Radical Carbofluorination of Unactivated Alkenes with Fluoride Ions

Zhonglin Liu, He Chen, Ying Lv, Xinqiang Tan, Haigen Shen, Hai-Zhu Yu, and Chaozhong Li

J. Am. Chem. Soc. 2018, 140, 6169-6175

Nikhil Tasker Wipf Group Current Literature

May 26, 2018

Nikhil Tasker @ Wipf Group Page 1 of 18 6/23/2018

Why fluorine?

• About 1/3 of drugs approved by the FDA contain fluorine

• Reduce basicity of nearby functional groups

• Increase stability and slow down hydrolytic metabolism

• Introducing fluorine on aliphaticsremains a problem

Nikhil Tasker @ Wipf Group 25/26/18

Org. Biomol. Chem., 2016, 14, 8398–8427Chem. Rev., 2014, 114, 2432−2506

O

OH

OHOH

N

F

NH

O

Atorvastatin(Lipitor)

Cholesterol and triglyceride levels

OO S FO

H

H

F

FO

O

O

Fluticasone propionateAnti-inflammatory

OS

N

HN

N

O

F FF

Lanzoprazole(Prevacid)

Gastric acid

O

N

F

NHN

O

OH

Ciprofloxacin(Ciprobay)Antibacterial

OH

HOH H

S O

FF

F F

F

FulvestrantEstrogen receptor antagonist

HO CF2CF3

8 steps

Fluorinated building block

Nikhil Tasker @ Wipf Group Page 2 of 18 6/23/2018

Some current methods

• Nucleophilic fluorination (HF/pyridine, TBAF)• Dual reactivity: base and nucleophile• Deoxyfluorination (DAST, Deoxofluor)

• Requires an alcohol

• Hypervalent halogen-based fluorination (IPy2BF4, p-Tol-IF2)

• Electrophilic fluorination (“F+”)• N-F, O-F, Xe-F, F-F bonds

• Low selectivity, difficult preparation, high toxicity

• Catalytic methods improve selectivity and yields, but usually still implement these reagents

5/26/18 Nikhil Tasker @ Wipf Group 3

Chem. Rev., 2015, 115, 9073−9174Chem. Soc. Rev., 2016, 45, 6270-6288

I FF

Difluoroiodotoluene

CO2Me CO2Me

FF

Or Nu: 55%dr 95:5

N+N+

F

Cl

Selectfluor

2 BF4-

Nu: Nu-F

NSF FF

DAST

R R’

OH

R R’

F

Nikhil Tasker @ Wipf Group Page 3 of 18 6/23/2018

Carbofluorination

5/26/18 Nikhil Tasker @ Wipf Group 4

R2

R1 SelectFluor, AgNO3 (0.2 eq)

H2O/CH2Cl2/AcOH/H3PO450 ºC, 24 h

44-92%

O

OHF

R1 R2

I

X

Pd2(dba)3 (5 mol%)Ligand (20-30 mol%)

AgF (1.5 eq)n

R RX

CH2F

n

NTs

R

OTBSBF3

.OEt2 (2.0 eq)

CH2Cl2 (2.5 mM)rt, 10 min40-83%

NTs

FR

X

HN NH2

OAcSelectFluor

MeCN/H2Ort, 3 h

25-57%

R

X

R

OAc

FOrg.Chem.Front.,2017,4,565–568Chem.Sci.,2013,4,1216–1220J.Org.Chem.,2013,78,5521−5529Chem.Eur.J.,2014,20,15344– 15348

Nikhil Tasker @ Wipf Group Page 4 of 18 6/23/2018

Title Paper

• Fluorotrichloromethylation

• Carbofluorination with alkyl chlorides• Inter/intramolecular

• Fluorotrifluoromethylation

• Mechanistic studies studies

5/26/18 Nikhil Tasker @ Wipf Group 5

R1

R2

CCl4 (2.0 eq)[Cu(L3)F2].H2O (1.2 eq)

[Ag] (2.0 eq)

MeCN, N2, 80 ºC, 12 h

FR2

Cl3CR1

O

O

CN

CsF (2.0 eq), [CF3] (1.7 eq)Cu(OTf)2 (30 mol %)

L3 (40 mol %), BC (20 mol %)hv (11 W)

