Surreal illustration of a molecule transforming into a vibrant organic shape, symbolizing metal-free chemistry.

Unlock the Power of Sulfur Heterocycles: A New Era in Metal-Free Chemistry

Nico Varela in Science & Nature August 2025 • 4 min read.

"Discover the groundbreaking synthesis of isothiochroman-3-ones, revolutionizing organic chemistry with sustainable, metal-free oxidative cyclization of alkynyl thioethers."

Isothiochroman-3-ones, vital sulfur heterocycles, are integral to numerous bioactive molecules, finding applications as aminopeptidase inhibitors, agrochemical fungicides, and herbicides. Despite their significance, conventional synthesis methods are plagued by limitations such as multi-step processes, restricted substrate scope, inaccessible precursors, and low efficiency.

The increasing demand for efficient and flexible synthetic routes has fueled the need for innovative approaches. Metal-catalyzed intermolecular N-oxide oxidation of alkynes has garnered attention, leading to various synthetic methodologies. However, these methods often rely on transition metals like rhodium, palladium, and zinc.

Recent studies have explored metal-free alkyne oxidations, offering sustainable alternatives. Now, a groundbreaking development has emerged: a Brønsted acid-catalyzed oxidative C-H functionalization of alkynyl thioethers. This novel method facilitates the synthesis of valuable isothiochroman-3-ones under mild reaction conditions, boasting a broad substrate scope and wide functional group tolerance. Furthermore, this metal-free oxidation promotes formal N-H insertion involving an unexpected 1,2-sulfur migration, leading to useful 1,4-benzothiazin-3-ones.

How Does This Metal-Free Oxidative Cyclization Work?

Surreal illustration of a molecule transforming into a vibrant organic shape, symbolizing metal-free chemistry.

The process begins with readily prepared internal alkynyl thioethers. These are then subjected to a catalyst, such as HNTf2, and an oxidant, like 2,6-dibromopyridine N-oxide, under specific reaction conditions. This results in the formation of isothiochroman-3-ones.

The success of this method lies in its ability to accommodate a variety of substituents on the aromatic ring. Alkynyl thioethers bearing electron-withdrawing groups (e.g., F, Cl, Br, CN, and CO2Me) and electron-donating groups (e.g., Me and MeO) all participate effectively in the oxidative cyclization, yielding high percentages of the desired products.

Here are some key highlights of the metal-free oxidative cyclization process:

Broad Substrate Scope: Works with both terminal and internal alkynyl thioethers.
Mild Conditions: Achieves high yields under gentle reaction conditions.
Functional Group Tolerance: Compatible with a wide range of functional groups.
Metal-Free: Eliminates the need for toxic and expensive metal catalysts.
Scalable: Demonstrated feasibility for gram-scale synthesis, enhancing its practical application.

The reaction mechanism involves the initial attack of 2,6-dibromopyridine N-oxide on the Brønsted acid-activated thioynol ether, leading to the formation of a vinyl sulfide intermediate. This intermediate then undergoes an intramolecular SN2' pathway, resulting in the desired product and regenerating the proton catalyst.

The Future of Sustainable Organic Synthesis

The development of this metal-free oxidative cyclization marks a significant step forward in sustainable organic synthesis. By eliminating the need for metal catalysts and offering a broad substrate scope with mild reaction conditions, this method provides a practical and efficient route for the synthesis of valuable isothiochroman-3-ones and related compounds. This innovative approach paves the way for future advancements in metal-free chemistry, promising greener and more sustainable synthetic methodologies.

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This article is based on research published under:

DOI-LINK: 10.1021/acs.orglett.8b03462, Alternate LINK

Title: Synthesis Of Isothiochroman-3-Ones Via Metal-Free Oxidative Cyclization Of Alkynyl Thioethers

Subject: Organic Chemistry

Journal: Organic Letters

Publisher: American Chemical Society (ACS)

Authors: Ying-Qi Zhang, Xin-Qi Zhu, Yang-Bo Chen, Tong-De Tan, Ming-Yang Yang, Long-Wu Ye

Published: 2018-11-16

Everything You Need To Know

What are the key components and reaction conditions that enable the metal-free oxidative cyclization to produce isothiochroman-3-ones?

This metal-free oxidative cyclization relies on a Brønsted acid catalyst, such as HNTf2, and an oxidant, 2,6-dibromopyridine N-oxide, to transform readily prepared internal alkynyl thioethers into isothiochroman-3-ones under specific reaction conditions. The reaction's success hinges on accommodating various substituents on the aromatic ring, allowing alkynyl thioethers with electron-withdrawing and electron-donating groups to participate effectively.

What are the drawbacks of the conventional methods used to synthesize isothiochroman-3-ones, and why was a new approach needed?

Traditional methods for synthesizing isothiochroman-3-ones suffer from several limitations. These include multi-step processes, a restricted substrate scope, inaccessible precursors, and generally low efficiency. This has driven the need for more innovative and efficient synthetic approaches, leading to the exploration of metal-free alternatives.

What are the primary benefits of using this metal-free oxidative cyclization method compared to traditional metal-catalyzed reactions?

The metal-free oxidative cyclization method offers several key advantages. It features a broad substrate scope, working with both terminal and internal alkynyl thioethers. It operates under mild reaction conditions, achieving high yields while being compatible with a wide range of functional groups. Crucially, it eliminates the need for toxic and expensive metal catalysts, and it has demonstrated feasibility for gram-scale synthesis, enhancing its practical application.

Can you explain the step-by-step mechanism of the Brønsted acid-catalyzed oxidative C-H functionalization, specifically focusing on how isothiochroman-3-ones are formed?

The reaction mechanism begins with the attack of 2,6-dibromopyridine N-oxide on the Brønsted acid-activated thioynol ether, which leads to the formation of a vinyl sulfide intermediate. This intermediate then undergoes an intramolecular SN2' pathway, resulting in the desired isothiochroman-3-one product and regenerating the proton catalyst. The 1,2-sulfur migration leading to 1,4-benzothiazin-3-ones is an unexpected but valuable outcome.

What is the broader significance of this metal-free oxidative cyclization in the field of organic synthesis, and what future advancements might stem from this approach?

This innovation represents a significant advancement in sustainable organic synthesis by providing a practical and efficient route for synthesizing isothiochroman-3-ones and related compounds without relying on metal catalysts. This method paves the way for greener and more sustainable synthetic methodologies. It's important to note that while the method produces isothiochroman-3-ones and 1,4-benzothiazin-3-ones, there could be further exploration of byproduct formation and optimization for specific substrate classes.