Transition-metal-free halocarbocyclisation of acrylamides using K2S2O8

Article abstract of DOI:10.3184/174751917X14944355549177

A novel and direct transition-metal-free oxidative halocarbocyclisation of acrylamides using inexpensive KX (X= I, Br, Cl) and K2S2O8 has been developed. This methodology not only provides an efficient way to construct valuable halogenated oxindoles in go

Full text of DOI:10.3184/174751917X14944355549177

352 RESEARCH PAPER
VOL. 41 JUNE, 352–357
JOURNAL OF CHEMICAL RESEARCH 2017
Transition-metal-free halocarbocyclisation of acrylamides using K S O
8
2
2
a
a
a
b
Haiwei Ye *, Liping Zhou , Yunhua Chen and Jun Qiu
a
Chemical Pharmaceutical Research Institute, Taizhou Vocational & Technical College, Taizhou 318000, P.R. China.
Shanghai Engineering Research Centre of Stable Isotope, Shanghai Research Institute of Chemical Industry, Shanghai 200062, P.R. China
b
A novel and direct transition-metal-free oxidative halocarbocyclisation of acrylamides using inexpensive KX (X= I, Br, Cl) and K S O has
2
2 8
been developed. This methodology not only provides an efficient way to construct valuable halogenated oxindoles in good to excellent
yields, but also represents a novel strategy for C–X and C–C bond formation.
Keywords: transition-metal-free, halocarbocyclisation, acrylamides, oxindoles
Oxindole frameworks have demonstrated significant potential
for use in a wide range of pharmaceutical and biological
applications such as an N-methyl-D-aspartic acid antagonist and
In an initial study, we chose the N,2-dimethyl-N-
phenylacrylamide (1a) and KI as the model reactants. K S O
2
2
8
1
was used as the oxidant to examine suitable reaction conditions
and the results are summarised in Table 1. A number of solvents,
including H O, THF/H O, DMF/H O, acetone/H O, CH CN/
2
3
calcium channel blocker as well as having anti-angiogenic, anti-
4
5
cancer and analgesic effects. Therefore, many methodologies
2
2
2
2
3
6
–9
for the synthesis of oxindoles have been developed. It is
worth noting that the direct transition-metal-free tandem C–H
functionalisation/cyclisation of unactivated alkenes for the
synthesis of various halogenated oxindoles is still an extremely
H O and CH CN, were screened at 80 °C for 8h (Table 1, entries
2 3
1–7). Moderate yields of the desired product 2a were obtained
using H O, THF/H O, DMF/H O and CH CN as solvent (Table
2
2
2
3
1, entries 1–3 and 6). It should be noted that a good yield of
10–13
14
attractive yet challenging task.
Recently Zhu and co-workers
the desired product 2a was obtained using acetone/H O as the
2
realised an elegant approach for the synthesis of iodooxindoles
solvent (Table 1, entry 4). To our delight, further optimisation
showed that CH CN/H O (1:1) gave the best yield of 94% (Table
15,16
by using PhI(OAc) and I [Scheme 1, Eqn (1)]. Gulder’s group
2
2
3
2
have developed the first organocatalytic bromocarbocyclisation
utilised in an effective method for the synthesis of bromooxindoles
using NBS as the Br source [Scheme 1, Eqn (2)]. When our
1, entry 5). To establish the reaction conditions that improve
the reaction, several oxidants such as K S O , phenyliodinium
2
2
8
diacetate, PhIO, tert-butyl hydroperoxide (TBHP) and O were
17
2
independent studies were being carried out, Guo’s group
screened in CH CN/H O (1:1) at 80 °C for 8h (Table 1, entries
3
2
reported a similar method for the synthesis of halogenated
oxindoles by using (NH ) S O as the oxidant and NH X (X= I,
a
4
2
2
8
4
Table 1 Screening of reaction conditions
Br or Cl) as the halide source [Scheme 1, Eqn (3)].
Although several elegant studies on the halocarbocyclisation
of N-arylacrylamides have been accomplished, it is still highly
desirable to develop new strategies to prepare halogenated
oxindoles that are highly efficient and utilise cheap substrates
and oxidants. Here we report a transition-metal-free cascade
halocarbocyclisation of arylacrylamides using the very cheap
KX (X= I, Br, Cl) and K S O in aqueous solution, which allows
b
Entry
Oxidant
K S O
Solvent
H2O
T (°C)
80
80
80
80
80
80
80
80
80
80
80
r.t.
Yield (%)
47
31
52
82
94
1
2
3
4
5
6
7
8
9
2
2
8
8
8
8
8
8
2
2
8
K S O
THF/H O (1:1)
2
2
2
highly efficient access to oxindoles by cascade C–X and C–C bond
formation.
K S O
DMF/H O (1:1)
2
2
2
K S O
Acetone/H O (1:1)
2
2
2
K S O
CH CN/H O (1:1)
2
2
3
2
K S O
CH CN
54
2
2
3
–
CH CN/H O (1:1)
n.d.
n.d.
n.d.
73
54
n.d.
72
3
2
TBHP
CH CN/H O (1:1)
3 2
c
O2
CH CN/H O (1:1)
3 2
1
0
PIDA
PhIO
CH CN/H O (1:1)
3 2
1
1
CH CN/H O (1:1)
3
2
1
2
K S O
CH CN/H O (1:1)
2
2
8
8
8
3
2
1
3
K S O
CH CN/H O (1:1)
50
100
80
80
2
2
3
2
1
4
K S O
CH CN/H O (1:1)
92
2
2
3
2
d
1
5
K S O
CH CN/H O (1:1)
64
2
2
8
8
3
2
e
16
K S O
CH CN/H O (1:1)
93
2
2
3
2
a
Reaction conditions: 1a (0.25 mmol), K S O (2 equiv.) and KI (2 equiv.) in CH CN/H O
2
2
8
3
2
(
1:1, 2.5 mL) with stirring at different temperature for 6 h. n.d. = not detected.
b
Isolated yield.
