Facile one pot microwave assisted solvent-free synthesis of novel spiro-fused pyran derivatives via the three-component condensation of ninhydrin with malononitrile and active methylene compounds

Article abstract of DOI:10.1002/jccs.200500083

Three-component condensation of ninhydrin, malononitrile, and some nucleophilic reagents in the presence of piperidine under microwave irradiation without solvent afforded the corresponding spiro-fused pyran derivatives. The structures of the products were proved by elemental analyses, IR, ¹H NMR and MS spectroscopy.

Full text of DOI:10.1002/jccs.200500083

Journal of the Chinese Chemical Society, 2005, 52, 563-567
563
Facile One Pot Microwave Assisted Solvent-Free Synthesis of Novel
Spiro-Fused Pyran Derivatives via the Three-Component Condensation of
Ninhydrin with Malononitrile and Active Methylene Compounds
Raafat M. Shaker*, Alaa F. Mahmoud and Fathy F. Abdel-Latif
Chemistry Department, Faculty of Science, El-Minia University, El-Minia, Egypt
Three-component condensation of ninhydrin, malononitrile, and some nucleophilic reagents in the pres-
ence of piperidine under microwave irradiation without solvent afforded the corresponding spiro-fused pyran
derivatives. The structures of the products were proved by elemental analyses, IR, 1H NMR and MS spectros-
copy.
Keywords: Ninhydrin; Malononitrile; Nucleophilic reagents; Spiropyrans.
INTRODUCTION
RESULTS AND DISCUSSION
The reaction allowed the synthesis of new spiro-type
compounds as an important target in chemical synthesis be-
cause of their expected biological activities1,2 and the study
of the peri- and regioselectivity of this reaction. Particular at-
tentions have been focused on spiropyrans due to their poten-
tial applications to industrial fields.3-5 Furthermore, pyrans
and fused pyrans are biologically interesting compounds
with antibacterial activities,6 antifungal activities,7 antitumor
activity,8 and hypotensive effects.9 On the other hand, nin-
hydrin is a unique tricarbonyl compound which is widely
used in biochemical and medical settings for the analysis of
amino acids.10 Recently, microwave irradiation has been
widely used in the synthesis of heterocyclic compounds with
good yields and short reaction time.11-14 A dry media tech-
nique by microwave heating has attracted much attention15-18
and offers several advantages: solvents are often expensive,
toxic, difficult to remove in the case of aprotic dipolar sol-
vents with high boiling points, and are agents that pollute the
environment. The absence of solvent also reduces the risk of
hazardous explosions when the reaction takes place in a
closed vessel in the microwave oven. In view of the above-
mentioned findings and as a part of our program aimed at the
development of new simple and efficient procedures for the
synthesis of spiro19-21 and condensed22-25 heterocyclic deriva-
tives, the present work is aimed at synthesizing different
spiro-fused pyrans via the three-component condensation of
ninhydrin with malononitrile and active methylene com-
pounds under microwave irradiation without solvent.
The hitherto synthesized compounds were prepared
according to the sequence of reactions that are illustrated in
Schemes I-III. Thus, 6-amino-5-cyano-3-oxo-1-phenyl-
spiro-4,2¢-[indan-1¢,3¢-dione]-2H,4H-pyrano[2,3-c]pyrazole
(7) was prepared by the reaction of ninhydrin (1) with
malononitrile (2) and 1-phenyl-pyrazolidine-3,5-dione (3) in
the presence of a catalytic amount of piperidine under micro-
wave irradiation without solvent for 3 minutes (Scheme I).
The structure of compound 7 was established from its
elemental analysis and spectral data (Table 1). The gross for-
mula, C21H12N4O4, of compound 7 was confirmed by the
mass spectrum, which exhibited the molecular ion at m/z 384.
Its IR spectrum showed a strong absorption band of the nitrile
group at 2220 cm-1 and intense bands at 3330-3200 cm-1 indi-
cating the presence of stretching vibrations of an NH2 and NH
1
groups. The H NMR spectrum of 7 in DMSO-d6 demon-
strated a characteristic singlet at d 3.4 for the NH2, a multiplet
at d 7.3-7.7 for the aromatic protons, and a singlet at d 9.1
ppm for the NH proton.
The formation of 7 was rationalized in terms of the ini-
tial formation of 2-(dicyano-methylene)-indan-1,3-dione
(4)26 followed by the addition of the active methylene reagent
3 (Michael donors) to the activated double bond in 4 (Michael
acceptors) forming acyclic intermediate Michael adducts 6.
The subsequent intramolecular cyclization of 6 by the addi-
tion of the enol OH to the cyano group formed the isolated
product.27 The different course of the reaction can probably
be explained by the formation of an intermediate 5, which re-
* Corresponding author. E-mail: rmshaker@yahoo.com

