Interaction of quinolines polyfluorinated on the benzene moiety with sodium and potassium amides in liquid ammonia

Article abstract of DOI:10.1016/j.jfluchem.2012.01.007

The interaction of 5,6,7,8-tetrafluoro- (1) and 5,7,8-trifluoro-6- (trifluoromethyl)quinoline (2) with sodium or potassium amide in liquid ammonia proceeds as a nucleophile (NH₂^-) addition on the 2-position of the pyridine ring, the respective adducts being oxidized to give the respective quinoline-2-amines. In the case of 1 the amide addition is concurrent with aminodefluorination on the 6- and 7-positions. 5,6,8- (3), 5,7,8-trifluoro- (4) and 5,7-difluoroquinolines (5) with one amide equivalent undergo deprotonation of the CH bond flanked by two ortho-fluorine atoms to produce the respective long-lived quinolinyl anions, which can be used as nucleophilic synthons as exemplified by their methylation to yield respective 6- and 7-methylpolyfluoroquinolines. With an excess of potassium amide the originally generated quinolinyl anions add an amide anion on the 2- or 4-position.

Full text of DOI:10.1016/j.jfluchem.2012.01.007

Journal of Fluorine Chemistry 136 (2012) 32–37
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Interaction of quinolines polyfluorinated on the benzene moiety with sodium and
potassium amides in liquid ammonia
Larisa Yu. Gurskaya, Galina A. Selivanova, Vitalij D. Shteingarts *
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russian Federation
A R T I C L E I N F O
A B S T R A C T
Article history:
The interaction of 5,6,7,8-tetrafluoro- (1) and 5,7,8-trifluoro-6-(trifluoromethyl)quinoline (2) with
Received 23 November 2011
Received in revised form 17 January 2012
Accepted 25 January 2012
Available online 4 February 2012
ꢀ
sodium or potassium amide in liquid ammonia proceeds as a nucleophile (NH
2
) addition on the 2-
position of the pyridine ring, the respective adducts being oxidized to give the respective quinoline-2-
amines. In the case of 1 the amide addition is concurrent with aminodefluorination on the 6- and 7-
positions. 5,6,8- (3), 5,7,8-trifluoro- (4) and 5,7-difluoroquinolines (5) with one amide equivalent
undergo deprotonation of the C–H bond flanked by two ortho-fluorine atoms to produce the respective
long-lived quinolinyl anions, which can be used as nucleophilic synthons as exemplified by their
methylation to yield respective 6- and 7-methylpolyfluoroquinolines. With an excess of potassium
amide the originally generated quinolinyl anions add an amide anion on the 2- or 4-position.
ß 2012 Elsevier B.V. All rights reserved.
Keywords:
Polyfluorinated quinolines
Methylquinolines
Aminoquinolines
Potassium (sodium) amide
Deprotonation
Polyfluorinated quinolinyl anions
Oxidative dehydroamination
1
. Introduction
Fluorine containing heterocyclic compounds are of increased
added to the 2-position of the pyridine moiety to yield
corresponding 2-substituted quinolines after oxidation of initially
formed 1,2-dihydroquinolines [7]. However, at 18 8C quinoline 1
with PhMgBr gave some amount of the phenyldefluorination
product. This suggests the primary fast addition of the nucleophile
at the 2-position to be reversible and followed by fluorine
replacement in the benzene ring.
Finding-out a dependence of these competing reactions from
the nature of the nucleophile and reaction conditions is of the
paramount value to plan syntheses using polyfluorinated quino-
lines as ‘‘building blocks’’. In this context, charged N-centered
nucleophiles (metal amides) are of significant interest as the
aminofunctionalization of both the hetero- and carbocyclic parts of
the quinoline skeleton is important for the molecular design of
potentially bioactive fluorinated quinoline derivatives. Aiming on
this, the present work is devoted to study the reaction of quinolines
polyfluorinated on the benzene moiety with potassium and
sodium amides in liquid ammonia at ꢀ55 ꢁ ꢀ33 8C.
interest because many of them possess biological activity [1]. An
appreciable place among them is being held by quinolines with one
or two fluorine atoms in the benzene fragment [2–4]. Quinolines
with three or four fluorine atoms in the benzene ring were studied
sporadically for a long time [5], obviously owing to their small
availability. However, the research of this field was markedly
activated recently [6–8] thanks to developing the simple and
concise synthesis of their precursors – polyfluorinated anilines
nonsubstituted in ortho-position to the amino group, based on
selective ortho-hydrodehalogenation of their more accessible
ortho-halogenated analogues.
