Synthesis of substituted pyrazino[5,6-b]pyrimidine and some indole derivatives

Article abstract of DOI:10.1080/10426500802590228

Refluxing dimethyl acetylenedicarboxylate (DMAD) or 1,2-dibenzoylacetylene with isatin-3-thiosemicarbazone or isatin-3-thiocarbohydrazone in methanol produced 3-substituted oxindoles in good yields. Reaction of equimolecular amounts of 5,6-diamino-urasil-

Full text of DOI:10.1080/10426500802590228

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Synthesis of Substituted
Pyrazino[5,6-b]pyrimidine and
Some Indole Derivatives
Navabeh Nami a , Masoumeh Hosseinzadeh a , Nasrin
Nami b & Mina Haghdadi c
a Department of Chemistry, Islamic Azad University,
Ghaemshahr, Mazandaran, Iran
b Department of Chemistry, Islamic Azad University,
Amol, Mazandaran, Iran
c Department of Chemistry, Islamic Azad University,
Babol, Mazandaran, Iran
Version of record first published: 03 Nov 2009
To cite this article: Navabeh Nami, Masoumeh Hosseinzadeh, Nasrin Nami & Mina
Haghdadi (2009): Synthesis of Substituted Pyrazino[5,6-b]pyrimidine and Some
Indole Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 184:11,
2846-2855
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Phosphorus, Sulfur, and Silicon, 184:2846–2855, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802590228
Synthesis of Substituted Pyrazino[5,6-b]pyrimidine
and Some Indole Derivatives
Navabeh Nami,1 Masoumeh Hosseinzadeh,1 Nasrin Nami,2
and Mina Haghdadi3
1Department of Chemistry, Islamic Azad University, Ghaemshahr,
Mazandaran, Iran
2Department of Chemistry, Islamic Azad University, Amol,
Mazandaran, Iran
3Department of Chemistry, Islamic Azad University, Babol,
Mazandaran, Iran
Refluxing dimethyl acetylenedicarboxylate (DMAD) or 1,2-dibenzoylacetylene with
isatin-3-thiosemicarbazone or isatin-3-thiocarbohydrazone in methanol produced
3-substituted oxindoles in good yields. Reaction of equimolecular amounts of 5,6-
diamino-urasil-solfate, trans-(1R,2R)-diaminocyclohexane, and 3,4-diamino-1,2,4-
triazol-5-methyl hydrochlorid with isatin in ethanol (85%) afforded tetracyclic ring
systems and ring-opened products in mild reaction conditions.
Keywords
Indolo[2,3-b]-4a,5,6,7,8,8a-hexahydroquinoxaline; isatin-3-substituted;
pyrazino[5,6-b]pyrimidine; triazolo [4,3:3ꢀ,2ꢀ]triazino[5, 6-b]indole
INTRODUCTION
Five and six membered ring of heterocyclic compounds have occupied
a prominent place among various classes of organic compounds for
their diverse biological activities.1 Among a wide variety of heterocy-
cles that have been explored for developing pharmaceutically impor-
tant molecules, isatin(1H-indole-2,3-dione) derivatives have played an
important role in medicinal chemistry.2–9 Isatins are synthetically ver-
satile substrates, where they can be used for the synthesis of a large
variety of compounds, such as indoles and quinolines, and as raw mate-
rial for drug synthesis.10–11 Isatins have also been found in mammalian
tissue.12 In continuation of our work on the synthesis of heterocyclic
Received 3 March 2008; accepted 22 October 2008.
The authors are thankful to the Islamic Azad University of Ghaemshahr for their
support.
Address correspondence to Navabeh Nami, Department of Chemistry, Islamic Azad
University, Ghaemshahr, Mazandaran, Iran. E-mail: Navabehnami@yahoo.com
2846