564 J. Chin. Chem. Soc., Vol. 52, No. 3, 2005
Shaker et al.
Scheme I
O
O
CN
CN
O
O
+ 3
O
1
+
4
O
CN
O
CN
O
O
O
O
CN
MW
CN
CN
OH
N
N
3 min.
CN
H
H
N
O
N
+ 2
2
Ph
Ph
6
O
O
+
O
N
O
N
H
H
N
O
O
N
Ph
Ph
5
3
O
O
O
CN
N
H
N
O
NH2
Ph
7
Scheme II
acted with malononitrile to give 7 (Scheme I).
Structural proof was obtained through a two-compo-
nent condensation of 4 with 3 under the previous conditions.
Further confirmation of structure 7 was made by comparison
with an authentic sample, prepared from the reaction of 1
with 2 and 3 using the conventional thermal28,29 method in
refluxing ethanol containing a catalytic amount of piperidine
H3C
N
O
O
CN
+
O
+
O
N
CN
H
8
2
1
1
9 min.
for 4 hours, which showed agreement by MP, IR, and H
MW
NMR data.
Similarly, 3-methyl-3-pyrazolin-5-one 8 was reacted
with 1 and 2 under the previous conditions to give the corre-
sponding spiropyrano[2,3-c]pyrazole 9A, which can exist in
the tautomeric form 9B, and its structure was deduced on the
basis of analytical and spectral data (Scheme II and Table 1).
Its IR spectrum showed the NH2 and NH absorption bands at
3500-3200 cm-1, a strong absorption band of the nitrile group
at 2200 cm-1, and bands at 1740 cm-1 and 1700 cm-1 for the
two carbonyl groups. The 1H NMR spectrum of 9 in DMSO-
d6 demonstrated a characteristic singlet at d 1.6 for the methyl
protons, a singlet at d 6.2 for the amino group, a multiplet at d
7.6-8.2 due to the phenyl protons, and a singlet at d 10.9 ppm
for the NH proton. However, the question about whether the
hydrogen atom is positioned at the N(1) or N(2) atom of the
pyranopyrazoles remains unclear. In the literature, there is no
consensus of opinion regarding the structures of pyranopyr-
azoles derived from pyrazol-5-ones.30-36
O
O
O
O
H3C
H3C
H
CN
CN
N
N
N
O
NH2
N
O
NH2
H
9A
9B
The efficiency of the above reactions prompted us to
extend this procedure to the synthesis of different fused spi-
ropyran derivatives. Thus, ninhyrin (1) reacted with 2 and
1-methylhydantoin (10), tetrahydrofuran-2,4-dione (11), 2-
indolinone (12), and barbituric acid derivatives 13a-c to give
the corresponding spiropyrans 14-17, respectively (Scheme
III). The structures of compounds 14-17 were deduced from
their elemental analyses and their IR, MS and 1H NMR spec-
tra (Table 1). For example, the elemental analysis of com-

