Copper(II) Triflate Catalyzed Regioselective and Enantioselective Propargylation of Isatin Derivatives by Using Allenylboronic Acid Pinacol Ester

Article abstract of DOI:10.1002/ejoc.201701745

We report a simple protocol for the synthesis of homopropargyl alcohols with isatin derivatives under milder conditions for the first time. The excellent regioselectivity and yields were observed with copper triflate as a Lewis-acid catalyst and allenylboronic acid pinacol ester as a nucleophile in aqueous media. A gram-scale synthesis was done to check the efficiency of the protocol with retention in selectivity. Further one-step functionalization of these homopropargyl alcohols was established as the synthetic application of these alkynes. The enantioselective synthesis of these chiral propargyl alcohols has also been explored for the first time with an enantiomeric ratio up to 12:88.

Full text of DOI:10.1002/ejoc.201701745

A Journal of
Accepted Article
Title: Copper(II) triflate catalyzed regioselective and enantioselective
propargylation of Isatin derivatives using Allenylboronic acid
pinacol ester
Authors: NAVEEN GUPTA, Rajkumar Tak, Mohz Nazish, Ajay Jakhar,
Noor-ul H. Khan, and Rukhsana I. Kureshy
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701745
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European Journal of Organic Chemistry
10.1002/ejoc.201701745
FULL PAPER
Copper(II) triflate catalyzed regioselective and enantioselective
propargylation of Isatin derivatives using Allenylboronic acid
pinacol ester
Naveen Gupta,[a,b] Rajkumar Tak,[a,b] Mohd Nazish,[a,b] Ajay Jakhar,[a,b] Noor-ul H. Khan,*[a,b] and
Rukhsana I. Kureshy,[a,b]
Abstract: We report
a
simple protocol for the synthesis of
biological activity of great interest. These active moieties form a
core skeleton of many active alkaloids.[16] Our group also reported
homopropargyl alcohols with isatin derivatives under milder
conditions for the first time. The excellent regioselectivity and yields
were observed using copper triflate as a Lewis acid catalyst and
allenylboronic acid pinacol ester as a nucleophile in aqueous media.
The gram level synthesis was done to check the efficiency of the
protocol with retention in selectivity. Further one-step functionalization
of these homopropargyl alcohols was established as the synthetic
application of these alkynes. The enantioselective synthesis of these
chiral propargyl alcohols also been explored for the first time with an
enantiomeric ratio up to 12:88.
[17]
oxindole derivatives as potential antibacterial agents.
In this
direction Nair et al. in 2003,[ first reported the Barbier type
propargylation of isatin derivatives but this required toxic bromide
source and use of less economical Indium[18] required in
stoichiometric amounts under strictly anhydrous conditions. The
regioselectivity was satisfactory with fewer substrate scope. Later
in 2005 Alcaide et al.,[19] made little advancement in the protocol
using the similar strategy in aqueous media with limited substrate
scope. On the other hand, the racemic and enantioselective
addition of alkynes to isatin is well explored.[ However, terminal
end capping of the alkynes limits its further functionalization to get
oxindole and spiroxindole derivatives. These alkynes and
alcohols can help further functionalization of this oxindole
molecules.[ Due to it’s importance in the total synthesis of
natural products, these molecules inspired us to functionalize the
isatin derivatives with propargyl group to circumvent the
limitations of the earlier reports.
14]
20]
Introduction
21]
Homopropargylic alcohols derived from ketone or aldehyde
constitutes are present as a fundamental structural entity in many
of the bioactive compounds.[1] These molecules are key synthons
of active natural products[2] aiding in the synthesis of complex
molecules like rhizopodin the bongkrekic acids.[3] The
advancements made so far in the development of the new
Accordingly, we have outlined a simple, cost-effective protocol for
regioselective propargylation of isatin derivatives using
allenylboronic acid pinacol ester as a nucleophile with copper as
a Lewis acid catalyst[9a, 9b, 9d, 22] in aqueous media. The exciting
methodology for functionalized tertiary alcohols use
a
stoichiometric amount of propargyl metal species.[1c, 4] However,
recent trends in this area of organic transformation reactions have
used allenylboronic acid pinacol ester[5] as the starting material for
[23]
properties were observed in aqueous media, like high reactivity,
high yields, low reaction time even though the isatin derivatives
were not soluble in the reaction media. Purification was affected
by simple filtration through a cotton plug of silica for the removal
of metal salt. The protocol developed is high atom efficient,
yielded propargyl alcohols in excellent yields with high
regioselective
organocatalyst
propargylation
and
allenylation
using
[
5b, 5e, 6]
and different metals viz. Ag, Zn,[8] Cu[9] as
[7]
Lewis acids.[ However, the site selection for the formation of
propargyl and allenyl substitutes remain a challenging task owing
to the formation of stable allenyl and less stable propargyl
intermediates.[11] With these upsurge developments for
regioselective and enantioselective propargylation, the substrate
10]
regioselectivity without the aid of any ligand precursor which is
required for site selection for ketones.[9a, 9c] The enantioselective
synthesis of propargylic alcohols is also explored with retention in
regioselectivity with enantiomeric ratio up to 15:85 To the best of
our knowledge, this general catalytic protocol for the
regioselective propargylation of isatins using allenylboronic acid
pinacol ester has not been reported before.
[
5e, 8b, 9a, 12]
ketones,[1a, 7a,
scope has been restricted to aldehydes,
1
2]
[7b, 9d, 12-13]
and keto esters.[5b] However, the
imines,
regioselective and enantioselective propargylation of isatin, i.e.,
alpha-keto lactams have rarely been explored.[14]
More importantly, propargylation of isatin derivatives[15] furnishes
3-Substituted 3-hydroxyindolin-2-ones which possess diverse
Results and Discussion
Our initial investigation involved the catalytic run of isatin 1a and
allenylboronic acid pinacol ester 2a (Table 1). Under neat
conditions for 24 h, no traces of products were observed (Table 1,
[
[
a]
b]
N. Gupta, R. Tak, A. Jakhar, Dr. N. H. Khan, Dr. R. I. Kureshy
Inorganic Materials and Catalysis Division
CSIR-Central Salt and Marine Chemicals Research Institute
G. B. Marg, Bhavnagar-364 002, Gujarat, India
E-mail: khan251293@yahoo.in
N. Gupta, R. Tak, A. Jakhar, , Dr. N. H. Khan, Dr. R. I. Kureshy
Academy of Scientific and Innovative Research
CSIR-Central Salt and Marine Chemicals Research Institute
G. B. Marg, Bhavnagar-364 002, Gujarat, India
2
entry 1). However, when 10 mol % CuCl was used for the same
catalytic run, the reaction was sluggish with a low yield of
propargyl alcohol (Table 1, entry 2). Intrigued by the results
obtained, we screened different metal source to explore the
reactivity and effects of metals salt on the propargylation of isatin
derivatives. Use of CuCl showed some success regarding
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European Journal of Organic Chemistry
10.1002/ejoc.201701745
FULL PAPER
selectivity and yield (Table 1, entry 3). Therefore with this little
success, we screened copper metal with different counterions.
With the use of acetylacetonate as counterion, the regioselectivity
of the propargyl alcohols was retained compared to fluoride ion
conditions, therefore in this protocol we preferred the use of
copper salts over silver for regioselective and enantioselective
propargylation of isatin derivatives.
(
Table 1, entry 4) with an increase in the yield (Table 1, entry 5).
Table 2 Screening of solvents[a]
Table 1 Screening of metal source for propargylation of Isatin derivatives[a]
Entry
Solvent
Dioxane
Time
Propargyl:
Allene[
Yield %[c]
b]
Entry
Lewis Acid
-
mol
%
Conversion
%
Time
Propargyl:
Allene[
Yield
%
b]
[c]
1
2
2 h
2 h
nd
nd
68
1
2
3
4
5
6
7
8
9
-
-
24 h
3 h
nd
-
Ethyl
acetate
85:15
CuCl
CuCl
2
10
10
10
10
10
10
10
10
10
10
5
35
92:8
95:5
93:7
94:6
99:1
97:3
>99:1
98:2
>99:1
>99:1
>99:1
93:7
25
43
65
80
99
99
99
95
98
30
99
80
3
4
5
6
7
8
9
MTBE
MeOH
DCM
2 h
2 h
2 h
2 h
20 m
2 h
1 h
90:10
95:5
96:4
98:2
100
35
92
40
30
99
20
99
52
3 h
CuF
2
75
3 h
Cu(acac)
2
95
3 h
Toluene
Cu(OAc)₂
100
100
100
100
100
40
1 h
2
H O
Cu(OTf).Tol
1 h
ACN
THF
80:20
100
Cu(OTf)
CF CO Ag
AgOTf
AgNO
2
30 m
40 m
30 m
1 h
3
2
[
a] Solvent 2 ml, RT, isatin 1a (0.5 mmol), 2a allenyl boronic pinacol ester (1.2
10
11
12
13
1
equiv.); [b] Selectivity determined by HPLC and H NMR; (MTBE-Meta tert-Butyl
Ether; DCM- Dichloromethane; ACN-Acetonitrile); [c] Isolated yield
3
Screening of solvents under the above optimized condition
revealed that the site selection was affected by polar solvent and
nonpolar solvents with no specific trend. Site selectivity was
adversely affected when ethyl acetate, MTBE, and acetonitrile
used as a solvent (Table 2, entries 2, 3 and 8). Whereas methanol,
DCM, and Toulene were shade better (Table 2, entries 4-6).
