Chapter 1 Triethylamine-mediated synthesis of bioactive heterocycles

Acknowledgments: The authors thank the Vellore Institute of Technology, Vellore, Tamil Nadu, India, for providing “VIT SEED GRANT-SG20210” to carry out this investigation successfully.

1.1 Introduction

Organic bases typically contain proton acceptors, but this is not always the case, and the use of base-promoted organic reactions has recently gained prominence [1]. They generally have nitrogen atoms that are easy to protonate. In amines and other heterocyclic compounds containing nitrogen, the nitrogen atom has a single pair of electrons that can act as proton acceptors. Triethylamine (TEA), also known as N,N-diethylethanamine (Et3N), is a colorless, water-soluble liquid that has a wide range of applications as an organocatalyst in chemical transformations [2]. Thus, the lone pair on nitrogen can act as a base. It functions in a variety of chemical syntheses as a solvent and a basic catalyst. In synthetic organic chemistry, TEA is recognized as a flexible and effective organocatalyst that is also inexpensive, easy to handle, nontoxic and reasonably safe. TEA is a mildly hydrogen-bond basic, dipolar/polarizable, weakly cohesive, non-hydrogen-bond acidic solvent. Compared to the other solvents, TEA has more occurrences of the creation of catalytic transformation products.

TEA should be defined for its first usage as a versatile reagent with applications ranging from photochemistry, electrochemistry and organic reactions. This chapter mainly focuses on applications of TEA photochemically and electrochemically and in organic reactions. It is useful for deprotonation and scavenging protons, for the formation of new compounds, and as a sensitizer photochemically [3]. In electrochemical experiments, TEA can be added as a supporting electrolyte to increase the conductivity of the solution and to stabilize the potential of the electrode [4]. It can also function as a solvent and a complexing agent. A typical organic base called TEA is frequently employed in organic chemistry reactions as a catalyst or reagent [5]. Additionally, TEA can also be used to complex metal ions and promote typical organic reactions (Figure 1.1).

Figure 1.1: Triethylamine properties and main fields of applications.

1.2 Triethylamine-promoted photocatalytic reactions

1.2.1 Photocatalytic triethylamine-mediated synthesis of 1,4-substituted 1,2,3-triazoles

Click chemistry has one of the most effective alternatives to synthesize 1,2,3-triazole. This study by Kumar et al. [6] uses a bipyrimidine-bridging ligand to coordinate the photocatalyst’s ruthenium photosensitizer unit with the manganese carbonyl complex. It offers quick electron transfer for a contact-free in situ reduction of Cu(II) to Cu(I) with TEA acting as a sacrificial donor. This led to a faster reaction rate than when the photosensitizer and Mn complex were physically mixed together in the reaction mixture, but the yield was still constrained by alkyne–alkyne homocoupling. Ru(bpy)2Cl2 and Mn(bpm)(CO)3Br were combined to create a bimetallic complex, [Ru(bpy)2(bpm)Mn(CO)3Br](PF6)2, which was then precipitated with ammonium hexafluorophosphate to produce an in situ Cu reduction of 1,4-disubstituted 1,2,3-triazole. The [3 + 2] cycloaddition of the azide and alkynes is facilitated by Cu(I) metal coordination. By regenerating the catalyst, the intermediate is then subjected to protonation, producing 1,4-disubstituted-1,2,3-triazoles (Figure 1.2).

Figure 1.2: Photocatalytic triethylamine-mediated synthesis of 1,4-substituted 1,2,3-triazoles.

The effective electron mobility occurs through Ru–Mn to Cu(II) via the pyrimidine-bridging ligand which is stabilized by [C2H5]3N–[C2H5]3N+✶. The mechanistic steps involved are explained in Figure 1.3.

Figure 1.3: Mechanistic details of role of TEA.

1.2.2 Reductive alkylation of difluoroalkyl halides using triethylamine as reductant

Miller et al. [7] described the creation of an improved photocatalytic method for reducing difluoroalkylation for different olefins. Under mild reaction conditions, these alkenes allow access to synthetically relevant noncanonical amino acid scaffolds. The starting materials, commercial difluoroalkyl halides, of experiments allowed the addition of various olefins, such as dehydroalanine residues toward considerable monomers. The currently described procedure uses TEA as the terminal reductant and an iridium photocatalyst to access the orthogonally protected residues in one step. Similar work was previously established using Hantzsch ester [8]. However, due to the problem of reactivity and undesired pathways, an efficient pathway using TEA as reductants is established.

When Et3N is oxidized, a radical cation is created, followed by the loss of a proton, producing the amino radical. Then, this species may engage in simple bromine atom abstraction from the precursor to produce the necessary difluoroalkyl radical and the iminium ion derived from Et3N. This radical in the presence of highly reducing iridium(II) species undergoes subsequent reactions to give product 2. Plausible mechanistic aspects are shown in Figure 1.4.

Figure 1.4: Photocatalytic triethylamine-mediated reductive alkylation of difluoroalkyl halides.

1.2.3 Triethylamine-mediated aerobic oxidation of sulfides

Due to the wide range of applications, selective oxidation of sulfides to sulfoxides has gained a great deal of interest. The most common semiconductor photocatalyst (TiO2) was found to show high performances. While carbazolic conjugated microporous polymers rose to benefit selective oxidation, pure polyimides [9] or PDA (polydopamine)-modified TiO2 failed to meet the requirements [10]. Polyimides bearing high lowest unoccupied molecular orbital had no recognizable photocatalytic activity and PDA-modified TiO2 could not achieve high selectivity. TEMPO (2,2,6,6-tetramethyl-1-piperidine N-oxyl) serves no purpose as a redox mediator in this process and is hence incapable. In order to increase the efficacy of the polyimide–TiO2 photocatalyst, a novel redox mediator was discovered. Lang et al. [11] found that TEA could increase the activity of polyimide–TiO2 catalysis by threefold. While an irradiation with 460 nm of blue light stimulates the reaction, TEA mediates the electron transfer between polyimide–TiO2 and sulfides, enabling oxidation of sulfides 3 to product 4 with high stereoselectivity. Detailed mechanistic aspects are demonstrated in Figure 1.5.

Figure 1.5: Triethylamine-mediated aerobic oxidation of sulfides`.