1 difluoromethylation and difluoroalkylation of (hetero ... · 1 difluoromethylation and...

3

Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, First Edition. Edited by Dominique Cahard and Jun-An Ma.© 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

1

1.1 Introduction

The difluoromethylation of arenes has been given increasing attention due to the unique properties of the difluoromethyl group (CF2H), which is considered as a bioisostere of hydroxyl and thiol groups and also as a lipophilic hydrogen bond donor [1]. Thus, the incorporation of CF2H into an aromatic ring has become an important strategy in medicinal chemistry [2]. Conventional method for the syn-thesis of difluoromethylated arenes relies on the deoxyfluorination of aromatic aldehydes with diethylaminosulfur trifluoride (DAST) [3]. However, this method has a modest functional group tolerance and high cost. Transition‐metal‐cata-lyzed cross‐coupling difluoromethylation is one of the most efficient strategies to access this class of compounds. Over the past few years, impressive achieve-ments have been made in this field [4]. In this chapter, we describe three modes of difluoromethylation of aromatics: nucleophilic difluoromethylation, catalytic metal difluorocarbene‐involved coupling reaction (MeDIC), and radical difluoromethylation.

1.2 Difluoromethylation of (Hetero)aromatics

1.2.1 Transition‐Metal‐Mediated/Catalyzed Nucleophilic Difluoromethylation of (Hetero)aromatics

Copper is the first transition metal that has been used for mediating nucleophilic difluoromethylation of (hetero)aromatics. In 1990, Burton et al. synthesized the first difluoromethyl copper complex by metathesis reaction between [Cd(CF2H)2] and CuBr [5]. However, the instability of this complex restricts its further syn-thetic applications [6]. In 2012, Hartwig and coworker found that using TMSCF2H (5.0 equiv) as source of fluorine to generate difluoromethyl copper in situ could

Difluoromethylation and Difluoroalkylation of (Hetero)Arenes: Access to Ar(Het)–CF2H and Ar(Het)–CF2RYu‐Lan Xiao and Xingang Zhang

Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, Center for Excellence in Molecular Synthesis, CAS Key Laboratory of Organofluorine Chemistry, 345 Lingling Road, Shanghai 200032, China

c01.indd 3 14-03-2020 20:52:44

1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes4

lead to the difluoromethylation of aryl iodides efficiently (Scheme 1.1a) [7], representing the first example of copper‐mediated difluoromethylation of aro-matics. In this reaction, however, only electron‐rich and ‐neutral aryl iodides were suitable substrates. A difluoromethylcuprate species [Cu(CF2H)2]− was proposed in the reaction. To overcome this limitation, Qing and coworkers reported a 1,10‐phen‐promoted copper‐mediated difluoromethylation of elec-tron‐deficient (hetero)aryl iodides with TMSCF2H (Scheme 1.1b) [8]. The role of the ligand is to stabilize the difluoromethyl copper species. In 2012, Prakash et al. also reported a copper‐mediated difluoromethylation of aryl iodides, employing n‐Bu3SnCF2H, instead of TMSCF2H, as the difluoromethylation reagent (Scheme 1.2) [9]. This method allowed difluoromethylation of electron‐deficient (hetero)aryl iodides, but electron‐rich partners produced low yields. A trans-metalation between n‐Bu3SnCF2H and CuI to generate CuCF2H species was pro-posed. Using similar strategy, Goossen and coworkers reported a Sandmeyer‐type copper‐mediated difluoromethylation of (hetero)arenediazonium salts with TMSCF2H (Scheme 1.3) [10].

In addition to the difluoromethylation of prefunctionalized aromatics, the copper‐mediated direct C─H bond difluoromethylation of heteroaromatics has also been reported, representing a more straightforward and atom/step‐ economic approach. Inspired by the oxidative trifluoromethylation reaction of

R

IR

CF2H

CuI (1.0 equiv) CsF (3.0 equiv)TMSCF2H (5.0 equiv)

30–91%

NMP, 120°C, 24 h

R = EDG

CF2H

Ph

CF2HMeO CF2HMe

Me

CF2H

O

Br88% 81% 48% 77%

R

IR

CF2H

CuCl (1.2 equiv)1,10-phen (1.2 equiv)TMSCF2H (2.4 equiv)

70–93%

t-BuOK (2.4 equiv)DMF, rt

R = EWG

CF2H

EtO2C

CF2H CF2H

N

CF2H

Cl

80% 78% 82% 74%

O2N NC

(a)

(b)

Scheme 1.1 Copper‐mediated difluoromethylation of aryl iodides with TMSCF2H.

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1.2 Difluoromethylation of (Hetero)aromatics 5

heteroaromatics [11], Qing and coworkers reported a copper‐mediated direct oxidative difluoromethylation of C─H bonds on electron‐deficient heteroarenes with TMSCF2H (Scheme 1.4) [12]. The use of 9,10‐phenanthrenequinone (PQ) as an oxidant was essential for the reaction. Regioselective difluoromethylation was favorable to the more acidic C─H bond, which was readily deprotonated by t‐BuOK base, to provide the desired products.

These copper‐mediated difluoromethylation reactions paved a new way to access difluoromethylated arenes. In these reactions, however, more than stoi-chiometric amount of copper salts were required. A more efficient and attractive alternative is the catalytic difluoromethylation. In 2010, Buchwald and cowork-ers reported the first example of palladium‐catalyzed trifluoromethylation of aryl chlorides with TESCF3 [13]. Direct adaptation of this strategy to difluoro-methylation resulted in inefficient transmetalation between the palladium

XR

I

XR

CF2H

CuI (1.3 equiv)KF (3.0 equiv)

nBu3SnCF2H (5.0 equiv)

32–82%X = CH, N

DMA, 100–120°C, 24 h

CF2H

CHO

CF2H

MeO2C

CF2H N CF2H

Br

53% 82% 78% 75%

Sn CF2HH3C

H3C CH3

F– –3.6

F– +3.6Sn CF2HCH3

FH3C

H3CCu I

DMF

+31.8

Sn

CH3FCH3

CF2H

H3C

CuI

FMD

–48.6

Cu CF2HDMF

+

Sn FH3C

H3C CH3

+

I–

DFT calculations

Scheme 1.2 Copper‐mediated difluoromethylation of (hetero)aryl iodides with n‐Bu3SnCF2H.

CF2HR

34–86%

TMSCF2H (2.5 equiv)

CuSCN (1.0 equiv)CsF (3.0 equiv)

DMF40°C, 1 h

Cu–CF2H

DMF, rt, 12 h

N2+BF4

–

R

t-BuONOHBF4

NH2R

CF2H CF2H

NH

CF2H

Ph N

CF2H

81% 67% 76% 54%

NC

O

Scheme 1.3 Copper‐mediated difluoromethylation of (hetero)arenediazoniums.

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catalyst and TMSCF2H. In 2014, Shen and coworkers developed a cooperative dual palladium/silver catalytic system with both bidentate phosphine 1,1′‐bis(diphenylphosphino)ferrocene (dppf) and N‐heterocyclic carbene (NHC) SIPr as the ligands (Scheme 1.5a) [14]. This system enabled difluoromethylation of electron‐rich and electron‐deficient aryl bromides and iodides with TMSCF2H

t-BuOK (4.5 equiv)NMP, rt, 6 h

CuCN (3.0 equiv)PQ (1.8 equiv)

TMSCF2H (3 equiv)X

Z

YHR

X

Z

YCF2HR

O O

PQ46–87%

O

NCF2H

MeO87%

O

NCF2H

NC77%

N

N

Me

CF2H

NC

NC

56%

O

NNCF2H

I48%

Scheme 1.4 Copper‐mediated oxidative difluoromethylation of heteroarenes.

Pd(dba)2 (5 mol%), DPPF (10 mol%)[(SIPr)AgCI] (20 mol%)

TMSCF2H (2 equiv)R

Br/I

R

CF2H

t-BuONa (2 equivdioxane or toluene, 80 °C, 4–6 h

)

58%~96%

N N

i-Pr

i-Pr

i-Pr

i-Pr

SIPr

XHet

Pd(dba)2 (5 mol%)DPEPhos (10 mol%)

Toluene, 80 °C, 6 h

N N

(SIPr)Ag(CF2H)

i-Pr

i-Pr i-Pr

i-Pr

Ag

CF2H

R

CF2HHetR

54%~95%X = Cl, Br, I

+

(dppf)Pd(0)

Pd(dppf)CF2H

Ar(SIPr)Ag CF2H

(SIPr)Ag XPd(dppf)X

Ar

Ar-X

Ar-CHF2H TMSCF2Ht-BuONa

CF2H

Ph86%

CF2H

t-BuO2C76%

CF2H

BnO84%

N

CF2H

58%

BnO

Proposed mechanism

(a)

(b)

Scheme 1.5 Palladium‐catalyzed difluoromethylation of aryl halides with (SIPr)Ag(CF2H).

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efficiently. An in situ generated difluoromethyl silver complex (SIPr)Ag(CF2H) was found to promote the transmetalation step and facilitate the catalytic cycle. Stoichiometric reaction showed that the reductive elimination of aryldifluoro-methyl palladium complex [Ar–Pd(Ln)–CF2H] is faster than that of aryltrifluoro-methyl palladium complex [Ar–Pd(Ln)–CF3], suggesting the different electronic effect between CF3 and CF2H. The method can also be extended to heteroaryl halides [15] and triflates (Scheme 1.5b) [15b], including pharmaceutical and agrochemical derivatives. Very recently, Sanford and coworkers demonstrated that the use of TMSCF2H can also lead to difluoromethylated arenes under pal-ladium catalysis (Scheme 1.6) [16]. The use of electron‐rich monophosphine ligands [BrettPhos and P(t‐Bu)3] allowed difluoromethylation of a series of elec-tron‐rich (hetero)aryl chlorides and bromides.

Using more reactive transmetalating zinc reagent (TMEDA)2Zn(CF2H)2 as fluorine source, Mikami and coworkers developed a palladium‐catalyzed difluo-romethylation of (hetero)aryl iodides and bromides (Scheme 1.7) [17]. Similar to Shen’s work, dppf was employed as the ligand in the reaction. This method exhibited broad substrate scope, where both electron‐rich and electron‐deficient aryl iodides were suitable substrates.

