The Pennsylvania State University

The Graduate School

Eberly College of Science

N-HETEROCYCLE SYNTHESIS VIA BIDENTATE-AUXILIARY

DIRECTED REMOTE C–H FUNCTIONALIZATION

A Dissertation in

Chemistry

by

William A. Nack

© 2016 William A. Nack

Submitted in Partial Fulfillment

of the Requirements

for the Degree of

Doctor of Philosophy

August 2016 The dissertation of William A. Nack was reviewed and approved* by the following:

Gong Chen

Associate Professor

Dissertation Advisor

Chair of Committee

Kenneth S. Feldman

Professor of Chemistry

Chair of the Graduate Program

Alexander T. Radosevich

Associate Professor of Chemistry

Charles T. Anderson

Assistant Professor of Biology

*Signatures are on file in the Graduate School

ii

ABSTRACT

Saturated N-heterocycles are useful motifs in medicinal chemistry, but their application often hinges on limited synthetic methods. We have developed a strategy for the synthesis of the

N-heterocycle 1,2,3,4-tetrahydroquinoline (THQ) using Pd-catalyzed C–H functionalization reactions. Beginning from an alkyl picolinamide, a picolinic acid (PA)-directed, Pd-catalyzed sp 3

C–H arylation reaction yields a 3-arylpropylpicolinamide intermediate. This intermediate is then cyclized via a sequence of ortho sp 2 C–H iodination followed by C–N cross coupling. We explored two methods for this critical iodination: a directed electrophilic aromatic substitution (EAS) method, and a Pd-catalyzed C–H iodination reaction. To demonstrate the scope of this strategy, a variety of substituted THQ scaffolds were synthesized, including (+)-angustureine. Finally, a mechanistic hypothesis for the directed EAS reaction is presented, integrating results from the recent literature with our own preliminary mechanistic studies.

In the second chapter, a room temperature diastereoselective Pd-catalyzed C–H arylation reaction of 8-aminoquinoline (AQ) coupled cycloalkane carboxylic acids is described. Pd- catalyzed bidentate-auxiliary directed C–H arylation has been applied extensively for the synthesis of aryl cycloalkane moieties of natural products. We developed an improved room temperature protocol for cycloalkane C–H arylation and explored its scope. Further C–H functionalization reactions of the arylated products have been examined, and a mechanistic hypothesis is put forth which rationalizes the diastereoselectivity of the reaction, as well as observed reactivity trends.

iii

TABLE OF CONTENTS

LIST OF FIGURES vi

LIST OF ABBREVIATIONS vii

ACKNOWLEDGEMENTS ix

CHAPTER 1. INTRODUCTION AND BACKGROUND

1.1. Saturated N-heterocycle synthesis via intramolecular dehydrogenative C–H amination 1

1.2. 1,2,3,4-tetrahydroquinoline synthesis via Pd-catalyzed IDCA 7

1.3. Picolinamide-directed, Pd-catalyzed C–H functionalization 12

1.4. 1,2,3,4-tetrahydroquinoline: A privileged scaffold in medicinal chemistry 13

1.5. Conventional synthetic approaches to 1,2,3,4-tetrahydroquinoline 15

CHAPTER 2. SYNTHESIS OF 1,2,3,4-TETRAHYDROQUINOLINE VIA C–

H FUNCTIONALIZATION

2.1. Preliminary and optimization studies regarding the remote iodination reaction 19

2.2. Scope of THQ synthesis

2.2.1. Scope of C–H arylation 26

2.2.2. Scope of C–H iodination: Directed EAS 28

2.2.3. Scope of C–H iodination: Pd-catalyzed C–H functionalization 30

2.2.4. Scope of Cu-catalyzed C–N cross coupling 31

2.3. Synthesis of (+)-angustureine 33

2.4. Scope of directing groups for directed EAS 39

2.5. Directed EAS: Precedent and mechanistic hypothesis

iv

2.5.1. Precedent for directed EAS 41

2.5.2. Mechanistic hypothesis 46

2.6. Synthesis of iodo-THQ isomers 49

CHAPTER 3. ARYL CYCLOALKANE SYNTHESIS VIA C–H

FUNCTIONALIZATION

3.1. Introduction: Aryl cycloalkanes in natural products 51

3.2. Optimization of room temperature C–H arylation reaction 53

3.3. Scope of cycloalkane derivatives 57

3.4. Scope of aryl iodide 58

3.5. Mechanistic experiments 59

3.6. Mechanistic hypothesis 61

3.7. Sequential functionalization of arylated products 67

3.8. Deprotection 69

3.9. Concluding remarks 70

CHAPTER 4. EXPERIMENTAL

4.1. Synthesis of THQ via remote C–H functionalization 72

4.2. Cycloalkane Arylation 118

REFERENCES 143

v

LIST OF FIGURES

Figure 1. Intramolecular cyclization approaches to N-heterocycle synthesis. 2

Figure 2. Simple THQ compounds with interesting biological activity. 14

Figure 3. Pharmaceuticals and pharmaceutical candidates containing the THQ group. 14

Figure 4. Several THQ natural products that are popular targets for total synthesis. 15

Figure 5. Barluenga and co-workers’ proposed intermediate. 21

Figure 6. THQ alkaloids isolated from Angostura trifoliata. 33

Figure 7. Mechanistic model proposed by Barluenga. 41

Figure 8. Key control substrates for directed EAS iodination. 47

Figure 9. Potential intermediates in the directed EAS iodination reaction. 48

Figure 10. All-octet intermediate stabilized by intramolecular hydrogen bonding. 48

Figure 11. Natural products synthesized using directed sp 3 C–H arylation. 52

Figure 12. Thermodynamic measurements of annulated cyclopentanes. 67

Figure 13. Distinctive 1H-NMR signals of compounds 59, 60, 61, 62. 76

Figure 14. Distinctive NMR signals of 67-68. 77

vi

LIST OF ABBREVIATIONS

THQ 1,2,3,4-tetrahydroquinoline

PA picolinic acid

AQ 8-aminoquinoline

IDCA intramolecular dehydrogenative C–H amination

EAS electrophilic aromatic substitution

THIQ tetrahydroisoquinoline

OA oxalyl amide

HFIP hexafluoro-2-propanol

DCE 1,2-dichloroethane

THF tetrahydrofuran

DMF dimethylformamide

Py pyridine

NIS N-iodosuccinimide

TfOH triflic acid

DMSO dimethylsulfoxide n-BuOH n-butanol t-amylOH tert -amyl alcohol

PhCF 3 α,α,α-trifluorotoluene

Phth Phthalimide

TCE 1,1,2,2-tetrachloroethane

PivOH Pivalic acid

vii

KIE Kinetic isotope effect

DMAP 4-dimethylaminopyridine

ArI aryl iodide

RCM ring closing metathesis

viii

ACKNOWLEDGMENTS

I am fortunate to have as productive and insightful doctoral adviser as Professor Gong

Chen. His guidance and direction have been invaluable. Contributions to my education from

Professors Ken Feldman, Ray Funk, and Scott Phillips have all been necessary for my success as a graduate student. I thank my colleagues in the Chen Laboratory, notably Drs. Gang He and Bo

Wang, for their collegiality. Finally, without the support of my wonderful parents Ruthlynne and

Stanley, sisters Julia and Lily, girlfriend Emily, and family dog Marley, I would not have been able to complete this challenging and worthwhile endeavor and I thank them all for their enduring patience and support.

ix

CHAPTER 1: INTRODUCTION AND BACKGROUND

1.1. Saturated N-heterocycle synthesis via intramolecular dehydrogenative C–H amination

Saturated N-heterocycles are abundant in natural products, pharmaceuticals and

agrochemicals. 1 In particular, saturated N-heterocycles have emerged as critical tools in medicinal

chemistry, where they impart scaffold rigidity and three-dimensionality, without the liabilities

associates with other aromatic and saturated ring types.2 However, general synthetic approaches to saturated N-heterocycles are largely limited to intramolecular substitution and addition reactions of functionalized precursors. More advanced synthetic methods using more readily available starting materials would provide more straightforward access to saturated N-heterocyclic chemical space, streamlining projects in medicinal chemistry.3,4

The most straightforward retrosynthetic disconnection for saturated N-heterocycles is at

the C–N bond, reducing the complexity of cyclic scaffolds to simpler acyclic amine precursors

(Figure 1). Nucleophilic substitution and addition reactions are commonly used to effect this

transformation. Whereas these reactions constitute a reliable approach, requisite pre-

functionalization of the carbon coupling partner represents a significant limitation. Recent

methodologies for metal-catalyzed intramolecular C–H insertion of nitrenes achieve this C–N

bond forming transformation without pre-functionalization of the carbon coupling partner;

however, the participating nitrogen atom must be masked as a narrow range of nitrene precursors.

Additionally, whereas nitrene-mediated C–H functionalization chemistry has been elegantly

applied to the synthesis of a range of 5 and 6-membered N-heterocycles, the applicability of these

methods is generally limited to weaker secondary and tertiary aliphatic C–H bonds. 5–8

1

R R DG N N N N H H H

X X H H

intramolecular nitrene addition substitution dehydrogenative C−H insertion C−H amination

Figure 1: Intramolecular cyclization approaches to N-heterocycle synthesis.

Recently, C–H functionalization has emerged as a means for N-heterocycle synthesis. 7,9,10

In particular, intramolecular dehydrogenative C–H amination reactions (IDCA) have been demonstrated which the N–H and C–H bonds of common amine precursors (e.g. 1), forming C–N cyclized products (e.g. 2) with the formal loss of H 2 (Scheme 1 ). A directing group is used to

promote an intramolecular C–H activation process, providing a metallacycle intermediate (e.g. 3).

Oxidation of this metallacycle is thought to yield a high valent species which decomposes via C–

N bond forming reductive elimination. This developing reaction manifold offers a powerful complement to more established methods, allowing the efficient synthesis of saturated heterocycles from aliphatic amines.

DG DG N metal catalyst H N oxidant H 1 DG 2 N M

3 Scheme 1: Schematic representation of intramolecular dehydrogenative C–H amination

approach to saturated N-heterocycle synthesis.

2

IDCA reactions were introduced in 2005 by Buchwald and co-workers. They demonstrated the synthesis of carbazoles via the coupling of unactivated aryl C–H and amide N–H bonds

(Scheme 2). 11 Under Pd catalysis, 2-phenylacetanilides bearing varied aryl substituents (e.g. 4) provided carbazole products (e.g. 5) in good yield.

Pd(OAc) (cat.) O 2 Cu(OAc)2 N O2 O H N ° toluene, 120 C

4 5, 94%

Scheme 2: Carbazole synthesis via Pd-catalyzed IDCA.

A Pd(II)/Pd(0) catalytic cycle was proposed. This proposed catalytic cycle involves

coordination of Pd by the amide group (6 to 7), electrophilic palladation (7 to 8), reductive elimination (9 to 10 ), then oxidation of the resulting Pd(0) to active Pd(II) by Cu(II) and O 2

(Scheme 3). However, the authors later revised this proposed mechanism.12

O O O H H N Pd(OAc)2 N H N Pd CoordinationOAc Carbopalladation Pd OAc -HOAc OAc

6 7 8

O

N O N Pd + Pd(0) -HOAc Reductive Elimination

9 10 Scheme 3: Original mechanistic hypothesis invoked for Pd-catalyzed synthesis of carbazoles via

IDCA.

3

In 2008, Gaunt and co-workers reported an improved carbazole synthesis starting from N- alkyl, benzyl or allyl protected 2-aminobiphenyls (e.g. 11 ) that proceeds at room temperature

(Scheme 4). 13 The authors isolated a trinuclear Pd(II) palladacycle bearing two molecules of substrate. Addition of PhI(OAc) 2 oxidant to this trinuclear palladacycle yielded carbazole product,

causing them to invoke a Pd(II)/Pd(IV) catalytic cycle.

Pd(OAc)2 (cat.) Bn N PhI(OAc)2 H N Bn toluene, 25 °C

11 12, 94%

Scheme 4: Carbazole synthesis via Pd-catalyzed IDCA at room temperature.

In 2008, Yu and co-workers reported the synthesis of β- and γ-lactams (e.g. 14 ) from the

N-methoxyhydroxamic acid derivatives of cinnamic and phenylacetic acids (e.g. 13 ) (Scheme 5).

Substituents at the benzylic position are required to reinforce cyclopalladation reactivity via the

Thorpe-Ingold effect.14,15 Also known as the gem -dimethyl effect, both terms describe the greater

facility of intramolecular cyclization reactions of more substituted linear precursors due to more

favorable reaction kinetics.16 A Pd(II)/Pd(IV) catalytic pathway was proposed. Murakami and co- workers reported a similar Pd-catalyzed IDCA reaction for oxindole synthesis from N- tosylphenylacetamide derivatives in 2009. 17

Pd(OAc)2 (cat.) O AgOAc, CuCl2 O ° N HN DCE, 100 C OMe OMe 13 14, 88%

Scheme 5: Oxindole synthesis via Pd-catalyzed IDCA.

4

In 2009, Yu and co-workers reported Pd-catalyzed sp 2 IDCA of triflate (Tf) protected

phenylethylamines (e.g. 15 ), providing indolines (e.g. 16 ) (Scheme 6). 18 1-Fluoropyridinium triflate, a two-electron oxidant, was the reagent of choice, but Ce(SO 4)2, a one-electron oxidant, was also effective. In contrast with Yu’s previous oxindole synthesis ( Scheme 5 ), where the gem - dimethyl effect was critical for good yields of product, substrates without α or β substituents

cyclized in good yields.

N F O HN N S S O CF3 Pd(OAc) (cat.) O O 2 CF DMF/DCE 3 15 ° 16, 75% 120 C

Scheme 6: Indoline synthesis via Pd-catalyzed IDCA.

In 2012, Daugulis and our own group concurrently reported the synthesis of indolines (e.g.

18 ) from picolinamide (PA) protected phenylethylamines (e.g. 17 ) using PhI(OAc) 2 oxidant

(Scheme 7). 19,20 Our group later reported improved conditions for indoline synthesis using reduced catalyst loadings (0.5 mol %) and lower reaction temperature.21 A variety of bidentate auxiliaries have since been applied for indoline synthesis, including the 2-pyridylsulfonyl (e.g. 19 ), 22 1,2,3-

triazole (e.g. 20 ),23 oxalyl amide (e.g. 21 ),24 and methoxyiminoacyl (e.g. 22 )25 directing groups.

Additionally, these bidentate-auxiliary directed reaction systems and similar systems are capable of sp 3 IDCA, generating azetidines and pyrrolidines as well as β and γ lactams. 26–28

5

Pd(OAc)2 (cat.) PhI(OAc) HN O 2 N ° Toluene, 80 C O N N

17 18, 88%

CO2Me N O N N N S O O O N O O Ar N N N N N iPr iPr MeO 19, 82% 20, 85% 21, 92% 22, 86% Scheme 7: Indoline synthesis via IDCA.

The mechanism of this transformation is thought to involve Pd(II) and Pd(IV) palladacycle intermediates ( Scheme 8 ). PA-directed C–H activation provides Pd(II) palladacycle 23 , which undergoes oxidative addition to give Pd(IV) palladacycle 24 . Reductive elimination provides the saturated N-heterocycle product (e.g. 25 ).

O O AcO N N O N PhI(OAc)2 II PdIV Pd N N oxidative AcO C−N L L N addition reductive elimination 23 24 25

Scheme 8 : Proposed mechanism for PA-directed Pd-catalyzed intramolecular

dehydrogenative amination.

6

1.2. 1,2,3,4-Tetrahydroquinoline synthesis via Pd-catalyzed IDCA

In contrast to the facility of indoline synthesis, the synthesis of 6 membered N-heterocycle

1,2,3,4-tetrahydroquinoline (THQ) via sp 2 IDCA has proven to be more challenging. Yu and co- workers noted the poor performance of 3-phenylpropyltriflylamide 26 in their IDCA reaction with

F+ oxidant ( Scheme 9). 29

Pd(OAc) (cat.) O 2 CF3 F+ oxidant S N H O N DMF/DCE Tf ° 120 C 26 27, 30%

Scheme 9: Synthesis of THQ via intramolecular dehydrogenative C–H amination.

Similarly, subjecting 3-phenylpropylpicolinamide 28 to reaction conditions used for highly efficient picolinamide-directed indoline formation 20 results in modest yields (Scheme 10 ).

Dibenzylphosphoric acid, (BnO) 2PO 2H, was found to significantly improve the yield of cyclized product, but the results remained modest. 30–32

Pd(OAc)2 (cat.)

PhI(OAc)2 O (BnO)2PO2H N ° N toluene, 110 C H N PA 29, 28 38%

Scheme 10 : Optimized PA-directed sp 2 IDCA for THQ synthesis.

The poor yield of these cyclizations can be explained by the required intermediacy of 7- membered palladacycle 31 (Scheme 11 ). Intramolecular cyclizations forming rings larger than 5

7 members suffer from increasingly unfavorable kinetics. 33 It is likely that intramolecular

cyclization/palladation of 30 at the distant ε position proceeds slowly, and the deactivation of

catalyst and oxidant at elevated temperature in solution outpaces the desired catalytic reactivity.

Thus in the context of chelation-directed C–H functionalization, the ε position is “remote” and

functionalization of this position is accordingly challenging, with few published reports. 34

H ε O +HOAc L Pd N N N L Pd N -HOAc OAc O 30 31

Scheme 11 : Intramolecular C–H activation to form 7-membered palladacycle.

In 2008, Yu and co-workers reported a multi-step protocol for THQ synthesis. Remote

halogenation of 32 provides di-iodinated intermediate 33 , and C–N cross coupling provides THQ

product 34 (Scheme 12 ).29

Pd(OAc)2 (cat.) PhI(OAc) I I 2 CuI I2 NHTf NHTf Cs2CO3

° DMF, 130 C I ° N DMF, 130 C Tf 32 33, 31% 34, 92%

Scheme 12 : Synthesis of THQ via a sequence of C–H iodination and C–N cross coupling.

A related challenge is synthesis of tetrahydroisoquinoline (THIQ) via sp 3 C–H bond

amination. While no protocol to accomplish this transformation directly has been achieved, Yu

8 and co-workers developed a tandem Fujiwara-Moritani C–H alkenylation/conjugate addition approach beginning from trifylamide 35 (Scheme 13 ).29

CF3 Pd(OAc) (cat.) CO Me O S O 2 2 AgOAc NH + NTf O DCE, 130 °C CO2Me O 35 O 36, 59% CF3 O S O NH

CO2Me

Scheme 13 : C–H alkenylation/aza-Michael approach to tetrahydroisoquinolines as reported by

Yu and co-workers.

Our own group also reported a stepwise approach beginning from picolinamide- protected benzylamines in 2011. 35 In this report, ortho sp 2 alkylation of benzylamine substrate 37 with

protected 2-iodoethanol 38 , followed by deprotection and functional group interconversion,

enabled the synthesis of THIQ 39 via intramolecular substitution reaction (Scheme 14 ). Both the

Yu approach as well as our own complement the classical Bischler-Napieralski and Pictet-

Spengler methods for tetrahydroisoquinoline synthesis and may be useful for certain targets. 36

9

Pd(OAc)2 (cat.) O MeO PA K2CO3, NaOTf N MeO OBn H N + I H ° N t-amylOH, O2, 125 C 37 38 OBn 39, 93%

MeO NH

40 Scheme 14 : Synthesis of tetrahydroisoquinoline via a key PA-directed sp 2 C–H alkylation

reaction.

When we entered the field in 2011, no practical solution to 1,2,3,4-tetrahydroquinoline

(THQ) synthesis via C–H functionalization had been reported to complete this useful PA-directed,

Pd-catalyzed saturated N-heterocycle synthesis platform. To address this challenge, we envisioned and successfully developed a general C–H functionalization-based strategy for THQ synthesis.37

In this approach, a PA-coupled aliphatic amine (e.g. 41 ) is subjected to sp 3 C–H bond arylation.

Remote C–H bond iodination of the resulting arylated amine (e.g. 42 ) via directed electrophilic aromatic substitution or Pd-catalyzed C–H iodination provides an iodinated intermediate (e.g. 43 ).

Finally, C–N cross coupling generates the PA-coupled THQ scaffold (e.g. 44 ) (Scheme 15).

Compared to most conventional approaches for THQ synthesis, this strategy begins from a less

functionalized arene or arylamine, offering a flexible and general complement to more specialized

conventional methods.

10

Remote C−H O C−H arylation iodination PA PA N I N I N I+ H N H H 42 or 43 41 + Pd(OAc)2 (cat.) Pd(OAc)2 /I

C−N cross coupling N PA 44

Scheme 15: Synthesis of THQ scaffold using the picolinamide directing group.

Following the publication of these results, Zhao and co-workers demonstrated that 3- phenylpropylamines coupled with their newly developed oxalyl amide (OA) directing group (e.g.

46 ) undergo efficient Pd-catalyzed IDCA with PhI(OAc) 2 oxidant, providing THQ products (e.g.

47 , Scheme 16). 24 In a later publication, Zhao and co-workers demonstrated sp 3 C–H arylation at

the γ position of OA-coupled alkyl amine substrates (e.g. 45 ).38

Pd(OAc)2 (cat.) O I OA Ag2CO3 N(iPr) N N 2 + H H MeO C MeO C O 2 mesitylene 2 ° 45 110 C 46, 60%

Pd(OAc)2 (cat.) PhI(OAc)2 MeO2C N hexafluoro-2-propanol OA ° 60 C 47, 82%

Scheme 16: Synthesis of THQ via intramolecular dehydrogenative C–H amination

11

1.3. Picolinamide-directed, Pd-catalyzed C–H functionalization

Our key reaction of picolinamide-directed Pd-catalyzed sp 3 C–H arylation (Scheme 17) was first published by Daugulis and co-workers in 2005,39 and had since been well explored.40

Around the same time, Sanford and Yu explored other N-based directing groups for Pd-catalyzed

C–H oxygenation, halogenation and arylation reactions. 9,10 These pioneering studies have led to extensive subsequent work demonstrating C–O, C–C, C–N and C–X bond forming reactions effected by bidentate auxiliaries.41,42

Pd(OAc)2 (cat.) O I AgOAc PA N + MeO N ° H N MeO 130 C H

76%

Scheme 17: Arylation of sp 3 C–H bonds of propylpicolinamides reported by Daugulis in 2005.

In Daugulis’ 2005 report, a Pd(II)/Pd(IV) catalytic cycle was postulated, which has since

been invoked to explain the majority of PA-directed Pd-catalyzed C–H functionalization reactions

(Scheme 18 ). In this catalytic cycle, coordination of Pd by the PA group brings the catalyst in

proximity to the target C–H bond with generation of acetic acid ( A). While the monomeric N,N -

chelated Pd(II) complex shown is the catalytically active species, a dimeric arrangement of these

monomers bridged by acetate ligands is a more stable off-cycle intermediate.43,44 Via a concerted

metalation-deprotonation mechanism featuring the participation of bound acetate ligand in a 6-

centered transition state,45–47 the target γ C–H bond is palladated and an organometallic palladacycle is formed (B). This Pd(II) palladacycle is then oxidized to a higher valent Pd(IV) intermediate via concerted oxidative addition (C).30,48,49 Finally, reductive elimination from

12

Pd(IV) forms the desired C–C bond (D).50–52 Protonolysis of the resulting Pd(II) complex releases

arylated product, and silver cation abstracts the iodide formed, regenerating the active Pd(OAc)X

catalyst (E).

O HN + AgI N O HN H N Pd(OAc) Ag+ 2 HOAc O N E A I II Pd N H L O O N PdII D O O N N reductive H PdII I N O elimination N AcO O N IV II Pd N Pd O N O L +HOAc B C concerted H oxidative metalation- addition I O deprotonation N O PdII O N N N II Pd N L PdII H N O L O + HOAc

Scheme 18 : Postulated Pd(II)/Pd(IV) catalytic cycle for bidentate-auxiliary directed C–H

functionalization.

1.4. 1,2,3,4-tetrahydroquinoline: A privileged scaffold in medicinal chemistry

The saturated N-heterocycle 1,2,3,4-tetrahydroquinoline appears frequently in biologically active molecules, and new synthetic approaches may streamline medicinal chemistry projects and enable access to desirable chemical space.53 For example, simple THQ compound 48 has been

13 observed in the human brain, and 49 exhibits analgesic activity one eighth as potent as morphine

(Figure 2).54

OH

N N H H

48 49

Figure 2: Simple THQ compounds that exhibit interesting biological activity.

Several notable pharmaceuticals contain the 1,2,3,4-tetrahydroquinoline motif, such as the antithrombotic argatroban and antiamebic quinfamide. An array of tetrahydroquinoline compounds have been studied as pharmaceutical candidates, notably the antiatherosclerotic torcetrapib and antipsychotic vabicaserin (Figure 3 ). Many other synthetic tetrahydroquinoline compounds exhibit biological activities.55

H N O H N O S O CF3 O HO C MeO N O 2 O N F3C N O H N CF N 3 Cl N N O NH2 H Cl O O OEt quinfamide argatroban torcetrapib vabicaserin (Janssen) (Teva) (Pfizer) (Wyeth/Pfizer)

Figure 3: Pharmaceuticals and pharmaceutical candidates containing the THQ group.

The tetrahydroquinoline scaffold also is frequently found in natural products (Figure 4 ).

Virantmycin, produced by Streptomyces nitrosporeus , has activity against both RNA and DNA viruses. Helquinoline is a potent antibiotic produced by Janibacter limosus . Finally, martinellic

14 acid is found in the roots of martinella iquitosensis , and is an antagonist for the bradykinin B 1 and

B2 receptors. These natural products have attracted considerable attention from total chemical synthesis groups.56–60

NH OMe N HN NH Cl H N

HO2C NH N N H OMe H N O OH H virantmycin helquinoline martinellic acid

Figure 4: Several THQ natural products that are popular targets for total synthesis.

1.5. Conventional synthetic approaches to 1,2,3,4-tetrahydroquinoline

The most common approach to THQ synthesis is reduction of the corresponding quinoline derivative. A variety of reducing metal reagents and hydrogenation catalysts are known to effect this reaction. 54 Recent research has focused on the development of more mild and environmentally friendly catalysts as well as enantioselective methods. 55 Rueping and co-workers demonstrated the organocatalytic transfer hydrogenation of quinolines (Scheme 19 ).61 Quinoline starting materials can be produced by a variety of classical reactions, such as the Combes, Friedlaender, and Skraup syntheses. 62

15

EtO2C CO2Et

N H Ar N N H O O 91%, 87% ee P OH O

(cat.) Ar ° Benzene, 60 C Scheme 19: Asymmetric reduction of quinolines by organocatalytic transfer hydrogenation.

Alternatively, quinolines are susceptible to attack by strong nucleophiles, providing 1,2-

dihydroquinolines which can be reduced or subjected to electrophilic addition reactions (Scheme

20 ).63 Synthesis strategies proceeding through quinoline intermediates are superior options for the

synthesis of simple THQ compounds. However, for many complex tetrahydroquinolines bearing

complex substitution patterns and stereogenic centers, construction of the heterocyclic ring may

provide a more efficient alternative.

Cbz H Cbz H N MgBr N N K CO , MeOH; H 2 3 ° THF, 0 C; m-CPBA, CH2Cl2 O OH CbzCl OCbz OH 45% 53% Scheme 20: Synthesis of THQ via 1,2-dihydroquinolines.

Intramolecular formation of the C aryl –N bond with arylamine nucleophile represents the most common approach for the construction of the heterocyclic ring (Scheme 21 ). Many reaction

manifolds have been used to effect this synthesis disconnection, including allylic amination (a) 64

16 hydroamination of alkynes (b),65 and conjugate addition reactions (c). 66 Other significant

methodologies include aminohalogenation of alkenes 67 and tandem reduction/C–N bond forming

protocols, beginning from nitroarenes.68 C–C bond forming approaches are less common, but

notably include multicomponent Povarov reactions.69

Pd(dba)2 (cat.) (S)-9-PBN LiOAc OAc (a) BSA NH N ° Ts THF, 20 C Ts

68%, 72% ee

Ph3PAuCH3 (cat.) (b) Ph NH N Ph 2 H O O P 97%, 97% ee O OH

° toluene, 25 C

Ar (cat.) O Ar OTMS O H NH (c) N H Cbz ° N CHCl3, -30 C Cbz H 70%, 92% ee

Scheme 21 : Examples of synthetic methods for synthesis of THQ by C aryl –N bond formation.

Methods for this C aryl –N bond formation approach necessarily proceed from an aryl amine rather than aliphatic amine nucleophile. The inverse disconnection of aliphatic amine and aromatic electrophile is largely inaccessible due to the lack of synthetic methods for aromatic ring

17 amination. However, Togo and co-workers have demonstrated that intramolecular amidation of 3- phenylpropylsulfonamides under photochemical conditions provides THQ products via sulfonamidyl radical intermediates ( Scheme 22 ). 70,71 This reaction is a variation on the Suárez

modification 72 to the Hofmann-Löffler-Freytag reaction, first reported in the 1880s, and most

commonly used for pyrrolidine synthesis. 73

O O PhI(OAc)2, I2 S N N H CF3 ° DCE, 70 C O S O hυ CF3 71% Scheme 22 : Intramolecular amidation to give THQ products as reported by Togo and co-

workers.

Inspired by Togo’s radical-based approach, our C–H functionalization based strategy begins from aryl iodide and aliphatic amine, thus inverting the conventional approach for C aryl –N

bond disconnection, which places the nucleophilic amine group on the aryl ring. This methodology

is a powerful complement to established methods for THQ synthesis, particularly for complex

THQs bearing stereogenic centers. Furthermore, aryl iodides and aliphatic amines are widely

available commercially and easily accessible via laboratory synthesis.

18

CHAPTER 2. SYNTHESIS OF 1,2,3,4-TETRAHYDROQUINOLINE VIA C–H

FUNCTIONALIZATION

2.1. Preliminary and optimization studies regarding the remote iodination reaction

Previously, we had observed that an IDCA approach to THQ synthesis performed poorly

(vide supra ). Building off of Yu’s early studies on THQ synthesis via C–H functionalization, we

envisioned that a sequence of picolinamide (PA)-directed sp 3 C–H arylation, followed by remote

C–H iodination, and finally cross-coupling, could provide a high yielding and versatile approach

(Scheme 23 ). From inception, it was clear the crux of the challenge would be achieving efficient

and selective iodination of the ortho C–H bond.

Remote C−H O C−H arylation iodination PA PA N I N I N I+ H N H H or + Pd(OAc)2 (cat.) Pd(OAc)2 /I

C−N cross coupling N PA

Scheme 23: Synthesis of THQ using the picolinamide auxiliary.

While the IDCA approach was unsuitable for a majority of 3-arylpropylpicolinamides, we were surprised to find that norbornane substrate 50 was notably more reactive and would undergo the reaction in good yield to give unique cyclized THQ product 51 (Scheme 24 ). The rigid norbornane scaffold is known to be especially reactive in similar reaction systems. 32,74

19

Pd(OAc)2 (cat.) PhI(OAc)2 (BnO)2PO2H N H ° N N toluene, 110 C PA O 50 51, 63%

Scheme 24 : Exceptionally reactive norbornane substrate 34 .

We turned towards the halogenation/cross-coupling approach for a more general strategy.

We were pleased to see that model substrate 52 reacted smoothly under conditions very similar to

Yu and coworkers’ (Scheme 25 ).22 We speculative a Pd(II)/Pd(IV) catalytic cycle is operative,

featuring oxidative addition with IOAc to give key palladacycle intermediate 53 .75 However, this reaction provided roughly equivalent amounts of mono- and di- iodinated products 54 and 55 .

