Acid-catalyzed reactions of 3-hydroxy-2-oxindoles with electron-rich substrates: Synthesis of 2-oxindoles with all-carbon quaternary center

Article abstract of DOI:10.1039/c3ob41482e

A Lewis acid catalyzed reaction of in situ generated 2H-indol-2-one (9) with various 2π and other electron-rich substrates has been developed. A variety of electron-rich substrates such as allyl/methallyltrimethylsilane, phenylacetylene, styrenes, acetophenone, and indoles have been used. The methodology provides a straightforward approach for the synthesis of 2-oxindoles with an all-carbon quaternary center at the pseudobenzylic position.

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Acid-Catalyzed Reactions of 3-Hydroxy-2-oxindoles with Electron-rich Substrates:
Synthesis of 2-Oxindoles with All-Carbon Quaternary Center†
Lakshmana K. Kinthada, Santanu Ghosh, Subhadip De, Subhajit Bhunia,
Dhananjay Dey, and Alakesh Bisai*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
10 †This paper is dedicated to Professor Hiriyakkanavar Ila, Jawaharlal Nehru Centre for Advanced Scientific Research
(JNCASR), Bangalore, India.
Lewis acid catalyzed reaction of in situ generated 2H- 45 variety of nucleophilic substitution reactions (for instance,
Friedel-Crafts alkylations of aromatic compounds with 3,3-
disubstituted-2-oxindole4 as electron-deficient partner), has
made them extensively used powerful synthetic tool to
realize different C-C bond forming events. In 1985, Baeyer
50 and Lazarus,5a for the first time, accessed symmetrical 3,3-
disubstituted oxindoles starting from isatin through
iterative electrophilic aromatic substitutions. In 1998, Olah
and co-workers5b reported a general synthetic route to
symmetrical 3,3-disubstituted oxindoles from isatins in
55 superacidic triflic acid (CF3SO3H, TfOH). Following this
indol-2-one (9) with various 2 and other electron-rich
15 substrates has been developed. A variety of electron-
rich substrates such as allyl/methallyltrimethylsilane,
phenylacetylene, styrenes, acetophenone, and indoles
have been used. The methodology provides
a
straightforward approach for the synthesis of 2-
20 oxindoles with an all-carbon quaternary center at the
pseudobenzylic position.
The development of efficient methodologies to forge an
all-carbon quaternary stereocenter1 remains an active area
25 in the realm of exploratory synthetic research. Towards
this, methods involving catalytic reagents/conditions are
comparatively more appealing and needs further
exploration.2 In this regard, 2-oxindoles bearing an all-
carbon quaternary stereocenters at the C-3(a) position
30 comprise a common structural motif in many biologically
active complex cyclotryptamine alkaloids, such as
idiospermuline (1a), calycosidine (1b)3 (Figure 1) having
tricyclic C(3a)-arylpyrroloindoline core (2) and hence, is a
fascinating synthetic target to achieve. The tricyclic core 2
35 has been reported to be synthesized from 3-allylated-2-
oxindole 3.
report,
Halperin,5c
Zolotukhin,5d
and
Bjӧrkling5e
independently reported similar approaches to a variety of
symmetrical and unsymmetrically substituted 2-oxindoles.
In 2006, Yadav and co-workers reported synthesis of
60 trisindole type structures utilizing Bi(OTf)3-catalyzed
condensation of isatin and indoles.5f
In 2004, Nicolaou et al.6a demonstrated that 3-hydroxy-
2-oxindole could be activated under the influence of
trifluoromethane sulfonic acid leading to the formation of
65 an all-carbon quarternary center at the pseudobenzylic
(3a)-position of 2-oxindole derivative. Their pioneering
work led to the efficient total synthesis of diazonamide A6a
and related structures. Further, in 2007, Padwa and co-
workers6b-c reported BF3.OEt2-catalyzed F-C alkylations as
70 well as intramolecular reactions of 3-hydroxy-2-oxindoles
with electron-rich 2-systems for the synthesis of
unsymmetrically substituted 2-oxindoles and spiro-
oxindole derivatives. Later, Neuville and Zhu et al.6d
reported trifluoroacetic acid promoted an intramolecular
75 double F-C alkylations to access spiro-oxindoles. Recently,
Zhou and coworkers studied Hg(ClO4)2.3H2O-catalyzed6e
F-C alkylations of electron-rich aromatics with 3-
hydroxyoxindoles and HClO4-catalyzed synthesis of -
quaternary esters or ketones6f and benzofuranones bearing
80 a quaternary center.6g Very recently, Zhu and co-workers6h
have reported a one-pot integrated Brønsted base-catalyzed
trichloroacetimidation of 3-hydroxyoxindoles followed by
Brønsted acid-catalyzed nucleophilic substitution reaction
to access a variety of unsymmetrically substituted 2-
40 Figure 1. Alkaloids (1a-b) sharing quaternary stereocenters.
3-Hydroxy-2-oxindole especially serves as a versatile
building block for the syntheses of many indole based
biologically active molecules. Their ability to undergo
This journal is © The Royal Society of Chemistry [year]
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Organic & Biomolecular Chemistry
Page 2 of 12
oxindoles. In addition, Lewis acid-activation strategy has
Initially the allylation reactions were carried out using
also been applied in the synthesis of variety of 2-oxindoles
1.5 equiv. of allyltrimethylsilane as 2 substrate with 1
equiv. of 3-hydroxy-2-oxindole 8a (inDsOitIu: 10g.e1n0V3ei9rea/wCteA3drOtiBc2l4eH1O4n-8li2nEe
45 indol-2-one 9) in presence of BF3.OEt2 and HClO4 at room
temperature and the results are summarized in table 1.
Among various solvents viz. c-hexane, diethylether, THF,
dichloroethane, ethylacetate, xylene, DMF, benzene,
toluene, and mesitylene screened (entries 1-10),
50 dichloroethane (entry 4) was found to be reasonably good
and provided 66% of 11a when 20 mol% of BF3.OEt2 was
used as catalyst. This encouraged us to carry out the
reactions in other chlorinated solvents such as
dichloromethane and chloroform. We found that, 20 mol%
55 of BF3.OEt2 afforded products in 68% and 94% yields in
dichloromethane and chloroform, respectively (entries 11
and 12).
containing heteroatom at the 3-position.7
Very recently, we have also shown an efficient Lewis
acid catalyzed Friedel-Crafts alkylations of phenols with 3-
alkyl-3-hydroxy-2-oxindole through the intermediacy of
2H-indol-2-one ring 4.8 The methodology was applied for
the synthesis of tetracyclic core 6 of azonazine 7 (Scheme
1).8 In case of 3-hydroxy-2-oxindoles, the Friedel-Crafts
10 alkylations are known to proceed through the formation of
2H-indol-2-one ring (Scheme 1). Similar kind of species
are also reported to be formed under base mediated
elimination of 3-halo-2-oxindoles and is well utilized in
the total synthesis of complex indole alkaloids via formal
15 cycloaddition processes.9,10 Continuing our efforts aiming
at the studies towards total synthesis of complex indole
alkaloids,11 herein, we report a Lewis acid catalyzed in situ
generation of 2H-indol-2-one ring from 3-aryl-3-hydroxy-
5
Table 1: Optimization of BF3.OEt2/HClO4-catalyzed allylation reactions.
60
2-oxindoles
8 and their subsequent reactions with
20 substrates having 2systems to generate 2-oxindoles
bearing an all-carbon quaternary center at the
pseudobenzylic position.
time yielda,b
entry
8ac
solvent
temp.
cat. (mol%)
1.
2.
3.
4.
5.
6.
7.