Besides the aryl halides, benzoic acid chlorides were also a competent coupling partner. With (DMPU)2Zn(CF2H)2 as the difluoromethylating reagent, Ritter and coworkers developed a palladium‐catalyzed decarbonylative difluoromethyla-tion of benzoic acid chlorides (Scheme 1.8) [18]. This reaction proceeded under

R

Cl/Br

R

CF2H

Yields up to 87%

Condition A: Pd(dba)2 (3 mol%), BrettPhos (4.5 mol%),CsF (2 equiv), dioxane, 100 °C, 16–36 h

+ TMSCF2HConditions

Condition B:Pd(Pt-Bu3)2 (5 mol%), CsF (2 equiv),dioxane, 100–120 °C, 16–36 h

CF2H

Ph

87%

N

60% 60%

O

O

S

N38%

OMe

MeO PCy2i-Pr i-Pr

i-Pr

BrettPhos

CF2H CF2H CF2H

Scheme 1.6 Palladium‐catalyzed difluoromethylation of aryl halides with TMSCF2H.

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mild reaction conditions with good functional group tolerance. The use of monophosphine ligand RuPhos is critical in promoting the decarbonylation and subsequent difluoromethylation.

RCl

OPd(dba)2 (5 mol%), RuPhos (6 mol%)

(DMPU)2Zn(CF2H)2 (1 equiv)

Dioxane, 23 °C, 1 hR

63–93%

CF2H

CF2H

Ph

91%

CF2H

72%

Ph

CF2H

82%

NO

N

F

CF2H

93%

MeMe

Me Me

Me

(RuPhos)Pd(0)

(RuPhos)Pd(II)Cl

ArO

Ar Cl

O

(DMPU) Zn(CF H)X2 2X = CF2H or Cl

(DMPU)2ZnClX(RuPhos)Pd(II)

CF2H

ArO

(RuPhos)Pd(II)Ar

CF2H

ArCF2H

CO

Proposed mechanism

Scheme 1.8 Palladium‐catalyzed decarbonylative difluoromethylation of benzoic acid chlorides with (DMPU)2Zn(CF2H)2.

R

Br/IR

CF2HPd(dba)2 (5 mol%), dppf (10 mol%)

(TMEDA)Zn(CF2H)2 (2 equiv)

1,4-Dioxane, 120 °C, 6 h

39–99%

CF2H

O2N80%

CF2H

MeO86%

CF2H

Cl82%

N

NN

NO

AcO

AcO OAc

Cl

CF2H

61%

Fe

PPh2

PPh2

DPPF

Scheme 1.7 Palladium‐catalyzed difluoromethylation of aryl bromides/chlorides with (TMEDA)Zn(CF2H)2.

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Copper can also be used as the catalyst for the difluoromethylation. In 2016, Mikami and coworkers reported a ligand‐free copper‐catalyzed difluoromethyl-ation of (hetero)aryl iodides (Scheme 1.9), in which a cuprate [Cu(CF2H)2]− spe-cies may be involved in the reaction [19], in agreement with Hartwig’s hypothesis [7].

For all these copper‐mediated or catalyzed difluoromethylation reactions, a difluoromethyl copper species was proposed as the key intermediate. However, the nature and properties of the unstable copper species have not been system-atically investigated. In 2017, Sanford and coworkers reported the synthesis, reactivity, and catalytic applications of an isolable (IPr)Cu(CF2H) complex (Scheme 1.10) [20]. Unlike the previous supposition [5, 6], this complex is stable in solution at room temperature for at least 24 hours, suggesting that the bimo-lecular decomposition pathway is relatively slow. A variety of aryl electrophiles could react with this (IPr)Cu(CF2H) complex to furnish the corresponding dif-luoromethylated arenes smoothly. Based on this fundamental research, a cop-per‐catalyzed difluoromethylation of aryl iodides with TMSCF2H has been developed by employing IPrCuCl as the catalyst.

Although palladium‐ and copper‐catalyzed nucleophilic difluoromethylation reactions have been developed, the development of fluoroalkylation catalyzed by earth‐abundant transition metals remains appealing. In 2016, Vicic and cow-orker reported a nickel‐catalyzed difluoromethylation of (hetero)aryl iodides,

CuI (2–10 mol%)(DMPU)2Zn(CF2H)2 (2 equiv)

R

I

R

CF2H

DMPU, 60 °C, 24 h5–94%

CF2H

CO2Et

CF2H CF2H

CNN

N

Br

92% 60% 91%

CF2H

MeO5%

CuIL2Zn(CF2H)2 + L2Zn(CF2H)I

L2Zn(CF2H)I + L2ZnI2

CuCF2H [Cu(CF2H)2]–

[O][Cu(CF2H)4]–

Detected by 19F NMR Inactive

L = DMPU

CuCF2HI

Ar

Ar–I

Ar–CF2H

HF2C CF2H HFC CFH+

Proposed mechanism

Scheme 1.9 Copper‐catalyzed difluoromethylation of aryl iodides with (DMPU)2Zn(CF2H)2.

c01.indd 9 14-03-2020 20:52:46


bromides, and triflates with (DMPU)2Zn(CF2H)2 (Scheme 1.11) [21]. This is the first example to use (DMPU)2Zn(CF2H)2 as the difluoromethylation reagent. The reaction underwent difluoromethylation smoothly with electron‐deficient substrates, but electron‐rich aryl iodides or aryl bromides were not applicable to the reaction.

1.2.2 Catalytic Metal‐Difluorocarbene‐Involved Coupling (MeDIC) Reaction

Difluorocarbene is an electrophilic ground‐state singlet carbene. As an important intermediate, difluorocarbene has privileged applications in various areas [22]. However, the intrinsic electrophilic nature of difluorocarbene limits its reaction types [23]. Usually, difluorocarbene is used to react with heteroatom nucleophiles (O, S, N, P) to produce heteroatom‐substituted difluoromethylated compounds [24] or to react with alkenes/alkynes to prepare gem‐difluorocyclopropanes

(DMPU)2ZnCF2H

CF2H

(dppf)Ni(COD) (15 mol%)

DMSO, 25 °C, 24 h R

XR

CF2H

Yields up to 91%X = Cl, Br, I

CF2H

Ph

X = Br 78%X = I 74%

CF2H

NC

X = Br 79%X = I 91%

S

CF2H

X = Br 65%X = I 51%

N

CF2H

X = Br 53%X = I 60%

Scheme 1.11 Nickel‐catalyzed difluoromethylation of aryl halides with (DMPU)2Zn(CF2H)2.

IPrCuCI (10 mol%)TMSCF2H (2 equiv)

CsF (3 equiv)R

I

R

CF2H N N

Cu

CI

i-Pr

i-Pr

i-Pr

i-Pr

IPrCuCI

Dioxane/toluene 3 : 1 120 °C, 20 h Yields up to 92%

CF2H

NC64%

CF2H

PhO66%

CF2H

71%

Br CF2H

N78%

N N

Cu

CI

RR t-BuONa

–NaCl

N N

Cu

Ot-Bu

RR TMSCF2H

–TMSOt-Bu

N N

Cu

CF2H

RR

From (IPr)CuCl 51%From (SIPr)CuCl 82%

Scheme 1.10 (NHC)CuCl‐catalyzed difluoromethylation of aryl iodides with TMSCF2H.

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/gem‐difluorocyclopropenes [25]. The use of transition metal to tune the reactivity of difluorocarbene would provide a promising strategy to develop new types of difluorocarbene transfer reaction. However, because of the inherently low reac-tivity of known isolated metal‐difluorocarbene complexes compared to their non-fluorinated counterparts [26], it is of great challenge to apply metal‐difluorocarbene to the catalytic cross‐coupling. The catalytic MeDIC reaction had not been reported until Zhang and coworkers reported a palladium‐catalyzed difluoro-methylation of arylboronic acids with BrCF2CO2Et in 2015 (Scheme 1.12) [27]. This reaction represents the first example of a catalytic MeDIC reaction by exhib-iting excellent functional group tolerance (even toward bromide and hydroxyl groups) and being compatible with both electron‐rich and electron‐deficient arylboronic acids. Compared to the catalytic nucleophilic difluoromethylation of aromatics, the advantages of this reaction are broad substrate scope and the use of inexpensive and readily available fluorine source without requiring a multistep synthetic procedure. The combination of bidentate phosphine ligand Xantphos and additive hydroquinone is essential for reaction efficiency. Kinetic studies showed that a potassium salt BrCF2CO2K was generated in situ at the initial stage, which served as a difluorocarbene precursor in the reaction. Mechanistic studies revealed that an aryl group migration to the palladium difluorocarbene carbon pathway was not involved in the reaction.

Inspired by this palladium‐catalyzed MeDIC reaction, Zhang and cowork-ers employed ClCF2H as the fluorine source for the difluoromethylation (Scheme 1.13) [28]. ClCF2H is an inexpensive and abundant industrial chemical used for the production of fluorinated polymers [22], representing an ideal and the most straightforward difluoromethylating reagent. The reaction allowed dif-luoromethylation of a wide range of (hetero)arylboronic acids and esters and was used for difluoromethylation of a series of biologically active molecules, includ-ing pharmaceuticals, agrochemicals, and natural products. Most remarkably, the late‐stage difluoromethylation of biologically active molecules through a sequen-tial C–H/C–CN borylation [29] and difluoromethylation process proceeded smoothly, thus providing a straightforward route for applications in drug discov-ery and development. Deuterium‐labeling experiments demonstrated that arylb-oronic acids, hydroquinone, ClCF2H, and even water were the proton donors.

Xiao and coworkers reported a difluoromethylation of arylboronic acids with Ph3P+CF2COO− (PDFA), but electron‐deficient arylboronic acids were not suit-able substrates (Scheme 1.14) [30]. A palladium(0) difluorocarbene trimer [Pd(CF2)(PPh3)]3 was isolated. Stoichiometric reaction of this [{Pd(CF2)(PPh3)}3] complex with arylboronic acid demonstrated that this palladium difluorocar-bene cluster was not an active species in the reaction.

1.2.3 Transition‐Metal‐Catalyzed Radical Difluoromethylation of (Hetero)aryl Metals/Halides and Beyond

Owning to the electron‐withdrawing effect of fluorine atom, perfluoroalkyl halides can be readily initiated by a low‐valent transition metal to generate a radi-cal via a single electron transfer (SET) pathway [31]. A nickel‐catalyzed perfluoroalkylation of aromatics with perfluoroalkyl iodides was reported in

c01.indd 11 14-03-2020 20:52:46

PdC

I 2(P

Ph 3

) 2 (

5 m

ol%

)X

antp

hos

(7.5

mol

%)

Hyd

roqu

inon

e (2

.0 e

quiv

) F

e(ac

ac) 3

(3.

