Lewis-Acid-Catalysed Reaction of 3-Hydroxy-2-oxindoles with Terminal Alkynes: Synthetic Approaches to the Pyrroloindoline Alkaloids

Article abstract of DOI:10.1002/ejoc.201700507

Lewis-acid-catalysed reaction of 3-hydroxy-2-oxindoles with a variety of terminal alkynes has been developed. The key step involves alkylation of 3-aryl (or) 3-alkyl, 3-hydroxyoxindoles with terminal alkyne as π-electron-rich system to give a variety of 2-oxindoles with an all-carbon quaternary centre. On further extension of this method, a variety of spiro-2-oxindoles have been synthesized in high yields. The aforementioned methodology has been used in addressing the cyclotryptamine alkaloids linked with aryl group at the pseudobenzylic position.

Full text of DOI:10.1002/ejoc.201700507

DOI: 10.1002/ejoc.201700507
Full Paper
Quaternary Centres | Very Important Paper |
Lewis-Acid-Catalysed Reaction of 3-Hydroxy-2-oxindoles with
Terminal Alkynes: Synthetic Approaches to the Pyrroloindoline
Alkaloids
Lakshmana K. Kinthada,[a] K. Naresh Babu,[a] Dikshaa Padhi,[a][‡] and and Alakesh Bisai*[a]
Abstract: Lewis-acid-catalysed reaction of 3-hydroxy-2-ox- On further extension of this method, a variety of spiro-2-
indoles with a variety of terminal alkynes has been developed. oxindoles have been synthesized in high yields. The aforemen-
The key step involves alkylation of 3-aryl (or) 3-alkyl, 3-hydroxy- tioned methodology has been used in addressing the cyclo-
oxindoles with terminal alkyne as π-electron-rich system to give tryptamine alkaloids linked with aryl group at the pseudo-
a variety of 2-oxindoles with an all-carbon quaternary centre. benzylic position.
Introduction
oxindoles 5a and 5b were used as precursors for the synthesis
of physostigmine (4c).[8]
The alkynyl functionality derived from the direct addition of a
terminal alkyne onto an electron-deficient species provides a
great synthetic platform for further derivatisation.[1] The addi-
tion of an acetylide gives the opportunity to connect two com-
plex fragments while carrying out a convergent synthesis and
generating a stereocentre. The activation of terminal alkynes
and their reactions with a variety of electron-deficient species is
one of the most important strategies for C–C bond formation.[2]
Recently, a direct addition reaction of alkynes with sp–sp3 C–C
bond formation in the presence of metal triflates was reported
by Jiao et al., and this drew our attention (Scheme 1).[3]
Scheme 1. Literature report on Csp–Csp3 bond-forming reaction by Jiao et al.
Over the past decade, considerable attention has been given
to 2-oxindole derivatives,[4] which play an important role in syn-
thetic organic chemistry.[5] 2-Oxindoles and spiro-fused 2-
oxindoles are of great interest to synthetic chemists, as they are
encountered in many biologically active natural products (e.g.,
3a, 3b and 4a–4d; Figure 1).[6] They are also used as building
blocks for alkaloids and pharmaceuticals.[7] For example, the 2-
Figure 1. Spiro-fused 2-oxindoles (3a and 3b), pyrroloindoline alkaloids (4a–
4d), and important building blocks (5 and 6).
In view of the demand for efficient, economic, and environ-
mentally friendly processes, the development of direct catalytic
carbon–carbon bond-forming reactions between 3-hydroxy-2-
oxindoles and unmodified substrates is an important task. One
of the most powerful methods for the construction of
all-carbon quaternary centres[9] involves the activation of 3-
hydroxy-2-oxindoles by a Lewis acid, followed by reaction with
a suitable nucleophile through the formation of a reactive 2H-
indol-2-one ring.[9] These processes are interesting as they may
[a] Department of Chemistry, Indian Institute of Science Education and
Research Bhopal,
Bhopal Bypass Road, Bhouri, Bhopal 462066, Madhya Pradesh, India
E-mail: alakesh@iiserb.ac.in
http://home.iiserb.ac.in/~alakesh/
[‡] Current address: Department of Chemistry,
Veer Surendra Sai University of Technology,
Burla, Sambalpur, Odisha, India
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201700507.
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be extended to their enantioselective variants to access a vari-
ety of enantioenriched 2-oxindoles containing an all-carbon
quaternary stereogenic centre.[10,11] Therefore, research into
other catalytic reactions to synthesize 2-oxindoles containing
an all-carbon quaternary centre is highly desirable. Recently,
our group reported the efficient Lewis-acid-catalysed activation
of 3-alkyl-3-hydroxy-2-oxindoles with various electron-rich sub-
strates.[12] Encouraged by the report of Jiao (Scheme 1),[3] in
this paper, we report an inexpensive and environmentally be-
nign FeCl3-catalysed reaction of 3-hydroxy-2-oxindoles 7 with
terminal alkynes (Scheme 2).[13]
Table 1. Optimisation of the Lewis-acid-catalysed reactions of 3-hydroxy-2-
oxindole with phenylacetylene.[a]
Entry Catalyst (mol-%) Solvent
Temp. Time Yield
Recovered
[°C]
[h]
[%]
7a [%]
1
2
3
4
5
6
7
8
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
In(OTf)3 (10)
Sn(OTf)2 (10)
Cu(OTf)2 (10)
Bi(OTf)3 (10)
Sc(OTf)3 (10)
AgOTf (10)
Yb(OTf)3 (10)
InCl3 (10)
CHCl3
(CH2Cl)2
PhMe
MeCN
xylene
CH2Cl2
(CH2Cl)2
CHCl3
(CH2Cl)2
PhMe
25
25
25
25
25
25
50
60
80
110
70
130
40
80
80
80
80
80
80
80
80
80
80
80
80
80
24
24
24
24
24
24
8
5
4
1
6
1
12
4
8
7
5
6
6
5
43
49
12
21
–
22
32
61
39
92
27
13
19
–
15
49
21
12
–
–
–
–
–
56
–
20
72
–
Scheme 2. Our proposed addition of a terminal alkyne onto a 3-hydroxy-2-
oxindole.
32
66
78
85
43
36
42
69
85[d]
72
76
74
68
25
67
55
18
82[e]
67
61
68
9
Results and Discussion
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
MeCN
xylene
For past few years, our group has been investigating protocols
for the alkylation of 3-hydroxy-2-oxindoles that efficiently gov-
ern the formation of alkylated 3,3-disubstituted oxindoles con-
taining all-carbon quaternary stereocentres.[12] We thought that
the use of terminal alkynes as electron-rich substrates would
generate a variety of 2-oxindole intermediates of synthetic im-
portance. Initially, optimisation studies for the alkylation of 3-
hydroxy-2-oxindole 7a were carried out, using phenylacetylene
as a nucleophile, and running the reactions in the presence of
In(OTf)3 (10 mol-%) in different solvents at room temperature
(Table 1, entries 1–6).[13] We observed that a maximum 49 %
yield of 11a was isolated when 1,2-dichloroethane (DCE) was
used as solvent (Table 1, entry 2). Surprisingly, no traces of
phenylacetylene addition product 9a were observed in this re-
action. The yield of 11a increased to 66–78 %, when the reac-
tion was carried out at elevated temperature (Table 1, entries 7
and 8). To our delight, an 85 % yield was observed when the
reaction was carried out at 80 °C (4 h) in 1,2-dichloroethane
(Table 1, entry 9). We found that carrying out the reaction under
reflux conditions in toluene, acetonitrile, xylene, and dichloro-
methane gave the product in 43, 36, 42, and 69 % yields, re-
spectively (Table 1, entries 10–13).
CH2Cl2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
SnCl4 (10)
AlCl3 (10)
FeCl3 (10)
In(OTf)3 (5)
Sn(OTf)2 (5)
FeCl3 (5)
6
6
6
7
8
7
–
–
–
[a] Reactions were carried out with 7a (1.0 mmol), phenylacetylene
(3.0 mmol), in solvent (5 mL). [b] Isolated yields after column chromatogra-
phy. [c] Starting materials were isolated in most cases. [d] Conditions A:
Sn(OTf)2 (10 mol-%), (CH2Cl)2, 80 °C. [e] Conditions B: FeCl3 (10 mol-%),
(CH2Cl)2, 80 °C.
with 1.5–2 equiv. of phenylacetylene in the presence of
Sn(OTf)2 (10 mol-%), 11a was formed in 70–72 % isolated yield.
Therefore, based on our exhaustive optimisation, we decided
Next, a variety of Lewis acids including metal triflates and to use two sets of reaction conditions to check the substrate
metal halides (all 10 mol-%) were tested in refluxing 1,2-di- scope, i.e., conditions A: Sn(OTf)2, (10 mol-%), (CH2Cl)2, 80 °C;
chloroethane (Table 1, entries 14–23). Of the various Lewis acids and conditions B: FeCl3 (10 mol-%), (CH2Cl)2, 80 °C.
tested, Sn(OTf)2 (Table 1, entry 14) and FeCl3 (entry 23) were
also found to be suitable, giving product 11a in 85 and 82 %
yields, respectively, in 4–6 h. When the catalyst loading was
decreased to 5 mol-%, we observed that In(OTf)3, Sn(OTf)2, and
FeCl3 gave product 11a in 67, 61, and 68 % yields, respectively
(Table 1, entries 24–26).
Thus, using these standard conditions, the scope of the reac-
tion was tested with 3-hydroxy-2-oxindole 7a with various ter-
minal alkynes under standard conditions A [Sn(OTf)3 (10 mol-
%), (CH2Cl)2, 80 °C] and conditions B [FeCl3 (10 mol-%), (CH2Cl)2,
80 °C] (Scheme 3). We found that when a terminal alkyne bear-
ing an electron-withdrawing group, such as 4-fluorophenylacet-
We also found that the use of 3 equiv. of phenyl acetylene ylene, was used the reaction required a somewhat longer time
was the optimum amount to obtain the product in good yield to form product 11b (reaction time 9 h, 65–69 % yields). Gratify-
(Table 1). When the reaction of 7a (1 equiv.) was carried out ingly, aromatic alkynes containing electron-donating groups
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gave the products in 3–6 h in moderate to good yields (51–
81 %). Besides the expected products, we also observed the
formation of acetophenone derivatives in 12–23 % isolated
yields.
