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Fluorination Chemistry
Fluorination
Chemistry
2
Let Sigma-Aldrich Assist You With All of Your
Fluorination Needs
Fluorine has a profound ability to alter the biological properties
of a compound due to its electronegativity and small size. In
pharmaceutical research, fluorine is often introduced into the target
compound to improve bioavailability and enhance the metabolic
stability profile.
However, the general and practical fluorination of functionalized
molecules continues to be a highly researched area.
We are pleased to feature an ever-expanding portfolio of fluorination
reagents and fluorinated building blocks to assist fluorination,
difluoromethylation and trifluoromethylation.
Did you know?
At least 8 out of the 39 FDA approved drugs in 2012 were small molecules containing fluorine?
…. and that Sigma-Aldrich is your trusted resource for reagents and building blocks to
incorporate fluorine to assist in obtaining your next hit?
To learn more, visit
Aldrich.com/fluoro
O
Cl
F3C
O
O
N
H
N
H
NHMe
N
Order 800-325-3010
O
MeHN
F
Stivarga®
Bayer Healthcare
Aldrich.com
F
Technical Service 800-325-5832
Me O
Me
N
N
CN
S
Xtandi®
Astellas Pharma
CF3
Fluorination Chemistry
Fluorination
The high toxicity/corrosivity of HF renders any fluorination
technology that precludes its use or generation highly valuable to
synthetic chemists. With this in mind, Aldrich Chemistry provides
a versatile toolbox of fluorine reagents for both nucleophilic and
electrophilic methods.
Classically, the source of electrophilic fluorine has been fluorine gas,
which is highly toxic and a strong oxidizer. The Aldrich catalog has
a growing portfolio of milder, safer and highly stable alternatives
for electrophilic fluorination. These reagents have shown excellent
utility in several applications, ranging from electrophilic aromatic
substitution to formation of α-fluoro-keto species.
In the mode of nucleophilic fluorination, we provide fluoride sources
for direct displacement of alcohols, additions to aldehydes, ketones
and carboxylic acids in highly chemoselective fashions for small
molecule synthesis as well as poly-fluorination for materials synthesis.
O
F
"F "
R
H3C
N
CH3
SF3
CH3
SF3
N
H3CO
SF3
OCH3
F
R
t-Bu
F
F
S
N
BF4
H3C
F
CH3
N
S
CH3
F
BF4
O
DAST
Deoxo-Fluor®
FluoleadTM
XtalFluor-M®
XtalFluor-E®
235253
774642
494119
94327
94324
734039
719447
719439
(1.0 M in dichloromethane)
Figure 1. Nucleophilic Fluorination
"F "
X
F
Cl
N
N
2BF4
N
F
XFn
2BF4
N
H3C
Selectfluor®
439479
Figure 2. Electrophilic Fluorination
Selectfluor® II
716219
OTf
N
F
OTf
323659
Cl
N
F
Cl
738123
PhO2S
F
N
SO2Ph
NFSI
392715
3
4
Aldrich Chemistry now features an innovative fluorinating reagent,
PhenoFluor™ (SFL00001), which is capable of producing a wide range
of aryl fluorides directly from the corresponding phenol (tolerant of
several aryl functional group), without requiring functionalization of
the free alcohol through common approaches, e.g. sulfonylation.1
OH
Phenofluor was also shown to accomplish late-stage fluorination of
highly functionalized free alcohols. This unprecedented display of
regioselectivity further demonstrates the value of this reagent in
late-stage derivatization.
R
i-Pr
i-Pr
N
Me HO Me Me
Me
Me
i-Pr F
OH
OH O
OH O
O
Me HO Me Me
F i-Pr
Me
Me
OH
PhenoFluor
SFL00001
Me
OH O
OH O
Me
O
Me
Late-Stage
O
O
N
TM
O
Me
Et
F
No Preactivation
R
Derivatization
O
Et
O
Me
OH
O
Me
F
Me
Me
Me
Me
References: (1) Tang, P.; Wang, W.; Ritter, T. J. Am. Chem. Soc. 2011, 133, 11482. (2) Sladojevich, F.; Arlow, S. L.; Tang, P.; Ritter, T. J. Am. Chem. Soc. 2013, 135, 2470.
Additional Fluorinated Building Blocks:
755028
755036
755206
755303
756849
757047
758205
758485
759333
759392
759996
763616
Aldrich.com
Order 800-325-3010
Technical Service 800-325-5832
Fluorination Chemistry
Difluoromethylation
The difluoromethyl group (R-CF2H) has recently garnered much attention in drug, agrochemical and material research since it is isoteric to a
carbinol group (CH2OH). The Aldrich catalog has innovative sources for
installing the difluoromethyl group through nucleophilic addition and
radical functionalization of C-H bonds. Nucleophlic difluoromethylation
of carbonyls and imines using (Difluoromethyl)trimethylsilane (744050)
and Difluoromethyl phenyl sulfone (742600) was developed by Jinbo
Hu and coworkers.
O O
S
CF2H
Zinc difluoromethanesulfinate (DFMS, 767840), developed in the
Baran lab, can directly add CF2H to heterocycles under open flask
conditions making it very operationally simple to carry out difluoromethylation. A wide range of heteroaromatic substrates are compatible (namely nitrogen-containing heterocycles) and several functional
groups are tolerated in presence of DFMS.
Me
Me Si CF2H
Me
742600
X
"CF2H "
R
X = O, N
RX
CF2H
R
744050
Figure 3. Nucleophilic Difluoromethylation
References: (1) Shen, X.; Ni, C.; Hu, J. Helv. Chim. Acta 2012, 95, 6606-6610. (2) Zhao, Y.; Huang, W.; Zheng, J.; Hu, J. Org. Lett. 2011, 13, 5342-5345.
