Reaction of quinolines fluorinated at the benzene ring with nitrogen-centered nucleophiles

Article abstract of DOI:10.1007/s11172-009-0134-z

A primary functionalization of quinolines polyfluorinated at the benzene ring (5, 7-difluoro-, 5, 7, 8-trifluoro-, 5, 6, 8-trifluoro-, 8-chloro-5, 7-difluoro-, 5, 6, 7, 8-tetrafluoro-, and 5, 7, 8-trifluoro-6-(trifluoromethyl) quinolines) by the reaction

Full text of DOI:10.1007/s11172-009-0134-z

Russian Chemical Bulletin, International Edition, Vol. 58, No. 5, pp. 1049—1061, May, 2009
1049
Reaction of quinolines fluorinated at the benzene ring
with nitrogenꢀcentered nucleophiles
L. Yu. Safina,a G. A. Selivanova,a I. Yu. Bagryanskaya,a and V. D. Shteingartsa,b
a N. N. Vorozhtsov Institute of Organic Chemistry,
Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent’eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. Eꢀmail: shtein@nioch.nsc.ru
b Novosibirsk State University,
2 ul. Pirogova, 630090 Novosibirsk, Russian Federation
A primary functionalization of quinolines polyfluorinated at the benzene ring (5,7ꢀdifluoroꢀ,
5,7,8ꢀtrifluoroꢀ, 5,6,8ꢀtrifluoroꢀ, 8ꢀchloroꢀ5,7ꢀdifluoroꢀ, 5,6,7,8ꢀtetrafluoroꢀ, and 5,7,8ꢀtrifluoroꢀ
6ꢀ(trifluoromethyl)quinolines) by the reaction with nitrogenꢀcentered nucleophiles (aqueous
and liquid ammonia, hydrazine hydrate, piperidine) has been studied. If the molecule of
fluorinated quinoline contains three or four halogen atoms, their combined orientation effect
outweighs the influence of the heterocycle N atom. It was found that the orientation of
substitution in the reactions of 5,6,8ꢀtrifluoroꢀ and 5,7,8ꢀtrifluoroꢀ6ꢀ(trifluoromethyl)quinolines
with piperidine depends on temperature, because the enthalpy control of the ratio of the rates
of competing reactions changes to the entropy control. Nineteen new quinoline derivatives
containing F atoms and amino or modified amino groups in the benzene ring have been
obtained.
Key words: fluorinated quinolines, ammonia, piperidine, hydrazine hydrate, aromatic
nucleophilic substitution, fluorinated aminoquinolines.
framework is conditioned by the absence of these atoms
at the activated positions of the heterocyclic fragment.
Examples of such transformations include the action
of various elementꢀcentered nucleophiles (MeONa,
Me2PSiMe3, and Me2AsSiMe3) on quinolines fluorinated
at the benzene ring.17—20 A study of the reactions of
difluoroquinolines of this type with sodium methoxide in
DMSO showed that electrophilic activity of the C atoms
of the benzene fragment decreases in the order C(5) >
C(7) > C(6), C(8) due to the activating effect of the
heterocycle.20 In the case of quinolines containing three
or four F atoms in the benzene ring, the ratio of the rates
of substitution is determined by a combined effect of the
heterocycle and substituents in the benzene ring,17—19 with
position 7 becoming the most active due to the orientaꢀ
tion effect of the F atoms.
An amino group is used as one of the promising funcꢀ
tional groups in the development of pathways for deeper
functionalization of polyfluorinated quinolines. By now,
a basic approach to the synthesis of quinolines containing
an amino group and F atoms in the benzene fragment
consisted in the reduction of the corresponding nitro
derivatives,21—23 that to a certain extent limited the scope
of compounds of the type under consideration available
To study fluorineꢀcontaining heterocyclic compounds
is of special interest because many of them possess bioꢀ
logical activity.1,2 Quinolines fluorinated at the benzene
ring are among such compounds.3—8 Their derivatives,
fluoroquinolones, are known as antimicrobial medicines
with a wide range of action.9—12 In addition, quinolines
fluorinated at the benzene ring can be used as starting
compounds for preparing biologically active derivatives
by the reaction of nucleophilic substitution of the fluorine
atom (see, for example, Ref. 13). In this connection, it is
an actual problem to develop methods for the synthesis of
new compounds from the series of quinolines fluorinated
at the benzene ring.
It is obvious that general approach to the synthesis
of potentially biologically active functionalized fluoroꢀ
quinolines consists in nucleophilic substitution of F
atoms in polyfluorinated compounds of this series. There
are described just a few reactions of nucleophilic substituꢀ
tion in perfluorinated quinoline and its homologs, in which
F atoms at positions 2 and (predominantly) 4 of the pyriꢀ
dine ring undergo the substitution.14—16 Functionalization
of quinoline at the benzene ring is also of considerable
interest,5—13 but, as it follows from the aforesaid, the subꢀ
stitution of F atoms in the benzene ring of the quinoline
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1022—1033, May, 2009.
1066ꢀ5285/09/5805ꢀ1049 © 2009 Springer Science+Business Media, Inc.

1050
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
Safina et al.
Scheme 1
for the study. The formation of 7ꢀaminoꢀ5,6,8ꢀtrifluoroꢀ
quinoline upon the action of ammonia on 5,6,7,8ꢀtetraꢀ
fluoroquinoline17,18 represents the only example of the
substitution of a F atom for an amino group in quinolines
polyfluorinated at the benzene ring.
The present work is devoted to the study of reactions
of quinolines containing F atoms in the benzene fragment
with aqueous and liquid ammonia, piperidine, and hydrꢀ
azine hydrate in order to find out how direction of
aminodefluorination depends on the number and arrangeꢀ
ment of F atoms in the substrate, as well as on the nature
of nucleophile.
Results and Discussion
Conditions and results of the transformations studied
are given in Table 1. The ratios of the reaction products
were inferred from the NMR spectra of their mixtures.
The compounds synthesized for the first time were isoꢀ
lated by TLC and completely characterized, their 1H and
19F NMR spectra are given in Table 2.
The reaction of 5,7ꢀdifluoroquinoline (1) with aqueꢀ
ous ammonia in a steel autoclave at 150 °C furnished
5ꢀaminoꢀ7ꢀfluoroquinoline (2) and 7ꢀaminoꢀ5ꢀfluoroꢀ
quinoline (3) in the ratio 3.4 : 1.0 (Scheme 1; see Table 1,
entry 1).
X = H (1—3), F (4—6), Cl (7—9)
value calculated starting from the δF value for the parent
quinoline 1 (see Ref. 20) with allowance for the increꢀ
ment24 responsible for the introduction of an amino group
instead of F atom in metaꢀposition. It turned out that of
two electrophilic centers occupied by F atoms, position 5
is more active during ammonolysis of quinoline 1 with
aqueous ammonia, which agrees with orientation of subꢀ
stitution of the F atom upon the action of sodium
methoxide on the same substrate in DMSO.20
The earlier undescribed amines 2 and 3 were isolated
in the individual state and characterized. An assignment
of signals in their 19F NMR spectra is based on a compariꢀ
son of the chemical shifts observed (δF) with the δcalc
Table 1. The reaction of compounds 1, 4, 7, 10, 13, and 20 with nucleophiles
Entry
Reagent (number of mmoles)
Conditions
Content of the reaction products
Yield (%)
in the mixture (mol.%)*
Polyfluoroꢀ
Nucleophile
Т/°C
Time
quinoline
/h
1
2
3
4
5
6
7
8
1 (0.60)
4 (0.56)
7 (0.56)
Aqueous NH3
The same
150
150
150
150
130
80
9
3
3
8
3
3
2
6
8
22 (1); 68 (2); 20 (3)
11 (4); 12 (5); 77 (6)
18 (8); 77 (9)
8 (10); 43 (11); 46 (12)
3 (13); 16 (14); 79 (15)
4 (13); 18 (14); 71 (15)
15 (16); 76 (17)
7 (13); 13 (18); 68 (19)
86 (21)
5 (21); 84 (22)
32 (2); 9 (3)
64 (6)
9 (8); 52 (9)
35 (11); 13 (12)
55 (15)
»»
»»
»»
10 (0.56)
13 (1.00)
13 (1.00)
13 (1.00)
13 (1.00)
20 (0.80)
20 (0.80)
20 (0.80)
Liquid NH3
C5H10NH (20.2)
Hydrazine hydrate (2.5) 102
Liquid NH3
Aqueous NH3
C5H10NH (16.0)
—
106
3.8 (16); 40 (17)
—
68 (21)
55 (22)
33 (23); 3.5 (24);
11 (25)
9
10
11
10—15
60
50
12
24
49.6 (23); 12.5 (24); 20 (25)
12
13
14
15
20 (0.40)
20 (0.20)
10 (0.28)
10 (0.55)
C5H10NH (8.1)
C5H10NH (4.0)
C5H10NH (7.1)
C5H10NH (29.4)
106
17
17
2
20 (20); 5.3 (23); 10.6 (24); 59 (25)
10 (20); 59 (23); 11 (24); 9 (25)
12 (10); 17 (27); 69 (28)
32 (25)
120
333
12
—
—
67 (28)
106
10 (27); 89 (28)
* According to the 19F NMR spectra; in cases when the overall content of compounds specified is less than 100%,
unidentified components are present in the mixtures.

