Iron-Catalyzed Amino-Oxygenation and Aminofluorination of Olefins

Georgia State University ScholarWorks @ Georgia State University

Chemistry Theses Department of Chemistry

8-11-2015

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Recommended Citation Sears, Jeffrey, "Iron-Catalyzed Amino-Oxygenation and Aminofluorination of Olefins." Thesis, Georgia State University, 2015. https://scholarworks.gsu.edu/chemistry_theses/77

This Thesis is brought to you for free and open access by the Department of Chemistry at ScholarWorks @ Georgia State University. It has been accepted for inclusion in Chemistry Theses by an authorized administrator of ScholarWorks @ Georgia State University. For more information, please contact [email protected]. IRON-CATALYZED AMINO-OXYGENATION AND AMINOFLUORINATION OF

OLEFINS

JEFFREY D. SEARS

Under the Direction of Hao Xu, PhD

ABSTRACT

The first chapter of the thesis describes an iron(II)-catalyzed intermolecular amino- oxygenation of alkenes. This amino-oxygenation method is found to be compatible with a broad range of synthetically valuable alkenes and affords the corresponding 1,2-amino alcohols with excellent regio- and diastereoselectivity. Additionally, practical synthetic procedures for the amino-oxygenation of styrene, a fully functionalized glycal, and indene are described. The second chapter of the thesis describes a regioselective and diastereoselective iron(II)-catalyzed intermolecular aminofluorination of alkenes using nucleophilic fluorinating reagents. This method affords new vicinal amino fluorides that were previously difficult to prepare. In both the amino-oxygenation and aminofluorination reactions, bench-stable hydroxylamine derivatives functioned as both the oxidant and amination reagents. Preliminary mechanistic studies suggested that an iron-nitrenoid is a possible reactive intermediate on both reaction pathways.

These new difunctionalization strategies represent efficient alternatives to current amino- oxygenation and aminofluorination methods.

INDEX WORDS: selective catalysis, iron, olefin, oxidation, amination, fluorination

IRON-CATALYZED AMINO-OXYGENATION AND AMINOFLUORINATION OF

OLEFINS

JEFFREY D. SEARS

A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of

Masters of Organic Chemistry

in the College of Arts and Sciences

Georgia State University

2015

OLEFINS

JEFFREY D. SEARS

Committee Chair: Hao Xu

Committee: Hao Xu

Alfons Baumstark

Ivaylo Ivanov

Electronic Version Approved:

Office of Graduate Studies

College of Arts and Sciences

Georgia State University

July 2015 iv

DEDICATION

To my parents Carolyn and Michael Sears. v

ACKNOWLEDGEMENTS

I would like to thank Professor Hao Xu. I probably never would have realized my interest in chemical research if it were not for a random hallway conversation about battery technology and catalysis. I will always be grateful for the guidance and support he has provided throughout my undergraduate and graduate studies. It has been a privilege to be a part of his research group.

I would like to thank each member of the Xu group, past and present, for their help. I have had the distinct pleasure to become close friends with many of them. I am especially grateful to Dr. Dengfu Lu and Chengliang Zhu for their mentorship. I will always be appreciative of their patience. Additionally, I thank Dr. Dengfu Lu, Chengliang Zhu and Yongan Yuan for proofreading this thesis.

I would also like to thank Professor Alfons Baumstark for his guidance during my graduate studies. His attention to detail and enthusiasm for education have left a lasting impression on me. Lastly, I would like to thank all members of my committee, Professors Ivaylo

Ivanov, Hao Xu, and Alfons Baumstark for their review of this thesis.

TABLE OF CONTENTS

ACKNOWLEDGEMENTS ...... v

LIST OF TABLES ...... viii

LIST OF FIGURES ...... ix

1 INTRODUCTION ...... 1

1.1 Fe(II)-Catalyzed Intermolecular Amino-Oxygenation of Alkenes ...... 1

1.2 Fe(II)-Catalyzed Intermolecular Aminofluorination of Alkenes ...... 6

2 EXPERIMENT ...... 10

2.1 General Information ...... 10

2.1.1 General Procedures...... 10

2.1.2 Materials ...... 10

2.1.3 Instrumentation ...... 10

2.1.4 Other Abbreviation Used ...... 11

2.2 Iron(II)-Catalyzed Alkene Amino-Oxygenation ...... 11

2.2.1 Synthesis of Acyloxyl Carbamates (2a and 2b) ...... 11

2.2.2 Synthesis of Nitrogen-based Tri-dentate Ligands ...... 13

2.2.3 Procedure for the Iron-Catalyzed Gram-Scale Glycal Amino-Oxygenation .... 16

2.3 Iron(II)-Catalyzed Alkene Aminofluorination ...... 20

2.3.1 Synthesis of Acyloxyl Carbamate 2d ...... 20

2.3.2 General Procedure A for the Iron-Catalyzed Alkene Aminofluorination .. 21 vii

2.3.3 General Procedure B for the Iron-Catalyzed Alkene Aminofluorination .. 22

3 RESULTS AND DISCUSSION ...... 24

3.1 Fe(II)-Catalyzed Amino-Oxygenation of Alkenes ...... 24

3.2 Fe(II)-Catalyzed Aminofluorination of Alkenes ...... 35

4 CONCLUSIONS ...... 43

APPENDIX ...... 45

4.1 Aminofluorination (AF) NMR Spectra (1H, 13C, and 19F) ...... 45

REFERENCES ...... 48

viii

LIST OF TABLES

Table 1: Iron-Ligand Complex and Acyloxyl Carbamate Relationship for the Amino-

Oxygenation of Styrene ...... 25

Table 2: Iron-L1 Catalyzed Amino-Oxygenation Substrate Scope ...... 28

Table 3: Iron-L2 Catalyzed Amino-Oxygenation Substrate Scope ...... 34

Table 4: Iron-L1 Catalyzed Aminofluorination Substrate Scope ...... 40

LIST OF FIGURES

Figure 1: Osmium-Catalyzed Sharpless Olefin Aminohydroxylation1l ...... 2

Figure 2: A Selected Example of Palladium-Catalyzed Aminoacetoxylation of Alkenes1h2

Figure 3: A Selected Example of Palladium-Catalyzed Olefin Amino-Oxygenation for the

Synthesis of Tetrahydrofurans1a ...... 3

Figure 4: Copper-Catalyzed Asymmetric Intramolecular Amino-Oxygenation of

Alkenes1i ...... 3

Figure 5: Copper(II)-Catalyzed Amino-Oxygenation of Alkenes with Sulfonyl

Oxaziridines1j ...... 4

Figure 6: Iron-Catalyzed Amino-Oxygenation of Alkenes with Sulfonyl Oxaziridines1k . 5

Figure 7: Iron(II)-Catalyzed Intramolecular Amino-Oxygenation of Alkenes with

Functionalized Hydroxylamines6 ...... 6

Figure 8: Representative Pharmaceuticals with Fluorines7 ...... 6

Figure 9: Palladium-Catalyzed Intramolecular Aminofluorination of Alkenes9 ...... 7

Figure 10: Palladium-Catalyzed Intermolecular Aminofluorination of Styrenes Using

NFSI10 ...... 7

Figure 11: Silver-Catalyzed Radical Intramolecular Aminofluorination of Alkenes in

Aqueous Media11 ...... 8

Figure 12: Enantioselective Fluoroamination: 1,4-Addition to Conjugated Dienes Using

Anionic Phase-Transfer Catalysis12 ...... 8

Figure 13: Iron(II)-Catalyzed Intramolecular Aminofluorination of Alkenes4c ...... 9

Figure 14: Synthesis of Acyloxyl Carbamats 2a-c ...... 26 x

Figure 15: Practical Synthetic Procedure: Iron-Catalyzed Amino-Oxygenation of

Representative Alkenes ...... 30

Figure 16: Iron-L1 Catalyzed Amino-Oxygenation of trans-beta-Me-Styrene ...... 31

Figure 17: Synthesis of Phenanthroline-Oxazoline Hybrid Ligand (L2) ...... 32

Figure 18: Iron-L2 Catalyzed Amino-Oxygenation of trans- and cis-beta-Me-Styrene .. 33

Figure 19: Working Mechanistic Hypothesis for the Iron-Catalyzed Amino-Oxygenation of Alkenes4b ...... 35

Figure 20: Previous Iron-Catalyzed Methods ...... 36

Figure 21: Preliminary Results of the Iron-Catalyzed Aminofluorination of Styrene...... 36

Figure 22: Working Hypothesis of N-O Bond Cleavage and Interaction with XtalFluor-E

...... 37

Figure 23: Synthesis of Acyloxyl Carbamate 2d ...... 38

Figure 24: Crystal Structure of the Amino-Oxygenation Active Catalyst4b ...... 38

Figure 25: Iron-L2 Catalyzed Aminofluorination of trans-beta-Me-Styrene ...... 42

Figure 26: Iron-Catalyzed Aminofluorination of a Radical Clock: Probing the Mechanism

...... 42

Figure 27: Iron-Catalyzed Aminofluorination of 2,3-Dimethyl-but-1-ene: Evidence for a

Carbocation Intermediate ...... 43

1 Figure 28: H NMR (CDCl3, 400 MHz), A-O Indene ...... 45

13 Figure 29: C NMR (CDCl3, 100 MHz), A-O Indene ...... 46

1 Figure 30: H NMR (bezene-d6, 400 MHz), A-O Glycal ...... 47

13 Figure 31: C NMR (CDCl3, 100 MHz), A-O Glycal ...... 48

1 INTRODUCTION

Extensive research into the simultaneous transfer of nitrogen and another heteroatom has led to the discovery of numerous organo-, precious and non-precious metal catalyzed difunctionalizations.1 A demand for non-precious metal catalysts in industrial difunctionalization processes, due to their low cost and toxicity, has promoted research efforts in numerous groups.1b, 1e, 1i-k, 2

The iron-catalyzed difunctionalization of alkenes has been an ongoing project in our research group. We have explored the use of an iron nitrenoid in several transformations.1o, 3 Our recent success in iron-catalyzed intramolecular amino-heteroatom difunctionalization processes has stimulated the pursuit of intermolecular extensions.4 Herein, the iron-catalyzed intermolecular amino-oxygenation and aminofluorination of olefins are described.

