Highly functionalized dispiro oxindole-pyrrolo[1,2-c]thiazole-piperidone hybrid: Synthesis, characterization and theoretical investigations on the regiochemistry

Article abstract of DOI:10.1016/j.molstruc.2016.05.061

The synthesis of highly functionalized dispiro oxindole-pyrrolo[1,2-c]thiazole-piperidone hybrid has been achieved regioselectively employing microwave-assisted three-component 1,3-dipolar cycloaddition. Structural elucidation of the compound has been acc

Full text of DOI:10.1016/j.molstruc.2016.05.061

Accepted Manuscript
Highly functionalized dispiro oxindole-pyrrolo[1,2-c]thiazole-piperidone hybrid:
Synthesis, characterization and theoretical investigations on the regiochemistry
Raju Suresh Kumar, Abdulrahman I. Almansour, Natarajan Arumugam, Saied M.
Soliman, Raju Ranjith Kumar, Hazem A. Ghabbour
PII:
S0022-2860(16)30507-5
10.1016/j.molstruc.2016.05.061
MOLSTR 22575
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 22 March 2016
Revised Date: 14 May 2016
Accepted Date: 17 May 2016
Please cite this article as: R. Suresh Kumar, A.I. Almansour, N. Arumugam, S.M. Soliman, R. Ranjith
Kumar, H.A. Ghabbour, Highly functionalized dispiro oxindole-pyrrolo[1,2-c]thiazole-piperidone hybrid:
Synthesis, characterization and theoretical investigations on the regiochemistry, Journal of Molecular
Structure (2016), doi: 10.1016/j.molstruc.2016.05.061.
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ACCEPTED MANUSCRIPT
Highly functionalized dispiro oxindole–pyrrolo[1,2-c]thiazole–piperidone
hybrid: Synthesis, characterization and theoretical investigations on the
regiochemistry
Raju Suresh Kumar,a,* Abdulrahman I. Almansour,a Natarajan Arumugam,a Saied M.
Soliman,b,c Raju Ranjith Kumar,d,* Hazem A.Ghabboure,f
The synthesis of highly functionalized dispiro oxindole–pyrrolo[1,2-c]thiazole–
piperidone hybrid has been achieved regioselectively employing microwave-assisted
three-component 1,3-dipolar cycloaddition. Structural elucidation of the compound has
been accomplished using NMR spectroscopy and further confirmed by single crystal X-
ray crystallographic studies. The cycloaddition was found to proceed by normal
electronic demand (NED) character with a significant high charge transfer (0.1247eV)
from the 1,3-dipole to the dipolarophile. The regiochemistry has been explained using the
local reactivity descriptors obtained from the DFT calculations. The DFT optimized
molecular structure agreed well with the X-ray results.
H
O
S
N
N
H
N
H
O
O
6
O

ACCEPTED MANUSCRIPT
Highly functionalized dispiro oxindole-pyrrolo[1,2-c]thiazole-piperidone hybrid:
Synthesis, characterization and theoretical investigations on the regiochemistry
Raju Suresh Kumar,a,* Abdulrahman I. Almansour,a Natarajan Arumugam,a Saied M. Soliman,b,c
Raju Ranjith Kumar,d,* Hazem A.Ghabboure,f
aDepartment of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh
11451, Saudi Arabia
bDepartment of Chemistry, College of Science & Arts, King Abdulaziz University, P.O. Box 344,
Rabigh 21911, Saudi Arabia
cDepartment of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia,
Alexandria 21321, Egypt
dDepartment of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai
625 021, Tamil Nadu, India
eDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O.
Box 2457, Riyadh 11451, Saudi Arabia
fDepartment of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura
35516, Egypt.
Abstract
The synthesis of highly functionalized dispiro oxindole–pyrrolo[1,2-c]thiazole–piperidone
hybrid has been achieved regioselectively employing microwave-assisted three-component 1,3-
dipolar cycloaddition. Structural elucidation of the compound has been accomplished using
NMR spectroscopy and further confirmed by single crystal X-ray crystallographic studies. The
molecular structure of the compound crystallized in monoclinic, P21/c, a = 11.6182 (2) Å, b =
12.2466 (2) Å, c = 21.7061 (3) Å, β = 103.018 (1)°, V = 3009.04 (8) Å3, Z = 4. The
cycloaddition was found to proceed by normal electronic demand (NED) character with a
significant high charge transfer (0.1247eV) from the 1,3-dipole to the dipolarophile. The
regiochemistry has been explained using the local reactivity descriptors obtained from the DFT
calculations. The DFT optimized molecular structure agreed well with the X-ray results.
*Corresponding author: Tel: +91-9655591445; E-mail: raju.ranjithkumar@gmail.com (Ranjith Kumar R); Tel:+966-
4675907; fax: +966-4675992; E-mail: sraju@ksu.edu.sa, drrajusureshkumar@gmail.com (Suresh Kumar R);
1

