Pyridazine, oxazine, pyrrole, and pyrrolo[1,2-a]quinazoline derivatives from malononitrile dimer

Article abstract of DOI:10.1002/hc.10199

2-Amino-1,1,3-tricyano-3-bromopropene was obtained from bromination of 2-amino-1,1,3-tricyanopropene (malononitrile dimer) with N-bromosuccinimide. This bromo derivative reacts with hydrazine hydrate, phenyl hydrazine, and hydroxylamine hydrochloride to a

Full text of DOI:10.1002/hc.10199

Heteroatom Chemistry
Volume 14, Number 7, 2003
Pyridazine, Oxazine, Pyrrole,
and Pyrrolo[1,2-a]quinazoline Derivatives
from Malononitrile Dimer
Abdellatif M. Salah Eldin
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
Received 27 May 2003
dazines, polysubstituted pyrrole, and pyrrolo-fused
ABSTRACT: 2-Amino-1,1,3-tricyano-3-bromoprop-
derivatives were required. 2-Amino-1,1,3-tricyano-3-
ene was obtained from bromination of 2-amino-
bromopropene (3) seemed a good candidate to fulfill
1,1,3-tricyanopropene (malononitrile dimer) with N-
this objective via its reaction with the hydrazine hy-
bromosuccinimide. This bromo derivative reacts with
drate, phenyl hydrazine, hydroxylamine hydrochlo-
hydrazine hydrate, phenyl hydrazine, and hydroxyl-
ride, and aromatic amines 10 to produce pyri-
amine hydrochloride to afford pyridazine and ox-
dazines, oxazine, N-aryl pyrrole, and pyrrolo[1,2-
azine derivatives, respectively. In base-catalyzed reac-
a]quinazoline derivatives. This prompted us to inves-
tions with primary aromatic amines and anthranilic
tigate the reaction of 2-amino-1,1,3-tricyanopropene
acid derivatives, it produces N-aryl pyrrol-3,5-
(1) [8,9] with bromine, aiming to obtain the
dicarbonitrile and pyrrolo[1,2-a]quinazolin-5-imine,
monosubstituted product 3. An aqueous suspen-
or pyrrolo[1,2-a]quinazolin-5-one derivatives, respec-
sion of 1 mol of 1 reacted readily with 2 mol of
tively. The structures of the newly synthesized hete-
bromine to yield the substitution product 2-amino-
rocycles were established on the basis of elemental
1,1,3-tricyano-3,3-dibromopropene (2) (Scheme 1,
ꢀ
C
analyses and spectral data.
2003 Wiley Periodicals,
Table 1), the same behavior of 1 with bromine has
been reported [8]. The desired product 3 could be
obtained by treating 1 with N-bromosuccinimide
(NBS) in dimethylformamide (DMF) at room tem-
perature in 68% yield (Scheme 1, Tables 1 and 2).
The 1H NMR spectrum of 3 showed a singlet for
NH2 at δ = 4.20 and two singlets at δ = 4.82 and
4.92 ppm which integrated for 1H. The appearance of
two singlets for this proton may be explained by the
presence of two geometrical isomers. It can be sug-
gested that the bromination took place on the methy-
lene group of 1 to produce 3a, which is tautomeric
to 3b via the ion pair 3c. Mass spectral measure-
ments, 13C NMR, and analytical data are in complete
agreement with the substitution product 3 (Tables 1
and 2).
Inc. Heteroatom Chem 14:612–616, 2003; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.10199
INTRODUCTION
Synthesis of pyrroles and fused pyrroles is known
[1,2]. In the last few years we have been involved
in a program aiming to develop azoles and their
fused derivatives of anticipated activity as biodegrad-
able agrochemicals [3–7]. In the context of this
program, some new functionally substituted pyri-
Correspondence to: Abdellatif M. Salah Eldin, Graduate School
of Bioscience and Biotechnology, Tokyo Institute of Technology,
4259 Nagatsuta, Midori-ku Yokohama 226-8501, Japan; e-mail:
Compound 3 has been utilized in a number of
transformations. For example, the reaction of com-
pound 3 with hydrazine hydrate, phenyl hydrazine,
asalahel@bio.titech.ac.jp.
c
ꢀ
2003 Wiley Periodicals, Inc.
612

