I: BUCHWALD-HARTWIG-YAGUPOL'SKII AMINATION and THE SYNTHESIS OF DI- AND TRI-SUBSTITUTED OLEFINS USING Pd- PEPPSI-IPr
II; MECHANISTIC INTERPRETATIONS OF THE NEGISHIALKYL- ALKYL CROSS COUPLING PROTOCOL USING NMR SPECTROSCOPY
Stephanie Anne Avola
A Thesis Submitted to the Faculty of Graduate Studies In Partial Fulfilment of the Requirements for the Degree of Master of Science
Graduate Program in Chemistry York University Toronto, Ontario
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The first part of this research is aimed at the application of Pd-PEPPSI-IPr
(PEPPSI = Pyridine Enhanced Precatalyst Preparation Stabilization Initiation) as the
(pre)catalyst in a variety of metal-catalyzed cross-coupling reactions. Previous success with Pd-PEPPSI-IPr in Negishi, Kumada and Suzuki-Miyaura protocols promoted the exploration of this catalyst in the Buchwald-Hartwig-YagupoPskii (BHY) amination and in the sequential coupling of 1,1-dihalo-l-alkene type compounds. Pleasingly, the BHY
Amination proved successful in both strong base (KlOBu, Na'OBu) and mild base
(CS2CO3) conditions, generating a diverse library of coupled products. Interestingly, under CS2CO3 conditions, the electronics of the aryl halide and the basicity of the amine play key roles in the success of this coupling. After further investigation, it was confirmed that the aryl halide employed in the BHY amination followed a Hammet-type trend whereby the more electron-deficient aryl halides coupled more quickly and with greater yield than their electron-rich counterparts. Unfortunately, the same success was not obtained when trying to expand Pd-PEPPSI-IPr to Negishi and Suzuki-Miyaura couplings of 1,1-dibromo-l-alkene-type substrates to generate complex di- and tri- substituted olefins. Pd-PEPPSI-IPr was ineffective as a stereospecific cross-coupling catalyst in these sequential cross-coupling reactions. The optimization of various reaction parameters (solvent, temperature, additive, concentration etc.), together with a change of substrate, had minimal effect on the production of the desired di-substituted product.
iv Abstract
The second part of this research is directed toward exploring the mechanism of the transmetallation step for the Negishi alkyl-alkyl cross-coupling reaction by changing reaction conditions and employing NMR spectroscopy. Initial exploration in this area a few years ago led to a discovery that LiBr, in stoichiometric amounts, was an essential additive for successful Negishi alkyl-alkyl cross-coupling. Previous literature suggests that this is due, in part, to the inability of the alkyl-zinc reagent to undergo transmetallation; therefore requiring the additive to enhance reactivity and ultimately promote transmetallation. From this knowledge a 4000-level research project was conducted that evaluated a slew of additives and solvents as alternatives to LiBr in the
Negishi alkyl-alkyl protocol. The study concluded that >1 eq. of LiBr was the most effective additive in a 2:1 THF: DMI solvent mixture, but the reasons for this remained unclear. Intrigued by this phenomenon and by the uncertainty surrounding the mechanism of this reaction, NMR spectroscopy was utilized as a tool to observe and characterize the different XH, 13C and 7Li environments in solution in an effort to gain further insight into the transmetallation step in the catalytic cycle. The NMR data collected is consistent with our experimentation and is in line with previous research in this area, which suggests that the LiBr is required to further enhance the reactivity of the alkyl-zinc reagent making it capable of transmetallation onto the Pd catalyst and therefore promoting successful coupling. DEDICATION
This work is dedicated to my family and friends for all their love and support during my education. I also want to thank my two most beautiful companions, Angel and Honey, who love me unconditionally and greet me everyday with kisses and wagging tails.
VI ACKNOWLEDGEMENTS
I would like to acknowledge my major research advisor Dr. Michael Organ for his support and encouragement. Also, I would like to thank my committee members Dr. Pierre G. Potvin and Dr. Ed Lee-Ruff for their assistance in completing this project. A special thank you to Dr. Howard Hunter who was extremely helpful and supportive in his assistance with the NMR Spectroscopy studies. Finally I would like to thank my fellow graduate students for their help, friendship and laughter.
VI1 Table of Contents
Abstract Part 1 iv
Abstract Part 2 v
Dedication vi
Acknowledgements vii
List of Tables x
List of Figures xii
List of Schemes xv
List of Abbreviations xvi
Chapter 1: Introduction
1.1 Organometallic Chemistry and Homogeneous Catalysis 1
1.2 Palladium as the transition metal for cross-coupling catalysis 2
1.3 Carbon-Nitrogen Bond Formation: The Buchwald-Hartwig- Yagupol'skii Amination 5
1.4 PEPPSI as the Pd-based catalyst 9
1.5 Pd-PEPPSI as a catalyst in the cross-coupling reactions
of 1,1 -dibromoalkenes 11
1.6 Plan of Study 13
Chapter 2: Results and Discussions
2.1 Buchwald-Hartwig-YagupoPskii Substrate Study 15
2.2 Buchwald-Hartwig-Yagupol'skii Base Optimization Study 17
2.3 CS2CO3 and the Buchwald-Hartwig-Yagupol'skii Reaction 19 2.4 Conclusion 31
2.5-1 PEPPSI as a catalyst in the cross-coupling reactions of 1,1-dibromoalkenes 32
2.6 Conclusion 41
PART 2
Chapter 3: Introduction
3.1 LiBr as an additive in the Pd-PEPPSI catalyzed sp3-sp3 Negishi Cross-Coupling Reaction: A !H, 13C, 7Li-NMR spectroscopy study 42
3.2 Plan of study 48
Chapter 4: Results and Discussion
4.1 LiBr as an additive in the Pd-PEPPSI-IPr catalyzed sp3-sp3 Negishi Cross-coupling: A 'H, 7Li- NMR study 49
4.2 Conclusion 75
Part 3
ChapterS: Experimental
5.1 The Pd-PEPPSI-IPr catalyzed Buchwald Hartwig Animation 76
5.2 Pd-PEPPSI-IPr in the Negishi and Suzuki cross-coupling reactions of 1,1- dibromo-1-alkene type substrates 92
5.3 LiBr as an additive in the Pd-PEPPSI catalyzed sp3-sp3 Negishi Cross-Coupling Reaction: A H, Li, and "Zn NMR spectroscopy study 98
PART 4: References 105
ix List of Tables
Parti
Table 2.1: Pd-PEPPSI-IPr catalyzed animations utilizing strong base 16
Table 2.2: Initial Base Screenng of the Buchwald-Hartwig-YagupoPskii Reaction in DMF 17
Table 2.3: A solvent study with KOH in the Buchwald-Hartwig-YagupoPskii Reaction 18
Table 2.4: Temperature and Concentration study in DMI and THF using KOH as the base for the Buchwald-Hartwig-Yagupol'skii Reaction 19
Table 2.5: Re-optimization of the CS2CO3 protocol in the Buchwald-Hartwig- Yagupol' skii reaction 21
Table 2.6: Electronic substrate study for Pd-PEPPSI-IPr catalyzed animation
using Cs2C03 24
Table 2.7: N-methylaniline for Pd-PEPPSI-IPr catalyzed aminations with Cs2C03 28
Table 2.8: Substrate study with Nitrogen containing aryl substrates for Pd-PEPPSI-IPr catalyzed amination using Cs2C03 29
Table 2.9: Evaluation of Pd-PEPPSI-IPr as a catalyst for the Negishi cross-coupling employing compound 49 35
Table 2.10: Evaluation of Pd-PEPPSI-IPr as a catalyst for Suzuki-Miyaura cross-coupling employing compound 49 36
Table 2.11: Evaluation of Pd-PEPPSI-IPr as a catalyst for Negishi cross-coupling employing substrate 48 with phenylzinc bromide 39
Table 2.12: Evaluation of Pd-PEPPSI-IPr as a catalyst for Suzuki-Miyaura cross-coupling of 48 with phenylboronic acid 40
x Part 2
Table 4.1: Substrate study of Negishi cross-couplings with sp3 and sp2 centers 50
Table 4.2: Summary of lU and 13C NMR shift differences for n-butyl zinc bromide and dibutylzinc 59
XI List of Figures
Parti
Figure 1.1: General simplified mechanism for Pd-catalyzed cross -coupling reactions 4
Figure 1.2: General simplified mechanism for Pd-catalyzed C-N cross coupling reaction 7
Figure 1.3: Highly-active phosphine ligands in Pd-catalyzed amination reactions 8
Figure 1.4: The imidazolium salt IPrHCl [IPr = l,3-bis(2,6-diisopropylphenyl)
imidazol-2-ylidene 8
Figure 1.5: Organ group PEPPSI series 9
Figure 2.1: Effect of electron-poor or electron-rich/?ara-substituents on the Lewis acidity of Pd and its effect on amine coordination 23 Figure 2.2: Effect of p-substituted aryl halides (varying Hammett sigma constants (crp)) on isolated yields 25
Figure 2.3: Effect of p-substituted aryl halides (varying Hammett sigma constants (crp)) on initial reaction rates for Pd-PEPPSI-IPr 26
Part 2
Figure 3.1: A proposed zincate intermediate required for successful transmetallation in the Negishi reaction 44
Figure 4.1: Effects of increasing equivalents of LiBr in the Negishi
alkyl-alkyl cross coupling reaction 51
Figure 4.2: Possible formation of a higher order zincate reagent by LiBr 52
Figure 4.3: Effect of varying ZnBr2 or ZnCL. equivalents on the Negishi alkyl-alkyl cross coupling reaction 53 xn Figure 4.4: 'H-NMR spectroscopy of n-butylzinc bromide (1M, DMI) in a 2:1 THF:DMI solution 55
Figure 4.5: DEPT-135 of rc-butylzinc bromide (1M, DMI) in a 2:1
THF: DMI solution 56
l Figure 4.6: U NMR spectrum of dibutyl zinc (1M, ET20) 58
13 Figure 4.7: C NMR spectrum of dibutyl zinc (1M, Et20) 59
Figure 4.8: *H NMR spectrum of Dibutylzinc in a solution of THF:DMI (2:1) 60
Figure 4.9:13C NMR spectrum of Dibutylzinc in a solution of THF:DMI (2:1) 61
Figure 4.10: The proposed transition state of Me2Zn during alkyl exchange 62
Figure 4.11: ^-NMR spectra of «-butylzinc bromide in 2:1 THF: solution with doping of LiBr 63 Figure 4.12: 2D-COSY-NMR spectrum with H-butylzinc bromide and 0.75 equivalents of LiBr in a 2:1 THF: DMI solution 65
Figure 4.13: The proposed tetrahedral coordination of n-butyl zinc bromide in DMI solution 66
Figure 4.14: 7Li-NMR spectra of w-butylzinc bromide in 2:1 THF:DMI solution, with doping of LiBr 68
Figure 4.15: Overlay 7Li-NMR spectra of n-butylzinc bromide in a 2:1 THF:DMI solution with 1.2 eq. LiBr 69
Figure 4.16: !H-NMR spectra at -9.99°C for a 2:1 THF: DMI solution with «-butylzinc bromide [LiBr (0-1 eq.)] 72
Figure 4.17:13C-NMR spectra at -9.99°C for a 2:1 THF: DMI solution with n-butylzinc bromide [LiBr (0-1 eq.)] 72
Figure 4.18: XH-NMR spectra at -9.99°C for «-butylzinc bromide in a 2:1 THF: DMI solution [LiBr (0-1 eq)] 73
Figure 4.19: 13C-NMR spectra at 9.99°C for n-butylzinc bromide in a 2:1 THF: DMI solution [LiBr (0-1 equiv.)] 73 xiii Figure 4.20: Variable Temperature (VT) NMR spectroscopy for w-butylzinc bromide ina2:l THF.DMI solution 74
xiv List of Schemes
Parti
Scheme 1.1: The reported first cross-coupling reaction with Grignard reagents by the Kumada group 2
Scheme 1.2: The first reported cross-coupling reaction with Grignard reagents by the Corriu group 3
Scheme 1.3: The animation reaction of free amines reported independently by Buchwald and Hartwig 4
Scheme 1.4: Sequential cross-coupling approach to di- and tri-substituted olefins 11
Scheme 2.1: Negishi's use of Pd-NHC complexes for the synthesis of (IE)-I,3-trienes 33
Scheme 2.2: Corey-Fuchs reaction to generate methyl 4-(2,2-dibromovinyl) benzoate 34
Scheme 2.3: Synthetic pathway for the formation of methyl-7,7-dibromohept- 6-enoate from e- Caprolactone 37
Part 2
Scheme 3.1: Preparation of Rieke Zinc 43
Scheme 3.2: Preparation of w-butylzinc bromide with Huo's protocol 43
Scheme 3.3: Preliminary investigation of zinc activation 45
Scheme 3.4: The Schlenk Equilibrium with organozinc reagents 46
Scheme 3.5: The aggregative behaviour of organozinc reagents
in varying solvents 46
Scheme 3.6: The effect of bridging ligands on the exchange of organozinc reagents...47
Scheme 4.1: Knochel's proposal of the activation of iPrMgCl with LiCl 52
Scheme 4.2: Modified Schlenk equilibrium prior to LiBr addition 66
Scheme 4.3: Modified Schlenk equilibrium upon addition of LiBr 70 xv List of Abbreviations acac = acetylacetone dba = dibenzylideneacetone dpephos=Bis(2-diphenylphosphinophenyl)ether dppb = diphenylphosphinobutane dppe = diphenylphosphinoethane
DME = dimethoxyethane
DMF = domethylformamide
DMI = l,3-dimethyl-2-imidazolidinone
DMSO = dimethylsulfoxide
THF = tetrahydrofuran
NMP = l-methyl-2-pyrrolidione
xvi Part I
Chapter 1: Introduction
1.1 Organometallic chemistry and homogeneous catalysis
Organometallic compounds can be defined as substrates that contain, to some extent, a polarization between the metal and carbon atoms.1 Since the synthesis of the first platinum organometallic compound by Zeise in 1827, (K[PtCl3(CH2=CH2)],2 the area of organometallic chemistry has grown enormously, and with rapid speed, with most of its applications to synthetic organic chemistry being developed in recent decades. This budding interest can be attributed to the high selectivity of organometallic complexes in organic synthesis (i.e. catalysis), and to the interesting roles that metals play in biological
systems (e.g. enzymes, hemoglobin etc.).
A very significant application of some organometallic compounds is their ability to act as homogeneous catalysts in reactions where the substrates are all in the same phase. In these reactions, transition metal complexes operate by bringing substrates together; they can activate the substrates via coordination, and decrease the activation
energy of the reaction.4 For these reasons, homogeneous catalysis can provide simple,
more facile routes to synthesize diverse organic and inorganic compounds in the
laboratory that would normally be slower under conventional methods.
The success of organometallic catalysts in a multitude of organic reactions lies in
their ability to modify the environment of the metal by ligand exchange. The
coordination of different types of ligands to transition metals can alter their behaviour
and reactivity in ways that make the catalyst more suiTable for one particular organic
1 transformation above another.5 In fact it is well established in this area of chemistry that both the rate and selectivity of a given process can be optimized to the desired level by manipulating the ligand environment.5 Hence, understanding the role played by the ligand is key to improving catalytic efficiency, turnover, and ultimately yield.
