-
Xiangbo ZhaoMacmillan Group Meeting
October 9th, 2019
Selective C-F bond Functionalization in Multifluoroarenes and
Trifluoromethylarens
F
X
F
F
F
F
F
X
F
X
F F
FR
X
F F
R
-
Strategies for the Synthesis of Organofluorine Compounds
C-F bond formation & C-F bond cleavage
Organofluorine Compounds
F
F
HN
O
NH
OF F
Cl
Cl
Teflubenzuron insecticide
F F
N
N NN
OH
NN
Fluconazole antifungal
F
F
FNH2
N
O
NN
N
CF3Januvia® (sitagliptin) antidiabetic
N
O S
FF N
N
HIV-1 reverse Transcriptase inhibitor
N
F
HN
O
MeMeHO
HO Lipitor® (atorvastatin) cholesterol and triglyceraldehyde
regulatorHO2C
FF
FF
F
NIr
O
O
Me
Me2
C-F (or F-containing moiety) Bond Formation
Selective C-F bond Activation and Functionalization
-
Content Outline
Selective C-F bond functionalization in aromatic fluorides
Selective C-F bond functionalization in
trifluoromethylarenes
Nucleophilic Substitution SNAr
Photocatalytic reduction
X
F F
FR
X
F F
R
SET & Photocatalysis
Anonic or Cationic Mechanism
F
X
F
F
F
F
F
X
F
Defluorinative Functionalization Via Benzynes
-
F
F
HN
O
NH
OF F
Cl
Cl
Teflubenzuron insecticide
F
F
FNH2
N
O
NN
N
CF3
Januvia® (sitagliptin) antidiabetic
F
F
F
F
F
NIr
O
O
Me
Me2
An organic LED molecule
Senaweera, S.; Weaver, J. D. Aldrichimica Acta 2016, 49, 45.
Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.
H
HDG
F+ reagent
DG-assisted C-H Fluorination
Catalyst
FnR
XF- or F+ reagent
X = halide, BR3, SnR3Flourination of Prefunctionalized
arenes
X
Fn
Partially fluorinated aromatics
n = 2-4
Selective C-F bond Activation
F
X
F
F
F
F
Commercially available
Selective C-F bond Functionalization of Mutifluoroarenes
Introduction of the alternative approach to partially
fluorinated compounds
-
F
Rr.d.s
slow
F
RNu- Nu RNu
fastR = EWG
-F
SNAr
F > Cl > Br > I
Reactivity Order Comparision
SN2
I > Br > Cl > F
Aromatic Halides Aliphatic Halides
CNX Pyrrole
THF, 65 ◦C
CNN
X Yield
F 100%
Cl 70%Br 10%
Thomas, S.; Collins, C. J.; Singaram, B. J. Org. Chem. 2001, 66,
1999.
Petrov, V. Fluorinated Heterocyclic Compounds, New Jersey,
2009.Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.
General Reactivity: Effects of Fluorine on Nuclephilic
Substitution
F
F
Very activating
δ+Nu- F
F
Activating
Nu-δ+
F
F
Slightly Deactivating
δ+Nu-
Selective C-F Bond Functionalization in Aromatic Fluorides
Nucleophilic substitution of aromatic fluorides (SNAr)
-
Petrov, V. Fluorinated Heterocyclic Compounds, New Jersey,
2009.Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.
Regioselectivity Pattern
F
Nu1
Nu2
F
F
F
1,4-disubstituted tetrafluorobenzene
Nu
Nu
F
F
F
F
Nu2
Nu1
Nu1
Nu2
F
F
1,2-disubstituted tetrafluorobenzene
Nu
Nu
Nu
Nu
Nu
Nu
1,2,4,5-tetrasubstituted 3,6-difluorobenzene
Hexasubstituted benzene
SNArNu-
F
F
F
F
F
F
Perfluorobenzene
Selective C-F Bond Functionalization in Aromatic Fluorides
Nucleophilic substitution of hexafluorobenzene
◆ Perfluoro-substitution dramatically lowers the energy of the
π* orbitals, making the aryl ring more susceptible to nucleophilic
attack
◆ After monosubstitution, the second substitution occurs
regioselectively at C-4 carbon, irrespective of the electronic
nature of the first substituent.
