Three-component condensation for the construction of novel spirooxindoles

Article abstract of DOI:10.1055/s-0032-1316836

A new route for the synthesis of novel spirooxindoles from isocyanides, dialkyl acetylenedicarboxylates, and N-substituted isatylidene derivatives through [3+2] cycloaddition has been developed. This method has several advantages, such as high regioselectivity, high yields, readily available starting materials, and one-pot operations. The synthetic alkyne-containing spirooxindoles could also be used in the selective synthesis of triazole-containing-spirocyclic compounds using a copper azide-alkyne cycloaddition-(CuAAC) reaction. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316836

PAPER
▌375
paper
Three-Component Condensation for the Construction of Novel Spirooxindoles
Novel Spirooxindoles
Fei Ji, Mu Sun, Mei-fang Lv, Wen-bin Yi, Chun Cai*
Chemical Engineering College, Nanjing University of Science and Technology, Nanjing 210094, P. R. of China
Fax +86(25)84315030; E-mail: c.cai@mail.njust.edu.cn
Received: 13.11.2012; Accepted after revision: 05.12.2012
erocyclic synthesis.4 Of special interest in this area are re-
Abstract: A new route for the synthesis of novel spirooxindoles
actions between isocyanides and activated alkynes. It has
from isocyanides, dialkyl acetylenedicarboxylates, and N-substitut-
been shown that the addition of isocyanides to electron-
withdrawing alkynes, such as dialkyl acetylenedicarbox-
ed isatylidene derivatives through [3+2] cycloaddition has been de-
veloped. This method has several advantages, such as high
regioselectivity, high yields, readily available starting materials, ylates, generates zwitterionic intermediates. The active
and one-pot operations. The synthetic alkyne-containing spirooxin-
doles could also be used in the selective synthesis of triazole-
containing spirocyclic compounds using a copper azide–alkyne
tive methylene-containing compounds,9 to form heterocy-
cycloaddition (CuAAC) reaction.
intermediates could be trapped by a third component, e.g.
aldehydes,5 amides,6 oximes,7 carboxylic acids,8 and ac-
cles. Recently, multicomponent reactions involving isatin
derivatives, dialkyl acetylenedicarboxylates, and isocya-
nides have attracted the interest of many researchers. In
Key words: multicomponent reaction, spirooxindoles, [3+2] cy-
cloaddition, CuAAC reaction, triazoles
2003, Esmaeili and co-workers reported that the treatment
of isocyanides and dialkyl acetylenedicarboxylates with
Spirooxindoles are attractive targets in organic synthesis
N-substituted isatin derivatives led to the efficient synthe-
sis of novel γ-spiro-iminolactones (Scheme 1).10 Later,
Sabbaghan and co-workers used N-unsubstituted isatins
to obtain 1-(3-furyl)-1H-indole-2,3-diones in excellent
yields (Scheme 1).11
because of their high pronounced biological activity as
well as their wide utility as synthetic intermediates for al-
kaloids, medical candidates, and clinical pharmaceuticals
(Figure 1).1 Research focused on the synthesis of these
compounds is, therefore, of interest in organic synthesis,
and numerous successful examples of the synthesis of di-
versely structured spirooxindoles have been recorded in
recent years.2
In views of these previous results, we envisaged that a
novel multicomponent reaction based on the above [3+2]
cycloaddition could be accessed if N-substituted isatyli-
denes were employed as substrates instead of isatin deriv-
atives. To our satisfaction, we found that three-component
condensation of N-substituted isatylidenes, dialkyl acetyl-
enedicarboxylates, and isocyanides proceeded smoothly,
giving the desired products in excellent yields (Scheme
1).
Et
N
Me
N
O
O
N
H
Initial studies focused on the optimization of the three-
component reaction of N-substituted isatylidenes (R1 =
R2 = CN) (0.5 mmol), diethyl acetylenedicarboxylate (0.6
mmol), and tert-butyl isocyanide (0.6 mmol) for the syn-
thesis of 1 as a model reaction. Various solvents and tem-
peratures were considered (Table 1). It was found that
tetrahydrofuran was the best choice of solvent (cf. entries
1–7 with 8–10) and that higher temperatures could in-
crease the yield efficiently (cf. entry 10 with 8 and 9). At
the same time, this reaction did not require a catalyst and
proceeded to give 1 in high yield.
NH
Cl
O
N
horsfiline
CRF receptor antagonists
Figure 1 Alkaloids, medical candidates, and clinical pharmaceuti-
cals containing the spirooxindole skeleton
Multicomponent reactions (MCRs) are one of the most
powerful and significant tools in organic synthesis. They
are widely utilized to generate high levels of diversity, be-
cause they allow more than two building blocks to be
combined in a practical, time-saving, and one-pot opera-
tion, affording complex structures by simultaneous for-
mation of two or more bonds.3 Multicomponent reactions
between nucleophiles and activated alkynes have received
much attention from organic chemists, particular for het-
Under the optimized conditions, a variety of N-substituted
isatylidenes, dialkyl acetylenedicarboxylates, and isocya-
nides were employed to evaluate the substrate scope of the
reaction. All of the spirooxindoles 2–14 were obtained in
good yields (Scheme 2). As anticipated, these reactions
proceeded very cleanly under reflux in tetrahydrofuran.
