71
5	[Ru(cod)Cl2]	dppp	^tBuOK	80
6	[Ru(cod)Cl2]	dppf	^tBuOK	41
7	[Ru(cod)Cl2]	(S)-BINAP	^tBuOK	50
8	[Ru(cod)Cl2]	(S,S)-CHIRAPHOS	^tBuOK	20
9	[Ru(cod)Cl2]	(R,R)-NORPHOS	^tBuOK	52
10	[Ru(cod)Cl2]	dppe	^tBuOLi	43
11	[Ru(cod)Cl2]	dppe	K2CO3	54
12	[Ru(cod)Cl2]	dppe	CS2CO3	70
13	[Ru(cod)Cl2]	dppe	KOH	91
14^c	[Ru(cod)Cl2]	dppe	KOH	20
15^d	[Ru(cod)Cl2]	dppe	KOH	67
16^e	[Ru(cod)Cl2]	dppe	KOH	90
17^f	[Ru(cod)Cl2]	dppe	KOH	75
18	[Ru(cod)Cl2]		KOH	13
19		dppe	KOH	0

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Taking the optimal reaction conditions in hand, the methylation of C(sp³)–H bonds in a broad range of aryl sulfones derivatives was investigated (Scheme 2). The variation of Ar¹ adjacent to the sulfonyl group was first examined. Sulfones with electron-donating groups (CH₃–, CH₃O– and ^tBu–) gave relatively lower yield (2b, 83%; 2c, 80%; 2d, 78%) than that with an electron-withdrawing group (CF₃–, 2e, 88%). The substituted position on Ar¹ had a strong influence on the reaction yield, and the ortho-substituted aryl sulfones produced 2i in the lowest yield of 41%. It was noteworthy that when substrates bearing a halogen atom like Cl or Br at the para-position of Ar¹ lead to the desired products 2f and 2g successfully under the modified reaction conditions using weak base K₂CO₃, while meta- or ortho-halo-substituted sufones provided the targeted products in moderate to good yields. In addition, disubstituted sulfones reacted with methanol smoothly to generate the targeted products 2j and 2k in 75% and 83% yields, respectively. Thienyl and naphthyl group were aslo tolerated in this transformation, producing 2l and 2m in excellent yields. Delightfully, alkyl sufones like cyclohexylsulfone 1n still perfomed well to deliver the corresponding product 2n in 52% yield via heating up to 150 °C. Surprisingly, other alcohols such as propanol and butanol reacted with sulfone 1a successfully to offer the expected products 2o and 2p in moderate yields. Next, the variation of Ar² was screened. Both electron-donating groups and electron-withdrawing groups underwent this reaction efficiently to give the desired products (2q–2y) in 77–88% yields, in which no obvious electronic and steric effects were observed. Pleasingly, the para-halogenated substrates 1s and 1t were compatible with this process, therefore offering a changce for further manupilation. Notably, multiple substituents of aryl moieties were also allowed in this reaction (2z and 2aa). Interestingly, sulfones with fused (hetero)-aromatic rings were found to be promising substrates to provide the corresponding α-methylated products 2ab–2ad in up to 86% isolated yield. Unfortunately, no product was observed while introducing alkyl substituted sulfones as starting materials.

Scheme 2 Substrate scope of sulfones. Reaction conditions: 1 (0.5 mmol), [Ru(cod)Cl₂] (2.5 mol%), dppe (3.5 mol%), KOH (0.5 mmol), 2.0 mL of MeOH, 120 °C, 24 h. Isolated yields. ^aK₂CO₃ was used instead of KOH. ^b150 °C. ^cPropanol was used instead of MeOH. ^dButanol was used instead of MeOH. ^eBy-product was formed via cyclopropanation.

Dibenzo[b,e]thiepin-11(6H)-one 5,5-dioxide constitutes the fundamental structure of many products with biological activities including antidepressant, antipsychotic, antibacterial, anti-inflammatory and antifungal, and antidepressant activity.³⁰ The substrate scope of this reaction was finally extended to the catalytic α-methylation of dibenzo[b,e]thiepin-11(6H)-one 5,5-dioxide (Scheme 3), providing the methylated dibenzo[b,e]thiepin-11(6H)-one 5,5-dioxide derivatives in 58–65% yields (4a–4d).

