Studies on spiroheterocycles, Part III: Synthesis of diazaspiroundecanetetraone derivatives containing biologically active heterocycles

Article abstract of DOI:10.1080/10426500802274260

Barbituric acid 2 upon Michael addition with dibenzal acetones 1a-c afforded the corresponding diazaspiro derivatives 3a-c. The base-catalyzed condensation of 3a-c with various aromatic aldehydes produces diarylidine derivatives 4a-l. The diarylidene compounds 4a-l on condensation with hydrazine, phenyl hydrazine, hydroxylamine, urea, guanidine carbonate, and hydrazine hydrate with acetic acid afforded their respective in situ oxidized products 5, 6, 7, 8, 9, and 10. The structures of the compounds are ascertained from their analytical and spectral data. Some of the compounds are screened for their biological activities against E. coli, B. cirroflagellosus, A. niger, and C. albicans.

Full text of DOI:10.1080/10426500802274260

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Studies on Spiroheterocycles,
Part III: Synthesis of
Diazaspiroundecanetetraone
Derivatives Containing
Biologically Active
Heterocycles
Rajani K. Behera a , Ajay K. Behera a , Rosy Pradhan
a , Anita Pati a & Manabendra Patra a
a Organic Synthesis Laboratory, Department of
Chemistry , Sambalpur University , Burla, Orissa,
India
Published online: 19 Feb 2009.
To cite this article: Rajani K. Behera , Ajay K. Behera , Rosy Pradhan , Anita Pati
& Manabendra Patra (2009) Studies on Spiroheterocycles, Part III: Synthesis of
Diazaspiroundecanetetraone Derivatives Containing Biologically Active Heterocycles,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:3, 753-765, DOI:
10.1080/10426500802274260
To link to this article: http://dx.doi.org/10.1080/10426500802274260
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Phosphorus, Sulfur, and Silicon, 184:753–765, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802274260
Studies on Spiroheterocycles, Part III: Synthesis of
Diazaspiroundecanetetraone Derivatives Containing
Biologically Active Heterocycles
Rajani K. Behera, Ajay K. Behera, Rosy Pradhan,
Anita Pati, and Manabendra Patra
Organic Synthesis Laboratory, Department of Chemistry, Sambalpur
University, Burla, Orissa, India
Barbituric acid 2 upon Michael addition with dibenzal acetones 1a–c afforded
the corresponding diazaspiro derivatives 3a–c. The base-catalyzed condensation of
3a–c with various aromatic aldehydes produces diarylidine derivatives 4a–l. The
diarylidene compounds 4a–l on condensation with hydrazine, phenyl hydrazine,
hydroxylamine, urea, guanidine carbonate, and hydrazine hydrate with acetic acid
afforded their respective in situ oxidized products 5, 6, 7, 8, 9, and 10. The structures
of the compounds are ascertained from their analytical and spectral data. Some
of the compounds are screened for their biological activities against E. coli, B.
cirroflagellosus, A. niger, and C. albicans.
Keywords Barbituric acid; diarylidene; dibenzal acetone; spiroheterocycles
INTRODUCTION
Derivatives of barbituric acid and thiobarbituric acid have attracted the
attention of researchers in synthetic organic chemistry, as well as in
medicinal chemistry, for a long time due to their exceptionally diverse
biological activities, such as fungicidal,1 sedatives,2,3 antibacterial,4
herbicidal,5 and antiviral,6 etc. Spiro compounds are found to ex-
hibit various biological activities, such as fungicidal,7−11 herbicidal,12
bactericidal,13,14 anticonvulsant,15 anti-inflammatory,16antianxiety,17
etc. Keeping in view the above facts, some work has been reported on the
synthesis of spiro compounds containing barbiturates/thiobarbiturates
Received 22 April 2008; accepted 16 June 2008.
The authors wish to thank the Department of Science & Technology, Govt. of India
and University Grant Commission, New Delhi for FIST and DRS support.
Address correspondence to Rajani K. Behera, Organic Synthesis Laboratory, Depart-
ment of Chemistry, Sambalpur University, Jyoti Vihar, Burla 768 019, Orissa, India.
E-mail: rajanibehera@yahoo.co.in
753

