Pd(0)-Catalyzed Chemoselective Deacylative Alkylations (DaA) of N-Acyl 2-Oxindoles: Total Syntheses of Pyrrolidino[2,3- b]indoline Alkaloids, (±)-Deoxyeseroline, and (±)-Esermethole

Article abstract of DOI:10.1021/acs.joc.8b01101

We report an efficient Pd(0)-catalyzed deacylative allylation of N-acyl 3-substituted 2-oxindoles via the coupling of in situ generated nucleophiles (3 and 4) with allyl electrophiles for the synthesis of a variety of 2-oxindoles with C3-quaternary centers. Gratifyingly, this alkylation process is found to be highly chemoselective in nature, where a C-C bond formation is completely predominant over a C-N bond formation. A variety of key intermediates were synthesized utilizing an aforementioned methodology.

Full text of DOI:10.1021/acs.joc.8b01101

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Article
Pd(0)-Catalyzed Chemoselective Deacylative Alkylations (DaA)
of N-Acyl-2-oxindoles: Total Syntheses of Pyrrolidino[2,3-
b]indoline Alkaloids, (±)-Deoxyeseroline and (±)-Esermethole
Nivesh Kumar, Vipin R. Gavit, Arindam Maity, and Alakesh Bisai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01101 • Publication Date (Web): 30 Jul 2018
Downloaded from http://pubs.acs.org on July 30, 2018
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Pd(0)-Catalyzed Chemoselective Deacylative Alkylations
(DaA) of N-Acyl-2-oxindoles: Total Syntheses of
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Pyrrolidino[2,3-b]indoline Alkaloids, (±)-Deoxyeseroline
and (±)-Esermethole
Nivesh Kumar, Vipin R. Gavit, Arindam Maity, and Alakesh Bisai*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal,
Bhopal Bypass Road, Bhauri, Bhopal - 462 066, Madhya Pradesh, India
TOC GRAPHIC
ABSTRACT
We report an efficient Pd(0)-catalyzed deacylative allylations of N-acyl-3-substituted 2-
oxindoles via coupling of in situ generated nucleophiles (3 and 4) with allyl electrophiles, for
the synthesis of a variety of 2-oxindoles with C3-quaternary centers. Gratifyingly, this
alkylation process is found to be highly chemoselective in nature, where a C-C bond
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formation is completely predominant over a C-N bond formation. A variety of key
intermediates were synthesized utilizing aforementioned methodology.
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INTRODUCTION
1
Palladium(0)-catalyzed decarboxylative allylation (DcA) [Tsuji-Trost allylation] provides
opportunity for the allylation of relatively non-stabilized ketone enolates from allyl -
2
, 3
ketoesters or allyl enol carbonates via elimination of CO2. Since the approach is chemically
4
mild to produce various functionalized intermediates, hence finds huge application in the
5-6
total synthesis of complex natural products. However, a major limitation of DcA reactions
is that it leads to incorporation of the allyl electrophile and the nucleophile into the same
6
a-b
6c-d
reactant molecule via an ester linkage
or carbonate.
In this context, palladium(0)-
catalyzed deacylative allylation (DaA) of -nitroketone derivatives (pKa ~ 17) by Grenning
7
8, 9
and Tunge opens up a unique avenue to access unsymmetrically substituted 1,6-dienes.
Their pioneering report also suggests that a facile retro-Claisen activation to produce enolates
1
0a
10b
(pKa ~ 18-25), and nitrile stabilized anions (pKa ~ 23) undergoes alkylations to afford
1
1
diverse products.
2-Oxindoles bearing an all-carbon quaternary center constitutes a prominent class of
heterocycles that represent important building blocks found in a wide variety of several
12
pharmaceuticals. Recently, we have reported an efficient Pd(0)-catalyzed deacylative
allylation (DaA) of 2-oxindoles sharing acyl functionality at 3-position (see, I in Scheme 1)
with readily available allylic alcohols by employing Pd(0)-catalysis under mild reaction
13a
conditions. This reaction presumably goes through a retro-Claisen reaction to generate
nucleophile (see, II and III) and electrophile (see, IV), which were reacted in the presence of
catalytic Pd(0) to afford a wide variety of products with quaternary centers at the
13a
pseudobenzylic position of N-alkyl 2-oxindoles (see, V) under mild reaction conditions.
Gratifyingly, the same strategy works equally well for dimeric 2-oxindole system furnishing
products with vicinal quaternary center in favour of meso-isomer as major product. Utilizing
this methodology we have reported concise total syntheses of dimeric pyrroloindoline
1
3
alkaloids, meso-folicanthine and meso-chimonanthine.
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Scheme 1. Our hypothesis of N-deacylative alkylations (N-DaA).
N-Unsubstituted 2-oxindoles sharing with a quaternary centers at the pseudobenzylic
position are the privileged structural scaffolds in organic synthesis. These are found to
be the building blocks for the synthesis of a number of pharmaceutically important
compounds and natural products. We hypothesized that an allylic alkoxide may induce
a N-deacylation of an appropriately substituted N-acyl-2-oxindole
as active intermediate via anion (Scheme 1). This enolate would then react with
Pd(II)- -allyl complex generated in situ by reaction of allyl acetate and Pd(0) to
furnish various 2-oxindoles with a quaternary center. However, since anion and
enolate have several bond forming possibilities (N-center of anion is relatively
soft), a chemoselective C-C bond forming reaction would be challenging and worth
1 to form enolate 4
3
4

3
4
3
1
3
testing. Herein, we describe a novel strategy involving Pd(0)-catalyzed deacylative
allylation of N-acyl-2-oxindole via coupling of in situ generated nucleophiles with
allyl electrophiles (Scheme 1).
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RESULTS AND DISCUSSION
At the outset, we started optimization of deacylative allylation (DaA) with N-
methoxycarbonyl 3-benzyl 2-oxindole (1a) with allyl alcohol in the presence of catalytic
Pd(0) and a suitable base. Following exhaustive optimization (Table 1), we observed that
deacylative alkylation (DaA) can be carried out with 1a (0.25 mmol, 1 equiv) in the presence
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t
of either NaH (1.2 equiv) or KO Bu (1.2 equiv) and 1 mol% Pd(PPh ) in toluene at room
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temperature, to afford the desired 2-oxindole 6a in 91% and 89% yields, respectively (Table
).
