Transcript The Pentafluorosulfanyl Group: A Substituent is Born

The Pentafluorosulfanyl Group:
A Substituent is Born
Joseph B. Binder
Raines Lab
September 14, 2006
“Substituent of the Future”
O
F5SCF2CF2
NO 2
F
O
N N
O
N
NO 2
SF5
N
O
Energetic Materials
SF5
F3C CF3
O
High Performance Polymers
SF5
-SF5
Cl
F 5S
H 2N
N
C3H 7
O
Liquid Crystals
NH 2
NH 2
Pharmaceuticals
Cl
N
O S
N
CN
CF3
Pesticides
2
A. M. Thayer, Chem. Eng. News 2006, 84, 27-32.
Outline
•
•
•
•
•
Background
Synthetic Strategies: Aliphatics
Synthetic Strategies: Aromatics
Applications
Conclusions and Outlook
3
Why Fluorinate Organics?
• Fluorination imparts unusual properties
– Small size
– Lipophilic
– High electronegativity
– Low reactivity
W. R. Dolbier, Jr.,Chimica Oggi 2003, 21, 66-69.
4
Options for Fluorination
F
F
F
C
F3CS
F
F3CO
F F
F S
F F
• Why choose –SF5?
–
–
–
–
More bulky
More lipophilic
More electron-withdrawing
More chemically inert
W. R. Dolbier, Jr.,Chimica Oggi 2003, 21, 66-69.
5
Properties: Size
• Very bulky
• Larger cross-sectional area than –CF3
P. G. Nixon, et al., Chem. Mater. 2000, 12, 3108-3112.
6
Properties: Lipophilicity
• πx = logPx – logPH
X
OCH2COOH
(P = 1-octanol/water partition coefficient)
X
SCF3 SF5 OCF3 CF3
πx
1.58 1.50
F
NO2
1.21 1.07 0.13 0.11
• πx can correlate with bioavailability
R. E. Banks (Ed.), Organofluorine Chemicals and Their Industrial
Applications, 1979.
7
Properties: Electronics
• Electron-withdrawing
NO2
COOH
SF5
COOH
CF3
COOH
SCF3
COOH
OCF3
COOH
F
COOH
pKa 4.60
4.82
5.11
5.15
5.16
5.28
0.73
0.61
0.44
0.40
0.39
0.28
50:50 EtOH:H 2O

F
F
2.60 D
F
F F
S F
F F
3.44 D
W. A. Sheppard, J. Am. Chem. Soc. 1962, 84, 3072-76; C. J. Byrne, et
al., J. Chem. Soc., Perkin Trans. 2 1987, 1649-53; J. Shorter, Pure
Appl. Chem. 1997, 69, 2497-2510.
8
Properties: Stability
• Typically thermally stable >300 °C
• Inert to wide range of transformations
• More stable than –CF3
COO -
CF3
CF3
98% H 2SO4, 90-95 °C
1 M NaOH, 2h
NH2
NH2
SF5
SF5
2 M NaOH, 48h
NH2
COOH
recovered
SO 2F
98% H 2SO4, 98-100 °C
W. A. Sheppard, J. Am. Chem. Soc. 1962, 84, 3064-72; R. D.
Bowden, et al., Tetrahedron 2000, 56, 3399-3408.