Aminodefluorination of quinolines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
1051
Table 2. The 19F and 1Ha NMR spectra of fluorinated quinolines (R are substituents in the benzene ring) in acetoneꢀd6
Comꢀ
pound
δ
exp [δcalc]b, J/Hz
RC(5)
RC(6)
RC(7)
RC(8)
2
3
5
6
5.58 (br.s, 2 H, NH2)
6.63 or 6.94 (dd,
JH,Fꢀo = 11, JH,Hꢀm = 2)
6.84 (dd, 1 H,
JH,Hꢀm = 1.5, JF,Hꢀo = 12)
6.84 (dd, 1 H,
JH,Fꢀo = 13, JH,Fꢀm = 6)
7.05 (dd, 1 H,
JH,Fꢀm = 6, JH,Fꢀo = 12)
6.80 (d, 1 H, JH,Fꢀo = 12)
53.3 [51.4] (t, 1 F,
2 JF,Hꢀo = 11)
5.51 (br.s, 2 Н, NH2)
6.63 or 6.94 (dd, 1 H,
JH,Fꢀo = 11, JH,Hꢀm = 2)
6.96 (d, 1 H, JH,Hꢀm = 1.5)
38.8 [39.7] (d, 1 F,
JF,Hꢀo = 12)
5.71 (br.s, 2 Н, NH2)
26.6 [25.1] (dd, 1 F,
JF,Fꢀo = 20, JF,Hꢀo = 13)
5.50 (br.s, 2 Н, NH2)
–4.7 [–2.1] (dd, 1 F,
JF,Fꢀo = 20, JF,Hꢀm = 6)
5.7 [8.9] (dd, 1 F,
35.1 [34.8] (dd, 1 F,
JF,Fꢀp = 18, JF,Hꢀo = 12)
6.00 (br.s, 2 Н, NH2)
38.0 [39.4] (d, 1 F, JF,Hꢀo = 11) 6.77 (d, 1 H, JH,Fꢀo = 11)
8.1 [12.5] (dd, 1 F,
JF,Fꢀp = 19, JF,Hꢀm = 7)
–4.3 [1.5] (dd, 1 F,
JF,Fꢀo = 20, JF,Hꢀm = 7)
7.7 [7.7] (dd, 1 F,
JF,Fꢀp = 15, JF,Fꢀo = 18)
24.4 (dm, 1 F, JF,Fꢀp =15)
JF,Fꢀp = 18, JF,Hꢀm = 6)
8
9
11
53.5 [53.7] (d, 1 F, JF,Hꢀo = 12)
4.62 (br.s, 2 Н, NH2)
7.2 (dd, 1 H,
JH,Fꢀm = 7, JF,Hꢀo = 12)
6.78 (dd, 1 H,
5.30 (br.s, 2 Н, NH2)
33.7 [30.5] (dd, 1 F,
JF,Fꢀp = 19, JF,Hꢀo = 12)
5.85 (br.s, 2 Н, NH2)
12
15
16
23.8 [22.2] (dd, 1 F,
JF,Fꢀo = 20, JF,Hꢀo = 13)
8.5 [7.6] (dd, 1 F,
JF,Hꢀm = 7, JF,Hꢀo = 13)
5.65 (br.s, 2 Н, NH2)
10.4 [14] (dd, 1 F,
JF,Fꢀp = 15, JF,Fꢀm = 10)
7.6 (ddd, 1 F, JF,Fꢀo = 17,
JF,Fꢀp = 15, JF(8),H(4) = 1.5)
23.5 (d, 1 F, JF,Fꢀp = 16)
JF,Fꢀo = 18, JF,Fꢀm = 10)
3.29—3.34 (br.m, 4 Н,
NC5H10); 1.62—1.79
(br.m, 4 Н, NC5H10);
1.68 (br.m, 2 Н, NC5H10
17.4 (dd, 1 F, JF,Fꢀo = 18, 3.28—3.33 (br.m, 4 Н,
JF,Fꢀm = 4) NC5H10); 1.60—1.76
(br.m, 6 Н, NC5H10
20.7 (dd, 1 F, JF,Fꢀo = 17,
JF,Fꢀm = 4)
)
17
8.7 (dd, 1 F, JF,Fꢀo = 18,
JF,Fꢀp = 16)
)
18c
19c
21
13.6 (ddd, 1 F, JF,F = 17.5,
JF,Fꢀm = 7.5, JF,H = 2) or
13.1 (br.d, 1 F, JF,F = 18.5)
7.7 (dd, 1 F, JF,Fꢀo = 18.5,
JF,Fꢀp = 15.5)
6.47 (br.s, 1 Н, NHNH2) 13.6 (ddd, 1 F, JF,F = 17.5,
JF,Fꢀm = 7.5, JF,H = 2) or
6.9 (br.t, 1 F,
2 JF,F = 17.0—18.5)
13.1 (br.d, 1 F, JF,F = 18.5)
10.3 (ddd, 1 F,
6.62 (br.s, 1 Н, NHNH2)
12.5 (br.dd, 1 F,
JF,Fꢀp = 15.5, JF,Fꢀm = 8.5)
JF,Fꢀo = 18.5, JF,Fꢀm = 8.5,
JF,H = 2)
6.32 (br.s, 2 Н, NH2)
109.4 (d, 3 F, CF3,
21.9 [19.3] (m, 1 F,
–4.1 [0.9] (d, 1 F,
JF,Fꢀo = 18)
–5.1 (d, 1 F, JF,Fꢀo = 18)
9.1 (d, 1 F, JF,Fꢀo = 18)
JF,CF ꢀo = 24)
JF,CF ꢀo = 24, JF,Fꢀo = 18)
3
3
22d
23e
7.48 (br.s, 2 Н, NH2)
3.13—3.21 (br.m, 4 Н,
NC5H10); 1.68—1.79 (br.m,
26.7 (d, 1 F, JF,Fꢀo = 18)
24.6 (m, 1 F, JF,Fꢀo = 18,
106.2 (d, 3 F, CF3,
JF,CF ꢀo = 28)
JF,CF ꢀo = 28)
3
3
6 Н, NC5H10
)
24
40.2 (m, 1 F, JF,CF ꢀo = 36,
JF,Fꢀp = 19)
108.7 (d, 3 F, CF3,
3.27, 3.08 (both m, 2 Н each, 29.0 (br.d, 1 F,
NC5H10); 1.85, 1.44 (both m, JF,Fꢀp = 19)
1 Н each, NC5H10); 1.72 (m,
3
JF,CF ꢀo = 36)
3
4 Н, NC5H10
37.5 (q, 1 F,
)
25e
26e
35.1 (q, 1 F,
105.7 (dd, 3 F, CF3,
3.36—3.42, 1.75—1.83 (both
br.m, 4 Н each, NC5H10);
1.64—1.72 (br.m, 2 Н, NC5H10
3.10—3.17, 3.34—3.40 (both
br.m, 4 H each, NC5H10);
1.61—1.81 (br.m, 12 H,
JF,CF ꢀo = 28)
JF,CF ꢀo = 28, 20)
JF,CF ꢀo = 20)
3
3
3
)
3.10—3.17, 3.34—3.40
(both br.m, 4 H each,
2 NC5H10); 1.61—1.81
106.1 (d, 3 F, CF3,
39.5 (q, 1 F,
JF,CF ꢀo = 29.5)
JF,CF ꢀo = 29.5)
3
3
(br.m, 12 H, 2 NC5H10
)
2 NC5H10)
27
28
24.1 (dd, 1 F, JF,Fꢀp = 20,
JF,Нꢀm = 8)
3.22—3.27, 1.72—1.81
(both br.m, 4 Н each,
NC5H10); 1.60—1.69
7.4 (dd, 1 H, JН,Fꢀo = 13,
JН,Fꢀm = 8)
35.0 (dd, 1 F, JF,Fꢀp = 20,
JF,Hꢀo = 13)
(br.m, 2 Н, NC5H10
23.9 (dd, 1 F, JF,Fꢀo = 20, 7.1 (dd, 1 H, JН,Fꢀo = 13,
JF,Hꢀo = 13) JН,Fꢀm = 8)
)
2.9 (dd, 1 F, JF,Fꢀo = 20,
JF,Нꢀm = 8)
3.31—3.37, 1.77—1.85 (both
br.m, 4 Н each, NC5H10);
1.60—1.69 (br.m, 2 Н,
NC5H10
)
a In the 1H NMR spectra of all the quinoline derivatives, the signals for the pyridine fragment are observed, δ: 8.6—9.2 (H(2)),
7.2—7.8 (H(3)), 8.2—8.8 (H(4)), JH(3),H(4) = 8.0—8.5 Hz, JH(2),H(3) = 4.0 Hz, JH(2),H(4) = 1.5 Hz (see Ref. 28). In addition, the spectra
of compounds 5, 6, 11, 12, 15, 16—19 and 21—28 exhibit the spinꢀspin coupling constants JH(4),F(8) = 1.5 Hz.
b Calculated starting from the δ value for the parent compound20,25 with allowance for the increment responsible for the introduction
of an amino group instead of a fluorine atom.24
c Solution in 1,4ꢀdioxane; the signals of the protons of the hydrazo group in the spectra of quinolines 18 and 19 overlap with the signals
of unreacted hydrazine hydrate.
d In DMSOꢀd6.
e In CDCl3.

