Br?nsted Acid Promoted Regioselective C-3 Arylation and Heteroarylation of Spiro-epoxyoxindoles for the Construction of All Carbon Quaternary Centres: A Detailed Study

Article abstract of DOI:10.1002/ejoc.201801524

An efficient strategy for the synthesis of all carbon quaternary centres has been developed via Br?nsted acid-promoted highly regioselective intermolecular Friedel–Crafts reactions of heteroarenes or arenes with spiro-epoxyoxindoles. In addition, we have successfully performed the ring opening reaction in relatively cheap condition using water as a solvent. Beneficially, we have utilized the methodology as the key step for the synthesis of advanced precursors of various natural and unnatural indole alkaloids.

Full text of DOI:10.1002/ejoc.201801524

A Journal of
Accepted Article
Title: Brønsted Acid Promoted Regioselective C-3 Arylation and
Heteroarylation of Spiro-epoxyoxindoles for the Construction of
All Carbon Quaternary Centres: A Detailed Study
Authors: Saumen Hajra, Subrata Maity, Sayan Roy, Ramkrishna Maity,
and Srikrishna Samanta
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801524
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801524
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European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
Brønsted Acid Promoted Regioselective C-3 Arylation and
Heteroarylation of Spiro-epoxyoxindoles for the Construction of
All Carbon Quaternary Centres: A Detailed Study
Saumen Hajra,*[a] Subrata Maity,#[a,b] Sayan Roy, #[a] Ramkrishna Maity and Srikrishna Samanta[a]
[a]
Abstract: An efficient strategy for the synthesis of all carbon
quaternary centres has been developed via Brønsted acid promoted
highly regioselective intermolecular Friedel-Crafts reactions of
heteroarenes or arenes with spiro-epoxyoxindoles. In addition, we
have successfully performed the ring opening reaction in relatively
cheaper condition using water as a solvent. Beneficially, we have
utilized the methodology as the key step for the synthesis of
advanced precursors of various natural and unnatural indole
alkaloids.
Rh-catalysed multicomponent reaction of 3-diazooxindoles,
indoles and aldehydes,[ (vii) Cu-catalysed dearomatization of
9]
[10]
indoleacetamides with 3-indolylphenyliodonium salts
are
worthy of attention. However the preparation of 3-aryl oxindole
moiety is sparse in literature.[11-13] Only few reports are there
such as (i) Hetero-Claisen reaction of nitrones with
alkylarylketenes,[
11]
(ii) Cu catalysed dearomatisation of
tryptamine derivative with aryl-iodonium salt, [12] (iii) Lewis acid
catalysed F-C alkylation of 3-hydroxy-2-oxindole.[13] Thus
construction of both these functionalities from
a common
precursor through a concise and divergent manner is very much
necessary. A straightforward strategy for the synthesis of these
Introduction
subunits could be
a regioselective F-C reaction of easily
accessible spiro-epoxyoxindole with heteroarenes and arenes.
Our continuous research interest in exploring the reactivity of
three membered reactive intermediates[14] led us to envisage the
Generation of all-carbon quaternary stereocentre always
[1]
remains a demanding venture in organic synthesis. In this
context, development of quaternary centre particularly at the C3-
position of oxindole captured considerable research enthusiasm
of synthetic community because of the incredible prevalence of
such molecules in numerous natural products. Among these, 3a-
Lewis acid catalysed F-C reaction of spiro-epoxyoxindoles with
arenes as well as heteroarenes. After the affirmative
presumption, recently, we have successfully reported the Lewis-
acid catalysed efficient F-C reaction of spiro-epoxyoxindoles
with indoles and arenes to obtain both the functionalities
(
3-indolyl)-hexahydropyrrolo-[2,3-b] indole[2] is
a
unique
structural framework present in various bisindole alkaloids viz.
gliocladine A, B, gliocladin C, bionectin A, B, leptosin D with
tremendous biological and pharmacological activities. Similarly,
Scheme 1). [15]
(
[3]
SMe
O
HN
3
-aryl oxindole moiety is also existed in diazonamide A,
O
S
HN
NMe
HO
O
O
HN
R
azonazine, naseseazine, XEN 907, XEN 402, displaying a wide
range of biological activities (Figure 1). As a consequence,
development of a unique synthetic strategy to avail 3, 3-
disubstituded oxindole is highly desirable.
NMe
R
NMe
SMe
N S
N
N
O
N
H
H
O
N
H
N
H
H
H
O
gliocladine C, R = Me
gliocladine A, R = OH bionectin A, R = H
gliocladin C
A numerous synthetic strategy towards the construction of 3, 3′-
bisindole have been reported so far in literature. The examples
of (i) Mukaiyama-aldol reaction of 3-(3-indolyl)-2-siloxyindole
gliocladine B, R - H
bionectin b, R = CH(OH)Me
leptosin D, R = i-Pr
T988A, R = CH
Cl
Me
O
Me
Me
Me
N
N
Cl
2
OH
O
[
4]
[5]
HO
HN
O
O
with aldehyde, (ii) acyl migration of indolyl carbonates, (iii) Pd-
catalysed allylic alkylation of 3-aryl-3′-oxindoles with allenes, [
NH
HN
6]
MeN
NH
O
(
iv) organocatalytic conjugate addition of indoles to isatin derived
O
nitroalkenes and α,β-unsturated aldehydes,[7] (v) α-alkylation of
carbonyl compounds with 3-hydroxy-3-indol-3’-yloxindoles, [8] (vi)
NH
O
diazonamide A
O
H
N
O
azonazine Ac
O
NH
H
N
H
O
O
NH
O
[a]
Prof. Dr. S. Hajra, Mr. S. Maity, Mr. S. Roy, Mr. R. Maity, Mr. S.
Samnata
R1
O
N
H
O
N
Centre of Biomedical Research, Sanjay Gandhi Post-Graduate
Institute of Medical Sciences Campus, Raebareli Road, Lucknow
R2
N
N
5 11
C H
2
26014, India.
H
O
E-mail: saumen.hajra@cbmr.res.in
naseseazine A (R
naseseazine B (R
= H, R
2
= Me)
XEN 907
spiro[benzofuran]-3,3'-oxindole
1
Homepage: https://saumencbmr.weebly.com/
Mr. S. Maity
Department of Chemistry, Indian Institute of Technology Kharagpur,
Kharagpur 721302, India.
S.M. and S.R. contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
1
, R = (CH ) )
2
2 3
[
b]
#
Figure 1. Representative natural and unnatural indole alkaloids sharing all-
carbon quaternary centre.
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European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
was also proceeded well with the assistance of catalytic amount
of Brosted acid. To confirm it, we performed the model reaction
between N-methyl spiro-epoxyoxindole 1a and indole employing
various Brønsted acids in different temperature. Our previous
result with Lewis acid (Scheme 1) convinced us to perform the
reaction in DCE solvent. But unfortunately the reaction was not
completed at 0 °C using 10 mol% of orthophosphoric acid.
Raising the temperature to 25 °C accomplished the F-C reaction
with 81% isolated yield of the regioselectively desired 3-(3-
indolyl)-oxindole-3-methanol product (Table 1, entries 1 and 2).
Next we changed the Brønsted acids to increase the yield of the
desired product. But we were unfortunate to acquire significant
amount of desired product with catalytic amount of benzoic acid,
p-nitro benzoic acid, triflic acid (entries 3-5). Eventually, we were
delighted to achieve the desired F-C product in presence of 10
mol% of trifluoroacetic acid (TFA) with excellent isolated yield
(92%) within 6 h at 25 °C (entry 6). Further increase of the
Brønsted acid did not affect the yield or time, on the contrary
diminishing the amount of Brønsted acid decelerated the
reaction with incomplete conversion. Thus 10 mol% of TFA in
DCE at 25 °C was the most accepted condition.
Scheme 1. Designed F-C reaction of spiro-epoxyoxindole with carbon
nucleophile.
Thus, spiro-epoxyoxindole has been emerged as a common
precursor for the generation of all carbon quaternary centre prior
to the synthesis of various indole alkaloids or their core
structures. After this initial success, we are again exploring
alternative catalysts/solvents combination for the F-C reaction of Method A: Optimisation with Brønsted acids
spiro-epoxyoxindole. Eventually, we have observed that catalytic in organic solvent
amount of Brønsted acid in organic solvent can also activate the
[16]
spiro-epoxide
and lead to regioselective ring opening at the
Table 1. Optimisation of reaction conditions (Method A)a
tertiary centre by the carbon nucleophiles likely indoles and
arenes. Moreover, we have recently reported catalyst free on-
water ring opening reaction of spiro-aziridineoxindole and indole.
[17]
This result again encourages us to find an environment
friendly greener approach for this ring-opening reaction. Herein
we incorporated a detailed study of the Brønsted acid assisted
regioselective F-C reaction of spiro-epoxides and comparison
with the Lewis acid catalysed reactions along with its scopes,
limitations and prosperous applications.
entry
Brønsted Acid
temp (°C)
time (h)
Yieldb (%)
1
2
3
4
.
H
H
3
3
PO
PO
4
4
0
24
8
25
81
Results and Discussion
.
.
.
25
25
25
25
25
25
25
benzoic acid
p-nitro benzoic acid
triflic acid
24
24
24
6
N.R
15
As we mentioned earlier, epoxides are versatile and privileged
framework to synthesis a various indole alkaloids with immense
biological significance. Now regioselective ring opening at the
tertiary centre of spiro-epoxides[15], [18] with different carbon
nucleophiles lead to the formation of all carbon quaternary
centre. Friedel-Crafts reaction is one of such highly efficient
atom-economic C-C bond forming reaction, although there are
very few efficient approaches for intermolecular F-C reaction of
5.
31
6
.
TFA
92
c
7.
8.
TFA
6
90
[19]
TFAd
24
46
epoxide.
Thus this method for the spiroepoxide demands
thorough reconnaissance.
aN-Methyl spiro-epoxy oxindole 1a (0.28 mmol), indole 2a (0.85 mmol) and
Brønsted acid (10 mol %) in solvent (2 mL) were stirred at specified
temperature. bIsolated Yield. 20 mol % of TFA; 5 mol % of TFA; NR: No
c
d
reaction.
Reaction with Indoles
After successful optimisation, we wished to generalise the
method. With this intention, we executed the F-C reaction with
an assemblage of spiro-epoxyoxindoles and indoles. Almost all
After initial success with Lewis acid, we tried to find out some
other milder catalyst condition for this F-C reaction. During our
research, we observed that the F-C reaction of spiro-epoxide
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European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
the cases, we achieved similar yield to that of our previously
mentioned Lewis acid condition. Only electron withdrawing
group on both spiro-epoxide as well as indole demanded more
time for complete conversion (Scheme 2).
N-benzyl indoles, we obtained regioselectively desired product
3,3′-bisindole along with 15-20 % of 3,2′-bisindole as a side
product. But when we performed the same reaction with electron
withdrawing protecting group, viz. N-benzoyl indole we gained
exclusively C(3)-C(3′) product with very good (78% to 82%)
isolated yield.
R3
R3
N
O
H
NH
HO
R2
2
CH CO H (1.0 equiv.) R2
N
3
2
N R3
O
2' R3
HO
O
O
N
R1
H O, 80 °C,
R2
R2
2
N
R1
TFA (10 mol %)
O
O
1
3
N
R1
N
R1
3'
Br
DCE, 25 °C,
1
NH
HO
Me
NH
HO
HO
NH
Me
Bn
Me
F
Bn
N
N
N
O
HO
HO
HO
O
O
N
Me
N
Me
N
Me
3b; 22 h, 62%
O
O
N
Me
O
3
a; 12 h, 68%
3c; 24 h, 65%,
N
Me
N
Br
Bn
3c'; 14 h, 69%
3
a'; 8 h, 63%
3b'; 10 h, 72%
NH
NH
HO
NH HO
HO
F
Me
Bn
Bz
N
N
O
N
HO
HO
HO
O
O
O
N
Bn
Me
N
Me
N
Bn
O
O
N
Bn
N
Bn
N
3
g; 30 h, 59%
3i; 36 h, 60%
3j; 40 h, 61%
Me
3f'; 14 h, 78%
Br
MeO
3
d'; 10 h, 67%
3e'; 12 h, 70%
HO
NH
HO
NH
HO
NH
Bz
Bz
N
Bz
N
F
HO
N
HO
HO
O
O
Me
O
N
N
Me
N
H
O
O
O
Bn
k; 40 h, 52%
MeO
N
N
N
3
3l; 7 h, 65%
3m; 18 h, 66%
Bn
3g'; 16 h, 79%
Bn
3i'; 13 h, 79%
MeO
3h'; 12 h, 80%
Bz
N
HO
NH
MeO
Bz
HO
NH
MeO
HO
NH
HO
N
HO
Me
MeO
O
O
O
O
N
Me
O
N
Me
N
Me
N
N
Me
3
Bn
j'; 13 h, 81%
H
n; 24 h, 66%
3o; 26 h, 62%
3p; 26 h, 64%
3
3k'; 11 h, 82%
MeO
HO
MeO
Br
Scheme 3. Substrate scope of F-C reaction of spiro-epoxides and N-protected
indoles (Method A).
NH
HO
NH HO
NH
O
O
O
Method B: Optimisation of on-water Reaction
N
N
H
N
Bn
q; 36 h, 63%
H
3
3r; 12 h, 60%
3s; 12 h, 61%
Water has a long history as a reaction medium in organic
chemistry.[20] As a solvent, it possesses a very interesting
Scheme 2. Substrate scope of F-C reaction of spiro-epoxides and indoles
property due to its extensive H-bonding ability. According to
Jung-Marcus theory,[21] approximately 25% of water molecules
having free OH groups at the interface are available for potential
H-bonding with the substrate on the surface. Recently, we
discovered catalyst-free on-water regio- and stereoselective ring
opening of spiroaziridine oxindoles with indoles. [17] This led us to
(
Method A). The yields in parenthesis are for the reactions under the Lewis
[
15a]
acid condition.
Not only unprotected indoles, we also performed the reaction
with N-protected indoles (Scheme 3). With N-methyl as well as
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European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
presume that water can also activate spiro-epoxyoxindole similar
to that of spiro-aziridine. But the extent of H-bonding is less in
case of spiro-epoxide compare to spiroaziridine (Scheme 4).
This attributed to the incomplete reaction, but with substantial
amount of yield (Table 2, entry 1). To increase the H-bonding
activity, we then planned to use different Brønsted acids as a
promoter. We initiated our inspection with the model substrate
N-methyl spiro-epoxyoxindole 1a with indole using TFA as a
promoter in aqueous medium. While 0.5 equiv. of TFA yielded
Employing ortho-phosphoric acid instead of TFA did not
increase the yield (entries 5, 6). On the contrary, more acidic
triflic acid reduced the yield of the desired product due to C3-
protonation of indole (entry 7). Next we applied relatively less
acidic acetic acid which led to the clean reaction profile. With 0.5
equiv. of acetic acid at 50 °C rendered 42% yield, while
increasing the temperature as well as amount of acetic acid up
to 1.0 equiv. improved the yield up to 68% (entries 8-10).
3
R3
R
41% yield at 50 °C, 1.0 equiv. of TFA afforded up to 50-52%
yield (entries 2-4).
N
O
H
NH
HO
R2
2
CH CO H (1.0 equiv.) R2
3
2
O
O
N
R1
H O, 80 °C,
2
N
R1
1
3
Br
NH
HO
Me
NH
HO
HO
NH
Me
O
O
O
N
Me
N
Me
N
Me
3b; 22 h, 62%
3
a; 12 h, 68%
3c; 24 h, 65%,
Scheme 4. Mode of activation of spiro-aziridine vs spiro-epoxide on-water
Table 2. Optimisation of reaction conditions (Method B).a
Br
NH
NH
HO
NH HO
HO
F
O
O
O
N
N
N
Me
Bn
Bn
HO
NH
O
3
g; 30 h, 59%
3i; 36 h, 60%
3j; 40 h, 61%
Bronsted acid (eqv.)
Water, temp, time
Br
MeO
O +
O
N
Me
N
N
H
Me
1a
2a
Brønsted
3a
HO
NH
HO
NH
HO
NH
F
entry
acid
temp
(°C)
time (h)
yieldb
(%)
O
O
(equiv.)
O
N
N
N
H
Bn
k; 40 h, 52%
Me
1
2
3
4
5
6
7
8
9
-
50
50
50
80
50
80
80
50
50
80
80
24
24
24
24
24
24
24
24
16
12
08
28
41
50
52
50
52
30
42
60
68
50
3
3l; 7 h, 65%
3m; 18 h, 66%
MeO
MeO
TFA (0.5)
TFA (1.0)
TFA (1.0)
HO
NH
MeO
HO
NH
MeO
HO
NH
Me
O
O
O
H
H
3
PO
PO
4
4
(1.0)
(1.0)
N
N
Me
; 26 h, 62%
N
Me
; 24 h, 66%
Me
3
Me
; 26 h, 64%
3
n
3o
3p
Br
MeO
HO
triflic acid (1.0)
acetic acid (0.5)
acetic acid (1.0)
MeO
NH
HO
NH HO
NH
O
O
O
1
0
acetic acid (1.0)
N
N
N
Bn
q; 36 h, 63%
H
H
1
1
acetic acid (12)
3
3r; 12 h, 60%
3s; 12 h, 61%
a
N-Methyl spiro-epoxy oxindole 1a (0.28 mmol), indole 2a (0.85 mmol) and
Scheme 5. Substrate scope of on-water F-C reaction of spiro-epoxides and
indoles (Method B).
Brønsted acid in water (2 mL) were stirred at specified temperature. bIsolated
Yield.
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European Journal of Organic Chemistry
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FULL PAPER
In contrast, a large excess of acetic acid (water/acetic acid =
epoxide ring opening is expected to occur at less substituted
benzylic center compare to more hindered pseudobenzylic
position of oxindole unit; moreover, the generation of
carbocationic nature at α-to carbonyl is very unlikely. To explore
the reactivity, trisubstituted spiro-epoxyoxindole (±)-6 was
subjected under optimised conditions (Method A). As expected,
it afforded compound (±)-7, generated from the less substituted
benzylic position attack by indole as a major one compared to
the more hindered C3-attack (±)-7′. The reaction was found to
be very slow with incomplete conversion.
9
1
:1) led to messy reaction with reduced yield (entry 11). Thus
.0 equiv. of acetic acid in water at 80 °C was the most suitable
condition here.
With these optimised conditions in hand, we desired to extend
the substrate scope for the Brønsted acid promoted on-water
ring opening reaction of spiro-epoxyoxindoles with indoles
(Scheme 5). All the electron donating as well as electron
withdrawing groups of spiro-epoxyoxindoles were well-tolerated
under optimised condition. All underwent smooth reaction
rendering the desired 3, 3′-bisindoles with moderate yield. It was
also observed that all the spiro-epoxides irrespective of
substitution or protection required longer times for completion
than the previously described methods. Due to the nucleophilic
character of water, we obtained a minor amount (15-20%) of
water adduct product in all the cases. Along with a minute
amount of acetate adduct (<10%) was also detected during the
course of the reaction. These unwanted side reactions
decreased the overall yield of the desired 3,3′ bisindole
methanols 3.
Scheme 7. Reaction of tri-substituted spiro-epoxyoxindole (±)-6 and indole 2a
(Method A)
We also unveiled the F-C reaction of spiro-epoxyoxindole with 3-
substituted indole which might provide the bisindole with vicinal
all-carbon quaternary centers. Consequently, compound 1c was
treated with 3-methyl indole 4a under Brønsted acid catalysed
condition in organic solvent (DCE) (Scheme 6). Interestingly, it
Reaction with Arenes
afforded tetrahydrospirofuro-bisindole 5a′ having vicinal all- Method A: Optimisation with Brønsted acids
carbon quaternary centers as a diastereomeric mixture along in organic solvent
with 2,3-bisindole 5a. It seemed epoxide opening with 3-methyl
indole followed by intramolecular cyclization of the intermediate
imine X afforded the tricyclic tetrahydrofuroindole core. Next we
also examined the similar kind of reaction between N-benzyl
spiro-epoxide 1b and 3-methyl N-benzoyl indole 4b under the
same Method A. Consequently, both the reactions manifested
identical outcome.
