Palladium-Catalyzed Carbohalogenation of Sterically Congested Alkynes: An Intramolecular Approach to the

Synthesis of Vinyl Halides

by

Perry Jacob Caulford Menzies

A thesis submitted in conformity with the requirements for the degree of Masters of Science

Department of Chemistry University of Toronto

© Copyright by Perry Jacob Caulford Menzies 2014

ii

Palladium-Catalyzed Carbohalogenation of Sterically Congested Alkynes: An Intramolecular Approach to the Synthesis of Vinyl

Halides

Perry Jacob Caulford Menzies

Masters of Science

Department of Chemistry

University of Toronto

2014

Abstract

Pd catalyzed cross coupling reactions are extensively used to effect a multitude of organic

transformations. The recent advent of carbon–halogen reversible oxidative addition has

introduced C–X bond forming as a viable catalytic process. These carbohalogenation reactions

are ideal because the reactive halide functionalities are retained in the products, however several

limitations in the methodology still remain. Specifically, carbohalogenations using aryl

bromides and chlorides and the formation of vinyl halide products are desirable transformations

that have been elusive.

Cyclopropene substrates were initially examined as intermolecular carbohalogenation coupling

partners but these substrates were not found to be amenable to carbohalogenation. The focus

shifted to using alkynes as intramolecular coupling partners. These substrates were found to

successfully undergo cyclization, forming vinyl halide products. Additionally, aryl iodides,

bromides and chlorides all react to form the corresponding vinyl halides. The reaction

parameters were examined, a substrate scope was developed and mechanistic studies were

performed.

iii

Acknowledgements

I owe the success of this degree to several amazing people and would like to thank each in turn.

First and foremost, I would like to thank Professor Mark Lautens for the opportunity to work in

his lab and for his exceptional guidance. I have improved tremendously under his supervision

and have learned to tackle challenges pragmatically. I would also like to thank Christine Le and

Dave Petrone for their continual advice and support. Christine always challenged me to examine

my chemistry more rigorously and to think about the underlying theoretical implications more

critically. Dave has been a fantastic resource for theoretical discussions and technical skills. I

have learned a lot from these skilled chemists and am fortunate to have had the opportunity to

work with them. I would also like to thank all the members of the Lautens group for helpful

advice, discussions and support.

Additionally, I would like to thank my family for their support, especially my mom for being

incredibly encouraging. I would also like to thank my friends, who have always been there to

help relieve the stress. Finally, I would like to dedicate this work to my dad. You taught me

more than you ever knew.

iv

Table of Contents

Abstract ...................................................................................................................................... ii

Acknowledgements ................................................................................................................... iii

List of Abbreviations ................................................................................................................. vi

List of Tables ............................................................................................................................ ix

List of Schemes .......................................................................................................................... x

Chapter 1 Palladium-Catalyzed Carbohalogenation of Sterically Congested Alkynes: An

Intramolecular Approach to the Synthesis of Vinyl Halides ........................................................ 1

1.1 Introduction .................................................................................................................. 1

1.1.1 Cross Coupling Reactions .................................................................................... 1

1.1.2 Elementary Steps in Catalysis............................................................................... 3

1.1.3 Carbon–Halogen Reductive Elimination in Catalysis ............................................ 6

1.1.4 Diverging from Classical Heck-Type Reactivity ................................................... 7

1.1.5 Development of the Carbohalogenation Reaction ................................................. 8

1.1.6 Limitations of Carbohalogenation ...................................................................... 15

1.2 Results and Discussion ............................................................................................... 15

1.2.1 Intermolecular Cyclopropene Coupling Partners................................................. 15

1.2.2 Intramolecular Alkyne Coupling Partners ........................................................... 17

1.2.3 Reaction Optimization ........................................................................................ 20

1.2.4 Examination of the Substrate Scope ................................................................... 22

v

1.2.5 Isomerization Experiments ................................................................................. 31

1.2.6 Preliminary Investigation of Product Reactivity.................................................. 34

1.2.7 Conclusions and Future Work ............................................................................ 36

1.3 Experimental .............................................................................................................. 37

1.3.1 General Considerations ...................................................................................... 37

1.3.2 Starting Material Synthesis and Characterization ................................................ 38

1.3.3 Synthesis and Characterization of Cyclized Products .......................................... 58

1.3.4 Isomerization Experiments ................................................................................. 64

1.3.5 Radical Probing Studies ..................................................................................... 66

1.3.6 Aromatization Experiment ................................................................................. 66

Appendix A: Crystallographic Data .......................................................................................... 68

Appendix B: NMR Spectra ....................................................................................................... 70

vi

List of Abbreviations

1H NMR proton nuclear magnetic resonance

13C NMR carbon nuclear magnetic resonance

° C degrees Celsius

δ chemical shift

μL microlitre

Ar aryl

aq. aqueous

Ac acetyl

atm atmosphere

bs broad singlet

conv. conversion

d doublet; days

dd doublet of doublets

DART direct analysis in real time

DCE 1,2-dichloroethane

DCM dichloromethane

Decomp. decomposition

DMA dimethylacetamide

DMAP 4-dimethylaminopyridine

DMF N,N-dimethylformamide

dppf 1,1′-bis(diphenylphosphino)ferrocene

d.r. diastereomeric ratio

dt doublet of triplets

ee enantiomeric excess

EI electron impact

eq. equation

equiv. equivalents

ESI electron spray ionization

Et ethyl

Et2O diethyl ether

vii

EtOAc ethyl acetate

g grams

h hours

HRMS high resolution mass spectrometry

Hz hertz

J coupling constant

m multiplet

LDA lithium diisopropylamide

M molar

mp melting point

M+ parent molecular ion

Me methyl

MeCN acetonitrile

mg milligrams

MHz megahertz

min minutes

mL millilitres

mmol millimoles

MS mass spectrometry

MsOH methanesulfonic acid

n.r. no reaction

nBu n-butyl

nBuLi n-butyllithium

NMR nuclear magnetic resonance

NOE nuclear Overhauser effect

PtBu3 tri-tert-butylphosphine

PhH benzene

PhMe toluene

Piv pivalate

PMP 1,2,2,5,5-pentalmethylpiperidine

ppm parts per million

viii

p-TsOH·H2O p-toluenesulfonic acid monohydrate

pyr pyridine

q quartet

Qphos 1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene

ref. reference

rt room temperature

s singlet

sat. saturated

SM starting material

Sphos 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl

t triplet

TEMPO 2,2,6,6-Tetramethyl-1-piperidinyloxy, free radical

tt triplet of triplets

tBu tert-butyl

THF tetrahydrofuran

TIPS triisopropylsilyl

TLC thin layer chromatography

TMS trimethylsilane

Ts tosyl (p-toluenesulfonyl)

X halogen; I, Br or Cl

Xphos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

ix

List of Tables

Table 1: Intermolecular domino carbohalogenation attempts with cyclopropene substrates. .... 17

Table 2: Reaction optimization. .............................................................................................. 22

Table 3: Vinyl halide substrate scope. ..................................................................................... 26

x

List of Schemes

Scheme 1: General cross coupling reaction schemes (top) and catalytic mechanisms (bottom). . 2

Scheme 2: Possible stereochemical outcomes in Heck products. ............................................... 4

Scheme 3: C–X reductive elimination from PdII species. ........................................................... 5

Scheme 4: Formation of C2 substituted indoles via tandem cross coupling and formation of 2-

bromoindoles via a reversible oxidative addition protocol........................................................... 7

Scheme 5: Anionic trapping and direct arylation of palladium intermediates that cannot undergo

β-hydride elimination. ................................................................................................................ 8

Scheme 6: First examples of the carbohalogenation reaction. .................................................. 10

Scheme 7: Carbohalogenations by the Tong and Jiang groups. ................................................ 11

Scheme 8: Catalytic cycle of the carbohalogenation reaction................................................... 12

Scheme 9: Halide exchange and domino carbohalogenation reactions. .................................... 13

Scheme 10: Carbohalogenation of diiodinated substrates. ....................................................... 14

Scheme 11: Intermolecular carbohalogenations with alkynes. ................................................. 15

Scheme 12: Potential pathway for carbopalladation of cyclopropene substrates. ..................... 16

Scheme 13: Synthesis of 2-iodostyrene and cyclopropene substrates. ...................................... 16

Scheme 14: Synthesis of tethered alkynyl aryl halide substrates. ............................................. 18

Scheme 15: Initial carbobromination hit and aromatization under slightly acidic conditions. ... 18

Scheme 16: Synthesis of phenyl and TIPS substrates. ............................................................. 19

Scheme 17: Second generation carbobromination substrates. .................................................. 20

Scheme 18: Substrate synthesis protocols. .............................................................................. 23

Scheme 19: Synthesis of additional substrates. ........................................................................ 24

Scheme 20: Preparation of substrates with a substituent at the methylene alpha to the alkyne. 28

xi

Scheme 21: Reaction of substrates with substituents at the methylene alpha to the alkyne. ...... 29

Scheme 22: Nitrogen tethered substrate synthesis and reactivity. ............................................ 29

Scheme 23: Synthesis of enyne substrate and subjection of terminal alkyne substrates to

reaction conditions. .................................................................................................................. 30

Scheme 24: Six-membered ring precursor substrate synthesis and substrate reactivity. ........... 31

Scheme 25: Isomerization and radical probing experiments. ................................................... 32

Scheme 26: Proposed mechanism of reconstitutive cyclization via carbohalogenation. ........... 34

Scheme 27: Aromatization of reconstitutive cyclization products and possible route to carbenes.

................................................................................................................................................. 35

Scheme 28: Initial investigation into subsequent cross coupling of carbobromination products.

................................................................................................................................................. 35

Scheme 29: Attempt to epoxidize the carbobromination products. .......................................... 36

1

Chapter 1

Palladium-Catalyzed Carbohalogenation of Sterically Congested Alkynes: An Intramolecular Approach to the Synthesis of Vinyl

Halides

1.1 Introduction

1.1.1 Cross Coupling Reactions

Pd catalyzed cross couplings are a diverse and versatile class of reactions for forming C–C

bonds. Many variations of cross coupling reactions exist, including the Suzuki, Heck, Stille and

Negishi reactions.1 The applicability of these catalytic reactions has been widely explored and

their impact on the scientific community has been recognized by the 2010 Nobel Prize in

Chemistry.2

In the Suzuki, Stille and Negishi reactions, coupling occurs between an organohalide electrophile

and an organometallic nucleophile, which is mediated by a Pd0 catalyst (Scheme 1, left cycle).

3

The reaction commences with oxidative addition of the catalytically active Pd0Ln species into the

C–X bond of the electrophile. Transmetallation with the organometallic reagent then occurs

where the PdII intermediate exchanges the halide for the nucleophile, forming a new Pd–C bond.

The cycle concludes with reductive elimination, regenerating the catalytically active Pd0 species

while producing a new C–C bond.

1 Nicolau, K.C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442-4489. 2 Nobel Prize website: The Nobel Prize in Chemistry in 2010

http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2010 (accessed April 4, 2013). 3 Negishi, E.-i. J. Organomet. Chem. 2002, 653, 34-40.

2

Scheme 1: General cross coupling reaction schemes (top) and catalytic mechanisms (bottom).

The Heck reaction differs from these cross coupling reactions in two ways: an olefin coupling

partner is used instead of an organometallic reagent and the catalytic cycle proceeds via some

different elementary steps.4 The reaction commences with oxidative addition of the Pd

0Ln

species into an Ar–X bond (Scheme 1, right cycle). The olefin then coordinates to this species,

which inserts into the Pd–Ar bond and forms a new C–C bond. The functionalized olefin is then

formed by β-hydride elimination with concomitant release of HX from the Pd species. When

aryl triflates are used in place of aryl halides the Pd species in the catalytic cycle are formally

cationic due to the non-coordinating nature of the triflate counterion.

4 Dieck, H. A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 1133-1136.

3

1.1.2 Elementary Steps in Catalysis

The Suzuki, Stille, Negishi and Heck reactions all commence with oxidative addition into an Ar–

X bond. The active Pd0Ln catalyst adds into the bond by donating a pair of electrons, forming a

Pd–C and a Pd–X bond. Electron deficient Ar–X bonds are more prone to insertion and strongly

σ-donating ligands promote this process by increasing the electron density at Pd. The order of

aryl halide propensity towards oxidative addition is I > Br > Cl >> F, which directly correlates

with the bond dissociation energies of the aryl halide bond.5

Aryl chlorides and sterically hindered aryl halides typically have low reactivity towards

oxidative addition because these bonds are strong or hard to access. Counterintuitively,

sterically bulky ligands can promote these challenging oxidative additions. Bulky ligands are

electron rich and are strong σ-donors, which facilitate oxidative addition, however the bulkiness

would seem to hinder addition into sterically hindered substrates. The answer to this apparent

contradiction is that bulky ligands stabilize coordinatively unsaturated Pd0 species, which have

vacant coordination sites for new bond formation. Bis-ligated Pd(PR3)2 species with bulky PR3

ligands are stable and the mechanism of oxidative addition for these species has been shown to

change from associative to dissociative as the steric bulk of PR3 increases.6 Additionally, mono-

ligated Pd(PR3) species have been shown to be the active species for oxidative addition when

PR3 is extremely bulky.7,8,9

The mono-ligated Pd(PR3) species are more coordinatively

unsaturated than bis-ligated Pd(PR3)2 species and thus are more reactive towards oxidative

addition.

The Heck reaction diverges from the Suzuki, Stille and Negishi reactions in that after oxidative

addition an olefin coordinates to an open coordination site on the LnPdArX intermediate.

Carbopalladation then occurs in a syn fashion via a concerted mechanism and this process can

lead to either linear or branched products. The regiochemistry of carbopalladation depends on:

1) the steric effects of the ligands, 2) the electronic nature of the Pd species and 3) the

5 Sheppard, T. D. Org. Biomol. Chem. 2009, 7, 1043-1052. 6 Galardon, E.; Ramdeehul, S.; Brown, J. M.; Cowley, A.; Hii, K. K. (M.); Jutand, A. Angew. Chem. Int. Ed. 2002,

41, 1760-1763. 7 Christmann, U.; Vilar, R. Angew. Chem. Int. Ed. 2005, 44, 366-374. 8 Stambuli, J. P.; Bühl, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9346-9347. 9 Stambuli, J. P.; Incarvito, C.D.; Bühl, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 1184-1194.

4

substituents on the olefin.10

These Pd intermediates are capable of β-hydride elimination, which

also occurs in a syn fashion via a concerted mechanism and releases the product olefin.

Together, syn-carbopalladation and syn-β-hydride elimination usually produce either 1,1-

disubstituted or E olefins (Scheme 2). 1,1-Disubstituted olefins are formed from linear Pd

intermediates while E olefins arise from branched Pd intermediates. Though E olefins are

predominant, Z olefins can be formed when R is small and the steric interaction between R and

Ar is small. The E:Z ratio is usually governed by Curtin-Hammett kinetics, however non-Curtin-

Hammett distributions may also be observed. The latter can occur at elevated temperatures by

Pd-mediated isomerization.

Scheme 2: Possible stereochemical outcomes in Heck products.

Reductive elimination is the last step in many cross coupling reactions and is the microscopic

reverse of oxidative addition. As a result, reductive elimination is promoted by the opposite

electronic effects. Electron rich coupling partners undergo reductive elimination more readily

because they have weaker Pd–C bonds with less ionic character.11

This process is also promoted

by electron withdrawing ligands that reduce electron density at Pd, weakening the Pd–C bonds.

Additionally, reductive eliminations to form carbon–heteroatom bonds are largely affected by the

electronic properties of the heteroatom coupling partner. Electron rich N or O coupling partners

undergo more facile reductive elimination than electron deficient heteroatom partners.

Reductive elimination to form C–N bonds occurs more readily than C–O bonds when similar

10 Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009-3066. 11 Hartwig, J. F. Inorg. Chem. 2007, 46, 1936-1947.

5

substituents on the heteroatom are present. Additionally, trends in electronic effects for carbon–

heteroatom reductive eliminations are consistent with C–C reductive eliminations, indicating the

non-bonding heteroatom electrons are not involved in these processes.

Reductive elimination, like oxidative addition, can be promoted by sterically bulky ligands.

Reductive elimination from sterically encumbered species is favourable because it relieves steric

congestion and reduces the coordination number of palladium. However, bulky ligands are also

strong σ-donors, which should impede reductive elimination. Nonetheless, these ligands

promote challenging reductive eliminations indicating that steric effects override electronic

effects. This is portrayed in Buchwald-Hartwig aminations and etherifications, the development

of which has hinged on the use of bulky ligands.12

Furthermore, C–N and C–O reductive

eliminations are more difficult than C–C reductive eliminations, which correlates to the

increased strength of Pd–N and Pd–O bonds relative to Pd–C bonds.

More recently, carbon–halogen reductive elimination has been realized. In a seminal report,

Hartwig and coworkers showed the very bulky PtBu3 ligand promotes reductive elimination from

dimeric ArPdIIX species to form aryl halide products in a stoichiometric fashion (Scheme 3).

13

Later work showed the dimers were being cleaved to form three-coordinate monomeric PdII

species, from which reductive elimination was occurring.14,15

This transformation is

remarkable because it challenges the longstanding belief that oxidative additions into aryl halide

bonds are irreversible.

Scheme 3: C–X reductive elimination from PdII species. Adapted from ref. 13.

12 Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046-2067. 13 Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 1232-1233. 14 Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 13944-13945. 15 Roy, A. H.; Hartwig, J. F. Organometallics, 2004, 23, 1533-1541.

6

1.1.3 Carbon–Halogen Reductive Elimination in Catalysis

The paradigm of C–X reductive elimination from PdII species was extended to a catalytic

application by the Buchwald group to form aryl fluorides, bromides and iodides from aryl

triflates.16,17,18

Shortly thereafter, our group identified a catalytic application of reversible

oxidative addition in the formation of 2-bromoindoles. Fang and Lautens have pioneered the

synthesis of C2 substituted indoles from gem-dibromoolefins via a tandem cross coupling

protocol (Scheme 4).19

These reactions proceed through a putative 2-bromoindole intermediate.

However, in the absence of an external nucleophile for the second cross coupling reaction, 2-

bromoindole was not observed. It was hypothesized that Pd was irreversibly adding into the

newly formed Ar–Br bond leading to a catalytic dead end.