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Table 1: Optimization of N-deacylative allylation (N-DaA) of (±)-1a.
b
entr
catalyst
base solvent temp
ligand
time
%
% of
3a
a
y
(6a)
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Pd (dba)
NaH
THF
70 °C ---
70 °C ---
4 h
5 h
44% 38%
25% 53%
46% 39%
42% 33%
59% 25%
65% 21%
62% 14%
79% 8%
87% --
2
3
t
Pd (dba)
KO Bu THF
2
3
Pd(OAc)2 NaH
THF
70 °C PPh (10 mol%) 4 h
3
t
Pd(OAc)2 KO Bu PhMe
25 °C PPh (10 mol%) 5 h
3
Pd(OAc)2 NaH
Pd(OAc)2 NaH
Pd(OAc)2 NaH
Pd(OAc)2 NaH
Pd(OAc)2 NaH
Pd(OAc)2 NaH
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
25 °C PPh (10 mol%) 4 h
3
25 °C L1 (5 mol%)
25 °C L2 (10 mol%)
25 °C L3 (5 mol%)
25 °C L4 (5 mol%)
25 °C L5 (5 mol%)
25 °C ---
4 h
5 h
6 h
5 h
1
1
0
1
4 h
90% --
c
Pd(PPh3)4 NaH
12 h
12 h
14 h
12 h
14 h
91% --
c
t
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Pd(PPh3)4 KO Bu PhMe
25 °C ---
89% --
c
c
1
1
1
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5
Pd(PPh3)4 NaH
Pd(PPh3)4 NaH
Pd(PPh3)4 NaH
Et O
25 °C ---
62% 15%
70% 20%
67% 17%
2
CH Cl2 25 °C ---
2
c
DMSO 25 °C ---
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c
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Pd(PPh3)4 NaH
Pd(PPh3)4 NaH
dioxane 25 °C ---
MeCN 25 °C ---
13 h
13 h
12 h
12 h
12 h
56% 21%
83% --
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Pd (dba)
NaH
NaH
NaH
PhMe
DMSO 25 °C ---
PhH 25 °C ---
25 °C ---
69% 13%
65% 10%
65% 17%
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reactions were carried out by using 0.25 mmol of 1a with 0.30 mmol of allyl alcohol under argon
b
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atmosphere. isolated yield after column purification. 1 mol% Pd-catalyst used.
This standard condition of deacylative alkylation (DaA) was applied to a variety of
substrates.
Scheme 2: Synthesis of N-carboxymethyl 3-substituted 2-oxindoles.
The optimization using a variety of N-acyl substrates 1a-d, showed that N-carboxymethyl 3-
substituted 2-oxindoles are good substrates for efficient DaA process (Scheme 2).
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a,b
Scheme 3: Effect of different N-acyl groups on N-DaA.
With an optimized N-methoxycarbonyl as acyl group, 1a was reacted with a variety of allyl
alcohols as pro-electrophiles to afford a library of 2-oxindoles with a C3-quaternary center
(Scheme 3). As obvious from scheme 2, our optimized conditions could afford a variety of
products with moderate to good yields.
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column chromatography.
Scheme 4: Substrates scope of Pd(0)-catalyzed N-DaA.
Interestingly, crotyl, tiglyl, and cinnamyl type alcohols afforded products 6c (Scheme 2), 6d-
e, and 6h (Scheme 3) with complete regioselectivity, where only linear alkylations were
observed. These reactions proceed through the formation of π-allyl palladium intermediates
and the linear isomer was exclusively obtained as E-isomer (E:Z = 100:0). Aralyl alcohols
furnished products 6f-g in 80-89% isolated yields. However, cinnamyl type alcohol having a
-naphthyl as aryl group furnished in 4:1 regioselectivity in favoured of linear alkylation
(see, 6i-j, Scheme 3).
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We then sought to explore our strategy to prenylated, reverse-prenylated, and geranylated
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hexahydropyrrolo[2,3-b]indole natural products. To realize this we proposed a direct
incorporation of the prenyl, reverseprenyl, or geranyl group at the 3-position of 2-oxindole
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products via Pd-catalyzed deacylative allylation involving retro-Claisen activation. In case
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Gratifyingly, geranyl alcohol as a pronucleophile afforded product 6m as a liner product as
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exclusive one.
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b
toluene in the presence of 1 mol% Pd(PPh ) under argon atmosphere. isolated yield after silica gel
3 4
column chromatography.
a,b
Scheme 5: Substrates scope of N-DaA.
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Later, a variety of 3-substution on N-methoxycarbonyl 2-oxindoles were reacted with allyl,
methallyl, and cinnamyl alcohols as pro-electrophiles, under optimized condition of DaA
(
Schemes 4 and 5). These reactions afforded a variety of products in good to excellent yields,
where again linear selectivities were observed in case of cinnamyl alcohol (Schemes 4 and 5).
a
reactions were carried out by using 0.25 mmol of 1m-o with 0.30 mmol of substituted allyl alcohol in
b
toluene in the presence of 1 mol% Pd(PPh ) under argon atmosphere. isolated yield after silica gel
3
4
column chromatography.
a,b
Scheme 6: Substrates scope of N-DaA.
Further, recent reports on direct benzylation of nitriles in the presence of benzyl alcohols by
17
18
Tunge prompted us to explore our deacylative methodology even further. The proposed
3
catalytic cycle for these transformations invoke a cationic η -benzyl-palladium intermediate
1
9
which is less common since aromaticity is disrupted. Therefore, to demonstrate the scope of
this deacylative alkylation variant subsequent investigation on direct deacylative benzylation
(
DaB) of N-methoxycarbonyl 2-oxindoles was undertaken. Impressively, a variety of 2-
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oxindoles with C3-benyl quaternary centers can be synthesized under optimized conditions
(Scheme 6).
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3 4
after silica gel column chromatography.
a,b
Scheme 7: Substrates scope of Pd(0)-catalyzed N-DaB.
The generation of all-carbon quaternary centers is complicated by the presence of vicinal
tertiary stereocenters due to increased steric demands and the introduction of requisite
2
0
diastereocontrol. Therefore, further utility of our approach was shown to forge vicinal
tertiary, quaternary centers in 2-oxindole systems (Scheme 8). Gratifyingly, a number of such
structural motifs 10a-f can be synthesized using secondary allyl alcohols as pro-electrophiles
in 76-92% yields with dr up to ~2:1 (Scheme 8).
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a
reactions were carried out by using 0.25 mmol of 1a and 1m with 0.30 mmol of substituted allyl
b
alcohol in toluene in the presence of 1 mol% Pd(PPh ) under argon atmosphere. isolated yield after
3
4
silica gel column chromatography.
a-b
Scheme 8: Syntheses of 2-oxindoles with vicinal quaternary-tertiary centers via N-DaA.
Later, synthetic versatility of our DaA was shown using N-acyl 2-indole methylcarbonates
1a-c, where allylation was carried out using 2.2 equiv. of allyl alcohol to furnished products
1
12a-e in good yields (Scheme 10). A variety of substrates 11b-c were synthesized following
Scheme 9. Isatin was reacted with ArMgBr at 0 ºC in tetrahydrofuran for 12 h to afford 3-aryl
3
-hydroxy 2-oxindoles 2a-c, which were reduced with triethylsilane in the presence of
trifluoroacetic acid to afford 3-aryl 2-oxindoles 2d in 85% yield (Scheme 9). Compound 2d
was reacted with imidazolyl carbonyl reagent to furnish 11d in 65% yield. In another
sequence, 2a-b were reduced with triethylsilane in the presence of trifluoroacetic acid
followed by reaction with 2 equivalent of chloromethyl formate to afford compounds 11b-c
in 52-60% yields over 3 steps (Scheme 9).
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Scheme 9: Synthesis of N-carboxymethyl 3-substituted 2-indolyl methylcarbonates.