1052
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
Safina et al.
The ammonolysis of 5,7,8ꢀtrifluoroquinoline (4)
under the same conditions gives rise to 5ꢀaminoꢀ
7,8ꢀdifluoroquinoline (5) and 7ꢀaminoꢀ5,8ꢀdifluoroꢀ
quinoline (6) in the ratio ~1.0 : 6.5 (Scheme 1; see Table 1,
entry 2). The latter product was isolated and characterꢀ
ized. Chemical shifts δF in the 19F NMR spectra of amines
5 and 6 are in good agreement with the calculated, as it
Scheme 2
was described for quinolines 2 and 3, values of δcalc
.
It should be noted that all the signals are characterized
by doublet splittings with the spinꢀspin coupling conꢀ
stants J = 15—20 Hz related, as it was shown earlier,19,25
to the interaction of the F atoms in orthoꢀ and paraꢀ
positions to each other in the benzene fragment of the
quinoline molecule. Thereby, the structure of 8ꢀaminoꢀ
5,7ꢀdifluoroquinoline is excluded. Compound 5 was also
obtained alternatively (see below).
The ammonolysis of 8ꢀchloroꢀ5,7ꢀdifluoroquinoline
(7) afforded 5ꢀaminoꢀ8ꢀchloroꢀ7ꢀfluoroquinoline (8) and
7ꢀaminoꢀ8ꢀchloroꢀ5ꢀfluoroquinoline (9) in the ratio ~1 : 4
(Scheme 1; see Table 1, entry 3). The products 8 and 9
were isolated and characterized. The δF value for the F(7)
atom in the 19F NMR spectrum of amine 8 is close to the
δF value for the analogous atom in amine 2, whereas δF for
F(5) atom in the spectrum of amine 9, to the correspondꢀ
ing characteristic of compound 3. In both cases, the
experimental chemical shifts agree with the calculated
values (see Table 2).
A predominant substitution of the F(7) atom by the
amino group in compounds 4 and 7 agrees with the orienꢀ
tation realizing in the reaction of quinoline 4 with eleꢀ
mentꢀcentered nucleophiles,19 in contrast to a predomiꢀ
nant aminodefluorination of quinoline 1 at position 5.
This testifies that a combined effect of three halogen
atoms outweighs the influence of the heterocycle N atom.
This is also indicated by the change in the ratio of
aminodefluorination products at positions 5 and 7 from
1.0 : 6.5 to 1 : 4 going from trifluoroquinoline 4 to difluoroꢀ
chloroquinoline 7, which agrees with the ratio of the
orientation effects of F and Cl atoms in the reactions of
nucleophilic substitution in polyfluorinated benzenes.26
The reaction of 5,6,8ꢀtrifluoroquinoline (10) with
aqueous ammonia under conditions specified above
results in 6ꢀaminoꢀ5,8ꢀdifluoroquinoline (11) and
8ꢀaminoꢀ5,6ꢀdifluoroquinoline (12) in the ratio ~1 : 1
(Scheme 2; see Table 1, entry 4).
tively, in the naphthalene27 and quinoline25 molecules. In
the H NMR spectra of quinolines containing no F(8)
atom, only doublet splittings of the H(4) signal are obꢀ
served, which is characteristic of the spinꢀspin interaction
of the pyridine ring protons.24
1
The result of ammonolysis of compound 10 indicates
that, despite the presence of F(5) atom, the substitution
takes place only at positions 6 and 8, which are not actiꢀ
vated by the N atom of the heterocycle. In the case when
amine 11 is formed, such a direction of substitution
agrees with that observed for the methoxydefluorination
of 1,2,4ꢀtrifluorobenzene26 and is an additional evidence
that a combined orientation effect of F atoms outweighs
the influence of the heterocycle. The formation of comꢀ
pound 12, possibly, is due to the inductive effect of the
heterocycle N atom.
The reaction of 5,6,7,8ꢀtetrafluoroquinoline (13) with
aqueous ammonia at 130 °C produces 6ꢀaminoꢀ5,7,8ꢀtriꢀ
fluoroquinoline (14) and 7ꢀaminoꢀ5,6,8ꢀtrifluoroquinoꢀ
line (15) in the ratio 1 : 5. The latter was isolated in the
individual state in 55% yield (Scheme 3; see Table 1,
entry 5).
Quinoline 15 has been described earlier as the only
product (21% yield) in the reaction of tetrafluoroquinoline
13 with aqueous ammonia.17,18 In this case, the authors
did not analyze composition of the mixture of products by
NMR spectroscopy, which apparently did not allow them
to find out the presence of the minor product 14 in it.
Quinoline 14 was obtained from 5,7,8ꢀtrifluoroquinolineꢀ
6ꢀcarboxamide.25 The 19F NMR spectrum of amine 15
exhibits the doublets of doublets at δF 7.7, 8.7, and 10.4.
This excludes the structures of 5ꢀaminoꢀ6,7,8ꢀtrifluoroꢀ
and 8ꢀaminoꢀ5,6,7ꢀtrifluoroquinolines, since the signal
for the F(8) atom in the first case or for the F(5) atom in
the second should be expected in the region δF 2.0—3.0
due to the electronꢀdonating effect of the amino group in
Chemical shifts δF in the 19F NMR spectra of both
compounds agree with the calculated values (see Table 2).
The presence of splittings with J = 20 Hz in all the signals
and the absence of signals in the region 24—27 ppm
exclude the structure of 5ꢀaminoꢀ6,8ꢀdifluoroquinoline.
The 1H NMR spectra of all the mentioned above quinolines
containing F(8) atom exhibit indicative doublet splitꢀ
ting of the signal due to the F(8)—H(4) coupling with
JH(4),F(8) = 1.5 Hz, which has been found earlier for the
interaction of H and F atoms at positions 4 and 8, respecꢀ