As depicted earlier, intermolecular F-C reaction of benzenoid
arenes[22] at the tertiary carbon forming all carbon quaternary
centre is still a demanding task. In this regards, we visualized
that the reaction of benzenoid arenes, particularly phenols with
the spiro-epoxides can solve the issue. Moreover this efficient
methodology
provides
a
direct
access
to
3-
Me
R3
aryloxindolemethanols which can be further manipulated to
synthesise different scaffolds with paramount significance. As
discussed earlier, we also want to find out some lenient catalysts
other than metal triflates to perform the F-C reaction of spiro-
epoxyoxindole with arenes.
N
OH
O
N
R3
4
Me
O
O
N
TFA (cat.)
DCE, 25 °C
10-12 h
N
As executed earlier, we also performed the model reaction
between N-methyl spiro-epoxyoxindole 1a and p-cresol 8a using
various Brønsted acids in different temperature in DCE (Table 3).
At the outset, the reaction was not completed at 0 °C using 10
mol% of orthophosphoric acid. Raising the temperature to 25 °C,
accomplished the regioselective F-C reaction with 90% isolated
yield of the desired product (Table 3, entries 1 and 2). Next we
applied catalytic amount of benzoic acid, p-nitrobenzoic acid,
triflic acid and acetic acid both in 0 °C as well as 25 °C, but
ended up with unsatisfied results (entries 3-7). Ultimately, by
applying 10 mol% of trifluoroacetic acid (TFA) at 0 °C, we were
able to isolate the desired 3-aryl-3-hydroxymethyl oxindole
product 9a with excellent isolated yield (92%) within 4 h (entry 9).
Raising the temperature to 25 °C did not show any further
improvement. Thus once again TFA was emerged to be the best
Brønsted acid catalyst for both the F-C reaction of spiro-
epoxides.
R1
R1
1
c
X
R3
H
Me
O
N
HO
N
R3
Me
O
+
O
N
N
R1
1
R
a; R1 = H, R = H, 50%
b; R1 = Bn, R3 = Bz, 51%
3
5a'; R1 = H, R3 = H, 36%
5
5b'; R1 = Bn, R3 = Bz, 39%
5
C3-C2 dimer
dr: 5:1
Scheme 6. Reaction of spiro-epoxyoxindole
Brønsted acid.
1 and 3-methylindole 4 with
The protocol was further elaborated towards the reaction of
trisubstituted spiro-epoxyoxindole (±)-6 (Scheme 7), having two
N N
possible reactive sites. Brønsted acid mediated S 1/S 2 type
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European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
R3
Table 3. Optimisation of reaction conditions for C3-arylation (Method A)a
OH
HO
O
HO
8
R2
R2
R3
TFA (10 mol %)
O
O
N
R1
DCE, 25 °C, time
N
R1
1
9
HO
HO
HO
HO
HO
HO
Me
Me
Me
Yieldb (%)
O
O
N
Bn
O
entry
Brønsted Acid
temp (°C)
time (h)
24
8
N
Me
N
1
2
3
4
5
6
7
8
9
1
.
H
H
3
PO
PO
4
4
0
25
9
a; 4 h, 92% (94%) 9b; 5 h, 71 % (74%)
9c; 5 h, 72% (73%)
.
3
25
0
90
HO
HO
HO
OH
HO
HO
HO
.
benzoic acid
p-nitrobenzoic acid
triflic acid
24
24
24
24
24
24
4
N.R
N.R
N.R
15
O
O
.
0
O
N
Me
N
Bn
N
Me
.
0
9
d; 3.5 h, 72% (74%) 9e; 3.5 h, 71% (76%) 9f; 3 h, 76% (79%)
.
benzoic acid
p-nitrobenzoic acid
triflic acid
25
25
25
0
HO
N
OH
HO
HO
OH
HO
HO
HO
.
20
Me
Me Me
O
O
O
.
40
N
Bn
N
Bn
Bn
.
TFA
92
9g; 4 h, 70% (74%) 9h; 7 h, 79% (84%) 9i; 4 h, 73% (78%)
0.
TFA
25
4
91
HO
N
HO
N
HO
HO
HO
HO
aN-Methyl spiroepoxy oxindole 1a (0.57 mmol), p-cresol 8a (1.7 mmol) and
Brønsted acid (10 mol %) in solvent (2 mL) were stirred at specified
MeO
Me MeO
Cl
Me
O
O
O
b
temperature. Isolated Yield.
N
Bn
Bn
9k; 8 h, 71% (70%)
Me
9l; 3 h, 72% (78%)
After fruitful Optimization, we wanted to unveil this method with a
collection of spiro-epoxides and phenols (Scheme 8). In all
cases, we obtained almost similar yield of the desired product to
that of our previously reported Lewis acid catalysed result.[15] Not
only 4-substituted phenols but -naphthol and resorcinol also
rendered regioselectively desired ortho-arylated products.
Moreover, we also performed the F-C reaction of spiro-epoxides
with sesamol and 4-tBu phenol under this optimised Brønsted
acid catalysed condition. These also afforded the
regioselectively the desired products with high yields. The
9
j; 6 h, 70% (76%)
HO
HO
HO
O
O
O
O
HO
O
O
HO
HO
O
N
O
O
N
N
H
Me
Bn
9
o; 5 h, 86%
9m; 4 h, 84%
9n; 4 h, 82%
HO
HO
HO
HO
O
O
HO
O
HO
t
Me
O MeO
Bu
compound 9o, an advanced precursor, could be transformed to
XEN907 in two steps. [15b]
O
O
O
N
Bn
N
N
Bn
9q; 8 h, 78%
Bn
9r; 9 h, 79 %
9
p; 6 h, 81%
Scehme 8. Substrate scope for the F-C reaction of spiro-epoxides and
phenols (Method A). The yields in parenthesis are for the reactions under the
[
15b]
Lewis acid condition.
We again continued the F-C reaction with electron rich
benzenoid arenes like anisole, 1,2-dimethoxy, 1,3- dimethoxy,
1,4-dimethoxy, 1,2,3-trimethoxybenzenes, pyrrole, benzofuran in
the presence of 10mol % TFA (Figure 2). These arenes also
reacted fluently under this condition to afford the regioselectively
desired 3-aryl-3-hydroxymethyloxindoles with high yields.
Whereas methoxyarenes bestowed exclusively 4-substituted
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European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
products, other heteroarenes such as pyrrole, benzofuran
reacted through their usual reactive centres.
H
OH
R
OH
R
HO
O
8
TFA (10 mol %)
R2
R2
O
O
O
DCE, 0 °C, time
N
N
R1
R1
11
1
OH
HO
OH
OH
HO
HO
O
N
Bn
O
N
Me
N
1
1a; 1 h, 95% 11b; 2 h, 86 %
11c; 5 h, 87%
OH
OH
OH
HO
HO
HO
Me
MeO
O
O
O
N
N
N
Me
11e; 4 h, 93%
OH
H
Me
Bn
11f; 5 h, 86%
1
1d; 1 h, 92%
OH
OH
HO
HO
HO
Me
Me
MeO
O
O
O
N
N
N
Figure 2. Substrate scope for the F-C reaction of spiroepoxides and
benzenoid arene (Method A). The yields in parenthesis are for the reactions
under the Lewis acid condition.[
Bn
H
H
11g; 2 h, 82%
11h; 2 h, 90%
11i; 2 h, 88%
15b]
Me
OH
Me
OH
HO
HO
We further carried out the F-C reaction with 4-unsubstitued
phenol, m-cresol and o-cresol (Scheme 9). Unlikely the Lewis
acid condition, Brønsted acid catalysed F-C reactions provided
the consistent para-arylated products with respect to hydroxyl
group of phenols. This might be due to the fact, Lewis acid
chelated between the phenol and spiro-epoxide (Scheme 10),
hence phenol reacted through the proximal ortho-position, but
the result was inconsistent with the change of the protecting
group as well as the substitution on spiro-epoxides. In contrast,
O
O
N
N
Me
1j; 4 h, 93%
Me
11k; 8 h, 87%
1
Scheme 9. Substrate scope for the F-C reaction of spiro-epoxides and 4-
unsubstitued phenols (Method A).
Brønsted acid can only activate the spiro-epoxide
protonation (Scheme 8), thus phenol reacts with this activated
spiro-epoxide through the sterically less hindered para-position
1
by
H
O
H
HO
HO
MLn
O
MLn
O
(TS2). Carbonyl group of carboxylic acid may act as a Lewis
O
R2
O
R2
N
base, thus it might simultaneously activate both the spiro-
epoxide and phenol through proton donation and proton
acceptor, respectively. The phenol might, therefore, prefer to
attack through para-position via macrocycle transition state TS3
O
R2
O
R1
N
R1
N
R1
R1 = Me, R2 = H, 95%
R1 = Bn, R2 = H, 86%
6
-membered
transition state
(Scheme 11). The consistent result also ratified our assumption.
Scheme 10. Mode of F-C reaction of spiro-epoxyoxindole with phenol under
Lewis acid catalysed condition.
Method B: Optimisation of on-water Reaction
As depicted earlier, we were again in search of environmentally
sound condition for regioselective ring opening reaction of spiro-
epoxyoxindole with arene.
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European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
6
2% yield (Table 4; entries 2, 3). Using ortho-phosphoric acid as
HO
R2
HO
well as highly acidic triflic acid did not increase the yield (entries
4, 5). Finally, we were privileged enough to apply relatively less
acidic acetic acid which led to the clean reaction profile. While
H
OH
O
O
RCO
2
O
R2
N
R1
N
0.5 equiv. acetic acid rendered 52% yield, increasing the amount
R1
OH
of acetic acid up to 1 equiv. improved the yield up to 79%
(entries 6, 7). On the other hand, large excess of acetic acid
(water/acetic acid = 9:1) led to uncleaned reaction with less yield
(entry 8). Thus 1 equiv. acetic acid in water at 50 °C was the
most acceptable condition for water mediated Brønsted acid
promoted F-C reaction of spiro-epoxides with arenes.
1
TS2
HO
O
H
H
O
O
R
H
R2
O
R
O
O
N
O
R1
H
O
1
1
O
On the basis of the above stated optimisation, we wanted to
R2
O
R2
O
extend the substrate scope with
a collection of spiro-
N
R1
N
R1
epoxyoxindoles and phenols (Scehme 12). All the reactions
underwent in a smooth way under this optimized conditions
irrespective of the protecting groups.
1
TS3
Scheme 11. Mode of F-C reaction of spiro-epoxyoxindole with phenol under
Brønsted acid catalysed condition.
R3
OH
HO
O
8
HO
R2
CH CO H (1.0 equiv.) R2
R3
In this regard, water has been considered as an advantageous
solvent not only for its benign nature but also for its extensive H-
bonding property. To the outset, we executed the ring opening
reaction only in water but we were ended up with unsatisfactory
result (Table 4, entry 1). We then anticipated that addition of
different Brønsted acids along with water may increase the H-
bonding capacity. We thus began our journey with the model
substrate N-methyl spiro-epoxyoxindole with p-cresol employing
TFA as a promoter in water. While 0.5 equiv. of TFA provided
3
2
O
O
H2O, 80 °C, time
N
N
R1
R1
9
1
HO
HO
HO
HO
HO
HO
Me
Me
Me
O
O
N
Bn
O
N
N
Me
9
a; 6 h, 79%
9b; 9 h, 68 %
9c; 8 h, 66%
50% yield at 50 °C, 1 equiv. of TFA afforded up to
Table 4. Optimisation of reaction conditions for C3-arylation (Method B).a
HO
HO
OH
HO
HO
HO
HO
O
O
O
N
N
N
Me
Bn
Me
9
d; 7 h, 66%
9e; 10 h, 67%
9f; 6 h, 69%
HO
HO
HO
OH
HO
HO
HO
MeO
Me
MeO
O
O
O
N
Bn
j; 12 h, 62%
HO
yieldb
(%)
N
N
Bn
entry
Brønsted
equiv.)
acid
temp
(°C)
time (h)
(
Bn
9
g; 9 h, 61%
9
9k; 10 h, 63%
1
2
3
4
5
6
7
8
-
50
50
50
50
50
50
50
50
24
12
08
12
12
12
06
06
28
50
62
48
36
52
79
55
HO
HO
HO
HO
OH
HO
TFA (0.5)
TFA (1.0)
Me
Me
Me
Me
Cl
O
O
O
N
N
N
Me
9s; 8 h, 69%
Me
Me
9t; 6 h, 68%
H
3
PO
4
(1.0)
9
l; 14 h, 60%
OH
OH
triflic acid (1.0)
OH
HO
HO
HO
acetic acid (0.5)
acetic acid (1.0)
acetic acid (12)
O
O
O
N
N
N
Me
11a; 6 h, 88%
Bn
11b; 7 h, 81%
H
11d; 5 h, 88%
aN-Methyl spiroepoxy oxindole 1a (0.57 mmol), p-cresol 8a (1.7 mmol) in
solvent (2 mL) were stirred at specified temperature. bIsolated Yield.
Scheme 12. Substrate scope for the on-water F-C reaction of spiro-epoxides
and phenols (Method B).
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European Journal of Organic Chemistry
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FULL PAPER
Moreover, electron donating as well as electron withdrawing
substituents on spiro- epoxyoxindole did not impede the F-C
reaction. In all cases good to moderate yield of the
regioselectively desired o- arylated products was gained. All the
spiro-epoxides took longer reaction times for completion than
the method A. Unlike on-water reaction of indole, we did not
observed any water adduct or acetate adduct. This might be due
to the fact, these reactions required relatively lesser time in
contrast to the previously described reactions with indoles.
Moreover, we again examined the F-C reaction with simple
phenol under this condition. As expected, this results also
manifested the consistent para-arylated product with respect to
hydroxyl group of phenol. Here only these reactions took longer
time than that of method A; while the yield was almost similar.
Furthermore, the F-C reaction with phenol was elaborated with
trisubstituted spiro-epoxyoxindole (±)-6 (Scheme 13), as we
performed earlier with indole. Brønsted acid in organic solvent
condition (Method A) was tested for the reaction. Unlike the
reaction of indole (Scheme 5), here we ended up with an
unexpected 3-aryl oxindole product 13. Possibly, the opening
product 3-hydroxymethyl-3-aryl oxindole 12 underwent retro
aldol kind of reaction to afford this interesting product 13.
Thus it was earlier proposed that these F-C reactions could only
N
proceed through 2H-indol-2-one 14 via S 1 type mechanism
(Scheme 14).[
15]
At this point, the arenes/heteroarenes can
easily add to the planar C3-position of the reactive indol-2-one
intermediate 14 to afford the 3-aryl/heteroaryl oxindoles 3/8/9/11
with excellent regioselectivity. Recently, we found that chiral
spiroaziridine oxindoles undergo regio- and stereoselective ring
opening reaction at the C3 centre with retention of
configuration.[17] This results led us to reinvestigate the
mechanism of ring-opening reactions of spiroepoxy oxindoles 1.
Thus to understand the ring-opening mechanism of spiroepoxide
and also with a view towards asymmetric F-C reaction, we
synthesized non-racemic spiro-epoxide 19 via Corey-
Chaykovsky reaction of chiral isatin 18 (Scheme 15). To
synthesize non-racemic spiroepoxide 19, we started to
synthesize the compound 16 by Cu (I) catalyzed amination
between iodobenzene and (S)-(-)-α-methylbenzylamine 15.
Isatin 17 was synthesized in toluene employing oxalyl chloride.
Further
phenylethyl)indoline-2,3-dione 18. Heating of suspended mixture
of chiral isatin 18, trimethyl sulfonium iodide (TMSI) and Cs CO
in CH
CN gave chiral spiroepoxides 19 and 19ʹ as a mixture of
:1 ratio. The chiral epoxides could be separated by silica-gel
bromination
afforded
the
(S)-5-bromo-1-(1-
2
3
3
1
column chromatography. It is to be noted that without bromo-
substitution the diastereomeric spiroepoxides were found to be
non-separable.
Scheme 13. Reaction of tri-substituted spiro-epoxyoxindole 6 and phenol.
Mechanistic Overview
All the above reactions exclusively produced C3-aryl/heteroaryl
oxindoles 3/9/10/11. Mechanistically, both
arenes/heteroarenres at the highly steric congested tertiary
N
S 2 attack of
Scheme 15. Preparation of non-racemic spiroepoxides 19/19ʹ.
centre of spiroepoxides 1 and unlike generation of positive
charge at the -position of carbonyl group via direct S 1
N
mechanism are ruled out.
Scheme 14. Plausible mechanism for the ring-opening F-C reaction of
spiroepoxides and arenes/heteroarenes
Scheme 16. F-C reaction of non-racemic spiro-epoxyoxindole 19/19′ and p-
cresol.
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European Journal of Organic Chemistry
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FULL PAPER
After successful synthesis of two diastereomeric and non-
racemic spiroepoxides 19 and 19ʹ, these were independently
subjected to the F-C reaction with p-cresol both under Method A
as well as Method B (Scheme 16). Interestingly, both gave ring-
opening product 20 with 1:1 diastereoselectivity under both the
stirred at the same temperature and monitored by TLC. On completion,
the reaction was quenched with saturated aqueous solution of
NaHCO
3
, extracted with EtOAc (3×5 mL), washed with brine solution
SO Combined organic layers
and dried over anhydrous Na
2
4
.
concentrated and purified by silica gel flash chromatography using
EtOAc/hexane (7:3) to afford the desire product 3a (0.077 g, 92%).
conditions (Methods
A and B). This revealed that the
stereoselectivity of the chiral spiro-epoxides 19/19′ were not
carried over to the F-C reaction. It, therefore, must be proceed
through a common intermediate, where stereochemistry of the
spiro-center was destroyed. Thus the reactive intermediate for
General procedure for on-water ring-
opening reaction of spiro-epoxyoxindole
this F-C reaction of spiroepoxides was proposed to be 2H-indol- with indole (Method B):
2-one intermediate 21. These results once again proved our
presumption.
To a stirring suspended solution of spiro-epoxy oxindole 1a (0.050 g,
.28 mmol) and indole 2a (0.100 g, 0.85 mmol) in deionised water (2
0
mL) at 80 °C was added glacial acetic acid (16 μL, 0.28 mmol). The
resulting solution was stirred at the same temperature and monitored
by TLC. On completion, the reaction was quenched with saturated
Conclusion
aqueous solution of NaHCO
with brine solution and dried over anhydrous Na
3
, extracted with EtOAc (3×5 mL), washed
SO Combined
2
4
.
organic layers concentrated and purified by silica gel flash
chromatography using EtOAc/hexane (7:3) to afford the desire product
In summary, we have developed a highly efficient, versatile
protocol for the synthesis of all carbon quaternary centers at
the C3-position of oxindole. Apart from previously performed
Lewis acid catalysed F-C reactions, we have developed
Brønsted acid assisted regioselective ring-opening of a range
of spiro-epoxyoxindoles with indoles and arenes in organic
solvent as well as on-water as an alternative. In contrast to the
Lewis acid catalysed condition, simple phenol preffered to
react through its less hindered para-position under Brønsted
acid conditions. Thus by altering the conditions, we can simply
switch the reactivity of phenol. Although on-water reaction
provides relatively less yield than the other methods; still it
introduces a relatively cheaper approach for the F-C reaction
of spiro-epoxides. The ring opening reactions are easily
monitored up to gram scale in these methods. Finally, we have
3a (0.055g, 68%).