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Introduction
1,3-Dipolar cycloadditions constitute a highly versatile and prevailing tool for the construction of
pharmacologically important hybrid heterocycles [1-3]. Spirooxindoles are attractive synthetic
targets because of their prevalence in many natural products such as rychnophyilline [4],
alstonisine [5], strychnofoline [6] and spirotryprostatin A [7] and their applications in medicine
and therapeutics (Fig. 1) [4,8-9]. Spirooxindoles have also been found to target the p53−MDM2
interaction [10]. Pyrrolothiazoles are the central skeletons for numerous alkaloids and
pharmacologically important compounds [11,12] and display wide array of biological activities,
enabling their use as hepatoprotective [13], antibiotic [14], antidiabetic [15], anticonvulsant [16],
anti-inflammatory [17], antileukemic agents [18] besides being used in the treatment for
Alzheimer disease [19]. Heterocycles possessing piperidone sub-unit also gains importance as
antitumor agents [20] in addition to being useful synthons for the construction of complex
molecules [21]. Hence it is conceivable that the integration of piperidone, spirooxindole and
pyrrolothiazole into a molecule may result in the discovery of new leads.
H
O
Me
H
H
N
H
Me
N
H
O
H
HO
N
O
NH
H
N
O
N
H
Me
Strychnofoline
Alstonisine
O
H
Et
N
H
N
OMe
CO2Me
MeO
H
N
O
O
N
H
HN
O
Spirotryprostatin A
Rychnophylline
Figure 1 Representative naturally occurring spirooxindole heterocyclic hybrids
Microwave-assisted organic reactions have received much attention in recent years in
view of the numerous advantages. Due to the rapid and uniform dielectric heating, it is
2

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conceivable that microwave-assisted reactions occur in much lesser time in contrast to reactions
under conventional heating and thus consequently leads to cleaner reactions with enhanced yield
and fewer side products. Recently several investigations pertaining to the utility of microwave in
synthetic organic chemistry have been reported, which targets wither to improve the classical
organic reactions or to promote new reactions [22]. However, the utility of microwave irradiation
to carry out multi-component reactions is an emerging technique.
Although the scope of 1,3-dipolar cycloaddition reaction in the synthesis of spiro
compounds has been broadened by the use of different dipolarophiles [23-27], to the best of our
knowledge, the utilization of compounds with piperidone sub unit embedded with three
unsaturated double bonds as dipolarophlies has been less explored. As part of our ongoing
investigations in the construction and/or biological screening of novel heterocycles [21,28-34],
herein we report the synthesis and X-ray analysis of dispiro oxindole–pyrrolo[1,2-c]thiazole–
piperidone hybrid. In addition we also intend to investigate the regiochemistry of the
cycloaddition through DFT calculations.
Results and Discussion
Initially, the synthesis of 3,5-bis(4-methoxyphenylmethylidene)piperidin-4-one (2) was
accomplished following
a
literature method [35]. Subsequently 1-allyl-3,5-bis(4-
methoxyphenylmethylidene)piperidin-4-one (3) was prepared by the reaction of 2 with allyl
chloride in acetone (Scheme 1). The structure of 3 was confirmed by NMR spectroscopic (vide
supplementary) and X-ray crystallographic studies [36] (Fig. 2).
Scheme 1 Synthesis of 1-allyl-3,5-bis(4-methoxyphenylmethylidene)piperidin-4-one 3
3

