Nucleophilic substitutions in 6,7-difluoroquinoxalines

Article abstract of DOI:10.1016/S0022-1139(00)00345-6

The reactions of 6,7-difluoroquinoxalines with a number of nucleophiles, such as cycloalkylimines, hydrazine, sodium hydroxide and alkoxides have been shown to result in substitution of either one or two fluoro atoms depending on the nature of nucleophiles.

Full text of DOI:10.1016/S0022-1139(00)00345-6

Journal of Fluorine Chemistry 107 (2001) 71±80
Nucleophilic substitutions in 6,7-di¯uoroquinoxalines
V.N. Charushina,*, G.A. Mokrushinaa, A.V. Tkachevb
aOrganic Chemistry Department, Urals State Technical University, 620002 Ekaterinburg, Russia
bNovosibirsk Institute of Organic Chemistry, Acad. Lavrentjev Ave. 9, Novosibirsk 630090, Russia
Received 25 May 2000; accepted 6 September 2000
Abstract
The reactions of 6,7-di¯uoroquinoxalines with a number of nucleophiles, such as cycloalkylimines, hydrazine, sodium hydroxide and
alkoxides have been shown to result in substitution of either one or two ¯uoro atoms depending on the nature of nucleophiles.
# 2001 Elsevier Science B.V. All rights reserved.
Keywords: Fluoroquinoxalines; Synthesis; 1H, 13C and 19F NMR
1. Introduction
(bromo, iodo) quinoxalines with hydroxyl-amine in the
presence of sodium methoxide gave the corresponding 5-
amino derivatives, while amination of 6-nitro-7-¯uoroqui-
noxaline under the same conditions was accompanied by the
displacement of the 7-¯uorine atom with the methoxy group
yielding two products, i.e. 5-amino-6-nitro-7-¯uoroquinoxa-
line and 5-amino-7-methoxy-6-nitroquinoxaline (65%)
[9±11].
The ability of ¯uorine atoms in 6,7-di¯uoroquinoxaline to
undergo nucleophilic displacement reactions has not pre-
viously been studied, although an enhanced reactivity of
¯uoroaromatics towards nucleophiles is a well-recognised
phenomenon [12].
Many organic molecules containing the quinoxaline moi-
ety are known to be biologically active compounds [1,2]. In
particular, 6,7-dialkoxy derivatives proved to inhibit tyro-
sine kinase of some receptors [3,4], while 6,7-dialkyl
(alkoxy, halogeno or cyano) substituted 5-nitroquinoxalines
are active as glycine receptor antagonists [5]. A series of
condensed quinoxalines have been patented as anticancer
compounds [6].
Substituted quinoxalines of different types are usually
prepared by: (1) condensation reactions of the correspond-
ing ortho-phenylenediamines with 1,2-dioxo compounds or
(2) by electrophilic or nucleophilic substitution in the qui-
noxaline nucleus. Substituted ortho-phenylenediamines are
not always readily accessible, so introduction of a substi-
tuent into the pyrazine or benzene moiety of quinoxalines is
more attractive. Nucleophilic substitution in halonitroqui-
noxalines has recently been described by J. Nasielski and co-
workers [7±11], who have shown that results of the reaction
of 5-chloro-6-nitroquinoxaline with nucleophiles depend on
the nature of the nucleophilic reagents [7]. Thus, the reaction
of 5-chloro-6-nitroquinoxaline with piperidine results in
substitution of the chlorine atom, while in the reaction with
sodium methoxide two products are formed, i.e. 5-methoxy-
6-nitroquinoxaline and of 5-chloro-6-methoxyquinoxaline
(5%). The reaction of 5-chloro-6-nitroquinoxaline with
para-thiocresol affords 5,6-diarylthio substituted quinoxa-
line as the only product [8]. Amination of 6-nitro-7-chloro
2. Results and discussion
In this paper we wish to report the results of our studies on
the reactivity of 6,7-di¯uoroquinoxaline (1) and 2-methyl-
6,7-di¯uoroquinoxaline (9) towards amines, hydrazine
hydrate, aqueous sodium hydroxide and alcoholic solutions
of potassium hydroxide.
In the reactions of (1) with amines the ability of the
¯uorine atoms to undergo displacement reactions has been
found to depend greatly on the nature of nucleophiles.
Highly nucleophilic pyrrolidine and hydrazine hydrate react
with (1) easily on 1 h re¯ux in acetonitrile or ethanol
affording 6-¯uoro-7-pyrrolidino- (2) and 6-¯uoro-7-hydra-
zino (5) derivatives in high yields (Table 1). Morpholine and
thiomorpholine react with (1) in acetonitrile (re¯ux for 3 h)
only in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) (Scheme 1 and Table 1). All our attempts to carry out
* Corresponding author. Fax: ‡7-3432-74-54-40.
E-mail address: charushin@prm.uran.ru (V.N. Charushin).
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 3 4 5 - 6

72
V.N. Charushin et al. / Journal of Fluorine Chemistry 107 (2001) 71±80
Table 1
attack in the substitution of the second ¯uorine atom
(Scheme 2 and Table 1).
