Metal-free synthesis of polysubstituted oxazoles via a decarboxylative cyclization from primary α-amino acids
Sustainable Chemical Processes volume 1, Article number: 8 (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.
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
Initially, the reaction of phenylglycine (1a) with 2-bromoacetophenone (2a) was chosen as a model reaction to optimize the reaction conditions. We studied the reaction of 0.7 mmol of 1a and 0.5 mmol of 2a, with 1 mmol of tert-butyl hydroperoxide (TBHP, 70% aqueous solution) as the oxidant and 20 mol% of molecular iodine as the catalyst. The reaction mixture was heated in N,N-dimethylacetamide (DMA, 2 mL) under air at 70°C for 5 h. The decarboxylative cyclization product 2,5-diphenyloxazole (3a) was obtained with 50% isolated yield (Table 1, entry 1). It was found that catalyst iodine was crucial for this reaction. Only trace amounts of the desired product were observed in the absence of iodine (entry 2). The replacement of catalyst iodine by copper oxide resulted in the decrease of the reaction yield (entry 3). Also, the loading of iodine had an influence on this reaction (entries 4 and 5). For instance, at loadings below or above 20 mol% of iodine, reduced yields were obtained. Besides, the base could affect this reaction. The reaction yield slightly increased when sodium carbonate (0.5 mmol) was added as base. (entry 6) After screening various bases, sodium carbonate proved to be the best base affording 3a with 54% yield (entries 6–9). Subsequently, different oxidants, such as DTBP, m-CPBA, K2S2O8, were examined in this reaction. After examination, TBHP gave the highest yield (compared entries 10–12 with entry 6). In addition, we investigated influence of temperature and time on the reaction. Lowering the reaction temperature slightly increased the reaction yield (entry 13). When the reaction was carried out at 25°C for 24 h, a yield of 60% was obtained (entry 14). Finally, the highest yield of 70% was obtained when the reaction was carried out at 25°C for 4 h and then at 60°C for another 4 h, as shown in entry 15 of Table 1.
The scope of the reaction
With the optimized reaction conditions in hand, we investigated the scope of the decarboxylative cyclization reaction (Figure 1). A series of primary α-amino acids were employed as the reaction substrates. Normally, phenylglycine, glycine, alanine, norvaline, valine, isoleucine, leucine and phenylalanine performed well in this reaction to give the corresponding substituted oxazoles with satisfactory yields (3a-3h). However, when the primary α-amino acids containing active hydrogen on the side chains, such as lysine, arginine and serine, were employed as the start materials, the decarboxylative cyclizations were blocked. Generally, electron-donating substituent (3b-3d) and the substituent with steric effect (3e-3g) had negative influence on this reaction. As for 2-bromoacetophenones, the substituent on the aromatic ring had a negative influence on the reaction yield regardless of the electron-donating groups or electron-withdrawing groups on the phenyl ring of R2 (3i-3p). It was noted that the decarboxylative cyclization also proceeded smoothly to give the corresponding products with moderate yields when 2-bromopropiophenone was employed as the reaction substrate (3q-3s). When a heterocycle compound, 2-bromo-1-(pyridin-4-yl)ethanone, was chosen as the reaction substrate, the reaction also afforded the corresponding product in 52% yield (3t).
Research of the reaction mechanism
To explore the reaction process, several control experiments were carried out (Scheme 1, see details of control experiments in Additional file 1). Firstly, when 2-bromoacetophenone was employed as substrate alone under reaction condition, no benzoylformaldehyde was obtained (eq. 1). This implied that benzoylformaldehyde was not the reaction intermediate. On the other hand, when radical scavengers, such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 1,4-benzoquinone or acrylonitrile, were added to the reaction system respectively, the yield of 3a was sharply reduced from 70% to less than 15% (eq. 2). This indicated that the reaction should undergo a radical pathway.
