Photoredox Catalysis with 10-Phenyl-10H- Phenothiazine and Synthesis of a Photocatalytic Chiral Proline-Based Organocatalyst

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Photoredox catalysis with 10-phenyl-10H- phenothiazine and synthesis of a photocatalytic chiral proline-based organocatalyst

Master Thesis in Organic Chemistry

Panagiotis Lamprianidis

Molecular Science and Engineering

School of Engineering Sciences in Chemistry Biotechnology and Health (CBH)

Supervisor: Prof. Peter Dinér

January 2020

Summary in English

Photoredox catalysis applications for the purpose of new synthetic routes in organic and sustainable chemistry are hot topics in organic synthesis today. In the present study, the synthesis of a chiral proline-based organocatalyst functionalized with 10-phenyl-10H-phenothiazine (PTH) photocatalytic moieties is investigated and attempted for the first time. PTH, an organic photocatalyst, is studied for its photocatalytic activity in different organic reactions, such as dehalogenation of aromatic halides and the pinacol coupling reaction between aromatic aldehydes. These transformations are otherwise difficult to achieve without a suitable catalyst and the reactions were performed with moderate to high yields.

Sammanfattning på svenska

Applikationer av photoredox-katalys med syftet att generera nya syntetiska vägarinom organisk och hållbar kemi är populära ämnen i organisk syntes idag. I denna studien undersöktes för första gången syntesen av en kiral prolinbaserad organokatalysator som är funktionaliserad med fotokatalytiska enheter (10- fenyl-10H-fenotiazin (PTH)). Den fotokatalytiska aktiviteten av PTH studerades för olika organiska reaktioner, såsom t.ex. dehalogenering av aromatiska halider och pinacolkopplingar mellan aromatiska aldehyder. Dessa transformationer är annars svåra att uppnå utan en lämplig fotokatalysator och reaktionerna utfördes med måttliga till höga utbyten.

Table of Contents

1. Introduction……………………………………………………………………………………..5 1.1 Organocatalysis and enantioselectivity………………………………………...5 1.2 Enamines in organocatalysis and SOMO catalysis...... 5 1.3 Photocatalysis……………………………………………………………………………..6 2. Aim and approach……………………………………………………………………………..7 3. Theoretical background…………………………………………………………………….7 3.1 The Grignard reaction………………………………………………………………….7 3.2 Cross-coupling reactions……………………………………………………………...7 3.2.1 Ullmann-type coupling………………………………………………………….8 3.2.2 The Buchwald-Hartwig amination…………………………………………8 3.3 PTH……………………………………………………………………………………………..9 4. Results and discussion……………………………………………………………………..10 5. Conclusion and outlook…………………………………………………………………....24 6. Acknowledgements………………………………………………………………………….25 7. References……………………………………………………………………………………....26 8. Appendix…………………………………………………………………………………………27 8.1 Experimental……………………………………………………………………………..27 8.1.1 Part A - Synthesis of a photocatalytic organocatalyst……………27 8.1.2 Part B - Photocatalysis with PTH…………………………………………32 8.2 ESI-MS spectra………………………………………………………………………….36 8.3 1H NMR spectra………………………………………………………………………...37

Table of Abbreviations

CDCl3 deuterated chloroform d deuterated DCM dichloromethane DI deionized DMSO dimethyl sulfoxide dr diastereomeric ratio equiv equivalents ESI-MS electrospray ionization mass spectrometry EtOAc ethyl acetate h hours HA Brønsted acid MeCN acetonitrile min minutes MS mass spectrometry NBu3 tri(n-butyl)amine n-BuLi n-butyllithium NMR nuclear magnetic resonance PTH 10-phenyl-10H-phenothiazine PE petroleum ether Ph phenyl PhI iodobenzene RBF round-bottom flask Rf retention factor RT room temperature THF tetrahydrofuran TLC thin-layer chromatography TS transition state ΔG‡ Gibbs free energy of activation

1. Introduction

1.1 Organocatalysis and enantioselectivity

Organic reactions usually occur through the lowest possible energy maximum known as the transition state, TS, with a specific activation energy, ΔG‡, for a given reaction mechanism. The mechanism of a reaction can be modified by the use of catalysts which promote the reaction by lowering the activation energy barrier and thereby facilitating the conversion from reactants to products. Catalysis can be divided into homogeneous and heterogeneous catalysis. In homogenous catalysis the reaction between the substrate and the catalyst occurs in same phase (e.g. solution phase), while in heterogenous catalysis the reaction takes place in the interface between different phases (e.g. solid-liquid phases). Catalysis is also categorized into metal-, bio-, organo-, photo-catalysis depending on the type of catalyst used in the reaction. The main concept of organocatalysis entails the use of organic compounds in substoichiometric amounts to accelerate the rate of organic reactions. Apart from being cost efficient and environmentally friendly, organocatalysts are also often insensitive to moisture and oxygen which renders them ideal for applications in organic synthesis. The use of chiral organocatalysts opens the opportunity to perform reactions in a stereoselective manner and thereby yielding enantiopure products via the so called enantioselective organocatalysis. In enantioselective organocatalysis, a chiral organocatalyst can control the formation of one enantiomer over the other and thereby lead to an enantiomeric excess of one of the enantiomers. Chiral compounds are of high importance in biological functions and so enantioselective synthesis is crucial in the production of pharmaceuticals.

1.2 Enamines in organocatalysis and SOMO catalysis

One common class of chiral organocatalysts are amine-based compounds and most usually a secondary cyclic amine, such as a pyrrolidine-, piperidine- or morpholine-based derivative.[1] Proline-based organocatalysts are the most ubiquitous in use due to the ease of their preparation directly from the naturally abundant amino acid L-proline providing an already predefined chirality. Proline-based derivatives, being cyclic amines, show supreme reactivity as organocatalysts due to the exposed lone pair of electrons on the amine nitrogen. Proline-based catalysts activate carbonyl compounds via the iminium ion and enamine intermediate. Enamines are a class of compounds which can form easily by the addition of a primary or secondary amine to a ketone or aldehyde. Enamine formation plays a central role in the organocatalytic function of amines. The starting ketone or aldehyde of interest reacts with substoichiometric amounts of the amine organocatalyst to form a stable enamine via the iminium ion, which can further react with an electrophilic reagent to form the desired compound (Figure 1). The enamine is finally hydrolyzed to regenerate the amine organocatalyst, while at the same time releasing the final product and completing the catalytic cycle.

Macmillan and co-workers developed the enamine activation to include a Singly Occupied Molecular Orbital (SOMO) activation mode. SOMO is a molecular orbital containing only a single unpaired electron, ubiquitously known as a radical. Enamines can form an iminyl radical upon oxidation with ceric ammonium nitrate (CAN) through a single electron transfer mechanism (SET).[2] The iminyl radical can further react with electron rich olefins with high enantioselectivity.

