An efficient catalyst free synthesis of nitrogen containing spiro heterocycles via [5 + 1] double Michael addition reaction

Article abstract of DOI:10.1039/c4ra00521j

2,4-Diazaspiro[5.5]undecane-1,3,5,9-tetraones and 3-thioxo-2,4- diazaspiro[5.5]undecane-1,5,9-triones have been synthesized via double Michael addition of 1,5-diaryl-1,4-pentadien-3-one with active methylene compounds such as N,N-dimethyl barbituric acid, barbituric acid, thio-barbituric acid and N,N-diphenyl thiobarbituric acid in ethylene glycol at 100°C in the absence of any catalyst to give high yields within a short reaction time. The structure has been confirmed by X-ray analysis. The single-crystal structure of the diazaspiro compound revealed that the C_Ar-H...π, π-π stacking and intermolecular hydrogen bonding interactions act as major driving forces for crystal packing. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra00521j

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An efficient catalyst free synthesis of nitrogen
containing spiro heterocycles via [5 + 1] double
Michael addition reaction†
Cite this: RSC Adv., 2014, 4, 13313
*
Komal Aggarwal, Kanika Vij and Jitender M. Khurana
2,4-Diazaspiro[5.5]undecane-1,3,5,9-tetraones and 3-thioxo-2,4-diazaspiro[5.5]undecane-1,5,9-triones
have been synthesized via double Michael addition of 1,5-diaryl-1,4-pentadien-3-one with active
methylene compounds such as N,N-dimethyl barbituric acid, barbituric acid, thio-barbituric acid and
N,N-diphenyl thiobarbituric acid in ethylene glycol at 100 ꢀC in the absence of any catalyst to give high
yields within a short reaction time. The structure has been confirmed by X-ray analysis. The single-crystal
structure of the diazaspiro compound revealed that the CAr–H/p, p–p stacking and intermolecular
hydrogen bonding interactions act as major driving forces for crystal packing.
Received 18th January 2014
Accepted 24th February 2014
DOI: 10.1039/c4ra00521j
www.rsc.org/advances
and 3-thioxo-2,4-diazaspiro[5.5]undecane-1,5,9-trione deriva-
tives2–6 have been synthesized by triethanolamine as catalyst in
1. Introduction
different solvents under reux. All the reported methods have
some limitations, such as long reaction times, limited substrate
scope and invoke the application of a catalyst for the synthesis of
these biologically active compounds.
Our group has been focusing on development of synthetic
methodologies for the synthesis of novel heterocycles.14 There-
fore, we decided to investigate the synthesis of spiro barbitu-
rates and thiobarbiturates using environmentally benign
methodologies.
Spiro compounds having cyclic structures fused at a central
carbon are of recent interest due to their interesting conforma-
tional features and their structural importance in biological
systems.1 Nitrogen heterocycles are present in many compounds
of practical importance ranging from pharmaceutical agents to
biological probes. Diazaspiro[5.5]undecane-1,3,5,9-tetraones
and 3-thioxo-2,4-diazaspiro[5.5]undecane-1,5,9-triones show a
wide range of biological and therapeutic properties such as
antibacterial,2 potent sedative-hypnotic3 and CNS depressant
properties.4 They are also known to exhibit anticonvulsant,5 and
fungicidal6 properties. On the other hand, barbituric acid has
been used as a disperse dye with strong uorescence and as
yellow organic pigment.7–9 In this regard, efficient and facile
methodologies for constructing nitrogen containing spiro
heterocycles are valuable.
Michael reaction is one of the most versatile processes in
organic synthesis.10–12 The intermolecular double-Michael reac-
tions are particularly powerful tools for assembling complex
cyclic products from simple acyclic starting materials. Over the
last few decades, a certain number of syntheses in presence of
catalyst for compounds containing quaternary carbon center via
double Michael addition have been reported.13 In addition there
are few reports on the synthesis of diazaspiro[5.5]undecane
derivatives despite their importance. Literature survey
revealed that the 2,4-diazaspiro[5.5]undecane-1,3,5,9-tetraone
2. Results and discussion
This is the rst report of a simple, inexpensive, and fairly
efficient catalyst free synthesis of diazaspiro compounds
containing barbiturates/thiobarbiturates moieties via the
double Michael addition of dibenzalacetone derivatives and
N,N-dimethylbarbituric acid/barbituric acid/thiobarbituric acid
in ethylene glycol (EG) at 100 ꢀC. We attempted reaction of
dibenzylidene acetone (1a) and N,N-dimethyl barbituric acid
(2a) with different basic catalysts in solvents like ethylene
glycol, PEG-400, morpholine and ionic liquids. We obtained
the desired 2,4-dimethyl-7,11-diphenyl-2,4-diazaspiro[5.5]-
undecane-1,3,5,9-tetraone (3a) in varying amounts under
different conditions. When we attempted the above reaction in
absence of any catalyst for comparison, we realized that a
good amount of product (40%) was obtained when the reac-
tion was carried out in ethylene glycol at 50 ꢀC for 24 h.