Yields of products in the reactions of 6,7-difluoroquinoxaline (1) with
nucleophiles
Primary linear alcohols (methanol, ethanol, n-propanol,
n-butanol) cause the displacement of both ¯uorine atoms,
yielding 6,7-dialkoxyquinoxalines (8a±d) as the major pro-
ducts together with minor 6-¯uoro-7-alkoxy-quinoxalines
(7a±d) formed in 5±11% yields. In the reaction of (1) with
iso-butanol the yield of the mono-substitution product (7e) is
in the same range (ꢁ7%), the reaction with iso-propanol
results in a 1:3 mixture of mono- and disubstituted products
(7f) and (8f), while the reaction of (1) with sec-butanol
affords mainly the mono-substitution product, i.e. 6-¯uoro-
7-(1-methylpropoxy)quinoxaline (7g) in 68% yield. 2,2,3,3-
Tetra¯uoropropanol, which is less nucleophilic and more
bulky as compared with propanol, transforms the substrate
into mono- and disubstitution products (7h) and (8h). The
same behaviour occurs for 2,2,2-tri¯uoroethanol affording
only the mono-substitution product (7i) in 20% yield
(Table 1). The products (8a±d), (7f±h) and (8f) were isolated
as individual compounds, while (7a±d), (7e), (7i) and (8h)
Nucleophile
Preparative and NMRa yields (%)
Mono-substitution
product
Disubstitution
product
Pyrrolidine
(2) 87
(3) 77
±
Morpholine
±
Thiomorpholine
Hydrazine hydrate
Sodium hydroxide
Methanol
(4) 72
(5) 84
±
±
(6) 67
±
(7a) 5a
(7b) 5a
(7c) 11a
(7d) 10a
(7e) 7a
(7f) 18
(7g) 68
(7h) 44 ‡ 5a
(7i) 20a
(8a) 69 ‡ 3a
(8b) 65 ‡ 2a
(8c) 66a
(8d) 68 ‡ 2a
(8e) 58 ‡ 7a
(8f) 54
Ethanol
n-Propanol
n-Butanol
iso-Butanol
iso-Propanol
sec-Butanol
±
2,2,3,3-Tetrafluoropropanol
2,2,2-Trifluoroethanol
(8h) 25a
±
a Determined by 1H NMR.
1
were merely identi®ed from the H and 19F NMR spectra
substitution of a ¯uorine atom in (1) with aniline, benzyla-
mine or diethylamine (even in the presence of DBU) failed
and resulted in isolation of the starting material (1). On the
other hand, a ¯uorine atom in (1) is easily displaced with the
hydroxy group on 1 h re¯ux in 2 N aqueous sodium hydro-
xide to give 6-¯uoro-7-hydroxyquinoxaline (6) in 67% yield
(Scheme 1).
(Tables 1 and 2).
We tried to estimate the transfer of electronic effects of
substituents in the pyrazine ring and their in¯uence on the
ability of both ¯uorine atoms in the benzene ring to be
displaced by nucleophiles. To do that we studied the reac-
tions of 2-methyl-6,7-di¯uoroquinoxaline (9), bearing the
methyl group as the simplest inductive (‡I) substituent with
pyrrolidine, hydrazine hydrate, aqueous sodium hydroxide
and alcohols in the presence of potassium hydroxide.
In contrast to 6,7-di¯uoroquinoxaline, compound (9)
reacts with pyrrolidine only in the presence of 1,8-diazabi-
cyclo[5.4.0]undec-7-ene, yielding a mixture containing two
isomeric mono-substitution products (10a) and (11a) and the
starting material (9) (4.5:1:1.7, determined by intensities of
Structures of 6-¯uoro-7-substituted quinoxalines (2±6)
1
1
were proved by H and 19F NMR. In the H NMR spectra
of (2±6), the doublets of the H5 and H8 atoms are very
characteristic due to speci®c coupling constants 3J(H5±F6)
and 4J(H8±F6) (Table 2). Two doublets of H2 and H3 atoms
of the pyrazine ring demonstrate the coupling constants
3JꢀH2 H3† ˆ 2:1 2:3 Hz which are typical for pyrazines
[13].
1
H3 resonances at 8.86, 8.59 and 8.45 ppm in the H NMR
The reaction of 6,7-di¯uoroquinoxaline (1) with alcohols
(used as solvents) in the presence of potassium hydroxide is
controlled mainly by steric hinderance for nucleophilic
spectra). The reaction of 2-methylquinoxaline (9) with
hydrazine hydrate is also non-regio-selective and results
in two isomeric hydrazino derivatives (10b) and (11b)
Scheme 1

Table 2
1H NMR spectral data for 6,7-disubstituted quinoxalines in DMSO-d6