16 Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; García-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009,

325, 1661-1664. 17 Shen, X.; Hyde, A. M.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14076-14078. 18 Pan, J.; Wang, X.; Zhang, Y.; Buchwald, S. L. Org. Lett. 2011, 13, 4974-4976. 19 Fang, Y.-Q.; Lautens, M. J. Org. Chem. 2008, 73, 539-549.

7

Scheme 4: Formation of C2 substituted indoles via tandem cross coupling and formation of 2-

bromoindoles via a reversible oxidative addition protocol. Adapted from ref. 19.

Newman and Lautens later showed 2-bromoindoles could be formed by employing the bulky

PtBu3 as the ligand whereby oxidative addition into the newly formed aryl bromide bond was

rendered reversible (Scheme 4).20

Furthermore, the presence of another aryl halide bond was

also tolerated. Polyhalogenated compounds are difficult substrates for cross coupling reactions

due to chemo- and regioselectivity issues. However, these substrates are synthetically useful

because each aryl halide provides a handle for functionalization. Reversible oxidative addition

presents a new strategy for orthogonal cross coupling of polyhalogenated materials.

1.1.4 Diverging from Classical Heck-Type Reactivity

Olefin products of the Heck reaction can only be released from the catalyst after β-hydride

elimination. However, the use of alkyne and gem-disubstituted olefin coupling partners can lead

to vinyl PdII and neopentyl Pd

II intermediates, respectively, that do not possess a β-hydrogen.

These substrates can be diverted through alternative catalytic termination sequences leading to

difunctionalized olefins and regeneration of the active catalyst. For instance, anionic trapping

employs an external nucleophile that displaces the halide bound to Pd and this new Pd

intermediate can undergo reductive elimination (Scheme 5).21

This procedure has been utilized

by Grigg and Zhu in tandem cyclization/anion capture processes using hydride, organoboron,

organotin and cyanide nucleophiles to produce complex ring systems.22,23,24,25

Neopentyl PdII

intermediates have also been coupled to inter- and intramolecular C–H activation processes by

Fagnou and Zhu, respectively, resulting in direct arylation products (Scheme 5).26,27

The lack of

20 Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2010, 132, 11416-11417. 21 Burns, B.; Grigg, R.; Sridharan, V.; Worakun, T. Tetrahedron Lett. 1988, 29, 4325-4328. 22 Burns, B.; Grigg, R.; Santhakumar, V.; Sridharan, V.; Stevenson, P.; Worakun, T. Tetrahedron 1992, 48, 7297-

7320. 23

Grigg, R.; Sansano, J. M.; Santhakumar, V.; Sridharan, V.; Thangavelanthum, R.; Thornton-Pett, M.; Wilson, D.

Tetrahderon 1997, 53, 11803-11826. 24 Fretwell, P.; Grigg, R.; Sansano, J. M.; Sridharan, V.; Sukirthalingham, S.; Wilson, D.; Redpath, J. Tetrahedron,

2000, 56, 7525-7539. 25 Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem. Eur. J. 2007, 13, 961-967. 26 René, O.; Lapointe, D.; Fagnou, K. Org. Lett. 2009, 11, 4560-4563. 27 Piou, T.; Neuville, L.; Zhu, J. Org. Lett. 2012, 14, 3760-3763.

8

β-hydrogens in these examples allows the intermediates to be trapped by an external nucleophile,

which can then undergo reductive elimination.

Scheme 5: Anionic trapping and direct arylation of palladium intermediates that cannot undergo

β-hydride elimination. Adapted from ref. 21-27.

1.1.5 Development of the Carbohalogenation Reaction

9

Carbon–halogen reductive elimination is a very attractive alternative mechanistic conclusion to

the Heck reaction. The products of this pathway contain a new C–C bond while retaining the

reactive halide functionality in a new C–X bond, which can be employed for further reactivity.

C–X reductive elimination from PdIV

species is well precedented in the literature.28,29,30

In these

reactions shuttling occurs between PdII and Pd

IV species and the electron deficiency of Pd

IV

facilitates reductive elimination. However, Heck reactions proceed through PdII intermediates

and it is necessary to induce C–X reductive elimination from these species in order for this to be

a viable alternative termination sequence. Equipped with the paradigm of reversible oxidative

addition and the utility of PdII intermediates that cannot undergo β-hydride elimination our group

sought to develop a new catalytic process that employs C–X reductive elimination as the final

elementary step. This goal has led to the development of the carbohalogenation reaction, which

has blossomed into an active area of research.

The first examples of carbohalogenation were intramolecular reactions between aryl iodides and

a tethered 1,1-disubstituted alkene (Scheme 6).31

The exceptionally bulky and electron rich

Qphos ligand is the most efficacious ligand for facilitating these reactions. These

carbohalogenation reactions exhibit high functional group tolerance, can be used to form

heterocycles and carbocycles, and can be used to form five- or six-membered rings.

Intermolecular variants between aryl iodides and norbornene are also possible because these

substrates lack a syn-β-hydrogen; in these cases PtBu3 serves as the best ligand (Scheme 6).

Radical trapping experiments showed the intramolecular reactions were unaffected by the

addition of TEMPO or galvinoxyl while the yields of the intermolecular reactions were only

slightly decreased. These data suggest carbohalogenation is not occurring by a radical

mechanism.

28 Fahey, D. R. J. Chem. Soc. D. 1970, 417a. 29 Li, Y.; Liu, X.; Jiang, H.; Feng, Z. Angew. Chem. Int. Ed. 2010, 49, 3338-3341. 30 Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147-1169. 31 Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 1778-1780.

10

Scheme 6: First examples of the carbohalogenation reaction. Adapted from ref. 31.

The Tong group has also reported carbohalogenation reactions using a different catalyst/ligand

set. Intermolecular reactions between alkynyl iodides and norbornene can be achieved to

produce norbornyl iodides (Scheme 7).32

The regiochemistry of this coupling was shown to be

heavily solvent dependent. Additionally, vinyl iodides with a tethered 1,1-disubstituted olefin

undergo intramolecular carbohalogenation to form six-membered heterocycles.33

Preliminary

mechanistic investigations suggested these reactions are not occurring via a radical mechanism.

Jiang and coworkers have employed similar conditions for intramolecular carbohalogenation of

alkyl iodides with a tethered 1,1-disubstituted olefin to form five-membered heterocycles

(Scheme 7).34

Mechanistic studies suggest these reactions occur via a Pd-mediated radical

process rather than a reversible oxidative addition process.

32 Liu, H.; Chen, C.; Wang, L.; Tong, X. Org. Lett. 2011, 13, 5072-5075. 33 Liu, H.; Li, C.; Qiu, D.; Tong, X. J. Am. Chem. Soc. 2011, 133, 6187-6193. 34 Liu, H.; Qiao, Z.; Jiang, X. Org. Biomol. Chem. 2012, 10, 7274-7277.

11

Scheme 7: Carbohalogenations by the Tong and Jiang groups. Adapted from ref. 32-34.

Computational studies have been performed on our substrates using Pd(PtBu3)2 to elucidate the

catalytic cycle.35

Based on these studies a mechanism for Pd catalyzed carbohalogenation of

alkenes was proposed (Scheme 8). The active PdL2 catalyst exchanges a ligand for the substrate,

which undergoes oxidative addition into the aryl iodide bond. Isomerization of the substrate

positions the olefin for coordination with Pd and subsequent carbopalladation produces the

heterocyclic system. This intermediate undergoes C–X reductive elimination to form the new

alkyl iodide bond and the product exchanges with a ligand to reform the active PdL2 catalyst.

The key to the success of these substrates is the inability to undergo β-hydride elimination. This

is necessary to avoid the formation of Heck-type products, which is a significantly more

energetically favourable process than C–X reductive elimination. When β-hydride elimination is

blocked, C–I reductive elimination can occur and is the rate-limiting step, with a calculated

energy barrier of 24.9 kcal/mol. The activation barrier for reductive elimination is higher for

bromides and chlorides, which correlates well to the trend in bond dissociation energies for the

palladium halide species.36

Consequently, analogous carbobromination and carbochlorination

35 Lan, Y.; Liu, P.; Newman, S. G.; Lautens, M.; Houk, K. N. Chem. Sci. 2012, 3, 1987-1995. 36 Liu, H.; Li, C.; Qiu, D.; Tong, X. J. Am. Chem. Soc. 2011, 133, 6187-6193.

12

reactions that produce the corresponding alkyl bromides and chlorides, respectively, have

remained elusive.

Scheme 8: Catalytic cycle of the carbohalogenation reaction. Adapted from ref 35.

The utility of carbohalogenation has been intensely explored by our group. Aryl bromides can

be used in place of aryl iodides to produce alkyl iodides via a bromide-to-iodide exchange

process using an external source of iodide anion (Scheme 9).37

Although the corresponding alkyl

bromides could not be accessed, this method provides an alternative to using aryl iodides, which

are the most expensive and least abundant of the aryl halides. In the presence of a second

tethered olefin the alkylPdIILnX intermediate can react further in a domino process to access

37 Newman, S. G.; Howell, J. K.; Nicolaus, N.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 14916-14919.

13

more complex ring systems in a diastereoselective fashion.38

These domino and halide exchange

processes can be used in conjunction leading to greater synthetic versatility.

Scheme 9: Halide exchange and domino carbohalogenation reactions. Adapted from ref. 37-38.

Carbohalogenation is also very useful for orthogonal functionalization of polyhalogenated

substrates. Oxidative additions have traditionally been irreversible processes and cross couplings

of polyhalogenated substrates have presented a challenge. Selective functionalization is

substrate dependent and typically requires differences in halide reactivity.39

However,

intramolecular carbohalogenation of diiodinated substrates proceeds without product inhibition

of the catalyst, which is enabled by reversible oxidative addition (Scheme 10).40

The catalyst is

able to reversibly add into either aryl iodide bond and facilitates cyclization only when inserted

at the site amenable to carbohalogenation. Addition of a Heck acceptor leads to orthogonal

reactivity where carbohalogenation occurs at one aryl iodide while Heck coupling occurs at the

other (Scheme 10). In these examples, 1,2,2,6,6-pentamethylpiperidine (PMP) was found to be

the optimal base and was required to achieve full conversion in the carbohalogenation reaction

(Scheme 10, top). It is believed that PMP acts as a sterically bulky ligand for the Pd catalyst,

promoting reductive elimination out of the non-productive Ar–I bond. In the tandem

carbohalogenation-Heck process PMP also acts as a good amine base for the Heck coupling

38 Petrone, D. A.; Malik, H. A.; Clemenceau, A.; Lautens, M. Org. Lett. 2012, 14, 4806-4809. 39 Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036-1045. 40 Petrone, D. A.; Lischka, M.; Lautens, M. Angew. Chem. Int. Ed. 2013, 52, 10635-10638.

14

(Scheme 10, bottom). These diiodinated substrates highlight the utility of reversible oxidative

addition as a protocol to overcome the traditional challenges of polyhalogenated substrates.

Scheme 10: Carbohalogenation of diiodinated substrates. Adapted from ref. 40.

The aforementioned examples of carbohalogenation utilize 1,1-disubstituted olefin coupling

partners to produce neopentyl alkyl iodides. Alkynes are also suitable coupling partners because

the resulting vinyl PdIILnX intermediate formed cannot undergo β-hydride elimination.

Intermolecular domino carbohalogenation reactions between alkynes and aryl iodides bearing a

pendant olefin have successfully yielded alkyl iodides (Scheme 11).41

These reactions go

through a putative vinyl palladium(II) iodide intermediate, suggesting vinyl iodides may be

accessible via carbohalogenation. However, attempts to produce the corresponding vinyl iodides

from alkynes and aryl iodides lacking a pendant olefin were unsuccessful.

41 Jia, X.; Petrone, D. A.; Lautens, M. Angew. Chem. Int. Ed. 2012, 51, 9870-9872.

15

Scheme 11: Intermolecular carbohalogenations with alkynes. Adapted from ref. 41.

1.1.6 Limitations of Carbohalogenation

Despite the current success of carbohalogenation this method still has some limitations.

Substrates that possess syn-β-hydrogens are not amenable to carbohalogenation because β-

hydride elimination is a significantly more favourable process than C–X reductive elimination.

Additionally, while carbohalogenations can be performed diastereoselectively, little work on

enantioselective variants has been published.42

Development of analogous carbobromination and

carbochlorination reactions also presents a challenge since the activation barriers to reductive

elimination from these halides are larger than for iodide. Additionally, the use of alkyne

coupling partners to produce vinyl halides would significantly expand the scope of this method

because vinyl halides are a useful class of electrophile for cross coupling reactions. These

challenges present exciting possibilities for expanding the versatility of carbohalogenation. The

work described herein focuses on the challenges of expanding carbohalogenation to include

bromides and chlorides and employing alkyne coupling partners to produce vinyl halides.

Preliminary efforts on utilizing cyclopropenes as coupling partners are also briefly described.

1.2 Results and Discussion

1.2.1 Intermolecular Cyclopropene Coupling Partners

Initial investigations into expanding the utility of carbohalogenation focused on utilizing

cyclopropenes in the intermolecular domino carbohalogenation reaction previously developed by

our group with alkynes.43

Cyclopropenes were attractive coupling partners because conversion

to the corresponding cyclopropanes would be thermodynamically driven by the release of

significant ring strain energy and cyclopropanes appear in many natural products.44

These

42 Newman, S. G.; Howell, J. K.; Nicolaus, N.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 14916-14919. 43 Jia, X.; Petrone, D. A.; Lautens, M. Angew. Chem. Int. Ed. 2012, 51, 9870-9872. 44 Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2002, 124, 11566-11567.

16

substrates were potentially suitable for carbohalogenation because syn-carbopalladation would

produce a RPdIIX intermediate that lacks a syn-β-hydrogen (Scheme 12).

Scheme 12: Potential pathway for carbopalladation of cyclopropene substrates.

To test this hypothesis, 2-iodostyrene 1.73 was synthesized according to a two-step literature

procedure (Scheme 13).45

Additionally, cyclopropene 2.3 was prepared according to a two-step

literature procedure.46

The asymmetric cyclopropene 2.4 was previously prepared in our group

and was used as received.

Scheme 13: Synthesis of 2-iodostyrene and cyclopropene substrates.

The two cyclopropenes were tested with 2-iodostyrene 1.73 under a variety of conditions. Initial

results were not promising and in all cases led to complex mixtures of products (Table 1). These

45 Serra, S. Tetrahedron: Asymmetry 2011, 22, 619-628. 46 Briones, J. F.; Davies, H. M. L. Org. Lett. 2011, 13, 3984-3987.

17

reactions proceeded with full consumption of the cyclopropene substrate, which was added in

excess, but incomplete conversion of the 2-iodostyrene. This suggested the cyclopropene either

decomposed or polymerized under the conditions. Control experiments with cyclopropene 2.3 in

the absence of 2-iodostyrene led to one isolable product with a very simple 1H NMR spectrum.

Together with MS data this product appeared to be an oligomer, indicating the cyclopropene

substrates oligomerize in the presence of the Pd catalyst. It was hypothesized that

oligomerization consumed the cyclopropene, precluding intermolecular carbohalogenation. We

therefore decided to investigate other substrates for carbohalogenation.

Table 1: Intermolecular domino carbohalogenation attempts with cyclopropene substrates.

1.2.2 Intramolecular Alkyne Coupling Partners

The focus of the project shifted to developing intramolecular carbohalogenation reactions with

alkyne coupling partners to produce vinyl halides. Although our group’s previous intermolecular

carbohalogenation attempts to produce vinyl halides were unsuccessful, the majority of

successful carbohalogenations are intramolecular so we sought to develop the methodology

18

using a tethering strategy. To this end, we synthesized alkynyl aryl iodide 2.5 and alkynyl aryl

bromide 2.6 via a Mitsunobu protocol (Scheme 14).47

Scheme 14: Synthesis of tethered alkynyl aryl halide substrates.

Reaction of alkynyl aryl iodide 2.5 under conditions previously developed in our group led only

to decomposition.48

However, reaction of alkynyl aryl bromide 2.6 led to the corresponding

cyclized vinyl bromide product 2.7 (Scheme 15). The product had a 1H NMR spectrum similar

to the starting material; 5J coupling between the methyl and methylene protons was still observed

but these peaks were shifted downfield. Upon leaving this product in CDCl3 (ca. 2 h) the

benzofuran product 2.8 along with decomposition products were observed (Scheme 15).

Coupling was now observed between the methyl and methine protons, along with coupling

between the methine proton and the new aromatic proton at the C2 position. These results were

very significant for two reasons: 1) vinyl halides had never been made via carbohalogenation and

2) brominated products could not previously be accessed from aryl bromides via

carbohalogenation. The vinyl bromide 2.7 was very sensitive to trace acid, making it difficult to

purify and characterize, so we sought to develop a better substrate.

Scheme 15: Initial carbobromination hit and aromatization under slightly acidic conditions.

With the knowledge that steric factors play a significant role in promoting carbohalogenation we

endeavored to incorporate elements of steric bulk into our substrates. Substrate 2.9 with a

phenyl group at the terminal position of the alkyne was prepared according to a Mitsunobu

47 Durandetti, M.; Hardou, L.; Clément, M.; Maddaluno, J. Chem. Commun. 2009, 4753-4755. 48 Jia, X.; Petrone, D. A.; Lautens, M. Angew. Chem. Int. Ed. 2012, 51, 9870-9872.

19

protocol (Scheme 16). Additionally, substrate 2.10 with a TIPS group at the terminal position of

the alkyne was prepared. This substrate was not known in the literature so a two-step synthesis

was developed. 2-Bromophenol was first alkylated with propargyl bromide and the terminal

alkyne was subsequently TIPS protected (Scheme 16).49,50

Scheme 16: Synthesis of phenyl and TIPS substrates.

Reaction of the phenyl substrate led to recovered starting material, however the TIPS substrate

reacted cleanly and furnished predominantly cis-2.12 accompanied by a small amount of trans-

2.12 (Scheme 17).51

cis-2.12 was the expected product and likely arose from cis-

carbopalladation while trans-2.12 was believed to arise from Pd mediated isomerization. The

details of the isomerization process were examined and are discussed later in this section. X-ray

crystallographic data confirmed the structure of cis-2.12 and the presence of the vinyl bromide

moiety.

