© 2016 Zuxiao Zhangufdcimages.uflib.ufl.edu/UF/E0/05/05/40/00001/ZHANG_Z.pdf · photo-redox...

PHOTO-REDOX CATALYZED RADICAL CASCADE REACTIONS: EFFICIENT

METHODS TO CONSTRUCT VARIOUS HETEROCYCLES BEARING CF2H

By

ZUXIAO ZHANG

A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL

OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT

OF THE REQUIREMENTS FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA

2016

To my Family

4

ACKNOWLEDGMENTS

I would especially like to thank my supervisor, Dr. William R. Dolbier, for not only the

invaluable guidance, encouragement but also for supporting my ideas. He is a true example of

what a great scientist should be – hard worker, honest and a great professor. It has been a

rewarding experience and great honor to work with him.

I want to take this opportunity to express my sincere gratitude to Dr. Castellano, Dr.

Smith, Dr. Aponick and Dr. Huigens for their kind help, suggestions and time they have spent as

my supervisory committee members.

I deeply appreciate my parents as well as my brother for their unconditional love, support

and encouragement, without which I cannot become a doctor.

To all my labmates, especially Miles Rubinski, thank you for all the great times,

discussions and help. I hope I live enough to return all their kindness and care.

Finally, last but not the least, I want to thank all the friends outside who are too many to

mention individually, for their support and friendship.

5

TABLE OF CONTENTS

page

ACKNOWLEDGMENTS ...............................................................................................................4

LIST OF TABLES ...........................................................................................................................7

LIST OF FIGURES .........................................................................................................................8

LIST OF ABBREVIATIONS ........................................................................................................10

ABSTRACT ...................................................................................................................................11

CHAPTER

1 INTRODUCTION ..................................................................................................................13

1.1 Recent Development of Difluoromethylation Reactions ..................................................13 1.2 Photo-Redox Emerged Novel Methodologies in Organic Chemistry ..............................17

2 TANDEM INSERTION /CYCLIZATION REACTIONS OF DIFLUOROMETHYL

AND 1,1- DIFLUOROALKYL RADICALS WITH BIPHENYL ISOCYANIDES .............21

2.1 Introduction .......................................................................................................................21

2.2 Screening Conditions ........................................................................................................23 2.3 Substrates Scope of Difluoromethylation of Isocyanides .................................................25

2.4 Substrate Scope of Other Gem-Difluoroalkylation of Isocyanides ..................................27 2.5 Proposed Mechanism and Conclusion ..............................................................................28

2.6 Experimental Section ........................................................................................................29

3 INTRAMOLECULAR AMINODIFLUOROMETHYLATION OF UNACTIVATED

ALKENES ..............................................................................................................................43

3.1 Introduction .......................................................................................................................43

3.2 Probable Mechanism ........................................................................................................45 3.3 Optimization of Reaction Conditions ...............................................................................45 3.4 Substrate Scope .................................................................................................................47 3.5 Probe of Mechanism and Conclusion ...............................................................................49 3.6 Experiment Section ...........................................................................................................51

4 INTRAMOLECULAR DIFLUOROMETHYLATON OF N-

BENZYLACRYLAMIDES COUPLED WITH A DEAROMATIZING

SPIROCYCLIZATION ..........................................................................................................63

4.1 Introduction .......................................................................................................................63 4.2 Optimization of Reaction Conditions ...............................................................................65

4.3 Substrate Scope of Photoredox Catalyzed Difluoromethylation/spirocyclization ...........67

6

4.4 Photo-redox Catalyzed Difluoromethylation/Dearomatization with Other

Fluoroalkyl Radical Source .................................................................................................70 4.5 Substrates Scope with SO2 Group Retained .....................................................................71 4.6 Proposed Mechanism and Conclusion ..............................................................................72

4.7 Experimental Section ........................................................................................................73

5 INTRAMOLECULAR FLUOROALKYLARYLATION OF UNACTIVATED

ALKENES ..............................................................................................................................96

5.1 Introduction .......................................................................................................................96 5.2 Screening of Reaction Conditions ....................................................................................98

5.3 Difluoromethylation Coupled with Construction of 6-Membered-ring Carbocycles .....100 5.4 Other Fluoroalkyl Radical Source Scope .......................................................................102

5.5 Proposed Mechanism and Conclusion ............................................................................103 5.6 Experimental Section ......................................................................................................105

LIST OF REFERENCES .............................................................................................................119

BIOGRAPHICAL SKETCH .......................................................................................................124

7

LIST OF TABLES

Table page

2-1 Screening conditions of difluoromethylation of byphenyl isonitriles................................24

3-1 Optimization of reaction conditions of photo-redox catalyzed difluoromethylation

reactions .............................................................................................................................46

4-1 Optimization of reaction conditions of difluoromethylation/dearomatization.a ................67

5-1 Screening conditions of intermolecular carbo difluoromethylation of unactivated

alkenes..............................................................................................................................100

8

LIST OF FIGURES

Figure page

1-1 Difluoromethylation Reagents. ..........................................................................................14

1-2 Difluoromethylation of aromatic compounds. ...................................................................15

1-3 Transition metal catalyzed cross coupling reactions. ........................................................16

1-4 Di-functionalization type difluoromethylation of alkenes. ................................................17

1-5 Reprehensive photoredox catalysis mechanistic scheme. ..................................................18

1-6 Representative photoredox catalysis combined with HAR and PCET reactions. .............19

1-7 Example of photoredox catalysis acting as co-oxidant to generate the key

intermediate........................................................................................................................20

1-8 Example of photoredox catalysis combined with chiral lewis acid catalyst. .....................20

2-1 Preparation of 6-(difluoromethyl)phenanthridine.. ............................................................23

2-2 Substrate scope of other gem-difluoroalkylation of isocyanides.. .....................................26

2-3 Substrate scope of other gem-difluoroalkylation of isocyanides.. .....................................27

2-4 Proposed mechanism of difluoromethylation of biphenyl isonitriles. ...............................28

2-5 Synthesis of biphenyl isocyanides. ....................................................................................29

2-6 Synthesis of difluoroalkyl radical source reagents. ...........................................................30

3-1 Photo-redox catalyzed difluoromethylation reactions. ......................................................44

3-2 Probable mechanism of photo-redox catalyzed difluoromethylation reactions. ................45

3-3 Substrate scope of photo-redox catalyzed difluoromethylation reactions. ........................48

3-4 Probe of mechanism of photo-redox catalyzed difluoromethylation reactions. ................50

3-5 Two step example of photo-redox catalyzed difluoromethylation reactions. ....................50

3-6 Synthesis substrates of photo-redox catalyzed difluoromethylation reactions. .................52

4-1 Photo-redox catalyzed difluoromethylation of unsaturated bonds. ...................................64

4-2 Substrate scope of photoredox catalyzed difluoromethylation/spirocyclization ...............69

9

4-3 Photo-redox catalyzed difluoromethylation/dearomatization with other fluoroalkyl

radical source. ....................................................................................................................71

4-4 Substrates scope with SO2 group retained. ........................................................................72

4-5 Proposed mechanism of difluoromethylation/dearomatization. ........................................73

5-1 Representative drugs and bioactive molecules (top). Proposed fluoroalkylated tetralin

derivatives synthesis from carbo fluoroarylation of unactivated -arylalkenes

(bottom)..............................................................................................................................98

5-2 Difluoromethylation coupled with construction of 6-membered-ring carbocycles. ........101

5-3 Difluoromethylation coupled with construction of 5-membered-ring carbocycles. ........102

5-4 Construction of 6-membered-ring carbocycles bearing other fluoroalkyl groups. ..........103

5-5 Proposed mechanism of difluoromethylation coupled with construction of 6-

membered-ring carbocycles .............................................................................................104

10

LIST OF ABBREVIATIONS

ATRA

Cl

Cu

Dap

DAST

DCE

DFMS

DMPU

Equiv

5-exo-trig

fac-Ir(ppy)3

HAT

hv

mL

mmol

Ni

NMR

OH

PCET

rt.

SET

SO2

TMS

Zn

Atom transfer radical addition

Chloride

Copper

2,8-bis(4-methoxyphenyl)-1,9-phenanthroline

Diethylaminosulfur trifluoride

1,2-Dichloroethane

1,3-Dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone

1,3-Dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone

Equivalence

5 members ring closure is outside the ring that is being formed

Tris[2-phenylpyridinato-C2,N]iridium(III)

Hydrogen atom transfer

Under light conditions

Milliliter

Millimole

Nickel

Nuclear magnetic resonance

Hydroxyl

Proton coupled electron transfer

Room temperature

Single electron transfer

Sulfur dioxide

Trimethylsilyl

Zinc

11

Abstract of Dissertation Presented to the Graduate School

of the University of Florida in Partial Fulfillment of the

Requirements for the Degree of Doctor of Philosophy

PHOTO-REDOX CATALYZED RADICAL CASCADE REACTIONS: EFFICIENT

METHODS TO CONSTRUCT VARIOUS HETEROCYCLES BEARING CF2H

By

Zuxiao Zhang

December 2016

Chair: William R. Dolbier, Jr

Major: Chemistry

Our group developed CF2HSO2Cl as a CF2H radical source and this reagent is easily

prepared in large quantities from cheap, readily available starting materials. CF2HSO2Cl,

combined with a photoredox catalyst, proved to be an efficient method to generate the CF2H

radical, which showed good reactivity towards electron deficient carbon-carbon double bonds.

Considering the limited methodologies to incorporate CF2H into organic molecules and their

promising potential use in drug design, several photoredox catalyzed difluoromethylation

reactions were investigated.

Using visible-light photoredox conditions, difluoromethylation and 1,1-difluoroalkylation

of biphenyl isocyanides allowed the synthesis of a series of 6-(difluoromethyl)- and 6-(1,1-

difluoroalkyl)phenanthridines via tandem addition/cyclization/oxidation processes. The reactions

were carried out in wet dioxane at room temperature using fac-Ir(ppy)3 as catalyst to form a large

variety of substituted phenanthridine products in good to excellent yield.

A photo-redox catalyzed aminodifluoromethylation reaction of unactivated alkenes has

been developed using HCF2SO2Cl as the HCF2 radical source. Sulfonylamides were active

nucleophiles in the cyclization processes to form pyrrolidines, and esters were found to cyclize to

12

form lactones. Thus, a variety of pyrrolidines and lactones were obtained in medium to excellent

yield. In order for the cyclization reactions to be efficient, a combination of copper catalyst

(Cu(dap)2Cl) and silver carbonate was crucial to suppress a competing chloro, difluoroalkylation

process.

A visible light-mediated difluoromethylation of N-benzylacrylamides with HCF2SO2Cl

as the HCF2 radical precursor is described. The reaction incorporates a tandem

cyclization/dearomatization process to afford various difluoromethylated 2-azaspiro[4.5]deca-

6,9-diene-3,8-diones bearing adjacent quaternary stereocenters under mild conditions in

moderate to excellent yields.

A photo-redox catalyzed difluoromethylation reaction of unactivated alkenes, coupled

with C(sp2)-C(sp3) bond formation was established. It’s the first example of introduction of the

difluoromethyl group into the tetralin skeleton system. Furthermore, this reaction provided a

unified strategy to introduce other valuable perfluoroalkyl and partially fluorinated alkyl groups

into tetralin, indene or indoline derivatives under mild conditions in moderate to excellent yield.

