"on Water" Direct Organocatalytic Cyanoarylmethylation of Isatins for the Diastereoselective Synthesis of 3-Hydroxy-3-cyanomethyl Oxindoles

Article abstract of DOI:10.1021/acs.joc.8b03194

An "on water" organocatalytic cyanoarylmethylation of aryl acetonitrile to isatins is developed, giving products in high yields and up to excellent diastereoselectivities. A remarkable enhancement of reaction rates and diastereoselectivities by water was observed under mild conditions. Moreover, this approach provides a highly efficient and environmentally benign access to thermodynamic 3-hydroxy-3-cyanomethyl oxindoles.

Full text of DOI:10.1021/acs.joc.8b03194

Subscriber access provided by ECU Libraries
Article
“On water” direct organocatalytic cyanoarylmethylation of isatins for
the diastereoselective synthesis of 3-hydroxy-3-cyanomethyl oxindoles
Yong Zhang, Liang Luo, Jin Ge, Su-Qiong Yan, Yan-Xin Peng, Ya-
Ru Liu, Jin-Xiang Liu, Chong Liu, Tianqiong Ma, and Hai-Qing Luo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03194 • Publication Date (Web): 13 Mar 2019
Downloaded from http://pubs.acs.org on March 13, 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 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
“On water” direct organocatalytic cyanoarylmethylation of
isatins for the diastereoselective synthesis of 3-hydroxy-3-
cyanomethyl oxindoles
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
Yong Zhang,a* Liang Luo,a Jin Ge,a Su-Qiong Yan,a Yan-Xin Peng,a Ya-Ru Liu,a Jin-Xiang Liu,a
Chong Liu, c* Tianqiong Mab* and Hai-Qing Luoa
a
Key Laboratory of Organo-pharmaceutical Chemistry, Gannan Normal University, Ganzhou 341000, China
b
c
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou, Gansu 730000, China
Inorganic Systems Engineering group, Chemical Engineering Department, Delft University of Technology, Van der
Maasweg 9, 2629 HZ Delft, The Netherlands
Fax: +86 (0)797 8393536; E-mail: yong_zhanggnnu＠126.com; matq13@lzu.edu.cn; C.Liu-4@tudelft.nl
ABSTRACT: An “on water” organocatalytic cyanoarylmethylation of aryl acetonitrile to isatins is developed, giving
products in high yields and up to excellent diastereoselectivities. A remarkable enhancement on reaction rates and
diastereoselectivities by water was observed under mild conditions. Moreover, this approach provides a highly efficient
and environmental access to thermodynamic 3-hydroxy-3-cyanomethyl oxindoles.
INTRODUCTION
Water, in contrast to organic solvents, is an unquestionably cheap, safe, and environmentally
benign solvent in nature. Use of water will reduce the use of harmful organic solvents and
represents an important subject in green chemistry.1 In addition, due to its unique physicochemical
properties, water can give completely new reactivity as compared to commonly used organic
solvents.2 In many cases, significant improvement on reaction rates and selectivities are observed
in water.3 Furthermore, in some cases, the reaction does not take place in the absence of water.4
Therefore, extensive research efforts have focused on the use of water as a reaction medium in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
organic synthesis, and great success has been achieved.5 However, pursuing practical organic
reactions in water for stereoselective synthesis of value-added products are still highly desirable.
Alkylnitriles constitute an important class of nitrogen-containing compounds frequently found
in many natural products and pharmaceutically interesting compounds (Figure 1).6 Moreover, the
nitrile group can be easily converted into other functional groups, such as amine, aldehyde, amide
and carboxylic acid.7 Therefore, great effort has been devoted to the synthesis of functional
alkylnitriles.8 In this contribution, the aldol-type cyanoalkylation of aldehydes have been
intensively studied9, giving versatile functionalized -hydroxy nitriles. In contrast, the use of more
challenging ketones, as acceptors in cyanoalkylations is rare. To realize such transformations, metal
catalysts10, metalated alkylnitriles11 or excess base12 were found to be necessary. There are,
however, no reports on metal-free catalytic stereoselective addition of simple alkylnitriles to ketone.
As part of our continuing interest in “on water” reactions3f, 13 ，herein we report the first
organocatalytic direct cyanoarylmethylation of isatins on water (Scheme 1). This approach
provides a facile access to diastereoselective synthesis of 3-hydroxy-3-cyanomethyl oxindoles.
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. Representative natural products and pharmaceuticals.
ACS Paragon Plus Environment

Page 3 of 26
The Journal of Organic Chemistry
The Journal of Organic Chemistry
1
2
3
4
5
6
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
Scheme 1. On water organocatalytic cyanoarylmethylation of isatins.
RESULTS AND DISCUSSION
Initially, the model reaction of the N-methyl isatin 1a and phenyl acetonitrile 2a was investigated
under various base catalytic conditions (Table 1). Using water as the reaction medium, we were
pleased to find that the reaction catalyzed by diethylamine afforded the desired -hydroxy nitrile
3a in 83% yield with a diastereomeric ratio of 88:12 (entry 1). Screening of the base catalysts found
that DBU improved both the yield and the diastereomeric ratio (entry 2), whereas other bases such
as DMAP, DABCO, imidazole, K2CO3 and KOH displayed inferior catalytic activities. We also
tested some chiral base catalysts to see if this reaction can proceed with enantioselectivity control.
However, poor results (<10% ee) has been obtained for the moment (see supporting information
for details).
Table 1 Screening of catalysts for the cyanoarylmethylation reaction of N-methyl isatin 1a
with phenyl acetonitrile 2a a
Entry
Cat.
t [h]
10
4
Yield [%]b
dr [%]c
88:12
98:2
1
2
3
4
5
6
Et2NH
DBU
83
96
82
46
<5
52
DMAP
DABCO
Imidazole
KOH
26
48
48
48
70:30
68:32
nd
73:27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
K2CO3
48
27
58:42
a Unless otherwise noted, the reaction was performed with 0.2 mmol of 1a, 0.24 mmol of 2a and 20 mol% of
catalyst in 0.5 mL water. b Isolated yield. c Determined by 1H NMR analysis. 20 mol% catalyst was used.
7
8
9
Subsequently, the solvent effect on the reaction outcome was examined with DBU as the catalyst
(Table 2). It was found that this catalytic process is quite solvent dependent. Several organic
solvents were evaluated and gave much lower transformation efficiency, even with a prolonged
reaction time (48 h). In addition, the dehydration product 4a instead of 3a was obtained as the major
product when organic solvents such as DCM, MeCN and MeOH were used. The reaction was
greatly accelerated under “on water” condition to give the -hydroxy nitrile 3a in very good yield
(96%) with excellent diastereoselectivity (98:2). Interestingly, the dehydration process was
completely suppressed under such “on water” condition. Additional experiment showed that the
catalyst loading could be lowered to 10 mol% with only a slight effect on reaction efficiency (entry
10). Single-crystal X-ray analysis of 3a unambiguously confirmed that the cyanoarylmethylation
product has an anti-configuration14.
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
Table 2 Solvent effect on the DBU catalyzed addition of 2a to 1a a
Entry
1
Solvent
DCM
t [h]
48 h
3a/4aYield [%]b dr [%]c
9/67
9/64
38/25
66/28
52/3
70/7
nd
2
3
4
5
6
MeCN
DMF
48 h
48 h
48 h
48 h
48 h
nd
65:35
65:35
76:24
79:21
DMSO
Dioxane
THF
ACS Paragon Plus Environment

