Late-Stage Deoxyfluorination of ���Alcohols with PhenoFluor
Sladojevich, F.; Arlow, S. I.; Tang, P.; Ritter, T. J. Am. Chem. Soc. 2012, ASAP DOI: 10.1021/ja3125405
Kara George Rosenker Current Literature 23 February 2013
Me
OH
Me
O
OMeO
Me
O
Me
OH
Me
O
Me
MeO
MeMe
OH
Me
OHHO Me
OH
Me
O
OMeO
Me
O
Me
OH
Me
O
Me
MeO
MeMe
F
Me
OHHO
predictable and selective deoxyfluorination
N NiPr
iPr
iPr
iPrF FPhenoFluor
71%
Fluorine in Medicinal Chemistry • The carbon fluorine bond plays an integral role in agrochemicals,
pharmaceuticals, materials, and imaging • Approximately 20% of all pharmaceuticals contain fluorine • Strategies for the introduction of fluorine atoms in medicinal
chemistry: • Metabolic stability by blocking metabolically labile sites • Modulate the physicochemical properties such as lipophilicity
or basicity • Enhance binding affinity to a target protein
• Non-natural 18F is the most commonly used positron-emitting isotope for molecular positron emission tomography (PET) imaging in oncology
(a) Vitaku, E.; Ilardi, E. A.; Njarðarson, J. T. Top 200 Pharmaceutical Products by US Retail Sales in 2011. (b) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637. (c) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (e) Jens Langner, J.; retrieved from http://en.wikipedia.org/wiki/File:PET-MIPS-anim.gif#filelinks
Lipitor (Pfizer)$7.7 billion (2011)
NNH
O
F
OH OH
OH
O
Lexapro(Forest Laboratories)
$2.9 billion (2011)
O
N
N
F
Me
H
H
F
F
Me
O
HO
S
O
F
OO
HO
HO
OH HN
O
Advair Diskus (GSK)$4.6 billion
Carbon-Fluorine Bond Formation • Despite fluorine’s importance, carbon-fluorine bond formation still represents
a formidable synthetic challenge • Only 21 biosynthesized natural molecules containing fluorine are known and
no fluoroperoxidase is known • Conventional fluorination reactions are generally limited to very simple
molecules, with reliable fluorination of more complex molecules at specific positions being difficult
• New methods to incorporate fluorine into complex organic molecules are crucial to the progress of the field
Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637. Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470. O’Hagan, D.; Harper, D. B. Asymmetric Fluoroorganic Chemistry; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
O
OHO2C CO2H
F
OHHO2C
F
OOS
O
OH2N
FHO OH
N
N
NN
NH2
F CO2H
fluoroacetate fluorocitrate nucleocidin
ω-fluoro-oleic acid
Carbon-Fluorine Bond Formation • Despite fluorine’s importance, carbon-fluorine bond formation still represents
a formidable synthetic challenge • Only 21 biosynthesized natural molecules containing fluorine are known and
no fluoroperoxidase is known • Conventional fluorination reactions are generally limited to very simple
molecules, with reliable fluorination of more complex molecules at specific positions being difficult
• New methods to incorporate fluorine into complex organic molecules are crucial to the progress of the field
Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637. Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470. O’Hagan, D.; Harper, D. B. Asymmetric Fluoroorganic Chemistry; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
OHR
R1R2
FR
R1R2
Deoxyfluorination Reagents: DAST and Deoxo-Fluor®
• Reported by Middleton in 1975 as the first bench-stable deoxyfluorinating reagent and a useful alternative to SF4
• DAST suffers from poor thermal stability and potentially hazardous scale-up
• Deoxo-Fluor® was introduced in 1999 and is a significant competitor to DAST for deoxyfluorination reactions due to its improved thermal stability
Middleton, W.J. J. Org. Chem. 1975, 40, 574. Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. J. Org. Chem. 1999, 64, 7048. Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M. Chem. Commun. 1999, 215.
