Ultrasound-assisted sequential multicomponent strategy for the combinatorial synthesis of novel coumarin hybrids

Article abstract of DOI:10.1021/co500092b

The present investigation reports an easy access to a library of novel spiro-oxindole-pyrrolizine or pyrrolo[1,2-c]thiazole fused coumarin hybrid heterocycles through a one-pot sequential four-component reactions of 2,2-dimethyl-1,3-dioxane-4,6-dione, salicylaldehydes, isatins, and cyclic α-amino acids under ultrasound irradiation.

Full text of DOI:10.1021/co500092b

Research Article
pubs.acs.org/acscombsci
Ultrasound-Assisted Sequential Multicomponent Strategy for the
Combinatorial Synthesis of Novel Coumarin Hybrids
Selvaraj Kanchithalaivan, Remani Vasudevan Sumesh, and Raju Ranjith Kumar*
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu India
*
S Supporting Information
ABSTRACT: The present investigation reports an easy access to a library of novel spiro-oxindole−pyrrolizine or pyrrolo[1,2-
c]thiazole fused coumarin hybrid heterocycles through a one-pot sequential four-component reactions of 2,2-dimethyl-1,3-
dioxane-4,6-dione, salicylaldehydes, isatins, and cyclic α-amino acids under ultrasound irradiation.
KEYWORDS: sequential, spiro-oxindole, coumarin, pyrrolizine, pyrrolothiazole, 1,3-dipolar cycloaddition
INTRODUCTION
in liquid. This induces intense local heating, which promotes
4,5
■
organic reactions to occur.
The 1,3-dipolar cycloadditions (DPC) of azomethine ylides to
On the other hand, spiro-oxindoles are found in severa6l
activated olefins offer a facile entry toward five-membered
bioactive natural products, such as spirotryprostatins A and B,
10
1
nitrogen heterocycles. In particular, investigations pertaining
7
8
9
horsfiline, rhynchophylline, formosanine, and elacomine.
to the DPC of nonstabilized azomethine ylides generated in situ
from the decarboxylative condensation of α-amino acids and
nonenolizable ketones to dipolarophiles with exocyclic alkenes
resulting in the formation of dispiro heterocycles have received
The synthetic analogs of these heterocycles have also been
11
shown to display significant biological activities. In addition,
coumarin containing natural products as well as its synthetic
heterofused systems are endowed with wide array of biological
13
2
12
significant attention. However, reports on the DPC of these
properties which includes antidiabetic, anticoagulant,
14 15 16
1
,3-dipoles with endocyclic alkenes to form monospiro fused
anticancer, antitubercular, anti-HIV and AChE inhib-
3
17
heterocycles are scarce. Consequently, the present work
reports for the first time the synthesis of novel spiro-
oxindole/acenaphthelene−pyrrolizine/pyrrolo[1,2-c]thiazole
fused coumarin hybrid heterocycles through DPC of
azomethine ylides under ultrasound-irradiation.
ition. The present work also pertains to our continuous effort
in the synthesis of novel heterocycles employing one-pot
18
multicomponent reactions.