The obvious general approach to functionalization of quinolines
polyfluorinated on the benzene ring is based on their reaction with
nucleophiles. Earlier these quinolines were shown to undergo
fluorine substitution in the benzene fragment by neutral
N-centered (aqueous ammonia [5,8], piperidine, N
2 4 2
H –H O [8]),
P- and As-centered (Me MEMe ; E = P, As; M = Si, Sn [7]) and
charged O-centered (MeONa) [5,7,9] nucleophiles. Unlike this,
3
2
2. Results and discussion
charged C-nucleophiles (organic Mg- and Li-compounds) at ꢀ72 8C
The reaction of quinoline 1 with three equivalents of sodium
or potassium amide in liquid ammonia at ꢀ55 ꢁ ꢀ33 8C after
quenching with ammonium chloride gave a mixture of the
aminodefluorination products – previously known 6-amino-
5,7,8-trifluoro (6) and 7-amino-5,6,8-trifluoroquinoline (7) (1:3
ratio, corresponding to the regioselectivity of fluorine substitution
*
Corresponding author at: N.N. Vorozhtsov Novosibirsk Institute of Organic
Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Avenue
9
0
, 630090 Novosibirsk, Russian Federation. Fax: +7 383 3309752.
E-mail address: shtein@nioch.nsc.ru (V.D. Shteingarts).
022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2012.01.007

L.Y. Gurskaya et al. / Journal of Fluorine Chemistry 136 (2012) 32–37
33
Table 1
Interaction of quinolines polyfluorinated via benzene moiety with Na(K)NH
2
in liquid ammonia.
Conditions
Entry
Reagents (g, mmol)
Quinoline
Quencher (g, mmol)
Mass of product
mixture (g)
Products distribution: content
a
(mol.%) , NMR yield (%)
Metal
T (8C)
t (min)
1
2
3
4
5
6
7
8
9
1 (0.13, 0.65)
1 (0.17, 0.85)
1 (0.20, 1.00)
1 (0.14, 0.70)
1 (0.13, 0.65)
1 (0.32, 1.59)
1 (0.17, 0.84)
1 (0.13, 0.65)
2 (0.20, 0.80)
2 (0.22, 0.88)
2 (0.25, 1.00)
3 (0.22, 1.20)
3 (0.20 1.09)
3 (0.20, 1.12)
4 (0.20, 1.09)
4 (0.29, 1.58)
4 (0.13, 0.74)
4 (0.22, 1.20)
5 (0.28, 1.70)
5 (0.33, 2.00)
5 (0.12, 0.73)
K (0.08, 2.05)
K (0.10, 2.56)
K (0.12, 3.08)
Na (0.056, 2.43)
K (0.09, 2.31)
K (0.19, 4.87)
Na (0.062, 2.70)
K (0.08, 2.05)
Na (0.056, 2.42)
Na (0.071, 3.09)
K (0.13, 3.33)
Na (0.037, 1.61)
Na (0.075, 3.28)
K (0.18, 4.62)
Na (0.031, 1.33)
K (0.075, 1.91)
K (0.115, 2.95)
K (0.19, 4.87)
Na (0.048, 2.09)
K (0.094, 2.41)
K (0.11, 2.82)
NH
4
Cl (0.22, 4.11)
(0.61, 3.84)
ꢀ33
ꢀ33
ꢀ55
ꢀ33
ꢀ33
ꢀ33
ꢀ33
ꢀ33
ꢀ33
ꢀ35
ꢀ33
ꢀ33
ꢀ33
ꢀ33
ꢀ33
ꢀ55
ꢀ55
ꢀ33
ꢀ33
ꢀ33
ꢀ33
5
5
0.11
0.07
0.18
0.13
0.12
0.07
0.16
0.05
0.19
0.17
0.19
0.24
0.19
0.03
0.21
0.29
0.085
0.06
0.28
0.35
0.05
1, 35, 30; 6, 21, 18; 7, 44, 38
1, 83, 34; 11, 17, 7
KMnO
4
NH
4
NH
4
NH
4
Cl (0.33, 6.17)
Cl (0.26, 4.86)
Cl (0.25, 4.67)
10
10
10
10
60
60
60
18
18
30
180
30
30
30
30
30
30
30
30
1, 41, 37; 6, 15, 14; 7, 43, 39
1, 34, 32; 6, 18, 17; 7, 46, 43
1, 29, 27; 6, 19, 18; 7, 49, 45
KMnO
NH Cl (0.29, 5.42)
KMnO (0.48, 3.04)
NH Cl (0.26, 4.86)
4
(1.08, 6.82)
1, 3, 0.7; 6, 3, 0.7; 7, 9.5, 2; 11, 82, 18
1, 22, 22; 6, 20, 21; 7, 58, 60
1, 2, 0.8; 6, 5, 2; 7, 16, 6; 11, 68, 25
2, 85, 81; 12, 5.5, 5
4
4
4
1
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
7
8
9
0
1
KMnO
KMnO
4
4
(0.68, 4.33)
(0.74, 4.67)
2, 7, 5; 14, 90, 69
2, 12, 9; 14, 82, 62
CH
NH
KMnO
3
I (0.23, 1.60)
Cl (0.35, 6.56)
(0.99, 6.26)
15, 90, 96
4
3, 92, 87; 17, 5, 5
4
3, 7, 1; 18, 89, 13
CH
CH
3
I (0.23, 1.60)
I (0.34, 2.41)
20, 95, 99
3
4, 13, 13; 20, 85, 83
KMnO
KMnO
4
4
(0.65, 4.13)
(1.07, 6.77)
4, 50, 33; 21, 46, 30; 22, 4, 2.5
4, 16, 5; 21, 46, 13; 22, 35, 10
5, 2, 2; 24, 90, 88
CH
CH
3
I (0.30, 2.09)
I (0.34, 2.41)
3
5, 4, 4; 24, 88, 93
KMnO
4
(0.62, 3.95)
5, 81, 34; 25, 13, 5; 26, 5, 2
a
In the cases, when total content of the named compounds is below 100%, unidentified components are present.