OH O SF
NEt2F
O SF
NEt2 FSFF F
NEt2
FHF
Et2N S FF F
Et2NS
NEt2
F F
ExplosiveSF4
90 °CEt2N S FF F
N
Me
SF3
Me
DAST
MeO NOF3SMe
coordination prevents decomposition
NSF3
MeO OMe
Deoxo-Fluor®
Deoxyfluorination Reagents: XtalFluor-E® and XtalFluor-M®
• In 2009, Courturier and co-workers reported the preparation and use of XtalFluor-E® and XtalFluor-M®
• XtalFluor-E® and XtalFluor-M® are crystalline reagents that are relatively safe and cost-efficient to prepare
• The reactions require the addition of either an HF�amine reagent or DBU for efficient transformation
• The XtalFluor® reagents are typically more selective and reduce the levels of elimination side products often observed with DAST and Deoxo-Fluor®
L’Heureux, A.; Beaulieu, F.; BenneJ, C.; Bill, D. R.; Clayton, S.; LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M. J. Org. Chem. 2010, 75, 3401. Beaulieu, F.; Beauregard, L.-‐P.; Courchesne, G.; Couturier, M; LaFlamme, F.; L’Heureux, A. Org. Le4. 2009, 11, 5050.
ROHXtalFluor-E
RO SF
NEt2
F
H
Et3N⋅3HF
F
RF
[DBU-H]+ DBU
RO S
F
NEt2F
RO S
F
NEt2F
Me Me
NSF2 BF4
XtalFluor-E®O
NSF2 BF4
XtalFluor-M®
N
Me
SF3
Me
DAST
NSF3
MeO OMe
Deoxo-Fluor®
Deoxyfluorination Reagents: Fluolead™ and TFEDMA, ���Yarovenko’s and Ishikawa’s reagents
• There reagents are generally prepared by the addition of Et2NH to the corresponding halogenated alkene
• This group of reagents can suffer from formation of ester and amide side products
(a) Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc. 2010, 132, 18199. (b) Takaoka, A.; Iwakiri, H.; Ishikawa, N. Bull. Chem. Soc. Jpn. 1979, 52, 3377. (c) Petrov, V. A.; Swearingen, S.; Hong, W.; Petersen, W. C. J. Fluorine Chem. 2001, 109, 25. (d) Yarovenko, N. N.; Raksha, M. S. Zh. Obshch. Khim. 1959, 29, 2159.
OH O
NEt2
CF3
F
O
NEt2
CF3
F
F
F
FIshikawa's
reagent
• In 2010, Umemoto and co-workers introduced the second generation PhSF3, which is marketed as Fluolead™
• More chemically stable than PhSF3, and more more thermally stable than DAST because of the stronger C-S bond in Fluolead™
• Ishikawa’s, Yarovenko’s, and TFDMA reagents fluorinate a wide range of primary and secondary alcohols to provide alkyl fluorides
NMe
Me
FF
FH Cl
NMe
Me
FF
H F F
FF
NMe
Me
FF
FH F
Yarovenko's reagent Ishikawa's reagent
TFEDMAR
OH
R
OIshikawa's
reagent
Et2N
CF3
F
RF CF3
O
NEt2
Me Me
tBu
SF3
Fluolead™
Deoxyfluorination Reagent: PhenoFluor
• PhenoFluor was first reported by Ritter and co-workers in 2011 for deoxyfluorination of phenols
• PhenoFluor is commercially available from Sigma-Aldrich • PhenoFluor is a crystalline, nonexplosive solid that can be handled in air, but
hydrolyzes upon prolonged storage in a wet atmosphere • PhenoFluor can be stored in a dry toluene solution for at least 2 months
without detectable decomposition
Tang, P.; Wang, W.; RiJer, T. J. Am. Chem. Soc. 2011, 133, 11482-‐11484. Tang, P.; Wang, W.; RiJer, T. WO 2012/142162
MeO
OH
3 equiv CsFtoluene, 110 °C MeO
F
82%
PhenoFluor
N NiPr
iPr
iPr
iPrF F
PhenoFluor
PhenoFluor: Proposed Mechanism • Ritter and co-workers propose that the mechanism for fluorination proceeds via a 2-
phenoxyimidazolium bifluoride salt
Tang, P.; Wang, W.; RiJer, T. J. Am. Chem. Soc. 2011, 133, 11482-‐11484.
MeO
OH N NiPr
iPr
iPr
iPrO
OMe
H
HF
F
toluene, 23 °C
N NiPr
iPr
iPr
iPrF FMeO
F
67%
3 equiv CsF
toluene-d8, 110 °C
N NiPr
iPr
iPr
iPrF F
OH
N NiPr
iPr
iPr
iPrF
N NiPr
iPr
iPr
iPrF O ArH
B
N NiPr
iPr
iPr
iPrF O Ar
N NiPr
iPr
iPr
iPrO
F
F
Ar
N NiPr
iPr
iPr
iPrO Ar
MeO
F
HF2
PhenoFluor: Proposed Mechanism • Ritter and co-workers propose that the mechanism for fluorination proceeds via a 2-
phenoxyimidazolium bifluoride salt
Tang, P.; Wang, W.; RiJer, T. J. Am. Chem. Soc. 2011, 133, 11482-‐11484.
