Post on 04-Aug-2020
Recent Advances in Radical Mediated Csp3–H Bond Fluorination
Stoltz/Reisman Literature MeetingZainab Al Saihati
November 17, 2017
• Properties & Importance of Fluorine Containing Compounds
• C–H Activation and Fluorination Challenges
• Overview of Organic Compounds Fluorination
• Recent Advances of Radical Mediated C–H Fluorination– Metal-Catalyzed C–H Fluorination– Metal-Free Catalyzed C–H Fluorination
Outline
Properties & Importance of Fluorine Containing Compounds
O NH
CF3!HCl N
O
OH
OF
NNH!HCl
Prozac Ciprobay
Diederich, Science, 2007, 317, 1881. Meanwell, J. Med. Chem., 2015, 58, 8315–8359.
O
F
F
NH2
N
NHN
DPP-4 inhibition activity
F
OH
NF
NH
NH
F
NH
O
F
↑ potency
↓ pKa
↑ permeability
↓ clearance
conformational constraint
pharmacokinetic properties
• Alkanes are relatively inert • C–H alkanes have high BDE ~ 90 – 100 kcal/mol.
Perutz, Chem Rev 1996, 96, 3125––3146.Rayner, JACS 1990, 112, 2530–2536.
Zhen, JACS 2000, 122, 6783–6784.Jones, JACS 2001, 123, 7257–7270.
Luo Y–R. Handbook of Bond Dissociation Energies in Organic Compounds. CRC Press, Boca Raton.
Challenges of C–H Alkanes Activation
• C–F bond formation is a challenging:– due to fluorine’s high electronegativity– the high hydration energy of fluoride anion
• In nature, haloperoxidase enzymes give rise to thousands of organochlorides and organobromides, but no fluoroperoxidase enzyme has been identified.
• Other Challenges Include:– Lack of solubility of alkali metal fluorides in organic solvents– Dearth of metal catalysts for selective C–F coupling reactions– Slow rate of most fluorination methods
Challenges of C–H Fluorination
OHHO
ClCl
NH
O
Br
HN
O
Br
Overview of Modern Organic Compounds Fluorination
NucleophilicFluorination
ElectrophilicFluorination
RadicalFluorination
Formation of a Single C–F
Bond
RX
R1 R2
X
RF
R1 R2
F
Source of F-
R
R1 R2
R3
RF
Source of F+ R1 R2
R3F
R
R1 R2
R3
RF
Source of F R1 R2
R3F
Recent Advances in Metal-Catalyzed Radical Mediated C–H Fluorination
Manganese Catalyzed Aliphatic C–H Fluorination
N
N N
NMn
F
F
IV
Mn(TMP)Cl (6 - 8 mol%) AgF (3 equiv) TBAF (0.3 equiv)
PhIO (6-8 euqiv)MeCN/CH2Cl2, 6 - 8h
HR R F
Groves, Science 2012, 337, 1322–1325.
simple alkankes, amides, ester, teriary alkohol,
terpenoids, ketones,sterioids
Manganese Catalyzed Aliphatic C–H Fluorination
H OAc
Mn(TMP)Cl (8mol%) AgF (3 equiv) TBAF (0.3 equiv)
PhlO (8 equiv) F OAc
PhIPhIO
MnVO
FRH
R
MnIVOH
F
AgF
AgOH
N
N N
NMn
F
F
IV
MnIII
F
R
R F
Groves, Science 2012, 337, 1322–1325.
Manganese Catalyzed Aliphatic C–H Fluorination
Manganese Catalyzed Aliphatic C–H Fluorination
H OAc
Mn(TMP)Cl (8mol%) AgF (3 equiv) TBAF (0.3 equiv)
PhlO (8 equiv) F OAc
PhIPhIO
MnVO
FRH
R
MnIVOH
F
AgF
AgOH
N
N N
NMn
F
F
IV
MnIII
F
R
R F
Groves, Science 2012, 337, 1322–1325.
Copper Promoted C–H Bond Fluorination via Radical Chain Propagation
Entry Substrate Product Yield [%] t [h] T [°C]
1 75[c] 3 25
2 40[c] 3 0
3 66[b] 1 81
[a] 10 mol% KI. [b] 1.2 equiv KI. [c] No KI.
