Chemistry of dimedone for synthesis of oxygen-, nitrogen-, and sulfur-containing heterocycles from 2-(3-hydroxy-5,5-dimethylcyclohex-2- enylidene)malononitrile

Article abstract of DOI:10.1080/00397911.2011.614713

A series of new oxygen-, nitrogen-and sulfur-containing spiro heterocycles was synthesized by reactions of 2-(3-hydroxy-5,5-dimethylcyclohex-2-enylidene) malononitrile with some active methylene and bidentate compounds.

Full text of DOI:10.1080/00397911.2011.614713

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Chemistry of Dimedone for Synthesis
of Oxygen-, Nitrogen-, and Sulfur-
Containing Heterocycles from 2-(3-
Hydroxy-5,5-dimethylcyclohex-2-
enylidene)malononitrile
Poulomi Majumdar a , Prajna Parimita Mohanta a , Rajani K. Behera a
& Ajaya Kumar Behera a
a Organic Synthesis Laboratory, School of Chemistry, Sambalpur
University, Odisha, India
Accepted author version posted online: 21 Feb 2012.Version of
record first published: 21 Dec 2012.
To cite this article: Poulomi Majumdar , Prajna Parimita Mohanta , Rajani K. Behera & Ajaya Kumar
Behera (2013): Chemistry of Dimedone for Synthesis of Oxygen-, Nitrogen-, and Sulfur- Containing
Heterocycles from 2-(3-Hydroxy-5,5-dimethylcyclohex-2-enylidene)malononitrile, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:6, 899-914
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Synthetic Communications1, 43: 899–914, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.614713
CHEMISTRY OF DIMEDONE FOR SYNTHESIS
OF OXYGEN-, NITROGEN-, AND SULFUR-
CONTAINING HETEROCYCLES FROM 2-(3-
HYDROXY-5,5-DIMETHYLCYCLOHEX-2-
ENYLIDENE)MALONONITRILE
Poulomi Majumdar, Prajna Parimita Mohanta,
Rajani K. Behera, and Ajaya Kumar Behera
Organic Synthesis Laboratory, School of Chemistry, Sambalpur University,
Odisha, India
GRAPHICAL ABSTRACT
Abstract A series of new oxygen-, nitrogen- and sulfur- containing spiro heterocycles was
synthesized by reactions of 2-(3-hydroxy-5,5-dimethylcyclohex-2-enylidene)malononitrile
with some active methylene and bidentate compounds.
Keywords Active methylene; bidentates; dimedone; malononitrile; spiro heterocycles
INTRODUCTION
Malononitrile is a commonly known and widely used reagent in the synthesis of
heterocyclic compounds, pharmaceuticals, pesticides, fungicides, solvatochromic dyes,
and charge-transfer salts. The unique reactivity of this compound has led to its wide-
spread applications in organic chemistry, similar to or even more than other such acids
such as malonate and cyanoacetic esters.[1] Alkylidenemalononitriles (a,b-unsaturated
nitriles) containing an activated double bond together with reactive CN groups are
Received July 4, 2011.
Address correspondence to Ajaya Kumar Behera, Organic Synthesis Laboratory, School of
Chemistry, Sambalpur University, Jyoti Vihar, Burla 768019, Odisha, India. E-mail: ajaykumar.behera@
yahoo.com
899

900
P. MAJUMDAR ET AL.
also common reagents utilized in heterocylic synthesis.[2–7] It has also been well known
that dimedone is a versatile precursor for synthesis of a number of heterocycles.[8]
Furthermore, the synthesis of spiro compounds has drawn considerable attention of
chemists, because of their interesting conformational features[9,10] and their structural
implications on biological systems.[11–21]
The syntheses, reactions, and biological activities of compounds containing pyra-
zole, [22–27] pyrimidine, [28–32] pyranopyrimidine, [33–35] thiazole, [36] thiazolidinone, [37–42]
pyrrole[43–46] or thiazine stand as an ever- expanding area of research in heterocyclic
chemistry, and these structural moieties appear in a large number of chemotherapeutic
agents and natural products.
The biological importance of spiro-compounds and nitrogen, oxygen, and sul-
fur heterocycles, along with our continued interest in the synthesis of heterocycles,[47]
led us to synthesize spiro heterocycles using 2-(3-hydroxy-5,5-dimethylcyclohex-
2-enylidene)malononitrile derivative 3 as the synthetic precursor obtained from
dimedone and malononitrile.
RESULTS AND DISCUSSION
The base- catalyzed condensation of dimedone 1 with malononitrile resulted in
the formation of the 2-(3-hydroxy-5,5-dimethylcyclohex-2-enylidene)malononitrile
derivative 3 rather than compound 2 (Scheme 1).
Initially, dimedone 1 was treated with 2 equivalents molar ratio of a malononi-
trile in the presence of a catalytic amount of piperidine in refluxing ethanol targeting
dienylidene malononitrile 2 as the product. The analytical and spectral data of the
product did not match the expected structure 2. These data suggest structure 3 for
the product. The results of elemental analyses is compatible with 3. Further, the
product 3 was supported by the infrared (IR) spectrum with characteristic signals
of the nitrile and hydroxy groups at 2216 cmꢀ1 and 3174–3236 cmꢀ1, respectively,
and [M ꢀ 1]þ ion peak at m=z 187 in the mass spectrum. The PMR spectrum of 3
exhibited four distinct separate singlets at d 1.09, 2.23, 2.54, and 6.18 corresponding
to six protons of the gem dimethyl group present at C-5 and two methylene protons
each at C-6, C-4, and enylidene proton at C-2, respectively. The distinct peaks at d
27.8, 32.8, 42.4, 42.5, 100.1 and 113.6, 114 corresponding to two gem dimethyl
Scheme 1. Synthesis of 2-(3-hydroxy-5,5-dimethylcyclohex-2-enylidene)malononitrile.

