Impact of substituents on the isatin ring on the reaction between isatins with ortho-phenylenediamine

Article abstract of DOI:10.1080/00397911.2010.491596

The reaction of different substituted isatins with ortho-phenylenediamine in acetic acid has been investigated. While electron-donor substituents on isatin shift the reaction toward classical 6H-indolo[2,3-b]quinoxaline ring closure, electron-withdrawing

Full text of DOI:10.1080/00397911.2010.491596

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Impact of Substituents on the Isatin Ring
on the Reaction Between Isatins with
Ortho-Phenylenediamine
Reza Dowlatabadi a , Ali Khalaj a , Sima Rahimian a , Maedeh
Montazeri a , Mohsen Amini a , Ahmadreza Shahverdi b & Elham
Mahjub a
a Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Department of Medicinal Chemistry, Tehran University of Medical
Sciences, Tehran, Iran
b Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Department of Pharmaceutical Biotechnology, Tehran University of
Medical Sciences, Tehran, Iran
Version of record first published: 20 Apr 2011.
To cite this article: Reza Dowlatabadi , Ali Khalaj , Sima Rahimian , Maedeh Montazeri , Mohsen
Amini , Ahmadreza Shahverdi & Elham Mahjub (2011): Impact of Substituents on the Isatin Ring on the
Reaction Between Isatins with Ortho-Phenylenediamine, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 41:11, 1650-1658
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Synthetic Communications1, 41: 1650–1658, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.491596
IMPACT OF SUBSTITUENTS ON THE ISATIN RING ON
THE REACTION BETWEEN ISATINS WITH
ORTHO-PHENYLENEDIAMINE
Reza Dowlatabadi,1 Ali Khalaj,1 Sima Rahimian,1
Maedeh Montazeri,1 Mohsen Amini,1 Ahmadreza Shahverdi,2
and Elham Mahjub1
1Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Department of Medicinal Chemistry, Tehran University of Medical Sciences,
Tehran, Iran
2Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Department of Pharmaceutical Biotechnology, Tehran University of Medical
Sciences, Tehran, Iran
GRAPHICAL ABSTRACT
Abstract The reaction of different substituted isatins with ortho-phenylenediamine in acetic
acid has been investigated. While electron-donor substituents on isatin shift the reaction
toward classical 6H-indolo[2,3-b]quinoxaline ring closure, electron-withdrawing groups
enhance the formation of 3-(20-amino-50-substituted)-quinoxaline-2(1H)-ones. The
structures of all synthesized compounds were assigned by using infrared, mass, 1H NMR,
13
13
13
C NMR, C-1H HSQC, and C-1H heteronuclear multiple bond correlation (HMBC)
spectroscopic data.
Keywords 3-(20-Amino-50-substituted)-quinoxaline-2(1H)-one; 6H-indolo[2,3-b]quinoxa-
line; heterocycles; NMR spectroscopy; rearrangements
Received December 22, 2009.
Address correspondence to Reza Dowlatabadi, Faculty of Pharmacy and Pharmaceutical Sciences
Research Center, Department of Medicinal Chemistry, Tehran University of Medical Sciences, Tehran,
Iran. E-mail: dolataba@tums.ac.ir
1650

ISATIN RING SUBSTITUTION
1651
INTRODUCTION
The reaction of isatin analogs with ortho-phenylenediamines has been the
subject of several investigations.[1–3] It has been shown that the solvent used in the
reaction can shift the reaction towards the formation of different products.[2,4]
6H-Indolo[2,3-b]quinoxalines are the main products when the reaction solvent
is acetic acid, while isatin-3-imines as well as 6H-indolo[2,3-b]quinoxalines are
obtained when tetrahydrofuran (THF), benzene, or methanol are used as the
reaction solvent,[2] and by using N,N-dimethylacetamide and high temperature
spirobenzimidazoles are the main products.[2]
Although the solvent is a key factor influencing the product of reactions, the
diamine used in the reaction has also a dominant role in the formation of various
products.[3,5–9] For instance, reaction of isatin with 4,5-diamino-1,3-dimethyluracil,
4,5-diaminopyrimidine, or 1,2-diamino-naphthalene resulted in the formation of
spirobenzimidazoles. On the other hand, a mixture of linear and spiro compounds
were isolated when 9,10-diaminophenanthrene was used in the reaction,[3,5] and with
2,3-diamino-naphthalene a quinoxaline derivative was isolated from the reaction
mixture.[3]
In the present paper, we report the influence of different substituents on the
isatin ring on the outcome of the reaction between some isatin analogs and
ortho-phenylenediamine. Furthermore, complete NMR assignment of all novel deri-
vatives as well as previously synthesized compounds is reported.
