Heterocyclic synthesis with nitriles: Synthesis of some new thiophene, pyridazine, oxazine, thiopyran, pyrrole, and pyrrolo[1,2-b]pyridazine derivatives

Article abstract of DOI:10.1080/00397910500184727

2-Phenyl-1,1,3-tricyanopropene[α-(cyanomethyl)benzylidene- malononitrile] undergoes bromination with N-bromosuccinimide (NBS) to afford 2-phenyl-1,1,3-tricyano-3-bromopropene: [α(bromocyanomethyl)benzylidene malononitrilel. This bromo derivative undergoes reactions with sodium hydrogen sulfide, hydrazine hydrate, phenyl hydrazine, hydroxylamine hydrochloride, ethyl thioglycollate, urea derivatives, and cyanacetohydrazide to afford thiophene, 4H-pyridazines, 4H-oxazine and 4H-thiopyran, N-substituted pyrrole, and pyrrolof[1,2-b]pyridazine derivatives respectively. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500184727

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Heterocyclic Synthesis with
Nitriles: Synthesis of Some
New Thiophene, Pyridazine,
Oxazine, Thiopyran, Pyrrole,
and Pyrrolo[1,2‐b]pyridazine
Derivatives
Fathy M. Abdelrazek a
a Chemistry Department, Faculty of Science, Cairo
University, Giza, Egypt
Version of record first published: 18 Aug 2006
To cite this article: Fathy M. Abdelrazek (2005): Heterocyclic Synthesis with Nitriles:
Synthesis of Some New Thiophene, Pyridazine, Oxazine, Thiopyran, Pyrrole, and
Pyrrolo[1,2‐b]pyridazine Derivatives, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 35:17, 2251-2258
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Synthetic Communicationsw, 35: 2251–2258, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500184727
Heterocyclic Synthesis with Nitriles:
Synthesis of Some New Thiophene,
Pyridazine, Oxazine, Thiopyran, Pyrrole,
and Pyrrolo[1,2-b]pyridazine Derivatives
Fathy M. Abdelrazek
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
Abstract: 2-Phenyl-1,1,3-tricyanopropene[a-(cyanomethyl)benzylidene-malononitrile]
undergoes bromination with N-bromosuccinimide (NBS) to afford 2-phenyl-1,1,3-
tricyano-3-bromopropene: [a(bromocyanomethyl)benzylidene malononitrile]. This
bromo derivative undergoes reactions with sodium hydrogen sulfide, hydrazine
hydrate, phenyl hydrazine, hydroxylamine hydrochloride, ethyl thioglycollate, urea
derivatives, and cyanacetohydrazide to afford thiophene, 4H-pyridazines, 4H-
oxazine and 4H-thiopyran, N-substituted pyrrole, and pyrrolo[1,2-b]pyridazine
derivatives respectively.
Keywords: Thiophene, pyridazine, oxazine, thiopyran, pyrrole derivatives
In the past few years we have been involved in a program aiming to develop
new, simple procedures for the synthesis of functionally substituted hetero-
cycles of anticipated biological activity that can be used as biodegradable agro-
chemicals, from available laboratory starting materials.[1–4] In the context of
this program some new functionally substituted pyridazine, pyrrole, and
pyrrolo-fused derivatives were required. a-(Cyanomethyl) benzylidenemalono-
nitrile 1[5] (Scheme 1) seemed to be a good candidate to fulfill our objective via
Received in the UK December 8, 2004
This work has been presented at the 9th Ibn Sina international conference on pure
and applied heterocyclic chemistry, held 11–14 December, 2004 at Sharm El Sheikh,
Egypt, and organized by the Egyptian Society of Heterocyclic Chemistry, Conference
Book p. 194.
Address correspondence to Fathy M. Abdelrazek, Chemistry Department, Faculty
of Science, Cairo University, Giza, Egypt. E-mail: prof_fmrazek@yahoo.com
2251