Figure 1. Iminium, enamine and SOMO catalysis.[2]

1.3 Photocatalysis: transition metal and organic photocatalysts

Photocatalysis is a type of catalysis that utilizes light to accelerate the rate of a reaction. It is usually conducted by using transition metal coordination complexes of ruthenium and iridium, such as Ru(bpy)3 and Ir(ppy)3 as well as organic photocatalysts such as anthracene and perylene derivatives. Organic photocatalysts, even though not as robust, efficient, easily handled and recycled as their metal coordination complex counterparts, can find useful applications in green chemistry, such as photoredox-catalyzed dehalogenations of aromatic compounds. Organic photocatalysts are potentially more easily accessible compounds compared to the precious transition metal complexes based on rhodium, iridium and ruthenium.[3] The fact that no toxic heavy metals are involved, and thus there is no need for specialized processing before waste disposal, is a critical factor to consider.

Organic chemistry provides a whole set of different kinds of functionalities to choose from, thus organic photocatalysts can be very diverse in structure, but all of them are sharing the same characteristic of easy excitation of electrons upon exposure to light from the HOMO to the LUMO of the molecule. Conjugated polycyclic aromatic compounds are commonly used for the purpose of photocatalysis, with notable examples being perylene diimides (PDI), acridine-, xanthene-, phenothiazine- and anthracene-type derivatives with relatively small HOMO/LUMO energy band gaps, meaning that they can be easily excited by UV and even visible light.

2. Aim and approach

The present study is divided into two parts, which includes the synthesis of a new photocatalytic organocatalyst (part A) and the evaluation of 10-phenyl-10H- phenothiazine (PTH) as an effective photocatalyst to assist in the dehalogenation of aryl halides as well as in a pinacol-type coupling of aromatic aldehydes (part B). The aim of part A was to synthesize a PTH-functionalized proline-based organocatalyst with the objective to test its photocatalytic activity and the possibility to promote enantioselective reactions. The synthetic strategies devised and the attempted reactions will be presented and discussed and the experimental procedures of the synthesis work are presented in the ‘appendix’. The aim of part B was to study the photocatalytic activity of PTH in the dehalogenation of aryl halides and halogenated aromatic aldehydes, as well as the photoredox-catalyzed pinacol coupling of aromatic aldehydes.

3. Theoretical background

3.1 The Grignard reaction

The Grignard reaction is a common synthetic route to the formation of new C-C bonds in order to expand the backbone of a molecular structure. [4] An alkyl or aryl halide is reacted with magnesium metal to yield an organomagnesium compound known as a “Grignard reagent”, of the form RMgX, almost exclusively in ether which stabilizes the formed Grignard reagent. The Grignard reagent is further reacted with the desired electrophile, usually a carbonyl compound (ketone, aldehyde or ester), to form a new C-C bond and yield an alcohol after workup with an aqueous solution of a weak acid (e.g. plain water or NH4Cl aqueous solution), as shown in Figure 2 below.

Figure 2. The Grignard reaction.[4]

For the scope of this study a Grignard reagent of the bromide of PTH was prepared in order to react with a proline ester derivative discussed in the experimental part of this report (appendix).

3.2 Cross-coupling reactions

Cross-coupling reactions are performed with the use of a transition metal catalyst, most commonly palladium, platinum, ruthenium, copper and nickel. Notable cross-coupling reactions are the Heck, Suzuki, Kumada, Sonogashira, Negishi. Stille and Buchwald-Hartwig reactions. For the scope of this study firstly an Ullmann-type coupling, discussed in the following paragraph, was used to form

the bromide of PTH from 10H-phenothiazine and 1-bromo-4-iodobenzene and the 2-Cl-PTH from 2-chloro-10H-phenothiazine and iodobenzene. Then a Buchwald- Hartwig amination was used to couple 10H-phenothiazine with a chiral bis(4- bromophenyl) derivative of L-proline.

3.2.1 Ullmann-type coupling

The original Ullmann coupling reaction uses copper metal or copper salts to achieve the homo-coupling of aryl halides. Very high temperatures are usually required for this reaction to obtain good yields, usually not exceeding 50%. The Ullmann coupling reaction can also be utilized to achieve cross-couplings between aryl halides and amines and is then referred to as an Ullmann-type coupling, despite the fact that it is not a homo-coupling. The catalytic cycle is presented in Figure 3 below.

Figure 3. Ullmann-type catalytic cycle.[5]

3.2.2 Buchwald-Hartwig amination

The Buchwald-Hartwig cross-coupling is selectively used for the amination of aryl halides. This type of cross-coupling reaction involves the use of a palladium catalyst coordinated complex with phosphine ligands (L). The ligands are usually bidentate in order to sterically hinder the undesired β-hydride elimination side reaction that would otherwise occur on the amine. The catalytic cycle is presented in Figure 4 below and the β-hydride elimination reaction is shown in the center of the cycle, yielding an iminium cation and the reduced aryl halide, instead of a cross-coupling.

Figure 4. The Buchwald-Hartwig catalytic cycle.[6]

3.3 PTH

The aim with the present study was initially to synthesize an amine-based photocatalyst containing a 10-phenyl-10H-phenothiazine (PTH) moiety. 10- phenyl-10H-phenothiazine (PTH) is an organic photocatalyst with a high reduction potential (E1/2* = −2.1 V vs. SCE) that is significantly higher than Ir(ppy)3 (E1/2* = −1.7 V vs. SCE)[3] and was utilized for the dehalogenation of aryl halides and aromatic halogenated aldehydes.[3] In previous studies PTH has been used successfully in photocatalyzed reactions of stable enamines with phenyl radicals produced by Single Electron Transfer (SET) from the PTH photoredox catalyst.[7]

Figure 5. 10-phenyl-10H-phenothiazine advantages and applications.[3]

4. Results and discussion

Part A: Synthesis of a PTH-functionalized L-proline organocatalyst:

Restrosynthetic analysis:

Step 1:

Step 2:

The synthesis was firstly approached by attempting to couple the proline ester derivative (3) with PTH-Br (1) using the Grignard reaction. PTH-Br was synthesized beforehand using an Ullmann-type coupling of 10H-phenothiazine with 1-bromo-4-iodobenzene. 1H NMR showed conversion of starting PTH-Br to PTH and unreacted proline ester derivative (3) still present, which was not the expected outcome. The presence of unreacted starting proline ester was confirmed by TLC (eluent: 5:1 petr.ether:EtOAc). This procedure was repeated 3 times (scaled down) and once with microwave heating giving approximately the same results.

Lithium-halogen exchange:

Retrosynthetic analysis alternative:

Step 1:

Step 2:

The above procedure was repeatedly unsuccessful, so a lithium-halogen exchange reaction was applied to the PTH-Br with n-BuLi to obtain the organolithium PTH reagent which was going to be reacted with the proline ester derivative (1). This was again proved unsuccessful after characterization with 1H NMR and another procedure was planned. Compound (7) was synthesized from proline ester (1) with p-dibromobenzene in a Grignard reaction. This compound was isolated and purified with flash column chromatography and was later reacted with 10H- phenothiazine in a Buchwald-Hartwig cross-coupling reaction using RuPhos-G2 palladium precatalyst. This step was unsuccessful producing a mixture of difficult to characterize products. Flash column chromatography on silica gel was used to isolate the different compounds of the mixture, each of which was characterized by NMR and ESI-MS. None of the isolated compounds matched the expected product (4).