F
F
F
R
H
R
catalys 2: KB(C6F5)4 (10 mol%)Selectfluor (2.2 equiv)
NHPI (10 mol%)MeCN
R
F
R
N N
Ph PhCu
catalyst 1:
I
N
N
Cl
F2BF4-
Selectfluor
N
O
O
OH
NHPI
Lectka, ACIE 2012, 51, 10580––10583.Lectka, JACS 2014, 136, 9780–9791.
Copper Promoted C–H Bond Fluorination via Radical Chain Propagation
Entry Substrate Product Yield [%] t [h] T [°C]
4 72[a] 2 81
5 63[b] 2 81
6 53[c] 24 25
[a] 10 mol% KI. [b] 1.2 equiv KI. [c] No KI.
R
H
R
catalys 2: KB(C6F5)4 (10 mol%)Selectfluor (2.2 equiv)
NHPI (10 mol%)MeCN
R
F
R
N N
Ph PhCu
catalyst 1:
I
N
N
Cl
F2BF4-
Selectfluor
N
O
O
OH
NHPI
F
9 9F
F
Lectka, ACIE 2012, 51, 10580––10583.Lectka, JACS 2014, 136, 9780–9791.
Copper Promoted C–H Bond Fluorination via Radical Chain Propagation
Entry Substrate Product Yield [%] t [h] T [°C]
7 28[c] 24 25
8 47[b] 3 25
9 56[b] 1.5 81
[a] 10 mol% KI. [b] 1.2 equiv KI. [c] No KI.
R
H
R
catalys 2: KB(C6F5)4 (10 mol%)Selectfluor (2.2 equiv)
NHPI (10 mol%)MeCN
R
F
R
N N
Ph PhCu
catalyst 1:
I
N
N
Cl
F2BF4-
Selectfluor
N
O
O
OH
NHPI
O O
F
O O
OAc4
OAc4F
Lectka, ACIE 2012, 51, 10580––10583.Lectka, JACS 2014, 136, 9780–9791.
F
Copper Promoted C–H Bond Fluorination via Radical Chain Propagation
R
H
R N
N
Cl
H
2BF4-
R R
N
N
Cl
F
2BF4-R R
F
N
N
Cl
2BF4-
LnCuI LnCuIIF
N
N
Cl
F2BF4-
Lectka, ACIE 2012, 51, 10580–10583.Lectka, JACS 2014, 136, 9780–9791.
Iron Catalyzed Benzylic C–H Fluorination
Fe(acac)2 (0.1 equiv)Selectfluor (2.2 equiv)
N NCl
F
2BF4-
Selectfluor
F F
(44%) (48%) (40%)
MeCN, rt, 24 h
Lectka, J. Org. Chem. 2013, 78, 11082–11086.
OH
F
Br
ArR
ArR
FO O
2
Fe2+
Fe(acac)2
CNO O
OEt
F
(75%, 4:1)
O
OMePh
F
(51%)
O
N O
O
(40%)
F
Cl
O
OEt
Premilinary Evidence of Radical Involved Fluorination
FeII
Flourination conditions F + fluorinated isomers
Decatungstate Anion Catalyzed C–H Fluorination under Photo–irradiation
h! ("=365 nm), NFSI (1.5 equiv)NaHCO3 (0.1 equiv), TBADT (0.02 equiv)
TBADT = Tetra-n-butylammonium decatungstate, C64H144N4O32W10
NSFI
(14%)
MeCN, 16 h
Britton, ACIE 2014, 53, 4690–4693.
R1 R2
H
R1 R2
FS NO
OS
F O
O
Substrate Major Product(s)
O O O
F F
(17%, β:α = 2:1) (14%)
O
O
O
O
OAc OAc OAc
(13%) (15%, β:α = 2.4:1)
F
(34%)
Substrate Major Product(s)
(45%)
O
OEt
O
OEtF
O
OMe
O
OMe
O
OMeF
F
(8%)
AcO AcO AcO F
F(20%) (20%)
Decatungstate Anion Catalyzed C–H Fluorination under Photo–irradiation
Decatungstate Anion Catalyzed C–H Fluorination under Photo–irradiation
h! ("=365 nm), NFSI (1.5 equiv)NaHCO3 (0.1 equiv), TBADT (0.02 equiv)
TBADT = Tetra-n-butylammonium decatungstate, C64H144N4O32W10
NSFI
(14%)
MeCN, 16 h
Britton, ACIE 2014, 53, 4690–4693.