Scheme 1.
in quinoline 1 by various nucleophiles [7,8]) in 60–80% total NMR
quenching by KMnO
4
) to disappear from the product mixtures
yield with the appreciable amount of 1 (Table 1, entries 1, 3–5, 7).
soon with the reaction progress, amines 6 and 7 being formed only.
However, it is evident from the data presented in Table 1 that the
product distribution was only little dependent on the reaction time
and temperature. Even after 5 min (the time needed for the
substrate to dissolve) comparable quantities of amines 2 and 6/7
were formed, the appreciable amount of 1 being returned (entries
1, 2). In these experiments, the total conversions of 1 in a mixtures
of adduct 10 and amines 6/7 (presuming that the quantity of 10 in
entry 1 is proportional to that of 11 in entry 2 and the quantities of
6 and 7 in entry 2 are proportional to those in entry 1) were
calculated as 75–80% and 65–70%, respectively. These evaluations
are satisfactorily consistent (at least, not contradictive) with each
other, taking into account the short reaction time and that the
work-up procedure can somewhat adulterate the initial composi-
tion of the mixture (Table 1, entries 3–8). However, within 10 min,
at almost full conversion of 1 (entry 6), both 1 and 11 are present in
the product mixtures obtained after the respective reaction
quenching (entries 3–6). Moreover, even within 60 min (entries
7, 8) the product distribution changes (if any) rather slowly in favor
ꢀ
Certainly, amines 6 and 7 react with the second NH
2
equivalent to
produce the respective quinolinylamide anions 8 and 9 (Scheme 1).
In the aggregate with literary data on high reactivity of
quinolines [10] with alkaline metal amides, the significant return
of the starting compound suggested that, besides the attack on the
ꢀ
polyfluorobenzene moiety, the NH
2
addition to the pyridine ring
occurs to yield the anionic adduct 10 (Scheme 1). This adduct is
obviously stable under the reaction conditions but decomposes to
1
by NH
reaction of 1 with an excess of KNH
adding KMnO , gave a mixture of the previously unknown 2-
4
Cl. Such a viewing was born out by the fact that the
2
at ꢀ33 8C, being completed by
4
amino-5,6,7,8-tetrafluoroquinoline (11) (for 10 min ꢂ80% in the
product mixture and 13% isolated yield) together with small
quantities of 6 and 7 (Table 1, entries 6 and 8). Quenching of the
4
reaction with KMnO is accompanied by abundant tarring, which
evidently results from oxidation of the principal part of anions 8
and 9 and probably from their interaction with the starting and
formed quinolines. This assumption accords with the decrease in
the total mass of identified products compared to quenching with
of 6 and 7. This prompts one to prefer the alternative conclusion,
ꢀ
NH
4
Cl and with correspondence of the content of amine 11 in the
consisting in the NH
2
additions to C-2 to be practically
product mixture with the quantity of recovered 1 in entries 3–5.
irreversible within the monitoring time and to occur in parallel
with its additions to C-6 and C-7. In this case the observed product
ratio is basically caused by similar rates of the competing reactions
(Scheme 1).
One may consider two ratiocinations of the above results. The
ꢀ
first one suggests the initial fast reversible addition of NH
2
to C-2
of quinoline 1 followed by the slower but irreversible aminode-
fluorinations on C-6 and C-7. In this case, assuming the back decay
of 10 to be fast, one could expect the compounds originating from
Unlike this, 5,7,8-trifluoro-6-(trifluoromethyl)quinoline (2)
with three equivalents of NaNH
2
in liquid ammonia at ꢀ33 8C
1
0 (quinoline 1 upon quenching by NH
4
Cl or amine 11 upon
for 1 h after quenching by NH Cl gave mainly the starting material
4

3
4
L.Y. Gurskaya et al. / Journal of Fluorine Chemistry 136 (2012) 32–37
Scheme 2.
with a trace admixture of previously known 5-amino-7,8-difluoro-
yield (Scheme 4, Table 1, entry 14), while the major part (ꢂ85%) of
19
6
-(trifluoromethyl)quinoline (12) as shown by F NMR [8] (Table
the reacting material being tarred. These results reveal that anion
ꢀ
1
, entry 9). That the return of the starting compound is due to back
16 adds the excess NH
2
on the 4-position to give dianion 19.
