(±)-CSA catalyzed one-pot synthesis of 6,7-dihydrospiro[indole-3, 1′-isoindoline]-2,3′,4(1H,5H)-trione derivatives: Easy access of spirooxindoles and ibophyllidine-like alkaloids

Article abstract of DOI:10.1016/j.tetlet.2014.01.154

The domino dehydration/condensation/cyclization sequence reaction of cyclic enaminones with 3-hydroxy-3-ethoxycarbonylisoindolin-1-one derivatives has been successfully realized for the first time in toluene at 90 C by using a catalytic amount of commercially available inexpensive (±)-CSA (30 mol %). Gratifyingly, this novel domino protocol provides good to excellent yields of previously unknown class of 1-aryl/alkyl-substituted 6,7-dihydrospiro[indole- 3,1′-isoindoline]-2,3,4(1H,5H)-trione derivatives. Moreover, biologically attractive spirooxindoles and ibophyllidine-like alkaloids have been prepared.

Full text of DOI:10.1016/j.tetlet.2014.01.154

Tetrahedron Letters 55 (2014) 1863–1867
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
( )-CSA catalyzed one-pot synthesis
of 6,7-dihydrospiro[indole-3,10-isoindoline]-2,30,4(1H,5H)-trione
derivatives: easy access of spirooxindoles and ibophyllidine-like
alkaloids
⇑
Anvita Srivastava, Shaikh M. Mobin, Sampak Samanta
Department of Chemistry, Indian Institute of Technology Indore, Indore 452017, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The domino dehydration/condensation/cyclization sequence reaction of cyclic enaminones with 3-
hydroxy-3-ethoxycarbonylisoindolin-1-one derivatives has been successfully realized for the first time
in toluene at 90 °C by using a catalytic amount of commercially available inexpensive ( )-CSA (30 mol %).
Gratifyingly, this novel domino protocol provides good to excellent yields of previously unknown class of
1-aryl/alkyl-substituted 6,7-dihydrospiro[indole-3,10-isoindoline]-2,3,4(1H,5H)-trione derivatives. More-
over, biologically attractive spirooxindoles and ibophyllidine-like alkaloids have been prepared.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 26 October 2013
Revised 10 January 2014
Accepted 13 January 2014
Available online 11 February 2014
Keywords:
Domino
Brønsted acid catalyst, CSA
Cyclic enaminones
Spiroisoindolinone
Spirooxindole
Ibophyllidine-like alkaloid
The spirocyclic compounds are one of the most important
classes of building blocks found in a variety of natural products
and pharmacophores.1 Due to their unique structural features, they
are commonly employed for chiral ligands, and organometallic
complexes in addition to their traditional roles as synthetic
intermediates.2 Apart from that, their several synthetic analogues
show a broad range of biological activities.3 Owing to their
immense applications in various fields, a large number of protocols
have been developed to construct this motif.1–3 Even with such
progress, the development of metal-free based new synthetic
strategies for easier access of spiroisoindolinone compounds
remains a great challenge for organic and medicinal chemists.
3-Substituted isoindolin-1-ones and their spiro cyclic deriva-
tives are important privileged structures in a variety of pharmaco-
phore exhibiting a broad range of therapeutic activities (Fig. 1).4 On
the other hand, dihydroindol-2-one derivatives also exhibit
potential biological activities toward human ELOVL6 inhibitors
(Fig. 1).5 Therefore, it will be a great idea to assemble these two
important privileged scaffolds into one molecule in a spiro manner
which may lead to a series of possible pharmacologically exciting
spiroisoindolinone fused heterocycles.
Literature survey shows that little progress has been made
toward the synthesis6 of spiroisoindolinone, which includes silver
carbonate catalyzed spirolactonization of 3-propargyl-substituted
isoindolin-1-one,6a Rh-(III) catalyzed C–H activation reaction of
cyclic diazo compound with O-pivaloyl benzhydroxamic acids6b
and heterocyclization of 2-iodobenzoyl chloride with ketimines
using palladium.6c
As far as we are aware, there is no such method available for the
synthesis of 6,7-dihydrospiro[indole-3,10-isoindoline]-2,3,4(1H,5H)-
trione derivatives including the use of transition metal catalyst. To
address this synthetic challenge, we sought to devise a metal-free
one-pot reaction that would involve simple starting materials.
