Consecutive one-pot versus domino multicomponent approaches to 3-(Diarylmethylene)oxindoles

Article abstract of DOI:10.3390/molecules22030503

Based on consecutive one-pot conditions combining three palladium-catalyzed reactions (Sonogashira, Heck and Suzuki-Miyaura reactions), a more efficient domino multicomponent method has been successfully developed to access a wide variety of 3-(diarylmethylene)oxindoles. Microwave irradiation and use of a silver salt were the most important factors to achieve high yields and stereoselectivity.

Full text of DOI:10.3390/molecules22030503

molecules
Article
Consecutive One-Pot versus Domino Multicomponent
Approaches to 3-(Diarylmethylene)oxindoles
Sunhwa Park, Jiyun Lee, Kye Jung Shin, Euichaul Oh and Jae Hong Seo *
Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea,
Bucheon-si, Gyeonggi-do 420-743, Korea; sunalovegs@catholic.ac.kr (S.P.); ljiy727@catholic.ac.kr (J.L.);
kyejung@catholic.ac.kr (K.J.S.); eoh@catholic.ac.kr (E.O.)
* Correspondence: jaehongseo@catholic.ac.kr; Tel.: +82-2-2164-6531; Fax: +82-2-2164-4059
Academic Editor: Richard A. Bunce
Received: 27 February 2017; Accepted: 17 March 2017; Published: 22 March 2017
Abstract: Based on consecutive one-pot conditions combining three palladium-catalyzed reactions
(Sonogashira, Heck and Suzuki-Miyaura reactions), a more efficient domino multicomponent
method has been successfully developed to access a wide variety of 3-(diarylmethylene)oxindoles.
Microwave irradiation and use of a silver salt were the most important factors to achieve high yields
and stereoselectivity.
Keywords: consecutive one-pot reaction; domino reaction; 3-(diarylmethylene)oxindole;
palladium-catalyzed reaction; microwave irradiation
1. Introduction
Multicomponent reactions (MCRs) are generally understood as reactions in which three or more
substrates are added at the beginning of the reaction to afford the products via two or more chemical
transformations [
complex skeletons from simple substrates, securing diversity of products in a less time-consuming and
more economical manner compared with the corresponding stepwise approaches [ ]. These features of
MCRs have attracted much interest among synthetic chemists in the pharmaceutical industry aiming
to apply MCRs to create a wide variety of small molecule libraries [ ]. Various heterocycles have
also been synthesized via MCRs [ ], especially utilizing transition metal catalysts [ ]. Recently, as part
of our ongoing efforts to find efficient synthetic methods for biologically active skeletons,
we reported two such methods [ ] for the preparation of 3-(diarylmethylene)oxindoles (Scheme 1),
1]. Inherently, well-designed MCRs can provide an efficient synthetic method for
2
3–5
6
7
8,9
which are attracting increased interest due to their recently identified biological activities, such as
AMPK activation [10] and anti-breast-cancer activity [11]. Both of our methods involve a simple
propiolamide
1, and commercially available aryl iodides and arylboronic acids as starting
materials to produce 3-(diarylmethylene)oxindoles via three successive palladium-catalyzed reactions:
the Sonogashira, Heck, and Suzuki-Miyaura reactions. However, there is a big difference between
the two methods in terms of the reaction process. The first method, u◦nder thermal conditions, begins
1 and aryl iodide at 60 C to give Sonogashira adduct 2,
with the Sonogashira reaction of propiolamide
which then proceeds through Heck and Suzuki-Miyaura reactions upon the addition of arylboronic acid
◦
and elevation of the reaction temperature to 90 C [
8
]. It is worth noting that the addition of a silver salt
(AgOTf) with the arylboronic acid enhances the E/Z stereoselectivity of unsymmetrically substituted
3-(diarylmethylene)oxindoles. In contrast, the second method, under microwave-assisted conditions,
requires neither a second addition, nor a temperature change [9]. Although both methods are
one-pot reactions, the first method is a consecutive one-pot reaction requiring more than two separate
operations, whereas the second method is a domino MCR, which offers a more efficient chemical
transformation but makes it harder to achieve optimal conditions. Herein, we report our efforts
Molecules 2017, 22, 503; doi:10.3390/molecules22030503
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to develop efficient domino MCRs from consecutive one-pot conditions and wide screening of
the substrate scope of the resulting domino MCRs, which contributes to our understanding of the
mechanism of the reaction and could inform future studies on MCRs.
Scheme 1. Consecutive one-pot versus domino MCR approach to 3-(diarylmethylene)oxindoles.
2. Results and Discussion
To verify the possibility of domino MCRs, we started with the addition of all three substrates
(propiolamide 1, aryl iodide and arylboronic acid) at the beginning of the reaction, which were
then exposed to t◦he same reaction conditions for the consecutive one-pot reaction (Pd(PPh3)4, CuI,
◦
NaOAc, DMF; 60 C for 1.5 h, then 90 C for 24 h) (Table 1). A silver salt (AgOTf) was not added in this
preliminary study because it does not affect reaction progress, but mainly enhances the stereoselectivity
of unsymmetrically substituted products. The main concern of this study was possibility of the direct
Suzuki-Miyaura reaction between aryl iodide and arylboronic acid, to produce biphenyl byproducts
However, the formation of biphenyl compounds was less than 15% for both symmetric (entries 1–3)
and unsymmetric products (entries 4–10). The yield and E/Z stereoselectivity were also similar to those
4.
4
of consecutive one-pot conditions. These results imply that aryl iodide reacted first with propiolamide
rather than arylboronic acid at the initial temperature (60 C), to produce the corresponding Sonogashira
adduct 2 that was then transformed into the desired 3 at a higher temperature (90 ◦C).
1
◦
In spite of the promising preliminary results, the E/Z stereoselectivity for unsymmetrically
substituted products was still poor without silver salt (Table 1; entries 5–10). Thus, we investigated the
ability of silver salt to improve the stereoselectivity of the products (Table 2). In the initial screening of
silver salts, AgOTf showed the best enhancement of stereoselectivity without any compensatory loss
of product yield [8]. Subsequently, more intensive screenings for silver salts revealed that Ag3PO4 is
a better additive for this purpose, as shown in Table 2. When Ag3PO4 was added at the beginning of
the reaction with all substrates, stereoselectivity was enhanced as expected, but yields decreased with
the formation of a substantial amount of the biphenyl product
4 (20%–40% yield). Silver salt might
hamper the Sonogashira reaction between and aryl iodide, allowing more aryl iodide to undergo the
1
direct Suzuki-Miyaura reaction with arylboronic acid.
To solve the problem of low yield with the addition of silver salt, we screened various
phosphine ligands, expecting improvement of yield while maintaining good stereoselectivity
(Table 3, entries 1–5). Bidentate phosphine ligands are known as effective ligands for the cationic
pathway of palladium-catalyzed reactions [12]. Unfortunately, the addition of bidentate ligands
(dppp, dppb and dppf) did not afford the desired product 3f (entries 1–3). When P(o-tol)3 was added,
3f was obtained in poor yield (13%) (entry 4). Addition of PPh3 showed a promising result (entry 5;

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50% yield, 5:1 E/Z ratio) but was still less effective than the consecutive one-pot conditions with
Ag3PO4 (Table 2, entry 2; 86% yield, 9:1 E/Z ratio). Interestingly, elevation of the initial reaction
temperature to 90 ◦C, which removed the additional temperature change operation, provided 3f in
67% yield with a 7.5:1 E/Z ratio (entry 6). When the reaction temperature was further increased
(150 ◦C), the reaction rate increased but yield and stereoselectivity decreased slightly (entries 6 and 7).
These results showed that high reaction temperature reduced the hampering effect of silver salt on the
initial Sonogashira reaction.
Table 1. Preliminary results of thermal domino MCRs 1.
Consecutive One-Pot 4,5
Yield (%) 2
Yield (%) 2
R1
R2
E/Z Ratio 3
4
3
Entry
Yield (%) 2
E/Z Ratio 3
1
2
3
H
MeO
Cl
NO2
H
H
H
MeO
Cl
NO2
H
MeO
Cl
NO2
MeO
Cl
NO2
H
H
4a
4b
4c
4d
4e
4f
4g
4e
4f
–
–
–
15
14
12
5
–
–
10
3a
3b
3c
3d
3e
3f
3g
3e
3f
68
50
86
66
66
78
75
59
84
80
–
–
–
81
85
80
67
52
57
52
70
77
73
–
–
–
4 5
5
–
–
1:2
2:1
1:1.1
1.5:1
1:2.4
1:13
1:1
1:1
1:1
1.6:1
1:3.4
1:10
6
7 5
8
9
10 6
1
H
4g
3g
Reaction conditions:
1
(1.0 eq), aryl iodide (1.1 eq), arylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %), CuI (5 mol %),
NaOAc (3 eq), DMF (0.05 M), 60 ◦C, 1.5 h, then 90 ◦C, 24 h; Isolated yield or combined yield of isolated
2
E- and Z-isomers; 3 Ratio between isolated E- and Z-isomers; 4 Reaction conditions:
1 (1.0 eq), aryl iodide (1.1 eq),
Pd(PPh3)4 (10 mol %), CuI (5 mol %), NaOAc (3 eq), DMF (0.05 M), 60 ◦C, 1.5 h, then arylboronic acid (1.2 eq), 90 ◦C,
24 h; 5 Reported data in reference [8]; 6 Reaction temperature was raised from 60 ◦C to 110 ◦C.
Table 2. Effect of silver salt on thermal domino MCRs 1.
Consecutive
Consecutive
One-Pot (Ag3PO4) 4
One-Pot (AgOTf) 4,5
Yield
(%) 2
Yield
(%) 2
E/Z
R1
R2
4
3
Entry
Ratio 3
Yield
(%) 2
E/Z
Ratio
Yield
(%) 2
E/Z
Ratio
1
2
H
H
H
MeO 4e
Cl 4f
NO2 4g
45
20
25
3e
3f
3g
42
39
50
3.5:1
4.5:1
4:1
63
86
66
10:1
9:1
3:1
70
45
56
2.5:1
7:1
5.2:1
3 6
1
Reaction conditions:
1 (1.0 eq), aryl iodide (1.1 eq), arylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %), CuI (5 mol %),
NaOAc (3 eq), Ag3PO4 (1.1 eq), DMF (0.05 M), 60 ◦C, 1.5 h, then 90 ◦C, 24 h; 2 Isolated yield or combined yield of
isolated E- and Z-isomers; 3 Ratio between isolated E- and Z-isomers; 4 Reaction conditions:
(1.0 eq), aryl iodide
1
(1.1 eq), Pd(PPh3)4 (10 mol %), CuI (5 mol %), NaOAc (3 eq), DMF (0.05 M), 60 ◦C, 1.5 h, then arylboronic acid
(1.2 eq), silver salt (1.1 eq), 90 ◦C, 24 h; 5 Reported data in reference [
60 ◦C to 110 ◦C.
8
]; 6 Reaction temperature was raised from

