Heterocycles [c]-Fused onto indoloquinoxaline. Synthesis of novel pyrano[2',3':4,5]indolo[2,3-b]quinoxalin-2-ones

Article abstract of DOI:10.5560/ZNB.2012-0131

A synthesis of 4-methylpyrano[2,3-e]indole-2,8,9-trione (5) is achieved from 7-amino-4- methylcoumarin by adopting the classical Sandmeyer methodology. The cyclocondensation reaction of pyrano-isatin 5 with the appropriately substituted o-phenylenediamines 6 in polyphosphoric acid proceeded regioselectively to furnish the respective pyrano[2',3':4,5]indolo[2,3-b] quinoxalines 7a - c. Structural assignments of the new compounds are based on microanalytical and spectral (IR, MS and NMR) data.

Full text of DOI:10.5560/ZNB.2012-0131

Heterocycles [c]-Fused onto Indoloquinoxaline. Synthesis of Novel
Pyrano[2’,3’:4,5]indolo[2,3-b]quinoxalin-2-ones
Almeqdad Y. Habashneha, Mustafa M. El-Abadelaha, Mohammed M. Abadlehb, and
Wolfgang Voelterc
a
Chemistry Department, Faculty of Science, The University of Jordan, Amman, Jordan
College of Pharmacy, Taibah University, Al Madinah Almonawarrah, 41477, Saudia Arabia
Interfakulta¨res Institut fu¨r Biochemie, Universita¨t Tu¨bingen, Hoppe-Seyler-Straße 4, 72076
b
c
Tu¨bingen, Germany
Reprint requests to Prof. Dr. W. Voelter. E-mail: wolfgang.voelter@uni-tuebingen.de or Dr. A. Y.
Habashneh. E-mail: a.habashneh@ju.edu.jo
Z. Naturforsch. 2012, 67b, 725 – 730 / DOI: 10.5560/ZNB.2012-0131
Received May 17, 2012
A synthesis of 4-methylpyrano[2,3-e]indole-2,8,9-trione (5) is achieved from 7-amino-4-
methylcoumarin by adopting the classical Sandmeyer methodology. The cyclocondensation reac-
tion of pyrano-isatin 5 with the appropriately substituted o-phenylenediamines 6 in polyphosphoric
acid proceeded regioselectively to furnish the respective pyrano[2’,3’:4,5]indolo[2,3-b]quinoxalines
7a – c. Structural assignments of the new compounds are based on microanalytical and spectral (IR,
MS and NMR) data.
Key words: 7-Aminocoumarin, Regioselective Cyclization, Pyrano[2,3-e]indole-2,8,9-trione,
o-Phenylenediamines, Cyclocondensation
Introduction
The parent 6H-indolo[2,3-b]quinoxaline system 1
(Fig. 1), an analog of the cytotoxic agent ellipticine,
had been first synthesized in 1895 [1] via cyclocon-
densation of isatin with o-phenylenediamine. Follow-
ing this versatile route, several derivatives of 1 were
prepared and intensely studied [2 – 16]. Derivatives of
this tetracyclic heteroaromatic system are important
DNA interchelators [5 – 8], some of which display an-
titumor activity [5 – 7], while others are useful agents
for the treatment of autoimmune disease [9] and mul-
tiple sclerosis [10]. Certain derivatives with basic ap-
pendages at the N(6)-position, such as 2 [8] (Fig. 1),
Fig. 1. Model indolo[2,3-b]quinoxalines.
exhibit potent antiviral activity [11 – 14] against e. g., These hybrid pentacyclic heterocycles might have
herpes simplex virus type 1 (HSV-1), cytomegalo virus potential bioactivity arising from the combination
(CMV) and vericella-zoster virus (VZV). Compound of bioactive entities of which the coumarin system
2 (referred to as B-220) and its congeners are believed (benzo[b]pyran-2-one/rings A, B) constitutes an inte-
to act via inhibition of the decapsidation process of the gral part. It is noteworthy that coumarins are widely
virus [11 – 16].
distributed in nature, found in various parts of plants
In the present study, we wish to report on the syn- and make up an important part of human diet [17 – 19].
