"on Water" Catalytic Aldol Reaction between Isatins and Acetophenones: Interfacial Hydrogen Bonding and Enamine Mechanism

Article abstract of DOI:10.1021/acs.joc.9b00441

"On water" catalytic aldol reaction catalyzed by polyetheramine (D230) has been developed for easy access to 3-substituted 3-hydroxyindolin-2-ones through the reaction between various substituted isatins and acetophenones/cyclic ketones in high yields under room temperature. Systematic mechanism investigation uncovers the secret for the on water catalytic aldol reaction: comparison of the heterogeneous and homogeneous reaction circumstances with yields of 95 and 20%, respectively, indicates the on-water reaction dominating; interfacial hydrogen bonding between isatin with H₂O is tested based on the downfield shift of the C2 and C3's ¹³C NMR signals when water was added to the CDCl₃ solution of isatin; Lewis base polyetheramine D230 catalyzes the aldol reaction via the enamine mechanism verified by in situ NMR and ESI-MS analysis.

Full text of DOI:10.1021/acs.joc.9b00441

Subscriber access provided by Bethel University
Article
“On water” catalytic Aldol reaction between isatins and
acetophenones: interfacial hydrogen bonding and enamine mechanism
Jinsong Han, Jin-Lei Zhang, Weiqiang Zhang, Ziwei Gao, Li-Wen Xu, and Yajun Jian
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00441 • Publication Date (Web): 22 May 2019
Downloaded from http://pubs.acs.org on May 31, 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 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
“On water” catalytic Aldol reaction between isatins and
acetophenones: interfacial hydrogen bonding and enamine
mechanism
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
Jinsong Han,a Jin-Lei Zhang,a Wei-Qiang Zhang, a Ziwei Gao, a Li-Wen Xu*a,b and Yajun Jian*a
a.Key Laboratory of Applied Surface and Colloid Chemistry, MOE, School of Chemistry and
Chemical Engineering, Shaanxi Normal University, Xi’an, 710062, P. R. China. Fax: +86-29-
81530727;
b.Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of
Education, Hangzhou Normal University, Hangzhou, 310012, P. R. China.
ABSTRACT: ‘‘On water’’ catalytic aldol reaction catalyzed by polyetheramine (D230) has
been developed for easy access to 3-substituted-3-hydroxyindolin-2-ones through the reaction
between various substituted isatins and acetophenones / cyclic ketones in high yields under
room temperature. Systematic mechanism investigation uncover the secret for the ‘‘on water’’
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 33
1
2
3
4
5
6
7
8
9
catalytic aldol reaction: comparison of the heterogeneous and homogeneous reaction
circumstance, with yield as 95% and 20% respectively, indicates on-water reaction dominating;
interfacial hydrogen bonding between isatin with H2O tested based on downfield shift of C2
and C3’s 13C NMR signal when water added to the CDCl3 solution of isatin; Lewis base
polyetheramine D230 catalyze the aldol reaction via enamine mechanism verified by in-situ
NMR and ESI-MS analysis.
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
Introduction
Many chemists holding the subconscious belief solubility is a prerequisite for reactivity, so
even for organic reaction taken place in water involved reaction medium, many efforts have
been made to make organic substrates more soluble, including transforming insoluble substrates,
adding surfactant, etc.1 Therefore, water solely as the reaction solvent is least to be considered
in the organic synthesis community. However, “On water” reaction, pioneered and
conceptualized by Breslow 2 and Sharpless 3 respectively, where the transition state occurs at
the organic side of the organic-water interface, often shown better reactivity has still attracted
more attention.1c-e Based on experimental and computational studies, hydrogen bonding at
water-organic interfaces are acknowledged as the main driving force for the “on water”
reaction.4 However, from the point of practical view, there are scare approach to predict if one
organic reaction suitable to adopt “on water” condition.
Isatins, by reacting with nucleophile or other reaction counterpart, could be transformed
to various 3-hydroxy-2-oxindoles and other related oxindole derivatives,5 prevalent present in
large number of natural products and biologically active compounds.6 Many of those
ACS Paragon Plus Environment

Page 3 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
transformations taken place in pure water medium, primarily catalysed by either amine-7 or
amide-based8 organo-catalyst, were usually unclaimed as “on water” reaction and the water
usage was often aimed to make the reaction greener, so many facts that “on water” reaction
concerned were not well illustrated during investigation, such as distinguishing in-water and
on-water mode, as well as the role H2O plays, not to mention that Brønsted acid7a, 8 were always
employed as cocatalyst to activate isatin. For those claimed “on water” catalytic reaction,
although it has been widely thought that isatins can be activated by interfacial hydrogen
bonding, no direct evidence was shown.9 We anticipate once the interfacial hydrogen bonding
formed, hydrogen atom from water molecule served as hydrogen bond donor will make C2 and
C3 in isatin more electrophilic, and such chemical surrounding variation might be reflected by
13C NMR. (Figure 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
Besides the water’s activation on isatin via interfacial hydrogen bonding, base were always
needed to activate nucleophile counterpart to assure the reaction completed in shorter time, like
tertiary amine DABCO,9a, 10 Et3N,11 while catalyst free condition9b, 12 can last to 2 days.
However, stronger Lewis basicity for tertiary base, compared with primary amine, sometimes
cause side reactions, like condensation or rearrangement, so milder base are still worth to
explore.9b, 13 As far as we surveyed, no report have been disclosed with primary amine as
catalyst in an ‘on water’ mode for the aldol reaction between isatins and nucleophiles yet.
Polyetheramine, are amine terminated polyoxypropylenes, has several hydrogen bonding
acceptor atoms (O, N atom), which might helpful to drag the nucleophilic part to the periphery
of the water-organic interface. Herein, we report our findings about “on water” aldol reaction
catalyzed by polyetheramine (D230, n~2.5) via enamine mechanism in high efficiency.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 33
1
2
3
4
5
O
H2N
NH2
n
6
7
8
9
Polyetheramine
more hydrogen
bond acceptor
Hydrophobic interior
more electrophilic
HN
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
NH2
H
O
O
O
n
H
H
O
H
H
H
O
NH
O
H
H
O
H
O
H
O
H
H
O
H
H
H
H
O
interfacial
O
O
H
H
hydrogen-bond
networks
H
H
Figure 1 proposed transition state for “on water” catalytic Aldol reactions between isatins and
acetophenones via enamine mechanism.
Results and discussion
Our screening started with isatin 1a and acetophenone 2a in H2O at room temperature using
various commercial available primary amine as catalyst, and according results are displayed in
Table 1. Screening test suggested Lewis base catalyst is indispensable, as no product was
detected when catalyst are absent (entry 1). In general, catalyst having better water solubility
proceeded the reaction more efficiently, which are more obvious in a series of commercial
available polyetheramine (entry 6-8). As the degree of polymerization decreases, the reaction
yield elevated from 12% to 95% yield, where upon the employment of D-230 (n~2.5), the aldol
adduct could be generated in 95% yield (entry 8). It seems more hydrophilic polyetheramine
guarantees better productivity, so D-132 which bearing just one propylene oxide group was
synthesized according to the López-Calahorra’s procedure.14 However, D-132 showed much
worse catalytic activity over the model reaction, and only led the product in 25% yield (entry
9). Taken the results in entry 6-9 together, D230 performed best in those polyetheramine
analogues, which maybe attributed to two requirements for the optimal catalyst, one is to
provide enough number of hydrogen bonding acceptor atoms (O, N atom) to maintain the
ACS Paragon Plus Environment

