A retro-Diels-Alder approach to oxazoles and imidazoles

Eissenstat, Michael A.; Weaver, John D.

doi:10.1021/jo00064a029

Cited by 28 publications

(9 citation statements)

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“…14) Hydroxylation with OsO 4 and methylmorpholine N-oxide 15) in acetone/water afforded a 74% yield of glycol 4, which upon treatment with dimethoxypropane gave acetonide 5. An attempt to convert 5 into diamine 7 in one step by heating with KOH in methanol at 155°C afforded a complex mixture including only traces of the desired product, while a two-steps process, heating of compound 5 with KOH in methanol at 65°C, isolation of the resulting imidazolone 6, and heating of 6 with KOH in methanol at 155°C in a sealed tube, 16) afforded a good yield of a product that could be by identified as 7 by 1 H-NMR spectroscopy. Due to the lability and volatility of this kind of compounds, 16) 7 was used in the next step without further pu-rification.…”

Section: Resultsmentioning

confidence: 99%

“…An attempt to convert 5 into diamine 7 in one step by heating with KOH in methanol at 155°C afforded a complex mixture including only traces of the desired product, while a two-steps process, heating of compound 5 with KOH in methanol at 65°C, isolation of the resulting imidazolone 6, and heating of 6 with KOH in methanol at 155°C in a sealed tube, 16) afforded a good yield of a product that could be by identified as 7 by 1 H-NMR spectroscopy. Due to the lability and volatility of this kind of compounds, 16) 7 was used in the next step without further pu-rification. Thus, crude 7 was condensed with benzil in THF with acetic acid as catalyst, and the resulting dihydropyrazine (8) was aromatized in 86% yield by refluxing with 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1-2-dicarbonitrile (DDQ) in toluene for 2.5 h. Attempts to achieve mild cleavage of the acetonide moiety of compound 9 (treatment with 60% AcOH or HCO 2 H, at r.t. or under reflux, or with HClO 4 or BF 3 · OEt 2 at r.t.) were all unsuccessful, the starting material being recovered or intractable mixtures of unidentified products being obtained.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of Novel Purinyl-1'-homocarbanucleosides Based on a Cyclopenta[b]pyrazine System

Balo

López

Caamaño

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis of Novel Purinyl-1'-homocarbanucleosides Based on a Cyclopenta[b]pyrazine System

Balo

López

Caamaño

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…First time imidazole was prepared in 1858. Now-a-days several methods of sythesis of imidazoles are available some of these are given below in Schemes 1-9 [20][21][22][23][24][25][26][27][28][29]. From alkene, carbon monoxide and ammonia [25].…”

Section: Synthesis Of Imidazole and Their Derivativesmentioning

confidence: 99%

Studies on Imidazole and Its Derivatives with Particular Emphasis on Their Chemical/biological Applications as Bioactive Molecules/Intermediated to Bioactive Molecule

kumar¹,

Kumar²,

Raj³

2017

Curr Synthetic Sys Biol

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Imidazoles are heterocycles with five-member ring structure heterocyclic compounds have gained very remarkable place in recent years because of their exceptional pharmacological activities. The imidazole nucleus is a main synthetic strategy in drug discovery. Imidazole is a planar five-member ring system having N atom at 1 and 3 positions. The systemic name for the compound is 1, 3 diazoles, one of the N bear an H atom and other to be termed as a pyrrole type N. Imidazole was first named as glyoxaline. It is amphoteric in nature, and it has susceptibility to be attacked by electrophile and nucleophile. It is a constituent of the purine nucleus and histidine amino acid, 4-amino imidazole-5-carboxamide found naturally as a riboside. This interesting group of heterocyclic compounds has wide range biological activities such as, analgesic, anti-inflammatory anticancer, antiviral, anthelmintic, anticonvulsant, antiulcer, antimicrobial, anti-allergic activity etc. Various methods employed for the synthesis of imidazole's and their chemical structure reactions offer enormous scope in the field of medicinal chemistry.