Therefore, we believed that the desired product could be
obtained without any catalyst. Subsequently, we carried out
the reaction of dibenzylidene acetone (1a) and N,N-dimethyl
barbituric acid (2a) in ethylene glycol at 60 ꢀC which yielded
52% of product aer 12 h, reaction at 80 ꢀC gave 60% of
Department of Chemistry, University of Delhi, Delhi-110007, India. E-mail:
jmkhurana1@yahoo.co.in; jmkhurana@chemistry.du.ac.in; Fax: +91 1 27667624;
Tel: +91 11 2766772
† Electronic supplementary information (ESI) available: Copies of NMR spectra
for all compounds. CCDC 951532. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4ra00521j
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Table 1 Optimization of reaction conditions for double Michael addition reactionsa
Entry
Solvent
Temperature
Time
Yield (%)
1
2
3
4
5
6
7
8
EG
EG
EG
EG
50 ꢀ
60 ꢀ
80 ꢀ
C
C
C
24 h
12 h
4 h
30 min
24 h
24 h
24 h
24 h
40b
52b
60b
91
100 ꢀ
rt
C
c
EG
—
c
EtOH
MeOH
Water
Reux
Reux
Reux
—
—
c
c
—
a
b
Reaction conditions: dibenzylidene acetone (1 mmol), N,N-dimethyl barbituric acid, different solvents, different temperature. Reaction was
incomplete. c No reaction.
product aer 4 h and reaction at 100 ꢀC was complete in 30 enolate form (4). This enolate form (4) adds to the divinyl ketone
min and yielded 91% of the desired product aer work up. (1) by intermolecular Michael addition reaction to produce
However, there was no reaction even aer 24 h at room intermediate (6). The next step involves the intramolecular
temperature (entries 1–5, Table 1). When the reaction was Michael addition reaction of the intermediate enolate form (7)
performed in ethanol, methanol or water as solvent to the vinyl ketone component of the molecule in such a
under reux, there was no reaction even aer 24 h (Table 1, manner that the more stable product with aryl groups in the
entries 6–8).
equatorial position is formed thus leading to high stereo-
Subsequently reactions of other diarylidene acetones with selectivity (3 and 5).
ꢀ
N,N-dimethyl barbituric acid in ethylene glycol at 100 C were
The formation of the product 3b was conrmed through
1
also complete in 35–55 min and gave the corresponding spectral analysis, as shown in Fig. 3. The H NMR spectrum of
2,4-dimethyl-7,11-diphenyl-2,4-diazaspiro[5.5]undecane-1,3,5, 3b, exhibited one doublet of doublet for H3 and H5 protons at
9-tetraone derivatives (3a–e, Fig. 1) in good yields. We then 3.92 d with J ¼ 14.3 Hz and 4.4 Hz. The CH2 protons of C2 and
attempted the reactions of diarylidene acetones with barbituric C6 positions appeared as one doublet of doublet of H2(e) and
acid under same reaction conditions. Expectedly, these H6(e) at 2.53 d with J ¼ 15.02 Hz and 4.4 Hz and one triplet of
substrates also underwent smooth, double Michael addition to H2(a) and H6(a) at 3.63 d with 14.6 Hz. Furthermore, the struc-
give the corresponding spiro derivatives namely 7,11-diphenyl- ture of 3b was also determined by the single crystal X-ray crys-
2,4-diazaspiro[5.5]undecane-1,3,5,9-tetraones in good yields tallography. Single crystals suitable for X-ray diffraction were
(3f–j, Fig. 1).
grown by vapour diffusion of hexane into chloroform solution
The scope and generality of the reaction was further exam- of 3b at room temperature. X-ray diffraction structure of 3b is
ined by replacing barbituric acid with thiobarbituric acid and shown in Fig. 4.