R1 R2
H
R1 R2
FS NO
OS
F O
O
Substrate Major Product(s)
O O O
F F
(17%, β:α = 2:1) (14%)
O
O
O
O
OAc OAc OAc
(13%) (15%, β:α = 2.4:1)
F
(34%)
Substrate Major Product(s)
(45%)
O
OEt
O
OEtF
O
OMe
O
OMe
O
OMeF
F
(8%)
AcO AcO AcO F
F(20%) (20%)
F
Decatungstate Anion Catalyzed C–H Fluorination under Photo–irradiation
Britton, ACIE 2014, 53, 4690–4693.
Fluorination of Natural Product Sclareolide
Reaction Conditions:NSFI (1.5 Equiv)
TBADT (0.02 equiv)h! ("=365 nm)
NH3Cl
O
OMe
O
H
H
reaction conditionsNaHCO3, MeCN
O
H
HO
H
HF
F
(58%, α:β = 4:1) (10%)
+
Fluorination of Amino Acid Derrivatives
reaction conditionsMeCN/H2O
NH3Cl
O
OMeNH3Cl
O
OMeF
F
(40%, α:β = 1:1) (19%, α:β = 1:1)
+
Decatungstate Anion Catalyzed C–H Fluorination under Photo–irradiation Proposed Mechanism
W10O324-
W*
R1 R2
(PhSO2)2N W10O325-H+
(PhSO2)2N H h!
R1 R2
H
R1 R2
F
(PhSO2)2N F
h! ("=365 nm), NFSI (1.5 equiv)NaHCO3 (0.1 equiv), TBADT (0.02 equiv)
MeCN, 16 hR1 R2
H
R1 R2
F
Britton, ACIE 2014, 53, 4690–4693.
Silver–Catalyzed Oxidative Benzylic C–H Bonds Difluorination of Arenes
AgNO3 (10 - 20 mol%) Na2S2O8 (0.5 - 5.0 equiv)
Selectfluor (3.0 - 5.0 equiv)N N
ClF
2BF4-
Selectfluor
H
(85% NMR yield, 5H h) (42%, 3 h) (65% NMR yield, 5 h) (68% NMR yield, 5 h)
(74%, 3 h)
R1
HH
R1
FF
MeCN/H2O, 60 - 80 °C
Tang, ACIE 2014, 53, 5955–5958.
NH2
(84%, 3 h)
t-Bu(53%, 3 h)
(75% NMR yield, 5 h)
F
F
t-Bu
R
F F FF
F F
FF
F F
F
F
F
(93%, 3 h)
Ph
H
FF
R
O
O
Ph
OH2N
CO2H
HFF
Cl(88%, 3 h)
CO2H F
HF
Br(88%, 3 h)
CO2Me F
HF
(82%, 3 h)
F
HF
N
Silver–Catalyzed Benzylic C–H Bonds Difluorination of Arenes Proposed Mechanism
AgNO3, Na2S2O8 SelectfluorR1
HH
R1
FF
MeCN/H2O, 60 - 80 °CR R
AgI + S2O82- AgI + SO4
2- + SO4-
AgI + AgII + SO42-SO4
-
R
HH
AgIAgII
R
H
N F N
R
FH
R
FH
R
F
R
FF
AgI + AgII +N NH
Tang, ACIE 2014, 53, 5955–5958.
Transition–Metal Free Oxidative Aliphatic C–H Fluorination
K2S2O8 (1.0 - 2.0 equiv)Selectfluor II (2.5 equiv)
N NCH3
F
2PF6-
Selectfluor II
O
(98%) (46% NMR Yield) (78%)
(65% NMR yield)
MeCN/H2O, 50 °C
Tang, Org Chem Front 2015, 2, 806–810.
