Synthesis of α-Aryl Oxindoles by Friedel-Crafts Alkylation of Arenes

Article abstract of DOI:10.1021/acs.joc.0c00370

α-Aryl oxindoles are accessed from isatin via a two-step procedure involving a phospha-Brook rearrangement and a Friedel-Crafts alkylation in a one-pot procedure. The use of 1,1,1,3,3,3-hexafluoro-2-propanol as solvent significantly extended the reaction

Full text of DOI:10.1021/acs.joc.0c00370

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Synthesis of #-Aryl-Oxindoles by Friedel-Crafts Alkylation of Arenes
Balaji Vasantrao Rokade, and Patrick Jerome Guiry
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00370 • Publication Date (Web): 07 Apr 2020
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The Journal of Organic Chemistry
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Synthesis of -Aryl-Oxindoles by Friedel-Crafts Alkylation of Arenes
Balaji V. Rokade, and Patrick J. Guiry*
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Centre for Synthesis and Chemical Biology (CSCB), Synthesis and Solid State Pharmaceutical Centre (SSPC), School of
Chemistry, University College Dublin (UCD), Belfield, Dublin 4, Ireland
Supporting Information Placeholder
Ar
Ar
O
Deoxygenation
Ar
O
Ar
O
O
then Ar-H
N
N
N
R
Me
R
28 examples
Ar = 2,4,6-(OCH3)3C6H2
up to 93% yield
95% yield, 92% ee
Transition metal-free
Good selectivity
Stoichiometric use of arenes
Scalable
Wide substrate scope
ABSTRACT: -Aryl-oxindoles are accessed from isatin via a two-step procedure involving a phospha-Brook rearrangement
and a Friedel-Crafts alkylation in a one-pot procedure. The use of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvent
significantly extended the reaction substrate scope to include relatively less electron rich arenes including benzene. This
new alkylation method is fast, straightforward and allows for the direct introduction of the oxindole moiety onto a range of
aromatic compounds including phenols. Additionally, the application of arylated products was shown in decarboxylative
asymmetric allylation and protonation.
Oxindoles are an important class of compound because
of their presence in various natural products and
biologically active molecules.1 -Aryl-oxindoles are
synthetically interesting as they have found various
applications in biology and pharmaceutical chemistry
(Figure 1).2 -Aryl-oxindoles have also been employed as a
substrates in various asymmetric organic transformations3
including allylation,3a amination,3b halogenation,3c and
thiocyantion.3d
reagents4 ii) the acylation of N-substituted oxindoles with
allyl chloroformate using strong base followed by arylation
involving aryllead triacetate and then decarboxylative
protonation;5 iii) aryl Grignard reagent addition to isatin to
generate a tertiary alcohol followed by reductive
a) Literature reports
i)
ii)
O
O
rmate
Py
o
N
N
f
,
acid
3
R
R
R # H
Pd/Ni
chloro
formic
R = H, alkyl
Ar-X
,
Allyl
2.
ArPb(OAc)
catalysis
Cl
Cl
1.
F
HO
Pd/dppe
OMe
OH
OMe
3.
Cl
Cl
iv)
v)
1) TsNHNH2
2) aq. NaOH
3) base, R-X
O
Ar
O
O
O
O
cat. i-Pr2NEt
(PhO)2P(O)H then
N
N
N
F3C
F3C
H
H
H
O
O
O
cat. Pd/XPhos
(ArBO)3, base or
TfOH (cat.)
ArH (5 equiv)
Pd/liga
N
Bn
N
R
N
R
I
II
III
BMS-204352
O
O
(potassium channel openers) (potassium channel openers)
(anti-cancer agent)
Ar
B
R # H
O
K
Cl
NaO
or
Cl
acid
F3C
HO
nd
t
Bu
HO
Pd/C
ArMgBr
e/Lewis
N
O
then
O
Ar
H2N
N

N
HCl
NEt2
hydrid
iii)
vi)
O
O
N
R
O
N
R
X
IV
V
SM-130686
Tetrahydropyrimido[1,2-a]indole
(hypoglycaemic agents)
(growth hormone secretagogue receptor)
R = H, alkyl
R = alkyl; X = Br, Cl
b) Present work
Figure 1. -Aryl-oxindole containing pharmaceutically active
molecules.
OPO(OEt)2
O
N
R
O
Ar
Na2CO3 (cat.)
(EtO)2P(O)H
TfOH (cat.)
3
ArH (
)
To date, various methods have been developed for the
synthesis of -aryl-oxindoles (Figure 2a). Selected existing
approaches for the synthesis of -aryl-oxindoles involve: i)
the transition metal-catalysed reaction of N-substituted
O
O
N
R
N
R
1
2
4
Figure 2. Strategies for the synthesis of -aryl-oxindoles.
oxindoles
with
aryl
halides/pseudohalides/boron
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deoxygenation using Pd/C or hydride reagents in the TfOH, we further investigated the activity of a few weaker
presence of strong Lewis acids;3e,6 iv) the reaction of N-
substituted oxindoles with a catalytic amount of Hunig ’s
base and diphenylphosphite followed by a Pd-catalysed
reaction with aryl boron reagents;7 v) a multistep reaction
where the -carbonyl group of isatin is converted into the
corresponding diazo compound in three steps followed by
base-mediated reaction with aryl boroxines or a triflic acid
catalysed reaction with excess amount of electron rich
Bronsted acids, including methanesulfonic acid (MSA),
para-toluenesulfonic acid (p-TSA), camphorsulfonic acid
(CSA) and trifluoroacetic acid (TFA) using CH3CN as the
solvent (entries 16-19). All of these Bronsted acids also
formed the expected Friedel-Crafts alkylation product 4a
but only after relatively longer reaction times (12 to 24 h).
Finally, we settled with the optimised reaction conditions
which includes 2a as limiting reagent with 1.5 equivalent
of 1,3,5-trimethoxybenzene and 10 mol% TfOH in
acetonitrile (0.6 M) at 60 ˚C for 2 h.
1
2
3
4
5
6
7
8
arenes;8 and vi)
a
metal-catalysed intramolecular
9
cyclisation.9 Despite these advances, the use of transition
metal catalysis, aryl halides/pseudohalides/boron
reagents, toxic aryllead reagents, a limited substrate scope
in terms of requiring a protected N-H group and the use of
the sterically bulkier aryl moiety, multistep synthesis, and
the requirement of using a syringe pump - all these
approaches have limitations. Bearing these factors in mind
and with our interest in synthesis of -aryl-carbonyl
compounds,10 we proposed a new catalytic method for the
synthesis of -aryl-oxindoles involving Friedel-Crafts
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Table 1. Optimisation studiesa
OMe
OPO(OEt)2
OMe
catalyst (10 mol%)
OMe
O
MeO
+
O
solvent (0.6 M)
temp, time
N
MeO
OMe
H
NH
4a
2a
3a
temp (° time conversion
entry
catalyst solvent
FeCl3 DCE
alkylation of arene using
a novel oxindole coupling
C)
rt
rt
rt
(h)
48
48
48
48
24
24
3
(%)b
nd
partner, diethyl (2-oxoindolin-3-yl) phosphate 2, in situ
derived from isatin (Figure 2b).
1
2
3
4
5
6
7
8
Cu(OTf)2 DCE
Zn(OTf)2 DCE
Sc(OTf)3 DCE
Sc(OTf)3 DCE
Sc(OTf)3 THF
Sc(OTf)3 MeNO2
Sc(OTf)3 CH3CN
nd
nd
50
The alkylating oxindole coupling partner 2a was
prepared by employing a base-catalysed phospha-Brook
rearrangement of isatin (1a) with diethylphosphite
(Scheme 1).11
rt
60
60
60
60
rt
60
60
60
60
60
rt
60
60
60
60
60
60
>99
>99
>99
>99
65
>99
>99
>99
>99
>99(82)c
>50
>99
>99
>99
>99d
>99(85)c
nd
Scheme 1. Synthesis of oxindole coupling partner
2
O
OPO(OEt)2
(EtO)2POH (1 equiv)
Na2CO3 (10 mol%)
9
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
MSA
p-TSA
CSA
TFA
TfOH
None
DCE
DCE
THF
48
24
24
24
2
O
O
10
11
12
13
14
15
16
17
18
19
20
21
CH3CN (0.6 M)
60 C, 2 h
N
N
H
H
1a
2a,
98%
MeNO2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
HFIP
We then commenced the optimisation of our key step
involving catalytic C-H alkylation of 1,3,5-
2
trimethoxybenzene (3a) (Table 1). We realised that 2a
under Lewis or Bronsted acidic conditions would generate
an electrophilic oxindole coupling partner. Lewis acids
such as FeCl3, Cu(OTf)2, or Zn(OTf)2 in dichloroethane at
room temperature did not furnish the expected product
after 48 h, although, we were glad to see that the use of
Sc(OTf)2 afforded product 4a in 50% yield (entries 1 to 4).