R
H
HF2C
X
O
S
O
Zn
O
O
S
CF2H
CF2H
R
X
Baran DFMS
767840
Reference: Fujiwara, Y.; Dixon, J. A.; O'Hara, F.; Funder, E. D.; Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95-100.
Additional Difluoromethyl Building Blocks:
722472
729973
730475
733261
733962
733997
734934
759341
5
6
Trifluoromethylation
Trifluoromethylation has been a rapidly growing field in chemical
research, one that has interfaced elegantly with catalysis in crafting
new chemical methodologies for placing trifluoromethyl groups onto
molecules. In the arena of stoichiometric reagents, Aldrich offers three
classes of reagents amendable to trifluoromethylation.
For nucleophilic trifluoromethylation, the Ruppert-Prakash reagent
(488712, 819062) has long been a staple for adding CF3 to carbonyls
and imines. This reagent has also been featured in several publications
in tandem with transition metal catalysis to install CF3 to several motifs.
More recently, trifluoromethylation by a radical process has been
developed in the Baran (771406) and Hartwig (777692) groups. The
Baran TFMS reagent, like the DFMS reagent, can be used to convert
aryl and heteroaryl C-H bonds directly into C-CF3 bonds under mild
conditions. Trifluoromethylator® is one of the more robust reagents
used to form C-CF3 bonds from aryl and vinylogous iodides.
"CF3 "
R
X = O, N
SH
Me
Me Si CF3
Me
Ruppert-Prakash
488712
91862
(~2.0 M in THF)
RX
O
S
Zn
O
O
O
S
N
CF3
Baran TFMS
771406
CF3
N
Cu
CF3
Trifluoromethylator®
777692
Figure 5. Radical Trifluoromethylation
S CF3
X = O, N
N
HO O
F3C
F3C
R
"CF3 "
CF3
X = H, I
A new nucleophilic trifluoromethylation source was developed by the
Colby group. The Colby Trifluoromethylation Reagent (L511315) is an
air-stable solid that adds CF3 to ketones and thiols under mildly basic
conditions. The major by-products from this reaction are DBU and
trifluoroacetate, which are both considered benign.
X
" CF3 "
X
CF3
N
H
Colby Trifluoromethylation
Reagent
L511315
The Aldrich portfolio also offers electrophilic sources of
trifluoromethyl groups. Notably, the Togni I (696641, 754218)
and Togni II (771147) reagents can provide highly selective
trifluoromethylation of a wide range of substrates. The Togni II
reagent is offered as a safer alternative for shipping and storage,
available as a mixdown formulation with Celatom® that can either be
easily isolated by washing
away Trifluoromethylation
the adsorbent or even used directly.
Electrophilic
Figure 4. Nucleophilic Fluorination
X
F3C
I
O
Me
"CF3 "
F3C
I
O
O
Me
Togni Reagent
696641
754218
X CF3
Togni II Reagent
771147
S
X
CF3
483869 (R = BF4 )
483877 (R = OTf )
Figure 6. Electrophilic Trifluoromethylation
Reference: Fiederling, N.; Hallar, J.; Schramm, H. Org. Process Res. Dev., 2013, 17, 318.
For a complete listing of the Baran Reagents, which promote
innate C-H functionalization of aryl and heteroaryl motifs, visit
Aldrich.com/baranreagents
Aldrich.com
Order 800-325-3010
Technical Service 800-325-5832
Fluorination Chemistry
Additional Trifluoromethyl Building Blocks:
725838
725846
725854
725870
725889
728470
728616
728683
728748
729957
729981
730009
730025
730173
730181
730467
730483
733237
733989
734004
737232
737240
754994
755001
755230
For our complete portfolio of fluorinated
reagents and building blocks, visit
Aldrich.com/fluoro
7
Invest in Your Synthesis!
Sigma-Aldrich Has the Tools for Fluorination!
Ace all-PTFE filter reactor assembly
These PTFE filter reactors can be used for fluorine chemistry and
with strong alkaline compounds that can etch glass. The head, head
joints, body, stirrer-bearing, bottom filter assembly with valve, and
stirring shaft with agitator are all PTFE. Even the O-Rings are PTFE
encapsulated. The filter supports are polypropylene. The bottom
filter assembly is either #50 or #80 Ace-Thred™ and threads in/out for
easy capture of filtrate, or for cleaning. A Halar® coated stainless steel
internal coil is included (in the 1 L size) for heating or cooling the
contents. IKA RW 20 over head stirrer recommended.
Capacity
250 mL
500 mL
Joints
24/40
24/40
Cat. No.
Z690368
Z690473
1L
24/40
Z690503
IKA® RW 20 Digital Overhead Stirrer
• With digital display (LED)
•Robust, slim line, ergonomic design
•With constant power-drive
•Two speed ranges for universal use from 60 - 2,000 rpm
•Push-through agitator shafts (only when stationary)
Volts
110
230
IKA
9011601
901160X
Cat. No.
Z645087
Z645095
For product pricing and ordering information, visit
Aldrich.com/labware
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Improve the Quality of Life
Order/Customer Service (800) 325-3010 • Fax (800) 325-5052
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Development/Custom Manufacturing Inquiries
(800) 244-1173
Safety-related Information sigma-aldrich.com/safetycenter
©2013 Sigma-Aldrich Co. LLC. All rights reserved. SAFC, SIGMA-ALDRICH, and ALDRICH are trademarks of Sigma-Aldrich Co. LLC, registered in the US and other countries. Add Aldrich is a trademark
of Sigma-Aldrich Co. LLC. Celatom is a registered trademark of EP Minerals, LLC. IKA is a registered trademark of IKA-Werke GmbH & Co. KG Trifluoromethylator is a registered trademark of Catylix,
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