Page 5 of 26
The Journal of Organic Chemistry
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7
Toluene
MeOH
H2O
48 h
48 h
4 h
81/8
96:4
nd
8
trace/92
96/0
9
98:2
99:1
10d
H2O
18 h
86/0
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 Unless otherwise noted, the reaction was performed with 0.2 mmol of 1a, 0.24 mmol of 2a and 20 mol%
of catalyst in 0.5 mL solvent. b Isolated yield by column chromatography. c Determined by 1H NMR analysis.
d 10 mol% of the catalyst was used, isolated yield by washing process.
Most importantly, this “on water” reaction is operationally straightforward and scalable to gram
scale (Figure 2). After the complete conversion of N-methyl isatin (indicated by a color change
from red to yellow), the desired product 3a was obtained in highly pure form by simple filtration
and washing with water and petroleum ether, which is a key intermediate for the synthesis of ()-
CPC-1 analogue 6.
Figure 2. Gram scale synthesis of 3a.
The substrate scope of the reaction was investigated after deriving the optimized reaction
conditions. First, we studied variation of the isatins (Table 3). Both electron-donating (5-Me and
5-OMe) and electron-withdrawing (5-OCF3, 5-F, 5-Cl and 5-Br) groups on the oxindole were
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
tolerable to afford the desired -hydroxy nitriles in good to excellent yields and
diastereoselectivities (3b-3g). Moreover, substitution was viable at the 4-position, 6-position and
7-position of the oxindole, and disubstitution was also feasible. In all the cases, the desired product
was formed in excellent yields and very good dr values (3h-3l). It is worth noting that N-
benzylisatin and isatin with a free NH group were also well-tolerated to furnish the desired product
in high yields with good to excellent dr values (3m, 3n). Other ketones, such as
trifluoroacetophenone, acetophenone, methyl benzoylformate and cyclohexanone were not suitable
for this cyanoarylmethylation reaction under our conditions. In addition, the reaction of
benzaldehyde with phenyl acetonitrile led to the formation of a dehydrated product (see supporting
information for details).
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

Page 7 of 26
The Journal of Organic Chemistry
The Journal of Organic Chemistry
1
2
3
4
Table 3 The scope of addition reaction a
5
6
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
a Unless otherwise noted, the reaction was performed with 0.2 mmol of 1, 0.24 mmol of 2a and 10 mol% of
1
catalyst in 0.5 mL water. The yield refers to the isolated product. The dr value determined by H NMR
analysis. b 20 mol% of the catalyst was used.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
Table 4 The scope of addition reaction a
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
a Unless otherwise noted, the reaction was performed with 0.2 mmol of 1a, 0.24 mmol of 2 and 10 mol% of
DBU in 0.5 mL water. The yield refers to the isolated product. The dr value determined by 1H NMR analysis.
b DABCO was used as the catalyst. c 20 mol% of DBU was used.
ACS Paragon Plus Environment

Page 9 of 26
The Journal of Organic Chemistry
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Next, we investigated variation on the benzyl nitriles. As shown in Table 4. The electronic nature
of benzyl nitriles has a noticeable influence on the reaction yields and diastereoselectivities.
Generally, benzyl nitriles bearing electron-withdrawing (4-CF3, 4-F, 4-Cl, 4-Br and 4-NO2) groups
gave more satisfactory results than those with electron-donating (4-OMe and 4-Me) groups. The
sterically more demanding 1-naphthyl substrate had no negative effect on the reaction (5h).
Pleasingly, satisfactory results in term of yield and diastereoselectivity were also achieved with the
nitriles containing heterocycles such as thiophene and benzofuran (5i, 5j and 5k).
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
During the investigation of substrate scope, a time-dependent dr changes of some products were
observed (Figure 3). For instance, the reaction of N-methyl-5-fluoro isatin (1e) with phenyl
acetonitrile 2a was anti-selective at early stage. Upon prolonging the reaction time, the
diastereoselectivity of this reaction changed from anti to syn. After stirring for 18 hours, the product
3e was obtained in excellent syn-selectivity (95:5), and no more changes in the dr was observed
from then on. Moreover, when products (3e-3g) with low dr were treated with 20 mol% DBU in
water for 20 h, a significant improvement of dr was observed. These results suggested that the
reaction is reversible in the presence of DBU when using water as the reaction medium, and
thermodynamically controlled leading to the more stable adduct. To the best of our knowledge, this
reaction represents the first example of “on water” mediated diastereoselective changes.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
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
Figure 3. Time dependent changes in diastereomeric ratio.
To understand the effect of thermodynamic stability on the product diastereoselectivity, we
performed DFT calculations to compare the energy differences between the syn- and anti-adducts
for 3a and 3e (Figure 4). As the products show poor solubility in water solvent, both the molecular
state in water solvent and the solid state were analyzed using cluster and periodic models (16
molecules per unit cell), respectively. For both 3a and 3e, the molecular anti-isomer shows a higher
stability than its syn-isomer with a lower energy of 6 kJ/mol. However, the further calculations on
periodic unit cells indicate that although the anti-3a still shows a higher stability than syn-3a with
a favored energy by 50 kJ/mol, the stability of syn-3e unit cell increases significantly with a
decreased energy by -110 kJ/mol in comparison with the anti-3e. This indicates that the syn-isomer
of 3e is the thermodynamic product in its solid state, which is consistent with the experimental
observations. As the products are mostly insoluble in reaction conditions, we speculate the
selectivity of thermodynamic products for different substrates is controlled by the diastereomer
ACS Paragon Plus Environment

Page 11 of 26
The Journal of Organic Chemistry
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
stability at solid state, and such stability differences may be induced by the different stacking of
the diastereomer molecules with distinct hydrogen-bonding interaction and steric effect in the
crystals.
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
Figure 4. Optimized product structures of (a) cluster models and (b) respective periodic unit
cells.
On the basis of previous reports15, a transition state involving an oil-water interface was assumed
to explain the high efficiency of this process. As illustrated in Figure 5, the deprotonation of phenyl
acetonitrile 2a is facilitated by the synergistic effect of water and base. Through the interactions
with hydrogen-bond networks at the phase boundary, the dicarbonyl group of the electrophile and
nitrile group of the pro-nucleophile might be organized at the periphery of the oil droplet, while the
hydrophobic part is orientated within the hydrophobic interior. Consequently, the free hydroxyl
groups at the interface effectively activated the reactants and stabilized the transition state.
Moreover, the dehydration process could be suppressed when using water as the sole solvent.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
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
Figure 5. Proposed reaction mechanism.
In summary, we have developed an “on water” efficient strategy for the organocatalytic addition
of aryl acetonitriles to isatins. The reaction rate and selectivity were greatly enhanced under “on
water” conditions. The changes of diastereoselectivity was observed in this “on water” catalytic
process. Moreover, this process provides a highly efficient and environmentally benign approach
for the diastereoselective synthesis of 3-hydroxy-3-cyanomethyl oxindoles, a structural scaffold for
various natural product analogues and pharmaceutical agents.
EXPERIMENTAL SECTION
General Information. NMR spectra were recorded on a liquid NMR spectrometer (400 MHz for
1H and 100 MHz for 13C) using CDCl3 as the solvent. The residual proton in CDCl3 (δ = 7.27)
1
served as an internal standard for H NMR, and the 13C-atom of CDCl3 was used as an internal
standard (δ = 77.16) for 13C NMR. Chemical shifts are reported in ppm and the coupling constants
J are given in Hz. The following abbreviations were used to explain the multiplicities: s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). Infrared spectra were recorded on an
FT-IR spectrometer, and only major peaks were reported in cm-1. The high-resolution mass spectra
(HRMS) were recorded on an electrospray ionization (ESI) apparatus using Orbitrap mass
spectrometry. General procedure for the preparation of starting materials isatins and benzyl nitriles
were commercially available. Unless otherwise noted, analytical grade solvents and commercially
available reagents were used without further purification.
General procedure for the synthesis of N-protected isatins 1 (GP-1)16: N-alkylated isatin
ACS Paragon Plus Environment