RESULTS AND DISCUSSION
■
Recently, more focus is dedicated toward the DPC of
azomethine ylides to olefins under ultrasound-irradiation, which
offer a simple route for the construction of complex
Initially, coumarin-3-carboxylic acid 2 was synthesized from the
reaction of 2,2-dimethyl-1,3-dioxane-4,6-dione and salicylalde-
hyde 1{1} following literature procedure. In the next step, the
19
4
heterocycles. Under these conditions, it has been observed
1
,3-dipolar cycloaddition of 2 with azomethine ylide generated
that the cycloaddition proceeds through a diradical ylide rather
than a concerted pathway. In general, organic reactions under
ultrasound-irradiation are more advantageous when compared
to conventional procedures in view of its milder reaction
condition, improved selectivity, high yields in shorter reaction
time, simple experimental procedure and workup and energy
in situ from the reaction of isatin 3{1} and proline 4{1} was
investigated under ultrasound irradiation (Scheme 1). The
reaction occurred smoothly at 50 °C affording a colorless
precipitate after 1 h of irradiation, which was filtered, washed
Received: June 12, 2014
Revised: August 1, 2014
Published: August 18, 2014
5
conservation. Ultrasound-irradiation leads to cavitation,
namely, formation, growth, and implosive collapse of bubbles
©
2014 American Chemical Society
566
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ACS Combinatorial Science
Research Article
Scheme 1. Synthesis of Spiro-oxindole−Pyrrolizine/pyrrolo[1,2-c]thiazole-Fused Coumarin Hybrids 5
Table 1. Comparative Yield of 5 under Conventional and Ultrasound Conditions
R1
R2
R3
X
yield (%)
a,
b
yield (%)
c
mp (°C)
entry
compd
1
2
3
4
5
6
7
8
9
5{1,1,1}
5{1,2,1}
5{1,3,1}
5{2,1,1}
5{2,2,1}
5{2,3,1}
5{3,1,1}
5{3,2,1}
5{3,3,1}
5{4,1,1}
5{4,2,1}
5{4,3,1}
5{5,1,1}
5{5,2,1}
5{5,3,1}
5{1,1,2}
5{1,2,2}
5{1,3,2}
5{2,1,2}
5{2,2,2}
5{2,3,2}
5{3,1,2}
5{3,2,2}
5{3,3,2}
5{4,1,2}
5{4,2,2}
5{4,3,2}
5{5,1,2}
5{5,2,2}
5{5,3,2}
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
H
H
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
S
62
56
60
52
60
55
58
59
60
64
55
57
62
61
59
60
55
58
54
56
50
60
61
60
55
55
58
59
56
55
95
95
94
95
94
96
95
95
95
94
94
96
95
95
96
87
82
89
81
86
87
80
82
88
86
84
91
87
90
92
217−218
168−169
166−167
162−163
217−218
241−242
210−211
217−218
235−236
172−173
210−211
218−219
168−169
225−226
168−169
247−248
156−157
257−258
217−218
193−194
265−266
257−258
185−186
162−163
264−265
249−250
263−264
241−242
233−234
239−240
H
Cl
H
CH3
H
Br
Br
Cl
Br
CH3
H
Cl
Cl
Cl
Cl
CH3
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
NO2
NO2
NO2
Cl
Cl
CH3
H
Cl
Cl
Cl
CH3
H
H
H
Cl
S
H
CH3
H
S
Br
S
Br
Cl
S
Br
CH3
H
S
Cl
S
Cl
Cl
S
Cl
CH3
H
S
NO2
NO2
NO2
Cl
S
Cl
S
CH3
H
S
S
Cl
Cl
S
Cl
CH3
S
a
b
c
Isolated yield after column chromatography. Conventional heating. Ultrasound irradiation.
with water and dried to obtain novel 6b,7,8,9-tetrahydro-6H-
spiro[chromeno[3,4-a]pyrrolizine-11,3′-indoline]-2′,6-
It is significant to note that under ultrasound irradiation the
stepwise, as well as the one-pot sequential, procedure afforded
5{1,1,1} in quantitative yields. As the product is precipitated in
the reaction vessel, no column chromatographic purification is
required thereby eliminating the use of large quantity of volatile
solvents. Furthermore, under these conditions the necessity to
monitor the reaction progress employing thin layer chromatog-
raphy is not required as well.
Moreover, for comparison the above reaction was performed
under conventional method, wherein the reactants 2, isatin
3{1}, and proline 4{1} were refluxed in methanol. The reaction
proceeds well with the formation of 5{1,1,1} but failed to attain
completion even after 6 h of continuous reflux. At this stage the
reaction mixture was cooled to room temperature and
quenched with crushed ice. The precipitate after column
(
6aH,11aH)-dione 5{1,1,1} in 97% yield.