20 mol% BF3.OEt2
20 mol% BF3.OEt2
20 mol% BF3.OEt2
20 mol% BF3.OEt2
20 mol% BF3.OEt2
20 mol% BF3.OEt2
20 mol% BF3.OEt2
c-hexane
Et2O
25 °C 10 h
21%
10%
48%
72%
81%
12%
90%
64%
82%
25 °C
25 °C
25 °C
25 °C
25 °C
25 °C
7 h
THF
9 h
08%
3 h
66%
DCE
10 h
8 h
traces
14%
EtOAc
xylene
12 h
traces
DMF
8.
9.
20 mol% BF3.OEt2
20 mol% BF3.OEt2
25 °C
25 °C
25 °C
5 h
4 h
5 h
39%
42%
33%
68%
94%
benzene
toluene
mesitylene
CH2Cl2
40%
34%
40%
21%
--
25
Scheme 1: F-C alkylation approach to the azanozine core.
10. 20 mol% BF3.OEt2
11. 20 mol% BF3.OEt2
12. 20 mol% BF3.OEt2
13. 10 mol% BF3.OEt2
14. 10 mol% BF3.OEt2
15. 5 mol% BF3.OEt2
16. 5 mol% BF3.OEt2
17. 20 mol% HClO4
At the outset, we attempted the possibility of addition
of allyltrimethylsilane onto the reactive 2H-indol-2-one
30 ring 9 to affect allylation reactions. We thought that the
generation of well established silyl-stabilized -
carbocation12 intermediate 10a by the reaction of 2H-indol-
2-one 9 with allyltrimethylsilane (Scheme 2), could be
stabilized by amide nitrogen to form intermediate 10b.
35 Intermediate 10b would then afford the allylated product
11 on subsequent removal of Me3SiOH.
25 °C
25 °C
25 °C
25 °C
25 °C
40 °C
25 °C
2 h
2 h
3 h
3 h
5 h
2 h
0.5 h
CHCl3
CH2Cl2
62%
93%
60%
71%
95%
11%
--
CHCl3
CHCl3
CHCl3
17%
08%
--
CHCl3
CH2Cl2
CHCl3
CH2Cl2
CHCl3
CHCl3
CH2Cl2
18. 20 mol% HClO4
19. 10 mol% HClO4
20. 10 mol% HClO4
21. 5 mol% HClO4
22. 5 mol% HClO4
23. 5 mol% HClO4
25 °C
25 °C
25 °C
25 °C
40 °C
25 °C
0.5 h
0.5 h
0.5 h
1 h
89%
91%
86%
82%
85%
76%
--
--
--
--
--
--
0.5 h
1 h
24. 10 mol% BF3.OEt2
25. 10 mol% HClO4
CH3CN
CH3CN
25 °C
25 °C
2 h
1 h
49%
54%
32%
--d
65 areactions were carried out on a 0.5 mmol of 8a with 0.75 mmol of
b
allyl/methallylsilane in 2.5 mL of solvent. isolated yields after column
chromatography. cisolated starting materials. ddecomposition of the rest of
the mass balance.
40 Scheme 2: Working hypothesis of allylation reactions.
2
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Organic & Biomolecular Chemistry
Interestingly, 10 mol% of BF3.OEt2 also afforded
products 11a in 93% yields in chloroform (entry 14).
However, on further decrease in catalyst loading to 5 40 and 75% yields, respectively, at room temperature (entries
In(OTf)3 (condition D) each resulted in the formation of
allylated 2-oxindole derivatives 11a in 88%, 80%, 66%,
View Article Online
DOI: 10.1039/C3OB41482E
mol%, the yield of the reaction dropped down to 60%
(entry 15). On the other hand, 10 mol% of HClO4 afforded
products in 89% and 91% yields in dichloromethane and
chloroform, respectively (entries 18 and 19), whereas, 5
mol% of HClO4 afforded products in 82-85% yields
(entries 21 and 22). We found that acetonitrile13 was not a
7, 10, 13, and 16).
5
10 good choice as solvent and afforded products in 49-54%
yields when the reactions were carried out at room
temperature in the presence of 10 mol% of BF3.OEt2 and
HClO4, respectively. Thus, we decided to carry out the
allylation reactions in the presence of 10 mol% of each
15 BF3.OEt2 and HClO4 as catalysts in chloroform at room
temperature.
45 Figure 2. 3-Hydroxy-3-aryl-2-oxindoles used in this study.
H
N
H
N
O
10 mol% cat
CHCl3, rt
O
R
SiMe3
Table 2: Optimization using metal-triflates.
+
Ar
R
up to 92%
Ar
OH
R = H or Me
(8)
(11)
H
H
N
metal triflates,
CHCl3, temp
N
O
O
SiMe3
H
N
+
H
N
H
N
O
O
O
OH
OMe
OMe
8a
(11a)
(
)
20
OMe
(11b)
(11c)
(11a)
OMe
OMe
32%, 12 h (A)b
39%, 3 h (B)b
19%, 12 h (BF3.OEt2)a
41%, 12 h (HClO4)a
88%, 1.5 h (A)
80%, 1.0 h (B)
93%, 2 h (BF3.OEt2)a
91%, 0.5 h (HClO4)a
90%, 1.5 h (A)
92%, 1.0 h (B)
55%, 2.5 h (BF3.OEt2)a
67%, 1.5 h (HClO4)a
H
H
H
O
N
O
N
O
N
Me
Me
N
H
N
H
OMe
(11d)
(11e)
(11f)
62%, 2 h (A)
59%, 2 h (B)
52%, 2.5 h (BF3.OEt2)a
74%, 2.5 h (HClO4)a
60%, 2 h (A)
56%, 2 h (B)
57%, 2.5 h (BF3.OEt2)a
80%, 2.5 h (HClO4)a
80%, 1.5 h (A)
82%, 1.5 h (B)
74%, 3 h (BF3.OEt2)a
79%, 2.5 h (HClO4)a
50 Reactions were carried out on a 1.0 mmol of 8 with 3.0 mmol of silane
a
reagent in 5 mL of CHCl3. 10 mol% of catalysts and 1.5 mmol of silane
b
reagent were used. starting materials were recovered for rest of the mass
balance. condition A: 10 mol% Sn(OTf)2; condition B: 10 mol%
Bi(OTf)3.
55
aReactions were carried out on a 1.0 mmol of 8a with 3.0 mmol of
Figure 3: Reactions of 3-hydroxy-2-oxindoles with allyl/methallyl
trimethylsilane.
25 allyltrimethylsilane in 5 mL of CHCl3. bIsolated yields after column
c
chromatography. Starting materials were isolated in most of the cases.
dcondition A: 10 mol% Sn(OTf)2; econdition B: 10 mol% Bi(OTf)3;
fcondition C: 10 mol% Cu(OTf)2; gcondition D: 10 mol% In(OTf)3
Having the optimized condition in hand, various 3-
60 hydroxy-2-oxindoles (8a-e, Figure 2) were reacted with
allylsilane/methallyl trimethylsilane in chloroform in the
presence of 10 mol% of Sn(OTf)2 (condition A), Bi(OTf)3
(condition B), and 10 mol% of each BF3.OEt2 and HClO4
as catalysts to furnish various 2-oxindole moeities bearing
65 an all-carbon quaternary stereocenters at 3-position. To our
delight, these reactions worked without event to generate
desired allylated/methallylated products 11a-f in moderate
to excellent yields (Figure 3), except in the case of
substrate 8b which afforded only 19-41% of allylated
30
Next, we screened the reaction in the presence of a
variety of metal triflates and the results are shown in table
2. It was found that 20 mol% of metal triflates such as
Sc(OTf)3, Zn(OTf)2, Ag(I)OTf, Cu(I)OTf, Ce(OTf)3, and
Yb(OTf)3 were inefficient in providing 11a in good yields
35 (entries 1-5 and 14). After exhaustive optimization (table
2), we found that 10 mol% Sn(OTf)2 (condition A),
Bi(OTf)3 (condition B), Cu(OTf)2 (condition C), and
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Page 4 of 12
product 11b. This led us to a conclusion that, in order to 50 with acetophenone in the presence of Lewis acids.
