Ligand Effects on Cobalt-Catalyzed Hydrofunctionalization of Olefins

Home , Oxazoline, Phenylsilane

THESIS

Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in

the Graduate School of The Ohio State University

Bryan F. Cunningham

Graduate Program in Chemistry

The Ohio State University

2016

Master's Examination Committee:

Professor T. V. RajanBabu, Advisor

Professor Jon R. Parquette

Bryan F. Cunningham

2016

ABSTRACT

With a significant amount of early chemistry focusing on the stoichiometric hydrofunctionalization of olefins, it has not been until recent years that chemists have had access to the powerful metal-catalyzed equivalents. With its advent, metal-catalyzed hydrofunctionalization has broadened the scope of reactivity and made strides towards the ultimate goals of atom-economy and multiplication of chirality in the synthesis of useful molecules. In its simplest form, metal-centered catalysis can be described as reactions catalyzed with a metal M, which must be stabilized in a useful conformation and electronic configuration with ligand L. The M(L) combination can be varied by the metal and the ligand, with the ligand having a large effect on the reactivity of the complex through sterics and electronics. Herein we discuss ligand effects on a variety of metal-catalyzed hydrofunctionalizations, including hydrosilylation, hydroboration and hydrovinylation. Ligands explored include Nishiyama’s Bis(oxazolinyl)pyridine, and

Schmalz’s Phosphine-Phosphite ligands. The details of the synthesis and application of these ligands is described, as well improvements to previously described methods.

Dedicated to Violet Mae Fagan - Chemist and Maverick

iii

ACKNOWLEDGMENTS

Dr. Diana L. Fagan (Mother)

Rich M. Cunningham (Father)

Dr. T.V. RajanBabu (Advisor)

Dr. John A. Jackson (Mentor)

OSU Chemistry Faculty (Professors)

Babu Group Members (Friends)

S.B. (Koala)

VITA

July 27th, 1989………...... Born – Los Angeles, California

May 2013 ...... B.S. Chemistry

Youngstown State University

2013-2016 ...... Teaching Associate

The Ohio State University

FIELDS OF STUDY

Major Field: Chemistry

TABLE OF CONTENTS

Abstract……………………………………………………………………………………ii

Dedication………………………………………………………………………...………iii

Acknowledgments……………………………………………………………………...…iv

Vita………………………………………………………………………………………...v

Fields of Study…………………………………………………………………………….v

Table of Contents…………………………………………………………………………vi

List of Schemes…………………………………………………………………………...ix

List of Tables……………………………………………………………………………...x

List of Figures…………………………………………………………………………….xi

List of Abbreviations…………………………………………………………………….xii

Chapter 1: Bis(oxazolinyl)pyridine Ligands………………………………………………1

1.1 Background and Significance…………………………………………………………1

vi 1.2 Synthesis………………………………………………………………………………5

1.3 Hydrosilyation…………………………………………………………………………6

1.4 Conclusion…………………………………………………………………………….9

1.5 Experimental Procedures……………………………………………………………...9

1.5.1 General Methods…………………………………………………………….9

1.5.2 Synthesis of Bis(oxazolinyl)pyridine (PyBox) Ligands…………………...10

Chapter 2: Phosphine-Phosphite Ligands………………………………………………..16

2.1 Background and Significance………………………………………………………..16

2.2 Synthesis and a Novel Alternative…………………………………………………...22

2.3 Hydroboration of Simple, Linear 1,3-Dienes………………………………………..26

2.4 Hydrovinylation of Simple, Linear 1,3-Dienes………………………………………32

2.5 Conclusion…………………………………………………………………………...38

2.6 Experimental Procedures…………………………………………………………….39

2.6.1 General Methods…………………………………………………………...39

2.6.2 Synthesis of Phosphine-Phosphite Ligands………………………………..41

2.6.3 Alternative Synthesis………………………………………………………48

vii

2.6.4 (L)CoCl2 Complexes……………………………………………………….49

2.6.5 Hydroboration and Oxidation……………………………………………...49

2.6.6 Hydrovinylation……………………………………………………………52

Bibliography……………………………………………………………………………..55

Appendix A: 1H and 13C NMR Spectra from Chapter 1…………………………………62

Appendix B: 31P, 1H, 13C NMR Spectra and Gas Chromatograms from Chapter 2……..71

viii

LIST OF SCHEMES

Scheme 1.1. Nishiyama Synthesis of PyBox (1989)……………………………………...2

Scheme 2.1. General Synthesis of Phosphine-Phosphite Ligand (2000)………………...17

Scheme 2.2. P-O to P-C Migration of Borane-Protected Phosphinite…………………...19

Scheme 2.3. General Synthesis of Phosphine-Phosphite Ligand (2002)………………...19

Scheme 2.4. General Synthesis of Phosphine-Phosphite Ligand (2012)………………...23

Scheme 2.5. General Synthesis of Phosphoramidite Ligand…………………………….25

Scheme 2.6. Novel General Synthesis of Phosphine-Phosphite Ligand (New Method)...25

Scheme 2.7. Possible Products of Metal-Catalyzed Hydrovinylation 1,3-Dienes……….32

Scheme 2.8. Schmalz Cobalt-Catalyzed 1,4-Hydrovinylation of 2,3-Dimethyl-1,3-

Butadiene…………………………………………………………………..34

Scheme 2.9. Schmalz Cobalt-Catalyzed Hydrovinylation of Substituted Vinylarene…...36

LIST OF TABLES

Table 1.1. Hydrosilylation of 4-Methylstyrene……………………………………………8

Table 2.1. Effect of Ligands on Rhodium-Catalyzed Hydroformylation………………..21

Table 2.2. Phosphorus NMR; Jpp Coupling Values of Phosphine-Phosphite Ligands…..21

Table 2.3. RajanBabu Cobalt-Catalyzed Hydroboration of Simple 1,3-Dienes…………29

Table 2.4. Cobalt Catalyzed Hydroboration of 1,3-Nonadiene………………………….31

Table 2.5. RajanBabu Cobalt-Catalyzed Hydrovinylation of Simple 1,3-Dienes……….33

Table 2.6. Cobalt-Catalyzed Hydroboration of 1,3-Nonadiene………………………….35

Table 2.7. Cobalt-Catalyzed Hydrovinylation of Styrene……………………………….37

LIST OF FIGURES

Figure 1.1. Neutral and Reduced Forms of PDI and PyBox………………………………4

Figure 1.2. Common Metal-Catalyzed Hydrosilylation Products………………………...7

Figure 2.1. Evolution of Metal-Catalyzed Hydroboration 1,3-Dienes…………………..28

LIST OF ABREVIATIONS

atm atmospheres br broad (NMR)

BINOL 1,1'-bi-2-naphthol n-Butyl normal-butyl t-Butyl tertiary-butyl

˚C degrees Celsius

HBCat catechol borane conv conversion

δ chemical shift in parts per million

DABCO 1,4-diazabicyclo[2.2.2]octane

DCM dichloromethane

DIPA N,N-diisopropylamine

xii

DMAP 4-Dimethylaminopyridine

DMF N,N-dimethylformamide d doublet (NMR) dd doublet of doublets (NMR) dt double of triplets (NMR) ee enantiomeric excess

E entgegen (trans)

Eq Equation equiv equivalent(s)

Et ethyl

EtOAc ethyl acetate g gram(s) h hour(s)

Hz hertz i-Pr isopropyl

IPO iminopyridine-oxazoline

xiii

J coupling constant in hertz (NMR)

L ligand; liter(s)

MAO methylaluminoxane m milli; multiplet (NMR)

M mega; metal; molarity

Me methyl

min minute(s) mol mole(s)

NBS N-bromosuccinimide

NMR nuclear magnetic resonance

PDI bis(imino)pyridine

Ph phenyl

PyBox bis(oxazolinyl)pyridine

Pyr pyridine

π pi

HBPin Pinacolborane

xiv q quartet (NMR) rt room temperature s singlet (NMR)

TADDOL α,α,α',α'-tetraaryl-2,2-disubstituted 1,3-dioxolane-4,5-dimethanol

TMA trimethylamine t triplet (NMR)

THF tetrahydrofuran

THP tetrahydropyranyl acetal

TLC thin layer chromatography

Z zusammen (cis)

Chapter 1: Bis(oxazolinyl)pyridine Ligands

1.1 Background and Significance

First synthesized in 1989 by Nishiyama and coworkers1, bis(oxazolinyl)pyridine

(PyBox) ligands are well known to today’s chemists, and have proven themselves as flexible and selective ligands in metal-catalyzed asymmetric catalysis. Easy and cheap to produce, their modular synthesis allows for easy tuning of their unique electronic and steric characteristics. To date, PyBox has found use in more than thirty types of reactions2, including hydrofunctionalization, a well-studied class of reactions allowing for the functionalization of typically non-reactive olefins, and the focus later discussion.