RESULTS AND DISCUSSION
NMR and IR spectroscopic data of synthesized compounds in this study
1
revealed the formation of two different classes of compounds. In the H NMR of
all the compound prepared by the reaction of isatin, methoxy isatin, and methyl isa-
tins with ortho-phenylenediamine, only one exchangeable hydrogen with chemical
shift between 11.62 and 12.83 ppm was observable. This hydrogen can be assigned
as the NH of indole moiety of the final structure. Several aromatic peaks were
1
observable in the H NMR spectra of compounds 3a–h as well as aromatic and ali-
phatic peaks in the 1H NMR spectra of compounds 3i and 3j. (Compounds 3i and 3j
were prepared by the application of 1,2-diamino-1-cyclohexene instead of
orthophenylene-diamine in the reaction.) Assignments of these peaks have been per-
formed by 13C-1H heteronuclear multiple bond correlation (HMBC) spectra.
1H-decoupled 15N NMR spectrum of compound 3a from this class of compounds
was clearly indicative of the presence of three nitrogens in its structure. It must be
mentioned that no carbonyl peaks were observable in the 13C NMR and IR spectra
of this class of compounds. Based on these data, 6H-indolo[2,3-b]quinoxaline ring
structure is assigned for compounds 3a and 3j. Compound 3k was prepared by
nitration of compound 3a, and determination of position of nitro group was per-
formed by acquiring 13C-1H HMBC spectrum by observation of cross peaks between
C9 and H10, and H8 in the spectrum and observation of a cross peak between H8
1
and C6a. A peak with chemical shift of ꢀ264.46 ppm in H-decoupled 15N NMR
spectrum of compound 3a corresponds to indole nitrogen, while two other peaks
observed at ꢀ120.70 ppm and ꢀ73.78 ppm correspond to quinoxaline nitrogens.

1652
R. DOWLATABADI ET AL.
The corresponding 15N NMR values for compound 3d were recorded as
ꢀ266.63 ppm, ꢀ120.19 ppm, and ꢀ73.22 ppm respectively, which shows that inser-
tion of a methoxy group at position 9 of the ring has very little influence on the
nitrogen chemical shifts.
When 5-nitro, 5-bromo, or 5-fluoro isatin were used in the reaction, the
spectroscopic pattern of products was completely different. Apart from the NH
peak observable between 12.56 and 12.64 ppm, another broad peak exchangeable
with deuterium corresponding to two hydrogens was also found in the
1H NMR spectra of compounds 4a–c. Furthermore, a strong peak between
1646 cmꢀ1 and 1665 cmꢀ1 in the IR spectra was indicative of the presence of an ami-
dic carbonyl group in the structure of these compounds, and this finding was
confirmed by observation of a carbonyl peak between 148 ppm and 153 ppm in their
13C NMR spectra.
Among all the probable products that could be expected or assumed from this
reaction, 13C NMR data reject the formation of spirobenzimidazole structure as no
peak corresponding to a quaternary spiro carbon (around 68 ppm) could be found in
the spectrum.[4]
1
Based on the position of carbonyl peak in IR spectra and also H and 13C
NMR and HMBC spectroscopic data of compounds 4a–c, the ring structure of
3-(20-amino-50-substituted)-quinoxaline-2(1H)-one is assigned for this class of
compounds. It has been previously reported that 3-(20-aminophenyl)-quinoxaline-
2(1H)-one was prepared by the reaction of o-phenylenediamine with isatin in alka-
line media.[4] 3-(20-Hydroxyphenyl)-quinoxaline-2(1H)-one was also prepared by
reaction of benzofuran-2,3-dione with o-phenylenediamine.[10] It could be concluded
that insertion of an electron-withdrawing group on the isatin analog shifts the
reaction intermediate towards the cleavage of the isatin ring and formation of
quinoxaline-2(1H)-one structure 4 instead of elimination of the hydroxyl group
Scheme 1. Formation of 6H-indolo[2,3-b]quinoxaline and 3-(20-amino-50-substituted)-quinoxaline-
2(1H)-one rings.