To our delight, a chemoselective allylation can be envisioned using 1.05 equiv. of allyl
alcohol as pro-electrophile, to afford 3-aryl-3-allyl 2-oxindoles 13a-b in synthetically useful
yields (Scheme 10).
a
reactions were carried out by using 0.25 mmol of 11a-c with 0.625 mmol (2.5 equiv.) of allyl alcohol
or methallyl alcohol [for products 12a-e] in toluene in the presence of 1 mol% Pd(PPh ) under argon
3
4
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b
c
atmosphere. isolated yield after column purification. 0.263 mmol (~1.05 equiv.) of allyl alcohol was
used for chemoselective allylations [for products 13a-b].
Scheme 10: DaA of N-acyl-enolcarbonates 11a-c and a chemoselective allylation for the
a-c
1
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synthesis of 13a-b.
Further effort was put forward for a one-pot domino deacylative allylation-Heck reaction
sequence, to afford a number of C3-cinnamylated 2-oxindoles 14a-e and 6c in moderate
yields (Scheme 11).
a
reactions were carried out by using 0.25 mmol of 1a and 1m with 0.30 mmol of allyl alcohol and
0.30 mmol of haloarenes in toluene in the presence of 1 mol% Pd(OAc) and 3 mol% of PPh at 90 ˚C
2
3
b
under argon atmosphere. isolated yield after silica gel column chromatography.
a,b
Scheme 11: Domino N-DaA-arylation sequence.
Further, it has been shown that secondary alcohol such as phenylvinylcarbinol is a good pro-
electrophile, which afforded products 8e and 6c through highly regioselective DaA in 84-
8
7% yields with linear products (Scheme 12). Interestingly, alcohol 16a afforded products 6k
and 6l in 82% yields with 1.5:1 (l:b) regioisomeric ratio in favor of linear product (Scheme
2).
1
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a
reactions were carried out by using 0.25 mmol of 1a and 1m with 0.30 mmol of allyl alcohols in
b
toluene at 90 ˚C in the presence of 1 mol% Pd(PPh ) under argon atmosphere. isolated yield after
3
4
silica gel column chromatography.
a,b
Scheme 12: Further substrate scope of N-DaA.
However, to our disappointment, alcohols 16b-d are not good substrates for the DaA
reactions. We have found that N-methoxycarbonyl 2-oxindoles 17a and 1p, with different
electronic and steric properties, are not suitable for DaA reaction. N-Methoxycarbonyl 2-
oxindoles 17a was synthesized from isatin as per reactions sequence shown in Scheme 13. In
case of substrate 1p, we encountered with deacylative protonation product (17b was isolated
in 85% yields) as shown in Scheme 13.
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Scheme 13: Substrates failed under N-DaA.
We further tested our methodology for an efficient one-pot domino Pd(0)-catalyzed DaA
followed by an intramolecular Heck cyclization (Scheme 14). It was noteworthy to observe
16
that N-H free spiro-fused 2-oxindole 18 was obtained in 75% yield under reflux.
a
reaction was carried out by using 0.25 mmol of 1f with 0.30 mmol of allyl alcohol at 90 ˚C.
Scheme 14: An efficient one-pot N-deacylative allylation-Heck sequenece of 1f.
Having successful execution of catalytic deacylative alkylations (DcA), we then procedded
for the development of enantioselective version of our methodology (Scheme 15). Towards
this, we have utilized N-acyl 2-oxindole 11d for deacylative alkylation with allyl alcohol in
the presence of 2.5 mol% Pd (dba) and 7.5 mol% (S,S)-L under argon atmosphere. After
2
3
exhaustive optimization, it was found that a maximum of 23% ee was observed when methyl
tert-butylether was used as solvent at 0 C (entry 6).
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c
entr
catalyst
solvent
temp
ligand
time
%
% of ee
(12f)
a
y
(12f)
1.
2.5 mol% THF
Pd (dba)
25 °C
7.5 mol%
(S,S)-L
12 h
65%
05%
2
3
2.
2.5 mol% PhMe
Pd (dba)
25 °C
25 °C
7.5 mol%
(S,S)-L
9 h
69%
72%
78%
76%
72%
52%
12%
08%
20%
10%
23%
20%
2
3
3.
2.5 mol% Et O
7.5 mol%
(S,S)-L
6 h
2
Pd (dba)
2
3
4
.
2.5 mol% MTBE 25 °C
Pd (dba)
7.5 mol%
(S,S)-L
10 h
10 h
12 h
24 h
2
3
5.
2.5 mol% CH Cl 25 °C
7.5 mol%
(S,S)-L
2
2
Pd (dba)
2
3
6.
2.5 mol% MTBE 0 °C
Pd (dba)
7.5 mol%
(S,S)-L
2
3
7.
2.5 mol% MTBE -10 °C
Pd (dba)
7.5 mol%
(S,S)-L
2
3
a
reactions were carried out by using 0.20 mmol of 11d with 0.30 mmol of allyl alcohol in the presence
b
of 2.5 mol% Pd (dba) and 7.5 mol% (S,S)-L under argon atmosphere. isolated yield after silica gel
2
3
c
column chromatography. ee’s were determined using chiral HPLC column (OD-3).
Scheme 15: Catalytic enantioselective deacylative alkylations (DcA).
Later, the application of N-deacylative alkylations strategy for the synthesis of
pyrrolidino[2,3-b]indoline was undertaken. The cyclic pyrrolidino[2,3-b]indoline [see; 19a-e
(Figure 1)] is the fundamental building block of cyclotryptamine alkaloids. This ring system
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is found exclusively in the cis-configuration with an all-carbon quaternary stereocenter in
almost all alkaloids, presumably because of the higher level of ring strain in the trans-
stereoisomer. They are reported to prevent the hydrolysis of acetylcholine by
acetylcholinesterase at the transmitted sites of acetylcholine so as to effect the enhancement
2
1
1
1
1
1
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of acetylcholine, and therefore, act as an acetylcholinesterase inhibitor. We envisioned that
the pyrroloindoline alkaloids can be accessed from 3-allyl 3-methyl 2-oxindole 12a (Scheme
9
).
Figure 1: Representative pyrrolidino[2,3-b]indoline alklaoids.
Towards this end, we have elaborated (±)-12a for the synthesis of a variety of advanced
intermediates required for formal total synthesis of cyclotryptamine alkaloids. Towards this
direction, 2-oxindole (±)-12a was N-methylated using MeI in the presence of NaH to afford
compound (±)-20a in 92% yield (Scheme 16). The olefin functionality of 2-oxindole (±)-20a
was oxidized to afford aldehyde (±)-20b in 90% yield over 2 steps. Later, aldehyde (±)-20b
was reacted with methylamine hydrochloride followed by reduction using LiAlH to
4
complete total synthesis of naturally occurring pyrrolidino[2,3-b]indoline, (±)-deoxyeseroline
22a
[
(±)-19a] in 85% yields over 2 steps (Scheme 16). Later, total synthesis of (±)-esermethole
19c) was achieved from (±)-deoxyeseroline [(±)-19a] in two steps. Towards this, (±)-19a
(
was reacted with HBr in DMSO at 80 ºC for 45 min to afford bromocompound, which was
then reacted with NaOMe in the presence of Cu(I)I to complete total synthesis of (±)-
2
1a
esermethole (19c) in 49% over 2 steps.