1.1 Fe(II)-Catalyzed Intermolecular Amino-Oxygenation of Alkenes

The first example of a catalytic amino-oxygenation reaction was reported by K. B.

Sharpless and coworkers in 1976.1l They demonstrated how a tert-alkyl imido osmium compound catalyzes the stereospecific vicinal amino-oxygenation of alkenes. The trihydrate of

Chloramine-T2 undergoes a reaction with a catalytic amount of osmium tetroxide in the presence of an alkene to produce regioisomeric amino-oxygenation products and residual NaCl (Figure 1).

This work inspired additional efforts to uncover catalytic amino-oxygenation methods with higher regioselectivity and broader substrate scope.1f, 1h-k, 1n, 1o, 2a, 2b, 4b-d, 5 2

Figure 1: Osmium-Catalyzed Sharpless Olefin Aminohydroxylation1l

Since the amino-oxygenation discovered by Sharpless, broadly applicable amino- oxygenation methods have been limited. However, Sorenson and coworkers recently reported a palladium-catalyzed ring-forming amino-oxygenation of alkenes (Figure 2).1h They showed how activation of an alkene by Pd(OAc)2 in the presence of Bu4NOAc generates an amino-palladated intermediate which, followed by a mild oxidation using PhI(OAc)2 reductively eliminates to afford the amino-oxygenated products.

Figure 2: A Selected Example of Palladium-Catalyzed Aminoacetoxylation of Alkenes1h

Sanford and Desai disclosed a diastereoselective conversion of 3-alken-1-ols into 3- aminotetrahydrofurans using a PdII/PdIV catalytic cycle.1a They demonstrated how a terminal alkenyl substrate and phthalimide in the presence of a catalytic amount of Pd(OAc)2 and AgBF4 and iodine reagent produces the 3-amidotetrahydrofuran product (Figure 3). This diastereoselective reaction was found to proceed through an σ-alkyl Pd species, followed by an 3 intramolecular oxidative functionalization to afford tetrahydrofuran products with excellent diastereoselectivity.

Figure 3: A Selected Example of Palladium-Catalyzed Olefin Amino-Oxygenation for the Synthesis of Tetrahydrofurans1a `

Despite the success of these palladium-catalyzed strategies, mild and earth abundant metal-catalyzed alternatives are needed for large scale industrial amino-oxygenation processes.

Chemler and coworkers demonstrated how copper catalyzes an intramolecular amino- oxygenation reaction which accesses a variety of chiral pyrrolidines and indolines. This copper(II)-catalyzed asymmetric amino-oxygenation proceeds through the cyclization of N- sulfonyl-2-allyl aniline substrate and subsequent nucleophilic attack of TEMPO to afford the amino-oxygenated indoline product (Figure 4). The use of a chiral bisoxazoline bi-dentate ligand provided the highest asymmetric induction. The discovery of TEMPO as an oxygen species as well as a promotor for copper turnover [Cu(I) to Cu(II)] rid the use of external oxidants, such as

MnO2 peripherally increased the yield and enantioselectivity.

Figure 4: Copper-Catalyzed Asymmetric Intramolecular Amino-Oxygenation of Alkenes1i

Another copper-catalyzed amino-oxygenation method with a broad substrate scope was reported by Tehshik Yoon and coworkers in 2007.1j In their initial studies they hypothesized a sulfonyl oxaziridine reagent in the presence of a copper catalyst would provide sufficient epoxidation of styrene. They observed the regioselective formation of aminal instead of the expected epoxide (Figure 5). They expanded the substrate scope to numerous styrenyl alkenes and four examples of non-styrenyl alkenes. It was proposed that the reaction proceeds by Lewis acid activation [Cu(TFA)2] of the oxaziridine and nucleophilic attack by the alkene. Subsequent ring closer onto the resultant benzylic cation affords the amino-oxygenated product. Two advantages of this method were its high regioselectivity and its applicability to a broad range of alkenes. However, a long reaction time and less than desirable diastereomeric ratios (dr) of cis- and trans-amino-oxygenated products were reported as well. Additionally, the poor reactivity of alkenes unable to sufficiently stabilize the carbocation intermediate, such as 1-hexene, gave low yield (15%).

Figure 5: Copper(II)-Catalyzed Amino-Oxygenation of Alkenes with Sulfonyl Oxaziridines1j

Yoon and Williamson expanded upon the use of oxaziridine reagents in metal-catalyzed

1k amino-oxygenation reactions. An iron(III)-salt [Fe(acac)3] as catalyst and a nosyl oxaziridine reagent in the presence of a variety of alkenes produced the opposite amino-oxygenated regioisomer than reported in the copper(II)-catalyzed method (Figure 6). Several improvements of this Fe(III) method over the previously reported Cu(II) were demonstrated. First, the substrate scope was expanded to include dienes, 1,1-disubstituted alkenes, and en-ynes. Second, the reaction time was reduced significantly and the dr of products showed marked improvement. 5

Lastly, 1-hexene was shown to have higher reactivity under the iron-catalyzed condition (57% yield compared with 15% under copper-catalyzed conditions).

Figure 6: Iron-Catalyzed Amino-Oxygenation of Alkenes with Sulfonyl Oxaziridines1k

Yoon and coworkers’ copper(II)- and iron(III)-catalyzed amino-oxygenation methods provide means to access 1,2-aminoalcohols in either regioisomeric form. Later, Williamson and

Yoon reported an asymmetric version, using iron triflimide and a chiral ligand.2b They observed that the amino-oxygenated products in all cases were formed with excellent cis diastereoselectivity. Through a controlled experiment they discovered that the high diastereoselectivity is a consequence of a selective reaction with one of the enantiomers of the racemic oxaziridine.1k

Despite Chemler, Yoon, and other researchers’ important discoveries, nonprecious metal- catalyzed alkene amino-oxygenation methods with a broader substrate scope and regio- and stereoselectivity complementary to known methods are needed for practical use in industry. To date, an intermolecular alkene amino-oxygenation mediated by an iron nitrenoid intermediate has not been reported. Unlike Yoon’s reaction involving the oxaziridine reagent acting in a kinetic resolution fashion, the generation of an iron nitrenoid allows for greater ease in manipulating chemo-, region-, and stereoselectivity through the use of different ligands.

However, unlike other metal nitrenoids, one drawback to an iron nitrenoid mediated N-atom transfer is its tendency to proceed through radical pathways.

We recently reported an iron-catalyzed intramolecular amino-oxygenation reaction

(Figure 7).4d Our mechanistic studies suggested that an iron nitrenoid is a potential intermediate 6 in this stereoconvergent transformation and the stereoselectivity is changed with different N- based ligands. With this success we focused on expanding this method to an intermolecular version.

Figure 7: Iron(II)-Catalyzed Intramolecular Amino-Oxygenation of Alkenes with Functionalized Hydroxylamines6

1.2 Fe(II)-Catalyzed Intermolecular Aminofluorination of Alkenes

Molecules containing fluorine atoms benefit from increased lipophilicity and better biological activities than their corresponding non-fluorinated analogs. As a consequence, fluorine containing drugs make up 20% of all pharmaceutical drugs.7 Amongst popular fluorinated pharmaceuticals are the anti-depressant fluoxetine and the cholesterol-lowering drug atorvastatin

Figure 8: Representative Pharmaceuticals with Fluorines7

(Figure 8). Fluorine’s utility in medicinal chemistry has led to the development of many metal- catalyzed synthetic methods for the incorporation of fluorine atoms. In addition to deoxyfluorination protocols, an extensive amount of research into sp2 and sp3 C‒F bond formation has been developed.8 Recently, several examples of selective alkene aminofluorination have emerged. 7

Guosheng Liu et al developed a palladium-catalyzed intramolecular aminofluorination of unactivated alkenes whereby an alkene undergoes Pd(II)-mediated trans-aminopalladation.9 A postulated Pd(II)-intermediate undergoes an oxidation step by PhI(OPiv)2/AgF. Direct reductive elimination from the Pd(IV)-intermediate affords the aminofluorinated product in 84% yield

(Figure 9). This highly regioselective intramolecular aminofluorination method represents a very efficient method for the generation of fluoro-containing cyclic amines. The same author later reported a

Figure 9: Palladium-Catalyzed Intramolecular Aminofluorination of Alkenes9

Pd(II)-catalyzed intermolecular aminofluorination of styrenes using N-fluorobenzenesulfonimide

(NFSI) as a source of nitrogen and fluorine (Figure 10).10 Two key features of this method include the possible presence of a fluoropalladium-intermediate and the requirement of bi- dentate nitrogen based ligands. Under optimal conditions, aminofluorination product was obtained in good yield with some difluoroamine observed as well. Although mechanistically interesting, the practical use of this method remains limited as electron deficient styrenes are not well tolerated under the reaction conditions. Generally, the substrate scope is limited to only styrenyl alkenes.

Figure 10: Palladium-Catalyzed Intermolecular Aminofluorination of Styrenes Using NFSI10

Li and coworkers reported a silver-catalyzed radical aminofluorination of alkenes.11 A combination of Ag(I)-catalyst and Selectfluor in the presence of alkene produced the aminofluorinated product in moderate to good yield (up to 90%) (Figure 11). The Ag(I) catalyst generates amidyl radicals and also serves as a fluorine atom transfer reagent.

