Studies on the synthesis of spiroheterocycles and their derivatives using dimedone as synthetic precursor

Article abstract of DOI:10.1080/00397911.2018.1460759

Diarylidene ketones 1a–c, formed by the condensation of acetone with diverse appropriate aryl aldehydes undergo Micheal reaction with dimedone to afford the desired spiro compounds 2a–c. The spirodiarylidene derivatives 3a–l on cyclisation with hydrazine, phenyl hydrazine, hydroxyl amine, urea, thiourea and guanidine carbonate furnish the respective insitu oxidized pyrazole 4a–l, phenylpyrazole 5a–l, isoxazole 6a–l, pyrimidine 7a–l, aminopyrimidine 8a–l. The antibacterial activities of the synthesized compounds have been investigated against the gram negative Escherichia coli and gram positive bacteria Staphylococcus aureus.

Full text of DOI:10.1080/00397911.2018.1460759

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Studies on the synthesis of spiroheterocycles and
their derivatives using dimedone as synthetic
precursor
Poulomi Majumdar, Prajna Parimita Mohanta, Sankarshan Sahu & Ajaya
Kumar Behera
To cite this article: Poulomi Majumdar, Prajna Parimita Mohanta, Sankarshan Sahu
& Ajaya Kumar Behera (2018): Studies on the synthesis of spiroheterocycles and their
derivatives using dimedone as synthetic precursor, Synthetic Communications, DOI:
10.1080/00397911.2018.1460759
To link to this article: https://doi.org/10.1080/00397911.2018.1460759
Published online: 11 Jun 2018.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2018.1460759
Studies on the synthesis of spiroheterocycles and their
derivatives using dimedone as synthetic precursor
Poulomi Majumdar, Prajna Parimita Mohanta, Sankarshan Sahu, and
Ajaya Kumar Behera
Organic Synthesis Laboratory, School of Chemistry, Sambalpur University, Burla, India
ABSTRACT
ARTICLE HISTORY
Received 25 November 2017
Diarylidene ketones 1a–c, formed by the condensation of acetone
with diverse appropriate aryl aldehydes undergo Micheal reaction
with dimedone to afford the desired spiro compounds 2a–c. The spi-
rodiarylidene derivatives 3a–l on cyclisation with hydrazine, phenyl
hydrazine, hydroxyl amine, urea, thiourea and guanidine carbonate
furnish the respective insitu oxidized pyrazole 4a–l, phenylpyrazole
5a–l, isoxazole 6a–l, pyrimidine 7a–l, aminopyrimidine 8a–l. The anti-
bacterial activities of the synthesized compounds have been investi-
gated against the gram negative Escherichia coli and gram positive
bacteria Staphylococcus aureus.
KEYWORDS
Antibacterial activities;
dimedone; isooxazole;
pyrazole; pyrimidine;
spiroheterocycles
GRAPHICAL ABSTRACT
Ar
O
O
O
HC
HC
CHAr
CHAr
+
O
O
O Ar
Ar'CHO
Ar
O
CHAr'
O
Ar
Ar
O
CHAr'
O
Ar
CHAr'
O
Ar = C6H5, p- MeOC6H4, p-ClC6H4
Ar' = C6H5, p- MeOC6H4, p-ClC6H4 , p-BrC6H4
Diarylidene ketone undergo Micheal rection with dimedone to afford
the spiro compounds followed by cyclisation with some bidentate
ligands to furnish the respective insitu oxidized pyrazole, phenylpyra-
zole, isoxazole, pyrimidine, aminopyrimidine derivatives and the syn-
thesized compounds were screened for their antibacterial activities.
CONTACT Ajaya Kumar Behera
ajaykumar.behera@yahoo.com
Organic Synthesis Laboratory, School of Chemistry,
Sambalpur University, Burla, Odisha, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher's website.
ß 2018 Taylor & Francis