Page 13 of 26
The Journal of Organic Chemistry
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
derivatives were prepared from commercially available isatins with different alkyl halides in the
presence of K2CO3 in DMF at room temperature. MeI or BnBr (10.2 mmol, 3.0 equiv) was added
to a stirred solution of isatin (3.4 mmol, 1.0 equiv) and K2CO3 (8.5 mmol, 2.5 equiv) in DMF and
stirred for 12 h at room temperature. The reaction mixture was quenched with water and extracted
with dichloromethane (3 x 20 mL). The combined organic phases were washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude residue was then purified
by column chromatography (eluent: PE/EA = 10/1-4/1, v/v) to provide compounds 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
1-methylindoline-2,3-dione (1a)16: Compound 1a was prepared by GP-1. Red solid, 465.8 mg,
85% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.63-7.60 (m, 2H), 7.14 (t, J = 7.6 Hz, 1H), 6.90
(d, J = 7.6 Hz, 1H), 3.26 (s, 3H).
1,5-dimethylindoline-2,3-dione (1b)17: Compound 1b was prepared by GP-1. Red solid, 327.6
mg, 55% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.42-7.40 (m, 2H), 6.80-6.78 (m, 1H), 3.23
(s, 3H), 2.34 (s, 3H).
5-methoxy-1-methylindoline-2,3-dione (1c) 17: Compound 1c was prepared by GP-1. Red solid,
227.5 mg, 35% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.17-7.13 (m, 2H), 6.81 (d, J = 8.0 Hz,
1H), 3.80 (s, 3H), 3.22 (s, 3H).
1-methyl-5-(trifluoromethoxy)indoline-2,3-dione (1d) 18: Compound 1d was prepared by GP-1.
Orange solid, 291.7 mg, 35% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.49-7.48 (m, 2H), 6.96-
6.94 (m, 1H), 3.28 (s, 3H).
18
5-fluoro-1-methylindoline-2,3-dione (1e) : Compound 1e was prepared by GP-1. Red solid,
304.6 mg, 50% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.36-7.32 (m, 2H), 6.89-6.86 (m, 1H),
3.26 (s, 3H).
5-chloro-1-methylindoline-2,3-dione (1f) 18 : Compound 1f was prepared by GP-1. Red solid,
365.8 mg, 55% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.59-7.57 (m, 2H), 6.87 (d, J = 8.0 Hz,
1H), 3.26 (s, 3H).
5-bromo-1-methylindoline-2,3-dione (1g) 17: Compound 1g was prepared by GP-1. Red solid,
571.3 mg, 70% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.74-7.71 (m, 2H), 6.82 (d, J = 8.0 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 26
The Journal of Organic Chemistry
1
2
3
4
1H), 3.26 (s, 3H).
5
6
7
8
9
6-bromo-1-methylindoline-2,3-dione (1h)18:Compound 1h was prepared by GP-1. Orange solid,
653.0 mg, 80% yield.1H NMR (400 MHz, CDCl3) δ (ppm) 7.46 (d, J = 8.0 Hz, 1H), 7.31-7.28 (m,
1H), 7.09 (d, J = 1.6 Hz, 1H), 3.25 (s, 3H).
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
19
7-bromo-1-methylindoline-2,3-dione (1i) : Compound 1i was prepared by GP-1. Red solid,
285.7 mg, 35% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.72 (dd, J = 8.0, 1.2 Hz, 1H), 7.58 (dd,
J = 7.2, 1.2 Hz, 1H), 7.02-6.69 (m, 1H), 3.66 (s, 3H).
20
7-chloro-1-methylindoline-2,3-dione (1j) : Compound 1j was prepared by GP-1. Red solid,
332.5 mg, 50% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.55-7.52 (m, 2H), 7.09-7.05 (m, 1H),
3.64 (s, 3H).
1,5,7-trimethylindoline-2,3-dione (1k) 17: Compound 1k was prepared by GP-1. Red solid, 321.7
mg, 50% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.25 (s, 1H), 7.14 (s, 1H), 3.48 (s, 3H), 2.51
(s, 3H), 2.27 (s, 3H).
4,7-dichloro-1-methylindoline-2,3-dione (1l) 21: Compound 1l was prepared by GP-1. Orange
solid, 625.7 mg, 80% yield.1H NMR (400 MHz, CDCl3) δ (ppm) 7.44 (d, J = 8.8 Hz, 1H), 7.01 (d,
J = 8.8 Hz, 1H), 3.64 (s, 3H).
1-benzylindoline-2,3-dione (1n)16: Compound 1n was prepared by GP-1. Red solid, 766.4 mg,
95% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.63-7.61 (m, 1H), 7.49 (td, J = 8.0, 1.2 Hz, 1H),
7.38-7.27 (m, 5H), 7.10 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.94 (s, 2H).
General reaction procedure for “On water” cyanoarylmethylation reaction. N-protected isatin
1a (32.2 mg, 0.20 mmol), phenyl acetonitrile 2a (28.1 mg, 0.24 mmol) and 0.5 mL H2O were stirred
at room temperature, then DBU (3.0 μL, 0.02 mmol) was added. The reaction mixture was stirred
for the indicated time. After the reaction was completed (indicated by color change from red to
yellow), the solid product was filtered, washed by water and dried under vacuum to afford the
product 3a in high yield, purity and diastereoselectivity. Some products were purified by column
ACS Paragon Plus Environment