Figure 11: Silver-Catalyzed Radical Intramolecular Aminofluorination of Alkenes in Aqueous Media11

Toste and coworkers recently reported an asymmetric 1,4-aminofluorocyclization of 1,3- diene using a phase transfer catalyst and Selectfluor as the electrophilic fluorine source (Figure

12).12 This mild organocatalyzed aminofluorination allows for the fluorination of previously

Selectfluor-incompatible substrates.

Figure 12: Enantioselective Fluoroamination: 1,4-Addition to Conjugated Dienes Using Anionic Phase-Transfer Catalysis12

Despite these important metal-catalyzed aminofluorination methods, a direct iron- catalyzed aminofluorination of alkenes has not yet been reported. Recently our group reported an iron(II)-catalyzed diastereoselective intramolecular aminofluorination of alkenes with Et3N•3HF 9

(Figure 13).4c Fe(II) in the presence of a coordinating ligand catalyzed the aminofluorination of a functionalized hydroxylamine in the presence of XtalFluor-E and Et3N•3HF to afford aminofluorinated products. The reaction readily transforms allylic alcohol derivatives to β-fluoro primary amines and amino acids after simple derivatization. With this success we focused on expanding this method to an intermolecular version.

Figure 13: Iron(II)-Catalyzed Intramolecular Aminofluorination of Alkenes4c

2 EXPERIMENT

2.1 General Information

2.1.1 General Procedures

All reactions were performed in flame-dried round bottom flasks and vials. Stainless steel

needles and cannula were used to transfer air- and moisture-sensitive liquids. Flash

chromatography was performed using silica gel 60 (230-400 mesh) from Sorbent

Technologies.

2.1.2 Materials

Commercial reagents were purchased from Sigma Aldrich, Fluka, EM Science, and

Lancaster and used as received. All solvents were used after being freshly distilled unless

otherwise noted.

2.1.3 Instrumentation

The 1H, 13C, and 19F NMR spectra were recorded on a Bruker UltraShield-400 (400

1 MHz) spectrometer. H chemical shifts are referenced to the residual proton of CDCl3 at

13 7.26 ppm. C chemical shifts are referenced to the carbon atom of CDCl3 at 77.0 ppm.

19 F chemical shifts are referenced to the fluorine atom of FC6H4OCH3 at -124.44 ppm.

Abbreviations: s = singlet, br = broadened, d = doublet, t = triplet, q = quartet, m =

multiplet.

The mass spectra were obtained at the Georgia State University mass spectrometry

facility and recorded using a Micromass Platform II single quadruple instrument. Infrared

(IR) spectra were obtained using a Perkin Elmer Spectrum 100 FT-IR spectrometer.

Abbreviations of absorption strength: s = strong, m = medium, w = weak. 11

2.1.4 Other Abbreviation Used

EtOH‒ethanol, EtOAc‒ethyl acetate, THF‒tetrahydrofuran, MeOH‒methanol, Et2O‒

diethyl ether, CH2Cl2‒dichloromethane, TEA‒triethylamine, MeCN‒acetonitrile, MS‒

molecular sieves, CDI‒1,1′-carbonyldiimidazole, Troc‒2,2,2-trichloroethoxycarbonyl,

DCC‒N,N′-dicyclohexylcarbodiimide, TLC‒thin layer chromatography, Et3N•3HF‒

triethylamine trihydrofluoride

2.2 Iron(II)-Catalyzed Alkene Amino-Oxygenation

2.2.1 Preparation of Acyloxyl Carbamates (2a and 2b)4b

Procedure for the synthesis of N-hydroxyl tert-butyl carbamate:

N-hydroxyl tert-butyl carbamate was prepared from hydroxylamine hydrochloride with Boc2O, according to a known procedure. A suspension of NH2OH•HCl (9.6 g, 0.14 mol) and K2CO3 (7.2 g, 0.07 mol) in 60 mL of Et2O and 2 mL of H2O was stirred for about 1 h at room temperature with evolution of CO2 gas. A solution of Boc2O (20.0 g, 92 mmol) in 40 mL of Et2O was then added drop-wise at 0 °C and the suspension was stirred at room temperature for 12 h. The organic phase was decanted and the solid was washed with 30 mL of Et2O two times and the organic layers were combined and concentrated. Recrystallization from a cyclohexane/toluene mixture afforded the desired product.

To a 250 mL flame-dried round bottom flask equipped with a stir bar, a N-hydroxyl tert-butyl carbamate (20 mmol), 4.01 g of 2,4-dichlorobenzoic acid (21 mmol) and 80 mL of anhydrous

CH2Cl2 were added. The flask was cooled to -15 °C. 4.53 g of DCC (22 mmol, dissolved in 20 mL of anhydrous CH2Cl2) solution was then added drop-wise. The reaction mixture was stirred at the same temperature for additional 30 min until the N-hydroxyl tert-butyl carbamate was fully consumed. The white precipitate (N,N′-dicyclohexylurea) was removed by filtration and the filtrate was concentrated in vacuo and dissolved again in 30 mL of Et2O. The solution was cooled to -20 °C for 2 h and filtered again to remove additional precipitate. The organic layer was then concentrated in vacuo and the residue was recrystallized from hexanes and EtOAc to afford corresponding acyloxyl carbamate 2a as a white solid (yield 75%).

Procedure for the preparation of N-hydroxyl trichloroethyl carbamate: A flame-dried 100 mL round bottom flask equipped with a stir bar was charged with 1.78 g of CDI (11 mmol) in 40 mL of anhydrous THF. The suspension was cooled to 0 °C and 0.72 mL of trichloroethanol (10 mmol) was added drop-wise. The mixture was stirred for 1 hour at room temperature. The mixture was then cooled to 0 °C and 1.04 g of NH2OH•HCl (15 mmol) and 0.82 g of imidazole

(12 mmol) were added simultaneously in one portion. The reaction was warmed to room temperature and monitored by TLC until the trichloroethyl imidazole ketone was consumed. The mixture was then filtered and concentrated in vacuo. The residue was dissolved in 40 mL of

EtOAc and washed with 20 mL of aqueous 1 M HCl three times. The organic layer was dried 13

over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography to afford 1.16 g of N-hydroxyl trichloroethyl carbamate as a white solid (73 % yield).

Procedure for the preparation of acyloxyl carbamate 2b: A 250 mL flame-dried round bottom flask equipped with a stir bar was charged with 4.16 g of N-hydroxyl trichloroethyl carbamate

(20 mmol, 1.0 equiv), 2.56 g of benzoic acid (21 mmol, 1.05 equiv) and 80 mL of anhydrous

CH2Cl2. The mixture was cooled to 0 °C and 4.53 g of DCC (22 mmol, 1.10 equiv) dissolved in

20 mL of anhydrous CH2Cl2 was then added drop-wise. The reaction mixture continued stirring at the same temperature until the N-hydroxyl trichloroethyl carbamate was full consumed

(monitored by TLC). The white precipitate by-product, N,N′-dicyclohexylurea, was removed by filtration and the filtrate was concentrated in vacuo and dissolved again in 30 mL of Et2O. The solution was cooled to -40 °C for 2 hours and filtered again to remove additional precipitate. The solution was concentration in vacuo and the residue was recrystallized from hexanes and EtOAc to afford the 4.42 g of the acyloxyl carbamate 2b as a white solid (71 % yield).

2.2.2 Preparation of Nitrogen-based Tri-dentate Ligands

Ligand L1 was synthesized according to a literature procedure:13

Procedure for the preparation of alcohol S1: 14

To flame-dried 100 round bottom flask fitted with a stir bar and reflux condenser was added 3.34 g of 2,6-pyridinecarboxylic acid (20 mmol). The flask was evacuated and backfilled with N2 twice then 30 mL of SOCl2 and 0.2 mL of DMF were added. The reaction was heated to reflux for 3 h. The yellow solution was cooled to room temperature and concentrated in vacuo to afford the 2,6-pyridinedicarbonyl dichloride as a white solid which was used directly in the next step.

Under N2 atmosphere a solution of 6.23 g of 2-amino-2-methyl-1-propanol (70 mmol) and 10.1 g of Et3N (100 mmol) in 70 mL of CH2Cl2 were added 3.34 g of 2,6-pyridinedicarbonyl dichloride dissolved in 30 mL of CH2Cl2 drop-wise at 0 °C. After the reaction mixture was stirred at room temperature for 16 h, the pink colored suspension was poured onto 60 mL of ice-water which was then extracted with 60 mL of CH2Cl2 three times. The combined organic layers were washed with 20 mL of water and 20 mL of brine and then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified through a silica gel flash column to afford 3.53 g of product S1 (57 % yield over 2 steps).

A 100 mL round bottom flask fitted with a stir bar and reflux condenser was charged with 3.09 g of S1 (10 mmol) dissolved in 40 mL of toluene. 4.35 mL of SOCl2 (60 mmol) was added via a syringe and the mixture was heated to reflux. The reaction was monitored by TLC. When S1 disappeared the reaction was cooled to 0 °C and quenched with 30 mL of saturated NaHCO3.

The organic layer was extracted with 30 mL of EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was filtered through a short silica pad with EtOAc as an eluent and concentrated. The resultant oil was dissolved in 50 mL of anhydrous THF under N2 atmosphere and cooled to 0 °C. In three portions, 2 g of NaH (50 mmol, 60% in mineral oil) was added to the solution and then warmed to room temperature. The reaction was monitored by TLC. Once the starting material was fully 15 consumed, the reaction mixture was filtered through a Celite pad, concentrated and purified through a silica gel flash column to provide 2.02 g of ligand L1 as a white solid (74% yield over two steps).