5 m

ol%

)B

(OH

) 2B

rCF

2CO

2Et

RC

F2H

RS

tyre

ne (

20 m

ol%

)K

2CO

3, d

ioxa

ne, 8

0 °C

(2

equ

iv)

R =

ED

G, E

WG

33–8

7%

:CF

2L n

Pd

CF

2vi

a:

CF

2H

EtO

O

80%

CF

2H

73%

MeO

OM

e

CF

2H

TM

S

72%

NO

F

OH

CF

2H

F58

%

O

Me

Me

PP

h 2P

Ph 2

Xan

tph

os

OH

OH

Hyd

roq

uin

on

e

Sche

me

1.12

Pal

ladi

um‐c

atal

yzed

difl

uoro

met

hyla

tion

of a

rylb

oron

ic a

cids

with

bro

mod

ifluo

roac

etat

e vi

a a

diflu

oroc

arbe

ne p

athw

ay.

c01.indd 12 14-03-2020 20:52:46

ClC

F2H

Pd 2

(dba

) 3 (

2.5

mol

%)

Xan

tpho

s (7

.5 m

ol%

)H

ydro

quin

one

(2.0

equ

iv)

(10

equi

v)

BR

CF

2HR

K2C

O3

(4.0

equ

iv)

Dio

xane

, 110

°C

B =

B(O

H) 2

, Beg

, Bne

op• K

OH

, B(Oi-P

r)3L

i

R =

ED

G, E

WG

45–9

5%

:CF

2

L nP

dC

F2

via:

O

CF

2HOMe

Me

O

O

MeM

e

80%

N

O

CF

2H

Me C

O2M

eM

eO45

%

N

NN

S

Me

OO

OM

e

MeO

CF

2H

72%

72%

Gra

m s

cale

H O

Me

NH

Boc

Me

Me

CF

2H

O

Me

NH

Boc

Me

Me

O

CN

F O

Me

On-

Bu

O

O

CF

2HF O

Me

On-

Bu

O

(1)

C–H

bor

ylat

ion

(2)

C–B

difl

uoro

met

hyla

tion

(1)

C–C

N b

oryl

atio

n

(2)

C–B

difl

uoro

met

hyla

tion

CF

2H

OO

OE

t

Me

Me

Sche

me

1.13

Pal

ladi

um‐c

atal

yzed

difl

uoro

met

hyla

tion

of a

ryl b

oron

s w

ith c

hlor

odifl

uoro

met

hane

via

a

diflu

oroc

arbe

ne p

athw

ay.

c01.indd 13 14-03-2020 20:52:47

PD

FA

B(O

H) 2

R

Pd(

PP

h 3) 4

(20

mol

%)

1,3-

Cyc

lope

ntad

ione

(1

equi

v)H

2O (

2.5

equi

v), C

a(O

H) 2

(4

equi

v)

p-X

ylen

e, 9

0 °C

, 3 h

CF

2HR

Ph

3P+ C

F2C

O2–

(5 e

quiv

)

R =

ED

G23

–86%

:CF

2

L nP

dC

F2

via:

CF

2H

MeO

83%

78%C

F2H

CF

2H

86%

OC

F2H

68%

OO

1,3-

Cyc

lop

enta

dio

ne

Sche

me

1.14

Pal

ladi

um‐c

atal

yzed

difl

uoro

met

hyla

tion

of a

rylb

oron

ic a

cids

with

PD

FA v

ia a

difl

uoro

carb

ene

path

way

.

c01.indd 14 14-03-2020 20:52:47


1989 by Huang and coworker [32]. A radical initiated by nickel(0) was involved in the reaction, but no fluoroalkyl nickel species was generated. A nickel‐catalyzed radical difluoromethylation of aromatics (Scheme 1.15a) was reported in 2018 by Zhang and coworkers [33] on the basis of their previous work on the nickel‐ catalyzed difluoroalkylation of arylboronic acids with difluoroalkyl halides [34]. The reaction exhibited high functional group tolerance and allowed difluoro-methylation of a variety of arylboronic acids with simple and readily available bromodifluoromethane (BrCF2H) as the fluorine source. A combined (2 + 1) ligand system [34b,c] (a bidentate ligand and a monodentate ligand) was employed to promote the relatively low reactivity of BrCF2H and facilitate catalytic cycle. Radical inhibition, radical clock, and electron paramagnetic resonance (EPR)

BrCF2HTHF, 80 °C, 17 h

B(OH)2R

CF2HR

Ni(PPh3)2Br2 (5 mol%)bpy (10 mol%), DMAP (5 mol%)

K2CO3 (4.0 equiv)

BrCF2HDioxane, 80 °C, 24 h

B(OH)2R

CF2HR

Ni(OTf)2 (5 mol%)ditBuBpy (5 mol%), PPh3 (10 mol%)

K2CO3 (3.0 equiv)

51–92%

37–93%

CF2HMeO

OMe

CF2H

EtO

O

CF2H

TMS NPh

CF2H

70%80%83%85%

NiILn

Ar–NiILn

Ar–Ni+II(Ln)Br

NiIIILn

Br

Ar

HF2C

ArCF2H

•CF2H

BrCF H2

ArB(OH)2

Single electron transfer

CF2H

Ph

92%

CF2H

EtO

O86%

CF2H

PhO

69%

CF2H

53%

OO

Proposed mechanism

N Nbpy

N NditBuBpy

t-Bu t-Bu

(a)

(b)

Scheme 1.15 Nickel‐catalyzed difluoromethylation of arylboronic acids with bromodifluoromethane.

c01.indd 15 14-03-2020 20:52:47


experiments demonstrated that a difluoromethyl radical was involved in the reaction. Based on the mechanistic studies and previous reports [35], a Ni(I/III) catalytic cycle involving a radical was proposed. Similar to Zhang’s studies, Wang and coworkers reported a nickel‐catalyzed cross‐coupling of BrCF2H with arylb-oronic acids using PPh3 as the co‐ligand (Scheme 1.15b) [36].

Later on, Zhang and coworkers extended this (2 + 1) ligand system to the nickel‐catalyzed cross‐coupling between (hetero)aryl chlorides/bromides and ClCF2H [37], representing the first example of nickel‐catalyzed reductive cross‐coupling between organoelectrophiles and fluoroalkyl halides (Scheme 1.16). The reaction exhibited remarkably broad substrate scope, including a range of pharmaceuticals, without preformation of aryl metals. The reaction can be scaled up to 10 g scale without loss of reaction efficiency, providing a practical application of ClCF2H in life and materials sciences. Radical clock and control experiments revealed that a difluoromethyl radical generated by direct cleavage of C─Cl bond in ClCF2H was involved in the reaction. Stoichiometric reaction of aryl nickel complex [ArNi(ditBuBpy)X] with ClCF2H and reaction of difluoro-methyl nickel complex [HCF2Ni(ditBuBpy)X] with aryl chloride showed that the reaction started from the oxidative addition of aryl halides to Ni(0). This is in

R

CIHet

NiCI2 (10 mol%)Ligand (5 mol%)

DMAP (20 mol%)MgCI2 (4.0 equiv)

Zn (3.0 equiv)3Å MS, DMA, 60 °C

R

CF2HCICF2H

(6.5 equiv)

Het

N N

H2N NH2

LigandYields up to 92%

CF2H

ON

72%

NBoc

Me

CF2H

84%

NH

NOMe

O CO2Me

CF2H

76%

NH

NOMe

Me O

OH

CF2H91%, 10.5 g

[Ni0]

[Ar–NiII–Cl]

[Ar–NiI]

[Ar–NiII–Cl]

CF2H

[Ar–NiIII–CF2H]

[NiI]

Ar–Cl

ZnAr–CF2H

Zn [Ni0]

[Ar–NiII–Cl]

[Ar–NiIII–CF2H][NiI]

Ar–Cl

Ar–CF2H

Zn

[NiII]

CF2H

ClCF2H

ClCF2H

a. Radical-Cage rebound process b. Radical chain mechanism

+

R

BrHet

Ni(PPh3)2Br2 (10 mol%)bpy (10 mol%)KI (0.4 equiv)

R

CF2HBrCF2H

(1.0 equiv)

Het

Yields up to 91%

Zn (2.0 equiv)DMPU, 60 °C, 6 h

Proposed mechanism

Scheme 1.16 Nickel‐catalyzed reductive difluoromethylation of aryl chlorides and bromides.

c01.indd 16 14-03-2020 20:52:47


contrast to palladium‐catalyzed difluoromethylation of arylboronic acids and esters with ClCF2H, in which a difluorocarbene pathway is involved in the reac-tion [28]. This nickel‐catalyzed reductive process can also be applied to BrCF2H with high efficiency and good functional group tolerance (Scheme 1.16) [38].

The nickel‐catalyzed reductive difluoromethylation has also been extended to photoredox catalysis. Recently, McMillan and coworkers reported a method to access difluoromethylated (hetero)arenes through cross‐coupling of (hetero)aryl bromides with BrCF2H by combining nickel catalysis (NiBr2·4,4′‐di‐tert‐butyl‐2,2′‐bipyridine [dtbbpy]) with iridium photocatalysis {[Ir(dF(CF3)ppy)2(dtbbpy)]PF6} (Scheme 1.17) [39]. A pathway involving silyl radical‐medi-

XR

Br

Ir photocatalyst (1 mol%)NiBr2 dtbbpy (5 mol%)(TMS)3SiH (1.05 equiv)2,6-Lutidine (2.0 equiv)

XR

CF2HBrCF2H

(1–2 equiv)45–85%

DME, blue LEDs, 18 h

Ir photocatalyst

N

N

N

NIr

tBu

tBu

CF3

CF3F

FF

F

PF6–

(dtbbpy)Ni0Ln

N NiII ArBr

N

N NiIII–ArCF H2

N(dtbbpy)NiILn

Ar–CF2H

Ar–Br

CF2H

IrII

IrIII

*IrIII

Br

Br

hvvisible light excitation

Br(TMS)3SiH

–HBr(TMS)3Si

BrCF2H(TMS)3SiBr CF2H+

Formation of difluoromethyl radical:

N N

NS

CF2H

O

OMe

OMe

MeO

66%

N N

SNH2O

O

CF2H

F3C

64%

N

MeO

Me

O

CF2H

CO2Me82%

Proposed mechanism

SET

Scheme 1.17 Metallaphotoredox difluoromethylation of aryl bromides with bromodifluoromethane.

c01.indd 17 14-03-2020 20:52:48


ated halogen abstraction to generate difluoromethyl radical was proposed. One advantage of this method is that various N‐containing heteroaromatics were applicable to the reaction, providing an alternative access to difluoromethylated (hetero)aromatics.