13

CHAPTER 1

INTRODUCTION

1.1 Recent Development of Difluoromethylation Reactions

Fluorine substituents and fluoroalkyl groups have been widely recognized as playing a

strategic role in pharmaceutical research and drug development due to their demonstrated ability

to enhance properties related to biological activity, such as improved lipophilicity, metabolic

stability, and bioavailability.1 Therefore substantial effort has been devoted to the development

of synthetic methods for introduction of the fluorine substituent and fluoroalkyl groups into

various organic building block molecules. Foremost among them has been the development of

methods for incorporation of the trifluoromethyl group, work extending over the last few

decades.2 In contrast, methods for introduction of partially fluorinated alkyl groups has been

much more limited.3 In particular, the difluoromethyl group, which can offer a more lipophilic

H-bond donor than either an OH or NH is of great current interest.4 Traditional methods for the

synthesis of difluoroalkylated molecules generally involved the use of expensive and highly

reactive reagents such as SF4, diethylaminosulfur trifluoride (DAST), and other related reagents

to carry out deoxyfluorination of aldehydes and ketones.5 Furthermore, adding to the many

undesirable aspects of these methodologies, they also generally suffer from poor functional

group tolerance. Consequently, the development of new methods for introduction of CF2H and

other gem-difluoro alkyl groups into organic compounds remains a challenging and worthwhile

endeavor.

Compared with introduction of CF3, there are two challenges regarding installing CF2H.

First the CF2H reagents are relatively limited, even though several bench stable and easily

accessible difluoromethylation reagents have been developed very recently (Figure 1-1).

14

Second, the CuCF2H species which would be ideal to realize the cross coupling is not as stable as

CuCF3.8a Recently, there has been increasingly impressive work in the area of direct introduction

of the difluoromethyl group into organic compounds based on the development of new reagents.

Figure 1-1. Difluoromethylation Reagents.

The construction of C(sp2)-CF2H can be accomplished by several different strategies in

order to incorporate the CF2H group onto aromatic and heteroaromatic compounds mainly via

radical processes or cross coupling reactions (Figure 1-2). For instance, in 2012, Baran’s group

developed a new reagent Zn(SO2CF2H)2 which under oxidative conditions generates the

difluoromethyl radical that can afford difluoromethylated heterocycles.6 In the same year,

Hartwig and Prakash independently reported copper mediated difluoromethylation of aryl

iodides using trimethylsilyl difluoromethane (TMSCF2H) and tributyl(difluoromethyl) stannane

(n-Bu3SnCF2H), respectively, as their sources of difluoromethyl.7 Shen and coworkers realized

15

difluoromethylation of aryl iodides and bromides using TMSCF2H with copper and silver as co-

catalysts.8 Then Vivic and coworker realized nickel catalyzed difluoromethylation using

(DMPU)2Zn(CF2H)2 (1-c) as the difluoromethyl source (Figure 1-3).9 Also using the same

reagent copper and palladium catalyzed cross coupling difluoromethylation were realized in

2016.10 Xiao group also realized the difluoromethylation of phenyl boronic acid via palladium

catalyzed difluorocarbene transfer.11 The Goossen group also reported a Sandmeyer

difluoromethylation of aryl diazonium salts.12

Figure 1-2. Difluoromethylation of aromatic compounds.

16

Figure 1-3. Transition metal catalyzed cross coupling reactions.

In contrast, the methods to construct C(sp3)-CF2H are relatively limited. The

difunctionalization type of difluoromethylation would be an ideal way to construct C(sp3)-CF2H.

Thus, a well-designed radical cascade reaction could be an the efficient way to introduce CF2H

into complex organic molecules. There are only a handful of examples about this type of

reactions that have been reported (Figure 1-4). For instance, Qing group reported the visible-

light-induced hydrodifluoromethylation of alkenes with bromodifluoromethylphosphonium

bromide (1-g) which used THF and water as hydrogen source.13 In 2016 Akita group realized the

photoredox catalyzed oxydifluoromethylation of alkenes using reagent 1-e to access CF2H-

containing alcohols.14 In the same year Tan’s group developed a silver catalyzed

difluoromethylation reaction that produced 5-exo-trig cyclization onto an aryl ring to construct

oxindoles.15 In 2015, Hu and coworkers reported a novel fluoroalkylative aryl migration of

conjugated N-arylsulfonylated amides.16 Our group developed one of CF2HSO2Cl, which showed

good reactivity with photoredox catalysts to generate the CF2H radical under greener and milder

conditions. The CF2H radical is more nucleophilic than CF3 radical, therefore it can react with

various electron deficient C=C bonds. For example, our 2014 report of the photo-redox catalyzed

17

difluoromethylation of N-arylacrylamides, which was accompanied by a tandem 5-exo-trig

cyclization onto the aryl ring to construct oxindoles.17 There are also methodologies which have

been reported to construct various compounds which contain hetero atom CF2H bonds, such as

N-CF2H, O-CF2H as well as S-CF2H.18

Figure 1-4. Di-functionalization type of difluoromethylation of alkenes.

1.2 Emergence of novel Photo-Redox Methodologies in Organic Chemistry

Since the breakthrough of pairing of organocatalysis and photocatalysis by the

MacMillan group and contemporary reports by the groups of Yoon and Stephenson, photoredox

catalysis has enjoyed particularly active and intense study.19 Most of the photoredox catalytic

reactions follow the mechanistic schemes shown as Figure 1-5.20 The photoredox catalyst could

be excited by visible light and following the single electron transfer process to generate the

active intermediate. According to the primary direction of the electron transfer with respect to

the excited state of the catalyst, the catalytic circle can be categorized as follows: the oxidative

quenching cycle, where the excited catalyst serves as an electron donor to reduce the substrate or

oxidant; or the reductive quenching cycle, where the excited catalyst serves an electron acceptor

to oxidize the substrate or reductant. In both cycle, the photoredox catalyst could act both as

strong reductant and oxidant, the only extra energy it needed was supplied by photons.

18

Figure 1-5. Representative photoredox catalysis mechanistic scheme.

In particular, photoredox catalysis shows very good compatibility with other catalysis,

such as transition metal, Lewis acid or hydrogen atom transfer reagents. As a result, numerous

elegant works have been reported based on multi-catalytic systems.21 People can manipulate

every single step to furnish different transformations such as the generation of carbon radicals,

19

the generated radical coupling with transition metal catalysts and reductive elimination from the

transition metal center. Usually the photoredox catalyst simply act as a greener SET reagent,

which generates the active carbon centered radical, which is followed by traditional radical

reactions, in the end a stable radical being formed which oxidized by the hypervalent photoredox

catalyst to complete the catalytic circle. During the radical generation step, the photoredox

catalyst can combine with HAT reagents or Bronsted base to activate strong chemical bonds via

HAT or PCET pathways (Figure 1-6).21d, 22 Also in the following step, the carbon centered

radical could react with transition metals such as copper and nickel to realize cross coupling.23

Also the photoredox catalyst could act as a co-oxidant to generate hypervalent metal centers

which could promote reductive elimination (Figure 1-7).24 In addition, the photoredox catalyst

could catalyze unsymmetrical cycloaddition reactions combined with Lewis acid which go

through a radical pathway (Figure 1-8).19b

Figure 1-6. Representative photoredox catalysis combined with HAR and PCET reactions.

20

Figure 1-7. Example of photoredox catalysis acting as co-oxidant to generate the key

intermediate.

Figure 1-8. Example of photoredox catalysis combined with chiral Lewis acid catalyst.

Therefore, photoredox catalysis have several advantages compared with traditional redox

chemistry: first, photoredox catalysis can generate active intermediates via a single electron

transfer process under greener and milder conditions. Also in most cases, no strong external

oxidant or reductant is needed. Second, both a strong oxidant and a reductant can exist

simultaneously in the reaction, which facilitates various novel transformations via unprecedented

mechanisms.

The most common efficient pathways for introducing CF2R, CF3 and other fluorinated

alkyl groups are via a radical pathway, which is ideally suited to take advantage of photoredox

catalysis. Recently several reports have shown the power of photoredox catalysis in fluorine

chemistry.23a, 25 Considering the limits to installing Csp3-CF2H bond in organic molecules, we

wish to utilize the advantage of photoredox catalysis to introduce the CF2H group into organic

molecules using the reagent, difluoromethyl sulfonyl chloride which were developed by our

group as a difluoromethyl radical precursor.

21

CHAPTER 2

TANDEM INSERTION /CYCLIZATION REACTIONS OF DIFLUOROMETHYL AND 1,1-

DIFLUOROALKYL RADICALS WITH BIPHENYL ISOCYANIDES

2.1 Introduction

The introduction of fluorine-containing alkyl groups into molecules has attracted

researchers’ interest for several decades because of the beneficial properties that their presence

can bestow, including enhanced reactivity, lipophilicity, and bioactivity.1 A host of elegant

approaches have been developed to introduce fluoro substitutents and fluorinated alkyl groups, in

particular the trifluoromethyl group, into diverse skeletons.2 However, methodologies to

introduce CF2H have been considerably less studied.3 Traditional methods for the synthesis of

difluoroalkylated molecules generally involved the use of expensive and highly reactive reagents

such as SF4, diethylaminosulfur trifluoride (DAST), and other related reagents to carry out

deoxyfluorination of aldehydes and ketones.5 In addition to the many undesirable aspects of

these methodologies, they also generally suffer from poor functional group tolerance. Therefore

the development of new methods for introduction of CF2H and other gem-difluoro alkyl groups

into organic compounds remains a challenging and worthwhile endeavor.

Reprinted (adapted) with permission from (Zhang, Z.; Tang, X. J.; Dolbier, W. R., Jr. Org.

Lett. 2015, 17, 4401.). Copyright (2015) American Chemical Society

22

Recently there has been much excellent work in the area of direct introduction of the

difluoromethyl group into aromatic and heteroaromatic compounds mainly via radical processes

or cross coupling reactions.6-8 For instance, in 2012, Baran’s group developed a new reagent

Zn(SO2CF2H)2 which under oxidative conditions generates the difluoromethyl radical that will

allow difluoromethylation of heterocycles.6 In the same year, Hartwig and Prakash

independently reported copper mediated difluoromethylation of aryl iodides using trimethylsilyl

difluoromethane (TMSCF2H) and tributyl(difluoromethyl) stannane (n-Bu3SnCF2H),

respectively, as their sources of difluoromethyl.7 Shen and his coworker realized

difluoromethylation of aryl iodides and bromides using TMSCF2H with copper and silver as co-

catalyst.8 The Goossen group also reported Sandmeyer difluoromethylation of aryl diazonium

salts.12

The phenanthridine core occurs widely in natural products and biological molecules.26

One effective method for preparing phenanthridines bearing substituents at the 6-position has

involved reactions of various radicals, including trifluoromentyl, with 2-isocyano-1,1’-

biphenyl.27-28 With respect to the difluoromethyl group, thus far only Yu’s group has reported a

method for difluoromethylation of isocyanides, in his case using a stepwise strategy involving

initial reaction with the carboethoxydifluoromethyl radical (Figure 2-1-a).29 The direct

difluoromethylation of isocyanides is still unreported.

23

Figure 2-1. Preparation of 6-(difluoromethyl)phenanthridine. Originally reported in Zhang, Z.;

Tang, X. J.; Dolbier, W. R., Jr. Org. Lett. 2015, 17, 4401.

In recent work, our group has demonstrated that, under photoredox catalysis, CF2HSO2Cl

can be a very good difluoromethyl radical precursor, with the generated radical showing good

reactivity towards both electron-rich and electron-poor double bonds.17, 30 We envisioned that a

similarly-generated CF2H radical would react with 2-isocyano-1,1’-biphenyl (1a), with the

intermediate radical then cyclizing with subsequent oxidation and deprotonation to form 6-

(difluoromethyl)-phenanthridine (Figure 2-1-b).

2.2 Screening Conditions

To test our hypothesis, 1a was used as substrate under the photoredox conditions that we

had used previously to generate the difluoromethyl radical, using fac-Ir(ppy)3 as catalyst with 1

mol % loading. Considering their previously-determined significance, several bases were

examined (Table 2-1). Unfortunately, only trace amounts of product were detected when using

Na2CO3 and K2HPO4 (entries 1 and 2), and looking at a few other bases did not improve the

situation, with 1a largely remaining unreacted (entries 3-7). Solvent dependence was then

examined. Using K2HPO4 as base, highly polar solvents were found to be ineffective (entries 8-

24

10), but combining dioxane with a small amount of water led to 54% of the desired product

(entry 11). Other Ir photoredox catalysts gave similar results (entry 12 and 13). However,

changing the base to Na2CO3 led to an increase in yield to 84%, which was considered to be

satisfactory (entry 14). It should be mentioned that only 20% of product was obtained in the

absence of water (entry 15). The exact effect of water is still unclear, but it is probable that water

promotes the solubility of the base in dioxane.