Increasing the reaction temperature to 60 ˚C in
dichloroethane showed complete conversion to the
product (entry 5). Changing the solvent to
tetrahydrofuran, nitromethane or acetonitrile furnished
the product 4a quantitatively (entries 6-8). Interestingly,
the use of triflic acid gave the alkylation product 4a in 65%
conversion after prolonged reaction time (48 h) at room
temperature (entry 9). After heating the reaction to 60 ˚C,
quantitative conversion to 4a was achieved in 24 h.
Changing the solvent to tetrahydrofuran or nitromethane
showed similar results as dichloroethane (24 h for full
conversion) whereas the use of acetonitrile as solvent
drastically reduced the reaction time to 2 h. Subsequently,
reducing the amount of 1,3,5-trimethoxybenzene from 3 to
1.5 equivalents did not have a negative impact on the
conversion and product 4a was isolated in 82% yield.
However, the same reaction at room temperature dropped
the conversion to 50%, even after 12 h reaction time
(entry 15). Encouraged by the high catalytic activity of
12
12
12
24
24
2
HFIP
5
aReaction conditions: 2a (0.6 mmol), 3a (1.8 mmol), catalyst
(0.060 mmol), solvent (0.6 M). bConversions were determined
by 1H NMR spectroscopic analysis of the crude reaction,
isolated yields in parentheses. c1.5 equivalent of 3a. d1.5
equivalent of TFA.
Interestingly, this optimised reaction condition was not
suitable for less electron rich arene substrates such as
toluene and benzene as only trace amounts of expected
products were formed. Therefore, further optimisation of
the reaction conditions was required to achieve the best
results for such substrates. Recent reports of the use of
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as a solvent in
organic synthesis drew our attention.12 The initial work of
Moran showed that the application of HFIP as a solvent in
catalytic reactions with TfOH drastically increased the
reaction rate.13 Interestingly, the use of HFIP as a solvent in
our study provided full conversion to the expected product
4a after 2 h, similar results to that in CH3CN using 3a as
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The Journal of Organic Chemistry
the arene source (compare entries 14 and 20). Since HFIP product 4h as a mixture of ortho- and para-isomers (1:8.9)
1
2
3
4
5
6
7
8
itself can act as a strong hydrogen-bond donor, a control
reaction was carried out without a catalytic amount of
TfOH (entry 21). This reaction resulted in no product
formation suggesting no possible background reaction
without TfOH.
in 90% yield. The application of 1,3- and 1,2-xylenes (3i-
3j) afforded the products 4i and 4j as single isomers in
80% and 85% yields, respectively. The application of
toluene (3k) produced 4k in 81% yield with a 1:4.4 ratio
of ortho- and para-isomers. Similarly, deuterated toluene
(3l) afforded product 4l in 93% yield in a 1:4.1 ortho:para
ratio. The use of diphenylmethane (3m) and allylbenzene
(3n) furnished the expected products 4m and 4n, although
in moderate yields of 41% and 38%, respectively, but as
single isomers. Interestingly, C-H alkylation of the less
reactive aromatic compound, benzene (3o), furnished the
expected product 4o albeit in a 39% yield. The heterocycle
indole 3p also furnished the 3-alkylation product 4p in a
low yield of 27% using methanesulfonic acid instead of
TfOH due to the decomposition of product observed
subsequently. Additionally, electronically poor arenes such
as bromo-, chloro- and iodobenzene were also tested
which afforded arylated products in only trace amounts.
The use of aniline was not successful due to the observed
decomposition under the present reaction conditions.
After optimisation of both steps independently, we
decided to develop a one pot procedure for this C-H
alkylation strategy wherein diethyl (2-oxoindolin-3-yl)
phosphate (2a) was prepared in situ from isatin (1a)
followed by the addition of 1,3,5-trimethoxybenzene (3a)
and a catalytic amount of TfOH. Gratifyingly, this approach
selectively furnished the product 4a in 76% yield in CH3CN
and 68% in HFIP (Scheme 2). A similar reaction on a large
scale (10 mmol, 1.47 g) in acetonitrile furnished 4a in 56%
yield.
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Scheme 2. One pot procedure for the synthesis of -
aryl-oxindoles
O
(EtO)2POH (1 equiv)
Na2CO3 (10 mol%)
3a
(1.5 equiv)
TfOH (20 mol%)
4a
2a
O
CH3CN (0.6 M)
60 C, 2 h
Scheme 3. Substrate scope with various arenesa,b
CH3CN or HFIP (0.6 M)
60 °C, 2 h
N
H
76%a and 56%b (CH3CN)
68%a (HFIP)
1a
(EtO)2POH (1 equiv), Na2CO3 (10 mol%)
CH3CN (0.6 M), 60 °C, 2 h
O
Ar
O
O
3
Ar-H or Ar-OH ( ) (1.5 equiv)
b
aReaction performed on 0.6 mmol scale. Reaction performed
N
N
H
H
TfOH (20 mol%)
on 10 mmol scale.
1a
4b-t
CH3CN or HFIP (0.6 M), 60 °C, 2 h
As observed, the use of catalytic amounts of TfOH with
HFIP as solvent provided improved results compared to
acetonitrile with less reactive aromatic compounds. As a
result, we explored a substrate scope with both solvent
systems to compare their reactivity. The percentage yields
quoted within the following text refers to those reactions
carried out in HFIP, whereas Scheme 3 shows both results
for comparison. It was also observed that the yields of the
expected alkylated products dropped slightly when the
reaction was carried out in one pot compared to the
stepwise reaction procedure.
OMe
OMe
OMe
OMe
MeO
MeO
OMe
OMe
OMe
OMe
4d
4e
48%
74%
4b
4c
76% (2 vs 4, 1:10.3)
75% (2 vs 4, 1:9.5)
65%c
89%c
62%c
92%c
OMe
Br
Me
O
O
OMe
Me
4f
4g
4h
i
4
45% (1:0.6:0.7)d
78% (1:0.6:0.7)d
13%c
77%c
58%e (2 vs 4, 1:4)
90%e (2 vs 4, 1:8.9)
45%c,e
80%c,e
We investigated the scope of the reaction by reacting
isatin 1a in a one pot fashion with a range of arenes (3b-
3p) (Scheme 3). Initially, the reaction of variously
D
D
D
D
substituted
methoxybenzene
analogues
(3b-3h)
Me
Me
proceeded smoothly under the optimised reaction
conditions to provide C-H alkylated products (4b-4h) in
good to excellent yields (74-90%). It is important to note
that, for a few of the arene substrates there is a possibility
of forming a mixture of ortho- and para-isomers of
Me
CD3
Ph
4m
4j
4k
4l
30%c,e
85%c,e
6%e (2 vs 4, 1:4.3)
81%e (2 vs 4, 1:4.4) 93%e (2 vs 4, 1:4.1)
5%e (2 vs 4, 1:4)
nr
41%c
alkylated
products.
The
reaction
of
1,2,3-
trimethoxybenzene (3b) selectively furnished the product
4b in 89% yield. Similarly, 1,2,4-trimethoxybenzene
afforded selectively 4c as the only isomer in 92% yield.
The use of dimethoxybenzenes such as 1,3-
dimethoxybenzene (3d) provided alkylated product 4d in
75% yield along with a minor amount of the other
regioisomer (1:9.5 ratio of 2- vs 4- alkylation). Later, 1,4-
dimethoxybenzene (4e) reacted smoothly to afford the
only possible isomer 4e in 74% yield. The use of 2-
methoxynaphthalene as the arene source provided the
product 4f in 78% yield as an unidentified mixture of
regioisomers (1:0.6:0.7 ratio). The bromo-substituted 1,3-
benzodioxole (3g) furnished product 4g as a single isomer
in 77% yield. The reaction of anisole (3h) afforded the
NH
OH
4q
4n
nr
4o
nr
4p
nr
85% (2 vs 4, 1:5.2)
80% (2 vs 4, 1:3.5)
38%c
39%e
27%c
OH
Br
Cl
OH
OH
4t
4r
4s
85% (1:1:0.6)d
90% (1:0.9:0.6)d
80% (4 vs 6, 1.7:1)
58% (4 vs 6, 1:0)
79% (4 vs 6, 1.6:1)
84% (4 vs 6, 1:0)
aIsolated yield – yield using CH3CN or HFIP solvent. Only the
major isomer is illustrated where more than one product was
b
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identified. cOnly isomer. dUnidentified mixture of regioisomers
H
OPO(OEt)2
OPO(OEt)2
O
e5 equivalent of Ar-H used.
1
2
3
4
5
6
7
8
(EtO)2POH
Na2CO3
TfOH
HFIP
1a
O
After investigating the scope of various aromatic
compounds, we turned our attention towards selective C-H
alkylation of phenols (3q-3t) with isatin (1a) (Scheme 3).
The reaction of 1a with phenol (3q) furnished the C-H
alkylation product 4q in 80% yield as a mixture of ortho-
and para-isomers in a 1:3.5 ratio. Next, ortho-substituted
bromophenol (3r) and chlorophenol (3s), yielded selective
para C-H alkylation products (4r-4s) in good to excellent
yields (58-84%). The use of 2-naphthol (3t) furnished
product 4t in 90% yield as an unidentified mixture of
regioisomers in a 1:0.9:0.6 ratio. Finally, it is important to
note that the yield of products (4b-4t) were consistently
better (except 4d, 4q, and 4r) with HFIP as a solvent
compared to when acetonitrile was employed as solvent.