49 Hoogboom, J.; Swager, T. M. J. Am. Chem. Soc. 2006, 128, 15058-15059. 50 Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem. Eur. J. 2007, 13, 961-967. 51 The nomenclature cis and trans refers to the apparent cis or trans nature of the carbopalladation step. In all cases,

except 2.40 (see Scheme 22), the olefin geometries of cis and trans products are E and Z, respectively.

20

Scheme 17: Second generation carbobromination substrates. aCombined yield of cis-2.12 and

trans-2.12 determined from 1H NMR analysis of the crude reaction mixture using 1,3,5-

trimethoxybenzene as an internal standard. bDetermined from

1H NMR analysis of the crude

reaction mixture.52

1.2.3 Reaction Optimization

The reaction conditions used to obtain our initial hit were adopted from previous work in our

group so we endeavored to explore the reaction parameters and optimize the conditions (Table

2).53

A variety of different catalysts were explored and Pd(Qphos)2 proved to be superior

(entries 1-4). Several different amine bases were then tested and PMP was shown to be the most

effective (entry 4-9). The amount of PMP added could be reduced to 0.25 equivalents without

any erosion in yield (entry 10). The addition of extra Qphos ligand was then tested and found to

have no effect on the yield with this amount of PMP (entries 10-11). By increasing the catalyst

52 NMR yield and cis:trans ratio determined by D. A. Petrone. 53 Jia, X.; Petrone, D. A.; Lautens, M. Angew. Chem. Int. Ed. 2012, 51, 9870-9872.

21

loading to 7.5 mol% in the absence of Qphos the yield could be improved back to the level under

the initial conditions (entry 12). Although the catalyst loading was increased, the concomitant

absence of added Qphos ligand and reduced equivalents of the expensive PMP base was

considered ideal.

We then shifted our focus to the reaction kinetics and endeavored to perform NMR experiments

to elucidate reaction rates.54

The reaction components were mixed, placed into an oil bath

preheated to 110 °C and an aliquot was taken every subsequent 5 min for 1 h. Surprisingly, 1H

NMR analysis of the aliquots showed the reaction was complete after 5 min. This discovery led

us to reoptimize the reaction by adjusting the temperature and time parameters (Scheme 19).

The reaction was found to be complete after 15 min at 50 °C and removal of PMP altogether at

this temperature led to no erosion in yield (entry 13). A final attempt to decrease the catalyst

loading at higher concentration led to a decrease in yield and with these additional screens the

conditions in entry 13 were taken to be fully optimized.

54 Performed with the assistance of D.A. Petrone.

22

Table 2: Reaction optimization.

aThe conversion, combined yields, and cis:trans ratio were determined by integrating the

appropriate peaks in the crude 1H NMR using 1,3,5-trimethoxybenzene as an internal standard.

bCatalyst activated using KOtBu (10 mol%).

cReaction run at 0.15 M.

1.2.4 Examination of the Substrate Scope

With the optimized conditions in hand, we endeavoured to evaluate the substrate scope and

functional group tolerance of the reaction. Several substrates were synthesized according to the

two-step alkylation protocol described in the previous section (Scheme 18). However, this

23

procedure generated silicon-containing side products that were difficult to separate from the

products. A second protocol was developed whereby TIPS propargyl bromide 2.17 was first

prepared and 2-bromophenols were then alkylated. This second protocol was not without its

drawbacks however; silicon-containing side products were generated during preparation of TIPS

propargyl bromide 2.17. These side products could not be separated from 2.17 so the crude

mixture was used in the subsequent alkylation step,

Scheme 18: Substrate synthesis protocols.

Two additional substrates were synthesized utilizing alternative protocols (Scheme 19). A

substrate with a terminal tBu substituent was synthesized. The corresponding

tBu propargyl

alcohol 2.27 was first prepared according to a literature procedure and was then coupled to 2-

bromophenol via a Mitsunobu protocol. Additionally, 2.29 was synthesized according to a

literature procedure.55

55 Tsuji, H.; Yamagata, K.-I.; Itoh, Y.; Endo, K.; Nakamura, M.; Nakamura, E. Angew. Chem. Int. Ed. 2007, 46,

8060-8062.

24

Scheme 19: Synthesis of additional substrates.

These additional substrates were tested under the optimized reaction conditions (Table 3). The

sterically encumbering naphthalene moiety produced the desired product with the TIPS and

naphthyl groups in close proximity to one another (entry 2). The steric clash between these

groups may lead to axial chirality in the product and investigations into this possibility are

underway. Additionally, both electron withdrawing groups (entries 3-6) and electron donating

groups (entry 7) were well tolerated. Furthermore, aryl iodide 2.25 produced the corresponding

vinyl iodide (entry 8). This product was relatively unstable, which would explain why no vinyl

iodide products from the initial alkynyl aryl iodide substrate bearing a terminal Me substituent

could be isolated. Aryl chloride 2.26 also reacted to produce the corresponding vinyl chloride

(entry 9). The more forcing conditions and incomplete conversion reflected the increased

difficulty of reversible oxidative addition into aryl chloride bonds relative to aryl iodides and

bromides. To the best of our knowledge, entry 9 represents the first example of a

carbochlorination reaction. The success of aryl iodide and chloride substrates was important

because they show this reaction is amenable to all three halides that are typically used in cross

coupling reactions. Substrates with other sterically bulky substituents at the terminal position of

the alkyne, such as TBS (2.22, entry 10) and tBu (2.28, entry 11), also reacted. The lower yield

for substrate 2.22 and more forcing conditions required for substrate 2.28 reflected the decreased

steric bulk of the terminal substituents as compared to TIPS. In the case of 2.28, the geometrical

configurations of cis-2.39 and trans-2.39 were confirmed by NOE experiments (see

Experimental section). Carbocycles could also be formed by this method although more forcing

25

conditions were required (entry 12). This was attributed to the flexibility of the carbon tether

and a low population of the reactive rotamer. Additionally, only one product isomer was

observed, which suggested the oxygen tether in the other substrates facilitated isomerization to

the trans products.

26

Table 3: Vinyl halide substrate scope.

27

aCombined yield of cis and trans products.

bRatio determined from

1H NMR analysis of the

crude mixture. cConditions: Pd(Qphos)2 (5 mol%), Qphos (5 mol%), PMP (1.0 equiv.), 110 °C,

72 h. dConditions: Pd(Qphos)2 (10 mol%), 110 °C, 1 h.

eIsomers are inseparable by flash

column chromatography. eConditions: Pd(Qphos)2 (7.5 mol%), PMP (0.25 equiv.), 110 °C, 18 h.

Full conversion was unattainable.56

56 Reactions in entries 3,4 & 6 performed by D. A. Petrone. Reactions in entries 2 & 7 performed by C. M. Le.

28

Several other substrates were prepared to test under the reaction conditions. In an effort to

prevent aromatization and decomposition substituents were introduced at the methylene carbon

alpha to the alkyne. The mono methyl substrate 2.42 was prepared according to a two-step

Mitsunobu/TIPS protection protocol (Scheme 20). The gem-dimethyl substrate 2.44 was

prepared according to a similar protocol although more forcing conditions were required to react

the tertiary alcohol (Scheme 20). The ester substrate 2.46 was also prepared according to

another two-step ester coupling/methylation protocol.57

Scheme 20: Preparation of substrates with a substituent at the methylene alpha to the alkyne.

The mono methyl substrate 2.42 yielded the desired product under the reaction conditions but the

product was very unstable and could not be purified by chromatography (Scheme 21). The gem-

dimethyl substrate 2.44 was not very reactive and yielded only trace amounts of the desired

product (Scheme 21). Finally, the ester substrate 2.46 was completely unreactive, leading only

to recovered starting material (Scheme 21). This could be due to an unfavourable electronic

effect of the ester functionality on the alkyne, inhibiting carbopalladation.

57 Okamoto, K.; Hayashi, T.; Rawal, V. H. Chem. Commun. 2009, 4815-4817.

29

Scheme 21: Reaction of substrates with substituents at the methylene alpha to the alkyne.

Substrates with a nitrogen tether were also synthesized and tested. Substrates 2.48 and 2.49 were

prepared according to a two-step Ts protection/alkylation protocol (Scheme 22).58

Although

these substrates reacted, the products were very unstable and could not be purified or

characterized (Scheme 22).

Scheme 22: Nitrogen tethered substrate synthesis and reactivity.

58 Kamal, A.; Reddy, J. S.; Bharathi, E. V.; Dastagiri, D. Tetrahedron Lett. 2008, 49, 348-353.

30

The enyne 2.51 had been tested previously in our group for carbobromination using the

Pd2(dba)3/tBuBrettPhos catalyst system, yielding trace amounts of product (Scheme 23).

59 We

synthesized this compound according to a literature procedure to test under our new conditions.60

Additionally, we tested our terminal alkynyl aryl bromide 2.10 previously synthesized.

However, both of these substrates decomposed under the reaction conditions (Scheme 23).

Preparation of enyne substrates with a sterically bulky group at the terminal position are

currently underway.

Scheme 23: Synthesis of enyne substrate and subjection of terminal alkyne substrates to

reaction conditions.

Finally, six-membered-ring precursor substrates were prepared. Substrate 2.53 was prepared

according to the Mitsunobu/TIPS protection protocol (Scheme 24). Additionally, substrate 2.55

with a gem-dimethyl group at the position alpha to the alkyne was prepared according to a two-

step alkylation/TIPS protection protocol.61

However, both of these substrates failed to produce

the corresponding six-membered rings. Substrate 2.53 decomposed under the reaction

conditions while substrate 2.55 did not react (Scheme 24).

59 Newman, S. Reversible Oxidative Addition in Palladium Catalysis: New Methods for Carbon–Carbon and

Carbon–Heteroatom Bond Formation. Ph.D Thesis, The University of Toronto, 2012. 60 Kan, S. B. J.; Anderson, E. A. Org. Lett. 2008, 10, 2323-2326. 61 Feng, Y.-S.; Xie, C.-Q.; Qiao, W.-L.; Xu, H.-J. Org. Lett. 2013, 15, 936-939.

31

Scheme 24: Six-membered ring precursor substrate synthesis and substrate reactivity.

1.2.5 Isomerization Experiments

The presence of trans products was very interesting because the cis-carbopalladation step should

have yielded exclusively cis products. To investigate this phenomenon, we subjected pure

samples of cis-2.39 and trans-2.39 to the reaction conditions (Scheme 25). In both cases, a

mixture of cis/trans products was obtained in a ratio consistent with that observed when starting

directly from substrate 2.28. Furthermore, no isomerization was observed under thermal

conditions in the absence of catalyst. Pd mediated isomerization was also observed with TIPS-

containing products in the absence of PMP at lower temperatures.62

cis-2.33 and trans-2.33 were

subjected to the lower temperature conditions and a mixture of cis/trans products was obtained,

62 Reactions performed by D.A Petrone.

32

again consistent with the ratio observed when starting directly from substrate 2.21. Radical

probing experiments were also performed to probe for the presence of radical intermediates.

Substrate 2.28 was subjected to the reaction conditions in the presence of TEMPO or galvinoxyl

and no change in the cis:trans ratio was observed (Scheme 25). Furthermore, no radical adducts

were observed, which suggested this reaction was not occurring via a radical mechanism.

Scheme 25: Isomerization and radical probing experiments. aRatios determined by

1H NMR

analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as an internal standard.

33

Based on these results and the computational experiments performed on our group’s earlier

substrates, we propose the following mechanism (Scheme 26):63

Oxidative addition followed by

carbopalladation produces intermediate 2.58, which can either undergo reductive elimination to

form cis-2.60 or isomerize to 2.59. We believe this isomerization process goes through a PdII

carbenoid, which has a freely rotatable bond to the heterocycle. Similar PdII carbenoids have

been reported in the literature.64,65,66,67,68

The carbenoid can be represented in two zwitterionic

forms and we believe our system favours these species due to a stabilizing effect from the β-

silicon. Additionally, the cation is stabilized through resonance with the aromatic ring and a lone

pair of electrons on the oxygen atom. However, the nature of the carbenoid is likely substrate

dependent. Once isomerization has occurred, reductive elimination from this intermediate can

produce trans-2.60 and regenerate the active catalyst.

63

Lan, Y.; Liu, P.; Newman, S. G.; Lautens, M.; Houk, K. N. Chem. Sci. 2012, 3, 1987-1995. 64 Krasovskiy, A.; Lipshutz, B. H. Org. Lett. 2011, 13, 3818-3821. 65 Lu, G.-P.; Voigtritter, K. R.; Cai, C.; Lipshutz, B. H. Chem. Commun. 2012, 48, 8661-8663. 66 Lu, G.-P.; Voigtritter, K. R.; Cai, C.; Lipshutz, B. H. J. Org. Chem. 2012, 77, 3700-3703. 67 Fruchey, E. R.; Monks, B. M.; Patterson, A. M.; Cook, S. P. Org. Lett. 2013, 15, 4362-4365. 68 Amatore, C.; Bensalem, S.; Ghalem, S.; Jutand, A. J. Organomet. Chem. 2004, 689, 4642-4646.

34

Scheme 26: Proposed mechanism of reconstitutive cyclization via carbohalogenation.

1.2.6 Preliminary Investigation of Product Reactivity

The products of these reactions contained an exocyclic olefin and as noted, one of the

decomposition products was aromatization to form the corresponding benzofuran. Deliberate

attempts to aromatize cis-2.33 under acidic conditions were successful, leading to 2.63 (Scheme

27). It is believed that aromatization may also occur under basic conditions and exploration of

this possibility is currently underway. These new aromatic products contain a geminal

relationship between a silicon and a leaving group at a benzylic-like position, which may be

35

amenable to alpha elimination to form the corresponding carbene. Investigations into this

possibility are currently underway.

Scheme 27: Aromatization of reconstitutive cyclization products and possible route to carbenes.

The vinyl bromide motif was potentially amenable to subsequent cross coupling reactions.

Initial one-pot reactions in the presence of a cyanide nucleophile led only to the

carbobromination products (Scheme 28). A two-pot protocol was also applied, whereby the

carbobromination product was subjected to Pd catalyzed cyanation conditions (Scheme 28).

However, this only led to decomposition of the starting material. Further investigations into

appropriate coupling partners is currently underway.

Scheme 28: Initial investigation into subsequent cross coupling of carbobromination products.

The tetrasubstituted olefin was potentially amenable to epoxidation. The products of these

reactions would contain a heavily substituted epoxide and nucleophilic ring opening could lead

36

to two adjacent quaternary centres. DMDO was chosen as the ideal epoxidizing agent because it

was very mild and only generates acetone as a by-product. Conversely, mCPBA was not

suitable because the presence of m-chlorobenzoic acid could catalyze aromatization. To this end,

DMDO was freshly prepared according to a literature procedure.69

However, attempts to

epoxide the tetrasubstituted olefin only led to recovered starting material (Scheme 29). Failure

to epoxidize the olefin was likely due to steric congestion.

Scheme 29: Attempt to epoxidize the carbobromination products.

1.2.7 Conclusions and Future Work

Carbohalogenation is an exciting new field of Pd catalyzed chemistry. This chemistry is

amenable to a wide range of substrates, can be used to make five- or six-membered heterocycles

and carbocycles, is highly functional group tolerant and can be applied to inter- and

intramolecular reactions. The initial work described in this thesis aimed to expand the scope of

carbohalogenation to include cyclopropene coupling partners in intermolecular

carbohalogenation. However, these substrates were found to oligomerize under the reaction

conditions and were not suitable for carbohalogenation.

The project focus was shifted to intramolecular carbohalogenation with alkyne coupling partners,

which developed into a very fruitful pursuit. Tethered alkynes were found to cyclize with aryl

halides, forming vinyl halide products. These Pd(Qphos)2 catalyzed reactions were remarkably

fast and were found to proceed at mild temperatures. The presence of a bulky substituent at the

terminal position of the alkyne was necessary for reactivity and was believed to promote the C–

X reductive elimination step of catalysis. Both electron withdrawing and electron donating

69 Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124, 2377.

37

substituents on the aryl ring were well tolerated and both oxygen heterocycles and carbocycles

could be formed. Additionally, aryl iodides, bromides and chlorides all reacted, which

significantly expanded the breadth of carbohalogenation. Furthermore, the presence of both cis

and trans products led to a proposed catalytic cycle based on earlier computational studies.

Isomerization of the cis-carbopalladation product was believed to occur via a zwitterionic Pd

carbenoid species and reductive elimination from either isomer led to the mixture of alkene

geometries.

Preliminary investigations showed the products could be aromatized to the corresponding

benzofuran under acid catalysis and these products may be amenable to carbene chemistry.

Furthermore, initial investigations of subsequent cross coupling reactions were not very

promising, however a plethora of other coupling protocols may be explored. Armed with the

knowledge that substrate steric factors can also promote reductive elimination, several other

substrate designs may be amenable to carbohalogenation. In particular, the use of other

heteroatom tethers would significantly expand the utility of this reaction. Further investigations

towards these ends are currently underway.70

The future of carbohalogenation promises to be

prosperous.

1.3 Experimental

1.3.1 General Considerations

Commercial reagents were purchased from Sigma Aldrich, Strem or Alfa Aesar and used without

further purification. Palladium catalysts were supplied by Johnson Matthey and are commercially

available from Alfa Aesar. Pd[P(tBu)3]2 and Pd(Q-phos)2 were kept in an argon-filled glovebox

for long term storage. Small quantities were removed from the glovebox in a vial so that

reactions could be weighed out in the air. Unless otherwise stated, all catalytic reactions were

carried out under an inert atmosphere of dry argon or dry nitrogen utilizing glassware that was

oven (120°C) or flame dried and cooled under argon, whereas the work-up and isolation of the

products from the catalytic reactions were conducted on the bench-top using standard techniques.