Box ligands are that which contain two oxazoline rings, separated by a spacer, typically an alkyl chain. Building from previous success in the enantioselective hydrosilylation of ketones by Brunner’s group in 19843, Nishiyama and coworkers set out to design new chiral, C2-symmetric tridentate pyridine ligands for use in the rhodium(III) catalyzed hydrosilylation of ketones1. It would be remiss to continue without mentioning

Brunner’s significant work with Schiff base4 and pyridine oxazoline ligands5 (1), which

Nishiyama and coworkers clearly drew their inspiration from for the synthesis of PyBox

(2).

PyBox’s distinction was in the two chiral oxazoline rings with bulky alkyl groups, making it chiral and C2 symetric axially. This allowed for chiral recognition at one face of the substrate coordinated to the metal, which was illustrated in the same paper as its synthesis, attaining a high enantioselectivity in the hydrosilylation of ketones (up to 95% ee)1. Another attraction of PyBox was it’s cheap, easy and modular synthesis starting from pyridine-2,6-dicarbozylic acid, allowing for easy screening of ligands.

Scheme 1.1. Nishiyama Synthesis of PyBox (1989)

As described in Nishiyama’s original 1989 paper, PyBox can be obtained in just four steps from pyridine-2,6-dicarboxylic acid (Scheme 1.1). Much of the original derivation was first explored by Nishiyama using the rhodium(III) catalyzed hydrosilyation of ketones as a benchmark. Nishiyama went on to show a significant oxazoline substituent effect on the enantioselectivity and reaction rate of the rhodium catalyzed hydrosilylation of ketones6. In general, it can said that selectivity trends follows sterics (Me < Et ≈ Bn < iPr) 2. Furthermore, substitution at the 4-position of the pyridine ring with an electron withdrawing group was shown to increase reaction rate7. Further derivation by Nishiyama after the year 2000 included a simple oxazoline (3) for the cyclization of diyenes8 and a hydroxymethyl oxazoline (4), which showed excellent enantioselectivity (96-97% ee) in the Ru(II) catalyzed cyclopropantion of styrene in aqueous media9.

The first notable use of PyBox in the hydrofunctionalization of olefins was the

Ru(II)PyBox catalyzed polymerization of ethylene in the prescence of methylaluminum

3 oxide (MAO) in 199810, which was overshadowed by the Brookhart-Gibson-Dupont

Discovery, which utilized the more industry friendly metals nickel, iron and cobalt, complexed with the bis(imino)pyridine (PDI) ligand11-13. PyBox was later shown to complex with iron and cobalt as well and may also possess some of the same electronic characteristics that have made the more widely researched PDI (discovered in 195614) so successful.

In a study by Stupka and coworkers, Pybox was shown to stabilize the Co(I)

I 15 species [Co (Pybox)2][ClO4] , which is indicative of a redox-active, non-innocent ligand.

It is easy then to draw a parallel to PDI, which is treated as a radical anion16 (Figure 1.1), and is known to procede through the mono-methylated Co(I) species [(PyBox)M-Me][x-

MAO] under MAO activated ethylene polymerization conditions17.

Figure 1.1. Neutral and Reduced Forms of PDI and PyBox

Interestingly, iminopyridine-oxazoline (IPO) ligands, which share the electronic and steric effects of both PyBox and PDI, have been shown to be effective in the enantioselective hydroboration of 1,1-disubstituted aryl alkenes18 and the asymmetric iron catalyzed hydrosilylation of 1,1-disubstituted alkenes19 Taking this into consideration, we decided to investigate further the potential of PyBox in the hydrofunctionalization of olefins.

1.2 Synthesis

PyBox 2a was synthesized by the original method reported in 19891 (Scheme

1.1). The only modification made was the decision to carry over all intermediates unpurified after the crude products were shown to be relatively pure by proton NMR. L-

20 Valinol was prepared via the known reduction of L-valine with NaBH4 and I2 in THF .

The simple PyBox 3 was synthesized according to a modified method21, but with insignificant changes. It was hoped that the subsequent complexation and reaction of these two ligands would help illustrate the significance of the oxazoline substituent effect on any subsequent hydrofunctionalization reactions.

1.3 Hydrosilylation

First discovered in 1979 by Parish and Coworkers22, transition metal catalyzed hydrosilylation has become a useful tool for the functionalization of olefins. To date, platinum catalysts such as Karstedt’s catalyst have proven very successful in industrial applications23. However, hydrosilylation by precious metals is very inneficient, with much of the starting material being wasted on side reactions (Figure 1.2). More recent work has focused on the more efficient and environmentally friendly late 3d transition metals such as iron24, cobalt and nickel, with some of the highest catalytic activities

(nearing the rate of Pt) being seen in iron PDI catalysts25. Iron catalysts have produced some astonishing results including the high selcitivities for the linear hydrosilylated product (>99%)26, much greater than that seen in the precious metals. Selectivity is still an issue however in the hydrosilylation of styrene derivatives27, 28, typically producing a mixture of 1,2-hydrosilylated products. Despite recent advances in cobalt catalyzed hydrosilylation providing a diversified substrate scope with high selectivity29, the cobalt catalyzed hydrosilylation of styrene had yet to be reported in literature. As such, it seemed the next logical step to explore the cobalt catalyzed hydrosilylation.

Figure 1.2. Common Metal-Catalyzed Hydrosilylation Products

For this study, conducted by Balaram Raya of the RajanBabu group, 4-methyl styrene, a standard in hydrofunctionalization reactions, was chosen as a benchmark substrate. PyBox ligands 2a and 3 were complexed with CoCl2 to give (L)Co(II)Cl2 using known procedures (PDI 5 included for the sake of completion). The air-stable

(L)Co(II)Cl2 was then reduced in-situ with sodium triethylborohydride (NaEt3BH)

in the presence of phenylsilane (PhSiH3) in toluene. The exothermic addition was controlled by cooling the addition to -78⁰C before warming the reaction to r.t. and allowing it to stir for time (t) to produce a ratio of silane 6 (Table 1.1).

Ligand Entry Time (t) % yield % conversion 6a % conversion 6b (L)

1 2a 5 h 89 22† 78

2 3 8 h 92 4 96

3 5 5 h 91 0 100 †Chiral Ligand, 72% ee observed Methods: Raya, Balaram. Unpublished Results

Table 1.1. Hydrosilylation of 4-Methylstyrene

Initial screenings were first performed with derivatives of PDI, all of which gave poor conversions except PDI 5 which gave the linear 6b exclusively in excellent yield

(entry 3). PyBox 2a and 3 both gave mixtures of 6a and 6b, however. Interestingly, reaction with the chiral 2a resulted in a moderate ee of 72% observed for the markovnikov product 6a (entry 1). Recently Huang and coworkers published an example of exclusive markovnikov hyrdrosilylation of terminal non-aromatic alkenes catalyzed by

O 30 a phospinite-iminopyridine (P NN)Co(II)Cl2 system . Taking this into consideration, it

8 would be interesting to postulate the potential role of a BOX moiety towards the potential enantioselective markovnikov hydrosilylation of olefins.

1.4 Conclusion

Since the first synthesis by Nishiyama, PyBox and its derivatives have proven themselves a valuable tool in for synthetic chemists. Originally developed for the rhodium(III) catalyzed hydrosilylation of ketones, PyBox has been used in more than 30 types of reactions, including the polymerization of ethylene. PyBox owes some of its success to its electronic effects which parallel PDI. In our first application of PyBox towards the hydrofunctionalization of olefins, we have described moderate selectivity

(96%) in the first cobalt catalyzed hydrosilylation of 4-methylstyrene, and have hopefully shown the potential of the BOX moiety for future asymmetric hydrosilylations of olefins.

1.5 Experimental Procedures

1.5.1 General Methods

Air-sensitive reactions were conducted under an inert atmosphere of argon using

Schlenk techniques. Solvents were freshly distilled from the appropriate drying agents under nitrogen. L-Valine was purchased from Acros Organics (99%) and used as received. NaBH4 was purchased from Oakwood Chemical and used as received. I2 was purchased from Alfa Aesar (99.5%) and used as received. Pyridine-2,6-dicarboxylic acid

9 was purchased from Acros Organics (99%) and used as received. SOCl2 was purchased from Sigma Aldrich (≥99%) and used as received. 2-Aminoethanol was purchased from

Acros Organics (99%) and distilled before use. Triethylamine was purchased from Acros

Organics (99%) and used as received. All Analytical TLC was performed on Siliccycle pre-coated (0.25 mm) silical gel 60 F254 plates. Flash column chromatography was carried out on silica gel 40 (Sorbtech Chemicals).

1 13 31 H, C and P NMR spectra were recorded at r.t. in CDCl3 with a Bruker 400 MHz

Avance III. Chemical shifts (δ) are reported in parts per million (ppm). Multiplicities are abbreviated as follows: s = singlet, d = doublet, , t = triplet, , q = quartet, m = multiplet.

Coupling constants (J) are presented with absolute values in Hz.

