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Fluorina)on Chemistry: A Tale of Two Reagents Brandon Reinus January 23 rd , 2013
Transcript of Fluorinaon*Chemistry:*gbdong.cm.utexas.edu/seminar/old/Organofluorine_Brandon Reinus.p… ·...
Fluorina)on Chemistry: A Tale of Two Reagents
Brandon Reinus
January 23rd, 2013
Outline
• Historical Development
• The C-‐F bond • Fluorine, Who cares?
• Fluorine, Isn’t it toxic?
• Fluorina)on Reac)ons
Historical Development
• In 1890 Moissan claimed to have isolated CF4, it was later found he was incorrect in his report.
• In 1892 Swarts also started working on prepara)on of fluorocarbons by
exchange, usually from the chloro compounds. He was the sole author publishing in the field of organo-‐fluorine chemistry for 25 years!
• Midgley and Henne picked up aYer swarts in the 30’s and developed fluoro-‐
methanes and ethanes as refrigerants, bringing more funding to the field.
Cl + MFx MFxClF-
(HF)F
2F2 CF4C +
H. Moissan, Compt. Rend., 110, 276 (1890) F. Swarts, Bull. Acad. Roy. Belg., [3], 24, 474 (1892) T. Midgley and A. L. Henne, Ind. Eng. Chem., 22, 542 (1930)
Historical Development
• In 1937 Simons and Block found mercury promoted the reac)on between carbon and fluorine and isolated several purely fluorinated compounds.
• Simons proposed these highly fluorinated compounds may be
chemically resistant to UF6. • Use of fluorcarbons in the machinery for enriching U caught a lot of
chemists acen)on and the field really took off. • Polytetrafluoroethylene (Teflon), was patented in 1941. • Research in organofluorine chemistry has slowly caught on and has
become very acrac)ve recently due to the prevalence on F in pharmaceu)cals.
J. H. Simons and L. P. Block, J. Amer. Chem. Soc., 59, 1407 (1937) R.J. Plunkec, U.S. Pat. 2,230,654 (Feb. 4, 1941)
The C-‐F Bond, and more
• Fluorine forms strong bonds to carbon, ~115 Kcal/mol, making it rela)vely stable to metabolic degrada)on, and making elemental fluorine highly reac)ve.
• The van der Waals radii is 1.47 compared to 1.20 Angstrom for H. Also the bond length is closer to that of C – O bond, sugges)ng it is more like an alcohol sterically speaking; however, it is oYen considered an isostere of H.
• The more F added to a carbon the stronger and shorter all of the fluorine bonds become.
CF
F FF
CF
F FF
no bond resonance
J. H. Simons and L. P. Block, J. Amer. Chem. Soc., 59, 1407 (1937) R.J. Plunkec, U.S. Pat. 2,230,654 (Feb. 4, 1941) Chem. Rev. 2008, 108, PR1-‐PR43
Fluorine, Who Cares?
Journal of Fluorine Chemistry 100 (1999) 127-‐133 Nat. Prod. Rep., 2004, 21, 773-‐784
• ~ 3000 halogen containing natural products
• Fluorine is the most abundant halogen
in the crust, yet there are only 13 secondary metabolites containing F
• Of the 13, only 6 discrete natural
products. • Fluoride is a poor nucleophile in water
and can not be oxidized to X+ by haloperoxidases, resul)ng in it’s extremely low bioavailability in surface water (1.3ppm vs 3000ppm for chloride)
O
O
F
Plant and Animal Enzymes HO2C CO2H
HO2C OH
F
FluorocitrateFluoroacetate
Toxic...
F CO2H
F CO2HO
F
OH
OHCO2H
w-fluorooleic acid
O
F
N
NN
NNH2
O
OHOHHHHF
OSH2NO
O
Fluorine Containing 'Natural Products'
OH
NH3
CO2
F
Fluorine, Who Cares?
HN
N
F
O
O
O
O
HN
N
F
O
O
O
O
HN
N
F
O
O
O
HN
N
F
O
O
H2NHN
O
HN
NH
F
O
O5-fluoruracil
Derivatives:
Possible Natural Products
• Biologists and biochemists have been equally intrigued in fluorine over the last
several decades and have shown certain plants that don’t generally produce fluorinated metabolites will in the presence of elevated levels of fluoride
• A so-‐called ‘fluorinase’ enzyme has been isolated that is responsible for
fluorina)ng metabolites in a certain bacteria species.
