Fluorination of Organic Com pounds
Baran Group Meeting
05/24/2008
Introduction
Reaction Types
•F2: Isolated in 1886 by Moissan; 13th most abound element; only 13 naturally
occurring organic compound are known.
•The usefulness of fluorinated material was first realized during the “Manhattan
Project” (manipulation of UF6)
•Fluorine Effects:
Enhanced thermal stability (C-F 107 kcal/mol)
Increased lipophilicity to enhance bioavailability
Mimicking of enzyme substrate (comparable in size to H, 1.47Å vs 1.20Å)
Isoelectronic effects to –O- and -OH
The high electronegativity of fluorine frequently alerts chemical reactivity
Blocking effect in metabolic transformations
C
F
Shun Su
C
F
C
F
!+ C
!
-
C
F
C
C
F
F
C
CF3
C
!*
F
•Utility of some highly fluorinated compound:
Coolants and aerosol propellants: CCl2F2, CF2Cl-CFCl2, cyclo-C4F8
Fire extinguisher: CF3Br, CF2ClBr
Inhalation anaesthesis: THF-F8, Dioxane-F8
Surfactants: C7F15 to C10F21-SO3H
Polymers: high melting point; high thermal and chemical stability
Blood substitutes: perfluorinated cycloalkanes, amines, and O-heterocycles
Perfluorinated solvents and reagents
Reviews
General Reviews:
Chemistry of Organic Fluorine Compound II: A Critical Review ACS, 1995.
ACIEE 1981, 20, 647.
Organic Process Research & Development 2008, 12, 305.
Electrophilic Fluorination: Tetrahedron 2004, 60, 1435.
Fluoroaromatic Compounds: Aldrichimica Acta 1988, 21, 3.
DAST: Synthesis 2002, 2561.
Selectfluor: ACIEE 2005, 44, 192.
BrF3: Acc. Chem. Res. 2005, 38, 803.
XeF2:Tetrahedron 1995, 51, 6605.
Electrochemical Fluorination: Tetrahedron 1999, 55, 12431.
gem-Difluoromethylene Compounds: Tetrahedron 1996, 52, 8619.
Trifluoromethylation: Tetrahedron 1992, 48, 6555.
•Electrophilic Fluorination
•Fluorinated Synthons
•Nucleophilic Fluorination
•Electrochemical Fluorination
Fluorination Reagents
Inorganic Reagents: AgF 2, CoF3, CsSO 4F, HgF 2, RbSO 4F, PbF2(OAc)2,
Tl(O 2CCF3)3
Ammonium Fluorides: Et3N.3HF (TREAT-HF), (HF)x.Pyr (Olah's Reagent)
PPHF
Hypofluorites: CH3COOF, CF3COOF, CF3OF, FOClO3
N-Fluoro Reagents:
Cl
F
N
F
Ph
N
OTf -
F
O O
O
BF4-
S
N
O
S
NSFI
S
O
Me
Me
Me
N
Ph
F
selectfluor
Me
F
N
O
S
O
F
O
Fluoroaminosulfuranes: Et2NSF3 (DAST), (Me2N)3S(Me)3SiF2 (TASF)
Other Reagents: PhIF2, BF3, XeF2
sp3-C-F
R-O-R'
R-F
R'=H: DAST, SF 4/Et3N or Pyr, CHClFCF 2NEt2, (HF)x.Pyr (benzylic primary OH)
O
O
OC
Me
OH
DAST, DCM
0o C, 30 min
77%
OH
Me
OC
Me
F
F
Me
P erk in 1 1981 , 427
Fluorination of Organic Com pounds
Baran Group Meeting
05/24/2008
sp3-C-F
Shun Su
sp3-C-F
R-O-R'
