Green Chemistry in Chemical Education and

Synthetic Applications of Sulfinamides

Björn Blomkvist

Doctoral Thesis

Stockholm 2020

Akademisk avhandling som med tillstånd av Kungliga Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av doktorsexamen i kemi med inriktning mot organisk kemi fredagen den 24 januari kl 10.00 i sal F3, KTH, Lindstedtsvägen 26, Stockholm. Avhandlingen försvaras på engelska. Opponent är Prof. José Alemán, Universidad Autónoma de Madrid, Spanien.

I

ISBN 978-91-7873-400-9

ISSN 1654-1081

TRITA-CBH-FOU-2020:1

© Björn Blomkvist, 2020

Universitetsservice US AB, Stockholm

II

Voor mijn liefste

III Björn Blomkvist, 2020: “Green Chemistry in Chemical Education and Synthetic Applications of Sulfinamides”, KTH Chemical Science and Engineering, Royal Institute of Technology, SE-100 44 Stockholm, Sweden. Abstract

The preparation of chiral molecules, i.e. compounds that are not identical to their mirror image, is of great interest in the field of organic chemistry. The preparation of a enantiomerically pure molecules is crucial in the development of new pharmaceuticals, agrochemicals and more, since the building blocks of life are chiral and the interactions between enantiomers and receptor are different. Furthermore, an important aspect of chemistry is sustainability, developing new synthetic procedures where green chemistry has been incorporated.

In chapter 2, the use of Brønsted acid catalysis as well as a combined Brønsted acid and aminocatalytic procedure for the preparation of the chiral synthon tert- butane N-sulfinyl imine. Using HBF4Y
6H
6
86I6ANHI
<6K:
I=:
HJA;>CNA>B>C:
in high yields in 2 h. Changing the catalyst to HBF4Y
6C9
6C>A>ne both improved the yields and shortened the reaction time to only 30 min. JGI=:GBDG:
 --calculations were performed for both catalytic systems, providing a proposed mechanism suggesting a six-membered cyclic transition state as the key transition state.

In chapter 3 a light-assisted method for the preparation of chiral unnatural amino acids is presented. Via a photoredox-catalyzed decarboxylation of carboxylic acids, a carbon radical is generated that adds stereoselectively to an N-sulfinyl imine. This method allows for green synthesis of non-natural amino acids, and compared to previous methods, we have extended the radical source to include carboxylic acids.

In chapter 4, the use of green chemistry in B.Sc. level teaching is explored through an experimental design project for third-year students, using green chemistry as basis for analysis of literature procedures. Following this, the procedure is implemented in a first-year B.Sc. course. This is proven to be an efficient way to increase the students understanding of organic chemistry, as well as an efficient way to teach green chemistry.

Keywords: Sulfinamide, Green Chemistry, Chiral Auxiliary, Photoredox, Teaching.

IV Sammanfattning på svenska Framställandet av kirala molekyler är av stort intresse inom den organiska kemin. Framställandet av enantiomeriskt rena föreningar är av stort intresse när det gäller nya läkemedel, jordbrukskemikalier eller andra områden eftersom naturens byggstenar är kirala och interaktionen mellan enantiomerer och receptorer är olika. Vidare är hållbarhet en viktig aspekt inom kemin, utvecklandet av nya syntetiska procedurer med en analys baserad på grön kemi är därför av vikt.

I kapitel 2 användskatalytiskt, samt kombinationen av Brønsted syra och aminokatalys i framställandet av den kirala hjälpgruppen tert-butan N-sulfinyl iminen. HBF4 dietyleterat ger iminen på två timmar vid rumstemperatur. När det katalytiska systemet byts till kombinationen av HBF4 dietyleterat och anilin förbättrats utbytet efter 
B>CJI:G
/>96G:
=6G
FT-beräkning utförts för båda de katalytiska systemen och en mekanism föreslagits. I slutet på kapitlet utvärderas metoderna baserat på grön kemi och syntetisk användbarhet, vidare presenteras en jämförelse med i litteraturen förekommande procedurer.

I kapitel 3 diskuteras en ljusaktiverad syntetisk metod för framställandet av kirala aminer. Genom fotoredox-katalyserad dekarboxylering genereras en kol- radikal som selektivt adderar till N-sulfinyliminen. :I
=RG
RG
:C

I kapitel 4 utforskas grön kemi i utbildning på kandidat-nivå genom ett projekt i experimentdesign för tredjeårs studenter med de 12 principerna för grön kemi som utgångspunkt för analys och modifikationer. :C
JIK:8@A69:
EGD8:9JG:C
implementerades sedan i en första-års kurs i organisk kemi där studenterna utför :ME:G>B:CI:C
D8=
9>H@JI:G6G

:II6
=6G
K>H6I
H><
K6G6
:II
:;;:ktivt sätt att både öka förståelse och intresse för organisk kemi, så väl som ett effektivt sätt att lära studenter om vikten av grön kemi.

Nyckelord: Sulfinamid, Grön Kemi, Kiral Hjälpgrupp, Fotoredox, Undervisning.

V Abbreviations Ac Acetyl boc tert-butoxycarbonyl Bz Benzoyl ( Cyclooctadiene  >:I=NA:I=:G  - :CH>IN
Functional Theory ' :DMNG>7DH:CJ8A:>8
68>9 dr >6HI:G:DB:G>8
G6I>D ECTS European credit transfer and accumulation system ee Enantiomeric excess Et Ethyl ! Y Tetrafluoroboric acid diethyletherate i-Pr iso-Propyl kcal Kilocalories LUMO Lowest unoccupied molecular orbital MS Molecular sieves '," Non-steroidal anti-inflammatory drug OTf Trifluoromethyl sulfonate Ph Phenyl ppy 2-phenylpyridine RT Room temperature TFA Trifluoroacetic acid

VI List of Publications

This thesis is based on the following papers, referred to in the text by their Roman numerals I-IV:

I. HBF4·DEE-Catalyzed Formation of Sulfinyl Imines: Synthesis and Mechanistic Studies Blomkvist, B., >CTG
) Tetrahedron Lett. 2018, 59, 1249‒1253

II. -/(
%1(
%3-(
1-/-1) = Catalysed Formation of Sulfinyl Imines Blomkvist, B., >CTG
) - ChemistrySelect 2019, 4, 7431‒7436

III. Stereoselective Synthesis of Unnatural α-Amino Acids Through Visible Light-Promoted Decarboxylative C-Radical Addition to a Glyoxylate-Derived Sulfinyl Imine Shatskiy, A., Blomkvist, B., Liu, J.-Q., >CTG
)
$RG@RH
& 

IV. Student-Driven Development of Greener Chemistry in Undergraduate Teaching: Synthesis of Lidocaine Revisited Josephson, P., Nykvist, V., Qasim, W., Blomkvist, B., >CTG
) J. Chem. Educ. 2019, 96, 1389‒1394

Papers not included in this thesis:

I. Chiral Sulfinamides as Highly Enantioselective Organocatalysts >CTr, P., Sadhukhan, A., Blomkvist, B. ChemCatChem. 2014, 6, 3063‒3066

VII Table of Contents

Abstract ...... IV Sammanfattning på svenska ...... V Abbreviations ...... VI List of Publications ...... VII Table of Contents ...... VIII 1. Introduction...... 1 1.1 Synthesis and Green Chemistry ...... 1 1.2 Catalysis ...... 2 1.3 Chirality ...... 4 1.4 Preparation of Optically Pure Compounds ...... 5 1.5 Chiral Auxiliaries in Organic Synthesis...... 6 1.6 Sulfinamides as Chiral Auxiliaries ...... 7 1.7 Aim and Content of the Thesis ...... 9 2. Catalytic Formation of Sulfinyl Imines (Papers I‒II)...... 10 2.1 Preparation of N-sulfinyl Imines ...... 10 2.2 Brønsted Acid Catalysis with HBF4•DEE ...... 10 2.3 Covalent Aminocatalysis with Aniline/HBF4•DEE...... 14 2.3.1 Mechanistic Studies of the Aminocatalytic Reaction ...... 18 2.4 Synthetic Applications ...... 21 2.5 Comparison of Synthetic Methods for the Preparation of Sulfinyl Imine ...... 22 3. Photoredox Enabled Synthesis of Non-Natural Amino Acids (Paper III) ...... 24 3.1 Photoredox-Catalyzed Preparation of Chiral Amines ...... 24 3.2 Photoredox-catalyzed Addition to N-sulfinyl Imines ...... 25 3.3 Conclusion ...... 28 4. Green Chemistry in Teaching (Paper IV) ...... 29 4.1 Student-Driven Development of “Green” Procedures ...... 29 4.2 B.Sc. Degree Project ...... 29 4.3 Results ...... 30 4.4 Implementation in the Course Lab ...... 31 4.5 Conclusions...... 33 5. Concluding Remarks & Outlook ...... 35 6. Acknowledgements ...... 37 7. Appendix ...... 39 8. Bibliography ...... 40

VIII

1. Introduction 1.1 Synthesis and Green Chemistry There is an increasing concern about the human impact on our planet, from how we utilize the earth’s limited natural resources to how much waste and emission that is generated by mankind and how it affect the planet’s ecosystem. Several important agreements have been made that aim at lowering our carbon dioxide emissions and decreasing our dependency on fossil fuel. The Paris agreement,1 ratified by 185 countries, has the ambitious goal to limit the global temperature increase to 1.5 °C before the end of this century. In a similar way, the Agenda 2030 agreements includes 17 goals towards a more sustainable world, including creating a sustainable industry, clean water for all people and fighting global warming.2 These goals send a clear message that everyone needs to contribute, including e.g. the general public, the educational institutions and the chemical industries. To reach these goals, new innovation and approaches are needed to tackle the problems related to emission, which also includes the processes of production and patterns of consumption. Oil remains a primary feedstock for a large part of the chemical industry, and while climate-conscious people minimize their use of plastic, the ideal solution is overcoming the limitation to petroleum based materials and find ways to make use of a renewable feedstock.

Several different ideas3 about quantifying and lowering the waste production and resource use and improving the efficiencies in chemical processes were brought together and defined as the concept Green chemistry by

Figure 1. The 12 principles of green chemistry sorted in to the four major categories: natural resource and energy consumption (orange), waste reduction and synthesis optimization (blue), safety (green) and limiting risk of exposure (purple)

Paul Anastas (Figure 1).4 These principles are now important guidelines for developing greener processes and syntheses in academia, pharmaceutical and

1 chemical industries. The 12 principles of green chemistry can be divided into four major categories which are 1) minimization of waste and optimization of synthesis; 2) safety and hazards 3) efficient use of natural resources and energy and 4) limiting risks of exposure. The ultimate way to prevent waste in a chemical reaction is to not generate waste in the first place. Prevention of waste generation can be achieved by reducing derivatization, such as the use of protecting groups, increasing the atom economy (the ratio of the molar masses of starting materials and the molar mass of the product), and by applying catalysis instead of stoichiometric reagents. In addition, a significant part of the waste and energy consumption in an organic reaction is often generated by the solvent and can either be substantially reduced, by minimizing the amount (or by running the reaction without solvent) or recycling of the solvent. Safer chemistry can be realized using less toxic solvents and reactants and avoiding hazardous reactions. Future risks can be avoided by designing safer chemicals to minimize risks if an accident would occur and to use degradable chemicals. Furthermore, using chemicals from renewable sources and minimizing energy consumption reduces the environmental impact of chemical processes.