However, these results could not compete with water (Table 2,
entry 7) except for THF (Table 2, entry 9) with similar results
which suffered a little more prolonged reaction time. Fast reaction
rate could be attributed to the fact that transmetallation (B/Cu
exchange)[11] occurred rapidly in aqueous media owing to its high
solubility in water forming stable allenyl intermediate to afford
propargyl alcohols in high yields.
Cu(OTf)
2
2
100
100
1 h
Cu(OTf)
2
2.5 h
[
(
a] Solvent THF 2 ml, Isatin 1a (0.5 mmol), Allenylboronic acid pinacol ester 2a
0
1.2 equivalent), RT: Room temperature 25 C; [b] Selectivity determined by
1
HPLC and H NMR; [c] Isolated yield of propargyl alcohol 3aa
Under similar conditions, we found that copper acetate furnished
excellent with less reaction time (Table 1, entry 6). Copper II
triflate (Table 1, entry 8) was found to be best in comparison to
copper I triflate as site selection was little less 97:3 for propargyl
alcohol (Table 1, entry 7). Silver salts are also known to catalyze
the propargylation of ketones only with the aid of ligands for site
selection.[7a] However, with an isatin derivative screening of silver
metal source, revealed that propargylation occurred with high
regioselectivity in each case (Table 1, entries 9, 10 and 11), albeit
poor yield with silver nitrate salt (Table 1, entry 11). This behavior
of silver and copper showed that the counter ions are assisting in
the reactivity and nature of metal in the regioselectivity. Lowering
of catalyst loading to 5 mol % did not affect the regioselectivity but
the reaction time was increased up to 1 h (Table 1, entry 12).
Furthur decrease in the catalyst loading to 2 mol% affected the
site selectivity as well as yield (Table 1, entry 13). So the optimum
catalyst loading was 5 mol%. Since copper metal is economical
and practically viable than silver and also not requiring stringent
With the optimized condition in hand (5 mol% of copper II triflate
and using 2a nucleophile in H O as a green solvent, we
2
investigated the different N-protected and unprotected isatins.
With unprotected isatins irrespective of the electron donating and
electron withdrawing groups the reaction completed within 30 m
with excellent yields (Table 3, entries 1-11). However, substitution
at N1 with allyl, phenyl, and methyl could complete the reaction
within 10-15 m (Table 3, entries 12, 13 and 14). Furthur
substitution on the aromatic ring with electron donating and
electron withdrawing groups with substituted N1 group required
little more time for completion (Table 3, entries 15 -18). Changing
the bulkiness at the N1 position to trityl group still affected only in
the reaction time (Table 3, entry 21) when compared with benzyl
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European Journal of Organic Chemistry
10.1002/ejoc.201701745
FULL PAPER
substitution (Table 3, entries 19 and 20). We have found that all
the substrates with either electron withdrawing or electron
donating groups reacted well with 2a to yield propargyl alcohols
in high yields and selectivity. The site selection was retained in all
the cases irrespective of the substituents. To explore the practical
utility of this protocol gram level reaction was also carried out with
excellent yields and retention in selectivity. After the successful
synthesis of the propargyl alcohols, we explored the synthetic
utility of the terminal alkyne 3aa Scheme 1 In the presence of 2
mol% of palladium catalyst and 10 mol% copper iodide in neat
triethylamine. The Sonogashira cross-coupling reaction (Scheme
Phox.[32] Our initial screening proceeded with BINAP L1 with
different metals ions (Table 4, entries 1-4) with 5 mol% catalyst
Table 3 Substrate scope for the propargylation of isatin derivatives[a]
1
-a) of compound 3aa with ethyl 4-iodobenzene proceeded in
Entry
R1
R2
Time [m]
Product
(Yield)[c]
high yield to afford 5aa, a compound synthesized for the first time
using coupling reaction. Selective reduction[24] of the compound
3
aa could also be made in the presence of 3 mol % of Lindlar
1
2
3
4
5
6
7
8
9
H
H
20
25
15
30
25
18
20
15
15
20
25
20
10
10
15
20
25
25
22
15
15
40
3aa
3ba
3ca
3da
3ea
3fa
99
98
95
97
94
95
97
95
95
96
97
95
96
95
95
96
98
93
96
97
95
98
catalyst in MeOH at ambient temperature to give homoallyl
alcohol in high yields (Scheme 1-b). We further explored the
application of the synthesized compounds for Huisgen 1,3-dipolar
cycloaddition[25] to yield triazole 7aa in excellent yield (Scheme 1-
H
5 Cl
5 Br
5 F
H
c) in less time, a class of compounds possessing microbial
H
activity.[
26]
The hydration adduct
rhodium salt and CTAB as a surfactant in wet THF with poor yield
Scheme 1-d).
[27]
was also achieved using
H
5 NO
2
(
H
5 Me
H
5 OMe
3ga
3ha
3ia
H
5 OCF
4 Br
6 Cl
7 F
4, 7-Cl
H
3
H
10
11
11
12
13
14
15
16
17
18
19
20
21
H
3ja
H
3ka
3la
H
Allyl
Ph
Me
Me
Me
Me
Me
3ma
3na
3oa
3pa
3qa
3ra
H
H
5 Cl
5 Me
4 Br
5 Br
H
3sa
3ta
-CH
-CH
2
Ph
2
Ph
5 F
H
3ua
3va
-C(Ph)
3
[
a] Typical reaction conditions: Isatin derivative 1a (0.50 mmol), allenylboronic
2
acid pinacol ester 2a (1.2 equivalent) in 2 ml H O, temperature maintained at
2
After column chromatography
Scheme 1 Synthetic transformations of 3-hydroxy-3-(prop-2-yn-1-yl)indolin-2-
one
0C; [b] Selectivity determined by HPLC analysis, >99:1% in all cases; [c]
5
loading, it was found that copper II triflate to best with retention in
regioselective with satisfactory enantiomeric ratio 72:28 (Table 4,
entry 4). Increase in the catalyst loading to 10 mol% could furnish
chiral alcohols with increased enantiomeric ratio 78:22 (Table 4,
entry 5). However, when L2 and L3 were screened, L2 did not
give better results as L1 (Table 4, entries 6) and L3 gave racemic
After the successful synthesis of the racemic propargyl alcohols,
we next tried asymmetric synthesis of these tertiary alcohols
which is reported for the first time. We screened different class of
privileged ligands viz. Phosphines,[28] Salen,[29] Binol,[30] Box,[31]
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European Journal of Organic Chemistry
10.1002/ejoc.201701745
FULL PAPER
product (Table 4, entry 7). Preliminary investigations in the
7[b]
L3 (12)
L4 (12)
L5 (12)
L6 (12)
L7 (12)
L8 (12)
L4 (12)
Cu(OTf)
2
(10)
60:40
>99:1
>3:97
77:23
66:34
83:17
>99:1
100
100
90
51:49
18:82
rac
asymmetric synthesis of this chiral propargyl alcohol revealed that
SEGPHOS[28c] worked well in combination with the copper metal
among the bidentate phosphine ligands screened L1-L4 (Figure
[b]
8
Cu(OTf) (10)
2
9[b]
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
(10)
(10)
(10)
(10)
(10)
2
2
2
2
2
1) with enantiomeric ratio up to 18:82 (Table 4, entry 8). To
10[b]
95
rac
improve the enantioselectivity, we also screened other class of
ligands. We found that the salen L5 with diphenyl as a chiral
backbone could afford the product with reverse selectivity i.e.