Compound R6
R7
Chemical shifts (d) (ppm)
Coupling constants (Hz)
H2
H3
H5
H8
R6 (R7)
3J(H2±H3) 4J(H5±F6)
4J(H8±F6)
(2)
(3)
F
Pyrrolidino
Morpholino
Thiomorpholino
Hydrazino
OH
8.65 da
8.84 da
8.83 da
8.67 da
8.79 da
8.87 da
8.69 s
8.53 da
8.77 da
8.76 da
8.54 da
8.73 da
8.81 da
8.69 s
7.70 d
7.81 d
7.84 d
7.61 d
7.82 d
7.87 d
7.40 s
7.87 d
7.37 s
7.88 d
7.37 s
7.73 d
7.37 s
7.86 d
7.35 s
7.85 d
7.40 s
7.87 d
7.02 d
7.49 d
7.52 d
7.42 d
7.45 d
7.65 d
7.40 s
7.46 d
7.37 s
7.63 d
7.37 s
7.63 d
7.37 s
7.70 d
7.35 s
7.64 d
7.40 s
7.66 d
3.52 (m, 4H, NCH2), 1.96 (m, 4H, CH2)
3.83 (m, 4H, OCH2), 3.22 (m, 4H, NCH2)
3.48 (m, 4H, SCH2), 2.83 (m, 4H, NCH2)
4.35 (s br, 2H,NH), 3.31 (s br, 1H, NH)
11.15 (s, 1H, OH)
2.0
2.0
2.0
2.0
2.0
2.3
±
13.3
13.7
12.7
12.7
13.3
11.8
±
9.0
9.2
9.1
9.1
9.0
9.0
±
F
(4)
(5)
F
F
(6)
F
(7a)
(8a)
(7b)
(8b)
(7c)
(8c)
(7d)
(8d)
(7e)
(8e)
(7f)
(8f)
(7g)
F
OCH3
OCH3
OCH3
4.05 (s, 3H, CH3)
3.97 (s, 6H, CH3)
F
OC2H5
8.84 da
8.78 da
4.26 (dd, 2H, CH2), 1.35 (t, 3H, CH3)
4.24 (dd, 4H, CH2), 1.45 (t, 6H, CH3)
4.25 (t, 2H, OCH2), 1.90 (m, 2H, CH2), 1.12 (t, 3H, CH3)
4.11 (t, 4H, OCH2), 1.90 (m, 4H, CH2), 1.12 (t, 6H, CH3)
4.15 (t, 2H, OCH2), 1.67 (m, 4H, CH2), 0.97 (t, 3H, CH3)
4.15 (t, 4H, OCH2), 1.67 (m, 8H, CH2), 0.97 (t, 6H, CH3)
3.67 (d, 2H, OCH2), 2.20 (m, 1H, CH), 1.35 (d, 6H, CH3)
3.98 (d, 4H, OCH2), 2.25 (m, 2H, CH), 1.10 (d, 12H, CH3)
5.0 (m, 1H, CH), 1.46 (d, 6H, CH3)
2.3
11.9
8.8
OC2H5
OC2H5
8.67 s
8.86 da
8.67 s
8.85 da
8.67 s
8.84 da
8.67 s
8.80 da
F
O(CH2)2CH3
O(CH2)2CH3
O(CH2)2CH3
O(CH2)3CH3
O(CH2)3CH3
OCH2CH(CH3)2
2.14
2.2
2.1
2.1
2.2
1.8
1.8
11.9
11.9
11.7
11.7
11.8
11.6
11.6
8.8
8.9
8.9
8.8
8.9
8.9
8.9
F
O(CH2)3CH3
F
8.68 s
6.82 da
8.66 s
8.85 da
8.68 s
8.75 da
8.66 s
8.79 da
OCH2CH(CH3)2 OCH2C(CH3)2
F
OCH(CH3)2
OCH(CH3)2
F
OCH(CH3)2
OCH(CH3)CH2CH3 8.86 da
8.67 s
8.67 s
8.80 da
4.82 (m, 2H, CH), 1.37 (d, 12H, CH3)
4.75 (m, 1H, CH), 1.80 (m, 2H, CH2), 1.33 (d, 3H, CH3),
1.07 (t, 3H, CH3)
(7h)
(8h)
(7i)
F
OCH2(CF2)2H
OCH2(CF2)2H
OCH2CF3
8.90 da
8.80 s
8.91 da
8.87 da
8.80 s
8.86 da
7.95 d
7.72 s
7.96 s
7.90 d
7.72 d
7.89 s
6.65 (m, 1H, CH), 4.95 (m, 2H, CH2)
6.60 (m, 2H, CH), 4.85 (m, 4H, CH2)
5.12 (m, 2H, CH2)
OCH2(CF2)2H
F
a The assignments might be interchanged.

74
V.N. Charushin et al. / Journal of Fluorine Chemistry 107 (2001) 71±80
Scheme 2. R ˆ methyl (a); ethyl (b); n-propyl (c); n-butyl (d); iso-butyl (e); iso-propyl (f); sec-butyl (g); 2,2,3,3-tetrafluropropyl (h); 2,2,2-trifluoroethyl (i).
1
(6:1, according to the H NMR spectra, see Table 3 and
Scheme 3).
neither 5J(C3±F6) nor 5J(C2±F7) are observed in the spectra
(Table 4). The latter is also substantiated by the 13C NMR
spectra of 2-methyl-6-¯uoro-7-ethoxyquinoxaline (12a): the
coupling 6J(C2±F6) is just the same (3.2 Hz) with no
coupling between C3 and F6 (Table 4 and Scheme 5).
Another important feature of the 13C NMR spectrum of
(12a) is that the carbon C4a is coupled with both H3 and F6:
3JꢀC4a H3† ˆ 10:8 and 3JꢀC4a F6† ˆ 11:8 Hz, which
enable us to make unequivocal assignments of the ring
junction carbon resonances as well as to establish the
position of substituents in the benzene ring (Scheme 5).
It should be noted that similar values for 3J(C4a±F6)
have been measured in the 13C NMR spectra of a number
of 6-¯uoroquinoxalines, such as 6-¯uoro-7-morpholinoqui-
noxaline (12.0 Hz), 6-¯uoro-7-thiomorpholinoquinoxaline
(11.3 Hz), and 1-ethyl-6-¯uoro-7-morpholinoquinoxali-
nium tetra¯uoroborate (13.0 Hz). The evidence for the
structure of the latter salt has been obtained by X-ray
analysis [14].
Heating of (9) in aqueous 2N sodium hydroxide resulted
in no reaction, however treatment of (9) with alcoholic
solutions of potassium hydroxide gave mono- and disub-
stitution products (Scheme 4).