The nickel‐catalyzed difluoromethylation of arylmetals with difluoromethyl halides has also been applied to the cross‐coupling between arylmagnesium bro-mides and difluoroiodomethane (ICF2H) (Scheme 1.18) [40]. In contrast to the previous difluoromethylation via a Ni(I/III) catalytic cycle [33], a Ni(0/II) cata-lytic cycle was proposed by Mikami and coworkers [40] to be likely involved in the reaction. This plausible mechanism was supported by the stoichiometric reaction of a difluoromethyl nickel(II) complex with PhMgBr. Radical clock experiment showed that the free difluoromethyl radical was unlikely involved in the reaction. They also used ICF2H as the difluoromethylating reagent and developed a palladium‐catalyzed difluoromethylation of arylboronic acids with ICF2H (Scheme 1.19) [41]. Preliminary mechanistic studies revealed that the reaction started from the oxidative addition of ICF2H to Pd(PPh3)4; the resulting square‐planar trans‐(PPh3)2Pd(II)(CF2H)I complex underwent transmetalation to provide cis‐(PPh3)2Pd(CF2H)Ph, which subsequently underwent a ligand

MgBrR + ICF2H

Ni(cod)2 (2.5 mol%)TMDEA (2.5 mol%)

THF, 0 °C to rt, 1 h

CF2HR

42–99%(1.5 equiv)

CF2H

Ph89%

CF2H

MeS82%

CF2H

79%

CF2H

33%

NCEtO2C

N

NNi

I

CF2H

N

N

NiAr

CF2H

Ar–MgBr

MgBrI

N

N

Ni0

Ar–CF2H

ICF2H

Oxidative addition

Reductive elimination

Transmetalation

Proposed mechanism

Scheme 1.18 Nickel‐catalyzed difluoromethylation of aryl magnesium reagents with iododifluoromethane.

c01.indd 18 14-03-2020 20:52:48


exchange with DPEphos, followed by reductive elimination to produce the dif-luoromethylated aromatics.

In addition to the nickel‐catalyzed radical difluoromethylation, the use of inex-pensive, nontoxic, and environmentally benign iron as the catalyst has also been given increasing attention. In 2018, Hu and coworkers reported an iron‐cata-lyzed difluoromethylation of arylzinc reagents with difluoromethyl 2‐pyridyl sulfone (Scheme 1.20a) [42]. Generally, moderate to high yields were obtained with electron‐rich substrates, but less reactivity was showed by electron‐defi-cient substrates. Preliminary mechanistic studies showed that a difluoromethyl radical, generated via SET pathway from difluoromethyl 2‐pyridyl sulfone, was involved in the reaction. In the same year, Zhang and coworkers also developed an iron‐catalyzed difluoromethylation (Scheme 1.20b) [43], in which a bulky diamine ligand with a butylene group substituted at one carbon atom of ethylene backbone in N,N,N′,N′‐tetramethyl‐ethane‐1,2‐diamine (TMEDA) was used to promote the reaction. During the reaction/catalysis process, the corresponding iron complex can be changed from five‐coordinate to more electron‐deficient four‐coordinate, thus improving its catalytic efficiency. This iron‐catalyzed dif-luoromethylation has later been extended to ICF2H by Mikami and coworkers (Scheme 1.20c) [44]. In contrast, no ligand was required in this reaction, mainly owing to the different reactivity between BrCF2H and ICF2H.

1.2.4 Radical C─H Bond Difluoromethylation of (Hetero)aromatics

The direct C─H bond difluoromethylation of (hetero)aromatics represents a more straightforward alternative. Over the past a few years, important progress has been made in this field, providing synthetically convenient routes for

B(OH)2R + ICF2H

Pd(PPh3)4 (10 mol%)DPEphos (10 mol%)

K3PO4 (2 equiv)

Toluene/H2O = 10 : 1 60 °C, 24 h

CF2HR

33–98%(1.5 equiv)

CF2H

Ph89%

CF2H

TMS90%

CF2H

29% 68%NH2 O

CF2H

ZnR + ICF2H

Pd2(dba)3 (5 mol%)Xantphos (11 mol%)

THF, rt, 20 h

CF2HR

12–97%(1.5 equiv)

2

CF2H

97%

CF2H

67%

CF2H

52%CN

MeO CF2H

49%EtO2C

OPPh2 PPh2

DPEphos

O

MeMe

PPh2 PPh2

Xantphos

Scheme 1.19 Palladium‐catalyzed difluoromethylation of arylboronic acids or aryl zinc reagents.

c01.indd 19 14-03-2020 20:52:48


applications in organic synthesis. In 2012, Baran and coworkers developed a new difluoromethylating reagent Zn(SO2CF2H)2 (DMFS) that allowed difluoromethyl-ation of a range of N‐containing heteroarenes in the presence of t‐BuOOH via a radical pathway (Scheme 1.21) [45]. Regiochemical comparisons showed that the difluoromethylation preferred to occur at relatively more electron‐deficient car-bon, suggesting a nucleophilic character of the difluoromethyl radical generated from DMFS.

The use of inexpensive and readily available difluoromethylating reagents via the C─H bond difluoromethylation would be more attractive in terms of cost efficiency. In 2017, Maruoka and coworkers developed a hypervalent iodine rea-gent with readily available difluoroacetic acid as the ligand (Scheme 1.22) [46]. Upon irradiation of this difluoromethylating reagent with UV, a series of N‐het-eroarenes can be difluoromethylated at relatively more electron‐deficient carbons via a difluoromethyl radical process. The regioselectivity of this reaction

Ar2ZnN

SO O

H

F F Ar CF2H

Fe(acac)3 (20 mol%)TMEDA (2.0 equiv)

THF, –40 °C to rt, 2 h36–96%

MgBrR + BrCF2H

FeBr (10 mol%)2L1 (10 mol%)

THF/dioxane, rt, 90 min

CF2HR Me2N NMe2

L1

(a)

41–91%

MeO

CF2H

F3C

CF2H NMe

CF2HF CF2H

O

88% 68% 92% 80%

Ph

CF2H

F3C

CF2H

85% 91%

CF2H

TMS

CF2H

65%

MeO

OMe63%

MgBrR + ICF2H

Fe(acac)3 (2.5 mol%)

THF, –20 °C, 30 min

CF2HR

16–94%

Ph

CF2H

PhO

CF2H

84% 85%

CF2H CF2H

53%55%

EtO

O N

(b)

(c)

Scheme 1.20 Iron‐catalyzed difluoromethylation of aryl zinc reagents or aryl magnesium reagents.

c01.indd 20 14-03-2020 20:52:48


is same as that of Baran’s method [45], implying the same nucleophilic character of difluoromethyl radical generated from these two new reagents. However, only low to moderate yields were obtained.

The direct use of difluoroacetic acid as the difluoromethylating reagent has also been reported almost contemporaneously. Nielsen and coworkers employed AgNO3/K2S2O8 as the oxidants to generate difluoromethyl radical from difluoro-acetic acid (Scheme 1.23) [47]. This process allowed difluoromethylation at elec-tron poor carbons adjacent to the nitrogen atom in N‐heteroarenes. Similarly, low to moderate yields were obtained. Further investigation showed that a bis‐difluoromethylation could also be occurred by increasing the reaction temperature.

In parallel to Nielsen’s work, Qing and coworkers described a direct difluoro-methylation of phenanthridines and 1,10‐phenanthrolines with TMSCF2H (Scheme 1.24) [48]. The reaction used PhI(OCOCF3)2 or N‐Chlorosuccinimide (NCS) as the oxidant, and silver salt as the additive, providing the corresponding difluoromethylated heteroarenes in low to moderate yields. A pathway was pro-

Het H

Zn(SO2CF2H)2 (2.0–4.0 equiv)t-BuOOH (4.0–6.0 equiv)

TFA (1.0 equiv)Het CF2H

CH2CI2:H2O (2.5 : 1), 23 °C

30–90%

N CF2H

O OEt

N

MeO

O

CF2H

4

2 6N

MeO

O

CF2H

4

2 6

OMe

66%45%

C2 : C4 : C61.5 : 1.5 : 2

79%C2 : C4 : C6

1 : 1 : 2

N

N

HN

OMe

MeO

CF2H

90%

N

NHN

H

H

Zn(SO2CF2H)2t-BuOOH

CH2CI2/H2O(50%)

N

NHN

H

CF2H

NaSO2CF3

(50%)C5 : C2 4 : 1N

NHN

CF3

H

5

2

5

2 2

5

Scheme 1.21 Radical difluoromethylation of heteroarenes with Zn(SO2CF2H)2.

Het H Het CF2H

20–77%

ArI(OCOCF2H)2 (2.0 equiv)hv (400 nm)

CDCl3, rt, 14 h

N

N

N

OMe

MeO

CF2H

48%

Me

N CF2H

O OEt

47%

N

N

O

Cl

CF2H

O

Me

Me

55%

N NMe

HF2CCO2Me

22%

Scheme 1.22 Radical difluoromethylation of heteroarenes with ArI(OCOCF2H)2.

c01.indd 21 14-03-2020 20:52:49


posed for the reaction to involve a nucleophilic addition of difluoromethyl anion to the heteroarenes, followed by aromatization process, but a difluoromethyl radical pathway cannot be ruled out.

1.3 Difluoroalkylation of Aromatics

In addition to difluoromethylated aromatics, other difluoroalkylated aromatics also have important applications in medicinal chemistry and materials science due to the unique properties of difluoromethylene group (CF2). The incorpora-tion of CF2 at the benzylic position not only can improve the metabolic stability

N H

CF2HCOOH (2 equiv)AgNO3 (0.5 equiv), K2S2O8 (5 equiv)

CH3CN/H2O: 2/1, 50 °C, 5–24 h N CF2HHet Het

N CF2H

OPh

62%

N CF2H

CN

61%

N

CF2H

32%

N

N Cl

CF2H

36%

N H

[H+]

N HH

CF2H

NH

CF2HH

(1) –H+

(2) –HN CF2H

CF2HCOOH CF2HCOO

–CO2

Ag2+ Ag+

H+

S2O82– SO42–Proposed mechanism

Scheme 1.23 Radical difluoromethylation of heteroarenes with HCF2COOH.