Scheme 4. Plausible mechanism for the formation of aryl methyl ketones
from acetylenes.
Scheme 3. Substrate scope of the Lewis-acid-catalysed reactions of 3-
hydroxy-2-oxindoles with arylacetylenes; reactions were carried out using 7a
(1.0 mmol) and arylacetylene (3.0 mmol), in dichloroethane (5 mL) in the
presence of catalyst (10 mol-%) at 80 °C [conditions A: Sn(OTf)2 (10 mol-%),
(CH2Cl)2, 80 °C; conditions B: FeCl3 (10 mol-%), (CH2Cl)2, 80 °C]. Isolated yields
after column chromatography. LA = Lewis acid.
A plausible mechanism for the formation of the aryl methyl
ketone by-product is shown in Scheme 4. Acetylenes are known
for their ability to make π-bonding interactions with transition
metals, and similar activation of acetylenes has been reported
with FeIII, CuI, etc.[10] The Lewis acid is involved in the catalytic
transformation of the acetylene into the corresponding aryl
methyl ketone 12. The acetylene is activated by FeIII or SnII un-
der reflux conditions in the presence of water to allow the for-
mation of an enol of type 13b, via activated alkyne complex
13a. This enol is then converted into aryl methyl ketone 12
(Scheme 4).
Scheme 5. Substrate scope using different arylacetylenes; reactions were car-
ried out using 7b (1.0 mmol) and arylacetylene (3.0 mmol) in dichloroethane
(5 mL) in the presence of catalyst (10 mol-%) at 80 °C [conditions A: Sn(OTf)2
(10 mol-%), (CH2Cl)2, 80 °C; conditions B: FeCl3 (10 mol-%), (CH2Cl)2, 80 °C].
Isolated yields after column chromatography.
Next, we planned to test the use of different 3-aryl-3-
hydroxy-2-oxindoles as electron-deficient partners in the reac-
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tion (Scheme 4). Thus, the N-alkylated 3-hydroxy-2-oxindole 7b products 14a–14d were formed in good yields. In all these
was used as electron-deficient partner. A variety of aryl acetyl- cases, acetophenone derivatives were also always obtained in
enes were used to give products 11h–11m in 54–86 % isolated up to 16 % yield.
yields (Scheme 5).
To demonstrate the versatility of this approach, we planned
Furthermore, a variety of N-methyl 3-hydroxy-2-oxindoles to extend the method to 3-methyl-3-hydroxy-2-oxindole 15
7b–7d were used under standard conditions to give products (Scheme 7). However, our efforts towards this end led either to
14a–14c in synthetically useful yields (Scheme 6). To further no reaction or to decomposition of the starting material (many
test the scope of this approach, the reaction was carried out spots on TLC). We could only isolate 35 % of the acetophenone
using 3-methoxy 3-aryl 2-oxindoles 7e–7h (Scheme 6), and and 49 % of the recovered starting material 15, in addition to
a complex mixture (Scheme 7).
Scheme 7. Use of 3-alkyl-3-acetoxy-2-oxindoles; reactions were carried out
using 7a (1.0 mmol) and arylacetylene (3.0 mmol) in dichloroethane (5 mL)
in the presence of catalyst (20 mol-%) at 80 °C [conditions A: Sn(OTf)2
(20 mol-%), (CH2Cl)2, 80 °C; conditions B: FeCl3 (20 mol-%), (CH2Cl)2, 80 °C].
Isolated yields after column chromatography.
Our unsuccessful efforts led us to think of increasing the
reactivity of the 3-hydroxy-2-oxindole by converting it into its
acetate derivative (Scheme 7). We reasoned that the reactivity
of the acetylated starting material could be enhanced by the
catalyst through the formation of a cyclic transition state of
type 17. Gratifyingly, as expected, we were able to synthesize
N-alkylated 2-oxindoles 18a and 18b with an all-carbon quater-
nary centre in moderate yields (27–64 %) in the presence of a
Lewis acid (20 mol-%; conditions A and B) in refluxing dichloro-
ethane (Scheme 7).
A proposed mechanism for the Lewis-acid-catalysed reaction
of alkynes with ( )-7 to give ( )-11 is shown in Scheme 8. In
the case of 3-hydroxy-2-oxindoles, Friedel–Crafts alkylations are
known to proceed through the formation of a 2H-indol-2-one
ring (Scheme 2).[12] Similar species are also reported to be
formed during the base-mediated elimination of 3-halo-2-
oxindoles, and they are also used in the total synthesis of com-
plex indole alkaloids in formal cycloaddition processes.[14] In
the presence of the Lewis acid, 3-hydroxy-/methoxy-2-indoles
of type 7 form intermediates 22 and 23 (Scheme 8), which can
react with terminal alkynes to form vinylic carbocation inter-
Scheme 6. Substrate scope using different 3-hydroxy/methoxy-2-oxindoles;
mediate 24a. The latter reacts with a water molecule to form
reactions were carried out using 7a (1.0 mmol) and arylacetylenes (3.0 mmol)
product 11 or 14. Alternatively, in-situ-generated aceto-
in dichloroethane (5 mL) in the presence of catalyst (10 mol-%) at 80 °C
phenone can react with intermediate 23 to give product 11 or
14. We believe that intermediate carbocation 24a is attacked
[conditions A: Sn(OTf)2 (10 mol-%), (CH2Cl)2, 80 °C; conditions B: FeCl3
(10 mol-%), (CH2Cl)2, 80 °C]. Isolated yields after column chromatography.
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intramolecularly by the basic amide oxygen of the oxindole, reacts with the phenolic OH group to give product 21a in iso-
giving rise to a five-membered ring, which, upon aqueous lated yields of up to 69 % (Scheme 9). This process is quite
workup, gives the final product, in contrast to Jiao's report general, and a variety of terminal arylacetylenes also gave spiro-
(Schemes 1 and 2).[3]
fused products 21a–21e in synthetically useful yields
(Scheme 10).
Scheme 10. Lewis-acid-catalysed reactions of alkynes; reactions were carried
out using 19 (1.0 mmol) and arylacetylene (3.0 mmol) in dichloroethane
(5 mL) in the presence of catalyst (10 mol-%) at 80 °C [conditions A: Sn(OTf)2
(10 mol-%), (CH2Cl)2, 80 °C; conditions B: FeCl3 (10 mol-%), (CH2Cl)2, 80 °C].
Isolated yields after column chromatography.
Scheme 8. Reaction of 3-aryl-3-hydroxy-2-oxindole 19 and mechanistic con-
siderations; reactions were carried out using 19 (1.0 mmol) and phenylacet-
ylene or acetophenone (3.0 mmol) in dichloroethane (5 mL) in the presence
of catalyst (10 mol-%) at 80 °C [conditions A: Sn(OTf)2 (10 mol-%), (CH2Cl)2,
80 °C; conditions B: FeCl3 (10 mol-%), (CH2Cl)2, 80 °C]. Isolated yields after
column chromatography.
We also investigated whether the reaction proceeds by an
SN1-type process (i.e., involving a carbocation intermediate 23).
To shed light on the mechanistic details, we synthesized 3-(3-
aryl)-3′-hydroxy-2-oxindole (+)-19 (Scheme 11). We carried out
the enantioselective addition of sesamol in the presence of
cinchona based catalyst 28 (10 mol-%) (Scheme 11), as reported
by Chimni et al.[15] This gave (+)-19 in 90 % yield with 90 % ee.
This compound was then treated with MeI in the presence of
We then thought of trapping the vinylic carbocation inter-
mediate 24a that is formed during the addition of acetylene to
the electron-deficient site. To this end, we carried out a reaction
with substrate 19, in which the 3-hydroxy-2-oxindole moiety
is substituted with a 2-hydroxyaryl functionality, with phenyl
acetylene (Scheme 8). Interestingly, this reaction gave a spiro-
fused 2-oxindole 21a in 63–69 % isolated yield. A similar result
was obtained when the reaction was carried out in the pres-
ence of acetophenone 20 as nucleophile. This investigation
gave some insight into the actual mechanism of the reaction
(Scheme 9).
Scheme 9. Reaction of 3-aryl-3-hydroxy-2-oxindole 19.
In the presence of the Lewis acid, 3-hydroxy-2-oxindole 19
forms an intermediate alkyl aryl ketone 25, which subsequently
Scheme 11. Thiourea-catalysed synthesis of enantioenriched 3-aryl-3-
hydroxy-2-oxindole.
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NaH to give 3-(3-aryl)-3′-methoxy-2-oxindole (–)-27 in 88 % sponding C-3a-aryl pyrroloindoline 35 (Scheme 13). Thus, com-
yield with 90 % ee.
pound 11k was converted into the corresponding aryl ester 31
in 74 % isolated yield by treatment with m-chloroperbenzoic
acid (m-CPBA) in a literature-known Baeyer–Villiger oxid-
ation.[16]
With enantioenriched 3-(3-aryl)-3′-methoxy-2-oxindole (–)-
27 in hand, indirect evidence for the formation of a 2H-indol-
2-one intermediate (see intermediate 22 in Scheme 8) was in-
vestigated (Scheme 12). We treated compound (–)-27 with
Next, trans-esterification of aryl ester 31 was carried out us-
phenylacetylene under the standard conditions (conditions A ing K2CO3 and EtOH to give ethyl ester 32 in 87 % yield
and B). Interestingly, this reaction gave product 29 with 3.5 % (Scheme 13). This was then reduced with lithium borohydride
ee, clearly indicating the involvement of intermediate (LiBH4) to give primary alcohol 33 in 67 % yield, which was
23 (similar to intermediate 22). This result proves that the further oxidized using the Swern oxidation procedure to give
Lewis-acid-catalysed reaction of 3-hydroxy-/methoxy-2-oxin- aldehyde 34 in 79 % yield.[17] Intermediate aldehyde 34 was
doles with arylacetylene probably proceeds by an SN1 pathway converted into tricyclic C-3a-aryl pyrroloindoline 35 through
(Scheme 12).
imine formation using methylamine hydrochloride followed by
reductive cyclisation in the presence of LiAlH4 in refluxing THF
to give ( )-35 in 78 % yield over two steps (Scheme 13). In
another sequence, direct reduction of ethyl ester 32 using
LiAlH4 in THF gave the corresponding cyclized furoindoline
product ( )-36 (Scheme 13).