The reaction of (9) with ethanol yielded isomeric mono-
substitution products (12a) and (13a) ca. 6:1 (87% overall
yield) and diethoxy derivative (14a) (13% yield). The reac-
tion of (9) with 2,2,3,3-tetra¯uoropropanol gave mono-
substitution product (12b) in 40% yield, while 2,2,2-tri¯uor-
oethanol did not react with the substrate (9).
These experimental data indicate that C6 and C7 carbon
atoms in 2-methyl-6,7-di¯uoroquinoxaline (9) differ signif-
icantly towards nucleophilic attack: the ¯uorine F7 is more
easily displaced by nucleophiles than F6, yielding predo-
minantly 6-¯uoro-7-alkoxy substituted 2-methylquinoxa-
lines. Evidence for the structure of (12a) was provided by
13C NMR spectra (Table 4). Two resonances, C2 and C3, in
the 13C NMR spectrum of 2-methyl-6,7-di¯uoroquinoxaline
In conclusion, it is worth to note that when using nucleo-
philic displacement reactions for structural modi®cations
of 6,7-di¯uoroquinoxalines, one should realise that these
reactions are rather sensitive to both electronic effects of
(9) can be easily distinguished (1JC3
feature of this system is the existence of long-range cou-
plings 6J(C2±F6) and 6J(C3±F7) (3.2 Hz both), while
ˆ 181:8 Hz). The
H3
Scheme 3. Nu ˆ pyrrolidino (a); hydrazino (b).
Scheme 4. R ˆ ethyl (a); 2,2,3,3-tetrafluoropropyl (b).

Table 3
1H NMR spectral data for 2-methyl-6,7-disubstituted quinoxalines in DMSO-d6
Compound
R6
R7
Chemical shifts (d) (ppm)
Coupling constants (Hz)
C2±CH3
H3
H5
H8
R6 (R7)
3J (H5±F6)
4J (H8±F6)
4J (H5±F7)
4J (H8±F7)
(9)
F
F
Pyrrolidino
2.73
2.70
2.67
2.60
2.51
2.65
2.66
2.66
2.68
2.61
8.68
8.59
8.45
8.45
8.59
8.76
8.75
8.76
8.80
8.58
7.81a
7.55
7.54
7.54
7.50
7.81
7.77
7.87
7.89
7.32
7.72a
6.92
6.98
7.36
7.42
7.63
7.53
7.78
7.80
7.29
11.1
14.9
±
8.0
9.5
±
7.6
±
11.2
±
(10a)
(11a)
(10b)
(11b)
(12a)
(13a)
(12b)
(13b)
(14a)
F
3.49 (m, 4H, NCH2), 1.97 (m, 4H, CH2)
3.25 (m, NCH2), 2.46 (m, CH2)
4.30 (br, s, NH), 3.30 (br, s, NH),
4.30 (br, s, NH), 3.30 (br, s, NH),
4.24 (dd, 2H, CH2), 1.45 (t, 3H, CH3)
4.44 (dd, 2H, CH2), 1.43 (t, 3H, CH3)
6.62 (m, CH), 4.86 (m, CH2)
Pyrrolidino
F
14.9
±
9.5
±
F
NHNH2
12.7
±
8.9
±
NHNH2
F
F
OC2H5
13.0
±
8.8
±
11.3
±
7.6
±
OC2H5
F
F
8.8
±
11.9
±
OCH2(CF2)2H
F
11.6
±
9.2
±
OCH2(CF2)2H
OC2H5
6.62 (m, CH), 4.86 (m, CH2)
9.1
±
11.6
±
OC2H5
4.44 (dd, 4H, CH2), 1.43 (t, 6H, CH3)
±
±
a The assignments might be interchanged.

76
V.N. Charushin et al. / Journal of Fluorine Chemistry 107 (2001) 71±80
Table 4
13C NMR spectral data for some quinoxalines in CDCl3
Characteristics
Compounds
d (ppm)
nJ (Hz)
7h
9
12a
C2
144.56
183.1
11.2
154.03
±
152.87
±
1J(C2±H2)
2J(C2±H3)
6J(C2±F6)
10.0
3.2
10.2
3.2
3.1
C3
C5
144.03
183.4
11.3
145.97
181.8
±
143.85
1J(C3±H3)
2J(C3±H2)
6J(C3±F7)
181.1
±
±
3.2
114.08
167.2
18.2
±
114.78a
167.7
17.1
1.7
112.96
165.6
18.5
±
1J(C5±H5)
2J(C5±F6)
3J(C5±F7)
4J(C5±H8)
±
1.5
±
C6
C7
C8
C1a
154.05
258.1
6.0
151.58
255.2
6.0
153.96
255.3
5.9
1J(C6±F6)
2J(C6±H5)
3J(C6±F7)
4J(C6±H8)
±
16.2
9.0
±
10.1
10.2
148.49
152.29
256.2
6.1
150.36
1J(C7±F7)
2J(C7±H8)
2J(C7±F6)
3J(C7±H5)
±
±
b
b
b
b
14.5
15.9
9.1
b
110.54
164.4
±
114.33a
167.8
17.2
1.6
108.64
162.5
±
1J(C8±H8)
2J(C8±F7)
3J(C8±F6)
4J(C8±H5)
2.0
2.9
±
1.5
±
140.83
3.2
139.35
b
140.37
2J(C1a±H8)
3J(C1a±H2)
3J(C1a±F7)
3J(C1a±H5)
2.9
±
9.8
±
±
10.9
±
b
6.5
6.5
C4a
139.53
2.9
138.01
b
136.39
2.7
2J(C4a±H5)
3J(C4a±H3)
3J(C4a±F6)
3J(C4a±H8)
b
11.2
11.5
6.4
10.8
12.3
11.8
b
6.7
22.38 (CH3), 14.32, 64.81 (OC2H5)
Others
22.34 (CH3)
a The assignments might be interchanged.
b Difficult to measure due to overlap of multiplets.
substituents which are present even in the pyrazine ring as
well as to nucleophilic character and effective volume of the
reagents.
