Titanocene(III) Chloride-Mediated Reductions of Oxazines, Hydroxamic Acids, and <i>N</i>-Hydroxy Carbamates

Cesario, Cara; Tardibono, Lawrence P.; Miller, Marvin J.

doi:10.1021/jo802184y

Cited by 59 publications

(41 citation statements)

References 34 publications

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“…Selective reduction of the N-O bond of compound 7b was achieved using a titanium-mediated reduction procedure which gave analog 34 in good yield. 48 Acetylation of compound 7b was achieved using acetic anhydride which provided analog 35 in excellent yield.…”

Section: Resultsmentioning

confidence: 99%

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N–O Chemistry for Antibiotics: Discovery of N-Alkyl-N-(pyridin-2-yl)hydroxylamine Scaffolds as Selective Antibacterial Agents Using Nitroso Diels–Alder and Ene Chemistry

et al. 2011

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The discovery, syntheses, and structure-activity relationships (SAR) of a new family of heterocyclic antibacterial compounds based on N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds are described. A structurally diverse library of ~100 heterocyclic molecules generated from Lewis acid-mediated nucleophilic ring opening reactions with nitroso Diels-Alder cycloadducts and nitroso ene reactions with substituted alkenes was evaluated in whole cell antibacterial assays. Compounds containing the N-alkyl-N-(pyridin-2-yl)hydroxylamine structure demonstrated selective and potent antibacterial activity against the Gram-positive bacterium Micrococcus luteus ATCC 10240 (MIC90 = 2.0 μM or 0.41 μg/mL) and moderate activity against other Gram-positive strains including antibiotic resistant strains of Staphylococcus aureus (MRSA) and Enterococcus faecalis (VRE). A new synthetic route to the active core was developed using palladium-catalyzed Buchwald-Hartwig amination reactions of N-alkyl-O-(4-methoxybenzyl)hydroxylamines with 2-halo-pyridines that facilitated SAR studies and revealed the simplest active structural fragment. This work shows the value of using a combination of diversity-oriented synthesis (DOS) and parallel synthesis for identifying new antibacterial scaffolds.

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Section: Resultsmentioning

confidence: 99%

“…48 Activated zinc (65 mg, 1.00 mmol) was added to a solution of Cp 2 TiCl 2 (124.0 mg, 0.50 mmol) in 3 mL of anhydrous THF in a flame-dried round bottom flask purged with argon. This mixture was stirred at rt for 45 min.…”

Section: Methodsmentioning

confidence: 99%

N–O Chemistry for Antibiotics: Discovery of N-Alkyl-N-(pyridin-2-yl)hydroxylamine Scaffolds as Selective Antibacterial Agents Using Nitroso Diels–Alder and Ene Chemistry

et al. 2011

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“…Gän-gige Reagentien und Verfahren, die die N-O-Bindungsspaltung erleichtern, sind Molybdänhexacarbonyl ([Mo(CO) 6 ]), [96,97] Zink in Essigsäure, die katalytische Hydrierung, Samariumdiiodid [98,99] und Titanocen(III)-chlorid. [100] Weitere Methoden zur reduktiven Spaltung der N-OBindung nutzen photochemische [101] und enzymatische [102] sowie andere chemische [103] Prozesse. Die reduktive Spaltung der N-O-Bindung des monocyclischen 1,2-Oxazins 80 ergab die 1,4-Aminoalkohole 81, die unter Einwirkung von Mangandioxid cyclisierten und einen Zugang zu den Pyrrolen 82 ermöglichten (Schema 14).…”

Section: Spaltung Der N-o-bindungunclassified

Hetero‐Diels‐Alder‐Reaktionen von Nitrosocarbonylverbindungen als nützliches Verfahren in der organischen Synthese

Bodnar¹,

Miller

2011

Angewandte Chemie

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Organische Transformationen, die in einem einzigen Reaktionsschritt mehrere kovalente Bindungen aufbauen, zählen zu den leistungsfähigsten Verfahren in der organischen Synthese. Hetero‐Diels‐Alder(HDA)‐Reaktionen von Nitrosocarbonylverbindungen ermöglichen die stereospezifische Einführung von Kohlenstoff‐Stickstoff‐ und Kohlenstoff‐Sauerstoff‐Bindungen in einem einzigen Syntheseschritt und bieten einen direkten Zugang zu 3,6‐Dihydro‐1,2‐oxazinen. In diesem Aufsatz werden die Entwicklung der Nitrosocarbonyl‐HDA‐Reaktion und der Nutzen der daraus erhältlichen Oxazinringe bei der Synthese verschiedener wichtiger biologisch aktiver Verbindungen beschrieben.

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“…These cycloadducts have become valuable key intermediates for the synthesis of biologically interesting molecules especially because they offer plethora of modification possibilities including N-O bond cleavage mediated by titanocene(III) chloride,[1] Mo(CO) 6 [2;3] or other reducing agents providing ready access to 1,4-amino alcohols. [4;5] Before or after N-O reduction, the double bond can be hydroborated or oxidized to give epoxides, diols or even diacids after complete cleavage.…”

Section: Introductionmentioning

confidence: 99%

Solid-Phase Synthesis of ɤ-Lactone and 1,2-Oxazine Derivatives and Their Efficient Chiral Analysis

et al. 2016

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Derivatives of 3-methyl-3,6-dihydro-2H-1,2-oxazine-6-carboxylic acid prepared by regioselective hetero Diels-Alder reaction of arylnitroso compounds with sorbic acid were used for solid-phase synthesis of a library of derivatives that included modification of carboxylic group, dihydroxylation of double bond and cleavage of N-O bond. Derivatives of 2,3,4-trihydroxyhexanoic acid obtained from 3,6-dihydro-2H-1,2-oxazines after double bond dihydroxylation and N-O cleavage were used for simple and stereoselective formation of chiral lactones derived from 3,4-dihydroxydihydrofuran-2(3H)-one. The final compounds obtained as a mixture of stereoisomers were analyzed with use of chiral HPLC and SFC. HPLC analyses were not successful for all derivatives or required lengthy chromatography. On the other hand SFC afforded much shorter analyses and was effective for all studied derivatives. The method of synthesis and analysis is thus suitable for future study of stereoselective synthesis of lactones and other derivatives from single oxazine derivatives and application of high-throughput synthesis on solid-support and combinatorial chemistry.

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Titanocene(III) Chloride-Mediated Reductions of Oxazines, Hydroxamic Acids, and N-Hydroxy Carbamates

Abstract: Titanocene (III) chloride (Cp2TiCl), generated in situ, reduces N-O bonds of various substrates in good to excellent yields (72–95%). Reactions may be performed with stoichiometric Cp2TiCl or with catalytic Cp2TiCl.

Cited by 59 publications

References 34 publications

N–O Chemistry for Antibiotics: Discovery of N-Alkyl-N-(pyridin-2-yl)hydroxylamine Scaffolds as Selective Antibacterial Agents Using Nitroso Diels–Alder and Ene Chemistry

N–O Chemistry for Antibiotics: Discovery of N-Alkyl-N-(pyridin-2-yl)hydroxylamine Scaffolds as Selective Antibacterial Agents Using Nitroso Diels–Alder and Ene Chemistry

Hetero‐Diels‐Alder‐Reaktionen von Nitrosocarbonylverbindungen als nützliches Verfahren in der organischen Synthese

Solid-Phase Synthesis of ɤ-Lactone and 1,2-Oxazine Derivatives and Their Efficient Chiral Analysis

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