Journal of Fluorine Chemistry 100 (1999) 127-‐133 Nat. Prod. Rep., 2004, 21, 773-‐784
• 5-‐fluorouracil and four deriva)ves were isolated from a sponge in the South China Sea, but it is unclear whether the sponge was incorpora)ng fluorine or simply deriva)zing 5FU that was pollu)ng the waters.
Fluorine, Who Cares?
• Around a 1/3 of agrochemicals contain fluorine and around 1/5 of pharmaceu)cals contain fluorine. (over 150 have come to market since the first in 1957)
• These companies are interested in fluorine because it can change the binding
interac)ons, metabolic stability, physical proper)es, and reac)vity. • Fluorine can change the way a compound is metabolized (phase I P450), it can
change the solubility of a compound (becer oral availability), and fluorine forms many unique bioisosteres.
Journal of Fluorine Chemistry 100 (1999) 127-‐133 Nat. Prod. Rep., 2004, 21, 773-‐784 Science 317, 1881 (2007) J. Med. Chem., 2008, 51, 4359
F3C
OHN
HClN
F
NH
O
COO
OHOH
1/2 Ca2+N
O
N
F
HN
O
OH
HCl
Prozac Lipitor Ciprobay
Fluorine, Isn’t it toxic?
• Although fluoroacetate is toxic, most organo-‐fluorides are not toxic. Fluoroacetate is an excep)on, because it inhibits an important enzyme of the TCA cycle.
• Fluoride ion is toxic however, but organic compounds rarely release fluoride ion, lethal dose of NaF is 5-‐10g. (not very lethal)
• Upon hea)ng of Teflon (polytetrafluoroethylene), small molecules containing
fluorine can be given off through decomposi)on, and it has been shown that these molecules are lethal to birds and may cause flu-‐like symptoms for humans, but you have to heat the pans to temperatures that are unreasonable for cooking.
Baselt, RC (2008). Disposi)on of toxic drugs and chemicals in man. Dupont, Key Ques)ons about Teflon, accessed Jan, 2013,
Fluorina)on Reac)ons
N
F
NH
O
COO
OHOH
Lipitor
Start from pre-fluorinatedbuilding blocks
After-the-fact fluorination
10% F2 / N2
Simple Materials
Electrophilic Fluorination
Nucleophilic Fluorination
Complex Materials • Elemental fluorine is extremely reac)ve, but can be used on an industrial scale with simple compounds, the different products can be isolated and sold.
• The compounds used in laboratories to add fluorine are generally not atom economical.
• However, if you want to install the fluorine yourself you have lots of reac)ons available to you
Fluorina)on Reac)ons
J. Chem. Soc., Perkin Trans. I, 2002, 2190-‐2197 Beilstein Journal of Organic Chemistry 2006, 2, No. 19
Fluorination with F2
Aromatics:
Alkanes:
Mechanism:
F2
Typical Reactivity
F
FF2 or Selectfluor
FFH
Via: Selectfluor:
N
N
F
Cl
x2 BF4
• Fluorina)on of aroma)cs with fluorine gas will give you your typical product distribu)ons you see with electrophilic aroma)c subs)tu)on
• Fluorina)on of alkanes is believed to go through an electrophilic mechanism rather than a radical mechanism, this was ra)onalized by the fact that Selecrluor generally gave the same products as elemental fluorine.
• Vicinal fluorides are not prac)cally prepared via fluorina)on of alkenes
Chambers, Chem. Commun., 2000, 959-‐960
Fluorina)on Reac)ons
Problem: Elemental fluorine easily reacts with aroma)cs, alkanes, and reacts with alkenes Solu)on: Develop more selec)ve fluorina)ng reagents
N
N
F
Cl
x2 BF4N
SF3
Selecrluor DAST
Electrophilic Fluorina)on • As men)oned previously, due to the difficulty in handling fluorine, selec)ve and
user friendly fluorina)on reagents were sought out • The 1950’s development of Perchloryl fluoride FClO3, a very dangerous gas,
inspired the development of perfluoro-‐N-‐fluoropiperidine. Which was successful at fluorina)ng a handful of stabilized sodium salts.