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Table 3. Phosphine ligand effect and further optimization 1.
Entry
Phosphine Ligand
Conditions
Yield (%) 2
E/Z Ratio 3
◦
◦
1
2
3
4
5
6
7
8
dppp
dppb
dppf
P(o-tol)3
PPh3
PPh3
PPh3
PPh3
60 C, 1.5 h then 90 C, 24 h
0
0
0
13
50
67
45
61
-
-
-
◦
◦
60 C, 1.5 h then 90 C, 24 h
◦
◦
60 C, 1.5 h then 90 C, 24 h
◦
◦
60 C, 1.5 h then 90 C, 24 h
3.5:1
5:1
7.5:1
3.5:1
3.5:1
◦
◦
60 C, 1.5 h then 90 C, 24 h
◦
90 C, 24 h
◦
150 C, 1.5 h
◦
150 C, 3 h
1 Reaction conditions:
1 (1.0 eq), phenyl iodide (1.1 eq), 4-chlorophenylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %), CuI
(5 mol %), NaOAc (3 eq), Ag3PO4 (1.1 eq), phosphine ligand (30 mol %), DMF (0.05 M), conditions; 2 Combined yield
of isolated E- and Z-isomers; 3 Ratio between isolated E- and Z-isomers. dppp: 1,3-bis(diphenylphosphino)propane;
dppb: 1,4-bis(diphenylphosphino)-butane; dppf: 1,10-bis(diphenylphosphino)ferrocene.
Considering the above results, we decided to test microwave irradiation conditions, which are
known for acceler◦ating sluggish thermal reactions [13
–15] (Table 4). Reactions with microwave
irradiation at 100 C, for 10, 30 and 60 min, increased yields from 46% to 80% with increasing
reaction time, and the stereoselectivity in all three cases was very high (9:1~18:1 E/Z ratio, entries 1–3).
Higher reaction temperatures (110 and 130 ◦C) made it possible to complete the reaction in a shortest
time (10 min) with good yield and stereoselectivity (entries 4 and 5). The best result was obtained at
150 ◦C, presenting 99% yield and a 13:1 E/Z ratio (entry 6). At 160 ◦C, the reaction was completed in
5 min to give 3f in 98% yield with slightly lower stereoselectivity (7.5:1 E/Z ratio) (entry 7).
Table 4. Optimization of microwave reactions 1.
◦
Entry
Temp ( C)
Time (min)
Yield (%) 2
E/Z Ratio 3
1
2
3
4
5
100
100
100
110
130
150
160
150
150
150
150
10
30
60
10
10
10
5
10
10
10
10
46
67
80
54
92
99
98
92
36
35
79
12:1
18:1
9:1
7:1
13:1
13:1
7.5:1
8:1
1:1.2
1:1.5
10:1
6
7
8 4
9 5
10 6
11 7
1
Reaction conditions:
1 (1.0 eq), phenyl iodide (1.1 eq), 4-chlorophenylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %),
CuI (5 mol %), NaOAc (3 eq), Ag3PO4 (1.1 eq), PPh3 (30 mol %), DMF (0.05 M), microwave irradiation, temperature
2
3
and time on table; Combined yield of isolated E- and Z-isomers; Ratio between isolated E- and Z-isomers;
Reaction without PPh3; 5 Reaction without Ag3PO4; 6 Reaction without PPh3 and Ag3PO4; 7 Two equivalents of
4
Ag3PO4 were used without NaOAc.

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Based on these favorable results under microwave conditions, we decided to investigate the
effects of additives on microwave-assisted reactions by performing a blank test. Without phosphine
ligand (PPh3), the reaction still proceeded smoothly, to provide 3f in slightly lower yield and
stereoselectivity (entry 8; 92% yield, 8:1 E/Z ratio). However, the removal of silver salt (Ag3PO4)
dramatically decreased the yield (36%) and stereoselectivity (1:1.2 E/Z ratio) (entry 9). Without both
PPh3 and Ag3PO4, the lowest yield (35%) and stereo-inverted selectivity (1:1.5 E/Z ratio) were obtained
(entry 10). Interestingly, the addition of two equivalents of Ag3PO4 without base (NaOAc) still provided
product 3f in moderate yield and stereoselectivity (entry 11). Thus, under microwave irradiation
conditions, silver salt seems to be a crucial additive not only for good stereoselectivity, but also for
high yield.
With optimized microwave-assisted conditions in hand, we investigated the substrate scope for
the synthesis of symmetrically substituted 3-(diarylmethylene)oxindoles (Table 5). Regardless of the
substituents on the aryl group, all reactions gave the desired products 3a–d in good yield (entries 1–4).
To verify the effect of silver salt, control experiments without Ag3PO4 were also performed.
As expected, the absence of silver salt decreased the yield of all reactions. However, the degree
of yield reduction appears to be related to the electronic effect of the substituent on the aryl group.
The formation of 3b bearing the electron-donating methoxy group at the 4-position was hardly affected
by the absence of Ag3PO4 (75% vs. 55%); whereas the yields for 3d with the electron-withdrawing
nitro group at the same position changed dramatically, from 90% to 9%, without addition of Ag3PO4.
This suggests that the positive effect of Ag3PO4 on the domino MCRs is due in part to enhancing the
last Suzuki-Miyaura reaction step [16].
Table 5. Substrate scope for symmetric products and the effect of silver salt 1.
2
With Ag3PO4
Yield (%) 3
Without Ag3PO4
Yield (%) 3
R
3
Entry
1
2
3
4
H
MeO
Cl
3a
3b
3c
75
75
72
90
27
55
15
9
NO2
3d
1
Reaction conditions:
1 (1.0 eq), aryl iodide (1.1 eq), arylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %), CuI (5 mol %),
NaOAc (3 eq), PPh3 (30 mol %), with or without Ag3PO4 (1.1 eq), DMF (0.05 M), microwave irradiation, 150 ◦C,
10 min; 2 Reported data in reference [9]; 3 Isolated yield.
Next, we tested the effect of our reaction conditions on the synthesis of unsymmetrically
substituted 3-(diarylmethylene)oxindoles having electronically different substituents at the 4-position
of the phenyl group (Table 6). All reactions provided products 3e–g in good yield (80%–99%).
Stereoselectivity for each reaction was more than 8:1, giving the expected stereoisomer as the major
product, except in the reaction with 4-methoxyphenyl iodide, in which the E/Z ratio of 1.2:1 resulted in
a little more of the stereo-inverted E-isomer than the Z-isomer. This exceptional case will be revisited
later through extensive screening of the reaction conditions. To confirm the ligand effect on our domino
MCRs, all reactions were tested again without PPh3, which resulted in similar but slightly lower
yield and stereoselectivity. The addition of PPh3 did not enhance the reaction as much as silver salt,
but nevertheless surely plays a meaningful role in producing good yield and stereoselectivity of the
domino MCRs.

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Table 6. Basic substrate scope for unsymmetric products and the ligand effect 1.
2
With PPh3
Yield (%) 3
Without PPh3
R1
R2
3
Entry
E/Z Ratio 4
Yield (%) 3
E/Z Ratio 4
1
2
3
4
5
6
H
H
H
MeO
Cl
NO2
MeO
Cl
NO2
H
H
H
3e
3f
3g
3e
3f
85
99
89
80
85
88
8:1
13:1
9.5:1
1.2:1
1:15
88
92
86
68
81
84
8:1
8:1
9:1
1.6:1
1:18
1:>20
3g
1:>20
1
Reaction conditions:
1 (1.0 eq), aryl iodide (1.1 eq), arylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %), CuI (5 mol %),
NaOAc (3 eq), with or without PPh3 (30 mol %), Ag3PO4 (1.1 eq), DMF (0.05 M), microwave irradiation, 150 ◦C,
2
3
10 min; Reported data in reference [
9
]; Isolated yield or combined yield of isolated E- and Z-isomers;
4
Ratio between isolated E- and Z-isomers.
To widen the application of the reaction, a more expanded substrate scope was investigated
(Table 7). The reaction of 4-acetoxyphenylboronic acid showed relatively low yield (45%) but
high stereoselectivity (10:1 E/Z ratio) (entry 1). Unlike 4-methoxyphenyl iodide, the reaction of
4-acetoxyphenyl iodide presented good yield and stereoselectivity (entry 2), representing an alternative
way to synthesize the Z-isomer with an oxygen atom at the 4-position of the phenyl group.
Moreover, 3-(diarylmethylene)oxindoles with substituents at the 3-position of the phenyl group were
easily prepared by our domino MCRs, regardless of the electronic effect of the substituent (entries 3–10).
When the yield was moderate, addition of two equivalents of arylboronic acid increased the yield up to
94%, accompanied by slightly lower stereoselectivity (entries 5 and 10). It is worth pointing out that the
reaction of 3-methoxyphenyl iodide showed good stereoselectivity (1:8 E/Z ratio, entry 7). This result
suggests that the position of the methoxy group on the aryl iodide is important for determining the
stereoselectivity of the reaction. 2-Chloro and 2-methoxyphenylboronic acids were good substrates for
the reaction, providing 3l and 3m in good yield (entries 11 and 12); however, no product was formed
in the reaction of 2-nitrophenylboronic acid (entry 13). 2-Methoxyphenyl iodide reiterated the problem
of low stereoselectivity, as well as 4-methoxyphenyl iodide (entry 14). The reaction of 2-chlorophenyl
iodide resulted in good yield and stereoselectivity (entry 15), while the 2-nitrophenyl iodide was a poor
substrate for the reaction, giving product 3n in very low yield (entry 16). Taken together, the above
results suggest that our domino MCRs have broad substituent tolerance for both aryl iodide and
arylboronic acid, producing good yield and stereoselectivity except for 2- or 4-methoxyphenyl iodide
and the 2-nitro substituent.
Next, we tried to solve the low stereoselectivity problem for the reaction with 4-methoxyphenyl
iodide (Table 8). We focused on the amount of Ag3PO4, which seems to play a crucial role in
achieving good stereoselectivity in the domino MCRs. Increasing the amount of Ag3PO4 showed
little improvement of stereoselectivity, but rather reduced the yield (entries 2–4). Other silver salts
were not as effective as Ag3PO4 (entries 5–8). Then, we lowered the reaction temperature. At 130 ◦C,
stereoselectivity increased slightly (1:1.5 E/Z ratio, entry 9). At 100 ◦C, the reaction rate was much
slower and a longer reaction time was needed to achieve reasonable yield. The reaction for 1 h at
100 ◦C provided the best stereoselectivity (1:4 E/Z ratio) with good yield (70% entry 10). A longer
reaction time (3 h) at 100 ◦C increased the yield to 79% but decreased stereoselectivity (1:3 E/Z ratio,
entry 11). Thus, in the case of poor stereoselectivity, modification of the reaction temperature and time
of the reaction can offer a solution.