N,N-diphenylthiobarbituric acid. All the reactions proceeded
X-ray crystal structure analysis of 3b conrms the preferred
smoothly under identical conditions leading to the formation cis conguration of the cyclohexanone ring with regard to the
of 7,11-diphenyl-3-thioxo-2,4-diazaspiro[5.5]undecane-1,5,9-tri- two substituted phenyl rings and also the presence of a plane of
ones and 2,4,7,11-tetraphenyl-3-thioxo-2,4-diazaspiro[5.5]unde- symmetry in a molecule. For compound 3b, the chair like
cane-1,5,9-triones in high yields (5a–j, Fig. 2). It was also conformation is strongly preferred, because both the
observed that the double Michael addition reaction of diary- substituted phenyl rings can be accommodated in equatorial
lidine acetone derivatives with thiobarbituric acid proceeded positions (Fig. 5).
faster as compared to N,N-diphenylthiobarbituric acid. All the
In X-ray analysis of compound 3b, there are some intra-
products were characterized by spectral data.
molecular interactions between the phenyl ring and the
A plausible mechanism for the formation of diazaspiro nitrogen atoms of barbituric acid ring (CAr–H/N–CH3), with
˚
derivatives (3 and 5) is proposed in Scheme 1. We believe that the distance 3.15–3.44 A (Fig. 6). The structure also involves
the presence of the reactive –OH groups in ethylene glycol play a weak intermolecular p–p aromatic stacking interactions
major role15 in promoting its activity for the formation of between centroids of the p-rings with a centroid–centroid
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Fig. 1 Double Michael addition of diarylidene acetone derivatives with barbituric acid and N,N-dimethyl barbituric acid in ethylene glycol at
100 ꢀC.
˚
distance of 5.028–7.774 A and the angle between the planes of role to stabilize the packing of the molecule. In the packing
two p-rings approaching 90ꢀ as shown in Fig. 7. Moreover, weak diagram (Fig. 7) the molecules are linked through the inter-
attractive C–H/p interactions between the hydrogen of phenyl molecular hydrogen bonding interactions between the CAr–H/
˚
ring and centroid of the phenyl ring, with a distance of 3.329 O with bond distance of 2.715–3.111 A. Donor–accepter bond
˚
and 4.568 A are also observed. This indicates that the aromatic– distances suggest that the hydrogen atom of the phenyl ring is
aromatic stabilization is perhaps more due to C–H/p type of expected to involve in hydrogen-bonding with the oxygen atoms
interactions rather than p–p stacking interactions.
of cyclohexanone and barbituric acid rings. The distances of the
Besides the p–p stacking and the C–H/p interactions, donor–H, acceptor/H, donor/acceptor and donor–H/
intermolecular hydrogen bonding interactions also play vital acceptor angles are presented in Table 2.
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Fig. 2 Double Michael addition of diarylidene acetones with thiobarbituric acid and N,N-diphenyl thiobarbituric acid in ethylene glycol at 100 ꢀC.
3. Conclusion
4. Experimental
In conclusion, we have reported a highly efficient, catalyst free All the starting materials were of GR quality of Merck and all
synthesis of diazaspiro compounds via intermolecular and solvents used were of HPLC grade. Melting points were deter-
intramolecular double Michael addition reaction using mined on a Tropical Lab equip apparatus and are uncorrected.
ethylene glycol as an inexpensive and commercially available IR (KBr) spectra were recorded on Perkin-Elmer FTIR spectro-
media. This method not only offers substantial improvements photometer and the values are expressed as nmax cmꢁ1. Mass
in the reaction rates, yields and also avoids the use of hazardous spectral data were recorded on Agilent 6520 Q-Tof (ESI-HRMS)
catalyst. We also examined the crystal structure and packing of mass spectrometer. The 1H NMR and 13C NMR spectra were
diazaspiro compound.
recorded on Jeol JNM ECX-400P at 400 MHz and 100 MHz,
13316 | RSC Adv., 2014, 4, 13313–13321
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Scheme 1 Plausible mechanism for the synthesis of diazaspiro compounds in ethylene glycol.
4.1. General procedure for the synthesis of diazaspiro
compounds
In a general procedure, diarylidene acetone (1 mmol), N,N-
dimethyl barbituric acid/barbituric acid/thiobarbituric acid/
N,N-diphenyl thiobarbituric acid (1 mmol) and 2 mL of ethylene
glycol were taken in a 50 mL round bottomed ask. The reaction
mixture was heated in an oil-bath maintained at 100 ꢀC and the
progress of the reaction was monitored by TLC using ethyl
acetate–petroleum ether (30 : 70) as eluent for disappearance of
diarylidene acetone. Aer completion of the reaction (Fig. 1 and
2), the reaction mixture was allowed to cool to room tempera-
ture and water (2 mL) was added dropwise with stirring. The
solid was ltered at pump and washed with water. The product
was recrystallized from ethanol. The products were identied by
their spectral data.
Fig. 3 1H NMR of 3b.