Table 2-1. Screening conditions of difluoromethylation of byphenyl isonitriles.a,b Originally

reported in Zhang, Z.; Tang, X. J.; Dolbier, W. R., Jr. Org. Lett. 2015, 17, 4401.

entry catalyst solvent base yield, %

1 Ir(ppy)3 CH3CN Na2CO3 trace

2 Ir(ppy)3 CH3CN K2HPO4 trace

3 Ir(ppy)3 CH3CN Ag2CO3 ND

4 Ir(ppy)3 CH3CN K2CO3 ND

5 Ir(ppy)3 CH3CN K3PO4 ND

6 Ir(ppy)3 CH3CN KOAc ND

7 Ir(ppy)3 CH3CN NaOAc ND

8 Ir(ppy)3 DMF K2HPO4 ND

9 Ir(ppy)3 DMAc K2HPO4 ND

10 Ir(ppy)3 NMP K2HPO4 ND

11c Ir(ppy)3 dioxane K2HPO4 54

12c, d Cat. 1 dioxane K2HPO4 63

13c, e Cat. 2 dioxane K2HPO4 56

14c Ir(ppy)3 dioxane Na2CO3 84

15 Ir(ppy)3 dioxane Na2CO3 20

a Reactions were run with 0.1 mmol of 2-1a, 0.2 mmol of HCF2SO2Cl, 0.2 mmol of

base, and 0.001 mmol of catalyst in 1 mL of solvent under visible light. b All yields were based

on 2-1a using fluorobenzene as internal standard. c 4-6 mg water as additive. d Cat 1:

[Ir{df(CF3)ppy}2(dtbpy)]PF6 e Cat.2: [Ir(dtbpy)(ppy)2]PF6

25

2.3 Substrate Scope of Difluoromethylation of Isocyanides

To study the scope of the reaction, various biarylisonitriles were tested (Figure 2-2). A

variety of substituents, both electron-rich and electron-poor, on the isonitrile arene moiety,

including methyl (1b), carbomethoxy (1g), methoxy (1e, 1f), fluoro (1d) and CF3 (1c), produced

the corresponding products in good to excellent yields. Substitution on the other phenyl ring

indicated that the reaction did not tolerate electron-poor substituents on this ring, with

compounds 2n and 2o being formed in poor yield. Otherwise, it appears that this reaction is quite

versatile with respect to substitution and multisubstitution of the two phenyl rings.

26

Figure 2-2. Substrate scope of other gem-difluoroalkylation of isocyanides. Originally reported

in Zhang, Z.; Tang, X. J.; Dolbier, W. R., Jr. Org. Lett. 2015, 17, 4401.

27

2.4 Substrate Scope of Other Gem-Difluoroalkylation of Isocyanides

To further explore the application of the tandem reaction, RCF2X was employed under

the optimized condition (Figure 2-3). Since the PhCF2Br is liquid and easier to prepare than the

respective sulfonyl chloride, it was used as the precursor of the PhCF2 radical instead of the

sulfonyl chloride. Using a higher temperature and 2% loading of catalyst, very good yields were

able to be obtained for a variety of substrates.

Figure 2-3. Substrate scope of other gem-difluoroalkylation of isocyanides. Originally reported

in Zhang, Z.; Tang, X. J.; Dolbier, W. R., Jr. Org. Lett. 2015, 17, 4401.

28

Additionally, CH3CF2SO2Cl proved effective as a source of 1,1-difluoroethyl radical for

addition to the isocyanides, leading to formation of the corresponding phenanthridine products

(4) in in good yield.

2.5 Proposed Mechanism and Conclusion

A photoredox catalytic cycle was proposed as the mechanism of these reactions, based on

precendent (Figure 2-4). Firstly, the excited Ir catalyst reduces the sulfonyl chloride to form the

difluoromethyl radical, which then adds to the isonitrile to generate the imidoyl radical A, which

cyclizes on the arene to give cyclohexadienyl radical B. Then B is oxidized by the high-valent

catalyst to form cationic intermediate C, with regeneration of catalyst. Finally intermediate C is

depronated to form the product.

Figure 2-4. Proposed mechanism of difluoromethylation of biphenyl isonitriles. Originally

reported in Zhang, Z.; Tang, X. J.; Dolbier, W. R., Jr. Org. Lett. 2015, 17, 4401.

In conclusion, the first example of difluoromethyl and 1,1-difluoroakyl radical isonitrile

insertion reactions which afford phenanthridine derivatives under mild conditions is reported.

The difluoromethyl radical as well as α,α-difluorobenzyl or 1,1,-difluoroethyl radicals exhibited

29

excellent reactivity with isonitriles. The respective sulfonyl chlorides were excellent precursors

for the difluoromethyl and 1,1-difluoroethyl radicals, whereas bromodifluoromethylbenzene

proved effective as the precursor for the α,α-difluorobenzyl radical.

2.6 Experimental Section

All reactions were carried out under N2 atmosphere. All anhydrous solvents were

purchased from Aldrich and stored over 4A molecular sieves. Reagents were purchased at

commercial quality and were used without further purification. All NMR spectra were run using

CDCl3 as solvent, unless otherwise specified. 1H NMR spectra were recorded at 500 MHz or 300

MHz, and chemical shifts are reported in ppm relative to TMS. 19F NMR spectra were recorded

at 282 MHz, and chemical shifts are reported in ppm relative to CFCl3 as the external standard.

13C NMR spectra were recorded at 125 MHz or 75 MHz with proton decoupling, and chemical

shifts are reported in ppm relative to CDCl3 (-77.0 ppm) as the reference. The visible light was

generated from a fluorescent light bulb (daylight GE Energy Smart™, 26 W, 1600 lumens).

HCF2SO2Cl, CH3CF2SO2Cl and PhCF2Br were prepared according to literature procedures.

All substrates were prepared according to literature procedures, and their 1H NMR data

were consistent with those reported in the literature (Figure 2-5).28a

Figure 2-5. Synthesis of biphenyl isocyanides.

30

Difluoromethyl sulfonyl chloride was prepared according to literature procedures, and its

1H NMR and 19F NMR were consistent with those reported in the literature (Figure 2-6).17

Figure 2-6. Synthesis of difluoroalkyl radical source reagents.

1,1-difluoroethene (3.84g, 60 mmol, 2 equiv) (VDF) was introduced into 100 mL EtOH

in a sealed tube or autoclave that was cooled with a liquid nitrogen bath. To this solution was

added p-Cl-benzylthiol (4.75g, 30 mmol, 1 equiv) and NaOH (0.6g, 15 mmol, 0.5 equiv) the

sealed tube or autoclave, and the solution stirred at 80 oC overnight. The EtOH was then

removed, in vacuo, and the residue taken up in ether (50 mL). The ether solution was washed

with water, and dried over Na2SO4, filtered and concentrated in vacuo. This gave 2-S1 as a

colorless oil (5.12g, 77% yield) which was used in the next step without further purification.

1H NMR (CDCl3, 300MHz): δ 7.28 (br, 4H), 4.04(s, 2H), 1.91(t, J = 16.7Hz); 19F NMR

(CDCl3, 282MHz): δ -61.2 (q, J = 17Hz); 13C NMR (CDCl3, 75MHz): δ 135.4, 130.3, 129.3,

128.7, 31.8, 26.2 (t, J = 25Hz).

The 2-S2 obtained as described above was slurried in 10 mL of H2O in a 50 mL one-

necked flask, and cooled in a -10 ℃ brine-water bath. Chlorine gas was then slowly bubbled into

the mixture until the mixture became yellow. The two phase mixture was poured into a

31

separating funnel, the lower layer decanted, and then washed with brine, and dried over Na2SO4.

Purification by distillation over P2O5 gave 1.96 g (52%) of CH3CF2SO2Cl (2-S2).

1H NMR (CDCl3, 300MHz): δ 2.17(t, J = 17.9Hz); 19F NMR (CDCl3, 282MHz): δ -89.7

(q, J = 17.3 Hz); 13CNMR (CDCl3, 75MHz): δ 125.2 (t, J = 299 Hz), 18.0 (t, J = 21 Hz).

HRMS(ESI) [M-Cl]-, calcd for C2H3F2O2S-: 128.9827, found 128.9823.

The bromo-α, α-difluorotoluene was prepared according to literature procedures, and its

1H NMR and 19F NMR was consistent with the reported in the literature.31

To an oven-dried 17 × 60 mm (8 mL) borosilicate vial equipped with a magnetic stirrer,

were added 2-isocyanobiphenyl (35.8 mg, 0.2 mmol), fac-Ir(ppy)3 (1.2 mg, 0.002 mmol, 0.001

eq) and Na2CO3 (43 mg, 0.4 mmol, 2.0 equiv). To this mixture were added 2 mL Dioxane, 8 mg

deionized water and CF2HSO2Cl (60 mg, 0.4 mmol, 2 equiv) under a blanket of nitrogen. The

vial was sealed, and stirred under visible light at room temperature for 18 hr. After this time, the

dioxane was removed in vacuo, and the residue purified by column chromatography on silica gel

eluting with hexanes/ethyl acetate (12:1). This gave product 2a as a white solid (37.5 mg, 82%

yield).

6-(difluoromethyl)phenanthridine (2-2a)

1H NMR (500 MHz, cdcl3) δ 8.65 (d, J = 8.4 Hz, 1H), 8.57 (d, J = 6.1 Hz, 2H), 8.20 (d, J

= 7.8 Hz, 1H), 7.88 (t, J = 7.7 Hz, 1H), 7.81 – 7.69 (m, 3H), 7.03 (t, J = 54.4 Hz, 1H). 13C NMR

(126 MHz, cdcl3) δ 151.3 (t, J = 26.4 Hz), 142.4 (s), 133.7 (s), 131.1 (s), 130.5 (s), 129.0 (s),

128.6 (s), 127.7 (s), 126.4 (t, J = 4.2 Hz), 124.9 (s), 122.3 (s), 122.1 (s), 118.4 (t, J = 243.5 Hz).

19F NMR (282 MHz, cdcl3) δ -110.6 (dd, J = 54.4, 2.0 Hz, 2F). HRMS (ESI) calcd. For (M+H+)

230.0776, found: 230.0767.

32

6-(difluoromethyl)-2-methylphenanthridine (2-2b)

Prepared according to general method and isolated in 74% yield after chromatography as

a white solid (36.0 mg): 1H NMR (500 MHz, cdcl3) δ 8.59 (d, J = 8.4 Hz, 1H), 8.55 (d, J = 8.2

Hz, 1H), 8.30 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H),

7.57 (d, J = 8.1 Hz, 1H), 7.02 (t, J = 54.4 Hz, 1H), 2.62 (s, 3H). 13C NMR (126 MHz, cdcl3) δ

150.5 (t, J = 26.4 Hz), 140.8 (s), 138.88 (s), 133.6 (s), 131.0 (s), 130.9 (s), 130.4 (s), 127.7 (s),

126.4 (t, J = 4.2 Hz), 124.9 (s), 122.6 (s), 122.4 (s), 121.8 (s), 118.6 (t, J = 243.2 Hz), 22.2 (s).

19F NMR (282 MHz, cdcl3) δ -110.4 (dd, J = 54.5, 1.2 Hz, 2F). HRMS (ESI) calcd. For (M+H+)

244.0932, found: 244.0938.