2252
F. M. Abdelrazek
Scheme 1.

Heterocyclic Synthesis with Nitriles
2253
brominating and then reacting the bromo derivative with suitable reagents.
Thus, compound 1 was allowed to react with N-bromosuccinimide in dimethyl-
formamide (DMF) at room temperature to afford the bromo derivative 2
(Scheme 1) in 70% yield. The IR spectrum of 2 showed absorption bands at
nmax 2215, 2207, and 2198cm21, corresponding to CN groups, respectively.
The 1H NMR spectrum of this bromo derivative revealed an aromatic
multiplet (5H) at d ¼ 7.10–7.35 and two singlets at d ¼ 4.95 and 5.10ppm inte-
grated for (1H). The appearance of these two singlets for this proton may be
attributed to the presence of two position isomers. These data can only be inter-
preted in terms of the allylic rearrangement product 2b. It can be assumed that
the bromination took place on the methylene group of 1 to afford 2a. In solution,
structure 2a seems to be interchangeable with 2b via the ion pair 2c and both
structures (2a and 2b) are present in a state of dynamic equilibrium. In
support of this assumption is the fact that both of the position isomers 2a and
2b are present in solution (from the 1H NMR and 13C NMR data; see the exper-
imental section). Furthermore, all nucleophilic substitution products of 2 show
that the attack is on C-3, which agrees with an SN1 mechanism in which the Br2
is lost in the first step, leaving the allyl cation, which is then attacked by the
nucleophile. The direction of attack is apparently controlled by the steric
factors, which favor the attack on C-3. Mass spectral measurements and analyti-
cal data are in complete agreement with structures 2a and 2b (see the exper-
imental section). Analogous behavior of a similar bromo derivative has been
previously observed.[6]
Compound 2 reacts with sodium hydrogen sulfide in refluxing ethanol to
afford a dark yellowish-brown solid product. The IR spectrum of this product
revealed the presence of amino and cyano absorption bands at n 3450–3350
(NH2) and 2215 and 2208 (CN) cm21. Elemental analysis of this product
showed the disappearance of the bromine atom and showed that it is in good
agreement with structure 4 (Scheme 1). It is assumed that the bromine atom in
compound 2 is substituted by SH to afford the intermediate 3, which brings
about cyclization by addition to one of the CN groups under these basic con-
ditions to afford the thiophene derivative 4. Mass spectral measurements and
the 1H NMR spectrum are consistent with structure 4. Compound 4 could also
be obtained by reacting 1 with elemental sulphur in presence of a basic
catalyst according to the literature methods.[7] The identity of the two products
was inferred from mp, TLC analysis, and analytical data.
Compound 2 reacts with hydrazine hydrate, phenyl hydrazine, hydroxyl-
amine hydrochloride, and ethyl thioglycollate in the presence of sodium acetate
to afford dark-colored solid products. Structures 6a, 6b, 8, and 10 were
assigned to these products respectively on the basis of their analytical and
spectral data (experimental section). The formation of these products is
assumed to proceed via the initial elimination of HBr to afford the acyclic inter-
mediates 5, 7, and 9 respectively, followed by either a Michael or a Thorpe-
Ziegler[8] cyclization to afford the final isolable products (Scheme 1). This
behavior is similar to a previously reported work on related systems.[6,9–11]