4.2. Spectral data
respectively using TMS as an internal standard. The chemical
shi values are recorded on d scale and the coupling constants
4.2.1. 2,4-Dimethyl-7,11-diphenyl-2,4-diazaspiro[5.5]unde-
(J) are in hertz. X-ray intensity data were collected on an Oxford cane-1,3,5,9-tetraone (3a).19 White solid, yield: 91%, mp 150–
Diffraction Xcalibur CCD diffractometer with graphite mono- 152 ꢀC; 1H NMR (400 MHz, CDCl3) d: 2.59, 2.63 (dd, 2H, J ¼ 14.6
˚
chromated Mo Ka radiation (l ¼ 0.71073 A) at 298 K. The data Hz, 4.4 Hz), 2.86 (s, 3H, –NCH3), 3.01 (s, 3H, –NCH3), 3.69 (t, 2H,
was collected at 293 K and the structures were resolved by direct J ¼ 14.6 Hz), 3.99, 4.03 (dd, 2H, J ¼ 13.9 Hz, 4.4 Hz), 7.05–7.07
methods and rened by full-matrix least-squares on F2 (m, 4H, Ar-H), 7.23–7.26 (m, 6H, Ar-H).
(SHELXL-97).16 All calculations were carried out using the
4.2.2. 2,4-Dimethyl-7,11-di(4-methylphenyl)-2,4-diazaspiro-
[5.5]undecane-1,3,5,9-tetraone (3b). White solid, yield: 80%, mp
WinGX package of the crystallographic programs.†17
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Fig. 4 X-ray crystal structure of 3b.†
Fig. 5 X-ray crystallographic structure of compound 3b with indication of the plane of symmetry.
159 ꢀC; 1H NMR (400 MHz, CDCl3) d: 2.24 (s, 6H, ArCH3), 2.53,
2.57 (dd, 2H, J ¼ 15.02 Hz, 4.4 Hz), 2.86 (s, 3H, –NCH3), 3.00 (s,
3H, –NCH3), 3.63 (t, 2H, J ¼ 14.6 Hz), 3.92, 3.97 (dd, 2H, J ¼ 14.3
Hz, 4.4 Hz), 6.91 (d, 4H, Ar-H, J ¼ 8.0 Hz), 7.00 (d, 4H, Ar-H, J ¼
8.0 Hz); 13C NMR (100 MHz, CDCl3) d: 28.03, 28.45, 30.92, 42.77,
49.75, 60.46, 128.82, 129.13, 134.61, 135.39, 149.30, 168.53,
170.33, 207.14; IR (KBr, cmꢁ1) nmax ¼ 2922, 1781, 1676, 1423,
1379, 1125, 819, 806; HRMS (ESI) m/z [M+ + H] calculated for
C
25H27N2O4 419.1971, found 419.1963.
4.2.3. 7,11-Bis(4-chlorophenyl)-2,4-dimethyl-2,4-diazaspiro-
[5.5]undecane-1,3,5,9-tetraone (3c). White solid, yield: 82%, mp
225 ꢀC; 1H NMR (400 MHz, CDCl3) d: 2.53, 2.57 (dd, 2H, J ¼ 14.6
Hz, 4.4 Hz), 2.85 (s, 3H, –NCH3), 3.00 (s, 3H, –NCH3), 3.67 (t, 2H,
J ¼ 14.6 Hz), 3.92, 3.96 (dd, 2H, J ¼ 13.9 Hz, 4.4 Hz), 6.91 (d, 4H,
Ar-H, J ¼ 8.0 Hz), 7.00 (d, 4H, Ar-H, J ¼ 8.0 Hz); 13C NMR (100
MHz, CDCl3) d: 27.85, 28.27, 43.02, 50.07, 60.96, 127.27, 129.45,
134.05, 138.27, 149.79, 169.05, 170.77, 208.56; IR (KBr, cmꢁ1
)
Fig. 6 Intramolecular hydrogen bonding interactions in the crystal
nmax ¼ 2956, 2925, 1718, 1676, 1449, 1423, 1379, 1284, 1124, 754; packing along b-axis of 3b.
13318 | RSC Adv., 2014, 4, 13313–13321
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Fig. 7 Intermolecular hydrogen bonding interactions, p/p stacking and C–H/p interactions in the crystal of 3b.
Table
2 Intermolecular and intramolecular hydrogen bonding
(400 MHz, DMSO-d6): 2.44, 2.48 (dd, 2H, J ¼ 15.4 Hz, 4.4 Hz),
3.49 (t, 2H, J ¼ 14.6 Hz), 3.96, 3.99 (dd, 2H, J ¼ 14.3 Hz, 4.4 Hz),
7.13 (d, 4H, Ar-H, J ¼ 7.3 Hz), 7.27–7.34 (m, 6H, Ar-H), 11.20 (s,
1H, –NH), 11.46 (S, 1H, –NH).