Conclusions
We have demonstrated the Lewis-acid-catalysed reaction of 3-
substituted-3-hydroxy-2-oxindoles with terminal alkynes for the
synthesis of a variety of 2-oxindoles and spiro-fused 2-
oxindoles, sharing an all-carbon quaternary centre at the pseu-
dobenzylic position. The reaction has a wide substrate scope in
terms of both 3-hydroxy-2-oxindoles and terminal alkynes.
Since water is the only by-product, this transformation is atom
efficient and environmentally benign. These reactions proceed
via an in-situ-generated reactive 2H-indol-2-one intermediate of
type 22, and this has been proved experimentally. This strategy
has been used for the efficient synthesis of C-3a-pyrroloindoline
structural motifs 35, which are present in a number of cyclo-
tryptamine alkaloids.[18] We believe that enantioselective vari-
ants of this method, using chiral Lewis acids, could be an excel-
lent strategy to synthesize 2-oxindoles containing an all-carbon
quaternary stereogenic centre.
Scheme 12. Reaction of enantioenriched 3-aryl-3-hydroxy-2-oxindole 27 with
phenylacetylene.
Having successfully synthesized various 2-oxindole deriva-
tives containing an all-carbon quaternary stereocentre at the
pseudobenzylic position using our efficient approach, we went
on to examine the conversion of 2-oxindole 11k into the corre-
Experimental Section
General Methods: Unless otherwise stated, reactions were carried
out using oven-dried glassware, and Teflon-coated magnetic stirrer
bars were used to stir the reactions. Syringes were used to transfer
solvents and liquid reagents. Tetrahydrofuran (THF), and diethyl
ether (Et2O) were distilled from sodium/benzophenone ketyl. Di-
chloromethane (CH2Cl2) was distilled from calcium hydride. All
other solvents, including nitromethane, MeOH, EtOAc, DMF, and di-
chloroethane (DCE), and also all reagents, were used as received.
Reaction temperatures above 25 °C were maintained using an oil
bath on a magnetic stirrer. Thin-layer chromatography (TLC) was
carried out using silica gel precoated plates (0.25 mm) 60 (F-254),
which were visualized by UV irradiation and cerium molybdate
stain. Silica gel of particle size 230–400 or 100–200 mesh was used
for flash chromatography. A digital melting-point apparatus was
used to record melting points (Jyoti Scientific AN ISO 9001:2000).
1H NMR spectra were recorded with 400, 500, and 700 MHz spec-
trometers, and 13C NMR operating frequencies were 100, 125, and
175 MHz, respectively. Chemical shifts (δ) are reported in ppm, and
Scheme 13. Synthetic approach to C-3a-arylpyrroloindoline 35 and C-3a-aryl-
furoindoline 36.
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spectra were calibrated using the residual solvent signals (CDCl3:
δ = 7.24 ppm for 1H NMR, and δ = 77.0 ppm for 13C NMR; [D6]DMSO:
δ = 2.50 ppm for 1H NMR, and δ = 39.5 ppm for 13C NMR). Data for
1H NMR spectra are reported as follows: chemical shift (multiplicity,
coupling constants, number of protons). The following abbrevia-
tions are used: s (singlet), d (doublet), t (triplet), q (quartet), m (mul-
tiplet), br. (broad). IR spectra were recorded with an FTIR instrument
(Spectrum BX), and are reported in frequency of absorption (cm–1).
Only selected IR absorbances are reported. High-resolution mass
spectrometry (HRMS) data was recorded with a MicrOTOF-Q-II mass
spectrometer using methanol as solvent.
127.2, 122.8, 122.0, 109.6, 77.4, 44.0, 23.7, 20.6 ppm. IR (film): ν =
˜
3420, 1733, 1613, 1490, 1366, 1238, 1100, 699 cm–1
.
3-Methoxy-3-(6-methoxybenzo[d][1,3]dioxol-5-yl)-1-methylind-
olin-2-one [( )-27]: 3-Hydroxy-2-oxindole ( )-19 (1.0 mmol) was
dissolved in DMF (5 mL) in an oven-dried round-bottomed flask
equipped with a magnetic stirrer bar at room temperature under a
nitrogen atmosphere. NaH (2.5 equiv., 2.5 mmol) was added por-
tionwise at 0 °C. MeI (2.5 equiv., 2.5 mmol) was then added drop-
wise by syringe. The reaction mixture was stirred for 1 h at –30 °C,
and then it was brought to room temperature. When TLC showed
that the reaction was complete, the reaction was quenched by the
slow addition of water, and the mixture was diluted with EtOAc
(10 mL). The mixture was transferred to a separatory funnel, and
washed with water (30 mL). The organic phase was dried with anhy-
drous Na2SO4, and concentrated with a rotary evaporator under
vacuum. The residue was purified by flash chromatography to give
alkylated product ( )-27 (95 %) as a brown solid.
For the synthesis of compounds 7a–7d and 15a, see ref.[12b] and
for 7e, see ref.[12c]
General Procedure for the Synthesis of N-Protected 3-Acetoxy-
2-oxindoles ( )-16: 3-Hydroxy-2-oxindole (1.0 mmol) was dissolved
in DMF (4 mL) in an oven-dried round-bottomed flask equipped
with a magnetic stirrer bar at room temperature under a nitrogen
atmosphere. NaH (1.2 equiv., 1.2 mmol) was added portionwise at
0 °C. Acetic anhydride was then added dropwise by syringe. The
reaction mixture was stirred for 2 h at 0 °C, and then it was brought
to room temperature. When the reaction was complete, the reac-
tion was quenched by the slow addition of water, and then the
mixture was diluted with EtOAc (10 mL). The mixture was trans-
ferred to a separatory funnel, and washed with water (30 mL). The
organic phase was dried with anhydrous Na2SO4, and concentrated
with a rotary evaporator under vacuum. The residue was purified
by flash chromatography to give the acylated product.
Rf = 0.45 (30 % EtOAc in hexane). M.p. 187–192 °C.1H NMR
(400 MHz, CDCl3): δ = 7.43 (s, 1 H), 7.30–7.26 (m, 1 H), 6.98–6.95 (m,
2 H), 6.83 (d, J = 7.75 Hz, 1 H), 6.36 (s, 1 H), 5.91–5.90 (m, 2 H), 3.34
(s, 3 H), 3.28 (s, 3 H), 3.13 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 175.5, 150.9, 147.7, 145.0, 141.8, 129.6, 128.3, 124.4, 122.8, 121.7,
107.6, 107.2, 101.3, 96.0, 80.4, 57.1, 51.7, 26.2 ppm. IR (film): ν =
˜
3378, 2919, 2356, 1715, 1604, 1469, 1159, 1038, 873, 823, 755,
626 cm–1
.
For the synthesis and characterisation of compounds ( )-19, ( )-27,
(+)-19, and (+)-27 see ref.[15]
General Procedure for the Synthesis of Compounds ( )-11a–
11m and 12a–12c: Hydroxy-2-oxindole 7a or 7b (1.0 mmol) was
dissolved in DCE (5 mL) in an oven-dried round-bottomed flask
equipped with a magnetic stirrer bar at room temperature. The
Lewis acid (10 mol-%, 0.1 mmol) was added at room temperature.
Phenylacetylene (3 equiv., 3.0 mmol) was then added dropwise by
syringe. The reaction mixture was stirred for 4–6 h at 80 °C. When
TLC showed that the reaction was complete, the reaction was
quenched with water, and the mixture was diluted with CH2Cl2
(10 mL). The organic layer was separated using a separatory
funnel. The organic phase was dried with anhydrous Na2SO4, and
concentrated with a rotary evaporator under vacuum. The crude
product was purified by flash chromatography to give the acylated
product.
1,3-Dimethyl-2-oxoindolin-3-yl Acetate [( )-16a]: Yellowish gel.
Rf = 0.5 (30 % EtOAc in hexane). 1H NMR (400 MHz, CDCl3): δ =
7.27–7.23 (td, J = 7.76, 1.12 Hz, 1 H), 7.17 (d, J = 7.32 Hz, 1 H), 7.00–
6.96 (m, 1 H), 6.78 (d, J = 7.8 Hz, 1 H), 3.17 (s, 3 H), 1.97 (s, 3 H),
1.53 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 175.3, 168.9, 143.4,
129.6, 129.2, 122.7, 122.0, 108.4, 77.3, 26.4, 23.1, 20.6 ppm. IR (film):
ν = 3457, 1733, 1616, 1472, 1373, 1243, 1100, 764, 479 cm–1
.
˜
1-Benzyl-3-methyl-2-oxoindolin-3-yl Acetate [( )-16b]: Yellowish
gel. Rf = 0.5 (30 % EtOAc in hexane). 1H NMR (400 MHz, CDCl3): δ =
7.37–7.30 (m, 4 H), 7.27–7.23 (m, 2 H), 7.18–7.13 (td, J = 7.8, 1.0 Hz,
1 H), 7.02–6.98 (t, J = 7.4 Hz, 1 H), 6.65 (d, J = 7.8 Hz, 1 H), 5.02–
4.88 (m, 2 H), 2.07 (s, 3 H), 1.65 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 175.3, 168.9, 142.3, 135.6, 129.5, 129.2, 128.8, 127.5,
3-(4-Methoxyphenyl)-3-(2-oxo-2-phenylethyl)indolin-2-one [( )-
11a]: Yellow solid (85 %). Rf = 0.50 (50 % EtOAc in hexane). 1H NMR
(400 MHz, CDCl3): δ = 7.99 (s, 1 H), 7.91–7.89 (m, 2 H), 7.58–7.53 (m,
1 H), 7.45–7.41 (m, 2 H), 7.40–7.36 (m, 2 H), 7.28–7.24 (m, 2 H), 7.03
(td, J = 7.58, 0.98 Hz, 1 H), 6.98 (d, J = 7.66 Hz, 1 H), 6.89–6.85 (m,
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2 H), 4.19–4.08 (m, 2 H), 3.80 (s, 3 H) ppm. For the synthesis and
characterisation of compound ( )-11a, see ref.[13]
.