70 Currently being undertaken by C. M. Le.

38

Solvents and solutions were transferred by syringe or cannula. Tetrahydrofuran was distilled

from sodium and benzophenone ketal, toluene was distilled over sodium, triethylamine and

diisopropylamine were distilled from potassium hydroxide, and anhydrous N,N

dimethylformamide was purchased from Aldrich and used as received. Reactions were

monitored by Thin Layer Chromatography (TLC) using EM Separations pre-coated silica gel 0.2

mm layer UV 254 fluorescent sheets, and visualization was accomplished with 250 nm UV light

followed by immersion in KMnO4 or p-anisaldehyde stain. Organic solutions were concentrated

by rotary evaporation at reduced pressure (15 – 30 torr, house vacuum) at 25-50 °C. Flash

chromatography was performed using Ultra Pure 230-400 mesh silica gel purchased from

Silicycle. NMR characterization data was collected at 296 K on a Varian Mercury 300, Varian

Mercury 400, Varian 600, or a Bruker Avance III spectrometer operating at 300, 400, 500, or

600 MHz for 1H NMR, and 75, 100, 125, or 150 MHz for

13C NMR.

1H NMR spectra were

internally referenced to the residual solvent signal (CDCl3 = 7.26 ppm) or TMS (0 ppm). 13

C

NMR spectra were internally referenced to the residual solvent signal (CDCl3 =77.0 ppm) and

are reported as observed. Data for 1H NMR are reported as follows: chemical shift (δ ppm),

integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =

broad), coupling constant (Hz). Melting point ranges were determined on a Fisher-Johns Melting

Point Apparatus and are reported uncorrected. IR spectra were obtained using a Shimadzu FTIR-

8400S FT-IR spectrometer on NaCl plates. All reported E/Z ratios in data section are those

obtained from 1H NMR analysis of the crude reaction mixtures using a 4 second relaxation delay.

NMR yields for the optimization section were obtained by 1H NMR analysis of the crude

reaction mixture using a 10 second relaxation delay and 1,3,5-trimethoxybenzene as an internal

standard. High resolution mass spectra (HRMS) were obtained on a micromass 70S-250

spectrometer (EI) or an ABI/Sciex QStar Mass Spectrometer (ESI) or a JEOL AccuTOF medel

JMS-T1000LC mass spectrometer equipped with a IONICS® Direct Analysis in real Time

(DART) ion source at Advanced Instrumentation for Molecular Structure (AIMS) in the

Department of Chemistry at the University of Toronto.

1.3.2 Starting Material Synthesis and Characterization

1-iodo-2-(prop-1-en-2-yl)benzene (1.73):

39

The title compound was prepared according to a two-step literature procedure.71

A solution of

methyl magnesium iodide (3 M in Et2O, 37.5 mL, 113 mmol, 2.25 equiv.) was cooled to 0 °C. A

solution of methyl-2-iodobenzoate (7.36 mL, 50.0 mmol, 1.00 equiv.) in Et2O (37.5 mL) was

added dropwise over 30 min via syringe pump, the solution was warmed to rt and stirred for 2 h.

The reaction was poured into ice cold sat. aq. NH4Cl (70 mL) and extracted with Et2O (3 x 50

mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4 and

concentrated in vacuo to afford 2-(2-iodophenyl)propan-2-ol (11.25 g, 86%). To a solution of 2-

(2-iodophenyl)propan-2-ol (11.25 g, 42.9 mmol, 1.00 equiv.) in benzene (125 mL) was added

hydroquinone (0.025 g, 0.225 mmol, 0.2 mol%) and p-TsOH·H2O (1.62 g, 8.54 mmol, 20

mol%). The mixture was heated at 120 °C for 3 h and the water was removed via a Dean-Stark

apparatus. The reaction was washed with sat. aq. NaHCO3 (50 mL), then brine (50 mL), dried

over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel

chromatography (100% hexanes) to afford 1.73 as a clear oil (6.07 g, 58%). The characterization

data are consistent with the literature. 1H NMR (500 MHz, CDCl3): δ 7.84 (1H, ddd, J = 7.9,

1.2, 0.4 Hz), 7.30 (1H, ddd, J = 7.5, 7.5, 1.2 Hz), 7.18 (1H, ddd, J = 7.5, 1.8, 0.4 Hz), 6.94 (1H,

ddd, J = 7.9, 7.5, 1.8 Hz), 5.25 – 5.20 (1H, m), 4.89 (1H, dq, J = 1.9, 1.0 Hz), 2.07 (3H, dd, J =

1.6, 1.0 Hz). 13

C NMR (125 MHz, CDCl3): δ 148.8, 148.4, 139.2, 128.5, 128.4, 128.0, 116.0,

96.9, 23.9.

dimethyl cycloprop-2-ene-1,1-dicarboxylate (2.3):

71 Serra, S. Tetrahedron: Asymmetry 2011, 22, 619-628.

40

The title compound was prepared according to a two-step literature procedure.72

To a solution of

dimethyl malonate (2.97 mL, 26.1 mmol, 1.00 equiv.) in MeCN (20 mL) was added Na2CO3

(8.50 g, 61.5 mmol, 2.40 equiv.). Mesyl azide (2.96 mL, 35.0 mmol, 1.40 equiv.) was added

slowly and the reaction was stirred at rt for 25 h. The reaction was washed successively with sat.

aq. NH4Cl (20 mL), 1 M aq. NaOH (20 mL) then brine (20 mL). The organic phase was dried

over Na2SO4, concentrated in vacuo and purified by silica gel chromatography (40-100%

Et2O/pentanes) to afford dimethyl 2-diazomalonate as a yellow oil (2.08 g, 50%). A solution of

dimethyl 2-diazomalonate (0.237 g, 1.50 mmol, 1.00 equiv.) in TMS acetylene (5.3 mL) was

heated to 45 °C. A solution of Rh2(octanoate)4 (0.003 g, 0.004 mmol, 0.25 mol%) in TMS

acetylene (1.8 mL) was added over 16 h via syringe pump. The mixture was refluxed for 1 h and

the TMS acetylene was removed via distillation. The residue was dissolved in THF (7.8 mL)

and 10% aq. K2CO3 (3 mL) was added dropwise. The solution was stirred at 0 °C for 30 min,

then at rt for 30 min. The solution was washed with brine (2 x 20 mL) and the organic phase was

dried over MgSO4 and concentrated in vacuo. Purification via silica gel chromatography (30-

50% Et2O/pentanes) afforded 2.3 as a yellow oil (0.057 g, 24%). Characterization data are

consistent with the literature. 1H NMR (500 MHz, CDCl3): δ 6.91 (2H, s), 3.73 (6H, s).

13C

NMR (125 MHz, CDCl3): δ 171.3, 102.4, 52.5, 29.8.

1-iodo-2-(but-2-yn-1-yloxy)benzene (2.5):

The title compound was prepared according to a literature procedure.73

A solution of 2-

iodophenol (1.10 g, 5.00 mmol, 1.00 equiv.), 2-butyn-1-ol (0.40 mL, 5.40 mmol, 1.08 equiv.)

and triphenylphosphine (1.312 g, 5.00 mmol, 1.00 equiv.) in THF (20 mL) was cooled to 0 °C.

DIAD (1.01 mL, 5.00 mmol, 1.00 equiv.) was added dropwise, the reaction was warmed to rt

and stirred for 40 min. The mixture was diluted with Et2O (25 mL) then washed with 0.5 M aq.

NaOH (2 x 25 mL) and water (25 mL). The organic phase was dried over MgSO4 and

72 Briones, J. F.; Davies, H. M. L. Org. Lett. 2011, 13, 3984-3987. 73 Durandetti, M.; Hardou, L.; Clément, M.; Maddaluno, J. Chem. Commun. 2009, 4753-4755.

41

concentrated in vacuo and the obtained solid was suspended in pentanes (25 mL) and sonicated.

The solids were filtered off and the filtrate was concentrated in vacuo. The crude mixture was

purified via flash chromatography (100% pentanes) to afford 2.5 as a colourless oil (0.743 g,

55%). Characterization data are consistent with the literature. 1H NMR (400 MHz, CDCl3): δ

7.78 (1H, dd, J = 7.7, 1.6 Hz), 7.31 (1H, ddd, J = 8.3, 7.4, 1.6 Hz), 6.99 (1H, dd, J = 8.3, 1.3 Hz),

6.74 (1H, ddd, J = 7.7, 7.4, 1.3 Hz), 4.72 (2H, q, J = 2.3 Hz), 1.86 (3H, t, J = 2.3 Hz). 13

C NMR

(100 MHz, CDCl3): δ 156.9, 139.9, 129.6, 123.3, 113.3, 86.9, 84.6, 73.9, 57.9, 4.0.

1-bromo-2-(but-2-yn-1-yloxy)benzene (2.6):

A solution of 2-bromophenol (0.53 mL, 5.00 mmol, 1.00 equiv.), 2-butyn-1-ol (0.40 mL, 5.40

mmol, 1.08 equiv.) and triphenylphosphine (1.312 g, 5.00 mmol, 1.00 equiv.) in THF (20 mL)

was cooled to 0 °C. Diisopropylazodicarboxylate (1.01 mL, 5.00 mmol, 1.00 equiv.) was added

dropwise, the reaction was warmed to rt and stirred for 40 min. The mixture was diluted with

Et2O (25 mL) then washed with 0.5 M aq. NaOH (2 x 25 mL) and water (25 mL). The organic

phase was dried over MgSO4 and concentrated in vacuo and the obtained solid was suspended in

pentanes (25 mL) and sonicated. The solids were filtered off and the filtrate was concentrated in

vacuo. The crude mixture was purified via flash chromatography (5% Et2O/pentanes) to afford

2.6 as a colourless oil (0.534 g, 48%). 1H NMR (300 MHz, CDCl3): δ 7.54 (1H, dd, J = 7.9, 1.6

Hz), 7.27 (1H, ddd, J = 8.3, 7.4, 1.6 Hz), 7.06 (1H, dd, J = 8.3, 1.4 Hz), 6.87 (1H, ddd, J = 7.9,

7.4, 1.4 Hz), 4.73 (2H, q, J = 2.3 Hz), 1.85 (3H, t, J = 2.3 Hz). 13

C NMR (100 MHz, CDCl3): δ

154.4, 133.6, 128.4, 122.6, 114.2, 112.5, 84.5, 73.7, 57.6, 3.9. IR (neat, cm-1

): 2306, 2231, 1588,

1476, 1279, 1145, 1051, 1031. HRMS (DART): Calc’d for [C10H10BrO]+ [M+H]

+ 224.9915

found 224.9916

1-bromo-2-((3-phenylprop-2-yn-1-yl)oxy)benzene (2.9):

42

A solution of 2-bromophenol (0.53 mL, 5.00 mmol, 1.00 equiv.), 3-phenylprop-2-yn-1-ol (0.67

mL, 5.40 mmol, 1.08 equiv.) and triphenylphosphine (1.312 g, 5.00 mmol, 1.00 equiv.) in THF

(20 mL) was cooled to 0 °C. Diisopropylazodicarboxylate (1.01 mL, 5.00 mmol, 1.00 equiv.)

was added dropwise. The reaction was warmed to rt and stirred for 40 min. The mixture was

diluted with Et2O (25 mL) then washed with 0.5 M aq. NaOH (2 x 25 mL) and water (25 mL).

The organic phase was dried over MgSO4 and concentrated in vacuo and the obtained solid was

suspended in pentanes (25 mL) and sonicated. The solids were filtered off and the filtrate was

concentrated in vacuo. The crude mixture was purified via flash chromatography (5%

Et2O/pentanes) to afford 2.9 as a colourless oil, which solidifies after storing at -20 °C and

remains a solid (0.705 g, 49%). Characterization data are consistent with the literature.74

1H

NMR (400 MHz, CDCl3): δ 7.57 (1H, dd, J = 7.9, 1.6 Hz), 7.46-7.40 (2H, m), 7.37-7.27 (4H,

m), 7.17 (1H, dd, J = 8.3, 1.4 Hz), 6.89 (1H, ddd, J = 7.6, 7.6, 1.4 Hz), 5.01 (2H, s). 13

C NMR

(100 MHz, CDCl3): δ 154.4, 133.7, 132.0, 128.9, 128.5, 128.4, 122.9, 122.3, 114.7, 112.7, 87.9,

83.5, 57.9.

General Procedure A:

1-bromo-2-(prop-2-yn-1-yloxy)benzene (2.10): A dry flask was sequentially charged with

K2CO3 (0.987 g, 7.14 mmol, 2.23 equiv.), DMF (15 mL), 2-bromophenol (0.32 mL, 3.00 mmol,

1.00 equiv.) and propargyl bromide (80 wt% in toluene, 0.39 mL, 3.46 mmol, 1.08 equiv.). The

reaction was stirred at rt overnight and quenched with water (100 mL). The aqueous phase was

74 Komeyama, K.; Yamada, T.; Igawa, R.; Takaki, K. Chem. Commun. 2012, 48, 6372-6374.

43

extracted with Et2O (3 x 100 mL) and the combined organic phase washed sequentially with

saturated aqueous NH4Cl (100 mL) and brine (100 mL). The organic phase was dried over

MgSO4 and concentrated in vacuo. The crude mixture was purified via flash chromatography

(10% Et2O/pentanes) to afford 2.10 as a colourless oil (0.605 g, 96%). Characterization data are

consistent with the literature.75

1H NMR (400 MHz, CDCl3): δ 7.56 (1H, dd, J = 7.9, 1.7 Hz),

7.28 (1H, ddd, J = 8.3, 7.5, 1.7 Hz), 7.07 (1H, dd, J = 8.3, 1.4 Hz), 6.89 (1H, ddd, J = 7.9, 7.5,

1.4 Hz), 4.78 (2H, d, J = 2.4 Hz), 2.54 (1H, t, J = 2.4 Hz). 13

C NMR (100 MHz, CDCl3): δ

154.1, 133.7, 128.5, 123.0, 114.4, 112.6, 78.1, 76.3, 57.0.

(3-(2-bromophenoxy)prop-1-yn-1-yl)triisopropylsilane (2.11): Prepared from 2.10 according

to a procedure described by Zádný et. al.76

A solution of diisopropylamine (0.37 mL, 2.63

mmol, 1.05 equiv.) in THF (2 mL) was cooled to 0 °C and n-butyllithium (2.71 M in hexanes,

0.92 mL, 2.50 mmol, 1.00 equiv.) was added dropwise. The solution was stirred for 40 min at 0

°C, then cooled to -78 °C. A solution of 1-bromo-2-(prop-2-yn-1-yloxy)benzene (2.50 mmol,

0.528 g, 1.00 equiv.) in THF (1 mL) was added slowly. The mixture was stirred for 1.5 h, after

which TIPSCl (0.60 mL, 2.75 mmol. 1.10 equiv.) was added dropwise. The solution was

warmed slowly to rt and stirred for 2 h. The reaction was quenched with water (20 mL) and

extracted with Et2O (3 x 20 mL). The organic phase was dried over MgSO4 and concentrated in

vacuo. The crude mixture was purified via flash chromatography (100% pentanes) to afford the

desired product as a clear oil (0.768 g, 84%). 1H NMR (400 MHz, CDCl3): δ 7.54 (1H, dd, J =

7.9, 1.6 Hz), 7.25 (1H, ddd, J = 8.3, 7.7, 1.6 Hz), 7.14 (1H, dd, J = 8.3, 1.4 Hz), 6.86 (1H, ddd, J

= 7.9, 7.7, 1.4 Hz), 4.82 (2H, s), 1.02 (21H, s). 13

C NMR (100 MHz, CDCl3): δ 154.3, 133.5,

128.3, 122.8, 115.2, 112.7, 101.5, 90.3, 58.0, 18.6, 11.2. IR (neat, cm-1

): 2177, 1278, 1054,

1033. HRMS (DART): Calc’d for [C18H31BrNOSi]+ [M+NH4]

+ 384.1358 found 384.1358.

1-bromo-2-(prop-2-yn-1-yloxy)naphthalene (2.13):

The title compound was prepared according to General Procedure A (5.00 mmol

scale), purified by flash chromatography (5% Et2O/pentanes) and isolated as an

orange solid (1.177 g, 90%). Characterization data are consistent with the

75 Girard, A.; Lhermet, R.; Fressigné, C.; Durandetti, M.; Maddaluno, J. Eur. J. Org. Chem. 2012, 2895-2905. 76 Žádný, J.; Jančaŕik, A.; Andronova, A.; Šámal, M.; Chocholoušová, J. V.; Vacek, J.; Pohl, R.; Šaman, D.;

Cisařová, I.; Stará, I. G.; Starý, I. Angew. Chem. Int. Ed. 2012, 51, 5857-5861.

44

literature.77

1H NMR (400 MHz, CDCl3): δ 8.25 (1H, d, J = 8.6 Hz), 7.85-7.77 (2H, m), 7.58

(1H, ddd, J = 8.2, 6.9, 1.1), 7.48-7.37 (2H, m), 4.90 (2H, d, J = 2.4 Hz), 2.55 (1H, t, J = 2.4 Hz).

13C NMR (100 MHz, CDCl3): δ 152.2, 133.3, 130.6, 128.9, 128.2, 127.9, 126.6, 125.0, 116.0,

110.6, 78.5, 76.4, 58.0.

(3-((1-bromonaphthalen-2-yl)oxy)prop-1-yn-1-yl)triisopropylsilane (2.18):

The title compound was prepared from 2.13 according to General Procedure

A (1.50 mmol scale), purified by flash chromatography (1% Et2O/pentanes)

and isolated as a yellow solid (0.558 g, 89%). mp = 53-54 °C. 1H NMR

(400 MHz, CDCl3): δ 8.27-8.21 (1H, m), 7.82-7.76 (1H, m), 7.57 (1H, ddd, J

= 8.3, 6.8, 1.3), 7.48 (1H, d, J = 9.0 Hz), 7.42 (1H, d, J = 8.0, 6.9, 1.2 Hz), 4.94 (2H, s), 1.00

(21H, s). 13

C NMR (100 MHz, CDCl3): δ 152.5, 133.3, 130.6, 128.6, 128.2, 127.7, 126.5, 124.8,

116.6, 110.7, 101.8, 90.4, 59.0, 18.6, 11.2. IR (CHCl3, cm-1

): 2176, 1274, 1058, 1023. HRMS

(DART): Calc’d for [C22H33BrNOSi]+ [M+NH4]

+ 434.1515 found 434.1525.

