Synthesis of 3-Aroyl-2-(polyfluoroalkyl)quinoxalines and 3-Aroyl-2-(polyfluoroalkyl)benzo[g]quinoxalines from Lithium 3-(Fluoroalkyl)-1,3-diketonates

Article abstract of DOI:10.1134/S107042801906023X

A one-pot procedure has been developed for the synthesis of 3-aroyl-2-(polyfluoroalkyl)quinoxalines and 3-aroyl-2-(polyfluoroalkyl)benzo[g]quinoxalines by nitrosation of lithium 3-(polyfluoroalkyl)-1,3-diketonates and subsequent reaction with benzene-1,2-diamine or naphthalene-2,3-diamine, respectively.

Full text of DOI:10.1134/S107042801906023X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 6, pp. 890–893. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 6, pp. 967–971.
SHORT
COMMUNICATIONS
Dedicated to Full Member of the Russian Academy of Sciences
O.N. Chupakhin on his 85th anniversary
Synthesis of 3-Aroyl-2-(polyfluoroalkyl)quinoxalines
and 3-Aroyl-2-(polyfluoroalkyl)benzo[g]quinoxalines
from Lithium 3-(Fluoroalkyl)-1,3-diketonates
V. I. Filyakovaa,* N. S. Boltachevaa, and V. N. Charushina
a Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Yekaterinburg, Russia
*e-mail: filver@mail.ru
Received April 11, 2019; revised April 23, 2019; accepted April 24, 2019
Abstract—A one-pot procedure has been developed for the synthesis of 3-aroyl-2-(polyfluoroalkyl)quinox-
alines and 3-aroyl-2-(polyfluoroalkyl)benzo[g]quinoxalines by nitrosation of lithium 3-(polyfluoroalkyl)-1,3-
diketonates and subsequent reaction with benzene-1,2-diamine or naphthalene-2,3-diamine, respectively.
Keywords: fluorinated lithium 1,3-diketonates, benzene-1,2-diamine, naphthalene-2,3-diamine, 3-benzoyl-2-
polyfluoroalkylquinoxalines, 3-aroyl-2-polyfluoroalkylbenzo[g]quinoxalines.
DOI: 10.1134/S107042801906023X
Fluorine-containing heterocycles occupy an impor-
tant place among biologically active compounds, and
their significance for medicine and technology con-
tinuously increases [1, 2].
stepwise synthesis is impossible because of instability
of the corresponding oxime [5].
In fact, by successive treatment of diketonates 6a–
6d with sodium nitrite and diamine 2 or 3 without
isolation of intermediate oximes 1, we obtained com-
pounds 4a, 4b, 5a, 5c, and 5d in 60 to 75% yield. It
should be noted that only one-pot protocol made it
possible to isolate and characterize previously un-
known compound 5d. Our attempts to synthesize
oxime 1d by nitrosation of lithium diketonate 6d
resulted in the formation of decomposition product,
3-(4-methoxyphenyl)-2-oxopropanenitrile. However,
neither compounds 4 and 5 nor benzo(naphtho)di-
azepine derivatives 7 and 12 were formed as the major
products from lithium diketonates 6e–6h containing
a longer fluoroalkyl substituent [RF = C3F7, H(CF2)4,
C4F9, C6F13]. According to the GC/MS data, the
qualitative composition of the product mixtures was
the same as in the reactions of oximes 1 with diamines
2 and 3 (compounds 7–15) [3], but the major com-
ponents were benzo- or naphthoimidazoles 8 and 13
which could be synthesized by simpler methods [6].
