An official website of the United States government
Abstract Friedel-Crafts Arylation (the Scholl reaction) is the coupling of two aromatic rings with the aid of a strong Lewis or Brønsted acid. This historically significant C–C bond forming reaction normally leads to aromatic products, often as oligomeric mixtures, dictated by the large stabilization gained upon their rearomatization. The coordination of benzene by a tungsten complex disrupts the natural course of this reaction sequence, allowing for Friedel-Crafts Arylation without rearomatization or oligomerization. Subsequent addition of a nucleophile to the coupled intermediate leads to functionalized cyclohexenes. In this work, we show that by coordinating benzene to tungsten through two carbons (dihapto-coordinate), a rarely observed double protonation of the bound benzene is enabled, allowing its subsequent coupling to a second arene without the need of a precious metal or Lewis acid catalyst.
more »
« less
Synergistic Brønsted/Lewis acid catalyzed aromatic alkylation with unactivated tertiary alcohols or di- tert -butylperoxide to synthesize quaternary carbon centers
Dual Brønsted/Lewis acid catalysis involving environmentally benign, readily accessible protic acid and iron promotes site-selective tert -butylation of electron-rich arenes using di- tert -butylperoxide. This transformation inspired the development of a synergistic Brønsted/Lewis acid catalyzed aromatic alkylation that fills a gap in the Friedel–Crafts reaction literature by employing unactivated tertiary alcohols as alkylating agents, leading to new quaternary carbon centers. Corroborated by DFT calculations, the Lewis acid serves a role in enhancing the acidity of the Brønsted acid. The use of non-allylic, non-benzylic, and non-propargylic tertiary alcohols represents an underexplored area in Friedel–Crafts reactivity.
more »
« less
- Award ID(s):
- 1919677
- PAR ID:
- 10380124
- Date Published:
- Journal Name:
- Chemical Science
- Volume:
- 13
- Issue:
- 12
- ISSN:
- 2041-6520
- Page Range / eLocation ID:
- 3539 to 3548
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
The efficient and modular diversification of molecular scaffolds, particularly for the synthesis of diverse molecular libraries, remains a significant challenge in drug optimization campaigns. The late-stage introduction of alkyl fragments is especially desirable due to the high sp³-character and structural versatility of these motifs. Given their prevalence in molecular frameworks, C(sp²)−H bonds serve as attractive targets for diversification, though this process often requires difficult pre-functionalization or lengthy de novo syntheses. Traditionally, direct alkylations of arenes are achieved by employing Friedel–Crafts reaction conditions using strong Brønsted or Lewis acids. However, these methods suffer from poor functional group tolerance and low selectivity, limiting their broad implementation in late-stage functionalization and drug optimization campaigns. Herein, we report the application of a novel strategy for the selective coupling of differently hybridized radical species, which we term dynamic orbital selection. This mechanistic paradigm overcomes common limitations of Friedel-Crafts alkylations via the in situ formation of two distinct radical species, which are subsequently differentiated by a copper-based catalyst based on their respective binding properties. As a result, we demonstrate herein a general and highly modular reaction for the direct alkylation of native arene C−H bonds using abundant and benign alcohols and carboxylic acids as the alkylating agents. Ultimately, this solution overcomes the synthetic challenges associated with the introduction of complex alkyl scaffolds into highly sophisticated drug scaffolds in a late-stage fashion, thereby granting access to vast new chemical space. Based on the generality of the underlying coupling mechanism, dynamic orbital selection is expected to be a broadly applicable coupling platform for further challenging transformations involving two distinct radical species.more » « less
-
Abstract The direct Friedel–Crafts‐type coupling and dedinitrogenation reactions of vinyldiazo compounds with aromatic compounds using a metal‐free strategy are described. This Brønsted acid catalyzed method is efficient for the formation of α‐diazo β‐carbocations (vinyldiazonium ions), vinyl carbocations, and allylic or homoallylic carbocation species via vinyldiazo compounds. By choosing suitable nucleophilic reagents to selectively capture these intermediates, both trisubstituted α,β‐unsaturated esters, β‐indole‐substituted diazo esters, and dienes are obtained with good to high yields and selectivity. Experimental insights implicate a reaction mechanism involving the selective protonation of vinyldiazo compounds and the subsequent release of dinitrogen to form vinyl cations that undergo intramolecular 1,3‐ and 1,4‐ hydride transfer processes as well as fragmentation.more » « less
-
A highly stereoselective synthesis of ( E )-δ-boryl- anti -homoallylic alcohols is developed. In the presence of a Lewis acid, aldehyde allylation with α-boryl-( E )-crotylboronate gave δ-boryl- anti -homoallylic alcohols in good yields with excellent E -selectivity. The E -vinylboronate group in the products provides a useful handle for cross-coupling reactions as illustrated in the fragment synthesis of chaxamycins.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/d1sc06422c
