cis-Specific Hydrofluorination of Alkenylarenes under Palladium Catalysis by an Ionic Pathway

Dr. Enrico Emer

Professor V. Gouverneur Group Chemistry Research Laboratory – University of Oxford

1Oxford, Friday 31st 2014

2

Organofluorine Compounds: Applications

The introduction of a fluorine atom in an organic molecule changes its physical and chemical properties. This unique behavior implies: •  Wide applications in medicinal chemistry, agrochemical industry and material science •  20-25% of drugs in the pharmaceutical pipeline contain at least one atom of fluorine •  Use of the 18F radioisotope in the synthesis of tracers for Positron Emission Tomography

For fluorine in medicinal chemistry see: Fluorine in Medicinal Chemistry and Chemical Biology, Ed. I. Ojima, Wiley, 2009; Chem. Soc. Rev. 2008, 37, 320-330; Chem. Rev. 2008, 108, 1943-1981; Chem. Rev. 2014, 114, 2432-2506.

O

Me HHO

MeO

Me

HF

F

OMe

OS F

fluticasone propionate (GSK)Steroidal anti-inflammatory drug

OH

HO

O

Me

O

O

Me

Me

F

PGF2α analogueProstaglandin analogue

OHO

18F

OH

HOOH

[18F]FDG2-Deoxy-2-[18F]fluoro-D-glucose

F

COOMe

F-ibuprofen methyl esterNon-steroidal anti-infiammatory drug

F

F3C

OH

F

i-Pr

Cholesteryl Ester Transfer Protein (CETP) inhibitor

NCOOH

OHOHiPr

F

Ph

PhHNO2C

atorvastatin (Lipitor) Pfizerlowering blood cholesterol

3

Harsh reaction conditions: - Narrow substrate scope - Relative low selectivity

- Poor functional group tollerance

Hydrofluorination of Alkenes - Literature Precedent

R NHF-SbF5

3) Synthesis of β-fluoroamines by hydrofluorination using superacid HF-SbF5:

-20 °CR N

F

yield 57-85%

F. Zunino et al, Chem. Commun. 2007, 3198-3200

1) Hydrofluorination of Alkenes with Poly-Hydrogen Fluoride/Pyridine Reagents:

G. A. Olah et al, Synthesis 1973, 779-780

R2

R1 R4

R3

(HF)x · C5H5N / THF

0 °CR2

R1R4

R3

H

F

2) Hydrofluorination of Alkenes with Stable Dimethyl Ether/Poly(Hydrogen Fluoride) Complex:

G. A. Olah et al, J. Am. Chem. Soc. 2002, 124, 7728-7736

R2

R1 R4

R3

DMEHF

-20-0 °CR2

R1R4

R3

H

FDMEHF: Dimethyl ether/poly(hydrogen fluoride)

yield 77-94%

4

Metal-Catalysed Hydrofluorination - Literature Precedent

Boger et al., J. Am. Chem. Soc. 2012, 134, 13588-13591. Shigehisa et al., Org Lett. 2013, 15, 5158-5161.

5

Pd-Catalysed Hydrofluorination of Alkenylarenes: Our Approach

FH

Pd(IV)2+FH

Pd(II)+

H- source

Pd(II)2+

Pd(II)+H

H

F+ source

DCationic intermediate

B

C

A

6

Pd(IV) & Pt(IV)-Mediated Benzylic Fluorination: Literature Precedent

7

Entry F+ Source H- Source Conv [%][a] 2a [%][a] 3a [%][a]

1 A iPr3SiH > 95 30 0

2 B iPr3SiH > 95 34 0

3 C iPr3SiH 25 11 12

4 D iPr3SiH > 95 0 23

5 XeF2 iPr3SiH 72 16 28

6 A PhSiH3 > 95 0 31

7 A NaBH4 > 95 18 48

8 A Bu3SnH 9 < 5 0

Screening of Reaction Conditions

[a]Determinedby1HNMRspectroscopybypeakintegra@onusing1-fluoro-3-nitrobenzeneasaninternalreference.

