Synthesis and SNAr reactions of new dioxins and predioxins

Article abstract of DOI:10.1016/S0045-6535(00)00399-4

A method for two-step synthesis of dioxin derivatives containing the perfluoropyridine ring has been suggested. It consists of the preparation of corresponding predioxin in the first stage and its cyclization in the next stage. A number of new predioxins have been synthesized using the interaction of polyhalogenpyridines with pyrocatechin and its 4,5-dihaloid derivatives. Formation of dioxins on the basis of not very active arenes occurs smoothly without the necessity for the isolation of predioxin intermediates. For the first time, an interaction of polyhalogenpyridine-containing dioxins and predioxins with nucleophiles of various types (alkyl and arylamines, propylenediamine, hydroxyl anion, and ammonia) has been studied. It was shown that the pyridine fragment does not change the fundamental rules of orientation influence of substituents detemined for non-heterocyclic polyfluorinated arenes. The presence of the labile fluorine atoms reveals a possibility for various modifications of dioxins and predioxins.

Full text of DOI:10.1016/S0045-6535(00)00399-4

Chemosphere 43 ,2001) 493±495
Synthesis and SNAr reactions of new dioxins and predioxins
*
Vladimir V. Litvak , Olga A. Korshunova, Eugenia G. Saikovich
Insititute of Bioorganic Chemistry, Siberian Branch of Russian Academy of Sciences, pr. Lavrentyev 8, 630090 Novosibirsk,
Russian Federation
Abstract
A method for two-step synthesis of dioxin derivatives containing the per¯uoropyridine ring has been suggested. It
consists of the preparation of corresponding predioxin in the ®rst stage and its cyclization in the next stage. A number
of new predioxins have been synthesized using the interaction of polyhalogenpyridines with pyrocatechin and its 4,5-
dihaloid derivatives. Formation of dioxins on the basis of not very active arenes occurs smoothly without the necessity
for the isolation of predioxin intermediates. For the ®rst time, an interaction of polyhalogenpyridine-containing dioxins
and predioxins with nucleophiles of various types ,alkyl and arylamines, propylenediamine, hydroxyl anion, and
ammonia) has been studied. It was shown that the pyridine fragment does not change the fundamental rules of ori-
entation in¯uence of substituents detemined for non-heterocyclic poly¯uorinated arenes. The presence of the labile
¯uorine atoms reveals a possibility for various modi®cations of dioxins and predioxins. Ó 2001 Elsevier Science Ltd.
All rights reserved.
Keywords: Polyhalogenpyridine-containing dioxins; Predioxins
1. Introduction
2. Materials and methods
Among the numerous studies of dioxins, the special
classes of heterocyclic compounds ,Kunzevich et al.,
1996) are few considering their chemistry. We believe
new compounds possessing useful properties can be
discovered amidst some dioxin derivatives, e.g., anti-
dotes of toxic dioxins ,Romkes et al., 1987) or model
compounds for studying the functions of dioxins in or-
ganisms. Incomplete diaryl ethers, predioxins are of in-
terest as percursors of dioxins and their probable
metabolities. Dioxins and predioxins containing pyri-
dine ring with the labile ¯uorine atoms are convenient
objects for preparing various derivatives. Some alter-
natives of modi®cations of dioxins and predioxins have
been proposed in this work, which continues our earlier
investigations ,Simagina et al., 1995, 1997).
2.1. Synthesis of predioxins +1a-g)
A mixture of substrate ,2 g), nucleophile, and potash
,molar ratio 1:1:1.2) in 10 ml of water was stirred at 50±
60°C during 3±5 h. The products were isolated, puri®ed
and identi®ed as described below.
2.2. Synthesis of dioxins from predioxins +2a-g)
2 g of predioxin obtained as described above was
added gradually during 1 h to the suspension of potash
in a solvent ,50 ml of DMF or DMSO) at 100±120°C.
The products were isolated, puri®ed and identi®ed as
described below.
2.3. One-stage synthesis of dioxins +3a-d)
* Corresponding author. Fax: +7-3832-333-677.
E-mail address: litvak@niboch.nsc.ru,V.V. Litvak).
A mixture of substrate ,2 g), nucleophile, and calci-
nated potash ,molar ratio, 1:1:1.2) in 10 ml of DMSO
0045-6535/01/$ - see front matter Ó 2001 Elsevier Science Ltd. All rights reserved.
PII: S 0 0 4 5 - 6 5 3 5 , 0 0 ) 0 0 3 9 9 - 4