R-SH
R-F
HF/CF3OF, HF/F2, HF/NCS
R-F
R'= -OTs and analogues: KF, CsF, TREAT-HF, TBAF
OTs
HS
F
Me
CO 2H
Me
COOMe
COOMe
KF, 18-C-6
DMF, 70oC
73% RO
RO
NH2
J. Org. Chem. 19 76, 47 , 3107.
R-F
Te tr ahedr on Let t . 1979, 20, 20 23
R-MgX
HO
CO 2Me
HO
F
Selectfluor
R-F
R2
R1
OH
Electrophilic
Fluorination
Reagents
T et rahed ron Let t. 1 989, 30 , 3711
R-N
R-F
Ph
O
F
80-120oC
Ph
Ph
N
R
F
R
F
PhCOCHN2
NCCH2CH2N3
F
NXS, PPHF
-15-25oC
NO BF4CHCl3, 25o C
N
O
OTHP
Alkene fluorination
R1
R3
R4
R1
R3
R2
F
R4
A = H: HF, HF.Pyr, polyvinylpyridium poly(hydrogen fluoride)
A = F: TREAT-HF or PPHF/Selectfluor or (CF3SO2)NF, XeF 2, CsSO4F
A = Cl, Br, I: NXS/TREAT-HF or PPHF
A = RO, RCOO, OH: Selectfluor or (CF3SO 2)NF/ROH, RCOOH, H2O
H
Cl 49%; Br 63%; I 62%
[NCCH2CH2N4O+ BF4-]
50%
NCCH2CH2F
J. O rg. Chem. 19 79, 44, 2 923.
OTHP
O
J . Am. Chem. Soc. 199 0, 112, 8 563.
R2
PhCOCHFX
OTBS
C H2 OMe
F TfO -
Me3 SiO
Ph
J. O rg. Chem. 19 79, 44, 3 872.
+
M eOH 2C
A
R-CHN2: Diazoalkanes-- acyl fluoride/HF/KF; Dizaoketonss-- HF.Pyr, NXS/HF.Pyr
R-N3: NO +BF 4-
F
O
Ph
RNH2
Ph
R2
R1
OTBS
R-NH2: NaNO 2/PPHF (! -amino acids); 2,4,6-triphenylpyrlium flouride (1o alkyl,
benzylic)
R-F
O
OR3
49%
XeF2
R-CO 2H
Formation of ! -fluoro carbonyl compounds:
PPHF
O
CO2 H
spray-dried KF, CsF, AgF, AgBF4, TBAF, HgF2
CO2 Me
O
Me
Me
NH2
R-Cl/Br/I
Epoxide Opening: CsF, KF, TREAT-HF, PPHF, DSAT, SF4
O
F
HF, CF3OF
-78o C
NBS, Et3N.3HF
Et2O, 0-20 o C
78%
H
F
Br
Sy nthesis 198 7, 562.
Fluorination of Organic Com pounds
Baran Group Meeting
05/24/2008
sp3-C-F
sp2-C-F
R-H
R-F
H
Ph
F
H
F2, XeF 2, CsSO4F, CF 3OF,
NO 2BF 4/HF.Pyr
S
Br
CF3OF, CsSO 4F, AgF/TiO2/hv
S
R1
R2
R3
SnMe3
XeF 2, AgOTf
F
OH
Me
J . Or g. Che m. 1993, 58, 27 91.
Me OR
Me
O
J. Am. Chem. S oc . 1976, 98 , 3034.
R1
A
F
R2
H
I
N
Se Ph
/Et3N.3HF
Li
R1
E+, FR2
E
F
R2
O
Me
C5H11
Te tr ahedr on 1993, 49 , 3291.
PhSO2NF-tBu
R1
F
Ph
R1
ArF
F
tBuONO
NaBF4
CHO
F
HO
MeO
F
hv
CHO
HO
MeO
CHO
J. Med. Chem 1979, 2 2, 1493
Ar-NR3
R2
N2+ BF4 -
NH2
R2
HO
H
elimination
LDA, THF
62%
Balz-Schiemann reaction: NaNO2/HCl/HBF 4, tBuONO/NaBF4/hv
MeO
R1
Cl
Cl
Ar-NH2
O
H
Me
Ar-F
O
A = Se:
R2
OH
XeF2, AgOTf
J . Fluorine Che m. 1988, 41 , 425.
R2
R1
F
C5H11
F
sp -C-F
BuLi
R3
DCM, rt, 52%
Ph
R2
R2
generated via fluorinated synthons
RO
2
R1
R1
sp-C-F
F
A = F: F2
A = Cl, Br, I: NXS,PPHF
A = H: HF
Ph
Me
CF3OF
35%
R1
O
F
Br
R=CF3CO
SePh
SnMe3
OR
F
[O]
T et ra hed ron Let t. 1990, 31 , 973.
O
Me
O
Ph
Br
O
Me
F
PhSeF
O
F
XeF 2
or
Selectfluor
Br
RO
Shun Su
ArF
KF/CsF in DMSO
Fluorination of Organic Com pounds
Baran Group Meeting
05/24/2008
Ar-F
Shun Su
Ar-F
RC6H4F
RC6H4NO 2
F-: KF, CsF, TBAFanh
Me
O
R = NO2, CN, CHO, SO3Me, COCl, SO2Cl, CF 3
MeO
N
J . F luor ine Chem. 199 0, 48, 1 89.