754
R. K. Behera et al.
moieties.18−30 Reddy et al.23,24 have synthesized 7,11-diaryl-2,4-
diazaspiro[5.5]undecane-1,3,5,9-tetrones, which are found to have
good antifungal and antibacterial characteristics. Kokel25 has
reported the synthesis of 4,5-annulated-2-dimethylamino-1,3,8,10-
tetraaza-spiro [5.5]-1,4-undecadiene-7,9,11(3H,8H,10H)triones from 2-
dimethylaminooxazolo[5,4-d]pyrimidine-4,6-diones. Kotha et al.26 have
synthesized spiro annulated derivatives obtained from the ring clos-
ing metathesis of diallylated products, which were obtained from
barbituric/thiobarbituric acid and β-dicarbonyl compounds. Shaabani
et al.27,28 have synthesized 3,3-dimethyl-(7S,11R)-bis(4-methylphenyl)-
2,4-dioxa-8,10-diazaspiro[5.5]undecane-1,5,9-triones by the reaction of
an aldehyde, urea, and barbituric acid derivatives using microwave ir-
radiation under solvent-free conditions. Jursic and Stevens29 have re-
ported the synthesis of 5,6-dihydro-1,3-dimethyl-5,6-di [1ꢀ,3ꢀ-dimethyl-
2ꢀ,4ꢀ,6ꢀ-trioxopyrimidin(5ꢀ,5ꢀ)yl)]furo[2,3-d]uracil. Renard et al.30 have
synthesized spirodeoxyribosylbarbituric acid and spirocyclopentylbar-
bituric acid in order to evaluate their possible use as building blocks
in modified oligonucleotide synthesis. Therefore, the present work de-
scribes the synthesis of spiroheterocycles containing barbituric acid
moiety.
RESULTS AND DISCUSSION
Michael addition of barbituric acid (2) with the appropriate divinyl
ketone (1) in ethanol and triethanolamine yielded the required spiro
compounds (3a–c) (Scheme 1). The IR spectrum of the spiro compound
3a (Ar = C6H5) shows three carbonyl peaks at 1752, 1711, and 1689
1
cm−1. The peak at 3256 cm−1 corresponds to the -NH groups. The H
NMR spectrum of 3a shows two doublet of doublets center at δ 2.48,
δ 3.99 and a triplet center at δ 3.55 corresponding to two equatorial
protons at C-8 and C-10, two axial protons at C-7 and C-11, and two
SCHEME 1

Studies on Spiroheterocycles, Part III
755
axial protons at C-8 and C-10 respectively. The spectrum also shows
two broad singlets at δ 11.2 and δ 11.5 for the -NH protons, which is
confirmed from an earlier report.30 The aromatic protons resonate at
δ 7.14–7.31 in the form of a multiplet. The 13C NMR spectrum of 3a
shows peaks at δ 173.0, 172.0, 171.0, 59.0, 49.0, and 44.8 corresponding
to the carbonyl carbons, spiro carbon, -CH2, and –CH, respectively. The
three very closely spaced peaks due to carbons of the aromatic rings
1
appear in the region δ 128–129. The IR, H NMR, and 13C NMR data
are in conformity with the proposed structure of the compound as 3a.
SCHEME 2
The base-catalyzed condensation of the spiro compound 3a–c with
different aldehydes afforded the diarylidene compounds 4(a–l) (Scheme
2). The IR spectrum of 4a (Ar = Arꢀ = C6H5) shows the carbonyl peaks
of cyclohexanone ring at 1707 cm−1. The shift of the carbonyl peak to
lower frequency may be due to its conjugation with the exocyclic double
bond.
1
The H NMR spectrum of 4a (Ar = Ar’ = C6H5) shows two protons
singlet at δ 3.6 corresponding to the two axial protons at C-7 and C-
11.The two doublet of doublet observed in the 1H NMR spectrum of 3a
(Ar = C6H5) corresponding to four protons at C-8 and C-10 disappeared
in the spectrum of 4a because of condensation with benzaldehyde at
C-8 and C-10. In the 13C NMR spectrum of 4a (Ar = Ar’ = C6H5), the
absence of the peak at δ 49.0 corresponding to CH2 group as observed
in the spectrum of 3a and the appearance of a new peak at δ 120.0 in
the spectrum of 4a confirms the formation of dibenzylidene compound.
The diarylidene compounds 4(a–l) upon condensation with hy-
drazine, phenyl hydrazine, hydroxylamine, urea, guanidine carbonate,
and hydrazine hydrate with acetic acid afforded their respective in situ
oxidized products 5, 6, 7, 8, 9, and 10 (Scheme 3).
The disappearance of the carbonyl frequency at 1707 cm−1 in the
IR spectra of 5, 6, 7, 8, 9, and 10 confirms the installation of pyrazole,
phenyl pyrazole, isoxazole, and pyrimidine moieties in 4. In the case of
8, a broad band in the region 3300–3400 cm−1 is due to the -OH group.