Ligand L2 was synthesized from 2-cyanophenanthroline using a modified literature procedure to obtain higher overall yield14:

A flame-dried 100 mL round bottom flask equipped with a stir bar was charged with 4.10 g of 2- cyanophenathroline dissolved in 60 mL of anhydrous methanol. 108 mg of NaOMe (2 mmol) was added to the reaction. The reaction mixture was stirred at room temperature and monitored via TLC until the starting material was fully consumed. The reaction was then quenched with

0.22 mL of acetic acid and the mixture was filtered and concentrated in vacuo. The residue was dissolved in 100 mL of toluene (instead of benzene) together with 1.87 g of 2-amino-2-methyl-1- propanol (21 mmol) and 380 mg of p-TsOH•H2O (2 mmol). The reaction mixture was heated to reflux with a Dean-Stark apparatus until the intermediate was fully consumed. After the reaction was cooled to room temperature, the solvent was removed in vacuo and the residue was purified through a silica gel flash column to afford 3.6 g of L2 as a white solid (65% yield). 16

2.2.3 Procedure for the Gram-Scale Iron-Catalyzed Glycal Amino-Oxygenation

To a flame-dried 3-dram vial equipped with a stir bar were added 277 mg of Fe(NTf2)2 (0.45 mmol) and 123 mg of L1 (0.45 mmol). The vial was evacuated and backfilled with N2 three times and 3 mL of anhydrous CH2Cl2 and 1 mL of MeCN were added via syringes and the mixture was stirred at room temperature for 20 min. To a flame dried 25 mL round bottom flask equipped with a stir bar were added 800 mg of freshly activated 4Å molecular sieves, 1.03 g of functionalized glycal (3.0 mmol) and 1.38 g of 2a (4.5 mmol). The flask was also evacuated and backfilled with N2 three times and then 6.0 mL of anhydrous CH2Cl2 was added via a syringe.

Both solutions were degassed with brief evacuation and backfilling with N2 twice. The catalyst solution was then added through a syringe pump over 30 min to the flask at -30 °C. The reaction was kept stirring at -30 °C for 1.5 h after the addition was complete. The reaction was quenched with 6 mL of saturated NaHCO3 aqueous solution and stirred vigorously for 10 min. The organic layer was separated and the aqueous layer was extracted with 6 mL of CH2Cl2 two times followed by 6 mL of EtOAc two times. The combined organic layers were dried over anhydrous

Na2SO4 and concentrated in vacuo. 8 was isolated through a silica gel flash column as colorless oil (Et2O/hexanes: from 5‒20%).

(4aR,6R,7R,8R,8aR)-7-((tert-Butoxycarbonyl)amino)-2,2-dimethyl-8-

((triisopropylsilyl)oxy)hexahydropyranol[3,2-d][1,3]dioxin-6-yl 2,4-dichlorobenzoate (AO2) 17

20 -1 Yield: 1.24 g (1.92 mmol, 64%); [α]D = +88.4 (c 1.0, CH2Cl2). IR vmax (ATR, neat)/cm : 2942

1 (m), 2866 (m), 1724 (s), 1585, 1499, 1368, 1269, 1130 (s), 982 (s). H NMR (400 MHz, C6D6) δ

7.41 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 1.7 Hz, 1H), 6.77 (brd, J = 2.5 Hz, 1H), 6.55 (d, J = 8.4 Hz,

1H), 4.87 (d, J = 8.7 Hz, 1H), 4.38 (t, J = 8.2 Hz, 1H), 4.18 (t, J = 9.4 Hz, 1H), 3.88 (td, J = 10.1

5.3 Hz, 1H), 3.70 (dd, J = 10.6, 5.1 Hz, 1H), 3.47 (t, J = 10.6 Hz, 1H) 3.39 (t, J = 9.3 Hz, 1H),

13 1.42 (s, 9H), 1.36 (s, 3H), 1.21 (d, J = 9.1 Hz, 21H), 1.19 (s, 3H). C NMR (100 MHz, CDCl3) δ

163.6, 155.0, 139.4, 134.5, 133.8, 131.3, 127.5, 99.7, 94.3, 80.0, 74.6, 71.3, 66.5, 62.0, 55.2,

+ 28.9, 28.3, 18.8, 18.3, 18.2, 12.8. HRMS (ESI, m/z): calcd for C30H46Cl2NO8Si⁻, [M – H ],

646.2375, found 646.2352.

Synthetic Procedure for the Gram Scale Iron-Catalyzed Styrene Amino-Oxygenation

To a flame-dried 3-dram vial equipped with a stir bar were added 177 mg of Fe(OTf)2 (0.5 mmol) and 137 mg of L1 (0.5 mmol). After the vial was evacuated and backfilled with N2 three times, 5 mL of CH2Cl2 and 1 mL of MeCN were added via syringes and the mixture was stirred at room temperature for 20 min. To a flame dried 100 mL round bottom flask equipped with a stir bar were added 3 g of freshly activated 4Å molecular sieves and 3.82 g of acyloxyl carbamate 2b (10 mmol). The flask was evacuated and backfilled with N2 three times before 45 mL of anhydrous CH2Cl2 was added via a syringe. Both solutions were degassed with brief evacuation and backfilled with N2 twice. Subsequently, 1.26 mL of freshly distilled styrene (11 mmol) was added to the flask and the catalyst solution was added through a syringe pump over

30 min at -15 °C. The reaction was kept stirring for 1.5 h at the same temperature and quenched 18

with 30 mL of NaHCO3 aqueous solution. The organic layer was separated from the aqueous phase, which was extracted with 30 mL of CH2Cl2 two times followed by 30 mL of EtOAc two times. The combined organic layers were concentrated in vacuo. The residue (a mixture of 3 and

4) was dissolved in 40 mL of THF/H2O (3:1) mixed solvent and cooled to 4 °C. After the addition of 1.9 g of p-TsOH•H2O (10 mol), the reaction was stirred at the same temperature and monitored by TLC until 3 was consumed (~1 h). The reaction mixture was then concentrated in vacuo, treated with 50 mL of NaHCO3 aqueous solution and extracted with 40 mL of EtOAc three times. The organic layers were concentrated in vacuo and the residue was dissolved again in 40 mL of THF/MeOH/H2O (2:2:1) mixture. After adding 0.6 g of LiOH (25 mmol), the mixture was stirred at room temperature for 3 h and then quenched with 25 mL of HCl (1.0 M).

After removal of THF and MeOH in vacuo, the aqueous phase was extracted with 30 mL of

EtOAc three times. The combined organic layers were dried over anhydrous Na2SO4 and concentrated 5 was isolated through a silica gel flash column (acetone/hexanes from 10‒33%).

5-Phenyloxazolidin-2-one15

Yield: 1.22 g (7.47 mmol, 75% overall yield). It is a known compound and the characterization is in accordance with the literature precedent.

Synthetic Procedure for the Gram-Scale Iron-Catalyzed Indene Amino-Oxygenation

To a flame-dried 3-dram vial equipped with a stir bar were added 615 mg of Fe(NTf2)2 (1.0 mmol) and 273 mg of L1 (1.0 mmol). After the vial was evacuated and backfilled with N2 three 19

times, 7.5 mL of CH2Cl2 and 2.5 mL of MeCN were added via syringes and the mixture was stirred at room temperature for 20 min. To a flame dried 100 mL round bottom flask equipped with a stir bar were added 3 g of freshly activated 4Å molecular sieves and 3.82 g of acyloxyl carbamate 2b (10 mmol). The flask was evacuated and backfilled with N2 three times before 40 mL of anhydrous CH2Cl2 was added via a syringe. Both solutions were degassed with brief evacuation and backfilled with N2 twice. Subsequently, 1.28 mL of freshly distilled indene (11 mmol) was added to the flask and the catalyst solution was added by syringe pump over 30 min at -15 °C. The reaction was kept stirring for 0.5 h at the same temperature and quenched with 30 mL of NaHCO3 aqueous solution and stirred vigorously for an additional 10 min. The organic layer was separated from the aqueous phase, which was extracted with 30 mL of CH2Cl2 two times and 30 mL of EtOAc two times. The combined organic layers were dried over anhydrous

Na2SO4 and concentrated in vacuo. 10 was isolated as a white solid (dr > 20:1) through a silica gel flash column (acetone/hexanes from 2‒10%).

2-(((2,2,2-Trichloroethoxy)carbonyl)amino)-2,3-dihydro-1H-inden-1-yl 2,4- dichlorobenzoate

-1 Yield: 3.54 g (7.10 mmol, 71%); m.p. 130‒131 °C. IR vmax (ATR, neat)/cm : 3352 (w), 2952

1 (w), 1717 (w), 1853 (m), 1515 (m). H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 1H), 7.64

(d, J = 7.4 Hz, 1H), 7.48 (s, 1H), 7.41‒7.35 (m, 1H), 7.31 (d, J = 9.8 Hz, 3H), 6.35 (d, J = 5.5

Hz, 1H), 5.66 (d, J = 8.6 Hz, 1H), 4.93‒4.66 (m, 3H), 3.38 (dd, J = 15.4, 7.4 Hz, 1H), 3.08 (dd, J

13 = 15.5, 8.2 Hz, 1H). C NMR (100 MHz, CDCl3) δ 164.5, 154.2, 141.5, 138.7, 138.3, 134.3, 20

133.0, 131.0, 130.1, 128.4, 127.5, 127.2, 127.1, 125.0, 95.4, 77.9, 74.7, 53.8, 36.9. HRMS (ESI,

- m/z): calcd for C19H14Cl6NO4- [M + Cl ], 529.9059, found 529.9054.