CHEMISTRY OF DIMEDONE
901
carbons, C-5, C-6, C-4, C-2, and two nitrile carbons, respectively, along with pro-
nounced signals at d 177, 174.7, and 68.4 assignable to C-1, C-3, and C(CN)2,
respectively, in the 13C NMR spectrum serve as a conclusive evidence in favor of
3. We also examined this reaction using 1 equivalent of malononitrile and in different
solvents (i.e. dioxane and dimethylformamide [DMF]). In all the reaction conditions
the same 2-(3-hydroxy-5,5-dimethylcyclohex-2-enylidene)malononitrile
3
was
formed, suggesting Knoevenagel condensation of malononitrile with one of the
carbonyl groups of 1.
The failure in the formation of dienylidene malononitrile 2 is almost certainly
due to enolization in 1. In CDCl3 solution it is clearly a mixture of the two tautomers.
1H-NMR and 13C-NMR of the mixture with the peaks of the dione is depicted by
stars (ꢁ) in Fig. 1 and Fig. 2, respectively. The majority of the sample is indeed
5,5-dimethylcyclohexane-1,3-dione (dimedone) 1A. The other component has a simi-
lar spectrum and is a similar compound, 1B: It has the six-proton singlet for the CMe2
group and the two CH2 groups at the side of the ring; it also has five signals in its 13
C
NMR spectrum (Fig. 2). However, it has a sharp signal at d 5.5 in the double-bond
region. It also has two different sp2 carbon atoms. All this fits the enol structure
(Fig. 3). These forms are in equilibrium and cannot be separated at room temperature.
Dimedone is just one example of the class of dicarbonyl compounds, which contain
substantial amounts of enol and may even be completely enolized in polar solvents.
This enol is very stable. The main reason is that this unique (1,3) arrangement of
the two carbonyl groups leads to enols that is conjugated like a carboxylic acid (Fig. 4).
It is interesting to note that the two CH2 groups in the ring seemed to be the
same, though they are different (a and b), and the delocalization also does not make
them the same. This must mean that the enol is in rapid equilibrium with another
identical enol. Thus, this is not delocalization because a proton is moving: It is
tautomerism (Fig. 5). Thus the two enols equilibrate fast with each other in CDCl3
solution but equilibrate slowly enough with the keto form for the two spectra to be
recorded at the same time. In CD3OD solution, the 1H NMR and 13C NMR spectra
show that only the enol form exists, presumably stabilized by hydrogen bonding
(Fig. 6).[48,49]
Figure 1. PMR spectra of dimedone.

902
P. MAJUMDAR ET AL.
Figure 2. 13C NMR spectra of dimedone.
2-(3-Hydroxy-5,5-dimethylcyclohex-2-enylidene)malononitrile derivative 3 was
reacted with bidentate nucleophiles, namely thiourea, thioacetamide, thiosemicarba-
zide, urea, semicarbazide, and guanidine hydrochloride, with a view to achieving the
corresponding aza spiro derivatives 4 (Scheme 2).
The first endeavor started on a refluxing equimolar mixture of malononitrile
derivative 3 and thiourea in the presence of a catalytic amount of different bases such
as piperidine, triethyl amine, triethanol amine, pyridine, and sodium acetate in etha-
=
=
nol with a view to obtaining spiro derivative 4a (R NH2, X S). Suprisingly, in all
the cases the isolated product was found to be the same malononitrile derivative 3 on
the basis of their physical, analytical, and infrared (IR) spectral data. However, the
reaction of malononitrile derivative 3 and thiourea in acetic acid in a oil bath at
150 ꢂC led to an unusual 4-oxo-3-aza-spiro[5.5]undeca-2,7-diene-5-carbonitrile 5a
=
=
(R NH2, X S) in moderate yield. The elemental analyses of the products ruled
out the formation of the expected spiro compound 4a, but it is agreeable to structure
5a. In the 1H NMR spectra of the product, two separate doublets appearing at d 2.51
(J ¼ 21 Hz) and d 2.26 (J ¼ 21 Hz) are attributable to each methylene protons at C-11
and C-9 of the cyclohexane ring, respectively. The C-5 and C-7 protons appeared as
Figure 3. Keto-enol tautomerism of dimedone.

CHEMISTRY OF DIMEDONE
903
Figure 4. Delocalization in the enol form of dimedone.
Figure 5. Equilibration of the enol form of dimedone.
singlets at d 5.97 and d 6.17, respectively. The unambiguous formation of spiran 5a
was favored by the appearance of distinct singals at d 169.1, 117.9, and 54.3 assign-
able to carbonyl, C N, and spiro carbon, respectively in the 13C NMR spectrum.
=
The peaks at d 48.6, 94.9, 117.3, and 168.2 were observed due to carbons at C-5,
C-7, CN, and C-8, respectively. The structural assignments made on the basis of
1
the H and 13C NMR spectra of compound 5a was supported by its IR spectrum
which showed appearance of characteristic absorption bands at 3346, 3209, 2196,
and 1658 cmꢀ1 due to the OH, NH2, nitrile, and carbonyl groups, respectively.
The possible mechanism involves initially the in situ hydrolysis of one of the nitrile
group of 3 in acetic acid medium and subsequent Michael addition of the mercapto
groups at the ethylenic double bond followed by cyclization through nucleophilic
attack of the imino group at the amidic carbonyl via intramolecular elimination of
amonia to give the cyclized spiro derivatives 5.
Figure 6. Crystalline dimedone contains chains of molecules, in the enol form, linked by hydrogen bonds.

904
P. MAJUMDAR ET AL.
Scheme 2. Synthesis of aza spiro derivatives 5.
Under the similar reaction conditions described previously, another series of aza
spiro derivatives 6 was obtained on treatment of 2-(3-hydroxy-5,5-dimethylcyclohex-2-
enylidene)malononitrile derivative 3 separately with mercaptoacetic acid or glycine
(Scheme 3). A similar mechanism for this series of azaspiro heterocycles has been
attributed as discussed previously. During the reaction, the nucleophilic addition of
Scheme 3. Synthesis of aza spiro derivatives 6–10.