494
V.V. Litvak et al. / Chemosphere 43 +2001) 493±495
was stirred at 120±130°C during 30±60 min. Isolation
and analysis of the products see below.
DMSO, would stipulate the creation of additional steric
hindrances in predioxins due to the formation of sol-
vating shell around the nucleophilic centers. Moreover,
solvation of heteroatom would be a barrier to substi-
tution of the most labile ¯uorine atoms in o-position to
nitrogen in the pyridine cycle. Indeed, the best results
have been obtained when water was used as a solvent.
The corresponding predioxins are formed with a high
yield ,65±80%) in the reactions of poly¯uorinated pyri-
dines with a small excess of pyrocatechin or its dihalo-
gen derivative under moderate heating in water in the
presence of potash.
2.4. SNAr reactions of dioxins and predioxins
A mixture of dioxin ,2 g), nucleophile, and calcinated
potash ,molar ratio, 1:n:1.2, where n increased from 1 to
6 with a decrease in the strength of nucleophile) was
added to 10 ml DMSO or DMF. The reaction mixture
was stirred in DMSO at 20°C for 30 min ,2.5 h for
ammonia). In the case of DMF, the reaction was carried
out at 20°C for 20 min ,propylenediamine), at 70°C for
20 min ,di-n-propylamine), and at 150°C for 10 h ,ani-
line). The substitution in predioxins was carried out in
DMSO at 20°C for 10±30 min or in acetonitrile at 60±
70°C for 3 h using the component molar ratio 1:1:1.2 for
all nucleophiles.
2.5. Isolation and analysis of the products
After completion of the reactions, the mixtures were
diluted with water. The products were extracted by
chloroform and puri®ed by recrystallization from car-
bon tetrachloride, propanol, acetone, or ethanol or by
distillation. The structure of compounds was proved by
the element analysis and IR and 1H, 19F, and 13C NMR-
spectroscopy.
Formation of dioxins by the reaction of substituted
penta¯uorobenzenes with dichloropyrocatechin occurs
readily with a high yield ,70±85%).
3. Results and discussion
The synthesis of incomplete ether ,1a) is accompa-
nied by the formation of an appreciable amount of
complete ether ,2) even if the excess of pyrocatechin is
used.
Dioxins containing poly¯uorinated pyridine ring,
however, cannot be modi®ed in the same manner be-
cause the intermolecular reaction of intermediate pre-
dioxins with corresponding pyrocatechin leads to the
complex mixture of products. It is reasonable, therefore,
to perform the synthesis by two stages ®rst of which is
the formation and isolation of predioxins. The second
stage should be cyclization under conditions excluding
an intermolecular reaction. For this purpose, predioxins
obtained as described above were added gradually into a
big volume of an aprotic solvent containing anhydrous
It can be explained by the competition for the sub-
strate between the more acidic hydroxy group of predi-
oxin and those of pyrocatechin, despite essential steric
hindrances in the predioxin molecule due to the presence
of the tetra¯uoropyridine fragment. The use of a protic
solvent, which can solvate anions stronger than aprotic

V.V. Litvak et al. / Chemosphere 43 +2001) 493±495
potash. In this case, pyridine-containing dioxins are
formed with a high yield ,60±90%).
495
One can predict successful reactions of dioxins and
predioxins with strong nucleophiles. There is also a
possibility of subsitution of the second ¯uorine atom in
the dioxin and predioxin molecules.
Reactions of dioxins and predioxins with nucleo-
philes of medium strength occur under rather mild
conditions giving products of substitution of one ¯uo-
rine atom ,in p-position to C1 atom) with high yields
,70±95%). Although the interaction with aniline, a weak
nucleophile, requires more stringent conditions, the yield
of reaction products is still acceptable ,50%).
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