Aminodefluorination of quinolines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
1053
Scheme 3
assign unambiguously, but, reasoning from their posiꢀ
tions, they belong to the two remained fluorine atoms,
viz., F(5) and F(7) in quinoline 16 and F(6) and F(8)
in quinoline 17. A broadening of these signals observed,
apparently, is due to the interaction of the F atoms speciꢀ
fied with the protons of the orthoꢀlocated piperidine fragꢀ
ment. In the 19F NMR spectrum of quinoline 16, for the
signal at δF 7.6 in addition to the splittings indicated, the
doublet splitting with J = 1.5 Hz is also observed, which
can be assigned only to the interaction with the H(4)
proton (see above). This confirms the assignment given
for the structures.
In the reaction of quinoline 13 with hydrazine hydrate
in boiling dioxane, 5,7,8ꢀtrifluoroꢀ6ꢀhydrazinoquinoline
(18) and 5,6,8ꢀtrifluoroꢀ7ꢀhydrazinoquinoline (19) are
formed in the ratio ~1 : 5 (Scheme 3; see Table 1, entry 8).
The assignment of the signals in the 19F NMR spectra of
compounds 18 and 19 (see Table 2) was made similarly to
that described above for amines 16 and 17. We failed in
isolation of the products 18 and 19 in the individual state,
however, their structures are confirmed by the fact that
the action of the Fehling’s solution on their mixture leads
to the corresponding trifluoroquinolines 4 and 10 in the
ratio ~1 : 6, whereas the treatment with benzaldehyde, to
7ꢀ(2ꢀbenzylidenehydrazino)ꢀ5,6,8ꢀtrifluoroquinoline as
the major product.
i
X
Products
NH —H O
NH
2
NC H
NHNH
2
14 + 15
16 + 17
18 + 19
3
2
HNC H
5
10
5 10
N H
2
4
Fehling’s
solution
The research results on the reactions of quinoline 13
with ammonia, piperidine, and hydrazine indicate that a
modification of the nitrogenꢀcentered nucleophile by the
introduction of an alkyl substituent or an amino group
exhibiting electronꢀdonating αꢀeffect does not signifiꢀ
cantly affect the direction of substitution of the F atom in
the benzene ring of the quinoline molecule. A predomiꢀ
nant substitution of the F(7) atom in all the cases agrees
with orientation of the substitution in the reactions of this
substrate with other nucleophilic reagents17—19 and results
from the combined orientation effects of the heterocycle
N atom and the F atoms. For the latter, such an effect is
similar to that observed in analogous reactions of polyꢀ
fluorinated benzenes and naphthalenes.28,29 However, a
predominance of substitution of the F(7) atom, activated
by the combined orientation effect of the fluorine atoms,
over substitution of the F(5) atom, activated by the heteroꢀ
cycle, testifies that the influence of the first structural
factor specified is predominant.
The reaction of 5,7,8ꢀtrifluoroꢀ6ꢀ(trifluoromethyl)ꢀ
quinoline (20) with liquid ammonia at 10—15 °C gives
rise to the only product, viz., 5ꢀaminoꢀ7,8ꢀdifluoroꢀ
6ꢀ(trifluoromethyl)quinoline (21) (Scheme 4; see Table 1,
entry 9). Its structure was established based on the Xꢀray
diffraction data. Heating of aminoquinoline 21 with sulꢀ
furic acid leads, obviously, resulting from the hydrolysis
of the trifluoromethyl group and subsequent decarboxylaꢀ
tion, to amine 5 in 60% yield, which was obtained as the
minor product during ammonolysis of quinoline 4 (see
paraꢀposition.24 A direction of aminodefluorination of
quinoline 13 is similar to that in the reactions of this
substrate with sodium methoxide17—19 and the reagents
Me2EMMe3 (E = P, M = Si, Sn; E = As, M = Si).19
The reaction of quinoline 13 with liquid ammonia at
80 °C in an autoclave leads to amines 14 and 15 in the
ratio ~1 : 4 (see Table 1, entry 6). Therefore, the same
orientation of the substitution is realizing as in the case of
aqueous ammonia.
From the aforesaid, it can be concluded that the variaꢀ
tions in the medium and temperature have little effect on
the orientation of aminodefluorination of quinoline 13.
To find out how the type of nitrogenꢀcentered nucleoꢀ
phile affects the direction of this reaction, we studied
reactions of quinoline 13 with piperidine and hydrazine
hydrate.
The reaction of quinoline 13 with boiling piperidine
for the first time produces 5,7,8ꢀtrifluoroꢀ6ꢀpiperidinoꢀ
quinoline (16) and 5,6,8ꢀtrifluoroꢀ7ꢀpiperidinoquinoline
(17) in the ratio ~1 : 5 (Scheme 3; see Table 1, entry 7).
The 19F NMR spectrum of quinoline 16 (see Table 2)
exhibits the signal at δF 7.6 consisting of doublet splittings
with JF,F = 15.0 and 17 Hz, based on which it was
assigned to the F(8) atom. Similarly, the signal at δF 8.7 in
the 19F NMR spectrum of quinoline 17, having doublet
splittings with JF,F = 16 and 18 Hz, was assigned to the
F(5) atom. In addition, the spectra of both compounds
exhibit two downfield signals, which were impossible to

1054
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
Safina et al.
Scheme 4
5,8ꢀdifluoroꢀ7ꢀpiperidinoꢀ6ꢀ(trifluoromethyl)quinoline
(24) and 5,7ꢀdifluoroꢀ8ꢀpiperidinoꢀ6ꢀ(trifluoromethyl)ꢀ
quinoline (25) in the ratio 4.0 : 1.0 : 1.6 (Scheme 5; see
Table 1, entry 11). All the products were isolated and
characterized as individual compounds.
Scheme 1). The major product of the reaction of quinoꢀ
line 20 with aqueous ammonia at 60 °C is 5ꢀaminoꢀ
7,8ꢀdifluoroquinolineꢀ6ꢀcarbonitrile (22) (Scheme 4; see
Table 1, entry 10) formed apparently from amine 21 by
ammonolysis of the trifluoromethyl group. Analogous
transformations are reported in the literature (see, for
example, Ref. 30). The close values of δF in the 19F NMR
spectra of compounds 21 (except the signal for the
CF3 group) and 22, as well as the presence of characterisꢀ
tic absorption bands at 2223 cm–1 (C≡N) and 3389 and
3357 cm–1 (N—H) in the IR spectrum of the latter
confirm the structure assigned to product 22.
A plausible reason that position 5 is the most active
during ammonolysis of quinoline 20 (as well as during
ammonolysis of quinoline 1) is a predominance of a comꢀ
bined influence of the heterocycle and trifluoromethyl
group as a substituent possessing strong electronꢀwithꢀ
drawing effect over the collective effect of the F atoms
present in the same ring. It cannot be excluded that posiꢀ
tion 5 is activated by the trifluoromethyl group to a greater
extent than position 7 due to the fact that in the molecule
of the starting compound 20 (CCDC 663072 in the
Cambridge Structural Database System, see Ref. 31),
the C(5)—C(6) bond (an average distance (dav) is 1.359 Å)
is shorter than the C(6)—C(7) bond (dav = 1.405 Å).
The reaction of 5,7,8ꢀtrifluoroꢀ6ꢀ(trifluoromethyl)ꢀ
quinoline (20) with piperidine at 50 °C furnishes 7,8ꢀdiꢀ
fluoroꢀ5ꢀpiperidinoꢀ6ꢀ(trifluoromethyl)quinoline (23),
The structure of the major product, amine 23, was
inferred from the Xꢀray diffraction data. In the 19F NMR
spectrum of compound 23, the multiplet at δF 24.6, assigned
to the F(7) atom, contains quartet (1 : 3 : 3 : 1) splitting
with JF,F = 28 Hz, which is due to the interaction with the
F atoms of the CF3 group, the signal of which at δF 106.2
has the corresponding doublet splitting (see Table 2). Simiꢀ
larly, the signal at δF 40.2 in the 19F NMR spectrum of
compound 24 is assigned to the F(5) atom and the interꢀ
action with the CF3 group results in the quartet splitting
with the spinꢀspin coupling constant JF,F = 36 Hz, which
is significantly higher than the value of JF,F for quinoline
23, obviously, due to the closer spatial proximity of the
F(5) atom to the CF3 group as compared to the F(7)
atom. In the 19F NMR spectrum of compound 25, the
signal for the CF3 group at δF 105.7 contains the doublet
splittings with JF,F = 28 and 20 Hz, which are observed for
the signals assigned to the F(5) and F(7) atoms, respecꢀ
tively (cf. with the data for compound 20 in Ref. 25).
Quinoline 20 in boiling piperidine is converted to a
mixture of the same quinolines 23—25, but in another
ratio, 1 : 2 : 11 (see Table 1, entry 12). Therefore, under
these conditions, a product of substitution of the F(8)
Scheme 5

