Rapid and facile synthesis of spiro[indole-3,3′-[1,2,4]triazol]-2(1H) -ones

Article abstract of DOI:10.3184/030823410X12698845637794

Various 4′-aryl-5′-phenyl-2′,4′- dihydrospiro[indole-3,3′-[1,2,4]triazol]-2(1H)-ones have been synthesised by reaction of amidrazones with 2-(2-oxoindolin-3-ylidene)malononitrile.

Full text of DOI:10.3184/030823410X12698845637794

200 RESEARCH PAPER
APRIL, 200–202
JOURNAL OF CHEMICAL RESEARCH 2010
Rapid and facile synthesis of spiro[indole-3,3p-[1,2,4]triazol]-2(1H)-ones
Ashraf M. Mohamed, Musaed A. Alsharari and Ashraf A. Aly*
Chemistry Department, College of Science, Al-Jouf University, Sakaka, Al-Jouf, Kingdom of Saudi Arabia
Various 4p-aryl-5p-phenyl-2p,4p-dihydrospiro[indole-3,3p-[1,2,4]triazol]-2(1H)-ones have been synthesised by reaction
of amidrazones with 2-(2-oxoindolin-3-ylidene)malononitrile.
Keywords: amidrazones,
[1,2,4]triazol]-2(1H)-ones
2-(2-oxoindolin-3-ylidene)malononitrile
and
4p-aryl-5p-phenyl-2p,4p-dihydrospiro[indole-3,3p-
1,2,4-Triazole moieties have been incorporated into a wide
variety of therapeutically interesting drug candidates including
anti-inflammatory, CNS stimulants, sedatives, antianxiety
compounds, antimicrobial agents,1–3 and antimycotics such
as voriconazole, fluconazole and intraconazole.4,5 There are
marketed drugs containing the 1,2,4-triazole group which are
known to have antimycotic effects e.g., alprazolam6 and tri-
azolam.17 Amidrazones are an important class of amidines,
since they can be used as synthons for 1,2,4-triazolo com-
pounds and other heterocyclic systems.7,8 Amidrazones pos-
sessing three nitrogen nucleophiles are essential components
of molecules exhibiting high biological activities, e.g.,
lamotrigine and sildenafil (Viagra).9 Previously investigations
described the reactions of amidines and their analogues
with π-acceptors and various heterocycles.10–12 Aly et al have
recently reviewed the use of hydrazinecarbothioamide,
thiocarbohydrazide and other derivatives in the synthesis of
heterocycles.13 Interestingly, a very convenient procedure to
synthesise 1,2,4-triazoles in one step has been demonstrated,
by a rapid reaction of amidrazones with 2-(1,3-dioxoindan-
2-ylidene)malononitrile.14 Accordingly, we have now investi-
gated the reactions of amidrazones 1a–e with 2-(2-oxoindolin-
3-ylidene)malononitrile (2) as electron π-deficient acceptor,
aiming to obtain heterocyclic compounds which might have
biological activities.
minutes to yield, after chromatographic purification and recys-
tallization, compounds 4a–e (66–80%). We chose amidrazones
1a–e having aryl groups with electron donating and withdraw-
ing substitutents on the benzene ring, in order to examine the
effect of electron demand on the course of reaction.
The structure assignment of compounds 4a–e is well estab-
lished using traditional spectroscopic tools such as IR, NMR
(1H, 13C) and mass spectra, in addition to elemental analyses.
Compounds 4a–e showed IR absorption peaks for NH groups
at nmax = 3350–3330 cm–1 along with broad bands at nmax
=
1680–1695 cm–1 corresponding to the carbonyl groups. The
mass spectra of compounds 4a–e showed the molecular peaks,
albeit not as the base peaks. For example, 4a showed a molec-
ular ion peak at m/z = 340 (68%), and the elemental analysis
confirmed the molecular formula as C21H16N4O. The mass
spectra of all compounds 4a–e contain similar fragments at
m/z = 91, 113, and 160 (see Fig. 1). The 1H NMR spectrum of
4ashowed the fused phenyl protons at dH = 7.90 (t, 2 H, J = 7.0
Hz) and 7.85 (d, 2 H, J = 7.8 Hz), whilst two NH-protons were
observed as broad singlets at dH = 6.5 and 8.0. The observed
13C NMR signals of 4a confirmed the proposed structure of 4a
by the appearance of spiro-C at dC = 89.0, whilst the C-2 and
C=N carbons resonated at dC = 168.2 and 156.6 respectively.
The chemical shifts (δC) of some distinctive carbons of com-
pounds 4a and 4b are shown in Fig. 2. The observation of two
NH-signals, but no CH-proton or carbon signals, is consistent
with structures 4a–e but excludes the isomeric triazoles 5a–e
(Scheme 1).
Results and discussion
Scheme 1 outlines the reaction of 1a–e with 2 in dry ethyl
acetate under N2 atmosphere. The reaction proceeded in a few
Scheme 1 Synthesis of new 4p-aryl-5p-phenyl-2p,4p-dihydrospiro[indole-3,3p-[1,2,4]triazol]-2(1H)-ones 4a–e.
* Correspondent. ashrafaly63@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2010 201
Fig. 3 Hydrogen bond in compound 4a.
Fig. 1 Mass fragmentation patterns of compound 4a.
The molecular modelling (MM2)15 of 4a, as an example,