Presumably, imidazoles 8 and 9 are products of
transformations of 1,5-diazepines 7 in acid medium
[6, 7]. Correspondingly, naphthoimidazoles 13 and 14
By reacting 4-aryl-1,1,1-trifluorobutane-2,3,4-tri-
one 3-oximes 1 with benzene-1,2-diamine (2) and
naphthalene-2,3-diamine (3) we previously synthe-
sized new quinoxaline derivatives: 3-aroyl-2-(trifluoro-
methyl)quinoxalines 4 and 3-aroyl-2-(trifluoro-
methyl)benzo[g]quinoxalines 5. However, analogous
reactions of oximes 1 containing a longer polyfluoro-
alkyl group (RF = C3F7, H(CF2)4, C4F9, C6F13) led to
the formation of complex mixtures of condensation
and fragmentation products at different ratios [3]. In
this communication, we report the results of one-pot
synthesis of compounds 4 and 5 directly from the
corresponding lithium 3-(polyfluoroalkyl)-1,3-diketo-
nates 6 without preliminary isolation of oximes 1. This
approach was successfully utilized by us in the syn-
thesis of 5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-
amine [4] and 5-hydroxy-5-(polyfluoroalkyl)-1,2-
oxazol-4(5H)-one oximes [5]. In particular, the one-pot
procedure allowed us to obtain 5-hydroxy-3-methyl-5-
(trifluoromethyl)-1,2-oxazol-4(5H)-one oxime whose
890

SYNTHESIS OF 3-AROYL-2-(POLYFLUOROALKYL)QUINOXALINES
891
NH2
NH2
NH2
NH2
O
O
NOH
N
N
R
R
RF
R
2
3
2
3
1
N
RF
N
RF
O
O
4a, 4b
1a–1d
5a, 5c, 5d
NaNO2, AcOH
RF
R
(1) NaNO2, AcOH; (2) 2
(1) NaNO2, AcOH; (2) 3
One pot
One pot
OLi
O
6a–6h
i: NaNO2, AcOH; RF = CF3 (a–c), HCF2 (d), C3F7 (e), H(CF2)4 (f), C4F9 (g), C6F13 (h); R = Ph (a, e–h), 4-MeC6H4 (b),
2,4-Me2C6H3 (c), 4-MeOC6H4 (d).
R
H
N
H
N
N
N
N
N
R
O
NOH
RF
R
N
N
R
CN
RF
7
8
9
10
11
R
H
N
H
N
N
N
N
R
NOH
RF
R
N
N
N
RF
12
13
14
15
are formed from naphthodiazepines 12. Quinoxalines
11 and benzo[g]quinoxalines 15 are products of the
reaction of ketonitriles 10 with diamines 2 and 3,
respectively.
procedure avoids a number of operations related to the
isolation of oximes 1 and provides substantial econ-
omy of time and chemicals and reduction of wastes.
Therefore, it conforms to the green chemistry and
atom economy principles.
Despite limitations related to the length of the poly-
fluoroalkyl substituent, the described procedure can be
regarded as a convenient method for the synthesis of
2-(difluoromethyl)- and 2-(trifluoromethyl)-substituted
quinoxaline derivatives 4 and 5 whose range could be
extended via variation of the R substituent in 6 and of
the 1,2-diamine component. In particular, using the
one-pot procedure, we synthesized new compounds 5c
and 5d. It should be emphasized that introduction of
a di- or trifluoromethyl group into molecules of bio-
logically active heterocycles, undoubtedly including
quinoxaline derivatives, offers a great potential for
drug design [8–12].
Thus, we have developed an efficient one-pot
procedure for the synthesis of 3-aroyl-2-(difluoro-
methyl)- and 3-aroyl-2-(trifluoromethyl)quinoxalines
and -benzo[g]quinoxalines 4 and 5 on the basis of
accessible fluoroalkyl-containing building blocks,
lithium 1,3-diketonates 6 [13–15]. The proposed
Lithium diketonates 6a–6h were prepared accord-
ing to the procedure described [13]; their character-
istics were given in [15]. Compounds 6c and 6d were
not reported previously.
Lithium (Z)-4-(2,4-dimethylphenyl)-1,1,1-tri-
fluoro-4-oxobut-2-en-2-olate (6c). Yield 34 g (71%),
white powder, mp 315–316°C. IR spectrum, ν, cm–1:
582 m (O–Li), 691 m, 799 m, 1138 s (C–F), 1185 s
(C–F), 1243 m (C–F), 1280 s (C–F), 1301 s (C–F),
1473 s, 1524 m (C=Carom), 1621 (C=C–C=O), 2955 br
1
(O–H). H NMR spectrum (DMSO-d6), δ, ppm: 2.27 s
(3H, CH3), 2.33 s (3H, CH3), 5.62 s (1H, =CH),
3
7.00 s (1H, Harom), 7.03 d (1H, Harom, J = 7.60 Hz),
3
7.26 d (1H, Harom, J = 7.60 Hz). 19F NMR spectrum
(DMSO-d6): δF 87.85 ppm, s (CF3).
