Baran Group Meeting Fluorination of Organic Com pounds Shun Su

05/24/2008

Introduction Reaction Types

•Electrophilic Fluorination •Nucleophilic Fluorination
•F2: Isolated in 1886 by Moissan; 13th most abound element; only 13 naturally •Fluorinated Synthons •Electrochemical Fluorination
occurring organic compound are known.
•The usefulness of fluorinated material was first realized during the “Manhattan Fluorination Reagents
Project” (manipulation of UF6)
•Fluorine Effects: Inorganic Reagents: AgF 2, CoF3, CsSO 4F, HgF 2, RbSO 4F, PbF2(OAc)2,
Enhanced thermal stability (C-F 107 kcal/mol) Tl(O 2CCF3)3
Increased lipophilicity to enhance bioavailability
Ammonium Fluorides: Et3N.3HF (TREAT-HF), (HF)x.Pyr (Olah's Reagent)
Mimicking of enzyme substrate (comparable in size to H, 1.47Å vs 1.20Å) PPHF
Isoelectronic effects to –O- and -OH
Hypofluorites: CH3COOF, CF3COOF, CF3OF, FOClO3
The high electronegativity of fluorine frequently alerts chemical reactivity
Blocking effect in metabolic transformations N-Fluoro Reagents:
Me Me
!+ C F C F F Cl Me Me
C F C F - F O O O O
C F ! C CF3 C
C C F S S
!* N Ph N Ph N F
N N
S F
•Utility of some highly fluorinated compound: F OTf - F BF4- F
O O S
Coolants and aerosol propellants: CCl2F2, CF2Cl-CFCl2, cyclo-C4F8 selectfluor NSFI O O
Fire extinguisher: CF3Br, CF2ClBr
Inhalation anaesthesis: THF-F8, Dioxane-F8 Fluoroaminosulfuranes: Et2NSF3 (DAST), (Me2N)3S(Me)3SiF2 (TASF)
Surfactants: C7F15 to C10F21-SO3H
Polymers: high melting point; high thermal and chemical stability Other Reagents: PhIF2, BF3, XeF2
Blood substitutes: perfluorinated cycloalkanes, amines, and O-heterocycles
Perfluorinated solvents and reagents
sp3-C-F
Reviews
General Reviews: R-O-R' R-F
Chemistry of Organic Fluorine Compound II: A Critical Review ACS, 1995.
ACIEE 1981, 20, 647. R'=H: DAST, SF 4/Et3N or Pyr, CHClFCF 2NEt2, (HF)x.Pyr (benzylic primary OH)
Organic Process Research & Development 2008, 12, 305. O O
Electrophilic Fluorination: Tetrahedron 2004, 60, 1435.
Fluoroaromatic Compounds: Aldrichimica Acta 1988, 21, 3. DAST, DCM
OC OC
DAST: Synthesis 2002, 2561. OH 0o C, 30 min F
Selectfluor: ACIEE 2005, 44, 192. 77%
BrF3: Acc. Chem. Res. 2005, 38, 803. Me Me Me Me
OH F
XeF2:Tetrahedron 1995, 51, 6605. P erk in 1 1981 , 427
Electrochemical Fluorination: Tetrahedron 1999, 55, 12431.
gem-Difluoromethylene Compounds: Tetrahedron 1996, 52, 8619.
Trifluoromethylation: Tetrahedron 1992, 48, 6555.
Baran Group Meeting Fluorination of Organic Com pounds Shun Su
05/24/2008

sp3-C-F sp3-C-F
R-O-R' R-F R-SH R-F
HF/CF3OF, HF/F2, HF/NCS
R'= -OTs and analogues: KF, CsF, TREAT-HF, TBAF
Me Me
OTs F HS F
CO 2H HF, CF3OF CO2 H
Me -78o C Me
COOMe COOMe NH2
NH2
J. Org. Chem. 19 76, 47 , 3107.
KF, 18-C-6 R-Cl/Br/I R-F
DMF, 70oC
spray-dried KF, CsF, AgF, AgBF4, TBAF, HgF2
RO 73% RO
Te tr ahedr on Let t . 1979, 20, 20 23
Selectfluor XeF2
R-MgX R-F R-CO 2H R-F
Epoxide Opening: CsF, KF, TREAT-HF, PPHF, DSAT, SF4

CO2 Me HO CO 2Me Formation of ! -fluoro carbonyl compounds:

O
PPHF OR3 O
O Electrophilic R2
49% HO F R2
O R1
Fluorination R1
OH Reagents
T et rahed ron Let t. 1 989, 30 , 3711 F
R-N R-F OTBS F OTBS

R-NH2: NaNO 2/PPHF (! -amino acids); 2,4,6-triphenylpyrlium flouride (1o alkyl,

M eOH 2C N C H2 OMe
F TfO -
benzylic) Me3 SiO OTHP O OTHP
O O
Ph Ph J . Am. Chem. Soc. 199 0, 112, 8 563.

