Transition-metal-free approach to synthesis of indolines from N-(ortho-chloromethyl)aryl amides and iodonium ylides

Article abstract of DOI:10.1016/j.tetlet.2013.08.096

A transition-metal-free method for the synthesis of indolines has been developed. In the presence of K₂CO₃, the cyclization reaction of N-(ortho-chloromethyl)aryl amides and iodonium ylides proceeded smoothly at room temperature in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2013.08.096

Tetrahedron Letters 54 (2013) 6049–6052
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Transition-metal-free approach to synthesis of indolines
from N-(ortho-chloromethyl)aryl amides and iodonium ylides
⇑
Hui Huang, Yuan Yang, Xiaoyun Zhang, Weilan Zeng, Yun Liang
National & Local Joint Engineering Laboratory for New Petro-chemical Materials and Fine Utilization of Resources, Key Laboratory of Chemical Biology and Traditional
Chinese Medicine Research, Ministry of Education, Hunan Normal University, Changsha, Hunan 410081, China
Beijing National Laboratory for Molecular Sciences, Beijing 100871, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A transition-metal-free method for the synthesis of indolines has been developed. In the presence of
K2CO3, the cyclization reaction of N-(ortho-chloromethyl)aryl amides and iodonium ylides proceeded
smoothly at room temperature in moderate to good yields.
Received 5 June 2013
Revised 15 August 2013
Accepted 24 August 2013
Available online 31 August 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
N-(ortho-Chloromethyl)aryl amide
Iodonium ylide
Indoline
Transition-metal free
Indolines are important building blocks in a vast number of bio-
logically active natural products1 and pharmacologically active
compounds.2 The synthesis of this privileged structure has at-
tracted significant interest and numerous synthetic methodologies
have been developed for recent years.3–10 Most of these
approaches to construct indolines were focused on transition-me-
tal-catalyzed C–N or C–C bond formation.4 However, because of
the high catalyst loading demand in some of these processes and
heavy metal residues in product, the application is restricted to
the costly and large workload in purification. Recently, transi-
tion-metal-free approaches for the synthesis of indolines have
been extensively studied, which include radical-mediated
reactions,5 intramolecular carbolithiation,6 and phenyliodine(III)-
mediated reactions.7 Moreover, Hao and co-workers reported a
cyclization of 2-aminophenethylethanols with common carboxylic
acids to form N-acyl indolines in the presence of PPh3, CCl4, and
NEt3.8 Stoltz and co-workers reported a coupling reaction of readily
available N-acyl dehydroamino esters with aryne precursors to
produce indolines.9 Ruano et al. developed an asymmetric tandem
reaction to facilitate the one-pot synthesis of optically pure fluori-
nated indolines from 2-(p-tolylsulfinyl)benzylcarbanions and N-
PMP-fluorinated imines.10 Although many useful and interesting
methods were reported, synthetic methods for the synthesis of
indolines, are still in great demand. In addition, diverse starting
materials and synthetic strategies are desired to make indoline
derivatives more readily accessible.
In 2012, Xiao and co-workers reported the synthesis of indoles
from sulfur ylides and N-(ortho-chloromethyl)aryl amides.11 The
process was initiated by the addition of sulfur ylide to the aza-oqu-
inodimethane intermediate, generated in situ from N-(ortho-chlo-
romethyl)aryl amide under the basic conditions. This step was
followed by cyclization with loss of dimethylsulfide to generate
indoline intermediate (Scheme 1). Due to the previous research
of iodonium ylides,12 we envisioned that it would react with
N-(ortho-chloromethyl)aryl amides to construct indolines as sulfur
Xiao's work
R2
R2
R2
R1
S
R1
R1
Cl
R3
+
N
N
Ts
R3
R3
H
NHTs
This work
R4
R4
R1
R2
R1
R2
IPh
Cl
NHTs
R3
+
N
R3
Ts
Scheme 1. Synthesis of indolines by cyclization of N-(ortho-chloromethyl)aryl
amides with iodonium ylides.
⇑
Corresponding author. Tel.: +86 731 8887 2576; fax: +86 731 8887 2531.