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“…Inspired by their elegant pioneer work, we studied the alkylation of 11 with different alkyl iodides under our conditions. We were pleased to find that the cross-coupling reaction was carried out smoothly affording 2-alkyl-4-iodooxazole as the only coupling product in good yields (entries [11][12][13][14]. Confirmation of this selectivity was exemplified by lithiation of 4-iodooxazole 9j with nBuLi, and quenching with H 2 O to obtain the known compound 2-butyloxazole.…”

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confidence: 99%

“…Confirmation of this selectivity was exemplified by lithiation of 4-iodooxazole 9j with nBuLi, and quenching with H 2 O to obtain the known compound 2-butyloxazole. 14 To the best of our knowledge, there is no literature precedent about the regioselective 2-alkylation on 2,4-di-iodooxazole. This result implies that the current method is applicable to the synthesis of differentially substituted 2,4-di-alkyl-oxazoles, a Unless otherwise noted, 2-iodooxazole (0.094 mmol, 1.0 equiv), n-C 3 H 7 CH 2 -I (1.3 equiv), t-BuLi (3.0 equiv), 9-methoxy-BBN (3.42 equiv), Et 2 O (1 mL), DMF (1 mL), the palladium catalyst precursors (10%), AsPh 3 (15%), Cs 2 CO 3 (4.0 equiv), K 3 PO 4 (3.0 equiv), NaOH (4.0 equiv), and H 2 O (24.0 equiv) were used.…”

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confidence: 99%

An efficient preparation of 2-alkyl-oxazoles from 2-iodooxazoles

Zhang

Lee

Liu

et al. 2013

Tetrahedron Letters

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a b s t r a c tAn efficient synthesis toward 2-alkyl substituted oxazoles has been achieved through Suzuki cross-coupling reaction. Treatment of various alkyl iodides with 9-MeO-BBN, followed by in situ palladium-catalyzed carbon-carbon formation with 2-iodooxazoles obtained the 2-alkyl substituted oxazoles in good to excellent yields. Regioselective C2-alkylation on 2,4-di-iodooxazole under the same reaction conditions was firstly disclosed.Ó 2013 Elsevier Ltd. All rights reserved.Oxazoles are widely distributed in natural products, and many of them possess significant biological activities including antifungal, cytotoxic, and anthelmintic properties.1 Oxazoles have also been utilized as important building blocks in organic syntheses and drug developments. 2,3 The potent biological activity and the prevalence of oxazoles in natural products and drug candidates have stimulated intensive interests in the synthesis of these heterocycles.2b,2d-gAs an important structural motif, 2-alkyl substituted oxazole ring has been found in many oxazole-containing natural products, including the phenoxan, 1g noricumazoles, 4 hennoxazoles, 1f and leiodolides A & B.1d Conventional synthesis of 2-alkyl oxazoles was conducted in multistep reaction, 2f,5 and to the best of our knowledge, direct alkylation at the C2 position is challenging and has very limited success to date. 6 Due to the structural significance in drug development, it has a strong demanding to explore new synthetic methodologies to access this highly functionalized heterocycles in a straightforward and efficient way. Herein, we wish to report our result for the synthesis of 2-alkyl-oxazole via Suzuki-Miyaura cross-coupling reaction between 2-iodooxazoles and alkylboronates.In our efforts toward the total synthesis of leiodolides (Fig. 1), showing potential cytotoxicity against HCT-116 human colon carcinoma cells, 1d we have recently reported the stereoselective synthesis of the C22-C31 fragment of leiodolide A employing a diastereoselective Seebach alkylation and a Brown's P2-Ni catalyzed cis-alkyne semihydrogenation in the presence of a vinyl iodide. 7 To build fragments C1-C17 of leiodolide A, we eagerly required a method for the facile assembly of this densely functionalized 2-alkyl-substitution oxazole derivative, exemption from multistep construction of the oxazole ring. The exploration started from a direct alkylation on oxazole C-2 position through C-2 lithiation and a subsequent quenching with an electrophile, using ethyl oxazole-4-carboxylate (3) and iodomethane (4) as the testing system. Treatment of 3 with lithium base (LiHMDS or t-BuLi) in anhydrous THF, with or without 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), resulted in the recovery of major starting materials. In order to exclude the electron-withdrawing effect of carboxylate at C4-position, TBS group protected substrate 4-(tert-butyl-dimethylsilyloxy)methyloxazole (5) was applied, unfortunately, no desired product was observed. Attempted C-2 alkylation on oxazole through lithium-h...

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A retro-Diels-Alder approach to oxazoles and imidazoles

Cited by 28 publications

References 0 publications

Synthesis of Novel Purinyl-1'-homocarbanucleosides Based on a Cyclopenta[b]pyrazine System

Synthesis of Novel Purinyl-1'-homocarbanucleosides Based on a Cyclopenta[b]pyrazine System

Studies on Imidazole and Its Derivatives with Particular Emphasis on Their Chemical/biological Applications as Bioactive Molecules/Intermediated to Bioactive Molecule

An efficient preparation of 2-alkyl-oxazoles from 2-iodooxazoles

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