thesis of indolo[2,3-b]quinoxalines condensed with 2- Besides, coumarin derivatives exhibit good cell perme-
pyranone, exemplified by 7a – c as shown in Scheme 1. ability, have been shown to be tolerated physiologi-
c
ꢀ 2012 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com

726
A. Y. Habashneh et al. · Heterocycles [c]-Fused onto Indoloquinoxaline
Scheme 1. (i) 4% aq. HCl; (ii) Cl3CCH(OH)2·H2O/Na2SO4; (iii) NH2OH·HCl; (iv) 95% H2SO4, 90 oC, 2 h; (v) PPA
(polyphosphoric acid), 140 oC, 2 h.
cally, and possess a broad range of pharmacological ogy; the former pyranoindole, an unmethylated iso-
properties, including anti-coagulant, anti-tumor, and mer of 5, represents the first coumarin-based tri-
anti-inflammatory activities [20].
cyclic condensed system with an isatin moiety. Cy-
clocondensation of the presently synthesized trione 5
with an appropriately substituted o-phenylenediamine
6 in polyphosphoric acid (PPA) at 140 ◦C afforded
Results and Discussion
4-Methylpyrano[2,3-e]indole-2,8,9(7H)-trione (5), the corresponding target pyrano[2’,3’:4,5]indolo[2,3-
a pyrano-isatin which served as key intermediate, b]quinoxalin-2-ones (7a – c) (Scheme 1). The produc-
is prepared from 7-amino-4-methylcoumarin (3), us- tion of compounds of type 7 is initiated by the forma-
ing the classical Sandmeyer methodology [21 – 28] tion of the intermediate carbinolamine 7A (Scheme 2)
(Scheme 1). Thus, interaction of compound 3, ac- which suffers dehydration to produce the correspond-
cessible from m-aminophenol [29, 30], with chloral ing pyrano-isatin-9-imine (anti-7B). This latter imine
hydrate and hydroxylamine hydrochloride produced derivative is presumed to undergo facile anti-syn iso-
the respective isonitroso derivative 4. Subsequent re- merization upon protonation; the cyclocondensation
gioselective intramolecular cyclization (at the C-8 lo- of the syn-isomer 7C, involving the suitably located
cus) in conc. H2SO4 furnished the desired deriva- amino and lactam carbonyl groups, delivers the desired
tive 5 in 65% overall yield. Recently, a pyrano[3,2- pentacyclic system 7.
e]indole-1,2,7(3H)-trione has been prepared [31] from
The IR, MS and NMR spectral data and micro-
6-aminocoumarin by a similar Sandmeyer methodol- analyses for the new compounds 4, 5 and 7 are in

A. Y. Habashneh et al. · Heterocycles [c]-Fused onto Indoloquinoxaline
727
Scheme 2.
accordance with their assigned structures; details are C-4, between 6-H and each of C-4a and C-9a, as well
given in the Experimental Section. Thus, the mass as between CH3 protons and each of C-3 and C-4a.
spectra display the correct molecular ion peaks for For compounds 7a – c, long-range correlations are also
which the measured high-resolution (HRMS) data are observed between 3-H and C-4a, 5-H and C-4/C-13c,
in good agreement with the calculated values. DEPT 6-H and C-4a/C-13b, 9-H and C-12a/C-11, as well as
and 2D (COSY, HMQC, HMBC) experiments showed between 12-H and C-8a/C-10. However, the δ values
1
correlations that helped in the H and 13C signal as- for each of the carbon pairs 8a/12a, 9/12 and 10/11,
signments of most of the different carbons and their and their attached protons 9/12 and 10-CH3/11-CH3
attached/neighboring hydrogens. Long-range corre- (belonging to the quinoxaline ring E in 7a – c), could
lations for compound 4 are observed between 5- not be assigned with certainty and are given as inter-
H and each of C-7, C-8a and C-4, between 6-H changeable.
and each of C-8 and C-4a, between 3-H and C-4a,
as well as between the CH3 protons and each of Experimental Section
C-3 and C-4a. Long-range correlations for compound 5
are observed between 5-H and each of C-6a, C-9b and chased from Acros and were used as received: Chloral hy-
The following chemicals, used in this study, were pur-

728
A. Y. Habashneh et al. · Heterocycles [c]-Fused onto Indoloquinoxaline
drate, 3-aminophenol, methoxycarbonyl chloride, hydroxyl- (C-2), 161.3 (O=C-NH). – C12H10N2O4 (246.22): calcd. C
amine hydrochloride, polyphosphoric acid [84% phospho- 58.54, H 4.09, N 11.38; found C 58.39, H 4.03, N 11.26.
rus (as P2O5)]. IR spectra were recorded from KBr discs – HRMS ((−)-ESI): m/z = 245.05676 (calcd. 245.05623 for
on a Nicolet Impact-400 FT-IR spectrophotometer. 1H and C12H9N2O4, [M–H]−).