The photoredox catalysis potential of PTH was tested with different aromatic aldehyde substrates after the synthesis part was unsuccessful to show the effectiveness of PTH as an organic photocatalyst. The pinacol coupling was an unexpected outcome of this study.

The results presented below regard Part B of this study, i.e. the photocatalytic applications of PTH for: i) the radical dehalogenation of aryl halides and halogenated aromatic aldehydes[3] ii) the photoredox-catalyzed pinacol coupling of benzaldehyde and substituted benzaldehydes and the effect of a strong carboxylic acid on the reaction rate[3, 8] iii) the photoredox-catalyzed pinacol coupling of an electron-deficient aromatic aldehyde, namely 2-formylpyridine, and the investigation of the effect of chiral acids on the reaction rate and the diastereo- and enantiomeric ratios of the resulting products.[3, 8, 9]

Table 1. Photoredox-catalyzed dehalogenation of iodobenzene.

Time NMR yield Conversion [min] [%] [%]

5 69.5 72.3

10 76.4 82.6

15 76.4 88.3

20 76.2 91.6

30 78.9 95.4

Conditions: 0.1 mmol PhI, 0.5 mmol NBu3, 0.5 mmol HCOOH, 0.2 mmol 1,4- dimethoxybenzene (internal standard), 5 mol% PTH, T = RT, 40 W 390 nm LED, inert atmosphere (N2) in MeCN-d3 in sealed NMR tubes.

The table above (Table 1) shows the dehalogenation of iodobenzene with increasing time of exposure to irradiation. The conversion compared to the NMR yield shows that not significant amounts of side products form, since their percentage difference does not exceed 20%. The fact that the difference between NMR yield and conversion is increasing slightly as exposure time increases could be due to many factors, e.g. side product formation, change of the concentration of internal standard due evaporation of the solvent.

Table 2. Photoredox-catalyzed dehalogenation of 4-iodo-benzaldehyde.

Time NMR yield Conversio [min] [%] n [%]

5 67.2 90.5

15 64.2 89.4

30 68.0 92.0

Conditions: 0.1 mmol 4-iodo-benzaldehyde, 0.5 mmol NBu3, 0.5 mmol HCOOH, 0.2 mmol 1,4-dimethoxybenzene (internal standard), 5 mol% PTH, T = RT, 40 W 390 nm LED, inert atmosphere (N2) in MeCN-d3 in sealed NMR tubes.

Table 3. Photoredox-catalyzed dehalogenation of 4-bromo-benzaldehyde.

Time NMR yield Conversion [min] [%] [%]

15 5.5 75.4

30 3.1 > 99

Conditions: 0.1 mmol 4-bromo-benzaldehyde, 0.5 mmol NBu3, 0.5 mmol HCOOH, 0.2 mmol 1,4-dimethoxybenzene (internal standard), 5 mol% PTH, T = RT, 40 W 390 nm LED, inert atmosphere (N2) in MeCN-d3 in sealed NMR tubes.

Table 4. Photoredox-catalyzed dehalogenation of 4-chloro-benzaldehyde.

Time NMR yield Conversion [min] [%] [%]

15 4.7 76.5

30 4.7 > 99

Conditions: 0.1 mmol 4-chloro-benzaldehyde, 0.5 mmol NBu3, 0.5 mmol HCOOH, 0.2 mmol 1,4-dimethoxybenzene (internal standard), 5 mol% PTH, T = RT, 40 W 390 nm LED, inert atmosphere (N2) in MeCN-d3 in sealed NMR tubes.

Figure 6. Pinacol coupling of benzaldehyde products.

The dehalogenation of 4-iodo-benzaldehyde is shown to proceed smoothly and with minimal side products, while for the other two (4-bromo- and 4-chloro- benzaldehyde) the dehalogenation is much slower than the obvious side reaction(s) occurring, which was later found to be a pinacol coupling of the aldehydes through a photoredox-catalyzed ketyl radical intermediate (Scheme 1). Benzaldehyde was tested alone for the pinacol reaction using 5 mol% PTH and NBu3. The reaction conditions for the pinacol coupling were then changed by adding formic acid in different amounts (Tables 5-7). Figure 6 above shows the distinct singlets in 1H NMR around 5 ppm for the meso compound and the mixture of enantiomers dl, products of the pinacol coupling of benzaldehyde.

Scheme 1. Pinacol coupling, ketyl radical intermediate.

Table 5. Photoredox-catalyzed pinacol coupling of benzaldehyde (2 equiv NBu3).

Time NMR yield Conversion [min] [%] [%]

30 59.2 66.7

60 99.2 99.2

Conditions: 0.075 mmol benzaldehyde, 0.15 mmol NBu3, 0.075 mmol 1,4- dimethoxybenzene (internal standard), 5 mol% PTH, T = RT, 40 W 390 nm LED, inert atmosphere (N2) in MeCN-d3 in sealed NMR tubes.

Table 6. Photoredox-catalyzed pinacol coupling of benzaldehyde (2 equiv NBu3 + 2 equiv HCOOH).

Time NMR yield Conversion [min] [%] [%]

10 59.3 68.1

20 93.3 > 99

40 94.8 > 99

Conditions: 0.075 mmol benzaldehyde, 0.15 mmol NBu3, 0.15 mmol HCOOH, 0.075 mmol 1,4-dimethoxybenzene (internal standard), 5 mol% PTH, T = RT, 40 W 390 nm LED, inert atmosphere (N2) in MeCN-d3 in sealed NMR tubes.

Table 7. Photoredox-catalyzed pinacol coupling of benzaldehyde (5 equiv NBu3 + 5 equiv HCOOH).

Time NMR yield Conversion [min] [%] [%]

10 49.6 94.1

20 92.6 97.0

40 97.0 99.3

Conditions: 0.075 mmol benzaldehyde, 0.375 mmol NBu3, 0.375 mmol HCOOH, 0.075 mmol 1,4-dimethoxybenzene (internal standard), 5 mol% PTH, T = RT, 40 W 390 nm LED, inert atmosphere (N2) in MeCN-d3 in sealed NMR tubes.

100 90 80 70 60

50 NBu3 40 NBu3 + HCOOH (2 equiv)

NMR yield [%] yield NMR 30 NBu3 + HCOOH (5 equiv) 20 10 0 0 20 40 60 Time [min]

Figure 7. Photoredox-catalyzed pinacol coupling of benzaldehyde.

As one can see in the diagram above (Fig. 7) the pinacol coupling reaction proceeds with higher than 90% yield. Conversion follows the same trend, indicative of the absence of any significant side reactions. Comparing the pinacol coupling with only tributylamine and the one with the addition of formic acid (HCOOH) one can clearly observe a significant acceleration of the reaction when HCOOH is present. For all of the above experiments the diastereomeric ratio meso : dl was found to be around 1 : 1.1.

