Friedel-Crafts alkylations of electron-rich aromatics with 3-hydroxy-2-oxindoles: Scope and limitations

Article abstract of DOI:10.1039/c4ob01264j

A Lewis acid-catalyzed nucleophilic addition of electron rich aromatics with 3-hydroxy-2-oxindoles 5 was developed. The reaction is believed to proceed through the 2H-indol-2-one ring system 9, which eventually reacts with various electron-rich aromatics to afford a variety of 2-oxindoles with an all-carbon quaternary center at the pseudobenzylic position (4, 8, 13, and 16) in high yields. The methodology provides an expeditious route to the tetracyclic core (3) of diazonamide (1), and azonazine (2) as well as the tricyclic core of asperazine (6a), idiospermuline (6b), and calycosidine (6c) viz. C(3a)-arylpyrroloindolines 7 having an all-carbon quaternary center on further synthetic elaboration.

Full text of DOI:10.1039/c4ob01264j

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Friedel–Crafts alkylations of electron-rich
aromatics with 3-hydroxy-2-oxindoles:
scope and limitations†‡
Cite this: Org. Biomol. Chem., 2014,
12, 8152
Lakshmana K. Kinthada, Santanu Ghosh, K. Naresh Babu, Mohd. Sharique,
Soumava Biswas and Alakesh Bisai*
A Lewis acid-catalyzed nucleophilic addition of electron rich aromatics with 3-hydroxy-2-oxindoles 5
was developed. The reaction is believed to proceed through the 2H-indol-2-one ring system 9, which
eventually reacts with various electron-rich aromatics to afford a variety of 2-oxindoles with an all-carbon
quaternary center at the pseudobenzylic position (4, 8, 13, and 16) in high yields. The methodology
provides an expeditious route to the tetracyclic core (3) of diazonamide (1), and azonazine (2) as well as
the tricyclic core of asperazine (6a), idiospermuline (6b), and calycosidine (6c) viz. C(3a)-arylpyrroloindolines
7 having an all-carbon quaternary center on further synthetic elaboration.
Received 17th June 2014,
Accepted 7th August 2014
DOI: 10.1039/c4ob01264j
www.rsc.org/obc
Few enantioselective organocatalytic approaches to construct
3,3-disubstituted 2-oxindoles have also been reported in the
Introduction
The development of efficient methodologies to construct an literature. These include asymmetric reactions with prochiral
all-carbon quaternary stereocenter1 remains a challenging task 3-alkyl/aryl-2-oxindoles18 as donors as well as some dipolar
in organic chemistry. In this regard, alkaloids sharing an all- cycloaddition strategies using 3-alkylidene 2-oxindoles.19
carbon quaternary stereocenter2 at the pseudobenzylic posi- Other approaches involve photo-Fries rearrangement,20
tion such as diazonamide A (1),3 azonazine (2),4 asperazine Hofmann–Martius rearrangement21 and nucleophilic addition
(6a),5 idiospermuline (6b),6 calycosidine (6c)6 (Fig. 1) and to the 3-halo-2-oxindoles through the formation of reactive
many others7 constitute an important class of those exhibiting 2H-indol-2-one rings.22
a diverse range of biological activities and have hence gained
One of the classical ways to synthesize 3,3-disubstituted
much synthetic interest.8 Consequently, the development of 2-oxindoles involves a Friedel–Crafts alkylation23 of electron-rich
novel synthetic strategies to access 3,3-disubstituted oxindole aromatics with isatins24 or 3-alkyl/aryl-3-hydroxy-2-oxindoles.25
derivatives which can eventually be utilized in the synthesis of In fact, the total synthesis of diazonamide A (1)25a (Fig. 1)
these fascinating synthetic targets is of paramount importance. by Nicolaou et al. beautifully indicates the application of this
Prominent methods for the synthesis of 3,3-disubstituted strategy where the 3-hydroxy-2-oxindole compound could be
2-oxindoles include the derivatization of other heterocycles,9 activated under the influence of trifluoromethane sulfonic
intramolecular Heck type reactions,10 arylation of amides,11 acid leading to the formation of an all-carbon quaternary
variants of the Stolle reaction,12 the Gassman sulfonium ylide center at the pseudobenzylic (3a)-position of the 2-oxindole
reaction,13 photoinduced studies,14a,b the hetero Claisen derivative. Their pioneering work led to the efficient total syn-
approach,14c,d radical cyclization approaches,15 transition- thesis of diazonamide A3 (1) and related structures.
metal-catalyzed reactions,16 and oxidative coupling reaction.17
Towards this end, recently, we have reported an efficient
reaction of 3-aryl-3-hydroxy-2-oxindoles 5 with a variety of 2-π
electron rich substrates such as allyl/methallyl trimethylsilane,
phenylacetylene, acetophenone (via keto–enol tautomeriza-
tion), styrene, and indoles (see Scheme 1).26
Department of Chemistry, Indian Institute of Science Education and Research Bhopal,
Bhopal, M.P.-462 066, India. E-mail: alakesh@iiserb.ac.in
†This paper is dedicated to Professor Ganesh Pandey on the occasion of his
An architecturally interesting indole alkaloid, azonazine4 (2)
(Fig. 1), has recently been isolated from a Hawaiian marine
sediment-derived fungus Aspergillus insulicola, having a unique
hexacyclic dipeptide structure with a similar tetracyclic core to
that of diazonamide A (1) (Fig. 1). While working in the area of
60th Birthday.
‡Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, NMR spectra. CCDC 1007347–1007349 for ( )-4q,
( )-16a, and ( )-7. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ob01264j
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Scheme 2 Lewis acid-catalyzed F–C alkylations of electron-rich
aromatics.
Lewis acid-catalyzed activation of 3-alkyl-3-hydroxy-2-oxindoles
followed by nucleophilic attack with electron-rich aromatics.
Results and discussion
3-Hydroxy 2-oxindoles serve as versatile building blocks in the
syntheses of various indole alkaloids of immense biological
importance. Their ability to undergo a variety of nucleophilic
substitution reactions has made them extensively used as
powerful synthetic tools to realize different C–C bond forming
events. Towards this end, the Lewis acid catalyzed Friedel–
Crafts alkylations of aromatic compounds with electron-
deficient partners has prevalently been utilized in the for-
mation of C–C bonds in organic synthesis, but there are
limited reports on similar transformations involving 3-hydroxy
2-oxindole for the synthesis of 3,3-disubstituted-2-oxindoles
and, therefore, needs further exploration.
Fig. 1 Indole alkaloids (1, 2, and 6a–c) sharing an all-carbon quaternary
stereocenter and our approach.
The reactivities of 2H-indol-2-one ring (9) were tested in the
presence of Lewis acid-catalyzed activation of 3-alkyl/aryl-3-
hydroxy 2-oxindoles followed by nucleophilic attack with various
nucleophiles. At the outset, we carried out our studies taking
3-hydroxy 2-oxindole 5a as the electron-deficient partner for
the Friedel–Crafts alkylation of p-cresol. The optimization
studies for the Friedel–Crafts alkylation were performed with
p-cresol and 5a using BF3·OEt2 (Table 1) in different solvents
under reflux. We could obtain products in 51–54% yields with
24–40% of recovered 5a when the reactions were carried out in
aromatic solvents such as xylene, toluene, mesitylene and
benzene along with a multitude of spots on TLC (thin layer
chromatography). Acetonitrile as the solvent afforded the
product in only 56% yield with decomposition of the remain-
ing reaction mixture. We hypothesized that there is a possi-
bility of addition of acetonitrile to the intermediate 11 under a
Ritter type process.31 However, other solvents such as ethylace-
tate, diethylether, N,N-dimethylformamide, and tetrahydro-
furan were found to be inefficient, leading to recovery of 5a in
84–90% yields. Interestingly, chlorinated solvents were found
to be good, and it was observed that 50 mol%, 25 mol%, and
10 mol% of BF3·OEt2 in refluxing dichloromethane afforded
product 4a in 90%, 62%, and 38% yields, respectively, along
Scheme 1 Our report on C-centered nucleophiles.
development of methodologies for the synthesis of 2-oxi-
ndoles,27,28 we have reported an efficient Lewis acid-catalyzed
Friedel–Crafts alkylation of 4-substituted phenol29 (Scheme 2)
with 3-hydroxy 2-oxindoles to synthesize various 3,3-disubstituted
2-oxindoles having an all-carbon quaternary center at the pseudo-
benzylic position. We have also employed this methodology in the
construction of the tetracyclic core (3) of azonazine (2) from an
advanced 2-oxindole intermediate 4a in two steps viz. reduction of
2-oxindole followed by MnO2-promoted intramolecular oxidative
cyclization.30 We, herein, elaborate the scope and limitations of
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Table 1 Optimization of BF3·OEt2–HClO4-catalyzed F–C alkylations
Table 2 Optimization using Lewis acids
Entry Cat. (mol%)
Solvent
Temp. Time Yielda,b 8ac
Entry Lewis acid
Solvent
Temp. Time Yielda,b
1.
2.
3.
4.
5.
6.
7.
8.
50 mol% BF3·OEt2 CH2Cl2
25 mol% BF3·OEt2 CH2Cl2
25 mol% BF3·OEt2 CH2Cl2
40 °C 06 h 90%
40 °C 16 h 62%
40 °C 24 h 38%
—
1.
2.
3.
4.
5.
6.
7.
8.
Sc(OTf)3 (50 mol%)
In(OTf)3 (50 mol%)
Zn(OTf)2 (50 mol%) CH2Cl2
Zn(OTf)2 (50 mol%) CH2Cl2
Cu(OTf)2 (50 mol%) CH2Cl2
Sn(OTf)2 (50 mol%) CH2Cl2
CH2Cl2
CH2Cl2
25 °C
25 °C
25 °C
45 °C
25 °C
25 °C
25 °C
45 °C
45 °C
45 °C
45 °C
45 °C
45 °C
45 °C
45 °C
45 °C
45 °C
25 °C
45 °C
45 °C
45 °C
45 °C
45 °C
24 h
24 h
24 h
12 h
24 h
18 h
24 h
4 h
10%
46%
Traces
Traces
24%
42%
40%
95%
92%
92%
56%
90%
82%
53%
92%
91%
91%
94%
93%
94%
86%
79%
65%
89%
93%
95%
93%
83%
87%
90%
92%
73%
85%
82%
19%
32%
—
—
—
14%
09%
33%
12%
15%
19%
20%
28%
—
10 mol% BF3·OEt2 ClCH2CH2Cl 80 °C 04 h 97%
20 mol% BF3·OEt2 CHCl3 50 °C 06 h 83%
10 mol% BF3·OEt2 ClCH2CH2Cl 80 °C 04 h 93%
10 mol% BF3·OEt2 CHCl3 50 °C 10 h 70%
5 mol% BF3·OEt2 ClCH2CH2Cl 80 °C 12 h 85%
5 mol% BF3·OEt2 CHCl3 50 °C 16 h 54%
ClCH2CH2Cl 25 °C 16 h 75%
FeCl3 (50 mol%)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
In(OTf)3 (50 mol%)
In(OTf)3 (25 mol%)
In(OTf)3 (10 mol%)
FeCl3 (50 mol%)
Ce(OTf)3 (50 mol%) CH2Cl2
Ce(OTf)3 (25 mol%) CH2Cl2
Ce(OTf)3 (10 mol%) CH2Cl2
Cu(OTf)2 (50 mol%) CH2Cl2
Cu(OTf)2 (25 mol%) CH2Cl2
Cu(OTf)2 (10 mol%)
Bi(OTf)3 (50 mol%)
Bi(OTf)3 (25 mol%)
Bi(OTf)3 (10 mol%)
Sn(OTf)2 (50 mol%) CH2Cl2
Sn(OTf)2 (25 mol%) CH2Cl2
Sn(OTf)2 (10 mol%) CH2Cl2
9.
9.
5 h
7 h
10.
11.
12.
13.
14.
15.
16.
17.
18.
20 mol% HClO4
20 mol% HClO4
20 mol% HClO4
10 mol% HClO4
10 mol% HClO4
10 mol% HClO4
10 mol% HClO4
5 mol% HClO4
5 mol% HClO4
10.
11.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
CHCl3
CH2Cl2
25 °C 16 h 69%
25 °C 16 h 61%
18 h
12 h
12 h
16 h
12 h
14 h
12 h
12 h
12 h
10 h
14 h
14 h
15 h
3 h
3 h
3 h
3 h
4 h
4 h
4 h
4 h
6 h
ClCH2CH2Cl 25 °C 16 h 62%
CHCl3 25 °C 16 h 54%
ClCH2CH2Cl 80 °C 5 h
CHCl3 50 °C 5 h
ClCH2CH2Cl 80 °C 8 h
CHCl3 50 °C 8 h
96%
89%
89%
78%
—
08%
15%
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
a Reactions were carried out on a 0.5 mmol of 5a with 1.5 mmol
of p-cresol in
4
mL of solvent. b Isolated yields after column
chromatography. c Isolated starting materials.
Sn(OTf)2 (10 mol%) ClCH2CH2Cl 80 °C
with 19–32% recovery of 5a in two subsequent cases (entries
1–3, Table 1). On the other hand, refluxing chloroform also
afforded products in synthetically useful yields of 54–83%
(Table 1, entries 5, 7, and 9). Interestingly, changing the
solvent to a high boiling dichloroethane afforded 4a in high
yields (20 mol% and 10 mol% of BF3·OEt2 in refluxing dichloro-
ethane afforded products in 97% and 93%, respectively
(entries 4 and 6)) with faster rates. Further, the Friedel–Crafts
alkylations of p-cresol with 3-methyl 3-hydroxy 2-oxindole (5a)
were carried out in the presence of HClO4 in dichloroethane
and chloroform. We found that 10 mol% HClO4 in refluxing
dichloroethane and chloroform afforded products in 96% and
89%, respectively, whereas 5 mol% of HClO4 afforded 4a in
Cu(OTf)2 (10 mol%)
In(OTf)3 (10 mol%)
Bi(OTf)3 (10 mol%)
Cu(OTf)2 (5 mol%)
Sn(OTf)2 (5 mol%)
In(OTf)3 (5 mol%)
Bi(OTf)3 (5 mol%)
Cu(OTf)2 (2 mol%)
In(OTf)3 (2 mol%)
Bi(OTf)3 (2 mol%)
ClCH2CH2Cl 80 °C
ClCH2CH2Cl 80 °C
ClCH2CH2Cl 80 °C
ClCH2CH2Cl 80 °C
ClCH2CH2Cl 80 °C
ClCH2CH2Cl 80 °C
ClCH2CH2Cl 80 °C
ClCH2CH2Cl 80 °C
ClCH2CH2Cl 80 °C
ClCH2CH2Cl 80 °C
6 h
6 h
a Reactions were carried out on a 0.50 mmol of 5a with 1.50 mmol of
p-cresol in 4 mL of CH2Cl2 or ClCH2CH2Cl. b Isolated yields. Condition
A: In(OTf)3; condition B: Cu(OTf)2; condition C: Bi(OTf)3.