In an attempt to synthesize 5{1,1,1} via a one-pot sequential
procedure without isolating the intermediate 2, the reactants
,2-dimethyl-1,3-dioxane-4,6-dione and 1{1} in water was
2
subjected to ultrasound irradiation at 50 °C. After 30−40
min a colorless precipitate was formed in the reaction mixture
indicating the formation of 2. To this, a mixture of isatin 3{1}
and proline 4{1} dissolved in methanol was added and the
ultrasound irradiation continued at 50 °C (Scheme 1). As the
reaction progressed the mixture became homogeneous and
after 45 min of irradiation, a colorless solid precipitated from
the mixture, which was filtered and dried to obtain 5{1,1, 1} in
95% yield (Table 1).
5
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Research Article
Figure 1. Diversity of reagents.
chromatographic purification afforded 5{1,1,1} in 62% yield
(
Table 1). Apparently, the ultrasound irradiation method was
found to be more advantageous over conventional heating for
the synthesis of 5{1,1,1}.
The above ultrasound-assisted one-pot sequential procedure
was then employed for the synthesis of a library of novel spiro-
oxindolo-pyrrolizine/pyrrolo[1,2-c]thiazole fused coumarin
hybrid heterocycles 5 by varying the salicylaldehyde 1, isatin
3
and cyclic α-amino acid 4 (Figure 1). The data in Table 1
disclose that this protocol works well with all the substrates
affording excellent yields of the products when compared to the
conventional heating, wherein the yields were less than 62%.
The structure of all the coumarin hybrid heterocycles 5 is in
complete agreement with the elemental analysis, ESI mass, IR,
and NMR spectroscopic data. As a representative example, the
mass spectrum of 5{1,1,1} has a characteristic molecular ion
Figure 2. H and 13C chemical shifts of 5{1,1,1}.
1
+
peak at 347.25 (M ). The IR spectrum of 5{1,1,1} shows
−1
strong absorptions at 1758 and 1729 cm due to the two
carbonyl groups. In the proton NMR spectrum of 5{1,1,1}, a
doublet at 3.93 ppm (J = 11.1 Hz) can be readily assigned to
11a-CH on the basis of its multiplicity. From the H,H-COSY of
11a-CH, the doublets of doublets at 3.11 ppm (J = 11.1, 3.3
Hz) is due to 6a-CH. The coupling constant value of 11.1 Hz
discloses that 11a-H and 6a-H are cis. Further, it is evident from
the H,H-COSY of 6a-CH that the triplets of doublets at 4.73
ppm (J = 7.1, 3.3 Hz) accounting for one proton is due to 7-
CH. The C,H-COSY correlations assigns the carbon signals at
4
8
1
4.0, 47.9, and 67.8 ppm to C-11a, 6a, and 7 respectively. The
-, 9-, and 10-CH protons appear as multiplets in the range
2
.71−3.14 ppm and the NH of the oxindole ring gives a broad
singlet at 8.16 ppm. The carbon signals at 76.9, 167.6, and
Figure 3. ORTEP diagram of 5{5,3,1}.
177.8 ppm are due to spiro carbon C-11 and the carbonyl
carbons at C-6 and C-2′ respectively (Figure 2).
The structure of 5 elucidated from the NMR spectroscopic
studies was further confirmed from single crystal X-ray data.
The ORTEP diagram of 5{5,3,1} shown in Figure 3 discloses
reaction of 2,2-dimethyl-1,3-dioxane-4,6-dione and salicylalde-
hydes 1 affords the intermediate arylidene 6, which undergoes
an intramolecular cyclization via nucleophilic attack of OH on
the carbonyl carbon followed by elimination of acetone to yield
the coumarin-3-carboxylic acid 2. Simultaneously, the con-
densation of isatins and proline or 1,3-thiazolone-4-carboxylic
20
that H-11a and H-6a are cis, whereas H-6a and H-7 are trans.
