Fluorinated Synthons
Baran GM 5/25/2013
R. Gianatassio
GM Focus: Interesting applications of fluorinated starting materials and reagents therein.
To Be Covered:
Not Covered:
1. Rongalite: "The Confused Sulfinate Salt"
General/"Traditional" Fluorination Reagents and techniques:
2. "The Nitrogen Walk"
i.e. Selectfluor,NFSI, DAST, XeF2, AgF2 (see Fluorination GM
3. Perfluoroheteroaromatics and "Mirror Image Logic"
by S. Su (2008))
4. N-Fluoropyridinium Salts and "The Fluorine Walk"
5. "The Negative Fluorine Effect" and the "chemical chameleon"
Rongalite: "The Confused Sulfinate"
J. of Flourine Chemistry, 64 (1993) 37-46
HOCH 2SO2Na
4 R'
R'
NaHCO
3
3 General Isomer Distribution:
+ RF X
R
R
C2:C3:C4 = 1:4:4
CH3CN/H 2O
2
N
N
60-75°C
Observed byproducts:
52-68%
RFH and RFSO2Na
RF X:
R, R'= H,CH 3
C6F13I
RF=C6F13, C7F15,
C7F15I
C8F17, Cl(CF 2)6
C F I
8 17
Cl(CF 2)6Br
*Bicarb. kept rxn slightly basic and prevent dissociation of Rongalite.
*Also works on pyrroles (selective C2 substitution), quinolines and isoquinolines.
*Pyrazine and imidazole were problematic.
Rongalite With Olefins
Chin. J. Chem., 358 (1990)
RFI +
RFI +
O
HOCH 2SO2Na
NaHCO 3
HOCH 2SO2Na
NaHCO 3
CH3CN/H 2O
60-75ϒC
α-pinene
HOCH 2SO2-
SO2•- + HOCH 2•
SO2•- + RFI
RF•+ I - + SO2
RF•+
RF
RF
N
-H +
•
Zn
RF
N
N
The "Nitrogen Walk"
J. Org. Chem. 1991,56, 6313-6320
F
N
hυ
N
N
N
F
8.3%
O
RF
F
N
RF
hυ
N
N
F
23%
I
F
I(CF 2)2-O-(CF 2)2SO3Na +
CH3CN/H 2O
60-75°C
(CF 2)2-O-(CF 2)2SO3Na
I
Good FG compatibility
F
N
N
hυ
N
+
N
N
F
HOCH 2SO2Na HO
NaHCO 3
OH
FYI: Rongalite
$250/5KG= $0.05/g
Aldrich
•
N
RF
I
CH3CN/H 2O
60-75°C
General Mechanism:
N
N
19%
2.6%
Perfluorinated Heterocycles as Synthons?
perfluoroheteroaromatic systems
F
N
F
F
N
F
F
F
F
F
<
F
N
F
N
F
F
perfluoropyrazine perfluoropyridine
F
F
F
F
<
F
F
F
F
<
F
F
<
F
N
F
F
F
F
N
N
perfluoropyridazine
perfluoroisoquinoline perfluoroquinoline
bp (°C) = 54
bp (°C) = 84
bp (°C) = 212
bp (°C) = 212
bp (°C) = 117
heteroaromatic systems
N
<
N
N
N
pyrazine
pyridazine
bp (°C) = 115
<
<
bp (°C) =208
<
N
N
quinoline
pyridine
bp (°C) = 238
bp (°C) = 115.5
N
isoquinoline
bp (°C) = 243
Increasing base strength
*All perfluoroheteroaromatic compounds are weak bases - a fluorine atom placed ortho to the nitrogen atom significantly decreases the
basicity of the system.
*Boiling points: Lower bp is attributed to lower intermolecular forces and low basicities of fluorocarbon systems that compensate for the
increase in mass upon replacing hydrogen by fluorine.
General synthesis of perfluoroheteroaromatic heterocycles (many other methods available).
Cl
N
(i) Cl 2
Cl
(ii) PCl 5
Cl
F
Cl KF, 480°C
N
Petrov, V. Fluorinated Heterocyclic Compounds, New Jersey, 2009.
Cl
autoclave
F
F
F
N
F
Perfluoroheteroaromatics: "Mirror Image" Chemistry
F
F
F
F
Nucleophilic substitution of perfluorinated heteroaromatic systems
occurs at sites that:
1) are para to the ring nitrogen
2) maximize the number of activating ortho and meta F atoms
3) minimize the number of F atoms para to the site of attack
Nuc
N
Nuc
F Nuc
F
F
F
N
H
F
F
-F
F
F
F
N
F
Meisenheimer Intermediate
Favored sites of attack for SN Ar
"Mirror Image" to:
Elec
H Elec
Elec
-H
F
F
F
Wheland Intermediate
F
N
F
F
F
F
F
F
N
N
F
F
F
N
N
F
N
F
F
N
F
General Reactivity: Effects of Fluorine on Nucleophilic Substitution
Nuc
Nuc
F
δ+
Nuc
F
δ−
F
Very Activating
F
δ−
F
Activating
F
F
N
F
F
F
F
F
Nuc
ortho N activating
1 ortho F activating
2 meta F activating
1 para F deactivating
N
F
F
F
F
F
N
F
N
F
Nuc 2
Nuc 3
N
Nuc1
Nuc 2
F
Nuc 4
Nuc 4
Nuc1
F
meta N not activating para N activating
Nuc 2
2 ortho F activating
2 ortho F activating
1 meta F activating
2 meta F activating
1 para F deactivating
Petrov, V. Fluorinated Heterocyclic Compounds, New Jersey, 2009.