ISATIN RING SUBSTITUTION
1653
Scheme 2. Selective long range 1H-13C heteronuclear shift correlations measured for compounds IIId (left)
and IVa (right).
and typical ring-closure reaction, which results in the formation of indolo[2,3-b]-
quinoxaline ring 3 (Scheme 1).
In 1H-decoupled 15N NMR spectrum of compound 4a, four peaks were
observable. The peak observed at ꢀ292.19 ppm corresponds to the NH2 20, and its
chemical shift correlates well with the previously reported chemical shift data of sub-
stituted anilines.[11] The peak at ꢀ226.56 ppm corresponds to NH1 and the peak at
ꢀ59.40 ppm corresponds to N4 of quinoxaline structure. Finally, the NO2 group was
observable at ꢀ9.67 ppm.
EXPERIMENTAL
Melting points were determined on a Reichert hot-stage apparatus and are
1
uncorrected (Depew, USA). H NMR and 13C NMR spectra were recorded on a
Varian Unity Plus 400 (Palo Alto, USA) or Bruker Avance 500 (Rheinstetten,
Germany) spectrometers. Chemical shifts (d) were reported in part per million
(ppm) relative to tetramethylsilane (TMS) as internal standard. Correlation spec-
troscopy (COSY), gradient 13C-1H (HSQC), and 13C-1H HMBC spectra were
acquired with standard pulse sequences on an Avance 500-MHz instrument.
15
1H-decoupled N spectra were recorded using a flip angle of 30ꢁ and prescan delay
of 5 s. The nitrogen chemical shifts were reported with respect to neat nitromethane
as external reference compound. Infrared (IR) spectra were recorded on a Nicolet
Magna Fourier transform (FT)–IR 550 spectrometer (Madison, WI, USA) (potass-
ium bromide, t ¼ cmꢀ1). Mass spectra were obtained on a Finnigan TSQ-70 instru-
ment (San Jose, CA, USA) at 70 eV. Isatin, o-phenylenediamine, and 1,2-diamino-1-
cyclohexene were purchaced from Merck (Darmstadt, Germany). 5-Bromo-isatin
was purchased from Fluka (Buchs, Switzerland). 5-Methyl-isatin was purchased
from Sigam-Aldrich (Taufkirchen, Germany). 5-Nitro-isatin was purchased from
Aldrich (Milwaukee, USA). 5-Methoxy, 4-methyl, 6-methyl, and 7-methyl-isatin,
7-ethyl-isatin, 6,7-dimethyl-isatin, and 5-fluoro-isatin were prepared by previously
described methods.[12–17]
General Procedure for the Preparation of 6H-Indolo[2,3-
b]quinoxalines 3a–h and 3-(20-Amino-50-substituted)-quinoxaline-
2(1H)-ones 4a–c
A solution of o-phenylenediamine (0.007 mol) and isatin analogs (0.007 mol)
in 20 ml of glacial acetic acid was refluxed overnight. After cooling to room

1654
R. DOWLATABADI ET AL.
temperature the reaction solvent was evaporated to half of its original volume. For
most compounds the crude products precipitated instantly. In the cases in which no
precipitate appeared, the reaction mixture was poured into 25 ml of water. The
resulting precipitate was filtered off, washed with ether, and purified by crystalliza-
tion from methanol=acetic acid.
Preparation of 1,2,3,4-Tetrahydro-6H-indolo[2,3-b]quinoxaline 3i and
9-Methyl-1,2,3,4-tetrahydro-6H-indolo[2,3-b]quinoxaline 3j
These compounds were prepared according to the above described procedure
but by application of 1,2-diamino-1-cyclohexene instead of ortho-phenylenediamine
in the reaction. The final products were purified by flash chromatography.
