Selective hydrodechlorination of fluorinated arylamines

Article abstract of DOI:10.1016/j.jfluchem.2004.06.006

Chlorine-containing polyfluorinated anilines and meta-phenylenediamines undergo selective hydrodechlorination easily upon reduction by zinc in aqueous ammonia. A new approach is thus provided to synthetically valuable, partially fluorinated arylamines based on utilizing polyfluorochloroarenes, which are available as intermediates of perfluoroarene production from perchloroarenes. When chlorine atoms are present in positions both ortho and para to the amino group, para chlorine is initially eliminated. Based on this reaction, a one-pot synthesis of partially fluorinated 4-aminopyridines from 3,5-dichlorotrifluoro- and 3-chlorotetrafluoropyridine has been realized.

Full text of DOI:10.1016/j.jfluchem.2004.06.006

Journal of Fluorine Chemistry 125 (2004) 1829–1834
Selective hydrodechlorination of fluorinated arylamines
Galina A. Selivanovaa, Larisa Yu. Gurskayaa,b, Leonid M. Pokrovskiia,
Vitaliy F. Kollegova, Vitaliy D. Shteingartsa,b,*
aN.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 Lavrentiev Avenue, Novosibirsk 630090, Russia
bNovosibirsk State University, Pirogova Street 2, Novosibirsk 630090, Russia
Received 30 March 2004; received in revised form 8 June 2004; accepted 15 June 2004
Available online 17 July 2004
Abstract
Chlorine-containing polyfluorinated anilines and meta-phenylenediamines undergo selective hydrodechlorination easily upon reduction by
zinc in aqueous ammonia. A new approach is thus provided to synthetically valuable, partially fluorinated arylamines based on utilizing
polyfluorochloroarenes, which are available as intermediates of perfluoroarene production from perchloroarenes. When chlorine atoms are
present in positions both ortho and para to the amino group, para chlorine is initially eliminated. Based on this reaction, a one-pot synthesis of
partially fluorinated 4-aminopyridines from 3,5-dichlorotrifluoro- and 3-chlorotetrafluoropyridine has been realized.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Reductive hydrodechlorination; Zinc; Aqueous ammonia; Polyfluorinated arylamines; Aminopyridines
1. Introduction
[6], copper upon heating in water [7], the Zn–Cu couple [8]
or Zn–NiCl2–bipyridyl complex [9] in aqueous DMF, or zinc
in aqueous ammonia [10]. Two or three chlorine atoms can
be sequentially removed from tetrafluorodichloro- or tri-
fluorotrichlorobenzenes via reduction by metals [8,10]. One
of the few types of functionalized polyhaloarenes involved
in such transformations are amines. Perfluorochloro-4-ami-
nopyridines [4,5] and polychloroanilines [11] were hydro-
dechlorinated by dihydrogen on a Pd catalyst. Ammonolysis
of perfluorochlorobenzenes by aqueous ammonia in a steel
autoclave, leading to polyfluorochloroanilines and polyphe-
nylenediamines, also gave hydrodechlorination products as
by-products [12,13].
Polyfluorochloroarenes and polyfluorochloropyridines
containing two or three chlorine atoms are accessible,
primarily as isomer mixtures, as intermediates in the synth-
esis of hexafluorobenzene from hexachlorobenzene [1] and
pentafluoropyridine from pentachloropyridine [2], respec-
tively. Nevertheless, they have not found application as
starting materials in fine organic synthesis. Their applica-
tion, is especially important for developing new synthetic
approaches to the functional derivatives of partially fluori-
nated arenes, particularly arylamines, valuable intermedi-
ates for the synthesis of biologically active substances [3–5],
because current synthesis, based on consecutive introduction
of several fluorine atoms into the aromatic ring, are cumber-
some and inefficient.
We have developed a general approach to partially fluori-
nated arylamines based on the sequence of noncatalytic or
catalytic ammonolysis of perfluorochlorobenzenes and
hydrodechlorination of the resulting perfluorochloroanilines
and polyphenylenediamines. Of particular interest are
amines with an unsubstituted ortho position relative to
the amino group for the preparation of polyfluorobenzohe-
terocycles. Procedures for the first stage of this scheme have
already been described [12,13]; the present work examines
hydrodechlorination of polyfluorochloroarylamines with a
simple reducing system, previously applied to selective
hydrodehalogenation of polyfluoroarenes, zinc in aqueous
ammonia [10,14,15]. Using this system, N-acetyl derivatives
A promising approach is the reverse strategy, namely,
moving from accessible perfluoro- and perfluorochloroar-
enes toward less fluorinated compounds through selective
dehalogenation, which in the series of polyfluoroarenes was
mainly developed for compounds containing no functional
groups. Thus, selective hydrodechlorination of polyfluoro-
chloroarenes can be achieved with dihydrogen on a catalyst
* Corresponding author. Tel.: þ7 383 234 4171; fax: þ7 383 234 4752.
