Transformations of 6,7-difluoroquinoxaline with Indoles: Synthesis of Indole-Substituted 6,7-difluoroquinoxalines and Tris(indol-3-yl)methane Derivatives

Article abstract of DOI:10.1007/s10600-017-2036-x

6,7-Difluoroquinoxaline (1) reacted with 1- and 2-methylindoles (2a and 2b) with heating in AcOH to give products from substitution of H in the heterocyclic fragment (3a and 3b) and tris(indol-3-yl)methane derivatives (4a and 4b).

Full text of DOI:10.1007/s10600-017-2036-x

DOI 10.1007/s10600-017-2036-x
Chemistry of Natural Compounds, Vol. 53, No. 3, May, 2017
TRANSFORMATIONS OF 6,7-DIFLUOROQUINOXALINE
WITH INDOLES: SYNTHESIS OF INDOLE-SUBSTITUTED
6
,7-DIFLUOROQUINOXALINES AND
TRIS(INDOL-3-YL)METHANE DERIVATIVES
Yu. A. Azev,1* O. S. Ermakova, M. A. Ezhikova,
1
2
1
,2
1
1
M. I. Kodess, V. S. Berseneva, and I. S. Kovalev
6
,7-Difluoroquinoxaline (1) reacted with 1- and 2-methylindoles (2a and 2b) with heating in AcOH to give
products from substitution of H in the heterocyclic fragment (3a and 3b) and tris(indol-3-yl)methane derivatives
4a and 4b).
(
Keywords: 2-indolyl derivatives of 6,7-difluoroquinoxaline, tris(indol-3-yl) methanes.
Quinoxaline derivatives with various types of biological activity have been discovered [1, 2]. Quinoxaline derivatives,
i.e., quinoxidine and dioxidine, are known antimicrobial agents [3]. Recently, substitution of the H in the aromatic core of
6
,7-difluoroquinoxaline by several C-nucleophiles and of an F atom by amines were reported [4]. Indole and its derivatives
are widely used as heterocyclic C-nucleophiles to prepare products of C–C bonding to various heterocyclic substrates [5]. The
search for effective biologically active compounds among indole derivatives is promising because the indole core is the basic
framework or a component part of several important natural compounds, including the amino acid tryptophan, the neuromediator
serotonin, and the antibiotic turbomycin A.
In continuation of the development of efficient methods for preparing 6,7-difluoroquinoxaline derivatives using
SNH-functionalization of C–H bonds [5], we studied the direct substitution of H in these compounds during reactions with
indoles.
F
N
R
2
N
R
1
F
F
N
N
F
N
2
a,b
R
2
N
R
1
1
3a,b
R
1
H
N
N
F
F
R
2
R
2
N
R
1
N
5
N
R
1
R
2
4
a,b
a: R = CH , R = H; b: R = H, R = CH
3
1
3
2
1
2
Scheme 1
) Yeltsin Ural Federal University, Ekaterinburg, 620002, Russia, e-mail: azural@yandex.ru; 2) I. Ya. Postovsky
1
Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Ekaterinburg, 620990, Russia, e-mail:
nmr@ios.uran.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 3, May–June, 2017, pp. 441–443. Original article
submitted August 4, 2016.
0
009-3130/17/5303-0519 ©2017 Springer Science+Business Media New York
519