Aminodefluorination of quinolines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
1055
atom predominates. And vice versa, if the reaction is
carried out at reduced temperature (17 °C), the content of
the product of substitution of the F(5) atom increases:
quinolines 23—25 are formed in the ratio 5.7 : 1.0 : 1.0
(see Table 1, entry 13). A possibility of interconversion of
isomers 23—25 is excluded by the fact that the keeping of
quinoline 20 with piperidine at 17 °C with subsequent
reflux resulted in compounds 23—25 in qualitatively simiꢀ
lar ratio 3 : 1 : 1. Some decrease in the content of quinoꢀ
line 23 in the mixture of isomeric products of monosubꢀ
stitution, most likely, is due to its partial transformation
to 7ꢀfluoroꢀ5,8ꢀdipiperidinoꢀ6ꢀ(trifluoromethyl)quinoline
(26) (the content in the mixture is 38% according to
the 19F NMR spectra). To confirm this, the latter was
obtained by the reaction of quinoline 23 with piperidine
in 83% yield (see Scheme 5).
From the data considered above, it follows that there
exists a temperature dependence of orientation of piperiꢀ
dinodefluorination of quinoline 20 with isokinetic tempeꢀ
rature in the range of 50—100 °C and at low temperatures
(17—50 °C), i.e., in the region of the enthalpy control,
substitution of the F atom at position 5 predominates,
whereas at high temperatures (>100 °C), i.e., in the
region of the entropy control, at position 8.
Such a temperature dependence of orientation of subꢀ
stitution of F atom by the piperidine residue was also
found for quinoline 10. For instance, the reaction of the
latter with piperidine at 17 °C leads to 5,8ꢀdifluoroꢀ6ꢀpiꢀ
peridinoquinoline (27) and 5,6ꢀdifluoroꢀ8ꢀpiperidinoꢀ
quinoline (28) in the ratio 1 : 4 (Scheme 6; see Table 1,
entry 14), whereas in boiling piperidine, the products
specified are formed in the ratio 1 : 9 (see Table 1, entry 15).
A predominant isomer 28 was isolated and characterized
as an individual compound.
such a splitting is absent in the 1H NMR spectrum of quinoꢀ
line 28.
Therefore, in contrast to the ammonolysis of comꢀ
pound 10 proceeding with the formation of the substituꢀ
tion products of the F atoms at positions 6 and 8 in virtuꢀ
ally equal amounts, the reaction of the same substrate
with piperidine leads predominantly to the product of
substitution at position 8, i.e., quinoline 28, the fraction
of which on temperature elevation increases similarly to
the observed for quinoline 20. In contrast to the latter, in
the case of quinoline 28 the isokinetic temperature apparꢀ
ently is in the region of low temperatures.
The temperature dependence of orientation of piperiꢀ
dinodefluorination found can presumably be interpreted
as follows. A predominant substitution of the F(5) atom
in the reaction of quinoline 20 with piperidine at 17—50 °C
is determined by the electronic effect of the N atom of the
pyridine ring, which in this case is amplified by the effect
of the CF3 group. The entropyꢀcontrolled predominant
substitution of the F(8) atom in the reaction of comꢀ
pounds 10 and 20 with piperidine at elevated temperaꢀ
ture, possibly, is due to the specific interaction of the
piperidine fragment with the N atom of the heterocycle in
the transition state, i.e., the formation of the intramoꢀ
lecular hydrogen bond (the structure 29). In contrast to
this, an additional molecule of piperidine is involved into
the formation of the hydrogen bond in the transition state
for the substitution of the F(5) atom (the structure 30), as
a result, the entropy of solvation for this transition state is
more negative than in the first case. Similar interpretation
has also been suggested for the dependence of the ratio of
rates for orthoꢀ and paraꢀalkoxydefluorination of fluoroꢀ
nitrobenzenes versus the structure of the alcohol alkyl
group.32
Scheme 6
Similar interactions, apparently, take also place in the
transition states of aminodefluorination of compounds 1
and 20. However, it can be suggested that in this case the
differences in the entropy of solvation of transition states
of competing reactions are less than during piperidinoꢀ
defluorination. This is due to the fact that the fragment of
the structure of transition state corresponding to the
ammonia molecule incoming in the substrate has a possiꢀ
bility to form three hydrogen bonds and, therefore, a
relative decrease in the number of molecules involving
In the 19F NMR spectra of compounds 27 and 28, the
signals for all the F atoms have the doublet splittings with
JF,F = 15—20 Hz, which should not be observed in the
case of 6,8ꢀdifluoroꢀ5ꢀpiperidinoquinoline. In the
1H NMR spectrum of quinoline 27, a characteristic
doublet splitting of the signal for the proton H(4)
with JH(4),F(8) = 1.5 Hz is observed (see above), whereas

1056
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
Safina et al.
into the solvation as a result of formation of intramolecular
hydrogen bond in the transition state for the substitution
at position 8 as compared to position 5 is not that high.
To sum up, note that in the reactions of quinolines
fluorinated at the benzene ring under study with nitroꢀ
genꢀcentered nucleophiles (aqueous and liquid NH3,
N2H4—H2O, and C5H10NH), a direction of aminoꢀ
defluorination is determined by the ratio of the influence of
the heterocycle and orientation effect of the F atoms and
3.53 Å
a
N(2)
F(4)
F(6A)
F(4A)
F(5)
Fig. 2. πꢀStacking interaction in the crystals of compound 21.
C(5)
C(9)
C(4)
C(6)
C(3)
F(6)
F(5A)
3.53 Å
C(7)
C(2)
C(10)
C(8)
F(2)
N(1)
F(3)
3.53 Å
b
C(15)
C(16)
C(14)
Fig. 3. πꢀStacking interaction in the crystals of compound 23.
when these two effects oppose each other, the latter has a
predominance. In the reactions of 5,6,8ꢀtrifluoroquinoline
and 5,7,8ꢀtrifluoroꢀ6ꢀ(trifluoromethyl)quinoline with
piperidine, it was found that the orientation of aminoꢀ
defluorination depends on temperature, which is obviꢀ
ously due to the change of the enthalpy control at low
temperature to the entropy control upon its elevation.
The spatial structures of compounds 21 and 23 are
given in Fig. 1 (the Xꢀray diffraction data). Analysis of
molecular geometry and intermolecular interactions was
performed using the PLATON program33,34 (Table 3).
The quinoline framework of these molecules is virtually
plane, the meanꢀsquare deviation of atoms from the plane
is 0.015 and 0.030 Å for compounds 21 and 23, respecꢀ
tively. The piperidine ring in the molecule of 23 has the
"chair" conformation. The values of similar bond disꢀ
tances and bond angles in the molecules of 21 and 23
coincide within 3σ and are close to the average statistical
values.35 Geometry of the heterocycle is analogous to that
for nonfluorinated quinoline.36 In the fluorinated ring of
quinolines 21 and 23, the bonds C(7)—C(8) (1.346(5)
and 1.341(3) Å, respectively) and C(8)—C(10) (1.404(5)
C(17)
C(13)
F(3)
N(12)
F(4)
C(5)
C(4)
C(11)
C(3)
C(9)
C(6)
F(5)
C(10)
C(7)
C(2)
N(1)
C(8)
F(2)
F(1)
Fig. 1. Spatial structure of compounds 21 (a) and 23 (b) according
to the Xꢀray diffraction data.