Easily accessible cyclic enaminones have been used as versatile
reactive intermediates in multicomponent reactions and domino
processes for expedient synthesis of various heterocycles and total
synthesis of natural products.7 In this regard, domino process8 is
one of the most suitable and practical approaches for assembling
a diverse range of structural and stereochemical architectures
in an efficient manner. Recently, we have reported on camphor-
10-sulfonic catalyzed domino Friedel–Crafts reaction for the
preparation of 3-ethoxycarbonyl-3-indolylisoindolin-1-ones and
spiroisindolin-1-one fused heterocycle.9 Against these back-
grounds, we envisioned that cyclic enaminone 2 may efficiently
be involved in the condensation–cyclization reaction with cyclic
⇑
Corresponding author. Tel.: +91 731 2438742.
E-mail address: sampaks@iiti.ac.in (S. Samanta).
http://dx.doi.org/10.1016/j.tetlet.2014.01.154
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

1864
A. Srivastava et al. / Tetrahedron Letters 55 (2014) 1863–1867
Cl
MeO
OMe
Ph
O
O
O
O
N
N
N
O
CF3
HN
N
NR
N
Me
O
O
H
Me
Me
N
N
Ph
O
O
H
N
O
O
O
Human ELOVL6
Human ELOVL3
Aldolase Inhibitors
O
(+)-Lennoxamine
(R)-Pazinaclone
Figure 1. Natural product and biologically active compounds that have isoindolin-1-one and dihydroindol-2-one moieties.
ketimine 4 in the presence of Brønsted acid to access this
spirocyclic compound 3 (Scheme 1). During our continuing efforts
toward the development of metal-free based domino protocols as
well as synthesis of N-heterocycles,10 we report a simple, mild,
and robust procedure for the synthesis of 1-aryl/alkyl-substi-
tuted-6,7-dihydrospiro[indole-3,10-isoindole]-2,30,4(1H,5H)-trione
derivatives via a domino dehydration/condensation/cyclization
sequence reaction of cyclic enaminones with 3-ethoxycarbonyl-
3-hydroxyisoindolin-1-one derivative using ( )-CSA as a Brønsted
acid catalyst.
Table 1
Domino reaction of 5,5-dimethyl-3-(phenylamino)cyclohex-2-enone (2aa) with 3-
ethoxycarbonyl-3-hydroxyisoindolin-1-one (1a)a
O
O
O
Catalyst (30 mol%)
Solvent, heating
O
NH
NH
CO2Et
Me
Me
O
PhHN
HO
1a
N
Ph
Me
Me
2aa
3aaa
Entry
Catalyst
Solvent
T (°C)
T (h)
Yieldb (%)
In order to establish the optimal conditions, we tested the mod-
el reaction between 3-ethoxycarbonyl-3-hydroxyisoindolin-1-one
(1a) and 5,5-dimethyl-3-(phenylamino)cyclohex-2-enone (2aa)
under a variety of reaction conditions (solvent, catalyst and tem-
perature). The results are summarized in Table 1. It was observed
that ( )-camphor-10-sulfonic acid was unable to trigger this
reaction at room temperature in CH2Cl2 medium (Table 1, entry
2). However, at 40 °C, after 24 h, a very low yield (19%) of 6,6-di-
methyl-1-phenyl-6,7-dihydrospiro[indole-3,10-isoindole]-
1c
2c
3
4
5
Nil
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Toluene
Toluene
Xylene
rt
rt
40
60
24
24
24
24
24
24
24
24
24
24
24
40
24
24
24
30
30
NR
NR
19
37
45
82
79
25
51
79
77
33
72
73
74
69
57
CSA
CSA
CSA
CSA
CSA
CSA
CSA
CSA
CSA
CSA
TCA
pTSA
TFA
TfOH
H2SO4
HCl
60
90
90
90
90
110
120
90
90
90
90
90
90
6
7
8d
9
EtOH
Dioxane
Toluene
Xylene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
10
11
12
13
14
15
16
17
2,30,4(1H,5H)-trione (3aaa) was obtained (entry 3). The product
was fully characterized by its spectroscopic data (1H, 13C NMR
and HRMS). Gratifyingly, these significant results motivated us to
examine this domino reaction in detail. For this catalyst, further
screening of other organic solvents such as toluene, CHCl3, xylene,