O2 (1 atm).
c
d
e
K S O (1 equiv.).
2
2 8
Scheme 1 Halocarbocyclisation of acrylamides.
K S O (3 equiv.).
2 2 8
*
Correspondent. E-mail: 43838856@qq.com

JOURNAL OF CHEMICAL RESEARCH 2017 353
a
8
–13). The transformation did not proceed with TBHP and O2
Table 2 Metal-free halocarbocyclisation of different N-arylacrylamides
(
Table 1, entries 8–9). It was found that K S O showed higher
2
2
8
efficiency compared with the other oxidants and thus was
chosen as the oxidant for further optimisation. Furthermore,
screening of the reaction temperature revealed that 80 °C gave
the best result (Table 1, entry 8). The ratios of 1a to K S O
8
b
Entry
1
Substrate
Product
Yield (%)
94%
I
I
2
2
O
were also examined and it was found that the ratio 1a/K S O =
N
O
N
2
2
8
1
a
2a
1:2 was preferable. Therefore, we chose the acrylamide together
I
with KI (2 equiv.) and K S O (2 equiv.) in CH CN/H O (1:1) at
2
2
8
3
2
O
2
3
N
O
N
95%
92%
8
0 °C for 6 h as our optimised reaction conditions.
Varioussubstrateswerenowsubjectedtothereactionunderthe
1b
2b
I
optimised conditions and representative results are summarised
in Table 2. For N-aryl-N,2-dimethylmethacrylamides bearing
various electron-donating substituents (e.g. Me, t-Bu, OMe, OEt)
in the ortho-position of the aromatic ring, the substrates could
be converted successfully into the desired products in excellent
yields (92–98%, Table 2, substrates 1b–e). Interestingly, when
a 4-methoxy or a 4-ethoxy group was present on the aromatic
ring of the acrylamide, inseparable mixtures of regioisomers
O
N
O
N
1c
2c
O
I
O
O
N
9
8%
2d
4
5
N
O
O
I
I
2
d:2d’= 2:1
1d
O
N
2d'
(
2d:2d’ = 2:1, 2e:2e’ = 1.5:1) were isolated in 98% and 96%
O
I
O
overall yields respectively. It is noteworthy that lower yields
O
N
N
(trace–63%) were formed when electron-withdrawing groups
2e
96%
N
O
(
F, Cl, Br) were present in the para-position (Table 2, 2f–h).
O
I
I
2e:2e’= 1.5:1
1e
O
However, N-arylacrylamides bearing a CF substituent in the
3
para-position failed to produce a corresponding product (Table
2e'
F
I
2
, 2i). Furthermore, the substrates bearing meta substituents
F
O
on the N-arylacrylamides were well tolerated and readily
converted into a mixture of two regioisomers in moderate to
good yields (62–89%) with poor regioselectivity (Table 2, 2j–k
and 2j’–k’). The N-arylacrylamides containing ortho-position
substituent groups were compatible with the process and a steric
hindrance effect was observed (Table 2, 2l–m). For example,
when the position of the methyl group on the aromatic ring of
the N-arylacrylamide was changed from para to meta to ortho,
the yields decreased from 95% to 89% to 79% (Table 2, 2b, 2j
and 2l). In addition, a 2,4-disubstituted N-arylacrylamide was
well tolerated and afforded the desired oxindole in good yield
6
7
8
9
N
O
N
Trace
51%
1f
2f
Cl
Br
Cl
I
O
N
O
N
1g
2g
Br
I
O
N
O
O
N
63%
Trace
1h
2h
F
3
C
I
F
3
C
O
N
N
1
i
2i
(
Table 2, 2n). Gratifyingly, when the benzene ring was changed
I
I
I
O
to a naphthalene one, the substrate also successfully formed the
analogous product in 91% yield (Table 2, 2o).
N
8
9%
2j
10
N
O
I
2j:2j’= 1.7:1
Encouraged by the above results, we subjected more
N-arylacrylamides to the optimised conditions. To our delight,
an investigation into different N-protecting groups revealed
that the electron-donating protecting groups such as ethyl
and n-butyl were appropriate for the reaction and furnished
the corresponding oxindoles in very good yields (Table 3,
1j
O
N
2
j'
Br
I
O
N
62%
2k:2k’= 3.1:1
B
r
N
O
2k
11
4
a, 4b). A substrate bearing N-benzyl was tolerated but only
a trace amount of the desired oxindole was isolated (Table 3,
c). Unfortunately, replacement of the methyl substituent with
I
1
k
O
Br
I
N
4
2
k'
hydrogen, acetyl or Boc failed to produce the corresponding
products (Table 3, 4d–f). In addition, an α-substituted olefin
bearing a phenyl group did provide the desired product in good
yield (Table 3, 4g). Tetrahydroisoquinoline structural motifs are
I
O
12
N
O
N
79%
76%
1
l
2l
I
I
18
O
common components in many biologically active compounds
13
N
O
N
and a tricyclic oxindole derivative was obtained in excellent
yield from the corresponding tetrahydroquinoline substrate
O
O
1
m
2
m
I
I
(
Table 3, 4h). However, when the framework of the substrate
O
14
N
O
79%
91%
N
was changed by replacing the heteroatom N by O, none of the
desired product was observed (Table 3, 4i).