Lithium (Z)-1,1-difluoro-4-(4-methoxyphenyl)-4-
oxobut-2-en-2-olate (6d). Yield 3.7 g (79%), white
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

FILYAKOVA et al.
892
powder, mp 243–245°C. IR spectrum, ν, cm–1: 543 m
(O–Li), 786 m, 1028 m, 1054 m (C–F), 1113 m (C–F),
1173 s (C–F), 1255 s (C–F), 1351 s (C–F), 1455 s
(C=C), 1504 s, 1533 m, 1568 m, 1597 s (C=Carom),
2JCF = 36.19 Hz), 141.90, 144.37, 150.22, 192.82
(C=O). 19F NMR spectrum (CDCl3): δF 97.99 ppm, s
(CF3). Found, %: C 69.49; H 3.79; N 7.51 F 14.80.
C22H15F3N2O. Calculated, %: C 69.47; H 3.97;
N 7.36, F 14.98.
1
1614 m (C=C–C=O), 2970 br (O–H). H NMR spec-
trum (DMSO-d6), δ, ppm: 3.80 s (3H, OCH3), 5.94 t
[3-(Difluoromethyl)benzo[g]quinoxalin-2-yl]-
(4-methoxyphenyl)methanone (5d). Yield 0.5 g
(65%), white powder, mp 172–173°C. IR spectrum, ν,
cm–1: 1042 s (C–F), 1079 s (C–F), 1119 s (C–F),
1150 m (C–F), 1170 m (C–F), 1274 s (C–F), 1441 m
(C=C), 1512 m (C=N), 1592 s (C=N), 1649 s (C=O).
1H NMR spectrum (CDCl3), δ, ppm: 3.91 s (3H,
OCH3), 7.01 d (2H, Harom, J = 8.90 Hz), 7.23 t (1H,
HCF2, J = 54.90 Hz), 7.64–7.68 m (2H, Harom), 8.08 d
(2H, Harom, J = 8.90 Hz); 8.10–8.18 m (2H), 8.76 s
(1H), and 8.84 s (1H) (Harom). 13C NMR spectrum
3
(1H, HCF2, J = 55.60 Hz), 6.03 s (1H, =CH), 6.95 d
3
(2H, Harom, J = 8.80 Hz), 7.82 d (2H, Harom
,
3J = 8.80 Hz). 19F NMR spectrum (DMSO-d6):
δF 39.88 ppm, d (HCF2, 3J = 55.60 Hz).
Reaction of lithium diketonates 6 with arenedi-
amines 2 and 3 (general procedure). A solution of
1.15 mol of sodium nitrite in 2–3 mL of water was
added with stirring to a solution of 1 mol of diketonate
6 in 4–8 mL of acetic acid, maintaining the tempera-
ture at 10°C. The mixture was stirred for 1 h at room
temperature, 1 mol of diamine 2 or 3 was added, and
the mixture was kept until the initial compounds disap-
peared (TLC). The mixture was poured into water and
extracted with methylene chloride, the extract was
filtered through a layer of silica gel (in some cases,
column chromatography was applied with methylene
chloride as eluent), the filtrate was concentrated, and
hexane was added until a solid precipitated. The pre-
cipitate was filtered off and dried in air.
(CDCl3), δC, ppm: 55.61, 96.09, 111.78 t (HCF2, JCF
=
243.08 Hz), 114.01, 114.58, 126. 77, 127.98, 128.64,
128.75, 128.77, 133.44, 134.96, 135.03, 135.56,
136.58, 146.57 t (C3, JCF = 23.77 Hz), 149.27,
164.66, 190.83, (C=O). 19F NMR spectrum (CDCl3):
δF 43.36 ppm, d (HCF2, J = 54.90 Hz). Found, %:
C 69.22; H 3.73; N 7.71, F 10.44. C21H14F2N2O2. Cal-
culated, %: C 69.23; H 3.87; N 7.69, F 10.43.