2-bromo-4-chloro-1-(prop-2-yn-1-yloxy)benzene (2.14)

The title compound was prepared according to General Procedure A (5.00

mmol scale), purified by flash chromatography (5% Et2O/pentanes) and

isolated as a white solid (1.142 g, 93%). mp = 52-53 °C. 1H NMR (400 MHz,

CDCl3): δ 7.56 (1H, d, J = 2.5 Hz), 7.26 (1H, dd, J = 8.7, 2.5 Hz), 7.00 (1H, d, J = 8.7 Hz), 4.76

(2H, d, J = 2.4 Hz), 2.55 (1H, t, J = 2.4 Hz). 13

C NMR (100 MHz, CDCl3): δ 153.0, 133.5,

128.6, 127.7, 115.4, 113.5, 78.0, 77.0, 57.6. IR (CHCl3, cm-1

): 3297, 2124, 1050, 1019. HRMS

(DART): Calc’d for [C9H7BrClO]+ [M+H]

+ 244.9368 found 244.9368.

(3-(2-bromo-4-chlorophenoxy)prop-1-yn-1-yl)triisopropylsilane (2.19):

The title compound was prepared from 2.14 according to General

Procedure A (2.50 mmol scale), purified by flash chromatography (1%

Et2O/pentanes) and isolated as a yellow oil (0.726 g, 72%). 1H NMR (400

MHz, CDCl3): δ 7.54 (1H, d, J = 2.5 Hz), 7.22 (1H, dd, J = 8.8, 2.5), 7.07

77 Šarčevic, N.; Zsindely, J.; Schmid, H. Helv. Chim. Acta. 1973, 56, 1457-1476.

45

(1H, d, J = 8.8 Hz), 4.79 (2H, s), 1.02 (21H, s). 13

C NMR (100 MHz, CDCl3): δ 153.2, 133.0,

128.1, 127.1, 115.8, 113.3, 100.9, 90.9, 58.3, 18.6, 11.2. IR (neat, cm-1

): 2177, 1288, 1050,

1029. HRMS (DART): Calc’d for [C18H30BrClNOSi]+ [M+NH4]

+ 418.0967 found 418.0960.

3-bromo-4-(prop-2-yn-1-yloxy)benzonitrile (2.15):

The title compound was prepared according to General Procedure A (3.20

mmol scale), purified by flash chromatography (30% EtOAc/hexanes) and

isolated as a white solid (0.689, 91%). mp = 103-105 °C. 1H NMR (400

MHz, CDCl3): δ 7.85 (1H, dd, J = 2.0, 0.3 Hz), 7.61 (1H, dd, J = 8.6, 2.0 Hz), 7.12 (1H, dd, J =

8.6, 0.3 Hz), 4.85 (2H, d, J = 2.4 Hz), 2.60 (1H, t, J = 2.4 Hz). 13

C NMR (125 MHz, CDCl3): δ

157.6, 137.1, 133.0, 117.7, 113.7, 113.0, 106.3, 77.5, 76.8, 57.1. IR (CHCl3, cm-1

): 3283, 2227,

2127, 1051, 1016. HRMS (DART): Calc’d for [C10H7BrNO]+ [M+H]

+ 235.9711 found

235.9711.

3-bromo-4-((3-(triisopropylsilyl)prop-2-yn-1-yl)oxy)benzonitrile (2.20):

The title compound was prepared from 2.15 according to General

Procedure A (1.50 mmol scale), purified by flash chromatography (20-30%

CH2Cl2/hexanes gradient) and isolated as a white solid (0.133 g, 23%). mp

= 55-56 °C. 1H NMR (500 MHz, CDCl3): δ 7.84 (1H, d, J = 2.0 Hz), 7.57

(1H, dd, J = 8.6, 2.0 Hz), 7.19 (1H, d, J = 8.6 Hz), 4.89 (2H, s), 1.06-0.97 (21H, m). 13

C NMR

(125 MHz, CDCl3): δ 157.8, 137.0, 132.7, 117.8, 114.4, 113.1, 106.1, 99.8, 92.0, 58.1, 18.6,

11.2. IR (CHCl3, cm-1

): 2229, 1236, 1052, 1025. HRMS (DART): Calc’d for

[C19H30BrN2OSi]+ [M+NH4]

+ 409.1311 found 409.1315.

1-bromo-4-fluoro-2-(prop-2-yn-1-yloxy)benzene (2.16):

The title compound was prepared according to General Procedure A (5.00 mmol

scale), purified by flash chromatography (5% Et2O/pentanes) and isolated as a

white solid (1.091 g, 95%). Characterization data are consistent with the

literature.78

1H NMR (400 MHz, CDCl3): δ 7.49 (1H, dd, J = 8.8, 6.2 Hz), 6.84 (1H, dd, J =

10.3, 2.7 Hz), 6.64 (1H, ddd, J = 8.8, 8.1, 2.7 Hz), 4.77 (2H, d, J = 2.4 Hz), 2.58 (1H, t, J = 2.4

78 Takeda Pharmaceutical. Fused Benzene Derivative and Use. U.S. Patent 7,649,001, July 13, 2005.

46

Hz). 13

C NMR (100 MHz, CDCl3): δ 162.6 (d, J = 246.8 Hz), 155.0 (d, J = 10.2 Hz), 133.9 (d, J

= 9.5 Hz), 109.7 (d, J = 22.4 Hz), 106.7, (d, J = 3.8 Hz), 102.6 (d, J = 27.0 Hz), 77.4, 76.9, 57.2.

19F NMR (376 MHz, CDCl3): δ −111.56 to −111.73 (m).

(3-(2-bromo-5-fluorophenoxy)prop-1-yn-1-yl)triisopropylsilane (2.21):

The title compound was prepared from 2.16 according to General Procedure

A (2.50 mmol scale), purified by flash chromatography (1% Et2O/pentanes)

and isolated as a yellow oil (0.741 g, 77%). 1H NMR (400 MHz, CDCl3): δ

7.47 (1H, dd, J = 8.7, 6.2 Hz), 6.93 (1H, dd, J = 10.5, 2.8 Hz), 6.62 (1H,

ddd, J = 8.7, 2.8 Hz), 4.81 (2H, s), 1.03 (21H, s). 13

C NMR (100 MHz, CDCl3): δ 162.5 (d, J =

246.4 Hz), 155.1 (d, J = 10.3 Hz), 133.7 (d, J = 9.5 Hz), 109.4 (d, J = 22.5 Hz), 106.8 (d, J = 3.8

Hz), 103.3 (d, J = 27.0 Hz), 100.6, 91.3, 58.1, 18.6, 11.2. 19

F NMR (376 MHz, CDCl3): δ

−112.21 to −112.40 (m). IR (neat, cm-1

): 2178, 1290, 1164, 1046, 1019. HRMS (DART):

Calc’d for [C18H30BrFNOSi]+ [M+NH4]

+ 402.1264 found 402.1272.

General Procedure B:

(3-bromoprop-1-yn-1-yl)triisopropylsilane (2.17): Prepared according to a procedure

described by Swager et. al.79

A solution of propargyl bromide (80 wt% in toluene, 1.10 mL, 10.0

mmol, 1.00 equiv.) in THF (29 mL) was cooled to -78 °C and n-butyllithium (2.71M in hexanes,

3.70 mL, 10 mmol, 1.00 equiv) was added dropwise. The solution was stirred at -78 °C for 10

min, then TIPSCl (2.14 mL, 10.0 mmol, 1.00 equiv.) was added dropwise. The solution was

warmed slowly to rt and stirred for 2.5 hrs. The reaction was quenched with sat. aq. NH4Cl (50

mL) and extracted with Et2O (3 x 30 mL). The organic phase was dried over MgSO4 and

concentrated in vacuo to afford a crude mixture of the title compound, which was determined to

be ~52% pure by 1H NMR and used without further purification. The characterization data are

79 Hoogboom, J.; Swager, T. M. J. Am. Chem. Soc. 2006, 128, 15058-15059.

47

consistent with the literature.80

1H NMR (200 MHz, CDCl3): δ 3.94 (2H, s, product), 1.07 (21H,

s, product), 1.05 (19H, s, by-product).

(3-(2-bromo-6-fluoro-4-nitrophenoxy)prop-1-yn-1-yl)triisopropylsilane (2.23): A dry flask

was charged sequentially with K2CO3 (0.308 g, 2.23 mmol, 2.23 equiv.), DMF (1.0 mL), 2-

bromo-5-fluoro-4-nitrophenol (.236 g, 1.00 mmol, 1.00 equiv.) and 2.17 (0.486 g, 1.08 equiv.).

The reaction was stirred at rt overnight and quenched with water (10 mL). The aqueous phase

was extracted with Et2O (3 x 10 mL) and the combined organic phase washed sequentially with

saturated aqueous NH4Cl (10 mL) and brine (10 mL). The organic phase was dried over MgSO4

and concentrated in vacuo. The crude mixture was purified via flash chromatography (2%

Et2O/pentanes) to afford the desired product as a yellow oil (0.187 g, 44%). 1H NMR (300

MHz, CDCl3): δ 8.28 (1H, dd, J = 2.7, 1.8 Hz), 7.96 (1H, dd, J = 10.7, 2.7 Hz), 5.07 (2H, d, J =

1.0 Hz), 0.95 (21H, s). 13

C NMR (100 MHz, CDCl3): δ 154.9 (d, J = 255.0 Hz), 148.5 (d, J =

12.5 Hz), 143.3 (d, J = 8.8 Hz), 124.3 (d, J = 3.2 Hz), 118.8 (d, J = 3.7 Hz), 112.2 (d, J = 25.0

Hz), 99.6, 92.2, 62.1 (d, J = 7.9 Hz), 18.5, 11.1. 19

F NMR (376 MHz, CDCl3): δ −120.83 to

−120.96 (m). IR (neat, cm-1

): 2179, 1534, 1471, 1270, 1074, 1025. HRMS (DART): Calc’d for

[C18H26BrFNO3Si]+ [M+H]

+ 430.0849 found 430.0868.

(3-(2-bromo-4-methoxyphenoxy)prop-1-yn-1-yl)triisopropylsilane (2.24):

The title compound was prepared according to General Procedure B (1.00

mmol scale), purified by flash chromatography (3% Et2O/pentanes) and

isolated as a yellow oil (0.307 g, 77%). 1H NMR (300 MHz, CDCl3): δ

7.12-7.07 (2H, m), 6.79 (1H, dd, J = 9.0, 3.0 Hz), 4.74 (2H, s), 3.76 (3H,

s), 1.02 (21H, s). 13

C NMR (75 MHz, CDCl3): δ 155.0, 148.6, 118.7, 117.2, 113.7, 113.6, 101.8,

89.9, 59.0, 56.0, 18.6, 11.2. IR (neat, cm-1

): 2176, 1278, 1210, 1045, 1023. HRMS (DART):

Calc’d for [C19H33BrNO2Si]+ [M+NH4]

+ 414.1464 found 414.1474.

(3-(2-iodophenoxy)prop-1-yn-1-yl)triisopropylsilane (2.25):

The title compound was prepared according to General Procedure B (1.00 mmol

scale), purified by flash chromatography (10% CH2Cl2/hexanes) and isolated as

a yellow oil (0.291 g, 70%). 1H NMR (300 MHz, CDCl3): δ 7.77 (1H, dd, J =

80 Inoue, M.; Nakada, M. Angew. Chem. Int. Ed. 2006, 45, 252-255.

48

7.8, 1.6 Hz), 7.28 (1H, ddd, J = 8.3, 7.4, 1.6 Hz), 7.06 (1H, dd, J = 8.3, 1.4 Hz), 6.73 (1H, ddd, J

= 7.8, 7.4, 1.4 Hz) 4.80 (2H, s), 1.02 (21H, s). 13

C NMR (75 MHz, CDCl3): δ 156.5, 139.6,

129.3, 123.4, 113.9, 101.5, 90.2, 86.9, 58.0, 18.6, 11.2. IR (neat, cm-1

): 2176, 1277, 1029, 1052.

HRMS (DART): Calc’d for [C18H31INOSi]+ [M+NH4]

+ 432.1220 found 432.1224.

(3-(2-chlorophenoxy)prop-1-yn-1-yl)triisopropylsilane (2.26):

The title compound was prepared according to General Procedure B (0.76 mmol

scale), purified by flash chromatography (15% CH2Cl2/hexanes) and isolated as

a light yellow oil (0.144 g, 56%). 1H NMR (300 MHz, CDCl3): δ 7.36 (1H,

dd, J = 7.8, 1.3 Hz), 7.24-7.14 (2H, m), 6.93 (1H, ddd, J = 7.8, 6.7, 2.1 Hz),

4.82 (2H, s), 1.02 (21H, s). 13

C NMR (75 MHz, CDCl3): δ 153.3, 130.4, 127.5, 123.5, 122.3,

115.3, 101.4, 90.3, 57.9, 18.6, 11.2. IR (neat, cm-1

): 2176, 1278, 1063, 1032. HRMS (DART):

Calc’d for [C18H28ClOSi]+ [M+H]

+ 323.1600 found 323.1594.

(3-(2-bromophenoxy)prop-1-yn-1-yl)(tert-butyl)dimethylsilane (2.22):

The title compound was prepared from 2.10 according to General Procedure A

using TBSCl (2.50 mmol scale), purified by flash chromatography (1%

Et2O/pentanes) and isolated as a clear oil (0.225 g, 28%). 1H NMR (400 MHz,

CDCl3): δ 7.54 (1H, dd, J = 7.9, 1.6 Hz), 7.29-7.23 (1H, m), 7.11 (1H, dd, J =

8.3, 1.4 Hz), 6.87 (1H, ddd, J = 7.9, 7.7, 1.4 Hz), 4.78 (2H, s), 0.89 (9H, s), 0.09 (6H, s). 13

C

NMR (100 MHz, CDCl3): δ 154.3, 133.6, 128.3, 122.9, 115.1, 112.8, 100.3, 92.1, 58.0, 26.1,

16.6, -4.7. IR (neat, cm-1

): 2179, 1251, 1054, 1031. HRMS (DART): Calc’d for

[C15H25BrNOSi]+ [M+NH4]

+ 342.0889 found 342.0902.

(4-(2-bromophenyl)but-1-yn-1-yl)triisopropylsilane (2.29):

49

Prepared according to a procedure described by Tsuji et. al.81

A solution of 1-(triisopropylsilyl)-

1-propyne (2.49 mL, 10.4 mmol, 1.04 equiv.) in THF (20 mL) was cooled to -78 °C and nBuLi

(2.4 M in hexane, 4.33 mL, 10.4 mmol, 1.04 equiv.) was added dropwise over 20 min via syringe

pump. The mixture was stirred at -78 °C for 2.5 h and a solution of 2-bromobenzyl bromide

(2.50 g, 10.0 mmol, 1.00 equiv.) in THF (10 mL) was added dropwise over 30 min via syringe

pump. The solution was stirred at rt for 13 h, concentrated in vacuo and the residue was taken up

in pentanes and filtered through a plug of silica. The filtrate was concentrated in vacuo and

purified by vacuum distillation (200 °C, 5.6 mm Hg) to afford the title compound (2.54 g, 70%).

The characterization data are consistent with the literature. 1H NMR (400 MHz, CDCl3): δ 7.54

(1H, dd, J = 8.0, 1.3 Hz), 7.33 (1H, dd, J = 7.6, 1.7 Hz), 7.23 (1H, ddd, J = 8.0, 7.5, 1.3 Hz), 7.08

(1H, ddd, J = 8.0, 7.5, 1.7 Hz), 2.99 (2H, t, J = 7.2 Hz), 2.62 (2H, t, J = 7.2 Hz), 1.13-0.98 (21H,

m). 13

C NMR (100 MHz, CDCl3): δ 139.6, 132.6, 130.9, 127.9, 127.2, 124.2, 107.5, 81.2, 35.4,

20.1, 18.6, 11.2.

1-bromo-2-((4,4-dimethylpent-2-yn-1-yl)oxy)benzene (2.28):

4,4-dimethylpent-2-yn-1-ol (2.27): The title compound was prepared according to a literature

procedure.82

To a solution of 3,3-dimethyl-1-butyne (0.74 mL, 6.00 mmol, 1.00 equiv.) in THF

(15 mL) at 0 °C was added nBuLi (2.49 M in hexane, 2.41 mL, 6.00 mmol, 1.00 equiv.)

dropwise. Paraformaldehyde (0.18 g, 6.00 mmol, 1.00 equiv.) was added and the mixture was

refluxed for 17 h. The reaction was diluted with Et2O (20 mL), washed with water (20 mL) and

the aqueous phase was extracted with Et2O (2 x 20 mL). The combined organic phase was dried

over MgSO4, concentrated in vacuo and purified via flash chromatography (40% Et2O/hexanes)

to afford 2.27 as a yellow oil (0.414 g, 61%). Characterization data are consistent with the

81 Tsuji, H.; Yamagat, K.; Itoh, Y.; Endo, K.; Nakamura, M.; Nakamura, E. Angew. Chem. Int. Ed. 2007, 46, 8060-

8062. 82 Hoffman La Roche. Novel Imidazo[1,2-A]pyridine and imidazo[1,2-B]pyridazine Derivatives. U.S. Patent WO2009077334, June 25, 2009.

50

literature. 1H NMR (300 MHz, CDCl3): δ 4.24 (2H, d, J = 6.0 Hz), 1.54 (1H, t, J = 6.0 Hz), 1.22

(9H, s). 13

C NMR (125 MHz, CDCl3): δ 95.2, 76.9, 51.8, 31.3, 27.8.

1-bromo-2-((4,4-dimethylpent-2-yn-1-yl)oxy)benzene (2.28): A solution of 2-bromophenol

(0.32 mL, 3.00 mmol, 1.00 equiv.), 4,4-dimethylpent-2-yn-1-ol 2.27 (0.43 mL, 3.24 mmol, 1.08

equiv.) and triphenylphosphine (0.787 g, 3.00 mmol, 1.00 equiv.) in THF (12 mL) was cooled to

0 °C. Diisopropylazodicarboxylate (0.59 mL, 3.00 mmol, 1.00 equiv.) was added dropwise. The

reaction was warmed to rt and stirred for 40 min. The mixture was diluted with Et2O (25 mL)

then washed with 0.5 M aq. NaOH (2 x 25 mL) and water (25 mL). The organic phase was dried

over MgSO4 and concentrated in vacuo and the obtained solid was suspended in pentanes (25

mL) and sonicated. The solids were filtered off and the filtrate was concentrated in vacuo. The

crude mixture was purified via flash chromatography (10% CH2Cl2/hexanes) to afford the

desired product as a colourless oil, which solidifies after storing at -20 °C and remains solid.