1n
2n
I
I
To realise such
a
transition-metal-free oxidative
O
15
N
O
N
halocarbocyclisation, we tested different inorganic halogen salts
in combination with K S O for the conversion of model substrate
1
o
2o
2
2
8
1a into oxindoles 2a, 5a and 6c (Table 4). Iodine salts, such as
a
All reactions were carried out in the presence of 1a–o, KI (0.5 mmol, 2.0 equiv.), K S O
2 8
2
o
NaI and NH I were tolerated under the reaction conditions and
(2.0 equiv.) in CH CN/H O (1:1, 5 mL) at 80 C for 6 h.
4
3 2
b
afforded the corresponding diiodooxindoles in 94 and 52% yields
Isolated yield.

354 JOURNAL OF CHEMICAL RESEARCH 2017
a
Table 3 Metal-free halocarbocyclisation of different arylacrylamides
Table 4.Halocarbocyclisation of N,2-dimethyl-N-phenylacrylamide using
a
different halogen salts
H
2
equiv K S O
8
X
X
Cl
O
-
X
2
2
+
O
or
CH CN/H O (1:1
N
O
3
2
)
N
N
H
0 oC, 6 h
8
1
a
2
a, 5a
6c
b
Entry
1
Substrate
Product
Yield (%)
89%
b
Entry
Halide
NaI
NH4I
KBr
NaBr
KCl
NaCl
KF
Product
2a
2a
5a
5a
6c
6c
7a
Yield (%)
I
1
2
3
4
5
6
7
94
52
87
84
65
66
0
I
I
I
O
N
O
O
O
N
3a
4a
I
O
2
3
N
N
82%
-
a
Reaction conditions: 1a (0.25 mmol), K S O (2 equiv.) and halogen salt (2 equiv.) in
n Bu
2 2 8
n-Bu
CH CN/H O (1:1, 2.5 mL) with stirring at 80 °C for 6 h.
3
b
3
2
4b
b
Isolated yield.
I
H
O
Cl
O
Cl
O
N
Bn
Trace
0%
2 equiv K S O
2 2
8
N
+
+
KCl
[1]
[2]
[3]
Bn
N
O
3
CH CN/H
2
O (1:1)
C 6 h
N
N
3
c
4c
o
,
H
80
6b, 0%
6c, 65%
1a
I
I
O
H
4
5
N
O
O
N
Cl
O
Cl
H
2 equiv K S O
2 2
8
H
+
+
KCl
KCl
O
3
d
4d
N
O
O
CH
3
CN/H
2
O (1:1)
N
N
o
,
H
80
C 6 h
I
I
O
3a
8b, 0%
6c, 68%
0
%
N
Ac
N
H
Cl
Ac
Cl
O
2
equiv K S O
2 2
8
3
e
4e
+
+
O
N
3
CH CN/H
2
O (1:1)
N
N
H
I
I
o ,
80
C 6 h
Ph
9b, 78%
Ph
O
6
7
N
Boc
O
0%
9a
9c, 0%
N
Boc
Scheme 2 Investigation of the N-demethylation reaction.
3
f
4f
I
To gain insight into the above N-demethylatiion reaction,
I
several more experiments were conducted (Scheme 2). When
the oxidative cyclisation of KCl and 1a was carried out under
the optimised conditions, the N-demethylated product 6c
was produced in 65% yield and the desired product 6b was
not observed [Scheme 2, Eqn (1)]. Similarly, replacement of
87%
O
N
O
O
N
4g
3
g
I
I
1
a with the N-ethylacrylamide (3a), gave the N-deethylated
O
N
N
product 6c in 68% yield and no 6b was observed [Scheme 2,
Eqn (2)]. Surprisingly, the N,N-diphenyl-2-methacrylamide
(9a) could give the desired product 9b with good yield and
the N-dephenylated product 9c was not found [Scheme 2, Eqn
3)]. We speculate that the N-demethylated and N-deethylated
product 6c may be generated by oxidation–hydrolysis of the
N-methyl and N-ethyl group of the substrates with K S O in
8
9
91%
0%
3
h
4h
I
I
(
O
O
O
O
3
i
4i
2
2
8
CH CN/H O (1:1).
a
3
2
All reactions were carried out in the presence of 3a–i, KI (0.5 mmol, 2.0 equiv.), K S O
2 8
2
o
Based on the above experiments, a plausible mechanism for
(
2.0 equiv.) in CH CN/H O (1:1, 5 mL) at 80 C for 6h.
Isolated yield.
3 2
1
4–17
b
our methodology is hypothesised on the basis of literature
.
Scheme 3 illustrates our proposed pathway. Initially, KX (X=I,
Br, Cl) reacts with the persulfate ion to form the halogen. Then,
the addition of the halogen to the activated alkene 1a results in
the formation of halonium ion A, followed by intramolecular
carbocyclisation to generate the corresponding Wheland
intermediate B, followed by proton loss to afford intermediate
C. Further electrophilic halogenation of C affords the
dihalogenated oxindoles 2a and 5a. In addition, with KCl as the
halogen salt, the oxidation of the intermediate C using K S O
respectively (Table 4, entries 1 and 2). When KBr and NaBr
were used as sources of bromide ion halocarbocyclisation went
smoothly and the desired dibromooxindole 5a was formed in good
yields (Table 4, entries 3 and 4). Surprisingly, when KCl and NaCl
were employed as chlorine sources, only product 6c was isolated in
moderate yields by an N-demethylation reaction (Table 4, entries
5
and 6). KF as a fluoride source demonstrated very poor activity
2
2
8
and no fluorooxindole product was observed (Table 4, entry 7).
and HClO as the synergistic oxidants generates the intermediate

JOURNAL OF CHEMICAL RESEARCH 2017 355
X
K S O
1
a
X
2
2
8
2 -
X
X2
N
O
N
O
(X= I, Br, Cl)
A
B
H
Cl
H O
Cl
Cl
2
/ H
2
O
X
2
-
N
O
K
S
O
HCOOH
N
O
2
2
8
N
O
H
6c
O
D
C
X2
X= I
(
,
Br)
X
X
N
O
2a
Scheme 3 Plausible mechanism for the formation of 2a and 6c.