All of the compounds described in this paper are novel.
SYNTHESIS 2013, 45, 0375–0381
Advanced online publication: 21.12.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316836; Art ID: SS-2012-F0884-OP
© Georg Thieme Verlag Stuttgart · New York

376
F. Ji et al.
PAPER
previous work:
O
N
O
COOEt
benzene
N
+
CH2OOEt
O
EtOOC
+
COOEt
O
N
Me
N
Me
O
O
O
N
anhyd Et2O
Ph
PhOC
COPh
+
N
+
O
PhOC
N
H
O
HN
this work:
R1
R6
N
R1
R2
COOR5
R2
THF
R5OOC
COOR5
COOR5
R4
N
R6
+
+
O
reflux
N
R4
O
R3
N
R3
Scheme 1 Comparison of previous work with ours
Table 1 Effect of Solvents and Temperature on the Reactiona
N
NC
CN
COOEt
NC
NC
COOEt
O
EtOOC
COOEt
+
+
O
N
N
N
Bn
Bn
1
Entry
Solvent
Temp (°C)
Yieldb (%)
1
EtOH
78
40
45
56
40
30
45
2
CH2Cl2
toluene
EtOAc
Et2O
3
108
77
4
5
34
c
6
H2O
100
80
–
c
7
PEG400–H2O
THF
–
8
25
62
78
84
9
THF
45
10
THF
65
a Reaction conditions: benzyl isatylidene (0.5 mmol), diethyl acetylenedicarboxylate (0.6 mmol), tert-butyl isocyanide (0.6 mmol), solvent (2
mL), 24 h, sealed tube.
b Isolated yield.
c No reaction.
Synthesis 2013, 45, 375–381
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Spirooxindoles
377
R6
R1
N
COOR5
R2
R1
R2
THF
R5OOC
COOR5
COOR5
N
R6
R4
+
+
O
reflux
N
R4
O
R3
N
R3
N
N
N
NC
NC
COOEt
COOEt
COOEt
NC
NC
NC
NC
COOEt
O
COOEt
COOEt
O
O
N
N
N
Br
Bn
Bn
Bn
3 78%
2 87%
1 84%
N
N
COOEt
N
COOEt
COOEt
NC
NC
NC
NC
NC
NC
COOEt
O
COOEt
O
COOEt
O
N
N
N
Br
Bn
Bn
Bn
6 91%
4 82%
5 90%
N
N
N
COOMe
COOMe
COOMe
NC
NC
NC
NC
NC
NC
COOMe
COOMe
O
COOMe
O
O
N
N
N
Br
Bn
Bn
Bn
9 83%
8 77%
7 85%
N
N
N
COOMe
COOMe
COOMe
NC
NC
NC
NC
NC
NC
COOMe
O
COOMe
O
COOMe
O
N
N
N
Br
Me
12 86%
Me
Me
11 92%
10 72%
N
COOEt
N
NC
EtOOC
COOEt
NC
NC
COOEt
O
COOEt
O
N
N
Bn
13 87%
14 78%
Scheme 2 Synthesized spirooxindoles
To examine the regioselectivity of this [3+2] cycloaddi- The structures of the new spirooxindoles were fully char-
1
tion, methyl propiolate was employed as an unsymmetri- acterized by mass spectrometry, H and 13C NMR spec-
cal alkyne, the yield and regioselectivity of the resultant troscopy, and elemental analysis. The structure of 7 was
product 15 were very good (Scheme 3).
also confirmed by single-crystal X-ray analysis (Figure
2).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 375–381

378
F. Ji et al.
PAPER
N
H
NC
NC
NC
CN
O
THF
COOMe
MeOOC
H
+
N
+
reflux
O
N
N
Bn
Bn
15 72%
Scheme 3 Regioselectively synthesized spirooxindole
medicinal chemistry programs. Thus, we tried to explore
the feasibility of the synthesis of triazole-containing spi-
rooxindoles. With the help of the copper-catalyzed azide–
alkyne cycloaddition (CuAAC),14 the synthetic alkyne-
containing spirooxindoles 13 reacted with an azide to pro-
vide triazole-containing spirooxindoles 16 and 17 in high
yields (Figure 3).
N
NC
NC
N
COOEt
COOEt
NC
NC
COOEt
O
COOEt
O
N
N
Figure 2 Single-crystal X-ray analysis of 7
N
N
N
N
N
N
On the basis of the well-established chemistry of isocya-
nides,12 it is conceivable that the initial event is the forma-
tion of zwitterionic species A from isocyanides and
dialkyl acetylenedicarboxylates. The zwitterionic species
A can add to the electrophilic C=C bond of B resulting in
the formation of C, which then undergoes cyclization to
deliver the final product D. Although less likely, the pos-
sibility of concerted 1,3-dipolar cycloaddition cannot be
dismissed at the present time (Scheme 4).