Substituted Pyrazino[5,6-b]pyrimidine
2847
SCHEME 1
systems containing nitrogen and sulfur,13 we describe here the synthe-
sis of new isatin derivatives with isatin-3-imines and tetracyclic ring
systems.
RESULTS AND DISCUSSION
Reaction of isatin-3-thiosemicarbazone 1 with 1,2-dibenzoylacetylene
214 yielded 2-(2-oxo-1,2-dihydroindol-3-yliden)hydrazon-4-phenyl-1,3-
thiazol-5-methylidenbenzoyl 3 (Scheme 1). The structure of compound
3 was deduced from its elemental analyses and its IR, 1H, and 13C NMR
spectrum. The 1H NMR of compound 3 exhibited a broad resonance at
δ 10.61 ppm arising from the NH proton along with a sharp singlet
signal from the exomethylene proton C=CH in the region δ 7.38 ppm.
We can assume that in the reaction of 1 with 2, the sulfur and nitro-
gen nucleophiles add to the activated triple bond (by Michael type addi-
tion) and C=O under cyclocondensation reaction. The reaction of isatin-
3-thiocarbohydrazone 4 with 1,2-dibenzoylacetylene 2 and dimethyl
acetylenedicarboxylate in methanol afforded 2-(2-oxo-1,2-dihydroindol-
3-yliden)hydrazon-5-phenyl-1,3,4-thiadiazin-6-methylidenbenzoyl
5
and 2-(2-oxo-1,2-dihydroindol-3-ylidene)hydrazone-4,8-dihydro-pyrano
[2,3-e]-1,3,4-thiadiazin-6,7,8-trimethylcarboxylate 7, respectively
(Scheme 2). The 1H NMR spectrum of compound 5 exhibited two broad
peaks at δ 10.34 and 9.87 ppm arising from NH protons along with a
sharp singlet from exomethylene proton C=CH in the region δ 7.14
ppm. The IR spectrum of the reaction product 5 showed NH stretching
at 3428 and 3169 cm−1, and two CO groups stretching at 1704 and
1693 cm−1
.
TLC and the NMR spectrum of compound 7 showed that only a sin-
gle, pure compound was present. The 1H NMR spectrum of compound 7
showed no CH stretching for C=CH exomethylene present in structure

2848
N. Nami et al.
SCHEME 2
6, and the appearance of a sharp singlet at δ 3.65 ppm for one C-CH
group also was indicative of the formation of 7. The IR spectrum of this
reaction product showed NH stretching at 3252–3326 cm−1. The mass
spectrum of this compound displayed a molecular ion peak at appropri-
ate m/z 487. Any initial fragmentation involves loss from or complete
loss of the side chain and section of the ring systems. These data indi-
cated that a Michael type addition and Diels–Alder [4+2] cycloaddition
reaction have occurred to afford 7. The reaction took place via first
addition of S and NH2 groups of the isatin-3-thiocarbohydrazone to
acetylene bond and C=O groups of DMAD by Michael type addition
and water elimination. The reaction likely took place through the in-
termediate formation of 6 followed by Diels–Alder [4+2] cycloaddition
reaction to give 7 (Scheme 3).
Several members of the tetracyclic ring system 6H-indolo[2,3-
b]quinoxaline 8, first synthesized15 in 1895 by Schunck and March-
lewski from isatin (indole-2,3-diones) 11 and o-phenylenediamine,
have been intensely studied16 because some derivatives with
basic side chains in the 6-position, such as 2,3-dimethyl-6-(2-
dimethylaminoethyl)-6H-indolo[2,3-b]quinoxaline 8b, exhibit potent
antiviral activity, against, e.g., HSV-1, CMV, and VZV.17 The condensa-
tion between isatin and o-phenylenediamine, depending on the solvent
used, gives rise to three different products (8a, 9, or 10) (Scheme 4). In
acidic solvents, such as acetic acid, the linear product 8a is the domi-
nating product. The spiro compound 9 reportedly has been obtained in a
high yield when the reaction was performed in N-methyl-2-pyrrolidone,
whereas the ring-opened quinoxalinone 10 was the major product when
THF or benzene was used as solvent.18–20
As indicated in Scheme 5, the reaction of isatin (1H-indole-
2,3-dione) 11 with 5,6-diamino-urasil-sulfate 12, trans-(1R,2R)-
diaminocyclohexane (DACH) 14, and 3,4-diamino-1,2,4-triazol-5-