A plausible mechanism for the formation of spiro-coumarin
hybrid heterocycles 5 via ultrasound irradiation, as well as
conventional heating is depicted in Scheme 2. Initially, the aldol
21
acid affords the spiro intermediate 7. The decarboxylation of
5
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Scheme 2. Plausible mechanism for the formation of 5
Scheme 3. Synthesis of Spiro-acenaphthenequinone−Pyrrolizine/Pyrrolo[1,2-c]thiazole-Fused Coumarin Hybrids 12
7
under ultrasound irradiation forms the diradical ylide 8a,
whereas under conventional heating forms the ylide 8b. The
,3-dipolar cycloaddition of 8a and 8b with 2 proceeds through
reaction. However, formation of 11 can be visualized from the
cycloaddition of either 8c or 8d with 2 via 10b, which
presumably is less favored due to the electrostatic repulsion
between the carbonyl of coumarin ring and that of the
approaching azomethine ylide dipole (Scheme 2). This
regiochemistry is also evident from the single crystal X-ray
studies (Figure 3).
Further, with a view to extend the scope of the above one-pot
four-component sequential protocol, isatins were replaced with
acenaphthenequinone 3{4} (Scheme 3). Because of the
1
a diradical mechanism (via 9a) and a concerted pathway,
respectively, to afford the adduct 10a followed by the
spontaneous decarboxylation of 10a to afford 5.
The above sequential reaction proceeds regioselectively
affording a single isomer of the product 5 under both
ultrasound irradiation as well as conventional heating. The
other regioisomer 11 is not formed during the course of the
5
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Research Article
solubility issue of acenaphthenequinone in aqueous conditions,
the reaction failed to occur. However, the three-component
reaction of 2, 3{4} and 4{1−2} under ultrasound irradiation
afforded novel spiro-acenaphthenequinone−pyrrolizine/
pyrrolo[1,2-c]thiazole fused coumarin hybrids 12 in good
yields in 45−60 min (Table 2). The structure of these
heterocycles 12 was elucidated with the help of NMR
spectroscopy.
performed in a Bandelin-Sonorex Ultrasonic Bath (Super RK)
with a frequency of 35 kHz and a power of 230 W. The internal
dimensions of the ultrasonic cleaner tank were 240 × 140 ×
100 mm with liquid holding capacity of 3L. Silica gel-G plates
(Merck) were used for TLC analysis with a mixture of
petroleum ether (60−80 °C) and ethyl acetate as eluent. The
solvents and all reagents used in this study were purchased
from commercial suppliers.
General Procedure for the Synthesis of 5. Ultrasound
Irradiation. A reaction flask with the appropriate salicylalde-
hyde (1{1−5}, 1 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-
dione (1 mmol) in water (7 mL) was located at the maximum
energy area in the ultrasonic bath and the surface of the
reactants was placed slightly lower than the level of the water.
The mixture was subjected to ultrasonic irradiation of low
power at 50 °C for about 30 min. To this, a mixture of
appropriate isatin (3{1−3}, 1 mmol) and proline or 4-
thiazolidinecarboxylic acid (4, 1 mmol) dissolved in methanol
Table 2. Yield and Melting Point of 12
entry
compd
R1
R2
X
yield (%)
mp (°C)
31
32
33
34
35
36
37
38
39
40
12{1,4,1}
12{2,4,1}
12{3,4,1}
12{4,4,1}
12{5,4,1}
12{1,4,2}
12{2,4,2}
12{3,4,2}
12{4,4,2}
12{5,4,2}
H
H
H
H
Cl
H
H
H
H
Cl
H
CH2
CH2
CH2
CH2
90
89
84
82
88
92
86
80
89
92
197−198
234−235
228−229
217−218
211−212
226−227
238−239
240−241
230−231
247−248
Br
Cl
NO2
Cl
CH2
H
S
Br
Cl
S
S
S
S
(
7 mL) was added. The irradiation was continued until the
completion of the reaction (∼45−60 min), during which the
product precipitated from the reaction mixture, which was
filtered and dried to obtain pure 5.
