Chinese Chemical Letters  2014, Vol.25 Issue (04):545-548   PDF    
Visible-light photoredox-mediated oxidation of N-methyl tertiaryamines under catalyst free conditions:Direct synthesis of methylene-bridged bis-1,3-dicarbonyl compounds
Xiao-Jun Daia, Xiao-Liang Xua, Dong-Ping Chengb, Xiao-Nian Lia     
a Institute of Industrial Catalysis, College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, China;
b College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
Abstract: Mediated by visible light-induced photoredox catalysis and free of other catalysts, a new and efficient synthesis of methylene-bridged bis-1,3-dicarbonyl derivatives has been developed. A variety of N-methyl tertiaryamines and 1,3-dicarbonyl compounds were investigated in this reaction.
Key words: Photochemistry     Oxidation     Aliphatic tertiaryamine     Catalyst free    
1. Introduction

The catalytic oxidation of sp3 C-H bond adjacent to a nitrogen atom to form a new carbon-carbon or carbon-hetero bond has been widely applied in organic synthesis [1]. Using the iminium ions generated from the direct oxidation of tertiaryaminesin situ, Strecter reaction,Mannich reaction,aza-Henry reactions and so on have been successfully realized [2]. Recently,visible light photoredox catalysis aroused great interest due to its green chemistry characteristics [3]. Many metal complexes and organic dyes were frequently used as photocatalysts in photoredox chemistry [4, 5]. In particular,several highly efficient chemical transformations were established using Ir or Ru photocatalysts [5]. The photocatalytic oxidation of tertiaryamines is a very important research topic.

Kobayashi reported that a Ru complex,in the presence of visible light,catalyzed the cross oxidative coupling of 1,3-diphenylpropane-1,3-dione and tertiary aliphatic amines to form methylenebridged bis-1,3-dicarbonyl compounds [6, 7]. However,in the course of our study,it was found that without metal photocatalyst, 1,3-diphenylpropane-1,3-dione and N,N-dimethylcyclohexylamine reacted smoothly to give the methylene-bridged bis-1,3-dicarbonyl compounds even using only visible light,albeit in very low yield. Although the exact mechanism was unclear,the observation may be ascribed to the differences in reaction conditions between Kobayashi’s and ours. 2. Experimental

All reactions were carried out without the exclusion of air or moisture. Toluene,cyclohexane,DCE,DCM,DMSO,DMF,EtOAc, 1,4-dioxane and MeCN were analytical reagents and used directly as received.N,N-dimethylcyclohexylamine,N,N-dimethylbutylamine,N,N-dimethylbenzylamine,N,N-dimethylaniline,N,N,N',N' -tetramethylethane-1,2-diamine,N-methyldiisopropylamine,Nmethyldicyclohexylamine were purchased from the Sigma- Aldrich company and used directly as received. 1,3-Dicarbonyl compounds were prepared according to literature procedures [8]. 1H NMR and 13C NMR spectra were recorded at ambient temperature in CDCl3on a Bruker AMX-500 MHz instrument with TMS as an internal standard. Low-resolution MS was obtained using EI or ESI ionization. HRMS was obtained using ESI ionization.

General procedure for the preparation of compounds2:toa mixture of 1,3-diphenylpropane-1,3-dione1a(0.5 mmol) and 9/1 (v/v) DMSO/H2O (2 mL) in a 10 mL two-necked round-bottom flask was addedN-methyl-dicyclohexanamine (0.25 mmol). The resulting mixture was stirred under 1 atm of O2(balloon) for 24 h at ambient temperature under the irradiation by three 45 W white fluorescent bulbs (Arrow BHSL 45) at a distance of 5 cm. Then the reaction mixture was washed three times with dilute hydrochloric acid. Purification was done by column chromatography on silica gel (200-300 mesh) using petroleum ether and ethyl acetate (5:1- 10:1) as the eluent to give the pure product 2a.