1.2 Catalysis The concept of catalysis was first described by the Swedish chemist Jöns Jacob Berzelius in 1835,5 but long before the scientific understanding of catalysis it has been occurring around us, and even in us, for example in the early, primitive life that was dependent on enzymes to survive.

A catalyst is a compound that, when participating in a reaction increases the rate of the reaction without being consumed.6 This acceleration is achieved as the catalyst lowers the activation barrier of the rate-limiting step (Figure 2, compare ‡ ‡ DG cat and DG uncat.) and as it is not consumed in the reaction it is generally used in substoichiometric or catalytic amounts. A catalyst lowers the activation ‡ energy (DG ) without affecting the reaction energy (∆Greact), i.e. the equilibrium of a reversible reaction remains unchanged in the catalytic cycle. The reduced activation barrier can increase the rate of a reaction by several orders of magnitude and thereby decreasing the reaction time to a point where it is practically useful.

Catalysts can be divided into homogeneous and heterogeneous catalysts. If the reaction between catalyst and reactants occurs in the same phase, typically in solution, it is referred to as homogeneous catalysis, while if the reaction occurs at the interface between phases, typically on the solid surface of the catalyst in on organic solvent, it is referred to as heterogeneous catalysis. Additionally,

2

Figure 2. Reaction coordinate diagram for uncatalyzed reaction and a catalyzed reaction catalysts are divided into metals, enzymes (or biocatalysts) and organic catalysts. In the metal catalysis a lot of important C-C bond forming reactions can be found such as palladium-catalyzed Heck reaction7 and the Suzuki cross- coupling.8 A widely applied biocatalytic reaction is the acyl transfer reactions that is catalyzed by a group of enzymes called lipases.9 In organocatalysis, small organic molecules are utilized as catalysts to promote a wide range of reactions.10 One class of the most utilized organocatalysts are proline and proline derivatives that can activate substrates via both iminium- and enamine activation.11 In covalent catalysis and nucleophilic catalysis, the catalyst makes covalent bonds with the substrate that gives new steric or electronic properties to the substrate, which can dramatically change the reactivity. Other types of activation modes are possible in organocatalysis e.g. Brønsted acid catalysis, Lewis acid catalysis, covalent catalysis, hydrogen-bonding catalysis, counter- ion catalysis, nucleophilic catalysis. In Brønsted acid/base catalysis, an acid or a base activates a reactant followed by an attack by the nucleophile on the electrophile.

Two examples of different types of organocatalysis are Brønsted acid and covalent catalysis that have relevance in this thesis. Brønsted acid catalysis generally involves protonation of a reactant, e.g. a carbonyl moiety, thus polarizing the electron density and decreasing the energy level of the lowest unoccupied molecular orbital (LUMO) of the electrophile (Figure 3).

3 H O N O H N HX O R R R R Covalent activation Brønsted acid activation

Figure 3. Activation modes of and covalent activation through generation of an iminium ionand Brønsted acid catalysis.

One example of covalent catalysis is the formation of an iminium ion via an attack of an amine on a carbonyl compound followed by elimination of water. The iminium ion has a lower energy level of the LUMO and an increased partial positive charge on the iminium carbon, which increases the reactivity toward nucleophiles (Figure 3).

1.3 Chirality Chirality is a property of asymmetry and an object is said to be chiral if it cannot be superimposed on its mirror image.12 A common example of a chiral object is our hands; a left and right hand are mirror images but it is not possible to superimpose the right hand onto the left hand. For organic molecules, the most common chirality occurs in molecules in which an atom, usually a carbon, has four unique substituents and no plane of symmetry, which gives rise to two possible stereoisomers. The two mirror images of a compound with a single chiral feature (point, axis etc.) are called enantiomers. If a compound has more than one chiral feature, e.g. two stereogenic centers, four different stereoisomers are possible and the stereoisomers that are not identical to the mirror image are referred to as diastereomers. In nature, all living organisms are built of chiral building blocks with the same handedness, such as sugars and amino acids.13

A B COOH HOOC OH HO * H H * OH HO NH2 H2N

C D

Cl Cl

Figure 4. Different types of chirality: A) point chirality, B) axial chirality, C) planar chirality and D) helical chirality.

In addition to point chirality at a single stereogenic center, the asymmetry can exists around an axis or a plane, also known as axial and planar chirality,

4 respectively. Another type of chirality is helical chirality, which is commonly found in macromolecules, such 6H
9:DMNG>7DCJ8A:>8
68>9
'
 >

Protein receptors are built from chiral amino acids and are therefore by their nature also chiral. Thus, the interaction between a protein receptor and the different enantiomers of a given chiral molecule can differ and lead to different physiological responses.14 For example, Naproxen exists as two enantiomers and (S)-naproxen is a non-steroidal anti->C;A6BB6IDGN
9GJ<
',"
HDA9
DK:G the counter in pharmacies around the world, while (R)-naproxen causes liver poisoning.15

O O O O

HO OH

(S)-naproxen (R)-naproxen NSAID Causes liver damage Figure 5. The two enantiomers of naproxen.

The different response of enantiomers in biological systems highlights the importance to control the enantiopurity of chiral small-molecule drugs.16-17

1.4 Preparation of Optically Pure Compounds The synthesis of chiral molecules is a vital part of organic chemistry. Even though a chemical reaction generates a chiral center it will not be enantioenriched unless a chiral reagent or catalyst is employed. In the absence of stereocontrol, a synthesis will lead to a racemate, i.e. a 1:1 mixture of the two enantiomers. There are four general approaches to obtaining enantiopure compounds; 1) resolution, 2) chiral pool, 3) asymmetric synthesis and 4) chiral auxiliaries (Figure 6).18

Chiral pool Stereoselective synthesis Resolution (chiral compound) (prochiral compound) (racemic compound)

Stereospecific synthesis Chiral auxiliary Kinetic resolution Chiral catalysis Chromatography Classical resolution

Optically pure compound

Figure 6. General strategies for the preparation of optically pure compounds.

The chiral pool strategy uses nature’s unparalleled ability to provide optically pure compounds, such as amino acids, sugars or other chiral natural products, and transforming the initial chiral pool compound to the desired target structure

5 through a stereospecific synthesis, avoiding racemization. However, starting with a racemic mixture different resolution strategies can be employed to achieve a separation of the two enantiomers, either through crystallization or chromatographic resolution. Kinetic resolution is the employment of a chiral catalyst to selectively react one enantiomer, leaving the other unreacted. Another approach to access enantiomerically pure compounds is asymmetric synthesis in which a chiral catalyst is applied to a reaction with a prochiral reactant for inducing stereoselectivity. Similar to asymmetric catalysis, chiral auxiliaries are used on prochiral reactants, where the chiral auxiliaries covalently bound to a substrate through pre-functionalization of a reactant in order to create a chiral environment for the reaction. Here, the chiral auxiliary determines the stereochemistry of the product in a stereoselective manner, the so called diastereoselectivity. After the reaction, the auxiliary is removed and, if possible, isolated for reuse.

1.5 Chiral Auxiliaries in Organic Synthesis Chiral auxiliaries are powerful tools in the preparation of enantiopure compounds. Corey and co-workers19 (1975) and Trost and co-workers20 (1980) initiated the development of the field of chiral auxiliaries >C
>:AH-Alder reactions, which prior to the multitude of transition metal-catalyzed cross- couplings was a key reaction for the formation of carbon‒carbon (C‒C) bonds.

BnO

BnO OH O Ph AlCl3 HOR* = OR* o CH2Cl2, -55 C OR* O

O O O H Ph O B(OAc)3 + OMe Ph H OH O O OH O OMe O

Figure 7. Highly selective Diels-Alder reaction through the use of 8-phenylmenthol (top) and O-methyl-mandelic acid (bottom) as chiral auxiliary.

In the work by Corey and co-workers, 8-phenylmenthol was used as a chiral auxiliary for the synthesis of a key precursor in the preparation of prostaglandins (Figure 7). The chiral auxiliary, 8-phenylmenthol, was obtained in a four-step procedure requiring multiple crystallographic resolutions. On the other hand, Trost and co-workers applied O-methyl-mandelic acid in the reaction between 5-hydroxy-1,4-naphthalenedione and an electron-rich diene (Figure 7).

6 Chiral oxazolidinones, developed by the Evans group, are among the most versatile and widely used chiral auxiliaries. The use of oxazolidinones as chiral auxiliaries have successfully been applied to a wide range of reactions, such as aldol additions,21 >:AH-Alder reactions,22 Morita-Baylis-Hillman reactions,23 a- alkylations24 and Michael reactions25 (Figure 8), and in several total syntheses.24

O O 1) LDA O O 2) MeI O N R O N R Me Ph Ph

Figure 8. Evans’ auxiliary used in asymmetric a-alkylation of carbonyl compounds.

1.6 Sulfinamides as Chiral Auxiliaries Amines are among the most common functional groups in pharmaceuticals26 and a large part of these compounds are chiral, which indicates that asymmetric synthesis of enantiopure amines is of great importance to the pharmaceutical industry.27 Sulfinamides are a class of chiral auxiliaries with a chiral center in the sulfur position (Figure 9) and is widely used as a chiral auxiliary in the preparation of chiral amines.28 "C

I=:
6K>H
GHI
ID
G:EDGI
the preparation of racemic benzene-sulfinyl imines29. However, enantiopure sulfinamides were first prepared by the Ellman group in 1997. The procedure developed by Ellman and co-workers involves the asymmetric oxidation of di- tert-butyl bisulfide with a vanadium(IV) catalyst, followed by the nucleophilic cleavage of the S‒S bond with lithium amide with inversion of stereochemistry (Figure 9). The sulfinamide is reacted with aldehydes or ketones in order to generate N-sulfinyl imines that contain the chiral auxiliary moiety. These chiral imines are versatile synthons and can be reacted with a variety of nucleophiles to yield chiral building blocks, such as syn- and anti aminoalcohols,30-34 a- branched- and a,a-dibranched amines,35-36 and a- and b-amino acids.37-44

Ellman’s initial report of the use of N-sulfinyl imines involved the diastereoselective addition of Grignard reagents.35, 45 The Lewis basicity of the sulfinyl oxygen is believed to be key to the high stereoselectivity, where the addition is proposed to proceed through a six-membered transition state where the sulfinyl oxygen is chelated to the metal center. The chelation between the sulfinyl oxygen and the metal center is supported by the experimentally determined absolute stereochemistry of the product, which matches the expected stereoselectivity if the reaction occurred via a six-membered transition state. In addition, the highest selectivity is observed in non-coordinating solvents, such 46 as CH2Cl2, which supports a chelated six-membered transition state.

