Chinese Chemical Letters  2015, Vol.26 Issue (09): 1158-1160   PDF    
New efficient synthesis of 2, 5, 6-trisubstituted oxazolo[5, 4-d]pyrimidi-7(6H)-ones via an oxazolyliminophosphorane
Guo-Ping Zenga, Chang-Quan Caib, Fen Tana, Ming-Wu Dingb     
a Hubei Province Key Laboratory of Purification and Application of Plant Anti-cancer Active Ingredients, Hubei University of Education, Wuhan 430205, China;
b Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Central China Normal University, Wuhan 430079, China
Abstract: A new efficient synthesis of 2, 5, 6-trisubstituted oxazolo[5, 4-d]pyrimidi-7(6H)-ones by consecutive aza-Wittig reaction was developed. The sequential three-component reaction of oxazolyliminophosphorane 4, isocyanates and amines produced 2, 5, 6-trisubstituted oxazolo[5, 4-d]pyrimidi-7(6H)-ones 7 in good overall yields in the presence of catalytic amount of EtONa.
Key words: Oxazolo[5, 4-d]pyrimidi-7(6H)-one     Aza-Wittig reaction     Iminophosphorane     Carbodiimide    
1. Introduction

Oxazoles represent an important class of heterocycles because they are found as the building block in a multitude of natural products and possess broad spectrum of biological properties in medicinal chemistry [1, 2, 3]. The structural diversity and complexity of the oxazoles has generated much interest in the development of mild methods for their synthesis. The oxazolo[5, 4, d]pyrimidi- 7(6H)-one system,a kind of fused oxazole,is of great importance because of its structural similarity with guanine. Some derivatives of oxazolo[5, 4, d]pyrimidi-7(6H)-one have shown remarkable biological properties such as antitumor activities [4],whereas others were evaluated as brain A2A adenosine receptor antagonists or as ricin and shiga toxin inhibitors [5, 6]. The methods described for the preparation of this ring system either involves cyclization of properly substituted 5-(acylamino)-4-hydroxypyrimidines in the presence of dehydrating agent,or reaction starting from 5-amino- 4-ethoxycarbonyl(cyano)oxazoles [7, 8, 9, 10, 11, 12, 13, 14]. However,most of the methods often require relatively harsh acid,dehydrating conditions or heating at high temperature,and there is no report of a generally useful synthesis of 2,5,6-trisubstituted oxazolo[5,4- d]pyrimidi-7(6H)-ones starting from easily accessible 5-amino- 4-ethoxycarbonyloxazoles.

The aza-Wittig reactions of iminophosphoranes with carbonyl compounds provide one of the best method for the construction of C55N double bond under mild and neutral conditions. This type of reaction has recently applied widely in the synthesis of nitrogencontaining heterocyclic compounds with structural diversity [15, 16, 17, 18]. The aza-Wittig reactions between iminophosphoranes with isocyanates produce high reactive carbodiimides,which may be used in preparing many heterocycles in further sequential reactions [19, 20]. Recently we have been interested in the synthesis of various heterocycles via aza-Wittig reaction,with the aim of evaluating their biological activities [21, 22, 23, 24, 25, 26]. Herein we wish to reported a new efficient synthesis of 2,5,6-trisubstituted oxazolo[5, 4, d]pyrimidi-7(6H)-ones from an oxazolyliminophosphorane 4,isocyanates and amines.

2. Experimental

Unless otherwise noted,all materials were commercially available and were used directly without further purification. All solvents were redistilled before use. 1H NMR spectra were recorded on a Mercury-Plus 400 spectrometer in CDCl3 with TMS as the internal reference. MS spectra were determined using a Trace MS 2000 organic mass spectrometer. IR were recorded on a PE-983 infrared spectrometer as KBr pellets with absorption in cm-1. Elemental analyses were performed on a Vario EL III elemental analysis instrument. Melting points were taken on an X- 4 binocular microscope melting point apparatus (Beijing Tech Instruments Co.,Beijing,China) and are uncorrected. The ethyl 5-amino-2-methyloxazole-4-carboxylate 3 were prepared according to the reported method [27].

2.1. Preparation of iminophosphorane 4

To a mixture of ethyl 5-amino-2-methyloxazole-4-carboxylate 3 (1.36 g,8 mmol),PPh3 (3.14 g,12 mmol) and C2Cl6 (2.84 g, 12 mmol) in dry CH2Cl2 (40 mL),was added dropwise Et3N (2.42 g, 24 mmol) at room temperature. After stirred for 3 h,the solvent was removed under reduced pressure and the residue was recrystallized from ethanol-ether (1:3) to give iminophosphorane 4 as pale yellow crystals (2.68 g,yield 78%),mp[3TD$DIF]: 121-123 ℃. 1H NMR (400 MHz,CDCl3): δ 7.82-7.27 (m,15H,Ar-H),4.31 (q,2H, J = 6.8 Hz,OCH2),2.12 (s,3H,CH3),1.37 (t,3H,J = 7.0 Hz,CH3). IR (KBr,cm-1): 1699,1621,1563,1439,1268,1172. MS (70 eV) m/z (%): 430 (M+,50),262 (100),183 (51),108 (13). Anal. Calcd. for C25H23N2O3P (430.4): C,69.76; H,5.39; N,6.51. Found: C,70.01; H, 5.25; N,6.27.