756
R. K. Behera et al.
SCHEME 3
The broad band at 3400 cm−1 in the IR spectrum of 9 may be attributed
to a -NH2group. The 1H NMR spectra of the compounds 5–10 display a
broad multiplet at δ 6.3–7.6, corresponding to aromatic protons, along
with a singlet at δ 3.45–3.76 for the axial protons at C7and C11.
ANTIMICROBIAL ACTIVITY
Antimicrobial activity was carried out against two pathogenic bacte-
ria, E. coli and B. cirroflagellosus, and A. niger and C. albicans were
the fungal strains. The reference drugs used were Norfloxocin and
Griseofalvin, respectively, with DMF as solvent control. The cup-plate
method19−20 was used, and nutrient agar was the culture media. Nor-
floxocin showed a zone of inhibition of 28 mm against E. coli and 25
mm against B. cirroflagellosus. Griseofalvin exhibited a zone of 30 mm
against both fungi A. niger and C. albicans. The results of antibacterial
and antifungal screening showed that most of the compounds exhibit
moderate activity (zone of inhibition 17 to 23 mm) against both bacteria
and both fungi, as shown in Table I.

Studies on Spiroheterocycles, Part III
757
TABLE I Antibacterial and Antifungal Activities of Some
Compounds, 4–10
Zone of inhibition
Comp. No.
E. coli
B. cirroflagellosua
A. niger
C. albicaus
4c
4d
4g
4h
4i
4j
4k
4l
5a
5b
5c
5g
5k
5l
6b
6c
6e
6g
6j
6k
6l
7c
7e
7g
7i
++
+
++
+
+
++
++
++
+
+
++
+ + +
+
++
+
++
++
+
+
++
++
+
+ + +
++
+
++
+ + +
++
++
++
+
++
+
++
++
++
++
+ + +
++
++
++
++
+
+
+
++
++
+
++
++
++
++
++
++
+
++
++
++
+
+ + +
+
+
+ + +
+
++
++
++
+ + +
++
+
++
+ + +
++
+
++
++
+
++
+
++
++
++
+
+
++
+
+ + +
+
++
++
++
+ + +
++
+
++
+ + +
++
+
++
++
+
++
+
7j
7k
7l
8b
8c
8g
8i
++
++
++
+
+
++
++
++
+ + +
++
+
+ + +
+
++
++
++
+ + +
++
+
++
++
+
++
+
++
+
+
8j
++
++
++
+
+
8k
8b
8c
8g
9b
9c
9e
9g
9j
+ + +
++
++
+ + +
++
++
++
++
++
+
++
+ + +
+
++
++
+
++
++
+
+
++
++
++
+ + +
++
+ + +
+
++
+
+
++
+
++
(Continued on next page)

