© 2016 zuxiao zhangufdcimages.uflib.ufl.edu/uf/e0/05/05/40/00001/zhang_z.pdf · photo-redox...
TRANSCRIPT
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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
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© 2016 Zuxiao Zhang
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To my Family
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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.
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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
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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
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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
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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
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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
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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
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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
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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.
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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).
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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
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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.
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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
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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.
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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,
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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.
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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.
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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
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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.
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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-
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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
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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.
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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.
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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.
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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
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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.
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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
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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.
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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)
Prepared according to general method and isolated in 53% yield after chromatography as
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)
Prepared according to general method and isolated in 79% yield after chromatography as
a white solid (39.0 mg): 1H NMR (500 MHz, cdcl3) δ 8.56 (d, J = 8.2 Hz, 1H), 8.47 (d, J = 8.3
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
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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)
Prepared according to general method and isolated in 61% yield after chromatography as
a white solid (31.6 mg): 1H NMR (500 MHz, cdcl3) δ 8.55 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 9.0
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)
Prepared according to general method and isolated in 81% yield after chromatography as
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.
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34
methyl 6-(difluoromethyl)-8-methylphenanthridine-3-carboxylate (2-2g)
Prepared according to general method and isolated in 98% yield after chromatography as
a white solid (59.0 mg): 1H NMR (500 MHz, cdcl3) δ 8.83 (s, 1H), 8.53 (d, J = 7.1 Hz, 2H), 8.33
(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)
Prepared according to general method and isolated in 92% yield after chromatography as
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)
Prepared according to general method and isolated in 75% yield after chromatography as
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).
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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).
HRMS (ESI) calcd. For (M+H+) 262.0838, found: 262.0837.
6-(difluoromethyl)-8-methoxy-2-methylphenanthridine (2-2j)
Prepared according to general method and isolated in 93% yield after chromatography as
a white solid (50.7 mg): 1H NMR (500 MHz, cdcl3) δ 8.48 (d, J = 9.2 Hz, 1H), 8.21 (s, 1H), 8.03
(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)
Prepared according to general method and isolated in 67% yield after chromatography as
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
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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)
Prepared according to general method and isolated in 56% yield after chromatography as
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)
Prepared according to general method and isolated in 66% yield after chromatography as
a white solid (36.5 mg): 1H NMR (500 MHz, cdcl3) δ 8.46 (d, J = 9.3 Hz, 2H), 8.20 (s, 1H), 8.02
(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).
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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)
Prepared according to general method and isolated in 79% yield after chromatography as
a white solid (25.5 mg): 1H NMR (500 MHz, cdcl3) δ 8.54 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 8.2
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),
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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)
Prepared according to general method and isolated in 77% yield after chromatography as
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)
Prepared according to general method and isolated in 81% yield after chromatography as
a white solid (30.5 mg): 1H NMR (500 MHz, cdcl3) δ 8.83 (s, 1H), 8.58 (d, J = 8.5 Hz, 2H), 8.31
(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)
Prepared according to general method and isolated in 71% yield after chromatography as
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),
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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)
Prepared according to general method and isolated in 84% yield after chromatography as
a white solid (29.3 mg): 1H NMR (500 MHz, cdcl3) δ 8.54 (d, J = 9.3 Hz, 1H), 8.27 (s, 1H), 8.10
(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)
Prepared according to general method and isolated in 79% yield after chromatography as
a white solid (27.9 mg): 1H NMR (500 MHz, cdcl3) δ 8.58 (d, J = 8.8 Hz, 1H), 8.38 (s, 1H), 8.30
(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 =
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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)
Prepared according to general method and isolated in 66% yield after chromatography as
a white solid (24.9 mg): 1H NMR (500 MHz, cdcl3) δ 9.14 (s, 1H), 8.69 (d, J = 8.7 Hz, 1H), 8.39
(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)
Prepared according to general method and isolated in 83% yield after chromatography as
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)
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41
Prepared according to general method and isolated in 63% yield after chromatography as
a white solid (16.4 mg): 1H NMR (500 MHz, cdcl3) δ 8.68 (d, J = 8.1 Hz, 1H), 8.53 (d, J = 8.3
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)
Prepared according to general method and isolated in 60% yield after chromatography as
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).
HRMS (ESI) calcd. For (M+H+) 288.1116, found: 288.1206.
methyl 6-(1,1-difluoroethyl)-8-methylphenanthridine-3-carboxylate (2-4g)
Prepared according to general method and isolated in 63% yield after chromatography as
a white solid (19.8 mg): 1H NMR (500 MHz, cdcl3) δ 8.82 (s, 1H), 8.55 (d, J = 8.5 Hz, 2H), 8.45
(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),
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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.
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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
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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
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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
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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.
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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.
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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.
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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.
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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
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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
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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
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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)
Prepared according to general method and isolated in 80% yield after chromatography as
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).
HRMS (ESI) calcd. For (M+H+) 334.1283, found: 334.1286.
3-(2,2-difluoroethyl)-2-tosyl-2-azaspiro[4.4]nonane (3-2f)
Prepared according to general method and isolated in 75% yield after chromatography as
a colorless oil (54.2 mg): 1H NMR (500 MHz, cdcl3) δ 7.72 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.1
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
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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).
HRMS (ESI) calcd. For (M+NH4+) 361.1756, found: 361.1774.
3-(2,2-difluoroethyl)-2-tosyl-2-azaspiro[4.5]decane (3-2g)
Prepared according to general method and isolated in 90% yield after chromatography as
a white solid (67.5 mg): 1H NMR (500 MHz, cdcl3) δ 7.71 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.1
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
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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)
Prepared according to general method and isolated as a mixture of diastereomers in 83%
yield after chromatography as a colorless oil (50.5 mg): 1H NMR (500 MHz, cdcl3) δ 7.71 (d, J
= 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)
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56
Prepared according to general method and isolated as a mixture of diastereomers in 74%
yield after chromatography as a colorless oil (49.1 mg): 1H NMR (500 MHz, cdcl3) δ 7.70 (d, J
= 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).
HRMS (ESI) calcd. For (M+H+) 332.1490, found: 332.1504.
4-(4-chlorophenyl)-2-(2,2-difluoroethyl)-1-tosylpyrrolidine (dr = 1.3:1) (3-2k)
Prepared according to general method and isolated as a mixture of diastereomers in 66%
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
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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)
Prepared according to general method and isolated in 48% yield after chromatography as
a colorless oil (27.8 mg): 1H NMR (500 MHz, cdcl3) δ 7.72 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.0
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)
Prepared according to general method and isolated as a mixture of diastereomers in 93%
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
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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).
HRMS (ESI) calcd. For (M+NH4+) 361.1756, found: 361.1773.
2-(2,2-difluoroethyl)-1-tosyloctahydro-1H-indole (dr = 1.5:1) (3-2n)
Prepared according to general method and isolated as a mixture of diastereomers in 95%
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