• N-‐F reagents quickly caught on and many different compounds and their reac)vity's were published
F2CF2C C
F2
CF2
CF2NF
NO2
Na
+NO2
F
Banks, Chem. Ind. (london), (1964) 1864.
F2CF2C C
F2
CF2
CF2NF
N
N
F
Cl
2x BF4N OF
NF
FNF
XSO ON RF
Selectfluor
Journal of Fluorine Chemistry 87 (1998) 1-‐17 Angew. Chem. Int. Ed. 2005, 44, 192-‐212
Selecrluor
• Selecrluor is an easily handled solid, is resistant to elevated temperatures, and is rela)vely nontoxic: LD50 = 640mg/kg in adult rats
NN
dabco
DCM
40 oCNN Cl NaBF4
CH3CN20oC
Cl
NN ClBF4
F2NaBF4
CH3CN-35oC
NN ClBF42X
F
Preparation of Selectfluor
multiton quantities/ year
• Tuning the reac)vity of Selecrluor can be achieved by changing the alkyla)ng reagent and the counter-‐ion, it has been shown that these can enhance the solubility, changing the fluorina)ng agent’s reac)vity.
Journal of Fluorine Chemistry 87 (1998) 1-‐17 Angew. Chem. Int. Ed. 2005, 44, 192-‐212
J. Org. Chem. 1999, 64, 5264
J. Fluorine. Chem. 1999, 100, 157
Selecrluor O O R O
Selectfluor
AcetonitrileRT
F
O
OR
Selectfluor
AcetonitrileOoC
O
OF
90%
alpha-Fluorination of steroids
fluorination of beta-ketoesters
O
O RO
F-TEDA-BF4
DMF, -50 to 20oC
O
O RO
F
94%
PO(OEt)2
SO2Ar
F-TEDA-BF4
DMF, RT
PO(OEt)2
SO2Ar
F
61%
O O
NR2
O O
NR2F F
Lal, J. Org. Chem. 1993, 58,2791 Herrinton, Org. Process Res. Dev. 1997, 1, 217
Lal, J. Org. Chem. 1993, 58,2791
• Ketones must first be converted to the enol-‐acetates
• Both alpha and gamma fluorina)on can be achieved
• Beta-‐ketoesters are good substrates and can be fluorinated twice
Selecrluor
+F
F60% 40%
F-TEDA-BF4
AcetonitrileReflux
F-TEDA-BF4
AcetonitrileReflux
F F+
F
65% 32%
O
CO2Me
O
O
OF-TEDA-BF4
AcetonitrileReflux
O
CO2Me
O
O
OF
22%
Electrophilic Aromatic Substitution
OHSelectfluor
AcetonitrileF
O
60%
HO
Selectfluor
Acetonitrile O
F
84%
O
HO
O
O
Selectfluor
Acetonitrile
F
90%
4-fluorocyclohexadienones
J. Fluorine Chem. 68 (1994) 201 Sharif, Chem. Soc., Perkin Trans. 1 (1996) 2069
Zupan, Synlec 1999, 9, 1375
• Fluorina)on of phenols gives 4-‐fluorocyclohexadienones as products
• Fluorina)on of most aroma)cs gives subs)tu)on products
Selecrluor
Fluorination of Syrene and Phenylacetylene
Ph
Me
F-TEDA-BF4
CH3CN, H2O, RT
F-TEDA-BF4
CH3CN, CH3OH, RT
F-TEDA-BF4
CH3CN, H2O, Reflux
F-TEDA-BF4
CH3CN, H2O, Reflux
FOH
OF
OPh
F F
OMe
F F
OSelectfluor
ROHCH3CN
O
FOR
NH
Selectfluor
H20CH3CN
NH
FO
71%
NH
NH
N
O
OR
H RSelectfluor
CH3CN / THFNH
NN
O
O
F
HR
H R
Fluorination of Activated Alkenes
Wong, J. Org. Chem. 1999, 64, 5264 Shibata, Org. Lec. 2000, 2, 693 Kirk, Angew. Chem. 2001, 40, 4461
Zupan, Bull. Chem. Soc. Jpn. 69, (1996) 169.
