Metal-free synthesis of polysubstituted oxazoles via a decarboxylative cyclization from primary α-amino acids
© Li et al.; licensee Chemistry Central Ltd. 2013
Received: 14 March 2013
Accepted: 5 June 2013
Published: 21 June 2013
The ubiquitous oxazoles have attracted more and more attention in both industrial and academic fields for decades. This interest arises from the fact that a variety of natural and synthetic compounds which contain the oxazole substructure exhibit significant biological activities and antiviral properties. Although various synthetic methodologies for synthesis of oxazols have been reported, the development of milder and more general procedure to access oxazoles is still desirable.
In this manuscript, a novel method for synthesis of polysubstituted oxazoles was developed from metal-free decarboxylative cyclization of easily available primary α-amino acids with 2-bromoacetophenones.
The method was simple, and this reaction could be carried out smoothly under mild and metal-free conditions. By virtue of this method, various polysubstituted oxazoles were obtained from the primary α-amino acids with moderate yields.
KeywordsMetal-free Synthesis Oxazoles Oxidation Decarboxylative cyclization α-amino acids
Oxazoles are a kind of attractive heterocycles not only because of their unique structures and varied applications [1, 2] but also they serve as structural elements for a variety of natural products, pharmaceuticals and bioactive compounds [3–5]. For example, the diazonamide and phorboxazole families [6, 7], oxazole motif-containing bioactive natural products, exhibit anticancer properties. Moreover, oxazole derivatives can be employed as fluorescent dyes , corrosion inhibitors  and also as chiral ligands for transition-metal catalysts in asymmetric synthesis [10, 11]. Owing to the important applications of oxazole derivatives, various synthetic methodologies for these compounds have been reported. Generally, the procedures for the synthesis of oxazoles include the cyclodehydration of acyclic precursors [12–16], the oxidation of oxazolines [17–19] and the coupling of the prefunctionalized oxazoles with organometallic reagents [20–22]. In light of these applications, the development of milder and more general procedure to access oxazoles is still desirable. To the best of our knowledge, metal-free synthesis of polysubstituted oxazoles is rare although several methods for the synthesis of oxazoles have emerged recently [23–31].
α-Amino acids are readily available, inexpensive and stable starting materials from nature. Therefore, using α-amino acids as the nitrogen-containing motifs to construct heterocycles are very attractive synthetic method. Many reactions about the decarboxylative of α-amino acids have been developed in recent years [32–42]. For example, Fu and our group have reported the synthesis of quinazolinones via a decarboxylative coupling of α-amino acids [43, 44]. On the basis of this work, herein we report a new decarboxylative cyclization reaction to construct polysubstituted oxazoles containing the moiety of primary α-amino acids under metal-free conditions.
Results and discussion
Optimization of reaction conditions
Optimization of reaction conditions [a]
The scope of the reaction
Research of the reaction mechanism
Infrared samples were recorded on a Perkin-Elmer 2000 FTIR spectrometer and all IR data were given in cm-1. NMR spectra were recorded on Brucker AVANCE 300 NMR spectrometer. The chemical shifts (δ) and coupling constants (J) were expressed in ppm and Hz respectively. HRMS was recorded on a Micromass UK LTD GCT spectrometer. Melting points were determined on a Beijing Tech Instrument Co., LTD X-6 melting point apparatus and are uncorrected. Unless otherwise indicated, all compounds and reagents were purchased from commercial suppliers and used without further purification.
General procedure for the synthesis of polysubstituted oxazoles
1a (105.8 mg, 0.7 mmol), 2a (99.5 mg, 0.5 mmol), I2 (50.8 mg, 0.2 mmol), DMA (2 mL) and TBHP (70% aqueous solution, 1 mmol) were placed in a tube (10 mL) and sealed with a thin film. Then the reaction mixture was stirred at 25°C for 4 h, heated up to 60°C and stirred at this temperature for another 4 h. After that, the resulting mixture was cooled to the room temperature, diluted with water, extracted with ethyl acetate. The organic phase was washed with saturation sodium chloride solution, dried and filtrated. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column separation (petroleum ether:ethyl acetate = 10:1) to give 3a (154.7 mg, 70%) as light yellow solid, mp = 70–72°C.
Other oxazoles were prepared via similar procedures, for details of their characterization data and NMR spectra, see Additional file 1.
In summary, a new metal-free decarboxylative cyclization of available primary α-amino acids with 2-bromoacetophenones was developed for the synthesis of polysubstituted oxazoles. A series of oxazoles can be obtained with moderate yields under mild conditions. It is attractive for chemists and chemical industries because oxazoles are useful synthetic intermediates for bioactive compounds.
We are grateful to the Natural Science Foundation of China (20932002, 20972144, 20772118, 21272222, J1030412 and 21172205), the Ministry of Science & Technology of China (2010CB912103), the Chinese Academy of Sciences, and the Graduate Innovation Fund of USTC for support.
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