Dissatisfied with this result, we sought a different solution.

O I N IV Pd N X I O L 53 PA + N I N PA Pd(OAc)2 (cat.) I N H N H PhI(OAc)2 H 55 52 I2 54, 44% , 37% ° DMF, 130 C

Scheme 25 : Pd-catalyzed C–H iodination approach for the halogenation of 52 .

In 2007, Barluenga and co-workers reported a uniquely ortho selective electrophilic

aromatic iodination reaction using bis (pyridine)iodonium (I) tetrafluoroborate (Barluenga’s

reagent) 76 with phenethyl trifluoroacetamide substrates (e.g. 56 ) in dilute acidic solvent ( Scheme

26 ). The authors observe remarkable selectivity for the more sterically hindered ortho position as

20 opposed to para (57 vs. 58 ). A single example of an ortho selective iodination reaction directed by the picolinamide group was presented. 77,78

- Py BF4 I+ Py H • NHCOCF NHCOCF HBF4 Et2O 3 3 N CF3 + I I O CH2Cl2/CF3CO2H ° 25 C 56 57, 85% 58, 3% (30:1 or tho:para)

Scheme 26 : Selective ortho iodination of phenethyl trifluoroacetamide substrates.

Barluenga and co-workers’ mechanistic model features a protonated amide intermediate stabilized by intramolecular hydrogen bonding ( Figure 5 ). An interaction between the fluorine

atoms of the trifluoroacetamide group and the iodonium cation provides a pathway for ortho - selective intramolecular aromatic iodination.

Y- R N O H

F F I+ F X

Figure 5 : Barluenga and co-workers’ proposed intermediate.

With 1.1 equiv of Barluenga’s reagent in mixed trifluoroacetic acid/dichloromethane solvent, desired product 60 was produced in excellent yield from substrate 59 (Table 1 , Entry 2).

We then observed that N-iodosuccinimide (NIS) was similarly selective when the reaction was cooled to 0 °C (Entry 3). Notably, the reaction performs poorly without tetrafluoroboric acid (Entry

7) and neither strong Lewis acid (Entry 5) or Brønsted acid (Entry 4) are satisfactory substitutes.

21

O I I+ PA N N + + H H N I I I 59 60 61 62

Entry Reagents (equiv) Solvents Temp 60 61/62

(°C)/h (% (%

yield) yield)

1 IPy 2•BF 4 (1.5), HBF 4•OEt 2 CF 3CO 2H/CH 2Cl 2 (1:10) 25/2 60 5/24

(3)

2 IPy 2•BF 4 (1.1), HBF 4•OEt 2 CF 3CO 2H/CH 2Cl 2 (1:10) 25/2 88 6/3

(2.2)

3 NIS (1.1), HBF 4•OEt 2 (4) CF 3CO 2H/CH 2Cl 2 (1:9) 0/4 90 4/3

4 NIS (1.1), TfOH (4) CF 3CO 2H/CH 2Cl 2 (1:9) 0/4 41 26/4

5 NIS (1.1), BF 3•OEt 2 (4) CF 3CO 2H/CH 2Cl 2 (1:9) 0/4 68 28/<2

6 NIS (1.5), HBF 4•OEt 2 (4) CF 3CO 2H/CH 2Cl 2 (1:9) 0/4 48 4/26

7 NIS (1.1) CF 3CO 2H/CH 2Cl 2 (1:9) 0/4 30 24/<2

Table 1 : Optimization of directed EAS reaction with NIS.

This iodinated intermediate 63 was cyclized via Buchwald-Hartwig type coupling under

Cu catalysis, using a procedure reported by Fukuyama and co-workers (Scheme 27 ).79 Reaction

of cyclized THQ 64 with sodium hydroxide or hydride reagents yielded deprotected product 65 .

We then explored the scope of this THQ synthesis strategy and explored the mechanism of the

iodination reaction ( vide infra ).

22

CuI (cat.) NaOH O ° CsOAc MeOH/H2O, 80 C, 81% N H N N N ° ° DMSO, 90 C PA or LiAlH4, THF, 0 C, 82% H I ° or LiEt BH, THF, 0 C, 86% 63 3 64, 93% 65

Scheme 27: Cyclization via C–N cross coupling, followed by deprotection via hydrolysis or

reduction.

In the course of our substrate scope studies, we observed strongly electron donating substituents overrode the directed EAS ortho selectivity, and directed EAS reactions of substrates

bearing strongly withdrawing groups did not react at all under the standard reaction conditions

(Scheme 28 ).

I O N O I • O HBF4 Et2O

N PA CH2Cl2/CF3CO2H N H N ° 0 C H

I I I H I H H H N N N PA N PA PA MeO PA OMe F NO2

Not observed 50% Not observed Not observed (5:4 ortho:x)

Scheme 28: Substrate scope limitations of the directed EAS reaction. x = unidentified iodinated

regioisomers.

23

To address this limitation in scope, a screen of reaction conditions for the selective ortho iodination of substrate 66 was conducted. Using the standard directed electrophilic iodination protocol, substrate 66 provides only para-iodinated product 68 (Table 2 , Entries 1 and 2). Using the Pd-catalyzed C–H iodination method we had previously dismissed for poor mono-iodination selectivity ( Scheme 25 ) we obtained moderate yields of the desired product 67 (Entry 3).

Interestingly, the undesired electrophilic aromatic substitution reaction can occur under these conditions, but is outcompeted by the catalytic process, as evidenced by the efficient formation of

68 under the standard reaction conditions without Pd catalyst (Entry 4). Other oxidant and solvent combinations are not selective for desired product 67 , including conditions employed for PA- directed benzylamine halogenation (Entries 5-9). 80 The yield was of 67 was improved by manipulating the alkali carbonate base. While use of K 2CO 3 (Entry 10) or 2 equiv of KHCO 3 results in diminished reaction yield (Entry 11), a single equivalent of KHCO 3 (Entry 12) or Na 2CO 3

(Entry 13) provide improved yield.

OMe OMe O OMe I+ PA N N + H 24hrs H N I 66 67I 68 Entry Reagents (equiv) Solvent T (oC) % yield

67 68

1 NIS (1.5), HBF 4 • EtO 2 (4.0) CF 3CO 2H/ 0 <2 68

CH 2Cl 2

2 NIS (1.5) CF3CO2H/ 0 <2 82

CH2Cl2

3 Pd(OAc) 2 (10 mol%), I 2 (2.0), PhI(OAc) 2 (2.0) DMF 110 43 25

24

4 I2 (2.0), PhI(OAc) 2 (2.0), KHCO 3 (1.0) DMF 110 <2 64

5 Pd(OAc) 2 (10 mol%), NIS (1.5) chlorobenzene 110 <2 74

6 Pd(OAc) 2 (10 mol%), NaI (1.5), NaIO3 (1.5), n-BuOH 110 <2 <2

K2S2O8 (2.0)

7 Pd(OAc) 2 (10 mol%), I 2 (2.0), K 2S2O8 (2) DMF 110 <2 60

8 Pd(OAc) 2 (10 mol%), I 2 (2.0), PhI(OAc) 2 DCE 110 16 58

(2.0), KHCO 3 (1.0)

9 Pd(OAc) 2 (10 mol%), I 2 (2.0), PhI(OAc) 2 dioxane 110 13 65

(2.0), KHCO 3 (1.0)

10 Pd(OAc) 2 (10 mol%), I 2 (2.0), PhI(OAc) 2 DMF 110 14 11

(2.0), K 2CO 3 (1.0)

11 Pd(OAc) 2 (10 mol%), I 2 (2.0), PhI(OAc) 2 DMF 110 45 12

(2.0), KHCO 3 (2.0)

12 Pd(OAc) 2 (10 mol%), I 2 (2.0), PhI(OAc) 2 DMF 110 75 9

(2.0), KHCO 3 (1.0)

13 Pd(OAc) 2 (10 mol%), I 2 (2.0), PhI(OAc) 2 DMF 110 80 8

(2.0), Na 2CO 3 (1.0)

Table 2 : Optimization of Pd-catalyzed remote C–H iodination of 3-phenylpropylpicolinamides.

Thus, two complementary solutions for this ε C–H iodination were found: a Pd-catalyzed

C–H iodination reaction or a directed electrophilic aromatic iodination reaction (e.g. 69 to 70 ,

Scheme 29 ). Cyclization of the iodinated products under Cu catalysis yields the THQ scaffold 71 .

25

I O N O

• HBF4 Et2O

CF3CO2H/CH2Cl2 ° 25 C, 82% O CuI (cat.) CsOAc N PA H N ° 69 I N DMSO, 90 C N H 93% PA Pd(OAc)2 (cat.) 70 71 PhI(OAc)2 I2

° DMF, 130 C, 48%

Scheme 29 : Approach to THQ synthesis using remote C–H iodination reactions.

2.2. Scope of THQ synthesis

2.2.1. Scope of C–H arylation

A variety of 3-arylpropylamine derivatives were prepared via sp 3 C–H arylation for transformation ultimately into THQ products (Scheme 30 ). Notably, the arylation of methylene

C–H bonds provides poor yield of product and requires more forcing conditions (e.g. 74 ). Aryl iodides bearing bulky ortho substituents provide considerably lower yield of arylated product (e.g.

80 and 83 ), however smaller ortho substituents are less problematic (e.g. 81 and 84-86 ).81 1,2-

Dihalides provided poor yield of arylated product (e.g. 87 ). Further arylation at the benzylic position of our mono-arylated products to give di-arylated compounds was not observed.

Substrates bearing α substituents exhibited increased reactivity, likely due to the Thorpe-Ingold effect. 82

26

Pd(OAc)2 (cat.) H I Ag2CO3 N N PA H (BnO)2PO2H N + toluene/t-amylOH, 110 °C O

Cl Br H H H N N N PA PA PA

72, 54%b 73, 40% 74, 29% CF H Cl 3 H N H PA N Cl PA N CO2Me O O PA CF3

75, 82% 76, 83% 77, 81% CO2Me F OMe H H H N N N PA PA PA

78, 86% 79, 87% 80, 36%b OMe H NO 2 H N H PA N N PA PA

81, 81% 82, 81% 83, 28%b

F

F I H H H N N N H PA PA PA N PA 84, 60% 85, 94% 86, 58% 87, 31%

Scheme 30 : sp 3 C–H arylation of propylpicolinamides to give 3-arylpropylpicolinamides.

bPrepared under different reaction conditions, using excess of aryl iodide as solvent.

27

2.2.2. Scope of C–H iodination: Directed EAS

These 3-arylpropylpicolinamide intermediates were then subjected to ortho iodination under our optimized reaction conditions with NIS ( Scheme 31 ). Substrates bearing aryl esters, halogens, and alkyl groups perform very well, while substrates bearing more strongly withdrawing or donating functionality were problematic. Good yields were obtained from certain electron-poor substrates using additional equivalents of NIS and HBF 4 • Et 2O at 25 °C (e.g. 94-96 ). For meta substituted aromatics, complete selectivity was observed for the less hindered ortho position (e.g.

90 , 91 , and 96 ). Just as in the arylation reactions, the Thorpe-Ingold effect confers increased yields to α substituted substrates (e.g. 88 vs. 89 ). Fluorine exerts a powerful para directing effect in EAS reactions. 83,84 As a result, while a m-fluoro substrate gave desired product 97 , ortho - fluoro substrates gave undesired products 98 and 99 .

28

I O N N H O N H HBF • Et O N O 4 2 PA I CH2Cl2/CF3CO2H ° 0 C

I I H H I H N N PA PA N PA

88, 82% 89, 83% 90, 88% (12:1 ortho:para) (13:1 ortho: x) (12:1 ortho: x)

I I Br I H H H N N N PA Cl PA PA CO2Me 91, 90% 92, 92% 93, 74% (12:1 ortho:x) (20:1 or tho:x) (4:1 ortho:di-ortho)

CF3 Cl I H I I H H N Cl PA N N O O PA MeO2C PA CF3 94, 75% 95, 82% 96, 77% (15:1 ortho:x)b (15:1 ortho:x)b (20:1 ortho:x)b

F I I H N H F PA I N H PA N F PA 97, 81% 98, 89% 99, 90% (20:1 ortho:para) (12:1 para:x) (12:1 para:x)

Scheme 31 : Iodination of 3-arylpropylpicolinamides. Yields are isolated yield of desired mono

ortho -iodinated product. x = Unidentified iodinated regioisomers. di-ortho = corresponding di-

b ortho iodinated product. More forcing conditions at 25 °C with excess NIS and HBF 4 • Et 2O.

29

2.2.3. Scope of C–H iodination: Pd-catalyzed C–H functionalization

PA-directed, Pd-catalyzed C–H iodination works well for many substrates that are too

activated or deactivated for directed electrophilic iodination ( Scheme 32 ). A significant

shortcoming of the Pd-catalyzed method is that the yield of mono-iodinated product from para

substituted or unsubstituted substrates will be diminished due to formation of an ortho di-iodinated

product (e.g. 84 ). However, substrates bearing ortho or meta NO 2, F, and OMe groups, which are

incompatible with the directed electrophilic iodination method, were selectively iodinated in good

yield. Arenes bearing meta-substituents (e.g. 104 ) were selectively iodinated at the less hindered

ortho position. Notably, the rigid aryl norbornane scaffold is incompatible with directed EAS

protocol, but was iodinated selectively at the ortho position under Pd-catalyzed conditions to give

106 and 107 without the formation of regioisomeric side products.

30

Pd(OAc)2 (cat.) PhI(OAc)2,I2 I O NaHCO3

° PA N DMF, 130 C N H N H

I I I H H H N N N PA PA PA I 100, 72% OMe 101 (2:1 mono:di) , 75% 102, 72%

I I I H H H N N N PA MeO PA PA NO2 F 104, 68% 105, 65% 103, 68%

F

I I NH NH PA PA b 106, 85% 107, 56%

Scheme 32 : PA-directed, Pd-catalyzed C–H iodination of 3-arylpropylpicolinamide derivatives.

b Performed with Na 2CO 3 rather than NaHCO 3.

2.2.4. Scope of Cu-catalyzed C–N cross coupling

Subjecting our iodinated intermediates obtained via directed EAS and Pd-catalyzed C–H iodination to Cu-catalyzed cross coupling provided THQ products (Scheme 33 ). THQ 112 bearing an α CF 3 substituent was partially hydrolyzed under the basic cyclization conditions. Overall, the scope of this tetrahydroquinoline synthesis was found to include THQs bearing alkyl, ester, and

31 trifluoromethyl substituents at each saturated position (C2-C4). Targets bearing substituents at aromatic positions C5-C7 are accessible, but meta substituted substrates (e.g. 117 ) are iodinated

selectively at the less hindered ortho position, preventing the synthesis of THQs bearing solely C8

aromatic substituents.

CuI (cat.) CsOAc PA N ° H DMSO, 90 C N I PA

Cl

N N Br N N CO2Me PA PA PA PA

108, 83% 109, 87% 110, 80% 111, 82%

Cl O O MeO2C F

N N Cl N CF3 N PA CF3 PA PA PA

112, 79%b 113, 72% 114, 80% 115, 81%

F NO2 MeO

N N N N N PA PA PA PA PA 116, 96% 117, 94% 118, 47% 119, 85% 120, 78% Scheme 33 : Cyclization of iodinated 3-arylpropylpicolinamides to THQ derivatives via Cu

catalyzed C–N cross coupling. bCombined yield of PA-coupled (24%) and deprotected (48%)

product.

32

2.3. Synthesis of (+)-angustureine

(–)-Angustureine 121 one of several THQ alkaloids isolated from the bark of Angostura trifoliata , a shrub indigenous to the mountains of Venezuela (Figure 6 ).85,86 Extracts of this bark have been used in Venezuelan folk medicine to treat dyspepsia, dysentery, diarrhea, and fever, and isolated angustureine exhibits promising activity against chloroquine-resistant strains of malaria.

Due to their chirality and moderate complexity, angustureine and its congeners have become benchmarks for new THQ synthesis methodology.87

OH N N

OCH3 121, angustureine 122, galipeine

OCH3 N N O O OCH3 123, cuspareine 124, galipinine

Figure 6 : THQ alkaloids isolated from Angostura trifoliata.

The absolute configuration of natural angustureine was assigned by total synthesis by Zhou

and co-workers in 2003.88 Ir-catalyzed hydrogenation of 125 using the biaryl chiral phosphine ligand (R)-MeO-Biphep provided 126 . Reductive amination of 126 yielded 127 , which matched the optical rotation of natural angustureine. Zhou and co-workers later reported a similar synthesis of (+)-angustureine via enantioselective Ir-catalyzed hydrogenation with (S)-segphos ligand. 89

33

Several other authors have demonstrated concise enantioselective hydrogenation approaches for angustureine and congeners.61,90,91

[Ir(COD)Cl]2 (R)-MeO-Biphep HCHO, HOAc

N N I2, toluene H NaBH3CN ° H2 (700 psi) 25 C 125 ° 126 25 C , 92%, 94% ee

N

127 (−)-angustureine 94%

Scheme 34 : Synthesis of (–)-angustureine via Ir-catalyzed enantioselective hydrogenation.

In comparison, enantioselective syntheses that involve construction of the heterocyclic ring generally require longer synthetic sequences. Yamamoto and co-workers used an intramolecular hydroamination of 128 , providing 129 , in route to (–)-angustureine ( Scheme

35 ). 92 8 steps were required to arrive at 128 from 2-iodoaniline.

34

Pd2(dba)3 I 8 steps (R,R)-RENORPHOS NH N Pr NH ° 2 Pr toluene, 120 C

128 129 48%, 52% ee Pd/C

H2

° MeOH, 25 C N H

(−)-angustureine 85%

Scheme 35 : Synthesis of (–)-angustureine via intramolecular hydroamination.

Fustero and co-workers subjected 130 to organocatalytic intramolecular conjugate

addition to produce the THQ scaffold in their synthesis of (+)-angustureine (Scheme 36 ).66

Preparation of 130 from 2-nitrophenylacetic acid required six steps.

organocatalyst (cat.) COOH O O 6 steps PhCO2H NH H N H ° CHCl , -30 C NO2 Cbz 3 Cbz 130 131, 68% >90% ee 3 steps

N 52%

+ ( )-angustureine

Scheme 36: Synthesis of (+)-angustureine via intramolecular conjugate addition.

You and co-workers achieved the synthesis of (–)-angustureine via an allylic amination

reaction (Scheme 37 ).93 Ir-catalyzed allylic amination of o-aminostyrene 132 and allyl diethyl

35 phosphate 133 provided 134 . Protection with trifluoroacetate followed by ring closing metathesis

using a modified 2 nd generation Hoveyda-Grubbs catalyst provided 1,2-dihydroquinoline

derivative 135 . Reduction and methylation provided (–)-angustureine.

[Ir(dbcot)Cl]2 (cat.) phosphine ligand

K3PO4 + H C5H11 OPO(OEt)2 N ° NH2 THF, 50 C (2 steps) 133 134 132 , 91%

1) TFAA, NEt3 CH2Cl2, 0 °C 3 steps N N 2) 2 mol% Ru catalyst COCF3 ° toluene, 80 C (−)-angustureine 135, 87% 80%

Scheme 37 : Synthesis of (–)-angustureine via Ir-catalyzed allylic amination.

Two further approaches which bear resemblance to You and co-workers’ synthesis are

worthy of mention. Several years earlier, Nishida and co-workers used a Mitsunobu reaction of

136 and 137 to access 138 , which was then subjected to a similar RCM reaction to produce 139 in

route to (+)-angustureine (Scheme 38a ).94 Concurrently with You and co-workers, Helmchen and co-workers used a Ir-catalyzed allylic amination of 140 and 141 to provide intermediate 142 .

Following hydroboration of 142 to give 143 , intramolecular Suzuki coupling provided produced

(+)-angustureine (Scheme 38b ).95

36

(a) + NH HO N Ts Ts 136 137 138

N Ts 139

Br Br Br (b) OCO2Me + NH NH C H NH2 5 11 C5H11 C5H11 BR2 140 141 142 143

N H 144

Scheme 38 : Other approaches to angustureine featuring RCM (a) and allylic amination/Suzuki

coupling (b).

We sought to demonstrate the utility of our methodology by synthesizing (+)-angustureine via C–H functionalization (Scheme 39 ). Beginning from (S)-3-octanol, Mitsonubo reaction with phthalimide, imide hydrazinolysis and amide coupling provided picolinamide 145 . Arylation of

145 with iodobenzene proceeded in good yield to give 146 , and iodination followed by cross coupling generated the THQ scaffold 148 . Finally, deprotection and methylation provided (+)-

angustureine 149 . This synthesis represents a conceptually unique strategy to angustureine synthesis, which is competitive with other approaches featuring C–N bond formation.

37

I

3 steps H HN HO N 38% Pd(OAc)2 (cat.), Ag2CO3, ° PA PA 145 toluene, 110 C 146, 83%

O I CuI (cat.) O N I CsOAc • N HBF4 Et2O HN ° DMSO, 90 C PA CH2Cl2/CF3CO2H PA ° 148 0 C 147 (81%, 2 steps)

2 steps N 79% 149 (+)-angustureine 20% yield (8 steps)

Scheme 39 : Synthesis of (+)-angustureine via PA-directed C–H functionalization.

Boysen and co-workers later used a directed iodination protocol inspired by our own to complete their synthesis of the THQ drug candidate vabicaserin (Scheme 40 ).96

38

I O N O O O CF3 CF3 O CF3 CuI (cat.) I NH • NH HBF4 Et2O CsOAc N

CH2Cl2/CF3CO2H DMSO ° ° -20 C 90 C 98% 94% (86:14 or tho:par a)

HN

N

(+)-Vabicaserin

Scheme 40 : Synthesis of vabicaserin via directed EAS/C–N cross coupling reported by Boysen

and co-workers.

2.4. Scope of directing groups for directed EAS

To broaden the scope of this underutilized directed iodination chemistry and gain insight into the mechanism, a variety of substrates bearing different directing groups were prepared and subjected to our standard iodination protocol (Scheme 41 ). Several bidentate directing groups employed for metal-catalyzed C–H functionalization were capable of directing the iodination reaction: Yu-Wasa auxiliary 159 ,97 8-aminoquinoline 160 ,39 and pyridylmethylamine 161 .98

However, pyridyl sulfonamide 158 , a common C–H functionalization auxiliary, 99 did not provide ortho selectivity. The highest yield of ortho iodinated product was obtained from 2- phenylethylpicolinamide compound 154 , with shorter linker lengths (e.g. benzylpicolinamide 153 )

39 and longer linker lengths (e.g. 4-phenylbutylpicolinamide 155 ) providing diminished yield. The

results from substrates 150 -152 will be discussed in detail in Section 2.5.2.

I O N O DG DG n • n HBF4 Et2O

CH2Cl2/CF3CO2H ° 0 CI

O O O N N H O N N I I 150, 99% I 151, 97% 152, 97% (3:5 ortho:par a) (3:5 ortho:para) (6:1 ortho:para)

H H N H N PA N PA I PA I 153, 88% 154, 98% I 155, 90% (2:1 ortho:par a) (24:1 or tho:para) (3:1 ortho:para)

O O O O O S N CF3 S N H N CF3 H H I N I I 156, 90% 157, 98% 158, 92% (12:1 ortho:para) (3:5 ortho:para) (1:3 ortho:para)

F F CF O O 3 O N N F N H H H N F N I I I 159, 98% 160, 91% 161, 96% (7:1 ortho:par a) (9:1 ortho:para) (2:1 ortho:para)

Scheme 41 : Scope of directing groups capable of effecting directed electrophilic iodination.

40

2.5. Directed EAS: Precedent and mechanistic hypothesis

2.5.1. Precedent for directed EAS

To explain the ortho selective iodination of trifluoroacetamides with Barluenga’s reagent,

Barluenga proposed a mechanistic model where acceptance of a hydrogen bond by the trifluoromethyl group stabilized a protonated amide intermediate, and an interaction between fluorine and iodonium cation results in intramolecular delivery of iodonium and ortho -selective

EAS (Figure 7 ).

Y- R N O H

F F I F X

Figure 7: Mechanistic model proposed by Barluenga.

Directing effects in electrophilic aromatic substitution were first observed in 1927, when

Skraup observed ortho selectivity in the bromination of phenol (Scheme 42a).100 More recently, several authors have reported directed ortho halogenation of phenols (e.g. 165 ) using amine catalysts (e.g. 166, Scheme 42b ). In these systems, N-haloamines are formed in situ and hydrogen bonding between the amine N and phenol O–H group is invoked to explain selectivity (e.g.

169 ).101–105 However, isolated chloroamines are not competent chlorinating reagents, so this

mechanistic model is likely incomplete.

41

O Na NaOBr, H2O; OH OH (a) + H O+ 3 Br Br

162 163 164 H 2 : 1 N

(cat.) 166 SO2Cl2 (b) OH OH + OH ° benzene, 25 C Cl Cl tBu 165 O 167, 95% 168, 1% H Cl N

169

Scheme 42 : Directed halogenations of phenol.

Directed EAS reactions of alkylbenzenes bearing distal carbonyl functionality have been widely observed with halogen and nitronium electrophiles. Wigfield and co-workers examined directed ortho nitration of acetanilides in 1967 (Scheme 43 ).106 They observed that nitration of

170 in mixed sulfuric and nitric acid yields almost entirely para -nitrated acetanilide 172 (Scheme

43a). However, reaction with preformed nitronium reagents NO 2BF 4 or NO 2OAc results selective

formation of the ortho nitration product 171 (Scheme 43b). They implicate 173, bearing an O–

NO 2 bond, as the key intermediate leading to ortho selective electrophilic aromatic substitution.

42

H NO2 H H SO , HNO H N N 2 4 3 N (a) + O ° O 0 C O O2N

170 171, 4% 172, 71%

H NO2 H NO2BF4 H N N N (b) + O ° O CH3CN, -30 C O O2N

170 H 171, 72% 172, 18% N

O NO2 X-

173

Scheme 43: Directed ortho -nitration of acetanilide as reported by Wigfield and co-workers.

Similarly, in 1998, Strazzolini and co-workers performed the nitration of various

alkylbenzenes using dilute HNO 3 in CH 2Cl 2 and compared the results to the outcomes of

107 conventional nitrations in mixed H2SO 4/HNO 3 (Scheme 44 ). For ester substrate 174 , conventional mixed acid nitration provided equal amount of ortho and para nitration products

(Scheme 44a). However, nitration of 174 with dilute HNO 3 in CH 2Cl 2 resulted in selective formation of ortho nitration product 175 (Scheme 44b ). The authors implicate 177 , bearing an O–

NO 2 bond, as a key intermediate which decomposes via intramolecular ortho - selective

electrophilic aromatic substitution. Dilute HNO 3 in CH 2Cl 2 also effected the ortho -selective nitration of carboxylic acids, esters, carboxamides, aldehydes and ketones (e.g. 178 , Scheme 44c ).

43

NO2 O HNO3,H2SO4 O O + O ° O (a) 0 C O O2N

174 175, 50% 176, 50%

NO2 O HNO3 O O + (b) O O ° O N CH2Cl2, 0 C O 2

174 O 175, 82% 176, 18%

O NO2 177

NO2 HNO3 + O (c) O ° O N CH2Cl2, 0 C O 2

178 179, 91% 180, 5% Scheme 44 : Directed ortho nitration of alkylbenzenes as reported by Strazzolini and co-workers.

In 2006, Easton and co-workers studied the chlorination of phenylalkylamines and

phenylalkylamides.108 Subjecting substrate 181 to chlorination in acetic acid solvent resulted in a

60:40 mixture of 182 and 183 . However, conducting the chlorination of 181 in α,α,α- trifluorotoluene or CCl 4 solvent resulted in the selective formation of ortho- chlorinated product

182 (Scheme 45a). The authors noted the formation of a precipitate immediately following the addition of amine to Cl 2 solution. Isolation and characterization of this precipitate revealed it to be

N-chloroamine hydrochloride 184 , and propose decomposition of 184 via intramolecular electrophilic aromatic chlorination yields ortho chlorinated products. Phenylalkylamides (e.g. 185 ) also undergo ortho selective chlorination under similar conditions ( Scheme 45b ).

44

Cl NH2 2 NH2 NH2 (a) + ° CCl4, 25 C Cl Cl

181 H 182, 85% 183, 5% N Cl • HCl 184

Cl2 NH2 NH2 NH2 + (b) O ° O O PhCF3, 25 C Cl Cl

185 186, 60% 187, 30% Scheme 45: Selective ortho chlorination of phenylalkylamines and phenylalkylamides as

reported by Easton and co-workers.

The authors observe the formation of 189 in the chlorination reaction of phenylalkylamide

188 . However, isolated 189 is stable for extended periods in CCl 4 solvent at 25 °C. Supported by kinetics data, they propose that in the presence of Cl 2 and HCl, O-chloroimidate 190 exists in equilibrium with starting material 188 and N-chloroamide 189 , and that 190 , bearing an O–Cl bond, is the reactive intermediate in the ortho selective chlorination reaction (Scheme 46 ).

45

Cl 2 H NH N 2 Cl O HCl O 188 189

HCl, Cl2 HCl, Cl2

NH

O Cl 190

Scheme 46 : Proposed intermediacy of O-chloroimidate.

In a 2010 report, Miller and co-workers reported an enantioselective bromination of

biaryls using a peptide organocatalyst. Their mechanistic model invokes hydrogen bonding

between the biaryl and organocatalyst, which delivers the bromonium cation from a carbonyl O–

Br bond.109

2.5.2. Mechanistic hypothesis

Several of the compounds examined in our directing group study were chosen to provide insight into potential intermediates of the directed EAS iodination reaction (Figure 8 ). Substrates

191 -193 were subjected to the iodination reaction under the standard conditions, and their

performance in the directed iodination reaction was extended to the general substrate 194 to rule

out potential intermediates ( Figure 9 ).

46

O O O

N O N H N N I I I 191, 97% 192, 97% 193, 99% (6:1 ortho:par a) (3:5 ortho:para) (3:5 or tho:para)

O

N H N I 194, 82% (12:1 ortho:para)

Figure 8 : Key control substrates for directed EAS iodination.

The effectiveness of N-methylated substrate 191 rules out intermediates featuring

coordination of the iodonium cation by the amide N, such as 195 and 196 (Figure 9 ). However,

the ineffectiveness of ester 192 suggests that the amide N is still critical for the directing mechanism. Thus, we assumed that the amide N participates in the directing mechanism through the formation of a protonated amide intermediate, as shown in potential intermediates 195-200 .

Substrate 192 also demonstrates that the pyridyl N is not the sole coordinating moiety for

the iodonium cation (e.g. intermediate 197 ). Intermediate 198 , featuring chelation of the iodonium cation by both the amide O and pyridyl N, is feasible . However, a chelating interaction with the

iodonium cation is unlikely given the observed preference for 10 electron iodine complexes to

exist in a linear geometry. 110,111

Finally, the ineffectiveness of benzamide 193 demonstrates that the pyridyl N is still necessary for the directing mechanism, ruling out intermediate 199 . The pyridyl N could participate in the directing mechanism through stabilization of the protonated amide intermediate via intramolecular hydrogen bonding (e.g. 200 ).

47

L + O OH I HO Ph N Ph N Ph N N H N I+ I+ H N L L 195 197 199

L I+ + O HO I H O N Ph N Ph N N Ph N N H I+ H

196 198 200

Figure 9 : Potential intermediates in the directed EAS iodination reaction.

Alternatively, a similar 8 electron iodine complex can be formulated, with the protonated pyridine N donating a stabilizing intramolecular hydrogen bond ( 201 , Figure 10 ).