dioxane, and EtOH was carried out under heating conditions (en-
tries 4–9). The results clearly demonstrated that at 90 °C, toluene
and xylene provided the highest yields (82% and 79% respectively,
entries 6 and 7) of targeted spiro product 3aaa than those using
other organic solvents (entries 8 and 9). On further increasing
the reaction temperature from 90 °C to 120 °C in xylene, no
improvement in yield (77%) and reaction time was observed (entry
11). Considering the lower boiling point of toluene, it was chosen
as the best solvent for all the further reactions. Next, we examined
several well known Brønsted acid catalysts namely pTSA, trichloro-
acetic acid (TCA), TFA, TfOH, H2SO4, and HCl for this domino pro-
cess. As shown in Table 1, all these catalysts were able to
promote this reaction effectively (except TCA, 33% yield, entry
12), resulting in moderate to good yields of desired compound
3aaa (57–74%, entries 13–17).
A reasonable mechanism for the formation of compound 3aaa
has been proposed as shown in Scheme 2. This domino reaction
is thought to proceed via an iminium ion mode of activation mech-
anism. At first, cyclic ketimine 4a is generated from 1a through a
dehydration process. In the second step, the nitrogen atom of cyclic
ketimine 4a is protonated by CSA to form cyclic iminium ion 5,
which is subsequently attacked by cyclic enaminone 2aa, leading
to intermediate 6. The latter undergoes an imine-enamine tautom-
erism to form condensation product 7, which, finally, is converted
into 3aaa via intramolecular cyclization.
a
Unless otherwise mentioned, all the reactions were carried out with compound
1a (0.2 mmol), 2aa (0.25 mmol) and catalyst (0.06 mmol, 30 mol %) in specified dry
solvent (0.5 mL) and temperature.
b
Yield of isolated product after column chromatography.
NR = no reaction.
Reaction was performed in the sealed tube.
c
d
1-one derivatives 1 under our standard conditions. The results
are summarized in Table 2. As is evident in Table 2, a series of
six-membered cyclic enaminones derived from several aromatic
amines with various substituents on phenyl rings (entries 1–9)
condensed efficiently (74–85%) with substrate 1a, providing a
straightforward way to construct the previously unknown class
of spiro products possessing both isoindolin-1-one and dihydroin-
dol-2-one frameworks. Importantly, N-benzyl substituted cyclic
enaminone (entry 10) also resulted in good yield when substrate
1a was employed. Not only 1a but also 5-halide-substituted 3-eth-
oxycarbonyl-3-hydroxyisoindolin-1-ones (1b–e) too were wit-
nessed to be good enamine acceptors. For example, after 24 h,
high yield (80–85%) of the corresponding products (3baa–3eaa,
entries 11–14) were obtained when 5,5-dimethyl-3-(phenylami-
no)cyclohex-2-enone (2aa) was used. Similarly, substrate 1a
underwent clean reactions of several 3-(arylamino)-cyclohex-2-
enones by this protocol providing the corresponding anticipated
products in good yields (75–78%, entries 15–17). By this synthetic
operation, several functional groups including Me, OMe, Bn, Cl, Br,
With these acceptable results in hand, we examined the scope
of this domino process by using several N-aryl/alky-substituted
cyclic enaminones 2 with 3-ethoxycarbonyl-3-hydroxyisoindolin-

A. Srivastava et al. / Tetrahedron Letters 55 (2014) 1863–1867
Condensation
NH
1865
O
N
O
O
O
R1
O
R1
R1
NH
CO2Et
N
O
Acid
Acid
CO2Et
RHN
HO
R
3
1
2
4
Dehydration
Cyclization
Scheme 1. Domino strategy for the synthesis of spiroisoindolin-1-one fused heterocycle 3.
