Interaction of polyfluorinated 2-chloroquinolines with ammonia

Article abstract of DOI:10.1016/j.tet.2017.01.026

We have studied the interaction of polyfluorinated (in the benzene moiety) 2-chloroquinolines with liquid and aqueous ammonia as an approach to the synthesis of halogen-containing aminoquinolines. 5,7-Difluoro-, 5,6,8-trifluoro-, and 5,7,8-trifluoro-2-chloroquinolines mostly form products of substitution of the Cl atom, whereas 5,7-difluoro-2,6-dichloroquinoline, 5,6,7,8-tetrafluoro-, and 6,7-difluoro-2-chloroquinolines yield products of substitution of an F atom at various positions. The replacement of liquid ammonia with aqueous causes an increase in the proportion of the products of aminodechlorination relative to the products of aminodefluorination. For 2-chloro-6,8-difluoroquinoline this replacement leads to 2-amino-6,8-difluoroquinoline as the main product instead of the 8-amino-derivative. Activation energy values estimated by DFT calculations for the reactions in question agree with the reaction regioselectivity observed experimentally.

Full text of DOI:10.1016/j.tet.2017.01.026

Accepted Manuscript
Interaction of polyfluorinated 2-chloroquinolines with ammonia
Alexandrina D. Skolyapova, Galina A. Selivanova, Evgeny V. Tretyakov, Tatjana F.
Bogdanova, Lyudmila N. Shchegoleva, Irina Yu. Bagryanskaya, Larisa Yu. Gurskaya,
Vitalij D. Shteingarts
PII:
S0040-4020(17)30039-X
10.1016/j.tet.2017.01.026
TET 28396
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 September 2016
Revised Date: 29 December 2016
Accepted Date: 9 January 2017
Please cite this article as: Skolyapova AD, Selivanova GA, Tretyakov EV, Bogdanova TF, Shchegoleva
LN, Bagryanskaya IY, Gurskaya LY, Shteingarts VD, Interaction of polyfluorinated 2-chloroquinolines
with ammonia, Tetrahedron (2017), doi: 10.1016/j.tet.2017.01.026.
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ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Interaction of polyfluorinated 2-chloroquinolines with ammonia
a
a,
a
a
Alexandrina D. Skolyapova , Galina A. Selivanova ∗ , Evgeny V. Tretyakov , Tatjana F. Bogdanova ,
a
a, b
a
a, 1
Lyudmila N. Shchegoleva , Irina Yu. Bagryanskaya , Larisa Yu. Gurskaya , and Vitalij D. Shteingarts
a
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9 Ac. Lavrentiev Avenue, Novosibirsk 630090, Russia
Novosibirsk State University, 2 Pirogova Str., Novosibirsk 630090, Russia
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We have studied the interaction of polyfluorinated (in the benzene moiety) 2-chloroquinolines
with liquid and aqueous ammonia as an approach to the synthesis of halogen-containing
aminoquinolines. 5,7-Difluoro-, 5,6,8-trifluoro-, and 5,7,8-trifluoro-2-chloroquinolines mostly
form products of substitution of the Cl atom, whereas 5,7-difluoro-2,6-dichloroquinoline,
5,6,7,8-tetrafluoro-, and 6,7-difluoro-2-chloroquinolines yield products of substitution of an F
atom at various positions. The replacement of liquid ammonia with aqueous causes an increase
in the proportion of the products of aminodechlorination relative to the products of
aminodefluorination. For 2-chloro-6,8-difluoroquinoline this replacement leads to 2-amino-6,8-
difluoroquinoline as the main product instead of the 8-amino-derivative. Activation energy
values estimated by DFT calculations for the reactions in question agree with the reaction
regioselectivity observed experimentally.
Available online
Keywords:
Polyfluorinated 2-chloroquinolines
Nucleophilic substitution
Ammonia
Polyfluorinated aminoquinolines
DFT calculations
2009 Elsevier Ltd. All rights reserved
.
1
. Introduction
approach provided a relatively simple route for the synthesis of a
broad family of 2-chloroquinolines polyfluorinated on the
benzene moiety.
Compounds containing the quinoline core possess a broad
range of biological activities and are widely used in
8
1
1,2
pharmacology. Fluorinated quinolines are of special interest,
The amino group is one of the functional groups that is
promising in terms of the development of methods for more
profound functionalization of polyfluorinated quinolines. This
can explain the emergence of relatively novel studies devoted to
the development of methods for introduction of an amino group
into polyfluoroquinolines. In particular, the interaction of
polyfluorinated quinolines with uncharged nitrogen-centered
nucleophiles was shown to lead to substitution of a fluorine atom
because the presence of several fluorine atoms in a quinolone – in
3
addition to its possible specific effects on bioactivity – makes
functionalization of the benzene moiety considerably easier and
4
potentially more diverse. Substituted quinolines are also known
to easily form chelate complexes with Zn and Al cations; these
complexes show enhanced fluorescence as compared with the
5
quinolines themselves. The use of fluorinated quinolines may
shed light on the fundamental relationship between the number
and location of fluorine atoms in the benzene ring, and on the
complexation reaction with metal ions as well as physical
properties of the metal complexes.
Until recently, the polyfluorinated quinolines were a group of
compounds that were difficult to obtain. Fortunately, convenient
methods of selective hydrodehalogenation of perfluoroarenes
9
in the benzene ring, whereas charged nitrogen-centered
10
nucleophiles are added to the pyridine moiety. The reaction of
the perfluorinated quinoline with benzylamine was found to yield
11
substitution products of the fluorine atom at position 2 or 4.
Regarding previous research on fluorinated quinolines containing
a Cl atom at position 2, in the reactions with nitrogen-centered
nucleophiles (ethylamine, acetamide, and piperazine) only
(
and particularly ortho-hydrodefluorination of readily available
monofluoroderivatives
were
studied.
They
undergo
N-acetylpolyfluoroarylamines using zinc in aqueous ammonia)
aminodechlorination exclusively, forming the corresponding 2-
6
were developed recently. The same method was also applied to
12
aminoquinolines. With 2-chloroquinolines containing two or
selective hydrodechlorination of polyfluorochloroarylamines
more fluorine atoms in the benzene ring, the ratio of the rates of
substitution of fluorine and chlorine atoms may start favoring the
process of aminodefluorination, which can lead to useful (in
7
without their prior transformation into N-acetyl derivatives. This
—
——
∗
Corresponding author. Tel.: +7-383-330-6859; fax: +7-383-330-9752; e-mail: galseliv@nioch.nsc.ru
Deceased 12.02.2015
1

2
Tetrahedron
terms of synthesis) functionalization of the
A
b
C
en
C
ze
E
ne
P
m
T
o
E
ie
D
ty. MAte
NU
tra
flu
S
or
C
oq
R
ui
I
noline 1a but markedly easier than ammonolysis of
P
T
Here we studied the interaction of 5,6,7,8-tetrafluoro- (1a), 5,6,7-
trifluoro- (1b), 5,7,8-trifluoro- (1c), 5,7-difluoro- (1d), 6,7-
difluoro- (1e), and 6,8-difluoro- (1f) 2-chloroquinolines and 2,6-
dichloro-5,7-difluoroquinoline (1g) with aqueous or liquid
ammonia in order to determine the dependence of the orientation
of aminodehalogenation on reaction conditions and on the
number and positions of fluorine atoms in the substrate. Starting
materials 1a-1g were synthesized by literature methods, from
polyfluoroanilines obtained as described in supporting
information. The new 3,4-difluoroanilide of cinnamic acid (1ea),
difluoroquinoline 1e, where aminodefluorination again starts to
dominate (Table 1, compare entries 1–3 with 4). Nonetheless, the
interaction of 1e with liquid ammonia produced 2-amino-6,7-
difluoroquinoline (9), 6-amino-2-chloro-7-fluoroquinoline (10),
and 7-amino-2-chloro-6-fluoroquinoline (11) in the ratio 4:1:15
(Ω = 0.2) with yields 14%, 4%, and 65%, respectively (Table 1,
entry 4).
8
That is, two ortho-arranged fluorine atoms at positions 6 and 7
turned out to be sufficient for predominance of
aminodefluorination, and the presence of para-arranged fluorine
atoms was not crucial for the direction of the reaction.
6
,7-difluoroquinolin-2-one (1eb), 4-chloro-3,5-difluoroanilide of
cinnamic acid (1ga), 6-chloro-5,7-difluoroquinolin-2-one (1gb), 6,8-
difluoroquinolin-2-one (1fb), and the known 2,4-difluoroanilide of
cinnamic acid (1fa) described in the experimental section were
obtained as reaction intermediates in the synthesis of 1e-1g.
The reaction of difluoroquinoline 1d with liquid ammonia
yields 2-amino-5,7-difluoroquinoline (12) mostly, and two
isomeric products of aminodefluorination: 5-amino-2-chloro-7-
fluoroquinoline (13) and 7-amino-2-chloro-5-fluoroquinoline
(
14) in the ratio 15:4:1, Ω = 2.9 (Table 1, entry 5). Therefore, in
2
. Result and discussion
the case of 1d, the aminodechlorination is preferred due to the
inductive effect of the nitrogen atom of the heterocycle. The
formation of quinoline 12 (as well as isomeric 4-amino-5,7-
difluoroquinoline) was observed previously in a reaction of 5,7-
difluoroquinoline with potassium amide, but compound 12 was
not isolated. Quinolines 12–14 were obtained with yields of
49%, 11%, and 3%, respectively. Regioselectivity of
aminodefluorination of 1d at position 5 corresponded closely to
that for the interaction of 5,7-difluoroquinoline with aqueous
2
.1. Reactions with liquid ammonia
The reaction of quinoline 1a with liquid ammonia at 70 °C in
a steel autoclave leads to a substitution of both the chlorine atom
and fluorine atom resulting in formation of 2-amino-5,6,7,8-
tetrafluoroquinoline (2), 6-amino-2-chloro-5,7,8-trifluoro- (3),
and 7-amino-2-chloro-5,6,8-trifluoroquinoline (4) in the ratio
10
1
:1:12, respectively (Table 1, entry 1).
Aminoquinolines 3 (5%) and 4 (65%) are new compounds.
9
ammonia.
Quinoline 2 (5%) was obtained earlier via the interaction of
Ammonolysis of 1g by liquid ammonia also leads to three
products: 2-amino-6-chloro-5,7-difluoroquinoline (15), isomeric
5-amino-2,6-dichloro-7-fluoroquinoline (16), and 7-amino-2,6-
dichloro-5-fluoroquinoline (17) in the ratio 1:7:1, Ω = 0.1 (Table
1, entry 6). Novel aminoquinolines 15–17 were obtained with
yields 7%, 53%, and 11%, respectively. Therefore, introduction of
a chlorine atom at position 6 leads to noticeable activation of the
benzene cycle in the reaction with ammonia in comparison with
its structural analog 1d and allows for introduction of an amino
group mostly at position 5.
10
5
,6,7,8-tetrafluoroquinoline with potassium amide (11%).
The predominance of aminodefluorination
aminodechlorination, characterized by Ω ≈ 0.1, where Ω is a
molar ratio of aminodechlorination product to
over
aminodefluorination products, points to a stronger activating
effect of the four fluorine atoms relative to the nitrogen of the
heterocycle. Aminodefluorination of 1a is realized at position 7
(
6-NH /7-NH ≈ 1:11) and is consistent with orientation of the
2 2
substitution of a fluorine atom in 5,6,7,8-tetrafluoroquinoline
under the influence of either liquid or aqueous ammonia (6-
Like quinoline 1d, difluoroquinoline 1f contains meta-
arranged to each other fluorine atoms, but its ammonolysis by
liquid ammonia at 90 °C leads to 2-amino-6,8-difluoroquinoline
(18) and 8-amino-2-chloro-6-fluoroquinoline (19), with
predominance of the product of aminodefluorination, ꢀ = 0.3
(Table 1, entry 7). Quinolines 18 and 19 are isolated with the
yield 20% and 59%, respectively. Orientation of
aminodefluorination of 1f is consistent with the orientation of
methoxydefluorination of 6,8-difluoroquinoline by means of
sodium methylate, where only the substitution of the fluorine
9
NH /7-NH2
=
1:5 and 1:4 respectively). The observed
2
regioselectivity is the result, on the one hand, of the influence of
atoms F(5) and F(8), which deactivate each other but at the same
time activate atoms F(6) and F(7), and on the other hand, of the –
M-effect of the N atom of the heterocycle.