Synthesis and characterization of all products are described in Supporting information. 3. Results and discussion

Our initial studies focused on the visible light-mediated reaction of 1,3-diphenylpropane-1,3-dione1aandN,N-dimethylcyclohexylamine. Unfortunately,the reaction proved to be very sluggish and the starting material could not be fully consumed within 30 h (Table 1,entry 1). VariousN-methyl tertiaryamines as potential methylene donors were examined. To our disappointment,all aliphaticN-methyl tertiaryamines tried led to the desired product with very low yields. WhenN,N-dimethylaniline was introduced,the reaction resulted in a complex mixture (Table 1, entry 4).

Table 1
Evaluation of tertiaryamines as methylene donors.a

However,it was interesting to find that the photocatalytic reaction ofN-methyldicyclohexylamine was significantly faster, compared with other N-methyl tertiaryamines. This reaction could occur in all solvents tried. It was gratifying that,in contrast to other solvents (Table 2),the desired product was obtained in 70% isolated yield after 24 h using DMSO as a solvent (Table 2, entry 5).

Table 2
Solvent screening.a

Based on these results,various conditions were evaluated. It was found that strong light emission could accelerate the reaction. Interestingly,use of H2O as a solvent also resulted in high yields (Table 3,entry 3). The mixed solvent of DMSO and H2O gave reasonable result as well. Importantly,no conversion was observed when the reaction was conducted in the dark (Table 3,entries 8 and 9). Under O2,the reaction was more rapid than under air,while a very slow background reaction was observed under N2. These observations indicated that oxygen was essential in this reaction.

Under the optimized conditions,the scope of this photonmediated coupling reaction was investigated. In general a variety of different dicarbonyl nucleophiles (Table 4),including aryl and alkyl 1,3-diketones,b-ketoesters and 1,3-diester,could react withN-methyl-dicyclohexylamine. Substrates containing substituents like Me and OMe on the aryl rings underwent the reaction smoothly (Table 4,entries 2 and 3). For substrates with halogenated phenyl rings,a fluoro appeared to be more favorable than a bromo and some unidentified compounds formed in certain reactions (Table 4,entries 4 and 5). Substrates with alkyl ketone moieties gave lower yields of the product (Table 4,entry 7). When b-ketoesters were utilized as substrates,the reactions resulted in modest yields (Table 4,entries 8-10). In the case of ethyl 3-oxo-3-phenylpropanoate 1h,the desired product 2h was obtained in 39% yield,accompanied by 39% of a de-ethoxycarboxylated product 2h'.

Table 3
Solvent and light source screening.a

Table 4
Substrate scope.a

A plausible mechanism for the reaction is proposed in Scheme 1. We reasoned that the 1,3-dicarbonyl compounds are effective photo mediators. Upon irradiation,1is excited providing 1*,which is then reductively quenched by3to produce a radical anion of 1 and amine radical cation 4 via a single electron transfer process.1 is regenerated with the assistance of dioxygen,and the resulting oxygen radical anion abstracts a proton in the methyl group in radical cation 4 to generate the iminium intermediate 5. Subsequently,nucleophilic trapping of 5 with 1 results in the oxidative coupling product 5. The desired product 2 is formed by either a direct nucleophilic substitution reaction or a tandem Cope elimination and Michael additionviaintermediate 7.

Scheme 1. Proposed reaction mechanism.
4. Conclusion

In summary,without any other photocatalyst,we have developed a useful protocol for the synthesis of methylenebridged bis-1,3-dicarbonyl compounds in aqueous media using visible light photoredox catalysis. In contrast to the similar reactions reported in recent literature,the mechanism of this reaction needs more experimental studies. Further investigations into the mechanism of this reaction under visible light are currently underway. Acknowledgment

The authors are grateful to Zhejiang Provincial Natural Science Foundation of China (No. LY12B02017). Appendix A. Supplementary data

Supplementary data associated with this article can be found,in the online version,at

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