I O H N Ph N H

201 Figure 10: All-octet intermediate stabilized by intramolecular hydrogen bonding.

Thus, the overall mechanistic model is as follows. The rate determining step in this directed

EAS reaction is the formation of arenium ion due to the endothermic loss of aromaticity. We envision the iodonium cation is present in the reaction solution as a variety of species, bearing trifluoroacetic acid, diethyl ether, water, succinimide, or tetrafluoroborate ligands. Coordination of iodonium by the substrate through the amide O, with a supporting hydrogen bonding interaction from the pyridyl N (e.g. 200 or 201 ), provides a lower energy intramolecular EAS transition state, allowing it to kinetically outcompete the intermolecular reaction. However, in light of recent

48 studies demonstrating the intermediacy of arene-halogen charge-transfer complexes,112–116 and the plausibility of mechanistic pathways not involving arenium ions, 117 this mechanistic model is

likely oversimplified.

2.6. Synthesis of iodo-THQ isomers

To demonstrate the utility of this strategy, we synthesized iodinated THQ compounds 202 -

205 from common intermediate 206 (Scheme 47 ). Pd-catalyzed C–H iodination of 207 gave 208 , which was cyclized to give 5-iodo THQ 202 . 6-iodo THQ 203 was obtained through electrophilic aromatic iodination of 210 with NIS; substitution occurs cleanly at C7 due to the presence of the activating amino substituent. Subjecting 206 to sp 3 C–H arylation with 1,4-diiodobenzene gave

211 , which was ultimately transformed into 7-iodo THQ 205 . The synthesis of 8-iodo THQ 204 presented a challenge, as mono C8 substituted THQs are not accessible via directed EAS or Pd- catalyzed C–H iodination. To synthesize 204 , a PA-directed sp2 C–H iodination reaction of THQ

210 was developed. In α,α,α-trifluorotoluene solvent, the competing EAS process is effectively suppressed, and 210 undergoes a selective Pd-catalyzed sp 2 C–H iodination at C8. Several groups

have published similar C–H functionalization reactions of THQ at the C8 position. 118–121

49

Pd(OAc)2 (cat.) I O I N H N I Ag CO Pd(OAc)2 (cat.), Ag2CO3 2 3 ° ° toluene, 110 C 206 toluene, 110 C 67% 39%

PA N 207 H • PA NIS, HBF4 Et2O I N H CH2Cl2/CF3CO2H 211 Pd(OAc) (cat.), ° 2 0 C, 76% PhI(OAc)2,I2, KHCO3, ° DMF, 130 C NIS • 69% HBF4 Et2O CH2Cl2/CF3CO2H PA ° I N 0 C H 209

CuI (cat.), CsOAc, ° DMSO, 90 C, 93% I PA I I N H 212 PA I N N H 210 PA 208 CuI (cat.) CuI (cat.) CsOAc NIS ° Pd(OAc)2, NIS DMSO, 90 C CsOAc CH Cl /CF CO H ° ° 2 2 3 2 PhCF , 110 C DMSO, 90 C ° 3 62% (2 steps) 0 C, 88% 55% 69%

I I

N N I N N PA I PA PA PA 5-iodo-THQ 6-iodo-THQ 8-iodo-THQ 7-iodo-THQ 202 203 204 205

Scheme 47 : Synthesis of aryl-I THQ regioisomers via C–H functionalization.

50

CHAPTER 3. ARYL CYCLOALKANE SYNTHESIS VIA C–H

FUNCTIONALIZATION

3.1. Introduction: Aryl cycloalkanes in natural products

Aryl cycloalkane motifs are present in terpenoid and lignan natural products. As a result, cycloalkyl substrates have been recognized as key model substrates for C–H functionalization reactions. A cyclohexane substrate was included in Daugulis’ original 2005 report of the 8- aminoquinoline bidentate directing group ( Scheme 48 ). 39,40 Cyclohexane carboxylic acid substrate

213 , when subjected to the general sp 3 C–H bond arylation protocol, produced homo-di-arylated

compound 214 with cis diastereoselectivity.

OMe

Pd(OAc)2 (cat.) AgOAc O I O + AQ N N H MeO ° H N Neat, 90 C 213 OMe 214, 69%

Scheme 48 : First example of bidentate-auxiliary directed functionalization of a cycloalkane.

Later, Pd-catalyzed bidentate-auxiliary directed C–H functionalization of a cycloalkane was a key step in Baran’s synthesis of the proposed structure of multiple psuedodimeric cyclobutane natural products,122–124 Maimone’s synthesis of podophyllotoxin, 125 and Sun’s

synthesis of scopariusicide A (Figure 11 ).126

51

MeO OMe OH O O O O O OMe OMe N O H O O H CH3 N O O MeO H CH3 O CH O MeO OMe 3 MeO OMe

piperarborenine B podophyllotoxin scopariusicide A (Baran 2011) (Maimone 2014) (Sun 2015)

Figure 11: Natural products synthesized using directed sp 3 C–H arylation; arrows indicate the

bond formed.

Many groups have contributed to the development of C–H functionalization reactions of

cycloalkanes. Yu and co-workers have reported enantioselective C–H functionalizations of the

smaller cycloalkanes: cyclopropane 127 and cyclobutane, 128 as well as cyclopropylmethylamines. 129

Other authors have contributed reports describing Pd-catalyzed bidentate-auxiliary directed C–H functionalization for the modification of saturated heterocycles 130–134 norbornanes, 74 cyclopropanes, 135,136 cyclobutanes, 137 as well as larger rings 138 and more complex fused rings, adamantane 139 and pinanamine 140 (bicyclo[3.1.1]heptan-3-amine). Shuto and co-workers disclosed a unique functionalization of a tertiary C–H bond of cyclopropane to give a quaternary center, a rarity in bidentate C–H functionalization reactions proceeding through organometallic mechanisms.141,142 However, a recent publication describing a failed C–H functionalization

approach to the synthesis of an indane-containing natural product illustrates that this methodology

is still challenging to apply and requires further development.143

52

3.2. Optimization of room temperature C–H arylation reaction

The 8-aminoquinoline (AQ) directing group facilitates the most diverse array of transformations and can functionalize electronically and sterically challenging sp 3 C–H bonds. 144

However, when we entered this area in 2014, no mono-selective C–H functionalization protocol for the desymmetrization of cycloalkane carboxylic acids had been reported. Previously, we developed a successful solution to a similar mono-selectivity issue in the sp 3 C–H bond arylation of alanine substrate 215 through extensive optimization, enabling the reaction to run at room temperature ( Scheme 49 ). 145 At room temperature, phenylalanine product 216 was obtained in good yield, whereas at elevated temperature 217 was the major product. Accordingly, we sought

more optimized reaction conditions that would allow us to run the arylation reaction of 218 at a lower temperature, hopefully providing the desired mono-arylated product 219 via kinetic control in a similar fashion (Table 3 ).

Pd(OAc)2 (cat.) O O O NPhth AQ NPhth AQ PhI, AgOCOCF3 NPhth N N N H + H H N TCE/H2O ° 25 C

215 216, 88% 217, <2%

Scheme 49: Room temperature arylation of 8-aminoquinoline coupled alanine.

Reaction of 218 under previously reported conditions at elevated temperature gave di- arylated product 220 as the major product (Entries 1 and 2). Reaction conditions using AgOCOCF 3 base, which was uniquely effective in our previous alanine mono-arylation reaction, gave little product (Entries 3-6). However, Ag 2CO 3 base in dichloromethane or 1,1,2,2-tetrachloroethane was

53 more effective, providing the desired mono-arylated product in good yield after 2 days at room temperature (Entries 7 and 8). Other solvents were notably less effective (Entries 9-11).

Surprisingly, commonly used carboxylic acid additives provided diminished yield (Entries 12 and

13). 146

MeO MeO Pd(OAc)2 (10 mol%) O ArI (2 equiv) O + AQ N O N H N AQ H N H

OMe 218 219 220

Entry Reagents (equiv.) Solvents T (°C)/ time (h) % Yield % Yield

219 220

1 AgOAc Neat 70/24 <5 73

2 AgOAc (2) toluene 110/24 38 62

3 AgOCOCF 3 (2) dioxane 25/48 <5 <5

4 AgOAc (2), CF 3CO 2H (2) dioxane 25/48 <5 <5

5 AgOCOCF 3 (2) tAmylOH 25/48 <5 <5

6 AgOCOCF 3 (2) CH 2Cl 2 25/48 <5 <5

7 Ag 2CO 3 (1) CH 2Cl 2 25/48 85 <5

8 Ag 2CO 3 (1) TCE 25/48 85 <5

9 Ag 2CO 3 (1) toluene 25/48 21 <5

10 Ag 2CO 3 (1) dioxane 25/48 11 <5

11 Ag 2CO 3 (1) tAmylOH 25/48 15 <5

54

12 Ag 2CO 3 (1), AcOH CH 2Cl 2 25/48 71 <5

13 Ag 2CO 3 (1), PivOH CH 2Cl 2 25/48 68 <5

Table 3 : Optimization of the mono-arylation of substrate 218 .

3.3. Scope of cycloalkane derivatives

A series of cycloalkyl substrates was prepared and subjected to the reaction conditions

(Scheme 50 ). Yield, diastereoselectivity, and mono- vs. di- arylation selectivity were observed to be highly substrate dependent. Cyclopropyl substrate 221 did not react at 25 °C, but we were pleased to see that higher homologs up to cycloheptane 225 were arylated in good-to-moderate yield. The yield of arylated product clearly decreases with increasing ring size from cyclobutane

222 to cycloheptane 225 . Acyclic substrates 226 -229 were less reactive, with the exemption of 2- ethylbutyric acid substrate 226. The greater reactivity of 226 is surprising, as the functionalization of methyl C–H bonds is generally more facile than that of methylene C–H bonds in similar reaction systems. Conformational rigidity imposed by syn pentane strain best explains the difference in yield between 2-ethylbutyric acid substrate 226 and 2-methylpropanoic acid substrate 230 .

We were disappointed to find that several heterocyclic substrates did not react usefully at

25 °C (e.g. Proline substrate 230 ). Bicyclic substrates (e.g. 231) were also unreactive, as previously reported. 143 Similarly, α substituted substrates (e.g. methyl cyclohexane substrate 232 ) have

previously been recognized as poorly reactive in these Pd-catalyzed, bidentate-auxiliary directed

sp 3 C–H functionalization systems, 124 and no α substituted substrates provided arylated product at

25 °C.

55

The effect of substitution at other positions of the cycloalkanes was unpredictable. For example, stereoisomeric 1,4-aminocyclohexane carboxylic acids 233 and 234 exhibited notably

divergent reactivity. The cis isomer 234 provided yields of arylated compound greater than that of

the parent cyclohexane. In contrast, trans stereoisomer 233 provided poor yield of arylated

compound. Yu and co-workers made a similar observation in a related Pd-catalyzed C–H

iodination reaction system directed by an oxazoline group. 147 The low reactivity of 230-232 is

difficult to rationalize, but the disparate reactivity of 233 and 234 can be rationalized by analysis of conformational analysis of the intermediate palladacycles (vide infra ).

56

OMe Pd(OAc) (cat.) 2 R O Ag2CO3 R O ° AQ CH2Cl2, 25 C N O H N + AQ I R R N H N R H OMe R MeO OMe O O AQ O N AQ AQ O H N N AQ H H N H

OMe OMe OMe

222, 96% 224, 69% 221, NR 223, 80% (1:2 mono:di) (3:1 mono:di)

O O O AQ AQ N N AQ H H N H MeO OMe OMe 226, 55% 225, 50% 227, 23% (7:2 mono:di)

OMe O Cbz O AQ N N AQ H O N NPhth H MeO AQ N H 228, 30% 229, 19% 230, NR OMe AQ O NH O AQ O N AQ H N H H N Boc 233, tr ans, 33% 231, NR 232, NR 234, cis, 89%

Scheme 50 : Substrate scope of room temperature C–H arylation of cycloalkane carboxylic acids.

57

3.4. Scope of aryl iodide

We then proceeded to test the reaction with a variety of aryl iodides (Scheme 51 ). A

generalized trend of higher reactivity with aryl iodides bearing electron donating groups, and lower

reactivity with aryl iodides bearing electron withdrawing groups was observed (e.g. para nitro

substrate 237 vs. para methoxy substrate 226 ). For steric reasons, ortho substituted aryl iodides

are less reactive than para (e.g. 223 vs 239 ). 81

R Pd(OAc)2 (cat.) O Ag CO O O 2 3 AQ CH Cl , 25 °C N AQ 2 2 H N n + N I H H R n n N R

R

O O O O AQ AQ AQ AQ N N N N H H H H

Br CO2Me NO2

235, 57% 236, 53% 237, 50% 238, 68%

O O O O AQ AQ AQ AQ N N N N H H H H

NO2 CO Me MeO 2 NO2

240, 48% 241, 89% 242, 74% 239, 24% (5:2 mono:di) (1:2 mono:di) (1:2 mono:di)

Scheme 51: Scope of aryl iodide coupling partner in C–H arylation of cycloalkanes at 25 °C. All

yields are combined yield of isolated mono and di-arylated product.

58

3.5. Mechanistic experiments

In preparation for a kinetic isotope effect study, substrate 243 was deuterated. Subjecting

243 to multiple repetitions of Pd(OAc) 2 in AcOD yielded 244 in >95% purity (Scheme 52 ).

O O D D Pd(OAc) (cat.) AQ N 2 N H H N AcOD, 90 °C D 3 repetitions D 243 244

Scheme 52 : Deuteration of cyclopentane substrate 243 .

Deuterated compound 245 was subjected to C–H arylation with iodobenzene in parallel to

the protiated analog 247 (Scheme 53 ). The reactions were conducted in CDCl 3, and aliquots of the parallel reactions were taken every hour and analyzed by 1H NMR spectroscopy. Yields of 246 and 248 were obtained from analysis of these spectra, and a kinetic isotope effect value of 4.4 was obtained. A parallel experiment was chosen over intramolecular and intermolecular competition experiments as it would be challenging to deconvolute the 1H NMR spectra obtained from these competition experiments. However, we acknowledge that the precision of a parallel KIE experiment is limited due to experimental error.

59

Pd(OAc) (cat.) D O 2 D D O Ag CO AQ D 2 3 N PhI (2 equiv) H N D H D CDCl3, 25 °C D 245 246

Pd(OAc)2 (cat.) O Ag CO H O 2 3 AQ H N AQ PhI (2 equiv) N H H H CDCl3, 25 °C H 247 248

kH/D ~ 4.4

Scheme 53 : Parallel KIE experiments.

A similar parallel KIE experiment provided a value of 1.2 for the room temperature arylation of protected alanine substrate 249 and 251 (Scheme 54 ).148 These disparate KIE

measurements may reflect a difference in mechanism between the C–H arylation reactions of

cyclopentane 247 and alanine 251 . The small KIE (1.2) observed with protected alanine 251

indicates that C–H palladation is not the turnover-limiting step in this C–H arylation reaction, and

proceeds at a rate similar to or faster than the turnover-limiting oxidative addition step. In contrast,

the significant KIE (4.4) observed for the arylation of cyclopentane substrate 247 indicates that C–

H palladation is the turnover-limiting step.

60

Pd(OAc)2 (cat.) PhI O O AgOCOCF3 KHCO NPhth NPhth 3 N N H H N N D D D 1,1,2,2-tetrachloroethane ° D D 249 25 C 250

Pd(OAc)2 (cat.) PhI AgOCOCF O O 3 KHCO NPhth NPhth 3 N N H H N N H H H 1,1,2,2-tetrachloroethane ° H H 25 C 251 252

KH/D ~ 1.2

Scheme 54 : Results of a similar parallel KIE experiment conducted on an alanine substrate.

However, C–H palladation in these systems is known to be reversible, demonstrated by the deuteration reaction of cycloalkane 243 (Scheme 52 ). Thus it cannot be ruled out that the isotope effect observed in the arylation of cyclopentane substrates reflects an equilibrium isotope effect rather than a change in the turnover-limiting step, although it is difficult to rationalize why an equilibrium isotope effect would appear for cyclopentane 247 and not alanine 251 .

3.6. Mechanistic hypothesis

Using precedent from similar AQ-directed sp 3 C–H functionalization reactions, the higher reactivity of smaller rings and the divergent reactivity of stereoisomeric 1,4-aminocyclohexane

61 carboxylic acids 233 and 234 (Scheme 50 ) can be rationalized by conformational analysis of the

palladacycle intermediates.

Rao and co-workers reported AQ-directed Pd-catalyzed sp 3 C–H alkoxylation reactions of cycloalkane substrates in 2014. 149 Notably, unlike our AQ-directed sp 3 C–H arylation reaction

explored above, Rao and co-workers obtained diastereomeric mixtures of alkoxylation products.

For instance, substrate 253 provided a 2:1 mixture of cis and trans products 254 and 255 (Scheme

55 ). Interestingly, the amount of trans -alkoxylation product obtained increased with increasing

steric bulk of the alcohol used, and only trans alkoxylation product was obtained when methanol was replaced with isopropyl alcohol in the alkoxylation of 253 .

AcO I O O O OMe O OMe O AQ AQ N N + N H Pd(OAc) (cat.) H H N 2 MeOH, 100 °C

253 254, 33% 255, 17%

Scheme 55 : sp 3 C–H alkoxylation reported by Rao and co-workers.

In the course of their mechanistic investigation, Rao and co-workers reacted a full equivalent of Pd(OAc) 2 with cyclohexane substrate 253 and isolated the resulting palladacycles.

They report that both cis (256 ) and trans (257 ) palladacycles were obtained (Scheme 56 ).48

62

O O O Pd(OAc)2 (1 equiv) N + N N H Pd N Pd N N pyridine N N CH3CN ° 80 C

253 256, 60% 257, 30%

Scheme 56: Formation of cis and trans palladacycles from the stoichiometric reaction of

Pd(OAc) 2 with cyclohexane substrate 253 .

Reaction of this inseparable mixture of palladacycles 256 and 257 with I(III)–OMe oxidant yielded the corresponded cis and trans mono-methoxylated compounds 258 and 259 (Scheme 57).

OMe I O O O O AQ AQ 256 + 257 N + N H H MeOH (2:1 ratio) ° OMe OMe 25 C 258, 41% 259, 34%

Scheme 57 : Reaction of cis and trans palladacycles with I(III)–OMe oxidant performed by Rao

and co-workers.

The formation of cis and trans products 258 and 259 from the corresponding palladacycles

256 and 257 suggests that the operative oxidative addition and reductive elimination processes are

stereoretentive. Our own group concluded that these organometallic processes were stereoretentive

in a similar sp 3 C–H alkylation reaction with secondary alkyl iodides. 30 Assuming that stereoretentive oxidative addition and reductive elimination steps are operative in the sp 3 C–H

arylation reaction in question, and that both cis and trans palladacycles similar to 256 and 257 are

63 formed under the reaction conditions, we postulate that trans palladacycle (e.g. 257 ) is not susceptible to oxidative addition of aryl iodide or C–C bond forming reductive elimination. A scenario where the both cis and trans palladacycles are formed and are roughly degenerate in

energy, but where only the cis palladacycle undergoes further reaction to yield cis arylated product,

explains some substrate scope limitations observed during investigation of this room temperature

sp 3 C–H arylation reaction of cycloalkanes.

The divergent reactivity of cis 1,4-aminocyclohexane 260 (Scheme 58 ) and trans 1,4-

aminocyclohexane 261 (Scheme 59 ) can be rationalized. Palladation of cis -1,4-aminocyclohexane

260 results in the formation of cis palladacycle 262 and trans palladacycle 263 (Scheme 58 ). In

its only accessible chair conformation (excluding the possibility of a trans di-axial ring junction)

trans palladacycle 263 experiences a penalizing 1,3-diaxial interaction, which diminishes its

population relative to cis palladacycle 262 . The yield of arylation of substrate 260 is thus enhanced

by the greater population of reactive cis palladacycle 262 and diminished population of unreactive

trans palladacycle 263 .

O O O AQ Pd(OAc)2 N N + N H Pd N Pd N BocHN BocHN BocHN L L 260 262 263

O AQ AQ AQ N N N O Pd O BocHN Pd BocHN Pd NHBoc

Scheme 58: Rationalization of the enhanced reactivity of cis 1,4-aminocyclohexane carboxylic

acid.

64

Similarly, palladation of trans 1,4-aminocyclohexane 261 yields cis palladacycle 264 and trans palladacycle 265 . Palladacycle 265 does not experience a penalizing 1,3-diaxial interaction, and should be a more significant contributor to the equilibrium between 264 and 265 than 263 is to the equilibrium between 262 and 263 . The greater population of unreactive trans palladacycle results in diminished overall yield of the transformation.

O O O AQ Pd(OAc)2 N N + N H Pd N Pd N BocHN BocHN BocHN L L 261 264 265

O AQ AQ N AQ N BocHN Pd N O BocHN Pd O Pd NHBoc

Scheme 59 : Rationalization of the diminished reactivity of trans 1,4-aminocyclohexane

carboxylic acid.

This model can be extended to explain the observed trend of diminished reactivity with

increased ring size for unsubstituted cycloalkane homologs 266 -269 (Scheme 60 ).

65

MeO

Pd(OAc) 2 O O ArI, Ag2CO3 AQ N N ° H H CH Cl , 25 C n n N 2 2

OMe O O AQ O O N AQ AQ H N N AQ H N H H

OMe OMe OMe OMe

266, 96% 268, 69% 269, 50% 267, 80% (1:2 mono:di) (3:1 mono:di)

Scheme 60 : Reactivity of cycloalkane homologs to room temperature sp 3 C–H arylation.

Assuming that the enthalpies of formation of the intermediate cis and trans palladacycles

resemble the ethalpies of formation of the corresponding bicyclic alkanes (Figure 12 ), this

reactivity trend can be rationalized using our mechanistic model. The thermodynamic data shown

for compounds 271 -273 was obtained from a report by Schleyer and co-workers. 150

Thermodynamic data was not available for either diastereomer of 270 , but it is well known that cis ring fusion is considerably more stable. 151 Similarly, cis -271 is more stable than trans -271 by 6

kcal/mol. However, the trans isomer is more stable for cycloalkanes 272 and 273 , albeit by a

relatively small quantity. Thus for cyclobutane (e.g. 266 ) and cyclopentane (e.g. 267 ) substrates

in our arylation reactions, it can be postulated that the intermediate cis palladacycles are more

stable than the unreactive trans palladacycles, resulting in their greater reactivity relative to

cyclohexane (e.g. 268 ) and cycloheptane (e.g. 269 ) homologs.

66

270 271 272 273 bicyclo[3.2.0]heptane bicyclo[3.3.0]octane bicyclo[4.3.0]nonane bicyclo[5.3.0]decane

∆ exptl. Hf, cis NA -22.3 -30.41 -31.1 ∆ exptl. Hf, trans NA -16.3 -31.45 -31.4

(kcal/mol)

Figure 12 : Thermodynamic measurements of annulated cyclopentanes.

It must be noted that more cis palladacycle than trans palladacycle is formed in Rao’s experiments with a cyclohexane substrate ( Scheme 56 ), in contrast with the greater thermodynamic stability of trans-272 , so our analogy with bicyclic alkanes is imperfect.

3.7. Sequential functionalization of arylated products

Our mono-arylated cycloalkane products were then subjected to a further C–H functionalization reaction at the remaining β methylene C–H bond (Scheme 61 ). Arylation ( 274 ), alkylation (275 ), and olefination (276 ) C–C bond forming reactions were achieved in good yield.

However, an attempt at C–H acetoxylation instead provided fused β-lactam 278 . Under the same conditions, an arylated cyclohexane substrate provided a mixture of β-lactam 279 and acetoxylated product 280 .

67

O O Pd(OAc)2 (cat.) AQ R' N Reagents N H N H

n n

R R

O2N O O AQ O O EtO C 2 N AQ AQ H N N H H NO2

OMe OMe 274, 79% 275, 95% 276, 60%

O QA AQ OAc O N N O AQ N H +

NO2 OMe OMe 278, 83% 279, 51% 280, 20%

Scheme 61 : Sequential functionalization of arylated cycloalkane substrates.

The formation of fused β-lactams can be rationalized by competing reductive elimination pathways of Pd(IV) intermediate 282 obtained from PhI(OAc) 2 oxidation of palladacycle 281

(Scheme 62 ). The competition between C–O and C–N reductive elimination in these systems is

well-precedented, 21,152,153 and significant effort has been invested to overcome the reaction’s substrate dependence. 19,20,26,27,154–156

68

AQ O OAc O N AQ O N PhI(OAc)2 N H H + N Pd(OAc)2 (cat.) ° toluene, 60 C OMe OMe OMe 20% 51%

Pd(OAc) 2 CO reductive elimination CN reductive elimination OAc O OMe O OMe oxidation by N N N IV PdII N Pd PhI(OAc)2 L AcO L

281 282

Scheme 62 : Different reductive elimination pathways of Pd(IV) palladacycle intermediate,

leading to acetoxylated or cyclized products.

3.8. Deprotection

The AQ group of arylated product 283 was removed through activation with a Boc group

followed by hydrolysis with Li 2O2 in 60% yield over 2 steps (Scheme 63 ).

O O AQ 1. Boc2O, DMAP N OH H CH3CN, 25 °C

2. LiOH, H2O2 H2O/THF, 0-25 °C, 60% (2 steps) OMe OMe 284 283 Scheme 63 : Deprotection of the AQ group.

69

3.9. Concluding remarks

The 1,2,3,4-tetrahydroquinoline (THQ) motif occurs frequently in biologically active molecules. We have developed a conceptually unique approach to THQ synthesis using C–H functionalization reactions. Starting from a 3-propylpicolinamide derivative, a sequence of sp 3 C–

H arylation, ortho sp 2 C–H iodination, and C–N cross coupling produces the THQ scaffold. Two

different approaches to the ortho C–H iodination have been developed: a directed EAS reaction

and a Pd-catalyzed C–H functionalization reaction. Together, these methods form a strategy for

THQ synthesis that is easily applied, broad in scope, and offers synthetic logic orthogonal to

conventional methods (Scheme 64 ).

Directed EAS

I Cross-coupling O and amide hydrolysis N PA PA H N Pd(OAc)2 (cat.) N I N N H H H THQ Pd-catalyzed C−H iodination

Scheme 64 : Overview of THQ synthesis via C–H functionalization.

C–H functionalization reactions of cycloalkanes have been the focus of intense research

interest, and have been featured in multiple natural product syntheses. An improved protocol for

8-aminoquinoline directed, Pd-catalyzed arylation of cycloalkane substrates was developed, which

provides a more selective and mild reaction. This reaction provided unexpected access to fused β- lactam structures via sequential C–H functionalization. Furthermore, this mild reaction served as

70 a platform from which to investigate difficult-to-study mechanistic aspects of Pd catalyzed, bidentate-auxiliary directed C–H arylation (Scheme 65 ).

O Pd(OAc)2 (cat.) O N I H AQ N N H

Scheme 65 : Arylation of cyclohexane carboxylic acid substrates.

The functionalization of C–H bonds represents a frontier in organic chemistry research.

Our contributions to this frontier consist of investigations of these reactions for use in complex

molecule synthesis, yielding useful synthetic methods as well as inspiration for further studies.

New reactions, and mechanistic study of those reactions, has yielded new and broader

understanding of the processes underlying C–H bond functionalization. However, despite this

progress represented by this contribution and many others, much mechanistic understanding and

reaction development remains to be accomplished in order to realize the potential of bidentate-

auxiliary directed C–H bond functionalization in laboratory organic synthesis.

71

CHAPTER 4: EXPERIMENTAL

4.1. Synthesis of THQ via remote C–H functionalization

4.1.1. Reagents: N-iodosuccinimide (97%, Alfa Aesar), I 2 (99%, Acros), PhI(OAc) 2 (98%, Alfa

Aesar), HBF 4 • OEt 2 (SKU 400068, Aldrich), CF 3CO 2H (99.5+%, Alfa Aesar), CuI (99.999%,

Aldrich), CsOAc (99%, Aldrich), LiEt 3BH (1 M in THF, Alfa Aesar), Pd(OAc) 2 (98%, Aldrich),

Ag 2CO 3 (99%, Aldrich), (BnO) 2PO 2H (98%, Acros) were used as received unless otherwise noted.

157 IPy 2 • BF 4 was prepared following a literature protocol. The following solvents were obtained from a JC Meyer solvent dispensing system and used without further purification: CH 2Cl 2 and toluene. Flash chromatography was performed using 230-400 mesh SiliaFlash 60 ® silica gel

(Silicycle Inc).

4.1.2. Instruments: NMR spectra were recorded on Bruker CDPX-300, DPX-300, DRX-400 instruments and calibrated using residual solvent peaks as internal reference. Multiplicities are recorded as: s = singlet, d = doublet, t = triplet, dd = doublet of doublets, m = multiplet. High resolution ESI mass experiments were operated on a Waters LCT Premier instrument.

72

4.1.3. Preparation of alkyl picolinamide substrates.

N CO H NHPA NH2 2 + EDCI, HOBt, DIPEA CF CF3 3 CH Cl 4-1 4-2 2 2 4-3

NHPA NHPA NHPA MeO2C NHPA F3C NHPA NHPA NHPA 4-4 4-5 4-6 4-7 4-8 4-9 4-10

Picolinamide substrates were prepared from commercially available alkyl amines and picolinic acid using the standard EDCI-mediated amide coupling conditions. Syntheses of compounds 4-7,

4-9 and 4-10 have been previously reported. 20,158 The general procedure for the preparation of the

remaining compounds: A mixture of amine (1.0 equiv), picolinic acid (1.1 equiv), EDCI (1.1

equiv), HOBt • H2O (1.1 equiv), and DIPEA (3.0 equiv) in anhydrous DCM (0.2 M) was stirred

at room temperature overnight. Water was added and the mixture was extracted with DCM. The

combined organic layers were washed with water and brine, dried over anhydrous Na 2SO 4, and

concentrated in vacuo . The resulting residue was purified by silica gel flash chromatography

(Hex/EtOAc) to give the desired picolinamide product.

NHPA

4-4

39 1 Compound 4-4 (known compound ) was isolated in 67% yield. H NMR (CDCl 3, 300 MHz,

ppm): δ 8.50 (m, 1H), 8.17 (d, J = 7.8 Hz, 1 H), 8.06 (s, 1H), 7.82 (td, J = 7.7, 1.7 Hz, 1H), 7.39

(m, 1H), 3.43 (q, J = 6.9 Hz, 2H), 1.68 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).

73

NHPA

4-5

1 Compound 4-5 was isolated in 80% yield (Rf = 0.50, 25% EtOAc in Hex). H NMR (CDCl 3, 300

MHz, ppm): δ 8.53 (d, J = 4.5 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H), 7.84 (td, J = 7.7, 1.6

Hz, 1H), 7.41 (m, 1H), 3.31 (t, J = 6.6 Hz, 2H), 1.94 (m, 1H), 0.97 (d, J = 6.7 Hz, 6H); 13 C NMR

(CDCl 3, 75 MHz, ppm) δ 164.04, 149.85, 147.80, 137.06, 125.81, 121.91, 46.52, 28.51, 19.98;

+ HRMS : calculated for C 10 H15 N2O [M+H ]: 179.1179; found: 179.1182.

