Chinese Chemical Letters  2014, Vol.25 Issue (01):55-57   PDF    
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Liang-Yan Cui, Sheng-Hai Guo, Bin Li, Xin-Ying Zhang, Xue-Sen Fan.Synthesis of cyclopentenyl and cyclohexenyl ketones via [3 + 2] and [4 + 2] annulations of 1,2-allenic ketones[J]. Chin. Chem. Lett., 2014,25(01): 55-57   
Synthesis of cyclopentenyl and cyclohexenyl ketones via [3 + 2] and [4 + 2] annulations of 1,2-allenic ketones
Liang-Yan Cui, Sheng-Hai Guo, Bin Li, Xin-Ying Zhang, Xue-Sen Fan     
* Corresponding authors at:School of Chemistry and Chemical Engineering, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory for Environmental Pollution Control, Henan Normal University, Xinxiang 453007, China
Received:2013-6-18, Revised:2013-9-17, online:2013-11-13.
E-mail addresses:xuesen.fan@htu.cn
Abstract: In this paper, an efficient synthesis of cyclopentenyl ketones and cyclohexenyl ketones through tertiary phosphine catalyzed [3 + 2] and [4 + 2] annulations of 1,2-allenic ketones with activated alkenes has been developed. Compared with published synthetic methods on cyclopentenyl ketones and cyclohexenyl ketones, the protocols developed in this paper have the advantages such as readily available starting materials, mild reaction conditions and high efficiency.
Key words: Cyclopentenyl ketone     Cyclohexenyl ketone     1,2-Allenic ketone     Phosphine-catalyzed annulation    
1. Introduction

As versatile and efficient synthetic building blocks, 1,2-allenic ketones have been used in the preparation of a plethora of organic compounds of synthetic and biological interest [1], such as pyranone [2], 2-alkynyl-1,5-diketones [3], 2H-chromenes [4], furans [5], difuranyl ketones [6], functionalized benzenes [7], bicycle[5.3.0]deca-1,3,5-trienes [8], bicyclic nucleosides [9], etc. Meanwhile, since the pioneering works made by Lu et al. that cyclcopentene derivatives could be formed from phosphine catalyzed [3 + 2] annulation of 2,3-butadienoate with electrondeficient olefins [10], various annulations using this strategy have been realized to afford a variety of carbocycles and heterocycles with high efficiency [11]. It is noted, however, that most of these annulations were accomplished with allenoates and a similar annulation reaction with 1,2-allenic ketones is surprisingly limited [12]. Based on these facts, and as a continuation of our recent interests in exploring 1,2-allenic ketones as valuable synthetic intermediates, we were interested in studying the phosphine catalyzed annulation of 1,2-allenic ketones with electron-deficient olefins to develop practical and efficient protocols for the preparation of cyclopentenyl ketones and cyclohexenyl ketones. In this regard, we herein report our preliminary results.

2. Experimental

2.1. General

The1,2-allenicketones,2-benzylidenemalononitrilesandethyl 2-cyano-3-arylacrylates in this report were prepared based on literature procedures. The 1H NMR and 13C NMR spectra were recorded at 400 MHz and 100 MHz, respectively. Chemical shifts were reported in ppm from tetramethylsilane (TMS) as internal standard inCDCl3 solution.Multiplicitywas indicated as follows: s (singlet); d (doublet); t (triplet); m (multiplet); dd (doublet of doublets), etc. and coupling constants were given in Hz. The conversion of starting materials was monitored by thin layer chromatography (TLC) using silica gel plates (silica gel 60 F254, 0.25 mm) and components were visualized by observation under UV light (254 and 365 nm). Experimental procedure and spectroscopic data aredetailed inSupporting information.

2.2. Preparation of cyclopentenyl ketones (3 and 4)

To a flask containing 1,2-allenic ketone (1, 0.5 mmol) and 2- benzylidenemalononitrile (2, 0.5 mmol) in toluene (5 mL) at r.t., PPh3 (0.1 mmol) was added with stirring. Upon completion as indicated by TLC analysis, the resulting mixture was concentrated. The crude residue was purified by column chromatography on silica gel eluting with EtOAc/hexane (1:5) to give cyclopentenyl ketones (3 and 4).

2.3. Preparation of cyclohexenyl ketones (6 and 8)

To a flask containing 1,2-allenic ketone (5, 0.5 mmol) and 2- benzylidenemalononitrile (2, 0.5 mmol) in toluene (5 mL) at r.t., PPh3 (0.25 mmol) was added with stirring. Upon completion as indicated by TLC analysis, the resulting mixture was concentrated. The crude residue was purified by column chromatography on silica gel eluting with EtOAc/hexane (1:5) to give cyclohexenyl ketones (6). Cyclohexenyl ketones (8) were prepared by the reaction of 5 and ethyl 2-cyano-3-arylacrylates (7) through a similar procedure and were formed as a mixture of diastereoisomers while one of the isomers was formed as a main product and was isolated as the pure form by column chromatography.