Page 5 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
nucleophilic part at the periphery of the water-organic interface, the other is to avoid to be too
long molecule to be dragged to the water-organic interface. The other exception was that
ethylene diamine with pretty high water solubility showed poor catalytic efficiency (entry 2).
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 1. Lewis base catalyst screening for aldol reactiona
O
O
O
10 mol% Lewis base catalyst
H2O, 25oC
HO
O
N
O
H
N
2a
1a
H
3aa
Catalysts’ Solubility in H2Ob
Entry Catalyst
Yieldc (%)
(mol∙L-1)
1
2
3
4
5
6
7
8
9
--
--
0
Ethylenediamine
8.8
13
0
1-naphthylmethylamine
<10-5
<10-5
0.21
<10-5
1.0
chitosan
0
Polyethyene polyamine-275
31
12
37
95
25
D-2000
D-400
D-230
D-132d
1.9
2.5
a Unless otherwise noted, reaction conditions are as following: 0.34 mmol of 1a, 0.37
mmol of 2a and 10 mol% of catalyst were stirred in 2 mL H2O at 25oC for 4 h. b not
specifically tested but designated according Butler’s criteria.1d c Isolated yield. D-132
d
was commercial unavailable, and was synthesized following López-Calahorra’s
procedure.14
Moreover, to test the practicality of optimized conditions, we conducted the aldol reaction
on a gram scale as following: water insoluble 1a, 2a, and 10 mol% D230 were stirred on 25
mL H2O. As shown in Figure 2, with the proceeding of the reaction, characteristic reddish
colour of isatin 1a disappeared, and white solid product 3aa accumulated gradually. After 4 h
reaction, 3aa was isolated at a yield of 90%.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 33
1
2
3
4
5
6
7
8
O
O
HO
O
10 mol% D230
H2O, 25oC
O
O
N
H
N
H
9
2a
1a
3aa
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
1.635 g, 90% yield
4 h Stirring
Figure 2. “on water” aldol reaction of 1a and 2a at 1 gram scale.
To further demonstrate the generality of the novel developed method, isatins and ketones
were varied respectively (Table 2). Initially, various acetophenones were examined, and it was
exciting to find that the well-established strategy were also efficient for most substituted
acetophenones, no matter electron-donating or electron-withdrawing groups attached (3aa-3aj),
as 3-hydroxy-2-oxindoles could be generated in 64-90% yield. What need to point out is that
for the substrates bearing electron-donating groups, elevated temperature are required to assure
satisfying yield (3ai, 3aj). In addition, heteroaryl ketones, such as thienyl, furyl, pyridyl, were
also well tolerated under the standard conditions, through which aldol adducts could be
produced in 72-82% yield (3ak-3an). After examination of various acetophenones, we then
extended the reaction to different isatins. It was gratifying to find the standard conditions were
also workable when substituent are -OMe (3ba), -Me (3ca), -Br (3da), -Cl (3ea), corresponding
3-hydroxy-2-oxindoles could be delivered in good yield. However, when the substituent are too
electron-deficient, like -CF3, the reaction yield could drop to 39% (3fa). We also examined two
ACS Paragon Plus Environment

Page 7 of 33
The Journal of Organic Chemistry
1
2
3
4
5
C6-substitued isatins, usually commercial scare, and 89% (3ga) and 85% (3ha) yield product
6
7
could be generated respectively.
8
9
Table 2. Generality examination of the aldol reactiona
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
O
R2
O
HO
O
10 mol% D230
H2O, 25oC
O
O
N
R1
R2
2a-n
H
N
R1
H
1a-f
3aa-3an, or 3ba-3ha
Cl
Cl
Br
Cl
O
HO
O
HO
O
HO
O
HO
O
HO
O
O
O
O
O
N
N
N
N
H
H
N
H
H
H
3aa
, 95%
3ae
, 82%
3ab
, 84%
3ad
, 85%
3ac
, 87%
Br
F
OMe
O
HO
O
HO
O
HO
O
O
HO
OH
HO
O
O
O
O
O
N
N
N
H
N
N
H
H
H
H
b
3ag
, 74%
NO2
3af
b
, 80%
3ah
, 81%
3aj
, 64%
N
3ai
, 80%
S
O
O
O
O
HO
O
HO
HO
HO
O
O
O
O
N
N
N
N
H
H
H
H
3am
, 82%
3a
n
, 72%
3ak
, 46%
3al
, 83%
O
HO
O
HO
O
HO
O
HO
Cl
O
Br
O
O
O
O
N
H
N
N
N
H
H
H
3ea
, 93%
3ba
3ca
3da
, 82%
, 85%
, 69%
O
O
O
HO
HO
HO
O
O
O
N
H
N
N
H
Cl
Br
CF3
3fa
H
3ha
, 85%
3ga
, 89%
, 39%
a
Unless otherwise noted, reaction conditions are as following: 0.34 mmol of 1b-s, 0.37 mmol of
2b-s and 10 mol% of catalyst were stirred in 2 mL at 25 oC H2O for 4 h. b The reaction was taken
place at 80 oC.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 33
1
2
3
4
5
6
7
8
9
Subsequently, optimal reaction conditions were also applied to the addition between cyclic
ketones and various isatins. As shown in Table 3, when cyclohexanone were used as
nucleophilic part (4aa-4fa), more satisfying yield could be obtained at room temperature for 4h
stirring, however, under cyclopentanone’s circumstance (5aa-5fa), better diastereoselectivity
were given.
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 3. Generality examination of the aldol reactiona,b
O
O
HO
O
n
10 mol% D-230
H2O, 25oC
R
O
R
O
N
N
n
H
H
n =1 or 2
4aa-4fa
5aa-5fa
, or
1a-f
O
O
O
O
HO
HO
HO
HO
Br
Cl
O
O
O
O
N
H
N
N
N
H
H
H
4aa,
4ba,
75%
68%
4ca,
4da
, 70%
81%
1.2:1
1.8:1
1.9:1
1.2:1
O
O
O
O
HO
HO
HO
HO
O
Br
O
O
O
O
N
N
N
N
H
H
H
H
CF3
5ba
3.0:1
, 64%
4ea
4fa
5aa
, 70%
2.6:1
, 65%
, 76%
2.0:1
1.5:1
O
O
O
O
HO
HO
HO
HO
O
Cl
O
O
O
O
N
N
N
N
H
H
H
H
CF3
5ca
, 46%
5da
, 32%
5ea
, 32%
5fa
, 42%
1.8:1
3.4:1
4.0:1
4.0:1
a Unless otherwise noted, reaction conditions are as following: 0.34 mmol of 1b-f, 0.37 mmol of
6a and 10 mol% of catalyst were stirred in 2 mL at 25oC H2O for 4 h. b Distereoisomer ratio
was determined by 1H NMR for crude mixtures.
Though from the visual appearance, above reactions are heterogeneous and should be
viewed as on water reaction. However, isatin (0.013 M in H2O) and acetophenone (0.051 M)
ACS Paragon Plus Environment

Page 9 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
are not absolute insoluble in water, just at the borderline between on-water and in-water
condition, according to Butler and Coyne.1c, 1d To evaluate our case, we carried out the reaction
under in-water homogenous circumstance, leading to only 20% yield product though. Based on
the reaction result, it is reasonable to draw the conclusion that our reaction are on-water
dominated. (Scheme 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
O
O
HO
O
10 mol% D230
H2O, 25oC, 4 h
O
O
N
H
N
H
2a
1a
3aa
Yield: 95%
Yield: 20%
Heterogeous
Homogeous
Scheme 1. Comparison of the reaction efficiency at different solvation state with water as sole
solvent.
We also evaluated solvent effect on the model reaction to further verify H2O’s distinctive
acceleration, with the results presented in Figure 3. No product was produced in less polar
solvent, such as hexane, THF, even in more polar acetonitrile. Until much polar DMF were
employed as solvent, 5% product can be isolated then. Prontonic solvent have substantially
proceeded the reaction, where 17% and 20% yield aldol product was generated in MeOH and
EtOH respectively. The more efficient solvent is CF3CH2OH, in which 29% yield product could
be produced. We ascribe such yield improvement to the significant pKa discrepancy, more
acidic CF3CH2OH (12.4, vs 16.0 for EtOH)15,16 is more prone to form hydrogen bonding.
However, H2O was proved to be the best solvent at our hand that the aldol adduct could be
obtained in 95% yield. Analysing the solvent optimization experiments, it is no abrupt to drawn
a conclusion that protonic solvent guarantee better proceeding of the aldol reaction, very likely
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 33
1
2
3
4
5
6
7
in that hydrogen bonding formed between isatins and H2O resulted in the electrophilicity
enhancement for isatins, also mentioned in previous literatures. 9
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
100
80
60
40
20
0
Solvent
Figure 3. Solvent effect on D230 catalyzed aldol reaction of 1a and 2a.
Above solvent examination display H2O’s unique acceleration effect macroscopically,
however, more microscopic inherent causes to explain such substantial changes are more
intriguing. It was acknowledged that the water’s acceleration effect originates from the
interfacial hydrogen bonding formed between water and isatins, however, direct evidence was
missing.9 Upon the formation of interfacial hydrogen bonding, hydrogen atom from water
molecule served as hydrogen bond donor will make C3 in isatin more electrophilic, therefore,
it is rational to infer downfield shifting of 3-C=O’s 13C signal. As expected, during NMR
titration experiment, as water added gradually to the solution of isatin in CDCl3, carbon signal
of 2- and 3- C=O downfield shifted simultaneously, specifically from 182.69 and 158.95 ppm
to 182.83 and 159.05 ppm when 500 μL water was added, indicating the possible formation of
hydrogen bonding between isatins and H2O. (Figure 4a). However, alternative explanation for
the downfield shift of C-2 and C-3 signal maybe attributed to the increased polarity of solvent
originated from water additives. To dig out which factor predominates our system, we carried
ACS Paragon Plus Environment