1
3
D, followed by hydrolysis to afford the N-demethylated product
c.
In summary, we have demonstrated an efficient transition-
(s, 3H), 1.51 (s, 3H); C NMR (100 MHz, CDCl , ppm): δ 177.5, 143.4,
3
6
137.8, 135.4, 131.8, 110.5, 85.6, 50.1, 26.8, 23.4, 10.2; HRMS m/z (ESI)
calcd for C H NOI : [M + Na] : 449.8828; found: 449.8838.
-(Iodomethyl)-1,3,5-trimethylindolin-2-one (2b): Yellow oil;
H NMR (400 MHz, CDCl , ppm): δ 7.14 (d, J = 8.0 Hz, 1H), 7.08
s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 3.52 (d, J = 10.0 Hz, 1H), 3.41 (d,
J = 10.0 Hz, 1H), 3.23 (s, 3H), 2.37 (s, 3H), 1.51 (s, 3H); C NMR (100
MHz, CDCl , ppm): δ 177.9, 140.8, 132.6, 132.3, 128.9, 123.5, 108.0,
8.7, 26.4, 23.0, 21.2, 11.0; HRMS m/z (ESI) calcd for C H NOI: [M +
+
11 11
2
14
3
metal-free oxidative halocarbocyclisation of acrylamides
with halogen salts by sequential intermolecular addition and
intramolecular substitution for the synthesis of monohalogenated
and dihalogenated oxindoles using K S O as oxidant. This
1
3
(
13
2
2
8
3
methodology provides an economical and efficient way for the
construction of halogen-containing oxindoles, which avoids
expensive transition metals and oxidants. Further applications of
this transformation to other simple substrates and the synthesis
of more valuable compounds are underway in our group.
4
12 14
+
Na] : 338.0018; found: 337.9997.
-tert-Butyl-3-(iodomethyl)-1,3-dimethylindolin-2-one (2c): Yellow
oil; H NMR (400 MHz, CDCl , ppm): δ 7.34 (dd, J = 2.0, 8.0 Hz, 1H),
5
1
3
7
.24 (d, J = 2.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 3.83 (d, J = 9.6 Hz,
1
H), 3.75 (d, J = 9.6 Hz, 1H), 3.22 (s, 3H), 1.43 (s, 3H), 1.33 (s, 9H);
Experimental
13
C NMR (100 MHz, CDCl , ppm): δ 177.9, 146.5, 141.4, 131.7, 125.6,
3
Melting points were taken on a WRS-2A micro melting point apparatus
and are uncorrected. All reagents and solvents were of analytical
grade and purchased from Sigma-Aldrich Co. and used without
additional purification. H NMR and C NMR spectra were obtained
at 400 MHz and 100 MHz respectively on a Bruker AVANCE Ⅲ HD
120.5,108.1, 58.0, 49.3, 34.9, 31.8, 26.7, 10.9; HRMS m/z (ESI) calcd
+
for C H NOI: [M + Na] : 380.0487; found: 380.0494.
1
5
20
14
3
-(Iodomethyl)-5-methoxy-1,3-dimethylindolin-2-one (2d), 6-iodo-
-(iodomethyl)-5-methoxy-1,3-dimethylindolin-2-one (2d’), 2d/2d’ =
:1:Yellow oil.
1
13
10
3
2
4
00MHz instrument. Chemical shifts (δ ppm) were referenced to
1
For 2d: H NMR (400 MHz, CDCl , ppm): δ 6.90 (d, J = 2.4 Hz, 1H),
3
1
tetramethylsilane, solvent or residual protio-solvent. Data for H NMR
are recorded as follows: chemical shift (δ, ppm), multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet or unresolved,
br = broad singlet, coupling constant(s) in Hz, integration). Mass
spectra were recorded using a PE SCLEX QSTAR spectrometer. For
6
.84 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H), 3.51
(
d, J = 9.6 Hz, 1H), 3.40 (d, J = 9.6 Hz, 1H), 3.22 (s, 3H), 1.51 (s, 3H);
13
C NMR (100 MHz, CDCl , ppm): δ 177.9, 156.5, 137.0, 134.5, 113.0,
3
110.7, 108.8, 56.3, 49.4, 26.8, 23.3, 11.1; HRMS m/z (ESI) calcd for
C H NO I: [M + Na] : 353.9967; found: 353.9975.
+
12
14
2
+
1
Cl and Br containing products m/z values are given for the [M + H]
For 2d’: H NMR (400 MHz, CDCl , ppm): δ 7.29 (s, 1H), 6.87 (s,
3
isotopomers. Purification was done by column chromatography on
silica gel (200–300 mesh) with petroleum ether (30–60 °C)/ethyl
acetate as the eluent.