NO2
Cl
Conventional Method. A reaction flask with appropriate
salicylaldehyde (1{1−5}, 1 mmol) and 2,2-dimethyl-1,3-
dioxane-4,6-dione (1 mmol) in water (7 mL) was refluxed
for 30 min. To this a mixture of appropriate isatin (3{1−3}, 1
mmol) and proline or 4-thiazolidinecarboxylic acid (4, 1 mmol)
dissolved in methanol (7 mL) was added. The heating was
continued for 5−6 h with regular TLC analysis. Then the
reaction mixture was poured into ice cold water and the
precipitate was filtered and subjected to column chromato-
graphic purification (80:20 v/v petroleum ether:ethyl acetate
mixture) to afford pure 5.
CONCLUSIONS
■
In conclusion, we have developed a facile one-pot four-
component sequential protocol for the regioselective synthesis
of hitherto unreported spiro-oxindole−pyrrolizine or pyrrolo-
thiazole fused coumarin hybrid heterocycles under ultrasound-
irradiation. The reaction afforded excellent yields of the
products in significantly lesser time in contrast to the
conventional heating wherein yields were less than 62%. The
reaction proceeds through a sequential aldol condensation−
intramolecular cyclization−1,3-dipolar cycloaddition−decar-
boxylation in one-pot without the isolation and/or purification
of intermediates. Furthermore, spiro-acenaphthenequinone−
pyrrolizine or pyrrolothiazole fused coumarins were also
obtained following a three-component protocol under ultra-
sound-irradiation.
Compound 5{1,1,1}: Obtained as colorless solid; yield 95%;
1
mp 217−218 °C; H NMR (300 MHz, CDCl ) δ 1.71−1.89
3
(m, 2H), 1.93−1.98 (m, 1H), 2.56−2.65 (m, 1H), 2.89−2.93
(m, 1H), 3.11 (dd, J = 11.3, 3.2 Hz, 1H), 3.04−3.14 (m, 1H),
3.93 (d, J = 11.1 Hz, 1H), 4.73 (td, J = 7.1, 3.1 Hz, 1H), 6.34
(d, J = 7.8 Hz, 1H), 6.70−6.76 (m, 1H), 6.82 (d, J = 7.8 Hz,
1
H), 6.95 (d, J = 8.1 Hz, 1H), 7.01−7.18 (m, 2H), 7.31−7.36
13
EXPERIMENTAL PROCEDURE
(
m, 1H), 7.53 (d, J = 7.5 Hz, 1H), 8.16 (brs, 1H) ppm;
C
■
General. Melting points were measured in open capillary
tubes and are uncorrected. Electrospray ionization mass
spectrometry (ESI-MS) analyses were recorded in LCQ Fleet,
Thermo Fisher Instrument in negative ion mode. The collision
voltage and ionization voltage were −70 V and −4.5 kV,
respectively, using nitrogen as atomization and desolvation gas.
The desolvation temperature was set at 300 °C. The scan range
of mass spectrum was 300−2000 m/z. The relative amount of
each component was determined from the LC−MS chromato-
gram, using the area normalization method. Infrared spectra
were recorded on a JASCO FT-IR instrument using KBr
NMR (75 MHz, CDCl ) δ 26.5, 33.7, 44.0, 47.9, 51.1, 67.9,
3
76.9, 110.7, 116.8, 117.3, 122.3, 123.7, 125.9, 127.4, 129.0,
130.2, 142.6, 151.2, 167.6, 177.8 ppm; Anal. Calcd for
C H N O C, 72.82; H, 5.24; N, 8.09; Found C, 72.98; H,
21 18 2 3
+
5.14; N, 8.11; ESI-MS m/z calcd [M + H] 347.13, found
347.25; FT IR (cm ) 3434, 3058, 1758, 1729, 1619, 1471,
1168, 773.