N
N
H
H
2a
-HOP(O)(OEt)2 HFIP
Ph
Benzene
O
O
N
-H
N
H
H
9
4o
A
10
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diethyl-(2-oxoindolin-3-yl)-phosphate
(2a).
This
intermediate is then activated in the presence of catalytic
amounts of TfOH (20 mol%) to generate the electrophilic
oxindole species (A) which subsequently reacts with
benzene to generate 3-phenyl-oxindole (4o). We believe
that HFIP plays an important role in stabilising the
electrophilic oxindole intermediate (A) due to its high
ionising power with low nucleophilicity.12,13
After exploring the reaction of a wide range of aromatic
compounds (3b-3t) with isatin (1a), we turned our
attention to study the effect of employing different N-
substituted isatin derivatives (1b-1e, Scheme 4). The
reaction of 1,3,5-trimethoxybenzene (3a) with N-
benzylated (1b), N-allylated (1c), N-propargylated (1d)
and N-methylated (1e) analogues of isatin furnished the
expected alkylated products (4u-4x) in good to moderate
yields (52-64%). Similarly, the effect of various
substitutions at the 5-position of isatin was also studied
(1f-1i, Scheme 4). The isatins with 5-halo substituents
such as bromo (1f), chloro (1g) and fluoro (1h) reacted
smoothly with 3a to furnish the expected alkylated
products (4y-4aa) in 62%, 67% and 56% yields,
respectively. Finally, 5-methoxyisatin (1i) upon reaction
with 3a afforded product (4ab) in excellent yield (88%).
Additionally, the synthetic utility of arylated products
was shown in the synthesis of quaternary and tertiary
arylated chiral products (Scheme 6). The starting material,
enol carbonate 5, required for palladium-catalysed
decarboxylative asymmetric allylation and protonation
was prepared from 4a in 80% yield (Scheme 6a). The enol
carbonate 5 upon reaction with catalytic amounts of
Pd(dba)3.CHCl3 and (R,R)-ANDEN-phenyl-Trost ligand
furnished product 6 with a quaternary chiral center in an
excellent ee of 91% and 94% yield (Scheme 6b).3a,5,14
Similarly, 5 when reacted under palladium catalysis using
(1R,2S)-(-)-ephedrine as a chiral proton source furnished a
-aryl-oxindole 7 in 42% ee and 95% yield (Scheme 6b).15
Scheme 4. Substrate scope with various N-alkylated
and 5-substituted isatinsa
Scheme 6. Synthetic applications
a) Synthesis of enol carbonate 5
OMe
NaOtBu (1.5 equiv.)
Ar
Ar
O
(EtO)2POH (1 equiv), Na2CO3 (10 mol%)
CH3CN (0.6 M), 60 °C, 12 to 24 h
allyl chloroformate (1.5 equiv.)
R2
O
OCO2allyl
MeO
R2
OMe
O
THF, 0 C to rt, 4 h
N
N
O
Me
4a
Ar = 2,4,6-(OCH3)3C6H2
b) Decarboxylative asymmetric allylation and protonation
Me
N
R1
3a
(1.5 equiv), TfOH (20 mol%)
CH3CN or HFIP (0.6 M), 60 °C, 2 h
5
N
R1
4s-4ab
80% yield
1b-1i
1 = Bn, R2 = H; 50% (60%)
1 = H, R2 = Br; (62%)
R
1 = H, R2 = Cl; (67%)
1 = H, R2 = F; (56%)
1 = H, R2 = OMe; (88%)
4u,
4v
4y,
R
R
, R1 = Allyl, R2 = H; 71% (64%)
4z,
O
O
, R1 = Propargyl, R2 = H; 65% (52%)
, R1 = Methyl, R2 = H; 52% (60%)
R
4w
4x
4aa,
4ab,
NH
HN
Ar
Pd2(dba)3·CHCl3 (2.5 mol%)
R
PPh2 Ph2P
(R,R)-ANDEN-phenyl-Trost (6.5 mol%)
O
aIsolated yield – yield using CH3CN (HFIP) as solvent.
Toluene (0.033 M), N2
rt, 18 h
N
(R,R)-ANDEN-phenyl-Trost
Me
We propose the following reaction mechanism for this
novel two step aromatic C-H alkylation (Scheme 5).
Initially diethylphosphite reacts with isatin (1a) in the
presence of a catalytic amount of Na2CO3 (10 mol%) to
generate
6
91% ee, 94% yield
5
Ar = 2,4,6-(OCH3)3C6H2
Ar

Pd(Ph3P)4 (2.5 mol%)
(1R,2S)-()-ephedrine (1.2 equiv.)
OH
H
O
THF, 25 C, 20 min
N
N
Ph
Me
Me
Scheme 5. Proposed reaction mechanism
Me
(1R,2S)-()-ephedrine
7
42% ee, 95% yield
To conclude, we report an efficient, easy and versatile
method for the synthesis of -aryl-oxindoles by using
Friedel-Crafts alkylation of aromatic compounds with an
electrophilic alkylating oxindole coupling partner. The
alkylating oxindole precursor was synthesised by using a
base-catalysed phospha-Brook rearrangement of readily
available isatin with diethylphosphite. This methodology
allows for the selective installation of the oxindole moiety
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onto aromatic compounds, including phenols, with good trimethoxybenzene (3a, 0.90 mmol) and TfOH (20 mol%)
1
2
3
4
5
6
7
8
levels of regioselectivity.
were added, followed by CH3CN or hexafluoroisopropanol
(HFIP) (1 mL, 0.6 M). The reaction mixture was stirred at
the same temperature (60 ° C) until the completion of
reaction (2 h). The crude reaction mixture was directly
purified by flash column chromatography on silica gel to
get the product.
EXPERIMENTAL SECTION
1. General Information
Unless otherwise noted, all commercial reagents were
used as received without further purification.
Tetrahydrofuran (THF) were obtained from a PureSolv-
300-3-MD dry solvents dispenser. Acetonitrile and toluene
were dried using standard protocols. Standard Schlenk
techniques were employed for moisture sensitive
reactions. Column chromatography was performed on
Davisil LC60A 40-63 micron silica gel. Thin-layer
chromatography (TLC) was performed on aluminium-
backed sheets purchased from Merck pre-coated with
silica gel 60 F254. NMR spectra were recorded in
(Note: It is important to note that the complete removal of
acetonitrile from the first step is necessary before adding
HFIP and TfOH to obtain better yields of the products)
9
2.4 General procedure for synthesis of 4 from 1
10
11
12
13
14
15
16
17
18
19
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23
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27
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54
55
56
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58
59
60
In a 10 mL screw-cap glass vial equipped with a
magnetic stirrer, isatin (1, 0.6 mmol), Na2CO3 (0.06 mmol)
and diethylphosphite (0.6 mmol) were added, followed by
CH3CN (1 mL, 0.6 M). The reaction mixture was stirred at
60 ° C in preheated oil bath until the disappearance of
isatin (1) (2 to 12 h). Then Ar-H or Ar-OH (3, 0.90 mmol)
and TfOH (20 mol%) were added, followed by CH3CN or
hexafluoroisopropanol (HFIP) (1 mL, 0.6 M). The reaction
mixture was stirred at the same temperature (60 °C) until
the completion of reaction (2 h). The crude reaction
mixture was directly purified by flash column
chromatography on silica gel to get the product.
deuterated
chloroform
(CDCl3)
or
deuterated
dimethylsulfoxide (DMSO-D6). 1H NMR spectra were
recorded on VarianInova spectrometers (300, 400 and 500
MHz). 13C NMR spectra were recorded on 300, 400, 500
and 600 MHz Varian-Inova spectrometers (75, 101,125
and 150 MHz). HRMS were measured on
a
Micromass/Waters LCT mass spectrometer. Infrared
spectra were recorded on a FT-IR spectrometer and are
reported in terms wavenumbers ( ν max) with units of
reciprocal centimetres (cm-1). Supercritical fluid
2.5 Procedure for synthesis of enol carbonate 5
In a 25 mL round bottom flask equipped with a magnetic
stirrer, arylated oxindole (4a, 0.415 mmol, 1 equiv.) and
NaOtBu (0.622 mmol, 1.5 equiv.) was added in dry THF (5
mL) and reaction mixture stirred at 0 °C for 15 minutes. At
this point allylchloroformate (0.622 mmol, 1.5 equiv.) is
added to the reaction mixture and it was stirred at room
temperature until the completion of reaction (4 h). Then
reaction was quenched with small amount of water
followed by work up with EtOAc (50 mL) and purification
by flash column chromatography on silica gel resulted the
product enol carbonate 5 as a white solid.
chromatography (SFC) was performed on
a Waters
Acquity UPC2 ® instrument with Chiralpak® IA-3 and IB-3
columns. Optical rotation measurements were recorded
using a Schmidt-Haensch Unipol L2000 polarimeter at 589
nm and are quoted in units of deg dm-1 cm3 g-1
(concentration c is given in g/100 mL).