Cl
16 85%
17 83%
Figure 3 Triazole-containing spirooxindoles synthesized
In conclusion, an efficient, atom-economic, environmen-
tally friendly, and highly regioselective method for the
preparation of the novel spirooxindoles using readily
available starting materials in tetrahydrofuran is reported.
The prominent advantages of this method are operational
simplicity, good yields, no catalyst, and the easy workup
procedure employed. In addition, the further functional-
In addition, triazoles also show some special biological
activity.13 The significant biological activity of spirooxin-
doles and triazoles emphasized the need to develop effi-
cient synthetic strategies to access these scaffolds and
increase the structural diversity for drug discovery and
R1
R2
R6
N
R4
O
COOR5
COOR5
R2
N
R3
B
R6
R1
COOR5
R5OOC
COOR5
N
N
R6
+
R4
O
Michael addition
COOR5
N
R3
C
A
cycloaddition
R6
N
R1
addition–cyclization
COOR5
R2
COOR5
R4
O
N
D
R3
Scheme 4 Possible mechanism for the formation of spirooxindoles
Synthesis 2013, 45, 375–381
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Spirooxindoles
379
Anal. Calcd for C31H29BrN4O5: C, 60.30; H, 4.73; N, 9.07. Found:
C, 60.21; H, 4.56; N, 9.28.
ization of novel spirooxindoles with the CuAAC reaction
also provided efficient methods to prepare libraries of en-
riched spirocyclic compounds.
Diethyl 1′-Benzyl-6′-bromo-5,5-dicyano-4-(cyclohexylimino)-
2′-oxo-1′,2′-dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-di-
carboxylate (4)
All materials were obtained from commercial suppliers and used
without further purification. All melting points are uncorrected.
White solid; yield: 0.263 g (82%); mp 142–144 °C.
1
1H NMR (500 MHz, CDCl3): δ = 0.91 (m, 1 H), 1.01 (m, 2 H), 1.42
(m, 6 H), 1.65 (m, 3 H), 1.86 (m, 4 H), 3.97 (m, 1 H), 4.14 (m, 2 H),
4.83 (m, 2 H), 5.06 (m, 2 H), 7.02 (s, 1 H), 7.34 (m, 7 H).
13C NMR (125 MHz, CDCl3): δ = 12.51, 12.86, 13.10, 22.60, 22.93,
24.33, 31.32, 32.01, 32.48, 39.83, 44.24, 61.58, 61.87, 62.25, 63.04,
109.22, 109.69, 110.45, 112.83, 120.75, 121.31, 124.60, 125.55,
125.74, 126.00, 126.62, 127.34, 128.10, 133.00, 136.12, 139.73,
143.98, 144.64, 148.54, 150.11, 158.98, 160.20, 161.42, 169.09,
169.62.
Mass spectra were taken on Shimadzu LCMS-2020. H and 13C
NMR spectra were recorded at 500 MHz and 125 MHz in CDCl3,
respectively, and referenced to internal TMS. Elemental analyses
were performed on a Yanagimoto MT3CHN recorder.
Dimethyl 1′-Benzyl-4-(tert-butylimino)-5,5-dicyano-2′-oxo-
1′,2′-dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-dicarboxyl-
ate (7); Typical Procedure
To a soln of benzyl isatylidene (0.5 mmol, 1 equiv) and dimethyl
acetylenedicarboxylate (0.6 mmol, 1.2 equiv) in THF (2.5 ml) in a
sealed tube, tert-butyl isocyanide (0.6 mmol, 1.2 equiv) was added.
The mixture was stirred under reflux for 24 h. The solvent was re-
moved under reduced pressure and the residue was purified by flash
column chromatography (silica gel) to give 7.
MS (ESI): m/z = 643 [M + H].
Anal. Calcd for C33H31BrN4O5: C, 61.59; H, 4.86; N, 8.71. Found:
C, 61.78; H, 4.96; N, 8.52.
Diethyl 1′-Benzyl-4-(tert-butylimino)-5,5-dicyano-5′-methyl-2′-
oxo-1′,2′-dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-dicar-
boxylate (5)
Diethyl 1′-Benzyl-4-(tert-butylimino)-5,5-dicyano-2′-oxo-1′,2′-
dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-dicarboxylate (1)
White solid; yield: 0.225 g (84%); mp 170–172 °C.
White solid; yield: 0.249 g (90%); mp 151–153 °C.
1H NMR (500 MHz, CDCl3): δ = 0.85 (m, 3 H), 1.39 (m, 3 H), 1.54
(s, 9 H), 3.87 (m, 1 H), 4.08 (m, 1 H), 4.40 (m, 2 H), 5.03 (m, 2 H),
6.87 (d, J = 8.0 Hz, 1 H), 7.16 (m, 1 H), 7.31 (m, 1 H), 7.37 (m, 3
H), 7.44 (d, J = 18.5 Hz, 2 H), 7.49 (d, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 12.35, 12.99, 29.25, 44.14, 58.91,
61.23, 61.50, 109.36, 110.61, 121.90, 122.66, 124.74, 126.64,
127.08, 127.91, 130.41, 133.54, 142.91, 144.33, 159.34, 161.11,
169.52.