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Figure 2 ORTEP diagram of 3
Having synthesized the dipolarophile 3, the optimization of reaction conditions for the
cycloaddition was studied by taking an equimolar mixture of 1-allyl-3,5-bis(4-methoxyphenyl-
methylidene)piperidin-4-one 3, isatin 4 and thiazolidine-4-carboxylic acid 5. The reaction in
ethanol (90 min), methanol (60 min), methanol:dioxane mixture (1:1 v/v; 60 min) or dioxane (60
min) under reflux, afforded the dispiro oxindole–pyrrolo[1,2-c]thiazole–piperidone, 6 in 62, 70,
67 or 69 % yield, respectively. Subsequently, the same reaction was examined under microwave
irradiation in a focused microwave synthesizer with a view to improve the yield and reduce the
reaction time. An equimolar mixture of 3, 4 and 5 without any solvent was irradiated with
o
microwave at 90 C for 10 min. The reaction mixture was extracted with ethylacetate and
subjected to column chromatographic purification to obtain the product 6 in 76% isolated yield.
Further, in order to ensure thorough mixing of the reactants, the same reaction was also
performed after the addition of 4-5 drops of DMF. As expected, the reaction was completed in 5
minutes affording the product 6 in 85%. Apparently, an increase in the yield of the product was
observed under microwave method when compared to the conventional heating.
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Scheme 2. Synthesis of dispiro oxindole–pyrrolo[1,2-c]thiazole–piperidone 6
The structure of 6 was elucidated using elemental analysis, FT-IR, 1H, 13C and 2D NMR
1
spectroscopic data. In the H NMR spectrum of 6, the doublet at 4.40 ppm (J 10.0 Hz) can be
readily assigned to H-4, which show H,H-COSY correlation (vide supplementary) with the
multiplet in the range 4.65-4.70 ppm assignable to H-4a. The J value presumably reveals that H-
4 and H-4a are trans. The C,H-COSY correlation of H-4 and H-4a assigns the signals at 49.21
and 69.16 ppm to C-4 and C-4a respectively. This assignment is further confirmed from the
DEPT 135 spectrum. Furthermore, H-4 shows HMBCs with C-3 and C-2 spiro carbons at 76.80
and 72.78 ppm, respectively apart from showing HMBCs with the carbonyl carbon C-4′ at
197.66 ppm and the ipso and ortho carbons of the para-methoxy phenyl ring at C-4. The H,H-
COSY correlation of H-4a assigns the multiplets at 2.73-2.82 and 2.98-3.01 ppm to 5-CH2. The
doublet at 3.68 ppm (J 6.5 Hz) and the multiplet at 3.50-3.56 ppm is due to 7-CH2. The doublet
and the multiplet at 1.92 ppm (J 13.0 Hz) and 3.50-3.56 ppm are due to 2′-CH2 protons whereas
the multiplets at 2.73-2.82 ppm and 3.50-3.56 ppm are due 6′-CH2 protons of the 4-pyridone
ring. Furthermore, these protons show HMBCs with C-4′ apart from showing HMBCs with C-7′
at 60.53 ppm. The C,H-COSY correlation of C-7′ assigns the doublet of doublets at 3.15 ppm (J
13.5, 4.5 Hz) and the multiplet at 2.73-2.82 to 7′-CH2 protons. From H,H-COSY spectrum, the
multiplets at 5.59-5.67 ppm and 4.95-5.02 ppm can be assigned to H-8′ and 9′-CH2 respectively.
The NH proton of the oxindole ring appears as a singlet at 8.46 ppm and the aromatic protons
1
13
appear as multiplets at 6.65-7.30 ppm. For better understanding, the H and C NMR chemical
shift assignment of 6 are shown in Fig. 3.
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Figure 3 Selected 1H and 13C chemical shifts of 6
X-ray crystallographic study of a single crystal of 6 [37] (Fig. 4) confirms the structure
elucidated from NMR spectroscopic studies. The crystallographic data, conditions used for the
intensity data collection and some features of the structure refinements are listed in Table 1 and
the selected geometric parameters are listed in Table 2. In the crystal structure of compound 6,
the unit cell contains one independent molecule composed of a pyrrolo[1,2-c]thiazole ring (C7-
C12/S1/C13/N2) which make dihedral angles nearly perpendicular with all spiro linked rings viz.
oxindole ring (C1-C8/N1), pyridinone ring (C9/C20-C22/N3/C23) and phenyl ring (C14-C19)
85.68°, 84.04° and 79.67°, respectively (Fig. 4). In the crystal structure, two intermolecular N–
H⋅⋅⋅O and C–H⋅⋅⋅O hydrogen bonds are observed to form a network like structure (Fig. 5 and
Table 3).
Table 1 The crystal and experimental data of compound 6
Crystal data
Chemical formula
C35H35N3O4S
MW
593.72
Crystal system, space group
Monoclinic, P21/c
Temperature (K)
a, b, c (Å)
α, β, γ (°)
V (Å3)
100
11.6182 (2), 12.2466 (2), 21.7061 (3)
103.018 (1)
3009.04 (8)
4
Z
6

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Radiation type
Mo Kα
0.15
µ (mm−1)
Crystal size (mm)
Data collection
0.52 × 0.30 × 0.17
Diffractometer
Bruker APEX-II CCD diffractometer
Absorption correction
Tmin, Tmax
Multi-scan SADABS Bruker 2014
0.925, 0.974
No. of measured, independent and
observed [I > 2σ(I)] reflections
Rint
38512, 9623, 7064
0.046
Refinement
R[F2 > 2σ( F2)], wR( F2), S
No. of reflections
No. of parameters
No. of restraints
0.053, 0.132, 1.03
9623
394
0
H atoms treated by a mixture of independent and
constrained refinement
0.39, −0.36
H-atom treatment
ꢀρmax, ꢀρmin (e Å−3)
Table 2 Selected geometric parameters (Å, °) of compound 6
S1—C12
S1—C13
O1—C8
O2—C17
O2—C31
O3—C20
O4—C28
O4—C35
1.8340 (16)
1.8377 (17)
1.2322 (18)
1.3655 (19)
1.434 (2)
1.2230 (19)
1.3645 (18)
1.430 (2)
N1—C1
N1—C8
N2—C7
N2—C11
N2—C13
N3—C22
N3—C23
N3—C32
1.4046 (19)
1.3540 (19)
1.4665 (18)
1.4650 (19)
1.4523 (19)
1.465 (2)
1.4602 (19)
1.465 (2)
C12—S1—C13
C17—O2—C31
C28—O4—C35
C1—N1—C8
C7—N2—C11
C7—N2—C13
C11—N2—C13
C22—N3—C23
C22—N3—C32
C23—N3—C32
N1—C1—C2
N1—C1—C6
N2—C7—C6
N2—C7—C9
N2—C7—C8
O1—C8—C7
93.34 (7)
O1—C8—N1
N1—C8—C7
N2—C11—C12
N2—C11—C10
S1—C12—C11
S1—C13—N2
O2—C17—C16
O2—C17—C18
O3—C20—C21
O3—C20—C9
N3—C22—C21
N3—C23—C9
O4—C28—C27
O4—C28—C29
N3—C32—C33
125.49 (14)
108.60 (12)
104.13 (13)
99.98 (11)
103.85 (11)
103.73 (10)
115.81 (14)
124.40 (14)
121.89 (12)
120.73 (12)
110.45 (12)
107.95 (11)
116.14 (14)
123.92 (14)
111.94 (13)
116.87 (13)
116.42 (13)
111.53 (12)
108.16 (11)
120.05 (12)
109.60 (11)
109.40 (11)
112.03 (12)
113.74 (12)
127.47 (14)
109.72 (12)
111.62 (12)
101.94 (10)
111.62 (10)
125.53 (13)
7