4.2.7. 7,11-Di(4-methylphenyl)-2,4-diazaspiro[5.5]undecane-
1,3,5,9-tetraone (3g).20 White solid, yield: 88%, mp 266–268 ꢀC;
1H NMR (400 MHz, CDCl3): 2.26 (s, 3H, –ArCH3), 2.56, 2.59 (dd,
2H, J ¼ 15.4 Hz, 4.4 Hz), 3.62 (t, 2H, J ¼ 14.6 Hz), 3.90, 3.94 (dd,
2H, J ¼ 13.9 Hz, 4.4 Hz), 6.99–7.05 (m, 8H, Ar-H), 7.67 (s, 1H,
–NH), 7.83 (s, 1H, –NH).
geometries of the 3ba (A˚, ꢀ
)
D–H/A (ꢀ)
˚
˚
˚
D–H/A
D–H (A)
H/A (A)
D/A (A)
C45–H45/O5i
C37–H37/O7ii
C21–H21/N2iii
C36–H36/N3iv
C40–H40/N4iv
1.212
0.931
0.930
0.931
0.930
2.715
3.111
3.445
3.275
3.342
3.301
3.637
3.391
3.385
3.315
108.17
117.63
85.5
88.7
80.4
a
Note: D, donor; A, acceptor. Symmetry codes: (i) ꢁ1 + x, ꢁ1 + y, z; (ii) 2
ꢁ x, 3 ꢁ y, 2 ꢁ z; (iii) x, y, z; (iv) 2 ꢁ x, 2 ꢁ y, 1 ꢁ z.
4.2.8. 7,11-Bis(4-chlorophenyl)-2,4-diazaspiro[5.5]undecane-
1,3,5,9-tetraone (3h).6 White solid, yield: 81%, mp 238–240 C;
ꢀ
HRMS (ESI) m/z [M+ + H] calculated for C23H21Cl2N2O4 1H NMR (400 MHz, CDCl3) d: 2.57, 2.61 (dd, 2H, J ¼ 14.7 Hz, 4.4
459.0878, found 459.0869.
Hz), 3.58 (t, 2H, J ¼ 14.6 Hz), 3.92, 3.95 (dd, 2H, J ¼ 13.9 Hz, 4.4
4.2.4. 7,11-Bis(4-uorophenyl)-2,4-dimethyl-2,4-diazaspiro- Hz), 7.07 (d, 4H, Ar-H, J ¼ 8.1 Hz), 7.25 (d, 4H, Ar-H, J ¼ 8.8 Hz),
[5.5]undecane-1,3,5,9-tetraone (3d). White solid, yield: 85%, mp 7.98 (s, 1H, –NH), 8.14 (s, 1H, –NH).
154 ꢀC; 1H NMR (400 MHz, CDCl3) d: 2.55, 2.59 (dd, 2H, J ¼ 14.6
4.2.9. 7,11-Bis(4-uorophenyl)-2,4-diazaspiro[5.5]undecane-
Hz, 4.4 Hz), 2.88 (s, 3H, –NCH3), 3.02 (s, 3H, –NCH3), 3.64 (t, 2H, 1,3,5,9-tetraone (3i). Pale yellow solid, yield: 84%, mp 137 ꢀC; 1H
J ¼ 14.6 Hz), 3.95, 3.96 (dd, 2H, J ¼ 13.9 Hz, 4.4 Hz), 6.91 (d, 4H, NMR (400 MHz, DMSO-d6) d: 1.73 (dd, 2H, J ¼ 12.46 Hz, 2.96
Ar-H, J ¼ 8.0 Hz), 7.00 (d, 4H, Ar-H, J ¼ 8.0 Hz); 13C NMR (100 Hz), 2.77 (t, 2H, J ¼ 13.28 Hz), 3.74 (dd, 2H, J ¼ 13.9 Hz, 3.6 Hz),
MHz, CDCl3) d: 27.96, 28.39, 42.97, 49.57, 60.85, 115.89 (d, J2 ¼ 7.06–7.16 (m, 8H, Ar-H), 11.18 (s, 1H, –NH), 11.24 (s, 1H, –NH);
21.9 Hz), 129.16 (d, J3 ¼ 8.6 Hz), 132.78 (d, J4 ¼ 2.9 Hz), 149.32, 13C NMR (100 MHz, DMSO-d6) d: 35.60, 46.86, 63.92, 115.49 (d,
162.43 (d, J1 ¼ 239 Hz), 168.78, 170.51, 207.42; IR (KBr, cmꢁ1
)
J2 ¼ 22.9 Hz), 129.89 (d, J3 ¼ 7.6 Hz), 134.59 (d, J4 ¼ 2.9 Hz),
nmax ¼ 3049, 2927, 1719, 1675, 1510, 1424, 1226, 1162, 835; 148.85, 161.51 (d, J1 ¼ 243.1 Hz), 170.34, 172.78, 206.54; IR (KBr,
HRMS (ESI) m/z [M+ + H] calculated for C23H21F2N2O4 427.1469, cmꢁ1) nmax ¼ 3221, 2926, 2854, 1714, 1509, 1364, 1227, 1161,
found 427.1460.