1H NMR (500 MHz, CDCl3): δ = 0.84 (m, 3 H), 1.37 (m, 3 H), 1.52
(s, 9 H), 2.32 (s, 3 H), 3.86 (m, 1 H), 4.07 (m, 1 H), 4.38 (m, 2 H),
4.98 (m, 2 H), 6.73 (d, J = 8.0 Hz, 1 H), 7.14 (m, 1 H), 7.33 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 12.35, 12.96, 20.07, 29.22, 44.09,
58.82, 61.22, 61.50, 109.14, 110.63, 110.72, 121.80, 125.30,
126.59, 127.00, 127.85, 130.74, 132.49, 133.63, 140.44, 144.50,
159.38, 161.16, 169.42.
MS (ESI): m/z = 553 [M + H].
MS (ESI): m/z = 539 [M + H].
Anal. Calcd for C32H32N4O5: C, 69.55; H, 5.84; N, 10.14. Found: C,
69.36; H, 5.64; N, 10.34.
Anal. Calcd for C31H30N4O5: C, 69.13; H, 5.61; N, 10.40. Found: C,
69.04; H, 5.81; N, 10.20.
Diethyl 1′-Benzyl-5,5-dicyano-4-(cyclohexylimino)-5′-methyl-
2′-oxo-1′,2′-dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-di-
carboxylate (6)
Diethyl 1′-Benzyl-5,5-dicyano-4-(cyclohexylimino)-2′-oxo-1′,2′-
dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-dicarboxylate (2)
White solid; yield: 0.245 g (87%); mp 150–152 °C.
White solid; yield: 0.263 g (91%); mp 115–117 °C.
1H NMR (500 MHz, CDCl3): δ = 0.76 (m, 1 H), 0.87 (m, 2 H), 1.26
(m, 1 H), 1.36 (m, 5 H), 1.62 (m, 3 H), 1.81 (m, 4 H), 3.85 (m, 1 H),
4.04 (m, 2 H), 4.40 (m, 2 H), 4.98 (m, 2 H), 6.85 (d, J = 16.0 Hz, 1
H), 7.11 (m, 1 H), 7.33 (m, 1 H), 7.37 (m, 4 H), 7.40 (m, 2 H).
1H NMR (500 MHz, CDCl3): δ = 0.83 (m, 1 H), 0.94 (m, 2 H), 1.42
(m, 6 H), 1.67 (m, 2 H), 1.85 (m, 5 H), 2.33 (s, 3 H), 3.91 (m, 1 H),
4.09 (m, 2 H), 4.43 (m, 2 H), 5.04 (m, 2 H), 6.76 (d, J = 8.0 Hz, 1
H), 7.17 (m, 2 H), 7.35 (m, 5 H).
13C NMR (125 MHz, CDCl3): δ = 12.38, 12.83, 13.06, 22.59, 22.92,
24.29, 31.30, 31.98, 32.45, 38.86, 39.03, 39.20, 40.09, 44.06, 61.33,
61.51, 61.77, 62.19, 62.88, 109.38, 122.32, 122.57, 122.70, 124.55,
126.65, 127.10, 127.92, 130.51, 133.53, 140.46, 142.66, 144.37,
148.83, 158.97, 160.33, 169.14, 169.08.
13C NMR (125 MHz, CDCl3): δ = 12.34, 12.44, 12.86, 13.09, 20.07,
22.63, 22.97, 24.35, 31.34, 32.00, 32.48, 40.19, 44.09, 61.33, 61.51,
61.77, 62.17, 62.87, 109.15, 109.40, 109.51, 121.75, 122.37,
125.21, 125.47, 126.67, 127.05, 127.90, 130.84, 132.40, 133.70,
135.85, 140.25, 140.41, 144.60, 149.01, 150.59, 159.09, 160.45,
161.62, 169.11, 169.65.
MS (ESI): m/z = 565 [M + H].
MS (ESI): m/z = 579 [M + H].
Anal. Calcd for C33H32N4O5: C, 70.20; H, 5.71; N, 9.92. Found: C,
70.10; H, 5.52; N, 9.86.
Anal. Calcd for C34H34N4O5: C, 70.57; H, 5.92; N, 9.68. Found: C,
70.38; H, 5.71; N, 9.89.
Diethyl 1′-Benzyl-6′-bromo-4-(tert-butylimino)-5,5-dicyano-2′-
oxo-1′,2′-dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-dicar-
boxylate (3)
Dimethyl 1′-Benzyl-4-(tert-butylimino)-5,5-dicyano-2′-oxo-
1′,2′-dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-dicarboxyl-
ate (7)
White solid; yield: 0.240 g (78%); mp 118–120 °C.
