Transition-metal-free addition reaction for the synthesis of 3-(aminobenzylidene/aminoalkylidene)indolin-2-ones and its synthetic applications

Article abstract of DOI:10.1021/acs.joc.9b01771

A novel and efficient transition-metal-free approach for the exclusive synthesis of Z-3-(aminobenzylidene/aminoalkylidene)indolin-2-ones in high yield from 2-oxindole and aryl/alkyl nitrile in the presence of LiOtBu and 2,2′-bipyridine system is described. In addition, we disclosed a new approach towards the metal-free fluorination using selectfluor and the C=C bond cleavage using CuI and environmentally benign O₂.

Full text of DOI:10.1021/acs.joc.9b01771

Subscriber access provided by Stony Brook University | University Libraries
Article
Transition-Metal-Free Addition Reaction
for the Synthesis of 3-(aminobenzylidene/
aminoalkylidene)indolin-2-ones and Its Synthetic Applications
Girish Singh Bisht, and Boopathy Gnanaprakasam
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01771 • Publication Date (Web): 26 Sep 2019
Downloaded from pubs.acs.org on September 30, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Transition-Metal-Free Addition Reaction for the
Synthesis of 3-
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
(aminobenzylidene/aminoalkylidene)indolin-2-ones
and Its Synthetic Applications
Girish Singh Bisht and Boopathy Gnanaprakasam*
Department of Chemistry, Indian Institute of Science Education and Research, Pune-411008,
India.
ABSTRACT: A novel and efficient transition-metal-free approach for the exclusive syntheses of
Z-3-(aminobenzylidene/aminoalkylidene)indolin-2-ones in high yield from 2-oxindole and
aryl/alkyl nitrile in the presence of LiOtBu and 2,2’-bipyridine system is described. In addition,
we disclosed a new approach towards the metal-free fluorination using selectfluor and the C=C
bond cleavage using CuI and environmentally benign O2.
INTRODUCTION
Nitriles are structurally distinctive, abundant, inexpensive and one of the most frequently
used precursors in synthetic chemistry. Due to their well-recognized versatile chemical
reactivity, nitriles play an important role in both academic and industrial application.1 The
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 44
1
2
3
4
5
6
7
8
9
addition reaction is one of the fundamentally important and extensively used reactions in organic
chemistry, which falls in the greener approach due to high atom economy and less byproduct
formation.2 Among various organic intermediates, enaminones are versatile building blocks for
the synthesis of various heterocyclic compounds.3 Hence, the addition reaction of α-carbon
nucleophiles generated from carbonyl compounds with nitriles to construct enaminones is an
appealing transformation in organic synthesis. In academia, numerous protocols are described for
the synthesis of enaminones by C-nucleophilic addition to nitriles such as, i) via C-H activation
by using hydride complexes of Iridium and Rhenium4; ii) from 1,3-dicarbonyl and nitriles in
presence of Lewis acid5; iii) Zn and Ti catalyzed addition reaction6 and miscellaneous reactions.7
Interestingly, Yu and co-workers developed a Cu-catalyzed synthesis of enaminones assisted by
2,2’-bipyridine ligand system (Scheme 1).8 The main drawbacks of this approach includes the
use of a metal catalyst and limited only to aromatic nitriles. Recently, Rao and Hilt group
described the synthesis of enaminones by modification of classical Blaise reaction via in situ
generation of organo Zn nucleophiles.9 Despite this reaction being a straight forward practice for
the synthesis of enaminones, the major drawbacks of this method includes; i) use of a
stoichiometric amount of Zn and In metal, ii) utilizes genotoxic haloketone, iii) pre-
functionalization of carbonyl compounds, iv) requires TMSCl as an additive, and v) tedious
acidic work-up. Besides, transition metal-mediated addition reaction of nitrogen nucleophile to
the nitrile to access synthetic intermediates, common building blocks and materials are well
studied.10 Transition-metal-free reactions are highly fascinating and of considerable importance
in synthetic methods due to many advantages over transition metal-mediated reactions.11 For
instance, transition metal complexes are usually expensive, the difficulty of separation of
transition-metal residues from desired products which is not suitable for pharmaceuticals, less
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
ACS Paragon Plus Environment
2

Page 3 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
abundant in nature and much sensitive to air/moisture. Alkali metal tert-butoxides bases such as
KOtBu, LiOtBu, and NaOtBu are used as a powerful base in organic synthesis. Interestingly,
KOtBu base has been widely used for single electron transfer reactions and metal-free cross-
coupling reactions of aryl halides with arenes.12 Derivatives of 3-(aminomethyl)indolin-2-one are
prominently used asa useful intermediate in natural product synthesis.13 Further, this scaffold is
responsible for a various therapeutic activity such as intoxicating antifungal, anticancer, antiviral,
and Aurora B inhibitor. For instance, Nintedanib (Ofev) and BIBF 1000 was used for the
treatment of idiopathic pulmonary fibrosis (IPF) and Hesperidin identified as Aurora B inhibitor
(Figure 1).14
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
Figure 1. Bioactive 3-(aminoarylidene)indolin-2-one derivatives
As a result of broader and attractive therapeutic application, several synthetic approaches have
been developed for the synthesis of 3-(aminomethylene)-oxindoles. In 2008, Li and coworkers
developed carboamination/C-H activation of the alkyne for the synthesis of (E)-(2-oxindolin-
3-ylidene)phthalimide in the presence of Pd(OAc)2 and PhI(OAc)2.15 Moreover, Murakami group
prepared 3-(amidoalkylidene)oxindoles using palladium-catalyzed intramolecular amidative
cyclization reaction for the C-C bond formation which consist of intermolecular C-N bond
formation across a carbon-carbon triple bond by using phosphine as a ligand and isocyanates as
starting material,
which subsequently underwent
hydrolysis
to
furnish
3-
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 44
1
2
3
4
5
6
7
8
(aminoalkylidene)oxindoles.16 Interestingly, Cossy research group accomplishes the synthesis of
3-(aminoalkylidene)oxindole by nucleophilic addition of amine derivatives on pre-functionalized
starting material 3-(arylchloromethylene)oxindoles under microwave irradiation.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
Scheme 1. State of the Art for the Addition Reaction of 2-Oxindole with Nitrile
Albeit various approaches reported for the synthesis of 3-(aminoalkylidene)oxindoles, pre-
functionalization of 2-oxindole,18 use of toxic starting material, multistep reactions and use of an
expensive metal catalyst were main drawbacks. To the best of our knowledge, metal-free
ACS Paragon Plus Environment
4