NHPA 4-6

1 Compound 4-6 was isolated in 82% yield (Rf = 0.50, 25% EtOAc in Hex). H NMR (CDCl 3, 400

MHz, ppm): δ 8.43 (d, J = 4.7 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 8.01 (s, 1H), 7.74 (m, 1H), 7.31

(m, 1H), 3.39 (q, J = 6.5 Hz, 2H), 1.55-1.47 (m, 2H), 1.36-1.26 (m, 2H), 0.86 (t, J = 7.5 Hz, 3H);

13 C NMR (CDCl 3, 75 MHz, ppm) δ 164.05, 149.92, 147.83, 137.11, 125.84, 121.93, 38.94, 31.56,

+ 19.98, 13.60; HRMS : calculated for C 10 H15 N2O [M+H ]: 179.1179; found: 179.1185.

F3C NHPA 4-8

1 Compound 4-8 was isolated in 77% yield (Rf = 0.50, 15% Acetone in Hex). H NMR (CDCl 3, 400

MHz, ppm): δ 8.58 (d, J = 4.5 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.89 (t,

J = 7.7 Hz, 1H), 7.49-7.45 (m, 1H), 4.73-4.65 (m, 1H), 2.03-1.96 (m, 1H), 1.74-1.65 (m, 1H), 1.06

13 (t, J = 7.4 Hz, 3H); C NMR (CDCl 3, 75 MHz, ppm) δ 164.61, 148.74, 148.18, 137.44, 130.89,

74

127.16, 126.70, 123.42, 122.55, 119.69, 52.50, 52.10, 51.69, 51.29, 21.64, 9.67; HRMS :

+ calculated for C 10 H12 F3N2O [M+H ]: 233.0896; found: 233.0898.

4.1.4 Optimization of ortho iodination reactions

PA N H I 60 Compound 60 was independently prepared in 31% yield via Pd-catalyzed arylation of substrate 4-

9 with 1,2-diiodobenzene using the general conditions A described in section 4.1.5. (Rf = 0.60,

1 25 % EtOAc in Hex). H NMR (CDCl 3, 300 MHz, ppm): δ 8.55 (d, J = 4.2 Hz, 1H), 8.23 (d, J =

7.8 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.88 (td, J = 7.7, 1.6 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.44-

7.40 (m, 1H), 7.27-7.24 (m, 2H), 6.90-6.83 (m, 1H), 4.34-4.25 (m, 1H), 2.89-2.73 (m, 2H), 1.90-

13 1.82 (m, 2H), 1.35 (d, J = 6.6 Hz, 3H); C NMR (CDCl 3, 75 MHz, ppm) δ 163.65, 150.01, 147.97,

144.25, 139.44, 137.32, 129.48, 128.43, 127.79, 126.06, 122.17, 100.41, 45.07, 37.59, 37.49,

+ 21.09; HRMS : calculated for C 16 H18 IN 2O [M+H ]: 381.0458; found: 381.0470.

PA N H I 61

Compound 61 (R f = 0.60, 25 % EtOAc in Hex) was independently prepared in 48% yield via Pd- catalyzed arylation of substrate 4-9 with 1,4-diiodobenzene using the general conditions A

1 described in section 4.1.5. H NMR (CDCl 3, 300 MHz, ppm): δ 8.54 (d, J = 4.1 Hz, 1H), 8.21 (d,

J = 7.8 Hz, 1H), 7.89-7.82 (m, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.44-7.40 (m, 1H), 6.96 (d, J = 8.2

Hz, 2H), 4.28-4.18 (m, 1H), 2.68 (t, J = 7.9 Hz, 2H), 1.93-1.83 (m, 2H), 1.30 (d, J = 6.6 Hz, 3H);

75

13 C NMR (CDCl 3, 75 MHz, ppm) δ 163.45, 149.80, 147.87, 141.26, 137.22, 130.41, 126.01,

+ 122.04, 90.85, 44.81, 38.35, 31.97, 21.06; HRMS : calculated for C 16 H18 IN 2O [M+H ]: 381.0458; found: 381.0471.

I PA N H I 62 Compound 62 was prepared via Pd-catalyzed C–H iodination as described below. 1H NMR (500

MHz, CDCl 3) δ 8.54 (d, J = 3.3 Hz, 1H), 8.25 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 7.85 (t, J = 7.4 Hz,

1H), 7.79 (d, J = 7.8 Hz, 2H), 7.47-7.37 (m, 1H), 6.49 (t, J = 7.8 Hz, 1H), 3.64 (q, J = 6.6 Hz, 2H),

13 3.23-3.09 (m, 2H), 1.95-1.82 (m, 2H); C NMR (126 MHz, CDCl 3) δ 164.50, 150.10, 148.15,

145.39, 140.24, 137.50, 129.64, 126.22, 122.38, 99.10, 44.50, 39.21, 28.42; HRMS : calculated

+ for C 15 H14 I2N2O [M+H ]: 492.9268, found: 492.9281.

I PA + PA N I N H H + + I I I 59 60 61 62

1H-NMR δ 2.70, t 2.89, m 6.96, d 2.68, t 3.15, m H 6.85, m H H H I H PA H PA PA PA N N N N H H H H H I I H I 59 60 61 62 6.46, t

Figure 13 : Distinctive 1H-NMR signals of compounds 59 , 60 , 61 , 62 .

Directed EAS protocol : Substrate 59 (0.2 mmol) and I + precursor were dissolved in anhydrous

CH 2Cl 2. TFA or CH 3CO 2H and Lewis or Bronsted acid were added, and the reaction mixture was

76 stirred under Ar at the chosen temperature for 2-4 hours. Solvents were then removed in vacuo or with stream of N 2. The residue was re-dissolved in CH 2Cl 2, washed with aq. NaHCO 3, aq.

Na 2S2O3, brine, dried over anhydrous Na 2SO 4, and concentrated in vacuo . The resulting residue

1 was dissolved in CDCl 3 for H-NMR analysis.

MeO MeO MeO H H I+ H H H H Pd(OAc)2 (10 mol%) + PA PA PA N I N N H H H 66 67 I 68 δ δ δ 2.74 (t, J = 7.2 Hz) 2.93 (t, J = 7.4Hz) 2.65 (t, J = 7.5Hz) Figure 14 : Distinctive NMR signals of 67-68 .

Pd-catalyzed protocol : A mixture of compound 66 (50.8 mg, 0.2 mmol, 1.0 equiv), Pd(OAc) 2

(4.5 mg, 0.02 mmol, 0.1 equiv), PhI(OAc) 2 (129 mg, 0.4 mmol, 2.0 equiv) and I 2 (101.6 mg, 0.4 mmol, 2.0 equiv) in DMF (2 mL) in a 10 mL glass vial (purged with Ar, sealed with PTFE cap) was heated at 130 oC for 24 hours. The mixture was cooled to rt, diluted with EtOAc, washed with

aq. Na 2S2O3, water, brine, dried over anhydrous Na 2SO 4, and concentrated in vacuo . The resulting

residue was dissolved in CDCl 3 for 1H-NMR analysis.

OMe

PA I N H 67

1 H NMR (400 MHz, CDCl 3) δ 8.56 (d, J = 4.1 Hz, 1H), 8.35 (s, 1H), 8.21 (d, J = 7.8 Hz, 1H),

7.84 (td, J = 7.7, 1.6 Hz, 1H), 7.43-7.41 (m, 2H), 6.89-6.81 (m, 2H), 3.84 (s, 3H), 3.49 (q, J = 6.6

Hz, 2H), 2.93 (t, J =7.4 Hz, 2H), 1.90-1.83 (m, 2H); 13 C NMR (101 MHz, CDCl3) δ 164.33,

77

157.53, 152.20, 150.35, 148.13, 147.68, 137.42, 132.97, 131.73, 128.68, 126.10, 122.32, 110.42,

+ 102.02, 100.08, 55.86, 38.71, 31.91, 28.54; HRMS calculated for C 16 H17 IN 2O2 [M+H ]: 397.0407,

Found: 397.0410.

OMe

PA N H I 68

1 H NM R (400 MHz, CDCl 3) δ 8.54 (d, J = 4.5 Hz, 1H), 8.22 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H) 7.84-

7.81 (m, 1H), 7.44-7.39 (m, 3H), 6.59 (d, J = 8.2 Hz, 1H), 3.80 (s, 3H), 3.45 (m, 2H), 2.65 (t, J =

13 7.5 Hz, 2H), 1.92-1.85 (m, 2H); C NMR (101 MHz, CDCl 3) δ 164.28, 157.44, 150.12, 148.07,

138.44, 137.38, 136.01, 132.76, 126.10, 122.22, 112.63, 82.96, 55.48, 38.79, 29.73, 27.14; HRMS

+ calculated for C 16 H17 IN 2O2 [M+H ]: 397.0407, Found: 397.0411.

4.1.5. Removal of PA group

NaOH ° MeOH/H2O, 80 C, 81% N N ° PA or LiAlH4, THF, 0 C, 82% H ° or LiEt BH, THF, 0 C, 86% 64, 93% 3 65 Three protocols were developed for the deprotection of the PA group:

Protocol A: Compound 64 (50 mg, 0.22 mmol, 1.0 equiv) was dissolved in a mixture of

MeOH/H 2O (0.5/0.5 mL), NaOH (13 mg, 0.33 mmol, 1.5 equiv) was then added. The mixture was

heated to 80 oC and stirred for 12 hours. Water was added and the mixture was extracted with

DCM. The combined organic layers were washed with water and brine, dried over anhydrous

Na 2SO 4, and concentrated in vacuo . The residue was purified by silica gel flash chromatography

78

1 to give 65 (24 mg) in 81% yield. H NMR (CDCl 3, 300 MHz, ppm): δ 7.02-6.97 (m, 2H), 6.66 (t,

J = 7.2 Hz, 1H), 6.51 (d, J = 7.7 Hz, 1H), 3.83 (s, 1H), 3.34-3.30 (m, 2H), 2.82 (t, J = 6.4 Hz, 2H),

2.01-1.93 (m, 2H).

Protocol B: Compound 64 (47.7 mg, 0.2 mmol, 1.0 equiv) was dissolved in THF (1 mL) at 0 oC,

and LiAlH 4 (15.2 mg, 0.4 mmol, 2.0 equiv) was then added. After 1.5 hours, the reaction was quenched by addition of saturated NH 4Cl followed by 1N NaOH, and extracted with DCM. The combined organic layers was washed with water and brine, dried over anhydrous Na 2SO 4, and concentrated in vacuo . The residue was purified by silica gel flash chromatography to give the desired product 65 in 82% yield.

Protocol C : 159 Compound 64 (47.7 mg, 0.2 mmol, 1.0 equiv) was dissolved in THF (1 mL) at 0 o C, and a solution of LiEt 3BH (0.6 mL, 0.6 mmol, 3.0 equiv) was then added. After 1.5 hours, the reaction was quenched by addition of saturated NH 4Cl followed by 1N aq. NaOH, and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous

Na 2SO 4, and concentrated in vacuo . The residue was purified by silica gel flash chromatography

to give the desired product 65 in 86% yield.

4.1.6. Procedure for the Pd-catalyzed C-H arylation reaction

Two general procedures were used for the Pd-catalyzed PA-directed C(sp 3)−H arylations:

Arylation protocol A was for compounds 73-79 , 81, 82 , 84-87 .

A mixture of picolinamide (1.0 equiv), aryl iodide (1.5 equiv), Pd(OAc) 2 (0.1 equiv), Ag 2CO 3 (1.5

79

o equiv) and (BnO) 2PO 2H (0.2 equiv) in t-AmylOH (0.2 M) was heated at 110 C under Ar for 24 hours. The reaction mixture was cooled to rt, diluted with EtOAc, filtered through a pad of celite, and concentrated in vacuo . The resulting residue was purified by silica gel flash chromatography

(Hex/EtOAc) to give arylated product.

Arylation protocol B was used for 72, 80 , 83 .39

A mixture of picolinamide (1.0 equiv), aryl iodide (5.0 equiv), Pd(OAc) 2 (0.1 equiv), and AgOAc

(1.2 equiv) was heated at 150 oC under Ar for 24 hours (no solvent). The reaction mixture was

cooled to rt, diluted with EtOA C, filtered through a pad of celite, and concentrated in vacuo . The

resulting residue was purified by silica gel flash chromatography (Hex/EtOAc) to give the arylated

product.

PA N H

59

1 Compound 59 was isolated in 82% yield (Rf = 0.30, 33% EtOAc in Hex). H NMR (CDCl 3, 300

MHz, ppm): δ 8.53 (d, J = 4.8 Hz, 1 H), 8.22 (d, J = 7.8 Hz, 1 H), 7.95 (d, J = 7.7 Hz, 1 H), 7.85-

7.76 (m, 1H), 7.39-7.35 (m, 1H), 7.26-7.15 (m, 5H), 4.31-4.21 (m, 1H), 2.73 (t, J = 8.5 Hz, 2 H),

13 1.96-1.83 (m, 2H), 1.30 (d, J = 6.6 Hz, 3 H); C NMR (CDCl 3, 75 MHz, ppm) δ 163.90, 150.39,

148.25, 142.06, 137.63, 128.67, 126.33, 126.12, 122.51, 45.43, 45.40, 39.10, 32.85, 21.41;

+ HRMS : calculated for C 16 H19 N2O [M+H ]: 255.1492; found: 255.1498.

80

PA N H 72

1 Compound 72 was isolated in 54% yield (Rf = 0.40, 20% Acetone in Hex). H NMR (CDCl 3, 300

MHz, ppm): δ 8.54 (d, J = 4.1 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.10 (s, 1H), 7.87 (td, J = 7.7, 1.6

Hz, 1H), 7.44-7.39 (m, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.03-6.99 (m, 3H), 3.55 (q, J =6.9 Hz, 2H),

13 2.72 (t, J = 7.5 Hz, 2H), 2.32 (s, 3H), 2.02-1.92 (m, 2H); C NMR (CDCl 3, 75 MHz, ppm) δ

164.15, 149.86, 147.87, 141.24, 137.75, 137.16, 129.06, 128.19, 126.54, 125.92, 125.27, 121.98,

+ 38.92, 33.08, 31.14, 21.27; HRMS : calculated for C 16 H19 N2O [M+H ]: 255.1492; found:

255.1500.

Cl

PA N H 73

Compound 73 was isolated in 40% yield (Rf = 0.40, 25% EtOAc in Hex, a bis -arylated product on

1 both methyl groups was obtained as the major side product). H NMR (CDCl 3, 300 MHz, ppm):

δ 8.54 (m, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.14 (s, 1H), 7.87 (td, J = 7.7, 1.7 Hz, 1H), 7.44-7.40 (m,

1H), 7.22-7.13 (m, 3H), 7.07 (d, J = 6.9 Hz, 1H), 3.47-3.33 (m, 2H), 2.79 (dd, J = 13.6, 6.0 Hz,

1H), 2.47 (dd, J = 13.6, 8.5 Hz, 1H), 2.14-2.07 (m, 1H), 0.96 (d, J = 6.7 Hz, 3H); 13 C NMR

(CDCl 3, 75 MHz, ppm) δ 164.36, 149.82, 147.99, 142.42, 137.32, 134.02, 129.54, 129.06, 127.28,

+ 126.13, 126.11, 122.14, 45.01, 40.70, 35.55, 17.52; HRMS : calculated for C 16 H18 ClN 2O [M+H ]:

289.1102; found: 289.1110.

81

PA Br N H 74

1 Compound 74 was isolated in 29% yield (Rf = 0.40, 25% EtOAc in Hex). H NMR (CDCl 3, 300

MHz, ppm): δ 8.52 (d, J = 4.1 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.96 (s, 1H), 7.85 (td, J = 7.7, 1.7

Hz, 1H), 7.42-7.38 (m, 3H), 7.11 (d, J = 8.3 Hz, 2H), 3.41-3.33 (m, 2H), 2.81-2.76 (m, 1H), 1.96-

13 1.86 (m, 2H), 1.28 (d, J = 7.0 Hz, 3H); C NMR (CDCl 3, 75 MHz, ppm) δ 164.14, 149.81, 147.98,

145.46, 137.27, 131.55, 128.69, 126.05, 122.01, 119.77, 37.80, 37.67, 37.39, 22.31; HRMS :

+ calculated for C 16 H18 BrN 2O [M+H ]: 333.0597; found: 333.0606.

CO2Me PA N H

75

1 Compound 75 was isolated in 82% yield (Rf = 0.30, 25% EtOAc in Hex). H NMR (CDCl 3, 400

MHz, ppm): δ 8.59 (d, J = 3.0 Hz, 1H), 8.53 (d, J = 7.8 Hz, 1H), 8.20 (d, J = 7.7 Hz, 1H), 7.87 (t,

J = 7.6 Hz, 1H), 7.45 (t, J = 5.3 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.97 (s, 1H), 6.94 (d, J = 7.5

Hz, 1H), 4.89 (q, J = 7.5 Hz, 1H), 3.76 (s, 3H), 2.71-2.62 (m, 2H), 2.36-2.29 (m, 1H), 2.21 (s, 6H),

13 2.17-2.09 (m, 1H); C NMR (CDCl 3, 75 MHz, ppm) δ 172.29, 163.92, 149.15, 148.02, 137.82,

137.08, 136.24, 133.92, 129.53, 129.49, 126.19, 125.56, 122.04, 52.13, 51.93, 34.04, 31.15, 19.48,

+ 19.06; HRMS : calculated for C 19 H23 N2O3 [M+H ]: 327.1703; found: 327.1714.

CF3 Cl PA N H Cl 76

82

1 Compound 76 was isolated in 83% yield (Rf = 0.40, 15% Acetone in Hex). H NMR (CDCl 3, 300

MHz, ppm): δ 8.57-8.55 (m, 1H), 8.22-8.19 (m, 1H), 8.15 (d, J = 10.0 Hz, 1H), 7.92 (td, J = 7.7,

1.7 Hz, 1H), 7.51-7.47 (m, 1H), 7.31-7.26 (m, 2H), 7.03 (dd, J = 8.2, 2.1 Hz, 1H),4.83-4.75 (m,

13 1H), 2.74 (t, J = 8.2 Hz, 2H), 2.26-2.20 (m, 1H), 2.04-1.98 (m, 1H); C NMR (CDCl 3, 75 MHz, ppm) δ 164.54, 148.52, 148.29, 140.48, 137.65, 132.54, 130.56, 130.43, 130.39, 127.97, 126.98,

123.24, 122.74, 50.93, 50.53, 50.12, 49.71, 30.82, 29.91; HRMS : calculated for C 16 H14 Cl 2F3N2O

[M+H +]: 377.0430; found: 377.0438.

4-9, Pd(OAc) , 2 O O O O NH O O I Ag CO , (BnO) PO H 2 NaNO2,H2SO4,KI 2 3 2 2 PA 19% 81% N H 77 4-11 CF 4-12 CF3 CF3 3 Compound 4-12 was prepared following a known procedure. 160 To an ice cooled solution of 4-11

(810 mg, 3.5 mmol, 1.0 equiv) in water (13 mL), was added conc. H 2SO 4 (1.5 mL) dropwise. A

solution of NaNO 2 (609 mg, 8.8 mmol, 2.5 equiv) in water (2 mL) was added dropwise, and the

reaction solution was stirred for 30 min. Then a solution of KI (1.47 g, 8.8 mmol, 2.5 equiv) in

water (2 mL) was added slowly. After 24 hours, the aqueous phase was extracted with EtOAc. The

combined organic phase was washed with sat. Na 2S2O3, 1 N HCl, sat. NaHCO 3 and brine respectively, dried over anhydrous Na 2SO 4, and concentrated in vacuo . The resulting residue was

purified by silica gel flash chromatography (Hex/EtOAc) to give the desired product 224 mg. R f

1 = 0.70, 25% EtOAc in Hex; H NMR (CDCl 3, 300 MHz, ppm): δ 7.73 (d, J = 1.5 Hz, 1H), 7.67

13 (dd, J = 8.5, 1.6 Hz, 1H), 7.39 (dd, J = 8.5, 1.7 Hz, 1H), 6.78 (s, 1H); C NMR (CDCl 3, 75 MHz,

ppm) δ 157.81, 153.95, 141.70, 141.26, 140.82, 140.39, 134.33, 126.75, 126.07, 126.04, 123.10,

119.44, 116.65, 116.57, 116.50, 116.42, 115.79, 112.99, 99.17. HRMS : calculated for

+ C20 H18 F3N2O3 [M+H ]: 391.1264; found: 391.1272.

83

1 Compound 77 (Rf = 0.10, 20% EtOAc in Hex) was isolated in 81% yield. H NMR (CDCl 3, 300

MHz, ppm): δ 8.49 (d, J = 4.5 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.89-7.80 (m, 2H), 7.59 (d, J =

8.0 Hz, 1H), 7.42-7.38 (m, 1H), 7.26-7.19 (m, 2H), 6.68 (s, 1H), 4.30-4.21 (m, 1H), 2.84 (t, J =

13 7.1 Hz, 2H), 1.98-1.90 (m, 2H), 1.32 (d, J = 6.6 Hz, 3H); C NMR (CDCl 3, 75 MHz, ppm) δ

163.40, 158.68, 154.19, 149.63, 148.39, 147.71, 141.62, 141.19, 140.76, 140.32, 137.13, 126.79,

125.92, 125.37, 124.83, 124.81, 123.14, 121.95, 119.49, 116.86, 115.83, 114.75, 114.68, 114.60,

+ 114.53, 111.09, 44.68, 37.62, 32.41, 20.92; HRMS : calculated for C 20 H18 F3N2O3 [M+H ]:

391.1264; found: 391.1272.

MeO2C

PA N H 78

1 Compound 78 was isolated in 86% yield (Rf = 0.25, 25% EtOAc in Hex). H NMR (CDCl 3, 300

MHz, ppm): δ 8.52 (d, J = 4.2 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.85-

7.79 (m, 3H), 7.42-7.36 (m, 2H), 7.32 (t, J = 7.6 Hz, 1H), 4.29-4.19 (m, 1H), 3.87 (s, 3H), 2.77 (d,

13 J = 7.7 Hz, 2H), 1.94-1.86 (m, 2H), 1.30 (d, J = 6.6 Hz, 3H); C NMR (CDCl 3, 75 MHz, ppm) δ

166.43, 163.09, 149.53, 147.48, 141.61, 136.77, 132.57, 129.68, 128.85, 127.91, 126.62, 125.56,

+ 121.60, 51.42, 44.52, 37.97, 31.88, 20.52; HRMS : calculated for C 18 H21 N2O3 [M+H ]: 313.1547; found: 313.1557.

F PA N H

79

1 Compound 79 was isolated in 87% yield (Rf = 0.30, 25% EtOAc in Hex). H NMR (CDCl 3, 300

84

MHz, ppm): δ 8.53 (d, J = 4.2 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.86 (td,

J = 7.8, 1.6 Hz, 1H), 7.42-7.38 (m, 1H), 7.22-7.15 (m, 1H), 6.96-6.80 (m, 3H), 4.29-4.19 (m, 1H),

13 2.72 (t, J = 7.9 Hz, 2 H), 1.97-1.82 (m, 2H), 1.30 (d, J = 6.6 Hz, 3H); C NMR (CDCl 3, 75 MHz,

ppm) δ 164.37, 163.51, 161.12, 149.86, 147.84z, 144.30, 144.30, 137.20, 129.70, 129.59, 125.97,

123.95, 123.91, 122.04, 115.15, 114.88, 112.67, 112.39, 44.86, 38.29, 32.20, 32.18, 20.94;

+ HRMS : calculated for C 16 H18 FN 2O [M+H ]: 273.1398; found: 273.1400.

OMe

PA N 80 H

1 Compound 80 was isolated in 36% yield as a colorless oil. H NMR (400 MHz, CDCl 3) δ 8.56

(d, J = 4.5 Hz, 1H), 8.28 (s, 1H), 8.22 (d, J = 5.7 Hz, 1H), 7.85 (td, J = 7.7, 1.6 Hz, 1H), 7.44-7.39

(m, 1H), 7.21-7.15 (m, 1H), 6.91-6.84 (m, 1H), 3.85 (s, 3H), 3.49 (q, J = 6.7 Hz, 2H), 2.74 (t, J =

13 7.2 Hz, 2H), 1.96-1.89 (m, 2H); C NMR (126 MHz, CDCl 3) δ 163.87, 157.06, 149.81, 147.67,

136.90, 129.62, 129.32, 126.92, 125.65, 121.73, 120.21, 109.89, 54.83, 38.38, 29.52, 26.94.

+ HRMS : calculated for C 16 H19 N2O2 [M+H ]: 271.1441; found: 271.1443.

PA N H 81

1 Compound 81 was prepared in 81% yield as a colorless oil. H NMR (500 MHz, CDCl 3) δ 8.55

(d, J = 4.1 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.85 (td, J = 7.7, 1.6 Hz,

1H), 7.42 (m, 1H), 7.19-7.05 (m, 4H), 4.35-4.24 (m, 1H), 2.77-2.62 (m, 2H), 2.30 (s, 3H), 1.92-

13 1.79 (m, 2H), 1.34 (d, J = 6.6 Hz, 3H); C NMR (126 MHz, CDCl 3) δ 163.71, 150.14, 148.03,

85

140.07, 137.49, 135.86, 130.28, 128.79, 126.16, 126.11, 126.08, 122.33, 45.52, 37.69, 30.01,

+ 21.18, 19.35; HRMS : calculated for C 17 H20 N2O [M+H ]: 269.1649, found: 269.1652.

MeO

PA N H 82

1 Compound 82 was prepared in 81% yield as a colorless oil. H NMR (500 MHz, CDCl 3) δ 8.52

(d, J = 4.2 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.82 (td, J = 7.7, 1.6 Hz,

1H), 7.39 (ddd, J = 7.4, 4.8, 0.9 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.74

(s, 1H), 6.69 (dd, J = 8.2, 2.0 Hz, 1H), 4.33-4.15 (m, 1H), 3.76 (s, 3H), 2.68 (t, J = 8.0 Hz, 2H),

13 1.99-1.79 (m, 2H), 1.29 (d, J = 6.6 Hz, 3H); C NMR (126 MHz, CDCl 3) δ 163.61, 159.67,

150.06, 147.96, 143.43, 137.39, 129.36, 126.09, 122.23, 120.76, 114.05, 111.27, 55.12, 45.16,

+ 38.66, 32.65, 21.15; HRMS : calculated for C 17 H20 N2O2 [M+H ]: 285.1598, found: 285.1604.

NO2

PA N H 83

1 Compound 83 was prepared in 28% yield as a colorless oil. H NMR (500 MHz, CDCl 3) δ 8.52

(d, J = 4.2 Hz, 1H), 8.18 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.88 (dd, J = 8.1, 0.8 Hz, 1H), 7.82 (td,

J = 7.7, 1.6 Hz, 1H), 7.49 (td, J = 7.6, 1.1 Hz, 1H), 7.44-7.38 (m, 1H), 7.37 (d, J = 7.7 Hz, 1H),

13 7.34-7.28 (m, 1H), 3.54 (m, 2H), 3.03-2.92 (m, 2H), 2.00 (m, 2H); C NMR (126 MHz, CDCl 3)

δ 164.48, 149.87, 149.28, 148.10, 137.45, 136.63, 133.15, 132.09, 127.27, 126.22, 124.88, 122.23,

+ 39.10, 30.62, 30.61; HRMS : calculated for C 15 H15 N3O3 [M+H ]: 286.1186, found: 286.1188.

86

H N PA 84

1 Compound 84 was prepared in 60% yield white solid. H NMR (400 MHz, CDCl 3) δ 8.13 (d, J =

4.2 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 7.4 Hz, 1H), 7.36-7.30 (m, 2H), 7.27-7.13 (m,

3H), 7.09-7.07 (m, 1H), 4.14 (td, J = 9.0, 3.2 Hz, 1H), 2.98 (s, 1H), 2.80-2.78 (m, 2H), 2.30 (s,

3H), 2.10-1.98 (m, 2H), 1.93-1.85 (m, 1H), 1.76-1.70 (m, 1H), 1.52-1.46 (m, 1H), 1.37-1.31 (m,

13 1H); C NMR (101 MHz, CDCl 3) δ 162.74, 149.78, 147.47, 138.53, 137.47, 136.84, 131.01,

127.41, 126.25, 126.17, 125.52, 121.52, 52.85, 52.23, 46.33, 38.56, 38.31, 28.91, 27.68, 20.74;

+ HRMS calculated for C 20 H22 N2O [M+H ]: 307.1805; Found: 307.1809.

F

H N PA 85

1 Compound 85 was prepared in 94% yield as a white solid. H NMR (400 MHz, CDCl 3) δ 8.16

(dd, J = 4.7, 0.6 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.72 (td, J = 7.8, 1.5 Hz, 1H), 7.40-7.25 (m,

3H), 7.24-7.19 (m, 1H), 7.12 (t, J = 7.5 Hz, 1H), 6.99-6.89 (m, 1H), 4.11 (td, J = 8.8, 3.8 Hz, 1H),

3.00 (s, 1H), 2.92 (s, 1H), 2.84 (t, J = 3.8 Hz, 1H), 2.04-1.99 (m, 1H), 1.94–1.80 (m, 2H), 1.78-

13 1.70 (m, 1H), 1.54-1.45 (m, 1H), 1.40-1.29 (m, 1H); C NMR (101 MHz, CDCl 3) δ 163.13,

162.90, 160.68, 149.90, 147.52, 137.06, 129.62, 129.57, 127.97, 127.88, 127.71, 127.56, 125.71,

124.42, 124.39, 121.79, 116.08, 115.85, 52.86, 48.51, 46.66, 46.63, 38.31, 37.88, 28.50, 27.86;

+ HRMS calculated for C 19 H19 FN 2O [M+H ]: 311.1554, Found: 311.1556.

87

4.1.7. Ortho -iodination of different substrates with NIS via directed EAS

Two iodination protocols were used for ortho C-H iodination via directed EAS.

Protocol A: Substrate (0.2 mmol, 1 equiv) and NIS (49.5 mg, 0.22 mmol, 1.1 equiv) were

o dissolved in anhydrous CH 2Cl 2 (27 mL) and cooled to 0 C under Ar. CF 3CO 2H (3 mL) and HBF 4•

o Et 2O (0.11 mL, 0.8 mmol, 4 equiv) were added, and the reaction mixture was stirred at 0 C for 4

hours. Solvents were then removed in vacuo or with stream of N 2. The residue was redissolved in

CH 2Cl 2 (15 mL), washed with aq. NaHCO 3, aq. Na 2S2O3, brine, dried over anhydrous Na 2SO 4, and concentrated in vacuo . The resulting residue was purified by silica gel flash chromatography or

preparative TLC to give the iodinated products.

Protocol B uses 3.3 equiv of NIS and 12 equiv of HBF 4•Et 2O. The iodination was performed at

room temperature for 20 hours with a substrate concentration of 2.5 mM in 9:1

dichloromethane/trifluoroacetic acid. All operations remain unchanged from Protocol A. Protocol

B was used for compounds 94 , 95 , and 96 .

Regioisomeric ortho and para -iodinated products of substrates 90 and 95 cannot be separated using silica gel chromatography. An isomeric mixture of products was obtained and characterized by 1H-NMR. These mixtures were used in the subsequent Cu-mediated cyclization reaction to give

THQ products, which can be readily isolated in high purity. The para-iodinated intermediates do

not cyclize.

88

PA N H I 88

1 H NMR (CDCl 3, 300 MHz, ppm): δ 8.55-8.54 (m, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.18 (s, 1H),

7.88-7.79 (m, 2H), 7.45-7.40 (m, 1H), 7.30-7.23 (m, 2H), 6.91-6.85 (m, 1H), 3.59 (q, J = 6.9 Hz,

13 2H), 2.86-2.80 (m, 2H), 2.00-1.90 (m, 2H); C NMR (CDCl 3, 75 MHz, ppm) δ 164.63, 150.22,

148.31, 144.28, 139.81, 137.62, 129.76, 128.72, 128.17, 126.38, 122.45, 100.79, 39.16, 38.48,

+ 30.44; HRMS : calculated for C 15 H16 IN 2O [M+H ]: 367.0302; found: 367.0310. Rf = 0.1, 20 %

EtOAc in Hex.