Substituted Pyrazino[5,6-b]pyrimidine
2849
SCHEME 3
SCHEME 4

2850
N. Nami et al.
SCHEME 5

Substituted Pyrazino[5,6-b]pyrimidine
2851
methyl hydrochlorid 16 in ethanol 85% afforded 3-(2-aminophenyl)-6,8-
dihydroxy-pyrazino[5,6-b]pyrimidine 13a, 4aR,11aR-6H-indolo[2,3-
b]-4a,5,6,7,8,8a-hexahydroquinoxaline 15a, and 10H-3-methyl-1,2,4-
triazolo[4,3:3ꢀ,2ꢀ]-1,2,4-triazino[5,6-b]indole 17a, respectively. The con-
densation of isatin with o-phenylenediamine in refluxing methanol has
been reported18 to produce a mixture of 8a (39%), 10 (30%), and only
traces of the spiro compound 9. Now, in a similar experiment in ethanol
85% using compounds 14 and 16 as partners to isatin, the linear com-
pounds 15a and 17a (which can be considered as a higher homologue
of 8) were obtained as the sole products, while none of the possible
spiro products or the ring-opened products was observed. The reaction
of isatin and compound 12 in ethanol 86% gave ring-opened product
13a. Two different nucleuphilic groups in compounds 12, 14, and 16
offer the possibility of structures 13b, 15b, and 17b (Scheme 5), but
the spectroscopic data showed compounds 13a, 15a, and 17a.
The IR spectrum of 13a exhibits a characteristic carbonyl at 1710
cm−1, OH at 3300–3490 cm−1, NH2 at 3185 cm−1, and NH at 3398 cm−1
.
1
The H NMR spectrum features signals at 10.67 and 11.93 ppm from
the OH groups and a signal at 10.57 ppm from the NH. The strong
deshielding of the amide proton showed an intramolecular hydrogen
bond NH.=O in compound 13a. The mass spectrum of 13a showed
1
m/z = 271 (M+) for C12H9N5O3. The IR and H NMR spectrum of
compound 15a clearly indicated the NH group at 3438 cm−1 and δ 6.73
ppm, respectively. The mass spectrum of this compound displayed a
1
molecular ion peak at 225 m/z value. The H NMR spectrum of 17a
included a 3H singlet from the methyl group (2.74 ppm) and a broad
signal (12.18 ppm) from the NH function.
CONCLUSIONS
In conclusion, a general and convenient synthesis of functionalized
C=S and NH2 has been developed using a nucleophilic reaction. The
main advantages of these reactions are mild reaction conditions. In
this article, we have shown that simple indole-2,3-dione is reacted with
1,2-diamino compounds in ethanol (85%) resulting in conversion to
tetracyclic compounds and a ring-opened product.
EXPERIMENTAL
Trans-(1R,2R)-DACH and 5,6-diamino-urasil-sulfate were purchased
from Aldrich Chemical Company. The other chemicals and sol-
vents were purchased from Merck Chemical Company. 1,2-
Dibenzoylacetylene was prepared by the method in the literature.14 The

2852
N. Nami et al.
melting points were obtained using an Electrothermal IA 9100 Digital
melting point apparatus. The IR spectra were recorded on a Bruker
IFS-88 instrument (the samples as KBr disks for the range 4000–400
cm−1). The 1H and 13C NMR spectra were recorded on a Bruker AC-300
spectrometer (1H, 300.134 MHz; 13C, 75.469 MHz) using TMS as an
internal standard. Mass spectrometric measurements were made on
an Agilent Technologies 6890 N Network GC system. The C, H, and N
analyses were performed by the microanalytical service of the NIOC
Research Institute of Petroleum Industry.
General Procedure
A mixture of two reactants was heated to reflux in methanol (40 mL)
for 2 h. The progress of the reaction was monitored by TLC, using n-
hexane:ethylacetate (4:1). The solution was cooled and the separated
solid was filtered. The crude product was purified by recrystallization
from methanol.
2-(2-Oxo-1,2-dihydroindol-3-yliden)hydrazon-4-phenyl-1,3-
thiazol-5-methylidenbenzoyl (3)
3 was obtained from the reaction of isatin-3-thiosemicarbazone (10
mmol, 2.24 g) 1 with 1,2-dibenzoylacetylene (10 mmol, 2.34 g) 2, and
this compound was obtained as an orange powder from methanol. Yield
77%, mp: 271–272◦C; MS: m/z 436 (M+); FT-IR: NH 3428, 3169, CO
1693 cm−1; 1H NMR (DMSO-d6) δ 10.61 (br, 1H, NH), 7.81 (d, J = 7.6
Hz, 1H, Ar-H), 7.68 (m, 1H, Ar-H), 7.61 (d, J = 7.6 Hz, 1H, Ar-H), 7.49
(m, 5H, Ar-H), 7.38 (s, 1H, C = CH), 7.24 (m, 4H, Ar-H), 7.04 (m, 1H,
Ar-H), 6.88 (s, 1H, Ar-H); 13C NMR (DMSO-d6) δ 118.8 (C-Ar), 124.6
(CH = C), 121.4 (C-Ar), 123.8 (C-Ar), 125.3 (C-Ar), 126.1 (C-Ar), 127.9
(C-Ar), 128.7 (C-Ar), 130.4 (C-Ar), 131.6 (C-Ar), 131.9 (C-Ar), 132.4 (C-
Ar), 134.0 (C- Ar), 136.1 (C-Ar), 137.1 (C-Ar), 145.7 (C = CH), 151.0
(NH-C = O), 154.2 (C = N-N = ), 159.1 (C = N), 162.8 (C = N), 177.3 (C
= O). Anal. Calcd. for C25H16N4O2S: C, 68.81; H, 3.67; N, 12.84. Found:
C, 68.78; H, 3.66; N, 12.83.
2-(2-Oxo-1,2-dihydroindol-3-yliden)hydrazon-5-phenyl-1,3,4-
thiadiazin-6-methylidenbenzoyl (5)
5 was obtained from the reaction of isatin-3-thiocarbohydrazone (10
mmol, 2.35 g) 1 with 1,2-dibenzoylacetylene (10 mmol, 2.34 g) 2, and
this compound was obtained as yellow crystals from methanol. Yield
73%, mp: 187–188◦C; MS: m/z 451 (M+); FT-IR: NH 3428, 3169, CO
1704, 1693 cm−1; 1H NMR (DMSO-d6) δ 10.34 (br, 1H, NH), 9.87 (br, 1H,
NH), 8.16 (m, 2H, Ar-H), 7.88 (m, 3H, Ar-H), 7.80 (d, J = 7.5 Hz, 1H,