(0.482 g, 60%). mp = 53-54 °C. 1H NMR (500 MHz, CDCl3): δ 7.54 (1H, dd, J = 7.9, 1.6 Hz),

7.26 (1H, ddd, J = 8.3, 7.4, 1.6 Hz), 7.10 (1H, dd, J = 8.3, 1.4 Hz), 6.86 (1H, ddd, J = 7.9, 7.4,

1.4 Hz), 4.75 (2H, s), 1.20 (9H, s). 13

C NMR (75 MHz, CDCl3): δ 154.6, 133.5, 128.3, 122.6,

114.9, 112.7, 97.2, 73.2, 57.9, 30.8, 27.6. IR (CHCl3, cm-1

): 2239, 1032, 996. HRMS (DART):

Calc’d for [C13H16BrO]+ [M+H]

+ 267.0385 found 267.0386.

1-bromo-2-(but-3-yn-2-yloxy)benzene (2.41): A solution of 2-bromophenol (1.07 mL, 10.0

mmol, 1.00 equiv.), 1-methyl-2-propyn-1-ol (0.78 mL, 10.0 mmol, 1.00 equiv.) and

triphenylphosphine (2.62 g, 10.0 mmol, 1.00 equiv.) in THF (40 mL) was cooled to 0 °C.

Diisopropylazodicarboxylate (1.97 mL, 10.0 mmol, 1.00 equiv.) was added dropwise, the

reaction was warmed to rt and stirred for 40 min. The mixture was diluted with Et2O (50 mL)

then washed with 0.5 M aq. NaOH (2 x 50 mL) and water (50 mL). The organic phase was dried

over MgSO4 and concentrated in vacuo and the obtained solid was suspended in pentanes (50

mL) and sonicated. The solids were filtered off and the filtrate was concentrated in vacuo. The

51

crude mixture was purified via flash chromatography (1% Et2O/pentanes) to afford the desired

product as a colourless oil. (1.68 g, 75%). 1H NMR (500 MHz, CDCl3): δ 7.55 (1H, dd, J = 7.9,

1.4 Hz), 7.27 (1H, ddd, J = 8.2, 7.4, 1.6 Hz), 7.16 (1H, dd, J = 8.2, 1.6 Hz), 6.89 (1H, ddd, J =

7.9, 7.4, 1.4 Hz), 4.88 (1H, qd, J = 6.6, 2.1 Hz), 2.51 (1H, d, J = 2.1 Hz), 1.74 (3H, d, J = 6.6 Hz)

13C NMR (125 MHz, CDCl3): δ 154.2, 133.6, 128.4, 123.1, 116.4, 113.4, 82.6, 74.7, 65.4, 22.3.

(3-(2-bromophenoxy)but-1-yn-1-yl)triisopropylsilane (2.42): Prepared from 2.41 according

to a procedure described by Zádný et. al.83

A solution of diisopropylamine (0.15 mL, 1.05

mmol, 1.05 equiv.) in THF (1 mL) was cooled to 0 °C and n-butyllithium (2.71 M in hexanes,

0.37 mL, 1.00 mmol, 1.00 equiv.) was added dropwise. The solution was stirred for 40 min at 0

°C, then cooled to -78 °C. A solution of 2.41 (1.00 mmol, 0.225 g, 1.00 equiv.) in THF (0.5 mL)

was added slowly. The mixture was stirred for 1.5 h, after which TIPSCl (0.24 mL, 1.10 mmol,

1.10 equiv.) was added dropwise. The solution was warmed slowly to rt and stirred for 2 h. The

reaction was quenched with water (20 mL) and extracted with Et2O (3 x 20 mL). The organic

phase was dried over MgSO4 and concentrated in vacuo. The crude mixture was purified via

flash chromatography (100% pentanes) to afford 2.42 as a colourless oil (0.332 g, 87%). 1H

NMR (400 MHz, CDCl3): δ 7.55 – 7.50 (1H, m), 7.24 – 7.20 (2H, m), 6.85 (1H, ddd, J = 7.9,

5.7, 3.2 Hz), 4.89 (1H, d, J = 6.6 Hz), 1.73 (3H, d, J = 6.6 Hz), 1.01 (21H, s). 13

C NMR (100

MHz, CDCl3): δ 154.2, 133.2, 128.0, 122.7, 117.0, 113.4, 106.0, 87.6, 66.1, 22.4, 18.5, 11.1.

1-bromo-2-((2-methylbut-3-yn-2-yl)oxy)benzene (2.43): The title compound was prepared

according to a literature procedure.84

To a solution of 2-methylbut-3-yn-2-ol (1.67 mL, 17.3

mmol, 1.15 equiv.) in CH3CN (10 mL) at 0 °C was added DBU (3.36 mL, 22.5 mmol, 1.50

equiv.). Trifluoroacetic anhydride (2.09 mL, 15.0 mmol, 1.00 equiv.) was added dropwise over

83 Žádný, J.; Jančaŕik, A.; Andronova, A.; Šámal, M.; Chocholoušová, J. V.; Vacek, J.; Pohl, R.; Šaman, D.;

Cisařová, I.; Stará, I. G.; Starý, I. Angew. Chem. Int. Ed. 2012, 51, 5857-5861. 84 Clark, J. D.; Davis, J. M.; Favor, D.; Fay, L. K.; Franklin, L.; Henegar, K. E.; Johnson, D. S.; Nichelson, B. J.;

Ou, L.; Repine, J. T.; Walters, M. A.; White, A. D.; Zhu, Z. [1,8]naphthyridin-2-ones and related compounds for the

treatment of schizophrenia. U.S. Patent US2005043309, February 24, 2005.

52

20 min via syringe pump and the solution was stirred at 0 °C for 40 min. Meanwhile, a second

solution of 2-bromophenol (1.60 mL, 15.0 mmol, 1.00 equiv.) in CH3CN (10 mL) was cooled to

0 °C and DBU (2.92 mL, 19.5 mmol, 1.30 equiv.) and CuCl2 (6.0 mg, 4.5 μmol, 0.3 mol%) were

added. The 2-bromophenol solution was added to the 2-methylbut-3-yn-2-ol solution dropwise

over 20 min via cannula. The solution was stirred at 0 °C for 2 h, then stored in the fridge

overnight. The solution was concentrated in vacuo and the residue was taken up in hexanes (20

mL). The solution was washed with water (20 mL) and the aqueous phase was extracted with

hexanes (3 x 20 mL). The combined organic phase was washed sequentially with 1 M aq. HCl

(20 mL), 1 M aq. NaOH (2 x 20 mL) and brine (20 mL). The organic phase was dried over

MgSO4 and concentrated in vacuo to afford 2.43 as a clear oil (1.47 g, 41%). The

characterization data are consistent with the literature. 1H NMR (400 MHz, CDCl3): δ 7.62 (1H,

dd, J = 8.3, 1.5 Hz), 7.54 (1H, dd, J = 7.9, 1.7 Hz), 7.23 (1H, ddd, J = 8.3, 7.3, 1.5 Hz), 6.92 (1H,

ddd, J = 7.9, 7.3, 1.5 Hz), 2.59 (1H, s), 1.71 (6H, s). 13

C NMR (100 MHz, CDCl3): δ 152.9,

133.2, 127.8, 123.9, 121.4, 117.0, 86.0, 74.01, 73.95, 29.5.

(3-(2-bromophenoxy)-3-methylbut-1-yn-1-yl)triisopropylsilane (2.44): Prepared from 2.43

according to a procedure described by Zádný et. al.85

A solution of diisopropylamine (0.15 mL,

1.05 mmol, 1.05 equiv.) in THF (1 mL) was cooled to 0 °C and n-butyllithium (2.71M in

hexanes, 0.37 mL, 1.00 mmol, 1.00 equiv.) was added dropwise. The solution was stirred for 40

min at 0 °C, then cooled to -78 °C. A solution of 2.43 (1.00 mmol, 0.239 g, 1.00 equiv.) in THF

(0.5 mL) was added slowly. The mixture was stirred for 1.5 h, after which TIPSCl (0.24 mL,

1.10 mmol, 1.10 equiv.) was added dropwise. The solution was warmed slowly to rt and stirred

for 2 h. The reaction was quenched with water (20 mL) and extracted with Et2O (3 x 20 mL).

The organic phase was dried over MgSO4 and concentrated in vacuo. The crude mixture was

purified via flash chromatography (100% pentanes) to afford 2.44 as a colourless oil (0.170 g,

43%). 1H NMR (400 MHz, CDCl3): δ 7.69 (1H, dd, J = 8.2, 1.5 Hz), 7.52 (1H, dd, J = 8.0, 1.7

Hz), 7.18 (1H, ddd, J = 8.2, 7.3, 1.7 Hz), 6.88 (1H, ddd, J = 8.0, 7.3, 1.5 Hz), 1.72 (3H, s), 1.04

(21H, s). 13

C NMR (100 MHz, CDCl3): δ 153.2, 133.1, 127.6, 123.7, 121.6, 117.0, 109.5, 87.0,

74.8, 30.0, 18.5, 11.1.

85 Žádný, J.; Jančaŕik, A.; Andronova, A.; Šámal, M.; Chocholoušová, J. V.; Vacek, J.; Pohl, R.; Šaman, D.;

Cisařová, I.; Stará, I. G.; Starý, I. Angew. Chem. Int. Ed. 2012, 51, 5857-5861.

53

2-bromophenyl propiolate (2.45): 2-Bromophenol (1.07 mL, 10.0 mmol, 1.00 equiv.), 4-

dimethylaminopyridine (0.012 g, 0.10 mmol, 0.01 equiv.) and propiolic acid (1.30 mL, 21.0

mmol, 2.10 equiv.) were dissolved in CH2Cl2 (20 mL) and cooled to 0 °C. N,N-

Dicyclohexylcarbodiimide (2.27 g, 11.0 mmol, 1.10 equiv.) was added portionwise, the solution

was warmed to rt and stirred overnight. The reaction was concentrated in vacuo and purified by

silica gel chromatography (15% EtOAc/hexanes) to afford a light yellow oil (1.52 g, 63%). 1H

NMR (300 MHz, CDCl3): δ 7.70 – 7.58 (1H, m), 7.42 – 7.32 (1H, m), 7.25 – 7.09 (2H, m), 3.12

(1H, s). 13

C NMR (75 MHz, CDCl3): δ 147.2, 133.6, 129.2, 128.6, 128.1, 123.4, 115.8, 77.4,

73.8.

2-bromophenyl 3-(triisopropylsilyl)propiolate (2.46): 2-Bromophenyl propiolate 2.45 (0.225

g, 1.00 mmol, 1.00 equiv.) was dissolved in THF (10 mL) and cooled to -78 °C. Lithium

hexamethyldisilazide (1.0 M in THF, 1.2 mL, 1.20 mmol, 1.20 equiv.) was added dropwise and

stirred for 30 min. Triisopropylsilyl chloride (0.21 mL, 1.20 mmol, 1.20 equiv.) was added

dropwise, the solution was stirred for 30 min and warmed to rt over 1 h. The solution was stirred

overnight, quenched with sat. aq. NH4Cl (10 mL) and the organic phase was concentrated in

vacuo. The crude material was taken up in Et2O (10 mL) and washed with water (3 x 10 mL).

The organic phase was dried over MgSO4, concentrated in vacuo and purified by silica gel

chromatography (15% EtOAc/hexanes) to afford a clear oil (0.026 g, 7%). 1H NMR (400 MHz,

CDCl3): δ 7.51 (1H, dd, J = 7.9, 1.7 Hz), 7.15 (1H, ddd, J = 8.2, 7.4, 1.7 Hz), 6.90 (1H, dd, J =

8.2, 1.5 Hz), 6.79 (1H, ddd, J = 7.9, 7.4, 1.5 Hz), 1.34 (3H, septet, J = 7.3 Hz), 1.14 (18H, d, J =

7.3 Hz). 13

C NMR (100 MHz, CDCl3): δ 153.0, 133.4, 128.1, 121.9, 119.7, 115.1, 18.0, 13.0.

54

N-(2-bromophenyl)-4-methylbenzenesulfonamide (2.47): The title compound was prepared

according to a literature procedure.86

A solution of 2-bromoanaline (2.26 mL, 20.0 mmol, 1.00

equiv.) and TsCl (4.58 g, 24.0 mmol, 1.20 equiv.) in water (200 mL) was stirred at rt for 24 h.

The reaction was extracted with Et2O (3 x 50 mL), the combined organic phase dried over

MgSO4 and concentrated in vacuo. The crude material was purified by silica gel

chromatography (20% EtOAc/hexanes) to afford a yellow solid (1.50 g, 23%). The

characterization data are consistent with the literature.87

1H NMR (400 MHz, CDCl3): δ 7.68-

7.63 (m, 3H), 7.40 (dd, J = 8.0, 1.6 Hz, 1H), 7.26 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 7.21 (d, J = 8.0

Hz, 2H), 6.98-6.94 (m, 3H), 2.37 (s, 3H). 13

C NMR (100 MHz, CDCl3): δ 144.2, 135.8, 134.7,

132.6, 129.7, 128.6, 127.3, 126.3, 122.5, 115.7, 21.6.

N-(2-bromophenyl)-N-(but-2-yn-1-yl)-4-methylbenzenesulfonamide (2.48): A dry flask was

sequentially charged with K2CO3 (1.66 g, 12.0 mmol, 4.81 equiv.), DMF (25 mL), 2.47 (0.816 g

mL, 2.50 mmol, 1.00 equiv.) and 1-bromo-2-butyne (0.25 mL, 2.89 mmol, 1.15 equiv.). The

reaction was stirred at 60 °C overnight and quenched with water (50 mL). The aqueous phase

was extracted with Et2O (3 x 50 mL) and the combined organic phase washed sequentially with

sat. aq. NH4Cl (50 mL) and brine (50 mL). The organic phase was dried over MgSO4 and

concentrated in vacuo. The crude mixture was purified via flash chromatography (40%

EtOAc/hexanes) to afford the desired product (0.902 g, 95%). 1H NMR (400 MHz, CDCl3): δ

7.74 – 7.68 (2H, m), 7.63 (1H, dd, J = 7.7, 1.7 Hz), 7.31-7.17 (m, 5H), 4.70 (1H, d, J = 17.2 Hz),

4.08 (1H, d, J = 17.2 Hz), 2.45 (3H, s), 1.66 (3H, t, J = 2.4 Hz). 13

C NMR (100 MHz, CDCl3): δ

143.6, 137.6, 137.0, 133.8, 132.2, 130.1, 129.3, 128.1, 127.7, 125.8, 81.8, 73.0, 40.9, 21.6, 3.4.

N-(2-bromophenyl)-4-methyl-N-(3-(triisopropylsilyl)prop-2-yn-1-yl)benzenesulfonamide

(2.49): A dry flask was sequentially charged with K2CO3 (0.665 g, 4.81 mmol, 4.81 equiv.),

86 Kamal, A.; Reddy, J. S.; Bharathi, E. V.; Dastagiri, D. Tetrahedron Lett. 2008, 49, 348-353. 87 René, O.; Lapointe, D.; Fagnou, K. Org. Lett. 2009, 11, 4560-4563

55

DMF (10 mL), 2.47 (0.326 g, 1.00 mmol, 1.00 equiv.) and 2.17 (0.293 g, 1.06 mmol, 1.06

equiv.). The reaction was stirred at 60 °C overnight and quenched with water (50 mL). The

aqueous phase was extracted with Et2O (3 x 50 mL) and the combined organic phase washed

sequentially with saturated aqueous NH4Cl (50 mL) and brine (50 mL). The organic phase was

dried over MgSO4 and concentrated in vacuo. The crude mixture was purified via flash

chromatography (10% EtOAc/hexanes) to afford the desired product as a yellow oil (0.445 g,

85%). 1H NMR (400 MHz, CDCl3): δ 7.71 (2H, d, J = 10.2 Hz), 7.66 – 7.61 (1H, m), 7.27 (1H,

d, J = 10.2 Hz), 7.23 – 7.16 (3H, m), 4.81 (1H, d, J = 18.2 Hz), 4.26 (1H, d, J = 17.9 Hz), 2.43

(3H, s), 0.92 (21H, s). 13

C NMR (100 MHz, CDCl3): δ 144.0, 137.6, 137.4, 134.1, 132.6, 130.5,

129.9, 128.2, 127.9, 126.3, 100.9, 87.5, 41.4, 21.9, 18.7, 11.4.

dimethyl 2-(2-bromoallyl)-2-(prop-2-yn-1-yl)malonate (2.51): The title compound was

prepared according to a two-step literature procedure.88

A suspension of NaH (60% dispersion

in oil, 0.48 g, 12.0 mmol, 1.20 equiv.) in THF (20 mL) was cooled to 0 °C and dimethyl

malonate (1.53 mL, 10.0 mmol, 1.00 equiv.) was added dropwise. The mixture was stirred for

30 min, warmed to rt and a solution of 2,3-dibromoprop-1-ene (1.07 mL, 11.0 mmol, 1.10

equiv.) in THF (10 mL) was added dropwise. The mixture was stirred at rt for 18 h and

quenched with sat. aq. NH4Cl (30 mL). The aqueous phase was extracted with Et2O (3 x 30

mL), the combined organic phase washed with brine, dried over MgSO4 and concentrated in

vacuo. The crude material was purified by silica gel chromatography (0-10% EtOAc/pentanes)

to afford 2.50 as a light yellow oil (0.193 g, 8%). A suspension of NaH (60% dispersion in oil,

10.4 mg, 0.26 mmol, 1.30 equiv.) in THF (0.7 mL) was cooled to 0 °C and 2.50 (50.2 mg, 0.2

mmol, 1.00 equiv.) in THF (0.5 mL) was added dropwise. Propargyl bromide (60 wt% in

toluene, 35.7 mg, 0.24 mmol, 1.20 equiv.) was added dropwise and the reaction was refluxed

overnight. The reaction was quenched with sat. aq. NH4Cl (3 mL). The aqueous phase was

extracted with Et2O (3 x 3 mL), the combined organic phase washed with brine, dried over

88 Kan, S. B. J.; Anderson, E. A. Org. Lett. 2008, 10, 2323-2326.

56

MgSO4 and concentrated in vacuo. The crude material was purified by silica gel

chromatography (0-20% EtOAc/pentanes) to afford 2.51 as a colourless oil (24.6 mg, 43%). The

characterization data are consistent with the literature. 1H NMR (400 MHz, CDCl3): δ 5.83 (1H,

t, J = 0.6 Hz), 5.63 (1H, d, J = 1.6 Hz), 3.77 (6H, s), 3.31 (2H, br s), 2.93 (2H, d, J = 2.7), 2.05

(1H, t, J = 2.7 Hz). 13

C NMR (100 MHz, CDCl3): δ 169.5, 126.1, 122.9, 78.6, 72.1, 56.0, 53.0,

42.9, 22.2.