9
Outline
• Background
• Synthetic Strategies: Aliphatics
– Vigorous Fluorination
– SF5X Addition
– Incorporation of -SF5 Building Blocks
• Synthetic Strategies: Aromatics
• Applications
• Conclusions and Outlook
10
First Organic –SF5 Derivative
• Unexpected product
– Attempted preparation of CF3SF
– Produced more highly fluorinated CF3SF5
CH3SH
CS2
CoF3, Cu
250-275 °C
CoF3, Cu
200-250 °C
CF3SF5 + CF4 + CHF3 + SF6
20%
CF3SF5 + CF4 + SF6
40%
• Attractive properties sparked interest
– Very chemically inert
– Excellent electrical insulator
G. A. Silvey, et al., J. Am. Chem. Soc. 1950, 72, 3624-6;
R. Geballe, et al., J. Appl. Phys. 1950, 21, 592-4.
11
Vigorous Fluorination
• Harsh conditions
• Many side products
• Electrochemical
[(CH3CH2)NCH2CH2S]2
(CH3CH2CH2)2S
HF, Simons Cell
HF, Simons Cell
• Elemental Fluorine
(CH3)3CCH2SH
[(CH3)2CH] 2S
F2/He, Cu
-120 °C to rt
F2/He, Cu
-120 °C to rt
(CF3CF2)2NCF2CF2SF5 13%
CF3CF2CF2SF5
15%
(CF3CF2CF2)2SF4 10%
(CF3)3CCF2SF5 25%
CF3CF2CF2SF5 29%
F. W. Hoffmann, et al., J. Am. Chem. Soc. 1957, 79, 3424-9; A. F. Clifford, et al., 12
J. Chem. Soc. 1953, 2372-5; H. N. Huang, et al., Inorg. Chem. 1991, 30, 789-94.
SF5X Addition
• Photochemical addition
– Allows introduction of –SF5 selectively at unsaturation
– Requires specialized conditions
Cl
SF5Cl +
h, CFCl3
KOH, Et2O
rt, 2h,
OH sealed ampule SF5
F 5S
rt, 1.5 h
OH
76% OH
76%
h rt
SF5Cl +
CH3 sealed tube
Cl
F5S
V. K. Brel, Synthesis 2005, 1245-1250; J. R. Case, et al., J. Chem.
Soc. 1961, 2066-70.
13
SF5X Addition
• Thermal addition
– Effective with both SF5Cl and more reactive SF5Br
– Requires specialized conditions
Cl
SF5Cl +
SF5Br +
90°C, 2 d
(CH2)8OAc autoclave
F5S
84%
rt (7d), 40°C (20h), 55°C (2h)
autoclave
COOMe
(CH2)8OAc
Br
F 5S
COOMe
88%
– Side reactions include formal XF addition
SF5Cl +
rt, 18h
Cl
17% +
F
ClF product
Cl
14%
SF5
Expected
J. R. Case, et al., J. Chem. Soc. 1961, 2066-70; R. Winter, et al., J. Fluorine 14
Chem. 2001, 107, 23-30; R. Winter, et al., J. Fluorine Chem. 2000, 102, 79-87.
SF5X Addition: Mechanism
• Mechanistic observations
SF5Br +
F
SF5Br +
F
F
F
F
F
rt
7d thermal
30 min h
rt
7d thermal
30 min h
F 5S
Br
+ F5S
F
erythro
F
F
threo
F
F 5S
Br
F
T:E 1.83 dark
Br T:E 1.94 h
+ F5S
T:E 2.17 dark
Br T:E 2.15 h
F
A. D. Berry, et al., J. Org. Chem. 1978, 43, 365-7.
15
SF5X Addition: Mechanism
• Proposed mechanism
– Consistent with stereochemical outcome
– Sterically governed ·SF5 addition
Initiation:
SF5 + X
SF5X
Propagation:
R + SF5
F 5S
R
X
F5S
R + SF5X
F 5S
R
A. D. Berry, et al., J. Org. Chem. 1978, 43, 365-7.
+ SF5
16
SF5X Addition: Et3B Initiation
•
•
Allows moderate conditions
Avoids side reactions
Cl
SF5Cl, 0.1 eq Et 3B, hexane
98%, >9:1 dr
-30 to -20°C, 1 h
SF5
H2C C CH2
n-Pr
•
n-Pr
SF5Cl, 0.1 eq Et 3B, hexane
-30 to -20°C, 1 h
SF5Cl, 0.1 eq Et 3B, hexane
-30 to -20°C, 1 h
Cl
F5S
F5S
80%
n-Pr
93%
n-Pr
Cl
Ineffective with electron-deficient alkenes
OEt
O
SF5Cl or SF5Br
0.1 eq Et3B, hexane
-30 to -20°C, 1 h
No addition product
W.R. Dolbier, et al. J. Fluorine Chem. In Press; S. A. Mohand, et al., Org.