1H NMR (500 MHz, CDCl3): δ = 0.94 (m, 3 H), 1.39 (m, 3 H), 1.54
(s, 9 H), 3.93 (m, 1 H), 4.11 (m, 1 H), 4.40 (m, 2 H), 5.02 (m, 2 H),
7.14 (s, 1 H), 7.36 (m, 7 H).
13C NMR (125 MHz, CDCl3): δ = 12.46, 13.02, 29.25, 44.23, 59.06,
61.52, 61.60, 110.50, 112.84, 120.80, 124.54, 125.64, 125.89,
126.57, 127.32, 128.07, 132.96, 143.95, 144.16, 159.23, 160.94,
169.46.
White solid; yield: 0.217 g (85%); mp 128–130 °C.
1H NMR (500 MHz, CDCl3): δ = 1.54 (s, 9 H), 3.51 (s, 3 H), 3.93
(s, 3 H), 5.04 (m, 2 H), 6.88 (d, J = 8.0 Hz, 1 H), 7.16 (m, 1 H), 7.39
(m, 7 H).
13C NMR (125 MHz, CDCl3): δ = 29.24, 44.10, 52.00, 52.09, 59.00,
109.50, 110.54, 121.66, 122.72, 124.57, 126.59, 127.07, 127.92,
130.54, 133.54, 142.78, 144.24, 159.83, 161.51, 169.37.
MS (ESI): m/z = 617 [M + H].
MS (ESI): m/z = 511 [M + H].
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 375–381

380
F. Ji et al.
PAPER
Anal. Calcd for C29H26N4O5: C, 68.22; H, 5.13; N, 10.97. Found: C,
68.11; H, 5.32; N, 10.78.
1H NMR (500 MHz, CDCl3): δ = 1.53 (s, 9 H), 2.38 (s, 3 H), 3.34
(s, 3 H), 3.62 (s, 3 H), 3.92 (s, 3 H), 6.90 (d, J = 8.0 Hz, 1 H), 7.23
(s, 1 H), 7.29 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 20.16, 26.37, 29.24, 52.01, 52.07,
58.94, 108.08, 110.34, 110.59, 121.64, 125.10, 130.97, 132.49,
141.15, 144.38, 159.86, 161.54, 169.11.
Dimethyl 1′-Benzyl-6′-bromo-4-(tert-butylimino)-5,5-dicyano-
2′-oxo-1′,2′-dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-di-
carboxylate (8)
White solid; yield: 0.226 g (77%); mp 135–137 °C.
1H NMR (500 MHz, CDCl3): δ = 1.54 (s, 9 H), 3.56 (s, 3 H), 3.93
MS (ESI): m/z = 449 [M + H].
(s, 3 H), 5.00 (m, 2 H), 7.03 (s, 1 H), 7.34 (m, 7 H).
Anal. Calcd for C24H24N4O5: C, 64.28; H, 5.39; N, 12.49. Found: C,
64.19; H, 5.52; N, 12.28.
13C NMR (125 MHz, CDCl3): δ = 29.23, 44.22, 52.19, 59.15,
110.40, 112.96, 120.55, 124.67, 125.74, 126.53, 127.31, 128.08,
132.95, 143.80, 144.02, 159.72, 161.33, 169.32.
Diethyl 4-(tert-Butylimino)-5,5-dicyano-2′-oxo-1′-(prop-2-
ynyl)-1′,2′-dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-di-
carboxylate (13)
MS (ESI): m/z = 589 [M + H].
White solid; yield: 0.212 g (87%); mp 122–124 °C.
Anal. Calcd for C29H25BrN4O5: C, 59.09; H, 4.28; N, 9.51. Found:
C, 59.20; H, 4.42; N, 9.72.
1H NMR (500 MHz, CDCl3): δ = 0.94 (m, 3 H), 1.38 (m, 3 H), 1.53
(s, 9 H), 2.33 (d, J = 1.5 Hz, 1 H), 3.98 (m, 1 H), 4.09 (m, 1 H), 4.40
(m, 2 H), 4.55 (d, J = 17.5 Hz, 1 H), 4.80 (d, J = 17.5 Hz, 1 H), 7.23
(m, 2 H), 7.48 (d, J = 7.5 Hz, 1 H), 7.52 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 12.46, 12.97, 27.22, 29.24, 58.96,
61.32, 61.53, 61.91, 72.29, 74.62, 109.31, 110.20, 110.49, 121.85,
123.03, 124.70, 130.50, 141.72, 144.16, 159.17, 161.00, 168.57.
Dimethyl 1′-Benzyl-4-(tert-butylimino)-5,5-dicyano-5′-methyl-
2′-oxo-1′,2′-dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-di-
carboxylate (9)
White solid; yield: 0.217 g (83%); mp 128–130 °C.
1H NMR (500 MHz, CDCl3): δ = 1.54 (s, 9 H), 2.34 (s, 3 H), 3.52
(s, 3 H), 3.93 (s, 3 H), 5.02 (m, 2 H), 6.76 (d, J = 8.5 Hz, 1 H), 7.16
(d, J = 8.0 Hz, 1 H), 7.26 (s, 1 H), 7.31 (m, 1 H), 7.36 (m, 2 H), 7.39
(d, J = 19.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 20.13, 29.24, 44.07, 52.01, 52.08,
58.94, 109.24, 110.58, 121.61, 125.17, 126.58, 127.00, 127.88,
130.90, 132.53, 133.68, 140.33, 144.40, 159.89, 161.57, 169.29.