1078; HRMS (ESI) m/z [M+ + H] calculated for C21H17F2N2O4
4.2.5. 7,11-Bis(4-bromophenyl)-2,4-dimethyl-2,4-diazaspiro- 399.1156, found 399.1150.
[5.5]undecane-1,3,5,9-tetraone (3e). White solid, yield: 84%, mp
4.2.10. 7,11-Bis(4-bromophenyl)-2,4-diazaspiro[5.5]undecane-
215 ꢀC; 1H NMR (400 MHz, CDCl3) d: 2.53 (dd, 2H, J ¼ 14.6 Hz, 1,3,5,9-tetraone (3j). Creamish solid, yield: 82%, mp 139 ꢀC; 1H
4.1 Hz), 2.88 (s, 3H, –NCH3), 3.03 (s, 3H, –NCH3), 3.59 (t, 2H, J ¼ NMR (400 MHz, DMSO-d6) d: 2.42–2.46 (m, 1H), 2.64–2.82 (m,
14.6 Hz), 3.92 (dd, 2H, J ¼ 14.2 Hz, 4.5 Hz), 6.91 (d, 4H, Ar-H, J ¼ 1H), 3.46–3.51 (m, 1H), 3.69–3.75 (m, 1H), 3.92–3.99 (m, 2H),
8.6 Hz), 7.35 (d, 4H, Ar-H, J ¼ 8.2 Hz); 13C NMR (100 MHz, 6.98–7.05 (m, 4H, Ar-H), 7.47–7.53 (m, 4H, Ar-H), 11.33 (s, 1H,
CDCl3) d: 28.04, 28.67, 42.70, 49.92, 60.29, 122.79, 128.99, –NH), 11.55 (s, 1H, –NH); 13C NMR (100 MHz, DMSO-d6) d:
129.26, 131.96, 132.23, 135.90, 149.11, 168.43, 170.20, 207.10; IR 42.32, 48.04, 64.07, 121.38, 130.02, 131.76, 136.81, 148.75,
(KBr, cmꢁ1) nmax ¼ 2925, 1710, 1680, 1420, 1378, 1283, 1075, 170.49, 171.57, 206.54; IR (KBr, cmꢁ1) nmax ¼ 3220, 2926, 2854,
829; HRMS (ESI) m/z [M+ + H] calculated for C23H21Br2N2O4 1712, 1375, 1217, 1075; HRMS (ESI) m/z [M+ + H] calculated for
548.9848, found 548.9829.
C
21H17Br2N2O4 520.9535, found 520.9527.
4.2.6. 7,11-Diphenyl-2,4-diazaspiro[5.5]undecane-1,3,5,9-
4.2.11. 7,11-Diphenyl-3-thioxo-2,4-diazaspiro[5.5]undecane-
1
1
tetraone (3f).6 White solid, yield: 84%, mp 275–277 ꢀC; H NMR 1,5,9-trione (5a).18 White solid, yield: 86%, mp 254–256 C; H
ꢀ
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1
ꢀ
NMR (400 MHz, CDCl3) d: 2.62, 2.66 (dd, 2H, J ¼ 15.4 Hz, 4.4 248–250 C, H NMR (400 MHz, CDCl3) d: 2.68 (d, 2H, J ¼ 13.9
Hz), 3.64 (t, 2H, J ¼ 15.4 Hz), 3.95, 3.99 (dd, 2H, J ¼ 14.7 Hz, 4.4 Hz), 3.71 (t, 2H, J ¼ 13.9 Hz), 4.18 (d, 2H, J ¼ 13.2 Hz), 6.52 (s,
Hz), 7.12–7.15 (m, 4H, Ar-H), 7.27–7.28 (m, 6H, Ar-H), 8.35 (s, 2H, Ar-H), 6.82 (s, 2H, Ar-H), 7.31–7.46 (m, 16H, Ar-H).
1H, –NH), 8.55 (S, 1H, –NH).