PA N H I 89

Spectral characterization for compound 89 can be found in section 4.1.4.

PA N H I 90

1 H NMR (CDCl 3, 300 MHz, ppm): δ 8.54 (d, J = 4.5 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.19 (s,

1H), 7.87 (td, J = 7.7, 1.4 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.44-7.39 (m, 1H), 7.05 (s, 1H), 6.71

(d, J = 7.9 Hz, 1H), 3.58 (q, J =6.8 Hz, 2H), 2.80 (t, J = 7.6 Hz, 2H), 2.26 (s, 3H), 1.98-1.80 (m,

13 2H); C NMR (CDCl 3, 75 MHz, ppm) δ 164.29, 149.91, 148.00, 143.66, 139.15, 138.29, 137.28,

130.39, 128.87, 126.05, 122.10, 96.36, 38.94, 38.03, 30.20, 20.88; HRMS : calculated for

+ C16 H18 IN 2O [M+H ]: 381.0458; found: 381.0468. R f = 0.4, 20% Acetone in Hex.

89

Cl PA N H I 91

1 H NMR (CDCl 3, 300 MHz, ppm): δ 8.54-8.52 (m, 1H), 8.22 (dd, J = 6.8, 0.8 Hz, 2H), 7.86 (td,

J = 7.7, 1.7 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.43-7.39 (m, 1H), 7.20 (d, J = 2.5 Hz, 1H), 6.89

(dd, J = 8.4, 2.6 Hz, 1H), 3.51-3.43 (m, 2H), 2.91 (dd, J = 13.6, 5.7 Hz, 1H), 2.57 (dd, J = 13.6,

13 8.6 Hz, 1H), 2.23-2.16 (m, 1H), 1.02 (d, J = 6.7 Hz, 3H); C NMR (CDCl 3, 75 MHz, ppm) δ

164.56, 149.98, 148.14, 145.04, 140.66, 137.47, 134.48, 130.46, 128.23, 126.24, 122.37, 98.07,

+ 45.38, 45.03, 34.51, 17.49; HRMS : calculated for C 16 H17 ClIN 2O [M+H ]: 415.0069; found:

415.0081. Rf = 0.1, 17 % EtOAc in Hex.

PA N H Br I 92

1 H NMR (CDCl 3, 300 MHz, ppm): δ 8.50 (d, J = 4.5 Hz, 1H), 8.17 (d, J = 7.7 Hz, 1H), 8.07 (s,

1H), 7.94 (d, J = 2.1 Hz, 1H), 7.85 (td, J = 7.6, 1.4 Hz, 1H), 7.44-7.37 (m, 2H), 7.09 (d, J = 8.4

Hz, 1H), 3.46-3.37 (m, 2H), 3.20-3.13 (m, 1H), 1.97-1.85 (m, 2H), 1.24 (d, J = 6.8 Hz, 3H); 13 C

NMR (CDCl 3, 75 MHz, ppm) δ 164.33, 149.92, 148.10, 147.62, 141.45, 137.39, 131.86, 127.60,

126.17, 122.16, 120.38, 101.84, 40.91, 37.65, 37.27, 21.46; HRMS : calculated for C 16 H17 BrIN 2O

+ [M+H ]: 458.9563; found: 458.9570. R f = 0.1, 20 % EtOAc in Hex.

CO2Me PA N H I 93

1 H NMR (CDCl 3, 300 MHz, ppm): δ 8.62-8.58 (m, 2H), 8.20 (d, J = 7.8 Hz, 1H), 7.88 (td, J = 7.7,

90

1.7 Hz, 1H), 7.53 (s, 1H), 7.46-7.42 (m, 1H), 6.98 (s, 1H), 4.90-4.83 (m, 1H), 3.79 (s, 3H), 2.79-

13 2.72 (m, 2H), 2.30-2.18 (m, 1H), 2.14 (s, 6H), 2.11-2.04 (m, 1H); C NMR (CDCl 3, 75 MHz,

ppm) δ 172.44, 164.30, 149.45, 148.38, 140.53, 140.12, 137.39, 137.22, 136.98, 130.87, 126.49,

122.39, 96.48, 52.62, 52.14, 36.27, 33.27, 19.37, 18.86; HRMS : calculated for C 19 H22 IN 2O3

+ [M+H ]: 453.0670; found: 453.0679. R f = 0.60, 33% EtOAc in Hex.

CF3 Cl PA N H Cl I 94

1 H NMR (CDCl 3, 300 MHz, ppm): δ 8.59 (d, J = 4.6 Hz, 1H), 8.27-8.22 (m, 2H), 7.92 (t, J = 7.7

Hz, 1H), 7.84 (s, 1H), 7.52-7.47 (m, 1H), 7.29 (s, 1H), 4.89-4.79 (m, 1H), 2.83-2.78 (m, 2H), 2.25-

13 2.15 (m, 1H), 2.01-1.91 (m, 1H); C NMR (CDCl 3, 75 MHz, ppm) δ 164.63, 148.59, 148.36,

143.13, 140.29, 137.70, 133.03, 131.46, 130.65, 127.02, 126.91, 123.18, 122.87, 97.01, 51.01,

+ 50.60, 50.19, 49.78, 36.03, 28.85; HRMS : calculated for C 16 H13 Cl 2F3IN 2O [M+H ]: 502.9396;

found: 502.9407. R f = 0.50, 25% EtOAc in Hex.

O O

PA I N 95 H CF3

1 H NMR (CDCl 3, 300 MHz, ppm): δ 8.53 (d, J = 3.9 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.06 (s,

1H), 7.87 (d, J = 7.7 Hz, 1H), 7.44-7.40 (m, 1H), 7.29 (s, 1H), 6.72 (s, 1H), 4.37-4.27 (m, 1H),

13 2.92 (t, J = 8.0 Hz, 2H), 1.91-1.83 (m, 2H), 1.36 (d, J = 6.6 Hz, 1H); C NMR (CDCl 3, 75 MHz, ppm) δ 163.84, 158.36, 154.42, 150.47, 149.91, 148.09, 140.48, 140.04, 137.54, 135.50, 135.47,

126.31, 123.15, 122.40, 119.49, 117.97, 116.19, 116.12, 116.04, 113.49, 94.91, 45.05, 38.17,

91

+ 37.06, 21.26; HRMS : calculated for C 20 H17 F3IN 2O3 [M+H ]: 517.0230; found: 517.0237. R f =

0.30, 25 % EtOAc in Hex.

MeO C PA 2 N H I 96

1 H NMR (CDCl 3, 300 MHz, ppm): δ 8.53-8.51 (m, 1H), 8.21-8.18 (m, 1H), 8.03 (d, J = 7.8 Hz,

1H), 7.85-7.80 (m, 3H), 7.48 (dd, J = 8.3, 2.1 Hz, 1H), 7.42-7.38 (m, 1H), 4.32-4.27 (m, 1H), 3.86

13 (s, 3H), 2.87-2.81 (m, 2H), 1.89-1.81 (m, 2H), 1.35 (d, J = 6.6 Hz, 3H); C NMR (CDCl 3, 75

MHz, ppm) δ 166.89, 163.95, 150.23, 148.26, 145.13, 140.00, 137.62, 130.66, 130.19, 128.69,

126.37, 122.49, 106.94, 52.51, 45.48, 37.89, 37.67, 21.32; HRMS : calculated for C 18 H20 IN 2O3

+ [M+H ]: 439.0513; found: 439.0518. R f = 0.13, 25 % EtOAc in Hex.

F PA N H I 97

1 H NMR (CDCl 3, 300 MHz, ppm): δ 8.55 (d, J = 4.4 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.00 (d, J

= 8.0 Hz, 1H), 7.88 (td, J = 7.7, 1.3 Hz, 1H), 7.73 (dd, J = 8.6, 5.7 Hz, 1H), 7.45-7.41 (m, 1H),

7.01(dd, J = 9.6, 2.8 Hz, 1H), 6.67 (td, J = 8.4, 2.9 Hz, 1H), 4.35-4.25 (m, 1H), 2.81 (t, J = 5.7 Hz,

13 2H), 1.89-1.69 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H); C NMR (CDCl 3, 75 MHz, ppm) δ 164.62,

163.62, 161.34, 149.88, 147.93, 146.52, 146.43, 140.38, 140.28, 137.29, 126.05, 122.15, 116.59,

116.30, 115.24, 114.95, 93.07, 93.03, 44.97, 37.60, 37.15, 21.01; HRMS : calculated for

+ C16 H17 FIN 2O [M+H ]: 399.0364; found: 399.0373. Rf = 0.60, 25 % EtOAc in Hex.

92

F I

H N PA 99

1 H NMR (500 MHz, CDCl 3) δ 8.26 (d, J = 4.2 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.72 (td, J = 7.7,

1.5 Hz, 1H), 7.61 (d, J = 6.0 Hz, 1H), 7.51-7.44 (m, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.29 (dd, J =

6.7, 4.9 Hz, 1H), 6.66 (dd, J = 10.3, 8.7 Hz, 1H), 4.05 (td, J = 8.5, 3.7 Hz, 1H), 2.92 (s, 1H), 2.90

(s, 1H), 2.79 (s, 1H), 2.00 (dd, J = 13.5, 8.7 Hz, 1H), 1.82 (m, 1H), 1.78-1.63 (m, 2H), 1.52-1.39

13 (m, 1H), 1.39-1.28 (m, 1H); C NMR (126 MHz, CDCl 3) δ 162.89, 162.62, 160.65, 149.65,

147.66, 138.43, 138.39, 137.08), 136.80, 136.74, 130.69, 130.57, 125.80, 121.70, 118.21, 118.02,

87.51, 87.48, 52.84, 48.36, 46.39, 46.36, 38.03, 37.86, 37.85, 28.46, 27.50; HRMS : calculated for

+ C19 H18 FIN 2O [M+H ]: 437.0521; found: 437.0520.

4.1.8. Pd-catalyzed ortho iodination

A mixture of picolinamide substrate (0.2 mol, 1.0 equiv), Pd(OAc) 2 (4.5 mg, 0.02 mol, 0.1 equiv),

I2 (102 mg, 0.4 mol, 2.0 equiv), PhI(OAc) 2 (129 mg, 0.4 mol, 2.0 equiv), and KHCO 3 (20 mg, 0.2

mol, 1.0 equiv) in DMF (4 mL) in a 10 mL glass vial (purged with Ar, sealed with PTFE cap) was

heated at 110 oC for 24 hours. Then the reactions mixture was cooled to room temperature and water was added. The mixture was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried over Na 2SO 4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the iodinated product.

93

PA I N H 100 Compound 100 was isolated in 47% yield as a colorless oil. Spectral data from compound 100 produced via Pd-catalyzed C–H iodination is consistent with that produced via directed EAS iodination.

PA I N H 101

1 Compound 101 was isolated in 75% yield as a colorless oil. H NMR (500 MHz, CDCl 3) δ 8.54

(d, J = 4.1 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.84 (td, J = 7.7, 1.5 Hz,

1H), 7.64 (d, J = 7.8 Hz, 1H), 7.41 (m, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.74 (t, J = 7.7 Hz, 1H), 4.40-

4.28 (m, 1H), 2.93-2.81 (m, 2H), 2.36 (s, 3H), 1.83-1.69 (m, 2H), 1.37 (d, J = 6.6 Hz, 3H); 13 C

NMR (126 MHz, CDCl 3) δ 163.82, 150.13, 148.08, 142.46, 137.66, 137.46, 137.32, 130.62,

127.83, 126.16, 122.33, 101.93, 45.70, 35.67, 35.06, 21.10, 21.02; HRMS : calculated for

+ C17 H19 IN 2O [M+H ]: 395.0615; found: 395.0614.

I H N PA OMe 102 Spectral characterization for compound 102 can be found in section 4.1.4.

94

I H N PA

NO2 103

1 Compound 103 was isolated in 68% yield as a colorless oil. H NMR (500 MHz, CDCl 3) δ 8.55

(d, J = 4.2 Hz, 1H), 8.24 (s, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.85 (td, J =

7.7, 1.5 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.42 (dd, J = 6.6, 4.9 Hz, 1H), 7.04 (t, J = 8.0 Hz, 1H),

13 3.64 (q, J = 6.6 Hz, 2H), 3.04-2.94 (m, 2H), 2.11-1.97 (m, 2H); C NMR (126 MHz, CDCl 3) δ

164.56, 150.38, 149.99, 148.16, 144.03, 137.92, 137.51, 128.58, 126.25, 124.54, 122.37, 102.96,

+ 39.29, 35.39, 29.30; HRMS : calculated for C 15 H14 IN 3O3 [M+H ]: 412.0153; found: 412.0153.

I H N MeO PA

104

1 Compound 104 was isolated in 68% yield as a colorless oil. H NMR (500 MHz, CDCl 3) δ 8.54

(d, J = 4.3 Hz, 1H), 8.21 (d, J = 7.7 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.84 (t, J = 7.2 Hz, 1H),

7.62 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 6.6, 5.2 Hz, 1H), 6.82 (d, J = 2.7 Hz, 1H), 6.47 (dd, J = 8.6,

2.7 Hz, 1H), 4.37-4.20 (m, 1H), 3.75 (s, 3H), 2.88-2.66 (m, 2H), 1.85 (m, 2H), 1.33 (d, J = 6.6 Hz,

13 3H); C NMR (126 MHz, CDCl 3) δ 163.76, 160.16, 150.15, 148.07, 145.43, 139.94, 137.48,

126.18, 122.35, 115.47, 114.10, 88.91, 55.43, 45.20, 37.84, 37.55, 21.22; HRMS : calculated for

+ C17 H19 IN 2O2 [M+H ]: 411.0564, found: 411.0564.

95

F

I NH PA 106

1 Compound 106 was isolated in 53% yield as a white solid. H NMR (500 MHz, CDCl 3) δ 8.13 (d,

J = 4.0 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.71 (td, J = 7.7, 1.6 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H),

7.39 (d, J = 5.5 Hz, 1H), 7.32-7.19 (m, 1H), 7.04 (dd, J = 11.4, 8.7 Hz, 1H), 6.84 (td, J = 7.9, 5.5

Hz, 1H), 4.05 (dd, J = 14.0, 6.0 Hz, 1H), 3.30 (d, J = 4.5 Hz, 1H), 2.98 (s, 1H), 2.88 (s, 1H), 2.08

13 (m, 2H), 1.95-1.80 (m, 1H), 1.80-1.61 (m, 1H), 1.45-1.31 (m, 2H); C NMR (126 MHz, CDCl 3)

δ 162.81, 160.60, 158.60, 149.80, 147.37, 137.12, 136.89, 136.87, 129.87, 129.75, 128.84, 128.77,

125.71, 121.77, 117.65, 117.44, 102.56, 102.52, 56.76, 56.73, 52.71, 47.92, 40.48, 40.40, 39.06,

+ 39.00, 29.99, 25.49; HRMS : calculated for C 19 H18 FIN 2O [M+H ]: 437.0521; found: 437.0516.

I NH PA 107

1 Compound 107 was isolated in 56% yield as a colorless oil. H NMR (400 MHz, CDCl 3) δ 8.16

(d, J = 4.1 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 7.0 Hz, 1H), 7.70 (td, J = 7.7, 1.6 Hz,

1H), 7.27-7.24 (m, 2H), 7.09 (s, 1H), 6.75 (t, J = 7.3 Hz, 1H), 4.06 (td, J = 8.8, 3.0 Hz, 1H), 3.27

(s, 1H), 3.18 (s, 1H) 2.99 (s, 1H), 2.56 (s, 3H), 2.16-1.89 (m, 3H), 1.80-1.77 (m, 1H), 1.42-1.37

13 (m, 2H); C NMR (101 MHz, CDCl 3) δ 162.89, 149.86, 147.46, 139.42, 136.99, 133.51, 127.19,

125.68, 121.70, 60.21, 52.22, 49.65, 41.22, 38.70, 30.65, 25.22, 23.14. HRMS : calculated for

+ C20 H22 IN 2O [M+H ]: 433.0771; found: 433.0770.

96

4.1.9. Cu-catalyzed cyclization reactions.

Procedure for CuI-catalyzed cyclization:79 A mixture of ortho -iodinated compound (0.2 mmol,

1.0 equiv), copper iodide (3.8 mg, 0.02 mmol, 0.1 equiv), and CsOAc (96 mg, 0.5 mmol, 2.5 equiv)

in DMSO (2 mL) was heated at 90 oC under Ar for 20 hours. The reaction mixture was cooled to rt, diluted with EtOAc, washed with water and brine, dried over anhydrous Na 2SO 4, and concentrated in vacuo . The resulting residue was purified by silica gel flash chromatography to give the cyclized product.

N PA

64

1 Compound 64 (Rf = 0.15, 33% EtOAc in Hex) was isolated in 93% yield. H NMR (CDCl 3, 300

MHz, ppm): δ 8.51 (d, J = 4.2 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.29-

7.25 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.02 (t, J = 7.9 Hz, 1H), 6.88 (s, 2H), 3.94 (t, J = 6.1 Hz,

13 2H), 2.88 (t, J = 6.6 Hz, 2H), 2.09-2.00 (m, 2H); C NMR (CDCl 3, 75 MHz, ppm) δ 168.17,

154.59, 148.71, 138.49, 136.54, 131.18, 128.46, 125.49, 124.59, 124.54, 124.27, 123.51, 44.51,

+ 26.74, 23.70; HRMS : calculated for C 15 H15 N2O [M+H ]: 239.1179; found: 239.1188.

N PA 4-13

1 Compound 4-13 (Rf = 0.20, 33% EtOAc in Hex) was isolated in 86% yield. H NMR (CDCl 3, 300

MHz, ppm): δ 8.48 (s, 1H), 7.62 (t, J = 7.1 Hz, 1H), 7.29-7.26 (m, 1H), 7.23-7.19 (m, 1H), 7.15

97

(d, J = 7.4 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.86-6.83 (m, 1H), 6.63 (s, 1H), 4.83 (s, 1H), 2.82-

13 2.71 (m, 2H), 2.45-2.39 (m, 1H), 1.59-1.47 (m, 1H), 1.28 (d, J = 6.5 Hz, 3H); C NMR (CDCl 3,

75 MHz, ppm) δ 168.00, 155.03, 149.03, 137.27, 136.36, 127.77, 126.12, 125.88, 125.06, 124.16,

+ 123.37, 49.55, 31.72, 25.51, 19.54; HRMS : calculated for C 16 H17 N2O [M+H ]: 253.1355; found:

253.1338.

N PA 108

1 Compound 108 (Rf = 0.20, 33% EtOAc in Hex) was isolated in 83% yield. H NMR (CDCl 3, 300

MHz, ppm): δ 8.51 (s, 1H), 7.68-7.66 (m, 1H), 7.46 (s, 1H), 7.24 (s, 1H), 6.94 (s, 1H), 6.68 (s,

13 1H), 3.90 (s, 2H), 2.83 (t, J = 6.6 Hz, 2H), 2.23 (s, 3H), 2.04-2.00 (m, 2H); C NMR (CDCl 3, 75

MHz, ppm) δ 168.19, 154.93, 148.90, 136.65, 134.31, 131.17, 129.15, 126.39, 124.56, 124.32,

+ 123.67, 44.54, 26.88, 23.91, 20.85; HRMS : calculated for C 16 H17 N2O [M+H ]: 253.1355; found:

253.1360.

Cl

N PA 109

1 Compound 109 (Rf = 0.20, 33% EtOAc in Hex) was isolated in 87% yield. H NMR (CDCl 3, 400

MHz, ppm): δ 8.51 (s, 1H), 7.76 (t, J = 7.4 Hz, 1H), 7.57 (d, J = 6.9 Hz, 1H), 7.31 (t, J = 5.8 Hz,

1H), 7.10 (s, 1H), 6.87 (s, 1H), 4.06 (s, 1H), 3.36 (dd, J = 12.1, 9.7 Hz, 1H), 2.95 (dd, J = 16.4,

5.5 Hz, 1H), 2.51 (dd, J = 16.3, 9.4 Hz, 1H), 2.16 (s, 1H), 1.07 (d, J = 5.8 Hz, 3H); 13 C NMR

98

(CDCl 3, 75 MHz, ppm) δ 168.37, 154.37, 148.80, 136.96, 136.79, 131.94, 129.68, 128.68, 125.68,

+ 125.63, 124.71, 123.94, 51.56, 35.28, 29.45, 19.00; HRMS : calculated for C 16 H16 ClN 2O [M+H ]:

287.0946; found: 287.0951.

Br N PA 110

1 Compound 110 (Rf = 0.40, 33% EtOAc in Hex) was isolated in 80% yield. H NMR (CDCl 3, 300

MHz, ppm): δ 8.50 (s, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.32-7.26 (m, 1H),

7.16-7.06 (m, 3H), 3.94-3.90 (m, 1H), 3.86-3.78 (m, 1H), 2.94-2.88 (m, 1H), 2.20-2.10 (m, 1H),

13 1.68-1.56 (m, 1H), 1.35 (d, J = 6.9 Hz, 3H); C NMR (CDCl 3, 75 MHz, ppm) δ 168.38, 154.19,

148.85, 139.30, 136.95, 135.00, 128.15, 127.69, 127.52, 124.81, 123.93, 118.73, 43.75, 31.74,

+ 30.64, 20.38; HRMS : calculated for C 16 H16 BrN 2O [M+H ]: 331.0441; found: 331.0449.

N CO2Me PA 111

1 Compound 111 (Rf = 0.15, 33% EtOAc in Hex) was isolated in 82% yield. H NMR (CDCl 3, 300

MHz, ppm): δ 8.44 (s, 1H), 7.69 (t, J = 7.0 Hz, 1H), 7.50 (s, 1H), 7.23 (s, 1H), 6.87 (s, 1H), 6.22

(s, 1H), 5.20 (t, J = 8.0 Hz, 1H), 3.70 (s, 3H), 2.72 (t, J = 5.7 Hz, 2H), 2.56 (s, 1H), 2.11 (s, 3H),

13 1.87 (s, 4H); C NMR (CDCl 3, 75 MHz, ppm) δ 172.13, 168.31, 154.13, 148.77, 136.51, 135.25,

134.39, 133.20, 128.64, 126.26, 124.51, 124.05, 56.26, 52.37, 28.29, 25.53, 19.33, 19.18; HRMS :

+ calculated for C 19 H21 N2O3 [M+H ]: 325.1547; found: 325.1554.

99

Cl Cl

Cl N CF3 Cl N CF3 PA H 112 112-1

Both 112 and 112-1 were obtained. Compound 112 (Rf = 0.40, 33% EtOAc in Hex) was isolated

1 in 31% yield. H NMR (CDCl 3, 300 MHz, ppm): δ 8.33 (d, J = 4.6 Hz, 1H), 7.80 (td, J = 7.7, 1.4

Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.30-7.26 (m, 2H), 6.70 (s, 1H), 5.63-5.50 (m, 1H), 2.79-2.75

13 (m, 2H), 2.69-2.58 (m, 1H), 2.06-1.93 (m, 1H); C NMR (CDCl 3, 75 MHz, ppm) δ 168.07,

152.67, 148.51, 137.64, 137.12, 133.94, 130.08, 129.69, 128.90, 127.38, 127.21, 125.29, 124.45,

+ 123.45, 53.07, 52.66, 52.25, 51.84, 24.74, 24.54; HRMS : calculated for C 16 H12 Cl 2F3N2O [M+H ]:

375.0273; found: 375.0281.

1 Compound 112-1 was isolated in 48% yield. H NMR (CDCl 3, 300 MHz, ppm): δ 7.04 (s, 1H),

6.66 (s, 1H), 4.17 (s, 1H), 3.88-3.82 (m, 1H), 2.81-2.68 (m, 2H), 2.10 (q, J = 6.3 Hz, 2H); 13 C

NMR (CDCl 3, 75 MHz, ppm) δ 141.51, 131.17, 130.46, 130.31, 127.44, 123.71, 120.86, 120.83,

115.64, 53.06, 52.66, 52.25, 51.85, 23.58, 20.27, 20.25; HRMS : calculated for C 10 H7Cl 2F3 [M-

H-]: 267.9913; found: 267.9906.

O O

N

CF3 PA 113

1 Compound 113 (Rf = 0.20, 33% EtOAc in Hex) was isolated in 72% yield. H NMR (CDCl 3, 300

MHz, ppm): δ 8.34 (s, 1H), 7.73-7.68 (m, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.24-7.20 (m, 2H), 6.91

100

(s, 1H), 6.62 (s, 1H), 4.90 (s, 1H), 2.91 (d, J = 6.5 Hz, 2H), 2.52-2.48 (m, 1H), 1.63-1.54 (m, 1H),

13 1.32 (d, J = 6.5 Hz, 3H); C NMR (CDCl 3, 75 MHz, ppm) δ 168.22, 158.96, 154.02, 151.30,

148.82, 141.32, 140.88, 136.99, 135.05, 124.69, 123.93, 122.98, 121.95, 119.32, 116.46, 115.40,

+ 115.32, 115.25, 111.38, 49.71, 31.13, 26.09, 19.67; HRMS : calculated for C 20 H16 F3N2O3 [M+H ]:

389.1108; found: 389.1112.

MeO2C

N PA 114

1 Compound 114 (Rf = 0.20, 33% EtOAc in Hex) was isolated in 80% yield. H NMR (CDCl 3, 300

MHz, ppm): δ 8.42 (d, J = 4.0 Hz, 1H), 7.83 (s, 1H), 7.68 (t, J = 6.7 Hz, 1H), 7.52 (d, J = 7.4 Hz,

1H), 7.45 (d, J = 7.7 Hz, 1H), 7.26-7.21(m, 1H), 6.71 (d, J = 6.8 Hz, 1H), 4.83-4.77 (m, 1H), 3.84

(s, 3H), 2.85 (t, J = 6.6 Hz, 2H), 2.44-2.33 (m, 1H), 1.65-1.54 (m, 1H), 1.27 (d, J = 6.5 Hz, 3H);

13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.27, 166.75, 154.41, 148.91, 141.77, 136.72, 132.11,

129.59, 127.22, 126.18, 125.63, 124.65, 123.72, 52.08, 49.80, 30.86, 25.01, 19.20; HRMS :

+ calculated for C 18 H19 N2O3 [M+H ]: 311.1390; found: 311.1403.

F

N PA 115

1 Compound 115 (Rf = 0.20, 33% EtOAc in Hex) was isolated in 81% yield. H NMR (CDCl 3, 300

MHz, ppm): δ 8.48 (s, 1H), 7.67 (t, J = 7.1 Hz, 1H), 7.36 (s, 1H), 7.24 (s, 1H), 6.88 (d, J = 8.4 Hz,

1H), 6.57 (s, 2H), 4.81 (s, 1H), 2.78-2.69 (m, 2H), 2.40 (s, 1H), 1.58-1.49 (m, 1H), 1.27 (d, J = 6.5

101

13 Hz, 3H); C NMR (CDCl 3, 75 MHz, ppm) δ 167.88, 161.45, 158.21, 154.77, 148.93, 136.55,

133.20, 127.40, 127.29, 124.29, 123.41, 114.53, 114.23, 112.90, 112.60, 49.50, 31.36, 25.63,

+ 19.33; HRMS : calculated for C 16 H16 FN 2O [M+H ]: 271.1241; found: 271.1245.

N PA 116

1 Compound 116 was isolated in 96% yield as a colorless oil. H NMR (500 MHz, CDCl 3) δ 8.43

(d, J = 1.8 Hz, 1H), 7.55 (s, 1H), 7.26 (s, 1H), 7.16 (s, 1H), 6.82 (d, J = 7.3 Hz, 1H), 6.69 (s, 1H),

6.40 (s, 1H), 4.83 (s, 1H), 2.72 (m, 1H), 2.65-2.47 (m, 1H), 2.32 (m, 1H), 2.22 (s, 3H), 1.58 (m,

13 1H), 1.19 (d, J = 6.6 Hz, 3H); C NMR (126 MHz, CDCl 3) δ 167.85, 155.05, 148.83, 136.64,

136.31, 135.54, 130.31, 126.38, 125.02, 124.00, 123.95, 123.26, 48.46, 30.56, 21.74, 19.2, 18.36;

+ HRMS : calculated for C 17 H18 N2O [M+H ]: 267.1492; found: 267.1495.

MeO

N PA 117

1 Compound 117 was isolated in 94% yield as a pale yellow oil. H NMR (500 MHz, CDCl 3) δ 8.50

(s, 1H), 7.60 (s, 1H), 7.21 (s, 2H), 6.69 (s, 1H), 6.34 (s, 2H), 4.90 (s, 1H), 3.72 (s, 3H), 2.73 (m,

13 2H), 2.43 (s, 1H), 1.49 (s, 1H), 1.25 (d, J = 6.4 Hz, 3H); C NMR (126 MHz, CDCl 3) δ 167.49,

157.00, 155.13, 148.99, 136.56, 127.13, 124.11, 123.40, 112.88), 111.47, 55.43, 49.34, 32.31,

+ 26.45, 19.87; HRMS : calculated for C 17 H18 N2O2 [M+H ]: 283.1441; found: 283.1442.

102

NO2

N PA 118

1 Compound 118 was isolated in 47% yield as a yellow solid. H NMR (500 MHz, CDCl 3) δ 8.48

(s, 1H), 7.79 (t, J = 7.4 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.38-7.29 (m,

1H), 7.14 (s, 1H), 7.08 (s, 1H), 3.94 (t, J = 6.0 Hz, 2H), 3.14 (t, J = 6.6 Hz, 2H), 2.06 (m, 2H); 13 C

NMR (126 MHz, CDCl 3) δ 168.75, 153.76, 149.48, 148.78, 140.83, 137.28), 129.69, 125.85,

+ 125.18, 124.40, 120.79, 44.98, 23.78, 23.30; HRMS : calcullated for C 15 H13 N3O3 [M+H ]:

284.1030; found: 284.1030.

N PA

119

1 Compound 119 was isolated in 85% yield as an off white solid. H NMR (500 MHz, CDCl 3) δ

8.59 (s, 1H), 7.77 (s, 1H), 7.57 (s, 1H), 7.32 (s, 1H), 6.87 (s, 2H), 2.91 (s, 1H), 2.42 (s, 1H), 2.31

(m, 4H), 1.93-1.71 (m, 2H), 1.72-1.58 (m, 1H), 1.53 (dd, J = 13.5, 7.3 Hz, 2H); 13 C NMR (126

MHz, CDCl 3) δ 167.44, 155.51, 148.97, 137.09, 136.04, 135.91, 129.63, 126.06, 125.73, 124.47,

123.68, 121.58, 46.97, 44.67, 39.78, 34.46, 29.81, 29.19, 24.89, 19.58; HRMS : calculated for

+ C20 H20 N2O [M+H ]: 305.1649; found: 305.1650.