• Electron rich alkenes or alkenes that react to give stabilized carboca)ons will react with selecrluor
Selecrluor
OSnMe3
O
F-TEDA-BF4
Acetonitrile, RT OF
O
52%
F-TEDA-BF4
Acetonitrile, RTNSnMe3
TsN
F
Ts 40%
TlF-TEDA-BF4
Acetonitrile, RT
R
R
+
F
R
R
35%
Sn and Tl Conversion to F
TMSPh
TMSPh
TMSPh
Selectfluor (1 equiv)
Acetonitrile
Selectfluor (2.5 equiv)
Acetonitrile
Selectfluor (2.5 equiv)
Acetonitrile / MeOH
FPh
FPh
FAcHN
FPh
FO
32%
70%
75%
TMS Conversion to F
Widdowson, J. Chem. Soc., Perkin Trans. 1 (1995) 2965 Widdowson, Tetrahedron 50 (1994) 1899 Sik, J. Chem. Soc., Perkin Trans. (1992) 1891
Gouverneur, Chem. Commun. 2001, 233
• Quick method for producing F18 labeled compounds
• Vinyl stannanes and silanes will react via electrophilic fluorina)on to give an array of products.
Selecrluor
N
N
H
O
HO
HH F
N
N
H
O
H
HHO F
N
N
H
H
HHO F
N
N
H
HO
HH F
23a 23b
23d23c
Chiral N-F Reagents Synthesized From Selectfluor
Improved enantioselective fluorinations were observedwith a new class of charged [N!F]+ reagents. Selectfluor wasused to prepare the N-fluoroammonium derivatives 23a–d ofcinchona alkaloids by transfer fluorination (Figure 3,Scheme 26).[66–68] The fluorinated reagents 23a–d were
tested in the enantioselective fluorination of the sodiumenolate of 2-methyl-1-tetralone, providing the product in upto 98% yield and with up to 50% ee (Table 8). Higherenantioselectivities (up to 94% ee) were later observed withmodified N-fluoro cinchona alkaloids.[69] In a similar manner,enantioselective fluorinations with a reagent combination of acinchona alkaloid derivative and 1 were demonstrated(Table 9).[70] This method bypasses the isolation of the N-fluoroammonium salt and therefore constitutes a one-pot
procedure, in which a mixture of the cinchona alkaloid and 1can be added to a variety of substrate types, including silylenol ethers. Both cyclic and acyclic carbonyl compounds werefluorinated in good to excellent yields with selectivitiessometimes greater than 90% ee by this method, which isalso useful for b-keto esters (up to 80% ee) and acyclic b-cyano esters (up to 87% ee). Significant progress has beenmade in the development of an enantioselective electrophilicfluorination method. In most cases cinchona alkaloids andselectfluor have been used in a transfer fluorination to accessthe corresponding chiral electrophilic fluorination reagents.This strategy has proved to be very practical, especiallybecause of the commercial availability of the cinchonaalkaloid derivatives.
A major breakthrough would be the development ofcatalytically active enantioselective fluorination reagents. Thesystematic investigation of the catalytic activity of varioustransition-metal complexes in the electrophilic fluorination ofketones led to the discovery that the taddol-modified(taddol=a,a,a’,a’-tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5-di-methanol) titanium complexes 24a and 24b are highlyefficient catalysts for the enantioselective fluorination of b-keto esters (Scheme 27).[71] It was hypothesized that theinteraction of the ketoester with the Lewis acidic catalystinduces enolization, and that the resulting enol is thenfluorinated enantioselectively with 1. This mechanistic ration-alization is supported by previous reports of a rate enhance-ment in the fluorination of ketones with N-fluoropyridiniumsalts in the presence of zinc(ii) chloride.[10] Further mecha-nistic details[72] were reported.
6.Mechanism of Fluorination with Selectfluor:Electron Transfer or SN2 Reaction?
