Reverse Polarity Reductive Functionalization of Tertiary Amides via a Dual Iridium Catalyzed Hydrosilylation & SET Strategy

A new strategy for the mild generation of synthetically valuable α-amino radicals from robust tertiary amide building blocks has been developed. By combining Vaska’s complex-catalyzed tertiary amide reductive activation and photochemical single electron reduction into a streamlined tandem process, metastable hemiaminal intermediates were successfully transformed into nucleophilic α-amino free radical species. This umpolung approach to such reactive intermediates was exemplified through coupling with an electrophilic dehydroalanine acceptor, resulting in the synthesis of an array of α-functionalized tertiary amine derivatives, previously inaccessible from the amide starting materials. The utility of the strategy was expanded to include secondary amide substrates, intramolecular variants and late stage functionalization of an active pharmaceutical ingredient. DFT analyses were used to establish the reaction mechanism and elements of the chemical system that were responsible for the reaction’s efficiency.

Download Full-text

A New Strategy for Solid-Phase Depsipeptide Synthesis Using Recoverable Building Blocks

Organic Letters ◽

10.1021/ol047653v ◽

2005 ◽

Vol 7 (4) ◽

pp. 597-600 ◽

Cited By ~ 14

Author(s):

Fernando Albericio ◽

Klaus Burger ◽

Javier Ruíz-Rodríguez ◽

Jan Spengler

Keyword(s):

Solid Phase ◽

Building Blocks ◽

New Strategy

Download Full-text

Selective Extraction of Platinum(IV) from the Simulated Secondary Resources Using Simple Secondary Amide and Urea Extractants

Separations ◽

10.3390/separations8090139 ◽

2021 ◽

Vol 8 (9) ◽

pp. 139

Author(s):

Yuki Ueda ◽

Shintaro Morisada ◽

Hidetaka Kawakita ◽

Keisuke Ohto

Keyword(s):

Electrical Equipment ◽

Selective Extraction ◽

Extraction Process ◽

Secondary Amide ◽

Separation And Purification ◽

Secondary Resources ◽

Tertiary Amide ◽

Third Phase ◽

Simulated Effluent ◽

Secondary Amides

The recycling of rare metals such as platinum (Pt) from secondary resources, such as waste electronic and electrical equipment and automotive catalysts, is an urgent global issue. In this study, simple secondary amides and urea, N-(2-ethylhexyl)acetamide, N-(2-ethylhexyl)octanamide, and 1-butyl-3-(2-ethylhexyl)urea, which selectively extract Pt(IV) from a simulated effluent containing numerous metal ions, such as in an actual hydrometallurgical process, were synthesized and achieved efficient Pt(IV) stripping using only water. Comparison of Pt(IV) extraction behavior with a tertiary amide without N–H moieties suggests that the secondary amides and urea extractants effectively use hydrogen bonding to the hexachloroplatinate anion by N–H moieties. Examining the conditions for the third phase formation revealed that the secondary amide extractant with the longest alkyl chain can be used in the extraction process for a long time without forming any third phase, despite its lower Pt(IV) extraction capacity. The practical trial with simple compounds developed in this study should contribute to the development of Pt separation and purification processes.

Download Full-text

General α-Amino 1,3,4-Oxadiazole Synthesis via Late-Stage Reductive Functionalization of Tertiary Amides and Lactams

10.26434/chemrxiv.14664672 ◽

2021 ◽

Author(s):

Daniel Matheau-Raven ◽

Darren J. Dixon

Keyword(s):

Carboxylic Acid ◽

Late Stage ◽

Coupling Reaction ◽

Reductive Activation ◽

Mild Conditions ◽

Drug Molecules ◽

Drug Conjugates ◽

Iminium Ion ◽

Tertiary Amides ◽

Coupling Partner

An iridium-catalyzed reductive three-component coupling reaction for the synthesis of medicinally relevant α-amino 1,3,4-oxadiazoles from abundant tertiary amides or lactams, carboxylic acids, and (N-isocyanimino) triphenylphosphorane, is described. Proceeding under mild conditions using (<1 mol%) Vaska’s complex (IrCl(CO)(PPh3)2) and tetramethyldisiloxane to access the key reactive iminium ion intermediates, a broad range of structurally complex α-amino 1,3,4-oxadiazole architectures were efficiently accessed from diverse carboxylic acid feedstock coupling partners. Extension to α-amino heterodiazole synthesis was readily achieved by exchanging the carboxylic acid coupling partner for C-, S-, or N-centered Brønsted acids, and provided rapid and modular access to these desirable, yet difficult-to-access, heterocycles. Furthermore, the high chemoselectivity of the catalytic reductive activation step allowed the late-stage functionalization of 10 drug molecules, including the synthesis of novel heterodiazole-fused drug-drug conjugates.

Download Full-text

Enzymatic single-electron reduction and aerobic cytotoxicity of tirapazamine and its 1-oxide and nor-oxide metabolites

Chemija ◽

10.6001/chemija.v29i4.3843 ◽

2018 ◽

Vol 29 (4) ◽

Cited By ~ 1

Author(s):

Jonas Šarlauskas ◽

Aušra Nemeikaitė-Čėnienė ◽

Audronė Marozienė ◽

Lina Misevičienė ◽

Mindaugas Lesanavičius ◽

...