103

F

N PA

120

1 Compound 120 was isolated in 78% yield as a colorless oil. H NMR (400 MHz, CDCl 3) δ 8.59

(d, J = 4.0 Hz, 1H), 7.81-7.77 (m, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.35 (dd, J = 6.9, 5.1 Hz, 1H),

7.01 (s, 1H), 6.74 (t, J = 8.6 Hz, 1H), 4.42-4.38 (m, 1H), 3.08 (s, 1H), 2.50 (s, 1H), 2.27 (s, 1H),

1.84-1.79 (m, 2H), 1.57-1.63 (m, 1H), 1.56-1.52 (m, 1H), 1.26-1.21 (m, 2H); 13 C NMR (101 MHz,

CDCl 3) δ 167.72, 161.40, 158.99, 154.98, 148.95, 137.64, 137.19, 126.79, 124.75, 123.77, 119.02,

118.82, 118.71, 118.68, 110.52, 110.30, 45.51, 42.71, 38.82, 34.77, 29.15, 24.64; HRMS

+ calculated for C 19 H17 FN 2O [M+H ]: 309.1398, Found: 309.1402.

4.1.10. Synthesis of (+)-angustureine.

PhthN 4-14 3-octanol (1.59 mL, 10 mmol, 1 equiv) was dissolved in THF (50 mL), PhthNH (1.765 g, 12 mmol,

o 1.2 equiv) and PPh 3 (3.148 g, 12 mmol, 1.2 equiv) were added. The mixture was cooled to 0 C,

and DEAD (40 wt % in toluene, 5.47 mL, 12 mmol, 1.2 equiv) was added. The reaction mixture

was warmed to rt and stirred under Ar overnight. The mixture was then concentrated in vacuo and

the residue suspended in Et 2O/Hexanes (4/1), and filtered through a short silica plug and concentrated in vacuo and purified by silica gel flash chromatography to give 4-14 as a clear oil

1 (1.90 g, 73%). Rf = 0.15, 10% EtOAc in Hex. H NMR (CDCl 3, 400 MHz, ppm): δ 7.82-7.77 (m,

2H), 7.70-7.66 (m, 2H), 4.13-4.05 (m, 1H), 2.09-1.99 (m, 2H), 1.79-1.65 (m, 2H), 1.30-1.21 (m,

104

13 6H), 0.86-0.79 (m, 6H); C NMR (CDCl 3, 75 MHz, ppm) δ 168.86, 133.86, 133.84, 133.81,

131.89, 123.19, 123.09, 123.07, 53.97, 32.20, 31.50, 26.38, 25.61, 22.54, 14.02, 11.19; HRMS :

+ calculated for C 16 H22 NO 2 [M+H ]: 260.1645; found: 260.1649.

H N PA 145

Compound 4-14 (1.9 g, 7.3 mmol, 1.0 eq.) was dissolved in MeOH (30 mL), and H 2NNH 2.H 2O

(1.8 mL, 36.6 mmol, 5.0 equiv) was added at rt. The resulting mixture was stirred overnight before

water was added and extracted with DCM. The combined organic layers were washed with water

and brine, dried over anhydrous Na 2SO 4, and concentrated in vacuo . The resulting residue was

dissolved in dry DCM (30 mL), and to this solution picolinic acid (1.1 g, 8.8 mmol, 1.2 equiv),

EDCI (1.7 g, 8.8 mmol, 1.2 equiv), HOBt.H 2O (1.2 g, 8.8 mmol, 1.2 equiv) and DIPEA (2.6 mL,

14.6 mmol, 2.0 equiv) were added. The resulting mixture was stirred overnight. Water was added

and the mixture was extracted with DCM. The combined organic layers were washed with water

and brine, dried over anhydrous Na 2SO 4, and concentrated in vacuo . The resulting residue was

purified by silica gel flash chromatography to give 145 (880 mg, 51%). Rf = 0.15, 10% EtOAc in

1 hexanes; H NMR (CDCl 3, 300 MHz, ppm): δ 8.56 (d, J = 4.5 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H),

7.85-7.81 (m, 2H), 7.42-7.38 (m, 1H), 4.09-3.97 (m, 1H), 1.66-1.49 (m, 4H), 1.37-1.26 (m, 6H),

13 0.96 (t, J = 7.4 Hz, 3H), 0.85 (s, 3H); C NMR (CDCl 3, 75 MHz, ppm) δ 164.22, 150.48, 148.26,

137.64, 126.28, 122.59, 51.11, 35.18, 32.14, 28.45, 26.02, 22.89, 14.37, 10.67; HRMS : calculated

+ for C 14 H23 N2O [M+H ]: 235.1805; found: 235.1814.

105

HN PA 146 A mixture of picolinamide 146 (0.880 g, 3.76 mmol, 1.0 equiv), PhI (0.44 mL, 3.95 mmol, 1.05

equiv), Pd(OAc) 2 (84 mg, 0.376 mmol, 0.1 equiv), Ag 2CO 3 (1.55 g, 5.64 mmol, 1.5 equiv),

(BnO) 2PO 2H (0.209 g, 0.752 mmol, 0.2 equiv), and LiCl (0.159 g, 3.76 mmol, 1.0 equiv) in mixed solvent of toluene (6.6 mL) and t-AmylOH (0.73 mL) was heated at 110 oC under Ar for 24 hours.

The reaction mixture was cooled to rt, diluted with EtOAc, filtered through a pad of celite, and

concentrated in vacuo . The resulting residue was purified by silica gel flash chromatography to

1 give 146 (970 mg, 83% yield). H NMR (CDCl 3, 300 MHz, ppm): δ 8.56 (d, J = 4.6 Hz, 1H), 8.24

(d, J = 7.8 Hz, 1H), 7.90-7.82 (m, 2H), 7.44-7.40 (m, 1H), 7.28-7.12 (m, 5H), 4.24-4.15 (m, 1H),

2.74-2.67 (m, 2H), 2.00-1.77(m, 2H), 1.69-1.49 (m, 2H), 1.39-1.27 (m, 6H), 0.88(m, 3H); 13 C

NMR (CDCl 3, 75 MHz, ppm) δ 163.58, 149.78, 147.64, 141.63, 136.95, 128.04, 128.03, 125.69,

125.45, 121.90, 48.95, 37.02, 35.10, 32.23, 31.43, 25.35, 22.46, 13.77; HRMS : calculated for

+ C20 H27 N2O [M+H ]: 311.2118; found: 311.2127.

N PA 148 Compound 146 (310 mg, 1.0 mmol, 1.0 equiv) was dissolved in a mixture of DCM/TFA (9/1, 200

o mL) and cooled to 0 C. HBF 4.OEt 2 (549 µL, 4.0 mmol, 4.0 equiv) and NIS (247 mg, 1.1 mmol,

1.1 equiv) were added. The resulting mixture was stirred for 4 hours before solvent was removed.

The residue was dissolved in DCM and washed with saturated NaHCO 3, saturated Na 2S2O3 and brine, then dried over anhydrous Na 2SO 4, and concentrated in vacuo . The crude product was

106 dissolved in DMSO (10 mL), and CuI (19.1 mg, 0.1 mmol, 0.1 equiv), CsOAc (480 mg, 2.5 mmol,

2.5 equiv) were added. The reaction mixture was heated at 90 oC under argon for 20 hours then cooled to rt, and diluted with ethyl acetate, washed with water and brine, dried over anhydrous

Na 2SO 4, concentrated in vacuo . The resulting residue was purified by silica gel flash

1 chromatography to give the cyclized product 148 (251 mg, 81%). H NMR (CDCl 3, 400 MHz, ppm): δ 8.46 (s, 1H), 7.58 (s, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.99 (t, J =

7.0 Hz, 1H), 6.80 (s, 1H), 6.43 (s, 1H), 4.83 (s, 1H), 2.85-2.73 (m, 2H), 2.39 (s, 1H), 1.73-1.64 (m,

13 2H), 1.36-1.25 (m, 7H), 0.85-0.82 (m, 3H); C NMR (CDCl 3, 75 MHz, ppm) δ 167.87, 155.02,

148.80, 137.48, 136.18, 132.77, 127.84, 125.89, 125.62, 124.90, 123.90, 123.15, 52.61, 33.10,

+ 31.59, 29.20, 25.36, 24.95, 22.41, 13.95; HRMS : calculated for C 20 H25 N2O [M+H ]: 309.1961; found: 309.1970.

N

149 Compound 149 (117 mg, 0.38 mmol, 1.0 equiv) was dissolved in THF (2 mL) at 0 oC, and a solution of LiEt 3BH (1.1 mL, 1.1 mmol, 3.0 equiv) was added. After 2 hours, the reaction was

quenched by addition of saturated NH 4Cl followed by 1N NaOH, and extracted with CH 2Cl 2. The combined organic layers were washed with water and brine, dried over anhydrous Na 2SO 4, and

concentrated in vacuo . The residue was dissolved in dry THF (4 mL), and MeI (59 µL, 0.95 mmol,

o 2.5 equiv), K 2CO 3 (210 mg, 1.52 mmol, 4.0 equiv) were added. The solution was heated at 80 C overnight. The reaction mixture was cooled to rt, diluted with EtOAc, filtered through a pad of celite, and concentrated. The resulting residue was purified by flash chromatography to give 149

1 (65 mg, 79%). H NMR (CDCl 3, 300 MHz, ppm): δ 7.14 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 7.2 Hz,

107

1H), 6.64 (t, J = 7.3 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 3.28-3.24 (m, 1H), 2.96 (s, 3H), 2.89-2.78

(m, 1H), 2.72-2.64 (m, 1H), 1.95-1.88 (m, 2H), 1.67-1.55 (m, 1H), 1.46-1.33 (m, 7H), 0.95 (t, J =

13 6.4 Hz, 3H); C NMR (CDCl 3, 75 MHz, ppm) δ 145.45, 128.72, 127.14, 121.88, 115.26, 110.46,

59.02, 38.04, 32.15, 31.25, 25.86, 24.47, 23.65, 22.80, 14.18; HRMS : calculated for C 15 H24 N

[M+H +]: 218.1903; found: 218.1909.

4.1.11. Mechanistic study of iodination reaction with control substrates.

General description : Control substrates were prepared via standard coupling methods. Iodination of these substrates was performed using Protocol A. The reaction mixtures were analyzed using

1H-NMR based on established patterns. No isolation of iodinated products was performed.

O O NEt3,CH2Cl2 Ph NH2 + Cl N 25 °C H 150 Compound 150 is a known compound 161 and was prepared following the reported procedure from

benzoyl chloride and 3-phenylpropylamine. Iodination of compound 150 : >95% conversion, 36%

o-I, 63% p-I.

O O DCC, DMAP Ph OH + OH O N CH2Cl2 N 25 °C 151 Synthesis of 151 : Picolinic acid (123 mg, 1 mmol, 1 equiv), DCC (206 mg, 1 mmol, 1 equiv), and

DMAP (6 mg, 0.05 mmol, 0.05 equiv) was dissolved in 10 mL of CH 2Cl 2. 3-phenyl-1-propanol

108

(0.14 mL, 1 mmol, 1 equiv was added and the mixture was stirred for 2 hours at RT. The reaction mixture was filtered through celite, washed with brine, and dried over anhydrous Na 2SO 4. The

residue was purified by silica gel flash chromatography to give 151 as a clear oil in 64% yield (R f

1 = 0.25, 3:2 Hex/EtOAc). H NMR (CDCl 3, 300 MHz, ppm): δ 8.75 (m, 1H), 8.08 (dd, J = 7.8, 1.0

Hz, 1H), 7.81(td, J = 7.7, 1.7 Hz, 1H), 7.44-7.41 (m, 1H), 7.26-7.15 (m, 5H), 4.44 (t, J = 6.7 Hz,

13 2H), 2.78-2.69 (m, 2H), 2.19-2.03 (m, 2H); C NMR (CDCl 3, 75 MHz, ppm) δ 165.18, 149.93,

148.13, 141.06, 137.03, 128.48, 128.43, 126.91, 126.06, 125.14, 65.28, 32.19, 30.72, 30.16;

+ HRMS : calculated for C 15 H16 NO 2 [M+H ]: 242.1176; found: 242.1180. Iodination of 151: >95%

conversion, 37% o-I, 60% p-I.

O ° O NaH, THF, 0 C; N N H ° N MeI, 25 C N 152-1 152 Synthesis of 152: To the solution of compound 152-1 (240 mg, 1 mmol, 1 equiv) in THF (20 mL)

at 0 oC was added NaH (95%, 67 mg, 2.8 mmol, 2.8 equiv). The reaction was warmed to rt and

stirred for 1 hr under Ar. MeI (0.56 mL, 9 mmol, 9 equiv) was then added and the reaction was

stirred overnight. The reaction mixture was dissolved in water and extracted with CH 2Cl 2. The combined organic layers were washed with brine, dried over anhydrous Na 2SO 4, and concentrated

in vacuo . The residue was purified by silica gel flash chromatography to give 152 as an oil in 90%

1 yield. H NMR (CDCl 3, 300 MHz, ppm, ratio of rotamers: ~1/1.2): δ 8.59 (d, J = 4.8 Hz, 1H),

8.51 (d, J = 5.7 Hz, 1H), 7.81-7.72 (m, 2H), 7.64-7.55 (m, 2H), 7.33-7.17 (m, 10H), 7.07-7.04 (m,

2H), 3.63 (t, J = 7.5 Hz, 2H), 3.41 (t, J = 7.6 Hz, 2.3H), 3.11 (s, 3.6H), 3.02 (s, 2.7H), 2.75 (t, J =

13 7.7 Hz, 2H), 2.50 (t, J = 7.6 Hz, 2.3H), 2.04-1.92 (m, 4.4H); C NMR (CDCl 3, 75 MHz, ppm) δ

169.18, 168.75, 154.69, 154.46, 148.26, 141.59, 140.91, 137.07, 136.98, 128.40, 128.37, 128.36,

109

128.18, 125.95, 125.91, 124.33, 124.26, 123.42, 123.30, 50.53, 47.70, 36.98, 33.49, 33.15, 32.66,

+ 29.68, 28.53, 22.73; HRMS : calculated for C 16 H19 NO 2 [M+H ]: 255.1492; found: 255.1497.

Iodination of 152: >95% conversion. 82% o-I, 15% p-I.

O NH EDCI, HOBt, DIPEA 2 + H OH N PA N CH2Cl2 25 °C 153 Compound 153 is a known compound 35 and was prepared from benzylamine and picolinic acid

using EDCI coupling. Iodination of 153: >95% conversion. 53% o-I, 35% p-I, 10% o-di-I.

O H EDCI, HOBt, DIPEA N + OH PA NH2 N CH2Cl2 154 25 °C Compound 154 is a known compound 20 and was prepared from 2-phenylethyl-1-amine and

picolinic acid using standard EDCI-mediated coupling. Iodination of 154: >95% conversion. 94%

o-I.

H O N EDCI, HOBt, DIPEA PA + OH NH N CH2Cl2 2 ° 25 C 155 Compound 155 was isolated in 82% yield as a clear oil using standard EDCI-mediated coupling.

1 Rf = 0.18, Hex/EtOAc: 3/1. H NMR (CDCl 3, 300 MHz, ppm): δ 8.50-8.48 (m, 1H), 8.19 (dd, J =

7.8, 1.0 Hz, 1H), 8.07 (s, 1H), 7.80-7.75 (m, 1H), 7.37-7.34 (m, 1H), 7.27-7.16 (m, 2H), 7.15-7.14

13 (m, 3H), 3.50 (t, J = 6.8 Hz, 2H), 2.65 (t, J = 7.1 Hz, 2H), 1.73-1.61 (m, 4H); C NMR (CDCl 3,

110

75 MHz, ppm) δ 164.40, 150.16, 148.16, 142.27, 137.48, 128.58, 128.48, 126.21, 125.95, 122.31,

+ 39.41, 35.68, 29.43, 28.92; HRMS : calculated for C 16 H19 N2O [M+H ]: 255.1492; found :

255.1497. Iodination of 155: >95% conversion. 68% o-I, 22% p-I, 10% o-di-I.

° O O MeOH, 25 C + Ph NH2 N CF3 O CF3 H 156 Compound 156 is a known compound 78 was prepared following the reported procedure in 95% yield. Iodination of 156: >95% conversion. 83% o-I, 7% p-I, 10% x.

O O Tf O, NEt ,CH Cl 2 3 2 2 S Ph NH2 N CF3 H 157 Compound 157 is a known compound 18 and was prepared following the reported procedure from

triflic anhydride and 3-phenylpropyl-1-amine. Iodination of 157: >95% conversion. 36% o-I, 62%

p-I.

O O O O S NEt3, CH2Cl2 S Ph NH2 + N Cl H N 25 °C N 158

Synthesis of 158: 3-phenylpropyl-1-amine (0.14 mL, 1 mmol, 1 equiv) was dissolved in CH 2Cl 2

o (4 mL) and NEt 3 (0.42 mL, 3 mmol, 3 equiv). At 0 C. pyridine-2-sulfonyl chloride (0.36 mL, 3 mmol, 3 equiv) was added dropwise and the reaction was warmed to rt and stirred overnight. The reaction mixture was diluted with H 2O and washed with sat. NaHCO 3, brine, dried over anhydrous

Na 2SO 4, then concentrated in vacuo . The residue was purified by silica gel flash chromatography

111

1 (Hex/EtOAc) to give 158 as a white solid in 40% yield (Rf = 0.37, Hex/EtOAc: 1/1). H NMR

(CDCl 3, 300 MHz, ppm): δ 8.72 (d, J = 4.5 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.94 (td, J = 7.8, 1.6

Hz, 1H), 7.50-7.46 (m, 1H), 7.28-7.10 (m, 5H), 5.64 (t, J = 6.1 Hz, 1H), 3.11 (q, J = 6.7 Hz, 2H),

13 2.66 (t, J = 7.4 Hz, 2H), 1.92-1.78 (m, 2H); C NMR (CDCl 3, 75 MHz, ppm) δ 157.64, 150.29,

141.25, 138.39, 128.70, 128.63, 126.96, 126.29, 122.63, 43.33, 32.91, 31.64; HRMS : calculated

+ for C14 H17 N2O2S [M+H ]: 277.1005; found: 277.1011 . Iodination of 158: >95% conversion. 20%

o-I, 72% p-I.

NH2 F F F Toluene, F CF O O 3 + ° Ph Cl F F 110 C N F H CF3 F 159

Compound 159 was prepared follow the reported procedure: 162 Hydrocinnamoyl chloride (169 mg,

1.0 mmol) was added to a vigorously stirring solution of 2,3,5,6-tetrafluoro-4-

(trifluoromethyl)aniline (233 mg, 1.0 mmol) in anhydrous toluene (1 mL). The reaction mixture was stirred for 12 h at 110 oC. The reaction mixture was concentrated in vacuo and purified by

1 silica gel flash chromatography to give 159 (253 mg, 69%). R f = 0.40, 15% EtOAc in hexanes. H

NMR (CDCl 3, 300 MHz, ppm): δ 7.35-7.30 (m, 2H), 7.26-7.23 (m, 3H), 6.87 (s, 1H), 3.10 (t, J =

13 7.4 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H); C NMR (CDCl 3, 75 MHz, ppm) δ 169.97, 139.88, 128.95,

+ 128.46, 126.86, 38.28, 31.37; HRMS : calculated for C 16 H11 F7NO [M+H ]: 366.0723; found:

366.0727. Iodination of 159: >95% conversion. 86% o-I, 12% p-I.

112

O O NEt3,CH2Cl2 + N Cl H N H 2 ° N N 25 C 160 Compound 160 is a known compound and was prepared following the reported procedure, from

hydrocinnamoyl chloride and 8-aminoquinoline. 39 Iodination of 160: >95% conversion. 82% o-I,

9% p-I.

O O EDCI, HOBt, DIPEA H2N OH + N N H CH2Cl2 N 25 °C 161 Compound 161 was isolated in 85% yield as an off-white solid via EDCI-mediated coupling. 1H

NMR (CDCl 3, 300 MHz, ppm): δ 8.50-8.48 (m, 1H), 7.66 (td, J = 7.7, 1.8 Hz, 1H), 7.28-7.16 (m,

7H), 6.90 (s, 1H), 4.54 (d, J = 5.1 Hz, 2H), 3.04 (t, J = 7.4 Hz, 2H), 2.62-2.53 (m, 2H); 13 C NMR

(CDCl 3, 75 MHz, ppm) δ 172.25, 156.54, 148.96, 140.95, 136.85, 128.54, 128.44, 126.22, 122.39,

+ 122.13, 44.53, 38.34, 31.73; HRMS : calculated for C 15 H17 N2O [M+H ]: 241.1335; found:

241.1339. Iodination of 161: >95% conversion. 66% o-I, 30% p-I.

4.1.12. Synthesis of iodo-THQ regioisomers.

Pd(OAc)2 (10 mol%) PhI(OAc)2 (4.0 equiv) I I I2 (4.0 equiv) CuI (10 mol%) KHCO3 (1.0 equiv) CsOAc (2.5 equiv) PA o PA o N DMF, 130 C, 24 h, 69% I N DMSO, 90 C, 20 h, 69% N H H PA 208 207 202

113

I

PA I N H 208 208 was obtained using a modified Pd-catalyzed iodination protocol. Compound 207 (48 mg, 0.2 mmol, 1.0 equiv), PhI(OAc) 2 (260 mg, 0.8 mmol, 4.0 equiv), I 2 (200 mg, 0.8 mmol, 4.0 equiv),

Pd(OAc) 2 (4.5 mg, 0.02 mmol, 0.1 equiv), and KHCO 3 (20 mg, 0.2 mmol, 1.0 equiv) were

dissolved in anhydrous DMF (6 mL, 0.03M) in a 10 mL vial. 4Å molecular sieves (200mg) was

added and the reaction vial was purged with Ar and sealed with a PTFE cap. The mixture was

stirred at 25º C for 1 hr, then heated to 130 ºC for 24 hrs. The reaction mixture was cooled to room

temperature, diluted with EtOAc, then washed with aq. Na 2S2O3 (sat.), H 2O, and brine. The organic

layer was dried over anhydrous Na 2SO 4, filtered, and concentrated in vacuo . The resulting residue

was purified by silica gel flash chromatography to give 208 in 69% yield as a white solid.

I

N PA 202 Compound 202 was obtained from compound 208 using the standard Cu-catalyzed cross coupling

1 protocol in 69% yield as a white solid. H NMR (500 MHz, CDCl 3) δ 8.50 (s, 1H), 7.74 (t, J = 7.2

Hz, 1H), 7.56 (s, 2H), 7.39-7.27 (m, 1H), 7.15-6.70 (m, 1H), 6.62 (s, 1H), 3.89 (s, 2H), 2.85 (t, J

13 = 6.6 Hz, 2H), 2.24-1.85 (m, 2H); C NMR (126 MHz, CDCl 3) δ 168.24, 154.39, 148.84, 139.78,

137.03, 135.60, 133.47, 127.04, 125.37, 124.77, 124.08, 101.42, 44.72, 33.65, 24.56; HRMS:

+ calculated for C 15 H13 IN 2O [M+H ]: 365.0145, found: 365.0150.

114

I NIS (1.1 equiv)

N TFA/DCM = 1/9, 88% N PA PA 210 203 Compound 203 was prepared from compound 210 using EAS iodination with NIS. Picolinamide substrate 210 (47.6 mg, 0.2 mmol, 1 equiv) and NIS (49.5 mg, 0.22 mmol, 1.1 equiv) were

dissolved in a mixture of anhydrous CH 2Cl 2 (27 mL) and TFA (3 mL) at room temperature. After

16 hours, solvents were removed in vacuo or with stream of N 2. The residue was redissolved in

CH 2Cl 2 (15 mL), washed with aq. NaHCO 3, aq. Na 2S2O3, brine, dried over anhydrous Na 2SO 4, and concentrated in vacuo . The resulting residue was purified by silica gel flash chromatography to

1 give the iodinated product 203 in 88% yield as a yellow solid. H NMR (500 MHz, CDCl 3) δ 8.49

(s, 1H), 7.73 (t, J = 7.4 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.47 (s, 1H), 7.33-7.27 (m, 1H), 7.19 (s,

1H), 6.94-6.17 (m, 1H), 3.88 (s, 2H), 2.80 (t, J = 6.6 Hz, 2H), 2.09-1.94 (m, 2H); 13 C NMR (126

MHz, CDCl 3) δ 168.31, 154.35, 148.87, 137.51, 137.02, 134.67, 126.53, 124.78, 123.98, 88.85,

+ 26.71, 23.57; HRMS : calculated for C 15 H13 IN 2O [M+H ]: 365.0145; found: 365.0146.

Pd(OAc)2 (15 mol%) NIS (2.5 equiv) N trifluorotoluene, 100 oC, 24 h, 55% N PA I PA

210 204

Compound 210 (48 mg, 0.2 mmol, 1.0 equiv), NIS (113 mg, 0.5 mmol, 2.5 equiv), and Pd(OAc) 2

(6.5 mg, 0.03 mmol, 0.015 equiv) were dissolved in α,α,α-trifluorotoluene (2 mL, 0.1M) in a 10 mL vial. The vial was purged with Ar, sealed with a PTFE cap, and heated to 100º C. After 24hrs, the reaction was cooled to room temperature, filtered through a pad of celite and eluted with

EtOAc. The filtrate was washed with aq. Na 2S2O3 (sat.), dried over anhydrous Na 2SO 4, and

115 concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to

give 204 as a white solid (40 mg, 55%). The NMR spectra of 204 at room temperature in CDCl 3

1 represents a 2:1 mixture of rotamers. H NMR (500 MHz, CDCl 3) δ 8.72 (s, 1H), 8.06 (d, J = 3.8

Hz, 2H), 7.93-7.80 (m, 4H), 7.77 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 7.2 Hz, 2H), 7.46-7.34 (m, 3H),

7.24-7.08 (m, 6H), 6.90 (t, J = 7.7 Hz, 1H), 6.82 (t, J = 7.7 Hz, 2H), 4.78 (m, 2H), 4.25-4.13 (m,

1H), 3.54-3.41 (m, 1H), 3.21-3.06 (m, 2H), 2.90-2.72 (m, 6H), 2.47-2.32 (m, 2H), 2.17-2.03 (m,

13 1H), 1.87-1.64 (m, 3H); C NMR (126 MHz, CDCl 3) δ 168.48, 167.54, 154.31, 153.92, 148.91,

147.10, 143.54, 141.59, 138.79, 138.23, 137.76, 137.19, 137.06, 136.62, 136.00, 128.52, 127.83,

127.72, 127.43, 125.86, 125.31, 124.73, 96.30, 94.76, 47.00, 42.69, 27.76, 26.62, 25.02, 24.54;

+ HRMS : calculated for C15 H13 IN 2O [M+H ]: 365.0145, found: 365.0145.

Pd(OAc)2 10 mol% I Ag2CO3 (1.5 equiv) (BnO) PO H (0.2 equiv) + 2 2 PA o PA N I t-AmylOH, Ar, 110 C, I N H 24 h, 39% 211 H 206

NIS (1.1 equiv) CuI (10 mol%) CsOAc (2.5 equiv) HBF4 Et2O (4.0 equiv) PA I I N o I N DCM/TFA = 9/1, 0 oC, 4 h H DMSO, 90 C, 20 h PA 212 62% (two steps) 205

PA I N H 211 Compound 211 was isolated in 39% yield as a pale yellow oil using C–H arylation protocol A. 1H

NMR (500 MHz, CDCl 3) δ 8.54 (d, J = 4.3 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.07 (s, 1H), 7.84

(td, J = 7.7, 1.6 Hz, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.42 (m, 1H), 6.96 (d, J = 8.2 Hz, 2H), 3.50 (m,

13 2H), 2.73-2.60 (m, 2H), 2.00-1.89 (m, 2H); C NMR (126 MHz, CDCl 3) δ 164.43, 150.01,

116

148.16, 141.23, 137.59, 137.50, 130.65, 126.26, 122.30, 91.13, 39.00, 32.95, 31.20; HRMS :

+ calculated for C 15 H16 IN 2O [M+H ] : 367.0302, found: 367.0305.

PA I I N H 212 Compound 212 was prepared via the standard directed electrophilic aromatic iodination protocol, and was applied directly to the next step.

I N PA 205 Compound 205 was isolated in 62% yield (over 2 steps) as a colorless oil via the standard cross

1 coupling protocol. H NMR (500 MHz, CDCl 3) δ 8.51 (s, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.58 (d, J

= 7.0 Hz, 1H), 7.40-7.27 (m, 2H), 7.24-6.93 (m, 1H), 6.86 (d, J = 8.0 Hz, 1H), 3.88 (t, J = 5.6 Hz,

13 2H), 2.80 (t, J = 6.6 Hz, 2H), 2.12-1.95 (m, 2H); C NMR (126 MHz, CDCl 3) δ 168.38, 154.29,

148.82, 139.98, 137.05, 133.56, 133.55, 130.31, 124.88, 124.04, 89.49, 44.97, 26.79, 23.59;

+ HRMS : calculated for C 15 H13 IN 2O [M+H ]: 365.0145, found: 365.0147.

117

4.2. Aryl cycloalkane arylation

4.2.1. Reagents : All commercial materials were used as received unless otherwise noted.

Anhydrous solvents were obtained from a JC Meyer solvent dispensing system and used without further purification. Flash chromatography was performed using 230-400 mesh SiliaFlash 60® silica gel (Silicycle Inc.). Pd(OAc) 2 (98%, Aldrich), silver carbonate (99%, Aldrich), silver acetate

(99%, Alfa Aesar), dichloromethane (99.5%, Merck) were used in Pd-catalyzed reactions. 8-

aminoquinoline (AQ) was purchased from Matrix Scientific and used without further purification.

cis -4-aminocyclohexanecarboxylic acid and trans -4-aminocyclohexanecarboxylic acid were

purchased from Chem-Impex International.

4.2.2. Instruments: NMR spectra were recorded on Bruker CDPX-300, DPX-300, DRX-400

instruments and calibrated using residual solvent peaks as internal reference. Multiplicities are

recorded as: s = singlet, d = doublet, t = triplet, dd = doublet of doublets, td = triplet of doublets,

br s = broad singlet, m = multiplet. High resolution ESI mass experiments were operated on a

Waters LCT Premier instrument.

118

4.2.3. Preparation of Substrates:

O O O O AQ AQ AQ AQ N N N N H H H H

ref [1] ref [2] ref [3] ref [4]

O O O O Cbz O AQ AQ AQ AQ AQ N N N N N N H H H H H NPhth ref [5] ref [2] ref [6] ref [2] ref [7]

O O AQ AQ N N H H ref [1] ref [1] All known compounds were prepared following the reported procedure and spectra data are consistent with those reported in the literature. 31,39,40,132,154,163–165

EDCI (1.5 equiv) O NH2 O DMAP (0.2 equiv) N AQ OH + N ° H DCM, 0-25 C, 24 h BocHN BocHN 4-15, 82% Trans -boc-4-aminocyclohexanecarboxylic acid (2 mmol, 487 mg, 1.0 equiv), DMAP (0.4 mmol,

50 mg, 0.2 equiv), and 8-aminoquinoline (1.6 mmol, 231 mg, 0.8 equiv) were dissolved in CH 2Cl 2

(2 mL). The reaction was cooled to 0 oC in an ice bath and EDCI (3.0 mmol, 466 mg, 1.5 equiv) was added. The reaction was then allowed to warm to RT. After 24hours, the reaction mixture was washed with water, sat. NaHCO 3, and brine. The organic layer was dried over anhydrous MgSO 4.