1H), 3.90 (s, 3H), 3.49 (d, J = 9.6 Hz, 1H), 3.41 (d, J = 9.6 Hz, 1H), 3.21
13
(s, 3H), 1.51 (s, 3H); C NMR (100 MHz, CDCl , ppm): δ 177.7, 155.1,
3
138.2, 134.6, 119.3,107.3, 85.2, 57.6, 49.3, 26.8, 23.2, 10.8; HRMS m/z
+
An oven-dried Schlenk tube was charged with 1a–o, 3a–i or 9a
(ESI) calcd for C H NO I : [M + Na] : 479.8933; found: 479.8942.
12
13
2 2
(
0.5 mmol), KX (X = I, Br, Cl, 1 mmol) and K S O (2.0 equiv.) in
5-Ethoxy-3-(iodomethyl)-1,3-dimethylindolin-2-one (2e), 5-ethoxy-
6-iodo-3-(iodomethyl)-1,3-dimethylindolin-2-one (2e’), 2e/2e’ =
2
2
8
o
CH CN/H O (1:1, 5 mL). The reaction mixture was stirred at 80 C
3
2
for 6 h monitored by TLC. The mixture was then allowed to cool to
1.5:1: Yellow solid; m.p. 98 °C.
For 2e: H NMR (400 MHz, CDCl , ppm): δ 6.90 (d, J = 2.4 Hz, 1H),
1
room temperature and was quenched with H O (10 mL). This mixture
2
3
was extracted with EtOAc (3 × 10 mL) and the combined organic
layers were dried with Na SO , concentrated under reduced pressure
6.83 (d, J = 2.4 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 4.02 (q, J = 6.8 Hz,
2H), 3.51 (d, J = 9.8 Hz, 1H), 3.40 (d, J = 9.8 Hz, 1H), 3.22 (s, 3H), 1.50
2
4
13
and dried under high vacuum. The residue was purified by flash
chromatography on silica gel [petroleum ether (30–60 °C)/ethyl
acetate] to obtain the desired products.
(s, 3H), 1.42 (t, J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl , ppm): δ
3
177.6, 155.4, 137.9, 134.1, 113.4, 111.0, 108.6, 64.1, 49.0, 26.4, 23.1,15.0,
+
10.9; HRMS m/z (ESI) calcd for C H NO I: [M + Na] : 368.0123;
13
16
2
1
0
5
-Iodo-3-(iodomethyl)-1,3-dimethylindolin-2-one
(2a): White
found: 368.0135.
14
1
1
solid; m.p. 130−131 °C (lit. 129–130 °C); H NMR (400 MHz, CDCl ,
For 2e’: H NMR (400 MHz, CDCl , ppm): δ 7.29 (s, 1H), 6.86 (s,
3
3
ppm): δ 7.65 (dd, J =1.2, 8.0 Hz, 1H), 7.54 (d, J = 1.2 Hz, 1H), 6.67 (d,
J = 8.4 Hz, 1H), 3.50 (d, J = 9.6 Hz, 1H), 3.37 (d, J = 9.6 Hz, 1H), 3.22
1H), 4.10 (q, J = 6.8 Hz, 2H), 3.48 (d, J = 10.0 Hz, 1H), 3.41 (d, J = 10.0
Hz, 1H), 3.20 (s, 3H), 1.51 (s, 3H), 1.48 (t, J = 6.8 Hz, 3H); C NMR
13

356 JOURNAL OF CHEMICAL RESEARCH 2017
(
8
100 MHz, CDCl , ppm): δ 177.3, 154.1, 136.6, 133.9, 118.8, 107.3,
J = 1.6, 8.0 Hz, 1H), 7.91 (s, 1H), 7.76–7.48 (m, 3H), 3.81 (s, 3H), 3.56
(d, J = 10.0 Hz, 1H), 3.40 (d, J = 10.0 Hz, 1H), 1.54 (s, 3H); C NMR
3
13
6.0, 66.2, 49.0, 26.5, 23.1, 15.0, 10.5; HRMS m/z (ESI) calcd for
+
C H NO I : [M + Na] : 493.9090; found: 493.9098.
(100 MHz, CDCl , ppm): δ 179.5, 140.1, 135.1, 134.2, 131.6, 129.8,
1
3
15
2
2
3
17
5
-Chloro-3-(iodomethyl)-1,3-dimethylindolin-2-one (2g): White
128.0, 126.8, 122.6, 122.4,92.1, 48.7, 31.2, 23.7, 9.8; HRMS m/z (ESI)
17
1
+
solid; m.p. 80–81 °C (lit. 79–81 °C); H NMR (400 MHz, CDCl ,
calcd for C H NOI : [M + Na] : 499.8984; found: 499.8995.
3
15 13
2
ppm): δ 7.31 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H),
1-Ethyl-5-iodo-3-(iodomethyl)-3-methylindolin-2-one (4a): Yellow
1
3
.51 (d, J = 9.8 Hz, 1H), 3.39 (d, J = 9.8 Hz, 1H), 3.24 (s, 3H), 1.52
oil; H NMR (400 MHz, CDCl , ppm): δ 7.64 (dd, J = 1.2, 8.0 Hz,
3
13
(s, 3H); C NMR (100 MHz, CDCl , ppm): δ 177.4, 142.5, 133.4,
1H), 7.53 (d, J = 1.2 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 3.91–3.82 (m,
3
1
29.1, 128.7, 123.5,109.1, 49.2, 26.9, 23.6, 10.1; HRMS m/z (ESI) calcd
1H), 3.71–3.62 (m, 1H), 3.52 (d, J = 10.0 Hz, 1H), 3.36 (d, J = 10.0 Hz,
1H), 1.50 (s, 3H), 1.27 (t, J = 7.2 Hz, 1H); C NMR (100 MHz, CDCl3,
+
13
for C H NOICl: [M + Na] : 357.9472/359.9422 (100:32); found:
1
1
11
3
57.9486/359.9428 (56:19).
ppm): δ ppm 177.8, 142.9, 137.5, 134.8, 132.3, 109.8, 85.8, 49.7, 34.7,
+
5
-Bromo-3-(iodomethyl)-1,3-dimethylindolin-2-one (2h): Yellow
23.5, 12.8, 10.2; HRMS m/z (ESI) calcd for C H NOI : [M + Na] :
12
13
2
1
solid; m.p. 102–104 °C; H NMR (400 MHz, CDCl , ppm): δ 7.47
463.8984; found: 463.8991.