The mechanism of fluorination with N!F reagents hasbeen a subject of debate since their introduction. There aretwo possible mechanistic pathways: single-electron transfer(SET) or nucleophilic SN2 substitution. As shown inScheme 28, both SET and SN2 pathways lead to the sameproduct, in this case a fluorinated carbocation. Banks and co-workers initially voiced support for a SET mechanism to
Figure 3. N-Fluoroammonium derivatives of cinchona alkaloids forenantioselective electrophilic fluorination.[66–68]
Scheme 26. Synthesis of the fluorinated cinchona alkaloid F-CD-BF4.[66–
68]
Table 8: Enantioselective fluorination with [N!F]+ cinchona alkaloids(see Figure 3).[66–68]
[N!F]+ ee [%] Configuration Yield [%]
23a 50 S 9823b 40 R 7023c 27 R 8723d 20 S 98
Table 9: Enantioselective fluorination with a combination of DHQB and1.[70]
R n ee [%] Configuration Yield [%]
Me 1 53 R 93Et 1 73 R 100Bn 1 91 R 86Me 2 40 R 94Et 2 67 R 71Bn 2 71 S 95
C.-H. Wong et al.Reviews
204 ! 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org Angew. Chem. Int. Ed. 2005, 44, 192 – 212Improved enantioselective fluorinations were observedwith a new class of charged [N!F]+ reagents. Selectfluor wasused to prepare the N-fluoroammonium derivatives 23a–d ofcinchona alkaloids by transfer fluorination (Figure 3,Scheme 26).[66–68] The fluorinated reagents 23a–d were
tested in the enantioselective fluorination of the sodiumenolate of 2-methyl-1-tetralone, providing the product in upto 98% yield and with up to 50% ee (Table 8). Higherenantioselectivities (up to 94% ee) were later observed withmodified N-fluoro cinchona alkaloids.[69] In a similar manner,enantioselective fluorinations with a reagent combination of acinchona alkaloid derivative and 1 were demonstrated(Table 9).[70] This method bypasses the isolation of the N-fluoroammonium salt and therefore constitutes a one-pot
procedure, in which a mixture of the cinchona alkaloid and 1can be added to a variety of substrate types, including silylenol ethers. Both cyclic and acyclic carbonyl compounds werefluorinated in good to excellent yields with selectivitiessometimes greater than 90% ee by this method, which isalso useful for b-keto esters (up to 80% ee) and acyclic b-cyano esters (up to 87% ee). Significant progress has beenmade in the development of an enantioselective electrophilicfluorination method. In most cases cinchona alkaloids andselectfluor have been used in a transfer fluorination to accessthe corresponding chiral electrophilic fluorination reagents.This strategy has proved to be very practical, especiallybecause of the commercial availability of the cinchonaalkaloid derivatives.
A major breakthrough would be the development ofcatalytically active enantioselective fluorination reagents. Thesystematic investigation of the catalytic activity of varioustransition-metal complexes in the electrophilic fluorination ofketones led to the discovery that the taddol-modified(taddol=a,a,a’,a’-tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5-di-methanol) titanium complexes 24a and 24b are highlyefficient catalysts for the enantioselective fluorination of b-keto esters (Scheme 27).[71] It was hypothesized that theinteraction of the ketoester with the Lewis acidic catalystinduces enolization, and that the resulting enol is thenfluorinated enantioselectively with 1. This mechanistic ration-alization is supported by previous reports of a rate enhance-ment in the fluorination of ketones with N-fluoropyridiniumsalts in the presence of zinc(ii) chloride.[10] Further mecha-nistic details[72] were reported.
6.Mechanism of Fluorination with Selectfluor:Electron Transfer or SN2 Reaction?
The mechanism of fluorination with N!F reagents hasbeen a subject of debate since their introduction. There aretwo possible mechanistic pathways: single-electron transfer(SET) or nucleophilic SN2 substitution. As shown inScheme 28, both SET and SN2 pathways lead to the sameproduct, in this case a fluorinated carbocation. Banks and co-workers initially voiced support for a SET mechanism to
Figure 3. N-Fluoroammonium derivatives of cinchona alkaloids forenantioselective electrophilic fluorination.[66–68]
Scheme 26. Synthesis of the fluorinated cinchona alkaloid F-CD-BF4.[66–
68]
Table 8: Enantioselective fluorination with [N!F]+ cinchona alkaloids(see Figure 3).[66–68]
[N!F]+ ee [%] Configuration Yield [%]
23a 50 S 9823b 40 R 7023c 27 R 8723d 20 S 98
Table 9: Enantioselective fluorination with a combination of DHQB and1.[70]
R n ee [%] Configuration Yield [%]
Me 1 53 R 93Et 1 73 R 100Bn 1 91 R 86Me 2 40 R 94Et 2 67 R 71Bn 2 71 S 95
C.-H. Wong et al.Reviews
204 ! 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org Angew. Chem. Int. Ed. 2005, 44, 192 – 212
Shiro, JACS, 2001, 123, 7001
Roques, Org. Lec. 2000, 2, 3699 Roques, Tet. Lec. 2001, 42, 1867 Takeuchi, JACS, 2000, 122, 10728
• Chinchona alkaloids were fluorinated with selecrluor and used in enan)oselec)ve transforma)ons
DAST • DAST and Deoxofluor are by far the most useful nucleophilic fluorina)on
reagents, DAST has been around since 1975.