2
P. MAJUMDAR ET AL.
Ar
O
O
O
O
HC
HC
CH3
CHAr
EtOH
EtOH
NaOH
O
+
ArCHO
O
O
+
TEOA
CHAr
CH3
Ar
1a-c
2
3a-c
Ar = C6H5, p- MeOC6H4, p-ClC6H4
Scheme 1. Synthesis of spiro compounds 3a–c.
Introduction
Dimedone is an alicyclic compound having 1,3-dicarbonyl groups flanked by a methy-
lene group and exists in a tautomeric trans-enolized form where intermolecular hydro-
gen bonding[1] does exist. It is an excellent synthetic precursor due to the presence of
C-1, C-2, and C-3 reactive centres. In addition, dimedone is a unique compound for
construction of partially hydrogenated fused heterocycles.[2] A wide range of practical
applications of dimedone include their uses as versatile precursors for synthesis of
numerous hetero and spirocyclic compounds,[3–5] xanthene derivatives[6] with their
industrial[7] and synthetic[8] applications, photo-antiproliferative,[9] anticancer[10] agents
and also as reagent for various analytical determinations.[11] Moreover, the fused hetero-
cyclic ring systems are important scaffolds in medicinal chemistry and appear in several
natural and synthetic compounds of significant pharmacological properties.[12]
Spiroheterocycles are of considerable interest because of their conformational restriction
associated to the structural rigidity which steers the biological activity.[13]
In continuation of our earlier work,[14] the present effort has been focused on spiroli-
zation of versatile dimedone precursor with diarylidene ketones and later the spiran
formed underwent condensation with diverse arylaldehydes in the cyclohexanone moiety
to form its diarylidene derivatives. Thereafter, the diarylidene intermediate has been the
focal point for systematic installation of biologically active heterocyclic units such as
pyrazole, isoxazole and pyrimidine onto the a,b-unsaturated scaffold of spiro frame
work. However, the findings of dimedone chemistry here is in contrast with our earlier
piece of the research work.[15] The spirolization appears due to manipulation of reactiv-
ity of C-2 carbon.
Results and discussion
The diarylideneacetones 1a–c were prepared[16–18] by the condensation of aryl aldehydes
and acetone in ethanolic NaOH. Subsequently, the reaction of diarylideneacetones 1a–c
with dimedone 2 was performed in presence of triethanolamine (TEOA) via Michael
addition to afford spiro compounds 3a–c (Scheme 1). The analytical and spectral data
suggest the formation of spiro derivatives 3a–c. The IR spectrum of 3a (Ar ¼ C6H5) fur-
nishes two characteristic sharp peaks at 1714 and 1680 cmꢀ1 corresponding to carbonyl
stretchings of dimedone and cyclohexanone rings, respectively.
The PMR spectrum of 3a (Ar ¼ C6H5) gives two separate singlets at d ¼ 1.60 and 2.01
corresponding to six protons of gem dimethyl groups at C-3 and four methylene

