Ring fluorination of non-activated aromatic compounds

Details Ring fluorination of non-activated aromatic compounds Ring fluorination of non-activated aromatic compounds

2001-10-23

2003-10-21

Shah, Mukund J. (Department: 1624)

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

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S182000, C544S215000, C544S216000, C544S217000, C544S218000, C544S219000

Reexamination Certificate

active

06635760

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to the use of tri(halo- or trifluoromethyl) substituted N-fluorotriazinium salts to fluorinate non-activated aromatic compounds (i.e. unsubstituted aromatic compounds and aromatic compounds having one or more electron-withdrawing substituents).
Fluorination is an important process in many areas of industry, in particular where the synthesis of specialty chemicals is concerned. Known fluorination methods are conveniently categorized according to the perceived manner in which the fluorinating agents provide fluorine for combination with an active site in an organic molecule, namely as fluorine atom (F
•
), fluoride ion (F
−
) or, conceptually, fluoronium ion (F
+
). Fluorinations involving fluorine atom are notoriously exothermic and non-selective, hence “light” strategic fluorination of organic compounds (that is, the introduction of one or two fluorine substituents or a trifluoromethyl group at key molecular sites) rests on the availability of versatile ranges of nucleophilic and electrophilic sources of fluorine. Of late, the use of N-fluoro compounds has become one of the most widely used methods for the selective formation of carbon-fluorine bonds via “electrophilic” mechanisms. A recent comprehensive review of this synthetic methodology contains no reference to N-F reagents derived from triazines (see G. G. Furin in Methods of Organic Chemistry (Houben-Weyl): Volume E10a; Organofluorine Compounds (ed. B. Baasner, H. Hagemann, and J. C. Tatlow), Georg Thieme Verlag, Stuttgart, 1999, pp. 432-499.
1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (so-called F-TEDA-BF
4
) is a known, commercially available (under the trade name “Selectfluor”) fluorinating agent and is useful as a general purpose fluorinating agent. However this material has only a moderate fluorinating power and is able to fluorinate benzene only under forcing conditions, for example under reflux for 24 hours. The chemistry of F-TEDA-BF
4
has been reviewed by R. E. Banks in J. Fluorine Chemistry 87 (1998) 1-17, the whole content of which is incorporated herein by reference.
N-Fluoropyridinium salts and ring-substituted analogues thereof, e.g. N-fluoropyridinium triflate, are known for use as a fluorinating agent but have relatively low fluorinating power. U.S. Pat. No. 4,828,764 discloses that certain N-fluoro-N-perfluoroalkyl or perfluoroaryl sulfonamides including, inter alia, those of the formula R
f
SO
2
NFR are electrophilic fluorinating agents. In this formula R
f
represents a perfluorinated C
1
-C
30
alkyl, C
3
-C
30
cycloalkyl, C
6
-C
14
aryl substituted C
1
-C
10
alkyl or a C
6
-C
14
aryl group and R represents a C
1
-C
30
alkyl, C
3
-C
30
cycloalkyl, C
6
-C
14
aryl substituted C
1
-C
10
alkyl, or C
6
-C
14
aryl group optionally substituted with one or more inert substituents including, inter alia, fluorine and, when R
f
is trifluoromethyl, R alternatively can represent perfluoromethyl-sulfonamido. The preferred fluorinating agents are stated to be N-fluorobis-(trifluoromethanesulfonyl)imide (R
f
═CF
3
and R=CF
3
SO
2
), known as DesMarteau's Reagent, and N-fluoro-N-methyltrifluoromethanesulfonamide (R
f
═CF
3
and R=CH
3
). DesMarteau's Reagent is a powerful electrophilic fluorinating agent which is capable of converting benzene to fluorobenzene at room temperature but is hazardous, time-consuming and expensive to prepare requiring eight or nine reaction steps from readily available material. Only a very limited number of other known fluorinating agents are strong enough to fluorinate benzene without forcing conditions but they often provide relatively low yields or require special precautions. Those reported to fluorinate benzene include, in addition to DesMarteau's Reagent, CF