Synthesis of Novel Spiro-Fused Pyrans
J. Chin. Chem. Soc., Vol. 52, No. 3, 2005 565
Table 1. Characterization data of the prepared compounds
M. P. (°C)
Cryst.
Solvent.
(Yield)
Analytical Data
Calcd./Found (%)
Mol. For.
(Mol. Wt)
Compd.
Spectral Data
C
H
N
S
7
189-190
(EtOH)
(92%)
C21H12N4O4 65.63
(384.35) 65.56
3.15
3.18
14.58
14.66
IR (umax/cm-1): 3330, 3250 (NH2), 3200 (NH), 2220
(CN), 1690, 1660 (CO), 1600, 1580 (C=C, C=N); 1H-
NMR: d 3.4 (s, 2H, NH2), 7.3-7.7 (m, 9H, Ar-H), 9.1 (s,
1H, NH); MS: 384 (M+, 23%).
9
250-252
(EtOH)
(83%)
C16H10N4O3 62.75
(306.28) 62.72
3.29
3.33
18.29
18.35
IR (umax/cm-1): 3500, 3400 (NH2), 3200 (NH), 2200
(CN), 1740, 1700 (CO), 1640, 1590 (C=C, C=N); 1H-
NMR: d 1.6 (s, 3H, CH3), 6.2 (s, 2H, NH2), 7.6-8.2 (m,
4H, Ar-H), 10.9 (s, 1H, NH).
14
265-267
(EtOH)
(91%)
C16H10N4O4 59.63
3.13
3.15
17.38
17.35
IR (umax/cm-1): 3450, 3400 (NH2), 3250 (NH), 2200
(CN), 1745, 1700, 1675 (CO), 1620, 1580 (C=C, C=N);
1H-NMR: d 2.5 (s, 3H, CH3), 7.9-8.4 (m, 6H, Ar-H and
NH2), 10.7 (s, 1H, NH).
(322.28)
59.60
15
258-260
(EtOH)
(87%)
C16H8N2O5
(308.25)
62.34
62.39
2.62
2.57
9.09
9.05
IR (umax/cm-1): 3400, 3330 (NH2), 2210 (CN), 1760,
1740, 1720 (CO), 1640, 1590 (C=C, C=N); 1H-NMR: d
5.2 (s, 2H, CH2), 8.0 (s, 2H, NH2), 8.3-8.5 (m, 4H, Ar-H);
MS: 308 (M+, 19%).
16
246-248
(EtOH)
(95%)
C20H11N3O3 70.38
3.25
3.22
12.31
12.26
IR (umax/cm-1): 3400, 3300 (NH2), 3240 (NH), 2200
(CN), 1740, 1700 (CO), 1625, 1590 (C=C, C=N); 1H-
NMR: d 7.2 (s, 2H, NH2), 7.7-8.1 (m, 8H, Ar-H), 10.2 (s,
2H, 2NH); MS: 341 (M+, 65%).
(341.33)
70.50
17a
17b
17c
183-185
(EtOH)
(95%)
C16H8N4O5
(336.27)
57.15
57.23
2.40
2.50
16.66
16.55
IR (umax/cm-1): 3400, 3330 (NH2), 3200 (NH), 2200
(CN), 1745, 1720, 1700 (CO), 1600 (C=C, C=N); 1H-
NMR: d 4.50 (s, 2H, NH2), 7.8-8.2 (m, 4H, Ar-H), 9.8 (s,
2H, 2NH); MS: 336 (M+, 35%).
210-212
(EtOH)
(94%)
C16H8N4O4S 54.54
(352.33) 54.50
2.29
2.40
15.90
16.05
9.10 IR (umax/cm-1): 3450, 3300 (NH2), 3200 (NH), 2200
8.97 (CN), 1740, 1715, 1690 (CO), 1640, 1600 (C=C, C=N);
1H-NMR: d 4.55 (s, 2H, NH2), 7.6-8.1 (m, 4H, Ar-H),
9.85 (s, 2H, 2NH); MS: 352 (M+, 15%).
242-244
(EtOH)
(90%)
C20H16N4O4S 58.81
(408.44) 58.73
3.95
3.90
13.72
13.78
7.85 IR (umax/cm-1): 3400, 3300 (NH2), 2200 (CN), 1740,
8.01 1715, 1690 (CO), 1660, 1590 (C=C, C=N); 1H-NMR: d
1.01-1.14 (t, 3H, J = 6.9 Hz, CH3), 1.26-1.39 (t, 3H, J =
6.9 Hz, CH3), 3.96-4.38 (q, 2H, J = 6.9 Hz, CH2), 4.51-
4.62 (q, 2H, J = 6.9 Hz, CH2), 7.8 (s, 2H, NH2), 7.9-8.2
(m, 4H, Ar-H); MS: 408 (M+, 33%).
19
280-282
(CH3CN)
(96%)
C18H12N2O4 67.50
(320.31) 67.55
3.78
3.80
8.75
8.66
IR (umax/cm-1): 3400, 3350 (NH2), 2200 (CN), 1740,
1700, 1675 (CO), 1640, 1590 (C=C, C=N). 1H-NMR: d
2.1-2.35 (m, 6H, 3CH2), 7.5 (s, 2H, NH2), 7.8-8.2 (m, 4H,
Ar-H); MS: 320 (M+, 35%).
pound 16 supported the proposed structure molecular for-
mula as C20H11N3O3. The 1H NMR spectrum of 16 revealed
two broad singlets at d 7.2 and 10.2 ppm, assigned to the NH2
and NH protons, respectively, and at d 7.7-8.1 ppm assigned
to the aromatic protons. Furthermore, its mass spectrum gave
the molecular ion peak at m/z 341 (M+, 65%) which was
found to be in good agreement with the assigned structure.
1,3-Cyclohexanedione (18) when subjected to the pre-
vious reaction conditions gave the spiro-4,2¢-[indan-1¢,3¢-
dione]pyran 19 (Scheme III). The structure of compound 19
was established on the basis of analytical and spectroscopic
data. Its IR spectrum showed absorption bands at 3400-3350
(NH2), 2200 (CN) and 1740, 1700, 1675 (C=O) cm-1. The 1H
NMR as well as the mass spectra agreed with the proposed
structure of 19 (Table 1).
EXPERIMENTAL
All melting points were recorded on a Gallen Kamp ap-