Screening of Reaction Conditions

8

Entry Concentration of 1a (M)

Selectfluor

(equiv) H- Source (equiv) Conv [%][a] 2a [%][a] 3a [%][a]

1 0.05 2.0 iPr3SiH (2.0) > 95 30 0

2 0.025 2.0 iPr3SiH (2.0) > 95 35 0

3 0.025 2.0 iPr3SiH (1.5) > 95 41 0

4 0.025 1.5 iPr3SiH (1.5) 37 22 0

5 0.025 3.0 iPr3SiH (1.5) > 95 54 0

6 0.025 3.0 Et3SiH (1.5) > 95 69 0

7[b] 0.025 3.0 Et3SiH (1.5) > 95 48 15

8[c] 0.025 3.0 Et3SiH (1.5) 10[d] 0 0

9 0.025 3.0 - < 5 0 0

[a]Determinedby1HNMRspectroscopybypeakintegra@onusing1-fluoro-3-nitrobenzeneasaninternalreference.[b]Reac@onperformedatRT.[c]Reac@oncarriedoutintheabsenceofPd(PPh3)4.[d]Traceamountof4awasdetectedby1HNMRspectroscopy.

+

F

1a 2a 4a

Ph Ph Ph

3a

Ph+

OHPd(PPh3)4 (10 mol%)Selectfluor ·2BF4

- Silane

MeCN, 0 °C, 2h

Hydrofluorination of Alkenylarenes: Substrate Scope

9[a] Determined by 1H and 19F NMR.

10

Determination of syn-Hydrofluorination on 2x

Stereochemicalassignmentofan#-2xandsyn-2x

cis-Specific Hydrofluorination of Alkenylarenes: Suggested Catalytic Cycle

11

LnPd(II)

LnPd(II)H

FH

LnPd(IV)FH

Pd(II)LnH

Et3SiH + [ox]

Et3SiF + [red]

[ox]

[red]

C

D

E

B

A

NN

Cl

F2 BF4 N

NCl

BF4"F+ BF4

-"[ox] [red]

]

]

]

] 2+ +

2+

+

Deuterium-Labelling Experiment on 1b: 1H NMR Spectra

Stacked 1H NMR spectra corresponding to the in-situ generation of 2b (top) and (2-2H)-2b (bottom)

12

Stacked decoupled 19F NMR spectra corresponding to the in-situ generation of 2b (top) and (2-2H)-2b (bottom)

Deuterium-Labelling Experiments on 1b: 19F NMR Spectra

13

Cis-Specific Deuterofluorination of (E)-1y

14

Stereochemical assignment of syn-2y:

15

Cis-Specific Deuterofluorination of (Z)-1y

Stereochemical assignment of anti-2y:

16

Electrophilic Fluorination of η3-Benzyl Complex I

17

Pd-Catalysed Enantioselective Hydrofluorination:

Electrophilic Fluorination of η3-Benzyl Complex I

{[(R)-T-BINAP]Pd}+ TfO- II(10 mol%)

XeF2 (3.0 equiv.)Et3SiH (1.5 equiv.)DCM (0.025 M), -20 °C, 1 h

(S)(S)

(S)-2w, 34%, 36% ee

F

1w

(R)(R)

PhNH

XeF2 (1.5 equiv.)

CD2Cl2,-40 °C, 20 hretention

(S)(S)

(S)-2w, 82%, 80% ee

(R)-6, 84%, 71% ee

c)

a)

Me

HPd(R)-T-BINAP

(S)

F

PhNH2, PPh3

benzene, 40 °C, 20 hinversion

Selectfluor (1.2 equiv.)

CD3CN, r.t., 120 hretention

(S)(S)

(S)-2w, 36%, 36% ee

b)

F

II

OTf

Me

H(S)

PdL

L

*

Reductive elimination:retention

F

2+

Me

H(S)

OTf PdLL

*

NH2-Ph

Nucleophilic addition:inversion

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•  Anovelpalladium-catalysedhydrofluorina@onofalkenesthroughsequen@alH-andF+addi@onhasbeendescribed;

•  Themechanismofthisreac@oninvolvesanionicpathwayandisdis@nctfromknownhydrofluorina@ons

involvingradicalintermediates;

•  The HF addi@on across the double bond is highly regioselec@ve and characterised by the unique cisspecificity;

•  Themethodology isbestsuitedforalkenylareneswhichcanbetransformedinarangeoffunc@onalisedbenzylfluorides;

•  Thefirstcataly@cenan@oselec@vehydrofluorina@onisalsodisclosed

Conclusions

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Acknowledgment

• Professor Véronique Gouverneur, Dr. John Brown • Lukas Pfeifer • The VG Group

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