Lett. 2002, 4, 3013-3015.
17
Versatility of –SF5 Derivatives
• Cycloadditions
– Diels-Alder reaction
SF5
F 5S
SF5
+
COOH 110°C, 10h
COOH
endo 51%
exo 17%
COOH
– [3+2] Dipolar cycloadditions
Cl
NOH
+
F 5S
n=1,2
F5S
n
Ar
+
Cl
CH2N2
Et3N, -40°C, 3-4h
Ar = Ph, p-C6H4F
O N
Cl
F 5S
Ar
n
90-95%
Et2O
0°C, 80 min
HN
N
SF5 +
51%
N
HN
SF5
34%
V. K. Brel, Synthesis 2006, 339-343; F. W. Hoover, et al., J. Org. Chem.
1964, 29, 3567-70; V. K. Brel, Synthesis 2006, 2665-267-0.
18
Versatility of –SF5 Alkyl Halides
ICF2CF2I
+
CF2CF2
+
S2F10
R = SF5CF2CF2-
O
150°C
4h
50%
R
R
Acrylate Monomers
O
SF5CF2CF2I
Aromatics
SF5CF2CF2CH2CH2SiCl3
Silanes
SF5CF2CF2CH2CH2I
SF5CF2CF2CH2CH2OH
Alcohols
R
N(SO 2CF3)2
N
NMe
Ionic Liquids
P. G. Nixon, et al., J. Fluorine Chem. 2004, 125, 553-560; R. P. Singh, et
al., Inorg. Chem. 2003, 42, 6142-6146; P. G. Nixon, et al., J. Fluorine
Chem. 1998, 91, 13-18; R. J. Terjeson, et al., J. Fluorine Chem. 1997, 82,
73-78; R. Winter, et al., Chem. Mater. 1999, 11, 3044-3049.
19
Synthetic Strategies: Aliphatics
•
•
•
•
Initially limited to harsh fluorinations
Selective SF5X addition preferred
More accessible through Et3B initiation
Versatility of aliphatic SF5-derivatives
20
Outline
• Background
• Synthetic Strategies: Aliphatics
• Synthetic Strategies: Aromatics
– Vigorous Fluorination
– SF5X Addition
– Incorporation of -SF5 Building Blocks
• Applications
• Conclusions and Outlook
21
AgF2 Fluorination
• First reported by Sheppard
SF5
S
5 eq AgF2/Cu
R
9-30%
60°C (1h), 130°C (2h)
R
2
R = H, m-, p-NO2
• Versatile reactivity of –SF5 benzenes
H 2O/H+
F5SC6H 4NO2
H2/Pt
F5SC6H 4NH2
HONO
HX
F5SC 6H4N2+X CuBr
HBr
F5SC6H 4COOH
F5SC6H 4CH(CH3)OH
F5S C6H4CH CH 2
F5SC 6H4OH
CO 2
F5SC6H 4Br
Mg, CH3I, Et2O
O
H
W. A. Sheppard, J. Am. Chem. Soc. 1960, 82, 4751-2;
W. A. Sheppard, J. Am. Chem. Soc. 1962, 84, 3064-72.
22
AgF2 Fluorination: Further Study
• Extended to o-fluorine substituents
– Steric bulk may stop reaction at -SF3 stage
– o-Substituent may be interchanged
R
F
S
R=F
2
NH2
SF5
AgF2/Cu, autoclave
60°C (2h), 130°C (3h)
NO2
NO2 18%
SF5
NH4OH
130°C (5h)