3. Experimental
1
Melting points are uncorrected. H, 13C and 19F NMR
spectra were recorded in DMSO-d6 or CDCl3 solutions (1±
5 wt.%) using a Bruker WP-80 (80 MHz for 1H, 75 MHz for
19F) and a Bruker DRX-500 (500 MHz for 1H, 125 MHz for
13C) spectrometers. Chemical shifts are given in ppm and
were calculated for proton and carbon spectra relative to
Scheme 5

V.N. Charushin et al. / Journal of Fluorine Chemistry 107 (2001) 71±80
77
C
H
N
the solvent signals used as the internal standards: CDCl3
Calculated for C12H12FN3S
Found
57.81
57.49
4.85
4.69
16.85
16.85
(dH ˆ 7:240, dC ˆ 76:900), DMSO-d6 (dH ˆ 2:500,
dC ˆ 39:500), whereas ¯uorine chemical shifts were deter-
mined by using addition of hexa¯uorobenzene as the inter-
nal standard (dF ˆ 0:000). Fluorine resonances were taken
from proton coupled spectra.
3.4. Preparation of 6-fluoro-7-hydrazinoquinoxaline (5)
6,7-Di¯uoroquinoxaline (1) (332 mg; 0.002 mol) was
added to a solution of hydrazine hydrate (98%) (0.6 ml;
0.012 mol) in ethanol (5 cm3) and the reaction mixture was
re¯uxed for 0.5 h to produce yellow crystals. The mixture
was cooled to room temperature, and the crystals were
isolated by ®ltration followed by recrystallisation from
ethanol to give 6-¯uoro-7-hydrazinoquinoxaline (5),
(300 mg; 84%) mp 2258C (decomp.). 19F NMR (DMSO):
d, 125.8 (ddd, F6, JF±H ˆ 12:7 and 9.1 Hz, JF NH ˆ
1:8 Hz) ppm.
3.1. Preparation of 6-fluoro-7-pyrrolidinoquinoxaline (2)
Pyrrolidine (284 mg; 0.33 cm3; 0.004 mol) was added
to a solution of 6,7-di¯uoroquinoxaline (1) (332 mg;
0.002 mol) in acetonitrile (5 cm3) and the mixture was
re¯uxed for 1 h, cooled to room temperature and poured
into water (20 cm3). The precipitate was separated by ®ltra-
tion and recrystallised from 50% aqueous ethanol to give 6-
¯uoro-7-pyrrolidinoquinoxaline (2), (380 mg; 87%) mp 88±
898C. 16F NMR (DMSO): d, 117.95 (dd, F6, J ˆ 13:3 and
9.0 Hz) ppm.
C
H
N
Calculated for C8H7FN4
Found
53.93
53.72
3.96
4.11
31.45
31.60
C
66.34
66.45
H
5.57
5.68
N
19.34
19.03
Calculated for C12H12FN3
Found
3.5. Preparation of 6-fluoro-7-hydroxyquinoxaline (6)
6,7-Di¯uoroquinoxaline (1) (1.66 g; 0.01 mol) was added
to a 2N solution of NaOH (10 cm3), the reaction mixture was
re¯uxed for 1 h, cooled to room temperature, and treated
with acetic acid to adjust pH to 6±7. The precipitate obtained
was separated by ®ltration. Recrystallisation from ethanol
gave 6-¯uoro-7-hydroxyquinoxaline (6), (1.1 g; 67%) mp
220±2308C (decomp.). 19F NMR (DMSO): d, 127.0 (dd,
F6, J ˆ 13:3 and 9.0 Hz) ppm.
3.2. Preparation of 6-fluoro-7-morpholinoquinoxaline (3)
Morpholine (390 mg; 0.3 cm3; 0.004 mol) was added to a
solution of 6,7-di¯uoroquinoxaline (1) (332 mg; 0.002 mol)
and DBU (610 mg; 0.6 cm3; 0.002 mol) in acetonitrile
(5 cm3) and the reaction mixture was re¯uxed for 3 h, cooled
to room temperature and treated with acetic acid to adjust pH
6±7 and extracted with dichloromethane. The combined
extracts were dried over anhydrous Na2SO4 and ®ltered.
Removal of the solvent gave a solid which was recrystallised
from water to give 6-¯uoro-7-morpholinoquinoxaline (3),
(360 mg; 77%) mp 103±1048C (lit. mp 101±1028C [14]. 19F
NMR (DMSO): d, 116.18 (dd, F6, J ˆ 13:7 and 9.2 Hz)
ppm.
C
H
N
Calculated for C8H5FN2O
Found
58.54
57.86
3.07
3.01
17.07
16.90
3.6. Reaction of 6,7-difluoroquinoxaline (1) with alcohols
in the presence of potassium hydroxide
3.6.1. Methanol
C
H
N
6,7-Di¯uoroquinoxaline (1) (5 g; 0.33 mol) was added to
a solution of KOH (5 g; 0.89 mol) in methanol (60 cm3) and
the reaction mixture was re¯uxed for 1 h. The solvent was
distilled off and the solid residue was suspended in cold
water (20 cm3), ®ltered off and dried. Recrystallisation from
acetic acid gave 6,7-dimethoxyquinoxaline (8a), (4.3 g;
69%) mp 148±1498C (lit. mp 150±1518C [15]).
