Metal-free hydrosulfonylation of α,β-unsaturated ketones: synthesis and application of γ-keto sulfones

γ-Keto sulfones are versatile building blocks and valuable intermediates in organic synthesis and pharmaceutical chemistry. Motivated by their excellent properties, we herein report a green, convenient, metal-free hydrosulfonylation method for a variety of ynones, vinyl ketones, and sodium sulfinates in the absence of stoichiometric oxidants. This operationally simple protocol provides straightforward and practical access to a wide range of γ-keto sulfones with broad functional group tolerance from easily available starting materials. Moreover, the β,γ-unsaturated keto sulfones could further react with 2,3-butadienoate to generate cyclopentenes in phosphine-mediated [3 + 2] cycloaddition.

The methodology features a convenient, mild, efficient, C–S sulfonylation approach without the use of any metal catalysts and stoichiometric oxidants.

As a useful common structural fragment in a broad number of pharmaceuticals¹ and functional materials,² keto sulfones are usually present in promising biologically active molecules such as Casodex,³VCAM-1 (ref. 4) and anti-HIV-1 (ref. 5) (Fig. 1). Furthermore, a valuable synthetic impression is associated with the role of reactive intermediates in various high-demand synthetic transformations,⁶ including total synthesis.⁷ Owing to their excellent properties, and efficient and practical synthesis methods keto sulfones are in high demand.Open in a separate windowFig. 1Representative biologically active γ-keto sulfones.In the past decades, a variety of protocols have been developed to construct β-keto sulfones.⁸ Whereas succinct synthetic routes toward structurally related γ-keto sulfones are scarce,⁹ traditionally, γ-keto sulfones were synthesized via the nucleophilic substitution of sodium sulfinates by 2-chlorovinyl ketones,¹⁰ the elimination of the bromo derivatives of saturated keto sulfones¹¹ and the oxidation of the corresponding sulfides or sulfoxides.¹² However, the principal drawback is that these procedures were strongly limited by multiple steps, narrow substrate scope, or poor stereoselectivity.Indeed, several streamlined strategies for the preparation of γ-keto sulfones involves addition reaction of alkenes or alkynes have been developed.¹³ Li''s group¹⁴ reported the synthesis of (E)-vinyl sulfones through Pd-catalyzed conjugate additions of alkynes with 1,2-bis(phenylsulfonyl)ethane. In 2013 Jiang and co-workers¹⁵ showed that a Pd-catalyzed sulfonylation of alkynoates with sodium sulfinates affords γ-keto sulfones (Scheme 1a). Li and coworkers¹⁶ reported that BPO triggered the hydrosulfonylation of chalcones with arylsulfonyl hydrazides producing γ-keto sulfones. Subsequently, Bi''s group¹⁷ developed a Ag₂CO₃-promoted sulfonylation of allyl/propargyl alcohols with sodium sulfinates for the preparation of γ-keto sulfones (Scheme 1b). Nevertheless, most cases still have to use large excess oxidants, noble metal catalysts, or require high temperatures. Accordingly, an efficient, mild and practical method to furnish γ-keto sulfones is worthwhile studying.Open in a separate windowScheme 1Methods for the synthesis of γ-keto sulfones.With growing demand for sustainable chemistry, an “ideal” reaction system for such transformations would be “metal-free” due to cost efficiency and possible advantages regarding toxicity, as well as selectivity. With this intent, we herein describe a simple and efficient acid-mediated sulfonylation of sodium sulfinates and α,β-unsaturated ketones for the selective synthesis of γ-keto sulfones (Scheme 1c). The significant advantages of this method are high efficiency, metal-free and mild reaction conditions, thus providing a potential application in natural product synthesis and medicinal chemistry.Further studies were commenced with the optimization of the conditions for the hydrosulfonylation of the ynone 1f with sodium benzosulfonate 2a (13e and acetyl chloride/H₂O,¹⁹ as used in the previous study, were completely ineffective due to several unknown complex products being formed (entry 1). Gratifyingly, the desired γ-keto sulfone 3fa was isolated in a 49% yield (E/Z = 90 : 10) as the major product for the reaction mediated by AcOH (entry 3). Encouraged by this initial result, we screened an array of acids. The results showed that 4-chlorobenzoic acid (PCBA) gave the best result, leading to the isolation of γ-keto sulfone 3fa in a yield of 80% (E/Z = 98 : 02) (entries 4–15). Solvent screening indicated that mesitylene could improve the yield to 85% (E/Z = 95 : 05) (entry 21). Further investigations on the reduced usage of PCBA to 2.0 equivalents, the yield of 3fa was slightly reduced (entry 22, 83% yield, E/Z = 95 : 05). The amounts of sodium benzosulfonate 2a and the reaction temperature have deleterious effects on the reaction yields (entries 23–27). Thus, the optimized reaction conditions were successfully established as 1f (1.0 equiv.), 2a (2.5 equiv.), PCBA (2.0 equiv.), and mesitylene (2.0 mL) at 30 °C in this process.Optimization of the reaction conditions^a