89% yields, along with 8% of recovered 5a (entry 17, Table 1). Although, under similar conditions, 25–50 mol% of Ce(OTf)3
These studies led us to conclude that 10 mol% BF3·OEt2 and and Sn(OTf)2 provided high yields of products (79–90% iso-
HClO4 in refluxing dichloroethane were optimal to achieve 4a lated yields) (entries 13, 14, 22, and 23), but 10 mol% of these
in high yields (Table 1).
catalysts afforded only 53% and 65% yields (entries 15 and
Further, we anticipated various metal triflate-catalyzed 24), respectively, where 29–32% starting materials were recov-
Friedel–Crafts alkylations of p-cresol with 3-hydroxy 2-oxindole ered from the reaction mixture.
(5a) (Table 2). It was observed that the reaction was sluggish
Changing the solvent to dichloroethane, 10 mol% of Sn-
despite higher catalyst loadings in dichloromethane at room (OTf)2, Cu(OTf)2, In(OTf)3, and Bi(OTf)3 furnished 4a in 89%,
temperature and 10–46% of yields were obtained (entries 1–7). 93%, 95%, and 93%, respectively (entries 25–28, Table 2).
However, under refluxing dichloromethane, 25–50 mol% of Interestingly, 5 mol% of these catalysts afforded 4a in the
In(OTf)3, Cu(OTf)2, and Bi(OTf)3 afforded 4a in 91–95% yields range of 83–92% yields (entries 29–32, Table 2). It is important
(entries 8–9, 16–17, and 19–20). Further optimization (Table 2) to note that 2 mol% of Cu(OTf)2, In(OTf)3, and Bi(OTf)3 was
showed that in refluxing dichloromethane 10 mol% of also efficient and afforded products in refluxing dichloro-
In(OTf)3 (condition A), Cu(OTf)2 (condition B), and Bi(OTf)3 ethane in synthetically useful 73%, 85%, and 82% yields,
(condition C) provided the F–C alkylation product 4a in 92% respectively. However, based on our optimization studies, in
(entry 10), 91% (entry 18), and 94% (entry 21), respectively. practice, 5–10 mol% of these catalysts were used for efficient
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Friedel–Crafts reaction of p-cresol with 3-hydroxy 2-oxindole 5a
Phthalimido and succinimido protected 3-aminoethyl-
in refluxing dichloroethane (Table 2). Thus, we considered 3-hydroxy-2-oxindoles 5h–i28 were prepared in two steps viz.
revisiting our methodology in refluxing dichloroethane, and N-protection of tryptamine with phthalic anhydride and
for that purpose a set of three different optimized conditions succinic anhydride in refluxing toluene to afford 12a–b and
was chosen viz. In(OTf)3 (condition A), Cu(OTf)2 (condition B), the latter upon CeCl3·7H2O-promoted oxidation using IBX
and Bi(OTf)3 (condition C).
afforded 5h–i in 56–65% yields (Scheme 4).
With the optimized conditions in hand, the reaction was
Under optimized conditions, substrates 5a–c were treated
extended to a variety of substrates shown in Fig. 2. A range of with p-cresol and 4-tert-butyl phenol as electron-rich partners
3-alkyl/aryl 3-hydroxy 2-oxindoles were synthesized directly and the results are summarized in Scheme 5. We found that
from isatin. 3-Allyl-3-hydroxy 2-oxindoles 5d–f and 5k were syn- p-cresol and 4-tert-butyl phenol were efficiently added to 5a
thesized in very good to excellent yields from N,N-dimethyl- under optimized conditions to furnish products 4a–b in
formamide (DMF) catalyzed reactions of isatins and 86–95% yields only in 3 h (Scheme 5). In the case of halogen
allyltrichlorosilane (Scheme 3).32
substituted 3-hydroxy-2-oxindoles 5b–c, the reaction rates were
a little slower than the one with no substitution (5a). Evidently,
the electron-withdrawing halogen substituent hampers the for-
Scheme 4 Synthesis of 3-hydroxy-2-oxindole ( ) 5h–i.
Fig. 2 3-Hydroxy-2-oxindoles 5a–s used in this study.
Scheme 5 Substrates scope using 3-hydroxy-2-oxindoles 5a–c. [Reac-
tions were carried out on a 0.50 mmol of 5 with 1.50 mmol of p-cresol
or 4-tert-butylphenol in 4 mL of ClCH2CH2Cl (DCE) at 80 °C and iso-
lated yields column chromatography. Condition A: 10 mol% In(OTf)3;
condition B: 10 mol% Cu(OTf)2; condition C: 10 mol% Bi(OTf)3.]
Scheme 3 Synthesis of allylated 3-hydroxy-2-oxindoles 5d–f, and 5k.
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Scheme 7 Synthesis of N-methyl-3-hydroxy-2-oxindoles 5j and 5s.
Scheme 6 Substrates scope using 3-hydroxy-2-oxindoles 5d–f and 5h.
[Reactions were carried out on a 0.50 mmol of 5 with 1.50 mmol
of p-cresol or 4-tert-butylphenol in 4 mL of ClCH2CH2Cl (DCE) at
80 °C and isolated yields after column chromatography. Condition A:
10 mol% In(OTf)3; condition B: 10 mol% Cu(OTf)2; condition C: 10 mol%
Bi(OTf)3.]
mation of the electron-deficient 2H-indol-2-one ring system of
the type 11.
Further, 3-hydroxy-2-oxindoles 5d–f were also tested with
p-cresol and p-tBu-phenol and found as suitable electron-
deficient partners furnishing Friedel–Crafts alkylation products
4g–l in up to 93% isolated yields (Scheme 6). Similarly, 2-oxindole
5h bearing an aminoethyl protected functionality afforded
products 4m–n in 72–89% yields under optimized conditions.
These compounds could also serve as advanced intermediates
for the core structure of diazonamide (1) and azonazine (2) as
well as C(3a)-arylpyrroloindolines of the type 7 as shown in Fig. 1.
Later, to test whether N-methyl-3-hydroxy-2-oxindoles also
shows similar reactivity towards Friedel–Crafts alkylations, we
employed N-methyl-3-hydroxy-2-oxindoles 5j and 5s under
optimized conditions. These oxindole substrates were syn-
thesized in 86–88% yields via a direct Grignard reactions of
N-methylisatin (Scheme 7).
Scheme 8 Substrates scope using N-methyl-3-hydroxy-2-oxindoles
5j–k. [Reactions were carried out on a 0.50 mmol of 5 with 1.50 mmol
of p-cresol or 4-tert-butylphenol in 4 mL of ClCH2CH2Cl at 80 °C and
isolated yields are reported after column chromatography. Condition A:
10 mol% In(OTf)3; condition B: 10 mol% Cu(OTf)2; condition C: 10 mol%
Bi(OTf)3.]
Delightfully, we found that 5j–k works equally well as elec-
tron-deficient partners in refluxing dichloroethane in the pres-
ence of 10 mol% of In(OTf)3 (condition A), Cu(OTf)2
(condition B), and Bi(OTf)3 (condition C) and afforded pro-
ducts 4o–r in 75–91% yields (Scheme 8). One of the F–C alkyl-
ation products (4q: CCDC 1007347) gave a suitable crystal for
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Scheme 9 Synthesis of N-methyl-3-methoxy-2-oxindoles 5l–n.
X-ray analysis, which unambiguously proved the formation of
all-carbon quaternary center.
After the successful use of N-methyl substrates 5j–k, we
then probed the reactivity of 3-alkoxy-2-oxindoles such as 5l–n
as electron-deficient partners in Friedel–Crafts alkylations.
Towards this, few N-methyl-3-alkyl-3-methoxy 2-oxindoles 5l–n
were prepared via N,O-dimethylation of 3-hydroxy-2-oxindoles
5a–b and 5d in the presence of NaH in DMF to afford products
in 79–87% yields (Scheme 9).
We found that 2-oxindole substrates 5l–n can also be acti-
vated in the presence of Lewis acids without event, to effect
Friedel–Crafts reactions in the presence of 10 mol% of metal
triflates in refluxing dichloroethane furnishing products 4o–t
in the range of 85–95% yields (Scheme 10).
Further, we set forth to investigate a general method for the
reaction of phenol with 3-hydroxy-2-oxindoles 5a, 5d and 5g–h
as substrates in the presence of catalytic Lewis acids. We
found that 10 mol% of metal triflates such as In(OTf)3 (con-
dition A), Cu(OTf)2 (condition B), and Bi(OTf)3 (condition C)
afforded products 13a–d in up to 86% yields under refluxing
dichloroethane (Scheme 11). Notably, in all cases phenol
reacts exclusively at the p-position to afford compounds 13a–d.
Also, 2-oxindole products having propargyl, allyl, and N-phtha-
limide protected 2-aminoethyl groups such as 13b–d could
serve as important intermediates for the synthesis of C-(3a)-
pyrroloindoline of the type 7 in high yields (Fig. 1).
Scheme 11 Substrates scope of Friedel–Crafts alkylations using
phenol. [Reactions were carried out on a 0.50 mmol of 5 with 1.5 mmol
of p-cresol or 4-tert-butylphenol in 4 mL of ClCH2CH2Cl at 80 °C and
isolated yields are reported after column chromatography. Condition A:
5 mol% In(OTf)3; condition B: 5 mol% Cu(OTf)2; condition C: 5 mol%
Bi(OTf)3.]
Mechanistically, the reaction could proceed through the for-
mation of 2H-indol-2-one (11) (Scheme 12) formed upon treat-
ment of 3-hydroxy-2-oxindole (5) with a Lewis acid as per the
literature report.25c The electron-rich p-position of phenol
derivatives could easily react with 2H-indol-2-one (11) to afford
Scheme 10 Substrates scope using N,O-dimethyl-3-hydroxy-2-oxi-
ndoles 5l–n. [Reactions were carried out on a 0.50 mmol of 5 with
1.50 mmol of p-cresol or 4-tert-butylphenol in 4 mL of ClCH2CH2Cl at
80 °C and isolated yields are reported after column chromatography.
Condition A: 10 mol% In(OTf)3; condition C: 10 mol% Bi(OTf)3.]
Scheme 12 Proposed mechanism for F–C alkylations of phenols.
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the required products with excellent regioselectivity. Alterna- refluxing dichloromethane and dichloroethane identified as
tively, the reaction could also follow a path where intermediate optimal solvents of choice, we anticipate metal triflate-cata-
(11) forms twice during the course of the reaction, initially lyzed Friedel–Crafts alkylations of anisole with 3-hydroxy 2-oxi-
from the starting 3-hydroxy-2-oxindole (5) in the presence of ndole (5d) using Zn(OTf)2, Cu(OTf)2, Sn(OTf)2, Bi(OTf)3, In-
Lewis acid and at a later stage from the 3-O-aryloxy-2-oxindoles (OTf)3, and these results are shown in Table 3. We found that
(14) via a C–O bond breaking through a dissociated ion pair 20 mol% of Zn(OTf)2, Cu(OTf)2, Sn(OTf)2, Bi(OTf)3, and In-
following a photo-Fries type rearrangement as reported by (OTf)3 in refluxing dichloroethane (DCE) afforded the Friedel–
Magnus (Scheme 12).20 In the latter case, one would expect a Crafts alkylation product 8a in 32%, 75%, 80%, 90%, and
regioisomeric (para : ortho) mixture of products. However, the 92%, respectively (entries 2, 6, 10, 14, and 15). The results in
exclusive formation of p-substituted products (13) (Scheme 11), Table 3 also clearly indicate that dichloroethane is a better
together with the literature report on the thermal and acid- choice than dichloromethane as a solvent. On further optimi-
catalyzed rearrangement of 3-N-aryl-2-oxindoles and 3-O- zation, it was observed that 10 mol% of In(OTf)3 (entry 16,
aryloxy-2-oxindoles (14) into 3-(p-aminoaryl)-2-oxindoles21 and condition A) and Bi(OTf)3 (entry 19, condition C) in refluxing
3-(p-hydroxyaryl)-2-oxindoles (13),20 respectively, following a dichloroethane afforded 8a in 89% and 90%, respectively.
photo-Fries20 or Hofmann–Martius rearrangement21 supports Thus, based on the optimized results, conditions A and C were
a direct attack of the p-position of electron-rich phenols to chosen for further studies.
2H-indol-2-one (11) simply leading to the final products.
As expected, under optimized conditions (condition A:
Later, the Friedel–Crafts alkylation was extended to various 10 mol% In(OTf)3 and condition C: 10 mol% Bi(OTf)3 in
electron-rich aromatics other than phenol derivatives such as refluxing dichloroethane), 5a and 5d as electron-deficient
anisole, veratrole, resorcinol dimethylether, furan, thioanisole, substrates afforded a variety of Friedel–Crafts alkylation pro-
pyrroles, indoles, etc. with 3-hydroxy 2-oxindoles (5). Towards ducts in the presence of electron-rich partners such as anisole,
this end, we again initiated our optimization with 3-allyl catechol, dimethylether, resorcinol dimethylether, and quinol
3-hydroxy 2-oxindole 5d as a model substrate with 3 equiv. of dimethylether (Fig. 3). In all cases 2-oxindole products having
anisole in the presence of various Lewis acids (Table 3). By an all-carbon quaternary center were achieved in 82–93%
yields (Fig. 3). The reaction could also be extended to
substrates having an acetylinic group such as 5g to afford pro-
Table 3 Optimization of F–C alkylations of anisole in the presence of
various Lewis acids
ducts 8i–k in 82–89% yields in 8–10 h. It is noteworthy that 2-
oxindoles having allyl and propargyl groups at the C-3 position
of 2-oxindoles such as 8a–d and 8i–k have the potential for
further functionalization by exploiting allylic/acetylinic func-
tional groups.33
Further, the reaction was extended to substrates 5h–i
having
a
phthalimido/succinimido-protected aminoethyl
group at the 3-position of 2-oxindoles (Scheme 4). Under opti-
mized conditions A and C, a variety of products possessing an
all-carbon quaternary stereocenter at the pseudobenzylic C(3a)-
position such as 8l–t could be achieved in up to 92% yields
from 5h–i (Fig. 4). Importantly, 2-oxindoles having a furan
scaffold at the C-(3a) position such as 8o and 8t could also be
synthesized in 65–82% yields. The latter could serve as an
excellent synthetic intermediate to access various indole alka-
loids following oxidative cleavage of the furan moiety.34
Having established the practical viability of exploring the
nucleophilic attack on 3-alkyl-3-hydroxy-2-oxindoles, we next
investigated the reaction of 3-aryl-3-hydroxy-2-oxindoles 5o–s
(Fig. 2). Our interest in 3,3-diaryloxindoles 15a–c (Fig. 5) is due
to their immense biological activities such as mineralocorto-
coid receptor antagonists, anti-cancer, anti-bacterial, anti-
protozoal, and anti-inflammatory activities.25c,35,36 Few members
of this group are also used as laxatives.36e It has also been
identified that 3,3-diphenyl-2-oxindole 15a (Fig. 5), could be
used as Ca2+-depleting translation initiation inhibitors as
shown by Halperin and co-workers.25b
Recovered
Entry Cat. (mol%)
Solvent Temp. Time Yielda,b 5dc
1.