Based on the results described above and previous reports [27, 28, 45, 46], a plausible mechanism for this decarboxylative cyclization was proposed as follows (Scheme 2). Initially, compound A, formed by the substitution reaction of 1a with 2a, which can be transformed following two pathways: (a) I+, generated by the oxidation of iodine, could oxidize A to radical intermediate B, which eliminates one molecular of CO2 to generate radical C, which is further oxidized to imine D or its isomer E. Subsequently, F is obtained by intramolecular nucleophilic addition of E. Finally, the desired product (3a) is given by deprotonation and oxidation of F; (b) G is formed from the oxidation of A. Then 3a is obtained through H, I, J, K following a process similar to path a.
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.
Turchi IJ, Dewar MJS: Chemistry of oxazoles. Chem Rev. 1975, 75: 389-437. 10.1021/cr60296a002.
Rechavi D, Lemaire M: Enantioselective catalysis using heterogeneous Bis(oxazoline) ligands: which factors influence the enantioselectivity?. Chem Rev. 2002, 102: 3467-3494. 10.1021/cr020008m.
Wang WL, Yao DY, Gu M, Fan MZ, Li JY, Xing YC, Nan FJ: Synthesis and biological evaluation of novel bisheterocycle-containing compounds as potential anti-influenza virus agents. Bio Med Chem Lett. 2005, 15: 5284-5287. 10.1016/j.bmcl.2005.08.046.
Jin Z: Muscarine, imidazole, oxazole and thiazole alkaloids. Nat Prod Rep. 2009, 26: 382-445. 10.1039/b718045b.
Jin Z: Muscarine, imidazole, oxazole, and thiazole alkaloids. Nat Prod Rep. 2011, 28: 1143-1191. 10.1039/c0np00074d.
Wang B, Hansen TM, Weyer L, Wu D, Wang T, Christmann M, Lu Y, Ying L, Engler MM, Cink RD, et al: Total synthesis of phorboxazole a via de novo oxazole formation: convergent total synthesis. J Am Chem Soc. 2010, 133: 1506-1516.
Zhang J, Ciufolini MA: An Approach to the Bis-oxazole Macrocycle of Diazonamides. Org Lett. 2010, 13: 390-393.
Tang JS, Verkade JG: Chiral auxiliary-bearing isocyanides as synthons: Synthesis of strongly fluorescent (+)-5-(3,4-dimethoxyphenyl)-4- N- (4S)-2-oxo-4-(phenylmethyl)-2-oxazoli dinyl carbonyl oxazole and its enantiomer. J Org Chem. 1996, 61: 8750-8754. 10.1021/jo961554g.
Iddon B: Synthesis and reactions of lithiated monocyclic azoles containing 2 or more hetero-atoms .2. oxazoles. Heterocycles. 1994, 37: 1321-1346. 10.3987/REV-93-SR9.
Desimoni G, Faita G, Jørgensen KA: C2-Symmetric chiral Bis(oxazoline) ligands in asymmetric catalysis. Chem Rev. 2006, 106: 3561-3651. 10.1021/cr0505324.
Hargaden GC, Guiry PJ: Recent applications of oxazoline-containing ligands in asymmetric catalysis. Chem Rev. 2009, 109: 2505-2550. 10.1021/cr800400z.
Ferrini PG, Marxer A: A New synthesis of oxazole. Angew Chem Int Ed. 1963, 2: 99-99.
Nesi R, Turchi S, Giomi D: New perspectives in oxazole chemistry: synthesis and cycloaddition reactions of a 4-nitro-2-phenyl Derivative1. J Org Chem. 1996, 61: 7933-7936. 10.1021/jo9608580.
Arcadi A, Cacchi S, Cascia L, Fabrizi G, Marinelli F: Preparation of 2,5-disubstituted oxazoles from N-propargylamides. Org Lett. 2001, 3: 2501-2504. 10.1021/ol016133m.
Shi B, Blake AJ, Lewis W, Campbell IB, Judkins BD, Moody CJ: Rhodium carbene routes to oxazoles and thiazoles. Catalyst effects in the synthesis of oxazole and thiazole carboxylates, phosphonates, and sulfones. J Org Chem. 2009, 75: 152-161.
Ritson DJ, Spiteri C, Moses JE: A silver-mediated One-step synthesis of oxazoles. J Org Chem. 2011, 76: 3519-3522. 10.1021/jo1025332.