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Figure 4 ORTEP diagram of 6
Figure 5 A view of the crystal packing of the title compound showing network structure. Dashed
lines indicate weak hydrogen bonds
Table 3 Hydrogen-bond geometry (Å, °) of compound 6
D—H···A
D—H
0.84 (2)
0.9900
H···A
2.02 (2)
2.4600
D···A
2.8514 (17)
3.179 (2)
D—H···A
172.8 (19)
129.00
N1—H1N1···O1i
C32—H32A···O4ii
Symmetry codes: (i) −x+1, −y, −z; (ii) −x+1, y+1/2, −z−1/2.
8

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A plausible reaction pathway to validate the formation of dispiro oxindole–pyrrolo[1,2-
c]thiazole–piperidone 6 is depicted in Scheme 3. The reaction of isatin 4 and thiazolidine-4-
carboxylic acid 5 by dehydration and successive decarboxylation furnishes the azomethine ylide
8, which are known to exist in the isomeric forms 8a and 8b. Probably, the azomethine ylide, viz.
8a undergoes cycloaddition with 1-allyl-3,5-bis(4-methoxyphenylmethylidene)piperidin-4-one 3
via path 1 furnishing 6. The regioselectivity observed in the reaction may be explained by the
fact that the electron-rich carbon of the 1,3-dipole 8a prefers to add over the electron-deficient
carbon of the α,β-unsaturated moiety of the dipolarophile 3. The other possible regioisomer 7
was not observed in the reaction. In this section, a theoretical investigation of the regioselectivity
of this cycloaddition reaction in the frame work of DFT calculations was performed.
Scheme 3 Proposed mechanism for the formation of spiroheterocyclic hybrid 6
9

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Table 4 shows the values of the FMO energies (eV), the electronic chemical potentials
and the global electrophilicity of the reactants. Figure 6 presents a schematic representation of
the possible interactions between the FMOs (HOMOdipole–LUMOdipolarphile) and (HOMOdipolarphile
–
LUMOdipole). From Table 4 and Figure 6, we can notice that the HOMOdipolarphile– LUMOdipole gap
is larger (3.861 eV) than the HOMOdipole–LUMOdipolarphile gap (3.024 eV). Hence the main
interaction occurs between the HOMO of 8 and the LUMO of 3. Consequently, this
cycloaddition reaction has NED character. Moreover, the electronic chemical potential of 8 (-
3.2770 eV) is higher than that for 3 (-3.6953 eV) indicating that charge transfer occurs from the
dipole 8 to dipolarphile 3, which is in agreement with the FMO analysis. The amount of charge
transfer from the dipole 8 to dipolarophile 3 is calculated to be 0.1247e. At the transition state
structure, the dipole fragment is positive while the dipolarophile is negative which confirm the
NED.
Table 4 The FMO energies (E), electronic chemical potential (ꢀ), nucleophilicty (N) and
electrophilicity (ω) indices for the reactants.
Reactant
EH
EL
ꢀ
ω
N
3
8
-5.5523 -1.8384 -3.6953 1.8385 3.5688
-4.8627 -1.6912 -3.2770 1.6930 4.2583
Figure 6 Possible interactions between the FMOs
10