R
SYNTHETIC COMMUNICATIONSV
3
3.81 (t)
3.65 (t)
Ha
2.01 (s)
1.60 (s)
Ha
He
O
H3C
H3C
2.54 (dd)
2.54 (dd)
1
5
10
2
11
7
6
9
3
O
8
4
He
1.60 (s)
2.01 (s)
O
Ha
3.65 (t)
3.81 (t)
Ha
Figure 1. 1H NMR assignment of compound 3a.
protons at C-2 and C-4 of dimedone ring, respectively. The equivalence of four protons
at C-2 and C-4 may be accounted for planarity of dimedone ring due to presence of
two carbonyl groups at C-1 and C-5. A doublet of doublet centred at d ¼ 2.54
0
(JH8–H 8 ¼ 14.8 Hz and JH8–H7 ¼ 3.6 Hz) for the two equatorial protons at C-8 and C-10,
0
0
a triplet at d3.65 (JH 8–H8 ¼ JH 8–H7 ¼ 14.8 Hz) for the two axial protons at C-8 and C-10
0
and another doublet of doublet resonating at d ¼ 3.81 (JH8–H 8 ¼ 14.8 Hz and
JH8–H7 ¼ 3.6 Hz) for two axial protons at C-7 and C-11 are compatible to the proposed
spiran 3a (Fig. 1). It is supportive by a complex multiplet at d ¼ 7.07–7.29 correspond-
ing to 10 protons of two phenyl groups attached to C-7 and C-11. The axial protons at
C-8 and C-10 experience down field shift as compared to their equatorial protons due
to anisotropy effect of the carbonyl group.
The 13C NMR spectrum of this compound gives signals at d ¼ 213.0, 211.5, 208.5,
69.5, 56.09, 54.10, 50.7, 43.70, 28.67 and 28.5 corresponding to two carbonyl functions
of dimedone ring(C-1 and C-5), carbonyl group of cyclohexanone moiety (C-9), spiro
carbon (C-6), methylene carbon (C-8 and C-10), quarternary carbon (C-3), methylene
carbon (C-2 and C-4), methane carbon (C-7 and C-11) and methyl carbon, respectively.
The signals for the quarternary carbon atom of the phenyl groups linked to C-7 and C-
11, meta carbons, ortho carbons and para carbon appear at d ¼ 138.6, 128.9, 128.6 and
127.9, respectively which are compatible with the proposed structure 3a. The supple-
mentary evidence in support of the formation of the spiran was obtained from its EI-
MS spectrum which gave [M þ 1] peak at m/z 375.
The spirans 3a–c were refluxed with different aryl aldehydes in presence of EtONa in
2:1 molar ratio to afford the spiro diarylidene derivatives 4a–l (Scheme 2).
The IR spectrum of the spiro dibenzylidene 4a (Ar ¼ Ar0¼C6H6) gives two sharp
peaks at 1707 and 1656 cmꢀ1 corresponding to two carbonyl functions at two different
structural environment. The shift for the carbonyl stretching of cyclohexanone ring
from 1680 to 1656 cmꢀ1 may be attributed to conjugation of two exocyclic double bonds
and almost no appreciable change in the other carbonyl absorption ensures the forma-
tion of the dibenzylidene derivatives. The PMR spectrum of dibenzylidene derivatives 4a
shows a sharp singlet at d ¼ 4.01 in lieu of a doublet of doublet for the two axial protons
at C-7 and C-11. The disappearance of doublet of doublet and the triplet of 3a
(Ar ¼ C6H6) corresponding to four protons at C-8 and C-10 ascertains the condensation
of two ketomethylene groups with benzaldehyde at the aforesaid positions. On the

4
P. MAJUMDAR ET AL.
Ar
Ar
O
O
CHAr'
O
Ar
O
NaOC2H5
O
+
Ar'CHO
O
Ar
3a-c
CHAr'
4 a-l
Ar = C6H5, p- MeOC6H4, p-ClC6H4;
Ar' = C6H5, p- MeOC6H4, p-ClC6H4 , p-BrC6H4
Scheme 2. Synthesis of spiro diarylidene derivatives 4a–l.
contrary, three separate multiplets centred at d ¼ 6.93–6.98, 7.21–7.30 and 7.43–7.48
each corresponds to four, eight and eight phenyl protons. In addition, a sharp singlet at
d ¼ 8.30 is attributed to two exo-olefinic protons. 13C NMR spectrum of this compound
shows characteristic signals at d ¼ 154, 122.15, 115.06, 63.06, 55.7, 52.0, 46.20 and 31.0
corresponding to carbonyl carbons, exomethylene sp2 carbons, carbons adjacent to car-
bonyl carbon at C-8 and C-10, sp3 spiro carbon, methylene carbon at C-2 and C-4,
quarternary carbon at C-3 methine carbons at C-7 and C-11 and methyl carbons,
respectively. The two signals at d ¼ 141.0 and 138.0 corresponding to quarternary carbon
of the phenyl rings linked to exomethylene carbon and cyclohexanone ring besides the
closely spaced six signals in the range of d ¼ 126.7–132.65 for other carbon atoms of the
phenyl rings. The formation of diarylidene compound is also evident from its EI-MS
spectrum with the molecular ion peak (M þ 1) at m/z 551.
The diarylidene derivatives 4a–l on Michael addition and subsequent dehydrative cyc-
lization with hydroxylamine, hydrazine, phenyl hydrazine, guanidine carbonate, urea
and thiourea afforded their respective in situ oxidized products 5a–l–10a–l (Scheme 3).
The driving force for this in situ oxidation is the aromatization of the newly
build heterocyclic rings similar to the results reported earlier.[16] In the IR spectra of
5a–l, 6a–l, 7a–l, 8a–l, 9a–l and 10a–l, the carbonyl stretching frequencies at
1656 cmꢀ1 disappear.
The PMR spectra of all these compounds 5a–l–10a–l display a complex multiplet
appearing in the range of d ¼ 6.46–7.80 due to presence of large number of aromatic
protons and a multiplet at d ¼ 8.02–8.37 for one exo-olefinic proton. In addition, four
separate singlets appear in the range of d ¼ 1.0–1.16, 2.20–2.50, 3.87–4.25 and 4.17–4.45
corresponding to methyl proton, methylene protons at C-2 and C-4 and each methine
protons at C-7 and C-11, respectively. However, the PMR spectrum of 6a
(Ar ¼ Ar0¼C6H5) shows an additional broad singlet at d ¼ 10.43 for –NH proton which
underwent exchange with D2O. Similarly, another broad singlet at d ¼ 10.05 was
observed for phenolic –OH protons in the PMR spectrum of the compound 9a
(Ar ¼ Ar0¼C6H6) whereas a singlet at d ¼ 6.05 in the PMR spectrum of 8a
(Ar ¼ Ar0¼C6H6) has been attributed for –NH2 protons.
Moreover, the substrate 4a–l having a –C ¼ C–CO– (a,b unsaturated carbonyl) is an
ambient electrophile where the carbonyl carbon is hard and b-carbon is the soft
centre.[19] The conjugation of the double bonds with the phenyl ring reduces the extent
its conjugation with the carbonyl group. Since hydrazine and phenylhydrazine are hard
nucleophiles and their –NH2 group attacks the hard centre of the carbonyl carbon