E-mail address: liangyun1972@126.com (Y. Liang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.096

6050
H. Huang et al. / Tetrahedron Letters 54 (2013) 6049–6052
ylides. Here in, we reported a transition-metal-free and mild
cyclization of N-(ortho-chloromethyl)aryl amides with iodonium
ylides for the synthesis of indolines.
O
O
O
K2CO3
Ph
Cl
NH
+
Ph CH3CN
N
R
Initially, the cyclization of N-(2-(chloromethyl)phenyl)-4-meth-
ylbenzenesulfonamide (1a) with methyl 2-phenyliodonio-3-oxo-
butanoate (2a) was selected for optimization of reaction
conditions, and the results are summarized in Table 1. Our investi-
gation started by an attempted cyclization of substrate 1a with 2a
in CH2Cl2 at room temperature in the presence of Cs2CO3 as base,
and the desired product 3a could be isolated in 44% yields (entry
1). This result encouraged us to develop a transition-metal-free
system to synthesize indolines. Then, a variety of solvents, such
as toluene, THF, and CH3CN were screened. Results indicated that
solvent (CH3CN) is the best for this cyclization reaction (entries
1–4). Subsequently, the effects of base (including inorganic base
K2CO3, KOH, NaHCO3, K3PO4, CsOAc, NaOAc, CsF, LiOt-Bu, NaOEt
and organic base DABCO, NEt3) (entries 5–15) were examined.
K2CO3 was found to give the best result. Finally, the amount of base
and reaction temperature were evaluated. Relatively low yields
were found when the reaction was carried out in 0 and 60 °C (en-
tries 16 and 17), and the yields of 3a did not lead to an obvious
improvement when the amount of K2CO3 was increased to
5.0 equiv. Thus, the optimized reaction conditions were as follows:
1a (0.30 mmol), 2a (0.36 mmol), K2CO3 (2.5 equiv), in CH3CN
(2 mL) at room temperature.
IPh
2b
O
R
1a-c
3b-d
O
O
O
Ph
Ph
Ph
N
S O
N
S
N
O
S O
O
O
O
O
O
O
F
3c, 60%
3b, 74%
3d, 50%
a
1
2b
(0.36 mmol), K2CO3 (2.5
Reaction conditions: (0.3 mmol),
equiv),solvent (2 mL), 2 h, room temperature. b Isolated yield.
Scheme 2. Cyclization of N-(2-(chloromethyl)phenyl)-benzenesulfonamides with
2-phenyliodonio-1-phenylbutane-1,3-dione.
dependence in the following order: 4-methylbenesulfonyl > bene-
sulfonyl > 4-fluorobenesulfonyl. We believe this observation sup-
ported the formation of indolines via an addition and N-
alkylation process.
Since such an addition and cyclization process are supposed, we
then investigated the effect of 4-methylbenesulfonyl, benesulfonyl,
and 4-fluorobenesulfonyl substituents on the N-(2-(chloro-
methyl)phenyl)-sulfonamide (Scheme 2). As expected, 74% yield
was obtained when N-(2-(chloromethyl)phenyl)-4-methylben-
zenesulfonamide was applied. In the reaction of N-(2-(chloro-
methyl)phenyl)-4-fluorobenzenesulfonamide, only 50% yield was
observed. A comparison of the reaction yields from N-(2-(chloro-
With the standard reaction conditions in hand, the scope of the
cyclization of N-(2-(chloromethyl)phenyl)-4-methylbenzenesulf-
onamide with various iodonium ylides were investigated, and the
results are summarized in Table 2. The results demonstrated that
the yields were affected by the structures of the two reaction
partners to some extent. Firstly, a number of 2-phenyliodonio-3-
oxobutanoates (2c–2i) were evaluated, and they all were found
to be suitable substrates for the cyclization with N-(2-(chloro-
methyl)phenyl)-4-methylbenzenesulfonamide under the standard
conditions (entries 1–7). For instance, when substrate 2c bearing
an allyl group, was treated with N-(2-(chloromethyl)phenyl)-4-
methylbenzenesulfonamide 1a and K2CO3 in room temperature,
indoline 3e was formed in 61% yield (entry 1). Substrate 2h and
2i containing a halo group or methoxyl group was also tolerated
well under the same conditions (entries 6 and 7). Subsequently,
the reaction of 1a with the iodonium ylide of dimethyl malonate
2j was conducted smoothly in 41% yield under the standard condi-
tions (entry 8). Interestingly, the reaction of 1a with 2-phenyliod-
onio-3-oxo-3-phenylpropanenitrile (2k) was conducted smoothly
in 27% yield under the standard conditions (entry 9). We were hap-
py to observe that 2-phenyliodonio-2,4-diones (2l-n) could also
react with N-(2-(chloromethyl)phenyl)-4-methylbenzenesulfona-
mide efficiently in moderate yields (entries 10–12). 3-Phenyliodo-
nio-pentane-2,4-dione (2l), for example, was treated with 1a to
afford the corresponding products 3n in 70% yield (entry 10).