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Domingo et al. classified electrophiles based on the electrophilicity index as strong (ω>
1.50 eV), moderate (1.50 > ω > 0.80 eV) and marginal (ω< 0.80 eV). On other hand,
nucleophiles could be classified as strong (N > 3.00 eV), moderate (3.00 > N > 2.00 eV) and
marginal (N < 2.00 eV) [38-40]. As a result, 8 could be considered as a strong electrophile and
nucleophile, whereas 3 is a strong electrophile and moderate nucleophile. Based on the values of
nucleophilicity index (N) listed in Table 4, the dipole 8 has higher nucleophilicity (4.2583 eV)
than the dipolarphile (3.5688eV). On other hand, the electrophilicity index (ω) of 8 (1.6930 eV)
is lower than 3 (1.8385 eV). As a result, 8 is the nucleophile while 3 is the electrophile in this
reaction, in agreement with the NED character CA reaction.
The local electrophilicity indices ωk and Nk of atom k were used to explain the
regioselectivity of the studied CA reaction. The values of the Fukui indices (ꢀꢂ and ꢀꢃ) and
ꢁ
ꢁ
local electrophilicity indices (ωk and Nk) are reported in Table 5. Scheme 4 depicts these
interactions for better visualization. In the studied CA reaction, the most favorable two-center
interaction takes place between C15 and C17 of 3 as electrophile and C16 and C8 of 8 as
nucleophile, respectively. These results are in agreement with the experimental findings, which
afforded 6 and not 7.
Table 5 Electrophilic and nucleophilic Fukui indices and local electrophilicities for the reactive
atoms of 3 and 8.
Reactant
3
8
C15
-0.1205
C17
-0.0142
C8
-0.0398
C16
-0.1544
ꢀꢂ
ꢀꢂ
ꢁ
ꢁ
ꢀꢃ
ꢀꢃ
-0.0027
-0.0846
-0.1855
-0.1853
ꢁ
ꢁ
ωk
0.2215
0.0049
Nk
0.6575
0.7889
Scheme 4 Favorable interactions using local electrophilicity indices
11

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Molecular mechanism
The above cycloaddition may presumably occur along the two regioisomeric pathways as
shown in Scheme 3. The geometries of the two TSs are given in Figure 7 together with the newly
forming bond lengths. Table 6 reports the energies (a.u.) and relative energies (kcal/mol). The
potential energy surfaces (PESs) corresponding to all the reaction channels, are illustrated in
Figure 8. Based on the calculated energy difference between the product and reactants, the
product 6 is more stable thermodynamically than 7. On other hand, the calculated activation
energies of the different reaction pathways between 3 and 8 showed that the pathway 1 (adduct
6) is the most favored kinetically in comparison with pathway 2 (product 7). The large energy
difference (10.78 Kcal/mol) between the two cycloaddition TSs confirmed that 6 is the only
product that could be formed in this reaction as observed experimentally.
TS1
TS2
Figure 7 The four transition state structure for the CA reaction
Table 6 Energies and relative energies (∆E) of the reactants, transition states and products.
System
E(a.u.)
∆E (Kcal/mol)a
-1209.5491
-1007.9056
-2217.4459
-2217.4287
-2217.4864
-2217.4799
3
8
5.48451
16.26471
-19.94534
-15.83885
TS1
TS2
6
7
aThe energies of the TSs and products are
referred to the sum [E3+E8].
12

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Figure 8 Energy profiles, in kcal/mol for the two pathways of the CA reactions.
Optimized molecular structure of 6
The optimized molecular structure of 6 done by using B3LYP/6-31G(d,p) is shown in
Figure 9. The calculated bond distances and bond angles are given in Table 7 and Table S1
(Supplementary data). Figure 10 shows the correlations between the calculated and experimental
geometric parameters (bond distances and angles). The correlation between the calculated and
experimental bond distances and angles gave correlation coefficients (R2) of 0.9963 and 0.9798,
respectively. Moreover, the root mean square deviation (RMSD) of the bond distances and
angles are 0.011 Å and 1.05˚, respectively. As a result, the geometric parameters are well
predicted.
13

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Figure 9 The optimized molecular structure of 6
Table 7 The calculated and experimental bond distances of 6
Parameter
R(1-26)
R(1-29)
R(2-20)
R(3-37)
R(3-62)
R(4-42)
R(5-57)
R(5-74)
R(6-9)
R(6-20)
R(7-19)
R(7-24)
R(7-29)
R(8-44)
R(8-47)
R(8-66)
R(9-10)
R(9-18)
R(10-12)
R(12-14)
R(14-16)
R(16-18)
R(18-19)
R(19-20)
R(21-22)
Calc.
X-ray
Parameter
1.834 R(21-42)
1.838 R(21-47)
1.232 R(22-24)
1.366 R(22-32)
1.434 R(24-26)
1.223 R(32-33)
1.365 R(32-40)
1.430 R(33-35)
1.405 R(35-37)
1.354 R(37-38)
1.466 R(38-40)
1.465 R(42-43)
1.452 R(43-44)
1.464 R(43-50)
1.460 R(50-52)
1.465 R(52-53)
1.385 R(52-60)
1.391 R(53-55)
1.393 R(55-57)
1.390 R(57-58)
1.396 R(58-60)
1.389 R(66-69)
1.518 R(69-71)
1.562 R(2-49)
1.563 R(19-21)
Calc.
X-ray
1.855
1.860
1.222
1.367
1.418
1.228
1.360
1.421
1.400
1.377
1.463
1.456
1.448
1.459
1.459
1.466
1.390
1.404
1.400
1.396
1.402
1.389
1.524
1.571
1.577
1.546
1.538
1.532
1.516
1.528
1.406
1.400
1.390
1.401
1.399
1.397
1.494
1.513
1.359
1.456
1.416
1.409
1.385
1.404
1.401
1.391
1.505
1.333
2.303
1.622
1.541
1.529
1.524
1.507
1.515
1.396
1.393
1.390
1.393
1.389
1.393
1.484
1.507
1.345
1.462
1.406
1.395
1.384
1.396
1.386
1.386
1.498
1.317
2.341
1.609
14