achieve better yields, the substrates must contain electron-
donating group. 2-Oxindoles of the type 11a-d are known
to be potential intermediates for the synthesis of C-(3a)-
arylpyrroloindoline 2, a common structural motif present
Noticeably, 10 mol% each of Sn(OTf)2 (condition A),
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Bi(OTf)3 (condition B), Cu(OTf)2 (condition C) and
DOI: 10.1039/C3OB41482E
In(OTf)3 (condition D) in refluxing dichloromethane,
5
afforded 2-oxindole 12a in 48%, 46%, 40%, and 42%
in many complex alkaloids (see, 1a-b in figure 1).14 We 55 yields, respectively (Scheme 4). Similar efficiencies were
believe that, the 2-oxindoles 11e-f could serve as an
advanced intermediate for the synthesis of bis-indole based
alkaloids.15
observed when the reactions were carried out in refluxing
chloroform (up to 51% yields of 12a). This study suggests
that an unmasked ketone can be added to the 3-aryl-3-
hydroxy-2-oxindole under the influence of Lewis acid, via
10
The outcome of the allylation chemistry of the in situ
generated 9 encouraged us to check the addition of 60 the keto-enol tautomerization.
terminal alkyne to the reactive 2H-indol-2-one 9 (Scheme
3). To our delight, on subjecting 3-hydroxy-2-oxindole 8a
with phenylacetylene in presence of Lewis acids such as 10
15 mol% each of Sn(OTf)2 (condition A), Bi(OTf)3 (condition
B), Cu(OTf)2 (condition C) and In(OTf)3 (condition D) in
refluxing dichloromethane, we could achieve 12a in 68%,
65%, 62%, and 70% yields, respectively (Scheme 3). We
also found similar efficiencies when the reactions were
20 conducted in refluxing chloroform. Notably, there were no
traces of phenylacetylene addition product 13 being
formed. The methodology was further extended to
substrate 8d which led to the formation of 12b (up to 60%
yields) in almost similar efficiency (Scheme 3). The single
25 crystal X-ray analysis of products 12a and 12b
unambiguously proved the formation of 2-oxindoles
having an all-carbon quaternary center at the
pseudobenzylic position.
Reactions were carried out on a 1.0 mmol of 8a with 3.0 mmol of
65 acetophenone in 5 mL of solvent and 10 mol% Lewis acids were used in
all cases.
Scheme 4: Reactions of ±8a with acetophenone.
70
Next, we tested the possibility of the reactions of 3-
hydroxy-2-oxindoles 8a-b with styrene as 2substrates in
the presence of Lewis acids.
30
35
75
80
Reactions were carried out on a 1.0 mmol of 8a with 5.0 mmol of
styrenes in 5 mL of CH2Cl2. condition A: 10 mol% Sn(OTf)2; condition
B: 10 mol% Bi(OTf)3; condition C: 10 mol% Cu(OTf)2; condition D: 10
mol% In(OTf)3.
X-ray of 12a (CCDC 933799)
X-ray of 12b (CCDC 933800)
40
Reactions were carried out on a 1.0 mmol of 8a with 3.0 mmol of
phenylacetylene in 5 mL of solvent. a10 mol% Lewis acids were used in
all cases.
Scheme 5: Reactions of 3-hydroxy-2-oxindoles with styrene.
45 Scheme 3: Lewis acid catalyzed phenylacetylene addition to ±8a.
Interestingly, on subjecting styrene with 3-hydroxy-2-
85 oxindole 8a in the presence of Lewis acids such as 10
mol% each of Sn(OTf)2 (condition A), Bi(OTf)3 (condition
Further, we envisioned that similar 2-oxindole 12a could
be achieved from a reaction of 3-hydroxy-2-oxindole 8a
4
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Organic & Biomolecular Chemistry
B), Cu(OTf)2 (condition C) and In(OTf)3 (condition D) in
of 18b. At this point, third equiv of indole could add to the
Michael acceptor 18c, which upon subsequent
refluxing dichloromethane,16 afforded 2-oxindole 14a in
72%, 64%, 40%, and 72% yields, respectively (Scheme 5)
along with 7-10% of 15a. These reactions were found to be
View Article Online
rearomatization could furnish produDcOt I1: 170..11903T9h/Ce3OuBn4u1s4u8a2lE
product was confirmed by X-ray analysis (Scheme 7).
5
quite general to afford products 14a-d in moderate to good 45 Literature report revealed that, synthesis of compound of
yields (Scheme 5). Interestingly, the 2-oxindoles of the
type 14 were also found to be potential intermediates for
various complex alkaloids shown in figure 1.15
the type 17 has been reported via InCl3-catalyzed self-
addition.19a
Further, encouraged by the precedence of cesium
10 carbonate promoted reaction of 3-halo-2-oxindoles with 3-
substituted indoles by Funk et al. in the synthesis of
perophoramidine,9a we then looked into the possibility of a
Lewis-acid catalyzed reaction of 3-hydroxy-2-oxindoles
with indole (Scheme 6). We found that, 10 mol% of
15 Sn(OTf)2 (condition A) and Cu(OTf)2 (condition C) can
afforded various trisindoles (16a-f) in good to excellent
yields.17 In the event, we have shown an efficient synthesis
of trisindole 16e (Scheme 6), a metabolite from vibrio sp.
isolated from a sponge,18 in 84-90% yields.
20
50
55
X-ray structure of 17 (CCDC 950651)
60 Scheme 7: Reaction of 3-hydroxy 3-methyl 2-oxindole (8f) with indole.
In summary, an efficient Lewis acid-catalyzed reactions
of 3-hydroxy-3-aryl-2-oxindoles ±8 with a variety of
electron rich substrates such as phenylacetylene,
65 allyltrimethylsilane, styrene, and indole has been
developed. A wide variety of 2-oxindoles bearing an all-
carbon quaternary center at the pseudobenzylic position
have been synthesized utilizing our methodologies. Further
efforts toward the development of enantioslective
70 approaches as well as application of this methodology in
the synthesis of architecturally interesting indole alkaloids
are currently in progress in our laboratory.
Reactions were carried out on a 1.0 mmol of 8 with 2.0 mmol of indoles
in 5 mL of CH2Cl2. condition A: 10 mol% Sn(OTf)2; condition C: 10
25 mol% Cu(OTf)2.
Scheme 6: Reactions of 3-hydroxy-2-oxindoles with indole.
However, to our surprise, when 3-hydroxy 3-methyl 2-
30 oxindole 8f was reacted with 2 equiv of indole under the
influence of 10 mol% In(OTf)3, the reaction led to the
formation of unusual product 17 in 55% yield along with
52% of recovered 2-oxindole 8f (Scheme 7). This clearly
demonstrates the high reactivity of 3-aryl-3-hydroxy-2-
35 oxindole 8a-e (Figure 2) as compared to 3-alkyl-3-
hydroxy-2-oxindole such as 8f. We speculated that,
because of low reactivity of ±(8f), indole could be
activated in the presence of In(OTf)3 to form an
intermediate (18a) which then reacts with second equiv of
40 indole to afford Michael acceptor 18c via the intermediacy
75
Materials and Methods
Unless otherwise stated, reactions were performed in
oven-dried glassware fitted with rubber septa under a
nitrogen atmosphere and were stirred with Teflon-coated
80 magnetic stirring bars. Liquid reagents and solvents were
transferred via syringe using standard Schlenk techniques.