Scheme 3 Substrate scope of dibenzo[b,e]thiepin-11(6H)-one 5,5-dioxides 3. Reaction conditions: 3 (0.5 mmol), [Ru(cod)Cl₂] (2.5 mol% mmol), dppe (3.5 mol% mmol), KOH (0.5 mmol), 2.0 mL of MeOH, 120 °C, 24 h. Isolated yields.

To demonstrate the scalability and utility of this method, we applied it in a gram-scale experiment and functional group transformations (Scheme 4). Initially, a 5 mmol scale of sulfone 1 reacted with MeOH smoothly to offer the desired product 2a in 1.04 g, 85% yield after 36 h (Scheme 4-1). Next, two desulfonative coupling reactions were conducted, as shown in Scheme 4-2. Using 4-anthpy as a catalyst, the desulfonative borylation of benzyl sulfone 2a procceded successfully to give benzyl boronic ester 5a in 65% yield.³¹ Alkene 6a was generated from a nickel catalyzed Kumada reaction of 2a with Grignard reagents in excellent yield.³² Finally, sulfone 2i could underwent a Pd-catalyzed intramolecular cyclization to deliver a versatile 6-methyl-6H-benzo[c]thiochromene 5,5-dioxide 7i in 35% yield (Scheme 4-3). Furthermore, to broaden the application of our approach, we were also devoted to synthesis of compound 2ac, a potent inhibitor of inflammatory cytokines that mentioned above. Terminal sulfone B was obtained in 52% yield after 24 h (Scheme 4-4).

Scheme 4 Gram-scale reaction and transformations.

In order to get a preliminary understanding of the reaction mechanism, we carried out several control experiments. Initially, we confirmed that unsaturated aryl sulfone 8a was produced in 80% yield using paraformaldehyde instead of methanol in absence of Ru catalyst (Scheme 5, eqn (1)). Next, the unsaturated aryl ester 8a that was observed in the time-course experiment was reacted in the presence of the Ru catalyst to give α-methylated sulfone 2a in 92% (Scheme 5, eqn (2)). Moreover, a deuterium labeling reaction using methanol-d₄ was attempted, which gave the deuterated product 2a′ in 91% yield with 94% deuteration (Scheme 5, eqn (3)). Based on these observations and previous literature,³³ we believed that a sulfone carbanion addition to an in situ generated aldehyde formed via catalytic dehydrogenation and subsequent catalyst mediated reduction of the alkene by hydrogen may be involved.

Scheme 5

Conclusions

In conclusion, we have developed a Ru-catalyzed methylation of sulfones using methanol as a sustainable C1 building block. The reaction requires a stoichiometric amount of base and generates only water as a byproduct. A series of value-added methylated sulfones with various functional groups are produced under the reaction conditions from readily available substrates. It is anticipated that this methylation reaction will inspire more new findings and find various applications in future.

Experimental

General procedure for the synthesis of compound 2 and 4

A mixture of [Ru(cod)Cl₂] (2.5 mol%), dppe (3.5 mol% mmol), KOH (0.5 mmol), aryl sulfone 1 or 3 (0.5 mmol) and methanol (2.0 mL) was stirred at 120 °C for 24 h under Ar in a pressure tube (ACE pressure tube, 15 mL). After cooling to room temperature, the reaction was diluted with ethyl acetate (10 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (10 mL) for three times. The combined organic layer was washed by brine and dried over magnesium sulfate and the volatiles were removed under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate = 30 : 1–10 : 1) to give the methylated products 2 and 4.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the National Natural Science Foundation of China (No. 22078298, 21978271, 21706234, and 21676253) and the Natural Science Foundation of Zhejiang Province of China (No. LY19B060011) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data of all the compounds. See DOI: 10.1039/d0qo01171a

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