2.
3.
4.
5.
6.
7.
8.
20 mol% Zn(OTf)2 CH2Cl2 40 °C 24 h 10%
20 mol% Zn(OTf)2 DCE 80 °C 24 h 32%
10 mol% Zn(OTf)2 CH2Cl2 40 °C 24 h Trace
10 mol% Zn(OTf)2 DCE 80 °C 24 h 25%
20 mol% Cu(OTf)2 CH2Cl2 40 °C 24 h 12%
20 mol% Cu(OTf)2 DCE 80 °C 24 h 75%
10 mol% Cu(OTf)2 CH2Cl2 40 °C 24 h Trace
10 mol% Cu(OTf)2 DCE 80 °C 24 h 61%
20 mol% Sn(OTf)2 CH2Cl2 40 °C 24 h 10%
20 mol% Sn(OTf)2 DCE 80 °C 24 h 80%
10 mol% Sn(OTf)2 CH2Cl2 40 °C 24 h Trace
10 mol% Sn(OTf)2 DCE 80 °C 24 h 69%
20 mol% Bi(OTf)3 CH2Cl2 40 °C 24 h 71%
72%
55%
87%
62%
79%
14%
90%
24%
78%
9%
84%
17%
19%
—
—
—
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
20 mol% Bi(OTf)3 DCE
20 mol% In(OTf)3 DCE
10 mol% In(OTf)3 DCE
80 °C 24 h 90%
80 °C 24 h 92%
80 °C 24 h 90%
80 °C 30 h 78%
5 mol% In(OTf)3
DCE
10%
53%
—
10 mol% Bi(OTf)3 CH2Cl2 40 °C 24 h 38%
10 mol% Bi(OTf)3 DCE
5 mol% Bi(OTf)3 DCE
80 °C 24 h 89%
80 °C 30 h 76%
15%
a Reactions were carried out on a 0.2 mmol of 5d with 0.6 mmol of
anisole in 2.0 mL of solvent. b Isolated yields after column
chromatography. c Condition A: 10 mol% In(OTf)3; condition C:
10 mol% Bi(OTf)3.
We found that, 3-hydroxy-3-aryl-2-oxindoles 5o–s as elec-
tron-deficient partners resulted in comparatively faster and
efficient reactions working in just 5 mol% of catalyst loading.
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Fig. 3 Substrate scopes of Friedel–Crafts alkylations. [Reactions were
carried out on a 0.2 mmol of 5 with 0.6 mmol of electron-rich arene in
2.0 mL of DCE (1,2-dichloroethane) at 80 °C. Isolated yields after purifi-
cation. Condition A: 10 mol% In(OTf)3; condition C: 10 mol% Bi(OTf)3.]
N-Unsubstituted-3-aryl-2-oxindoles such as 5o–p were used to
effect the Friedel–Crafts alkylations of p-cresol, p-tBu-phenol,
and phenol as electron-rich substrates. To our delight, we
could synthesize a variety of products having unsymmetrical
3,3-diarylated 2-oxindoles 16a–f in good to excellent yields (up
to 95% yields) in the presence of only 5 mol% of Lewis acids
in only 2–4 h under refluxing dichloroethane (Scheme 13).
Similarly, N-methyl-3-hydroxy-2-oxindole 5s was also found to
be a good substrate for F–C alkylation reactions, which furn-
ished 2-oxindoles 16g–i in excellent yields in just 2 h in reflux-
ing dichloroethane. Gratifyingly, one of the 3,3-diarylated 2-
oxindoles (16a: CCDC 1007348) provided X-ray suitable for ana-
lysis, which unambiguously proved the structure of F–C alky-
lation adducts.
Fig. 4 Further substrate scopes of Friedel–Crafts alkylations. [Reactions
were carried out on a 0.2 mmol of 5 with 0.6 mmol of electron-rich
arene in 2.0 mL of DCE (1,2-dichloroethane) under reflux. Isolated yields
after column chromatography. Condition A: 10 mol% In(OTf)3; condition
C: 10 mol% Bi(OTf)3.]
Further, the F–C alkylations were extended to 3-aryl-2-
oxindoles such as 5o–r in the presence of anisole as an electron-
rich substrate, which afforded symmetrical and unsymmetrical
3,3-diarylated 2-oxindoles 16j–m in 73–91% yields
(Scheme 14). We also found that, pyrrole and N-tosylated
pyrrole could also be used as electron-rich aromatics which
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Fig. 5 Important 3,3-diaryl 2-oxindoles 15a–c.
afforded F–C alkylation products 16n–o in good yields in the
presence of 5 mol% of In(OTf)3 (condition A) and Bi(OTf)3
(condition C). We found that indole could react with
3-hydroxy-2-oxindoles 5p–r only in the presence of 2 mol% of
metal triflates to afford 16p–r in 82–91% yields (Scheme 14).26
Along similar lines, N-methylindole furnished product 16s in
82–84% yields in the presence of 5 mol% of metal triflates
(Scheme 14).37
It is important to note that the reactions are faster when
3-hydroxy 3-aryl 2-oxindoles (5o–s) contain an aromatic group
at the 3-position. We believe that this might be due to the
pseudo dibenzylic nature of the 2H-indol-2-one ring system of
the types 9a–b (in the case of 5o–s) as shown in Fig. 6, which
gets further stabilized by the additional aromatic ring as com-
pared to 3-hydroxy 3-alkyl 2-oxindoles 5a–d.
We further checked the efficiency of Lewis acid catalyzed
F–C alkylations with aromatic amines. We observed only 18–22%
yield of 17a, when reactions were carried out with 1 equiv. of
N-methylaniline in the presence of 10 mol% catalysts under
refluxing dichloroethane (Scheme 15). The inefficiency of F–C
alkylations might be due to deactivation of metal triflates in
the presence of the basic nature of aromatic amines. There-
fore, it was decided to carry out the reactions using N-pro-
tected aniline, such as acetanilide,37 where the basicity level of
aniline is notably suppressed by an acetyl group. Interestingly,
when acetanilide was used as an electron-rich partner, F–C
alkylation products 17b–c were isolated in 62–78% yields with
just 5 mol% catalyst loading (Scheme 15).37
Eventually, we were interested in synthesizing few advanced
intermediates from the 2-oxindole products such as the tetra-
cyclic core of azonazine (2) through a reductive cyclization
approach as shown in Scheme 16. Efforts in this direction led
to either a multitude of products or incomplete reductions of
the 2-oxindole moiety. In the case of reduction using LiAlH4
we could isolate the over-reduced product 18 which on sub-
sequent acetylation afforded bis acetylated product 19 in 72%
yield over 2 steps (Scheme 16). Although it was disappointing
at the first instance, this led us to consider exploiting intra-
molecular oxidative coupling of intermediate 18 to craft the
Scheme 13 Substrates scope of Friedel–Crafts alkylations using
phenol. [Reactions were carried out on
a 0.50 mmol of 5 with
1.50 mmol of p-cresol or 4-tert-butylphenol in 4 mL of ClCH2CH2Cl at
80 °C and isolated yields are reported after column chromatography.
Condition A: 5 mol% In(OTf)3; condition C: 5 mol% Bi(OTf)3.]
tetracyclic core (3) as originally reported by Nicolaou for diazo- iminium intermediate 20c via the intermediacy of 20b. The
namide A 1.30
phenoxide of 20c then reacts with the iminium ion intramole-
Gratifyingly, when compound 18 was treated with MnO2 in cularly to afford the tetracyclic core 3a.28 On subsequent treat-
refluxing benzene, it leads to the formation of tetracyclic core ment with acetic anhydride and triethylamine, the tetracyclic
3a in 72% yield.28 Mechanistically, α-elimination of intermedi- core 3a was converted to N-acetyl compound 3b resembling the
ate Mn(IV)-complex 20a under oxidative environment forms an core structure of azonazine (2) in 85% yield (Scheme 17).
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Scheme 15 Friedel–Crafts alkylations using aromatic amine. [Reactions
were carried out on a 0.3 mmol of 5 with 0.3 mmol of aniline derivatives
in 2 mL of 1,2-dichloroethane. Condition A: 5 mol% In(OTf)3; condition
C: 5 mol% Bi(OTf)3. a10 mol% Lewis acids were used.]
Scheme 16 Reductive cyclization approach to 3.
Scheme 14 Scopes using 3-aryl-3-hydroxy-2-oxindoles. [Reactions
were carried out on a 0.2 mmol of 5 with 0.6 mmol of anisole in 2 mL of
1,2-dichloroethane. Isolated yields after column chromatography. Con-
dition A: 5 mol% In(OTf)3; condition C: 5 mol% Bi(OTf)3.]
Scheme 17 Crafting the tetracyclic core 3a via oxidative coupling.
Fig. 6 Proposed reactive intermediates (9a–b).
shown in Scheme 18. The cleavage of the phthalide group of 8l
using hydrazine hydrate followed by treatment with (Boc)2O
leads to the bis-Boc protected compound 21 in 80% overall
yields over 2 steps. The reduction of N-Boc protected amide
Further, in search of the core structure of naturally occur-
ring alkaloids such as asperazine (6a), idiospermuline (6b),
and calycosidine (6c) (Fig. 1), one of the F–C alkylation pro-
ducts was converted into C-(3a)-aryl pyrrolindoline38 7 as
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Material and methods
Chemicals and reagents were purchased from commercial
sources and used without further purification. Unless
otherwise stated, reactions were performed in an oven-dried
glassware fitted with rubber septa under an inert atmosphere
and were stirred with Teflon-coated magnetic stirring
bars. Tetrahydrofuran (THF) and toluene were distilled over
sodium/benzophenone ketyl. Dichloromethane, chloroform,
and dichloroethane were distilled over calcium hydride. All
other solvents such as DMF, acetonitrile, methanol were used
as received. Thin layer chromatography was performed using
Silicagel 60 F-254 precoated plates (0.25 mm) and visualized by
UV irradiation, anisaldehyde stain and other stains. Silicagel
of particle size 100–200 mesh was used for flash chromato-
graphy. 1H and 13C NMR spectra were recorded on 400,
500 MHz spectrometers with 13C operating frequencies of 100,
125 MHz, respectively. Chemical shifts (δ) are reported in ppm
relative to the residual solvent (CDCl3) signal (δ = 7.26 for
Scheme 18 Synthesis of C-3(a)-aryl pyrroloindoline 7. [Reaction con-
ditions: (a) NH2-NH2·H2O, MeOH–CH2Cl2, 25 °C, 12 h; (b) (Boc)2O, Et3N,
CH2Cl2, DMAP (cat.), 25 °C, 24 h; (c) NaBH4, THF–MeOH, 0 °C, 10 min
then CSA, 25 °C, 4 h.]
1
1H NMR and δ = 77.0 for 13C NMR). Data for H NMR spectra
are reported as follows: chemical shift (multiplicity, coupling
constants, number of hydrogen). Abbreviations are as follows:
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br
(broad). IR spectra were recorded on a FT-IR system (Spectrum
BX) and are reported in frequency of absorption (cm−1). Only
selected IR absorbencies are reported. High-Resolution Mass
Spectrometry (HRMS) and Low-Resolution Mass Spectrometry
(LRMS) data were recorded on MicrOTOF-Q-II mass spectro-
meter using methanol as the solvent.
Caution! HClO4 has a powerful oxidizing property. Although
the use of 70% aqueous solution of HClO4 as the catalyst
could reduce the potential danger associated with HClO4, it is
important to take special care while carrying out the reaction.
For important information, see: http://en.wikipedia.org/wiki/
Perchloric_acid.
functionality of 2-oxindole 21 in the presence of NaBH4 led to
the formation of lactol intermediate which upon cyclization in
the presence of camphorsulfonic acid (CSA) constructs the tri-
cyclic core 7 in 71% yield over 2 steps.39 The X-ray structure of
7 (CCDC 1007349) unambiguously proved the formation of
C-(3a)-aryl pyrroloindoline.40
Conclusion
For synthesis and characterization of 5a–d, 5g–h, 4a–h,
In summary, we developed an efficient approach toward the 4m–n, 13a–d, 18, 19, 3a, and 3b, see ref. 28. For synthesis and
Lewis acid-catalyzed Friedel–Crafts alkylations of phenol characterization of 5o–r, 8a–b, and 16p–r see ref. 26.
derivatives and electron-rich aromatics with a variety of
General procedure for DMF-catalyzed allylations to isatins
(Scheme 3)
3-hydroxy-2-oxindoles. The current Friedel–Crafts alkylation
strategy relies on the utility of the 2H-indol-2-one ring (9),
formed in the presence of Lewis acids, to afford oxindole To a stirred solution of N-methyl isatin (11.0 mmol, 1.0 equiv.)
derivatives (4, 8, 13, and 16) possessing an all-carbon quatern- in DMF (10 mL) at 0 °C was added allyltrichlorosilane
ary stereocenter at the C(3a)-position. We applied this method- (13.2 mmol, 1.2 equiv.). Then the mixture was stirred for 1 h at
ology in the synthesis of the tetracyclic core (3) of diazonamide 0 °C. Upon completion of the reaction (Judged by running
A (1) and azonazine (2) through a late-stage intramolecular oxi- TLC), the reaction mixture was quenched by adding H2O and
dative coupling. Further synthetic viability is shown by con- extracted with 40% EtOAC–hexane (50 mL × 3). The combined
structing C-(3a)-aryl pyrrolindoline subunits 3a, which could organic layers were dried over anhydrous Na2SO4 and concen-
be an advanced intermediate to access a variety of naturally trated under reduced pressure. The crude mixture was purified
occurring oxindole based alkaloids. We believe that nucleo- by column chromatography by using EtOAC and hexane to
philic addition to the 2H-indol-2-one ring (9) using a chiral afford the desired product.
Lewis acid-complex could be one of the promising platforms
to accomplish these targets in an enantioenriched form.
3-Allyl-5-chloro-3-hydroxyindolin-2-one (5e)
Further exploration towards this as well as its application in Yield 86%. The product was obtained as a yellowish solid, Rf =
the synthesis of complex alkaloids is currently under active 0.43 (40% EtOAc in hexane). 1H NMR (400 MHz, 0.4 mL
investigation.