1.5.2 Synthesis of Bis(oxazolinyl)pyridine (PyBox) Ligands

L-Valinol20: In a 250 mL round bottom flask purged with nitrogen, L-valine (4.99 g,

42.63 mmol, 1.0 equiv) and NaBH4 (4.01 g, 106.06 mmol, 2.5 equiv) were dissolved in

THF (100 mL) and cooled to 0⁰C. A solution of I2 (11.18 g, 43.88 mmol, 1.0 equiv) in

THF (35 mL) was then added dropwise via cannula while maintaining the reaction temperature below 6⁰C. The reaction mixture was then warmed to r.t., vented with

10 nitrogen, and refluxed at 60⁰C overnight. After cooling to r.t., the reaction mixture was quenched with MeOH (25 mL), and all solvent was removed under vacuum to produce a white solid paste which was immediately redissolved in a 20% KOH solution (125 mL) and let stir overnight. The resulting solution was extracted with DCM (3x 50 mL) and the organic layers were combined, dried with NaSO4 and reduced under vacuum. The resulting liquid was then purified via bulb-to-bulb distillation to yield L-valinol (1.95 g,

1 44%) as a colorless, viscous liquid. H NMR (400 MHz; CDCl3) δ 5.30 (1H, s), 3.64 (1H, dd, J1 = 10.4 Hz, J2 = 4.0 Hz), 3.26 (1H, dd, J1 = 10.4 Hz, J2 = 8.9 Hz), 2.54 (1H, m),

1.55 (1H, m), 1.05 (1H, dd, J1 = 16.6 Hz, J2 = 6.2 Hz), 0.92 (6H, app t, J = 6.3 Hz). The data agreed with reported values.

Pyridine-2,6-dicarbonyl Dichloride: In a 25 ml roundbottom flask fitted with a reflux condenser and trap (saturated KOH), pyridine-2,6-dicarboxylic acid (1.3934 g, 8.34 mmol, 1 equiv) was dissolved in SOCl2 (9.50 mL, 13.08 mmol, 1.6 equiv) and the reaction mixture was refluxed overnight. After cooling to r.t., excess SOCl2 was removed under reduced pressure to yield a crude, off-white dichloride, which was carried over to

1 the next step. H NMR (400 MHz; CDCl3) δ 8.36, (2H, d, J = 7.84 Hz), 8.15 (1H, dd, J1 =

8.2 Hz, J2 = 7.4 Hz). The data agreed with reported values.

N2,N6-Bis[(S)-2-hydroxy-1-iso-propylethyl]pyridine-2,6-dicarboxamide31: In a 100 mL three-neck roundbottom flask fitted with a flow control adapter, L-valinol (2.16 g,

20.89 mmol, 2.5 equiv) was dissolved in DCM (8 mL), then a solution of NaOH (1 M, 50 mL, 49.84 mmol 6.0 equiv) was added and cooled to 0⁰C. Crude pyridine-2,6-dicarbonyl dichloride (1.70 g, 8.34 mmol, 1.0 equiv) in DCM (8 mL) was added subsurface slowly at

0⁰C and stirred at this temperature for 5 minutes before being warmed to r.t. and stirred vigorously overnight. The resulting white suspension was filtered over filter paper and the white solid was washed with cold H2O and cold DCM before being dried under vacuum to yield crude dicarboxamide (3.93 g), which was carried over to the next step.

1 H NMR (400 MHz; CDCl3) δ 8.35 (2H, d, J = 7.8 Hz), 8.05 (1H, dd, , J1 = 7.6 Hz, J2 =

7.6 Hz), 3.95 (2H, m), 3.84 (4H, br s), 2.65 (2H, br s), 2.12-2.04 (2H, m), 1.67 (2H, s),

1.04 (12H, app dd, J1 = 9.7 Hz, J2 = 6.8 Hz). The data agreed with reported values.

2,6-Bis[(S)-4,5-dihydro-1-isopropyloxazol-2-yl)pyridine (2a)31: In a 25 mL roundbottom flask fitted with a reflux condenser, crude N2,N6-Bis[(S)-2-hydroxy-1-iso- propylethyl]pyridine-2,6-dicarboxamide (3.93 g, 11.64 mmol, 1.0 equiv) was dissolved in

DCM (9.5 mL) under nitrogen, then SOCl2 (1.26 mL, 17.32 mmol, 1.5 equiv) was added and the reaction mixture was refluxed for 3 h. The reflux was stopped and the reaction flask was cooled to 0⁰C and quenched carefully with deionized H2O. The aqueous layer was separated and extracted with DCM (3x 5 mL), and the organic layers were combined and dried under vacuum. The resulting white solid was redissolved in MeOH (75 mL) and a solution of NaOH (25 mL, 12% w/v) was added and stirred for 72 h. The resulting solution was extracted with DCM (3x 50 mL) and the solvent removed under vacuum to give a crude, white solid which was twice recrystallized from hot EtOAc and Hexanes

1 (1:1) to yield 2a (0.65 g, 19%) as a white, fluffy solid. H NMR (400 MHz; CDCl3) δ

8.21 (2H, d, J = 7.8 Hz), 7.84 (1H, dd, J1 = 7.8 Hz, J2 = 7.8 Hz), 4.5 (2H, dd, J1 = 9.6 Hz,

J2 = 8.5 Hz), 4.22 (2H, dd, J1 = 8.4 Hz, J2 = 8.4 Hz), 4.16-4.10 (2H, m), 1.92-1.80 (2H,

13 m), 1.04 (6H, d, J = 6.7 Hz), 0.93 (6H, d, J = 6.8 Hz); C NMR (400 MHz; CDCl3) δ

162.4, 147.1, 137.2, 125.8, 73.1, 71.1, 33.0, 19.2, 18.4. The data agreed with reported values.

N2,N6-Bis(2-chloroethyl)pyridine-2,6-dicarboxamide21: In a 100 mL roundbottom flask, 2-aminoethanol (1.45 mL, 23.98 mmol, 2.5 equiv), and triethylamine (4.0 mL,

28.70 mmol, 3 equiv) were combined in DCM (29 mL) at r.t. and stirred for 10 min. The solution was then cooled to 0⁰C, and a solution of pyridine-2,6-dicarbonyl dichloride

(1.94 g, 9.50 mmol, 1 equiv) in DCM (29 mL) was added dropwise over 8 min – a white precipitate formed immediately, and the suspension was stirred for 24 h. The reaction flask was then fitted with a reflux condenser connected to a base trap, and purged with nitrogen. The reaction mixture was cooled to 0⁰C and SOCl2 (19.0 ml, 268 mmol, 28 equiv) was added carefully, then warmed to r.t. and refluxed at 49⁰C for 2 h. The reaction mixture was cooled to r.t. and excess SOCl2 was removed under vacuum by adding toluene. The resulting solid was triturated with DCM (30 mL), and The solution was washed with saturated sodium bicarbonate solution (15 mL), water (15 mL), and brine

(15 mL), then dried with magnesium sulfate. The solvent was removed under vacuum and the resulting solid was purified by silica column (EtOAc/Hexanes, 2:1) to yield the

1 dicarboxamide (1.16 g, 42%) as an off-white solid. H NMR (400 MHz; CDCl3) δ 8.38

(2H, d, J = 7.8 Hz), 8.07 (1H, dd, , J1 = 7.6 Hz, J2 = 8.1 Hz), 3.91-3.87 (4H, m), 3.79-

3.76 (4H, m), 1.54 (2H, s). The data agreed with reported values.

2,6-Bis(4,5-dihydrooxazol-2-yl)pyridine (3)21: In a 100 mL roundbottom flask fitted with a reflux condenser, N2,N6-Bis(2-chloroethyl)pyridine-2,6-dicarboxamide (1.18 g,

4.02 mmol, 1 equiv) was dissolved in MeOH (40 mL), then KOH (0.57 g, 10.11 mmol,

2.4 equiv) was added and the reaction mixture was stirred at reflux for 4 h. The solvent was removed under vacuum and the resulting solid was triturated with DCM (30 mL) and filtered. The filtrate was washed with H2O (3x 15 mL) and brine (15 mL) to yield 3 (0.68

1 g, 78%) as a white solid. H NMR (400 MHz; CDCl3) δ 8.17 (2H, d, J = 7.8 Hz), 7.87

13 (1H, dd, J1 = 7.7 Hz, J2 = 7.7 Hz), 4.54 (4H, t, J = 9.6 Hz), 4.13 (4H, t, J = 9.7 Hz); C

NMR (400 MHz; CDCl3) δ 163.6, 147.0, 137.5, 125.7, 68.5, 55.3. The data agreed with reported values.

Chapter 2: Phosphine-Phosphite Ligands

2.1 Background and Significance

Despite the widespread success of bidendate ligands (P/P, P/N, etc), new methods for the modular synthesis of such ligands was needed. In response to this, Schmalz and

Coworkers developed a new, modular ligand architecture partly inspired by the successful chiral catalysts based on modular ligands of the ferrocenyl, chiral oxazoline and binapthyl types. Following a new synthetic strategy described in 2000 (Scheme 2.1),

Schmalz and coworkers developed a library of modular bidendate chelating ligands by varying substituents L1 and L2 - abbreviated by their coordinating atoms P/P, P/N, P/S,

2 1 32 and P/Se [L = P(OR)2, P(NR2)OR; L = PPh2, P(iPr)2 / CONMe2 / SAr, SR / SePh] .

