6-芳氧基噁唑并[5,4-d]嘧啶-7(6H)-酮衍生物的合成与杀菌活性（英文）
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摘要
许多噁唑并嘧啶酮衍生物具有良好的生物活性,研究其合成新方法及其生物活性具有重要意义.该论文利用噁唑基膦亚胺1与异氰酸酯发生aza-Wittig反应生成噁唑基碳二亚胺2,再在碱催化下与各种酚作用,以良好的产率制得了6-芳氧基噁唑并[5,4-d]嘧啶-7(6 H)-酮衍生物4.该类化合物4具有良好的杀菌活性,如化合物4d和4j在100μg/mL浓度时对黄瓜灰霉病菌表现出92%和100%的抑制率,优于商品化杀菌剂三唑酮.
6-Aryloxyoxazolo[5,4-d]pyrimidi-7(6 H)-ones 4 were prepared in good overall yields by base catalyzed reaction of various phenols with carbodiimides 2,which were obtained from the aza-Wittig reaction of oxazolyliminophosphorane 1 with isocyanates.Some of 6-aryloxyoxazolo[5,4-d]pyrimidi-7(6 H)-ones 4 exhibited good fungicidal activities.For example,compound 4 dand 4 j showed 92% and 100%inhibitive activity against Botrytis cineapers at 100μg/mL,superior to the commercial Triadimefon.
6-Aryloxyoxazolo[5,4-d]pyrimidi-7(6 H)-ones 4 were prepared in good overall yields by base catalyzed reaction of various phenols with carbodiimides 2,which were obtained from the aza-Wittig reaction of oxazolyliminophosphorane 1 with isocyanates.Some of 6-aryloxyoxazolo[5,4-d]pyrimidi-7(6 H)-ones 4 exhibited good fungicidal activities.For example,compound 4 dand 4 j showed 92% and 100%inhibitive activity against Botrytis cineapers at 100μg/mL,superior to the commercial Triadimefon.
引文
[1]GUO P,HUANG J H,HUANG Q C,et al.Synthesis of novel 1,3-oxazole derivatives with insect growth inhibiting activities[J].Chinese Chem Lett,2013,24:957-961.
[2]WANG S L,SHI Y J,HE H B,et al.Synthesis and bioactivity of novel pyrazole oxime derivatives containing oxazole ring[J].Chinese Chem Lett,2015,26:672-674.
[3]CHOI M J,NO E S,THORAT D A,et al.Synthesis and biological evaluation of aryloxazole derivatives as antimitotic and vascular-disrupting agents for cancer therapy[J].J Med Chem,2013,56:9008-9018.
[4]YIN S,TANG C,WANG B,et al.Design,synthesis and biological evaluation of novel EGFR/HER2dual inhibitors bearing a oxazolo[4,5-g]quinazolin-2(1 H)-one scaffold[J].Eur J Med Chem,2016,120:26-36.
[5]CHEN C L,LIU F L,LEE C C,et al.Ring fusion strategy for the synthesis of anthra[2,3-d]oxazole-2-thione-5,10-dione homologues as DNA topoisomerase inhibitors and as antitumor agents[J].Eur J Med Chem,2014,87:30-38.
[6]LI D,GAO N,ZHU N,et al.Discovery of the disubstituted oxazole analogues as a novel class anti-tuberculotic agents against MDR-and XDR-MTB[J].Bioorg Med Chem Lett,2015,25:5178-5181.
[7]ZAHANICH I,KONDRATOV I,NAUMCHYK V,et al.Phenoxymethyl 1,3-oxazoles and 1,2,4-oxadiazoles as potent and selective agonists of free fatty acid receptor 1(GPR40)[J].Bioorg Med Chem Lett,2015,25:3105-3111.
[8]SENGER J,MELESINA J,MAREK M,et al.Synthesis and biological investigation of oxazole hydroxamates as highly selective histone deacetylase 6(HDAC6)inhibitors[J].JMed Chem,2016,59:1545-1555.
[9]MALOTHU N,BHANDARU J S,KULANDAIVELU U,et al.Synthesis,in vitro antimycobacterial evaluation and docking studies of some new 5,6,7,8-tetrahydropyrido[4’,3’:4,5]thieno[2,3-d]pyrimidin-4(3 H)-one schiff bases[J].Bioorg Med Chem Lett,2016,26:836-840.