Preparation of 9-Nitro-6H-indolo[2,3-b]quinoxaline 3k
A solution of 1g of 6H-indolo[2,3-b]quinoxaline 3a in 2 ml of concentrated sul-
furic acid was cooled to 0–2 ꢁC, and a precooled mixture of 2 ml concentrated nitric
acid and 2 ml concentrated sulfuric acid was added to it gradually while the tempera-
ture was maintained below 5 ꢁC. After all the acidic mixture was added, the solution
was maintained at room temperature for 1 h. Subsequently, the mixture was poured
on 20 g of crushed ice, and the resulting precipitate was filtered off, washed with
ether, and purified by crystallization from methanol=acetic acid.
Selected Data
1
6H-Indolo[2,3-b]quinoxaline 3a. Yield 88%; mp 288–289 ꢁC; H NMR: d
12.01 (s, 1H, NH), 8.36 (d, 1H, J ¼ 7.5 Hz, H10), 8.26 (d, 1H, J ¼ 8 Hz, H1 or
H4), 8.08 (d, 1H, J ¼ 8.5 Hz, H1 or H4), 7.81 (t, 1H, J ¼ 7.5 Hz, H2 or H3),
7.70–7.75 (m, 2H, H2 or H3 and H8), 7.59 (d, 1H, J ¼ 8.5 Hz, H7), 7.37 (t, 1H,
J ¼ 8.5 Hz, H9) ppm; 13C NMR: d 145.81 (C5a), 143.96 (C4a or C11a), 140.11
(C10b), 139.75 (C10a), 138.55 (C4a or C11a), 131.25 (C10), 129.00 (C1 or C4),
128.67 (C2 or C3), 127.43 (C1 or C4), 125.87 (C2 or C3), 122.19 (C9), 120.64
(C8), 118.95 (C6a) 111.94 (C7) ppm; 15N NMR: d ꢀ73.78 (N quinoxaline),
ꢀ120.70 (N quinoxaline), ꢀ264.46 (N indole) ppm; IR (KBr): V 3085, 2926, 1616,
1455, 1404, 1336, 1243, 1203, 1137, 742 cmꢀ1; MS: m=z 219.2 (Mþ, 100%), 218.2
(60%), 191 (5%).
10-Methyl-6H-indolo[2,3-b]quinoxaline 3b. Yield 66%; mp 319–320 ꢁC;
1H NMR: d 12.01 (s, 1H, NH), 8.24 (d, 1H, J ¼ 8.4 Hz, H1 or H4), 8.05 (d, 1H,
J ¼ 8.4 Hz, H1 or H4), 7.80 (t, 1H, J ¼ 8.4 Hz, H2 or H3), 7.71 (t, 1H, J ¼ 8.4 Hz,
H2 or H3), 7.58 (t, 1H, J ¼ 8 Hz, H8), 7.39 (d, 1H, J ¼ 8 Hz, H7), 7.15 (d, 1H,
J ¼ 8 Hz, H9), 3.04 (s, 3H, methyl) ppm. 13C NMR: d 146.01 (C5a), 144.45 (C4a
or C11a), 141.83 (C10b), 139.87 (C10), 139.85 (C10a), 138.52 (C4a or C11a),
128.87 (C1 or C4), 128.36 (C2 or C3), 127.39 (C1 or C4), 125.79 (C2 or C3),
122.08 (C9), 121.97 (C8), 116.55 (C6a), 111.99 (C7), 22.03 (methyl) ppm; IR
(KBr): V 764, 1014, 1137, 1306, 1403, 1588, 1614, 2914, 3083 cmꢀ1; MS: m=z
233.2 (Mþ, 100%), 232.2 (50%).

ISATIN RING SUBSTITUTION
1655
1
9-Methyl-6H-indolo[2,3-b]quinoxaline 3c. Yield 70%; mp 295–296 ꢁC; H
NMR: d 11.90 (s, 1H, NH), 8.23 (d, 1H, J ¼ 8.4 Hz, H1 or H4), 8.16 (d, 1H,
J ¼ 3.2 Hz, H10), 8.05 (d, 1H, J ¼ 8.4 Hz, H1 or H4), 7.80 (t, 1H, J ¼ 8.4 Hz, H2
or H3), 7.71 (t, 1H, J ¼ 8.4 Hz, H2 or H3), 7.53 (d, 1H, J ¼ 8.4 Hz, H7), 7.48 (dd,
1H, J ¼ 8.4 Hz, J ¼ 3.2 Hz, H8), 2.51 (s, 3H, methyl) ppm; 13C NMR: d 146.01
(C5a), 142.09 (C4a or C11a), 140.08 (C10b), 139.71 (C10a), 138.49 (C4a or C11a),
132.41 (C10), 129.68 (C9), 129.00 (C1 or C4), 128.57 (C2 or C3), 127.39 (C1 or
C4), 125.75 (C2 or C3), 121.96 (C8), 119.02 (C6a), 111.69 (C7), 20.83 (methyl)
ppm; IR (KBr): V 3134, 2919, 1619, 1588, 1490, 1368, 1204, 1122, 810, 758 cmꢀ1
MS: m=z 233.2 (Mþ, 100%), 232.2 (40%).