2 1 Since then, the Phosphine-Phosphite ligand derivatives 7 (L = P(OR)2 / L = PPh2) in particular have found considerable success in the hydrofunctionalization of olefins, including hydroformylation33, hydrovinylation34-37 and hydrocyanation38, 39. This success is due partly to their modular nature, allowing for easy ligand-screening.

Scheme 2.1. General Synthesis of Phosphine-Phosphite Ligand (2000)

Initial applications included the asymmetric rhodium catalyzed hydroboration of styrene, in which ligand 7a provided up to 81% ee with 98% yield and 98% seclectivity for the linear product40. Additionally, it was in this study that Schmalz first documented

the significant effects of the ligand tooth L2. For instance, the ligands with TADDOL- derived L2-position (7a) performed much better than those derived from other chiral diols such as the binapthyl 7b. Additionally, variations within the aromatic backbone had significant effects. For instance, the hydroquinone derived 7a was more reactive and selective than it’s phenol-derived counterpart (7c). Such changes in selectivity based on variations of the modular ligand skeleton showed the potential of phosphine-phosphite ligands as a class of easily tunable ligands.

In his first departure from the original library, Schmalz and coworkers described the rhodium-catalyzed hydroboration of a functional styrene to establish the first

(benzylic) stereocenter (93% ee) in the total synthesis of trans-7,8-dimethoxycalamenene with ligand 8. It was in this work that the significant effect of the R1 substituent ortho to the phosphite moiety was noted, and as such a new class of ligands of the general structure 9 were developed.

However, the original method, requiring a THP deprotection ortho to R1 did not tolerate bulky substituents (R1 = i-Pr, t-Bu), requiring a new synthetic method to be developed41.

The most significant change was the addition of a P-O to P-C migration (Scheme 2.2) of an ortho-lithiated and borane-protected aryl phosphinite (10). Such a migration bypasses the limitation of the original synthesis, as well as eliminating the need for protection of the phenol, reducing the overall synthesis from 5 to 4 steps (Scheme 2.3). Further exemplifying the ingenuity this work, this rearrangement replaces the very air sensitive phosphine-phenol with its air-stable, borane-protected counterpart (11).

Scheme 2.2. P-O to P-C Migration of Borane-Protected Phosphinite

Scheme 2.3. General Synthesis of Phosphine-Phosphite Ligand (2002)

Since then, Schmalz and Coworkers have continued to investigate the effects alterations to ligand type 9 and expand the scope of reactions catalyzed by its complexes.

In 2010, their rhodium-catalyzed hydroformylation of functionalized olefins33 illustrated the importance of subtle alterations to the R1 ortho substituent (Table 2.1). In general, as steric bulk increases at R1, so does the reactivity and selectivity. In fact, with no steric bulk ortho to the phosphinite moiety (entry 1), the reaction does not proceed at all. Upon further evaluation, phosphorus NMR revealed a direct relationship between the Jpp values

1 and the size of the ortho substituent R (Table 2.2), with the Jpp increasing seemingly linearly with the steric bulk on the phenyl backbone. It was postulated then that the R1 substituent acts as a “handle” to fine-tune the ligand conformation and so too the active pocket of the resulting complex. The R2 substituent has little effect on selectivity, as also illustrated by subsequent studies42.

Entry R1 (12) R2 (12) Conv. (%) Branched:Linear % ee 1 H H 1 ─ <3 (n.d.) 2 Me H 36 98:2 36 3 i-Pr H 61 98:2 60 4 Ph H 47 98:2 80 5 t-Bu H 60 98:2 81 6 t-Bu t-Bu 35 98:2 80

Table 2.1. Effect of Ligands on Rhodium-Catalyzed Hydroformylation

R2 (12) δ (PR ) Entry R1 (12) δ (P(OR) ) [ppm] 3 J [Hz] 3 [ppm] pp 1 H H 135.3 -16.7 13.3 2 Me H 145.9 -18.0 66.8 3 i-Pr H 145.8 -18.1 67.0 4 Ph H 144.5 -17.3 87.5 5 t-Bu H 138.4 -20.4 128.1 6 t-Bu t-Bu 138.2 -18.8 151.3

Table 2.2. Phosphorus NMR; Jpp Coupling Values of Phosphine-Phosphite Ligands

Now with a tunable, easily modified ligand, Schmalz and coworkers continued to make advances in the area of hydrofunctionalization, including nickel-catalyzed hydrocyanation (up to 86% ee in vinylarenes and 97% ee in cyclic vinylarenes)38, 39 and cobalt-catalyzed hydrovinylation34-37 – the later being discussed in greater detail later in this chapter.

2.2 Synthesis and a Novel Alternative

In 2012, Schmalz and Coworkers published an improved synthesis of their modular ligands in an attempt to produce a more reliable and scalable protocol43. Despite being four linear steps, the process requires significant commitment to reagent and product purification (Scheme 2.4). The process requires the recrystallization of NBS, column purification of 14, sublimation of DABCO (used in two steps), column purification of 15, column purification of the mother liquor after an incomplete recrystallization of 16, and the column purification of the acid- and air-sensitive 17. All purification steps only become more cumbersome as the reaction is scaled up.

Additionally, further attention must be made in ensuring that all reagents are used fresh

(e.g., contaminated BH3-THF reduces 15 yield) and all intermediate products are kept dry.

Despite most products being air stable, all phosphorylation reactions are very water and air sensitive, and much care is needed in eliminating any exposure to moisture, including the azeotroping of all intermediates. Reported here is a streamlined synthesis (described

22 in greater detail in the experimental procedures), eliminating some of the time-consuming purification steps detailed in Schmalz and coworker’s update synthesis.

Scheme 2.4. General Synthesis of Phosphine-Phosphite Ligand (2012)

In the presence of catalytic N,N-diisopropylamine (DIPA), phenol 13 is first reacted with NBS via a soxhlet extractor to produce 14 in moderate to good yield. A soxhlet extractor was used to circumvent the low solubility of NBS in DCM. It was found that use of a soxhlet extractor did not deter the formation of dibrominated products as reported. The resulting bromophenol 14 was purified by flash column chromatography, and then converted to the borane-protected phosphinite 15 in quantitative yields, eliminating the need for an additional large-scale column. Crude 15 was then subjected to n-BuLi in a facile reaction to give borane-protected phosphine 16. Both to streamline the

23 method and avoid any product decomposition, crude 16 was crystalized once as initially described, but instead of purifying the mother liquor by column, the solvent of the mother liquor was removed and the remaining solid was recrystallized again to give pure 16 with no remarkable decrease in yield as compared to the Schmalz procedure. Borane-protected phosphine 16 was then converted to crude ligand 17 with success being limited by the purity of DABCO, which still must be sublimed in large scale. A major modification needed was the addition of 1% Et3N to the eluent of the subsequent column purification of 17. Without this, much product decomposition results, and smears on the column, making isolation impossible. Additionally, all intermediates still required careful azeotroping before being subjected to subsequent reactions. Overall, the process is less efficient than advertised.

In an attempt to avoid the lengthy process detailed above, a new alternative synthesis was envisioned, taking inspiration from the synthesis of the phosphoramidite ligand 19 (Scheme 2.5), first developed by Feringa and Coworkers44. Starting from the chosen diol, TADDOL, ligand 22 was successfully synthesized in three linear steps for the first time as described below (Scheme 2.6).

Scheme 2.5. General Synthesis of Phosphoramidite Ligand

Scheme 2.6. Novel General Synthesis of Phosphine-Phosphite Ligand (New Method)

Phosphine 21a was synthesized from 2,4-di-tert-butylphenol in two steps (~ 45% yield) according to known procedure45, and must be stored under inert atmosphere. In one pot, TADDOL was reacted with 3.1 equivalents of DMAP in toluene-D8 (taking into account the later deprotonation of 21a), followed by the addition of 1.0 equivalents PCl3.

Upon addition of 21a, additional THF-D8 was added to aid in dissolution of precipitate,

25 which must be taken into consideration in any future methods. After stirring for 40 h, ligand 22 was observed in 89% conversion by phosphorus NMR. After a facile silica column to remove any starting material remaining, 22 was isolated in improved purity compared to the Schmalz method. An attempt was made to expand this method to the

2,4-dimethyl variant, but was not successful due to 21b failing to crystalize out. Further optimization is needed to expand this method to the scope of the original Schmalz method.

2.3 Hydroboration of Simple, Linear 1,3-Dienes

First reported in 1984 by Nӧth and Mannig46, the catalytic hydroboration of alkynes and alkenes has gone on to attract considerable attention with the number of citations of the original paper exceeding 300. Since then, there has been much research on the metal-catalyzed hydroboration of olefins, however little of it has focused on simple, linear 1,3 dienes (Figure 2.1).

In 1989 Suzuki and coworkers reported the first hydroboration of the relatively unreactive 1,3-dienes with catecholborane (normally unreactive as well) in the prescence of Pd(PPh3)4 or Rh4(CO)12. Pd(0), providing the 1,4 product 23b (R=alkyl) in high regio- and stereo-selectivity; Rh(0) proved to be relatively unreactive to linear 1,3-dienes47.