Page 5 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
nucleophilic addition reaction of the enolate of the cyclic amide with a nitrile to afford 3-
(aminobenzylidene/aminoalkylidene)indolin-2-ones derivatives is not documented.
7
8
9
RESULT AND DISCUSSIONS
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
Herein,
we
delineate
a
transition
metal-free
synthesis
of
3-
(aminobenzylidene/aminoalkylidene)indolin-2-ones from 2-oxindole and nitrile using
LiOtBu/2,2′-bipyridine base ligand system. This method endues direct synthesis of the cyclic
enamide without pre-functionalization which is allowed to use easily accessible, inexpensive
starting material and bench stable ligand. To establish a procedure for the synthesis of 3-
(aminobenzylidene/aminoalkylidene)indolin-2-ones, we started initial optimization by heating a
o
dry acetonitrile solution to 100 C containing 2-oxindole and LiOtBu/2,2′-bipyridine as a model
reaction. A control experiment was performed by heating the reaction mixture containing 2-
oxindole, acetonitrile (ACN) and a catalytic amount of Phenanthroline or 2,2′-bipyridine, in
absence of a base, results in no reaction (Table 1, entry 1 and entry 18). Reaction with carbonate
salts such as Cs2CO3, K2CO3, failed to give 3-(aminoethylidene)indolin-2-one 3a (Table 1, entries
2 and 3). While this reaction with KOH results in a trace amount of desired product 3a.
Interestingly, the addition of KOtBu results in a slight improvement in the yield of product 3a
(Table 1, entry 5). On changing ligand to bathophenanthroline (L2) a decrease in yield was
noticed (Table 1, entry 6). Interestingly, the addition of 2,2′-bipyridine ligand (L3), product 3a
was isolated in 30% yield (Table 1, entry 7). Further increasing the quantity of base a slight
increase in yield was observed (Table 1, entry 8). After the above findings with tert-butoxide,
changing the counter cation of tert-butoxide such as NaOtBu and LiOtBu resulted in 40 and 60%
yield, respectively (Table 1, entries 9 and 10). Upon increasing the amount of LiOtBu from 2 to
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 44
1
2
3
4
5
6
3.5 eq., a slight increase in yield was observed (Table 1, entry 11). There was no improvement in
yield when the reaction was performed for 48 hrs.
7
8
9
Table 1. Optimization for the Addition Reaction of 2-Oxindole and Acetonitrilea
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
entry
base (eq.)
ligand (mol %)
yield (%)
1
2
3
4
5
─
Phenanthroline or 2,2′-Bipyridine
Phenanthroline
Phenanthroline
Phenanthroline
Phenanthroline
Bathophenanthroline
2,2′-Bipyridine
2,2′-Bipyridine
2,2′-Bipyridine
2,2′-Bipyridine
2,2′-Bipyridine
2,2′-Bipyridine
2,2′-Bipyridine
2,2′-Bipyridine
2,2′-Bipyridine
2,2′-Bipyridine
-
no reaction
no reaction
no reaction
Traces
Cs2CO3 (1 eq.)
K2CO3 (1 eq.)
KOH (1 eq.)
KOtBu (1 eq.)
25
6
7
8
KOtBu (1 eq.)
KOtBu (1 eq.)
KOtBu (2 eq.)
10
30
35
40
60
65
9
NaOtBu (2 eq.)
LiOtBu (2 eq.)
LiOtBu (3.5 eq.)
LiOtBu (3.5 eq.)
LiOtBu (3.5 eq.)
LiOtBu (3.5 eq.)
LiOtBu (3.5 eq.)
LiOtBu (3.5 eq.)
LiOtBu (3.5 eq.)
10
11
12b
13c
14d
15e
16f
17f
no reaction
no reaction
15
traces
65
46
Reaction Conditions: aligand (0.025 mmol), 2-oxindole (0.25 mmol), base (see table) and dry
acetonitrile (2 mL) were heated in a sealed tube for 24 hrs. b2 mL DMF was used as a solvent. c2
mL DMSO was used as a solvent. d 2 mL 1,4-dioxane was taken as a solvent. e2 mL toluene was
taken as a solvent. f2 mL THF was taken as a solvent.
After obtaining satisfactory yield with acetonitrile, the solvent study was performed by heating
a reaction mixture containing 0.6 ml of acetonitrile, oxindole, ligand, and base. Polar solvents
such as DMF and DMSO was inefficient to give the desired product 3a (Table 1, entry 12). The
poor yield was observed in the case of 1,4-dioxane as a solvent (Table 1, entry 13). Traces
ACS Paragon Plus Environment
6

Page 7 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
amount of product was observed when toluene was taken as a solvent. Gratifyingly, by using
THF as a solvent in this addition reaction afforded 65% yield of the product 3a (Table 1, entry
15).
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
Scheme 2. Substrate Scope for the Base Promoted Addition Reaction
Reaction conditions: 2-oxindole (0.25 mmol), nitrile (0.5 mmol), 2,2′-bipyridine (0.025 mmol)
o
b
and THF (2 mL) were heated in a sealed tube at 100 C for 24 hrs. In case of substrate 3b, 3k
c
and 3s, 4 eq. of benzonitrile has been taken. In case of substrate 3s, large scale synthesis (i.e.
223 mg, 1 mmol scale) has been performed.
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 44
1
2
3
4
5
6
7
8
9
With optimized conditions in hand, we started to survey the substrate scope for the transition-
metal-free addition reaction. Thus, the reaction of 2-oxindole with ACN provided 3-(1-
aminoethylidene)indolin-2-one 3a in 65% yield. The product 3a was well characterized by
spectroscopic techniques and X-ray analysis (Scheme 2). To our delight, this reaction afforded
exclusively Z-selective product 3a which might be due to the hydrogen bonding of amine with
amide carbonyl group. Furthermore, deuterated acetonitrile afforded corresponding deuterated
derivative 3a’ in 62% yield. Upon reaction of 2-oxindole with benzonitrile, product 3b was
isolated in 70% yield. It was observed that excess of benzonitrile needed for better yield of the
product 3b. In the case of (4-chlorophenyl)acetonitrile, addition reaction proceeded smoothly to
yield the desired product 3c in 74%. Likewise, when this reaction was examined with
substituted oxindole, for instance, 7-chloro-2-oxindole and 6-chloro-2-oxindole proceeded
smoothly. Thus, the reaction of 7-chloro-2-oxindole with benzonitrile and 3-bromobenzonitrile
afforded the respective products 3d, 3e in 60% and 84% yield. Moreover, this transformation
was tolerant to a functional group, for instance, highly electron-withdrawing -CF3 group to
afford product 3-(amino(4-(trifluoromethyl)phenyl)methylene)-7-chloroindolin-2-one 3f in 83%
yield. Similarly, the reaction of 6-chloro-2-oxindole with acetonitrile, 3-bromobenzonitrile and
4-(trifluoromethyl)benzonitrile afforded corresponding products 3g, 3h, 3i in 30%, 74%, and
30% yield respectively. In the case of lower yield reactions, the starting material was recovered.
The generality of this reaction was then investigated with N-protected oxindole. This approach
was highly efficient for N-methyl-2-oxindole. Addition reaction of N-methyl-2-oxindole with
acetonitrile, benzonitrile, and 3-bromobenzonitrile afforded corresponding products 3j, 3k, 3l in
65%, 64%, and 80% yield respectively. Besides, substituted nitrile such as 2-Bromo-4-
methylbenzonitrile afforded corresponding product 3m in 60% yield. Further, when 4-
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
ACS Paragon Plus Environment
8

Page 9 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(Trifluoromethyl)benzonitrile was treated with N-methyl oxindole afforded corresponding
product 3o in 93% yield. Moreover, the addition reaction was performed with arylmethyl nitriles
namely, (4-chlorophenyl)acetonitrile, p-tolylacetonitrile and 4-methoxyphenylacetonitrile to
furnish corresponding products 3p, 3q, and 3r in good yields. The transition metal-free reaction
of 1-benzylindolin-2-one with nitriles proceeds smoothly to afford (Z)-3-
(amino(aryl)methylene)-1-benzylindolin-2-one derivatives 3s-3u in good yields.
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
Installation of fluorine at 3-position of 2-oxindole represents a prime approach for the
preparation of biologically active 3-fluorooxindole derivatives. In this regard, we examine
synthetic applicability of synthesized 3-(aminobenzylidene/aminoalkylidene)indolin-2-ones for
the synthesis of 3-fluoro-2-oxindole derivatives via sp2 C=C functionalization.
Scheme 3. Chemical Properties of 3-(Aminobenzylidene/aminoalkylidene)indolin-2-ones
Towards Electrophilic Fluorinationa and the C=C Bond Cleavageb
aReaction conditions for Fluorination: 3-(aminobenzylidene/aminoalkylidene)indolin-2-ones
3 (0.3 mmol), selectfluor (0.45 mmol) were kept at rt for 16 hrs. ( In case of 3a methanol and
acetonitrile used as
a
solvent). bReaction conditions for C=C Cleavage: 3-
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 44
1
2
3
4
5
6
(aminobenzylidene/aminoalkylidene)indolin-2-ones 3 (0.1 mmol), CuI (0.06 mmol), DMSO (2
mL) were heated in a sealed tube at 120 oC under O2 balloon for 16 hrs. The isolated yield of the
corresponding N-protected isatin 4 is given. cMixture of product isolated and % yield calculated
d
from NMR. Large scale synthesis (i.e. 500 mg, 1.5 mmol scale) has been performed with these
7
substrates.
8
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
To our delight, when the selectfluor was added in acetonitrile (ACN) containing 3-
(amino(phenyl)methylene)indolin-2-one, complete conversion of starting material was observed
after 16 hrs. The reaction mixture was purified by column chromatography to afford inseparable
1
products 6a and 6a, (Scheme 3). The yield of the 6a and 6a’ was determined from H-NMR. To
expand the scope of this method, other 3-(aminobenzylidene/aminoalkylidene)indolin-2-ones
derivatives were subjected under similar reaction condition to obtained corresponding products
6b, 6c, and 6d in moderate to good yields (Scheme 3). The pure product of 6c was obtained by
recrystallization and confirmed by the spectroscopic analysis.
The oxidative cleavage of C=C to provide corresponding carbonyl derivatives is one of the most
fundamental transformation and ubiquitous approach used in organic chemistry. This
transformation is well explored using various oxidants via metal and metal-free approaches for
alkenes to afford only carbonyl compounds.19 To study the oxidative cleavage of the 3-
(aminobenzylidene/aminoalkylidene)indolin-2-ones derivatives to get carbonyl compounds and
nitrile, a set of reaction was studied in the presence of metal and oxidants. Thus, we investigated
Cu-mediated C=C bond cleavage of 3-(aminobenzylidene/aminoalkylidene)indolin-2-ones
derivatives using environmentally benign O2. A control experiment was performed in the
absence of catalyst, no reaction was observed. To our surprise, the solution of compound 3j in
DMSO was treated with 60 mol% of CuI in presence of oxygen balloon, oxidative C=C bond
cleavage of 3j was observed (Scheme 3). The scope of this novel approach was further studied
with other substrates 3k, 3l, 3n, 3o, 3s, 3t, and 3u under similar reaction condition (Scheme 3).
ACS Paragon Plus Environment
10