• DAST will detonate if heated to about 90 C, so you have to be more careful when using it than you do with Selecrluor, but it is s)ll rela)vely safe and easy to handle.
• Deoxyfluor has the same reac)vity of DAST, but is more thermally stable.
NTMS
+ SF4 NSF3
+ TMSF
Shreeve, synthesis, 2000, 2561
Diethylaminosulfurtrifluoride
DAST
OH
OH
Ph OHPh
OH
OOH
OBnBnO
BnO
Deoxofluor, DCM
-78 to RT
Deoxofluor, DCM
-78oC
Deoxofluor, DCM
RT
Deoxofluor, DCM
RT
F
F
Ph FPh
F
OF
OBnBnO
BnO
44%
96%
72%
98%
Fluorination of Alcohols
Prozonic, Chem. Commun. 1999, 215 Cheng, J. Org. Chem. 1999, 64, 7048 Shreeve, j. Fluorine Chem. 2002, 116, 23 Ball, J. Org. Chem, 2000, 65, 4984
• Rate of the reac)on is dependent on the steric accessibility of the alcohol
OHS N R
R
F F
F+ O SH N
F F R
RO S N
F F R
R+ HF
O S N
F F R
R F-F
+ HF
Proposed
• Similar mechanism to PBr3 and SOCl2
DAST
O
O
O
O
O
3.0 equiv DAST
DCM Reflux
3.0 equiv DAST
DCM RT
1.7 equiv DAST
DCM RT
1.7 equiv DAST
DCM RT
F F
F F
FF
FF
FF
95%
94%
63%
85%
Reaction of DAST with Various Carbonyls
O
OH
O
Cl
O
F
Deoxofluor
DCM Oo C
Deoxofluor
DCM Oo C
Deoxofluor
48 hr Neat
O
F
O
F
CF3
96%
95%
58%
Reactions with Acids
Prozonic, Chem. Commun. 1999, 215 Cheng, J. Org. Chem. 1999, 64, 7048 Shiji, 2001, 23, 296, Chem. Abstr. 136: 183600g
Prozonic, Chem. Commun. 1999, 215 Cheng, J. Org. Chem. 1999, 64, 7048
• Aldehydes and ketones can be converted to the difluorides
• Acids can be converted to the acid fluoride or trifluoromethyl at longer dura)ons
DAST
O DASTFF
F
F+ Gave Mixture of 4 products
Hudlicky, Journal of Fluorine Chemistry, 36 (1987) 373-384
DAST With Epoxides
DASTHOO
O
F
DAST Ring expansion
Gree, Org. Lett. 2002, 4, 451
NSF3
O
O
O
OTMS
O
O
F
16% ee
Enantioselective Variation
Sampson, J. Chem. Soc. Perkin Trans. I 1989, 1650
• Epoxides are difficult substrates
• Unique c-‐c bond cleavage of epoxides
• Enan)oselec)ve nucleophilic fluorina)on with DAST – like compounds is ineffec)ve
Metals in Fluorina)on
• Selecrluor and DAST can be used for a wide variety of fluorina)ons • They are both much more mild and user friendly reagents than Fluorine gas
• Neither Selecrluor or DAST translated very well into an enan)oselec)ve process.