Importantly, 74% yield of an interesting spiro[cyclohexane-1,20-
indoline]-2,6-dione product 3p was obtained in the reaction of
substrate 1a with ylide 2n (entry 12). Finally, the effect of
substitutional groups on N-(2-(chloromethyl)phenyl)-4-methyl-
benzenesulfonamide was screened. For example, 1,2-substitutent
indoline 3q was obtained in the yield of 56% when substrate
methyl)phenyl)-sulfonamide indicated
a
significant sulfonyl
Table 1
Optimization of reaction conditionsa
O
O
O
Cl
Base
Solvent, Rt
+
O
OEt
NH
Ts
N
IPh
2a
OEt
Ts
1a
3a
Entry
Base
Solvent
Yield of 3ab (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16c
17d
18e
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KOH
NaHCO3
K3PO4
CsOAc
NaOAc
CsF
LiOt-Bu
NaOEt
DABCO
NEt3
K2CO3
K2CO3
K2CO3
CH2Cl2
Toluene
THF
44
33
56
59
68
20
20
57
56
57
61
31
60
0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
N-(2-(1-chloroethyl)phenyl)-4-methylbenzenesulfonamide
(1d)
15
65
63
69
was applied. N-(2-(Chloromethyl)phenyl)-4-methylbenzenesulf-
onamide bearing electron-withdrawing group such as Cl (1e) or
electron-donating group such as OMe (1f) on benzene ring
afforded the corresponding indolines in 40% and 48% yields.
Importantly, the acetyl substituted indolines were found to
undergo the elimination and isomerization to afford indoles.
For example, the acetyl substituted indulines 3a and 3n could
be readily converted into corresponding indoles 4 and 5 in
a
Reaction conditions: 1a (0.30 mmol), 2a (0.36 mmol), base (2.5 equiv), solvent
(2 mL), 2 h, room temperature.
b
Isolated yield.
In 0 °C.
In 60 °C.
Base (5 equiv).