[10]SAGAR S R,AGARWAL J K,PANDYA D H,et al.Design,synthesis and biological evaluation of novel pyrazolopyrimidinones as DPP-IV inhibitors in diabetes[J].Bioorg Med Chem Lett,2015,25:4428-4433.
[11]MARSHALL A J,LILL C L,CHAO M,et al.Exploring the isoform selectivity of TGX-221related pyrido[1,2-a]pyrimidinone-based Class IA PI 3-kinase inhibitors:Synthesis,biological evaluation and molecular modeling[J].Bioorg Med Chem,2015,23:3796-3808.
[12]RODRIGUES M V N,BARBOSA A F,DA SILVA J F,et al.9-Benzoyl 9-deazaguanines as potent xanthine oxidase inhibitors[J].Bioorg Med Chem,2016,24:226-231.
[13]BERTRAND S M,ANCELLIN N,BEAUFILS B,et al.The discovery of in vivo active mitochondrial branched-chain aminotransferase(BCATm)inhibitors by hybridizing fragment and HTS hits[J].J Med Chem,2015,58:7140-7163.
[14]BANOTHU J,BAVANTHULA R.Brnsted acidic ionic liquid catalyzed highly efficient synthesis of chromeno pyrimidinone derivatives and their antimicrobial activity[J].Chinese Chem Lett,2012,23:1015-1018.
[15]CLAIBOME C F,CRITCHLEY S,LANGSTON S P,et al.Heteroaryl compounds useful as inhibitors of E1activating enzymes[P].PCT Int Appl WO 2008019124,2008-02-14.
[16]HOLSCHBACH M H,BIER D,STUSGEN S,et al.W.Synthesis and evaluation of 7-amino-2-(2(3)-furyl)-5-phenylethylamino-oxazolo[5,4-d]pyrimidines as potential A2Aadenosine receptor antagonists for positron emission tomography(PET)[J].Eur J Med Chem,2006,41:7-15.
[17]MILLER D J,RAVIKUMAR K,SHEN H,et al.Structure-based design and characterization of novel platforms for ricin and shiga toxin inhibition[J].J Med Chem,2002,45:90-98.
[18]WEI H,LI Y,XIAO K,et al.Synthesis of polysubstituted pyridines via a one-pot metal-free strategy[J].Org Lett,2015,17:5974-5977.
[19]WELSCH S J,UMKEHRER M,KALINSKI C,et al.Synthesis of substituted imidazolines by an Ugi/Staudinger/aza-Wittig sequence[J].Tetrahedron Lett,2015,56:1025-1029.
[20]RAMAZANI A,KHOOBI M,TORKAMAN A,et al.One-pot,four-component synthesis of novel cytotoxic agents 1-(5-aryl-1,3,4-oxadiazol-2-yl)-1-(1H-pyrrol-2-yl)methanamines[J].Eur J Med Chem,2014,78:151-156.
[21]OKAMOTO K,SHIMBAYASHI T,TAMURA E,et al.Palladium-catalyzed Aza-Wittig-type condensation of isoxazol-5(4 H)-ones with aldehydes[J].Chem Eur J,2014,20:1490-1494.
[22]HU Y,LI X,WAN B.NIS-mediated ring-closure/opening cascade reactions of allylamides:an expedient route to oxazolines[J].Tetrahedron,2015,71:6935-6943.
[23]LI W J,LI Q,LIU D L,et al.Synthesis,fungicidal activity and sterol 14α-demethylase binding interaction of 2-azolyl-3,4-dihydroquinazolines on Penicillium digitatum[J].J Agric Food Chem,2013,61:1419-1426.
[24]YUAN D,KONG H H,DING M W.New efficient synthesis of 1H-pyrimido[2,1-b]quinazoline-2,6-diones via a tandem aza-Wittig/nucleophilic addition/intramolecular cyclization/isomerization reaction starting from the Baylis-Hillman adducts[J].Tetrahedron,2015,71:419-423.