Pyridazine, Oxazine, Pyrrole, and Pyrrolo[1,2-a]quinazoline Derivatives from Malononitrile Dimer 613
SCHEME 1
and hydroxylamine hydrochloride afforded solid
products for which structures 5, 7, and 9, respec-
tively, were assigned (Scheme 1) on the basis of an-
alytical and spectral data (Tables 1 and 2). Their for-
mation is assumed to proceed via the acyclic inter-
mediates 4, 6, and 8, respectively [10].
Compound 3 was also found to be useful for the
synthesis of pyrrole and pyrrolo-fused derivatives.
Thus, 3 reacts with the aromatic amines 10a–d (ani-
line, p-anisidine, p-toluidine, and p-chloroaniline,
respectively) in refluxing ethanol catalyzed by potas-
sium carbonate to afford solid products 12a–d. The
TABLE 1 Physical and Analytical Data of the Newly Prepared Compounds
Analysis: Calcd. (Found) (%)
Yield
(%)
Mol. Formula
(Mol. Wt.)
mp (◦C) (Solvent)
m/e
C
H
N
X
2
3
5
7
9
152–154 (Aq. EtOH)
125–127 (EtOH)
190–192 (EtOH)
225–227 (EtOH/DMF) 75
159–161 (EtOH)
85 C6H2Br2N4 (289.92)
68 C6H3BrN4 (211.02) 210, 212 34.15 (34.10) 1.43 (1.50) 26.55 (26.50) 37.87 (38.00)
24.86 (24.90) 0.70 (0.90) 19.33 (19.50) 55.12 (55.20)
70 C6H6N6 (162.15)
12H10N6 (238.25)
44.44 (44.60) 3.73 (3.80) 51.83 (52.00)
60.50 (60.70) 4.23 (4.30) 35.27 (35.20)
44.17 (44.10) 3.09 (3.20) 42.93 (43.10)
64.56 (64.70) 4.06 (4.10) 31.37 (31.30)
61.65 (61.60) 4.38 (4.40) 27.65 (27.50)
65.81 (65.90) 4.67 (4.70) 29.52 (29.40)
55.93 (56.10) 3.13 (3.00) 27.18 (27.30) 13.76 (13.70)
62.90 (63.10) 3.25 (3.10) 33.85 (33.90)
62.65 (62.60) 2.85 (3.00) 28.10 (28.00)
C
238
163
223
253
62 C6H5N5O (163.14)
60 C12H9N5 (223.23)
65 C13H11N5O (253.26)
12a 162 (EtOH)
12b 204 (EtOH)
12c 215 (EtOH)
12d 232 (EtOH/DMF)
13 228 (EtOH/DMF)
14 202 (EtOH)
58
60
59
64
C
C
C
C
13H11N5 (237.26)
12H8ClN5 (257.68)
13H8N6 (248.24)
13H7N5O (249.23)
248