-
Selective C-F Bond Functionalization in Aromatic Fluorides
One example of nucleophilic substitution of
hexafluorobenzene
F
F
F
F
F
F 43%(Mes)2PH, n-BuLi
F
P(Mes)2
P(Mes)2
F
F
F
PhLi, THF
54%
Ph
P(Mes)2
P(Mes)2
Ph
F
F
Sasaki, S.; Tanabe, Y.; Yoshifuji, Y. Bull. Chem. Soc. Jpn.
1999, 72, 563.
Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050.
An interesting application: the preparation of anhydrous
TBAF
Bu4NF (TBAF)Anhydrous
F
F
F
F
F
F -35 ◦CTBACN, CH3CN
CN
CN
CN
NC
NC
CN65%
+
PhCH2Br
PhCH2F-35 ◦C, < 5 min
100%
-
F
N
F
F
F
F
Pentafluoropyridine
62
345
SNAr
Nu-F
N
Nu1
Nu3
F
Nu2
Nu2
N
Nu1
Nu3
F
Nu4
Nu3
N
Nu1
Nu4
F
Nu2
Regioselectivity Pattern
Petrov, V. Fluorinated Heterocyclic Compounds, New Jersey,
2009.Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.
Selective C-F Bond Functionalization in Aromatic Fluorides
Nucleophilic substitution of pentafluoropyridine
CF3
F
F
F
F
F
F
F
N
F
F
F
F
< <F
F
F
F
F
Reactivity
◆ Nucleophilic substitution occurs regioselectively stepwise
◆ First carbon-4, then carbon-2, finally carbon-3.
◆ Three kinds of different nucleophiles can be introduced
stepwise.
most reactiveleast reactive
mediun reactive
-
Petrov, V. Fluorinated Heterocyclic Compounds, New Jersey,
2009.
Selective C-F Bond Functionalization in Aromatic Fluorides
Some applications of nucleophilic substitution of
pentafluoropyridine
F
N
F
F
F
F
a. PhC=NHNH2, Na2CO3
NF
F
F
NHN
Ph
b. LDA, THF, rt
NF
F
NMe
NHN
Ph
91%
PhCH2NHMe, THF, 150◦CMicrowave
54%
Ph
CH3NHCH2CH2NHCH3
NaHCO3, MeCN, reflux97%
NF
F
F
NN
MeONa, MeOH reflux, 2 days
NMeO
F
F
NN
Et2NLi, THFreflux
76%
NMeO
F
N
NN
64%
PhSO2Na, DMF 140 ◦C, 22 h
F
N
S
F
F
F
PhO
O
89%
CH3NHCH2CH2NHCH3NaHCO3, MeCN, reflux
N
N
S
F
F
N
PhO
O
67%
a. PhC=NHNH2, Na2CO3b. LDA, THF, rt
N
S
F
F
OO
NH
N
85%
Ph
-
Petrov, V. Fluorinated Heterocyclic Compounds, New Jersey,
2009.
Selective C-F Bond Functionalization in Aromatic Fluorides
Nucleophilic substitution of perfluoroheteroaromatic systems
F
N
F
F2
34F
F
F
F
Perfluoroquinoline
F
F
N
F
1
6
F
F
F
F
Perfluoroisoquinoline
N
N
F
F
F
F2
4
Perfluoropyrimidine
F
NN
F
F
F 4
Perfluoropyridazine
F
N
N
F
F
F
Perfluoropyrazine
N
N
N
F
F F
Perfluoro-1,3,5-triazine
◆ Favored sites of attack for SNAr occurs at sites that are para
or ortho to the ring nitrogen
Difficult to get mono only (highly activated)
-
Yudin, A. K.; Zheng, J.; Lough, A. Org. Lett. 2000, 2, 41Masson,
E.; Schlosser, M. Eur. J. Org. Chem. 2005, 4401
Selective C-F Bond Functionalization in Aromatic Fluorides
Defluorinative functionalization via benzynes
X
H
R RLi
a
X = Br, I c
ba. Lithium-halogen exchange
b. Nucleophilic replacement
c. Deprotonation
F
H
R RLi
a
c
b
Lithium halogen exchange favoured Ortho-hydrogen deprotonation
favoured
ClF
F
F
FF
n-BuLi, Hexane-15 ºC
F
F
F
F
S
OMeF
F
F
FOMe63%
n-BuLiF
Li(THF)nTHF
Benzyne
F
H
R R R-LiF ◆ Elimination of LiX follows the
order of LiBr < LiCl < LiF.