Page 15 of 26
The Journal of Organic Chemistry
The Journal of Organic Chemistry
1
2
3
4
chromatography (eluent: PE/EA = 4/1, v/v).
5
6
7
8
9
2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-phenylacetonitrile (3a): pale yellow solid; 47.9
mg, 86% yield, 99:1 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.96 (dd, J = 7.2 Hz, 0.8 Hz, 1H),
7.34-7.30 (m, 1H), 7.23-7.19 (m, 1H), 7.17-7.14 (m, 1H), 7.07-7.04 (m, 2H), 6.75 (d, J = 7.2 Hz,
2H), 6.61 (d, J = 8.0 Hz, 1H), 5.17 (s, 1H), 3.73 (s, 1H), 2.84 (s, 3H); 13C {1H} NMR (100 MHz,
CDCl3) δ (ppm) 175.6, 143.4, 131.0, 129.0, 128.8, 128.7, 128.2, 126.2, 125.0, 123.6, 118.5, 109.1,
77.6, 46.2, 26.2. IR (KBr): v 3348 2921 2245 1735 1709 1613 1469 1114 694 cm-1. HRMS
(ESI/Orbitrap) m/z: [M + Na]+ Calcd for C17H14N2O2Na 301.0947; Found 301.0955.
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
2-(3-hydroxy-1,5-dimethyl-2-oxoindolin-3-yl)-2-phenylacetonitrile (3b): yellow solid; 56.1
mg, 96% yield, 99:1 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.78 (s, 1H), 7.17 (t, J = 7.2 Hz, 1H),
7.12-7.05 (m, 3H), 6.78 (d, J = 7.6 Hz, 2H), 6.50 (d, J = 7.6 Hz, 1H), 4.89 (s, 1H), 3.80 (s, 1H),
2.82 (s, 3H), 2.41 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 175.4, 141.0, 133.4, 131.2,
129.2, 128.8, 128.8, 128.2, 126.2, 125.7, 118.5, 108.7, 77.7, 46.4, 26.2, 21.3. IR (KBr): v 3265
2918 2245 1713 1620 1498 1367 1117 699 cm-1. HRMS (ESI/Orbitrap) m/z: [M + Na]+ Calcd for
C18H16N2O2Na 315.1104; Found 315.1113.
2-(3-hydroxy-5-methoxy-1-methyl-2-oxoindolin-3-yl)-2-phenylacetonitrile (3c): white solid;
53.0 mg, 86% yield, 98:2 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.56 (d, J = 2.0 Hz, 1H), 7.18
(t, J = 7.2 Hz, 1H), 7.10 (t, J = 7.6 Hz, 2H), 6.89-6.83 (m, 3H), 6.49 (d, J = 8.8 Hz, 1H), 4.84 (s,
1H), 4.16 (s, 1H), 3.86 (s, 3H), 2.80 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 175.2,
156.7, 136.5, 129.1, 128.8, 128.7, 128.2, 127.2, 118.4, 115.9, 111.7, 109.5, 78.0, 56.1, 46.5, 26.2.
IR (KBr): v 3296 2836 2245 1703 1495 1291 1050 697 cm-1. HRMS (ESI/Orbitrap) m/z: [M + H]+
Calcd for C18H16N2O3H 309.1234; Found 309.1227.
2-(3-hydroxy-1-methyl-2-oxo-5-(trifluoromethoxy)indolin-3-yl)-2-phenylacetonitrile
(3d):
yellow solid; 68.8 mg, 95% yield, 99:1 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.79 (s, 1H), 7,23-
7.19 (m, 2H), 7.15-7.11 (m, 2H), 6.96-6.92 (m, 2H), 6.56 (d, J = 8.8 Hz, 1H), 4.45 (d, J = 7.6 Hz,
1H), 4.16 (br, 1H), 2.86 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 175.2, 145.4 (q, 3JCF=
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
2.1 Hz), 141.8, 129.2, 128.6, 128.5, 127.4, 124.2, 119.3, 117.8, 109.4, 77.7, 46.6, 26.3. IR (KBr):
v 3270 2932 2250 1714 1496 1254 1214 1167 1113 703 cm-1. HRMS (ESI/Orbitrap) m/z: [M +
H]+ Calcd for C18H13F3N2O3H 363.0951; Found 363.0949.
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
2-(5-fluoro-3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-phenylacetonitrile (3e): white solid; 14.3
mg, 86% yield, 95:5 dr; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.23-7.22 (m, 3H), 7.16-7.06 (m,
5H), 6.81-6.78 (m, 1H), 4.95 (s, 1H), 2.89 (s, 3H); 13C {1H} NMR (100 MHz, DMSO-d6) δ (ppm)
173.9, 157,7 (d,1JCF = 237.0 Hz), 139.3 (d, 4JCF = 1.6 Hz), 130.0, 129.3 (d, 3JCF = 7.9 Hz), 129.0,
128.5, 128.0, 118.2, 116.2 (d, 2JCF = 23.1 Hz), 112.6 (d, 2JCF = 25.1 Hz), 109.5 (d, 3JCF= 8.2 Hz),
76.3, 43.7, 25.8. IR (KBr): v 3334 2923 2239 1703 1625 1490 1474 1112 662 cm-1. HRMS
(ESI/Orbitrap) m/z: [M + Na]+ Calcd for C17H13FN2O2Na 319.0853; Found 319.0858.
2-(5-chloro-3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-phenylacetonitrile (3f): pale yellow
solid; 37.2 mg, 92% yield, 99:1 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.90 (s, 1H), 7.31 (dd, J
= 8.4 Hz, 2.0 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.15-7.11 (m, 2H), 6.89-6.87 (m, 2H), 6.53 (d, J =
8.4 Hz, 1H), 4.78 (br, 1H), 4.08 (s, 1H), 2.83 (s, 3H); 13C {1H} NMR (100MHz, CDCl3) δ (ppm)
175.3, 141.9, 131.0, 129.3, 129.1, 128.7, 128.5, 128.5, 127.8, 125.5, 118.1, 110.0, 77.6, 46.4, 26.3.
IR (KBr): v 3269 3068 2945 2250 1713 1609 1490 1364 1117 700 cm-1. HRMS (ESI/Orbitrap)
m/z: [M + Na]+ Calcd for C17H13ClN2O2Na 335.0558; Found 335.0564.
2-(5-bromo-3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-phenylacetonitrile (3g): white solid;
33.9 mg, 91% yield, 97:3 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.02 (d, J = 2.0 Hz, 1H), 7.47
(dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.23-7.20 (m, 1H), 7.16-7.13 (m, 2H), 6.93 (d, J = 7.2 Hz, 2H), 6.47
(d, J = 8.4 Hz, 1H), 4.34 (s, 1H), 4.26 (s, 1H), 2.83 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ
(ppm) 174.6, 142.4, 134.0, 129.2, 128.8, 128.6, 128.5, 128.3, 127.9, 117.9, 116.5, 110.2, 46.6, 26.2.
IR (KBr): v 3263 2967 2250 1712 1605 1487 1114 699 cm-1. HRMS (ESI/Orbitrap) m/z: [M +
Na]+ Calcd for C17H13BrN2O2Na 379.0053; Found 379.0061.
2-(6-bromo-3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-phenylacetonitrile (3h): white solid;
62.8 mg, 88% yield, 81:19 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.76 (d, J = 8.0 Hz, 1H), 7.34-
ACS Paragon Plus Environment

Page 17 of 26
The Journal of Organic Chemistry
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7.31 (m, 1H), 7.22-7.18 (m, 1H), 7.17-7.12 (m, 2H), 6.94-6.90 (m, 2H), 6.72 (d, J = 2.0 Hz, 1H),
4.65 (s, 1H), 4.44 (s, 1H), 2.79 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 175.0, 144.5,
129.7, 129.2, 128.8, 128.5, 126.6, 126.4, 124.9, 124.8, 118.1, 112.2, 77.4, 46.5, 26.2. IR (KBr): v
3385 2924 2250 1718 1607 1493 1373 1062 698 cm-1. HRMS (ESI/Orbitrap) m/z: [M + Na]+ Calcd
for C17H13BrN2O2Na 379.0053; Found 379.0062.
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
2-(7-bromo-3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-phenylacetonitrile (3i): pale yellow
solid; 62.8 mg, 88% yield, 96:4 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.86 (d, J = 7.6 Hz, 1H),
7.46-7.44 (m, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.18-7.14 (m, 2H), 7.09-7.05 (m, 1H), 6.90 (d, J = 8.0
Hz, 2H), 4.44 (s, 1H), 3.86 (br, 1H), 3.19 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 175.7,
140.6, 136.6, 129.3, 129.0, 128.7, 128.5, 124.9, 124.1, 117.9, 102.9, 77.1, 47.0, 29.8. IR (KBr): v
3357 2924 2248 1710 1454 1116 699 cm-1. HRMS (ESI/Orbitrap) m/z: [M + Na]+ Calcd for
C17H13BrN2O2Na 379.0053; Found 379.0060.
2-(7-chloro-3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-phenylacetonitrile (3j): yellow solid;
1
59.8 mg, 96% yield, 95:5 dr; H NMR (400 MHz, CDCl3) δ (ppm) 7.83 (dd, J = 7.2 Hz, 1.2 Hz,
1H), 7.26-7.22 (m, 2H), 7.16-7.11 (m, 3H), 6.88 (d, J = 7.6 Hz, 2H), 4.55 (s, 1H), 4.44 (s, 1H), 3.16
(s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 175.5, 139.2, 133.3, 129.3, 128.7, 128.7, 128.5,
124.5, 123.6, 117.9, 116.2, 47.0, 29.6. IR (KBr): v 3282 2926 2248 1713 1606 1461 1116 699 cm-
1. HRMS (ESI/Orbitrap) m/z: [M + Na]+ Calcd for C17H13ClN2O2Na 335.0558; Found 335.0563.
2-(3-hydroxy-1,5,7-trimethyl-2-oxoindolin-3-yl)-2-phenylacetonitrile (3k): white solid; 56.0
mg, 91% yield, 99:1 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.62 (s, 1H), 7.18 (d, J = 6.8 Hz, 1H),
7.10-7.09 (m, 2H), 6.85 (s, 1H), 6.74 (d, J = 6.0 Hz, 2H), 4.84 (s, 1H), 3.69 (s, 1H), 3.07 (s, 3H),
2.36 (s, 3H), 2.26 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 176.1, 138.8, 135.1, 133.2,
129.5, 128.8, 128.8, 128.1, 126.9, 123.4, 120.4, 118.4, 77.1, 46.6, 29.5, 21.0, 18.6. IR (KBr): v
3422 2921 2242 1728 1704 1105 700 cm-1. HRMS (ESI/Orbitrap) m/z: [M + Na]+ Calcd for
C19H18N2O2Na 329.1260; Found 329.1270.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2-(4,7-dichloro-3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-phenylacetonitrile (3l): white solid;
60.4 mg, 87% yield, 96:4 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.25 (d, J = 7.6 Hz, 1H), 7.19-
7.15 (m, 2H), 7.13 (d, J = 8.8 Hz, 1H), 7.02-6.99 (m, 3H), 5.05 (s, 1H), 3.80 (s, 1H), 3.23 (s, 3H);
13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 173.6, 141.2, 134.1, 130.4, 129.4, 128.8, 128.6, 128.3,
125.1, 125.1, 116.7, 114.8, 77.4, 43.9, 29.5. IR (KBr): v 3385 2935 2248 1709 1600 1449 1112
699 cm-1. HRMS (ESI/Orbitrap) m/z: [M + H]+ Calcd for C17H12Cl2N2O2H 347.0349; Found
347.0354.
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
2-(3-hydroxy-2-oxoindolin-3-yl)-2-phenylacetonitrile (3m): white solid; 42.3mg, 80% yield,
84:16 dr; 1H NMR (400 MHz, MeOD) δ (ppm) 7.79 (d, J = 8.0 Hz, 1H), 7.28-7.18 (m, 3H), 7.15-
7.10 (m, 3H), 6.97-6.95 (m, 2H), 6.62 (d, J = 8.0 Hz, 1H), 4.52 (s, 1H); 13C {1H} NMR (100 MHz,
MeOD) δ (ppm) 178.6, 143.2, 131.7, 131.1, 130.2, 129.7, 129.3, 128.5, 126.2, 123.6, 120.0, 111.2,
78.5, 46.7. IR (KBr): v 3345 3181 2926 2248 1735 1709 1613 1469 1114 752 cm-1. HRMS
(ESI/Orbitrap) m/z: [M + Na]+ Calcd for C16H12N2O2Na 287.0791; Found 287.0798.
2-(1-benzyl-3-hydroxy-2-oxoindolin-3-yl)-2-phenylacetonitrile (3n): white solid; 62.4 mg, 88%
yield, 99:1 dr; 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.74 (d, J = 7.2 Hz, 1H), 7.36 (td, J = 7.6
Hz, 1.2 Hz, 1H), 7.27-7.11 (m, 8H), 6.89 (d, J = 7.6 Hz, 2H), 6.61 (d, J = 6.8 Hz, 2H), 6.53 (d, J =
8.0 Hz, 1H), 4.75 (s, 1H), 4.72 (d, J = 16.4 Hz, 1H), 4.47 (d, J = 16.4 Hz, 1H); 13C {1H} NMR (100
MHz, DMSO-d6) δ (ppm) 174.2, 142.5, 135.1, 130.3, 129.8, 129.0, 128.7, 128.4, 128.3, 127.0,
126.9, 126.4, 124.4, 122.7, 119.3, 109.4, 76.2, 44.7, 42.6. IR (KBr): v 3438 3034 2907 2248 1724
1613 1491 1368 1048 697 cm-1. HRMS (ESI/Orbitrap) m/z: [M + H]+ Calcd for C23H18N2O2H
355.1441; Found 355.1446.
2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-(4-(trifluoromethyl) phenyl)acetonitrile (5a):
white solid; 65.8 mg, 95% yield, 99:1 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.98 (d, J = 7.6 Hz,
1H), 7.38-7.32 (m, 3H), 7.23 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 7.6 Hz, 1H),
5.50 (s, 1H), 3.54 (s, 1H), 2.87 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 175.5, 143.3,
ACS Paragon Plus Environment