Page 11 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
After completion of this reaction, 1-methylindoline-2,3-dione 4a and 1-benzylindoline-2,3-dione
4b were isolated in moderate to good yield (Scheme 3). Further, the formation of the
corresponding nitrile as the other fragment product for the C=C cleavage was isolated and
confirmed by GC-MS analysis (see figure S2-S5 in the SI).
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
Scheme
4.
Cu-Catalyzed
C-N
Bond
Formation
Using
3-
(Aminobenzylidene/aminoalkylidene)indolin-2-ones
Reaction conditions:
3-(aminobenzylidene/aminoalkylidene)indolin-2-ones (0.1 mmol),
bromobenzene (0.15 mmol), 2,2′-bipyridine (0.01 mmol), CuI (0.01 mmol), Cs2CO3 (0.15
mmol) and DMF (2 mL) were heated in a sealed tube at 140 oC for 24 hrs.
Next, the application of 3-(aminobenzylidene/aminoalkylidene)indolin-2-ones derivatives have
been investigated toward the C-N bond formation reaction. To perform this strategy, Ullmann
coupling has been performed using the compounds 3j, 3o with aryl halides in the presence CuI
and BPY led to the products 8a, 8b, and 8c in 65%, 71% and 66% isolated yields, respectively
(Scheme 4).
ACS Paragon Plus Environment
11

The Journal of Organic Chemistry
Page 12 of 44
1
2
3
4
5
6
Scheme 5. Mechanistic Studies
7
8
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
Mechanistically, there are two possible way for the formation of 3-(aminobenzylidene)indolin-2-
ones derivatives. The first pathway involves ligand exchange followed by the nucleophilic attack
(Scheme 6a). Initially, 2,2′-bipyridine (BPY) in the presence of LiOtBu generates a complex
-
A11a,20a. Next ligand exchange in the complex A between coordinated OtBu and the nucleophile
generated from 2-oxindole and LiOtBu to form complex B. To analyze the reaction intermediate,
the crude reaction mixture was examined in HRMS after 4 hrs. The HRMS of the reaction
ACS Paragon Plus Environment
12

Page 13 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
mixture indicates m/z 296.1373 which corresponds to the intermediate B as (M+H)+ (see figure
S1 in the SI). The oxindole in complex B could attack on the electrophilic nitrile group of the
intermediate C20e and subsequent proton abstraction from the t-BuOH results in intermediate C.
Finally, intermediate D isomerizes to form the 3-(amino(phenyl)methylene)indolin-2-one.
Scheme 6a. Plausible Mechanism via Ligand Exchange Followed by Nucleophilic Attack
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
In the second pathway, the product 3b can be formed via SET mechanism (Scheme 6b). To
understand SET mechanism, an addition reaction of 2-oxindole with acetonitrile was performed
with radical-quenchers. In the case of the 2,2,6,6-tetramethylpiperidine-1-oxyl quencher, no
ACS Paragon Plus Environment
13

The Journal of Organic Chemistry
Page 14 of 44
1
2
3
4
5
6
7
8
9
reaction was observed (Scheme 5). Whereas the use of α-methylstyrene resulted in a decrease in
the yield significantly (Scheme 5). Moreover, when the reaction was performed with lower
loading of radical scavengers there was no improvement in product yield (Scheme 5). Further,
these reaction were performed with radical quencher 2,2,6,6-tetramethylpiperidine-1-oxyl or α-
methylstyrene in absence of the bipyridine (BPY) results product 3a in 15% and 40% yield
respectively (Scheme 5). These experimental evidences suggest that the addition of C-
nucleophile generated from 2-oxindole to the C≡N of nitrile derivatives can be proceeded
through the radical pathway.
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
Scheme 6b. Plausible Mechanism via a SET Pathway
On the basis of our experimental observation and from the literature precedence, 11a, 20 a plausible
SET mechanism is proposed (Scheme 6b). Initially, the complex A undergoes the SET process to
generate complex E and the intermediate F. The intermediate G generated by the reaction of 2-
oxindole and LiOtBu reacts with complex E via SET process to generate the 2-oxindole radical
H and the intermediate A. Further, upon reaction of 2-oxindole radical H with nitrile radical F
subsequent proton abstraction from the t-BuOH results the intermediate I. The isomerization of
ACS Paragon Plus Environment
14

Page 15 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
intermediate I deliver the product 3b. Although this mechanism was tentatively proposed, further
investigation about this mechanism is under progress.
7
8
9
CONCLUSIONS
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
In conclusion, we have established a transition metal-free approach for the synthesis of 3-
(aminobenzylidene/aminoalkylidene)indolin-2-ones by using easily available nitriles and 2-
oxindole. The addition of oxindole to aromatic/aliphatic nitriles proceeded smoothly to afford
exclusively selective Z-3-(aminobenzylidene/aminoalkylidene)indolin-2-ones derivatives in
excellent yields. This addition reaction proceeded via SET mechanism proven by experimental
evidences. Synthetic application of the 3-(aminobenzylidene/aminoalkylidene)indolin-2-ones
derivatives developed a novel metal-free fluorination to generate C3-fluorinated 2-oxindole
derivatives. In addition, we have developed a new approach for the efficient and amine group
facilitated C=C cleavage using Cu-catalyst and environmentally benign oxidant without any
additives or ligands. In addition, Cu-mediated Ullmann coupling reaction of 3-
(aminobenzylidene/aminoalkylidene)indolin-2-ones derivatives with aryl halide was successfully
demonstrated to synthesize biologically important core structure of the drug intermediate in
moderate yield. Further investigation for the mechanism on the addition reaction is under
progress in our lab.
EXPERIMENTAL SECTION
General information and data collection:
All the nitriles and oxindole derivatives were purchased from Sigma-Aldrich. Deuterated
solvents were used as received. All the solvents used were dry grade and stored over 4Å
molecular sieves. Column chromatographic separation was performed over 100-200 mesh size
1
silica-gel. Visualization was accomplished with UV light and iodine. The H and 13C{1H} NMR
ACS Paragon Plus Environment
15

