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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
18
• 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
19
Acknowledgment
• Professor Véronique Gouverneur, Dr. John Brown • Lukas Pfeifer • The VG Group
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