K2S2O8-promoted C–Se bond formation to construct α-phenylseleno carbonyl compounds and α,β-unsaturated carbonyl compounds期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

K2S2O8-promoted C–Se bond formation to construct α-phenylseleno carbonyl compounds and α,β-unsaturated carbonyl compounds

Authors:

Xue-Yan Yang Ruizhe Wang Lu Wang Jianjun Li Shuai Mao San-Qi Zhang Nanzheng Chen

Affiliation:

Department of Medicinal Chemistry, School of Pharmacy, Xi''an Jiaotong University, Xi''an Shaanxi 710061 PR China.; Department of Chemistry, School of Science, MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi''an Jiaotong University, Xi''an Shaanxi 710049 PR China ; The Thoracic Surgery Department of the First Affiliated Hospital of Xi''an Jiaotong University, Xi''an Shaanxi 710061 PR China

Abstract:

A novel K₂S₂O₈-promoted C–Se bond formation from cross-coupling under neutral conditions has been developed. A variety of aldehydes and ketones react well using K₂S₂O₈ as the oxidant in the absence of catalyst and afford desired products in moderate to excellent yields. This protocol provides a very simple route for the synthesis of α-phenylseleno carbonyl compounds and α,β-unsaturated carbonyl compounds.

K₂S₂O₈-promoted C–Se bond formation from the cross-coupling of C(sp³)–H bond adjacent to carbonyl group with diphenyl diselenide under metal-free conditions.

Selenium (Se) is an essential trace mineral nutrient that exerts multiple and complex effects on human health.¹ Selenium has been widely applied in a variety of fields such as the organic synthesis, catalysis, agriculture chemistry, materials science and even the environment protection.² Se-containing compounds have attracted vast interest because of their extensive bioactive functions and important roles in chemical reactions.³ As metabolites of Se in humans, phenylseleno (–SePh) groups are extremely important.⁴ It has been reported that SePh-containing compounds can act as redox agents suitable for targeting cancer cells or play a role in steroid chemistry. Several reported SePh-containing compounds that imitate glutathione peroxidase, like ebselen,⁵ that act as redox agents suitable for targeting cancer cells (naphthoquinone derivatives)⁶ or are important in steroid chemistry (estrogen derivatives)⁷ are shown in Fig. 1. Furthermore, α-phenylseleno carbonyl compounds have a special place since these substances also serve as versatile intermediates in organic synthesis.⁸ They can be converted into the corresponding synthetically useful α,β-unsaturated aldehydes or ketones through oxidation by H₂O₂ or NaIO₄ followed by selenoxide elimination⁹ and Sahani''s group has used α-phenylselanyl ketones as substrates to obtain α-arylated ketones through organic photoredox catalysis.¹⁰ Open in a separate window Fig. 1Examples of Se-containing biologically active compounds.Oxidative functionalization of carbonyl compounds has been known since 1935 (ref. 11) and was studied further by Saegusa, Mislow, Baran and others.¹² While there generally exist various means, either direct or indirect, of accessing particular target molecules, in order to continue to advance this field, we must constantly study more efficient and green methods. Currently, several procedures have been developed for the preparation of α-phenylseleno aldehydes and ketones. One typical method to synthesize such compounds is by using an enolate coupling reaction.¹³ This approach suffers from the use of a stoichiometric amount of a strong base and metal oxidant to produce the enolate followed by an oxidative coupling reaction (see Scheme 1). In 2015, Yan''s group demonstrated that with the participation of a suitable oxidant, ketones can undergo direct oxidation functionalization.¹⁴ Despite the improvement of not using strong base, it still needed multiple times the amount of metal-free oxidants. In addition, K₂S₂O₈ was found to be a useful oxidant in oxidative reactions because of its characteristics of easy availability, good stability, and low toxicity. Thus, studies focusing on the development of K₂S₂O₈-mediated oxidative reactions meet the requirement of sustainable chemistry.¹⁵ Based on our research on the functionalization of the C(sp³)–H bond, and in connection to our continued interest in developing efficient metal-free functionalization strategies,¹⁶ herein we report an efficient K₂S₂O₈-mediated C–Se bond formation for the synthesis of α-phenylseleno carbonyl compounds.Open in a separate window Scheme 1Synthesis of α-phenylseleno carbonyl compounds (M = metal).Initially, we utilized acetone (1a) as a standard substrate to evaluate the coupling of C(sp³)–H bonds adjacent to a carbonyl group with diphenyl diselenide (2). Treatment of 1a with 1.0 equiv. of (NH₄)₂S₂O₈ in DMSO at 80 °C under air for 3 h afforded the desired product 3a in 29% yield (17 Then various reaction parameters were screened, including the oxidant, solvent, and temperature. A range of oxidants such as PhI(OAc)₂, IBX, Ag₂O, Na₂S₂O₈, K₂S₂O₈, and oxone were tested, and K₂S₂O₈ showed the highest efficiency (entries 2–7). The solvent also played a key role in this transformation. The product yield decreased when DMSO was replaced by DMF, DMA, CH₃CN or EtOH (entries 8–11). Taking the place of air with argon, the reaction gave the desired product 3a in a similar yield (87%) (entry 12). Notably, a similar yield of 3a was obtained by lowering the amount of K₂S₂O₈ to 0.5 equiv. (entry 13). However, a further decrease of the oxidant amount resulted in a lower yield of 3a (entry 14). The reaction temperature had little influence on the reaction efficiency, and 80 °C was still the best choice (entries 15 and 16). A control experiment revealed that K₂S₂O₈ was necessary for the success of this reaction (entry 17).Optimization of the reaction conditions^a^,^b