The Journal of Organic Chemistry
Page 16 of 44
1
2
3
4
5
6
7
8
9
spectra were recorded on 400 and 100 MHz respectively, using a Bruker or JEOL spectrometers.
Abbreviations used in the NMR follow-up experiments: b, broad; s, singlet; d, doublet; t, triplet;
q, quartet; td, dd doublet of triplet and double doublet; m, multiplet, tt, triplet of triplets and ddd,
doublet of doublet of doublets. High-resolution mass spectra were obtained with Waters-synapt
G2 using electrospray ionization (ESI-TOF). Infrared (ATR) spectra were obtained with a
Bruker Alpha-E infrared spectrometer and FTIR spectra were recorded on pressed pellets of
powder samples diluted with KBr on NICOLET 6700 spectrophotometer.
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
A)
General
Experimental
Procedure
for
the
Synthesis
of
3-
(aminobenzylidene/aminoalkylidene)indolin-2-ones: To an oven dried 20 mL resealable
pressure tube (equipped with rubber septum), 2-oxindole (0.25 mmol), LiOtBu (0.875 mmol),
nitrile (0.5 mmol) and 2,2'-bipyridine (0.025 mmol) was added in THF under N2 atmosphere
using N2 balloon. Then, the tube was purged with N2 and quickly removed septum and sealed
o
with a cap using a crimper. The reaction mixture was stirred at 100 C for 24 hrs on a preheated
oil bath. After cooling to room temperature, the reaction mixture was diluted by DCM and
MeOH. After concentration under reduced pressure, the residue was purified by 100-200 mesh
silica-gel column chromatography (EtOAc:hexane= 35:65 to 65:35) for substrates 3a-3i and
(EtOAc:hexane = 20:80 to 40:60) for substrates 3j-3u.
B) General Experimental Procedure for C=C Bond Cleavage of 3-(
aminobenzylidene/aminoalkylidene)
indolin-2-ones
using
CuI/O2:
3-
(aminobenzylidene/aminoalkylidene)indolin-2-ones (0.1 mmol), CuI (0.06 mmol) were charged
in a 10 mL round bottom flask equipped with stirring bar. DMSO (2 mL) was added and the
mixture was stirred at 120 oC on preheated oil bath for 16 hrs under oxygen atmosphere by using
an oxygen balloon. After cooling down to room temperature, water was added, and the resulting
ACS Paragon Plus Environment
16

Page 17 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
mixture was extracted with ethyl acetate three times using 50 mL of solvent each time. The
organic layers were combined and dried over Na2SO4. After removing the solvent under reduced
pressure, the residue was purified by using column chromatography (EtOAc:hexane = 15:85 to
25:75).
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
C) General Experimental Procedure for Synthesis of 3-subsitituted-3-fluoro-oxindoles: 3-
(aminobenzylidene/aminoalkylidene)indolin-2-ones (0.3 mmol), selectfluor (0.45 mmol) were
charged in a 10 mL round bottom flask equipped with stirring bar. Acetonitrile (2 mL) was
added and the mixture was stirred at rt. for 16 hrs. After 16 hrs, water was added in the reaction
mixture and the resulting mixture was extracted with ethyl acetate three times using 50 mL of
solvent each time. Further, solvent dried over Na2SO4. After removing the solvent under reduced
pressure, the residue was purified by using column chromatography (EtOAc:hexane = 10:90 to
15:85).
D) General Experimental Procedure for Radical Inhibition: To an oven dried 20 mL
resealable pressure tube (equipped with rubber septum), 2-oxindole (0.25 mmol), LiOtBu (0.875
mmol), nitrile (2 ml), 2,2'-bipyridine (0.025 mmol) and 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) (1 equiv.) or α-methylstyrene (1 equiv.) were added under N2 atmosphere using N2
balloon. Then, the tube was purged with N2 and quickly removed septum and sealed with a cap
o
using a crimper. The reaction mixture was stirred at 100 C for 24 hrs on a preheated oil bath.
After cooling to room temperature, the reaction mixture was diluted by DCM and MeOH. After
concentration under reduced pressure, the residue was purified by 100-200 mesh size silica-gel
column chromatography.
ACS Paragon Plus Environment
17

The Journal of Organic Chemistry
Page 18 of 44
1
2
3
4
5
6
7
8
E) General Experimental Procedure for Ullmann coupling Reaction: To a solution of 3-
(aminobenzylidene/aminoalkylidene)indolin-2-ones (0.1 mmol) in dry DMF, CuI (0.01 mmol),
Cs2CO3 (0.15 mmol), 2,2′-bipyridine (0.01 mmol) and bromobenzene (0.15 mmol) was added in
9
o
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
inert atmosphere and the mixture was stirred at 140 C for 24 hrs on a preheated oil bath. After
cooling to room temperature, brine solution was added, and the mixture was extracted with
CH2Cl2 three times using 50 mL of solvent each time and washed with brine solution 5-6 times,
further solvent dried over Na2SO4 and evaporated under reduced pressure. The residue was
purified by column chromatography (EtOAc:hexane = 15:85 to 20:80)
F) Analytical data for the product:
3-(1-aminoethylidene)indolin-2-one (3a): Prepared according to general procedure A, using 2-
oxindole (33 mg, 0.25 mmol), LiOtBu (70 mg, 0.8 ml, 0.875 mmol), dry acetonitrile (0.6 ml) and
2,2'-bipyridine (3.9 mg, 0.025 mmol) to afford 3-(1-aminoethylidene)indolin-2-one 3a (28 mg,
1
65%) as a yellow crystalline solid. H NMR (400 MHz, Methanol-d4): δ 7.32 – 7.28 (m, 1H),
7.00 – 6.90 (m, 3H), 4.61 (s, 1H), 2.44 (s, 3H). 13C{1H} NMR (100 MHz, Methanol-d4) δ 163.1,
136.5, 126.8, 123.2, 121.7, 119.4, 110.1, 95.1, 21.1. FTIR (neat): 3342, 3182, 1618, 1535, 1459
cm-1. HRMS: (ESI-TOF) m/z: (M+H)+ calculated for C10H11N2O, 175.0871; found: 175.0870.
3-(1-aminoethylidene-2,2,2-d3)indolin-2-one (3a’): Prepared according to general procedure A,
using 2-oxindole (33 mg, 0.25 mmol), LiOtBu in THF 1M (0.8 ml, 0.875 mmol), acetonitrile-d3
(0.6 ml) and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to afford 3-(1-aminoethylidene-2,2,2-
d3)indolin-2-one 3a’ (27 mg, 62%) as a white solid. 1H NMR (400 MHz, Methanol-d4): δ 7.28 (d,
J = 6.5 Hz, 1H), 6.99 – 6.88 (m, 3H), 2.41 (s, 1H). 13C{1H}NMR (100 MHz, Methanol-d4) δ
171.8, 163.0, 136.6, 126.8, 123.2, 121.7, 119.3, 110.1, 95.1, 21.1. FTIR (neat): 3343, 3197,
ACS Paragon Plus Environment
18

Page 19 of 44
The Journal of Organic Chemistry
1
2
3
4
5
1653, 1537, 1463 cm-1. HRMS: (ESI-TOF) m/z: (M+H)+ calculated for C10H8D3N2O, 178.1059;
found: 178.1057.
6
7
8
9
3-(amino(phenyl)methylene)indolin-2-one (3b)21: Prepared according to general procedure A,
using 2-oxindole (33 mg, 0.25 mmol), LiOtBu (70 mg, 0.875 mmol), benzonitrile (103 mg, 1
mmol) and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to afford 3-(amino(phenyl)methylene)indolin-
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
1
2-one 3b (41 mg, 70%) as a yellow solid. H NMR (400 MHz, CDCl3): δ 9.52 (s, 1H), 8.14 (s,
1H), 7.61 – 7.50 (m, 5H), 6.96 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8 Hz, 1H), 6.66 (t, J = 8 Hz, 1H),
13
6.29 (d, J = 8 Hz, 1H), 5.20 (s, 1H). C{1H} NMR (100 MHz, CDCl3) δ 171.0, 159.7, 136.0,
135.7, 130.6, 129.3, 127.9, 124.7, 123.6, 120.7, 118.6, 109.2, 96.0. FTIR (neat): 3353, 3186,
1735, 1617, 1545, 1470 cm-1. HRMS: (ESI-TOF) m/z: (M+H)+ calculated for C15H13N2O,
237.1027; found: 237.1030.
3-(1-amino-2-(4-chlorophenyl)ethylidene)indolin-2-one (3c): Prepared according to general
procedure A, using 2-oxindole (33 mg, 0.25 mmol), LiOtBu (70 mg, 0.875 mmol), 2-(4-
chlorophenyl)acetonitrile (75.5 mg, 0.5 mmol) and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to
afford 3-(1-amino-2-(4-chlorophenyl)ethylidene)indolin-2-one 3c (52 mg, 74%) as a white solid
1
partially soluble in chloroform. H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 8.45 (s, 1H), 7.41 -
7.37 (m, 2H), 7.30 - 7.27 (m, 3H), 7.08 (td, J = 7.6, 1.1 Hz, 1H), 7.01- 6.96 (m, 2H), 5.06 (s,
13
1H), 4.16 (s, 2H). C{1H} NMR (100 MHz, CDCl3) δ 170.6, 159.6, 135.6, 134.0, 132.2, 131.0,
129.5, 124.8, 123.4, 121.2, 118.9, 109.4, 95.7, 39.3. FTIR (neat): 3350, 3122, 1653, 1614, 1534,
1462 cm-1. HRMS (ESI-TOF) m/z: (M+H)+ calculated for C16H14ClN2O, 285.0794; found:
285.0793.
ACS Paragon Plus Environment
19