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Table 7. Expanded substrate scope for unsymmetric products 1.
Entry
R1
R2
3
Yield (%) 2
E/Z Ratio 3
1
2
3
H
4-AcO
H
H
H
4-AcO
H
3h
3h
3i
3j
3j
3k
3i
3j
3k
3k
3l
3m
3n
3l
45
82
98
72
94
93
85
81
65
94
81
84
0
10:1
1:8
9:1
3-MeO
3-Cl
3-Cl
3-NO2
H
H
H
H
2-MeO
2-Cl
2-NO2
H
H
H
4
10:1
7.5:1
12:1
1:8
1:13
1:>20
1:>20
6.5:1
8:1
5 4
6
H
7
8
9
3-MeO
3-Cl
3-NO2
3-NO2
H
H
H
2-MeO
2-Cl
2-NO2
10 4
11
12
13
14
15
16
-
57
85
17
1.2:1
1:14
1:>20
3m
3n
1
Reaction conditions:
1 (1.0 eq), aryl iodide (1.1 eq), arylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %), CuI (5 mol %),
PPh3 (30 mol %), NaOAc (3 eq), Ag3PO4 (1.1 eq), DMF (0.05 M), microwave irradiation, 150 ◦C, 10 min;
2
4
3
Isolated yield or combined yield of isolated E- and Z-isomers; Ratio between isolated E- and Z-isomers;
Two equivalents of arylboronic acid were used.
Table 8. Further optimization for the reaction with 4-methoxyphenyl iodide 1.
◦
Entry
Silver Salt (eq)
Temp ( C)
Time (min) Yield (%) 2
E/Z Ratio 3
1
2
3
Ag3PO4 (1.1)
Ag3PO4 (1.5)
Ag3PO4 (2.0)
Ag3PO4 (4.0)
Ag2CO3 (1.1)
AgBF4 (1.1)
AgOTf (1.1)
AgOAc (1.1)
Ag3PO4 (1.1)
Ag3PO4 (1.1)
Ag3PO4 (1.1)
150
150
150
150
150
150
150
150
130
100
100
10
10
10
10
10
10
10
10
10
60
180
80
85
61
41
56
12
25
0
1.2:1
1:1
1:1.3
1:1.5
1.3:1
3:1
2.3:1
-
1:1.5
1:4
4 4
5
6
7
8
9
10
11
70
70
79
1:3
1 Reaction conditions:
CuI (5 mol %), PPh3 (30 mol %), NaOAc (3 eq), silver salt, DMF (0.05 M), microwave irradiation, indicated
1 (1.0 eq), 4-methoxylphenyl iodide (1.1 eq), phenylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %),
2
3
temperature and time in table; Combined yield of isolated E- and Z-isomers; Ratio between isolated E- and
Z-isomers; 4 No base (NaOAc) was used.
Our next challenge was to expand the substrate scope to heteroaryl groups (Table 9). The 3- or
4-pyridinyl group was introduced by our domino MCRs in good yield and high stereoselectivity
(entries 1 and 2). The reaction with 3-benzothiophenylboronic acid provided the desired product in

Molecules 2017, 22, 503
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52% yield and 16:1 E/Z ratio (entry 3). Interestingly, in this reaction, unexpected byproduct
5 was
isolated; the structure of
(2D) nuclear magnetic resonance (NMR) experiments. The formation of tricyclic compound
explained by insertion of an acetyl group originating from the base (NaOAc). The formation of
5
was elucidated by intensive one-dimensional (1D) and two-dimensional
would be
was
5
5
easily removed by the use of the more heteroarylboronic acid (2 eq, entry 4); 2-benzothiophenylboronic
acid and 3-furanylboronic acid showed similar activity in domino MCRs (entries 5–8), although the
stereoselectivity of the reaction with 2-benzothiophenylboronic acid was much lower than for the
others (entries 5 and 6).
Table 9. Substrate scope with heteroarylboronic acids 1.
Entry
Het-Ar-B(OH)2
3
Yield (%) 2
E/Z Ratio 3
5 (%) 2
1
3o
77
>20:1
0
2
3
3p
3q
86
52
14:1
16:1
0
25
4 4
3q
83
8.5:1
0
5
3r
3r
56
97
1.3:1
1.3:1
19
0
6 4
7
3s
3s
68
97
9:1
6:1
10
0
8 4
1
Reaction conditions:
1 (1.0 eq), phenyl iodide (1.1 eq), heteroarylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %),
CuI (5 mol %), PPh3 (30 mol %), NaOAc (3 eq), Ag3PO4 (1.1 eq), DMF (0.05 M), microwave irradiation, 150 ◦C,
10 min; 2 Isolated yield or combined yield of isolated E- and Z-isomers; 3 Ratio between isolated E- and Z-isomers;
4
Two equivalents of heteroarylboronic acid were used.
Next, we investigated the possibility of derivatization of propiolamide
1 (Table 10). When the
N-substituent of propiolamide was changed to a H or a Bn group, the reactions showed good yield and
1
moderate stereoselectivity (entries 1 and 2). Under standard conditions, one carbon-extended substrate
◦
6c showed low yield (35%, entry 3). The yield increased to 45% at higher reaction temperature (180 C)
but almost no stereoselectivity was observed (1.1:1 E/Z ratio, entry 4). Propiolate ester 6d turned
out to be a poor substrate for our domino MCRs, giving both a low yield and poor stereoselectivity
(entry 5). All results implied that applying our microwave-assisted domino MCRs to the synthesis of
other heterocycles is possible, but needs further study for optimization of each reaction.

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Table 10. N-Substituent effect and application to other heterocycles 1.
Entry
6
X
7
Yield (%) 2
E/Z Ratio 3
N
H
1
6a
7a
85
2.2:1
2
3
6b
6c
7b
7c
98
35
3.3:1
2.5:1
4 4
5
6c
7c
45
35
1.1:1
1.1:1
6d
7d
1
Reaction conditions:
6 (1.0 eq), phenyl iodide (1.1 eq), 4-chlorophenylboronic acid (1.2 eq), Pd(PPh3)4 (10 mol %),
CuI (5 mol %), PPh3 (30 mol %), NaOAc (3 eq), Ag3PO4 (1.1 eq), DMF (0.05 M), microwave irradiation, 150 ◦C,
10 min; 2 Combined yield of isolated E- and Z-isomers; 3 Ratio between isolated E- and Z-isomers; 4 Reaction was
run at 180 ◦C.
In all of the above results, the stereoselectivity of the domino MCRs varied depending on the
substrate. One of the reasons for this could be the isomerization of product
3 under the reaction
conditions. Thus, we exposed pure (Z)- and (E)-isomers of 3e to the standard reaction conditions
(Table 11). Both (Z)- and (E)-3e showed very low isomerization rates (<15%), regardless of the addition
of Ag3PO4. This suggests that isomerization of the product would not be a main reason for low
stereoselectivity, and the enhancing effect of the silver salt on stereoselectivity is not caused by
suppressing the isomerization of the initial products.
Table 11. Isomerization studies 1.
Entry Starting Material
Silver Salt
Conversion Rate (%)
1
2
3
4
(Z)-3e
(Z)-3e
(E)-3e
(E)-3e
Ag3PO4
2
2
15
6
-
Ag3PO4
-
1
Reaction conditions: (Z)- or (E)-3e (1.0 eq), Pd(PPh3)4 (10 mol %), CuI (5 mol %), PPh3 (30 mol %), NaOAc (3 eq),
with or without Ag3PO4 (1.1 eq), DMF (0.05 M), microwave irradiation, 150 ◦C, 10 min.
Based on all of the above results, we propose a mechanism for our domino MCRs and
isomerization (Scheme 2). The domino reaction begins with the Sonogashira reaction of propiolamide
1
with aryl iodide to afford adduct . The fact that the biphenyl byproduct was not detected under
2
4
microwave-assisted conditions demonstrates that the Sonogashira reaction is more favorable than the
Suzuki-Miyaura reaction between aryl iodide and arylboronic acid. In the second step, the bromo

Molecules 2017, 22, 503
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substituent of
2
reacts with Pd catalyst to produce vinyl palladium intermediate
I, the stereochemistry
of which would be the E-configuration due to the syn-addition mechanism of the migratory insertion
step [17]. Without the silver salt, isomerization of to IV probably occurred via a zwitterionic
palladium carbenoid intermediate II III 18 19]. This isomerization mechanism is supported by
I
/
[ ,
low stereoselectivity of the reaction with 2-methoxy- and 4-methoxyphenyl iodide. Both substrates
could have additional resonance structures (IIa or IIb), which increase the stability of II to facilitate
the isomerization rate between
of or IV with arylboronic acid to give product 3A or 3B, respectively. Addition of the silver salt
changes the catalytic pathway of the palladium-catalyzed reaction from neutral to cationic to give the
cationic vinyl palladium intermediate 16 20]. The cationic character on the palladium of decreases
the possibility of isomerization from to VI, probably due to the instability of the corresponding
zwitterionic palladium carbenoid species. Thus, 3A would mainly be obtained by Suzuki-Miyaura
reaction of . Another benefit achieved by the addition of silver salt is the enhancing effect on
I and IV. The last step of the reaction is a Suzuki-Miyaura reaction
I
V
[
,
V
V
V
reaction rate. We already discussed that the silver salt seems to facilitate the last Suzuki-Miyaura step
(Table 5). In addition, our previous work proved that the silver salt was an effective additive to also
increase the rate of Sonogashira reaction [
factors for the current domino MCRs.
9]. Thus, microwave irradiation and the silver salt are key
R2
R1
R2
Br
R1
Pd
Br
R1
(HO)2B
I
R1
Br
N
N
O
Heck
reaction
Suzuki-Miyaura
reaction
Sonogashira
reaction
O
O
Me
N
Me
O
R2
N
Me
2
1
Me
I
3A
with
Ag salt
without
Ag salt
(HO)2B
Suzuki-Miyaura
reaction
R1
R1
Br
Pd
Br
OMe
Pd
Pd
R1 = 4-MeO
R1
R1
Pd
Pd
O
Br
O
O
O
O
N
Me
N
N
N
N
Me
Me
Me
Me
III
V
II
R1 = 2-MeO
IIa
VI
MeO
Pd
R1
R1
R2
Br
(HO)2B
Pd
R2
Br
O
N
Me
IIb
Suzuki-Miyaura
reaction
O
O
N
Me
N
Me
3B
IV
Scheme 2. Proposed mechanisms of domino multicomponent reactions (MCRs) and isomerization.
3. Experimental Section
3.1. General Information
Microwave reactions were conducted in a Biotage Initiator+ microwave reactor (Biotage AB,
Uppsala, Sweden). The wattage was automatically adjusted to maintain the desired temperature
for the desired period of time. All reactions were performed under an argon atmosphere with
dry solvents, unless otherwise stated. Dry methylene chloride (CH2Cl2) tetrahydrofuran (THF)
and acetonitrile (CH3CN) were obtained from an Ultimate Solvent Purification System (JC Meyer
Solvent System, Laguna Beach, CA, USA). All commercially available reagents were purchased
and used without further purification. Reactions were monitored by thin-layer chromatography