c
d
e

H. Huang et al. / Tetrahedron Letters 54 (2013) 6049–6052
6051
Table 2
Cyclization of N-(2-(chloromethyl)phenyl)- benzenesulfonamides with iodonium ylidesa
R4
R4
R1
R2
R1
R2
IPh
K2CO3
Cl
R3
+
CH3CN, Rt
N
NHTs
R3
1f
Ts
3
1
2
1e
: R3 = H, R4 = Me; : R3 = 3-Cl; R4 = H; : R3 = 3,4-(OMe)2, R4 = H
1d
Entry
1
1
Iodonium yield
Indolineb (%)
Entry
9
1
Iodonium yield
Indolineb (%)
CN
O
O
O
O
NC
O
O
O
O
N
Ts
O
1a
1a
IPh
N
O
IPh
2c
O
Ts
3e, 61%
O
2k
3m, 27%
O
O
Ph
O
O
O
O
2
3
4
5
6
1a
1a
1a
1a
1a
10
11
12
13
14
15
1a
1a
1a
1a
1e
1f
IPh
2d
IPh
2l
N
Ts
N
Ts
O
O
Ph
3n, 70%
3f, 69%
O
O
O
O
O
O
Ph
Ph
O
Ph
Ph
O
O
IPh
2e
IPh
2m
N
Ts
N
O
O
Ts
3o, 49%
3g, 40%
O
O
O
O
O
O
O
O
IPh
2f
N
Ts
N
IPh
2n
Ts
O
O
3p, 74%
3h, 64%
O
O
O
O
Ph
O
Ph
O
O
O
IPh
2g
N
N
Ts
IPh
2n
O
O
Ts
3q, 56%
3i, 30%
O
O
Cl
O
O
O
O
Cl
O
O
IPh
N
Ts
N
Ts
IPh
2n
Cl
O
2h
3r, 40%
3j, 68%
O
O
OMe
O
O
O
O
MeO
MeO
Ph
MeO
O
Ph
O
7
8
1a
1a
N
IPh
IPh
2b
N
Ts
O
Ts
O
2i
3s, 48%
3k
, 54%
O
O
O
O
O
O
O
IPh
2j
N
O
Ts
3l, 41%
a
Reaction conditions: 1a (0.30 mmol), 2 (0.36 mmol), K2CO3 (2.5 equiv), solvent (2 mL), 2 h, room temperature.
Isolated yield.
b
95% and 99% yield under the basic conditions (Scheme 3). Reac-
tion of this type could have been used in the synthesis of 2-
substituted indoles.
A working mechanism as outlined in Scheme 4 was proposed
for the present reaction on the basis of the previously reported
mechanism.11–13 Firstly, N-(2-chlorobenzyl)-4-methylbenzenesulf-
onamide was converted into the aza-o-quinodimethane intermedi-
ate A under the basic conditions. Then, aza-o-quinodimethane
underwent Michael addition and N-alkylation with iodonium ylide
to generate product indoline by loss of an iodobenzene.

6052
H. Huang et al. / Tetrahedron Letters 54 (2013) 6049–6052
O
References and notes
O
KOH (2.5 equiv)
CH3CN, rt, 20 h
O
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N
H
, 95%
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Ts
3a
4
5
O
O
KOH (2.5 equiv)
CH3CN, rt, 20 h
O
N
N
H
, 99%
Ts
3n
Scheme 3. Synthesis of 2-substituted indoles by the elimination of the acetyl
substituted indolines.
O
O
Michael
addition
O
Cl
O
Base
N-alkylation
N
I
OEt
NHTs
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Ts
OEt
A
Ph
2a
Ts
3a
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1a
Scheme 4. Proposed reaction pathway for the synthesis of indolines from N-(ortho-
chloromethyl)aryl amides with iodonium ylides.
In summary, we have outlined a transition-metal-free strategy
for the preparation of indolines. In the presence of K2CO3, N-
(ortho-chloromethyl)aryl amides successfully underwent Michael
addition and N-alkylation with iodonium ylide at room tempera-
ture to afford the corresponding indolines in moderate to good
yields. Further studies of the reaction scope and mechanism are
currently underway in our laboratory.
Acknowledgments
We thank the Natural Science Foundation of China (21072054),
New Teachers’ Fund for Doctor Stations, Ministry of Education of
China (20094306120003), Training Program Foundation for the
Young Talents by Hunan Normal University of China (ET21003),
Hunan Provincial Natural Science Foundation of China (12JJ2009),
Scientific Research Fund of Hunan Provincial Education Depart-
ment (12A095) and Aid Program for Science and Technology Inno-
vative Research Team in Higher Educational Institutions of Hunan
Province for financial support.
11. Yang, Q.-Q.; Xiao, C.; Lu, L.-Q.; An, J.; Tan, F.; Li, B.-J.; Xiao, W.-J. Angew. Chem.,
Int. Ed. 2012, 51, 9137.
Supplementary data
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Supplementary data (experimental procedures and character-
ization data for all new compounds and copies of NMR spectra)
associated with this article can be found, in the online version,
athttp://dx.doi.org/10.1016/j.tetlet.2013.08.096.