CDCl3, 0.1 mL DMSO-D6) δ 9.49 (brs, 1H), 7.31–7.34 (m, 1H),
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7.16–7.21 (m, 1H), 6.80 (t, J = 7.88 Hz, 1H), 5.57–5.69 (m, 1H), 134.3, 133.0, 129.0, 126.5, 114.6, 79.3, 40.4, 38.2, 33.1; IR
5.07–5.11 (m, 2H), 4.98 (brs, 1H), 2.69–2.76 (m, 1H), 2.57–2.64 (film) νmax 3730, 3336, 2929, 2360, 1696, 1583, 1404, 1140,
(m, 1H); 13C NMR (100 MHz, 0.4 mL CDCl3, 0.1 mL DMSO-D6) 1051, 745, 424 cm−1; HRMS (ESI) m/z 297.0851 [(M + Na)+; cal-
δ 179.2, 140.1, 133.1, 130.8, 128.6, 126.8, 124.4, 119.4, 110.9, culated for [C14H14N2O4 + Na]+: 297.0846]; MP 188–191 °C.
75.9, 42.4; IR (film) νmax 3248, 2663, 1708, 1469, 1180, 1088,
770 cm−1; HRMS (ESI) m/z 224.0473 [M + H]+; calculated for
General procedure for Grignard addition to isatins (Scheme 7)
[C11H11ClNO2]+: 224.0458; MP 184–187 °C.
To a stirred solution of N-methyl isatin (9.93 mmol, 1.0 equiv.)
3-Allyl-5-bromo-3-hydroxyindolin-2-one (5f)
in dry THF (20 mL) at 0 °C was added RMgBr (11.92 mmol,
1.2 equiv.). Then the mixture was stirred for 1 h at 0 °C,
allowed to warm to rt and stirred for 10 h. Upon completion of
the reaction, the reaction mixture was quenched by adding
saturated NH4Cl solution and extracted with EtOAC. The com-
bined organic layers were dried over anhydrous NaSO4 and
concentrated under reduced pressure. The crude mixture was
purified by column chromatography by using EtOAC and a
hexane mixture as eluents to afford the desired product.
Yield 92%. The product was obtained as a yellowish solid, Rf =
0.45 (40% EtOAc in hexane). 1H NMR (400 MHz, 0.4 mL
CDCl3, 0.1 mL DMSO-D6) δ 9.58 (br, 1H), 6.99–7.19 (m, 2H),
6.44–6.52 (m, 1H), 5.28–5.38 (m, 1H), 4.79 (m, 2H), 3.93 (brs,
1H), 2.29–2.49 (m, 2H); 13C NMR (100 MHz, 0.4 mL CDCl3,
0.1 mL DMSO-D6) δ 179.1, 140.5, 133.4, 131.6, 130.8, 127.3,
119.5, 114.2, 111.5, 75.9, 42.4; IR (film) νmax 3665, 2355, 1700,
1446, 1181, 1119, 1080 cm−1; HRMS (ESI) m/z 267.9940
[M + H]+; calculated for [C11H11BrNO2]+: 267.9968; MP
192–195 °C.
3-Hydroxy-1,3-dimethylindolin-2-one (5j)
Yield 86%. The product was obtained as a yellowish solid, Rf =
0.49 (50% EtOAc in hexane). H NMR (400 MHz, CDCl3) δ 7.39
3-Allyl-3-hydroxy-1-methylindolin-2-one (5k)
1
Yield 82%. The product was obtained as a reddish solid, Rf =
(d, J = 7.28 Hz, 1H), 7.30 (t, J = 7.68 Hz, 1H), 7.08 (t, J = 7.48 Hz,
1H), 6.82 (d, J = 7.76 Hz, 1H), 3.53 (brs, 1H), 3.17 (s, 3H), 1.59
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 178.8, 142.8, 131.6,
129.6, 123.4, 123.3, 108.5, 73.7, 26.2, 24.8; IR (film) νmax 3399,
1
0.39 (40% EtOAc in hexane). H NMR (400 MHz, CDCl3) δ 7.37
(d, J = 7.36 Hz, 1H), 7.31 (m, 1H), 7.08 (t, J = 7.48 Hz, 1H), 6.81
(d, J = 7.72 Hz, 1H), 5.57–5.68 (m, 1H), 5.05–5.10 (m, 2H), 3.16
(s, 1H), 2.56–2.75 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 177.9,
143.2, 130.5, 129.8, 129.6, 124.1, 123.1, 120.3, 108.4, 76.0, 42.9,
26.2; IR (film) νmax 3575, 1696, 1612, 1465, 1384, 1307, 1213,
1092, 933, 754, 639, 426 cm−1; HRMS (ESI) m/z 204.1020
[M + H]+; calculated for [C12H14NO2]+: 204.1019; MP 132–137 °C.
1701, 1374, 1301, 1252, 1175, 1095, 1031, 943, 826, 757 cm−1
;
HRMS (ESI) m/z 178.0860 [M + H]+; calculated for [C10H12NO2]+:
178.0863; MP 154–159 °C.
3-Hydroxy-3-(4-methoxyphenyl)-1-methylindolin-2-one (5s)
Synthesis of 5i from 12b (Scheme 4)
Yield 88%. The product was obtained as a yellowish solid, Rf =
0.49 (50% EtOAc in hexane). Rf = 0.48 (30% EtOAc in hexane).
1H NMR (400 MHz, CDCl3) δ 7.24–7.33 (m, 4H), 7.06 (t, J = 7.32
Hz, 1H), 6.85 (d, J = 7.76 Hz, 1H), 6.78–6.81 (m, 2H), 4.08 (brs,
1H), 3.73 (s, 3H), 3.16 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 177.8, 159.5, 143.4, 132.3, 131.8, 129.7, 127.0, 124.9, 123.5,
113.9, 108.6, 55.3, 26.5; IR (film) νmax 3305, 1699, 1660,
1618, 1428, 1219, 1130, 750 cm−1; HRMS (ESI) m/z 292.0930
[M + Na]+; calculated for [C16H15NO3 + Na]+: 292.0944.
A round-bottom flask was charged with N-succinimido pro-
tected tryptamine (5 mmol, 1.0 equiv.) in MeCN and H2O
(9 : 1) and then kept at 0 °C. IBX (12.5 mmol, 2.5 equiv.) was
added in one portion followed by the addition of cerium(III)
chloride heptahydrate, and then stirring was continued for
1 h. Upon completion of the reaction (as judged by TLC), the
reaction mixture was quenched at 0 °C with saturated aqueous
NaHCO3 (15 mL for 5 mmol). Then the reaction mixture was
diluted with 100 mL of CH2Cl2. The whole reaction mixture
was taken in a separatory funnel and extracted with CH2Cl2
(50 mL × 2). The organic filtrate was dried over Na2SO4 and
General procedure of N,O-dimethylations (Scheme 9)
concentrated in a rotary evaporator under reduced pressure. A flame-dried round-bottom flask was charged with 3-substi-
The crude products were purified by flash chromatography tuted 3-hydroxy 2-oxindole (1.0 mmol, 1.0 equiv.) in DMF
(1 : 1–1 : 2 hexanes–EtOAc) to afford compound (5i) in 65% yield. (6 mL) and then NaH (2.2 mmol, 2.2 equiv.) was added to it at
0 °C. After 5 minutes of stirring at the same temperature, MeI
1-(2-(3-Hydroxy-2-oxoindolin-3-yl)ethyl)pyrrolidine-2,5-dione (5i)
(Scheme 4)
(2.5 mmol, 2.5 equiv.) was added. The reaction mixture was
stirred at 0 °C for 2 h. Upon completion of the reaction
The product was obtained as a white solid, Rf = 0.34 (EtOAc). (Judged by running TLC), the reaction mixture was quenched
1H NMR (400 MHz, DMSO) δ: 10.25 (brs, 1H), 7.27–7.13 by adding a saturated NH4Cl solution and extracted with
(m, 2H), 6.97–6.91 (m, 1H), 6.80–6.77 (m, 1H), 5.98 (s, 1H), EtOAC. The combined organic layers were dried over anhy-
3.52–3.39 (m, 2H), 2.43 (m, 4H), 2.01–1.84 (m, 2H); 13C NMR drous NaSO4 and concentrated under reduced pressure. The
of one rotamer (100 MHz, DMSO) δ: 183.8, 182.8, 147.9, 136.7, crude mixture was purified by column chromatography by
134.2, 129.1, 126.9, 115.0, 79.3, 48.3, 39.6, 33.1; 13C NMR of using EtOAC and hexane as an eluent to afford the desired
another rotamer (100 MHz, DMSO) δ: 183.5, 182.6, 146.7, product.
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3-Methoxy-1,3-dimethylindolin-2-one (5l)
(s, 1H), 7.06 (d, J = 8.23 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J =
8.03 Hz, 1H), 6.71 (d, J = 8.17 Hz, 1H), 5.28–5.38 (m, 1H), 5.00
(d, J = 16.93 Hz, 1H), 4.93 (d, J = 10.20 Hz, 1H), 3.17 (dd, J =
13.25, 8.35 Hz, 1H), 2.95 (dd, J = 13.32, 6.12 Hz, 1H), 2.22
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 183.8, 152.8, 139.2,
133.5, 131.1, 130.0, 129.7, 128.4, 128.3, 128.2, 125.4, 124.1,
120.1, 118.7, 111.5, 57.1, 39.8, 20.8; IR (film) νmax 3281, 1699,
Yield 81%. The product was obtained as a yellowish solid, Rf =
0.39 (30% EtOAc in hexane). 1H NMR (400 MHz, CDCl3)
δ 7.32–7.28 (m, 2H), 7.09–7.06 (m, 1H), 6.82 (d, J = 7.72 Hz,
1H), 3.19 (s, 3H), 2.97 (s, 3H), 1.50 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 176.5, 143.5, 129.7, 128.6, 123.7, 123.1, 108.4, 79.6,
53.0, 26.1, 23.8; IR (film) νmax 3558, 2934, 1715, 1615, 1455,
1374, 1304, 1114, 1247, 1061, 1025, 820 cm−1; HRMS (ESI) m/z
192.1022 [M + H]+; calculated for [C11H14NO2]+: 192.1019; MP
79–82 °C.
1621, 1479, 1332, 1234, 1182, 1117, 925, 895, 815, 740 cm−1
;
HRMS (ESI) m/z 314.0955 [M
+
H]+; calculated for
[C18H17ClNO2]+: 314.0942.
3-Allyl-3-methoxy-1-methylindolin-2-one (5m)
3-Allyl-3-(5-(tert-butyl)-2-hydroxyphenyl)-5-chloroindolin-2-one (4j)
(Scheme 6)
Yield 79%. The product was obtained as a yellowish oil, Rf =
0.52 (40% EtOAc in hexane). 1H NMR (400 MHz, CDCl3)
δ 7.28–7.34 (m, 2H), 7.07–7.10 (m, 1H), 6.82 (d, J = 7.76 Hz,
1H), 5.46–5.56 (m, 1H), 4.95–5.00 (m, 2H), 3.18 (s, 3H), 3.00
(s, 3H), 2.55–2.74 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 175.7,
143.9, 130.6, 129.8, 126.7, 124.5, 122.9, 119.6, 108.3, 82.5, 53.0,
41.9, 26.0; IR (film) νmax 3546, 2935, 1715, 1615, 1469, 1374,
1307, 1250, 1119, 1032, 991, 924, 860, 755 cm−1; HRMS (ESI)
m/z 218.1175 [M + H]+; calculated for [C13H16NO2]+: 218.1176.
The product was obtained as a colorless gel, Rf = 0.52 (30%
EtOAc in hexane). H NMR (400 MHz, CDCl3) δ 9.20 (br, 2H),
1
7.17–7.23 (m, 3H), 7.13 (br, 1H), 6.84 (m, 1H), 6.80 (d, J = 8.19
Hz, 1H), 5.31–5.41 (m, 1H), 5.05 (d, J = 16.55 Hz, 1H), 4.95 (d,
J = 10.07 Hz, 1H), 3.32 (dd, J = 13.63, 8.22 Hz, 1H), 2.96 (dd, J =
13.65, 6.33 Hz, 1H), 1.21 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 183.3, 153.5, 143.1, 138.9, 132.9, 131.3, 128.5, 128.3, 126.6,
126.42, 126.40, 125.0, 122.5, 120.1, 119.1, 58.3, 39.6, 34.3, 31.5;
IR (film) νmax 3352, 1697, 1620, 1479, 1241, 1133, 924, 887,
819, 740 cm−1; HRMS (ESI) m/z 356.1427 [M + H]+; calculated
for [C21H23ClNO2]+: 356.1412.
5-Chloro-3-methoxy-1,3-dimethylindolin-2-one (5n)
Yield 87%. The product was obtained as a yellowish solid, Rf =
0.59 (40% EtOAc in hexane). 1H NMR (400 MHz, CDCl3)
δ 7.25–7.29 (m, 2H), 6.75 (d, J = 8.20 Hz, 1H), 3.17 (m, 3H),
2.99 (m, 3H), 1.50 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 176.0,
142.0, 130.4, 129.6, 128.6, 124.2, 109.4, 79.6, 53.2, 26.2, 23.7;
IR (film) νmax 3430, 2933, 1729, 1611, 1425, 1341, 1260,
1138 cm−1; HRMS (ESI) m/z 226.0630 [M + H]+; calculated for
[C11H13ClNO2]+: 226.0629; MP 118–121 °C.
3-Allyl-5-bromo-3-(2-hydroxy-5-methylphenyl)indolin-2-one (4k)
(Scheme 6)
The product was obtained as a yellowish gel, Rf = 0.49 (30%
EtOAc in hexane). H NMR (400 MHz, CDCl3) δ 9.01 (br, 1H),
1
8.82 (br, 1H), 7.25–7.29 (m, 2H), 6.93 (m, 2H), 6.73 (m, 1H),
6.67 (m, 1H), 5.28–5.39 (m, 1H), 5.02 (d, J = 16.96 Hz, 1H), 4.93
(d, J = 10.19 Hz, 1H), 3.21 (dd, J = 13.50, 8.15 Hz, 1H), 2.94 (dd,
J = 13.47, 6.35 Hz, 1H), 2.22 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 183.3, 153.0, 139.6, 133.7, 131.2, 131.1, 130.1, 129.7,
128.4, 128.3, 123.8, 120.1, 118.9, 115.6, 112.0, 57.2, 39.7, 20.8;
IR (film) νmax 3382, 1696, 1618, 1475, 1265, 1118, 1045, 926,
881, 815, 739 cm−1; HRMS (ESI) m/z 358.0443 [M + H]+; calcu-
lated for [C18H17BrNO2]+: 358.0437.