Table 8. Photoredox-catalyzed pinacol coupling of substituted benzaldehydes (5 equiv NBu3 + 5 equiv HCOOH).

Total exposure time: NMR Conversion 40 min yield [%] [%]

benzaldehyde 76 > 99

o-tolualdehyde 89 99

4-t-butyl-benzaldehyde 77 99

Total exposure time: NMR Conversion 60 min yield [%] [%]

m-tolualdehyde 87 > 99

4-fluoro-benzaldehyde 75 > 99

p-anisaldehyde 41 64

Conditions: 0.075 mmol aldehyde, 0.375 mmol NBu3, 0.375 mmol HCOOH, 0.075 mmol 1,4-dimethoxybenzene (internal standard), 5 mol% PTH, T = RT, 40 W 390 nm LED, inert atmosphere (N2) in MeCN-d3 in sealed 2 ml vials.

The substrate scope of the photoredox-catalyzed pinacol coupling of different aromatic benzaldehydes with PTH is presented in Table 8 above. Some differences in the reaction rates were observed and so several different aldehydes were tested qualitatively for their kinetics in this specific reaction following the guidelines of a reference publication[8]. The results are presented in the diagram below (Figure 8). The diastereomeric ratio meso : dl was also found to vary slightly between 0.8 and 1 depending on the ring substituent, with the most notable example being o- tolualdehyde indicating a contribution of steric effects to the pinacol coupling. While for most aldehydes it was close to the one found for R=H (benzaldehyde), for o-tolualdehyde it was close to 1 : 2.

100 90 80 70 4-CF3-benzaldehyde 60 methyl-4-formyl-benzoate 50 p-anisaldehyde 40 o-tolualdehyde 30 p-tolualdehyde Conversion [%] Conversion 20 4-tbutyl-benzaldehyde 10 4-fluoro-benzaldehyde 0 m-tolualdehyde 0 10 20 30 40 Time [min]

Figure 8. Conversion of substituted benzaldehydes in the photoredox-catalyzed pinacol coupling with PTH. Conditions: 0.1 mmol aldehyde (1 equiv), 0.2 mmol NBu3 (2 equiv), 0.2 mmol HCOOH (2 equiv), 5 mol% PTH, T = RT, 40 W 390 nm LED, inert atmosphere (N2) in MeCN-d3 in sealed NMR tubes.

One can observe in the diagram above (Fig. 8) that the most strongly electron donating ring substituents can decrease the conversion of the pinacol coupling. Namely, p-anisaldehyde having a strongly electron donating methoxy (MeO-) substituent shows the least conversion of all the tested aldehydes. Weakly electron withdrawing groups on the ring, such as fluoro-substituent, and the moderately electron withdrawing MeCO2- ester functionality, show an increase in the overall conversion and rate of the reaction. On the other hand, strongly electron withdrawing, such as -CF3, and weakly electron donating groups, such as alkyl substituents, keep the reaction at an intermediate rate and conversion.

The variations observed in these results can be attributed to the increase or decrease in the stability of the ketyl radical intermediate imposed by the character of each substituent on the aromatic ring. By rendering the molecule more electron-rich in the case of electron donating groups or electron-poor in the case of electron withdrawing groups the radical intermediate stability is changed and so is the reactivity and consequently the reaction rate.

4-nitro-benzaldehyde (strongly electron withdrawing) was also tested but the results were not interpretable since there were side products formed to a significant extent rendering it unusable for the scope of the investigation of this photoredox-catalyzed pinacol coupling of aromatic aldehydes.

The photoredox-catalyzed pinacol coupling with PTH was also tested for 2- formylpyridine with the assistance of three different chiral acids, hypothesized to affect the diastereo- and enantiomeric ratios. In accordance to a reference publication[9] investigating Minisci-type reactions, enantiopure binaphthyl phosphoric acid was utilized to enantioselectively synthesize a pyridine derivative with the assistance of radical photoredox-catalysis by an iridium photocatalyst. The results are shown in Table 9 below.

It was assumed that the acid can hydrogen bond to the carbonyl oxygen or to the pyridine nitrogen affecting the reaction rate and the diastereo- and/or enantiomeric ratios.

Table 9. Photoredox-catalyzed pinacol coupling of 2-formylpyridine using different chiral acids.

Diastereomeric Chiral acid NMR Conversion ratio (*) yield [%] [%] meso : dl

1 13 68 1 : 2.5

2 39 87 1 : 3.3

3 22 71 1 : 1.7

(no acid) 22 30 1 : 3.3

Conditions: 0.1 mmol 2-formylpyridine, 0.5 mmol NBu3, 0.1 mmol 1,4- dimethoxybenzene (internal standard), 5 mol% PTH, T = RT, 40 W 390 nm LED, inert atmosphere (N2) in MeCN-d3 in sealed 2 ml vials. Total exposure time = 40 min.

(*) To three out of four of the samples was added 10 mol% of one of the following chiral acids in each:

1. (S)-(-)-BINOL (0.01 mmol, 2.9 mg)

2. (R)-(-)-1,1’-binaphthyl-2,2’-diyl hydrogenphosphate (0.01 mmol, 3.5 mg)

3. (S)-1,1’-binaphthyl-2,2’-disulfonimide (0.01 mmol, 4 mg)

In the fourth sample no acid was added in order to be used as a control for the reaction.

As one can observe, the addition of 10 mol% of a binaphthyl chiral acid from the ones listed above (*) can affect the reaction rate with a notable increase for chiral acid (2) in the observed NMR yield, while there is a decrease in reaction rate upon addition of chiral acid (1) reflected on the lower NMR yield obtained. Chiral acid (3) did not appear to affect the reaction rate since the NMR yield obtained was equivalent to the one obtained from the control sample, even though there was a notable increase in the conversion of the starting material from ~30 to 70%, indicative of a side reaction taking place. The diastereomeric ratios (dr) upon the addition of chiral acids (1) and (3) seemed to be also affected while for chiral acid (2) the dr was found to be the same as for the control. Regarding the enantiomeric ratio for this reaction an HPLC measurement is needed from an instrument equipped with a chiral column so as to get an enantiomeric resolution in the resulting chromatogram and this was left to be investigated in a later experiment.

5. Conclusion and outlook

In this study, PTH was proven to be an effective organic photocatalyst for at least two types of organic reactions. More specifically, dehalogenation of aryl halides was accomplished for times as short as even 10 minutes of exposure to 390 nm, 40 W light. Additionally, pinacol coupling, a reaction that normally requires the use of a metal catalyst like magnesium which can bind to the carbonyl oxygen atoms and facilitate the reaction, was rendered possible for aromatic aldehydes such as benzaldehyde and 2-formylpyridine with yields as high as ~95% and 40% respectively, even without the use of such a metal catalyst.