Purification by silica gel flash column chromatography (EtOAc/Hex) gave 4-15 as a white solid

1 in 82% yield. H NMR (400 MHz, CDCl 3) δ 9.84 (s, 1H), 8.80 – 8.66 (m, 2H), 8.07 (d, J = 8.2

Hz, 1H), 7.49 – 7.40 (m, 1H), 7.37 (dd, J = 8.2, 4.2 Hz, 1H), 4.56 (s, 1H), 3.47 (s, 1H), 2.36 (t, J

= 12.1 Hz, 1H), 2.10 (d, J = 9.1 Hz, 2H), 1.73 (q, J = 12.2 Hz, 2H), 1.41 (s, 9H), 1.19 (q, J = 12.0

119

13 Hz, 1H). C NMR (101 MHz, CDCl 3) δ 173.90, 155.23, 148.13, 138.38, 136.35, 134.42, 127.89,

127.34, 121.58, 121.42, 116.43, 79.13, 49.09, 45.88, 32.66, 28.60, 28.44. HRMS : calculated for

+ C21 H28 N3O3 [M+H ]: 370.2125; found: 370.2118.

EDCI (1.5 equiv) O NH2 O DMAP (0.2 equiv) N AQ OH + N ° H DCM, 0-25 C, 24 h BocHN BocHN

4-16, 74% Coumpound 4-16 was prepared in 74% yield following the same procedure as compound 4-15 . 1H

NMR (400 MHz, CDCl 3) δ 9.92 (s, 1H), 8.84-8.72 (m, 2H), 8.16 (d, J = 8.3 Hz, 1H), 7.59-7.37

(m, 3H), 4.82-4.73 (m, 1H), 3.80 (m, 1H), 2.59 (m, 1H), 2.03-1.72 (m, 8H), 1.44 (s, 9H); 13 C NMR

(101 MHz, CDCl 3) δ 155.33, 148.26, 138.49, 136.53, 134.54, 128.03, 127.53, 121.72, 121.54,

+ 116.50, 79.22, 44.33, 29.68, 28.53, 25.03. HRMS : calculated for C 21 H28 N3O3 [M+H ]: 370.2125; found: 370.2117.

4.2.4 Reaction optimization

MeO

O O O Ar-I AQ AQ AQ ( 2 equiv) N N N H H + H H Pd(OAc)2 (10 mol%) H H OMe OMe 218 219 d 3.26 (m)220 d 2.80 (m) Reactions were performed in 4 mL capped vials according to the conditions listed in Table 3 at a

0.2 mmol scale. After completion, the reactions were diluted with dichloromethane (5 mL) and

120 filtered through a pad of Celite. Following evaporation, the crude residue was dissolved in 600 µL of deuterated chloroform for 1H-NMR analysis. Dibromomethane (34.8 mg, 0.2 mmol, 1 equiv,

set the integration of this singlet peak around 4.95 ppm as 1.00) was added as internal standard for

determining the yield. Yields of mono- and di-arylated product were determined as follows:

Yield ( 219 ) = integration of ( δ 3.26) × 200%

Yield ( 220 ) = integration of ( δ 2.80) × 100%

4.2.5. AQ-directed Pd-catalyzed C–H arylation at room temperature

Ar-I (2 equiv) O Pd(OAc)2 (10 mol%) O AQ Ag CO (1 equiv) AQ N 2 3 N H CH2Cl2, rt, 2d H n n Ar

A mixture of amide (0.2 mmol, 1 equiv), aryl iodide (0.4 mmol, 2 equiv), Ag 2CO 3 (55mg, 0.2 mmol, 1 equiv), and Pd(OAc) 2 (4.5 mg, 0.1 equiv, 0.02 mmol) in CH 2Cl 2 (1 mL) was stirred

vigorously at room temperature for 2 days. Then the mixture was filtered through a pad of celite

and eluted with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by silica gel flash column chromatography to give the arylated products.

O AQ N H

OMe 222 Compound 222 was isolated in 32% yield as a pale yellow solid and its spectra data are consistent

with those reported in the literature. 137

121

MeO

O AQ N H

OMe 222-1 Compound 222-1 was isolated in 64% yield as a colorless oil and its spectra data are consistent

with those reported in the literature. 137

O AQ N H

OMe

223

1 Compound 223 was isolated in 80% yield as a colorless oil. H NMR (400 MHz, CDCl 3) δ 9.29

(s, 1H), 8.67 (d, J = 3.0 Hz, 1H), 8.53 (d, J = 6.9 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.54 – 7.31 (m,

3H), 7.18 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 8.4 Hz, 2H), 3.48 (s, 4H), 3.25 (dd, J = 13.1, 7.7 Hz,

1H), 2.36 (td, J = 13.0, 7.7 Hz, 1H), 2.30 – 2.13 (m, 2H), 2.13 – 2.00 (m, 2H), 1.81 (dd, J = 19.5,

13 9.0 Hz, 1H). C NMR (101 MHz, CDCl 3) δ 172.96, 157.89, 147.67, 138.14, 135.95, 134.39,

133.14, 128.79, 127.62, 127.14, 121.23, 120.90, 115.95, 113.42, 54.85, 52.95, 49.42, 31.10, 28.42,

+ 24.39. HRMS: calculated for C 22 H23 N2O2 [M+H ]: 347.1754; found: 347.1750.

122

MeO

O AQ N H

OMe 223-1 Compound 223-1 was isolated in 4% yield as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 9.15

(s, 1H), 8.59 (dd, J = 4.0, 1.4 Hz, 1H), 8.50 (d, J = 6.7 Hz, 1H), 7.99 (dd, J = 8.2, 1.1 Hz, 1H), 7.40

– 7.35 (m, 1H), 7.33 (d, J = 8.6 Hz, 5H), 7.30 (dd, J = 8.2, 4.2 Hz, 1H), 6.68 (d, J = 8.7 Hz, 4H),

3.68 (d, J = 7.1 Hz, 2H), 3.57 (s, 6H), 3.46 (t, J = 5.9 Hz, 1H), 2.77 (td, J = 7.4, 2.8 Hz, 2H), 2.31

13 (t, J = 6.0 Hz, 2H). C NMR (75 MHz, CDCl 3) δ 170.77, 157.99, 147.68, 138.17, 135.99, 134.35,

133.27, 128.89, 127.67, 127.17, 121.25, 121.00, 116.17, 113.60, 60.24, 55.08, 49.53, 29.02;

+ HRMS : calculated for C 29 H29 N2O3 [M+H ]: 453.2173; found: 453.2169.

O AQ N H

OMe

224 Compound 224 was isolated in 54% yield as a colorless oil and spectra data are consistent with those reported in the literature. 39

123

OMe

O AQ N H

OMe

224-1

Compound 224-1 was isolated in 17% yield as a white solid and spectra data are consistent with

those reported in the literature. 39

O AQ N H

OMe 225

1 Compound 225 was isolated in 43% yield as a colorless oil. H NMR (500 MHz, CDCl 3) δ 9.17

(s, 1H), 8.66 (dd, J = 4.1, 1.5 Hz, 1H), 8.55 (dd, J = 7.5, 1.2 Hz, 1H), 8.08 (dd, J = 8.2, 1.1 Hz,

1H), 7.47 – 7.34 (m, 3H), 7.14 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 8.7 Hz, 2H), 3.45 (s, 3H), 3.30 –

3.23 (m, 1H), 3.05 (dd, J = 14.3, 6.5 Hz, 1H), 2.36 (dt, J = 14.9, 8.0 Hz, 1H), 2.15 (dd, J = 10.2,

5.1 Hz, 2H), 1.97 (t, J = 8.7 Hz, 4H), 1.55 (t, J = 8.7 Hz, 2H), 1.53 – 1.41 (m, 1H). 13 C NMR (75

MHz, CDCl 3) δ 173.97, 157.78, 147.77, 138.29, 137.41, 136.17, 134.60, 128.81, 127.81, 127.39,

121.38, 121.00, 116.18, 113.61, 55.03, 53.51, 47.38, 31.43, 30.81, 29.38, 28.93, 26.73; HRMS :

+ calculated for C 24 H27 N2O2 [M+H ] : 375.2067; found: 375.2062.

124

O AQ N H

OMe

226

1 Diastereomer A was isolated in 27% yield as a colorless oil. H NMR (300 MHz, CDCl 3) δ 9.90

(s, 1H), 8.89 (d, J = 7.0 Hz, 1H), 8.83 (d, J = 4.0 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.64 – 7.51 (m,

2H), 7.48 (dd, J = 8.2, 4.3 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 3.79 (s, 3H),

3.04 (dq, J = 14.6, 7.2 Hz, 1H), 2.47 (td, J = 10.4, 2.8 Hz, 1H), 1.76 – 1.51 (m, 2H), 1.31 (d, J =

13 6.9 Hz, 3H). C NMR (75 MHz, CDCl 3) δ 174.27, 158.26, 148.27, 137.38, 134.37, 128.60, 128.17,

127.61, 121.74, 121.65, 116.75, 113.98, 58.66, 55.36, 42.47, 25.05, 21.12, 12.34; HRMS :

+ calculated for C 22 H25 N2O2 [M+H ]: 349.1911; found: 349.1898.

1 Diastereomer B was isolated in 16% yield as a colorless oil. H NMR (300 MHz, CDCl 3) δ 9.48

(s, 1H), 8.80 – 8.70 (m, 1H), 8.65 (dd, J = 6.8, 1.9 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 7.51 – 7.32

(m, 3H), 7.19 (d, J = 8.5 Hz, 2H), 6.68 (d, J = 8.6 Hz, 2H), 3.59 (s, 3H), 3.12 (dt, J = 14.3, 7.1 Hz,

1H), 2.53 (dd, J = 14.7, 8.3 Hz, 1H), 1.95 – 1.74 (m, 2H), 1.37 (d, J = 7.0 Hz, 3H), 1.01 (t, J = 7.3

13 Hz, 3H). C NMR (75 MHz, CDCl 3) δ 173.71, 158.04, 148.06, 137.56, 136.27, 128.26, 127.83,

127.49, 121.55, 121.12, 116.29, 113.71, 58.71, 55.09, 41.84, 23.33, 19.20, 12.42; HRMS :

+ calculated for C 22 H25 N2O2 [M+H ]: 349.1911; found: 349.1902.

125

OMe

O AQ N H

OMe

226-1 Compound 226-1 was isolated in 12% yield and spectra data are consistent with those reported in the literature. 163

O AQ N H MeO 227 Compound 227 was isolated in 23% yield as a white solid and spectra data are consistent with those reported in the literature. 166

O AQ N H NPhth MeO

228

Compound 228 was isolated in 30% yield as a white solid and spectra data are consistent with

those reported in the literature. 167

126

OMe

O AQ N H

229

Compound 229 was isolated in 19% yield as a colorless oil and spectra data are consistent with those reported in the literature. 168

OMe

O AQ N H BocHN 233 Compound 233 was prepared in 33% yield as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 9.50

(s, 1H), 8.73 (d, J = 2.7 Hz, 1H), 8.59 (dd, J = 5.5, 3.4 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.56 –

7.33 (m, 3H), 7.19 (d, J = 8.5 Hz, 2H), 6.70 (d, J = 8.5 Hz, 2H), 4.47 (s, J = 73.8 Hz, 1H), 3.70 (s,

1H), 3.60 (s, 3H), 3.08 (t, J = 11.9 Hz, 1H), 2.59 (t, J = 10.4 Hz, 1H), 2.40 – 2.14 (m, 3H), 1.96

(dd, J = 23.5, 12.5 Hz, 1H), 1.44 (s, J = 9.8 Hz, 11H), 1.37 – 1.28 (m, 1H). 13 C NMR (75 MHz,

CDCl 3) δ 173.20, 148.06, 136.35, 135.49, 134.63, 128.26, 127.40, 121.71, 116.55, 113.97, 55.09,

+ 53.03, 45.11, 29.44, 28.41; HRMS : calculated for C 28 H34 N3O4 [M+H ]: 476.2544; found:

476.2527.

127

OMe

O AQ N H BocHN 234 Compound 234 was prepared in 89% yield as a white solid. 1H NMR (300 MHz, CDCl3) δ 9.18

(s, 1H), 8.62 (d, J = 7.1 Hz, 1H), 8.57 (d, J = 3.1 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.53 – 7.35 (m,

2H), 7.32 (dd, J = 8.2, 4.2 Hz, 1H), 7.16 (d, J = 8.3 Hz, 2H), 6.65 (d, J = 8.3 Hz, 2H), 4.69 (d, J =

7.9 Hz, 1H), 3.69 (s, 1H), 3.53 (s, 3H), 3.03 (d, J = 13.0 Hz, 1H), 2.94 (s, 1H), 2.38 (dd, J = 24.4,

12.2 Hz, 1H), 2.25 (d, J = 12.5 Hz, 1H), 2.05 (d, J = 13.1 Hz, 2H), 2.01 – 1.77 (m, 3H), 1.44 (s,

13 11H). C NMR (75 MHz, CDCl 3) δ 172.71, 158.10, 155.38, 147.76, 138.15, 136.06, 135.21,

134.38, 128.37, 127.73, 127.19, 121.39, 121.22, 116.09, 113.78, 79.08, 54.98, 50.04, 47.52, 44.33,

+ 33.61, 28.84, 28.48; HRMS : calculated for C 28 H34 N3O4 [M+H ]: 476.2544; found: 476.2526.

O AQ N H

Br 235

1 Compound 235 was isolated in 57% yield as a pale yellow solid. H NMR (300 MHz, CDCl 3) δ

9.31 (s, 1H), 8.68 (dd, J = 4.0, 1.3 Hz, 1H), 8.50 (dd, J = 5.6, 3.3 Hz, 1H), 8.09 (dd, J = 8.2, 1.4

Hz, 1H), 7.50 – 7.31 (m, 3H), 7.14 (s, 4H), 3.46 (dd, J = 16.7, 8.1 Hz, 1H), 3.28 (dd, J = 12.8, 7.7

Hz, 1H), 2.44 – 2.28 (m, 1H), 2.28 – 2.12 (m, 2H), 2.13 – 2.00 (m, 2H), 1.92 – 1.74 (m, 1H). 13 C

NMR (75 MHz, CDCl 3) δ 172.69, 147.99, 140.39, 136.29, 134.28, 131.19, 129.79, 127.86, 127.33,

121.56, 121.35, 120.20, 116.26, 52.95, 49.75, 31.01, 28.70, 24.51; HRMS : calculated for

128

+ C21 H20 BrN 2O [M+H ] : 395.0754; found: 395.0744.

O AQ N H

CO2Me 236

1 Compound 236 was isolated in 53% yield as a colorless oil. H NMR (300 MHz, CDCl 3) δ 9.32

(s, 1H), 8.61 (d, J = 2.7 Hz, 1H), 8.47 (d, J = 5.6 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.1

Hz, 2H), 7.45 – 7.27 (m, 5H), 3.69 (s, 3H), 3.51 (dd, J = 16.7, 8.1 Hz, 1H), 3.30 (dd, J = 12.6, 7.5

Hz, 1H), 2.44 – 2.23 (m, 2H), 2.20 – 1.94 (m, 3H), 1.90 – 1.65 (m, 1H). 13 C NMR (75 MHz,

CDCl 3) δ 172.40, 166.74, 147.77, 146.88, 138.03, 135.99, 134.03, 129.30, 127.89, 127.9, 127.06,

121.23, 121.14, 116.04, 52.793, 51.65, 49.99, 30.74, 28.68, 24.44; HRMS : calculated for

+ C23 H23 N2O3 [M+H ] : 375.1703; found: 375.1704.

O AQ N H

NO2 237

1 Compound 237 was isolated in 50% yield as a pale yellow oil. H NMR (300 MHz, CDCl 3) δ 9.35

(s, 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.45 (d, J = 4.2 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.4

Hz, 2H), 7.51 – 7.30 (m, 5H), 3.59 (dd, J = 16.2, 8.2 Hz, 1H), 3.46 – 3.25 (m, 1H), 2.49 – 2.29 (m,

2H), 2.28 – 2.21 (m, 1H), 2.21 – 2.01 (m, 3H), 1.86 (dd, J = 16.8, 6.7 Hz, 1H). 13 C NMR (75 MHz,

CDCl3) δ 172.19, 149.56, 147.99, 146.46, 138.16, 136.44, 133.96, 128.90, 127.85, 127.31, 123.35,

+ 121.63, 116.33, 53.05, 50.06, 31.03, 28.95, 24.74. HRMS: calculated for C 21 H20 N3O3 [M+H ] :

129

362.1499; found: 362.1495.

O AQ N H

238

1 Compound 238 was isolated in 68% yield as a colorless oil. H NMR (500 MHz, CDCl 3) δ 9.35

(s, 1H), 8.68 (dd, J = 4.0, 1.3 Hz, 1H), 8.53 (d, J = 6.4 Hz, 1H), 8.04 (dd, J = 8.2, 1.2 Hz, 1H), 7.45

– 7.33 (m, 3H), 7.30 (d, J = 7.5 Hz, 2H), 7.06 (t, J = 7.7 Hz, 2H), 6.89 (t, J = 7.3 Hz, 1H), 3.53 (dd,

J = 17.6, 8.0 Hz, 1H), 3.32 (dd, J = 13.3, 7.9 Hz, 1H), 2.45 – 2.34 (m, 1H), 2.35 – 2.26 (m, 1H),

13 2.24 – 2.15 (m, 1H), 2.15 – 2.05 (m, 2H), 1.90 – 1.76 (m, 1H). C NMR (75 MHz, CDCl 3) δ

172.73, 147.63, 141.10, 138.06, 135.90, 134.25, 127.92, 127.82, 127.53, 127.06, 126.11, 121.18,

+ 120.86, 115.86, 52.81, 50.03, 30.90, 28.56, 24.43. HRMS : calculated for C 21 H21 N2O [M+H ] :

317.1648; found: 317.1644.

O AQ N H

MeO 239

Compound 239 was isolated in 24% yield as a white solid and its spectral data are consistent with

those reported in the literature. 40

130

O AQ N H

CO2Me

240

1 Compound 240 was isolated in 33% yield as a white solid. H NMR (300 MHz, CDCl 3) δ 9.24 (s,

1H), 8.62 (d, J = 7.2 Hz, 1H), 8.58 (d, J = 4.0 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.9

Hz, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 3H), 7.34 (dd, J = 8.3, 4.3 Hz, 2H), 3.78 (s,

3H), 3.09 (d, J = 5.5 Hz, 2H), 2.56 (dd, J = 22.4, 10.4 Hz, 1H), 2.26 (d, J = 12.4 Hz, 1H), 2.12 (d,

J = 12.8 Hz, 1H), 2.02 (d, J = 14.8 Hz, 1H), 1.92 (d, J = 4.2 Hz, 1H), 1.92 (d, J = 4.2 Hz, 1H), 1.91

– 1.74 (m, 2H), 1.65 (d, J = 12.9 Hz, 2H), 1.48 (dd, J = 24.5, 12.4 Hz, 1H). 13 C NMR (75 MHz,

CDCl 3) δ 172.69, 167.13, 150.09, 147.87, 138.24, 136.23, 134.38, 129.74, 128.12, 127.82, 127.34,

121.41, 121.28, 116.25, 51.94, 48.60, 45.90, 29.95, 26.64, 26.07, 21.75; HRMS : calculated for

+ C24 H26 N2O3 [M+H ] : 389.1860; found: 389.1860.

CO2Me

O AQ N H

CO2Me

240-1

1 Compound 240-1 was isolated in 15% yield as a white solid. H NMR (300 MHz, CDCl 3) δ 8.57

(s, 1H), 8.40 (d, J = 6.7 Hz, 1H), 8.36 (d, J = 3.3 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 8.1

Hz, 4H), 7.39 (d, J = 7.9 Hz, 4H), 7.36 – 7.29 (m, 2H), 7.22 (dd, J = 8.1, 4.2 Hz, 1H), 3.75 (s, 5H),

3.31 – 3.11 (m, 3H), 2.80 (qd, J = 12.9, 3.1 Hz, 2H), 2.26 (d, J = 12.8 Hz, 1H), 1.83 (d, J = 11.2

131

13 Hz, 2H), 1.66 (dd, J = 27.0, 13.7 Hz, 2H). C NMR (75 MHz, CDCl 3) δ 170.25, 166.99, 149.32,

129.81, 128.37, 127.69, 127.05, 121.44, 121.13, 56.334, 51.93, 47.80, 26.38, 25.35; HRMS :

+ calculated for C 32 H31 N2O5 [M+H ]: 523.2227; found: 523.2218.

O AQ N H

NO2

241

1 Compound 241 was isolated in 25% yield as a white solid. H NMR (300 MHz, CDCl 3) δ 9.39 (s,

1H), 8.65 (d, J = 2.7 Hz, 1H), 8.52 – 8.33 (m, 1H), 8.14 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.72 (d,

J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.47 – 7.29 (m, 3H), 7.18 (t, J = 7.9 Hz, 1H), 4.15 (dd, J

= 17.1, 8.2 Hz, 1H), 3.79 (d, J = 6.5 Hz, 1H), 2.86 – 2.67 (m, 1H), 2.67 – 2.53 (m, 1H), 2.52 – 2.25

13 (m, 2H). C NMR (75 MHz, CDCl 3) δ 170.60, 148.03, 147.92, 142.93, 138.04, 136.23, 133.89,

133.37, 128.96, 127.71, 127.15, 122.56, 121.56, 121.42, 121.35, 116.11, 47.59, 42.59, 24.74,

+ 20.56. HRMS : calculated for C 20 H18 N3O3 [M+H ]: 348.1343; found: 348.1328.

NO2

O AQ N H

NO2

241-1

Compound 241-1 was isolated in 64% yield as a white solid and spectra data are consistent with those reported in the literature. 137

132

O AQ N H

NO2 242

1 Compound 242 was isolated in 27% yield as a pale yellow oil. H NMR (300 MHz, CDCl 3) δ 9.46

(s, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.58 – 8.37 (m, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.4 Hz,

2H), 7.53 – 7.30 (m, 5H), 4.17 (dd, J = 16.6, 8.1 Hz, 1H), 3.84 (s, 1H), 2.89 – 2.69 (m, 1H), 2.69

– 2.54 (m, 1H), 2.54 – 2.28 (m, 2H). 13 C NMR (75 MHz, CDCl3) δ 170.71, 148.91, 148.03, 136.59,

133.97, 128.25, 127.94, 127.43, 123.47, 121.67, 116.50, 47.79, 42.92, 25.06, 20.96. HRMS :

+ calculated for C 20 H18 N3O3 [M+H ]: 348.1343; found: 348.1348.

O2N O AQ N H

NO2 242-1 Compound 242-1 was isolated in 47% yield as a yellow solid and its spectral data are consistent with those reported in the literature. 137

4.2.6. Kinetic isotope effect study

O O D D AQ AQ Pd(OAc)2 (cat.) N N H H AcOD, 90 °C D 3 repetitions D 244 243

133

O D D AQ N H D D 157

A mixture of 243 (481 mg, 2 mmol, 1.0 equiv), Pd(OAc) 2 (45 mg, 0.2 mol, 0.1 equiv) in CH 3CO 2D

(5 mL) in a 12 mL glass vial (purged with Ar, sealed with PTFE cap) was heated at 90 oC. After

24 hours, the reaction was cooled to RT, filtered through a pad of celite and eluted with EtOAc.

The filtrate was concentrated in vacuo and the residue was subjected to the deuteration reaction a

second time following the same procedure. The product was purified by silica gel flash column

chromatography (10% EtOAc/Hex) to give 300 mg (62% yield) of 244 as a white solid. 1H NMR

(300 MHz, CDCl 3) δ 9.83 (s, 1H), 8.77 (d, J = 7.5 Hz, 1H), 8.73 (d, J = 2.8 Hz, 1H), 8.04 (d, J =

8.2 Hz, 1H), 7.51 – 7.39 (m, 1H), 7.35 (dd, J = 8.3, 4.2 Hz, 1H), 2.87 (s, 1H), 1.69 (dq, J = 13.9,

13 6.7 Hz, 4H). C NMR (75 MHz, CDCl 3) δ 174.99, 147.99, 138.24, 136.22, 134.64, 127.81,

127.30, 127.20, 121.45, 121.14, 116.19, 46.96, 25.87, 25.76; HRMS : calculated for C 15 H13 D4N2O

[M+H +]: 245.1586; found: 245.1576.

Measurement of Kinetic Isotope effect:

R O O R R AQ R AQ Ph-I (2 equiv) N N R H H R Pd(OAc)2 (10 mol%) R Ag2CO3 (1 equiv) CDCl3, 25 °C 247 R = H 245 R = D Deuterated substrate 245 (98 mg, 0.4 mmol, 1.0 equiv) or protiated substrate 247 (96 mg, 0.4

mmol, 1.0 equiv) were added to separate 10 mL vials. Iodobenzene (90 µL, 0.8 mmol, 2.0 equiv),

Pd(OAc) 2 (9 mg, 0.04 mol, 0.1 equiv), Ag 2CO 3 (110 mg, 0.4 mol, 1 equiv), and CDCl 3 (2 mL,

134

0.2M) were then added to each substrate. The resulting reaction mixture was stirred vigorously for

6 hours. Every hour, stirring was stopped and the solids suspended in the reaction mixture were allowed to settle. 0.1 mL of supernatant was removed by syringe and dissolved in 400 µL CDCl 3

1 for H NMR measurement. K H/D (~4.4) was estimated based on the ratio of arylation yield.

Time (h) 1 2 3 4 5 6

Yield of R = H (%) 1.1 4.2 5.3 7.5 10.5 14.1

Yield of R = D (%) 0.4 1.9 1.6 2.5 2.4 3.3

Kinetic Isotope Effect 16 14 y = 2.3x - 0.8 12 R² = 0.9759 10 8 6

Yield (%) 4 y = 0.5179x + 0.175 2 R² = 0.9031 0 -2 0 1 2 3 4 5 6 7 Time (h)

Deuterated substrate 27 Undeuterated substrate 1

KH/K D = 2.3/0.5179 = 4.4

135

4.2.7. Pd-catalyzed sequential C-H functionalization of cycloalkyl carboxamides

p-NO -PhI (2 equiv) 2 O2N Pd(OAc)2 (10 mol%) O Ag2CO3 (1 equiv) AQ O N (BnO)2PO2H (20 mol%) H AQ ° N PhMe, Ar, 110 C, 24 h H

OMe

274-1 OMe 274, 79%

Compound 274-1 (34.6 mg, 0.1 mmol, 1.0 equiv), Pd(OAc) 2 (2.2 mg, 0.01 mmol, 0.1 equiv),

Ag 2CO 3 (27.5 mg, 0.1 mmol, 1.0 equiv), 1-iodo-4-nitrobenzene (49.8 mg, 0.2 mmol, 2 equiv),

(BnO) 2PO 2H (5.5 mg, 0.02 mol, 0.2 equiv) and PhMe (0.5 mL) were added to a 10 mL vial. The vial was flushed with argon, sealed with a PTFE cap, and heated to 110 oC with stirring. After 24

hours, the reaction was cooled to RT, filtered through a pad of celite and eluted with EtOAc. The

filtrate was concentrated in vacuo and the residue purified by silica gel flash column chromatography (30% EtOAc/Hex) to give 37mg (79% yield) of 274 as a yellow solid. 1H NMR

(300 MHz, CDCl 3) δ 9.12 (s, 1H), 8.57 (d, J = 2.7 Hz, 1H), 8.49 – 8.29 (m, 1H), 8.13 – 7.92 (m,

3H), 7.55 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 5.0 Hz, 3H), 7.33 (d, J = 4.1 Hz, 1H), 7.29 (d, J = 8.7

Hz, 2H), 6.65 (d, J = 8.6 Hz, 2H), 3.87 – 3.65 (m, 2H), 3.54 (s, J = 10.0 Hz, 4H), 2.92 – 2.66 (m,

13 2H), 2.50 – 2.24 (m, 2H). C NMR (75 MHz, CDCl 3) δ 169.95, 158.26, 149.66, 147.84, 146.44,

138.10, 136.21, 133.88, 132.35, 128.88, 128.77, 127.73, 127.16, 123.47, 121.53, 121.46, 116.31,

+ 113.74, 59.99, 55.12, 49.79, 49.64, 28.92, 28.69; HRMS : calculated for C 28 H26 N3O4 [M+H ]:

468.1918; found: 468.1906.

136

EtO2C I (2 equiv)

Pd(OAc)2 (10 mol%) O CO2Et O AQ Ag2CO3 (1 equiv) AQ N (BnO) PO H (20 mol%) N H 2 2 H

° NO2 PhMe, Ar, 110 C, 24 h NO2

275-1 275, 95%

Compound 275-1 (69.5 mg, 0.2 mmol, 1.0 equiv), Pd(OAc) 2 (4.5 mg, 0.02 mol, 0.1 equiv),

Ag 2CO 3 (55 mg, 0.2 mol, 1 equiv), ethyl iodoacetate (47 µL, 0.4 mol, 2.0 equiv), (BnO) 2PO 2H

(11.1 mg, 0.04 mol, 0.2 equiv) and PhMe (1 mL) were added to a 10 mL vial. The vial was flushed

with argon, sealed with a PTFE cap, and heated to 110 oC with stirring. After 24 hours, the reaction was cooled to RT, filtered through a pad of celite and eluted with EtOAc. The filtrate was concentrated in vacuo and the residue purified by silica gel flash column chromatography (25%

1 EtOAc/Hex) to give 82 mg (95% yield) of 275 as a white solid. H NMR (300 MHz, CDCl 3) δ

9.69 (s, 1H), 8.74 (dd, J = 4.2, 1.6 Hz, 1H), 8.47 (dd, J = 7.1, 1.8 Hz, 1H), 8.08 (dd, J = 8.0, 1.6

Hz, 2H), 7.89 (dd, J = 8.1, 1.4 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.47 – 7.27 (m, 5H), 4.08 – 3.80

(m, 4H), 3.32 – 3.07 (m, 1H), 3.01 – 2.75 (m, 2H), 2.71 (d, J = 6.8 Hz, 1H), 2.65 (d, J = 6.9 Hz,

13 1H), 2.63 – 2.44 (m, 1H), 1.02 (t, J = 7.1 Hz, 3H). C NMR (75 MHz, CDCl 3) δ 172.59, 169.52,

148.15, 148.08, 143.25, 138.17, 136.32, 133.96, 132.98, 128.88, 128.62, 128.04, 127.81, 127.18,

121.90, 121.64, 121.14, 116.36, 60.37, 51.48, 39.00, 35.49, 31.23, 30.910, 13.98; HRMS :

+ calculated for C 24 H24 N3O5 [M+H ]: 434.1710; found: 434.1705.

137

O

O I O O AQ N H (2 equiv) N AQ H Pd(OAc)2 (10 mol%) AgOAc (2 equiv) OMe 276-1 ° OMe DCE, Ar, 60 C, 22 h 276, 60%

Compound 276-1 (34.6 mg, 0.1 mol, 1.0 equiv), Pd(OAc) 2 (2.2 mg, 0.01 mol, 0.1 equiv), AgOAc

(33.4 mg, 0.2 mol, 2 equiv), 3-iodocyclohex-2-enone (44.4 mg, 0.2 mol, 2.0 equiv) and DCE (0.5

mL) were added to a 10 mL vial. The vial was flushed with argon, sealed with a PTFE cap, and

heated to 60 oC with stirring. After 24 hours, the reaction was cooled to RT, filtered through a pad of celite and eluted with EtOAc. The filtrate was concentrated in vacuo and the residue purified

by silica gel flash column chromatography (40% EtOAc/Hex) to give 26mg (60% yield) of 276 as

1 a yellow solid. H NMR (300 MHz, CDCl 3) δ 9.28 (s, 1H), 8.64 (d, J = 3.0 Hz, 1H), 8.56 – 8.42

(m, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.57 – 7.32 (m, 3H), 7.23 (d, J = 8.5 Hz, 2H), 6.61 (d, J = 8.5

Hz, 2H), 6.08 (s, 1H), 3.60 (dd, J = 15.9, 9.4 Hz, 1H), 3.51 (s, 2H), 3.48 – 3.39 (m, 1H), 3.22 (dd,

J = 14.2, 7.4 Hz, 1H), 2.71 – 2.51 (m, 2H), 2.44 (td, J = 11.3, 5.5 Hz, 2H), 2.31 – 2.13 (m, 3H),

13 2.10 (dd, J = 18.3, 11.0 Hz, 1H), 1.84 (dt, J = 12.2, 6.1 Hz, 2H). C NMR (75 MHz, CDCl 3) δ

199.98, 170.04, 165.45, 158.27, 147.98, 136.23, 132.22, 128.85, 127.83, 127.34, 126.17, 121.52,

116.40, 113.72, 57.63, 55.10, 51.37, 49.39, 37.52, 29.63, 28.36, 26.27, 22.90; HRMS : calculated

+ for C 28 H29 N2O3 [M+H ]: 441.2173; found: 441.2175.