Tetrahydrofuran (THF) and diethyl ether (Et2O) were
distilled
over
sodium/benzophenone
ketyl.
Dichloromethane (CH2Cl2), toluene, and benzene were
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Organic & Biomolecular Chemistry
Page 6 of 12
distilled over calcium hydride. All other solvents such as
(100 MHz, 0.1mL DMSO-D6, in 0.5 mL CDCl3) δ 179.1,
DMSO, DMF, dioxane and reagents such as bromoarenes, 60 159.1, 142.3, 134.2, 133.9, 129.6, 127.3, 125.2, 122.4,
isatins, electron-rich arenes etc. were used as received,
unless otherwise noted. Thin layer chromatography was
performed using Merck Silicagel 60 F-254 precoated plates
(0.25 mm) and visualized by UV irradiation, anisaldehyde
stain and other stains. Silicagel from Merck (particle size
100-200 mesh) was used for flash chromatography.
Melting points were recorded on a digital melting point
113.9, 110.2, 77.3, 55.5; IR (film) υmaxD3O2I:5130.,102V39i9e1/w8CA,3rO1tiBc7l4e31O24n,8li2nEe
1510, 1253, 1177, 1105, 1034 cm-1; HRMS (ESI) m/z
278.0802 [(M + Na)+; calculated for [C15H13NO3 + Na]+:
278.0788]; MP 188-190 ºC.
5
65
(±)-3-Hydroxy-3-phenylindolin-2-one ±(8b): 87% yield,
1
Rf = 0.54 (50% EtOAc in hexane), yellowish solid. H
10 apparatus from Jyoti Scientific (AN ISO 9001:2000) and
NMR (400 MHz, 0.1 mL DMSO-d6, 0.5 mL CDCl3) δ:
10.05 (br, s, 1H), 7.32-7.38 (m, 2H), 7.08-7.27 (m, 5H),
are uncorrected. 1H and 13C NMR spectra were recorded on
Bruker 400, 500 MHz spectrometers with 13C operating 70 6.83-6.95 (m, 2H), 6.36 (br, s, 1H); 13C NMR (100 MHz,
frequencies of 100, 125 MHz, respectively. Chemical
0.1mL DMSO-d6, in 0.5 mL CDCl3) δ: 179.4, 142.1,
141.5, 133.7, 129.3, 128.2, 127.6, 125.8, 125.0, 122.3,
110.3; IR (film) υmax 3292, 2918, 1700, 1617, 1472, 1325,
757 cm-1; HRMS (ESI) m/z 248.0658 [(M + Na)+;
shifts (δ) are reported in ppm relative to the residual
1
15 solvent signal (δ = 7.26 for H NMR and δ = 77.0 for 13C
1
NMR). Data for H NMR spectra are reported as follows:
chemical shift (multiplicity, coupling constants, number of 75 calculated for [C14H11NO2 + Na]+: 248.0682]; MP 207-209
hydrogens). Abbreviations are as follows: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), br (broad).
20 IR spectra were recorded on a FT-IR system (Spectrum
BX) from PerkinElmer spectrometer and are reported in
ºC.
(±)-3-(3,4-Dimethoxyphenyl)-3-hydroxyindolin-2-one
±(8c): 83% yield, Rf = 0.44 (50% EtOAc in hexane),
frequency of absorption (cm-1). Only selected IR 80 yellowish solid. 1H NMR (400 MHz, 0.1 mL DMSO-D6,
absorbencies are reported. High resolution mass spectral
data were obtained from the Central Instrumentation
25 Facility (CIF) at the Indian Institute of Science Education
and Research (IISER) Bhopal.
0.5 mL CDCl3) δ 9.55 (s, 1H), 7.03-7.09 (m, 3H), 6.86 (t, J
= 7.92 Hz, 1H), 6.72-6.77 (m, 1H), 6.59-6.62 (m, 2H),
6.53 (s, 1H), 3.7 (br, s, 3H), 3.67 (br, s, 3H); 13C NMR
(100 MHz, 0.1mL DMSO-D6, in 0.5 mL CDCl3) δ 179.6,
85 148.7, 148.5, 141.6, 133.4, 133.1, 129.2, 125.0, 122.4,
118.0, 110.7, 110.3, 109.4, 77.6, 55.8; IR (film) υmax 3321,
1716, 1274, 1188, 1110, 922, 747, 628 cm-1; HRMS (ESI)
m/z 304.1345 [(M + NH4)+; calculated for [C16H15NO4 +
NH4]+: 304.1339]; MP 146-148 ºC.
Caution! HClO4 is a powerful oxidizing agent. Although
the use of 70% aqueous solution of HClO4 (only shows
30 strong acid features and no oxidizing properties) as the
catalyst could reduce the potential danger associated with
HClO4, still special care should be taken while carrying out
the reaction. For more information, please follow:
http://en.wikipedia.org/wiki/Perchloric_acid.
90
(±)-3-(Benzo[d][1,3]dioxol-5-yl)-3-hydroxyindolin-2-one
±(8d): 74% yield, Rf = 0.49 (50% EtOAc in hexane),
1
35
yellowish solid. H NMR (400 MHz, 0.1mL DMSO-D6,
General procedure for the synthesis of 3-hydroxy-
0.5 mL CDCl3) δ 9.96 (s, 1H), 7.12-7.17 (m, 2H), 6.92 (m,
2oxindoles ±(8a-d):20 A flame-dried round-bottom flask 95 2H), 6.83 (d, J = 7.72 Hz, 1H), 6.72-6.74 (m, 1H), 6.63 (d,
was charged with isatin (5 mmol, 1.0 equiv.) in anhydrous
THF (20 mL) and the round bottom flask was placed at 0
40 ºC. To this reaction mixture aryl Grignard reagent (12.5
mmol, 2.5 equiv.) was added drop-wise via a syringe. The
J = 8.12 Hz, 1H), 6.28 (s, 1H), 5.86 (d, J = 2.88 Hz, 1H),
3.07 (1H, exchangeable); 13C NMR (100 MHz, 0.1mL
DMSO-D6, in 0.5 mL CDCl3) δ 179.3, 147.6, 147.1, 142.0,
135.3, 133.5, 129.3, 125.0, 122.3, 119.1, 110.2, 107.8,
reaction was slowly allowed to warm up to room 100 106.8, 101.0, 77.5; IR (film) υmax 3385, 2917, 1713, 1698,
temperature (1 h) and stirring was continued for 4-5 hours.
Upon completion of the reaction (judged by TLC), the
45 reaction mixture was quenched at 0 ºC with saturated
aqueous NH4Cl (5 mL). The whole mixture was filtered
1608, 1462, 1244, 1175, 1107, 1031 cm-1; HRMS (ESI)
m/z 292.0590 [(M + Na)+; calculated for [C15H11NO4 +
Na]+: 292.0580]; MP 228-231 ºC.
through a celite-bed and washed with diethyl ether. The 105 General procedure of allylations/methallylation of ±8.
organic layer was evaporated under reduced pressure and
the crude mixture was purified by a silica-gel column
50 chromatography.
A flame-dried round-bottom flask was charged with ±8
(1.0 mmol) in chloroform (6.0 mL) at room temperature.
To this reaction mixture was added 10 mol% Lewis acid
followed by the addition of allyl/methallytrimethylsilanes
(±)-3-Hydroxy-3-(4-methoxyphenyl)indolin-2-one ±(8a): 110 (1.5 mmol). The reaction mixture was stirred and the
79% yield, Rf = 0.51 (50% EtOAc in hexane), yellowish
solid. H NMR (400 MHz, 0.1mL DMSO-D6, 0.5 mL
55 CDCl3) δ 10.33 (s, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.18 (d, J
= 8.2 Hz, 1H), 7.11 (d, J = 7.08 Hz, 1H), 6.97 (t, J = 7.24
progress of the reaction monitored by TLC (approx. 2 h).