1.2 Palladium as the transition metal for cross-coupling catalysis
Palladium is one of the most extensively studied metals in catalysis because of its versatility and extensive applicability in a multitude of organic reactions. Among the most important Pd-catalyzed reactions are those which involve the formation of new C-C bonds such as oligomerization and polymerization of alkenes, carbonylation of alkenes
and organic halides, Wacker oxidation of alkenes, allylic alkylation, etc.6 Over the last
30 years, an alternative strategy for C-C bond formation has been developed and has
gained wide-spread attention and application in the synthetic organic community. The
coupling of organometallic reagents with organohalides, otherwise known as "cross-
coupling", first came to light in 1972 with the nickel-catalyzed reaction of Grignard reagents with 1-alkenyl or aryl bromides and chlorides, independently reported by
Kumada and Tamao7a (Scheme 1.1) as well as Corriu and Masse7b (Scheme 1.2). Since this time, a plethora8'9
Scheme 1.1: The first cross-coupling reaction with Grignard reagents reported by the Kumada group
89% Cl Q-MgBr ^ NiCI2(dppe), Q^
Et20, RT, 24h
2 Scheme 1.2: The first cross-coupling reaction with Grignard reagents reported by Corriu
^"O 70%
Et20, RT of various organometallic reagents (organotins, organoborons, organozincs etc.) and aryl halide or pseudo-halide partners (aryl, alkyl, alkenyl, vinyl etc.) have been investigated and expanded the scope of transition metal cross-coupling catalysis to include the formation of C-X (O, N, P, Si, S etc.) bonds in addition to C-C bonds in a highly stereospecific manner.9 Over time, Pd, not Ni, has become the more attractive transition metal for these coupling reactions, due to its more favourable reactivity with softer organometallic coupling partners and its ability to maintain the stereochemical integrity of alkyl and alkenyl starting materials.6 There are four oxidation states for palladium that are encountered in organometallic chemistry: Pd(0), Pd(I), Pd(II) and Pd(IV). The reduction from Pd(II) to Pd(0) alters the reactivity of the metal as it changes the palladium center from electrophilic to nucleophilic, marking the start of the palladium catalytic cycle. The initial step is referred to as oxidative addition, subsequently followed by transmetallation, and reductive elimination to yield the coupled organic fragments (Figure 1.1). Oxidative addition involves the addition of R-X (R=alkyl, aryl, vinyl; X= halide or triflate) to Pd(0) via insertion into the covalent bond to generate two 'new' bonds to Pd, which in the process oxidizes Pd(0) to Pd(II) (Figure 1.1). Transmetallation involves 3 oxidative addition Figure 1.1: General simplified mechanism for Pd-catalyzed cross -coupling reactions the transfer of the nucleophile from the metal in the organometallic reagent to palladium while the counter-ion, i.e. X= halide or triflate, moves in the opposite direction. The success of this process is attributed to the differences in electronegativities between the two metals.11 Finally, reductive elimination 'couples' the two groups bound to Pd to yield the desired product and Pd(0) is regenerated; hence the catalytic nature of Pd. Popular organometallic coupling partners include, but are not limited to, organotin (Stille),12 organoboron (Suzuki-Miyaura),13 organozinc (Negishi),14 organosilicon (Hiyama),15 and organomagnesium (Kumada-Tamao-Corriu)7 reagents. More recently, free amines (Buchwald-Hartwig-YagupoPskii Animation)16"18 have been successful in C- N bond formation under Pd catalysis. 4 1.3 Carbon-Nitrogen bond formation: The Buchwald-Hartwig-Yagupol'skiiAmination The first palladium-catalyzed formation of aryl C-N bonds was reported in 1983 by Migita and co-workers.19a The reaction utilized aryl bromides and aminotin reagents under a Pd phosphine catalyst system {[(o-tol^PkPdCk) to yield efficient preparation of the corresponding aniline in moderate to good yield.19a Although a ground-breaking discovery, the application of such a protocol was limited by the necessity to use thermally and moisture-sensitive tributyltin amides. The following year, Boger and Panek revealed an intramolecular amination with a free amine to achieve the P-carboline skeleton toward the total synthesis of lavendamycin using a stoichiometric amount of Pd(PPli3)4.19b In 1985, the use of catalytic amounts of palladium was reported by YagupoPskii and co- coworkers to produce various substituted polynitro- and poly(trifiuoromethylsulfonyl)- substituted diphenylamines via the coupling of suiTable functionalized aryl chlorides with anilines in the presence of sodium hydride base and 10 mol% PhPdI(PPh3)2.19c In 1995, the two research groups of Buchwald17 and Hartwig18 independently reported successful catalytic animations of aryl bromides with free amines.20 Employing NaO/-Bu as base, the two groups were able to positively effect catalytic C-N bond formation (Scheme 1.3). Since then their extensive work in the area has made the Buchwald-Hartwig-Yagupol'skii (BHY) amination one of the foremost carbon-nitrogen bond-forming reactions utilized today.6'9'21 Currently aryl halides, triflates and tosylates are coupled efficiently with aryl and alkyl amines, amides, sulfonamides, imines and nitrogen containing heterocycles using a variety of reaction conditions.6'9'21 5 Scheme 1.3: The amination reaction of free amines reported independently by Buchwald and Hartwig 2 mol% rLHUUcUPd(dba)22/[(o-tol)3]'UU-iui,3j22Pr MR2R3 1 + H-NR2R3 or [(o-tol)3P] PdCI2 rr^^ RV^ NaOf-Bu "*" R^ Toluene 65or110°C The proposed catalytic cycle (Figure 1.2) begins with the oxidative addition of a Pd(0) species into the carbon halide or psuedo-halide bond. The second step requires coordination of the amine, where at temperatures below 50 °C, subsequent deprotonation results in formation of an anionic amido complex, whereas at temperatures above 50 °C, a neutral tri-coordinated species is preferred. The last step is reductive elimination to yield the product simultaneously with the regeneration of Pd(0) free to rejoin the cycle.6'9'12'22 In recent literature, both Buchwald and Hartwig have shown that the supporting ligands on the metal center play a critical role in the efficiency of catalytic amination.23 To date, the most commonly employed ligands for Pd are bulky monodentate orbidentate phosphinesPX (X=P, N, O)23 (Figure 1.3), with Buchwald's biaryl phosphine (6) having the broadest applicability in Pd-catalyzed animations.24'25 Recently, N-heterocyclic carbene (NHC) ligands, first investigated by Arduengo,26have been utilized as ligands for palladium in the arylation reaction and show great promise.27 Nolan et al.2B reported Pd(dba)3 and an imidazolium chloride could form an active catalyst in situ for the amination of aryl chlorides. The imidazolium salt IPrHCl [IPr = l,3-bis(2,6- diisopropylphenyl)imidazol-2-ylidene (Figure 1.4) was found to provide efficient 6 W + nL catalyst precursor HOf-Bu ) { KOf-Bu \ L = Phosphine or NHC other bases used include NaO-f-Bu, KOH, Cs2C03 Figure 1.2: General simplified mechanism for Pd-catalyzed C-N cross-coupling reaction transformation in this catalytic system, however the use of an in situ generation of the Pd- NHC complex was not without shortcomings. One major unattractive feature in earlier NHC-based protocols was the in situ generation of the free carbene from a precursor azolium salt in the presence of a Pd(II) or Pd(0) source.29 Aside from the potential wasting of precious Pd and ligand precursor, the uncertainty of catalyst formation makes reactions variable and unreliable and removes the ability to construct meaningful rate studies. The uncertainty surrounding the stoichiometry and composition of the active species has therefore retarded mechanistic interpretation from the results, hence impeding 7 11 ^ x^ ~PPh2 PPh, , PPft, t^^r^f .Jl J!. .J PhP-. "*.>. ^-^s .,'•' Me. 1 V- R r *«* T PCyTO , &&. Me*N, '"PPh, 24 M ? ' R = OMe 4 R = Ph m r % R = NMe2 S2- R=Cy' i243 R = Pfflu, Figure 1.3. Highly-active phosphine ligands in Pd-catalyzed amination reactions. Figure 1.4 The imidazolium salt IPrHCl [IPr = l,3-bis(2,6-diisopropylphenyl)imidazol- 2-ylidene both the understanding and further development of this process.30 Taken together, the aforementioned factors have slowed widespread adoption of NHC-based methodology in cross-coupling protocols. For these reasons, we and others ' have developed well- defined NHC-palladium precatalysts. 1.4 PEPPSI as the Pd-based catalyst Our lab has been successful in the development of well-defined, air- and moisture- sTable NHC-palladium (II) precatalysts known as the Pd-PEPPSI series (Figure 1.5). Compared to the common trialkylphosphines, NHC's are easier to handle, safer to work with as some phosphines are pyrophoric, and ultimately better o donors leading to enhanced electronic properties of the metal to which they are bound.27 The benefit of this last property allows coupling partners that would normally be resistant or slow to undergo oxidative addition (i.e. alkyl and aryl chlorides) to have the ability to partake in the catalytic cycle, since there is enhanced electron density on the Pd(0) metal. As well, the steric environment imposed by the bulky N-aryl groups on the imidazolium ring serves to facilitate reductive elimintion of the desired coupled product. These catalysts have already demonstrated great success in the Suzuki-Miyuara (SM),31 Figure 1.5: Organ group PEPPSI series (Pyridine Enhanced Pre-catalyst Preparation, Stabilization and Initiation). 9 Negishi, and Kumada-Tamao-Corriu (KTC) reactions (projects directed at the Negishi and Suzuki protocols are discussed at length later in this report). In a continuing effort to increase the ease -of- use and therefore wider employment of NHC methodology, we have chosen to focus on the employment of these catalysts in the Buchwald-Hartwig-Yagupol'skii (BHY) protocol. A major drawback with the BHY amination is the need for a strong base (eg. O'Bu) to deprotonate the amine partner, because such conditions are not functional group-tolerant and/or industry-friendly.3 The employment of a weaker base (i.e. CSCO3), whose functional group tolerance is far greater that that of the aforementioned bases, would be ideal for the widespread application of this protocol. The use of cesium salts in a variety of synthetic conversions has received increasing interest in the last two decades.2911 The benefits of employing cesium salts in organic synthesis are exemplified in reactions such as Pd-catalyzed Suzuki-Miyaura coupling or the Buchwald-Hartwig-Yagupol'skii amination. " The unique effect of cesium salts stems from the special properties of the cesium cation: it has a very large atomic radius, a low charge density and a high polarizability. Bases like sodium or potassium tert-butoxide are too strong and thus induce side reactions, while bases like potassium carbonate are too weak or not soluble enough to participate in the desired reaction.38 The higher cost of cesium is offset by clear advantages such as higher yields, shorter reaction times, and milder reaction conditions.36 To design a reaction that is both efficient and tolerant of functional groups, the choice of a base that is neither too strong 10 nor too weak is essential. For these reasons, CS2CO3 was selected and optimized for the Buchwald-Hartwig-Yagupol' skii amination. 1.5 Pd-PEPPSI-IPr as a catalyst in the cross-coupling reactions of 1,1-dibromoalkenes The stereoselective synthesis of di- and trisubstituted alkenes still remains an intriguing goal in organic synthesis.40 Although this structural unit appears in a variety of natural products and materials,40 general, yet fully stereoselective approaches to compounds of this class remain a challenge.40 Depending on the array of functionality and types of organic groups desired to be proximal to the alkene, a number of diverse approaches to di- and trisubstituted alkenes can be chosen. The Wittig and other carbonyl olefination reactions41 have played a dominant role in these syntheses; but these reactions often fail to display high stereoselectivities. Alternatively, a more highly stereoselective approach employing hydrometalation42 and carbometalation42 'c' 43' u of alkynes results in the difficulty of the former to synthesize trisubstituted alkenes in a highly regioselective manner, and a non-convenient route to (£)-alkenes for the latter. Scheme 1.4: Sequential cross-coupling approach to di- and tri-substituted olefins *\# -^ . R^R2 __^ . R3-Y* X-CI Efretc Bfe'PdCata|yst R1 Base, Pd Catalyst R1 X-CI.Bretc. R3= aryl> a,kyl) alkenyl R4= aryl, alkyl, alkenyl M= Zn, B(OH)2, Mg, Sn etc. M= Zn> B(0H)z Mg> Sn etc One approach to stereodefmed di- and trisubstituted alkenes is stepwise cross- coupling of readily available 1,1-dihaloalkenes (Scheme 1.4). The reaction is thought to 11 proceed through a succession of three basic steps previously summarized in Scheme 3. Earlier work in this area from Minato and Tamao revealed that organomagnesium and organozinc reagents could be partnered with 1,1-dichloroalkenes to afford several trisubstituted alkenes via two-pot sequential couplings.45 In 1999, Shen and Wang applied the Stille coupling12 to the disubstitution of 1,1-dibromo-l-alkenes.4 Most recently, Negishi and co-workers reported that the palladium complexes PdCl2(dpephos) and Pd(PPti3)4 successfully catalyzed various stereoselective cross-couplings using 1,1- dihaloalkenes.47 Furthermore, Soderquist and co-workers investigated the double- intermolecular Suzuki-Miyaura cross-coupling reaction (methylation/methylation) of 1,1- dibromo-l-alkenes47 and also applied a related protocol to the formation of various cyclic compounds.48 Based on the success of the aforementioned protocols, and in a continuing effort to enhance the scope and utility of Pd-PEPPSI-IPr as a universal cross-coupling catalyst, 1,1-dibromosubstituted alkenes were subjected to conditions optimized by Organ et al. for the Negishi34 and Suzuki-Miyaura31 protocols. 12 Plan of Study To begin, PaVPEPPSI-IPr was selected as the (pre)catalyst to initiate the investigation and optimization of the Buchwald-Hartwig-YaguoPskii amination. This was due to the enhanced reactivity and turnover of Pd-PEPPSI-IPr compared with Pd- PEPPSI-IEt and Pd-PEPPSI-IMes in previous studies involving the Negishi, Suzuki- Miyaura and Kumada cross-coupling protocols. Initially, stronger and more common bases for this protocol i.e. tert-butoxides, were investigated; however the goal was to create an industrially friendly amination protocol that would maintain the chemical integrity of sensitive functional groups e.g. esters, ketones, aldehydes. Moving away from these harsher bases, milder bases such as carbonates and phosphates were examined. The reaction parameters of the Buchwald-Hartwig-Yagupol'skii amination were re-optimized in an effort to achieve comparable yields and substrate complexity to the stronger base protocol. After re-optimization proved unsuccessful, the focus of the project shifted to conducting experiments aimed at understanding the mechanism of this reaction. Aryl substrates with different electronics were investigated to see what role, if any, electronics played in the success of this mild-base protocol. Furthermore, amines were examined to determine if basicity was also a factor for successful amination with a mild base. To this end, a rate study and Hammett analysis37 was also conducted to shed light on the mechanism of this popular cross-coupling reaction. To further expand the scope and versatility of Pd-PEPPSI-IPr 1,1-dihalo-l- alkene-type substrates were synthesized and subjected to Negishi and Suzuki-Miyaura cross-coupling conditions to generate stereospecific di- and tri-substituted olefins. 13 Although a slew of organometallic reagents are available for cross-coupling catalysis, the Suzuki-Miyaura and the Negishi reactions were most attractive because many suiTable organometallic reagents are readily available from commercial sources or can be easily prepared. Moreover, these two protocols are well known for their functional group tolerance, which would aid in the synthesis of organic compounds possessing a wide variety of functional groups. Methyl 4-(2,2-dibromovinyl)benzoate and methyl 7,7- dibromohept-6-enoate were the alkenes selected for this project. Although the Negishi and Suzuki-Miyaura conditions had previously been optimized, further optimization of these two protocols was necessary to generate successful coupling. 14 PARTI Chapter 2: Results and Discussion 2.1: Buchwald-Hartwig- Yagupol'skii Substrate Study Previous work in the Organ group demonstrated the success of complex 12 in the formation of C-N bonds. Optimization studies revealed that potassium or sodium t- butoxide (KOfBu, NaO'Bu) in anhydrous dimethoxyethane (DME) led to moderate to excellent yields (70-80%) with 4-phenylmorpholine (26) as the amine. From these promising results, a more complex and diversified substrate study was conducted. The focus was to generate more 'drag-like' structures through the use of more functionalized, heteroatom-containing substrates. The results were very pleasing as difficult substrates were able to couple cleanly and efficiently using the general conditions shown in Table 2.1). Notably, sterically-encumbered aryl chlorides (see products 18 and 20) or amines (see products 20, 22 and 23) all coupled in high yields. We were also pleased to find that a variety of heterocycles (see products 14-17, 19, and 21-23) were compatible with this protocol. The reaction between the highly sterically-hindered substrates 2,6- diisopropylaniline and 2-chloro-m-xylene, affording 20 in 90% yield, is noteworthy. Despite the better-than-average results depicted in Scheme 2.1, it was obvious that the success of this reaction was heavily reliant on the use of a strong base (i.e. KO'Bu/Na'OBu) to effectively deprotonate the amine and allow coupling to occur. As previously mentioned, functional group tolerance is one of the main concerns when a strongly basic environment is used. Under these conditions, groups like methyl and ethyl esters, enolizable ketones or nitro groups would also react. Therefore, the chemical 15 integrity of these substrates, throughout the Buchwald-Hartwig-Yagupol'skii catalytic cycle, would not be maintained. Although the 'strong base' protocol produced complex compounds that were only obtainable previously with highly active phosphine systems,23,24 we were motivated to expand the scope of this reaction to include milder bases that have not proven useful in this protocol with NHC catalysis. To this end, further investigation into the Buchwald-Hartwig-Yagupol'skii animation reaction utilizing milder, more functional group-tolerant bases was undertaken. Table 2.1. Pd-PEPPSI-IPr catalyzed aminations utilizing strong base , 12,2mol% , H R R 1 R1 R -CI + ^N^ ffiuOK(1.5equiv), DME^ ^N' 3 R RT, 24h R3 1.2 equiv Reactions were performed in duplicate and the average isolated yield reported. a Reactions were performed at 50°C.b reactions were performed using NaO'Bu . 