Intramolecular nucleophilic substitution of hydrogen in (quinoxalinyl-2)aminovinyl derivatives as a new approach to pyrrolo- and indolo[2,3-6]quinoxalines

Article abstract of DOI:10.1081/SCC-200025595

Pyrrolo[2,3-b]- and indolo[2,3-e]quinoxalines were obtained by the reaction of 2-aminoquinoxalines with ketones followed by the intramolecular displacement of hydrogen at C-3 in (quinoxalinyl-2)aminovinyl derivatives.

Full text of DOI:10.1081/SCC-200025595

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Intramolecular Nucleophilic
Substitution of Hydrogen in
(Quinoxalinyl‐2)aminovinyl
Derivatives as a New
Approach to Pyrrolo‐ and
Indolo[2,3‐b]quinoxalines
S. K. Kotovskaya a , V. N. Charushin b , N. M.
Perova a , M. I. Kodess b & O. N. Chupakhin b
a Department of Organic Chemistry , Urals State
Technical University , Ekaterinburg, Russia
b Institute of Organic Synthesis , Ural Branch of
the Russian Academy of Sciences , S. Kovalevskaya
St. 20, Ekaterinburg, 620219, Russia
Published online: 10 Jan 2011.
To cite this article: S. K. Kotovskaya , V. N. Charushin , N. M. Perova , M. I. Kodess
& O. N. Chupakhin (2004) Intramolecular Nucleophilic Substitution of Hydrogen
in (Quinoxalinyl‐2)aminovinyl Derivatives as a New Approach to Pyrrolo‐ and
Indolo[2,3‐b]quinoxalines, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 34:14, 2531-2537, DOI:
10.1081/SCC-200025595
To link to this article: http://dx.doi.org/10.1081/SCC-200025595

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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 14, pp. 2531–2537, 2004
Intramolecular Nucleophilic Substitution of
Hydrogen in (Quinoxalinyl-2)aminovinyl
Derivatives as a New Approach to
Pyrrolo- and Indolo[2,3-b]quinoxalines
1
S. K. Kotovskaya,1 V. N. Charushin,2, N. M. Perova,
*
M. I. Kodess,2 and O. N. Chupakhin2
1Department of Organic Chemistry, Urals State Technical University,
Ekaterinburg, Russia
2Institute of Organic Synthesis, Ural Branch of the Russian Academy of
Sciences, Ekaterinburg, Russia
ABSTRACT
Pyrrolo[2,3-b]- and indolo[2,3-b]quinoxalines were obtained by the reac-
tion of 2-aminoquinoxalines with ketones followed by the intramolecular
displacement of hydrogen at C-3 in (quinoxalinyl-2)aminovinyl
derivatives.
*
Correspondence: V. N. Charushin, Institute of Organic Synthesis, Ural Branch of the
Russian Academy of Sciences, S. Kovalevskaya St. 20, Ekaterinburg 620219, Russia;
Fax: þ7 3432-745191; E-mail: charushin@prm.uran.ru.
2531
DOI: 10.1080/SCC-200025595
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2532
Kotovskaya et al.
INTRODUCTION
Condensed pyrazines and quinoxalines are of general interest and several
synthetic procedures to obtain these heterocyclic systems have been described
in the literature.[1,2] As far as pyrrolo[2,3-b]quinoxalines are concerned, a very
common approach is based on condensation of ortho-phenylenediamines with
the corresponding 2,3-dioxopyrroles.[1] An alternative way to 1H-pyrrolo[2,3-
b]quinoxalines involves annelation of the pyrrole ring, which takes place in the
reaction of 2-cyanomethylquinoxalines with ammonia or primary amines.[1]
The data on the synthesis of 5H-pyrrolo[2,3-b]pyrazines are limited to a few
examples of the thermal cyclizations of pyrazinylhydrazones.[1,3,4]
We have earlier reported that the tandem diaddition reactions (AN–AN) of
1,3-C,N-bifuctional nucleophiles on the two neighboring C55N bonds of the pyr-
azine ring enable one to obtain tetrahydropyrazines fused with the pyrrole ring
(Sch. 1).[5,6] In addition, we have recently described a new methodology for the
synthesis of fused quinoxalines, which is based on nucleophilic displacement of
hydrogen (SHN), as illustrated by the intramolecular reaction in which quinoxali-
nyl hydrazones are converted into pyrazolo[3,4-b]quinoxalines (Sch. 2).[7]
In this paper, we wish to report a facile synthesis of pyrrolo[2,3-b]-
and indolo[2,3-b]-quinoxalines through intramolecular SHN-reactions of
(quinoxalinyl-2)aminovinyl derivatives obtained from 2-aminoquinoxalines
1a,b (Schs. 3 and 4). The starting 6,7-difluoro-2-aminoquinoxaline 1a was
obtained from 2-amino-6,7-difluoro-3-cyanoquinoxaline-1,4-dioxide,[8]
while 2-aminoquinoxaline 1b was prepared according to the known pro-
cedure from ortho-phenylenediamine and alloxane.[9,10] We have found
that the reaction of 2-aminoquinoxalines 1a,b with an excess of acetylace-
tone proceeds very smoothly at reflux in acetic acid, thus affording
1H-pyrrolo[2,3-b]quinoxalines 5a,b in good yield. The reaction appears to
involve the formation of azomethynes 2a,b which can tautomerize to enam-
ines 3a,b. Enamines 3a,b undergo intramolecular cyclization via nucleo-
philic attack at the unsubstituted C-3 of the pyrazine ring, thus affording
the adducts 4a,b. Dihydroquinoxalines 4a,b have a tendency to restore the
Scheme 1.