7 t-Bu

N OH

t-Bu OH O t-Bu S S S S VO(acac)2, H2O2, rt

O O LiNH2 S S S o NH2 NH3, THF, -78 C

O O O S S S H N H N H2N 2 2

Figure 9. Synthesis of t-butane sulfinamide by Ellman (top), examples of commercially available sulfinamides (bottom) (R)-tert-butane sulfinamide, (R)-p- toluene sulfinamide and (R)-2,4,6-trimethylbenzene sulfinamide, all are also available as the corresponding (S)-enantiomer.

The six-membered chair-like transition state is common, but in the reduction of N-sulfinyl ketimines the choice of reductant influences the geometry of the transition state, and hence the stereoselectivity. The reduction of a sulfinyl ketimine using sodium borohydride yield one diastereomer in high selectivity through a closed transition state. However, the opposite diastereomer is obtained using the bulkier L-selectride (tri-i-butyl borohydride) as reductant (Figure 10).47 The more bulky L-selectride makes the six-membered, closed transition state too crowded, and thereby unfavorable, and the mechanism proceeds through an open transition state.

‡ O O O M H S S NaBH HN N 4 t-Bu S N Ph Ph Me Me Ph Me

O O H M ‡ S S L-Selectride HN N Me N Ph Ph Me Ph Me O t-Bu

Figure 10. Access to both diastereomers of sulfinamides through reduction of ketimines.

After the reaction, the chiral auxiliary is subsequently removed by treatment with acid and yields the corresponding amine after work-up. Cleaving the S-N bond leaves the sulfinyl group, in the form of the sulfinate ester or sulfinyl chloride. The sulfinamide can potentially be regenerated and reused but

8 treatment with acid epimerizes the sulfur center. Chiral alcohols, such as N- methylephedrine, have been employed to recycle sulfinamides.48

1.7 Aim and Content of the Thesis This thesis deals with two topics in the field of organic chemistry, specifically catalysis and green chemistry. The thesis covers the synthesis of chiral molecules with the focus on chiral auxiliaries in general and more specifically the use of tert-butane sulfinyl imines, synthesis of sulfinyl imines and their use in the synthesis of chiral amines. Additionally, the topic of green chemistry in both research and teaching labs will be covered where the focus will be on the use of green chemistry as a driving force for undergraduate student learning.

9

2. Catalytic Formation of Sulfinyl Imines (Papers I‒II) 2.1 Preparation of N-sulfinyl Imines Sulfinamides are used as chiral auxiliaries through the preparation of N-sulfinyl imines. The condensation of sulfinamides with ketones can only be achieved through the use of large excess of Lewis acids, such as Ti(OEt)4, at elevated temperatures, while the aldimines can be prepared through several other 45 49 procedures, such as pyridinium p-toluene sulfonate, Cs2CO3, 4Å molecular 50 51 52 sieves, Yb(OTf)3 , KHSO4 , PTSA or HClO4 immobilized on silica combined with sonication or grinding53-54 or pyrrolidine55 (Figure 11). Usually, most procedures for preparing sulfinyl imines from aldehydes require elevated temperatures, large excess of at least one reagent (most often the aldehyde) or long reaction times to reach completion. Additionally, several of the procedures employ stoichiometric reagents and only a few efficient catalytic procedures have been reported.53-55

O Pyrrolidine / PPTS/ O O S Ti(OEt)4 O Yb(OTf)3 / 4Å MS… S N S N + NH R = Me Ph R 2 R = H Ph Ph H Figure 11. Preparation of N-sulfinyl imines.

2.2 Brønsted Acid Catalysis with HBF4•DEE In an attempt to develop a more efficient catalytic protocol for the formation of sulfinyl imines of aldehydes, a study of possible Lewis acids catalysts were initiated. Initially, carbocations were pursued as Lewis acid catalysts to promote the reaction between benzaldehyde and (R)-tert-butane sulfinamide. As a model reaction, the condensation between 4-nitrobenzaldehyde and (R)-tert-butane sulfinamide was studied. The use of catalytic amounts of tritylium tetrafluoroborate (10 mol%) in CH2Cl2 provided the sulfinyl imine in 70% conversion after 2 h. In order to improve the conversion of the reaction, molecular sieves (4Å) were added as desiccant to drive the reaction to completion, which previously was shown in the pyrrolidine-catalyzed formation of imines.55 However, the addition of molecular sieves decreased both the rate and the conversion dramatically, giving only 35% conversion over 20 h. The difference in reactivity suggests that the trityl carbocation reacts with the formed

10 water and generates triphenylmethanol and tetrafluoroboric acid that acts as a Brønsted acid catalyst. This observation prompted us to investigate several different Brønsted acids as catalysts in the sulfinyl imine formation in a series of experiments aimed to optimize the reaction conditions (Table 1).

Table 1. Screening of different acids and additives for the formation of the sulfinyl imine from benzaldehyde and tert-butane sulfinamide.a

O O S O HX, desiccant N R + S H2N R RT, Solvent A: R = t-Bu B: R = p-Tol

Entry HX (mol %) sulfinamide :H>886CI
Solvent Conv. (%) (equiv.) b 1 HBF4 (10) A 4Å MS Toluene 66 2 AcOH (10) A 4Å MS Tolueneb 0 b 3 MeSO3H (10) A 4Å MS Toluene 46 b 4 p-NO2-BzOH (10) A 4Å MS Toluene 0 b 5 HBF4 (10) A MgSO4 (1) Toluene 69 c 6 HBF4 (10) A MgSO4 (1) Toluene 80 c 7 MeSO3H (10) A MgSO4 (1) Toluene 61

8 HBF4 (10) A MgSO4 (1) CH2Cl2 89 c 9 HBF4 (10) A MgSO4 (1) Et2O 68 c 10 HBF4 (10) A MgSO4 (1) EtOH 17 c 11 HBF4 (10) A MgSO4 (1) MeCN 38

12 HBF4 (5) A MgSO4 (1) CH2Cl2 71

13 HBF4 (2.5) A MgSO4 (1) CH2Cl2 50

14 HBF4 (1) A MgSO4 (1) CH2Cl2 21

15 HBF4 (5) A MgSO4 (3) CH2Cl2 61

16 HBF4 (10) A MgSO4 (3) CH2Cl2 88

17 HBF4 (5) A MgSO4 (5) CH2Cl2 68 d 18 HBF4 (10) A MgSO4 (1) CH2Cl2 94 e e 19 HBF4 (10) B MgSO4 (1) CH2Cl2 37(48) a Reagents and conditions: benzaldehyde (0.25 mmol, 0.25 M), (R)-tert-butane sulfinamide (0.275 mmol), magnesium sulfate (0.25 mmol), HBF4•DEE (10 mol%), 2 h, RT. Conversion determined by NMR b c d e 5% THF as co-solvent. 5% CH2Cl2 as co-solvent. Benzaldehyde (1.0 M). After 18 h. In toluene, with 5% THF as a co-solvent, weaker Brønsted acids, such as acetic acid and p-nitrobenzoic acid, in the presence of 4Å molecular sieves did not give any conversion to the product in 2 hours (Table 1, entries 2 and 4, respectively). On the other hand, the more acidic tetrafluoroboric acid diethyl etherate (HBF4Y
6C9
B:I=NA
HJA;DC>8
68>9
EGDBDI:9
I=:
HJA;>CNA
>B>C:
;DGB6I>DC
giving 66% and 46% conversion, respectively (Table 1, entries 1 and 3). Replacing 4 Å molecular sieves with anhydrous magnesium sulfate led to a

11 small increase in the conversion (Table 1, entry 5). Using 5% dichloromethane in toluene as co-solvent increased the conversion further and suggests that tetrafluoroboric acid diethyl etherate is more efficient than methane sulfonic acid (80% compared to 61% conversion, respectively, Table 1 entries 6 and 7). Changing the solvent to only dichloromethane led to an even higher conversion (89%, Table 1 entry 8) while diethyl ether, ethanol and acetonitrile showed significantly lower conversion (Table 1, entries 9–11). Lowering the catalyst loading while increasing the amount of magnesium sulfate did not improve the conversion (Table 1, entries 12‒17). An increase of the concentration of the reaction (from 0.25 M to 1 M) led to an increase in conversion (94% conversion, Table 1 entry 18). Finally, the procedure was evaluated in the condensation reaction between benzaldehyde and (R)-p-toluene sulfinamide, but even after 18 hours of reaction only a moderate conversion could be observed (48%

Table 2. Substrate scope for sulfinyl imine formation from aliphatic and aromatic aldehydes and tert- butane sulfinamide.a

O O HBF4 (10 mol%) S + S H N R O R N 2 MgSO4, CH2Cl2 RT, 2h

O O O O S S S S N N N N O2N Ph O2N 1, 93% yield 2, 88% yield 3, 94% yield 4, 97% yield

O O O O S S S S N N OH N N MeO Br

NC 5, 91% yield 6, 92% yield 7, 93% yield 8, 97% yield

O O O O S S S N N S N N O

9, 82% yield 10, 94% yield 11, 91% yield 12, 92% yield O O S S N N BocHN

Ph 13, 94% yield 14, 83% yield a Reagents and conditions: benzaldehyde (0.25 mmol, 1.0 M), (R)-tert-butane-sulfinamide (0.275 mmol) and magnesium sulphate (0.25 mmol), HBF4•DEE (10 mol%), CH2Cl2 (0.25 mL), 2 h, R

12 Using the optimized condition, the sulfinyl imine derived from benzaldehyde and the (R)-tert-butane sulfinamide was obtained in high isolated yield after purification using flash chromatography (93% yield, Table 2, compound 1), while the bulkier 1-naphthaldehyde gave a slightly lower yield (88% yield, Table 2, compound 2). More substituted aromatic aldehydes with electron- withdrawing or electron-donating substituents, such as nitro, cyano, methoxy and hydroxy groups, all furnished the products in good yields (91–97%, Table 2, compounds 3 – 7), as did the halogenated 3-bromobenzaldehyde (97% yield, Table 2, compounds 8). The heteroaromatic 2-furfural gave a relatively low yield (82%, Table 2, compound 9) Furthermore, the aliphatic aldehydes cyclohexane aldehyde, tert-butyl aldehyde and 3-phenylpropionaldehyde all gave good yields (91 – 94%, Table 2, compounds 10–12). The a,b-unsaturated 1-cyclohexene aldehyde also provided the product in good yield (94%, Table 2, compound 13). Additionally, (S)-N-Boc-phenylalaninal was converted to the sulfinyl imine product in slightly decreased yield (83%, Table 2, compound 14). Notably, no racemization was observed at the stereogenic carbon which suggests that no enolization occurs during the acidic reaction conditions. were performed. First, the initial state of the system was investigated. At the ‒  -
A:K:A
D;
I=:DGN
I=:
EGDIDC6I:9
9>:I=NA
:I=:G
L>I=
 4 as counter ion was set as the initial state of the acid and was compared with the relative stability of the other possible protonated species. Benzaldehyde protonation by HBF4Y
was found to be an unfavorable reaction, while both N-protonated sulfinamide and O-protonated sulfinamide were both favored over the protonated diethyl ether (-1.38 and -10.5 kcal mol-1, respectively). Thus, the calculations suggest that the O-protonated sulfinamide is the most stable specie (Figure 12, 

A. O-protonated ether B. N-protonated SA O F S H3N O H F B F F F F F B F 0 -1.38

C. Protonated aldehyde D. O-protonated SA F F B F H O F F Ph H B F O F F S H H2N 4.67 -10.5 Figure 12. Relative Gibb’s free energies for four possible initial states at M062X/6- 311+G(d,p)–CPCM (CH2Cl2, UFF) level of theory.