CHEMISTRY OF DIMEDONE
905
the mercapto or amino group to the exocyclic double bond of 3 and subsequent dehy-
drative cyclization afforded the spiro derivatives 6. In the PMR spectrum of compound
=
6a (X NH), two separate doublets centered at d 4.04 (J ¼ 6 Hz) and d 4.13(J ¼ 6 Hz)
for one proton each at C-2, respectively, and a triplet resonating at d 8.67 (JNH, Ha=
¼ 6 Hz) assignable to N1-H suggest the formation of spiro[4.5]dec-6-ene-4-
Hb
carboxylic acid amide 6a. The OH and NH2 protons appeared as singlets at d 13.07
and 9.07, respectively. In the 13C NMR spectrum of 6a, the signals for spiro and car-
bonyl carbons appeared at d 49, 173.6 (amidic carbonyl) and, 200(C3¼O), respectively.
The active methylene compounds cyanoacetamide or 2-cyanomalonohydrazide,
3-phenyl-2-(phenylimino)thiazolidin-4-one, and barbiturates on refluxing with 2-(3-
hydroxy-5,5-dimethylcyclohex-2-enylidene)malononitrile derivative 3 under the same
reaction conditions described earlier formed the azaspiro derivatives 7, 8, and 9,
respectively (Scheme 3). The reaction pathway initially follows a similar in situ
hydrolysis of one of the nitrile groups of 3 in acetic acid medium and simultaneous for-
mation of the carbanion of the active methylene compound followed by nucleophilic
addition at the ethylenic bond and cyclization to give the spiro derivatives 7, 8, and 9.
=
In the IR spectrum of 7a (R H), the emergence of two broad peaks at about
3342 and 3221 and a sharp peak at 2204 cmꢀ1 corresponding to -OH, -NH, and
-CꢃN stretching frequency, respectively, along with the carbonyl peak at
1662 cmꢀ1, suggests the formation of 7a. The structure of 7a has been confirmed
on the basis of its PMR spectrum, which exhibits two distinct singlets at d 5.79
and 5.96 for two protons at C-5 and C-1 and one proton at C-7, respectively.
Two characteristic broad singlets centered at d 8.18 and 8.47 assignable to N3-H,
and OH, respectively, are agreeable to the proposed structure 7a. The 13C NMR
spectrum of 7a showed peaks at d 47.5 and 169.1 for spiro and carbonyl carbons,
respectively.
The appearance of a sharp peak at 1724 cmꢀ1 corresponding to carbonyl stretch-
ing frequency in the IR spectrum along with two bands at 2214 and 3439 cmꢀ1 assign-
able to nitrile and hydroxyl groups, respectively, tentatively suggests the structure of
the product as tetrahydro-2H-spiro[cyclohex-1-ene]-3,70-pyran[2,3-d]thiazole] 8. The
PMR spectral data display five separate singlets at d 0.99, 2.47, 2.51, 4.17, and 5.98,
corresponding to six methyl protons of the gem dimethyl group present at C-5, two
methylene protons each at d C-4, C-6, one proton each of C-60 and C-2, respectively,
along with a complex multiplet for 10 aromatic protos at d 6.86–7.55, and in the 13
C
NMR spectrum signals due to the spiro and carbonyl carbon appeared at d 48 and
168.2, respectively, confirming the formation of spiro 8.
In the IR spectrum, the appearance of bands at 1737, 1691, and 1656 cmꢀ1
assignable to carbonyl groups along with additional peaks at 3468, 3385,
3126–3180, and 2214 cmꢀ1 for OH, 0NH, and CN stretching frequency suggest the
=
structure of spiro[cyclohex-1-ene-3,9 -pyrano[2,3-d]pyrimidine] derivative 9a (R H,
=
=
=
X O). The PMR spectrum of 9a (R H, X O) gave five distinct singlets centered at
d 12.79, 10.19, 9.91, 6.66, and 4.39 assignable to OH, N-20, N-40, C-2, and C-70, respect-
ively. The appearance of two singlets at d 2.48 and 2.25 corresponding to methylene
protons at C-4 and C-6, respectively, along with peaks at d 52.3 (spiro C-80), 150.6
(C3’¼O), 164.2 (C1’¼O), and 169 (C6’¼O) in the 13C NMR spectrum, confirms the for-
0
=
mation of the spiro[cyclohex-1-ene-3,9 -pyrano[2,3-d]pyrimidine] derivative 9a (R H,
=
X O).