allenyl alcohol was formed with no chiral induction (Table 4, entry
1 [
1
b]
96
rac
2[b]
1
100
100
63:37
15:85
9).Use of L6 BINOL and L7 PyBOX as a chiral ligand also afforded
1 [
3
c]
racemic products (Table 4, entries 10 and 11). L8 Phox ligand was
found to give satisfactory er and regioselectivity among the L5-L7
screened. With the optimized catalyst SEGPHOS in hand, we
[
a] Reaction conditions: Argon Atmosphere, Isatin derivative (1a, 0.1 mmol),
Allenylboronic acid pinacol ester 2a (1.2 equivalent), solvent 1 ml THF, [b]
temp.= -40 0C; [c] temp.= -78 0C to -40 0C; [d] Determined on HPLC; [e]
0
tried to lower the temperature to -78 C and we found that there
was increase in the enantiomeric ratio. Under the optimized
condition, L4 (Table 4, entry 13) with N-Methyl isatin (3oa) taken
as a model substrate, we could achieve chiral propargylic alcohols
in enantiomeric ratio 15:85. The use of strong base is to suppress
the formation allenyl products and formation of Cu-alkoxide
complex for smooth Cu/B exchange forming stable allenyl Cu-
species for asymmetric propargylation.[11]
Determined on HPLC, Chiracel IC; Hexane:IPA
Table 5 Substrate scope for enantioselective propargylation
Entry
Product
Conversion
%
Yield
92
Time
24 h
24 h
24 h
18 h
16 h
20 h
24 h
20 h
20 h
Selectivity
%[
er[a]
a]
1
2
1
2
3
4
5
6
7
8
9
R =H, R =H,
97
100
100
100
100
100
100
100
95:5
100
81:19
72:27
82:18
15:85
19:81
12:88
31:69
80:20
24:76
3aa
1
R =H,
95
92
2
R =5F, 3da
1
R =H,
100
100
100
100
95
95
2
R =5Me, 3fa
1
Figure
1
Ligands screened for enantioselective propargylation of isatin
R =Me,
98
2
derivatives
R =H, 3oa
1
Table 4 Optimization for enantioselective propargylation of Isatin derivatives[a]
R =Me,
96
2
R =5Me,3qa
1
R =Me,
98
2
R =4Br,3ra
1
R =Me,
90
2
R =5Br,3sa
1
R =Bn,
100
100
95
2
R =H,3ta
Entry
Ligand
mol %)
Metal source
(mol %)
Selectivity[d]
3oa:4oa
Conversion
[%]
e. r.[e]
1
R =Trityl,
98
(
2
R =H, 3va
1[b]
2[b]
3[b]
4[b]
L1 (6)
L1 (6)
L1 (6)
L1 (6)
L1 (12)
L2 (12)
Cu(OAc)
(5)
93:7
98
73:27
63:37
70:30
72:28
78:22
63:37
2
[a] Determined on HPLC, Chiracel IC, and ADH-Column; Hexane: IPA
CuCl (5)
65:35
97:3
95
Substrate scope showed that the unprotected isatin was less
tolerated with er 81:19 (Table 5, entry 1). Electron donating group
at 5 position had a similar effect (Table 5, entry 3) but detrimental
when changed with electron withdrawing fluoro at 5 position
Cu(OTf).Tol (5)
100
100
100
100
Cu(OTf)
Cu(OTf)
Cu(OTf)
2
2
2
(5)
>99:1
>99:1
94:6
(
Table 5, entry 2). Changing the bulkiness of isatin with benzyl at
5[b]
(10)
(10)
N1 could also furnish similar result as unprotected isatin, but site
selectivity was compromised (Table 5, entry 8). Substitution at N1
position with methyl group gave better enantioselectivity with er
6[b]
15:85 (Table 5, entry 4). With N-Me isatin bearing electron
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European Journal of Organic Chemistry
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FULL PAPER
withdrawing group at 5 position had negative effect in achieving
chiral product. The er dropped to 31:69 (Table 5, entry 7). With 5-
Me as substituent we got satisfactory results but little lower er with
exchange[9b, 22] with allenyl boronate to form copper propargyl
species[11] which isomerises to form active allenyl intermediate.[9a]
This active allenyl copper species forms the complex with oxygen
of the isatin moiety forming a six membered transition state to
transfer intermolecular propargyl group to the isatin derivative
forming alkoxide isatin. This alkoxide ion reacts with another
allenyl boronate to regenerate active species, thus completing the
catalytic cycle. The allene copper species coordinates to isatin in
such a way that the phenyl rings on the phosphine ligands provide
more steric hindrance leaving behind cage like structure for
nucleophilic attack for chiral induction.
3oa (Table 5, entry 5). However bromo at 4 position gave best
result with er upto 12:88 (Table 5, entry 6). Further substitution
with trityl at N1 position afforded chiral alcohols in 24:76 er (Table
5, entry 9). The maximum er we achieved with N-Methyl isatin with
Bromo at 4-position up to 12:88 (Table 5, entry 6). The results
obtained states that the enantioselectivity is not only affected by
the substituents but the steric factor is also playing a vital role is
transfer of chirality.
New peak 212.22 ppm
Cu propargyl species
24 h
2
.01 ppm
Mechanistic Insights
Cu propargyl species
0 min
9
11
B-21.13 ppm
90 min
218.04 ppm peak
60 min
disappears
6
0 min
0 min
10 min
1
Allenyl boronate + Cu(OTf)
2
0 min
218.04 ppm
Allenyl boronate + Cu(OTf)
2
11
B-29.11 ppm
5
min
Figure 3 13C NMR experiment using Allenylboronic acid pinacol ester 2a and
Cu(OTf)
2
Figure 2 11B NMR using allenylboronic acid pinacol ester 2a and Cu(OTf)
2
To investigate the mechanism of the reaction NMR analysis was
done. Smooth transmetallation of Cu/B exchange[11] was
1
1
observed in B NMR (Figure 2) with a new peak at 21.31 ppm
Allene 11B-29.11 ppm). 13C NMR spectra (Figure 3) shows that
(
the peak at 218.04 ppm completely diminishes. New peaks were
observed at 70-80 ppm, and the characteristic peak of propargyl
metal[
33]
appeared at 2.10 ppm which reveals that smooth
transmetallation has taken place with the formation of Cu-
propargyl species. The appearance of a new peak at 212.22 ppm
after 24
h shows that allenyl species has formed from
isomerization of copper propargyl species. Therefore, NMR
experiments showed that in the presence of copper initially,
transmetallation takes place with Cu/B exchange, followed by the
formation of copper propargyl species. After that, the
isomerization takes place to form allenyl species with acts a
nucleophile for the propargylation of isatins. Similar observations
were recorded when NMR experiments were conducted with the
aid of phosphine ligand. 11B NMR experiments performed with
copper metal complex showed that the transmetallation still
occurs with the generation of two new peaks at 21.43 and 19.17
ppm. Appearance of new peak at 212.27 ppm in 13C NMR
corresponding to allene arose due to the isomerization of the
copper propargyl species, peak at 2.45 ppm (see supporting
information).
Figure 3 Proposed catalytic cyclic
A probable mechanism is given in Figure 4, based on the above
spectroscopic studies established copper alkoxide B/Cu
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European Journal of Organic Chemistry
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Conclusions
purified using short column chromatography to yield highly pure propargyl
alcohols. The final products were characterized using physicochemical
methods viz. H NMR, 13C NMR, and HRMS technique.
1
We have developed a mild protocol for the propargylation of the
isatin derivatives using allenylboronic acid pinacol ester as a
nucleophile. Our improved protocol is simple, non-toxic and
requires aqueous media for the regioselective propargylation
using inexpensive copper metal. The reaction conditions are well
tolerated for protected and unprotected isatin derivatives to afford
tertiary alcohols with excellent selectivity and yields. The
methodology developed was also extended for the
enantioselective catalysis with enantiomeric ratio up to 12:88. A
gram level synthesis was done to explore the practicality of the
method developed. The protocol was also realized for the
coupling reaction and selective reduction on a gram level scale.
The protocol was also extented for Huisgen 1,3-dipolar
cycloaddition and hydration of these alkynyl alcohols. To the best
of our knowledge, this is the first example where propargyl
3
9
=
7
2
-hydroxy-3-(prop-2-yn-1-yl) indolin-2-one (3aa): white solid; yield
2% ; melting point: 164-166 C; H NMR (600 MHz, CD OD) δ 7.36 (d, J
3
0
1
7.3 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.79 (d, J =
.8 Hz, 1H), 2.75 (dd, J = 16.3, 2.6 Hz, 1H), 2.61 (dd, J = 16.1, 2.3 Hz, 1H),
.06 (s, 1H) ppm; 13C NMR (151 MHz, CD
3
OD) δ 180.92, 143.24, 132.04,
130.92, 125.43, 123.75, 111.22, 79.01, 76.51, 71.90, 28.72 ppm; HRMS
(ESI, +ve) m/z calcd. for (C11
Optical Rotation: [α]27
AD-H, hexanes/2-propanol = 90:10, flow rate = 1.0 mL/min) t major = 16.8
min, t minor = 19.2 min.
+
H
10NO
2
) [M ]: 188.0712, found 188.0706;
o
D
3
= -22.6 (c = 1, CHCl ); HPLC (Daicel Chiralcel
5-chloro-3-hydroxy-3-(prop-2-yn-1-yl) indolin-2-one (3ba): white solid;
0
1
3
yield 98%; melting point: 212-214 C; H NMR (600 MHz, CD OD) δ 7.43
(s, 1H), 7.25 (dd, J = 8.1, 1.3 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 2.83 (dd, J
16.3, 2.3 Hz, 1H), 2.68 (dd, J = 16.4, 2.3 Hz, 1H), 2.20 (s, 1H) ppm; 13
=
C
alcohols have been synthesized in
a regioselective and
3
NMR (151 MHz, CD OD) δ 180.37, 141.85, 133.85, 130.63, 128.82,
enantioselective manner with broad substrate scope. Attempt to
achieve high enantioselectivity and computational studies are
underway in our laboratory and will be reported in due course.