Assuming that the presence of para-arranged fluorine atoms
may determine the direction of aminodehalogenation, we
introduced into the reaction compounds 1b and 1c lacking a
fluorine atom either at position 6 or 7. In both cases, products of
aminodechlorination [2-amino-5,6,8-trifluoroquinoline (5) and 2-
amino-5,7,8-trifluoroquinoline (7), respectively] turn out to be
the main products, whereas the products of aminodefluorination
13
atom at position 8 was observed. In both compounds, position 8
is activated by both the -I effect of the nitrogen atom of the
heterocycle and the meta-atom of fluorine.
[
6-amino-2-chloro-5,8-difluoroquinoline (6) and 7-amino-2-
Ammonolysis of 1f at 150 °C, i.e., at the temperature above
14
chloro-5,8-difluoroquinoline (8)] are formed in small amounts:
for 1b Ω ≈ 49.0, for1c Ω ≈ 11.2(Table 1, entries 2 and 3). It should
be noted that orientation of aminodefluorination 1b and 1c is in
critical for ammonia (Tcrit ≈ 132 °C), leads to formation of
compound 19, also as the main product (Table 1, entry 8), albeit
19
at a greater value of ꢀ = 0.5. F NMR spectroscopy and gas
chromatography with mass spectrometry (GC-MS) detected trace
amounts of 2,8-diamino-6-fluoroquinoline (20) in the reaction
mixture. Thus, elevation of the temperature of the reaction above
critical does not change the direction of ammonolysis but
noticeably affects the ratio of products.
agreement with the results of ammonolysis of 5,6,8-trifluoro- and
9
5
,7,8-trifluoroquinolines by aqueous ammonia.
Only quinoline 7 (55%) was previously known and obtained
with the yield of 12% by the interaction of 5,7,8-
10
trifluoroquinoline with potassium amide.
The other
aminoquinolines, 5 (70%), and 8 (11%), were obtained for the
first time. Ammonolysis of trifluoroquinolines 1b and 1c by
liquid ammonia is somewhat more difficult than that of

Table 1. Conditions and results of the reaction of polyfluorinated 2-chloroquinolines 1a–g with liquid ammonia
ACCEPTED MANUSCRIPT
Time,
h
a
Amount in a mixture, mol %,
according to NMR F and GC-MS
b
№
Quinoline
Т, °C
Products,isolatedyield
19
ꢀ
1
7
0
9
2(7),3(8),4(85)
5(98),6(2)
≈0.1
49.0
11.2
1
a
2,5%
3,5%
4,65%
2
3
70
12
12
1b
5,70%
6
70
1c(2),7(90),8(8)
1
c
7,55%
9,14%
8,11%
10,4%
4
5
9
0
24
24
1e(2),9(19),10(5),11(74)
1d(2),12(73),13(20),14(5)
≈0.2
1e
11,65%
70
2.9
1
d
12,49%
15,7%
13,11%
16,53%
19,59%
19
14,3%
6
7
7
0
12
28
24
15(11),16(75),17(14)
1f(2),18(24),19(74)
18(33),19(63),20(4)
≈0.1
≈0.3
0.5
1g
17,11%
90
1
f
18,20%
8
1
f
150
18
20
a
After thin layer chromatography (TLC).
b
A molar ratio of the aminodechlorination product to the aminodefluorination products
2
.2. Reactions with aqueous ammonia
5–8 (Table 2, entries 3 and 4). In addition, we registered products
of substitution of a chlorine atom with a hydroxy group: 5,6,8-
trifluoroquinoline-2-one (22) and 5,7,8-trifluoroquinoline-2-one
(23) as well as a product of double substitution: 2,7-diamino-5,8-
difluoroquinoline (24).
In aqueous ammonia, ammonolysis requires somewhat more
rigid reaction conditions than in liquid ammonia (a dipolar
aprotic solvent) because the molecules of ammonia in an aqueous
solution are solvated and are also partially in the state of the
Ammonolysis of 1d in aqueous ammonia at 120 °C leads, just
as in liquid ammonia, to formation of 2-aminoquinoline 12 as the
main product and minor products of aminodefluorination: 13 and
14 (Table 2, entry 5). At the same time, the contribution of
aminodechlorination becomes even more dominant (Ω = 8.0 in
aqueous ammonia, and Ω = 2.9 in liquid ammonia).
+
conjugated acid NH , and their nucleophilicity is lower. For
4
example, to achieve high conversion, we had to keep 1a at 85 °C
for 24 h. Meanwhile, except for the products of monosubstitution
2
–4, which were obtained earlier during ammonolysis of 1a in
liquid ammonia, we detected a minor product of double
substitution: 2,7-diamino-5,6,8-trifluoroquinoline (21) (Table 2,
entry 1). During ammonolysis at 100 °C, the proportion of 21
increased appreciably (Table 2, entry 2). It should be noted that
aminodehalogenation of 1a proceeds mostly in the benzene
moiety both in liquid ammonia and in aqueous, but the share of
aminodechlorination increases from Ω = 0.1 in liquid ammonia to
Stirring of 1e with aqueous ammonia at 120 °C causes
incomplete conversion of the substrate (77%) and formation of
1
9
aminoquinolines 9–11 in the ratio Ω ≈ 0.7 (according to F NMR
spectroscopic data). Minor amounts of 6,7-difluoroquinoline-2-
one (1eb) are also detected (Table 2, entry 6). Thus, the use of
aqueous ammonia instead of the liquid one raises Ω substantially
(from 0.2 to 0.7).
0
.5 in aqueous ammonia.
Ammonolysis of 1b and 1c in aqueous ammonia at 120 °C,
just as in liquid ammonia, leads to formation of aminoquinolines

4
Tetrahedron
Table 2. Conditions and results of the react
A
ion
C
o
C
f p
E
o
P
ly
T
flu
E
o
D
rina
MANU
ted
2
-ch
lo
S
ro
C
qu
R
in
I
olines 1a–g with aqueous ammonia.
P
T
Time,
h
a
Amount in a mixture, mol %,
according to NMR F and GC-MS
b
№
Quinoline
Т, °C
Products,isolatedyield
19
ꢀ
1
2
3
85
24
1a(10),2(30)3(3),4(55),21 (2)
2(25),3(8),4(41),21 (26)
1b(8),5(80),6(1),22(11)
0.5
1
a
2
,38%
3,5%
4,47%
4,33%
21
21
1a
100
120
3
7
2,23%
3,14%
80.0
c
1b
5,52%
6
22
4
5
120
120
7
7(87),8(3),23(4),24(6)
29.0
8.0
1c
c
7,52%
8
23
24
10
1d(10),12(80),13(5),14(5)
1d
12,38%
13,3%
14
6
7
8
9
120
150
100
100
22
10
1
1e(23),9(30),10(2),11(44),1eb(1)
18(55),19(17),20(6),1fb(22)
1g(71),15(11),16(13),17(5)
≈0.7
3.2
1
e
9
, 25%
10,4%
11,37%
1eb
1f
18
19
20
1fb
0.6
1g
15
16
17
1g(13),15(27),16(34),17(13),
5
25(10),26(3)
1g
15
16
17
25
26
a
b
c
After thin layer chromatography (TLC).
A molar ratio of the aminodechlorination product to the aminodefluorination products.
8
Known compound .
Quinoline 18 is the main product during ammonolysis of 1f in
aqueous ammonia at 150 °C, in contrast in liquid ammonia
quinolones 1eb and 1fb are precursors of 1e and 1f and are
presented in the experimental section. Formation of
diaminoquinolines 20, 21, 24, 25, and 26 may have occurred due
to the higher-temperature ammonolysis with aqueous ammonia
versus liquid ammonia (see Supporting data). Reliable
determination of the structure of the products required holding X-
ray studies of a number of key compounds. XRD data for
compounds 1e-g, 1ea, 1ga, 4, 5, 11, 12, 16, 18 and 19 are
presented in Supporting data.
19
(
Table 2, entry 7). According to F NMR data, appreciable
amounts of 6,8-difluoroquinoline-2-one (1fb) and small amounts
of quinoline 20 were obtained.
The reaction of 1g with aqueous ammonia at 100 °C with low
conversion leads to aminoquinolines 15–17 in the ratio ~2:2.5:1,
respectively, at ꢀ = 0.6 (Table 2, entry 8). That is, again, as in the
above cases, the proportion of 2-aminoquinoline increases in
comparison with ammonolysis in liquid ammonia (ꢀ = 0.1). If
reaction time is increased (Table 2, entry 9), then the products of
diamination (2,5-diamino-6-chloro-7-fluoroquinoline (25) and
Thus, orientation of aminodehalogenation of quinolines 1a–e,
g in aqueous ammonia resembles that previously observed in
liquid ammonia, but the proportion of the products of
aminodechlorination at position 2 increases in comparison with
the transformations in liquid ammonia for all the substrates. In
contrast, in the case of quinoline 1f, the process of
aminodechlorination starts to dominate. Possible reasons for
acceleration of aminodechlorination in aqueous ammonia include
2
,7-diamino-6-chloro-5-fluoroquinoline (26)) are formed in
addition to aminoquinolines 15–17.
Earlier, it has been shown that side reactions can occur during
amination of polyfluorinated arenes in a steel autoclave in
15
aqueous or alcohol-based solvents. It is possible that these
1
5
reactions can explain the formation of quinolones 22, 23, 1eb,
catalysis of this reaction by the metallic walls of the autoclave
or a specific interaction of the substrate with the solvent
8
and 1fb. Quinolones 22 and 23 are known compounds. New

(
protonation of the heterocyclic nitrogen) or a combination of the
for the interaction of quinoline 1d with ammonia as an example.
ACCEPTED MANUSCRIPT
two factors.
The calculated potential energy curves have no clear-cut minima
between the reagents and products, corresponding to the
Meisenheimer complexes. For compound 1d, the substitution at
position 2 is kinetically preferable (the lowest height of the
activation barrier), that is, in accordance with the experimental
data.
2
.3. Computational results.
To interpret the experimentally observed patterns of
nucleophilic substitution in fluorinated 2-chloroquinolines, we
performed quantum-chemical calculations of the respective
reaction pathways by the DFT method using B3LYP and
CAMB3LYP functionals with the standard basis set 6-31+G(d).
The reaction transition states were located. The types of
stationary structures that we found (a minimum or transition
state) were determined by the normal vibration analysis
accompanied by intrinsic reaction coordinate (IRC) calculations.
All the calculations were conducted by means of the GAMESS
Table 3. The calculated activation energies (kcal/mol) for
reactions of quinolines 1a–g and A–E with ammonia (C-PCM
H O/CABM3LYP/6-31+G(d)).
2
Position in quinoline skeleton
Main product
calc actual
Comp.
2
5
6
7
8
1
a
22.3 23.5 24.2 20.5 25.5
7
2
2
2
7
8
5
2
2
7
7
2
7
2
2
2
7
2
5
16
package.
