Novel four-component route to the synthesis of spiro[indoline-3,4′- pyridine]-3′-carboxylate derivatives

Article abstract of DOI:10.1016/j.tet.2011.03.032

An effective route to spiro[indoline-3,4′-pyridine]-3′- carboxylate derivatives is described. This involves reaction of isatin, 1-phenyl-2-(1,1,1-triphenyl-λ⁵-phosphanylidene)-1-ethanone, and benzylamine derivatives or aliphatic amines in the p

Full text of DOI:10.1016/j.tet.2011.03.032

Tetrahedron 67 (2011) 3519e3523
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel four-component route to the synthesis of spiro[indoline-3,40-pyridine]-
30-carboxylate derivatives
*
Abdolali Alizadeh , Javad Mokhtari
Department of Chemistry, Tarbiat Modares University, PO Box 14115-175 Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
An effective route to spiro[indoline-3,40-pyridine]-30-carboxylate derivatives is described. This involves
Article history:
reaction of isatin, 1-phenyl-2-(1,1,1-triphenyl-l
5-phosphanylidene)-1-ethanone, and benzylamine
Received 18 November 2010
Received in revised form 24 February 2011
Accepted 14 March 2011
derivatives or aliphatic amines in the presence of alkyl acetoacetate (1,3-dicarbonyl compounds) in dry
methanol under reflux conditions. The reactive 1:1 enaminone, which is obtained from the addition of
Available online 21 March 2011
the amine to 1,3-dicarbonyl compound, adds to the a,b-unsaturated ketone, which is formed from the
reaction of isatin and 1-phenyl-2-(1,1,1-triphenyl-l
5-phosphanylidene)-1-ethanone, to produce the alkyl
Keywords:
Isatin
Ylide
Benzylamine
Alkyl acetoacetate
Multicomponent reaction
10-benzyl-20-methyl-2-oxo-60-phenyl-10H-spiro[indoline-3,40-pyridine]-30-carboxylate derivatives in
excellent yields.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Exploring novel pharmacological agents with the minimum
number of synthetic steps and less time is a major challenge for
chemists.1 In general, the conventional approach involves the use of
multistep reactionsequences, which are typicallyassociated withlow
yields,highcost, andtediousisolationandpurificationof theresulting
products. However, as a significant strategy, superior to the conven-
tional one, multicomponent reactions (MCRs) offer a valuable solu-
tionforsuchasituation.2e7 MCRsconstituteahighlyeffectiveone-pot
procedure that has many advantages, including atom economy8 and
facile synthesis of molecules that have interesting biological proper-
ties using readily available starting materials.
CH3
H
N
N
O
N
O
H
H
HN
O
N
O
OCH3
H
pteropodine
spirotryprotain B
The indole core represents an interesting pharmacophore, which
displays wide-ranging biological and pharmacological properties.9
Furthermore, 30-spirooxindoles, formed by sharing of the 3-carbon
atom, have been of interest to organic chemists because they exhibit
interesting biological properties.10e12 Forinstance, spirotryprostatin
B, a natural alkaloid isolated from the fermentation broth of Asper-
gillus fumigatus, has been identified as a novel inhibitor of micro-
tubule assembly,13 and pteropodine and isopteropodine have been
shown to modulate the function of muscarinic serotonin receptors
(Fig.1).14 Therefore, a number of methods have been reported for the
preparation of spirooxindole derivatives.15e17
Fig. 1. Naturally occurring and biologically active spirocyclic oxindoles.
Hantzsch 1,4-dihydropyridines are easily prepared from the
Hantzsch reaction or its modifications.18,19 In recent years, it was
found that drugs, such as nifedipine and niguldipine undergo redox
processes during their metabolism catalyzed by cytochrome P-450
in the liver.20 Furthermore, 1,4-dihydropyridines are well-known
compounds as a consequence of their pharmacological profile as
the most important calcium channel modulators.21,22 For example,
amlodipine besylate, nifedipine, and related dihydropyridines are
Ca2þ channel blockers, are rapidly emerging as one of the most
important classes of drugs for the treatment of cardiovascular
diseases including hypertension.