After the completion of the reaction, 3 mL of saturated
bicarbonate solution was added to the reaction mixtures
and extracted three times with dichloromethane (3 X 5
1
Hz, 1H), 6.88 (t, J = 6.52 Hz, 1H), 6.52 (s, 1H), 3.72 (s, 115 mL). The organic layers were collected and dried over
3H), [3.38 (H2O) in DMSO-D6], 2.51 (DMSO); 13C NMR
anhydrous MgSO4 and concentrated in vacuum. The crude
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 12
Organic & Biomolecular Chemistry
product was purified over silica gel by column
chromatography using ethylacetate in petroleum ether as 60 (±)-3-allyl-3-(1H-indol-3-yl)indolin-2-one ±(11e): Rf =
View Article Online
eluents.
0.65 (50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3)
δ: 8.22 (brs, 1H), 8.14 (brs, 1H), 7.29D(OdI,: 1J0=.1083.93/2C3HOzB,4114H82),E
7.23 (m, 1H), 7.07-7.14 (m, 4H), 6.99 (t, J = 7.48 Hz, 1H),
6.88-6.94 (m, 2H), 5.47-5.58 (m, 1H), 5.09 (d, J = 16.96
5
(±)-3-Allyl-3-(4-methoxyphenyl)indolin-2-one ±(11a): Rf
= 0.75 (40% EtOAc in hexane). H NMR (400 MHz,
1
CDCl3) δ: 8.97 (br, s, 1H), 7.32 (d, J = 8.32 Hz, 2H), 7.25 65 Hz, 1H), 4.95 (d, J = 10.08 Hz, 1H), 3.06-3.21 (m, 2H);
(m, 2H), 7.09 (t, J = 7.4 Hz, 1H), 7.96 (d, J = 7.68 Hz,
1H), 6.87 (d, J = 8.32 Hz, 2H), 5.48 (m, 1H), 5.07 (d, J =
13C NMR (100 MHz, CDCl3) δ: 180.4, 140.7, 136.8, 132.9,
132.1, 128.1, 125.5, 124.9, 123.0, 122.6, 122.2, 120.2,
119.7, 119.3, 114.8, 111.3, 109.7, 52.9, 40.7; IR (film) υmax
3273, 2926, 2855, 1699, 1621, 1471, 1352, 1225, 1182,
10 17.0 Hz, 1H), 4.96 (d, J = 10.08 Hz, 1H), 3.79 (s, 3H),
3.04 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 180.9, 158.8,
141.1, 132.6, 132.4, 131.4, 128.2, 128.1, 125.3, 122.4, 70 923, 741 cm-1; HRMS (ESI) m/z 289.1349 [(M + H)+;
119.2, 114.0, 110.1, 56.3, 55.2, 41.7; IR (film) υmax 3236,
3078, 2932, 2835, 1701, 1616, 1512, 1470, 1292, 1250,
15 1184, 1034, 922, 745 cm-1; HRMS (ESI) m/z 280.1330
[(M + H)+; calculated for [C18H18NO2]+: 280.1332]; MP
92-95 ºC.
calculated for [C19H17N2O]+: 289.1335].
(±)-3-(1H-indol-3-yl)-3-(2-methylallyl)indolin-2-one
1
±(11f): Rf = 0.66 (50% EtOAc in hexane). H NMR (400
75 MHz, DMSO-D6) δ: 10.98 (s, 1H), 10.47 (s, 1H), 7.28 (m,
2H), 7.16 (t, J = 7.52 Hz, 1H), 7.04 (d, J = 7.24 Hz, 1H),
6.95 (t, J = 7.32 Hz, 1H), 6.87 (m, 3H), 6.73 (t, J = 7.48
Hz, 1H), 4.59 (s, 1H), 4.52 (s, 1H), 3.36 (DMSO), 3.16 (d,
J = 12.88 Hz, 1H), 2.98 (d, J = 12.88 Hz, 1H), 1.33 (s,
3-Allyl-3-phenylindolin-2-one ±(11b): Colorless gel, Rf =
20 0.78 (40% EtOAc in hexane). 1H NMR (400 MHz, CDCl3)
δ: 8.32 (br, s, 1H), 7.40-7.42 (m, 2H), 7.32-7.36 (m, 2H),
7.26-7.29 (m, 2H), 7.23-7.25 (m, 1H), 7.11 (td, J = 7.56, 80 3H); 13C NMR (100 MHz, CDCl3) δ: 180.0, 142.7, 141.2,
1.04 Hz, 1H), 6.96 (m, 1H), 5.45 - 5.54 (m, 1H), 5.06 -
5.12 (m, 1H), 4.96 - 4.99 (m, 1H), 3.03 - 3.13 (m, 2H),
25 1.25 - 1.45 (hexane); 13C NMR (100 MHz, CDCl3) δ:
180.2, 140.8, 139.4, 132.4, 132.2, 128.6, 128.2, 127.4,
137.1, 133.7, 128.3, 125.5, 125.2, 123.8, 121.8, 121.4,
119.7, 118.9, 115.6, 115.2, 112.0, 109.7, 52.9, 43.5,
24.3;IR (film) υmax 3247, 2922, 1708, 1618, 1472, 1329,
1225, 1171, 1105, 1020, 900, 822, 745 cm-1; HRMS (ESI)
127.0, 125.4, 122.5, 119.4, 110.0, 57.0, 41.0; IR (film) 85 m/z 303.1504 [(M + H)+; calculated for [C20H19N2O]+:
υmax 3247, 3075, 2928, 1695, 1617,1514, 1465, 1184, 748
303.1492].
cm-1.
30
General procedure for the phenyl acetylene addition to
3-Allyl-3-(3,4-dimethoxyphenyl)indolin-2-one
±(11c):
±8. A flame-dried round-bottom flask was charged with ±8
Colorless gel, Rf = 0.63 (40% EtOAc in hexane). 1H NMR 90 (1.0 mmol, 1.0 equiv.) in dichloromethane or chloroform
(400 MHz, CDCl3) δ: 8.79 (br, s, 1H), 7.25 (m, 2H), 7.09
(td, J = 7.56, 0.96 Hz, 1H), 6.99 (d, J = 2.2 Hz, 1H), 6.95
35 (m, 1H), 6.90 (dd, J = 8.44, 2.2 Hz, 1H), 6.80 (d, J = 8.52
Hz, 1H), 5.48 (m, 1H), 5.07 (dd, J = 17.07, 1.79 Hz, 1H),
(6 mL) under inert atmosphere. To this reaction mixture,
10 mol % Lewis acid was added at room temperature
followed by the addition of 3 equiv. of phenyl acetylene.
Finally, the reaction mixture was reflux at 40-50 ºC for
4.96 (dd, J = 10.27, 1.83 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 95 indicated time. Upon completion of the reaction (judged by
3H), 3.03 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 180.7,
148.9, 148.4, 141.0, 140.9, 132.3, 131.8, 128.2, 125.3,
40 122.4, 119.4, 119.3, 111.0, 110.6, 110.1, 56.5, 55.9, 55.8,
41.9 ; IR (film) υmax 3290, 3213, 2932, 2835, 1713, 1620,
the TLC), the reaction mixture was cooled to room
temperature and diluted with 15 mL of dichloromethane
and then it was extracted with 5 mL of saturated sodium
bicarbonate. The organic layers were dried over sodium
1516, 1470, 1258, 1234, 1146, 1026, 741 cm-1; HRMS 100 sulphate and the crude materials were purified by flash
(ESI) m/z 310.1447
[(M+H)+; calculated for
chromatography using EtOAc and petroleum ether to
afford products ±(12a-b).