-
Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.Laev, S. S.;
Shteingarts, V. D. Tetrahedron Lett. 1997, 38, 3765.
Selective C-F bond functionalization in Aromatic Fluorides
C-F bond reduction of aromatic fluorides via low-valent
metals
F
F
F
F
F
F
HexafluorobenzeneE1/2 Ar0/-1= -2.81 V
BDE(C-F)= 145 kcal/mol
F
N
F
F
F
F
E1/2 Ar0/-1= -2.12 VPentafluoropyridine
BDE(C-F)= 127 kcal/mol
◆ Li, Na, K in liquid ammonia ◆ Lithium naphthalene ◆ Activated
Mg powder ◆ CeCl3, LiAlH4
Hydrodefluorination almost no selectivity
◆ Large excess of reductants◆ Limited substrate scope
FR
FF
F
F
R = CN, CH2OH
R
H
F
F
F
Zn (6.0 eq) aq. NH3
F
> 70% yield
rt, 10 h
FR
FF
F
F
R = NHAc, CO2H
R
FF
F
F
H
> 70% yield
Zn (6.0 eq) aq. NH3
rt, 10 h
-
Photocatalytic C-F reduction and Functionalization in Aromatic
Fluorides
Introduction of Weaver group’s work on photocatalytic C-F
functionalization
F
NF
F
F
H
HR2HN
H2C=NHR2Hydrodefluorination
R
C-F alkylation
F
NF
F
F
R
H
C-F arylation
R
H F
NF
F
F
R
F
NF
F
F
R
R
C-F alkenylation
Ir(ppy)3
Ir*(ppy)3
hv
Ir(ppy)3
F
N
F
F
F
F
F
N
F
F
F
F
F-F
NF
F
F
Key radical Intermediate
HR2N
HR2HN
Ir
N
N
E1/2 [Ir(III)/(II)]= -2.19 Vfac-Ir(ppy)3
Senaweera, S.; Weaver, J. D. Aldrichimica Acta 2016, 49, 45.
Jimmie Weaver
◆ Photocatalysis can make perfluoroaryl radical catalytically
and in a controlled manner in situ.
◆ The outer sphere nature of the electron transfer might avoid
the problematic catalyst–fluoride intermediates and lead to higher
TONs.
-
Photocatalytic C-F reduction and Functionalization in Aromatic
Fluorides
Weaver group’s work: Photocatalytic hydrodefluororination
Fn
RIr(ppy)3 (0.5 mol%)
DIPEA, MeCN, 45 ºCBlue LEDs, 24h
Fn-1
R
H
F
N
H
F
F
F
93%
FH
FF
F
F
90%
FH
CO2MeF
F
F
75%
FH
CF3
F
F
F
95%
HCN
NH2
F
F
F
82%
H
N
NHAc
F
F
F97%
F
N
NMeAc
F
F
H100%
H
N
F
F
F
F
78%
Cl
N
F
F
F
F
3-chlorotetrafluoropyridine
from
FH
CO2MeF
F
H
FH
CF3
F
F
H
86% 73%
FNHAc
CF3
F
H
H
74%
HH
FF
F F F F
F F
85%
Senaweera, S. M.; Singh, A.; Weaver, J. D. J. Am. Chem. Soc.
2014, 136, 3002.