3
OF, XeF
2
, NF
4
+
, BF
4
−
, N
2
F
+
AsF
6
−
, N-fluoropentachloropyridium triflate, perfluoro-[N-fluoro-N-(4-pyridyl)methanesulfonamide] and N-fluoro-2,6-bis(methoxycarbonyl)pyridinium triflate. Very few of these compounds, only NF
4
+
BF
4
−
and XeF
2
, are known to fluorinate aromatic substrates having electron-withdrawing substituents such as nitrobenzene.
N-Fluorotriazinium salts of the following Formula A are known:
wherein:
(i) X=H & Y
−
=AsF
6
−
(Ref.1—see below)
(ii) X=F & Y
−
=AsF
6
−
(Ref. 2—see below)
(iii) X=F & Y
−
=BF
4
−
(Ref. 3—see below) and
(iv) X=Cl & Y
−
=AsF
6
−
(Refs. 2 & 4—see below).
The N-fluorotriazinium salts of Formula A are reported to be oxidizing agents of use in, for example, organometallic chemistry. The cationic component of compounds of Formula A in which X is H, F and Cl have been described as “oxidative fluorinators” and a qualitative scale for their oxidizing strength and that of NF
4
+
has been computed ab initio (Ref. 3—see below).
Ref. 1=Broschag et al. Inorg. Chim. Acta, 205 (1993) 167-173;
Ref. 2=Schleyer et al. Inorg. Chem. 32 (1993) 1523-1524;
Ref. 3=Schulz and Klapötke J. Organometal. Chem. 480 (1994) 195-197; and
Ref. 4=Broschag et al. Z. Anorg. Allg. Chem., 620 (1994) 1132-1136.
There is a statement in Schleyer et al. that 1-fluoro-2,4,6-trichloro-s-triazinium hexafluoroarsenate (Formula A; X=Cl; and Y
−
=AsF
6
−
) “is a promising fluorination agent” but no further details were provided or subsequently reported. It is believed that uses of the compounds of Formula A other than as oxidizing agents was not contemplated or investigated. In particular, there is no disclosure in the prior art of any of these compounds being evaluated as oxidative fluorinators (as distinct from non-fluorinating oxidizing agents) despite the computed values reported in Refs. 3 and 4.
BRIEF SUMMARY OF THE INVENTION
We have now surprisingly found that tri(halo- or trifluoromethyl) substituted N-fluorinated triazinium salts are sufficiently strong electrophilic fluorinating agents that they will readily fluorinate non-activated aromatic compounds. The N-fluorotriazinium salts can be represented by the following Formula I:
in which:
three A moieties are independently CR, where each R is independently halogen or trifluoromethyl;
two A moieties are independently Z, where each Z is independently nitrogen or a quaternary nitrogen atom; and
Y
−
is a counterion or group of counterions which are inert to chemical attack by fluorine.
DETAILED DESCRIPTION OF THE INVENTION
In its broadest aspect, the present invention provides a method of fluorinating a substrate selected from the group consisting of unsubstituted aromatic compounds and aromatic compounds having one or more electron-withdrawing substituents which comprises contacting the substrate with a tri(halo- or trifluoromethyl) substituted N-fluorotriazinium salt.
The N-fluorotriazinium salts are of the following Formula I:
wherein:
three A moieties are independently CR, where each R is independently halogen or trifluoromethyl;
two A moieties are independently Z, where each Z is independently nitrogen or a quaternary nitrogen atom; and
Y
−
is a counterion or group of counterions which are inert to chemical attack by fluorine.
It is presently preferred that the triazinium compounds are 1,2,4-triazinium compounds of the following Formula IA or, especially, 1,3,5-triazinium compounds of the following Formula IB:
wherein:
R
1
, R
2
and R
3
are independently halogen or trifluoromethyl;
Z
1
and Z
2
are independently nitrogen or a quaternary nitrogen atom; and
Y
−
is a counterion or group of counterions which are inert to chemical attack by fluorine.
As mentioned above, the N-fluoro-triazinium salts of Formula I are remarkably strong fluorinating agents capable of room temperature fluorination of unsubstituted aromatic substrates such as benzene and aromatic substrates having one or more electron-withdrawing substituents such as chlorobenzene or nitrobenzene.
Usually,

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