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(TLC) on silica gel plates (Merck TLC Silica Gel 60 F254, Darmstadt, Germany) using UV light,
PMA (an ethanolic solution of phosphomolybdic acid) or ANIS (an ethanolic solution of p-anisaldehyde)
as visualizing agent. Purification of products was conducted by column chromatography through
silica gel 60 (0.060–0.200 mm). NMR spectra were obtained on Bruker AVANCE III 500 MHz
(Bruker Corporation, Billerica, MA, USA) using residual undeuterated solvent or tetramethylsilane
(TMS) as an internal reference. Stereochemistry of products was assigned by careful 1D- and 2D-NMR
studies (see supporting information). High-resolution mass spectra (HR-MS) were recorded on
an Agilent 6530 Q-TOF (Agilent, Santa Clara, CA, USA) using ESI (electrospray ionization) or a JEOL
JMS-700 (JEOL, Tokyo, Japan) using EI (electron impact) or FAB (fast atom bombardment).
3.2. Preparation of Substrates 1 and 6
N-(2-Bromophenyl)-N-methylpropiolamide (1) [21]: To a stirred suspension of NaH (44 mg, 60% in mineral oil,
1.1 mmol, 1.1 equiv.) in THF (5.0 mL) was added a ◦solution of N-(2-bromophenyl)propiolamide [
8]
(
6a, 224 mg, 1.0 mmol, 1.0 equiv.) in THF (5 mL) at 0 C. After 30 min stirring, MeI (0.08 mL, 1.3 mmol,
1.3 equiv.) was added dropwise at the same temperature. Then, the temperature was gradually raised
◦
◦
to 25 C. The mixture was stirred for 6 h at 25 C and diluted with sat. aq. NH4Cl (50 mL). The mixture
was extracted with EtOAc (50 mL 2). The combined organic layer was dried (Na2SO4), filtered,
×
and concentrated under reduced pressure. The crude residue was purified by column chromatography
(silica gel, hexanes−EtOAc 5:1) to yield N-methylpropiolamide 1 (212 mg, 89% yield) as an off-white
solid; m.p. = 73.2 ◦C (lit. [21] 88–89 ◦C); Rf = 0.32 (silica gel, hexanes
EtOAc 4:1); IR (film) 3221, 2107,
−
1646, 1372, 763 cm−1; 1H-NMR (CDCl3, 7:1 atropisomeric mixture, major peaks):
1.0 Hz, 1H), 7.41–7.21 (m, 3H), 3.25 (s, 3H), 2.73 (s, 1H) ppm; 13C-NMR (CDCl3):
δ
7.68 (dd, J = 8.0,
δ
153.3, 141.7, 133.9,
133.8, 130.5, 130.4, 129.9, 129.3, 128.9, 128.8, 123.8, 80.0, 78.9, 76.1, 39.0, 35.4 ppm; HRMS (ESI-TOF):
calcd. for C10H879BrNO [M + H+]: 237.9868, found 237.9872.
N-Benzyl-N-(2-bromophenyl)propiolamide (6b): To a stirred suspension of NaH (22 mg, 60% in mineral
oil, 0.54 mmol, 1.2 equiv.) and tetrabutylammonium iodide (TBAI, 33 mg, 0.89 mmol, 2.0 equiv.)
in DMF (2.0 mL) was added a solution of N-(2-bromophenyl)propiolamide [
8
] (6a, 100 mg, 0.45 mmol,
◦
1.0 equiv.) in DMF (5 mL) at 0 C. After 30 min stirring, BnBr (0.11 mL, 1.3 mmol, 2.0 equiv.) was added
dropwise at the same temperature. The mixture was stirred for additional 30 min at 0 ◦C and diluted
with Et2O (50 mL) and sat. aq. NH4Cl (1 mL). The organic layer was separated and washed with water
(10 mL
×
3). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure.
The crude residue was purified by column chromatography (silica gel, hexanes EtOAc 6:1) to yield
N-benzylpropiolamide 6b (92 mg, 65% yield) as a white solid; m.p. = 52.5 ◦C; Rf = 0.3 (silica gel,
−
1
hexanes
atropisomeric mixture, major peaks)
6.84 (dd, J = 12.9, 6.9 Hz, 1H), 5.58 (d, J = 14.3 Hz, 1H), 4.16 (d, J = 14.1 Hz, 1H), 2.73 (s, 1H) ppm;
−
EtOAc 5:1); IR (film) 3214, 3064, 2106, 1640, 722, 697, 697 cm−1; H-NMR (CDCl3, 7:1
δ
7.67 (dd, J = 7.8, 1.8 Hz, 1H), 7.28–7.26 (m, 3H), 7.24–7.19 (m, 4H),
13C-NMR (CDCl3)
δ 153.3, 139.7, 136.0, 133.7, 132.1, 130.4, 129.6, 128.9, 128.8, 128.7, 128.1, 128.0, 124.2,
79.2, 76.2, 51.2; HRMS (EI): calcd. for C16H1279BrNO [M+]: 313.0102, found 313.0099.
N-(2-Bromobenzyl)-N-methylpropiolamide (6c): To a stirred solution of commercially available
1-(2-bromophenyl)-N-methylmethanamine (565 mg, 2.8 mmol, 1.0 equiv.) and propiolic acid (0.21 mL,
◦
3.4 mmol, 1.2 equiv.) in CH2Cl2 (30 mL) was added DCC (700 mg, 3.4 mmol, 1.2 equiv.) at 0 C.
Then, the reaction temperature was raised to r.t. After 1.5 h, the reaction mixture was diluted with
CH2Cl2 (200 mL), and then washed with aq. 2N-HCl (5 mL) and sat. aq. NaHCO3 (20 mL). The organic
layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was
purified by column chromatography (silica gel, hexanes
an off-white solid; m.p. = 53.1 ◦C; Rf = 0.3 (silica gel, hexanes
2926, 2107, 1644, 1401 cm−1; 1H-NMR (CDCl3, 1.3:1 atropisomeric mixture):
−
EtOAc 3:1) to yield 6c (675 mg, 95% yield) as
EtOAc 2:1); IR (film) 3283, 3215, 3061,
= 7.59 (d, J = 8.0 Hz,
−
δ
1H, major), 7.56 (d, J = 8.0 Hz, 1H, minor), 7.35 (t, J = 7.5 Hz, 1H, major), 7.30 (t, J = 7.5 Hz, 1H, minor),
7.19 (t, J = 7.8 Hz, 2H, major), 7.16 (d, J = 7.8 Hz, 2H, minor), 4.91 (s, 2H, major), 4.75 (s, 2H, minor),

Molecules 2017, 22, 503
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3.09 (s, 1H, major), 3.20 (s, 1H, minor), 2.94 (s, 3H, major), 3.18 (s, 3H, minor), ppm; 13C-NMR (CDCl3):
δ = 154.4 (major), 154.2 (minor), 135.3 (major), 135.3 (minor), 133.5 (major), 133.3 (minor), 129.8 (major),
129.6 (minor), 129.5 (minor), 128.4 (major), 128.3 (major), 128.2 (minor), 80.0 (minor), 79.4 (major),
76.0 (minor), 75.9 (major), 54.9 (major), 50.0 (minor), 36.5 (minor), 32.7 (major) ppm; HRMS (EI): calcd. for
C23H18ClNO [M+]: 250.9946, found 250.9944.
2-Bromophenyl propiolate (6d): To a stirred solution of 2-bromophenol (124 mg, 0.717 mmol), propiolic
acid (0.665 mL, 1.08 mmol, 1.5 equiv.) and 4-(dimethylamino)pyridine (8.8 mg, 0.072 mmol, 0.1 equiv.)
in CH2Cl2 (3.5 mL) was added DCC (222 mg, 1.08 mmol, 1.5 equiv.) at 0 ◦C. After 30 min the reaction
mixture was diluted with CH2Cl2 (60 mL) and sat. aq. NaHCO3 (20 mL). The organic layer was
separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was
purified by column chromatography (silica gel, hexanes
as a colorless oil; Rf = 0.25 (silica gel, hexanes
EtOAc 20:1); IR (film) 3280, 1741, 1470, 1206, 752 cm−1
1H-NMR (CDCl3):
= 7.64 (dd, J = 7.8, 1.4 Hz, 1H), 7.37–7.34 (m, 1H), 7.19–7.16 (m, 2H), 3.14 (s, 1H) ppm;
−
EtOAc 20:1) to yield 6d (115 mg, 71% yield)
−
;
δ
13C-NMR (CDCl3):
δ = 150.1, 147.3, 133.7, 128.8, 128.3, 123.6, 115.9, 77.7, 73.9 ppm; HRMS (EI): calcd.
for C9H5BrO2 [M+]: 223.9473, found 223.9472.
3.3. General Procedure for Microwave-Assisted Reactions
A microwave reaction vial was charged with 1 or 6 (0.15 mmol, 1.0 equiv.), aryl iodide (0.17 mmol,
1.1 equiv.), aryl boronic acid (0.18 mmol, 1.2 equiv.), CuI (0.0075 mmol, 5 mol %), NaOAc (0.45 mmol,
3.0 equiv.), Pd(PPh3)4 (0.015 mmol, 10 mol %), Ag3PO4 (0.17 mmol, 1.1 equiv.) and DMF (3 mL).
The reaction vial was sealed and exposed to microwave irradiation conditions with indicated time
and temperature (150 ◦C, 10 min; representative conditions). The mixture was cooled to 25 ◦C and
diluted with EtOAc (100 mL). Organic layer was washed with H2O (20 mL
then dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified
×
3) and brine (20 mL),
by column chromatography (silica gel, hexane:EtOAc) to yield 3-(diarylmethylene)oxindoles 3 or 7.
◦
◦
3-(Diphenylmethylene)-1-methylindolin-2-one (3a) [22]: Yellow solid; m.p. = 165.9 C (lit. [22] 153.2–154.9 C);
Rf = 0.33 (silica gel, hexanes
EtOAc 4:1); IR (film) 3054, 2923, 1700, 1606, 1469 cm−1; 1H-NMR (CDCl3):
= 7.45 7.41 (m, 3H), 7.37–7.32 (m, 7H), 7.17 (td, J = 7.5, 1.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H),
−
δ
−
6.68 (td, J = 7.5, 1.0 Hz, 1H), 6.42 (dd, J = 7.5, 1.0 Hz, 1H), 3.21 (s, 3H) ppm; 13C-NMR (CDCl3):
δ = 167.0, 154.7, 143.5, 141.5, 140.1, 130.1, 129.5, 129.3, 129.2, 129.1, 128.9, 128.0, 124.4, 123.4, 123.3, 121.5,
107.8, 26.0 ppm; HRMS (ESI-TOF): calcd. for C22H17NO [M + H+]: 312.1388, found 312.1394.
3-(Bis(4-methoxyphenyl)methylene)-1-methylindolin-2-one (3b): Brown solid; m.p. = 192.2 ◦C; Rf = 0.2
(silica gel, hexanes δ = 7.29–7.24
EtOAc 4:1); IR (film) 3017, 1691, 1603, 1251 cm−1; 1H-NMR (CDCl3):
−
(m, 4H), 7.14 (td, J = 8.0, 1.5 Hz, 1H), 6.93 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 9.0 Hz, 2H), 6.77 (d, J = 8.0 Hz, 1H),
6.70 (td, J = 8.0, 1.5 Hz, 1H), 6.57 (dd, J = 7.5, 0.5 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.22 (s, 3H) ppm;
13C-NMR (CDCl3):
δ = 167.3, 161.0, 160.8, 155.1, 142.8, 133.9, 132.9, 132.4, 132.1, 128.0, 124.3, 122.7,
122.5, 121.3, 114.2, 113.2, 107.7, 55.5, 55.4, 26.0 ppm; HRMS (ESI-TOF): calcd. for C24H21NO3 [M + H+]
372.1600, found 372.1611.
:
◦
3-(Bis(4-chlorophenyl)methylene)-1-methylindolin-2-one (3c): Yellow solid; m.p. = 134.4 C; Rf = 0.33
(silica gel, hexanes
δ = 7.41 (dd, J = 7.0, 2.0 Hz, 2H), 7.33 (dd, J = 7.0, 2.0 Hz, 2H), 7.26–7.20 (m, 5H), 6.78 (d, J = 8.0 Hz, 1H),
6.73 (td, J = 7.5, 1.0 Hz, 1H), 6.52 (d, J = 7.5 Hz, 1H), 3.20 (s, 3H) ppm; 13C-NMR (CDCl3):
= 166.7,
−
EtOAc 4:1); IR (film) 3054, 2927, 1699, 1606, 1486, 1089 cm−1; 1H-NMR (CDCl3):
δ
151.4, 143.5, 139.3, 138.0, 135.7, 135.6, 131.7, 131.1, 129.5, 129.4, 128.3, 125.1, 123.2, 122.8, 121.7, 108.1,
26.0 ppm; HRMS (ESI-TOF): calcd. for C22H15Cl2NO [M + H+]: 380.0609, found 380.0612.
◦
3-(Bis(4-nitrophenyl)methylene)-1-methylindolin-2-one (3d): Brown solid; m.p. = 244.5 C; Rf = 0.21
1
(silica gel, hexanes
−
EtOAc 3:1); IR (film) 3073, 1703, 1601, 1517, 1486, 1344, 1098 cm−1; H-NMR
(CDCl3): δ = 8.34 (dd, J = 7.0, 2.0 Hz, 2H), 8.24 (dd, J = 7.0, 2.0 Hz, 2H), 7.56 (dd, J = 7.0, 2.0 Hz, 2H),
7.48 (dd, J = 7.0, 2.0 Hz, 2H), 7.29 (dd, J = 7.5, 1.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.76 (td, J = 8.0,