-
Photocatalytic C-F reduction and Functionalization in Aromatic
Fluorides
Weaver group’s work: Photocatalytic Alkylation of
Fluoroarenes
F
NF
F
NHEtO2C
O
H
OCO2Me
CO2Me61%
F
F
F
OMe
O
H
60%CO2Me
F
NF
F
F
Me
HO MeH
52%rr > 20:1
F
NF
F
F
Cl H
76%rr > 20:1
Cl
NF
F
F
F
SNAr Photocatalysis
$ 1.84/g
Cl
NF
F
F
MeO2C
DIPEAthen, HCl
O
OO
O
FnIr(ppy)3 (0.25 mol%)
DIPEA (1.2 eq), MeCN, 45 ºCargon, Blue LEDs
Fn-1
alkylAlkene (6.0 eq)
Singh, A.; Kubik, J. J.; Weaver, J. D. Chem. Sci. 2015, 6,
7206
Photocatalytic Reductive Alkylation
Ir(ppy)3
DIPEA, MeCN
OCO2Me
CO2Me
Photocatalytic Hydrodefluorination
NH
F
F
MeO2C HO
CO2Me
CO2MeIr(ppy)3DIPEA, MeCN
45%Overall yield
-
Photocatalytic C-F reduction and Functionalization in Aromatic
Fluorides
Weaver group’s work: Photocatalytic Arylation of
Fluoroarenes
F
NF
F
F
OMe
MeO OMe
70%
F
NF
F
F
NMe
50%
F
NF
F
F
CN
58%
F
NF
F
F
N
NHAc
70%
F
NF
F
F
NN
NHMe
57%
F
NF
F
F
Key radical Intermediate
H
RF
NF
F
F
RH F
NF
F
F
R
C-F arylation product
eH+
Oxidativere-aromatization
Fn
Ir(ppy)3 (0.25 mol%)
DIPEA (1.2 eq), MeCN, 0 ºCargon, Blue LEDs
Fn-1
Ar+ Ar-H KHCO3 (1.2 eq)
Senaweera, S.; Weaver, J. D. J. Am. Chem. Soc. 2016, 138,
2520.
-
Photocatalytic C-F reduction and Functionalization in Aromatic
Fluorides
Weaver group’s work: Photocatalytic Alkenylation and Energy
Transfer
F
NF
F
F
Key radical Intermediate
F
NF
F
F
R
R
F
NF
F
F
Electron-transfer product
HR2HN
H2C=NHR2
R
F
NF
F
F
Energy-transfer product
RIr Pcat.
F
NF
F
F
i-Pr
74%Z/E = 25:1
F
NF
F
F
61%Z/E = 25:1
OH
F
NF
F
F
OH
Me
51%Z/E = 25:1
Ir
N
N
Ir(ppy)3
F
NF
F
F
i-Pr
66%E/Z = 2:1
F
NF
F
F 71%E/Z = 7:1
HO
F
NF
F
F
OH
Me
84%E/Z = 2.6:1
Ir
N
N
Ir(t-Buppy)3
Singh, A.; Fennell, C. J.; Weaver, J. D. Chem. Sci. 2016, 7,
6796
-
Photocatalytic C-F reduction and Functionalization in Aromatic
Fluorides
Weaver group’s work: Photocatalytic Alkenylation and Energy
Transfer
F
NF
F
F
F
+t-Bu
Ir
N
N
F
F
F
photocatalyst with smaller steric volume
F
NF
F
F
t-Bu
85%Z/E = 24:1
F
NF
F
F
t-Bu
77%E/Z = 25:1
Ir
N
N
photocatalyst with larger steric volume
2 5
Ir
N
NIr
N
NF
3
F
1
Ir
N
NCF3
F3C
CF3
4
◆ The plot of log(Z:E) as a function of the radius of the
catalyst shows a linear correlation
◆ The plot of Log(Z:E) vs the photocatalyst’s emissive energy
revealed no correlation
Singh, A.; Fennell, C. J.; Weaver, J. D. Chem. Sci. 2016, 7,
6796
-
X
F F
FR
X
F F
R
SET & Photocatalysis
Anonic or Cationic Mechanism
Content Outline
Selective C-F bond functionalization in aromatic fluorides
F
X
F
F
F
F
F
X
F
Nucleophilic Substitution SNAr
Defluorinative Functionalization Via Benzynes
Photocatalytic reduction
Selective C-F bond functionalization in
trifluoromethylarenes
-
N
O S
FF N
N
HIV-1 reverse Transcriptase inhibitor
F FNH
NNN
NH2O
MeMe
O
HN
Grownth hormone secretagogue
F F
H
F
NN
NN
Me
NR2B antagoinst
F F
RAr
⍺,⍺-difluorobenzylic structure
◆ Enhanced bioavailability, metabolic stability.◆ Serving as
bioisosteres of aryl ethers ◆ Lipophilic hydrogen bond donors
(ArCF2H).