The Journal of Organic Chemistry
Page 20 of 44
1
2
3
4
5
6
7
8
9
3-(amino(phenyl)methylene)-7-chloroindolin-2-one (3d): Prepared according to general
procedure A, using 7-chloro-2-oxindole (41 mg, 0.25 mmol), LiOtBu (70 mg, 0.875 mmol),
benzonitrile (104 mg, 1 mmol) and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to afford to 3-
(amino(phenyl)methylene)-7-chloroindolin-2-one 3d (40 mg, 60%) as a yellow solid partially
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
1
soluble in chloroform. H NMR (400 MHz, CDCl3+CCl4) δ 9.62 (s, 1H), 8.28 (s, 1H), 7.63 –
7.47 (m, 5H), 6.94 (d, J = 8 Hz, 1H), 6.59 (t, J = 8 Hz, 1H), 6.16 (d, J = 8 Hz, 1H), 5.35 (s, 1H).
13C{1H} NMR (100 MHz, CDCl3+CCl4) δ 160.7, 135.7, 133.1, 130.8, 129.4, 127.8, 126.2, 123.1,
121.4, 116.8, 114.6, 96.2. FTIR (KBr): 3452, 3166, 1654, 1608, 1528, 1491, 1479 cm-1. HRMS
(ESI-TOF) m/z: (M+H)+ calculated for C15H12ClN2O, 271.0638; found: 271.0647.
3-(amino(3-bromophenyl)methylene)-7-chloroindolin-2-one (3e): Prepared according to general
procedure A, using 7-chloro-2-oxindole (41 mg, 0.25 mmol), LiOtBu (70 mg, 0.875 mmol), 3-
bromobenzonitrile (91 mg, 0.5 mmol) and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to afford 3-
(amino(3-bromophenyl)methylene)-7-chloroindolin-2-one 3e (73 mg, 84%) as a yellow solid
1
partially soluble in chloroform. H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 7.98 (s, 1H), 7.73
(dt, J = 2.8, 1.7 Hz, 2H), 7.50 (dt, J = 8, 1.4 Hz, 1H), 7.44 (t, J = 8 Hz, 1H), 6.97 (dd, J = 8, 0.8
Hz, 1H), 6.65 (t, J = 8.0 Hz, 1H), 6.19 (d, J = 8 Hz, 1H), 5.25 (s, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ 169.6, 158.0, 136.8, 133.3, 132.6, 130.4, 130.2, 126.0, 125.1, 122.8, 121.1, 116.2,
116.1, 114.2, 95.8. FTIR (KBr): 3385, 3199, 1653, 1625, 1536, 1470 cm-1. HRMS (ESI-TOF)
m/z: (M+H)+ calculated for C15H11BrClN2O, 348.9743; found: 348.9739.
3-(amino(4-(trifluoromethyl)phenyl)methylene)-7-chloroindolin-2-one (3f): Prepared according
to general procedure A, using 7-chloro-2-oxindole (41 mg, 0.25 mmol), LiOtBu (70 mg, 0.875
mmol), 4-(trifluoromethyl)benzonitrile (85.5 mg, 0.5 mmol) and 2,2'-bipyridine (3.9 mg, 0.025
mmol) to afford 3-(amino(4-(trifluoromethyl)phenyl)methylene)-7-chloroindolin-2-one 3f (70
ACS Paragon Plus Environment
20

Page 21 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
mg, 83%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 8.04 (s, 1H), 7.84 (d, J =
8 Hz, 2H), 7.70 (d, J = 8 Hz, 2H), 6.98 (dd, J = 8, 1 Hz, 1H), 6.64 (t, J = 8.0 Hz, 1H), 6.10 (d, J
= 8 Hz, 1H), 5.28 (s, 1H). 13C{1H} NMR (100 MHz, Methanol-d4) δ 171.8, 161.9, 140.3, 134.2,
133.1 (q, J = 32.4 Hz), 129.7, 127.3, 126.9 (q, J = 3.7 Hz), 123.9 (q, J = 269.8 Hz), 123.5, 122.0,
116.9, 115.4, 95.5 FTIR (KBr): 3474, 2926, 1667, 1605, 1545, 1440 cm-1. HRMS (ESI-TOF)
m/z: (M+H)+ calculated for C16H11ClF3N2O, 339.0512; found: 339.0520.
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-(1-aminoethylidene)-6-chloroindolin-2-one (3g): Prepared according to general procedure A,
using 6-chloro-2-oxindole (41 mg, 0.25 mmol), LiOtBu in THF 1M (0.8 ml, 0.875 mmol), dry
acetonitrile (1 ml), and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to afford 3-(1-aminoethylidene)-6-
chloroindolin-2-one 3g (15 mg, 30%) as a light red color solid. 1H NMR (400 MHz, DMSO-d6) δ
10.34 (s, 1H), 9.34 (s, 1H), 8.14 (s, 1H), 7.19 (d, J = 8 Hz, 1H), 6.87 (dd, J = 7.6, 2.0 Hz, 1H),
6.81 (d, J = 4 Hz, 1H), 2.36 (s, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ 169.5, 161.4, 136.5,
125.5, 124.4, 119.3, 118.7, 108.2, 92.5, 20.5. FTIR (KBr): 3485, 3140, 1639, 1540, 1469 cm-1.
HRMS (ESI-TOF) m/z: (M+H)+ calculated for C10H10ClN2O, 209.0481; found: 209.0482.
3-(amino(3-bromophenyl)methylene)-6-chloroindolin-2-one (3h): Prepared according to general
procedure A, using 6-chloro-2-oxindole (41 mg, 0.25 mmol), LiOtBu (70 mg, 0.875 mmol), 3-
bromobenzonitrile (91 mg, 0.5 mmol) and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to afford 3-
(amino(3-bromophenyl)methylene)-6-chloroindolin-2-one 3h (65 mg, 75%) as a yellow solid. 1H
NMR (400 MHz, CDCl3) δ 9.44 (s, 1H), 9.33 (s, 1H), 7.74 – 7.67 (m, 2H), 7.48 (dt, J = 7.6, 1.4
Hz, 1H), 7.42 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 1.9 Hz, 1H), 6.67 (dd, J = 8.3, 2.0 Hz, 1H), 6.19
(d, J = 8.3 Hz, 1H), 5.36 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 171.0, 157.7, 137.5, 136.7,
133.9, 131.0, 130.8, 129.3, 126.6, 123.4, 122.8, 120.9, 119.2, 109.8, 95.7. FTIR (KBr): 3382,
ACS Paragon Plus Environment
21