Cl regenerates quinoline 3, whereas
transformation of the stable adduct 13 is illustrated by obtaining
the previously unknown 2-amino-5,7,8-trifluoro-6-(trifluoro-
methyl)quinoline (14) (49% isolated yield) as the only product
Protonation of 19 by NH
4
oxidation produces mainly tar, probably due to oxidation of both
16 and 19, and affords a minor amount of 18 (Scheme 3). The
aminodefluorination of anion 16 does obviously not occur, as
after oxidizing the reaction mixture by KMnO
entries 10, 11). Comparison of this result with that for 1 suggests
the 6-CF group to effectively stabilize adduct 13 (Scheme 2) and to
4
(Scheme 2, Table 1,
otherwise one could reasonably expect the quenching by NH
4
Cl to
3
give corresponding aminoquinoline(s). The evident reason for this
favor its formation in the competition with aminodefluorination.
is the nucleophile repulsion by the negative
the benzene moiety.
s-charge located in
In going from quinolines 1 and 2 to 3–5, besides nucleophilic
ꢀ
attacks of NH
2
on the pyridine and benzene moieties, the
The reaction of quinoline 4 with one equivalent of NaNH
ꢀ33 8C or KNH at ꢀ55 8C in liquid ammonia and subsequent
quenching with CH I gave 5,7,8-trifluoro-6-methylquinoline (20)
2
at
opportunity appears of deprotonation of the C–H bond neighbored
by two ortho-fluorine atoms (analogously to polyfluorinated
benzenes [11]). It turned out that precisely this reaction channel
is strongly prevailing. So, after quinoline 3 was kept with an
2
3
almost exclusively (97% and 85% isolated yield, respectively)
(Scheme 4, X = F; Table 1, entries 15 and 16). Using an excess of
equivalent quantity of NaNH
2
in liquid ammonia at ꢀ33 8C for
KNH
2
at ꢀ55 8C and oxidizing the mixture with KMnO
4
gave a
3
0 min and subsequent treatment of the reaction mixture with
ꢂ12:11:1 mixture of quinoline 4, 2-amino-5,7,8-trifluoroquinoline
(21) and 4-amino-5,7,8-trifluoroquinoline (22) in ꢂ60% overall
yield calculated on the consumed starting material (Table 1, entry
3
CH I led to 5,6,8-trifluoro-7-methylquinoline (15) as the only
product isolated in 72% yield (Scheme 3, Table 1, entry 12). To
check whether the initially formed 7-quinolinyl anion 16 can
17). The reaction of 4 with an excess of KNH
2
at ꢀ33 8C completed
ꢀ
further react with NH
equivalents of NaNH
quenching with NH
2
, 3 was involved in the reaction with three
under the same conditions for 3 h. After
Cl the starting quinoline was almost
by oxidation gave amines 21 and 22 in a ꢂ1.3:1 ratio and 12% and
2
6% isolated yield, respectively (Table 1, entry 18). Thus, the initially
ꢀ
4
formed 6-quinolinyl anion 23 (X = F) adds NH
2
just as 16,
completely recovered (Table 1, entry 13) and only traces of known
however, with slightly different and obviously temperature
dependent orientation. Analogous temperature dependence was
19
[
8] 8-amino-5,6-difluoroquinoline (17) were detected by F NMR.
ꢀ
However, quenching the reaction with KMnO led to previously
4
reported for the NH
2
addition to nonfluorinated quinoline [10].
or KNH at
I gave 5,7-difluoro-6-
unknown 4-amino-5,6,8-trifluoroquinoline (18) isolated in 11%
Keeping quinoline 5 with one equivalent of NaNH
33 8C and quenching the reaction with CH
methylquinoline (24) in 39% isolated yield (Scheme 4; Table 1,
2
2
ꢀ
3
entries 19, 20), whereas oxidation of the mixture, which was
2
obtained with an excess of KNH gave mainly the starting
compound and small amounts (less than 20% in total) of 2-
amino-5,7-difluoroquinoline (25) and 4-amino-5,7-difluoroquino-
line (26) in a ratio of ꢂ2.5:1 (Scheme 4; Table 1, entry 21). It is not
excluded that the lower yield of these amines compared to similar
products from 4 reflects a dependence of the 2- and 4-position
electrophilicities of originally formed anions 23 on the fluorination
degree of the benzene moiety.
Quinolines 20–22 and 24 have been obtained for the first time.
ꢀ
Thus, the aggregate of the above results reveals the excess NH
2
addition on the 2- an 4-positions of the 6- and 7-quinolinyl anions
generated by deprotonation of quinolines 3–5. The data obtained
do not present a reliable basis to rigorously judge about the real
regioselectivity of this reaction, first of all due to the low product
yields achieved by the oxidative quenching, and about the factors
governing this regioselectivity. Nevertheless, comparing the
product distributions displayed by quinoline 4 at ꢀ55 and
Scheme 3.
ꢀ
33 8C allows one to surmise that the kinetically favored addition
occurs at the 2-position, being followed by a partial isomerization
of the initially formed dianionic 2-NH -adduct to the 4-NH
2
2
-
adduct. Taking into account the high nucleophilicity of the amide
anion, the kinetically preferable 2-addition is assumed to proceed
via an early transition state and to be directed mainly by factors
associated with the substrate, first of all by the nitrogen inductive
effect. As for theoretical evaluation of the relative stability of the
2
dianionic 2- and 4-NH -adducts, respective quantum chemical
Scheme 4.
calculations should be performed. However, some preliminary

L.Y. Gurskaya et al. / Journal of Fluorine Chemistry 136 (2012) 32–37
35
Table 2
1
a
19
H
and F NMR chemical shifts (ppm) and coupling constants (Hz) for amino- and methylpolyfluoroquinolines.