6-(difluoromethyl)-2-(trifluoromethyl)phenanthridine (2-2c)


a white solid (31.4 mg): 1H NMR (500 MHz, cdcl3) δ 8.85 (s, 1H), 8.69 (d, J = 8.3 Hz, 1H), 8.61

(d, J = 8.5 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 6.6 Hz, 2H), 7.82 (t, J = 7.7 Hz, 1H),

7.02 (t, J = 54.4 Hz, 1H). 13C NMR (126 MHz, cdcl3) δ 153.4 (t, J = 26.6 Hz), 143.8 (s), 133.5

(s), 131.9 (s), 131.6 (s), 130.20 (dd, J = 65.3, 32.4 Hz), 128.67 (s), 126.71 (t, J = 4.4 Hz), 125.02

(dd, J = 5.9, 2.9 Hz), 124.6 (s), 123.1 – 122.8 (m), 122.6 (s), 122.4 (s), 119.9 (d, J = 4.4 Hz),

118.0 (t, J = 249.9 Hz). 19F NMR (282 MHz, cdcl3) δ -62.1 (s, 3F), -110.9 (d, J = 54.2 Hz, 2F).

HRMS (ESI) calcd. For (M+H+) 298.0650, found: 298.0655.

6-(difluoromethyl)-2-fluorophenanthridine (2-2d)



Hz, 1H), 8.16 (dd, J = 9.0, 5.7 Hz, 1H), 8.11 (dd, J = 10.0, 2.5 Hz, 1H), 7.86 (t, J = 7.7 Hz, 1H),

7.75 (t, J = 7.2 Hz, 1H), 7.48 (td, J = 8.9, 2.6 Hz, 1H), 6.99 (t, J = 54.4 Hz, 1H). 13C NMR (126

33

MHz, cdcl3) δ 163.4 (s), 161.4 (s), 150.8 (t, J = 27.4 Hz), 139.3 (s), 133.3 (d, J = 3.7 Hz), 133.1

(d, J = 9.3 Hz), 131.3 (s), 128.5 (s), 126.6 – 126.2 (m), 122.6 (s), 122.49 (s), 118.4 (t, J = 243.3

Hz), 118.2 (d, J = 24.5 Hz), 107.3 (d, J = 23.5 Hz). 19F NMR (282 MHz, cdcl3) δ -109.9 (dd, J =

14.9, 8.6 Hz, 1F), -110.6 (d, J = 54.4 Hz, 2F). HRMS (ESI) calcd. For (M+H+) 248.0682, found:

248.0683.

6-(difluoromethyl)-2-methoxyphenanthridine (2-2e)



Hz, 1H), 7.87 – 7.81 (m, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.38 (dd, J = 9.0, 2.2 Hz, 1H), 7.00 (t, J =

54.5 Hz, 1H), 4.02 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 159.8 (s), 148.9 (t, J = 26.4 Hz), 137.8

(s), 133.3 (s), 132.2 (s), 130.8 (s), 127.9 (s), 126.5 (d, J = 4.1 Hz), 126.4 (d, J = 2.8 Hz), 122.7

(s), 122.5 (s), 119.2 (s), 118.7 (t, J = 242.8 Hz), 103.0 (s), 55.8 (s). 19F NMR (282 MHz, cdcl3) δ

-110.2 (dd, J = 54.4, 1.6 Hz, 2F). HRMS (ESI) calcd. For (2M+H+) 519.1690, found: 519.1674.

6-(difluoromethyl)-3-methoxy-8-methylphenanthridine (2-2f)


a white solid (44.2 mg): 1H NMR (500 MHz, cdcl3) δ 8.43 (t, J = 9.1 Hz, 2H), 8.28 (s, 1H), 7.67

(d, J = 8.5 Hz, 1H), 7.56 (d, J = 2.6 Hz, 1H), 7.35 (dd, J = 9.0, 2.5 Hz, 1H), 7.00 (t, J = 54.4 Hz,

1H), 3.98 (s, 3H), 2.59 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 160.1 (s), 151.5 (t, J = 26.1 Hz),

143.9 (s), 136.8 (s), 133.2 (s), 132.1 (s), 125.6 (t, J = 3.9 Hz), 123.3 (s), 121.9 (d, J = 5.1 Hz),

120.0 (s), 119.3 (s), 118.4 (t, J = 243.4 Hz), 110.1 (s), 55.8 (s), 21.9 (s). 19F NMR (282 MHz,

cdcl3) δ -110.9 (dd, J = 54.5, 1.9 Hz, 2F). HRMS (ESI) calcd. For (M+H+) 274.1038, found:

274.1038.

34

methyl 6-(difluoromethyl)-8-methylphenanthridine-3-carboxylate (2-2g)



(s, 1H), 8.29 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 6.99 (t, J = 54.4 Hz, 1H), 4.01 (s, 3H),

2.62 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 166.7 (s), 152.1 (t, J = 26.5 Hz), 141.7 (s), 139.4 (s),

133.5 (s), 132.7 (s), 131.1 (s), 130.2 (s), 128.5 (s), 128.3 (s), 126.0 (t, J = 4.1 Hz), 123.3 (s),

122.9 (s), 122.4 (s), 118.4 (t, J = 243.6 Hz), 52.6 (s), 22.10 (s). 19F NMR (282 MHz, cdcl3) δ -

111.0 (dd, J = 54.4, 1.6 Hz, 2F). HRMS (ESI) calcd. For (M+H+) 302.0987, found: 302.0994.

6-(difluoromethyl)-2,8-dimethylphenanthridine (2-2h)


a white solid (47.3 mg): 1H NMR (500 MHz, cdcl3) δ 8.52 (d, J = 8.5 Hz, 1H), 8.31 (s, 2H), 8.05

(d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.00 (t, J = 54.5 Hz, 1H),

2.63 (s, 3H), 2.61 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 150.2 (d, J = 52.7 Hz), 140.6 (s), 138.8

(s), 137.8 (s), 132.9 (s), 131.5 (s), 130.5 (s), 130.3 (s), 125.7 (t, J = 4.0 Hz), 125.0 (s), 122.8 (s),

122.3 (s), 121.7 (s), 118.7 (t, J = 243.0 Hz), 22.2 (s), 22.0 (s). 19F NMR (282 MHz, cdcl3) δ -

110.6 (dd, J = 54.5, 1.7 Hz, 2F). HRMS (ESI) calcd. For (M+H+) 258.1089, found: 258.1081.

6-(difluoromethyl)-8-fluoro-2-methylphenanthridine (2-2i)


a white solid (39.1 mg): 1H NMR (500 MHz, cdcl3) δ 8.61 (dd, J = 9.1, 5.3 Hz, 1H), 8.27 (s, 1H),

8.17 (d, J = 9.8 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.66 – 7.54 (m, 2H), 6.97 (t, J = 54.3 Hz, 1H),

2.64 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 164.2 – 159.2 (m), 150.1 – 148.9 (m), 140.6 (s),

139.5 (s), 130.9 (s), 130.5 (s), 130.3 (s), 125.0 (d, J = 8.6 Hz), 124.6 (s), 124.0 – 123.4 (m),

121.6 (s), 120.5 (d, J = 24.0 Hz), 118.5 (t, J = 243.0 Hz), 111.2 (dt, J = 22.5, 4.4 Hz), 22.3 (s).

35

19F NMR (282 MHz, cdcl3) δ -110.9 (d, J = 54.4 Hz, 2F), -111.0 (ddd, J = 9.6, 8.1, 5.3 Hz, 1F).


6-(difluoromethyl)-8-methoxy-2-methylphenanthridine (2-2j)



(d, J = 8.3 Hz, 1H), 7.85 (s, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.45 (dd, J = 9.0, 2.4 Hz, 1H), 7.00 (t,

J = 54.5 Hz, 1H), 3.98 (s, 3H), 2.61 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 158.7 (s), 149.4 (t, J =

26.3 Hz), 138.8 (s), 130.2 (s), 129.8 (s), 127.9 (s), 124.9 (s), 123.9 (s), 123.8 (t, J = 1.9 Hz),

122.1 (s), 121.2 (s), 118.8 (t, J = 243.0 Hz), 114.2 (s), 105.8 (t, J = 4.5 Hz), 55.5 (s), 22.1 (s). 19F

NMR (282 MHz, cdcl3) δ -111.7 (d, J = 54.4 Hz, 2F). HRMS (ESI) calcd. For (M+H+) 274.1038,

found: 274.1061.

6-(difluoromethyl)-2-methyl-[1,3]dioxolo[4,5]phenanthridine

4-(difluoromethyl)-8-methyl-[1,3]dioxolo[4,5]phenanthridine (2-2k)


a white solid (38.5 mg): Major: 1H NMR (500 MHz, c6d6) δ 8.17 (d, J = 8.4 Hz, 1H), 8.06 (s,

1H), 7.71 (s, 1H), 7.54 (s, 1H), 7.18 (d, J = 9.1 Hz, 1H), 7.02 (t, J = 54.7 Hz, 1H), 5.21 (s, 2H),

2.23 (s, 3H). 13C NMR (126 MHz, c6d6) δ 151.4 (s), 149.5 (t, J = 26.3 Hz), 148.7 (s), 141.41 (s),

138.2 (s), 132.0 – 131.7 (m), 130.9 (s), 130.3 (s), 128.4 (s), 125.4 (s), 121.7 (s), 119.7 (t, J =

242.8 Hz), 103.8 (t, J = 4.7 Hz), 101.9 (s), 100.5 (s), 21.9 (s). 19F NMR (282 MHz, c6d6) δ -110.2

(d, J = 54.7 Hz, 2F). Minor: 1H NMR (500 MHz, cdcl3) δ 8.24 (s, 1H), 8.23 (d, J = 8.9 Hz, 1H),

8.11 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.38 (t, J = 54.3 Hz,

2H), 6.28 (s, 2H), 2.62 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 147.2 (t, J = 22.8 Hz), 146.5 (s),

142.7 (s), 140.2 (s), 139.3 (s), 131.0 (s), 130.3 (s), 128.6 (s), 124.7 (s), 121.7 (s), 116.6 (s), 113.8

36

(s), 112.8 (t, J = 241.6 Hz), 109.5 (s), 102.4 (s), 22.3 (s). 19F NMR (282 MHz, cdcl3) δ -118.4 (d,

J = 54.3 Hz, 2F). HRMS (ESI) calcd. For (M+H+) 288.0831, found: 288.0836.

6-(difluoromethyl)-2-methylbenzofuro[2,3]phenanthridine (2-2l)


a white solid (37.3 mg) : 1H NMR (500 MHz, C6D6) δ 9.35 (s, 1H), 8.60 (d, J = 8.6 Hz, 1H),

8.23 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 8.3 Hz,

1H), 7.29 (d, J = 8.2 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 55.0 Hz, 1H ), 7.11 (t, J = 7.4

Hz, 1H), 2.41 (s, 3H). 13C NMR (126 MHz, C6D6) δ 156.9 (s), 152.5 (s), 150.5 (t, J = 26.0 Hz),

142.1 (s), 139.2 (s), 131.1 (s), 130.8 (s), 127.0 (s), 125.7 (s), 123.7 (s), 123.7 (s), 123.5 (s), 122.6

(m), 121.62 (s), 121.58 (s), 121.54 (m), 121.3 (s), 120.2 (s), 119.73 (t, J = 252.2 Hz), 112.2 (s),

22.3 (s). 19F NMR (282 MHz, C6D6) δ -109.7 (dd, J = 54.7, 2.0 Hz, 2F). HRMS (ESI) calcd. For

(M+H+) 334.1038, found: 334.1049.