E-mail address: shtein@nioch.nsc.ru (V.D. Shteingarts).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.06.006

1830
G.A. Selivanova et al. / Journal of Fluorine Chemistry 125 (2004) 1829–1834
Table 1
Reactions of compounds 1–3, 7, 13, 14, 18 with Zn in aqueous ammonia
Entry
Starting
Quantity
(g)
Time (h)
Molar ratio
Substrate
Yield of
Product distribution
(wt.%, GLC)
compound
mixture (g)
Zn
NH4Cl
1
2
3
4
5
1a
0.3
0.3
0.2
3.6
0.3
17
48
1
1
1
1
1
10
4
–
0.27
0.26
0.10
2.41
0.26
4 (65); 5 (20); 6 (3.5)
9 (61); 10 (3)
10 (80); 12 (10)
15 (70); 16 (8)
19 (91)
7b
–
7c
13d
18
24
10
10
10
10
–
18
144
–
a An isomer mixture was used: 63% para-isomer 1, 5% meta-isomer 2, and 21% ortho-isomer 3, (wt.%, GLC).
b The starting material, containing 83% amine 7 and 9% amine 8 (wt.%, GLC), was used, and obtained from ammonolysis of 1,2,4,6-tetrafluoro-3,5-
dichlorobenzene [13], together with 5% aqueous ammonia.
c A mixture containing 83% amine 7 and 9% amine 8 (wt.%, GLC) was used, together with 30% aqueous ammonia.
d A 6:1 mixture of amines 13 and 14 was used, together with 30% aqueous ammonia.
of perfluoroanilines smoothly undergo selective hydrode-
fluorination at positions ortho to the acetoamido group [15].
Chlorine removal from the position para to the amino
group is preferred and stepwise exchange of two chlorine
atoms by hydrogen in 7 can occur with hydrodechlorination
of 9. Isomer 8, which is present in the starting material,
formed 3,4,5-trifluoro-2-chloroaniline 11.
2. Results and discussion
Polyfluoroarene reduction with zinc in aqueous ammonia
can be promoted by ammonium and zinc salts [10,14,15]. To
obtain amine 10, reduction of 7 was carried out and an 8:1
mixture of 10 and 3,4,5-trifluoroaniline 12 (formed from 11)
was obtained (entry 3, Table 1).
The starting materials, reaction conditions, product ratios,
and yields are reported in Table 1. Reduction of a mixture of
tetrafluorochloroanilines 1–3 (the product of noncatalytic
ammonolysis of pentafluorochlorobenzene [12]) resulted in
a mixture of previously reported tetrafluoroanilines 4–6 in a
ratio close to that of the starting mixture of 1–3 (Scheme 1,
entry 1, Table 1).
Preferential para-chlorine substitution by hydrogen,
found in the case of the reduction of 7 (see above), would
afford 3,5-difluoro-2-chloroaniline 15 via the reduction of
a mixture of 3,5-difluoro-2,6-dichloroaniline 13 and 3,5-
difluoro-2,4-dichloroaniline 14 (the product of noncatalytic
ammonolysis of 1,3,5-trifluoro-2,6-dichlorobenzene [13]).
Indeed, 15 with a small admixture of 3,5-difluoroaniline 16
was obtained from the mixture of 13 and 14 with zinc in
aqueous ammonia (Scheme 3, entry 4, Table 1).
Seeking to perform monodechlorination of 3,5,6-tri-
fluoro-2,4-dichloroaniline 7 (the starting material used
was the 9:1 mixture of 7 and 3,4,5-trifluoro-2,6-dichloroani-
line 8 [13]), we took into account that the extent of poly-
fluoroarene hydrodefluorination by zinc in aqueous
ammonia decreases with ammonia concentration and sub-
strate to zinc ratio [10]. The reaction conducted with 5%
aqueous ammonia and 1:4 substrate to zinc ratio mainly gave
3,5,6-trifluoro-2-chloroaniline 9 with a minor admixture of
2,3,5-trifluoroaniline 10 (Scheme 2, entry 2, Table 1).
Although the above reactions provide mixtures of amines,
in some cases the latter are believed to be usable as starting
materials for further synthesis without separation. This has
been demonstrated by synthesis of unknown 5,7-difluoro-8-
chloroquinoline 17 (Scheme 4) from 15 with an admixture of
16 via Skraup cyclization in 90% yield.