125.68, 112.31, 78.57, 76.37, 72.12, 49.00, 28.49 ppm; HRMS (ESI, +ve)
+
9 2
m/z calcd. for (C11H NO Cl) [M ] 222.0322, found 222.0327
5
-bromo-3-hydroxy-3-(prop-2-yn-1-yl) indolin-2-one (3ca): white solid;
0
1
yield 95%; melting point: 194-196 C; H NMR (600 MHz, CD
s, 1H), 7.32 (dd, J = 8.1, 2.1 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 2.13 (t, J =
3
OD) δ 7.50
(
2
1
.4 Hz, 1H) ppm; 13C NMR (151 MHz, CD
OD) δ 180.21, 142.31, 134.21,
3
33.58, 128.50, 115.92, 112.78, 78.57, 76.30, 72.13, 49.00, 28.50 ppm;
Experimental Section
+
HRMS (ESI, +ve) m/z calcd. for (C11
H NO
9
2
Br) [M ]: 265.9817, found
All isatin derivatives, Allenylboronic acid pinacol ester were commerically
available from TCI chemicals and were used as received. Silver salts,
copper salts, Sodium L-ascorbate, used were purchased from Sigma
Aldrich. Trityl Bromide, Benzyl bromide and Methyl iodide were purchased
from spectrochem India. Chiral phosphine ligands were purchased from
Sigma-Aldrich and used as received. Lindlar catalyst was purchased from
Sigma Aldrich. HPLC grade water was used for catalytic reaction run for
racemic products and reactions were performed in air unless otherwise
stated. Chiral reactions were carried out in an atmosphere of argon. THF
was dried under refluxing potassium metal and stored under Argon.
Potassium t-butoxide and iodobenzene was purchased from ACROS
organics. N-protection of Isatin was done according to published literature
procedure. Jeol 600 Hz instrument was used to record 1H and 13C NMR
265.9818
5-fluoro-3-hydroxy-3-(prop-2-yn-1-yl) indolin-2-one (3da): white solid;
0
1
yield 92% ; melting point: 206-208 C; H NMR (600 MHz, CD
3
OD) δ 7.15
(d, J = 7.7 Hz, 1H), 6.92 (t, J = 9.1 Hz, 1H), 6.80 – 6.74 (m, 1H), 2.76 (d, J
=
13
16.2 Hz, 1H), 2.61 (d, J = 16.2 Hz, 1H), 2.12 (d, J = 1.8 Hz, 1H) ppm;
C NMR (151 MHz, CD OD) δ 180.71, 161.35, 159.77, 139.06, 133.71,
3
1
7
33.66, 116.97, 116.81, 113.15, 112.98, 111.91, 111.86, 78.61, 76.57,
2.06, 28.53 ppm; HRMS (ESI, +ve) m/z calcd. for (C11 NO
F+Na+)
= -28.2 o (c
); HPLC (Daicel Chiralcel AD-H, hexanes/2-propanol = 90:10,
flow rate = 1.0 mL/min) t major = 14.2 min, t minor = 20.2 min.
H
8
2
+
27
[M+Na ]: 228.0437, found 228.0444; Optical Rotation: [α]
D
=
1, CHCl
3
Spectra in deuterated methanol or chloroform using TMS
3
-hydroxy-5-nitro-3-(prop-2-yn-1-yl) indolin-2-one (3ea): white solid;
1
(Tetramethylsilane) as an internal standard. H NMR data was recorded
0
1
yield 94%; melting point: 186-188 C; H NMR (600 MHz, CD
3
OD) δ 9.36
as a doublet, triplet, double doublet and multiplet, coupling constant (Hz).
ESI was used to calculate high-resolution mass spectra. Melting point was
recorded on MEL-TEMP electrothermal and reported uncorrected. The
progress of the reaction was monitored on TLC (Merck Silica gel aluminum
sheet) and analysed under UV (254 nm). Column chromatography was
performed using silica gel (100-200), ethyl acetate and hexane as an
eluent for purification of compounds. Analysis of the chiral products was
performed using High-pressure liquid chromatography (HPLC) Shimadzu
UFLC instrument, using column Chiracel® IC and ADH.
(
d, J = 2.1 Hz, 1H), 9.27 (dd, J = 9.1, 2.2 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H),
3
.95 (dd, J = 16.3, 3.1 Hz, 1H), 3.77 (dd, J = 16.2, 2.4 Hz, 1H), 3.27 (t, 6.0
OD) δ 196.28, 180.67, 149.47,
44.71, 133.00, 127.71, 121.13, 111.01, 78.32, 75.95, 72.42, 28.40 ppm;
Hz, 1H) ppm; 13C NMR (151 MHz, CD
3
1
+
9 2 4
HRMS (ESI, +ve) m/z calcd. for (C11H N O ) [M ]: 233.0562, found
2
33.0553
3
-hydroxy-5-methyl-3-(prop-2-yn-1-yl) indolin-2-one (3fa): white solid;
0
1
yield 95%; melting point: 195-197 C; H NMR (600 MHz, CD
3
OD) δ 7.28
(
s, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 2.82 (dd, J =
General Method for the synthesis of the propargylation alcohols
derivatives 3aa-3ta using 2a
1
2
1
6.2, 2.7 Hz, 1H), 2.69 (dd, J = 16.2, 2.6 Hz, 1H), 2.32 (s, 3H), 2.15 (t, J =
.6 Hz, 1H) ppm; 13C NMR (151 MHz, CD
3
OD) δ 180.80, 140.56, 133.28,
31.93, 131.02, 125.92, 110.84, 78.93, 76.47, 71.73, 49.00, 28.59, 21.14
To a 5 ml sample vial equipped with stirrer bar was added 5 mol % (9 mg,
+
ppm; HRMS (ESI, +ve) m/z calcd. for (C12
2
H
12NO
2
) [M ]: 202.0868, found
0.025 mmol) of copper (II) triflate in 2 ml of distilled water. The reaction
02.0863; Optical Rotation: [α]27
= -45.8 o (c = 1, CHCl
D
3
); HPLC (Daicel
was stirred for 5 min until the complete dissolution of the salt. Now 1.2
equivalent of 2a allenylboronic acid pinacol ester was added followed by
addition of 1a-1t (0.5 mmol) isatin. The reaction was allowed to stir for 15
m- 1 h depending on the substrate. The reaction was monitored on TLC
Chiralcel AD-H, hexanes/2-propanol = 90:10, flow rate = 1.0 mL/min) t
major = 14.7 min, t minor = 24.6 min.
3
-hydroxy-5-methoxy-3-(prop-2-yn-1-yl) indolin-2-one (3ga): white
(25:75 Ethyl acetate: Hexane for –NH unprotected isatin and 15:85 Ethyl
0
1
solid; yield 97%; melting point: 195-197 C; H NMR (600 MHz, CD
3
OD) δ
.08 (d, J = 2.5 Hz, 1H), 6.81 (dd, J = 8.5, 2.5 Hz, 1H), 6.77 (d, J = 8.4 Hz,
H), 3.75 (s, 3H), 2.81 (dd, J = 16.2, 2.6 Hz, 1H), 2.66 (dd, J = 16.2, 2.7
acetate: Hexane for –NH protected isatin derivatives). After the completion
of the reaction, the reaction mass was extracted with ethyl acetate and
7
1
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701745
FULL PAPER
Hz, 1H), 2.16 (t, J = 2.6 Hz, 1H) ppm; 13C NMR (151 MHz, CD
(ESI, +ve) m/z calcd. for (C17
286,0844
H
13NO
+Na ) [M+ Na ]: 286.0844, found
+
+
3
OD) δ
2
1
7
80.76, 157.51, 136.14, 133.10, 115.52, 112.19, 111.56, 78.88, 76.73,
1.85, 56.21, 49.00, 28.64 ppm; HRMS (ESI, +ve) m/z calcd. for
+
+
(
12 3
C H11NO +Na ) [M+ Na ]: 240.0637, found 240.0643
3
-hydroxy-1-methyl-3-(prop-2-yn-1-yl) indolin-2-one (3oa): white solid;
yield 98%; melting point: 160-162 C; 1H NMR (600 MHz, CDCl
0
3
) δ 7.55
3
-hydroxy-3-(prop-2-yn-1-yl)-5-(trifluoromethoxy)
indolin-2-one
(d, J = 7.2 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.83
(d, J = 7.8 Hz, 1H), 3.92 (s, 1H), 2.90 (dd, J = 16.3, 2.1 Hz, 1H), 2.72 (dd,
J = 16.3, 2.1 Hz, 1H), 1.97 (t, J = 21.7 Hz, 1H) ppm; 13C NMR (151 MHz,
0
1
(3ha): white solid; yield 95%; melting point: 162-164 C; H NMR (600 MHz,
CD
.87 (d, J = 16.2 Hz, 1H), 2.70 (d, J = 16.6 Hz, 1H), 2.23 (s, 1H) ppm; 13C
NMR (151 MHz, CD OD) δ 180.66, 145.86, 142.10, 133.64, 123.98,
19.29, 111.83, 78.51, 76.35, 72.18, 28.51, 25.02 ppm; HRMS (ESI, +ve)
3
OD) δ 7.42 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H),
2
CDCl
3
) δ 177.02, 143.42, 130.17, 129.26, 124.26, 123.43, 108.57, 77.79,
3
74.64, 71.4, 28.83, 26.38 ppm; HRMS (ESI, +ve) m/z calcd. for
+
+
1
(C12
[α]
H
11NO
2
+Na ) [M+Na ]: 224.0687, found 224.0676; Optical Rotation:
+
+
27
o
m/z calcd. for (C12
H NO
8
3
F+Na ) [M+ Na ] 294.0354, found 294.0359
D
= -31.6 (c = 1, CHCl
3
); HPLC (Daicel Chiralcel IC, hexanes/2-
propanol = 85:15, flow rate = 1.0 mL/min) t minor = 16.0 min. t major =
12.4 min.