3-[2-(4-Methoxy-3-methylphenyl)-2-oxoethyl]-3-(4-methoxy-
phenyl)indolin-2-one [( )-11e]: Red gel (56 %). Rf = 0.47 (50 %
1
EtOAc in hexane). H NMR (400 MHz, CDCl3): δ = 8.08 (s, 1 H), 7.74
(dd, J = 8.54, 1.98 Hz, 1 H), 7.67 (m, 1 H), 7.35 (d, J = 8.81 Hz, 2 H),
7.20 (t, J = 7.54 Hz, 2 H), 6.98 (t, J = 7.25 Hz, 1 H), 6.92 (d, J =
7.19 Hz, 1 H), 6.83 (d, J = 8.82 Hz, 2 H), 6.77 (d, J = 8.54 Hz, 1 H),
4.12–3.97 (m, 2 H), 3.84 (s, 3 H), 3.76 (s, 3 H), 2.17 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 194.7, 180.8, 161.9, 159.0, 141.8, 132.6,
131.6, 130.7, 129.0, 128.2, 127.9, 126.8, 124.4, 122.1, 114.1, 110.1,
3-[2-(4-Fluorophenyl)-2-oxoethyl]-3-(4-methoxyphenyl)indolin-
2-one [( )-11b]: Yellow gel (69 %). Rf = 0.56 (50 % EtOAc in hex-
ane). 1H NMR (400 MHz, CDCl3): δ = 8.22 (s, 1 H), 7.93–7.91 (m, 2
H), 7.38–7.36 (m, 2 H), 7.27–7.23 (m, 2 H), 7.11–7.08 (m, 2 H), 7.04
(td, J = 7.55, 0.88 Hz, 1 H), 6.98 (d, J = 7.78 Hz, 1 H), 6.88–6.87 (m,
2 H), 4.13–4.07 (m, 2 H), 3.78 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 194.4, 180.7, 159.1, 141.8, 132.3, 131.2, 130.7, 130.7,
128.3, 127.9, 124.3, 122.2, 115.8, 115.7, 114.1, 110.2, 55.3, 52.9,
109.2, 55.5, 55.3, 53.0, 46.5, 29.7 ppm. IR (film): ν = 3584, 2350, 1710,
˜
1598, 1504, 1254, 1183, 1138, 1023, 813, 745, 624, 584 cm–1. HRMS
(ESI): calcd. for C25H24NO4 [M + H]+ 402.1700; found 402.1704.
46.8 ppm. IR (film): ν = 3248, 2923, 2851, 1708, 1599, 1504, 1470,
˜
1252, 1224, 1184, 1033, 834, 755, 580 cm–1. HRMS (ESI): calcd. for
C23H19FNO3 [M + H]+ 376.1343; found 376.1370.
3-[2-(3-Isopropyl-4-methoxyphenyl)-2-oxoethyl]-3-(4-methoxy-
phenyl)indolin-2-one [( )-11f]: Yellow gel (62 %). Rf = 0.52 (50 %
EtOAc in hexane). 1H NMR (400 MHz, CDCl3): δ = 8.54 (s, 1 H), 7.77–
7.75 (m, 2 H), 7.37 (d, J = 8.77 Hz, 2 H), 7.24–7.18 (m, 2 H), 7.00–
6.93 (m, 2 H), 6.84 (d, J = 8.93 Hz, 2 H), 6.79 (d, J = 9.22 Hz, 1 H),
4.14–4.01 (m, 2 H), 3.85 (s, 3 H), 3.76 (s, 3 H), 3.31–3.21 (m, 1 H),
1.18–1.15 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.8, 181.1,
161.0, 159.0, 142.0, 137.2, 132.7, 131.6, 129.3, 128.2, 128.0, 126.4,
124.4, 122.0, 114.1, 110.3, 109.5, 55.6, 55.3, 53.1, 46.5, 26.8, 22.4,
3-(4-Methoxyphenyl)-3-[2-oxo-2-(p-tolyl)ethyl]indolin-2-one
[( )-11c]: Yellow gel (81 %). Rf = 0.54 (50 % EtOAc in hexane). 1H
NMR (400 MHz, CDCl3): δ = 8.55 (s, 1 H), 7.77 (d, J = 8.11 Hz, 2 H),
7.35 (d, J = 8.87 Hz, 2 H), 7.22–7.17 (m, 4 H), 6.99–6.91 (m, 2 H),
6.83 (d, J = 8.81 Hz, 2 H), 4.15–4.02 (m, 2 H), 3.75 (s, 3 H), 2.36
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 195.6, 181.0, 159.0,
144.1, 142.0, 134.0, 132.5, 131.5, 129.3, 128.2, 128.2, 127.9,
124.3, 122.1, 114.1, 110.3, 55.3, 53.1, 46.6, 21.6 ppm. IR (film): ν =
˜
22.4 ppm. IR (film): ν = 3255, 2960, 2925, 2850, 2360, 1716, 1598,
˜
3848, 2916, 1697, 1606, 1469, 1250, 1179, 1035, 833, 805, 732,
581 cm–1. HRMS (ESI): calcd. for C24H22NO3 [M + H]+ 372.1594; found
372.1609.
1510, 1470, 1253, 1183, 1117, 1033, 824, 754, 576 cm–1, HRMS (ESI):
calcd. for C27H28NO4 [M + H]+ 430.2013; found 430.2013.
3-[2-(3,4-Dimethoxyphenyl)-2-oxoethyl]-3-(4-methoxy-
3-(4-Methoxyphenyl)-3-[2-(4-methoxyphenyl)-2-oxoethyl]ind-
phenyl)indolin-2-one [( )-11g]: Yellow gel (57 %). Rf = 0.41 (50 %
1
olin-2-one [( )-11d]: Yellow gel (71 %). Rf = 0.42 (50 % EtOAc in EtOAc in hexane). H NMR (400 MHz, CDCl3): δ = 8.27 (s, 1 H), 7.55
hexane). 1H NMR (400 MHz, CDCl3): δ = 8.21 (s, 1 H), 7.84 (d, J =
8.89 Hz, 2 H), 7.34 (d, J = 8.90 Hz, 2 H), 7.19 (t, J = 7.55 Hz, 2 H),
6.98 (t, J = 7.59 Hz, 1 H), 6.92 (d, J = 8.00 Hz, 1 H), 6.84 (t, J =
9.13 Hz, 4 H), 4.11–3.98 (m, 2 H), 3.81 (s, 3 H), 3.75 (s, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 194.4, 180.9, 163.6, 159.0, 141.8, 132.6,
(dd, J = 8.30, 1.54 Hz, 1 H), 7.36–7.33 (m, 3 H), 7.22–7.18 (t, J =
8.13 Hz, 2 H), 6.98 (t, J = 7.41 Hz, 1 H), 6.93 (d, J = 7.8 Hz, 1 H),
6.84–6.80 (m, 3 H), 4.12–4.00 (m, 2 H), 3.90 (s, 3 H), 3.81 (s, 3 H),
3.75 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.5, 180.8, 159.0,
153.5, 149.0, 141.8, 132.5, 131.5, 129.7, 128.2, 128.0, 124.4, 122.7,
131.5, 130.3, 129.5, 128.2, 127.9, 124.4, 122.1, 114.1, 113.7, 110.2, 122.1, 114.1, 110.1, 109.9, 56.1, 56.0, 55.3, 53.0, 46.4 ppm. IR (film):
55.5, 55.3, 53.0, 46.5 ppm. IR (film): ν = 3045, 2812, 2374, 2190, ν = 3320, 2934, 2837, 1715, 1594, 1510, 1417, 1262, 1158, 1022,
˜
˜
1687, 1487, 1259, 891, 745 cm–1. HRMS (ESI): calcd. for C24H22NO4 756, 734, 575 cm–1. HRMS (ESI): calcd. for C25H24NO5 [M + H]+
[M + H]+ 388.1543; found 388.1555.
418.1649; found 418.1645.
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3-[2-(4-Methoxy-3-methylphenyl)-2-oxoethyl]-3-(4-methoxy-
phenyl)-1-methylindolin-2-one [( )-11k]: Pale yellow gel (62 %).
Rf = 0.45 (30 % EtOAc in hexane). 1H NMR (400 MHz, CDCl3): δ =
7.71 (dd, J = 8.56, 2.03 Hz, 1 H), 7.65 (m, 1 H), 7.36–7.23 (m, 4 H),
7.01 (t, J = 7.42 Hz, 1 H), 6.91 (d, J = 7.74 Hz, 1 H), 6.82 (d, J =
8.91 Hz, 2 H), 6.76 (d, J = 8.62 Hz, 1 H), 4.10–3.96 (m, 2 H), 3.84 (s,
3 H), 3.75 (s, 3 H), 3.27 (s, 3 H), 2.16 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 194.6, 179.1, 161.9, 158.9, 144.8, 131.9, 131.7, 130.7,
129.0, 128.2, 128.1, 128.0, 126.7, 124.0, 122.1, 114.0, 109.1, 108.4,
3-[2-(4-Fluorophenyl)-2-oxoethyl]-3-(4-methoxyphenyl)-1-meth-
ylindolin-2-one [( )-11h]: Yellow gel (71 %). Rf = 0.53 (30 % EtOAc
in hexane). 1H NMR (400 MHz, CDCl3): δ = 7.87–7.84 (m, 2 H), 7.35–
7.29 (m, 3 H), 7.25–7.23 (m, 1 H), 7.07–7.01 (m, 3 H), 6.92 (d, J =
7.61 Hz, 1 H), 6.82 (d, J = 8.85 Hz, 2 H), 4.09–4.00 (m, 2 H), 3.75 (s,
3 H), 3.26 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.3, 178.8,
159.0, 144.8, 131.6, 131.4, 130.7, 130.6, 128.4, 127.9, 124.0, 122.2,
115.8, 115.5, 114.1, 108.5, 55.3, 52.5, 47.0, 26.7 ppm. IR (film): ν =
˜
3410, 3056, 2934, 2837, 1709, 1599, 1470, 1374, 1254, 1183, 1032,
834, 755, 737, 576 cm–1. HRMS (ESI): calcd. for C24H21FNO3 [M + H]+
390.1500; found 390.1498.