NO2 61%
R = Cl, Br, Ar
No -SF5
product
A. M. Sipyagin, et al., J. Fluorine Chem. 2001, 112, 287-295.
23
AgF2 Fluorination: Further Study
• Investigation of electronic effects
– Electron-poor substrate essential
– May be limited to –NO2 and -CF3
F
F
SF5
S
R = NO2
AgF2/Cu, autoclave
60°C (2h), 130°C (3h)
NO2 18%
R = Br
2
AgF2/Cu, autoclave
60°C (2h), 130°C (3h)
No -SF5
product
R
A. M. Sipyagin, et al., J. Fluorine Chem. 2001, 112, 287-295.
24
Direct Fluorination
• F2 fluorination recently achieved
– Improved yield relative to AgF2 process
– Extended to other substituents including –CF3
– Less expensive but operationally difficult
S
SF5
F2/N2 (1:9 v/v)
NO2
2
MeCN/-5°C
6 to 24h
39-41%
R
m-, p-NO2
NO2
NO2
S
F2/N2 (1:9 v/v)
2
MeCN/-5°C
6 to 24h
SF3
major isolated product
25
R. D. Bowden, et al., Tetrahedron 2000, 56, 3399-3408.
SF5X Addition
• Et3B-catalyzed addition
– No extensive purification until final step
– High yielding and operationally simple
SOCl2
CCl4, rt, 2h
Cl
SF5Cl
Et3B, DCM
Cl -20°C, 18h
F5S
SF5
Cl
NaOEt
rt, 15 min
EtOH
Cl
Cl
76% overall
• De novo aryl ring synthesis
– Allows unusual substitution patterns
+ F 5S
120°C, 19h
hydroquinone
F 5S
chloranil
p-xylene, reflux, 2h
50%
T. A. Sergeeva, et al., Org. Lett. 2004, 6, 2417-2419;
F. W. Hoover, et al., J. Org. Chem. 1964, 29, 3567-70.
F5S
71%
26
Building Block Approach
• Many m-, p-SF5 derivatives available
F 5S
X = NO2, NH2, Br, OH, I, CN, COOH, COCl, CH2NH2
X
• Allow a variety of transformations
B(OH)2
Ph
Suzuki
F 5S
OR
F 5S
Suzuki 96%
Stille 76%
Ph
SF5
I
Sonogashira
Stille
Sn(Bu)2
O
75%
Heck
OMe
F5S
Ph
COOMe
65%
R. D. Bowden, et al., Tetrahedron 2000, 56, 3399-3408.
27
Synthetic Strategies: Aromatics
•
•
•
•
•
Accessible with AgF2 or F2
Requires electron-poor substrates
May be constructed from aliphatics
Participate in usual aromatic reactions
Convenient building blocks available
28
Outline
•
•
•
•
Background
Synthetic Strategies: Aliphatics
Synthetic Strategies: Aromatics
Applications
– Thin films and polymers
– Liquid crystals
– Biologically-active compounds
• Conclusions and Outlook
29
Applications of -SF5 Derivatives
• Often used as –CF3 replacement
• Yet displays unique behavior
F3C CF3
O
O
O(CH2)2(CF2)2SF5
Polymer Thin Films
SF5
Cl
H 2N
O S
N
SF5
SF5
N
O
O
High Performance Polymers
Cl
N
O
C3H7
F 5S
N
CN
CF3
Pesticides
N
O
NH 2
Liquid
Crystals
NH 2
Pharmaceuticals
30
Polyimide Polymers
• High performance condensation polyimides
– Thermal stability
– Strength
– Flexibility
O
CF3
O
+
H2N
O
NH2
• Trifluoromethylation
– More transparent
– Better properties
for electronics
– Increased strength
O
O
O
O
-H2O
O
O
CF3
O
N
O
N
O
P. M. Hergenrother, Angew. Chem., Int. Ed. Engl. 1990, 29, 1262-8.
31
SF5-Functionalized Polyimides
• Properties of –SF5 may enhance polyimides
SF5
SF5
O2N
S
AgF2, Cu
H2/PtO2
60 to 130°C, 4.5 h
O2N
2
NO2
7%
NO2
H2N
NH2
83%
DASP
• DASP condensed with several dianhydrides
SF5
1. Dianhydride, DMA
H2N
NH2
2. Cure, 300°C
Polyimides
A. Jesih, et al., Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.) 1993,
34, 383-4; A. K. St. Clair, et al., Polym. Prepr. (Am. Chem. Soc., Div. Polym.