−1
Compound 5{1,1,2}: Obtained as colorless solid; yield 87%;
1
mp 247−248 °C; H NMR (300 MHz, CDCl
) δ 2.89 (dd, J =
3
10.8, 6.9 Hz, 1H), 3.31 (d, J = 9.3 Hz, 1H), 3.49 (dd, J = 10.8,
6.9 Hz, 1H), 3.88 (d, J = 9.3 Hz, 1H), 4.01 (d, J = 10.5 Hz,
1H), 4.13 (d, J = 10.5 Hz, 1H), 4.85 (t, J = 6.9 Hz, 1H), 6.29
(d, J = 7.5 Hz, 1H), 6.77−6.85 (m, 2H), 6.99 (d, J = 8.4 Hz,
1H), 7.14−7.23 (m, 2H), 7.37 (t, J = 7.7 Hz, 1H), 7.68 (d, J =
6.9 Hz, 1H), 7.68 (brs, 1H) ppm; 13C NMR (300 MHz,
1
13
pellets. The H C and 2D NMR spectra were recorded on
Bruker Avance 300 MHz spectrometer with TMS as the
internal standard and CDCl or DMSO-d was used as solvent.
3
6
Standard Bruker software was used throughout. Chemical shifts
are given in parts per million (δ-scale) and the coupling
constants are given in Hertz. Elemental analyses were
performed on PerkinElmer 2400 Series II CHNS analyzer.
The single crystal X-ray data set for compound 5{5,3,1} was
collected on Bruker Kappa APPEXII diffractometer with Mo
Kα (λ = 0.71073 Å) radiation. SHELXTL software was used for
structure solution and refinement. Ultrasonication was
CDCl ) δ 39.1, 45.9, 48.2, 55.7, 70.4, 76.6, 77.2, 110.8, 116.9,
3
117.2, 123.1, 124.0, 125.5, 126.1, 127.5, 129.6, 130.7, 142.1,
151.4, 165.9, 178.1 ppm; Anal. Calcd for C H N O S C,
20
16
2
3
65.92; H, 4.43; N, 7.69; Found C, 65.94; H, 4.40; N, 7.64.
General Procedure for the Synthesis of 12. A reaction
flask with appropriate coumarin-3-carboxylic acid (2, 1 mmol),
acenaphthenequinone (3{4}, 1 mmol) and proline or 4-
5
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Research Article
thiazolidinecarboxylic acid (4, 1 mmol) in methanol (10 mL)
was located at the maximum energy area in the ultrasonic bath
and the surface of the reactants was placed slightly lower than
the level of the water. The mixture was subjected to ultrasonic
irradiation of low power at 50 °C for about 45−60 min until
the completion of the reaction during which the product
precipitated from the reaction mixture, which was filtered and
dried to obtain pure 12.
(c) Watanabe, S.; Tada, A.; Tokoro, Y.; Fukuzawa, S.-I. Bifunctional
AgOAc/ThioClickFerrophos complex-catalyzed asymmetric 1,3-dipo-
lar cycloaddition of azomethine ylides with aryl- and alkylidene
malonates. Tetrahedron Lett. 2014, 55, 1306−1309. (d) Maheswari, S.
U.; Perumal, S. An expedient domino three-component [3 + 2]-
cycloaddition/ annulation protocol: Regio- and stereoselective
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stereocentres. Tetrahedron Lett. 2013, 54, 7044−7048.