2.3 Iron(II)-Catalyzed Alkene Aminofluorination

2.3.1 Synthesis of Acyloxyl Carbamate 2d

Procedure for the preparation intermediate I: A flame-dried 100 mL round bottom flask equipped with a stir bar was charged with 1.22 g of benzoic acid (10 mmol) in 40 mL of anhydrous

CH2Cl2. The suspension was cooled to 0 °C and 1.78 g of CDI (11 mmol) was added in three portions. The mixture was stirred at 0 °C until all starting material was consumed. 1.04 g of

NH2OH•HCl (15 mmol) was added in one portion. The reaction was warmed to room temperature and monitored by TLC until the benzoyl imidazole ketone was consumed. The mixture was then warmed to room temperature. The reaction mixture was then washed with H2O several times and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo

(water bath not exceeding 30 °C). The crude product was purified by flash chromatography to afford 603 mg of clear oil product I (40 % yield). It was then stored at -78 °C until taken to the next step.

Procedure for the preparation of acyloxyl carbamate 2d: A flame-dried 100 mL round bottom flask equipped with a stir bar was charged with 739 mg of hexafluoro-2-propanol (4.4 mmol) in

25 mL of anhydrous THF. The suspension was cooled to 0 °C and 784 mg of CDI (11 mmol) 21 was added in three portions. The mixture was stirred at 0 °C until all starting material was consumed (confirmed by 19F NMR). 603 mg of I (4.4 mmol) in anhydrous THF was added dropwise via syringe. The reaction was warmed to room temperature and monitored by TLC until the hexafluoroisopropoxyl imidazole ketone was consumed. The mixture was then warmed to room temperature. The reaction mixture was quenched with 20 mL of 1.0 M HCl and extracted with 30 mL of Et2O three times. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography

(hexanes/EtOAc) and recrystallized from hexanes and EtOAc to afford 655 mg of acyloxyl carbamate 2d as a white solid (45% yield).

2.3.2 General Procedure A for the Iron-Catalyzed Alkene Aminofluorination

To a flame-dried 2-dram vial equipped with a stir bar were added 10.2 mg of Fe(NTf2)2 (0.015 mmol) and 4.5 mg of L1 (0.015 mmol). After the vial was evacuated and backfilled with N2 three times, 1.0 mL of CH2Cl2 and 0.05 mL of MeCN were added via syringes and the mixture was stirred at room temperature for 20 min. To a flame dried 2-dram vial equipped with a stir bar were added 40 mg of freshly activated 4Å molecular sieves and 0.12 mmol of acyloxyl carbamate. The vial was evacuated and backfilled with N2 three times before 0.5 mL of anhydrous CH2Cl2 was added via a syringe. To another flame dried 2-dram vial equipped with a stir bar was added XtalFluor-E (2.5‒5.0 equiv). After evacuation and backfilling with N2 three times, 1.0 mL of anhydrous CH2Cl2 was added via a syringe. All three solutions were degassed with brief evacuation and backfilled N2 two times. Et3N•3HF (1.5‒3.0 equiv) was added to the vial containing XtalFluor-E (fluorine source). Subsequently, 0.1 mmol alkene was added to the vial containing the acyloxyl carbamate. The substrate vial was lowered to -30 °C and the fluorine source (1 mL) was added in one portion followed by addition of the catalyst solution via a 22 syringe pump over 20 min at -30 °C. The reaction was kept stirring for 2.0 h at the same temperature and then warmed up to -15 °C. The reaction was quenched with 2.0 mL of NaHCO3 aqueous solution. The organic layer was separated from the aqueous phase, which was extracted with 3.0 mL of CH2Cl2 two times and 3.0 mL of EtOAc two times. The combined organic layers were concentrated in vacuo. The product was obtained through flash silica gel column.

2.3.3 General Procedure B for the Iron-Catalyzed Alkene Aminofluorination

Under an inert atmosphere, 40 mg of freshly activated 4 Å molecular sieves was weighed into a

2-dram vial equipped with a stir bar. 0.01 mmol of Fe(X)2•L1 solid complex was added. After the vial was evacuated and backfilling with N2 two times, 0.5 mL of anhydrous CH2Cl2 was added via a syringe and cooled to -30 °C. To another vial equipped with a stir bar and 40 mg of 4

Å molecular sieves, was added XtalFluor-E (2.5‒5.0 equiv) and Et3N•3HF (1.5‒3.0 equiv)

(fluorine source). After the vial was evacuated and backfilled with N2 two times, 1.0 mL of anhydrous CH2Cl2 was added via a syringe. To another dry 2-dram vial was added 0.12 mmol of acyloxyl carbamate (2). After the vial was evacuated and backfilled twice with N2, 0.5 mL of anhydrous CH2Cl2 was added via a syringe. 0.1 mmol of alkene was added to the vial containing

Fe(X)2•L1 solid complex followed by the addition of the fluorine source in one portion via syringe and the dropwise addition of 2 via a syringe. The reaction was quenched with 2.0 mL of

NaHCO3 aqueous solution. The organic layer was separated from the aqueous phase, which was extracted with 3.0 mL of CH2Cl2 two times followed by 3.0 mL of EtOAc two times. The combined organic layers were concentrated in vacuo. The product was obtained through flash silica gel column.

*NMR spectra for the acyloxyl carbamate 2d and the aminofluorinated products can be found in the Appendix section. 23

3 RESULTS AND DISCUSSION

3.1 Fe(II)-Catalyzed Amino-Oxygenation of Alkenes

Previous mechanistic studies of the iron-catalyzed intramolecular amino-oxygenation

suggested that an iron nitrenoid was a possible reactive intermediate. We hypothesized that

a balance between reactivity and stability of the generated iron nitrenoid intermediate is

needed in order for the intermolecular amino-oxygenation reaction to be effective. Our

initial attempts to develop an intermolecular alkene amino-oxygenation with the catalyst

previously used for the intramolecular amino-oxygenation failed due to a lack of

reactivity. We explored a variety of different iron catalysts and amination reagents. In

doing so entirely new procedures for the intermolecular amino-oxygenation method were

discovered. This developed method tolerates a broad range of alkenes including

cyclopentadienes, enol ethers, and glycals: all incompatible with previous amino-

oxygenation methods.

Styrene 1 was chosen as a representative substrate for determining which iron catalysts and

amination reagents were optimal for the reaction (Table 1). Standard Schlenk-line

techniques were used to perform the reactions outside of the glovebox and freshly

activated molecular sieves were used to remove moisture. Initial screenings suggested that

iron(II)-N,N’-bi-dentate ligand complexes are ineffective for the intermolecular reaction

while nitrogen-based tri-dentate ligands, including an achiral bisoxazoline PyBOX ligand

L1 and a phenanthroline-oxazoline hybrid ligand L2 were effective. The amino-

oxygenation of 1 afforded both the alkyl oxazoline 3 and a protected amino alcohol 4 with

good to excellent combined yields and regioselectivity complementary to osmium-based 25 methods. Amino-oxygenation products, 3 and 4 can readily be converted into the oxazolidinone 5 through the same hydrolytic procedure. We

Table 1: Iron-Ligand Complex and Acyloxyl Carbamate Relationship for the Amino-Oxygenation of Styrene

a b Molecular sieves were used to remove deleterious moisture. Reactions were carried out under N2 in 1 h and

then quenched with saturated NaHCO3 solution. The crude mixture was first subjected to an acidic condition

with TsOH (1.0 equiv) and then to a basic condition with LiOH (2.5 equiv) to afford 5. cConversion was

measured by GC. dIsolated yield. eAn oxazolidinone was isolated directly without the additional step (41%

yield).

explored a range of bench stable acyloxyl carbamates in an effort to optimize the reactivity of styrene. The acyloxyl carbamates were prepared from NH2OH•HCl (Figure 14). The weakening of the N‒O bond was induced by the attachment of electronegative moieties on

either side which in the presence of a Lewis acid such as Fe(OTf)2 cleaved the bond 26 generating the iron nitrenoid. Acyloxyl carbamates 2a‒c all accomplished the amino- oxygenation of styrene but the more electrophilic ones (2b and 2c versus 2a, entries 1‒3) enhanced the overall yield. The combination of Fe(OTf)2‒L1 and acyloxyl carbamate 2b provided the best overall yield. The less bulky Fe(OTf)2‒L2 complex was found to be less reactive and complementary reactivity was seen with the Fe(NTf2)2‒L1 complex (entries 4 and 5).

Figure 14: Synthesis of Acyloxyl Carbamats 2a-c

This amino-oxygenation method was found to tolerate a broad range of alkenes (Table 2).4b

We examined a number difficult substrates which have proven difficult for other amino- oxygenation methods and iron-based amination approaches. Allyl silane was examined because it is a challenging substrate for known iron-based amination methods. The amino- oxygenation was accomplished using the most electronegative acyloxyl carbamate 2c with excellent regioselectivity (entry 3, 78% yield). Enol ethers, another difficult substrate, gave corresponding amino alcohols with good yield and dr (entries 4 and 5, 72 and 77%; up to 27 dr > 20:1). Expansion to a fully functionalized glycal proceeded smoothly under a modified amino-oxygenation condition with less oxidative 2a affording 2-amino-α-sugar 8 with a decent yield and excellent dr (entry 6, 63% yield and dr >20:1 at both C1 and C2 positions). Several other alkenyl substrates were shown to be reactive using Fe(X)2 (X =

OTf or NTf2) and the bisoxazoline PyBOX ligand L1.