2254
F. M. Abdelrazek
Pyrroles and fused pyrrole derivatives have recently received consider-
able attention because of their synthetic and pharmaceutical importance,
and different approaches for their synthesis have been developed.[12,13] In
the past few years we have reported several syntheses of pyrrole deriva-
tives.[14,15] In the present work we explore the synthetic potentialities of 2
to obtain some novel N-substituted pyrroles and pyrrolo-fused pyridazine.
Thus, compound 2 was allowed to react with either urea, thiourea, or
guanidine to afford pyrrole N-amide, N-thioamide, or N-amidine derivative
12a–c respectively presumably via the acyclic intermediates 11. The
reaction of 2 with cyanoacetohydrazide apparently follows the same
pathway to afford the nonisolable acyclic intermediate 13 but in this case a
further cyclization took place via the addition of the active methylene to the
CN group to afford the pyrrolo[1,2-b]pyridazine derivative 14. Elemental
analyses and spectral data are in complete agreement with the proposed struc-
tures 12a–c and 14 (see the experimental section).
EXPERIMENTAL
Melting points were determined on an electrothermal (9100) apparatus and are
uncorrected. IR spectra were recorded as KBr pellets on a Perkin-Elmer 1430
spectrophotometer. The 1HNMR and 13CNMR spectra were taken on a Varian
Gemini 300-MHz spectrometer in DMSO-d6 using TMS as internal standard
and chemical shifts are expressed in d (ppm) values. Assignments were made
by correlation of the off-resonance decoupled 13CNMR spectra and determi-
1
nation of the H chemical shifts. 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, Egypt.
Bromination of l: Preparation of 2-Phenyl-1,1,3-tricyano-
3-bromopropene 2
To a solution of 1.93 g (0.01 mol) of 1 in 25 mL of dry DMF was added 1.78 g
(0.01 mol) of NBS. The reaction mixture was stirred for 4 h at room tempera-
ture and then left overnight. The mixture was then poured on ice-cold water
and acidified with a few drops of HC1 whereupon a solid precipitate
appeared, which was filtered off and recrystallized from ethanol to afford
1.9 g, (70%) of 2 as reddish-violet crystalline solid, mp 185–1878C.
Found: C, 52.65; H, 2.45; Br, 29.20; N, 15.40. C12H6BrN3 (m/e 271 and
273) requires C, 52.97; H, 2.22; Br, 29.37; N, 15.44. nmax 2215, 2207, 2198
(CN) cm21. dH (300 MHz, DMSO-d6) 4.95, 5.10 (2s, 1H), 7.10–7.35
(m, 5H, phenyl H). d C 35.45 (d), 92.8 (d) (C-3), 114.90, 116.45, 117.20
(CN groups), 126.85–134.20 (arom. C), 134.45 (s), 43.42 (s) (C-1), 172.28
(s), 163.5 (s) (C-2).

Heterocyclic Synthesis with Nitriles
2255
2-Amino-4-phenylthiophene-3,5-dicarbonitrile 4
To a solution of 2.72g (0.01 mol) of 2 in 25mL of ethanol was added 0.56g
(0.01mol) of sodium hydrogen sulfide and the reaction mixture was heated on
a water bath for 1 h. The mixture was allowed to cool down, then poured on
ice-cold water and acidified with HC1 unntil neutral. The dark greenish-brown
precipitate that had formed was filtered off and recrystallized from ethanol to
afford 1.5 g (67%) of 4, mp 242–2448C. Found: C, 64.10; H, 3.20; N, 18.40;
S, 14.20. C12H7N3S (m/e ¼ 225) requires C, 63.98; H, 3.13; N, 18.65; S,
14.23. nmax (KBr) 3450 and 3350 (NH2), 2208, 2215 (CN) cm21. dH
(300 MHz, DMSO-d6) 5.5 (s, 2H, NH2, exch.), 7.18–7.50 (m, 5H, arom. H).
This compound was found to be identical with an authentic sample obtained
from the reaction of 1 with elemental sulfur as described in the literature.[7]
Reaction of 2 with Hydrazine Hydrate and Phenyl Hydrazine
(General Procedure)
To a solution of 2.72 g (0.01 mol) of 2 in 25 mL of ethanol was added an excess
of hydrazine hydrate (ꢀ2 mL) or 1.08 g (0.01 mol) of phenyl hydrazine, and the
reaction mixture was refluxed for 2 h in each case, after which it was left
overnight. The solid precipitates that formed were filtered off and recrystallized
from EtOH/DMF (1 : 1) to afford 6a and 6b respectively.
6-Amino-4-phenyl-1,4-dihydropyridazine-3,5-dicarbonitrile 6a
Brown crystalline solid, mp 201–2038C (EtOH/DMF) (1.7 g, 75%). Found:
C, 64.50; H, 4.10; N, 31.50. C12H9N5 (m/e ¼ 223) requires C, 64.56; H,
4.06; N, 31.37. nmax (KBr) 3450–3255 (NH and NH2), 2222, 2217 (CN).
dH (300 MHz, DMSO-d6) 3.95 (s, 1H,4-H), 4.4 (s, 2H, NH2, D2O exch.),
7.1–7.4 (m, 5H, arom. H), 8.1 (bs, 1H, NH, exch).
6-Ammo-1,4-diphenyl-1,4- dihydropyridazine-3,5-dicarbonitrile 6b
Coffee-brown crystalline solid, mp 232–2338C (EtOH/DMF) (2.3 g, 76%).
Found: C, 72.50; H, 4.50; N, 23.60. C18H13N5 (m/e ¼ 299), requires C,
72.23; H, 4.38; N, 23.40. nmax (KBr) 3400–3200 (NH2), 2215 and 2205
(CN) cm21. dH (300 MHz, DMSO-d6) 4.0 (s, 1H, 4-H), 6.52–7.65 (2 m,
10H, arom. H), 7.80 (s, 2H, NH2, exch).
6-Amino-4-phenyl-4H-1,2-oxazine-3,5-dicarbonitrile 8
To a mixture of 2.72 g (0.01 mol) of 2 and 0.7 g (0.01 mol) of hydroxylamine
hydrochloride in 30 mL of ethanol was added a solution of potassium
carbonate (2.76 g; 0.02 mol in a minimum amount of water), and the reaction