Page 11 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
out similar NMR titration experiment for indole, where the hydrogen bond forming points 2-
and 3- carbonyl were truncated from isatin.17 As shown in Figure 4b, only slightly signal shift
less than 0.01 ppm was detected. So polarity increase of solvent contribute much less than
hydrogen bonding formation under our circumstance, and the interfacial hydrogen bonding
should be formed between isatin and water.
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
13
Figure 4. C NMR titration experiment of isatin (4a) and indole’s (4b) CDCl3 solution with
various amount of water added resulting biphasic system: 0 μL (black line); 100 μL (red line);
500 μL (blue line).
Besides water’s activation on isatins via hydrogen bonding, catalyst D-230 also play key
role in the reaction, as no product can be detected without its presence. Concerning the reaction
pathway of aldol reaction, when amine was used as Lewis base catalyst, two possible
mechanism may involve: enol or enamine. For tertiary amine, such as Et3N, DABCO, enol
mechanism predominates; however enamine mechanism often takes the lead when primary
amine were employed.18 To shed light if our reaction proceeded via enamine mechanism, we
1
explored the interaction between D230 and acetophenone 2a with in situ H NMR spectra
recorded simultaneously. (Scheme 2) As shown in Figure 5a, when incubated in water for 4 hrs
(red spectra), a set of new signals 7.28, 7.12 and 2.30 ppm was shown up which highly likely
correspondent to imine I, however, extending reaction time doesn’t improve further conversion.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 33
1
2
3
4
5
6
7
8
9
To further confirm our judgement, we incubated the reaction mixture in toluene for 24 hrs
(purple spectra), and more complete conversion taken place thus suggested the production of
imime I, whose identity was also verified by ESI-MS analysis, with the m/z value at 351.2642
correspondent to [M+H] +. (Figure 5b)
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
O
H2N
NH2
D230
O
n
O
H2O, 50oC
N
NH2
n
2a
I
Scheme 2. Imine I’s formation through 2a and D230.
Figure 5. (a) in situ 1H NMR spectra of the interaction between D230 and acetophenone 2a in
various solvent for different time; (b) partial ESI-MS (+) spectra for the signal of imine I.
Taken all the above mechanism exploration information together, a plausible transition
state is shown in Figure 6. The acceleration effect of water most relied on the existence free –
OH at the water side of the water-oil phase boundary area, providing considerable chance to
form hydrogen bond with organic reactants. Specifically, acetophenone 2a react with D230 to
form imine I, subsequent tautomerization leading to enamine II. At the periphery of the oil
droplet, hydrogen bonding are formed between free –OH with isatin and enamine II, thus two
reaction sites are brought close to each other lowing the activation barrier.
ACS Paragon Plus Environment

Page 13 of 33
The Journal of Organic Chemistry
1
2
3
4
5
Hydrophobic interior
6
O
7
8
9
O
+
H2N
NH2
n
D230
2a
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
I
O
NH2
N
n
HN
II
NH2
O
H
O
1a
O
n
H
H
O
H
H
H
O
NH
O
H
H
O
H
O
H
H
H
H
H
O
interfacial
H
O
H
O
O
hydrogen-bond
networks
O
H
H
H
H
Figure 6. Proposed transition state.
Conclusions
In conclusion, we have developed an efficient green procedure to form a series of 3-hydroxy-
2-oxindoles via “on water” catalytic aldol reaction. More importantly, by doing NMR titration
experiment, we not only provided direct evidence for the formation of interfacial hydrogen
bonding, but also provide simple and feasible techniques to screen out suitable substrates via
on water catalytic mechanism.
EXPERIMENTAL SECTION
General Methods. Reagents were purchased from commercial sources and were used as
received unless mentioned otherwise. Reactions were monitored by thin layer chromatography
using silica gel.1H,13C and 19F NMR spectra were recorded on a Bruker (600 MHz for 1H, 13C,
2D) NMR spectrometer by using DMSO-d6 as a solvent. For 1H NMR, tetramethylsilane (TMS)
served as internal standard (δ = 0) and 1H NMR chemical shifts are reported in ppm downfield
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 33
1
2
3
4
5
6
7
8
9
of tetramethylsilane and referenced to residual solvent peak (DMSO-d6 at 2.5 ppm and 3.33
ppm) unless otherwise noted. The data are reported as follows: chemical shift, integration,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet and m = multiplet), and coupling
constant in Hz. For 13C NMR, DMSO-d6 was used as internal standard (δ =39.53) and spectra
were obtained with complete proton decoupling. D-132 was synthesized following López-
Calahorra’s 3-step procedure from starting material 2-amino-1-propanol,14 with its NMR
spectras shown in 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
General procedure for the synthesis of 3-substituted-3-hydroxy-indolin-2-one.
A mixture of isatins (0.34 mmol), ketones (0.374 mmol), and polyetheramine D-230 (8.5
µL, 10 mol%) was charged into a 25 mL Schlenk tube with a magnetic stirring bar. Water (2
mL) was subsequently added by syringe. Then the reaction system was placed in room
temperature with magnetic stirring for 4h. After completion of the reaction, as indicated by
TLC analysis, the reaction mixture was extracted with EtOAc, dried over Na2SO4, and purified
via Silica gel flask column chromatography (eluent: petroleum ether: EtOAc = 2:1) to give the
desired product.
Procedure of Gram-Scale Synthesis for synthesis of 3aa.
A mixture of isatin 1a (1 g, 6.80 mmol), acetophenone 2a (0.88 mL, 7.48 mmol), and
polyetheramine D-230 (0.17 mL, 10 mol%) was charged into a 100 mL round-bottomed flask
with a magnetic stirring bar. Water (25 mL) was subsequently added by syringe. Then the
reaction system was placed in room temperature with magnetic stirring for 4h. After completion
of the reaction, as indicated by TLC analysis, the reaction mixture was extracted with EtOAc,
ACS Paragon Plus Environment