16 2.2: Buchwald-Hartwig-Yagupol'skii Base Optimization Study Table 2.2 displays the results from the initial base screening conducted in dimethylformamide (DMF). As is apparent, the initial results were discouraging. Entry 1 provided the greatest conversion of 25 to 26 (60%) whereas every other base attempted led to poor conversion. Table 2.2: Initial Base Screenng of the Buchwald-Hartwig-Yagupol'skii Reaction in DMF 12, (4mol%) ^ CL /-^5^/cl 3 ecluiv base J f ] DMF ^ ^N C + \T ^^ 70°C,24h °s^ H 1.2 equiv 24 25 26 Entry Base % Conversion" 1 KOH 60 2 KOH(aq) (1M) 0 3 K2C03 39 4 Cs2C03 16 5 CS2C03(aq)(lM) 0 (92% SM) 6 NaC03 0 7 K3PO4 30 8 K3P04(aq)(lM) 6 9 Cs(OH)2 11 10 KOAc 0 11 NaOAc 0 "Percent conversion against a calibrated internal standard (undecane); reactions were performed in duplicate and the average conversion reported The addition of water to the solution with entries 2, 5, and 8 did nothing to improve the overall outcome as poorer conversions were obtained than with anhydrous base. The moderate result in entry 1 prompted a solvent (Table 2.3), temperature and concentration screening (Table 2.4) of potassium hydroxide under the conditions outlined 17 in both Tables. l,3-Dimemyl-2-imidazolidinone (DMI) proved most successful in the production of 26 with an isolated yield of 69% (Table 2.3, entry 4). The use of toluene (Table 2.3, entry 6) and THF (Table 2.3, entry 7) also proved successful with 66% and 65%, respectively. The best conditions from Table 2.3 (entries 4 and 6) were then Table 2.3: A solvent study with KOH in the Buchwald-Hartwig-Yagupol'skii Reaction 12,(4mol%) ^O,^ /^^Cl KOH (3 equiv) solvent r^^N' \^ 70°C, 24h • ~0 H 1.2 equiv 24 25 26 Entry Solvent % Conversion" 1 DMF 39 2 Dioxane 61(49) 3 DME 42 4 DMI 70 (69) 5 Methanol 0 6 Toluene 65(65) 7 THF 68 (66) 8 DMSO 59 9 Acetonitrile 0 10 Isopropanol 0 " Percent conversion against a calibrated internal standard (undecane); reactions were performed in duplicate, and the average conversion is reported. The number in parentheses indicate the average isolated yield (in duplicate). subjected to a temperature and concentration screening to determine the best combination of solvent, temperature and concentration for successful coupling. As shown in Table 2.4, increasing the reaction temperatures from 70°C to 80°C, and employing a 1M reaction concentration increased conversion from moderate to excellent (88%). 18 Table 2.4: Temperature and Concentration study in DMI and THF using KOH as the base for the Buchwald-Hartwig-YagupoFskii Reaction 12,(4mo!%) r^i •°N „CI KOH (3 equiv) solvent L 1 temp, 24h • 0 H 1.2 equiv 24 25 26 Entry Solvent Conditions FfeMW 1 DMI 80°C 75 2 THF 70°C 77 3 DMI 80°C, 0.5M 79 4 THF 70°C,0.5M 82 5 DMI 80°C, 1M 83 6 THF 70°C, 1M 88 "Reaction were isolated by column chromatography, in duplicate, with the average yield reported. Notwithstanding the success of potassium hydroxide in this reaction, the presence of hydroxide in solution still creates a strongly basic environment that is capable of destroying sensitive functionalities in the starting substrates. Therefore, there was still a desire to search further into this reaction mechanism and employ a 'milder' base such as 2 Cs2C03 (pKa 10.3, HCCV •> C03 ; pKa 15.74, H20 -» OH). To date, there are few successful reports in the literature using Cs2C03 as the base for this reaction and none that show success under a Pd-NHC catalyst system.27' 28, 33 Inspired from a result by a colleague, Nilofar Hadei, who obtained a moderate yield of 26 with Cs2C03 in a 1M solution of dimethoxyethane (DME), the intent was to continue with this investigation. 2. 3: CS2CO3 and the Buchwald-Hartwig-Yagupol'skii Reaction Given that CS2CO3 could function as a base in the Buchwald-Hartwig- Yagupol'skii reaction, many conditions were tried that included change of halide source, 19 equivalents of base employed, temperature, and solvent, to observe if the yields could be further enhanced. This was indeed the case as DME, with 3 equivalents of CS2CO3, provided very good conversion and yield (Table 2.5, entries 15) for phenylmorpholine. Similarly, THF (Table 2.5, entry 23) at 70°C was also successful (the reaction was sealed and pressurized). Interestingly, the use of anhydrous CS2CO3 was critical for amination as entries 1, 2, 5-9, 13 and 14 gave poor conversions compared with entry 15. Furthermore, employment of K2CO3 in this reaction (Table 2.5, entries 3, 4, 16 and 17) was unsuccessful. With these results in hand, the intention was to move forward with a more diverse and complex substrate study; however, attempts to expand the substrate scope to form more complex products using these conditions proved unsuccessful. In fact, these conditions only worked for morpholine and chlorobenzene. To help explain these results, the electronics of the BHY reaction were investigated with the intent that these studies may provide necessary mechanistic information. From ongoing computational studies that have been disclosed,3113 we believe the rate-limiting step for our Pd catalyst in organometallic-based cross-coupling reactions (i.e. SM, Negishi, KTC) to be the transmetallation step (see Figure 1.1) where the second coupling partner is transferred from the organometallic reagent (nucleophile) to the Pd center (electrophile). Although different, amine coordination in the Buchwald-Hartwig-Yagupol'skii Amination cycle (Figure 1.2) is comparable to transmetallation with an organometallic reagent (Figure 1.1) since both require an electron-deficient Pd center for successful exchange/coordination. That being said, the difference in yields observed when changing 20 Table 2.5: Re-optimization of the Cs2C03 protocol in the Buchwald-Hartwig-Yagupol'skii reaction 12, (4mol%) ^ Cs2C03 (3 equiv) i 3 24h • H 1.2 equiv 24 25 26 iinfry Base Halide Equiv. Solvent [M] Temp Additive % Conversion" (°Q 1 Cs2C03 CI 3 DME 80 - 12 2 Cs2C03 CI 3 DME 80 H20 0 3 K2C03 CI 3 DME 80 - 0 4 K2C03 CI 3 DME 80 H20 0 5 Cs2C03 Br 3 DME 80 - 9 6 Cs2C03 CI 4 DME 80 - 10 7 Cs2C03 CI 4 DME 0 5 80 - 10 8 Cs2C03 CI 5 DME 80 - 9 9 Cs2C03 CI 5 DME 0 5 80 - 10 10 Cs2C03 CI 3 Toluene 80 - 0 11 Cs2C03 CI 3 Dioxane 100 - 0 12 Cs2C03 CI 3 Aniline 100 - 0 13 Cs2C03 CI 3 DME 100 - 11 14 Cs2C03 CI 3 DME 120 - 13 M 15 Cs2C03 CI 3 DME 80 - 80 (79) C 16 K2C03 CI 3 DME 80 - 8 C 17 K2C03 CI 3 DME 80 - 9 18 Cs2C03 CI 3 DMF 80 - 60" 19 Cs2C03 CI 3 Dioxane 80 - 51" 20 Cs2C03 CI 3 DMI 80 - 12* 21 Cs2C03 CI 3 Methanol 80 - 0" 22 Cs2C03 CI 3 Toluene 80 - 48' w 23 Cs2C03 CI 3 THF 70 - 87 (72) 24 Cs2C03 CI 3 DMSO 80 - 0 25 Cs2C03 CI 3 Acetonitrile 80 - 0 26 Cs2C03 CI 3 Isopropanol 80 - 0 "GC yie d against a calibrated internal standard (undeca le; ; reactions were jerformed in duplicate, and the average conversions reported. Reactions were isolated by column chromatography, in duplicate, c with the average yield reported in brackets. K2C03 was ground with a mortar and pestle to observe any d changes in solubility and yield. Reactions were performed using Cs2C03 stored in the glove box under an inert atmosphere. 21 bases (i.e. strong to mild) in the BHY animation suggests the deprotonation of the Pd- bound amine, not amine coordination, as most likely being the rate-determining step of this process. Although there has been extensive mechanistic work by both Buchwald49 and Hartwig with phosphine ligands, to date there has been one DFT computational paper on the BHY arylation with carbene ligands.51 Unfortunately, this work does not contain calculations of the deprotonation step of the Pd-bound amine to confirm this theory. However, our previous publications,21a"b'31'35 have demonstrated that the strongly a-donating NHC ligand would render the oxidative addition facile, and the steric bulk of the IPr ligand would enhance the rate of reductive elimination. To probe the importance of electron rich vs. poor substrates, aryl halides with varying electronic properties (i.e. electron-donating or withdrawing-groups) were tested. We proposed that aryl halides possessing electron-withdrawing substituents, upon successful oxidative addition, would pull electron density away from the Pd catalyst in solution, thus creating a more electrophilic palladium complex to facilitate amine coordination onto palladium and ultimately increase the catalyst turnover (Figure 2.1). Conversely, strongly electron-donating oxidative addition partners would suppress turnover as too much electron density is added to Pd thus decreasing its electrophilicity and ultimately hindering amine coordination. Keeping the amine as 24, the results appeared to confirm our theory as the yields steadily increased as the electron- withdrawing ability of the aryl substrate increased (see Table 2.6, Figure 2.2) along with the initial reaction rates (Figure 2.3). In contrast, the yields generated for aryl substrates with electron-donating groups (30, 19) decreased significantly, hence proving that the 22 electronics of the substrates play an important role in the success of this reaction with our Pd-NHC catalyst. The results suggest that more electron-deficient coupling partners (e.g. 'R = OMe, Me, H, CF3, N02' Substituent will affect Lewis acidity of Pd 9 NHC Pd-X Degree of amine coordination is dependent on Lewis acidity of Pd. At shorter distances, the PKA R2N—H by weaker bases (i.e. Cs2C03). Figure 2.1: Effect of electron-poor or electron-rich para-substituents on the Lewis acidity of Pd and its effect on amine coordination. NO2) are more successful in achieving high yields and thus successful amination than electron-donating substituents (e.g. OMe). Although l-chloro-4-fluorobenzene, the aryl amination partner of 29, is more electron-deficient than 1-chlorobenzene, the aryl amination partner of 26, we never able to achieve a yield higher than 67% for this coupling reaction. This was the only case where the yields did not follow the electronic trend that we had observed for the other substrates. The reasons for this anomaly remain unclear; however, a plausible explanation may lie on a competition between the C-F bond and the C-Cl or C-Br bond for oxidative addition, ultimately slowing the catalytic cycle and possibly increasing catalyst death. The mass balance of 29 was un-reacted starting material, and this was confirmed using both GC/MS and 'H-NMR analysis. No other by products were observed in the reaction mixture, suggesting that the aforementioned explanation may be the case. To rule out the possibility that these results are due to different rates of oxidative addition, and not amine coordination or subsequent deprotonation, we subjected the same 23 halide partners to the Suzuki-Miyaura reaction (Figure 2.2, reaction 2) and found that all aryl chlorides gave essentially the same level of reaction. Moreover, the yields of Table 2.6 Electronic substrate study for Pd-PEPPSI-IPr catalyzed animation using Cs2C03 R 12, (4mol%) x Cs C0 (3 equiv) 2 3 ^ DME f^N' X R 80°C, 24hrs °s/ 1.2-1.5 equiv 1.0 equiv 24 R=CF3, N02 OMe etc X= CI, Br 0 N"^ 27 X= Cl, 92% 22 X= Q, 96% X= Cl, 80% X=Br,94% X= Br. 98% X= Br, 78% sKJ 28 ^ JCTV X= Cl, 38% x=a, 16% X= Cl, 67% X= Br, 35% X=Br,27% X=Br,64% Reactions were performed in duplicate and the average isolated yield reported. The mass balance for all products shown was starting material. Buchwald-Hartwig-Yagupol'skii amination were identical for aryl bromides and chlorides carrying the same /?-substituent. Taken together, these results are consistent with the notion that oxidative addition is not the rate-determining step with the IPr NHC ligand. 24 X 12, 4mot% C!?5??iL?f*L 0 N DME,8G C,;NH H r R reaction 1 CI S(OH}i, 12, 2mol% KaC03i3aqyiv) 1,4-dfewarte v^ 60*0,2* ^l^^- R reaction 2 too 90 70 * 60 ,1 > 50 •a j§ 40 "3 * 30 20 10 I 0 R"NOj R»CF, R«H R«CHI» R-OCH; 0» 0.778 O.-0.S40 o» 0.000 0»-0,170 0,^-0.268 Decreasing Ms •Reaction 1,X«Br I I Reaction 1, X •"• CI Reaction 2 Figure 2.2: Effect of p-substituted aryl halides (varying Hammett constants (op) on isolated yields (24 h) for Pd-PEPPSI-IPr (12)-catalyzed amination (reaction 1) and Suzuki-Miyaura reaction (reaction 2). Reactions were performed in duplicate and the average isolated yield is reported. 25 5 R»NOj R = CF3 R«H R«CH3 R»OCHs af" 0.778 af« 0.540 ap«° 0.000 o,,--0.170 ap •« -0.268 Decreasing HamtaettOp Constant ' """"'; "~\ • Reaction 1, X - Br • Reaction 1, X - CI Figure 2.3: Effect of p-substituted aryl halides (varying Hammett constants (op) on initial reaction rates for Pd-PEPPSI-IPr (12)- catalyzed amination (reaction 1). Reaction rates were calculated from the linear portion (t=0 to 240 min) of a product concentration versus time plot. Reactions were performed on a 2 mmol scale (aryl halide) with 3 mmol morpholine, 3mmol CS2CO3 and 4 mol% of 1 in 2 mL 1,2-dimethoxyethane (DME) at 80°C. Products were quantified by GC/MS analysis using undecane (100 ul mmol"1 of aryl halide) as a calibrated internal standard. With these results in hand, we wanted to examine the amine partner. We theorized that coordination of the amine to the Pd center in our catalyst was affected by the nucleophilicity of the nitrogen lone pair (nucleophilicity can be approximated by the pKa value of the amine). Since we can confirm that the electron-withdrawing ability of The aryl halide is crucial to the success of this reaction, we also wanted to predict the best amine partner for successful coupling. JV-Methyl aniline was chosen for a comparative study, since it has a lower pKa than morpholine. By examining Table 2.7, it is apparent that the aforementioned reactions did not proceed as well with a lower pKa-amine as they 26 did with a higher pKa-amine. Noteworthy is the fact that the electronic properties of the aryl substituent still play an active role in the overall success of the reaction. As expected, products 30 and 31 were the highest yielding due to the electronic nature of the aryl substrate. Based on these results, we can rationalize that higher pKa-amines are less acidic, hence more basic and ultimately more nucleophilic toward the Pd catalyst during the catalytic cycle. This in turn, aids in the amine coordination process and subsequent deprotonation, which, as mentioned previously, we believe is the rate-limiting step. Although Hartwig has disclosed mechanistic reports stating that the presence of nucleophilic alkoxides49 and amines lead to alternative catalytic cycle pathways, the nature of the predominant ligand (NHC in our case vs. phosphine) cannot be completely comparable to his findings with phosphine-based systems. Since their initial appearance as ligands in the cross-coupling field, NHC's have been tagged as "phosphine mimics" although this title is not entirely accurate. There are significant differences in the electronic properties49 and in the steric topology of the active catalyst between each ligand class, thus the assumption that both types of ligands would behave the same way mechanistically, is invalid. Recently, a computational study of the Heck-Mizoroki reaction exemplified these differences by revealing a predominant cationic pathway, where olefin insertion is the rate-determining step for Pd-NHC catalysts in contrast with a neutral pathway where oxidative addition is the rate-determining step for Pd-phosphine catalysts. A closer look at the results from the electronic and amine study (Tables 2.6 and 2.7; Figure 2.2) reveals that the low acidity of amines (pKa~35) must require that deprotonation be facilitated by complexation of the amine to the oxidative addition 27 intermediate A (Figure 1.2) acting as a Lewis acid. A relatively electron-poor palladium center should promote a correspondingly high degree of amine coordination (B, Figure 1.2). This will serve to lower the pKa of the amine proton, which is particularly important for the comparatively weak carbonate bases. 49b'52 It must also be taken into account that Table 2.7: N-methylaniline for Pd-PEPPSI-IPr catalyzed animations with Cs2C03. 12, 4mol% X Cs2C03 DME I N-Ar-R X 80°C, 24h R a o R= Me, OMe, N02 1.2 Equiv X= CI, Br ^ O CF^ O NO, x=Cl,21% 30 x=Cl. 25% 31 x=Br, 24% x=Br. 29% I I .N. .N Cr O' x=Cl,0% 32 x=Cl, 17% 33 x=BrO% x=Br, 14% Reactions were performed in duplicate and the average isolated yield is reported. this step is very sensitive to the steric bulk of the amine.50 Once the aryl halide undergoes oxidative addition, the aryl moiety becomes a ligand on palladium, therefore, a Hammett analysis was conducted (Figure 2.3) and the results follow this trend. Thus, based on these mechanistic interpretations, we concluded that successful amination employing Pd- PEPPSI-IPr and CS2CO3 had to meet two criteria: 1) the amine must be 28 sufficiently nucleophilic to form B (Scheme 1.5) and/or 2) the organo halide must be sufficiently electron-deficient. Equipped with this rationale, we then evaluated the CS2CO3 conditions with a variety of heterocycle-containing coupling partners that fulfilled the above criteria. In line with the previous results, 2-chloropyrazine worked Table 2.8: Substrate study containing aryl and hetero-aryl substrates for Pd-PEPPSI-IPr catalyzed amination using CS2CO3.0 ,X 12(4mol%) ^NRR, F^RNH + f\ Cs,CO,,DMg fj^V R*^ 80°C24h R^ x=Cl, 86% 34 x=Cl,93% 35 ^^ x=CL 89% 36 x=Cl, 90% 16 N N vO" "N x=Cl,92% 37 x=Ci,95% 38 x=Cl, 86% 39 x=Cl,69% 40 s 6 ^o^ -°^ x=Cl,83% 41 x=Cl,96% 42 x=CL62% 43 x=CL98% 18 JO t\. „ J^Y ^ 6 a^ 60 6 x=Cl,31% 44 x=CL90% 45 x=Cl, 96% 22 x=CL 10% 46 "Reactions were performed in duplicate and the average isolated yield reported. 