13C NMR spectra were recorded on a 500 MHz spectrometer
4-Methylpyrano[2,3-e]indole-2,8,9(7H)-trione (5)
(Bruker Avance-III). Chemical shifts are expressed in ppm
(δ units), with TMS as internal standard; J values for 1H-
Compound 4 (2.46 g, 10 mmol) was added portion-wise
1H coupling constants are given in Hertz. High-resolution
to 95% sulfuric acid (25 mL) at ∼55 ◦C with stirring. There-
mass spectra (HRMS) were acquired (in positive or nega-
tive mode) using the electrospray ion trap (ESI) technique by
collision-induced dissociation on a Bruker Apex-4 (7-Tesla)
instrument. The samples were dissolved in acetonitrile, di-
luted in spray solution (methanol-water 1 : 1 v/v + 0.1%
formic acid) and infused using a syringe pump with a flow
rate of 2 µL. min−1. External calibration was conducted us-
ing arginine cluster in a mass range m/z =175 – 871. Ele-
mental analyses were performed on a Euro Vector elemental
analyzer, model EA 3000.
after, the temperature of the reaction mixture was raised
to 90 ◦C and maintained there for 2 h. The resulting so-
lution was then cooled to r. t., treated with crushed ice
(200 g), and allowed to stand overnight. The precipitated
brown product was filtered, washed successively with hot
water (4×30 mL), cold methanol (10 mL), and dried. Yield:
0.8 g (35%); m. p. 325 – 328 ◦C. – IR (KBr): ν = 3464,
3191, 3088, 3054, 2989, 1765, 1719, 1629, 1586, 1388,
1326, 1270, 1221, 1163, 1083, 892, 862 cm−1. – H NMR
(500 MHz, [D6]DMSO): δ = 2.39 (s, 3H, 4-CH3), 6.30 (s,
1H, 3-H), 6.86 (d, J = 8.3 Hz, 1H, 6-H), 7.97 (d, J = 8.3 Hz,
1H, 5-H), 11.43 (s, 1H, N-H/exchangeable with D2O). –
1
7-Amino-4-methylcoumarin (3)
This compound, required in the present study, was pre- 13C NMR (125 MHz, [D6]DMSO): δ = 18.8 (4-CH3), 105.1
pared according to a literature procedure [29, 30] which (C-9a), 108.8 (C-6), 112.2 (C-3), 115.7 (C-4a), 136.4 (C-
involves interaction of m-aminophenol with methoxycar- 5), 150.4 (C-6a), 154.0 (C-4), 154.1 (C-9b), 159.1 (C-2),
bonyl chloride as the initial step; the resulting N-protected 159.8 (C-8), 180.0 (C-9). – C12H7NO4 (229.19): calcd. C
m-aminophenol underwent cyclocondensation upon reac- 62.89, H 3.08, N 6.11; found C 62.67, H 3.03, N 6.02. –
tion with ethyl acetoacetate and conc. sulfuric acid, fol- HRMS ((+)-ESI): m/z = 252. 02673 (calcd. 252.02728 for
lowed by removal of the N-protecting group (via treatment C12H7NO4Na, [M+Na]+).
with sodium hydroxide) to deliver the title compound; m. p.
7H-4-Methylpyrano[2’,3’:4,5]indolo[2,3-b]quinoxalin-
2(2H)-one (7a)
225 – 226 ◦C (lit. [29, 30]: m. p. 226 – 227 ◦C).