RNH2 80-120oC Alkene fluorination

R F R1 R3 R1 R3
Ph O Ph Ph N Ph A F
F F
R R2 R4 R2 R4
R-CHN2: Diazoalkanes-- acyl fluoride/HF/KF; Dizaoketonss-- HF.Pyr, NXS/HF.Pyr A = H: HF, HF.Pyr, polyvinylpyridium poly(hydrogen fluoride)
A = F: TREAT-HF or PPHF/Selectfluor or (CF3SO2)NF, XeF 2, CsSO4F
NXS, PPHF A = Cl, Br, I: NXS/TREAT-HF or PPHF
PhCOCHN2 PhCOCHFX A = RO, RCOO, OH: Selectfluor or (CF3SO 2)NF/ROH, RCOOH, H2O
-15-25oC F
Cl 49%; Br 63%; I 62% H
J. O rg. Chem. 19 79, 44, 3 872.
R-N3: NO +BF 4- NBS, Et3N.3HF
NO BF4-
+
50% Et2O, 0-20 o C
NCCH2CH2N3 [NCCH2CH2N4O+ BF4-] NCCH2CH2F
CHCl3, 25o C 78% H Sy nthesis 198 7, 562.
J. O rg. Chem. 19 79, 44, 2 923. Br
Baran Group Meeting Fluorination of Organic Com pounds Shun Su
05/24/2008
sp3-C-F sp2-C-F
F F
R-H R-F O PhSeF [O]
O SePh O
Ph Ph Ph
H F
H F T et ra hed ron Let t. 1990, 31 , 973.

R1 R2 R1 R2
XeF 2, AgOTf
F2, XeF 2, CsSO4F, CF 3OF, CF3OF, CsSO 4F, AgF/TiO2/hv
NO 2BF 4/HF.Pyr R3 SnMe3 R3 F
SnMe3 F
S S F
XeF 2
or OH OH
Br Selectfluor Br XeF2, AgOTf
Br Br
O O DCM, rt, 52%
J . Or g. Che m. 1993, 58, 27 91. Me Me
O C5H11 O C5H11
Me
OR Me OR Me Me
Te tr ahedr on 1993, 49 , 3291.

Me CF3OF Me
35%
F
sp-C-F
RO generated via fluorinated synthons
RO
R=CF3CO J. Am. Chem. S oc . 1976, 98 , 3034.
F
Cl F
Ph LDA, THF
2 62% Ph
sp -C-F Cl
R1 A J . Fluorine Che m. 1988, 41 , 425.
R1 R2
F R2 Ar-F
O
A = F: F2 Ar-NH2 ArF
A = Cl, Br, I: NXS,PPHF A = Se: N Se Ph /Et3N.3HF
Balz-Schiemann reaction: NaNO2/HCl/HBF 4, tBuONO/NaBF4/hv
A = H: HF
O

R1 R2 R1 R2 R1 R2 NH2 N2+ BF4 - F

BuLi PhSO2NF-tBu HO tBuONO HO
HO hv
NaBF4
H I H Li H F
MeO CHO MeO CHO MeO CHO
R1 R1 F R1 F J. Med. Chem 1979, 2 2, 1493
E+, F- elimination
Ar-NR3 ArF
R2 E R2 R2 KF/CsF in DMSO
Baran Group Meeting Fluorination of Organic Com pounds Shun Su
05/24/2008