[C19H20NO3]+: 310.1438].
45
(±)-3-(4-methoxyphenyl)-3-(2-methylallyl)indolin-2-one
(±)-3-(4-methoxyphenyl)-3-(2-oxo-2-phenylethyl)
±(11d): Colorless solid, Rf = 0.75 (40% EtOAc in hexane). 105 indolin-2-one ±(12a): Rf = 0.42 (30% EtOAc in hexane).
1H NMR (400 MHz, CDCl3) δ: 9.00 (br, 1H), 7.34 (m,
2H), 7.21-7.28 (m, 2H), 7.09 (td, J = 7.52, 1 Hz, 1H),
50 6.95-6.96 (m, 1H), 6.86 (m, 2H), 4.63-4.68 (m, 2H), 3.79
1H NMR (400 MHz, CDCl3) δ: 7.98 (s, 1H), 7.90 (m, 2H),
7.56 (tt, J = 6.8, 1.2 Hz, 1H), 7.43 (m, 2H), 7.38 (m, 2H),
7.23-7.27 (m, 2H), 7.03 (td, J= 7.52, 0.96 Hz, 1H), 6.98 (d,
J = 7.64 Hz, 1H), 6.85-6.89 (m, 2H), 4.13 (ABq, J = 18
(s, 3H), 3.24 (d, J = 13.24 Hz, 1H), 2.92 (d, J = 13.28 Hz,
1H), 1.41 (br, 3H); 13C NMR (100 MHz, CDCl3) δ: 181.4, 110 Hz, 2H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
158.8, 141.2, 140.9, 132.5, 128.3, 128.1, 128.0, 125.9,
122.2, 115.3, 113.9, 110.2, 56.5, 55.3, 45.2, 23.7; IR (film)
55 υmax 3248, 3078, 2928, 1694, 1616, 1512, 1470, 1443,
1292, 1184, 1034, 748 cm-1; HRMS (ESI) m/z 316.1308
195.9, 180.6, 159.0, 141.7, 136.3, 133.3, 132.4, 131.3,
128.6, 128.0, 127.9, 124.3, 122.2, 114.1, 110.1, 55.3, 52.9,
46.9; IR (film) υmax 2925, 1706, 1616, 1471, 1254, 1184,
1106, 1033, 752 cm-1; HRMS (ESI) m/z 358.1440]; [(M +
[(M + Na)+; calculated for [C19H19NO2 + Na]+: 316.1349]; 115 H)+; calculated for [C23H20NO3 ]+: 358.1438]; MP 140-143
MP 85-90 ºC.
ºC.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7

Organic & Biomolecular Chemistry
Page 8 of 12
(±)-3-(4-methoxystyryl)-3-phenylindolin-2-one ±(14b):
1
(±)-3-(benzo[d][1,3]dioxol-5-yl)-3-(2-oxo-2-phenylethyl) 60 Rf = 0.40 (30% EtOAc in hexane). H NMR (400 MHz,
indolin-2-one ±(12b): Rf = 0.51 (50% EtOAc in hexane).
1H NMR (400 MHz, CDCl3) δ: 8.02 (brs, 1H), 7.85 (d, J =
7.36 Hz, 2H), 7.52 (t, J = 7.41 Hz, 1H), 7.39 (t, J = 7.80
Hz, 2H), 7.20 (m, 2H), 6.97 (td, J = 14.38, 7.59 Hz, 3H),
CDCl3) δ: 7.90 (brs, 1H), 7.25-7.35 (m, 8H), 7V.1ie9w A(drt,iclJe O=nline
7.20 Hz, 1H), 7.08 (m, 1H), 6.97 (d, J = 7.72 Hz, 1H), 6.82
(d, J = 8.72 Hz, 2H), 6.51 (ABq, J = 16.08 Hz, 2H), 3.78
(S, 3H); 13C NMR (100 MHz, CDCl3) δ: 178.8, 159.5,
DOI: 10.1039/C3OB41482E
5
6.84 (dd, J = 8.27, 1.88 Hz, 1H), 6.71 (d, J = 8.21 Hz, 1H), 65 140.2, 140.1, 132.5, 131.3, 129.2, 128.7, 128.3, 127.9,
5.91 (s, 2H), 4.09 (ABq, J = 18 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ: 195.8, 180.4, 148.0, 147.1, 141.7, 136.3,
10 133.4, 133.1, 132.2, 128.6, 128.4, 128.0, 124.4, 122.3,
120.2, 110.2, 108.2, 107.6, 101.2, 53.2, 46.9; IR (film)
υmax 3229, 2928, 1716, 1608, 1509, 1472, 1253, 1024, 755
cm-1; HRMS (ESI) m/z 372.1246]; [(M + H)+; calculated
for [C23H18NO4 ]+: 372.1230].
127.6, 127.5, 126.5, 126.0, 122.9, 114.0, 110.1, 60.0, 55.3;
IR (film) υmax 3246, 2926, 1708, 1618, 1510, 1472, 1248,
1176, 1034, 753 cm-1; LRMS (ESI) m/z 342.1543]; [(M +
H)+; calculated for [C23H20NO2 ]+: 342.1489].
70
(±)-3-(4-methoxyphenyl)-3-styrylindolin-2-one ±(14c):
1
Rf = 0.60 (30% EtOAc in hexane), yellowish solid. H
15
NMR (400 MHz, CDCl3) δ: 7.83 (brs, 1H), 7.36 (m, 2H),
7.26-7.29 (m, 4H), 7.20 (m, 2H), 7.09 (t, J = 7.44 Hz, 1H),
Experimental procedure for the acetophenone addition
to ±8. A flame-dried round-bottom flask was charged with 75 6.95 (d, J = 7.72 Hz,1H), 6.84 (d, J = 8.84 Hz, 2H), 6.63
±8 (1.0 mmol, 1.0 equiv.) in dichloromethane or
chloroform (6 mL) under inert atmosphere. To this reaction
20 mixture, 10 mol % Lewis acid was added at room
temperature followed by the addition of (3.0 mmol, 3.0
(d, J = 16.08 Hz, 1H), 6.53 (d, J = 16.08 Hz,1H), 3.76 (s,
3H); 13C NMR (100 MHz, CDCl3) δ: 178.8, 159.1, 140.2,
136.5, 132.5, 131.9, 131.6, 129.0, 128.7, 128.6, 128.3,
127.9, 126.6, 125.9, 122.9, 114.2, 110.2, 59.4, 55.3; IR
equiv.) of acetophenone. Then the reaction mixture was 80 (film) υmax 3112, 2924, 1713, 1615, 1472, 1251, 1034, 971,
reflux at 40-50 ºC for 8-9 h. Upon completion of the
reaction (judged by running TLC), the reaction mixture
25 was cooled to room temperature and diluted with 15 mL of
dichloromethane and extracted with 5 mL of saturated
746 cm-1; HRMS (ESI) m/z 342.1481]; [(M + H)+;
calculated for [C23H20NO2 ]+: 342.1489]; MP 181-184 ºC.