With the initial state at hand, the potential energy surface of the formation of the sulfinyl imine from the O-protonated sulfinamide and benzaldehyde was investigated (Figure 13).

13 F F B F O H C F Ph F O H H 25 O F H2N S O F F B H S Ph N F 20 20.9 20.9 F G B F F F 15 H H O O B H S Ph O 12.6 12.5 Ph N H H D 10 O O O F S S F F H2N Ph B N H2 F F 5 5.4 F B F F 3.2 F E Gibbs free energy (kcal/ mol) B 0 0.0 F F F F A HO F H HO -2.0 F B O F O H S O H Ph N F F -5 S Ph F B H S H2N F O N S Ph H2N + H2O

Figure 13. Gibbs free energy diagram for HBF4DEE-catalyzed formation of the sulfinyl imine at the M062X/6-311+G(d,p)–CPCM (CH2Cl2, UFF) level of theory.

The addition of the sulfinamide to the aldehyde proceeds via a six-membered chair-like transition state (C) to yield the protonated hemiaminal intermediate (D). In the transition state, which is located 20.9 kcal mol‒1 above the reactants, the hydroxyl bond and the C-N-bond are formed in a concerted fashion (Figure 13 A and C). From the protonated hemiaminal D, a proton transfer from the nitrogen to the sulfinyl oxygen occurs to form the intermediate E. The dehydration and formation of the C‒N double bond occurs via transition state F, which is located 20.9 kcal mol‒1 above the reactants. In transition state F, the O- sulfinyl proton is transferred to the departing water molecule. The relative Gibb’s free energies of activation for the catalytic cycle show that transition states C and F are similar. The final step was the release of the product and regeneration of the O-protonated sulfinamide, this occurs at ‒2.0 kcal mol‒1 meaning that the overall process is exothermic.

2.3 Covalent Aminocatalysis with Aniline/HBF4•DEE Formation of imines through the condensation between aldehyde or ketone and amines or amine derivatives, such as sulfinamides, hydroxylamines and hydrazides is important due to the value of imines in chemistry and biology.28, 46 Typically, the reaction between an aldehyde/ketone and an amine requires activation by an acid (Lewis or Brønsted acid) with the subsequent removal of

14 water. Another type of amine containing compounds are hydrazides and hydroxylamines that have increased stability due to the α-effect and have been utilized in bioconjugation in aqueous solution using aniline as a promoter.56 Early work by Jencks,57 6C9
6LHDCH
6C9
8D-workers58-60 expanded the concept of aniline promoted preparation of hydrazones and oximes at physiological pH showing the potential for both dynamic chemistry and bioconjugation (Figure 14, A).61-63

A. Accelerating effect of excess aniline in the formation of oximes and hydrazones R’ H2N

H Ar R’ O N N Excess R’NH2 H2O R H Acidic media R H R H H2O

B. Pyrrolidine-catalysed formation of sulfin- and sulfonimines, oximes, hydrazones

N R’ H O N (10 mol%) N R’NH 2 H O R H 2 R H CH2Cl2, 60 °C R H MS (4 Å) Figure 14. Previous procedures for the preparation of oximes, hydrazones and sulfinyl imines

Furthermore, several different additives, such as acetic acid, NaCl and trifluoroacetic acid (TFA), increased the rate of the aniline-promoted formation of oximes.64-65 A serious drawback with the aniline-promoted preparation of oximes and hydrazones in aqueous solutions is that it typically requires large excess of aniline for the reaction to reach completion in a reasonable reaction time. More recently, Cid and co-workers reported on a general aminocatalytic procedure for the synthesis of N-p-toluene sulfinyl imines, sulfonyl imines and N-phosphinoyl imines, in dichloromethane using catalytic amounts of pyrrolidine (10 mol%) at 60 °C (Figure 14, B).55 The authors suggested that the reaction proceeded via covalent catalysis and that the formation of a iminium ion was responsible for the efficient catalysis.

In the light of the previous amine-promoted formation of imines by aniline and pyrrolidine in the preparation of imines, hydrazones and oximes, we were interested in investigating if the aniline catalyst in combination with HBF4Y
could efficiently promote the sulfinyl imine formation. Therefore, several Brønsted acids was tested in combination with aniline in the reaction between tert-butanesulfinyl imine from benzaldehyde (Figure 15).

15

Figure 15. Evaluation of catalytic system for the preparation of N-sulfinyl imine from 4-nitrobenzaldehyde and tert-butane sulfinamide as measured by 1H NMR. Reaction between 4-nitrobenzaldehyde and (S)-tert-butane sulfinamide in CH2Cl2 (1 M)

Using 2.5 mol% aniline without any acid additive showed a slow conversion to the sulfinyl imine, providing merely 10% conversion in 90 minutes of reaction. The addition of a weak Brønsted acid (acetic acid) did not accelerate the reaction significantly. The use of only HBF4Y

BDA
i.e. without aniline, was considerably more efficient then the combination of Brønsted acid and aniline. Changing to the stronger Brønsted acid TFA (5 mol%) in combination with aniline (2.5 mol%) clearly accelerated the formation of the product compared to the acid-catalyzed reaction. However, the combination of aniline (2.5 mol%) and HBF4Y

BDA
A:9
ID
6C
:K:C
;6HI:G
G:68I>DC
6C9
G:68=:9
6lmost full conversion (over 95%) in merely 45 minutes. From these results, it is clear that the combined effect from aniline and a strong Brønsted acid shows a strong increase of the rate of the reaction and, hence we evaluated the aniline/HBF4Y
 
BDA


BDA
86I6ANI>8
HNHI:B
;DG
K6G>DJH
6A9:=N9:
substrates. After screening a few solvents, CH2Cl2 was found to be a superior solvent in terms of reaction rate and conversion. However, from a green perspective CH2Cl2 is far from optimal, and therefore we also investigated i- propyl acetate as a green alternative for the reaction (Table 3). The reaction with benzaldehyde proceeded rapidly and with excellent yield in CH2Cl2, while i- PrOAc provided the product in a slightly lower yield and required prolonged reaction time (Table 3, entries 1 and 2). Overall, the reaction proceeded in excellent yields for aryl aldehydes containing either electron-donating or electron-withdrawing substituents, such as nitro-, methoxy, hydroxy- and cyano substituents in both CH2Cl2 and i-PrOAc (Table 3, entries 3–14) with the

16 Table 3. Synthesis of sulfinyl imines from different aldehydes using aniline (2.5 mol%) with HBF4•DEE (5 mol%) in dichloromethane and iso-propyl acetate at room temperature.a

O O O Aniline (2.5 mol%) S S N H N (5 mol%) R H 2 HBF4
MgSO4, DCM R H

entry R solvent Time Yield [h] b 1 Ph CH2Cl2 0.5 99% 2 Ph i-PrOAc 2 88%

3 4-nitrophenyl CH2Cl2 0.5 98% 4 4-nitrophenyl i-PrOAc 2 90%

5 3-nitrophenyl CH2Cl2 0.5 98% 6 3-nitrophenyl i-PrOAc 2 94%

7 4-cyanophenyl CH2Cl2 0.5 99% 8 4-cyanophenyl i-PrOAc 2 95%

9 4-methoxyphenyl CH2Cl2 0.5 97% 10 4-methoxyphenyl i-PrOAc 2 94%

11 3-methoxyphenyl CH2Cl2 0.5 97% 12 3-methoxyphenyl i-PrOAc 2 93%

13 salicyl CH2Cl2 0.5 99% 14 salicyl i-PrOAc 2 95%

15 2-furfural CH2Cl2 0.5 96% 16 2-furfural i-PrOAc 2 90%

17 3-bromophenyl CH2Cl2 0.5 98% 18 3-bromophenyl i-PrOAc 2 92%

19 1-naphtyl CH2Cl2 0.5 98% 20 1-naphtyl i-PrOAc 2 91%

21 2-PhEt CH2Cl2 0.5 97% 22 2-PhEt i-PrOAc 2 93% aReagents and conditions: aldehyde (0.25 mmol, 1.0 M), (R)-tert-butanesulfinamide (0.275 mmol) and magnesium sulfate (0.25 mmol), aniline (2.5 mol%), HBF4Y

BDA
!2Cl2 (0.25 mL), room temperature. b Isolated yield. exception of the reaction with 4-nitrobenzaldehyde in i-PrOAc (90% yield, Table 3, entry 4). The reaction with the heteroaromatic 2-furfural gave excellent yield in CH2Cl2 and a lower yield in i-PrOAc (Table 3, entries 17 and 18), but considerably higher than the HBF4Y-catalyzed procedure. The reaction with 3-bromobenzaldehyde in CH2Cl2 gave excellent yield of the product, while i- PrOAc gave a slightly lower yield (Table 3, entries 17 and 18). The bulky 1- naphthaldehyde substrate proceeded to excellent yield in CH2Cl2 and in good yield in i-PrOAc (Table 3, entries 19 and 20). The aliphatic 3- phenylpropionaldehyde provided the corresponding product in excellent yield in CH2Cl2 and in good yield in i-PrOAc (Table 3, entries 21 and 22).

17 In conclusion, the aniline/HBF4Y
HNHI:B
>H
6
8A:6G
>BEGDK:B:CI
DK:G
I=:
Brønsted acid protocol, where a higher catalyst loading of HBF4Y

mol%) and longer reaction times are needed to reach full conversion (2 hours). In the aniline/HBF4Y
procedure, only 5 mol% of tetrafluoroboric acid is used together with 2.5 mol% aniline with a reaction time of merely 30 min. Furthermore, the yields are consistently higher with the combined aminocatalysis and Brønsted acid catalysis compared to the Brønsted acid catalyzed procedure. The most notable improvement is observed in the reaction with 2-furfural in which the Brønsted acid protocol displayed a yield of 82% (Table 2, entry 9), while the amino- and Brønsted acid procedure yielded the product in excellent yields in both CH2Cl2 and i-PrOAc (96% and 90%, respectively).