(68%)
R H R F
OF
O
O F
3 O
O
t-Bu
F
NC
O
OF
X
(X = Cl, 67%)(X = Br, 91%)
OMe
OF
OF
NPhth
F
(71%)
Br
F FNO2
(71% NMR yield) (63%) (61%)
OMe
OF
Transition–Metal Free Oxidative Aliphatic C–H Fluorination
Late Stage Fluorination of Complex Molecules
Reaction Conditions:K2S2O8 (1.0 - 4.0 equiv)Selectfluor II (2.5 equiv)
O
H
H
reaction conditions
O
H
HF
(69%)
H
MeCN/H2O, 50 °C
OOH
AcO H H
OAc
O OMe
OOH
AcO H F
OAc
O OMe
reaction conditionsMeCN/H2O, 50 °C
(42%)
Tang, Org Chem Front 2015, 2, 806–810.
Transition–Metal Free Oxidative Aliphatic C–H Fluorination
S2O82- SO4
-Δ
R R1
HR2
R R1
R2
R R1
FR2
SO4- HSO4
-N F N
Proposed Mechanism
Kinetic Deuterium Isotope Effect
K2S2O8 Selectfluor II
MeCN/H2O, 50 °C+
D12
+
D11
F
F
Tang, Org Chem Front 2015, 2, 806–810.
KIE = 1.8
Vanadium–Catalyzed Fluorination of C–H Bonds
V2O3 (2- 10 mol%)Selectfluor (0.2 - 1.5 equiv)
N NCl
F
2BF4-
Selectfluor
(74%, 20 h) (47%, 48 h)
(47% NMR yield)
MeCN, 23 °C
Chen, Org Chem Front 2014, 1, 468–472.
R H R F
Cl
(35%, 24 h)
O
(61%, 48 h, α:β= 9:1)
OH
F
COOH
Ft-Bu
F
F
(70%, 20 h)
F
(12% NMR yield)
OPh
OF
(85% NMR yield)
OMe
OF
(53%, 24 h)
OF
O
O
F
KIE Study of Vanadium–Catalyzed Fluorination of Aliphatic C–H Bonds
Kinetic Deuterium Isotope Effect
MeCN, 23 °C, 3 h+
D12
+
D11
F
F
V2O3 (10 mol%)Selectfluor (1.0 equiv) 4
:1
kH/kD = 4
Chen, Org Chem Front 2014, 1, 468–472.
Uranyl Nitrate Catalyzed C–H Fluorination Under Visible Light Irradiation
h!1 mol% UO2(NO3)2•H2O
1.5 NSFI
(>95%) (42%)
(trace)
(32%)
MeCN, 23 °C, 16 h
Sorensen, ACIE 2016, 55, 8923–8927.
(55%, mixed fluorinated isomers at non-terminal positions)
R H R FNSFI S N
O
OS
F O
O
F FF
F O
n= 3-5
F
O
F
(26%, C2:C3 = 1.6:1)
F F
NC
(trace) (trace)
O O O
O
O
(0%)
Silver Catalyzed Fluorination of C–H Bonds Using Unprotected Amino Acids
AgNO3 (20 mol%)Selectfluor (2.0 - 5.0 equiv) N N
ClF
2BF4-
SelectfluorMeCN/H2O, 35 °C 24 hAr R
H
Ar R
F
(41%)
i-Pr
F
F
F
(38%)
F
Baxter, Org Lett 2017, 19, 2949–2952.
+H2N OH
O
Ph
F
F
Ph Ph
FF
Ph
F FF
OAc
OF
BPin N
N
F
N
CO2Me
Br
MeO
O F
(76%)
(2.0 - 5.0 euqiv)
(64%)
(89%, NMR yield) trace (75%) (30%)
(45%) (46%) (22%) (62%)
Silver Catalyzed Fluorination of C–H Bonds Using Unprotected Amino Acids
Two Mechanistic Scenarios for Ag(I) Oxidation
Ag(I) + N NCl
F Ag(III) F N NCl
+
Ag(I) + N NCl
F Ag(II) F N NCl
++
Mechanistic Studies
Baxter, Org Lett 2017, 19, 2949–2952.