A synthetically attractive amino-oxygenation of indene (entry 7) gave the corresponding 2- amino-indanol in good yield and excellent dr (71%, dr > 20:1). An en-yne proved to be an excellent regioselective amino-oxygenation substrate (entry 8, 62% yield).

A number of dienyl substrates were also amino-oxygenated with moderate to good yield

(entry 9‒11, 54‒84%). A 1,1-disubstitued alkene and an unactivated alkene showed moderate reactivity under the iron-catalyzed amino-oxygenation condition (entries 12 and

13, 51 and 48% yield, respectively). 28

Table 2: Iron-L1 Catalyzed Amino-Oxygenation Substrate Scope 29

a Reactions were carried out under N2 atmosphere in 2 h unless stated otherwise.

bIsolated yield. cReaction time: 1 h. dThe crude mixture was treated with TsOH and LiOH.

eReaction temperature: -40 °C. fCatalyst loading: 20 mol%; reaction temperature: 0 °C.

g h i Reaction time: 12 h. Reaction temperature: -30 °C. Fe (NTf2)2: 15 mol%; L1: 15 mol%.

j Catalyst loading: 15 mol% Fe(OTf)2.

The iron-catalyzed amino-oxygenation of styrene, a glycal, and indene were conducted on a gram-scale to demonstrate the practical use of this method (entry 1, 6, and 7, respectively). The reaction of 1.14 g of styrene with 3.81 g of acyloxyl carbamate produced the oxazolidinone AO1 in good isolated yield (75 % over two steps) (A, Figure

Figure 15: Practical Synthetic Procedure: Iron-Catalyzed Amino-Oxygenation of Representative Alkenes

15). The gram-scale amino-oxygenation of a glycal was demonstrated for its relevance in glycol-biology where 2-amino glycosides are needed. The amino-oxygenation was 31 performed successfully to afford AO2 without erosion of yield or dr (B). Additionally, cis-

2-amino indanol, a valuable synthetic building block was synthesized by a gram-scale amino-oxygenation procedure to afford AO3 without erosion of yield or dr (C). The gram- scale amino-oxygenations were highly successful with only a small loss of yield for the amino-oxygenation of styrene. This demonstrated the potential for this amino-oxygenation method to find practical use in industrial applications.

Another unique characteristic of this iron-catalyzed method is its ability to tolerate substrates with labile C‒H bonds. The amino-oxygenation of trans-β-methyl styrene using

Fe(OTf)2 and ligand L1 as the catalytic complex yielded undesirable hydrogen abstraction products (Figure 16). We hypothesized that the substrate was undergoing hydrogen-

Figure 16: Iron-L1 Catalyzed Amino-Oxygenation of trans-beta-Me-Styrene

abstraction due to the bulky coordination of the iron-L1 catalyst. To test this, a smaller phenantholine-oxazoline hybrid ligand L2 was used, the preparation of which requires a four step procedure (Figure 17)14. Initial oxidation of phenanthroline by hydrogen peroxide in AcOH afforded the yellow-brown solid, N-oxide phenanthroline J. Activation of J by 32 benzoyl chloride in the presence of trimethylsilyl cyanide afforded a light brown precipitate of 2-cyano-phenanthroline K. To obtain ligand L2, K was subjected to esterification conditions using sodium methoxide (NaOMe) in methanol. After 20 min the imide intermediate was obtained in quantitative yield as a yellow oil. In 1,2- dichloroethane, the imide intermediate and amino alcohol, 1-amino-2-methyl-2-propanol, were heated under reflux until the cyclization was completed to afforded ligand L2.

Figure 17: Synthesis of Phenanthroline-Oxazoline Hybrid Ligand (L2)

The new iron-L2 catalyst promoted the amino-oxygenation of trans-β-methyl styrene and cis-β-methyl styrene in good combined yield and better regioselectivity than the Sharpless osmium-based method for both the trans- and cis-β-methyl styrene (Figure 18)1l.

Figure 18: Iron-L2 Catalyzed Amino-Oxygenation of trans- and cis-beta-Me-Styrene

The Fe(OTf)2‒L2 complex exhibited improved compatibility with cyclopentadiene as well as other substrates with similar reactivity (Table 3). The combination of Fe(OTf)2‒L2 and the less oxidative acyloxyl carbamide 2a produced the oxazolidinone of cyclopentadiene with decent yield and excellent dr (entry 1, dr >20:1). Similarly cyclohexadiene was efficiently converted to its corresponding oxazolidinone under the same condition. A regioselectivity complementary to the Sharpless amino-oxygenation of cyclohexadiene was observed (entry 2). Lastly, 1,3-decadiene and 2,3-dimethyl-buta-1,3-diene were transformed into their corresponding oxazolidinones in good yield (entries 3 and 4). 34

Table 3: Iron-L2 Catalyzed Amino-Oxygenation Substrate Scope

a Reactions were carried out under N2 atmosphere in 2 h unless stated otherwise.

bIsolated yield.

Through a series of controlled experiments we were able to formulate a working mechanistic hypothesis (Figure 19).4b First, the iron-ligand complex reductively cleaves the N‒O bond of the acyloxyl carbamate reagent 2c, possibly converting it to the iron nitrenoid A. A may then initiate radical amination with an alkenyl substrate 1 to afford radical species B1 with its conformer B2 in equilibrium. Presumably, B1 can be further oxidized by the iron-center to a carbocation B3, which will be rapidly captured by the neighboring carboxylate group there by affording 2.

Alternatively, oxidative carboxylate ligand transfer may directly occur with B2 to afford a protected amino alcohol. Initial electron transfer from B2 to the iron center followed by capturing of the oxidation product B4 by the carboxylate to deliver 3. When the substituent (R3) has a less significant radical-stabilizing effect, B1 and B2 are relatively short-lived high energy 35 species; thereore the oxidative neighboring group participation through B1 may be favored to afford 2. However, when the radical species is strongly stabilized by the substituent and relatively long-lived, the ligand transfer from the iron-center through B2 may become the dominant pathway to afford 3.

Figure 19: Working Mechanistic Hypothesis for the Iron-Catalyzed Amino-Oxygenation of Alkenes4b

3.2 Fe(II)-Catalyzed Aminofluorination of Alkenes

Given the successes of a previously reported iron(II)-catalyzed intramolecular alkene aminofluorination and intermolecular alkene amino-oxygenation, we proposed that an iron- catalyzed intermolecular alkene aminofluorination was possible (Figure 19). We hypothesized that nitrogen atom transfer from an iron nitrenoid intermediate to an alkenyl substrate followed by fluorine atom transfer from an external source would generate the corresponding aminofluorination products. 36

Figure 20: Previous Iron-Catalyzed Methods

Our initial attempts at the styrene aminofluorination under a series of catalytic conditions yielded the desired aminoflurionated product (a), amino-oxygenated products (b and c) as well as a

MeCN-trapped compound (d) (Figure 20). Several different factors contributed to the product

Figure 21: Preliminary Results of the Iron-Catalyzed Aminofluorination of Styrene

distribution. The ratio of XtalFluor-E/Et3N•3HF is very important as we found that a ratio of

1.7:1 minimizes the generation of amino-oxygenation products b and c while affording the aminofluorination product a in excellent yield. We developed a working hypothesis based upon previous mechanistic studies of the iron-catalyzed alkene amino-oxygenation and a controlled 37 aminofluorination of styrene with and without XtalFluor-E. Presumably, the Lewis acid,

XtalFluor-E traps the carboxylate nucleophile (f) generated from N‒O bond cleavage of 2 while an iron nitrenoid e is generated (Figure 21).16

Figure 22: Working Hypothesis of N-O Bond Cleavage and Interaction with XtalFluor-E

Upon further experimentation it was found that acyloxyl carbamate 2d in the presence of a catalytic amount of iron triflimide (Fe(NTf2)2) and an achiral bisoxazoline PyBOX ligand L1 yielded the aminofluorinated product a in high yield. The highly reactive acyloxyl caramate 2d was synthesized in several steps (Figure 22). Benzoic acid is activated by 1,1′- carbonyldiimidazole at 0 °C. A hydroxylamine nucleophile is generated upon addition of hydroxylamine hydrochloride which subsequently attacks the benzoyl imidazole ketone yielding amine I. The resultant amine decomposes rapidly, so after purification it was stored at -78 °C until needed for the next step. Meanwhile, hexafluoroisopropanol is activated by 1,1′- carbonyldiimidazole in a separate reaction vessel until all starting material was consumed

(confirmed by 19F NMR). Afterwards, amine I was added dropwise and following addition to the hexafluoroisopropanol imidazole ketone, acyloxyl carbamate 2d was formed. 38

Figure 23: Synthesis of Acyloxyl Carbamate 2d

A special approach to the minimization of product d (Figure 20) had to be taken following two observations. A previously obtained X-ray crystal structure of the amino-oxygenation active catalyst suggested that the coordination of one MeCN molecule to the iron center is necessary for catalyst reactivity (Figure 24).4b

Figure 24: Crystal Structure of the Amino-Oxygenation Active Catalyst4b

Furthermore, the homogeneity of the premixed catalyst solution is based upon the amount of

MeCN used as solvent. Knowing that MeCN is necessary for catalyst reactivity and catalyst 39 solubility, two different procedures were developed. The first procedure introduced the premixed catalyst (in CH2Cl2/MeCN mixed solvent (~60:1) as a homogenous red solution through slow addition over 20 min (procedure A). The second procedure sought to minimize use of MeCN as a solvent by premixing Fe(NTf2)2 and L1, concentrating the solution in vacuo to yield a red-orange solid and adding it to the reaction vessel prior to other reagents or styrene (procedure B).

Procedure B gave a significant increase in yield for styrene aminofluorination (78% vs. 88%,

Table 4, entry 1).