2.3.1 Mechanistic Studies of the Aminocatalytic Reaction

The mixing of aniline and HBF4Y
>C
!2Cl2 leads to the formation of a white precipitate which suggest that the anilinium salt, assumed to be the active catalyst, is not present in the solution. However, the assumptions regarding the mechanism has been focused around a homogeneous catalyst. The O-protonated sulfinamide was assumed to be the initial state of the HBF4Y-catalyzed procedure, we questioned whether something similar could occur in the dual amino/Brønsted acid catalytic system. Therefore, we undertook a 19F NMR HIJ9N
D;
I=:
86I6ANHI
9>HHDAJI>DC
>C
2Cl2 using hexafluorobenzene as internal standard. Mixing equimolar amount of aniline and HBF4Y
>C
2Cl2 led to

+ – PhNH3 BF4 (100%)

E) C6F6

+ – PhNH3 BF4 (90%)

D) C6F6

+ – PhNH3 BF4 (50%) C) C6F6

+ – PhNH3 BF4 (30%) C F B) 6 6

C6F6 + – A) PhNH3 BF4 (2%)

Figure 16. 19F NMR spectroscopic studies of the solvation of anilinium tetrafluoroborate catalyst in CD2Cl2 upon sulfinamide addition. A) 1.0 equiv. B) 2.0 equiv. C) 4 equiv. D) 6 equiv. E) 10 equiv.

18 a precipitate and the 19F NMR spectrum showed only traces of the catalyst in solution. However, upon addition of one equivalent of (S)-tert-butane sulfinamide a small fraction of the catalyst (2%) was dissolved (Figure 16, A). Addition of an additional equivalent of sulfinamide led to 30% catalyst being dissolved (Figure 16, B) and upon addition of 4 equivalents of sulfinamide, 50% of the catalyst was dissolved (Figure 16, C). Further addition (6‒10 equiv.) led to complete dissolution of the catalyst (90‒100%, Figure 16,  E). This suggests that the sulfinamide form hydrogen bonds to the anilinium salt, thereby facilitating its solvation.

The experimental observations in figure 16 was confirmed bN
 -
86A8JA6I>DCH
where hydrogen bonding between the anilinium and the sulfinyl oxygen leads to a stabilization of the anilinium complex (3.1 kcal/mol). Additional solvation by another sulfinamide led to further stabilization (5.1 kcal/mol) compared to the anilinium tetrafluoroborate (Figure 17). With the initial state of the catalyst at hand, the potential energy surface of the aminocatalytic formation of sulfinyl imine was investigated (Figure 18).

NH - H N O H O 2 BF4 2 H BF - S t-Bu S Ph N 4 S t-Bu S t-Bu NH2 t-Bu NH2 O O - Ph NH3BF4 H NH2 H O S H N H t-Bu Ph ΔG = 0 kcal mol-1 ΔG = -3.1 kcal mol-1 ΔG = -5.1 kcal mol-1

Figure 17. Calculated solvation of anilinium tetrafluoroborate at the M062X/6 311+G(d,p)–CPCM (CH2Cl2, UFF) level of theory. - The starting state A is the combination of the initial state of the catalyst and the reactants (aldehyde and sulfinamide), which is presumed to be in a fast equilib- rium with the protonated aniline imine stabilized with a sulfinamide molecules (B). The mechanism for the condensation reaction of aniline and benzaldehyde was omitted in this investigation. From complex B, the protonated imine is attacked by the sulfinamide in a chair-like six-membered transition state (TS1), with a Gibbs free energy of activation of 16.7 kcal mol‒1 in CH2Cl2 (17.2 kcal mol‒1 in i-PrOAc), forming complex C (14.6 kcal mol-1). Via a proton transfer from the sulfinamide nitrogen in intermediate C to the aniline nitrogen in >CI:GB:9>6I:

A:69H
ID
6
BDG:
HI67A:
8DBEA:M
 
@86A
BDA‒1 in CH2Cl2, 6.45 kcal mol‒1 in i-PrOAc). The reaction proceeds through a second transition state (TS2) in which the elimination of aniline and formation of the imine double bond occurs. The transition state has a Gibbs free energy of activation of 15.6 kcal mol‒1 in CH2Cl2 (16.6 kcal mol‒1 in i-PrOAc), which suggests that the sulfinamide addition to the protonated aniline imine (TS1) is the rate-limiting step of the reaction. Finally, the aniline leaves and the product is released and a

19 new molecule of sulfinamide coordinates to the catalyst. The overall reaction is exothermic at -2 kcal mol‒1
GDB
I=:H:
 --calculations a mechanism can be proposed (figure 19).

20 16.7 (17.2) 15.6 TS1 (16.6) TS2 15 C 14.6 E (15.3) 13.4 (15.4) 10

D 5 5.6 (6.45)

Gibbs free energy (kcal/ mol) B A 0 0.0 0.49 (1.19) F -2.0 (-2.1) -5

Figure 18: Gibbs’s free energy diagram of the sulfinylimine formation using the aminocatalytic procedure at the M062X/6-311+G(d,p)–CPCM (CH2Cl2, UFF) and M062X/6-311+G(d,p)–CPCM (EthylEthanoate, UFF) (in parenthesis) level of theory.

O F S O N tBu F B F H F H2N H NH S t 2 O Bu H H2O O tBu S H O H N t S t Bu NH2 Bu A Ph S NH2 F F F F O B F H Ph B N F F F O H S Ph NH2 H N t B Bu Ph H N O H F F TS1 S t E F F B N Bu Ph H B F F O H F t F F F O H H S Bu F F B TS2 PhN B Ph H S tBu N F NH FF F O 2 N H H H H H S Ph N N tBu H PT C D H Figure 19. Proposed mechanistic cycle of the aminocatalytic formation of sulfinyl imine. PT = proton transfer.

20 2.4 Synthetic Applications The aminocatalytic method was found to be fast, reliable and easy to performed, and displays a large tolerance to different solvents. The synthetic utility was demonstrated in a gram-scale reaction as well as a two-step, one-pot reaction. First, a gram-scale reaction was carried out between 4-nitrobenzaldehyde and (S)-tert-butane sulfinamide (8 mmol), using the aniline/HBF4Y
86I6ANI>8
system, yielding 2 grams of the desired product in 95% yield (Figure 20).

O O HBF4 DEE (5 mol%) S O Aniline (2.5 mol%) N + S H2N MgSO4, CH2Cl2, O2N 30 min O2N 95% yield, 2 g

Figure 20. Gram-scale preparation of N-sulfinyl imine.

Previously, Batey and co-workers has demonstrated the diastereoselective arylation of N-sulfinyl imines with arylboronic acids and a rhodium(I) catalyst in a dioxane/water solvent mixture.66 J:
ID
I=:
L>9:
IDA:G6C8:
D;
9>;;:G:CI
solvents for the aniline/HBF4Y
86I6ANI>8
HNHI:B
6
I:A:H8DEed sulfinyl imine formation and rhodium catalyzed arylation approach was evaluated in a one-pot, two-step reaction. First, the reaction forming the N-sulfinyl imine from p-CF3- benzaldehyde was carried out in dioxane, which was formed in high conversion after 3 hours. To the crude reaction mixture, without any work-up or purification, were added water, triethyl amine, boronic acid and the rhodium catalyst, and the reaction was additionally stirred for 3 hours. (Figure 21).

O S H2N

Aniline (2.5 mol%) O [Rh(I)L(CH3CN)2] O O HBF4 DEE (5 mol%) S L=COD (5 mol%) S N HN R Dioxane, 3h, RT Dioxane:water (2:1) R NEt3, PhB(OH)2 R Ph R = p-CF3-phenyl 3h, RT 85% yield, 98:2 dr

Figure 21. One-pot, two-step reaction yielding a chiral amine through diastereoselective arylation of N-sulfinyl imines.

After purification with flash chromatography, the one-pot, two-step procedure yielded the arylated product in 85% yield and excellent diastereoselectivity (98:2 dr), which is comparable to the original protocol (94% yield, 97:3 dr).66

21 2.5 Comparison of Synthetic Methods for the Preparation of Sulfinyl Imine In terms of applicability and usefulness, it is clear that the combined aminocatalytic and Brønsted acid catalyzed procedure is superior in terms of reaction time and higher yields. Additionally, the crude product of the aminocatalytic procedure can be purified over a short silica gel plug, while the Brønsted acid-catalyzed procedure requires full chromatographic purification. Before discussing the value of these procedures, from the point of green chemistry it must be noted that the use of auxiliaries can be considered as a less preferred method of synthesis according to the 12 green principles, but the N- sulfinyl imine is considered a versatile and reliable synthon for the synthesis of different amine derivatives.

The state-of-the-art for the preparation of N-sulfinyl aldimines is generally considered to be the pyrrolidine-catalyzed procedure developed by Cid and co- workers.55 The procedure developed by the Cid group utilizes pyrrolidine (10 mol%) in dichloromethane (0.33 M) at 60 °C in the presence of 4Å MS (1 gram/mmol) and no excess of either aldehyde or sulfinamide. The crude reaction mixture is purified by filtration through a silica gel pad. The procedures presented in this thesis uses either 10 mol% tetrafluoroboric acid diethyl etherate or a combination of 5 mol% tetrafluoroboric acid diethyl etherate and 2.5 mol% aniline. The reaction is carried out in dichloromethane (1.0 M) at room temperature with 1.1 equivalent of sulfinamide (Table 4). The difference in catalyst loading is negligible and not a significant parameter. All three described methods use CH2Cl2 which not only is derived from a non-renewable feedstock but might also be carcinogenic. The higher concentration in the aniline protocol means that three times less solvent is used for the same amount of starting material. In addition, about eight times as much desiccant is used in the pyrrolidine-based procedure compared to the other protocols.

Table 4. Comparative overview of the green chemistry evaluation of the different procedures presented in this thesis alongside the pyrrolidine-based procedure. 55 Catalyst Pyrrolidine HBF4 Et2O HBF4 Et2O HBF4 Et2O + Aniline + Aniline Catalyst loading (mol%) 10 10 5 + 2.5 5 + 2.5

Solvent CH2Cl2 CH2Cl2 CH2Cl2 i-PrOAc Temperature ( ) 60 RT RT RT

Concentration℃ (M) 0.33 1 1 1 Excess reactant (%) 0 10 10 10 :H>886CI
6BDJCI
1 0.12 0.12 0.12 (g/mmol)

22

Furthermore, since the Brønsted acid-catalyzed protocol requires a full chromatographic purification a lot of extra solvent is consumed. However, higher conversions were obtained in the HBF4Y/aniline protocol as well as the pyrrolidine-based procedure, requiring only a short filtration through silica gel to obtain the pure product. However, when CH2Cl2 is replaced with i-PrOAc, a greener solvent, a big problem associated with these procedures is alleviated. The pyrrolidine-based procedure works best for the p-toluene sulfinamide, while the anilinium protocol only works well for tert-butane sulfinamide, and for that reason these procedures could be considered complementary. In Chapter 2.4 it was shown that the anilinium procedure can be used in a one-pot, two-step fashion that can be a major benefit from the point of green chemistry, since no purification and no extra solvent is needed.