Page 19 of 26
The Journal of Organic Chemistry
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
133.0, 131.4, 131.1 (q, 2JCF = 32.8 Hz), 129.2, 125.8, 125.1 (q, 3JCF = 3.7 Hz), 125.0, 123.8, 123.7
(q, 1JCF = 270.8 Hz), 117.9, 109.6, 45.8, 26.3. IR (KBr): v 3410 2921 2359 1707 1613 1325 1116
1069 755 cm-1. HRMS (ESI/Orbitrap) m/z: [M + Na]+ Calcd for C18H13F3N2O2Na 369.0821; Found
369.0823.
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
2-(4-fluorophenyl)-2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)acetonitrile (5b): white solid;
50.4 mg, 85% yield, 99:1 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.92 (d, J = 7.6 Hz, 1H), 7.36
(td, J = 7.6 Hz, 1.2 Hz, 1H), 7.24-7.20 (m, 1H), 6.89-6.87 (m, 2H), 6.82-6.78 (m, 2H), 6.61 (d, J =
7.6 Hz, 1H), 4.36 (s, 1H), 4.12 (br, 1H), 2.87 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm)
1
3
175.4, 162.9 (d, JCF = 247.5 Hz), 143.4, 131.2, 130.6 (d, JCF = 8.4 Hz), 125.9, 125.0, 125.0 (d,
4JCF = 3.3 Hz), 123.8, 118.3, 115.3 (d, 2JCF = 21.7 Hz), 109.1, 77.6, 45.6, 26.2. IR (KBr): v 3340
2926 2248 1713 1698 1613 1511 1246 1116 757 cm-1. HRMS (ESI/Orbitrap) m/z: [M + Na]+ Calcd
for C17H13FN2O2Na 319.0853; Found 319.0862.
2-(4-chlorophenyl)-2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)acetonitrile (5c): white solid;
56.7 mg, 91% yield, 97:3 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.93 (d, J = 7.6 Hz, 1H), 7.34
(td, J = 8.0 Hz, 1.2 Hz, 1H), 7.22-7.18 (m, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.69-6.66 (m, 3H), 5.34
(s, 1H), 3.65 (s, 1H), 2.89 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 175.4, 143.4, 135.1,
131.2, 130.1, 128.5, 127.7, 125.9, 125.0, 123.7, 118.1, 109.3, 45.6, 26.3. IR (KBr): v 3397 2923
2250 1708 1613 1494 1470 1093 757 cm-1. HRMS (ESI/Orbitrap) m/z: [M + Na]+ Calcd for
C17H13ClN2O2Na 335.0558; Found 335.0565.
2-(4-bromophenyl)-2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)acetonitrile (5d): white solid;
63.6 mg, 89% yield, 97:3 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.92 (d, J = 8.0 Hz, 1H), 7.35
(t, J = 7.6 Hz, 1H), 7.23-7.19 (m, 3H), 6.72-6.70 (m, 2H), 6.65 (d, J = 7.6 Hz, 1H), 4.78 (s, 1H),
4.04 (br, 1H), 2.89 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 175.1, 143.3, 131.5, 131.3,
130.4, 128.1, 125.7, 125.0, 123.9, 123.3, 118.0, 109.2, 77.4, 45.8, 26.3. IR (KBr): v 3386 2914
2245 1707 1613 1493 1470 1115 755 cm-1. HRMS (ESI/Orbitrap) m/z: [M + Na]+ Calcd for
C17H13BrN2O2Na 379.0053; Found 379.0062.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-(4-nitrophenyl)acetonitrile (5e): white solid; 43.5
mg, 67% yield (this compound was found to be relatively unstable in organic solvent), 99:1 dr; 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.99-7.97 (m, 2H), 7.94 (d, J = 7.2 Hz, 1H), 7.39 (td, J = 8.0 Hz,
1.2 Hz, 1H), 7.26-7.24 (m, 1H), 7.14-7.12 (m, 2H), 6.64 (d, J = 7.6 Hz, 1H), 4.42 (s, 1H), 4.17 (s,
1H), 2.90 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 174.4, 148.2, 143.1, 136.1, 131.7,
130.0, 125.1, 125.0, 124.2, 123.5, 117.2, 109.2, 77.3, 46.2, 26.3. IR (KBr): v 3324 3075 2905 2247
1701 1616 1521 1345 1112 764 cm-1. HRMS (ESI/Orbitrap) m/z: [M + H]+ Calcd for C17H13N3O4H
324.0979; Found 324.0986.
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
2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-(4-methoxyphenyl)acetonitrile (5f): pale yellow
solid; 29.5 mg, 48% yield, 58:42 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.91 (d, J = 7.2 Hz, 1H),
7.34-7.31 (m, 1H), 7.22-7.19 (m, 1H), 6.80 (d, J = 2.0 Hz, 2H), 6.61-6.58 (m, 3H), 4.36 (s, 1H),
4.16 (s, 1H), 3.70 (s, 3H), 2.85 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 175.0, 159.8,
143.3, 131.0, 130.0, 125.9, 125.0, 123.7, 120.9, 118.5, 113.7, 108.7, 77.5, 55.3, 45.8, 26.2. IR
(KBr): v 3385 3066 2922 2243 1708 1614 1513 1470 1252 755 cm-1. HRMS (ESI/Orbitrap) m/z:
[M + Na]+ Calcd for C18H16N2O3Na 331.1053; Found 331.1063.
2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-(4-methyphenyl)acetonitrile (5g): white solid;
30.4 mg, 52% yield, 70:30 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.92 (d, J = 7.2 Hz, 1H), 7.35-
7.32 (m, 1H), 7.21 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 7.6 Hz, 2H), 6.59 (d, J
= 8 Hz, 1H), 4.31 (s, 2H), 2.85 (s, 3H), 2.22 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm)
175.0, 143.4, 138.8, 131.0, 129.6, 129.1, 129.0, 128.7, 126.0, 125.1, 123.7, 118.5, 108.7, 77.5, 46.3,
26.1, 21.2. IR (KBr): v 3275 3057 2919 2243 1708 1614 1469 1114 759 cm-1. HRMS
(ESI/Orbitrap) m/z: [M + Na]+ Calcd for C18H16N2O2Na 315.1104; Found 315.1109.
2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-(naphthalen-1-yl)acetonitrile (5h): pale yellow
solid; 62.6 mg, 95% yield, 96:4 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.04 (d, J = 8.4 Hz, 1H),
7.85-7.79 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.56-7.52 (m, 1H), 7.50-7.46 (m, 1H), 7.35 (td, J = 8.0
Hz, 1.2 Hz, 1H), 7.20 (td, J = 7.6 Hz, 0.8 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 7.05 (dd, J = 7.2 Hz,
ACS Paragon Plus Environment