R
SYNTHETIC COMMUNICATIONSV
5
Ar'
O
O
Ar
O
N
CHAr'
Ar
5a-l
Ar'
Ar'
O
O
Ar
NH
N
Ar
Ar
O
O
S
NH
N
NH2OH
CHAr'
N
Ar
H
N2H4
CHAr'
C
S
N
10a-l
H
Ar
O
O
6a-l
CHAr'
O
2
P
h
N
Ar'
CHAr'
H
Ar
N
2
H
Ar
O
O
2
Ph
N
N
Ar'
4a-l
O
O
Ar
N
OH
CHAr'
N
Ar
7a-l
CHAr'
Ar
9a-l
Ar'
Ar
Ar
O
Ar = C6H5, p- MeOC6H4, p-ClC6H4;
Ar' = C6H5, p- MeOC6H4, p-ClC6H4 , p-BrC6H4
N
NH2
N
CHAr'
O
8a-l
Scheme 3. Reaction of diarylidene derivatives 4a–l with different bidentate ligands.
giving rise to hydrazones which subsequently underwent cyclization and in situ oxida-
tion to form compound 6a–l and not the alternate structure. In case of hydroxylamine,
the nucleophilicity of nitrogen is increased due to adjacent oxygen atom, thus making it
a harder nucleophile[20] (a-effect). Hence the attack of –NH2 at carbonyl occurs first
forming the isoxazole 5a–l and not the alternate structure. On the basis of elemental
analyses, IR and PMR spectra of the compounds 5a–l–10a–l suggest the installation of
isoxazole, pyrazole, phenylpyrazole, aminopyrimidine, hydroxypyrimidine and pyrimidi-
nethione moieties, respectively in 4a–l.[14,21]
Antimicrobial study
All the synthesized compounds were screened for their antibacterial activity in vitro
against gram negative bacteria Escherichia coli and gram positive bacteria Staphylococcus
aureus using penicilin-G, erythromycin, ampicilin, cephalothin, clindamycin, co-trimoxa-
zole and kanamycin as standard using Disk diffusion method. Most of the compounds
showed moderate to good activities towards the aforesaid bacteria chosen by using
400 lg/ml (w/v) in DMSO. Chloro and methoxy substituents usually enhance the activ-
ities so much so that they are even comparable to standard drugs used in these