F
Nuc1
F
Nuc 3
F
N
F
F
F
Nuc1
F
F
F
F
Regioselectivity Pattern
Nuc
F
N
F
F
δ−
Slightly Deactivating
Nuc
F
F
F
δ+
δ+
F
F
F
F
N
N
Nuc 3
Nuc 2
N
N
Nuc1
Nuc 2
position of Nuc 2
is dependent on Nuc1
Nuc 2
N
Nuc1
Nuc 2
Nuc 2
Nuc 3
Nuc 2
N
N
N
Nuc1
N
Nuc1
N
Nuc1
can get mono, difficult to
get mono only
bis, or tri
(highly activated)
"Mirror Image Logic" Examples
*a reaxys search showed 1134 reactions with
(1) as starting material
Biologically active compounds using "Mirror Logic"
(used by Novartis and others)
R
N
F
N
NH
F
F
N
N
N
MeO
N
N
iii
N
F
MeO
64%
O
N
N
F
F
F
O
N
O
76%
54%
NH
v
F
ii
N
F
N
NH
F
iv
F
N
N
F
F
F
O
N
i
F
F
F
(1)
F
N
N
97%
F
F
O
N
N
N
H
iv
F
F
O
O
F
N
F
i
F
F
O
S
Substitution via Radical:
O
F
N
N
N
Reagents and Conditions: i, CH3NHCH 2CH 2NHCH 3, NaHCO 3, MeCN, reflux;
ii. MeONa, MeOH, reflux, 2d; iii, Et 2NLi,THF, reflux; iv, (a) PhC=NHNH 2, NaHCO 3, MeCN, reflux,
(b) LDA, THF, rt; v, PHCH 2NHMe, THF, 150°C; microwave; vi, PHSO 2Na, DMF, 140°C
Petrov, V. Fluorinated Heterocyclic Compounds, New Jersey, 2009.
CO 2Me
F 3C
F
S
O
N
F
O
N
R
F
91%
S
O
F
F
N
F
PH 2CO
cyclohexane,
hυ (300-350nm)
F
F
F
N
F
via:
H
F
F
F
N
H
F
Carbenes from N-Fluoropyridinium Salts: Featuring the "Fluorine Walk"?
base
N
F
H
F
N
N
F
F
N
-H
O
F
-H
H
O
+ FCH 2Cl
N
F
F
2O
N
O
O
NH
N
N
N
Me
O
Br
N
DC
N
Cl
F
Me
F
F
N
N
N
F
N
N
F
N
N
M
O
Cl
Cl
FH
O
CH 2Br 2
Br
Br
N
N
O
N
O
O
F
F
F
F
"Fluorine Walk"
O
N
-H
F
H
F
N
O
Tetrahedron Lett. 1987 , 28(24), 2705-2708.
O
N
O
H
F
N
N
or
N
O
O
F
The Negative Fluorine Effect (NFE)
NFE Overview: "Fluorine substitution on the carbanionic C poses a negative effect in many
nucleophilic fluorination reactions." Top Curr Chem (2012) 308:25-44
(
Factor 1
R2 +
R1
)
or
2F + R )
( R1
desired fluoroalkylation reaction
E+
R1
R2 F
R2 F
n
B.
R1
R1
R2
S
R1
R2
R
O
se
Ba
R
Na/Hg
RCH 2CF 2H
O
t-Bu
H
F F
S
N
O
R2
R1 2 CF 2H
R
OH
R
S
N
Ph
2
NH 2
1 is "CF 2H -" synthetic
equivalent
R2 F
R1
and
MLn
R2 F
t-Bu
S
H
NBn 2
Bn
1. Na/Hg
2. HCl (dioxane)
CH 2F
N
H 2+Cl-
O
H
F
t-Bu
S
H
N
O Ph
S
t-Bu
N
H
CFHSO 2Ph
N
H
n
1. LiHMDS
2. Na/Hg
O O
S
H
R1
O
F
tBuOK
OH
R
H
F
1
RCH 2X
R CHCF 2H
CF 2SO2Ph
R
O
Ph
t-Bu
O O
S
R
RCH 2CF 2SO2Ph
X
O
M
4 Methods for Modulating the NFE
A. Change fluorine atoms
B. Slightly change neighboring groups (R1,R 2)
C. Enhance generation of carbene species
D. Change the metal counterion M or covalent bond
to M
1. LiHMDS
CH 2F 2. Na/Hg
R
D
O
CF 2H
X S
M
Na/Hg
HO
Mg/
R 3SiCl
H
Li
R1
R2
F
R1
D.