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140.0
130.0
120.0
110.0
100.0
90.0
y = 0.9931x + 0.6726
R² = 0.9798
80.0
80.0
90.0
100.0
110.0
120.0
130.0
140.0
Calculated bond angles
2.5
2.3
2.1
1.9
1.7
1.5
1.3
1.1
y = 1.0127x - 0.0232
R² = 0.9963
1.1
1.3
1.5
1.7
1.9
2.1
2.3
2.5
Calculated bond distance
Figure 10 The correlation graphs between the calculated and experimental geometric parameters
15

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Natural atomic charges
The charges at the different atomic sites were calculated using natural bond orbital
method at the B3LYP/6-31G(d,p) method. The natural atomic charges are listed in Table 8. It
could be seen that, the most negative atomic sites are oxygen and nitrogen atoms as those sites
have high electronegativity. The natural charges at the O and N-atoms are in the range of -0.5120
to -0.6260 and -0.5028 to -0.6275, respectively. As a result, the C-atoms attached to these sites
are expected to have the highest positive charge values. The most electropositive C-atom is C20
(+0.7030) as this carbon is bonded to two of the strong electronegative atoms. Moreover, the
calculations predicted the S-atom to have electropositive nature (+0.1777). All the H-atoms have
positive natural charges where the most electropositive H-site is amino group proton (H78)
which has natural charge of +0.4381. A graphical representation of the charge density
distribution at the different atomic site of 6 is shown in figure 11. This molecular electrostatic
potential map gave indication on the reactive site for electrophilic and nucleophilic attack. The
blue regions represent the regions with high electron deficiency and those are related to the
reactive sites for nucleophilic attack. In contrast, the negative red regions -the most electron rich-
represent the most reactive sites for electrophilic attack. As can be seen from The MEP figure
shown in Fig. 11, the most reactive electrophilic sites are those related to the carbonyl O-atoms
(O4 and O2) while the most nucleophilic site is the amine proton (H78). On other hand, dipole
moment is an important electronic parameter which is related to the charge distribution among
different atomic sites. The dipole moment of 6 is calculated to be 7.4818 Debye which indicate
the high polarity of the studied compound probably due to the large number of electronegative
atoms.
16

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Figure 11 Molecular electrostatic potential (MEP) map of 6
Table 8 The natural atomic charges of 6
Atom
NAC
Atom
H 27
H 28
C 29
H 30
H 31
C 32
C 33
H 34
C 35
H 36
C 37
C 38
H 39
C 40
H 41
C 42
C 43
C 44
H 45
H 46
C 47
H 48
H 49
C 50
H 51
C 52
NAC
0.2498
0.2608
-0.3823
0.2242
0.2515
-0.0713
-0.2236
0.2413
-0.2705
0.2498
0.3169
-0.3184
0.2416
-0.2070
0.2489
0.5714
-0.1310
-0.2866
0.2555
0.2092
-0.2806
0.2283
0.2667
-0.1301
0.2555
-0.1129
Atom
C 53
H 54
C 55
H 56
C 57
C 58
H 59
C 60
H 61
C 62
H 63
H 64
H 65
C 66
H 67
H 68
C 69
H 70
C 71
H 72
H 73
C 74
H 75
H 76
H 77
H 78
NAC
-0.1949
0.2435
-0.2741
0.2534
0.3384
-0.3250
0.2453
-0.1753
0.2435
-0.3276
0.2315
0.2057
0.2050
-0.2891
0.2619
0.2057
-0.2302
0.2294
-0.4342
0.2151
0.2238
-0.3300
0.2352
0.2089
0.2089
0.4381
S
1
2
3
4
5
6
7
8
9
0.1777
-0.6206
-0.5209
-0.5795
-0.5120
-0.6275
-0.5173
-0.5028
0.1752
-0.2799
0.2406
-0.2178
0.2410
-0.2597
0.2414
-0.1980
0.2642
-0.0801
0.0816
0.7030
-0.0919
-0.2686
0.2854
-0.0584
0.2344
-0.5795
O
O
O
O
N
N
N
C
C 10
H 11
C 12
H 13
C 14
H 15
C 16
H 17
C 18
C 19
C 20
C 21
C 22
H 23
C 24
H 25
C 26
17

