Zinc-mediated synthesis of 3-alkynyl-3-hydroxyindolin-2-ones by addition of iodoalkynes to isatins

Article abstract of DOI:10.1016/j.tetlet.2016.11.124

An efficient and economical method was developed for synthesis of 3 alkynyl-3-hydroxyindolin-2-ones by addition of iodoalkynes to isatins using zinc dust.

Full text of DOI:10.1016/j.tetlet.2016.11.124

Accepted Manuscript
Zinc-mediated synthesis of 3-Alkynyl-3-hydroxyindolin-2-ones by addition of
iodoalkynes to isatins
Vinay K. Singh, Abhishek Upadhyay, Rana Krishna Pal Singh
PII:
S0040-4039(16)31615-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.124
TETL 48410
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 October 2016
25 November 2016
29 November 2016
Please cite this article as: Singh, V.K., Upadhyay, A., Krishna Pal Singh, R., Zinc-mediated synthesis of 3-
Alkynyl-3-hydroxyindolin-2-ones by addition of iodoalkynes to isatins, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.11.124
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2
Graphical Abstract
Zinc-mediated synthesis of 3-Alkynyl-3-hydroxy
indolin-2-ones by addition of iodoalkynes to isatins
Leave this area blank for abstract info.
Vinay K. Singh, Abhishek Upadhyay, Rana Krishna Pal Singh*
O
R3
HO
Zn, THF, 60oC
4-5 h, 75- 91 %
R3
I
O
R2
R2
O
N
R1
N
R1

1
TetrahedronLetters
Zinc-mediated synthesis of 3-Alkynyl-3-hydroxyindolin-2-ones by addition of
iodoalkynes to isatins
Vinay K. Singh, Abhishek Upadhyay, Rana Krishna Pal Singh*
Electrochemical laboratory of green synthesis, Department of Chemistry, University of Allahabad, Allahabad 211002, India
 Corresponding author. Tel.: +91 532 2465287; fax: +91 532 2460533; E-mail address: rkp.singh@rediffmail.com (R.K.P.Singh)
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient and economical method was developed for synthesis of 3 alkynyl-3-hydroxyindolin-2-ones by addition
of iodoalkynes to isatins using zinc dust.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Two component reaction,
C-C bond formation
Isatin
Nucleophilic addition reaction
zinc mediated
Over the past 3 decades, the development of transition metal
catalyzed cross-coupling reactions has revolutionized techniques
for the formation of carbon–carbon bonds. 3-substituted 3-
hydroxyl-2-oxindole is an important structural unit which exists
in many natural products showing diverse biological activities
such as potent antioxidant, anticancer, anti-HIV, and
neuroprotective properties.1 It is present in many drugs such as
dioxibrassinine, maremycin B, and SM-130686 (Figure 1)2. This
is important structural motif in proteasome inhibitors like TMC-
95A/B.3 Literature surveys revealed that various derivatives of 3-
hydroxyoxindole moiety were also found in various alkaloids
such as donaxaridine, dioxibrassinine, welwitindolinone C, and
3-hydroxyglucoisatisin.4
to unsaturated bonds have been reported. In these studies, the
additions of organozinc to aldehydes are one of the most reliable
processes and thus gain much attention from chemists. Low cost,
minimum toxicity prompted us to use zinc mediated reaction for
C-C bond formation.
O
R3
HO
Zn, THF, 60oC
4-5 h,75- 91 %
R3
I
O
R2
R2
O
N
R1
N
R1
Scheme 1. Synthesis of 3-hydroxy-3(alkynyl) indol-2-one.
Zinc is a cheap and commercially available catalyst
with high tolerance to air and moisture. In this context zinc
mediated reaction is important for the extension of C-C bond. To
our knowledge, no examples of zinc-catalyzed nucleophilic
addition of iodoalkynyl to isatins to form 3-hydroxy-3(alkynyl)
indol-2-one has been reported in literature. Herein, we would like
to report for the first time preparation of 3-hydroxy-3(alkynyl)
indol-2-one by zinc dust under very mild condition.
S
O
H
Br
HO
SMe
NH
S
R
HO
NH
O
HO
O
HN
O
H
O
N
H
Br
N
N
Convolutamydines A-E
H
R
In 1963, Ried reported the synthesis of 3-hydroxy-3-
Maremycin B
Dioxibrassinine
A: R= CH2COCH3
B: R= CH2CH2Cl
C: R= CH3
(antibiotic)
(phenyl-ethynyl) indol-2-one for the first time, with a low yield
of 28%.11 Hao and co-workers reported the addition of terminal
Figure 1. Biologically active 3-hydroxyl- 2-oxindole
alkynes to isatins, and
a series of achiral 3-alkynyl-3-
hydroxyindolin-2-ones were prepared in moderate yields in the
presence of a zinc reagent as a promoter.12 In recent years
addition of terminal alkynes to isatins using transition metals
attracted the organic chemists and several methods have been
disclosed.13 As a part of our ongoing effort towards the synthesis
of medicinally important molecules.14 We are demonstrating here
a zinc mediated new protocol for the synthesis of 3-hydroxy-
3(alkynyl) indol-2-one.
Furthermore, isatin is a versatile synthetic intermediate for
biologically active compound which served as scaffold in a
number of natural and synthetic substituted indoles.
Isatins with their multifunctionality and diversity of
transformations are synthetically versatile substrates and many
efforts have been made toward the synthesis of these compounds.
Addition of alkynyl halides to carbonyl compounds is a direct
chain extension reaction.5 Many novel protocols involving the
use of transition-metal catalysts, such as iridium,6 rhodium,7
zinc,8 cobalt,9 and copper,10 for the addition of terminal alkynes
In this letter, we describe the addition of iodoalkynyl to
isatin and (N-substituted) isatins promoted by zinc without

