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Roles forFluorine inMedicinal
Chemistry
Contents

1. Introduction
2. Fluorination
3. Difluoromethylation
4. Trifluoromethylation
5. SummaryPhysical Properties of Fluorine! Its van der Waals radius is closer to that of oxygen as is its
electronegativity! The strongly electron withdrawing nature of fluorine substitution isespecially evident in its effect on the acidity of neighboring functionalgroups.

Changes in pKa can have effects on a number of different parameters inlead optimization including physicochemical properties (solubility, log D),
binding affinities (potency, selectivity), and absorption, distribution,
metabolism, excretion (ADME).


Launched Drugs Containing Fluorine 1957-2006 " The number of fluorine-containing launched drugs as a percentage ofthe total number of launched drugs has remained relatively constant(green bars)
" Fluorinated drugs have constituted approximately 5-15% of the total
number of launched drugs worldwide over the past 50 years with a
noticeable increase in the past 5 years.
Fluorine in Pharmaceuticals
1. Selectivity (off target effects)
2. Metabolic Clearance
A particularly labile site of metabolic oxidation can be blocked byfluorination without adversely effecting affinity.

3. Brain Penetration
4. Protein Binding
These interactions may occur between fluorine and a protein
directly, may be bridged by a sphere of solvation, or may occur byalterations in the conformation of the molecule.

Modulating Potency & Selectivity by Introduction ofFluorine (1)Potent inhibitors of β-amyloid cleaving enzyme (BACE)

Threefold improvementin cellular potency

excellent selectivity
could be achieved,particularly against
Cat-DBioorg. Med. Chem. Lett. 2008, 18, 1022. Modulating Potency & Selectivity by Introduction ofFluorine (2)Superimposition of 6-sultam The substituents which
had been shown to forma H-bond to Asn-294, or
which would bind more
tightly in the S1 pocket isneeded.

Effect of fluorine might be observed in the sultam series.
Bioorg. Med. Chem. Lett. 2008, 18, 1022.

Effects of Fluorine on Pharmacokinetic Parameters &Drug-Like Properties (Metabolic Stability)
Linopirdine (24) was among the first clinical compounds that enhanced
potassium-evoked release of acetylcholine in preclinical models of AD.

Short and variable half-life&poor BBB penetration # Lowering pKa and reducing metabolic N-oxidation# Led to a signficant improvement in brain-to-plasma ratio
J. Med. Chem. 1998, 41, 4615.

Solubility
The powerful electron-withdrawing effect of fluorine can strongly affectthe polarity of nearby functional groups, modulating properties including
pKa and hydrogen-bonding capabilities.
The fluorine serves to polarize the NH bond of the adjacent urea,
rendering it a more potent hydrogen bond donor and thereby enhancing
solvation by water.
Protein Binding (covalent)
The cannabinoid receptor system (CB1R) regulates feeding behavior• SAR of CB1R inverse agonists

Displayed irreversible toxic binding
The initial lead 49 had poor oral bioabvailabilitySmall Summary (1)! The presence of this one atom can influence metabolic stability, brain
exposure, off-target selectivity, protein binding, and affinity for the
primary biological target.

! Therefore, striking the correct balance of drug-like properties will remaina recurring challenge in lead optimization but strategies utilizing
fluorine’s impact on these properties will continue to influence thesuccess of many drug discovery programs.
Contents

1. Introduction
2. Fluorination
3. Difluoromethylation

Antozonite (2012)

4. Trifluoromethylation
5. Summary

Liquid FluorineElectrophilic Fluorinationcf) Mr. Saitou’s M2 Lit. Seminar

Fluorinating Reagents
• Fluorine gas, hypofluorites, fluoroxysulfates, perchloryl fluoride High reactivity
• XeF2 : more stable electrophilic fluorination sourceStill limits the tolerance of this reagent to FG.• Crystalline, benchtop-stable fluorinating reagents



The Fluorination of Arenes (C-M to C-F)
Sn, Hg, Pb, Ge, Si, B

F 2, XeF2, OF2, HOF.....