Ar-F Ar-F
RC6H4NO 2 RC6H4F
O Me F O Me
F-: KF, CsF, TBAFanh R = NO2, CN, CHO, SO3Me, COCl, SO2Cl, CF 3 o
MeO
N Me 1. nBuLi, THF, -78 C MeO
N Me
J . F luor ine Chem. 199 0, 48, 1 89. 2. NFSI, THF, -78oC
Ar-X Ar-F 65%
MeO MeO
F-: KF, KF/(Ph)4PBr, (n-Bu4N)HF2, TBAFanh Te tr ahedr on Let t . 1994, 3 5, 34 65.
CHO CHO
Ar-H Ar-F
Cl Cl TBAFanh F F
For electron rich Ar: CsSO4F, Cf3OF, CH3COOF, Selectfluor
DMSO, rt Pyr-NF.OTf, XeF2
>90%
ACIE E 20 06, 45 , 2720. OH OH
OH
XeF2, DCM tBu tBu AlCl 3
Ar-I+-ArBF 4- Ar-F + ArI tBu tBu
-60 to 0oC PhMe
49% 40-50 oC
I F 85%
KF, DMF F F
120oC, 54% Biosc i. Biot ech. Bioc he m. 1994, 5 8, 59 4

BF4-
For unactived Ar: AgF2, XeF 2/HF, CF3OF, CsSO4F, Hg(O2CCF 3)2,
J. F luor ine Chem. 19 82, 21, 3 85.
Tl(O2CCF 3)3, Pb(OAc)4

Ar-M Ar-F
O O gem-CF2
S

M = Li: (PhSO2)2NF, (CF3SO 2)2NF, N F

S O F F
O O DAST
or
R2 R2
OTf-

Me O
F
O O R1 SF 4/HF R1
S
M = MgX: selectfluor, Me N F N
N F
S
Me O O
ZHN ZHN ZHN ZHN
NEtZ NEtZ
M = B(OH)2: CsSO4F, (HOCH2CH2)2NMe/CsSO4F F

O DAST O
M = SiR3: F2, CsSO4F, XeF2 O F
O O O O O O
N 62% N
M = SnR3: F2, CsSO4F, CF3OF, CH3CO 2F MeMe O MeMe O
NHZ NHZ
M = HgX: CF 3OF Carbohy dr at es Resear ch 19 93, 238 , 147.
Baran Group Meeting Fluorination of Organic Com pounds Shun Su
05/24/2008
gem-CF2 gem-CF2
NH2 OH Difluoromethylene Synthons:
S S XF F F N N F F
or R Cl/Br/I
or CF2BrCl CF2Br2 CF 2Br2/PPh 3 PhMe2SiCF2R F 2C:
X+/F- F F
OR1 R R F
Conditions: BrF, IF, NXS/PPHF, O
Conditions: IF, NIS or NBS/PPHF
NOBF4/PPHF F F Br/Sn/Si F F
P R2 Li/BR'2 F
(EtO)2 CF2 H
S O O F F F F
F F
R2
F+ R2
R1 OR2 R1 OR2 R1 R1
F F Ar-CF3
Conditions: DAST, BF3 F F Ar-CX3 to Ar-CF3
NBS or NIS/F- R1 R2 R2 X = Cl: SbF3, HF anh, AlCl3/FCCl3, HF/CCl4
R1
AgF Conditions: PPHF CX3 = CS2H: XeF2; CX3 = CO2H: DSAT, SF4/HF
F F
CX2 or CF2
R2 The use of CuCF3 with Ar-Cl/Br/I
AgBF4 Conditions: PPHF/NXS R1 Preparation: Cu(I)/CF3SiR3, Cu(I)/(CF3)ZnX, Cu/ICF 3, Cu/BrCF 3, Cu/(CF3)2Hg
X X
Cu(I)/CF 3CO 2M, Cu/CF3N(NO)SO2CF3, Cu/CF3SO 2Cl, Cu/CF2Br2
C8 H17 C8H17 O O
I CF3
IF HN CF3Br/Cu HN
Ph3 CO
O 60o C, 78% Ph3CO
70% N O N
F
H2NN O O
F J . Am. Chem. Soc. 1 987, 10 9, 896.