NH

TMSCF2H (3.0 equiv)t-BuOK (3.0 equiv), silver salt (1.0 equiv)

Oxidant (3.0 equiv), rt

NCF2H

NCF2H

MeO

63% 58%

NNCF2H

NNCF2H

Cl Cl

67% 32%

Silver salt: AgOAc or AgClOxidant: PhI(TFA)2 or NCS

R

NCF2H

R

Scheme 1.24 Oxidative difluoromethylation of phenanthridines and 1,10‐phenanthrolines with TMSCF2H.

c01.indd 22 14-03-2020 20:52:49

1.3 Difluoroalkylation of Aromatics 23

of biologically active molecules but also can enhance the acidity of its neighbor-ing groups [49]. However, except for the conventional difluorination of ketoaromatics with DAST, general and efficient methods for highly selective introduction of CF2R into organic molecules to access these valuable compounds had been less explored before 2012 [4]. The transition‐metal‐catalyzed cross‐coupling difluoroalkylation would be an attractive strategy, as it can directly con-struct (Het)Ar─CF2R bonds in an efficient and controllable manner. In particular, this strategy can enable late‐stage difluoroalkylation of biologically active mole-cules without the need of multistep synthesis. Nevertheless, the difficulty in selectively controlling the catalytic cycle to access the desired difluoroalkylated aromatics posed problems with such strategy. Difluoroalkylated metal species have a different instability compared with their non‐fluorinated counterparts due to decomposition or protonation to generate by‐products [50]; this has increased attention on the subject and impressive achievements have been made over the past a few years [4]. Here, we specifically focus on the transition‐metal‐catalyzed difluoroalkylation of aromatics, including phosphonyldifluoromethyl-ation and difluoroacetylation. The direct difluoroalkylation of C─H bond via a radical process will not be discussed in this session, as comprehensive reviews have been described previously [4].

1.3.1 Transition‐Metal‐Catalyzed Phosphonyldifluoromethylation of (Hetero)aromatics

Phosphonyldifluoromethyl groups (CF2PO(OR)2) have important applications in medicinal chemistry and chemical biology because CF2 is a bioisopolar and bioisostere of oxygen and replacing the oxygen atom of phosphoryl ester with CF2 results in a phosphate mimic that can protect against hydrolysis. For instance, an aromatic ring bearing this functional group can act as a protein tyrosine phosphatase (PTPase) inhibitor with significant bioactivity [51]. However, only a few methods to access aryldifluoromethylphosphonates have been developed before 2012 [52]. In 1996, Burton and coworker reported the first example of copper‐mediated phosphonyldifluoromethylation of aryl iodides with bromocadmiumdifluoromethylphosphate (BrCdCF2PO(OEt)2) (Scheme 1.25a) [52a]. The reaction was carried out under mild conditions and exhibited good functional group compatibility. However, the use of excessive toxic

R

IR

CF2P(O)(OEt)2CuI (1.16 equiv)

BrCdCF2P(O)(OEt)2 (1.66 equiv)

65–88%DMF, rt, 3 h

(a)

R

IR

CF2P(O)(OEt)2CuBr (2.0 equiv)

BrZnCF2P(O)(OEt)2 (2.0 equiv)

17–99%DMF, rt, 7–150 h

(b)

Scheme 1.25 Copper‐mediated phosphonyldifluoromethylation of aryl iodides with difluoromethylphosphonyl cadmium or zinc reagents.

c01.indd 23 14-03-2020 20:52:49


cadmium reagents restricts its widespread synthetic applications. In this context, Shibuya and coworkers replaced BrCdCF2PO(OEt)2 with a zinc analogue (BrZnCF2PO(OEt)2) reagent and furnished the corresponding Ar–CF2PO(OEt)2 smoothly (Scheme 1.25b) [52b]. This reaction required 2.0 equiv of copper salt due to the instability of the difluoromethylphosphonate copper–zinc complex.

To overcome this limitation, in 2012 Zhang and coworkers reported the first example of copper‐catalyzed cross‐coupling of iodobenzoates with BrZnCF2PO(OEt)2 (Scheme 1.26) [53]. To stabilize the difluoromethylphospho-nate copper–zinc complex, 1,10‐phenanthroline (Phen) was used as the ligand and an ester group was employed as a chelating group ortho to the iodide to facilitate the oxidative addition of copper to the Ar─I bond. The reaction showed high reaction efficiency and excellent functional group tolerance. A Cu(I/III) catalytic cycle was proposed for this reaction, which was further sup-ported by computational studies by Jover [54], in which the Zn(II) salt can act as a linker to connect both the chelating group and the copper catalyst. When replacing the ester on aromatic ring with a removable and versatile triazene group, the aryl bromides were also suitable substrates for this reaction. The resulting triazene‐containing products could serve as a good platform for diversity‐oriented synthesis, providing a wide range of Ar–CF2PO(OEt)2 that are otherwise difficult to prepare (Scheme 1.27) [55].

+ BrCF2P(O)(OEt)2

CuI (0.1 equiv)Phen (0.2 equiv)

Zn (2.0 equiv)Dioxane, 60 °C

24-48 h

R

CO2MeI

R

CO2MeCF2P(O)(OEt)2

X2Zn .CuCF2P(O)(OEt)2

R

DG

IMCF2P(O)(OEt)2

R

DG

CuCF2P(O)(OEt)2I

Cu(I)BrZnCF2P(O)(OEt)2

BrCF2P(O)(OEt)2

Zn

R

DGI

R

DGCF2P(O)(OEt)2

CO2MeCF2P(O)(OEt)2

95%

CO2MeCF2P(O)(OEt)2

80%

Me

CO2MeCF2P(O)(OEt)2

NO260%

CO2MeCF2P(O)(OEt)2

OMe

54%

MeO

53–95%

Proposed mechanism

Scheme 1.26 Copper‐catalyzed cross‐coupling of bromozinc‐difluorophosphonate with 2‐iodobenzoates.

c01.indd 24 14-03-2020 20:52:50

NN

N

I/Br

+

CuC

N (

10 m

ol%

)

Liga

nd (

20 m

ol%

)

Zn

(3.0

equ

iv)

Dio

xane

, 60

°C

RN

NN

CF

2P(O

)(O

Et)

2

R

NN

Me

Me

Me

Me

Liga

nd

CF

2P(O

)(O

Et)

2C

F2P

(O)(

OE

t)2

Ph

CF

2P(O

)(O

Et)

2

CF

3

CF

2P(O

)(O

Et)

2

Me

BF

3 . E

t 2O 8

3%

Pd(

OA

c)2

(10

mol

%)

Sty

rene

, B

F3. E

t 2O

93%

(1)

MeI

, 100

°C

(2)

PdC

l 2(P

Ph 3

) 2 (

10 m

ol%

)

CuI

(0.

1 eq

uiv)

, Et 3

N

TM

S

Pd(

OA

c)2

(5 m

ol%

)B

F3 .

Et 2

O

Pd(

OA

c)2

(5 m

ol%

)B

F3 .

Et 2

O

85%

97%

4-C

F3-

C6H

4B(O

H) 2

3-M

e-C

6H4B

(OH

) 2

H

NN

N

CF

2P(O

)(O

Et)

2

CF

2P(O

)(O

Et)

2

TM

S

82%

2 s

teps

BrC

F2P

(O)(

OE

t)2

40–9

1%

Sche

me

1.27

Cop

per‐

cata

lyze

d cr

oss‐

coup

ling

of b

rom

ozin

c‐di

fluor

opho

spho

nate

with

iodo

/bro

mo‐

aryl

tria

zene

s an

d fu

rthe

r tr

ansf

orm

atio

ns.

c01.indd 25 14-03-2020 20:52:50


Chelating group free transition‐metal‐catalyzed phosphonyldifluoromethyla-tion of (hetero)aromatics would be a more attractive strategy. In 2014, Zhang and coworkers developed a palladium‐catalyzed cross‐coupling of BrCF2PO(OEt)2 with arylboronic acids (Scheme 1.28) [56], representing the first example of cata-lytic difluoroalkylation of organoborons. The use of bidentate ligand Xantphos was essential in the promotion of the reaction probably due to the wide bite angle of Xantphos. This method paved a new way for the selective difluoroalkylation of aromatics. The reaction allowed the preparation of a variety of Ar–CF2PO(OEt)2, including a PTPase inhibitor. Preliminary mechanistic studies showed that a difluoroalkyl radical generated via an SET pathway was involved in the reaction. Recently, Poisson and coworkers also reported a palladium‐catalyzed phospho-nyldifluoromethylation to prepare Ar–CF2PO(OEt)2 (Scheme 1.29) [57]. The reaction employed aryl iodides as the coupling partner, and stoichiometric amount of phosphonyldifluoromethyl copper (CuCF2PO(OEt)2) was needed.

As an alternative, Qing and coworkers reported a copper‐mediated oxidative cross‐coupling between arylboronic acids and TMSCF2PO(OEt)2 (Scheme 1.30) [58]. Stoichiometric copper complex CuTc and excess of Ag2CO3 were needed. This strategy can also be extended to oxidative cross‐coupling of PhSO2CF2Cu with arylboronic acids [59]. Later on, Poisson and coworkers employed (hetero)aryl iodonium and aryl diazonium salts as the coupling partners, enabling the phosphonyldifluoromethylation (Scheme 1.31) [60]. Vinyl and alkynyl iodonium salts were also suitable substrates, thus demonstrating the generality of this method. In 2018, Amii and coworkers replaced (hetero)aryl iodonium salts with (hetero)aryl iodides and developed a copper‐mediated cross‐coupling between (hetero)aryl iodides and TMSCF2PO(OEt)2 (Scheme 1.32) [61]. They investigated the catalytic phosphonyldifluoromethylation, but only three electron‐deficient (hetero)aryl iodides with 42–69% yields were obtained by using 0.1–0.2 equiv CuI.