(±)-3-(4-methoxyphenyl)-3-(4-methoxystyryl)indolin-2-
sodium bicarbonate. The organic layers were dried over 85 one ±(14d): Rf = 0.58 (30% EtOAc in hexane), yellowish
anhydrous Na2SO4 and the crude materials were purified
by flash chromatography using EtOAc and petroleum to
30 afford compound ±(12a).
gel. 1H NMR (400 MHz, CDCl3) δ: 8.33 (brs, 1H), 7.25-
7.16 (m, 5H), 7.12 (d, J=7.36 Hz, 1H), 7.01 (t, J = 7.52 Hz,
1H), 6.90 (d, J = 7.68 Hz, 1H), 6.78-6.74 (m, 4H), 6.39-
6.45 (ABq, J = 16.13, 1H), 3.71 (s, 3H), 3.69 (s, 3H) ; 13
C
General procedure for the reaction of ±8 with styrene. 90 NMR (100 MHz, CDCl3) δ: 179.4, 159.4, 159.0, 140.2,
A flame-dried round-bottom flask was charged with ±8
(1.0 mmol, 1.0 equiv.) in dichloromethane (6 mL) under
35 inert atmosphere. To this reaction mixture, 10 mol %
Lewis acid was added followed by the addition of 5 equiv.
132.8, 132.2, 131.0, 129.2, 128.7, 128.2, 127.9, 126.8,
125.8, 122.8, 114.1, 113.9, 110.3, 59.4, 55.3; IR (film)
υmax 3111, 2920, 1712, 1610, 1465, 1248, 1000, 968, 742
cm-1; HRMS (ESI) m/z 372.1611]; [(M + H)+; calculated
of styrene. Finally, the reaction mixture was reflux at 40 ºC 95 for [C24H22NO3 ]+: 372.1594].
for 6-9 h. Upon completion of the reaction (monitored by
running TLC), the reaction mixture was cooled to room
40 temperature and diluted with 15 mL of dichloromethane
and extracted with 5 mL of saturated sodium bicarbonate.
(±)3-(2-hydroxy-2-phenylethyl)-3-(4-methoxyphenyl)
indolin-2-one ±(15a): Rf = 0.25 (50% EtOAc in hexane),
yellowish gel. 1H NMR (400 MHz, CDCl3) δ: 8.89 (s, 1H),
The organic layers were dried over sodium sulphate and 100 7.23 (m, 8H), 7.09 (t, J=7.52 Hz, 2H), 6.95 (d, J = 7.68 Hz,
the crude materials were purified by flash chromatography
to afford ±(14) and trace amount of compound ±(15).
.
1H), 6.78 (d, J = 8.68 Hz, 2H), 4.36 (d, J = 9.92, 1H), 3.72
(s, 3H), 3.66 (m, 1H), 3.03 (m, 1H), 2.46 (d, J = 13.04 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ: 182.2, 158.8, 144.7,
142.1, 132.8, 132.1, 128.4, 128.3, 127.9, 127.3, 125.5,
45
(±)-3-phenyl-3-styrylindolin-2-one ±(14a): Rf = 0.71
1
(50% EtOAc in hexane), yellowish solid. H NMR (400 105 125.0, 122.4, 113.9, 110.7, 71.6, 55.3, 55.2, 47.1; IR (film)
MHz, CDCl3) δ: 8.91 (brs, 1H), 7.40-7.44 (m, 2H), 7.36-
7.40 (m, 3H), 7.30-7.32 (m, 3H), 7.24 (m, 2H), 7.23 (m,
υmax 3368, 2926, 1715, 1617, 1509, 1251, 1185, 1035, 755
cm-1; LRMS (ESI) m/z 358.1478; [(M + H)+; calculated
for [C23H22NO3]+: 358.1438].
50 1H), 7.12 (td, J = 7.52, 0.92 Hz, 1H), 7.03 (d, J = 7.72 Hz,
1H), 6.74 (d, J = 16.04 Hz, 1H), 6.59 (d, J = 16.08 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ: 178.9, 140.3, 140.2, 110 General Procedure for the reaction of ±8 with indoles.
136.4, 132.4, 131.9, 128.8, 128.7, 128.6, 128.4, 127.9,
127.6, 127.5, 126.7, 125.9, 122.9, 110.3, 60.1; IR (film)
55 υmax 3214, 2925, 1715, 1472, 1326, 1208, 971, 748 cm-1;
LRMS (ESI) m/z 312.1378]; [(M + H)+; calculated for
[C22H18NO]+: 312.1383]; MP 179-182 ºC.
A flame-dried round-bottom flask was charged with ±8
(1.0 mmol, 1.0 equiv.) in dichloromethane (6 mL) under
inert atmosphere. To this reaction mixture, 10 mol %
Lewis acid was added at room temperature followed by the
115 addition of 2 equiv. of indole. Finally, the reaction mixture
was reflux at 40 ºC for 6-9 h. Upon completion of the
8
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Organic & Biomolecular Chemistry
reaction, the reaction mixture was cooled to room
1240, 1038, 743 cm-1; HRMS (ESI) m/z 391.1058]; [(M +
temperature and diluted with 15 mL of dichloromethane 60 Na)+; calculated for [C23H16N2O3 + Na]+: 391.1053]; MP
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DOI: 10.1039/C3OB41482E
and then it was extracted with 5 mL of saturated sodium
bicarbonate. The organic layers were dried over sodium
sulphate and the crude materials were purified by flash
chromatography using EtOAc and petroleum ether to
afford compound ±(16a-f).
159-163ºC.
5
1H,1''H-[3,3':3',3''-terbenzo[b]pyrrol]-2'(1'H)-one
1
(16e): Rf = 0.50 (50% EtOAc in hexane). H NMR (400
65 MHz, CDCl3) δ: 8.13 (s, 1H), 8.02 (brs, 2H), 7.33 (d, J =
7.8 Hz, 3H), 7.28 (d, J = 8.12 Hz, 2H), 7.20 (t, J = 7.56
(±)-3-(1H-indol-3-yl)-3-(4-methoxyphenyl)indolin-2-one
Hz, 2H), 7.10 (t, J = 7.40 Hz, 2H), 6.89-6.96 (m, 6H); 13
C
10 ±(16a): Rf = 0.48 (50% EtOAc in hexane), colorless solid.
NMR (100 MHz, CDCl3) δ: 179.5, 139.9, 137.0, 134.5,
128.1, 125.9, 125.6, 124.4, 122.7, 122.1, 121.3, 119.5,
1H NMR (400 MHz, CDCl3) δ: 9.20 (brs, 1H), 8.25 (brs,
1H), 7.25 (d, J = 8.52 Hz, 3H), 7.21 (d, J = 8.28 Hz, 2H), 70 115.2, 111.3, 109.9, 53.1; IR (film) υmax 3402, 2923, 1697,
7.09 (m, 2H), 6.93 (q, J = 7.12, 2H), 6.76 (m, 4H), 3.71 (s,
3H); 13C NMR (100 MHz, CDCl3) δ: 180.9, 158.8, 140.1,
15 137.1, 134.7, 132.2, 129.1, 128.0, 125.8, 125.5, 124.3,
122.7, 122.1, 121.5, 119.5, 116.1, 113.9, 111.5, 110.4,
1614, 1470, 1334, 1098, 1014, 741cm-1 ; HRMS (ESI) m/z
364.1434]; [(M + H)+; calculated for [C24H18N3O]+:
364.1444]; MP 282-285 ºC.
57.6, 55.2; IR (film) υmax 3334, 2933, 1715, 1695, 1682, 75 (±)-5-bromo-1H,1''H-[3,3':3',3''-terbenzo[b]pyrrol]-
1616, 1506, 1472, 1250, 1180, 1101, 826, 744 cm-1;
HRMS (ESI) m/z 355.1452]; [(M + H)+; calculated for
20 [C23H19N2O2]+: 355.1441]; MP 118-121 ºC.