2
Among THF and Et2O, THF is best solvent in which we get
maximum yield.
employing specific ligands to form 3-hydroxy-3-(alkynyl)indol-
2-one analogues.
Table 1: Optimization of reaction conditionsa
We were pleased to find that reaction works with all
types of isatins (Table 2, entries 3a-3p).
OH
O
Zinc dust
I
O
N
O
THF
N
2a
Table 2
1a
3a
Substrate scope for the preparation of 3-hydroxy-
3(alkynyl) indol-2-one
O
HO
R3
R2
Entry
Zn (Mole)
Solvent
Temp
Yield (%)
R2
Zinc dust
THF
I
R3
O
O
N
N
R1
R1
3a-3p
a-c
2
1
1
0.10
0.10
0.50
1.0
5.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
THF
0 oC
rt
n.d.
10
2
THF
HO
HO
HO
3
THF
rt
20
O
O
O
N
N
4
THF
rt
30
N
H
3b
4 h, 89%
3c
4 h, 88%
3a
4 h, 90%
5
THF
rt
30
6
THF
60 oC
35 oC
80 oC
80 oC
60 oC
80 oC
80 oC
80 oC
80 oC
80 oC
30 oC
90
MeO
7
Et2O
70
OH
OH
HO
8
Benzene
Dioxane
Xylene
Toluene
DMF
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
O
N
N
O
O
N
9
3f
4 h, 91%
10
11
12
13
14
15
16
3e
4 h, 90%
3d
4 h, 89%
CH3CN
Methanol
DMSO
CH2Cl2
HO
Cl
HO
HO
O
N
O
O
N
N
Bn
CF3
3i
3g
3h
4 h, 91%
4 h, 87%
4 h, 89%
HO
a
HO
HO
All reactions were run with 1a (1.0 mmol), 2a (1.0 mmol), and Zn (0.1-5
mmol) in various solvents (3 mL) under different temperature in a 10 mL r.b.
flask for 4 - 5 h and reaction mixture was monitored by TLC.
O
O
O
N
H
N
N
CF3
CF3
F
Cl
3j
3k
4 h, 91%
4 h, 90%
Initially, we selected 1-ethylindoline-2,3-dione (1a) and
Iodoethynyl benzene (2a) as the model starting materials to
optimize the reaction. It was found that amount of zinc and
solvent played crucial role in the reaction, from (Table 1 entries
3l
4 h, 91%
Ph
HO
N
HO
N
HO
o
F3CO
I
1-16). Reaction mixture was initially tested at 0 C no product
O
O
O
N
was obtained (Table 1 entry 1), when the reaction was warmed to
room temperature with 0.1 mmol of zinc, 10% of product was
formed (Table 1 entry 2). Addition of zinc to reaction mixture
improves the yield up to 30 % (Table 1, entries 3-5).
3o
3n
4 h, 90%
3m
5 h,81%
4 h, 91%
a For experimental procedure, see supporting information.
b All compounds are known and were characterized by comparison of their
spectral data with those reported in the literature13.
After screening the amount of zinc it is worthy to note
that zinc loading failed to promote the reaction yield under room
temperature (Table 1, entries 4-5). However when the reaction
was refluxed with zinc in THF for 4h gave the product with 90 %
yield (Table 1, entry 6). Thus, one equivalent of zinc was
necessary to obtain optimum yields in this transformation. With
the success of this reaction, we studied the scope and generality
of this transformation. We attempted similar transformation in
various solvent such as diethyl ether, benzene, dioxane, xylene,
toluene, DMF, acetonitrile, benzene, DMSO, CH2Cl2 among
these solvent (Table 1, entries 6-16), we found that THF and
Et2O were solvents in which reaction proceeded. The reaction did
not proceed in CH3CN, DMSO or DMF and the starting materials
were recovered even after heating the solution upto 80 oC for 6 h.
c Yields of isolated pure compounds 3a.
The scope of iodoalkynes and isatins were also
examined (Table 2 entries 3a-3p), it is observed that when
Iodoethynyl benzene is used as alkylating agent we found good
yield. However when 1-iodo-1-hexyne is used as alkylating agent
we found poor yield (Table 2 entriey 3p). Mechanistically, we
believe that zinc inserts into the iodoalkyne forming alkynyl zinc
iodide which coordinates with oxygen and activate the carbonyl
group, facilitating nucleophilic addition yielding 3-hydroxy-3-
(alkynyl)indol-2-one.