Chem.) 1993, 34, 385-6.
32
SF5-Functionalized Polyimides
• Improved glass transition temperature (Tg)
– Average 13°C higher than –CF3 analog
– Allows use at higher temperatures, harsher conditions
• Consistently higher density
• Lower solubility
O
N
O
F3C CF3
O
N
O
SF5
Tg = 305 °C
ε (10 GHz) = 2.51
ρ = 1.559 g/cm3
Colorless
A. K. St. Clair, et al., Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.)
1993, 34, 385-6; A. K. St. Clair, et al., US Pat. 5,302,692 1994.
33
SF5-Functionalized Polyacrylates
• Monomer synthesis:
O
SF5(CF2)2(CH2)2I +
O
OAg
CH 3CN
reflux, 27h
O(CH2)2(CF2)2SF5
20%
• Photoinitiated polymerization
– Homopolymer or copolymer with HEMA
O
O(CH2)2(CF2)2SF5
+
O
Irgacure 261, h
Homo- or copolymer films
10 to 12 h
OH
O
HEMA
34
R. Winter, et al., Chem. Mater. 1999, 11, 3044-3049.
X-Ray Photoelectron Spectroscopy
• Quantitative elemental analysis for surfaces
• Identify elements and bonding state
• Analyzed thickness depends on angle of
incidence (θ)
– Limited by photoelectron mean free path
– Increasing angle reduces the accessible depth
H. R. Thomas, et al., Macromolecules 1979, 12, 323-329.
35
SF5-Functionalized Polyacrylates
O
• XPS of copolymer:
O(CH2)2(CF2)2SF5
– 50Å depth, varying %HEMA
– Nonstoichiometric -SF5
surface enrichment
+
O
O
OH
% atom
Wt % SF5 monomer
F
S
C
1
25.8 2.4 51.6
10
30.5 3.3 48.2
100
41.7 5.1 38.5
100 (theory)
47.4 5.3 36.8
100% HEMA (theory)
0
0 66.7
36
R. Winter, et al., Chem. Mater. 1999, 11, 3044-3049.
SF5-Functionalized Polyacrylates
• XPS of 1% SF5-monomer film
– Varying composition controls depth of fluorous layer
Wt % SF5 Analysis
Monomer Depth (Å)
% atom
F
S
C
1
20
42.0 5.1 40.4
50
50
42.2 5.3 41.1
Composition Depth Profile
• Surface enrichment of –SF5 side chains
– Fluorous components “bloom” to surface
– Allows unique surface chemistry at low monomer%
R. Winter, et al., Chem. Mater. 1999, 11, 3044-3049.
37
Liquid Crystals: Design
• Twisted-nematic cell:
• Switching voltage
affects power usage
• Voltage response determined by dielectric
anisotropy (Δε)
• Δε correlates with molecular dipole
P. Kirsch, et al., Angew. Chem., Int. Ed. 2000, 39, 4216-4235;
38
Liquid Crystals: Design
• Improve Δε with polarizing head groups
C3H7
X
Prototypic Liquid
Crystal (LC)Scaffold
X = CF3  = 8.6
X = CN  = 21.1
X = SF5  = 22.2 (calculated, PM3)