614 Salah Eldin
TABLE 2 IR, 1H, and 13C NMR Data of the Newly Prepared Compounds
IR (cm−1
)
1H, 13C NMR (DMSO-d6)
3
3430–3250 (NH2), 2220, 2205, 2195 (CN) 4.20 (s, 2H, NH2, D2O-exchangeable), 4.82, 4.92 (2s, 1H)
δC; 34.44 (C-3), 115.24, 116.45, 117.11 (CN), 135.45 (C-1), 159.28
(C-2)
5
7
3540–3290 (NH, NH2), 2220, 2215 (CN)
3450–3200 (NH2), 2220, 2210 (CN)
2.95 (s, 2H, NH2), 4.10 (s, 1H, H-5), 4.47 (s, 2H, NH2) 7.81–8.05 (b, 1H,
NH)
2.70 (s, 2H, NH2, D2O-exchangeable), 4.30 (s, 2H, NH2,
D2O-exchangeable), 7.01–7.32 (m, 6H, Ar H, H-4)
3.10 (s, 2H, NH2), 4.70 (s, 2H, NH2), 5.20 (s, 1H, H-4)
2.90 (s, 2H, NH2, D2O-exchangeable), 4.75 (s, 2H, NH2,
D2O-exchangeable), 7.15–7.84 (m, 5H, Ar H)
9
12a
3400–3200 (NH2), 2222, 2212 (CN)
3390–3210 (NH2), 2220, 2205 (CN)
12b
3380–3250 (NH2), 2215, 2205 (CN)
3.12 (s, 2H, NH2, D2O-exchangeable), 3.75 (s, 3H, OCH3), 4.55 (s, 2H,
NH2, D2O-exchangeable), 7.15–7.75 (m, 4H, Ar H)
δC; 54.83 (OCH3), 115.92, 117.07 (CN), 118.25, 122.05, 131.48, 145.59
(C-arom), 129.22 (C-3), 134.66 (C-4), 144.76 (C-2), 150.34 (C-5)
3.25 (s, 2H, NH2, D2O-exchangeable), 2.38 (s, 3H, CH3), 4.85 (s, 2H,
NH2, D2O-exchangeable), 7.18–7.65 (m, 4H, Ar H)
3.18 (s, 2H, NH2, D2O-exchangeable), 4.40 (s, 2H, NH2,
D2O-exchangeable), 7.20–7.55 (m, 4H, Ar H)
12c
12d
13
3350–3240 (NH2), 2222, 2206 (CN)
3380–3260 (NH2), 2215, 2205 (CN)
3445–3185 (NH, NH2), 2225, 2210 (CN)
4.45 (s, 2H, NH2), 7.10 (s, 1H, NH), 7.25–7.68 (m, 4H, Ar H), 9.88 (s,
1H, NH)
14
3460–3240 (NH, NH2), 2225,
2207 (CN), 1685 (CO)
4.65 (s, 2H, NH2), 7.35–8.10 (m, 4H, Ar H), 10.15 (s, 1H, NH)
δC; 116.10, 118.25 (CN), 120.60 (C-9), 125.95 (C-7), 126.38 (C-5a),
127.34 (C-6), 129.65 (C-2), 133.20 (C-8), 135.75 (C-3), 140.05
(C-9a), 145.45 (C-1), 153.12 (C-3a), 168.48 (C-5)
IR spectra showed in each case, absorptions at 3390–
In summary, we have demonstrated the simple
routes for the synthesis of new polysubstituted pyri-
dazines, oxazines, pyrroles, and pyrrolo-fused het-
erocycles from easily obtainable starting materials.
Research along this direction is in progress.
3210, 2220, and 2205 cm−1 attributed to NH2 and CN
1
groups, respectively (Tables 1 and 2). The H NMR
spectra of compounds 12a–d showed two broad
D2O-exchangeable NH2 proton singlets at δ = 2.90–
4.75 ppm and a multiplet at δ = 7.15–7.84 ppm for the
aromatic protons. 12a–d are assumed to be formed
via elimination of HBr to afford the intermediates
11a–d, followed by cyclization to afford the final
products 12a–d (Scheme 2). A similar behavior of
bromo derivatives with aromatic amines has been
reported [11,12].
EXPERIMENTAL
Melting points were determined on an electrother-
mal (9100) apparatus and are uncorrected. The IR
spectra were recorded as KBr pellets on a Perkin-
1
Elmer 1430 spectrophotometer. The H NMR and
Compound 3 reacts with anthranilonitrile 10e in
refluxing ethanol in the presence of triethylamine to
afford the dihydropyrrolo[1,2-a]quinazolin-5-imine
13 presumably via the acyclic intermediate 11e,
which is assumed to undergo an addition of NH
group to CN group (Tables 1 and 2). Under sim-
ilar reaction conditions, compound 3 reacts with
anthranilic acid (10f) or methyl anthranilate (10g)
to produce the dihydropyrrolo[1,2-a]quinazolin-5-
one 14 apparently via loss of water or methanol re-
spectively. 13C NMR data agree with structure 14
(Table 2). Compound 14 could be obtained quantita-
tively from 13 upon refluxing the latter in ethano-
lic HCl. TLC matched the two products and no
depression of melting point was obtained on ad-
mixture with 14 prepared by the present method
[4,5].
13C NMR spectra were taken on a VXR 300 MHz
spectrometer in DMSO-d6 using TMS as internal
standard. Mass spectra were taken on a Shimadzu
GCMS-GB 1000 PX (70 eV). Elemental analyses were
carried out by the Microanalytical Center at Cairo
University. 2-Amino-1,1,3-tricycanopropene (1) was
prepared as described [8,9].
2-Amino-1,1,3-tricyano-3,3-dibromopropene (2)
To a suspension of 6.6 g (0.05 mol) of 1 in 75 ml
of water was added slowly 16 g (5.15 ml; 0.1 mol)
of bromine with shaking. The solid was collected by
filtration, washed with water, and dried. The yield
was 85% (12.32 g); crystallization from EtOH–water;
mp 152–154◦C [lit. 155◦C] [8].

