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

• 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


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.



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.



4 72[a] 2 81

5 63[b] 2 81

6 53[c] 24 25


R

H

R


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




7 28[c] 24 25

8 47[b] 3 25

9 56[b] 1.5 81


R

H

R


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


F


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%)


(45%)

O

OEt

O

OEtF

O

OMe

O

OMe

O

OMeF

F

(8%)

AcO AcO AcO F

F(20%) (20%)




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


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%)


(45%)

O

OEt

O

OEtF

O

OMe

O

OMe

O

OMeF

F

(8%)

AcO AcO AcO F

F(20%) (20%)

F


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


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


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%)



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


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%)


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.


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

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

Documents