1-n-Butyl-5-iodo-3-(iodomethyl)-3-methylindolin-2-one
Yellow oil; H NMR (400 MHz, CDCl , ppm): δ 7.66 (dd, J = 1.6, 8.0
Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 3.84–3.65
m, 2H), 3.51 (d, J = 10.0 Hz, 1H), 3.35 (d, J = 10.0 Hz, 1H), 1.72–1.63
3
(dd, J = 1.8, 8.0 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H), 6.78 (d, J = 8.0 Hz,
(4b):
1H), 3.53 (d, J = 9.8 Hz, 1H), 3.42 (d, J = 9.8 Hz, 1H), 3.23 (s, 3H),
1
3
13
1.51 (s, 3H); C NMR (100 MHz, CDCl , ppm): δ 177.6, 142.6,
3
133.2, 130.8, 127.7, 116.5,109.5, 48.9, 26.7, 23.8, 10.3; HRMS m/z
(
+
(
ESI) calcd for C H NOIBr: [M + Na] : 401.8966/403.8946; found:
11 11
(m, 2H), 1.43–1.33 (m, 2H), 1.50 (s, 3H), 0.96 (t, J = 7.2 Hz, 1H);
4
01.8976/403.8952 (27:31).
-Iodo-3-(iodomethyl)-1,3,4-trimethylindolin-2-one (2j), 5-iodo-
13
C NMR (100 MHz, CDCl , ppm): δ 177.7, 143.1, 137.8, 135.1, 131.9,
3
1
4
5
1
09.5, 85.5, 49.6, 38.9, 29.5, 20.1, 13.6, 9.8; HRMS m/z (ESI) calcd for
14
3
-(iodomethyl)-1,3,6-trimethylindolin-2-one (2j’), 2j/2j’ = 1.7:1:
+
C H NOI : [M + Na] : 491.9297; found: 491.9306.
1
4
17
2
Yellow oil.
14
5
-Iodo-3-(iodomethyl)-1-methyl-3-phenylindolin-2-one
(4g):
1
For 2j: H NMR (400 MHz, CDCl , ppm): δ 7.63 (s, 1H), 6.79 (s, 1H),
o
14
1
3
White solid; m.p. 145–147 C (lit. 147–148 °C); H NMR (400 MHz,
3.49 (d, J = 9.8 Hz, 1H), 3.37 (d, J = 9.8 Hz, 1H), 3.21 (s, 3H), 2.48 (s,
CDCl , ppm): δ 7.75 (dd, J = 1.4, 8.0 Hz, 1H), 7.67 (d, J = 1.4 Hz, 1H),
3
3H), 1.49 (s, 3H).
7
.43–7.41 (m, 2H), 7.38–7.33 (m, 3H), 6.75 (d, J = 8.0 Hz, 1H), 4.03 (d,
1
For 2j’: H NMR (400 MHz, CDCl , ppm): δ 7.82 (d, J = 8.4 Hz, 1H),
13
3
J = 9.6 Hz, 1H), 3.74 (d, J = 9.6 Hz, 1H), 3.24 (s, 3H); C NMR (100
6
1
.50 (d, J = 8.4 Hz, 1H), 3.65 (d, J = 10.0 Hz, 1H), 3.59 (d, J = 10.0 Hz,
MHz, CDCl , ppm): δ 175.8, 143.8, 137.9, 137.0, 133.4, 133.1, 128.9,
3
H), 3.22 (s, 3H), 2.42 (s, 3H), 1.59 (s, 3H).
1
28.2, 126.8, 110.6, 85.3, 56.5, 26.6, 9.8; HRMS m/z (ESI) calcd for
13
C NMR (100 MHz, CDCl , ppm): δ 177.8, 177.7, 144.0, 143.9,
+
3
C H NOI : [M + Na] : 511.8984; found: 511.8995.
16 13 2
142.0, 139.3, 137.3, 132.8, 132.3, 131.0, 110.6, 108.3, 95.1, 92.0, 51.0,
8
-Iodo-1-(iodomethyl)-1-methyl-5,6-dihydro-1H-pyrrolo[3,2,1-ij]
4
8.6, 28.9, 26.6, 26.5, 23.7, 23.2, 10.5, 8.2; HRMS m/z (ESI) calcd for
14
1
quinolin-2(4H)-one (4h): Yellow oil; H NMR (400 MHz, CDCl ,
3
+
C H NOI : [M + Na] : 463.8984; found: 463.8997.
12
13
2
ppm): δ 7.44 (s, 1H), 7.41 (s, 1H), 3.79–3.65 (m, 2H), 3.48 (d, J = 9.6
4
-Bromo-3-(iodomethyl)-1,3-dimethylindolin-2-one (2k), 6-bromo-
Hz, 1H), 3.38 (d, J = 9.6 Hz, 1H), 2.81–2.72 (m, 2H), 2.03–1.97 (m,
3
-(iodomethyl)-1,3-dimethylindolin-2-one (2k’), 2k/2k’ = 3.1:1:
13
2
H), 1.51 (s, 3H); C NMR (100 MHz, CDCl , ppm): δ 176.0, 138.7,
3
Yellow solid; m.p. 104 °C.