55.5, 55.3, 52.5, 46.8, 26.7, 16.2 ppm. IR (film): ν = 3417, 2922, 2850,
˜
1712, 1681, 1599, 1509, 1469, 1347, 1252, 1169, 1029, 832, 797, 755,
585, 578 cm–1. HRMS (ESI): calcd. for C26H26NO4 [M + H]+ 416.1856;
found 416.1834.
3-(4-Methoxyphenyl)-1-methyl-3-[2-oxo-2-(p-tolyl)ethyl]-
indolin-2-one [( )-11i]: Yellow gel (86 %). Rf = 0.51 (30 % EtOAc in
hexane). 1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 7.90 Hz, 2 H),
7.35 (d, J = 8.69 Hz, 2 H), 7.30 (t, J = 7.97 Hz, 1 H), 7.24 (d, J =
6.57 Hz, 1 H), 7.17 (d, J = 7.89 Hz, 2 H), 7.02 (t, J = 7.41 Hz, 1 H),
6.92 (d, J = 8.02 Hz, 1 H), 6.82 (d, J = 8.68 Hz, 2 H), 4.12–4.00 (m, 2
H), 3.75 (s, 2 H), 3.27 (s, 2 H), 2.36 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 195.5, 179.0, 159.0, 144.8, 144.1, 134.0, 131.8, 131.6,
129.2, 128.3, 128.1, 127.9, 124.0, 122.1, 114.0, 108.4, 55.3, 52.5,
3-[2-(3-Isopropyl-4-methoxyphenyl)-2-oxoethyl]-3-(4-methoxy-
phenyl)-1-methylindolin-2-one [( )-11l]: Yellow gel (61 %). Rf =
1
0.53 (30 % EtOAc in hexane). H NMR (400 MHz, CDCl3): δ = 7.75–
7.72 (m, 2 H), 7.38–7.24 (m, 4 H), 7.03 (t, J = 7.36 Hz, 1 H), 6.93 (t,
J = 7.78 Hz, 1 H), 6.85–6.77 (m, 3 H), 4.12–4.00 (m, 2 H), 3.85 (s, 3
H), 3.76 (s, 3 H), 3.28 (s, 3 H), 3.26–3.22 (m, 1 H), 1.17–1.14 (m, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 194.7, 179.1, 161.0, 159.0,
144.8, 137.2, 132.0, 131.8, 129.3, 128.3, 128.0, 127.9, 126.3, 124.1,
122.1, 114.0, 109.5, 108.4, 55.5, 55.3, 52.6, 46.8, 26.8, 26.7, 22.5,
47.0 ppm. IR (film): ν = 3054, 2932, 2836, 1711, 1607, 1510, 1504,
˜
22.4 ppm. IR (film): ν = 3054, 2961, 2838, 1731, 1598, 1505, 1372,
1347, 1251, 1181, 1033, 823, 756, 594 cm–1. HRMS (ESI): calcd. for
˜
1347, 1170, 1117, 755, 577 cm–1. HRMS (ESI): calcd. for C28H30NO4
[M + H]+ 444.2169; found 444.2195.
C
25H24NO3 [M + H]+ 386.1751; found 386.1763.
3-(4-Methoxyphenyl)-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1- 3-[2-(3,4-Dimethoxyphenyl)-2-oxoethyl]-3-(4-methoxyphenyl)-
methylindolin-2-one [( )-11j]: Yellow gel (77 %). Rf = 0.48 (30 %
EtOAc in hexane). 1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 8.90 Hz,
2 H), 7.35 (d, J = 8.92 Hz, 2 H), 7.30 (td, J = 9.02, 1.00 Hz, 1 H), 7.29–
7.23 (m, 1 H), 7.02 (t, J = 7.31 Hz, 1 H), 6.91 (d, J = 7.75 Hz, 1 H),
6.83 (t, J = 8.61 Hz, 4 H), 4.10–3.98 (m, 2 H), 3.81 (s, 3 H), 3.75 (s, 3
H), 3.27 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 194.4, 179.0,
1-methylindolin-2-one [( )-11m]: Red gel (62 %). Rf = 0.41 (30 %
EtOAc in hexane). H NMR (400 MHz, CDCl3): δ = 7.52 (dd, J = 8.42,
1.84 Hz, 1 H), 7.37–7.24 (m, 5 H), 7.02 (t, J = 7.40 Hz, 1 H), 6.91 (d,
J = 7.77 Hz, 1 H), 6.81 (t, J = 9.07 Hz, 3 H), 4.11–3.99 (m, 2 H), 3.87
(s, 3 H), 3.79 (s, 3 H), 3.73 (s, 3 H), 3.26 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 194.5, 179.0, 159.0, 153.4, 149.0, 144.8, 131.9,
1
163.6, 159.0, 144.8, 131.9, 131.7, 130.3, 129.6, 128.3, 128.0, 124.0, 131.6, 129.7, 128.3, 128.0, 124.1, 122.6, 122.1, 114.0, 110.1, 109.9,
122.1, 114.0, 113.7, 108.4, 55.5, 55.3, 52.5, 46.8, 26.7 ppm. IR (film):
108.4, 56.1, 55.9, 55.3, 52.5, 46.7, 26.7 ppm. IR (film): ν = 2934, 2834,
1712, 1607, 1510, 1470, 1347, 1259, 1160, 1023, 757, 742, 544,
˜
ν = 3054, 2932, 2836, 1711, 1607, 1510, 1504, 1347, 1251, 1181,
˜
1033, 823, 756, 594 cm–1. HRMS (ESI): calcd. for C25H24NO4 [M + H]+ 446 cm–1. HRMS (ESI): calcd. for C26H26NO5 [M + H]+ 432.1805; found
402.1700; found 402.1676.
432.1785.
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1
hexane). H NMR (400 MHz, CDCl3): δ = 7.84–7.82 (m, 2 H), 7.50 (t,
J = 7.42 Hz, 1 H), 7.40–7.34 (m, 4 H), 7.31 (td, J = 7.76, 1.01 Hz, 1
H), 7.25–7.24 (m, 1 H), 7.05–7.01 (m, 1 H), 6.92 (d, J = 7.72 Hz, 1 H),
6.83 (d, J = 8.93 Hz, 1 H), 4.14–4.03 (m, 2 H), 3.75 (s, 3 H), 3.27 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 195.9, 178.9, 159.0, 144.8,
136.4, 133.2, 131.7, 131.5, 128.5, 128.4, 128.0, 127.9, 124.1, 122.2,
1-(4-Methoxy-3-methylphenyl)ethan-1-one [( )-12a]: Yellow gel
(12 %). Rf = 0.49 (5 % EtOAc in hexane). H NMR (400 MHz, CDCl3):
δ = 7.79 (dd, J = 8.57, 2.20 Hz, 1 H), 7.75 (m, 1 H), 6.82 (d, J =
8.46 Hz, 1 H), 3.86 (s, 3 H), 2.52 (s, 3 H), 2.22 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 197.1, 161.8, 130.9, 129.8, 128.5, 126.7, 109.2,
114.1, 108.5, 55.3, 52.5, 47.1, 26.7 ppm. IR (film): ν = 3055, 2990,
˜
1
2950, 2100, 1707, 1622, 1480, 1344, 1250, 1220, 1070, 1495, 1250,
799, 620 cm–1. HRMS (ESI): calcd. for C24H22NO3 [M + H]+ 372.1594;
found 372.1599.
55.5, 26.3, 16.2 ppm. IR (film): ν = 2931, 2848, 2347, 1671, 1601,
˜
1495, 1355, 1292, 1259, 1169, 1143, 1029, 805, 730 cm–1
.
1-(3-Isopropyl-4-methoxyphenyl)ethan-1-one [( )-12b]: Pale
green liquid (17 %). Rf = 0.59 (5 % EtOAc in hexane). 1H NMR
(400 MHz, CDCl3): δ = 7.74 (d, J = 2.81 Hz, 1 H), 7.79 (dd, J = 8.41,
2.15 Hz, 1 H), 6.84 (d, J = 8.38 Hz, 1 H), 3.87 (s, 3 H), 3.35–3.24 (m,
1 H), 2.54 (s, 3 H), 1.22–1.20 (m, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 197.2, 160.9, 137.1, 130.1, 128.3, 126.5, 109.5, 55.5, 26.8,
3-(3,4-Dimethoxyphenyl)-1-methyl-3-(2-oxo-2-phenylethyl)-
indolin-2-one [( )-14b]: Red liquid (75 %). Rf = 0.44 (30 % EtOAc
1
in hexane). H NMR (400 MHz, CDCl3): δ = 7.84–7.82 (m, 2 H), 7.50
(t, J = 7.33 Hz, 1 H), 7.38 (t, J = 7.79 Hz, 2 H), 7.33–7.29 (m, 1 H),
7.26 (d, J = 7.32 Hz, 1 H), 7.12–7.10 (m, 1 H), 7.03 (t, J = 7.51 Hz, 1
H), 6.93–6.89 (m, 2 H), 6.76 (d, J = 8.50 Hz, 1 H), 4.13–4.02 (m, 2 H),
3.82 (s, 6 H), 3.27 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 195.9,
178.8, 149.0, 148.6, 144.8, 136.4, 133.3, 131.9, 131.4, 128.5, 128.4,
128.0, 124.1, 122.1, 119.2, 111.0, 110.4, 108.5, 56.0, 55.9, 52.6, 47.5,
26.3, 22.4 ppm. IR (film): ν = 3025, 2915, 2900, 1701, 1625, 1478,
˜
1320, 1299, 1227, 1128, 1022, 795, 670, 634 cm–1
.