FHowever, the substrate scope is limited due to the high reactivity of thereagent, and often results in unselective fluorination.

The fluorination of Grignard reagents with electrophilic is narrow in scope
due to the basicity and nucleophilicity of the aryl magnesium reagents.
Knochel, P. et al. Angew. Chem. Int. Ed. 2010, 49, 2215. 

Palladium-Catalyzed ortho-Fluorination
M. S. Sanford, et al. JACS, 2006, 128, 7134.

Harsh condition
J. -Q. Yu, et al. JACS, 2009, 131, 7520.

Limited to orthoposition
Couldn’t prevent the difluorination
Carbon-Fluorine Reductive Elimination (1) T. Ritter, et al. JACS, 2008, 130, 10060.
T. Ritter, et al. ACIE, 2008, 47, 5993.

[Mechanism]

pyridyl-sulfonamidestabilized aryl palladium
complexesCarbon-Fluorine Reductive Elimination (2) The computedenergy difference(∆H298) between 1and 1b is 2.2
kcal•mol-1 favoring 1.
• Methods employed in this mechanistic study 

T. Ritter, et al. JACS, 2010, 132, 3793.

 

Proposed Mechanism of C-F Reductive Elimination
T. Ritter, et al. JACS, 2010, 132, 3793.

O-sulfonamide
dissociation of thehexacoordinate
Pd(IV) complex 1 toform a cationic,
pentacoordinate
complex

Ligand rearrangement
may take place for C-F
reductive elimination. Reductive eliminationfrom pentacoordinatetransition metal
complexes likely proceedsfrom distorted trigonal
bipyramidal structures.

 Palladium(III)-Catalyzed Fluorination (1)Only two catalytic reactions have been reported that provide a generalroute to functionalized aryl fluorides.
Buchwald, S. L. et al. Science, 2009, 325, 1661.
Ritter, T. et al. JACS, 2010, 132, 12150.

• Ritter, T. et al. JACS, 2013, 135, 14012.

For arylboronic acid derivatives, slow transmetalation of the arene fromboron to the transition metal complex is frequently a hurdle.

propose a mechanism thatproceeds without theformation of organopalladium
intermediates.
 

Palladium(III)-Catalyzed Fluorination (2)[Proposed Mechanism]

T. Ritter, et al. JACS, 2013, 135, 14012.

" Synthesis and X-ray Structure of Pd(III)Intermediate For recent reviews of Pd(III) complexes;
Ritter, T. et al. JACS, 2012, 134, 12002.
Ritter, T. et al. Top. Organomet. Chem. 2011, 503, 129.
Ritter, T. et al. Acc. Chem. Res. 2012, 45, 840.

Contents

1. Introduction
2. Fluorination
3. Difluoromethylation4. Trifluoromethylation
5. SummaryDifluomethylation (introduction)
The increased acidity of XF2C-H compared to XFHC-H facilitates theformation of F2CX-

Nuc H

ClCF 2H,

Nuc H

Zn(CF3)Br, Cd(CF3)2, Bi(CF 3)3 /AlCl3,

Nuc CF 2H
Nuc CF 2H

phenol, thiophenol…
JACS. 1985, 107, 5014.

All of which react through difluorocarbene intermediates.

An electrophilic reagent for the direct introduction of a “CF2H+”
building block is yet to be reported.

Electrophilic Difluoromethylation G. K. S. Prakash, et al. Org. Lett. 2007, 9, 1863.

The reagent did not give the corresponding difluoromethylated products witheither phenols, carbon-based nucleophiles, or primary/secondary amines.
• The successful difluoromethylation of S, N, and C nucleophiles

Hu, J. et al. Org. Lett. 2009, 11, 2109.



Radical Difluoromethylation of Heteroarene

[Zn](SO2CF2H)2

Baran, P. S. et al. JACS. 2012, 134, 1494.