The Journal of Organic Chemistry
Page 22 of 44
1
2
3
4
5
3180, 1643, 1610, 1544, 1484 cm-1. HRMS (ESI-TOF) m/z: (M+H)+ calculated for
C15H11BrClN2O, 348.9733; found: 348.9726.
6
7
8
9
3-(amino(4-(trifluoromethyl)phenyl)methylene)-6-chloroindolin-2-one (3i): Prepared according
to general procedure A, using 6-chloro-2-oxindole (41 mg, 0.25 mmol), LiOtBu (70 mg, 0.875
mmol), 4-(trifluoromethyl)benzonitrile (85.5 mg, 0.5 mmol) and 2,2'-bipyridine (3.9 mg, 0.025
mmol) to afford 3-(amino(4-(trifluoromethyl)phenyl)methylene)-6-chloroindolin-2-one (25 mg,
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
1
30%) as a yellow solid partially soluble in chloroform. H NMR (400 MHz, CDCl3) δ 9.57 (s,
1H), 8.27 (s, 1H), 7.72 (m, 2H), 7.50 (d, J = 8 Hz, 1H), 7.43 (t, J = 8 Hz, 1H), 6.97 (d, J = 8.0
13
Hz, 1H), 6.64 (t, J = 8 Hz, 1H), 6.18 (d, J = 8 Hz, 1H), 5.30 (s, 1H). C{1H} NMR (100 MHz,
Acetone-d6) 171.3, 159.6, 140.5, 138.5, 132.3 (q, J = 32.2 Hz), 129.8, 129.1, 128.8, 126.9 (q, J =
3.8 Hz), 126.1 (q, J = 3.9 Hz), 125.0 (q, J = 269.8 Hz), 124.2, 120.5, 119.3, 109.8, 95.2. FTIR
(KBr): 3398, 3161, 1665, 1605, 1574, 1555 cm-1. HRMS (ESI-TOF) m/z: (M+H)+ calculated for
C16H11ClF3N2O, 339.0512; found: 339.0511.
3-(1-aminoethylidene)-1-methylindolin-2-one (3j): Prepared according to general procedure A,
using 1-methylindolin-2-one (36 mg, 0.25 mmol), LiOtBu in THF 1M (70 mg, 0.875 mmol), dry
acetonitrile (0.6 ml), and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to afford 3-(1-aminoethylidene)-
1-methylindolin-2-one 3j (30 mg, 65%) as a light red solid. 1H NMR (400 MHz, Methanol-d4) δ
7.31 – 7.27 (m, 1H), 7.02 (td, J = 7.5, 1.3 Hz, 1H), 6.96 (dd, J = 7.6, 1.3 Hz, 1H), 6.94 – 6.90 (m,
13
1H), 4.59 (s, 2H), 3.27 (s, 3H), 2.41 (s, 3H). C{1H} NMR (100 MHz, Methanol-d4) δ 170.0,
162.7, 138.2, 126.0, 123.2, 122.1, 119.2, 108.5, 94.5, 25.8, 21.1. IR (neat): 3282, 3124, 1700,
1623, 1532, 1464 cm-1. HRMS (ESI-TOF) m/z: (M+H)+ calculated for C11H13N2O, 189.1028;
found: 189.1033.
ACS Paragon Plus Environment
22

Page 23 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
3-(amino(phenyl)methylene)-1-methylindolin-2-one (3k)22: Prepared according to general
procedure A, using 1-methylindolin-2-one (36 mg, 0.25 mmol), LiOtBu (70 mg, 0.875 mmol),
benzonitrile (103 mg, 1 mmol), and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to afford 3-
9
1
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
(amino(phenyl)methylene)-1-methylindolin-2-one 3k (40 mg, 64%) as a white solid. H NMR
(400 MHz, CDCl3) δ 9.53 (s, 1H), 7.64 – 7.48 (m, 5H), 7.03 (td, J = 7.7, 1.0 Hz, 1H), 6.86 (d, J =
8 Hz, 1H), 6.70 (td, J = 7.7, 1.0 Hz, 1H), 6.32 (d, J = 8 Hz, 1H), 5.17 (s, 1H), 3.37 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 169.6, 159.0, 138.4, 136.1, 130.5, 129.2, 127.9, 123.8,
123.5, 120.6, 118.3, 107.4, 95.8, 25.7. IR (Neat): 3339, 3178, 1606, 1542, 1473 cm-1. HRMS
(ESI-TOF) m/z: (M+H)+ calculated for C16H15N2O, 251.1184; found: 251.1182.
3-(amino(3-bromophenyl)methylene)-1-methylindolin-2-one (3l): Prepared according to general
procedure A, using 1-methylindolin-2-one (36 mg, 0.25 mmol), LiOtBu (70 mg, 0.875 mmol), 3-
bromobenzonitrile (91 mg, 0.5 mmol) and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to afford 3-
(amino(3-bromophenyl)methylene)-1-methylindolin-2-one 3l (65 mg, 80%) as a yellow solid. 1H
NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 7.72 – 7.67 (m, 2H), 7.50 (dd, J = 8, 3.9 Hz, 1H), 7.43 –
7.38 (m, 1H), 7.06 (td, J = 8, 0.8 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.77 – 6.69 (m, 1H), 6.33 (d,
J = 8 Hz, 1H), 5.19 (s, 1H), 3.36 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.4, 156.7,
138.6, 137.9, 133.5, 130.93, 130.90, 126.7, 123.9, 123.4, 123.2, 120.9, 118.3, 107.6, 96.1, 25.7.
IR (neat): 3450, 3267, 1604, 1532, 1459 cm-1. HRMS (ESI-TOF) m/z: (M+H)+ calculated for
C16H14BrN2O, 329.0289; found: 329.0290.
3-(amino(2-bromo-4-methylphenyl)methylene)-1-methylindolin-2-one (3m): Prepared according
to general procedure A, using 1-methylindolin-2-one (36 mg, 0.25 mmol), LiOtBu (70 mg, 0.875
mmol), 2-bromo-4-methylbenzonitrile (98 mg, 0.5 mmol), and 2,2'-bipyridine (3.9 mg, 0.025
mmol) to afford 3-(amino(2-bromo-4-methylphenyl)methylene)-1-methylindolin-2-one 3m (51
ACS Paragon Plus Environment
23

The Journal of Organic Chemistry
Page 24 of 44
1
2
3
4
5
mg, 60%) as a light red solid. 1H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 7.58 (s, 1H), 7.28 (dd,
J = 8, 4.4 Hz, 2H), 7.03 (td, J = 8, 1.1 Hz, 1H), 6.85 (d, J = 8 Hz, 1H), 6.71 (td, J = 8, 1.0 Hz,
6
7
8
13
1H), 5.93 (d, J = 8 Hz, 1H), 5.13 (s, 1H), 3.36 (s, 3H), 2.45 (s, 3H). C{1H} NMR (100 MHz,
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
CDCl3) δ 169.4, 156.5, 142.0, 138.5, 134.1, 133.8, 129.5, 129.1, 123.7, 123.6, 121.08, 121.04,
118.0, 107.5, 96.8, 25.7, 21.2. FTIR (KBr): 3475, 3274, 2924, 1662, 1628, 1613, 1555, 1466,
1432 cm-1. HRMS (ESI-TOF) m/z: (M+H)+ calculated for C17H16BrN2O, 343.0446; found:
343.0442.
3-(amino(4-chlorophenyl)methylene)-1-methylindolin-2-one (3n)22: Prepared according to
general procedure A, using 1-methylindolin-2-one (36 mg, 0.25 mmol), LiOtBu (70 mg, 0.875
mmol), 4-chlorobenzonitrile (68.5 mg, 0.5 mmol), and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to
afford 3-(amino(4-chlorophenyl)methylene)-1-methylindolin-2-one 3n (39 mg, 56%) as a yellow
1
color solid. H NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 7.58 – 7.43 (m, 4H), 7.05 (td, J = 7.7,
1.0 Hz, 1H), 6.86 (d, J = 8 Hz, 1H), 6.73 (td, J = 7.6, 1.0 Hz, 1H), 6.36 (d, J = 8 Hz, 1H), 5.12 (s,
1H), 3.36 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.5, 157.4, 138.5, 136.6, 134.5, 129.56,
129.51, 123.8, 123.5, 120.8, 118.3, 107.6, 96.1, 25.7. IR (neat): 3312, 3152, 1632, 1535, 1482,
1466 cm-1. HRMS (ESI-TOF) m/z: (M+H)+ calculated for C16H14ClN2O, 285.0794; found:
285.0790.
3-(amino(4-(trifluoromethyl)phenyl)methylene)-1-methylindolin-2-one
(3o)22:
Prepared
according to general procedure A, using 1-methylindolin-2-one (36 mg, 0.25 mmol), LiOtBu (70
mg, 0.875 mmol), 4-(trifluoromethyl)benzonitrile (85.5 mg, 0.5 mmol) and 2,2'-bipyridine (3.9
mg, 0.025 mmol) to afford 3-(amino(4-(trifluoromethyl)phenyl)methylene)-1-methylindolin-2-
one 3o (74 mg, 93%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 7.82 (d, J = 8
Hz, 2H), 7.70 (d, J = 8 Hz, 2H), 7.05 (td, J = 7.6, 1.1 Hz, 1H), 6.86 (d, J = 8 Hz, 1H), 6.71 (td, J
ACS Paragon Plus Environment
24