3. Results and discussion

As an initial consideration, cyclopentenyl ketones are attractive synthetic targets due to their frequent applications in organic synthesis and related areas [13]. While several efficient synthetic methods toward cyclopentenyl ketones have been developed [13, 14], new methods carried out under mild conditions and starting from readily available substrates are still highly desirable. For this purpose, the envisioned [3 + 2] annulation was studied by using 1-(3-chlorophenyl)-buta-2,3-dien-1-one (1a) and 2-benzylidenemalononitrile (2a) as model substrates. After several trials, we were pleased to find that when 1a and 2a were treated with PPh3 (20 mol%) in toluene at r.t. for 1 h, the expected cyclopentenyl ketone, as a mixture of two regioisomers (3a and 4a), was obtained in a total yield of 82% (Table 1, entry 1). The generality and scope of this method was investigated by employing several aryl and alkyl substituted allenic ketones (1), as well as various 2-benzylidene malononitriles (2). As shown in Table 1, the reaction is compatible with an array of aryl allenic ketones bearing either electronwithdrawing or electron-donating substituents (entries 1-9). It is also notable that benzyl and phenylethyl substituted allenic ketones not only participate in this tandem reaction smoothly, but also give the corresponding cyclopentenyl ketones with high regioselectivity (entries 10-11).

Table 1
Synthesis of cylcopentenyl ketones.a
Having established an efficient protocol for the preparation of cyclopentenyl ketones, our attention then moved to the synthesis of cylcohexenyl ketones which are important building blocks of many biologically active natural products and pharmaceuticals [15]. In spite of their importance, an efficient synthetic method toward cyclohexenyl ketones is very limited [15, 16]. Our proposed synthesis of cylcohexenyl ketones is inspired by Kwon’s synthesis of cyclohexenes through phosphine catalyzed [4 + 2] annulation of 2-methylene-but-3-enoate with electron-deficient olefins [11]. We envisioned that substitution of the hydrogen at the inner position of the allenic moiety of 1,2-allenic ketone should block the a-attack of the zwitterionic intermediate formed through reaction between 1,2-allenic ketones and phophspine. Therefore, it will undergo a γ-addition to electron-deficient olefins to give a sixmembered ring. Indeed, treating a mixture of 2-methyl-1- phenylbuta-2,3-dien-1-one (5a) and 2-(4-methoxybenzylidene)- malononitrile (2f) in the presence of PPh3 in toluene at r.t. for 3 h resulted in the formation of the desired cyclohexenyl ketone (6a) in a yield of 80% (Table 2, entry 1). Using conditions optimized for the formation of 6a, a series of cyclohexenyl ketones were prepared (Table 2). Several characteristics of this annulation reaction are noteworthy. Firstly, various substituents on the aromatic rings are tolerated (Table 2, entries 1-8). Furthermore, we noticed that Kwon’s synthesis of cylcohexenes with allenoates by using PPh3 as a catalyst gave a mixture of two regioisomers [11d]. Interestingly, we found that with 1,2-allenic ketone as substrate, the annulation catalyzed by PPh3 afford only one isomer.

Table 2
Synthesis of cylcohexenyl ketones (Ⅰ).a
As a further aspect, the scope of the above described [4 + 2] Table 1 annulation was extended to another class of electron-deficient olefins, ethyl 2-cyano-3-arylacrylate (7). As expected, the annulation occurred smoothly with 7 to give the corresponding cyclohexenyl ketones (8) in good to excellent yields (Table 3). It is also noteworthy that, in addition to the methyl group, the reaction also tolerates with an ethyl group attached to the inner position of the allene moiety, thus resulting in a tetrasubstituted cyclohexenyl moiety (Table 3, entries 8-9).

Table 3
Synthesis of cylcohexenyl ketones (Ⅱ).a
A tentative pathway for the formation of cylcohexenyl ketone (6) is depicted in Scheme 1. Nucleophilic conjugate addition of triphenyl phosphine to the allenic ketone (5) triggers the tandem reaction with the formation of intermediate A. Subsequent addition of A to the electron-deficient olefin (2) gives intermediate B, which then converts to the allylic phosphonium intermediate C through proton transfer. Subsequently, the intramolecular conjugate addition of the newly formed anion on the unsaturated ketone moiety gives intermediate D, and finally, expulsion of the phosphine catalyst furnishes the cyclohexenyl ketone 6.

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Scheme 1.Plausible mechanism for the formation of cylcohexenyl ketone (6).
4. Conclusion

In summary, we have studied the tertiary phosphine catalyzed [3 + 2] and [4 + 2] annulation of 1,2-allenic ketones with activated alkenes. Through these reactions, several cyclopentenyl ketones and cyclohexenyl ketones were prepared with high efficiency under mild conditions. It was also observed that compared with analog reactions of allenoates, the phosphine catalyzed annulations of allenic ketones could be realized under much milder conditions with higher regioselectivity.

Acknowledgments

We are grateful to the National Natural Science Foundation of China (Nos. 21172057, 21272058), and the Research Fund for the Doctoral Program of Higher Education (No. 20114104110005) for financial support.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2013. 10.008.

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