Molecules 2017, 22, 503
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1.0 Hz, 1H), 6.45 (d, J = 7.5, 1H), 3.20 (s, 3H) ppm; 13C-NMR (CDCl3):
δ
= 166.0, 148.4, 148.1, 147.1, 146.3,
145.6, 144.3, 130.9, 130.6, 130.4, 127.5, 124.8, 123.63, 123.61, 122.2, 121.4, 108.7, 26.1; HRMS (ESI-TOF):
calcd. for C22H15 N3O5 [M + H+]: 402.1092, found 402.1097.
◦
(E)-3-((4-Methoxyphenyl)(phenyl)methylene)-1-methylindolin-2-one ((E)-3e) [22]: Yellow solid; m.p. = 162.7 C
◦
(lit. [22] 163.8–164.3 C); Rf = 0.26 (silica gel, hexanes
−
EtOAc 4:1); IR (film) 3053, 2927, 1696, 1603, 1508,
= 7.39–7.25 (m, 7H), 7.17 (td, J = 7.5, 1.5 Hz, 1H), 6.93 (dd, J = 7.0,
2.0 Hz, 2H), 6.78–6.67 (m, 3H), 3.87 (s, 3H), 3.20 (s, 3H) ppm; 13C-NMR (CDCl3):
= 167.1, 160.8, 154.9,
1469, 1250 cm−1; 1H-NMR (CDCl3):
δ
δ
143.3, 140.6, 133.6, 132.7, 131.7, 130.5, 129.3, 129.0, 128.6, 127.9, 122.9, 121.4, 114.3, 107.8, 55.5, 26.0 ppm;
HRMS (ESI-TOF): calcd. for C23H19NO2 [M + H+]: 342.1494, found 342.1498.
◦
−1
(Z)-3-((4-Methoxyphenyl)(phenyl)methylene)-1-methylindolin-2-one ((Z)-3e) [23]: Yellow solid; m.p. = 153.0 C
◦
(lit. [23] 163.8–164.3 C); Rf = 0.24 (silica gel, hexanes
−
EtOAc 4:1); IR (film) 2931, 1696, 1604, 1250 cm
;
,
1H-NMR (CDCl3):
δ
= 7.46–7.40 (m, 3H), 7.32–7.29 (m, 4H), 7.15 (t, J = 13.0 Hz, 1H), 6.88 (dd, J = 7.0
2.0 Hz, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.66 (t, J = 7.5 Hz, 1H), 6.32 (d, J = 7.5 Hz, 1H), 3.84 (s, 3H),
3.23 (s, 3H); 13C-NMR (CDCl3):
δ = 167.1, 161.0, 154.9, 143.0, 141.7, 132.7, 131.9, 129.9, 129.3, 129.0,
128.4, 123.9, 123.0, 121.4, 113.2, 107.7, 55.4, 26.0 ppm; HRMS (ESI-TOF): calcd. for C23H19NO2 [M + H+]
342.1494, found 342.1503.
:
◦
(E)-3-((4-Chlorophenyl)(phenyl)methylene)-1-methylindolin-2-one ((E)-3f): Yellow solid; m.p. = 54.8 C;
1
Rf = 0.35 (silica gel, hexanes
−
EtOAc 4:1); H-NMR (CDCl3):
δ
= 7.41–7.18 (m, 9H), 7.19 (td, J = 7.5
,
1.0 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.73 (td, J = 7.5, 1.0 Hz, 1H), 6.53 (dd, J = 7.5, 0.5 Hz, 1H),
3.20 (s, 3H) ppm; δ = 166.8, 153.0, 143.6, 139.8, 139.7, 135.5, 131.1, 130.2, 129.42,
13C-NMR (CDCl3):
129.37, 129.2, 128.1, 124.7, 123.2, 123.0, 121.6, 108.0, 26.0 ppm; HRMS (EI): calcd. for C22H16ClNO [M+]:
345.0920, found 345.0919.
(Z)-3-((4-Chlorophenyl)(phenyl)methylene)-1-methylindolin-2-one ((Z)-3f): Yellow solid; m.p. = 59.0 ◦C:
Rf = 0.37 (silica gel, hexanes
−
EtOAc 4:1); IR (film) 3054, 1698, 1606, 1486, 1335, 1090 cm−1
;
1H-NMR (CDCl3):
δ
= 7.48–7.43 (m, 3H), 7.35–7.27 (m, 6H), 7.17 (td, J = 7.5, 1.0 Hz, 1H),
6.77 (d, J = 8.0 Hz, 1H), 6.68 (td, J = 7.5, 1.0 Hz, 1H), 6.42 (dd, J = 7.5, 0.5 Hz, 1H), 3.20 (s, 3H) ppm;
13C-NMR (CDCl3): δ = 166.9, 153.0, 143.5, 141.0, 138.4, 135.3, 131.6, 129.51, 129.50, 129.2, 129.1,
128.2, 124.7, 123.4, 123.2, 121.6, 107.9, 26.0 ppm; HRMS (EI): calcd. for C22H16ClNO [M+]: 345.0920,
found 345.0916.
(E)-1-Methyl-3-((4-nitrophenyl)(phenyl)methylene)indolin-2-one ((E)-3g) [22]: Yellow solid; m.p. = 201.2 ◦C
(lit. [22] 198.8–200.8 ◦C); Rf = 0.25 (silica gel, hexanes
−
EtOAc 4:1); IR (film) 3056, 1701, 1604, 1519,
1
1469, 1345 cm−1; H-NMR (CDCl3):
δ = 8.30 (t, J = 4.25 Hz, 2H), 7.54 (d, J = 9.0 Hz, 2H), 7.41–7.21
(m, 6H), 6.80 (d, J = 8.0 Hz, 1H), 6.71 (t, J = 7.75 Hz, 1H), 6.36 (d, J = 7.5 Hz, 1H), 3.21 (s, 3H) ppm;
13C-NMR (CDCl3):
δ = 166.4, 150.9, 148.2, 147.9, 143.9, 138.8, 130.6, 130.0, 129.9, 129.7, 128.3, 125.7, 124.4,
123.3, 122.4, 121.8, 108.3, 26.1 ppm; HRMS (EI): calcd. for C22H16N2O3 [M+]: 356.1161, found 356.1161.
(Z)-1-Methyl-3-((4-nitrophenyl)(phenyl)methylene)indolin-2-one ((Z)-3g): Yellow solid; m.p. = 186.6 ◦C;
Rf = 0.28 (silica gel, hexanes
= 8.22 (dd, J = 7.0, 1.5 Hz, 2H), 7.50–7.44 (m, 5H), 7.32 (dd, J = 8.0, 2.0 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H),
6.80 (d, J = 8.0 Hz, 1H), 6.73 (t, J = 7.75 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 3.20 (s, 3H) ppm; 13C-NMR
−
EtOAc 4:1); IR (film) 3057, 1699, 1603, 1510, 1342 cm−1; 1H-NMR (CDCl3):
δ
(CDCl3):
δ = 166.6, 150.8, 147.8, 147.0, 143.9, 140.0, 130.7, 129.9, 129.8, 129.4, 129.2, 126.1, 123.7,
123.4, 122.4, 121.9, 108.2, 26.0 ppm; HRMS (ESI-TOF): calcd. for C22H16N2O3 [M + H+]: 357.1239,
found 357.1249.
◦
(E)-4-((1-Methyl-2-oxoindolin-3-ylidene)(phenyl)methyl)phenyl acetate ((E)-3h): Yellow solid; m.p. = 137.0 C;
Rf = 0.28 (silica gel, hexanes
= 7.39–7.36 (m, 3H), 7.35–7.34 (m, 2H), 7.33–7.31 (m, 2H), 7.20–7.19 (m, 1H), 7.18–7.16 (m, 2H),
6.77 (d, J = 7.8 Hz, 1H), 6.71 (td, J = 7.7, 0.8 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 3.20 (s, 3H), 2.34 (s, 3H) ppm;
13C-NMR (CDCl3):
= 169.2, 166.9, 153.6, 151.5, 143.5, 139.9, 138.7, 130.9, 130.2, 129.3, 129.0, 128.0, 124.6,
−
EtOAc 4:1); IR (film) 3053, 2925, 1700, 1605, 1195 cm−1; 1H-NMR (CDCl3):
δ
δ