Page 15 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
dried over Na2SO4, and purified via Silica gel flask column chromatography (eluent: petroleum
ether: EtOAc = 2:1) to give the desired product 3aa as pale yellow solid in 90% yield (1.635
g).
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
Procedure for the synthesis of 3aa in homogeneous fashion.
Acetophenone 2a (3.4 μL, 0.028 mmol), and polyetheramine D-230 (0.65μL, 10 mol%)
was added to the homogenous aqueous solution of isatin 1a [3.8 mg (0.026mmol) dissolved in
2 mL water] in a 25 mL Schlenk tube with a magnetic stirring bar. After stirring at room
temperature for 4h, the reaction mixture was terminated by adding 10 mL EtOAc and internal
standard p-iodoanisole (2.4 mg, 0.010 mmol), partial organic phase solution was dried, and re-
dissolved in DMSO-d6 for 1H NMR experiment, showing 3aa was produced in 20% yield.
3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one (3aa). Pale yellow solid (86.3 mg, 95%).
mp 196–198oC; 1H NMR (600 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.94 – 7.85 (m, 2H), 7.62 (s,
1H), 7.49 (t, J = 7.8 Hz, 2H), 7.27 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 1.0 Hz, 1H), 6.85 (s, 1H),
6.80 (d, J = 7.7 Hz, 1H), 6.05 (s, 1H), 4.06 (d, J = 17.5 Hz, 1H), 3.58 (d, J = 17.5 Hz, 1H);
13C{1H}NMR (151 MHz, DMSO-d6) δ 196.4, 178.3, 142.9, 136.1, 133.4, 131.7, 128.88, 128.68,
127.9, 123.6, 121.1, 109.4, 73.0, 45.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C16H13NO3Na 290.0788, Found 290.0783.
3-(2-(4-chlorophenyl)-2-oxoethyl)-3-hydroxyindolin-2-one (3ab). Pale yellow solid (86
mg, 84%). mp196–197oC; 1H NMR (600 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.90 (d, J = 8.6 Hz,
2H), 7.56 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 7.3 Hz, 1H), 7.16 (s, 1H), 6.85 (s, 1H), 6.80 (d, J =
7.7 Hz, 1H), 6.08 (s, 1H), 4.04 (d, J = 17.5 Hz, 1H), 3.56 (d, J = 17.4 Hz, 1H). 13C{1H}NMR
(151 MHz, DMSO-d6) δ 195.5, 178.2, 142.8, 138.3, 134.9, 131.6, 129.9, 128.9, 128.8, 123.6,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 33
1
2
3
4
5
6
121.1, 109.4, 73.0, 45.7. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C16H12ClNO3Na
324.0398, Found 324.0392.
7
8
9
3-(2-(3-chlorophenyl)-2-oxoethyl)-3-hydroxyindolin-2-one (3ac). Pale yellow solid (89
mg, 87%). mp198–200oC; 1H NMR (600 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.86 (dd, J = 8.3,
4.8 Hz, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.53 (s, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 0.9
Hz, 1H), 6.86 (s, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.08 (s, 1H), 4.07 (d, J = 17.5 Hz, 1H), 3.56 (d,
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
13
J = 17.5 Hz, 1H); C{1H}NMR (151 MHz, DMSO-d6) δ 195.6, 178.2, 142.8, 138.0, 133.6,
133.1, 131.5, 130.7, 129.0, 127.6, 126.7, 123.7, 121.1, 109.4, 73.0, 45.9; HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C16H12ClNO3Na 324.0398, Found 324.0392.
3-(2-(2-chlorophenyl)-2-oxoethyl)-3-hydroxyindolin-2-one (3ad). Pale yellow solid (87
mg, 85%). mp189–190 oC; 1H NMR (600 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.48 (s, 3H), 7.39
(s, 1H), 7.31 (d, J = 7.3 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.81 (d, J =
7.7 Hz, 1H), 6.13 (d, J = 0.4 Hz, 1H), 3.88 (d, J = 17.0 Hz, 1H), 3.53 (d, J = 17.0 Hz, 1H);
13C{1H}NMR (151 MHz, DMSO-d6) δ 198.6, 177.9, 142.7, 138.0, 132.4, 131.1, 130.4, 129.6,
129.2, 129.1, 127.3, 123.9, 121.2, 109.5, 73.0, 49.5; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C16H12ClNO3Na 324.0398, Found 324.0392.
3-(2-(4-bromophenyl)-2-oxoethyl)-3-hydroxyindolin-2-one (3ae). Pale yellow solid (96
mg, 82%). mp194–196oC; 1H NMR (600 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.82 (d, J = 8.5 Hz,
2H), 7.69 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 7.3 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.85 (t, J = 7.5
Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.09 (s, 1H), 4.04 (d, J = 17.4 Hz, 1H), 3.56 (d, J = 17.4 Hz,
13
1H); C{1H}NMR (151 MHz, DMSO-d6) δ 195.7, 178.2, 142.8, 135.2, 131.7, 131.6, 130.0,
ACS Paragon Plus Environment

Page 17 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
129.0, 127.5, 123.7, 121.1, 109.4, 73.0, 45.7; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C16H12BrNO3Na 367.9893, Found 367.9884.
7
8
9
3-(2-(3-bromophenyl)-2-oxoethyl)-3-hydroxyindolin-2-one (3af). Pale yellow solid (93.8
mg, 80%). mp192–193 oC; 1H NMR (600 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.99 (s, 1H), 7.89
(d, J = 7.8 Hz, 1H), 7.82 (dd, J = 8.0, 1.0 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 7.3 Hz,
1H), 7.19 – 7.13 (m, 1H), 6.86 (t, J = 7.3 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.07 (s, 1H), 4.06
(d, J = 17.4 Hz, 1H), 3.55 (d, J = 17.4 Hz, 1H); 13C{1H}NMR (151 MHz, DMSO-d6) δ 195.5,
178.2, 142.8, 138.2, 136.0, 131.5, 130.9, 130.5, 129.0, 127.0, 123.7, 122.1, 121.1, 109.4, 73.0,
45.8. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H12BrNO3Na367.9893, Found 367.9884.
3-(2-(4-fluorophenyl)-2-oxoethyl)-3-hydroxyindolin-2-one (3ag). Pale yellow solid (71.7
mg, 74%). mp198–200 oC; 1H NMR (600 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.97 (dd, J = 8.8,
5.5 Hz, 2H), 7.31 (t, J = 8.8 Hz, 2H), 7.26 (d, J = 7.2 Hz, 1H), 7.16 (td, J = 7.6, 1.0 Hz, 1H),
6.85 (t, J = 7.3 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.06 (s, 1H), 4.05 (d, J = 17.4 Hz, 1H), 3.56
(d, J = 17.4 Hz, 1H); 13C{1H}NMR (151 MHz, DMSO-d6) δ 195.1, 178.2, 165.9, 164.2, 142.9,
133.0, 131.7, 131.0(d, JC-F = 9.0 Hz), 128.9, 123.6, 121.1,115.7, 115.5, 109.4, 73.0, 45.7; 19F
NMR (376 MHz, DMSO-d6) δ -105.7. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
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
C16H12FNO3Na 308.0693, Found 308.0691.
3-hydroxy-3-(2-oxo-2-(p-tolyl)ethyl)indolin-2-one (3ah). Pale yellow solid (77.4 mg,
1
81%). mp 191–193oC; H NMR (600 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.78 (d, J = 8.2 Hz,
2H), 7.29 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 7.3 Hz, 1H), 7.15 (td, J = 7.6, 0.9 Hz, 1H), 6.84 (t, J
= 7.4 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.03 (s, 1H), 4.02 (d, J = 17.5 Hz, 1H), 3.54 (d, J =
17.4 Hz, 1H), 2.35 (s, 3H); 13C{1H}NMR (151 MHz, DMSO-d6) δ 195.9, 178.3, 143.8, 142.9,
133.8, 131.8, 129.2, 128.8, 128.0, 123.5, 121.0, 109.3, 73.0, 45.6, 21.1; HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C17H15NO3Na 304.0944, Found 304.0939.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 33
1
2
3
4
5
3-hydroxy-3-(2-(4-methoxyphenyl)-2-oxoethyl)indolin-2-one (3ai). Pale yellow solid (80.8
6
7
1
mg, 80%). mp 181–183oC; H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.92 – 7.80 (m,
8
9
2H), 7.25 (d, J = 7.2 Hz, 1H), 7.15 (td, J = 7.7, 1.2 Hz, 1H), 7.05 – 6.96 (m, 2H), 6.84 (td, J =
7.5, 0.8 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.01 (s, 1H), 3.99 (d, J = 17.3 Hz, 1H), 3.82 (s, 3H),
3.51 (d, J = 17.3 Hz, 1H); 13C{1H}NMR (151 MHz, DMSO-d6) δ 194.7, 178.4, 163.2, 142.9,
131.8, 130.2, 129.2, 128.8, 123.5, 121.0, 113.8, 109.3, 73.0, 55.5, 45.4; HRMS (ESI-TOF) m/z:
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
[M + Na]+ calcd for C17H15NO4+Na 320.0893, Found 320.0888.
3-hydroxy-3-(2-(2-hydroxyphenyl)-2-oxoethyl)indolin-2-one (3aj). Pale yellow solid (61.6
mg, 64%). mp 197–198oC; 1H NMR (600 MHz, DMSO-d6) δ 11.32 (s, 1H), 10.28 (s, 1H), 7.80
(d, J = 6.8 Hz, 1H), 7.48 (t, J = 7.0 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H),
6.95 – 6.89 (m, 2H), 6.87 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.09 (s, 1H), 4.09 (d, J
= 17.7 Hz, 1H), 3.65 (d, J = 17.7 Hz, 1H);13C{1H}NMR (151 MHz, DMSO-d6) δ 201.3, 178.2,
160.1, 142.8, 136.0, 131.6, 130.7, 128.9, 123.6, 121.1, 120.8, 119.2, 117.5, 109.4, 72.9, 47.2;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H13NO4Na 306.0737, Found 306.0733.
3-hydroxy-3-(2-(4-nitrophenyl)-2-oxoethyl)indolin-2-one (3ak). Pale yellow solid (48.8
mg, 46%). mp 190–191oC; 1H NMR (600 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.94 (s, 1H), 7.47
(d, J = 3.5 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.85 (t, J = 7.4 Hz, 1H),
6.77 (d, J = 7.7 Hz, 1H), 6.67 (d, J = 1.9 Hz, 1H), 6.10 (s, 1H), 3.79 (d, J = 16.3 Hz, 1H), 3.31
(d, J = 16.3 Hz, 1H); 13C{1H}NMR (151 MHz, DMSO-d6) δ 195.9, 178.0, 150.0, 142.7, 140.7,
131.4, 129.4, 129.1, 123.8, 121.2, 109.5, 73.0, 46.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C16H12N2O5Na 335.0638, Found 335.0635.
3-hydroxy-3-(2-oxo-2-(thiophen-3-yl)ethyl)indolin-2-one (3al). Pale yellow solid (77 mg,
83%). mp 180–182oC; 1H NMR (600 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.97 (dd, J = 21.9, 4.3
ACS Paragon Plus Environment