For 2k: H NMR (400 MHz, CDCl , ppm): δ 7.21 (d, J = 4.0 Hz, 2H),
6
1
36.2, 133.4, 129.5, 122.8, 84.7, 49.9, 38.9, 24.3, 22.7, 20.9, 10.3; HRMS
1
+
3
m/z (ESI) calcd for C H NOI : [M + Na] : 475.8984; found: 475.8998.
13 15 2
.85–6.81 (m, 1H), 4.02 (d, J = 9.8 Hz, 1H), 3.55 (d, J = 9.8 Hz, 1H),
16
5
-Bromo-3-(bromomethyl)-1,3-dimethylindolin-2-one (5a): Brown
3.25 (s, 3H), 1.68 (s, 3H).
o
16
1
solid; m.p. 92–93 C (lit. 91 °C); H NMR (400 MHz, CDCl , ppm):
1
3
For 2k’: H NMR (400 MHz, CDCl , ppm): δ 7.25 (dd, J = 1.8, 8.0
Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 1.8 Hz, 1H), 3.50 (d,
J = 10.0 Hz, 1H), 3.39 (d, J = 10.0 Hz, 1H), 3.23 (s, 3H), 1.51 (s, 3H).
3
δ 7.44 (dd, J =1.6, 8.0 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 6.74 (d, J = 8.0
Hz, 1H), 3.65 (d, J = 10.0 Hz, 1H), 3.57 (d, J = 10.0 Hz, 1H), 3.22 (s,
13
3
H), 1.46 (s, 3H); C NMR (100 MHz, CDCl , ppm): δ 177.1, 142.5,
13
3
C NMR (100 MHz, CDCl , ppm): δ 177.7, 145.4, 144.6, 131.5, 130.5,
3
133.7, 131.4, 126.3, 115.4, 109.6, 49.4, 36.5, 26.5, 22.2; HRMS m/z
130.0, 128.8, 125.5, 124.0, 122.3, 119.0,111.9, 107.3, 51.6, 48.5, 26.5,
+
(
ESI) calcd for C H NOBr : [M + Na] : 353.9105/355.9085/357.9064;
11 11 2
2
+
6.4, 22.9, 20.0, 10.0, 6.9; HRMS m/z (ESI) calcd for C H NOBrI: [M
11 11
found 353.9111/355.9094/357.9070 (23:43:19).
-(Chloromethyl)-3-methylindolin-2-one (6c): White solid; m.p.
+
Na] : 401.8966/403.8946; found: 401.8977/403.8949 (47:52).
3
1
4
5
-Iodo-3-(iodomethyl)-1,3,7-trimethylindolin-2-one (2l): Yellow
o
1
6
7–68 C; H NMR (400 MHz, CDCl , ppm): δ 9.08 (br, 1H), 7.34–7.27
14
o
1
3
solid; m.p. 159−161 °C (lit. 160 C); H NMR (400 MHz, CDCl ,
ppm): δ 7.41 (s, 1H), 7.34 (s, 1H), 3.49 (s,1H), 3.48 (d, J = 10.0 Hz,
3
(
1
m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 3.87 (d, J =
0.8 Hz, 1H), 3.80 (d, J = 10.8 Hz, 1H), 1.51 (s, 3H). C NMR (100
13
1
3
1H), 3.32 (d, J = 10.0 Hz, 1H), 2.55 (s, 3H), 1.48 (s, 3H); C NMR
MHz, CDCl , ppm): δ 178.1, 143.1, 132.6, 129.4, 126.3, 121.8, 115.4,
3
(100 MHz, CDCl , ppm): δ 178.0, 141.0, 140.7, 135.5, 129.3, 122.4,
3
+
5
9.7, 49.4, 21.8; HRMS m/z (ESI) calcd for C H NOCl: [M + Na] :
10
10
100.0, 85.2, 48.1, 29.7, 23.2, 18.7, 10.2; HRMS m/z (ESI) calcd for
218.0349/220.0319; found: 218.0357/220.0327 (39:12).
+
C H NOI : [M + Na] : 463.8984; found: 463.8988.
12
13
2
3
-(Chloromethyl)-3-methyl-1-phenylindolin-2-one (9b): White
5
-Iodo-3-(iodomethyl)-7-methoxy-1,3-dimethylindolin-2-one (2m):
o
1
solid; m.p. 129–131 C; H NMR (400 MHz, CDCl , ppm): δ 7.53
1
3
White solid; m.p. 97−99 °C; H NMR (400 MHz, CDCl , ppm): δ
3
(t, J = 8.0 Hz, 2H), 7.43–7.42 (m, 3H), 7.37 (d, J = 7.6 Hz, 1H), 7.26
7.40 (d, J = 2.0 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 3.87 (s, 3H), 3.68
(t, J = 8.0 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H),
(d, J = 10.8 Hz, 1H), 3.43 (d, J = 10.8 Hz, 1H), 3.39 (s, 3H), 1.61 (s,
3
.95 (d, J = 10.4 Hz, 1H), 3.84 (d, J = 10.4 Hz, 1H), 1.57 (s, 3H);
13
3H); C NMR (100 MHz, CDCl , ppm): δ 177.6, 156.1, 138.3, 134.1,
3
13
C NMR (100 MHz, CDCl , ppm): δ 177.9, 143.5, 133.6, 130.4, 129.3,
3
119.3, 108.1, 85.4, 58.0, 49.3, 26.7, 23.4, 10.9; HRMS m/z (ESI) calcd
1
28.4, 128.1, 126.2, 123.8, 123.7, 110.4, 59.5, 49.8, 21.9; HRMS m/z
+
for C H NO I : [M + Na] : 479.8933; found: 479.8939.