Molecules 2017, 22, 503
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123.22, 123.20, 122.2, 121.6, 107.9, 26.0, 21.4 ppm; HRMS (EI): calcd. for C24H19NO3 [M+]: 369.1365,
found 369.1366.
◦
(Z)-4-((1-Methyl-2-oxoindolin-3-ylidene)(phenyl)methyl)phenyl acetate ((Z)-3h): Yellow solid; m.p. = 134.8 C;
Rf = 0.20 (silica gel, hexanes
(CDCl3): = 7.46–7.41 (m, 3H), 7.37–7.35 (m, 2H), 7.32–7.30 (m, 2H), 7.16 (td, J = 7.7, 1.0 Hz, 1H),
7.11–7.08 (m, 2H), 6.77 (d, J = 7.7 Hz, 1H), 6.67 (td, J = 7.7, 0.8 Hz, 1H), 6.38 (d, J = 7.6 Hz, 1H),
3.21 (s, 3H), 2.30 (s, 3H) ppm; 13C-NMR (CDCl3):
= 169.3, 166.9, 153.7, 151.5, 143.4, 141.2, 137.2, 131.7,
−
EtOAc 4:1); IR (film) 3053, 2928, 1768, 1605, 1197, 1094 cm−1; 1H-NMR
δ
δ
129.6, 129.4, 129.1, 128.9, 124.5, 123.4, 123.3, 121.6, 121.0, 107.8, 26.0, 21.4 ppm; HRMS (EI): calcd. for
C24H19NO3 [M+]: 369.1365, found 369.1366.
(E)-3-((3-Methoxyphenyl)(phenyl)methylene)-1-methylindolin-2-one ((E)-3i): Yellow solid; m.p. = 53.0 ◦C;
Rf = 0.26 (silica gel, hexanes
1H-NMR (CDCl3):
= 7.37–7.33 (m, 6H), 7.16 (td, J = 7.7, 1.1 Hz, 1H), 6.98 (ddd, J = 8.3, 2.6, 0.9 Hz, 1H),
6.77 (dt, J = 9.9, 1.9 Hz, 1H), 6.84 (dd, J = 2.5, 1.6 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.69 (td, J = 7.7, 1.0 Hz, 1H),
6.48 (d, J = 7.3 Hz, 1H), 3.77 (s, 3H), 3.20 (s, 3H) ppm; 13C-NMR (CDCl3):
= 166.9, 160.1, 154.4, 143.5,
−
EtOAc 4:1); IR (film) 3287, 3055, 2937, 1700, 1604, 1469, 1094, 698 cm−1
;
δ
δ
142.7, 139.9, 130.2, 130.0, 129.2, 128.9, 128.0, 124.4, 123.5, 123.3, 121.7, 121.6, 115.0, 114.5, 107.8, 55.5,
26.0 ppm; HRMS (EI): calcd. for C23H19NO2 [M+]: 341.1416, found 341.1417.
(Z)-3-((3-Methoxyphenyl)(phenyl)methylene)-1-methylindolin-2-one ((Z)-3i): Yellow solid; m.p. = 118.2 ◦C;
Rf = 0.21 (silica gel, hexanes
−
EtOAc 4:1); IR (film) 3535, 3055, 2927, 2214, 1700, 1604, 1096,
= 7.43–7.41 (m, 3H), 7.33–7.29 (m, 3H), 7.15 (td, J = 7.7, 1.0 Hz,
1
734 cm−1; H-NMR (CDCl3):
δ
1H), 6.95 (d, J = 7.8 Hz, 1H), 6.91 (dd, J = 8.3, 1.9 Hz, 1H), 6.83 (t, J = 1.9 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H),
6.66 (td, J = 7.7, 1.0 Hz, 1H), 6.42 (d, J = 7.6 Hz, 1H), 3.76 (s, 3H), 3.20 (s, 3H) ppm; 13C-NMR (CDCl3):
δ = 166.8, 159.3, 154.3, 143.5, 141.5, 141.3, 129.31, 129.27, 129.1, 128.94, 128.93, 124.5, 123.3, 122.5, 121.5,
115.7, 114.4, 107.8, 55.4, 26.0 ppm; HRMS (EI): calcd. for C23H19NO2 [M+]: 341.1416, found 341.1422.
(E)-3-((3-Chlorophenyl)(phenyl)methylene)-1-methylindolin-2-one ((E)-3j): Yellow solid; m.p. = 130.2 ◦C;
Rf = 0.25 (silica gel, hexanes
= 7.44–7.41 (m, 1H), 7.39–7.35 (m, 4H), 7.34–7.31 (m, 3H), 7.23 (dt, J = 9.8, 1.9 Hz, 1H), 7.18 (td, J = 7.7
1.1 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.71 (td, J = 7.7, 0.7 Hz, 1H), 6.44 (d, J = 7.7 Hz, 1H), 3.20 (s, 3H) ppm;
−
EtOAc 4:1); IR (film) 3055, 3016, 1699, 1470, 1095 cm−1; 1H-NMR (CDCl3):
δ
,
13C-NMR (CDCl3):
δ = 166.7, 152.5, 143.6, 143.1, 139.4, 135.1, 130.4, 130.0, 129.4, 129.34, 129.30, 128.1,
127.6, 125.0, 123.3, 122.9, 121.7, 108.0, 26.0 ppm; HRMS (EI): calcd. for C22H16ClNO [M+]: 345.0920,
found 345.0920.
(Z)-3-((3-Chlorophenyl)(phenyl)methylene)-1-methylindolin-2-one ((Z)-3j): Yellow solid; m.p. = 143.2 ◦C;
Rf = 0.31 (silica gel, hexanes
(CDCl3): = 7.47–7.43 (m, 3H), 7.34–7.29 (m, 4H), 7.28–7.26 (m, 2H), 7.18 (td, J = 7.7, 1.1 Hz, 1H),
6.78 (d, J = 7.7 Hz, 1H), 6.68 (td, J = 7.7, 1.1 Hz, 1H), 6.44 (d, J = 7.7 Hz, 1H), 3.21 (s, 3H) ppm; 13C-NMR
−
EtOAc 4:1); IR (film) 3055, 3016, 1699, 1607, 1470, 1098 cm−1; 1H-NMR
δ
(CDCl3):
δ = 166.7, 152.4, 143.6, 141.9, 140.7, 134.0, 129.8, 129.5, 129.3, 129.28, 129.21, 129.1, 129.0,
128.2, 125.1, 123.4, 122.9, 121.6, 107.9, 26.0 ppm; HRMS (EI): calcd. for C22H16ClNO [M+]: 345.0920,
found 345.0918.
◦
(E)-1-Methyl-3-((3-nitrophenyl)(phenyl)methylene)indolin-2-one ((E)-3k): Yellow solid; m.p. = 186.9 C;
Rf = 0.32 (silica gel, hexanes
−
EtOAc 2:1); IR (film) 3055, 3017, 1699, 1528, 1350, 1096 cm−1
;
1H-NMR (CDCl3):
δ
= 8.33–8.30 (m, 1H), 8.19 (t, J = 1.9 Hz, 1H), 7.71 (dt, J = 10.3, 1.9 Hz,
1H), 7.64 (t, J = 7.9 Hz, 1H), 7.41–7.38 (m, 3H), 7.32–7.30 (m, 2H), 7.20 (td, J = 7.7, 1.1 Hz, 1H),
6.80 (d, J = 7.8 Hz, 1H), 6.67 (td, J = 7.7, 1.0 Hz, 1H), 6.32 (d, J = 7.7 Hz, 1H), 3.21 (s, 3H) ppm; 13C-NMR
(CDCl3):
δ = 166.4, 150.7, 148.9, 143.9, 143.0, 138.9, 135.6, 130.3, 130.0, 129.8, 129.7, 128.3, 125.8,
124.5, 124.0, 123.0, 122.4, 121.8, 108.3, 26.1 ppm; HRMS (EI): calcd. for C22H16N2O3 [M+]: 356.1161,
found 356.1159.
(Z)-1-Methyl-3-((3-nitrophenyl)(phenyl)methylene)indolin-2-one ((Z)-3k): Yellow solid; m.p. = 168.1 ◦C;
Rf = 0.28 (silica gel, hexanes
EtOAc 3:1); IR (film) 3055, 3017, 1698, 1527, 1348, 1094 cm−1; 1H-NMR
−

Molecules 2017, 22, 503
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(CDCl3):
1H), 7.49–7.45 (m, 3H), 7.34–7.32 (m, 2H), 7.20 (td, J = 7.7, 0.9 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H),
6.70 (td, J = 7.7, 0.7 Hz, 1H), 6.49 (d, J = 7.7 Hz, 1H), 3.20 (s, 3H) ppm; 13C-NMR (CDCl3):
= 166.6,
δ = 8.23–8.21 (m, 1H), 8.17–8.16 (m, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.53 (t, J = 8.0 Hz,
δ
150.6, 148.2, 143.8, 141.7, 140.1, 136.1, 129.84, 129.80, 129.5, 129.3, 128.9, 126.0, 125.0, 123.7, 123.6, 122.5,
121.9, 108.1, 26.1 ppm; HRMS (EI): calcd. for C22H16N2O3 [M+]: 356.1161, found 356.1159.
(E)-3-((2-Methoxyphenyl)(phenyl)methylene)-1-methylindolin-2-one ((E)-3l): Yellow solid; m.p. = 188.5 ◦C;
1
Rf = 0.33 (silica gel, hexanes
(CDCl3):
7.05 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.69 (t, J = 7.7 Hz, 1H),
6.23 (d, J = 7.8 Hz, 1H), 3.63 (s, 3H), 3.19 (s, 3H) ppm; 13C-NMR (CDCl3):
= 166.7, 156.4, 151.4, 143.4,
−
EtOAc 4:1); IR (film) 2918, 2849, 1701, 1604, 1094 cm−1; H-NMR
= 7.44–7.40 (m, 3H), 7.36–7.32 (m, 3H), 7.21 (dd, J = 7.5, 1.5 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H),
δ
δ
139.7, 130.5, 130.3, 129.6, 129.2, 128.7, 128.5, 127.6, 125.0, 123.5, 123.0, 121.7, 121.5, 112.2, 107.6, 55.9,
25.9 ppm; HRMS (EI): calcd. for C23H19NO2 [M+]: 341.1416, found 341.1419.
(Z)-3-((2-Methoxyphenyl)(phenyl)methylene)-1-methylindolin-2-one ((Z)-3l): Yellow solid; m.p. = 139.3 ◦C;
Rf = 0.24 (silica gel, hexanes
1H-NMR (CDCl3):
= 7.40 (s, 5H), 7.34–7.31 (m, 1H), 7.19–7.14 (m, 2H), 6.97 (td, J = 7.5, 0.8 Hz, 1H),
6.93 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 7.7 Hz, 1H), 6.68 (td, J = 7.7, 0.9 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H),
3.70 (s, 3H), 3.17 (s, 3H) ppm; 13C-NMR (CDCl3):
= 166.8, 156.7, 150.6, 143.6, 140.9, 130.4, 129.7, 129.6,
−
EtOAc 4:1); IR (film) 3053, 2925, 2854, 1704, 1606, 1469, 1095 cm−1
;
δ
δ
128.9, 128.8, 128.7, 128.6, 125.5, 123.3, 122.8, 121.4, 120.7, 111.4, 107.7, 55.8, 25.9 ppm; HRMS (EI): calcd.
for C23H19NO2 [M+]: 341.1416, found 341.1419.
(E)-3-((2-Chlorophenyl)(phenyl)methylene)-1-methylindolin-2-one ((E)-3m): Yellow solid; m.p. = 164.6 ◦C;
Rf = 0.33 (silica gel, hexanes
= 7.53–7.51 (m, 1H), 7.49–7.47 (m, 2H), 7.41–7.36 (m, 5H), 7.34–7.32 (m, 1H), 7.18 (td, J = 7.7, 1.1 Hz,
1H), 6.77 (d, J = 7.7 Hz, 1H), 6.69 (td, J = 7.7, 1.0 Hz, 1H), 6.04 (d, J = 7.7 Hz, 1H), 3.21 (s, 3H) ppm;
−
EtOAc 4:1); IR (film) 3053, 2918, 1703, 1605, 1095 cm−1; 1H-NMR (CDCl3):
δ
13C-NMR (CDCl3):
δ = 166.4, 150.1, 143.6, 140.0, 137.9, 132.5, 130.7, 130.0, 129.9, 129.7, 129.3, 129.1,
127.8, 125.7, 123.1, 123.0, 122.0, 107.9, 26.0 ppm; HRMS (EI): calcd. for C22H16ClNO [M+]: 345.0920,
found 345.0921.
(Z)-3-((2-Chlorophenyl)(phenyl)methylene)-1-methylindolin-2-one ((Z)-3m): Yellow solid; m.p. = 199.5 ◦C;
Rf = 0.34 (silica gel, hexanes
(CDCl3): = 7.49–7.43 (m, 6H), 7.32–7.29 (m, 2H), 7.25–7.21 (m, 2H), 6.79 (d, J = 7.8 Hz, 1H),
6.75 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 7.7 Hz, 1H), 3.19 (s, 3H) ppm; 13C-NMR (CDCl3):
= 166.6, 149.3,
−
EtOAc 4:1); IR (film) 3054, 3017, 2931, 1706, 1606, 1099 cm−1; 1H-NMR
δ
δ
144.0, 140.1, 139.4, 132.3, 129.8, 129.6, 129.4, 129.3, 129.2, 129.0, 128.9, 127.1, 126.4, 123.5, 122.1, 121.6,
108.0, 26.0 ppm; HRMS (EI): calcd. for C22H16ClNO [M+]: 345.0920, found 345.0920.
◦
(Z)-1-Methyl-3-((2-nitrophenyl)(phenyl)methylene)indolin-2-one ((Z)-3n): Yellow solid; m.p. = 206.6 C;
Rf = 0.27 (silica gel, hexanes
EtOAc 2:1); IR (film) 3063, 3021, 2930, 1700, 1522 cm−1; 1H-NMR (CDCl3):
−
δ
= 8.15 (dd, J = 8.2, 1.0 Hz, 1H), 7.66 (td, J = 7.6, 1.1 Hz, 1H), 7.54–7.51 (m, 2H), 7.43–7.40 (m, 5H),
7.24–7.21 (m, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.75–6.74 (m, 2H), 3.15 (s, 3H) ppm; 13C-NMR (CDCl3):
δ = 166.8, 148.4, 147.7, 143.9, 138.1, 136.9, 133.7, 130.7, 129.7, 129.6, 129.0, 128.9, 125.2, 125.0, 123.4, 122.0,
121.8, 108.1, 26.0 ppm; HRMS (EI): calcd. for C22H16N2O3 [M+]: 356.1161, found 356.1163.
◦
(E)-1-Methyl-3-(phenyl(pyridin-3-yl)methylene)indolin-2-one ((E)-3p): Yellow solid; m.p. = 159.0 C;
Rf = 0.24 (silica gel, hexanes
1H-NMR (CDCl3):
= 8.73 (brs, 2H), 7.62 (d, J = 7.8 Hz, 1H), 7.42–7.36 (m, 4H), 7.33–7.30 (m, 2H),
7.19 (td, J = 7.7, 1.1 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.70 (td, J = 7.7, 1.0 Hz, 1H), 6.42 (d, J = 7.5 Hz, 1H),
−
EtOAc 2:1); IR (film) 3732, 3052, 2926, 1700, 1470, 1095, 749, 698 cm−1
;
δ
3.21 (s, 3H) ppm; 13C-NMR (CDCl3):
δ = 166.5, 150.3, 150.0, 143.7, 139.4, 137.2, 130.1, 129.5, 129.5,
128.2, 125.7, 123.0, 122.8, 121.8, 108.1, 26.0 ppm; HRMS (EI): calcd. for C21H16N2O [M+]: 312.1263,
found 312.1262.
(Z)-1-Methyl-3-(phenyl(pyridin-3-yl)methylene)indolin-2-one ((Z)-3p): Yellow oil; Rf = 0.12 (silica gel,
hexanes δ = 8.58 (d, J = 17.9 Hz, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.48–7.44
EtOAc 2:1); 1H-NMR (CDCl3):
−