Page 19 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Hz, 2H), 7.28 (d, J = 7.3 Hz, 1H), 7.22 (t, J = 4.3 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 6.86 (t, J =
7.5 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.11 (s, 1H), 3.95 (d, J = 16.7 Hz, 1H), 3.47 (d, J = 16.7
Hz, 1H); 13C{1H}NMR (151 MHz, DMSO-d6) δ 189.3, 178.1, 143.5, 142.7, 135.1, 133.9, 131.3,
129.0, 128.8, 123.8, 121.1, 109.4, 73.0, 45.9; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C14H11NO3SNa 296.0352, Found 296.0348.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(2-(furan-3-yl)-2-oxoethyl)-3-hydroxyindolin-2-one (3am). Pale yellow solid (71.7 mg,
82%). mp 195–196oC; 1H NMR (600 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.94 (s, 1H), 7.47 (d, J
= 3.5 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.85 (t, J = 7.4 Hz, 1H), 6.77
(d, J = 7.7 Hz, 1H), 6.67 (d, J = 1.9 Hz, 1H), 6.10 (s, 1H), 3.79 (d, J = 16.3 Hz, 1H), 3.31 (d, J
= 16.3 Hz, 1H); 13C{1H}NMR (151 MHz, DMSO-d6) δ 184.3, 178.0, 151.6, 148.0, 142.6, 131.1,
129.0, 123.9, 121.1, 119.1, 112.5, 109.4, 73.0, 45.2; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C14H11NO4Na 280.0580, Found 280.0577.
3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one (3an). Pale yellow solid (65.6 mg,
72%). mp 154–155oC; 1H NMR (600 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.94 (s, 1H), 7.47 (d, J
= 3.5 Hz, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.85 (t, J = 7.4 Hz, 1H), 6.77
(d, J = 7.7 Hz, 1H), 6.67 (d, J = 1.9 Hz, 1H), 6.10 (s, 1H), 3.79 (d, J = 16.3 Hz, 1H), 3.31 (d, J
= 16.3 Hz, 1H); 13C{1H}NMR (151 MHz, DMSO-d6) δ 197.7, 178.3, 152.2, 149.2, 142.8, 137.6,
131.6, 128.9, 127.9, 123.6, 121.14, 121.05, 109.4, 73.0, 44.9; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C15H12N2O3Na 291.0740, Found 291.0738.
3-hydroxy-5-methoxy-3-(2-oxo-2-phenylethyl)indolin-2-one (3ba). Pale yellow solid (85.9
mg, 85%). mp 157–159oC; 1H NMR (600 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.89 (d, J = 7.5 Hz,
2H), 7.62 (s, 1H), 7.50 (t, J = 7.7 Hz, 2H), 6.96 (s, 1H), 6.72 (d, J = 2.3 Hz, 2H), 6.05 (s, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 33
1
2
3
4
5
6
7
8
9
13
4.06 (d, J = 17.4 Hz, 1H), 3.64 (s, 3H), 3.57 (d, J = 17.4 Hz, 1H); C{1H}NMR (151 MHz,
DMSO-d6) δ 196.4, 178.2, 154.6, 136.2, 136.1, 133.3, 132.9, 128.7, 127.9, 113.3, 111.0, 109.6,
73.4, 55.4, 45.7; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H15NO4Na 320.0893, Found
320.0895.
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-hydroxy-5-methyl-3-(2-oxo-2-phenylethyl)indolin-2-one (3ca). Pale yellow solid (66 mg,
69%). mp 161–163oC; H NMR (600 MHz, DMSO-d6) δ 10.15 (s, 1H), 7.88 (d, J = 7.4 Hz,
1
2H), 7.62 (s, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.09 (s, 1H), 6.96 (d, J = 7.7 Hz, 1H), 6.69 (d, J =
7.8 Hz, 1H), 5.99 (s, 1H), 4.02 (d, J = 17.6 Hz, 1H), 3.57 (d, J = 17.5 Hz, 1H), 2.17 (s, 3H);
13C{1H}NMR (151 MHz, DMSO-d6) δ 196.4, 178.3, 140.4, 136.2, 133.3, 131.8, 129.8, 129.0,
128.7, 127.9, 124.3, 109.1, 73.1, 45.8, 20.6; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C17H15NO3Na 304.0944, Found 304.0943.
5-bromo-3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one (3da). Pale yellow solid (96.2
mg, 82%). mp:184–186oC; H NMR (600 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.89 (d, J = 7.7
1
Hz, 2H), 7.64 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.6 Hz, 3H), 7.35 (d, J = 8.2 Hz, 1H), 6.79 (d, J
= 8.2 Hz, 1H), 6.20 (s, 1H), 4.16 (d, J = 17.9 Hz, 1H), 3.63 (d, J = 17.9 Hz, 1H); 13C{1H}NMR
(151 MHz, DMSO-d6) δ 196.5, 177.9, 142.3, 136.0, 134.3, 133.5, 131.5, 128.7, 127.9, 126.7,
112.8, 111.3, 73.0, 45.7; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H12BrNO3Na 367.9893,
Found 367.9890.
5-chloro-3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one (3ea). Pale yellow solid (95.2
mg, 93%). mp 184–186oC; 1H NMR (600 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.90 (d, J = 7.5 Hz,
2H), 7.63 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.40 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 8.3
Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.21 (s, 1H), 4.16 (d, J = 17.8 Hz, 1H), 3.64 (d, J = 17.8 Hz,
ACS Paragon Plus Environment