F F
FAr
Trifluoromethylareneswidely available
Single C-F bond Cleavage
PhF2C F
PhFHC F
PhH2C F
BDE (kcal/mol)115
99
106
F F
FAr
SET
Metal, e-, UV light
F F
RAr
large excess of reductantspoor selectivity, limited scope
Selective C-F bond functionalization of
Trifluoromethylarenes
Inroduction of the transformation challenge from ArCF3 to
ArCF2R
Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.
-
F F
SiF
Ph Ph
MeO
81%
F F
SiF
Ph Ph
Me
78%
F F
SiF
Ph PhF3C
26%
F F
Cl
SiF
Ph PhF3C
50%
F F
O
SiF
Ph Ph
OOMe
OMe
54%
F F
FR1
SiH
Ph Ph
Nucleophile (5.0 eq) Ph3CBF4 (1.2 eq)CH2Cl2 / (CF3)2CHOH (1:1),
0○C, 10 min
F F
NuR1
SiF
Ph PhEasily Activatable with a base
Nu = allylsilane, Cl-, Carboxylic acid.
F F
F
SiH
Ph Ph
Ph3CBF4
Hydride abstraction
F F
F
SiPh
PhBF4-
F
F
SiPh Ph
BF4-
F
+
SiMe3F F
SiF
Ph Ph C-F bond Cleavage
Ph3CH
Me3SiBF4
Yoshida, S.; Shimomori, K.; Kim, Y.; Hosoya, T. Angew. Chem.,
Int. Ed. 2016, 55,10406.
Selective C-F bond functionalization of
Trifluoromethylarenes
Yoshida group’s work: Ortho-silylium cation mediated C-F bond
cleavage of trifluoromethylarenes
-
NMe
FF
O
CN
58%
NMe
FF
O
CN
MeO
80%
NMe
FF
O
CN
t-Bu
82%
NMe
FF
O
CN
Cl
59%
F
NMe
FF
O
CO2Et
35%
NMe
FF
O
CN
53%
NMe
FF
O
SO2N(Et)2
57%
NMe
FF
O
N
CO2Et
34% (16%b)
F
Me
b: yield of the didefluorinated product
Photocatalytic C-F bond Functionalization in
Trifluoromethylarenes
König group’s work: Meriging photocatalysis with Lewis acid
Activation
Chen, K.; Berg, N.; Gschwind, R.; König, B. J. Am. Chem. Soc.
2017, 139, 18444.
N
R2O
R1 + F
F F
fac-Ir(ppy)3 (1.0 mol%)TMP (2.0 eq) HBpin (3.0 eq)
DCE, 20 ºC, N2, 455 nm, 24 hAr R1
N
R2
ArFF
O
HN
Me
Me
Me
MeBPin
Borenium cation
-
Photocatalytic C-F bond Functionalization in
Trifluoromethylarenes
König group’s work: Meriging photocatalysis with Lewis acid
Activation
Chen, K.; Berg, N.; Gschwind, R.; König, B. J. Am. Chem. Soc.
2017, 139, 18444.