MS (ESI): m/z = 487 [M + H].
Anal. Calcd for C27H26N4O5: C, 66.65; H, 5.39; N, 11.52. Found: C,
66.56; H, 5.47; N, 11.36.
Triethyl 1′-Benzyl-4-(tert-butylimino)-5-cyano-2′-oxo-1′,2′-di-
hydrospiro[cyclopent-2-ene-1,3′-indole]-2,3,5-tricarboxylate
(14)
MS (ESI): m/z = 525 [M + H].
White solid; yield: 0.228 g (78%); mp 142–144 °C.
Anal. Calcd for C30H28N4O5: C, 68.69; H, 5.38; N, 10.68. Found: C,
68.50; H, 5.18; N, 10.77.
1H NMR (500 MHz, CDCl3): δ = 0.85 (m, 3 H), 1.04 (m, 3 H), 1.39
(m, 3 H), 1.44 (s, 9 H), 3.83 (m, 2 H), 4.08 (m, 2 H), 4.40 (m, 2 H),
4.94 (d, J = 16.0 Hz, 1 H), 5.12 (d, J = 15.5 Hz, 1 H), 6.78 (d,
J = 8.0 Hz, 1 H), 6.90 (m, 1 H), 7.05 (d, J = 7.5 Hz, 1 H), 7.28 (m,
2 H), 7.36 (m, 2 H), 7.46 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 12.37, 12.49, 13.19, 28.86, 43.93,
57.99, 60.69, 60.78, 62.69, 108.94, 114.81, 121.66, 123.47, 123.95,
126.68, 126.84, 127.79, 129.57, 134.03, 143.19, 149.66, 159.94,
161.86, 162.62, 171.47.
Dimethyl 4-(tert-Butylimino)-5,5-dicyano-1′-methyl-2′-oxo-
1′,2′-dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-dicarboxyl-
ate (10)
White solid; yield: 0.157 g (72%); mp 138–140 °C.
1H NMR (500 MHz, CDCl3): δ = 1.52 (s, 9 H), 3.35 (s, 3 H), 3.60
(s, 3 H), 3.91 (s, 3 H), 7.01 (d, J = 8.0 Hz, 1 H), 7.19 (m, 1 H), 7.43
(d, J = 7.5 Hz, 1 H), 7.50 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 26.37, 29.23, 52.09, 58.98,
108.40, 110.31, 110.56, 121.66, 122.71, 124.44, 130.68, 143.55,
144.28, 159.82, 161.48, 169.17.
MS (ESI): m/z = 586 [M + H].
Anal. Calcd for C33H35N3O7: C, 67.68; H, 6.02; N, 7.17. Found: C,
67.48; H, 5.87; N, 7.25.
MS (ESI): m/z = 435 [M + H].
Methyl (E)-1′-Benzyl-4-(tert-butylimino)-5,5-dicyano-2′-oxo-
1′,2′-dihydrospiro[cyclopent-2-ene-1,3′-indole]-2-carboxylate
(15)
Anal. Calcd for C23H22N4O5: C, 63.59; H, 5.10; N, 12.90. Found: C,
63.34; H, 5.22; N, 12.79.
Purple solid; yield: 0.168 g (72%); mp 154–156 °C.
Dimethyl 6′-Bromo-4-(tert-butylimino)-5,5-dicyano-1′-methyl-
2′-oxo-1′,2′-dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-di-
carboxylate (11)
1H NMR (500 MHz, CDCl3): δ = 1.50 (s, 9 H), 2.34 (s, 3 H), 3.62
(s, 3 H), 4.99 (d, J = 15.5 Hz, 1 H), 5.07 (d, J = 15.5 Hz, 1 H), 6.76
(d, J = 8.0 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H), 7.19 (s, 1 H), 7.30 (m,
1 H), 7.37 (m, 2 H), 7.43 (d, J = 7.5 Hz, 2 H), 7.51 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 20.20, 29.64, 44.00, 50.97, 51.94,
58.69, 59.33, 109.19, 110.51, 111.32, 122.36, 124.99, 126.53,
126.97, 127.91, 130.60, 131.53, 132.31, 133.74, 140.24, 146.71,
154.54, 160.80, 169.77.
White solid; yield: 0.235 g (92%); mp 180–182 °C.
1H NMR (500 MHz, CDCl3): δ = 1.53 (s, 9 H), 3.34 (s, 3 H), 3.64
(s, 3 H), 3.91 (s, 3 H), 7.18 (d, J = 1.5 Hz, 1 H), 7.29 (d, J = 8.0 Hz,
1 H), 7.33 (d, J = 1.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 26.51, 29.23, 52.09, 52.25, 59.14,
110.11, 110.42, 112.06, 120.54, 124.78, 125.64, 143.80, 144.76,
159.72, 161.29, 169.11.