• -CN head group solvates ionic impurities
• -SF5 combines high dipole moment and
lipophilicity for excellent LC properties
P. Kirsch, et al., Angew. Chem., Int. Ed. 2000, 39, 4216-4235;
P. Kirsch, et al., Angew. Chem., Int. Ed. 1999, 38, 1989-1992.
39
Liquid Crystals: Synthesis
Br
SF5
C3H 7
SF5
O
C3H 7
SF5
O
O
C5H11
SF5
C3H7
O
SF5
S
C3H 7
SF5
C3H 7
S
P. Kirsch, et al., Angew. Chem., Int. Ed. 1999, 38, 1989-1992.
SF5
40
Liquid Crystals: Synthesis
Br
1. tBuLi, Et2O, -78°C
2. 4-propylcyclohexanone, -78°C to rt
3. TsOH, PhCH3
C3H 7
SF5
C3H 7
H2, Pd/C
THF
SF5
25%
Br
SF5
C3H7
C5H11
C 3H 7
S
S
SF5
55%
SF5
C3H7
SF5
C3H7
O
SF5
O
O
O
SF5
SF5
P. Kirsch, et al., Angew. Chem., Int. Ed. 1999, 38, 1989-1992.
41
Liquid Crystals: Results
• Δε improved, but lower than anticipated
C3H7
X
X = CF3
X = CN
X = SF5
X = SF5




= 8.6
= 21.1
= 22.2 (calculated, PM3)
= 12.0 (experimental)
• Calculated vs. experimental structure
C-S-Feq angle
αcalc = 95.6°
αexp = 92.3°
F
S F
• Suggests o-substitution may improve Δε
42
P. Kirsch, et al., Angew. Chem., Int. Ed. 1999, 38, 1989-1992.
Liquid Crystals: o-Substitution
• o-Fluorination enhances Δε
• o-Fluorination reduces -SF5 contribution
F
C3H 7
X
X = CF3  = 21.5
X = SF5  = 21.4
F
F
F F
S F
F F
F
F
F
F F
S F
F F
F F
S F
F F
F
F
P. Kirsch, et al., Eur. J. Org. Chem. 2005, 3095-3100.
43
Liquid Crystals: Trifluoromethylation
• Axial-CF3 expected to increase polarity
C3H 7
X
 = 13.0
X = CF3
X = SF5
 = 14.3
X = SF4CF3   = 10.6
• Reduced polarity may result from
F F
deformed C-S-Feq angle
S CF
3
F F
• Promising for bioactive
SF4CF3
compounds
x = 2.13 (SF5 1.23)
p = 0.68 (SF5 0.68)
P. Kirsch, et al., Eur. J. Org. Chem. 2006, 1125-1131.
44
Biologically-Active Compounds
• Provides a means to modulate activity
• May improve bioavailability
SF5
Cl
H2N
Cl
F5S
N
N
N
O
O S
NH2
NH 2
CN
CF3
Insecticide
Pharmaceutical
45
Pesticides: Fipronil
• Fipronil introduced in US by Rhône-Poulenc
in 1996
• Marketed in Frontline®, Maxforce®,
Combat® for flea/tick, roach control
CF
• Blocks GABA-gated chloride
channels
Cl
Cl
3
H2N
N
N
O S
CN
CF3
M. J. O'Neil (Ed.), The Merck Index: An Encyclopedia of Chemicals,
Drugs, and Biologicals, 13th ed., 2001.
46
Pesticides: SF5-Fipronil
• Synthesis
SF5
SF5
SF5
1. HONO, H 2SO4
NCS
MeCN
2.