8-chloro-6-(difluoromethyl)-2-methylphenanthridine (2-2m)



(d, J = 8.3 Hz, 1H), 7.74 (dd, J = 8.9, 1.8 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 6.96 (t, J = 54.3 Hz,

1H), 2.62 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 149.4 (t, J = 26.8 Hz), 140.7 (s), 139.5 (s), 133.8

(s), 131.9 (s), 131.6 (s), 131.2 (s), 130.5 (s), 125.7 (t, J = 4.6 Hz), 124.3 (s), 124.1 (s), 123.3 (t, J

= 1.8 Hz), 121.7 (s), 118.4 (t, J = 243.2 Hz), 22.2 (s). 19F NMR (282 MHz, cdcl3) δ -110.4 (d, J =

54.3 Hz, 2F). HRMS (ESI) calcd. For (M+H+) 278.0543, found: 278.0537.

fac-Ir(ppy)3 catalyzed directly difluorophenylmethylation of isocyanides. General

procedure as exemplified for 6-(difluoro(phenyl)methyl)phenanthridine (2-3a).

37

To an oven-dried 17 × 60 mm (8 mL) borosilicate vial equipped with a magnetic stirrer,

were added 2-isocyanobiphenyl (18 mg, 0.1 mmol), fac-Ir(ppy)3 (0.12 mg, 0.002 mmol, 0.002

equiv) and Na2CO3 (21 mg, 0.2 mmol, 2.0 equiv). To this were added 2 mL dioxane and

PhCF2Br (27 mg, 0.13 mmol, 1.3 equiv), and the mixture covered with a blanket of nitrogen. The

vial was sealed and the reaction mixture stirred under visible light at 80 ℃ for 18 hr. After this

time, the dioxane was removed by concentration in vacuo, and the residue was purified by

column chromatography on silica gel eluting with hexanes/ethyl acetate (12:1) gave the title

product as a white solid (25.3 mg, 83% yield).

6-(difluoro(phenyl)methyl)phenanthridine (2-3a)

1H NMR (500 MHz, cdcl3) δ 8.69 (d, J = 8.4 Hz, 1H), 8.60 (d, J = 9.0 Hz, 1H), 8.37 (d, J

= 8.8 Hz, 1H), 8.26 – 8.21 (m, 1H), 7.83 (t, J = 7.7 Hz, 1H), 7.80 – 7.71 (m, 2H), 7.66 (d, J = 7.3

Hz, 2H), 7.62 (t, J = 7.8 Hz, 1H), 7.51 – 7.38 (m, 3H). 13C NMR (126 MHz, cdcl3) δ 153.2 (t, J =

28.2 Hz), 142.3 (s), 136.8 (t, J = 26.2 Hz), 134.1 (s), 131.3 (s), 130.8 (s), 130.3 (s), 129.1 (s),

128.6 (s), 128.5 (s), 127.6 (s), 127.5 (t, J = 5.0 Hz), 126.3 (t, J = 5.5 Hz), 124.8 (s), 123.1 (s),

122.5 (s), 122.1 (s), 120.4 (s). 19F NMR (282 MHz, cdcl3) δ -88.0 (s, 2F). HRMS (ESI) calcd.

For (M+H+) 306.1089, found: 306.1077.

6-(difluoro(phenyl)methyl)-2-fluorophenanthridine (2-3d)



Hz, 1H), 8.25 – 8.14 (m, 2H), 7.85 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 7.5 Hz, 3H), 7.46 (dd, J =

19.1, 10.2 Hz, 4H). 13C NMR (126 MHz, cdcl3) δ 163.4 (s), 161.4 (s), 152.6 (t, J = 30.2 Hz),

139.1 (s), 136.7 (t, J = 26.1 Hz), 133.6 (dd, J = 12.0, 6.7 Hz), 130.9 (s), 130.3 (s), 128.5 (s),

128.3 (s), 127.6 (t, J = 4.9 Hz), 126.3 (s), 123.1 (s), 122.7 (s), 120.4 (s), 118.2 (d, J = 2.9 Hz),

38

118.0 (d, J = 3.0 Hz), 107.1 (d, J = 23.6 Hz). 19F NMR (282 MHz, cdcl3) δ -87.9 (s, 2F), -110.4

(dd, J = 15.6, 8.0 Hz, 1F). HRMS (ESI) calcd. For (M+H+) 324.0995, found: 324.0987.

6-(difluoro(phenyl)methyl)-3-methoxy-8-methylphenanthridine (2-3f)


a white solid (26.9 mg): 1H NMR (500 MHz, cdcl3) δ 8.42 (t, J = 8.1 Hz, 2H), 8.08 (s, 1H), 7.66

(d, J = 6.6 Hz, 2H), 7.60 (t, J = 6.2 Hz, 2H), 7.44 (d, J = 7.4 Hz, 3H), 7.34 (dd, J = 9.0, 2.5 Hz,

1H), 3.97 (s, 3H), 2.48 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 160.1 (s), 153.2 (t, J = 27.6 Hz),

143.6 (s), 137.0 (t, J = 26.3 Hz), 136.3 (s), 132.7 (s), 132.3 (s), 130.2 (s), 128.5 (s), 126.7 (t, J =

4.8 Hz), 126.3 (t, J = 5.5 Hz), 123.0 (s), 122.3 (s), 121.9 (s), 120.3 (s), 119.9 (s), 119.0 (s), 110.5

(s), 55.8 (s), 22.0 (s). 19F NMR (282 MHz, cdcl3) δ -87.8 (s, 2F). HRMS (ESI) calcd. For

(M+H+) 350.1351, found: 350.1361.

methyl 6-(difluoro(phenyl)methyl)-8-methylphenanthridine-3-carboxylate (2-3g)



(d, J = 8.5 Hz, 1H), 8.26 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 6.9 Hz, 2H), 7.52 – 7.40

(m, 3H), 3.99 (s, 3H), 2.56 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 166.8 (s), 154.0 (t, J = 29.2

Hz), 141.4 (s), 139.0 (s), 136.5 (t, J = 25.8 Hz), 133.3 (d, J = 2.0 Hz), 133.0 (d, J = 4.1 Hz),

131.4 (s), 130.3 (s), 130.1 (s), 128.4 (s), 128.4 (s), 128.2 (s), 127.1 (s), 126.4 (s), 123.9 (s), 123.0

(s), 122.2 (s), 120.7 (t, J = 244.4 Hz), 52.5 (d, J = 4.6 Hz), 22.2 (s). 19F NMR (282 MHz, cdcl3) δ

-88.1 (s, 2F). HRMS (ESI) calcd. For (M+H+) 378.1300, found: 378.1287.

6-(difluoro(phenyl)methyl)-8-fluoro-2-methylphenanthridine (2-3i)


a white solid (23.9 mg): 1H NMR (500 MHz, cdcl3) δ 8.65 (dd, J = 9.1, 5.3 Hz, 1H), 8.31 (s, 1H),

39

8.09 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 11.1 Hz, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.56 (dd, J = 14.1,

5.4 Hz, 2H), 7.50 – 7.39 (m, 3H), 2.64 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 162.1 (s), 160.1 (s),

151.9 – 151.0 (m), 140.3 (s), 139.2 (s), 136.4 (t, J = 26.2 Hz), 131.1 (d, J = 2.4 Hz), 130.7 (d, J =

4.0 Hz), 130.5 (d, J = 1.8 Hz), 130.4 (s), 128.5 (s), 126.3 (t, J = 5.5 Hz), 125.0 (d, J = 8.7 Hz),

124.3 (s), 121.4 (s), 120.4 (s), 120.3 – 119.7 (m), 112.4 – 111.8 (m), 22.3 (s). 19F NMR (282

MHz, cdcl3) δ -88.4 (s, 2F), -111.2 (ddd, J = 10.4, 7.9, 5.5 Hz, 1F). HRMS (ESI) calcd. For

(M+H+) 338.1151, found: 338.1154.

6-(difluoro(phenyl)methyl)-8-methoxy-2-methylphenanthridine (2-3j)



(d, J = 8.3 Hz, 1H), 7.65 (d, J = 8.5 Hz, 3H), 7.53 (d, J = 8.4 Hz, 1H), 7.43 (q, J = 6.8 Hz, 4H),

3.81 (s, 3H), 2.63 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 158.4 (s), 151.2 (t, J = 27.9 Hz), 139.9

(s), 138.7 (s), 136.9 (t, J = 26.2 Hz), 130.9 (d, J = 3.2 Hz), 130.2 (s), 129.9 (d, J = 5.2 Hz), 128.5

(s), 128.3 (s), 126.2 (s), 124.9 (s), 124.4 (s), 124.0 (s), 121.6 (d, J = 4.4 Hz), 121.2 (d, J = 2.0

Hz), 120.3 (t, J = 243.9 Hz), 107.2 (d, J = 5.2 Hz), 55.5 (d, J = 7.4 Hz), 22.3 (d, J = 3.8 Hz). 19F

NMR (282 MHz, cdcl3) δ -89.2 (s, 2F). HRMS (ESI) calcd. For (M+H+) 350.1351, found:

350.1359.

8-chloro-6-(difluoro(phenyl)methyl)-2-methylphenanthridine (2-3m)



(s, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 7.1 Hz, 2H), 7.59 (d, J =

8.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 3H), 2.64 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 151.2 (t, J =

40

29.2 Hz), 140.4 (s), 139.1 (s), 136.3 (t, J = 26.2 Hz), 133.4 (s), 132.0 (s), 131.1 (d, J = 4.1 Hz),

131.0 (d, J = 3.1 Hz), 131.0 (d, J = 2.5 Hz), 130.2 (s), 128.4 (s), 126.5 (t, J = 5.6 Hz), 126.2 (t, J

= 6.3 Hz), 124.1 (s), 123.9 (d, J = 15.4 Hz), 121.4 (s), 120.4 (t, J = 243.9 Hz), 110.7 – 108.8 (m),

22.1 (s). 19F NMR (282 MHz, cdcl3) δ -87.9 (s, 2F). HRMS (ESI) calcd. For (M+H+) 354.0856,

found: 354.0847.

methyl 6-(difluoro(phenyl)methyl)-2-methylphenanthridine-8-carboxylate (2-3o)



(d, J = 13.7 Hz, 2H), 8.11 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 5.4 Hz, 2H), 7.64 (d, J = 7.7 Hz, 1H),

7.45 (d, J = 6.2 Hz, 3H), 3.98 (s, 3H), 2.66 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 166.3 (s), 152.6

(s), 141.2 (s), 139.1 (s), 136.5 (s), 136.5 (t, J = 26.1 Hz), 131.8 (s), 131.0 (s), 130.2 (s), 130.2 –

130.1 (m), 129.6 (s), 128.7 (s), 128.4 (s), 126.1 (s), 123.9 (s), 122.7 (s), 122.4 (s), 122.1 (s),

120.3 (t, J = 244.2 Hz), 110.4 – 109.4 (m), 52.5 (d, J = 4.5 Hz), 22.1 (s). 19F NMR (282 MHz,

cdcl3) δ -88.2 (s, 2F). HRMS (ESI) calcd. For (M+H+) 378.1200, found: 378.1299.

6-(1,1-difluoroethyl)phenanthridine (2-4a)


a white solid (20.1 mg): 1H NMR (500 MHz, cdcl3) δ 8.67 (t, J = 9.7 Hz, 1H), 8.57 (d, J = 7.9

Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.79 – 7.69 (m, 1H), 2.36 (t, J = 19.5

Hz, 1H). 13C NMR (126 MHz, cdcl3) δ 153.0 (t, J = 31.0 Hz), 142.1 (s), 134.0 (s), 130.9 (s),

130.8 (s), 128.9 (s), 128.4 (s), 127.7 (t, J = 6.3 Hz), 127.6 (s), 124.9 (s), 126.2 – 122.2 (m), 122.8

(s), 122.4 (s), 122.1 (s), 23.2 (t, J = 26.1 Hz). 19F NMR (282 MHz, cdcl3) δ -83.4 (q, J = 19.4 Hz,

2F). HRMS (ESI) calcd. For (M+H+) 244.0932, found: 244.0941.