906
P. MAJUMDAR ET AL.
On the other hand, the cyclocondensation of 2-(3-hydroxy-5,5-
dimethylcyclohex-2-enylidene)malononitrile derivative 3 with bidentate nucleophiles
(namely phenyl hydrazine and hydrazine hydrate) under the reaction condition
discussed previously formed the 1,2-diaza-spiro[4.5]dec-6-ene-4-carbonitrile 10
=
(Scheme 3). The IR spectra of 10a (R Ph) gave two sharp peaks at 1676 and
2206 cmꢀ1 corresponding to carbonyl and nitrile group along with a broad peak at
3275 cmꢀ1 for NH and OH group, indicating the formation of 1,2-diaza-spiro[4.5]-
dec-6-ene-4-carbonitrile 10a. The PMR spectrum of compound 10a shows two singlets
at d 6.22 and d 5.75 for protons at C-6 and C-4, respectively, along with two separate
multiplets resonating at d 7.09–7.12, and 7.28–7.36 for five phenyl protons equivocally
suggest the formation of 1,2-diaza-spiro[4.5]dec-6-ene-4-carbonitrile 10a. A broad
singlet was observed for NH proton at d 9.23. In the 13C NMR spectrum of 10a the
signals for spiro and carbonyl carbons appeared at d 56.5 and 168.9, respectively.
In summary, an efficient route to obtain a wide range of spiro heterocyclic scaf-
folds, which have the potential for useful biological properties, has been developed.
Moreover, the exploitation of one of the carbonyl functions of dimedone for conden-
sation with malonitrile and subsequent spirolization of enylidene malononitrile inter-
mediate takes place with various bidentate nucleophiles and active ketomethylene
compounds to build up spiroheterocycles.
EXPERIMENTAL
Melting points were taken in open capillaries using sulfuric acid bath and are
uncorrected. Purity of the products were checked by thin-layer chromatography
(TLC) on silica gel G (BDH) using toluene–ethylacetate (4:1) as irrigant. IR spectra
were recorded with a Shimadzu FTIR Prestige-21 spectrophotometer in KBr using
the diffuse reflectance spectra (DRS) technique. NMR spectra were recorded on Varian
400-MHz (1H, 400 MHz; 13C, 100 MHz) and Bruker Avance III 500-MHz (500Hz for
1H, 125 MHz for 13C) NMR spectrometers in CDCl3 or dimethylsulfoxide (DMSO),
unless otherwise stated. Chemical shifts are expressed in parts per million downfield
from tetramethylsilane (TMS) as an internal standard. Data are given in the following
order: d value, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad), number of protons, and coupling constants J (given in hertz). The mass spectra
were taken on an API 2000 LC-MS mass spectrometer. Elemental analyses were per-
formed by Flash 2000 elemental analyzer and were in agreement with the calculated
values within ꢄ0.4%. All the reagents and solvents were of the best grade available
and were used without further purification.
Preparation of 2-(3-Hydroxy-5,5-dimethylcyclohex-2-enylidene)
malononitrile (3)
A mixture of dimedone 1 (10 mmol, 1.4 g), malononitrile (10 mmol, 0.47 mL)
and 3 drops of piperidine in dry ethanol (25 mL) was refluxed with stirring for 6 h.
The reaction set was allowed to cool at room temperature and poured into crushed
ice. The yellow solid thus separated out was filtered, dried, and recrystallized from
aqueous ethanol to get the golden yellow crystals of compound 3. Yield 75%; mp
118 ꢂC. IR (KBr, DRS): nmax=cmꢀ1 2216 (-CN), 3174–3236 (-OH); 1H NMR

CHEMISTRY OF DIMEDONE
907
(500 MHz, CDCl3): dH (ppm) 1.09 (s, 6H, 2 ꢅ Me), 2.23 (s, 2H, C6-H), 2.54 (s, 2H,
C4-H), 6.18 (s, 1H, C2-H); 13C NMR (125 MHz, CDCl3): dc (ppm) 27.8 (2 ꢅ Me),
32.8 (C-5), 42.4 (C-6), 42.5 (C-4), 68.4 [C(CN)2], 100.1 (C-2), 113.6 (CN), 114
(CN), 177 (C-1), 174.7 (C-3). ES-MS, m=z: 187 [M ꢀ 1]þ (100%). Anal. calcd. for
C11H12N2O: C, 70.21; H, 6.38; N, 14.89. Found: C, 70.05; H, 6.25; N, 14.74.
Preparation of Aza Spiro Derivative (5)
General procedure. A mixture of enylidene malononitrile 3 (2 mmol),
sodium acetate (2 mmol), and appropriate bidentates thiourea, thioacetamide, thio-
semicarbazide, urea, semicarbazide, guanidine hydrochloride (2 mmol) was refluxed
in acetic acid (15 ml) on an oil bath at 150 ꢂC for 6 h. The reaction set was allowed to
cool at room temperature and the solution was poured into crushed ice and neutra-
lized with NaHCO3 solution. The solid thus separated out was filtered, dried, and
recrystallized from ethanol.
2-Amino-8-hydroxy-10,10-dimethyl-4-oxo-1-thia-3-aza-spiro[5.5]undeca
-2,7-diene-5-carbonitrile (5a). Yield 82%; mp 158 ꢂC. IR (KBr, DRS): nmax=cmꢀ1
1
1658 (-C O), 2196 (-CN), 3209 (-NH2), 3346(-OH); H NMR (400 MHz, DMSO):
=
dH(ppm) 1.08 (s, 6H, 2 ꢅ Me), 2.26 (d, 2H, J ¼ 21 Hz, 1 ꢅ C9-H,
1 ꢅ C11-H), 2.51 (d, 2H, J ¼ 21 Hz, 1 ꢅ C9-H, 1 ꢅ C11-H), 5.97 (s, 1H, C5-H),
6.17 (s, 1H, C7-H); 13C NMR (100 MHz, DMSO): dc(ppm) 27.3 (Me), 27.4 (Me),
31.8 (C-9), 32.5 (C-10), 41.4 (C-11), 48.6 (C-5), 54.3 (C-6), 94.9 (C-7), 117.3 (CN),
117.9 (C-2), 168.2 (C-8), 169.1 (C-4). ES-MS, m=z: 265 [M]þ (100%). Anal. calcd.
for C12H13N3O2: C, 54.34; H, 5.66; N, 15.85. Found: C, 54.09; H, 5.39; N, 15.60.
8-Hydroxy-2,10,10-trimethyl-4-oxo-1-thia-3-aza-spiro[5.5]undeca-2,7-
diene-5-carbonitrile (5b). Yield 76%; mp 264 ꢂC. IR (KBr, DRS): nmax=cmꢀ1
1
=
1647 (-C O), 2212 (-CN), 3340 (-OH); H NMR (400 MHz, DMSO): dH(ppm)
1.00 (s, 6H, 2 ꢅ Me), 2.24–2.55 (m, 4H, 2 ꢅ C9-H, 2 ꢅ C11-H), 2.70 (s, 3H, Me),
5.77 (s, 1H, C5-H), 8.29 (s, 1H, C7-H), 12.20 (bs, 1H, OH); 13C NMR (100 MHz,
DMSO): dc(ppm) 27.2 (Me), 27.3 (Me), 27.4 (Me), 31.8 (C-9), 32.5 (C-10), 41.4
(C-11), 48.6 (C-5), 54.3 (C-6), 94.9 (C-7), 115.6 (CN), 116.1 (C-2), 168.1 (C-8),
169.1(C-4). ES-MS, m=z: 263 [M ꢀ 1]þ (100%). Anal. calcd. for C13H16N2O2S: C,
59.09; H, 6.06; N, 10.61. Found: C, 58.84; H, 5.80; N, 10.33.
2-Hydrazino-8-hydroxy-10,10-dimethyl-4-oxo-1-thia-3-aza-spiro[5.5]
undeca-2,7-diene-5-carbonitrile (5c). Yield 79%; mp 195 ꢂC. IR (KBr, DRS):
1
max=cmꢀ1 1687 (-C O), 2208 (-CN), 3240, 3284 (-NH, -NH2); H NMR
=
n
(400 MHz, DMSO): dH(ppm) 0.99 (s, 6H, 2 ꢅ Me), 2.27–2.47 (m, 4H, 2 ꢅ C9-H,
2 ꢅ C11-H), 5.68 (bs, 2H, NH2), 5.97 (s, 1H, C5-H), 6.3 (s, 1H, C7-H), 10.54 (bs,
1H, NH), 10.95 (bs, 1H, OH); 13C NMR (100 MHz, DMSO): dc(ppm) 27.3 (Me),
27.4 (Me), 31.8 (C-9), 32.5 (C-10), 41.4 (C-11), 48.7 (C-5), 54.2 (C-6), 94.3 (C-7),
117.3 (CN), 118 (C-2), 168.2 (C-8), 170 (C-4). ES-MS, m=z: 279 [M ꢀ 1]þ (100%).
Anal. calcd. for C12H16N4O2S: C, 51.43; H, 5.71; N, 20.00. Found: C, 51.16; H,
5.50; N, 19.75.
2-Amino-8-hydroxy-10,10-dimethyl-4-oxo-1-oxa-3-aza-spiro[5.5]undeca
-2,7-diene-5-carbonitrile (5d). Yield 80%; mp 245 ꢂC. IR(KBr, DRS): nmax=cmꢀ1