General procedure for Friedel–Crafts alkylations of
electron-rich aromatics with 3-hydroxy-2-oxindoles in
the presence of Lewis acids
A flame-dried round-bottom flask was charged with 3-substi-
tuted 3-hydroxy 2-oxindole (0.5 mmol, 1.0 equiv.) in dichloro-
ethane (4 mL) and then Lewis acid was added to the reaction
mixture at room temperature. After 5 minutes of stirring at
room temperature, electron-rich aromatics (1.5 mmol, 3.0
equiv.) was added to it. The reaction mixture was stirred at
room temperature for 5 minutes and then it was heated under
reflux at 80 °C for the indicated time. Upon completion of the
reaction ( judged by running TLC), the reaction mixture was
cooled to room temperature. Most of the volatile components
were evaporated under reduced pressure and the crude materials
were directly purified by flash chromatography using EtOAc and
petroleum ether to afford Friedel–Crafts alkylation products.
3-Allyl-5-bromo-3-(5-(tert-butyl)-2-hydroxyphenyl)indolin-2-one (4l)
(Scheme 6)
The product was obtained as a colorless gel, Rf = 0.53 (30%
EtOAc in hexane). H NMR (400 MHz, CDCl3) δ 9.18 (brs, 1H),
1
8.36 (br, 1H), 7.38 (m, 2H), 7.19 (dd, J = 8.37, 1.94 Hz, 1H),
7.10 (m, 1H), 6.86 (d, J = 8.35 Hz, 1H), 6.80 (d, J = 7.87 Hz, 1H),
5.30–5.40 (m, 1H), 5.04 (d, J = 16.95 Hz, 1H), 4.95 (d, J =
10.17 Hz, 1H), 3.35 (dd, J = 13.45, 8.10 Hz, 1H), 2.92 (dd, J =
13.73, 6.39 Hz, 1H), 1.20 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 183.1, 153.4, 143.1, 139.4, 133.3, 131.4, 131.3, 129.2, 126.6,
125.0, 122.5, 120.2, 119.1, 115.5, 112.1, 58.1, 39.7, 34.3, 31.5;
3-Allyl-5-chloro-3-(2-hydroxy-5-methylphenyl)indolin-2-one (4i)
(Scheme 6)
The product was obtained as a yellowish gel, Rf = 0.48 (30% IR (film) νmax 3289, 2964, 1699, 1475, 1273, 1131, 924, 885,
1
EtOAc in hexane). H NMR (400 MHz, CDCl3) δ 9.21 (br, 1H), 818, 740 cm−1; HRMS (ESI) m/z 400.0927 [M + H]+; calculated
8.84 (br, 1H), 7.13 (s, 1H), 7.06 (d, J = 8.23 Hz, 1H), 6.97 for [C21H23BrNO2]+: 400.0907.
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3-(2-Hydroxy-5-methylphenyl)-1,3-dimethylindolin-2-one (4o)
(Scheme 8)
5-Chloro-3-(2-hydroxy-5-methylphenyl)-1,3-dimethylindolin-
2-one (4s) (Scheme 10)
The product was obtained as a light greenish gel, Rf = 0.52 The product was obtained as a white solid, Rf = 0.42 (20%
1
(20% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ 9.91 EtOAc in hexane). H NMR (400 MHz, CDCl3) δ 8.84 (br, 1H),
(s, 1H), 7.35–7.41 (m, 2H), 7.22–7.26 (m, 1H), 6.96 (m, 2H), 7.31 (dd, J = 8.34, 1.43 Hz, 1H), 7.22 (m, 1H), 6.92 (d, J = 8.06
6.89 (m, 1H), 6.78 (d, J = 1.53 Hz, 1H), 3.22 (s, 3H), 2.14 Hz, 1H), 6.82–6.85 (m, 2H), 6.73 (d, J = 8.03 Hz, 1H), 3.19
(s, 3H), 1.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 182.2, 154.5, (s, 3H), 2.20 (s, 3H), 1.80 (s, 3H); 13C NMR (100 MHz, CDCl3)
142.5, 132.7, 129.9, 129.1, 128.5, 128.3, 125.8, 124.9, 123.3, δ 181.8, 153.5, 141.4, 135.2, 135.1, 129.9, 129.3, 128.5, 128.2,
119.8, 109.1, 52.9, 26.6, 22.4, 20.6; IR (film) νmax 3318, 2929, 128.0, 125.3, 124.7, 118.9, 109.7, 52.4, 26.7, 22.5, 20.7; IR
1676, 1447, 1268, 1122, 797, 742 cm−1; HRMS (ESI) m/z (film) νmax 3303, 2921, 1694, 1610, 1423, 1350, 1275, 1221,
268.1319 [M + H]+; calculated for [C17H18NO2]+: 268.1332.
1146, 739 cm−1; HRMS (ESI) m/z 302.0980 [M + H]+; calculated
for [C17H17ClNO2]+: 302.0942; MP 213–217 °C.
3-(5-(tert-Butyl)-2-hydroxyphenyl)-1,3-dimethylindolin-2-one (4p)
(Scheme 8)
3-(5-(tert-Butyl)-2-hydroxyphenyl)-5-chloro-
1,3-dimethylindolin-2-one (4t) (Scheme 10)
The product was obtained as a white solid, Rf = 0.43 (15%
EtOAc in hexane). H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H),
1
The product was obtained as a white solid, Rf = 0.44 (20%
7.37–7.41 (m, 2H), 7.24–7.27 (m, 1H), 7.19 (dd, J = 8.39,
2.32 Hz, 1H), 7.04 (s, 1H), 6.95 (m, 2H), 3.23 (s, 3H), 1.88 (s,
3H), 1.16 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 182.2, 154.4,
142.6, 132.7, 128.5, 126.3, 125.8, 124.9, 124.1, 123.1, 119.4,
109.2, 53.4, 34.2, 31.5, 26.6, 22.5; IR (film) νmax 3340, 2959,
1
EtOAc in hexane). H NMR (400 MHz, CDCl3) δ 9.26 (br, 1H),
7.33 (dd, J = 8.33, 1.24 Hz, 1H), 7.27 (brs, 1H), 7.17 (dd, J =
8.38, 1.84 Hz, 1H), 7.07 (brs, 1H), 6.83–6.88 (m, 2H), 3.21
(s, 3H), 1.84 (s, 3H), 1.21 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 181.8, 153.7, 142.7, 141.3, 134.9, 128.5, 128.3, 126.4, 125.7,
124.4, 123.8, 118.9, 109.9, 53.0, 34.3, 31.5, 26.8, 22.6; IR (film)
νmax 3365, 2965, 1696, 1460, 1276, 1109, 824, 740 cm−1; HRMS
(ESI) m/z 344.1450 [M + H]+; calculated for [C20H23ClNO2]+:
344.1412; MP 167–169 °C.
1675, 1614, 1455, 1376, 1280, 1149, 1025, 821, 745 cm−1
;
HRMS (ESI) m/z 310.1804 [M + H]+; calculated for [C20H24NO2]+:
310.1802; MP 189–194 °C.
3-Allyl-3-(2-hydroxy-5-methylphenyl)-1-methylindolin-2-one (4q)
(Scheme 8)
The product was obtained as a white solid, Rf = 0.54 (20% 3-Allyl-3-(2,4-dimethoxyphenyl)indolin-2-one (8c) (Fig. 3)
1
EtOAc in hexane). H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H),
The product was obtained as a light yellow gel, Rf = 0.64 (40%
7.37–7.42 (m, 2H), 7.25 (m, 2H), 6.92–6.99 (m, 3H), 6.79
EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 8.91 (brs, 1H),
(s, 1H), 5.22–5.33 (m, 1H), 4.98 (d, J = 16.98 Hz, 1H), 4.89 (d,
7.51 (d, J = 8.65 Hz, 1H), 7.15 (td, J = 7.52, 1.52 Hz, 1H), 6.92
J = 10.08 Hz, 1H), 3.40 (dd, J = 13.72, 8.22 Hz, 1H), 3.20 (s, 3H),
(td, J = 7.48, 0.88 Hz, 1H), 6.86 (m, 2H), 6.58 (dd, J = 8.64, 2.54
2.95 (dd, J = 13.70, 6.21 Hz, 1H), 2.13 (s, 3H); 13C NMR
Hz, 1H), 6.4 (d, J = 2.52 Hz, 1H), 5.49 (m, 1H), 5.06 (m, 1H),
(100 MHz, CDCl3) δ 181.0, 154.7, 143.1, 132.1, 130.0, 129.9,
4.95 (m, 1H), 3.86 (s, 3H), 3.46 (s, 3H), 3.01 (d, J = 7.12, 2H);
129.0, 128.8, 128.6, 126.6, 123.4, 123.1, 120.2, 119.5, 109.1,
13C NMR (100 MHz, CDCl3) δ: 182.2, 160.4, 158.2, 141.5, 134.2,
131.8, 128.1, 127.3, 122.8, 122.0, 121.8, 119.1, 109.0, 104.5,
57.8, 39.3, 26.5, 20.6; IR (film) νmax 3318, 2921, 1681, 1611,
1470, 1378, 1269, 1140, 919, 820, 755 cm−1; HRMS (ESI) m/z
100.1, 55.5, 55.4, 53.9, 40.8; IR (film) νmax 3429, 3410, 1620,
294.1469 [M + H]+; calculated for [C19H20NO2]+: 294.1489; MP
1585, 1504, 1416, 1304, 1265, 1207, 1142, 1034, 926, 837, 791,
138–142 °C.
733 cm−1; HRMS (ESI) m/z 310.1449 [M + H]+; calculated
[C19H20NO3]+: 310.1438.
3-Allyl-3-(5-(tert-butyl)-2-hydroxyphenyl)-1-methylindolin-2-one
(4r) (Scheme 8)
3-Allyl-3-(2,5-dimethoxyphenyl)indolin-2-one (8d) (Fig. 3)
The product was obtained as a yellowish gel, Rf = 0.48 (15%
1
EtOAc in hexane). H NMR (400 MHz, CDCl3) δ 10.48 (s, 1H), 79% yield, white solid, Rf = 0.59 (50% EtOAc in hexane).
7.39 (m, 2H), 7.26 (t, J = 7.29 Hz, 1H), 7.20 (dd, J = 8.37, 2.36 1H NMR (400 MHz, CDCl3) δ: 8.55 (brs, 1H), 7.17 (d, J = 2.76
Hz, 1H), 7.07 (d, J = 2.35 Hz, 1H), 6.96 (t, J = 8.41 Hz, 2H), Hz, 1H), 7.12 (td, J = 7.4, 1.24 Hz, 1H), 6.91–6.83 (m, 3H),
5.22–5.32 (m, 1H), 4.99 (d, J = 16.75 Hz, 1H), 4.89 (d, J = 10.11 6.79–6.71 (m, 2H), 5.53–5.42 (m, 1H), 5.06–5.01 (m, 1H),
Hz, 1H), 3.45 (dd, J = 13.74, 8.11 Hz, 1H), 3.21 (s, 3H), 2.94 4.95–4.92 (m, 1H), 3.81 (s, 3H), 3.37 (s, 3H), 2.97 (d, J = 8 MHz,
(dd, J = 13.76, 6.29 Hz, 1H), 1.16 (s, 9H); 13C NMR (100 MHz, 2H); 13C NMR (100 MHz, CDCl3) δ: 181.5, 153.9, 151.6, 141.5,
CDCl3) δ 181.0, 154.5, 143.2, 142.5, 132.1, 130.0, 128.7, 126.5, 133.8, 131.6, 130.8, 127.5, 122.9, 122.1, 119.3, 115.0, 113.8,
126.4, 125.4, 122.9, 122.7, 119.7, 119.5, 109.2, 58.3, 39.5, 34.3, 112.4, 109.0, 56.5, 55.9, 54.3, 40.7; IR (film) νmax 3184, 2358,
31.5, 26.5; IR (film) νmax 3399, 2963, 1678, 1614, 1469, 1376, 1704, 1616, 1471, 1289, 1230, 1057, 918, 803, 757, 665 cm−1
;
1244, 1135, 825, 754 cm−1; HRMS (ESI) m/z 336.1954 [M + H]+; HRMS (ESI) m/z 332.1224 [(M
+
Na)+; calculated for
calculated for [C22H26NO2]+: 336.1958.
[C19H19NO3 + Na]+: 332.1257]; MP 175–181 °C.
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3-(4-Methoxyphenyl)-3-methylindolin-2-one (8e) (Fig. 3)
1254, 1180, 825, 748, 636 cm−1; HRMS (ESI) m/z 286.0830
[M + Na]+; calculated for [C17H13NO2 + Na]+: 286.0838;
MP 163–165 °C.
Yellow gel, Rf = 0.43 (50% EtOAc in hexane). 1H NMR
(400 MHz, CDCl3) δ 9.27 (brs, 1H), 7.13–7.16 (m, 2H), 7.11 (dd,
J = 8.96, 1.26 Hz, 1H), 7.02 (dt, J = 7.36, 0.48 Hz, 1H), 6.95 (td,
J = 7.46, 0.99 Hz, 1H), 6.86 (d, J = 7.69 Hz, 1H), 6.74 (m, 2H),
3.67 (s, 3H), 1.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 182.9,
158.8, 140.6, 135.8, 132.6, 128.0, 127.8, 124.3, 122.7, 114.0,
110.4, 55.3, 52.2, 23.5; IR (film) νmax 3190, 1693, 1616,
1512, 1470, 1107, 1030, 745 cm−1; HRMS (ESI) m/z 276.1048
[(M + Na)+; calculated for [C16H15NO2 + Na]+: 276.0995].
3-(3,4-Dimethoxyphenyl)-3-ethynylindolin-2-one (8j) (Fig. 3)
The product was obtained as a light yellow-colored solid, Rf =
0.65 (50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 8.99
(brs, 1H), 7.28 (m, 2H), 7.12 (t, J = 7.56 Hz, 1H), 7.06 (d, J =
2.15 Hz, 1H), 7.0 (d, J = 7.69 Hz, 1H), 6.87 (m, 1H), 6.8 (m, 1H),
3.86 (s, 6H), 2.57 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 176.6,
149.1, 149.0, 140.3, 132.0, 129.7, 129.3, 125.1, 123.6, 119.0,
111.1, 110.6, 110.4, 81.1, 72.9, 55.94, 55.92, 52.2; IR (film) νmax
3429, 2924, 1713, 1616, 1512, 1470, 1261, 1138, 1022,
752 cm−1; HRMS (ESI) m/z 316.0947 [M + Na]+; calculated for
[C18H15NO3 + Na]+: 316.0944; MP 154–156 °C.
