Synthesis of oxetane and azetidine ethers as ester isosteres by Brønsted acid catalysed alkylation of alcohols with 3-aryl-oxetanols and 3-aryl-azetidinols

Organic & Biomolecular Chemistry, Journal Year: 2023, Volume and Issue: 21(27), P. 5553 - 5559

Published: Jan. 1, 2023

Oxetanes and azetidines continue to draw significant interest in medicinal chemistry, as small, polar non-planar motifs. also represent interesting surrogates for carbonyl-containing functional groups. Here we report a synthesis of 3,3-disubstituted oxetane- azetidine-ethers, with comparisons made the ester group. The tertiary benzylic alcohols 4-membered rings are selectively activated using Brønsted acid catalysis reacted simple form ethers maintain oxetane ring intact. This approach avoids use strong bases halide alkylating agents allows alcohol libraries be leveraged. Oxetane demonstrate excellent chemical stability across range conditions an improved vis-à-vis analogous esters under basic reducing conditions.

Language: Английский

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Electrochemical Synthesis of C(sp³)‐Rich Amines by Aminative Carbofunctionalization of Carbonyl Compounds

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(26)

Published: April 23, 2024

Abstract Alkylamines form the backbone of countless nitrogen‐containing small molecules possessing desirable biological properties. Despite advances in amine synthesis through transition metal catalysis and photoredox chemistry, multicomponent reactions that leverage inexpensive materials to transform abundant chemical feedstocks into three‐dimensional α‐substituted alkylamines bearing complex substitution patterns remain scarce. Here, we report design a catalyst‐free electroreductive manifold merges amines, carbonyl compounds carbon‐based radical acceptors under ambient conditions without rigorous exclusion air moisture. Key this aminative carbofunctionalization process is chemoselective generation nucleophilic α‐amino intermediates readily couple with electrophilic partners, providing straightforward access architecturally intricate drug‐like scaffolds which are inaccessible by conventional means.

Language: Английский

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Harnessing Oxetane and Azetidine Sulfonyl Fluorides for Opportunities in Drug Discovery

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 12, 2024

Four-membered heterocycles such as oxetanes and azetidines represent attractive emergent design options in medicinal chemistry due to their small polar nature potential significantly impact the physiochemical properties of drug molecules. The challenging preparation these derivatives, especially a divergent manner, has severely limited combination with other medicinally biologically important groups. Consequently, there is substantial demand for mild effective synthetic strategies access new oxetane azetidine derivatives molecular scaffolds. Here, we report development use sulfonyl fluorides (OSFs) (ASFs), which behave precursors carbocations an unusual defluorosulfonylation reaction pathway (deFS). small-ring are activated under thermal conditions (60 °C), generated reactive intermediates couple broad range nucleophiles. Oxetane heterocyclic, -sulfoximine, -phosphonate prepared, several do not have comparable carbonyl analogs, providing chemical motifs elements discovery. Alternatively, SuFEx anionic accesses oxetane-sulfur(VI) derivatives. We demonstrate utility novel OSF ASF reagents through synthesis 11 showcasing subsequent diversification facile inclusion into programs. Moreover, propose application linker incorporation pendant groups suitable common conjugation reactions. Productive deFS reactions E3 ligase recruiters pomalidomide related provide degrader PROTAC linkers.

Language: Английский

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Forging C−S Bonds on the Azetidine Ring by Continuous Flow Photochemical Addition of Thiols and Disulfides to Azetines

European Journal of Organic Chemistry, Journal Year: 2023, Volume and Issue: 26(33)

Published: June 14, 2023

Abstract A strategy for anti ‐Markovnikov hydroalkyl/aryl thiolation and disulfidation of 2‐azetines under continuous flow conditions has been developed. Thiyl radicals are generated from thiols or disulfides subsequently propagate into the azetine unsaturation to forge C−S bond shape a secondary radical intermediate. This carbon‐centered chain transfers another thiol via hydrogen atom transfer (HAT) disulfide regenerate key thiyl intermediates. The use technology ensures efficient irradiation reaction mixture leading extremely fast, robust, scalable protocols. Furthermore, ethyl acetate was adopted as an environmentally responsible solvent.