2256
F. M. Abdelrazek
mixture was refluxed for 2 h. The mixture was left to cool to room temperature,
then poured on crushed ice and neutralized with HC1. The brownish precipitate
that appeared was filtered off and recrystallized from ethanol to give 1.5 g
(70%) of 8, mp 169–1708C (EtOH). Found: C, 64.50; H, 3.75; N, 25.10.
C12H8N4O (m/e ¼ 224) requires C, 64.28; H, 3.60; N, 24.99. nmax (KBr)
3441–3220 (NH2), 2225 and 2209 (CN) cm21. dH (300 MHz, DMSO-d6)
4.16 (s, 1H, 4-H), 7.05–7.25 (m, 5H, arom. H), 7.84 (s, 2H, NH2).
Ethyl 3-Amino-4,6-dicyano-5-phenyl -4H-thiopyran-2-carboxylate 10
To a mixture of 2.72 g (0.01 mol) of 2 and 1.20 g (0.01 mol) of ethyl thiogly-
collate in 30 mL of ethanol was added 1.64 g (0.02 mol) of sodium acetate.
The mixture was stirred at room temperature for 4 h, and then was poured on
crushed ice and neutralized with HC1. The dark-colored precipitate thus
formed was filtered off and recrystallized to afford 2 g (65%) of 10, brown crys-
talline solid, mp 185–1878C. Found: C, 61.50; H, 3.90; N, 13.40; S, 10.20.
C16H13N3O2S (m/e ¼ 311) requires C, 61.72; H, 4.21; N, 13.50; S, 10.30.
n
max (KBr) 3425–3255 (NH2), 2199 and 2210 (CN), 1705 (C55O) cm21. dH
(300 MHz, DMSO-d6) 1.35 (t, J ¼ 7 Hz, 3H, Me), 4.05 (s, 1H, 4-H), 4.2
(q, J ¼ 7 Hz, 2H, CH2), 7.10–7.35 (m, 5H, arom. H), 8.4 (s, 2H, NH2); d C;
14.1(q), 35.1(d), 61.2(t), 101(s), 105.3(s), 113.5(s), 116.3(s), 126.4(d),
127.8(d), 128.5(d), 136.1(s), 152.8(s), 164.8(s) (cf. Scheme 1).
Reaction of 2 with Urea Derivatives and Cyanoacetohydrazide
(General Procedure)
To a solution of 2 (2.72 g; 0.01 mol) in 30 ml of DMF was added 0.01 mol of
urea, thiourea, guanidine nitrate, or cyanoacetohydrazide followed by a
catalytic amount of triethylamine (0.01 mol of the same reagent in the case
of guanidine nitrate). The respective reaction mixtures were refluxed for
3 h, left to cool, poured on cold water, and neutralized with HC1. The precipi-
tates were filtered off and recrystallized to afford the following.
2-Amino-3,5-dicyano-4-phenylpyrrole-N-carboxamide 12a
Grey crystalline solid, mp 215–2178C (EtOH/DMF) (1.76 g, 70%). Found: C,
62.50; H, 3.50; N, 27.60. C13H9N5O (m/e ¼ 251) requires C, 62.15; H, 3.61;
N, 27.87. nmax (KBr) 3400–3220 (NH2), 2212 and 2200 (CN), 1660 (C55O)
cm21. dH (300 MHz, DMSO-d6) 4.8 (s, 2H, NH2), 7.12–7.56 (m, 5H, arom.
H), 8.32 (s, 2H, NH2, exch).
2-Amino 3,5-dicyano-4-phenylpyrrole-N-thiocarboxamide 12b
Reddish-brown crystalline solid, mp 187–1898C (EtOH/DMF) (1.9 g, 72%.
Found: C, 58.50; H, 3.50; N, 26.60; S, 12.40. C13H9N5S (m/e ¼ 267)