Regarding the synthesis of a proline-based organocatalyst equipped with PTH as a photocatalytic moiety, if in the end this proves to be rendered possible, it would be very interesting to investigate the synergistic capabilities of the organocatalytic action of the amine functionality combined with the already proven photocatalytic activity of PTH. Reactions such as the α-substitution of aliphatic aldehydes, with the assistance of PTH to initiate the aryl radical intermediate, would be rendered much more accessible and cost-efficient, since as stated above, organic photocatalysts such as PTH are much more environmentally friendly and economical than their transition metal coordination-complex analogues.

6. Acknowledgements

Firstly, I would like to express my gratitude to my supervisor and organic chemistry professor, Prof. Peter Dinér, for accepting me in his research group, for all of the guidance, support and patience throughout this difficult process and for teaching me organic chemistry and of course for funding my research with the highest quality standards possible and for always being available to answer my countless questions from the beginning of this study until its completion.

I would also like to thank my organic chemistry professors, Prof. Markus Kärkäs and Prof. Helena Lundberg, for teaching me organic chemistry and contributing to my thesis in every way possible and for their patience and willingness to answer my numerous questions throughout this semester. I would also like to thank Prof. Markus Kärkäs for the LED equipment that I used in the photocatalytic part of the study and Dr. Andrey Shatskiy for helping me use it successfully.

I am more than grateful for the help, guidance, patience and everyday support of my lab colleagues and supervisors, Dr. Björn Blomkvist and Giampiero Proietti, PhD candidate. Without your help the completion of this study and thesis would not be possible. I wish to you the best of luck and success in your current and future research and I am going to miss your enlightening conversations and ideas.

I would also like to thank Prof. Zoltan Szabo, Brian, Jian-Quan, Daniele, Oleskandr, Antanas, Piret, Christiana and all of the researchers in the Organic Chemistry Department for their help and guidance in various everyday lab tasks and questions and helping me to get to know the place since the beginning of my thesis.

Finally, I would like to thank my family and close friends for their everyday support and love throughout this difficult procedure. To close with, I would like to dedicate this work to my father who throughout his life has always encouraged me and inspired me towards science and progress and with his contribution I have been able to stand where I am right now.

7. References

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9. Rupert S.J. Proctor, Holly J. Davis et al., Catalytic enantioselective Minisci- type addition to heteroarenes. Science 2018, 360, 6387, 4. doi: 10.1126/science.aar6376.

10. Rey, Y.P., Zimmer, L.E., Sparr, C., Tanzer, E.‐M., Schweizer, W.B., Senn, H.M., Lakhdar, S. and Gilmour, R. (2014), Molecular Design Exploiting a Fluorine gauche Effect as a Stereoelectronic Trigger. Eur. J. Org. Chem. 2014: 1202-1211. doi:10.1002/ejoc.201301730.

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8. Appendix

8.1 Experimental

8.1.1 Part A - Synthesis of a photocatalytic organocatalyst

Synthesis of 10-(4-bromophenyl)-10H-phenothiazine (PTH-Br) (1) PTH-Br was prepared from 10H-phenothiazine and 1-bromo-4-iodobenzene following the Ullmann-type coupling reaction scheme shown below (Scheme 2). Into a 250 ml round-bottom flask equipped with a magnetic stirrer were added 10H-phenothiazine (4.225 g, 21.2 mmol, 1 equiv), 1-bromo-4-iodobenzene (6.2 g, 22 mmol, 1.03 equiv), K2CO3 (3.9 g, 28.2 mmol, 1.33 equiv) and copper sulfate pentahydrate (0.257 g, 1.03 mmol, 0.05 equiv). The reaction mixture was stirred at 600 rpm and heated to 170 °C. The reaction mixture appeared initially as a slurry, and only after 30 minutes a dark homogeneous solution was observed. After 3 h of reaction it was noticed that the reaction turned into a purple color. The conversion was monitored with TLC (eluent: petroleum ether). The total heating time was 6 h after which the reaction was diluted with toluene (10 ml) and then ethyl acetate (40 ml) after lowering the temperature to 130 °C. Heating was turned off after 30 min and the mixture left to cool to RT. Two layers had formed (one green aqueous and one red organic) and a greyish solid at the interface was also present.

Scheme 2. Synthesis of PTH-Br 1

The organic layer was kept and the aqueous discarded. The organic layer and the solid were washed 3 times with water and the solid was triturated separately with EtOAc. The organic phases were combined and dried over anhydrous MgSO4. The mixture was vacuum filtered, solids discarded and the filtrate evaporated under reduced pressure, then dried under high vacuum. The same procedure was repeated once more (batch 2). % yield = 3% (batch 1), 44% (batch 2). Yield was calculated after purification with flash column chromatography on silica gel (eluent: petroleum ether). 1H NMR (400 MHz, DMSO-d6) δ: 7.82 (d, J = 7.0 Hz, 2H), 7.37 (d, J = 7.0 Hz, 2H), 7.13 (d, J = 7.5 Hz, 2H), 6.99 (t, J = 7.5 Hz, 2H), 6.91 (t, J = 7.5 Hz, 2H), 6.28 (d, J = 8.4 Hz, 2H).

Synthesis of 2-chloro-10-phenyl-10H-phenothiazine (PTH-2-Cl) (2) PTH-2-Cl was prepared from 2-chloro-10H-phenothiazine and iodobenzene following the Ullmann-type coupling reaction scheme shown below (Scheme 3).

2 Scheme 3. Synthesis of PTH-2-Cl

2-chloro-10H-phenothiazine (3.506 g, 15.0 mmol, 1 equiv) was added together with iodobenzene (2 ml, 18 mmol, 1.2 equiv), copper (I) iodide (1.428 g, 7.5 mmol, 0.5 equiv), ethylenediamine (500 μl, 7.5 mmol, 0.5 equiv), potassium carbonate (6.365 g, 46 mmol, 3.1 equiv) and toluene (100 ml) in a 250 ml round-bottom flask. A reflux condenser was attached and the reaction flask was put in an oil bath set to 130 °C. The reaction was left to proceed under reflux for approx. 24 hours. A TLC sample taken and conversion was observed (eluent: petroleum ether). The solids were filtered (mostly inorganic salts) and triturated with ethyl acetate and the combined organic layers washed with H2O, then brine and dried over anhydrous MgSO4. The solvent was evaporated and gave a crude yield of 5.36 g that was purified with flash column chromatography on silica gel (eluent: petroleum ether) yielding the product. % yield (after purification) = 7%. 1H NMR (400 MHz, DMSO-d6) δ: 7.71 (t, J = 7.0 Hz, 2H), 7.60 (t, J = 7.9 Hz, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.08 (m, 2H), 6.96-6.86 (m, 3H), 6.12 (d, J = 7.9 Hz, 1H), 6.02 (s, 1H).

L-Proline ester derivative (3) 1-ethyl 2-methyl (S)-pyrrolidine-1,2-dicarboxylate

1H NMR (400 MHz, CDCl3) δ: 4.35 (dd, 1H), 4.21-4.05 (m, 2H), 3.74 (d, J = 6.2 Hz, 3H), 3.64-3.43 (m, 2H), 2.30-2.16 (m, 1H), 2.07-1.85 (m, 3H), 1.33-1.17 (m, 3H).