3-(Hydroxymethyl)-3-(1H-indol-3-yl)-1-methylindolin-2-one
(3a):
The product was prepared by following general procedures and was
obtained as brown solid (0.075 g, 90% for Method A, 0.056 g, 68% for
-1
1
Method B). mp 215-216 °C. FT-IR (ν cm ): 3019, 2400, 1682, 1215. H
NMR (400 MHz, (CD ) SO): 11.04 (br. s, 1H), 7.32-7.29 (m, 3H),7.14
3
2
(d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.94 - 7.03 (m, 2H), 6.81
(d, J = 8.4 Hz, 1H), 6.75(t, J = 6.8 Hz, 1H ), 4.95 (t, J = 4.8 Hz, 1H),
4
.28 (dd, J = 10.2 Hz, J = 5.5 Hz, 1H), 4.19 (dd, J = 10.2 Hz, J = 5.5
13
Hz, 1H), 3.21(s, 3H). C NMR (100MHz, (CD
3
)
2
SO): .3, 144.4,
1
1
C
40.2, 136.4, 132.2, 127.8, 125.2, 124.0, 123.2, 122.0, 121.0, 119.2,
18.5, 111.5, 108.0, 64.8, 54.5, 26.1. HRMS (ESI-TOF) m/z: Calcd for
+
18
H
17
N
2
O
2
[M+H] 293.1290, found 293.1281.
synthesized
a conceptually new diastereoselective spiro-
3-(5-Bromo-1H-indol-3-yl)-3-(hydroxymethyl)-1-methylindolin-2-
epoxide and the corresponding opening of such epoxide with
arene initially reveals a probable mechanistic insight of the ring
opening reaction. This result strongly supports our presumption
that the indol-2-one is mechanism for the spiro-
epoxyoxindoles. We have the intention to continue our
research efforts towards the amplification of this concept with
other carbon as well as heteroatomic nucleophiles and to find
one (3b): According to the general procedure, the title compound was
prepared. After column purification the product was obtained as white
solid (0.075 g, 71% for Method A, 0.065 g, 62% for Method B). mp 210-
-1
1
212 °C. FT-IR (ν cm ): 3025, 2400, 1685, 1220. H NMR (400 MHz,
CD SO): 11.29 (br.s, 1H), 7.34-7.31 (m, 1H), 7.30-7.29 (m, 2H),
.20 (d, J = 7.3 Hz, 1H), 7.11 - 7.09 (m, 4H), 5.03 (t, J = 5.2Hz, 1H),
.28 (dd, J = 10.0Hz, J = 5.2 Hz,1H), 4.15(dd, J = 10.0 Hz, J = 5.2
(
3 2
)
7
4
13
3 2
Hz,1H), 3.19 (s, 3H). C NMR (100MHz, (CD ) SO): 177.1, 144.3
out
a precise mechanistic aspect of such ring opening
(
1
2C), 135.2, 131.5, 128.1, 127.0, 125.2, 124.2, 123.5, 122.1, 121.9,
reactions.
13.7, 111.2, 108.2, 64.8, 54.5, 26.1. HRMS (ESI-TOF) m/z: [M+H]+
2 2
Calcd for C18H17BrN O 371.0395; found 371.0384.
3
-(Hydroxymethyl)-3-(1H-indol-3-yl)-1,5,7-trimethylindolin-2-one
Experimental Section
(3c): According to the general procedure, the title compound was
prepared. After column purification the product was obtained as white
solid (0.055 g, 70% for Method A, 0.047 g, 65% for Method B). mp 196-
198 °C. FT-IR (ν cm-1): 3020, 2405, 1679, 1221. H NMR (400 MHz,
1
General procedure for ring-opening
reaction of spiro-epoxyoxindole with
indole under Brønsted acid catalysed
condition (Method A):
(
6
CD
.84-6.83 (m, 2H), 6.76-6.74 (m, 2H), 4.90 (t , J = 5.2 Hz, 1H), 4.24 (dd,
J = 10.0 Hz, J = 5.0 Hz, 1H), 4.13 (dd, J = 10.0 Hz, J = 5.0 Hz, 1H),
3 2
) SO): 11.02-11.01 (m, 1H), 7.29-7.27 (m, 2H), 6.97 (s, 1H),
13
3.46 (s, 3H), 2.58 (s, 3H), 2.15 (s, 3H). C NMR (100MHz, CD
3
)
2
SO):
178.0, 139.7, 136.4, 132.9, 131.7, 130.5, 125.3, 123.1, 122.6, 121.0,
1
19.3, 118.7, 118.5, 112.1, 111.5, 65.2, 53.9, 29.1, 20.5, 18.5. HRMS
To a stirring solution of spiro-epoxyoxindole 1a (0.050 g, 0.28 mmol)
and indole 2a (0.100 g, 0.85mmol) in dry 1, 2-dichloroethane (2 mL) at
+
(ESI-TOF) m/z: [M+H] calcd for C20
H
21
N
2
O
2
321.1603; found 321.1592.
25°C was added TFA (2 μL, 0.028 mmol). The resulting solution was
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European Journal of Organic Chemistry
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FULL PAPER
3
-(5-Bromo-1H-indol-3-yl)-3-(hydroxymethyl)-1,5,7-
1-Benzyl-3-(hydroxymethyl)-3-(1H-indol-3-yl)indolin-2-one
(3i):
According to the general procedure, the title compound was prepared.
After column purification the product was obtained as white solid (0.048
trimethylindolin-2-one (3d): According to the general procedure, the
title compound was prepared. After column purification the product was
obtained as white solid (0.067 g, 67% for Method A). mp 201-202 °C.
1
g, 66% for Method A, 0.043 g, for Method B). H NMR (400 MHz,
-1
1
FT-IR (ν cm ): 3018, 2407, 1684, 1220. H NMR (400 MHz, (CD
3
)
2
SO):
3 2
(CD ) SO) :  11.09 (br. s., 1H), 7.39 - 7.32 (m, 4H), 7.31 - 7.28 (m,

6
10.95 - 11.08 (1H, m), 7.22 - 7.37 (2H, m), 6.91 - 7.06 (1H, m), 6.82 -
.91 (2H, m), 6.66 - 6.82 (2H, m), 4.90 (1H, t, J = 5.2 Hz), 4.24 (1H, dd,
4H), 6.98 – 6.74 (m, 5H), 5.11 (br. s., 1H),5.06 ( d, J = 16 Hz, 1H), 4.92
(d, J = 15.6 Hz, 1H), 4.39 ( dd, J = 9.0 Hz, 3.2 Hz, 1H), 4.25( dd, J = 9.0
Hz, J = 3.2 Hz, 1H ). C NMR (100MHz, (CD ) SO): 177.6, 143.4,
3 2
13
J = 9.9 Hz, J = 5.4 Hz), 4.13 (1H, dd, J = 9.9 Hz, J = 4.9 Hz), 3.46 (3H,
s), 2.58 (3H, s), 2.15 (3H, s). 13C NMR (100MHz, (CD
SO): 178.0,
39.7, 136.4, 132.9, 131.7, 130.5, 125.3, 123.1, 122.6, 121.0, 119.3,
18.7, 118.5, 112.1, 111.5, 65.2, 53.9, 29.1, 20.5, 18.5. HRMS (ESI-
19BrN 399.0708; found 399.0703.
3
)
2
136.44, 136.38, 132.3, 128.4, 127.6, 127.4, 127.3, 125.2, 124.2, 123.3,
122.1, 121.0, 119.3, 118.4, 116.1, 111.4, 108.7, 65.0, 54.6, 42.9.
1
1
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24
21 2 2
H N O 369.1603; found
TOF) m/z: [M+H]+ Calcd for C20
H
2
O
2
369.1595.
5-Bromo-3-(hydroxymethyl)-3-(1H-indol-3-yl)-1-methylindolin-2-
1-Benzyl-3-(5-bromo-1H-indol-3-yl)-3-(hydroxymethyl)
indolin-2-
one (3e): According to the general procedure, the title compound was
one (3j): According to the general procedure, the title compound was
prepared. After column purification the product was obtained as white
solid (0.074 g, 84% for Method A, 0.053 g, 61% for Method B). 1H NMR
(400 MHz, (CD ) SO): 11.09 (br. s., 1H), 7.39 - 7.32 (m, 4H), 7.31 -
3 2
7.28 (m, 4H), 6.98 – 6.74 (m, 5H), 5.11 (br. s., 1H), 5.06 ( d, J = 16 Hz,
prepared. After column purification the product was obtained as white
-1
solid (0.050 g, 70% for Method A). mp 201-202 °C. FT-IR (ν cm ):
3
1
020, 2402, 1682, 1220. 1H NMR (400 MHz, (CD
H), 7.54-7.43 ( m, 1H ), 7.42-7.32 (m, 2H), 7.30-7.20 (m, 1H), 7.08 (d,
3
)
2
SO):  11.12 (br. s,
J = 8.3 Hz, 1H), 7.04-6.95 (m, 1H), 6.88-6.62 (m, 2H), 5.07 (t, J = 5.2
1H), 4.92 (d, J = 15.6 Hz, 1H), 4.39 ( dd, J = 9.0 Hz, 3.2 Hz, 1H),
4.25( dd, J = 9.0 Hz, J = 3.2 Hz, 1H ). C NMR (100 MHz, (CD ) SO):
3 2
177.6, 143.4, 136.44, 136.38, 132.3, 128.4, 127.6, 127.4, 127.3,
13
13
Hz, 1H), 4.24 (2H, d, J = 5.3 Hz), 3.22 (s, 3H). C NMR (100MHz,
CD SO): 177.1, 144.3 (2C), 135.2, 131.5, 128.1, 127.0, 125.2,
24.2, 123.5, 122.1, 121.9, 113.7, 111.2, 108.2, 64.8, 54.5, 26.1, 54.7,
(
3
)
2
1
2
125.2, 124.2, 123.3, 122.1, 121.0, 119.3, 118.4, 116.1, 111.4, 108.7,
+
+
6.3. HRMS (ESI-TOF) m/z calcd for C18
H
17BrN
2
O
2
: [M+H] 371.0395,
65.0, 54.6, 42.9. HRMS (ESI-TOF) m/z: [M+H] Calcd for C24
H
20BrN
O
2 2
found 371.0384.
447.0708; found 447.0699.
5-Bromo-3-(5-bromo-1H-indol-3-yl)-3-(hydroxymethyl)-1-
1-Benzyl-3-(5-bromo-1H-indol-3-yl)-5-fluoro-3-
methylindolin-2-one (3f): According to the general procedure, the title
compound was prepared. After column purification the product was
obtained as white solid (0.055 g, 63% for Method A). mp 218-220 °C.
(hydroxymethyl)indolin-2-one (3k): According to the general
procedure, the title compound was prepared. After column purification
the product was obtained as brown solid (0.063 g, 74% for Method A,
-1
1
1
FT-IR (ν cm ): 3019, 2400, 1683, 1215. H NMR (400 MHz, (CD

3
)
2
SO):
11.29 (br. s, 1H), 7.34-7.29 (m, 3H), 7.21(s, 1H), 7.12-7.09(m, 3H),
.03 (t, J = 5.2 Hz, 1H), 4.28 (dd, J = 10.2 Hz, J = 5.2 Hz), 4.14 (dd, J =
0.2 Hz, J = 5.2 Hz, 1H), 3.19 (s, 3H). 13C NMR (100MHz, (CD
SO): 
0.044 g, 52% for Method B). H NMR (400 MHz, (CD
3
)
2
SO): 11.39
(1H, m), 7.41 - 7.46 (1H, m), 7.36 - 7.40 (2H, m), 7.32 (2H, d, J = 8.4
Hz), 7.20 - 7.30 (2H, m), 7.11 - 7.17 (2H, m), 6.97 - 7.11 (2H, m), 6.92
(1H, dd, J = 8.7 Hz, J = 4.4 Hz), 5.25 (1H, t, J = 5.2 Hz), 4.99 (2H, q, J
= 16.2 Hz),4.4 (1H, dd, J = 10.0 Hz, J = 4.4 Hz), 4.23 (1H, dd, J = 10.0
5
1
1
1
3 2
)
76.7, 143.7, 135.2, 134.1, 130.8, 127.0, 126.8, 125.4, 123.7, 121.5,
14.1, 113.8, 111.3, 110.5, 110.3, 64.7, 54.7, 26.3. HRMS (ESI-TOF)
13
Hz, J = 4.8Hz). C NMR (100 MHz, (CD
3 2
) SO): 177.2, 158.60 (d, J =
m/z: [M+H]+ Calcd for C18
H15Br N O 448.9500; found 448.9498.
235.5 Hz, 2C), 139.6, 136.3 (d, J = 8 Hz, 2C), 134.4 (d, J = 8.0 Hz, 2C),
2 2 2
1
1
1
28.5, 127.3 (d, J = 6.0 Hz,2C), 125.1, 123.4, 121.1, 119.1, 118.5,
13.8 (d, J = 22.6 Hz, 2C), 112.1(d, J = 24.1 Hz, 2C),111.6, 110.8,
09.4 (d, J = 8 Hz, 2C), 109.3, 64.8, 55.1, 43.0. HRMS (ESI-TOF) m/z:
5
-Fluoro-3-(hydroxymethyl)-3-(1H-indol-3-yl)-1-methylindolin-2-one
(3g): According to the general procedure, the title compound was
[
M+H]+ Calcd for C24
H19BrFN O 465.0614; found 465.0610.
2 2
prepared. After column purification the product was obtained as white
solid (0.056 g, 71% for Method A, 0.046 g, 59% for Method B). H NMR
1
(400 MHz, (CD
3
)
2
SO): 11.1(br. s, 1H), 7.33 - 7.31 (2H, m), 7.1 - 7.0
3-(Hydroxymethyl)-3-(1H-indol-3-yl)indolin-2-one (3l): According to
(m, 3H), 6.9 – 6.7 (m, 4H), 5.02 (t, J = 5.2 Hz, 1H), 4.27 (dd, J = 10.2
the general procedure, the title compound was prepared. After column
Hz, J = 4.7 Hz, 1H), 4.21 (dd, J = 10.2 Hz, J = 4.7 Hz 1H), 3.21(s, 3H).
purification the product was obtained as brown solid (0.06 g, 70% for
13
1
C NMR (100 MHz, (CD
40.6, 136.4, 134.2, 125.1, 123.4, 121.1, 119.0, 118.7, 113.8 (d, J = 23
Hz, 2C), 112.0 (d, J = 25 Hz, 2C), 111.6, 110.9, 108.8, 64.7, 55.0, 26.3.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18
311.1196; found
3
)
2
SO): 177.1, 158.5(d, J = 235.5 Hz, 2C),
Method A, 0.055 g, 65% for Method B). H NMR (400 MHz, (CD
3
)
2
SO):
1
 11.20 - 11.36 (1H, m), 10.51 (1H, s), 7.32 - 7.42 (1H, m), 7.30 (1H, d,
J = 9.2 Hz), 7.18 - 7.26 (2H, m), 7.02 - 7.17 (4H, m), 6.72 - 7.02 (3H,
13
H
16FN
2
O
2
m), 5.02 (1H, t, J = 5.1 Hz), 4.21 - 4.26 (1H, m), 4.11 - 4.15 (1H, m).
NMR (100MHz, (CD
24.4, 123.1, 121.2, 121.0, 119.3, 118.4, 111.8, 111.5, 109, 64.8, 54.8.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C17
279.1134; found
79.1121.
C
311.1187.
3 2
) SO): 179.2, 143.0, 136.4, 133.1, 127.6, 125.4,
1
15 2 2
H N O
3-(5-Bromo-1H-indol-3-yl)-5-fluoro-3-(hydroxymethyl)-1-
2
methylindolin-2-one (3h): According to the general procedure, the title
compound was prepared. After column purification the product was
obtained as white solid (0.060 g, 60% for Method A). 1H NMR (400
3-(Hydroxymethyl)-3-(5-methoxy-1H-indol-3-yl)-1-methylindolin-2-
one (3m): According to the general procedure, the title compound was
MHz, (CD
3 2
) SO): 11.08 - 11.10 (br. 1H), 7.33 - 7.31 (m, 3H), 7 – 6.8
(
m, 4H), 5.1 – 5.0 (m, 1H), 4.31 (d, J = 10.0 Hz, 1H), 4.20 (d, J = 10.0
prepared. After column purification the product was obtained as gummy
13
1
Hz, 1H), 3.38 (s, 3H). C NMR (100MHz, (CD
J = 235.5 Hz, 2C), 140.5, 135.2, 133.5 (d, J = 8.7 Hz, 2C), 126.9,
25.3, 123.6, 121.7, 114.3, 114.0(d, J = 29 Hz, 2C), 112.3(d, J = 24.8
Hz, 2C), 111.2, 110.5, 109.0 (d, J = 8 Hz, 2C), 64.7, 55.0, 26.3. HRMS
ESI-TOF) m/z: [M+H]+ Calcd for
15BrFN 389.0301; found
89.0300.
3
)
2
SO):176.9, 158.5(d,
liquid (0.06 g, 66% for Method B). H NMR (400 MHz, (CD
3
)
2
SO):
10.89 (br.s, 1H), 7.34-7.29 (m, 1H), 7.26-7.25(m, 1H),7.20 (d, J = 8.8
Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.04-6.98 (1H, m), 6.71-6.56 (m, 1H ),
6.15-6.26 (m, 1H), 4.88-5.00 (m, 1H ), 4.30 (dd, J = 10.0 Hz, J = 5.2
Hz), 4.17 (dd, J = 10.0Hz, J = 5.2 Hz,1H), 3.49 (s, 3H), 3.21(s, 3H).
1
(
3
C
18
H
2 2
O
13
CNMR (100MHz, (CD
3 2
) SO): 177.3, 152.6, 144.5, 132.1, 131.5,
127.8, 125.5, 124.1, 123.8, 122, 112.1, 111.1, 110.8, 107.9, 101.2,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
6
4.5, 54.9, 54.5, 26.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
323.1396; found 323.1384.
= 5.3 Hz), 3.22 (s, 3H). 13C NMR (100MHz, (CD
143.1, 132.9, 131.6, 127.7, 125.7, 124.5, 123.8, 121.3, 112.0, 111.3,
10.6, 108.9, 101.7, 64.6, 55.0, 54.9. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C18 309.1239; found 309.1235.
3 2
) SO): 179.1, 152.6,
19 19 2 3
C H N O
1
17 2 3
H N O
3-(Hydroxymethyl)-3-(5-methoxy-1H-indol-3-yl)-1,5,7-
trimethylindolin-2-one (3n): According to the general procedure, the
title compound was prepared. After column purification the product was
obtained as white solid (0.056 g, 66% for Method B). 1H NMR (400
3-(5-Bromo-1H-indol-3-yl)-3-(hydroxyl methyl) indolin-2-one (3s):
According to the general procedure, the title compound was prepared.
After column purification the product was obtained as white solid (0.066
MHz, (CD
3 2
) SO):  10.86 (br. s, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.19 (d, J
-1
=
8.4 Hz, 1H), 6.86 (s, 1H), 6.78 (s, 1H), 6.64 (dd, J = 8.8 Hz, J = 2.5
g, 61% for Method B). mp 217-218 °C. FT-IR (ν cm ): 3405, 3019,
1
Hz, 1H), 6.34-6.21 (d, J= 2 Hz, 1H), 4.91 (br. s, 1H), 4.27 (d, J = 10.0
Hz,1H), 4.12 (d, J = 10.0 Hz, 1H), 3.53 (s, 3H), 3.47 (s, 3H), 2.58 (s,
2400, 1685, 1212. H NMR (400 MHz, (CD
3
)
2
SO):  11.28 (1H, br. s),
10.51 (1H, s), 7.28 - 7.37 (2H, m), 7.19 - 7.26 (1H, m), 7.07 - 7.16 (3H,
3
1
1
H), 2.17 (s, 3H). 13C NMR (100MHz, (CD
39.8, 132.8, 131.6, 131.5, 130.6, 125.6, 123.6, 122.7, 118.7, 112.0,
3
)
2
SO): 177.9, 152.6,
m), 6.86 - 7.01 (2H, m), 5.02 (1H, t, J = 5.1 Hz), 4.18 - 4.28 (1H, m),
13
3 2
4.09 - 4.18 (1H, m). C NMR (100MHz, (CD ) SO):  178.9, 142.8,
11.7, 110.8, 101.1, 64.8, 54.8, 53.9, 29.1, 20.5, 18.4. HRMS (ESI-
135.1, 132.5, 127.9, 127.1, 125.0, 124.5, 123.5, 121.7, 121.4, 113.6,
TOF) m/z: [M+H]+ Calcd for C21
H
N
O
351.1709; found 351.1699.
111.5, 111.1, 109.1, 64.8, 54.7. HRMS (ESI-TOF) m/z: [M+Na] Calcd
+
23
2
3
2 2
for C17H13BrN O 381.0038; found 381.0020.