1b
23.1 27.2 26.8
21.9 26.8
25.9
23.2 27.9
25.3
The influence of polar media was taken into account within
the conductorlike polarizable continuum model (C-PCM). For
aqueous ammonia, we used the model solvent H O with built-in
parameters ε (the dielectric constant) = 78 and Rsolv (the solvent
radius) = 1.39 Å. For liquid ammonia, the parameters were set on
the basis of literature data: ε = 21 and 9 for temperatures −20 and
1
c
1
d
23.2 24.4
2
1
e
25.1
25.8
28.5 24.7
28.8
1f
24.0
1
g
22.4 22.0 34.0 23.1
23.3 28.9
17
1
20 °С, respectively, and Rsolv = 1.9 Ǻ as the average of 1.95
18
A
28.8
and 1.85 Ǻ as described elsewhere.
The calculations were carried out for all halogen-substituted
positions of the quinoline backbone of compounds 1a–g and also
for 5,8-difluoro- (A), 7,8-difluoro- (В), 6,7,8-trifluoro- (С),
B
C
D
E
23.6
23.5
25.5 26.2
26.5 22.6 23.8
23.4 23.3 26.3 22.7
24.7 26.4 29.2
5
,6,7-trifluoro- (D), and 5,6-difluoro-2-chloroquinolines (E),
whose transformations have not yet been studied. Both
functionals yielded similar results. The activation energy values
(
defined as the difference between total energies of the reaction
As the chemical experiments showed, replacement of liquid
transition state and prereaction complex) that were obtained in
CAMB3LYP calculations are shown in Table 3. Note that the
differences in activation energies obtained for various positions
are more pronounced in CAMB3LYP calculations in comparison
with B3LYP ones, and these differences describe the reaction
regioselectivity somewhat better. All the transition states found
are structurally similar to σ-complexes. In accordance with the
calculation results, the reactions proceed as a one-stage process.
Note that analogous results have also been obtained by other
ammonia with aqueous one increases the proportion of the
substitution product at position 2 for all the compounds studied.
Using quinoline 1f as an example, we examined the influence of
solvent polarity by varying its dielectric permittivity ε (Table 4).
The height of activation barriers was calculated for the following
values of ε: 78 (water), 21 and 9 (liquid ammonia at −20 °С and
17
1
20 °С, respectively), and 1.0 (vacuum). We found that the
lower the dielectric permittivity, the lower is the barrier of
activation for the substitution at position 8 and smaller the
difference between the barriers for substitution at positions 2 and
19
researchers.
8
. The tendency obtained in the calculations agrees well with that
observed in chemical experiments.
Table 4. The calculated activation energies (kcal/mol) for the
reaction of 1f with ammonia taking into account the dielectric
permittivity (C-PCM/B3LYP/6-31+G(d)).
Position in quinoline core
occupied by halogen
Main product
(calc.)
ε
Comp.
2
6
8
2
2
2
3
4.8
29.7
26.6
2
2
2
8
78
21
9
4.9
5.5
1.0
30.1
31.1
39.6
25.6
26.0
30.6
1
f
1
The results of the calculations describe well the observed
increase in reactivity of fluoroquinolines in terms of
Figure 1. A section of the potential energy surface along the
reaction coordinate for quinoline 1d with aqueous ammonia.
Stationary structures for the substitution at position 2 are
shown (С-PCM/CAMB3LYP/6-31+G(d)).
a
nucleophilic substitution as the number of fluorine atoms
increases. Besides, the calculations reproduce the observed
patterns of influence of the relative position of fluorine atoms in
the benzene moiety on the direction of the reaction. Our results
suggest that this calculation may predict regioselectivity for
ammonolysis of quinolines A–E.
A characteristic view of a section of the potential energy
surface (PES) along the reaction coordinate is shown in Figure 1

6
Tetrahedron
ACCEPTED MANUSCRIPT
3
. Conclusion
4.3. Synthesis
Orientation of a halogen substitution is determined by the
Starting materials: known compounds (1a, 1b, 1c, and 1d) and
new ones (1e, 1f, and 1g) were obtained as described previously
8
totality of electron effects of the heterocycle and halogen atoms
depending on their position. For several polyfluorinated (on the
benzene ring) 2-chloroquinolines in the reaction with liquid or
aqueous ammonia, we found that 5,7-difluoro-, 5,6,8-trifluoro-,
and 5,7,8-trifluoro-2-chloroquinoline mostly form products of
substitution of a chlorine atom, whereas 2,6-dichloro-5,7-
difluoroquinoline, 5,6,7,8-tetrafluoro-, and 6,7-difluoro-2-
chloroquinoline mostly form products of substitution of fluorine
atoms at various positions of the benzene ring. The share of
(see Supporting Information for details). Aminoquinolines 2–19
(except 6) were isolated by TLC on plates with the fixed layer of
the sorbent (silica gel LSL254 5/40 µm with addition of 13 wt%
plaster) with visual control during irradiation of the dried plate
with UV light. Separated fractions were eluted from the sorbent
by means of acetone.
4
.4. Preparation of N-(polyfluorophenyl)cinnamamides (general
procedure).
products at position
2 increases relative to products of
aminodefluorination after replacement of liquid ammonia with
aqueous for all the substrates studied. The use of aqueous
ammonia instead of liquid for 2-chloro-6,8-difluoroquinoline
leads to a change from the predominant substitution of fluorine
and formation of 8-amino-2-chloro-6-fluoroquinoline to
substitution of chlorine and formation of 2-amino-6,8-
difluoroquinoline as the main product. At the level of C-
PCM/B3LYP/6-31+G(d) and C-PCM/CAMB3LYP/6-31+G(d),
we calculated the pathways of halogen substitution with an
amino group during an interaction of polyfluorinated 2-
chloroquinolines with ammonia. The transition states found are
similar in structure to σ-complexes, and their relative energies
correlate with the reaction regioselectivity.
To a mixture of fluoroaniline and K CO in acetone–water
cooled in an ice bath, cinnamoyl chloride was added in small
portions. The mixture was stirred at 0 °С for 2 h and held at
0 °С for 1 h. The precipitated material was filtered off, washed
2
3
2
with water and dried.
4
.4.1. 2,4-Difluoroanilide of cinnamic acid (1fa). A mixture of
2
,4-difluoroaniline (5.00 g, 38.76 mmol),
cinnamoyl chloride (6.50 g, 39.02 mmol),
K CO (8.08 g, 58.47 mmol) in acetone–
2
3
water (50.0 mL) gave 1fa (9.45 g, 94%).
1
White solid, mp: 140-141 °C, spectrum H NMR
20
13
coincides with
;
C NMR (126 MHz, DMSO-d ): δ
6
1
04.1 (dd, 1C, J=24.0, 26.8 Hz, C-3), 111.1 (dd, 1C, J=3.5, 21.8
Hz, C-5), 121.7 (s, 1C, C-8), 123.0 (dd, 1C, J=3.7, 11.7 Hz, C-1),
4
. Experimental section
1
1
25.1 (dd, 1C, J=2.3, 9.0 Hz, C-6), 127.8 (s, 2C, C-11, C-15),
29.0 (s, 2C, C-12, C-14), 129.9 (s, 1C, C-13), 134.7 (s, 1C, C-
4
.1. General methods
1
13
19
10), 140.8 (s, 1C, C-9), 153.7 (dd, 1C, J=12.3, 248.0 Hz, C-4),
158.4 (dd, 1C, J=11.0, 243.7 Hz, C-2), 164.0 (s, 1C, C-7).
NMR (282 MHz, CDCl ): δ 35.25 (bs, 1F, F-2), 46.74 (bs, 1F, F-
4).
H, C, and F NMR spectra were recorded on NMR
19
1
19
F
spectrometers Bruker AV-300 (300.13, 282.36 for H,
correspondingly), Bruker AV-400 (400.13 for H), Bruker DRX-
F
1
3
1
5
00 and Bruker Avance III 500 (500.13, 125.76, 470.51 for H,
13
1
9
1
1
3
C, and F, respectively). Chemical shifts (δ) of H and C are
4
.4.2. 4-Chloro-3,5-difluoroanilide of cinnamic acid (1ga). A
given in ppm relative to TMS using the solvent signals as the
internal standard (δH = 2.05 ppm, δC = 29.8 and 206.3 ppm for
acetone-d , δH = 2.50 ppm, δC = 39.5 ppm for DMSO-d , δH =
mixture of 4-chloro-3,5-difluoroaniline (1.65 g,
1
0.09 mmol), cinnamoyl chloride (1.70 g,
6
6
10.20 mmol), K CO3 (2.10 g, 15.20
2
7
.26 ppm, δC = 77.2 ppm for CDCl ), the internal standard for
3
mmol) in acetone–water (40.0 ml) gave
1ga (2.51 g, 85%). White solid, after
19
F spectra was C F (δ = –162.9 ppm). Melting points were
6
6
determined with a Mettler Toledo FP900 Termosystem. Infrared
IR) spectra were recorded by means of a Vector-22 instrument
crystallization from aqueous EtOH, mp: 184-185 °C;
Found: C, 61.31; H, 3.53; Cl, 12.00; F, 13.13; N, 4.87.
(
[
for samples pelleted with KBr (0.25%). UV spectra were
recorded on a Cary 5000 instrument with EtOH. GC-MS analysis
was performed 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. The precise molecular weights of ions were
determined by high-resolution mass spectrometry on a Thermo
Scientific DFS instrument, at ionizing energy of 70 eV.
Elemental analysis was carried out using a Euro EA 3000 C, H,
N-analyzer. Analysis of Cl was carried out by the mercurimetric
titration method, and analysis of F was carried out by a
spectrophotometric method.
C H ClF NO requires C, 61.34; H, 3.43; Cl, 12.07; F, 12.94; N,
15
10
2
-
1
4
.77]; IR (KBr) ν 3262 (NH), 1663 (C=O), 1624 (NH) cm ; UV
1
(EtOH) λ nm (lg ε): 221 (4.19), 302 (4.53); H NMR (300 MHz,
acetone-d ): δ 6.78 (d, 1H, JHH=15.6 Hz, H-8), 7.39-7.47 (m, 3H,
6
H-12, H-13, H-14), 7.59-7.68 (m, 4H, H-2, H-6, H-11, H-15),
1
3
7
.72 (d, 1H, JHH=15.6 Hz, H-9), 9.86 (bs, 1H, NH); C NMR
(
126 MHz, DMSO-d ): δ 101.6 (t, 1C, J=21.6 Hz, C-4), 103.0
6
(dd, 2C, J=1.9, 26.5 Hz, C-2, C-6), 121.2 (bs, 1C, C-8), 127.9 (s,
2
1
C, C-11, C-15), 129.0 (s, 2C, C-12, C-14), 130.1 (s, 1C, C-13),
34.3 (s, 1C, C-10), 139.5 (t, 1C, J=13.1 Hz, C-1), 141.5 (s, 1C,
C-9), 157.9 (dd, 2C, J=5.5, 244.9 Hz, C-3, C-5), 164.1 (s, 1C, C-
1
9
7
5
2
). F NMR (282 MHz, acetone): δ 49.73-49.83 (m, 2F, F-3, F-
+
); HRMS (EI): M , found 293.0416. C H ClF NO requires
93.0414.
4
.2. Computational section
15 10
2
All the calculations were performed with the GAMESS
16
4.4.3. 3,4-Difluoroanilide of cinnamic acid (1ea). A mixture of
package. The geometry of systems was optimized by the DFT
computational method using the global hybrid functionals
B3LYP and CamB3LYP with the 6-31+G(d) basis set. The
nature of each stationary point as a true minimum or a first-order
transition state was confirmed by calculating harmonic
frequencies. The effect of the solvent was taken into account
using the conductor polarizable continuum model (СPCM) with
parameters of the water, and parameters were taken from the
3
,4-difluoroaniline (5.79 g, 44.85 mmol),
cinnamoyl chloride (7.43 g, 44.60 mmol),
K CO (9.31 g, 67.37 mmol) in acetone–
2
3
water (50.0 mL) gave 1ea (10.37 g, 89%).