2. Experimental Procedures
2.1 Synthesis of 2a from 1a
In a 10 mL screw-cap glass vial equipped with a
magnetic stirrer, isatin (1a, 0.6 mmol), Na2CO3 (0.06
mmol) and diethylphosphite (0.6 mmol) were added,
followed by CH3CN (1 mL, 0.6 M). The reaction mixture
was stirred at 60 ° C in preheated oil bath until the
completion of reaction (2 h). The crude reaction mixture
was directly purified by flash column chromatography on
silica gel to get the product 2a.
2.6 Procedure for palladium-catalysed decarboxylative
asymmetric allylation
To a mixture of arylated enol carbonate (5, 25 mg,
0.0629 mmol, 1 equiv.), Pd2(dba)3·CHCl3 (1.62 mg, 0.00157
mmol, 2.5 mol%), and (R,R)-ANDEN-Phenyl-Trost ligand
(3.3 mg, 0.00408 mmol, 6.5 mol%) under N2 was added
toluene (0.033 M). The mixture was allowed to stir at room
temperature for 24 h. The solution was reduced in vacuo
and purified by flash column chromatography to yield (R)-
6 as a white solid (21 mg, 94% yield, 91% ee).
2.2 Synthesis of 4a from 2a
In a 10 mL screw-cap glass vial equipped with a
magnetic stirrer, diethyl (2-oxoindolin-3-yl) phosphate
(2a, 0.60 mmol), arene (3a, 0.90 mmol) and TfOH (20
mol%) were added, followed by CH3CN or
hexafluoroisopropanol (HFIP) (1 mL, 0.6 M). The reaction
mixture was stirred at 60 °C in preheated oil bath until the
completion of reaction (2 h). The crude reaction mixture
was directly purified by flash column chromatography on
silica gel to get the product.
2.7 Procedure for palladium-catalysed decarboxylative
asymmetric protonation
[Pd(PPh3)4] (1.8 mg, 2.5 mol%), (1R,2S)-(–)-ephedrine
(12.5 mg, 1.2 eq.) and arylated enol carbonate (5, 0.0844
mmol, 25 mg, 1 eq.) were added to a flame dried Schlenk
flask (10 mL) followed by anhydrous THF (2.5 mL). The
reaction mixture was stirred at 25 ° C for 20 min after
which reaction was quenched and the solvent was
removed in vacuo and the resulting residue purified by
flash column chromatography to obtain protonated
product 7 as a white solid in 95% yield and 45% ee.
2.3 One pot procedure for synthesis of 4a from 1a
In a 10 mL screw-cap glass vial equipped with a
magnetic stirrer, isatin (1a, 0.6 mmol), Na2CO3 (0.06
mmol) and diethylphosphite (0.6 mmol) were added,
followed by CH3CN (1 mL, 0.6 M). The reaction mixture
was stirred at 60 ° C in preheated oil bath until the
disappearance of isatin (1a) (2 to 12 h). Then 1,3,5-
(Note: Racemisation of chiral centre was observed over
the time or when reaction was kept for longer time due to
the highly acidic -proton of arylated oxindole product)
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3. Characterisation of products
Diethyl (2-oxoindolin-3-yl) phosphate (2a)16
The title compound was prepared according to the general
procedure 2.4.
1
2
3
4
5
6
7
8
Yellow solid. Melting point = 162-164 ˚C. Yield = 123 mg,
76% in CH3CN (2 vs 4, 1:10.3) and 121 mg, 75% in HFIP (2
vs 4, 1:9.5). Rf = 0.45 (50% ethyl acetate/cyclohexane). IR
(neat, cm-1): 3212, 2928, 1705, 1614, 1588, 1508, 1470,
1328, 1292, 1209, 1157, 1035. 1H NMR (500 MHz,
Chloroform-d) δ 8.70 (s, 1H), 7.22 – 7.14 (m, 1H), 7.03 (dd,
J = 7.9, 1.9 Hz, 2H), 6.95 (td, J = 7.5, 1.0 Hz, 1H), 6.90 (d, J =
7.9 Hz, 1H), 6.50 (d, J = 2.4 Hz, 1H), 6.47 (dd, J = 8.3, 2.5 Hz,
1H), 4.84 (s, 1H), 3.80 (s, 3H), 3.73 (s, 3H). 13C {1H} NMR
(126 MHz, Chloroform-d) δ 179.6, 160.5, 158.5, 141.4,
130.8, 130.6, 127.7, 124.3, 122.3, 118.0, 109.4, 104.8, 99.4,
55.7, 55.4, 47.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C16H16NO3 270.1125; Found 270.1124.
The title compound was prepared according to the general
procedure 2.1.
Colourless oil. Yield = 168 mg, 98%. Rf = 0.30 (50 % ethyl
1
acetate/cyclohexane). H NMR (300 MHz, Chloroform-d) δ
9.00 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.31 – 7.20 (m, 1H),
7.03 (td, J = 7.6, 1.1 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 5.57 (d,
J = 13.0 Hz, 1H), 4.38 – 4.02 (m, 4H), 1.35 (dtd, J = 11.1, 7.1,
1.2 Hz, 6H). 31P NMR (121 MHz, Chloroform-d) δ -1.17.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(2,4,6-Trimethoxyphenyl)indolin-2-one (4a)
The title compound was prepared according to the general
procedure 2.3.
Yellowish solid. Melting point = 219-221 ˚C. Yield = 147
mg, 82% in CH3CN and 153 mg, 85% in HFIP. Rf = 0.25
(50% ethyl acetate/cyclohexane). IR (neat, cm-1): 3205,
2935, 2839, 1703, 1608, 1594, 1469, 1418, 1329, 1206,
3-(2,5-Dimethoxyphenyl)indolin-2-one (4e)
The title compound was prepared according to the general
procedure 2.4.
1
1149, 1057. H NMR (500 MHz, Chloroform-d) δ 9.16 (s,
Yellow solid. Melting point = 151-152 ˚C. Yield = 78 mg,
48% in CH3CN and 119 mg, 74% in HFIP. Rf = 0.45 (50%
ethyl acetate/cyclohexane). IR (neat, cm-1): 3207, 2968,
1H), 7.14 (tt, J = 7.5, 1.2 Hz, 1H), 6.98 – 6.84 (m, 3H), 6.24
(d, J = 2.2 Hz, 1H), 6.07 (d, J = 2.2 Hz, 1H), 5.15 (s, 1H), 3.90
(s, 3H), 3.81 (s, 3H), 3.49 (s, 3H). 13C {1H} NMR (126 MHz,
Chloroform-d) δ 180.9, 160.9, 159.5, 159.0, 141.8, 130.9,
127.1, 123.5, 121.8, 109.2, 106.5, 91.7, 91.0, 56.0 (d), 55.8
(d), 55.4 (d), 42.7. HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C17H17NO4Na 322.1050; Found 322.1041.
1
2834, 1699, 1618, 1499, 1469, 1227, 1042. H NMR (400
MHz, Chloroform-d) δ 8.30 (s, 1H), 7.20 – 7.13 (m, 1H),
7.05 – 6.99 (m, 1H), 6.93 (td, J = 7.5, 1.0 Hz, 1H), 6.87 (d, J =
7.8 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 6.78 (dd, J = 8.9, 2.9 Hz,
1H), 6.67 (d, J = 3.0 Hz, 1H), 4.84 (s, 1H), 3.72 (s, 3H), 3.68
(s, 3H). 13C {1H} NMR (101 MHz, Chloroform-d) δ 178.7,
153.8, 151.8, 141.3, 130.2, 127.8, 126.7, 124.4, 122.4,
116.4, 113.3, 112.8, 109.3, 56.5, 55.7, 48.5. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C16H16NO3 270.1125; Found
270.1118.
3-(2,3,4-Trimethoxyphenyl)indolin-2-one (4b)
The title compound was prepared according to the general
procedure 2.4.
Yellowish solid. Melting point = 162-164 ˚C. Yield = 117
mg, 65% in CH3CN and 160 mg, 89% in HFIP. Rf = 0.40
(50% ethyl acetate/cyclohexane). IR (neat, cm-1): 3253,
2940, 1704, 1618, 1601, 1494, 1469, 1418, 1327, 1276,
1234, 1205, 1094. 1H NMR (500 MHz, Chloroform-d) δ 8.89
(s, 1H), 7.19 (td, J = 7.7, 1.2 Hz, 1H), 7.01 (d, J = 7.3 Hz, 1H),
6.96 (td, J = 7.5, 1.1 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.88 (d,
J = 8.5 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 4.69 (s, 1H), 3.86 (s,
3H), 3.85 (s, 3H), 3.63 (s, 3H). 13C {1H} NMR (126 MHz,
Chloroform-d) δ 179.6, 153.7, 152.0, 142.5, 141.6, 130.8,
127.9, 124.8, 124.3, 123.4, 122.3, 109.6, 107.3, 60.7, 60.6,
56.0, 49.1. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C17H17NO4Na 322.1050; Found 322.1050.