Compound
Structure
H
F
F
X
W
Y
N
Z
a
1
1
1
1
4
5
W= 2-NH
X, Y, Z = F
2
;
8.05 (dd, J(H-4, H-3) = 9, J(H-4, F-8) = 1, 1H, H-4),
ꢀ153.0 (dd, J(F-5, F-6) = 20, J(F-5, F-8) = 14.5, 1F, F-5),
6.77 (d, J(H-4, H-3) = 9, 1H, H-3), 5.29 (bs, 2H, NH
2
)
ꢀ156.6 (bt, J(F-7, F-8), J(F-7, F-6) ꢂ19.5, 1F, F-7), ꢀ157.2 (m,
6 5 6 7
1
F, F-8), ꢀ166.5 (bt, J
, J
F ;F
ꢂ 20, 1F, F-6)
F
;F
a
a
W= 2-NH
2
;
8.12 (dd, J(H-4, H-3) = 9, J(H-4, F-8) = 1, 1H, H-4),
6.79 (d, J(H-4, H-3) = 9, 1H, H-3), 5.35 (bs, 2H, NH
ꢀ56.6 (dd, J(F-5, CF
3
) = 25, J(F-7, F-8) = 19.5, 3F, CF
3
), ꢀ126.2
3
X = CF ; Y, Z = F
2
)
(bqd, 3J(F-5, CF
3
) = 25, J(F-5, F-8) = 18, 1F, F-5), ꢀ140.2 (m,
1
F, F-7), ꢀ158.6 (bt, J(F-7, F-8) = 19.5, J(F-5, F-8) = 18, 1F, F-8)
W= H; X, Z = F;
Y = CH
8.91 (dd, J(H-2, H-3) = 3, J(H-2, H-4) = 1, 1H, H-2),
8.36 (dt, J(H-4, H-3) = 8.5, J(H-4, H-2), J(H-4, F-8)
ꢀ131.9 (bd, J(F-8, F-5) = 19, 1F, F-8), ꢀ141.8 (bd, J(F-6, F-
5) = 19, 1F, F-6), ꢀ155.5 (t, J(F-8, F-5), J(F-6, F-5) ꢃ 19,
1F, F-5)
3
1
3
.5, 1H, H-4), 7.48 (dd, J(H-4, H-3) = 8.5, J(H-2, H-
) = 4, 1H, H-3), 2.45 (t, 2J(CH , F) = 2, 3H, CH
3
3
)
b
8
1
2
8
0
W= 4-NH
2
;
8.36 (d, J(H-2, H-3) = 5, 1H, H-2), 7.51 (td, 2
ꢀ123.3 (dd, J(F-5, F-8) = 18, J(F-8, H-7) = 10, 1F, F ), ꢀ142.8
ortho
X, Z = F; Y =H
J(H, F) = 10, J(H-7, F-5) = 7.5, 1H, H-7), 6.77 (d,
J(H-2, H-3) = 5, 1H, H-3), 6.44 (bs, 2H, NH
(dd, J(F-6, F-5) = 19, J(F-6, H-7) = 10.5, 1F, F-6), ꢀ147.8 to
5
2
)
ꢀ147.3 (m, 1F, F )
a
W= H; X = CH
Y, Z = F
3
;
8.94 (dd, J(H-2, H-3) = 4, J(H-2, H-4) = 1, 1H, H-2),
8.32 (dt, J(H-4, H-3) = 8.5, J(H-4, H-2), J(H-4, F-
ꢀ131.1 (dm, J(F-5, F-8) =19, 1F, F-5), ꢀ138.6 (dm, J(F-7,
F-8) = 18, 1F, F-7), ꢀ158.1 (bt, J(F-7, F-8), J(F-5, F-8) ꢃ 18,
1F, F-8)
8
) ꢃ 1, 1H, H-4), 7.45 (dd, J(H-4, H-3) = 8.5, J(H-2,
H-3) = 4, 1H, H-3), 2.41 (t, 2J(CH , F) =2, 3H, CH
8.02 (dd, J(H-4, H-3) = 9, J(H-4, F-8) = 1, 1H, H-4),
3
3
)
b
2
1
W= 2-NH
2
;
ꢀ125.7 (ddd, J(F-5, F-8) = 16.5, J(F-5, H-6) = 10, J(F-5, F-7) =2,
1F, F-5), ꢀ136.5 (ddd, J(F-7, F-8) = 18, J(F-7, H-6) = 11, J(F-5,
F-7) = 2, 1F, F-7), ꢀ159.7 (btd, 2J(F, F) = 17–18, J(F-8, H-6) =6,
1F, F-8)
ortho
X = H; Y, Z =F
6.96 (ddd,
), 6.95 (d, J(H-4, H-3) = 9, 1H, H-3), 6.57 (bs, 2H,
NH
J(H, F) = 11, 9, J(H-6, F-8) = 6, 1H, H-
6
2
)
b
2
2
4
W= 4-NH
2
;
8.37 (d, J(H-2, H-3) = 5, 1H, H-2), 7.19 (ddd,
ꢀ115.1 (m, 1F, F-5), ꢀ136.6 (ddd, J(F-7, F-8) = 19, J(F-7,
H-6) = 11, J(F-5, F-7) = 2.5, 1F, F-7), ꢀ154.8 (btd, 2J(F, F)
= 18–19, J(F-8, H-6) = 6, 1F, F-8)
ortho
X = H; Y, Z =F
J(H, F) = 13, 11, J(H-6, F-8) = 6, 1H, H-6), 6.71
(
2
d, J(H-2, H-3) = 5, 1H, H-3), 6.54 (bs, 2H, NH )
a
2
W, Z = H;
8.82 (bd, J(H-2, H-3) = 4, 1H, H-2), 8.25 (d, J(H-4,
H-3) = 8.5, 1H, H-4), 7.47 (bd, J(H-8, F-7) =10, 1H,
H-8), 7.32 (dd, J(H-4, H-3) = 8.5, J(H-2, H-3) = 4, 1H,
ꢀ112.9 (bt, J(F-7, H-8), J(F-7, F-5) ꢃ 9, 1F, F-7), ꢀ125.7
(1F, bd, J(F-7, F-5) = 9, F-5)
3
X = CH ; Y = F
3 3
H-3), 2.32 (bt, 2J(CH , F) = 2, 3H, CH )