The reactions of diketonates 6f, 6g, and 6h with
diamines 2 and 3 led to the formation of complex mix-
tures of products. According to the GC/MS data, the
major components of these mixtures were benzimid-
azole 8f and naphthoimidazoles 13g and 13h.
Phenyl[3-(trifluoromethyl)quinoxalin-2-yl]meth-
anone (4a). Yield 0.81 g (74%), white powder, mp 78–
79°C [3].
(4-Methylphenyl)[3-(trifluoromethyl)quinoxalin-
2-yl]methanone (4b). Yield 0.73 g (68%), white
powder, mp 108–109°C [3].
2-(1,1,2,2,3,3,4,4-Octafluorobutyl)-1H-benzimid-
azole (8f). Retention time 16.68 min; m/z 318 [M]+.
2-(1,1,1,2,2,3,3,4,4-Nanofluorobutyl)-1H-naph-
tho[2,3-d]imidazole (13g). Retention time 21.81 min;
m/z 386 [M]+.
(4-Phenyl)[3-(trifluoromethyl)benzo[g]quinoxa-
lin-2-yl]methanone (5a). Yield 1 g (63%), white
powder, mp 158–159°C [3].
2-(1,1,2,2,3,3,4,4,5,5,6,6,6-Tridecafluorohexyl)-
1H-naphtho[2,3-d]imidazole (13h). Retention time
22.30 min; m/z 486 [M]+.
(2,4-Dimethylphenyl)[3-(trifluoromethyl)benzo-
[g]quinoxalin-2-yl]methanone (5c). Yield 0.53 g
(58%), white powder, mp 146.2–146.6°C. IR spec-
trum, ν, cm–1: 1042 s (C–F), 1140 s (C–F), 1166 m
(C–F), 1200 s (C–F), 1413 m (C=C), 1557 m (C=N),
The fragmentation patterns of the molecular ions of
8f, 13g, and 13h were consistent with their structures.
1
1611 m (C=N), 1661 s (C=O). H NMR spectrum
The products were identified by GC/MS on a Trace
GC Ultra DSQ II instrument (USA); Thermo TR-5ms
quartz capillary column, 30 m×0.25 mm, film thick-
ness 0.25 μm; quadrupole mass detector; total ion
monitoring, a.m.u range 20–1000; electron impact
ionization (70 eV); oven temperature programming
from 40°C (3 min) to 280°C at a rate of 10 deg/min;
injector temperature 250°C, detector and interface
temperature 200°C; carrier gas helium, split ratio 1:50,
flow rate 1.0 mL/min.
(CDCl3), δ, ppm: 2.40 s (3H, CH3), 2.70 s (3H, CH3),
7.04 d (1H, Harom, J = 7.95 Hz), 7.21 s (1H, Harom),
7.44 d (1H, Harom, J = 7.95 Hz); 7.64–7.70 m (2H),
8.09–8.10 m (1H), 8.15–8.19 m (1H), 8.73 (1H), and
8.87 m (1H) (Harom). 13C NMR spectrum (CDCl3), δC,
ppm: 21.64, 21.96, 96.10, 119.65, 120.74 q (CF3,
1JCF = 276.3 Hz), 121.84, 126.33, 128.11, 128.37,
128.44, 128.66, 128.82, 128.10, 131.18, 133.35,
133.73, 134.94, 135.53, 136.01, 139.88, 141.47 q (C3,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 6 2019

SYNTHESIS OF 3-AROYL-2-(POLYFLUOROALKYL)QUINOXALINES
893
The 1H, 13C, and 19F NMR spectra were recorded on
a Bruker Avance-500 spectrometer relative to tetra-
methylsilane (1H, 13C) or C6F6 (19F) as internal
standard. The IR spectra (diffuse reflectance) of solid
samples were recorded in the range 400–4000 cm–1 on
a Perkin Elmer Spectrum One FT-IR instrument. The
elemental analyses were obtained with a Perkin Elmer
2400 analyzer.
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ACKNOWLEDGMENTS
This study was performed using the facilities of the
“Spectroscopy and Analysis of Organic Compounds”
joint center (Institute of Organic Synthesis, Ural
Branch, Russian Academy of Sciences).
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This study was performed under financial support
by the Russian Foundation for Basic Research (project
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The authors declare the absence of conflict of
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