N
N
H
H
HHO FNSF3
O
Electrophilic Fluorina)on With Pt
In screening a variety of electrophilic !uorine sources, it wasdiscovered that only XeF2 e"ectively competed with !-Helimination. Other less reactive F+ sources showed apredominance to exclusive !-H elimination to 3.13 In additionto the desired 1, over-!uorination to 4 was also observed. Sincecontrols showed that 1 does not react with XeF2 and acid isknown to enhance the F+ potential of XeF2,
14 we surmised thatthe HF byproduct of cyclization was activating the XeF2. Thisproblem was easily solved by the addition of TMSOMe as anHF sponge, which additionally obviates the need for a base.15
Optimization studies included testing multiple bisphos-phines, solvents, and other TMS-X derivatives.15 Once again(S)-xylyl-phanephos was uniquely enantioselective (!75%) forcontrolling the % ee of the cation-ole#n cascades. Of the testedHF scavengers, TMSOMe was the most e"ective inhibitor ofdouble !uorination, and like previous ionic cascades, nitro-methane was the optimum solvent. A catalyst formulationcomprised of 10 mol % (S)-(xylyl-phanephos)PtI2, 25 mol %AgBF4, 30 mol % NCC6F5, and stoichiometric quantities ofXeF2 and TMSOMe at 0 °C provided 1 in 67% yield and with a75% enantiomeric excess.16
These optimized conditions were subsequently applied to avariety of alcohol and phenol terminated dienes and trienes(Table 2). In most cases, a high conversion of substrateoccurred within 3 h; however, the reactions were allowed toproceed for 24 h at 0 °C to ensure complete consumption ofthe XeF2. For the substrate classes in Table 2, no Brønsted acidderived products such as 5 were observed, and a singlediastereomer consistent with stereoretentive !uorination of theintermediate P2Pt-alkyl cation was observed.As shown in Table 2, variants on the phenol termini were
well tolerated, except for "-naphthol (entry 3), whereincompetitive !uorination of the aryl ether product occurs evenwith TMSOMe. In situ monitoring indicated that aryl!uorination occurred after cyclization/Pt"C !uorination. Inthis case, extra XeF2 was used to compensate for thedi!uorination stoichiometry. Unexpectedly, para-substituentsimproved the ee’s (entries 4"7).Dienyl and trienyl alcohols and phenols were also viable
substrates though they behaved peculiarly. In the case of entries8 and 9, the yields were poor under standard conditions butcould be recovered by exchanging TMSOMe for a polystyrene-bound piperidine base (see Table 1). In contrast, the triene
alcohol in entry 10 performed better under the standardconditions. These base e"ects are not yet understood.In situ monitoring of a cyclization/!uorination of 2 indicated
that the alkyl cation (as the nitrile adduct, 6) serves as thecatalyst resting state (31P NMR). These data support ourcurrent view of the mechanism (Scheme 2) that has 6competitively undergoing !-H elimination or F+ attack togenerate a [Pt]IVR(F) dication, which undergoes a stereo-retentive reductive elimination to 1. Neither the [Pt]IV nor the
Scheme 2. Proposed Catalytic Cycle for ElectrophilicFluorination
Table 2. Catalytic Electrophilic Fluorinationa
aConditions: 10 mol % (S)-(xylyl-phanephos)PtI2, 25 mol % AgBF4,30 mol % NCC6F5, 1.1 equiv of TMS-OMe, 1.1 equiv of XeF2, 0.4 mLof CD3NO2, 0 °C, 24 h. Starting material is mass balance of reaction.bIsolated yield, % ee determined by chiral GC. cGC yield. dReactionrun using 1.6 equiv of XeF2.
ePercentage is !uorinated eliminationspecies only. fReaction with 20 mol % polystyrene-bound piperidinebase run with no TMS-OMe; see SI for details. gDue to the volatilityof this compound, a GC yield is reported. hContains 23% unidenti#edspecies; mass balance is unreacted starting materisl. Cannot separatethe unidenti#ed species from the product; therefore GC yield isreported.