Ar-X
Ar-F
2. NFSI, THF, -78oC
65%
CHO
TBAFanh
F
F
DMSO, rt
>90%
Ar-H
For electron rich Ar: CsSO4F, Cf3OF, CH3COOF, Selectfluor
Pyr-NF.OTf, XeF2
OH
tBu
O
M = Li: (PhSO2)2NF, (CF3SO 2)2NF,
Me
N
OTf-
Me
M = MgX: selectfluor,
F
F
F
O
O
O
F
AlCl 3
PhMe
40-50 oC
85%
F
For unactived Ar: AgF2, XeF 2/HF, CF3OF, CsSO4F, Hg(O2CCF 3)2,
Tl(O2CCF 3)3, Pb(OAc)4
S
O
OH
tBu
gem-CF2
O
S
N
XeF2, DCM
-60 to 0oC
49%
tBu
Biosc i. Biot ech. Bioc he m. 1994, 5 8, 59 4
J. F luor ine Chem. 19 82, 21, 3 85.
Ar-F
tBu
F
KF, DMF
120oC, 54%
BF4-
Ar-M
Me
N
Ar-F
OH
Ar-F + ArI
I
MeO
MeO
ACIE E 20 06, 45 , 2720.
Ar-I+-ArBF 4-
Me
O
Te tr ahedr on Let t . 1994, 3 5, 34 65.
CHO
Cl
Me 1. nBuLi, THF, -78 C
MeO
F-: KF, KF/(Ph)4PBr, (n-Bu4N)HF2, TBAFanh
Cl
F
o
O
R1
O
S
N
N
R2
DAST
or
SF 4/HF
F
F
R2
R1
F
S
Me
O
O
ZHN
ZHN
NEtZ
M = B(OH)2: CsSO4F, (HOCH2CH2)2NMe/CsSO4F
M = SiR3: F2, CsSO4F, XeF2
M = SnR3: F2, CsSO4F, CF3OF, CH3CO 2F
M = HgX: CF 3OF
O
O
O
N
MeMe
ZHN
O
DAST
O
O
O
NHZ
ZHN
62%
O
O
N
MeMe
NEtZ
F
F
O
O
NHZ
Carbohy dr at es Resear ch 19 93, 238 , 147.
Fluorination of Organic Com pounds
Baran Group Meeting
05/24/2008
gem-CF2
gem-CF2
F
F
XF
or
X+/FConditions: BrF, IF, NXS/PPHF,
NOBF4/PPHF
S
N
S
S
R1
F
OR2
N
or
Difluoromethylene Synthons:
OH
F
F
R1
OR2
R1
O
R2
R1
P
F
F
R1
Me
F
F
Ph3 CHN
Me
X
X
CO2 H
Ph3 CO
F
O
N
O
H
XeF2
F
F
F
F
O
CF3Br/Cu
60o C, 78%
CF3
HN
Ph3CO
O
O
N
J . Am. Chem. Soc. 1 987, 10 9, 896.
O
OBn
Me
OBn
Me F
OBn
Chem.Abst r . 1990, 11 3, 15298 2m
Ph3 CHN
F
F
XeF2, HF
DCM, 68%
OXeF
F
F
I
The use of F3C
Preparation: ICF3, BrCF3, Hg(CF3)2/hv, F3CSO2Na/tBuOOH, F3CCO2H/XeF2
F3CN(NO)SO 2Ph/hv, F3CN=NCF3/hv
OMe
OMe
F
O
F
O
CF2 H
Sy nlet t 1994, 265.
CF3
F3CN(NO)SO2Ph
J . Or g. Chem . 1983, 4 8, 4158 .
O
Li/BR'2
O
J . Or g. Chem . 1991, 5 6, 482 3.
CO2H
F
The use of CuCF3 with Ar-Cl/Br/I
Preparation: Cu(I)/CF3SiR3, Cu(I)/(CF3)ZnX, Cu/ICF 3, Cu/BrCF 3, Cu/(CF3)2Hg
Cu(I)/CF 3CO 2M, Cu/CF3N(NO)SO2CF3, Cu/CF3SO 2Cl, Cu/CF2Br2
R2
HN
2X
OBn KHMDS, TBSCl
then XeF2
F
X = Cl: SbF3, HF anh, AlCl3/FCCl3, HF/CCl4
CX3 = CS2H: XeF2; CX3 = CO2H: DSAT, SF4/HF
IF
O
Cl/Br/I
Ar-CX3 to Ar-CF3
R2
C8H17
F
Br/Sn/Si F
F
R
Ar-CF3
F
C8 H17
H2NN
R
F
F
F
Conditions: PPHF/NXS R1
70%
R2
F 2C:
R
OR1
CF2 H
PhMe2SiCF2R
R2
F
R2
CF 2Br2/PPh 3
O
(EtO)2
F+
Conditions: PPHF
AgF
CF2
or
AgBF4
CF2Br2
CF2BrCl
O
F
R1
NH2
Conditions: IF, NIS or NBS/PPHF
Conditions: DAST, BF3
NBS or NIS/FCX2
Shun Su
tBu
hv
50%
tBu
Tet r ahe dr on 1 982, 23 , 3929.