However soon after, Hayashi and coworkers would report the (dppe)Rh(I) catalyzed hydroboration of 4-phenyl,3-diene with catecholborane, giving mainly 1,2-linear product48. Nickel catalyzed hydroboration of 1,3 dienes was not reported until 1997 when

Zaidlewicz and coworkers reported the Ni(II) 1,2-hydroboration of simple 1,3-dienes with catecholborane. Similar reactions were attempted with (dppe)Co(II), but resulted in only a mixture of products (Iron totally failed)49. In 2009, by Ritter and coworkers described the iminopyridine- Fe(II) catalyzed hydroboration of 1,3-dienes, giving exclusively 1,4-product using Schiff-base ligands 26. This also marked a turning point in catalytic hydroboration with the first substitution of catecholborane (HBCat) with pincolborane (HBPin), which allowed access to column-stable boranes. Additionally,

Ritter showed significant ligand control, with the bulky 26b producing exclusively the

1,4 regioisomer 28b and the less sterically demanding 26a producing exclusively the 1,4 regioisomer 27b50. Later that year, Morken and coworkers would report the Ni(0) catalyzed 1,4-hydroboration of simple 1,3 dienes with pinacolborane as well.

Figure 2.1. Evolution of Metal-Catalyzed Hydroboration of 1,3-Dienes

To date, the only published work detailing the cobalt catalyzed hydroboration of linear, simple 1,3 dienes is Zaidlewicz’s work in 1997, which produced an mixture of products with an unreported composition. As such, the RajanBabu group has recently worked towards expanding the scope of cobalt-catalyzed hydroboration, including linear, simple 1,3-dienes. In an optimized procedure, diene was reacted with (dppp)CoCl2 in the prescence of MAO (an essential activator) and pinacolborane at r.t. to give mainly the 1,2 hydroboration product with high regioselectivity in a short amount of time(Table 2.3).

These results compliment those associated with the previously described Rh(I), Ni(II) and

Ni(0) systems, and greatly improved upon any past cobalt-catalyzed hydrboration of linear, simple 1,3-dienes.

Substrate Yield (%) 1,2 / 1,4

99 >99:1

44 >99:1

70 >99:1

Table 2.3. RajanBabu Cobalt-Catalyzed Hydroboration of Simple 1,3-Dienes (Unpublished Results by Kendra Dewese)

To expand upon these results, the newly synthesized library of phosphine- phosphite ligands were applied to similar reaction conditions. Initial complexation with

CoCl2 in THF according to the typical procedure proved ineffective as the resulting complexes did not crash out of hexanes as observed in bis-phosphine complexes. In turn, all subsequent complexations were merely removed of solvent under vacuum after stirring with CoCl2 in THF. Initial screenings of the corresponding complexes with nonadiene showed mixed results (Table 2.4).

Unfortunately, the new phosphine-phosphite ligands provided a mixture of regioisomers as well as isomerized starting material. However, it is interesting to note the steric effects of the ortho R ligand substituent on regio control. TADDOL ligand 30 (R=t-

Bu) provided 1,4 product in slight excess, while 31 (R=Me) provided the 1,2 product in excess. The BINOL ligands showed a reverse trend and the more bulky 32 (R=t-Bu) gave an excess of 1,2 product, while 33 gave 1,4 product in excess. While the demonstration of phosphine-phosphite steric effects is interesting, much work would be required to produce any useful results with these ligand in the hydroboration of simple, linear 1,3- dienes.

Entry SM (mg) L Time (h) 1,4 (%) 1,2 (%) Isom. (%)

1 30 30 20 56 44 0

2 100 30 3 47 27 26

3 30 31 20†† 30 48 22

4 100 32 3† 17 41 42

5 20 33 23††† 45 33 22 †Incomplete by GC ††Complete after 1 h in retrospect †††Complete < 7 h in retrospect

Table 2.4. Cobalt Catalyzed Hydroboration of 1,3-Nonadiene (As Advised by Kendra Dewese and Stanley Jing)

2.4 Hydrovinylation of Simple, Linear 1,3-Dienes

Since the original papers by Hata, Alderson and Wilke describing the addition of ethylene to a range of activated and unactivated olefins51-53, hydrovinylation of olefins has become a much-researched field. Most advances have been made in the nickel- catalyzed hydrovinylation, with the high catalytic activity being displayed, the most efficient being Wilke’s Ni(phosphine)(allyl)(X) catalyst (turnover frequency >625000

[propylene][Ni]-1[h]-1) 54. The nickle-catalyzed hydrovinylation of olefins has since been extensively developed by the RajanBabu group, displaying near perfect results (>99% conversion, >99% regioselectivity, 99% ee) on a wide range of substrates55, 56. However, simple 1,3-dienes failed in the nickel-catalyzed hydrovinylation, giving a mixture of products (Scheme 2.5), except for vinylcycloalkenes (an “easier” substrate) 57, 58. In response, the cobalt-catalyzed hydrovinylation of simple, linear 1,3-dienes was explored by the RajanBabu group.

Scheme 2.7 Possible Products of Metal-Catalyzed Hydrovinylation of 1,3-Dienes

The cobalt-catalyzed dimerization of ethylene was first reported by Ikeda and coworkers in 196859 and went largely forgotten until Hilt rediscovered the chemistry in

2001, describing the dimerization of 2,3-dimethyl-1,3-butadiene with substituted alkenes60. Since then, advances have been made both by the Hilt group61 and the

RajanBabu group. In 2012, the RajanBabu group described the cobalt-catalyzed 1,4- hydrovinylation of vinylcycloalkenes with high enantioselectivites (>98%)62 and building on their success, described the first hydrovinylation of simple, linear 1,3-dienes in 2015 with excellent results using bisphosphine ligands (P~P)63 (Table.2.5).

Entry Diene (R) (P~P) Temp. (⁰C)/time (h) Yield 35 (%) %ee

1 C5H11 (S,S)- BDPP -45/6 97 97

2 CH2CH2OBn (R,R)- DIOP -20/6 40* 99

3 CH2CH2OBn (S,S)- BDPP -10/9 >99 92 *Rest starting material

Table 2.5. RajanBabu Cobalt-Catalyzed Hydrovinylation of Simple 1,3-Dienes

Scheme 2.8. Schmalz Cobalt-Catalyzed 1,4-Hydrovinylation of 2,3-Dimethyl-1,3- Butadiene

Taking into consideration Hilt and Schmalz’s success with “SchmalzPhos” (34) in the cobalt-catalyzed hydrovinylation of 2,3-dimethyl-1,3-butadiene with substituted alkenes34-37 (Scheme 2.6), the library of ligands 30-33 was applied to the optimized 1,3- diene system described by this group (Table 2.6).

Entry L Activator Time (h) % Yield % 35 (ee) % 36 % 37 (ee) % 38

1 30 TMA 50% 23 h 40 69 (71) 6 20 (55) 5

2 30 Et2AlCl 30% 17 h 61 50 (12) 15 33 (8%) 2

3 32 TMA 50% 24 h 38 48 (10) 17 28 (12) 7

4 31 TMA 50% 24 h 30 40 (2) 14 31 (0) 15

5 33 TMA 50% 24 h 84 74 (2) 3 4 (4) 19

Table 2.6. Cobalt-Catalyzed Hydrovinylation of 1,3-Nonadiene (As Advised by Kendra Dewese and Stanley Jing)

Initial screening proved the new phosphine-phosphite system to be unreactive in the presence of MAO, and further screening was performed with TMA. Continuing the trend of low reactivity, the system also reacted too slowly to be monitored early in the

35 reaction, or did not react at all at -20⁰C, so the reactions were carried out at room temperature, with the reactions still requiring up to 24 h to completely convert the starting material. All reactions resulted in a mixture of products with preference for 1,4 hydrovinylation. Entry 5 showed the highest regioselectivity for 1,4-hydrovinylation, however it displayed poor enantioselectivity. It was the more bulky ligand 30 (entry 1) that provided the highest enantioselectivity (up to 71%). Reduction of the ortho R steric bulk (entry 4) only worsened the regio- and enantioselectivity. Replacing TMA with

64 65 Et2AlCl (entry 2) as described in literature increased the yield, but worsened both the regio- and enantioselectivity of ligand 30. Both BINOL based ligands (entries 3 and 4) showed little to no regio- and enantioselectivity. It would seem that steric bulk on both the aryl backbone and the phosphinite moiety is required for the success of this reaction, and bulkier phosphinit moieties may lead to better results.