Similarly to the hydrodehalogenation of monoamines,
from 2,5,6-trifluoro-4-chloro-1,3-phenylenediamine 18,
we obtained 2,5,6-trifluoro-1,3-phenylenediamine 19 in
85% yield (Scheme 5, entry 5, Table 1). Thus, a compound
with two amino groups can also be reduced by zinc in
aqueous ammonia, but the rate of its hydrodechlorination
is appreciably lower compared with the reaction of anilines
mentioned above.
Scheme 1.
We anticipated that with active substrates, subjected
to mild ammonolysis under conditions compatible with
those for polyfluorochloroarylamine hydrodechlorination
(Table 1), aminodefluorination and subsequent hydrode-
chlorination of the initially formed amine could be per-
formed as a one-pot process. Perfluorochloropyridines were
thought to be suitable substrates for this process, since their
Scheme 2.

G.A. Selivanova et al. / Journal of Fluorine Chemistry 125 (2004) 1829–1834
1831
Scheme 3.
one-pot process, after ammonolysis had been completed, we
added only zinc to the resulting 23 to obtain 26 as the major
product (entry 3, Table 2).
To perform analogous synthesis of 24 and 25 from 20 and
of 26 from 21 without separating the ammonolysis and
hydrodechlorination stages, 20 was treated with zinc and
aqueous ammonia. The reaction, however, yielded mixtures
(entries 5–7, Table 2). In the presence of ammonium chlor-
ide or zinc chloride, the product ratio changed slightly, if at
all (entries 8 and 9, Table 2). However, the presence of both
salts markedly increased the extent of transformation and the
89% content of 25 among the reaction products was
achieved (entries 10 and 11, Table 2). The interaction of
21 with zinc in aqueous ammonia for 24 h gave 26 in 70%
isolated yield (entry 4, Table 2).
Scheme 4.
Scheme 5.
electron deficiency favors both nucleophilic substitution and
the removal of halogen. The feasibility of a one-pot process
of this kind is demonstrated for 3,5-dichloropyridine 20 and
3-chlorotetrafluoropyridine 21.
3,5-Dichloro-2,6-difluoro-22 and 3-chloro-2,5,6-tri-
fluoro-4-aminopyridine 23 are formed when 20 and 21
are treated with aqueous ammonia [5,16] (Scheme 6). To
ascertain that dechlorination of 22 and 23 under the condi-
tions used in this study is feasible, we treated 22 with zinc
in aqueous ammonia and obtained a 2:1 mixture of 2,6-
difluoro-3-chloro-4-aminopyridine 24 and 2,6-difluoro-4-
aminopyridine 25.
To prepare 24 directly from 20 we took into account that
the rate of polyfluoroarene hydrodehalogenation decreases
with ammonia concentration [10,14]. Therefore, after stir-
ring 20 with 30% aqueous ammonia and subsequent treat-
ment with zinc in 15% ammonia at room temperature 24 was
obtained in 75% yield (entry 1, Table 2). Seeking to obtain
25, we considered that the presence of ammonium and
zinc chlorides promotes polyfluoroarene defluorination
[10,14,15]. Indeed, after stirring with aqueous ammonia
and then with zinc in the presence of these salts 20 gave
a mixture containing 70% of 25 (entry 2, Table 2) (cf. [17]).
To transform 21 to 2,3,6-trifluoro-4-aminopyridine 26 in a
For aminopyridines 22 and 23 reductive hydrodechlor-
ination of polyfluorochloro-4-aminopyridines by zinc in
aqueous ammonia has been demonstrated and a one-pot
synthesis of partially fluorinated 4-aminopyridines carried
out. Previously, aminopyridines 24–26 were prepared from
the same starting materials in two steps, by varying the
sequence of catalytic reduction and amination. Thus, pyr-
idines 20 and 21 were hydrodechlorinated on palladium to
form 2,4,6-trifluoropyridine (75%) and 2,4,5,6-tetrafluoro-
pyridine (80%), respectively [18], which gave with ammonia
in aqueous dioxane a 2:1 mixture of 25 and 2,4-difluoro-6-
aminopyridine in the former case and a 4:1 mixture of 26 and
2,4,5-trifluoro-6-aminopyridine in the latter [17]. Initial
ammonolysis of 20 and 21 [5,16] and subsequent hydrode-
chlorination of 22 and 23 on palladium furnished a mixture
of 24 and 25 isolated by chromatography in 57% and 33%
yields, respectively, in the first case, and 26 (96% yield) in
the latter [5]. 25 also formed upon catalytic hydrodechlor-
ination of 22 in 90% yield [4].