1.3.2 Transition‐Metal‐Catalyzed Difluoroacetylation of (Hetero)aromatics and Beyond

The versatile synthetic utility of ester moiety led to the increased attention on the difluoroacetylation of aromatics. In 1986, Kobayashi and coworkers reported the first example of copper‐mediated difluoroacetylation of aryl halides with dif-luoroacetate iodide (Scheme 1.33a) [62]. The reaction underwent difluoroacety-lation under mild conditions with good functional group compatibility. Several copper‐mediated difluoroacetylations of various aryl halides and aryl boronic acids have been reported [63]. However, excess of copper was needed. Later on, Amii and coworkers reported a copper‐catalyzed cross‐coupling of aryl iodides with TMSCF2CO2Et (Scheme 1.33b) [64]. The reaction facilitated the synthesis of difluoroacetylated arenes in 40–71% yields but was limited to electron‐defi-cient substrates. The resulting difluoroacetylated arenes were further used to prepare difluoromethylated arenes by sequential hydrolysis and decarboxylation. To overcome the substrate scope limitation of Amii’s method, Hartwig and cow-orker employed α‐silyldifluoroamides as the coupling partners and 18‐crown‐6 as the additive, enabling the efficient synthesis of aryl difluoroacetamides (Scheme 1.34) [65]. Both electron‐rich and electron‐ deficient aryl iodides were

c01.indd 26 14-03-2020 20:52:50

Pd(

PP

h 3) 4

(5

mol

%)

Dio

xane

, 80

°C

K2C

O3

(2.0

equ

iv)

R

B(O

H) 2

Xan

tpho

s (1

0 m

ol%

)+

BrC

F2P

(O)(

OE

t)2

CF

2P(O

)(O

Et)

2

CF

2P(O

)(O

Et)

2C

F2P

(O)(

OE

t)2

OO

CF

2P(O

)(O

Et)

2

EtO

2C

86%

70%

80%

(w

ith 3

Å M

S)

R

41%

(EtO

) 2(O

)PF

2C

CO

2Me

NH

Boc

PT

Pas

e in

hib

ito

r

OP

Ph 2

PP

h 2X

antp

hos

R =

PO

(OE

t)2,

CO

2Et,

CO

NR

1 R2

44–8

6%

Pd0

L n

ArP

dII LnC

F2R

BrP

dII LnC

F2R

BrP

dIL n

CF

2R+B

rCF

2R

ArB

(OH

) 2

Bas

e

Ar –

CF

2R

Pro

pose

d m

echa

nism

Sche

me

1.28

Pal

ladi

um‐c

atal

yzed

pho

spho

nyld

ifluo

rom

ethy

latio

n of

ary

lbor

onic

aci

ds w

ith

brom

odifl

uoro

phos

phon

ate.

c01.indd 27 14-03-2020 20:52:50


TMSCF2P(O)(OEt)2

CuSCN (1.0 equiv)CsF (3.0 equiv)

(2.5 equiv) MeCN/DMF, 0 °C to rt + R

CF2PO(OEt)2

CF2P(O)(OEt)2

MeO2C

CF2P(O)(OEt)2

51%71%

Yield up to 76%

CF2P(O)(OEt)2CF2P(O)(OEt)2

45%60%OMe

Br

RX

X = I(Ar)OTf/BF4 N2+BF4–

Scheme 1.31 Copper‐mediated phosphonyldifluoromethylation of aryl hypervalent iodides or aryl diazoniums with TMSCF2PO(OEt)2.

RI

TMSCF2P(O)(OEt)2

CuI (0.2 equiv)CsF (1.2 equiv)

(1.2 equiv)THF, 60 °C, 24 h

+ RCF2P(O)(OEt)2

CF2P(O)(OEt)2

50%

N CF2P(O)(OEt)2

42%

N CF2P(O)(OEt)2

69%NC

Scheme 1.32 Copper‐catalyzed phosphonyldifluoromethylation of (hetero)aryl iodides with TMSCF2PO(OEt)2.

R

B(OH)2

Ag2CO3 (1.5 equiv), pyridine 4 Å MS, DMF, 45 °C

R

CF2P(O)(OEt)2TMSCF2P(O)(OEt)2

CuTc (1.0 equiv)Phen (1.0 equiv)

31–81%

CF2P(O)(OEt)2 CF2P(O)(OEt)2

MeO2C

CF2P(O)(OEt)2

MeO72% 54% 40% 31%

SCF2P(O)(OEt)2

Scheme 1.30 Copper‐mediated oxidative phosphonyldifluoromethylation of arylboronic acids with TMSCF2PO(OEt)2.

R

IR

CF2P(O)(OEt)2PdCl2(PPh3)2 (5 mol%)

CuCF2P(O)(OEt)2 (1.0 equiv)

38–80%

CH3CN, 40 °C, 16 h Het Het

CF2P(O)(OEt)2

MeO

CF2P(O)(OEt)2

MeO2C

N CF2P(O)(OEt)2

Br N

N CF2P(O)(OEt)2

64% 58% 69% 46%

Scheme 1.29 Palladium‐catalyzed phosphonyldifluoromethylation of aryl iodides with difluorophosphonyl copper reagents.

c01.indd 28 14-03-2020 20:52:51


applicable to the reaction, providing an alternative access to difluoroacetylated arenes. The copper‐catalyzed C─H bond difluoroacetylation of furans and benzofurans with difluoroacetate bromide has also been reported by Poisson and coworkers (Scheme 1.35) [66]. A Cu(I/III) catalytic cycle was proposed based on no inhibition of the reaction by addition of radical inhibitor (tert‐butylhy-droxytoluene) or scavenger tetramethylpiperidinooxy (TEMPO) to the reaction.

ICF2CO2Me(3.0 equiv)

+CF2CO2Me

Cu powder(4.0 equiv)

DMSO, rt to 60 °C

(a)

XR R

X = Br, I 21–88%

(b)

I

R

CuI (20 mol%)KF (1.2 equiv)

CF2COOEt

R+DMSO, 60 °C

TESCF2COOEt

40–71% (19F NMR)

CF2COOEt

NC

CF2COOEt

EtO2C

CF2COOEt

Cl

Cl N CF2COOEt

71% 40% 42% 67%

CF2COOEt

R

CF2COOH

RMeOH/H2O

rt, 1–2 h

K2CO3KF (or CsF)

DMF or NMP

170–200 °C2–48 h

CF2H

R

CF2COOEt

NC

CF2COOEt

EtO2C

CF2COOEt

Br

N CF2COOEt

84% 74% 59% 89%

Preparation of difluoromethylated arenes via a decarboxylation process

Scheme 1.33 Copper‐mediated/catalyzed difluoroacetylation of aryl iodides/bromides and applications in the synthesis of difluoromethylated arenes.

RI

CuOAc (20 mol%)KF (1.2 equiv)

18-crown-6 (1.2 equiv)

Toluene, 100 °C

F F

O

NR2

R1

R

F F

O

N

71–97%

92%

F F

O

N

t-BuO2C73%

MeO

F F

O

N

85%

TMS+N

OR2

R1FF

O O O

N

F F

O

N

75%

Bn

Bn

Scheme 1.34 Copper‐catalyzed cross‐coupling of aryl iodides with α‐silyldifluoroamides.

c01.indd 29 14-03-2020 20:52:51

OR1

HR

K2C

O3

( 2

equi

v), D

MF

, 80

°C

CuI

(10

mol

%),

phe

n (1

2 m

ol%

)

OR1

CF

2CO

2Et

R

36–6

5%

OC

F2C

O2E

t

Pro

pose

d m

echa

nism

52%

(60

°C

)

OC

F2C

O2E

t

50%

OC

F2C

O2E

tA

cO

63%

(60

°C

)

OC

F2C

O2E

t

Ph

67%

BrC

F2C

O2E

t+

CuI

X

CuI

II CF

2CO

2Me

Br X

O

+C

uIII X

CF

2CO

2Me

OC

uIII

XCF

2CO

2Me

OH

BrC

F2C

O2E

t

Bas

e

Bas

e•H

X

OC

F2C

O2E

t

Sche

me

1.35

Cop

per‐

cata

lyze

d di

fluor

oace

tyla

tion

of fu

rans

and

ben

zofu

rans

with

bro

mod

ifluo

roac

etat

es a

nd

the

poss

ible

mec

hani

sm.

c01.indd 30 14-03-2020 20:52:52


The first example of palladium‐catalyzed difluoroacetylation of aromatics was reported by Zhang and coworkers in 2014 (Scheme 1.36) [56]. The combination of Pd(PPh3)4/Xantphos with CuI provided an efficient catalytic system to prepare difluoroacetylated arenes from arylboronic acids and difluoroacetate bromide. The reaction allowed difluoroacetylation of a variety of arylboronic acids with excellent functional group tolerance. Mechanistic studies revealed that a dif-luoroacetyl radical via an SET pathway was involved in the reaction. This strategy can also be extended to (hetero)aryl bromides. Later on, Hartwig and coworkers developed a palladium cross‐coupling of α‐trimethylsilyldifluoroacetamides with (hetero)aryl halides (Scheme 1.37a) [67]. Contrary to Zhang’s method, a palladacyclic complex containing PCy(t‐Bu)2 was used as the pre‐catalyst in this reaction. The mechanistic studies of the reductive elimination from arylpalla-dium difluoroacetate complexes showed that Xantphos with a wide bite angle facilitates the reductive elimination [68]. Recently, Liao, Hartwig, and coworkers also developed a palladium‐catalyzed cross‐coupling of aryl electrophiles with difluoroacetylzinc generated in situ from the reaction of BrCF2CO2Et with zinc (Scheme 1.37b) [69], providing an alternative route for applications in the syn-thesis of aryl difluoroacetates.

In addition to palladium‐catalyzed difluoroacetylation of prefunctionalized (hetero)arenes, Buchwald and coworker described a palladium‐catalyzed intra-molecular C─H bond difluoroalkylation from chlorodifluoroacetamides with BrettPhos as the ligand (Scheme 1.38) [70]. An intermolecular ruthenium‐cata-lyzed C–H difluoroacetylation of aromatics was reported by Ackermann and coworkers in 2017 (Scheme 1.39a) [71], in which a cooperative phosphine and carboxylate ligand system was used to promote the C–H difluoroacetylation. The reaction showed high meta‐selectivity with pyridine as the directing group. Mechanistic studies showed that an ortho C–H metalation was the initial step. Subsequently, the resulting ruthenium(II) complex reacted with the difluoroa-cetyl radical generated via an SET pathway from Ru(II) species to provide meta‐difluoroacetylated arenes. Simultaneously to Ackermann’s work, Wang and

B(OH)2+R1 BrCF2COR

2

Pd(PPh3)4 (5 mol%)Xantphos (10 mol%)

CuI (5 mol%)K2CO3 (4.0 equiv)

Dioxane, 80 °C

CF2COR2

R1

53–95%

CF2CO2Et

77%

CF2CO2Et

OHC

74%

MeO

OMe

CO2Me

HN

Ot-Bu

FF

91%71%

O

H

HH

EtO2CF2C

Estrone derivative

Scheme 1.36 Palladium‐catalyzed cross‐coupling of arylboronic acids with bromodifluoroacetate and bromodifluoroacetamides.

c01.indd 31 14-03-2020 20:52:52

TM

SC

F2C

ON

Et 2

Tol

uene

/dio

xane

(1

:1)

100

°C, 3

0 h

H2N

Pd

PC

y(tB

u)2

Cl

[Pd

]

82%

62–9

5%

[Pd]

(1–

3 m

ol%

)K

F (

3.0

equi

v)B

r+

RC

F2C

ON

Et 2

R

F3C

NE

t 2

OFF

81%

NE

t 2

OFF

O O62

%

NN

Et 2

OFF

67%

NE

t 2

OFF

N

[Pd(π-

cinn

amyl

)Cl] 2

(5

mol

%)

Xan

tpho

s (1

5 m

ol%

)Z

n (1

.5 e

quiv

), T

BA

T (

0.38

0–0.