2.2. General preparation of 2-methyl-5-amino-6-aryl-oxazolo[5, 4-d]pyrimidi-7(6H)-ones 7a-7i

To a solution of iminophosphorane 4 (0.86 g,2 mmol) in dry methylene dichloride (15 mL) was added aromatic isocyanate (2 mmol) under nitrogen at room temperature. After the reaction mixture was left unstirred for 8-12 h at 0-5 ℃,the solvent was removed off under reduced pressure and Et2O/ petroleum ether (1:2,10 mL) was added to precipitate triphenylphosphine oxide. Removal of the solvent gave carbodiimide 5,which were used directly without further purification. To the solution of carbodiimide 5 prepared above in CH3CN (15 mL) was added an amine (2 mmol). After the mixture was stirred for 0.5-4 h,several drops of EtONa in EtOH was added. The mixture was stirred for 4-8 h at room temperature under dry N2 protection. The solution was condensed and the residual was recrystallized from ethanol to give 2-methyl-5-amino-6-aryloxazolo[ 5,4-d]pyrimidi-7(6H)-ones 7a-7i.

3. Results and discussion

The ethyl 5-amino-2-methyloxazole-4-carboxylate 3 was easily prepared by acid catalytic cyclization of compound 2,which was obtained from ethyl cyanoactate 1,nitrous acid,Na2S2O4 and acetic anhydride [27]. Further treatment of 3 with triphenylphosphine, hexachloroethane and triethylamine produced iminophosphorane 4 in good yield (Scheme 1). The conversion of 5-amino-2- methyloxazole-4-carboxylate 3 to iminophosphorane 4 involves initial formation of dichlorotriphenyl phosphorane between reaction of triphenylphosphine with hexachloroethane,and further reaction with compound 3 to give iminophosphorane 4 in the presence of triethylamine.

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Scheme 1.Preparation of oxazolo[5, 4, d]pyrimidi-7(6H)-ones 7. (a) NaNO2/HOAc,then Na2S2O4/Ac2O,H2O,0-5 ℃,3 h,66%; (b) HCl,then NaHCO3,CH3COCH3,r.t.,2 h,89%; (c) Ph3P,C2Cl6,Et3N,CH2Cl2,r.t.,3 h,78%; (d) ArNCO,CH2Cl2,0-5 ℃,8-12 h; (e) HNR1R2,CH3CN,r.t.,0.5-4 h; (f) EtONa,CH3CN,r.t.,4-8 h,72%-87%.

Iminophosphorane 4 had good reactivity as it reacted with aromatic isocyanates even at low temperature (0-5 ℃). The carbodiimide intermediates 5 were produced and were then allowed to react with secondary amines to generate guanidines 6. In the presence of catalytic amount of sodium ethoxide,6 were easily converted to 5-dialkylamino oxazolo[5, 4, d]pyrimidi-7(6H)- ones 7 in satisfactory yields at room temperature under dry N2 protection. It is noteworthy that the reaction proceeds under mild conditions to give various substituted oxazolo[5, 4, d]pyrimidi- 7(6H)-ones 7,and the overall transformation is run in a simple onepot procedure from iminophosphorane 4 in good overall yields. The results are listed in Table 1. As indicated in Table 1,good yields were obtained whenever dialkylamines (compounds 7a,7c and 7h),cyclic amines (compounds 7e,7f,7g and 7i) or alkylarylamines (compound 7d) were used. The isolated yield of 7 was good even as the bulky di-iso-propylamine was applied (compound 7b).

The structure of compounds 7 was confirmed by their spectra data (Table 2). For example,the 1H NMR spectrum of 7a shows doublets at δ 2.84 due to -NCH2- group. The signals of CH3 appear at δ 2.54 as singlet. The signals of CH(CH3)2 appear at δ 1.84-1.80 as multiplets and δ 0.78 as doublets,respectively. The signals attributable to the Ar-Hs are found at δ 7.52-7.28 as mutiplets. The IR spectra of 7a revealed C55O absorption bands at 1713 cm-1. The MS spectrum of 7a shows molecular ion peak at m/z 354 with 93% abundance.

Table 1
Synthesis of 2,5,6-trisubstituted oxazolo[5, 4, d]pyrimidi-7(6H)-ones 7a-7i by aza-Wittig reaction at room temperature.

Table 2
Mp,IR,MS and 1H NMR of 7a-7i.
4. Conclusion

We described a new efficient synthesis of 2,5,6-trisubstituted oxazolo[5, 4, d]pyrimidi-7(6H)-ones,which are of considerable interest as potential biological active compounds or pharmaceuticals, by the aza-Wittig reaction. This protocol presented many advantages,such as good yields,mild reaction condition,readily available starting material,and simple purification procedure.

Acknowledgments

We gratefully acknowledge financial support of this work by the National Natural Science Foundation of China (No. 21172085), the Natural Science Foundation of Hubei Province (No. 2014CFB567) and the Open Foundation of Hubei Province Key Laboratory of Purification and Application of Plant Anti-cancer Active Ingredients.

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