White solid; mp: 147-148 °C; [Found: C, 69.64;
H, 4.22; F, 14.62; N, 5.39. C H F NO requires C,
15
11 2
6
9.49; H, 4.28; F, 14.66; N, 5.40]; IR (KBr) ν 3391 (NH),
-1
17,18
3304 (NH), 1668 (C=O), 1624 (NH) cm ; UV (EtOH) λ nm (lg
literature on liquid ammonia.

1
ε): 221 (4.21), 296 (4.48); H NMR (400 MHz, acetone-d ): δ
J=20.2, 22.6 Hz, C-6), 106.2 (dd, 1C, J=2.3, 18.5 Hz, C-9), 122.7
ACCEPTED MANUSCRIPT
6
6
.80 (d, 1H, JHH=15.7 Hz, H-8), 7.27 (td, 1H, J =J=9.0 Hz,
JHF=10.4 Hz, H-5); 7.37-7.46 (m, 4H, H-11, H-12, H-14, H-15),
.60-7.64 (m, 2H, H-6, H-13), 7.70 (d, 1H, JHH=15.7 Hz, H-9);
.00 (ddd, 1H, J=2.5, J =7.5, 13.2 Hz, H-2); 9.62 (bs, 1H, NH);
C NMR (126 MHz, acetone-d ): δ 109.4 (d, 1C, J=22.3 Hz, C-
), 116.2 (dd, 1C, J=3.4, 5.8 Hz, C-6), 118.1 (dd, 1C, J=1.1, 18.1
Hz, C-5), 122.3 (s, 1C, C-8), 128.7 (s, 2C, C-11, C-15), 129.8 (s,
C, C-12, C-14), 130.7 (s, 1C, C-13), 135.8 (s, 1C, C-10), 137.4
dd, 1C, J=3.0, 9.2 Hz, C-1), 142.3 (s, 1C, C-9), 146.9 (dd, 1C,
J=12.9, 242.0 Hz, C-4), 150.6 (dd, 1C, J=13.3, 243.5 Hz, C-3),
64.6 (s, 1C, C-7); F NMR (282 MHz, acetone): δ 18.50 (dddd,
F, J=4.0 Hz, J =7.5, 10.4 Hz, J = 21.8 Hz, F-4), 26.06 (ddd,
(bs, 1C, C-3), 131.7 (dd, 1C, J=1.7 Hz, J=3.2 Hz, C-4), 138.8
(dd, 1C, J=7.8, 13.7 Hz, C-10), 154.5 (dd, 1C, J=5.7, 252.7 Hz,
C-5), 158.1 (dd, 1C, J=4.8, 249.2 Hz, C-7), 161.5 (s, 1C, C-2);
HF
7
8
19
F NMR (282 MHz, DMSO-d ): δ 42.82 (dd, 1F, J =1.7 Hz,
6
HF
HF
1
3
J =3.9 Hz, F-5), 51.73 (dd, 1F, J =3.9 Hz, J =10.1 Hz, F-7);
FF
FF
HF
6
+
HRMS (EI): M , found 214.9946. C H ClF NO requires
9
4
2
2
2
14.9944.
2
(
4
.6. Preparation of 2-chloroquinolines (general procedure).
A mixture of quinolin-2-one and POСl was stirred at 95–100 °С
3
19
1
1
1
2
for 2 h and then cooled. Ice was added to the mixture. The
precipitated material was filtered off, washed with water and
dried.
HF
FF
+
F, J =9.0, 13.2 Hz, J =21.8 Hz, F-3); HRMS (EI): M , found
59.0799. C H F NO requires 259.0803.
HF
FF
15
11 2
4
.6.1. 2-Chloro-6,7-difluoroquinoline (1e). A mixture of 1eb and
4
.5. Preparation of quinolin-2-ones (general procedure).
5,6-difluoroquinolin-2-one in ratio 10:1 (2.42 g, 13.36 mmol) and
POCl3 (6.23 g, 40.64 mmol) gave 1e and 2-chloro-5,6-
difluoroquinoline in ratio 10:1 (2.28 g, 85%). After column
chromatography 1e (1.96 g, 73%). White solid; mp: 115 °C;
[Found: C, 53.97; H, 1.97; Cl, 17.65; F, 19.06; N, 6.95.
C H ClF N requires C, 54.16; H, 2.02; Cl, 17.76; F, 19.04; N,
A mixture of fluoroanilide of cinnamic acid and AlCl was
3
stirred at 110–120 °С for 2 h and after cooling ice water was
added to the mixture. The precipitated material was filtered off,
washed with water and dried.
9
4
2
7
2
.02]; UV (EtOH) λ nm (lg ε): 209 (4.66), 268 (3.53), 291 (3.41),
97 (3.47), 304 (3.67), 310 (3.63), 317 (3.82); H NMR (500
4
.5.1. 6,7-Difluoroquinolin-2-one (1eb). A mixture of 1ea (2.49 g,
1
9
.60 mmol) and AlCl (3.90 g, 29.24 mmol) gave 1eb and 5,6-
3
MHz, acetone-d ): 7.54 (d, 1H, JHH=8.7 Hz, H-3), 7.81 (dd, 1H,
6
difluoroquinolin-2-one in ratio 10:1, 1.38 g, the yield of mixture
9%. After sublimation and crystallization from EtOH, 1eb,
white solid; mp: 295 °C followed by decomposition; [Found: C,
9.76; H, 2.90; F, 20.70; N, 8.07. C H F NO requires C, 59.76;
J =7.7, 11.4 Hz, H-5), 7.94 (dd, 1H, J =8.7, 10.7 Hz, H-8),
HF
HF
7
13
8
.38 (d, 1H, JHH=8.7 Hz, H-4); C NMR (126 MHz, acetone-d6):
δ 114.7 (d, 1C, J=18.4 Hz, C-5), 115.7 (d, 1C, J=17.2 Hz, C-8),
5
9
5 2
1
1
23.6 (s, 1C, C-3), 125.2 (dd, 1C, J=1.5, 8.6 Hz, C-9), 139.9 (bd,
C, J=4.4 Hz, C-4), 145.9 (dd, 1C, J=1.3, 11.2 Hz, C-10), 150.9
H, 2.78; F, 20. 98; N, 7.73]; UV (EtOH) λ nm (lg ε): 209 (4.66),
68 (3.53), 291 (3.41), 297 (3.47), 304 (3.67), 310 (3.63), 317
2
1
(dd, 1C, J=15.7, 250.7 Hz, C-6), 151.9 (d, 1C, J=2.8 Hz, C-2),
(3.82); H NMR (300 MHz, DMSO-d ): 6.53 (d, 1H, JHH=9.6 Hz,
19
6
1
53.6 (dd, 1C, J=16.1, 253.7 Hz, C-7); F NMR (471 MHz,
H-3), 7.23 (dd, 1H, J =7.1, 11.6 Hz, H-5), 7.80 (dd, 1H, J =8.7,
1
NH); C NMR (126 MHz, DMSO-d ): δ 103.4 (d, 1C, J=21.2
Hz, C-8), 115.5 (dd, 1C, J=1.4, 18.3 Hz, C-5), 115.7 (dd, J=2.4,
HF
HF
acetone-d ): δ 27.53 (ddd, 1F, J =7.7, 10.7 Hz, J =20.6 Hz, F-
6
HF
FF
0.9 Hz, H-8), 7.86 (d, 1H, JHH=9.6 Hz, H-4), 11.85 (bs, 1H,
13
7), 32.20 (ddd, 1F, JHF=8.7, 11.4 Hz, JFF=20.6 Hz, F-6); HRMS
6
+
(EI): M , found 198.9998. C H ClF N requires 198.9995.
9 4 2
7
.4 Hz, 1C, C-3), 122.4 (d, 1C, J=2.6 Hz, C-9), 136.1 (d, 1C,
4
1
9
5
.6.2. 2-Chloro-6,8-difluoroquinoline (1f). A mixture of 1fb (2.35 g,
J=10.1 Hz, C-10), 139.2 (bs, 1C, C-4), 145.0 (dd, 1C, J=14.0,
2
1
2.98 mmol) and POCl (6.00 g, 39.14 mmol) gave 1f (2.32 g,
3
40.8 Hz, C-6), 150.9 (dd, 1C, J=14.8, 249.6 Hz, C-7), 161.7 (bs,
19
0%). After sublimation, white solid; mp: 111 °C; [Found: C,
4.00; H, 2.39; Cl, 17.89; F, 19.06; N, 7.18. C H ClF N requires
C, C-2); F NMR (282 MHz, DMSO-d ): δ 16.91 (ddd, 1F,
6
9
4
2
J =7.1, 10.9 Hz, J =23.1 Hz, F-7), 29.19 (ddd, 1F, J =8.7,
HF
FF
HF
C, 54.16; H, 2.02; Cl, 17.76; F, 19.04; N, 7.02]; UV (EtOH) λ nm
lg ε): 201 (4.63), 203 (4.62), 235 (4.61), 275 (3.38), 310 (3.10),
1
1.6 Hz, J =23.1 Hz, F-6).
FF
(
3
1
24 (3.11); H NMR (300 MHz, acetone-d ): 7.57 (ddd, 1H,
4
1
8
.5.2. 6,8-Difluoroquinolin-2-one (1fb). A mixture of 1fa (4.04 g,
6
JHH=2.7 Hz, J =9.0, 10.4 Hz, H-7), 7.62 (ddd, 1H, J =1.5, 9.0
5.58 mmol) and AlCl (6.60 g, 49.50 mmol) gave 1fb (2.31 g,
HF
HF
3
2%). After sublimation white solid; mp: 265 °C followed by
Hz, JHH=2.7 Hz, H-5), 7.66 (bd, 1H, JHH=8.7, H-3), 8.41 (dd, 1H,
13
decomposition; [Found: C, 59.46; H, 2.79; F, 20.96; N, 7.70.
C H F NO requires C, 59.68; H, 2.78; F, 20.98; N, 7.73]; IR
JHF=1.5, JHH=8.7 Hz, H-4); C NMR (126 MHz, acetone-d ): δ
6
107.1 (dd, 1C, J=22.5, 30.0 Hz, C-7), 108.2 (dd, 1C, J=5.0, 22.4
Hz, C-5), 125.4 (s, 1C, C-3), 129.5 (dd, 1C, J=2.6, 11.8 Hz, C-9),
135.9 (bd, 1C, J=12.3 Hz, C-10), 139.9 (dd, 1C, J=3.6, 4.9 Hz,
C-4), 151.1 (d, 1C, J=2.4 Hz, C-2), 158.4 (dd, 1C, J=13.6, 260.0
Hz, C-8), 160.5 (dd, 1C, J=11.5, 247.9 Hz, C-6); F NMR (282
MHz, acetone-d ): δ 43.44 (ddt, 1F, 2J =1.5 Hz, J =7.5 Hz,
9
5 2
-
1
(
KBr) ν 3018 (NH), 1668 (C=O), 1647 (NH) cm ; UV (EtOH) λ
nm (lg ε): 207 (4.34), 224 (4.46), 245 (4.02), 267(3.93), 276
1
(3.81), 335 (3.63); H NMR (500 MHz, DMSO-d ): δ 6.64 (d,
6
19
1
H, JHH=9.6 Hz, H-3), 7.43 (ddd, 1H, J=1.3, 8.8 Hz, JHH=2.6 Hz,
H-5), 7.45 (ddd, 1H, JHH=2.6 Hz, J=9.0, 11.2 Hz, H-7), 7.91 (dd,
1
6
HF
FF
13
H, J=1.3 Hz, JHH=9.6 Hz, H-4), 11.88 (bs, 1H, NH); C NMR
J =10.4 Hz, F-8), 53.52 (tdd, 1F, J=0.7 Hz, J =7.5 Hz,
HF
FF
(126 MHz, DMSO-d ): δ 105.5 (dd, 1C, J=21.8, 28.7 Hz, C-7),
+
6
2
J =9.0 Hz, F-6); HRMS (EI): M , found 198.9990. C H ClF N
HF 9 4 2
1
08.9 (dd, 1C, J=3.9, 22.7 Hz, C-5), 121.0 (dd, 1C, J=4.6, 10.6
requires 198.9995.