758
R. K. Behera et al.
TABLE I Antibacterial and Antifungal Activities of Some
Compounds, 4–10 (Continued)
Zone of inhibition
Comp. No.
E. coli
B. cirroflagellosua
A. niger
C. albicaus
9k
++
++
++
++
++
+ + +
++
++
+
++
+ + +
++
+
+ + +
++
10e
10i
10j
10k
++
++
++
++
++
(−) = inactive, (+) = weakly active (12–16 mm), (++) = moderately active (17–21
mm), and (+ + +) = highly active (22–30 mm).
In conclusion, we have developed a convenient synthetic route for
the synthesis of a number of spiroheterocycles containing cyclohexane
and barbituric acid nuclei. Biologically active moieties such as pyrimi-
dine, pyrazole, and isoxazole have been easily installed onto the spiro
framework.
EXPERIMENTAL
The melting points were determined on a Zenith apparatus and are
uncorrected. IR spectra were recorded on a Perkins Elmer FT-IR spec-
trophotometer using KBr disc.13C and 1H NMR spectra were recorded
on a Bruker AC 250 MHz NMR spectrometer and were recorded in
d6-DMSO, unless otherwise stated. Purity of the products was checked
by TLC, using silica gel “G” (BDH) and hexane-ethyl acetate as eluent.
Synthesis of Dibenzylidene Acetone (1a)
To a solution of NaOH (10 g in 100 mL of water) and ethyl alco-
hol (80 mL), acetone (3 mL, 0.05 mol) was added and stirred for
15 min. Then benzaldehyde (0.1 mol) was added in two phases and
stirred for 2 h at 25◦C. Yellow crystals thus separated were filtered,
washed with water, and crystallized from ethyl acetate. Yield 9 g
(73.2%), mp 112◦C, mixed mp 112◦C.31 4,4ꢀ-dianisalacetone32 1b and
4,4ꢀ-dichlorbenzalacetone33 1c were prepared according to the reported
procedure.

Studies on Spiroheterocycles, Part III
759
Synthesis of 7,11-Diphenyl-2,4-diaza-
spiro[5.5]undecane-1,3,5,9-tetraones (3a)
To a solution of barbituric acid (1.28 gm, 0.01 mol) in 1,4-dioxane
(30 mL) and dibenzal acetone (2.34 g, 0.01 mol) in ethanol (30 mL),
10 drops of triethanolamine were added. The mixture was refluxed
with stirring for 7 h. The reaction mixture was filtered, cooled, and
poured into ice-cold water. The solid so obtained was filtered, dried,
and crystallized from acetic acid. Yield 3.2 g (85%), mp 272◦C, Anal.
Calc. for C21H18O4N2: C, 66.67; H, 4.76; N, 7.41% Found: C, 66.52;
1
H, 4.92; N, 7.29%. IR: 3256 cm−1 (-NH) 1711, 1689 cm−1 (C O); H
NMR: δ 2.48 (dd, J = 15 Hz, 4Hz, 2H, equatorial-H at C8 & C10), 3.55
(t, J = 15 Hz, 2H, axial-H at C8 & C10), 3.99 (dd, J = 15Hz, 4Hz, 2H,
axial-H at C7 & C11), 7.14–7.31 (m, 10H, Ar-H), 11.2 ( bs, 1H, NH), 11.5
(bs, 1H, NH); 13C NMR: (d6-DMSO) δ 44.8, 49.0, 59.0, 128.1, 128.6,
128.8, 137.4, 171.0, 172.0, 173.0.
Synthesis of 8,10-Dibenzylidene-7-11-diphenyl-2,4-
diazaspiro[5.5]undecane-1,3,5,9-tetraones (4a)
A mixture of 3a (0.362 g, 0.001 mol), NaOC2H5 (0.002 mol) in ethanol
(10 mL), and benzaldehyde (0.21 g, 0.002 mol) was refluxed for 16 h.
The reaction mixture was filtered while hot, and then acidified with dil.
HCl after cooling. The solid that separated was filtered, washed with
cold water, dried, and crystallized from ethanol. Yield 0.53 g (75%),
mp 162◦C. Anal. Calcd for C35H26O4N2: C, 78.07; H, 4.83; N, 5.20; %
Found: C, 77.86; H, 4.78; N, 5.06; %. IR:1708 cm−1 (C = O);1H NMR:
δ 3.6 (s,2H, H at C7 & C11), 6.8–7.6 (m,22H, Ar-H and =CH), 11.1 (bs,
1H, NH), 11.4 (bs, 1H, NH);13C NMR: (d6-DMSO) δ 46.2, 54.7, 113.4,
120.0, 128.0–133.0 (aromatic carbon), 137.0, 170.0, 170.5, 172.0.
Synthesis of 8’-Benzylidene-1,3,5-trihydro-3’,5’,7’
triphenyl-2,4,6-trioxo-spiro[pyrimidine-5,6’-pyrazolo[3,
4-b]cyclohexane] (5a)
To a solution of 4a (0.107 g, 0.0002 mol) and hydrazine hydrate (0.01 g,
0.0002 mol) in ethanol (5 mL), two drops of piperidine were added, and
the mixture was refluxed on a water bath for 19 h. The reaction mixture
was concentrated, cooled, and poured into ice-cold water. The solid that
separated was filtered, washed with water, and crystallized from 95%
ethanol. Yield 0.08 g (80%), mp 132◦C. Anal. Calcd for C35H26O3N4: C,
76.36; H, 4.73; N, 10.18, Found: C, 76.44; H, 4.75; N, 10.20; %. IR: 3400
1
cm−1, 1678 cm−1, 1660 cm−1; H NMR: δ 3.62 (s, 2H, H at C7 & C11),