indicated that the bond distance between the NH proton
and the oxygen of the carbonyl group (C-2) is ~1.7 Å enabling
them to form a an intramolecular hydrogen bond (Fig. 3). The
calculated (CHEMNMR) chemical shift of the hydrazine-NH
proton is dH = 4.0), whereas its experimental value is dH = 6.50,
in accord with deshielding due to the hydrogen bond just
postulated. The angle between the plane N2–C3–N4 of the tri-
azole ring and the plane C2–C3–C3a of the indole is calculated
to be 105°.
Mechanistically, the reaction of 2 with 1a–e is considered to
involve addition of the hydrazino-NH of 1 to the ylidene
carbon in 2 to produce the intermediate23 (Scheme 1). Subse-
quently, elimination of malononitrile, followed by another
nucleophilic attack of the imino-NH via amidine-like addition
to the electrophilic carbon, gives the stable heterocyclic com-
pounds 4a–e (Scheme 1). The presence of electron donating
substituents such as methyl and methoxy para to the proximal
nitrogen atom in 1a–e (R2) increased the yields of products
4a–e, consistent with nucleophilic attack by this nitrogen.
Amidrazones 1a–e were prepared according to ref. 7. 2-(2-
Oxoindolin-3-ylidene)malononitrile (2) was prepared16 from isatin
(Merck).
Reaction of 1a–e with 2-(2-oxoindolin-3-ylidene)malononitrile (2)
General procedure
A 250 mL two-necked bottom flask was flame-dried under N2 atmo-
sphere and then cooled to room temperature. Absolute ethyl acetate
(100 mL) containing a mixture of 1a–e (1 mmol) and 2 (0.195 g
1 mmol) was added to this flask. The reaction mixture was further
stirred at room temperature for 10–30 min until the starting materials
were consumed (the reaction progress was monitored by TLC analy-
sis). The solvent was removed under vacuum and the residue was
separated by PLC (silica gel, toluene: ethyl acetate 5: 1). The obtained
products 4a–e were recrystallised from the stated solvents.
4p,5p-Diphenyl-2p,4p-dihydrospiro[indole-3,3p-[1,2,4]triazol]-2(1H)-
one (4a): Colourless crystals (0.24 g, 70%), m.p. (methanol) 160–
162 °C. IR: nmax = 3350 (NH), 3090–3010 (ArCH), 1695 (C=O), 1580
1
(C=C). H NMR: dH = 8.0 (br, s, 1 H, NH, exchangeable with D2O),
7.90 (t, 2 H, J = 7.0), 7.85 (d, 2 H, J = 7.8), 7.56–7.20 (m, 10 H, ArH),
6.50 (br, s, 1 H, NH, exchangeable with D2O). 13C NMR: dC = 168.2
(C=O), 156.6 (C=N), 142.0, 132.0, 131.0, 130.6 (ArC), 128.7, 128.4
(ArCH), 128.2, 127.4 (ArCH-p), 127.0, 126.8 (Ar2CH-o), 126.2,
126.0 (Ar2CH-m), 125.8, 118.6 (ArCH), 89.0 (spiro-C). MS (70 eV,
EI): m/z = 340 (68), 180 (28), 160 (24), 113 (26), 103 (40), 194 (60),
91 (100), 77 (28). Anal. Calcd for C H16N4O (340.381): C, 74.10; H,
4.74; N, 16.46. Found: C, 73.89; H, 241.70; N, 16.38.
Experimental
Melting points are uncorrected values. 1H NMR and 13C NMR spectra
1
(Bruker AM 400, H: 400.13 MHz, 13C: 100.6 MHz) were obtained
from CDCl3 solutions; the chemical shifts (δ) are given relative to
internal standard TMS, and coupling constants (J) are in Hz. For pre-
parative thin layer chromatography (PLC), glass plates (20 × 48 cm)
were covered with a slurry of silica gel Merck PF254 and air dried
using the solvents listed for development. Zones are detected by
quenching of indicator fluorescence upon exposure to 254 nm UV
light. Elemental analyses were carried out in the Microanalysis Center
of the Institut für Anorganische Chemie, Technische Universität
Braunschweig. Mass spectroscopy was performed with a Finnigan
Mat 8430 spectrometer at 70 eV, Institute of Organic Chemistry,
TU-Braunschweig. Germany. IR spectra were obtained on Shimadzu
470 spectrophotometer using potassium bromide pellets; absorption
maxima (nmax) are reported in cm–1.
4p-(4q-Methylphenyl)-5p-phenyl-2p,4p-dihydrospiro[indole-3,3p-
[1,2,4]triazol]-2(1H)-one (4b): Colourless crystals (0.27 g, 75%),
m.p. (ethanol) 228–230 °C. IR: nmax = 3330 (NH), 3090–3015 (ArCH),
1
2980–2870 (aliph.-CH), 1680 (C=O), 1610 (C=N), 1580 (C=C). H
NMR: dH = 8.20 (br, s, 1 H, NH, exchangeable with D2O), 8.10 (t, 2 H,
J = 7.0), 7.92 (d, 2 H, J = 7.8), 7.66–7.10 (m, 9 H, ArH), 6.30 (br, s,
1 H, NH, exchangeable with D2O), 2.32 (s, 3 H, CH ). 13C NMR:
dC = 168.8 (C=O), 156.6 (C=N), 142.2, 134.2, 132.4,3131.4, 131.2
(ArC), 129.0, 128.6 (ArCH), 128.4 (ArCH-p), 128.0, 127.6 (Ar2CH-
o), 127.2, 127.0 (Ar2CH-m), 126.5, 119.0 (ArCH), 89.6 (spiro-C),
22.1 (CH3-Ar). MS (70 eV, EI): m/z (%) = 354 (60), 326 (22), 263
(16), 251 (20), 160 (20), 113 (12), 110 (100), 91 (60), 91 (34), 77 (30).
Fig. 2 Assignment carbon signals and their δ values of compounds 4a and 4b.