Both procedures A and B were tested on a broad range of alkenes (representative examples in

Table 4). Specific use of either procedure A or B is substrate specific. A requirement for procedure A over B for some substrates is beyond our current understanding.

Table 4: Iron-L1 Catalyzed Aminofluorination Substrate Scope

a Reactions were carried out under N2 atmosphere.

b c 19 d e f g Isolated yield. Quantitative F NMR yield. XtalFluor-E/Et3N•3HF = 2.5:1.5; 3.0:1.8; 4.0:2.4; 5.0:3.0

h i j equiv. Alkene used in excess. XtalFluor-E/Et3N•3HF = 1.5+4.0 equiv:0.9+2.4 equiv. catalyst =

Fe(BF4)2•L1 solid complex

Generally, little difference in reactivity was found between electron-deficient and electron-rich styrenes. However, a higher concentration of Et3N•3HF was required for p-ester-styrene and p-

Me-styrene for sufficient aminofluorination (entries 3 and 4, 80% and 82%, respectively). The need for more fluorine source was common amongst other substrates as well.

Less reactive alkenes, which previously have been incompatible with other methods afforded their corresponding aminofluorinated products. Unactivated alkenes such as 1-octene have had little success with other aminofluorination methods, however by increasing catalyst loading (30 mol%), the aminofluorination of 1-octene was accomplished albeit in only moderate yield (entry

11, 60%).

Regioselectivity was evaluated using aliphatic diene and en-yne substrates. The aminofluorination of an aliphatic diene afforded the corresponding 1,2- and 1,4- aminofluorination products in excellent overall yield (entry 8, rr = 2.75:1 and 90%). An en-yne is an excellent substrate for the regioselective aminofluorination (entry 7, 75%).

Furthermore, we evaluated the synthetically attractive indene aminofluorination. Indene was reactive under the conditions however with low dr and good yield (entry 10, dr = 6.1:1, 72%).

While monitoring the reaction significant polymerization of indene was observed which is presumably responsible for a less than optimal yield.

Additionally, isoprene and a 1,1-disubstituted alkene were well tolerated under the aminofluorination conditions, affording products in good yield (entries 9 and 12, 76 and 70%, respectively) 42

An aminofluorination of trans-β-Me styrene was accomplished through the use of phenanthroline-oxazoline hybrid ligand L2 to minimize the hydrogen abstraction products observed under the iron-L1 aminofluorination condition. Much like the previously reported intermolecular trans-β-Me styrene amino-oxygenation, iron-L2 complex minimized hydride abstraction and delivered the desired product in good yield (Figure 23, 65%).

Figure 25: Iron-L2 Catalyzed Aminofluorination of trans-beta-Me-Styrene

In order to gain further mechanistic insight into this iron catalyzed fluorine atom transfer process, we performed several experiments. First, we evaluated a cyclopropyl-substituted alkene

Figure 26: Iron-Catalyzed Aminofluorination of a Radical Clock: Probing the Mechanism

as a radical clock probe under the reaction conditions and observed the presence of ring-opening products (Figure 24) with no 1,2-amino-oxygenation or fluorination observed. This result suggests that the reaction proceeds through a stepwise process that includes a radical amination step. 43

Next, to probe beyond the radical amination step, we subjected 2,3-dimethyl-but-1-ene to the reaction conditions. A significant amount of 1,2-hydride shift product (1,2-/1,3-AF product =

1.5:1, 68% overall yield) was observed (Figure 25). This result is suggestive of a carbocation intermediate which undergoes rearrangement to yield a tertiary carbocation with subsequent nucleophilic attack from a fluoride ion.

Figure 27: Iron-Catalyzed Aminofluorination of 2,3-Dimethyl-but-1-ene: Evidence for a Carbocation Intermediate

The early probing of the iron-catalyzed aminofluorination reaction was inconclusive; both experiments are suggestive of radical amination followed by carbocation generation and subsequent fluoride attack, however direct iron-fluorine atom transfer cannot be ruled out as a possible pathway. Additional evidence for a carbocation intermediate is provided by an observed aziridine formed over the course of the reaction. The asymmetric indene aminofluorination is currently being undertaken and should provide greater insight into the underlying mechanism.

4 CONCLUSIONS

This study documents the discovery of two viable systems for the amino-oxygenation and aminofluorination of alkenes mediated by an iron nitrenoid. The reactivity of the iron nitrene, generated from easily accessible acyloxyl carbamate compounds, is sensitive to the coordinating nitrogen based tri-dentate ligands L1 and L2. This suggests a potential for further improvement 44 in reactivity and the substrate scope of both methods. Already, the scope of these reactions is reflective of their high versatility as they access a wide range of alkenyl reactivity.

Furthermore, a gram-scale synthesis of an amino-oxygenated styrene, glycal, and indene substrates demonstrates the practical use of this method in industrial applications. A more detailed mechanistic study of both methods is needed in order to characterize catalyst reactivity and understand the iron nitrenoid intermediate.

A variety of alkene substrates were amino-oxygenated and aminofluorinated with moderate to excellent yield and high regioselectivity using Fe(II)•L1 and Fe(II)•L2 catalysts were shown to catalyze the amino-oxygenation and aminofluorinatin of a variety of alkenes with excellent regioselectivity and moderate to high yield. Currently, the mechanisms of both transformations are being explored.

APPENDIX

4.1 Gram-Scale Amino-Oxygenation NMR Spectra (1H and 13C)

7.790 7.769 7.646 7.628 7.485 7.378 7.360 7.322 7.298 7.282 6.360 6.346 5.674 5.652 4.807 4.789 4.760 3.411 3.393 3.373 3.354 3.112 3.092 3.074 3.053

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

0.97 1.00 0.99 1.04 3.64 1.00 0.86 3.00 1.01 1.04

1 Figure 28: H NMR (CDCl3, 400 MHz), A-O Indene 46

164.51 154.18 141.50 138.66 138.26 134.28 132.98 130.97 130.12 128.37 127.51 127.22 127.12 125.02 95.43 77.91 74.67 53.78 36.93

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

13 Figure 29: C NMR (CDCl3, 100 MHz), A-O Indene 47

7.418 7.397 6.933 6.766 6.556 6.535 4.878 4.856 4.382 4.365 4.208 4.184 4.161 3.915 3.890 3.878 3.853 3.718 3.706 3.692 3.679 3.500 3.474 3.447 3.417 3.394 3.371 1.418 1.358 1.216 1.189

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm

1.00 1.00 0.99 1.01 0.94 0.93 1.08 1.04 1.03 2.05 9.19 3.19

24.21

1 Figure 30: H NMR (bezene-d6, 400 MHz), A-O Glycal

163.56 155.04 139.38 134.54 133.78 131.29 127.49 99.66 94.26 80.03 74.60 71.32 66.53 62.01 55.18 28.93 28.31 18.77 18.29 18.19 12.75

210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

13 Figure 31: C NMR (CDCl3, 100 MHz), A-O Glycal

REFERENCES

1. (a) Desai, L. V.; Sanford, M. S., Construction of Tetrahydrofurans by PdII/PdIV- Catalyzed Aminooxygenation of Alkenes. Angew. Chem. Int. Ed. 2007, 46 (30), 5737-5740; (b) Benkovics, T.; Guzei, I. A.; Yoon, T. P., Oxaziridine-Mediated Oxyamination of Indoles: An Approach to 3-Aminoindoles and Enantioenriched 3-Aminopyrroloindolines. Angewandte Chemie (International ed. in English) 2010, 49 (48), 9153-9157; (c) Li, G.; Chang, H.-T.; Sharpless, K. B., Catalytic Asymmetric Aminohydroxylation (AA) of Olefins. Angewandte Chemie International Edition in English 1996, 35 (4), 451-454; (d) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B., Catalytic Asymmetric Dihydroxylation. Chemical Reviews 1994, 94 (8), 2483-2547; (e) Turnpenny, B. W.; Chemler, S. R., Copper-Catalyzed Alkene Diamination: Synthesis of Chiral 2-Aminomethyl Indolines and Pyrrolidines. Chemical science (Royal Society of Chemistry : 2010) 2014, 5 (5), 1786-1793; (f) Dequirez, G.; Ciesielski, J.; Retailleau, P.; Dauban, P., Catalytic Intermolecular Alkene Oxyamination with Nitrenes. Chemistry – A European Journal 2014, 20 (29), 8929-8933; (g) Gigant, N.; Dequirez, G.; Retailleau, P.; Gillaizeau, I.; Dauban, P., Catalytic Selective Oxyamidation of Cyclic Enamides using Nitrenes. Chemistry – A European Journal 2012, 18 (1), 90-94; (h) Alexanian, E. J.; Lee, C.; Sorensen, E. J., Palladium-Catalyzed Ring-Forming Aminoacetoxylation of Alkenes. J. Am. Chem. Soc. 2005, 127 (21), 7690-7691; (i) Fuller, P. H.; Kim, J.-W.; Chemler, S. R., Copper Catalyzed Enantioselective Intramolecular Aminooxygenation of Alkenes. J. Am. Chem. Soc. 2008, 130 (52), 17638-17639; (j) Michaelis, D. J.; Shaffer, C. J.; Yoon, T. P., Copper(II)- Catalyzed Aminohydroxylation of Olefins. J. Am. Chem. Soc. 2007, 129 (7), 1866-1867; (k) Williamson, K. S.; Yoon, T. P., Iron-Catalyzed Aminohydroxylation of Olefins. J. Am. Chem. Soc. 2010, 132 (13), 4570-4571; (l) Sharpless, K. B.; Chong, A. O.; Oshima, K., Osmium- catalyzed vicinal oxyamination of olefins by Chloramine-T. J. Org. Chem. 1976, 41 (1), 177- 179; (m) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M., Bis(oxazoline)-copper complexes as chiral catalysts for the enantioselective aziridination of olefins. Journal of the American Chemical Society 1993, 115 (12), 5328-5329; (n) Liu, G.; Stahl, S. S., Highly Regioselective Pd-Catalyzed Intermolecular Aminoacetoxylation of Alkenes and Evidence for cis-Aminopalladation and SN2 C−O Bond Formation. Journal of the American Chemical Society 2006, 128 (22), 7179-7181; (o) Mulcahy, J. V.; Du Bois, J., A Stereoselective Synthesis of (+)-Gonyautoxin 3. Journal of the American Chemical Society 2008, 130 (38), 12630-12631; (p) Sharpless, K. B.; Patrick, D. W.; Truesdale, L. K.; Biller, S. A., New reaction. Stereospecific vicinal oxyamination of olefins by alkyl imido osmium compounds. Journal of the American Chemical Society 1975, 97 (8), 2305-2307. 2. (a) Paderes, M. C.; Chemler, S. R., Diastereoselective Pyrrolidine Synthesis via Copper Promoted Intramolecular Aminooxygenation of Alkenes: Formal Synthesis of (+)-Monomorine. Organic Letters 2009, 11 (9), 1915-1918; (b) Williamson, K. S.; Yoon, T. P., Iron Catalyzed Asymmetric Oxyamination of Olefins. Journal of the American Chemical Society 2012, 134 (30), 12370-12373; (c) Lebel, H.; Lectard, S.; Parmentier, M., Copper-Catalyzed Alkene Aziridination with N-Tosyloxycarbamates. Organic Letters 2007, 9 (23), 4797-4800. 3. (a) Guthikonda, K.; Du Bois, J., A Unique and Highly Efficient Method for Catalytic Olefin Aziridination. Journal of the American Chemical Society 2002, 124 (46), 13672-13673; (b) Olson, D. E.; Su, J. Y.; Roberts, D. A.; Du Bois, J., Vicinal Diamination of Alkenes under Rh-Catalysis. Journal of the American Chemical Society 2014. 4. (a) Zhu, C.-L.; Tian, J.-S.; Gu, Z.-Y.; Xing, G.-W.; Xu, H., Iron(ii)-catalyzed asymmetric intramolecular olefin aminochlorination using chloride ion. Chemical Science 2015, 6 (5), 3044- 3050; (b) Lu, D.-F.; Zhu, C.-L.; Jia, Z.-X.; Xu, H., Iron(II)-Catalyzed Intermolecular Amino- 50