760
R. K. Behera et al.
7.0–7.4 (m, 21H, Ar-H and =CH), 9.8 (bs, 1H, NH), 11.0 (bs, 1H, NH),
11.3 (bs, 1H, NH).
Synthesis of 8ꢀ-Benzylidene-1,3,5-trihydro-
2ꢀ,3ꢀ,5ꢀ,7ꢀ-tetraphenyl-2,4,6-trioxo-spiro[pyrimidine-5,6ꢀ-
pyrazolo[3,4-b]cyclohexane]
(6a)
To a solution of 4a (0.107 g, 0.0002 mol) and phenyl hydrazine hy-
drate (0.02 g, 0.0002 mol) in ethanol (5 mL), two drops of piperidine
were added, and the mixture was refluxed on a water bath for 16 h.
The reaction mixture was concentrated, cooled, and poured into ice-
cold water. The solid that separated was filtered, washed with water,
and crystallized from ethanol. Yield 0.047 g (75%), mp 166◦C. Anal.
calcd. for C41H30O3N4: C, 78.59; H, 4.79; N, 8.95%, Found: C, 78.43;
H, 4.62; N, 8.79%. IR: 3300 cm−1, 1660 cm−1, 1674 cm−1, 1600 cm−1
;
1H NMR: δ 3.48 (s, 2H, H at C7 & C11), 6.36–7.55 (m, 26H, Ar-H and
=CH).
Synthesis of 8’-Benzylidene-1,3,5-trihydro-3’,5’,7’-trihenyl-
2,4,6-trioxo-spiro[pyrimidine-5,6’-isoxazole[3,4-b]cyclohexane]
(7a)
To a mixture of 4a (0.107 g, 0.0002 mol) and hydroxylamine hydrochlo-
ride (0.12 g, 0.0002 mol) in ethanol (5 mL), a few drops of KOH (2%)
were added and refluxed on a steam bath for 15 h. The reaction mixture
was concentrated, cooled, and poured into ice-cold water. The solid was
filtered, washed with water, and crystallized from ethanol. Yield 0.071
g (65%), m.p.132◦C. Anal. calcd. for C35H25O4N3: C,76.23; H, 4.54; N,
7.62 %, Found: C, 76.31; H, 4.80; N, 7.80%. IR: 1674 cm−1,1662 cm−1
,
1578 cm−1, 1382 cm−1; 1H NMR: δ 3.68 (s,2H, H at C7 & C11), 6.40–7.61
(m, 21H, Ar-H, =CH), 11.0 (bs, 2H, NH).
Synthesis of 9’-Benzylidene-1,3,5,-trihydro-2’-hydroxy-4’,6’,8’-
triphenyl-2,4,6,-trioxo-5-spiro[pyrimidine-5,7’-pyrimido[5,
6-b]cyclohexane] (8a)
To a mixture of 4a (0.107 g. 0.0002 mol) and urea (0.012g, 0.0002 mol)
in ethanol (5 mL), 5 drops of conc. HCl was added and refluxed on a
steam bath for 18 h. The reaction mixture was cooled and neutralized
with 5% NaOH solution. The solid product was filtered, washed several
times with water, and crystallized from acetic acid. Yield 0.083 g (72%),