3-(Hydroxymethyl)-3-(1H-indol-3yl)-5-methoxy-1-methylindolin-2-
one (3o): According to the general procedure, the title compound was
3-(1-benzyl-1H-indol-3-yl)-3-(hydroxymethyl)-1-methylindolin-2-one
prepared. After column purification the product was obtained as white
(3a′): The compound was prepared by following general procedure and
was obtained as white powder (0.068 g, 63% for Method A). H NMR
(400 MHz, (CD ) SO): δ 7.53 (s, 1H), 7.37 – 7.29 (m, 4H), 7.25 (d, J =
3 2
solid (0.048 g, 62% for Method B). 1H NMR (400 MHz, (CD
)
2
SO):
1.05 (br. s, 1H), 7.31 - 7.29 (m, 2H), 7.00-6.98 (m, 2H), 6.75 – 6.70
m, 4H), 4.95 (t, J = 5.2 Hz, 1H), 4.25 (dd, J = 9.6 Hz, J = 5.2 Hz, 1H),
.19 (dd, J = 9.6 Hz, J = 5.2 Hz, 2H), 3.18 (s, 3H). 13CNMR (100MHz,
CD SO):177.0, 155.3, 150.9, 137.9, 136.4, 133.6, 125.3, 123.3,
21.0, 119.2, 118.6, 111.9, 111.6, 111.5, 108.3, 64.8, 55.4, 54.9, 26.2.
323.1396; found
1
3
1
(
4
(
7.1 Hz, 1H), 7.22 – 7.19 (m, 2H), 7.15 (d, J = 7.3 Hz, 1H), 7.10 (d, J =
7.7 Hz, 1H), 7.00 (td, J = 7.1, 5.0 Hz, 2H), 6.80 (dt, J = 14.7, 7.5 Hz,
2H), 5.38 (s, 2H), 5.02 (t, J = 5.1 Hz, 1H), 4.28 (dd, J = 9.9, 5.4 Hz, 1H),
3 2
)
13
1
4.19 (dd, J = 9.9, 4.9 Hz, 1H), 3.21 (s, 3H). C NMR (100 MHz,
(CD SO): δ 177.2, 144.4, 138.2, 136.1, 132.0, 128.6, 127.9, 127.4,
127.2, 127.1, 125.9, 124.0, 122.1, 121.3, 119.6, 118.9, 111.3, 110.3,
08.2, 64.90, 54.5, 49.1, 26.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
383.1760; found 383.1765.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19
H
O
19
N
2
3
3 2
)
323.1384.
1
25 22 2 2
C H N O
3-(hydroxymethyl)-5-methoxy-3-(5-methoxy-1H-indol-3-yl)-1-
methylindolin-2-one (3p): According to the general procedure, the title
compound was prepared. After column purification the product was
obtained as white solid (0.049 g, 64% for Method B). H NMR (400
3-(hydroxymethyl)-1-methyl-3-(1-methyl-1H-indol-3-yl)indolin-2-
one (3b′): The compound was prepared by following general procedure
and was obtained as white powder (0.062 g , 72% for Method A). 1
H
1
MHz, (CD
3
)
2
SO): 10.89 (br. s, 1H), 7.26 - 7.25 (1H, m), 7.19 (d, J =
8.8 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.88 (1H, dt, J = 8.5 Hz, J = 1.3
3
NMR (600 MHz, CDCl ): δ 7.42 – 7.38 (m, 1H), 7.33 – 7.26 (m, 2H),
Hz, 1H), 6.76 (1H, d, J = 2.5 Hz), 6.22 - 6.21 (1H, m), 4.94 (t, J = 4.8
Hz, 1H), 4.26(dd, J = 10.0 Hz, J =5.0 Hz), 4.16( dd, J =10.0 Hz, J = 5.0
7.21 – 7.14 (m, 3H), 7.11 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H),
6.97 (t, J = 7.6 Hz, 1H), 4.51 (d, J = 10.9 Hz, 1H), 4.24 (d, J = 10.9 Hz,
13
13
Hz), 3.67 (s, 3H), 3.50 (s, 3.5), 3.18 (s, 3H). C NMR (100 MHz,
CD SO): 177.0, 155.4, 152.7, 138.0, 133.5, 131.5, 125.6, 123.8,
12.2, 111.9, 111.7, 111.2, 110.8, 108.2, 101.1, 64.5, 55.4, 55.3, 54.9,
6.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20
353.1501;
3
1H), 3.77 (s, 3H), 3.33 (s, 3H). C NMR (150 MHz, CDCl ): δ 177.9,
(
3
)
2
144.0, 137.4, 130.9, 128.6, 128.2, 124.4, 126.1, 122.9, 121.8, 120.2,
1
2
119.4, 110.1, 109.4, 108.4, 66.6, 54.5, 32.8, 26.5. HRMS (ESI-TOF)
+
H
21
N
2
O
4
m/z : [M+Na] Calcd for C19
H
18
N
2
O
2
329.1266; found 329.1252.
found 353.1490.
1-benzyl-3-(1-benzyl-1H-indol-3-yl)-5-fluoro-3-(hydroxymethyl)
1-Benzyl-3-(hydroxymethyl)-3-(5-methoxy-1H-indol-3-yl)indolin-2-
indolin-2-one (3c′): The compound was prepared by following general
one (3q): According to the general procedure, the title compound was
prepared. After column purification the product was obtained as white
procedure and was obtained as yellow powder (0.061 g, 69 % for
1
Method A). H NMR (400 MHz, (CD
3
)
2
SO): δ 7.61 (s, 1H), 7.43 – 7.36
solid (0.05 g, 63% for Method B). 1H NMR (400 MHz, (CD

)
SO):
10.93 (m, 1 H), 7.41 - 7.34 (m, 2 H), 7.33 - 7.29 (m, 1 H), 7.28 - 7.23
m, 3 H), 7.23 - 7.17 (m, 2 H), 7.15 (d, J = 6.8 Hz, 1 H), 6.99 (t, J = 7.6
Hz, 1 H), 6.92 (d, J = 7.8 Hz, 1 H), 6.67 - 6.56 (m, 1 H), 6.14 - 6.07 (m,
(m, 3H), 7.28 (dq, J = 24.2, 7.5 Hz, 8H), 7.10 – 6.99 (m, 3H), 6.92 (dd,
J = 8.3, 4.2 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 6.76 (t, J = 7.5 Hz, 1H),
5.41 (s, 2H), 5.26 (s, 1H), 5.06 (d, J = 15.9 Hz, 1H), 4.95 (d, J = 15.9
3
2
(
13
Hz, 1H), 4.41 (d, J = 5.6 Hz, 1H), 4.29 (d, J = 7.5 Hz, 1H). C NMR
(150 MHz, (CD SO): δ 177.1, 158.4 (d, J = 235.8 Hz, 2C), 139.5,
1
1
5
1
1
5
3
H), 5.14 - 5.09 (m, 1 H), 5.04 (d, J = 16 Hz, 1 H), 4.93 (d, J = 15.6Hz,
H), 4.41 ( dd, J = 10.0 Hz, J = 5.0 Hz, 1 H), 4.20 (dd, J = 10.0 Hz, J =
3 2
)
137.9, 136.1, 136.1, 128.4, 128.4, 127.3, 127.3, 127.2, 126.9, 125.7,
121.3, 119.5, 118.8, 113.8 (d, J = 23.1 Hz, 2C), 112.1 (d, J = 24 Hz,
2C), 110.6, 110.3, 109.4 (d, J = 7.95 Hz, 2C), 64.9, 55.1, 49.1, 42.9.
.0 Hz, 1H), 3.33 (s, 3 H). 13C NMR (100MHz, (CD
) SO): 177.6,
3 2
52.6, 143.6, 136.5, 132.2, 131.5, 128.4, 127.7, 127.24, 127.21, 125.5,
24.3, 123.9, 122.11, 112.1, 110.97, 110.83, 108.6, 101.1, 64.7, 54.67,
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C31
H
25FN
499.1798;
2
O
2
4.63, 40.1. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25
H
O
found 499.1779.
23
N
2
3
99.1709; found 399.1701.
1-benzyl-3-(hydroxymethyl)-3-(1-methyl-1H-indol-3-yl)indolin-2-one
3
-(Hydroxymethyl)-3-(5-methoxy-1H-indol-3-yl)indolin-2-one (3r):
(3d′): The compound was prepared by following general procedure and
was obtained as white powder (0.05 g, 67% for Method A). H NMR
(400 MHz, CDCl ): δ 7.40 – 7.21 (m, 9H), 7.17 (t, J = 7.5 Hz, 1H), 7.03
3
1
According to the general procedure, the title compound was prepared.
After column purification the product was obtained as gummy liquid
-1
(
0.057 g, 60% for Method B). FT-IR (ν cm ): 3020, 2400, 1688, 1220.
(dd, J = 18.3, 7.9 Hz, 2H), 6.93 – 6.84 (m, 2H), 5.02 (s, 2H), 4.64 – 4.53
1
13
H NMR (400 MHz, (CD
3
)
2
SO):  11.12 (br. s, 1H), 7.54-7.43 (m, 1H ),
.42-7.32 (m, 2H), 7.30-7.20 (m, 1H), 7.08 (d, J = 8.3 Hz, 1H), 7.04-
.95 (m, 1H), 6.88-6.62 (m, 2H), 5.07 (t, J = 5.2 Hz, 1H), 4.24 (2H, d, J
(m, 1H), 4.27 (d, J = 10.7 Hz, 1H), 3.78 (s, 3H), 2.41 (s, 1H). C NMR
7
6
(150 MHz, CDCl
3
): δ 178.1, 143.2, 137.4, 135.7, 130.9, 128.7, 128.5,
128.1, 127.6, 127.4, 126.1, 124.5, 122.9, 121.8, 120.3, 119.3, 110.2,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
1
09.4, 109.4, 66.8, 54.5, 44.0, 32.8. HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C25 405.1579; found 405.1561.
4.87 (m, 2H), 4.30 (d, J = 6.3 Hz, 1H), 3.99 (d, J = 9.1 Hz, 1H), 3.83 (d,
13
H
22
N
2
O
2
J = 9.2 Hz, 1H), 2.03 (s, 3H). C NMR (100 MHz, (CD
3
)
2
SO): δ 177.0,
1
1
7
69.5, 142.9, 140.5, 136.3, 136.3, 130.5, 130.4, 128.7, 128.6, 128.4,
28.3, 127.5, 127.4, 127.1, 126.5, 125.6, 123.1, 116.2, 108.8, 95.7,
3.5, 57.0, 53.1, 42.8, 20.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
1
-benzyl-3-(1-benzyl-1H-indol-3-yl)-3-(hydroxymethyl)-5-
methylindolin-2-one (3e′): The compound was prepared by following
32 26 2 3
C H N O 487.2022; found 487.2045.
general procedure and was obtained as white powder (0.062 g, 70% for
Method A). 1H NMR (600 MHz, CDCl
3
): δ 7.37 – 7.25 (m, 9H), 7.23 (d,
J = 8.3 Hz, 1H), 7.15 (d, J = 7.1 Hz, 2H), 7.11 (t, J = 7.2 Hz, 1H), 7.09 –
3-(1-benzoyl-1H-indol-3-yl)-1-benzyl-3-(hydroxymethyl)-5-
7
5
=
.03 (m, 3H), 6.90 (t, J = 7.9 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 5.34 –
methoxyindolin-2-one (3j′): The compound was prepared by following
.31 (m, 2H), 5.02 (d, J = 3.6 Hz, 2H), 4.60 – 4.56 (m, 1H), 4.25 (dd, J
general procedure and was obtained as white powder (0.072 g, 81 %).
13
1
10.8, 3.4 Hz, 1H), 2.40 (dd, J = 9.4, 3.6 Hz, 1H), 2.27 (s, 3H).
): δ 178.0, 140.8, 137.2, 136.9, 135.8, 132.5,
30.8, 128.9, 128.8, 128.7, 127.6, 127.55, 127.4, 126.8, 126.4, 125.2,
21.9, 120.5, 119.5, 111.2, 109.9, 109.2, 66.8, 54.5, 50.2, 44.1, 21.1.
495.2048; found
C
3 2
H NMR (600 MHz, (CD ) SO): δ 7.98 (d, J = 51.1 Hz, 1H), 7.75 (d, J =
NMR (150 MHz, CDCl
3
6.9 Hz, 2H), 7.55 (dt, J = 14.2, 7.0 Hz, 3H), 7.41 – 7.23 (m, 6H), 6.94 (t,
J = 7.3 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.78 – 6.69 (m, 1H), 6.51 (d, J
= 7.4 Hz, 1H), 6.36 (d, J = 6.6 Hz, 1H), 5.93 (s, 1H), 4.91 (d, J = 5.9 Hz,
2H), 4.33 (d, J = 6.5 Hz, 1H), 3.99 (d, J = 9.2 Hz, 1H), 3.87 (d, J = 9.2
1
1
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C32
H
N
O
28
2
2
13
495.2031.
Hz, 1H), 3.47 (s, 3H). C NMR (100 MHz, (CD
3
)
2
SO): δ 176.7, 169.5,
1
1
7
54.5, 143.0, 136.4, 136.3, 136.1, 130.4, 128.7, 128.4, 128.3, 127.5,
27.4, 127.1, 126.99, 126.9, 123.3, 116.2, 113.6, 112.4, 109.6, 95.7,
3.7, 57.3, 55.2, 53.2, 42.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
3
-(1-benzoyl-1H-indol-3-yl)-3-(hydroxymethyl)-1-methylindolin-2-
one (3f′): The compound was prepared by following general procedure
and was obtained as white powder (0.088 g, 78 % for Method A).
NMR (400 MHz, CDCl
1
C
32
H
26
N
2
O
4
503.1971; found 503.1992.
H
3
): δ 8.13 (s, 1H), 7.90 – 7.74 (m, 2H), 7.54 –
7
6
.46 (m, 3H), 7.29 (dd, J = 9.2, 4.4 Hz, 2H), 6.94 – 6.79 (m, 3H), 6.51 –
.38 (m, 2H), 6.27 (d, J = 6.6 Hz, 1H), 4.24 (d, J = 6.6 Hz, 1H), 4.06 (d,
3-(1-benzoyl-1H-indol-3-yl)-3-(hydroxymethyl)indolin-2-one
(3k′):
The compound was prepared by following general procedure and was
13
1
J = 9.1 Hz, 1H), 3.93 (d, J = 9.1 Hz, 1H), 3.28 (s, 3H). C NMR (100
MHz, CDCl ): δ 177.4, 170.5, 143.6, 142.9, 135.9, 130.7, 128.7, 128.3,
obtained as white powder (0.097 g, 82% for Method A). H NMR (400
3
3 2
MHz, (CD ) SO): δ 10.66 (s, 1H), 8.02 (s, 1H), 7.78 – 7.68 (m, 2H),
1
5
4
27.9, 127.4, 126.8, 125.9, 123.6, 122.2, 117.5, 108.0, 95.5, 74.2, 57.5,
7.58 – 7.49 (m, 3H), 7.29 (t, J = 7.8 Hz, 1H), 7.18 (t, J = 8.2 Hz, 1H),
6.93 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.75 (t, J = 7.6 Hz,
1H), 6.52 (d, J = 7.5 Hz, 1H), 6.27 (dd, J = 6.9, 3.9 Hz, 2H), 4.23 (d, J =
3.9, 26.5. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C25
20 2 3
H N O
19.1372; found 419.1355.
13
6
(
1
.7 Hz, 1H), 3.93 (d, J = 9.2 Hz, 1H), 3.76 (d, J = 9.2 Hz, 1H). C NMR
100 MHz, (CD SO): δ 178.8, 169.6, 142.9, 142.5, 136.4, 130.4,
28.6, 128.4, 127.8, 127.5, 127.1, 126.4, 125.8, 123.4, 120.9, 109.6,
Calcd for
3 2
)
3-(1-benzoyl-1H-indol-3-yl)-1-benzyl-3-(hydroxymethyl)indolin-2-
one (3g′): The compound was prepared by following general procedure
and was obtained as white powder (0.074 g, 79% for Method A).
NMR (400 MHz, (CD
1
95.7, 73.6, 57.3, 52.8. HRMS (ESI-TOF) m/z : [M+H]
383.1396; found 383.1401.
+
H
24 18 2 3
C H N O
3
)
2
SO): δ 8.01 (s, 1H), 7.75 (d, J = 6.4 Hz, 2H),
7
2
7
4
.55 (q, J = 7.3, 6.3 Hz, 3H), 7.34 (d, J = 4.3 Hz, 4H), 7.31 – 7.24 (m,
H), 7.19 (t, J = 7.6 Hz, 1H), 6.92 (dd, J = 16.6, 7.8 Hz, 2H), 6.81 (t, J =
.6 Hz, 1H), 6.47 (d, J = 7.4 Hz, 1H), 6.34 (dd, J = 6.7, 4.4 Hz, 2H),
.94 (s, 2H), 4.33 (d, J = 6.6 Hz, 1H), 4.00 (d, J = 9.3 Hz, 1H), 3.85 (d,
3a-methyl-2,3a,8,8a-tetrahydro spiro[furo[2,3-b]indol-3,3ʹ-indolin]-
2ʹ-one (5a′) : To a stirring solution of spiro-epoxy oxindole 1c (0.100g,
0.62mmol) and 3-Methyl indole 4a (0.244 g, 1.86 mmol) in dry 1,2-
dichloroethane (4 mL) at 0 °C (immersion bath) was added TFA (5µL,
0.06mmol). The resulting solution was stirred at the same temperature
and monitored by TLC. On completion (10 h), the reaction was
13
J = 9.2 Hz, 1H). C NMR (100 MHz, (CD
3
)
2
SO): δ 177.1, 169.6, 143.0,
1
1
4
42.9, 136.3, 130.5, 128.8 , 128.6, 128.5, 128.4, 127.6, 127.54, 127.2,
26.9, 125.8, 125.6, 123.4, 121.7, 116.3, 109.2, 95.7, 73.6, 57.0, 53.2,
2.9. HRMS (ESI-TOF) m/z : [M+H] Calcd for C31
+
H
24
N
2
O
3
473.1865;
quenched with saturated aqueous solution of NaHCO
EtOAc (3×10 mL), washed with brine solution and dried over anhydrous
Na SO . Combined organic layers concentrated and purified by silica
gel flash chromatography using EtOAc/hexane to afford the product 5a′
0.065 g, 36%). Compound 5a′ was obtained as diastereomeric mixture
3
, extracted with
found 473.1872.
2
4
1-allyl-3-(1-benzoyl-1H-indol-3-yl)-3-(hydroxymethyl)indolin-2-one
(
(3h′): The compound was prepared by following general procedure and
1
(5:1). Along with this diastereomer, compound 5a was formed through
C2-attack of 3-methyl indole 4a (50%).
was obtained as white powder (0.08 g, 80 %). H NMR (600 MHz,
(CD
3
)
2
SO): δ 8.01 (s, 1H), 7.74 (d, J = 6.9 Hz, 2H), 7.55 (dq, J = 14.5,
7
6
1
1
3
.1 Hz, 3H), 7.27 (dt, J = 26.5, 7.7 Hz, 2H), 6.99 (d, J = 7.8 Hz, 1H),
.92 (t, J = 7.4 Hz, 1H), 6.82 (t, J = 7.5 Hz, 1H), 6.49 (d, J = 7.5 Hz,
H), 6.32 (dd, J = 10.6, 7.1 Hz, 2H), 5.89 (ddt, J = 15.4, 10.2, 5.0 Hz,
H), 5.23 – 5.12 (m, 2H), 4.41 – 4.32 (m, 2H), 4.27 (d, J = 6.7 Hz, 1H),
.94 (d, J = 9.2 Hz, 1H), 3.82 (d, J = 9.2 Hz, 1H). 13C NMR (100 MHz,
Analytical data for major diastereomer: White solid (0.05 g, 29% for
1
Method A). H NMR (400 MHz, (CD
3
)
2
SO) :  10.50 (1H, s), 7.15 (1H,
t, J = 7.7 Hz), 6.96 - 7.01 (2H, m), 6.84 (1H, d, J = 7.7 Hz), 6.72 (1H, t,
J = 7.6 Hz), 6.55 (1H, d, J = 7.9 Hz), 6.41 (2H, d, J = 7.4 Hz), 6.32 (1H,
d, J = 7.4 Hz), 5.49 (1H, s), 3.94 (1H, d, J = 9.0 Hz), 3.68 (1H, d, J =
3 2
(CD ) SO): δ 176.6, 169.5, 142.9, 131.9, 130.4, 128.5, 128.4, 128.3,
13
1
7
27.5, 126.9, 125.8, 125.4, 123.4, 121.5, 116.9, 116.2, 109.1, 95.6,
3 2
9.0 Hz), 1.27 (3H, s). C NMR (100MHz, (CD ) SO):  178.4, 149.7,
3.7, 56.9, 53.1, 41.7. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
142.7, 130.0, 128.2, 128.2, 126.8, 126.3, 125.6, 120.3, 116.4, 109.0,
+
C
27
H
22
N
2
O
3
423.1079; found 423.1089.