(2) (a) Kia, Y.; Osman, H.; Kumar, R. S.; Murugaiyah, V.; Basiri, A.;
Compound 12{1,4,1}. Obtained as colorless solid; yield
Perumal, S.; Razak, I. A. A facile chemo-, regio- and stereoselective
synthesis and cholinesterase inhibitory activity of spirooxindole−
pyrrolizine−piperidine hybrids. Bioorg. Med. Chem. Lett. 2013, 23,
2979−2983. (b) Nayaka, M.; Rastogi, N.; Batra, S. Synthesis of
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draprakash, K.; Sankaran, M.; Uvarani, C.; Shankar, R.; Ata, A.;
Dallemer, F.; Mohan, P. S. A strategic approach to the synthesis of
novel class of dispiroheterocyclic derivatives through 1,3-dipolar
cycloaddition of azomethine ylide with (E)-3-arylidene-2,3-dihydro-
1
9
2
(
(
7
7
0%; mp 197−198 °C; H NMR (300 MHz, CDCl ) δ 1.81−
3
.00 (m, 3H), 2.68−2.80 (m, 2H), 3.13−3.18 (m, 2H), 3.24
dd, J = 11.4, 3.0 Hz, 1H), 4.23 (d, J = 11.4 Hz, 1H), 4.72−4.76
m, 1H), 6.33 (d, J = 7.5 Hz, 1H), 6.94−7.02 (m, 2H), 7.58−
.63 (m, 1H), 7.70−7.80 (m, 2H), 7.87 (d, J = 6.9 Hz, 1H),
.97 (d, J = 8.1 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H) ppm; 13
C
NMR (300 MHz, CDCl ) δ 26.4, 33.9, 42.8, 48.6, 51.6, 68.1,
3
8
1
2
3
0.2, 117.1, 117.3, 122.3, 122.4, 123.4, 126.0, 127.3,128.0,
28.3, 128.5, 130.7, 131.3, 131.4, 136.0, 143.0, 151.0, 167.8,
8
-nitro-4-quinolone. Tetrahedron Lett. 2013, 54, 3896−3901.
01.7 ppm; Anal. Calcd for C H NO C, 78.72; H, 5.02; N,
2
5
19
3
(d) Hazra, A.; Bharitkar, Y. P.; Maity, A.; Mondal, S.; Mondal, N. B.
Synthesis of tetracyclic pyrrolidine/isoxazolidine fused pyrano[3,2-
h]quinolines via intramolecular 1,3-dipolar cycloaddition in ionic
liquid. Tetrahedron Lett. 2013, 54, 4339−4342.
.67; Found C, 78.79; H, 4.93; N, 3.63.
Compound 12{1,4,2}: Obtained as colorless solid; yield
1
9
2%; mp 226−227 °C; H NMR (300 MHz, CDCl ) δ 2.98
3
(
dd, J = 10.5, 7.2 Hz, 1H), 3.41 (d, J = 9.9 Hz, 1H), 3.55 (dd, J
(3) (a) Dandia, A.; Jain, A. K.; Laxkar, A. K. Ethyl lactate as a
promising bio based green solvent for the synthesis of spiro-oxindole
derivatives via 1,3-dipolar cycloaddition reaction. Tetrahedron Lett.
=
10.8, 7.2 Hz, 1H), 3.86 (d, J = 9.9 Hz, 1H), 4.08−4.16 (m,
2H), 4.91 (t, J = 6.9 Hz, 1H), 6.00 (d, J = 7.5 Hz, 1H), 6.46−
6.51 (m, 1H), 6.99−7.09 (m, 2H), 7.60−7.66 (m, 2H), 7.81−
7.86 (m, 1H), 8.01 (d, J = 7.5 Hz, 2H), 8.09−8.11 (m, 1H)
2
013, 54, 3929−3932. (b) Chen, H.; Wang, S.-Y.; Xu, X.-P.; Ji, S.-J.
Facile three-component synthesis of spirooxindolepyrrololine ring
systems via1,3-dipolar cycloaddition with 1,4-naphthoquinone. Synth.