Scheme 2.9. Schmalz Cobalt-Catalyzed Hydrovinylation of Substituted Vinylarene

During the time of this work, Schmalz reported the 1,2-hydrovinylation of vinylarenes catalyzed by similar conditions (Scheme 2.9), with an expanded substrate

36 scope to include binapthyl, and hetero-substituted benzene substrates37. To confirm catalyst activity, as well as expand the reaction to an unreported substrate, the system detailed above was applied to 4-methylstyrene (Table 2.7). Application of the diene system (entries 1, 3-5)

Entry L Activator Time % yield 39 ee

1 30 TMA 50% 24 h 89 10

2 30 Et2AlCl 30% 17 h 79 84 3 32 TMA 50% 24 h 4 4

4 31 TMA 50% 24 h 46 4

5 33 TMA 50% 24 h 76 2

Table 2.7. Cobalt-Catalyzed Hydrovinylation of Styrene (As Advised by Stanley Jing and Balaram Raya)

37 resulted in low to good yields, but little enantioselectivity. A control experiment was ran

(entry 2) under the same conditions reported by Schmalz, resulting in a dramatic increase in enantioselectivity, confirming his results and the activity of the complexes reported here (L = 30-33). It is interesting to note the decrease in enantioselectivity with the addition of a tert-butyl substituent at the 4 position of the aryl backbone (entry 2) compared to the higher enantioselectivty observed under Schmalz conditions (Scheme

2.9). Perhaps this additional steric bulk is hindering the enantioselectivty in the diene system as well – similar to the steric effect of 4-substitution noted by Schmalz in hydroformylation (Table 2.1). Future efforts in the cobalt catalyzed hydrovinylation of linear, simple 1,3-dienes should include the exlusion of steric bulk at the 4-position in ligand 30, as well as investigate the effects of temperature on the Et2AlCl and TMA activated reaction.

2.5 Conclusion

Modular phosphine-phosphite ligands described by Schmalz, have been shown to be successful in metal-catalyzed hydrofunctionalization, despite their laborious synthesis.

Improving upon their synthetic shortcomings, a novel synthetic method was proposed, decreasing the total linear steps from 4 to 3 and greatly reducing time spent on purification. Relevant phosphine-phosphite ligands were then shown to affect the cobalt- catalyzed hydroboration of nonadiene, but resulted only in an undesired mixture. Efforts were then concentrated on the cobalt-catalyzed hydrovinylation of nonadiene, resulting in

38 moderate regioselectivity with good enantioselectivity (up to 71% ee) – vinylarenes were also investigated with no improvement on published results. The work enclosed should hopefully promote the investigation of new applications of aforementioned ligands, with the most promise being shown by phosphine-phosphite ligands.in the cobalt-catalyzed hydrovinylation of simple, linear 1,3-dienes.

2.6 Experimental Procedures

2.6.1 General Methods

Air-sensitive reactions were conducted under an inert atmosphere of argon using

Schlenk techniques. All products were azeotroped in benzene or toluene before use in subsequent reactions. Solvents were freshly distilled from the appropriate drying agents under nitrogen. Cellulose Soxhlet extractor thimbles were purchased from Fisher

Scientific. NBS was purchased from Oakwood Chemical and used as received. DIPA was purchased from Acros Organics and freshly distilled over calcium hydride before use.

2,4-dimethylphenol was purchased from Alfa Aesar (98%), and freshly distilled before use. 2,4-di-tert-butylphenol was purchased from Acros Organics (97%) and used as received. DABCO was purchased from Aldrich (98%) and purified by sublimation before use. ClPPh2 was purchased from Acros Organics (98%) and used as received. BH3-THF

(1 M in THF) was purchased from Acros Organics and used as received immediately. n-

Butyllithium (2.5 M in hexanes) was purchased from Acros Organics and used as received. PCl3 was purchased from Sigma Aldrich (99%), purified by distillation before

39 use and stored under argon at 5⁰C. (R)-BINOL was purchased from Chengyu Specialty

Chemical and dried under vacuum over P2O5 before use. (R,R)-TADDOL was

66 synthesized according to literature , and dried under vacuum over P2O5 before use.

DMAP was purchased from Alfa Aesar and recrystallized before use. CoCl2 was purchased from Alfa Aesar (99.7%) and used as received. MAO was prepared according to known procedures 67. Pinacolborane was purchased from Acros Organics (97%) and used as received. 1,3-Nonadiene was prepared according to known procedure68. 4-

Methylstyrene was purchased from Acros Organics (98%) and used as received. TMA was purchased from Aldrich (2.0 M in Toluene), and used as received. Et2AlCl was purchased from Aldrich (97%) and used as received. All Analytical TLC was performed on Siliccycle pre-coated (0.25 mm) silical gel 60 F254 plates. Flash column chromatography was carried out on silica gel 40 (Sorbtech Chemicals).

Isolated yields of hydroborated and hydrovinylated products were calculated based off of

% conversion by GC. Gas chromatographic analyses were performed on a HP 5890 using a HP-1 Methylsilicone column (30 m x 0.250 mm, 0.25 mm film thickness) and a FID detector. Enantiomeric excesses of chiral compounds were determined by chiral stationary phase gas chromatographic (CSP GC) analyses, which were performed on an

Agilent 7820A using a Cyclosil-B capillary GC column (25 m x 0.25 mm, 0.25 μm film thickness) using hydrogen as a carrier gas. Product masses were confirmed by GC-MS on an Agilent 6850 using a HP-5 phenyl methylsilicone column (30 m x 0.25 mm x 0.25 μm film thickness) and an Agilent 5975 MSD.

1 13 31 H, C and P NMR spectra were recorded at r.t. in CDCl3 with a Bruker 400 MHz

Avance III. Chemical shifts (δ) are reported in parts per million (ppm). Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet.

Coupling constants (J) are presented with absolute values in Hz.

2.6.2 Synthesis of Phosphine-Phosphite Ligands

2-Bromo-4,6-dimehtylphenol; Typical Procedure I 43: A 500 ml three-necked roundbottom flask was equipped with a Soxhlet extractor and a reflux condenser, then flame dried and cooled under argon. The Soxhlet extractor was fitted with an extraction thimble filled with NBS (16.23 g, 91.18 mmol, 1.1 equiv), and the apparatus was flushed with argon. The flask was charged with 2,4-dimethylphenol (10.0 mL, 82.76 mmol, 1.0 equiv), then dissolved in DCM (150 mL) and the soxhlet extractor was filled with additional

DCM (100 ml). DIPA (1.16 mL, 8.28 mmol, 0.1 equiv) was added to the reaction flask and the solution was stirred at reflux for 16 h. After cooling to r.t., the mixture was treated with 2 M H2SO4 (150 mL), transferred into a separatory funnel, and the organic layer was collected. The aqueous layer was extracted with MTBE (3x 100 mL), and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by a flash column

41 chromatography plug (cyclohexane-EtOAc, 20:1, 200 mL SiO2) to yield 81 (9.06 g, 54%)

1 as a yellow viscous liquid. H NMR (400 MHz; CDCl3) δ 7.11 (1H, s), 6.87 (1H, s), 5.37

(1H, s), 2.26 (3H, s), 2.23 (3H, s). The data agreed with reported values.

2-Bromo-4,6-di-tert-butylphenol43: Following typical procedure I, 2,4-di-tert- butyphenol (7.82 g, 37.9 mmol) was reacted with NBS (7.47 g, 41.96 mmol) and DIPA

(0.54 ml, 3.79 mmol) in DCM (250 mL total) to yield 33 (8.88 g, 82%) as a white solid.

1 H NMR (400 MHz; CDCl3) δ 7.24 (1H, d, J = 2.3 Hz), 7.16 (1H, d, J = 2.4 Hz), 5.56

(1H, s), 1.32 (9H, s), 1.20 (9H, s). The data agreed with reported values.

2-Boranatodiphenylphosphanyl-4,6-dimethylphenol; Typical Procedure II43: A 250 ml three-neck round bottom fitted with a flow control adapter was charged with bromophenol 81 (9.06 g, 45.06 mmol, 1 equiv) and DABCO (6.20 g, 55.30 mmol, 1.2 equiv), evacuated and placed under positive argon pressure. DCM (60 ml) was added to

42 the reaction flask and the resulting clear, colorless solution was stirred for 15 minutes at r.t, then cooled to 0⁰C C before ClPPh2 (1.8 M in DCM, 9.75 mL, 54.3 mmol, 1.2 equiv) was added dropwise by cannula over 30 minutes. The resulting white slurry was stirred for 10 minutes at 0⁰C, then allowed to warm to r.t. and stirred for 2 h. The reaction mixture was cooled again to 0⁰C and a solution of BH3-THF (1 M, 90.0 mL, 90.0 mmol,

2.0 equiv) was added dropwise via glass syringe. The suspension was stirred at 0⁰C for

10 min, then allowed to warm to r.t. and stirred for 1 h. The reaction mixture was quenched with deionized H20, the organic layer separated and the aqueous layer was extracted with MTBE (3x 75 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to yield a white solid.

The crude product was first aezeotroped in benzene, then dissolved in THF (130 mL) under argon and cooled to 0⁰C. Via glass syringe, n-BuLi (2.5 M in Hexanes, 27.0 mL,

67.5 mmol, 1.5 equiv) was added dropwise, resulting in a yellow to red solution which was stirred for 2 h at 0⁰C and then quenched with deionized H2O. The mixture was transferred into a separatory funnel and the organic layer was collected. The aqueous layer was extracted with MTBE (3x 100 mL) and the combined organic layers were washed with sat. aq. NH4Cl, dried over MgSO4, and filtered. Removal of solvent provided an oil which was subsequently recrystallized from 16:1 hexanes-EtOAc to

31 afford 93 (10.35 g, 69%) as a white crystalline solid. P NMR (400 MHz; CDCl3) δ 12.6

1 (d, J = 65.6 Hz); H NMR (400 MHz; CDCl3) δ 7.47-7.40 (6H, m), 7.37-7.32 (4H, m),

7.30 (1H, br. s), 7.01 (1H, br. s), 6.44 (1H, dd, J1 = 11.0 Hz, J2 = 1.5 Hz), 2.13 (3H, s),

2.04 (3H, s). The data agreed with reported values.