Page 21 of 26
The Journal of Organic Chemistry
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
0.8 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 5.33 (s, 1H), 3.72 (s, 1H), 2.58 (s, 3H); 13C {1H} NMR (100
MHz, CDCl3) δ (ppm) 174.9, 143.6, 133.6, 131.1, 130.7, 129.9, 128.8, 128.1, 126.8, 126.3, 126.2,
125.4, 125.2, 124.6, 123.7, 122.9, 118.8, 108.6, 77.4, 41.8, 26.0. IR (KBr): v 3298 3055 2929 2253
1698 1617 1469 1093 756 cm-1. HRMS (ESI/Orbitrap) m/z: [M + Na]+ Calcd for C21H16N2O2Na
351.1104; Found 351.1112.
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
2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)-2-(thiophen-2-yl)acetonitrile (5i): pale yellow solid;
43.2 mg, 76% yield, 98:2 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.93 (d, J = 7.6 Hz, 1H), 7.41
(td, J = 7.6 Hz, 1.2 Hz, 1H), 7.26-7.24 (m, 1H), 7.10-7.08 (m, 1H), 6.76-6.71 (m, 2H), 6.65 (d, J =
3.2 Hz, 1H), 4.46 (s, 1H), 4.42 (s, 1H), 2.96 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm)
175.0, 144.0, 131.4, 130.2, 128.9, 127.1, 126.6, 126.0, 125.1, 124.0, 117.8, 109.0, 41.6, 26.4. IR
(KBr): v 3262 2935 2253 1709 1613 1469 1112 759 cm-1. HRMS (ESI/Orbitrap) m/z: [M + Na]+
Calcd for C15H12N2O2SNa 307.0512; Found 307.0518.
2-(benzofuran-3-yl)-2-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)acetonitrile (5k): red solid; 35.0
mg, 55 % yield, 83:17 dr; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.01 (d, J = 7.2 Hz, 1H), 7.34-7.30
(m, 2H), 7.25-7.19 (m, 3H), 7.12-7.07 (m, 2H), 6.60 (d, J = 8.0 Hz, 1H), 5.25 (br, 1H), 4.26 (s, 1H),
2.77 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δ (ppm) 175.6, 154.8, 144.8, 143.6, 131.3, 126.6,
125.0, 124.9, 123.9, 123.1, 119.7, 117.7, 111.5, 109.9, 109.1, 76.9, 37.0, 26.2. IR (KBr): v 3347
3056 2918 2250 1710 1616 1115 705 cm-1. HRMS (ESI/Orbitrap) m/z: [M + Na]+ Calcd for
C19H14N2O3Na 341.0897; Found 341.0898.
General Procedure for the gram scale synthesis of 3a (Figure 2). N-protected isatin 1a (967.0
mg, 6.0 mmol), phenyl acetonitrile 2a (773.2 mg, 6.6 mmol) and H2O (9.0 mL) were stirred at room
temperature, then DBU (90.0 μL, 0.6 mmol) was added. The progress of the reaction can be
monitored by visualization of the color change of the reaction mixture from red (at the start of the
reaction) to yellow (at the end of the reaction). After stirring for the indicated time, the solid were
filtered, washed by H2O and Petroleum ether to afford 1.386 g (83%) of the desired product 3a
(99:1 dr).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 26
The Journal of Organic Chemistry
1
2
3
4
ASSOCIATED CONTENT
5
6
7
8
The Supporting Information is available free of charge on the ACS Publications website at DOI:
DFT computational details, full spectroscopic data for all new compounds and crystallographic
data for 3a, 4a and 3e (PDF)
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
Crystallographic file of product 3a (CIF)
Crystallographic file of product 4a (CIF)
Crystallographic file of product 3e (CIF)
AUTHOR INFORMATION
a Fax:(+86)-(0)797-8393536; phone: (+86)-(0)797-8393536; email: yong_zhanggnnu@126.com
b Email: matq13@lzu.edu.cn
c Email: C.Liu-4@tudelft.nl
ACKNOWLEDGEMENTS
We gratefully acknowledge the National Natural Science Foundation of China (Nos. 21502021,
21562003 and 51463002), the Jiangxi Province Education Department Science Fund (GJJ 461401)
and the Gannan Normal University Innovation Fund (CX170048) for financial support of this work.
C. Liu acknowledges the Netherlands Organization for Scientific Research (NWO) for the access
to SurfSARA computational facilities.
REFERENCES
[1] (a) Horváth, L. T.; Anastas, P. T. Introduction: Green Chemistry. Chem. Rev. 2007, 107, 2169-2173. (b)
Li, C.-J.; Trost, B. M. Green Chemistry for Chemical Synthesis. Pro. Natl. Acad. Sci. U. S. A. 2008, 105,
13197-13202. (c) Breslow, R. The Principles and Reasons for Using Water as a Solvent for Green
Chemistry. In Handbook of Green Chemistry [Online]; Anastas, P.-T., Li, C.-J., Eds.; Wiley-VCH:
Weinheim, 2010, 5, 1-29. (d) Simon, M.-O.; Li, C.-J. Green Chemistry Oriented Organic Synthesis in
Water. Chem. Soc. Rev. 2012, 41, 1415-1427.
[2] (a) Otto, S.; Engberts, J. B. F. N. Hydrophobic Interactions and Chemical Reactivity. Org. Biomol. Chem.
2003, 1, 2809-2820. (b) Butler, R. N.; Coyne, A. G. Water: Nature’s Reaction Enforcers-Comparative
Effects for Organic Synthesis “In-Water” and “On-Water”. Chem. Rev. 2010, 110, 6302-6337. (c)
ACS Paragon Plus Environment