3-(2-Methoxynaphthalen-1-yl)indolin-2-one (4f)
The title compound was prepared according to the general
procedure 2.4.
Yellow solid. Melting point = 196-198 ˚C. Yield = 78 mg,
45% in CH3CN (mixture of regioisomers in 1:0.6:0.7 ratio)
and 135 mg, 78% in HFIP (mixture of regioisomers in
1:0.6:0.7 ratio). Rf = 0.30 (50% ethyl acetate/cyclohexane).
IR (neat, cm-1): 3213, 2925, 2853, 1708, 1620, 1602, 1512,
1
1470, 1391, 1326, 1265, 1218, 1030. H NMR (500 MHz,
DMSO-d6) δ 10.83 (s, 1H), 10.56 (s, 1H), 10.46 (s, 1H), 8.33
(dt, J = 8.5, 0.9 Hz, 1H), 7.99 – 7.90 (m, 3H), 7.89 – 7.84 (m,
1H), 7.78 (q, J = 9.0 Hz, 2H), 7.64 (d, J = 1.7 Hz, 1H), 7.61 –
7.55 (m, 2H), 7.44 (ddd, J = 7.9, 6.8, 1.0 Hz, 1H), 7.38 (d, J =
9.0 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.27 – 7.18 (m, 3H), 7.18 –
7.09 (m, 3H), 7.06 (dd, J = 7.2, 1.2 Hz, 1H), 7.01 (d, J = 7.8
Hz, 1H), 6.95 (t, J = 7.4 Hz, 2H), 6.91 – 6.79 (m, 3H), 6.76
(td, J = 7.5, 1.1 Hz, 2H), 6.66 – 6.59 (m, 1H), 5.67 (t, J = 1.1
Hz, 1H), 5.45 (s, 1H), 4.86 (s, 1H), 4.01 (s, 2H), 3.86 (s, 3H),
3.55 (s, 3H). 13C {1H} NMR (126 MHz, DMSO-d6) δ 178.9,
178.3, 177.8, 157.7, 156.7, 155.2, 143.5, 143.2, 142.4,
134.2, 133.8, 133.2, 132.3, 131.1, 130.9, 130.7, 130.3,
129.6, 129.5, 129.5, 129.2, 129.0, 128.9, 128.6, 128.2,
127.7, 127.6, 127.5, 127.4, 127.2, 127.1, 125.3, 124.0,
123.8, 123.8, 123.7, 123.4, 123.2, 123.0, 122.2, 122.1,
121.4, 120.6, 119.3, 117.7, 115.5, 114.6, 110.2, 109.9,
109.2, 106.2, 57.7, 56.8, 55.6, 52.3, 45.0, 44.5. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C19H16NO2 290.1176; Found
290.1173.
3-(2,4,5-Trimethoxyphenyl)indolin-2-one (4c)
The title compound was prepared according to the general
procedure 2.4.
Brown solid. Melting point = 183-185 ˚C. Yield = 108 mg,
62% in CH3CN and 165 mg, 92% in HFIP. Rf = 0.25 (50%
ethyl acetate/cyclohexane). IR (neat, cm-1): 2941, 2838,
1
1708, 1594, 1458, 1424, 1324, 1204, 1149, 1116, 1066. H
NMR (500 MHz, Chloroform-d) δ 8.46 (s, 1H), 7.20 (tt, J =
7.6, 1.1 Hz, 1H), 7.06 – 7.01 (m, 1H), 6.97 (td, J = 7.4, 1.0 Hz,
1H), 6.91 (d, J = 7.8 Hz, 1H), 6.64 (s, 1H), 6.58 (s, 1H), 4.83
(s, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 3.72 (s, 3H). 13C {1H} NMR
(126 MHz, Chloroform-d) δ 179.3, 152.0, 149.4, 143.4,
141.3, 130.6, 127.80, 124.4, 122.4, 116.9, 113.9, 109.4,
98.7, 56.9, 56.7, 56.2, 48.1. HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C17H17NO4Na 322.1050; Found 322.1064.
3-(2,6-Dimethoxyphenyl)indolin-2-one (4d)8b
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3-(6-Bromobenzo[d][1,3]dioxol-5-yl)indolin-2-one
(4g)
19.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H16NO
238.1226; Found 238.1234.
1
2
3
4
5
6
7
8
9
The title compound was prepared according to the general
procedure 2.4.
3-(p-Tolyl)indolin-2-one (4k)17
The title compound was prepared according to the general
procedure 2.4.
Yellow solid. Melting point = 206-208 ˚C. Yield = 26 mg,
13% in CH3CN and 153 mg, 77% in HFIP. Rf = 0.55 (50%
ethyl acetate/cyclohexane). IR (neat, cm-1): 3210, 3011,
2898, 1704, 1618, 1502, 1472, 1407, 1326, 1235, 117,
1036. 1H NMR (500 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.25
(dt, J = 7.7, 1.1 Hz, 1H), 7.22 – 7.08 (m, 2H), 7.02 (td, J = 7.5,
1.0 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.36 (s, 1H), 5.95 (s,
2H), 5.28 (s, 1H). 13C {1H} NMR (151 MHz, Chloroform-d) δ
177.8, 148.0, 141.1, 129.8, 129.6, 128.5, 124.9, 122.8,
116.1, 112.8, 109.9, 108.3, 101.9, 51.9, 29.7. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C15H11NO3Br 331.9917; Found
331.9936.
Yellow solid. Melting point = 157-159 ˚C. Yield = 8 mg, 6%
in CH3CN (2 vs 4, 1:4.3) and 108 mg, 81% in HFIP (2 vs 4,
1:4.4). Rf = 0.70 (50% ethyl acetate/cyclohexane). IR (neat,
cm-1): 3210, 2922, 2853, 1704, 1618, 1511, 1471, 1327,
1
1297, 1220. H NMR (500 MHz, Chloroform-d) δ 9.60 (s,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H), 7.24 (ddd, J = 8.8, 7.1, 1.2 Hz, 1H), 7.19 (d, J = 7.8 Hz,
2H), 7.17 – 7.11 (m, 3H), 7.03 (td, J = 7.5, 1.0 Hz, 1H), 6.94
(d, J = 7.7 Hz, 1H), 4.63 (s, 1H), 2.36 (s, 3H). 13C {1H} NMR
(126 MHz, Chloroform-d) δ 179.5 (d), 141.9 (d), 137.4,
133.5, 129.9, 129.7, 128.4, 128.3, 125.1, 122.6, 110.2 (d),
52.5, 21.2. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C16H16NO 238.1232; Found 238.1239.
3-(4-Methoxyphenyl)indolin-2-one (4h)4a
The title compound was prepared according to the general
procedure 2.4.
3-(4-(Methyl-d3)phenyl-2,3,5,6-d4)indolin-2-one (4l)
The title compound was prepared according to the general
procedure 2.4.
Yellow solid. Melting point = 166-168 ˚C. Yield = 83 mg,
58% in CH3CN (2 vs 4, 1:4) and 129 mg, 90% in HFIP (2 vs
4, 1:8.9). Rf = 0.55 (50% ethyl acetate/cyclohexane). IR
(neat, cm-1): 3209, 2960, 2930, 2836, 1702, 1617, 1510,
Yellow solid. Melting point = 155-157 ˚C. Yield = 7 mg, 5%
in CH3CN (2 vs 4, 1:4) and 128 mg, 93% in HFIP (2 vs 4,
1:4.1). Rf = 0.70 (50% ethyl acetate/cyclohexane). IR (neat,
1
1485, 1470, 1247, 1216, 1179, 1031. H NMR (400 MHz,
1
cm-1): 3207, 2268, 1699, 1618, 1470, 1325, 1214. H NMR
Chloroform-d) δ 9.05 (s, 1H), 7.24 – 7.18 (m, 1H), 7.16 –
7.06 (m, 3H), 7.00 (td, J = 7.5, 1.1 Hz, 1H), 6.95 – 6.83 (m,
3H), 4.57 (s, 1H), 3.77 (s, 3H). 13C {1H} NMR (101 MHz,
Chloroform-d) δ 179.2, 159.1, 141.7, 129.9, 129.5, 128.4,
128.3, 125.2, 122.6, 114.4, 110.0, 55.3, 51.9. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C15H14NO2 240.1019; Found
240.1015.
(400 MHz, Chloroform-d) δ 9.49 (s, 1H), 7.24 – 7.18 (m,
1H), 7.10 (d, J = 7.4 Hz, 1H), 7.00 (td, J = 7.6, 1.1 Hz, 1H),
6.94 – 6.88 (m, 1H), 4.60 (s, 1H). 13C {1H} NMR (101 MHz,
Chloroform-d) δ 179.4, 141.9, 141.8, 137.1, 133.3, 129.9,
128.3, 128.1, 125.1, 122.6, 110.1 (d), 52.4. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C15H7D7NO 231.1509; Found
231.1523.