;
9-Methoxy-6H-indolo[2,3-b]quinoxaline 3d. Yield 69%; mp 309–310 ꢁC;
1H NMR: d 11.85 (s, 1H, NH), 8.23 (d, 1H, J ¼ 8.4 Hz, H1 or H4), 8.05 (d, 1H,
J ¼ 8.4 Hz, H1 or H4), 7.85 (d, 1H, J ¼ 2.4 Hz, H10), 7.79 (t, 1H, J ¼ 8.4 Hz, H2
or H3), 7.71 (t, 1H, J ¼ 8.4 Hz, H2 or H3), 7.51 (d, 1H, J ¼ 8.8 Hz, H7), 7.33 (dd,
1H, J ¼ 8.8 Hz, J ¼ 2.4 Hz, H8), 3.91 (s, 3H, methoxy) ppm; 13C NMR: d ¼ 146.68
(C5a), 140.64 (C4a or C11a), 140.16 (C10b), 139.00 (C10a), 138.84 (C4a or C11a),
129.46 (C1 or C4), 129.14 (C2 or C3), 127.92 (C1 or C4), 126.27 (C2 or C3),
120.90 (C8), 119.75 (C6a), 113.44 (C7), 104.89 (C10), 56.19 (methoxy) ppm;
15N NMR: d ꢀ73.22 (N quinoxaline), ꢀ120.19 (N quinoxaline), ꢀ266.63 (N indole)
ppm; IR (KBr): V 3373, 3137, 1490, 1435, 1278, 1213, 1027, 760 cmꢀ1; MS: m=z
249.2 (Mþ, 95%), 234.2 (100%), 206.2 (30%).
8-Methyl-6H-indolo[2,3-b]quinoxaline 3e. Yield 68%; mp > 320 ꢁC;
1H NMR: d 11.95 (s, 1H, NH), 8.22 (d, 1H, J ¼ 8 Hz, H1 or H4), 8.21 (d, 1H,
J ¼ 8 Hz, H10), 8.05 (d, 1H, J ¼ 8 Hz, H1 or H4), 7.79 (t, 1H, J ¼ 8 Hz, H2 or
H3), 7.70 (t, 1H, J ¼ 8 Hz, H2 or H3), 7.37 (s, 1H, H7), 7.18 (d, 1H, J ¼ 8 Hz,
H9), 2.54 (s, 3H, methyl) ppm. 13C NMR: d 145.70 (C5a), 144.03 (C4 or C11a),
141.10 (C10b), 139.49 (C10a), 138.57 (C4a or C11a), 136.30 (C8), 130.85 (C10),
129.22 (C1 or C4), 128.52 (C2 or C3), 127.34 (C1 or C4), 125.70 (C2 or C3), 121.90
(C9), 117.17 (C6a), 109.12 (C7), 19.16 (methyl), ppm; IR (KBr): V 3054, 1624,
1407, 1128, 754, 593 cmꢀ1; MS: m=z 233.2 (Mþ, 100%), 232.2 (50%), 108 (20%).