* Corresponding author. Tel.: þ98 21 8800663; fax: þ98 21 88006544; e-mail
addresses: abdol_alizad@yahoo.com, aalizadeh@modares.ac.ir.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.032

3520
A. Alizadeh, J. Mokhtari / Tetrahedron 67 (2011) 3519e3523
Table 2
The preparation of new 1,4-dihydropyridines with special
Synthetic results of spiro[indoline-3,40-pyridine]-30-carboxylate 3ael via four-
component reaction
properties is an active and attractive ongoing interdisciplinary re-
search area. Herein, as a part of our research program, which aims
to develop libraries of the aforementioned bioactive compounds,
and in a continuation of our interest in one-pot and multicompo-
nent reactions (MCRs),23 we now report a four-component reaction
Entry
R
R0
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
PhCH2
PhCH2
CO2Me
CO2Et
CO2Me
CO2Et
CO2Me
CO2Et
CO2Me
CO2Et
CO2Me
CO2Et
Me
2
3
3
3
2
3
2
3
4
4
6
5
12
12
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
80
84
81
78
85
82
79
74
79
81
78
80
d
p-ClC6H4CH2
p-ClC6H4CH2
o-ClC6H4CH2
o-ClC6H4CH2
p-MeC6H4CH2
p-MeC6H4CH2
Propyl
iso-Butyl
PhCH2
p-MeOC6H5
PhCH2
Allyl
of isatin, 1-phenyl-2-(1,1,1-triphenyl-l
5-phosphanylidene)-1-etha-
none, and amine 1 in the presence of 1,3-dicarbonyl compound 2 in
dry methanol at reflux to afford a series of spirooxindole derivatives
3 containing indoline-3,40-pyridine-30-carboxylate fragments in
74e85% yields (Table 1).
9
10
11
12
13
14
Table 1
CO2Me
Ph
Ph
Synthetic results of 3a under different reactions conditions
Entry
Solvent
Temp/ꢁC
Time/h
Isolated
yield (%)
d
1
2
3
4
5
Methanol
Ethanol
Acetonitrile
THF
Reflux
Reflux
Reflux
Reflux
Reflux
3
3
5
6
6
80
72
64
48
12
CH2, CH, and NH groups (
d
¼2.43, 3.35, 4.52, 5.05, and 8.36 ppm),
and the aromatic moieties gave rise to multiplets in the aromatic
Dichloromethane
region of the spectrum (
NMR spectrum of 3a showed 23 distinct resonances in agreement
with the suggested structure.
d
¼6.87e6.93 ppm). The 1H-decoupled 13C
2. Results and discussion
Although we have not established the mechanism of the
reaction experimentally, a possible explanation is proposed in
Scheme 2. Compound 3 could result from the initial addition of the
benzylamine to alkyl acetoacetate and subsequent attack of the
resulting reactive enaminone 5 on the compound 4 to yield in-
termediate 6. Cyclization of the intermediate 6 and subsequent loss
of H2O leads to compound 3.
The choice of an appropriate reaction medium is of crucial
importance for successful synthesis. Initially, the four-component
reaction ofisatin,1-phenyl-2-(1,1,1-triphenyl-l
5-phosphanylidene)-
1-ethanone, benzylamine, and methyl acetoacetate as a simple
model substrate was investigated to establish the feasibility of the
strategy and to optimize the reaction conditions (Scheme 1).
R
N
Me
O
O
Ph3P
R'
R-NH2
R'
O
O
+
N
O
Ph
H
N
H
1
2
3
Scheme 1. Synthesis of spiro[indoline-3,40-pyridine]-30-carboxylate derivatives.
O
Different solvents, such as methanol, ethanol, acetonitrile, tet-
rahydrofuran (THF), and dichloromethane were explored. The re-
sults are summarized in Table 1. As can be seen from Table 1, the
best results were obtained by heating the reaction mixture in
methanol at reflux, which yielded product 3a in high yield (Table 1,
entry 1).
O
O
Ph
Wittig reaction
-Ph3PO
Ph
O
+
O
PPh3
O
N
N
H
H
4
Encouraged by this success, we investigated the scope of the
reaction of isatin, 1-phenyl-2-(1,1,1-triphenyl-l
5-phosphanyli-
O
R
H
-H2O
OR
N
O
dene)-1-ethanone, amines 1, and 1,3-dicarbonyl compound 2. The
corresponding spiro[indoline-3,40-pyridine]-30-carboxylates 3ael
were synthesized in high yields (74e85%), and the results are
summarized in Table 2. It can be seen from Table 2 that the nature
of the aryl substituent in the benzylamines had no significant effect
on the final yield of the products. It was found that the reaction
with 1-phenylpropan-2-one does not occur (entries 13 and 14).