Molecules 2017, 22, 503
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(m, 3H), 7.33–7.31 (m, 3H), 7.19 (td, J = 7.7, 1.1 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.69 (td, J = 7.7, 1.0 Hz, 1H),
6.47 (d, J = 7.7 Hz, 1H), 3.21 (s, 3H) ppm; 13C-NMR (CDCl3):
= 166.9, 149.9, 143.7, 140.5, 137.4, 130.1,
δ
129.7, 129.5, 129.4, 129.3, 125.6, 123.5, 122.8, 121.7, 108.0, 26.1 ppm: HRMS (FAB): calcd. for C21H17N2O
[M + H+]: 313.1341, found 313.1342.
(E)-3-(Benzo[b]thiophen-3-yl(phenyl)methylene)-1-methylindolin-2-one ((E)-3q): Yellow solid; m.p. = 82.3 ◦C;
Rf = 0.24 (silica gel, hexanes
(CDCl3): = 7.93 (d, J = 8.1 Hz, 1H), 7.46–7.43 (m, 4H), 7.38–7.35 (m, 4H), 7.24 (t, J = 7.7 Hz, 1H),
7.14 (t, J = 7.7 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 6.60 (t, J = 7.7 Hz, 1H), 6.21 (d, J = 7.7 Hz, 1H),
3.23 (s, 3H) ppm = 166.7, 147.4, 143.4, 140.5, 139.2, 137.1, 130.0, 129.5, 129.4,
13C-NMR (CDCl3):
−
EtOAc 4:1); IR (film) 3055, 3010, 2929, 1698, 1606, 1094 cm−1; 1H-NMR
δ
;
δ
129.0, 128.0, 127.7, 125.9, 125.0, 124.9, 123.6, 123.1, 123.0, 121.8, 107.8, 26.0 ppm; HRMS (EI): calcd. for
C24H17NOS [M+]: 367.1031, found 367.1033.
◦
(Z)-3-(Benzo[b]thiophen-3-yl(phenyl)methylene)-1-methylindolin-2-one ((Z)-3q): Yellow solid; m.p. = 74.5 C;
Rf = 0.29 (silica gel, hexanes
= 7.86 (d, J = 8.1 Hz, 1H), 7.48–7.41 (m, 7H), 7.33–7.30 (m, 1H), 7.25–7.20 (m, 2H), 6.80 (d, J = 7.8 Hz, 1H),
6.72 (td, J = 7.7, 1.0 Hz, 1H), 6.66 (d, J = 7.1 Hz, 1H), 3.19 (s, 3H) ppm; 13C-NMR (CDCl3):
= 166.6,
−
EtOAc 4:1); IR (film) 3026, 2920, 1701, 1089, 750 cm−1; 1H-NMR (CDCl3):
δ
δ
146.8, 143.6, 140.5, 140.0, 138.1, 136.4, 129.6, 129.4, 129.2, 129.1, 128.3, 126.1, 124.5, 124.4, 123.4, 123.0,
122.9, 122.8, 121.5, 107.9, 26.1 ppm; HRMS (EI): calcd. for C24H17NOS [M+]: 367.1031, found 367.1027.
◦
(E)-3-(Benzo[b]thiophen-2-yl(phenyl)methylene)-1-methylindolin-2-one ((E)-3r): Yellow solid; m.p. = 173.7 C;
Rf = 0.27 (silica gel, hexanes:
−
EtOAc 4:1); IR (film) 3732, 3627, 2925, 2854, 1699, 1094, 747, 695 cm−1
;
,
1H-NMR (CDCl3):
δ
= 7.84–7.79 (m, 2H), 7.50 (d, J = 0.4 Hz, 1H), 7.44–7.37 (m, 7H), 7.20 (td, J = 7.7
1.2 Hz, 1H), 7.08 (dd, J = 7.8, 0.5 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 6.73 (td, J = 7.7, 1.0 Hz, 1H),
3.20 (s, 3H) ppm = 166.6, 146.3, 143.7, 143.2, 141.8, 139.7, 139.6, 130.0, 129.7, 129.6,
13C-NMR (CDCl3):
;
δ
128.1, 126.4, 126.1, 125.5, 124.9, 124.6, 123.5, 122.9, 122.7, 121.8, 108.0, 26.1 ppm; HRMS (EI): calcd. for
C24H17NOS [M+]: 367.1031, found 367.1035.
◦
(Z)-3-(Benzo[b]thiophen-2-yl(phenyl)methylene)-1-methylindolin-2-one ((Z)-3r): Yellow solid; m.p. = 160.7 C;
Rf = 0.39 (silica gel, hexanes
−
EtOAc 4:1); IR (film) 3733, 3054, 2926, 1694, 1470 1419, 1373, 1092, 745,
698 cm−1; 1H-NMR (CDCl3):
δ
= 7.77–7.75 (m, 3H), 7.55–7.48 (m, 3H), 7.41–7.38 (m, 2H), 7.33–7.31 (m, 2H)
,
7.14 (td, J = 7.7, 1.1 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 6.62 (td, J = 7.7, 1.0 Hz, 1H), 5.97 (dd, J = 7.7, 0.5 Hz, 1H),
3.28 (s, 3H) ppm; 13C-NMR (CDCl3):
= 166.6, 146.1, 143.2, 142.5, 141.6, 141.4, 139.2, 130.4, 129.5, 129.3,
δ
129.3, 129.0 125.7, 124.8, 124.7, 124.4, 123.9, 123.6, 122.2, 121.6, 107.8, 26.1 ppm; HRMS (EI): calcd. for
C24H17NOS [M+]: 367.1031, found 367.1035.
(E)-3-(Furan-3-yl(phenyl)methylene)-1-methylindolin-2-one ((E)-3s): Yellow solid; m.p. = 122.9; Rf = 0.20
(silica gel, hexanes
δ = 7.53 (t, J = 1.7 Hz, 1H), 7.40–7.34 (m, 7H), 7.21 (td, J = 7.7, 1.1 Hz, 1H), 6.85 (td, J = 7.7, 1.1 Hz, 1H),
6.79 (d, J = 7.7 Hz, 1H), 6.54 (dd, J = 1.8, 0.8 Hz, 1H), 3.18 (s, 3H) ppm; 13C-NMR (CDCl3):
= 166.9,
−
EtOAc 4:1); IR (film) 3137, 3052, 2928, 1606, 1093, 740 cm−1; 1H-NMR (CDCl3):
δ
145.2, 144.7, 143.6, 143.4, 140.2, 130.2, 129.4, 128.9, 128.0, 126.8, 124.0, 123.2, 123.1, 121.5, 111.9, 107.9,
26.0 ppm; HRMS (EI): calcd. for C20H15NO2 [M+]: 301.1103, found 301.1104.
(Z)-3-(Furan-3-yl(phenyl)methylene)-1-methylindolin-2-one ((Z)-3s): Yellow solid; m.p. = 132.5; Rf = 0.37
(silica gel, hexanes
EtOAc 4:1); IR (film) 3139, 3053, 2927, 1692, 1099, 733 cm−1; 1H-NMR (CDCl3):
−
δ = 7.73–7.72 (m, 1H), 7.50–7.47 (m, 3H), 7.40 (t, J = 1.7 Hz, 1H), 7.32–7.31 (m, 2H), 7.10 (td, J = 7.7, 1.1 Hz, 1H),
6.87 (dd, J = 1.9, 0.8 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H), 6.59 (td, J = 7.7, 1.1 Hz, 1H), 3.28 (s, 3H) ppm;
13C-NMR (CDCl3):
δ
= 166.9, 148.0, 144.8, 142.8, 142.1, 141.4, 129.2, 129.1, 129.0, 128.2, 125.7, 123.9, 123.5,
122.9, 121.4, 113.1, 107.6, 26.1 ppm; HRMS (EI): calcd. for C20H15NO2 [M+]: 301.1103, found 301.1102.
0
0
◦
◦
4,4 -Dinitro-1,1 -biphenyl (4d) [24]: Yellow solid; m.p. = 235.7 C (lit. [24] 235–237 C); Rf = 0.31 (silica gel,
1
hexanes
−
EtOAc 4:1); H-NMR (CDCl3):
δ
= 8.36 (d, J = 8.3 Hz, 4H), 7.79 (d, J = 8.3 Hz, 4H) ppm;
13C-NMR (CDCl3): δ = 148.2, 145.1, 128.5, 124.5 ppm.