Hz, C-9), 124.7 (bs, 1C, C-3), 124.8 (dd, 1C, J=1.6, 11.8 Hz, C-
1
2
1
0), 139.3 (dd, 1C, J=2.4, 3.6 Hz, C-4), 148.7 (dd, 1C, J=13.0,
49.3 Hz, C-8), 155.9 (dd, 1C, J=11.0, 239.8 Hz, C-6), 161.5 (bs,
4.6.3. 2,6-Dichloro-5,7-difluoroquinoline (1g). A mixture of 1gb
(1.38 g, 6.40 mmol)) and POCl (2.95 g, , 19.24 mmol) gave 1g
(1.30 g, 86%). White solid, mp: 139-141 °C followed by
3
19
C, C-2); F NMR (470 MHz, DMSO-d ): δ 35.98 (bd, 1F,
6
J=10.6 Hz, F-8), 43.47 (dt, 1F, J=2.6 Hz, 2J=8.9 Hz, F-6); HRMS
decomposition; [Found: C, 45.82; H, 1.21; F, 16.01; N, 6.21.
+
1
(
EI): M , found 181.0333. C H F NO requires 181.0334.
C
9
H
3
Cl
2
F
2
N requires C, 46.19; H, 1.29; F, 16.24; N, 5.99]; H
9
5 2
NMR (400 MHz, acetone-d ): 7.68 (dd, 1H, J=0.5 Hz, JHH=8.8
6
4
.5.3 6-Chloro-5,7-difluoroquinolin-2-one (1gb). A mixture of
ga (2.50 g, 8.51 mmol) and AlCl (3.42 g, 25.65 mmol) gave 1gb
Hz, H-3), 7.72 (ddd, 1H, JHH=0.7 Hz, J =2.1, 10.0 Hz, H-8),
HF
13
1
3
8.53 (dd, 1H, JHH=0.6, 8.8 Hz, H-4); C NMR (126 MHz,
(1.43 g, 78%). Dark-red solid, 293 °C followed by
acetone-d ): δ 109.3 (dd, 1C, J=20.1, 24.2 Hz, C-6), 110.5 (dd,
6
1
decomposition; H NMR (400 MHz, DMSO-d ): 6.58 (d, 1H,
JHH=9.8 Hz, H-3), 7.08 (dd, 1H, J =1.7, 10.1 Hz, H-8), 7.95 (d,
1
6
1C, J=4.7, 21.9 Hz, C-8), 116.1 (dd, 1C, J=1.9, 16.2 Hz, C-9),
124.0 (t, 1C, J=2.7 Hz, C-3), 133.2 (dd, 1C, J=2.2, 3.4 Hz, C-4),
147.0 (dd, 1C, J=4.3, 14.1 Hz, C-10), 154.1 (bd, 1C, J=0.5 Hz, C-
2), 155.3 (dd, 1C, J=5.4, 257.8 Hz, C-5), 159.6 (dd, 1C, J=4.3,
HF
13
H, JHH=9.8 Hz, H-4), 12.15 (bs, 1H, NH); C NMR (75 MHz,
DMSO-d ): δ 98.7 (dd, 1C, J=3.8, 25.3 Hz, C-8), 101.1 (dd, 1C,
6

8
Tetrahedron
1
9
2
51.8 Hz, C-7); F NMR (282 MHz, acetone-d ): δ 44.18 (dd,
2H, NH ), 7.37 (dd, 1H, J=0.6 Hz, JHH=8.7 Hz, H-3), 8.35 (dd,
2
13
ACCEPTED MANUSCRIPT
6
1
F, J =2.1 Hz, J =3.6 Hz, F-5), 52.72 (dd, 1F, J =3.6 Hz,
1H, J =1.5 Hz, JHH=8.7 Hz, H-4); C NMR (126 MHz, acetone-
HF
FF
FF
HF
+
J =10.0 Hz, F-7); HRMS (EI): M , found 232.9602. C H Cl F N
d6): δ 109.6 (dt, 1C, 2J=1.8 Hz, J=14.4 Hz, C-9), 120.4 (bs, 1C,
HF
9
3
2 2
requires 232.9605.
C-3), 130.1-130.4 (m, 1C, C-10), 132.8-133.0 (m, 1C, C-4),
1
35.0 (ddd, 1C, J=1.2, 3.1, 10.9 Hz, C-7), 140.1 (dm, 1C,
J=241.8 Hz, C-8), 140.3 (ddd, 1C, J=7.7, 12.0, 243.6 Hz, C-6),
41.9 (ddd, 1C, J=4.7, 15.9, 252.6 Hz, C-5), 152.1 (dt, 2J=1.0
4
.7. Reactions of polyfluorinated 2-chloroquinolines with liquid
3
NH (general procedure).
1
19
Hz, J=2.8 Hz, 1C, C-2); F NMR (282 MHz, acetone): δ 9.34
ddd, 1F, AB, J=0.6 Hz, J =10.3, 18.2 Hz, F-6), 9.59 (dd, 1F,
Quinolines were placed into a steel autoclave equipped with
two inlet/outlet valves. Then, 10 g of anhydrous liquid NH3
(
FF
AB, J =15.3, 18.2 Hz, F-5), 10.43 (ddd, 1F, J =1.5 Hz,
(without additional purification) was added into the autoclave via
FF
HF
+
J =10.3, 15.3 Hz, F-8); HRMS (EI): M , found 232.0006.
self-flow through a measuring funnel with back pressure cooled
to −33.8 °C and the autoclave was sealed. The reaction mixture
was heated up to the given temperature upon stirring by rotation
of the autoclave and kept under these conditions for the necessary
period. On completion, the autoclave was cooled, NH3 was
slowly vented through an outlet valve, and the products were
dissolved in CH Cl (50 mL), unless otherwise stated. The extract
was dried with MgSO , the solvent was filtered and evaporated,
and a solid residue was analyzed by GC-MS and F NMR
spectroscopy. Products were isolated using TLC.
FF
C H ClF N requires 232.0010.
9
4
3
2
4
.7.2. 2-Amino-5,6,8-trifluoroquinoline (5) and 6-amino-2-
chloro-5,8-difluoroquinoline (6). The mixture of 1b (100 mg,
.46 mmol) with liquid NH was heated for 12 h at 70 °C. The
0
3
crude product (75 mg) containing 5 and 6 was purified by TLC
2
2
(1:5 ethylacetate-hexane).
4
19
5: White solid (64 mg, 70%); R
0.32; mp: 233−234 °C;
requires
C, 54.55; H, 2.54; F, 28.76; N, 14.14]; IR (KBr) ν 3516 (NH),
f
[Found: C, 54.85; H, 2.54; F, 28.75; N, 13.97. C H F N
9 5 3 2
4
.7.1. 2-Amino-5,6,7,8-tetrafluoroquinoline (2), 6-amino-5,7,8-
-1
3
2
319 (NH), 3150 (NH), 1649 (NH) cm ; UV (EtOH) λ nm (lg ε):
trifluoroquinoline (3) and 7-amino-5,6,8-trifluoroquinoline (4).
The mixture of 1a (167 mg, 0.71 mmol) with liquid NH was
heated for 9 h at 70 °C. The solid residue was extracted with
acetone (50 mL). The extract was evaporated, crude product (144
mg) containing 2, 3 and 4 was purified by TLC (CH Cl ).
1
04 (4.35), 236 (4.20), 254 (4.32), 346 (3.37); H NMR (500
3
MHz, acetone-d ): δ 6.25 (bs, 2H, NH ), 7.07 (dd, 1H, J=0.7 Hz,
JHH=9.1 Hz, H-3), 7.38 (td, 1H, J =7.3 Hz, 2J =10.8 Hz, H-7),
8
6
2
HF
HF
13
.11 (dd, 1H, J=1.5 Hz, JHH=9.1 Hz, H-4); C NMR (126 MHz,
2
2
acetone-d ): δ 105.3 (bt, 1C, J=24.6 Hz, C-7), 115.2 (ddd, 1C,
6
2
: White solid (7 mg, 5%); R 0.14; mp: 234−236 °C; [Found:
J=2.2, 4.5, 14.1 Hz, C-9), 115.3 (bs, 1C, C-3), 130.1-130.3 (m,
1C, C-4), 135.7 (dt, 1C, 2J=1.9 Hz, J=12.8 Hz, C-10), 141.7
(ddd, 1C, J=4.8, 12.9, 247.3 Hz, C-5), 142.8 (ddd, 1C, J=11.4,
13.3, 240.7 Hz, C-6), 152.5 (ddd, 1C, J=3.4, 10.0 Hz, 250.8 Hz,
f
C, 50.15; H, 1.94; N, 12.90. C H F N requires C, 50.01; H, 1.87;
N, 12.96]; IR (KBr) ν 3507 (NH), 3325 (NH), 1661 (NH) cm ;
UV (EtOH) λ nm (lg ε) 239 (4.43), 249 (4.36), 338 (3.54); H
NMR (500 MHz, acetone-d ): δ 6.46 (bs, 2H, NH ), 7.04 (bd, 1H,
9
4
4
2
-
1
1
19
C-8), 159.1 (dd, 1C, J=0.9, 1.6 Hz, C-2); F NMR (470 MHz,
acetone-d ): δ 8.59 (ddd, 1F, JHF=7.3 Hz, JFF=18.0, 20.2 Hz, F-5),
16.79 (dd, 1F, JHF=10.8 Hz, JFF=20.2 Hz, F-6), 34.31 (dd, 1F,
6
2
J
=9.2 Hz, H-3), 8.08 (dd, 1H, J =1.5 Hz, JHH=9.2 Hz, H-4);
HH
6
HF
1
3
C NMR (126 MHz, acetone-d ): δ 110.4 (dm, 1C, J=14.4 Hz,
C-9), 114.8 (bs, 1C, C-3), 130.1-130.3 (m, 1C, C-4), 135.5-135.7
m, 1C, C-10); 135.4 (dtd, 1C, J=1.8, 244.2 Hz, 2J=15.1 Hz, C-
6
+
J
HF=10.8 Hz, JFF=18.0 Hz, F-8); HRMS (EI): M , found
(
198.0400. C requires 198.0399.
H F N
9 5 3 2
6
1
), 141.6 (dddd, 1C, J=1.9, 4.6, 10.1, 250.0 Hz, C-8), 141.9 (dtd,
C, J=4.8, 248.4 Hz, 2J=14.6 Hz, C-7), 142.6 (ddt, 1C, 2J=4.6
Compound 6 was not isolated; its NMR spectra were recorded
1
19
in a mixture of products. H NMR (300 MHz, CDCl
3
): δ 5.49 (bs,
Hz, J=10.6, 249.6 Hz, C-5), 160.1 (bs, 1C, C-2); F NMR (282
MHz, acetone): δ -5.58 (dddd, 1F, J=0.9 Hz, J =2.7, 19.6, 20.2
Hz, F-6), 4.54 (ddd, 1F, J=0.7 Hz, J =17.9, 19.6 Hz, F-7), 6.68
2
H, NH ), 7.26 (dd, 1H, J =7.6, 11.9 Hz, H-7), 7.50 (d, 1H,
2
HF
FF
JHH=8.9 Hz, H-3), 8.25 (ddd, 1H, J=0.3 Hz, J =1.7 Hz, JHH=8.9
HF
FF
19
Hz, H-4); F NMR (282 MHz, CDCl ): δ 9.29 (dd, 1F, J =7.6
3
HF
(
dddd, 1F, J =1.5 Hz, J =2.7, 14.0 Hz, 17.9 Hz, F-8), 10.35
HF FF
+
Hz, JFF=18.9 Hz, F-5), 32.91 (dd, 1F, JHF=11.9 Hz, JFF=18.9 Hz,
F-8).