Commun. 2011, 41, 3280−3288. (c) Rao, J. N. S.; Raghunathan, R. An
expedient synthesis of pyrrolidinyl spirooxindole grafted 3-nitro-
chromanes through 1,3-dipolar cycloaddition reaction of azomethine
ylides. Tetrahedron Lett. 2013, 54, 6568−6573. (d) Moshkin, V. S.;
Sosnovskikh, V. Y.; Roschenthaler, G.-V. Synthesis of benzopyrano-
pyrrolidines via 1,3-dipolar cycloaddition of nonstabilized azomethine
ylides with 3-substituted coumarins. Tetrahedron 2013, 69, 5884−
13
ppm; C NMR (300 MHz, CDCl ) δ 39.3, 46.2, 47.6, 56.0,
3
7
1
2
3
0.8, 80.0, 117.1, 117.4, 122.3, 122.4, 123.7, 126.3, 127.3, 128.6,
28.7, 129.4, 130.6, 130.8, 131.5, 135.3, 143.0, 151.3, 166.0,
03.0 ppm; Anal. Calcd for C H NO S C, 72.16; H, 4.29; N,
2
4
17
3
.51; Found C, 72.19; H, 4.33; N, 3.49.
ASSOCIATED CONTENT
Supporting Information
■
5
892. (e) Barman, P. D.; Sanyal, I.; Mandal, S. B.; Banerjee, A. K.
*
S
Application of azomethine ylides in the synthesis of carbohydrate-
derived spiroheterocycles. Synthesis 2011, 21, 3563−3568. (f) Lakshmi,
N. V.; Thirumurugan, P.; Jayakumar, C.; Perumal, P. T. An easy access
to novel spiro-fused pyrrolo benzo[b]thiophene 1,1-dioxide derivatives
via 1,3-dipolar cycloaddition using benzo[b]thiophene 1,1-dioxide.
Synlett 2010, 6, 955−961.
Experimental details and spectroscopic characterization of 5
1
13
and 12 and H and C spectra for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
E-mail: raju.ranjithkumar@gmail.com. Phone:
919655591445.
■
(4) (a) Hu, Y.; Zou, Y.; Wu, H.; Shi, D. A facile and efficient
ultrasound-assisted synthesis of novel dispiroheterocycles through 1,3-
dipolar cycloaddition reactions. Ultrason. Sonochem. 2012, 19, 264−
*
+
2
69. (b) Rezaei, S. J. T.; Nabid, M. R.; Yari, A.; Ng, S. W. Ultrasound-
Notes
promoted synthesis of novel spirooxindolo/spiroacenaphthen dicyano
pyrrolidines and pyrrolizidines through regioselective azomethine ylide
cycloaddition reaction. Ultrason. Sonochem. 2011, 18, 49−53. (c) Jadidi,
K.; Gharemanzadeh, R.; Mehrdad, M.; Darabi, H. R.; Khavasi, H. R.;
Asgari, D. A facile synthesis of novel pyrrolizidines under classical and
ultrasonic conditions. Ultrason. Sonochem. 2008, 15, 124−128.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
R.R.K., S.K., and R.V.S. thank the University Grants
Commission, New Delhi, for funds through Major Research
Project F. No. 42-242/2013 (SR) and Department of Science
and Technology, New Delhi, for funds under IRHPA program
for the high resolution NMR facility in the Department. K.S.
thanks the University Grants Commission, New Delhi, for the
Senior Research Fellowship.
(d) Bejan, V.; Mantu, D.; Mangalagiu, I. I. Ultrasound and microwave
assisted synthesis of isoindolo-1,2-diazine: A comparative study.
Ultrason. Sonochem. 2012, 19, 999−1002. (e) Chen, H.; Wang, S.-Y.;
Xu, X.-P.; Ji, S.-J. Facile three-component synthesis of spirooxindo-
lepyrrololine ring systems via 1,3-dipolar cycloaddition with 1,4-
naphthoquinone. Synth. Commun. 2011, 1, 3280−3288. (f) Chandra-
lekha, E.; Thangamani, A.; Valliappan, R. Ultrasound-promoted
regioselective and stereoselective synthesis of novel spiroindanedio-
nepyrrolizidines by multicomponent 1,3-dipolar cycloaddition of
azomethine ylides. Res. Chem. Intermed. 2013, 39, 961−972.
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