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4-Methoxy-1,10-biphenyl (4e) [25]: White solid, m.p. = 86.1 ◦C (lit. [25] 86–88 ◦C); Rf = 0.36 (silica gel,
hexanes δ = 7.57–7.52 (m, 4H), 7.44–7.41 (m, 2H), 7.33–7.30 (m, 1H),
EtOAc 10:1); 1H-NMR (CDCl3):
−
7.00–6.97 (m, 2H), 3.86 (s, 3H) ppm; 13C-NMR (CDCl3):
114.3, 55.5 ppm.
δ = 159.2, 140.9, 133.9, 128.9, 128.3, 126.9, 126.8,
◦
◦
4-Chloro-1,1
hexane); H-NMR (CDCl3):
(m, 2H), 7.38–7.34 (m, 1H) ppm; 13C-NMR (CDCl3):
127.1 ppm.
'
-biphenyl (4f) [26]: White solid, m.p. = 69.8 C (lit. [26] 71–73 C); Rf = 0.46 (silica gel,
1
δ = 7.56–7.54 (m, 2H), 7.53–7.50 (m, 2H), 7.46–7.43 (m, 2H), 7.42–7.39
δ = 140.2, 139.8, 133.5, 129.1, 129.0, 128.5, 127.7,
0
◦
◦
4-Nitro-1,1 -biphenyl (4g) [27]: Pale yellow solid; m.p. = 112.8 C (lit. [27] 112–113 C); Rf = 0.36 (silica gel,
hexanes δ = 8.32–8.29 (m, 2H), 7.76–7.73 (m, 2H), 7.64–7.62 (m, 2H),
EtOAc 10:1); 1H-NMR (CDCl3):
7.52–7.49 (m, 2H), 7.47–7.44 (m, 1H) ppm; 13C-NMR (CDCl3):
127.5, 124.3 ppm.
−
δ = 147.8, 147.2, 138.9, 129.3, 129.1, 127.9,
9-Methyl-4-phenylpyrano[2,3-b]indol-2(9H)-one (
hexanes
EtOAc 4:1); IR (film) 3055, 2924, 2853, 1732, 1527, 1470 cm−1; 1H-NMR (CDCl3): 7.65–7.64
(m, 2H), 7.57–7.54 (m, 3H), 7.35 (dd, J = 13.7, 8.1 Hz, 2H), 7.28 (td, J = 7.7, 1.1 Hz, 1H), 7.12–7.09 (m, 1H)
5
): Yellow solid; m.p. = 146.2 ◦C; Rf = 0.44 (silica gel,
−
,
5.91 (s, 1H), 3.85 (s, 3H) ppm; 13C-NMR (CDCl3):
123.3, 122.0, 121.0, 120.2, 109.7, 101.4, 95.1, 28.3 ppm; HRMS (EI): calcd. for C18H13NO2 [M+]: 275.0946,
found 275.0948.
δ = 161.0, 157.2, 153.2, 136.9, 134.4, 130.1, 128.9, 128.0,
◦
(E)-3-((4-Chlorophenyl)(phenyl)methylene)indolin-2-one ((E)-7a): Dark orange solid; m.p. = 83.5 C;
Rf = 0.31 (silica gel, hexanes
−
EtOAc 3:2); IR (film) 32,436, 2954, 2923, 2851, 1698, 1615, 1465 cm−1
;
,
1H-NMR (CDCl3):
δ
= 8.60 (brs, 1H), 7.46–7.26 (m, 9H), 7.07 (td, J = 7.7, 1.0 Hz, 1H), 6.70–6.61 (m, 2H)
6.47 (d, J = 7.8 Hz, 1H) ppm; 13C-NMR (CDCl3): 153.6, 140.6, 139.8, 139.5, 135.6, 131.2, 130.5, 129.6,
129.4, 129.2, 128.1, 124.8, 123.9, 123.4, 121.6, 109.6 ppm; HRMS (EI): calcd. for C23H18ClNO [M+]:
331.0764, found 331.0762.
(Z)-3-((4-Chlorophenyl)(phenyl)methylene)indolin-2-one one ((Z)-7a): Yellow solid; m.p. = 214.8 ◦C;
Rf = 0.26 (silica gel, hexanes ;
EtOAc 2:1); IR (film) 3247, 2953, 2923, 2853, 1732, 1699, 1485 cm−1
−
1H-NMR (CDCl3): δ = 8.22 (brs, 1H), 7.49–6.43 (m, 2H), 7.33–7.30 (m, 2H), 7.08 (td, J = 7.7, 1.1 Hz, 1H),
6.73 (d, J = 7.7 Hz, 1H), 6.63 (td, J = 7.7, 1.0 Hz, 1H), 6.37 (d, J = 7.8 Hz, 1H) ppm; 13C-NMR (CDCl3):
δ = 168.4, 153.5, 141.0, 140.7, 138.2, 135.5, 132.0, 129.6, 129.6, 129.2, 129.2, 128.2, 124.9, 124.0, 123.6, 121.6,
109.7 ppm; HRMS (EI): calcd. for C23H18ClNO [M+]: 331.0764, found 331.0762.
(E)-1-Benzyl-3-((4-chlorophenyl)(phenyl)methylene)indolin-2-one ((E)-7b): Yellow solid; m.p. = 144.4 ◦C;
1
Rf = 0.23 (silica gel, hexanes
(CD2Cl2):
7.47–7.43 (m, 2H), 6.53 (d, J = 7.7 Hz, 1H), 4.91 (s, 2H) ppm; 13C-NMR (CD2Cl2):
−
EtOAc 10:1); IR (film) 3059, 2923, 2852, 1699, 1345 cm−1; H-NMR
δ
= 7.47–7.44 (m, 2H), 7.42–7.31 (m, 11H), 7.30–7.26 (m, 1H), 7.08 (td, J = 7.7, 1.0 Hz, 1H),
= 166.8, 153.2,
δ
143.0, 140.24, 140.23, 136.9, 135.6, 131.3, 130.6, 129.6, 129.5, 129.3, 129.0, 128.2, 127.8, 127.7, 124.9, 123.53,
123.46, 121.8, 109.0, 43.7 ppm; HRMS (EI): calcd. for C23H18ClNO [M+]: 421.1233, found 421.1231.
(Z)-1-Benzyl-3-((4-chlorophenyl)(phenyl)methylene)indolin-2-one ((Z)-7b): Orange solid; m.p. = 132.8 ◦C;
1
Rf = 0.28 (silica gel, hexanes
(CD2Cl2):
6.69 (d, J = 7.8 Hz, 1H), 6.62 (td, J = 7.7, 1.0 Hz, 1H), 6.39 (dd, J = 7.7, 0.5 Hz, 1H), 4.89 (s, 2H) ppm;
13C-NMR (CD2Cl2):
= 166.9, 153.1, 143.0, 141.4, 139.0, 137.0, 135.2, 132.1, 129.7, 129.6, 129.5, 129.2,
−
EtOAc 10:1); IR (film) 3056, 2922, 2853, 1698, 1345 cm−1; H-NMR
= 7.49–7.44 (m, 3H), 7.35–7.31 (m, 10H), 7.08–7.05 (m, 1H), 7.05 (td, J = 7.7, 1.1 Hz, 1H),
δ
δ
129.0, 128.3, 127.8, 127.7, 124.9, 123.7, 123.6, 121.8, 108.9, 43.7 ppm; HRMS (EI): calcd. for C23H18ClNO
[M+]: 421.1233, found 421.1231.
(E)-4-((4-Chlorophenyl)(phenyl)methylene)-2-methyl-1,2-dihydroisoquinolin-3(4H)-one ((E)-7c): Dark orange
◦
solid; m.p. = 171.9 C; Rf = 0.15 (silica gel, hexanes
−
EtOAc 3:1); IR (film) 3211, 2923, 2851, 1642,
1399 cm−1; H-NMR (CDCl3):
7.15–7.12 (m, 3H), 6.98–6.94 (m, 3H), 6.85 (d, J = 7.8 Hz, 1H), 4.49 (s, 2H), 3.03 (s, 3H) ppm; 13C-NMR
δ = 7.36–7.30 (m, 4H), 7.29–7.27 (m, 1H), 7.18 (d, J = 7.0 Hz, 1H),
1

Molecules 2017, 22, 503
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(CDCl3):
δ = 165.8, 147.4, 141.7, 141.3, 134.8, 134.2, 133.8, 131.9, 130.1, 129.8, 129.6, 128.8, 127.9, 127.8,
127.27, 127.26, 125.3, 53.0, 35.3 ppm; HRMS (EI): calcd. for C23H18ClNO [M+]: 359.1077, found 359.1074.
(Z)-4-((4-Chlorophenyl)(phenyl)methylene)-2-methyl-1,2-dihydroisoquinolin-3(4H)-one ((Z)-7c): Gold solid;
m.p. = 174.5 ◦C; Rf = 0.26 (silica gel, hexanes EtOAc 3:1); IR (film) 3055, 2923, 2851, 1656, 1396 cm−1
;
−
1H-NMR (CDCl3):
δ = 7.33–7.35 (m, 4H), 7.18–7.15 (m, 4H), 7.11 (t, J = 7.1 Hz, 1H), 7.01–6.99 (m, 2H),
6.89 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 4.49 (s, 2H), 3.05 (s, 3H) ppm; 13C-NMR (CDCl3):
δ = 165.9, 147.7, 142.4, 140.5, 131.6, 134.8, 134.0, 133.6, 131.6, 130.4, 129.9, 128.6, 128.0, 127.9, 127.2, 127.1,
125.2, 53.0, 35.3 ppm; HRMS (EI): calcd. for C23H18ClNO [M+]: 359.1077, found 359.1076.
(E)-3-((4-Chlorophenyl)(phenyl)methylene)benzofuran-2(3H)-one ((E)-7d): Yellow solid; m.p. = 145.0 ◦C;
Rf = 0.26 (silica gel, hexanes
1H-NMR (CDCl3):
= 7.45–7.43 (m, 3H), 7.40–7.37 (m, 2H), 7.32–7.28 (m, 4H), 7.26–7.24 (m, 1H),
7.08 (d, J = 8.0 Hz, 1H), 6.85 (td, J = 7.7, 1.0 Hz, 1H), 6.60 (dd, J = 7.8, 0.8 Hz, 1H) ppm; 13C-NMR
−
EtOAc 20:1); IR (film) 3359, 3188, 3058, 2922, 1783, 1460, 1074, 761 cm−1
;
δ
(CDCl3):
δ = 166.5, 156.8, 153.7, 138.8, 138.6, 136.3, 131.9, 131.1, 130.5, 130.4, 130.2, 129.6, 129.5, 129.3,
128.5, 128.3, 124.2, 123.4, 122.9, 119.5, 111.0 ppm; HRMS (EI): calcd. for C21H13ClO2 [M+]: 332.0604,
found 332.0603.
(Z)-3-((4-Chlorophenyl)(phenyl)methylene)benzofuran-2(3H)-one ((Z)-7d): Yellow solid; m.p. = 106.4 ◦C;
Rf = 0.31 (silica gel, hexanes
1H-NMR (CDCl3):
= 7.51–7.49 (m, 1H), 7.48–7.45 (m, 2H), 7.36–7.34 (m, 2H), 7.32–7.30 (m, 2H),
7.29–7.27 (m, 2H), 7.22 (td, J = 7.8, 1.3 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 6.80 (td, J = 7.7, 1.1 Hz, 1H),
6.49 (dd, J = 7.8, 0.8 Hz, 1H) ppm; 13C-NMR (CDCl3):
= 166.7, 156.8, 153.7, 140.1, 137.2, 136.4, 131.9,
−
EtOAc 20:1); IR (film) 3057, 2921, 2850, 1784, 1460, 1064, 750 cm−1
;
δ
δ
130.3, 130.1, 129.5, 129.3, 128.5, 124.3, 123.4, 123.1, 119.6, 110.9 ppm; HRMS (EI): calcd. for C21H13ClO2
[M+]: 332.0604, found 332.0605.
4. Conclusions
In conclusion, consecutive one-pot conditions for the synthesis of 3-(diarylmethylene)oxindoles
were successfully converted to more efficient domino MCRs through investigation of ligands, additives,
and heating sources (thermal/microwave). Microwave irradiation facilitated domino MCRs and
the addition of silver salt proved crucial for high yield and stereoselectivity. A wide range of
substrates was tested to demonstrate that the domino MCRs are applicable to the synthesis of
3-(diarylmethylene)oxindoles bearing various substituents at the aryl or heteroaryl groups via three
palladium-catalyzed reactions, namely Sonogashira, Heck and Suzuki-Miyaura reactions.
Supplementary Materials: Supplementary materials are available online. copies of NMR spectra of compounds
and 3–7.
1
Acknowledgments: This research was supported by the Bio & Medical Technology Development Program
and Basic Science Research Program of the National Research Foundation funded by the Ministry of Science,
ICT & Future Planning, Korea (2013M3A9B5075840 and NRF-2014R1A1A1038332) and Research Fund 2013 of The
Catholic University of Korea.
Author Contributions: J.H.S. and K.J.S. conceived and designed the experiments; S.P. and J.L. performed
experiments; S.P. and J.L. analyzed data; E.O. contributed reagents/materials/analysis tools; J.H.S. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 3 and 7 are available from the authors.
©
2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).