Substituted Pyrazino[5,6-b]pyrimidine
2853
Ar-H), 7.71 (t, J = 7.6 Hz, 1H, Ar-H), 7.49 (m, 5H, Ar-H), 7.14 (s, 1H, =
CH), 7.19 (t, J = 7.6 Hz, 1H, Ar-H), 7.02 (d, J = 7.5 Hz, 1H, Ar-H); 13
C
NMR (DMSO-d6) δ 112.5 (C-Ar), 119.6 (CH = C), 122.4 (C-Ar), 122.8
(C-Ar), 126.3 (C-Ar), 127.1 (C-Ar), 128.9 (C-Ar), 129.5 (C-Ar), 129.7 (C-
Ar), 130.4 (C-Ar), 131.8 (C-Ar), 132.6 (C-Ar), 136.4 (C- Ar), 137.0 (C-
Ar), 138.1 (C-Ar), 144.2 (C = NNH-), 148.0 (C = CH), 152.0 (NH-C =
O), 159.1 (C = N), 167.8 (HN-C = N), 176.0 (C = O). Anal. Calcd. for
C25H17N5O2S: C, 66.52; H, 3.77; N, 15.52. Found: C, 66.49; H, 3.76; N,
15.55.
2-(2-Oxo-1,2-dihydroindol-3-ylidene)hydrazone-4,8-dihydro-
pyrano[2,3-e]-1,3,4-thiadiazin-6,7,8-trimethylcarboxylate (7)
7 was obtained from the reaction of isatin-3-thiocarbohydrazone (10
mmol, 2.35 g) 4 with dimethyl acetylenedicarboxylate (10 mmol, 1.42
g), and this compound was obtained as orange crystals from methanol.
Yield 89%, mp: 258–259◦C; MS: m/z 487 (M+); FT-IR: NH 3326, 3252,
CO 1734, 1699 cm−1; 1H NMR (DMSO-d6) δ 14.49 (br, 1H, NH), 12.26
(s, 1H, NH), 11.28 (s, 1H, NH), 7.67 (d, J = 7.5 Hz, 1H, Ar-H), 7.36 (t, J
= 7.6 Hz, 1H, Ar-H), 7.09 (t, J = 7.6 Hz, 1H, Ar-H), 6.93 (d, J = 7.5 Hz,
1H, Ar-H), 3.77 (s, 3H, OMe), 3.69 (s, 3H, OMe), 3.65 (s, 1H, CH), 3.38
(s, 3H, OMe); 13C NMR (DMSO-d6) δ 35.9 (CH), 50.6 (OMe), 51.4 (OMe),
51.8 (OMe), 117.5 (C- Ar), 115.9 (S-C), 117.3 (C = C), 120.6 (C-Ar), 121.1
(C-Ar), 125.0 (C- Ar), 132.2 (C-Ar), 137.1 (O-C = ), 138.3(C-Ar), 142.8
(C = NNH), 144.7 (HN-C-O), 152.4 (HN-C = O), 159.3 (C = O), 164.5 (C
= O), 164.8 (C = O), 165.0 (HN-C = N). Anal. Calcd. for C20H17N5O8S:
C, 49.28; H, 3.49; N, 14.37. Found: C, 49.30; H, 3.51; N, 14.39.
3-(2-Aminophenyl)-6,8-dihydroxy-pyrazino[5,6-b]pyrimidine
(13a)
13a was obtained from the reaction of isatin (1H-indole-2,3-dione)
(10 mmol, 1.47 g) 6 with 5,6-diamino-urasil-solfat (10 mmol, 2.40 g) 7,
and this compound was obtained as an orange powder from ethanol.
Yield 78%, mp: > 300◦C; MS: m/z 271 (M+); FT-IR: OH 3300–3490,
NH 3398, 3185, CO 1710 cm−1; 1H NMR (DMSO-d6) δ 11.93 (s,1H, OH),
10.67 (s, 1H, OH), 10.57 (s, 1H, NH), 7.26 (t, J = 7.5 Hz, 1H, Ar-H), 6.94
(m, 2H, Ar-H), 6.80 (d, J = 7.6 Hz, 1H, Ar-H), 6.73 (br, 2H, NH2); 13
C
NMR (DMSO-d6) δ 116.8 ( = C-NH), 117.2 (C-Ar), 118.5 (C-Ar), 120.7
(C-Ar), 123.4 (C-Ar), 126.8 (C-Ar), 128.6 (C-Ar), 152.7 (C = N), 153.4
(C = N), 156.1 (C-OH), 164.0 (N-C-N), 168.1 (C = O). Anal. Calcd. for
C12H9N5O3: C, 53.13; H, 3.32; N, 25.83. Found: C, 53.10; H, 3.35; N,
25.81.