12
13
2
2
+
(
ESI) calcd for C H NOCl: [M + Na] : 294.0662/296.0632; found:
16 14
4
-Iodo-3-(iodomethyl)-1,3,5,7-tetramethylindolin-2-one
(2n):
294.0651/296.0624 (27:8).
1
White solid; m.p. 112−114 °C; H NMR (400 MHz, CDCl , ppm): δ
3
6
.90 (s, 1H), 3.64 (d, J = 10.0 Hz, 1H), 3.58 (d, J = 10.0 Hz, 1H), 3.48
Acknowledgements
13
(s, 3H), 2.54 (s, 3H), 2.31 (s, 3H), 1.61 (s, 3H); C NMR (100 MHz,
We thank the Taizhou Technology Plan Projects (No. 162gy54),
the College Students’ Science and Technology Innovation
Project of Zhejiang Province (No. 2016R462005) and the
Scientific Research Projects of Zhejiang Education Department
(Y201636395) for financial support.
CDCl , ppm): δ 177.8, 141.2, 138.6, 134.1, 131.3, 121.6, 85.3, 49.7, 26.9,
3
2
3.5, 21.3, 19.9, 10.9; HRMS m/z (ESI) calcd for: C H NOI : [M +
13 15 2
+
Na] : 477.9141; found: 477.9152.
-Iodo-1-(iodomethyl)-1,3-dimethyl-1H-benzo[e]indol-2(3H)-
one (2o): Yellow oil; H NMR (400 MHz, CDCl , ppm): δ 8.38 (dd,
7
14
1
3

JOURNAL OF CHEMICAL RESEARCH 2017 357
6
7
Y.-M. Li, M. Sun, H.-L. Wang, Q.-P. Tian and S.-D. Yang, Angew. Chem.,
Int. Ed., 2013, 52, 3972.
W.-T. Wei, B.-M. Zhou, J.-H. Fan, W. Liu, R.-J. Song, Y. Liu, M. Hu, P. Xie
and J.-H. Li, Angew. Chem., Int. Ed., 2013, 52, 3638.
F. Yin and X.-S. Wang, Org. Lett., 2014, 16, 1128.
Received 19 December 2016; accepted 30 April 2017
Paper 1604490
https://doi.org/10.3184/174751917X14944355549177
Published online: 23 May 2017
8
9
B. Zhou, W. Hou, Y. Yang, H. Feng and Y. Li, Org. Lett., 2014, 16, 1322.
References
10 K. Matcha, R. Narayan and A.P. Antonchick, Angew. Chem., Int. Ed.,
013, 52, 7985.
L. Li, M. Deng, S.-C. Zheng, Y.-P. Xiong, B. Tan and X.-Y. Liu, Org. Lett.,
014, 16, 504.
12 T. Shen, Y. Yuan and N. Jiao, Chem. Commun., 2014, 50, 554.
13 J. Qiu and R. Zhang, Org. Biomol. Chem., 2014, 12, 4329.
14 H.-L. Wei, T. Piou, J. Dufour, L. Neuville and J. Zhu, Org. Lett., 2011, 13,
2244.
15 M. Stodulski, A. Goetzinger, S.V. Kohlhepp and T. Gulder, Chem.
Commun., 2014, 50, 3435.
16 D.C. Fabry, M. Stodulski, S. Hoerner and T. Gulder, Chem.-Eur. J., 2012,
18, 10834.
2
1
T.-H. Kang, Y. Murakami, K. Matsumoto, H. Takayama, M. Kitajima, N.
Aimi and H. Watanabe, Eur. J. Pharmacol., 2002, 455, 27.
11
2
2
A.M. Swensen, J. Herrington, R.M. Bugianesi, G. Dai, R.J. Haedo, K.S.
Ratliff, M.M. Smith, V.A. Warren, S.P. Arneric, C. Eduljee, D. Parker,
T.P. Snutch, S.B. Hoyt, C. London, J.L. Duffy, G.J. Kaczorowski and O.B.
McManus, Mol. Pharmacol., 2012, 81, 488.
3
J.L. Whatmore, E. Swann, P. Barraja, J.J. Newsome, M. Bunderson, H.D.
Beall, J.E. Tooke and C.J. Moody, Angiogenesis, 2002, 5, 45.
4
5
S. Peddibhotla, Curr. Bioact. Compd., 2009, 5, 20.
C. Abbadie, O.B. McManus, S.-Y. Sun, R.M. Bugianesi, G. Dai, R.J. Haedo,
J.B. Herrington, G.J. Kaczorowski, M.M. Smith, A.M. Swensen, V.A.
Warren, B. Williams, S.P. Arneric, C. Eduljee, T.P. Snutch, E.W. Tringham,
N. Jochnowitz, A. Liang, D.E. MacIntyre, E. McGowan, S. Mistry, V.V.
White, S.B. Hoyt, C. London, K.A. Lyons, P.B. Bunting, S. Volksdorf and
J.L. Duffy, J. Pharmacol. Exp. Ther., 2010, 334, 545.
17 M.-Z. Zhang, W.-B. Sheng, Q. Jiang, M. Tian, Y. Yin and C.-C. Guo, J. Org.
Chem., 2014, 79, 10829.
18 M. Ludwig, C.E. Hoesl, G. Höfner, and K.T. Wanner, Eur. J. Med. Chem.,
2006, 41, 1003.