Aminodefluorination of quinolines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
1057
Table 3. Crystallographic data and parameters of Xꢀray diffraction experiments for
compounds 21 and 23
Parameter
21
23
Molecular formula
Т/К
C
10H5F5N2
296
C15H13F5N2
296
Molecular weight
248.16
316.27
Crystal system
Space group
Orthorhombic
Pbca
Monoclinic
P21/c
Region of scanning, θ/deg
2.10—25.50
2.50—26.00
Parameters of unit cell
a/Å
b/Å
c/Å
β/deg
12.922(3)
7.684(2)
19.020(4)
10.9797(6)
12.3682(8)
10.3751(7)
96.561(6)
1399.7(2)
4
3
V/Å
1888.6(8)
8
1.746
Z
dcalc/g cm–3
1.501
0.136
μ/mm—1
0.176
Crystal size/mm
Number of reflections
measured
1.00×0.12×0.04
0.40×0.30×0.10
1764
1743
2918
2758
independent
Allowance for absorption
Transmission
Empirical
0.90—0.95
775
Empirical
0.93—0.96
1640
Number of reflections with I > 2σ(I)
Number of refining parameters
R1 for F > 4σ(F)
wR2 for all reflections
GOOF
203
199
0.0548
0.1992
0.99
0.0474
0.1366
1.02
and 1.402(3) Å, respectively) are somewhat shortened as
compared to those in nonfluorinated quinoline: for two
independent quinoline molecules, the average bond disꢀ
tances for C(7)—C(8) and C(8)—C(10) are 1.363 and
1.415 Å, respectively. However, these values are close to
the distances of analogous bonds in 1,2,3,4ꢀtetrafluoroꢀ
naphthalene: C(7)—C(8) is 1.349(3)Å, C(8)—C(10) is
1.404(3) Å (see Ref. 37). This means that a substitution of
the H atom for the F atom leads to a shortening of the
bond distances. Vice versa, due to the presence of subꢀ
stituents at positions 5 and 6, the bonds C(5)—C(9) and
C(5)—C(6) are elongated, respectively, to 1.443(5) and
1.391(5) Å in compound 21 and to 1.438(3) and 1.388(3) Å
in compound 23 as compared to nonfluorinated quinoline
(for two independent quinoline molecules, the average
bond distances for C(5)—C(9) and C(5)—C(6) are 1.413
and 1.360 Å, respectively36).
A crystal supramolecular architecture of compound
21 is determined by a πꢀstacking interaction of the arene—
polyfluoroarene type, due to which the staircaseꢀlike stacks
are formed (Fig. 2). The distance between the planes of
neighboring molecules is 3.533 Å, whereas the interꢀ
centroid distance is 3.657(2) Å. The stacks are bound to each
other by weak hydrogen bonds N—H...N (N(1)...H(2B) is
2.28(5) Å, the distance N(2)...N(1) is 3.091(5) Å, the
angle N(2)—H(2B)...N(1) is 154(5)°).
The molecules of compound 23 in crystal are packed
as the sandwichꢀlike herringꢀbone patterns (Fig. 3).38 Deꢀ
spite the presence of two bulky substituents, the herringꢀ
bone motive consists of pairs formed due to the πꢀstackꢀ
ing arene—polyfluoroarene interaction of the “headꢀtoꢀ
tail” type. The interplanar distance in the pairs is 3.53 Å,
the intercentroid, 3.596(1) Å. A structurizing interaction
for the herringꢀbone pattern, most likely, is the contact
N(1)...H(3A) shortened to 2.65 Å (the sum of the Van der
Waals radii is 2.74 Å).39
Experimental
1H and 19F NMR spectra were recorded on a Bruker ACꢀ200,
Bruker AVꢀ300, and Bruker AMꢀ400 spectrometers in acetoneꢀd6,
CDCl3, and DMSOꢀd6 for solutions of the individual compounds
and in CH2Cl2, for the reaction mixtures using C6F6 as the
internal standard.
Mass spectra (EI, 70 eV) were recorded on a Finnigan
MATꢀ8200 and DFS high resolution mass spectrometers.
Identification of components by GCꢀMS was performed on a
Hewlett—Packard G1081A instrument consisting of an HP 5890

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Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
Safina et al.
Series II gas chromatograph and an HP 5971 massꢀselective
detector (EI, 70 eV). Temperature conditions for the column:
2 min at 50 °C, further, 10 deg min–1, and 5 min at 280 °C. The
source of ions temperature was 173 °C. A 30×0.25×0.25 mm
column was filled with HP5 sorbent (5% of polydiphenyl, 95%
of polydimethylsiloxane), He was the carrier gas (1 mL min–1).
The data were collected at 1.2 scan s–1 in the region of masses
30—650 a.m.u.
with aqueous NH3 (0.1 g) (see Table 1, entry 1), products 2 and
3 were isolated using TLC (eluent, Et2O).
Quinoline 2 (Rf 0.35), the yield was 0.032 g (32%),
m.p. 137—138 °C. HRMS, found: m/z 162.0594 [M]+. C9H7FN2.
Calculated: M = 162.0593. MS, m/z (Irel (%)): 162 [M]+ (100),
161 (99), 142 (4), 136 (4), 135 (32), 134 (16), 115 (9), 108 (14),
107 (18), 81 (9), 57 (5), 28 (12). Quinoline 3 (Rf 0.12), the yield
was 0.009 g (9%), m.p. 158.0—159.5 °C. HRMS, found:
m/z 162.0592 [M]+. C9H7FN2. Calculated: M = 162.0593.
MS, m/z (Irel (%)): 162 [M]+ (100), 161 (5), 136 (7), 135 (76),
134 (21), 108 (19), 107 (20), 81 (12), 68 (5), 57 (6), 28 (15).
7ꢀAminoꢀ5,8ꢀdifluoroquinoline (6). From a mixture of products
of the reaction of compound 4 with aqueous NH3 (0.1 g) (see
Table 1, entry 2), quinoline 6 was isolated using TLC (eluent,
hexane—Et2O, 1 : 5) (Rf 0.32), the yield was 0.064 g (64%),
m.p. 136—138 °C. HRMS, found: m/z 180.0498 [M]+. C9H6F2N2.
Calculated: M = 180.0499. MS, m/z (Irel (%)): 180 [M]+ (100),
154 (5), 153 (45), 152 (17), 133 (9), 132 (6), 126 (8), 125 (9),
74.9 (4), 28 (13).
5ꢀAminoꢀ8ꢀchloroꢀ7ꢀfluoroquinoline (8) and 7ꢀaminoꢀ8ꢀ
chloroꢀ5ꢀfluoroquinoline (9). From a mixture of products of the
reaction of compound 7 with aqueous NH3 (0.1 g) (see Table 1,
entry 3), quinoline 9 was isolated using TLC (eluent, hexane—Et2O,
1 : 5) (Rf 0.46), the yield was 0.052 g (52%), m.p. 164—166 °C.
HRMS, found: m/z 196.01951 [M]+. C9H6ClFN2. Calculated
M = 196.02035. MS, m/z (Irel (%)): 198 [M + 2]+ (36), 197
[M + 1]+ (13), 196 [M]+ (100), 171 (10), 170 (6), 169 (33), 168
(10), 161 (13), 160 (17), 141 (6), 135 (5), 134 (39), 133 (15), 132
(11), 107 (12), 106 (6), 98 (8), 81 (4). A fraction with Rf 0.24
(0.016 g) was also collected, which contained 85% of quinoline
8. The latter was isolated by repeated (5 times) TLC (eluent,
hexane—Et2O, 1 : 3) as a fraction with Rf 0.45, the yield was
0.009 g (9%), m.p. 213—215 °C. HRMS, found: m/z 196.0201
[M]+. C9H6ClFN2. Calculated: M = 196.02035. MS, m/z
(Irel (%)): 198 [M + 2]+ (33), 197 [M + 1]+ (14), 196 [M]+ (100),
169 (11), 160 (7), 141 (6), 134 (12), 133 (4), 132 (5), 107 (6).
6ꢀAminoꢀ5,8ꢀdifluoroquinoline (11) and 8ꢀaminoꢀ5,6ꢀdiꢀ
fluoroquinoline (12). From a mixture of products of the reaction
of compound 10 with aqueous NH3 (0.1 g) (see Table 1, entry 4),
two fractions were isolated by TLC (eluent, hexane—Et2O, 1:5).
The fraction with Rf 0.67 (0.03 g) contained 87% of quinoline
12, from which it was isolated by double crystallization from
benzene, the yield was 0.013 g (13%), m.p. 83—84 °C. HRMS,
found: m/z 180.0503 [M]+. C9H6F2N2. Calculated: M = 180.0499.
MS, m/z (Irel (%)): 180 [M]+ (100), 179 (8), 154 (5), 153 (35),
152 (14), 133 (4), 126 (13), 125 (10), 90 (5), 75 (5), 28 (12).
The fraction with Rf 0.39 contained quinoline 11, the yield
IR spectrum was recorded on a Bruker Vectorꢀ22 spectroꢀ
meter in KBr pellets.
Xꢀray diffraction experiments were performed on a Bruker
P4 diffractometer (MoꢀKα irradiation, graphite monochromator,
2θ/θꢀscanning). Samples of crystals of compounds 21 and 23
were obtained by crystallization from CH2Cl2, their crystalꢀ
lographic data and parameters of Xꢀray experiments are given in
Table 3. The structures were decoded by the direct method using
the SHELXSꢀ97 program, refining of structural parameters was
performed using the SHELXLꢀ97 program (see Ref. 40).
Parameters for the structure 21 were refined using the least
squares method in the fullꢀmatrix anisotropicꢀisotropic (for the
H atoms) approximation. The trifluoromethyl group in the
molecule of 21 is disordered over two positions with the ratio of
weights 0.77 : 0.23 (2). The refining of parameters for the
structure 23 was performed by the least squares method in the
fullꢀmatrix anisotropic approximation for the nonhydrogen
atoms. Parameters of the H atoms were calculated in every cycle
of refining using the coordinates of the corresponding carbon
atoms (the riding model).
Commercial aqueous NH3 was saturated with gaseous
ammonia to the concentration of 32% (d = 0.883 g cm–3).
Commercial N2H4•H2O (98%) was used.
Quinolines 1, 4, 10, 13, and 20 were obtained according to
the procedures described earlier,25 the chlorineꢀcontaining
quinoline 7 was also synthesized according to the described
procedure.41
Individual compounds were isolated by TLC on plates with
binded layer of a sorbent (LSL254 silica gel, 5.0/0.4 mm with
13 wt.% of gypsum), visualization of dried plates were made
under the UV light. Separated fractions were washed off the
sorbent with acetone.
Reactions of quinolines with aqueous NH3 (general procedure).
A mixture of quinoline and aqueous NH3 (40 mL) was kept in a
80ꢀmL steel rotary autoclave. The products were extracted from
the cooled reaction mixture with CH2Cl2 (4×25 mL). The extract
was dried with MgSO4, the solvent was evaporated on a rotary
evaporator, a solid residue was analyzed by GCꢀMS and
19F NMR spectroscopy.
Reactions of quinolines 13 and 20 with liquid NH3 (general
procedure). A mixture of quinoline and liquid NH3 (30 mL) was
kept at required temperature in a 80ꢀmL steel rotary autoclave.
After completion of the reaction, NH3 was evaporated, a solid
residue was dissolved in CH2Cl2 (30 mL). The extract was dried
with MgSO4, the solvent was evaporated, a solid residue was
was 0.035 g (35%), m.p. 175—176 °C. HRMS, found:
m/z 180.0501 [M]+. C9H6F2N2. Calculated: M = 180.0499.
MS, m/z (Irel (%)): 180 [M]+ (100), 179 (4), 153 (13), 152 (13),
133 (15), 132 (6), 126 (4), 125 (6), 90 (7), 28 (13).
7ꢀAminoꢀ5,6,8ꢀtrifluoroquinoline (15). From a mixture of
products of the reaction of compound 13 with aqueous NH3
(0.17 g) (see Table 1, entry 5), a fraction with Rf 0.4—0.5 was
isolated using TLC (eluent, Et2O), which contained quinoline
15, the yield was 0.11 g (55%), m.p. 187—189 °C (the data in
Ref. 17: m.p. 186—187 °C).
5,7,8ꢀTrifluoroꢀ6ꢀpiperidinoquinoline (16) and 5,6,8ꢀtriꢀ
fluoroꢀ7ꢀpiperidinoquinoline (17). After completion of the reacꢀ
tion of quinoline 13 with piperidine (see Table 1, entry 7), the
1
analyzed by 19F and H NMR spectroscopy.
Reaction of quinolines with piperidine (general procedure).
A mixture of quinoline and piperidine was stirred at required
temperature. The reaction conditions and experimental results
are given in Table 1.
5ꢀAminoꢀ7ꢀfluoroquinoline (2) and 7ꢀaminoꢀ5ꢀfluoroquinoline
(3). From a mixture of products of the reaction of compound 1