6-(1,1-difluoroethyl)-2-fluorophenanthridine (2-4d)

41



Hz, 1H), 8.16 (d, J = 8.7 Hz, 2H), 7.88 (t, J = 7.4 Hz, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.48 (t, J =

7.4 Hz, 1H), 2.33 (t, J = 19.5 Hz, 3H). 13C NMR (126 MHz, cdcl3) δ 163.3 (s), 161.3 (s), 152.4

(td, J = 31.4, 2.7 Hz), 138.9 (s), 133.3 (d, J = 7.8 Hz), 130.9 (s), 128.3 (s), 127.8 (t, J = 6.4 Hz),

126.5 (d, J = 9.6 Hz), 124.2 (t, J = 238.4 Hz), 122.8 (s), 122.6 (s), 117.9 (d, J = 24.3 Hz), 107.2

(d, J = 23.4 Hz), 23.2 (td, J = 26.0, 3.8 Hz). 19F NMR (282 MHz, cdcl3) δ -83.5 (q, J = 19.2 Hz,

2F), -110.7 (dd, J = 15.5, 8.2 Hz, 1F). HRMS (ESI) calcd. For (M+H+) 262.0838, found:

262.0846.

6-(1,1-difluoroethyl)-3-methoxy-8-methylphenanthridine (2-4f)


a white solid (17.2 mg): 1H NMR (500 MHz, cdcl3) δ 8.47 – 8.35 (m, 3H), 7.65 (d, J = 8.2 Hz,

1H), 7.55 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 3.99 (s, 3H), 2.59 (s, 3H), 2.33 (t, J =

19.4 Hz, 3H). 13C NMR (126 MHz, cdcl3) δ 160.0 (s), 153.2 (t, J = 30.6 Hz), 143.4 (s), 136.4 (s),

132.8 (s), 132.6 (s), 132.2 (s), 126.8 (s), 124.1 (t, J = 238.9 Hz), 123.1 (dd, J = 12.6, 8.8 Hz),

122.0 (s), 121.8 (dd, J = 13.8, 8.0 Hz), 110.5 (s), 110.2 (d, J = 12.4 Hz), 57.9 – 53.4 (m), 23.5 (d,

J = 27.6 Hz), 22.0 (d, J = 28.4 Hz). 19F NMR (282 MHz, cdcl3) δ -83.7 (q, J = 19.2 Hz, 2F).


methyl 6-(1,1-difluoroethyl)-8-methylphenanthridine-3-carboxylate (2-4g)



(s, 1H), 8.29 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 4.02 (s, 3H), 2.63 (s, 3H), 2.34 (t, J =

19.5 Hz, 3H). 13C NMR (126 MHz, cdcl3) δ 166.8 (s), 153.7 (t, J = 31.4 Hz), 141.2 (s), 139.0 (s),

42

133.0 (s), 132.9 (s), 131.3 (s), 130.0 (s), 128.3 (s), 128.2 (s), 127.2 (t, J = 6.1 Hz), 124.2 (t, J =

238.8 Hz), 123.6 (s), 122.8 (s), 122.2 (s), 52.5 (s), 23.1 (t, J = 25.9 Hz), 22.2 (s). 19F NMR (282

MHz, cdcl3) δ -83.8 (qd, J = 19.5, 2.3 Hz, 2F). HRMS (ESI) calcd. For (M+H+) 316.1144, found:

316.1145.

43

CHAPTER 3

INTRAMOLECULAR AMINODIFLUOROMETHYLATION OF UNACTIVATED ALKENES

3.1 Introduction

Properties of organic molecules, such as metabolic stability, bioavailability, lipophilicity

and membrane permeability, play a crucial role in defining the efficacy of agrochemicals,

pharmaceuticals, and biomaterials.1 Among the commonly encountered fluoroalkyl groups,

difluoromethyl has drawn increasing attention,2 in part because CF2H can act as a more

lipophilic hydrogen bond donor than typical donors such as OH and NH.4 In addition, compared

with CF3, the methods available to introduce CF2H into organic compounds are relatively

limited.3 Recently much elegant difluoromethylation work had been reported, which mainly

focused on constructing difluoromethyl arenes and hetero arenes.6-8 Non-aromatic heterocycles

such as pyrrolidine are also of synthetic interest, such structures being present in a wide variety

of naturally-occurring and biologically active molecules.32 As a result the development of

efficient methods for the incorporation of CF2H into pyrrolidines is a subject worthy of attention.

Reprinted (adapted) with permission from (Zhang, Z.; Tang, X. J.; Thomoson, C. S.; Dolbier,

W. R., Jr. Org. Lett. 2015, 17, 3528.). Copyright (2015) American Chemical Society

44

Recently numerous papers reporting methods of difunctionalization of alkenes have

appeared.33 In addition, intramolecular difunctionalizations of olefins, including aminohalation,

carboamination, and oxyamination, have offered an efficient strategy for the introduction of

various functional groups while constructing such heterocycles.34 Aminofluorinations have also

been realized.35 Regarding fluoroalkylations, Buchwald’s group reported in 2012 the

oxytrifluoromethylation of unactivated alkenes using Togni’s reagent combined with a copper

catalyst.36 In 2014 Liu’s group, using a similar strategy, was successful in observing

aminotrifluoromethylation.37

Figure 3-1. Photo-redox catalyzed difluoromethylation reactions. Originally reported in Zhang,

Z.; Tang, X. J.; Thomoson, C. S.; Dolbier, W. R., Jr. Org. Lett. 2015, 17, 3528.

With the lack of a good electrophilic difluoromethylation reagent, it has remained a

challenge to carry out difluoromethylations in a similar manner. However, our research group

has recently focused efforts on the use of fluoroalkylsulfonyl chlorides for the purpose of

introduction of fluoroalkyl groups, via initial alkene addition. In particular, the CF2H radical

generated from single electron reduction of CF2HSO2Cl by a photo-redox catalyst has been

shown to have excellent reactivity towards electron deficient alkenes. The radical formed by

such additions could either undergo cyclization with an aromatic ring, or form a carbon-chlorine

bond through an ATRA process (Figure 3-1).17, 30

45

3.2 Probable Mechanism

In this part of work, we wish to establish a photo-redox catalyzed intramolecular

aminodifluoromethylation of unactivated alkenes under mild conditions. In designing this study

our hypothesis was that the CF2H radical should initially react with alkenes to form an alkyl

radical, which can then be oxidized by the catalyst to form a carbocation, which can then itself

be trapped intramolecularly by a not readily oxidizable nucleophile, such as the nitrogen of a

sulfonamide to produce a difluoromethylated pyrrolidine, as shown in the mechanistic scheme

below (Figure 3-2).

Figure 3-2. Probable mechanism of photo-redox catalyzed difluoromethylation reactions.

Originally reported in Zhang, Z.; Tang, X. J.; Thomoson, C. S.; Dolbier, W. R., Jr.

Org. Lett. 2015, 17, 3528.

3.3 Optimization of Reaction Conditions

To test our hypothesis we chose sulfonamide 3-1a as a model substrate that could be used

to optimize reaction conditions (Table 3-1). Initially, for the reaction with CF2HSO2Cl, IrIII(ppy)3

was tried as catalyst in CH3CN as solvent, using various bases under visible light (entries 1-4 ).

Unfortunately only the chloro, difluoromethylation (addition) product was detected, instead of

cyclization, which suggested that IrIV(ppy)3Cl could not oxidize the carbon radical intermediate

efficiently. In the absence of oxidation, the carbon radical abstracted the chlorine atom from

CF2HSO2Cl to propagate the simple addition reaction. Several reports indicate that copper

46

catalysts can be superior to Ir(ppy)3 for this oxidation step. Therefore it was decided to examine

Cu(dap)2Cl as the photoredox catalyst. Even though this catalyst has a lower oxidation potential

compared with Ir(ppy)3,38 it had earlier been shown to be efficient in the reductive step to

generate the CF2H radical from HCF2SO2Cl

Table 3-1. Optimization of reaction conditions of photo-redox catalyzed difluoromethylation

reactions.a Originally reported in Zhang, Z.; Tang, X. J.; Thomoson, C. S.; Dolbier,

W. R., Jr. Org. Lett. 2015, 17, 3528.

entry cat. base temp/ ℃ yield

1b 1 mol % Ir(ppy)3 Na2CO3 rt ND (26%)

2b 1 mol % Ir(ppy)3 K2HPO4 rt ND (60%)

3b 1 mol % Ir(ppy)3 Ag2CO3 rt ND (59%)

4b 1 mol % Ir(ppy)3 Cs2CO3 rt ND

5 0.75 mol % Cu(dap)2Cl Na2CO3 90 28% (33%)

6 0.75 mol % Cu(dap)2Cl K2CO3 90 9% (11%)

7 0.75 mol % Cu(dap)2Cl Cs2CO3 90 ND

8 0.75 mol % Cu(dap)2Cl K2HPO4 90 19% (20%)

9 0.75 mol % Cu(dap)2Cl K3PO4 90 33% (39%)

10 0.75 mol % Cu(dap)2Cl NaOAc 90 28% (31%)

11 0.75 mol % Cu(dap)2Cl KOAc 90 14% (16%)

12 0.75 mol % Cu(dap)2Cl Ag2CO3 100 50% (trace)

13 1 mol % Cu(dap)2Cl Ag2CO3 70 76% (trace)

14 0.3 mol % Cu(dap)2Cl Ag2CO3 70 51% (trace)

a Reactions were run with 0.1 mmol of 1a, 0.2 mmol of CF2HSO2Cl, 0.2 mmol of base, and

0.0001 mmol of catalyst in 1 mL of DCE. All yields were based on 1a using CF3CON(Me)2 as

the internal standard. b CH3CN as solvent.

47

Whereas, no cyclization had been observed when using the Ir catalyst, 28% of cyclization

product was observed along with 33% of addition product in the initial experiment using

Cu(dap)2Cl in DCE with NaCO3 as base at 90 oC (entry 5). To improve the yield and to suppress

chlorine addition product, Ag2CO3 was added to the reaction (entry 13), and as a result only trace

amounts of the chlorine addition product was observed, and the reaction gave the desired 3-2a as

the major product in 50% yield. Finally by lowering the temperature and increasing the amount

of catalyst to 1 mol %, the reaction displayed good chemo selectivity, giving a single product 3-

2a in 76% yield (entry 14).

3.4 Substrate Scope

Using this optimized protocol, the substrate scope was examined (Figure 3-3). The

protecting group on nitrogen proved to have a significant effect upon its efficacy in the reaction.

It was found that p-methoxybenzene-sulfonamide (3-1b) was a slightly better substrate, but that

the more electron deficient p-nitrobenzenesulfonamide (nosyl) substrate gave no observable

cyclization. Also, carboxamides, such as Boc (3-1d) and acetamide (3-1e) were ineffective

substrates.

48

Figure 3-3. Substrates scope of photo-redox catalyzed difluoromethylation reactions. Originally

reported in Zhang, Z.; Tang, X. J.; Thomoson, C. S.; Dolbier, W. R., Jr. Org. Lett.

2015, 17, 3528.

49

Then other substrates with gem-substituents (3-1f and 3-1g) were tested, with these reactions also

proceeding smoothly to provide product 3-2f and 3-2g in good yield. When a substituent was

introduced to the position α to nitrogen, the yield of the product (3-2h) was lowered slightly.

Mono-substituted or without gem-substituents substrates 3-1i – 3-1l were also compatible with

the reaction conditions, delivering products 3-2i – 3-2l in medium to good yield. Furthermore

both cis- and trans-cyclohexyl substrates 1m and 1n proceeded very well to provide products 3-

2m and 3-2n in excellent yield, as a mixture of diastereomers. However, a substrate with gem-

diphenyl substituents (3-1o) proved to be a reluctant reactant, with only 20% of product being

obtained.

To our surprise, when substrates with gem-diester substituents 3-1p and 3-1q were

examined, the lactone products 3-2p and 3-2q were isolated instead of the expected pyrrolidine.

This seemed to indicate that ester carbonyls are better nucleophiles in the reaction than a

sulfonamide nitrogen. Consistent with this supposition, ester 3-1r was an excellent substrate,

producing lactone (3-2r) in excellent yield.