MeCN, 80 ºC, 6 h

O

O

CNF3CF

BF4-

CF3

S

[CF3]

NN

Ph Ph

BC

R-Cl (2.0 eq)[Cu(L3)F2].H2O (1.2 eq)

[Ag] (2.0 eq)

MeCN, N2, 80 ºC, 12 h

FR

O

O

ArO

O

Ar

Nikhil Tasker @ Wipf Group Page 5 of 18 6/23/2018

Chlorine vs. Fluorine Atom Transfer

• CAT is a faster process than FAT

5/26/18 Nikhil Tasker @ Wipf Group 6

R

CCl4

Cu(I)F

+

+

Cl3C R

Cu(II)F Cl

+

Cl3C R

Cl

Cl3C R

F

Cu(II)F

Cu(II)Cl+

+

CAT

FAT

Nikhil Tasker @ Wipf Group Page 6 of 18 6/23/2018

Fluorotrichloromethylation Optimization

Nikhil Tasker @ Wipf Group 75/26/18

N N

R R

L1 (R = H)L2 (R = OMe)L3 (R = CO2Me)

N NAg

MeCN BF4-

[Ag]

yield (%) entry reagents (equiv) CAT FAT

1 Cu(OTf)2 (0.3), L1 (0.3), CsF (2.0) <5 02 CuF2 (0.7), L1 (0.7) 5 03 Cu(OTf)2 (0.7), L1 (0.7), AgF (2.0) 7 14 Cu(OTf)2 (0.7), L1 (2.7), AgF (2.0) 4 205 Cu(OTf)2 (0.7), L1 (0.7), CsF (2.0), [Ag] 27 526 Cu(OTf)2 (0.7), L2 (0.7), CsF (2.0), [Ag] 15 87 Cu(OTf)2 (0.7), L3 (0.7), CsF (2.0), [Ag] 24 638 Cu(OTf)2 (1.0), L3 (1.0), CsF (2.0), [Ag] 30 579 [Cu(L3)F2].H2O (1.0), [Ag] (2.0) 10 7110 [Cu(L3)F2].H2O (1.2), [Ag] (2.0) <5 7711 [Cu(L3)F2].H2O (1.0) 55 012 [Cu(L3)F2].H2O (1.2), AgBF4 (2.0) 7 1413 [Ag] (2.0) 0 0

ORconditions

CCl4 (2.0 eq)

MeCN, N280 ºC, 12 h

R = (p-CN-C6H4CO)

ORCl3C

Cl ORCl3C

F+

CAT FAT

Nikhil Tasker @ Wipf Group Page 7 of 18 6/23/2018

Fluorotrichloromethylation Scope

5/26/18 Nikhil Tasker @ Wipf Group 8

R1

R2

CCl4 (2.0 eq)[Cu(L3)F2].H2O (1.2 eq)

[Ag] (2.0 eq)

MeCN, N2, 80 ºC, 12 h

FR2

Cl3CR1

Cl3C O R

OF

R = p-CN-C6H4, 77%R = o-CO2Me-C6H4, 80%R = furan-2-yl, 71%

Cl3CHN

F

O

Br

73%

Cl3C NHTsF

65%

Cl3CF

Ph

iPr

58%

Cl3CF

OH

46%

Cl3C F Cl

Cl

81%

Cl3C O

OFPh

O66%

Ph

F

Cl3C

73%, dr 95:5

Cl3C

F

50%

N Ac

FCl3C

66%

Cl3CF

NPhth

11%

N N

MeO2C CO2Me

L3

N N

R R

L1 (R = H)L2 (R = OMe)L3 (R = CO2Me)

N NAg

MeCN BF4-

[Ag]

• Negligible CAT for 1,1’-disubstituted alkenes

• CAT predominated for monosubstituted

Nikhil Tasker @ Wipf Group Page 8 of 18 6/23/2018

Carbofluorination with Alkyl Chlorides

5/26/18 Nikhil Tasker @ Wipf Group 9

R-Cl (2.0 eq)[Cu(L3)F2].H2O (1.2 eq)

[Ag] (2.0 eq)

MeCN, N2, 80 ºC, 12 h

FR

O

O

ArO

O

Ar

F

O

O

Ar

Cl

F3C

Cl F

O

O

Ar

Cl Cl

O

H2N

F

O

O

Ar

MeO2C

MeO2C

Cl F

O

O

Ar

EtO2C

EtO2C

71% 36%

60% 56%

N N

MeO2C CO2Me

L3

N N

R R

L1 (R = H)L2 (R = OMe)L3 (R = CO2Me)