Page 21 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
1H); C{1H}NMR (151 MHz, DMSO-d6) δ 196.5, 178.0, 141.9, 136.0, 133.9, 133.5, 128.7,
128.6, 127.9, 125.1, 124.0, 110.8, 73.0, 45.7 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C16H12ClNO3Na 324.0398, Found 324.0394.
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-hydroxy-3-(2-oxo-2-phenylethyl)-7-(trifluoromethyl)indolin-2-one (3fa). Pale yellow
solid (44.4 mg, 39%). mp 192–193oC; 1H NMR (600 MHz, DMSO-d6) δ 10.78 (s, 1H), 7.93 –
7.86 (m, 2H), 7.61 (dd, J = 14.0, 7.4 Hz, 2H), 7.50 (t, J = 7.8 Hz, 2H), 7.46 (d, J = 8.0 Hz, 1H),
7.05 (t, J = 7.7 Hz, 1H), 6.32 (s, 1H), 4.20 (d, J = 18.0 Hz, 1H), 3.73 (d, J = 18.0 Hz, 1H);
13C{1H}NMR (151 MHz, DMSO-d6) δ 195.5, 178.2, 142.8, 138.2, 135.9, 131.5, 130.9, 130.5,
129.0, 127.0, 125.24 (q, JC-F = 4.3 Hz),123.7, 122.1, 121.1, 109.4 (q, JC-F = 32.5 Hz), 73.0, 45.8
ppm; 19F NMR (376 MHz, DMSO-d6) δ -59.71; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C17H12F3NO3Na 358.0661, Found 358.0656.
6-bromo-3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one(3ga).Pale yellow solid (68 mg,
89%). mp190–192oC; 1H NMR (600 MHz, DMSO) δ 10.43 (s, 1H), 7.89 (d, J = 7.6 Hz, 2H),
7.63 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 7.7 Hz,
1H), 6.97 (s, 1H), 6.17 (s, 1H), 4.10 (d, J = 17.8 Hz, 1H), 3.63 (d, J = 17.8 Hz, 1H) ppm;
13C{1H}NMR (151 MHz, DMSO-d6) δ 196.5, 178.1, 144.7, 136.0, 133.5, 131.2, 128.7, 127.9,
125.4, 123.7, 121.5, 112.2, 72.6, 45.7 ppm; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C16H12BrNO3Na 367.9898, Found 367.9900.
6-chloro-3-hydroxy-3-(2-oxo-2-phenylethyl)indolin-2-one(3ha).Pale yellow solid (71mg,
86%) mp 186-188oC; 1H NMR (600 MHz, DMSO) δ 10.45 (s, 1H), 7.89 (s, 2H), 7.62 (s, 1H),
7.50 (s, 2H), 7.31 (s, 1H), 6.92 (s, 1H), 6.84 (s, 1H), 6.18 (s, 1H), 4.11 (d, J = 17.0 Hz, 1H),
3.64 (d, J = 17.1 Hz, 1H) ppm; 13C{1H}NMR (151 MHz, DMSO-d6) δ 196.5, 178.2, 144.6,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 33
1
2
3
4
5
6
7
136.0, 133.5, 133.1, 130.7, 128.7, 127.9, 125.0, 120.8, 109.5, 72.6, 45.7 ppm; HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C16H12ClNO3Na 324.0403, Found 324.0404.
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
3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one(4aa). As a mixture of two diastereomers in
the ratio ∼1.2:1. Pale yellow solid (62.5 mg, 75%). Major isomer: 1H NMR (600 MHz, DMSO-
d6) δ 10.18 (s, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.18-7.15(m, 1H), 6.85 (d, J = 6.0 Hz, 1H), 6.79
(d, J = 7.7 Hz, 1H), 5.80 (s, 1H), 3.08 (dd, J = 13.2, 4.9 Hz, 1H), 2.59 (d, J = 11.8 Hz, 1H),
2.30 – 2.24 (m, 1H), 2.08-1.90 (m, 3H), 1.88-1.72 (m, 1H), 1.71-1.58 (m, 1H), 1.52-1.40 (m,
13
1H) ppm; C{1H}NMR (151 MHz, DMSO-d6) δ 209.1, 178.7, 143.4, 130.8, 128.5, 123.8,
1
120.8, 109.4, 73.9, 57.3, 41.4, 27.8, 26.7, 24.4 ppm. Minor isomer: H NMR (600 MHz,
DMSO-d6) δ 10.13 (s, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.15 – 7.11 (m, 1H), 6.87 (d, J = 6.0 Hz,
1H ), 6.75 (d, J = 7.6 Hz, 1H), 5.71 (s, 1H), 3.24 (dd, J = 12.8, 4.9 Hz, 1H), 2.37 (dd, J = 13.3,
6.0 Hz, 1H), 2.35-2.31 (m, 1H) , 2.08-1.90 (m, 3H), 1.88-1.72 (m, 1H), 1.71-1.58 (m, 1H), 1.52-
1.40 (m, 1H) ppm; 13C{1H}NMR (151 MHz, DMSO-d6) δ 209.8, 178.0, 142.8, 132.5, 128.5,
123.8, 121.0, 109.1, 73.7, 57.2, 42.2, 27.8, 26.6, 24.6 ppm. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C14H15NO3Na 268.0950, Found 268.0945.
5-bromo-3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one(4ba). As a mixture of two
diastereomers in the ratio ∼1.8:1. Pale yellow solid (75 mg, 68%). Major isomer: 1H NMR (600
MHz, DMSO-d6) δ 10.35 (s, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.30 (s, 1H), 6.77 (d, J = 7.9 Hz,
1H), 6.00 (s, 1H), 3.14-3.08 (m, 1H), 2.58 (d, J = 8.7 Hz, 1H), 2.32-2.27 (m, 1H), 2.00-1.90
13
(m, 3H), 1.86-1.80 (m, 1H), 1.72-1.66 (m, 1H), 1.53-1.40 (m, 1H) ppm. C{1H}NMR (151
MHz, DMSO-d6) δ 209.2, 178.2, 142.8, 133.3, 131.2, 127.4, 112.5, 111.4, 73.9, 57.4, 41.4,
27.7, 26.7, 24.4 ppm. Minor isomer: 1H NMR (600 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.44 (s,
ACS Paragon Plus Environment

Page 23 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1H), 7.33 (s, 1H), 6.72 (d, J = 7.8 Hz, 1H), 5.89 (s, 1H), 3.32-3.28 (m, 1H), 2.44-2.32 (m, 2H),
2.05-2.03 (m, 3H), 1.79-1.73 (m, 2H), 1.64-1.60 (m, 1H) ppm. 13C{1H}NMR (151 MHz,
DMSO-d6) δ 209.8, 177.6, 142.1, 135.1, 131.1, 126.7, 112.6, 111.0, 73.7, 57.1, 42.1, 27.6, 26.6,
24.5 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H14BrNO3Na 346.0055, Found
346.0047.
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
5-chloro-3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one(4ca). As a mixture of two
1
diastereomers in the ratio ~1.9:1. Pale yellow solid (76.2 mg, 81%). Major isomer: H NMR
(600 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.29-7.26(m, 1H), 7.25-7.23(m, 1H), 6.86 (d, J = 8.2
Hz, 1H), 6.04 (s, 1H), 3.15 (dd, J = 13.3, 4.9 Hz, 1H), 2.67-2.60 (m, 1H), 2.39-2.34 (m, 1H),
2.13-2.09 (m, 1H), 2.02-1.95 (m, 2H), 1.90 – 1.86 (m, 1H), 1.76 – 1.70 (m, 1H), 1.60-1.54 (m,
13
1H) ppm; C{1H}NMR (151 MHz, DMSO-d6) δ 209.2, 178.3, 142.3, 132.9, 128.4, 124.8,
1
124.1, 110.8, 74.0 , 57.4, 41.4, 27.6, 26.7, 24.4 ppm. Minor isomer: H NMR (600 MHz,
DMSO-d6) δ10.31 (s, 1H), 7.39-7.36 (m, 1H), 7.24-7.22 (m, 1H), 6.81 (d, J = 8.2 Hz, 1H), 5.94
(s, 1H), 3.38-3.32 (m, 1H), 2.48-2.39 (m, 2H), 2.09-2.07 (m, 1H), 2.06-2.03 (m, 1H), 1.85-1.80
(m, 2H), 1.70 – 1.64 (m, 1H), 1.54-1.49 (m, 1H) ppm; 13C{1H}NMR (151 MHz, DMSO-d6) δ
209.8, 177.7, 141.7, 134.6, 128.3, 125.0, 124.0, 110.5, 73.7, 57.0, 42.1, 27.7, 26.6, 24.5 ppm.
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H14ClNO3Na 302.0560, Found 302.0553.
3-hydroxy-5-methyl-3-(2-oxocyclohexyl)indolin-2-one(4da). As a mixture of two
diastereomers in the ratio ~1.1:1. Pale yellow solid (60 mg, 70%). Major isomer:1H NMR (600
MHz, DMSO-d6) δ 10.03 (s, 1H), 7.09 (s, 1H), 6.94 (d, J = 7.9 Hz, 1H), 6.63 (d, J = 7.8 Hz,
1H), 5.66 (s, 1H), 3.20 (dd, J = 12.9, 5.0 Hz, 1H), 2.61-2.55 (m, 1H), 2.21 (s, 3H), 2.35 – 2.30
(m, 1H), 2.07-1.98 (m, 3H), 1.78-1.73 (m, 1H), 1.63-1.58 (m, 1H), 1.47-1.43 (m, 1H) ppm;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 33
1
2
3
4
5
6
7
8
9
13C{1H}NMR (151 MHz, DMSO-d6) δ 209.0, 178.7, 140.9, 130.9, 129.4, 128.7, 125.5, 108.8,
74.0, 57.3, 41.5, 27.8, 26.7, 24.5, 20.7. Minor isomer: 1H NMR (600 MHz, DMSO-d6) δ 10.08
(s, 1H), 7.03 (s, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 5.75 (s, 1H), 3.06 (dd,
J = 13.3, 5.0 Hz, 1H), 2.40-2.36 (m, 1H), 2.22 (s, 3H), 2.29-2.23 (m, 2H), 1.97-1.90 (m, 1H) ,
1.85-1.79 (m, 2H), 1.69-1.64 (m, 1H), 1.53-1.48 (m, 1H) ppm; 13C{1H}NMR (151 MHz,
DMSO-d6) δ 209.7, 177.9, 140.3, 132.5, 129.7, 128.6, 124.5, 109.1, 73.9, 57.1, 42.2, 27.7, 26.6,
24.6, 20.7 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C15H17NO3Na 282.1106, Found
282.1100.
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-hydroxy-5-methoxy-3-(2-oxocyclohexyl)indolin-2-one(4ea). As a mixture of two
diastereomers in the ratio ~1.5:1. Pale yellow solid (60 mg, 65%). Major isomer : 1H NMR (600
MHz, DMSO-d6) δ 10.03 (s, 1H), 6.79 (d, J = 2.3 Hz, 1H), 6.76-6.73 (m, 1H), 6.70-6.68 (m,
1H), 5.83 (s, 1H), 3.68 (s, 3H), 3.06 (dd, J = 13.3, 5.0 Hz, 1H), 2.60-2.53 (m, 1H), 2.34-2.28(m,
1H), 2.00-1.90 (m, 3H), 1.84 – 1.42 (m, 3H) ppm; 13C{1H}NMR (151 MHz, DMSO-d6) δ 209.0,
178.5, 154.2, 136.7, 132.0, 112.7, 112.2, 109.5, 74.2, 57.3, 55.4, 41.5, 27.8, 26.6, 24.4 ppm.
Minor isomer: 1H NMR (600 MHz, DMSO-d6) δ 9.97 (s, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.72-
6.70 (m, 1H), 6.65 (d, J = 8.3 Hz, 1H), 5.72 (s, 1H), 3.67 (s, 3H), 3.24 (dd, J = 12.8, 5.0 Hz,
1H), 2.41-2.34 (m, 1H), 2.27-2.22 (m, 1H), 2.07-2.01 (m, 3H), 1.84-1.42 (m, 3H) ppm.
13C{1H}NMR (151 MHz, DMSO-d6) δ 209.7, 177.9, 154.5, 136.0, 133.7, 112.7, 111.4, 109.3,
74.2, 57.1, 55.3, 42.2, 27.8, 26.6, 24.6 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C15H17NO4Na 298.1055, Found 298.1050.
3-hydroxy-3-(2-oxocyclohexyl)-7-(trifluoromethyl)indolin-2-one(4fa). As a mixture of
two diastereomers in the ratio ~2.0:1. Pale yellow solid (80 mg, 76%). Major isomer :1H NMR
ACS Paragon Plus Environment

