Selective [2σ + 2σ] Cycloaddition Enabled by Boronyl Radical Catalysis: Synthesis of Highly Substituted Bicyclo[3.1.1]heptanes

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(7), P. 4304 - 4310

Published: Feb. 10, 2023

In contrast to the traditional and widely-used cycloaddition reactions involving at least a π bond component, [2σ + 2σ] radical between bicyclo[1.1.0]butanes (BCBs) cyclopropyl ketones has been developed provide modular, concise, atom-economical synthetic route substituted bicyclo[3.1.1]heptane (BCH) derivatives that are 3D bioisosteres of benzenes core skeleton number terpene natural products. The reaction was catalyzed by combination simple tetraalkoxydiboron(4) compound B2pin2 3-pentyl isonicotinate. broad substrate scope demonstrated synthesizing series new highly functionalized BCHs with up six substituents on 99% isolated yield. Computational mechanistic investigations supported pyridine-assisted boronyl catalytic cycle.

Language: Английский

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ortho-Selective Dearomative [2π + 2σ] Photocycloadditions of Bicyclic Aza-Arenes

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(22), P. 12324 - 12332

Published: May 26, 2023

Dearomative photocycloadditions are valuable chemical transformations, serving as an efficient platform to create three-dimensional molecular complexity. However, the photolability of original addition product especially within context ortho cycloadditions often causes undesired consecutive rearrangements, rendering these cycloadducts elusive. Herein, we report ortho-selective intermolecular photocycloaddition bicyclic aza-arenes including (iso)quinolines, quinazolines, and quinoxalines by utilizing a strain-release approach. With bicyclo[1.1.0]butanes coupling partners, this dearomative [2π + 2σ] cycloaddition enables straightforward construction C(sp3)-rich bicyclo[2.1.1]hexanes directly connected N-heteroarenes. Photophysical experiments DFT calculations revealed origin selectivity indicate that, in originally proposed energy transfer or direct excitation pathways, chain reaction mechanism is operative depending on conditions.

Language: Английский

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Lewis Acid Catalyzed Formal (3+2)‐Cycloaddition of Bicyclo[1.1.0]butanes with Ketenes

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(34)

Published: May 11, 2023

Design, synthesis and application of benzene bioisosteres have attracted a lot attention in the past 20 years. Recently, bicyclo[2.1.1]hexanes emerged as highly attractive for ortho- meta-substituted benzenes. Herein we report mild, scalable transition-metal-free protocol construction substituted bicyclo[2.1.1]hexan-2-ones through Lewis acid catalyzed (3+2)-cycloaddition bicyclo[1.1.0]-butane ketones with disubstituted ketenes. The reaction shows high functional group tolerance documented by successful preparation various 3-alkyl-3-aryl well 3,3-bisalkyl (26 examples, up to 89 % yield). Postfunctionalization exocyclic ketone moiety is also demonstrated.

Language: Английский

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Pyridine-Boryl Radical-Catalyzed [2π + 2σ] Cycloaddition of Bicyclo[1.1.0]butanes with Alkenes

ACS Catalysis, Journal Year: 2023, Volume and Issue: 13(7), P. 5096 - 5103

Published: March 30, 2023

Bicyclo[2.1.1]hexanes (BCHs) represent an intriguing class of structurally rigid hydrocarbons that can serve as the bioisosteres benzenoids in medicinal chemistry. Methods for synthesis BCHs are, however, limiting. Reported herein is a facile via strain-release-driven [2π + 2σ] cycloaddition bicyclo[1.1.0]butanes (BCBs) with alkenes facilitated by pyridine-boryl radical catalyst. The mild reaction conditions, broad substrate scope, and decent functional group tolerance this protocol render it appealing relevant fields drug design synthesis. Theoretical mechanistic studies reveal relay mechanism involved. Synthetic applications products are performed.