2-(Hydroxyimino)-N-(4-methyl-2-oxo-2H-chromen-7-yl)
A stirred suspension of o-phenylenediamine (6a) (1.1 g,
acetamide (4)
1 mmol) and 5 (2.3 g, 1 mmol) in PPA (20 g) was heated
Crystalline sodium sulfate (36 g), a hot solution of 7- at 135 – 140 ◦C (oil bath) for 2 h. After cooling to room
amino-4-methylcoumarin (3) (3.5 g, 20 mmol) in 4% aque- temperature, the reaction mixture was poured, with stir-
ous hydrochloric acid (25 mL), and a solution of hydrox- ring, onto crushed ice (60 g). The resulting brown precipi-
ylamine hydrochloride (4.6 g, 66 mmol) in water (10 mL) tate was collected under suction, washed successively with
were added successively to a solution of chloral hydrate water, ethanol and diethyl ether, and dried. Yield: 1.9 g
(3.3 g, 20 mmol) in water (10 mL). Thereafter, the reaction (63%); m. p. > 360 ◦C. – IR (KBr): ν = 3426, 3276, 3114,
mixture was refluxed with continuous stirring for 4 h, and 2976, 1710, 1605, 1466, 1384, 1309, 1211, 1129, 1078,
1
the resulting solution was filtered while hot. The precipitated 1046, 907, 843 cm−1. – H NMR (500 MHz, [D6]DMSO):
product was collected by suction filtration, washed with cold δ = 2.50 (s, 3H, 4-CH3), 6.37 (s, 1H, 3-H), 7.55 (d, J = 8.3
water and dried. Yield: 4.5 g (92%); m. p. 216 – 218 ◦C. – IR Hz, 1H, 6-H), 7.79 (dd, J = 7.7, 8.0 Hz, 1H, 10-H or 11-
(KBr): ν = 3286, 3179, 3136, 3109, 2928, 1690, 1621, 1589, H), 7.85 (dd, J = 8.0, 7.7 Hz, 1H, 11-H or 10-H), 8.05
1535, 1395, 1357, 1229, 1149, 1072, 1007, 922, 846 cm−1
.
(d, J = 8.3 Hz, 1H, 5-H), 8.11 (d, J = 8.3 Hz, 1H, 12-H
–
1H NMR (500 MHz, [D6]DMSO): δ = 2.43 (s, 3H, 4- or 9-H), 8.35 (d, J = 7.7 Hz, 1H, 9-H or 12-H), 12.55 (s,
CH3), 6.28 (s, 1H, 3-H), 7.66 (dd, J = 8.7, 2 Hz, 1H, 6- 1H, N-H/exchangeable with D2O). – 13C NMR (125 MHz,
H), 7.69 (s, 1H, N=CH), 7.73 (d, J = 8.7 Hz, 1H, 5-H), [D6]DMSO): δ = 19.3 (4-CH3), 107.3 (C-13b), 109.7 (C-6),
7.84 (d, J = 2 Hz, 1H, 8-H), 10.62 (s, 1H, N-H/exchangeable 112.3 (C-3), 113.9 (C-4a), 127.8 (C-10 or C-11), 128.8 (C-
with D2O), 12.32 (s, 1H, O-H/exchangeable with D2O). – 12 or C-9), 129.5 (C-5), 130.5 (C-11 or C-10), 130.5 (C-9
13C NMR (125 MHz, [D6]DMSO): δ = 18.4 (4-CH3), 106.8 or C-12), 138.8 (C-13a), 139.4 (C-8a or C-12a), 140.5 (C-
(C-6), 113.0 (C-3), 115.9 (C-4a), 116.3 (C-8), 126.3 (C-5), 12a or C-8a), 146.8 (C-7a), 148.0 (C-6a), 151.7 (C-13c),
142.2 (C-7), 144.3 (-C=N), 153.5 (C-8a), 154.0 (C-4), 160.4 155.7 (C-4), 161.2 (C-2). – C18H11N3O2 (301.30): calcd. C

A. Y. Habashneh et al. · Heterocycles [c]-Fused onto Indoloquinoxaline
729
71.75, H 3.68, N 13.95; found C 71.84, H 3.62, N 13.78. 7H-10,11-Dichloro-4-methylpyrano[2’,3’:4,5]indolo[2,3-
– HRMS ((+)-ESI): m/z = 302.09240 (calcd. 302.09295 for b]quinoxalin-2(2H)-one (7c)
C18H12N3O2, [M+H]+).