Page 25 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(600 MHz, DMSO-d6) δ 10.67 (s, 1H), 7.50-7.49 (m, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.08-7.02
(m, 1H), 6.08 (s, 1H), 3.16 (dd, J = 13.3, 4.9 Hz, 1H), 2.65-2.59 (m, 1H), 2.38-2.33 (m, 1H),
2.10-1.90 (m, 3H), 1.89-1.84 (m, 1H), 1.74-1.66 (m, 1H), 1.52-1.46 (m, 1H) ppm;
13C{1H}NMR (151 MHz, DMSO-d6) δ 209.2, 179.2, 140.9, 132.9, 128.5, 124.87 (q, JC-F = 4.4
Hz), 122.9, 121.0, 110.2 (q, JC-F = 32.5 Hz), 72.4, 57.5, 41.3, 27.4, 26.6, 24.4 ppm; 19F NMR
(376 MHz, DMSO-d6) δ -59.9 ppm. Minor isomer: 1H NMR (600 MHz, DMSO-d6) δ10.60 (s,
1H), 7.53-7.51(m, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.08-7.02 (m, 1H), 6.02 (s, 1H), 3.40-3.36 (m,
1H), 2.45-2.39 (m, 1H), 2.33-2.30 (m, 1H), 2.10-1.90 (m, 3H), 1.84-1.80 (m, 1H), 1.66-1.61
(m, 1H), 1.46-1.42 (m, 1H) ppm; 13C{1H}NMR (151 MHz, DMSO-d6) δ 209.9, 178.3, 140.3,
135.0, 127.0, 124.7 (q, JC-F = 4.4 Hz), 122.9, 121.1, 110.4 (t, JC-F = 32.5 Hz), 71.8, 57.4, 41.9,
27.7, 26.6, 24.6 ppm . 19F NMR (376 MHz, DMSO-d6) δ -59.7 ppm. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C15H14F3NO3Na 336.0823, Found 336.0817.
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-hydroxy-3-(2-oxocyclopentyl)indolin-2-one(5aa). As a mixture of two diastereomers in
the ratio ~2.6:1. Pale yellow solid (55 mg, 70%). Major isomer : 1H NMR (600 MHz, DMSO-
d6) δ 10.28 (s, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.19-7.16 (m, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.77
(d, J = 7.7 Hz, 1H), 5.96 (s, 1H), 2.92 – 2.85 (m, 1H), 2.26 – 2.06 (m, 3H), 1.95-1.89 (m, 1H),
1.76 – 1.67 (m, 2H) ppm; 13C{1H}NMR (151 MHz, DMSO-d6) δ 216.4, 178.2, 142.8, 130.0,
129.2, 124.6, 121.2, 109.5, 75.1, 54.8, 38.7, 24.5, 20.0 ppm. Minor isomer: 1H NMR (600 MHz,
DMSO-d6) δ 10.26 (s, 1H), 7.22-7.19 (m, 1H), 7.13 (d, J = 7.3 Hz, 1H), 6.93 (t, J = 7.5 Hz,
1H), 6.79 (d, J = 7.7 Hz, 1H), 5.91 (s, 1H), 2.85 – 2.79 (m, 1H), 2.25 – 2.06 (m, 3H), 2.03-1.97
(m, 1H), 1.86 – 1.77 (m, 2H) ppm; 13C{1H}NMR (151 MHz, DMSO-d6) δ 216.7, 177.6, 142.3,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 33
1
2
3
4
5
6
7
130.9, 129.1, 124.2, 121.6, 109.5, 75.0, 54.9, 39.0, 25.0, 19.6 ppm. HRMS (ESI-TOF) m/z: [M
+ Na]+ Calcd for C13H13NO3Na 254.0793, Found 254.0788.
8
9
5-bromo-3-hydroxy-3-(2-oxocyclopentyl)indolin-2-one(5ba). As a mixture of two
diastereomers in the ratio ~3.0:1. Pale yellow solid (67.2 mg, 64%). Major isomer :1H NMR
(600 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.49 (s, 1H), 7.39-7.36 (m, 1H), 6.75 (d, J = 8.2 Hz,
1H), 6.15 (s, 1H), 2.91 – 2.85 (m, 1H), 2.25 – 2.03 (m, 3H), 1.95 – 1.68 (m, 3H) ppm;
13C{1H}NMR (151 MHz, DMSO-d6) δ 216.2, 177.8, 142.1, 132.5, 131.9, 127.5, 112.9, 111.5,
75.0, 54.8, 38.6, 24.5, 20.0 ppm. Minor isomer: 1H NMR (600 MHz, DMSO-d6) δ 10.40 (s,
1H), 7.30 (s, 1H), 7.39-7.36 (m, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.11 (s, 1H), 2.97 – 2.91 (m,
1H), 2.25 – 2.03 (m, 3H), 1.95 – 1.68 (m, 3H) ppm; 13C{1H}NMR (151 MHz, DMSO-d6) δ
216.4, 177.2, 141.6, 134.0, 131.6, 127.0, 113.2, 111.4, 74.5, 54.4, 38.7, 24.8, 19.6 ppm. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C13H12BrNO3Na 331.9898, Found 331.9890.
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
5-chloro-3-hydroxy-3-(2-oxocyclopentyl)indolin-2-one(5ca). As a mixture of two
diastereomers in the ratio ~4.0:1. Pale yellow solid (41.5 mg, 46%). Major isomer :1H NMR
(600 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.25-7.23 (m, 1H), 6.79 (d, J
= 8.2 Hz, 1H), 6.15 (s, 1H), 2.92 – 2.85 (m, 1H), 2.24 – 2.19 (m, 1H), 2.15 – 2.06 (m, 2H), 1.95
– 1.90 (m, 1H), 1.89-1.82(m, 1H), 1.76-1.68 (m, 1H) ppm; 13C{1H}NMR (151 MHz, DMSO-
d6) δ 216.3, 178.0, 141.7, 132.1, 129.1, 125.2, 124.8, 111.0, 75.1, 54.9, 38.6, 24.5, 20.1 ppm.
Minor isomer: 1H NMR (600 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.26-7.24 (m, 1H), 7.18 (d, J =
1.8 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.13 (s, 1H), 2.99 – 2.82 (m, 1H), 2.26 – 2.19 (m, 1H),
2.15 – 2.06 (m, 2H), 1.95 – 1.90 (m, 1H), 1.89-1.82 (m, 1H), 1.76-1.68 (m, 1H) ppm;
13C{1H}NMR (151 MHz, DMSO-d6) δ 216.4, 177.4, 141.2, 133.5, 128.8, 125.5, 124.3, 110.9,
ACS Paragon Plus Environment