Calculated for C12H12FN3O
Found
61.79
61.76
5.19
5.20
18.02
18.20
3.3. Preparation of 6-fluoro-7-thiomorpholinoquinoxaline
(4)
Thiomorpholine (412 mg; 0.4 cm3; 0.04 mol) was added
to a mixture of 6,7-di¯uoroquinoxaline (1) (332 mg;
0.002 mol) and DBU (610 mg; 0.6 cm3; 0.02 mol) in acet-
onitrile (5 cm3) and the reaction mixture was re¯uxed for
5 h, cooled to room temperature and poured into water
(20 cm3). The crystalline precipitate was isolated by ®ltra-
tion. Recrystallisation from 50% aqueous ethanol gave 6-
¯uoro-7-thiomorpholinoquinoxaline (4), (360 mg; 72%) mp
111±1138C. 19F NMR (DMSO): d, 131.5 (dd, F6 J ˆ 12:7
and 9.1 Hz) ppm.
C
H
N
Calculated for C10H10N2O2
Found
63.15
63.29
5.30
5.36
14.73
14.84
The mother liquor was evaporated to dryness to give a
solid (0.45 g) containing additional 6-¯uoro-7-methoxyqui-
noxaline (7a) and 6,7-dimethoxyquinoxaline (8a) in the
ratio 1.5:1 (1H NMR). Overall yields of (7a) and (8a) are
given in Table 1. 19F NMR of (7a) (DMSO): d, 128.55 (dd,
F6, J ˆ 11:8 and 8.9 Hz) ppm.

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V.N. Charushin et al. / Journal of Fluorine Chemistry 107 (2001) 71±80
3.6.2. Ethanol
cold water (20 cm3), ®ltered off and dried. Recrystallisation
from ethanol gave 6,7-di(2-methylpropoxy)quinoxaline
(8e), (5.3 g; 58%) mp 57±588C.
6,7-Di¯uoroquinoxaline (1), (5 g; 0.33 mol) was added
to a solution of KOH (5 g; 0.89 mol) in ethanol (60 cm3)
and the reaction mixture was re¯uxed for 1 h. Cooling
to room temperature resulted in a solid which was
isolated by ®ltration. Recrystallisation from acetonitrile
(20 cm3) gave 6,7-diethoxyquinoxaline (8b), (4.7 g; 65%)
mp 125±1268C.
C
H
N
Calculated for C16H22N2O2
Found
70.04
69.86
8.08
8.00
10.21
10.14
The mother liquor was evaporated to dryness to give a
solid (1.3 g) containing additional 6-¯uoro-7-(2-methylpro-
poxy)quinoxaline (7e) and 6,7-di(2-methylpropoxy)qui-
noxaline (8e) in the ratio 1:1 (from 1H NMR spectra).
Overall yields of (7e) and (8e) are given in Table 1.
C
66.03
66.45
H
6.47
6.68
N
12.80
13.03
Calculated for C12H14N2O2
Found
The mother liquor was evaporated to dryness to give a
solid (0.55 g) containing 6-¯uoro-7-ethoxyquinoxaline (7b)
and 6,7-diethoxyquinoxaline (8b) in the ratio 2.5:1 (from 1H
NMR spectra). Overall yields of (7b) and (8b) are given in
Table 1. 19F NMR of (7b) (DMSO): d, 126.95 (dd, F6,
J ˆ 11:8 and 8.7 Hz) ppm.
3.6.6. iso-Propanol
6,7-Di¯uroquinoxaline (1) (5 g; 0.33 mol) was added to a
solution of KOH (5 g; 0.89 mol) in iso-propanol (60 cm3)
and the reaction mixture was re¯uxed for 1 h. Evaporation of
the solvent under reduced pressure left a solid which was
suspended in cold water (20 cm3), ®ltered off, dried and
recrystallised from acetonitrile to give 6-¯uoro-7-(iso-pro-
poxy)quinoxaline (7f), (1.2 g; 18%) mp 97±988C.
3.6.3. n-Propanol
6,7-Di¯uoroquinoxaline (1) (5 g; 0.33 mol) was added to
a solution of KOH (5 g; 0.89 mol) in n-propanol (60 cm3).
Evaporation of the solvent to dryness left a solid which was
suspended in a cold water (20 cm3), ®ltered off and dried.
Recrystallisation from 30% ethanol gave a mixture of
6-¯uoro-7-propoxyquinoxaline (7c) and 6,7-dipropoxyqui-
noxaline (8c) in the ratio 1:6 (from 1H NMR spectra).
Yields of (7c) and (8c) are given in Table 1. 19F NMR of
(7c) (DMSO): d, 127.35 (dd, F6, J ˆ 11:8 and 8.0 Hz)
ppm.
C
68.27
68.45
H
7.36
7.68
N
11.38
11.70
Calculated for C14H18N2O2
Found
19F NMR of (7f) (DMSO): d, 126.35 (dd, F6, J ˆ 11:8
and 8.9 Hz) ppm.
Evaporation of acetonitrile from the mother liquor left a
solid which was recrystallised from aqueous 50% ethanol to
give 6,7-di(iso-propoxy)quinoxaline (8f), (4.4 g; 54%) mp
63±648C.