Keyword(s):

Side Effects ◽

Anticancer Agent ◽

Redox Cycling ◽

Nitroaromatic Compounds ◽

Single Electron ◽

Reductive Activation ◽

Cell Nuclei ◽

Electron Reduction ◽

Phenylene Diamine

Aerobic cytotoxicity of 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ), a bioreductively activated hypoxia-specific anticancer agent, is responsible for TPZ side effects in chemotherapy. In order to clarify its mechanisms, we examined the aerobic cytotoxicity of TPZ and its main metabolites, 3-amino-1,2,4-benzotriazine-1-oxide and 3-amino-1,2,4-benzotriazine in murine hepatoma MH22a cells, and their reduction by NADPH:cytochrome P-450 reductase (P-450R) and ferredoxin:NADP+ reductase (FNR). Analogous studies of several quinones and nitroaromatic compounds with similar values of single-electron reduction midpoint potentials (E17) were carried out. In single-electron reduction by P-450R and FNR, the reactivity of TPZ and its monoxide was similar to that of quinones and nitroaromatics, and increased with an increase in their E17. The cytotoxicity of TPZ and its metabolites possessed a prooxidant character, because it was partly prevented by an antioxidant N,N’-diphenyl-p-phenylene diamine and desferrioxamine, and potentiated by 1,3-bis(2-chloroethyl)-1-nitrosourea. Importantly, the cytotoxicity of TPZ and, possibly, its 1-N-oxide, was much higher than that of quinones and nitroaromatics with similar values of E17 and redox cycling activities. A possible additional factor in the aerobic cytotoxicity of TPZ is its reductive activation in oxygen-poor cell nuclei, leading to the formation of DNA-damaging species similar to those forming under hypoxia.

Download Full-text

The ozonolysis of primary aliphatic amines in fine particles

Atmospheric Chemistry and Physics ◽

10.5194/acp-8-1181-2008 ◽

2008 ◽

Vol 8 (5) ◽

pp. 1181-1194 ◽

Cited By ~ 35

Author(s):

J. Zahardis ◽

S. Geddes ◽

G. A. Petrucci

Keyword(s):

Fine Particles ◽

Reaction System ◽

Tropospheric Chemistry ◽

Ozone Exposure ◽

Surface Barrier ◽

Secondary Amide ◽

Tertiary Amide ◽

Aerosol Mass ◽

Criegee Intermediates ◽

Species Specific

Abstract. The oxidative processing by ozone of the particulate amines octadecylamine (ODA) and hexadecylamine (HDA) is reported. Ozonolysis of these amines resulted in strong NO2– and NO3– ion signals that increased with ozone exposure as monitored by photoelectron resonance capture ionization aerosol mass spectrometry. These products suggest a mechanism of progressive oxidation of the particulate amines to nitroalkanes. Additionally, a strong ion signal at 125 m/z is assigned to the ion NO3– (HNO3). For ozonized mixed particles containing ODA or HDA + oleic acid (OL), with pO3≥3×10–7 atm, imine, secondary amide, and tertiary amide products were measured. These products most likely arise from reactions of amines with aldehydes (for imines) and stabilized Criegee intermediates (SCI) or secondary ozonides (for amides) from the fatty acid. The routes to amides via SCI and/or secondary ozonides were shown to be more important than comparable amide forming reactions between amines and organic acids, using azelaic acid as a test compound. Finally, direct evidence is provided for the formation of a surface barrier in the ODA + OL reaction system that resulted in the retention of OL at high ozone exposures (up to 10−3 atm for 17 s). This effect was not observed in HDA + OL or single component OL particles, suggesting that it may be a species-specific surfactant effect from an in situ generated amide or imine. Implications to tropospheric chemistry, including particle bound amines as sources of oxidized gas phase nitrogen species (e.g.~NO2, NO3), formation of nitrogen enriched HULIS via ozonolysis of amines and source apportionment are discussed.

Download Full-text

Hydride Reductions of 1H-Pyrrolo[2,1-c][1,4]-benzodiazepine-5,11-diones: Selective Reduction of Secondary Amides to Carbinolamines

Australian Journal of Chemistry ◽

10.1071/c98079 ◽

1998 ◽

Vol 51 (12) ◽

pp. 1121 ◽

Cited By ~ 4

Author(s):

Andrew G. Katsifis ◽

Meredith E. McPhee ◽

Damon D. Ridley

Keyword(s):

Selective Reduction ◽

Secondary Amide ◽

Tertiary Amide ◽

Secondary Amides

For the syntheses of radiolabelled pyrrolo[1,4]benzodiazepine antitumour antibiotics we required a method in which the unstable carbinolamine functionality was introduced prior to the radiolabel. In turn this required the selective reduction of a secondary amide in the presence of, inter alia, a tertiary amide. We report methods which can be used to achieve this outcome in a series of 1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones.

Download Full-text