Language: Английский

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Recent advances in the synthesis of 3,3-disubstituted oxetanes

Advances in heterocyclic chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 159 - 209

Published: Jan. 1, 2024

Language: Английский

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Synthesis of alcohols: streamlined C1 to Cn hydroxyalkylation through photoredox catalysis

Chemical Science, Journal Year: 2024, Volume and Issue: 15(29), P. 11337 - 11346

Published: Jan. 1, 2024

Naturally occurring and readily available α-hydroxy carboxylic acids (AHAs) are utilized as platforms for visible light-mediated oxidative CO 2 -extrusion furnishing radicals proved to be versatile C1 C n hydroxyalkylating agents.

Language: Английский

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From‐Neutral‐to‐Neutral Reductive Radical Coupling of Non‐Activated Alcohols and Styrenes

ChemistryEurope, Journal Year: 2023, Volume and Issue: 1(2)

Published: July 19, 2023

Abstract A reductive radical coupling reaction between non‐activated aliphatic alcohols and styrenes has been discovered through the use of low‐valent Ti‐mediated C−O bond homolysis. general application styrene derivatives in reactions remains a challenge organic synthesis. The preliminary investigation revealed that resulting benzyl intermediate behaves differently depending on minor steric differences around spin center, which results lack generality. addition 1,3,5‐trimethyl‐2,5‐cyclohexadiene uniformly hydrogenated radicals irrespective environments attacking radicals. Under optimal conditions, all tertiary, secondary, primary were applicable. In this study, successfully used directly as sources reacted with large number styrenes.

Language: Английский

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Radical Group Transfer of Vinyl and Alkynyl Silanes Driven by Photoredox Catalysis

The Journal of Organic Chemistry, Journal Year: 2023, Volume and Issue: 88(17), P. 12451 - 12463

Published: Aug. 15, 2023

Radical group transfer is a powerful tool for the formation of C-C bonds. These processes typically involve radical addition to π bonds, followed by fragmentation resulting cyclic intermediate. Despite advantageous lability organosilanes in this context, silicon-tethered acceptor groups have remained underexplored reactions. We report general photoredox-catalyzed protocol vinyl and alkynyl silanes onto sp3 carbons, using activated unactivated iodides as precursors. Our method displays high diastereoselectivity excellent functional tolerance, enables direct products situ ring opening. Mechanistic investigations revealed that reaction proceeds via an unusual dual catalytic cycle, overall redox-neutral process.

Language: Английский

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Electrochemical Synthesis of C(sp³)‐Rich Amines by Aminative Carbofunctionalization of Carbonyl Compounds

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(26)

Published: April 23, 2024

Abstract Alkylamines form the backbone of countless nitrogen‐containing small molecules possessing desirable biological properties. Despite advances in amine synthesis through transition metal catalysis and photoredox chemistry, multicomponent reactions that leverage inexpensive materials to transform abundant chemical feedstocks into three‐dimensional α‐substituted alkylamines bearing complex substitution patterns remain scarce. Here, we report design a catalyst‐free electroreductive manifold merges amines, carbonyl compounds carbon‐based radical acceptors under ambient conditions without rigorous exclusion air moisture. Key this aminative carbofunctionalization process is chemoselective generation nucleophilic α‐amino intermediates readily couple with electrophilic partners, providing straightforward access architecturally intricate drug‐like scaffolds which are inaccessible by conventional means.

Language: Английский

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C(sp³)−H (N‐Phenyltetrazole)thiolation as an Enabling Tool for Molecular Diversification

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(29)

Published: April 24, 2024

Abstract Methods enabling the broad diversification of C(sp 3 )−H bonds from a common intermediate are especially valuable in chemical synthesis. Herein, we report site‐selective ( N ‐phenyltetrazole)thiolation aliphatic and (hetero)benzylic using commercially available disulfide to access ‐phenyltetrazole thioethers. The thioether products readily elaborated diverse fragment couplings for C−C, C−O, or C−N construction. C−H functionalization proceeds via radical‐chain pathway involving hydrogen atom transfer by electron‐poor ‐phenyltetrazolethiyl radical. Hexafluoroisopropanol was found be essential reactions thiolation, with computational analysis consistent dual bonding radical imparting increased electrophilicity facilitate transfer. Substrate is limiting reagent all cases, reaction displays an exceptional functional group tolerance well suited applications late‐stage diversification.

Language: Английский

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