Electrophilic fluorination

Details Electrophilic fluorination Electrophilic fluorination

2001-10-23

2004-05-18

Qazi, Sabiha (Department: 1616)

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

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S066000, C544S180000

Reexamination Certificate

active

06737525

ABSTRACT:

CROSS REFERENCES TO RELATED APPLICATIONS
Not applicable
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable
BACKGROUND OF THE INVENTION
This invention relates to electrophilic fluorination and in particular to the use of N-fluorotriazinium salts as electrophilic fluorinating agents. The invention provides a method of electophilically fluorinating a substrate, especially an organic substrate using N-fluorotriazinium salt fluorinating agents and has particularly, but not exclusive, application to the fluorination of electron-rich species, for example activated aromatic compounds (i.e. carrying electron-donating substituents) or overt or covert carbanions. At least the preferred tri(halo or trifluoromethyl)-substituted N-fluorotriazinium salts are sufficiently strong fluorinating agents to readily fluorinate unsubstituted aromatic substrates and aromatic substrates 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 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
-C14 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-fluoropentachloropyridinium 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.
A copending US Patent Application of even date corresponding to and claiming priority from UK Patent No. 0026010.9 (filed Oct. 24th 2000) discloses and claims electrophilic fluorinating agents which are triazinium compounds of the following Formula B:
wherein:
three A moieties are independently CR, where each R is independently, hydrogen, halogen, hydroxyl, (primary, secondary or tertiary) amino, cyano, perfluorothio, hydroxysulfonyl, halosulfonyl, hydrocarbyloxysulfonyl, or a carbon-containing substituent selected from the group consisting of optionally substituted hydrocarbyl, hydrocarbyloxy, hydrocarbyloxycarbonyl, and hydrocarbylthio groups, and at least one R is neither hydrogen nor halogen;
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,
and oligomers or polymers thereof in which adjacent triazinium moieties are linked by a common R substituent.
BRIEF SUMMARY OF THE INVENTION
We have now found that N-fluorinated triazinium salts are excellent electrophilic fluorinating agents yet do not possess some of the drawbacks of known electrophilic fluorinating agents. These salts have a high fluorinating power which allows substrates which are difficult to fluorinate using known fluorinating agents to be fluorinated, especially electron-rich species such as, for example, carbanionic and/or activated aromatic substrates. Also they may be employed to fluorinate substrates which may presently be f

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