F
NH 2 HCl
O
R1
Method A: Nucleophilic Monofluoromethylation Reactions with 2
R 3SiCF2H
CF 2SO2Ph
C.
E
Method A: Nucleophilic Difluoromethylation Reactions with 1
HO
R2 F
R2 F
intrinsic reactivity of 3 toward E + (e.g. unmatched hard/soft nature
between 3 and E + results in higher activation barrier of desired
reaction and decreases r1 )
Factor 2
R1
R1
R2 F
r1
3
R1
A.
α-elimination reduces concentration of 3 and
decreases r1
(decreased nucleophilicity of 3 due to side reaction
with r 2)
r2
Negative Fluorine
Effect
F-
Taming NFE
CH 2F
H 2N
O Ph
NBn 2
Bn
Ph
N
H
n
OTs
CH3
CFHSO 2Ph
95.5 dr
CH3
98.6% ee
CH 2F
Org. Lett. 2006, 1693-1696
The Negative Fluorine Effect: Changing Neighboring Groups
Difluoromethylation of S-,N-, and C-Nucleophiles with 1.
Method B:
CHF 2
*The sulfone functionality
is a "chemical chameleon"
that is ideal for various types
of reactions.
R1
R2 F
R
S
CF 2H
O NTs
S
H
RSNa
1 F
NNa
Li
Ar
O O
S
O NTs
S
H
H
F
F
F
F
sulfoxime
sulfone
Fluorinated alkenes from nitrones.
H
F
N
F
O NTs
S
R1
2-pyridyl sulfone
F
*Slightly changing R groups results in dramatically different chemistry.
F
O
N
N
OH
F
+
R2
R3
2) H+
R2
R1
+
N
aldehydes
and ketones
O
R2
H +
F
H
F
N
R4
R3
1)n-BuLi, -78°C
2) 2, -78°C
3) rt, 3h
O O
S
RCH 2X
N
F
1.EtSNa
CH 2R
F
F F
S
O
O
R 2 R1
HN
Org. Lett. 2010, 1444-1447
H+
F
F
R1
R2
O O
S
O N
F
F
Et
SN
a
Na
O O
S
R1
R2 O
N
Na
2. H 2O2
R3
F
O
O O
S
CH 2R
O
F
F
14 Examples
up to >99% yield
O
Via:
O
R2
R1
24 examples
up to 94% yield
up to 99:1 Z/E
2
R1 = aryl
O O
S
O
1) Base
CF 2H
Ar
O O
S
N CF 2H
F
S
CH 2R
F
F
Angew. Chem. Int. Ed. 2011, 50, 2559 –2563
Angew. Chem. Int. Ed. 2013, 52, 3949 –3952
The Negative Fluorine Effect: Carbene, Counterion, M-X
O
D. Changing the Counterion
C. Enhance Generation of Carbene
TMSCF3
CF 2Cl
2011
O O
S
CF 2H +
t-Bu
S
LiHMDS
KHMDS or NaHMDS
R1
O
N
R2
THF, -78°C
2006
F
via:
F
O O
S
CF 2Cl
2007
CF 2Cl
+
O
KOH
HF 2C
KOH
NH
F
R1
R1 N
F
F
R2
R2
R6
R4
F
R1
F
R5
F
F F
intramolecular cyclization
O
Cu0
N
homocoupling
F
N
R2
Cu0
R3
I
R1
O
R
D. Modulation of M-X bond
R3
R4
O O
CsF,CuI
S
CF 2Cl
DMF, -30°C
O
R2 F F
N
1
R1
Cl
R2
O O
S
CF 2Cu
R2
O
O
Ph
R1
N
F F
O
TMSCF2Cl
Method A:
R6
n-Bu 4NCl (mol%)
16
Examples
TBAT
(5
mol%)
R1
20-94%
yield
-50°C
to
rt
12 Examples
Method
B:
NaI
(0.2eq.)
68-99% yield
65°C
R2
I
16 Examples
65~96% yield
R5
F
O
R
5 Examples
44-86% yield
O
Cu0, R 3-I
KOH
13 Examples
51-79% yield
N CF 2H
CF 2SO2Ph
cross-coupling
R
O O
S
CF 2Cl
N
H M
Org. Lett., 2008, 5377-5380
D. Modulation of M-X bond
HF 2C
O
CF 2SO2Ph
For Ketimines: Chelation-Controlled
2009
OH
S
O
2011
O NTs
S
CF 2Cl
CH3
CH3
tBu
TMSCF2Cl
O Ph
S
t-Bu
N
H
S
F
F
C
R1
R2
R3
X
O
O
Ph
R3
S
F
F