107.6, 100.2, 72.9, 60.7, 59.0, 21.4. HRMS (ESI-TOF) m/z: [M+H]
16 2 2
Calcd for C18H N O 293.1285; found 293.1296.
3-(1-benzoyl-1H-indol-3-yl)-1-benzyl-3-(hydroxymethyl)-5-
methylindolin-2-one (3i′): The compound was prepared by following
3-(Hydroxy methyl)-3-(3-methyl-1H-indol-2-yl)indolin-2-one (5a):
general procedure and was obtained as white powder (0.07 g, 79 %).
The compound was obtained as white solid (0.091 g, 50% for Method
1
1
H NMR (600 MHz, (CD
.8 Hz, 2H), 7.55 (dq, J = 13.9, 6.3 Hz, 3H), 7.42 – 7.22 (m, 6H), 6.99
d, J = 7.6 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H),
.46 (d, J = 7.3 Hz, 1H), 6.35 (d, J = 6.3 Hz, 1H), 6.10 (s, 1H), 4.95 –
3
)
2
SO): δ 7.98 (d, J = 50.3 Hz, 1H), 7.75 (d, J =
A). H NMR (400 MHz, (CD
3
)
2
SO): 10.64 (1H, s), 10.36 (1H, s), 7.37
6
(1H, d, J = 8.4 Hz), 7.29 (1H, d, J = 7.2 Hz), 7.22 - 7.27 (1H, m), 7.14 -
7.22 (1H, m), 7.06 (1H, s), 6.94 - 7.03 (2H, m), 6.88 (1H, d, J= 7.6 Hz),
(
13
6
4.97 (1H, t, J = 5.0 Hz), 4.10 - 4.16 (2H, m), 2.20 (3H, s). C NMR
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
(
1
100MHz, (CD
3 2
) SO):  179.3, 142.8, 136.2, 132.9, 131.0, 127.6, 126.8,
opening reaction of spiro-epoxyoxindole
with phenols (Method B):
25.2, 123.1, 121.2, 118.0, 117.3, 109.7, 109.2, 108.9, 66.0, 59.0, 9.6.
+
HRMS (ESI-TOF) m/z: [M+H] Calcd for C18
2
16 2 2
H N O 293.1285; found
93.1284.
To a stirring suspended-solution of spiro-epoxyoxindole 1a (0.100 g,
0.570 mmol), p-cresol 8a (0.185 g, 1.71 mmol) in deionised water (3
(3aS,8aR)-8-benzoyl-1'-benzyl-3a-methyl-3a,8a-dihydro-2H,8H-
mL) at 50 °C was added glacial acetic acid (32 μL, 0.57 mmol). The
resulting solution was stirred at the same temperature and monitored
by TLC. On completion (6 h), the reaction was quenched with saturated
spiro[furo[2,3-b]indole-3,3'-indolin]-2'-one (5b′) The compound
was prepared by following general procedure and was obtained as
gummy liquid (0.03 g, dr: 5:1, 32%). Analytical data for major
:
diastereomer: 1H NMR (400 MHz, (CD
7
(
6
aqueous solution of NaHCO
with brine solution and dried over anhydrous Na
3
, extracted with EtOAc (3×5 mL), washed
SO Combined
3 2
)
SO): δ 8.08 (s, 1H), 7.79 –
.71 (m, 2H), 7.60 – 7.52 (m, 3H), 7.31 (dt, J = 32.7, 6.4 Hz, 7H), 7.05
t, J = 7.3 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 7.4 Hz, 1H),
.71 (d, J = 7.4 Hz, 1H), 6.58 (d, J = 7.3 Hz, 1H), 5.89 (s, 1H), 5.01 (d,
J = 15.7 Hz, 1H), 4.83 (d, J = 15.7 Hz, 1H), 4.07 (d, J = 9.3 Hz, 1H),
2
4
.
organic layers concentrated and purified by silica-gel flash
chromatography using EtOAc/hexane (3:7) to afford the desired product
9a (0.125 g, 79%).
3
1
1
1
.85 (d, J = 9.3 Hz, 1H), 1.27 (s, 3H). 13C NMR (150 MHz, (CD
) SO): δ
3 2
76.2, 169.2, 143.5, 142.1, 136.1, 136.0 ,132.5, 130.4, 128.9, 128.6,
28.5, 128.3, 127.5, 127.4, 127.2, 126.6, 126.3, 123.4, 123.3, 121.3,
3-(2-Hydroxy-5-methylphenyl)-3-(hydroxymethyl)-1-methylindolin-
2-one (9a): The product was prepared by following general procedure
and was obtained as white solid (0.148g, 92% for Method A, 0.125g,
16.3, 109.1, 99.9, 73.1, 59.9, 57.6, 42.7, 20.7. HRMS (ESI-TOF) m/z:
+
-1
[M+H] Calcd for C32
H
26
N
2
O
3
487.2022; found 487.2003.
79%, for Method B). mp 159-161 °C. FT-IR (ν cm ): 3020, 2400, 1676,
1
1
215. H NMR (400 MHz, (CD
3
)
2
SO) : 9.01 (br. s, 1H), 7.17 (br. s, 2
H), 6.93 – 6.84 (m, 4H), 6.48 (d , J = 8 Hz, 1H), 4.91 (t, J = 5.0 Hz, 1H),
3
-(1-benzoyl-3-methyl-1H-indol-2-yl)-1-benzyl-3-
4
.22 (dd, J = 10.0, 5.0 Hz, 1H), 3.94 (dd , J = 9.8, 5.4 Hz), 3.13 (s, 3H),
(hydroxymethyl)indolin-2-one (5b): The compound was prepared by
13
3 2
2.27 (s, 3H). C NMR (100 MHz, (CD ) SO): 177.6, 156.2, 144.5,
following general procedure and was obtained as gummy liquid
1
137.7, 132.1, 128.6, 127.8, 127.7, 123.4, 122.1, 118.4, 112.2, 107.8,
6.2, 57.1, 26.1, 18.7. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
306.1106 ; found 306.1096.
(0.049g, 51 %) via C3-C2′ attack. H NMR (400 MHz, (CD
3
)
2
SO): δ
6
8
7
7
4
1
1
1
.30 (s, 1H), 7.68 (dd, J = 17.5, 7.0 Hz, 3H), 7.62 – 7.53 (m, 3H), 7.40 –
17 3
C H17NO
.28 (m, 6H), 7.25 – 7.16 (m, 3H), 7.07 (t, J = 7.4 Hz, 1H), 6.88 (d, J =
.7 Hz, 1H), 5.25 (t, J = 4.5 Hz, 1H), 5.04 – 4.90 (m, 2H), 4.25 (d, J =
.5 Hz, 2H), 2.18 (s, 3H). 13C NMR (150 MHz, (CD
67.7, 143.1, 136.2, 135.6, 134.9, 134.2, 131.6, 130.5, 128.5, 128.4,
27.8, 127.1, 126.9, 126.93, 125.1, 124.8, 122.5, 122.1, 118.9, 116.9,
14.5, 108.9, 65.9, 58.8, 42.7, 9.1. HRMS (ESI-TOF) m/z: [M+Na]+
3 2
) SO): δ 177.1,
1-Benzyl-3-(2-hydroxy-5-methylphenyl)-3-(hydroxymethyl)indolin-
2-one (9b): The product was prepared by following general procedure
and was obtained as white solid (0.100g, 71% for Method A, 0.095g,
-1
68% for Method B ). mp 147-148 °C. FT-IR (ν cm ): 3020, 2400, 1696,
1
Calcd for C32
H
26
N
2
O
3
509.1841; found 509.1818.
1214. H NMR (400 MHz, (CD
3
)
2
SO) :  9.12 (s, 1 H), 7.46 (br. s., 2 H),
7.36 - 7.28 (m, 2 H), 7.28 - 7.20 (m, 2 H), 7.06 (t, J = 7.6 Hz, 1 H), 6.95
(
(
4
9
d, J = 7.2 Hz, 1 H), 6.91 - 6.81 (m, 2 H), 6.66 (d, J = 7.9 Hz, 1 H), 6.54
d, J = 8.0 Hz, 1 H), 5.05 (t, J = 4.2 Hz, 1 H), 4.99 (d, J = 16.2 Hz, 1 H),
.84 (d, J = 16.1 Hz, 1 H), 4.30 (dd, J = 9.7 ,4.7 Hz, 1 H), 4.02 (dd, J =
3
-((1H-indol-3-yl)(phenyl)methyl)-3-hydroxy-1-methylindolin-2-one
(7) : The Compound was prepared according to general procedure
(Method A) and was obtained as diastereomeric mixture. From spiro-
13
.1, 6.1 Hz, 1 H), 2.24 (s, 3 H). C NMR (100 MHz, (CD
153.57, 145.04, 137.7, 132.6, 129.3, 129.2, 128.1, 127.2,
27.88, 127.81, 126.50, 124.03, 122.25, 116.09, 108.77, 66.07, 56.65,
3.82, 21.33. HRMS (ESI-TOF) m/z calcd for
[M+H]+
3 2
) SO): 
epoxyoxindole 6, compound 7 was obtained 5:1 diastereomeric mixture
white solid, 0.032 g, 45%). 1H NMR (400 MHz, CDCl
(
178.9,
1
4
(
3
):  7.29 - 7.42
3H, m), 7.26 (5H, br. s), 7.23 (1H, d, J = 7.6 Hz), 7.18 (1H, t, J = 7.7
23 3
C H21NO
Hz), 7.12 (1H, s), 7.00 - 7.08 (2H, m), 6.95 (1H, d, J = 7.9 Hz), 4.91
1H, s), 3.32 (3H, s). 1 C NMR (100MHz, CDCl
3
360.1600, found 360.1592.
(
3
): 176.5, 144.2, 136.6,
1
1
4
3
29.7, 129.1, 128.2, 127.6, 126.3, 124.8, 123.3, 122.7, 122.5, 122.3,
22.2, 119.8, 119.4, 119.2, 118.8, 111.3, 111.2, 110.8, 108.0, 62.6,
1-Allyl-3-(2-hydroxy-5-methylphenyl)-3-(hydroxymethyl)indoline-2-
one (9c): The product was prepared by following general procedure
and was obtained as white solid (0.110 g, 72% for Method A, 0.100g,
+
4.5, 29.7, 26.5. HRMS (ESI-TOF) m/z: [M+H] Calcd for C24
H
20
N
2
O
2
69.1598; found 369.1596.
-1
6
1
7
6% for Method B). mp 142-144 °C. FT-IR (ν cm ): 3019, 2399, 1692,
1
215. H NMR (400 MHz, (CD
3 2
) SO) :  9.06 (s, 1 H), 7.19 (s, 1 H),
General procedure for ring-opening reaction of spiro-
epoxyoxindoles with phenols (Method A):
.15 (t, J = 7.6 Hz, 1 H), 6.96 - 6.91 (m, 1 H), 6.91 - 6.85 (m, 2 H), 6.82
(
(
d, J = 7.8 Hz, 1 H), 6.51 (d, J = 8.1 Hz, 1 H), 5.95 - 5.70 (m, 1 H), 5.36
d, J = 17.1 Hz, 1 H), 5.14 (d, J = 10.3 Hz, 1 H), 4.96 (t, J = 4.9 Hz, 1
To a stirring solution of spiro-epoxyoxindole 1a (0.100 g, 0.570 mmol),
p-cresol 8a (0.185 g, 1.71 mmol) and 4Å molecular sieves (0.100 g) in
dry 1,2-dichloroethane (3 mL) at 0°C (immersion bath) was added TFA
H), 4.35 - 4.28 (m, 2 H), 4.25 (dd, J = 9.8 ,4.4 Hz, 1 H), 3.96 (dd, J =
1
3
9
1
1
3 2
.8 , 5.1 Hz, 1 H), 2.23 (s, 3 H). C NMR (100 MHz, (CD ) SO): 
77.8, 152.7, 144.3, 132.5, 132.4, 128.4, 128.3, 127.0, 125.8, 123.1,
21.3, 116.6, 115.2, 108.0, 65.1, 55.7, 41.7, 20.5. HRMS (ESI-TOF)
(
2 μL, 0.057 mmol). The resulting solution was stirred at the same
temperature and monitored by TLC. On completion (4 h), the reaction
was quenched with saturated aqueous solution of NaHCO , extracted
with EtOAc (3×5 mL), washed with brine solution and dried over
anhydrous Na SO . Combined organic layers concentrated and purified
+
m/z calcd for C19
H
19NO
3
[M+Na] 332.1263, found 332.1255.
3
3
2
-(Hydroxymethyl)-3-(1-hydroxynaphthalen-2-yl)-1-methylindolin-
-one (9d): The product was prepared by following general procedure
2
4
by silica-gel flash chromatography using EtOAc/hexane (3:7) to afford
the desired product 9a (0.148 g, 92%).
and was obtained as yellow solid (0.131 g, 72% for Method A, 0.120g,
-
1
6
1
4
6% for Method B). mp 170-172 °C. FT-IR (ν cm ): 3018, 2400, 1678,
215. H NMR (400 MHz, (CD
1
3 2
) SO):  9.41 (s, 1H), 7.38 - 7.28 (m,
H), 7.28 - 7.20 (m, 2H), 7.18 (d, J = 6.7 Hz, 1H), 7.13 (d, J = 8.5 Hz,
General procedure for on-water ring-
2H), 7.04 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 8.5
Hz, 2H), 5.16 - 5.04 (m, 1H), 4.99 (d, J = 15.9 Hz, 1H), 4.85 (d, J = 15.9
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
Hz, 1H), 4.17 - 4.03 (m, 2H). 13C NMR (100MHz, (CD
SO): 177.6,
3
)
2
3 2
(CD ) SO):  9.14 (s, 1 H), 9.09 (s, 1 H), 7.11 (d, J = 8.3 Hz, 1 H), 6.98
1
1
56.7, 143.3, 136.4, 131.7, 128.6, 128.2, 128.1, 127.8, 127.3, 127.1,
24.9, 122.2, 122.1, 115.4, 115.3, 109.0, 66.1, 58.1, 42.7. HRMS (ESI-
[M+Na]+ 342.1106, found 342.1098.
(d, J = 7.8 Hz, 1 H), 6.80 (d, J = 7.8 Hz, 1 H), 6.74 (s, 1 H), 6.20 (dd, J
= 2.4, 8.3 Hz, 1 H), 6.08 (d, J = 2.4 Hz, 1 H), 4.80 (t, J = 5.0 Hz, 1 H),
4.14 (dd, J = 4.8, 9.9 Hz, 1 H), 3.89 (dd, J = 5.5, 9.9 Hz, 1 H), 3.10 (s, 3
TOF) m/z calcd for C20H17NO
3
13
H), 2.19 (s, 3 H). C NMR (100MHz, (CD
3
)
2
SO): 178.5, 157.3, 155.9,
42.8, 133.0, 130.0, 128.2, 127.2, 123.9, 116.9, 107.0, 105.7, 102.9,
5.0, 55.4, 26.2, 20.8. HRMS (ESI-TOF) m/z calcd for C17 17NO
4
1
6
1-Benzyl-3-(hydroxymethyl)-3-(1-hydroxynaphthalen-2-yl)indolin-2-
H
one (9e): The product was prepared by following general procedure
and was obtained as white solid (0.111g, 71% for Method A, 0.104g,
[
M+Na]+ 322.1055, found 322.1051.
-1
6
1
7% for Method B). mp 163-165 °C. FT-IR (ν cm ): 3021, 2400, 1694,
214. 1H NMR (400 MHz, (CD
SO):  9.88 (s, 1 H), 8.12 (d, J = 8.1
3
)
2
1-Benzyl-3-(2-hydroxy-5-methylphenyl)-3-(hydroxymethyl)-5-
Hz, 1 H), 7.84 (d, J = 8.1 Hz, 1 H), 7.62 (d, J = 8.6 Hz, 1 H), 7.52 - 7.39
methoxyindolin-2-one (9j) : The product was prepared by following
(
m, 5 H), 7.34 (t, J = 6.8 Hz, 2 H), 7.31 - 7.23 (m, 1 H), 7.18 - 7.10 (m, 1
general procedure and was obtained as white solid (0.096g, 70% for
-1
H), 7.05 (d, J = 7.3 Hz, 1 H), 6.92 (t, J = 7.2 Hz, 1 H), 6.79 (d, J = 7.6
Hz, 1 H), 5.29 (br. s., 1 H), 5.14 (d, J = 15.9 Hz, 1 H), 4.86 (d, J = 16.1
Hz, 1 H), 4.36 (dd, J = 9.4 , 3.1 Hz, 1 H), 4.18 (dd, J = 9.5 , 4.2Hz, 1 H).
Method A, 0.085 g, 62% for Method B). mp 147-149 °C. FT-IR (ν cm ):
1
3020, 2404, 1699, 1211. H NMR (400 MHz, (CD
3
)
2
SO) :  9.15 (s, 1
H), 7.44 (d, J = 7.3 Hz, 2 H), 7.31 (t, J = 7.2 Hz, 2 H), 7.26 (d, J = 7.1
Hz, 1 H), 7.21 (br. s., 1 H), 6.90 (d, J = 7.8 Hz, 1 H), 6.68 - 6.62 (m, 1
H), 6.61 - 6.52 (m, 3 H), 4.96 (d, J = 16.1 Hz, 1 H), 4.82 (d, J = 15.9 Hz,
1
3
3 2
C NMR (100MHz, (CD ) SO): 178.8, 150.6, 143.8, 136.7, 133.5,
1
32.4, 128.5, 127.4, 127.3, 127.2, 125.9, 125.2, 124.8, 123.9, 122.1,
1
21.77, 120.677, 109.206, 108.4, 65.3, 56.77, 43.1. HRMS (ESI-TOF)
1 H), 4.32 (d, J = 9.8 Hz, 1 H), 3.99 (d, J = 9.8 Hz, 1 H), 3.60 (s, 3 H),
2.24 (s, 3 H). C NMR (100 MHz, (CD ) SO): 177.7, 154.9, 152.8,
3 2
[M+H]+ 396.1600, found 396.1602.
13
m/z calcd for C26
H
21NO
3
1
1
37.7, 136.9, 134.0, 128.6, 128.4, 128.4, 127.2, 127.0, 127.0, 125.5,
15.3, 111.0, 110.9, 108.1, 65.1, 56.4, 55.3, 43.0, 20.5. HRMS (ESI-
[M+H]+ 390.1705, found 390.1697.
3
(
-(2,4-Dihydroxyphenyl)-3-(hydroxymethyl)-1-methylindolin-2-one
9f): The product was prepared by following general procedure and was
obtained as white solid (0.123g, 76% for Method A, 0.110g, 69% for
TOF) m/z calcd for C24H23NO
4
-1
Method B). mp 184-186 °C. FT-IR (ν cm ): 3020, 2400, 1679, 1215.
1-Benzyl-3-(hydroxymethyl)-3-(1-hydroxynaphthalen-2-yl)-5-
methoxyindolin-2-one (9k): The product was prepared by following
general procedure and was obtained as yellow solid (0.107 g, 71% for
1
3 2
H NMR (400 MHz, (CD ) SO):  9.14 (s, 1 H), 9.10 (s, 1 H), 7.22 - 7.15
(
m, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 6.97 - 6.83 (m, 3 H), 6.20 (d, J = 8.4
-1
Hz, 1 H), 6.08 (s, 1 H), 4.82 (t, J = 4.3 Hz, 1 H), 4.17 (dd, J = 9.4, 4.2
Method A, 0.095 g, 63% for Method B). mp 151-152 °C. FT-IR (ν cm ):
13
1
Hz, 1 H), 3.91 (dd, J = 9.3, 5.3 Hz, 1 H), 3.12 (s, 3 H).