It was found during the work that 6,7-difluoroquinoxaline (1) reacted with methylindoles 2a and 2b with heating in
AcOH to give the corresponding H-substitution products 3a and 3b (Scheme 1). In addition to them, the corresponding
tris(indol-3-yl)methanes 4a and 4b were isolated from the reaction mixture in both instances. Furthermore, TLC and mass
spectrometry of the reaction mixtures identified 5,6-difluorobenzimidazole 5.
The obtained tris(indolylmethanes) 4a and 4b were identical to those in the literature. Compound 4a was synthesized
via condensation of 1-methyl-3-formylindole and 1-methylindole [6]; 4b or tris(2-methylindol-3-yl)methane, from 4,6-dichloro-
5
-nitropyrimidine and 2-methylindole [7].
It could be proposed that the direct H-substitution to give indolylquinoxalines 3 that was described by us passed
through the formation of ꢀ-adducts. Such ꢀ-adducts are usually oxidized using special oxidizing agents [5].
The final H-substitution products (3) formed during the transformations without adding special oxidants. Obviously,
generated intermediates were spontaneously oxidized by atmospheric O2.
It was shown previously that a C–C fragment was eliminated from the pyrazine core to form a tetrapyrazolylethane
derivative that was easily converted to dipyrazolylmethane during the reaction of 6,7-difluoroquinoxaline with 1-phenyl-3-
methylpyrazolone-5 in the presence of Et N [4].
3
Apparently, several processes were responsible for the newly observed transformation of quinoxalines. These were
competitive nucleophilic addition to the quinoxaline heterocyclic core of indole and a water hydroxyl, cleavage of one C=N
bond, cyclization of intermediate B, and substitution of the benzimidazole in intermediate C (Scheme 2).
R
1
R
1
R
1
N
N
R
2
N
R
2
H
R
2
R
2
NH
F
F
F
F
N
F
F
2
N
2a,b
2
a,b
2a,b
5 + 4a,b
R
1
1
N
N
H
N
H
O
H
N
H
O
R
2
N
A
B
C
R
1
a: R = CH , R = H; b: R = H, R = CH
3
1
3
2
1
2
Scheme 2
The quinoxaline derivatives acted in the described transformation as donors of C -fragments that linked three indole
1
molecules. The remaining part of the quinoxaline molecule converted into the benzimidazole derivative, i.e., the six-membered
heterocyclic fragment contracted to a five-membered one.
PMR spectra showed characteristic resonances for indole derivatives of difluoroquinoxalines 3 as a singlet for pyrazine
H-3 at 9.2–9.4 ppm; for derivatives of tris(indol-3-yl)methanes 4, as a singlet for the methane proton at 6.0–6.2 ppm. It is
noteworthy that the chemical shifts of the methyl protons of the 2-methylindoline fragments in 3b (2.80 ppm) and 4b
(
1.92 ppm) differed significantly, probably because of deshielding by the heteroaromatic ring in 3b.
Electron-impact (EI) mass spectra of 4a and 4b differed considerably. Thus, the main fragmentation pathway for 4a
was 403 (100) ꢁ 402 (44) ꢁ 271 (85) + 129 + H . Evidently, a hydrogen radical was initially cleaved from the molecular ion
2
(
Scheme 3). Then, the ion with m/z 402 decayed by releasing H (dehydrogenation) and formed indolyl and diindolylmethane
2
fragments through a P-process [8].
However, a similar rearrangement involving the H atoms was impossible for 2-methylindolyl derivative 4b because
the indolyl 2-position of the fragment was blocked by the methyl. The main mass spectrometric fragmentation pathway in this
ꢂ
instance was 403 (89) ꢁ 388 (100) ꢁ 257 (85) + 130 (14) + H . Apparently, it corresponded to initial cleavage of a methyl
radical and subsequent cleavage of an ion with m/z 388 and formation of the corresponding indolyl and diindolylmethane
fragments.
These characteristic mass spectrometric fragmentations of various methyl-derivatives of tris(indolylmethanes) are
interesting because they are convenient and practically useful diagnostic signatures for homologs of the antibiotic turbomycin
A [9].
The observed transformations of difluoroquinoxalines with indoles opens possibilities for synthesizing potentially
biologically active compounds that, in turn, can act as synthons for producing new derivatives.
520