2-Boranatodiphenylphosphanyl-4,6-di-tert-butylphenol43: Following typical procedure II, bromophenol 33 (10.00 g, 35.06 mmol) was reacted with DABCO (4.73 g,

42.17 mmol) and ClPPh2 (7.56 mL, 42.11 mmol) in DCM (70 mL) before BH3-THF (1 M,

70.0 mL, 70.0 mmol) was added. The crude was dissolved in 100 mL THF and reacted with n-BuLi (2.5 M in Hexanes, 21.0 mL, 52.5 mmol). The crude product was recrystallized from EtOAc to yield 73 (9.17 g, 65%) as a white crystalline solid. 31P NMR

1 (400 MHz; CDCl3) δ 13.75 (d, J = 58.3 Hz); H NMR (400 MHz; CDCl3) δ 7.58-7.46

(12H, m), 6.70 (1H, dd, J1 = 11.5 Hz, J2 = 2.4 Hz), 1.44 (9H, s), 1.14 (9H, s). The data agreed with reported values.

(3aR,8aR)-6-[ 2-(Diphenylphosphino)-4,6-di-methylphenoxy]-2,2-dimethyl-4,4,8,8- tetraphenyltetrahydro[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepine (31); Typical

Procedure III43: A flame-dried 50 mL two-neck Schlenk flask was charged with borane- protected phosphine 93 (0.79 g, 2.50 mmol, 1.0 equiv), DABCO (2.22 g, 19.82 mmol,

8.0 equiv), evacuated and placed under positive argon pressure. DCM (15 ml) was added to the reaction flask and the resulting clear, colorless solution was stirred for 10 minutes at r.t, then cooled to 0⁰C before PCl3 (2M in DCM, 0.26 ml, 2.97 mol, 1.2 equiv) was added dropwise by cannula over 15 minutes. The resulting white slurry was stirred for 30 minutes at 0⁰C, then allowed to warm to r.t. and stirred for 3 h. The reaction mixture was again cooled to 0⁰C and a solution of (R,R)-TADDOL (1.75 g, 3.77 mmol, 1.5 equiv) in

DCM (15 mL) was added dropwise by cannula over 15 minutes. The resulting white to off-white suspension was stirred for 30 minutes at 0⁰C, then allowed to warm to r.t. and stirred for 20 h. The reaction mixture was filtered over a short silica plug which was rinsed with DCM, and dried under vacuum. The resulting crude solid was dissolved in

4:1 cyclohexane-EtOAc (1% Et3N), and filtered through a Celite plug to remove insoluble byproducts. The remaining liquid was dried under vacuum to yield a crude white foam with a noticeable oily residue, then concentrated in 4:1 cyclohexane-EtOAc

(1% Et3N), and purified by flash column chromatography (cyclohexane-EtOAc, 4:1, 200

31 ml SiO2) under argon to yield ligand 99 (1.61 g, 81%) as a white foam. P NMR (400

1 MHz; CDCl3) δ 147.3 (d, J = 55.3 Hz), -18.1 (d, J = 55.8 Hz); H NMR (400 MHz;

CDCl3) δ 7.65 (2H, br. dd, J1 = 8.0 Hz, J2 = 1.9, 1.4 Hz), 7.43 (2H, dd, J1 = 8.0 Hz, J2 =

1.9, 1.4 Hz), 7.36-7.32 (4H, m), 7.19-7.09 (21H, m), 7.07-7.03 (2H, m), 6.85 (1H, br. d, J

= 1.4 Hz), 6.31 (1H, br. t, J = 2.6 Hz), 2.22 (3H, s), 2.00 (3H, s), 1.01 (3H, s), 0.27 (3H, s). The data agreed with reported values.

(3aR,8aR)-6-[ 2-(Diphenylphosphino)-4,6-di-tert-butylphenoxy]-2,2-dimethyl-4,4,8,8- tetraphenyltetrahydro[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepine (30) 43: Following typical procedure III, phosphine 73a (1.00 g, 2.46 mmol) was reacted with DABCO (2.24 g, 19.97 mmol) and PCl3 (0.26 mL, 2.97 mmol) in DCM (15 mL) before (R,R)-TADDOL

(1.60 g, 3.43 mmol) in DCM (15 mL) was added. The crude product was purified by flash column chromatography (cyclohexane-EtOAc, 40:1) to yield ligand 87 (1.11 g, 51%)

31 as a white foam. P NMR (400 MHz; CDCl3) δ 138.1 (d, J = 151.6 Hz), -18.8 (d, J =

1 151.3 Hz); H NMR (400 MHz; CDCl3) δ 7.45-7.38 (7H, m), 7.34-7.32 (3H, m), 7.24-

7.23 (2H, m), 7.15-7.09 (12H, m), 7.06-7.03 (4H, m), 6.97-6.95 (4H, m), 5.31 (1H, d, J =

8.2 Hz), 5.08 (1H, dd, J1 = 8.2 Hz, J2 = 1.2 Hz), 1.27 (9H, s), 1.00 (9H, s), 0.72 (3H, s),

0.37 (3H, s). The data agreed with reported values.

(11bR)-4-[2-(Diphenylphosphino)-4,6-dimethylphenoxy]dinaptho[2,1-d:1’,2’- f][1,3,2]dioxaphosphepine (33) 43: Following typical procedure III, phosphine 93 (0.80 g,

2.50 mmol) was reacted with DABCO (2.24 g, 19.97 mmol) and PCl3 (0.26 mL, 2.97 mmol) in DCM (15 mL) before (R)-BINOL (1.08 g, 3.80 mmol) in DCM (15 mL) was added. The crude product was purified by flash column chromatography (cyclohexane-

EtOAc, 2:1) to yield ligand 101 (1.51 g, 97%) as a white foam. 31P NMR (400 MHz;

1 CDCl3) δ 145.8 (d, J = 56.1 Hz), -16.73 (d, J = 56.3 Hz); H NMR (400 MHz; CDCl3) δ

7.87-7.61 (8H, m), 7.41 (1H, d, J = 8.9 Hz), 7.33-7.07 (13H, m), 6.92 (1H, br. s), 5.68

(1H, br. t, J = 2.9 Hz), 2.25 (3H, s), 2.04 (3H, s). The data agreed with reported values.

(11bR)-4-[2-(Diphenylphosphino)-4,6-di-tert-butylphenoxy]dinaptho[2,1-d:1’,2’- f][1,3,2]dioxaphosphepine (32) 43: Following typical procedure III, phosphine 73a (1.00 g, 2.49 mmol) was reacted with DABCO (2.25 g, 20.09 mmol) and PCl3 (0.26 mL, 2.97 mmol) in DCM (15 mL) before (R)-BINOL (1.07 g, 3.75 mmol) in DCM (15 mL) was added. The crude product was purified by flash column chromatography (cyclohexane-

EtOAc, 20:1) to yield ligand 89 (0.68 g, 39%) as a white foam. 31P NMR (400 MHz;

1 CDCl3) δ 142.5 (d, J = 144.9 Hz), -15.1 (d, J = 145.4 Hz); H NMR (400 MHz; CDCl3) δ

7.84-7.74 (3H, m), 7.62 (1H, d, J = 8.8 Hz), 7.41 (1H, d, J = 8.7 Hz), 7.33-7.22 (12H, m),

7.17-7.11 (3H, m), 6.85-6.81 (2H, m), 1.20 (9H, s), 1.04 (9H, s). The data agreed with reported values.

2.6.3 Alternative Synthesis

(3aR,8aR)-6-[ 2-(Diphenylphosphino)-4,6-di-tert-butylphenoxy]-2,2-dimethyl-4,4,8,8- tetraphenyltetrahydro[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepine (22); New Method:

In an argon atmosphere box, a 20 mL glass scintillation vial with a stir bar was charged with (R,R)-TADDOL (120 mg, 0.26 mmol, 1 equiv), DMAP ( 99 mg, 0.81 mmol, 3.1 equiv) and toluene-D8 (0.5 mL) at r.t.. PCl3 (23 μL, 0.26 mmol, 1 equiv) was added and a white precipitate formed. THF-D8 (300 μL) was added to aid in dissolution and the reaction mixture was stirred for 2 h before adding phenol 77, which was synthesized by known procedures. After stirring for 40 h, the reaction mixture was filtered through celite

31 over cotton with toluene-D8 to yield 77 in 89% conversion by P NMR. An aliquot was taken and filtered through a silica plug under nitrogen to yield pure 77, which was positively identified by comparison of NMR spectra with 87.