Contents

1. Introduction
2. Fluorination
3. Difluoromethylation
4. Trifluoromethylation
5. SummaryTrifluoromethylation (introduction)
! Difficulties of Trifluoromethylation
Only one other substituent can be varied.
Transition-metal-mediated trifluoromethylation is complicated by the strong
metal-CF3 bond .
1. the polar contribution of the bond
2. backbonding from filled metal d orbitals into the s*C-F bonds! Electrophilic trifluoromethylating reagents
In laboratory settings
Crystalline
Easily weighable reagents

In industrial process
Lower cost reagents
Such as CF3H, CF3I Pathway to Trifluoromethyl arenes
1. Innate Trifluoromethylation
CF3•
HCF3

" CF3+ "2. Programmed Trifluoromethylation
(DG)" CF3 -[M] "CF3(X)(X = Cl, Br, I, B(OH) 2) 

Cu-Catalyzed Trifluoromethylation of Aromatic compoundLanglois, B. R. et al. Tetrahedron. Letters. 1991, 32, 7525.

R2

R1

CF3SO2Na (4 eq)
tBuOOH (7 eq)
Cu(OSO 2CF3)2 (10 mol%)
CH3CN/H 2O, 20 ºC

Solid and bench-top-stable reagent

R2

R1

F 3C
Limited to electron-rich arene
Low yield

[Mechanism]

 

Radical Trifluoromethylation of Hereroarenes (1)Baran, P. S. et al. PNAS. 2011, 108, 14411.

 

Radical Trifluoromethylation of Hereroarenes (2)Baran, P. S. et al. PNAS. 2011, 108, 14411.

[Putative Mechanism]



Aromatic trifluoromethylation catalytic in copper (1) Urata and Fuchikami’s Works

Drawback of the protocols is the loading of CuI (1–1.5 equiv.) to complete
the desired reactions.

Amii’s WorkAmii, H. et al. Chem. Commun. 2009, 1909.



Aromatic trifluoromethylation catalytic in copper (2)Due to the sluggish regeneration of CuI in the second step, the net
transformation cannot supply sufficient amount of CuI.

[Diamine ligand]increase electron density at the metal centers
improve the nucleophilicity of the CF3
stabilize the soluble Cu(I) complexes

High yieldA Broadly Applicable Copper Reagent
Hartwing, J. F. et al. Angew. Chem. Int. Ed, 2011, 50, 3793.

Synthesis of 1,10-phen.-ligand

Up to 99% yield

Palladium-Catalyzed Trifluoromethylation
Buchwald, S. L. et al. Science 2010, 328, 1670.

No catalytic system with thissystem was reported.

See also
Grushin , V. V. et al. JACS,
2006, 128, 12644.

They use quantitative
amount of[(Xantphos)Pd(CF3)Ph]. 

Aryl-CF3 Bond-Forming Reductive Elimination (1) 
Sanford, M. S. et al. JACS. 2010, 132, 2878.

Pd(II)-mediated ArylCF3 bond-forming reactions remain limited by therequirement for specialized and expensive phosphine ligands, relatively highreaction temperatures, and the need for expensive Et3SiCF3.
• Synthesis of Pd(II) complexes• Reductive elimination from Pd(IV) complex

Aryl-CF3 Bond-Forming Reductive Elimination (2) 
Sanford, M. S. et al. JACS. 2011, 133, 7577.

Fluoride (the X-type ligand introduced to Pd(IV) by F+sources) might undergoslower reductive elimination than CF3.

modest to excellent yieldAryl-CF3 Bond-Forming Reductive Elimination (3) 
Sanford, M. S. et al. JACS. 2011, 133, 7577.

The addition of 1 equiv of NBu4OTf to the thermolysis of 4 significantly
slowed the initial rate of formation of Ar-CF3.
 

Aryl-CF3 Bond-Forming Reductive Elimination (4) • Room Temperature Arene Trifluoromethylation

• Reactivity of (tmeda)Pd(Aryl)(CF3) Complexes

Sanford, M. S. et al. JACS. 2011, 133, 7577.  Aryl-CF3 Bond-Forming Reductive Elimination (5) Sanford, M. S. et al. JACS. 2011, 133, 7577.
Sanford, M. S. et al. JACS. 2010, 132, 2878.