202 JOURNAL OF CHEMICAL RESEARCH 2010
Anal. Calcd for C22H18N4O (354.407): C, 74.56; H, 5.12; N, 15.81.
Found C, 74.40; H, 5.10; N, 15.70.
Anal. Calcd for C H18N O (354.407): C, 74.56; H, 5.12; N, 15.81.
Found C, 74.44; H2,25.08;4N, 15.68.
4p-(4q-Methoxyphenyl)-5p-phenyl-2p,4p-dihydrospiro[indole-3,3p-
[1,2,4]triazol]-2(1H)-one (4c): Colourless crystals (0.3 g, 80%),
m.p. (methanol) 190 °C. IR: nmax = 3338 (NH), 3087–3010 (ArCH),
Professor Ashraf A. Aly thanks the DAAD foundation for the
scholarship that enabled him to carry out NMR spectra analy-
sis in the Institute of Organic Chemistry, TU-Braunschweig
University, Germany.
1
2987–2860 (aliph.-CH), 1680 (C=O), 1610 (C=N), 1586 (C=C). H
NMR: dH = 8.30 (br, s, 1 H, NH, exchangeable with D2O), 8.10 (d,
2 H, J = 7.8), 7.80 (d, 2 H, J = 7.8), 7.70–7.12 (m, 7 H, ArH), 6.90 (m,
2 H, ArH), 6.40 (br, s, 1 H, NH, exchangeable with D2O), 3.90 (s, 3 H,
OCH3). 13C NMR: dC = 169.2 (C=O), 158.0 (C=N), 156.0, 134.4,
132.0, 131.2, 131.0 ArC), 129.2, 128.8 (ArCH), 128.2 (ArCH-p),
127.4 (Ar2CH-o), 127.0, 126.8 (Ar2CH-m), 122.0 (Ar2CH-o), 126.5,
119.0 (ArCH), 90.0 (spiro-C), 51.0 (CH3–Ar). MS (70 eV, EI):
m/z = 370 (56), 342 (22), 327 (22), 249 (30), 210 (77), 160 (24), 113
(28), 110 (100), 91 (22), 77 (20). Anal. Calcd for C22H18N4O2
(370.407): C, 71.34; H, 4.90; N, 15.13. Found: C, 71.30; H, 4.80; N,
15.08.
Received 25 January 2010; accepted 11 March 2010
Paper100979 doi: 10.3184/030823410X12698845637794
Published online: 28 April 2010
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1
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