Page 23 of 26
The Journal of Organic Chemistry
The Journal of Organic Chemistry
1
2
3
4
5
Lipshutz, B. H.; Ghorai, S. Transitioning Organic Synthesis from Organic Solvents to Water. What's Your
E Factor. Green Chem. 2014, 16, 3660-3679.
6
7
8
9
[3] For selected examples, see: (a) Rideout, D. C.; Breslow, R. Hydrophobic Acceleration of Diels-Alder
Reactions. J. Am. Chem. Soc. 1980, 102, 7816-7817. (b) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin,
V. V.; Kolb, H. C.; Sharpless, K. B. "On Water": Unique Reactivity of Organic Compounds in Aqueous
Suspension. Angew. Chem. Int. Ed. 2005, 44, 3275-3279. (c) Paladhi, S.; A. Chauhan; Dhara, K.; Tiwari,
A. K.; Dash, J. An Uncatalyzed Aldol Reaction of Thiazolidinediones. Green Chem. 2012, 14, 2990-
2995. (d) Paladhi, S.; Bhati, M.; Panda, D.; Dash, J. Thiazolidinedione-Isatin Conjugates via an
Uncatalyzed Diastereoselective Aldol Reaction on Water. J. Org. Chem. 2014, 79, 1473-1480. (e)
SaiPrathima, P.; Srinivas, K.; Rao, M. M. "On Water" Catalysis: an Expeditious Approach for the
Synthesis of Quaternary Centered 3-Hydroxy-3-(nitromethyl)indolin-2-one Derivatives. Green Chem.
2015, 17, 2339-2343. (f) Zhang, Y.; Wei, B.-W.; Lin, H.; Zhang, L.; Liu, J.-X.; Luo, H.-Q.; Fan, X.-L.
"On Water" Direct Catalytic Vinylogous Henry (Nitroaldol) Reactions of Isatins for the Efficient
Synthesis of Isoxazole Substituted 3-hydroxyindolin-2-ones. Green Chem. 2015, 17, 3266-3270. (g) Yu,
J.-S.; Liu, Y.-L.; Tang, J., Wang, X.; Zhou, J. Highly Efficient “On Water” Catalyst-Free Nucleophilic
Addition Reactions Using Difluoroenoxysilanes: Dramatic Fluorine Effects. Angew. Chem. Int. Ed. 2014,
53, 9512-9516. (h) Luque-Agudo, V.; Gil, M. V.; Román, E.; Serrano, J. A. "On Water" Reactivity
between Carbohydrate-Derived Nitroalkenes and Furans. Green Chem. 2016, 18, 3844-3851. (i) Dilauro,
G.; Dell'Aera, M.; Vitale, P.; Capriati, V.; Perna, F. M. Unprecedented Nucleophilic Additions of Highly
Polar Organometallic Compounds to Imines and Nitriles Using Water as a Non-Innocent Reaction
Medium. Angew. Chem. Int. Ed. 2017, 56, 10200-10203. (j) Hajra, S.; Roy, S. S.; Aziz, S. M.; Das, D.
Catalyst-Free "On-Water" Regio-and Stereospecific Ring-Opening of Spiroaziridine Oxindole:
Enantiopure Synthesis of Unsymmetrical 3,3'-Bisindoles. Org. Lett. 2017, 19, 4082-4085. (k) Zhu, S.;
Chen, C.; Xiao, M.; Yu, L.; Wang, L.; Xiao, J. Construction of the Tetrahydroquinoline Spiro Skeleton
via Cascade [1,5]-Hydride Transfer-Involved C(sp3)-H Functionalization "On Water". Green Chem.
2017, 19, 5653-5658. (l) Balaraman, K.; Ding, R. S.; Wolf, C. Stereoselective Synthesis of 3,3'-
Bisindolines by Organocatalytic Michael Additions of Fluorooxindole Enolates to Isatylidene
Malononitriles in Aqueous Solution. Adv. Synth. Catal. 2017, 359, 4165–4169. (m) Hikawa, H.; Ichinose,
R.; Kikkawa, S.; Azumaya, I. A Palladium-Catalyzed Dehydrative N-Benzylation/C-H Benzylation
Cascade of 2-Morpholinoanilines on Water. Green Chem. 2018, 20, 1297-1305. (n) Hikawa, H.; Ichinose,
R.; Kikkawa, S.; Zumaya, I. A Palladium-Catalyzed Dehydrogenation of Benzyl Alcohols for
Construction of 2-Arylbenzimidazoles "On Water". Asian J. Org. Chem. 2018, 7, 416-423.
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
[4] (a) Li, C.-J. Organic Reactions in Aqueous Media with a Focus on Carbon−Carbon Bond Formations:ꢀ
A Decade Update. Chem. Rev. 2005, 105, 3095-3166. (b) Li, C.-J.; Chen, L. Organic Chemistry in Water.
Chem. Soc. Rev. 2006, 35, 68-82. (c) Chan, T.-H.; Li, C.-J. Comprehensive Organic Reactions in Aqueous
Media, Wiley. New York, 2007. (d) Chanda, A.; Fokin, V. V. Organic Synthesis “On Water”. Chem. Rev.
2009, 109, 725-748. (e) Gawande, M. B.; Bonifacio, V. D. B.; Luque, R.; Branco, P. S.; Varma, R. S.
Benign by Design: Catalyst-Free in-Water, on-Water Green Chemical Methodologies in Organic
Synthesis. Chem. Soc. Rev. 2013, 42, 5522-5551.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
[5] (a) Grieco, P. A. Organic Synthesis in Water. Blackie, London, 1998. (b) Kobayashi, S.; Manabe, K.
Development of Novel Lewis Acid Catalysts for Selective Organic Reactions in Aqueous Media. Acc.
Chem. Res. 2002, 35, 209-217. (c) Sen, Z.-L.; Wang, S.-Y.; Chok, Y.-K.; Xu, Y.-H.; Loh, T.-P.
Organoindium Reagents: The Preparation and Application in Organic Synthesis. Chem. Rev. 2013, 113,
271-401. (d) Lindström, U. M. Stereoselective Organic Reactions in Water. Chem. Rev. 2002, 102, 2751-
2772. (e) Butler, R. N.; Coyne, A. G. Organic Synthesis Reactions on-Water at the Organic–Liquid Water
Interface. Org. Biomol. Chem. 2016, 14, 9945-9960. (f) Niu, R.; Xiao, J.; Liang, T.; Li, X.-W. Facile
Synthesis of Azaarene-Substituted 3-Hydroxy-2-oxindoles via Brønsted Acid Catalyzed sp3 C–H
Functionalization. Org. Lett. 2012, 14, 676-679. (g) Xiao, J.; Wen, H.; Wang, L.; Xu, L.-B.; Hao, Z.-H.;
Shao, C.-L.; Wang, C.-Y. Catalyst-Free Dehydrative SN1-Type Reaction of Indolyl Alcohols with
Diverse Nucleophiles “on Water”. Green Chem. 2016, 18, 1032-1037. (h) Guo, W. G.; Liu, X. H.; Liu,
Y.; Li, C. Chiral Catalysis at the Water/Oil Interface. ACS Catal. 2018, 8, 328-341. (i) Kitanosono, T.;
Masuda, K.; Xu, P.; Kobayashi, S. Catalytic Organic Reactions in Water toward Sustainable Society.
Chem. Rev. 2018, 118, 679-746. (j) Xie, P.-Z.; Wang, J.-Y.; Liu, Y.-N.; Fan, J.; Wo, X.-Y.; Fu, W.-S.;
Sun, Z.-L.; Loh, T.-P. Water-Promoted C-S Bond Formation Reactions. Nat. Commun. 2018, 9, 1321.
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
[6] (a) Fleming, F. F. Nitrile-Containing Natural Products. Nat. Prod. Rep. 1999, 16, 597-606. (b) Fleming,
F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. Nitrile-Containing Pharmaceuticals: Efficacious
Roles of the Nitrile Pharmacophore. J. Med. Chem. 2010, 53, 7902-7917. (c) Mesa, R. A.; Yasothan, U.;
Kirkpatrick, P. Ruxolitinib. Nat. Rev. Drug Discovery 2012, 11, 103-104.
[7] (a) Pappoport, Z.; Patai, S. Chemistry of the Cyano Group. Wiley, London, 1970. (b) Fleming, F. F.;
Wang, Q. Unsaturated Nitriles:ꢀ Conjugate Additions of Carbon Nucleophiles to a Recalcitrant Class of
Acceptors. Chem. Rev. 2003, 103, 2035-2078.
[8] López, R.; Palomo, C. Cyanoalkylation: Alkylnitriles in Catalytic C-C Bond-Forming Reactions. Angew.
Chem. Int. Ed. 2015, 54, 13170-13184.
[9] (a) Carlier, P. R.; Lam, W. W. F.; Wan, N. C.; Williams, I. D. Lithium Ephedrinate Mediated Aldol
Reaction of Arylacetonitriles: Thermodynamic Control of Enantioselectivity. Angew. Chem. Int. Ed. 1998,
37, 2252-2254. (b) Kisanga, P.; McLeod, D.; D'Sa, B.; Verkade, J. P(RNCH2CH2)3N-Catalyzed Synthesis
of Beta-Hydroxy Nitriles. J. Org. Chem. 1999, 64, 3090-3094. (c) Carlier, P. R.; Lo, C. W. S.; Lo, M. M.
C.; Wan, N. C.; Williams, I. D. HMPA Promotes Retro-Aldol Reaction, Resulting in Syn-Selective
Addition of Lithiated 1-Naphthylacetonitrile to Aromatic Aldehydes. Org. Lett. 2000, 2, 2443-2445. (d)
Suto, Y.; Kumagai, N.; Matsunaga, S.; Kanai, M.; Shibasaki, M. Direct Catalytic Aldol-Type Reactions
Using RCH2CN. Org. Lett. 2003, 5, 3147-3150. (e) Kumagai, N.; Matsunaga, S.; Shibasaki, M.
Cooperative Catalysis of a Cationic RutheniumComplex, Amine Base, and Na Salt: Catalytic Activation
of Acetonitrile as a Nucleophile. J. Am. Chem. Soc. 2004, 126, 13632-13633. (f) Goto, A.; Endo, K.;
Ukai, Y.; Irle, S.; Saito, S. RhI-Catalyzed Aldol-Type Reaction of Organonitriles under Mild Conditions.
Chem. Commun. 2008, 2212-2214. (g) Chakraborty, S.; Patel, Y. J.; Krause, J. A.; Guan, H. A Robust
Nickel Catalyst for Cyanomethylation of Aldehydes: Activation of Acetonitrile under Base-Free
Conditions. Angew. Chem. Int. Ed. 2013, 52, 7523-7526. (h) Sureshkumar, D.; Ganesh, V.; Kumagai, N.;
Shibasaki, M. Direct Catalytic Addition of Alkylnitriles to Aldehydes by Transition-Metal/NHC
Complexes. Chem.- Eur. J. 2014, 20, 15723-15726.
ACS Paragon Plus Environment