29 superbly with a variety of amines, as Table 2.8 suggests. This may, in part, be related to the chlorine being ortho to the nitrogen in the aromatic ring. This position is usually referred to as an 'activated' position since the nitrogen aids in the catalytic cycle by assisting in oxidative addition by further enhancing the electrophilicity of the Pd catalyst. This was definitely the case with this substrate study as all results using this substrate (34, 35, 36, 38, 40, 41 and 42) proved successful. We also discovered that a wide range of couplings could be promoted using CS2CO3 in the absence of this pyrazine substrate (Table 2.8). Substituted quinoline (22), and pyridine (37,39 and 43) derivatives were coupled with a variety of substituted amines in good to excellent yields. Noteworthy is the successful coupling of tetrazole (45) as this moiety is employed as a carboxylic acid surrogate in many drugs (e.g. Losartan®). Control reactions that did not contain Pd-PEPPSI-IPr were also performed for these 2-chloropyrazine substrates and generated yields of < 10% therefore confirming the necessity of the catalyst in these reactions. It is notable that catalyst loading could be reduced to 1 mol% without negatively affecting the yields. 30 2.4 Conclusion: Pd-PEPPSI-IPr (12) was shown as an effective catalyst for the Buchwald- Hartwig-Yagupol'skii Amination. The catalyst proved versatile in that it is successful under different conditions and can effectively couple diverse substrates generating moderate-to-excellent yields irrespective of base strength. Employing CS2CO3, a variety of aryl substrates with different electronic properties were tested and ultimately it was confirmed that higher yields are obtained when the aryl halide substituent is electron- withdrawing. Furthermore, changing morpholine to N-Methylaniline, which is a less basic amine, proved informative and suggested the catalyst is optimal when employing a more nucleophilic amine. Both these characteristics provide insight into the mechanism of the Buchwald-Hartwig-Yagupol'skii reaction with our Pd-NHC catalyst. Electron- withdrawing substituents aid in removing electron density from the Pd catalyst from the oxidative addition intermediates, which promotes amine coordination. The increased basicity of the amine assists this cycle by enhancing nucleophilicity, thus rendering it more willing to coordinate to the Pd center than more acidic amines. Therefore, the greater Lewis acidity of the Pd-center, the greater the amine coordination and ultimately the lower the pKa(NH) allowing for deprotonation by weaker bases. These findings are in line with the theory that the deprotonation of the Pdn-amine coordination complex is the rate-limiting step for this catalytic cycle. The couplings were also found to follow a Hammett-type correlation consistent with our mechanistic interpretation of the data. 31 2.5: PEPPSI as a catalyst in the cross-coupling reactions of 1,1-dibromoalkenes Building on the research of a previous group member who was successful in synthesizing stereospecific di- and tri-substituted olefins using 1,1-dihaloalkenes and PdCl2(dppb) or Pd(PPh3)4, it was decided to investigate the efficiency of using similar 1,1-dihaloalkenes for stereospecific cross-coupling reactions involving Pd-PEPPSI-IPr. Previously optimized results using Pd(PPh3)4, dimethyl 2-(3,3-dibromoallyl)-2- methylmalonate (47) and 4-(acetyl)phenylboronic acid at 50 °C for 4 hours with 3.0 equivalents of Na2CC>3 achieved an 83% yield of the mono-coupled Z-alkene (i.e. coupling of Br8)28 and 17% of the dicoupled product. The same reaction employing Negishi conditions with phenylzinc bromide proved unsuccessful with this substrate, although it was viable when methyl 7,7-dibromohept-6-enoate (48) was employed with phenylzinc bromide under PdCl2(dppb) catalysis to yield 84% of the mono-cross-coupled product (i.e. coupling of Br8)28. To date, there have been no reports of success with an NHC-based catalyst for sequential couplings using 1,1-dihaloalkenes. However, Negishi470 was able to use NHC-based catalysts to promote stereospecific conversions of mono-brominated dienes (e.g. (lZ)-2-bromo-l,3-dienes) into (l£)-l,3-dienes (Scheme 2.1). 32 The intent was to extend optimal Suzuki-Miyaura31and Negishi34 cross-coupling conditions employing Pd-PEPPSI-IPr to achieve selective mono-coupling with 1,1- Scheme2.1: Negishi's use of Pd-NHC complexes for the synthesis of (li?)-l,3-trienes. BrZn R4 4 5 , Br /R3 Br R XZnR R5 R4 R 1 U4 ¥ ^R ,! ^^ cat. [PdCBusPJd Ri Br R3 H' 5% [PdCI2(dpephos)] r ^ " or [PdCI2(dba)3] .>^^^ n„ and 4 NHC H R dihalo-1-alkene-type substrates resembling 47 and 48. Valeraldehyde was employed after being purified by distillation and then subjected to the Corey-Fuchs reaction53 to generate 1,1-dibromo-l-hexene. The reaction was successful, but the isolation of the product was problematic, as it co-chromatographed with unreacted PPI13. To make purification easier, the more polar methyl 4-formylbenzoate, another readily available aldehyde was selected. The Organ group has had success with similar styrene-type substrates in Suzuki-Miyaura cross-couplings, thus making this a reasonable choice. Large quantities of methyl 4-(2,2-dibromovinyl)benzoate (49) were synthesized (Scheme 2.2) and next subjected to Negishi and Suzuki cross-coupling reactions with Pd-PEPPSI- IPr (Tables 2.9 and 2.10). As the results suggest, the Negishi cross-coupling reactions with 49 were unsuccessful. Reactions performed in THF (Table 2.9, entries 1-4, 9-12, 17-20) provided none of the mono cross-coupled product, regardless of temperature or the addition of LiBr (Table 2.9, entries 2 and 10), while reactions run in a slightly more polar medium of 33 THF:DMI (2:1) were slightly better performing (Table 2.9, entries 7, 8, 15 and 16). While the dicoupled product (54) was not the product of choice for this reaction pathway, at elevated temperatures it was formed in greater quantity than the monocoupled product. Scheme 2.2: Corey-Fuchs reaction to generate methyl 4-(2,2-dibromovinyl)benzoate. O O CBr4,PPh3 Br (f-^V^O^ cf • I I DCM, 0-RT Br^y<^ 49 This suggests that at higher temperatures, the monocoupled product (50) is more reactive than the starting material, causing the desired product, once formed, to undergo a second cross-coupling cycle. Aside from 49, 50 and 54, ]H NMR spectroscopy and GC/MS analysis confirmed the presence of by-products 51, 52 and 53, the quantities of which varied depending on reaction conditions. We then turned our attention to the Suzuki-Miyaura reaction to see if we could obtain better cross-coupling results using this protocol. However the reaction fared more poorly (Table 2.10) and, in most cases, the product mixture was comprised mainly of starting material (Table 2.10, entries 1-4, 6-8) with the only successful monocoupled product formed with K2CO3 and dioxane at 60°C (Table 2.10, entries 5 and 9). The by products generated were the same in both reaction conditions; however, 51 was generated in lower yields compared to the Negishi reaction. The results show that at elevated temperatures 51 is formed in greater quantity; therefore, since the Negishi reaction was 34 Table 2.9: Evaluation of Pd-PEPPSI-IPr as a catalyst for the Negishi cross-coupling employing compound 49. Pd-PEPPSI-IPr(10mol%) Br (| "V^ O + || + R-ZnBr solvent _ A^A^ 50 —• -• - DR Br temp, 24hrs R =-P h R= 4-MeO-Ph R= nBu * Formed by homocoupling of R=Ph b Formed by homocoupling of R=4-MeO-Ph Reaction Conditions Conversion (%) Entry R Solvent T (°C) Additive 49 50 51 52 53 54 1 Ph THF rt none 80 0 4 - 16 0 2 Ph THF rt LiBr 75 0 6 - 17 0 3 Ph THF 50 none 63 0 14 - 13 0 4b Ph THF 70 none 43 0 37 - 15 5 5 Ph THF/DMI(2:1) rt none 86 0 4 - 10 0 6 Ph THF/DMI(2:1) rt LiBr 82 0 0 - 12 0 7b Ph THF/DMI(2:1) 50 none 65 10 15 - 10 0 8b Ph THF/DMI(2:1) 70 none 25 5 33 - 24 0 9 4-MeO-Ph THF rt none 87 3 0 9 - 0 10 4-MeO-Ph THF rt LiBr 84 5 0 11 - 0 11 4-MeO-Ph THF 50 none 75 0 16 9 - 0 12b 4-MeO-Ph THF 70 none 24 9 42 23 - 0 13 4-MeO-Ph THF:DMI(2:1) rt none 79 0 0 19 - 0 14 4-MeO-Ph THF:DMI(2:1) rt LiBr 75 0 0 21 - 0 15 4-MeO-Ph THF:DMI(2:1) 50 none 45 5 29 24 - 0 16b 4-MeO-Ph THF:DMI(2:1) 70 none 26 7 40 25 - 13 17 nBu THF rt LiBr 89 0 5 - - 0 18c nBu THF 50 LiBr 76 0 18 - - 0 19b nBu THF 70 LiBr 70 0 24 - - 0 20c nBu THF:DMI(2:1) rt LiBr 90 0 0 - - 0 21c nBu THF:DMI(2:1) 50 LiBr 84 0 13 - -' 0 c 22 nBu THF:DMI(2:1) 70 LiBr 77 0 19 - • - 0 Conversions were determined by H-NMR spectroscopy. All reactions were performed in duplicate with the average yield reported, isolated by column chromatography. c Homocoupling of the alkylzinc bromide (octane) accounted for the rest of the product mixture. sometimes performed at 70°C, 10°C higher than the Suzuki-Miyaura reaction, this may account for its decrease. It appeared that the vinylic proton was problematic in our chemistry since at elevated temperatures, 49 underwent E2-type elimination to yield 51 much faster than 35 oxidative addition of 12 into the carbon-halide bond of 49. From this, we decided to use an aliphatic aldehyde to generate the geminal dibromo olefin. We opted for 48, since this substrate was used previously in our lab and could be prepared readily. The synthesis of 48 began by performing a ring-opening of E-caprolactone (55) to generate methyl 5- oxopentanoate (16) (Scheme 2.3). This was followed by PCC oxidation to obtain the Table 2.10: Evaluation of Pd-PEPPSI-IPr as a catalyst for Suzuki-Miyaura cross-coupling employing compound 49. Br f**f 0 Pd-PEPPSI-IPr (10mol%) Br |fY "O' if^T' ~"°' + + S2 + K>-B(OHh solvent, base ^ ^XjiJ 50 Br^=A^ 5j I ' temp, 24h R^Ph Ri= 4-MeO-Ph a Formed by the homocoupling of R=Ph b Formed by the homocoupling of R=4-MeO-Ph Reaction Conditions Conversion (%) Entry R1 Solvent T(°C) Base 49 50 51 52 535 4 1" Ph THF 50 K2C03 80 0 4 15 - 0 b 2 Ph THF 50 Na2C03 78 0 10 11 - 0 3 Ph THF 60 K2C03 63 0 12 22 - 0 4 Ph Dioxane 50 K2C03 92 0 0 7 - 0 5 Ph Dioxane 60 K2C03 73 10 4 13 - 0 6 4-MeO-Ph THF 50 K2C03 87 0 0 - 13 0 7 4-MeO-Ph THF 60 K2C03 75 4 8 - 11 0 8 4-MeO-Ph Dioxane 50 K2C03 73 0 6 - 19 0 b 9 4-MeO-Ph Dioxane 60 K2C03 66 9 12 - 13 0 Conversions were obtained by H-NMR spectroscopy. All reactions were performed in duplicate with the average yield reported. b Isolated by column chromatography. aldehyde (56) and then a Corey-Fuchs53 reaction to provide methyl 7,7-dibromohept-6- enoate (48). Once synthesized, 48 was subjected to both the Negishi and Suzuki-Miyaura protocols using similar reaction conditions. From previous results, it was evident that at elevated temperatures, a great deal of starting material was undergoing base-mediated 36 E2-type elimination. We hoped to overcome this problem by varying the reaction temperature and the quantity of base (i.e. organometallic reagents) (Tables 2.11 and 2.12). Whereas the control reaction with PdC^dppb provided a yield of 65% of 58, similar to that previously stated, Pd-PEPPSI-IPr failed to provide any significant amount of product. Examining Tables 2.11 and 2.12 it is clear that an excess of the organometallic reagent is necessary to promote cross-coupling (Table 2.11, entries 11, Scheme 2.3: Synthetic pathway for the formation of methyl 7,7-dibromohept-6-enoate from e- Caprolactone. O O -0 MeOH,H2S04 HO. reflux, 16h 56 92% PCC Na(OAc)2 DCM O CBr4, pph3 O' 48 DCM, 0-RT O 57 48% 56% 14, 17; Table 2.12, entries 3, 5, 6), however, dicoupled product forms as well (Table 2.11, entries 15, 18; Table 2.12, entries 3, 6). Control reactions with no catalyst were also performed with both starting materials (48 and 49) and aliquots were characterized by !H-NMR and GC/MS to observe the different species present at both room temperature and at 70°C after 0.5 hours and 12 h of mixing time. For the room temperature reaction, the H-NMR showed no conversion of starting material. However, at 70 °C, a very 37 complex 'H-NMR spectrum was obtained from both reactions. GC/MS analysis confirmed the presence of 48, 52, and 60 for the control reaction with substrate 48, and 49, 52, and 51 for the control reaction with substrate 49. These results suggest that at elevated temperatures, both 48 and 49 undergo base-induced elimination. The origin of 52 is troublesome as no catalyst was added to afford the homocoupled product. After 12h, at room temperature, biphenyl 52 was also visible along with 48 and 49, however, decreased amounts of both starting materials and increased amounts of 52, 60 and 51 were present in the reaction at 70°C. All told, the more common phosphine-based catalysts, PdC^dppb and Pd(PPh3)4 outperformed Pd-PEPPSI-IPr in these reactions as they are able to produce viable amounts of the mono-coupled product at room temperatures. As explained previously, Negishi has shown that (lZ)-2-bromo-l,3-dienes47c, obtained by previously reported Pd- catalyzed trans-selective monoalkenylation of l,l-dibromo-l-alkenes,47a'54 can be further substituted with methyl, higher alkyl, and phenyl groups with nearly full retention of configuration, using the corresponding organozinc reagents in the presence of Pd catalysts containing NHCs. 7 The in-situ protocol of Pd2(dba)3 is employed with four molar equivalents of either N,N-bis(2,6-diisopropylphenyl)imidazolium chloride or tricyclohexylphosphane to afford the trisubstituted dienes (Scheme 2.1). Interestingly, the first substitution on 1,1-dibromo-l- alkenes are carried out using phosphine ligands to generate these (lZ)-2-bromo-l,3-diene substrates and then coupled a second time using 38 Table 2.11: Evaluation of Pd-PEPPSI-IPr as a catalyst for Negishi cross-coupling employing substrate 48 with phenylzinc bromide • PEPPSI-IPr (1 Omol%) Br O + Ph-ZnBr temp, 24h Reaction Conditions Conversion (%) Entry R2 Solvent T (°C) Equiv. 48 52 58 59 60 Zn 1 Ph THF rt 1 85 15 0 0 0 2 Ph THF rt 1.6 81 19 0 0 0 3b Ph THF rt 2 79 20 0 0 0 4 Ph THF 50 1 80 12 0 0 5 5 Ph THF 50 1.6 69 20 5 0 8 6b Ph THF 50 2 63 11 7 7 3 7 Ph THF 70 1 65 16 0 0 19 8 Ph THF 70 1.6 60 7 7 9 16 9 Ph THF 70 2 55 13 0 0 32 10 Ph THF:DMI(2 1) rt 1 80 20 0 0 0 llb Ph THF:DMI(2 1) rt 1.6 76 4 15 0 5 12 Ph THF:DMI(2 1) rt 2 72 11 6 9 0 13 Ph THF:DMI(2 1) 50 1 66 14 5 0 15 14b Ph THF:DMI(2 1) 50 1.6 63 7 19 9 0 15 Ph THF:DMI(2 1) 50 2 59 13 7 10 8 16 Ph THF:DMI(2 1) 70 1 45 19 0 0 35 17b Ph THF:DMI(2 1) 70 1.6 41 24 11 0 22 18 Ph THF:DMI(2 1) 70 2 35 21 4 13 27 "Conversions were obtained by H-NMR spectroscopy. All reactions were performed in duplicate with the average yield reported, isolated by column chromatography. 39 Table 2.12: Evaluation of Pd-PEPPSI-IPr as a catalyst for Suzuki-Miyaura cross-coupling of 48 with phenylboronic acid. PEPPSI-IPr (10mol%) solvent 3 K2C03 (1.5 equiv.) Br + R -B(OH)2 *" 3 ' temp, 24hrs R R3 = Ph ] a= homocoupling of R3=Ph Reaction Conditions Conversion (%)a Entry RJ Solvent Temp Equiv. 48 52 58 59 60 (°C) 1 Ph THF rt 1 83 12 0 0 4 2 Ph THF 50 1.5 63 21 3 0 13 3b Ph THF 60 2 30 24 7 12 24 4 Ph Dioxane rt 1 92 8 0 0 0 5b Ph Dioxane 50 1.5 73 14 7 0 6 6b Ph Dioxane 60 2 25 22 13 15 23 Conversions were obtained by H-NMR spectroscopy. All reactions were performed in duplicate with the average yield reported. Isolated by column chromatography NHC ligands. There has yet to be an example of NHC coupling between 1,1-dihalo-l- alkene-type substrates which may suggest that di-vinylogous halides pose a problem as substrates for catalysts based on NHC ligands. 40 2.6: Conclusion Thus far, Pd-PEPPSI-IPr has proven unsuccessful in Negishi and Suzuki-Miyaura cross-coupling reactions with 1,1-dibromo-l-alkene-type substrates. Optimization studies for both protocols have been conducted and have failed to produce the desired mono-coupled product. Future work may include altering the ligand environment around Pd through the synthesis of different NHC ligands with different groups on the imidazole nitrogen to test their viability in this protocol. 41 PART 2 Part 2 Chapter 3: Introduction 3.1 LiBr as an additive in the Pd-PEPPSI catalyzed sp3-sp3 Negishi Cross-Coupling Reaction: A H, C, Li-NMR spectroscopy study The Negishi coupling, first published in 1977, was the first reaction that allowed the preparation of unsymmetrical biaryls in good yields.14 The versatile nickel- or palladium-catalyzed coupling of organozinc compounds with various halides (aryl, vinyl, benzyl, or allyl) has broad scope due to the excellent functional group tolerance and high reactivity of organozinc reagents.14 There are many protocols available for the preparation of organozinc reagents; however, the two most recognizable methods involve Rieke zinc (Scheme 3.1)55 and a protocol by Hou. (Scheme 3.2)56 The first method generates highly reactive zinc via the treatment of Z11X2 with lithium naphthalide. Its high reactivity enables oxidative insertion of zinc into an alkyl bromide bond thus forming the organozinc reagent. The second procedure relies on the direct insertion of zinc metal (dust, powder, granule, shot) and catalytic amounts of h for zinc activation.5 Although both methods produce viable zinc reagents,57 earlier research in the Organ lab revealed that only reactions using commercially purchased Rieke zinc reagents underwent successful sp3-sp3 cross-coupling. Further confusion arose when attempts to make Rieke zinc in-house failed to produce successful coupling reactions.57 Previous research in this area by Knochel and colleagues58 suggests that this is due to the inability of the alkylzinc bromide to undergo transmetallation. After much investigation, it was discovered that commercially available Rieke zinc reagents contain LiCl, a by-product in 42 their formation. This may serve to activate organozinc reagents toward transmetallation via the proposed zincate (Figure 3.1).58 This information encouraged an Honours Scheme 3.1: Preparation of Rieke Zinc R-Br ZnX2 »- Zn* + 2 LiX +- R-ZnBr + 2 LiX THF THF,r.t. to reflux X = CI, Br or I Scheme 3.2: Preparation of n-butylzinc bromide with Huo's protocol cat. I2 'Br + Zn(s) ^ ^^-^^ZnBr DMI, 70°C 12hrs undergraduate research thesis that explored the effect of additives on the Pd-PEPPSI-IPr catalyzed Negishi alkyl-alkyl cross-coupling protocol.59 After an in-depth study that tested a multitude of additives and solvents, it was concluded that a stoichiometric amount of LiBr, in a 2:1 THF:DMI solvent system, proved most effective in generating coupled product From this notion, 2 equivalents of LiBr (based on the organozinc reagent) were added to a previously "ineffective" zinc reagent resulting in quantitative conversion to product (Scheme 3.3).60 Armed with these findings, along with the desire to further explore the exact role of LiBr in the Negishi alkyl-alkyl cross-coupling reactions, the attention was focused on the use of !H, 13C, and 7Li-NMR spectroscopy to characterize the various zinc- and 43 lithium-based species formed in situ. Research in this area has been limited, 61 and applied mainly to spectroscopic studies involving dialkyl zinc reagents.63'64 To date, e Zn- I R1 X= CI, Br, I A = additive Figure 3.1. A proposed zincate intermediate required for successful transmetallation in the Negishi reaction. there has