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Scheme 16: Total synthesis of (±)-deoxyeseroline (19a) and (±)-esermethole (19c).
In another sequence, aldehyde (±)-20b was directly transformed to furoindoline intermediate
2
2b
(±)-20d in 91% yield (Scheme 16). Since total syntheses of (±)-physostigmine [(±)-19d]
2
2c
and (±)-phenserine [(±)-19e]
are known from (±)-esermethole [(±)-19c], our efforts
culminated in total syntheses of these pyrrolidino[2,3-b]indoline alkaloids.
CONCLUSIONS
In summary, we have developed an efficient Pd(0)-catalyzed chemoselective N-deacylative
alkylations (DaA) of N-acyl-2-oxindoles with a variety of allyl alcohols. This methodology
was further extended with few benzyl alcohols to affect deacylative benzylation (DaB). A
number of N-H free 2-oxindoles with C3-quaternary centers can be synthesized in
synthetically useful yields under mild condition. Utilizing this strategy, total synthesis of
naturally occurring pyrrolidino[2,3-b]indoline, (±)-deoxyeseroline [(±)-19a] and (±)-
esermethole [(±)-19c] have been achieved in few steps. Further development towards the
enantioselective variant of this process as well as its application in total synthesis of
hexahydropyrrolo[2,3-b]indole alkaloids are under active investigation in our laboratory.
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EXPERIMENTAL SECTION
Materials and Methods
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Unless otherwise stated, reactions were performed in oven-dried glassware fitted with rubber
septa under an inert atmosphere and were stirred with Teflon-coated magnetic stirring bars.
Liquid reagents and solvents were transferred via syringe using standard Schlenk techniques.
Tetrahydrofuran (THF) and diethyl ether (Et O) were distilled over sodium/benzophenone
2
ketyl. Dichloromethane (CH Cl ), toluene, and benzene were distilled over calcium hydride.
2
2
All other solvents and reagents were used as received unless otherwise noted. Reaction
temperatures above 23 °C refer to oil bath temperature. Thin layer chromatography was
performed using silica gel 60 F-254 precoated plates (0.25 mm) and visualized by UV
irradiation, anisaldehyde stain and other stains. Silica gel of particle size 100-200 mesh was
used for flash chromatography. Melting points were recorded on a digital melting point
1
13
apparatus and are uncorrected. H and C NMR spectra were recorded 400, 500 MHz
1
3
spectrometers with C operating frequencies of 100, 125 MHz respectively. Chemical shifts
1
(δ) are reported in ppm relative to the residual solvent (CDCl ) signal (δ = 7.26 for H NMR
3
13
1
and δ = 77.0 for C NMR). Data for H NMR spectra are reported as follows: chemical shift
(multiplicity, coupling constants, and number of hydrogen). Abbreviations are as follows: s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). IR spectra were
-1
recorded on a FT-IR system and are reported in frequency of absorption (cm ). Only selected
IR absorbencies are reported. High-Resolution Mass Spectrometry (HRMS) and Low-
Resolution Mass Spectrometry (LRMS) data were recorded using methanol as solvent.
Synthesis of N-Acyl 2-Oxindoles (1a-o): To a stirred solution of 2-oxindole (1.50 mmol; 1.0
equiv) in EtOH (5 mL) at 25 ºC were added piperidine (30 µL, 0.30mmol, 0.20 equiv) and
corresponding aldehyde (1.50 mmol; 1.0 equiv). Then the reaction mixture was stirred for 8 -
1
2 h on refluxing. Upon consumption of starting material (monitored by TLC) the reaction
mixture was concentrated under reduced pressure.
The crude material was directly dissolved in 10 mL of CH Cl . To that solution, Et N (0.27
2
2
3
mL, 2.10 mmol, 2.1 equiv) followed by DMAP (0.224 g, 2.10 mmol, 2.0 equiv) and
corresponding chloroformate (0.14 mL, 2.10 mmol, 2.0 equiv) was added at 0 ºC, reaction
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mixture was stirred on 25 ºC. TLC analysis showed the complete consumption starting
material. Then the organic layer was diluted by CH Cl and washed with water (10 mL). The
2
2
collected organic layer was dried over anhydrous Na SO and concentrated under reduced
2
4
pressure and dried by using high vacuum pump.
0
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The crude material was dissolved in CH COOH (5 mL) open flask. To that Zn (1.37 g, 21.0
3
°
mmol, 20.0 equiv) and stirred over 25 C for 4 h. Upon completation of the reaction (judged
by TLC analysis), filtered through celite, and concentrated under reduced pressure. The crude
reaction mixture diluted with CH Cl and washed with saturated aqueous NaHCO solution
2
2
3
(
10 mL), and brine. The extracted organic layers were dried over anhydrous Na SO and
2 4
concentrated under reduced pressure and dried by using high vacuum pump. The crude
product was purified by flash chromatography using (20%-40% EtOAc in hexanes) mixture
as eluents to afford the desired product 1a-o.
Methyl 3-benzyl-2-oxoindoline-1-carboxylate (1a): 82% yield over 3 steps (1.06 mmol
1
scale) of (1a) as colorless solid. R = 0.29 (20% EtOAc in hexane); H NMR (400 MHz,
f
CDCl ) δ 7.81 (d, J = 8.4 Hz, 1H), 7.26-7.17 (m, 4H), 7.12-7.10 (m, 2H), 7.03 (td, J = 1.0,
3
7
.5 Hz, 1H), 6.79 (d, J = 7.5 Hz, 1H), 3.96 (s, 3H), 3.83 (q, J = 4.5 Hz, 1H), 3.46 (dd, J = 4.9,
13
13.7 Hz, 1H), 2.99 (q, J = 8.5 Hz, 1H); C NMR (100 MHz, CDCl ) δ 175.1, 151.4, 139.7,
3
1
2
37.0, 129.4, 128.4, 128.3, 127.2, 126.9, 124.4, 124.3, 115.0, 53.8, 47.5, 37.5; IR (film) υmax
-1
987, 1738, 1613, 1598, 1405, 1318, 1301, 1200, 1107, 971, 775, 702cm . HRMS (ESI-
+
TOF) m/z: [M + Na] Calcd for C H NO + Na 304.0944; Found 304.0952. MP = 106-110
1
7
15
3
ºC.
Ethyl 3-benzyl-2-oxoindoline-1-carboxylate (1b): 60% yield over 3 steps (1.06 mmol scale)
1
of (1b) as yellow gel. R = 0.25 (30% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ 7.83
f
3
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(
d, J = 8.2 Hz, 1H), 7.30-7.22 (m, 4H), 7.18-7.15 (m, 2H), 7.06 (t, J = 7.6 Hz, 1H), 6.81 (d, J
= 7.5 Hz, 1H), 4.50-4.45 (m, 2H), 3.88 (dd, J = 8.9, 4.6 Hz, 1H), 3.51 (dd, J = 13.8, 4.7 Hz,
13
1
1
3
H), 3.02 (dd, J = 13.7, 8.8 Hz, 1H), 1.46 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl ) δ
3
75.2, 150.8, 139.8, 137.1, 129.4, 128.4, 128.3, 127.2, 126.9, 124.4, 124.2, 114.9, 63.3, 47.5,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7.6, 14.3; IR (film) υmax 3015, 1842, 1798, 1641, 1495, 1381, 1332, 1201, 1105, 978, 703
-1
+
cm . HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H NO + Na 318.1101; Found
18
17
3
3
18.1100.