100MHz, (CD SO): 178.6, 157.4, 155.9, 145.2, 133.0, 128.3, 127.1,
23.1, 121.4, 116.9, 107.3, 105.8, 103.0, 65.1, 55.4, 26.2. HRMS (ESI-
C NMR
3021, 2406, 1696, 1211. H NMR (400 MHz, (CD
3
)
2
SO): 10.26 (s, 1
(
1
3
)
2
H), 8.13 (d, J = 8.3 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 7.51 (d, J = 7.3
Hz, 2 H), 7.42 - 7.35 (m, 2 H), 7.35 - 7.23 (m, 2 H), 6.98 (d, J = 8.6 Hz,
1 H), 6.95 - 6.87 (m, 2 H), 6.82 (d, J = 8.6 Hz, 1 H), 6.77 (dd, J = 2.4,
+
4
TOF) m/z: [M+Na] Calcd for C16H15NO 308.0899; found 308.0893.
8
4
1
1
.6 Hz, 1 H), 6.42 (d, J = 2.4 Hz, 1 H), 5.23 (t, J = 5.1 Hz, 1 H), 5.08 -
.91 (m, 2 H), 4.35 (dd, J = 5.0, 9.7 Hz, 1 H), 4.10 (dd, J = 5.7, 9.7 Hz,
1
(
-Benzyl-3-(2,4-dihydroxyphenyl)-3-(hydroxymethyl)indolin-2-one
9g) : The product was prepared by following general procedure and
was obtained as white solid (0.103, 70% for Method A, 0.089g, 61% for
13
H), 3.55 (s, 3 H). C NMR (100 MHz, (CD
3 2
) SO):  177.8, 155.4,
53.1, 136.6, 136.3, 135.1, 132.3, 128.6, 128.0, 127.5, 127.0, 126.1,
-1
125.4, 124.4, 124.0, 123.4, 122.8, 111.8, 111.0, 109.5, 107.2, 67.0,
57.8, 55.2, 43.4. HRMS (ESI-TOF) m/z calcd for C27
[M+H]+
26.1705, found 426.1694.
Method B). mp 164-165 °C. FT-IR (ν cm ): 3021, 2395, 1696, 1216.
1
H23NO
4
3 2
H NMR (400 MHz, (CD ) SO):  9.19 (s, 2 H), 7.44 (d, J = 7.4 Hz, 2
4
H), 7.35 - 7.28 (m, 2 H), 7.28 - 7.20 (m, 1 H), 7.17 (d, J = 8.6 Hz, 1 H),
7
6
.09 - 6.98 (m, 1 H), 6.94 (d, J = 7.2 Hz, 1 H), 6.86 (t, J = 7.3 Hz, 1 H),
.63 (d, J = 7.6 Hz, 1 H), 6.23 (d, J = 7.2 Hz, 1 H), 6.15 (s, 1 H), 4.99
Chloro-3-(2-hydroxy-5-methylphenyl)-3-(hydroxymethyl)-1-
(
6
(
1
5
3
d, J = 5.3 Hz, 1 H), 4.96 (br. s., 1 H), 4.90 - 4.76 (m, 1 H), 4.24 (d, J =
.0 Hz, 1 H), 3.98 (dd, J = 9.0, 4.0Hz, 1 H). 13C NMR (100 MHz,
CD SO): 178.5, 157.3, 155.9, 144.1, 136.9, 133.1, 128.4, 128.3,
27.2, 127.0, 126.8, 123.1, 121.3, 116.6, 107.8, 105.8, 102.8, 65.4,
methylindolin-2-one (9l): The product was prepared by following
general procedure and was obtained as white solid (0.109g, 72% for
-1
3
)
2
Method A, 0.09 g, 60% for Method B). mp 176-178 °C. FT-IR (ν cm ):
1
3021, 2406, 1675, 1211, 757. H NMR (400 MHz, (CD
3
)
2
SO):  9.08 (s,
5.3, 42.9. HRMS (ESI-TOF) m/z calcd for
C
22
H
19NO
4
[M+H]+
1 H), 7.25 (dd, J = 2.1, 8.2 Hz, 1 H), 7.18 (s, 1 H), 7.01 - 6.91 (m, 2 H),
6.89 (d, J = 7.9 Hz, 1 H), 6.51 (d, J = 7.9 Hz, 1 H), 5.01 (t, J = 5.0 Hz, 1
H), 4.29 (dd, J = 4.8, 9.8 Hz, 1 H), 3.92 (dd, J = 5.4, 9.8 Hz, 1 H), 3.14
62.1392, found 362.1385.
13
(
s, 3 H), 2.24 (s, 3 H). C NMR (100 MHz, (CD
3
)
2
SO): 177.7, 152.5,
1
-Benzyl-3-(2-hydroxy-5-methylphenyl)-3-(hydroxymethyl)-5-
1
1
C
44.3, 134.7, 128.5, 128.3, 127.1, 126.8, 125.3, 125.2, 123.1, 115.2,
methylindolin-2-one (9h): The product was prepared by following
08.6, 64.6, 55.8, 26.3, 20.4. HRMS (ESI-TOF) m/z calcd for
general procedure and was obtained as white solid (0.111g, 79% for
-1
1
17
H
16ClNO
3
[M+Na] 340.0716 found 340.0720.
+
Method A). mp 142-143 °C. FT-IR (ν cm ): 3022, 2398, 1697, 1214. H
NMR (400 MHz, (CD SO):  9.13 (s, 1 H), 7.45 (d, J = 7.8 Hz, 2 H),
.31 (t, J = 7.3 Hz, 2 H), 7.26 - 7.23 (m, 2 H), 6.90 - 6.85 (m, 2 H), 6.77
s, 1 H), 6.55 (t, J = 8.8 Hz, 2 H), 4.97 (d, J = 15.6 Hz, 2 H), 4.82 (d, J =
6.6 Hz, 1 H), 4.30 (d, J = 9.8 Hz, 1 H), 4.01 (d, J = 9.8 Hz, 1 H), 2.25
s, 3 H), 2.15 (s, 3 H). 13C NMR (100 MHz, (CD
SO): 178.0, 152.7,
3 2
)
7
(
1
3-(5-hydroxybenzo[d][1,3]dioxol-4-yl)-3-(hydroxymethyl)-1-
methylindolin-2-one (9m): The compound was prepared by following
general procedure (Method A) and was obtained as White solid (0.150
g , 84 % for Method A). mp 150-151 °C. FT-IR (ν cm ): 3360, 1710,
1263, 1023. H NMR (400 MHz, (CD
-1
(
3
)
2
1
141.9, 137.0, 132.6, 130.2, 128.5, 128.4, 128.3, 127.2, 127.1, 127.01,
3
)
2
SO): δ 9.04 (s, 1H), 7.19 (t, J =
1
(
27.0, 125.8, 123.9, 115.3, 107.7, 65.3, 55.8, 43.0, 20.7, 20.5. HRMS
7.6 Hz, 1H), 7.03 (s, 1H), 6.92 (dq, J = 15.4, 8.1, 7.6 Hz, 3H), 6.22 (s,
1H), 5.90 (s, 2H), 4.93 (t, J = 5.0 Hz, 1H), 4.13 (dd, J = 10.0, 4.7 Hz,
ESI-TOF) m/z calcd for C24H23NO
3
[M+H]+ 374.1756, found 374.1748.
13
1H), 3.85 (dd, J = 10.0, 5.3 Hz, 1H), 3.13 (s, 3H). C NMR (150 MHz,
(
CD SO): δ 178.0, 149.8, 146.1, 144.9, 139.5, 132.4, 127.0, 123.1,
3 2
)
3-(2,4-Dihydroxyphenyl)-3-(hydroxymethyl)-1,5-dimethylindolin-2-
1
21.2, 117.8, 107.9, 107.2, 100.6, 97.7, 64.9, 55.4, 26.1. HRMS (ESI-
one (9i) : The product was prepared by following general procedure
and was obtained as white solid (0.103 g, 73% for Method A). mp 158-
+
TOF) m/z: [M+Na] Calcd for C17
H
15NO
5
336.0848; found 336.0852.
-1
1
160 °C. FT-IR (ν cm ): 3020, 2405, 1696, 1212. H NMR (400 MHz,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
1
(
-benzyl-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-
hydroxymethyl)indolin-2-one (9n): The compound was prepared by
following general procedure and was obtained as White solid (0.127 g,
7.2 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.07 (t, J
= 5.0 Hz, 1H), 4.98 (d, J = 16.1 Hz, 1H), 4.87 (d, J = 16.1 Hz, 1H), 4.38
(dd, J = 9.8, 4.8 Hz, 1H), 4.03 (dd, J = 9.7, 5.3 Hz, 1H), 1.28 (s, 9H).
-1
13
8
1
2 % for Method A). mp 142-143 °C. FT-IR (ν cm ): 3362, 1705, 1260,
020. 1H NMR (400 MHz, (CD
SO): δ 9.14 (s, 1H), 7.44 (d, J = 7.2
3 2
C NMR (150 MHz, (CD ) SO): δ 178.1, 152.6, 144.0, 140.6, 136.8,
3
)
2
132.5, 128.3, 127.1, 126.9, 126.94 , 124.9, 124.6, 124.5, 123.3 , 121.4,
Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.10 – 7.03
m, 2H), 6.96 (d, J = 7.2 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 6.65 (d, J =
.7 Hz, 1H), 6.27 (s, 1H), 5.92 (s, 2H), 5.08 (t, J = 4.9 Hz, 1H), 4.97 (d,
J = 16.1 Hz, 1H), 4.83 (d, J = 16.0 Hz, 1H), 4.20 (dd, J = 9.9, 4.5 Hz,
114.9, 107.9, 65.1, 56.2, 42.9, 33.9, 31.5. HRMS (ESI-TOF) m/z:
+
(
7
[M+H] Calcd for C26
H
27NO
3
402.2069; found 402.2074.
3-(2-hydroxy-5-methylphenyl)-3-(hydroxymethyl)-1,5-
1
1
1
H), 3.92 (dd, J = 9.9, 5.2 Hz, 1H). 13C NMR (100 MHz, (CD
) SO): δ
3 2
dimethylindolin-2-one (9s): The product was prepared by following
general procedure and was obtained as white solid (0.108 g, 69% for
78.1, 149.9, 146.3, 144.0, 139.6, 136.9, 132.6, 128.4, 127.2, 127.0,
26.9, 123.2, 121.4, 117.6, 108.0, 107.9, 100.8, 97.7, 65.4, 55.5, 42.9.
-1
1
Method B). mp 142-144 °C. FT-IR (ν cm ): 3020, 2400 1680, 1045.
NMR (400 MHz, (CD SO) :  2.19 (s, 3 H) 2.23 (s, 3 H) 3.11 (s, 3 H),
.92 (dd, J=9.76, 4.89 Hz, 1 H),4.20 (dd, J=9.76, 4.88 Hz, 1 H) 4.87 (t,
H
HRMS (ESI-TOF) m/z : [M+H]+ Calcd for C23
H19NO 390.1341; found
5
3 2
)
390.1349.
3
J = 4.89 Hz, 1 H) 6.5-6.45 (m, 1 H) 6.75 (s, 1 H), 6.81(d, J= 8.0 Hz, 1
H) 6.85(d, J= 8.6 Hz, 1 H) 6.99 (d, J= 7.0 Hz, 1 H) 7.18 (s, 1 H) 8.99 (s,
3
-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-(hydroxymethyl)indolin-2-
13
one (9o): The compound was prepared by following general procedure
and was obtained as White solid (0.159 g, 86 % for Method A). mp
1 H). C NMR (100MHz, (CD
3 2
) SO):  178.1, 152.6, 142.9, 132.5,
130.0, 128.4, 128.2, 127.3, 126.9, 126.0, 123.9, 115.3, 107.0, 64.9,
-1
1
1
32-134 °C. FT-IR (ν cm ): 3350, 1680, 1250, 1018. H NMR (400
MHz, (CD SO): δ 10.24 (s, 1H), 9.11 (s, 1H), 7.08 (t, J = 7.6 Hz, 1H),
.02 (s, 1H), 6.90 (d, J = 7.1 Hz, 1H), 6.81 (t, J = 7.3 Hz, 1H), 6.76 (d, J
7.6 Hz, 1H), 6.24 (s, 1H), 5.90 (s, 2H), 4.95 (t, J = 5.0 Hz, 1H), 4.07
55.7, 26.2, 20.7, 20.5. HRMS (ESI-TOF) m/z calcd for C18
[M+Na] 320.1263, found 320.1258.
H
19NO
3
+
3
)
2
7
=
3-(2,4-Dihydroxyphenyl)-3-(hydroxymethyl)-1,5-dimethylindolin-2-
13
(
(
1
dd, J = 10.1, 4.6 Hz, 1H), 3.82 (dd, J = 10.1, 5.4 Hz, 1H). C NMR
100 MHz, (CD SO): δ 179.8, 150.1, 146.2, 143.3, 139.5, 133.3,
26.9, 123.7, 120.6, 117.9, 108.4, 108.2, 100.7, 97.8, 65.1, 56.0.
HRMS (ESI-TOF) m/z [M+Na]+ Calcd for C16
322.0691; found
one (9t) : The product was prepared by following general procedure
and was obtained as white solid (0.107g, 68% for Method B). mp 160-
3 2
)
-1
1
1
(
(
61 °C. FT-IR (ν cm ): 3020, 1678, 1215, 1049. H NMR (400 MHz,
CD SO):  9.14 (s, 1 H), 9.09 (s, 1 H), 7.11 (d, J = 8.3 Hz, 1 H), 6.98
d, J = 7.8 Hz, 1 H), 6.80 (d, J = 7.8 Hz, 1 H), 6.74 (s, 1 H), 6.20 (dd, J
2.4, 8.3 Hz, 1 H), 6.08 (d, J = 2.4 Hz, 1 H), 4.80 (t, J = 5.0 Hz, 1 H),
4.14 (dd, J = 4.8, 9.9 Hz, 1 H), 3.89 (dd, J = 5.5, 9.9 Hz, 1 H), 3.10 (s, 3
H
13NO
5
3 2
)
322.0699.
=
1-benzyl-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-(hydroxymethyl)-
13
5-methylindolin-2-one (9p): The compound was prepared by following
H), 2.19 (s, 3 H). C NMR (100MHz, (CD
3 2
) SO):  178.5, 157.3, 155.9,
general procedure and was obtained as White solid (0.123g, 81 % for
142.8, 133.0, 130.0, 128.2, 127.2, 123.9, 116.9, 107.0, 105.7, 102.9,
-1
Method A). mp 147-148 °C. FT-IR (ν cm ): 3355, 1690, 1251, 1015.
65.0, 55.4, 26.2, 20.8. HRMS (ESI-TOF) m/z calcd for C17
H
17NO
4
1
+
H NMR (400 MHz, (CD
3
)
2
SO): δ 9.13 (s, 1H), 7.42 (d, J = 7.2 Hz, 2H),
[M+Na] 322.1055, found 322.1051.
7
=
5
.30 (t, J = 7.3 Hz, 2H), 7.25 (d, J = 7.1 Hz, 1H), 7.07 (s, 1H), 6.86 (d, J
7.2 Hz, 1H), 6.77 (s, 1H), 6.53 (d, J = 7.9 Hz, 1H), 6.27 (s, 1H), 5.95 –
.90 (m, 2H), 5.07 (t, J = 4.9 Hz, 1H), 4.94 (d, J = 16.1 Hz, 1H), 4.81 (d,
1
(
-Benzyl-3-(hydroxymethyl)-3-(4-methoxyphenyl)indolin-2-one
10a) : The product was prepared by following general procedure and
was obtained as white solid (0.107g, 75%). mp 145-148 °C. FT-IR (ν
J = 16.1 Hz, 1H), 4.17 (dd, J = 9.9, 4.6 Hz, 1H), 3.89 (dd, J = 9.9, 5.3
Hz, 1H), 2.16 (s, 3H). 13C NMR (100 MHz, (CD
SO): δ 178.0, 149.9,
46.3, 141.7, 139.7, 137.0, 132.7, 130.2, 128.4, 127.2, 127.2, 127.1,
3
)
2
cm ): 3020, 2400, 1695, 1215, 1043. H NMR (400 MHz, (CD
.36 (d, J = 7.4 Hz, 1 H), 7.34 - 7.28 (m, 4 H), 7.28 - 7.23 (m, 3 H), 7.20
t, J = 7.7 Hz, 1 H), 7.10 - 7.01 (m, 1 H), 6.93 - 6.80 (m, 3 H), 5.15 (br.
s., 1 H), 5.00 (d, J = 16.1 Hz, 1 H), 4.86 (d, J = 16.1 Hz, 1 H), 4.14 (br.
-1
1
3 2
) SO): 
1
1
7
(
24.1, 117.8, 108.1, 107.8, 100.8, 97.8, 65.5, 55.6, 43.0, 20.8. HRMS
+
(ESI-TOF) m/z [M+H] Calcd for C24
H
21NO
5
404.1498; found 404.1508.
13
3 2
s., 2 H), 3.71 (s, 3 H). C NMR (100 MHz, (CD ) SO): 177.3, 158.4,
1-benzyl-3-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-3-(hydroxymethyl)-
143.2, 136.4, 131.5, 129.9, 128.5, 128.1, 127.8, 127.2, 127.0, 124.9,
5
-methoxyindolin-2-one (9q): The compound was prepared by
122.1, 113.9, 109.0, 65.9, 58.0, 55.1, 42.7. HRMS (ESI-TOF) m/z calcd
following general procedure and was obtained as White solid (0.116g,
for C23H21NO
3
[M+H]+ 360.1600, found 360.1590.
-1
78 % for Method A). mp 154-156 °C. FT-IR (ν cm ): 3315, 1688, 1257,
1
1010.
3 2
H NMR (600 MHz, (CD ) SO): δ 9.13 (s, 1H), 7.42 (d, J = 7.3
1
(
-Benzyl-3-(3,4-dimethoxyphenyl)-3-(hydroxymethyl)indolin-2-one
10b) : The product was prepared by following general procedure and
was obtained as white solid (0.123 g, 80%). mp 136-138 °C. FT-IR (ν
Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.25 (t, J = 7.1 Hz, 1H), 7.06 (s, 1H),
.67 – 6.62 (m, 1H), 6.62 – 6.58 (m, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.30
s, 1H), 5.92 (d, J = 9.9 Hz, 2H), 5.05 (t, J = 4.8 Hz, 1H), 4.94 (d, J =
6
(
-1
1
cm ): 3020, 2400, 1694, 1215, 1048. H NMR (400 MHz, (CD
3
)
2
SO) :
1
3
6.0 Hz, 1H), 4.81 (d, J = 16.0 Hz, 1H), 4.20 (dd, J = 9.8, 4.6 Hz, 1H),
.90 (dd, J = 9.7, 5.4 Hz, 1H), 3.62 (s, 3H). 13C NMR (150 MHz,

7
6
7.40 (d, J = 7.3 Hz, 1 H), 7.36 - 7.27 (m, 4 H), 7.27 - 7.22 (m, 1 H),
.22 - 7.16 (m, 1 H), 7.06 (t, J = 7.5 Hz, 1 H), 6.93 (d, J = 2.0 Hz, 1 H),
.91 - 6.85 (m, 2 H), 6.85 - 6.79 (m, 1 H), 5.14 (t, J = 5.0 Hz, 1 H), 4.98
3 2
(CD ) SO) δ 177.6, 154.9, 149.9, 146.3, 139.6, 137.4, 136.9, 133.9,
1
5
4
28.3, 127.1, 126.9, 117.5, 111.0, 110.9, 108.1, 100.7, 97.7, 65.3, 55.9,
(
d, J = 15.9 Hz, 1 H), 4.90 (d, J = 15.9 Hz, 1 H), 4.21 - 4.09 (m, 2 H),
.71 (s, 3 H), 3.67 (s, 3 H). C NMR (100 MHz, (CD ) SO) 177.3,
3 2
48.6, 148.2, 143.2, 136.4, 131.5, 130.4, 128.6, 127.9, 127.3, 127.1,
5.3, 43.0, 30.4. HRMS (ESI-TOF) m/z: [M+Na] + Calcd for C24
H21NO
6
3
1
1
13
42.1267; found 442.1243.
