In the Como Fluorine Conference, a substantial number of
lectures and presentations are on the methodology and applications of
installing the trifluoromethyl (CF3) groups into diverse organic
structures. It should not be too hard to understand that, given the extent
to which the incorporation of a single fluorine atom into an organic molecule
with biological relevance, can drastically alter its chemical properties,
metabolic stability or lipophilicity, the incorporation of more than 3 fluorine
atoms will dramatically change the potential inhibitory profiles of the
molecule, no matter in a positive or
negative manner. Indeed, with the interest in attaching even longer perfluoroalkyl
chains of the type CxFy (which is something more related
to my research work), and the introduction of a new sulfur-based functional
group, SCF3 , it should not be surprising to see a lot of research
work has appeared in the literature in these fields. In this article, I will
talk about some of the most important methods regarding electrophilic
perfluoroalkylation, and the new developments I have heard in the Como
Conference.
Many of the trifluoromethylation reactions involve either an
iodine-based (iodonium salt / hypervalent iodine) or a Group 6-based -onium
salt (O, S, Se, Te...). The preliminary investigations of these reagents will
eventually lead to 2 of the most common reagents, Togni's reagent and Umemoto's
reagent. I have talked about the use of these reagents in my blog before, and
don't be thrilled that you will regularly see these reagents in many of the
major journals from time to time. That only testifies how powerful these
reagents can be. Anyway, let's start with the background.
Iodonium salts have been known to transfer CF3 or
longer perfluoroalkyl chains to organic substrates. For example, the phenyl
iodonium salt can transfer different RF groups to the organic
molecules (Figure 1).
 |
| Figure 1 |
On the other hand, a sulfonium salt can also be a CF3-
carrier than leads to trifluoromethylation (Figure 2).
 |
| Figure 2 |
Togni's reagent
The hypervalent iodine-based Togni reagent has become a very
useful trifluoromethylation agent, and from the keynote lecture and the recent
publications (including a Chemical Review article) one can easily realize that
this reagent works for some many different functional groups, almost a CF3
can be incorporated into a differnt structure using the Togni reagent. Most of
the common Togni-type reagents involve either one of these skeletons (Figure 3).
 |
| Figure 3 |
Other than CF3 group, longer perfluoroalkyl
chains (CxFy) can also be incorporated into diverse
organic substrated by using Togni-type reagents (Figure 4).
 |
| Figure 4 |
There are numerous other lectures and poster presentations
regarding the trifluoromethylation.
A variation of the Togni's reagent can be used to substitute
a CF3 group to the trimethylsilyl group in the allyl trimethylsilane
substrate. The reaction is catalyzed by CuCl (20 mol%) at elevated temperature,
using an excess of the trifluoromethylating agent (Figure 5).
 |
| Figure 5 |
Umemoto's reagent
The Umemoto reagent is a sulfur-based salt which can act as
a nice source of CF3 for numerous organic substrates. The Umemoto reagent has been employed to install CF3
group into many important organic substrates and natural products. For example,
Umemoto reagent has been used to react with a stabilized enolate, giving a
trifluoromethyl group in between 2 carbonyl groups. When reacting with a
conjugated silyl enol ether, the CF3 group is incoroprated at the
end of the original conjuated system (Figure 6).
 |
| Figure 6 |
There also exists asymmetric trifluoromethylation reactions
involving copper catalysis.
By using a biphenyl substituted with 2 fluorine atoms, they
made their novel fluorinated Umemoto's reagent in 3 steps. While the initial
counteranion was OTf - , they were able to exchange the anion to BF4-
and Cl- by using NaBF4 and Bu4NCl
respectively. They have discovered that the identity of the counteranion can
affect the activity of their reagent, with the non-nucleophilic BF4-
version being the most active.
 |
| Figure 7 |
When they increased the number of fluorine atoms to 4 in
their core structure, the activity dramatically increased. With 4 fluorine
atoms, even the reagent with a - OTf - anion is still way more
active than the 2-fluorine substituted Umemoto reagent, with the BF4-
in it. Upon systematic investigation, they have found that the fluorine
atoms at the 2-position are strongly stabilizing, while the fluorine atoms on
the 4-position are destabilizing. Thus, the activity of the reagent comes as a
balance between these effects.
BF4-
version being the most active. |
| Figure 8 |
Of course, I have also asked a question that has
been fascinating me for quite some time - why are there non Umemoto reagents
for longer perfluoroalkyl chains (where x = 2 - 8 for CxFy,
for example)? Prof. Umemoto has answered it is possible, and another nice
professor has commented there are already alternative reagents for doing those
reactions.
Fluorination reagents
involving hypervalent iodine reagents
Another interesting piece of research I have heard is from
Dr. Stuart's group. They are doing fluorination reactions by using a
hypervalent iodine-based reagent (Figure 9).
 |
| Figure 9 |
The reagent is easy to prepare, and quite stable. They have
carried out fluorination reactions on substrates such as β- ketoesters,
including cyclic versions, which are more common in natural product synthesis.
This method should find a lot of use in future chemical synthesis.
They have also reported fluorocyclizations, where
fluorinated lactones or pyran-type products (or their nitrogen counterparts)
can be made, which has important biological significance. Szabo et. al. has
also carried out similar reseach on these.
Reference:
Modern Fluoroorganic Chemistry by P. Kirsch, Wiley VCH.
Synthesis, 1978, 835.
Chem. Rev., 2015, 115, 650.
Angew. Chem. 2012, 5, 8221.
Angew. Chem. Int. Ed., 2012, 51. 4577
Chem. Eur. J.,
2012, 18, 1279.
Chem. Commun., 2013, 49, 9263
RSC Adv., 2015, 5, 16501.