908
P. MAJUMDAR ET AL.
1
=
1662 (-C O), 2202 (-CN), 3215 (-NH2), 3344 (-OH); H NMR (400 MHz, DMSO): dH
(ppm) 1.03 (s, 6H, 2 ꢅ Me), 2.22 (d, 2H, J ¼ 21 Hz, 1 ꢅ C9-H, 1 ꢅ C11-H), 2.48 (d, 2H,
J ¼ 21 Hz, 1 ꢅ C9-H, 1 ꢅ C11-H), 5.98 (s, 1H, C5-H), 6.22 (s, 1H, C7-H); 13C NMR
(100 MHz, DMSO): dc (ppm) 27.7 (Me), 27.7 (Me), 32 (C-9), 32.3 (C-10), 41 (C-11),
47.1 (C-5), 56.2 (C-6), 100 (C-7), 117 (CN), 118 (C-2), 168.2 (C-8), 170 (C-4). ES-MS,
m=z: 249 [M]þ (100%). Anal. calcd. for C12H15N3O3: C, 57.83; H, 6.02; N, 16.87.
Found: C, 57.55; H, 5.78; N, 16.59.
2-Hydrazino-8-hydroxy-10,10-dimethyl-4-oxo-1-oxa-3-aza-spiro[5.5]un
deca-2,7-diene-5-carbonitrile (5e). Yield 75%; mp 200 ꢂC. IR (KBr, DRS): nmax
=
cmꢀ1 1699 (-C O), 2208 (-CN), 3269 (-NH, -NH2), 3469 (-OH); H NMR (400 MHz,
DMSO): dH (ppm) 1.00 (s, 6H, 2 ꢅ Me), 2.23–2.41(m, 4H, 2 ꢅ C9-H, 2 ꢅ C11-H), 5.65
(bs, 2H, NH2), 5.80 (s, 1H, C5-H), 6.32 (s, 1H, C7-H), 10.57 (bs, 1H, NH), 11.01 (bs,
1H, OH); 13C NMR (100 MHz, DMSO): dc(ppm) 27.6 (Me), 27.7 (Me), 32 (C-9), 32.3
(C-10), 41 (C-11), 47.1 (C-5), 56.2 (C-6), 100 (C-7), 117 (CN), 118 (C-2), 168.2 (C-8),
170 (C-4). ES-MS, m=z: 263[M ꢀ 1]þ (100%). Anal. calcd. for C12H16N4O3: C, 54.54;
H, 6.06; N, 21.21. Found: C, 54.30; H, 5.82; N, 20.96.
1
=
2-Amino-8-hydroxy-10,10-dimethyl-4-oxo-1,3-diaza-spiro[5.5]undeca
-2,7-diene-5-carbonitrile (5f). Yield 71%; mp 250 ꢂC. IR (KBr, DRS): nmax=cmꢀ1
1
=
1656 (-C O), 2202 (-CꢃN), 3221, 3286 (-NH, -NH2), 3338 (-OH); H NMR
(400 MHz, DMSO): dH(ppm) 0.96 (s, 6H, 2 ꢅ Me), 2.19–2.42(m, 4H, 2 ꢅ C9-H,
2 ꢅ C11-H), 5.67 (bs, 2H, NH2), 5.85 (s, 1H, C5-H), 6.41 (s, 1H, C7-H), 10.97 (bs,
1H, NH), 11.06 (bs, 1H, OH); 13C NMR (100 MHz, DMSO): dc (ppm) 27.6 (Me),
27.7 (Me), 32.2 (C-9), 32.6 (C-10), 41.6 (C-11), 48.7 (C-5), 54.9 (C-6), 95.5 (C-7),
117.4 (CN), 118.1 (C-2), 168.5 (C-8), 169.7 (C-4). ES-MS, m=z: 247[M ꢀ 1]þ
(100%). Anal. calcd. for C12H16N4O2: C, 58.06; H, 6.45; N, 22.58. Found: C, 57.80;
H, 6.23; N, 22.31.
Preparation of Spiro Derivative (6)
General procedure. A mixture of enylidene malononitrile 3 (2 mmol), sodium
acetate (2 mmol), and glycine=or thioglycolic acid (2 mmol) was refluxed in acetic acid
(15 ml) on an oil bath at 150 ꢂC for 6 h. The reaction set was allowed to cool at room
temperature, and the solution was poured into crushed ice and neutralized with
NaHCO3 solution. The solid thus separated out was filtered, dried, and recrystallized
from ethanol.
4-Cyano-7-hydroxy-9,9-dimethyl-3-oxo-1-aza-spiro[4.5]dec-6-ene-4-car-
boxylic acid amide (6a). Yield 80%; mp 230 ꢂC. IR (KBr, DRS): nmax=cmꢀ1 1658
1
=
=
(-C O), 1737 (-C O pyrrolidine ring), 2216 (-CꢃN), 3280 (-NH2), 3361 (-OH); H
NMR (400 MHz, DMSO): dH (ppm) 0.97 (s, 6H, 2 ꢅ Me), 2.30–2.5(m, 4H, 2 ꢅ C8-H,
, 2 ꢅ C10-H), 4.04 (d, 1H, J ¼ 6 Hz, 1 ꢅ C2-H), 4.13 (d, 1H, J ¼ 6 Hz, 1 ꢅ C2-H),
5.96(s, 1H, C6-H), 8.67 (t, 1H, J ¼ 6 Hz, N1-H), 9.07 (s, 2H, NH2), 13.07 (s, 1H,
OH); 13C NMR (100 MHz, DMSO): dc (ppm) 27.7 (2 ꢅ Me), 32 (C-8), 32.5 (C-9),
41 (C-10), 49 (C-5), 54 (C-2), 67.3 (C-4), 95.3 (C-6),þ114 (CN), 167.5 (C-7), 173.6
=
=
(C ONH2), 200 (C O). ES-MS, m=z: 263 [M] (100%). Anal. calcd. for
C13H17N3O3: C, 59.32; H, 6.46; N, 15.97. Found: C, 59.18; H, 6.33; N, 15.84.