[25]YAN Y M,RAO Y,DING M W.One-pot synthesis of multisubstituted benzimidazoles via sequential Ugi and catalytic aza-Wittig reaction starting from 2-aminobenzoyl azides[J].J Org Chem,2016,81:1263-1268.
[26]WANG Y,XIE H,PAN Y R,et al.Facile synthesis of 4-arylidene-1H-imidazol-5(4 H)-ones by a Ugi-aza-Wittig sequence[J].Synthesis,2014,46:336-342.
[27]曾国平,段连生,丁明武.新型四氢吡啶并噻吩并嘧啶-4(3H)-酮衍生物的合成[J].华中师范大学学报(自然科学版),2008,42:58-61.ZENG G P,DUAN L S,DING M W,Synthesis of tetrahydropyridothienopyrimidin-4(3 H)-one derivatives[J].J Central China Normal Univ(Nat Sci),2008,42:58-61.(Ch).
[28]ZENG G P,CAI C Q,TAN F,et al.New efficient synthesis of 2,5,6-trisubstituted oxazolo[5,4-d]pyrimidi-7(6 H)-ones via an oxazolyliminophosphorane[J].Chin Chem Lett,2015,26:1158-1160.
[2]WANG S L,SHI Y J,HE H B,et al.Synthesis and bioactivity of novel pyrazole oxime derivatives containing oxazole ring[J].Chinese Chem Lett,2015,26:672-674.
[3]CHOI M J,NO E S,THORAT D A,et al.Synthesis and biological evaluation of aryloxazole derivatives as antimitotic and vascular-disrupting agents for cancer therapy[J].J Med Chem,2013,56:9008-9018.
[4]YIN S,TANG C,WANG B,et al.Design,synthesis and biological evaluation of novel EGFR/HER2dual inhibitors bearing a oxazolo[4,5-g]quinazolin-2(1 H)-one scaffold[J].Eur J Med Chem,2016,120:26-36.
[5]CHEN C L,LIU F L,LEE C C,et al.Ring fusion strategy for the synthesis of anthra[2,3-d]oxazole-2-thione-5,10-dione homologues as DNA topoisomerase inhibitors and as antitumor agents[J].Eur J Med Chem,2014,87:30-38.
[6]LI D,GAO N,ZHU N,et al.Discovery of the disubstituted oxazole analogues as a novel class anti-tuberculotic agents against MDR-and XDR-MTB[J].Bioorg Med Chem Lett,2015,25:5178-5181.
[7]ZAHANICH I,KONDRATOV I,NAUMCHYK V,et al.Phenoxymethyl 1,3-oxazoles and 1,2,4-oxadiazoles as potent and selective agonists of free fatty acid receptor 1(GPR40)[J].Bioorg Med Chem Lett,2015,25:3105-3111.
[8]SENGER J,MELESINA J,MAREK M,et al.Synthesis and biological investigation of oxazole hydroxamates as highly selective histone deacetylase 6(HDAC6)inhibitors[J].JMed Chem,2016,59:1545-1555.
[9]MALOTHU N,BHANDARU J S,KULANDAIVELU U,et al.Synthesis,in vitro antimycobacterial evaluation and docking studies of some new 5,6,7,8-tetrahydropyrido[4’,3’:4,5]thieno[2,3-d]pyrimidin-4(3 H)-one schiff bases[J].Bioorg Med Chem Lett,2016,26:836-840.
[10]SAGAR S R,AGARWAL J K,PANDYA D H,et al.Design,synthesis and biological evaluation of novel pyrazolopyrimidinones as DPP-IV inhibitors in diabetes[J].Bioorg Med Chem Lett,2015,25:4428-4433.
[11]MARSHALL A J,LILL C L,CHAO M,et al.Exploring the isoform selectivity of TGX-221related pyrido[1,2-a]pyrimidinone-based Class IA PI 3-kinase inhibitors:Synthesis,biological evaluation and molecular modeling[J].Bioorg Med Chem,2015,23:3796-3808.
[12]RODRIGUES M V N,BARBOSA A F,DA SILVA J F,et al.9-Benzoyl 9-deazaguanines as potent xanthine oxidase inhibitors[J].Bioorg Med Chem,2016,24:226-231.