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Frontier Molecular Orbitals (FMOs)
The frontier molecular orbitals; HOMO and LUMO are the outermost molecular orbital
which offer a reasonable qualitative prediction of the excitation properties and the ability of
electron transport [41,42]. HOMO is the higher energy orbital containing electrons and so it acts
as an electron donor while LUMO is the lowest energy orbital that acts as an electron acceptor.
Also, the HOMO and LUMO are very popular quantum chemical parameters which determine
the molecular reactivity. The isodensity surface plots of HOMO and LUMO levels of the studied
compound are drawn using the same level of theory (Fig. 12). It can be seen from figure 12 that,
the electron density of HOMO is mainly localized over the thiazolidine which represent the
electron donor fragment of 6. The LUMO is localized mainly over the 4-methoxyphenyl and
piperidin-4-one moieties which act as the electron acceptor fragments of 6. The electronic
transition from HOMO and LUMO could be described as π→π* in which the electron flow takes
place from the thiazolidine π–molecular orbitals to the π*-molecular orbitals of the 4-
methoxyphenyl and piperidin-4-one moieties. The HOMO and LUMO energies are -5.6021 and -
1.8373 eV, respectively and hence the minimum energy of the electronic transition is 3.7647 eV.
The energies of HOMO and LUMO are negative, which indicates that the studied compound is
stable molecule [43].
HOMO
LUMO
Figure 12 The isodensity surface plots of HOMO and LUMO levels of 6
18

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Experimental
General methods
Chemistry
Melting points were recorded using open capillary tubes and are uncorrected. The 1H, 13C and 2-
D NMR spectra were recorded on a Bruker 400 or 500 MHz instruments (Faellanden,
Switzerland) in CDCl3 using TMS as internal standard. Standard Bruker software was used
throughout. Chemical shifts are given in parts per million (δ-scale) and the coupling constants
are given in Hertz. IR spectra were recorded on a Perkin Elmer system 2000 FT IR instrument
(KBr) (Shelton, AL, USA). Elemental analyses were performed on a Perkin Elmer 2400 Series II
Elemental CHNS analyzer (Waltham, MA, USA).
Synthesis of (3E,5E)-1-allyl-3,5-bis(4-methoxyphenylmethylidene)piperidin-4-one (3)
A equimolar mixture of (3E,5E)-3,5-bis(4-methoxyphenylmethylidene)piperidin-4-one (0.023 g),
allyl chloride (0.100 g) and K2CO3 (0.041 g) in 30 mL of acetone was stirred at room
temperature for 30 minutes. After completion of the reaction as evident from TLC, the excess
solvent was removed under vacuum and the crude product was extracted with ethyl acetate and
o
1
recrystallized from the same to afford the product as a yellow solid, (92%); Mp 97-99 C; H
NMR (400 MHz, CDCl3): δH 3.21 (d, 2H, J=6.4 Hz, 7'-CH2), 3.76-3.87 (m, 10H, 2'-CH2, 6'-CH2
and 2xOCH3), 5.12 (d, 1H, J=10.4 Hz, 9'-CH2), 5.22 (d, 1H, J=17.2 Hz, 9'-CH2), 5.78–5.85 (m,
1H, H-8'), 6.93 (d, 2H, J=8.8 Hz, ArH), 7.35 (d, 2H, J=8.8 Hz, ArH), 7.78 (s, 2H,
arylmethylidene). 13C NMR (100 MHz, CDCl3): δC 55.00, 55.71, 60.95, 114.50, 118.89, 128.41,
131.77, 132.73, 135.01, 136.49, 160.65, 187.60. Anal. calcd for C24H25NO3: C, 76.77; H, 6.71;
N, 3.73%; found: C, 76.95; H, 6.57; N, 3.81%.
General procedure for the synthesis of spiro[2.3″]oxindole-spiro[3.3′]-1′-allyl-5′-(4-
methoxyphenylmethylidene)tetrahydro-4′(1H)-pyridinone-4-(4-methoxyphenyl)hexahydro-
pyrrolo[1,2-c]thiazole (6).
An equimolar mixture of (3E,5E)-1-allyl-3,5-bis(4-methoxyphenylmethylidene)piperidin-4-one
3, isatin 4 and thiazolidine-4-carboxylic acid 5 with 4-5 drops of DMF was irradiated in a CEM
microwave synthesizer at 90 oC for 5 minutes. After completion of the reaction (TLC), water (50
mL) was added to the reaction mixture and extracted with ethyl acetate (3x30 mL). The excess
19