MeO
OH N NiPr
iPr
iPr
iPrO
OMe
H
HF
F
toluene, 23 °C
N NiPr
iPr
iPr
iPrF F
N NiPr
iPr
iPr
iPrF F
OH
N NiPr
iPr
iPr
iPrF
N NiPr
iPr
iPr
iPrF O ArH
B
N NiPr
iPr
iPr
iPrF O Ar
N NiPr
iPr
iPr
iPrO
F
F
Ar
N NiPr
iPr
iPr
iPrO Ar
MeO
F
HF2
PhenoFluor: Hydrogen Bonding
Tang, P.; Wang, W.; RiJer, T. J. Am. Chem. Soc. 2011, 133, 11482-‐11484.
MeO
F
<1%
MeO
F
<1%
MeO
F
2%
N NAr Ar
OAr'
ClCl HF2
N NAr Ar
OAr'
HF2
N NAr Ar
OAr'
HH PF6
3 equiv CsF
toluene-d8, 110 °C
3 equiv CsF
toluene-d8, 110 °C
3 equiv CsF
toluene-d8, 110 °C
MeO
OH N NiPr
iPr
iPr
iPrO
OMe
H
HF
F
toluene, 23 °C
N NiPr
iPr
iPr
iPrF F
MeO
F
67%
3 equiv CsF
toluene-d8, 110 °C
Title Paper: Deoxyfluorination of Aliphatic Alcohols • Modifications of the initial reaction conditions allowed for the deoxyfluorination of
aliphatic alcohols
Sladojevich, F.; Arlow, S. I.; Tang, P.; Wang, W.; RiJer, T. J. Am. Chem. Soc. 2012, ASAP. DOI: 10.1021/ja3125405
FmocHN CO2Me
HO
FmocHN CO2Me
Fdeoxyfluroinating reagent
FmocHN CO2Me
HO
FmocHN CO2Me
F
N NiPr
iPr
iPr
iPrF FPhenoFluor
74% in dioxane 80% in toluene
N NMe MeF F
N
Me
SF3
Me O
NSF2 BF4 N
SF3
MeO OMe
Me Me
tBu
SF3
DFI DAST XtalFluor-M® Deoxo-Fluor® Fluolead™
toluene
dioxane
reported optimizedconditions
<1%
2%
<1%
<1%
11%
3%
<1%
<1%
<1%
<1%
10%
<1%
<1%
<1%
<1%
Title Paper: Late-Stage Deoxyfluorination of Alcohols
Sladojevich, F.; Arlow, S. I.; Tang, P.; Wang, W.; RiJer, T. J. Am. Chem. Soc. 2012, ASAP. DOI: 10.1021/ja3125405
PhenoFluor
2.0 equiv EtNiPr22.0 equiv KF
2-20 h
OHR
R1R2
FR
R1R2
parent compoundyield%
solvent, temperature
• Chiral secondary alcohols could typically be deoxyfluorinated with inversion • Carbonyl functional groups are well tolerated
N
F
CO2MeBoc
O
F
OO
O
OMe
Me
MeMe
(2S, 4R)-4-hydroxy-proline92%
toluene, 80 °C
D-allofuranose83%
toluene, 80 °C
artemisinin79%
toluene, 80 °C
OO
H Me
HH
Me OO
FMe
reserpine82%
toluene, 80 °C
NNH
MeO
H
H
H
MeO2COMe
F
O
FMe
H
H
Me
H
OH
N
O
F
testosterone88%
toluene, 80 °C
77%toluene, 80 °C
epi-androterone84%
toluene, 80 °C
OMe
H
H
H
Me
HF
Sladojevich, F.; Arlow, S. I.; Tang, P.; Wang, W.; RiJer, T. J. Am. Chem. Soc. 2012, ASAP. DOI: 10.1021/ja3125405
• Secondary allylic alcohols afforded allylic fluorides consistent with an SN2 mechanism • Deoxyfluorination is site-selective and predictable
PhenoFluor
2.0 equiv EtNiPr22.0 equiv KF
2-20 h
OHR
R1R2
FR
R1R2
parent compoundyield%
solvent, temperature
galantamine80%, 10:1 dr
toluene, 80 °C
O
N
F
Me
MeO
morphine80%
CH2Cl2, 23 °C
O
F
H
BzO
N Me
ajmaline30%
CH2Cl2, 50 °C
NN F
MeMe
HO
H
methyl α-D-glucopyranoside43%
dioxane, 80 °C
O
OMe
HOHO
F
HO ivermectin B1a41%
toluene, 50 °C
O O O
OMe
MeMe
MeOOMe
Me
HO O
OO
MeF
OH
O
O
Me
MeMeH
Title Paper: Late-Stage Deoxyfluorination of Alcohols
Title Paper: Site-Selective Late-Stage Deoxyfluorination of Alcohols