Aminodefluorination of quinolines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
1059
reaction mixture was poured into H2O (20 mL), a precipitate
was filtered off, washed with H2O (5×5 mL), dissolved in CH2Cl2,
and dried with MgSO4. The solvent was evaporated, two fractions
were isolated from the solid residue (0.2 g) by repeated (3 times)
TLC (eluent, hexane—Et2O, 3 : 1).
Quinoline 16 was obtained from the fraction with Rf 0.46—0.62
(0.018 g) by sublimation at ~60—70 °C (10 Torr), the yield was
0.01 g (3.8%), m.p. 80.0—81.5 °C. Found (%): C, 63.33;
H, 4.71; F, 21.41; N, 10.52. C9H7FN2. Calculated (%):
C, 63.15; H, 4.92; F, 21.41; N, 10.52.
Quinoline 17 was obtained from the fraction with Rf 0.37—0.46
(0.149 g) by sublimation at ~75—80 °C (10 Torr), the yield was
0.1 g (39.7%), m.p. 75—77 °C. HRMS, found: m/z 266.1032
[M]+. C9H7FN2. Calculated: M = 266.1031. MS, m/z (Irel (%)):
266 [M]+ (91), 265 (100), 237 (5), 225 (18), 211 (11), 210 (36),
209 (44), 196 (9), 183 (6), 182 (19), 162 (12), 57.1 (6), 55.2 (10),
42 (5), 41 (9), 29 (6), 28 (16).
Reaction of quinolines 18 and 19 with Fehling’s solution.
A mixture of quinoline 13 (0.20 g, 1 mmol), hydrazine hydrate
(0.13 g, 2.5 mmol), and 1,4ꢀdioxane (6 mL) was refluxed for 6 h.
Then, the solution was decanted and the precipitate was washed
with dioxane (3×1 mL). The solvent was evaporated from
the combined solution on a rotary evaporator. A solution of
CuSO4•5H2O (1.44 g) in H2O (12 mL) and a solution of NaOH
(1.33 g) and К,Na tartrate (4.52 g) in H2O (12 mL) were added
to the solid residue containing quinolines 18 and 19. The mixture
was refluxed for 40 min and steam distilled. The products were
extracted with CH2Cl2 (4×15 mL) from the condensate, dried
with MgSO4, the solvent was evaporated on a rotary evaporator
to obtain a solid residue (0.12 g) containing quinolines 13 (6%),
10 (72 %), and 4 (13%) according to the 19F and 1H NMR
spectra.
7ꢀ(2ꢀBenzylidenehydrazino)ꢀ5,6,8ꢀtrifluoroquinoline. A mixꢀ
ture of quinoline 13 (0.20 g, 1 mmol), hydrazine hydrate (0.13 g,
2.5 mmol), and 1,4ꢀdioxane (6 mL) was refluxed for 6 h. Then,
the solution was decanted and the precipitate was washed with
dioxane (3×1 mL). The solvent was evaporated from the
combined solution on a rotary evaporator. Ethanol (2 mL), H2O
(2 mL), and benzaldehyde (0.19 g, 1.8 mmol) were added to the
solid residue. The reaction mixture was stirred for 15 min at
~40 °C (water bath) and 1 h at ~60 °C (water bath) and poured
into H2O (40 mL). A precipitate was filtered off, washed with
H2O (3×3 mL), and dried in vacuo over КOH. 7ꢀ(2ꢀBenzylideneꢀ
hydrazino)ꢀ5,6,8ꢀtrifluoroquinoline was obtained by crystalꢀ
lization from MeOH, the yield was 0.12 g (41%), m.p. 212—214 °C.
Found (%): C, 63.67; H, 3.29; F, 18.68; N, 13.60. C16H10F3N3.
Calculated (%): C, 63.79; H, 3.35; F, 18.92; N, 13.95. 19F NMR
(acetoneꢀd6), δ: 9.0 (dd, F(6), J = 15.5 Hz, 18 Hz); 13.9 (dm,
F(6) or F(8), J = 18 Hz). 1H NMR (acetoneꢀd6), δ: 10.10 (br.s,
1 H, NH); 7.35—7.48 (3 H); 7.54 (ddd, 1 H, H(3), J = 4 Hz,
8 Hz, 0.5 Hz); 7.72—7.76 (2 H); 8.30 (t, 1 H, HC=N, J = 2 Hz);
8.43 (dt, 1 H, H(4), J = 1.5 Hz, 1.5 Hz, 8.0 Hz); 8.92 (dd, 1 H,
H(2), J = 1.5 Hz).
5ꢀAminoꢀ7,8ꢀdifluoroquinolineꢀ6ꢀcarbonitrile (22). After the
autoclave reaction was completed (see Table 1, entry 10), a
precipitate was filtered off, washed with H2O (4×10 mL), dried
in vacuo over КOH, and crystallized from acetic acid to obtain
quinoline 22, the yield was 0.09 g (55%), m.p. 270—272 °C.
IR (KBr), ν/cm–1: 2223 (C—N); 3389 (N—H); 3357 (N—H).
HRMS, found: m/z 205.0451 [M]+. C10H5F2N3. Calculated:
M = 205.0446. MS, m/z (Irel (%)): 206 [M + 1] (12), 205 [M]+
(100), 204 (5), 178 (21), 177 (7), 158 (5), 151 (11), 150 (8).
5ꢀAminoꢀ7,8ꢀdifluoroquinoline (5). Aminoquinoline 21
(0.05 g, 0.2 mmol) and H2SO4 (1.3 mL) were stirred for 2 h at a
bath temperature of 160 °C, the mixture was poured into H2O
followed by addition of aqueous NaOH (10 mL, ~18%) and
extraction with CH2Cl2 (5×10 mL). The extract was dried with
MgSO4, the solvent was evaporated, and aminoquinoline 5 was
isolated from the residue by vacuum sublimation at 90—100 °C
(10 Torr), the yield was 0.023 g (63%), m.p. 181—182 °C. Found (%):
C, 60.32; H, 3.76; F, 20.29; N, 15.17. C9H6F2N2. Calcuꢀ
lated (%): C, 60.00; H, 3.36; F, 21.09; N, 15.55.
7,8ꢀDifluoroꢀ5ꢀpiperidinoꢀ6ꢀ(trifluoromethyl)quinoline (23),
5,8ꢀdifluoroꢀ7ꢀpiperidinoꢀ6ꢀ(trifluoromethyl)quinoline (24), and
5,7ꢀdifluoroꢀ8ꢀpiperidinoꢀ6ꢀ(trifluoromethyl)quinoline (25). After
the reaction was completed (see Table 1, entry 11), the mixture
was kept for 3 days at ~4 °C. A precipitate was filtered off,
washed with H2O, dissolved in CH2Cl2, and dried with MgSO4,
the solvent was evaporated. Quinoline 23 in the fraction with
Rf 0.38 was isolated from the solid residue by repeated (4 times)
TLC (eluent, hexane—CH2Cl2, 1 : 1), the yield was 0.031 g.
The filtrate was poured into H2O (30 mL), a precipitate was
filtered off, washed with H2O, dissolved in CH2Cl2, and dried
with MgSO4, the solvent was evaporated. Several fractions,
containing (according to the 19F NMR spectra) quinolines 23
(40%), 24 (17%), 25 (27%), and apparently 26 (11%) were
isolated from the solid residue using (twice) TLC (eluent,
hexane—CH2Cl2, 1 : 1).
The fraction with Rf 0.6 contained quinoline 25, the yield
was 0.027 g (11%).
Quinoline 23 (0.052 g) was isolated from the fraction with
Rf 0.26 (0.065 g) by sublimation at 70—80 °C (10 Torr), the
overall yield was 33%, m.p. 127—128 °C. Found (%): C, 56.86;
H, 4.24; F, 29.97; N, 8.90. C15H13F5N2. Calculated (%):
C, 56.96; H, 4.14; F, 30.04; N, 8.86.
The fraction with Rf 0.38 (0.027 g) containing (according
to the 19F NMR spectra) compound 24 (88%) was subjected
to repeated (12 times) TLC (eluent, hexane—CH2Cl2, 2 : 1)
to obtain the fraction with Rf 0.3—0.43 (0.015 g). From the
latter, quinoline 24 was isolated by sublimation at 60—65 °C
(10 Torr), the yield was 0.009 g (3.5%), m.p. 64.0—65.5 °C.
HRMS, found: m/z 315.0915 [M — 1]+. C15H12F5N2. Calcuꢀ
lated: M — 1 = 315.0993. MS, m/z (Irel (%)): 317 [M + 1]+
(7), 316 [M]+ (51), 315 [M — 1]+ (100), 297 (51), 275 (9),
261 (6), 260 (27), 259 (22), 246 (5), 241 (5), 239 (7),
232 (12).
5ꢀAminoꢀ7,8ꢀdifluoroꢀ6ꢀ(trifluoromethyl)quinoline (21).
From a mixture obtained by the reaction of compound 20 with
liquid NH3 (0.2 g) (see Table 1, entry 9), aminoquinoline 21 was
isolated by sublimation at 120—130 °C (10 Torr), the yield was
0.13 g (68%), m.p. 183.0—184.5 °C. Found (%): C, 48.32; H,
2.09; F, 38.20; N, 11.10. C10H5F5N2. Calculated (%): C, 48.40;
H, 2.03; F, 38.28; N, 11.29.
5,7ꢀDifluoroꢀ8ꢀpiperidinoꢀ6ꢀ(trifluoromethyl)quinoline (25).
In another experiment (see Table 1, entry 12), the reaction
mixture was poured into H2O (30 mL), a precipitate was filtered
off, washed with H2O (3×5 mL), dissolved in CH2Cl2, and dried
with MgSO4, the solvent was evaporated. The residue containing
(according to the 19F NMR spectra) quinoline 25 (58%)
was subjected to repeated (3 times) TLC (eluent, hexane—Et2O,