5
-chloro-3-hydroxy-1-methyl-3-(prop-2-yn-1-yl) indolin-2-one (3pa):
4
-bromo-3-hydroxy-3-(prop-2-yn-1-yl) indolin-2-one (3ia): white solid;
white solid; yield 96%; melting point: 142-144 0C; 1H NMR (600 MHz,
0
1
yield 95%; melting point: 192-193 C; H NMR (600 MHz, CD
3
OD) δ 7.16
CDCl
H), 3.96 (s, 1H), 3.17 (s, 3H), 2.89 (dd, J = 16.5, 2.6 Hz, 1H), 2.71 (dd, J
= 16.7, 2.6 Hz, 1H), 1.98 (t, J = 2.7 Hz, 1H) ppm;
13C NMR (151 MHz,
CDCl ) δ 176.66, 141.97, 130.83, 130.07, 128.92, 124.95, 109.59, 77.29,
3
) δ 7.53 (d, J = 2.1 Hz, 1H), 7.36 – 7.28 (m, 1H), 6.76 (d, J = 8.4 Hz,
(d, J = 4.1 Hz, 2H), 6.92 – 6.79 (m, 1H), 3.40 (dd, J = 16.0, 2.2 Hz, 1H),
1
2
1
1
.79 (dd, J = 15.9, 2.3 Hz, 1H), 2.06 (t, J = 2.1 Hz, 1H), 2.06 (t, J = 2.1 Hz,
H) ppm; 13C NMR (151 MHz, CD
3
OD) δ 180.01, 145.81, 132.48, 129.60,
3
27.76, 120.61, 110.43, 78.68, 78.24, 71.83, 49.15, 25.81 ppm; HRMS
+
+
74.67, 71.90, 28.82, 26.53 ppm; HRMS (ESI, +ve) m/z calcd. for
8 2
(ESI, +ve) m/z calcd. for (C11H NO Br+Na ) [M+Na ]: 287.9636, found
+
(
C
12
H11NO
2
Cl) [M ]: 236.0478, found 236.0470
287.9632
3
-hydroxy-1, 5-dimethyl-3-(prop-2-yn-1-yl) indolin-2-one (3qa): white
6
-chloro-3-hydroxy-3-(prop-2-yn-1-yl) indolin-2-one (3ja): white solid;
0
1
0
1
solid; yield 98%; melting point: 152-154 C; H NMR (600 MHz, CDCl
.37 (s, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 3.18 (s, 3H),
2.88 (dd, J = 16.2, 2.4 Hz, 1H), 2.71 (dd, J = 16.3, 2.5 Hz, 1H), 2.35 (s,
H) ppm; 13C NMR (151 MHz, CDCl
) δ 176.68, 141.09, 133.10, 130.48,
129.09, 125.04, 108.37, 77.81, 74.55, 71.61, 28.95, 26.43, 21.27 ppm;
3
) δ
3
yield 96%; melting point: 216-218 C; H NMR (600 MHz, CD OD ) δ 7.42
7
(
(
d, J = 7.9 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.90 (s, 1H), 2.83 (d, 1H), 2.71
d, J = 16.3 Hz, 1H), 2.19 (s, 1H); 13C NMR (151 MHz, CD
3
OD) δ 180.58,
3
3
1
2
2
44.55, 136.29, 130.56, 126.51, 123.36, 111.49, 78.63, 76.01, 72.00,
8.47 ppm; HRMS (ESI, +ve) m/z calcd. for (C11
44.0141, found 244.0139
+
+
8 2
H NO Cl+Na ) [M+Na ]:
+
+
HRMS (ESI, +ve) m/z calcd. for (C13
found 238.0844; Optical Rotation: [α]2
H
13NO
2
+Na ) [M+Na ]: 238.0844,
7
= -28.1 o (c = 1, CHCl
D
3
); HPLC
(
Daicel Chiralcel IC, hexanes/2-propanol = 85:15, flow rate = 1.0 mL/min)
7
-fluoro-3-hydroxy-3-(prop-2-yn-1-yl) indolin-2-one (3ka): white solid;
t minor = 14.1 min, t major = 18.3 min.
0
1
yield 97%; melting point: 210-212 C; H NMR (600 MHz, CD
3
OD) δ 7.28
(
2
d, J = 7.4 Hz, 1H), 7.10 – 7.02 (m, 2H), 2.84 (dd, J = 16.2, 3.1 Hz, 1H),
.73 (dd, J = 16.3, 2.7 Hz, 1H), 2.18 (t, J = 2.7 Hz, 1H) ppm; 13C NMR (151
4-bromo-3-hydroxy-1-methyl-3-(prop-2-yn-1-yl)indolin-2-one
(3ra):
1
white solid; yield 93%; melting point; ; H NMR (600 MHz, CDCl
3
) δ 7.22 –
MHz, CD
1
m/z calcd. for (C11
3
OD ) δ 180.27, 149.30, 147.69, 134.88, 130.12, 124.42, 124.38,
7
.20 (m, 1H), 6.78 (dd, J = 5.4, 3.1 Hz, 1H), 3.35 (dd, J = 16.1, 2.2 Hz, 1H),
3.31 (br, 1H), 3.19 (s, 3H), 3.01 (dd, J = 16.1, 2.5 Hz, 1H), 1.76 (s, 1H)
ppm; 13C NMR (151 MHz, CDCl
) δ 175.82, 146.02, 131.56, 127.35,
26.94, 119.43, 107.56, 71.14, 26.47, 26.22 ppm;HRMS (ESI, +ve) m/z
21.11, 117.68, 117.57, 78.57, 76.53, 71.95, 28.64 ppm; HRMS (ESI, +ve)
+
9 2
H NO F) [M ]: 206.0617, found 206.0615
3
1
4
, 7-dichloro-3-hydroxy-3-(prop-2-yn-1-yl) indolin-2-one (3la): white
+
+
0
1
calcd. for (C12
Rotation: [α]27
H10BrNO
2
+Na ) [M ]: 301.9793, found 301.9800; Optical
solid; yield 95%; melting point: 192-194 C; H NMR (600 MHz, CD
.27 (d, J = 9.1 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 3.30 (dd, J = 16.0, 2.3
Hz, 1H), 2.84 (dd, J = 16.0, 3.2 Hz, 1H), 2.13 (t, J = 2.7 Hz, 1H) ppm; 13C
NMR (151 MHz, CD OD) δ 179.30, 143.01, 131.97, 131.06, 129.25,
25.28, 115.03, 78.63, 77.85, 72.00, 25.81 ppm; HRMS (ESI, +ve) m/z
calcd. for (C11 NO Cl ) [M+]: 255.9932, found 255.9920
3
OD) δ
o
D
= -66.7 (c = 1, CHCl
3
); HPLC (Daicel Chiralcel IC,
7
hexanes/2-propanol = 85:15, flow rate = 1.0 mL/min) t minor = 9.8 min, t
major = 12.0 min.
3
1
5
-bromo-3-hydroxy-1-methyl-3-(prop-2-yn-1-yl)indolin-2-one (3sa):
white solid; yield 96%; melting point: ; 1H NMR (600 MHz, CDCl
) δ 7.68
d, J = 2.0 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 3.95
(s, 1H), 3.18 (s, 3H), 2.91 (dd, J = 16.2, 2.4 Hz, 1H), 2.73 (dd, J = 16.2, 2.3
Hz, 1H), 2.00 (t, J = 2.3 Hz, 1H) ppm; 13C NMR (151 MHz, CDCl
) δ 176.48,
42.43, 132.95, 131.11, 127.63, 116.13, 110.04, 77.21, 74.57, 71.89,
8.78, 26.46 ppm; HRMS (ESI, +ve) m/z calcd. for (C12 10BrNO
+Na+)
= -29.2 o (c = 1,
); HPLC (Daicel Chiralcel IC, hexanes/2-propanol = 90:10, flow rate
H
8
2
2
3
(
1
-allyl-3-hydroxy-3-(prop-2-yn-1-yl) indolin-2-one (3ma): white solid;
yield 96%; melting point: 136-138 C; 1H NMR (600 MHz, CDCl
0
3
) δ 7.54
d, J = 7.3 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.83
d, J = 7.9 Hz, 1H), 5.85 – 5.75 (m, J = 15.3, 10.4, 5.2 Hz, 1H), 5.26 (d, J
17.2 Hz, 1H), 5.20 (d, J = 10.4 Hz, 1H), 4.44 – 4.38 (m, 1H), 4.22 – 4.17
3
(
(
1
2
H
2
=
+
27
D
[M ]: 301.9793, found 301.9790; Optical Rotation: [α]
(m, 1H), 3.81 (s, 1H), 2.93 (dd, J = 16.4, 2.5 Hz, 1H), 2.78 (dd, J = 16.6,
.6 Hz, 1H), 1.93 (t, J = 2.1 Hz, 1H) ppm; 13C NMR (151 MHz, CDCl
CHCl
3
2
1
7
3
) δ
=
1.0 mL/min) t minor = 13.4 min, t major = 20.5 min.
