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Cycloaddition of Tosylmethyl Isocyanide with Styrylisoxazoles

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Cycloaddition of Tosylmethyl Isocyanide with Styrylisoxazoles molecules Article [3+2] Cycloaddition Cycloaddition of of Tosylmethyl Tosylmethyl Isocyanide withwith Styrylisoxazoles: Facile Facile Access to Polysubstituted 3- (Isoxazol-5-yl)pyrroles3-(Isoxazol-5-yl)pyrroles Xueming Zhang 1,, Xianxiu Xianxiu Xu Xu 22 andand Dawei Dawei Zhang Zhang 1,1,** 1 1 CollegeCollege of of Chemistry, Chemistry, Jilin Jilin University University,, Changchun Changchun 130012, 130012, China; China; [email protected] [email protected] 2 2 CollegeCollege of of Chemistry, Chemistry, Chemical Chemical Engineering Engineering and and Materials Materials Science, Science, Key Key Laboratory Laboratory of of Molecular Molecular and and NanoNano Probes, Probes, Ministry Ministry of of Education, Education, Shan Shandongdong Normal Normal University, University, Jinan Jinan 250014, 250014, China; China; [email protected]@sdnu.edu.cn * Correspondence:Correspondence: [email protected]; [email protected]; Tel.: Tel.: +86-431-878-36471 +86-431-878-36471 Received: 16 June 2017; Accepted: 3 3 July July 2017; Published: 7 7 July July 2017 2017 Abstract: A facile access to polysubstitutedpolysubstituted 3-(isoxazol-5-yl)pyrroles3-(isoxazol-5-yl)pyrroles was developed through [3+2] cycloaddition of of tosylmethyl isocyanide isocyanide (TosMIC) (TosMIC) and styrylisoxazoles. In In the the presence presence of of KOH, KOH, various styrylisoxazolesstyrylisoxazoles reactedreacted smoothly smoothly with with tosylmethyl tosylmethyl isocyanide isocyanide and and analogs analogs to deliver to deliver a wide a widerange range of 3-(isoxazol-5-yl)pyrroles of 3-(isoxazol-5-yl)pyrroles at ambient at ambient temperature. temperature. This This transformation transformation isis operationally simple, high-yielding, and displays broad substrate scope. Keywords: isoxazol-5-ylpyrroles;isoxazol-5-ylpyrroles; [3+2]cycloaddition; TosMIC; TosMIC; 3-methyl-4-nitro-5-styrylisoxazoles 1. Introduction Pyrrole derivatives are one of of the the most most relevant relevant he heterocyclesterocycles with with important important biological biological activities, activities, which includes antitumour, antibacterial, antiviral, anti-inflammatory, anti-inflammatory, antioxidative, and are also widely used in organic synthesissynthesis asas keykey heterocyclesheterocycles and/orand/or intermediates for for the preparation of natural compounds and related structures, and molecularmolecular sensorssensors [[1].1]. In this context, isoxazole substituted pyrroles pyrroles are are present present as as the the core core substructure substructure inin some some meaningful meaningful compounds, compounds, such such as isoxazolylpyrrolesas isoxazolylpyrroles I andI IIand areII inhibitorsare inhibitors to oral toand oral mouth and cancer mouth cell cancer and the cell activators and the to activators cellular tumorto cellular antigen tumor p53 antigen[2,3]. Isoxazolylpyrroles p53 [2,3]. Isoxazolylpyrroles III and IV are IIItheand key IVintermediatesare the key in intermediates the synthesis of in bioactivethe synthesis prodiginines of bioactive natural prodiginines products natural and thei productsr congeners, and their and congeners, the precursors and the structures precursors of phosphodiesterasestructures of phosphodiesterase inhibitors PDE-I inhibitors and PDE-II, PDE-I whic andh inhibitory PDE-II, which activity inhibitory toward cyclic activity adenosine- toward 3cyclic′,5′-monophosphate adenosine-30,50 -monophosphatephosphodiesterase, phosphodiesterase, respectively [4,5]. respectively Isoxazolylpyrroles [4,5]. Isoxazolylpyrroles V is a receptor Vforis recognitiona receptor for and recognition sensing purposes and sensing in aprotic purposes solvents in aprotic [6,7]. solvents(Figure 1). [6, 7]. (Figure1). N O Ph PhH2CN HO OH Br Ph O O N N N Br N O N H H EtOOC Ⅰ Ⅱ Ⅲ R4 1 O R H2N NH2 R3 N N O N R2 N O YH H Ⅳ Ⅴ Figure 1. ExamplesExamples of of biologically biologically active, isox isoxazole-substitutedazole-substituted pyrrole derivatives. Molecules 2017, 22, 1131; doi:10.3390/molecules22071131 doi:10.3390/molecules22071131 www.mdpi.com/journal/moleculeswww.mdpi.com/journal/molecules Molecules 2017, 22, 1131 2 of 11 Molecules 2017, 22, 1131 2 of 11 In the view of the applications of isoxazole substituted pyrrole, some synthetic methods have In the view of the applications of isoxazole substituted pyrrole, some synthetic methods have been been developed for their preparation. Among these known synthetic approaches, two main strategies developed for their preparation. Among these known synthetic approaches, two main strategies are are shown as follows: one is the construction of isoxazole ring from starting materials containing shown as follows: one is the construction of isoxazole ring from starting materials containing pyrrole pyrrole ring, such as the 1,3-dipolar cycloaddition reaction of 1,5-diphenyl-1,4-pentadien-3-one with ring, such as the 1,3-dipolar cycloaddition reaction of 1,5-diphenyl-1,4-pentadien-3-one with nitrile nitrile oxides in the presence of chloramine-T reported by Padmavathi et al. (Scheme 1, Equation (1)) oxides in the presence of chloramine-T reported by Padmavathi et al. (Scheme1, Equation (1)) [ 8], [8] , or [3+2]-cycloadditions of enaminone and hydroxylamine hydrochloride reported by Gomha et or [3+2]-cycloadditions of enaminone and hydroxylamine hydrochloride reported by Gomha et al. al. (Scheme 1, Equation (2)) [3]. In contrast, another synthetic strategy is through the construction of (Scheme1, Equation (2)) [ 3]. In contrast, another synthetic strategy is through the construction pyrrole ring from starting materials containing isoxazole ring , including the four-component of pyrrole ring from starting materials containing isoxazole ring , including the four-component coupling reaction of a functionalized silane, a nitrile, an aldehyde, and trimethylsilylcyanide by coupling reaction of a functionalized silane, a nitrile, an aldehyde, and trimethylsilylcyanide by Yb(OTf)3-catalyzed reported by Konakahara et al. (Scheme 1, Equation (3)) [9]. Despite these Yb(OTf)3-catalyzed reported by Konakahara et al. (Scheme1, Equation (3)) [ 9]. Despite these achievements, the development of novel methods for the convenient synthesis of the isoxazole achievements, the development of novel methods for the convenient synthesis of the isoxazole substituted pyrroles is still of great interest. substituted pyrroles is still of great interest. Scheme 1. Comparison between the selected existi existingng literature exampl exampleses and this work. In the past decades, a variety of elegant methods for the synthesis of pyrroles or oligofunctional pyrroles have been reported, including the classical Hantzsch reaction [10], [10], the Paal-Knorr cyclization reaction [[10],10], the vanvan LeusenLeusen cyclizationcyclization [[11],11], andand otherother cyclizationscyclizations [[11].11]. Among them,them, thethe [3+2][3+2] cycloaddition ofof tosylmethyltosylmethyl isocyanide isocyanide with with electron-deficient electron-deficient olefins, olefins, developed developed by by van van Leusen Leusen et al.,et al.,is one is one of theof the most most promising promising methods methods [12 [12–18].–18]. A A wide wide range range of of electron-deficientelectron-deficient olefins,olefins, such as α,β-unsaturated-unsaturated esters, esters, ketones ketones or or ni nitriles,triles, nitroolefins nitroolefins and and styrenes, styrenes, et etc.,c., are well tolerated in this reaction [[19–36].19–36]. 3-Methyl-4-nitro-5-alkenylisoxazoles, 3-Methyl-4-nitro-5-alkenylisoxazoles, developed developed by by Adamo Adamo et et al al.,., are excellent activated olefins,olefins, which which hold hold excellent excellent potential potential for thefor generationthe generation of diversity of diversity [37–40 ].[37–40]. In 2015, In Adamo 2015, Adamoand co-workers and co-workers reported reported an additional an additional reaction reaction of 3-methyl-4-nitro-5-alkenylisoxazoles of 3-methyl-4-nitro-5-alkenylisoxazoles and ethyl and ethylisocyanoacetate isocyanoacetate to give to enantioenriched give enantioenriche monoadducts;d monoadducts; then, resulting then, adducts resulting were adducts subsequently were subsequently cyclized to give 2,3-dihydropyrroles [41]. Although the stepwise synthesis of dihydropyrroles from styrylisoxazoles was developed [41], to our knowledge, the [3+2] cycloaddition Molecules 2017, 22, 1131 3 of 11 cyclized to give 2,3-dihydropyrroles [41]. Although the stepwise synthesis of dihydropyrroles from styrylisoxazoles was developed [41], to our knowledge, the [3+2] cycloaddition reaction of styrylisoxazoles with TosMIC for the synthesis of isoxazolylpyrroles has not been reported so far. As partMolecules of our 2017 continued, 22, 1131 efforts to develop the heterocyclization of TosMIC [42–47], we report3 of 11 herein an expedient and convenient one-pot synthesis of isoxazole-substituted pyrrole derivatives from [3+2] reaction of styrylisoxazoles with TosMIC for the synthesis of isoxazolylpyrroles has not been reported cycloadditionso far. As of part 3-methyl-4-nitro-5-styrylisoxazoles of our continued efforts to develop the with heterocyclization TosMIC and of analogs TosMIC (Scheme [42–47], we1, Equationreport (4)). Under basicherein conditions, an expedient various and convenient styrylisoxazoles one-pot synthesis reacted of smoothly isoxazole-substituted with TosMIC pyrrole and analogsderivatives to deliver a wide rangefrom [3+2] of polysubstituted cycloaddition of 3-methyl-4-nitro-5-styrylisoxazoles isoxazolylpyrroles
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