26.8 ppm. IR (film): ν = 2929, 2837, 2358, 1712, 1602, 1510, 1470,
˜
1348, 1245, 1139, 1128, 1029, 755, 605, 575, 544 cm–1
.
1-(3,4-Dimethoxyphenyl)ethan-1-one [( )-12c]: Colourless liquid
1
(23 %). Rf = 0.47 (5 % EtOAc in hexane). H NMR (400 MHz, CDCl3):
δ = 7.54 (dd, J = 8.32, 1.9 Hz, 1 H), 7.49 (d, J = 1.84 Hz, 1 H), 6.85
(d, J = 8.32 Hz, 1 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 2.53 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 196.8, 153.3, 149.0, 130.51, 123.3,
110.1, 110.0, 56.1, 56.0, 26.8 ppm. IR (film): ν = 3123, 2896, 2756,
˜
1889, 1703, 1699, 1563, 1231, 1078, 711 cm–1
.
General Procedure for the Synthesis of Compounds (14a–14c):
Compound 7b–7h (1.0 mmol) was dissolved in 1,2-dichloroethane
(DCE; 5 mL) in an oven-dried round-bottomed flask equipped with
a magnetic stirrer bar at room temperature. The Lewis acid (10 mol-
%, 0.1 mmol) was added at room temperature. Phenylacetylene
(3 equiv., 3.0 mmol) was then added dropwise by syringe. The reac-
tion mixture was stirred for 4–6 h at 80 °C. When TLC showed that
the reaction was complete, the reaction was quenched with water,
and the mixture was diluted with dichloromethane (10 mL). The
organic layer was separated with a separatory funnel. The organic
phase was dried with anhydrous Na2SO4, and concentrated in a
rotary evaporator under vacuum. The crude product was purified
by flash chromatography to give the acylated product.
3-(Benzo[d][1,3]dioxol-5-yl)-1-methyl-3-(2-oxo-2-phenyl-
ethyl)indolin-2-one [( )-14c]: Brown gel (77 %). Rf = 0.39 (30 %
EtOAc in hexane). 1H NMR (500 MHz, CDCl3): δ = 7.88–7.86 (m, 2
H), 7.56–7.53 (m, 1 H), 7.42 (t, J = 7.98 Hz, 2 H), 7.35 (td, J = 7.76,
1.12 Hz, 1 H), 7.29–7.27 (m, 1 H), 7.07 (td, J = 7.61, 0.70 Hz, 1 H),
7.02 (d, J = 1.90 Hz, 1 H), 6.96 (d, J = 7.76 Hz, 1 H), 6.88 (dd, J =
8.25, 1.96 Hz, 1 H), 6.75 (d, J = 8.25 Hz, 1 H), 5.95–5.94 (m, 2 H),
4.16–4.02 (m, 2 H), 3.31 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 195.8, 178.7, 148.0, 147.0, 144.7, 136.4, 133.3, 133.3, 131.6, 128.6,
128.5, 128.0, 124.2, 122.3, 120.1, 108.5, 108.1, 107.6, 101.2, 52.8, 47.1,
26.8 ppm. IR (film): ν = 3054, 2918, 2280, 1704, 1609, 1487, 1342,
˜
1239, 1033, 930, 737, 685 cm–1. HRMS (ESI): calcd. for C24H20NO4 [M
+ H]+ 386.1387; found 386.1392.
3-(6-Methoxybenzo[d][1,3]dioxol-5-yl)-1-methyl-3-(2-oxo-2-
phenylethyl)indolin-2-one [( )-29]: 3-Methoxy-2-oxindole (+)-27
(1.0 mmol) was dissolved in 1,2-dichloroethane (DCE; 5 mL) in an
oven-dried round-bottomed flask equipped with a magnetic stirrer
bar at room temperature. The Lewis acid (10 mol-%, 0.1 mmol) was
added, and then phenylacetylene (10; 3 equiv., 3.0 mmol) was
added dropwise by syringe. The reaction mixture was stirred for 6 h
at 80 °C. When TLC showed that the reaction was complete, the
reaction was quenched with water, and the mixture was diluted
with CH2Cl2 (10 mL). The organic layer was separated with a separa-
3-(4-Methoxyphenyl)-1-methyl-3-(2-oxo-2-phenylethyl)indolin-
2-one [( )-14a]: Pale brown gel (74 %). Rf = 0.50 (30 % EtOAc in
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tory funnel. The organic phase was dried with anhydrous Na2SO4,
and concentrated with a rotary evaporator under vacuum. The
crude product was purified by flash chromatography to give ( )-29
(86 %) as a pale brown solid.
(400 MHz, CDCl3): δ = 7.87–7.85 (m, 2 H), 7.52 (t, J = 7.41 Hz, 1 H),
7.42–7.38 (m, 4 H), 7.33 (t, J = 7.25 Hz, 2 H), 7.27–7.25 (m, 1 H),
7.13–7.08 (m, 2 H), 6.92 (t, J = 7.24 Hz, 1 H), 6.73 (d, J = 7.76 Hz, 1
H), 5.09–4.99 (m, 2 H), 3.79–3.69 (m, 2 H), 1.49 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 195.9, 180.7, 142.9, 136.4, 136.3, 133.8,
133.2, 128.7, 128.5, 128.0, 127.7, 127.4, 127.3, 122.2, 121.7, 109.3,
45.8, 45.4, 44.0, 25.5 ppm. IR (film): ν = 2925, 2851, 2360, 1617, 1615,
˜
1471, 1351, 1265, 1214, 1124, 739, 702 cm–1. HRMS (ESI): calcd. for
C24H22NO2 [M + H]+ 356.1645; found 356.1647.
General Procedure for the Synthesis of ( )-21a–21e: 3-Hydroxy-
2-oxindole (1.0 mmol) was dissolved in 1,2-dichloroethane (DCE;
5 mL) in an oven-dried round-bottomed flask equipped with a mag-
netic stirrer bar at room temperature. The Lewis acid (10 mol-%,
0.1 mmol) was added, followed by phenylacetylene (3 equiv.,
3.0 mmol) at room temperature. The reaction mixture was stirred
for 6–9 h at 80 °C. When TLC showed that the reaction was com-
plete, the reaction was quenched with water, and the mixture was
diluted with dichloromethane (10 mL). The organic layer was sepa-
rated with a separatory funnel. The organic phase was dried with
anhydrous Na2SO4, and concentrated with a rotary evaporator un-
der vacuum. The crude product was purified by flash chromatogra-
phy.
Rf = 0.47 (50 % EtOAc in hexane). M.p. 167–169 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.84–7.81 (m, 2 H), 7.49 (t, J = 7.52 Hz, 1 H),
7.37 (t, J = 7.77 Hz, 2 H), 7.28 (d, J = 7.49 Hz, 1 H), 7.20 (td, J = 7.54,
0.98 Hz, 1 H), 6.92–6.88 (m, 1 H), 6.85–6.81 (m, 2 H), 6.46 (s, 1 H),
5.90–5.87 (m, 2 H), 4.37 (d, J = 16.49 Hz, 1 H), 3.81–3.75 (m, 1 H),
3.51 (s, 3 H), 3.26 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 196.3,
179.2, 153.1, 147.5, 144.4, 141.5, 137.0, 133.1, 133.0, 128.4, 128.0,
127.8, 123.8, 122.2, 121.2, 108.1, 107.6, 101.4, 96.5, 56.8, 52.6, 44.1,
26.5 ppm. IR (film): ν = 3058, 2999, 2960, 1705, 1696, 1615, 1465,
˜
1380, 1283, 1222, 1110, 1099, 870, 720, 640 cm–1. HRMS (ESI): calcd.
for C25H22NO5 [M + H]+ 416.1492; found 416.1517.
General Procedure for the Addition of Phenylacetylene to 16a
and 16b: 3-Acetoxy-2-oxindole ( )-16a or ( )-16b (1.0 mmol) was
dissolved in 1,2-dichloroethane (DCE; 5 mL) in an oven-dried round-
bottomed flask equipped with a magnetic stirrer bar at room tem-
perature. The Lewis acid (20 mol-%, 0.2 mmol) was added, followed by
phenylacetylene (3 equiv., 3.0 mmol) at room temperature. The re-
action mixture was stirred for 9 h at 80 °C. When TLC showed that
the reaction was complete, the reaction was quenched with water,
and the mixture was diluted with dichloromethane (10 mL). The
organic layer was separated with a separatory funnel. The organic
phase was dried with anhydrous Na2SO4, and concentrated in a
rotary evaporator under vacuum. The crude product was purified
by flash chromatography.
( )-1-Methyl-6′-phenylspiro[indoline-3,8′-[1,3]dioxolo[4,5-
g]chromen]-2-one [( )-21a]: Yellow gel (69 %). Rf = 0.68 (50 %
EtOAc in hexane). 1H NMR (400 MHz, CDCl3): δ = 7.68–7.66 (m, 2
H), 7.38–7.30 (m, 4 H), 7.15 (d, J = 6.81 Hz, 1 H), 7.06 (t, J = 7.26 Hz,
1 H), 6.91 (d, J = 7.82 Hz, 1 H), 6.72 (s, 1 H), 5.95 (s, 1 H), 5.87–5.85
(m, 2 H), 5.18 (s, 1 H), 3.28 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 178.5, 150.7, 147.9, 146.4, 144.2, 142.9, 136.3, 133.5, 129.0, 128.9,
128.3, 125.3, 125.0, 123.5, 111.6, 108.2, 105.3, 101.5, 99.0, 96.1, 51.0,
26.7 ppm. IR (film): ν = 3410, 2917, 2849, 1716, 1608, 1479, 1291,
˜
1249, 1167, 1037, 857, 751, 694 cm–1. HRMS (ESI): calcd. for
C24H18NO4 [M + H]+ 384.1230; found 384.1229.