6
P. MAJUMDAR ET AL.
experiments. Compounds such as 6h, 6j, 6k, 7c, 7e, 7f and 8g showed good activities as
compared to the standard drugs used.
Conclusion
The fascinating art of synthetic design for annulations of cyclohexanone with pyrazole,
isoxazole and pyrimidine has been successfully explored through Michael addition of
spiro diarylidene derivatives with various ambient nucleophiles. In fact, the synthetic
precursor for building of the aforesaid heterocycles has been achieved in good yield by
successive spirolization of dimedone and diarylidene ketone and subsequent incorpor-
ation of exocyclic double bond on cyclohexanone moiety of the spiro hydrocarbon inter-
mediate. All the synthesized compounds have been screened for their antibacterial
activity in vitro against gram negative bacteria E. coli and gram positive bacteria S. aur-
eus and some of them exhibit moderate to good activity.
Experimental
Dibenzalacetone 1a, 4,40-dianisalacetone 1b, 4,40-dichlorobenzalacetone 1c, were pre-
pared according to the reported procedures.[16–18]
3,3-Dimethyl-7,11-diphenyl spiro[5,5] undecane-1,5,9-trione (3a–c)
To a solution of dimedone (0.01 mol) and dibenzalacetone (0.01 mol) in rectified spirit,
10 drops of triethanol amine were added. It was refluxed with stirring for 7 h. The reac-
tion mixture was concentrated and cooled. Solids thus separated were filtered, washed
with rectified spirit, dried and crystallized from rectified spirit.
8,10-Dibenzylidene-3,3-dimethyl-7,11-diphenyl spiro[5,5]undecane-1,5,9-
trione (4a–l)
A mixture of 3a–c (0.001 mol), benzaldehyde (0.002 mol) and sodium ethoxide
(0.002 mol) in ethanol was refluxed for 16 h. The reaction mixture was filtered, while
hot and acidified with dil. HCl after cooling it. The solid thus separated was filtered,
washed with water, dried and crystallized from ethanol.
Synthesis of spiro isoxazolo (5a–l)/spiro pyrazolo (6a–l, 7a–l) [3,4–b] cyclohexane
derivatives
To a mixture of 4a–l (0.001 mol) and hydroxylamine hydrochloride/hydrazine hydrate/
phenylhydrazine (0.001 mol) in ethanol, few drops of KOH/piperidine was added and
refluxed for 15–19 h. The reaction mixture was concentrated, cooled and poured into ice
cold water. The solid thus separated out was filtered, washed and recrystallized
from ethanol.