been no literature that uses NMR spectroscopy for studying organozinc compounds in solution as they apply to the Negishi reaction. While the use of additives to CO generate successful alkyl couplings is not a new concept in organometallic chemistry, ' 65'66 no research group has yet to disclose, with unequivocal data, the exact role of these additives in solution throughout the cross-coupling cycle. The reasons for this may be the difficulty in handling these sensitive reagents, such as their hydroscopicity, which means they must be handled with extreme care. Organozincates are characterized as anionic complexes where the central zinc atom is surrounded by 3 or 4 anionic ligands and stabilized via the corresponding counterions, with a general formula RaZn" M+ or RiZn"2 2M+.61 It is noteworthy that the preparation of the first alkali-metal "ate" compound actually predates by about six 44 decades the pioneering preparations of neutral organosodium and organolithium compounds by Schlenk62. This "ate" compound is sodium triethylzincate, "NaZnEt3"67, Scheme 3.3: Preliminary investigation of zinc activation 1 mol% NyN Cl-Pd-CI N Br ... .C) + ,ZnBr LiBr rt, 30 min (1.3equiv) No LiBr, 0% Conversion 2.6 equiv. LiBr, 100% Conversion synthesized by Wanklyn, in 1858 by the action of sodium on diethylzinc, which itself had been synthesized a few years earlier by Frankland. A century later, Wittig coined the term "ate" based on his realization that metal compounds with anionic formulations could be developed. He introduced lithium triphenylzincate, "LiZnPhs", as well as the analogous magnesium species, "LiMgPhs" (the first magnesiate) in an influential paper from 1951.69 Wittig rationalized the early chemistry of ates68 collectively in terms of an anionic activation, with the negative charge activating "anionically" all of the ligands surrounding the metal through an inductive effect. More than a decade later, this theory was corroborated by Tochtermann in an early review of "structures and reactions of organic ate-complexes" from 1966.70 Between 1966 and 1969, Brown, Seitz et ah, through detailed NMR spectroscopy studies, confirmed the formation of rapidly 45 equilibrating ate complexes of at least three distinct stoichiometrics by examining organolithium and organomagnesium solutions.71 In 1971 Evans and Fazakerley also used NMR spectroscopy as a tool to confirm that the position of the Schlenk Equilibrium for organozinc species lies predominantly to the right, favouring of the organozinc halide in both ethereal and hydrocarbon solvents (Scheme 3.4).72 This is in agreement with previous IR studies, as well as with Abraham and Rolfe73, who confirmed that ethylzinc iodide in tetrahydrofuran is essentially a monomeric species. This information is corroborated by the equilibrium constant, K, which was also determined by 'H-NMR spectroscopy, to be >500 at -70°C in THF.72 Further studies have shown that alkylzinc salts, like n-butylzinc bromide, display an aggregative behaviour, existing as tetramers in non-coordinating solvents (benzene) and as monomers in coordinating solvents (THF) (Scheme 3.5).61 Scheme 3.4: The Schlenk Equilibrium with organozinc reagents K 2 R2Zn + ZnX2 - 2RZnX K= [RznX] [R2Zn][ZnX2] Scheme 3.5: The aggregative behaviour of organozinc reagents in varying solvents Et Et x—2n x /.it * X^ I incooKEaaHBgsoiveass [ Zn-j—X inhvdrocaiboiigotraits "* [EtZnXkoiv. X^r-Zn Et \ Ei X = Cl,Br,OMe 46 In line with findings by Brown and Seitz, it is known that alkyl group exchange between alkylzinc halides is fast (Scheme 3.6) 61 and is further facilitated by the presence of a good bridging group with lone pairs. Consequently, bridged complexes, as displayed in Scheme 1.6, have been proposed as intermediates for this exchange and may help to explain the vital role of LiBr in the Negishi sp3-sp3 cross-coupling reaction. Hence, the information gathered from this data serves as a useful starting point for confirming, via various NMR spectroscopic techniques, the structure and activity of organozinc reagents in the presence of LiBr in solution. Scheme 3.6: The effect of bridging ligands on the exchange of organozinc reagents r _» i # R1 R^Zn + E2ZnX ^ Y RlR2Zo + R2ZrtX 47 Plan of Study In an effort to understand the mechanism of the Negishi alkyl-alkyl cross- coupling protocol, the relationship between w-butylzinc bromide and LiBr was investigated. For the first part of the study, varying amounts of LiBr were doped into the Negishi reaction to observe the effect on the yield. Our thought was that the amount of LiBr necessary in solution to facilitate quantitative coupling would provide necessary information with respect to the mechanism of this reaction. Z11X2 was also introduced to the reaction, in varying equivalents, to observe if the presence of an additional Zn source would aid or hinder the Negishi protocol. In the second part of the study, the goal was to observe the active species in situ in the Negishi alkyl-alkyl cross-coupling protocol using NMR spectroscopy. 'H, 13C, and 7Li nuclei were observed under simulated optimized Negishi conditions to confirm the appearance of higher-order zincates in solution, in agreement with the reported literature. «-Butylzinc bromide and dibutylzinc were synthesized, lithium halide free, and analyzed using ID and 2D NMR spectroscopy techniques. Once the organozinc compounds were confirmed, NMR samples were prepared containing M-butyzinc bromide, a solution of THF:DMI (2:1) and LiBr in varying amounts (0-1.5 equiv. based on n-butylzinc bromide) and analyzed using ]H, 13C, and 7Li NMR spectroscopy. Variable temperature (VT) experiments were also performed to observe the appearance of new peaks at lower temperatures when molecular movements are much slower. 48 PART 2 Chapter 4: Results and Discussion 4.1: LiBr as an additive in the Pd-PEPPSI-IPr catalyzed sp3-sp3 Negishi Cross- coupling: A *H, 7Li-NMR study The requirement for LiBr or LiCl as an additive for the cross-coupling of sp3 centres in the Negishi protocol was first realized in our lab (Scheme 3.3).34 After closer investigation, it was discovered that LiCl, a by-product in the formation of Rieke zinc reagents, is not removed from the commercially available materials. As such, a thorough additive study that investigated various metal and non-metal salts and solvents, at varying temperatures and solvent conditions was conducted 59 and it was observed that the addition of 2.0 equivalents of LiBr to a previously ineffective butyl-zinc reagent gave quantitative conversion of l-(3-bromopropyl)benzene to heptylbenzene in 0.5 hrs under Pd-PEPPSI-IPr catalysis (Scheme 3.3). In an effort to expand this protocol beyond heptylbenzene, a study consisting of diverse alkyl and aryl halides (or pseudo-halides) combined with functionalized organozinc reagents was performed and the results were extremely encouraging. Using LiBr as an additive, we were able to synthesize complex molecules by coupling various aryl or alkyl carbon centers with different aryl or alkyl organozinc reagents (Table 4.1). Although the results were pleasing, it was discovered that LiBr was required every time an sp3 organozinc reagent was employed. Aryl zinc reagents, whose centers are sp2-hybridized, did not require LiBr, thus raising the question of LiBr's involvement, mechanistically, each time an sp3 organozinc was coupled. 49 From this, we probed the minimum amount of LiBr necessary to facilitate quantitative conversion to heptylbenzene to gain insight into the mechanism of this reaction. The test reaction (Scheme 3.3) was run with «-butylzinc bromide prepared as per Scheme 3.2, making it lithium halide-free, and each reaction was set up to contain various amounts of LiBr (0-2.0 equiv. based on the organozinc reagent). The reactions were run in duplicate and each run was analyzed in triplicate with the average conversion Table 4.1: Substrate study of Negishi cross-couplings with sp3 and sp2 centers Pd-PEPPSI-IPr(12) 1 1 mol% R X + R2znBr R1-R2 (1.6 equiv.) THF/DMI(2:1) RT-50°C, 2h Reactions were performed in duplicate and the average isolated yield reported. recorded. Figure 4.1 clearly shows an exponential-type dependence on LiBr, ultimately plateauing at 1.2 equivalents suggesting there is an optimal amount of LiBr necessary to facilitate coupling. Any more LiBr above this point does little to improve the overall yield of the reaction as it has already reached a maximum (Figure 4.1). From these preliminary results, we suspected the bromide anion from the lithium salt may coordinate 50 to the zinc reagent, ultimately forming a higher ordered "zincate" species in situ which would improve the nucleophilicity of the organozinc for transmetallation with Pd during the catalytic cycle (Figure 4.2). Figure 4.1 also shows that the reaction still progresses, albeit with decreased conversion, with minimal amounts of LiBr indicating that an equilibrium is present. It is only with more than 1 equiv. that the equilibrium strongly favours progressing to completion. In line with this reasoning, Knochel and colleagues6515" d have recently disclosed a magnesiate complex that they believe is formed upon the addition of LiCl (1 equiv.) which serves to activate the inactive JPrMgBr toward metal- halogen exchange (Scheme 4.1). They propose that the need for stoichiometric LiCl Effect of varying LiBr equivalents on the sp3-sp3 Negishi Reaction 120 100 1 ip a 80 £ 60 m O u ^ 40 20 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 LiBr equiv. LiBr equiv. vs. % conversion Figure 4.1: Effects of increasing equivalents of LiBr in the Negishi alkyl-alkyl cross-coupling reaction. Reactions were analyzed by GC/MS against a calibrated internal standard (undecane); reactions were performed in triplicate and the average conversions reported. 51 with iPrMgCl-LiCl suggests that LiCl breaks the polymeric aggregates of iPrMgCl (66), producing the reactive complex 67 and that the 'ate' character of the newly formed magnesium species (67) may be responsible for the enhanced reactivity toward metal- halogen exchange.65 This theory also supports the known aggregation of alkylzinc and alkyl magnesium reagents (dimers, trimers etc) in solution, especially since the presence Scheme 4.1: Knochel's proposal of the activation of iPrMgCl with LiCl ,-C! JCI £! + 2LiCI E \-Mg Mg _ 2 ^-MJJ ii 2 EMg Li ''ci Vi 65 66 67 PI 2 ^Mg Li tl 66 of a halide provides the requisite bridging group (Scheme 3.6) to facilitate the formation of these bridged complexes. l To be fully convinced that LiBr was participating to activate the zinc reagent toward transmetallation, we decided to 'dope' the reaction with an inorganic zinc source (i.e. ZnBr2 or ZnCb) to act ^ as a scavenger of bromide and obseve its effect 2LiG on the Negishi sp3-sp3 protocol (Figure 2.3). If the LiBr is behaving as Knochel suggests, (Scheme 4.1) and as we believe (Figure 4.2), then the addition of Fig«re 4-2: Possible formation of a higher order zincate reagent by LiBr 52 addition of additional zinc should sequester the halide, rendering the organozinc less active toward transmetallation and halt any cross-coupling. By the Schlenk equilibrium (Scheme 3.4), the introduction of a zinc halide source (ZnBr2 or ZnCk) should further push the equilibrium in the direction of the alkylzinc halide, completely contrary to our theory of shutting down the catalytic cycle. However, a closer look reveals that this equilibrium does not take into account the added LiBr in solution which we believe has, to some extent, coordinated the alkyl zinc reagent to enhance transmetallation (Figure 4.2). If our hypothesis proves accurate, and the LiBr in solution is in fact coordinating the w-butylzinc bromide, the addition of a secondary zinc source would render the n- butylzinc bromide ineffective for transmetallation by sequestering the additional bromide ions in solution. This can be attributed to the enhanced electropositive zinc center of ZnBr2 or ZnCk in comparison to «-butylzinc bromide where there is only one halide. The more electropositive zinc center will 'attract' the additional bromide in solution, ultimately forming inorganic zincate complexes ZnBr3~, and/or ZnBr/" in competition with the organozincates. The results support our theory regarding the dependence of the alkyl-alkyl Negishi reaction on LiBr since the addition of even small amounts of either ZnBr2 or ZnCl2 (introduced simultaneously with LiBr) had a dramatic effect on the yield (Figure 4.3). This suggests that the additional zinc halide in solution is indeed behaving as a scavenger; competing with «-butylzinc bromide and sequestering the bromide ion. This situation essentially ties up the excess bromide ion in solution rendering it unavailable to activate the lower organozinc reagent toward transmetallation. 53 Addition of Zn Hsttide to the Negishi sp^-sp5 reaction a .2 > s o U 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 Zn Halide equiv. (based on organozinc) —•—ZnC12 -*— ZnBr2 ] L____„._-_--_.______j Figure 4.3: Effect of varying ZnBr2 or Z11CI2 equivalents on the Negishi alkyl-alkyl cross coupling reaction. Reactions were analyzed by GC/MS against a calibrated internal standard (undecane); reactions were performed in triplicate and the average conversion reported Although the use of additives in metal-catalyzed cross-coupling reactions of unactivated centers is not uncommon58' 65' 66 it is still an area that is mechanistically unexplored. Little is known about the nature of the "active" organozinc species formed in situ. We therefore decided to use NMR spectroscopy to examine these active species in solution and confidently gain further insight into the mechanism of this reaction. We began these studies by employing 'H, 13C, 7Li, and 67Zn NMR spectroscopy studies using D2O, LiCl in D2O, and Zn(NC>3)2 in D2O as an external reference and deuterium lock for the aforementioned nuclei. The D2O solutions were introduced in a sealed capillary into the NMR tube. To start, a solution of w-butylzinc bromide in DMI (1 M) was introduced 54 into a NMR tube, followed by THF to make up a 2:1 THF:DMI solution to simulate optimized Negishi conditions.34 Initially, the intent was to characterize known species in solution before introducing additives. «-Butylzinc bromide was synthesized with Huo's protocol56 (Scheme 1.2) to keep the organozinc halide-free. After a few attempts at observing Zn, we discovered it was a poor nucleus to observe, mainly due to its large quadrupolar moment, its low receptivity and the low symmetry of the zinc nucleus. Therefore, we chose to focus on 'H, 13C and 7Li NMR spectroscopy since these nuclei do not possess similar challenges. We wanted to confirm that the zinc reagent was indeed the organozinc halide and not the equivalent dialkyl zinc reagent that was responsible for the chemistry in our protocol (Scheme 3.3). Although the Schlenk62 equilibrium lies very well to the right (K > 500)72 for the alkylzinc halide, we wanted to use NMR spectroscopy to confirm this in our system. As literature would suggest, dialkylzinc reagents are far more reactive ' than their alkylzinc halide counterparts and as a result are employed in a variety of regio- and stereo-specific organic transformations.63, 64 Dialkylzincs are also highly pyrophoric reagents and extreme care is required for both their synthesis and application. Although the method used to synthesize many dialkyl zinc reagents is significantly different than that for alkyl zinc halides, and their properties are quite different (the former is pyrophoric while the latter is not) we wanted to remove all doubt that the organozinc reagent employed in the Negishi reaction was indeed w-butylzinc bromide. Figures 2.4 and 2.5 display the !H and 13C chemical shifts (5) of w-butylzinc bromide. D2O was 55 G\ f- o a\ n m (sj ;^ (N :•< ^ZnBr .2mL nBuZnBr, 0.1 mL IHF D20 Capillary THF DMI -CH2CH2ZnBr THF DMI -— C«3(CH2)3ZnBr -CH^CHJoZnBr h u *- -CH2ZnBr i ' ' ' ' I ' ' ' ' I . . . , | , , , . | .5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 .5 1.0 0.5 0.0 -0.5 ppm Figure 4.4: H-NMR spectrum of w-butylzinc bromide (1M, DMI) in a 2:1 THF: DMI solution. The relaxation time, dl, was set to 5 sec. employed as a lock for both !H and 13C and as a reference for JH. The -CH2- shift for THF (5 = 25 ppm) was used as a reference for 13C chemical shifts. The peak in the !H NMR sprectrum between 5 0-0.3 ppm (Figure 4.4) is consistent with a highly electron-rich carbon center and therefore indicative of the methylene carbon adjacent to the zinc metal. The DEPT-135 spectrum confirms that this carbon is indeed a -CH2- because its signal is positive (Figure 4.5). The absence of any starting material in both the 'H and 13C spectra is also consistent with the successful formation of n-butylzinc bromide from w-butyl bromide. To rule out the presence of 56 THF -CH^CH^ZnBr -CH2CI IjZnBr -, / -CH2ZnBr . ., ' ' r ' ''" CH^C^kZnBr DMI 95 90 8i> 8C 75 70 6b 60 55 SO 45 40 35 30 2b 20 15 10 5 ppm Figure 4.5: DEPT-135 spectrum of w-butylzinc bromide (1M, DMI) in a 2:1 THF: DMI solution. dialkylzinc in solution, dibutyl zinc was synthesizedj7 4 and subjected to a physical comparison with «-butylzinc bromide and similar NMR spectroscopy analysis. Based on physical appearance, the dibutylzinc reagent was much different than that of «-butylzinc bromide. The solution of dibutylzinc was slightly opaque and displayed pyrophoric characteristics i.e. fumes were observed in the reaction vessel and when aliquots were taken, and quenching with methanol provided a vigorous reaction. To contrast, n- butylzinc bromide was a grey transparent solution, no fuming was ever observed and quenching with methanol gave minor fizzing. Figures 4.6 and 4.7 display the *H and 13C spectra, respectively, of the dialkylzinc and exemplify the chemical shift differences (5) 57 in the two species as summarized in Table 4.2. Figure 4.6 shows minor differences in the methylene carbon shift (5 0.5-0.3 ppm) as compared to Figure 4.4 (8 0-0.3 ppm). The slight downfield shift for the methylene carbon that is attached to Zn of dibutylzinc suggests a more electropositive carbon center than the methylene carbon of w-butylzinc bromide. A closer look at both 13C spectra further confirms this notion, as the methylene carbon shift for w-butyl zinc bromide appears at 10 ppm (Figure 4.5) and 14 ppm (Figure 4.6) for the methylene carbon of the dibutylzinc, respectively. Dibutylzinc was also analyzed in a solution of THF:DMI (2:1) to rule out shift change due to solvent. For the DibutylZn in St20 EtoO EtoO j I |[CH3(CH2)3]2Zn [CH3CH2CH2CH2l2Zn jl l\-CH£.nCH2- i • • • • i • • • • i • • • • i • • • - i • • - i • • • • i • • • i • • • i • • • • i • • • • i • • • • i • • • • i • • • • i 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 ppm Figure 4.6: H NMR spectrum of dibutylzinc (1M, ET20). 