Benzyl 3-benzyl-2-oxoindoline-1-carboxylate (1c): 79% yield over 3 steps (1.06 mmol
1
scale) of (1c) as light yellow gel. R = 0.29 (30% EtOAc in hexane); H NMR (400 MHz,
f
CDCl ) δ 7.84 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.45-7.38 (m, 4H), 7.29-7.25 (m,
3
3
H), 7.17-7.15 (m, 2H), 7.07 (s, 1H), 6.83 (d, J = 7.5 Hz, 1H), 5.46 (s, 2H), 3.90 (dd, J = 8.8,
1
3
4.6 Hz, 1H), 3.55-3.47 (m, 1H), 3.04 (dd, J = 13.7, 8.8 Hz, 1H); C NMR (100 MHz,
CDCl ) δ 175.1, 150.7, 139.6, 137.1, 135.1, 129.4, 128.7, 128.5, 128.3, 128.1, 127.8, 127.2,
3
1
1
26.9, 124.4, 124.3, 115.0, 68.5, 47.5, 37.6; IR (film) υmax 1938, 1716, 1695, 1608, 1498,
-1
+
431, 1350, 1209, 1001, 962, 780, 703 cm . HRMS (ESI-TOF) m/z: [M + Na] Calcd for
C H NO + Na 380.1257; Found 380.1268.
23
19
3
1-Acetyl-3-benzylindolin-2-one (1d): 73% yield over 3 steps (1.06 mmol scale) of (1d) as
1
light colorless gel. R = 0.24 (30% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ 8.16
f
3
(d, J = 8.3 Hz, 1H), 7.31-7.22 (m, 4H), 7.14-7.10 (m, 3H), 6.91 (d, J = 7.5 Hz, 1H), 3.92 (dd,
J = 8.5, 4.7 Hz, 1H), 3.48 (dd, J = 13.7, 4.7 Hz, 1H), 3.09 (dd, J = 13.7, 8.4 Hz, 1H), 2.65 (s,
1
3
3
1
1
H).; C NMR (100 MHz, CDCl ) δ 177.7, 170.8, 140.5, 136.8, 129.4, 128.4, 128.3, 127.4,
3
27.0, 124.7, 124.1, 116.4, 47.6, 37.6, 26.7.; IR (film) υmax 3332, 2981, 1742, 1688, 1562,
-1
+
550, 1371, 908, 879, 850, 735 cm . HRMS (ESI-TOF) m/z: [M + Na] Calcd for
C H NO + Na 288.0995; Found 288.1009.
17
15
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Methyl 3-(4-fluorobenzyl)-2-oxoindoline-1-carboxylate (1e): 62% yield over 3 steps (0.15
1
mmol scale) of (1e) as yellow gel. R = 0.27 (30% EtOAc in hexane); H NMR (500 MHz,
f
CDCl ) δ 7.84 – 7.80 (m, 1H), 7.30 – 7.26 (m, 1H), 7.11 – 7.03 (m, 3H), 6.93 – 6.87 (m, 3H),
3
3
1
1
.99 (s, 3H), 3.85 (dd, J = 8.1, 4.7 Hz, 1H), 3.41 (dd, J = 13.9, 4.8 Hz, 1H), 3.07 (dd, J =
13
3.9, 8.1 Hz, 1H); C NMR (125 MHz CDCl ) δ 175.13, 161.99 (d, J = 245.2 Hz), 151.46,
3
39.85, 132.58, 132.55, 131.07 (d, J = 7.9 Hz), 128.62, 126.99, 124.45 (d, J = 23.7 Hz),
115.48, 115.31, 115.26, 54.04, 47.71, 36.68. IR (film) υmax 2987, 1741, 1600, 1572, 1531,
-1
+
1
441, 1291, 1260, 1059, 955, 907, 855, 752 cm . HRMS (ESI-TOF) m/z: [M + H] Calcd
for C H NFO + H 300.1030; Found 300.1041.
1
7
14
3
Methyl 3-(2-bromobenzyl)-2-oxoindoline-1-carboxylate (1f): 89% yield over 3 steps (1.06
1
mmol scale) of (1f) as yellow gel. R = 0.27 (30% EtOAc in hexane); H NMR (400 MHz,
f
CDCl ) δ 7.70 (brs, s, 1H), 7.29 – 7.23 (m, 2H), 7.12-7.01 (m, 3H), 6.93 – 6.84 (m, 2H), 3.96
3
1
3
(m, 1H), 3.62 (s, 3H), 3.47 (dd, J = 13.8, 9.0 Hz, 1H), 3.01 (dd, J = 13.7, 6.4 Hz, 1H); C
NMR (100 MHz, CDCl ) δ 173.9, 167.8, 160.7 (d, J = 247.7 Hz), 154.8, 136.0, 134.4, 134.3,
3
1
32.5, 130.4 (d, J = 8.3 Hz), 129.5, 128.5 (d, J = 14.5 Hz), 115.3 (d, J = 21.4 Hz), 52.51,
2.5, 36.5; IR (film) υmax 3069, 1749, 1639, 1590, 1372, 1306, 1109, 1100, 1069, 1033, 901,
5
-1
+
889, 835, 790 cm . HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H NBrO + Na
1
7
14
3
3
82.0049; Found 382.0046.
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Methyl 2-oxo-3-(4-(trifluoromethyl)benzyl)indoline-1-carboxylate (1g): 78% yield over 3
1
steps (1.06 mmol scale) of (1g) as yellow solid. R = 0.24 (20% EtOAc in hexane); H NMR
f
(
400 MHz, CDCl ) δ 7.82 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.30 – 7.21 (m, 3H),
3
7
1
.09 (td, J = 7.6, 1.1 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 3.98 (s, 3H), 3.90 (dd, J = 8.0, 4.9 Hz,
1
3
1
1
1
1
1
1
1
1
1
1
2
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2
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2
2
2
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3
3
3
3
4
4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
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0
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7
8
9
0
H), 3.47 (dd, J = 13.8, 4.8 Hz, 1H), 3.15 (dd, J = 13.8, 8.1 Hz, 1H); C NMR (100 MHz,
CDCl ) δ 174.7, 151.3, 141.01, 141.0, 140.9, 139.7, 129.8, 129.7, 129.2 (q, J = 3.8 Hz),
3
1
28.7, 126.6, 125.4 (q, J = 3.8 Hz), 124.5, 115.2, 53.9, 47.2, 36.9. ; IR (film) υmax 1851,
-1
1
709, 1631, 1581, 1543, 1440, 1375, 1308, 1121, 1043, 951, 906, 751, 790 cm . HRMS
+
(
ESI-TOF) m/z: [M + H] Calcd for C H NF O + H 350.0999; Found 350.1019. MP = 87-
1
8
14
3
3
9
2 ºC.