The structures of compounds 3ael were deduced from their
elemental analysis, mass, IR, and high-field 1H and 13C NMR spectra.
The mass spectrum of 3a displayed the molecular ion peak at m/z
436, which is in agreement with the proposed structure. The IR
spectrum of this compound showed absorption bands due to the
R-NH2
+
Me
Me
OR
1
2
5
R
NH
O
Me
R'
-H2O
Ph
O
4
5
3
+
N
H
one NH group at 3172 cmꢀ1 and the carbonyl groups at 1702 cmꢀ1
The 1H NMR spectrum of 3a showed five sharp singlets for 2CH3,
.
6
Scheme 2. Proposed mechanism.

A. Alizadeh, J. Mokhtari / Tetrahedron 67 (2011) 3519e3523
3521
3. Conclusion
47.5 (OCH2), 58.4 (Cspiro2), 108.7 (CH), 109.7 (C]CMe), 114.3 (CH of
Ar), 121.3 (CH of Ar), 122.4 (CH of Ar), 125.2 (4CH of Ar), 126.7 (2CH
of Ar), 126.9 (CH of Ar), 128.1 (CH of Ar), 128.4 (2CH of Ar), 130.2 (CH
of Ar), 131.2 (Cipso), 131.4 (C]CH), 135.80 (Cipso), 137.0 (Cipso), 137.1
(CeMe), 141.1 (Cipso), 164.3 (NC]O), 178.0 ppm (C]O).
In conclusion, an efficient, clean, and simple method for the prep-
aration of spiro[indoline-3,40-pyridine]-30-carboxylate derivatives us-
ing readily available starting materials is reported. These types of
heterocycles contain a number of functional groups that may be lead
to the biological activity of the title compounds. The reaction pro-
ceeds under neutral conditions with no bases or catalysts in high
yield and simple purification of the products are the advantages of
our work. The simplicity of the present procedure makes it an in-
teresting alternative to the complex multistep approaches.
4.2.3. Methyl
10-(4-chlorobenzyl)-20-methyl-2-oxo-60-phenyl-10H-
spiro[indoline-3,40-pyridine]-30-carboxylate (3c). White powder,
mp¼186e189 ꢁC, 0.38 g, yield 81%. IR (KBr) (nmax, cmꢀ1): 3186 (NH),
1702 (C]O), 1462 (Ar). Anal. Calcd for C28H23ClN2O3(470.95): C,
71.41; H, 4.92; N, 5.95%. Found: C, 71.35; H, 4.88; N, 5.93%. MS (EI,
70 eV): m/z (%)¼470 (Mþ, 8), 438 (58), 313 (95), 154 (16), 125 (79),
83 (100), 61 (16). 1H NMR (500.13 MHz, CDCl3): dH¼2.43 (3H, s,
CH3), 3.34 (3H, s, CH3), 4.49 (1H, s, CH), 5.00 (2H, s, CH2N),
6.83e7.35 (13H, m, 13CH of Ar), 8.73 (1H, s, NH). 13C NMR
(125.75 MHz, CDCl3): dC¼11.2 (CH3), 45.2 (CH2N), 46.5 (OCH3), 49.2
(Cspiro2), 108.5 (CH), 109.6 (C]CMe), 114.7 (CH of Ar), 121.3 (CH of
Ar), 122.4 (CH of Ar), 126.5 (4CH of Ar), 126.8 (CH of Ar), 128.3 (2CH
of Ar), 128.6 (2CH of Ar), 130.0 (CH of Ar), 130.8 (Cipso), 130.9 (Cipso),
132.8 (C]CH), 135.4 (Cipso), 135.7 (Cipso), 136.9 (CeMe), 140.9 (Cipso),
164.6 (NC]O), 179.8 ppm (C]O).
4. Experimental
4.1. General
Melting points were measured on an Electrothermal 9100
apparatus. Elemental analyses for C, H, and N were performed using
a Heraeus CHNeO-Rapid analyzer. IR spectra were recorded on
a Shimadzu IR-460 spectrometer. Mass spectra were recorded on
a FINNIGAN-MAT 8430 mass spectrometer operating at an ioniza-
tion potential of 70 eV. 1H and 13C NMR spectra were recorded at
500.1 and 125.7 MHz, respectively, on a BRUKER DRX 500-AVANCE
FT-NMR instrument with DMSO-d6 as a solvent. The reagents and
solvents were obtained from Fluka (Buchs, Switzerland) and used
without further purification.