Comparing the mechanisms obtained through computational and NMR studies of the aminocatalytic procedure and the Brønsted acid-catalyzed procedure, it shows that the activation energy is equal for both transition states (TS1 and TS2) in the Brønsted acid-catalyzed procedure, at 20.9 kcal mol‒1 while the sulfinamide addition to the protonated aniline imine is rate-limiting step (16.7 kcal mol‒1). It is difficult to directly compare the activation free energy of two different catalytic systems, but qualitatively the computations studies support that the aminocatalytic reaction is a faster reaction.

The mechanisms followed by the different procedures can be considered to be similar in the sense that the transition states appear very similar. Both transition states for the sulfinamide addition consist of a chair-like six-membered transition state where the electrophile and nucleophile are linked through the protonated carbonyl/imine moiety and the hydrogen-bonding sulfinyl oxygen.

23

3. Photoredox Enabled Synthesis of Non- Natural Amino Acids (Paper III) 3.1 Photoredox-Catalyzed Preparation of Chiral Amines The preparation of chiral amines from N-sulfinyl imines can be achieved through reaction with a great variety of nucleophiles. Several nucleophiles have previously been mentioned in this thesis, such as Grignard reagents, rhodium complexes and hydride reagents. In recent years, the application of photoredox generation of radicals have grown rapidly and have been used in the addition to different imines.67-68 Fu and MacMillan and co-workers developed a procedure for the preparation of chiral benzylamines using the combination of photoredox- catalyzed decarboxylation of a-amino acids and stereoselective arylation through a nickel complex.69 The free radical mechanism of the photoredox- based procedure offers several advantages over organometallic procedures. For example, Grignard reagents require low temperatures in order to provide good selectivity. Additionally, Grignard reagents have very low functional group tolerance and reductions with hydride reagents must be performed on ketimines, which are more difficult to prepare, in order to obtain a diastereomeric compound. Beyond the chemical benefits of photoredox catalysis, the use of light as part of the catalysis allows for simple starting materials to be activated under mild reaction conditions.

A Organometallic reagent O O S S R3M HN R N R2 2 R * R R1 1 3 B Hydride reagent O O S S NaBH4 HN R N R2 2 R * R R1 R3 1 3

C Photoredox catalysis (Alemán) O O R 3 O N O O S O S HN R N R2 Ir(ppy)3 2 R * R R1 Hantzsch ester 1 3

Figure 22. Selected methods for the functionalization of N-sulfinyl imines.

24 Recently, Alemán and co-workers reported a photoredox-catalyzed functionalization of N-sulfinyl imines in which radicals derived from redox- activated carboxylic acids added to the mesitylene-derived sulfinyl imine (Figure 22, C).70 The highly selective reaction applies Ir(III) as photocatalyst and Hantzsch ester as a stoichiometric reducing agent. Another approach to achieve radical decarboxylation was achieved by Baran and co-workers. They developed a procedure for the synthesis of non-natural amino acids using ethyl glyoxylate derived N-sulfinyl imines and activated carboxylic acids under nickel-catalyzed conditions. The activated carboxylic acid could in some cases be formed in situ by reacting the carboxylic acid with N-oxide-3,4,5,6- tetrachlorophthalimide, followed by decarboxylation and addition.71 However, in the work by Baran and co-workers, three equivalents of zinc are required alongside with a toxic nickel catalyst.71

3.2 Photoredox-catalyzed Addition to N-sulfinyl Imines By combining the photocatalytic chemistry by Alemán and co-workers70 and the ethyl glyoxylate derived N-sulfinyl imines by Baran and co-workers, there is a possibility to prepare chiral amino acid derivatives using photocatalysis. Furthermore, if the redox-active carboxylic ester is replaced by carboxylic acids, a rich variety of carbon-centered radical sources is commercially available. Therefore, we envisioned that a complementary and redox-neutral process could be developed through the direct decarboxylation of carboxylic acids.

O O S O S N 15a, Cs2CO3 HN + OH PhCF3 * t-Bu 440 nm LED O2N O2N Figure 23. Initial evaluation of the photocatalyzed addition of radicals to sulfinamides.

Initial attempts to probe the reaction were performed with the (S)-tert-butane sulfinyl imine derived from 4-nitrobenzaldehyde. Subjecting this compound to pivalic acid in the presence of photocatalyst 15a and Cs2CO3 in a,a,a- trifluorotoluene under visible light irradiation produced a complex mixture. This is in accordance with the previous report by Alemán, where tert-butane sulfinyl imine of benzaldehyde and a redox-active ester gave a complex mixture. Therefore, the tert-butane sulfinamide moiety was discarded and no further reactions with tert-butane derived sulfinyl imines were performed. Instead the (R)-mesitylene sulfinyl imine derived from ethyl glyoxylate was prepared and subjected to the same reaction conditions. Gratifyingly, this provided the desired addition product in 27% yield (dr £ 95:5, Table 5, entry 1). With these initial results at hand the next step was to optimize the reaction conditions (Table 5).

25 Table 5. Optimization of reaction conditions for the photoredox-catalyzed addition of pivalic acid to N- sulfinyl imine.a

Mes R 2 R 2 O O O EtO Base, PC EtO * N + OH N Mes HN Mes R1 BF4 S Solvent S 440 nm LED 1a: R1 = Me, R2 = H O O 1b: R1 = Ph, R2 = H 1 2 1c: R = Ph, R = Me

Entry PC Base Solvent Time NMR dr (equiv.) yield

1 15a, 1 mol% Cs2CO3, 0.2 PhCF3 20 min 27% ³ 95:5

2 15b, 5 mol% Cs2CO3, 0.2 PhCF3 60 min 73% ³ 95:5

3 15c, 5 mol% Cs2CO3, 0.2 PhCF3 60 min 78% ³ 95:5

4 15c, 5 mol% Cs2CO3, 0.2 PhF 20 min 10% ³ 95:5

5 15c, 5 mol% Cs2CO3, 0.2 CF3CH2OH 20 min 0% —

6 15c, 5 mol% 2,6-lutidine, PhCF3 20 min 0% — 0.2

7 15c, 5 mol% Li2CO3, 0.2 PhCF3 60 min 0% —

8 15c, 5 mol% K3PO4, 0.2 PhCF3 20 min 32% ³ 95:5 60 min 80% ³ 95:5 2 h 83% ³ 95:5

9 15c, 5 mol% K2CO3, 0.2 PhCF3 60 min 84% ³ 95:5

10 15c, 5 mol% K2CO3, 0.05 PhCF3 20 min 1% —

11 15c, 5 mol% K2CO3, 0.5 PhCF3 20 min 45% ³ 95:5 60 min 85% ³ 95:5

12 15c, 5 mol% K2CO3, 0.5 PhCF3 60 min 77% ³ 95:5 0.1 M

a 13 15c, 5 mol% K2CO3, 0.5 PhCF3 60 min 91% ³ 95:5

b 14 15c, 5 mol% K2CO3, 0.5 PhCF3 60 min 95% ³95:5

a,c 15 15c, 5 mol% K2CO3, 0.5 PhCF3 60 min 50% 7 : 1 a Reaction conditions: 0.1 mmol pivalic acid, 0.11 mmol N-sulfinyl imine 0.05 M, unless otherwise stated. Yields were determined by 1H NMR using 1,3,5-trimethoxybenzene as standard. a 0.12 mmol pivalic acid, 0.1 mmol N-sulfinyl imine. b 0.15 mmol pivalic acid, 0.1 mmol N-sulfinyl imine. c Using p- toluene N-sulfinyl imine.

The use of photocatalyst 15a gave a moderate yield (27%) but excellent diastereomeric selectivity (Table 5, entry 1). Changing to the related catalysts 15b and 15c dramatically improved the yield (73% and 78% respectively) after

26 60 minutes of irradiation (Table 5, entries 2 and 3), and further optimization was therefore performed with catalyst 15c. The catalyst was evaluated with fluorobenzene and 2,2,2-trifluoroethanol as solvents, but both gave very low or no yield of the desired product (Table 5, entries 4 and 5). Replacing Cs2CO3 with 2,6-lutidine and Li2CO3 yielded no product, while K3PO4 and K2CO3 provided the product in good yields (80% and 84% respectively after 1 h) that were comparable to Cs2CO3 (Table 5, entries 6–9). :8G:6H>C<
I=:
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base to 5 mol% provided only trace amount of the product. Increasing the loading of K2CO3 to 50 mol% increased the yield marginally (Table 5 entries 10 and 11). Furthermore, increasing the concentration of the reaction from 0.05 M to 0.1 M slightly decreased the yield (77 %, Table 5, entry 12). JG>C<
I=:
reaction, it seemed that the carboxylic acid was consumed faster than the N- sulfinyl imine, the ratio of the starting materials was therefore changed. Employing 1.2 equivalents of the carboxylic acid led to a notable increase in the yield (91% after 60 min) and further increase of the acid loading (1.5 equivalents) led to an additional increase in yield (95% after 60 min, Table 5, entries 13 and 14). p-Toluene sulfinyl imines provided the product with a moderate yield and stereoselectivity (50 % yield, 7:1 dr, Table 5, entry 15). With optimized conditions the next step was investigating the substrate scope (Table 6).

Table 6. Investigation of substrate scope for the addition of C-centered radical to N-sulfinyl imine, yields are NMR-yields

15c, 5 mol% H R Mes N CO2Et 1 K2CO3, 0.5 equiv. Mes N CO2Et S + R2 CO2H S O R3 0.05 M PhCF3, rt, N2 O 440 nm LED, 1 – 3 h R1 R3 (1.2 equiv.) R2

H H H H H Mes N CO Et Mes N CO Et Mes N CO Et Mes N CO Et Mes N CO2Et S 2 S 2 S 2 S 2 S Me Me Me O O O Me O O O Me Me Me Me Me O Me N Boc 91% (81%)a 46% 89% 31% 63%

H H H H H Mes N CO Et Mes N CO Et Mes N CO Et Mes N CO Et Mes N CO Et S 2 S 2 S 2 S 2 S 2 O O O O O NBoc

58% >95% (86%)a 35% 41% 22%

a Isolated yield

As seen in table 6, the tert-butyl carboxylic acid adds to the N-sulfinyl imine with high yield (91%). The bulkier 5-(2,5-dimethylphenoxy)-2,2-

27 dimethylpentanoic acid also adds to the imine, but with a notably lower yield (46%). 1-methyl-cyclohexanoic acid provides the product in good yield (89%), however, 1-boc-4-methylpiperidine-4-carboxylic acid gave significantly lower yield (31%). 3-methyloxetane-3-carboxylic acid and 1-phenylcyclopropane-1- carboxylic acid both provide the product in good yields (63% and 58% respectively). While N-Boc-proline gave excellent yield (>95%), cyclobutanoic acid gave a poor yield (35%). The primary carboxylic acids pentanoic acid and 3-phenylpentanoic acid gave low yields (41% and 22% correspondingly).