Page 25 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
= 7.7, 1.0 Hz, 1H), 6.23 (d, J = 8 Hz, 1H), 5.07 (s, 1H), 3.37 (s, 3H). C{1H} NMR (100 MHz,
CDCl3) δ 169.4, 156.8, 139.6, 138.6, 133.5(q, J = 32.6 Hz), 128.6, 126.36 (q, J = 3.7 Hz), 124.1,
123.8 (q, J = 270.8 Hz), 123.2, 120.9, 118.2, 107.7, 96.34, 25.73. FTIR (KBr): 3350, 3189, 1626,
1556, 1469 cm-1. HRMS (ESI-TOF) m/z: (M+H)+ calculated for C17H14F3N2O, 319.1058; found:
319.1058.
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-(1-amino-2-(4-chlorophenyl)ethylidene)-1-methylindolin-2-one (3p): Prepared according to
general procedure A, using 1-methylindolin-2-one (36 mg, 0.25 mmol), LiOtBu (70 mg, 0.875
mmol), 2-(4-chlorophenyl)acetonitrile (75.5 mg, 0.5 mmol) and 2,2'-bipyridine (3.9 mg, 0.025
mmol) to afford (3-(1-amino-2-(4-chlorophenyl)ethylidene)-1-methylindolin-2-one 3p (52 mg,
70%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 7.40 – 7.35 (m, 2H), 7.32 –
7.28 (m, 3H), 7.16 (td, J =7.7, 1.1 Hz, 1H), 7.03 (td, J =7.6, 1.1 Hz, 1H), 6.95 (d, J =8 Hz, 1H),
5.00 (s, 1H), 4.16 (s, 2H), 3.39 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.2, 158.9, 138.3,
133.9, 132.4, 130.9, 129.5, 123.9, 123.3, 121.1, 118.6, 107.7, 95.6, 39.2, 25.7. FTIR (KBr):
3306, 3137, 1625, 1606, 1537, 1488 cm-1. HRMS (ESI-TOF) m/z: (M+H)+ calculated for
C17H16ClN2O, 299.0951; found: 299.0951.
3-(1-amino-2-(p-tolyl)ethylidene)-1-methylindolin-2-one (3q): Prepared according to general
procedure A, using 1-methylindolin-2-one (36 mg, 0.25 mmol), LiOtBu (70 mg, 0.875 mmol), 2-
(p-tolyl)acetonitrile (65.5 mg, 0.5 mmol), and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to afford 3-
1
(1-amino-2-(p-tolyl)ethylidene)-1-methylindolin-2-one 3q (39 mg, 57%) as a white solid. H
NMR (400 MHz, CDCl3+CCl4) δ 9.71 (s, 1H), 7.33 (d, J = 8 Hz, 1H), 7.18 (s, 4H), 7.11 (dt, J =
7.7, 4.0 Hz, 1H), 7.00 (td, J = 7.7, 1.1 Hz, 1H), 6.91 (d, J = 8 Hz, 1H), 5.14 (s, 1H), 4.13 (s, 2H),
3.36 (s, 3H), 2.37 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3+CCl4) δ 169.1, 160.2, 138.1, 137.5,
130.5, 130.0, 129.7, 124.2, 122.9, 121.0, 118.6, 107.5, 95.0, 39.4, 25.6, 21.2. IR (neat): 3392,
ACS Paragon Plus Environment
25

The Journal of Organic Chemistry
Page 26 of 44
1
2
3
4
5
3186, 1634, 1528, 1466 cm-1. HRMS (ESI-TOF) m/z: (M+H)+ calculated for C18H19N2O,
279.1497; found: 279.1500.
6
7
8
9
3-(1-amino-2-(4-methoxyphenyl)ethylidene)-1-methylindolin-2-one (3r): Prepared according to
general procedure A, using 1-methylindolin-2-one (36 mg, 0.25 mmol), LiOtBu (70 mg, 0.875
mmol), 2-(4-methoxyphenyl)acetonitrile (73.5 mg, 0.5 mmol), and 2,2'-bipyridine (3.9 mg, 0.025
mmol) to afford 3-(1-amino-2-(4-methoxyphenyl)ethylidene)-1-methylindolin-2-one 3r (42 mg,
57%) as a yellow solid. 1H NMR (400 MHz, CDCl3+CCl4) δ 9.71 (s, 1H), 7.33 (d, J = 8 Hz, 1H),
7.23 – 7.18 (m, 2H), 7.11 (td, J =7.5, 0.9 Hz, 1H), 7.00 (td, J =7.7, 1.1 Hz, 1H), 6.93 – 6.87 (m,
3H), 5.12 (s, 1H), 4.11 (s, 2H), 3.81 (s, 3H), 3.36 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3+CCl4) δ 169.1, 160.4, 159.3, 138.1, 130.9, 125.3, 124.2, 122.9, 121.0, 118.6, 114.7,
107.5, 94.9, 55.3, 39.0, 25.6. FTIR (KBr): 3403, 3328, 3202, 1616, 1510, 1439 cm-1. HRMS
(ESI-TOF) m/z: (M+H)+ calculated for C18H19N2O2, 295.1446; found: 295.1449.
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-(amino(phenyl)methylene)-1-benzylindolin-2-one (3s): Prepared according to general
procedure A, using 1-benzylindolin-2-one (55.7 mg, 0.25 mmol), LiOtBu (70 mg, 0.875 mmol),
benzonitrile (103 mg, 1 mmol) and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to afford 3-
1
(amino(phenyl)methylene)-1-benzylindolin-2-one 3s (49 mg, 61%) as a yellow solid. H NMR
(400 MHz, CDCl3) δ 9.59 (s, 1H), 7.62 – 7.50 (m, 5H), 7.35 – 7.28 (m, 4H), 7.21-7.25 (m, 1H),
6.91 (td, J = 8, 1.0 Hz, 1H), 6.74 (d, J = 8 Hz, 1H), 6.66 (td, J = 8, 0.9 Hz, 1H), 6.31 (d, J = 8 Hz,
1H), 5.22 (s, 1H), 5.09 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.5, 159.3, 137.6, 137.2,
136.1, 130.6, 129.3, 128.7, 127.9, 127.3, 124.0, 123.5, 120.7, 118.4, 108.4, 95.7, 43.3. FTIR
(KBr): 3367, 3188, 1715, 1644, 1623, 1549, 1467 cm-1. HRMS (ESI-TOF) m/z: (M+H)+
calculated for C22H19N2O, 327.1497; found: 327.1495.
ACS Paragon Plus Environment
26