7-Methyl-6H-indolo[2,3-b]quinoxaline 3f. Yield 64%; mp > 320 ꢁC; 1H
NMR: d 12.08 (s, 1H, NH), 8.24 (d, 1H, J ¼ 8 Hz, H1 or H4), 8.17 (d, 1H, J ¼ 7.2 Hz,
H10), 8.07 (d, 1H, J ¼ 8 Hz, H1 or H4), 7.80 (t, 1H, J ¼ 8 Hz, H2 or H3), 7.72 (t, 1H,
J ¼ 8 Hz, H2 or H3), 7.51 (d, 1H, J ¼ 7.2 Hz, H8), 7.28 (t, 1H, J ¼ 7.2 Hz, H9), 2.58
(s, 3H, methyl) ppm; 13C NMR: d 146.15 (C5a), 143.16 (C4a or C11a), 141.15
(C10b), 140.13 (C10a), 138.64 (C4a or C11a), 131.85 (C10), 129.02 (C1 or C4),
128.64 (C2 or C3), 127.52 (C1 or C4), 125.94 (C2 or C3), 121.46 (C7), 120.76
(C9), 119.56 (C8), 118.65 (C6a), 16.67 (methyl) ppm; IR (KBr): V 3085, 2912,
1619, 1410, 1338, 1203, 1081, 748 cmꢀ1; MS: m=z 233.2 (Mþ, 100%), 232.2 (80%),
216.2 (10%).
7-Ethyl-6H-indolo[2,3-b]quinoxaline 3g. Yield 67%; mp > 320 ꢁC; 1H
NMR: d 12.07 (s, 1H, NH), 8.19 (d, 1H, J ¼ 7.2 Hz, H10), 8.07 (d, 1H, J ¼ 8 Hz,
H1 or H4), 7.80 (t, 1H, J ¼ 8 Hz, H2 or H3), 7.72 (t, 1H, J ¼ 8 Hz, H2 or H3),
7.54 (d, 1H, J ¼ 7.2 Hz, H8), 7.31 (t, 1H, J ¼ 7.2 Hz, H9), 2.98 (q, 2H, J ¼ 7.2 Hz,
CH2), 1.33 (t, 3H, J ¼ 7.2 Hz, CH3) ppm. 13C NMR: d 146.17 (C5a), 142.47 (C4a

1656
R. DOWLATABADI ET AL.
or C11a), 140.16 (C10b), 140.13 (C10a), 138.62 (C4a or C11a), 130.19 (C10), 129.02
(C1 or C4), 128.62 (C2 or C3), 127.61 (C7), 127.50 (C1 or C4), 125.91 (C2 or C3),
120.93 (C9), 119.65 (C8), 118.77 (C6a), 23.37 (CH2), 14.38 (CH3) ppm; IR (KBr):
V 3123, 2966, 1645, 1465, 1404, 1332, 1204, 748 cmꢀ1; MS: m=z 247.2 (Mþ,
100%), 232.2 (80%), 116.2 (20%).
7,8-Dimethyl-6H-indolo[2,3-b]quinoxaline 3h. Yield 63%; mp > 320 ꢁC;
1H NMR: d 11.93 (s, 1H, NH), 8.21 (d, 1H, J ¼ 8.4 Hz, H1 or H4), 8.05 (d, 1H,
J ¼ 8 Hz, H10), 8.04 (d, 1H, J ¼ 8.4 Hz, H1 or H4), 7.78 (t, 1H, J ¼ 8.4 Hz, H2 or
H3), 7.70 (t, 1H, J ¼ 8.4 Hz, H2 or H3), 7.19 (d, 1H, J ¼ 8 Hz, H9), 2.49 (s, 3H,
methyl), 2.45 (s, 3H, methyl) ppm; 13C NMR: d 146.45 (C5a), 143.59 (C4a or
C11a), 140.43 (C10b), 139.94 (C10a), 139.93 (C8), 138.59 (C4a or C11a), 128.86
(C1 or C4), 128.30 (C2 or C3), 127.41 (C1 or C4), 125.75 (C2 or C3), 122.94
(C10), 119.62 (C7), 119.15 (C9), 116.82 (C6a), 20.08 (methyl), 13.15 (methyl) ppm;
IR (KBr): V 3085, 1617, 1406, 1331, 1210, 1079, 758 cmꢀ1; MS: m=z 247.2 (Mþ,
100%), 246.2 (80%), 232.2 (85%), 219.2 (10%).