2'(1'H)-one ±(16f): Rf
= 0.52 (50% EtOAc in
1
hexane),colorless gel. H NMR (400 MHz, in 0.4 mL
CDCl3 and 0.1 mL DMSO-D6) δ: 9.82 (s, 1H), 9.57 (s, 1H),
9.52 (s, 1H), 7.39 (br, 1H), 7.24 (CDCl3), 7.14-7.20 (m,
(±)-3-(1H-indol-3-yl)-3-phenylindolin-2-one ±(16b): Rf 80 2H), 7.04-7.11 (m, 3H), 6.97 (dd, J = 8.56, 1.68 Hz, 1H),
1
= 0.54 (30% EtOAc in hexane), colorless solid . H NMR
(400 MHz, CDCl3) δ: 8.90 (s, 1H), 8.14 (s, 1H), 7.35 (m
25 2H), 7.26 (m, 5H), 7.24 (CDCl3), 7.19 (d, J = 8.08 Hz,
1H), 7.15 (t, J = 7.40 Hz, 1H), 7.09 (t, J = 7.32 Hz, 1H),
6.91 (t, J = 7.68 Hz, 1H), 6.86 (d, J = 7.64 Hz, 1H), 6.78
(m, 3H), 6.71 (t, J = 7.68 Hz, 1H), 2.52 (DMSO-D6); 13C
NMR (100 MHz in 0.4 mL CDCl3 and 0.1 mL DMSO-D6)
δ: 179.5, 141.0, 137.1, 135.9, 134.3, 127.9, 127.7, 125.9,
6.93 (m, 2H), 6.84 (d, J = 7.28 Hz, 1H), 6.79 (s, 1H); 13C 85 125.8, 125.2, 124.6, 124.1, 123.62, 123.60, 121.9, 121.4,
NMR (100 MHz, CDCl3) δ: 180.3, 140.2, 140.1, 137.1,
134.4, 128.5, 128.1, 127.9, 127.4, 125.8, 125.6, 124.4,
30 124.3, 122.7, 122.2, 121.6, 119.6, 119.5, 116.0, 111.4,
110.3, 58.2; IR (film) υmax 3308, 2926, 1706, 1618, 1472,
1334, 1264, 1102,741 cm-1; HRMS (ESI) m/z 347.1161];
[(M + Na)+; calculated for [C22H16N2O + Na]+: 347.1155];
MP 148-151 ºC.
120.9, 118.8, 114.6, 113.0, 112.0, 111.5, 109.9, 52.9; IR
(film) υmax 3412, 1664, 1472, 1026, 826, 765 cm-1; HRMS
(ESI) m/z 464.0348]; [(M
[C24H16BrN3O + Na]+: 464.0369].
+
Na)+; calculated for
90
2-(2,2-di(1H-indol-3-yl)ethyl)aniline (17):19 The product
was obtained as yellow crystalline solid [263 mg, 75%
1
35
(condition A)], Rf = 0.60 (50% EtOAc in hexane). H
(±)-3-(3,4-dimethoxyphenyl)-3-(1H-indol-3-yl)indolin-2-
NMR (400 MHz, CDCl3) δ: 7.89 (brs, 2H), 7.47 (d J =
one ±(16c): Rf = 0.40 (50% EtOAc in hexane), yellowish 95 7.95 Hz, 2H), 7.30 (d, J = 8.10 Hz, 2H), 7.12 (t, J = 7.66
solid. 1H NMR (400 MHz, CDCl3) δ: 8.70 (s, 1H), 8.21 (s,
12H), 7.26 (m, 2H), 7.09 (t, J = 7.60 Hz, 1h), 6.96 (m, 2H),
40 6.92 (m, 2H), 6.84 (m, 2H), 6.73 (d, J = 8.44 Hz, 1H), 3.81
(s, 3H), 3.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
Hz, 2H), 6.98-6.97 (m, 6H), 6.61 (t, J = 7.41 Hz, 1H), 6.54
(d, J = 7.78 Hz, 1H), 4.84 (t, J = 7.29 Hz, 1H), 3.41 (d, J =
7.34 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 144.7,
136.6, 130.3, 126.9, 126.8, 125.9, 121.8, 119.7, 119.6,
180.3, 148.8, 148.4, 140.0, 137.0, 134.5, 132.4, 128.1, 100 119.1, 118.7, 115.7, 111.0, 37.1, 34.5; IR (film) υmax 3412,
125.8, 125.7, 124.2, 122.7, 122.2, 121.3, 120.3, 119.6,
116.4, 111.7, 111.3, 110.8, 110.2, 57.6, 55.9, 55.8; IR
45 (film) υmax 3334, 1699, 1505, 1249, 1101, 1034, 826,
744cm-1; HRMS (ESI) m/z 385.1574]; [(M + H)+;
calculated for [C24H21N2O3]+: 385.1547]; MP 145-149 ºC.
2924, 2854, 1619, 1456, 1339, 1265, 1096, 743 cm-1;
HRMS (ESI) m/z 350.1649; [M - H]+; calculated for
[C24H21N3 - H]+: 350.1652; MP 288-291ºC.
105
Acknowledgements
(±)-3-(benzo[d][1,3]dioxol-5-yl)-3-(1H-indol-3-
50 yl)indolin-2-one ±(16d): Rf = 0.54 (50% EtOAc in
1
hexane), yellowish solid. H NMR (400 MHz, CDCl3) δ:
A.B. thanks the Council of Scientific and Industrial
8.89 (brs, 1H), 8.13 (s, 1H), 7.28 (d J = 7.92 Hz, 2H), 7.08- 110 Research (CSIR), New Delhi and the Department of
7.17 (m, 2H), 6.95 (t, J = 7.52 Hz, 2H), 6.78-6.86 (m, 4H),
6.67 (d, J = 8.12 Hz,1H), 5.86 (d, J = 2.56 Hz, 2H); 13C
55 NMR (100 MHz, CDCl3) δ: 180.3, 147.8, 146.9, 140.0,
137.1, 134.4, 134.0, 128.1, 125.7, 125.5, 124.2, 122.7,
Science and Technology (DST) for generous research
grants. L.K.K., S.G., S.D., and S.B. thank the CSIR, New
Delhi, for Senior Research Fellowship (SRF). We thank
Dr. Deepak Chopra, Assistant Professor of Chemistry,
122.2, 121.6, 121.2, 119.6, 116.1, 111.4, 110.3, 108.0, 115 IISER Bhopal for the assistance with X-ray
101.1, 57.8, 29.7; IR (film) υmax 3404, 2924, 1703, 1474,
crystallography. A.B. sincerely thanks to Professor Vinod
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Page 10 of 12
65 7140. (f) J. S. Yadav, B. V. SubbaReddy, K. U. Gayathri, S.
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5
Notes and References
Department of Chemistry, Indian Institute of Science Education
and Research Bhopal, Bhopal, M.P.–460 023, India.
10 †Electronic Supplementary Information (ESI) available:
Experimental procedures, characterization data, NMR spectra,
Crystallographic information of compounds ±12a (CCDC
933799), ±12b (933800), and 17 (CCDC 950651) See
DOI: 10.1039/b000000x/
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120 respectively.
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2005, 6, 711. (b) For a related approach, see; K. Fujino, E.
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View Article Online
DOI: 10.1039/C3OB41482E
5
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Page 12 of 12
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DOI: 10.1039/C3OB41482E
GRAPHICAL ABSTRACTS
Acid-Catalyzed Reactions of 3-Hydroxy-2-oxindoles with Electron-rich
Substrates: Synthesis of 2-Oxindoles with All-Carbon Quaternary Center†
Laksmana K. Kinthada, Santanu Ghosh, Subhadip De, Subhajit Bhunia, Dhananjay Dey, and
Alakesh Bisai*
Lewis acid-catalyzed reaction of 3-hydroxy-2-oxindoles ±8 with various 2π electron-rich substrates
has been investigated. The methodology provides a straightforward approach to the 2-oxindoles
sharing an all-carbon quaternary centers in good yields.