formation of 6, which was subsequently compared with
authentic material previously synthesized by our original
route. Additionally, a successful synthesis of trifluorobenzoic
acid 1 was accomplished with the desired isomer specificity
using the material formed from the new route.
In order to determine the structure of the phthalamic acid
as being that of either 11 or 12, attempts were made to
synthesize authentic samples of both. We hoped to open
up the phthalimide ring to produce both isomers by treatment
of trifluorophthalimide 5 with potassium bicarbonate,14 as
well as heating 5 with a water/THF mixture. Both attempts,
however, were unsuccessful. The fact that we were unable
to determine the structure as being 11 or 12 was not of
consequence as either one can be taken onto 1.
The defluorination reaction conditions developed in these
labs appear to be specific to N-substituted phthalimides.
Treatment of other protected phthalic acids such as tetrafluo-
rophthalonitrile with conditions developed by us (zinc and
aqueous sodium hydroxide) caused rapid hydrolysis leading
to tetrafluorophthalic acid. It is known that this compound
will not undergo defluorination but instead, under the reaction
conditions, will lead to phenolic type products, as shown
below.16
Typical isolated yields for the hydrodefluorination reaction
were excellent, ranging around 90%. Optimization of the
reaction conditions for the hydrodefluorination reaction
indicated that the best results were obtained by using just
over 2 equiv of NaOH and 3 equiv of zinc dust at a
temperature around 60 °C. We noticed an exotherm upon
addition of the zinc dust; therefore, on a large scale, the zinc
is best added portionwise over a period of 0.5 h. Assays of
the solid taken at the end of the reaction indicated that 78%
of 11 or 12 and 15% of 6 were being formed. This mixture
was formed in essentially the same ratio under various
reaction conditions. Increases in reaction times, as well as
the addition of extra sodium hydroxide, did not increase the
conversion of 11 or 12 to 6. We do not have an explanation
for the lack of further conversion to 6 past the typical 15%
seen at the end of the reaction.
Improvements in the Imidization of 7. The second
challenge overcome in the process optimization was an
improvement in the preparation of 8. This was achieved by
developing the imidization of 2 in commercial grade
sulfolane, thereby eliminating the need for glacial acetic acid
as a solvent. The use of sulfolane had the advantage of being
the same solvent needed for the next step in the reaction;
thus a costly solids isolation step was also eliminated.
Simply sparging anhydrous methylamine into a hot solution
of 2 in sulfolane led to a clean conversion to 7 in isolated
yields of around 90%.
In practice, however, 7 was not isolated. The water
formed during the imidization reaction could be simply
removed by distillation, and the resultant solution of 7 (in
dry sulfolane) was then ready for the halogen-exchange
reaction to 8 utilizing spray-dried potassium fluoride.1,8 The
sulfolane could be eventually recycled back to the imidization
reaction with a minimum of loss. It was important to keep
the amount of methylamine added to the reaction mixture
as close as possible to the theoretical amount. Any excess
led to byproducts (presumably N-methylanilines via displace-
ment of chloride on the ring) which led to lower yields in
the halogen-exchange reaction.
The success of the defluorination reaction, in terms of
both yield and selectivity, made it a promising alternative
which could be incorporated into a new synthesis of 1. The
sequence of chemical steps for the new synthetic route was
strikingly similar to the older hydrodechlorination route.1,4
The only differences, besides incorporation of the new
hydrodefluorination reaction in place of the hydrodechlori-
nation reaction, were (a) the imidization of 2 to 7 instead of
3 to 4 and (b) the halogen-exchange reaction of 7 to 8 instead
of 4 to 5. However, despite the similarity in the chemistry,
the effect on the yield was anything but similar. The oVerall
The reaction appears to be general for other substituted
phthalimides, such as the N-phenyl and N-ethyl derivatives.
In addition, exposure of N,N′-dimethylenebis(tetrafluo-
rophthalimide) (13) to the reaction conditions led to a 55%
isolated yield of 6.
For larger scale reactions, the intermediates were not
isolated after the defluorination reaction. The filtrate, after
removal of the zinc salts via filtration, was simply heated
with aqueous sulfuric acid, effecting hydrolysis to give
exclusively 6 as the product. Total overall isolated yields
for the conversion of 8 to 6 were typically in the 85-90%
range.
Attempts to remove a second fluorine by treatment of 5
under the reaction conditions were unsuccessful; no diflu-
orinated products could be obtained, despite forcing condi-
tions. This result is in contrast to the results from the
hydrodechlorination of 2, whereby one, two, or three chlorine
atoms could be removed in succession depending upon the
reaction conditions.15
(15) Fertel, L. B.; Callaghan, K. M., O’Reilly, N. J. J. Org. Chem. 1993, 58,
(14) Kamai, S. Jpn. Kokai Tokkyo Koho JP 02/145538, 1990; Chem. Abstr. 1991,
113, 152040c.
261.
(16) Kikuo, A.; Masayoshi, O. U.S. Patent 4,813,190, 1989.
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