Me
Me
Me
Me
O
O
O
O
S
O
O
O
O
O
HO3S
NH
N
NH
N H
-H2O
-CSA
CO2Et
1a'
CO2Et
H2O
HO
1a
CO2Et
CO2Et
O
4a
5
O
S
O
O
O
NHPh
2aa
Me
Me
O
O
O
O
O
NH
O
NH
NH
-EtOH
EtO
O
EtO2C
PhHN
H
O
HN
Ph
N
Ph
6
7
3aaa
Scheme 2. Proposed mechanism of this domino reaction.
I, F etc were well tolerated. Moreover, the desired product pos-
sesses a chiral quaternary carbon center at the 3-position on the
isoindolin-1-one ring which is flanked by dihydroindol-2-one moi-
ety for further elaborations.
resulting in hydrogenated product 10 with excellent diastereose-
lectivity (10a:10b = 19:1 dr, Scheme 5) and 87% yield of 10a. The
relative configuration of major isomer 10a (cis–cis) was unambig-
uously confirmed by its single crystal X-ray diffraction data
(Fig. 2, details in ESI). These results clearly revealed that stereose-
lective hydrogenation occurs at sterically less congested side of
C@C bond. Furthermore, we extended the major isomer 10a into
novel access of ibophyllidine-like alkaloid 11,14 which was ob-
tained in good yield (61%) via a Fischer indole reaction using phen-
ylhydrazine in AcOH medium at 120 °C under microwave
irradiation.
However, to our surprise, 5-membered cyclic enamines
(2ca–2cb) containing a
c-lactone moiety reacted with substrate
1a under the present conditions, affording only uncyclized
ethyl 3-oxo-1-(2-oxo-4-(arylamino)-2,5-dihydrofuran-3-yl)isoind-
oline-1-carboxylates (3aca–3acb) in excellent yields (87–90%,
Scheme 3).
Functionalized spirooxindole framework has been the subject
of growing interest in recent years because this motif is present
in a variety of drug candidates and natural products.11 Many of
In conclusion, we have developed a simple, efficient, and
straightforward method for the one-pot novel domino
dehydration/condensation/cyclization reactions of 3-ethoxycar-
their synthetic analogs exhibit
a broad range of biological
activities such as anti-microbial, anti-tumor, anti-diabetic, anti-
inflammatory, anti-tubercular etc.12 In view of great applications,
enormous efforts have been put into developing highly efficient
synthetic routes to prepare these important motifs.11,12 To the
best of our knowledge, there is no fruitful report on the metal-
free mediated preparation of spiro[indoline-3,10-isoindoline]-2,
3-dione. Toward this goal, we have realized that cyclohexene
moieties of spiro compounds 3aba and 3abe could be aromatized
in CHCl3 at 70 °C using NBS,13 leading to the corresponding
spirooxindole fused heterocycles 8 and 9 in high yields 83% and
89%, respectively (Scheme 4).
bonyl-3-hydroxyisoindolin-1-one
derivatives
with
several
cyclic enaminones to produce a series of biologically attractive
6,7-dihydrospiro[indole-3,1-isoindole]-2,3,4(1H,5H)-trione deriv-
atives using ( )-CSA as an inexpensive Brønsted acid catalyst.
In addition, a simple operation, mild, metal-free based catalytic
system, and high yields may open up a new synthetic avenue
for assembling of isoindolin-1-one and dihydroindol-2-one
moieties in a spiro fashion. Moreover, the spirooxindoles and
ibophyllidine-like alkaloids have been successfully prepared
for the first time through this methodology. Further
endeavors toward the development of enantioselective methods
as well as the applications of these spirocyclic compounds
are under investigation and will be communicated in due
course.