1,2,3,4-Tetrahydro-6H-indolo[2,3-b]quinoxaline 3i. Yield 41%; mp
1
253–254 ꢁC; H NMR: d 11.76 (s, 1H, NH), 8.12 (d, 1H, J ¼ 8 Hz, H10), 7.49–7.54
(m, 2H, H7 and H8 or H9), 7.23–7.28 (m, 1H, H8 or H9), 3.00–3.04 (m, 4H, CH2
2 & 3), 1.90–1.91 (m, 4H, CH2 1 & 4) ppm; 13C NMR: d 147.80 (C5a), 144.00
(C4a or C11a), 143.76 (C10b), 140.10 (C10a), 132.52 (C4a or C11a), 128.03 (C10),
120.52 (C8), 119.97 (C9), 119.33 (C6a), 111.89 (C7), 32.17 (C2 or C3), 31.65 (C2
or C3), 22.74 (C1 or C4), 22.50 (C1 or C4) ppm; IR (KBr): V 3134, 2936, 1401,
1314, 1194, 1138, 1103, 748 cmꢀ1; MS: m=z 223.2 (Mþ, 100%), 222.2 (50%).
9-Methyl-1,2,3,4-tetrahydro-6H-indolo[2,3-b]quinoxaline 3j. Yield 38%;
1
mp 275–276 ꢁC; H NMR: d 11.62 (s, 1H, NH), 7.92 (d, 1H, J ¼ 1.8 Hz, H10),
7.41 (d, 1H, J ¼ 8 Hz, H7), 7.34 (dd, 1H, J ¼ 8 Hz, J ¼ 1.8 Hz H8), 2.99–3.03 (m,
4H, CH2 2 & 3), 2.46(s, 3H, methyl), 1.90–1.91(d, 4H, J ¼ 5.2 Hz, CH2 1 & 4)
ppm; 13C NMR: d 147.54 (C5a), 144.21 (C4a or C11a), 143.47 (C10b), 138.33
(C10a), 132.44 (C4a or C11a), 129.37 (C10), 128.82 (C9), 120.24 (C8), 119.42
(C6a), 111.63 (C7), 32.16 (C2 or C3), 31.67 (C2 or C3), 22.76 (C1 or C4), 22.53
(C1 or C4), 21.01 (methyl) ppm; IR (KBr): V 3124, 2928, 2845, 1488, 1590, 1434,
1236, 1196, 1148, 1122, 791 cmꢀ1; MS: m=z 237.2 (Mþ, 100%), 236.2 (60%).
9-Nitro-6H-indolo[2,3-b]quinoxaline 3k. Yield 60%; mp > 320 ꢁC; 1H
NMR: d 12.83 (s, 1H, NH), 9.13 (d, 1H, J ¼ 2.5 Hz, H10), 8.58 (dd,1H, J ¼ 9 Hz
J ¼ 2.5 Hz, H8), 8.32 (dd, 1H, J ¼ 7.5 Hz J ¼ 1.5 Hz, H1 or H4), 8.15 (dd, 1H,
J ¼ 7.5 Hz, J ¼ 1.5 Hz, H1 or H4), 7.90 (td, 1H, J ¼ 7.5 Hz, J ¼ 1.5 Hz, H2 or H3),
7.83 (td, 1H, J ¼ 7.5 Hz J ¼ 1.5 Hz, H2 or H3), 7.76 (d, 1H, J ¼ 9 Hz, H7) ppm;
13C NMR: d 147.59 (C9), 146.89 (C5a), 141.19 (C4a or C11a), 140.56 (C10b),
139.16 (C10a), 139.05 (C4a or C11a), 129.86 (C2 or C3), 129.33 (C1 or C4),
127.83 (C1 or C4), 127.13 (C2 or C3), 126.42 (C8), 118.99 (C6a), 118.16 (C10),
112.53 (C7) ppm; IR (KBr): V 3088, 3022, 1614, 1516, 1470, 1337, 1118, 1086,
830, 753 cmꢀ1; MS: m=z 264.2 (Mþ, 100%), 234.2 (30%).