1,3-Dimethyl-3-(2-oxo-2-phenylethyl)indolin-2-one [( )-18a]:
Yellow gel (54 %). Rf = 0.33 (20 % EtOAc in hexane). 1H NMR
(400 MHz, CDCl3): δ = 7.82–7.80 (m, 2 H), 7.50 (t, J = 7.30 Hz, 1 H),
7.38 (t, J = 7.79 Hz, 2 H), 7.26–7.22 (m, 1 H), 7.12 (d, J = 7.09 Hz, 1
H), 6.96 (t, J = 7.30 Hz, 1 H), 6.88 (d, J = 7.79 Hz, 1 H), 3.72–3.61 (m,
2 H), 3.29 (s, 3 H), 1.43 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
196.1, 180.6, 143.9, 136.4, 133.7, 133.2, 128.5, 128.0, 127.9, 122.2,
121.8, 108.2, 46.0, 45.3, 26.5, 24.9 ppm. IR (film): ν = 3061, 2924,
˜
3852, 1711, 1614, 1488, 1467, 1352, 1216, 1180, 1002, 752, 698, 551,
419 cm–1. HRMS (ESI): calcd. for C18H18NO2 [M + H]+ 280.1332; found
280.1333.
6′-(4-Fluorophenyl)-1-methylspiro[indoline-3,8′-[1,3]diox-
olo[4,5-g]chromen]-2-one [( )-21b]: Pale yellow gel (69 %). Rf =
0.64 (50 % EtOAc in hexane). H NMR (400 MHz, CDCl3): δ = 7.66–
1
7.63 (m, 2 H), 7.32 (td, J = 7.65, 0.99 Hz, 1 H), 7.14 (d, J = 6.83 Hz,
1 H), 7.08–7.01 (m, 3 H), 6.91 (d, J = 7.80 Hz, 1 H), 6.70 (s, 1 H), 5.94
(s, 1 H), 5.87–5.85 (m, 2 H), 5.11 (s, 1 H), 3.27 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 178.4, 149.9, 148.0, 146.3, 144.3, 142.9, 136.1,
128.9, 126.9, 126.8, 125.3, 123.5, 115.4, 115.2, 116.6, 108.2, 105.3,
1-Benzyl-3-methyl-3-(2-oxo-2-phenylethyl)indolin-2-one [( )-
18b]: Yellow gel (43 %). Rf = 0.47 (20 % EtOAc in hexane). H NMR
101.5, 98.9, 95.9, 50.9, 26.7 ppm. IR (film): ν = 3353, 2921, 2360,
˜
1
1716, 1609, 1578, 1471, 1344, 1250, 1160, 1035, 840, 756 cm–1
.
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HRMS (ESI): calcd. for C24H17FNO4 [M + H]+ 402.1136; found
402.1116.
H), 5.06 (s, 1 H), 3.84 (s, 3 H), 3.34–3.25 (m, 4 H), 1.21–1.20 (m, 6 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 178.8, 157.6, 151.0, 147.8,
146.5, 144.0, 142.9, 136.8, 136.5, 128.8, 125.9, 125.4, 123.6, 123.5,
123.0, 111.8, 109.9, 108.2, 105.3, 101.4, 99.0, 94.1, 55.5, 51.0, 26.9,
26.7, 22.6, 226 ppm. IR (film): ν = 2953, 2914, 2861, 2369, 1717,
˜
1604, 1484, 1342, 1246, 1162, 1033, 739 cm–1. HRMS (ESI): calcd. for
C28H26NO5 [M + H]+ 456.1805; found 456.1792.
4-Methoxy-3-methylphenyl 2-[3-(4-methoxyphenyl)-1-methyl-
2-oxoindolin-3-yl]acetate [( )-31]: Compound 11k (1 equiv.,
1.0 mmol) was dissolved in dichloromethane (4 mL) in an oven-
dried round-bottomed flask equipped with a magnetic stirrer bar
under a nitrogen atmosphere at room temperature. Na2HPO4
(12 equiv., 12 mmol) was added, and then the mixture was treated
with m-CPBA (6 equiv., 6.0 mmol). The reaction mixture was stirred
for 6 h at room temperature. When TLC showed that the reaction
was complete, the reaction was quenched with water, and the mix-
ture was diluted with dichloromethane (10 mL). The organic layer
was separated with a separatory funnel. The organic phase was
dried with anhydrous Na2SO4, and concentrated in a rotary evapo-
rator under vacuum. The crude product was purified by flash chro-
matography to give ( )-31 (74 %) as a pale red solid.
1-Methyl-6′-(p-tolyl)spiro[indoline-3,8′-[1,3]dioxolo[4,5-
g]chromen]-2-one [( )-21c]: Pale yellow gel (68 %). Rf = 0.62 (50 %
EtOAc in hexane). 1H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 8.20 Hz,
2 H), 7.31 (td, J = 7.70, 0.94 Hz, 1 H), 7.16–7.13 (m, 3 H), 7.05 (t, J =
7.33 Hz, 1 H), 6.90 (d, J = 7.78 Hz, 1 H), 6.71 (s, 1 H), 5.94 (s, 1 H),
5.86–5.85 (m, 2 H), 5.12 (s, 1 H), 3.27 (s, 3 H), 2.34 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 178.6, 150.8, 147.9, 146.5, 144.1, 142.9,
138.9, 136.4, 130.8, 129.0, 128.8, 125.3, 124.9, 123.5, 111.7, 108.2,
105.3, 101.4, 98.9, 95.3, 51.0, 26.7, 21.3 ppm. IR (film): ν = 3318,
˜
2922, 1716, 1608, 1477, 1343, 1290, 1249, 1166, 1125, 1091, 1035,
755 cm–1. HRMS (ESI): calcd. for C25H20NO4 [M + H]+ 398.1387; found
398.1385.
Rf = 0.43 (20 % EtOAc in hexane). M.p. 89–92 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.39–7.35 (m, 2 H), 7.28 (d, J = 8.84 Hz, 2 H), 7.14 (t, J =
7.61 Hz, 1 H), 6.89 (d, J = 7.76 Hz, 1 H), 6.83 (d, J = 8.86 Hz, 2 H),
6.62 (d, J = 8.77 Hz, 1 H), 6.39 (dd, J = 8.72, 2.68 Hz, 1 H), 6.32 (d,
J = 2.51 Hz, 1 H), 3.77–3.73 (m, 4 H), 3.72 (s, 3 H), 3.38 (d, J =
15.76 Hz, 1 H), 3.16 (s, 3 H), 2.07 (s, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 178.1, 168.8, 159.1, 155.5, 144.8, 143.2, 131.0, 130.9,
128.8, 127.8, 127.7, 124.9, 123.3, 122.6, 118.8, 114.1, 110.1, 108.6,
6′-(4-Methoxy-3-methylphenyl)-1-methylspiro[indoline-3,8′-
[1,3]dioxolo[4,5-g]chromen]-2-one [( )-21d]: Pale yellow gel
(58 %). Rf = 0.57 (50 % EtOAc in hexane). 1H NMR (400 MHz, CDCl3):
δ = 7.49 (dd, J = 8.53, 2.03 Hz, 1 H), 7.44 (m, 1 H), 7.31 (td, J = 7.68,
1.08 Hz, 1 H), 7.15–7.14 (m, 1 H), 7.05 (t, J = 7.40 Hz, 1 H), 6.90 (d,
J = 7.78 Hz, 1 H), 6.79 (d, J = 8.58 Hz, 1 H), 6.72 (s, 1 H), 5.94 (s, 1
H), 5.86–5.84 (m, 2 H), 5.05 (s, 1 H), 3.83 (s, 3 H), 3.27 (s, 3 H), 2.20
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 178.7, 158.5, 150.7,
147.8, 146.5, 144.1, 142.9, 136.5, 128.8, 127.4, 126.4, 125.7, 125.3,
123.8, 123.5, 111.8, 109.5, 108.1, 105.3, 101.4, 98.9, 94.2, 55.4, 51.0,
55.6, 55.3, 52.8, 42.5, 26.7, 16.2 ppm. IR (film): ν = 3377, 2925, 2363,
˜
1717, 1609, 1506, 1254, 1210, 1157, 1033, 755, 427 cm–1. HRMS
(ESI): calcd. for C26H26NO5 [M + H]+ 432.1805; found 432.1809.
( )-Ethyl 2-[3-(4-methoxyphenyl)-1-methyl-2-oxoindolin-3-
yl]acetate [( )-32]: Compound 31 (1 equiv., 1.0 mmol) was dis-
solved in EtOH (5 mL) in an oven-dried round-bottomed flask
equipped with a magnetic stirrer bar at room temperature. K2CO3
(5 equiv., 5.0 mmol) was added, and the reaction mixture was stirred
for 14 h at room temperature. When TLC showed that the reaction
was complete, the reaction mixture was concentrated. Water was
added, followed by CH2Cl2 (10 mL). The organic layer was separated
with a separatory funnel. The organic phase was dried with anhy-
drous Na2SO4, and concentrated with a rotary evaporator under
vacuum. The crude product was purified by flash chromatography
to give ( )-32 (87 %) as a yellow gel.
26.7, 16.3 ppm. IR (film): ν = 3055, 2921, 2359, 1716, 1608, 1504,
˜
1485, 1370, 1251, 1167, 1140, 1037, 935, 756, 675, 540 cm–1. HRMS
(ESI): calcd. for C26H22NO5 [M + H]+ 428.1492; found 428.1521.