3-(2,4-Dimethylphenyl)indolin-2-one (4i)17
3-(4-Benzylphenyl)indolin-2-one (4m)
The title compound was prepared according to the general
procedure 2.4.
The title compound was prepared according to the general
procedure 2.4.
Yellow solid. Melting point = 171-173 ˚C. Yield = 64 mg,
45% in CH3CN and 114 mg, 80% in HFIP. Rf = 0.75 (50%
ethyl acetate/cyclohexane). IR (neat, cm-1): 3210, 2971,
Yellow solid. Melting point = 178-180 ˚C. Yield = 74 mg,
41% in HFIP. Rf = 0.75 (50% ethyl acetate/cyclohexane). IR
(neat, cm-1): 3209, 3026, 2920, 1707, 1619, 1453, 1297,
1186. 1H NMR (500 MHz, Chloroform-d) δ 9.34 (s, 1H), 7.35
– 7.15 (m, 10H), 7.13 (d, J = 7.4 Hz, 1H), 7.03 (td, J = 7.5, 1.1
Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 4.63 (s, 1H), 3.99 (s, 2H).
13C {1H} NMR (126 MHz, Chloroform-d) δ 179.2, 141.8,
140.8, 140.6, 134.2, 129.7, 129.5, 129.0, 128.6, 128.5,
128.3, 126.1, 125.2, 122.6, 110.1, 52.4, 41.6. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C21H18NO 300.1383; Found
300.1399.
1
1699, 1617, 1470, 1327, 1214, 1093, 1046. H NMR (500
MHz, Chloroform-d) δ 9.40 (s, 1H), 7.23 (tt, J = 7.7, 1.2 Hz,
1H), 7.14 – 6.67 (m, 6H), 4.85 (s, 1H), 2.32 (s, 6H). 13C {1H}
NMR (126 MHz, Chloroform-d) δ 179.5, 141.7, 137.4, 136.9,
131.9, 130.1, 128.1, 127.1, 124.7, 122.6, 110.0, 49.1, 26.9,
21.0 (d) (Due to broadening some of the peaks are
missing). HRMS (ESI-TOF) m/z: [M
C16H16NO 238.1226; found 238.1239.
+
H]+ calcd for
3-(3,4-Dimethylphenyl)indolin-2-one (4j)
3-(4-Allylphenyl)indolin-2-one (4n)
The title compound was prepared according to the general
procedure 2.4.
The title compound was prepared according to the general
procedure 2.4.
Red solid. Melting point = 178-180 ˚C. Yield = 43 mg, 30%
in CH3CN and 121 mg, 85% in HFIP. Rf = 0.75 (50% ethyl
acetate/cyclohexane). IR (neat, cm-1): 3206, 2969, 2920,
Yellow gum. Yield = 57 mg, 38% in HFIP. Rf = 0.75 (50%
ethyl acetate/cyclohexane. IR (neat, cm-1): 3257, 2972,
2924, 1702, 1619, 1471, 1326, 1218, 1086, 1046. H NMR
1
1
1702, 1618, 1470, 1326, 1232, 1215, 1193, 1096. H NMR
(500 MHz, Chloroform-d) δ 9.38 (s, 1H), 7.27 – 7.11 (m,
6H), 7.03 (td, J = 7.6, 1.0 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H),
6.01 – 5.93 (m, 1H), 5.16 – 5.06 (m, 2H), 4.63 (s, 1H), 3.40
(d, J = 6.9 Hz, 2H). 13C {1H} NMR (126 MHz, Chloroform-d) δ
179.2 (d), 141.8 (d), 139.5, 137.2, 134.2 (d), 129.8 (d),
129.2, 128.5, 128.3, 125.2 (d), 122.6, 116.0, 110.1 (d), 52.5
(d), 39.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C17H16NO 250.1226; Found 250.1227.
(500 MHz, Chloroform-d) δ 9.43 (d, J = 30.6 Hz, 1H), 7.24
(tt, J = 7.7, 1.1 Hz, 1H), 7.16 – 7.10 (m, 2H), 7.06 – 6.99 (m,
2H), 6.96 (dd, J = 11.8, 8.0 Hz, 2H), 4.59 (s, 1H), 2.26 (s,
3H), 2.25 (s, 3H). 13C {1H} NMR (126 MHz, Chloroform-d) δ
179.5 (d), 141.8 (d), 137.2, 136.1, 133.9, 130.2, 130.1,
129.7, 128.2, 125.9, 125.1, 122.6, 110.1 (d), 52.6, 19.8,
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3-Phenylindolin-2-one (4o)17
1293, 1219, 1046. 1H NMR (500 MHz, DMSO-d6) δ 10.48 (s,
1
2
3
4
5
6
7
8
1H), 10.14 (s, 1H), 7.21 (tt, J = 7.7, 1.1 Hz, 1H), 7.09 (d, J =
2.1 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.98 – 6.85 (m, 4H),
4.66 (s, 1H). 13C {1H} NMR (126 MHz, DMSO-d6) δ 177.6,
152.6, 143.1, 130.2, 130.0, 129.6, 128.6, 128.3, 125.2,
122.1, 120.0, 117.3, 109.9, 50.9. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C14H11NO2Cl 260.0473; Found 260.0487.
The title compound was prepared according to the general
procedure 2.4.
White solid. Melting point = 189-191 ˚C. Yield = 49 mg,
39% in HFIP. Rf = 0.70 (50% ethyl acetate/cyclohexane. IR
(neat, cm-1): 3212, 2923, 2853, 1709, 1618, 1471, 1325,
1219. 1H NMR (500 MHz, Chloroform-d) δ 9.31 (s, 1H), 7.40
– 7.34 (m, 2H), 7.34 – 7.29 (m, 1H), 7.28 – 7.21 (m, 3H),
7.14 (d, J = 7.4 Hz, 1H), 7.04 (td, J = 7.5, 0.9 Hz, 1H), 6.95 (d,
J = 7.8 Hz, 1H), 4.66 (s, 1H). 13C {1H} NMR (126 MHz,
Chloroform-d) δ 179.1, 141.8 (t), 136.5 (t), 129.7, 129.6,
129.0, 128.5 (t), 127.7, 125.2 (t), 122.7, 110.1 (t), 52.8 (t).
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C14H11NONa
232.0733; Found 232.0746.
3-(2-Hydroxynaphthalen-1-yl)indolin-2-one (4t)
The title compound was prepared according to the general
procedure 2.4.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yellow solid. Melting point = 247-249 ˚C. Yield = 140 mg,
85% in CH3CN (mixture of regioisomers in 1:1:0.6 ratio)
and 149 mg, 90% in HFIP (mixture of regioisomers in
1:0.9:0.6 ratio). Rf = 0.30 (50% ethyl acetate/cyclohexane.
IR (neat, cm-1): 3164, 1703, 1620, 1514, 1470, 1329, 1289,
3-(1H-Indol-3-yl)indolin-2-one (4p)18
1
1219, 1205, 1023, 1002. Mixture of regiosomers: H NMR
The title compound was prepared according to the general
procedure 2.4.
(500 MHz, DMSO-d6) δ 10.78 (s, 1H), 10.54 (s, 1H), 10.40
(s, 1H), 10.15 (s, 1H), 9.72 (s, 1H), 9.59 (s, 1H), 8.26 (d, J =
8.5 Hz, 1H), 7.85 (dd, J = 8.3, 1.3 Hz, 1H), 7.80 – 7.68 (m,
4H), 7.68 – 7.56 (m, 2H), 7.52 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H),
7.38 – 7.29 (m, 2H), 7.27 – 6.91 (m, 12H), 6.88 – 6.71 (m,
5H), 6.64 (d, J = 7.3 Hz, 1H), 5.61 (s, 1H), 5.39 (s, 1H), 4.83
(s, 1H). 13C {1H} NMR (126 MHz, DMSO-d6) δ 178.8, 178.5,
177.8, 154.9, 153.2, 143.7, 143.2, 142.5, 134.9, 132.9,
132.2, 131.2, 131.0, 129.7, 129.6, 129.1, 129.1, 129.0,
128.9, 128.5, 128.5, 128.4, 128.1, 128.1, 127.4, 127.2,
127.0, 127.0, 126.8, 125.3, 123.9, 123.3, 122.9, 122.8,
122.7, 122.1, 122.1, 121.3, 119.3, 118.6, 118.4, 116.5,
114.5, 110.1, 109.9, 109.1, 109.0, 52.3, 45.0, 44.5. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C18H13NO2Na 298.0838;
Found 298.0844.
Red gum. Yield = 40 mg, 27% in HFIP. Rf = 0.30 (50% ethyl
1
acetate/cyclohexane). H NMR (500 MHz, Chloroform-d) δ
8.80 (s, 1H), 8.28 (s, 1H), 7.34 – 7.33 (m, 1H), 7.28 – 7.26
(m, 1H), 7.24 – 7.21 (m, 1H), 7.18 – 7.14 (m, 2H), 7.07 (d, J
= 2.4 Hz, 1H), 7.02 (m, 1H), 6.98 (m, 1H), 6.92 (d, J = 7.8 Hz,
1H), 4.92 (s, 1H).