The first isolated example of a Pd(IV) complex containing aperfluoroalkyl ligand.

octahedral Pd(IV) species  Small Summary (2)The most significant, conceptual advances over the past decade in thearea of fluorination were made in the reactions that led to the formation ofC-F and C-CF3 bonds, most prominently by organo- and transition-metalcatalysis.
The most challenging transformation remains the formation of the parent
C-F bond, primarily due to 1. the high hydration energy of fluoride,2. strong metal–fluorine bonds,
3. and the highly polarized nature of bonds
to fluorine.
Fluorination reactions still lack general predictability and practicality.

Contents

1. Introduction
2. Fluorination
3. Difluoromethylation
4. Trifluoromethylation
5. SummaryPositron Emission Tomography (PET)
Positron emission tomography (PET) is a noninvasive imaging technology
used to observe and probe biological processes in vivo.
Although several positron-emitting isotopes can be used for PET imaging,fluorine-18 (18F) is the most clinically relevant radioisotope.
(15O : 2 min, 13N10min, 11C : 20 min, 18F : 110 min)

Conventional [18F]fluoride chemistry has been limited to nucleophilic
fluorination reactions.
" Nucleophilic radiochemical fluorination with [18F]fluoride Late-Stage Fluorination Reagent for PET Imaging
Ritter, T. et al. science 2011, 334, 639.

[Electrophilic [18F]-Pd(IV) fluorinating reagent ]

• Late-stage fluorination to form 18F-labeled aryl fluorides # overall synthesis time of less than 60 min.
# Radiochemical yields (RCYs) as low as 5% can provide
meaningful PET imagingSmall Summary (3)Despite these limitations, modern fluorination methods have madefluorinated molecules more readily available than ever before.
In particular, the modern methods have started to have an impact on researchareas that do not require large amounts of material, such as drug discoveryand PET.
The ideal fluorination reaction would be predictable, general, andfunctional-group tolerant, and a readily available, inexpensive catalyst.
References
T. Ritter, et al. Angew. Chem. Int. Ed. 2013, 52, 8214.
W. K. Hagmann, J. of Med. Chem. 2008, 51, 4359.
K. J. Hodgetts, et al. Annual Reports in Medicinal Chemistry 2010, 45, 429.

endFluorine as a BioisostereBioisosteric replacement
for a carboxylate anion Metabolic Stability (Experimental Date)

 General Scheme of Directed electrophilic fluorination
Sanford & Yu’s Works
DG

DG

Pd(II)

FH

ElectrophilicFluorinationF

C-H Activation

DG: coordinatinggroupDG
Pd(II)

 General Scheme of electrophilic fluorination
Ritter’s Works
Pd(II)M

F

ReductiveElimination

Transmetalation

PhF Pd(IV)Ln

M = B(OR) 2
SnR3

PhPd(II)LnOxidation

FSilver-Catalyzed Fluorination Difluorination 

Difluoromethylation and Trifluoromethylation Possible Mechanism of Toni’s Reagent

Equivalent ofphenoxoniumcation
nucleophilic
ligand exchange The exact mechanisms for the trifluoromethylation have not been firmly
established in many cases; the mechanism could occur by two SET or one
two-electron transfer concurrent with or followed by trifluoromethyl grouptransfer.
Possible Mechanism of Toni’s reagent (1)

CF3−Ph Reductive EliminationNucleophilic CF3

 Considerations of Pd-Complex (PET)LUMO

carries three formal positive charges
Late transition metals such as palladium, when in a high oxidation
state, can function as an oxidant and transfer a ligand to a nucleophile.
 Ligands are multidentate ligands that were selected to impart stability
on both 1 and 2 toward undesired reductive processes.
 An octahedral Pd(IV) complex was chosen to avoid undesirednucleophilic attack at the transition metal.
 Multidentate ligands in 2 feature aromatic substituents to prevent
nucleophilic attack on the carbon and nitrogen atoms coordinated topalladium.