4.2.19. 2,4-Diphenyl-3-thioxo-7,11-dip-tolyl-2,4-diazaspiro[5.5]-
4.2.12. 3-Thioxo-7,11-di(4-methylphenyl)-2,4-diazaspiro[5.5]- undecane-1,5,9-trione (5i).17 Yellow solid, yield: 80%, mp 238–
1
undecane-1,5,9-trione (5b).18 Pale yellow solid, yield: 91%, mp 240 ꢀC, H NMR (400 MHz, CDCl3) d: 1.80 (d, 1H, J ¼ 13.6 Hz),
236–238 ꢀC; 1H NMR (400 MHz, CDCl3) d: 1.84, 1.88 (dd, 2H, J ¼ 2.33 (d, 6H, –ArCH3, J ¼ 10.9 Hz), 2.53–2.57 (m, 1H), 2.90 (t, 1H,
13.2 Hz, 2.9 Hz), 2.24 (s, 3H, –ArCH3), 2.91 (t, 2H, J ¼ 13.6 Hz), J ¼ 13.9 Hz), 3.60 (t, 1H, J ¼ 14.6 Hz), 3.92 (s, 1H), 4.02–4.07 (m,
3.89, 3.93 (dd, 2H, J ¼ 13.5 Hz, 3.7 Hz), 6.99–7.04 (m, 8H, Ar-H), 1H), 6.47 (d, 1H, J ¼ 4.4 Hz, Ar-H), 6.58–6.65 (m, 1H, Ar-H), 6.75
8.30 (s, 1H, –NH), 8.32 (S, 1H, –NH).
(d, 1H, J ¼ 7.3 Hz, Ar-H), 6.95–6.99 (m, 1H, Ar-H), 7.10–7.21 (m,
4.2.13. 7,11-Bis(4-chlorophenyl)-3-thioxo-2,4-diazaspiro[5.5]- 7H, Ar-H), 7.32–7.46 (m, 6H, Ar-H), 7.62–7.66 (m, 1H, Ar-H).
undecane-1,5,9-trione (5c).2 Pale yellow solid, yield: 86%, mp
4.2.20. 7,11-Di(benzo[d][1,3]dioxol-5-yl)-2,4-diphenyl-3-thi-
238–240 ꢀC; 1H NMR (400 MHz, CDCl3) d: 1.83, 1.86 (dd, 2H, J ¼ oxo-2,4-diazaspiro[5.5]undecane-1,5,9-trione (5j). Yellow solid,
12.8 Hz, 3.7 Hz), 2.87 (t, 2H, J ¼ 13.6 Hz), 3.90, 3.94 (dd, 2H, J ¼ yield: 82%, mp 215 ꢀC, 1H NMR (400 MHz, CDCl3) d: 2.57, 2.61
13.5 Hz, 3.7 Hz), 7.05 (d, 4H, Ar-H, J ¼ 8.8 Hz), 7.20 (d, 4H, Ar-H, (dd, 2H, J ¼ 15.3 Hz, 4.4 Hz), 3.56 (t, 2H, J ¼ 14.6 Hz), 3.98–4.06
J ¼ 8.4 Hz), 8.69 (s, 1H, –NH), 8.73 (S, 1H, –NH).
(m, 2H), 6.00 (s, 2H, –CH2), 6.02 (d, 2H, J ¼ 5.12 Hz), 6.60–6.62
4.2.14. 7,11-Bis(4-uorophenyl)-3-thioxo-2,4-diazaspiro[5.5]- (m, 1H, Ar-H), 6.70–6.72 (m, 2H, Ar-H), 6.75–6.76 (m, 2H, Ar-H),
undecane-1,5,9-trione (5d). Dirty white solid, yield: 89%, mp 6.81–6.89 (m, 4H, Ar-H), 7.06–7.11 (m, 1H, Ar-H), 7.37–7.49 (m,
246–248 ꢀC; 1H NMR (400 MHz, DMSO-d6) d: 1.75, 1.78 (dd, 2H, J 6H, Ar-H), 7.60 (s, 1H, Ar-H), 7.64 (s, 1H, Ar-H); 13C NMR (100
¼ 12.8, 3.68 Hz), 2.78 (t, 2H, J ¼ 13.56 Hz), 3.75, 3.79 (dd, 2H, J ¼ MHz, CDCl3) d: 43.18, 50.64, 61.89, 101.59, 106.56, 108.13,
13.56, 3.68 Hz), 7.02–7.12 (m, 8H, Ar-H), 12.21 (s, 1H, –NH), 108.63, 121.99, 123.70, 125.05, 127.99, 128.05, 128.91, 129.03,
12.24 (s, 1H, –NH); 13C NMR (100 MHz, DMSO-d6) d: 35.85, 129.47, 129.66, 130.57, 138.53, 142.87, 147.98, 148.31, 167.76,
47.02, 60.12, 115.51 (d, J2 ¼ 21.0 Hz), 129.89 (d, J3 ¼ 7.6 Hz), 169.45, 178.61, 207.68; IR (KBr, cmꢁ1) nmax ¼ 3074, 2905, 1718,
134.54 (d, J4 ¼ 2.9 Hz), 161.5 (d, J1 ¼ 243.1 Hz), 167.92, 170.62, 1692, 1645, 1499, 1490, 1362, 1326, 1256, 1037, 930; HRMS (ESI)
177.60, 203.97; IR (KBr, cmꢁ1) nmax ¼ 3221, 2925, 1690, 1512, m/z [M+ + H] calculated for C35H27N2O7S 619.1539, found
1327, 1229, 1164, 841; HRMS (ESI) m/z [M+ + H] calculated for 619.1526.