2.6.4 (L)CoCl2 Complexes

Typical (L)CoCl2 Complexation Procedure: In an argon atmosphere glovebox, a schlenk flask was charged with Ligand L (0.13 mmol, 1 equiv), CoCl2 (0.13 mmol, 1 equiv), and removed from the glove box. THF was added (4.4 mL) and the reaction was stirred overnight. The solvent was evaporated under reduced pressure to yield (L)CoCl2.

2.6.5 Hydroboration and Oxidation

Typical Hydroboration Procedure (Table 2.4): In an argon atmosphere glovebox,

(L)CoCl2 (0.013 mmol, 0.05 equiv) and MAO (0.50 mmol, 2.5 equiv) were added to a schlenk flask, and removed from the box. DCM (2.4 mL) was added and the resulting brown solution was stirred for 5 min at r.t. before diene (0.25 mmol, 1 equiv) was added, immediately followed by the addition of pinacolborane (0.037 mL, 0.26 mmol, 1.05 equiv). The reaction was let stir at r.t. and monitored by GC (aliquots taken and quenched with methanol in ether). Upon complete conversion of starting material, the reaction was quenched with a small amount of methanol, diluted with ether and filtered through a

Celite plug. The excess solvent was removed on the rotovap and the crude mixture was purified by silica column (Pentanes – 2% ether/pentanes) to yield hydroborylated product.

(E)-4,4,5,5-Tetramethyl-2-(non-3-en-1-yl)-1,3,2-dioxaborolane: 1H NMR (400 MHz;

CDCl3) δ 5.48-5.34 (2H, m), 2.12-2.06 (2H, m), 1.96-1.91 (2H, m), 1.75-1.64 (2H, m),

13 1.34-1.2 (18H, m), 0.89-0.84 (3H, m); C NMR (400 MHz; CDCl3) δ 132.0, 130.1,

129.5, 124.1, 83.03, 32.6, 31.6, 29.5, 27.0, 22.5, 14.2; GC-MS (EI): m/z 252 (exact mass calcd. for C15H29BO2 252); GC (methyl silicone 120 °C): Rt 9.57 min. The data was consistent with a known sample.

(Z)-4,4,5,5-Tetramethyl-2-(non-2-en-1-yl)-1,3,2-dioxaborolane: Identified via positive comparison to known 1H, 13C NMR, and GC spectra; 1H NMR and GC integration ratios corresponded positively. GC-MS (EI): m/z 253 (exact mass calcd. for C15H29BO2 252);

GC (methyl silicone 120 °C): Rt 9.19 min. The data was consistent with a known sample.

2,4-Nonadiene: Identified via positive comparison to known 1H, 13C NMR, and GC spectra. GC-MS (EI): m/z 124 (exact mass calcd. for C9H16 124); GC (methyl silicone 50

°C): Rt 3.98 min. The data was consistent with a known sample.

Hydroboration-Oxidation Procedure: In an argon atmosphere glovebox,

(tBuTADDOL)CoCl2 (40.8 mg, 0.040 mmol, 0.05 equiv) and MAO (117.0 mg, 2.01 mmol, 2.5 equiv) were added to a schlenk flask, and removed from the box. DCM (8 mL) was added and the resulting brown solution was stirred for 5 min at r.t. before diene

(102.2 mg, 0.823 mmol, 1 equiv) was added, immediately followed by the addition of pinacolborane (0.13 mL, 0.861 mmol, 1.05 equiv). The reaction was let stir at r.t. and monitored by GC (aliquots taken and quenched with methanol in ether). Upon complete conversion of starting material, the reaction mixture was cooled to 0⁰C. 4M NaOH (1.6 mL) was added dropwise, shortly followed by an equally careful addition of 30% H2O2 (1 mL), and the reaction mixture was warmed to r.t. and let stir. After 30 min, the reaction mixture was diluted with 10 mL ether, neutralized to pH ≈ 7 with 10% H2SO4, then poured over 10 mL H2O. The organic layer was separated, and the aqueous layer extracted with ether (3x10 mL). The organic layers were recombined, dried over anhydrous MgSO4, filtered, reduced under vacuum and the crude product was purified by flash column chromatography (pentanes - 10% ether/pentanes), yielding a mixture of alcohols.

1 (Z)-Non-2-en-1-ol: H NMR (400 MHz; CDCl3) δ 5.56 (2H, m), 4.19 (2H, d, J = 6.1 Hz),

13 2.07 (2H, m), 1.33-1.19 (8H, m), 0.90-0.83 (3H, m); C NMR (400 MHz; CDCl3) δ

133.3, 128.5, 58.7, 31.8, 29.7, 29.0, 27.6, 22.7, 14.3; GC-MS (EI): m/z 142 (exact mass calcd. for C9H18O 142); GC (methyl silicone 100 °C): Rt 2.74 min. The data agreed with reported values69.

(E)-Non-3-en-1-ol: Identified via positive comparison to known 1H, 13C NMR, and GC spectra; 1H NMR and GC integration ratios corresponded positively. GC-MS (EI): m/z

142 (exact mass calcd. for C9H18O 142); GC (methyl silicone 100 °C): Rt 2.49 min. The data agreed with reported values70.

2.6.6 Hydrovinylation

Typical Hydrovinylation Procedure (Table 2.6): In an argon atmosphere glovebox,

(L)CoCl2 (0.013 mmol, 0.05 equiv) was added to a schlenk flask, removed from the box and purged with argon. DCM (2.4 mL) was added and the emerald green solution was stirred. A solution of activator (2.0 M, 0.060 mL, 0.12 mmol, 0.48 equiv) was added at r.t. and the solution was stirred for 5 min before being cooled to 0⁰C. The reaction flask was purged with ethylene via balloon and let stir for 5 min. Alkene (0.25 mmol, 1 equiv) was added and the reaction was allowed to warm to r.t. and was monitored by GC (aliquots taken and quenched with methanol in pentanes). After complete conversion of starting material, the reaction was quenched with a small amount of methanol, diluted with pentanes and run through a silica plug to yield hydrovinylated product.

1 (Z)-4-Vinyldec-2-ene (35): H NMR (400 MHz; CDCl3) δ 5.71 (1H, ddd, J1 = 17.1 Hz,

J2 = 10.2 Hz, J3 = 6.9 Hz), 5.50 (1H, dq, J1 = 6.8 Hz, J2 = 0.8 Hz), 5.21 (1H, ddq, J1 = 9.4

Hz, J2 = 9.4 Hz, J3 = 1.8 Hz), 4.98 (1H, ddd, J1 = 17.2 Hz, J2 = 3 Hz, J3 = 1.5 Hz), 4.93

(1H, ddd, J1 = 10.2 Hz, J2 = 1.8 Hz, J3 = 1.1 Hz), 3.05-2.98 (1H, m), 1.62 (3H, dd, J1 =

13 6.8 Hz, J2 = 1.8 Hz), 1.44-1.20 (8H, m), 1.44-1.19 (8H, m), 0.92-0.87 (3H, m); C NMR

(400 MHz; CDCl3) δ 142.0, 133.4, 124.0, 113.0, 41.4, 35.4, 32.1, 27.0, 22.5, 14.2, 13.2;

GC-MS (EI): m/z 152 (exact mass calcd. for C11H20 152); GC (methyl silicone 50 °C, 5 min; 15 °C / min): Rt 7.58 min. The data agreed with reported values71.

(E)-4-Vinyldec-2-ene (36): Identified via positive comparison to literature 1H, 13C NMR, and GC spectra; 1H NMR and GC integration ratios corresponded positively. GC-MS

(EI): m/z 152 (exact mass calcd. for C11H20 152); GC (methyl silicone 50 °C, 5 min; 15

°C / min): Rt 7.79 min. The data agreed with reported values71.

(E)-3-Methyldeca-1,4-diene (37): Identified via positive comparison to literature 1H, 13C

NMR, and GC spectra; 1H NMR and GC integration ratios corresponded positively. GC-

MS (EI): m/z 152 (exact mass calcd. for C11H20 152); GC (methyl silicone 50 °C, 5 min;

15 °C / min): Rt 8.13 min. The data agreed with reported values71.

1,4/1,5-Dodecadiene (38): GC-MS (EI): m/z 152 (exact mass calcd. for C11H20 152); GC

(methyl silicone 50 °C, 5 min; 15 °C / min): Rt 11.51 min.

1 1-(1-Methyl-2-propenyl)-4-methylbenzene (39): H NMR (400 MHz; CDCl3) δ 7.03

(4H, s), 5.91 (1H, dq, J1 = 16.9 Hz, J2 = 6.4 Hz), 4.98-4.91 (2H, m), 3.35 (1H, m), 2.24

13 (3H, s), 1.27 (3H, d, J = 7 Hz); C NMR (400 MHz; CDCl3) δ 143.6, 142.7, 135.7, 129.2,

127.2, 113.0, 42.9, 21.1, 20.9; GC-MS (EI): m/z 146 (exact mass calcd. for C11H14 146);

GC (methyl silicone 80 °C): Rt 3.92 min. The data was consistent with a known sample.

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Appendix A: 1H and 13C NMR Spectra from Chapter 2

63 64 65 66 67 68 69 70 Appendix B: 31P, 1H, 13C NMR Spectra and Gas Chromatograms from Chapter 2

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