MS (ESI): m/z = 467 [M + H].
MS (ESI): m/z = 513 [M + H].
Anal. Calcd for C28H26N4O3: C, 72.09; H, 5.62; N, 12.01. Found: C,
72.15; H, 5.54; N, 12.17.
Anal. Calcd for C23H21BrN4O5: C, 53.81; H, 4.12; N, 10.91. Found:
C, 53.98; H, 4.01; N, 10.98.
Diethyl 1′-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-4-(tert-bu-
tylimino)-5,5-dicyano-2′-oxo-1′,2′-dihydrospiro[cyclopent-2-
ene-1,3′-indole]-2,3-dicarboxylate (16); Typical Procedure
A soln of spirooxindole 13 (0.5 mmol), CuI (0.1 mmol), Et3N (0.5
mmol), and azide (0.5 mmol) were stirred at 40 °C for 24 h. When
the reaction was complete, the mixtures were concentrated to dry-
Dimethyl 4-(tert-Butylimino)-5,5-dicyano-1′,5′-dimethyl-2′-
oxo-1′,2′-dihydrospiro[cyclopent-2-ene-1,3′-indole]-2,3-dicar-
boxylate (12)
White solid; yield: 0.193 g (86%); mp 185–187 °C.
Synthesis 2013, 45, 375–381
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Spirooxindoles
381
ness under reduced pressure. The crude products were isolated by
flash column chromatography (silica gel).
Bartoli, G.; Melchiorre, P. Angew. Chem. Int. Ed. 2009, 48,
7200. (e) Wei, Q.; Gong, L. Z. Org. Lett. 2010, 12, 1008.
(f) Shintani, R.; Hayashi, S. Y.; Murakami, M.; Takeda, M.;
Hayashi, T. Org. Lett. 2009, 11, 3754. (g) Castaldi, M. P.;
Troast, D. M.; Porco, J. A. Org. Lett. 2009, 11, 3362.
(3) For reviews on domino reactions, see: (a) Ruijter, E.;
Scheffelaar, R.; Orru, R. V. A. Angew. Chem. Int. Ed. 2011,
50, 6234. (b) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt,
P. Chem. Eur. J. 2000, 6, 3321.
(4) (a) Oakes, T. R.; David, H. G.; Nagel, F. J. J. Am. Chem. Soc.
1969, 91, 4761. (b) Takizawa, T.; Obata, N.; Suzuki, Y.;
Yanagida, T. Tetrahedron Lett. 1969, 10, 3407. (c) Ugi, I.
Angew. Chem., Int. Ed. Engl. 1982, 21, 810. (d) Yavari, I.;
Maghsoodlou, M. T. J. Chem. Res., Synop. 1998, 386.
(5) (a) Reddy, B. V. S.; Reddy, A. M.; Somashekar, D.; Yadav,
J. S.; Sridhar, B. Synthesis 2010, 2571. (b) Terzidis, M. A.;
Stephanidou-Stephanatou, J.; Tsoleridis, C. A. J. Org.
Chem. 2010, 75, 1948.
(6) (a) Shaabani, A.; Sarvary, A.; Ghasemi, S.; Rezayan, A. H.;
Ghadari, R.; Ng, S. W. Green Chem. 2011, 13, 582.
(b) Adib, M.; Sayahi, M. H.; Nosrati, M.; Zhu, L. G.
Tetrahedron Lett. 2007, 48, 4195. (c) Yavari, I.; Alizadeh,
A.; Anary-Abbasinejad, M.; Bijanzadeh, H. R. Tetrahedron
2003, 59, 6083.
(7) (a) Alizadeh, A.; Rostamnia, S. Synthesis 2008, 57.
(b) Baharfar, R.; Jaafari, L.; Azimi, R. Chin. Chem. Lett.
2011, 22, 943.
White solid; yield: 0.263 g (85%); mp 118–120 °C.
1H NMR (500 MHz, CDCl3): δ = 0.84 (m, 3 H), 1.37 (m, 3 H), 1.52
(s. 9 H), 3.75 (m, 1 H), 3.98 (m, 1 H), 4.38 (m, 2 H), 5.02 (d, J = 15.5
Hz, 1 H), 5.21 (d, J = 16.0 Hz, 1 H), 5.41 (d, J = 15.0 Hz, 1 H), 5.51
(d, J = 15.0 Hz, 1 H), 7.17 (m, 1 H), 7.24 (m, 3 H), 7.34 (m, 3 H),
7.44 (m, 2 H), 7.66 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 12.32, 13.00, 29.23, 35.71, 53.34,
58.92, 61.26, 61.55, 109.73, 110.45, 110.67, 121.59, 122.23,
122.88, 124.62, 127.18, 127.76, 128.08, 130.69, 133.27, 141.02,
142.16, 144.26, 159.27, 161.01, 169.14.
MS (ESI): m/z = 620 [M + H].