(dd, 1F, J =14.0, 20.2 Hz, F-5); HRMS (EI): M , found
FF
2
16.0304. C H F N requires 216.0305.
9 4 4 2
4
.7.3. 2-Amino-5,7,8-trifluoroquinoline (7) and 7-amino-2-
chloro-5,8-difluoroquinoline (8). The mixture of 1c (100 mg,
0.46 mmol) with liquid NH was heated for 12 h at 70 °C. The
crude product (70 mg) containing 7 and 8 was purified by TLC
CH Cl ).
3
: White solid (8 mg, 5%); R 0.75; mp: 171 °C followed by
f
decomposition; IR (KBr) ν 3499 (NH), 3395 (NH), 3200 (NH),
-
1
3
1
2
666 (NH) cm ; UV (EtOH) λ nm (lg ε): 213 (4.40), 258 (4.61),
1
89 (3.62), 354 (3.68); H NMR (500 MHz, acetone-d ): δ 5.58
6
(
2
2
(
bs, 2H, NH ), 7.50 (d, 1H, J =8.8 Hz, H-3), 8.27 (dd, 1H,
2 HH
13
JHF=1.4 Hz, JHH=8.8 Hz, H-4); C NMR (126 MHz, acetone-d6):
δ 115.7 (ddd, 1C, J=1.2, 1.7, 15.5 Hz, C-9), 123.8 (td, 1C, J=1.2
Hz, 2J=2.7 Hz, C-3), 126.6 (t, 1C, J=16.2 Hz, C-6), 129.7-129.9
7: White solid (50 mg, 55%); R 0.32; mp: 230-232 °C.
f
1 19 10
Spectra H, F NMR coincide with literature data. IR (KBr) ν
-
1
3505 (NH), 3323 (NH), 3150 (NH), 1651 (NH) cm ; UV (EtOH)
13
(
(
m, 1C, C-10), 131.0 (td, 1C, 2J=2.2 Hz, J=3.5 Hz, C-4), 139.5
ddd, 1C, J=3.6, 7.7, 240.0 Hz, C-5), 142.3 (ddd, 1C, J=4.6, 11.1,
λ nm (lg ε): 201 (4.39), 245 (4.56), 331 (3.54); C NMR (126
MHz, acetone-d ): δ 97.3 (ddd, 1C, J=0.8, 24.7, 26.7 Hz, C-6),
6
2
1
1
1
2
51.1 Hz, C-8), 143.8 (ddd, 1C, J=9.2, 13.6, 247.2 Hz, C-7),
111.3 (dt, 1C, 2J=2.0 Hz, J=17.5 Hz, C-9), 113.6 (bt, 1C, J=3.0
Hz, C-3), 130.74 (td, 1C, 2J=2.1 Hz, J=4.5 Hz, C-4), 140.3 (td,
1C, 2J=5.3 Hz, J=9.4 Hz, C-10), 141.0 (ddd, 1C, J=5.3, 12.2,
245.7 Hz, C-8), 150.0 (ddd, 1C, J=12.3, 15.1, 245.1 Hz, C-7),
154.5 (ddd, 1C, J=3.9, 13.8, 249.8 Hz, C-5), 160.6 (d, 1C, J=1.0
19
48.7 (bs, 1C, C-2); F NMR (470 MHz, acetone-d ): δ 6.78 (bt,
6
F, J =15.9 Hz, F-8), 12.68 (dd, 1F, J =10.2, 15.2 Hz, F-7),
FF
FF
+
3.85 (dd, 1F, J =10.2, 16.7 Hz, F-5); HRMS (EI): M , found:
FF
32.0006. C H ClF N requires 232.0010.
9
4
3
2
+
Hz, C-2); HRMS (EI): M , found 198.0401, C H F N requires
9
5
3
2
4
: White solid (107 mg, 65%); R 0.48; mp: 168−169 °C;
f
1
98.0399.
[
Found: C, 46.20; H, 1.85; Cl, 15.04; F, 24.81; N, 11.97.
C H ClF N requires C, 46.48; H, 1.73; Cl, 15.24; F, 24.50; N,
8: White solid (11 mg, 11%); R 0.59; [Found: C, 50.14; H,
9
4
3
2
f
1
2.04]; IR (KBr) ν 3501 (NH), 3395 (NH), 3196 (NH), 1666
2.31. C H ClF N requires C, 50.37; H, 2.35]; IR (KBr) ν 3501
9 5 2 2
-1 1
-
1
(NH) cm ; UV (EtOH) λ nm (lg ε): 213 (4.44), 258 (4.64), 288
(NH), 3366 (NH), 3209 (NH), 1657 (NH) cm ; H NMR (400
1
(3.69), 353 (3.74); H NMR (500 MHz, acetone-d ): δ 5.85 (bs,
MHz, acetone-d ): δ 5.74 (bs, 2H, NH ), 7.06 (dd, 1H, J =6.4,
6
6
2
HF

1
1.4 Hz, H-6), 7.26 (d, 1H, J =8.7 Hz, H-3), 8.25 (dd, 1H,
F-5), 53.27 (ddd, 1F, J =7.3 Hz, J =9.4, 11.0 Hz, F-7); HRMS
FF HF
+
HH
ACCEPTED MANUSCRIPT
1
9
JHF=1.7 Hz, JHH=8.7 Hz, H-4); F NMR (282 MHz, acetone-d ):
(EI): M , found 180.0492. C H F N requires 180.0494.
9 6 2 2
6
δ 5.74 (ddd, 1F, J =1.7, 6.4 Hz, J =17.9 Hz, F-8), 36.86 (dd,
HF
FF
1
3: White solid (11 mg, 11%); R 0.63; mp: 136−138 °C;
f
1
F, J =11.4 Hz, J =17.9 Hz, F-5).
HF
FF
[
Found: C, 54.99; H, 3.29; N, 14.07. C H ClFN requires C,
9 6 2
4
.7.4. 2-Amino-6,7-difluoroquinoline (9), 6-amino-2-chloro-7-
54.98; H, 3.08; N, 14.25]; UV (EtOH) λ nm (lg ε): 219 (4.21),
1
fluoroqinoline (10), 7-amino-2-chloro-6-fluoroquinoline (11).
261 (4.46), 359 (3.52) nm; H NMR (400 MHz, acetone-d ): δ
6
The mixture of 1e (270mg, 1.35 mmol) with liquid NH was
6.04 (bs, 2H, NH ), 6.65 (dd, 1H, J =2.5 Hz, J =11.4 Hz, H-6),
3
2
HH
HF
heated for 24 h at 90 °C. The crude product – yellow powder
6.83 (ddd, 1H, JHH=0.7, 2.5 Hz, J =10.3 Hz, H-8), 7.32 (dd, 1H,
HF
(
258 mg) containing 9, 10, and 11 was purified by TLC (CH Cl ).
J=0.6 Hz, JHH=8.8 Hz, H-3), 8.52 (dd, 1H, JHH=0.7, 8.8 Hz, H-4);
2
2
13
1
C NMR (126 MHz, acetone-d ): δ 98.6 (d, 1C, J=28.3 Hz, C-6),
6
9
: White solid (34 mg, 14%); R 0.11; mp: 153−155 °C; H
f
1
1
00.9 (d, 1C, J=22.3 Hz, C-8), 114.9 (d, 1C, J=3.0 Hz, C-9),
19.7 (d, 1C, J=2.3 Hz, C-3), 135.0 (s, 1C, C-4), 148.6 (d, 1C,
NMR (400 MHz, acetone-d ): δ 6.08 (bs, 2H, NH ), 6.87 (d, 1H,
JHH=9.0 Hz, H-3), 7.32 (dd, 1H, J =7.8, 12.6 Hz, H-5), 7.57 (dd,
1
NMR (282 MHz, acetone-d ): δ 17.99 (ddd, 1F, J =7.8, 11.1 Hz,
J =21.4 Hz, F-7), 27.72 (ddd, 1F, J =9.0, 12.6 Hz, J =21.4 Hz,
F-6).
6
2
HF
19
J=14.5 Hz, C-5), 151.2 (d, 1C, J=15.9 Hz, C-10), 152.2 (s, 1C,
H, J =9.0, 11.1 Hz, H-8), 7.91 (d, 1H, JHH=9.0 Hz, H-4);
F
19
HF
C-2), 166.1 (d, 1C, J=244.5 Hz, C-7); F NMR (282 MHz,
6
HF
acetone): δ 55.58 (dd, 1F, J =10.3, 11.4 Hz, F-7); HRMS (EI):
HF
FF
HF
FF
+
M , found 196.0197. C H ClFN requires 196.0198.
9
6
2
1
14: White solid (3 mg, 3%); R
16 (4.28), 258 (4.33), 289 (3.62), 295 (3.63), 368 (3.50); H
NMR (400 MHz, aceton-d ): δ 5.76 (bs, 2H, NH ), 6.84 (d, 1H,
0.32; UV (EtOH) λ nm (lg ε):
f
1
1
0: White solid (10 mg, 4%); R 0.65; mp: 134−136 °C; H
f
2
NMR (400 MHz, acetone-d ): δ 5.39 (bs, 2H, NH ), 7.18 (d, 1H,
6
2
6
2
JHF=9.6 Hz, H-5), 7.31 (dd, 1H, J=0.5, JHH=8.6 Hz, H-3), 7.49 (d,
13
JHH=2.0 Hz, H-8), 6.87 (dd, 1H, JHH=2.0 Hz, JHF=12.0 Hz, H-8),
1
H, J =12.3 Hz, H-8), 8.06 (bd, 1H, JHH=8.6 Hz, H-4);
C
19
HF
7
.14 (d, 1H, JHH=8.6 Hz, H-3), 8.17 (d, 1H, JHH=8.6 Hz, H-4); F
NMR (126 MHz, acetone-d ): δ 109.2 (d, 1C, J=5.3 Hz, C-5),
12.6 (d, 1C, J=19.0 Hz, C-8), 122.3 (d, 1C, J=2.4 Hz, C-3),
26.7 (d, 1C, J=1.0 Hz, C-9), 137.6 (d, 1C, J=0.6 Hz, C-4), 138.7
6
NMR (282 MHz, acetone): δ 40.55 (d, 1F, J =12.0 Hz, F-5);
HF
1
1
+
HRMS (EI): M , found 196.0194. C H ClFN requires 196.0198.
9
6
2
(
d, 1C, J=15.0 Hz, C-6), 142.8 (d, 1C, J=12.4 Hz, C-10), 147.4
4.7.6. 2-Amino-6-chloro-5,7-fluorioquinoline (15), 5-amino-2,6-
dichloro-7-fluoroquinoline (16) and 7-amino-2,6-dichloro-5-
fluoroquinoline (17). The mixture of 1g (100 mg, 0.43 mmol)
19
(s, 1C, C-2), 155.9 (d, 1C, J=248.6 Hz, C-7); F NMR (282
MHz, acetone-d ): δ 37.43 (dd, 1F, J =9.6, 12.3 Hz, F-7);
HRMS (EI): M , found 196.0200, C H ClFN requires 196.0198.
6
HF
+
with liquid NH was heated for 12 h at 70 °C. The crude product
9
6
2
3
(
87 mg) containing 15, 16, and 17 was purified by TLC (CH Cl ).
2 2
1
1: White solid (172 mg, 65%); R 0.43; mp: 184−185 °C;
f
[
Found: C, 54.87; H, 3.22; Cl, 18.03; F, 9.96; N, 14.25.
