Post on 19-Oct-2020
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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
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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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1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes6
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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1.2 Difluoromethylation of (Hetero)aromatics 7
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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1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes8
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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1.2 Difluoromethylation of (Hetero)aromatics 9
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.
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1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes10
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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1.2 Difluoromethylation of (Hetero)aromatics 11
/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.
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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
.
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1.2 Difluoromethylation of (Hetero)aromatics 15
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
1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes16
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
1.2 Difluoromethylation of (Hetero)aromatics 17
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
1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes18
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
1.2 Difluoromethylation of (Hetero)aromatics 19
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
1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes20
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
1.2 Difluoromethylation of (Hetero)aromatics 21
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
1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes22
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
1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes24
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
1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes26
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
1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes28
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
1.3 Difluoroalkylation of Aromatics 29
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
1.3 Difluoroalkylation of Aromatics 31
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
1.3 Difluoroalkylation of Aromatics 33
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
1.3 Difluoroalkylation of Aromatics 35
[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
1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes36
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 Difluoroalkylation of Aromatics 37
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
1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes38
(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
1 Difluoromethylation and Difluoroalkylation of (Hetero) Arenes42
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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