Page 27 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3-(amino(3-bromophenyl)methylene)-1-benzylindolin-2-one (3t): Prepared according to general
procedure A, using 1-benzylindolin-2-one (55.7 mg, 0.25 mmol), LiOtBu (70 mg, 0.875 mmol),
3-bromobenzonitrile (91 mg, 0.5 mmol) and 2,2'-bipyridine (3.9 mg, 0.025 mmol) to afford 3-
(amino(3-bromophenyl)methylene)-1-benzylindolin-2-one 3t (70 mg, 70%) as a yellow solid. 1H
NMR (400 MHz, CDCl3) δ 9.49 (s, 1H), 7.72 – 7.66 (m, 2H), 7.52 – 7.48 (m, 1H), 7.40 (t, J = 8
Hz, 1H), 7.31 – 7.27 (m, 4H), 7.24 – 7.19 (m, 1H), 6.93 (td, J = 8, 1.0 Hz, 1H), 6.74 (d, J = 8 Hz,
1H), 6.72 – 6.65 (td, J = 8, 1.0 Hz, 1H), 6.32 (d, J = 8 Hz, 1H), 5.17 (s, 1H), 5.06 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3) δ 169.4, 157.0, 137.9, 137.8, 137.0, 133.6, 130.9, 128.7,
127.4, 127.3, 126.7, 123.9, 123.5, 123.2, 120.9, 118.4, 108.5, 96.0, 43.3. IR (neat): 3347, 3185,
1620, 1548, 1479 cm-1. HRMS (ESI-TOF) m/z: (M)+ calculated for C22H18BrN2O, 404.0524;
found: 404.0519.
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-(amino(4-(trifluoromethyl)phenyl)methylene)-1-benzylindolin-2-one (3u): Prepared according
to general procedure A, using 1-benzylindolin-2-one (55.7 mg, 0.25 mmol), LiOtBu (70 mg,
0.875 mmol), 4-(trifluoromethyl)benzonitrile (85.5 mg, 0.5 mmol), and 2,2'-bipyridine (3.9 mg,
0.025 mmol) to afford 3-(amino(4-(trifluoromethyl)phenyl)methylene)-1-benzylindolin-2-one 3u
(78 mg, 79%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 7.83 (d, J = 8.0 Hz,
2H), 7.72 (d, J = 8 Hz, 2H), 7.35 - 7.30 (m, 4H), 7.26 – 7.22 (m, 1H), 6.96 (td, J = 7.7, 1.0 Hz,
1H), 6.78 (d, J = 7.7 Hz, 1H), 6.70 (td, J =7.7, 1.0 Hz, 1H), 6.25 (d, J = 8 Hz, 1H), 5.19 (s, 1H),
5.09 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.3, 157.2, 139.4, 137.7, 136.9, 132.4 (q, J
= 32.6), 130.0, 128.7, 128.6, 127.4, 127.2, 126.30 (q, J = 3.7 Hz), 123.9, 123.8(q, J = 270.7 Hz),
123.4, 120.9, 118.2, 108.6, 95.9, 43.2. IR (neat): 3312, 3152, 1632, 1604, 1565, 1426 cm-1.
HRMS (ESI-TOF) m/z: (M+H)+ calculated for C23H18F3N2O, 395.1371; found: 395.1372.
ACS Paragon Plus Environment
27

The Journal of Organic Chemistry
Page 28 of 44
1
2
3
4
5
6
7
8
9
1-methylindoline-2,3-dione (4a)23: 3-(aminobenzylidene/aminoalkylidene)indolin-2-ones (3j,
3k, 3l, 3n, 3o) (0.1 mmol) and CuI (11 mg, 0.06 mmol) were allowed to react in 10 mL round
bottom flask according to method B to afford 1-methylindoline-2,3-dione (for yield see scheme
3) red solid 4a. 1H NMR (400 MHz, CDCl3 + CCl4) δ 7.60 (dd, J = 12.1, 4.4 Hz, 2H), 7.12 (t, J =
8 Hz, 1H), 6.88 (d, J = 8 Hz, 1H), 3.25 (s, 3H). 13C{1H} NMR(100 MHz, CDCl3 + CCl4) δ 183.3,
158.2, 151.6, 138.4, 125.4, 123.9, 117.6, 109.9, 26.3. IR (Neat): 1721 cm-1. HRMS (ESI-TOF)
m/z: (M+H)+ calculated for C9H8NO2, 162.0555; found: 162.0560.
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
1-benzylindoline-2,3-dione (4b)23: 3-(aminobenzylidene/aminoalkylidene)indolin-2-ones (3s, 3t,
3u) (0.1 mmol) and CuI (11 mg, 0.06 mmol) were allowed to react in 10 mL round bottom flask
according to method B to afford 1-benzylindoline-2,3-dione (for yield see scheme 3 main
article) red solid 4b. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.5 Hz, 1H), 7.47 (td, J = 7.8, 1.4
Hz, 1H), 7.38 – 7.28 (m, 5H), 7.09 (td, J = 7.6, 0.8 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 4.93 (s,
2H). 13C{1H} NMR (100 MHz, CDCl3+CCl4) δ 183.2, 158.3, 150.9, 138.3, 134.6, 129.2, 128.3,
127.5, 125.5, 123.9, 117.9, 111.1, 44.2. IR (Neat): 1732 cm-1. HRMS (ESI-TOF) m/z: (M+H)+
calculated for C15H12NO2, 238.0868; found: 238.0871.
3-bromobenzonitrile (5b): 3-(aminobenzylidene)indolin-2-ones (3l or 3t) (0.1 mmol) and CuI
(11 mg, 0.06 mmol) were allowed to react in 10 mL round bottom flask according to method B
to afford 3-bromobenzonitrile (for yield see scheme 3 main article) white solid 5b. 1H NMR (400
MHz, CDCl3) δ 7.81 – 7.77 (m, 1H), 7.75 (dd, J = 8.1, 1.0 Hz, 1H), 7.63 – 7.57 (m, 1H), 7.36 (t,
13
J = 7.9 Hz, 1H). C{1H} NMR (100 MHz, CDCl3) δ 136.2, 134.8, 130.8, 130.7, 122.9, 117.3,
114.2.
ACS Paragon Plus Environment
28

Page 29 of 44
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
3-acetyl-3-fluoroindolin-2-one (6a). 3-(1-aminoethylidene)indolin-2-one (52 mg, 0.3 mmol),
selectfluor (159.3 mg, 0.45 mmol), were allowed to react in 10 mL round-bottom flask according
to method C to afford inseparable mixture of 3-fluorooxindole24 (17 mg, 38%) and 3-acetyl-3-
9
1
fluoroindolin-2-one (22 mg, 38%) as a white solid. H NMR for 3-fluorooxindole24 (400 MHz,
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
CDCl3) δ 9.10 (s, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.40 – 7.35 (m, 1H), 7.11 (tt, J = 7.6 Hz, J = 0.8
13
Hz 1H), 6.92 (dd, J = 7.9, 0.4 Hz, 1H), 5.69 (d, J = 50.8 Hz, 1H). C{1H} NMR (100 MHz,
CDCl3) 171.7 (d, J = 20 Hz), 142.1 (d, J = 5.4 Hz), 131.6 (d, J = 3.3 Hz), 126.4 (d, J = 0.9 Hz),
19
123.4 (d, J = 2.8 Hz), 123.3 (d, J = 12 Hz), 111.1 (d, J = 1.2 Hz), 86.0 (d, J = 188.09 Hz). F
NMR (377 MHz, CDCl3) δ 193.8.
3-acetyl-3-fluoroindolin-2-one (6a): 1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 7.25 - 7.29 (m,
2H), 7.11 (tt, J = 7.6 Hz, J = 0.8 Hz 1H), 6.99 (d, J = 7.9 Hz, 1H), 2.40 (d, J = 3.6 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 200.0 (d, J = 30 Hz), 174.0 (d, J = 17.7 Hz), 142.7 (d, J =
5.3 Hz), 132.5 (d, J = 2.9 Hz), 125.1, 123.8 (d, J = 2.5 Hz), 123.5 (d, J = 14.9 Hz), 111.7, 96.3
(d, J = 203 Hz), 25.9. 19F NMR (377 MHz, CDCl3) δ 165.1. IR (Neat): 1721, 1620 cm-1. HRMS
(ESI-TOF) m/z: (M+H)+ calculated for C10H9FNO2, 194.0617; found: 194.0626.
3-benzoyl-3-fluoroindolin-2-one (6b): 3-(amino(phenyl)methylene)indolin-2-one (70 mg, 0.3
mmol), selectfluor (159.3 mg, 0.45 mmol), were allowed to react in 10 mL round-bottom flask
according to method C to afford inseparable mixture of 3-fluorooxindole (19 mg, 43%) and 3-
1
benzoyl-3-fluoroindolin-2-one 6b (33 mg, 43%) as a white solid. H NMR for 3-fluorooxindole
(400 MHz, CDCl3) δ 8.40 (s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.35 – 7.31 (m, 1H), 7.09 – 7.04 (m,
13
1H), 6.89 (d, J = 7.9 Hz, 1H), 5.70 (d, J = 50.8 Hz, 1H). C{1H} NMR (100 MHz, CDCl3) δ
171.6 (d, J = 21 Hz), 142.6 (d, J = 5.3 Hz), 131.6 (d, J = 3.3 Hz), 126.3 (d, J = 0.5 Hz), 123.5 (d,
ACS Paragon Plus Environment
29