Journal of the American Chemical Society Communication
dx.doi.org/10.1021/ja3116795 | J. Am. Chem. Soc. XXXX, XXX, XXX"XXXB
In screening a variety of electrophilic !uorine sources, it wasdiscovered that only XeF2 e"ectively competed with !-Helimination. Other less reactive F+ sources showed apredominance to exclusive !-H elimination to 3.13 In additionto the desired 1, over-!uorination to 4 was also observed. Sincecontrols showed that 1 does not react with XeF2 and acid isknown to enhance the F+ potential of XeF2,
14 we surmised thatthe HF byproduct of cyclization was activating the XeF2. Thisproblem was easily solved by the addition of TMSOMe as anHF sponge, which additionally obviates the need for a base.15
Optimization studies included testing multiple bisphos-phines, solvents, and other TMS-X derivatives.15 Once again(S)-xylyl-phanephos was uniquely enantioselective (!75%) forcontrolling the % ee of the cation-ole#n cascades. Of the testedHF scavengers, TMSOMe was the most e"ective inhibitor ofdouble !uorination, and like previous ionic cascades, nitro-methane was the optimum solvent. A catalyst formulationcomprised of 10 mol % (S)-(xylyl-phanephos)PtI2, 25 mol %AgBF4, 30 mol % NCC6F5, and stoichiometric quantities ofXeF2 and TMSOMe at 0 °C provided 1 in 67% yield and with a75% enantiomeric excess.16
These optimized conditions were subsequently applied to avariety of alcohol and phenol terminated dienes and trienes(Table 2). In most cases, a high conversion of substrateoccurred within 3 h; however, the reactions were allowed toproceed for 24 h at 0 °C to ensure complete consumption ofthe XeF2. For the substrate classes in Table 2, no Brønsted acidderived products such as 5 were observed, and a singlediastereomer consistent with stereoretentive !uorination of theintermediate P2Pt-alkyl cation was observed.As shown in Table 2, variants on the phenol termini were
well tolerated, except for "-naphthol (entry 3), whereincompetitive !uorination of the aryl ether product occurs evenwith TMSOMe. In situ monitoring indicated that aryl!uorination occurred after cyclization/Pt"C !uorination. Inthis case, extra XeF2 was used to compensate for thedi!uorination stoichiometry. Unexpectedly, para-substituentsimproved the ee’s (entries 4"7).Dienyl and trienyl alcohols and phenols were also viable
substrates though they behaved peculiarly. In the case of entries8 and 9, the yields were poor under standard conditions butcould be recovered by exchanging TMSOMe for a polystyrene-bound piperidine base (see Table 1). In contrast, the triene
alcohol in entry 10 performed better under the standardconditions. These base e"ects are not yet understood.In situ monitoring of a cyclization/!uorination of 2 indicated
that the alkyl cation (as the nitrile adduct, 6) serves as thecatalyst resting state (31P NMR). These data support ourcurrent view of the mechanism (Scheme 2) that has 6competitively undergoing !-H elimination or F+ attack togenerate a [Pt]IVR(F) dication, which undergoes a stereo-retentive reductive elimination to 1. Neither the [Pt]IV nor the
Scheme 2. Proposed Catalytic Cycle for ElectrophilicFluorination
Table 2. Catalytic Electrophilic Fluorinationa
aConditions: 10 mol % (S)-(xylyl-phanephos)PtI2, 25 mol % AgBF4,30 mol % NCC6F5, 1.1 equiv of TMS-OMe, 1.1 equiv of XeF2, 0.4 mLof CD3NO2, 0 °C, 24 h. Starting material is mass balance of reaction.bIsolated yield, % ee determined by chiral GC. cGC yield. dReactionrun using 1.6 equiv of XeF2.
ePercentage is !uorinated eliminationspecies only. fReaction with 20 mol % polystyrene-bound piperidinebase run with no TMS-OMe; see SI for details. gDue to the volatilityof this compound, a GC yield is reported. hContains 23% unidenti#edspecies; mass balance is unreacted starting materisl. Cannot separatethe unidenti#ed species from the product; therefore GC yield isreported.
Journal of the American Chemical Society Communication
dx.doi.org/10.1021/ja3116795 | J. Am. Chem. Soc. XXXX, XXX, XXX"XXXB
• Fluorina)on outcompetes B-‐hydride elimina)on!
Cataly)c Enan)oselec)ve Cycliza)on and C3-‐Fluorina)on of Polyenes, Gagne, JACS, ASAP
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N OH
AcO
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S Selectfluor
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OBnOBnOOBn
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HN
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OHSelectfluor
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2) Mechanism and Product
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N OH
AcO
N SF3
AcO
CH3F
CN
Richards, Tetrahedron Lecers, 2000, 41, 9351
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S Selectfluor
TEA
S F
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OBnOBnOOBn
OHBnO Selectfluor
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![Brain Amyloid Imaging · D = 6.7 nM AD brain 2014 2012 [18F]AV-45 florbetapir HN O CH 3 O N O 18 F K D = 3.1 nM AD brain Approved 18F-Labeled Amyloid Radiotracers [18F]3’F-PIB](https://static.fdocuments.in/doc/165x107/5ec436274d34d13b041ea689/brain-amyloid-imaging-d-67-nm-ad-brain-2014-2012-18fav-45-florbetapir-hn-o.jpg)