Language: Английский

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Catalytic Formal [2π+2σ] Cycloaddition of Aldehydes with Bicyclobutanes: Expedient Access to Polysubstituted 2‐Oxabicyclo[2.1.1]hexanes

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(34)

Published: June 12, 2023

Synthesis of bicyclic scaffolds has attracted tremendous attention because they are playing an important role as saturated bioisosteres benzenoids in modern drug discovery. Here, we report a BF3 -catalyzed [2π+2σ] cycloaddition aldehydes with bicyclo[1.1.0]butanes (BCBs) to access polysubstituted 2-oxabicyclo[2.1.1]hexanes. A new kind BCB containing acyl pyrazole group was invented, which not only significantly facilitates the reactions, but can also serve handle for diverse downstream transformations. Furthermore, aryl and vinyl epoxides be utilized substrates undergo BCBs after situ rearrangement aldehydes. We anticipate that our results will promote challenging sp3 -rich frameworks exploration BCB-based chemistry.

Language: Английский

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Photocatalyzed [2σ + 2σ] and [2σ + 2π] Cycloadditions for the Synthesis of Bicyclo[3.1.1]heptanes and 5- or 6-Membered Carbocycles

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(46), P. 25411 - 25421

Published: Nov. 7, 2023

We report the use of photocatalysis for homolytic ring-opening carbonyl cyclopropanes. In contrast to previous studies, our approach does not require a metal cocatalyst or strong reductant. The cyclopropanes can be employed both [2σ + 2σ] and 2π] annulation with either alkenes/alkynes bicyclo[1.1.0]butanes, yielding cyclopent-anes/-enes bicyclo[3.1.1]heptanes (BCHs), respectively. BCHs are promising bioisosteres 1,2,4,5 tetra-substituted aromatic rings. Mechanistic including density functional theory computation trapping experiment DMPO, support 1,3-biradical generated from cyclopropane as key intermediate these transformations.

Language: Английский

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Intermolecular Formal Cycloaddition of Indoles with Bicyclo[1.1.0]butanes by Lewis Acid Catalysis

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(48)

Published: Aug. 16, 2023

Abstract Herein, we develop a new approach to directly access architecturally complex polycyclic indolines from readily available indoles and bicyclo[1.1.0]butanes (BCBs) through formal cycloaddition promoted by commercially Lewis acids. The reaction proceeded stepwise pathway involving nucleophilic addition of BCBs followed an intramolecular Mannich form rigid indoline‐fused structures, which resemble indole alkaloids. This tolerated wide range BCBs, thereby allowing the one‐step construction various indoline polycycles containing up four contiguous quaternary carbon centers.

Language: Английский

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Silver‐Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes**

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(48)

Published: Oct. 12, 2023

Bicyclo[2.1.1]hexanes (BCHs) are becoming ever more important in drug design and development as bridged scaffolds that provide underexplored chemical space, but difficult to access. Here a silver-catalyzed dearomative [2π+2σ] cycloaddition strategy for the synthesis of indoline fused BCHs from N-unprotected indoles bicyclobutane precursors is described. The strain-release operates under mild conditions, tolerating wide range functional groups. It capable forming with up four contiguous quaternary carbon centers, achieving yields 99 %. In addition, scale-up experiment synthetic transformations cycloadducts further highlighted utility.

Language: Английский

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General Synthesis of 3‐Azabicyclo[3.1.1]heptanes and Evaluation of Their Properties as Saturated Isosteres**

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(39)

Published: May 26, 2023

Abstract A general approach to 3‐azabicyclo[3.1.1]heptanes by reduction of spirocyclic oxetanyl nitriles was developed. The mechanism, scope, and scalability this transformation were studied. core incorporated into the structure antihistamine drug Rupatidine instead pyridine ring, which led a dramatic improvement in physicochemical properties.

Language: Английский

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Synthesis of polysubstituted bicyclo[2.1.1]hexanes enabling access to new chemical space

Chemical Science, Journal Year: 2023, Volume and Issue: 14(36), P. 9885 - 9891

Published: Jan. 1, 2023

Crossed [2 + 2] cycloaddition yields bicyclo[2.1.1]hexanes with 11 different substitution patterns. ortho -, meta - and polysubstituted benzene bioisosteres, structures substituent patterns that go beyond aromatic chemical space can be prepared.

Language: Английский

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