Page 27 of 33
The Journal of Organic Chemistry
1
2
3
4
5
6
74.5, 54.4, 38.7, 24.8, 19.6 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H12ClNO3Na
288.0403,Found 288.0397.
7
8
9
3-hydroxy-5-methyl-3-(2-oxocyclopentyl)indolin-2-one(5da). As a mixture of two
diastereomers in the ratio ~4.0:1. Pale yellow solid (27 mg, 32%). Major isomer :1H NMR (600
MHz, DMSO-d6) δ 10.18 (s, 1H), 7.17 (s, 1H), 7.01-6.94 (m, 1H), 6.65 (d, J = 7.8 Hz, 1H),
5.92 (s, 1H), 2.88 – 2.85 (m, 1H), 2.23 (s, 3H), 2.21-2.17 (m, 1H), 2.14-2.04 (m, 2H), 1.95-1.88
(m, 1H), 1.87-1.78 (m, 1H),1.76-1.67 (m, 1H) ppm; 13C{1H}NMR (151 MHz, DMSO-d6) δ
216.4, 178.2, 140.3, 130.0, 129.3, 125.2, 109.2, 75.1, 54.7, 38.7, 24.6, 20.6, 20.1 ppm. Minor
isomer:1H NMR (600 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.16 (s, 1H), 7.01 – 6.94 (m, 1H), 6.67
(d, J = 7.8 Hz, 1H), 5.87 (s, 1H), 2.25 – 2.20 (m, 1H), 2.21 (s, 3H), 2.20-2.17 (m, 1H), 2.14-
2.04 (m, 2H), 1.95-1.88 (m, 1H), 1.87-1.78 (m, 1H), 1.76-1.67 (m, 1H) ppm; 13C{1H}NMR
(151 MHz, DMSO-d6) δ 216.7, 177.6, 139.8, 130.0, 129.2, 124.8, 109.2, 75.1, 53.7, 38.7, 25.0,
20.7, 19.6 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H15NO3Na 268.0950, Found
268.0944.
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-hydroxy-5-methoxy-3-(2-oxocyclopentyl)indolin-2-one(5ea). As a mixture of two
diastereomers in the ratio ~3.4:1. Pale yellow solid (28.5 mg, 32%). Major isomer : 1H NMR
(600 MHz, DMSO-d6) δ 10.13 (s, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.76-6.74 (m, 1H), 6.69 (d, J
= 8.4 Hz, 1H), 5.97 (s, 1H), 3.69 (s, 3H), 2.89 – 2.84 (m, 1H), 2.21-2.15(m, 1H), 2.14-2.00 (m,
2H), 1.96 – 1.82 (m, 2H), 1.75 – 1.68 (m, 1H) ppm; 13C{1H}NMR (151 MHz, DMSO-d6) δ
216.5, 178.1, 154.5, 135.9, 131.2, 113.6, 111.9, 109.8, 75.6, 55.5, 54.5, 38.7, 24.5, 20.0 ppm.
Minor isomer: 1H NMR (600 MHz, DMSO-d6) δ 10.10 (s, 1H), 6.79 – 6.77 (m, 2H), 6.71 (d, J
= 8.4 Hz, 1H), 5.94 (s, 1H), 3.68 (s, 3H), 2.83-2.80 (m, 1H), 2.21 – 2.15 (m, 1H), 2.14-2.00 (m,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 33
1
2
3
4
5
6
7
8
9
2H), 1.96 – 1.82 (m, 2H), 1.75 – 1.68 (m, 1H) ppm; 13C{1H}NMR (151 MHz, DMSO-d6) δ
216.7, 177.5, 154.8, 135.5, 132.2, 113.6, 111.2, 109.8, 75.3, 55.4, 53.9, 39.0, 25.0, 19.6 ppm.
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C14H15NO4Na 284.0899, Found 284.0893.
3-hydroxy-3-(2-oxocyclopentyl)-7-(trifluoromethyl)indolin-2-one(5fa). As a mixture of
two diastereomers in the ratio ~1.8:1. Pale yellow solid (43 mg, 42%). Major isomer : 1H NMR
(600 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.50-7.46 (m, 1H), 7.08 (t, J =
7.7 Hz, 1H), 6.23 (s, 1H), 2.98 – 2.92 (m, 1H), 2.30 – 2.14(m, 3H), 1.97-1.77 (m, 3H) ppm;
13C{1H}NMR (151 MHz, DMSO-d6) δ 216.1, 178.8, 140.3, 133.7, 132.0, 128.6, 125.6 (q, JC-F
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
= 4.4Hz), 121.4, 110.3 (q, JC-F = 32.6 Hz) , 73.5, 55.2, 38.5, 24.4, 20.0 ppm; F NMR (376
MHz, DMSO-d6) δ -60.0 ppm. Minor isomer: 1H NMR (600 MHz, DMSO-d6) δ 10.76 (s, 1H),
7.66 (d, J = 7.4 Hz, 1H), 7.45(d, J = 7.2 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.21 (s, 1H), 3.03 –
2.90 (m, 1H), 2.14 – 2.06 (m, 3H), 1.97-1.77 (m, 3H) ppm; 13C{1H}NMR (151 MHz, DMSO-
d6) δ 216.2, 178.1, 139.7, 133.7, 127.9, 125.3 (q, JC-F = 4.4 Hz), 122.7, 121.8, 110.6 (q, JC-F
=
32.6 Hz), 73.1, 54.5, 38.7, 24.7, 19.6 ppm; 19F NMR (376 MHz, DMSO-d6) δ -59.9 ppm. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C14H12F3NO3Na 322.0667, Found 322.0662.
13C NMR titration experiment for isatin and indole’s CDCl3 solution with water additives
To a solution of isatin in CDCl3 (0.9 mg in 0.5 mL) in a 1.5 mL centrifuge vial, certain
amount of water (0, 100 or 500 μL) was added, and shaken severely for 10 min, then transferred
to NMR tube, with 13C NMR experiment recorded on a Bruker (600 MHz) NMR spectrometer.
For indole’s NMR titration experiment, only difference is indole’s solution is 10 mg
dissolved in 0.5 mL CDCl3.
ASSOCIATED CONTENT
ACS Paragon Plus Environment

Page 29 of 33
The Journal of Organic Chemistry
1
2
3
4
5
Supporting Information
6
7
1H and 13C NMR spectra for D-132, all products, and 2D NMR for isatin 1a. This material is
8
9
available free of charge on the ACS Publications website.
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
AUTHOR INFORMATION
Corresponding Author
E-mail: liwenxu@hznu.edu.cn;
E-mail: yajunjian@snnu.edu.cn
ORCID
Li-Wen Xu: 0000-0001-5705-0015
Yajun Jian: 0000-0003-3068-6771
Notes
There are no conflicts to declare.
ACKNOWLEGEMENTS
This work was supported by the grant from National Natural Science Foundation of China
(21602129), Natural Science Basic Research Plan in Shaanxi Province of China (2017JM2020,
2017JM2001), Fundamental Research Funds for Central Universities (GK201803027), and the
111 Project (B14041). This work was also partially supported by ‘One Hundred Talented
People’ of Shaanxi Province. We thank our college Profs. Quan Gu, Jing Liu, and Hongyan
Wang for helpful discussions.
REFERENCES
1. (a) Itami, K.; Yoshida, J.-I. The use of hydrophilic groups in aqueous organic reactions. Chem. Rec.
2002, 2, 213-224; (b) Jimeno, C. Water in asymmetric organocatalytic systems: a global perspective.
ACS Paragon Plus Environment