N NAg

MeCN BF4-

[Ag]

• These substrates are inaccessible by other carbofluorination methods

Nikhil Tasker @ Wipf Group Page 9 of 18 6/23/2018

Intramolecular Carbofluorination

O

CCl3

NtBu

[Cu(L3)F2].H2O (1.2 eq)[Ag] (2.0 eq)

MeCN, N2, 80 ºC, 12 h NOtBu

F

ClCl

O

CCl3

NtBu

NOtBu

ClCl

F

O

CCl3

NtBu

NOtBu

ClCl F

73%5-exo

75%6-exo

24%7-endo

conditions

conditions

5/26/18 Nikhil Tasker @ Wipf Group 10

N N

MeO2C CO2Me

L3

N N

R R

L1 (R = H)L2 (R = OMe)L3 (R = CO2Me)

N NAg

MeCN BF4-

[Ag]

Nikhil Tasker @ Wipf Group Page 10 of 18 6/23/2018

Why fluorotrichloromethylation?

• Although the authors mention no specific reason…

• Some natural products contain trichloromethyl groups

• Pharmaceuticals (uncommon)

• Proof of concept

• Show it can work for alkyl chlorides (which is more useful)

5/26/18 Nikhil Tasker @ Wipf Group 11

N

O

O

CCl3N S

Barbamide

N

O O

O O

CCl3

Dysidin

O

HN

N S

NO

CCl3 CCl3

Dysidenin

Chem.AsianJ.,2011,6,2260– 2263

Nikhil Tasker @ Wipf Group Page 11 of 18 6/23/2018

Improvements?

• Stoichiometric copper

• Tri/dichloro substituents are uncommon• CF3 groups are more common

• Pursued fluorotrifluoromethylation

5/26/18 Nikhil Tasker @ Wipf Group 12

XeF2

CF3COOH/CH2Cl2PhPh

PhOF3C

Ph

CF3

O

Ph F

F F

F Ph

Ph

F3CPh

F

Ph

FPh

OO

CF3

PhCF3

J.Org.Chem.,1979,44,4120-4122Adv.Synth.Catal.,2015,357,2039– 2044

R1

R2

R3

TMSCF3 (3.0 eq)SelectFluor (3.0 eq)

AgOTf (2.0 eq)CsF (2.0 eq)

PhI(OAc)2 (1.0 eq)

DMF, -20 ºC R1R2

R3

FCF3

Nikhil Tasker @ Wipf Group Page 12 of 18 6/23/2018

Fluorotrifluoromethylation

entry variation yield (%)1 none 812 dark (no hv) 313 L3 in place of BC 284 BC in place of L3 455 without BC 216 without L3 377 without visible light and BC 08 without visible light and L3 109 without Cu(OTf)2 0

5/26/18 Nikhil Tasker @ Wipf Group 13

O

O

CN

CsF (2.0 eq), [CF3] (1.7 eq)Cu(OTf)2 (30 mol %)

L3 (40 mol %), BC (20 mol %)hv (11 W)

MeCN, 80 ºC, 6 h

O

O

CNF3CF

BF4-

CF3

SNN

Ph Ph

BC[CF3]Umemoto’s reagent

N N

MeO2C CO2Me

L3

Nikhil Tasker @ Wipf Group Page 13 of 18 6/23/2018

Fluorotrifluoromethylation Scope

R2

R1CsF, [CF3]

Cu(OTf)2, L3/BC

MeCN, 80 ºC, 6 hvisible light

F3C F

R2R1

5/26/18 Nikhil Tasker @ Wipf Group 14

F3CF

NBoc

Ts

84%

F3CF

Cl

Cl

82%

F3CF

O

O

O

Ph

73%

F3CF iPr

Ph

76%

F3CF

NPhth

60%cis/trans 50:50

F3CF

O

O

Ph

18%

O

O

CN

CsF (2.0 eq), [CF3] (1.7 eq)Cu(OTf)2 (30 mol %)

L3 (40 mol %), BC (20 mol %)hv (11 W)