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solvent was evaporated under reduced pressure. The resultant solid was dried in vacuum and
o
crystallized from ethyl acetate to obtain pure 6 as colorless solid, (84%); Mp 147-149 C; IR
1
(KBr) νmax 1608, 1620, 1631, 1708, 3390 cm-1; H NMR (500 MHz, CDCl3): δH 1.92 (d, 1H,
J=13.0 Hz, 2'-CH2), 2.73-2.82 (m, 3H, 5-CH2, 6'-CH2, 7'-CH2), 2.98–3.01 (m, 1H, 5-CH2), 3.15
(dd, 1H, J=13.5, 4.5 Hz, 7'-CH2), 3.50-3.56 (m, 3H, 7-CH2, 2'-CH2, 6'-CH2), 3.68 (d, 1H, J=6.5
Hz, 7-CH2), 3.79 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 4.40 (d, 1H, J=10.0 Hz, H-4), 4.65–4.70
(m, 1H, H-4a), 4.95-5.02 (m, 2H, 9'-CH2), 5.59–5.67 (m, 1H, H-8'), 6.66 (d, 1H, J=7.5 Hz, ArH),
6.79–6.81 (m, 3H, Ar-H and arylmethylidene), 6.84 (d, 2H, J=8.0 Hz, ArH), 6.94 (d, 2H, J=8.0
Hz, ArH), 6.97 (d, 1H, J=8.0 Hz, ArH), 7.12 (t, 1H, J=7.5 Hz, ArH), 7.26-7.30 (m, 3H, ArH),
13
8.46 (s, 1H, 1"-NH). C NMR (125 MHz, CDCl3): δC 33.65, 48.25, 49.21, 53.29, 55.23, 55.28,
55.33, 60.53, 69.16, 71.60, 72.78, 109.04, 113.81, 117.73, 121.72, 126.01, 127.67, 128.38,
129.10, 129.16, 130.35, 131.46, 131.97, 134.14, 137.19, 141.43, 158.63, 160.06, 178.87, 197.66.
Anal. calcd for C35H35N3O4S: C, 70.80; H, 5.94; N, 7.08%; found: C, 70.98; H, 5.81; N, 7.21%.
X-ray details
The compound 6 was obtained as single crystals by slow evaporation from ethyl acetate solution
of the pure compound at room temperature. Data were collected on a Bruker APEX-II CCD
diffractometer, equipped with graphite monochromatic Mo Kα radiation, λ = 0.71073 Å at 100
(2) K. Cell refinement and data reduction were carried out by Bruker SAINT. SHELXT [44, 45]
was used to solve structure. The final refinement was carried out by full-matrix least-squares
techniques with anisotropic thermal data for nonhydrogen atoms on ꢄ. CCDC 1450952 contains
the supplementary crystallographic data for this compound can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Computational details
Full geometry optimizations were carried out for the reactants, transition states (TSs) and
cycloaddition products (CAs) using the DFT with the B3LYP [46, 47] functional and the 6-
31G(d,p) basis set. All calculations were carried out with GAUSSIAN 03 [48]. The stationary
points were characterized by frequency calculations in order to verify that minima and transition
states have zero and one imaginary frequency, respectively. Each TS gave one negative
vibrational mode corresponding to the motion involving the formation of the newly forming C–C
bonds. The vibrational mode was assigned appropriately by means of visual inspection and
20

ACCEPTED MANUSCRIPT
animation using the Gaussview software [49]. The reported total energies include zero point
energy (ZPE) corrections are given at 298.15 K. Analysis of the frontier molecular orbital (FMO)
interactions, global electrophilicity index (ω), was calculated following the expression [50-53],
ω= (ꢁ2/2η), where ꢁ is the electronic chemical potential, ꢁ = (EH + EL)/2, and η is the chemical
hardness, η= (EL - EH). The nucleophilicity index, N [51], which is defined as N = EH(Nu)
-
EH(TCE), where tetracyanoethylene (TCE) is chosen as the reference [54,55]. The atomic
electronic population and DFT-based reactivity indices were computed using natural population
analysis (NPA) [56]. The local electrophilicity ωk and nucleophilicity Nk indices of atom k are
obtained by the help of Fukui index (fk) using equations:
ꢂ
ꢇ
ꢉ
ꢇ ꢉ
ꢅꢁ = ꢅꢀ = ꢅ[ꢆꢁ ꢈ + 1 − ꢆꢁ ꢈ ]
ꢁ
ꢃ
ꢇ ꢉ
ꢇ
ꢉ
ꢈꢁ = ꢈꢀ = ꢅ[ꢆꢁ ꢈ − ꢆꢁ ꢈ − 1 ]
ꢁ
Where qk(N), qk(N+1), qk(N-1) are the gross electronic population of site k in neutral, anionic,
and cationic systems, respectively [57]. The optimized structure of 3 and 8 are given in figure S9
(Supplementary data).
Conclusions
A sustainable microwave-assisted three-component 1,3-dipolar cycloaddition reaction has
been developed for the regioselective synthesis of highly functionalized dispiro oxindole–
pyrrolo[1,2-c]thiazole–piperidone hybrid 6. In order to rationalize the formation of 6, theoretical
calculation was performed. The results of the DFT calculations showed that the azomethine
ylide; 8 and the dipolarophile 3 act as strong nucleophile and electrophile, respectively wherein
the amount of charge transfer from 8 to 3 at the TS structure is 0.1247eV. The CAs reaction has
normal electronic demand (NED). The local reactivity indices (ωk and Nk) as well as the
transition state calculations indicated the regioselective formation of 6 is the most favored. The
high activation energy difference between the TSs suggested that the thermodynamically stable
product 6 is the only product that could be obtained, in agreement with experimental results.
Acknowledgments
The authors acknowledge the Deanship of Scientific Research at King Saud University for
Research Grant No. RGP-026.
21

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ACCEPTED MANUSCRIPT
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Highly functionalized dispiro oxindole–pyrrolo[1,2-c]thiazole–piperidone hybrid
has been achieved regioselectively
Structure was accomplished using NMR spectroscopy and X-ray crystallographic
studies
The formation of product has been explained using the local reactivity descriptors
obtained from the DFT calculations
DFT optimized molecular structure agree well with the X-ray results