WRITE-UP FOR PMR FELLOWSHIP JAN 2023 - DEC 2023

Pooja Yadav

WRITE-UP FOR PMR FELLOWSHIP JAN 2023 - DEC 2023

Progress Report

Sustainable synthesis of carbocycles and heterocycles via cascade reactions using photocatalysis:

Cascade reaction, also sometimes referred as tandem or domino reactions, represents one of the most significant class of organic reactions. Herein, two or more bond-forming steps take place under identical conditions without any additional reagents, catalysts or purification process, thereby providing a cost effective and sustainable synthetic route. Photoredox catalysis on the other hand involves a single electron transfer process which initiates a radical reaction among the substrates present under greener and mild conditions using visible light as the energy source. So, we aim to develop a mild method for sustainable synthesis of heterocycles and carbocycles via cascade reactions using photocatalysis. Heterocyclic and /or carbocyclic core is a common structural feature present in many natural products, biologically active compounds, and drugs. In general their synthesis involves multiple steps, harsh reaction conditions and lower (stereo)selectivity making the process less sustainable. In this direction, we first attempted the synthesis of highly functionalized quinolines and chromanes from the corresponding anilines and phenol derivatives respectively.

Chapter 1: Diastereoselective synthesis of highly functionalized tetrahydroquinoline and chromane cores:

1, n-enynes are identified as the most powerful and straightforward substrates for the synthesis of various functionalized heterocycles present in natural products and drugs. Traditionally, 1, n-enyne annulation is mediated either by radical-mediated processes or transition metal catalysis, which requires stochiometric amount of toxic/precious metal complex or radical initiators. Despite being a straightforward method to synthesize various heterocycles they have some drawbacks, such as poor atom economy, low chemo selectivity, which limits their usage in synthetic applications.

Chapter 1.1: Synthesis of functionalized tetrahydroquinolines

Tetrahydroquinoline core is present in various drugs and natural products like oxaminquine, nicainoprol etc. Tetrahydroquinoline cores generally synthesized from hydrogenation of quinolines which gives the mixture of diastereomers. So, we attempted diastereoselective synthesis of functionalized quinolines from the corresponding easily accessible ortho-alkynyl allyl aniline derivatives involving a cascade reaction process.

Chapter 1.2: Synthesis of functionalized chromanes

Similarly, Chromane core is very common in various natural products like flavonoids, flavones, and drugs like degulin etc. So, we attempted diastereoselective synthesis of functionalized chromanes from the corresponding easily accessible ortho-alkynyl allyl phenol derivatives involving a cascade reaction process.

Chapter 2: Chloro-sulfonylation of 1,7-enynes via cascade photoredox catalysis

1,7-enynes are versatile structural moieties, which are widely used for constructing various functionalized heterocycles like benzofuran, benzopyran, chromane, tetrahydroquinoline, etc., via radical-induced tandem cyclization. In general, 1,7-enyne tandem cyclizations are limited to unsubstituted or mono substituted heterocycles with limited examples for bifunctionalized systems. In this direction we attempted tandem cyclization of 1,7-enynes for accessing chloro-sulfonyl as the external functional group in an atom-economical manner.

Chapter 2.1: Synthesis of Z-selective 4-(chloromethylene)-tetrahydroquinoline derivative

Chapter 2.2: Synthesis of Z-selective 4-(chloromethylene)-chromane derivatives

Proposed Mechanism:

Photocatalyst (PC) on irradiation with 34W Kessil light, undergoes excitation, wherein it will donate its electron to tosyl chloride and generate tosyl radical and PC radical cation. The tosyl radical will then react with substrate I, to generate intermediate II, which undergoes cyclization to form radical intermediate III. Radical intermediate III then donates an electron to regenerate the photocatalyst, and form intermediate IV. This intermediate can react with the chloride ions present in the reaction mixture to give product V or alternatively it can react with water to give intermediate VI which then tautomerize to give the corresponding keto product.

Chapter 3: Synthesis of benzofuran derivatives via cascade electrochemistry

Benzofuran core is present in various natural product and drugs, e.g., Blasaminones A, Methoxsalen, Amiodorane etc. There are few reports on their synthesis with photoredox catalysis but the reported methods require various additives. Electrochemistry provides an alternative sustainable route to synthesize various organic molecules. So, we next attempted a method to synthesize benzofuran cores via cascade electro-organic synthesis.

Conclusion:

We have developed a sustainable methodology for the synthesis of functionalized quinolines and chromanes. We have explored various substrate scopes for same in moderate to good yields.
We have demonstrated their synthesis in gram scale.
Currently we are focusing on improving the yield of benzofuran derivatives and other synthetic applications of the project.

Future Plans:

Since carbocycles are also widely present in natural products and drugs derivatives, we are planning to synthesize highly functionalized carbocycles in a sustainable fashion.