Methyl 2-oxo-3-(4-(trifluoromethyl)benzyl)indoline-1-carboxylate (1h): 70% yield over 3
1
steps (1.06 mmol scale) of (1h) as colorless solid. R = 0.26 (20% EtOAc in hexane); H
f
NMR (400 MHz, CDCl ) δ 7.81 (d, J = 8.2 Hz, 1H), 7.25 (t, J = 1.4, 7.1 Hz, 1H), 7.06 – 6.99
3
(m, 3H), 6.83 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H), 3.97 (s, 3H), 3.80 (dd, J = 8.5, 4.7
1
3
Hz, 1H), 3.74 (s, 3H), 3.39 (dd, J = 13.9, 4.6 Hz, 1H), 2.97 (dd, J = 13.8, 8.5 Hz, 1H); C
NMR (100 MHz, CDCl ) δ 175.2, 158.5, 151.4, 139.7, 130.4, 128.9, 128.3, 127.3, 124.4,
3
1
24.3, 115.0, 113.8, 55.2, 53.9, 47.8, 36.6; IR (film) υmax 1880, 1706, 1658, 1601, 1573,
-1
+
1
509, 1441, 1430, 1398, 1073, 901, 855, 852, 730 cm . HRMS (ESI-TOF) m/z: [M + Na]
Calcd for C H NO + Na 236.1281; Found 334.1048. MP = 90-93 ºC.
1
8
17
4
Methyl 3-(3,4-dimethoxybenzyl)-2-oxoindoline-1-carboxylate (1i): 88% yield over 3 steps
1
(
1.06 mmol scale) of (1i) as yellow gel. R = 0.26 (30% EtOAc in hexane); H NMR (400
f
MHz, CDCl ) δ 7.79 (d, J = 8.2 Hz, 1H), 7.25 (td, J = 1.8, 8.5 Hz 1H), 7.06 (td, J = 7.5, 1.0
3
Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 6.62 (dd, J = 1.8, 10.2 Hz, 1H),
1
3
6
.54 (d, J = 13.8, 8.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ 175.2, 151.3, 148.6, 147.9,
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39.8, 129.1, 128.3, 127.3, 124.4, 124.3, 121.7, 115.1, 112.3, 110.9, 55.8, 55.7, 53.8, 47.7,
37.1.; IR (film) υmax 3041, 1801, 1716, 1616, 1598, 1357, 1200, 1098, 1036, 911, 901, 855,
-1
+
8
00, 735 cm . HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H NO + Na 364.1155;
19 19 5
Found 364.1145.
0
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3
4
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0
1
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8
9
0
1
2
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4
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8
9
0
1
2
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4
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8
9
0
1
2
3
4
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8
9
0
Methyl methyl 3-(3-methoxybenzyl)-2-oxoindoline-1-carboxylate (1j): 72% yield over 3
1
steps (1.06 mmol scale) of (1j) as colorless gel. R = 0.23 (20% EtOAc in hexane); H NMR
f
(400 MHz, CDCl ) 7.69 (brs, s, 1H), 7.28-7.25 (m, 2H), 7.17 – 7.08 (m, 2H), 6.74 – 6.70 (m,
3
2
H), 6.62 (m, 1H), 3.99 (m, 1H),, 3.71 (s, 3H), 3.64 (s, 3H), 3.49 (dd, J = 13.6, 8.7 Hz, 1H),
1
3
3.01 (dd, J = 13.6, 6.5 Hz, 1H); C NMR (100 MHz, CDCl ) δ 174.1, 159.6, 154.6, 140.2,
3
1
36.1, 129.5, 128.5, 128.3, 125.1, 125.0, 121.2, 114.4, 112.3, 77.2, 55.1, 52.5, 52.4, 37.5; IR
(film) υmax 2981, 1885, 1715, 1632, 1592, 1507, 1352, 1009, 1001, 982, 903, 851, 800, 771
-1
+
cm . HRMS (ESI-TOF) m/z: [M + H] Calcd for C H NO + H 312.1230; Found 312.1218.
18
17
4
Methyl 3-(2,3-dimethoxybenzyl)-2-oxoindoline-1-carboxylate (1k): 53% yield over 3 steps
1
(1.06 mmol scale) of (1k) as colorless solid. R = 0.24 (20% EtOAc in hexane); H NMR
f
(400 MHz, CDCl ) 7.86 (d, J = 8.2 Hz, 1H), 7.23 (td, J = 1.4, 8.1 Hz, 1H), 6.99 – 6.94 (m,
3
2H), 6.85 (dd, J = 8.2, 1.5 Hz, 1H), 6.72 (dd, J = 1.4, 6.9 Hz, 1H), 6.60 (d, J = 7.5 Hz, 1H),
4
1
1
.01-3.97 (m, 4H), 3.79 (s, 3H), 3.49 (dd, J = 13.6, 5.3 Hz, 1H), 2.87 (dd, J = 13.6, 9.7 Hz,
13
H); C NMR (100 MHz, CDCl ) δ 175.5, 152.8, 151.6, 147.7, 139.5, 131.5, 128.1, 127.7,
3
24.6, 124.2, 123.8, 122.9, 114.8, 111.4, 60.5, 55.7, 53.8, 45.9, 32.5; IR (film) υmax 1831,
-1
1659, 1539, 1503, 1404, 1189, 1103, 1100, 959, 938, 889, 851, 735, 701 cm . HRMS (ESI-
+
TOF) m/z: [M + Na] Calcd for C H NO + Na 364.1155; Found 364.1178. MP = 95-100
1
9
19
5
ºC.
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0
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Methyl 2-oxo-3-(2,3,4-trimethoxybenzyl)indoline-1-carboxylate (1l): 69% yield over 3
1
steps (1.06 mmol scale) of (1l) as colorless solid. R = 0.42 (40% EtOAc in hexane); H
f
NMR (400 MHz, CDCl ) 7.84 (dd, J = 8.1, 0.9 Hz, 1H), 7.21 (ddt, J = 8.9, 8.3, 1.2 Hz, 1H),
3
6
3
.97 (td, J = 7.6, 1.1 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 6.65 (td, J = 1.3, 2.5, 7.6 Hz, 1H),
.90 (dd, J = 9.2, 5.6 Hz, 1H), 3.83 (s, 6H), 3.81 (s, 3H), 3.39 (dd, J = 13.7, 5.6 Hz, 1H), 2.84
1
3
(
dd, J = 13.7, 9.2 Hz, 1H); C NMR (100 MHz, CDCl ) δ 175.4, 152.9, 152.2, 151.5, 142.2,
3
139.5, 128.0, 127.7, 125.0, 124.5, 124.1, 123.3, 114.8, 106.9, 60.7, 55.9, 53.7, 46.1, 32.3; IR
film) υmax 3059, 1755, 1690, 1599, 1401, 1365, 1340, 1109, 1081, 991, 935, 782, 735, 701
(
-1
+
cm . HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H NO + Na 394.1261; Found