76.80, 142.70, 130.98, 130.08, 129.21, 124.26, 123.40, 117.93, 109.54,
7.81, 74.70, 71.50, 42.59, 28.87 ppm; HRMS (ESI, +ve) m/z calcd. for
+
+
1-benzyl-3-hydroxy-3-(prop-2-yn-1-yl) indolin-2-one (3ta): white solid;
(
14 2
C H13NO +Na ) [M+ Na ]: 250.0844, found 250.0835
0
1
yield 95% ; melting point: 162-164 C; H NMR (600 MHz, CDCl
3
) δ 7.54
(
d, J = 7.3 Hz, 1H), 7.32 – 7.27 (m, J = 15.3, 7.5 Hz, 4H), 7.26 – 7.20 (m,
3
-hydroxy-1-phenyl-3-(prop-2-yn-1-yl) indolin-2-one (3na): waxy solid;
) δ 7.58 (d, J = 7.4 Hz, 1H), 7.53 –
.48 (m, J = 7.6 Hz, 2H), 7.43 – 7.37 (m, J = 9.1 Hz, 3H), 7.26 (t, J = 7.9
Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 4.11 (s, 1H), 2.98
d, J = 16.3 Hz, 1H), 2.90 (d, J = 16.3 Hz, 1H) ppm; 13C NMR (151 MHz,
CDCl ) δ 176.58, 143.60, 133.92, 130.02, 129.76, 128.93, 128.45, 126.54,
24.43, 123.84, 109.79, 77.71, 75.02, 71.45, 29.36, 24.83 ppm; HRMS
2
1
1
H), 7.07 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 5.03 (d, J = 15.8 Hz,
H), 4.74 (d, J = 15.8 Hz, 1H), 3.55 (br, 1H), 2.97 (dd, J = 16.4, 2.5 Hz,
H), 2.83 (dd, J = 16.6, 2.8 Hz, 1H), 1.92 (s, 1H) ppm; 13C NMR (151 MHz,
yield 95%; 1H NMR (600 MHz, CDCl
3
7
CDCl
24.26, 123.47, 109.67, 77.82, 74.82, 71.57, 44.08, 28.86 ppm; HRMS
ESI, +ve) m/z calcd. for (C19
+Na+) [M+]: 313.1079, found
3
) δ 177.25, 142.65, 135.31, 130.09, 129.24, 128.84, 127.84, 127.49,
(
1
(
3
H16NO
2
1
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701745
FULL PAPER
27
= -40.1 o (c = 1, CHCl
3
13.1073; Optical Rotation: [α]
D
3
); HPLC (Daicel
Selective reduction using Lindlar’s catalyst to form 3-allyl-3-
Chiralcel IC, hexanes/2-propanol = 85:15, flow rate = 1.0 mL/min) t major
hydroxyindolin-2-one (6aa)
=
13.8 min, t minor = 19.0 min.
In a dried sample vial equipped with a magnetic bar was added 3aa (187
mg, 1 mmol, 1.00 equiv.) and Lindlar catalyst was added (63 mg, 3 mol%
palladium w.r.t. 3aa) flushed with nitrogen balloon. To this was added dry
1
-benzyl-5-fluoro-3-hydroxy-3-(prop-2-yn-1-yl)indolin-2-one
(3ua):
white solid; yield 95%; melting point: 156-157 0C; 1H NMR (600 MHz,
CDCl
3
) δ 7.31 – 7.26 (m, 6H), 6.94 – 6.90 (m, J = 8.3, 2.3 Hz, 1H), 6.63
MeOH (2 ml). Now the nitrogen balloon was removed with exchange of H
2
(
dd, J = 8.6, 4.0 Hz, 1H), 5.02 (d, J = 15.8 Hz, 1H), 4.73 (d, J = 15.7 Hz,
atmosphere. Now the reaction was allowed to stir. The reaction was
monitored with the help of TLC. After the completion of the reaction, the
reaction mass was filtered through a pad of celite eluting with MeOH. The
organic layer was concentrated and dried in vacuo. The solid mass then
purified using silica gel chromatography using ethyl acetate and hexane
1
H), 3.58 (s, 1H), 2.96 (dd, J = 16.2, 2.4 Hz, 1H), 2.81 (dd, J = 16.2, 2.3
) δ 176.84,
70.59, 160.44, 135.00, 128.98, 128.05, 127.46, 74.79, 72.05, 44.28,
Hz, 1H), 1.96 (t, J = 2.6 Hz, 1H) ppm; 13C NMR (151 MHz, CDCl
3
1
2
3
+
+
8.99 ppm; HRMS (ESI, +ve) m/z calcd. for (C18
2
H14NO F+Na ) [M ]:
0
1
18.0906, found 318.0891
as solvent (179 mg); white solid; Yield 95%; melting point: 208-210 C; H
NMR (600 MHz, CDCl ) δ 8.77 (s, 1H), 7.34 (d, J = 7.3 Hz, 1H), 7.22 (t, J
7.6 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 5.66 – 5.57
(m, J = 16.7, 8.3 Hz, 1H), 5.10 – 5.04 (m, 2H), 3.88 (s, 1H), 2.72 (dd, J =
3.4, 6.3 Hz, 1H), 2.59 (dd, J = 13.4, 8.3 Hz, 1H); 13C NMR (151 MHz,
CDCl ) δ 180.61, 140.39, 130.40, 130.33, 129.71, 124.53, 123.13, 120.53,
10.56, 76.53, 42.78.
3
=
3
-hydroxy-3-(prop-2-yn-1-yl)-1-tritylindolin-2-one (3va): white solid;
0
1
yield 98%; melting point: 208-210 C; H NMR (600 MHz, CD
3
OD) δ 7.51
1
(
(
(
d, J = 7.9 Hz, 7H), 7.37 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.5 Hz, 7H), 7.16
t, J = 7.3 Hz, 4H), 6.96 (t, J = 7.5 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.32
d, J = 8.1 Hz, 1H), 2.89 (dd, J = 16.1, 2.1 Hz, 1H), 2.84 (dd, J = 16.1, 2.0
Hz, 1H), 2.35 (s, 1H) ppm; 13C NMR (151 MHz, CD
3
1
3
OD) δ 180.59, 144.63,
43.50, 131.93, 130.55, 129.01, 128.60, 127.87, 124.37, 123.70, 117.30,
9.57, 76.04, 75.92, 72.54, 29.42 ppm; HRMS (ESI, +ve) m/z calcd. for
1
7
(
6
8
Synthesis
of
3-hydroxy-3-((1-phenyl-1H-1,2,3-triazol-4-
yl)methyl)indolin-2-one (7aa) by Huisgen 1,3-dipolar cycloaddition
+
27
C
30
H
26NO
2
) [M ]: 432.1964, found 432.1958; Optical Rotation: [α]
9.0 (c = 1, CHCl ); HPLC (Daicel Chiralcel ADH, hexanes/2-propanol =
5:15, flow rate = 1.0 mL/min) t minor = 7.2 min, t major = 10.7 min.
D
= -
o
3
To a 25 ml round bottom flask equipped with magnetic bar was charged
3
aa (187 mg, 1 mmol, 1.00 equiv.) containing 10 ml of tert-butanol and
water in a ratio of 1:1. To the solution was added 5 mol% (12.4 mg, 0.05
mmol) of copper sulphate pentahydrate (CuSO4.5H O) and 10 mol% (2.0
Gram level synthesis of propargylation of Isatin derivative (3aa)
2
mg, 0.1 mmol) of sodium ascorbate. The solution was stirred for 10
minutes for the complete dissolution of the propargyl alcohol. Now phenyl
azide (120 mg, 1mmol, 1equiv.) was added and the reaction mass was
stirred for 1 h. The solution was then left for stirring at room temperature.
After 30 minutes the solution, the clear solution turned opaque and
precipitate was observed. TLC showed complete consumption of
propargyl alcohol. The crude product was then dried in-vacuo and
extracted with ethyl acetate. The product was purified on silica gel
chromatography using ethyl acetate and hexane as eluent to yield 7aa.
Final product was characterized by H NMR, 13C NMR and HRMS (yield
To a 25 ml round bottom flask equipped with a magnetic bar was added 5
mol % (90 mg, 0.25 mmol) of copper (II) triflate in 10 ml of distilled water.
The reaction was stirred for 5 m until the salt was completely dissolved.
Now 1.2 equivalent (6 mmol, 1ml) of 2a allenylboronic acid pinacol ester
was added. The solution was stirred for 10 minutes. Now the isatin 1a (735
mg, 5 mmol) was added in portions over a period of 10 minutes under ice
bath. The reaction was brought to RT and allowed to stir for 45 minutes- 1
hour. After the completion of the reaction, the reaction mass was extracted
with ethyl acetate and passed through a pad of celite to remove salt
contamination. The product obtained was of enough purity. The selectivity
of the product, ie. 3aa was more than >99% and yield 98% (920 mg).