Entry	Acid (x equiv.)	Solvent	Yieldb (%)	E/Zc
1	Buffer (pH = 3.5)	DMF	NR	—
2	Acetyl chloride/H2O	CHCl3	NR	—
3	AcOH (3.0)	Toluene	49	90 : 10
4	HCO2H (3.0)	Toluene	23	85 : 15
5	HCl (3.0)	Toluene	36	80 : 20
6	HNO3 (3.0)	Toluene	36	87 : 13
7	Benzoic acid (3.0)	Toluene	66	96 : 04
8	p-Toluic acid (3.0)	Toluene	52	96 : 04
9	4-Acetylbenzoic acid (3.0)	Toluene	57	96 : 04
10	4-Fluorobenzoic acid (3.0)	Toluene	73	98 : 02
11	PCBA (3.0)	Toluene	80	98 : 02
12	4-Bromobenzoic acid (3.0)	Toluene	72	95 : 05
13	PNBA (3.0)	Toluene	57	88 : 12
14	2-Naphthoic acid (3.0)	Toluene	48	94 : 06
15	2-Nitrobenzoic acid (3.0)	Toluene	29	94 : 06
16	PCBA (3.0)	o-Xylene	73	92 : 08
17	PCBA (3.0)	p-Xylene	70	90 : 10
18	PCBA (3.0)	m-Xylene	72	96 : 04
19	PCBA (3.0)	DMF	NR	—
20	PCBA (3.0)	MeOH	68	89 : 11
21	PCBA (3.0)	Mesitylene	85	95 : 05
22	PCBA (2.0)	Mesitylene	83	95 : 05
23	PCBA (1.2)	Mesitylene	76	91 : 09
24	PCBA (0.5)	Mesitylene	44	73 : 27
25d	PCBA (2.0)	Mesitylene	79	90 : 10
26e	PCBA (2.0)	Mesitylene	80	95 : 05
27f	PCBA (2.0)	Mesitylene	53	97 : 03