3-(3,4-Dimethoxyphenyl)-3-methylindolin-2-one (8f) (Fig. 3)
Yellowish gel, Rf = 0.39 (50% EtOAc in hexane). 1H NMR
(400 MHz, CDCl3) δ 9.14 (brs, 1H), 7.14 (td, J = 7.67, 1.23 Hz,
1H), 7.06 (d, J = 6.95 Hz, 1H), 6.97 (td, J = 7.53, 0.94 Hz, 1H),
6.88 (d, J = 7.71 Hz, 1H), 6.76–6.78 (m, 2H), 6.70–6.72 (m, 1H),
3.75 (s, 3H), 3.72 (s, 3H), 1.72 (s, 3H); 13C NMR (100 MHz,
3-(2,4-Dimethoxyphenyl)-3-ethynylindolin-2-one (8k) (Fig. 3)
CDCl3) δ 182.6, 148.9, 148.4, 140.5, 135.6, 133.0, 128.1, 124.3, The product was obtained as a yellow-colored solid, Rf = 0.68
122.7, 119.0, 111.1, 110.33, 110.32, 55.9, 55.8, 52.3, 23.7; IR (50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 9.32
(film) νmax 3306, 1697, 1616, 1516, 1469, 1257, 1026, 756 cm−1
;
(brs, 1H), 8.01 (d, J = 8.56 Hz, 1H), 7.19 (m, 1H), 6.96 (m, 3H),
HRMS (ESI) m/z 284.1281 [(M
+
H)+; calculated for 6.63 (dd, J = 8.58, 2.48 Hz, 1H), 6.38 (d, J = 2.44 Hz, 1H), 3.83
(s, 3H), 3.46 (s, 3H), 2.6 (s, 1H); 13C NMR (100 MHz, CDCl3)
[C17H18NO3]+: 284.1281].
δ: 178.0, 161.2, 157.3, 140.8, 132.5, 130.6, 128.3, 123.2, 122.8,
3-(2,4-Dimethoxyphenyl)-3-methylindolin-2-one (8g) (Fig. 3)
118.2, 109.9, 104.6, 99.9, 80.8, 74.1, 55.5, 55.4, 50.7; IR (film)
νmax 3275, 2928, 2855, 1724, 1612, 1504, 1470, 1207, 1034, 845,
756 cm−1; HRMS (ESI) m/z 316.0955 [M + Na]+; calculated for
[C18H15NO3 + Na]+: 316.0944; MP 180–183 °C.
Yellowish gel, Rf = 0.40 (50% EtOAc in hexane). 1H NMR
(400 MHz, CDCl3) δ 9.26 (brs, 1H), 7.40 (d, J = 8.58 Hz, 1H),
7.03 (td, J = 7.70, 1.30 Hz, 1H), 6.80 (d, J = 7.68 Hz, 1H),
6.72–6.77 (m, 1H), 6.48 (dd, J = 8.56, 2.54 Hz, 1H), 6.28 (d, J =
2.49 Hz, 1H), 3.70 (s, 3H), 3.34 (s, 3H), 1.63 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 184.4, 160.5, 158.1, 140.9, 136.6, 128.2,
127.2, 122.3, 122.1, 122.0, 109.5, 104.6, 100.0, 55.5, 55.4, 50.1,
23.7; IR (film) νmax 3248, 2927, 1712, 1612, 1504, 1211, 1030,
740 cm−1; HRMS (ESI) m/z 284.1309 [(M + H)+; calculated for
[C17H18NO3]+: 284.1281].
2-(2-(3-(4-Methoxyphenyl)-2-oxoindolin-3-yl)ethyl)isoindoline-
1,3-dione (8l) (Fig. 4)
The product was obtained as a light yellow-colored solid, Rf =
0.62 (50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 8.60
(brs, 1H), 7.73 (m, 2H), 7.63 (m, 2H), 7.31 (m, 3H), 7.15 (td, J =
7.72, 1.24 Hz, 1H), 6.97 (td, J = 7.6, 1.0 Hz, 1H), 6.93 (d, J =
7.76, 1H), 6.82 (m, 2H), 3.75 (s, 3H), 3.68 (m, 2H), 2.72 (m,
2H); 13C NMR (100 MHz, CDCl3) δ: 180.2, 167.9, 158.9, 140.9,
133.7, 131.9, 131.8, 131.1, 128.3, 127.9, 125.1, 123.0, 122.6,
114.0, 110.5, 55.2, 54.8, 34.9, 34.5; IR (film) νmax 3511, 2897,
1791, 1705, 1615, 1539, 1278, 1044, 901, 751 cm−1; HRMS (ESI)
m/z 435.1321 [M + Na]+; calculated for [C25H20N2O4 + Na]+:
435.1315; MP 156–159 °C.
3-(2,5-Dimethoxyphenyl)-3-methylindolin-2-one (8h) (Fig. 3)
88% yield, white solid, Rf = 0.60 (50% EtOAc in hexane).
1H NMR (400 MHz, CDCl3) δ: 8.52 (brs, 1H), 7.11–7.06 (m, 2H),
6.85–6.81 (m, 2H), 6.78–6.76 (m, 1H), 6.74–6.71 (m, 1H),
6.67–6.65 (m, 1H), 3.76 (s, 3H), 3.32 (s, 3H), 1.65 (s, 3H);
13C NMR (100 MHz, CDCl3) δ: 153.9, 151.4, 140.6, 136.2, 132.7,
130.9, 127.4, 122.5, 122.3, 115.1, 113.5, 112.4, 109.3, 56.4, 55.8,
50.4, 23.6; IR (film) νmax 3245, 2929, 1713, 1618, 1497, 1471,
1423, 1327, 1282, 1229, 1111, 1045, 927, 847, 803, 757, 696,
665, 594 cm−1; HRMS (ESI) m/z 306.1107 [(M + Na)+; calculated
for [C17H17NO3 + Na]+: 306.1101]; MP 156–160 °C.
2-(2-(3-(2,4-Dimethoxyphenyl)-2-oxoindolin-3-yl)ethyl)-
isoindoline-1,3-dione (8m) (Fig. 4)
The product was obtained as a light yellow solid, Rf = 0.59
(50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 9.11
(brs, 1H), 7.79 (m, 2H), 7.67 (m, 3H), 7.06 (td, J = 7.6, 1.4 Hz,
1H), 6.90 (m, 2H), 6.84 (td, J = 7.4, 0.92 Hz, 1H), 6.62 (dd, J =
3-Ethynyl-3-(4-methoxyphenyl)indolin-2-one (8i) (Fig. 3)
The product was obtained as a light yellow-colored solid, Rf = 8.68, 2.52 Hz, 1H), 6.40 (d, J = 2.52 Hz, 1H), 3.82 (m, 2H), 3.81
0.78 (50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 9.30 (s, 3H), 3.52 (s, 3H), 2.63 (m, 2H); 13C NMR (100 MHz, CDCl3)
(brs, 1H), 7.36 (m, 2H), 7.28 (m, 2H), 7.11 (td, J = 7.59, 0.88 Hz, δ: 182.0, 168.1, 160.4, 158.3, 141.1, 133.9, 133.8, 132.1, 128.3,
1H), 6.99 (d, J = 7.76 Hz, 1H), 6.87 (m, 2H), 3.80 (s, 3H), 2.57 127.5, 123.1, 122.9, 122.3, 120.8, 109.5, 104.7, 100.2, 55.5, 55.4,
(s, 1H); 13C NMR (100 MHz, CDCl3) δ: 170.1, 159.5, 140.5, 53.4, 52.5, 33.8; IR (film) νmax 3521, 2900, 1798, 1699, 1616,
132.2, 129.5, 129.2, 128.0, 125.0, 123.6, 114.2, 110.7, 81.1, 72.9, 1260, 1051, 925, 754 cm−1; LRMS (ESI) m/z 441.1531 [M − H]+;
55.3, 52.1; IR (film) νmax 3414, 2928, 1713, 1616, 1508, 1470, calculated for [C26H21N2O5]+: 441.1445; MP 172–175 °C.
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2-(2-(3-(3,4-Dimethoxyphenyl)-2-oxoindolin-3-yl)ethyl)-
isoindoline-1,3-dione (8n) (Fig. 4)
m/z 443.1609 [(M
443.1601]; MP 180–184 °C.
+
H)+; calculated for [C26H22N2O5]+:
The product was obtained as a light yellow solid, Rf = 0.58
(50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 8.86
(brs, 1H), 7.73 (m, 2H), 7.63 (m, 2H), 7.37 (d, J = 7.36 Hz, 1H),
7.17 (td, J = 7.68, 1.12 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 7.0 (td,
J = 7.56, 0.96 Hz, 1H), 6.95 (d, J = 7.64 Hz, 1H), 6.85 (dd, J =
8.48, 2.24 Hz, 1H), 6.72 (d, J = 8.56 Hz, 1H), 3.87 (s, 3H), 3.79
(s, 3H), 3.74 (m, 1H), 3.69 (m, 1H), 2.82 (m, 1H), 2.61 (m, 1H);
13C NMR (100 MHz, CDCl3) δ: 180.3, 168.0, 149.0, 148.4, 140.9,
133.8, 131.9, 131.7, 131.2, 128.3, 125.3, 123.0, 122.6, 119.2,
110.9, 110.6, 110.3, 55.9, 55.8, 55.0, 34.9, 34.4; IR (film) νmax
3514, 3317, 2931, 1775, 1705, 1616, 1516, 1261, 1026,
756 cm−1; HRMS (ESI) m/z 441.1463 [M − H]+; calculated for
[C26H21N2O5]+: 441.1445; MP 92–95 °C.
1-(2-(3-(4-Methoxyphenyl)-2-oxoindolin-3-yl)ethyl)
pyrrolidine-2,5-dione (8r) (Fig. 4)
The product was obtained as a white coloured gel, Rf = 0.72
(75% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 8.51
(brs, 1H), 7.26–7.22 (m, 4H), 7.07 (t, J = 7.44 Hz, 1H), 6.94 (d,
J = 7.68 Hz, 1H), 6.79 (m, 2H), 3.73 (S, 3H), 3.61–3.40 (m, 2H),
2.73–2.54 (m, 2H), 2.50–2.33 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ: 180.5, 177.1, 159.0, 141.1, 131.9, 131.2, 128.5, 127.8,
125.0, 122.6, 114.0, 110.6, 55.3, 54.9, 35.4, 33.6, 28.0; IR (film)
νmax 3405, 2850, 1700, 1509, 1406, 1252, 1185, 1029, 911, 825,
753 cm−1; HRMS (ESI) m/z 387.1294 [(M + Na)+; calculated for
[C21H20N2O4 + Na]+: 387.1315].
1-(2-(3-(4-(Methylthio)phenyl)-2-oxoindolin-3-yl)ethyl)-
pyrrolidine-2,5-dione (8s) (Fig. 4)
2-(2-(3-(Furan-2-yl)-2-oxoindolin-3-yl)ethyl)isoindoline-
1,3-dione (8o) (Fig. 4)
The product was obtained as a white-colored foam, Rf = 0.61
(75% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 8.97
(brs, 1H), 7.21–7.27 (m, 4H), 7.13 (m, 2H), 7.06 (t, J = 7.50 Hz,
1H), 6.93 (d, J = 7.73 Hz, 1H), 3.54–3.61 (m, 1H), 3.40–3.47 (m,
1H), 2.67–2.73 (m, 1H), 2.52–2.59 (m, 1H), 2.41–2.46 (m, 2H),
2.39 (s, 3H), 2.34–2.38 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ: 180.0, 177.1, 141.3, 137.9, 136.1, 131.6, 128.6, 127.2, 126.6,
125.0, 122.6, 110.7, 55.1, 35.3, 33.4, 28.0, 15.7; IR (film) νmax
3258, 1698, 1619, 1472, 1404, 1164, 1098, 911, 816, 733,
669 cm−1; HRMS (ESI) m/z 403.1086 [(M + Na)+; calculated for
[C21H20N2O3S + Na]+: 403.1087].
The product was obtained as a light yellow solid, Rf = 0.69
(40% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 8.34
(brs, 1H), 7.74 (m, 2H), 7.65 (m, 2H), 7.33 (m, 2H), 7.10 (td, J =
7.74, 1.22 Hz, 1H), 6.90 (m, 2H), 6.29 (m, 1H), 6.22 (m, 1H),
3.81 (m, 1H), 3.69 (m, 1H), 2.82 (m, 1H), 2.73 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 177.2, 167.9, 151.7, 142.9, 140.6,
133.7, 131.9, 129.8, 128.6, 124.6, 123.0, 122.7, 110.4, 110.3,
107.1, 52.2, 34.0, 33.2; IR (film) νmax 3391, 3210, 2920, 2851,
1713, 1678, 1470, 1404, 1377, 1192, 1115, 1076, 1030, 748,
718 cm−1; HRMS (ESI) m/z 395.1007 [M + Na]+; calculated for
[C22H16N2O4 + Na]+: 395.1002; MP 210–214 °C.
1-(2-(3-(Furan-2-yl)-2-oxoindolin-3-yl)ethyl)pyrrolidine-
2,5-dione (8t) (Fig. 4)
2-(2-(3-(4-(Methylthio)phenyl)-2-oxoindolin-3-yl)ethyl)-
isoindoline-1,3-dione (8p) (Fig. 4)
The product was obtained as a yellow-colored gel, Rf = 0.65
(75% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 8.64
(brs, 1H), 7.32 (d, J = 1.05 Hz, 1H), 7.29 (d, J = 7.45 Hz, 1H),
7.23 (td, J = 7.66, 1.00 Hz, 1H), 7.04 (t, J = 7.49 Hz, 1H), 6.93 (d,
J = 7.77 Hz, 1H), 6.25 (dd, J = 3.24, 1.87 Hz, 1H), 6.13 (d, J =
2.89 Hz, 1H), 3.61–3.69 (m, 1H), 3.41–3.48 (m, 1H), 2.71–2.78
(m, 1H), 2.57–2.63 (dt, J = 14.02, 5.87 Hz, 1H), 2.35–2.47 (m,
4H); 13C NMR (100 MHz, CDCl3) δ: 177.3, 177.0, 151.8, 142.9,
141.0, 129.9, 128.9, 124.4, 122.7, 110.5, 110.3, 107.0, 52.3, 34.9,
31.8, 27.9; IR (film) νmax 3447, 1698, 1615, 1468, 1406, 1172,
1011, 736, 430 cm−1; HRMS (ESI) m/z 347.1018 [(M + Na)+;
calculated for [C18H16N2O4 + Na]+: 347.1002].
The product was obtained as a light yellow gel, Rf = 0.54 (40%
EtOAc in hexane). H NMR (400 MHz, 0.5 mL CDCl3 + 0.1 mL
1
DMSO-d6) δ: 10.38 (brs, 1H), 7.67 (m, 4H), 7.1 (m, 6H), 6.86
(m, 2H), 3.51 (m, 2H), 3.22 (brs, H2O), 2.47–2.52 (m, 2H), 2.34
(brs, 3H); 13C NMR (100 MHz, 0.5 mL CDCl3 + 0.1 mL DMSO-
d6) δ: 179.1, 167.6, 142.3, 137.5, 136.6, 134.1, 131.9, 131.7,
128.3, 127.3, 126.3, 124.8, 123.0, 122.0, 110.5, 54.8, 34.5, 34.2,
15.4; IR (film) νmax 3391, 3256, 1713, 1647, 1396, 1184, 999,
825, 768, 714 cm−1; HRMS (ESI) m/z 429.1267 [M + H]+; calcu-
lated for [C25H21N2O3S]+: 429.1267.