b
ortho
2
5
W= 2-NH
2
;
7.99 (d, J(H-4, H-3) = 9, 1H, H-4), 6.98 (dm, J(H-8,
ꢀ109.9 (ddd,
J(H, F) = 10, 9.5, J(F-5, F-7) =7.5, 1F, F-7),
X, Z = H; Y =F
F-7) = 10.5, 1H, H-8), 6.87 (d, J(H-4, H-3) = 9, 1H, H-
ꢀ120.6 (dd, J(F-5, H-6) = 10, J(F-5, F-7) = 7.5, 1F, F-5)
ortho
3
1
), 6.79 (btd, 2
J(H, F) = 10, J(H-4, H-2) = 2.5,
2
H, H-6), 6.27 (bs, 2H, NH )
b,c
2
6
5
7
2
6
W= 4-NH
2
;
8.32 (1H, d, JH
6.62 (1H, d, JH
2
3
¼ 9 , H ), 7.00 (1H, H ),
ꢀ109.7 to ꢀ109.6 (1F, m, F ), ꢀ110.2 (1F, bq, 3J =9.5, F )
;H
;H
3
X, Z = H; Y =F
2
3
¼ 9 , H ), 6.43 (2H, bs, NH
2
)
a
b
c
Solution in CDCl
3
.
Solution in acetone-d
6
.
6
8
8
6
The signals of the H and H are hidden by the H signal of aminoquinoline 25 and H signal of quinoline 5.
2ꢀ
(Scheme 5) seem
speculation is possible, based on the presentation of the dianionic
adducts in terms of canonical structures depicting the negative
charge dispersion over the quinoline core. A peculiar feature of
these adducts is the destabilizing interaction of localized - and
delocalized -charges. From this point of view, the sets of
canonical structures for the 2- and 4-NH -adducts formed by
6-quinolinyl anion 23 (X = F) with NH
p
-
approximately equivalent, which is consistent with the ꢂ1.3:1
ratio of quinolines 21 and 22 obtained from 4 at ꢀ33 8C (Table 1,
entry 18).
s
p
Probably, the situation is similar for the reaction of 5 with
ꢀ
2
excess NH
2
(Scheme 5) also producing comparable amounts of
Scheme 5.

3
6
L.Y. Gurskaya et al. / Journal of Fluorine Chemistry 136 (2012) 32–37
2
- and 4-aminoquinolines (Table 1, entry 21). However, contrary to
correspondingly) using residual protons in the solvents CDCl
7.24 ppm), acetone-d 2.04 ppm), DMSO-d 2.50 ppm) and
ꢀ163 ppm) as internal standards.
GC–MS was performed using an Hewlett-Packard HP 5890
3 H
(d
this in the case of quinoline 3, despite the analogous consideration
in terms of canonical structures leads to the same prediction, only
6
(
d
H
6 H
(d
6 6 F
C F (d
4
-aminoquinoline 18 was obtained. Thus, only a more compre-
hensive experimental and computational study can explain this
disparity.
Series II gas chromatograph and HP 5971 (EI, 70 eV) mass-selective
detector using a HP5 MS capillary column (30 mm ꢄ 0.25 mm ꢄ
0.25 mm); the carrier gas was He, 1 mL/min.
1
19
3
.
= and F NMR spectral data
Exact molecular masses were determined by HRMS on a
Thermo Scientific DFS instrument, ionizing energy 70 eV.
The NMR characteristics of the first synthesized fluorinated
amino- and methylquinolines presented in Table 2 are as a whole
in line with those of both nonfluorinated [12] (including
aminoquinolines [12b,c]) and fluorinated on the benzene ring
5.1. General procedure
2 2
Polyfluoroquinoline was added to NaNH or KNH prepared in
[
7,9,13] quinolines. A specific feature of 2- and 4-aminoquinolines
is the influence of an amino group on fluorine chemical shifts ( ).