[13]BERTRAND S M,ANCELLIN N,BEAUFILS B,et al.The discovery of in vivo active mitochondrial branched-chain aminotransferase(BCATm)inhibitors by hybridizing fragment and HTS hits[J].J Med Chem,2015,58:7140-7163.
[14]BANOTHU J,BAVANTHULA R.Brnsted acidic ionic liquid catalyzed highly efficient synthesis of chromeno pyrimidinone derivatives and their antimicrobial activity[J].Chinese Chem Lett,2012,23:1015-1018.
[15]CLAIBOME C F,CRITCHLEY S,LANGSTON S P,et al.Heteroaryl compounds useful as inhibitors of E1activating enzymes[P].PCT Int Appl WO 2008019124,2008-02-14.
[16]HOLSCHBACH M H,BIER D,STUSGEN S,et al.W.Synthesis and evaluation of 7-amino-2-(2(3)-furyl)-5-phenylethylamino-oxazolo[5,4-d]pyrimidines as potential A2Aadenosine receptor antagonists for positron emission tomography(PET)[J].Eur J Med Chem,2006,41:7-15.
[17]MILLER D J,RAVIKUMAR K,SHEN H,et al.Structure-based design and characterization of novel platforms for ricin and shiga toxin inhibition[J].J Med Chem,2002,45:90-98.
[18]WEI H,LI Y,XIAO K,et al.Synthesis of polysubstituted pyridines via a one-pot metal-free strategy[J].Org Lett,2015,17:5974-5977.
[19]WELSCH S J,UMKEHRER M,KALINSKI C,et al.Synthesis of substituted imidazolines by an Ugi/Staudinger/aza-Wittig sequence[J].Tetrahedron Lett,2015,56:1025-1029.
[20]RAMAZANI A,KHOOBI M,TORKAMAN A,et al.One-pot,four-component synthesis of novel cytotoxic agents 1-(5-aryl-1,3,4-oxadiazol-2-yl)-1-(1H-pyrrol-2-yl)methanamines[J].Eur J Med Chem,2014,78:151-156.
[21]OKAMOTO K,SHIMBAYASHI T,TAMURA E,et al.Palladium-catalyzed Aza-Wittig-type condensation of isoxazol-5(4 H)-ones with aldehydes[J].Chem Eur J,2014,20:1490-1494.
[22]HU Y,LI X,WAN B.NIS-mediated ring-closure/opening cascade reactions of allylamides:an expedient route to oxazolines[J].Tetrahedron,2015,71:6935-6943.
[23]LI W J,LI Q,LIU D L,et al.Synthesis,fungicidal activity and sterol 14α-demethylase binding interaction of 2-azolyl-3,4-dihydroquinazolines on Penicillium digitatum[J].J Agric Food Chem,2013,61:1419-1426.
[24]YUAN D,KONG H H,DING M W.New efficient synthesis of 1H-pyrimido[2,1-b]quinazoline-2,6-diones via a tandem aza-Wittig/nucleophilic addition/intramolecular cyclization/isomerization reaction starting from the Baylis-Hillman adducts[J].Tetrahedron,2015,71:419-423.
[25]YAN Y M,RAO Y,DING M W.One-pot synthesis of multisubstituted benzimidazoles via sequential Ugi and catalytic aza-Wittig reaction starting from 2-aminobenzoyl azides[J].J Org Chem,2016,81:1263-1268.
[26]WANG Y,XIE H,PAN Y R,et al.Facile synthesis of 4-arylidene-1H-imidazol-5(4 H)-ones by a Ugi-aza-Wittig sequence[J].Synthesis,2014,46:336-342.
[27]曾国平,段连生,丁明武.新型四氢吡啶并噻吩并嘧啶-4(3H)-酮衍生物的合成[J].华中师范大学学报(自然科学版),2008,42:58-61.ZENG G P,DUAN L S,DING M W,Synthesis of tetrahydropyridothienopyrimidin-4(3 H)-one derivatives[J].J Central China Normal Univ(Nat Sci),2008,42:58-61.(Ch).
[28]ZENG G P,CAI C Q,TAN F,et al.New efficient synthesis of 2,5,6-trisubstituted oxazolo[5,4-d]pyrimidi-7(6 H)-ones via an oxazolyliminophosphorane[J].Chin Chem Lett,2015,26:1158-1160.