Oxygenation of Olefins through the N–O Bond Cleavage of Functionalized Hydroxylamines. J. Am. Chem. Soc. 2014, 136 (38), 13186-13189; (c) Lu, D.-F.; Liu, G.-S.; Zhu, C.-L.; Yuan, B.; Xu, H., Iron(II)-Catalyzed Intramolecular Olefin Aminofluorination. Org. Lett. 2014, 16 (11), 2912-2915; (d) Zhang, Y.-Q.; Yuan, Y.-A.; Liu, G.-S.; Xu, H., Iron(II)-Catalyzed Asymmetric Intramolecular Aminohydroxylation of Indoles. Organic Letters 2013, 15 (15), 3910-3913. 5. (a) Levites-Agababa, E.; Menhaji, E.; Perlson, L. N.; Rojas, C. M., Amidoglycosylation via Metal-Catalyzed Internal Nitrogen Atom Delivery. Organic Letters 2002, 4 (5), 863-865; (b) Padwa, A.; Stengel, T., Stereochemical Aspects of the Iodine(III)-Mediated Aziridination Reaction of Some Cyclic Allylic Carbamates. Organic Letters 2002, 4 (13), 2137-2139; (c) Sequeira, F. C.; Chemler, S. R., Stereoselective Synthesis of Morpholines Via Copper-Promoted Oxyamination of Alkenes. Organic letters 2012, 14 (17), 4482-4485. 6. Liu, G.-S.; Zhang, Y.-Q.; Yuan, Y.-A.; Xu, H., Iron(II)-Catalyzed Intramolecular Aminohydroxylation of Olefins with Functionalized Hydroxylamines. J. Am. Chem. Soc. 2013, 135 (9), 3343-3346. 7. Müller, K.; Faeh, C.; Diederich, F., Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317 (5846), 1881-1886. 8. (a) Furuya, T.; Kaiser, H. M.; Ritter, T., Palladium-Mediated Fluorination of Arylboronic Acids. Angewandte Chemie International Edition 2008, 47 (32), 5993-5996; (b) Liu, W.; Groves, J. T., Manganese-Catalyzed Oxidative Benzylic C–H Fluorination by Fluoride Ions. Angewandte Chemie International Edition 2013, 52 (23), 6024-6027; (c) Lozano, O.; Blessley, G.; Martinez del Campo, T.; Thompson, A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.; Borman, R.; Gouverneur, V., Organocatalyzed Enantioselective Fluorocyclizations. Angewandte Chemie International Edition 2011, 50 (35), 8105-8109; (d) Steiner, D. D.; Mase, N.; Barbas, C. F., Direct Asymmetric α-Fluorination of Aldehydes. Angewandte Chemie International Edition 2005, 44 (24), 3706-3710; (e) Akana, J. A.; Bhattacharyya, K. X.; Müller, P.; Sadighi, J. P., Reversible C−F Bond Formation and the Au-Catalyzed Hydrofluorination of Alkynes. Journal of the American Chemical Society 2007, 129 (25), 7736-7737; (f) Barker, T. J.; Boger, D. L., Fe(III)/NaBH4-Mediated Free Radical Hydrofluorination of Unactivated Alkenes. Journal of the American Chemical Society 2012, 134 (33), 13588-13591; (g) Beeson, T. D.; MacMillan, D. W. C., Enantioselective Organocatalytic α-Fluorination of Aldehydes. Journal of the American Chemical Society 2005, 127 (24), 8826-8828; (h) Hull, K. L.; Anani, W. Q.; Sanford, M. S., Palladium-Catalyzed Fluorination of Carbon−Hydrogen Bonds. Journal of the American Chemical Society 2006, 128 (22), 7134-7135; (i) Katcher, M. H.; Doyle, A. G., Palladium- Catalyzed Asymmetric Synthesis of Allylic Fluorides. Journal of the American Chemical Society 2010, 132 (49), 17402-17404; (j) Maimone, T. J.; Milner, P. J.; Kinzel, T.; Zhang, Y.; Takase, M. K.; Buchwald, S. L., Evidence for in Situ Catalyst Modification during the Pd-Catalyzed Conversion of Aryl Triflates to Aryl Fluorides. Journal of the American Chemical Society 2011, 133 (45), 18106-18109; (k) Wang, X.; Mei, T.-S.; Yu, J.-Q., Versatile Pd(OTf)2·2H2O- Catalyzed ortho-Fluorination Using NMP as a Promoter. Journal of the American Chemical Society 2009, 131 (22), 7520-7521; (l) Lee, E.; Kamlet, A. S.; Powers, D. C.; Neumann, C. N.; Boursalian, G. B.; Furuya, T.; Choi, D. C.; Hooker, J. M.; Ritter, T., A Fluoride-Derived Electrophilic Late-Stage Fluorination Reagent for PET Imaging. Science 2011, 334 (6056), 639- 642; (m) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; García-Fortanet, J.; Kinzel, T.; Buchwald, S. L., Formation of ArF from LPdAr(F): Catalytic Conversion of Aryl Triflates to Aryl Fluorides. Science 2009, 325 (5948), 1661-1664. 51

9. Wu, T.; Yin, G.; Liu, G., Palladium-Catalyzed Intramolecular Aminofluorination of Unactivated Alkenes. J. Am. Chem. Soc. 2009, 131 (45), 16354-16355. 10. Qiu, S.; Xu, T.; Zhou, J.; Guo, Y.; Liu, G., Palladium-Catalyzed Intermolecular Aminofluorination of Styrenes. J. Am. Chem. Soc. 2010, 132 (9), 2856-2857. 11. Li, Z.; Song, L.; Li, C., Silver-Catalyzed Radical Aminofluorination of Unactivated Alkenes in Aqueous Media. J. Am. Chem. Soc. 2013, 135 (12), 4640-4643. 12. Toste, F. D., et al, Enantioselective Fluoroamination: 1,4-Addition to Conjugated Dienes Using Anionic Phase-Transfer Catalysis. Angew. Chem. Int. Ed. 2013, 52 (30), 7724-7727. 13. Ito, F.; Nakamura, T.; Yorita, S.; Danjo, H.; Yamaguchi, K., Ionic probe attachment ionization mass spectrometry. Tetrahedron Letters 2009, 50 (46), 6252-6255. 14. Ryan, P. E.; Guenee, L.; Piguet, C., Monitoring helical twists and effective molarities in dinuclear triple-stranded lanthanide helicates. Dalton Trans. 2013, 42 (31), 11047-11055. 15. Jiang, H.-F.; Ye, J.-W.; Qi, C.-R.; Huang, L.-B., Naturally occurring α-amino acid: a simple and inexpensive catalyst for the selective synthesis of 5-aryl-2-oxazolidinones from CO2 and aziridines under solvent-free conditions. Tetrahedron Letters 2010, 51 (6), 928-932. 16. L’Heureux, A.; Beaulieu, F.; Bennett, C.; Bill, D. R.; Clayton, S.; LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M., Aminodifluorosulfinium Salts: Selective Fluorination Reagents with Enhanced Thermal Stability and Ease of Handling. The Journal of Organic Chemistry 2010, 75 (10), 3401-3411.