2-(2-(3-(2,5-Dimethoxyphenyl)-2-oxoindolin-3-yl)ethyl)-
isoindoline-1,3-dione) (8q) (Fig. 4)
White solid, Rf = 0.32 (50% EtOAc in hexane). 1H NMR
3-(2-Hydroxy-5-methylphenyl)-3-phenylindolin-2-one (16a)
(Scheme 13)
(400 MHz, CDCl3) δ: 8.45 (brs, 1H), 7.77–7.75 (m, 2H), The product was obtained as a white solid, Rf = 0.61 (30%
7.65–7.63 (m, 2H), 7.36 (d, J = 2.76 Hz, 1H), 7.06–7.02 (m, 1H), EtOAc in hexane). 1H NMR (500 MHz, CDCl3) δ 8.84 (s, 1H),
6.86–6.72 (m, 5H), 3.86 (s, 3H), 3.83–3.79 (m, 2H), 3.42 (s, 3H), 8.79 (brs, 1H), 7.29–7.32 (m, 4H), 7.18–7.20 (m, 2H), 7.14 (m,
2.67–2.48 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 181.1, 168.0, 2H), 7.09 (dd, J = 8.12, 1.74 Hz, 1H), 7.04 (d, J = 7.79 Hz, 1H),
154.2, 151.5, 141.0, 133.8, 133.6, 132.1, 129.7, 127.7, 123.1, 6.94 (d, J = 8.10 Hz, 1H), 6.82 (d, J = 1.83 Hz, 1H), 2.22 (s, 3H);
123.0, 122.4, 114.5, 114.0, 113.3, 109.4, 56.4, 56.1, 52.8, 33.8, 13C NMR (125 MHz, CDCl3) δ 183.3, 154.4, 140.1, 139.1, 132.9,
33.7; IR (film) νmax 3277, 2928, 1771, 1714, 1618, 1560, 1498, 130.6, 129.6, 129.3, 128.9, 128.5, 127.6, 127.3, 126.5, 124.8,
1470, 1400, 1371, 1230, 1187, 1027, 870, 719 cm−1; HRMS (ESI) 123.5, 119.9, 111.0, 62.8, 20.7; IR (film) νmax 3865, 3334, 1698,
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1608, 1484, 1235, 1038, 812, 750 cm−1; HRMS (ESI) m/z 3-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)indolin-2-one (16f)
316.1332 [M + H]+; calculated for [C21H18NO2]+: 280.1332; (Scheme 13)
MP 258–260 °C.
The product was obtained as a light yellowish gel, Rf = 0.49
(30% EtOAc in hexane). 1H NMR (400 MHz, 0.4 mL CDCl3,
0.1 mL DMSO-D6) δ 9.67 (br, 1H), 8.56 (br, 1H), 6.96–7.01
(m, 4H), 6.89 (d, J = 8.55 Hz, 2H), 6.81 (m, 1H), 6.75 (d, J = 7.67
Hz, 1H), 6.61 (d, J = 8.61, 2H), 6.56 (d, J = 8.56 Hz, 2H), 3.58
(s, 3H); 13C NMR (100 MHz, 0.4 mL CDCl3, 0.1 mL DMSO-D6)
δ 180.1, 158.4, 156.3, 141.0, 134.4, 134.3, 132.7, 129.4, 129.3,
127.8, 125.8, 122.0, 115.2, 113.5, 110.1, 61.4, 55.1; IR (film)
νmax 3473, 1651, 1250, 1181, 1026, 1004, 826, 764 cm−1; HRMS
(ESI) m/z 332.1290 [M + H]+; calculated for [C21H18NO3]+:
332.1281.
3-(5-(tert-Butyl)-2-hydroxyphenyl)-3-phenylindolin-2-one (16b)
(Scheme 13)
The product was obtained as a white solid, Rf = 0.67 (30%
1
EtOAc in hexane). H NMR (400 MHz, CDCl3) δ 9.23 (brs, 1H),
8.91 (s, 1H), 7.21–7.29 (m, 5H), 7.14 (m, 2H), 7.08 (m, 2H), 7.05
(d, J = 2.22 Hz, 1H), 7.00 (d, J = 7.77 Hz, 1H), 6.94 (d, J =
8.37 Hz, 1H), 1.18 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 183.7,
154.2, 142.8, 140.2, 139.3, 133.0, 128.9, 128.6, 127.6, 127.1,
126.9, 126.5, 126.3, 124.2, 123.3, 119.3, 111.3, 63.2, 34.3, 31.5;
IR (film) νmax 3303, 1694, 1610, 1472, 1494, 1266, 1244, 821,
740 cm−1; HRMS (ESI) m/z 358.1836 [M + H]+; calculated for
[C24H24NO2]+: 358.1802; MP 216–218 °C.
3-(2-Hydroxy-5-methylphenyl)-3-(4-methoxyphenyl)-1-
methylindolin-2-one (16g) (Scheme 13)
The product was obtained as a white solid, Rf = 0.58 (30%
EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H),
7.31–7.35 (m, 1H), 7.13 (m, 2H), 7.04 (dd, J = 8.11, 1.56 Hz,
1H), 6.96–7.01 (m, 3H), 6.89 (d, J = 8.10 Hz, 1H), 6.78 (m, 3H),
3.73 (s, 3H), 3.33 (s, 3H), 2.18 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 181.1, 158.8, 154.7, 142.1, 132.7, 132.4, 130.5, 129.4,
128.9, 128.4, 127.6, 127.0, 125.0, 123.5, 119.9, 114.2, 109.3,
61.8, 55.2, 26.9, 20.7; IR (film) νmax 3366, 2934, 1682, 1608,
1510, 1493, 1251, 1183, 1035, 910, 733 cm−1; HRMS (ESI) m/z
360.1609 [M + H]+; calculated for [C23H21NO3]+: 360.1594; MP
188–193 °C.
3-(4-Hydroxyphenyl)-3-phenylindolin-2-one (16c) (Scheme 13)
The product was obtained as a light yellow solid, Rf = 0.52
(30% EtOAc in hexane). 1H NMR (400 MHz, 0.4 mL CDCl3,
0.1 mL DMSO-D6) δ 9.73 (brs, 1H), 8.60 (brs, 1H), 6.77–7.10
(m, 11H), 6.59 (m, 2H); 13C NMR (100 MHz, 0.4 mL CDCl3,
0.1 mL DMSO-D6) δ 184.7, 161.1, 147.3, 145.7, 138.8, 137.2,
134.3, 133.1, 133.0, 132.7, 131.7, 130.7, 126.9, 120.1, 115.0,
67.0; IR (film) νmax 3420, 1673, 1241, 1026, 1002, 826,
763 cm−1; HRMS (ESI) m/z 302.1191 [M + H]+; calculated for
[C20H16NO2]+: 302.1176; MP 209–212 °C.
3-(5-(tert-Butyl)-2-hydroxyphenyl)-3-(4-methoxyphenyl)-
1-methylindolin-2-one (16h) (Scheme 13)
3-(2-Hydroxy-5-methylphenyl)-3-(4-methoxyphenyl)indolin-
2-one (16d) (Scheme 13)
The product was obtained as a white crystalline solid, Rf = 0.67
(30% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ 9.30
(s, 1H), 7.34 (td, J = 7.77, 1.53 Hz, 1H), 7.26 (m, 1H), 7.10 (m,
2H), 7.02 (d, J = 2.20 Hz, 1H), 6.90–6.98 (m, 4H), 6.77 (d, J =
8.77 Hz, 2H), 3.73 (s, 3H), 3.34 (s, 3H), 1.16 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 181.1, 158.8, 154.6, 142.3, 142.0, 132.8,
132.6, 128.4, 127.6, 126.9, 126.8, 125.9, 124.1, 123.3, 119.5,
114.2, 109.3, 62.1, 55.2, 34.2, 31.5, 26.9; IR (film) νmax 3291,
2958, 1679, 1614, 1505, 1470, 1359, 1274, 1185, 1035, 820,
749 cm−1; HRMS (ESI) m/z 402.2065 [M + H]+; calculated for
[C26H28NO3]+: 402.2064; MP 136–142 °C.
The product was obtained as a light yellow solid, Rf = 0.58
(30% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ 9.09
(s, 1H), 8.75 (s, 1H), 7.22–7.26 (m, 1H), 7.03–7.11 (m, 5H), 6.97
(d, J = 7.29 Hz, 1H), 6.88 (d, J = 8.10 Hz, 1H), 6.78–6.81 (m,
3H), 3.73 (s, 3H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 183.7, 158.9, 154.2, 139.3, 133.3, 132.0, 130.5, 129.3, 127.8,
127.0, 125.1, 123.4, 119.6, 114.3, 111.1, 62.1, 55.2, 20.7; IR
(film) νmax 3273, 2928, 1696, 1618, 1549, 1251, 1182, 1035,
750 cm−1; HRMS (ESI) m/z 346.1457 [M + H]+; calculated for
[C22H20NO3]+: 346.1438; MP 190–194 °C.
3-(5-(tert-Butyl)-2-hydroxyphenyl)-3-(4-methoxyphenyl)indolin-
2-one (16e) (Scheme 13)
3-(4-Hydroxyphenyl)-3-(4-methoxyphenyl)-1-methylindolin-
2-one (16i) (Scheme 13)
The product was obtained as a yellowish gel Rf = 0.62 (30% The product was obtained as a white solid, Rf = 0.51 (30%
EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ 7.28 (td,
8.86 (s, 1H), 7.21–7.27 (m, 2H), 7.03–7.11 (m, 5H), 6.98 (d, J = J = 7.73, 0.93 Hz, 1H), 7.21 (d, J = 7.18 Hz, 1H), 7.15 (d,
7.76 Hz, 1H), 6.92 (d, J = 8.39 Hz, 1H), 6.79 (d, J = 8.82 Hz, 2H), J = 8.84 Hz, 2H), 7.08 (t, J = 7.15 Hz, 1H), 6.99 (d, J = 8.69 Hz,
3.73 (s, 3H), 1.17 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 183.8, 2H), 6.90 (d, J = 7.79 Hz, 1H), 6.78 (M, 3H), 6.62 (d, J = 8.63 Hz,
158.9, 154.2, 142.7, 139.2, 133.4, 132.1, 128.5, 127.8, 127.0, 2H), 3.73 (s, 3H), 3.26 (s, 3H); 13C NMR (100 MHz, CDCl3)
126.8, 126.3, 124.2, 123.2, 119.2, 114.3, 111.2, 62.5, 55.2, 34.3, δ 178.8, 158.8, 155.5, 142.7, 133.8, 133.2, 129.52, 129.50, 128.2,
31.5; IR (film) νmax 3305, 2962, 1697, 1617, 1510, 1472, 1250, 125.9, 123.1, 115.5, 113.8, 108.7, 61.5, 55.3, 26.7; IR (film)
1183, 1035, 750 cm−1; HRMS (ESI) m/z 388.1919 [M + H]+; νmax 3370, 2933, 1695, 1610, 1512, 1470, 1373, 1302, 1252,
calculated for [C25H26NO3]+: 388.1907.
1182, 1034, 945, 830, 749 cm−1; HRMS (ESI) m/z 346.1433
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[M
+
H]+; calculated for [C22H20NO3]+: 346.1438; MP 3-(4-Methoxyphenyl)-3-(1H-pyrrol-2-yl)indolin-2-one (16n)
141–143 °C.
(Scheme 14)
The product was obtained as a brownish gel, Rf = 0.45 (30%
EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 2H),
7.25 (d, J = 8.19 Hz, 1H), 7.21 (td, J = 7.70, 1.01 Hz, 1H), 7.09
(t, J = 7.52 Hz, 1H), 6.98 (m, 2H), 6.91 (d, J = 7.72 Hz, 1H), 6.83
(m, 1H), 6.77 (m, 2H), 6.16 (m, 1H), 6.06 (m, 1H), 3.72 (s, 3H);
13C NMR (100 MHz, CDCl3) δ: 180.5, 158.9, 140.0, 133.9, 133.6,
128.3, 127.8, 125.5, 123.1, 119.1, 114.1, 110.5, 108.9, 107.9,
57.4, 55.3; IR (film) νmax 3799, 1625, 1460, 1281, 1250, 1090,
1020, 749 cm−1; HRMS (ESI) m/z 305.1278 [M + H]+; calculated
for [C19H17N2O2]+: 305.1285.
3-(4-Methoxyphenyl)-3-phenylindolin-2-one (16j) (Scheme 13)
The product was obtained as a light yellow-colored solid, Rf =
0.81 (40% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 9.11
(br, s, 1H), 7.31 (m, 5H), 7.22 (m, 4H), 7.06 (td, J = 7.56, 1.0 Hz,
1H), 6.98 (d, J = 7.72 Hz, 1H), 6.86 (m, 2H), 3.8 (s, 3H);
13C NMR (100 MHz, CDCl3) δ: 180.6, 158.9, 141.9, 140.2, 133.9,
133.5, 129.6, 128.5, 128.3, 128.2, 127.3, 126.2, 122.8, 113.8,
110.4, 62.4, 55.3; IR (film) νmax 3244, 2920, 2851, 1709, 1612,
1504, 1470, 1250, 1030, 752, 690 cm−1; HRMS (ESI) m/z
316.1321 [M + H]+; calculated for [C21H18NO2]+: 316.1332;
MP 119–121 °C.
3-(4-Methoxyphenyl)-3-(1-tosyl-1H-pyrrol-2-yl)indolin-2-one (16o)
(Scheme 14)
The product was obtained as a white solid, Rf = 0.35 (30%
EtOAc in hexane). H NMR (400 MHz, 0.5 mL CDCl3, 0.1 mL
3,3-Bis(4-methoxyphenyl)indolin-2-one (16k) (Scheme 14)
1
The product was obtained as a yellow-colored solid, Rf = 0.82
(50% EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 9.39
(br, s, 1H), 7.23 (m, 6H), 7.06 (m, 1H), 6.96 (d, J = 7.76 Hz, 1H),
6.86 (m, 4H), 3.79 (s, 6H); 13C NMR (100 MHz, CDCl3) δ: 181.0,
171.2, 158.8, 140.3, 134.3, 133.9, 129.5, 128.1, 126.0, 122.7,
113.9, 110.5, 61.8, 55.3; IR (film) νmax 3491, 2916, 1643, 1508,
1465, 1250, 1180, 1034, 826, 752 cm−1; HRMS (ESI) m/z
DMSO-D6) δ 9.25 (m, 1H), 7.67 (brs, 1H), 6.95–7.15 (7H), 6.80
(d, J = 7.58 Hz, 1H), 6.53–6.63 (m, 4H), 6.03 (m, 1H), 5.59
(m, 1H), 3.63 (s, 3H), 2.23 (s, 3H); 13C NMR (100 MHz, 0.5 mL
CDCl3, 0.1 mL DMSO-D6) δ 179.6, 159.1, 144.1, 142.29, 142.26,
136.4, 135.0, 131.6, 130.9, 129.5, 128.2, 126.7, 125.6, 125.3,
121.1, 120.6, 111.2, 110.2, 57.4, 55.2, 21.5; IR (film) νmax 1696,
1614, 1489, 1360, 1244, 1164, 1076, 808, 677, 591 cm−1; HRMS
(ESI) m/z 459.1399 [M + H]+; calculated for [C26H23N2O4S]+:
459.1373; MP 245–249 °C.