4.2.4. Ethyl 10-(4-chlorobenzyl)-20-methyl-2-oxo-60-phenyl-10H-spiro
[indoline-3,40-pyridine]-30-carboxylate (3d). White powder, mp¼
168e170 ꢁC, 0.38 g, yield 78%. IR (KBr) (nmax, cmꢀ1): 3178 (NH), 1699
(C]O), 1465 (Ar). Anal. Calcd for C29H25ClN2O3 (484.98): C, 71.82; H,
5.20; N, 5.78. Found: C, 71.78; H, 5.17; N, 5.76%. MS (EI, 70 eV): m/z
(%)¼484 (Mþ, 8), 438 (70), 313 (100), 154 (16), 125 (91), 105 (16), 89
(20). 1H NMR (500.13 MHz, CDCl3): dH¼0.95 (3H, t, 3JHH¼7.0 Hz, CH3),
2.44 (3H, s, CH3), 3.92 (2H, q, 3JHH¼3.8 Hz, CH2), 4.50 (1H, s, CH), 5.00
4.2. General procedure for the preparation of compounds
3ael, exemplified by 3a
A solution of 1-phenyl-2-(1,1,1-triphenyl-
l
5-phosphanylidene)-
(2H, s, CH2N), 6.84e7.51 (13H, m, 13CH of Ar), 8.35 (1H, s, NH). 13
C
1-ethanone (0.38 g, 1 mmol) and isatin (0.15 g, 1 mmol) was mag-
netically stirred in MeOH (3 mL) for 20 min. Then, benzylamine
(0.11 g, 1 mmol) and alkyl acetoacetate (1.2 mmol) were added
simultaneously. The reaction mixture was stirred for 3 h under
reflux conditions and the progress of the reaction was followed by
thin layer chromatography. After completion, the solvent was re-
moved under reduced pressure and the residue was purified by
column chromatography (n-hexane/EtOAc, 3:1).
NMR (125.75 MHz, CDCl3): dC¼11.4 (CH3), 13.6 (CH3), 45.2 (CH2N),
46.9 (OCH2), 58.5 (Cspiro2), 108.5 (CH), 110.0 (C]CMe), 114.6 (CH of
Ar), 121.4 (CH of Ar), 122.4 (CH of Ar), 126.6 (4CH of Ar), 126.7 (CH of
Ar),128.2 (2CH of Ar),128.5 (2CH of Ar),130.0 (CH of Ar),130.8 (Cipso),
131.0 (C]CH), 132.7 (Cipso), 135.4 (Cipso), 135.7 (Cipso), 136.7 (CeMe),
140.9 (Cipso), 164.2 (NC]O), 179.3 ppm (C]O).
4.2.5. Methyl 10-(2-chlorobenzyl)-20-methyl-2-oxo-60-phenyl-10H-
spiro[indoline-3,40-pyridine]-30-carboxylate (3e). White powder,
mp¼192e195 ꢁC, 0.40 g, yield 85%. IR (KBr) (nmax, cmꢀ1): 3205
(NH), 1702 (C]O), 1441 (Ar). Anal. Calcd for C28H23ClN2O3(470.95):
C, 71.41; H, 4.92; N, 5.95%. Found: C, 71.38; H, 4.85; N, 5.91%. MS (EI,
70 eV): m/z (%)¼470 (Mþ, 8), 438 (75), 313 (100), 296 (12), 154 (16),
125 (83), 105 (12), 89 (25), 71 (12). 1H NMR (500.13 MHz, CDCl3):
dH¼2.40 (3H, s, CH3), 3.36 (3H, s, CH3), 4.53 (1H, s, CH), 5.07 (2H, s,
CH2N), 6.63 (1H, d, 3JHH¼7.2 Hz, CH of Ar), 6.88 (1H, d, 3JHH¼7.6 Hz,
4.2.1. Methyl 10-benzyl-20-methyl-2-oxo-60-phenyl-10H-spiro[indoline-
3,40-pyridine]-30-carboxylate (3a). White powder, mp¼218e221 ꢁC,
0.35 g, yield 80%. IR (KBr) (nmax, cmꢀ1): 3172 (NH), 1702 (C]O), 1455
(Ar). Anal. Calcd for C28H24N2O3 (436.51): C, 77.05; H, 5.54; N, 6.42%.