Page 25 of 26
The Journal of Organic Chemistry
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
[10] (a) Xiao, Z.; Timberlake, J. W. Cerium (III) Chloride Mediated Nitrile Aldol Reactions: Enhanced
Diastereoselectivities Using a Chiral Organocerium Complex. Tetrahedron. 1998, 54, 4211-4222. (b)
Yazaki, R.; Kumagai, N.; Shibasaki, M. Direct Catalytic Asymmetric Addition of Allyl Cyanide to
Ketones. J. Am. Chem. Soc. 2009, 131, 3195-3197. (c) Yazaki, R.; Kumagai, N.; Shibasaki, M. Direct
Catalytic Asymmetric Addition of Allyl Cyanide to Ketones via Soft Lewis Acid/Hard Bronsted
Base/Hard Lewis Base Catalysis. J. Am. Chem. Soc. 2010, 132, 5522-5531. (d) Wang, G.-W.; Zhou, A.-
X.; Wang, J.-J.; Hu, R.-B.; Yang, S.-D. Palladium-Catalyzed sp2 and sp3 C–H Bond Activation and
Addition to Isatin toward 3-Hydroxy-2-oxindoles. Org. Lett. 2013, 15, 5270-5273.
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
[11] (a) Kaiser, E. M.; Hauser, C. R. Influence of Metallic Cation in Carbonyl Addition Reactions of Certain
Nitriles and Sulfones with Benzophenone. J. Am. Chem. Soc. 1967, 89, 4566-4567. (b) Fleming, F. F.;
Shook, B. C. Unsaturated Nitriles: Stereoselective MgO Eliminations. J. Org. Chem. 2002, 67, 3668-
3672.
[12] (a) Saravanan, M.; Satyanarayana, B.; Reddy, P. P. An Improved and Impurity-Free Large-Scale
Synthesis of Venlafaxine Hydrochloride. Org. Process Res. Dev. 2011, 15, 1392-1395. (b) Rao, V. U. B.;
Kumar, K.; Das, T.; K. Vanka; Singh, R. P. DBU-Mediated Diastereoselective Aldol-Type
Cyanomethylation of Isatins. J. Org. Chem. 2017, 82, 4489-4496.
[13] (a) Zhang, Y.; Wei, B.-W.; Zou, L.-N.; Kang, M.-L.; Luo, H.-Q.; Fan, X.-L. “On Water” Direct
Vinylogous Henry (Nitroaldol) Reactions of 3, 5-Dimethyl-4-nitroisoxazole with Aldehydes and
Trifluoromethyl Ketones. Tetrahedron, 2016, 72, 2472-2475. (b) Zhang, Y.; Wei, B.-W.; Wang, W.-X.;
Deng, L.-L.; Nie, L.-J.; Luo, H.-Q.; Fan, X.-L. Direct Vinylogous Oxidative Cross-Dehydrogenative
Coupling of 4-Nitroisoxazoles with N-Aryl Tetrahydroisoquinolines in Water under Air Conditions. RSC
Adv. 2017, 7, 1229-1232. (c) Han, M.-Y.; Lin, J.; Li, W.; Luan, W.-Y.; Mai, P.-L.; Zhang, Y. Catalyst-
Free Nucleophilic Addition Reactions of Silyl Glyoxylates in Water. Green Chem. 2018, 20, 1228-1232.
[14] CCDC 1846861, 1847207 and 1860176 contain the supporting crystallographic data for this paper.
[15] (a) Jung, Y.; Marcus, R. A. On the Theory of Organic Catalysis on Water. J. Am. Chem. Soc. 2007,
129, 5492-5502. (b) Thomas, L. L.; Tirado-Rives, J.; Jorgensen, W. L. Quantum Mechanical/Molecular
Mechanical Modeling Finds Diels-Alder Reactions Are Accelerated Less on the Surface of Water Than
in Water. J. Am. Chem. Soc. 2010, 132, 3097-3104. (c) Manna, A.; Kumar, A. Why Does Water
Accelerate Organic Reactions under Heterogeneous Condition? J. Phys. Chem. A. 2013, 117, 2446-2454.
(d) Sela, T.; Vigalok, A. Organic Synthesis "on Water" vs "on Liquids": A Comparative Analysis. Org.
Lett. 2014, 16, 1964-1967.
[16] Dhara, K.; Mandal, T.; Das, I.; Dash, J. Synthesis of Carbazole Alkaloids by Ring-Closing Metathesis
and Ring Rearrangement-Aromatization. Angew. Chem. Int. Ed. 2015, 54, 15831-15835.
[17] Ji, H. H; Zhu, Y. Z; Shao, Y; Liu. J; Yuan, Y; Jia, X. D. Active sp3 C-H Bond Oxidation Initiated sp3-
sp2 Consecutive C-H Functionalization of N-Arylglycine Amides: Construction of Isatins. J. Org. Chem.
2017, 82, 9859-9865.
[18] Lee, Y. C; Patil, S. S.; Golz, C.; Strohman, C.; Ziegler, S.; Kumar, K.; Waldmann, H. A Ligand-Directed
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 26
The Journal of Organic Chemistry
1
2
3
4
5
Divergent Catalytic Approach to Establish Structural and Functional Scaffold Diversity. Nat. Commun.
2016, 8, 14043.
6
7
8
[19] Luo, J. F; Zhao, Y. C; Xu, X; Zheng, J. L; Liang, H. Z. Cu-Catalyzed Oxidation of Indoles to Isatins.
Tetrahedron Lett. 2017, 58, 4591-4594.
9
[20] Bredenkamp, A; Mohr, F; Kirsch, S. F. Synthesis of Isatins through Direct Oxidation of Indoles with
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
IBX-SO3K/NaI. Synthesis-Stuttgart 2015, 47, 1937-1943.
[21] Hamdy, A. M; Al-Masoudi, N. A; Pannecouque, C; Rahman, Q; Villinger, A; Langer, P. Regioselective
Suzuki-Miyaura Reactions of 4, 7-Dichloro-N-methylisatin. Synthesis, Anti-HIV Activity and Modeling
Study. RSC Adv. 2015, 5, 107360-107369.
ACS Paragon Plus Environment