CHEMISTRY OF DIMEDONE
909
4-Cyano-7-hydroxy-9,9-dimethyl-3-oxo-1-thia-spiro[4.5]dec-6-ene-4-
carboxylic acid amide (6b). Yield 63%; mp 215 ꢂC. IR (KBr, DRS): nmax=cmꢀ1
=
=
1653 (-C O), 1724 (-C O pyrrolidine ring), 2200 (-CꢃN), 3199 (-NH2), 3405
(-OH);1H NMR (400 MHz, DMSO): dH (ppm) 0.99 (s, 6H, 2 ꢅ Me), 2.13–2.27(m,
4H, 2 ꢅ C8-H, 2 ꢅ C10-H), 3.72 (s, 2H, C2-H), 5.38 (s, 1H, C6-H), 8.62 (s, 2H,
NH2); 13C NMR (100 MHz, DMSO): dc (ppm) 27.3 (2 ꢅ Me), 31 (C-8), 31.9 (C-9),
39.9 (C-2), 41 (C-10), 48.2 (C-5), 67.3 (C-4), 95.3 (C-6), þ114 (CN), 167.5 (C-7), 173.3
=
=
(C ONH2), 199.3 (C O). ES-MS, m=z: 279 [M ꢀ 1] (100%). Anal. calcd. for
C13H16N2O3S: C, 55.71; H, 5.71; N, 10.00. Found: C, 55.43; H, 5.47; N, 9.71.
Preparation of Spiro Derivative (7)
General procedure. A mixture of enylidene malononitrile 3 (2 mmol), sodium
acetate (2 mmol), and cyanoacetamide=or 2-cyanomalonohydrazide (2 mmol) was
refluxed in acetic acid (15 ml) on an oil bath at 150 ꢂC for 6 h. The reaction set was
allowed to cool at room temperature, and the solution was poured into crushed ice
and neutralized with NaHCO3 solution. The solid thus separated out was filtered,
dried, and recrystallized from ethanol.
8-Hydroxy-10,10-dimethyl-2,4-dioxo-3-azaa-spiro[5.5]undec-7-ene-1,5-
dicarbonitrile (7a). Yield 70%; mp 196 ꢂC. IR (KBr, DRS): nmax=cmꢀ1 1662
1
=
(-C O), 2204 (-CN), 3221 (-NH2), 3342 (-OH); H NMR (400 MHz, DMSO): dH
(ppm) 0.97 (s, 6H, 2 ꢅ Me), 2.32 (d, 2H, J ¼ 22 Hz, 1 ꢅ C9-H, 1 ꢅ C11-H), 2.49 (d,
2H, J ¼ 22 Hz, 1 ꢅ C9-H, 1 ꢅ C11-H), 5.79 (s, 1H, C1-H & C5-H), 5.96 (s, 1H,
C7-H), 8.18 (s, 1H, N3-H), 8.47 (s, 1H, OH). 13C NMR (100 MHz, DMSO): dc
(ppm) 28 (2 ꢅ Me), 32 (C-10), 34.6 (C-11), 45.4 (C-9), 47.5 (C-6), 50.1 (C-1 & C-5),
þ
=
100 (C-7), 115 (CN), 169.1 (2 ꢅ C O), 172.3 (C-8). ES-MS, m=z: 272 [M ꢀ 1]
(100%). Anal. calcd. for C14H15N3O3: C, 61.54; H, 5.49; N, 15.38. Found: C, 61.43;
H, 5.34; N, 15.25.
3-Amino-8-hydroxy-10,10-dimethyl-2,4-dioxo-3-aza-spiro[5.5]undec-7-
ene-1,5-dicarbonitrile (7b). Yield 74%; mp 190 ꢂC. IR (KBr, DRS): nmax=cmꢀ1
1
1674 (-C O), 2212 (-CN), 3248 (-NH2), 3450 (-OH); H NMR (400 MHz, DMSO):
=
dH (ppm) 1.00 (s, 6H, 2 ꢅ Me), 2.36–2.49 (m, 4H, 2 ꢅ C9-H, 2 ꢅ C11-H), 5.52 (s,
1H, C1-H & C5-H), 5.81 (s, 1H, C7-H), 6.71 (s, 1H, N3-H), 10.50 (s, 1H, OH). 13C
NMR (100 MHz, DMSO): dc(ppm) 28 (2 ꢅ Me), 32 (C-10), 34.7 (C-11), 45.3 (C-9),
=
47.7 (C-6), 50 (C-1 & C-5), 100.1 (C-7), 115.1 (CN), 167.9 (2 ꢅ C O), 172.3 (C-8).
ES-MS, m=z: 287 [M ꢀ 1]þ (100%). Anal. calcd. for C14H16N4O3: C, 58.33; H, 5.56;
N, 19.44. Found: C, 58.14; H, 5.32; N, 19.20.
Procedure for Preparation of 1-Hydroxy-5,5-dimethyl-6’-cyano-5’-
oxo-3’-phenyl-2’-phenylimino-3’,5’,6’,7’-tetrahydro-2H-
spiro[cyclohex-1-ene-3,7’-pyran[2,3-d]thiazole] (8)
A mixture of enylidene malononitrile 3 (1 mmol, 0.19 g), sodium acetate
(1 mmol, 0.08 g), and 3-phenyl-2-(phenylimino)thiazolidin-4-one (1 mmol, 0.27 g)
was refluxed in acetic acid (15 ml) on an oil bath at 150 ꢂC for 6 h. The reaction set
was allowed to cool at room temperature, and the solution was poured into crushed