Anal. Calcd for C34H33N7O5: C, 65.90; H, 5.37; N, 15.82. Found: C,
65.75; H, 5.54; N, 15.87.
Diethyl 4-(tert-Butylimino)-1′-[(1-(4-chlorophenyl)-1H-1,2,3-
triazol-4-yl)methyl]-5,5-dicyano-2′-oxo-1′,2′-dihydrospiro[cy-
clopent-2-ene-1,3′-indole]-2,3-dicarboxylate (17)
White solid; yield: 0.265 g (83%); mp 128–130 °C.
1H NMR (500 MHz, CDCl3): δ = 0.96 (m, 3 H), 1.39 (m, 3 H), 1.54
(s, 9 H), 3.94 (m, 1 H), 4.05 (m, 1 H), 4.40 (m, 2 H), 5.08 (d, J = 16.0
Hz, 1 H), 5.38 (d, J = 16.0 Hz, 1 H), 7.20 (m, 2 H), 7.47 (m, 4 H),
7.65 (m, 2 H), 8.19 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 12.41, 13.02, 29.25, 35.66, 58.99,
61.44, 61.61, 109.54, 110.37, 110.98, 120.35, 120.52, 121.55,
123.08, 124.81, 128.91, 130.81, 133.62, 134.34, 141.72, 141.98,
144.15, 159.44, 160.97, 169.27.
(8) (a) Alizadeh, A.; Oskueyan, Q.; Rostamnia, S.; Ghanbari-
Niaki, A.; Mohebbi, A. R. Synthesis 2008, 2929.
(b) Alizadeh, A.; Rostamnia, S.; Zhu, L. G. Synthesis 2008,
1788. (c) Alizadeh, A.; Rostamnia, S.; Zhu, L. G.
Tetrahedron 2006, 62, 5641. (d) Alizadeh, A.; Rostamnia,
S.; Hu, M. L. Synlett 2006, 1592. (e) Azuaje, J.; Coelho, A.;
Maatougui, A. E.; Blanco, J. M.; Sotelo, E. ACS Comb. Sci.
2011, 13, 89.
MS (ESI): m/z = 640 [M + H].
Anal. Calcd for C33H30ClN7O5: C, 61.92; H, 4.72; N, 15.32. Found:
C, 61.76; H, 4.54; N, 15.47.
(9) (a) Shaabani, A.; Sarvary, A.; Rezayan, A. H.; Keshipour, S.
Tetrahedron 2009, 65, 3492. (b) Shaabani, A.; Ghadari, R.;
Sarvary, A.; Rezayan, A. H. J. Org. Chem. 2009, 74, 4372.
(10) Esmaeili, A. A.; Darbanian, M. Tetrahedron 2003, 59, 5545.
(11) Yavari, I.; Hossaini, Z.; Sabbaghan, M. Monatsh. Chem.
2007, 138, 107.
Acknowledgment
We thank financial supported by NUST research funding
(2011ZDJH07). We also acknowledge the Analysis and Testing
Center of Nanjing University of Science and Technology for NMR
analysis of this work.
(12) (a) Esmaeili, A. A.; Moradi, A.; Habibi, A. Synlett 2011,
2307. (b) Nair, V.; Menon, R. S.; Beneesh, P. B.; Sreekumar,
V.; Bindu, S. Org. Lett. 2004, 6, 767. (c) Shaabani, A.;
Rezayan, A. H.; Rahmati, A.; Sarvary, A. Synlett 2007,
1458.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(13) (a) Pibiri, I.; Buscemi, S. Curr. Bioact. Compd. 2010, 6, 208.
(b) Tripathi, R. P.; Yadav, A. K.; Ajay, A.; Bisht, S. S.;
Chaturvedi, V.; Sinha, S. K. Eur. J. Med. Chem. 2010, 45,
142. (c) Siddiqui, N.; Ahsan, W.; Alam, M. S.; Ali, R.; Jain,
S.; Azad, B.; Akhtar, J. Int. J. Pharm. Sci. Rev. Res. 2011, 8,
161.
Primary Data for this article are available online at
http://www.thieme-connect.com/ejournals/toc/synthesis and can be
cited using the following DOI:
m
irDyaraPtir
m
Dyr
1
at 0.4125/pd0036th.mPiryarDaZteanh1l01
C
hemyr
(14) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Tornøe, C.
W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057. (c) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108,
2952. (d) Niu, T. F.; Gu, L.; Yi, W. B.; Cai, C. ACS Comb.
Sci. 2012, 14, 309. (e) MacDonald, J. P.; Badillo, J. J.;
Arevalo, G. E.; Silva-García, A.; Franz, A. K. ACS Comb.
Sci. 2012, 14, 285.
References
(1) (a) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36,
127. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem. Int.
Ed. 2007, 46, 8748.
(2) (a) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (b) Marti, C.;
Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (c) Chen, X.
H.; Wei, Q.; Xiao, H.; Luo, S. W.; Gong, L. Z. J. Am. Chem.
Soc. 2009, 131, 13819. (d) Bencivenni, G.; Wu, L. Y.;
Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M. P.;
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 375–381