3.5 Probe of Mechanism and Conclusion

Since the chlorine addition product had been a significant side product in the absence of

AgCO3, a stepwise process was considered to be a mechanistic possibility. When chlorine

addition product (3-3g) was synthesized (Figure 3-4), and then treated with 2.0 equivalent silver

carbonate under the same reaction condition, only 16% of cyclization product was formed, with

77% of the starting material remaining. However, when 1 mol % Cu(dap)2Cl was added to the

reaction mixture, conversion of 3-3g was complete. What all of this indicates is that, under the

optimized conditions, either pathway (one or two step) to eventual cyclized product can be

effective, and the two pathways are likely competing.

50

Figure 3-4. Probe of mechanism of photo-redox catalyzed difluoromethylation reactions.

Originally reported in Zhang, Z.; Tang, X. J.; Thomoson, C. S.; Dolbier, W. R., Jr.

Org. Lett. 2015, 17, 3528.

Sometimes using a clear two step procedure may be preferred over the “one pot” method.

For example, when the two step procedure was used for gem-diphenyl substrate 3-1o, product 3-

2o was obtained in a significantly higher overall yield than when the one pot procedure was used

(Figure 3-5).

Figure 3-5. Two step example of photo-redox catalyzed difluoromethylation reactions. Originally

reported in Zhang, Z.; Tang, X. J.; Thomoson, C. S.; Dolbier, W. R., Jr. Org. Lett.

2015, 17, 3528.

In conclusion, CF2HSO2Cl can be used as a source of difluoromethyl radical to carry out

efficient photo-redox catalyzed intramolecular amino- and oxy-difluoromethylation reactions of

51

unactivated alkenes. In order for the cyclization reactions to be efficient, a copper catalyst

(Cu(dap)2Cl) in combination with silver carbonate was crucial to suppressing the competing

chloro, difluoroalkylation process. Using this procedure, a variety of pyrrolidines could be

efficiently synthesized in moderate to excellent yield. Esters exhibited even greater nucleophilic

reactivity to prepare lactones in very good yield.

3.6 Experiment Section

All reactions were carried out under N2 atmosphere. All anhydrous solvents were

purchased from Aldrich and stored over 4A molecular sieves. Reagents were purchased at

commercial quality and were used without further purification. All NMR spectra were run using

CDCl3 as solvent, unless otherwise specified. 1H NMR spectra were recorded at 500 MHz or 300

MHz, and chemical shifts are reported in ppm relative to TMS. 19F NMR spectra were recorded

at 282 MHz, and chemical shifts are reported in ppm relative to CFCl3 as the external standard.

13C NMR spectra were recorded at 125 MHz or 75 MHz with proton decoupling, and chemical

shifts are reported in ppm relative to CDCl3 (-77.0 ppm) as the reference. The visible light was

generated from a fluorescent light bulb (daylight GE Energy Smart™, 26 W, 1600 lumens).

HCF2SO2Cl was prepared by literature procedures.17

All substrates were prepared according to literature procedures, and their 1H NMR data

were consistent with those reported in the literature (Figure 3-6).39

52

Figure 3-6. Synthesis substrates of photo-redox catalyzed difluoromethylation reactions.

Cu(dap)2Cl catalyzed intramolecular aminodifluoromethylation of unactivated alkenes.

General method: To an oven-dried 17 × 60 mm (8 mL) borosilicate vial equipped with a

magnetic stirrer were added 0.2 mmol (53.4 mg) N-(2,2-dimethylpent-4-enyl)-4-

methylbenzenesulfonamide, 0.002 mmol (1.8-2.0 mg, 1%) Cu(dap)2Cl and 0.4 mmol (0.108 g,

2.0 equiv) Ag2CO3. 2 mL DCE and 0.4 mmol (60 mg, 2 equiv) CF2HSO2Cl were added, with the

mixture then being covered with nitrogen. The vial was sealed and protected by parafilm. The

reaction mixture was stirred under visible light at 75 ℃ for 18 h and then the DCE was removed

by rotary evaporation. The residue was purified by column chromatography on silica gel using

hexanes/ethyl acetate (5:1) as the eluent. The product 3-2a was obtained as a colorless oil (47.6

mg, 75% yield).

2-(2,2-difluoroethyl)-4,4-dimethyl-1-tosylpyrrolidine (3-2a)

1H NMR (500 MHz, cdcl3) δ 7.71 (d, J = 7.4 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 5.98 (tt, J

= 55.9, 3.9 Hz, 1H), 3.70 (qd, J = 9.2, 2.5 Hz, 1H), 3.16 (d, J = 10.7 Hz, 1H), 3.07 (d, J = 10.7

Hz, 1H), 2.91 – 2.75 (m, 1H), 2.43 (s, 3H), 2.21 – 2.04 (m, 1H), 1.80 (dd, J = 12.8, 7.3 Hz, 1H),

1.58 (dd, J = 12.5, 8.5 Hz, 2H), 1.03 (s, 3H), 0.45 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 143.84

53

(s), 134.34 (s), 129.84 (s), 127.74 (s), 116.18 (t, J = 239.6 Hz), 61.37 (s), 54.86 (s), 47.09 (s),

41.03 (t, J = 18.6 Hz), 37.57 (s), 26.48 (s), 25.70 (s), 21.68 (s). 19F NMR (282 MHz, cdcl3) δ -

114.7 (AB, ddt, J = 285.9, 56.8, 18.9 Hz, 1F), -116.6 (AB, ddt, J = 285.9, 55.2, 16.9 Hz, 1F).

HRMS (ESI) calcd. For (M+NH4+) 335.1599, found: 335.1603.

2-(2,2-difluoroethyl)-1-(4-methoxyphenylsulfonyl)-4,4-dimethylpyrrolidine (3-2b)


a colorless oil (53.4 mg): 1H NMR (500 MHz, cdcl3) δ 7.76 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.8

Hz, 2H), 5.98 (t, J = 56.1 Hz, 1H), 3.85 (s, 3H), 3.67 (d, J = 8.6 Hz, 1H), 3.09 (dd, J = 51.2, 10.7

Hz, 2H), 2.81 (q, J = 18.0 Hz, 1H), 2.19 – 2.04 (m, 1H), 1.79 (dd, J = 12.7, 7.2 Hz, 1H), 1.58

(dd, J = 12.5, 8.9 Hz, 1H), 1.02 (s, 3H), 0.46 (s, 3H). 13C NMR (126 MHz, cdcl3) δ 163.11 (s),

129.66 (s), 128.86 (s), 116.17 (t, J = 226.2 Hz), 114.24 (s), 61.26 (s), 55.62 (s), 54.88 – 54.57

(m), 46.92 (s), 40.92 (t, J = 20.0 Hz), 37.40 (s), 26.36 (s), 25.62 (s). 19F NMR (282 MHz, cdcl3) δ

-114.7 (AB, ddt, J = 285.9, 56.3, 18.8 Hz, 1F), -116.6 (AB, ddt, J = 285.9, 56.0, 17.4 Hz, 1F).


3-(2,2-difluoroethyl)-2-tosyl-2-azaspiro[4.4]nonane (3-2f)



Hz, 2H), 6.00 (tt, J = 56.3, 4.3 Hz, 1H), 3.67 (qd, J = 7.7, 3.7 Hz, 1H), 3.26 (d, J = 10.5 Hz, 1H),

3.08 (d, J = 10.6 Hz, 1H), 2.86 – 2.71 (m, 1H), 2.44 (s, 3H), 2.22 – 2.06 (m, 1H), 1.87 (dd, J =

12.6, 7.4 Hz, 1H), 1.68 (dd, J = 12.8, 7.7 Hz, 1H), 1.64 – 1.33 (m, 7H), 1.01 – 0.89 (m, 1H), 0.83

– 0.73 (m, 1H). 13C NMR (126 MHz, cdcl3) δ 143.72 (s), 134.09 (s), 129.70 (s), 127.65 (s),

116.08 (t, J = 238.9 Hz), 59.68 (s), 55.00 (t, J = 6.0 Hz), 48.65 (s), 44.74 (s), 40.87 (t, J = 20.0

Hz), 36.38 (d, J = 2.1 Hz), 24.40 (s), 24.26 (s), 21.57 (s). 19F NMR (282 MHz, cdcl3) δ -114.7

54

(AB, ddt, J = 285.9, 56.4, 18.4 Hz, 1F). -116.7 (AB, dddd, J = 285.9, 56.0, 18.6, 16.9 Hz, 1F).


3-(2,2-difluoroethyl)-2-tosyl-2-azaspiro[4.5]decane (3-2g)



Hz, 2H), 5.99 (tt, J = 56.2, 4.3 Hz, 1H), 3.63 (ddd, J = 16.3, 8.8, 3.3 Hz, 1H), 3.26 (d, J = 11.0

Hz, 1H), 3.11 (d, J = 11.1 Hz, 1H), 2.85 – 2.72 (m, 1H), 2.42 (s, 3H), 2.20 – 2.01 (m, 1H), 1.85

(dd, J = 13.0, 7.2 Hz, 1H), 1.52 (dd, J = 12.9, 8.8 Hz, 1H), 1.47 – 1.01 (m, 9H), 0.71 (ddd, J =

13.4, 9.5, 3.9 Hz, 1H), 0.55 (dd, J = 11.3, 6.5 Hz, 1H). 13C NMR (126 MHz, cdcl3) δ 143.83 (s),

134.18 (s), 129.80 (s), 127.69 (s), 117.17 (t, J = 236.8 Hz), 58.54 (s), 54.12 (s), 45.26 (s), 41.44

(s), 41.13 (t, J = 20.9 Hz), 36.51 (s), 33.99 (s), 25.88 (s), 23.79 (s), 22.91 (s), 21.65 (s). 19F NMR

(282 MHz, cdcl3) δ -114.7 (AB, ddt, J = 285.4, 56.4, 18.8 Hz, 1F), -116.5 (AB, ddt, J = 286.8,

55.6, 18.0 Hz, 1F). HRMS (ESI) calcd. For (M+NH4+) 375.1912, found: 375.1918.

5-(2,2-difluoroethyl)-2,3,3-trimethyl-1-tosylpyrrolidine (dr = 1.6:1) (3-2h)

Prepared according to general method and isolated as a mixture of diastereomers in 80%

yield after chromatography as a colorless oil (55.8 mg): 1H NMR (500 MHz, cdcl3) δ 7.73 (d, J

= 7.6 Hz, 2H (both isomers)), 7.33 (d, J = 7.9 Hz, 2H (major isomer)), 7.30 (d, J = 5 Hz, 2H

(minor isomer)), 6.01 (t, J = 60 Hz, 1H (major)), 5.94 (t, J = 60 Hz, 1H (minor)), 3.96 (m, 1H

(minor)), 3.61 (m, 1H (major)), 3.49 (m, 1H (minor)), 3.32 (m, 1H (major)), 2.88 (m, 1H (both)),

2.43 (d, J = 4.7 Hz, 3H), 2.15 (m, 1H (minor)), 2.03 (m, 2H (major)), 1,71 (m, 2H, minor)), 1.58

(m, 1H (minor), 1.21 (d, J = 6.7 Hz, 3H (major)), 1.15 (d, J = 7 Hz, 3H (minor)), 1.03 (s, 3H

(minor)), 0.89 (s, 3H (major)), 0.75 (s, 3H (minor)), 0.25 (s, 3H (major)); 13C NMR (126 MHz,

cdcl3) δ 143.75 (s), 143.17 (s), 139.17 (s), 134.39 (s), 129.75 (s), 129.69 (s), 127.70 (s), 127.09

55

(s), 116.40 (t, J = 239.3 Hz), 116.20 (t, J = 238.8 Hz), 66.48 (s), 66.28 (s), 53.98 (dd, J = 7.3, 4.8

Hz), 53.38 (t, J = 6.3 Hz), 44.92 (s), 44.64 (s), 41.66 (t, J = 20.0 Hz), 40.74 (s), 40.61 (t, J = 19.9

Hz), 39.92 (s), 27.15 (s), 26.80 (s), 23.44 (s), 22.19 (s), 21.63 (s), 21.56 (s), 20.46 (s), 14.26 (s).

