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Recent Advances in Radical Mediated Csp 3 –H Bond Fluorination Stoltz/Reisman Literature Meeting Zainab Al Saihati November 17, 2017

Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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Page 1: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

Recent Advances in Radical Mediated Csp3–H Bond Fluorination

Stoltz/Reisman Literature MeetingZainab Al Saihati

November 17, 2017

Page 2: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

• 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

Page 3: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 4: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

• 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

Page 5: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

• 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

Page 6: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 7: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

Recent Advances in Metal-Catalyzed Radical Mediated C–H Fluorination

Page 8: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 9: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 10: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

Manganese Catalyzed Aliphatic C–H Fluorination

Page 11: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 12: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 13: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 14: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 15: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 16: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 17: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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%)

Page 18: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

Decatungstate Anion Catalyzed C–H Fluorination under Photo–irradiation

Page 19: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 20: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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)

+

Page 21: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 22: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 23: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 24: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 25: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 26: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

Transition–Metal Free Oxidative Aliphatic C–H Fluorination

S2O82- SO4

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

Page 27: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 28: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 29: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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%)

Page 30: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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%)

Page 31: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 32: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 33: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

Recent Advances in Non-Metal Catalyzed Radical Mediated C–H Fluorination

Page 34: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 35: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 36: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 37: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 38: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 39: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 40: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 41: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 42: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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

Page 43: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 44: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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.

Page 45: Recent Advances in Radical Mediated Csp3–H Bond Fluorination · 2018-03-23 · Recent Advances in Radical Mediated Csp3–H Bond Fluorination Stoltz/ReismanLiterature Meeting Zainab

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