3.3 Conclusion A redox-neutral procedure for the preparation of non-natural a-amino acids using a light-activated radical-based methodology has been developed. The synthetic scope of the sulfinyl imines was expanded to include ethyl glyoxylate- derived N-sulfinyl imines and different commercially available carboxylic acids instead of the redox-active esters. These changes led to an overall improvement in the atom economy of the reaction compared to literature procedures. While the scope of the radical source is extended the scope of the N-sulfinyl imines remain limited.

28 4. Green Chemistry in Teaching (Paper IV) 4.1 Student-Driven Development of “Green” Procedures Strategies for sustainability have become an important part of the research and educational endeavors of academic institutions, including KTH, and universities have implemented new policies to drive research and education towards more sustainable development.72 The development of research regarding different aspects of sustainability is often driven by the opportunities to find funding, but implementing the changes into the experimental education is often costly and time consuming, and commonly, there is no dedicated time and budget for ;68JAIN
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Several different approaches have been tested to introduce Green chemistry in the curriculum, such as green case studies, dedicated courses in green chemistry and green chemistry laboratory experiments.73-84 However, another approach is to let B.Sc. students in the university’s own educational system develop new green chemistry experiments as a part of their B.Sc. degree project. In this way, new laboratory experiments can be developed without an overwhelming effort ;GDB
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)= students, and in addition, the B. Sc. students are also subjected to the topic of green chemistry. One key idea with this project is that green chemistry can act as a framework for the students to evaluate their reactions and make them reflect about green chemistry and sustainability. At KTH, the B.Sc. degree project is mandatory for all students and is conducted in groups of three B.Sc. students over one semester (15 ECTS). This student-driven approach was used to develop a new and greener experimental procedure for the first year organic chemistry course in the Chemical Engineering and Biotechnology programs at KTH.

A further reason to develop a new laboratory experiment is that some procedures are sub-optimal for a first year laboratory exercise. In the procedure we sought to replace, benzyl bromine was reacted with N-methylbenzyl amine in an SN2- reaction. The reason to replace this particular lab is mainly that one of the reactants, benzyl bromide, is a potent lachrymator, i.e. having properties similar to tear gas.

4.2 B.Sc. Degree Project The aim of the B. Sc. project was to improve the preparation of lidocaine, a local anesthetic, based on the principles of green chemistry while still keeping it within the limitation of the course laboratory setting. The laboratory

29 experiments in the undergraduate course are performed in 5 hours and during this time the reaction has to be performed, purified and, analyzed.

In previous procedures,85 lidocaine was synthesized in two steps; first a chloroacylation of 2,6-methylaniline, followed by a substitution reaction of diethyl amine on the a-carbon.

O O O NH 2 Cl Cl 3 equiv. N N Cl HN H HN AcOH Toluene

Figure 24. General approach to the synthesis of lidocaine.

Initially, three B. Sc. students were given the task to “greenify” the synthesis of lidocaine based on a synthesis by Reilly and co-workers (Figure 24).85 After approximately one week, the students presented their suggested “green” modifications to the existing procedures. Several different aspects of green chemistry were discussed and the following modifications were proposed to be tested; 1) “greener” solvents including solvents from bio-sourced feedstocks; 2) decreased reaction temperature; 3) the use of catalytic amounts of potassium iodide to promote a Finkelstein reaction; 4) different inorganic bases instead of large excess of diethylamine; 5) a two-step one-pot procedure (Figure 25).

Base, catalyst O O Cl equiv. N N HN H HN Solvent, T

Figure 25. The parameters in the box were evaluated and optimized during the project.

4.3 Results JG>C<
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,8
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included different aspects of green chemistry (Figure 26). In the first procedure, the fossil fuel-based solvent toluene was replaced with the greener solvent glycerol and the product was obtained in 70-85% yield after a recrystallization from heptane. In the second procedure, the students evaluated the possibility to catalyze the reaction by addition of potassium iodide and to decrease the excess of diethyl amine that was used in the original procedure. In the optimized procedure, a change of solvent to acetonitrile was beneficial for the Finkelstein

30 catalysis and, in addition, the excess diethyl amine could be decreased with the use of innocuous potassium carbonate. In the final procedure, the product was isolated via a crystallization without a decrease in the yield. Finally, a one-pot, two step procedure was developed in which both the acylation step and the SN2- reaction was performed without an intermediary purification.

O O Cl N N A: Solvent replacement HN H 3 equiv. HN Glycerol, 85 oC 1 h

KI 10 mol% O K2CO3 1.1 equiv. O Cl N HN N 1.1 equiv. B: Finkelstein catalysis, H HN use of bulk base MeCN, 82 oC 1 h

1) O Cl 1.1 equiv. Cl

K2CO3 2.2 equiv. O NH N 2 2) Et2NH 1.1 equiv. HN C: One-pot, two-step reaction KI 10 mol%

MeCN

Figure 26. The three procedures developed by the B.Sc. students.

4.4 Implementation in the Course Lab In order to evaluate the applicability of the developed procedures, the second procedure was chosen to be implemented into an organic chemistry course. Procedure B was chosen as the optimal procedure since it involved several different green chemistry aspects compared to the original procedure, such as catalytic promotion by potassium iodide, a greener solvent (acetonitrile instead of toluene) and lower reflux temperature (82 °C compared to 110 °C) and replacement of excess diethyl amine with innocuous potassium carbonate. This procedure was incorporated into the course “Organic chemistry, basic concepts and practice” in spring 2019 where 59 students performed the synthesis of lidocaine according to the new procedure. In order to introduce the green aspects of organic chemistry to the students, before the experiments started, the students were given a 15 minute introduction lecture to green chemistry. In addition to the short lecture, the students had to answer questions regarding green chemistry before performing the procedure. The procedure was performed within the allocated 5 hours and the students obtained yields that were generally good to

31 excellent and 78% of the students obtained a yield over 50% (figure 27). This clearly indicates that the procedure developed by the three B. Sc. students was implemented in a successful fashion.

18

15

12

9

6 No. of students of No. 3

0 0-15% 16-30% 31-45% 46-60% 61-75% 76-90% >90%

Obtained yields

Figure 27. The distribution of the students yields

In order to monitor the green chemistry learning outcomes of the new procedure, after the laboratory experiment the students answered a survey to assess their attitudes and knowledge about green chemistry (Table 7)

Table 7. Survey answered by 55 of the 59 students that performed the synthesis of lidocaine.

1 5 Mean

indicates indicates score How was your previous knowledge of Q1 green/sustainable chemistry prior to this course Very low Very high 2.31 experiment? Did the preparation and experimentation help you to Very Q2 improve your perception of green/sustainable Not at all 3.45 much chemistry Do you think it is important that green/sustainable Very Q3 chemistry is an integral part of your chemical Not at all 4.66 important engineering education? Do you think that green chemistry and sustainability Very Q4 Not at all 4.39 will be important in your future career? important

The survey showed that the students had a low knowledge about green chemistry prior to the laboratory session (Table 7, Q1: 2.31). The survey also showed that the students perception of green chemistry was improved by the preparation and experimentation (Table 7, Q2: 3.45). Furthermore, the students agreed that green chemistry is an important part of their education in chemical engineering and biotechnology and that green chemistry and sustainable development will be important to their future career (Table 7, Q3: 4.66 and Q4: 4.39). In relation to

32 the experiments, the students had to prepare a report in which they reflect over the aspects of green chemistry of the performed reaction and what implications an implementation of this synthesis on an industrial scale would have. The students commented on many aspects of the reaction, such as safety and toxicity as well as energy use and the fact that the reaction applies catalysis in order to lower the activation energy. From the reports, it is clear that the first-year undergraduate students are able to analyze their synthesis with regard to the 12 principles of Green Chemistry.

After the B.Sc. degree project was completed, the three B. Sc. students that developed the new procedures took a survey about their experience and learning from their degree project.

Table 8. Part of the survey answered by the three B.Sc. degree project students answered on a scale from 1 to 5

Mean 1 indicates 5 indicates score What is your overall impression of the B. Sc. Q1 Bad Good 5 Project? Did the B. Sc. project increase your Q2 Not at all Much 4.33 understanding of the concept green chemistry? How did the green chemistry project influence Less More Q3 4.67 your interest in organic chemistry? interested interested To what degree did you have to independently Q4 Not at all Much 4.67 think about green chemistry in the B. Sc. project?

All three students had a good impression of the degree project (Table 8, Q1:5.0) and it made them more interested in organic chemistry (Table 8, Q3:4.67). Throughout the project, they came to understand the concept of green chemistry significantly better than before the project (Table 8, Q2:4.33) and they all experienced that they had to think independently about green chemistry throughout the project (Table 8, Q4:4.67).

4.5 Conclusions We have successfully circumvented the time consuming and costly development of new laboratory experiment by utilizing B.Sc. students during their degree project. This has allowed the implementation of green chemistry in the laboratory course for first-year chemistry and biotechnology students. Furthermore, this allowed the removal of a problematic experiment, replacing it with a green and innocuous procedure to prepare an active pharmaceutical ingredient. The development process has allowed three students to work with problem-solving in a synthetic method development project related to green chemistry. The B. Sc. students report a great learning outcome both with regards

33 to organic chemistry and its connection to green chemistry. Furthermore, the procedure has been successfully integrated into the laboratory course, with an positive outcome.

34 5. Concluding Remarks & Outlook In chapter two the development of the Brønsted acid catalyzed condensation of aldehydes and tert-butane sulfinamide was realized with good yields in 2 hours. Using simple acids and a desiccant the synthesis proceeds at room temperature. JGI=:GBDG:
I=:
B:8=6C>HB
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I=GDJ<=
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 --calculations and notably the reaction follows a well-defined 6-membered transition state, as per our expectations. An improved method for the preparation of N-sulfinyl imines, again using the Brønsted acid HBF4 diethyl etherate but in conjunction with aniline. Lowering the catalyst loading from 10 mol% acid to 5 mol% acid and using 2.5 mol% aniline we were able to improve the yields as well as decrease the reaction time to only 30 minutes. Using  --calculations as well as experimental studies, we investigated the mechanism, including the initial state of the catalyst and the mechanistic cycle. Additionally, synthetic applications of the developed method was investigated and a gram-scale reaction as well as a one-pot, two step reaction was performed. In the one-pot, two step procedure, we combine our procedure with a Rh(I)-catalyzed reaction for the addition of arylboronic acid to the in situ formed N-sulfinyl imine. However, the second objective, developing a mild, catalytic method for the preparation of N-sulfinyl ketimines were unsuccessful and the attempts to solve this problem were excluded from the thesis. Sulfinamides will continue to see a lot of use in the coming years, through the formation of N-sulfinyl imines. The remaining scientific under the umbrella of Papers I and II is the catalytic formation of N-sulfinyl ketimines. They are more sterically demanding and less stable, but a mild catalytic procedure to form these imines will improve the applicability of this class of compounds, especially in large scale production.