15: White solid (7 mg, 8%); Rf 0.06; mp: 215−216 °C;
[Found: C, 50.19; H, 2.32; N, 12.75. C H ClF N requires C,
C H ClFN requires C, 54.98; H, 3.08; Cl, 18.03; F, 9.66; N,
9
6
2
9
5
2
2
1
4.25]; IR (KBr) ν 3453 (NH), 3304 (NH), 3188 (NH), 1647
50.37; H, 2.35; N, 13.05]; IR (KBr) ν 3491 (NH), 3323 (NH),
-
1
-1
(NH) cm ; UV (EtOH) λ nm (lg ε): 214 (4.60), 248 (4.53), 278
3146 (NH), 1663 (NH) cm ; UV (EtOH) λ nm (lg ε): 209 (4.37),
1
1
(3.71), 351 (4.01); H NMR (500 MHz, acetone-d ): δ 5.56 (bs,
244 (4.62), 265 (3.95), 336 (3.71); H NMR (400 MHz, acetone-
6
2
1
1
1
H, NH ), 7.16 (dd, 1H, J=0.6 Hz, JHH=8.5 Hz, H-3), 7.20 (bd,
d ): δ 6.37 (bs, 2H, NH ), 6.95 (dd, 1H, J=0.7 Hz, JHH=9.1 Hz, H-
2
6
2
H, J =8.6 Hz, H-8), 7.53 (d, 1H, J =11.6 Hz, H-5), 8.08 (bd,
3), 7.17 (ddd, 1H, J=0.7 Hz, J =2.0, 11.0 Hz, H-8), 8.04 (d, 1H,
HF
HF
HF
13
19
H, JHH=8.5 Hz, H-4); C NMR (126 MHz, acetone-d ): δ 110.4-
JHH=9.1 Hz, H-4); F NMR (282 MHz, acetone): δ 40.02 (bt, 1F,
6
10.5 (m, 1C, C-8), 111.5 (d, 1C, J=20.0 Hz, C-5), 119.1 (s, 1C,
J=2.4 Hz, F-5), 48.08 (dd, 1F, J =2.9 Hz, J =11.0 Hz, F-7);
FF
HF
+
C-3), 120.5 (d, 1C, J=9.5 Hz, C-9), 139.1 (d, 1C, J=5.4 Hz, C-4),
42.0 (d, 1C, J=15.9 Hz, C-7), 148.0 (s, 1C, C-2), 150.4 (d, 1C,
HRMS (EI): M , found 214.0103. C H ClF N requires
9 5 2 2
1
214.0104.
6: White solid (53 mg, 53%); R 0.54; mp: 202−204 °C;
19
J=2.6 Hz, C-10), 153.1 (d, 1C, J=246.2 Hz, C-6); F NMR (282
MHz, acetone-d ): δ 32.10 (dd, 1F, J =8.6, 11.6 Hz, F-6);
HRMS (EI): M , found 196.0197. C H ClFN requires 196.0198.
1
f
6
HF
+
[Found: C, 46.52; Cl, 30.58; F, 8.18. C
H Cl FN requires C,
9 5 2 2
9
6
2
4
6.78; Cl, 30.69; F, 8.22]; IR (KBr) ν 3472 (NH), 3389 (NH),
-
1
4
.7.5. 2-Amino-5,7-fluorioquinoline (12), 5-amino-2-chloro-7-
fluoroquinoline (13) and 7-amino-2-chloro-5-fluoroquinoline
14). The mixture of 1d (110 mg, 0.55 mmol) with liquid NH3
1618 (NH) cm ; UV (EtOH) λ nm (lg ε): 219 (4.34), 263 (4.60),
351 (3.55); H NMR (400 MHz, acetone-d ): δ 6.26 (bs, 2H,
1
6
(
NH ), 7.03 (dd, 1H, J =0.7 Hz, J =10.4 Hz, H-8), 7.41 (dd,
2
HH
HF
was heated for 24 h at 70 °C. The crude product (90 mg)
containing 12, 13, and 14 was purified by TLC (1:3 ethylacetate-
hexane).
1H, J=0.5 Hz, JHH=8.9 Hz, H-3), 8.61 (dd, 1H, JHH=0.7, 8.9 Hz,
13
H-4); C NMR (126 MHz, acetone-d ): δ 101.9 (d, 1C, J=22.5
6
Hz, C-8), 102.4 (d, 1C, J=22.7 Hz, C-6), 114.8 (s, 1C, C-9),
1
20.8 (d, 1C, J=2.4 Hz, C-3), 135.1 (d, 1C, J=1.7 Hz, C-4), 144.0
1
2: White solid (45 mg, 49%); R 0.14; mp: 153 −155 °C;
f
(d, 1C, J=4.9 Hz, C-5), 148.6 (d, 1C, J=15.3 Hz, C-10), 152.4 (s,
[
Found: C, 60.07; H, 3.04; F, 21.07; N, 15.03. C H F N requires
C, 60.00; H, 3.36; F, 21.09; N, 15.55]; IR (KBr) ν 3487 (NH),
325 (NH), 3136 (NH), 1661 (NH) cm ; H NMR (500 MHz,
acetone-d ): δ 6.25 (bs, 2H, NH ), 6.81 (ddd, 1H, JHH=2.4 Hz,
19
9
6
2
2
1
C, C-2), 160.7 (d, 1C, J=247.3 Hz, C-7); F NMR (282 MHz,
+
-
1
1
acetone-d
): δ 53.50 (d, 1F, JHF=10.4 Hz, F-7); HRMS (EI): M ,
6
3
found 229.9809. C H Cl FN requires 229.9808.
9
5
2
2
6
2
JHF=9.4, 10.3 Hz, H-6), 6.89 (d, 1H, JHH=9.1 Hz, H-3), 7.01
17: White solid (11 mg, 11%); R 0.20; mp: 215 °C with
f
(
dddd, 1H, J=0.7 Hz, J =1.4, 11.0 Hz, JHH=2.4 Hz, H-8), 8.03
decomposition; IR (KBr) ν 3476 (NH), 3323 (NH), 3202 (NH),
HF
13
-1
(d, 1H, JHH=9.1 Hz, H-4); C NMR (126 MHz, acetone-d ): δ
1643 (NH) cm ; UV (EtOH) λ nm (lg ε): 219 (4.27), 258 (4.39),
6
1
9
7.5 (dd, 1C, J=24.7, 29.3 Hz, C-6), 106.9 (dd, 1C, J=4.2, 21.1
288 (3.49), 366 (3.56); H NMR (400 MHz, acetone-d ): δ 6.01
6
Hz, C-8), 110.9 (dd, 1C, J=1.9, 16.0 Hz, C-9), 112.6-112.7 (m,
(bs, 2H, NH ), 7.09 (dd, 1H, J =0.7 Hz, J =1.6 Hz, H-8), 7.23
2
HH
HF
1
1
1
C, C-3), 130.7 (bd, 1C, J=4.5 Hz, C-4), 151.1 (dd, 1C, J=5.4,
5.0 Hz, C-10), 160.0 (dd, 1C, J=15.7, 252.8 Hz, C-5), 160.8 (s,
C, C-2), 163.6 (dd, 1C, J=15.2, 244.7 Hz, C-7); F NMR (282
(d, 1H, JHH=8.6 Hz, H-3), 8.23 (dd, 1H, JHH=0.7, 8.6 Hz, H-4);
13
C NMR (126 MHz, acetone-d ): δ 104.8 (d, 1C, J=3.3 Hz, C-7),
6
19
108.3 (d, 1C, J=18.6 Hz, C-9), 110.8 (d, 1C, J=16.3 Hz, C-8),
119.1 (d, 1C, J=2.3 Hz, C-3), 132.7 (d, 1C, J=3.4 Hz, C-4), 148.3
MHz, acetone): δ 42.57 (ddd, 1F, J =1.4, 10.3 Hz, J =7.3 Hz,
HF
FF
(d, 1C, J=3.4 Hz, C-6), 148.5 (d, 1C, J=4.4 Hz, C-10), 152.7 (s,

1
0
Tetrahedron
TE(2
1
C
9
1
C, C-2), 154.8 (d, 1C, J=252.6 Hz, C-5
A
);
F
C
N
E
M
P
R
D
82 MA(8
N
0 m
5%).
U
g
S
,
C
47
R
%)IPan
T
d, the fraction with R 0.84 contained 3 (8 mg,
f
+
MHz, acetone-d ): δ 41.43 (bs, 1F, F-5); HRMS (EI): M , found
6
2
29.9812. C H Cl FN requires 229.9808.
9 5 2 2
The compound 21 was not isolated, its NMR spectra was
19
4
.7.7. 2-Amino-6,8-difluoroquinoline (18), 8-amino-2-chloro-6-
recorded in mixture of products. F NMR (282 MHz, acetone): δ
-0.68 (dd, 1F, J =6.0, 19.4 Hz, F-6), 6.61 (dd, 1F, J =14.9, 19.4
fluoroquinoline (19). The mixture of 1f (135 mg, 0.68 mmol)
FF
FF
with liquid NH was heated for 28 h at 90 °C. The solid residue
Hz, F-5), 7.63 (ddd, 1F, J =1.6 Hz, J =6.0, 14.9 Hz, F-8).
3
HF FF
was extracted with acetone (50 mL). The extract was evaporated,
crude product (117 mg) containing 18 and 19 was purified by
TLC (CH Cl ).
Mixture of 1a (150 mg, 0.64 mmol) with aqueous NH3
30mL) was heated for 3 h at 100 °C. The crude product (134
(
2
2
mg) containing 2, 3, 4, and 21 was purified by TLC (CH Cl ).
2
2
1
8: White solid (24 mg, 20%); R 0.45; mp: 197-199 °C;
The fraction with R 0.14 contained 2 (32 mg, 23%), the fraction
f
f
[
Found: C, 59.64; H, 3.53; F, 21.08; N, 15.51. C H F N requires
with R 0.48 contained 4 (48 mg, 33%) and, the fraction with R
9
6
2
2
f
f
C, 60.00; H, 3.36; F, 21.09; N, 15.55]; IR (KBr) ν 3447 (NH),
0.75 contained 3 (20 mg, 14%).
-
1
3
2
306 (NH), 3163 (NH), 1657 (NH) cm ; UV (EtOH) λ nm (lg ε):
34 (4.47), 250 (4.33), 343 (3.59); H NMR (300 MHz, acetone-
1
4.8.2. 2-Amino-5,6,8-trifluoroquinoline (5) and 6-amino-2-
chloro-5,8-difluoroquinoline (6). The mixture of 1b (100 mg,
d ): δ 6.04 (bs, 2H, NH ), 6.96 (dd, 1H, J=0.8 Hz, JHH=8.9 Hz, H-
6
2
0
.46 mmol) with aqueous NH was heated for 7 h at 120 °C. The
3
3
1
), 7.13 (ddd, 1H, JHH=2.7 Hz, J =9.0, 10.9 Hz, H-7), 7.19 (ddd,
HF
crude product (71 mg) containing 1b, 5, 6, and 22 was purified
by TLC (CH Cl ). The fraction with R 0.32 contained 5 (48 mg,
2%). Spectrum F NMR of 22 in mixture coincides with.
H, J =1.4, 9.0 Hz, J =2.7 Hz, H-5), 7.92 (dd, 1H, J =1.4,
HF
HH
HF
13
2
2
f
JHH=8.9 Hz, H-4); C NMR (126 MHz, acetone-d ): δ 104.8 (dd,
19
8
6
5
1
1
C, J=23.2, 28.9 Hz, C-7), 107.4 (dd, 1C, J=4.7, 21.5 Hz, C-5),
15.1 (s, 1C, C-3), 125.1 (dd, 1C, J=4.6, 10.7 Hz, C-9), 135.7
4.8.3. 2-Amino-5,7,8-trifluoroquinoline (7) and 7-amino-2-
chloro-5,8-difluoroquinoline (8), 2,7-diamino-5,8-
difluoroquinoline (24). The mixture of 1c (97 mg, 0.45 mmol)
(dd, 1C, J=1.5, 10.9 Hz, C-10), 137.2 (dd, 1C, J=3.6, 4.6 Hz, C-
4
2
), 156.8 (dd, 1C, J=11.6, 240.0 Hz, C-6), 156.9 (dd, 1C, J=12.8,
54.0 Hz, C-8), 158.6 (bs, 1C, C-2); F NMR (282 MHz,
19
with aqueous NH was heated for 7 h at 120 °C. The crude
3
acetone-d ): δ 39.59 (ddt, 1F, 2J =1.4 Hz, J =4.1 Hz, J =10.9
product (71 mg) containing 7, 8, 23, and 24 was purified by TLC
(CH Cl ). The fraction with R 0.45 contained 7 (46 mg, 52%).