NH
Me
Me
Me
Me
TMP
Ir(III)* Ir(II)
Ir(III)
NH
Me
Me
Me
Me
A
hv
CF3
NC
SETReduction
CF3
NC
Lewis Acid ActivationCF2
NC
TMP-Bpin
TMP + F-Bpin
NMe
O
NMe
FF
O
CN
NH2
Me
Me
Me
Me
HN
Me
Me
Me
MeBPin
Borenium cationC
HBpin
TBP-Bpin
H2
Ir(III)* or A
NMe
FF
O
CN
TMP
CNMe
FF
O
CN
-
Photocatalytic C-F bond Functionalization in
Trifluoromethylarenes
Jui group’s work: Photocatalytic defluoroalkylation and
hydrodefluorination of trifluoromethylarenes
Ph
Ph
N O
E1/2 * = -1.70 Vttriplet = 480 ℳs
PC
F F
FR
PC (3 mol%)PhSH (10 mol%) DMSO, 100 ○C blue LEDs
+R1
R2 KO H
O+
F F
R1
R2
R
Unactivated Defluoroalylation
F F
FR
PC (2 mol%)
DMSO, 50 ○C blue LEDs, 24 h
CsO H
OF F
HR
Unactivated Hydrodefluorination
+
F F
FR
PTH (10 mol%)CySH (10 mol%)
5% H2O/DMSO23 ○C, blue LED, 24 h
+R1
R2 NaHO H
O+
F F
R1
R2
R
N
S
Ph PTH
E1/2 * = -2.10 Vtsinglet = 3 ns
R = EWG, eg., -CF3, -CN, -SO2NH2. Limited Scope
SH
= CySH
Activated
Wang, H.; Jui, N. T. J. Am. Chem. Soc. 2018, 140, 163.
Vogt, D. B.; Seath, C. P.; Wang, H.; Jui, N. T. J. Am. Chem.
Soc. 2019, 141, 13203.
-
Photocatalytic C-F bond Functionalization in
Trifluoromethylarenes
Jui group’s work: Photocatalytic defluoroalkylation and
hydrodefluorination of trifluoromethylarenes
P* P
P
hv
CF3
SET
Ar-CF3 Substrate
PhSH
PhS
HAT
MO H
OCO2, M+
SETHAT
Defluoroalkylation
F F
R
H
Direct HAT
F F
H
Hydrodefluorination
F F
F F-
Mesolytic Cleavage
F
F
Difluorobenzylic radical
R
F F
R
Radical anion Alkyl radical
Vogt, D. B.; Seath, C. P.; Wang, H.; Jui, N. T. J. Am. Chem.
Soc. 2019, 141, 13203.
-
SET Mediated Selective Defluoroallylation
Trifluoromethylarenes
Bandar group’s work: Fluoride-Induced direct ArCF3 coupling with
allylsilane
F3C CF3+ SiMe3
1.0 eq 2.0 eq
CsF (10 mol%)18-crown-6 (30 mol%)
TEMPO (1.2 eq)DME, 80 ◦C, N2, 15 h
ON
MeMe
MeMe
23% yield
◆ Traping experiment suggests ArCF3-enabled allyl radical
formation◆ No adduct observed in absence of ArCF3, or if PhCF3
used
Ar
F F
F
Activated1.0 eq
+R
SiMe3
CsF (10 mol%)18-crown-6 (30 mol%)
2.0 ~ 4.0 eqDME, 80 ◦C, N2, 15 h Ar
F F R
monoselective allylation
F F
OMe
F3C
85%
F F
Ph
NC
79%
F F
NSN
54%
F F
N OBn
Me
58%
F F
NMePh
F3C
43%
-
SET Mediated Selective Defluoroallylation
Trifluoromethylarenes
Bandar group’s work: Fluoride-Induced direct ArCF3 coupling with
allylsilane
Ar
F F
F
Activated1.0 eq
+R
SiMe3
CsF (10 mol%)18-crown-6 (30 mol%)
2.0 ~ 4.0 eqDME, 80 ◦C, N2, 15 h Ar
F F R
monoselective allylation
F F
OMe
F3C
85%
F F
Ph
NC
79%
F F
NSN
54%
F F
N OBn
Me
58%
F F
NMePh
F3C
43%
ArCF3 SiMe3Fnn-
Fluoride-induced SET reductions of ArCF3
SET and mesolytic Cleavage
- nF-- TMSF
Ar
F
F+
Ar
F F
Possible intermediates(discrete or formal species)
◆ Reactivity correlates with ArCF3 reduction potential◆ No yield
decrease in strict absence of light
-
Selective C-F bond functionalization in
trifluoromethylarenes
X
F F
FR
X
F F
R
F
X
F
F
F
F
F
X
F
Summary and Outlook
Selective C-F bond functionalization in aromatic fluorides
Photocatalytic reduction
Photocatalytic reduction
Transition-Metal Catalysis
Chem. Rev. 2015, 115, 931Chem. Rev. 2009, 109, 2119
J. Fluorine Chem. 2015, 179, 14