Silver Catalyzed Fluorination of C–H Bonds Using Unprotected Amino Acids
AgNO3 (20 mol%)Selectfluor (2.0 - 5.0 equiv) N N
ClF
2BF4-
SelectfluorMeCN/H2O, 35 °C 24 hAr R
H
Ar R
F
(41%)
i-Pr
F
F
F
(38%)
F
Baxter, Org Lett 2017, 19, 2949–2952.
+H2N OH
O
Ph
F
F
Ph Ph
FF
Ph
F FF
OAc
OF
BPin N
N
F
N
CO2Me
Br
MeO
O F
(76%)
(2.0 - 5.0 euqiv)
(64%)
(89%, NMR yield) trace (75%) (30%)
(45%) (46%) (22%) (62%)
Ag(II)Glyn
Ag(I)Glyn
N NCl
F
F N NCl
+ CO2HH2NGly
H2NAr H
SelectfluorH2N H + Ar F
Baxter, Org Lett 2017, 19, 2949–2952.
Recent Advances in Non-Metal Catalyzed Radical Mediated C–H Fluorination
Metal–Free C–H Fluorination Using N–Oxyl Radical
R
H
R MeCN (0.1 M), 50 °C R
F
R
cat: NDHPI (2.5 mol%)Selectfluor (2 equiv)
N NCl
F
2BF4-
Selectfluor
NN OH
O
OO
O
HO
NDHPI
F
BzO OBz
F
F
BzO
F
7
F
CO2Me
F NPhth
F
NHAc
OOH
F
MeOC
F
PhthN
F
(58%, 5 h) (48%, 8h) (45%, 5 h) (39%, 5 h)
(28%, 4 h) (61%, 4 h) (46%, 5 h)
(54%, dr = 3:2, 5 h) (86%, 4 h) (28%, 10 h)
Inoue, Org Lett. 2013, 15, 2160–2163.
Metal–Free C–H Fluorination Using N–Oxyl Radical
R
H
R
N
N
Cl
H 2BF4-
R R
N
N
Cl
F
2BF4-R R
F
N
N
Cl
2BF4-
R2N O
R2N OH
R2N OH
R
H
R MeCN (0.1 M), 50 °C R
F
R
cat: NDHPI (2.5 mol%)Selectfluor (2 equiv)
N NCl
F
2BF4-
Selectfluor
NN OH
O
OO
O
HO
NDHPI
Inoue, Org Lett. 2013, 15, 2160–2163.
Photocatalyzed Metal–Free Benzylic C–H Fluorination
CH3
HH
9-fluorenone
xanthone
N NCl
F
2BF4-
N NCH3
F
2BF4-
CH3
FH
CH3
FF
85%
83%
Chen, JACS 2013, 135, 17494–17500.
Photocatalyzed Metal–Free Benzylic C–H Monofluorination
visible light5 mol% 9-fluorenone2.0 equiv Selectfluor
N NCl
F
2BF4-
Selectfluor 9-fluorenone
F F
(85%, 6 h) (63%, 24 h) (49%, 48 h) (47%, 24 h)
(93%, 6 h) (81%, 72 h)
(36%, 24 h) (72%, 24 h)
R
HH/R`
O
R
FH/R`
MeCN, 27 °C
Chen, JACS 2013, 135, 17494–17500.
Cl
F
AcO
FBr
F
OCH3
F O
(52%, dr = 1:1, 84 h)
NPhth
F
OH
O
F
F
F
Cl
F FCl
(71%, 24 h) (46%, 48 h)
Cl
(65%, 96 h)
F
NC
X X
Photocatalyzed Metal–Free Bencylic C–H gem–Difluorination
visible light5 mol% xanthone
3.0 equiv Selectfluor IIN N
CH3
F
2BF4-
Selectfluor II xanthone
(85% NMR yield, 24 h) (64%, 24 h) (74% NMR yield, 24 h) (33%, 24 h)
(93%, 20 h)5 mol% 9-fluorenone
3.0 Selectfluor (54%, 24 h)
(51%, 24 h)
R
HH
R
FF
MeCN, 27 °C
Chen, JACS 2013, 135, 17494–17500.