75 e

quiv

)

TH

F, 6

0 °C

, 24

hB

rCF

2CO

2Et

X+

CF

2CO

2Et

RR

42–9

6%X

= B

r, O

Tf

(a)

(b)

Sche

me

1.37

Pal

ladi

um‐c

atal

yzed

difl

uoro

acet

ylat

ion

of a

ryl b

rom

ides

/trif

late

s.

c01.indd 32 14-03-2020 20:52:52


coworkers developed a ruthenium and palladium co‐catalyzed meta‐selective difluoroacetylation (Scheme 1.39b) [72]. Similarly, the ortho C–H metalation by ruthenium(II) was the initial step, but Pd(PPh3)4 was used as the radical initiator for the SET process (Scheme 1.40). Recently, a para‐selective difluoroacetylation of arenes has been reported by Zhao and coworkers with aniline derivatives as the coupling partners, in which a radical process was also involved in the reac-tion (Scheme 1.41) [73].

Although impressive achievements have been made in copper‐ and palladium‐catalyzed trifluoromethylation and difluoroalkylation of aromatics, the use of earth‐abundant nickel as a catalyst has been less explored due to the thermal stability of arylnickel(II) fluoroalkyl complexes [74]. In 2014, Zhang and cowork-ers reported the first example of a nickel‐catalyzed difluoroacetylation of arylbo-ronic acids with Cl/BrCF2CO2Et (Scheme 1.42) [34a]. The reaction exhibited broad substrate scope including drug derivatives and excellent functional toler-ance, with inexpensive Ni(NO3)2⋅6H2O as the catalyst and readily available bipy-ridine (bpy) as the ligand. Notably, a wide range of difluoroalkyl bromides (BrCF2R, R = CO2Et, CONR1R2, COAr, COR1, HetAr) were applicable to the reaction. A Ni(I/III) catalytic cycle was proposed for the reaction, in which a nickel(III) facilitates the reductive elimination of the arylnickel(III) fluoroalkyl complex. Recently, Sanford and coworkers confirmed that arylnickel(III) trifluo-romethyl complexes [(Ar)(CF3)Ni(III)LnX] are favorable for reductive elimina-tion [75]. Compared to the palladium‐ and copper‐catalyzed difluoroalkylation, the advantage of nickel‐catalyzed process is more general in terms of the sub-strate scope of difluoroalkyl halides and functional group tolerance. This strategy has also been applied to the nickel‐catalyzed cross‐coupling of bromodifluoro-acetamides with arylzinc reagents by using bisoxazoline as the ligand (Scheme 1.43) [76]. In addition to the nickel‐catalyzed difluoroacetylation, the cobalt‐catalyzed cross‐coupling of arylzinc reagents with bromodifluoroacetate has also been reported by Inoue and coworker(Scheme 1.44) [77].

N CF2Cl

O

R2

Pd2dba3 (2 mol%)BrettPhos (8 mol%)

K2CO3 (1.5 equiv)CPME, 120 °C, 20 h

NR2

F F

OMe

MeO PCy2i-Pr i-Pr

i-Pr

R1R1

BrettPhos

N

F FOMe

MeO

MeO

Me2N

O

O

66%

NMe

F F

O

68%

MeO

O

NBn

N

O

n-Pr

FF

76%Regioisomeric ratio: 5.6 : 1

N N

F F

O

70%

Ot-Bu

MeO

52–95%

Scheme 1.38 Palladium‐catalyzed intramolecular C─H bond difluoroalkylation with the aid of chlorodifluoroacetamides.

c01.indd 33 14-03-2020 20:52:52

DG

H

+

+

BrC

F2C

O2E

t

[Ru]

(10

mol

%)

P(4

-C6H

4CF

3)3

(20

mol

%)

Na 2

CO

3 (2

.0 e

quiv

)1,

4-D

ioxa

ne60

°C

, 18

h

DG

CF

2CO

Et

31–8

9%

NC

F2C

O2E

t

50%

NC

F2C

O2E

t

82%

NC

F2C

O2E

t

75%

N

Ru

Mes

CO

2

OO

Mes

Me

i-Pr

[Ru]

OM

eC

O2M

eF

N

NNNC

F2C

O2E

t

n-B

u78

%

DG

H

BrC

F2C

O2E

t[R

uCl 2

(p-c

ymen

e)] 2

(5

mol

%)

Pd(

PP

h 3) 4

(10

mol

%)

Na 2

CO

3 (2

.0 e

quiv

)

Ba(

OA

c)2

(0.1

5 eq

uiv)

1,4-

Dio

xane

90 °

C, 2

4 h

DG

CF

2CO

Et

53–8

4%

NC

F2C

O2E

t

76%

NC

F2C

O2E

t

55%

CF

2CO

2Et

79%

OM

e

NC

F2C

O2E

t

53%

N

Br

N

N

(a)

(b)

Sche

me

1.39

Dire

ctin

g‐gr

oup

prom

oted

ruth

eniu

m‐c

atal

yzed

met

a‐di

fluor

oace

tyla

tion

of a

rene

s.

c01.indd 34 14-03-2020 20:52:52


[RuCl2(p-cymene)]2

RuCl(OAc)(p-cymene)

Ba(OAc)2

BaCl2

Ru

Me i-Pr

N

Cl

R1

R2

H

Ru

Me i-Pr

N

L

R1

R2

H

Ru

Me i-Pr

N

L

R1

R2

CF2CO2EtH

Ru

Me i-Pr

N

L

R1

R2

CF2CO2Et

Na2CO3

NaHCO3, NaOAc

N

R1

R2

H

H

L

Cl–

Ligand exchange

FFOEt

O

FFOEt

OBr

Pd(0)Pd(I)

SET

Pd(0)NaHCO3, NaBr

Pd(I)Br, Na2CO3

SET

N

R1

R2

CF2CO2Et

Na2CO3, Ba(OAc)2, L

NaOAc, BaCl2, NaHCO3

Scheme 1.40 Possible mechanism of ruthenium/palladium co‐catalyzed meta‐difluoroacetylation of arenes with direction groups.

H

O

+ BrCF2CO2Et

Pd(PPh3)4 (5 mol%)KOAc (4 equiv), AgF (30 mol%)

PPh3 (30 mol%), Arn-Hexane or 1,4-dioxane

140 °C, 20 h

EtO2CF2C

O

74%

36–84%

(X) CF2CO2Et

O

(X)

OMe

S

O

EtO2CF2C

Me

CO2Me

52%

EtO2CF2C

O

63%

OH

Scheme 1.41 Palladium‐catalyzed para‐selective C─H bond difluoroacetylation of aryl ketones.

c01.indd 35 14-03-2020 20:52:53


R1B(OH)2

XCF2R+CF2R

R1

X = Br, 87%X = Cl, 76%a

K2CO3 (2.0 equiv)1,4-Dioxane, 60–80 °C

Ni(NO3)2 • 6H2O (2.5–5.0 mol%)bpy (2.5–5.0 mol%)

CF2CO2Et

X = Br, 81%X = Cl, 62%a

CF2CO2Et

MeO

CF2CO2Et

X = Br, 95%

X = Br, 88%

F F HN

O

X = Br, 93%

F F

O

X = Br, 96%X = Cl, 40%a

CF2CO2Et

EtO2C

O

H

HH

N

OF F

X = Br, 56%

X = Br, Cl

Br

a5 mol% PPh3 was added.

XNi(I)Ln ArB(OH)2

Ar Ni(I)Ln

BrCF2R

Ar–Ni(II)(Ln)Br+

CF2R

ArCF2R

Ar

X

CF2RLnNi(III)

Proposed mechanism

Scheme 1.42 Nickel‐catalyzed cross‐coupling of arylboronic acids with functionalized difluoroalkyl bromides and chlorides.

RZnCl

+ BrCF2CONR2TMEDA (1.6 equiv)

THF, 0 °C

R

F FNR2

O

Ligand20–96%

F FN

O

O

91%

F FN

O

O

MeO91%

F FN

O

O

F

96%

F FN

O

O

H

O 72%

NiCl2 DME ( 5 mol%)Ligand (6 mol%) O

N N

O

PhPh

Scheme 1.43 Nickel‐catalyzed cross‐coupling of aryl zinc reagents with bromodifluoroacetamides.

c01.indd 36 14-03-2020 20:52:53


1.3.3 Other Catalytic Difluoroalkylations of (Hetero)aromatics

In 2007, Shreeve and coworker reported the first example of a palladium‐cata-lyzed cross‐coupling between aryl bromides and difluoroenol silyl ether with a bulky electron‐rich monophosphine P(tBu)3 as the ligand (Scheme 1.45) [78]. However, toxic tin reagent was needed to promote the reaction and the substrate scope was relatively limited. In this context, Qing and coworkers developed a palladium‐catalyzed cross‐coupling of difluoromethyl phenyl ketone with aryl bromides in the presence of a base (Scheme 1.46a) [79]. This method is syntheti-cally convenient: no need to prepare difluoroenol silyl ether and use toxic tin reagent. Hartwig and coworkers found that the use of a cyclopalladium species as the catalyst could enable the difluoroalkylation with high efficiency and broad scope, even aryl chlorides were suitable substrates (Scheme 1.46b) [80]. Notably, the method can also be used for the preparation of difluoromethylated arenes by debenzoylation of the resulting products ArCF2COPh (Scheme 1.46).

In addition to the preparation of ArCF2COAr, the catalytic gem‐difluoroallyla-tion of aromatics has also been reported. In 2014, Zhang and coworkers developed a palladium‐catalyzed highly α‐selective gem‐difluoroallylation of arylboronic acids and esters with bromodifluoromethylated alkenes

ZnCl+R ·TMEDA BrCF2CO2Et

CoCl2 (5 mol%)Ligand (5 mol%) NMe2

NMe2Ligand

CF2CO2Et

R

48–79%

CF2CO2Et

74%

CF2CO2Et

F

70%

CF2CO2Et

MeO79%

CF2CO2EtO

O

53%

THF, rt

Scheme 1.44 Cobalt‐catalyzed cross‐coupling of aryl zinc reagents with bromodifluoroacetates.

