Trifluoromethylating reagents and synthesizing processes

Details Trifluoromethylating reagents and synthesizing processes Trifluoromethylating reagents and synthesizing processes

1999-06-17

2001-04-10

Gitomer, Ralph (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Sulfonic acids or salts thereof

Reexamination Certificate

active

06215021

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the transfer of a trifluoromethyl group to a desired substrate molecule and the formation of trifluoromethylating reagents. More particularly, the invention relates to trifluoromethyl derivatives of electron rich aromatic, heteroaromatic, and nonaromatic substrates.
BACKGROUND
The trifluoromethyl group (CF
3
) is an important structural moiety in diverse classes of bioactive organic molecules. The CF
3
group has a bigger van der Waals radius than that of a CH
3
group and the same electronegativity as oxygen (Table 1).
The C—F bond in trifluoromethylated compounds results in added stability and lipophilicity of the molecule. As a consequence, the introduction of a trifluoromethyl group into organic molecules often changes their physical, chemical, and physiological properties. Compounds containing the trifluoromethyl group are found in a variety of commercially important dyes, polymers, pharmaceuticals, and agrochemicals. The dye industry has found that trifluoromethylated chromophores exhibit increased light fastness compared with the nonfluorinated compounds. Trifluoromethylated polymers have high thermal stability and enhanced mechanical and electrical properties. Many
TABLE 1
van der Waals radius and electronegativity of different groups
Group/
van der Waals
Group/
atom
radius (Å)
atom
Electronegativity
CF
3
2.7
CF
3
3.5
CH
3
2.0
CH
3
2.3
CCl
3
3.5
C
2.5
F
1.4
F
4.0
H
1.2
H
2.1
O
1.5
O
3.5
Cl
3.0
of these polyfluorinated polymers find application as liquid crystals. In a wide variety of agrichemicals and pharmaceuticals, the properties of the trifluoromethyl group, i.e., to increase lipophilicity and to act as an inhibitor of enzyme action, are key reasons for incorporation. Thus, a variety of reagents have been developed in order to introduce the CF
3
group into organic molecules. Currently, there are three available methods for directly introducing a CF
3
group into target compounds: (i) organometallic based on CF
3
Cu, (ii) nucleophilic based on CF
3
SiMe
3
, and (iii) electrophilic based on S-(trifluoromethyl)dibenzothiophenium triflate.
By nucleophilic and electrophilic are meant techniques or reagents that will transfer a CF
3
group to an electron-deficient or electron-rich portion, respectively, of the target molecule. Organic molecules, while retaining electrical neutrality, will often show a partial separation of charge on their constituent atoms, especially due to the effect of electron-withdrawing or electron donating substituents. Aromatic rings and double and triple bonds are typical electron-rich environments. The presence of electron withdrawing substituents such as F
−
, Cl
−
, NO
2
−
, N(SO
2
CF
3
)
−
, N(SO
2
F)
2
−
, CN
−
can produce electron-deficient regions in molecules.
The introduction of a CF
3
group into an electron rich environment is becoming more and more important in organic and bioorganic synthesis. It is not a trivial task, however. It is extremely difficult to generate the CF
3
cation chemically, due to its high electronegativity (3.45). In 1984, Yagupol'skii reported two trifluoromethyl sulfonium salts, trifluormethyl-p-chlorophenyl(2,4-dimethylphenyl)sulfonium hexafluoroantimonate (1) and trifluoromethyl-p-chlorophenyl-p-anisylsulfonium hexafluoroantimonate (2), that were capable of acting as trifluoromethylating reagents. Yagupol'skii, L. M.; Kondratenko, N. Y.; Timofeeva, G. N.
Zh. Org. Khim
. 1984, 20, 115
; Chem. Abstr
. 1984, 100, 191494e. Compounds 1 and 2 react with sodium p-nitrothiophenolate in DMF to give p-nitrophenyl trifluoromethyl sulfide in high yield. However, 1 and 2 were synthesized from the extremely hygroscopic intermediate fluoro(trifluoromethyl)-p-chlorophenylsulfonium hexafluoroantimonate. Both products, 1 and 2, are also extremely hygroscopic. Furthermore, they are unreactive with the highly activated aromatic compound N,N-dimethylaniline.