1
2
81 mg, 92%) White Solid; Melting point: 262 0C; 1H NMR (600 MHz,
CD OD) δ 7.93 (s, 1H), 7.67 (d, J = 7.8 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H),
3
7
1
.43 (t, J = 7.4 Hz, 1H), 7.18 (dd, J = 17.9, 7.7 Hz, 2H), 7.00 (t, J = 7.5 Hz,
H), 6.76 (d, J = 7.8 Hz, 1H), 3.38 (d, J = 14.0 Hz, 1H), 3.32 (d, J = 14.4
Synthesis of 3-hydroxy-3-(3-phenylprop-2-yn-1-yl)indolin-2-one (5aa)
via Sonogashira coupling
3
Hz, 1H) ppm; 13C NMR (151 MHz, CD OD) δ 179.92, 142.16, 141.33,
1
1
36.96, 130.53, 129.57, 129.42, 128.65, 124.32, 122.33, 121.71, 120.06,
09.78, 75.83, 33.83 ppm; HRMS (ESI, +ve) m/z calcd. for (C17
14 4 2
H N O )
To a 10 ml round bottom flask equipped with magnetic bar was added 3
mmol (561 mg) of 3-hydroxy-3-(prop-2-yn-1-yl)indolin-2-one (3aa) with 2
+
[M+Na ]: 329.1014, found 329.1014.
2 3 2
mol % of PdCl P(Ph ) (47 mg) and 10 mol% copper Iodide. The flask was
Synthesis of 3-hydroxy-3-(2-oxopropyl)indolin-2-one (8aa) by
hydration of alkyne by RhCl .3H
sealed with rubber septum and purged with nitrogen for 5 minutes. To this
was added 1 ml of dry TEA and 4 mmol (816 mg) of iodobenzene and
stirred for 1.5 h at ambient temperature. Clear solution turned to yellowish
white precipitate. The solution was then diluted with water and extracted
with ethyl acetate. Resulting solid mass was concentrated in vacuo and
chromatographed using silica to get pure white solid. The product was
3
2
O
To a 5 ml round bottom flask equipped with magnetic bar was charged 3aa
187 mg, 1 mmol, 1.00 equiv.) containing 2 ml of THF and water in a ratio
of 8:2. To the solution was added 20 mol% (53 mg, 0.2 mmol) of
RhCl .3H O and 30 mol% (109 mg, 0.3 mmol) of CTAB as surfactant. The
(
1
characterized by H NMR, 13C NMR and HRMS (yield 774 mg, 98%); white
3
2
solution was stirred for 24 h at 70 0C. TLC did not show complete
consumption of propargyl alcohol. The crude product was removed from
heating and was then dried in-vacuo, extracted with ethyl acetate. The
product was purified on silica gel chromatography using ethyl acetate and
solid; Yield 98%; melting point: 220-222 C; 1H NMR (500 MHz, CD
δ 7.50 (d, J = 7.4 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.24 – 7.18 (m, J = 8.5,
.4 Hz, 3H), 7.15 (dd, J = 7.6, 1.5 Hz, 2H), 7.08 (t, J = 7.5 Hz, 1H), 6.92
0
3
OD)
4
(
d, J = 7.7 Hz, 1H), 3.06 (d, J = 16.2 Hz, 1H), 2.93 (d, J = 16.2 Hz, 1H);
1
1
3C NMR (126 MHz, CD
hexane as eluent to yield 8aa. Final product was characterized by HNMR,
3
OD) δ 181.04, 143.07, 132.44, 132.16, 130.79,
1
3
0
C NMR and HRMS (yield 61 mg, 30%) white solid; melting point: 170 C;
1H NMR (600 MHz, DMSO-D
) δ 10.17 (s, 1H), 7.19 (dd, J = 4.1, 3.6 Hz,
H), 7.13 (td, J = 7.7, 1.3 Hz, 1H), 6.86 (td, J = 7.5, 1.0 Hz, 1H), 6.72 (t, J
7.4 Hz, 1H), 5.93 (s, 1H), 3.23 (d, J = 16.6 Hz, 1H), 2.96 (d, J = 16.6 Hz,
1
2
2
29.22, 128.97, 125.27, 124.54, 123.70, 111.07, 84.61, 83.46, 76.90,
+
+
6
2
9.73; HRMS (ESI) m/z calcd. for (C17H13NO +Na ) [M ]: 286.0844, found
1
=
1
86.0852
H), 1.96 (s, 3H) ppm; HRMS (ESI, +ve) m/z calcd. for (C11
H
11NO
3
)
+
[M+Na ]: 228.0637, found 228.0633.
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European Journal of Organic Chemistry
10.1002/ejoc.201701745
FULL PAPER
Acknowledgements
Fandrick, J. Ogikubo, D. R. Fandrick, N. D. Patel, J. Saha, H. Lee, S. Ma,
N. Grinberg, C. A. Busacca, C. H. Senanayake, Org. Lett. 2013, 15,
1
214-1217; d) D. R. Fandrick, C. A. Hart, I. S. Okafor, M. A. Mercadante,
CSIR-CSMCRI Communication. No. 171/2017. Naveen is
thankful to AcSIR for Ph. D enrolment and acknowledges
Department of Science and Technology, New Delhi for INSPIRE
fellowship (Grant No. IF120764) for doctoral study. N. G. is
thankful to Dr. S. H. R Abdi for valuable inputs and suggestions.
Authors are also thankful to Analytical Science and Centralized
Instrumental Facility for instrument facilities.
S. Sanyal, J. T. Masters, M. Sarvestani, K. R. Fandrick, J. L. Stockdill, N.
Grinberg, N. Gonnella, H. Lee, C. H. Senanayake, Org. Lett. 2016, 18,
6192-6195.
10.
T. Sammakia, J. Am. Chem. Soc., 2002, 124, 1126-1126.
E. Vrancken, N. Alouane, H. Gerard and P. Mangeney, J. Org. Chem.
11.
12.
13.
2
007, 72, 1770-1779.
T. Thaima, F. Zamani, C. J. T. Hyland, S. G. Pyne, Synthesis-Stuttgart
017, 49, 1461-1480.
2
a) D. Chen, M. H. Xu, Chem. Commun. (Camb). 2013, 49, 1327-1329;
b) H. M. Wisniewska, E. R. Jarvo, Chem. Sci. 2011, 2, 807-810.
V. Nair, S. Ros, C. N. Jayan, S. Viji, Synthesis-Stuttgart. 2003, 16, 2542-
Keywords: Allenylboronic acid • Homopropargyl alcohol • Isatin
•
Copper • Oxindole
14.
2546.
1
5.
6.
G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112, 6104-6155.
1
.
a) H. M. Wisniewska, E. R. Jarvo, J. Org. Chem. 2013, 78, 11629-11636,
b) C. H. Ding and X. L. Hou, Chem. Rev. 2011, 111, 1914-1937; c) H.
Yamamoto, in Comprehensive Organic Synthesis, ed. I. Fleming,
Pergamon, Oxford, 1991, vol. 2, pp. 81-98; d) H. Yamamoto and D. L.
Usanov, in Comprehensive Organic Synthesis II (Second Edition),
Elsevier, Amsterdam, 2014, vol. 2, pp. 209-242; e) S. Yu and S. Ma,
Angew. Chem. Int. Ed. Engl. 2012, 51, 3074-3112.
1
a) H. B. Rasmussen, J. K. MacLeod, J. Nat. Prod. 1997, 60, 1152-1154;
b) Y. Q. Tang, I. Sattler, R. Thiericke, S. Grabley, X. Z. Feng, Eur. J. Org.
Chem. 2001, 261-267; c) C. V. Galliford, K. A. Scheidt, Angew. Chem.
Int. Ed. Engl. 2007, 46, 8748-8758; d) J. I. Jimenez, U. Huber, R. E.
Moore, G. M. L. Patterson, J. Nat. Prod. 1999, 62, 569-572.
1
7.
8.
N. Gupta, G. Bhojani, R. Tak, A. Jakhar, N.-u. H. Khan, S. Chatterjee, R.
I. Kureshy, ChemistrySelect. 2017, 2, 10902-10907.
2.
a) G. M. Cragg, P. G. Grothaus, D. J. Newman, Chem. Rev. 2009, 109,
1
a) Z. L. Shen, S. Y. Wang, Y. K. Chok, Y. H. Xu, T. P. Loh, Chem. Rev.
3012-3043; b) S. M. Dalby, I. Paterson, Curr. Opin. Drug. Disc. 2010, 13,
2013, 113, 271-401; b) J. Podlech, T. C. Maier, Synthesis-Stuttgart 2003,
633-655; c) S. Araki, H. Ito, Y. Butsugan, J. Org. Chem. 1988, 53, 1831-
1833.
777-794; c) D. Herkommer, S. Dreisigacker, G. Sergeev, F. Sasse, H.
Gohlke, D. Menche, Chemmedchem. 2015, 10, 470-489; d) G. J.
Lauquin, A. M. Duplaa, G. Klein, A. Rousseau, P. V. Vignais,
Biochemistry. 1976, 15, 2323-2327; e) K. J. Hale, M. G. Hummersone,
S. Manaviazar and M. Frigerio; Nat. Prod. Rep. 2002, 19, 413-453.
a) S. M. Dalby, J. Goodwin-Tindall, I. Paterson, Angew. Chem. Int. Ed.