6
HF
FF
HF
Hz, F-8), 43.72 (td, 1F, J =4.1 Hz, 2J =9.0 Hz, F-6); HRMS
FF
HF
2
2
f
+
19
8
(
EI): M , found 180.0490. C H F N requires 180.0494.
Spectrum F NMR of 23 in mixture coincides with.
9
6
2
2
1
9: White solid (78 mg, 59%); R 0.77; mp: 121 °C with
f
The compound 24 was not isolated, its NMR spectra recorded
19
decomposition; [Found: C, 54.75; H, 3.02; Cl, 17.85; F, 9.87; N,
4.21. C H ClFN requires C, 54.98; H, 3.08; Cl, 18.03; F, 9.66;
N, 14.25]; IR (KBr) ν 3476 (NH), 3354 (NH), 1630 (NH) cm ;
UV (EtOH) λ nm (lg ε): 260 (4.46), 349 (3.37); H NMR (500
MHz, acetone-d ): δ 6.77 (dd, 1H, J =2.6 Hz, J =11.1 Hz, H-
in mixture of products. F NMR (282 MHz, acetone): δ 3.61
(ddd, 1F, J =1.4, 6.2 Hz, J =17.3 Hz, F-8); 33.85 (dd, 1F,
1
9
6
2
HF
FF
-
1
J =11.4 Hz, J =17.3 Hz, F-8).
HF FF
1
4
.8.4. 2-Amino-6,7-difluoroquinoline (9), 6-amino-2-chloro-7-
fluoroqinoline (10) and 7-amino-2-chloro-6-fluoroquinoline (11).
6
HH
HF
7
), 6.80 (dd, 1H, JHH=2.6 Hz, J =9.5 Hz, H-5), 7.45 (d, 1H,
HF
13
Mixture of 1e (175 mg, 0.88 mmol) with aqueous NH (30mL)
3
JHH=8.6 Hz, H-3), 8.18 (d, 1H, JHH=8.6 Hz, H-4); C NMR (126
was heated for 22 h at 120 °C. The crude product (139 mg)
MHz, acetone-d ): δ 98.0 (d, 1C, J=23.6 Hz, C-5), 99.8 (d, 1C,
J=29.5 Hz, C-7), 124.1 (s, 1C, C-3), 129.3 (d, 1C, J=12.7 Hz, C-
), 135.6 (s, 1C, C-10), 140.0 (d, 1C, J=5.9 Hz, C-4), 147.2 (d,
C, J=2.7 Hz, C-2), 147.8 (d, 1C, J=14.0 Hz, C-8), 163.1 (d, 1C,
J=242.6 Hz, C-6); F NMR (282 MHz, acetone): δ 51.89 (dd,
6
containing 1e, 9-11, and 1eb was purified by TLC (1:2 CH Cl -
2
2
hexane). The fraction with R 0.10 contained 9 (40 mg, 25%), the
f
9
1
fraction with R 0.46 contained 11 (59 mg, 37%) and, the fraction
f
19
with R 0.60 contained 10 (7 mg, 4%).
f
+
1
F, J =9.5, 11.1 Hz, F-6); HRMS (EI): M , found 196.0196.
HF
4.8.5. 2-Amino-5,7-fluorioquinoline (12), 5-amino-2-chloro-7-
fluoroquinoline (13) and 7-amino-2-chloro-5-fluoroquinoline
C H ClFN requires 196.0198.
9
6
2
(
14). The mixture of 1d (94 mg, 0.47 mmol) with aqueous NH3
4
.7.8. 2,8-Diamino-6-fluoroquinoline (20). The mixture of 1f
was heated for 10 h at 120 °C. The crude product (68 mg)
containing 1d, 12-14 was purified by TLC (1:3 CH Cl -hexane).
The fraction with R 0.40 contained 12 (32 mg, 38%), the fraction
with R 0.93 contained 13 (3 mg, 3%).
(125 mg, 0.63 mmol) with liquid NH was heated for 24 h at
3
2
2
1
50 °C. The crude product (104 mg) contained 18, 19, and 20.
f
Compound 20 was not isolated, its NMR spectra were recorded
19
f
in a mixture of products. F NMR (282 MHz, DMSO): δ 42.71
bt, 1F, 2J =10.5 Hz, F-6).
(
HF
4.8.6. 2-Amino-6,8-difluoroquinoline (18), 8-amino-2-chloro-6-
fluoroquinoline (19) and 2,8-diamino-6-fluoroquinoline (20).
The mixture of 1f (100 mg, 0.50 mmol) with aqueous NH was
4
.8. Reactions of polyfluorinated 2-chloroquinolines with
3
aqueous NH (general procedure).
3
heated for 10 h at 150 °C. The crude product (68 mg) contained
A mixture of quinoline and aqueous NH (10 mL) was kept in
18-20 and 1fb.
3
a 50 mL steel rotary autoclave. The products were extracted from
the cooled reaction mixture with CH Cl (3×25 mL). The extract
4
.8.7. 2-Amino-6-chloro-5,7-fluorioquinoline (15), 5-amino-2,6-
dichloro-7-fluoroquinoline (16), 7-amino-2,6-dichloro-5-
fluoroquinoline (17), 2,5-diamino-6-chloro-7-fluoroquinoline
25) and 2,7-diamino-6-chloro-5-fluoroquinoline (26.) The
2
2
was dried with MgSO , the solvent was evaporated, a solid
4
19
residue was analyzed by GC-MS and F NMR spectroscopy. The
reaction conditions and yields of products are shown in Table 2.
(
mixture of 1g (100 mg, 0.43 mmol) with aqueous NH was
heated for 1 h at 100 C. The crude product (90 mg) contained 1g,
15-17.
3
o
4
.8.1. 2-Amino-5,6,7,8-tetrafluoroquinoline (2), 6-amino-5,7,8-
trifluoroquinoline (3) and 7-amino-5,6,8-trifluoroquinoline (4),
,7-diamino-5,6,8-trifluoroquinoline (21). Mixture of 1a (175
2
The mixture of 1g (154 mg, 0.66 mmol) with aqueous NH3
mg, 0.74 mmol) with aqueous NH (30mL) was heated for 24 h
3
(30 mL) was heated for 5 h at 100 °C. The crude product (91 mg)
at 85 °C. The crude product (163 mg) containing 1a, 2, 3, 4 and
contained 1g, 15-17, 25, and 26. The compound 25 was not
isolated, its NMR spectra recorded in mixture of products.
2
1 was purified by TLC (CH Cl ). The fraction with R 0.21
19
2
2
f
F
contained 2 (61 mg, 38%), the fraction with R 0.64 contained 4
f

Stupina, T. V.; Lipunova, G. N.; Charushin, N. V. J. Fluor. Chem.
2013, 150, 36–38.
NMR (282 MHz, acetone): δ 49.00 (d, 1F, J =11.4 Hz, F-7).
A
HF CCEPTED MANUSCRIPT
The compound 26 was not isolated, its NMR spectra recorded in
19
6. (a) Laev, S. S.; Evftefeev, V. U.; Shteingarts, V. D. J. Fluor.
Chem. 2001, 110(1), 43-46. (b) Laev, S. S.; Gurskaya, L. Y.;
Selivanova, G. A.; Beregovaya, I. V.; Shchegoleva, L. N.;
Vasil’eva, N. V.; Shakirov, M. M.; Shteingarts, V. D. Eur. J. Org.
Chem. 2007, 2, 306-316.
mixture of products. F NMR (282 MHz, acetone): δ 37.64 (bd,
1
F, J =1.1 Hz, F-5).
HF
X-ray structural analysis of 1e, 1f, 1g, 4, 5, 11, 12, 16, 18, 19
and starting materials 1ea and 1ga. CCDC 1481803 and 1481804
for 1e), 1481805 (for 1f), 1481806 (for 1g), 1481807 (for 4),
481809 (for 5), 1481808 (for 11), 1481810 (for 12), 1481811
for 16), 1481812 (for 18), 1481813 (for 19), 1481814 (for 1ga)
and 1481815 (for 1ea) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
7
.
Selivanova, G. A.; Gurskaya, L. Y.; Pokrovsky, L. M.; Kollegov,
V. F.; Shteingarts, V. D. J. Fluor. Chem. 2004, 125(12), 1829-
(
1
(
1
834.
8
9
.
.
Safina, L. Y.; Selivanova, G. A.; Koltunov, K. Yu.; Shteingarts,
V. D. Tetrahedron Lett. 2009, 50(37), 5245–5247.
Safina L. Yu.; Selivanova G. A.; Bagryanskaya I. Yu.; Shteingarts
V. D. Russian Chemical Bulletin, Int. Ed. 2009, 58(5), 1049–1061.
10. Gurskaya, L. Y.; Selivanova, G. A.; Shteingarts, V. D. J. Fluor.
Chem. 2012, 13, 32-37.
1
1. Fox, M. A.; Pattison, G.; Sandford, G.; Batsanov, A. S. J. Fluor.
Chem. 2013, 155, 62-71.
Acknowledgments
1
2. Leblond, B.; Chauvignac, C.; Taverne, T.; Beausoleil E.;
Casagrande, A.-S.; Desire, L.; Pando, M. P.; Donello, J. E.; Yang,
R. Patent US20120214837 A1., 23.08.12, ExonHit Therapeutics
SA (FR); ALLERGAN, INC (US), 133 pp. (b) Inglis, S. R.;
Stojkoski, C.; Branson, K. M.; Cawthray, J. F.; Fritz, D.;
Wiadrowski, E.; Pyke, S. M.; Booker, G. W. J. Med Chem. 2004,
Authors would like to acknowledge the Multi-Access
Chemical Service Center SB RAS for spectral and analytical
measurements. We are grateful to Dr. Ilia V. Eltsov, Roman Yu.
Peshkov (Novosibirsk State University) and Nadezhda V.
Pleshkova (NIOCH SB RAS) for recording NMR spectra. This
work was financially supported by the Russian Foundation for
Basic Research (grant 14-03-00108).
4
7(22), 5405–5417. (c) Zhou, D.; Stack, G. P.; Lo, J.; Failli, A.
A.; Evrard, D. A.; Harrison, B. L.; Hatzenbuhler, N. T.; Tram, M.;
Croce, S.; Yi, S.; Golembieski, J.; Hornby, G. A.; Lai, M.; Lin, Q.;
Schechter, L. E.; Smith, D. L.; Shilling, A. D.; Huselton, C.;
Mitchell, P.; Beyer, C. E.; Andree, T. H. J. Med. Chem. 2009,
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2(15), 4955–4959.
Supplementary data
1
3. Politanskaya, L. V.; Malysheva, L. A.; Beregovaya, I. V.;
Bagryanskaya, I. Yu.; Gatilov, Yu. V.; Malykhin, E. V.;
Shteingarts, V. D. J. Fluor. Chem. 2005, 126(11-12), 1502–1509.
4. Atherton, J. H.; Page, M. I.; Sun, H. J. Phys. Org Chem. 2013, 26
Supplementary data (Preparation of starting materials, NMR
spectra of new compounds, and XRD data) related to this
article can be found on the Internet at http://
1
1
(12), 1038–1043.
5. (a) Selivanova, G. A.; Pokrovskii, L. M.; Shteingarts, V. D. Russ.
J. Org. Chem. 2001, 37(3), 404-409. (b) Selivanova, G. A.,
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