Fluorination of Organic Com pounds
Baran Group Meeting
05/24/2008
Ar-CF3
NH2
O
NH2
S
O
NH2
CF3
CF 3
83% o:p=2.2:1
KF
72%
F3CSiR3
F3C
O
OSiEt 3
-CX3 to -CF3
The use of CuCF3
Aliphatic Cl/Br/I, vinyl Br/I/OH, benzyl OH
OTs
Cl 2
71%
C
J . Gen. Chem USSR 1958, 2 8, 2539.
CCl4,
HF, 100-150o C
H
R
R
J . Or g. Chem . 1979, 4 4, 2907.
OMe
OCCl3
Cl
Et3B
67%
OCF3
Cl
Cl 2, hv
P er kin 1 19 91, 627.
N
NCF3
Bull. S oc. Chim. Fr. 1986, 6, 9 25.
ArOH
CF3
NH2
N
NCF3
35%
CF3
ACIEE 1977, 16 , 854.
Other Methods
PhC
CLi +
COF2
F3 C
R2
CF3OF +
SF4
ArOCF3
J . Org. Chem. 1 964, 29 , 1.
ArOCOF
R2
hv
R1
R1
F
(Me2N)3S+CF3O- (TAS+ CF3O -)
46%
Se+ TfOCF3
PhC
CCF3
Zn, CF3I
ultrasound
MeO
O
Br
Te tr ahedr on Let t . 1990 , 31, 3579 .
MeO
F3CMX
H2C=CHCH2COCH3
+
hv
F 3CNO
Cl
HF
80-140oC
n-C5H11C(CF3)CHI-n-C5H11
F 3CNO
NH2
PhOCF3
53%
CH2
Tet r ahe dron Let t . 1990, 3 1, 3699.
F3CI
SbF3
PhOCCl3
OCF3
F3C
CuCF3
68%
The use of F3C•
Addition to alkenes and alkynes
+
RO-CF3
OH
T et rahedr on Le tt . 196 9, 47 , 4095.
n-C5H11CH=CH-n-C5H11
CF3
OSiMe3
J. Org. Chem. 19 91, 56 , 984.
PhOC(=S)Cl
C10H21CF3
F3CSiMe3
75%
CF3
J . Or g. Che m. 2000, 6 5, 88 48.
Alkane, alkene, and alkyne CF3
CuCF 3
HMPA
48%
O
O
O
J. Am. Chem . Soc . 1993, 11 5, 215 6.
C10H21I
Alkane, alkene, and alkyne CF3
Et3SiCF3
TfO -
Shun Su
OMe
OMe
H2C=CHCH2C(CF3)(CH3)OH
J. Am. Chem . Soc. 1985, 1 07 , 5186.
TAS+CF3O 65%
MeO
O
MeO
OCF3
OMe
OMe
Carbohy dr at e Chem . 1985, 4, 545.
Chem. Rev . 2005 , 105 , 827; Te tr ahedr on 1992 , 48, 655 5.
Fluorination of Organic Com pounds
Baran Group Meeting
05/24/2008
Enantioselective Monofluorination
Reagent Control
Substrate Control
O
O
O
N
1) Base
2) NFSI
Me
Ph
O
O
R
R
N
O
Me
86-99% de Ph
N+ BF4F Me
AcO
H
F
Me
H
MeO
NF
S
N
O
O
Catalyst Control
Metal-Mediated Catalyst Control
Np
Np
Np O
Me
Ti
O
Np O
O
N
Cl
Ph
Np
Np
Me
O
Cl
O
PAr2
N
Cu, Zn, Ni
PAr2
Ph
Cl
Cl
MeO
MeO
Pd cat 2.5 mol%
O
F
NSFI, Acetone, 0oC
N
F3C
93 ee%
O
N
F3C
Boc
Boc
J . Am . Che m. Soc. 2005 , 127 , 10164.
Organocatalysis
tBu
OMe
Me
O
OSiMe3
N
H
Ar
Ar
Pd
Ph
N Br+
N
Me
N
H
Me
O
H
H
tBu
N
For reviews: ACIE E 2008, 4 7, 1 179; 2006, 45 , 2172.
Shun Su