R
SYNTHETIC COMMUNICATIONSV
7
Synthesis of spiro pyrimido[5,6-b] cyclohexane derivatives (8a–l, 9a–l, 10a–l)
To a refluxing solution of 4a–l (0.001 mol) and guanidine carbonate/urea/thiourea
(0.001 mol) in ethanol (10 mL), few drops of NaOH solution were added and refluxed
for 16–18 h. The reaction mixture was cooled and neutralized. The solid product was
filtered, washed several times with water and crystallized.
Acknowledgments
The authors thank UGC (DRS-SAP), New Delhi for financial support, FIST-DST for providing
infrastructural research facility and SAIF, IIT, Chennai for recording NMR and Mass spectra. The
authors thank Prof. R.K. Behera for his valuable suggestions incorporated in this article. One of
the authors S. Sahu is thankful to UGC for granting Teacher Fellowship for Ph.D. program.
References
[1] Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry, 1st ed.; Oxford, UK:
Oxford University Press, 2000; p 532.
[2] Milan, M.; Viktor, M.; Rudolf, K.; Dusan, I. Preparation of Cyclic 1,3-Diketones and their
Exploration in the Synthesis of Heterocycles. Curr. Org. Chem. 2004, 8, 695–714.
[3] Heravi, M.M.; Zadsirjan, V.; Fattahi, B.; Nazari, N. Applications of Dimedone in the
Synthesis of Heterocycles: An Update. Curr. Org. Chem. 2016, 20, 1676–1735.
[4] Nikoofar, K.; Yielzoleh, F.M. A Concise Study on Dimedone: A Versatile Molecule in
Multi-Component Reactions, an Outlook to the Green Reaction Media. J. Saudi Chem.
Soc. 2017. DOI: 10.1016/j.jscs.2017.12.005.
[5] El Ashry, E.S.H.; Awad, L.F.; El Kilany, Y.; Ibrahim, E.I. Chapter 1 Dimedone: A Versatile
Precursor for Annulated Heterocycles. Adv. Heterocycl. Chem. 2009, 98, 1–141.
[6] Domling, A. Recent developments in isocyanide based multicomponent reactions in
applied chemistry. Chem. Rev. 2006, 106, 17–89.
[7] Saitoh, T.; Taguchi, K.; Hiraide, M. Derivatization of Formaldehyde with Dimedone and
Subsequent Sorption on Sodium Dodecylsulfate/Alumina Admicelles for Fluorometric
Analysis. Anal. Sci. 2002, 18, 1267–1268.
[8] Cremlyn, R.J.; Saunders, D. Chlorosulfonation of 9-Aryl 3,3,6,6-Tetramethyloctahydro-
xanthen-1,8-diones. Phosphorus Sulfur Silicon, 1993, 81, 73–82.
[9] Arya, K.; Tomar, R.; Rawat, D. S. Greener Synthesis and Photo-Antiproliferative Activity
of Novel Fluorinated Benzothiazolo[2,3-b]quinazolines. Med. Chem. Res. 2014, 23,
896–904.
[10] Sangshetti, J. N.; Lokwani, D. K.; Chouthe, R. S.; Ganure, A.; Raval, B.; Khan, F. A. K.
Shinde, D. B. Green Synthesis and Biological Evaluation of Some New Benzothiazolo [2,3-
b] Quinazolin-1-ones as Anticancer Agents. Med. Chem. Res. 2014, 23, 4893–4900.
[11] Bodini, M. E.; Pardo, J.; Arancibia, V. Spectrophotometric Determination of Selenium(IV)
with 5,5-Dimethyl-1,3-cyclohexanedione. Talanta, 1990, 37, 439–442.
[12] Horton, D. A.; Bourne, G. T.; Smythe, M. L. The Combinatorial Synthesis of Bicyclic
Privileged Structures or Privileged Substructures. Chem. Rev. 2003, 103, 893–930.
[13] Chen, H.; Daqing, S. Efficient One-Pot Synthesis of Novel Spirooxindole Derivatives via
Three-Component Reaction in Aqueous Medium. J. Comb. Chem. 2010, 12, 571–576.
[14] Behera, R. K.; Behera, A. K.; Pradhan, R.; Pati, A.; Patra, M. Studies on Spiroheterocycles,
Part II: Heterocyclization of the Spiro Compounds Containing Cyclohexanone and
Thiobarbituric Acid with Different Bidentate Nucleophilic Reagents. Synth. Commun.
2006, 36, 3729–3742.

8
P. MAJUMDAR ET AL.
[15] Majumdar, P.; Mohanta, P. P.; Behera, R. K.; Behera, A. K. Chemistry of Dimedone for
Synthesis of Oxygen-, Nitrogen-, and Sulfur- Containing Heterocycles from 2-(3-Hydroxy-
5,5-dimethylcyclohex-2-enylidene)malononitrile. Synth. Commun. 2013, 43, 899–914.
[16] Adams, R. Organic Synthesis; London: John Wiley, 1932; p 22.
[17] Bayer, A.; Villiger, V. Dibenzalaceton und Triphenylmethan. [Ein Beitrag zur Farbtheorie.]
Chem. Ber. 1902, 35, 1189–1201.
[18] Heilbron, I. M.; Hill, R. The Interaction of Ethyl Acetoacetate with Distyryl Ketones. Part
IV. Selective Addition to Unsymmetrical Chlorodistyryl Ketones. J. Chem. Soc. 1928,
2863–2870.
[19] Janathan, C.; Nick, G.; Stuart, W.; Peter, W. Organic Chemistry; Oxford, UK: Oxford
University Press; p 523.
[20] Fleming, I. Frontier Orbital and Organic Chemical Reaction; New York: John Wiley, 1970;
p 70.
[21] Behera, R. K.; Behera, A. K.; Pradhan, R.; Patra, M. Studies on Spiroheterocycles Part-I:
Installation of Biologically Active Heterocyclic Nuclei into Spiro Compounds Derived
from Cyclohexanone and Diphenyl Thiobarbituric Acid. Indian J. Chem. 2006, 45B,
933–942.