58 1 H sss If 1 / C-13 AV*GO /X^2f^x\ ai.buty.'Uinc .in EX20 Et20 Et20 [CH3(CH2)3]2Zn [CH3CH2(CH2)2]2Zn/ [CH3CH2CH2CH2]2Zn -« S M -CH2ZnCH2- i Jl . .A. Jr~ " 95 90 85 80 75 70 €5 SO 55 50 45 40 35 30 25 20 15 10 5 ppm Table 4.2: Summary of 'H and 13C NMR shift differences for nbutyl zinc bromide and dibutylzinc. Organozinc 'HNMR XHNMR 13C NMR 13C NMR signal chemical shift signal chemical (S) (ppm) shift (S) (ppm) CH3(CH2)3 ZnBr -CH2-ZnBr 0.3-0.0 -CH2-ZnBr 10 [CH3(CH2)3l2Zn (-CH2-)2Zn 0.5-0.3 (-CHr)2Zn 14 H NMR spectrum, the methylene carbon next to the zinc shifted slightly downfield and appeared at 8 0-0.3 ppm, identical to the H NMR position of w-butylzinc bromide (Figure 4.8); however, the 13C NMR spectrum remained unchanged (Figure 4.9). These findings for dibutylzinc are consistent with earlier *H and 13C NMR spectroscopy data which display chemical shifts of 6 0.37 for the cc-protons and 6 14.1 for the a-carbon.7 5 59 Although previous spectral data does not exist for «-butylzinc bromide, there are H and 13C NMR data for ethylzinc chloride and are consistent with a more upfield resonance for the methylene carbon from an organozinc halide.75 Figure 4.8: H NMR spectrum of Dibutylzinc in a solution of THFrDMI (2:1). The broad peaks of the !H spectra for both organozinc species may suggest a type of aggregation in solution similar to that described in Scheme 3.8 for organozinc halides and Figure 4.10 for dialkylzinc compounds. It is known that dialkylzincs exist as monomers in the solid state as well as in solution in both polar and nonpolar solvents.61 Although AG° is unfavourable for the association of simple dialkylzinc reagents, the bridging of alkyl groups between two zinc centers can provide low-energy pathways to 60 facilitate this intermolecular exchange.61 Density functional theory (DFT) calculations have been performed on dimethylzinc (Me2Zn) and suggest a loosely bound four-center transition state which arises from a loosely bound dimer (Figure 4.10). 03 W ^ C-13 dibutylZn IHF:DMI (2:1) k^K^humw^tf^^^j -JVifr^tftwi^^i^^^iiiii ^ AJ \vimnmn' \hr^CmmliHm • I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' • ' ' I ' ' ' ' I ' ' • ' I ' ' ' ' I ' ' ' ' I ' ' ' ' 1 ' ' ' ' I ' ' ' ' I ' ' ' ' 1 ' ' ' ' 1 ' ' ' ' I ' ' ' ' I ' ' ' ' ! ' ' ' ' I 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm Figure 4.9: C NMR spectrum of Dibutylzinc in a solution of THF:DMI (2:1). Conversely, for organozinc halides, the presence of a good bridging group with lone pairs (e.g. bromine) facilitates the exchange to create an intermediate like that in Figure 3.6. Although aggregation and exchange of these organozinc reagents occurs much faster than the NMR. time scale, the broadness of the proton peaks in both lR spectra may be attributed to a time-averaging of these 'bridged' complexes in solution. 61 Satisfied with these results, the next step was to observe the effect of LiBr on the organozinc reagent as varying amounts of the additive (0-1.5 equiv, based on the f~ 2-03A ^y—VZlk H3C-Z1-CH3 332A H3e~Z< ^ZB—CB3 2mk H3C—Zn-CHj S3 ' Figure 4.10: The proposed transition state (left) from the previously formed dimer (right) of Me2Zn during alkyl exchange. organozinc reagent) were doped into the NMR tube under otherwise identical conditions. Figure 4.11 shows an overlay of 'H-NMR spectra going stepwise from 0-1.5 equivalence of LiBr in a 2:1 THF: DMI solution of K-butylzinc bromide. The appearance of a peak at 5 0.25 ppm next to the Ctb-ZnBr shift at 8 0.15 increases until a maximum of 0.75 equivalents of LiBr are added. This 'new' peak is still visible, albeit with decreased intensity due to peak broadening, even as more equivalents of LiBr are added. To confirm the identity of this peak a 2D-COSY-NMR (Figure 4.12) was performed with the organozinc reagent and 0.75 equivalents of LiBr in solution. The peak at 5 0.25 ppm displays a correlation to the P-protons of n-butylzinc bromide. The appearance of this peak so far up field also suggests that it is near an electropositive nucleus i.e. zinc. At increased concentrations of LiBr, the appearance of this peak may suggest a higher-order aggregate forming in solution. If we assume that the bromide, from LiBr, is coordinating to the zinc in w-butylzinc bromide, then at elevated equivalents of LiBr, higher-order 62 n-Butylzinc bromide THF:DMI (2:1) 0 equiv. LiBr i n-Butylzinc bromide THF:DMI(2:1) 0.25 equiv. LiBr , 3V ••A.. \¥ Ah n-Butylzinc bromide THF:DMI(2:1) 0.50 equiv. LiBr % n-Butylzinc bromide THF:DMI (2:1) 0.75 equiv. LiBr • .a / n-Butylzinc bromide THF:DMI(2:1) 1.0 equiv. LiBr M n ? n-Butylzinc bromide THF:DMI(2:1) 1.25 equiv. LiBr , i %i n-Butylzinc bromide THF:DMI(2:1) ll I 1.50 equiv. LiBr t U' Figure 4.11: 'H-NMR spectra of n-butylzinc bromide in 2 from 0 (top) to 1.5 (bottom) equivalents of LiBr. zincates (Figure 4.2) may be forming and can account for the origin of this peak. Another interesting characteristic is observed when comparing the first *H spectra in Figure 4.12 (0 equivalents of LiBr) with all the subsequent 'H spectra (0.25-1.50 equivalents of LiBr). Evidently, the proton peaks become a lot sharper and more defined as the equivalents of LiBr is increased. This observation leans toward KnochePs proposal that the addition of LiCl, in his chemistry, serves to disassemble the magnesium dimer formed in solution to create a more reactive 'ate' complex (Scheme 4.1).65 The solvent peaks in the spectra are also broad suggesting some sort of aggregated state between the organozinc reagent and the solvent. This statement is an acceptable one since it is well known, especially for organomagnesium reagents, that solvent and concentration play major roles in the position of the Schlenk equilibrium and in the aggregation state of the organometallic reagent. 6 ' 76 In both organomagnesium and organozinc reagents, polar coordinating solvents (DMI, THF etc.) aid in keeping the organometallic reagent monomeric.62' 76 The difference in this associative behaviour between polar and non-polar solvents is attributed to the relative Lewis basicities of the two solvents. Solvent-metal bonding competes with the bridging characteristics of the halide; thus THF completes more favourably than Et20, which in turn competes more favourably than benzene.76b The synthesis of w-butylzinc bromide is performed in DMI, a relatively polar coordinating solvent (dielectric constant =37.60 at 25°C)77 which ultimately aids in keeping the organozinc reagent- solubilized and decreases the aggregation of «-butylzinc bromide in solution. We believe this is accomplished through the coordination (by donation of electron density) of the DMI oxygen to the zinc center 64 while in solution. Similarly, alkyl magnesium reagents (Grignard) have been shown to crystallize as monomeric trigonal bipyramidal complexes in THF having three THF ligands coordinated to the Mg center.76b This coordination type for magnesium differs from zinc since numerous studies have validated that the tetrahedral zinc complexes ppm . a 4 3 2 FF™ Figure 4.12: 2D-COSY-NMR with nbutylzinc bromide and 0.75 equivalents of LiBr in a 2:1 THF: DMI solution generally represent the optimal, least strained structures among various zinc polyhedra.78 Based on this knowledge, we can hypothesize that at least two molecules of DMI, at any given time, are coordinated to n-butylzinc bromide in solution (Figure 4.13) in an effort to lower energy levels by bringing zinc to a more tetrahedral state and ultimately increase 65 solvation. The combination of these observations, along with supporting literature,65 suggests a slight modification of the Schlenk equilibrium is necessary to fit our Negishi cross-coupling reaction prior to the addition of LiBr (Scheme 4.2). An equilibrium exists between the monomeric structure of the alkyl zinc reagent and the bridged dimer in solution. Although figure 2.11 provides insightful information regarding w-butylzinc bromide in the presence of LiBr, the data is still insufficient to make any solid Figure 4.13: The determinations as to the exact role, if any, of LiBr in the proposed tetrahedral coordination of w-butyl Negishi protocol. Building on KnochePs theory regarding the zinc bromide in DMI solution. role of LiCl in activating organomagnesium reagents, we decided to take a more intimate look at these various species in solution by using NMR spectroscopy to observe 7Li nuclei. The goal was to see, in real time, any changes with respect to the Li environment as more equivalents of LiBr were doped into the solution. The observation of different environments for Li+ would confirm that the Li+ in solution is no longer a simple counter ion for Br", rather it is part of different complexes that may help to explain the remainder of the Schlenk equilibrium once LiBr is introduced. Figure 4.14 is an overlay of 7Li Scheme 4.2: Modified Schlenk equilibrium prior to LiBr addition -KM. O ii -Br. -2 DMI R2Zn(DMI)n + ZnX2(DMI)n q R-Zrf' ;Zn-R 2RZnBr +2 DMI 1 O Br o 66 spectra of the step-wise addition of LiBr from 0-1.50 equivalents. Consistent with our theory and previous observations (Figure 4.1), there is only one peak between 0-0.75 equivalents of LiBr in solution suggesting that the Li is in the same environment throughout these stages. As we approach 1 equivalent, an appearance of a new peak is visible and suggests a new Li environment in accordance with our initial doping experiments (Figure 4.1). As we pass 1 equivalent, a third peak begins to emerge and we see three distinct chemical shifts, 5 -0.2 ppm, 8 -0.3 ppm, and 5 -0.6 ppm respectively. The different chemical shifts for the 7Li nuclei suggest that Li+ is coordinated in different environments throughout the transmetallation process and that these environments are concentration dependent with respect to LiBr. Once we remove LiBr from the equation by introducing a zinc halide source, as Figure 4.3 suggests, we should see these environments should disappear and the spectrum return to one single peak. These experiments were conducted by doping ZnBr2 into the NMR tube containing 1.25 equivalents of LiBr and the observations were consistent with our theory (Figure 4.15). As small equivalents (0-0.10 eq. based on the organozinc reagent) were doped into the tube, the presence of the second peak slowly diminished until it completely disappeared, leaving behind one single peak. Recalling our initial theory of forming a higher order zincate (Figure 4.2) upon addition of LiBr in solution, and with the understanding that a secondary zinc halide source terminates the catalytic cycle, we can add these findings to our modified Schlenk equilibrium to include the displacement of DMI as each equivalent of LiBr is introduced 67 n-Butylzinc bromide THF:DMI (2:1) 0 equiv. LiBr , 0.0 -0.5 n-Butylzinc bromide THF:DMI (2:1) 0.25 equiv. LiBr o.o -o.s -X.S ppn n-Butylzinc bromide THF:DMI(2:1) 0.50 equiv. LiBr -1.5 pgm n-Butylzinc bromide THF.DMI (2:1) 0.75 equiv. LiBr V_ —i—— -1,0 n-Butylzinc bromide THF:DMI(2:1) 1.00 equiv. LiBr iL 1.5 1.0 0.5 0.0 -o.s -1.0 -1.5 BP» n-Butylzinc bromide THF:DMI (2:1) 1.25 equiv. LiBr / 1.5 1.0 0.5 0.0 -0.5 -1.0 -1.5 PP" n-Butylzinc bromide THF:DMI (2:1) 1.50 equiv. LiBr J I ' • 1.5 1.0 0.5 0.0 -0.5 -1.0 -1.5 FP» Figure 4.14: 7Li-NMR spectra of n-butylzinc bromide in 2:1 THF:DMI solution, with doping, from 0 (top) to 1.5 (bottom) equivalents of LiBr. using a LiCl in D2O capillary as reference and lock. 68 nButylzinc bromide THF:DMI (2:1) 1.2 equiv. LiBr 0 equiv ZnBr2 M 3 2 1 -1 -2 -3 pp« nButylzinc bromide THF:DMI (2:1) 1.2 equiv. LiBr 0.05 equiv ZnBr2 J I 3 2 1 -1 -2 -3 ppm nButylzinc bromide THF:DMI(2:1) 1.2 equiv. LiBr 0.10 equiv ZnBr2 J I 3 2 1 0 -I -2 -j fipai Figure 4.15: Overlay 7Li-NMR spectra of n-butylzinc bromide in a 2:1 THF:DMI solution with 1.2 eq. LiBr. Top: 0.0 eq. of ZnBr2. Middle: 0.05 eq. ZnBr2. Bottom: 0.10 eq. ZnBr2. into the reaction (Scheme 4.3). Based on crystal field theory, bromide is a strong anionic ligand, and as such is able to displace the neutral DMI on the zinc center (Scheme 4.3).76c As the equivalents of LiBr are increased such that they reach a stoichiometirc amount in relation to the organozinc reagent, bromide has successfully displaced the DMI ligands once coordinated to zinc to generate the new dimer seen in Scheme 4.3. However, the increased electron density surrounding the zinc centres by the addition of these bromide ligands may be unfavourable, especially when electron repulsion is considered. This electron repulsion may strain the pseudotetrahedral configuration of 69 Scheme 4.3: Modified Schlenk equilibrium upon addition of EiBr -NCN- O U® ,Br. p /Br.. e R Zn(DMI) + ZnX (DMI) -2DMI 2 n 2 n "2RZnBr R-Zn Zn-R LiBr(1.0eq.) R-Zp /Zp-R +2 DMI O Br O ~%Br Br LiBr(1.0eq.) l2e 2 L.ie Br Br, Li© Br Br ' ei/ -. e 2 K/Zn—B r R-Zn /Zp-R I Br %Br Br the zinc centre and cause the dimer to dissociate, consistent with Knochel's theory (Scheme 4.1); thus a more reactive zincate is formed. Once ZnBr2 or ZnCk is introduced into the equation, the bromide ions that have displaced DMI and are now associated to the alkyl zinc centre are removed by the Z11X2 and the equilibrium is pushed to the left. This renders the «-btuylzinc bromide unreactive as it cannot become an "ate" complex and as such, cannot participate in transmetallation. To further prove the modified Schlenk equilibrium (Scheme 4.3), we decided to perform variable temperature (VT) NMR spectroscopy experiments as a means of slowing down molecular movement to possibly observe the different environments of the solvent and w-butylzinc reagent. If different organozinc species are formed in solution upon the addition of LiBr as Scheme 4.3 suggests, then VT experiments should confirm these theories by the appearance of new peaks suggesting different species in solution. Figures 4.16 and 4.17 display an overlay of 5H and 13C spectra for THF and DMI in 70 solution with increasing amounts of LiBr at -9.99°C. As is evident, the -CH3- peak (SIH 2.6-2.7 ppm and 813c 31 ppm) and the -CH2- peak (SIH 3.1-3.3 ppm and SBC45 ppm) for DMI are definitely split as the equivalence of LiBr increases. Noteworthy is that at all 3 equivalents and at the lowered temperature, THF still appears as two singlets in both the H and C spectra, indicating that it's environment has not changed significantly. Moreover, Figures 4.18 and 4.19 display similar splitting with respect to the methylene sift (SIH 0.0-0.1 ppm and 813c 10 ppm) and the -CH2- adjacent to the methylene moiety (SIH 0.75-0.85 ppm and Snc 14 ppm) for equivalent spectra with the organozinc reagent. The sample was also taken down to -15°C and -30°C where 3 peaks (813c 14 ppm, 813c 13 ppm, and 813c 12 ppm) are visible for the 13C spectra at -30°C suggesting different environments for -CEfe-ZnBr as per the modified Schlenk equilibrium (Figure 4.20). Overall, the data implies that different species are present in solution when LiBr is added to w-butylzinc bromide. The NMR data also suggests that separately, «-butylzinc bromide behaves as an aggregate; coordinating 2 or more DMI solvent molecules to increase solubility and become tetrahedral. The VT experiments also proved informative since they show the appearance of peaks at lower temperatures that are not present in the room temperature NMR spectroscopy data. While previous data already suggests the need for LiBr to activate the alkylzinc halide toward transmetallation, our NMR spectroscopy data has provided a plausible theory that can account for the increased activity of n-butylzinc bromide in the presence of LiBr in our Negishi alkyl-alkyl cross- coupling protocol (Figure 4.4). 71 ;i JJO 15 1>5 0.9 ppm » 5 «!-«.»€ 1) -/ <-„._„j H Ml 2.5 1,0 0.5. mi JJJSS -9.?*ic i ^t i M. ,..r„r..„,.__^..^....T._., Ml 2.5 J-» 1.5 1.0 «.3 «» Pf!» ile •'T^ I ' T 1 •"•~T~~ j • •! -r-r-f*- 45 m 55 59 45 « 35 .» x» 15 io 5 ''• I '••'(' I j J ' • ' ' » 15 10 5 ii ppm 1 I • ' • ' ( ' ' ' • I ' ' ' ' I ' L ' •' I ' ' ' ' 1 ' • • ' I ' ' ' ' 1 • ' ' • I • ' ' • 1 ' ' ' ' 1 ' ' ' • I L ' ' ' I ' ' ' ' I ' ' ' ' m ¥) 55 5e 45 *> 3s m 25 si 15 m 5 9 <$m Figure 2.16 (top): 'H-NMR spectra at -9.99°C for a 2:1 THF: DMI solution with w-butylzinc bromide at varying equivalents of LiBr (0-1 eq.). Figure 2.17 (bottom): 13C-NMR spectra at -9.99°C for a 2:1 THF: DMI solution with n-butylzinc bromide with varying equivalents of LiBr (0-1 eq.). 72 }1 I. j i _J> VL_ J UX_ X i • • • • i o.5*<>-*M$e 11 ! »_~/ V,_ jj '••• j VJU_ i £0 2,5 3.0 13. m ft$ 0.0 |> -%**C1*! VAA _X ->*A_ '"' I '""' I""' I 'I • "I ' "" '" ! I ' ' ' ' [ 33 » 10 1.5 1.0 »5 0.0 pfira ae«-».<»c J w*« w J>•* W*/ ^-IT^lMHHii^i.lMi.nrii.1'-'5-- -.? Nli 55 » 45 -IS 33 M 25 29 1.5 JS .5 0 as«n-o.»c u*^•MM^-vW^W*'*'****'*' * •$5 &> 55 50 45 40 15 (0 5 0 pjia -ft W I »1 w*» J U-—«-> 65 *« 55 58 45 4$ 35 50 25 io 15 M 5 G pj>m Figwre 2./S (top,): H-NMR spectra at -9.99°C for n-butylzinc bromide in a 2:1 THF: DMI solution at varying equivalents of LiBr (0-1 eq.). Figure 2.19 (bottom): 13C-NMR spectra at 9.99°C for n-butylzinc bromide in a 2.1 THF: DMI solution with varying equivalents of LiBr (0-1 eq.). 73 en r- r- H GO ID U> O CM CN CN OO O tH ffv t^ in •* H o «? co o r-i r- m oi c\i co v m m 13C at -15C 1.0 equiv LiBr nBuZnBr THF:DMI (2:1) iL JJlAtX««*>itog»*»<*^Vl»*«*'«'Aft*** W*v^^ Lw*l»*iM w*-rf#V^^ Jv-^ Hll_l JW u~ 75 65 60 55 10 COCNCMCOrO'O'iniO 3t3%«d',^ri-4*?,o]c^o4VDmr-cJiin r- r-i *o Hcnminr-icocMT-ivocorocj Hinw 13C at -30C 1.0 equiv LiBr nBuZnBr, THF:DMI (2:1) L, LL ' i •' •' i''' • i • •' • i'''' i'' •' i'''' i •''' i'''' i'''' i'''' i'''' i'''' i'''' i'''' i'''' i 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 ppm Figure 2.20: Variable Temperature (VT) NMR spectroscopy for nbutylzinc bromide in a 2:1 THF:DMI solution, (top) -15°C; (bottom) -30°C. 74 4.2: Conclusion Based on these experiments, it is our belief that LiBr is vital in the activation of the alkyl zinc reagent since it participates in an exchange with the DMI in solution, ultimately displacing it and rendering the overall organozinc species more reactive (Scheme 2.4). The LiBr does this gradually, displacing one DMI at a time, and allowing equilibrium to establish that places the -CtbZnBr, DMI, Li, and the Br in different environments, all of which are detected by NMR spectroscopy, both at room temperature ( H, C, Li) and as the temperature is lowered ( H, C). Piecing together previous experimental and NMR data, our theory of a modified Schlenk equilibrium is supported since the addition of 1 equiv. of LiBr is sufficient to moderately activate the organozinc reagent toward transmetallation by forming an RZnX2~ zincate. This is corroborated with the results in Figure 2.1 which show that at 1 equiv of LiBr, a moderate amount of heptylbenzene is formed thus confirming successful transmetallation. However, since this is in equilibrium (Scheme 2.4), at equivalents lower than 1, the concentration of LiBr in solution is too low to induce significant exchange with DMI; hence, minimal product is formed (Figure 2.1). Conversely, higher concentrations of LiBr in solution ( > leq.) promote quantitative conversion to product, suggesting the equilibrium is pushed strongly to the right (Figure 2.4) and a higher-ordered zincate, far more reactive to transmetallation, is formed (i.e. RZnXs)2". 