Intramolecular Nucleophilic Substitution of Hydrogen
2533
Scheme 2.
lost aromaticity and, indeed, the H-3a hydrogen atom is easily eliminated by
air oxidation to give 3-acetyl-2-methyl-1H-pyrrolo[2,3-b]quinoxalines 5a,b
(Sch. 3). In a similar way 2-aminoquinoxalines 1a,b react with cyclohexa-
none to afford indolo[2,3-b]-quinoxalines 6a,b (Sch. 4).
Evidence for the structure of 6a is provided by 1H- and 13C NMR; also the
mass-spectrometry and elemental analyses data are in good agreement with
the structure displayed (see Experimental Section). In the 1H NMR spectrum
of 8,9-difluoroindolo[2,3-b]quinoxaline 6a the H-7 and H-10 protons (d 7.96
3
and 8.00 ppm) appear as double doublets with JH,F ¼ 11.9 and 12.2 Hz and
4JH,F ¼ 8.6 Hz, while the NH proton of the pyrrole ring gives rise to a
broad singlet at d 11.68 ppm (Table 1). In the proton-decoupled 13C NMR
spectrum of 6a the resonance signal of C-5a can easily be assigned, since it
appears as a singlet at d 106.70 ppm due to electron-donating effect of the
Scheme 3.