566 J. Chin. Chem. Soc., Vol. 52, No. 3, 2005
Shaker et al.
Scheme III
paratus and are uncorrected. IR spectra (cm-1) were recorded
(as KBr pellets) on a Shimadzu 480 spectrophotometer. The
1H NMR spectra were measured in DMSO-d6 on 90 and 200
MHz (Varian EM-390 and Bruker WM-400) spectrometers
using TMS as an internal standard; the chemical shifts are ex-
pressed as d values (ppm). Mass spectra were determined on a
Finnigan MAT 8430 mass spectrometer operating at 70 eV.
Micro analytical data were performed by the Micro Analyti-
cal Unit at Cairo University.
(10 mL), the resulting solid product was collected by filtra-
tion and crystallized from the appropriate solvent (Table 1).
Alternative Synthesis of 7
Method (A)
A mixture of 4 (10 mmol) and 1-phenylpyrazolidine-
3,5-dione (3) (10 mmol) with a catalytic amount of piperidine
was treated as above to afford 7, mp 189-190 °C, mixed mp
188-189 °C.
Method (B)
Synthesis of spiro-4,2¢-[indan-1¢,3¢-dione]pyrans
Equimolar amounts (10 mmol) of ninhydrin (1) and
malononitrile (2) and 1-phenylpyrazolidine-3,5-dione (3) in
ethanol (50 mL) containing a few drops of piperidine was
heated under reflux for 4 h. The solid product formed was
collected by filtration and recrystallized from EtOH.
7,9,14-17a-c and 19 (General Procedure)
An equimolar mixture (10 mmol) of each of ninhydrin
(1), malononitrile (2), and active methylene reagents with a
catalytic amount of piperidine were thoroughly mixed in a
100 mL beaker and irradiated at 700 w in a Samsung M 9245
microwave oven for 3-10 minutes (monitored by TLC). The
reaction mixtures were cooled and after addition of methanol
Received December 14, 2004.

Synthesis of Novel Spiro-Fused Pyrans
J. Chin. Chem. Soc., Vol. 52, No. 3, 2005 567
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