3
(7)
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.
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Marco, A. Adv. Synth. Catal. 2013, 355, 1071; (h) Smirnov, P.;
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Marek, I. Angew. Chem., Int. Ed. 2013, 52, 13717.
Zn
O
R3
ZnI
R3
I
THF
R2
R3
O
N
R1
OH
R3
R3
R2
ZnI
O
R2
O
ZnI
O
N
R1
(8)
R2
O
O
N
N
H2O
R1
R1
Scheme 2. A plausible mechanism for the formation 3-
hydroxy-3-(alkynyl)indol-2-one.
(9)
(a) Nishimura, T.; Sawano, T.; Ou, K.; Hayashi, T. Chem. Commun.
2011, 47, 10142; (b) Sawano, T.; Ashouri, A.; Nishimura, T.;
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Sawano, T.; Ou, K.; Nishimura, T.; Hayashi, T. J. Org. Chem. 2013,
78, 8986.
In conclusion, we developed a highly efficient method
for the formation of 3-hydroxy-3-(alkynyl)indol-2-one. It is easy
and safe to handle at a large scale synthesis for preparation of the
final product.
(10)
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Chan, A. S. C. Angew. Chem., Int. Ed. 2003, 42, 5057. (b) Knopfel,
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Acknowledgments
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectra. Vinay K. Singh is grateful
to UGC, New Delhi, for the award of a DS Kothari postdoctoral
fellowship award No. F.4-2/2006 (BSR)/CH/14-15/0020 and A.
Upadhyay thanks UGC for financial support.
Supplementary data
Supplementary data (detailed experimental procedures,product
characterization, and NMR spectra of the products) associated with this
article can be found,in the online version,at http://
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4
Highlights of the paper:
 C–C bond formation reaction is a very
important transformation in organic chemistry.
 3-substituted 3-hydroxyl-2-oxindole showing
tremendous biological activity.
 Zinc dust is stable at low temperature, high
temperature and room temperature.
 Zinc has high tolerance of air and moisture easy
to handle in the reaction.
 Clean reaction conditions and an easy workup
procedure make this an attractive protocol.