1-bromo-2-(but-3-yn-1-yloxy)benzene (2.52): A solution of 2-bromophenol (0.53 mL, 5.00

mmol, 1.00 equiv.), 3-propyn-1-ol (0.41 mL, 5.40 mmol, 1.08 equiv.) and triphenylphosphine

(1.312 g, 5.00 mmol, 1.00 equiv.) in THF (20 mL) was cooled to 0 °C.

Diisopropylazodicarboxylate (1.01 mL, 5.00 mmol, 1.00 equiv.) was added dropwise. The

reaction was warmed to rt and stirred for 40 min. The mixture was diluted with Et2O (25 mL)

then washed with 0.5 M aq. NaOH (2 x 25 mL) and water (25 mL). The organic phase was dried

over MgSO4 and concentrated in vacuo and the obtained solid was suspended in pentanes (25

mL) and sonicated. The solids were filtered off and the filtrate was concentrated in vacuo. The

crude mixture was purified via flash chromatography (5% Et2O/pentanes) to afford 2.52 (0.350

g, 31%). 1H NMR (400 MHz, CDCl3): δ 7.54 (1H, dd, J = 7.7, 1.6 Hz), 7.29-7.23 (1H, m), 6.91

(1H, dd, J = 8.3, 1.4 Hz), 6.86 (1H, ddd, J = 7.7, 7.7, 1.4 Hz), 4.16 (2H, t, J = 7.2 Hz), 2.75 (2H,

td, J = 7.2, 2.7 Hz), 2.05 (1H, t, J = 2.7 Hz). 13

C NMR (100 MHz, CDCl3): δ 154.8, 133.5,

128.4, 122.4, 113.8, 112.5, 80.0, 70.1, 67.3, 19.5.

(4-(2-bromophenoxy)but-1-yn-1-yl)triisopropylsilane (2.53): Prepared from 2.52 according to

a procedure described by Zádný et. al.89

A solution of diisopropylamine (0.15 mL, 1.05 mmol,

1.05 equiv.) in THF (1 mL) was cooled to 0 °C and n-butyllithium (2.71M in hexanes, 0.37 mL,

1.00 mmol, 1.00 equiv.) was added dropwise. The solution was stirred for 40 min at 0 °C, then

cooled to -78 °C. A solution of 2.52 (1.00 mmol, 0.225 g, 1.00 equiv.) in THF (0.5 mL) was

89 Žádný, J.; Jančaŕik, A.; Andronova, A.; Šámal, M.; Chocholoušová, J. V.; Vacek, J.; Pohl, R.; Šaman, D.;

Cisařová, I.; Stará, I. G.; Starý, I. Angew. Chem. Int. Ed. 2012, 51, 5857-5861.

57

added slowly. The mixture was stirred for 1.5 h, after which TIPSCl (0.24 mL, 1.10 mmol, 1.10

equiv.) was added dropwise. The solution was warmed slowly to rt and stirred for 2 h. The

reaction was quenched with water (20 mL) and extracted with Et2O (3 x 20 mL). The organic

phase was dried over MgSO4 and concentrated in vacuo. The crude mixture was purified via

flash chromatography (8–15% CH2Cl2/hexanes) to afford 2.53 as a colourless oil (0.216 g, 57%).

1H NMR (300 MHz, CDCl3): δ 7.53 (1H, dd, J = 7.8, 1.6 Hz), 7.29-7.22 (1H, m), 6.93 (1H, dd, J

= 8.3, 1.4 Hz), 6.85 (1H, ddd, J = 7.8, 7.4, 1.4 Hz), 4.16 (2H, t, J = 7.4 Hz), 2.81 (2H, t, J = 7.3

Hz), 1.09-1.02 (21H, m). 13

C NMR (75 MHz, CDCl3): δ 154.9, 133.5, 128.4, 122.2, 113.8,

112.5, 103.8, 82.6, 67.7, 20.9, 18.6, 11.2.

1-bromo-2-(((2-methylbut-3-yn-2-yl)oxy)methyl)benzene (2.54): The title compound was

prepared according to a literature procedure.90

To a suspension of NaH (60% dispersion in oil,

0.36 g, 9.00 mmol, 1.80 equiv.) in THF (25 mL) was added 2-methylbut-3-yn-2-ol (0.49 mL,

5.00 mmol, 1.00 equiv.) and the mixture was stirred at rt for 45 min. A solution of 2-

bromobenzyl bromide (1.50 g, 6.00 mmol, 1.20 equiv.) and tetrabutylammonium iodide (92.3

mg, 0.25 mmol, 0.05 equiv.) in THF (10 mL) was added slowly and the reaction was stirred

overnight. The reaction was diluted with Et2O (20 mL) and washed with water (3 x 15 mL), then

brine (15 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The crude

material was purified by silica gel chromatography (3% Et2O/pentanes) to afford 2.54 (0.659 g,

52%). The characterization data are consistent with the literature. 1H NMR (300 MHz, CDCl3):

δ 7.57 – 7.49 (2H, m), 7.31 (1H, ddd, J = 7.5, 6.8, 1.3 Hz), 7.13 (1H, ddd, J = 9.2, 6.8, 1.1 Hz),

4.71 (2H, s), 4.71 (2H, s), 2.48 (1H, s), 1.59 (6H, s). 13

C NMR (75 MHz, CDCl3): δ 138.2,

132.3, 129.1, 128.6, 127.3, 122.4, 85.7, 72.5, 70.6, 65.8, 28.8.

(3-((2-bromobenzyl)oxy)-3-methylbut-1-yn-1-yl)triisopropylsilane (2.55): Prepared from 2.54

according to a procedure described by Zádný et. al.91

A solution of diisopropylamine (0.24 mL,

90 Feng, Y.-S.; Xie, C.-Q.; Qiao, W.-L.; Xu, H.-J. Org. Lett. 2013, 15, 936-939. 91 Žádný, J.; Jančaŕik, A.; Andronova, A.; Šámal, M.; Chocholoušová, J. V.; Vacek, J.; Pohl, R.; Šaman, D.;

Cisařová, I.; Stará, I. G.; Starý, I. Angew. Chem. Int. Ed. 2012, 51, 5857-5861.

58

1.73 mmol, 1.15 equiv.) in THF (1 mL) was cooled to 0 °C and n-butyllithium (2.5 M in

hexanes, 0.66 mL, 1.65 mmol, 1.10 equiv.) was added dropwise. The solution was stirred for 40

min at 0 °C, then cooled to -78 °C. A solution of 2.54 (1.50 mmol, 0.380 g, 1.00 equiv.) in THF

(1 mL) was added slowly. The mixture was stirred for 1.5 h, after which TIPSCl (0.35 mL, 1.65

mmol, 1.10 equiv.) was added dropwise. The solution was warmed slowly to rt and stirred for 2

h. The reaction was quenched with water (20 mL) and extracted with Et2O (3 x 20 mL). The

organic phase was dried over MgSO4 and concentrated in vacuo. The crude mixture was purified

via flash chromatography (15–25% CH2Cl2/hexanes) to afford 2.55 as a yellow oil (0.402 g,

65%). 1H NMR (300 MHz, CDCl3): δ 7.56-7.48 (2H, m), 7.30 (1H, ddd, J = 7.6, 7.6, 1.4 Hz),

7.15 – 7.08 (1H, m), 4.74 (2H, s), 1.58 (6H, s), 1.10-1.02 (21H, m). 13

C NMR (75 MHz,

CDCl3): δ 138.6, 132.2, 129.0, 128.4, 127.3, 122.3, 109.6, 84.9, 71.2, 66.0, 29.1, 18.6, 11.1

1.3.3 Synthesis and Characterization of Cyclized Products

General Procedure C:

Pd(Q-Phos)2 (5.0-7.5 mol%) was weighed into an oven-dried 2 dram vial equipped with a stir bar

and purged with argon for 5 minutes. A solution of aryl halide (0.100 mmol, 1.00 equiv.) in

toluene (1 mL, 0.1 M) was transferred to the vial, which was then sealed with a Teflon-lined cap

and placed in a pre-heated oil bath at the indicated temperature (50-110 °C). After the indicated

period of time, the reaction was cooled to room temperature, diluted with Et2O (1 mL), passed

through a plug of silica and concentrated in vacuo. The crude E/Z-mixture was purified by silica

gel flash column chromatography at the indicated mobile phase. Careful chromatographic

technique allowed separation of the major isomer from the minor isomer with isolated yields

ranging from 44-85%. The major isomer was judged to be >95% pure by 1H NMR, which

permitted full characterization.

59

General Procedure D:

Pd(Q-Phos)2 (5.0-10.0 mol%) was weighed into an oven-dried 2 dram vial equipped with a stir

bar and purged with argon for 5 minutes. A solution of aryl halide (0.100 mmol, 1.00 equiv.) and

PMP (1,2,2,6,6-pentamethylpiperidine) (0.25-1.0 equiv.) in toluene (1 mL, 0.1 M) was

transferred to the vial, which was then sealed with a Teflon-lined cap and placed in a pre-heated

oil bath at the indicated temperature (50-110 °C). After the indicated period of time, the reaction

was cooled to room temperature, diluted with Et2O (1 mL), passed through a plug of silica and

concentrated in vacuo. The crude E/Z-mixture was purified by silica gel flash column

chromatography at the indicated mobile phase. Careful chromatographic technique allowed

separation of the major isomer from the minor isomer with isolated yields ranging from 44-85%.

The major isomer was judged to be >95% pure by 1H NMR, which permitted full

characterization.

Note: In general, the vinyl halide products are not stable for prolonged periods (>2 h) in CDCl3.

The isolated products were stored neat under argon at -20 °C.

(E)-(benzofuran-3(2H)-ylidenebromomethyl)triisopropylsilane (cis-2.12):

The title compound was prepared according to General Procedure C from 2.11

with 7.5 mol% Pd(Q-Phos)2 at 50 °C for 15 min. The crude mixture was

purified by column chromatography (100% hexanes) and the major isomer

was isolated as a white solid (Combined isolated yield for 90:10 E/Z mixture = 34.1 mg, 93%;

Isolated yield for (E)-isomer = 44%). mp = 79-82 °C. 1H NMR (500 MHz, CDCl3): δ 8.70 (1H,

ddd, J = 8.0, 1.4, 0.5 Hz), 7.29 (1H, ddd, J = 8.1, 7.4, 1.4 Hz), 6.96 (1H, ddd, J = 8.0, 7.4, 1.1

Hz), 6.88 (1H, ddd, J = 8.1, 1.1, 0.5 Hz), 5.08 (2H, s), 1.46 (3H, septet, J = 7.5 Hz), 1.18 (18H,

d, J = 7.5 Hz). 13

C NMR (125 MHz, CDCl3): δ 165.1, 148.1, 131.6, 127.9, 127.6, 120.2, 115.8,

110.7, 76.1, 18.9, 13.0. IR (CHCl3, cm-1

): 1585, 1313, 1224, 1024, 1009. HRMS (DART):

Calc’d for [C18H28BrOSi]+ [M+H]

+ 367.1093 found 367.1078.

(Z)-(benzofuran-3(2H)-ylidenebromomethyl)triisopropylsilane (trans-2.12):

Isolated as a white solid (3.4 mg, 9%). mp = 95-98 °C. 1H NMR (500 MHz,

CDCl3): δ 7.59 (1H, dd, J = 8.4, 1.3 Hz), 7.25 (1H, ddd, J = 8.1, 7.5, 1.3 Hz),

6.90-6.86 (2H, m), 5.19 (2H, s), 1.65 (3H, septet, J = 7.5 Hz), 1.20 (18H, d, J =

60

7.5 Hz). 13

C NMR (125 MHz, CDCl3): δ 167.0, 151.6, 131.0, 123.8, 123.6, 120.4, 119.0, 111.6,

81.5, 19.2, 14.0. IR (CHCl3, cm-1

): 1607, 1464, 1314, 1226, 1048, 1018. HRMS (DART):

Calc’d for [C18H27BrClOSi]+ [M+H]

+ 367.1093 found 367.1098.

(E)-(bromo(naphtho[2,1-b]furan-1(2H)-ylidene)methyl)triisopropylsilane (2.30):

The title compound was prepared according to General Procedure C from

2.18 with 7.5 mol% Pd(Q-Phos)2 at 50 °C for 15 min. The crude mixture

was purified by column chromatography (1% Et2O/pentanes) and the major

isomer was isolated as a yellow solid (Combined isolated yield for 91:9 E/Z

mixture = 34.2 mg, 82%; Isolated yield for (E)-isomer = 74%). mp = 92-95 °C. 1H NMR (500

MHz, CDCl3): δ 8.15 (1H, dddd, J = 8.5, 1.3, 0.6, 0.6 Hz), 7.84 (1H, ddd, J = 8.8, 0.6, 0.6 Hz),

7.78 (1H, dddd, J = 8.1, 1.3, 0.6, 0.6 Hz), 7.52 (1H, ddd, J = 8.5, 6.8, 1.3 Hz), 7.35 (1H, ddd, J =

8.1, 6.8, 1.3 Hz), 7.12 (1H, d, J = 8.8 Hz), 5.13 (2H, s), 1.51 (3H, septet, J = 7.5 Hz), 1.24 (18H,

d, J = 7.5 Hz). 13

C NMR (125 MHz, CDCl3): δ 164.6, 150.3, 134.1, 130.3, 128.7, 128.6, 128.5,

125.5, 123.4, 119.4, 116.6, 112.4, 78.0, 19.0, 13.2. IR (CHCl3, cm-1

): 1588, 1521, 1237, 1038,

1019. HRMS (DART): Calc’d for [C22H29BrOSi]+ [M+H]

+ 417.1249 found 417.1252.

(E)-(bromo(5-chlorobenzofuran-3(2H)-ylidene)methyl)triisopropylsilane (2.31):

The title compound was prepared according to General Procedure C from

2.19 with 7.5 mol% Pd(Q-Phos)2 at 50 °C for 15 min. The crude mixture

was purified by column chromatography (0.5% Et2O/hexanes) and the

major isomer was isolated as a white solid (Combined isolated yield for

93:7 E/Z mixture = 36.6 mg, 91%; Isolated yield for (E)-isomer = 77%). mp = 106-108 °C. 1H

NMR (600 MHz, CDCl3): δ 8.69 (1H, dd, J = 2.3, 0.4 Hz), 7.24 (1H, dd, J = 8.6, 2.3 Hz), 6.79

(1H, dd, J = 8.6, 0.4 Hz), 5.09 (2H, s), 1.45 (3H, septet, J = 7.5 Hz), 1.18 (18H, d, J = 7.5 Hz).

13C NMR (125 MHz, CDCl3): δ 163.5, 146.9, 131.3, 129.0, 127.4, 125.1, 117.9, 111.5, 76.7,

18.9, 12.9. IR (CHCl3, cm-1

): 1464, 1263, 1227, 1007, 1082. HRMS (DART): Calc’d for

[C18H27BrClOSi]+ [M+H]

+ 401.0703 found 401.0693.

(E)-3-(bromo(triisopropylsilyl)methylene)-2,3-dihydrobenzofuran-5-carbonitrile (2.32):

The title compound was prepared according to General Procedure C from 2.20 with 7.5 mol%

Pd(Q-Phos)2 at 50 °C for 15 min. The crude mixture was purified by column chromatography

61

(6%-8% Et2O/hexanes gradient) and the major isomer was isolated as a

white solid (Combined isolated yield for 95:5 E/Z mixture = 31.0 mg,

79%; Isolated yield for (E)-isomer = 68%). mp = 123-125 °C. 1H NMR

(600 MHz, CDCl3): δ 9.02 (1H, dd, J = 1.7, 0.5 Hz), 7.56 (1H, dd, J =

8.5, 1.7 Hz), 6.92 (1H, dd, J = 8.5, 0.5 Hz), 5.15 (2H, s), 1.45 (3H, septet, J = 7.5 Hz), 1.18

(18H, d, J = 7.5 Hz). 13

C NMR (150 MHz, CDCl3): δ 167.8, 145.2, 135.7, 132.0, 128.7, 120.2,

119.5, 111.7, 103.8, 77.0, 18.8, 12.9. IR (CHCl3, cm-1

): 2225, 1601, 1479, 1006, 1068. HRMS

(DART): Calc’d for [C19H30BrN2OSi]+ [M+H]

+ 409.1311 found 409.1300.

(E)-(bromo(6-fluorobenzofuran-3(2H)-ylidene)methyl)triisopropylsilane (2.33):

The title compound was prepared according to General Procedure C from

2.21 with 7.5 mol% Pd(Q-Phos)2 at 50 °C for 15 min. The crude mixture

was purified by column chromatography (100% hexanes) and the major

isomer was isolated as a white solid (Combined isolated yield for 91:9 E/Z

mixture = 35.7 mg, 93%; Isolated yield for (E)-isomer = 85%). mp = 82-85 °C. 1H NMR (600

MHz, CDCl3): δ 8.66 (1H, dd, J = 8.9, 6.0 Hz), 6.66 (1H, ddd, J = 8.9, 8.9, 2.4 Hz), 6.57 (1H, dd,

J = 9.1, 2.4 Hz), 5.10 (2H, s), 1.44 (3H, septet, J = 7.5 Hz), 1.18 (18H, d, J = 7.5 Hz). 13

C NMR

(150 MHz, CDCl3): δ 166.5 (d, J = 13.3 Hz), 164.9 (d, J = 250.5 Hz), 146.6 (d, J = 1.6 Hz),

128.8 (d, J = 10.4 Hz), 124.0 (d, J = 2.7 Hz), 115.2 (d, J = 2.6 Hz), 107.4 (d, J = 22.6 Hz), 98.5

(d, J = 26.2 Hz), 77.0, 18.9, 12.9. 19

F NMR (566 MHz, CDCl3): δ −107.6 to –107.8 (m). IR

(CHCl3, cm-1

): 1600, 1486, 1141, 1099, 1013. HRMS (DART): Calc’d for [C18H27BrFOSi]+

[M+H]+ 385.0999 found 385.1008.