3-(4-Hydroxyphenyl)indolin-2-one (4q)4a
The title compound was prepared according to the general
procedure 2.4.
White solid. Melting point = 226-228 ˚C. Yield = 114 mg,
85% in CH3CN (2 vs 4, 1:5.2) and 108 mg, 80% in HFIP (2
vs 4, 1:3.5). Rf = 0.45 (50% ethyl acetate/cyclohexane. IR
(neat, cm-1): 3251, 2500, 1696, 1618, 1514, 1471, 1334,
1216. 1H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.35 (s,
1H), 7.19 (tt, J = 7.7, 1.1 Hz, 1H), 7.16 – 7.06 (m, 1H), 7.00
(d, J = 7.4 Hz, 1H), 6.96 – 6.66 (m, 8H), 4.58 (s, 1H). 13C {1H}
NMR (126 MHz, DMSO-d6) δ 178.2, 178.1, 156.9, 155.8,
143.2, 143.1, 131.2, 130.9, 129.8, 128.7, 128.3, 128.2,
127.9, 125.1, 125.0, 124.2, 122.0, 121.6, 119.4, 115.8,
115.8, 109.8, 109.4, 51.5, 48.6. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C14H12NO2 226.0863; Found 226.0868.
3-(3-Bromo-4-hydroxyphenyl)indolin-2-one (4r)
1-Benzyl-3-(2,4,6-trimethoxyphenyl)indolin-2-one
(4u)
The title compound was prepared according to the general
procedure 2.4.
Brown gum. Yield = 117 mg, 50% in CH3CN and 140 mg,
60% in HFIP. Rf = 0.70 (50% ethyl acetate/cyclohexane. IR
(neat, cm-1): 3006, 2939, 2839, 1704, 1608, 1594, 1487,
1464, 1341, 1204, 1149, 1113. 1H NMR (500 MHz,
Chloroform-d) δ 7.47 – 7.41 (m, 2H), 7.34 (t, J = 7.4 Hz, 2H),
7.30 – 7.25 (m, 1H), 7.15 – 7.09 (m, 1H), 6.97 (dt, J = 7.3,
1.3 Hz, 1H), 6.91 (td, J = 7.4, 1.0 Hz, 1H), 6.75 (d, J = 7.8 Hz,
1H), 6.26 (d, J = 2.2 Hz, 1H), 6.06 (d, J = 2.2 Hz, 1H), 5.22 (d,
J = 1.0 Hz, 1H), 5.16 (d, J = 15.6 Hz, 1H), 4.85 (d, J = 15.6 Hz,
1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.34 (s, 3H). 13C {1H} NMR
(126 MHz, Chloroform-d) δ 177.6, 160.9, 159.5, 158.9,
143.5, 136.6, 130.2, 128.5, 127.7, 127.4, 127.0, 123.3,
121.9, 108.3, 106.5, 91.6 (d), 90.9 (d), 56.1 (d), 55.6 (d),
55.4 (d), 43.9, 42.1 (d). HRMS (ESI-TOF) m/z: [M + H]+
calcd for C24H24NO4 390.1700; Found 390.1723.
The title compound was prepared according to the general
procedure 2.4.
Yellow solid. Melting point = 250-252 ˚C. Yield = 146 mg,
80% in CH3CN (4 vs 6, 1.7:1) and 105 mg, 58% in HFIP (4
vs 6, 1:0). Rf = 0.40 (50% ethyl acetate/cyclohexane. IR
(neat, cm-1): 3219, 2923, 1703, 1620, 1471, 1293, 1220,
1
1152. H NMR (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 10.22
(s, 1H), 7.25 – 7.19 (m, 2H), 7.06 – 7.01 (m, 1H), 6.95 (td, J
= 7.5, 1.1 Hz, 1H), 6.92 – 6.87 (m, 3H), 4.66 (s, 1H). 13C {1H}
NMR (126 MHz, DMSO-d6) δ 177.6, 153.6, 143.1, 132.9,
130.3, 130.0, 128.9, 128.6, 125.2, 122.2, 117.0, 109.9,
109.6, 50.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H11NO2Br 303.9968; Found 303.9965.
1-Allyl-3-(2,4,6-trimethoxyphenyl)indolin-2-one (4v)
The title compound was prepared according to the general
procedure 2.4.
3-(3-Chloro-4-hydroxyphenyl)indolin-2-one (4s)
Yellow solid. Melting point = 107-109 ˚C. Yield = 144 mg,
71% in CH3CN and 130 mg, 64% in HFIP. Rf = 0.65 (50%
ethyl acetate/cyclohexane. IR (neat, cm-1): 3399, 2940,
1697, 1609, 1595, 1488, 1465, 1359, 1341, 1205, 1150,
1115, 1047. 1H NMR (500 MHz, Chloroform-d) δ 7.23 –
7.15 (m, 1H), 7.00 – 6.89 (m, 2H), 6.83 (d, J = 7.7 Hz, 1H),
The title compound was prepared according to the general
procedure 2.4.
Yellow solid. Melting point = 204-206 ˚C. Yield = 123 mg,
79% in CH3CN (4 vs 6, 1.6:1) and 131 mg, 84% in HFIP (4
vs 6, 1:0). Rf = 0.40 (50% ethyl acetate/cyclohexane. IR
(neat, cm-1): 3263, 2920, 2850, 1703, 1620, 1501, 1472,
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The Journal of Organic Chemistry
6.24 (d, J = 2.3 Hz, 1H), 6.06 (d, J = 2.2 Hz, 1H), 5.92 (ddt, J =
56.0, 55.7, 55.4, 42.5. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C17H17NO4Br 378.0335; Found 378.0352.
1
2
3
4
5
6
7
8
17.2, 10.5, 5.3 Hz, 1H), 5.34 (dd, J = 17.2, 1.5 Hz, 1H), 5.26
(dd, J = 10.4, 1.5 Hz, 1H), 5.13 (s, 1H), 4.56 (ddt, J = 16.3,
5.2, 1.7 Hz, 1H), 4.32 (ddt, J = 16.3, 5.5, 1.6 Hz, 1H), 3.90 (s,
3H), 3.80 (s, 3H), 3.47 (s, 3H). 13C {1H} NMR (126 MHz,
Chloroform-d) δ 177.4, 160.8, 159.5, 158.8, 143.5, 132.2
(d), 130.1, 127.0, 123.3, 121.9, 117.2 (d), 108.2, 106.7, 91.6
(d), 90.9 (d), 56.0 (d), 55.7 (d), 55.4 (d), 42.4, 42.0 (d).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H22NO4
340.1543; Found 340.1543.
5-Chloro-3-(2,4,6-trimethoxyphenyl)indolin-2-one
(4z)
The title compound was prepared according to the general
procedure 2.4.
Brown solid. Melting point = 218-220 ˚C. Yield = 134 mg,
67% in HFIP. Rf = 0.25 (50% ethyl acetate/cyclohexane). IR
(neat, cm-1): 3203, 2967, 2939, 2840, 1705, 1609, 1594,
9
1
1499, 1476, 1324, 1305, 1205, 1151, 1114. H NMR (500
1-(Prop-2-yn-1-yl)-3-(2,4,6-trimethoxyphenyl)indolin-
2-one (4w)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, Chloroform-d) δ 8.76 (s, 1H), 7.12 (ddd, J = 8.3, 2.2,
1.0 Hz, 1H), 6.91 (t, J = 1.6 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H),
6.24 (d, J = 2.3 Hz, 1H), 6.07 (d, J = 2.2 Hz, 1H), 5.13 (s, 1H),
3.90 (s, 3H), 3.82 (s, 3H), 3.51 (s, 3H). 13C {1H} NMR (126
MHz, Chloroform-d) δ 180.1, 161.2, 159.4, 158.8, 140.2,
132.6, 127.2, 127.1, 124.0, 109.9, 105.5, 91.5, 90.9, 56.0,
55.7, 55.4, 42.6. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C17H17NO4Cl 334.0841; Found 334.0860.
The title compound was prepared according to the general
procedure 2.4.
Brown solid. Melting point = 154-156 ˚C. Yield = 131 mg,
65% in CH3CN and 105 mg, 52% in HFIP. Rf = 0.70 (50%
ethyl acetate/cyclohexane. IR (neat, cm-1): 3281, 2965,
2939, 2839, 1711, 1592, 1488, 1464, 1418, 1339, 1228,
1
1203, 1188, 1148, 1111, 1053, 1037. H NMR (500 MHz,
5-Fluoro-3-(2,4,6-trimethoxyphenyl)indolin-2-one
(4aa)
Chloroform-d) δ 7.29 – 7.22 (m, 1H), 7.04 (d, J = 7.8 Hz,
1H), 7.02 – 6.94 (m, 2H), 6.23 (d, J = 2.3 Hz, 1H), 6.04 (d, J =
2.2 Hz, 1H), 5.10 (d, J = 1.2 Hz, 1H), 4.81 (dd, J = 17.6, 2.6
Hz, 1H), 4.41 (dd, J = 17.6, 2.5 Hz, 1H), 3.90 (s, 3H), 3.80 (s,
3H), 3.50 (s, 3H), 2.25 (t, J = 2.5 Hz, 1H). 13C {1H} NMR (126
MHz, Chloroform-d) δ 177.0, 160.9, 159.3, 158.8, 142.4,
129.9, 127.1, 123.5, 122.3, 108.3, 106.7, 91.5 (d), 90.9 (d),
77.9, 71.6 (d), 56.0 (d), 55.8 (d), 55.4 (d), 41.9 (d), 29.7.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H20NO4
338.1387; Found 338.1382.