Clt-Bu
F
(40%, 24 h)
O
F
(>95% NMR yield, 24 h)
(72%, 16 h)
F
F
t-Bu
X O
O
FF
F F FF
FF F OH
FF
F F
F
F
F
FF
(91%, 20 h)5 mol% 9-fluorenone 3.0 Selectfluor
FF
X
Photocatalyzed Metal–Free Benzylic C–H Fluorination Proposed Mechanism
Chen, JACS 2013, 135, 17494–17500.
O
C C F
OH
N RR
RF
N RR
R
O
C H
N RR
RH
visible lightmetal-free catalysisis
fluorine donorAr R
HH
Ar R
FF
MeCN, 27 °Cor
Ar R
FH
Photocatalyzed Metal–Free Aliphatic C–H Fluorinationh! (CFL)
5 mol% - 20 mol% acetophenone1.0 - 1.5 equiv Selectfluor
N NCl
F
2BF4-
Selectfluor Acetophenone
(85% NMR yield, 6 h) (73%, 15 h)
(81%, 15 h) (< 5% NMR yield, 40 h)
(93%, 6 h)
(73%, 20 h)
MeCN, 27 °C
Chen, Chem Commun 2014, 50, 11701–11704.
OCH3
O
(85%, 48 h)NPhth
(71%, 30 h) (58% NMR yield, 24 h)
O
R H R F
F F
OH
OF F
OH
O
F
F
F
O
F
FF
O
Triethylborane–Initiated Radical C–H Fluorination Proposed Mechanism
Initiation
EtN
N
Cl
F
2BF4-
+ EtN
N
Cl 2BF4-
+F
Propagation
HN
N
Cl 2BF4-
+
HN
N
Cl 2BF4-
+
5 5
N
N
Cl 2BF4-
+
N
N
Cl 2BF4-
+
5 5
FF
F F
F F
OH
O
F
(47%) (50%)
(42%) (37%)
(47%)
(28%)
O
F
Ph
Lectka, J. Org. Chem. 2014, 79, 8895–8899.
Selectfluor (2.2 equiv)BEt3 (20 mol%)
MeCN, rt, 4 hR1 R2
H
R1 R2
F
Tetracyanibenzene Catalyzed Fluorination of Aliphatic C–H Bonds
h! = 302 nmTCB (0.1 equiv)
Selectfluor (2.2 equiv)
N NCl
F
2BF4-
Selectfluor
(58%) (46%, C5)
(62% NMR yield)
MeCN, 16 h
Lecktka, Chem Sci 2014, 5, 1175–1178.
(59% NMR yield2:2:1:1:,C2:C3:C4:C5)
(41% 2α : 10% 2α)
F
F
NPhth
(61%)
(73%, 1:1) (57%)
(54% NMR yield, 1:3)
F
O
O
CN
CNNC
NC
TCBR1 R2
H
R1 R2
F
F
O
O
5F
F
H
O
O
F
F 6
F
N
O
CF3
F
N
O
CF3
F
Hypothesized Mechanism of Tetracyanibenzene Catalyzed Fluorination of Aliphatic C–H Bonds
R1 R2
W10O325-H+
R1 R2
F
h!, TCB, Selectfluor
MeCN,R1 R2
H
R1 R2
F
CN
CNNC
NC
h!
TCB *R1 R2
H
R1 R2
H
TCB
Solv
Solv HN F
N
Solv HTCB
N H
Lecktka, Chem Sci 2014, 5, 1175–1178.
Tetracyanibenzene Catalyzed Fluorination of Benzylic C–H Bonds
h! = 302 nmTCB (10 mol%)
Selectfluor (2.2 equiv)
N NCl
F
2BF4-
SelectfluorMeCN, 24 h TCBAr R
H
Ar R
F
CN
CNNC
NC
(37% NMR yield) (62%)
OMe
(52%) (36%)
F
Br
FO
(47%)
F
NC(28%)
F
FF
NPhth
(65% NMR yield)
OH
OF
Ph
OF
CN
(58%)
NC(28%)
FSO2Ph
Lectka, Org Lett 2014, 216, 6339–6341.
Summary
• Presented the different systems and associated mechanisms of C–HFluorination
• Monofluorination vs. Difluorination• Compatibility with various functional groups:
– Aldehydes– Esters– Tertiary alcohols – Halogens– Amines– Carboxylic acids