Open in a separate window^aReaction conditions: 1f (0.1 mmol), 2a (0.25 mmol), acid (x equiv.), solvent (1.0 mL), 30 °C, 48 h.^bIsolated yields.^cDetermined by RP-HPLC.^dWith 2.0 equiv. 2a.^e50 °C.^f80 °C. PCBA = 4-chlorobenzoic acid. PNBA = p-nitrobenzoic acid.We then sought to explore the generality of the method for the synthesis of α,β-unsaturated γ-keto sulfones, using various ynones in reactions with 2a under the optimized conditions (Scheme 2). The reaction of the 1-phenylprop-2-yn-1-one 1a with 2a proceeded reasonably to provide an excellent yield of the corresponding γ-keto sulfone 3aa (97% yield, E/Z = 98 : 02). To our delight, the reaction worked successfully with a range of ynones 1 bearing various substituents on the aromatic ring. Substituents such as methyl, thiomethylmethoxy, phenyl, halogen and dimethylamino atoms could be tolerated and gave the corresponding products 3ba–3ja with high to excellent yields (71–98% yield) and stereoselectivity (E/Z = 82 : 18 to 98 : 02). Trifluoromethyl and nitro substituents on the aromatic ring were also compatible and products 3ka and 3la were afforded 95% and 71% yields, respectively. 9-Anthracenee-derived ynone successfully afforded 3ma in a 94% yield (E/Z = 98 : 02). The methyl group in the ortho or meta positions of the aromatic ring gave the desired γ-keto sulfones in 82% and 94% yield, respectively. The desired product 3pa bearing a pitavastatin unit could be readily prepared in a yield of 87%. When alkyl terminal alkynone 1q was subjected to the reaction, affording the desired product 3qa in 65% yield (E/Z = 97 : 03).1Open in a separate windowScheme 2Sulfonylation reaction of various terminal alkynones with 2a. All reactions were carried on 0.2 mmol scale in mesitylene (2.0 mL) and used 2.5 equiv. of 2a, 2.0 equiv. PCBA, at 30 °C. Yields of isolated products are reported. E/Z ratios were determined by RP-HPLC.Inspired by the above results, the nonterminal alkyne was used as the substrate to react with PhSO₂Na at 30 °C for 36 h. The reaction provided E and Z-β-sulfonyl-α,β-unsaturated carbonyl mixed compounds 3qa^13e (86% yield, E/Z = 1 : 1).The results of ynone 1a reacting with a number of sodium sulfinates under the optimized condition are depicted in Scheme 3. Gratifyingly, no matter whether the phenyl ring of sodium sulfinate was substituted with either a sterically hindered, electron-donating, or electron-withdrawing group, all of them smoothly furnished the corresponding products in moderate to excellent yields with a high range of E/Z ratios from 52 : 48 to 97 : 03 (3ab–3an). Likewise, 2-napthyl and cyclopropyl substituted sodium sulfinates were both effective in this reaction with a yield of 87% and 85%, respectively (3ao and 3ap). Additionally, l-10-camphorsulfonyl sulfinate 2q was also suitable for this reaction.Open in a separate windowScheme 3Sulfonylation reaction of terminal alkynone (1a) with sodium Sulfinates. All reactions were carried on 0.2 mmol scale in mesitylene (2.0 mL) and used 2.5 equiv. of 2, 2.0 equiv. PCBA, at 30 °C. Yields of isolated products are reported. E/Z ratios were determined by RP-HPLC.Interestingly, the treatment of the vinyl ketone 4a with PhSO₂Na (2a) under the standard conditions furnished sulfone 5aa (Scheme 4). The substrate scope was also explored in Scheme 4. Delightfully, it was perfectly tolerable to introduce both electron-donating (OCH₃ and Ph) and electron-withdrawing (F, Cl, and CN) groups at the para position of the phenyl ring, affording the corresponding products (5ba–5fa) in excellent yields. 4-Toluene sulfonate and cyclopropane sulfonate also reacted well with substrate 2a to form γ-keto sulfone in excellent yields. We were pleased to find that the β-trifluoromethylated enone 4h and trans-chalcone (4i–4j) could be successfully employed to give desired products (5ha–5ja, 55–61% yields). Unfortunately, no reaction occurred for 2-cyclopentenone.Open in a separate windowScheme 4Sulfonylation reaction of vinyl ketone with sodium sulfinates. All reactions were carried on 0.2 mmol scale in mesitylene (2.0 mL) and used 2.0 equiv. of 2a, 2.0 equiv. PCBA, at 30 °C. Yields of isolated products are reported. ^aAt 80 °C for 72 h.Additionally, the synthetic utility of the γ-keto sulfones obtained by the present method was explored (Scheme 5). Gram-scale ynone 1a was reacted with sodium benzosulfonate 2a to form product 3aa with an excellent E/Z ratio (A). Lu''s [3 + 2] cycloaddition of 2,3-butadienoate with α,β-unsaturated γ-keto sulfones 3 mediated by phosphine produced cycloadducts 6 (ref. 18) in good yields (B). Moreover, pyrazole derivative 6b could be efficiently obtained from 3aa under ultrasound (US) irradiation conditions (C). Next, γ-keto sulfone 3pa derived from the biologically active pitavastatin could also react with hydrazine to give a high yield of 6c (D).Open in a separate windowScheme 5Gram-scale preparation and further synthetic utilization.To understand the reaction mechanism, control reactions of 1a with 2a were examined (Scheme 6a). When 1a and 2a was subjected to the standard reaction conditions except using deuterated 4-chlorobenzoic acid system, the 3a were detected with 80% yield. An attempt to run the reaction of 1a and 2a in a anhydrous solvent system under an N₂ atmosphere also successfully delivered 3a in 97% yield.²⁰ The results unambiguously disclosed that the incorporated hydrogen atoms in 3a originated from acid rather than water. The reaction using 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,4-di-tert-butyl-4-methylphenol (BHT) as the radical scavengers showed no observable radical intermediates and unaffected desired products formation, which suggests that the radical process could be ruled out.²⁰ On the basis of the results presented above and previous reports, we propose the following mechanism in Scheme 6b. The 4-chlorobenzoic acid activates the carbonyl group in α,β-unsaturated ketones 1 (4) to afford intermediate I or tautomerize to intermediate II. Finally, sulfonyl anion can add to the unsaturated bond of intermediate II to afford the products 3 (5).Open in a separate windowScheme 6Mechanistic studies.