19F NMR (282 MHz, cdcl3) δ -114.5 (AB, ddt, J = 285.9, 54.1, 16.8 Hz, 1F). -116.3 (AB, dddd, J

= 285.9, 56.1, 19.2, 16.3 Hz, 1F). δ -114.6 (AB, ddt, J = 285.9, 56.4, 19.3 Hz, 1F). -116.5 (AB,

ddt, J = 285.9, 55.8, 16.8 Hz, 1F). HRMS (ESI) calcd. For (M+NH4+) 349.1756, found:

349.1770.

2-(2,2-difluoroethyl)-4-methyl-1-tosylpyrrolidine (dr = 1:1) (3-2i)



= 8.0 Hz, 2H (both isomers)), 7.33 (m, 2H (isomer A), 7.30 (m, 2H (isomer B), 6.03 (t, J = 56.1

Hz, 1H (both)), 3.80 (m, 1H (A)), 3.67 (m, 1H (B)), 3.57 (m, 1H (both)), 2.87 (m, 1H (A)), 2.62

(m, 1H (A)), 2.57 (m, 1H (B)), 2.44 (s, 3H (both)), 2.34 (m, 1H (B)), 2.08 (m, 1H (A)), 1.78 (m,

1H (B)), 1.44 (m, 1H (A)), 1.25 (m, 1H (both)), 0.90 (d, J = 6.5 Hz, 3H (A)), 0.83 (d, J = 6.5 Hz,

3H (B)). 13C NMR (126 MHz, cdcl3) δ 143.88 (s), 143.85 (s), 134.54 (s), 133.66 (s), 129.98 (s),

129.87 (s), 127.82 (s), 127.67 (s), 116.12 (t, J = 238.7 Hz), 116.09 (t, J = 238.6 Hz), 56.06 (s),

55.97 (t, J = 6.0 Hz), 55.86 (s), 55.17 – 54.97 (m), 41.46 (s), 41.26 (t, J = 20.3 Hz), 41.22 (t, J =

20.3 Hz), 39.69 (s), 32.82 (s), 31.65 (s), 21.68 (s), 17.03 (s), 16.51 (s). 19F NMR (282 MHz,

cdcl3) δ -115.0 (AB, ddt, J = 285.1, 56.4, 17.8 Hz, 1F). -116.9 (AB, dddd, J = 285.9, 55.5, 19.4,

16.3 Hz, 1F). δ -115.1 (AB, ddt, J = 285.9, 56.4, 16.9 Hz, 1F). -117.1 (AB, dddd, J = 285.9, 55.2,

21.6, 16.2 Hz, 1F). HRMS (ESI) calcd. For (M+NH4+) 304.1177, found: 304.1190.

2-(2,2-difluoroethyl)-4-isopropyl-1-tosylpyrrolidine (dr = 1.3:1) (3-2j)

56



= 8.1 Hz, 2H (both isomers)), 7.33 (m, 2H (both isomers)), 6.04 (tm, 1H (both)), 3.83 (m, 1H

(A), 3.66 (m, 1H (B)), 3.61 (m, 1H (both)), 2.94 (m, 1H (A)), 2.61 (m, 1H (B)), 2.43 (m, 3H

(both)), 1.75-2.33 (m, 3H (both), 1.00-1.31(m, 3H (both)), 0.83 (d, J = 8.4 Hz, 3H (A)), 0.80 (d,

J = 8.4 Hz, 3H (B)), 0.78 (d, J = 8.4 Hz, 3H (A)), 0.77 (d, J = 8.4 Hz, 3H (B)); 13C NMR (126

MHz, cdcl3) δ 143.75 (s), 134.40 (s), 133.55 (s), 129.83 (s), 129.76 (s), 127.64 (s), 127.50 (s),

119.61 – 112.49 (m), 55.89 (t, J = 6.1 Hz), 55.29 – 54.81 (m), 53.54 (s), 53.19 (s), 45.49 (s),

44.31 (s), 41.17 (t, J = 20.4 Hz), 40.97 (t, J = 20.4 Hz), 38.08 (s), 36.06 (s), 31.80 (s), 31.20 (s),

21.55 (s), 21.39 (s), 21.26 (s), 21.12 (s), 20.97 (s). 19F NMR (282 MHz, cdcl3) δ -114.9 (AB, ddt,

J = 284.8, 56.4, 17.7 Hz, 1F). -116.8 (AB, dddd, J = 285.6, 55.2, 18.6, 15.8 Hz, 1F). δ -115.2

(AB, ddt, J = 285.9, 56.4, 15.8 Hz, 1F). -117.2 (AB, dddd, J = 284.8, 56.4, 22.8, 15.8 Hz, 1F).


4-(4-chlorophenyl)-2-(2,2-difluoroethyl)-1-tosylpyrrolidine (dr = 1.3:1) (3-2k)


yield after chromatography as a colorless oil (52.8 mg): 1H NMR (500 MHz, cdcl3) δ 7.77 (d, J =

8.1 Hz, 2H (major isomer)), 7.72 (d, J = 8.0 Hz, 2H (minor)), 7.38 (d, J = 8.1 Hz, 2H (major)),

7.34 (d, J = 7.9 Hz, 2H (minor isomer)), 7.25 (d, J = 10.1 Hz, 3H (major)), 7.21 (d, J = 8.4 Hz,

2H (minor)), 7.00 (d, J = 8.2 Hz, 2H (major)), 6.92 (d, J = 8.3 Hz, 2H (minor)), 6.25 – 5.90 (m,

1H (both)), 3.99 (dd, J = 13.6, 7.7 Hz, 1H (minor)), 3.90 – 3.79 (m, 2H (major)), 3.72 (d, J =

14.0 Hz, 1H (minor)), 3.45 (s, 1H (minor)), 3.29 (t, J = 11.4 Hz, 1H (major)), 2.97 (t, J = 10.0

Hz, 1H (minor)), 2.79 – 2.61 (m, 1H (major)), 2.51 (m, 1H (major)), δ 2.47 (s, 3H (major)), 2.46

(s, 3H (minor)), 2.45 – 2.38 (m, 1H (both)), 2.28 – 2.10 (m, 1H (major)), 2.07 (dd, J = 12.7, 6.2

57

Hz, 1H (minor)), 1.82 (dd, J = 21.6, 12.1 Hz, 1H (major)). 1.74 (dd, J = 21.0, 12.4 Hz, 1H

(minor)). 13C NMR (126 MHz, cdcl3) δ 144.26 (s), 144.22 (s), 137.82 (s), 137.44 (s), 134.37 (s),

133.41 (s), 133.15 (s), 133.12 (s), 130.17 (s), 130.03 (s), 128.98 (s), 128.97 (s), 128.40 (s),

128.33 (s), 127.84 (s), 127.74 (s), 116.00 (t, J = 239.0 Hz), 67.24 (s), 42.50 (s), 41.28 (s), 41.18

(t, J = 20.4 Hz), 40.94 (t, J = 20.4 Hz), 40.43 (s), 38.25 (s), 21.75 (s). : 19F NMR (282 MHz,

cdcl3) δ -114.8 (AB, ddt, J = 287.1, 56.4, 16.6 Hz, 1F). -117.1 (AB, dddd, J = 285.9, 56.4, 18.6,

16.9 Hz, 1F). δ -115.1 (AB, ddt, J = 285.9, 56.4, 15.8 Hz, 1F). -117.3 (AB, dddd, J = 286.2, 56.4,

20.8, 15.8 Hz, 1F). HRMS (ESI) calcd. For (M+H+) 400.0944, found: 400.0929.

2-(2,2-difluoroethyl)-1-tosylpyrrolidine (3-2l)



Hz, 2H), 6.06 (tt, J = 56.2, 4.5 Hz, 1H), 3.83 – 3.74 (m, 1H), 3.47 – 3.38 (m, 1H), 3.24 – 3.15

(m, 1H), 2.43 (s, 3H), 2.37 (s, 1H), 2.12 – 1.94 (m, 1H), 1.85 – 1.72 (m, 1H), 1.71 – 1.63 (m,

2H), 1.50 (dt, J = 12.3, 6.2 Hz, 1H). 13C NMR (126 MHz, cdcl3) δ 143.88 (s), 134.13 (s), 129.95

(s), 127.75 (d, J = 4.4 Hz), 116.13 (t, J = 238.0 Hz), 55.15 (s), 49.18 (t, J = 4.7 Hz), 40.97 (t, J =

20.4 Hz), 32.00 (s), 24.14 (s), 21.68 (d, J = 4.1 Hz). 19F NMR (282 MHz, cdcl3) δ -115.1 (AB,

ddt, J = 285.1, 56.4, 15.8 Hz, 1F). -117.1 (AB, dddd, J = 285.9, 56.4, 21.7, 15.8 Hz, 1F). HRMS

(ESI) calcd. For (M+H+) 290.1021, found: 290.1032.

2-(2,2-difluoroethyl)-1-tosyloctahydro-1H-indole (dr = 1.8:1) (3-2m)


yield after chromatography as a colorless oil (67.1 mg): 1H NMR (500 MHz, cdcl3) 1H NMR

(500 MHz, cdcl3) δ 7.80 (d, J = 8.0 Hz, 2H (both)), 7.40 (d, J = 7.9 Hz, 2H (minor isomer)), 7.37

(d, J = 8.0 Hz, 2H (major isomer)), 6.12 (tt, J = 56.5 Hz, 4.5 Hz, 1H (minor)), 5.99 (tt, J = 56.5

58

Hz, 4.5 Hz, 1H (major)), 3.97 (t, J = 9.1 Hz, 1H (major)), 3.95 – 3.89 (m, 1H (major)), 3.74 –

3.64 (m, 2H (minor)), 2.91 – 2.67 (m, 1H (both)), 2.51 (s, 3H (minor)), 2.50 (s, 3H (major)),

2.47-2.45 (m, 1H (minor)), 2.31 – 2.22 (m, 1H (major)), 2.22-2.00 (m, 2H (both)), 2.00 – 1.83

(m, 1H (both)), 1.82 – 1.61 (m, 3H (both)), 1.60 – 1.44 (m, 2H (both)), 1.44 -0.86 (m, 3H

(both)). 13C NMR (126 MHz, cdcl3) δ 143.65 (s), 143.22 (s), 138.44 (s), 134.78 (s), 129.88 (s),

129.68 (s), 127.56 (s), 127.40 (s), 116.26 (s), 60.93 (s), 60.85 (s), 55.43 (s), 52.92 (s), 42.42 (s),

40.30 (s), 36.39 (s), 34.84 (s), 33.21 (s), 31.22 (s), 27.81 (s), 25.81 (s), 25.79 – 25.73 (m), 24.44

(s), 23.71 (s), 21.62 (s), 20.25 (s), 20.15 (s). 19F NMR (282 MHz, cdcl3) δ -113.73 – -118.31 (m).


2-(2,2-difluoroethyl)-1-tosyloctahydro-1H-indole (dr = 1.5:1) (3-2n)


yield after chromatography as a colorless oil (68.6 mg): 1H NMR (500 MHz, cdcl3) δ 7.81 (d, J =

8.3 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H (major isomer)), 7.45 (d, J = 8.2 Hz, 2H (major)), 7.39 (d, J

= 7.7 Hz, 2H (minor)), 6.14 (t, J = 56.5 Hz, 1H (both)), 4.30 – 4.21 (m, 1H (minor)), 3.89 (m, 1H

(major)), 2.8

© 2016 Zuxiao Zhangufdcimages.uflib.ufl.edu/UF/E0/05/05/40/00001/ZHANG_Z.pdf · photo-redox...

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