+
+
.
N
C
N
C
H
H
C
129
9
H
7
N
H
H
.
-H
2
C
C
N
-H
C
C
N
+
C
19
H
15
N
2
H
+
N
N
217 (85)
4
03 (100)
NH
402 (44)
+
.
+
NH
9 8
C H N
130 (14)
HN
.
H
H
3.
HN
-
-CH
H
C
C
+
18 13
C H N
2
57 (85)
NH
NH
4
03 (89)
388 (100)
Scheme 3
EXPERIMENTAL
PMR, F NMR, and 13C NMR spectra were recorded on BrukerAvance-500 andAvance-400 spectrometers. Chemical
19
1
19
13
shifts of H and F were measured vs. internal standards of TMS and C F , respectively; of C, vs. the solvent resonance
6
6
ꢃC = 39.5 ppm. EI mass spectra were taken on a Bruker Daltonics MicrOTOF-Q instrument with average ionizing potential
7
1
5 eV at 250°C.
Reaction of 6,7-Difluoroquinoxaline (1) with 1-Methylindole. Compound 1 (0.225 g, 1.35 mmol) was heated with
-methylindole (0.5 g, 3.8 mmol) in AcOH (3 mL) at 110°C for 35 h, cooled, and stored at 20–25 for 12 h. The resulting
precipitate was filtered off and recrystallized from DMF. Yield of tris(1-methylindol-3-yl)methane (4a), 0.060 g (12%),
+
mp 241–243°C [6]. The PMR spectrum was published [6]. Mass spectrum (EI, 70 eV), m/z (I , %): 404 (29), 403 (M , 100),
rel
4
02 (44), 272 (75), 271 (85), 257 (15).
The mother liquor from crystallization was diluted with H O (1:1). The resulting precipitate of 6,7-difluoro-2-(1-
2
1
methyl-1H-indol-3-yl)quinoxaline (3a) was filtered off. Yield 0.140 g (36%), mp 155–157ꢄÑ. Í NMR spectrum
(
500 MHz, DMSO-d , ꢃ, ppm, J/Hz): 3.93 (3Í, s, NCH ), 7.25 (1Í, ddd, J = 7.7, 7.0, 1.0, H-5ꢅ), 7.30 (1H, ddd, J = 8.1, 7.0, 1.2,
6 3
H-6ꢅ), 7.54 (1Í, br.d, J = 8.1, H-7ꢅ), 7.95 (1Í, dd, J = 10.9, 8.6, H-5), 8.01 (1Í, dd, J = 11.4, 8.4, H-8), 8.57 (1Í, s, H-2ꢅ), 8.73
(
1
(
1Í, br.s, J = 7.7, H-4ꢅ), 9.38 (1Í, s, H-3). 19F NMR spectrum (470.5 MHz, DMSO-d , ꢃ, ppm, J/Hz): 26.97 (1F, ddd, J = 22.3,
6
13
0.9, 8.4, F-6), 29.85 (1F, ddd, J = 22.3, 11.4, 8.6, F-7). C NMR spectrum (126 MHz, DMSO-d , ꢃ, ppm, J/Hz): 33.00
6
2
2
3
NCH ), 110.10 (C-7ꢅ), 111.51 (C-3ꢅ), 114.15 (d, J = 17.3, C-8), 114.69 (dd, J = 17.2, J = 1.3, C-5), 121.01 (C-5ꢅ),
3 CF CF CF
3
1
22.32 (C-4ꢅ), 122.62 (C-6ꢅ), 125.74 (C-3ꢅa), 132.81 (C-2ꢅ), 136.19 (d, J = 9.6, C-4a), 137.54 (C-7ꢅa), 139.28 (d,
CF
JCF = 10.1, C-8a), 144.38 (d, J = 2.7, C-3), 149.53 (dd, J = 250.1, J = 16.0, CF), 150.64 (d, J = 2.8, C-2), 151.17
3
5
1
2
5
CF
CF
CF
CF
1
2
+
(
dd, J = 251.5, J = 15.5, CF). Mass spectrum (EI, 70 eV), m/z (I , %): 295 (M , 100), 267 (16), 155 (11). C H F N .
CF CF rel 17 11 2 3
Reaction of 6,7-difluoroquinoxaline (1) with 2-methylindole was performed analogously. The reaction mixture
was evaporated in vacuo. The solid was worked up with EtOH (3–4 mL). The precipitate of tris(2-methylindol-3-yl)methane
1
(
4b) was filtered off and rinsed with EtOH. Yield 9%, mp > 300ꢄÑ (lit. [7] mp > 300ꢄÑ). Í NMR spectrum (400 MHz,
DMSO-d , ꢃ, ppm, J/Hz): 1.92 (9Í, s, CH ), 6.09 (1Í, s, CH), 6.60 (3Í, ddd, J = 7.9, 7.2, 1.0, H-5), 6.84–6.90 (6Í, m,
6
3
+
H-6, 7), 7.16 (3Í, dd, J = 7.9, 1.2, H-4), 10.37 (3Í, s, NH). Mass spectrum (EI, 70 eV), m/z (I , %): 404 (33), 403 (M , 89),
rel
4
02 (22), 272 (75), 271 (15), 257 (86), 256 (32).
The EtOH mother liquor was evaporated in vacuo. The solid was purified by preparative chromatography using
silica gel (0.040–0.063 ꢆm, Alfa Aesar) with elution by CHCl –EtOH (30:1). Bands with R 0.53 (EtOH) were extracted to
3
f
1
afford 6,7-difluoro-2-(2-methyl-1H-indol-3-yl)quinoxaline (3b). Yield 25%, mp 147–148ꢄÑ. Í NMR spectrum (400 MHz,
521

DMSO-d , ꢃ, ppm, J/Hz): 2.80 (3Í, s, ÑÍ ), 7.07–7.14 (2Í, m, H-5ꢅ, 6ꢅ), 7.35–7.39 (1Í, m, H-7ꢅ), 7.88–7.93 (2Í, m, H-5, 8),
6
3
1
9
8
(
.12–8.16 (1Í, m, H-4ꢅ), 9.21 (1Í, s, H-3), 11.57 (1Í, s, NH). F NMR spectrum (376 MHz, DMSO-d , ꢃ, ppm, J/Hz): 28.42
1F, ddd, J = 21.9, 10.8, 8.6, F-6), 30.87 (1F, ddd, J = 21.9, 11.2, 8.5, F-7). Mass spectrum (EI, 70 eV), m/z (I , %): 295 (M ,
6
+
rel
1
00), 155 (41), 130 (30). C H F N .
17 11 2 3
Products isolated from the origin were investigated by EI MS and gave ions with m/z 154, 127, and 100 in a 5:2:1
intensity ratio. An analogous pattern of ions was observed in the EI MS of the known 5,6-difluorobenzimidazole [10]
+
[
EI, 70 eV, m/z (I , %): 154 (M , 100), 127 (45), 100 (21)].
rel
The presence of 5,6-difluorobenzimidazole in the reaction products was also confirmed by TLC using silica gel as the
sorbent (0.040–0.063 ꢆm, Alfa Aesar) and authentic 5,6-difluorobenzimidazole with elution by CHCl –EtOH (6:1), R 0.39.
3
f
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