20
21
6
394.1263. MP = 118-124 ºC.
Methyl 2-oxo-3-(2,3,4-trimethoxybenzyl)indoline-1-carboxylate (1m): 69% yield over 3
1
steps (1.06 mmol scale) of (1m) as colorless gel. R = 0.28 (20% EtOAc in hexane); H NMR
f
(
400 MHz, CDCl ) 8.00 (dd, J = 8.2, 2.4 Hz, 1H), 7.45-7.37 (m, 1H), 7.32 (dd, J = 7.6, 1.8
3
Hz, 1H), 7.23 (td, J = 7.6, 2.4 Hz, 1H), 6.00-5.85 (m, 2H), 4.02 (brs, s, 3H), 3.71 (s, 3H),
1
.96-1.92 (m, 2H), 1.63 (s, 3H), 1.60-1.51 (m, 2H), 1.40 (m, 2H), 0.91 (s, 3H), 0.89 (s, 3H);
1
3
C NMR (100 MHz, CDCl ) δ 170.6, 168.7, 151.4, 139.6, 136.0, 132.6, 129.5, 127.5, 125.0,
3
1
24.6, 115.6, 62.1, 54.1, 53.3, 39.2, 33.9, 32.6, 28.6, 28.5, 21.3, 19.1; IR (film) υmax 2905,
-1
1
715, 1621, 1452, 1406, 1392, 1355, 1209, 1155, 1109, 1088, 980, 901, 845, 701 cm .

HRMS (ESI-TOF) m/z: [M  H] Calcd for C H NO - H 340.1907; Found 340.1900.
21
27
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Methyl 3-isobutyl-2-oxoindoline-1-carboxylate (1n): 70% yield over 3 steps (1.06 mmol
1
scale) of (1n) as green gel. R = 0.28 (20% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ
f
3
7
.89 (d, J = 8.2 Hz, 1H), 7.34-7.24 (m, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.14 (td, J = 7.5, 1.1
Hz, 1H), 3.99 (s, 3H), 3.57 (t, J = 7.0 Hz, 1H), 2.05-1.95 (m, 1H), 1.89-1.82 (m, 1H), 1.74-
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
.67 (m, 1H), 0.94 (dd, J = 9.1, 6.6 Hz, 6H); C NMR (100 MHz, CDCl ) δ 176.2, 151.6,
3
139.5, 128.5, 128.1, 124.5, 123.9, 115.1, 53.8, 44.2, 40.8, 25.1, 22.6, 22.3; IR (film) υmax
-1
2
068, 1685, 1613, 1414, 1272, 1200, 906, 903, 853, 817, 710, 702 cm . HRMS (ESI-TOF)
+
m/z: [M + Na] Calcd for C H NO + Na 270.1101; Found 270.1098.
14
17
3
Methyl 2-oxo-3-(pyridin-2-ylmethyl)indoline-1-carboxylate (1o): 57% yield over 3 steps
1
(
1.06 mmol scale) of (10) as durty color solid. R = 0.30 (40% EtOAc in hexane); H NMR
f
(400 MHz, CDCl ) 8.50 (dt, J = 4.9, 1.5 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.57 (td, J = 7.7,
3
1
.9 Hz, 1H), 7.1 (dd, J = 7.7, 5.0 Hz, 2H), 7.00 (td, J = 7.6, 1.1 Hz, 1H), 6.80 (d, J = 7.4 Hz,
H), 4.26 (dd, J = 7.9, 5.4 Hz, 1H), 4.01 (s, 3H), 3.56 (dd, J = 14.7, 5.4 Hz, 1H), 3.27 (dd, J =
1
1
3
14.7, 8.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 175.7, 157.2, 151.7, 149.3, 139.7, 136.4,
3
1
28.2, 127.7, 124.4, 123.9, 121.9, 114.9, 99.9, 53.9, 45.3, 39.1; IR (film) υmax 2939, 1652,
-1
1
518, 1503, 1489, 1436, 1415, 1238, 1216, 1209, 1151, 1109, 982, 933, 735 cm . HRMS
+
(
ESI-TOF) m/z: [M + H] Calcd for C H N O + H 283.1077; Found 283.1054. MP = 84-89
1
6
14
2
3
ºC.
Methyl 2-oxo-3-(pyridin-2-ylmethyl)indoline-1-carboxylate (1p): 67% yield over 3 steps
(
1.06 mmol scale) of (1p) as pale yellow gel (dr = 1.9:1). R = 0.29 (30% EtOAc in hexane);
f
1
H NMR (400 MHz, CDCl ) 7.99 (dd, J = 8.0, 6.6 Hz, 1H for minor isomer), 7.92 (d, J = 8.1
3
Hz, 1H for major isomer), 7.69 (d, J = 7.8 Hz, 1H for minor isomer), 7.33-7.28 (m, 2H for
major isomer & 2H for minor isomer), 7.19 (dd, J = 8.8, 6.3 Hz, 1H for major isomer), 4.04-
4
.03 (m, 3H for major isomer & 4H for minor isomer), 3.49 (d, J = 3.4 Hz, 1H for major
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isomer), 2.20-2.10 (m, 1H for major isomer & 1H for minor isomer), 1.90-1.83 (m, 1H for
major isomer), 1.80-1.77 (m, 1H for major isomer & 1H for minor isomer), 1.75-1.70 (m, 2H
for major isomer & 2H for minor isomer), 1.68-1.63 (m, 2H for major isomer & 3H for minor
isomer), 1.60-1.57 (m, 1H for major isomer & 2H for minor isomer), 1.41-1.31 (m, 1H for
1
3
1
1
1
1
1
1
1
1
1
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major isomer), 1.29-1.21 (m, 2H for major isomer & 2H for minor isomer); C NMR (100
MHz, CDCl ) δ 175.6 (2C), 151.5 (2C), 140.1 (2C), 128.1 (2C), 127.1 (2C), 124.4 (2C),
3
1
24.2 (2C), 114.9 (2C), 53.8 (2C), 51.9 (2C), 42.3 (2C), 29.7 (2C), 28.7 (2C), 26.6 (2C), 26.3
(2C), 25.9 (2C); IR (film) υmax 2872, 1619, 1495, 1482, 1376, 1313, 1260, 1173, 905, 896,
-1
+
7
31, 702 cm . HRMS (ESI-TOF) m/z: [M + Na] Calcd for C H NO + Na 296.1257;
16 19 3
Found 296.1236.
3-Hydroxy-3-(2-methoxyphenyl)indolin-2-one: The compound (2c) was obtained as yellow
1
solid (6.8 mmol scale; 1.5 g of product; 87% yield). R = 0.38 (50% EtOAc in hexane); H
f
NMR (500 MHz, DMSO-d ) δ = 10.28 (s, 1H), 7.87 (dd, J=7.7, 1.8, 1H), 7.28 (td, J=7.7, 1.8,
6
1H), 7.17 (td, J=7.5, 1.8, 1H), 7.06 (td, J=7.6, 1.1, 1H), 6.88 – 6.87 (m, 1H), 6.87 – 6.78 (m,
1
3
3
1
3
H), 6.44 (s, 1H), 3.40 (s, 3H); C NMR (125 MHz, DMSO-d ) δ = 178.9, 156.0, 143.4,
6
33.5, 130.9, 129.2, 129.1, 127.3, 124.0, 121.6, 120.7, 112.2, 109.5, 75.4, 56.0; IR (film)
656, 3458, 2326, 2250, 1715, 1580, 1421, 1380, 1214, 1104, 981, 890, 700 cm-1; HRMS
+
+
(ESI) m/z [M + Na] Calcd for [C H NO + Na] 278.0788; Found 278.0761.