2534
Kotovskaya et al.
Scheme 4.
enamine moiety, while the other quaternary carbon C-1a resonates as a doub-
7
let at 142.87 ppm with a long-range coupling constant JC-1a,F-9 ¼ 1.6 Hz.
The ring junction carbons of the pyrazine ring C-5b and C-11a resonate as doub-
lets at d 141.95 and 149.49ppm with long-range 13C–19F coupling constants
5
5JC-5b,F-8 ¼ 2.2 Hz and JC-11a,F-9 ¼ 1.1 Hz. The signals of methyne carbons
C-7 and C-10 can easily be assigned due to their multiplicities, however, it is
difficult todifferentiate betweenthesesignals, sincetheyhaveratherclosechemi-
cal shifts (d 113.81 and 113.25ppm) and values of coupling constants:
1JC,H ¼ 166.4 Hz, 2JC,F ¼ 16.8 (or 17.4Hz), and 3JC,F ¼ 1.1 Hz. The resonance
signals C-8 and C-9 (d 148.50 and 149.00ppm) can be identified due to one-bond
1
13C–19F couplings JC,F ¼ 246.4 Hz (or 247.2 Hz) and two-bond couplings
2JC,F ¼ 15.9Hz, but cannot be distinguished unequivocally (Table 1).
In conclusion, it is worth noting that the cyclizations observed appear to
be the first examples of using intramolecular SHN reactions for the synthesis
pyrrolo[2,3-b]- and indolo[2,3-b]quinoxalines.
EXPERIMENTAL
The 1H NMR spectra in [2H6]DMSO were recorded on a “Bruker”
WP-250 instrument (250 MHz). The 13C NMR spectra of 6a in [2H6]DMSO
were obtained on a “Bruker” DRX-400 spectrometer (100 MHz). Mass
spectra were recorded using a “Varian” MAT 311A spectrometer.
2-Amino-6,7-difluoroquinoxaline 1a
A solution of sodium dithionite (5.0g, 30.0mmol) in 80mL of water was
added dropwise to a suspension of 2-amino-3-cyano-6,7-difluoroquinoxaline

Intramolecular Nucleophilic Substitution of Hydrogen
2535
Table 1. 1H- and 13C NMR spectral data for indolo[2,3-b]quinoxaline 6a
in [2H6]-DMSO.
Characteristics
d (ppm)
nJ (Hz)
Compound 6a
113.81
16.8
C-7ꢀ
2J(C-7, F-8)
3J(C-7, F-9)
1J(C-7, H-7)
1.1
166.4
H-7ꢀ
8.00
12.2
3J(H-7, F-8)
4J(H-7, F-9)
8.6
113.25
C-10ꢀ
2J(C-10, F-9)
3J(C-10, F-8)
1J(C-10, H-10)
17.4
1.1
166.4
7.96
H-10ꢀ
C-8ꢀꢀ
C-9ꢀꢀ
C-1a
3J(H-10, F-9)
4J(H-10, F-8)
11.9
8.6
148.50
246.4
1J(C-8, F-8)
2J(C-8, F-9)
15.9
149.00
1J(C-9, F-9)
2J(C-9, F-8)
247.2
15.9
142.87
1.6
7J(C-1a, F-9)
C-5a
C-5b
106.70
141.95
5J(C-5b, F-8)
3J(C-6a, F-8)
3J(C-10a, F-9)
5J(C-11a, F-9)
2.2
135.92
C-6aꢀꢀꢀ
C-10aꢀꢀꢀ
C-11a
10.7
134.80
10.7
149.49
1.1
C-2, C-3, C-4, C-5
(CH2)4
NH
19.28, 21.93, 22.11, 23.54
1.91 (m, 4H), 2.79 (m, 4H)
11.68 (s)
,
,
ꢀ
ꢀꢀ ꢀꢀꢀ
Note:
interchanged with each other.
Assignments of the signals marked with asterisks can be