In 1990, Umemoto reported power-variable electrophilic trifluoromethylating reagents (FIG. 1) that can transfer the CF
3
group to different kinds of organic molecules. Umemoto, T.; Ishihara, S.
Tetrahedron Lett
. 1990, 31, 3579; Umemoto, T.; Ishihara, S.
J. Am. Chem. Soc
. 1993, 115, 2156. They react readily with strongly activated aromatic systems, e.g. N,N-dimethylaniline. Although these reagents are very useful, they are prepared by using multistep, inconvenient synthetic routes that require gaseous CF3I or CF3Br for the triflouromethylation reaction. These reagents, although available commercially, are expensive.
Umemoto also described several other trifluoromethylating reagents with varying power to transfer the CF
3
group, which are shown in FIG. 2. The synthesis of these reagents was described as time consuming, and in some cases the yields were poor. Umemoto, T.
Chem. Rev
. 1996, 96, 1757-77.
There is an evident need for trifluoromethylating reagents which can be synthesized by straightforward, economical, efficient methods, and which are stable and easy to handle, and which will transfer the CF
3
group in good yield to a wide variety of target molecules that have electron-rich centers.
SUMMARY OF THE INVENTION
Accordingly, it is one objective of this invention to provide a family of electrophilic trifluoromethylating reagents which can be synthesized by comparatively simple, inexpensive routes, and for which the reactivity can be varied according to need. By triflates is meant salts of the triflate anion (CF
3
SO
3
)
−
. The invention may be embodied in new trifluoromethyl diphenylsulfonium triflate compounds having the structure shown in FIG. 3 (referred to as the first embodiment), processes for making trifluoromethyl diphenylsulfonium triflate compounds (referred to as the second embodiment), and trifluoromethylation processes in which a trifluoromethyl group may be transfered to a desired substrate molecule (referred to as the third embodiment).
A composition of matter according to the first embodiment of the invention comprises a compound having the formula:
in which A comprises H or F and B comprises F, SCF
3
, OCF
3
, OCHF
2
, S
+
(CF
3
)C
6
H
5
, NO
2
or an NO
2
substituent. In another aspect of this embodiment, A comprises F and B comprises H in the above formula.
In a second embodiment of the invention, a process for preparing trifluoromethyl diphenylsulfonium triflate compounds corresponding to the formula:
comprises reacting phenyl trifluoromethyl sulfoxide or one of its derivatives with an aromatic compound in which A comprises H or F and B comprises H, F, SCF
3
, OCF
3
, OCHF
2
, S
+
(CF
3
)C
6
H
5
, NO
2
or an NO
2
substituent.
In a third embodiment of the invention, a trifluoromethylation process comprises reacting a trifluoromethyl diphenylsulfonium triflate compound corresponding to the formula:
with an electron rich substrate.
DETAILED DESCRIPTION
A. Preparation of Trifluoromethylating Reagents
Abbreviations used:
IR Infrared spectroscopy;
NMR Nuclear magnetic resonance spectroscopy;
EI-MS Electron Impact Mass spectroscopy; and
FAB
+
-MS Fast Atom Bombardment Mass spectroscopy.
Structures for intermediates and trifluoromethylating reagents were determined and confirmed by some or all of the following analytical techniques, as is well known in the art: IR spectroscopy;
1
H-,
13
C- and
19
F-NMR spectroscopy; EI- and FAB
+
mass spectroscopy; and chemical analysis.
19
F,
1
H and
13
C NMR spectra were obtained with a 200 MHZ NMR spectrometer using CDCl
3
as solvent unless otherwise indicated. Chemical shifts are reported with respect to (CH
3
)
4
Si or CFCl
3
. Products were separated by column chromatography with 70-230 mesh silica gel.


REFERENCES:
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patent: 4814480 (1989-03-01), Davidson
patent: 4814482 (1989-03-01), Davidson
patent: 4822904 (1989-04-01), Davidson
patent: 5475165 (1995-12-01), Palmer et al.
patent: 5817830 (1998-10-01), Therien et al.
Yang et al, “New Electrophilic Trifluoromethylating Agents” in J. Org. Chem. 1998, 63, 2656-2660.*
Umemoto, T

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