138

Pd(OAc)2 O (10 mol%) QA O AQ PhI(OAc)2 N N (2.5 equiv) H NO PhMe 2 NO2 ° 60 C, Ar, 24 h

278-1 278, 83%

Compound 278-1 (35 mg, 0.1 mmol, 1.0 equiv), Pd(OAc)2 (2.2 mg, 0.01 mol, 0.1 equiv),

PhI(OAc) 2 (80.5 mg, 0.25 mol, 2.5 equiv) and PhMe (1 mL) were added to a 10 mL vial. The vial

was flushed with argon, sealed with a PTFE cap, and heated to 60 oC with stirring. After 24 hours,

the reaction was cooled to RT, filtered through a pad of celite and eluted with EtOAc. The filtrate

was concentrated in vacuo and the residue purified by silica gel flash column chromatography

1 (15% EtOAc/Hex) to give 29 mg (83% yield) of 278 as a white solid. H NMR (300 MHz, CDCl 3)

δ 8.82 (d, J = 2.2 Hz, 1H), 8.45 (d, J = 7.1 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 8.2 Hz,

2H), 7.63 (d, J = 7.5 Hz, 1H), 7.59 – 7.34 (m, 4H), 5.43 (s, 1H), 4.26 (d, J = 9.0 Hz, 1H), 4.15 (dd,

J = 16.7, 9.5 Hz, 1H), 3.29 – 3.00 (m, 1H), 2.62 (dd, J = 13.9, 6.4 Hz, 1H). 13 C NMR (75 MHz,

CDCl 3) δ 166.82, 148.90, 148.21, 143.12, 139.78, 136.09, 133.77, 129.26, 129.02, 127.01, 123.32,

122.34, 121.73, 121.42, 119.35, 56.07, 53.81, 35.16, 33.77; HRMS : calculated for C 20 H16 N3O3

[M+H +]: 346.1181; found: 346.1181.

139

Pd(OAc) AQ O 2 OAc O (10 mol%) N AQ O AQ N PhI(OAc)2 N H (2.5 equiv) H + PhMe OMe ° OMe 60 C, Ar, 24 h OMe 279-1 279, 51% 280, 20%

AQ N O

279 OMe

Compound 279-1 (36 mg, 0.1 mol, 1.0 equiv), Pd(OAc) 2 (2.2 mg, 0.01 mol, 0.1 equiv), PhI(OAc) 2

(80.5 mg, 0.25 mol, 2.5 equiv) and PhMe (1 mL) were added to a 10 mL vial. The vial was flushed with argon, sealed with a PTFE cap, and heated to 60 oC with stirring. After 24 hours, the reaction

was cooled to RT, filtered through a pad of celite and eluted with EtOAc. The filtrate was

concentrated in vacuo and the residue purified by silica gel flash column chromatography (10%

1 EtOAc/Hex) to give 18.1mg (51% yield) of 279 as a colorless oil. H NMR (300 MHz, CDCl 3) δ

8.86 (d, J = 2.6 Hz, 1H), 8.50 (d, J = 7.1 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.56 (q, J = 8.4 Hz,

5H), 7.41 (dd, J = 8.3, 4.1 Hz, 2H), 6.92 (d, J = 8.5 Hz, 3H), 5.58 – 5.40 (m, 1H), 3.81 (s, 3H),

3.80 – 3.68 (m, 2H), 3.17 (ddd, J = 10.7, 6.3, 3.5 Hz, 1H), 2.19 – 1.73 (m, 5H), 1.79 – 1.40 (m,

13 4H). C NMR (75 MHz, CDCl 3) δ 169.05, 158.25, 148.96, 136.21, 134.54, 129.33, 129.15,

127.04, 123.87, 121.35, 113.93, 57.11, 55.38, 54.21, 38.37, 27.09, 22.70, 15.9; HRMS : calculated

+ for C 23 H23 N2O2 [M+H ] : 359.1754; found: 359.1748.

140

OAc O AQ N H

OMe 280

1 Compound 280 was isolated in 20% yield as a colorless oil. H NMR (300 MHz, CDCl 3) δ 9.18

(s, 1H), 8.66 – 8.53 (m, 2H), 8.06 (d, J = 7.1 Hz, 1H), 7.44 (q, J = 8.1 Hz, 2H), 7.35 (dd, J = 8.2,

4.2 Hz, 1H), 7.18 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.6 Hz, 2H), 5.40 (d, J = 2.3 Hz, 1H), 3.52 (s,

3H), 3.41 – 3.22 (m, 1H), 3.13 (s, 1H), 2.55 – 2.26 (m, 2H), 2.18 (s, 3H), 1.81 (dd, J = 23.7, 8.7

13 Hz, 4H). C NMR (75 MHz, CDCl 3) δ 170.59, 169.82, 158.21, 147.81, 136.11, 135.41, 134.28,

127.77, 127.26, 121.45, 113.92, 71.16, 55.07, 53.34, 40.58, 26.69, 26.21, 21.67, 21.086; HRMS :

+ calculated for C 25 H27 N2O4 [M+H ]: 419.1960; found: 419.1952.

4.2.7. Deprotection of AQ group

O O AQ 1. Boc2O, DMAP N OH H CH3CN, 25 °C

2. LiOH, H2O2 H2O/THF, 0-25 °C, 60% (2 steps) OMe OMe 284 283

Compound 283 (104 mg, 0.315 mmol, 1.0 equiv) was dissolved in CH3CN (3 mL) and DMAP (43

mg, 0.35 mmol, 0.1 equiv), Boc 2O (110 mg, 0.5 mmol, 1.6 equiv) was added. The reaction was

allowed to stir overnight at RT. The reaction was filtered through a pad of silica and eluted with

EtOAc. The solvent was then evaporated in vacuo and the residue applied directly to the next step.

Boc-protected product obtained above was dissolved in THF (2.0 mL) and H 2O (0.75 mL) and the

141

o reaction was cooled to 0 C, LiOH (15 mg) then H 2O2 (0.3 mL) were added. The reaction was held

o at 0 C for 3 hours, then another portion of LiOH (15 mg) and H 2O2 (0.3 mL) were added. After 3

additional hours, the reaction mixture was diluted with CH 2Cl 2, quenched with aq. Na 2S2O3, and acidified to pH 2 with 0.5 M HCl (aq). The aqueous layer was then extracted with CH 2Cl 2. The combined organic layers were then washed with brine and dried over anhydrous Na 2SO 4. The solvent was concentrated and the residue purified by column chromatography (10% CH 2Cl 2 in

1 MeOH) to give 40 mg of 284 as a white solid (60% yield). H NMR (500 MHz, CDCl 3) δ 7.13 (d,

J = 8.3 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 3.92 (t, J = 8.7 Hz, 1H), 3.78 (s, 2H), 3.47 (d, J = 3.1 Hz,

1H), 2.55 (t, J = 9.0 Hz, 1H), 2.29 (dd, J = 12.3, 9.0 Hz, 1H), 2.17 (dd, J = 10.6, 8.3 Hz, 1H). 13 C

NMR (125 MHz, CDCl 3) δ 178.99, 158.38, 132.75, 128.41, 113.70, 55.31, 45.01, 42.21, 25.10,

+ 20.32; HRMS : calculated for C 12 H15 O3 [M+H ]: 207.1016; found: 207.1026.

142

REFERENCES

(1) Joule, J.A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell: Oxford, 2000.

(2) Ritchie, T. J.; Macdonald, S. J. F.; Young, R. J.; Pickett, S. D. Drug Discov. Today 2011 ,

16 (3-4), 164–171.

(3) Thansandote, P.; Lautens, M. Chem. Eur. J. 2009 , 15 (24), 5874–5883.

(4) Mei, T.-S.; Kou, L.; Ma, S.; Engle, K.; Yu, J.-Q. Synthesis. 2012 , 44 (12), 1778–1791.

(5) Jeffrey, J. L.; Sarpong, R. Chem. Sci. 2013 , 4 (11), 4092–4106.

(6) Ye, L.-W.; Shu, C.; Gagosz, F. Org. Biomol. Chem. 2014 , 12 (12), 1833–1845.

(7) Louillat, M.-L.; Patureau, F. W. Chem. Soc. Rev. 2014 , 43 (3), 901–910.

(8) Collet, F.; Dodd, R. H.; Dauban, P. Chem. Commun. 2009 , 5061–5074.

(9) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010 , 110 (2), 1147–1169.

(10) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chemie Int. Ed. 2009 , 48 (28),

5094–5115.

(11) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005 , 127 (42), 14560–

14561.

(12) Tsang, W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.; Buchwald, S. L. J. Org. Chem.

2008 , 73 (19), 7603–7610.

(13) Jordan-Hore, J. A.; Johansson, C. C. C.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc.

2008 , 130 (48), 16184–16186.

(14) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008 , 130 (43), 14058–14059.

(15) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. Trans. 1915 , 107 (1080), 1080.

(16) Bachrach, S. M. J. Org. Chem. 2008 , 73 (6), 2466–2468.

143

(17) Miura, T.; Ito, Y.; Murakami, M. Chem. Lett. 2009 , 38 (4), 328–329.

(18) Mei, T.; Wang, X.; Yu, J. J. Am. Chem. Soc. 2009 , 131 (31), 10806–10807.

(19) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012 , 134 (1), 7–10.

(20) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012 , 134 (1), 3–6.

(21) He, G.; Lu, C.; Zhao, Y.; Nack, W. A.; Chen, G. Org. Lett. 2012 , 14 (12), 2944–2947.

(22) Mei, T.-S.; Leow, D.; Xiao, H.; Laforteza, B. N.; Yu, J.-Q. Org. Lett. 2013 , 15 (12),

3058–3061.

(23) Ye, X.; He, Z.; Ahmed, T.; Weise, K.; Akhmedov, N. G.; Petersen, J. L.; Shi, X. Chem.

Sci. 2013 , 4 (9), 3712–3716.

(24) Wang, C.; Chen, C.; Zhang, J.; Han, J.; Wang, Q.; Guo, K.; Liu, P.; Guan, M.; Yao, Y.;

Zhao, Y. Angew. Chemie Int. Ed. 2014 , 53 (37), 9884–9888.

(25) He, Y.-P.; Zhang, C.; Fan, M.; Wu, Z.; Ma, D. Org. Lett. 2015 , 17 (3), 496–499.

(26) Nack, W.; Chen, G. Synlett 2015 , 26 (18), 2505–2511.

(27) Zhang, Q.; Chen, K.; Shi, B.-F. Synlett 2014 , 25 (14), 1941–1945.

(28) Wan, J.-P.; Li, Y.; Liu, Y. Org. Chem. Front. 2016 .

(29) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chemie Int. Ed. 2008 , 47 (34), 6452–6455.

(30) Zhang, S.-Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2015 , 137 (1),

531–539.

(31) Zhang, S.-Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2013 , 135 (32),

12135–12141.

(32) Zhang, S.-Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013 ,

135 (6), 2124–2127.

(33) Casadei, M. A.; Galli, C.; Mandolini, L. J. Am. Chem. Soc. 1984 , 106 (4), 1051–1056.

144

(34) Li, J.-J.; Giri, R.; Yu, J.-Q. Tetrahedron 2008 , 64 (29), 6979–6987.

(35) Zhao, Y.; Chen, G. Org. Lett. 2011 , 13 (18), 4850–4853.

(36) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004 , 104 (7), 3341–3370.

(37) Nack, W. A.; He, G.; Zhang, S.-Y.; Lu, C.; Chen, G. Org. Lett. 2013 , 15 (13), 3440–3443.

(38) Han, J.; Zheng, Y.; Wang, C.; Zhu, Y.; Shi, D.-Q.; Zeng, R.; Huang, Z.-B.; Zhao, Y. J.

Org. Chem. 2015 , 80 (18), 9297–9306.

(39) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005 , 127 (38), 13154–

13155.

(40) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010 , 132 (11), 3965–3972.

(41) Rouquet, G.; Chatani, N. Angew. Chemie Int. Ed. 2013 , 52 (45), 11726–11743.

(42) Yang, X.; Shan, G.; Wang, L.; Rao, Y. Tetrahedron Lett. 2016 , 57 (8), 819–836.

(43) He, G.; Chen, G. Angew. Chemie Int. Ed. 2011 , 50 (22), 5192–5196.

(44) Cheng, T.; Yin, W.; Zhang, Y.; Zhang, Y.; Huang, Y. Org. Biomol. Chem. 2014 , 12 (9),

1405–1411.

(45) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Org. Chem. 2012 , 77 (1), 658–668.

(46) Ackermann, L. Chem. Rev. 2011 , 111 (3), 1315–1345.

(47) Wei, Y.; Tang, H.; Cong, X.; Rao, B.; Wu, C.; Zeng, X. Org. Lett. 2014 , 16 (8), 2248–

2251.

(48) Yang, X.; Sun, T.; Rao, Y. Chem. Eur. J. 2016 , 22 (10), 3273–3277.

(49) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009 , 131 (31), 11234–11241.

(50) Gary, J. B.; Sanford, M. S. Organometallics 2011 , 30 (22), 6143–6149.

(51) Camasso, N. M.; Pérez-Temprano, M. H.; Sanford, M. S. J. Am. Chem. Soc. 2014 , 136

(36), 12771–12775.

145

(52) Lanci, M. P.; Remy, M. S.; Kaminsky, W.; Mayer, J. M.; Sanford, M. S. J. Am. Chem.

Soc. 2009 , 131 (43), 15618–15620.

(53) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010 , 14 (3),

347–361.

(54) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996 , 52 (48), 15031–15070.

(55) Sridharan, V.; Suryavanshi, P. A; Menéndez, J. C. Chem. Rev. 2011 , 111 (11), 7157–

7259.

(56) Snider, B. B.; Ahn, Y.; O’Hare, S. M. Org. Lett. 2001 , 3 (26), 4217–4220.

(57) Ma, D.; Xia, C.; Jiang, J.; Zhang, J. Org. Lett. 2001 , 3 (14), 2189–2191.

(58) Powell, D. A.; Batey, R. A. Org. Lett. 2002 , 4 (17), 2913–2916.

(59) Ikeda, S.; Shibuya, M.; Iwabuchi, Y. Chem. Commun. 2007 , No. 5, 504–506.

(60) Davies, S. G.; Fletcher, A. M.; Lee, J. A; Lorkin, T. J. A.; Roberts, P. M.; Thomson, J. E.

Org. Lett. 2013 , 15 (8), 2050–2053.

(61) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chemie Int. Ed. 2006 , 45 (22),

3683–3686.

(62) Prajapati, S. M.; Patel, K. D.; Vekariya, R. H.; Panchal, S. N.; Patel, H. D. RSC Adv. 2014 ,

4 (47), 24463.

(63) Wender, P. A.; Zercher, C. K.; Beckham, S.; Haubold, E. M. J. Org. Chem. 1993 , 58 (22),

5867–5869.

(64) Hara, O.; Koshizawa, T.; Makino, K.; Kunimune, I.; Namiki, A.; Hamada, Y. Tetrahedron

2007 , 63 (27), 6170–6181.

(65) Han, Z.-Y.; Xiao, H.; Chen, X.-H.; Gong, L.-Z. J. Am. Chem. Soc. 2009 , 131 (26), 9182–

9183.

146

(66) Fustero, S.; Moscardó, J.; Jiménez, D.; Pérez-Carrión, M. D.; Sánchez-Roselló, M.; Del

Pozo, C. Chem. Eur. J. 2008 , 14 (32), 9868–9872.

(67) Frank, K. E.; Aubé, J. J. Org. Chem. 2000 , 65 (3), 655–666.

(68) Bunce, R. A.; Herron, D. M.; Ackerman, M. L. J. Org. Chem. 2000 , 65 (10), 2847–2850.

(69) Kouznetsov, V. V. Tetrahedron 2009 , 65 (14), 2721–2750.

(70) Togo, H.; Hoshina, Y.; Muraki, T.; Nakayama, H.; Yokoyama, M. J. Org. Chem. 1998 , 63

(15), 5193–5200.

(71) Moroda, A.; Furuyama, S.; Togo, H. Synlett 2009 , 2009 (08), 1336–1340.

(72) Francisco, C. G.; Herrera, A. J.; Suárez, E. J. Org. Chem. 2003 , 68 (3), 1012–1017.

(73) Jeffrey, J. L.; Sarpong, R. Chem. Sci. 2013 , 4 (11), 4092.

(74) Parella, R.; Babu, S. Synlett 2014 , 25 (10), 1395–1402.

(75) Courtneidge, J. L.; Lusztyk, J.; Pagé, D. Tetrahedron Lett. 1994 , 35 (7), 1003–1006.

(76) Barluenga, J. Pure Appl. Chem. 1999 , 71 (3), 431–436.

(77) Espuña, G.; Arsequell, G.; Valencia, G.; Barluenga, J.; Alvarez-Gutiérrez, J. M.;

Ballesteros, A.; González, J. M. Angew. Chemie Int. Ed. 2004 , 43 (3), 325–329.

(78) Barluenga, J.; Álvarez-Gutiérrez, J. M.; Ballesteros, A.; González, J. M. Angew. Chemie

Int. Ed. 2007 , 46 (8), 1281–1283.

(79) Kubo, T.; Katoh, C.; Yamada, K.; Okano, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron

2008 , 64 (49), 11230–11236.

(80) Lu, C.; Zhang, S.-Y.; He, G.; Nack, W. A.; Chen, G. Tetrahedron 2014 , 70 (27-28), 4197–

4203.

(81) Zhang, X.; He, G.; Chen, G. Org. Biomol. Chem. 2016 , 2–6.

(82) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. Trans. 1915 , 107 (1080), 1080–

147

1106.

(83) O’Hagan, D. Chem. Soc. Rev. 2008 , 37 (2), 308–319.

(84) Ault, A. J. Chem. Educ. 1966 , 43 (6), 329–330.

(85) Jacquemond-Collet, I.; Hannedouche, S.; Fabre, N.; Fourasté, I.; Moulis, C.

Phytochemistry 1999 , 51 (8), 1167–1169.

(86) Jacquemond-Collet, I.; Bessière, J.-M.; Hannedouche, S.; Bertrand, C.; Fourasté, I.;

Moulis, C. Phytochem. Anal. 2001 , 12 (5), 312–319.

(87) Muñoz, G. D.; Dudley, G. B. Org. Prep. Proced. Int. 2015 , 47 (3), 179–206.

(88) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003 ,

125 (35), 10536–10537.

(89) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chemie Int. Ed. 2006 , 45 (14),

2260–2263.

(90) Wang, Z.-J.; Zhou, H.-F.; Wang, T.-L.; He, Y.-M.; Fan, Q.-H. Green Chem. 2009 , 11 (6),

767.

(91) Wang, T.; Zhuo, L.-G.; Li, Z.; Chen, F.; Ding, Z.; He, Y.; Fan, Q.-H.; Xiang, J.; Yu, Z.-

X.; Chan, A. S. C. J. Am. Chem. Soc. 2011 , 133 (25), 9878–9891.

(92) Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2007 , 72 (17), 6577–6579.

(93) Ye, K.-Y.; He, H.; Liu, W.-B.; Dai, L.-X.; Helmchen, G.; You, S.-L. J. Am. Chem. Soc.

2011 , 133 (46), 19006–19014.

(94) Theeraladanon, C.; Arisawa, M.; Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry

2005 , 16 (4), 827–831.

(95) Satyanarayana, G.; Pflästerer, D.; Helmchen, G. Eur. J. Org. Chem. 2011 , 2011 (34),

6877–6886.

148

(96) Dziechciejewski, W. J.; Weber, R.; Sowada, O.; Boysen, M. M. K. Org. Lett. 2015 , 17

(17), 4132–4135.

(97) He, J.; Wasa, M.; Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2013 , 135 (9), 3387–3390.

(98) Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2009 , 131 (20), 6898–

6899.

(99) Rodríguez, N.; Romero-Revilla, J. A.; Fernández-Ibáñez, M. Á.; Carretero, J. C. Chem.

Sci. 2013 , 4 (1), 175–179.

(100) Skraup, S.; Beifuß, W. Berichte der Dtsch. Chem. Gesellschaft (A B Ser. 1927 , 60 (5),

1074–1077.

(101) Gnaim, J. M.; Sheldon, R. A. Tetrahedron Lett. 1995 , 36 (22), 3893–3896.

(102) Gnaim, J. M.; Sheldon, R. A. Tetrahedron Lett. 2004 , 45 (46), 8471–8473.

(103) Pearson, D. E.; Wysong, R. D.; Breder, C. V. J. Org. Chem. 1967 , 32 (7), 2358–2360.

(104) Saper, N. I.; Snider, B. B. J. Org. Chem. 2014 , 79 (2), 809–813.

(105) Smith, K.; Butters, M.; Nay, B. Tetrahedron Lett. 1988 , 29 (11), 1319–1322.

(106) Lynch, B. M.; Chen, C. M.; Wigfield, Y.-Y. Can. J. Chem. 1968 , 46 (7), 1141–1152.

(107) Strazzolini, P.; Giumanini, A. G.; Runcio, A.; Scuccato, M. J. Org. Chem. 1998 , 63 (4),

952–958.

(108) O’Connell, J. L.; Simpson, J. S.; Dumanski, P. G.; Simpson, G. W.; Easton, C. J. Org.

Biomol. Chem. 2006 , 4 (14), 2716–2723.

(109) Gustafson, J. L.; Lim, D.; Miller, S. J. Science 2010 , 328 (5983), 1251–1255.

(110) Álvarez-Rúa, C.; García-Granda, S.; Ballesteros, A.; González-Bobes, F.; González, J. M.

Acta Crystallogr. Sect. E Struct. Reports Online 2002 , 58 (12), o1381–o1383.

(111) Kim, Y.; Mckinley, E. J.; Christensen, K. E.; Rees, N. H.; Thompson, A. L. Cryst. Growth

149

Des. 2014 , 14 (12), 6294–6301.

(112) Rosokha, S. V.; Kochi, J. K. J. Org. Chem. 2002 , 67 (6), 1727–1737.

(113) Fukuzumi, S.; Kochi, J. K. J. Am. Chem. Soc. 1981 , 103 (24), 7240–7252.

(114) Kim, E. K.; Kochi, J. K. J. Am. Chem. Soc. 1991 , 113 (13), 4962–4974.

(115) Bosch, E.; Kochi, J. K. J. Org. Chem. 1994 , 59 (19), 5573–5586.

(116) Vasilyev, A. V.; Lindeman, S. V.; Kochi, J. K. Chem. Commun. 2001 , 909–910.

(117) Galabov, B.; Koleva, G.; Simova, S.; Hadjieva, B.; Schaefer, H. F.; Schleyer, P. V. R.

Proc. Natl. Acad. Sci. 2014 , 111 (28), 10067–10072.

(118) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chemie Int. Ed. 2008 , 47 (6), 1115–

1118.

(119) Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chemie

Int. Ed. 2007 , 46 (29), 5554–5558.

(120) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006 ,

128 (23), 7416–7417.

(121) Xiao, B.; Li, Y.-M.; Liu, Z.-J.; Yang, H.-Y.; Fu, Y. Chem. Commun. 2012 , 48 (40), 4854–

4856.

(122) Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc. 2011 , 133 (47), 19076–19079.

(123) Gutekunst, W. R.; Gianatassio, R.; Baran, P. S. Angew. Chemie Int. Ed. 2012 , 51 (30),

7507–7510.

(124) Gutekunst, W. R.; Baran, P. S. J. Org. Chem. 2014 , 79 (6), 2430–2452.

(125) Ting, C. P.; Maimone, T. J. Angew. Chemie Int. Ed. 2014 , 53 (12), 3115–3119.

(126) Zhou, M.; Li, X.-R.; Tang, J.-W.; Liu, Y.; Li, X.-N.; Wu, B.; Qin, H.-B.; Du, X.; Li, L.-

M.; Wang, W.-G.; Pu, J.-X.; Sun, H.-D. Org. Lett. 2015 , 17 (24), 6062–6065.

150

(127) Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu, J.-Q. J. Am. Chem. Soc. 2011 , 133

(49), 19598–19601.

(128) Xiao, K.; Lin, D. W.; Miura, M.; Zhu, R.; Gong, W.; Wasa, M.; Yu, J. J. Am. Chem. Soc.

2014 , 136 (22), 8138–8142.

(129) Chan, K. S. L.; Fu, H.-Y.; Yu, J.-Q. J. Am. Chem. Soc. 2015 , 137 (5), 2042–2046.

(130) Affron, D. P.; Bull, J. A. Eur. J. Org. Chem. 2016 , 2016 (1), 139–149.

(131) Affron, D. P.; Davis, O. A.; Bull, J. A. Org. Lett. 2014 , 16 (18), 4956–4959.

(132) Padmavathi, R.; Sankar, R.; Gopalakrishnan, B.; Parella, R.; Babu, S. A. Eur. J. Org.

Chem. 2015 , 2015 (17), 3727–3742.

(133) Parella, R.; Babu, S. A. J. Org. Chem. 2015 , 80 (4), 2339–2355.

(134) Yu, Q.-Y.; Zhong, H.-M.; Sun, W.-W.; Zhang, S.-J.; Cao, P.; Dong, X.-P.; Qin, H.-B.;

Liu, J.-K.; Wu, B. Asian J. Org. Chem. doi: 10.1002/ajoc.201600072

(135) Roman, D. S.; Charette, A. B. Org. Lett. 2013 , 15 (17), 4394–4397.

(136) Parella, R.; Gopalakrishnan, B.; Babu, S. A. Org. Lett. 2013 , 15 (13), 3238–3241.

(137) Parella, R.; Gopalakrishnan, B.; Babu, S. A. J. Org. Chem. 2013 , 78 (23), 11911–11934.

(138) Seki, A.; Takahashi, Y.; Miyake, T. Tetrahedron Lett. 2014 , 55 (17), 2838–2841.

(139) Lao, Y.-X.; Wu, J.-Q.; Chen, Y.; Zhang, S.-S.; Li, Q.; Wang, H. Org. Chem. Front. 2015 ,

2 (10), 1374–1378.

(140) Cui, W.; Chen, S.; Wu, J.-Q.; Zhao, X.; Hu, W.; Wang, H. Org. Lett. 2014 , 16 (16), 4288–

4291.

(141) Hoshiya, N.; Takenaka, K.; Shuto, S.; Uenishi, J. Org. Lett. 2016 , 18 (1), 48–51.

(142) Hoshiya, N.; Kobayashi, T.; Arisawa, M.; Shuto, S. Org. Lett. 2013 , 15 (24), 6202–6205.

(143) Calvert, M. B.; Sperry, J. Org. Biomol. Chem. 2016 .

151

(144) Tang, H.; Zhou, B.; Huang, X.; Wang, C.; Yao, J.; Chen, H. ACS Catal. 2014 , 4 (2), 649–

656.

(145) Wang, B.; Nack, W. A.; He, G.; Zhang, S.-Y.; Chen, G. Chem. Sci. 2014 , 5 (10), 3952.

(146) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006 , 128 (51), 16496–16497.

(147) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chemie Int. Ed. 2005 , 44 (14), 2112–2115.

(148) Wang, B.; Nack, W. A.; He, G.; Zhang, S.-Y.; Chen, G. Chem. Sci. 2014 , 5 (10), 3952.

(149) Shan, G.; Yang, X.; Zong, Y.; Rao, Y. Angew. Chemie Int. Ed. 2013 , 52 (51), 13606–

13610.

(150) Schleyer, P.V.R.; Williams, J. E.; Blanchard, K. R. J. Am. Chem. Soc. 1970 , 92 (8), 2377–

2386.

(151) Meinwald, J.; Tufariello, J. J.; Hurst, J. J. J. Org. Chem. 1964 , 29 (10), 2914–2919.

(152) Li, Q.; Zhang, S.-Y.; He, G.; Nack, W. A.; Chen, G. Adv. Synth. Catal. 2014 , 356 (7),

1544–1548.

(153) He, G.; Zhang, S.-Y.; Nack, W. A.; Li, Q.; Chen, G. Angew. Chemie 2013 , 125 (42),

11330–11334.

(154) Sun, W.-W.; Cao, P.; Mei, R.-Q.; Li, Y.; Ma, Y.-L.; Wu, B. Org. Lett. 2014 , 16 (2), 480–

483.

(155) Zhang, S.-J.; Sun, W.-W.; Cao, P.; Dong, X.-P.; Liu, J.-K.; Wu, B. J. Org. Chem. 2016 , 81

(3), 956–968.

(156) Zhang, Q.; Chen, K.; Rao, W.; Zhang, Y.; Chen, F.-J.; Shi, B.-F. Angew. Chemie Int. Ed.

2013 , 52 (51), 13588–13592.

(157) Chalker, J. M.; Wood, C. S. C.; Davis, B. G. J. Am. Chem. Soc. 2009 , 131 (45), 16346–

16347.

152

(158) Zhang, S. Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G. J. Am. Chem. Soc.

2012 , 134 (17), 7313–7316.

(159) Tanaka, H.; Ogasawara, K. Tetrahedron Lett. 2002 , 43 (25), 4417–4420.

(160) Bao, C.; Fan, G.; Lin, Q.; Li, B.; Cheng, S.; Huang, Q.; Zhu, L. Org. Lett. 2012 , 14 (2),

572–575.

(161) Roice, M.; Christensen, S. F.; Meldal, M. Chem. Eur. J. 2004 , 10 (18), 4407–4415.

(162) Yoo, E. J.; Ma, S.; Mei, T.; Chan, K. S. L.; Yu, J. J. Am. Chem. Soc. 2011 , 133 (20),

7652–7655.

(163) Gopalakrishnan, B.; Babu, S. A.; Padmavathi, R. Tetrahedron 2015 , 71 (43), 8333–8349.

(164) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006 , 8 (15), 3391–3394.

(165) Affron, D. P.; Davis, O. A.; Bull, J. A. Org. Lett. 2014 , 16 (18), 4956–4959.

(166) Ano, Y.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2011 , 133 (33), 12984–12986.

(167) Zhang, Q.; Chen, K.; Rao, W.; Zhang, Y.; Chen, F.-J.; Shi, B.-F. Angew. Chem. Int. Ed.

2013 , 3–8.

(168) Li, M.; Dong, J.; Huang, X.; Li, K.; Wu, Q.; Song, F.; You, J. Chem. Commun. 2014 , 50

(30), 3944–3946.

153

VITA

William Andrew Nack was born in New York City, New York on October 29, 1989 to

Ruthlynne Stein Nack and Stanley Barnett Nack. He graduated from Bayside High School of

Bayside, New York in 2007. Afterwards, he studied at the State University of New York, College at Geneseo, graduating in May 2011 with a Bachelor of Science degree in Chemistry. In August

2011, he entered The Graduate School in the Department of Chemistry at The Pennsylvania State

University.