1
5
13
3
Procedure for the synthesis of 2-oxindole (2d): In an oven-dried round-bottom flask was
charged with compound 3-hydroxy 2-oxindole (±)-2c (1.0 equiv) in dichloromethane (15 ml)
under argon atmosphere at RT. To this solution triethyl silane (5.0 equiv.) and TFA (6.0
equiv) was added at 0 ºC and stirring was continued for 13 h. After completion of the reaction
(
judged by TLC analysis under UV and I stain) 5% (w/v) aqueous solution of sodium citrate
2
was added drop wise to neutralize the mixture. The organic layer was separated and aqueous
layer was washed with CH Cl (2 X 10 mL). The combined organic layer was dried over
2
2
anhydrous Na SO and concentrated under reduced pressure. The crude product was purified
2
4
by flash chromatography with n-Hexane-EtOAc (6:4) to afford products (2d) as yellow solid.
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-(2-Methoxyphenyl)indolin-2-one: The compound (2d) was obtained as orange yellow
1
solid (3.9 mmol scale; 796 mg of product; 85% yield). R = 0.40 (50% EtOAc in hexane); H
f
NMR (400 MHz, CDCl ) δ = 9.71 (s, 1H), 7.31 (td, J = 7.9, 1.8, 1H), 7.20 – 7.28 (m, 2H),
3
1
3
7
.04 (d, J=7.4, 1H), 6.98 – 6.91 (m, 4H), 4.97 (s, 1H), 3.77 (s, 3H); C NMR (100 MHz,
CDCl ) δ = 180.1, 157.5, 141.8, 130.5, 130.2, 129.0, 127.8, 125.7, 124.2, 122.3, 121.0, 111.5,
3
1
09.8, 55.7, 48.6; IR (film) 3766, 3358, 2926, 2550, 1719, 1480, 1411, 1310, 1114, 1004,
+
+
901, 790, 600 cm-1; HRMS (ESI) m/z [M + Na] Calcd for [C H NO + Na] 262.0834;
1
5
13
2
Found 262.0846.
Procedure for acylation of 2-oxindole (11d): 2-Oxindole 2d (1.0 equiv) was dissolved in
anhydrous THF (2 mL) and then NaHMDS (1.1 equiv.) in THF (1 mL) was added at room
temperature, the resulting solution was stirred for 10 min and a solution of imidazole
carbamate (1.1 equiv.) in THF (0.5 mL) was added dropwise. The mixture was then allowed
to stir until complete consumption of oxindole was observed by TLC. The crude product was
concentrated in vacuo and purified by flash chromatography using a mixture of EtOAc and n-
hexanes as eluent.
Methyl 3-(2-methoxyphenyl)-2-oxoindoline-1-carboxylate (11d): The compound (15a)
was obtained as orange yellow solid (0.42 mmol scale; 60 mg of product; 49% yield). R =
f
1
0.40 (30% EtOAc in hexane); H NMR (500 MHz, CDCl ) δ 7.97 (d, J=8.2, 1H), 7.37 – 7.29
3
(m, 2H), 7.23 – 7.17 (m, 1H), 7.12 (td, J=7.5, 1.0, 1H), 7.05 (dt, J=7.5, 1.4, 1H), 6.98 (td,
13
J=7.5, 1.1, 1H), 6.90 (dd, J=8.3, 1.0, 1H), 4.92 (s, 1H), 4.06 (s, 3H), 3.68 (s, 3H); C NMR
(125 MHz, CDCl ) δ = 174.5, 157.1, 151.8, 139.7, 130.7, 129.4, 128.4, 128.1, 125.8, 124.6,
3
123.9, 121.0, 114.7, 111.7, 55.8, 53.8, 53.8; IR (film) 3886, 3438, 2933, 2600, 1720, 1520,
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+
1
421, 1380, 1234, 1104, 981, 700, 620 cm-1; HRMS (ESI) m/z [M + Na] Calcd for
+
[C H NO + Na] 320.0893; Found 320.0886.
1
7
15
4
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General Procedure for Deacylative Allylation of N-Moc-2-oxindole: A flame-dried 10 mL
Schlenk flask equipped with a stir bar was charged with NaH (1.2 equiv of 0.26, 8 mg) and
Pd(PPh ) (1.0 mol %, 0.001 mmol, 1.0 mg). To above flask 2 mL of dry toluene was added,
3
4
and allyl alcohol (0.30 mmol, 17 µL) followed by N-Moc-2-oxindole 1a (0.25 mmol) was
added in that order. The vessel was capped and wrapped in parafilm, and the system was
completely sealed over argon and allowed to react for 2 - 12 h. After the allotted reaction
time as determined by TLC (2 - 12 h), the reaction mixture was diluted with 5% EtOAc in
hexanes and subjected to silica gel chromatography (5% - 30% EtOAc in Hexanes) to yield
the pure product.
(±)-3-Allyl-3-benzylindolin-2-one (6a): Compound 6a was isolated in 92% yield (60.5 mg;
1
0
7
7
.25 mmol) as yellow gel; R = 0.24 (20% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ
f
3
.76 (s, 1H), 7.28 (d, J = 1.3 Hz, 2H), 7.19 (d, J = 7.4 Hz, 1H), 7.15 (t, J = 7.7 Hz, 1H), 7.09-
.04 (m, 2H), 6.91 (dt, J = 7.7, 1.6 Hz, 2H), 6.69 (d, J = 7.7 Hz, 1H), 5.54-5.43 (m, 1H), 5.06
(
dt, J = 17.0, 1.7 Hz, 1H), 4.94 (d, J = 10.1 Hz, 1H), 3.19 (d, J = 13.1 Hz, 1H), 3.10 (d, J =
1
3
1
1
3.1 Hz, 1H), 2.78-2.64 (m, 2H); C NMR (100 MHz, CDCl ) δ 181.4, 140.9, 135.8, 132.2,
3
31.2, 130.0, 127.9, 127.7, 126.5, 124.1, 121.9, 118.9, 109.7, 54.9, 43.1, 41.6; IR (film) υmax
-1
2180, 1695, 1615, 1435, 1401, 1339, 1310, 1009, 982, 931, 780, 735, 706 cm . HRMS (ESI-
+
TOF) m/z: [M + Na] Calcd for C H NO + Na 286.1202; Found 286.1198.
18 17
(
±)-(E)-3-Benzyl-3-(3-(p-tolyl)allyl)indolin-2-one (3a): Compound 3a was isolated as
1
yellow gel; R = 0.24 (40% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ 8.84 (brs, s,
f
3
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