C
21H17F2N2O3S 415.0928, found 415.0551.
4.2.15. 7,11-Bis(4-bromophenyl)-3-thioxo-2,4-diazaspiro[5.5]-
undecane-1,5,9-trione (5e). Pale yellow solid, yield: 84%, mp
250–252 ꢀC; 1H NMR (400 MHz, DMSO-d6) d: 2.43–2.44 (m, 1H),
2.63–2.85 (m, 2H), 3.85–3.07 (m, 1H), 3.71–3.77 (m, 1H), 3.93–
4.01 (m, 2H), 6.98–7.05 (m, 4H, Ar-H), 7.46–7.51 (m, 4H, Ar-H),
12.22–12.29 (b, 2H, –NH); 13C NMR (100 MHz, DMSO-d6) d:
35.58, 47.37, 64.03, 120.95, 130.13, 131.73, 137.57, 167.89,
170.94, 177.63, 206.17; IR (KBr, cmꢁ1) nmax ¼ 3186, 2925, 1700,
1524, 1369, 1321, 1216, 1151, 1073; HRMS (ESI) m/z [M+ + H]
calculated for C21H17Br2N2O3S 536.9306, found 536.9292.
4.2.16. 7,11-Di(benzo[d][1,3]dioxol-5-yl)-3-thioxo-2,4-diaz-
aspiro[5.5]undecane-1,5,9-trione (5f). Pale yellow solid, yield:
83%, mp 256–258 ꢀC; 1H NMR (400 MHz, DMSO-d6) d: 1.67, 1.70
(dd, 2H, J ¼ 12.8 Hz, 3.7 Hz), 2.66 (t, 2H, J ¼ 13.2 Hz), 3.62, 3.65
(dd, 2H, J ¼ 13.5 Hz, 3.7 Hz), 5.92 (s, 4H, –OCH2O–), 6.47–6.50
(m, 4H, Ar-H) 6.77 (d, 2H, Ar-H, J ¼ 8.0 Hz), 12.19 (bs, 2H, –NH);
13C NMR (100 MHz, DMSO-d6) d: 36.19, 47.66, 64.02, 101.06,
107.88, 108.38, 121.43, 131.83, 146.42, 147.41, 168.27, 170.85,
177.58, 206.48; IR (KBr, cmꢁ1) nmax ¼ 3206, 2900, 1727, 1686,
1520, 1488, 1355, 1315, 1242, 1159, 1040, 824; HRMS (ESI) m/z
[M+ ꢁ H] calculated for C23H17N2O7S 465.0756, found 465.0768.
4.2.17. 7,11-Bis(4-methoxyphenyl)-3-thioxo-2,4-diazaspiro-
[5.5]undecane-1,5,9-trione (5g).2 Yellow solid, yield: 88%, mp
207–209 ꢀC, 1H NMR (400 MHz, CDCl3) d: 1.83, 1.86 (dd, 2H, J ¼
12.8 Hz, 3.7 Hz), 2.88 (t, 2H, J ¼ 13.6 Hz), 3.72 (s, 6H, –OCH3),
3.87, 3.91 (dd, 2H, J ¼ 13.9 Hz, 3.7 Hz), 6.73 (d, 4H, J ¼ 8.8 Hz),
7.04 (d, 4H, J ¼ 8.8 Hz), 8.51 (s, 1H, –NH), 8.54 (s, 1H, –NH).
4.2.18. 2,4,7,11-Tetraphenyl-3-thioxo-2,4-diazaspiro[5.5]-
undecane-1,5,9-trione (5h).18 Pale yellow solid, yield: 80%, mp
Acknowledgements
KA and KV thank Council of Scientic & Industrial Research
(CSIR), New Delhi, India for the grant of Junior and Senior
Research Fellowships.
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