Entry	Oxidant (equiv.)	Solvent	Temp (°C)/time (h)	Yield^b (%)
1	(NH₄)₂S₂O₈ (1)	DMSO	80/3	29
2	PhI(OAc)₂ (1)	DMSO	80/6	<5
3	IBX (1)	DMSO	80/6	<5
4	Ag₂O (1)	DMSO	80/6	n.r.^c
5	Na₂S₂O₈ (1)	DMSO	80/3	70
6	K₂S₂O₈ (1)	DMSO	80/3	93
7	Oxone	DMSO	80/6	n.r.
8	K₂S₂O₈ (1)	DMF	80/3	52
9	K₂S₂O₈ (1)	DMA	80/3	67
10	K₂S₂O₈ (1)	MeCN	80/3	<5
11	K₂S₂O₈ (1)	EtOH	80/6	<5
12^d	K₂S₂O₈ (1)	DMSO	80/3	87
13	K ₂ S ₂ O ₈ (0.5)	DMSO	80/3	90 (92) ^e
14	K₂S₂O₈ (0.3)	DMSO	80/12	50
15	K₂S₂O₈ (0.5)	DMSO	40/8	85
16	K₂S₂O₈ (0.5)	DMSO	r.t./12^f	88
17	—	DMSO	80/6	n.r.

Open in a separate window^aReaction conditions: 1a (0.5 mmol), 2 (0.25 mmol), oxidant, solvent (2 mL), under air atmosphere.^bIsolated yield based on 1.^cn.r. = no reaction.^dUnder argon (1 atm) atmosphere.^eYield on a 5 mmol scale is given in parentheses.^fRoom temperature.With optimized reaction conditions in hands, we evaluated the scope of the reactions with a variety of ketones. A wide range of acyclic (

Open in a separate window^aReaction conditions: 1 (0.5 mmol), PhSeSePh (0.25 mmol), K₂S₂O₈ (0.25 mmol) and DMSO (2 mL), 80 °C, 3 h.^bIsolated yields based on 1.As important synthetic intermediates of drug molecules and complex chemicals, α,β-unsaturated carbonyl compounds could be prepared via direct α,β-dehydrogenation of ketones and aldehydes using oxidants such 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)¹⁸ and 2-iodoxybenzoic acid (IBX).¹⁹ Corresponding to direct oxidation methods are stepwise protocols which contain α-substitution of carbonyl compounds and subsequent elimination.Inspired by the research, and based on above synthesis of α-phenylseleno carbonyl compounds, we attempted to develop an efficient one-pot synthesis of α,β-unsaturated carbonyl compounds from carbonyl compounds. After extensive screening studies, we were pleased to find a desirable protocol; that is, after the reaction of the synthesis of α-phenylseleno carbonyl compounds was complete, H₂O₂ and pyridine in dichloromethane were added to the reaction bottle and stirred at 25 °C for 30 min (

Entry

Substrates

Products

Yield

71%

91%

87%

Open in a separate window^aAll reactions were performed with 1 (0.5 mmol), PhSeSePh (0.25 mmol), K₂S₂O₈ (0.25 mmol) and DMSO (2 mL) at 80 °C under air for 3 h. After the UV absorption of diphenyl diselenyl ether completely disappeared (monitored by TLC), the mixture was cooled to 25 °C, and then H₂O₂ (1.5 mmol), pyridine (1 mmol), DCM (3 mL) were added. The mixture was stirred at 25 °C for 30 min. Isolated yields based on 1.We next focused on the mechanism of this reaction. First, two radical-trapping reagents, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and 1,1-diphenylethylene (DPE) were added to the standard reaction system respectively. It was found that no product 3a was detected in both reactions (Scheme 2a and b). Then a visible light-promoted experiment was investigated. The reaction of 1a with 2 irradiated by a 18 W white LED in DMSO gave 3a in 41% yield after 12 hours (Scheme 2c). These results shown that the reaction may involve a radical process.Open in a separate window Scheme 2Control experiments for mechanistic study.Based on the experimental results and related reports, a possible mechanism was proposed (Scheme 3). In the initiation stage, S₂O₈²⁻ decomposed to form sulfate radicals SO₄˙⁻ by breaking of the O–O bond under heat condition.²⁰ Then SO₄˙⁻ reacted with carbonyl compounds to generate racial A. In the chain propagation stage, radical A reacted with diphenyl diselenide 2 to produce the α-phenylseleno carbonyl compounds product 3 and a phenylseleno radical B, which then reacted with another molecule of A to generate a new α-phenylseleno carbonyl compounds. Under oxidative conditions, 3 was oxidized to give α-carbonyl selenoxides C, which could decompose into α,β-unsaturated carbonyl compounds 4via selenoxide elimination.Open in a separate window Scheme 3Proposed reaction mechanism. Keywords:

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