Synthesis of (S)-1,1-bis(4-(10H-phenothiazin-10-yl)phenyl)tetrahydro- 1H,3H-pyrrolo[1,2-c]oxazol-3-one (L-Pro-(PTH)2) (4) using the Grignard of PTH-Br (1) All glassware was flame-dried or oven-dried overnight and then flushed with nitrogen. PTH-Br (1) (0.262 g, 0.74 mmol, 1.5 equiv) was added to a 10 ml flask with a rubber septum and flushed with nitrogen. A small crystal of iodine and pre-dried Mg turnings (18 mg, 0.74 mmol, 1.5 equiv) were added to a two-necked RBF followed by the addition of 10 ml dry THF with a syringe. The PTH-Br was diluted in 5 ml dry THF and the resulting solution

was added dropwise with a syringe over the course of 2 min to the reaction flask under stirring stirring,. At RT no color change was observed. Proline ester derivative (3) (5 ml solution of 0.1 ml (d ≈ 1 g/ml) in dry THF) was added dropwise over the course of 5 min to the reaction flask at RT. The reaction was left to stir overnight at RT and the next day it was cooled in an ice bath before workup. The reaction was quenched with aqueous saturated NH4Cl (20 ml) and an oily top layer separated. The water phase was extracted (x3) with diethyl ether (10 ml) and the organic layers were combined, dried over anhydrous MgSO4 and evaporated under reduced pressure. An oily yellow residue was recovered (300 mg).

Synthesis of (S)-1,1-bis(4-(10H-phenothiazin-10-yl)phenyl)tetrahydro- 1H,3H-pyrrolo[1,2-c]oxazol-3-one (L-Pro-(PTH)2) (4) using lithium-halogen exchange of PTH-Br with n-BuLi [10] All glassware was flame-dried and evacuated/backfilled with nitrogen. (177 mg, 0.5 mmol, 2.5 equiv) PTH-Br (1) was added in 3 ml dry diethyl ether in a 10 ml RBF with no dissolution occuring. 1 ml of dry THF was added and all of the compound was dissolved. n-BuLi (0.313 ml of 1.6 M solution in hexanes, 0.5 mmol, 2.6 equiv) was added over the course of 10 min with stirring at 0 °C. The reaction was left to stir for another 2 h at RT in order to obtain the PTH-Li. A cryostat was put in a dewar flask with acetone and set to -78 °C. The RBF containing the PTH- Li was put in the acetone bath until equilibration of temperature. A solution of proline ester derivative (3) (40 mg, 0.2 mmol, 1 equiv) was prepared in 2 ml dry diethyl ether and also put in the acetone bath to cool down. Then the PTH-Li solution was added dropwise to the proline ester solution with a syringe over the course of 30 min with vigorous stirring while monitoring the temperature. After all derivative (3) was added, the mixture was left stirring for another 2 h at -78 °C, after which the cryostat was set to 0 °C for 1 h. Then the cooling was turned off and the reaction was left to stir in the acetone bath in the dewar overnight while slowly warming up to RT. The reaction was removed from the acetone bath after 24 h (T ~10°C) and kept stirring at RT for another 3 h. The mixture was quenched with DI water and extracted with DCM (x3), dried over MgSO4 and evaporated under reduced pressure. TLC showed the presence of starting proline derivative (3) which was confirmed by 1H NMR. PTH was also found by 1H NMR implying that PTH-Li probably did not react and was quenched in the end, similarly to the case of the Grignard above.

Synthesis of (S)-1,1-bis(10-phenyl-10H-phenothiazin-2-yl)tetrahydro- 1H,3H-pyrrolo[1,2-c]oxazol-3-one (L-Pro-(2-PTH)2) (5) from the Grignard of PTH-2-Cl (2) 2-Cl-PTH (2) (100 mg, 0.323 mmol, 2.6 equiv) was added to a 5 ml vial and flushed with nitrogen and then 1 ml dry THF added to dissolve it. In another vial Mg turnings (pre-dried) (7.85 mg, 0.323 mmol, 2.6 equiv) were added and flushed with nitrogen, followed by the addition of 1 ml dry THF. The reaction flask was put in an oil bath at 70 °C with stirring and the PTH-2-Cl solution was added slowly. Nothing happened even after trying to initiate the reaction with a heat gun and prolonged heating at 70 °C. After 1 h of heating, the proline derivative

(3) (25 mg, 0.124 mmol, 1 equiv) was added as a 1 ml solution in dry THF dropwise at 0 °C. The reaction was left to heat up to RT while stirring overnight. TLC samples were taken at different time intervals and also the next day (~20 h after), which showed unconverted starting materials. No PTH was found by 1H NMR which shows that the Grignard in this case had not formed.

Synthesis of ethyl (S)-2-(bis(4-bromophenyl)(hydroxy)methyl)pyrrolidine- N-carboxylate (L-Pro-(Ph-4-Br)2) (6) “open-form” A solution of proline ester derivative (3) (533 mg, 2.65 mmol, 1 equiv) in 5 ml dry THF was prepared in a flame-dried and nitrogen flushed RBF. p-dibromobenzene (2.5 g, 10.6 mmol, 4 equiv) was also added in another RBF (flame-dried) in 5 ml dry THF. Mg turnings (265 mg, 10.9 mmol, 4.12 equiv) were crushed and put together in a reaction flask (flame-dried) together with a small amount of iodine in 25 ml dry THF. The Grignard was initiated as usual with a heat gun after adding a small amount of the dibromide until discoloration was observed. The rest of p-dibromobenzene was added dropwise with stirring over the course of 10 min while the reaction flask was immersed in an oil bath set to 70 °C and left stirring for ~2 h. The solution of (3) was placed in an acetone bath in a dewar and cooled down to -10 °C with a cryostat, while stirring, for 20 min. The flask with the formed Grignard was also placed in the cold acetone bath. When thermal equilibrium was reached, the solution of (3) was added dropwise to the Grignard over the course of 20 min. The cryostat was turned off and the flask was let stir in the acetone bath for 2.5 days, gradually heating up to RT. After 2.5 days the solution had turned orange. A TLC sample was taken (eluent: 5:1 PE:EtOAc) indicating conversion. The reaction was stopped by quenching with NH4Cl and afterwards extracted with CHCl3 (30 ml x3), the combined organic layers dried over anhydrous Na2SO4 and evaporated under reduced pressure, then high vacuum, to yield a yellow gel. Some crystals formed which were identified by 1H NMR to be p-dibromobenzene. TLC showed the presence of a lot of remaining p-dibromobenzene starting material due to the high excess used. 1H NMR in CDCl3 showed a matching of shifts for the desired product (open-form) with the reference.[11] The same process was repeated in a 2x scale and this time the reaction was left to stir at RT for 18 h instead of 2.5 days. All amounts and conditions were kept the same. Also the organic layers were this time washed with DI water before drying to remove any inorganic salts and filtered through celite resulting in a purer product. Crude yield = 3.2 g after drying. The open-form product was purified with flash column chromatography on silica gel (eluent: 7:1 PE:EtOAc). Yield after purification = 1.43 g (50%) for the open- form. A fraction with a lower Rf value which was later found to be the closed oxazolidinone form was also isolated (yield = 0.322 g (14%)). The purified product had the appearance of a colorless transparent gel. 1H NMR (400 MHz, CDCl3) δ: 7.44–7.40 (m, 4H), 7.36 (d, J = 7.0 Hz, 2H) 7.26–7.21 (m, 4H), 4.82 (dd, J = 9.0, 2.4 Hz, 1H), 4.20–4.04 (m, 2H), 3.51– 3.37 (m, 1H), 2.96 (m, 1H), 2.14–2.02 (m, 1H), 1.94–1.79 (m, 1H), 1.24 (t, J = 7.0 Hz, 3H), 0.90 (m, 1H).