910
P. MAJUMDAR ET AL.
ice and neutralized with NaHCO3 solution. The straw-yellow-colored solid thus
separated out was filtered, dried, and recrystallized from ethanol. Yield 89%; mp
1
160 ꢂC. IR (KBr, DRS): nmax=cmꢀ1 1724 (-C O), 2214 (-CN), 3439 (-OH); H
=
NMR (400 MHz, CDCl3): dH (ppm) 0.99 (s, 6H, 2 ꢅ Me), 2.47 (s, 2H, C4-H), 2.51
(s, 2H, C6-H), 4.17 (s, 1H, C60-H), 5.98 (s, 1H, C2-H), 6.86–7.55 (m, 10H, Ph-H).
13C NMR (100 MHz, CDCl3): dc (ppm) 28 (2 ꢅ Me), 34 (C-5), 38.2 (C-4), 42 (C-6),
48 (C-70), 49.3 (C-60), 68.2 (C-10a), 99 (C-2), 115.1 (CN), 116.3, 119.1, 122.9, 127.6,
129.3, 133.2, 140, 149.1 (10 ꢅ Ar-C), 156.7 (C-30a), 161.3 (C-20), 168.2 (C-50), 172.3
(C-1). ES-MS, m=z: 456[M ꢀ 1]þ (100%). Anal. calcd. for C26H23N3O3S: C, 68.27;
H, 5.03; N, 9.19. Found: C, 68.14; H, 4.87; N, 9.04.
Preparation of Spiro Derivative (9)
General procedure. A mixture of enylidene malononitrile 3 (1 mmol), sodium
acetate (1 mmol), and barbiturates (barbituric acid, 1,3-diphenyl thiobarbituric acid,
or thiobarbituric acid) (1 mmol) was refluxed in acetic acid (15 ml) on an oil bath at
150 ꢂC for 6 h. The reaction set was allowed to cool at room temperature and the
solution was poured into crushed ice and neutralized with NaHCO3 solution. The orange
colored solid thus separated out was filtered, dried, and recrystallized from ethanol.
1-Hydroxy-5,5-dimethyl-2’,4’-diphenyl-7’-cyano-1’,3’,6’-trioxo-1’,3’,4’,6’,
7’-pentahydro-2H-spiro[cyclohex-1-ene-3:8’-pyrano[2,3-d]pyrimidine] (9a).
Yield 80%; mp > 300 ꢂC. IR (KBr, DRS): nmax=cmꢀ1 1737, 1691, 1656 (-C O),
=
2214 (-CN), 3126–3180, 3385 (-NH), 3468 (-OH);1H NMR (400 MHz, DMSO): dH
(ppm) 1.25 (s, 6H, 2 ꢅ Me), 2.48 (s, 2H, C4-H), 2.25 (s, 2H, C6-H), 4.39 (s, 1H,
C70-H), 6.66 (s, 1H, C2-H), 9.91 (s, 1H, N40-H), 10.19 (s, 1H, N20-H), 12.79 (s,
1H, OH). 13C NMR (100 MHz, DMSO): dc (ppm) 27.9 (2 ꢅ Me), 33.3 (C-5), 43
(C-4), 44.6 (C-6), 51.3 (C-70), 52.3 (C-80), 85.9 (C-10a), 99.3 (C-2), 115 (CN), 150.6
0
0
0
0
(C3 ¼ O), 151 (C4 a), 164.2 (C1 ¼ O), 169 (C6 ¼ O), 172.12 (C-1). ES-MS, m=z: 317
[M]þ (100%). Anal. calcd. for C15H15N3O5: C, 56.78; H, 4.73; N, 13.25. Found: C,
56.59; H, 4.62; N, 13.09.
1-Hydroxy-5,5-dimethyl-8’-cyano-1’,6’-dioxo-3’-thioxo-1’,3’,4’,6’,7’-penta
hydro-2H-spiro[cyclohex-1-ene-3:8’-pyrano[2,3-d]pyrimidine] (9b). Yield 79%;
mp > 300 ꢂC. IR (KBr, DRS): nmax=cmꢀ1 1672 (-C O), 2167 (-CN), 3161, 3356
=
(-NH), 3531 (-OH);1H NMR (400 MHz, DMSO): dH(ppm) 1.26 (s, 6H, 2 ꢅ Me),
2.30 (s, 2H, C4-H), 2.08 (s, 2H, C6-H), 4.45 (s, 1H, C70-H), 6.96 (s, 1H, C2-H), 10.54
(s, 1H, N40-H), 11.45 (s, 1H, N20-H), 14.00 (s, 1H, OH). 13C NMR (100 MHz, DMSO):
dc(ppm) 27.3 (2 ꢅ Me), 33.3 (C-5), 42.9 (C-4), 44 (C-6), 50 (C-80), 51.3 (C-70), 88.6
(C-10a), 99.3 (C-2), 115 (CN), 159.9 (C4 a), 162 (C1 ¼ O), 169.1 (C6 ¼ O), 174.9
0
0
0
þ
0
(C-1), 177.9 (C3 ¼ S). ES-MS, m=z: 333 [M] (100%). Anal. calcd. for C15H15N3O4S:
C, 54.05; H, 4.50; N, 12.61. Found: C, 53.81; H, 4.25; N, 12.37.
1-Hydroxy-5,5-dimethyl-8’-cyano-1’,6’-dioxo-2’,4’-diphenyl-3’-thioxo-1’,
2’,3’,4’,6’,7’-hexahydro-spiro[cyclohex-1-ene-3:8’-pyrano[2,3-d]pyrimidine]
(9c). Yield 81%; mp 215 ꢂC. IR (KBr, DRS): nmax=cmꢀ1 1643, 1689 (-C O),
=
3280–3300 (-OH);1H NMR (400MHz, CDCl3): dH(ppm) 1.08 (s, 6H, 2 ꢅ Me), 2.19
(d, 2H, J ¼ 20.8 Hz, 1 ꢅ C4-H, 1 ꢅ C6-H), 2.50 (d, 2H, J ¼ 20.8 Hz, 1 ꢅ C4-H,