( )-6′-(3-Isopropyl-4-methoxyphenyl)-1-methylspiro[indoline-
3,8′-[1,3]dioxolo[4,5-g]chromen]-2-one [( )-21e]: Yellow gel
(62 %). Rf = 0.60 (50 % EtOAc in hexane). 1H NMR (500 MHz, CDCl3):
δ = 7.52–7.48 (m, 2 H), 7.33 (td, J = 7.65, 1.18 Hz, 1 H), 7.17 (d, J =
7.36 Hz, 1 H), 7.07 (t, J = 7.49 Hz, 1 H), 6.92 (d, J = 7.81 Hz, 1 H),
6.83 (d, J = 8.59 Hz, 1 H), 6.74 (s, 1 H), 5.95 (s, 1 H), 5.88–5.86 (m, 2
Rf = 0.43 (20 % EtOAc in hexane). 1H NMR (400 MHz, CDCl3): δ =
7.34–7.21 (m, 4 H), 7.10–7.06 (m, 1 H), 6.88 (d, J = 7.79 Hz, 1 H),
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6.79 (d, J = 8.91 Hz, 2 H), 3.92–3.78 (m, 2 H), 3.73 (s, 3 H), 3.52 (d,
J = 16.02 Hz, 1 H), 3.21 (s, 3 H), 3.17 (d, J = 16.12 Hz, 1 H), 0.95 (t,
J = 7.15 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 178.3, 169.6,
159.0, 144.6, 131.2, 131.2, 128.6, 127.8, 124.5, 122.4, 114.0, 108.3,
60.5, 55.3, 52.7, 42.3, 26.6, 13.9 ppm. IR (film): ν = 3055, 2921, 2359,
˜
1716, 1608, 1504, 1370, 1306, 1251, 1167, 1140, 1037, 935, 756, 673,
540 cm–1. HRMS (ESI): calcd. for C20H22NO4 [M + H]+ 340.1543; found
340.1553.
3a-(4-Methoxyphenyl)-8-methyl-3,3a,8,8a-tetrahydro-2H-
furo[2,3-b]indole [( )-36]: Compound ( )-32 (1.0 equiv.,
0.14 mmol) was dissolved in dry THF (2 mL) in a flame-dried round-
bottomed flask under a nitrogen atmosphere. LiAlH4 (5 equiv.,
0.73 mmol) was added at 0 °C in an ice bath, and then the mixture
was stirred for 2 h. When TLC showed that the reaction was com-
plete, the reaction mixture was quenched by the addition of ethyl
acetate at 0 °C. The mixture was then treated with water (slow and
H), 2.18 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 179.4, 158.8,
143.6, 132.1, 131.9, 128.4, 127.9, 124.6, 122.8, 114.0, 108.6, 59.4, 55.3,
54.4, 40.3, 26.5 ppm. IR (film): ν = 3422, 2933, 1697, 1610, 1512,
˜
1471, 1373, 1253, 1185, 1096, 1034, 829, 754 cm–1. HRMS (ESI):
calcd. for C18H20NO3 [M + H]+ 298.1453; found 298.1438.
3a-(4-Methoxyphenyl)-1,8-dimethyl-1,2,3,3a,8,8a-hexahydro-
pyrrolo[2,3-b]indole [( )-35]: DMSO (0.68 mmol, 5 equiv.) was dis-
dropwise addition) until a clear organic layer formed. The organic solved in dry dichloromethane (5 mL) in a flame-dried round-bot-
layer was separated with a separatory funnel. The organic phase
was dried with anhydrous Na2SO4, and concentrated in a rotary
evaporator under vacuum. The crude product was purified by flash
chromatography to give ( )-36 (94 %) as a colourless solid.
tomed flask, and the mixture was cooled to –78 °C. A solution of
(COCl)2 (0.50 mmol, 1.5 equiv.) in dichloromethane (2 mL) was then
added dropwise to the reaction mixture at –78 °C. The reaction
mixture was stirred for 30 min. Then a solution of compound 33
(0.33 mmol, 5 equiv.) in dry dichloromethane (2 mL) at –78 °C. The
reaction mixture was stirred for 2 h, and then Et3N (1.68 mmol,
5 equiv.) was added. The mixture was then stirred for a further 3 h,
and then the temperature was slowly allowed to increase from –78
to 0 °C. When TLC showed that the reaction was complete,water
and dichloromethane were added. The mixture was then separated
using a separatory funnel. The combined organic layers were dried
with anhydrous NaSO4, and concentrated under reduced pressure.
The crude product was used in the next step without further purifi-
cation.
Rf = 0.42 (30 % EtOAc in hexane). M.p. 80–84 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.18–7.14 (m, 2 H), 7.06 (td, J = 7.7, 0.9 Hz, 1 H), 6.90 (d,
J = 7.3 Hz, 1 H), 6.76 (d, J = 8.8 Hz, 2 H), 6.0 (t, J = 7.3 Hz, 1 H), 6.37
(d, J = 7.8 Hz, 1 H), 5.29 (s, 1 H), 4.05 (t, J = 7.8 Hz, 1 H), 3.70 (s, 3
H), 3.49–3.43 (m, 1 H), 2.88 (s, 3 H), 2.66–2.58 (m, 1 H), 2.37 (dd, J =
11.8, 4.4 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.3, 151.0,
136.0, 133.4, 128.4, 127.3, 124.1, 117.7, 113.9, 105.5, 105.5, 68.1, 60.7,
Crude aldehyde ( )-34 (0.40 mmol, 1 equiv.) was taken up in dry
THF (8 mL) in a flame-dried round-bottomed flask under an inert
atmosphere at room temperature. MgSO4 (180 mg) was added, fol-
lowed by Et3N (4.0 mmol, 10.0 equiv.) and MeNH2·HCl (4.0 mmol,
10.0 equiv.). The reaction mixture was stirred vigorously at room
temperature for 12 h. After this time, solid LiAlH4 (4.0 mmol,
10.0 equiv.) was added at room temperature. The reaction mixture
was placed in a preheated oil bath, and it was heated at 70 °C for
1.5 h. When TLC showed that the reaction was complete, the reac-
tion mixture was cooled down to room temp., and the reaction was
quenched by the careful addition of EtOAc (5 mL) and then satu-
rated aq. NaHCO3 (8 mL). The mixture was filtered through a Celite
pad, which was then washed with EtOAc. The organic layer was
separated with a separatory funnel. The aqueous layer was ex-
tracted with EtOAc (3 × 10 mL). The combined organic layers were
dried with anhydrous NaSO4, and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography to
55.3, 40.8, 30.7 ppm. IR (film): ν = 2931, 1606, 1490, 1387, 1297,
˜
1260, 1182, 1037, 950, 798, 740, 662, 608, 578 cm–1; HRMS (ESI):
calcd. for C18H20NO2 [M + H]+ 282.1505; found 282.1489.
3-(2-Hydroxyethyl)-3-(4-methoxyphenyl)-1-methylindolin-2-
one [( )-33]: Compound ( )-32 (1.0 equiv., 1.47 mmol) was dis-
solved in diethyl ether (7 mL) in a flame-dried round-bottomed flask
under a nitrogen atmosphere. The reaction mixture was treated
with MeOH (5 equiv., 7.37 mmol) at room temperature. Then the
solution was cooled down to 0 °C, and LiBH4 (2.5 equiv., 3.67 mmol)
was added at the same temperature. After 45 min, the reaction
mixture was allowed to reach room temperature. When TLC showed give ( )-35 (78 %) as a yellow liquid.
that the reaction was complete, the excess LiBH4 was quenched by
the addition of ethyl acetate at 0 °C. The mixture was then treated
with water (slow and dropwise addition) until a clear organic layer
formed. The organic layer was separated with separatory funnel.
The organic phase was dried with anhydrous Na2SO4, and concen-
trated in a rotary evaporator under vacuum. The crude product was
purified by flash chromatography to give ( )-33 (67 %) as a colour-
less solid.
Rf = 0.3 (70 % EtOAc in hexane). M.p. 143–146 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.30 (td, J = 7.6, 0.44 Hz, 1 H), 7.26 (d, J = 8.8 Hz, 2 H),
Rf = 0.42 (50 % EtOAc in hexane). 1H NMR (400 MHz, CDCl3): δ =
7.22 (d, J = 7.28 Hz, 1 H), 7.09 (t, J = 7.48 Hz, 1 H), 6.88 (d, J = 7.18 (d, J = 8.8 Hz, 2 H), 7.09 (td, J = 7.76, 0.88 Hz, 1 H), 6.88 (d, J =
7.8 Hz, 1 H), 6.8 (d, J = 8.84 Hz, 2 H), 3.73 (s, 3 H), 3.51–3.37 (m, 2
H), 3.19 (s, 3 H), 2.73–2.66 (m, 1 H), 2.36 (dt, J = 13.88, 5.92 Hz, 1
7.24 Hz, 1 H), 6.80 (d, J = 8.76 Hz, 2 H), 6.65 (t, J = 7.3 Hz, 1 H), 6.46
(d, J = 7.84 Hz, 1 H), 4.44 (s, 1 H), 3.76 (s, 3 H), 2.97 (s, 3 H), 2.91–
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˜
1250, 1183, 1123, 1037, 950, 830, 750, 604, 569 cm–1. HRMS (ESI):
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Acknowledgments
Financial support from the Science and Engineering Research
Board (SERB), the Department of Science and Technology (DST)
(Grant No.: SR/S1/OC-54/2011), and the Council of Scientific and
Industrial Research (CSIR) (Grant No.: 02(0013)/11/EMR-II) of the
Government of India is gratefully acknowledged. We thank Ms.
Anusha Upadhyay, IISER Bhopal, for X-ray structure analysis.
L. K. K. and K. N. B. thank the CSIR, New Delhi for research
fellowships, and D. P. is grateful to the Indian National Science
Academy (INSA) for an INSA-IASc-NASI Summer Research Fel-
lowship (2016). The facilities of the Department of Chemistry,
IISER Bhopal are gratefully acknowledged.
Keywords: Earth-abundant metals · Alkynes · Cyclization ·
Lewis acids · 2-Nitrogen heterocycles · Spiro compounds
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Received: April 10, 2017
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Quaternary Centres
L. K. Kinthada, K. N. Babu,
D. Padhi, A. Bisai* ........................... 1–15
Lewis-Acid-Catalysed Reaction of 3-
Hydroxy-2-oxindoles with Terminal
Alkynes: Synthetic Approaches to
the Pyrroloindoline Alkaloids
Lewis-acid-catalysed reaction of 3- quaternary centre. This reaction pre-
hydroxy-2-oxindoles with a variety of sumably goes through intermediate
terminal alkynes has been demon- 2H-indol-2-one, which has been
strated to give2-oxindoles/spiro-fused proved via some control experiments.
2-oxindoles sharing an all-carbon
DOI: 10.1002/ejoc.201700507
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