3-(2’-Amino-5’-nitrophenyl)-quinoxaline-2(1H)-one
4a. Yield
76%;
mp > 320 ꢁC; 1H NMR: d 12.64 (s, 1H, NH), 9.38 (d, 1H, J ¼ 3 Hz, H60), 8.04 (broad,

ISATIN RING SUBSTITUTION
1657
2H, NH2), 8.03 (dd, 1H, J ¼ 9 Hz J ¼ 3 Hz, H40), 7.91 (d, 1H, J ¼ 7 Hz, H5), 7.55 (t,
1H, J ¼ 7 Hz, H7), 7.33 (d, 1H, J ¼ 7 Hz, H8), 7.31 (t, 1H, J ¼ 7 Hz, H6), 6.91 (d, 1H,
13
J ¼ 9 Hz, H30) ppm; C NMR: d 154.76 (C50), 154.62 (C20), 153.36 (C2), 134.88
(C10), 131.71 (C4a), 130.96 (C8a), 130.31 (C7), 129.10 (C60), 128.32 (C5), 126.36
(C40), 1123.35 (C6), 115.72 (C30), 115.03 (C8), 114.68 (C3) ppm; 15N NMR: d
ꢀ9.67, ꢀ59.40 (N quinoxaline), ꢀ226.56 (N quinoxaline), ꢀ292.19 (N indole)
ppm; IR (KBr): V 3400, 3237, 1646, 1615, 624, 759, 1107, 1270, 1300, 1326,
1473 cmꢀ1; MS: m=z 282.2 (Mþ, 80%), 280.2 (100%), 255.2 (60%), 252.2 (25%),
224.2 (60%), 208.2 (80%), 181.2 (40%).
3-(2’-Amino-5’-bromophenyl)-quinoxaline-2(1H)-one 4b. Yield 71%; mp
1
249–250 ꢁC; H NMR: d 12.56 (s, 1H, NH), 8.35 (d, 1H, J ¼ 2 Hz, H60), 7.82 (d,
1H, J ¼ 8 Hz, H5), 7.52 (t, 1H, J ¼ 8 Hz, H7), 7.29–7.33 (m, 2H, H6 & H8), 7.27
13
(dd, 1H, J ¼ 8.8 Hz J ¼ 2 Hz, H40), 6.73 (broad, 2H, NH2), 6.78 (d, 1H, J ¼ 8.8 Hz,
H30) ppm; C NMR: d 154.55 (C20), 154.19 (C2), 148.01 (C10), 133.15 (C60),
132.99 (C40), 131.52 (C4a), 131.10 (C8a), 129.93 (C7), 128.07 (C5), 123.25 (C6),
118.52 (C3), 118.16 (C30), 114.90 (C8), 104.91 (C50) ppm; IR (KBr): V 3394, 3083,
1664, 1604, 1569, 1480, 1216, 817, 748, 600 cmꢀ1; MS: m=z 317.2 (M þ 2 100%),
315.2 (100%), 300.2 (20%), 289.2 (60%), 287.2 (55%), 235.2 (20%), 208.2 (25%).
3-(2’-Amino-5’-fluorophenyl)-quinoxaline-2(1H)-one 4c. Yield 70%; mp
1
262–263 ꢁC; H NMR: d ¼ 12.56 (s, 1H, NH), 8.05 (dd, 1H, J ¼ 11.6 Hz, J ¼ 3.2 Hz,
H60), 7.83 (d, 1H, J ¼ 8.4 Hz, H5), 7.51 (t, 1H, J ¼ 8.4 Hz, H7), 7.33 (d, 1H,
J ¼ 8.4 Hz, H8), 7.31 (t, 1H, J ¼ 8.4 Hz, H6), 7.05 (m, 1H, H40), 6.82 (dd, 1H,
J ¼ 8.8 Hz, J ¼ 5.2 Hz, H30), 6.51 (s, broad, 2H, NH2) ppm; 13C NMR: d 154.67
1
(C20), 154.08 (d, JCF ¼ 72 Hz, C50), 151.45 (C2), 145.63 (C10), 131.57 (C4a),
131.15 (C8a), 130.02 (C7), 128.12 (C5), 123.40 (C6), 119.31 (C3), 118.18 (d,
3
2
2JCF ¼ 22 Hz, C60), 117.17 (d, JCF ¼ 6 Hz, C30), 116.66 (d, JCF ¼ 24 Hz, C40),
114.97 (C8) ppm; IR (KBr): V 3391, 2853, 1660, 1491, 1429, 1235, 1168, 887, 751,
600 cmꢀ1 MS: m=z 255.2 (Mþ, 5%), 233.2 (5%), 149.2 (10%), 78.2 (75%), 63.2
(80%), 44.2 (100%).
ACKNOWLEDGMENT
This research was supported by a grant from the research council of Tehran
University of Medical Sciences.
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