75 CHAPTER 5: Experimental 5.1 The Pd-PEPPSI-IPr -catalyzed Buchwald-Hartwig-Yagupol'skii Amination General Experimental Procedures: All reagents were purchased from commercial sources and were used without further purification, unless indicated otherwise. Dry 1- methyl-2-pyrrolidinone (NMP), 7V,N-dimethyl-2-imidazolidinone (DMI), and 1,2- dimethoxyethane (DME) were purchased from Fluka, stored over 4 A molecular sieves, and handled under Argon. Anhydrous methanol, A^A^-dimethylformamide (DMF) and dimethylsulfoxide (DMSO) were purchased from Sigma-Aldrich Inc. and handled under argon. Tetrahydrofuran (THF) was distilled from sodium/benzophenone prior to use. Toluene was distilled from calcium hydride prior to use. All reaction vials (screw-cap threaded, caps attached, 17 x 60 mm) were purchased from Fischer Scientific. CDCI3 was purchased from Cambridge Isotopes. Thin-layer chromatography (TLC) was performed on Whattman 60 F254 glass plates and these were visualized by using UV light (254 nm), potassium permanganate, or phosphomolybdic acid stains. Column chromatography purification was carried out by using the flash technique on Silicycle silica gel 60 (230-400 mesh). NMR spectra were recorded on a Bruker AV 400 spectrometer or a Bruker AV 300 spectrometer, as indicated. The chemical shifts (5) for 'H are given in ppm referenced to the residual proton signal of the deuterated solvent. The chemical shifts (8) for C are referenced relative to the signal from the carbon of the deuterated solvent. Gas chromatography was performed on Varian Series GC/MS/MS 4000 System. Optical rotations were measured on a Perkin-Elmer Model 241 76 polarimeter by using 10 cm cells and the sodium D line at ambient temperature in the solvent specified (concentration c is given as g per 100 mL). General Procedure A: (Pd-Catalyzed amination utilizing KO'Bu/NaO'Bu ) (Table 2.1): In air, potassium tert-butoxide (1.5 mmol, 169 mg) and Pd-PEPPSI-IPr (12) (2 mol%, 13.6 mg) were weighed into a 3 mL screw-cap threaded vial that was sealed with a septum and purged with argon (3x). The amine (1.2 mmol) was added via syringe, and the reaction was allowed to stir for 2-3 minutes. DME (1 mL) was then injected via syringe followed by the aryl halide (1.0 mmol). If the aryl halide was a solid, it was introduced into the vial prior to purging with argon. At this time, the reaction mixture was stirred for 24 h at the indicated temperature, unless specified otherwise. The reaction mixture was filtered through a bed of Celite and washed with Et20. The filtrate was concentrated in vacuo and purified via silica gel flash chromatography. General Procedure B: (Pd-Catalyzed amination utilizing CS2CO3) (Tables 2.6, 2.7, 2.8; Figures 2.2, 2.3): In air, cesium carbonate (3.0 mmol, 980 mg) and Pd- PEPPSI-IPr (12) (4 mol%, 27 mg) were weighed into a 3 mL screw-cap threaded vial that was sealed with a septum and purged with argon (3x ). The aryl halide (1.0 mmol), the amine (1.5 mmol) and DME (1 mL) were subsequently added via syringe. If the aryl halide was a solid, it was introduced into the vial prior to purging with argon. The reaction mixture was stirred o for 24 h at 80 C, unless specified otherwise. At this time, the reaction mixture was filtered through a bed of Celite and washed with Et20. The filtrate was concentrated in vacuo and purified via silica gel flash chromatography. 77 Procedure for method C: (Pd-Catalyzed Suzuki-Miyara reactions) (Figure 2.3, Tables 2.10, 2.12). In air, a vial was charged with Pd-PEPPSI-IPr (12) (6.8 mg, 0.01 mmol), potassium carbonate (207 mg, 1.50 mmol), the boronic acid (0.6 mmol), and the organohalide (0.5 mmol). The vial was sealed with a septum and purged with argon (3x). Dioxane (2.0 mL) was added and the contents were stirred at 60 C for the specified period of time. The reaction mixture was then diluted with diethyl ether (2 mL) and transferred to a round-bottomed flask. The reaction vial was rinsed with additional diethyl ether (2 mL) and combined with the previously obtained solution. Each reaction was performed in duplicate and the contents were combined, concentrated onto silica gel, and purified by flash chromatography. °^^ iV-(4-Trifluoromethylphenyl)morpholine (14) (Tables 2.1, 2.6; Figures 2.2, 2.3): Following general procedure A (50 C), 200 mg of 14 (86% yield) were isolated (Rf = 0.3, 10% Et20 in pentane) as a white crystalline solid (m.p. 57-58°C; lit. m.p. 58C).79 Following general procedure A (RT), 213 mg of 14 (92%) were isolated. Following general procedure B, 213 mg of 14 (92% yield) were isolated. The spectral data were in accordance with those reported in the literature.80 78 00\ Hi.-MethoxyphenyI)pyrrolidin e (15) (Table 2.1): Following general procedure A (RT), 107 mg of 15 (60% yield) were isolated (Rf = 0.4, 10% Et20 in pentane) as a light yellow oil. The spectral data were in accordance with those reported in literature.81 O 4-(Pyridin-2-yl)morphoIine (16) (Table 2.1): Following general procedure A (50°C), 142 mg of 16 (87% yield) were isolated (Rf = 0.35, 50% Et20 in pentane) as a yellow oil. The spectral data were in accordance with those reported in literature.82 N N' 2-Piperidinylpyridine (17) (Table 2.1): Following general procedure A (RT), 135 mg of 17 (83% yield) were isolated (Rf = 0.3, 10% Et20 in pentane) as a colorless oil. The spectral data were in accordance with those reported in literature.83 rS>2,6-DimethyWV-(l-phenylethyI)aniline (18) (Tables 2.1, 2.8): Following general procedure A (RT), 176 mg of 18 (78% yield) were isolated (Rf = 0.4; 5% Et20 in pentane) as a yellow, viscous oil. Following general procedure B, 221 mg of 79 ! 18 (98%) were isolated. [a]§ = - 100.88 (c = 0.73, CHC13); H NMR (400 MHz, CDC13) 8: 7.45-7.25 (m, 5H), 7.05 (d, J= 7.5 Hz, 2H), 6.88 (t, J= 7.5Hz, 1H), 4.41 (q, J= 6.8 Hz, 1H), 3.24 (br. s, 1H), 2.26 (s, 6H), 1.60 ppm (d, J = 6.8 Hz, 3H) ; 13C NMR (75 MHz, CDC13) 5: 145.4, 145.0, 130.5, 128.9, 128.5, 127.0, 126.2, 121.7, 56.8, 22.7, 19.0 ppm. Anal. Calcd. for Ci6Hi9N: C 85.28, H 8.50, N 6.22; found: C 84.97, H 8.26, N 5.90. I I"" N' 0"~-" JV-(4-Methoxyphenyl)morpholme (19) (Tables 2.1, 2.6; Figures 2.2, 2.3): Following general procedure A (RT), 162 mg of 19 (84% yield, X = CI) were isolated (Rf = 0.2, step gradient, 10% ET2O in pentane followed by 25% Et20 in pentane) as a white crystalline solid (m.p. 67-68C; lit. m.p. 71-72°C).84 Following general procedure B, 52 mg of 19 (27% yield, X = CI) and 31 mg (16%, X = Br) were isolated. The spectral data were in accordance with those reported in the literature.85 A42,6-Dimethylphenyl)2,6-diisopropylaniline (20) (Table 2.1): Following general procedure A (RT), 253 mg of 20 (90% yield) were isolated (Rf = 0.3, 5% Et20 in pentane) as a colorless oil. The spectral data were in accordance with those or reported in literature. 80 H 4-methyl-A4fK)-l-phenylethyI)quinoIin-2-amine (21) (Table 2.1): Following general procedure A (50°C), 232 mg of 21 (88% yield) was isolated (Rf = 0.3; ! 20% diethyl ether in pentane) as a viscous, yellow oil. H NMR (400 MHz, CDC13) 5: 7.78-7.72 (m, 2H), 7.58-7.55 (m, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.39-7.35 (m, 2H), 7.30- 7.24 (m, 2H), 6.44 (s, 1H), 5.21-5.14 (m, 2 H), 2.52 (s, 3H), 1.64 ppm (d, J = 6.5 Hz, 13 3H); C NMR (75 MHz, CDC13) 5: 156.1 147.8, 145.2, 144.8, 129.3, 128.6, 127.0, 126.5, 126.0, 123.8, 123.6, 121.9, 111.0, 51.1, 23.7, 18.9 ppm. Anal. Calcd. for Ci8H18N2: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.60; H, 7.17; N, 10.43. (Sj-iV-(l-(Naphthalene-l-yl)ethyl)isoquinolin-3-amiiie (22) (Table 2.1): Following general procedure A (50°C), 286 mg of 22 (96% yield) were isolated (Rf = 0.4, 20% Et20 in pentane) as a pale-yellow solid (m.p. 53-56 C). Following general procedure B, 286 mg of 22 (96% yield) were isolated. [a]f = +28.18 (c=0.53, CHC13); 'H NMR (300 MHz, CDC13) 5: 8.27-8.15 (m, 1H), 8.06 (d, J = 6.0 Hz, 1H), 7.9-7.78 (m, 2H), 7.70-7.62 (m, 3H), 7.60-7.52 (m, 1H), 7.50-7.45 (m, 3H), 7.42-7.35 (m, 1H), 6.96 (d, J= 5.7 Hz, 1H), 6.35 (quin., J = 6.6 Hz, 1H), 5.45 (br. d, J= 6.9 Hz, 1H) 1.84 ppm 81 13 (d, J =6.6 Hz, 3H) ; C NMR (75 MHz, CDC13) S: 153.2, 141.7, 139.7, 137.2, 134.0, 131.5, 129.6, 128.7, 128.1, 127.2, 126.3, 125.8, 125.7, 125.4, 123.9, 122.6, 121.4, 118.0, 110.9, 46.3, 20.7 ppm. Anal. Calcd. for C20Hi8N2 : C 84.53, H 6.08, N 9.39; found: C 84.56; H 6.00, N 9.22. 7V-(2,6-diisopropylphenyl)isoquinolin-l-amine (23) (Table 2.1): Following general procedure A (RT), 146 mg of 23 (48% yield) were isolated (Rf = 0.3, ] 15% Et20 in pentane) as a viscous, yellow oil. H NMR (300 MHz, CDC13) 5: 8.28- 8.17 (d, J = 5.8 Hz, 1H), 7.89-7.83 (m, 1H), 7.67-7.61 (m, 1H), 7.55-7.49 (m, 2H), 7.01-6.97 (m, 1H), 6.77-6.70 (d, J = 6.1Hz, 2H), 6.50-6.46 (m, 1H), 4.02-4.0 (br. s, 1H) 3.18-3.12 13 (m, 2H), 1.35-1.29 ppm (d, J = 6.6 Hz, 12H); C NMR (75 MHz, CDC13) 6: 152.4, 142.7, 137.5, 136.3, 131.5, 130.2, 127.4, 125.7, 124.3, 120.6, 118.3, 115.9, 111.3, 27.5, 23.2 ppm. Anal. Calcd. for C21H24N2: C 82.85, H 7.95, N 9.20; found: C 81.29, H 7.65, N 9.09. iV-Phenylmorpholine (26) (Tables 2.1-2.6, Figures 2.2, 2.3): Following general procedure A (50°C), 155 mg of 26 (95% yield) were isolated (Rf= 0.35, 10% 86 Et20 in pentane) as a white, crystalline solid (m.p. 52-53°C; lit. m.p. 54-55°C). 82 Following general procedure A (RT), 147 mg of 26 (90%) were isolated. Following procedure B, 129 mg of 26 (79% yield) were isolated. The spectral data were in DA accordance with those reported in the literature. nN°2 4-(4-Nitrophenyl)morpholine (27) (Table 2.6, Figures 2.2, 2.3): Following general procedure B, 200 mg (96% yield, X = CI) and 204 mg (98% yield, X = Br) of 27 were isolated (Rf = 0.30, 50% Et20 in pentane) as a yellow/orange solid (m.p. 145-146°C; lit. m.p. 158-159°C).87 The spectral data were in accordance with those reported in the literature.88 N °^ 4-/>-Tolylmorpholine (28) (Table 2.6, Figures 2.2, 2.3): Following general procedure B, 62mg (35% yield, X=Br) and 67 mg (38% yield, X=C1) of 28 were isolated (Rf = 0.6, 10% Et20 in pentane) as white solid (m.p. 44-^17°C; lit m.p. 45-48°C). The spectral data were in accordance with those reported in the literature.88 F 4-(4-Fluorophenyl)morpholine (29) (Table 2.6): Following general procedure B, 116 mg (64% yield, X = CI) and 121 mg (67% yield, X = Br) of 29 were isolated (Rf = 0.30, 20% Et20 in pentane) as a light-yellow oil. The spectral data were in accordance with those reported in the literature.87 83 3 A^-methyl-A^-phenyl-4-(trifluoromethyl)aniline (30) (Table 2.7): Following general procedure B, 53 mg (21% yield, X = CI) and 61 mg (24% yield, X = Br) of 30 were isolated (Rf = 0.40, 20 vol % ether in pentane) as a light-yellow oil. The spectral data were in accordance with those reported in literature. 7 2 A'-methyl-4-nitro-N-phenylbenzenamine (31) (Table 2.7): Following general procedure B, 57 mg (25% yield, X = CI) and 66 mg (29% yield, X = Br) of 31 were isolated (Rf = 0.45, 20 vol % ether in pentane) as a light-yellow oil. The spectral data were in accordance with those reported in literature. ^•^ ./V-methyWV-phenylaiiiliiie (33) (Table 2.7): Following general procedure B, 36 mg (17% yield, X= CI) and 30 mg (14% yield, X = Br) of 33 were isolated (Rf = 0.5, 15 vol % ether in pentane) as a colourless oil. The spectral data were in accordance with those reported in literature. 89 84 ^^ 4-(Pyrazin-2-yl)morpholine (34) (Table 2.8): Following general procedure B, 142 mg of 34 (86% yield) were isolated (Rf = 0.4, Et20) as an off-white solid (m.p. 46-48°C). 'H NMR (300 MHz, CDC13) 5: 8.14 (d, J = 1.5 Hz, 1H), 8.10-8.04 (m, 1H), 7.91 (d, J = 2.4 Hz, 1H), 3.84 (t, /= 2.4 Hz, 4H), 3.58 ppm (t, J = 2.4 Hz, 4H); 13 C NMR (75 MHz, CDC13) 5: 155.1, 141.8, 133.6, 130.9, 66.5, 44.8 ppm. Anal. Calcd. for C8H„N30 : C 58.17, H 6.71, N 25.44; found: C 58.18, H 6.90, N 25.27. ' .N 2-(4-Phenylpiperazin-l-yl)pyrazine (35) (Table 2.8): Following general procedure B, 223 mg of 35 (93% yield) were isolated (Rf = 0.6, 90% Et20 in X pentane) as yellow crystals (m.p. 113-115°C). H NMR (300 MHz, CDC13) 5: 8.22 (d, J=1.5 Hz, 1H), 8.13-8.06 (m, 1H), 7.91 (d, .7=2.7 Hz, 1H), 7.38-7.27 (m, 2H), 7.05-6.90 13 (m, 3H), 3.79 (t, J=5.4 Hz, 4H), 3.34 ppm (t, J=5.4 Hz, 4H); C NMR (75 MHz, CDC13) 5: 155.0, 151.1,141.8,133.3,131.2, 129.3,120.4,116.5,49.1,44.6 ppm. Anal. Calcd. for Ci4Hi6N4 : C 69.97, H 6.71, N 23.32; found: C 70.27, H 6.58, N 23.15. 85 NT ^N' A'-Methyl-A'-phenyl-2-aminopyrazine (36) (Table 2.8): Following general procedure B, 165 mg of 36 (89% yield) were isolated (Rf= 0.35, 50% Et20 in pentane) as a viscous, yellow oil. The spectral data were in accordance with those reported in the literature.90 ^-^ 4-(6-methoxypyridin-2-yl)morpholine (37) (Table 2.8): Following general procedure B, 179 mg of 37 (92% yield) were isolated (Rf = 0.46, Et20) as a light brown liquid. The spectral data were in accordance with those reported in the literature.91 (X Af-AIlyl-yV-phenylpyraziii-2-amine (38) (Table 2.8): Following general procedure B, 201 mg of 38 (95% yield) were isolated (Rf = 0.2, 20% Et20 in pentane) as ! a yellow, viscous oil. H NMR (300 MHz, CDC13) 5: 8.10-8.06 (m, 1H), 7.89 (d, J= 1.5 Hz, 1H), 7.83 (d, J= 2.7 Hz, 1H), 7.48-7.39 (m, 2H), 7.31-7.25 (m, 3H), 6.05-5.96 (m, ,3 1H), 5.23-5.12 (m, 2H), 4.55 ppm (dt, J= 5.4, 1.5 Hz, 2H); C NMR (75 MHz, CDC13) 8: 154.2, 143.9, 141.5, 133.6, 133.0, 132.9, 130.0, 127.0, 126.7, 116.9, 52.7 ppm. Anal. Calcd. for Ci3H13N3: C 73.91, H 6.20, N 19.89; found: C 74.20; H 6.52, N 19.89. 86 O N N N,N-Diphenyl-6-methoxy-pyridin-2-amine (39) (Table 2.8): Following general procedure B, 238 mg of 39 (86% yield) were isolated (Rf = 0.27, step gradient, 20% Et20 in pentane followed by 30% Et20 in pentane) as a white solid (m.p. ! 74-76°C). H NMR (300 MHz, CDC13) 5: 7.45-7.40 (m, 1H), 6.15-6.09 (t, J = 4.6Hz, 1H), 5.95-5.89 (t, J = 5.3 Hz, 1H), 7.40-7.33 (m, 4H), 7.25-7.17 ppm (m, 6H), 3.75-3.69 (s, 3H); 13C NMR (75 MHz, CDCI3) 5: 161.6, 154.0, 143.6, 141.4, 129.9, 119.5, 118.7, 100.3, 95.8, 56.9 ppm. Anal. Calcd. for C18H16N20: C 78.24, H 5.84, N 10.14; found: C 77.87, H 5.34, N 10.24. rNi ° ^^ \ Ethyl l-(pyrazin-2-yl)piperidine-3-carboxylate (40) (Table 2.8): Following general procedure B, 164 mg of 34 (69% yield) were isolated (Rf = 0.3, Et20) as a viscous, yellow oil. The spectral data were in accordance with those reported in the literature.92 OJO AyV-Diphenylpyrazin-2-amine (41) (Table 2.8): Following general procedure B, 205 mg of 41 (83% yield) were isolated (Rf= 0.25, step gradient, 15% Et20 87 in pentane followed by 25% Et20 in pentane) as a pale yellow solid (m.p. 70-73 C). *H NMR (300 MHz, CDC13) 5: 8.15-8.08 (m, 2H), 7.99 (d, J= 2.7 Hz, 1H), 7.40-7.33 (m, 13 4H), 7.25-7.17 ppm (m, 6H); C NMR (75 MHz, CDC13) 8: 155.2, 144.7, 141.9, 136.2, 135.5, 129.8, 126.5, 125.7 ppm. Anal. Calcd. for Ci6Hi3N3 : C 77.71, H 5.30, N 16.99; found: C 77.40; H 5.44, N 16.66. s °— i\yV-Bis(2-methoxyethyl)-2-aminopyrazine (42) (Table 2.8): Following general procedure B, 203mg of 42 (96% yield) were isolated (Rf = 0.45, step gradient, 10% Et20 in pentane followed by 25% Et20 in pentane) as a viscous, yellow oil. ]H NMR (300 MHz, CDCI3) 5: 8.06 (d, J= 1.2 Hz, 1H), 7.95 (dd, J = 2.7, 1.7 Hz, 1H), 7.72 (d, J= 2.7 Hz, 1H), 3.71 (t, J=5.7 Hz, 4H), 3.54 (t, J= 5.7 Hz, 4H), 3.31 ppm 13 (s, 6H); C NMR (75 MHz, CDC13) 8: 153.9, 141.5, 131.5, 130.3, 70.4, 58.9, 48.7 ppm. Anal. Calcd. for CioH17N302 : C 56.85, H 8.11, N 19.89; found: C 56.85; H 8.21, N 19.92. °-- 6-Methoxy-iV^-bis(2-methoxyethyl)pyridin-2-amine (43) (Table 2.8): Foliowinggeneral procedure B, 149 mg of 43 (62% yield) were isolated (Rf= 0.25, step gradient, 5% EtaO in pentane followed by 20% Et20 in pentane) as a viscous, 88 l yellow oil. U NMR (300 MHz, CDC13) 5: 7.36 (t, J= 6.0 Hz, 1H), 6.09 (d, J= 6.0 Hz, 1H), 6.00 (d, J= 6.0 Hz, 1H), 3.86 (s, 3H), 3.72 (t, J= 4.6 Hz, 4 H), 3.60 (t, J= 4.6 Hz, 13 4H), 3.38 ppm (s, 6H); C NMR (75 MHz, CDC13) 5: 163.0, 156.7, 139.8, 96.8, 96.2, 70.7, 58.9, 52.7, 49.2 ppm. Anal. Calcd. for C12H20N2O3: C 59.98, H 8.39, N 11.66; found: C 60.39; H 8.11, N 11.99. N N ^* i\yV-diphenylpyridin-2-amiiie (44) (Table 2.8): Following general procedure B, 74mg of 44 (31% yield) were isolated (Rf = 0.35, 10% ET2O in pentane) as a pale pink solid (m.p. 105-107°C; lit. 105°C).93 The spectral data were in accordance with those reported in literature.93 ^^ l-MethyI-4-(l-phenyI-l//-tetrazoI-5-yI)piperazine (45) (Table 2.8): Following general procedure B, 221 mg of 45 (90% yield) were isolated (Rf = 0.25, 10% ] ethanol in ethyl acetate) as yellow solid (m.p. 84-87°C). H NMR (400 MHz, CDC13) 5: 7.60-7.40 (m, 5H), 3.25 (t, J= 4.4 Hz, 4H), 2.43(t, J= 4.4 Hz, 4H), 2.27 ppm (s, 3H); 13 C NMR (75 MHz, CDC13) 5: 157.4, 134.8, 129.8, 129.7, 123.7, 53.9, 48.5, 46.0 ppm. Anal. Calcd. for Ci2Hi6N6 : C 59.00, H 6.60, N 34.40; found: C 58.71, H 6.97, N 33.99. 89 'N Triphenylamine (46) (Table 2.8): Following general procedure B, 26mg of 46 (10% yield) were isolated (Rf = 0.2, 5% Et20 in pentane) as a light purple solid (m.p. 123-124°C; lit. 127-128°C).89 The spectral data were in accordance with those reported in literature.89 4-MethoxybiphenyI (Figures 2.2, 2.3) Following general procedure C, 146 mg of the title compound (79% yield) were isolated (Rf = 0.2, 10% ether in pentane) as a white solid (m.p. 86-87°C; lit. 85-87°C).94 The spectral data were in accordance with those reported in literature.94 0 ^^. 