MeCN, 80 ºC, 6 h

O

O

CNF3CF

BF4-

CF3

S

[CF3]

NN

Ph Ph

BC

N N

MeO2C CO2Me

L3

O

O

CN

CsF (2.0 eq), [CF3] (1.7 eq)Cu(OTf)2 (30 mol %)

L3 (40 mol %), BC (20 mol %)hv (11 W)

MeCN, 80 ºC, 6 h

O

O

CNF3CF

BF4-

CF3

S

[CF3]

NN

Ph Ph

BC

Nikhil Tasker @ Wipf Group Page 14 of 18 6/23/2018

Proposed Mechanism

5/26/18 Nikhil Tasker @ Wipf Group 15

NTs

CsF, [CF3]Cu(OTf)2, L3/BC

MeCN, 80 ºC, 10 h,visible light

NTs

F3CF

42%

HOC7H15HOC7H15

CF3

F

C7H15

F3COCsF, [CF3]

Cu(OTf)2, L3/BC

MeCN, 80 ºC, 10 h,visible light

67% 0%

N N

MeO2C CO2Me

L3

O

O

CN

CsF (2.0 eq), [CF3] (1.7 eq)Cu(OTf)2 (30 mol %)

L3 (40 mol %), BC (20 mol %)hv (11 W)

MeCN, 80 ºC, 6 h

O

O

CNF3CF

BF4-

CF3

S

[CF3]

NN

Ph Ph

BC

O

O

CN

CsF (2.0 eq), [CF3] (1.7 eq)Cu(OTf)2 (30 mol %)

L3 (40 mol %), BC (20 mol %)hv (11 W)

MeCN, 80 ºC, 6 h

O

O

CNF3CF

BF4-

CF3

S

[CF3]

NN

Ph Ph

BC

Nikhil Tasker @ Wipf Group Page 15 of 18 6/23/2018

Isolated Catalyst

5/26/18 Nikhil Tasker @ Wipf Group 16

N N

OO

OO

CuFF

N N

OO

OO

CuFF

N N

OO

OO

Cu

F

F

• Computational studies suggest perpendicular approach to plane of dimer results in insensitivity to steric factors

Nikhil Tasker @ Wipf Group Page 16 of 18 6/23/2018

UV/Vis Studies

• G – Cu(OTf)2, CsF

• C – Cu(OTf)2, CsF, L3, BC

• F – Cu(OTf)2, CsF, BC

• H – [Cu(L3)F2]·H2O

• J – BC

• Conclusion: BC helps to excite electron to initiate reaction. L3 increases rate of FAT.

5/26/18 Nikhil Tasker @ Wipf Group 17

O

O

CN

CsF (2.0 eq), [CF3] (1.7 eq)Cu(OTf)2 (30 mol %)

L3 (40 mol %), BC (20 mol %)hv (11 W)

MeCN, 80 ºC, 6 h

O

O

CNF3CF

BF4-

CF3

SNN

Ph Ph

BC[CF3]Umemoto’s reagent

N N

MeO2C CO2Me

L3

Nikhil Tasker @ Wipf Group Page 17 of 18 6/23/2018

Summary

• Mild and practical

• Broad scope and functional group tolerant

• Moderate to good yields

• L3, [Ag], Umemoto’s reagent = $$$

• Not stereoselective – substrate control

• Racemic mixtures (mostly) and best suited for achiral substrates/products

• Tri-substituted alkenes?

5/26/18 Nikhil Tasker @ Wipf Group 18

R1

R2

CCl4 (2.0 eq)[Cu(L3)F2].H2O (1.2 eq)

[Ag] (2.0 eq)

MeCN, N2, 80 ºC, 12 h

FR2

Cl3CR1

O

O

CN

CsF (2.0 eq), [CF3] (1.7 eq)Cu(OTf)2 (30 mol %)

L3 (40 mol %), BC (20 mol %)hv (11 W)

MeCN, 80 ºC, 6 h

O

O

CNF3CF

BF4-

CF3

S

[CF3]

NN

Ph Ph

BC

R-Cl (2.0 eq)[Cu(L3)F2].H2O (1.2 eq)

[Ag] (2.0 eq)

MeCN, N2, 80 ºC, 12 h

FR

O

O

ArO

O

Ar

Nikhil Tasker @ Wipf Group Page 18 of 18 6/23/2018