C
68.27
68.45
H
7.36
7.68
N
11.38
11.70
3.6.4. n-Butanol
Calculated for C14H18N2O2
Found
6,7-Di¯uoroquinoxaline (1) (5 g; 0.33 mol) was added to
a solution of KOH (5 g; 0.89 mol) in n-butanol (60 cm3) and
the reaction mixture was re¯uxed for 1 h. Evaporation of the
solvent under reduced pressure left a solid, which was
suspended in cold water (20 cm3), ®ltered off and dried.
Recrystallisation from acetonitrile gave 6,7-dibutoxyqui-
noxaline (8d), (6.2 g; 68%) mp 70±718C (lit. mp 65±
678C [16]).
3.6.7. sec-Butanol
6,7-Di¯uoroquinoxaline (1) (5 g; 0.33 mol) was added to
a solution of KOH (5 g; 0.89 mol) in sec-butanol (60 cm3)
and the reaction mixture was re¯uxed for 1 h. Evaporation of
the solvent left a solid which was suspended in cold water
(20 cm3), ®ltered off, dried and recrystallised from aqueous
50% ethanol to give 6-¯uoro-7-(1-methylpropoxy)quinoxa-
line (7g), (4.8 g; 68%) mp 51±528C.
C
70.04
69.96
H
8.08
8.26
N
10.21
10.20
Calculated for C16H22N2O2
Found
C
65.44
65.52
H
5.95
5.83
N
12.73
12.78
The mother liquor was evaporated to dryness to give a
solid (1.3 g) containing 6-¯uoro-7-ethoxyquinoxaline (7d)
and 6,7-diethoxyquinoxaline (8d) in the ratio 5:1 (from H
Calculated C12H13FN2O
Found
1
NMR spectra). Overall yields of (7d) and (8d) are given in
Table 1. 19F NMR (DMSO): d, 127.18 (dd, F6, J ˆ 11:8
and 8.9 Hz) ppm.
19F NMR of (7g) (DMSO): d, 127.35 (dd, F6, J ˆ 11:8
and 8.9 Hz) ppm.
3.6.5. iso-Butanol
3.6.8. 2,2,3,3-Tetrafluoropropanol
6,7-Di¯uoroquinoxaline (1) (5 g; 0.33 mol) was added to
a solution of KOH (5 g; 0.89 mol) in iso-butanol (60 cm3)
and the reaction mixture was re¯uxed for 1 h. Evaporation of
the solvent to dryness left a solid which was suspended in
6,7-Di¯uoroquinoxaline (1) (5 g; 0.33 mol) was added to
a solution of KOH (5 g; 0.89 mol) in 2,2,3,3-tetra¯uoropro-
panol (60 cm3) and the reaction mixture was re¯uxed for 1 h.
Evaporation of the solvent left a solid which was recrys-

V.N. Charushin et al. / Journal of Fluorine Chemistry 107 (2001) 71±80
79
tallised from iso-propanol to give 6-¯uoro-7-(2,2,3,3-
tetra¯uoropropoxy)quinoxaline (7h), (4.0 g; 44%), mp
125±1268C.
3.8.2. Hydrazine hydrate
6,7-Di¯uoro-2-methylquinoxaline (9) (300 mg; 0.00168
mol) was added to a solution of hydrazine hydrate (98%)
(0.6 ml; 0.012 mol) in ethanol (5 cm3) and the mixture was
re¯uxedfor2 htoformyellowcrystals.Themixturewascooled
toroomtemperatureandthecrystallineprecipitatewas®ltered
off and recrystallised from ethanol to give a mixture of 6-
¯uoro-7-hydrazino-2-methylquinoxaline (10b) and 6-hydra-
zino-7-¯uoro-2-methylquinoxaline (11b) in the ratio 6:1
C
49.33
49.52
H
3.10
3.23
N
9.59
9.45
Calculated for C11H7F5N2O
Found
19F NMR (DMSO): d, 126.35 (dd, 1F, F6, J ˆ 11:6,
8.9 Hz), 124.85 (br, 2F), 138.65 (dd, 1F), 139.32 (br,
1F) (CH2CF2CF2H) ppm.
1
The mother liquor was evaporated to dryness to give a
solid (3.4 g) containing 6-¯uoro-7-(2,2,3,3-tetra¯uoropro-
poxy)quinoxaline (7h) and 6,7-di(2,2,3,3-tetra¯uoropropox-
(from H and 19F NMR spectra) (250 mg; 78%).
C
56.24
56.72
H
4.72
4.51
N
29.15
29.45
Calculated for C9H9FN4
Found
1
y)quinoxaline (8h) in the ratio 1:5 (from H and 19F NMR
spectra).
19F NMR (DMSO): d, 127.85 (br) (10b), 126.48 (br)
(11b) ppm.
3.6.9. 2,2,2-Trifluoroethanol
6,7-Di¯uoroquinoxaline (1) (5 g; 0.33 mol) was added to
a solution of KOH (5 g; 0.89 mol) in 2,2,2-tri¯uoroethanol
(60 cm3) and the reaction mixture was re¯uxed for 1 h,
evaporated to dryness to gave solid, containing starting
6,7-di¯uoroquinoxaline (1) and 6-¯uoro-7-(2,2,2-tri¯uor-
oethoxy)quinoxaline (7i) in the ratio 4:1 (from 1H and
19F NMR spectra). 19F NMR (DMSO): d, 127.48 (dd,
F6, J ˆ 11:6, 8.8 Hz), 139.25 (t, 3F, CF3) ppm (7i).