2536
Kotovskaya et al.
1,4-dioxide[10] (1.0g, 4.2 mmol) in 80mL of ethanol. The reaction mixture was
stirred at 75–808C for 6 hr, and then cooled to 0–58C. Addition of cold water
(300–400 mL) and stirring for an additional hour at 5–108C gave a precipitate,
which was filtered off and recrystallized from ethanol to give yellow crystals.
1
Yield 0.67g (76%), mp 219–2218C. H NMR ([2H6]DMSO) d: 6.84 (br.s,
3
4
2H, NH2); 7.42 (dd, 1H, JHF ¼ 11.8Hz, JHF ¼ 8.1 Hz) and 7.58 (dd, 1H,
4
3JHF ¼ 11.0Hz, JHF ¼ 8.5 Hz), (H-5 and H-8); 8.25 (s, 1H, H-3). MS, m/z
(%): 181 (100) [Mþ], 154 (80), 127 (39), 112 (17), 100 (12). Anal. calcd for
C8H5F2N3: C, 53.04; H, 2.76; N, 24.56. Found: C, 52.94; H, 2.68; N, 24.62.
Typical Procedure for Preparation of 5a,b and 6a,b
An excess of ketone (4–5 mmol) was added to a solution of 1 mmol of
2-aminoquinoxaline 1a (or 1b) in 20–25 mL of acetic acid and the reaction
solution was kept under reflux for 10 hr for 5a and 6a (5 hr in case of com-
pounds for 5b and 6b). The reaction progress was monitored by TLC (silica
gel, EtOH–CHCl3 1 : 4), following the presence of the starting materials
1a,b. Compounds 5a and 6a were isolated from the reaction mixture by
adding cold water (100–150 mL) followed by filtration of the precipitate
and its recrystallisation from EtOH–H2O 2 : 1. For compounds 5b and 6b
the solvents were evaporated in vacuo (0.5–1.0 kPa) and the residue was
recrystallized from tetrachlorocarbon (5b) or EtOH–H2O 2 : 1 (6b).
1
For 5a: Yield 79%, mp 225–2268C. H NMR ([2H6]DMSO) d: 2.49
(s, 3H, CH3); 2.51 (s, 3H, COCH3); 8.00–8.25 (m, 2H, Ph); 12.80 (br.s, 1H,
NH). MS, m/z (%): 261 (53) [Mþ], 246 (100), 218 (7), 191 (10), 165 (6),
126 (15). Anal. calcd for C13H9F2N3O: C, 59.77; H, 3.45; N, 16.09. Found:
C, 60.30; H, 3.15; N, 15.86.
For 5b: Yield 64%, mp .2708C. 1H NMR ([2H6]DMSO) d: 2.85 (s, 3H,
CH3); 2.87 (s, 3H, COCH3); 7.65–7.68 (m, 2H, Ph); 7.98–8.13 (m, 2H, Ph);
12.69 (br.s, 1H, NH). MS, m/z (%): 225 (62) [Mþ], 210 (100), 187 (7), 155
(7), 105 (12), 90 (20). Anal. calcd for C13H11N3O: C, 69.33; H, 4.89;
N, 18.67. Found: C, 69.18; H, 4.95; N, 18.54.
1
For 6a: Yield 82%, mp 251–2538C. H NMR ([2H6]DMSO) d: 1.88–
1.94 [m, 4H, (CH2)2]; 2.73–2.85 [m, 4H, (CH2)2]; 7.89–8.07 (m, 2H, Ph);
7.98–8.13 (m, 2H, Ph); 12.69 (br.s, 1H, NH). MS, m/z (%): 259 (62) [Mþ],
231 (100), 218 (3), 190 (3), 165 (4), 139 (5), 130 (5). Anal. calcd for
C14H11F2N3: C, 64.86; H, 4.25; N, 16.22. Found: C, 64.70; H, 4.30; N, 16.01.
1
For 6b: Yield 58%, mp .3008C. H NMR ([2H6]DMSO) d: 1.86–1.93
[m, 4H, (CH2)2]; 2.74–2.87 [m, 4H, (CH2)2]; 7.61–7.64 (m, 2H, Ph);
7.96–8.09 (m, 2H, Ph); 11.58 (br.s, 1H, NH). MS, m/z (%): 223 (64) [Mþ],

Intramolecular Nucleophilic Substitution of Hydrogen
2537
195 (100), 181 (5), 154 (5), 129 (10), 112 (6), 102 (15). Anal. calcd for
C14H13N3: C, 75.33; H, 5.83; N, 18.83. Found: C, 75.12; H, 5.64; N, 19.06.
ACKNOWLEDGMENTS
The research described in this publication was supported partly by the US
Civilian Research and Development Foundation and the Russian Ministry of
Education (REC-005), by the Russian Foundation for Basic Research (grants
numbers 04-03-96090 and 02-03-32627), as well as by grant number
1766.2003.3 “Leading scientific schools.”
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Received in the USA March 2, 2004