Next, we turned our attention toward the stereoselective reduc-
tion of the double bond of compound 3aba under hydrogen atmo-
sphere using 10% Pd/C in EtOH at room temperature for 2 h,

1866
A. Srivastava et al. / Tetrahedron Letters 55 (2014) 1863–1867
Table 2
( )-CSA catalyzed one-pot synthesis of 6,7-dihydrospiro[indole-3,10-isoindole]-2,30,4(1H,5H)-trione derivative (3aaa–3abe)a
O
O
O
X
X
O
CSA (30 mol%)
Toluene, 90 °C
NH
NH
CO2Et
O
RHN
HO
N
R
1
2
3
O
1a:
X = H
O
2b
2a
1b: X = F
1c:
1d:
X = Cl
X = Br
Me
Me
HN
R
HN
R
1e: X = I
2a-R
2b-R
Entry
Product
Time (h)
Yieldb (%)
O
1
2
3aaa: R = C6H5
3aab: R = 4-MeC6H4
24
24
82
84
O
NH
3
4
5
6
7
3aac: R = 4-MeOC6H4
3aad: R = 4-FMeC6H4
3aae: R = 4-ClC6H4
3aaf: R = 4-BrC6H4
3aag: R = 4-IC6H4
24
28
27
27
24
81
79
85
84
80
O
N
R
Me
Me
O
8
9
3aah: R = 2-MeC6H4
3aai: R = 2-MeOC6H4
28
30
77
74
O
O
NH
O
N
R
Me
Me
O
NH
10
3aaj
24
87
O
N
PhH2C
Me
Me
O
11
12
13
14
3baa: X = F
3caa: X = Cl
3daa: X = Br
3eaa: X = I
24
24
24
24
82
80
85
83
X
O
NH
O
Me
Me
N
Ph
O
15
16
17
3aba: R = C6H5
3aba: R = 4-MeC6H4
3abe: R = 2-Cl-C6H4
24
24
24
76
78
75
O
NH
O
N
R
a
Unless otherwise mentioned, all reactions were carried out with compounds (1a–e, 0.2 mmol), cyclic enaminones (0.25 mmol) and ( )-CSA (0.06 mmol, 30 mol%) in
toluene (0.5 mL) at 90 °C.
b
Yield of isolated product after column chromatography.
O
O
O
O
O
O
NH
NH
O
O
OH
CSA ( 20 mol%)
NH
CO2Et
NH
O
NBS, CHCl3
EtO2C
RHN
O
Toluene, 90 °C
HO
1a
O
N
RHN
2ca:
70 °C, RT, 30 h
27 h
N
R
R
3aca:
R = C6H5
2cb: R = 4-MeC6H4
R = C6H5; 87%
3acb: R = 4-MeC6H4; 90%
8: R = C6H5, 83%
9: R = 4-ClC6H4, 89%
3aba: R = C6H5
3abe: R = 4-ClC6H4
Scheme 3. Condensation reaction between 1a and 5-membered cyclic enaminino
esters (2ca–cb).
Scheme 4. Synthesis of spirooxindole moiety.

A. Srivastava et al. / Tetrahedron Letters 55 (2014) 1863–1867
1867
O
O
N
O
H
NH
O
O
NH
H
N
NH
H
PhNHNH2
Pd/C, H2
O
O
O
AcOH, MW
120 °C, 40 min
300 psi
EtOH, 2 h, rt
N
Ph
N
H
H
Ph
Ph
3aba
11 (61%)
10 (10a:10b = 19:1 dr), 87% yield (10a)
Scheme 5. Highly diasteroselective reduction of C@C bond and synthesis of ibophyllidine-like compound.
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Acknowledgments
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Org. Biomol. Chem. 2013, 11, 7084; (d) Jaiswal, P. K.; Biswas, S.; Singh, S.;
Samanta, S. Org. Biomol. Chem. 2013, 11, 8410.
The authors thank the DST research grant (Project No. SB/S1/
OC-19/2013) for the generous financial support. A.S. is also thank-
ful to UGC for her fellowship.
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Supplementary data
Supplementary data (copies of 1H NMR and 13C NMR spectra of
all listed in Table 2 and Schemes 3–5, CCDC 965178) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.01.154.
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