3.8.3. Ethanol
6,7-Di¯uoro-2-methylquinoxaline (9) (0.5 g; 0.0028 mol)
was added to a solution of KOH (0.6 g; 0.011 mol) in
ethanol (10 cm3) and the reaction mixture was re¯uxed
for 1 h. Evaporation of the solvent left a solid which was
recrystallised from 30% ethanol to give 6-¯uoro-7-ethoxy-
2-methylquinoxaline (12a), (300 mg; 49%) mp 111±1128C.
C
H
N
3.7. Preparation of 6,7-difluoro-2-methylquinoxaline (9)
Calculated for C11H11FN2O
Found
64.07
64.25
5.38
5.58
13.58
13.43
4,5-Di¯uoro-1,2-phenylenediamine (10 g; 0,069 mol)
was added to a solution of iso-nitrosoacetone (5 g;
0.07 mol) in ethanol (20 cm3) and the reaction mixture
was re¯uxed for 15 min, cooled to room temperature and
poured into water (50 cm3). The precipitate was ®ltered off
and recrystallised from aqueous 33% ethanol to give 6,7-
di¯uoro-2-methylquinoxaline (9), (7.2 g; 60%), mp 125±
1268C. 19F NMR (DMSO): d, 135.25 (ddd, J ˆ 34:2, 11.1
and 8.0 Hz), 144.35 (ddd, J ˆ 34:2, 11.2 and 7.6 Hz)
ppm.
19F NMR (DMSO): d, 129.13 (dd, F6, J ˆ 11:6 and
8.9 Hz) ppm.
The mother liquor was evaporated to dryness to give a
solid (100 mg), containing an additional amount of 6-¯uoro-
7-ethoxy-2-methylquinoxaline (12a), 6-ethoxy-7-¯uoro-2-
methylquinoxaline (13a) and 6,7-diethoxy-2-methylqui-
1
noxaline (14a) in the ratio 2:1:1 (from H and 19F NMR
spectra). 19F NMR (DMSO): d, 129.13 (dd, F6, J ˆ 11:6
and 8.9 Hz) (12a), 129.13 (br) (13a) ppm.
C
H
N
Calculated for C9H6F2N2
Found
60.00
60.05
3.36
3.33
15.55
15.60
3.8.4. 2,2,3,3-Tetrafluoropropanol
6,7-Di¯uoro-2-methylquinoxaline (9) (0.5 g; 0.003 mol)
was added to a solution of KOH (0.6 g; 0.011 mol) in
2,2,3,3-tetra¯uoropropanol (10 cm3) and the reaction mix-
ture was re¯uxed for 1 h. Evaporation of the solvent left a
solid which was crystallised from 30% ethanol to give the
product (400 mg) containing 6,7-di¯uoro-2-methylquinoxa-
line (9), 6-¯uoro-7-(2,2,3,3-tetra¯uoropropoxy)-2-methyl-
quinoxaline (12b) and 6-(2,2,3,3-tetra¯uoropropoxy)-7-
¯uoro-2-methylquinoxaline (13b) in the ratio 4:2:1 (from
1H and 19F NMR spectra). 19F NMR (DMSO): d, 129.35
(br, t) (12b), 127.75 (br) (13b) ppm.
3.8. Reactions of 6,7-difluoro-2-methylquinoxaline with
nucleophiles
3.8.1. Pyrrolidine
Pyrrolidine (284 mg; 0.33 cm3; 0.004 mol) was added to a
solution of 6,7-di¯uoro-2-methylquinoxaline (9) (100 mg;
0.00056 mol) and DBU (100 mg; 0.1 ml; 0.0006 mol) in
acetonitrile (2 cm3) and the reaction mixture was re¯uxed
for 3 h. Evaporation of the solvent to dryness left a solid,
which was recrystallised from water to give a mixture of the
starting compound, 6-¯uoro-7-pyrrolidino-2-methylqui-
noxaline (10a) and 6-pyrrolidino-7-¯uoro-2-methylqui-
noxaline (11a) in the ratio 1:4.5:1.7 (from 1H and 19F
NMR spectra). 19F NMR (DMSO): d, 120.18 (br) (10a),
118.43 (br) (11a) ppm.
Acknowledgements
Financial support of this research by the Russian Founda-
tion for Basic Research (Grant No. 00-03-32785 and the

80
V.N. Charushin et al. / Journal of Fluorine Chemistry 107 (2001) 71±80
[5] WO 12417 (1995), C.A. 123 (1995) 314017.
[6] EP 672662 (1995), C.A. 124 (1996) 55985.
program ``Leading Scienti®c Schools''), the Russian Min-
istry of Science and Technology (Project No. 9.1.06), and
the US Civilian Research and Development Foundation for
the Independent States of the Former Soviet Union (CRDF)
(Award No. REC-005) is highly appreciated.
[7] R. Nasielski-Hinkens, M. Kaisin, D. Grendjean, et al., Bull. Soc.
Chem. Belg. 97 (1988) 919.
[8] J. Nasielski, C. Moucheron, R. Nasielski-Hinkens, Bull. Soc. Chem.
Belg. 101 (1992) 491.
[9] R. Nasielski-Hinkens, J. Kotel, T. Lecloux, J. Nasielski, Synth.
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[12] J.T. Welch, S. Eswarakrischnan, Fluorine in Bioorganic Chemistry,
Wiley, New York, 1991.
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