Found: C, 76.8; H, 5.51; N, 6.38%. MS (EI, 70 eV): m/z (%)¼438 (Mþ, 4),
404 (75), 313 (87), 296 (12), 154 (15), 91 (100), 69 (32), 57 (41). 1H
NMR (500.13 MHz, CDCl3): dH¼2.43 (3H, s, CH3), 3.35 (3H, s, CH3),
4.52 (1H, s, CH), 5.05 (2H, s, CH2N), 6.87e6.93 (5H, m, 5CH of Ar),
7.14e7.16 (1H, m, CH of Ar), 7.25e7.34 (8H, m, 5CH of Ar), 8.36 (1H, s,
NH). 13C NMR (125.75 MHz, CDCl3): dC¼11.3 (CH3), 45.1 (CH2N), 47.5
(OCH3), 49.17 (Cspiro2), 108.4 (CH), 109.4 (C]CMe), 114.4 (CH of Ar),
121.1 (CH of Ar), 122.3 (CH of Ar), 125.2 (4CH of Ar), 126.7 (CH of Ar),
126.8 (CH of Ar), 128.1 (CH of Ar), 128.3 (2CH of Ar), 130.5 (CH of Ar),
131.1 (Cipso), 131.3 (C]CH), 135.8 (Cipso), 136.9 (Cipso), 137.1 (CeMe),
140.8 (Cipso), 164.6 (NC]O), 179.6 ppm (C]O).
3
CH of Ar), 6.94 (2H, t, JHH¼6.2 Hz, 2CH of Ar), 7.15 (2H, t,
3JHH¼6.2 Hz, 2CH of Ar), 7.22e7.36 (7H, m, 7CH of Ar), 8.29 (1H, s, NH).
13C NMR (125.75 MHz, CDCl3): dC¼11.0 (CH3), 45.1 (CH2N), 45.4
(OCH3), 49.2 (Cspiro2),108.4 (CH),109.7 (C]CMe), 114.8 (CH of Ar), 121.5
(CHofAr),122.5(CHofAr),126.3(4CHofAr),126.8(CHofAr),127.0(CH
of Ar), 128.1 (CH of Ar), 128.3 (CH of Ar), 128.9 (CH of Ar), 129.8 (CH of
Ar), 130.7 (Cipso), 131.2 (Cipso), 131.3 (C]CH), 134.5 (Cipso), 135.8 (Cipso),
137.0 (CeMe), 140.8 (Cipso), 164.6 (NC]O), 179.4 ppm (C]O).
4.2.2. Ethyl 10-benzyl-20-methyl-2-oxo-60-phenyl-10H-spiro[indoline-
3,40-pyridine]-30-carboxylate (3b). White powder, mp¼210e214 ꢁC,
0.38 g, yield 84%. IR (KBr) (nmax, cmꢀ1): 3183 (NH), 1700 (C]O),
1461 (Ar). Anal. Calcd for C29H26N2O3 (450.53): C, 77.31; H, 5.82; N,
6.22%. Found: C, 77.27; H, 5.76; N, 6.17%. MS (EI, 70 eV): m/z (%)¼
450 (Mþ, 4), 404 (29), 313 (45), 220 (16), 105 (50), 91 (75), 69 (100),
55 (79). 1H NMR (500.13 MHz, CDCl3): dH¼0.94 (3H, t, 3JHH¼6.8 Hz,
CH3), 2.45 (3H, s, CH3), 3.88e3.92 (2H, m, CH2), 4.53 (1H, s, CH), 5.05
4.2.6. Ethyl 10-(2-chlorobenzyl)-20-methyl-2-oxo-60-phenyl-10H-spiro
[indoline-3,40-pyridine]-30-carboxylate (3f). White powder, mp¼
208e211 ꢁC, 0.39 g, yield 82%. IR (KBr) (nmax, cmꢀ1): 3168 (NH), 1703
(C]O), 1448 (Ar). Anal. Calcd for C29H25ClN2O3 (484.98): C, 71.82; H,
5.20; N, 5.78. Found: C, 71.76; H, 5.15; N, 5.77%. MS (EI, 70 eV): m/z
(%)¼484 (Mþ, 8), 438 (91), 411 (8), 313 (100), 296 (12), 125 (95), 89
3
(25). 1H NMR (500.13 MHz, CDCl3): dH¼0.96 (3H, t, JHH¼7.05 Hz,
3
CH3), 2.41 (3H, s, CH3), 3.92 (2H, q, JHH¼6.80 Hz, CH2), 4.53 (1H, s,
(2H, s, CH2N), 6.89e7.55 (14H, m, 14CH of Ar), 8.90 (1H, s, NH). 13
NMR (125.75 MHz, CDCl3): dC¼11.4 (CH3), 13.6 (CH3), 45.4 (CH2N),