Comparing the values of 2-aminoquinolines 11, 14, 21 and 25
liquid ammonia (30 mL) by the routine procedure and the mixture
was stirred at a given temperature for the required time (Table 1).
d
F
d
F
Then the reaction mixture was quenched by adding NH
(in both cases by portions during 5 min) or MeI (single portion) and
stirred for 10 min. After evaporation of NH products were
extracted with CH Cl
(5 mL ꢄ 15 mL). The extract was dried with
MgSO and analyzed by F and H NMR, GC–MS. Individual
compounds were isolated by TLC on a fixed sorbent (silica gel
LSL254 5/40 with 13 wt.% of gypsum). The separation result was
4 4
Cl, KMnO
and their precursors 1, 2, 4 [13] and 5 [12b], respectively, one can
see that all fluorine resonances are high-field shifted due to the
3
electron donating effect of the 2-NH
ꢂ8 ppm for 11) and F-8 (4–5 ppm for 11 and 14, ꢂ3 ppm for 21)
are naturally larger than those of F-5 and F-7 (0–2 ppm, ꢂ3 ppm for
F-5 of 14). The 4-NH group similarly influences the chemical shift
2
group. The shifts of F-6
2
2
1
9
1
(
4
2
m
values of F-6 and F-7 of 18, 22 and 26, but its effect toward F-5 in
going to these amines from their precursors 3–5 is qualitatively
different: the F-5 signal, contrary to the electron donating effect of
visualized by irradiation of a dried plate with UV light. The
separated fractions were extracted from the sorbent with acetone
2 2
or CH Cl .
4
-NH
reasonably accounted for by the through-space interaction of F-5
and 4-NH . In so doing, the F-5 substituent effect is obviously
2
, is low-field shifted by 6–10.5 ppm. This seems to be
5.2. 2-Amino 5,6,7,8-tetrafluoroquinoline (11)
2
modified in such a manner that F-8 of 18 and 22 also experience a
From the mixture formed after reaction of quinoline 1 with
low-field shift of 2–3.5 ppm.
KNH
(CH
11 (0.046 g, 13%); m.p. 201–203 8C (benzene). Anal. calcd for
N: C, 50.0; H, 1.9; F, 35.2; N, 13.0; found: C, 50.2; H, 2.0; F,
2
and quenching with KMnO
4
(Table 1, entry 6) by 7-fold TLC
The influence of the methyl group on
d
F
values of polyfluor-
2
2
Cl ; intermediate air-drying of the plate) isolated was amine
oquinolines is consistent with relevant literature data for
polyfluorinated benzene [14] and naphthalene [15] derivatives.
Upon its substitution for hydrogen in going from precursors 3–5 to
quinolines 15, 20 and 24, respectively, the near-by fluorine
resonances are broadened and high-field shifted by 4–5 ppm. The
imaginary introduction of a methyl group instead of fluorine in
going from 1 to 15 and 20 and from 5,6,7-trifluoroquinoline [16] to
10 6 3
C H F
35.4; N, 13.0.
5.3. 2-Amino-5,7,8-trifluoro-6-(trifluoromethyl)quinoline (14)
The residual parent compound was sublimated (50–70 8C/
10 mm Hg) from the mixture, formed after reaction of quinoline 2
2
4 causes deshielding of the neighboring fluorines, more strongly
for F-5 and F-8 (ꢂ21 ppm) than for F-6 and F-7 (16–18.5 ppm),
with KNH
amine 14 (0.13 g, 49%); m.p. 214–215.5 8C (benzene). Anal. calcd
for C10 : C, 45.1; H, 1.5; F, 42.5; N, 10.5; found: C, 45.2; H, 1.6;
F, 42.6; N, 10.5.
2 4
and quenching with KMnO (Table 1, entry 10), to give
obviously, because the C –C bond is shorter than the C –C one
a
b
b
b
(cf. [7,13,15]).
4 6 2
H F N
4
. Conclusions
5.4. 5,6,8-Trifluoro-7-methylquinoline (15)
The quinolines 1 and 2 react with sodium or potassium amides
ꢀ
in liquid ammonia to add NH
2
at the 2-position of the pyridine
From the mixture formed after reaction of quinoline 3 with
fragment, the corresponding quinoline-2-amines being obtained
by oxidation of thus formed adducts. Concurrently, quinoline 1 is
aminodefluorinated at C-6 and C-7. Unlike this, quinolines 3–5
undergo deprotonation on the C–H bond neighbored by two
fluorine atoms to generate respective quinolinyl anions. These
anions were shown to be useful substrates for electrophilic
NaNH
(hexane–CH
was methylquinoline 15 (0.17 g, 72%); m.p. 104.5–106 8C (subli-
mation at 55–65 8C/10 mm Hg). Anal. calcd for C10 N: C, 60.9;
2
and quenching with CH
3
I (Table 1, entry 11) by 3-fold TLC
2
Cl , 1:3; intermediate air-drying of the plate) isolated
2
6 3
H F
H, 3.1; F, 28.9; N, 7.1; found: C, 61.0; H, 3.3; F, 29.0; N, 6.9.
functionalization as exemplified by their methylation with CH
afford the respective methylquinolines in good yields. The excess
KNH adds to the 2- or 4-position of the pyridine fragment of
initially formed quinolinyl anions.