Synthesis of (S)-1,1-bis(4-bromophenyl)tetrahydro-1H,3H-pyrrolo[1,2- c]oxazol-3-one (L-Pro-(Ph-4-Br)2) (7) “closed-form” The open-form compound (6) was cyclized by stirring at RT in a 1 M NaOH in MeOH 50 ml solution for 18-20 h. The reaction was checked with TLC (eluent: 5:1 PE:EtOAc) showing conversion and then the mixture was evaporated under reduced pressure, diluted with water and extracted with CHCl3 (3x100 ml). A stable emulsion formed and brine was added to break it. The combined organic layers were dried over Na2SO4, evaporated under reduced pressure and then under high vacuum to yield a colorless gel. In the second run of the same reaction the cyclization step was performed exactly under the same conditions except for using DCM instead of CHCl3 to render the extraction easier (less stable emulsion formed) and also due to its lower boiling point which would help with the drying. The lower toxicity and environmental impact of DCM compared to CHCl3 are also notable, even though not significantly less. Batch 1 yield was insignificant and the compound difficult to purify. Yield (batch 2) = 1.1 g (90%). Both TLC and 1H NMR verified the presence of a side- product with similar structure perhaps resulting from the Grignard reaction (biphenyl derivative).1H NMR in CDCl3 showed the correct shifts for the desired product (closed-form).[11] The specific rotation was also measured with a polarimeter and was found [α]26D = -100°. This is not an absolute indication of enantiomeric purity but implies that at least some of the product is optically active. 1H NMR (400 MHz, CDCl3) δ: 7.50–7.46 (m, 4H), 7.39-7.34 (m, 4H), 7.22 (d, J = 7.0 Hz, 2H) 4.46 (dd, J = 10.3, 5.5 Hz, 1H), 3.79–3.66 (m, 1H), 3.31–3.19 (m, 1H), 2.06–1.80 (m, 2H), 1.77– 1.66 (m, 1H), 1.18–1.03 (m, 1H).

Synthesis of (S)-1,1-bis(4-(10H-phenothiazin-10-yl)phenyl)tetrahydro- 1H,3H-pyrrolo[1,2-c]oxazol-3-one (L-Pro-(PTH)2) (4) by the Buchwald- Hartwig coupling of (7) with 10H-phenothiazine[3] RuPhos-Pd-G2 precatalyst (15.53 mg, 0.02 mmol, 2 mol%) was put in a RBF (flame-dried) together with RuPhos (9.33 mg, 0.02 mmol, 2 mol%), 10H- phenothiazine (598 mg, 3mmol, 3 equiv) and NaOtBu (288 mg, 3 mmol, 3 equiv). The flask containing the powders was sealed with a rubber septum, put under high vacuum and backfilled with nitrogen (x3). 4-5 ml of dry 1,4-dioxane was added with a syringe and vigorous stirring to dissolve all solids. A solution of the dibromide (7) (437 mg, 1 mmol, 1 equiv) was prepared in 1 ml dry 1,4-dioxane and added slowly to the reaction flask with vigorous stirring. The reaction flask was immersed in an oil bath set to 110 °C and a reflux condenser was attached, on top of which was put a nitrogen balloon. The reaction was let stir for 5 h under reflux. The dioxane used was pre-dried with sodium/benzophenone and the water content was estimated with a Karl Fischer automatic titration and found ≤18 ppm. After 5 h a TLC sample was taken (eluent: 5:1 PE:EtOAc) and a 1H NMR spectrum in DMSO-d6 to monitor the reaction. There seemed to be conversion to some extent but the products were difficult to characterize. There was no reference spectrum for product (4) so ESI-MS was used to check for the molecular weights of the products obtained, again with no clear results. The crude product was purified with flash column chromatography on silica gel (eluent: 5:1 PE:EtOAc).

Five fractions were isolated, one of which was 10H-phenothiazine starting material. It is very probable that all of the fractions were oxidation and degradation products of phenothiazine and/or other byproducts. The MS spectra did not give the expected molecular weight, not even after the column purification, in great abundance for any of these fractions. The reaction was repeated once more on a smaller scale and with less solvent in a 5 ml sealed microwave vial, being more careful with the atmospheric exposure and contact with moisture so as to obtain as less phenothiazine degradation products as possible. The reaction ran indeed more smoothly, with a more homogeneous dissolution of all solids. This time the reaction was left to run at RT for 3 days after which a TLC, an ESI- MS (in MeOH) and a 1H NMR spectrum in DMSO-d6 was obtained. There seemed to be no conversion so far and the reaction vial was put in a microwave reactor set to 150 °C for 18 h. Again samples for TLC, ESI-MS and 1H NMR were taken and this time some conversion was observed (peaks of the starting dibromide had diminished) even though this does not again mean that the desired product was obtained. The MS did not show the expected molecular weight in great abundance again and so it was considered that this reaction might need a different approach in order to work, e.g. change of base to a softer one such as Cs2CO3 and/or change of solvent. A completely different plan in order to synthesize compound (4) might as well be needed.

8.1.2 Part B - Photocatalysis with PTH

Dehalogenation of aryl halides using PTH and 390 nm light in MeCN-d3 All of the samples in this section were irradiated using a Kessil PR160 40W 390 nm LED spotlight. A 5 mol% 10-phenyl-10H-phenothiazine (PTH) stock solution was prepared by dissolving 27.5 mg of PTH in 1 ml MeCN-d3. For the preparation of 1 ml MeCN-d3 samples, 1 equiv of iodobenzene was added (0.1 mmol) together with 2 equiv internal standard 1,4-dimethoxybenzene (0.2 mmol), 5 equiv tributylamine (0.5 mmol) and 5 equiv HCOOH (0.5 mmol) and 5 mol% PTH (0.005 mmol) as stated in a relevant article protocol[3]. Stock solutions were prepared for both iodobenzene and the internal standard to ease in the addition of correct amounts. All samples were prepared in 2 ml sealed vials under nitrogen atmosphere. The samples (0.5 ml of each) were put in evacuated and backfilled with nitrogen NMR tubes, sealed and then irradiated with 390 nm light for different time intervals, while 1H NMR spectra were obtained in between each run. Iodobenzene was irradiated for 5, 10, 15, 20 and 30 min. Dehalogenation was successful and the results are presented in the ‘results and discussion’ section.