1060
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
Safina et al.
2 : 1) to obtain the fraction with Rf 0.59—0.68 (0.10 g). Quinoline
25 was isolated from the latter by sublimation at 60—65 °C
(10 Torr), the yield was 0.08 g (32%), m.p. 56—57 °C.
Found (%): C, 56.91; H, 4.15; F, 29.85; N, 8.73. C15H13F5N2.
Calculated (%): C, 56.96; H, 4.14; F, 30.04; N, 8.86.
7ꢀFluoroꢀ5,8ꢀdipiperidinoꢀ6ꢀ(trifluoromethyl)quinoline (26).
A mixture of quinoline 23 (0.05 g, 0.2 mmol) and piperidine
(2.5 g, 29.4 mmol) was refluxed for 12 h. Then, the mixture
cooled to room temperature was poured into H2O (30 mL), a
precipitate was filtered off, washed with H2O (3×5 mL), disꢀ
solved in CH2Cl2, and dried with MgSO4, the solvent was
evaporated. Quinoline 26 was isolated from the residue by
sublimation at 100—110 °C (10 Torr), the yield was 0.05 g
(83%), m.p. 118—120 °C. Found (%): C, 63.53; H, 5.87;
F, 20.06; N, 11.01. C20H23F4N3. Calculated (%): C, 62.98;
H, 6.08; F, 19.92; N, 11.02.
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5,6ꢀDifluoroꢀ8ꢀpiperidinoquinoline (28). The mixture obtained
in the reaction of quinoline 10 with piperidine (see Table 1,
entry 14), was poured into water (30 mL), a precipitate was
filtered off, washed with H2O (3×5 mL), dissolved in CH2Cl2,
and dried with MgSO4, the solvent was evaporated. The residue
obtained was subjected to TLC (eluent, hexane—CH2Cl2, 1 : 1)
to obtain the fraction with Rf 0.22—0.66 (0.11 g). Quinoline 28
was isolated from the latter by sublimation at 60—70 °C (10 Torr),
the yield was 0.09 g (67 %), m.p. 83—84 °C. Found (%):
C, 68.82; H, 5.74; F, 15.32; N, 11.24. C14H14F2N2. Calcuꢀ
lated (%): C, 67.73; H, 5.68; F, 15.30; N, 11.28.
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The authors appreciate the help of S. S. Laev in developꢀ
ment of aminodefluorination procedure for fluorinated
quinolines.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 09ꢀ03ꢀ00248a).
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Received April 16, 2008