3
I to
5.5. 4-Amino-5,6,8-trifluoroquinoline (18)
Sublimation (100–105 8C/10 mm Hg) of the parent compound
2
from the mixture, formed after reaction of quinoline 3 with KNH
and quenching with KMnO (Table 1, entry 13), gave amine 18
(0.025 g, 11%); m.p. 193–195 8C. HRMS (EI): m/z [M] calcd. for
: 198.0399; found 198.0401.
2
4
+
5
. Experimental
9 5 3 2
C H F N
The quinolines 1 [13], 2 [13], 3 [13], 4 [13], 5 [17] were prepared
according to the literature protocols. Liquid NH
3
was purified by
5.6. 5,7,8-Trifluoro-6-methylquinoline (20)
distillation over metallic sodium to a cooled (ꢀ70 8C) reaction
vessel.
Prepared according to the general procedure (Table 1, entry 14)
in 97% yield; m.p. 103–105 8C (sublimation at 65–75 8C/10 mm
Hg). Anal. calcd for C10H F N: C, 60.9; H, 3.1; F, 28.9; N, 7.1; found:
6 3
1
19
H and F NMR spectra were recorded on a NMR spectrometer
1
19
Bruker AV-300 (300.13 MHz and 282.36 MHz for H and
F

L.Y. Gurskaya et al. / Journal of Fluorine Chemistry 136 (2012) 32–37
37
+
[3] (a) K. Saeki, R. Murakani, A. Kohara, N. Shimizu, H. Kawai, Y. Kawazoe, A. Hakur,
Mutat. Res. 441 (1999) 205–213;
C, 61.4; H, 3.1; F, 28.6; N, 7.0. HRMS (EI): m/z [M] calcd. for
N: 196.0369; found 196.0368.
10 6 3
C H F
K. Saeki, Yakugaku Zasshi. 120 (2000) 1373–1385;
(b) K. Saeki, T. Matsuda, T. Kato, K. Yamada, T. Mizutani, S. Matsui, K. Fukuhara, N.
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5.7. 2-Amino- (21) and 4-amino 5,7,8-trifluoroquinoline (22)
[
[
From the mixture, obtained after reaction of quinoline 4 with
[6] V.D. Shteingarts, J. Fluorine Chem. 128 (2007) 797–805.
[7] E.V. Panteleeva, V.D. Shteingarts, J. Grobe, B. Krebs, M.U. Triller, H. Rabeneck, Z.
Anorg. Allg. Chem. 628 (2002) 71–82.
potassium amide and KMnO
hexane–ethylacetate, 2:1; intermediate air-drying of the plate)
isolated were:
Amine 21 (0.027 g, 12%); m.p. 236–238 8C (benzene). Anal.
calcd for C : C, 54.2; H, 2.9; F, 28.8; N, 14.1; found: C, 54.6;
4
(Table 1, entry 17), by 3-fold TLC
(
[8] L.Yu. Safina, G.A. Selivanova, I.Yu. Bagryanskaya, V.D. Shteingarts, Russ. Chem.
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(b) F.W. Bergstrom, J. Am. Chem. Soc. 56 (1934) 1748–1751;
9 5 3 2
H F N
[
H, 2.5; F, 28.8; N, 14.1.
Amine 22 (0.014 g, 6%); m.p. 171.0–173.5 8C (EtOH–H
2
O, 1:1).
+
(c) F.W. Bergstrom, J. Org. Chem. 2 (1937) 411–430;
HRMS (EI): m/z [M] calcd. for C
9
H
5
F
3
N
2
: 198.0399; found:
(d) H. Tondys, H.C. Van der Plas, M. Wozniak, J. Heterocycl. Chem. 22 (1985) 353–
1
98.0400.
355;
(
(
e) M. M a˛ kosza, K. Wojciechowski, Chem. Rev. 104 (2004) 2631–2666;
f) M. M a˛ kosza, Synthesis (2011) 2341–2356.
5
.8. 5,7-Difluoro-6-methylquinoline (24)
[
[
[
11] A.A. Shtark, T.V. Chuikova, G.A. Selivanova, V.D. Shteingarts, Zh. Org. Khim. 23
1987) 2574–2580;
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(
Separation by 5-fold TLC (hexane–CH
2 2
Cl , 1:2) of the mixture,
(
obtained after interaction quinoline 5 with sodium amide and CH
3
I
(
Table 1, entry 18), gave methylquinoline 24 (0.079 g, 39%); m.p.
4
C
9–50 8C (sublimation 40–50 8C/10 mmHg). Anal. calcd for
N: C, 67.0; H, 3.9; F, 21.2; N, 7.8; found: C, 67.0; H, 3.9;
10 7 2
H F
F, 21.2; N, 8.0.
3
16.
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