The same protocol was followed for para-halogenated benzaldehydes, namely 4- chloro-, 4-bromo- and 4-iodo-benzaldehyde. Stock solutions (1 M) were prepared for each of these aldehydes to ease in the correct amount addition. The samples (0.5 ml each) were put in evacuated and backfilled with nitrogen NMR tubes, sealed and then irradiated with 390 nm light for different time intervals, while 1H NMR spectra were obtained in between each run, like in the procedure above. The NMR spectra revealed dehalogenation for short exposure times and preferentially for 4-iodo-benzaldehyde, while for longer times and especially for 4-chloro- benzaldehyde a side reaction was clearly taking over, while dehalogenation was

merely giving a minor product. The results are presented in the ‘results and discussion’ section.

Photoredox-catalyzed pinacol coupling of benzaldehyde with PTH and 390 nm light in MeCN-d3 The side reaction taking place upon exposure of aromatic aldehydes to near UV light in the presence of a photocatalyst, in this case PTH, was found to be a photoredox-catalyzed pinacol coupling.[8] The reaction was tested with 5 mol% PTH and NBu3 and also with and without the addition of HCOOH. A stock solution of benzaldehyde was prepared (0.75 M in MeCN-d3) to ease in the correct amount addition and also one of the internal standard 1,4-dimethoxybenzene (1 M in MeCN-d3). For the preparation of 1 ml MeCN-d3 samples 1 equiv of benzaldehyde was added (0.075 mmol) together with 2 equiv tributylamine (0.15 mmol), 1 equiv internal standard 1,4 dimethoxybenzene (0.075 mmol) and 5 mol% PTH (0.00375 mmol). All samples were prepared in 2 ml sealed vials under nitrogen atmosphere. The samples (0.5 ml from each) were put in evacuated and backfilled with nitrogen NMR tubes, sealed and then irradiated with 390 nm light for different time intervals, while 1H NMR spectra were obtained in between each run. Benzaldehyde was irradiated for a total of 60 min with almost complete conversion to the pinacol after 60 min (99%) and 59% after 30 min. 4-nitro- benzaldehyde was also tested using the same protocol but the results were difficult to interpret since many side-products with unresolved peaks appeared to have formed in the 1H NMR spectra, regardless of exposure time.

The same reaction was tested again following the same protocol and scale but this time with the addition of HCOOH and also with an increased amount of NBu3. A sample containing 2 equiv NBu3 and 2 equiv HCOOH as well as a sample containing 5 equiv NBu3 and 5 equiv HCOOH were prepared. Benzaldehyde was irradiated for 10, 20 and 40 min. The results are presented in the ‘results and discussion’ section.

Picture 1. Setup for the photochemical reactions with PTH (left: side view, right: top view).

Photoredox-catalyzed pinacol coupling of 2-formylpyridine with PTH and 390 nm light in MeCN-d3 and investigation of the effect of chiral acids on the reaction rate and diastereo- and enantiomeric ratios In four 2 ml glass vials were added 2-formylpyridine (1 equiv, 0.1 mmol, 9.5 μL), tributylamine (5 equiv, 0.5 mmol, 119 μL), internal standard 1,4- dimethoxybenzene (1 equiv, 0.1 mmol, 0.1 ml of 1M stock solution in MeCN-d3) and 5 mol% PTH (0.05 mmol, 50 μL of 0.1 M stock solution in MeCN-d3) together with 0.5 ml MeCN-d3 in each. To three of the vials was also added 10 mol% of the following chiral acids in each:

1. (S)-(-)-BINOL (0.01 mmol, 2.9 mg) 2. (R)-(-)-1,1’-binaphthyl-2,2’-diyl hydrogenphosphate (0.01 mmol, 3.5 mg) 3. (S)-1,1’-binaphthyl-2,2’-disulfonimide (0.01 mmol, 4 mg)

The fourth vial was used as a control and no chiral acid or HCOOH was added. All samples were degassed with vacuum and backfilled with nitrogen before exposure to light. All samples were placed at an equal distance from the 390 nm LED lamp and irradiated for a total of 40 min. The results are presented in the ‘results and discussion’ part. The same experiment was repeated with a control (no chiral acid or HCOOH added) and a sample containing (R)-(-)-1,1’-binaphthyl-2,2’-diyl hydrogenphosphate (scaled up x10) in 8 ml glass vials in 5 ml MeCN to try to isolate the pinacol product with flash column chromatography. Magnetic stir bars were added this time to aid in the homogeneous mixing of the samples. Total exposure time was 60 min under the same 390 nm LED used above. The isolation with flash column chromatography was successful (eluent 5% MeOH in DCM) even though tributylamine was also present in the final product in a 2:1 ratio of NBu3:product. Upon storage in the freezer some crystallization was observed but it was not further investigated due to time limitations. Crystallization could be a possible way to separate the final product from tributylamine. The enantiomeric ratio which could be estimated by HPLC using a chiral column was not rendered possible due to time limitations.

Picture 2. Setup for the preparatory scale of the pinacol coupling of 2-formylpyridine with PTH as a photocatalyst.

8.2 ESI-MS spectra

1. PTH-Br (1)

2. L-Pro(Ph-4-Br)2 oxazolidinone “closed” form (7)

8.3 1H NMR spectra

1. L-Proline ester derivative (3) (CDCl3)

2. PTH-Br (1) (DMSO-d6)

3. PTH (DMSO-d6)

4. PTH-2-Cl (2) (DMSO-d6)

5. L-Pro(Ph-4-Br)2 “open” form (6) (CDCl3)

6. L-Pro(Ph-4-Br)2 oxazolidinone “closed” form (7) (CDCl3)

7. 4-chloro-benzaldehyde 0 min, 390 nm, 5 mol% PTH (MeCN-d3)

8. 4-chloro-benzaldehyde 30 min, 390 nm, 5 mol% PTH (MeCN-d3)

9. 4-iodo-benzaldehyde 0 min, 390 nm, 5 mol% PTH (MeCN-d3)

10. 4-iodo-benzaldehyde 30 min, 390 nm, 5 mol% PTH (MeCN-d3)

11. Iodobenzene 0 min, 390 nm, 5 mol% PTH (MeCN-d3)

12. Iodobenzene 10 min, 390 nm, 5 mol% PTH (MeCN-d3)

13. Benzaldehyde pinacol 30 min, 390 nm, 5 mol% PTH (MeCN-d3)

14. Benzaldehyde pinacol 60 min, 390 nm, 5 mol% PTH (MeCN-d3)

15. 2-formylpyridine pinacol 40 min, 390 nm, 5 mol% PTH, control (MeCN- d3)

16. 2-formylpyridine pinacol 40 min, 390 nm, 5 mol% PTH, 10 mol% (S)- BINOL (MeCN-d3)