368.1255 [M
368.1257; MP 93–96 °C.
+ +
Na]+; calculated for [C22H19NO3 Na]+:
3-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)indolin-2-one (16l)
(Scheme 14)
3-(4-Methoxyphenyl)-3-(1-methyl-1H-indol-3-yl)indolin-2-one (16s)
(Scheme 14)
The product was obtained as a light yellow gel, Rf = 0.62 (50%
EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ: 9.18 (br, s,
1H), 7.22 (m, 4H), 7.06 (td, J = 7.55, 0.82 Hz, 1H), 6.96 (d, J =
7.76 Hz, 1H), 6.90 (d, J = 1.92 Hz, 1H), 6.84 (m, 2H), 6.79 (m,
2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ: 180.8, 158.8, 148.8, 148.4, 140.2, 134.1, 133.9, 133.8,
129.5, 128.1, 126.1, 122.7, 120.7, 113.8, 112.1, 110.7, 110.5,
61.9, 55.9, 55.8, 55.2; IR (film) νmax 3395, 2932, 2839, 1713,
1609, 1512, 1250, 1138, 1030, 814, 744 cm−1; HRMS (ESI)
m/z 398.1364 [M + Na]+; calculated for [C23H21NO4 + Na]+:
398.1368.
The product was obtained as a yellow solid, Rf = 0.35 (30%
EtOAc in hexane). H NMR (400 MHz, CDCl3) δ 9.19 (brs, 1H),
1
7.32–7.30 (m, 3H), 7.16–7.25 (m, 4H), 6.90–7.00 (m, 3H),
6.81–6.83 (m, 2H), 6.78 (s, 1H), 3.76 (s, 3H), 3.66 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 180.8, 158.8, 140.2, 137.8, 134.8,
132.3, 129.1, 128.7, 128.0, 126.3, 125.6, 122.6, 121.8, 121.7,
119.1, 114.9, 113.8, 110.4, 109.4, 57.4, 55.2, 32.7; IR (film) νmax
3255, 2933, 1710, 1618, 1471, 1250, 1034, 826, 741 cm−1
HRMS (ESI) m/z 369.1598 [M
H]+; calculated for
[C24H21N2O2]+: 369.1598; MP 201–202 °C.
;
+
General procedure for Friedel–Crafts alkylations of
3-(Benzo[d][1,3]dioxol-5-yl)-3-(4-methoxyphenyl)indolin-2-one
N-methylaniline and acetanilide with 5p and 5s (Scheme 15)
(16m) (Scheme 14)
A flame-dried round-bottom flask was charged with 5p or 5s
The product was obtained as a light yellow solid, Rf = 0.72 (0.3 mmol, 1.0 equiv.) in dichloroethane (2 mL) and Lewis acid
1
(50% EtOAc in hexane). H NMR (400 MHz, CDCl3) δ: 9.14 (br, was added to the reaction mixture at room temperature.
s, 1H), 7.18 (m, 4H), 7.02 (td, J = 7.56, 0.98 Hz, 1H), 6.92 (d, J = To this reaction mixture N-methylaniline or acetanilide
7.74 Hz, 1H), 6.79 (m, 3H), 6.69 (m, 2H), 5.89 (m, 2H), 3.74 (0.3 mmol, 1.0 equiv.) was added and it was heated under
(s, 3H); 13C NMR (100 MHz, CDCl3) δ: 180.6, 158.9, 147.8, reflux at 80 °C for the indicated time. Upon completion
146.9, 140.2, 135.6, 134.0, 133.5, 129.5, 128.2, 126.1, 122.8, ( judged by running TLC), the reaction mixture was cooled to
121.7, 113.9, 110.5, 109.3, 107.9, 101.1, 62.0, 55.3; IR (film) room temperature. Most of the volatiles were evaporated under
νmax 3414, 2924, 2851, 1705, 1612, 1477, 1242, 1180, 1034, 933, reduced pressure and the crude materials were directly puri-
806 cm−1; HRMS (ESI) m/z 382.1051 [M + Na]+; calculated for fied by flash chromatography using EtOAc and petroleum
[C22H17NO4 + Na]+: 382.1050; MP 182–184 °C.
ether to afford 17a–c.
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Organic & Biomolecular Chemistry
( )-3-(4-Methoxyphenyl)-3-(4-(methylamino)phenyl)-indolin-
2-one ( )-17a
The crude amine was taken in dichloromethane (8 mL) in
an oven-dried round-bottom flask and triethylamine
(4.0 mmol, 2.0 equiv.) was added to this at room temperature.
DMAP (0.4 mmol, 0.2 equiv.) was added to the reaction
mixture and finally (Boc)2O (4.0 mmol, 2.0 equiv.) in dichloro-
methane (1 mL) was added drop-wise by a syringe. The reac-
tion mixture was stirred at room temperature for 24 h (TLC
showed complete conversion of starting material). Water
(10 mL) was added to the reaction mixture and extracted with
dichloromethane (10 mL × 2). The organic layer was dried over
anhydrous MgSO4 and most of the volatile components were
evaporated under reduced pressure. The crude product was
purified by flash chromatography using EtOAc and petroleum
ether to afford bis-Boc 2-oxindole (21).
The product was obtained as a yellowish gel, Rf = 0.46 (40%
EtOAc in hexane). 1H NMR (500 MHz, CDCl3) δ 8.24 (s, 1H),
7.21–7.24 (m, 4H), 7.09–7.12 (m, 2H), 7.06 (td, J = 7.60, 1.02
Hz, 1H), 6.95 (d, J = 7.64 Hz, 1H), 6.84 (m, 2H), 6.56 (m, 2H),
4.33 (br, 1H), 3.79 (s, 3H), 2.82 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 180.5, 158.7, 148.5, 140.0, 134.5, 134.2, 130.0, 129.5,
129.2, 127.9, 126.2, 122.7, 113.8, 112.3, 110.0, 61.6, 55.3, 30.7;
IR (film) νmax 3702, 1689, 1514, 1243, 1175, 650 cm−1; HRMS
(ESI) m/z 345.1604 [M + H]+; calculated for [C22H21N2O2]+:
345.1598.
( )-N-(4-(3-(4-Methoxyphenyl)-2-oxoindolin-3-yl)-phenyl)-
acetamide ( )-17b
tert-Butyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-
3-(4-methoxyphenyl)-2-oxoindoline-1-carboxylate (21)
The product was obtained as a white solid, Rf = 0.43 (50%
EtOAc in hexane). 1H NMR (700 MHz, CDCl3) δ 8.24 (s, 1H),
7.21–7.24 (m, 4H), 7.09–7.12 (m, 2H), 7.06 (td, J = 7.60,
1.02 Hz, 1H), 6.95 (d, J = 7.64 Hz, 1H), 6.84 (m, 2H), 6.56
(m, 2H), 4.33 (br, 1H), 3.79 (s, 3H), 2.82 (s, 3H); 13C NMR
(175 MHz, CDCl3) δ 180.5, 158.7, 148.5, 140.0, 134.5, 134.2,
130.0, 129.5, 129.2, 127.9, 126.2, 122.7, 113.8, 112.3, 110.0,
61.6, 55.3, 30.7; IR (film) νmax 3666, 2844, 2546, 2329, 2142,
1660, 1516, 1242, 749 cm−1; HRMS (ESI) m/z 395.1370
[M + Na]+; calculated for [C23H20N2O3 + Na]+: 395.1366;
MP 121–124 °C.
The product was obtained as a colorless gel (773 mg, 80%),
80% yield, Rf = 0.52 (10% EtOAc in hexane). 1H NMR
(400 MHz, CDCl3) δ: 7.94 (d, J = 8.08 Hz, 1H), 7.39 (m, 1H),
7.27 (m, 2H), 7.22 (m, 2H), 6.84 (m, 2H), 4.44 (br, s, 1H), 3.78
(s, 3H), 2.94 (m, 2H), 2.68 (m, 1H), 2.40 (m, 1H), 1.64 (s, 9H),
1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ: 159.0, 155.5, 149.2,
139.7, 131.6, 130.0, 128.7, 128.0, 124.9, 124.86, 124.8, 115.4,
114.0, 84.4, 79.3, 55.3, 53.4, 38.0, 37.0, 28.3, 28.1; IR (film):
νmax 3392, 2979, 2932, 1762, 1732, 1607, 1512, 1480, 1368,
1347, 1290, 1252, 1151, 1101, 1034, 830, 754, 580 cm−1; HRMS
(ESI) m/z 500.2758 [M + NH4]+; calculated for [C27H34N2O6
+
NH4]+: 500.2755.
( )-N-(4-(3-(4-Methoxyphenyl)-1-methyl-2-oxoindolin-3-yl)-
phenyl)acetamide ( )-17c
Synthesis of bis-Boc-protected pyrroloindoline (7)
The product was obtained as a white solid, Rf = 0.32 (30%
An oven dried round-bottom flask was charged with 21
(0.5 mmol, 1.0 equiv.) in THF (2 mL) and the reaction mixture
was cooled to 0 °C. To this reaction mixture was added a
methanolic solution of NaBH4 (0.6 mmol, 1.2 equiv. in 2 mL
of MeOH) at 0 °C, and it was stirred for 10 min (TLC showed
complete consumption of starting material). Then, camphor-
sulfonic acid (CSA) (10.0 mmol, 20.0 equiv.) was added to the
reaction mixture and stirring was continued for 4 h. Upon
completion of the reaction, it was then diluted with 5 mL of
EtOAc and quenched with saturated NaHCO3 solution (5 mL).
The whole mixture was taken in a separatory funnel and
extracted with EtOAc (5 mL × 2). The organic layer was dried
over MgSO4 and most of the volatile components were evapor-
1
EtOAc in hexane). H NMR (500 MHz, CDCl3) δ 7.55 (brs, 1H),
7.39 (m, 2H), 7.33 (td, J = 7.70, 1.09 Hz, 1H), 7.23–7.25 (m, 1H),
7.15–7.18 (m, 4H), 7.10 (td, J = 7.56, 0.72 Hz, 1H), 6.94 (d, J =
7.76 Hz, 1H), 6.80–6.84 (m, 2H), 3.78 (s, 3H), 3.30 (s, 3H), 2.14
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 178.0, 168.4, 158.8,
142.9, 137.7, 137.1, 133.7, 133.2, 129.7, 129.0, 128.3, 125.5,
122.9, 119.9, 113.8, 108.6, 61.4, 55.3, 26.7, 24.5; IR (film) νmax
3729, 2848, 2631, 2333, 1675, 1517, 1258, 1184, 1035, 913,
818 cm−1; HRMS (ESI) m/z 409.1531 [M + Na]+; calculated for
[C24H22N2O3 + Na]+: 409.1523; MP 145–149 °C.
Synthesis of Boc-protected 2-oxindole (21)
An oven dried round-bottom flask was charged with 8l ated under reduced pressure. The crude pyrroloindoline was
(2.0 mmol, 1.0 equiv.) in MeOH (6 mL) and dichloromethane purified by flash chromatography using EtOAc and petroleum
(4 mL). To this reaction mixture was added hydrazine hydrate ether to afford bis-Boc pyrroloindole (7).
(8.0 mmol, 4.0 equiv.) at room temperature and it was stirred
Di-tert-butyl 3a-(4-methoxyphenyl)-3,3a-dihydropyrrolo[2,3-b]-
indole-1,8(2H,8aH)-dicarboxylate (7)
overnight. Upon completion of the reaction ( judged by
running TLC), saturated K2CO3 solution (2 mL) was added to
the reaction mixture and the whole mixture was taken in a The product was obtained as a white-colored gel (166 mg,
separatory funnel. The mixture was extracted with dichloro- 71%), as 3.4 : 1 rotameric ratio, Rf = 0.41 (10% EtOAc in
methane (10 mL × 2). The organic layer was dried over anhy- hexane), 1H NMR (400 MHz, CDCl3) (major rotamer)
drous MgSO4 and most of the volatile components were δ: 7.28–7.30 (m, 1H), 7.22–7.24 (m, 1H), 7.13–7.15 (m, 2H),
evaporated under reduced pressure. The crude primary amine 7.11–7.13 (m, 1H), 7.02–7.04 (m, 1H), 6.81–6.86 (m, 2H), 6.36
was used for the next step without isolation.
(s, 1H), 3.88–3.92 (m, 1H), 3.78 (s, 3H, –OMe), 2.95 (td, J =
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11.1, 6.0 Hz, 1H), 2.49–2.58 (m, 2H), 1.58 (s, 9H, Boc), 1.51
(s, 9H, Boc); 1H NMR (400 MHz, CDCl3) (minor rotamer)
δ: 7.24–7.28 (m, 1H), 7.11–7.14 (m, 2H), 7.07–7.09 (m, 1H),
6.84–6.86 (m, 2H), 6.77 (m, 1H), 6.70 (d, J = 7.7 Hz, 1H), 5.45
(s, 1H), 3.78 (s, 3H, –OMe), 3.73–3.75 (m, 1H), 3.10–3.15
(m, 1H), 2.58–2.64 (m, 2H), 1.55 (s, 9H, Boc), 1.48 (s, 9H, Boc);
IR (film) νmax 3410, 2929, 1706, 1514, 1480, 1395, 1367, 1253,
1165, 1038, 890, 751 cm−1; HRMS (ESI) m/z 467.2543 [M + H]+;
calculated for [C27H35N2O5]+: 467.2540.
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Acknowledgements
A. B. thanks the CSIR and DST, Govt. of India for generous
research grants. L. K. K. and S. G. thank the CSIR, New Delhi,
for Senior Research Fellowship (SRF). K. N. B. thanks CSIR for
a JRF. M. S. and S. B. thank IISER Bhopal for fellowships. We
are thankful to Mr Subhajit Bhunia for preliminary studies.
Our sincere thanks to Dr Sanjit Konar, IISER Bhopal for assist-
ance with the X-ray structure analysis. We sincerely thank
Professor Vinod K. Singh, Director, IISER Bhopal for excellent
research facilities.
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Org. Biomol. Chem., 2014, 12, 8152–8173 | 8173