Pyridazine, Oxazine, Pyrrole, and Pyrrolo[1,2-a]quinazoline Derivatives from Malononitrile Dimer 615
to cool to room temperature and was then filtered.
The solid product obtained was recrystallized from
DMF/EtOH (2:1) (1.79 g, 75%).
4,6-Diamino-4H-1,2-oxazine-3,5-dicarbonitrile
(9)
To a mixture of 2.11 g (0.01 mol) of 3 and 0.7 g
(0.01 mol) of hydroxylamine hydrochloride in 30 ml
of ethanol was added a solution of potassium carbon-
ate (2.76 g; 0.02 mol in a minimum amount of wa-
ter), and the reaction mixture was refluxed for 3 h.
The mixture was left to cool to room temperature,
and then poured on crushed ice and neutralized with
HCl. The precipitate was filtered off and crystallized
from EtOH (1.00 g, 62%).
3,5-Diamino-1-aryl-1H-pyrrole-2,4-
dicarbonitriles (12a–d): General Procedure
To a solution of 2.11 g (0.01 mol) of 3 in 30 ml
of ethanol was added 0.01 mol of the appropriate
primary aromatic amines 10a–d. The mixture was
stirred until a complete solution was observed, and
then a solution of potassium carbonate was added
dropwise (1.38 g; 0.01 mol, dissolved in the least
amount of water) while stirring. After complete ad-
dition the reaction mixture was refluxed for 2 h, left
to cool to room temperature, poured on ice-cold wa-
SCHEME 2
2-Amino-1,1,3-tricyano-3-bromopropene (3)
ter, and neutralized by HCl. The precipitated solids
were filtered off, washed with water, and recrystal-
lized from the proper solvent (Table 1).
To a solution of 13.2 g of 1 (0.1 mol) in 75 ml of dry
DMF was added 17.8 g (0.1 mol) of NBS. The reac-
tion mixture was stirred for 24 h at room tempera-
ture. The mixture was then poured on ice-cold water
and acidified with a few drops of HCl, whereupon a
precipitate appeared, which was filtered off and re-
crystallized from ethanol to afford 3 (14.35 g, 68%).
The Reaction of 3 with the Anthranilic Acid
Derivatives 10e–g
To a solution of 2.11 g (0.01 mol) of 3 in 30 ml
of ethanol was added 0.01 mol of either an-
thranilonitrile (10e), anthranilic acid (10f), or
methyl anthranilate (10g), and 0.01 mol of triethy-
lamine. The reaction mixture was refluxed for 4–6 h
(TLC control) and then left to cool overnight. The
respective precipitates were filtered off, and recrys-
tallized to afford 2-amino-1,3-dicyano-4,5-dihydro
pyrrolo[1,2-a]quinazolin-5-imine (13, 1.46 g, 59%)
4,6-Diamino-2,5-dihydropyridazine-3,5-
dicarbonitrile (5)
To a solution of 2.11 g (0.01 mol) of 3 in 25 ml of
ethanol was added an excess of hydrazine hydrate
(∼2 ml), and the reaction mixture was refluxed for
3 h, after which it was left overnight. The solid pre-
cipitate was filtered off and crystallized from EtOH
(1.14 g, 70%).
and
2-amino-1,3-dicyano-4,5-dihydropyrrolo[1,2-
a]quinazolin-5-one (14, 1.60 g, 64%), respectively.
4,6-Diamino-1-phenyl-1,4-dihydropyridazine-
3,5-dicarbonitrile (7)
Transformation of 13 into 14
To a solution of 2.48 g (0.01 mol) of 13 in 30 ml
of ethanol was added 5 ml of concentrated HCl and
the mixture was refluxed for 1 h. After cooling to
room temperature the reaction mixture was diluted
with cold water and neutralized with ammonia. The
A mixture of 2.11 g (0.01 mol) of 3 and 1.08 g
(0.01 mol) of phenyl hydrazine in 30 ml of ethanol
was refluxed for 3 h, whereupon a solid precipi-
tate appeared. The reaction mixture was allowed

616 Salah Eldin
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1993, 66, 1722–1726.
precipitate was collected by filtration and crystal-
lized to afford a product, which was identical to 14
in all respects.
[5] Abdelrazek, F. M.; Salah El-Din, A. M.; Mekky, A. E.
Tetrahedron 2001, 57, 1813–1817.
[6] Abdelrazek, F. M.; Salah El-Din, A. M.; Mekky, A. E.
Tetrahedron 2001, 57, 6787–6791.
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[8] Gabroni, R. A.; Coffman, D. D.; Howard E. G. J Am
Chem Soc 1958, 80, 2838–2840.
ACKNOWLEDGMENT
I express my deepest thanks to Prof. T. Kitazume for
valuable discussion and continuous help.
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