The title compound was prepared according to the general
procedure 2.4.
Brown solid. Melting point = 226-228 ˚C. Yield = 107 mg,
56% in HFIP. Rf = 0.25 (50% ethyl acetate/cyclohexane). IR
(neat, cm-1): 3214, 2939, 2841, 1706, 1609, 1595, 1484,
1
1458, 1418, 1205, 1190, 1153, 1115, 1038. H NMR (500
MHz, Chloroform-d) δ 8.65 (s, 2H), 6.84 (tdd, J = 8.5, 2.6,
1.3 Hz, 1H), 6.78 (dd, J = 8.5, 4.3 Hz, 1H), 6.69 (ddd, J = 8.1,
2.7, 1.2 Hz, 1H), 6.23 (d, J = 2.2 Hz, 1H), 6.07 (d, J = 2.2 Hz,
1H), 5.13 (d, J = 1.2 Hz, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.51
(s, 3H). 13C {1H} NMR (126 MHz, Chloroform-d) δ 180.4,
161.1, 159.4, 159.0 (d, J = 237.5 Hz), 158.9, 137.5, 132.6 (d,
J = 7.5 Hz), 113.3 (d, J = 23.7 Hz), 111.5 (d, J = 25 Hz), 109.3
(d, J = 7.5 Hz), 105.6, 91.6, 90.9, 56.0, 55.7, 55.4, 43.0 (d, J =
1.2 Hz). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C17H16NO4FNa 340.0956; Found 340.0953.
1-Methyl-3-(2,4,6-trimethoxyphenyl)indolin-2-one
(4x)
The title compound was prepared according to the general
procedure 2.4.
Yellow solid. Melting point = 126-128 ˚C. Yield = 98 mg,
52% in CH3CN and 113 mg, 60% in HFIP. Rf = 0.45 (50%
ethyl acetate/cyclohexane. IR (neat, cm-1): 3003, 2940,
2839, 1702, 1608, 1593, 1493, 1466, 1417, 1375, 1339,
1204, 1193, 1146, 1113. 1H NMR (300 MHz, Chloroform-d)
δ 7.31 – 7.19 (m, 1H), 7.03 – 6.90 (m, 2H), 6.84 (d, J = 7.8
Hz, 1H), 6.25 (d, J = 2.3 Hz, 1H), 6.05 (d, J = 2.3 Hz, 1H),
5.09 (s, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.47 (s, 3H), 3.30 (s,
3H). 13C {1H} NMR (126 MHz, Chloroform-d) δ 177.9, 160.8,
159.4, 158.8, 144.5, 130.2, 127.2, 123.3, 121.9, 107.2,
106.9, 91.7, 91.0, 56.0, 55.4, 42.0, 26.3. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H20NO4 314.1387; Found
314.1380.
5-Methoxy-3-(2,4,6-trimethoxyphenyl)indolin-2-one
(4ab)
The title compound was prepared according to the general
procedure 2.4.
Brown solid. Melting point = 175-177 ˚C. Yield = 174 mg,
88% in HFIP. Rf = 0.20 (50% ethyl acetate/cyclohexane). IR
(neat, cm-1): 3216, 2967, 2939, 2838, 1698, 1592, 1486,
1
1455, 1417, 1306, 1203, 1191, 1151, 1112, 1031. H NMR
(500 MHz, Chloroform-d) δ 8.85 (s, 1H), 6.77 (d, J = 8.4 Hz,
1H), 6.68 (ddd, J = 8.4, 2.6, 0.9 Hz, 1H), 6.55 (dd, J = 2.6, 1.3
Hz, 1H), 6.24 (d, J = 2.3 Hz, 1H), 6.08 (d, J = 2.2 Hz, 1H),
5.12 (s, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.71 (s, 3H), 3.51 (s,
3H). 13C {1H} NMR (126 MHz, Chloroform-d) δ 180.5, 160.9,
159.4, 159.0, 155.4, 135.3, 132.3, 111.7, 110.8, 109.3,
106.4, 91.7, 91.0, 56.0, 55.8, 55.7, 55.4, 43.1. HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C18H20NO5 330.1336; Found
330.1350.
5-Bromo-3-(2,4,6-trimethoxyphenyl)indolin-2-one
(4y)
The title compound was prepared according to the general
procedure 2.4.
Brown solid. Melting point = 213-215 ˚C. Yield = 140 mg,
62% in HFIP. Rf = 0.25 (50% ethyl acetate/cyclohexane. IR
(neat, cm-1): 3194, 2967, 2839, 1703, 1609, 1593, 1500,
1
1205, 1113. H NMR (500 MHz, Chloroform-d) δ 8.75 (s,
Allyl (1-methyl-3-(2,4,6-trimethoxyphenyl)-1H-indol-
2-yl) carbonate (5)5
1H), 7.29 – 7.25 (m, 1H), 7.04 (s, 1H), 6.75 (d, J = 8.2 Hz,
1H), 6.23 (d, J = 2.2 Hz, 1H), 6.07 (d, J = 2.3 Hz, 1H), 5.13 (s,
1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.51 (s, 3H). 13C {1H} NMR
(126 MHz, Chloroform-d) δ 180.0, 161.2, 159.4, 158.8,
140.6, 133.0, 130.0, 126.7, 114.6, 110.5, 105.4, 91.5, 90.9,
The title compound was prepared according to the general
procedure 2.5.
White solid. Melting point = 116-118 ˚C. Yield = 98 mg,
80%. Rf = 0.40 (50 % ethyl acetate/cyclohexane). IR (neat,
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The Journal of Organic Chemistry
Page 10 of 11
cm-1): 2937, 2838, 1772, 1607, 1581, 1456, 1218, 1158,
1125. H NMR (500 MHz, Chloroform-d) δ 7.34 – 7.28 (m,
Ireland (SFI) under grant numbers 12/RC/2275. BVR is
1
1
2
3
4
5
6
7
8
grateful for the award of a BEACON postdoctoral fellowship
(16/RC/23889). BVR also thanks to the SSPC and Irish
Research Council (IRC) for the award of a postdoctoral
fellowship (GOIPD/2015/453).
We acknowledge facilities provided by the Centre for
Synthesis and Chemical Biology (CSCB), funded by the Higher
Education Authority’s PRTLI. We thank Dr. Yannick Ortin for
NMR spectroscopic experiments and Dr. Jimmy Muldoon for
mass spectroscopic analysis
2H), 7.21 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.08 (ddd, J = 8.0,
7.1, 1.1 Hz, 1H), 6.27 (s, 2H), 5.95 (ddt, J = 17.1, 10.4, 5.8
Hz, 1H), 5.40 (dq, J = 17.2, 1.5 Hz, 1H), 5.32 (dq, J = 10.4, 1.2
Hz, 1H), 4.74 (dt, J = 5.8, 1.3 Hz, 2H), 3.89 (s, 3H), 3.72 (s,
6H), 3.68 (s, 3H). 13C {1H} NMR (126 MHz, Chloroform-d) δ
160.7, 159.1, 152.1, 139.6, 132.7, 130.9, 125.6, 121.2,
121.1, 119.5, 119.5, 109.0, 102.4, 94.3, 91.0, 69.5, 55.7,
55.4, 28.8. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C22H23NO6Na 420.1418; Found 420.1434.
9
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(R)-3-Allyl-1-methyl-3-(2,4,6-
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1-Methyl-3-(2,4,6-trimethoxyphenyl)indolin-2-one
(7)5b
The title compound was prepared according to the general
procedure 2.7.
Yield = 25 mg, 95%, 43% ee. SFC (Chiralpak IB-3,
CO2(l)/IPA, 99:1 to 60:40 over 5 minute, 3 mL min−1),
temp. 35 ˚C, 3.767 (major), 4.024 (minor) min. All other
physical and spectroscopic data were in complete
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acidity of -proton in product 7, slow racemisation was
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(4)
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
SFC traces and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*Email: p.guiry@ucd.ie
Notes
The authors declare no competing financial interest.
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Economical Versatile Method for the Construction of Chiral
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ACKNOWLEDGMENT
This publication has emanated from research conducted with
the financial support of the Synthesis and Solid State
Pharmaceutical Centre (SSPC), funded by Science Foundation
Kondoh, A.; Takei, A.; Terada, M. Novel Methodology for the
Efficient Synthesis of 3-Aryloxindoles: [1,2]-Phospha-Brook
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