Cl
NH2
SF5
CN
Cl
Cl
NH2
EtOOC
CN
Cl
N
N
1. NH4OH
2. CF3SCl
3. m- CPBA
CN
COOEt
CN
P. J. Crowley, et al., Chimia 2004, 58, 138-142.
Cl
H2N
Cl
N
N
O S
CN
CF3
47
Pesticides: Results
• SF5-fipronil consistently more potent
Compound
Fipronil -SF5
Fipronil
Strain
Musca
Musca Musca(R) Musca(R) Blattella
Blattella
LC50 (ppm)
15.42
1.38
1*
143.4
-SF5
3.21
(R) indicates dieldrin resistant strain
Musca domestica: housefly
Blattella germanica: German cockroach
X = SF5
X = CF3
Fipronil
0.5*
-SF5
*Relative potency
X
Cl
H2N
Cl
N
N
O S
CN
CF3
P. J. Crowley, et al., Chimia 2004, 58, 138-142;
R. Salmon, Int. Pat. App. WO 9306089 1993.
http://www.arkive.org/species/ARK/invertebrates_terrestrial_and_freshwater/Musca_domestica/
48
NHE Inhibitors
• Sodium-proton exchangers (NHEs)
–
–
–
–
Maintain intracellular pH
Seven identified isoforms (1-7)
NHE1 expressed in cardiac tissue, platelets
Involved in ischaemia and reperfusion injuries
• NHE inhibitors protect tissues during
– heart attack
– organ transplant
– cancer chemotherapy
49
B. Masereel, et al., Eur. J. Med. Chem. 2003, 38, 547-554.
Benzoylguanidine NHE Inhibitors
• Guanidinium mimics Na+ to block transport
• Benzoylguanidines more NHE1 selective
• HOE-694 among the first of class
N 4
HOE-694
O
N
S
O
O
NH2
NH2
• Enhanced by lipophilic bulk at 4-position
A. Schmid, et al., Biochem. Biophys. Res. Commun. 1992, 184, 112-17;
L. Counillon, et al., Mol. Pharmacol. 1993, 44, 1041-5; M. Baumgarth, et al.,
J. Med. Chem. 1997, 40, 2017-2034.
50
NHE Inhibitors: Synthesis
Br
N
O
F 5S
O
O
N
F 5S
Br
5°C, 1 h
NH2
85%
F5S
tBuONO, CuBr
5°C, 1 h
Br
NH2
Me
B
MeB
BMe
O
CsCO3, PdCl2(dppf)
DME, reflux, 5h
Br
F 5S
NH2
76%
F 5S
Zn(CN)2, Zn, PdCl2(dppf)
89%
O
DMA/H2O, 125°C, 3h
80%
CN
1. NaOH
F 5S
N
81%
O
NH 2
NH 2
2. SOCl2
3.
NH
H2N
NH2
51
G. Schubert, et al., Int. Pat. App. WO 2005047241 2005.
NHE Inhibitor: Evaluation
• IC50 for NHE1 in fibroblasts
SF5
F 5S
N
NH 2
O
O
O
NH 2
N
S
O
1st Generation: 14.5 nM
O
NH 2
NH 2
2nd Generation: 1.9 nM
• Improved bioavailability and half-life in vivo
relative to other NHE inhibitors
H.-W. Kleemann, US Pat. App. US 2003216476 2003;
H.-W. Kleemann, US Pat. App. US 2005043401 2005.
52
Applications of -SF5 Derivatives
• -SF5 enhances molecules with its
–
–
–
–
–
Chemical and thermal stability
Fluorous behavior
Electron-withdrawing character
Lipophilicity
Steric bulk
• Further systematic study needed
53
Conclusions
-SF5
• Displays unique and useful properties
• More accessible through recent
improvements in synthesis
• Beginning to impact industry through
applications as a fluorinated substituent
54
Outlook
• Substituent of the future
• Investigation of -SF5 only beginning
– Improved synthetic strategies
– Convenient reagents
– Understanding of functional characteristics
• Accessibility will drive applications
– When -SF5 is as easy to introduce as -CF3, it will
become as prevalent
55
Acknowledgements
• Professor Ron Raines
• Raines Lab
• Practice Talk Attendees
–
–
–
–
–
Frank Kotch
Matt Shoulders
Daniel Gottlieb
Katie Partridge
Kim Peterson
• Luke Lavis
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