C
CH), 5.07 (2H, s, CH2N), 6.66 (1H, d, 3JHH¼7.3 Hz, CH of Ar), 6.88 (1H,
3
3
d, JHH¼7.6 Hz, CH of Ar), 6.94 (2H, d, JHH¼4.2 Hz, 2CH of Ar),

3522
A. Alizadeh, J. Mokhtari / Tetrahedron 67 (2011) 3519e3523
7.14e7.36 (9H, m, 9CH of Ar), 8.45 (1H, s, NH). 13C NMR (125.75 MHz,
CDCl3): dC¼11.2 (CH3), 13.6 (CH3), 45.2 (CH2N), 52.9 (OCH2), 58.5
(Cspiro2), 108.6 (CH), 110.0 (C]CMe), 114.6 (CH of Ar), 121.4 (CH of Ar),
122.4 (CH of Ar), 126.3 (4CH of Ar), 126.7 (CH of Ar), 127.0 (CH of Ar),
128.1 (CH of Ar), 128.3 (CH of Ar), 128.9 (CH of Ar), 129.8 (CH of Ar),
130.6 (Cipso), 131.2 (Cipso), 131.3 (C]CH), 134.5 (Cipso), 135.8 (Cipso),
136.9 (CeMe), 140.9 (Cipso), 164.2 (NC]O), 179.5 ppm (C]O).
CH3), 0.71 (3H, d, 3JHH¼2.5 Hz, CH3), 0.92 (3H, t, 3JHH¼7.05 Hz, CH3),
3
1.75e1.80 (1H, m, CH), 2.56 (3H, s, CH3), 3.68 (2H, d, JHH¼7.1 Hz,
NCH2), 3.87 (2H, q, 3JHH¼6.9, 14.0 Hz, CH2), 4.42 (1H, s, CH), 6.85e6.92
(3H, m, 3CH of Ar), 7.11e7.51 (6H, m, 6CH of Ar), 8.50 (1H, s, NH). 13C
NMR (125.75 MHz, CDCl3): dC¼12.62 (CH3), 14.08 (CH3), 19.88 (CH3),
19.92(CH3), 29.32(CH(CH3)2), 45.66 (CH2), 51.41 (NCH2), 58.73 (Cspiro2),
108.95 (CH), 109.56 (C]CMe), 114.61 (CH of Ar), 121.77 (CH of Ar),
122.90 (CH of Ar),127.07 (2CH of Ar),128.35 (2CH of Ar),128.78 (Cipso),
131.75 (CH of Ar), 132.04 (CH of Ar), 135.84 (C]CH), 137.39 (Cipso),
137.03 (CeMe), 144.93 (Cipso), 164.82 (NC]O), 179.48 ppm (C]O).
4.2.7. Methyl 20-methyl-10-(4-methylbenzyl)-2-oxo-60-phenyl-10H-
spiro[indoline-3,40-pyridine]-30-carboxylate (3g). White powder,
mp¼201e203 ꢁC, 0.36 g, yield 79%. IR (KBr) (nmax, cmꢀ1): 3189 (NH),
1699 (C]O),1456 (Ar). Anal. Calcd for C29H26N2O3 (450.53): C, 77.31;
H, 5.82; N, 6.22%. Found: C, 77.23; H, 5.78; N, 6.15%. MS (EI, 70 eV): m/
z (%)¼450 (Mþ, 8), 418 (70), 313 (100), 285 (8), 105 (54), 77 (12). 1H
NMR (500.13 MHz, CDCl3): dH¼2.35 (3H, s, CH3), 2.45 (3H, s, CH3),
3.35 (3H, s, CH3), 4.54 (1H, s, CH), 5.02 (2H, s, CH2), 6.83 (2H, d,
3JHH¼7.7 Hz, 2CH of Ar), 6.92e6.94 (3H, m, 3CH of Ar), 7.14 (2H, d,
3JHH¼7.7 Hz, 2CH of Ar), 7.17 (1H, m, CH of Ar) 7.35 (3H, m, 3CH of Ar),
7.59 (1H, m, CH ofAr), 9.32(1H, s, NH).13C NMR(125.75 MHz, CDCl3):
dC¼11.8 (CH3), 21.1 (CH3), 45.9 (CH2N), 47.8 (OCH3), 50.8 (Cspiro2),
109.2 (CH), 109.9 (C]CMe), 114.9 (CH of Ar), 121.9 (CH of Ar), 122.9
(CH of Ar),125.6 (4CH of Ar),127.2 (CH of Ar),128.6 (2CH of Ar),129.5
(2CH of Ar),130.7 (CH of Ar),131.3 (Cipso),131.7 (Cipso),134.4 (C]CH),
136.3 (Cipso), 137.0 (Cipso), 137.8 (CeMe), 141.7 (Cipso), 165.2 (NC]O),
180.9 ppm (C]O).