Meyers AI, Tavares F: The oxidation of 2-oxazolines to 1,3-oxazoles. Tetrahedron Lett. 1994, 35: 2481-2484. 10.1016/S0040-4039(00)77149-8.
Meyers AI, Tavares FX: Oxidation of oxazolines and thiazolines to oxazoles and thiazoles. Application of the kharasch − sosnovsky reaction. J Org Chem. 1996, 61: 8207-8215. 10.1021/jo9613491.
Phillips AJ, Uto Y, Wipf P, Reno MJ, Williams DR: Synthesis of functionalized oxazolines and oxazoles with DAST and deoxo-fluor. Org Lett. 2000, 2: 1165-1168. 10.1021/ol005777b.
Ferrer Flegeau E, Popkin ME, Greaney MF: Suzuki coupling of oxazoles. Org Lett. 2006, 8: 2495-2498. 10.1021/ol060591j.
Lee K, Counceller CM, Stambuli JP: Nickel-catalyzed synthesis of oxazoles via C − S activation. Org Lett. 2009, 11: 1457-1459. 10.1021/ol900260g.
Williams DR, Fu L: General methodology for the preparation of 2,5-disubstituted-1,3-oxazoles. Org Lett. 2010, 12: 808-811. 10.1021/ol902833p.
Herrera A, Martinez-Alvarez R, Ramiro P, Molero D, Almy J: New easy approach to the synthesis of 2,5-disubstituted and 2,4,5-trisubstituted 1,3-oxazoles. The reaction of 1-(methylthio)acetone with nitriles. J Org Chem. 2006, 71: 3026-3032. 10.1021/jo052619v.
Graham TH: A direct synthesis of oxazoles from aldehydes. Org Lett. 2010, 12: 3614-3617. 10.1021/ol101346w.
Jiang H, Huang H, Cao H, Qi C: TBHP/I-2-mediated domino oxidative cyclization for One-Pot synthesis of polysubstituted oxazoles. Org Lett. 2010, 12: 5561-5563. 10.1021/ol1023085.
Zhao F, Liu X, Qi R, Zhang-Negrerie D, Huang J, Du Y, Zhao K: Synthesis of 2-(trifluoromethyl)oxazoles from beta-monosubstituted enamines via Phl(OCOCF3)(2)-mediated trifluoroacetoxylation and cyclization. J Org Chem. 2011, 76: 10338-10344. 10.1021/jo202070h.
Liu X, Cheng R, Zhao F, Zhang-Negrerie D, Du Y, Zhao K: Direct β-acyloxylation of enamines via PhIO-mediated intermolecular oxidative C–O bond formation and its application to the synthesis of oxazoles. Org Lett. 2012, 14: 5480-5483. 10.1021/ol3025583.
Xie J, Jiang H, Cheng Y, Zhu C: Metal-free, organocatalytic cascade formation of C-N and C-O bonds through dual sp3 C-H activation: oxidative synthesis of oxazole derivatives. Chem Commun. 2012, 48: 979-981. 10.1039/c2cc15813b.
Xue W-J, Li Q, Zhu Y-P, Wang J-G, Wu A-X: Convergent integration of two self-labor domino sequences: a novel method for the synthesis of oxazole derivatives from methyl ketones and benzoins. Chem Commun. 2012, 48: 3485-3487. 10.1039/c2cc18077d.
Zheng Y, Li X, Ren C, Zhang-Negrerie D, Du Y, Zhao K: Synthesis of oxazoles from enamides via phenyliodine diacetate-mediated intramolecular oxidative cyclization. J Org Chem. 2012, 77: 10353-10361. 10.1021/jo302073e.
Gao Q-H, Fei Z, Zhu Y-P, Lian M, Jia F-C, Liu M-C, She N-F, Wu A-X: Metal-free dual sp3 C–H functionalization: I2-promoted domino oxidative cyclization to construct 2,5-disubstituted oxazoles. Tetrahedron. 2013, 69: 22-28. 10.1016/j.tet.2012.10.072.
Cohen N, Blount JF, Lopresti RJ, Trullinger DP: A novel sterically mediated transformation of proline. J Org Chem. 1979, 44: 4005-4007. 10.1021/jo01336a066.