24.9, 122.1, 119.3, 111.7, 110.9, 109.0, 66.1, 58.3, 55.5, 42.7. HRMS
1-benzyl-3-(5-(tert-butyl)-2-hydroxyphenyl)-3-
(ESI-TOF) m/z calcd for C24
H23NO
4
[M+H]+ 390.1705, found 390.1698.
(hydroxymethyl)indolin-2-one (9r): The compound was prepared by
following general procedure and was obtained as White solid (0.126 g,
1
-benzyl-3-(2,4-dimethoxyphenyl)-3-(hydroxymethyl)indolin-2-one
-1
7
9 % for Method A). mp 168-170 °C. FT-IR (ν cm ): 3210, 1675, 1230,
(10c) : The product was prepared by following general procedure and
1
1096. H NMR (400 MHz, (CD
3
)
2
SO): δ 9.20 (s, 1H), 7.46 (d, J = 7.2
1
was obtained as white solid (0.125 g, 81%). H NMR (400 MHz,
Hz, 2H), 7.41 (d, J = 2.2 Hz, 1H), 7.32 (t, J = 7.3 Hz, 2H), 7.25 (t, J =
.2 Hz, 1H), 7.14 – 7.03 (m, 2H), 6.99 (d, J = 7.2 Hz, 1H), 6.87 (t, J =
(
CD
3 2
) SO) :  7.46 (d, J = 7.6 Hz, 2 H), 7.42 (d, J = 8.6 Hz, 1 H), 7.34
7
(t, J = 7.2 Hz, 2 H), 7.30 - 7.23 (m, 1 H), 7.15 - 7.02 (m, 1 H), 6.93 -
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
6
.83 (m, 2 H), 6.78 (d, J = 7.8 Hz, 1 H), 6.56 (d, J = 7.8 Hz, 1 H), 6.42
1H), 4.01 (dd, J = 10.9, 3.3 Hz, 1H), 3.24 (s, 3H), 2.28 (dd, J = 9.7, 3.6
Hz, 1H). C NMR (150 MHz, CDCl ): δ 176.99 , 143.89 , 128.90 ,
3
13
(s, 1 H), 5.13 - 4.95 (m, 2 H), 4.82 (d, J = 15.9 Hz, 1 H), 4.25 (dd, J =
1
3
1
1
0.0, 4.4 Hz, 1 H), 3.98 (dd, J = 9.4, 5.3 Hz, 1 H), 3.74 (s, 3 H), 3.20 (s,
128.81 , 126.18 , 124.62 , 123.06 , 118.69 , 108.67 , 108.08 , 107.18 ,
H). 13C NMR (101MHz , (CD
SO):  178.1, 159.7, 157.9, 144.0,
68.55 , 53.92 , 26.39 . HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
3
)
2
37.0, 132.7, 128.4, 128.2, 127.5, 127.1, 127.0, 122.9, 121.4, 120.6,
14 14 2 2
C H N O 265.0953; found 265.0940.
07.8, 104.8, 99.4, 65.3, 55.4, 55.2, 54.9, 43.0. HRMS (ESI-TOF) m/z
calcd for C24
H23NO
4
[M+H]+ 390.1705, found 390.1698.
3
(
-(hydroxymethyl)-3-(4-hydroxyphenyl)-1-methylindolin-2-one
11a): The compound was prepared by following general procedure
and was obtained as White solid (0.146g, 95% for Method A, 0.135g,
1-benzyl-3-(2,5-dimethoxyphenyl)-3-(hydroxymethyl)indolin-2-one
-1):
(10d) : The product was prepared by following general procedure and
88% for Method B). mp 170-172°C. FT-IR (ν cm 3270, 1708, 1230,
1029. H NMR (400 MHz, (CD
1
1
was obtained as white solid (0.106 g, 69%). H NMR (400 MHz,
3
)
2
SO): δ 9.38 (s, 1H), 7.35 – 7.27 (m,
(
CD
3
)
2
SO):  7.47 (d, J = 7.4 Hz, 2 H), 7.34 (t, J = 7.4 Hz, 2 H), 7.30 -
2H), 7.09 (dd, J = 7.9, 5.6 Hz, 3H), 7.02 (d, J = 7.7 Hz, 1H), 6.66 (s,
2H), 4.95 (t, J = 5.0 Hz, 1H), 4.02 (d, J = 5.1 Hz, 2H), 3.13 (s, 3H). 13
NMR (100 MHz, (CD SO): δ 177.18 , 156.49 , 144.21 , 131.47 ,
7
3
1
.23 (m, 1 H), 7.16 - 7.04 (m, 2 H), 6.96 - 6.84 (m, 2 H), 6.84 - 6.75 (m,
H), 5.15 (t, J = 5.0 Hz, 1 H), 5.06 (d, J = 16.1 Hz, 1 H), 4.81 (d, J =
6.1 Hz, 1 H), 4.27 (dd, J = 10.0, 4.7 Hz, 1 H), 3.99 (dd, J = 10.0, 5.4
SO): 
77.7, 153.3, 151.1, 144.1, 136.9, 132.2, 129.8, 128.4, 127.5, 127.2,
27.2, 123.1, 121.5, 114.9, 113.4, 112.1, 107.9, 65.1, 56.1, 55.4, 55.4,
3.0. HRMS (ESI-TOF) m/z calcd for C24
[M+H]+ 390.1705,
C
3 2
)
128.14 , 127.99 , 127.83 , 124.75 , 121.91 , 115.12 , 108.26 , 65.90 ,
13
57.88 , 26.07 . HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C16
Hz, 1 H), 3.76 (s, 3 H), 3.15 (s, 3 H). C NMR (100MHz , (CD
3
)
2
H15NO
3
1
1
4
292.0950 found 292.0931.
H
23NO
4
1
(
-benzyl-3-(hydroxymethyl)-3-(4-hydroxyphenyl)indolin-2-one
11b): The compound was prepared by following general procedure
and was obtained as White solid (0.118g, 86% for Method A, 0.11g,
found 390.1698.
-1
1
-Benzyl-3-(hydroxymethyl)-3-(2,3,4-trimethoxyphenyl)indolin-2-
81% for Method B). mp 147-149 °C. FT-IR (ν cm ): 3265, 1703, 1218,
1025. H NMR (400 MHz, (CD
1
one (10e) : The product was prepared by following general procedure
and was obtained as white solid (0128 g, 77%). 1H NMR (400 MHz,
3
)
2
SO) δ 9.42 (s, 1H), 7.36 – 7.11 (m,
9H), 7.04 (t, J = 7.4 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 8.6
Hz, 2H), 5.12 (t, J = 4.8 Hz, 1H), 4.99 (d, J = 16.0 Hz, 1H), 4.85 (d, J =
(CD
3 2
) SO):  7.47 (d, J = 7.6 Hz, 2 H), 7.38 - 7.29 (m, 2 H), 7.27 (d, J =
13
7
.1 Hz, 1 H), 7.22 (d, J = 8.8 Hz, 1 H), 7.17 - 7.01 (m, 1 H), 6.93 - 6.85
3 2
16.0 Hz, 1H), 4.18 – 4.05 (m, 2H). C NMR (150 MHz, (CD ) SO): δ
(
(
(
m, 2 H), 6.81 (d, J = 8.8 Hz, 1 H), 6.76 (d, J = 7.8 Hz, 1 H), 5.17 - 5.08
177.43 , 156.50 , 143.14 , 136.32 , 131.64 , 128.43 , 128.12 , 127.90 ,
127.63 , 127.14 , 126.95 , 124.79 , 121.99 , 115.18 , 108.85 , 65.94 ,
m, 2 H), 4.80 (d, J = 15.9 Hz, 1 H), 4.24 (dd, J = 9.7, 4.5 Hz, 1 H), 4.01
13
57.96 , 42.64 . HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22
dd, J = 9.9, 5.0 Hz, 1 H), 3.80 (s, 3 H), 3.63 (s, 3 H), 2.96 (s, 3 H).
SO): 178.1, 152.9, 151.0, 144.0, 141.7, 136.8,
33.1, 128.3, 127.4, 127.3, 127.1, 125.9, 123.2, 122.0, 121.6, 108.2,
07.0, 65.3, 60.0, 59.1, 55.8, 55.1, 43.0. HRMS (ESI-TOF) m/z calcd
[M+H]+ 420.1811, found 420.1804.
C
H19NO
3
NMR (100 MHz, (CD
1
1
3
)
2
346.1443; found 346.1449.
1-allyl-3-(hydroxymethyl)-3-(4-hydroxyphenyl)indolin-2-one (11c):
for C25H25NO
5
The compound was prepared by following general procedure and was
-1
obtained as White solid (0.127 g, 87%). mp 162-165 °C. FT-IR (ν cm ):
1
3
-(benzofuran-3-yl)-1-benzyl-3-(hydroxymethyl)indolin-2-one (10f):
3258, 1705, 1216, 1018.
3 2
H NMR (400 MHz, (CD ) SO): δ 9.41 (s,
The compound was prepared by following general procedure and was
1H), 7.33 (d, J = 6.7 Hz, 1H), 7.29 – 7.22 (m, 1H), 7.09 (dd, J = 11.2,
8.1 Hz, 3H), 6.93 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 8.7 Hz, 2H), 5.81 (ddt,
J = 17.1, 10.2, 4.7 Hz, 1H), 5.17 – 5.06 (m, 2H), 5.02 (t, J = 4.9 Hz,
1
obtained as White solid (0.117 g , 80%). H NMR (400 MHz, (CD
3
)
2
SO)
δ 7.64 – 7.57 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.40 – 7.30 (m, 5H),
.29 – 7.20 (m, 4H), 7.06 (t, J = 7.4 Hz, 1H), 6.94 – 6.85 (m, 2H), 5.43
t, J = 5.2 Hz, 1H), 5.05 (d, J = 16.1 Hz, 1H), 4.95 (d, J = 16.1 Hz, 1H),
7
1H), 4.30 (dd, J = 4.3, 2.0 Hz, 2H), 4.06 (dd, J = 4.8, 2.4 Hz, 2H). 13
NMR (100 MHz, (CD SO): δ 177.07 , 156.54 , 143.28 , 131.80 ,
C
(
4
3 2
)
1
3
.32 (dd, J = 10.0, 4.9 Hz, 1H), 4.24 (dd, J = 10.1, 5.7 Hz, 1H).
SO) δ 174.31, 153.98 ,143.18, 136.00 , 128.91 ,
28.51 , 127.59 , 127.25 , 126.94 , 124.45 , 124.30 , 122.94 , 122.44 ,
C
131.59 , 128.22 , 127.95 , 127.72 , 124.79 , 121.94 , 116.33 , 115.20 ,
+
NMR (150 MHz, (CD
1
1
3
)
2
108.87 , 65.88 , 57.95 , 41.43. HRMS (ESI-TOF) m/z: [M+H] Calcd for
C
18
H
17NO
3
296.1287; found 296.1293.
21.04 , 110.93 , 109.21 , 104.09 , 64.04 , 55.95 , 42.85 . HRMS (ESI-
+
TOF) m/z: [M+H] Calcd for C24
H
19NO
3
370.1443; found 370.1448.
3-(hydroxymethyl)-3-(4-hydroxyphenyl)indolin-2-one (11d): The
compound was prepared by following general procedure and was
obtained as White solid (0.145g , 92% for Method A, 0.135g, 88% for
Method B). mp 138-141 °C. FT-IR (ν cm-1): 3220, 1698, 1215, 1050. H
3
-(benzofuran-3-yl)-3-(hydroxymethyl)-1-methylindolin-2-one
1
(10g) : The compound was prepared by following general procedure
1
and was obtained as White solid (0.130g, 78%). H NMR (400 MHz,
3 2
NMR (400 MHz, (CD ) SO): δ 10.34 (s, 1H), 9.36 (s, 1H), 7.26 (d, J =
(
CD
3
)
2
SO) δ 7.60 – 7.56 (m, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.36 (dt, J =
.3, 3.7 Hz, 2H), 7.27 – 7.19 (m, 2H), 7.10 (d, J = 7.9 Hz, 2H), 6.81 (s,
H), 5.29 (t, J = 5.3 Hz, 1H), 4.24 (dd, J = 10.1, 5.1 Hz, 1H), 4.12 (dd, J
10.1, 5.6 Hz, 1H), 3.20 (s, 3H). 13C NMR (150 MHz, (CD
SO) δ
7.3 Hz, 1H), 7.19 (t, J = 7.1 Hz, 1H), 7.10 (d, J = 8.7 Hz, 2H), 6.98 (t, J
= 7.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 8.8 Hz, 2H), 4.94 (t,
7
1
=
1
1
5
3
13
J = 5.0 Hz, 1H), 4.00 (d, J = 5.4 Hz, 2H). C NMR (100 MHz,
(CD SO): δ 179.01 , 156.39 , 142.74 , 132.31 , 128.45 , 127.94 ,
3
)
2
3 2
)
73.82, 154.04 , 153.94 , 144.10 , 128.69 , 128.53 , 127.55 , 124.31 ,
24.10 , 122.79 , 122.20 , 120.87 , 110.85 , 108.46 , 104.05 , 64.11 ,
5.75 , 26.23 . HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C18
127.66 , 125.12 , 121.20 , 115.09 , 109.23 , 65.89 , 58.18 . HRMS (ESI-
+
TOF) m/z : [M+Na] Calcd for C15
H
13NO
3
278.0793; found 278.0774.
H15NO
3
16.0950 ; found 316.0954.
3-(hydroxymethyl)-3-(4-hydroxyphenyl)-1,5,7-trimethylindolin-2-
one (11e)
: The compound was prepared by following general
3
-(hydroxymethyl)-1-methyl-3-(1H-pyrrol-2-yl)indolin-2-one (10h):
procedure and was obtained as White solid (0.136g, 93%). mp 146-
-
1
1
The compound was prepared by following general procedure and was
obtained as Brown solid (0.106g, 77%). 1H NMR (600 MHz, CDCl
): δ
.36 (s, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.39 (t, J = 8.4 Hz, 1H), 7.20 (t, J
7.5 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.81 (t, J = 3.4 Hz, 1H), 6.12 (q,
148 °C. FT-IR (ν cm ): 3260, 1702, 1215, 1025.
H NMR (600 MHz,
3
(CD SO): δ 9.28 (s, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.92 (s, 1H), 6.84
3 2
)
9
=
(s, 1H), 6.67 (d, J = 8.7 Hz, 2H), 4.82 (t, J = 4.9 Hz, 1H), 4.03 (dd, J =
9.9, 4.9 Hz, 1H), 4.00 (dd, J = 10.0, 4.4 Hz, 1H), 3.38 (s, 3H), 2.52 (s,
13
J = 2.9 Hz, 1H), 6.01 (ddd, J = 3.7, 2.6, 1.5 Hz, 1H), 4.16 – 4.11 (m,
3 2
3H), 2.24 (s, 3H). C NMR (150 MHz, (CD ) SO): δ 177.75 , 156.26 ,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
139.47 , 132.25 , 131.62 , 130.40 , 128.74 , 127.85 , 123.13 , 118.84 ,
procedure and was obtained as White solid (0.140g, 87%). 1H NMR
1
14.97 , 65.81 , 57.15 , 28.98 , 20.40 , 18.33 . HRMS (ESI-TOF) m/z:
(400 MHz, (CD
7.7 Hz, 1H), 6.96 (t, J = 7.8 Hz, 1H), 6.87 – 6.81 (m, 1H), 6.62 (dd, J =
.5, 2.7 Hz, 1H), 6.43 (d, J = 2.5 Hz, 1H), 4.99 (t, J = 5.0 Hz, 1H), 4.16
dd, J = 9.7, 4.8 Hz, 1H), 3.95 (dd, J = 9.7, 5.4 Hz, 1H), 3.18 (s, 3H),
3 2
) SO) δ 9.28 (s, 1H), 7.36 – 7.23 (m, 2H), 7.02 (d, J =
+
[M+H] Calcd for C18
H
19NO
3
298.1443; found 298.1445.
8
(
1-benzyl-3-(hydroxymethyl)-3-(4-hydroxyphenyl)-5-
13
1.42 (s, 3H). C NMR (150 MHz, (CD
3 2
) SO) δ 177.58 , 156.08 , 144.44
methoxyindolin-2-one (11f): The compound was prepared by
,
137.70 , 132.09 , 128.54 , 127.73 , 127.64 , 123.36 , 122.05 , 118.38 ,
following general procedure and was obtained as White solid (0.114g,
6%). 1H NMR (400 MHz, (CD
112.22 , 107.77 , 66.15 , 57.08 , 26.02 , 18.64 . HRMS (ESI-TOF) m/z:
8
5
4
3
)
2
SO): δ 9.41 (s, 1H), 7.34 – 7.21 (m,
+
[M+H] Calcd for C17
H
17NO
3
284.1287; found 284.1292.
H), 7.13 (d, J = 8.2 Hz, 2H), 6.97 (s, 1H), 6.73 (dt, J = 15.4, 7.9 Hz,
H), 5.09 (t, J = 4.3 Hz, 1H), 4.96 (d, J = 16.0 Hz, 1H), 4.81 (d, J = 15.9
13
Hz, 1H), 4.11 (d, J = 4.4 Hz, 2H), 3.69 (s, 3H). C NMR (100 MHz,
CD SO): δ 177.18 , 156.53 , 155.25 , 136.54 , 136.41 , 130.02 ,
28.45 , 128.17 , 127.97 , 127.15 , 126.99 , 115.20 , 112.34 , 111.89 ,
09.19 , 65.85 , 58.43 , 55.44 , 42.70 . HRMS (ESI-TOF) m/z: [M+H]+
376.1549; found 376.1554.
3-(4-hydroxyphenyl)-1-methylindolin-2-one (13): Trisubstituted spiro-
epoxide was treated with phenol under standardised condition
Method A. The compound 13 was obtained as White solid (0.061g,
65%). H NMR (400 MHz, (CD
1H), 7.03 (dt, J = 15.1, 6.4 Hz, 3H), 6.92 (d, J = 8.4 Hz, 2H), 6.71 (d, J
=
(
1
(
1
1
3
)
2
6
1
3
)
2
SO) δ 9.39 (s, 1H), 7.30 (t, J = 7.6 Hz,
Calcd for C23
H
21NO
4
13
8.4 Hz, 2H), 4.67 (s, 1H), 3.16 (s, 3H). C NMR (150 MHz,
CD SO) δ 175.69 , 156.49 , 144.07 , 129.54 , 129.32 , 127.97 ,
27.50 , 124.32 , 122.16 , 115.39 , 108.40 , 50.40 , 26.06 . HRMS (ESI-
Calcd for C15H13NO2 262.0844 ; found 262.0823.
3 2
)
1-benzyl-3-(hydroxymethyl)-3-(4-hydroxyphenyl)-5-methylindolin-
2
-one (11g): The compound was prepared by following general
1
TOF) m/z: [M+Na]
+
procedure and was obtained as White solid (0.112g, 82%). H NMR
(400 MHz, (CD
3 2
) SO) δ 9.40 (s, 1H), 7.32 – 7.21 (m, 5H), 7.18 – 7.08
(m, 3H), 6.98 (d, J = 7.7 Hz, 1H), 6.70 (dd, J = 8.3, 3.2 Hz, 3H), 5.08 (t,
Synthesis of (S)-5-bromo-1-(1-phenylethyl)indoline-2,3-dione (18):
J = 4.8 Hz, 1H), 4.97 (d, J = 16.0 Hz, 1H), 4.82 (d, J = 16.0 Hz, 1H),
4
1
1
4
3
.10 (m, 2H), 2.26 (s, 3H). 13C NMR (100 MHz, (CD
) SO) δ 177.48 ,
3 2
(
S)-N-(1-phenylethyl)aniline (16): Compound 16 was prepared
56.49 , 140.82 , 136.41 , 131.77 , 130.93 , 128.44 , 128.32 , 127.94 ,
27.86 , 127.14 , 126.96 , 125.48 , 115.20 , 108.66 , 65.89 , 58.05 ,
23
according to literature procedure. A mixture of iodobenzene (2.8 g,
1
3.7 mmol), (S)-(-)-α-methylbenzylamine 15 (2.0 g, 16.5 mmol), K
2 3
CO
2.67 , 20.79. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23
H21NO
3
(4.5 g, 33.0 mmol), CuI (0.315 g, 1.65 mmol) and L-proline (0.38 g, 3.3
60.1600; found 360.1608.
mmol) in dry DMSO (17 mL) was heated at 80 °C for 18 h. After
completion the reaction mixture was cooled and extracted with EtOAc.