4.2.11. 30-Acetyl-10-benzyl-20-methyl-60-phenyl-10H-spiro[indoline-
3,40-pyridin]-2-one (5k). White powder, mp¼204e206 ꢁC, 0.33 g,
yield 78%. IR (KBr) (nmax, cmꢀ1): 3266 (NH), 1710 (C]O), 1625 (C]
O), 1418 (Ar). Anal. Calcd for C28H24N2O2 (420.51): C, 79.98; H, 5.75;
N, 6.66%. Found: C, 79.91; H, 5.68; N, 6.62%. MS (EI, 70 eV): m/z (%)¼
420 (Mþ, 4), 199 (20), 183 (16), 118 (25), 84 (100), 51 (65). 1H NMR
(500.13 MHz, CDCl3): dH¼2.28 (3H, s, CH3), 2.41 (3H, s, CH3), 4.46
(1H, s, CH), 5.07 (2H, s, CH2N), 6.88e6.95 (5H, m, 5CH of Ar),
7.28e7.69 (9H, m, 9CH of Ar), 7.71 (1H, s, NH). 13C NMR
(125.75 MHz, CDCl3): dC¼13.39 (CH3), 30.58 (CH3), 45.52 (NCH2),
52.82 (Cspiro2), 108.98 (CH), 121.55 (CH of Ar), 122.47 (CH of Ar),
125.58 (4CH of Ar), 127.18 (CH of Ar), 127.43 (CH of Ar), 128.41 (2CH
of Ar), 128.51 (2CH of Ar), 128.70 (Cipso), 128.91 (2CH of Ar), 130.48
(Cipso), 131.87 (CeMe), 131.89 (C]CH), 132.04 (Cipso), 132.12 (Cipso),
137.33 (Cipso), 165.14 (NC]O), 180. 18 ppm (C]O).
4.2.8. Ethyl 20-methyl-10-(4-methylbenzyl)-2-oxo-60-phenyl-10H-
spiro[indoline-3,40-pyridine]-30-carboxylate (3h). White powder,
mp¼214e216 ꢁC, 0.34 g, yield 74%. IR (KBr) (nmax, cmꢀ1): 3167
(NH), 1700 (C]O), 1452 (Ar). Anal. Calcd for C30H28N2O3 (464.56):
C, 77.56; H, 6.07; N, 6.03%. Found: C, 77.52; H, 6.03, N, 6.01%. MS
(EI, 70 eV): m/z (%)¼464 (Mþ, 12), 418 (100), 391 (4), 313 (83), 296
(8), 105 (58), 77 (8). 1H NMR (500.13 MHz, CDCl3): dH¼0.94 (3H, t,
3JHH¼6.8 Hz, CH3), 2.35 (3H, s, CH3), 2.34 (3H, s, CH3), 3.88e3.95
(2H, m, OCH2), 4.52 (1H, s, CH), 5.00 (2H, s, CH2N), 6.82e7.34 (13H,
m, 13CH of Ar), 8.63 (1H, s, NH). 13C NMR (125.75 MHz, CDCl3):
dC¼11.5 (CH3), 13.6 (CH3), 20.5 (CH3), 43.7 (CH2), 47.3 (OCH2), 58.4
(Cspiro2), 108.6 (CH), 109.7 (C]CMe), 114.2 (CH of Ar), 121.3 (CH of
Ar), 122.5 (CH of Ar), 125.1 (4CH of Ar), 126.7 (CH of Ar), 128.1 (2CH
of Ar), 129.0 (2CH of Ar), 130.4 (CH of Ar), 130.9 (Cipso), 131.2 (Cipso),
133.9 (C]CH), 135.8 (Cipso), 136.5 (Cipso), 137.1 (CeMe), 140.9
(Cipso), 164.3 (NC]O), 179.7 ppm (C]O).
