Synthesis of pyrimidine analogs of 2,6‐Di‐<i>tert</i>‐butylphenol antiinflammatory agents

Unangst, Paul C.; Connor, David T.; Kostlan, Catherine R.; Shrum, G. P.; Miller, Steven R.; Kanter, Gerald D.

doi:10.1002/jhet.5570320417

Cited by 6 publications

(4 citation statements)

References 11 publications

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“…Assembling and reduction of α-nitro ketones 12 is also frequently employed; however, most commonly, they are obtained by reaction of α-halo ketones with a suitable nitrogen source followed by functional group manipulation. The latter may include hydrolysis of hexamethylentetrammonium salts, phthalimide, and diformylimide 15 derivatives or reduction of azide, usually accomplished catalytically, or using a phosphorus(III) species (in the presence of a suitable electrophile, Staudinger reaction) .…”

Section: Resultsmentioning

confidence: 99%

Trifluoroacetic Anhydride-Mediated Solid-Phase Version of the Robinson−Gabriel Synthesis of Oxazoles

2005

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A traceless solid-phase synthesis of oxazoles 4 via Robinson-Gabriel reaction of solid-supported alpha-acylamino ketones 2 has been achieved. The reaction requires that the cyclization precursor be linked to a benzhydrylic-type linker (compounds 2) and that trifluoroacetic anhydride be used as the cyclodehydrating agent. The solvent has a dramatic effect on the latter reaction, which goes to completion and follows a cyclative-type mechanism only when an ethereal solvent is used. Different synthetic routes have been investigated toward assembling compounds 2. The most straightforward one, which we have validated more extensively, comprises the reaction of Merrifield alpha-methoxyphenyl (MAMP) resin with an alpha-amino ketone to form compounds 1, which are, in turn, acylated. Other methodologies and strategies allowing for the synthesis of compounds 1 that have been investigated include direct alkylation of Rink amide resin; reductive amination of the latter with alpha-keto aldehydes; reaction of MAMP resin with alpha-amino alcohols, followed by oxidation; and protection of Rink amide resin with either 2,4-dinitrosulfonyl or allyl group, followed by alkylation and removal of protecting group. In addition, we disclose a novel variant of the Ugi four-component reaction that allows for the preparation of compounds 2 in a single synthetic step.

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Section: Resultsmentioning

confidence: 99%

Trifluoroacetic Anhydride-Mediated Solid-Phase Version of the Robinson−Gabriel Synthesis of Oxazoles

2005

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“…Substituted 5‐pyrimidinols bearing an alkyl group in the 2‐position ( para to the phenolic moiety, 5 b , c ) were obtained by a procedure developed by Dornow and Hell11 and subsequently expanded by Connor and Kostlan as shown in Scheme 12. Thus, the appropriate α ‐halodiketone, prepared from the parent diketone as shown, was cyclized to the corresponding 4‐acyloxazole by treatment with ammonium acetate in acetic acid.…”

Section: Resultsmentioning

confidence: 99%

“…Synthesis of 2‐methyl‐4‐ tert ‐butyl‐5‐(2,2‐dimethylpropanoyl)oxazole :12 4‐Bromo‐2,2,6,6‐tetramethylheptan‐3,5‐dione (1.5 g, 5.7 mmol) and ammonium acetate (2.63 g, 34.2 mmol) were refluxed in acetic acid (60 mL) for 27 hours. The mixture was diluted with water adjusted to pH 5 by adding NaOH 0.5 M and extracted with ethyl acetate (3×20 mL).…”

Section: Methodsmentioning

confidence: 99%

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The Effect of Ring Nitrogen Atoms on the Homolytic Reactivity of Phenolic Compounds: Understanding the Radical‐Scavenging Ability of 5‐Pyrimidinols

Valgimigli

Brigati

Pedulli

et al. 2003

Chemistry A European J

107

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Six substituted 5-pyrimidinols were synthesized, and the thermochemistry and kinetics of their reactions with free radicals were studied and compared to those of equivalently substituted phenols. To assess their potential as hydrogen-atom donors to free radicals, we measured their O-H bond dissociation enthalpies (BDEs) using the radical equilibration electron paramagnetic resonance technique. This revealed that the O-H BDEs in 5-pyrimidinols are, on average, about 2.5 kcal mol(-1) higher than those in equivalently substituted phenols. The results are in good agreement with theoretical predictions, and confirm that substituent effects on the O-H BDE of 5-pyrimidinol are essentially the same as those on the Obond;H BDE in phenol. The kinetics of the reactions of these compounds with peroxyl radicals has been studied by their inhibition of the AIBN-initiated autoxidation of styrene, and with alkyl and alkoxyl radicals by competition kinetics. Despite their larger O-H BDEs, 5-pyrimidinols appear to transfer their phenolic hydrogen-atom to peroxyl radicals as quickly as equivalently substituted phenols, while their reactivity toward alkyl radicals far exceeds that of the corresponding phenols. We suggest that this rate enhancement, which is large in the case of alkyl radical reactions, small in the case of peroxyl radical reactions, and nonexistent in the case of alkoxyl radical reactions, is due to polar effects in the transition states of these atom-transfer reactions. This hypothesis is supported by additional experimental and theoretical results. Despite this higher reactivity of 5-pyrimidinols towards radicals compared to phenols, electrochemical measurements indicate that they are more stable to one-electron oxidation than equivalently substituted phenols. For example, the 5-pyrimidinol analogues of 2,4,6-trimethylphenol and butylated hydroxytoluene (BHT) were found to have oxidation potentials approximately 400 mV higher than their phenolic counterparts, but reacted roughly one order of magnitude faster with alkyl radicals and at about the same rate with peroxyl radicals. The 5-pyrimidinol structure should, therefore, serve as a useful template for the rational design of novel air-stable radical scavengers and chain-breaking antioxidants that are more effective than phenols.

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ChemInform Abstract: Synthesis of Pyrimidine Analogues of 2,6‐Di‐tert‐butylphenol Antiinflammatory Agents.

Unangst¹,

Connor²,

Kostlan³

et al. 1995

ChemInform

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Synthesis of Pyrimidine Analogues of 2,6-Di-tert-butylphenol Antiinflammatory Agents.-Some pyrimidine analogues of the well studied di-tert-butylphenol antiinflammatory agents Prifelone (cf. (IIIb)), Tebufelone (cf. (IV)) and 162 (cf. (VIII)) are synthesized with the aim to improve the aqueous solubility and so to increase the oral bioavailability by replacement of the benzene ring with a pyrimidine ring. -(UNANGST, P. C.; CONNOR, D. T.; KOSTLAN, C. R.; SHRUM, G. P.; MILLER, S. R.; KANTER, G.; J.

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Synthesis of pyrimidine analogs of 2,6‐Di‐tert‐butylphenol antiinflammatory agents

Cited by 6 publications

References 11 publications

Trifluoroacetic Anhydride-Mediated Solid-Phase Version of the Robinson−Gabriel Synthesis of Oxazoles

Trifluoroacetic Anhydride-Mediated Solid-Phase Version of the Robinson−Gabriel Synthesis of Oxazoles

The Effect of Ring Nitrogen Atoms on the Homolytic Reactivity of Phenolic Compounds: Understanding the Radical‐Scavenging Ability of 5‐Pyrimidinols

ChemInform Abstract: Synthesis of Pyrimidine Analogues of 2,6‐Di‐tert‐butylphenol Antiinflammatory Agents.

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