Thus, polyfluorochloroamines, like polyfluorochloroar-
enes having no amino group [10], are hydrodechlorinated
by zinc in aqueous ammonia. This is a fundamental differ-
ence between the reaction under study and hydrodefluorina-
tion of perfluoroarenes, which occurs in the same reductive
Scheme 6.

1832
G.A. Selivanova et al. / Journal of Fluorine Chemistry 125 (2004) 1829–1834
Table 2
One-pot reactions of compounds 20 and 21 with Zn in aqueous ammonia
Entry
Starting
Quantity
(g mmol)
Type of
Time (h) Molar ratio
Substrate
Yield of
Product distribution
compound
procedure
mixture (g) (wt.%, GLC)a
Zn
ZnCl2
NH4Cl
1b
2b
3d
4
20
20
21
21
20
20
20
20
20
20
20
1.0 (0.005)
1.0 (0.005)
1.3 (0.007)
0.3 (0.0016)
0.3 (0.0015)
0.3 (0.0015)
0.3 (0.0015)
0.3 (0.0015)
0.3 (0.0015)
0.3 (0.0015)
0.3 (0.0015)
Ac
A
A
Be
B
70
90
24
24
8
1
1
1
1
1
1
1
1
1
1
1
10
10
10
10
10
10
10
10
10
10
10
–
–
6
–
–
–
–
–
–
6
6
6
0.74
0.6
1.0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
22 (1); 24 (88); 25 (5)
10
–
24 (23); 25 (70)
23 (3); 26 (86)
23 (1); 26 (89)
–
5
–
22 (12) 24 (73); 25 (5)
24 (72); 25 (18)
24 (51); 25 (26)
24 (63); 25 (20)
24 (61); 25 (24)
24 (40); 25 (45)
24 (1); 25 (89)
6
B
12
24
24
24
24
140
–
7
B
–
8
B
10
–
9
B
10
11f
B
10
10
B
a In all experiments, some unidentified components were present in the mixture of products (4–9%).
b Initial aminodefluoronation for 5 h, then water was added.
c Procedure A—initial aminodefluoronation, then addition of zinc and salts.
d Initial aminodefluoronation was for 24 h.
e Procedure B—all components charged at the start.
f Ammonia concentration was 34% (r ¼ 0.88 G mLÀ1).
system [10,14] but is hindered by incorporation of an amino
group, so that additional modification, such as N-acetylation
is necessary [15] obviously to diminish the electron-donor
effect of the substituent.
acetone-d6 or CDCl3 using C6F6 and CHCl3 as internal
standards, respectively. The product mixtures were analyzed
by GLC on a Hewlett-Packard HP-5890 chromatograph
equipped with a thermal conductivity detector; injector
temperature 240 8C, detector temperature 280 8C, tempera-
It is believed that accepting an electron by the substrate is
the rate-limiting stage of the reactions under study, since
decay of the resulting radical anion is known to be a rather
rapid process [19–22]. If an electron was accepted by the
p*-LUMO in both cases, one could hardly expect any
significant difference in the influence of the amino group
on the efficient reaction rates of hydrodefluorination and
-dechlorination. Hence, this difference is suggested to be
caused by the difference in the character of the MOs
accepting an electron. For example, from hexafluorobenzene
a pseudo-p* type radical anion is formed [23] while chlor-
opentafluorobenzene produces a pseudo-s* type radical
anion with the MO of the odd electron which is essentially
the s*-MO of the C–Cl bond [24]. Since pentafluoroaniline,
unlike hexafluorobenzene, is not reduced by zinc in aqueous
ammonia at ambient temperature [15], substitution of the
amino group for fluorine obviously increases the energy of
p*-MOs, so that the electron affinity of pentafluoroaniline is
insufficient for the reduction to be realized. The same
substitution in polyfluorochlorobenzenes should change
the p*-MO energy in a similar way, but it likely exerts a
substantially smaller effect on energy of the s*-MO of the
C-Cl bond, so that during the reduction of polyfluorochlor-
oarylamines an electron enters MO mainly located on the
C–Cl bond with practically synchronous fragmentation on it.
ture programming from 40 to 280 8C at a rate of 108 minÀ1
;
capillary column 15 000 mm  0.53 mm, stationary phase
1.5 mm  10À3 mm HP-5 [diphenyl (5%)-methylpolysilox-
ane]; carrier gas helium, 5 mL minÀ1. The components were
quantitated using the internal normalization technique.