4,4'-Dimethoxybiphenyl (Figures 2.2, 2.3): Following general procedure C, 165 mg of the title compound (77% yield) were isolated (Rf = 0.3, 10% ether in pentane) as a white solid (m.p. 180-182°C; lit. 178-180°C)94 The spectral data were in accordance with those reported in literature.94 90 .0. F3C v 4-methoxy-4'-trifluoromethylbiphenyl (Figures 2.2, 2.3): Following general procedure C, 214 mg of the title compound (85% yield) were isolated 92 (Rf = 0.2, 10% ether in pentane) as a white solid (mp 125-126°C; lit. 124-125°C). The spectral data were in accordance with those reported in literature.94 °2N 4'-Methoxy-4-nitro-biphenyl (Figures 2.2, 2.3): Following general procedure C, 220 mg of the title compound (96% yield) were isolated (Rf = 0.35, 25% ether in pentane) as a light yellow solid (m.p. 104-106°C; lit. 107-108°C).95 The spectral data were in accordance with those reported in literature.95 4'-MethyI-4-methoxy-biphenyI (Figures 2.2, 2.3): Following general procedure C, 174 mg of the title compound (88% yield) was isolated (Rf = 0.2, 10% ether in pentane) as a white solid (m.p.l07-108°C; lit. 106-107°C).96 The spectral data were in accordance with those reported in literature.96 91 5.2 Pd-PEPPSI-IPr in the Negishi and Suzuki cross-coupling reactions of 1,1- dibromo-1-alkene type substrates General procedure D (Negishi sp -sp )( Tables 2.9, 2.11): In air, a vial was charged with Pd-PEPPSI-IPr (12) (6.8-34 mg, 2-10 mol%) and under an inert atmosphere ZnCl2 (0.8 mmol) and a stirrer bar were added. The vial was then sealed with a septum and purged with argon. THF (0.8 mL) was then added followed by the requisite Grignard reagent (0.8 mL, 1.0m in THF, 0.8 mmol) and stirring continued for 15 minutes, at which time a white precipitate formed. DMI (0.8 mL) was then added followed by the 1,1-dihalo-l- alkene (0.5 mmol) generating a 2:1 THF:DMI ratio in solution. The septum was replaced with a TeflonR-lined screw cap under an inert atmosphere and the reaction stirred for 24 h. After this time, the reaction mixture was diluted with diethyl ether (15 mL) and washed successively with NaaEDTA solution (1M; prepared from EDTA and 3 equiv of NaOH), water, and brine. After drying (anhydrous MgS04) the solution was filtered, the solvent removed in vacuo, and the residue purified by flash chromatography. 7 7 General Procedure E (Negishi sp -sp using PdChdppb): A solution of bromobenzene (1.10 equiv., 1.1 mmol, 116 uL) in THF (1 mL) at RT was added to magnesium turnings (1.4 equiv., 1.4 mmol, 34 mg) with stirring for 1 h. The resultant Grignard was transferred via cannula to a solution of 191 mg of anhydrous ZnCb (1.4 equiv., 1.4 mmol) in 2 mL THF. The resulting solution was stirred for 1.5 h at RT with a white precipitate forming, indicating metal-metal exchange. A solution of the 1,1-dihalo-l- alkene (1.0 equiv., 1.0 mmol, 300 mg), PdC^dppb (0.1 equiv., 0.1 mmol, 60 mg), in THF 92 (5 mL) was transferred via a cannula to the reaction mixture at 0°C and stirred for 5 h at RT. Distilled water (10 mL) was added to the reaction mixture and the aqueous layer was extracted with Et20 (3 x 20 mL). The combined organic extracts were dried with anhydrous MgS04, and the solvent was removed in vacuo and concentrated onto silica gel. Purification was performed by flash chromatography. Synthesis of Methyl 4-(2,2,-Dibromovinyl)benzoate O 0 CBr4, PPh3 DCM, 0-RT Br To a 0 °C solution of triphenylphosphine (2.8 equiv., 44.92 mmol, 11.8 g) and DCM (40 mL) was added carbon tetrabromide (1.4 equiv., 22.46 mmol, 7.5 g) under argon. Reaction was stirred for 20 minutes and the solution had a dark orange/brown appearance. After stirring, the solution was cooled to room temperature and methyl 4- formylbenzoate (1.0 equiv., 16.04 mmol, 2.63 g) was added as a solution in 40 mL DCM drop-wise to the cooled solution (total volume = 80 mL). The reaction was then stirred for 1 h at 25°C. Hexane was added to the reaction mixture with good stirring, and the resulting slurry was filtered through silica gel and rinsed twice with a mixed solvent of hexane and ether (1/1). The crude product was concentrated onto silica gel and purified by column chromatography with an ether/ hexane (1:1) solution (13.6mmol, 4.4 g, 85% yield) as a pale yellow solid (m.p. 108-110°C). Spectral data were in accordance with those previously reported.46 93 o (Z)-Methyl 4-(2-bromo-2-phenylvinyl)benzoate (50) (Tables 2.2-1, 2.2-2): Following general procedure C, 7-16 mg (4-10% yield) of 50 were isolated (Rf = 0.3 EtiO in pentane) as a pale yellow solid (m.p. 141-143°C). Following general procedure D, 8-16 mg (5-10%) of 50 was isolated. Following procedure G, 87 mg (55% ! yield) of 50 were isolated. H NMR (400 MHz, CDC13) 5: 8.04 (td, J= 1.7, 8.5 Hz, 2H), 7.74 (d, J = 8.3 Hz, 2H), 7.62 (m, 2H), 7.35 (m, 3H), 7.20 (s, 1H), 3.89 ppm (s, 3H); 13C NMR (100 MHz, CDCI3) 5: 166.6, 140.7, 140.5, 129.4, 129.3, 129.06, 129.03, 128.9, 128.3, 127.7, 126.2, 52.0 ppm. Anal. Calcd. for Ci6Hi3Br02: C, 60.59; H, 4.13; found: C, 60.69; H, 4.28. O Br—EEEK"^ Methyl 4-(bromoethynyl)benzoate (51) (Tables 2.2-1, 2.2-2): Following general procedure C, 8-18 mg (7-15% yield) of 51 was isolated (Rf = 0.35 25% Et20 in pentane) a viscous yellow oil. Following general procedure D, 13-23 mg (11-20% yield) of 51 was isolated. Spectral data were in accordance with those previously reported. 97 94 Methyl 4-(2, 2-Diphenylvinyl)benzoate (54) (Tables 2.2-1, 2.2-2): Following general procedure D, 18-22mg (12-14% yield) was isolated (Rf= 0.25 ] Et20 in pentane) as a yellow solid (m.p. 182-184°C). H NMR (400 MHz, CDC13) 5: 7.78 (d, J= 8.2 Hz, 2H), 7.25 (m, 8H), 7.16 (m, 2H), 7.04 (d, J= 8.0 Hz, 2H), 6.95 (s, 1H), 13 3.81 (s, 3H) ppm; C NMR (100 MHz, CDC13) 5: 166.6, 144.9, 142.8, 142.0, 139.7, 130.1, 129.3,129.1, 128.6, 128.2,127.88, 127.85,127.67, 126.61, 126.9, 51.8 ppm. Anal. Calcd. for C22Hi802: C, 84.05; H, 5.77. Found: C, 83.82; H, 5.82. Synthesis of Methyl 5-oxopentanoate (57) O O PCC,Na(OAc)2 O MeOH, H2S04 H0^ DCM H ^~ V > Y—~V reflux, 16h O 55 56 57 s-Caprolactone (55), 1.0 equiv, 100 mmol, 11.41 g) was dissolved in 300 mL of MeOH and 5 mL of cone. H2SC>4 was added. The resulting mixture was heated at reflux for 16h, cooled to RT, and the volume concentrated to approximately 20 mL. Distilled water (100 mL) was added and the pH was adjusted to 7. The aqueous layer was then extracted with Et20 (3x), the combined organic layers were dried over anhydrous MgSC>4, filtered, and concentrated in vacuo. The resulting crude methyl-5-hydroxyester (56) (13.4 g, 92% yield), was taken up in CH2C12 (300 mL) and then sodium acetate (2.6 g, 0.32 equiv., 32 mmol) and PCC (32.7 g, 1.5 equiv., 150 mmol) were added. After stirring at RT for 1.5 h, 95 pentane (1.2 L) was added, the mixture was filtered through Florisil, and the solvent was removed in vacuo. The crude mixture was concentrated onto silica gel, and purified by flash chromatography to yield 7.4 g (51 mmol, 56% yield) of 57. The physical data was in accordance with past synthesis.98 Synthesis of Methyl 7,7-dibromohept-6-enoate (48) 0 CBr4. PPh, •&- DCM, 0-RT *• To a solution of carbon tetrabromide (23.0 g, 2.0 equiv., 69.35 mmol) in CH2C12 (175 mL) was added 36.4 g of triphenylphosphine (4.0 equiv., 138.75 mmol) at RT. The resulting solution was stirred for 30 min., cooled to 0 °C, 5.0 g of 57 (1.0 equiv., 34.7 mmol) added, and the resulting solution was stirred for 5 min. After the addition of pentane (800 mL), the mixture was stirred for 30 min. and then filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (2% Et20 in pentane) providing 7.1 g (46% yield) of 48. 'H NMR (CDC13, 400 MHz) 8: 6.38 (t, J= 7.28 Hz, 1H), 3.66 (s, 3H), 2.33 (t, 7= 7.40 Hz, 2H), 2.12 (m, 2H), 1.65 (m, 2H), 1.46 ppm (m, 2H); 13C NMR (CDC13,100 MHz) 5: 173.79, 138.11, 89.12, 51.53, 33.70, 32.60, 27.24, 24.26 ppm. Anal. Calcd. for C8Hi2Br202: C, 32.03; H, 4.03; found: C, 32.15; H, 4.07. 96 Br O (Z) Methyl-7-bromo-7-phenyI-hept-6-enoate (58) (Tables 2.2-3, 2.2-4): Following general procedure C, 7-28mg (5-19% yield) of 58 was isolated (Rf = 0.26 in 10% Et20 in pentane) as a yellow liquid. Following general procedure D, 4-19mg (3-13% yield) of 58 was isolated. Following general procedure E, 103 mg (69% yield) of 58 was isolated. 'H NMR (CDCb, 400 MHz) 5: 7.51 (d, J = 9.2 Hz, 2H), 7.31 (m, 3H), 6.19 (t, J= 14.0 Hz, 1H), 3.68 (s,3H), 2.38 (m,4H), 1.73 (m, 2H), 1.55 (m, 2H) ppm; 13C NMR (CDCb, 100 MHz) 5: 173.98, 139.99, 131.10, 128.31, 128.21, 127.53, 125.81,51.51,33.87,32.10,27.89,24.53 ppm. Anal. Calcd. for C14HnBr02: C, 56.58; H, 5.77; found: C, 56.73; H, 5.86. Methyl 7,7-diphenylhept-6-enoate (59) (Tables 2.2-3, 2.2- 4): Following general procedure C, 18-22mg (12-15% yield) of 59 was isolated (Rf = 0.4 in 10% EtaO in pentane) as an oil. Following general procedure D, 10-19 mg (7-13% yield) of 59 was isolated. The spectral data were in accordance with those previously published." O Br-^^^/^^O^ Methyl 7-bromohept-6-ynoate (60) (Tables 2.2-3, 2.2-4): Following general procedure C, 5-11 mg of 60 were isolated as a light yellow oil. 97 Following general procedure D, 16-28mg (15-28% yield) were isolated (Rf = 0.30 in 20% Et20 in pentane). 'H NMR (CDCb, 400 MHz) 5: 3.67 (s, 3H), 2.27-2.23 (t, J = 9.8 Hz, 2H), 2.03 (t, J = 11.0 Hz, 2H), 1.70-1.67 (m, 2H), 1.48-1.45 (m, 2H); I3C NMR (CDCb, 100 MHz) 5: 173.14, 57.93, 51.97, 37.82, 32.73, 27.43, 23.97, 17.26 ppm. Anal. Calcd. for QHnBrCte: C, 43.86; H, 5.06; found: C, 44.25; H, 5.17. 53 LiBr as an additive in the Pd-PEPPSI catalyzed sp3-sp3 Negishi Cross-Coupling Reaction: A *H, 7Li, and 67"Zn NMR spectroscopy study General Spectroscopic Procedures: All NMR spectra were recorded on a Bruker AV 400 spectrometer or a Bruker DRX 600 spectrometer. The ID *H NMR spectra were acquired at 30° pulse angle with an approximate 5 second delay between pulses on samples that contained an D2O capillary for lock and HDO resonance for reference purposes. 13C NMR spectra were acquired under ^-decoupled conditions using D2O capillary for lock and THF solvent peak for the methylene carbon at 28.1 ppm as reference. The 2D HSQC, COSY and HMBC spectra were acquired with 1,024 data points in the direct observed domain and 128 or 256 data points in the indirect domain. The 2D data sets were processed with 1 zero-fill in both dimensions. ID 7Li NMR spectra were acquired on Bruker AV 400 referenced to a capillary of LiCl in D2O (1M). The Li resonance corresponding to the LiCl in the capillary was set to 0 ppm. 98 General procedure F (Negishi sp3-sp2)(Table 4.1): In air, a vial was charged with 12 (3.4 mg, 1 mol%) and under an inert atmosphere ZnCk (107 mg, 0.8 mmol) and a stirrer bar were added. The vial was then sealed with a septum and purged with argon. THF (0.8 mL) was added followed by the requisite Grignard reagent (0.8 mL, 1.0 M in THF, 0.8 mmol) and stirring continued for 15 minutes at which time a white precipitate formed. Under an inert atmosphere, LiBr (139.0 mg, 1.6 mmol), DMI (0.8 mL) and the organohalide or pseudohalide (0.5 mmol) was added. The septum was replaced with a TeflonR-lined screw cap under an inert atmosphere and the reaction stirred for 2 h. After this time, the mixture was diluted with diethyl ether (15 mL) and washed successively with Na3EDTA solution (1M; prepared from EDTA and 3 equiv of NaOH), water, and brine. After drying (anhydrous MgSCU) the solution was filtered, the solvent removed in vacuo, and the residue purified by flash chromatography. General procedure G (Negishi sp2-sp3) (Table 4.1): In air, a vial was charged with 12 (3.4 mg, 1 mol %) and under an inert atmosphere LiBr (139.0 mg, 1.6 mmol) and a stirrer bar were added. The vial was then sealed with a septum and purged with argon. THF (1.6 mL) was added and the suspension stirred until the solids had dissolved. After this time, the organozinc (0.8 mL, 1.0M in DMI) and the organohalide or pseudo halide (0.5 mmol) were added. The septum was replaced with a TeflonR-lined screw cap under an inert atmosphere and the reaction stirred for 2 h. After this time, the mixture was diluted with diethyl ether (15 mL) and washed successively with NasEDTA solution (1M; prepared from EDTA and 3 equiv of NaOH), water, and brine. After drying (anhydrous MgS04), 99 the solution was filtered, the solvent removed in vacuo, and the residue purified by flash chromatography. ./ l-Methoxy-2-((S)-3,7-dimethyloct-6-enyl)benzene (61) (Table 4.1) : Following general procedure F (THF/DMI, 2:1), 107 mg of 61 (87% yield) was isolated (Rf = 0.40, 5 vol% diethyl ether in pentane) as a clear viscous oil. [a\2§= +8.55 ! (c=2.29 in CH2C12); H NMR (400 MHz, CDC13) 5: 7.25-7.15 (m, 2H), 6.93 (t, J= 7.6 Hz, 1H), 6.88 (d, J= 8.1 Hz, 1H), 5.17 (t, J = 6.9 Hz, 1H), 3.87 (s, 3H), 2.72-2.58 (m, 2H), 2.11-1.97 (m, 2H), 1.74 (s, 3H), 1.65-1.40 (m, 7H), 1.30-1.17 (m, 1H), 1.00 ppm 13 (d, J=6.2 Hz, 3H); C NMR (100 MHz, CDC13) 5: 157.4, 131.6, 131.0, 129.7, 126.7, 125.1, 120.4, 110.2, 55.3, 37.1, 37.0, 32.5, 27.7, 25.8, 25.5, 19.6, 17.7 ppm. Anal. Calcd. for Ci7H260: C 82.87, H 10.64; found: C 83.02, H 10.92. / Trimethyl-[5-(2,4,6-trimethylphenyl)pent-l-ynyl]silane 62 (Table 4.1): Following general procedure G (THF/DMI, 2:1), 115 mg of 62 (89% yield) was isolated (Rf = 0.80, pentane) as a clear oil. *H NMR (300 MHz, CDC13) 5: 6.88 (s, 2H), 2.80-2.72 (m, 2H), 2.39 (t, J= 6.8 Hz, 2 H), 2.30 (s, 6H), 2.26 (s, 3H), 1.75-1.66 (m, 2H), 0.22 ppm (s, 9H); 13C NMR (100 MHz, CDCI3) 5: 136.1, 135.6, 135.1, 128.9, 100 107.3, 85.0, 28.5, 28.1, 20.8, 20.3, 19.7, 0.2 ppm. Anal. Calcd. for Ci7H26Si: C 79.00, H 10.14; found: C 78.69, H 10.42. I ^-Si— R, ' [5-(2-Methoxyphenyl)pent-l-ynyl]trimethylsilane 63 (Table 4.1): Following general procedure F (THF/DMI, 2:1), 113 mg of 63 (92% yield) was isolated (Rf=0.30, 5 vol% diethyl ether in pentane) as a clear viscous oil. !H NMR (400 MHz, CDC13) 8: 7.23-7.15 (m, 2H), 6.96-6.85 (m, 2H), 3.84 (s, 3H), 2.74 (t, J =7.5 Hz, 2H), 2.27 (t, J=7.4 Hz, 2H), 1.84 (quint, J = 7.7 Hz, 2H), 0.19 ppm (s, 9H); 13C NMR (100 MHz, CDCI3) 5: 157.5, 130.1, 130.0, 127.2, 120.3, 110.2, 107.7, 84.6, 55.2, 29.4, 28.8, 19.6, 0.2 ppm. Anal. Calcd. for Ci6H24SiO: C 73.79, H 9.29; found: C 73.34, H 9.47. ^^^^^y 3-phenyl-l-(4-fluorophenyl)propane (64) (Table 4.1): Following general procedure G (THF/DMI, 2:1), 97 mg of 64 (91% yield) was isolated l (Rf= 0.40, pentane) as a clear viscous oil. H NMR (400 MHz, CDC13) S: 7.31 (t, J= 8.0 Hz, 2H), 7.22 (t, J= 8.0 Hz, 3H), 7.18-7.12 (m, 2H), 6.99 (t, J=8.4 Hz, 2 H), 2.66 (q, J = 13 7.6 Hz, 4 H), 1.96 ppm (quint, J = 7.6 Hz, 2H); C NMR (100 MHz, CDC13): 5=161.2 (V(C,F)=242 Hz), 142.1, 137.8 (V(C,F)=2 Hz), 129.8 (V(C,F) = 8 Hz), 128.4, 128.3, 2 125.8, 115.0 ( J(C,F) = 21 Hz), 35.3, 34.6, 33.1 ppm. Anal. Calcd. for Ci5H15F: C 84.08, H 7.06; found: C 83.96, H 6.97. 101 6-benzo-[l,3]-dioxol-5-yl-2,2-dimethyIhexanenitrile (65) (Table 4.1): Following general procedure G (THF/DMI, 2:1), 99 mg of 65 (81% yield) was isolated (Rf = 0.25, 25 vol% diethyl ether in pentane) as a clear oil. *H NMR (300 MHz, CDC13) 5: 6.74 (d, J= 8.0 Hz, 1H), 6.69 (s, 1H), 6.63 (d, J= 8.0 Hz, 1H), 5.94 (s, 2 H), 2.58 (t, J= 7.6 Hz, 2 H), 1.67-1.59 (m, 2H), 1.57-1.50 (m, 4H), 1.35 ppm (s, 6H); 13 C NMR (100 MHz, CDC13) 5: 147.5, 145.6, 136.0, 125.2, 121.0, 108.7, 108.1, 100.7, 40.9, 35.4, 32.4, 31.7, 26.7, 24.8 ppm. Anal. Calcd. for C15H19O2N: C 73.44, H 7.81; found: C 74.05, H 7.65. "ZnBr General Procedure I (preparation of CH3(CH2)3ZnBr): A 25 mL round bottom flask, equipped with a stir bar, was flame dried and purged with argon 3x. Zinc dust (0.98 g, 15 mmol, 1.5 equiv) and iodine (0.13 g, 0.5 mmol, 0.05 equiv) were weighed into separate vials and then added under a cone of argon to the flame dried flask and sealed with a white septum. iVyV-dimethyl-2 imidazolidinone (DMI) (9 mL) was added to the flask and stirred for 5-10 minutes until a colour change from green to grey was observed. Once the solution was grey, 1-bromobutane (1 mL, 10 mmol, 1 equiv) was added via syringe to the solution and stirred. The solution was then placed in an oil bath at 70°C overnight.56 n-Butylzinc bromide was characterized using ID and 2D NMR spectroscopy methods. 102 3 3 General Procedure J (Negishi sp -sp with ZnCyZnBr2): In air, a vial was charged with 12 (3.4 mg,l mol%) and under an inert atmosphere LiBr (139.0 mg, 0.8 mmol), ZnCk (2.13-17.04 mg, 0.016-0.125 mmol) or ZnBr2 (3.52-28.15 mg, 0.016-0.125 mmol) and a stirrer bar were added. The vial was then sealed with a septum and purged with argon after which THF (1.6 mL) was added and the suspension was stirred until the solids dissolved. After this time, the organozinc (0.8 mL, 1.0m in DMI) and the organohalide or pseudohalide (0.5 mmol) was added. The septum was replaced with a TeflonR-lined screw cap under an inert atmosphere and the reaction stirred for 2 h. After this time, the mixture was diluted with diethyl ether (15 mL) and washed successively with Na3EDTA solution [lm; prepared from EDTA (ethylenediaminetetraacetic acid) and 3 equiv of NaOH], water, and brine. After drying (anhydrous MgS04) the solution was filtered, the solvent removed in vacuo, and the residue purified by flash chromatography. General Procedure K (preparation ofNMR sample): To an oven-dried NMR tube sealed with a white septum and purged with argon was added n-butyl zinc bromide (0.2 mL, 0.2 mmol, 1M) and 0.4 mL THF. To this solution, x ^L of LiBr in a 2:1 THF:DMI solution (0-180 uL, 0-1.50 equiv) was added to the NMR tube and characterized using ID and 2D NMR spectroscopy methods. Zn General Procedure L (preparation of dibutylzinc): A 25 mL round bottom flask, equipped with magnesium turnings (952 mg, 39.2 mmol, 1.96equiv), and a stir bar was flame dried and purged with argon 3x. Diethyl ether (2 mL) was added to the flask via syringe and the solution was stirred and occasionally heated to generate a 103 vigorous reaction. Once the Mg was activated, n-butyl bromide (2.15 mL, 20 mmol, 1.0 equiv.) in a solution of diethyl ether (10 mL) was added drop-wise at such a rate to maintain the vigorous reaction. The reaction was stirred for 2 hrs and the light purple solution was cannulated to a second 25 mL, flame-dried, round bottom flask. Anhydrous ZnBr2 (2.14 g, 9.6 mmol) was added to this ethereal solution under a cone of argon in an exothermic reaction. The resulting white suspension was stirred overnight to produce a light grey solution.74 Dibutylzinc was characterized using ID and 2D NMR spectroscopy methods. 104 Part 4: References [I] Organometallics (Ed.: C. Elschenbroich, A. Salzer), Wiley-VCH, Germany, 1992. [2] W.C. Zeise, Annalen der Physik und Chemie 1831, 97, 497. [3] The Organometallic Chemistry of the Transition Metals (Ed.: R.H. 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