In chapter three, the development of a light-activated functionalization of N- sulfinyl imines have been developed. Based on previous work by Alemán and co-workers and Baran and co-workers, we have expanded the scope of the radical-source, from redox-activated esters to simple carboxylic acids. While the substrate scope so far seem to be limited to tertiary carbons and stabilized secondary carbons, the reaction proceeds with low yields even for primary radical sources. This manuscript is based on preliminary data and initial optimizations and further work will be carried out. Chiral amines will always be an important motif in organic chemistry, and so will amino acids. Preparing non- natural amino acids with carboxylic acids instead of bulky redox-active esters is an important step forward, but the reaction needs a lot of work still. Finding an efficient ways to purify the reaction as well as a wider substrate scope with respect to carboxylic acids are goals for future work in this project. The high

35 chemo selectivity obtained through these radical processes allows for efficient preparation of diverse compounds, such as chiral amines. Photoredox catalyzed, electrochemical and other green radical sources have seen a large increase of interest within the organic chemistry community, something that will keep growing the better the procedures become.

Chapter four is focused on the application of green chemistry in the education of B.Sc. students were three third-year B. Sc. students as their diploma work developed a laboratory experiment for the first-year organic chemistry course at KTH. The work was to improve an organic synthesis procedure based on the 12 principles of green chemistry. The developed procedure had implemented several of the principles of green chemistry, such as catalysis, a greener solvent, lower reaction temperature and a less wasteful purification procedure. The laboratory experiment was successfully implemented in the first-year course in organic chemistry. Evaluations of the experience with the experiment were very positive, the students found it good in learning both organic chemistry in general and green chemistry specifically, the experience was shared by the third-year students. The development of new laboratory experiments and the incorporation of green chemistry in student learning is always going to be important. There are a lot left that could be done to improve the learning outcomes of the teaching- lab, and it will remain a costly and time-consuming activity for faculty and doctoral students. Finding positive ways to develop green chemistry laboratory experiments while giving third-year students a realistic taste of the world of research not only makes a a great diploma project, it is also a great way to improve the knowledge within the undergraduate student

36

6. Acknowledgements First and foreBDHI
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enthusiasm and fun to work, almost every day.

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Fredrik, Andrey, Robin, Anna, Shengjun, Quentin, Juho, Piret, Christiana, Linquin, Lizhou, Biaobiao, Bo, Fuguo, Xia and the rest of the past and present members of the organic chemistry department. For all the fun lunches, for the interesting discussions and the stuff I’ve learned from you, thank you! Thank you for making the Organic chemistry department a fun, creative and stimulating work environment!

My colleagues in the teaching lab, as well as the students I’ve met over the year, thank you! I’ve learned a lot from you, and it has been a lot of fun.

My first teachers, Christina, Olof and Krister, thank you for your efforts in teaching, if it wasn’t for you I would not have ended up in the field of organic chemistry. You have all stopped teaching here at KTH, and while new teachers have stepped up, I owe you my thanks!

A special thanks to my dear friend Anders Myrhammar for helping me solve the hardest problem of my thesis work, namely making the cover image.

Finally I want to thank my family. Tack för att ni alltid stöttat och trott på mig! Tack mamma och pappa, tack Linus, Kristin och mina underbara brorsbarn

37 Arvid, Märta och Knut. Ni ger mig så mycket glädje och kärlek! Thank you also my love, Marieke, for your positivity and for all your support and help, you are the best! (I=:GH
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Now I’m coming home, my dear!

38 7. Appendix The following is a clarification of my contribution to publications I – IV, as requested by KTH.

Paper I: I contributed to formulating the scientific problem. Performed all experiments and contributed to preparing the manuscripts.

Paper II: I contributed to formulating the scientific problem. Performed all experiments and contributed to preparing the manuscripts.

Paper III: I contributed to formulating the scientific problem. Performed some experiments and contributed to preparing the manuscript.

Paper IV: I contributed to formulating the scientific problem. Supervised B.Sc. students, performed some experiments and contributed to preparing the manuscript.

All papers are reprinted with permission from Elsevier (Paper I), Wiley-VCH (Paper II) and American Chemical Society (Paper IV)

39 8. Bibliography 1. The Paris agreement. https://unfccc.int/process-and-meetings/the-paris- agreement/the-paris-agreement. 2. målen, A. o. d. g. https://www.regeringen.se/regeringens-politik/globala- malen-och-agenda-2030/. 3. Trost, B. M., The atom economy — a search for synthetic efficiency. Science 1991, 254 (5037), 1471—1477. 4. Paul T. Anastas, J. C. W., Green chemistry: theory and practice. New York: Oxford University Press.: 1998. 
:GO:A>JH
#
#
*J:AFJ:H
"9T:H
HJG
JC:
CDJK:AA:
DG8:
6<>HH6CI
96CH
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Combinaisons des Corps Organiques. Annales de chimie et de physique 1836, 61, 146-151. 6. IUPAC. Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997). Online version (2019-) created by S. J. Chalk. ISBN 0-9678550-9-8. https://doi.org/10.1351/goldbook. 7. de Meijere, A.; Meyer, F. E., Fine Feathers Make Fine Birds: The Heck Reaction in Modern Garb. Angew. Chem. Int. Ed. 1995, 33 (23 24), 2379-2411. 8. Miyaura, N.; Yamada, K.; Suzuki, A., A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with- 1-alkenyl or 1- alkynyl halides. Tetrahedron Lett. 1979, 20 (36), 3437-3440. 
$JB6G
 
=6G
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$6CL6G
,
, 
GDGa, P. K., Lipase catalysis in organic solvents: advantages and applications. Biol Proced Online 2016, 18 (1), 2. 
6A@D
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Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications. Wiley VCH: 2013. 11. List, B., Proline-catalyzed asymmetric reactions. Tetrahedron 2002, 58 (28), 5573-5590. - 


&8'6J<=I

0
IUPAC. Compendium of Chemical Terminology 2nd ed. (the "Gold Book"). Blackwell Scientific Publications, Oxford: 1997. 13. Xiao, W.; Ernst, K.-H.; Palotas, K.; Zhang, Y.; Bruyer, E.; Peng, L.; Greber, T.; Hofer, W. A.; Scott, L. T.; Fasel, R., Microscopic origin of chiral shape induction in achiral crystals. Nat. Chem. 2016, 8, 326. 
JCC
&

)GDI:>C–Ligand Interactions: G:C:G6A
:H8G>EI>DC
eLS 2010. 15. Guo-*>6C<
%>C
*

2
#>: Fei Cheng, Chiral Drugs: Chemistry and Biological Action. John Wiley & sons: 2011. 
6A86I:GG6
 
b8FJ6G>86
"
-=:
B6G@:I
D;
8=>G6A
9GJG6A
HL>I8=:H
- versus de novo enantiomerically pure compounds. J. Pharmaceut. Biomed. 2018, 147, 323-340. 17. Agranat, I.; Caner, H.; Caldwell, J., Putting chirality to work: the strategy of chiral switches. Nat. Rev. Drug Discov. 2002, 1 (10), 753-768.

40 18. Paul Wyatt, S. W., Organic Synthesis: Strategy and Control. John Wiley & Sons Ltd.: Chichester, UK, 2007. 19. Corey, E. J.; Ensley, H. E., Preparation of an optically active prostaglandin intermediate via asymmetric induction. J. Am. Chem. Soc. 1975, 97 (23), 6908- 6909. 
-GDHI

& 
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%

BD9:A
;DG
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induction in th:
>:AH-Alder reaction. J. Am. Chem. Soc. 1980, 102 (25), 7595- 7596. 21. Heravi, M. M.; Zadsirjan, V., Oxazolidinones as chiral auxiliaries in asymmetric aldol reactions applied to total synthesis. Tetrahedron: Asymmetry 2013, 24 (19), 1149-1188. 22. Evans

 
=6EB6C
$
- 
>H6=6
#
HNBB:IG>8
>:AH-Alder cycloaddition reactions with chiral .alpha.,.beta.-unsaturated N- acyloxazolidinones. J. Am. Chem. Soc. 1988, 110 (4), 1238-1256. 
+:O:C9:
) 
)6>DI>
)
!
, 
D:A=D

>6HI:G:DH:A:8I>K:
pproach to Substituted Oxazolidinones from Morita–Baylis–Hillman Adducts. Synth. Commun. 2010, 41 (2), 227-242. 24. Heravi, M. M.; Zadsirjan, V.; Farajpour, B., Applications of oxazolidinones as chiral auxiliaries in the asymmetric alkylation reaction applied to total synthesis. RSC Adv. 2016, 6 (36), 30498-30551. 25. Nicolas, E.; Russell, K. C.; Hruby, V. J., Asymmetric 1,4-addition of organocuprates to chiral .alpha.,.beta.-unsaturated N-acyl-4-phenyl-2- oxazolidinones: a new approach to the synthesis of chiral .beta.-branched carboxylic acids. J. Org. Chem. 1993, 58 (3), 766-770. 26. Maslehat S, S. S., Arjenaki M. G. , Frequency and Importance of Six JC8I>DC6A
GDJEH
I=6I
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+DA:
>C
GJ<
>H8DK:GN Biosci. Biotech Res. Asia 2018, 15, 541-548. 27. Nikolai, L. N.; McClure, E. L.; MacLeod, S. L.; Wong, C. S., Stereoisomer quantification of the β-blocker drugs atenolol, metoprolol, and propranolol in wastewaters by chiral high-performance liquid chromatography–tandem mass spectrometry. J. Chromatogr. A 2006, 1131 (1), 103-109. 28. Robak, M. T.; Herbage, M. A.; Ellman, J. A., Synthesis and Applications of tert-Butanesulfinamide. Chem. Rev. 2010, 110 (6), 3600-3740. 
6K>H

 
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# 
$AJ<:G

0
=:B>HIGN
D;
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HJA;JG- nitrogen bond. VIII. N-Alkylidenesulfinamides. J. Am. Chem. Soc. 1974, 96 (15), 5000-5001. 30. Zhong, Y.-0 
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2 -Z.; Fang, K.; Izumi, K.; Xu, M.-H.; Lin, G.-Q., A !><=AN
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β-Amino Alcohols by Reductive Cross-Coupling of Chiral N-tert-Butanesulfinyl Imines with Aldehydes. J. Am. Chem. Soc. 2005, 127 (34), 11956-11957. 31. Evans, J. W.; Ellman, J. A., Stereoselective Synthesis of 1,2->HJ7HI>IJI:9
β-Amino Alcohols by Nucleophilic Addition to N-tert-Butanesulfinyl α- Alkoxyaldimines. J. Org. Chem. 2003, 68 (26), 9948-9957.

41 32. Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.; Nantermet, P. G., A facile three-step synthesis of 1,2-amino alcohols using the Ellman homochiral tert-butylsulfinamide. Tetrahedron Letters 2001, 42 (11), 2051-2054. 
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New General Method for the Asymmetric Synthesis of syn- and anti-1,3-Amino Alcohols. J. Am. Chem. Soc. 2003, 125 (37), 11276-11282. 34. Kochi, T.; Tang, T. P.; Ellman, J. A., Asymmetric Synthesis of syn- and anti- 1,3-Amino Alcohols. J. Am. Chem. Soc. 2002, 124 (23), 6518-6519. 
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