Br

RToluene, 85 °C, 8 h

CF2COPh

R+F

F OTMS

Ph

Pd(OAc)2 (5 mol%)t-Bu3P (10 mol%)

SnBu3F (3.0 equiv)

70–91%

CF2COPh CF2COPh CF2COPh CF2COPh

MeO NC91% 84% 90%

O2N76%

Scheme 1.45 Palladium‐catalyzed cross‐coupling of aryl bromides with difluoroenol silyl.

c01.indd 37 14-03-2020 20:52:54


(Scheme 1.47) [81]. Contrary to previous works using BrCF2PO(OEt)2 and BrCF2CO2Et as the coupling partners, this reaction was presumed to occur via a formal electrophilic difluoroalkylation pathway, probably because of stabilization of palladium intermediate by coordination with alkene, thus facili-tating the oxidative addition step via a two‐electron transfer process. The high α‐regioselectivity of this reaction (α/γ > 37 : 1) may be ascribed to the strong electron withdrawing effect of the CF2 group, which strengthens the Pd─CF2R bond. Remarkably, even when the Pd catalyst loading was decreased to 0.02 mol%, high α‐regioselectivity and good yield of gem‐difluoroallylated arene was still obtained on the 10 g scale reaction, thus demonstrating the good practicality of this protocol. This reaction can also be extended to gem‐difluoropropargylation

Br

R

Pd(OAc)2 (10 mol%)rac-BINAP (20 mol%)Cs2CO3 (2.0 equiv)

Xylene, 130 °C, 8–12 h

CF2COAr

R+HF2C

O

Ar

(2.0 equiv) 52–90%

X

RToluene, 100 °C, 24 h

CF2COAr

R+

(1.0 equiv)

[Pd] (0.5–2 mol%)Cs2CO3 (2.0 equiv)

or K3PO4(H2O) (4 equiv)

65–93%(2.0 equiv)

88%

O

FF

53%

O

FF

68%

O

FF

63%

O

FF

MeO F3C

OMe

HF2C

O

Ar HN.Pd P(tBu)Cy2Cl

[Pd]

O

FF

O

FF

O

FF

X = Br, 80%X = Cl, 80%

O

FF

MeO

X = Br, 93%X = Cl, 88%

X = Br, 84%X = Cl, 81%

X = Br, 86%X = Cl, 77%

NEtO

O

X

R

CF2H

R+

(2.0 equiv)

(1) [Pd] (1 mol%) K3PO4(H2O) (4 equiv) Toluene, 100 °C, 30 h

63–99%(1.0 equiv)

HF2C

O

Ph (2) KOH/H2O, 100 °C, 2 h

CF2H

X = Br, 92%X = Cl, 82%

O

O

CF2H

X = Br, 95%X = Cl, 94%

TMS

CF2H

X = Br, 77%

EtO2C

CF2H

X = Br, 83%X = Cl, 79%

N

One-pot synthesis of difluoromethylated arenes

(a)

(b)

Scheme 1.46 Palladium‐catalyzed cross‐coupling of aryl bromides/chlorides with α,α‐difluoroketones and one‐pot synthesis of difluoromethylated arenes.

c01.indd 38 14-03-2020 20:52:54

1.4 Outlook 39

of arylboronic acids and esters with high efficiency and regioselectivity (Scheme 1.48) [82]. Since carbon–carbon double bond and triple bond are syn-thetically versatile functional groups, these resulting difluoroalkylated arenes could serve as useful building blocks for diversity‐oriented synthesis, thus offer-ing good opportunities for applications in the organic synthesis and related chemistry.

Although impressive progress has been made in the catalytic difluoroalkyla-tion of aromatics, a π‐system adjacent to CF2 is required to activate the difluoro-alkylating reagents [4a, 83]. In 2013, Baran and coworkers developed a type of sodium α,α‐difluoroalkylsulfinate (NaSO2CF2alkyl) reagents for direct difluoro-alkylation of heteroarenes (Scheme 1.49) [84]. Similar to the difluoromethylating reagent DMFS, the reaction required tBuOOH to furnish the difluoroalkylated heteroarenes via a radical process. Zinc chloride was found to be critical for the reaction. The advantage of this protocol is the synthetic simplicity. However, the modest regioselectivity of this approach restricts its widespread synthetic applications.

In 2016, Zhang and coworkers reported a nickel‐catalyzed difluoroalkylation of (hetero)arylboronic acids with unactivated difluoroalkyl bromides (BrCF2–alkyl) (Scheme 1.50a) [34b]. A combined (2 + 1) ligand system was used to facilitate the formal oxidative addition of nickel to the BrCF2–alkyl. The reaction showed broad substrate scope with high efficiency. A nickel‐catalyzed reductive cross‐coupling between (hetero)aryl bromides and BrCF2–alkyl [85] and an iron‐cata-lyzed cross‐coupling of arylmagnesiums with BrCF2–alkyl have been reported by the same group (Scheme 1.50b,c) [43]. In 2018, Baran and coworkers also reported nickel‐catalyzed difluoroalkylation of arylzincs with difluoroalkyl sulfones, pro-viding an alternative access to difluoroalkylated arenes (Scheme 1.51) [86].

1.4 Outlook

We have comprehensively summarized the transition‐metal‐mediated/catalyzed difluoromethylation and difluoroalkylation of (hetero)aromatics. Several new types of difluoroalkylation reactions were developed and provided synthetically

R

B(OH)2

+ RBrF2C

Pd2(dba)3 (0.01–0.4 mol%)K2CO3 (3.0 equiv)

H2O (0.48 equiv)Dioxane, 80 °C

FF

FF

87% (28 : 1)

BnO

78% (17 : 1)

FF

Me

Me

Me

FF

HO

68% (19 : 1)

R1

R2R1

R2

53% (15 : 1)

Ph

FFEtO2C

FF

80% (10 : 1)10-gram scale

t-Bu

60–93%

Scheme 1.47 Palladium‐catalyzed gem‐difluoroallylation of organoborons with bromodifluoromethylated alkenes.

c01.indd 39 14-03-2020 20:52:54

80%

, gra

m s

cale

48%

TIP

SE

tO2C

TIP

SB

r

57%

Ar[

B]

+

RB

rR

Ar

OO

TIP

S

60%

5

[B] =

B(O

H) 2

[B] =

Bpi

n

FF

FF

FF

FF

FF

FF

Co

nd

itio

n A

: Pd

2(d

ba)

3 (0

.1–2

.5 m

ol%

), P

(o-T

ol) 3

(0.

6–15

mol

%),

K

2CO

3 or

Cs 2

CO

3 (3

.0 e

quiv

), d

ioxa

ne o

r to

luen

e, 8

0 °C

, 24

h

Co

nd

itio

n A

or

B

92%

77%

TIP

SE

tO2C

TIP

SB

r

FF

FF

39%

82%

TIP

SN

CT

IPS

FF

FF

O

Co

nd

itio

n B

: NiC

l 2·d

pp

e (2

.5 m

ol%

), b

py (

2.5

mol

%),

K2C

O3

(2.0

equ

iv),

dio

xane

, 80

°C, 2

4 h

[B] =

B(O

H) 2

Sche

me

1.48

Pal

ladi

um‐ o

r nic

kel‐c

atal

yzed

gem

‐difl

uoro

prop

argy

latio

n of

ary

lbor

onic

reag

ents

.

c01.indd 40 14-03-2020 20:52:54

1.4 Outlook 41

HHet CF2(CH2)6N3Het

DAAS-Na (3.0 equiv)ZnCl2 (1.5 equiv)

t-BuOOH (5.0 equiv)

TsOH·H2O or TFA (1.0 equiv)CH2Cl2:H2O or DMSO:H2O (2.5 : 1)

NaOSO

F F

N35

DAAS-Na

NN

O

CF2(CH2)6N3

O

OEt

OH42%

Camptothecin

N

CF2(CH2)6N3

Me2N NMe2

82%

N

CF2(CH2)6N3

AcO OAc50%

Bisacodyl

N

MeO

MeOMeO

MeO

HH

16%

17%

Papaverine

NH

NN N

OMeH

HH

8%

9%9%

Nevirapine

Acridine orange

Scheme 1.49 C─H bond difluoroalkylation of heteroarenes with DAAS‐Na.

R

B(OH)2+ BrCF2Alkyl

CF2AlkylR

92%

FF

78%

NiCl2·DME (5–10 mol%)ditBuBpy (5–10 mol%)

DMAP (20 mol%)

K2CO3 (2.0 equiv)Triglyme, 80 °C

Ph3

FF

Ph3

SO2Me

N N

t-Bu t-Bu

ditBuBpy

F46%

NBocF

F

72%

FF OH

Ac

83%a

PhFF

4N

N

a HetArB(OiPr)3Li was used.

32–95%

R

Br

+ BrCF2Alkyl

CF2AlkylR

NiBr2·diglyme (5 mol%)L2 (5 mol%)

NaI (80 mol%)

Zn (1.2 equiv)3 Å MS, DMPU, 80 °C N N

MeO OMe

L235–88%

R

Br

+ BrCF2Alkyl

CF2AlkylR

FeI1 (10 mol%)L1 (5 mol%)

THF/dioxane, rt, 90 min

24–90%

Me2N NMe2L1

(a)

(b)

(c)

Scheme 1.50 Nickel‐ or iron‐catalyzed difluoroalkylation of aromatics with unactivated difluoroalkyl bromides.

c01.indd 41 14-03-2020 20:52:55


convenient and cost‐efficient methods to prepare difluoroalkylated arenes that are of great interest in life and materials sciences. In particular, a new mode of difluoromethylation reaction, i.e. catalytic MeDIC, has been developed, which expands our understanding of metal difluorocarbene chemistry, and should influ-ence future thinking in the field. Mechanistic studies on difluoroalkylation reac-tions showed the differences between organofluorine chemistry and classical C–H chemistry, and thus it is imperative to develop new chemistry for fluoro-alkylation reactions. In future works, the development of environmental benign, cost‐efficient, and highly regioselective difluoroalkylation reactions from inex-pensive fluorine sources remains necessary. In particular, the direct C–H dif-luoroalkylation of heteroarenes with high regioselectivity and broad substrate scope should be considered in pharmaceutical, agrochemical, and advanced mate-rial applications. To meet the increasing demand from life science, such as design of bioactive peptides, protein engineering, probes for the investigation of enzyme kinetics, diagnosing neurodegenerative diseases and so on, the development of biocompatible fluoroalkylations, including site-selective fluoroalkylation of pep-tides, proteins, oligocarbohydrates and DNA, would be a promising research area.

References

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S

N NN

NPhO O

R2

F F

ZnClR1 +

Ni(acac)2·xH2O (5 mol%)bpy (5.5 mol%) CF2R

2

R1

Me

O O

55%

THF/NMP, rt

F

41%

NBoc

FF MsN

N OiPr

O

F F

FF

44%

Scheme 1.51 Nickel‐catalyzed difluoroalkylation of aryl zinc reagents with difluoroalkylated sulfones.

c01.indd 42 14-03-2020 20:52:55

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