Fan R, Li W, Wang B: A one-pot oxidative decarboxylation-friedel-crafts reaction of acyclic [small alpha]-amino acid derivatives activated by the combination of iodobenzene diacetate/iodine and iron dust. Org Biomol Chem. 2008, 6: 4615-4621. 10.1039/b815227f.
Zheng L, Yang F, Dang Q, Bai X: A cascade reaction with iminium Ion isomerization as the Key step leading to tetrahydropyrimido[4,5-d]pyrimidines. Org Lett. 2008, 10: 889-892. 10.1021/ol703049j.
Bi H-P, Chen W-W, Liang Y-M, Li C-J: A novel iron-catalyzed decarboxylative Csp3 − Csp2 coupling of proline derivatives and naphthol. Org Lett. 2009, 11: 3246-3249. 10.1021/ol901129v.
Bi H-P, Zhao L, Liang Y-M, Li C-J: The copper-catalyzed decarboxylative coupling of the sp3-hybridized carbon atoms of α-amino acids. Angew Chem Int Ed. 2009, 48: 792-795. 10.1002/anie.200805122.
Bi H-P, Teng Q, Guan M, Chen W-W, Liang Y-M, Yao X, Li C-J: Aldehyde- and ketone-induced tandem decarboxylation-coupling (Csp3 − Csp) of natural α-amino acids and alkynes. J Org Chem. 2010, 75: 783-788. 10.1021/jo902319h.
Zhang C, Seidel D: Nontraditional reactions of azomethine ylides: decarboxylative three-component couplings of α-amino acids. J Am Chem Soc. 2010, 132: 1798-1799. 10.1021/ja910719x.
Das D, Richers MT, Ma L, Seidel D: The decarboxylative strecker reaction. Org Lett. 2011, 13: 6584-6587. 10.1021/ol202957d.
Wang Q, Wan C, Gu Y, Zhang J, Gao L, Wang Z: A metal-free decarboxylative cyclization from natural [small alpha]-amino acids to construct pyridine derivatives. Green Chem. 2011, 13: 578-581. 10.1039/c0gc00753f.
Zhang C, Das D, Seidel D: Azomethine ylide annulations: facile access to polycyclic ring systems. Chem Sci. 2011, 2: 233-236. 10.1039/c0sc00432d.
Wang Q, Zhang S, Guo F, Zhang B, Hu P, Wang Z: Natural α-amino acids applied in the synthesis of imidazo[1,5-a]N-heterocycles under mild conditions. J Org Chem. 2012, 77: 11161-11166. 10.1021/jo302299u.
Xu W, Fu H: Amino acids as the nitrogen-containing motifs in copper-catalyzed domino synthesis of N-heterocycles. J Org Chem. 2011, 76: 3846-3852. 10.1021/jo2002227.
Yan Y, Wang Z: Metal-free intramolecular oxidative decarboxylative amination of primary [small alpha]-amino acids with product selectivity. Chem Commun. 2011, 47: 9513-9515. 10.1039/c1cc12885j.
Wan C, Gao L, Wang Q, Zhang J, Wang Z: Simple and efficient preparation of 2,5-disubstituted oxazoles via a metal-free-catalyzed cascade cyclization. Org Lett. 2010, 12: 3902-3905. 10.1021/ol101596s.
Wan C, Zhang J, Wang S, Fan J, Wang Z: Facile synthesis of polysubstituted oxazoles via a copper-catalyzed tandem oxidative cyclization. Org Lett. 2010, 12: 2338-2341. 10.1021/ol100688c.
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.
The authors declare that they have no competing interests.
In this research YL designed experimental procedures and carried out the experimental work. YL, FG and ZZ prepared this manuscript. ZW, who is corresponding author for this manuscript, evaluated the progress of the study. All authors read and approved the final manuscript.
Electronic supplementary material
Authors’ original submitted files for images
Below are the links to the authors’ original submitted files for images.
About this article
Cite this article
Li, Y., Guo, F., Zha, Z. et al. Metal-free synthesis of polysubstituted oxazoles via a decarboxylative cyclization from primary α-amino acids. sustain chem process 1, 8 (2013). https://doi.org/10.1186/2043-7129-1-8
- Decarboxylative cyclization
- α-amino acids