Combined organic layer was washed with brine, dried,concentrated and
3-(hydroxymethyl)-3-(4-hydroxyphenyl)-5-methylindolin-2-one
(
11h): The compound was prepared by following general procedure
purified by column chromatography to afford the desire product 16
1
1
and was obtained as White solid (0.138 g, 90%). H NMR (400 MHz,
3
(1.82 g, 56%) as yellow oil. H NMR (400 MHz, CDCl ):  7.53 - 7.51
(
CD
J = 7.1 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 8.7 Hz, 2H), 4.92
t, J = 5.0 Hz, 1H), 3.99 (d, J = 5.1 Hz, 2H), 2.27 (s, 3H). 13C NMR (150
MHz, (CD SO): δ 178.92 , 156.25 , 140.20 , 132.42 , 129.79 , 128.61 ,
27.85 , 127.79 , 125.65 , 115.00 , 108.86 , 65.75 , 58.14 , 20.77
3
)
2
SO): δ 10.24 (s, 1H), 9.35 (s, 1H), 7.11 – 7.06 (m, 3H), 6.99 (d,
(m, 2H), 7.50 - 7.45 (m, 2H), 7.39 - 7.36 (m, 1H), 7.25 - 7.23 (m, 2H),
6.80 (t, J = 7.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 2H), 4.64 (q, J = 6.7 Hz,
(
1H), 4.18 (br. s., 1H), 1.67 (d, J = 6.7 Hz, 3H). HRMS (ESI-TOF) m/z
+
3
)
2
calcd for C14
H
15N [M+H] 198.1283, found 198.1273.
1
+
3
.HRMS (ESI-TOF) m/z : [M+Na] Calcd for C16H15NO 292.0950; found
(S)-1-(1-Phenylethyl)indoline-2,3-dione (17): Compound 16 (1.32 g,
2
92.0957.
6.7 mmol) in toluene (20 mL) was added to a stirring solution of oxalyl
chloride (0.64 mL, 7.36 mmol) in toluene (15 mL ) at 0 °C. The resulting
slurry was heated to 65 °C for 2 h. After 2 h almost all the solvent was
removed by vaccuo and the residue was heated at 130 °C for 12 h. On
completion the reaction mixture was cooled, ice water was added and
extracted with EtOAc. Combined organic layer was dried, concentrated
3
-(hydroxymethyl)-3-(4-hydroxyphenyl)-5-methoxyindolin-2-one
(11i): The compound was prepared by following general procedure and
1
was obtained as White solid (0.131 g, 88%). H NMR (400 MHz,
(CD
3 2
) SO): δ 10.17 (s, 1H), 9.37 (s, 1H), 7.10 (d, J = 8.6 Hz, 2H), 6.88
(
s, 1H), 6.76 (s, 2H), 6.68 (d, J = 8.6 Hz, 2H), 4.94 (t, J = 5.0 Hz, 1H),
and purified by column chromatography to afford the product 17 (1.37
.99 (d, J = 5.0 Hz, 2H), 3.70 (s, 3H). 13C NMR (150 MHz, (CD
SO): δ
g, 82%) as red liquid. H NMR (400 MHz, CDCl
1
) :  7.69 (d, J = 7.3 Hz,
3
1
1
3
)
2
3
78.81 , 156.32 , 154.57 , 136.01 , 133.64 , 128.48 , 127.89 , 115.05 ,
1 H), 7.52 - 7.45 (m, 4 H), 7.45 - 7.34 (m, 2 H), 7.12 (t, J = 7.6 Hz, 1 H),
12.35 , 112.13 , 109.38 , 65.73 , 58.63 , 55.38. HRMS (ESI-TOF) m/z:
6.64 (d, J = 8.1 Hz, 1 H), 5.89 (q, J = 7.3 Hz, 1 H), 1.96 (d, J = 7.1 Hz, 3
+
13
[M+Na] Calcd for C16
H
15NO
4
308.0899; found 308.0904.
3
H). C NMR (100 MHz, CDCl ):  183.5, 158.1, 149.7, 138.0, 137.9,
1
28.8, 127.9, 126.5, 125.3, 123.4, 117.9, 112.4, 49.9, 16.2. HRMS
(ESI-TOF) m/z calcd for C16
H13NO
2
[M+H]+ 252.1025, found 252.1013.
3-(4-hydroxy-3-methylphenyl)-3-(hydroxymethyl)-1-methylindolin-
2
-one (11j): The compound was prepared by following general
1
procedure and was obtained as White solid (0.150g, 93%). H NMR
(S)-5-Bromo-1-(1-phenylethyl)indoline-2,3-dione (18): Compound 17
(2 g, 7.9 mmol) was taken in glacial acetic acid (40 mL) and stirred at
0 °C. Bromine (0.41 mL, 7.9 mmol) was added to the mixture dropwise
over 20 min at the same temperature. Then the reaction mixture was
heated to 25 °C. On completion (2 h), the reaction was quenched by
(
400 MHz, (CD
3
)
2
SO): δ 9.26 (s, 1H), 7.33 – 7.27 (m, 2H), 7.07 (t, J =
.5 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.99 – 6.96 (m, 1H), 6.89 (dd, J =
.4, 2.2 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 4.92 (t, J = 5.0 Hz, 1H), 4.02
7
8
(
(
d, J = 4.9 Hz, 2H), 3.13 (s, 3H), 2.04 (s, 3H). 13C NMR (150 MHz,
CD SO): δ 171.17 , 154.48 , 144.15 , 131.60 , 128.96 , 128.03 ,
27.67 , 125.11 , 124.63 , 123.55 , 121.79 , 114.32 , 108.12 , 65.82 ,
7.81 , 25.99 , 16.08 . HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
306.1106; found 306.1112.
3
)
2
addition of aqueous solution of Na
with brine solution and dried over anhydrous Na
2
S
2
O
3
, extracted with EtOAc, washed
SO .Combined
1
5
C
2
4
organic layers concentrated and purified by silicagel flash
chromatography using EtOAc/hexane (1:10) to afford the desire product
17
H
17NO
3
1
1
1
1
1
8 (2.36 g, 90 %) as red liquid. H NMR (400 MHz, CDCl
3
): δ 7.68 (br.s,
H), 7.46 – 7.32 (m, 6H), 6.45 (d, J = 8.8 Hz, 1H), 5.80 (q, J = 7.4 Hz,
3
2
-(4-hydroxy-2-methylphenyl)-3-(hydroxymethyl)-1-methylindolin-
-one (11k): The compound was prepared by following general
1
3
H), 1.87 (d, J = 7.2 Hz, 3H). C NMR (200 MHz , CDCl
3
):  182.4,
57.4, 148.4, 140.1, 137.6, 129.1, 128.2, 126.5, 119.2, 116.5, 114.1,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
50.1, 16.1. HRMS (ESI-TOF) m/z calcd for C16
H
12BrNO
2
[M+H]+
454.0835, found 454.0848.
330.0130, found 330.0128.
Chiral Spiroepoxides (19/19ʹ) :
General Procedure For spiro-
epoxyoxindole 1:
Compound 19 was prepared according to literature procedure.1, 2 In a
flame dried round bottomed flask trimethylsulphonium iodide (3.6 g,
In a flame dried round bottomed flask trimethylsulphonium iodide (2.53
g, 12.41 mmol) and cesium carbonate (8.086 g, 12.41 mmol) were
taken in dry acetonitrile (10 mL). The resulting mixture was stirred at
1
6.39 mmol) and cesium carbonate (10.67 g, 32.78 mmol) were taken
in dry acetonitrile (15 mL). The resulting mixture was stirred at 50 °C for
h under argon atmosphere. To this, a solution of 18 (1.8 g, 5.46 mmol)
1
5
0 °C for 1h under argon atmosphere. To this, a solution of N-
in dry acetonitrile (15 mL) was added slowly over 15min. After
completion of reaction (monitored by TLC), the mixture was filtered
through a celite bed. The filtrate was evaporated to dryness. The crude
product was purified by column chromatography (basic alumina) using
EtOAc/hexane (10:90) mixture as an eluent to afford the product 19/19ʹ
Methylisatin (1.0 g, 6.205mmol) in dry acetonitrile (10 mL) was added
slowly over 15min. After completion of reaction (monitored by TLC), the
mixture was filtered through a celite bed. The filtrate was evaporated to
dryness. The crude product was purified by column chromatography
(basic alumina) using EtOAc/hexane (20:80) mixture as an eluent to
(1.03 g, 55 %) as yellow gummy liquid with 1:1 diastereomeric mixture.
afford the pure product 1a (0.934 g, 86%).
Two diastereomers were separated by silica-gel column
chromatography and further purified by crystallization.
1-Methylspiro[indoline-3,2´-oxiran]-2-one (1a): The product was
prepared by following general procedure and was obtained as Pale
Data for >99:1 diastereomer of spiro-epoxyoxindole (19/19ʹ): The
1
-1
yellow solid (0.934g, 86%). H NMR (400 MHz, CDCl
3
):  7.34 - 7.47
compound was obtained as white solid. mp 150-152 °C. FT-IR (ν cm ):
019, 2400, 1731, 1215. 1H NMR (400 MHz, CDCl
(1H, m), 7.05 - 7.16 (2H, m), 6.93 (1H, d, J = 7.9 Hz), 3.60 (1H, d, J =
3
3
) : δ 7.36 (d, J = 4.5
13
6
.4 Hz), 3.45 (1H, d, J = 6.4 Hz), 3.29 (1H, s). C NMR (100 MHz,
Hz, 4H), 7.33 – 7.27 (m, 1H), 7.24 (dd, J = 8.4, 2.1 Hz, 1H), 7.20 (d, J =
CDCl ) : 171.4, 144.8, 130.2, 122.6, 122.3, 121.8, 108.6, 56.1, 53.8,
3
2
=
.0 Hz, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.86 (q, J = 7.2 Hz, 1H), 3.67 (d, J
13
26.4. HRMS (ESI-TOF) m/z: [M+H]
+
9 2
Calcd for C10H NO 176.0712;
6.7 Hz, 1H), 3.46 (d, J = 6.7 Hz, 1H), 1.83 (d, J = 7.2 Hz, 3H).
C
found 176.0709.
NMR (100 MHz, CDCl
3
): δ 171.3, 142.0, 138.4, 132.7, 128.8, 127.77,
1
26.6, 125.4, 125.3, 115.4, 112.9, 55.9, 54.5, 49.9, 16.08. HRMS (ESI-
+
TOF) m/z calcd for C17
H
14BrNO
2
[M+H] 344.0286, found 344.0288.
1-Benzylspiro[indoline-3,2´-oxiran]-2-one (1b): The product was
prepared by following general procedure and was obtained as yellow
1
solid (0.780g, 74%). H NMR (400 MHz, CDCl
3
):  7.43 - 7.34 (m, 6 H),
Data for <1:99 diastereomer of spiro-epoxyoxindole (19/19ʹ): The
-1
7.22 - 7.2 (m, 1 H), 7.16 – 7.12 (m, 1 H), 6.9 (d, J = 7.9 Hz, 1 H), 5.1 –
5.01 (m, 2 H), 3.75 (d, J = 6.6 Hz, 1 H), 3.6 (d, J = 6.6 Hz, 1 H). 13
NMR (100MHz, CDCl ):  171.8, 144.2, 135.3, 130.3, 128.8, 127.8,
27.4, 122.9, 122.6, 122.1, 109.8, 56.4, 54.2, 44.2. HRMS (ESI-TOF)
m/z: [M+H] Calcd for C16 252.1025; found 252.1019.
compound was obtained as gummy liquid. FT-IR (ν cm ): 3019, 2400,
1
C
1
732, 1216. H NMR (400 MHz, CDCl
3
): δ 7.44 – 7.26 (m, 6H), 7.23 (d,
J = 9.7 Hz, 2H), 6.47 (d, J = 8.2 Hz, 1H), 5.88 (q, J = 7.2 Hz, 1H), 3.66
d, J = 6.8 Hz, 1H), 3.48 (d, J = 6.7 Hz, 1H), 1.86 (d, J = 7.3 Hz, 3H).
3
1
(
1
3
+
H14NO
2
C NMR (100 MHz, CDCl
28.67 , 127.65 , 126.50 , 125.19 , 125.03 , 115.23 , 112.70 , 55.72 ,
4.50 , 49.68 , 16.05 . HRMS (ESI-TOF) m/z calcd for C17 14BrNO
3
): δ 170.9, 141.83 , 137.97 , 132.54 ,
1
5
[
H
2
Procedure For Spiro [indoline-3,2´-oxiran]-2-one (1c): To a stirring
solution of trimethylsulphonium iodide (1.0 g, 6.79 mmol) in dry DMF
M+H]+ 344.0286, found 344.0288.
(20 mL), sodium hydride (1.95 g, 40.77mmol) was added at 0 °C. The
resulting mixture was stirred at 25 °C for 1h under argon atmosphere to
generate sulphur ylide. After 1h the reaction mixture was stirred at -
3
-(2-Hydroxy-5-methylphenyl)-3-(hydroxymethyl)-1-(1-
phenylethyl)indolin-2-one (20) : To a stirring solution of 19/19′ (dr
99:1) or ( dr >1:99) (0.100 g, 0.29 mmol) and p-cresol (0.094 g, 0.87
2
0 °C. To this solution isatin (1.0 g, 6.796 mmol) in dry DMF (20 mL)
was added dropwise over 30 min. After completion of reaction
monitored by TLC), the mixture was filtered through a celite bed and
>
mmol) in dry 1,2-dichloroethane (4 mL) at -10 °C (immersion bath) was
added scandium triflate (0.014 g, 0.029 mmol) or TFA (2 μL, 0.029
mmol). The resulting solution was stirred at the same temperature and
monitored by TLC. On completion (3 h), the reaction was quenched
with saturated aqueous solution of NaHCO
washed with brine solution and dried over anhydrous Na
(
evaporate to dryness. The crude product was purified by column
chromatography (basic alumina) using EtOAc/hexane (20:80) mixture
as an eluent to afford the pure product (0.757g, 70%). 1H NMR (400
3
, extracted with EtOAc,
4
SO .
MHz, (CD
3 2
) SO): δ 10.80 (br. s, 1H), 7.31 - 7.16 (m, 1H), 7.14 - 7.13
2
(
m, 1H), 7.01-6.98 (m, 1H), 6.94 (d, J = 8 Hz, 1H), 3.58 (d, J = 6.8 Hz,
Combined organic layer was concentrated and purified by silicagel flash
chromatography using EtOAc/hexane to afford the product 20 (0.092 g,
13
1
H), 3.35 (d, J = 6.8 Hz, 1H). C NMR (100MHz, (CD
143.4, 130.4, 122.9, 121.9, 110.6, 110.5, 56.3, 53.3. HRMS (ESI-TOF)
m/z: [M+H] Calcd for C H NO 162.0555; found 162.0550.
3 2
) SO): δ 172.7,
-
1
7
3
0%) as gummy liquid with 1:1 diastereomeric mixture. FT-IR (ν cm ):
1
+
683, 3598, 3019, 2925, 2400, 1678, 1602, 1476, 1424, 1215, 757. H
9
7
2
3
NMR (400 MHz, CDCl ): δ 10.02 (s, 1H), 9.94 (s, 1H), 7.41 – 7.37 (m,
2
2
2
5
1
6
1
1
1
1
H), 7.35 (d, J = 6.0 Hz, 2H), 7.31 (q, J = 3.5, 3.1 Hz, 5H), 7.25 (d, J =
Procedure for 1-methyl-3´-phenylspiro[indoline-3,2´-oxiran]-2-one
(6): mixture of N-Methylisatin (1.0 g, 6.21 mmol), S-
.9 Hz, 2H), 7.15 (td, J = 7.0, 6.3, 3.8 Hz, 3H), 7.01 (dd, J = 8.1, 2.2 Hz,
H), 6.95 – 6.89 (m, 4H), 6.63 – 6.57 (m, 2H), 5.93 (q, J = 7.2 Hz, 1H),
.81 (q, J = 7.4 Hz, 1H), 4.88 (t, J = 10.0 Hz, 1H), 4.78 (t, J = 9.8 Hz,
H), 4.11 (dt, J = 10.3, 3.2 Hz, 2H), 2.19 (s, 6H), 1.83 (t, J = 7.4 Hz,
A
benzyltetrahydrothiophenium bromide ( 3.22 g, 12.41 mmol) in DMF (25
mL) was stirred for 10 minutes at -20 °C. To this mixture sodium
hydride (0.893 g, 18.61 mmol) were added. The resulting solution was
stirred at the same temperature and monitored by TLC. On completion
(1 h), the reaction was quenched with saturated aqueous solution of
NH4Cl, extracted with EtOAc, washed with brine solution and dried
H). 13C NMR (100 MHz, CDCl
): δ 180.4, 180.2, 153.8, 153.8, 141.8,
3
38.4, 129.9, 129.6, 129.5, 129.4, 129.2, 129.17, 129.1, 128.6, 128.5,
28.1, 128.07, 127.3, 126.4, 125.4, 122.7, 122.6, 121.2, 121.0, 118.95,
18.90, 111.8, 111.5, 65.2, 65.2, 65.2, 59.1, 58.9, 49.8, 49.1, 20.6,
2 4
over anhydrous Na SO . Combined organic layers concentrated and
purified by silicagel flash chromatography (15% EtOAc-hexane) to
6.3, 15.7. HRMS (ESI-TOF) m/z calcd for
C
24
H
22BrNO
3
[M+H]+
afford the tri-substituted spiro-epoxyoxindole 6 (cis/Trans =1:1).The
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801524
FULL PAPER
compound was obtained as yellow solid (0.704 g, 45%). 1H NMR (400
2030; c) E. C. Linton and M. C. Kozlowski, J. Am. Chem. Soc. 2008,
130, 16162-16163; d) T. A. Duffey, S. A. Shaw and E. Vedejs, J. Am.
Chem. Soc. 2009, 131, 14-15.
MHz, CDCl
3
): δ 7.50 – 7.38 (m, 5H), 7.33 – 7.27 (m, 1H), 6.89 (dt, J =
7
0
1
1
.8, 0.8 Hz, 1H), 6.79 (td, J = 7.6, 1.0 Hz, 1H), 6.49 (ddd, J = 7.5, 1.3,
.6 Hz, 1H), 4.85 (s, 1H), 3.33 (s, 3H). 13C NMR (100MHz, CDCl3): δ
71.7, 145.2, 133.2, 130.1, 128.6, 128.4, 126.7, 123.6, 122.4, 120.9,
08.6, 65.0, 61.6, 26.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
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European Journal of Organic Chemistry
10.1002/ejoc.201801524
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All-Carbon Quaternary Centre*
Saumen Hajra,[a]* Subrata Maity, #[a,b]
Sayan Roy,#[a] Ramkrishna Maity[a] and
Srikrishna Samanta[a]
Page No. – Page No.
Brønsted acid promoted highly regioselective intermolecular Friedel-Crafts (F-C)
reactions of spiroepoxyoxindoles with arenes and heteroarenes has been
developed in organic solvent as well as in aqueous medium for the efficient
synthesis of 3-aryl/heteroaryl-3-hydroxymethyl oxindoles with all-carbon quaternary
centre, which are advanced and versatile precursors for a wide range of indole
alkaloids.
Brønsted Acid Promoted
Regioselective C-3 Arylation and
Heteroarylation of Spiro-
epoxyoxindoles for the Construction
of All Carbon Quaternary Centres: A
Detailed Study
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