Engl. 2013, 52, 6517-6521; b) A. Francais, A. Leyva-Perez, G.
Etxebarria-Jardi, J. Pena, S. V. Ley, Chem-Eur. J. 2011, 17, 329-343; c)
B. M. Trost, G. Dong, Nature 2008, 456, 485-488.
1
9.
0.
B. Alcaide, P. Almendros, R. Rodriguez-Acebes, J. Org. Chem. 2005, 70,
198-3204.
3
2
a) Q. Chen, Y. Tang, T. Huang, X. Liu, L. Lin, X. Feng, Angew. Chem.
Int. Ed. Engl. 2016, 55, 5286-5289; b) N. Xu, D. W. Gu, J. Zi, X. Y. Wu,
X. X. Guo, Org. Lett, 2016, 18, 2439-2442; c) G. Chen, Y. Wang, S. Gao,
H. P. He, S. L. Li, J. X. Zhang, J. Ding, X. J. Hoa, J. Heterocyclic Chem.
3
.
.
2009, 46, 217-220; d) X. P. Fu, L. Liu, D. Wang, Y. J. Chen, C. J. Li,
4
a) T. Nakagawa, A. Kasatkin, F. Sato, Tetrahedron Lett. 1995, 36, 3207-
Green Chem. 2011, 13, 549-553.
3210; b) T. D. Haddad, L. C. Hirayama, J. J. Buckley, B. Singaram, J.
21.
P. T. O'Sullivan, W. Buhr, M. A. Fuhry, J. R. Harrison, J. E. Davies, N.
Feeder, D. R. Marshall, J. W. Burton, A. B. Holmes, J. Am. Chem. Soc.,
Org. Chem. 2012, 77, 889-898; c) X. F. Ma, J. X. Wang, S. X. Li, K. H.
Wang, D. F. Huang, Tetrahedron 2009, 65, 8683-8689; d) J. Munoz-
Bascon, I. Sancho-Sanz, E. Alvarez-Manzaneda, A. Rosales, J. E. Oltra,
Chem. - Eur. J. 2012, 18, 14479-14486; e) S. Liu, J. T. Kim, C. G. Dong,
Y. Kishi, Org. Lett. 2009, 11, 4520-4523.
2
004, 126, 2194-2207.
S. L. Shi, L. W. Xu, K. Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc.
010, 132, 6638-6639.
2
2.
3.
2
2
a) S. Ribe and P. Wipf, Chem Commun. 2001, 299-307; b) I. P.
Beletskaya, A. V. Cheprakov, in Organic Synthesis in Water, ed. P. A.
Grieco, Springer Netherlands, Dordrecht, 1998, DOI: 10.1007/978-94-
5.
a) D. L. Silverio, S. Torker, T. Pilyugina, E. M. Vieira, M. L. Snapper, F.
Haeffner, A. H. Hoveyda, Nature 2013, 494, 216-221; b) D. S. Barnett, S.
E. Schaus, 2011, 13, 4020-4023; c) A. S. Tsai, M. Chen, W. R. Roush,
Org. Lett. 2013, 15, 2325-2325; d) L. R. Reddy, Chem. Commun. (Camb).
011-4950-1_5, pp. 141-222; c) H. C. Hailes, App. Organomet. Chem.
1998, 12, 467-468.
2012, 48, 9189-9191; e) P. Jain, H. Wang, K. N. Houk, J. C. Antilla,
24.
25.
26.
R. A. Kunkalkar, D. Laha, R. A. Fernandes, Org. Biomol. Chem. 2016,
4, 9072-9079.
Angew. Chem. Int. Ed. Engl. 2012, 51, 1391-1394.
1
6
.
.
A. S. Tsai, M. Chen, W. R. Roush, Org. Lett. 2013, 15, 1568-1571.
a) B. L. Kohn, N. Ichiishi, E. R. Jarvo, Angew. Chem. Int. Ed. Engl. 2013,
V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew.
Chem. Int. Ed. Engl. 2002, 41, 2596-2599.
7
52, 4414-4417; b) C. A. Osborne, T. B. Endean, E. R. Jarvo, Org. Lett.
2015, 17, 5340-5343; c) H. Pellissier, Chem. Rev. 2016, 116, 14868-
14917.
a) N. Boechat, V. F. Ferreira, S. B. Ferreira, G. F. M. de Lourdes, C. d.
S. F. de, M. M. Bastos, S. C. M. Dos, M. C. Lourenco, A. C. Pinto, A. U.
Krettli, A. C. Aguiar, B. M. Teixeira, N. V. da Silva, P. R. Martins, F. A.
Bezerra, A. L. Camilo, G. P. da Silva, C. C. Costa, J. Med. Chem. 2011,
8.
a) D. R. Fandrick, J. Saha, K. R. Fandrick, S. Sanyal, J. Ogikubo, H. Lee,
F. Roschangar, J. J. Song, C. H. Senanayake, Org. Lett. 2011, 13, 5616-
5
4, 5988-5999; b) Z. C. Dai, Y. F. Chen, M. Zhang, S. K. Li, T. T. Yang,
L. Shen, J. X. Wang, S. S. Qian, H. L. Zhu, Y. H. Ye, Org. Biomol. Chem.
015, 13, 477-486.
5
619; b) D. R. Fandrick, K. R. Fandrick, J. T. Reeves, Z. Tan, C. S.
Johnson, H. Lee, J. J. Song, N. K. Yee, C. H. Senanayake, Org. Lett.
010, 12, 88-91; c) D. R. Fandrick, J. T. Reeves, J. M. Bakonyi, P. R.
2
2
2
7.
8.
J. Blum, H. Huminer, H. Alper, J. Mol. Catal. 1992, 75, 153-160.
a) J. Wassenaar, J. N. Reek, Org. Biomol. Chem. 2011, 9, 1704-1713;
b) A. Grabulosa, J. Granell, G. Muller, Coordin. Chem. Rev. 2007, 251,
Nyalapatla, Z. Tan, O. Niemeier, D. Akalay, K. R. Fandrick, W.
Wohlleben, S. Ollenberger, J. J. Song, X. Sun, B. Qu, N. Haddad, S.
Sanyal, S. Shen, S. Ma, D. Byrne, A. Chitroda, V. Fuchs, B. A.
Narayanan, N. Grinberg, H. Lee, N. Yee, M. Brenner, C. H. Senanayake,
J. Org. Chem. 2013, 78, 3592-3615; d) Y. Yamashita, Y. Cui, P. Xie, S.
Kobayashi, Org. Lett. 2015, 17, 6042-6045.
2
25-90; c) T. Saito, T. Yokozawa, T. Ishizaki, T. Moroi, N. Sayo, T. Miura
and H. Kumobayashi, Adv. Synth. Catal. 2001, 343, 264-267.
W.-Z. Zhang, X.-B. Lu, in Privileged Chiral Ligands and Catalysts, Wiley-
VCH Verlag GmbH & Co. KGaA, 2011, pp. 257-293.
29.
30.
31.
9.
a) D. R. Fandrick, K. R. Fandrick, J. T. Reeves, Z. Tan, W. Tang, A. G.
Capacci, S. Rodriguez, J. J. Song, H. Lee, N. K. Yee, C. H. Senanayake,
J. Am. Chem. Soc. 2010, 132, 7600-7601; b) K. R. Fandrick, D. R.
Fandrick, J. T. Reeves, J. Gao, S. Ma, W. Li, H. Lee, N. Grinberg, B. Lu,
C. H. Senanayake, J. Am. Chem. Soc. 2011, 133, 10332-10335; c) K. R.
M. Shibasaki, S. Matsunaga, in Privileged Chiral Ligands and Catalysts,
Wiley-VCH Verlag GmbH & Co. KGaA, 2011, pp. 295-332.
L. M. Stanley, M. P. Sibi, in Privileged Chiral Ligands and Catalysts,
Wiley-VCH Verlag GmbH & Co. KGaA, 2011, pp. 171-219.
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European Journal of Organic Chemistry
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32.
C. C. Bausch, A. Pfaltz, in Privileged Chiral Ligands and Catalysts, Wiley-
VCH Verlag GmbH & Co. KGaA, 2011, pp. 221- 256.
33.
W. Miao, L. W. Chung, Y. D. Wu, T. H. Chan, J. Am. Chem. Soc. 2004,
126, 13326-13334.
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European Journal of Organic Chemistry
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
Propargylation*
N. Gupta,R. Tak, M. Nazish, A. Jakhar,
N. H. Khan,* R. I. Kureshy
Cu(OTf)
2
, H
2
O
Cu+Ligand, THF
+



Selectivity >99%



Selectivity >99%
ee upto 76%
9 examples
Yield >95%,
21 examples
Page No. 1 – Page No. 11
Copper(II)
triflate
catalyzed
regioselective and enantioselective
propargylation of Isatin derivatives
using Allenylboronic acid pinacol
ester
*Copper triflate catalysed Regioselective propargylation of isatins in aqueous media. With this protocol we could achieve
propargyl alcohols in high yields with wide substrate scope. The enantioselective version was also explored to yield chiral
alcohols with er upto 12:88 which is reported for the first time.
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