O Me O Me OBn OBn
2X Chem.Abst r . 1990, 11 3, 15298 2m
Ph3 CHN OBn KHMDS, TBSCl Ph3 CHN OBn
then XeF2 The use of F3C
F
Me Me F Preparation: ICF3, BrCF3, Hg(CF3)2/hv, F3CSO2Na/tBuOOH, F3CCO2H/XeF2
J . Or g. Chem . 1991, 5 6, 482 3.
F3CN(NO)SO 2Ph/hv, F3CN=NCF3/hv
CO2H F
XeF2, HF OMe
DCM, 68% OMe
CO2 H F
CF3
J . Or g. Chem . 1983, 4 8, 4158 . F3CN(NO)SO2Ph
O OXeF O
O hv
XeF2 F CF2 H 50%
H F tBu tBu
Tet r ahe dr on 1 982, 23 , 3929.
Sy nlet t 1994, 265.
Baran Group Meeting Fluorination of Organic Com pounds Shun Su
05/24/2008
Ar-CF3 Alkane, alkene, and alkyne CF3
O O NH2
NH2 NH2 F3CSiR3
Et3SiCF3 O
O
S
TfO - F3CSiMe3 CF3
CF 3 CF3 KF 75%
83% o:p=2.2:1 72% O OSiMe3
O F3C OSiEt 3 J. Org. Chem. 19 91, 56 , 984.
CF3
J. Am. Chem . Soc . 1993, 11 5, 215 6. J . Or g. Che m. 2000, 6 5, 88 48.
RO-CF3
Alkane, alkene, and alkyne CF3 Cl 2 SbF3
PhOC(=S)Cl PhOCCl3 PhOCF3
-CX3 to -CF3 71% 53%
J . Gen. Chem USSR 1958, 2 8, 2539.
The use of CuCF3
Aliphatic Cl/Br/I, vinyl Br/I/OH, benzyl OH OH OCF3

OTs F3C CCl4, HF, 100-150o C

C10H21I CuCF 3 C10H21CF3 CuCF3
HMPA C CH2
48% 68% H
T et rahedr on Le tt . 196 9, 47 , 4095. Tet r ahe dron Let t . 1990, 3 1, 3699. R R
J . Or g. Chem . 1979, 4 4, 2907.
The use of F3C• OMe OCCl3 OCF3
Addition to alkenes and alkynes Cl Cl Cl
Cl 2, hv HF
Et3B
n-C5H11CH=CH-n-C5H11 + F3CI n-C5H11C(CF3)CHI-n-C5H11 80-140oC
67%
P er kin 1 19 91, 627.
Bull. S oc. Chim. Fr. 1986, 6, 9 25.
F 3CNO
SF4
NH2 NCF3 CF3 ArOH + COF2 ArOCOF ArOCF3
N J . Org. Chem. 1 964, 29 , 1.
F 3CNO hv
R2 F3 C R2
NH2 NCF3 35% CF3
N hv
CF3OF +
ACIEE 1977, 16 , 854. R1 R1 F

Other Methods
(Me2N)3S+CF3O- (TAS+ CF3O -)

46%
PhC CLi + PhC CCF3 O Br O OCF3
MeO TAS+CF3O - MeO
Se+ TfO-
Te tr ahedr on Let t . 1990 , 31, 3579 .
CF3 MeO OMe 65% MeO OMe
F3CMX
OMe OMe
H2C=CHCH2COCH3 Zn, CF3I Carbohy dr at e Chem . 1985, 4, 545.
H2C=CHCH2C(CF3)(CH3)OH
ultrasound J. Am. Chem . Soc. 1985, 1 07 , 5186.
Chem. Rev . 2005 , 105 , 827; Te tr ahedr on 1992 , 48, 655 5.
Baran Group Meeting Fluorination of Organic Com pounds Shun Su
05/24/2008

Enantioselective Monofluorination
Substrate Control Reagent Control

O O O O
N+ BF4- Me
R R F Me
N N AcO
O 1) Base O
H H
2) NFSI F
Me Me MeO NF
Ph 86-99% de Ph
S
N O O

Catalyst Control
Metal-Mediated Catalyst Control

Np Np Me Me
Np O O Cl O O
PAr2
Ti
N N PAr2
Pd
Np O O Cl
Np Np Ph Cu, Zn, Ni Ph
Cl Cl

MeO MeO
Pd cat 2.5 mol% F

O NSFI, Acetone, 0oC O

F3C N 93 ee% F3C N
Boc Boc
J . Am . Che m. Soc. 2005 , 127 , 10164.
Organocatalysis tBu
OMe
Me
O N Br-
+

OSiMe3 N Me O tBu
N H H
H Ar Ph N Me
Ar H

N
For reviews: ACIE E 2008, 4 7, 1 179; 2006, 45 , 2172.