This compound was prepared from 4,5-dichloro-1,2-
phenylenediamine (6c) (1.8 g, 1 mmol) and 5 (2.3 g, 1 mmol)
7H-4,10,11-Trimethylpyrano[2’,3’:4,5]indolo[2,3-
b]quinoxalin-2(2H)-one (7b)
by following the procedure and experimental conditions as
described above for 7a. Yield: 2.4 g (65%); m. p. > 360 ◦C.
– IR (KBr): ν = 3423, 3213, 3130, 3049, 2976, 1703,
1602, 1440, 1382, 1317, 1240, 1185, 1082, 1052, 980, 918,
866 cm−1. – 1H NMR (500 MHz, [D6]DMSO): δ = 2.54 (s,
3H, 4-CH3), 6.39 (s, 1H, 3-H), 7.52 (d, J = 8.4 Hz, 1H, 6-
H), 8.06 (d, J = 1.7 Hz, 1H, 5-H), 8.32 (s, 1H, 12-H or 9-H),
8.56 (s, 1H, 9-H or 12-H), 12.73 (s, 1H, N-H/exchangeable
with D2O). – 13C NMR (125 MHz, [D6]DMSO): δ = 19.2
(4-CH3), 106.7 (C-13b), 109.1 (C-6), 111.9 (C-3), 113.5 (C-
4a), 128.7 (C-12 or C-9), 129.3 (C-5), 130.3 (C-11 or C-
10), 132.0 (C-10 or C-11), 129.6 (C-9 or C-12), 138.4 (C-
8a or C-12a), 139.1 (C-12a or C-8a), 139.8 (C-13a), 146.3
(C-7a), 147.5 (C-6a), 150.9 (C-13c), 154.4 (C-4), 160.0 (C-
2). – C18H9Cl2N3O2 (370.19): calcd. C 58.40, H 2.45, N
11.35; found C 58.24, H 2.40, N 11.22. – HRMS ((+)-ESI):
m/z = 370.01446 (calcd. 370.01501 for C18H10Cl2N3O2,
[M+H]+).
This compound was prepared from 4,5-dimethyl-1,2-
phenylenediamine (6b) (1.4 g, 1 mmol) and 5 (2.3 g, 1 mmol)
by following the procedure and experimental conditions as
described above for 7a. Yield: 2.2 g (67%); m. p. > 360 ◦C.
– IR (KBr): ν = 3422, 3196, 3108, 2976, 1732, 1600, 1464,
1
1382, 1319, 1217, 1165, 1078, 1055, 918, 866 cm−1. – H
NMR (500 MHz, [D6]DMSO): δ = 2.53 (s, 3H, 4-CH3), 2.61
(s, 3H, 10-CH3 or 11-CH3), 2.64 (s, 3H, 11-CH3 or 10-CH3),
6.36 (s, 1H, 3-H), 7.49 (d, J = 8.5 Hz, 1H, 6-H), 7.84 (s, 1H,
12-H or 9-H), 7.99 (d, J = 8.5 Hz, 1H, 5-H), 8.10 (s, 1H, 9-
H or 12-H), 12.55 (s, 1H, N-H/exchangeable with D2O). –
13C NMR (125 MHz, [D6]DMSO): δ = 19.4 (4-CH3), 20.3
(11-CH3 or 10-CH3), 20.5 (10-CH3 or 11-CH3), 106.7 (C-
13b), 108.9 (C-6), 111.5 (C-3), 113.0 (C-4a), 127.1 (C-12
or C-9), 128.1 (C-5), 128.7 (C-9 or C-12), 136.9 (C-11 or
C-10), 137.4 (C-10 or C-11), 138.7 (C-8a or C-12a), 138.9
(C-12a or C-8a), 140.0 (C-13a), 145.6 (C-7a), 146.5 (C-
6a), 150.6 (C-13c), 154.7 (C-4), 160.3 (C-2). – C20H15N3O2
(329.35): calcd. C 72.94, H 4.59, N 12.76; found C 72.75, H
Acknowledgement
We are grateful to the Deanship of Scientific Research at
4.52, N 12.66. – HRMS ((+)-ESI): m/z = 330.12370 (calcd. the University of Jordan, Amman (Jordan) for financial sup-
330.12425 for C20H16N3O2, [M+H]+).
port.
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