2854
N. Nami et al.
4aR, 11aR-6H-Indolo[2,3-b]-4a,5,6,7,8,8a-
hexahydroquinoxaline (15a)
15a was obtained from the reaction of isatin (1H-indole-2,3-dione)
(10 mmol, 1.47 g) 6 with trans-(1R,2R)-diaminocyclohexane (DACH)
(10 mmol, 1.14 g) 9. It was obtained as red crystals from ethanol. Yield:
81%, mp: 257–258◦C; MS: m/z 225 (M+); FT-IR: NH 3438, C = N 1659
cm−1; 1H NMR (DMSO-d6) δ 9.02 (br, 1H, NH), 7.46 (d, J = 7.5 Hz, 1H,
Ar-H), 7.27 (d, J = 7.6 Hz, 1H, Ar-H), 6.85 (m, 2H, Ar-H), 3.17(m, 2H,
CH), 2.27 (m, 1H, CH), 1.99 (m, 1H, CH), 1.74 (m, 2H, CH2), 1.43 (m,
2H, CH2), 1.35 (m, 2H, CH2); 13C NMR (DMSO-d6) δ 20.1 (CH2), 21.5
(CH2), 30.4 (CH2), 31.8 (CH2), 59.8 (CH), 60.5 (CH), 115.4 (C- Ar), 117.2
(C- Ar), 123.0 (C-Ar), 124.8 (C-Ar), 129.1 (C-Ar), 138.4 (C = N), 140.3
(C-Ar), 148.9 (C = N). Anal. Calcd. for C14H15N3: C, 74.67; H, 6.67; N,
18.67. Found: C, 74.64; H, 6.70; N, 18.66.
10H-3-Ethyl-1,2,4-triazolo[4,3:3ꢀ,2ꢀ]-1,2,4-triazino[5,6-b]indole
(17a)
17a was obtained from the reaction of isatin (1H-indole-2,3-dione)
(10 mmol, 1.47 g) 6 with 3,4-diamino-1,2,4-triazol-5-methyl hydrochlo-
ride (10 mmol, 181 g) 11. It was obtained as orange crystals from
ethanol. Yield 68%, mp: > 300◦C; FT-IR: NH 3431, C = C 1615 cm−1; 1H
NMR (DMSO-d6) δ 12.18 (s, 1H, NH), 8.17 (d, J = 7.5 Hz, 1H, Ar-H),
7.70 (d, J = 7.6 Hz, 1H, Ar-H), 7.41 (d, J = 7.6 Hz, 1H, Ar-H), 7.31 (t,
J = 7.5 Hz, 1H, Ar-H), 2.74 (s, 3H, CH3); 13C NMR (DMSO-d6) δ 14.9
(CH3), 118.4 (C- Ar), 120.2 (C-Ar), 124.8 (C-Ar), 126.7 (C-Ar), 129.1
(C-Ar), 138.4 (C-Ar), 147.8 (C = N), 150.2 (N = C-NH), 152.5 (C = N),
155.8 (N = C-N). Anal. Calcd. for C11H8N6: C, 58.93; H, 3.57; N, 37.50.
Found: C, 58.87; H, 3.59; N, 37.46.
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