The products were identified by GCMS on a Hewlett-
Packard G1081A instrument consisting of an HP-5890
Series II gas chromatograph and an HP-5971 mass-selective
detector (IE, 70 eV) with an HP5 capillary column: (30 000
 0.25) mm  0.25 mm. The He flow (1 mL minÀ1) was
used as carrier gas. The following temperature regime
program was applied: 2 min at 50 8C, 50 to 280 8C at a rate
of 108 minÀ1, 5 min at 280 8C. Evaporator temperature was
280 8C. Ion source temperature was 173 8C. The scanning
velocity was 1.2 scan sÀ1 in the mass interval 30–650 amu.
The molecular weights were determined on a Finnigan
MAT-8200 high-resolution mass spectrometer.
Pyridines 20 and 21 were obtained from the chemical pilot
factory at the N.N. Vorozhtsov Novosibirsk Institute of
Organic Chemistry. Pyridine 22 was obtained from pyridine
20 according to [5]. 30% Aqueous ammonia (0.888)
G mLÀ1 was prepared by saturation of commercial aqueous
ammonia with gaseous ammonia. Mixtures of products were
separated by column chromatography on silica gel (40/
100 mm).
Analyses of product mixtures were performed by GLC,
GC–MS and NMR. The 19F NMR spectral data of 4 and 5
agree with the literature data [25], and those of 6 are
identical with the data of the authentic specimen [26].
The 19F NMR spectral data of compounds are consistent
3. Experimental
1
19F and H NMR spectra were recorded on Bruker WP-
200 and Bruker AM-400 instruments for 20% solutions in

G.A. Selivanova et al. / Journal of Fluorine Chemistry 125 (2004) 1829–1834
1833
with the literature data: 9 [13].11 [27], 10, 12 [28], 15 and 16
[28,29], 19 [12].
(dd, 1F, J ¼ 9 Hz, J ¼ 6 Hz, F-5) 55.8 (dd, 1F, J ¼ 9 Hz,
J ¼ 6 Hz, F-7) (the signals were assigned according to the
1
interpretation of 5,7-difluoroquinoline spectrum [31]); H
(CHCl3 int., d: 7.24) 7.55 (t, 2H, J ¼ 9 Hz, H-6), 7.72 (dd,
1H, J ¼ 9 Hz, J ¼ 4 Hz, H-3); 8.55 (dd, 1H, J ¼ 9 Hz, J ¼
2 Hz, H-4); 9.11 (dd, 1H, J ¼ 4 Hz, J ¼ 1.5 Hz, H-2). Found,
%: C 54.30, H 2.25, N 6.91, Cl 17.75, F 19.19. Calculated,
%: C 54.14, H 2.00, N 7.02, Cl 17.79, F 19.05. Found, m/z:
Mþ 199.00029, calculated for C9H4ClF2N 199.0003.
4. General procedure
A glass reaction vessel was charged with the substrate,
zinc, aqueous ammonia and, when necessary, zinc and
ammonium chlorides. After stirring under conditions spe-
cified in Tables 1 and 2, the reaction mixture was extracted
with CH2Cl2 (3 Â 30 mL), the extract was dried with
MgSO4, the solvent was evaporated and the solid residue
was analyzed by NMR, GLC and GC–MS.
Acknowledgements
The authors are grateful to the Russian Foundation for
Basic Research and to Dr. I.V. Zibareva for assistance in
accessing the STN International databases (grant 00-03-
40142) via STN Center at the N.N. Vorozhtsov Institute
of Organic Chemistry, Siberian Branch of the Russian
Academy of Sciences. We also thank Dr. L.N. Shchegoleva
for helpful discussions.
4.1. 3,5-difluoro-2-chloroaniline 15
3,5-difluoro-2-chloroaniline 15 (Entry 4, Table 1) (37%
yield) was isolated by chromatography (silica gel, methy-
lene chloride:benzene ¼ 1:1)
4.2. 2,6-Difluoro-3-chloro-4-aminopyridine 24
2,6-Difluoro-3-chloro-4-aminopyridine 24 (Entry 1,
Table 2) was obtained in 75% yield by recrystallization
of the crude product from petroleum ether (40–70 8C), mp
75–76 8C (84–85 8C [5]). NMR (solution in CDCl3), d/ppm:
19F (C6F6 int.) 89.0, 88.8; 1H (CHCl3 int., d: 7.24) 6.10 (C-
H), 4.52 (NH2). HRMS m/z: 163.99537 (Mþ), calculated for
C5H3ClF2N2 163.99528.
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