Heterocyclic Synthesis with Nitriles
2257
requires C, 58.41; H, 3.39; N, 26.20; S, 12.00. nmax (KBr) 3390–3210 (NH2),
2210 and 2200 (CN) cm21. dH (300 MHz, DMSO-d6) 5.1 (s, 2H, NH2), 7.15–
7.55 (m, 5H, arom. H), 8.30 (s, 2H, NH2, exch).
2-Amino-3,5-dicyano-4-phenylpyrrole-N-carboxamidine 12c
Yellowish-brown crystalline solid, mp 267–2688C (EtOH/DMF) (1.85 g,
74%). Found: C, 62.60; H, 4.30; N, 33.60. C13H10N6 (m/e ¼ 250) requires
C, 62.39; H, 4.03; N, 33.58. nmax (KBr) 3380–3185 (NH2 and NH), 2215
and 2205 (CN) cm21. dH (300 MHz, DMSO-d6) 4.9 (s, 2H, NH2), 7.1–7.5
(m, 5H, arom. H), 8.2 (s, 2H, NH2), 8.65 (s, 1H, NH).
4,7-Diamino-2-hydroxy-5-phenylpyrrolo[1,2-6b]pyridiazine-
3,6-dicarbonitrile 14
Brown crystalline solid, mp 292–2938C (EtOH/DMF) (2.0 g, 69%. Found: C,
62.20; H, 3.50; N, 28.60. C15H10N6O (m/e ¼ 290) requires C, 62.06; H, 3.47;
N, 28.95. nmax (KBr) 3460–3220 (NH2 and OH), 2220 and 2205 (CN) cm21
.
dH (300 MHz, DMSO-d6) 4.8 (s, 2H, NH2), 6.2 (s,1H, OH), 7.2–7.6 (m, 5H,
arom. H), 8.32 (s, 2H, NH2, exch.); d C; 94.6(s), 105.8(s), 113.5(s), 114.3(s),
115.6(s), 119.3(s), 125.1(s), 127.2(d), 128.4(d), 129.1(d), 136.5(s), 152,4(s),
169.8(s) (cf. Scheme 1).
ACKNOWLEDGMENT
The author thanks the Alexander von Humboldt Foundation (Germany) for
granting a fellowship, and the hospitality of Professor P. Metz, Institut fu¨r
Organische Chemie, TU Dresden, is also highly appreciated.
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