Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

Abstract

The focus of this review is to provide an overview of the field of organocatalysed photoredox chemistry relevant to synthetic medicinal chemistry. Photoredox transformations have been shown to enable key transformations that are important to the pharmaceutical industry. This type of chemistry has also demonstrated a high degree of sustainability, especially when organic dyes can be employed in place of often toxic and environmentally damaging transition metals. The sections are arranged according to the general class of the presented reactions and the value of these methods to medicinal chemistry is considered. An overview of the general characteristics of the photocatalysts as well as some electrochemical data is presented. In addition, the general reaction mechanisms for organocatalysed photoredox transformations are discussed and some individual mechanistic considerations are highlighted in the text when appropriate.

Keywords: C–H functionalisation; heterocycles; late-stage functionalisation; medicinal chemistry; organic dyes; organic photocatalysts; peptide chemistry; photoredox catalysis.

Figure 1

Depiction of the energy levels of a typical organic molecule and the photophysical processes it can undergo. A – absorption and emission, F – fluorescence, IC – internal conversion (non-radiative), ISC – intersystem crossing, P – phosphorescence.

Figure 2

General catalytic cycle of a photocatalyst in a photoredox organocatalysed reaction. [cat] – photocatalyst, [cat]*x – photocatalyst in x (x = S₀, S₁, T₁) state, ox – oxidised, red – reduced. ISC does not always occur.

Figure 3

Structures and names of the most common photocatalysts encountered in the reviewed literature.

Figure 4

General example of a reductive quenching catalytic cycle. [cat] – photocatalyst, [cat]* – photocatalyst in excited state, [sub] – substrate, [red] – reductant, [ox] – oxidant.

Figure 5

General example of an oxidative quenching catalytic cycle. [cat] – photocatalyst, [cat]* – photocatalyst in excited state, [sub] – substrate, [red] – reductant, [ox] – oxidant.

Scheme 1

Oxidative coupling of aldehydes and amines to amides using acridinium salt photocatalysis.

Figure 6

Biologically active molecules containing a benzamide linkage.

Scheme 2

The photocatalytic reduction of amino acids to produce the corresponding free or protected amines.

Scheme 3

The organocatalysed photoredox base-mediated oxidation of thiols to disulfides.

Scheme 4

C-Terminal modification of peptides and proteins using organophotoredox catalysis.

Scheme 5

The reduction and aryl coupling of aryl halides using a doubly excited photocatalyst (PDI).

Figure 7

Mechanism for the coupling of aryl halides using PDI, which is excited sequentially by two photons.

Scheme 6

The arylation of five-membered heteroarenes using arenediazonium salts under organophotoredox conditions.

Scheme 7

The C–H (hetero)arylation of five-membered heterocycles under Eosin Y photocatalysis.

Scheme 8

The C–H sulfurisation of imidazoheterocycles using Eosin B-catalyzed photochemical methods.

Scheme 9

The introduction of the thiocyanate group using Eosin Y photocatalysis.

Scheme 10

Sulfonamidation of pyrroles using oxygen as the terminal oxidant.

Scheme 11

DDQ-catalysed C–H amination of arenes and heteroarenes.

Scheme 12

Photoredox-promoted radical Michael addition reactions of allylic or benzylic carbons.

Figure 8

Proposed mechanistic rationale for the observed chemoselectivities.

Scheme 13

The photocatalytic manipulation of C–H bonds adjacent to amine groups.

Scheme 14

The perylene-catalysed organophotoredox tandem difluoromethylation–acetamidation of styrene-type alkenes.

Figure 9

Examples of biologically active molecules containing highly functionalised five membered heterocycles.

Scheme 15

The [3 + 2]-cycloaddition leading to the formation of pyrroles, through the reaction of 2H-azirines and alkynes via organophotoredox catalysis.

Figure 10

Proposed intermediate that determines the regioselectivity of the reaction.

Figure 11

Comparison of possible pathways of reaction and various intermediates involved.

Scheme 16

The acridinium salt-catalysed formation of oxazoles from aldehydes and 2H-azirines.

Scheme 17

The synthesis of oxazolines and thiazolines from amides and thioamides using organocatalysed photoredox chemistry.

Figure 12

Biologically active molecules on the market containing 1,3,4-oxadiazole moieties.

Scheme 18

The synthesis of 1,3,4-oxadiazoles from aldehyde semicarbazones using Eosin Y organophotocatalysis.

Scheme 19

The dimerization of primary thioamides to 1,2,4-thiadiazoles catalysed by the presence of Eosin Y and visible light irradiation.

Scheme 20

The radical cycloaddition of o-methylthioarenediazonium salts and substituted alkynes towards the formation of benzothiophenes.

Scheme 21

The dehydrogenative cascade reaction for the synthesis of 5,6-benzofused heterocyclic systems.

Figure 13

Trifluoromethylated version of compounds which have known biological activities.

Scheme 22

Eosin Y-catalysed photoredox formation of 3-substituted benzimidazoles.

Scheme 23

Oxidation of dihydropyrimidines by atmospheric oxygen using photoredox catalysis.

Scheme 24

Photoredox-organocatalysed transformation of 2-substituted phenolic imines to benzoxazoles.

Scheme 25

Visible light-driven oxidative annulation of arylamidines.

Scheme 26

Methylene blue-photocatalysed direct C–H trifluoromethylation of heterocycles.

Scheme 27

Photoredox hydrotrifluoromethylation of terminal alkenes and alkynes.

Scheme 28

Trifluoromethylation and perfluoroalkylation of aromatics and heteroaromatics.

Scheme 29

The cooperative asymmetric and photoredox catalysis towards the functionalisation of α-amino sp³ C–H bonds with electron-deficient olefins.

Scheme 30

Organophotoredox-catalysed direct C–H amidation of aromatics.

Scheme 31

Direct C–H alkylation of heterocycles using BF₃K salts. CFL – compact fluorescent lamp.

Figure 14

The modification of camptothecin, demonstrating the use of the Molander protocol in LSF.

Scheme 32

Direct C–H amination of aromatics using acridinium salts.

Scheme 33

Photoredox-catalysed nucleophilic aromatic substitution of nucleophiles onto methoxybenzene derivatives.

Scheme 34

The direct C–H cyanation of aromatics with a focus on its use for LSF.