4.2.12. Methyl
10-(4-methoxyphenyl)-20-methyl-2-oxo-60-phenyl-
10H-spiro[indoline-3,40-pyridine]-30-carboxylate (5l). White powder,
mp¼254e256 ꢁC, 0.35 g, yield 80%. IR (KBr) (nmax, cmꢀ1): 3170
(NH),1703 (C]O),1508 (Ar). Anal. Calcd for C27H22N2O3 (452.51): C,
74.32; H, 5.35; N, 6.19%. Found: C, 74. 68; H, 5.20; N, 6.17%. MS (EI,
70 eV): m/z (%)¼452 (Mþ, 4), 420 (25), 391 (8), 313 (10), 216 (12),
127 (15), 108 (46), 92 (75), 77 (100). 1H NMR (500.13 MHz, CDCl3):
dH¼2.34 (3H, s, CH3), 3.37 (3H, s, CH3), 3.79 (3H, s, CH3), 4.66 (1H, s,
CH), 6.79e6.98 (5H, m, 5CH of Ar), 7.14e7.28 (8H, m, 8CH of Ar),
8.40 (1H, s, NH). 13C NMR (125.75 MHz, CDCl3): dC¼12.77 (CH3),
45.62 (CH3), 49.77 (OCH3), 53.39 (Cspiro2), 108.91 (CH), 109.99 (C]
CMe), 114.10 (2CH of Ar), 121.97 (CH of Ar), 123.16 (CH of Ar), 127.23
(2CH of Ar), 127.65 (CH of Ar), 128.17 (2CH of Ar), 129.46 (CH of Ar),
129.82 (CH of Ar),130.43 (C]CH), 130.88 (Cipso), 131.01 (2CH of Ar),
131.55 (CeMe), 136.48 (Cipso), 138.62 (Cipso), 141.28 (Cipso), 159.01
(CeOMe),165.24 (NC]O), 180.22 ppm (C]O).
4.2.9. Methyl 20-methyl-2-oxo-60-phenyl-10-propyl-10H-spiro[indoline-
3,40-pyridine]-30-carboxylate (5i). White powder, mp¼212e214 ꢁC,
0.31 g, yield 79%. IR (KBr) (nmax, cmꢀ1): 3162 (NH), 2932 (CH), 1697
(C]O), 1469 (Ar). Anal. Calcd for C24H24N2O3 (388.46): C, 74.21; H,
6.23; N, 7.21%. Found: C, 74.16; H, 6.20, N, 7.12%. MS (EI, 70 eV): m/z
(%)¼388 (Mþ, 8), 356 (45), 313 (24), 296 (8),149 (35), 77 (64), 57 (100).1H
NMR (500.13 MHz, CDCl3): dH¼0.77 (3H, t, 3JHH¼7.3 Hz, CH3), 1.55e1.59
(2H, m, CH2), 2.53 (3H, s, CH3), 3.31 (3H, s, CH3), 3.72e3.75 (2H, m, NCH2),
4.41 (1H, s, CH), 6.86e6.91 (3H, m, 3CH of Ar), 7.10e7.56 (6H, m, 6CH of
Ar), 8.93 (1H, s, NH).13CNMR(125.75 MHz,CDCl3): dC¼11.09 (CH3),11.62
(CH3), 23.92 (CH2), 43.73 (CH2), 45.66 (NCH2), 46.06 (CH3), 49.47 (Cspiro2),
108.98 (CH),109.19 (C]CMe),114.62 (CH of Ar),121.80 (CH of Ar),122.94
(CH of Ar),127.10 (2CH of Ar),128.51 (2CH of Ar),131.07 (CH of Ar),131.66
(Cipso), 131.95 (CH of Ar), 135.50 (C]CH), 137.03 (Cipso), 137.03 (CeMe),
141.43 (Cipso), 165.21 (NC]O), 179.87 ppm (C]O).
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.03.032. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
References and notes
€
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3
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