Studies on Spiroheterocycles, Part III
761
◦
mp 162 C. Anal. calcd. for C36H26O4N4: C, 74.74; H, 4.50; N, 9.69%,
Found: C, 74.52; H, 4.38; N, 9.48%. IR: 3300–3400 cm−1 (broad), 1695
1
cm−1, 1660 cm−1, 1590 cm−1; H NMR: δ 3.66 (s, 2H, H at C7 & C11),
6.47–7.22 (m, 21H, Ar-H and =CH), 9.2 (bs, 1H, -OH), 11.2 (bs, 2H,
NH).
Synthesis of 2ꢀ-Amino-9ꢀ-benzylidene-1,3, 5-
trihydro-4ꢀ,6ꢀ,8ꢀ-triphenyl -2,4,6-trioxo-spiro[pyrimidine-5,7ꢀ-
pyrimido[5,6-b]cyclohexane] (9a)
To a refluxing solution of 4a (0.107 g, 0.0002 mol) and guanidine car-
bonate (0.036 g, 0.0002 mol) in ethanol (5 mL), a few drops of 40%
NaOH were added, and the mixture was refluxed for 16 h. The reac-
tion mixture was cooled and acidified with dil. acetic acid. The solid so
obtained was filtered, washed with water, and crystallized from acetic
acid. Yield 0.086 g (75%), mp 178◦C. Anal. Calcd. for C36H27O3N5: C,
74.87; H, 4.68; N,12.13%, Found: C, 74.51; H, 4.57; N, 12.07%. IR: 3400
1
cm−1, 1667 cm−1, 1660 cm−1, 1584 cm−1, H NMR: δ 3.68 (s, 2H, H at
C7 & C11), 6.38–7.31 (m, 21H, Ar-H and =CH), 8.3 (s, 2H, NH2), 11.1
(bs, 2H,NH).
Synthesis of 2ꢀ-Aceto-8ꢀ-benzelidene-
1,3,5-trihydro-3ꢀ,5ꢀ,7ꢀ-triphenyl-2,4,6-trioxo-spiro[pyrimidine-
5,6ꢀ-pyrazole[3,4-b]cyclohexane] (10a)
A solution of 4a (0.107 g, 0.0002 mol) and hydrazine hydrate (0.01 g,
0.0002 mol) in acetic acid (5mL) was refluxed for 10 h. The reaction
mixture was concentrated, cooled, and poured into ice-cold water. The
solid so obtained was filtered, dried, and crystallized from acetic acid.
Yield 0.080 g (68%), m.p 145◦C. Anal. calcd. for C37H28O4N4: C,75.00;
H, 4.72; N, 9.45%, Found: C,74.79; H, 4.68; N, 9.31%. IR: 3300 cm−1
,
1687 cm−1, 1660 cm−1, 1590 cm−1; 1H NMR: δ 2.6 (s, 3H, CH3CO-), 3.64
(s, 2H, H at C7 & C11), 6.41–7.28 (m, 21H, Ar-H and =CH), 11.1 (bs,
2H, NH).
The syntheses of all other derivatives such as 3b–c, 4b–l, 5b–l, 6b–l,
7b–l, 8b–l, 9b–l, and 10 b–l were carried out according to the de-
tailed procedure presented for the representative compounds above.
The spectral data of the compounds corroborate the proposed struc-
tures. However, their physical and analytical data have been given in
Table II.

762

763

764

Studies on Spiroheterocycles, Part III
765
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