CHEMISTRY OF DIMEDONE
911
1 ꢅ C6-H), 6.04 (s, 1H, C70-H), 6.17 (s, 1H, C2-H), 7.12–7.56(m, 10H, PhH), 12.23 (s,
1H, OH). 13C NMR (100 MHz, DMSO): dc (ppm) 27.9 (2 ꢅ Me), 33.2 (C-5), 42 (C-4),
44 (C-6), 51 (C-80), 51.2 (C-70), 79 (C-10a), 99.6 (C-2), 115.5 (CN), 128–130(closely
0
0
0
spaced six peaks), 139, 144 (Ar-C), 156.3 (C4 a), 162.2 (C1 ¼O), 169 (C6 ¼O), 173.9
þ
0
(C-1), 176.3 (C3 ¼S). ES-MS, m=z: 484 [M ꢀ 1] (100%). Anal. calcd. for
C27H23N3O4S: C, 66.80; H, 4.74; N, 8.66. Found: C, 66.56; H, 4.53; N, 8.38.
Preparation of Spiro Derivative (10)
General procedure. A mixture of enylidene malononitrile 3 (2 mmol), sodium
acetate (2 mmol), and phenyl hydrazine or hydrazinehydrate (2 mmol) was refluxed in
acetic acid (15 ml) on an oil bath at 150 ꢂC for 6 h. The reaction set was allowed to cool
at room temperature, and the solution was poured into crushed ice and neutralized
with NaHCO3 solution. The solid thus separated out was filtered, dried, and recrystal-
lized from ethanol.
7-Hydroxy-9,9-dimethyl-3-oxo-2-phenyl-1,2-diaza-spiro[4.5]dec-6-ene-
4-carbonitrile (10a). Yield 71%; mp 190 ꢂC. IR (KBr, DRS): nmax=cmꢀ1 1676
1
=
(-C O), 2206 (-CN), 3275 (-NH & -OH); H NMR (400 MHz, DMSO): dH (ppm)
1.06 (s, 6H, 2 ꢅ Me), 2.08–2.51(m, 2H, 1 ꢅ C8-H, 1 ꢅ C10-H), 2.71–2.82(m, 2H,
1 ꢅ C8-H, 1 ꢅ C10-H), 5.75(s, 1H, C4-H), 6.22 (s, 1H, C6-H), 7.09–7.12 (m, 2H,
Ph-H), 7.28–7.36(m, 3H, Ph-H), 9.23 (bs, 1H, NH). 13C NMR (100 MHz, DMSO):
dc (ppm) 28 (2 ꢅ Me), 31.6 (C-8), 32 (C-9), 42 (C-10), 46.2 (C-4), 56.5 (C-5), 95.1
=
(C-6), 117.3 (CN), 134.9, 121.6, 129, 124.4 (Ar-C), 168.9 (C O), 175.3 (C-7). ES-MS,
m=z: 296 [M ꢀ 1]þ (100%). Anal. calcd. for C17H19N3O2: C, 68.69; H, 6.40; N, 14.14.
Found: C, 68.52; H, 6.28; N, 14.02.
7-Hydroxy-9,9-dimethyl-3-oxo-1,2-diaza-spiro[4.5]dec-6-ene-4-carboni-
trile (10b). Yield 76%; mp 215 ꢂC. IR (KBr, DRS): nmax=cmꢀ1 1658 (-C O), 2214
=
(-CN), 3182, 3338 (-NH), 3379 (-OH); 1H NMR (400 MHz, DMSO): dH (ppm) 1.00
(s, 6H, 2 ꢅ Me), 2.03–2.45(m, 2H, 1 ꢅ C8-H, 1 ꢅ C10-H), 2.51–2.67(m, 2H,
1 ꢅ C8-H, 1 ꢅ C10-H), 5.78 (s, 1H, C4-H), 6.55 (s, 1H, C6-H), 8.61 (bs, 1H, NH),
9.35 (bs, 1H, NH). 13C NMR (100 MHz, DMSO): dc (ppm) 28 (2 ꢅ Me), 31.6
(C-8), 32.1 (C-9), 41.9 (C-10), 48.4 (C-4),þ57.5 (C-5), 96 (C-6), 117.4 (CN), 170
=
(C O), 175.3 (C-7). ES-MS, m=z: 221 [M] (100%). Anal. calcd. for C11H15N3O2:
C, 59.73; H, 6.79; N, 19.00. Found: C, 59.49; H, 6.56; N, 18.73.
ACKNOWLEDGMENTS
This work was supported by the University Grants Commission (UGC), New
Delhi. The author P.M. is grateful to UGC, for a research fellowship. The authors
thank Funding for Infrastructure in Science and Technology, Department of Science
and Technology, for providing facilities and NISER, Bhubaneswar, for providing
NMR spectral data.
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