Sladojevich, F.; Arlow, S. I.; Tang, P.; Wang, W.; RiJer, T. J. Am. Chem. Soc. 2012, ASAP. DOI: 10.1021/ja3125405
• Deoxyfluorination can be carried out at room temperature, allowing for fluorination of temperature sensitive substrates
• KF was not required
everolimus83%
CH2Cl2, 23 °C
oligomycin A71%
CH2Cl2, 23 °C to 0 °C
Me
OH
Me
O
OMeO
Me
O
Me
OH
Me
O
Me
MeO
MeMe
F
Me
OHHOOF
MeO
O O
Me
Me
MeO
OH
O
Me
ON
Me
OO
OHOMe
Me
OMe
Me
PhenoFluor
2.0 equiv EtNiPr22.0 equiv KF
2-20 h
OHR
R1R2
FR
R1R2
parent compoundyield%
solvent, temperature
Title Paper: Site-Selective Late-Stage Deoxyfluorination of Alcohols
Sladojevich, F.; Arlow, S. I.; Tang, P.; Wang, W.; RiJer, T. J. Am. Chem. Soc. 2012, ASAP. DOI: 10.1021/ja3125405
Me
O
Me
O
OMeO
Me
O
Me
O
Me
O
Me
MeO
MeMe
OH
Me
OHHO
tertiary alcoholnon-allylic
β,β'-disubsitutionhydrogen bonding
β,β'-disubsitution
selective fluorination siteoligomycin A
Me
OH
Me
O
OMeO
Me
O
Me
OH
Me
O
Me
MeO
MeMe
F
Me
OHHO
N NiPr
iPr
iPr
iPrF FPhenoFluor
71%
H H
• Primary alcohols are selectively deoxyfluorinated • Secondary alcohols react slower or not at all when they are β,β’-dibranched, unless it is allylic
• Hydroxyl groups engaged in hydrogen bonding are not reactive • Tertiary alcohols do not react, unless they are allylic
Deoxyfluorination with PhenoFluor: Mechanistic Considerations
Sladojevich, F.; Arlow, S. I.; Tang, P.; Wang, W.; RiJer, T. J. Am. Chem. Soc. 2012, ASAP. DOI: 10.1021/ja3125405
• The formation of elimination products could be reduced by increasing the reaction temperature from 23 °C to 80 °C
• The addition of DIPEA was beneficial to shorten the reaction time • KF was found to reduce side products resulting from elimination, but
was not generally required for the reaction to proceed
N NiPr
iPr
iPr
iPrF F
HO R
N NiPr
iPr
iPr
iPrF
N NiPr
iPr
iPr
iPrF ORH
B
N NiPr
iPr
iPr
iPrF OR
N NiPr
iPr
iPr
iPrO
R
N NiPr
iPr
iPr
iPrOF R
F
F
HF2
Conclusions and Outlook
Sladojevich, F.; Arlow, S. I.; Tang, P.; Wang, W.; RiJer, T. J. Am. Chem. Soc. 2012, ASAP. DOI: 10.1021/ja3125405
• A general method for selective, late-stage deoxyfluorination of complex aliphatic alcohols has been developed
• The substrate scope and functional group tolerance of this methodology surpass all
others reported to date • PhenoFluor has a better safety profile and higher chemoselectivity than other
deoxyfluorination reagents • One drawback is the molar mass (427 g/mol), which is convenient for subgram- and
gram-scale reactions, but is wasteful for larger-scale reactions • Extending this method to late-stage 18F radiolabeling would be useful for positron
emission tomography (PET) applications
PhenoFluor
2.0 equiv EtNiPr22.0 equiv KF
2-20 h
OHR
R1R2
FR
R1R2
OHR
R1R2
18FR
R1R2