(E)-(bromo(7-fluoro-5-nitrobenzofuran-3(2H)-ylidene)methyl)triisopropylsilane (2.34):

The title compound was prepared according to General Procedure C

from 2.23 with 7.5 mol% Pd(Q-Phos)2 at 50 °C for 15 min. The crude

mixture was purified by column chromatography (25%

CH2Cl2/hexanes) and the major isomer was isolated as a yellow solid

(Combined isolated yield for 90:10 E/Z mixture = 34.0 mg, 79%; Isolated yield for (E)-isomer =

51%). mp = 167-170 °C. 1H NMR (600 MHz, CDCl3): δ 9.45 (1H, dd, J = 2.0, 0.9 Hz), 8.05

(1H, dd, J = 9.8, 2.0 Hz), 5.31 (2H, s), 1.46 (3H, septet, J = 7.5 Hz), 1.19 (18H, d, J = 7.5 Hz).

13C NMR (150 MHz, CDCl3): δ 157.0 (d, J = 11.3 Hz), 146.8 (d, J = 250.8 Hz), 144.0 (d, J = 2.6

62

Hz), 140.0 (d, J = 7.0 Hz), 130.9 (d, J = 3.3 Hz), 122.2, 119.3 (d, J = 3.3 Hz), 114.6 (d, J = 19.9

Hz), 78.9, 18.8, 12.8. 19

F NMR (566 MHz, CDCl3): δ −136.25 to –136.44 (m). IR (CHCl3, cm-

1): 1534, 1332, 1072, 1010. HRMS (DART): Calc’d for [C18H26BrFNO3Si]

+ [M+H]

+ 430.0849

found 430.0855.

(E)-(bromo(5-methoxybenzofuran-3(2H)-ylidene)methyl)triisopropylsilane (2.35)

The title compound was prepared according to General Procedure C

from 2.24 with 7.5 mol% Pd(Q-Phos)2 at 50 °C for 15 min. The crude

mixture was purified by column chromatography (20%

CH2Cl2/hexanes) and the major isomer was isolated as a white solid

(Combined isolated yield for 90:10 E/Z mixture = 33.5 mg, 85%; Isolated yield for (E)-isomer =

62%). mp = 93-95 °C. 1H NMR (600MHz, CDCl3): δ 8.30 (1H, dd, J = 2.8, 0.4 Hz), 6.90 (1H,

dd, J = 8.8, 2.8 Hz), 6.78 (1H, dd, J = 8.8, 0.4 Hz), 5.06 (2H, s), 3.81 (3H, s), 1.45 (3H, septet, J

= 7.5 Hz), 1.18 (18H, d, J = 7.5 Hz). 13

C NMR (150 MHz, CDCl3): δ 159.6, 153.4, 148.4,

127.9, 118.6, 115.8, 112.3, 110.7, 76.5, 56.3, 18.9, 13.0. IR (CHCl3, cm-1

): 1559, 1486, 1206,

1073, 1015. HRMS (DART): Calc’d for [C19H30BrO2Si]+ [M+H]

+ 397.1199 found 397.1196.

(benzofuran-3(2H)-ylideneiodomethyl)triisopropylsilane (2.36):

The title compound was prepared according to General Procedure C from 2.25

with 7.5 mol% Pd(Q-Phos)2 at 50 °C for 15 min. The crude mixture was

purified by column chromatography (10% CH2Cl2/hexanes) and the title

compound was isolated as an inseparable E/Z-mixture (Combined isolated yield for 81:19 E/Z

mixture = 37.3 mg, 90%). (E)-isomer: 1H NMR (600 MHz, CDCl3): δ 8.99 (1H, ddd, J = 8.2,

1.3, 0.5 Hz), 7.32 (1H, ddd, J = 8.1, 7.3, 1.3 Hz), 7.01 (1H, ddd, J = 8.2, 7.3, 1.1 Hz), 6.88 (1H,

ddd, J = 8.1, 1.1, 0.5 Hz), 5.06 (2H, s), 1.55 (3H, septet, J = 7.5 Hz), 1.20 (18H, d, J = 7.5 Hz).

13C NMR (150 MHz, CDCl3): δ 166.1, 152.5, 132.0, 126.8, 124.2, 119.3, 110.9, 91.3, 77.5, 19.0,

14.0. (Z)-isomer: 1H NMR (600 MHz, CDCl3): δ 7.63 (1H, ddd, J = 8.0, 1.4, 0.5 Hz), 7.27-

7.23 (1H, m), 6.88 (1H, ddd, J = 8.0, 7.3, 1.1 Hz), 6.85 (1H, ddd, J = 8.2, 1.1, 0.5 Hz), 5.08 (2H,

s), 1.73 (3H, septet, J = 7.6 Hz), 1.21 (18H, d, J = 7.6 Hz). 13

C NMR (150 MHz, CDCl3): δ

168.0, 155.8, 131.1, 128.8, 123.7, 120.2, 112.0, 97.4, 88.7, 19.4, 15.1. E/Z mixture: IR (neat,

cm-1

): 1465, 1311, 1224, 1013. HRMS (DART): Calc’d for [C18H28IOSi]+ [M+H]

+ 415.0954

found 415.0952.

63

(E)-(benzofuran-3(2H)-ylidenechloromethyl)triisopropylsilane (2.37):

The title compound was prepared according to General Procedure D from 2.26

with 7.5 mol% Pd(Q-Phos)2 and PMP (0.25 equiv) at 110 °C for 18 h (82%

conversion of 2.26). The crude mixture was purified by column

chromatography (100% hexanes) and the major isomer was isolated as a white solid (Combined

isolated yield for 91:9 E/Z mixture = 23.9 mg, 74%; Isolated yield for (E)-isomer = 60%). mp =

67-70 °C. 1H NMR (400 MHz, CDCl3): δ 8.46 (1H, ddd, J = 7.9, 1.4, 0.6 Hz), 7.29-7.24 (1H,

m), 6.94 (1H, ddd, J = 7.9, 7.4, 1.1 Hz), 6.88 (1H, ddd, J = 8.1, 1.1, 0.6 Hz), 5.15 (2H, s), 1.41

(3H, septet, J = 7.4 Hz), 1.17 (18H, d, J = 7.4 Hz). 13

C NMR (125 MHz, CDCl3): δ 164.4,

146.1, 131.3, 128.0, 126.6, 124.8, 120.7, 110.5, 74.9, 18.8, 12.3. IR (CHCl3, cm-1

): 1586, 1464,

1315, 1225, 1019, 1005. HRMS (DART): Calc’d for [C18H28ClOSi]+ [M+H]

+ 323.1398 found

323.1585.

(E)-(benzofuran-3(2H)-ylidenebromomethyl)(tert-butyl)dimethylsilane (2.38):

The title compound was prepared according to General Procedure C from 2.22

with 7.5 mol% Pd(Q-Phos)2 at 50 °C for 8 h (76% conversion of 2.22). The

crude mixture was purified by column chromatography (100% hexanes) and

the major isomer was isolated as a white solid (Combined isolated yield for

86:14 E/Z mixture = 19.2 mg, 59%; Isolated yield for (E)-isomer = 50%). mp = 39-41 °C. 1H

NMR (500 MHz, CDCl3): δ 8.62 (1H, ddd, J = 8.0, 1.4, 0.5 Hz), 7.29 (1H, ddd, J = 8.2, 7.4, 1.4

Hz), 6.96 (1H, ddd, J = 8.0, 7.4, 1.1 Hz), 6.87 (1H, ddd, J = 8.2, 1.1, 0.5 Hz), 5.03 (2H, s), 1.02

(9H, s), 0.33 (6H, s). 13

C NMR (125 MHz, CDCl3): δ 165.2, 147.7, 131.7, 127.4, 127.2, 120.3,

115.0, 110.7, 76.2, 27.2, 19.2, -3.1. IR (CHCl3, cm-1

): 1586, 1470, 1225, 1024, 1007. HRMS

(DART): Calc’d for [C15H22BrOSi]+ [M+H]

+ 325.0623 found 325.0628.

(E)-3-(1-bromo-2,2-dimethylpropylidene)-2,3-dihydrobenzofuran (2.39):

The title compound was prepared according to General Procedure D from 2.28

with 10.0 mol% Pd(Q-Phos)2 at 110 °C for 1 h. The crude mixture was purified

by column chromatography (8-15% CH2Cl2/hexanes) and the major isomer was

isolated as a yellow oil (Combined isolated yield for 82:18 E/Z mixture = 15.8 mg, 59%; Isolated

yield for (E)-isomer = 54%). 1H NMR (500 MHz, CDCl3): δ 8.52 (1H, ddd, J = 8.1, 1.4, 0.5

Hz), 7.22 (1H, ddd, J = 8.0, 7.3, 1.4 Hz), 6.92 (1H, ddd, J = 8.1, 7.3, 1.1 Hz), 6.83 (1H, ddd, J =

64

8.0, 1.1, 0.5 Hz), 5.23 (2H, s), 1.37 (9H, s). 13

C NMR (125 MHz, CDCl3): δ 163.8, 132.6, 130.5,

128.2, 127.2, 127.0, 120.0, 110.1, 74.4, 41.9, 30.7. IR (neat, cm-1

): 1585, 1471, 1317, 1236,

1150, 1063, 1029. HRMS (DART): Calc’d for [C13H16BrOSi]+ [M+H]

+ 267.0385 found

267.0383. Note: 1D NOE data obtained. See p. 110 for spectra.

(Z)-3-(1-bromo-2,2-dimethylpropylidene)-2,3-dihydrobenzofuran (2.39):

Isolated as a white solid (4.0 mg, 15%). mp = 51-53 °C. 1H NMR (400 MHz,

CDCl3): δ 7.67 (1H, dd, J = 7.8, 1.3 Hz), 7.21 (1H, ddd, J = 8.2, 7.8, 1.3 Hz),

6.91 (1H, ddd, J = 7.8, 7.8 1.1 Hz), 6.86 (1H, dd, J = 8.2, 1.1 Hz), 5.05 (2H, s),

1.48 (18H, s). 13

C NMR (125 MHz, CDCl3): δ 166.6, 134.7, 129.9, 129.3,

127.5, 122.5, 120.3, 111.2, 80.7, 38.7, 30.3. IR (neat, cm-1

): 1605, 1448, 1366, 1227, 1068,

1012. HRMS (DART): Calc’d for [C13H16BrOSi]+ [M+H]

+ 267.0385 found 267.0374. Note:

1D NOE data obtained. See p. 112 for spectra.

(Z)-(bromo(2,3-dihydro-1H-inden-1-ylidene)methyl)triisopropylsilane (2.40):

The title compound was prepared according to General Procedure D from 2.29

with 5.0 mol% Pd(Q-Phos)2, PMP (1.0 equiv) and 10.0 mol% Q-Phos at 110

°C for 72 h. The crude mixture was purified by column chromatography

(100% pentanes) and the major isomer was isolated as a white solid. A Z/E-

mixture of >99:1 was observed and the major isomer was isolated as a white solid (20.9 mg,

57%). mp = 43-45 °C. 1H NMR (500 MHz, CDCl3): δ 8.76-8.73 (1H, m), 7.31-7.24 (3H, m),

2.97-2.93 (2H, m), 2.90-2.85 (2H, m), 1.55 (3H, septet, J = 7.5 Hz), 1.19 (18H, d, J = 7.5 Hz).

13C NMR (125 MHz, CDCl3): δ 154.3, 148.6, 142.3, 129.1, 128.0, 125.7, 125.1, 117.4, 36.1,

31.4, 19.1, 13.4. IR (CHCl3, cm-1

): 2358, 1572, 1466, 1256, 1072, 1020. HRMS (DART):

Calc’d for [C19H30BrSi]+ [M+H]

+ 365.1200 found 365.1317.

1.3.4 Isomerization Experiments

65

Pd(Q-Phos)2 (9.7 mg, 6.34 μmol. 7.5 mol%) was weighed into an oven-dried 2 dram vial

equipped with a stir bar and purged with argon for 5 minutes. A solution of vinyl halide (E)-2.33

(32.5 mg, 0.085 mmol, 1.00 equiv.) in toluene (0.85 mL, 0.1 M) was transferred to the vial,

which was then sealed with a Teflon-lined cap and placed in a pre-heated oil bath at 50 °C. After

15 min, the reaction was cooled to room temperature, diluted with Et2O (1 mL), passed through a

plug of silica and concentrated in vacuo. NMR yields and isomeric ratios were determined by

analysis of the crude 1H NMR using 1,3,5-trimethoxybenzene as an internal standard. The crude

material was purified by silica gel flash column chromatography (100% hexanes) to yield 2.33 as

a mixture of E/Z isomers (30.8 mg, 95%).

Pd(Q-Phos)2 (1.6 mg, 1.02 μmol, 7.5 mol%) was weighed into an oven-dried 2 dram vial

equipped with a stir bar and purged with argon for 5 minutes. A solution of vinyl halide (Z)-2.33

(5.2 mg, 0.014 mmol, 1.00 equiv.) in toluene (0.14 mL, 0.1 M) was transferred to the vial, which

was then sealed with a Teflon-lined cap and placed in a pre-heated oil bath at 50 °C. After 15

min, the reaction was cooled to room temperature, diluted with Et2O (1 mL), passed through a

plug of silica and concentrated in vacuo. NMR yields and isomeric ratios were determined by

analysis of the crude 1H NMR using 1,3,5-trimethoxybenzene as an internal standard. The crude

material was purified by silica gel flash column chromatography (100% hexanes) to yield 2.33 as

a mixture of E/Z isomers (4.5 mg, 85%).

66

1.3.5 Radical Probing Studies

Pd(Q-Phos)2 (5.0 mol%), Q-Phos (10 mol%) and TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl)

(1.00 equiv.) were weighed into an oven-dried 2 dram vial equipped with a stir bar and purged

with argon for 5 minutes. A solution of aryl halide 2.39 (0.100 mmol, 1.00 equiv.) and PMP

(1,2,2,6,6-pentamethylpiperidine) (1.0 equiv.) in toluene (1 mL, 0.1 M) was transferred to the

vial, which was then sealed with a Teflon-lined cap and placed in a pre-heated oil bath at 110 °C.

After 1 h the reaction was cooled to room temperature, diluted with Et2O (1 mL), passed through

a plug of silica and concentrated in vacuo. The conversion, yields and isomeric ratio were

determined by analysis of the crude 1H NMR using 1,3,5-trimethoxybenzene as an internal

standard (98% conversion, 74% (E)-isomer, 12% (Z)-isomer, 86:14 E/Z mixture).

1.3.6 Aromatization Experiment

A stirred solution of (E)-2.33 (32.8 mg, 0.085 mmol, 1.00 equiv.) in CH2Cl2 (0.4 mL) was cooled

to 0 °C. A solution of TFA in DCM (0.45 mL, 0.19 M, 1.00 equiv.) was added dropwise and the

mixture was stirred for 5 min. The solution was warmed to room temperature and stirred for 1 h,

during which the solution turned pink. The reaction was quenched with the addition of sat. aq.

NaHCO3 (1 mL), the organic phase separated and the aqueous phase extracted with DCM (3 x 1

mL). The combined organic phase was dried over MgSO4, passed through a plug of silica and

concentrated in vacuo to afford the title compound as a yellow oil (30.6 mg, 93%). 1H NMR

(400 MHz, CDCl3): δ 7.69 (1H, d, J = 0.7 Hz), 7.64 (1H, dd, J = 8.6, 5.3 Hz), 7.19 (1H, dd, J =

8.8, 2.3 Hz), 7.07 (1H, ddd, J = 9.3, 8.6, 2.3 Hz), 4.77 (1H, d, J = 0.7 Hz), 1.38 (3H, septet, J =

7.5 Hz), 1.20 (9H, d, J = 7.5 Hz), 1.08 (9H, d, J = 7.5 Hz). 13

C NMR (125 MHz, CDCl3): δ

161.3 (d, J = 243.1 Hz), 155.1 (d, J = 13.5 Hz), 144.1 (d, J = 4.0 Hz), 123.5 (d, J = 1.7 Hz),

121.4 (d, J = 1.2 Hz), 120.8 (d, J = 10.1 Hz), 111.2 (d, J = 24.1 Hz), 99.5 (d, J = 26.7 Hz), 27.3,

67

19.1 (d, J = 10.4), 12.0. 19

F NMR (376 MHz, CDCl3): δ −116.90 to –117.05 (m). IR (neat, cm-

1): 1622, 1486, 1259, 1135, 1091, 1019. HRMS (DART): Calc’d for [C18H27BrFOSi]

+ [M+H]

+

385.0999 found 385.1005.

68

Appendix A: Crystallographic Data

Table S3. Crystal data and structure refinement for (E)-2.12:

Identification code d13178

Empirical formula C18 H27 Br O Si

Formula weight 367.39

Temperature 147(2) K

Wavelength 0.71073 Å

Crystal system Monoclinic

Space group P 21/n

Unit cell dimensions a = 8.3270(11) Å = 90°.

b = 14.674(2) Å = 99.273(3)°.

c = 14.814(2) Å = 90°.

Volume 1786.5(4) Å3

Z 4

Density (calculated) 1.366 Mg/m3

Absorption coefficient 2.366 mm-1

F(000) 768

Crystal size 0.250 x 0.200 x 0.100 mm3

Theta range for data collection 1.966 to 27.519°.

Index ranges -10<=h<=10, -19<=k<=19, -19<=l<=19

Reflections collected 43219

Independent reflections 4105 [R(int) = 0.0210]

Completeness to theta = 25.242° 100.0 %

69

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 0.7456 and 0.6499

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 4105 / 0 / 196

Goodness-of-fit on F2 1.047

Final R indices [I>2sigma(I)] R1 = 0.0275, wR2 = 0.0712

R indices (all data) R1 = 0.0309, wR2 = 0.0735

Extinction coefficient n/a

Largest diff. peak and hole 0.872 and -0.806 e.Å-3

70

Appendix B: NMR Spectra

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