Selective 5-exo-trig Iodocyclization of N-tosyl-2-allylanilines in Water

Article abstract of DOI:10.2174/157017810791824829

Various 2-iodomethyl-N-tosylindolines are obtained in high yields from the reaction of N-tosyl-2-allylanilines with iodine in water at 50 °C.

Full text of DOI:10.2174/157017810791824829

440
Letters in Organic Chemistry, 2010, 7, 440-443
Selective 5-exo-trig Iodocyclization of N-tosyl-2-allylanilines in Water
Michalis Batistatosa, Manolis A. Fousterisa,b, Sotiris S. Nikolaropoulos*,a, Jean Le Brasb and
Jacques Muzartb
aLaboratory of Medicinal Chemistry, Department of Pharmacy, School of Health Sciences, University of Patras, 26500
Patras, Greece
bInstitut de Chimie Moléculaire, UMR 6229, CNRS-Université de Reims Champagne-Ardenne, BP 1039, 51687 Reims
Cedex 2, France
Received October 19, 2009: Revised March 25, 2010: Accepted April 19, 2010
Abstract: Various 2-iodomethyl-N-tosylindolines are obtained in high yields from the reaction of N-tosyl-2-allylanilines
with iodine in water at 50 °C.
Keywords: Iodocyclization, indolines, iodine, water.
The indoline core is a prevalent structural component
found in a variety of natural products and synthetic
compounds with diverse biological activities [1]. Because of
their promising pharmacological applications, indolines
serve as attractive synthetic targets and a number of
methodologies based on cyclization of aniline derivatives
[2,3] or radical-mediated additions [4] have been reported.
Also, domino Pd-catalyzed ortho-alkylation/amination [5] or
Cu-catalyzed amidation/nucleophilic substitution reactions
of substituted iodoarenes [6], PdII-catalyzed C-H activation
In contrast, PdII-catalysis has been used with excesses of
K2CO3 and CuX2 (X = Cl or Br) to mediate the
halocyclization of N-substituted-2-allylanilines [15]. These
catalytic conditions led however to a mixture of 5-endo and
6-exo cyclisation products.
Preliminary experiments carried out with 2-allylaniline as
substrate and various amounts of iodine led to complex
mixtures containing low amounts of the expected 2-
iodomethyl-indoline. Strong improvements of the results
have been obtained with the substitution of the nitrogen atom
I2
R
R
(1)
I
H2O, 50 °C
OH
O
Equation 1.
reactions of arylethylamines [7], and intramolecular
cyclizations of 2-p-tolylsulfinyl alkylbenzene derivatives [8]
have been referred. Additional functionalization of the
indoline core remains an open challenge for synthetic
chemists on the way to the construction of more complex
compounds [9].
of the substrate by a tosyl group [16]. Indeed, heating 4-
methoxy-N-tosyl-2-allylaniline (1a) with 4 equiv. of iodine
o
in water (2 mL/mmol of 1a) at 50 C for 2 h afforded 2-
(iodomethyl)-5-methoxy-1-tosylindoline [17] (2a) that has
been isolated in 81% yield after column chromatography
(Eq. 2; Table 1, run 1). Lowering the amount of I2 to 1.2
equiv. and increasing the reaction time to 3 h led to a similar
yield (Run 2) while the decrease to 1 equiv. resulted in 72%
yield (Run 3). Performing the iodocyclization in a 1:1
mixture of H2O/MeCN, with or without NaHCO3 as basic
additive, was not beneficial to the process (Runs 4 and 5). A
high yield can be obtained in the absence of water but an
extended reaction time is thus required (Runs 6 and 7).
Recently, we disclosed the water-promoted iodocy-
clization of 2-allylphenols (Eq. 1) [10]. The interest of this
procedure has been highlighted by Tripathi and co-workers
who have synthesized a range of 2-methylbenzofurans [11].
This urges us to exploit this methodology to synthesize 2-
iodomethyl-indolines. The iodocyclization of N-alkenyl-
amides has been reported using MeCN as the solvent and
excess of both t-BuOCl and NaI [12], I2 under basic or acidic
conditions [13], or a mixture of Chloramine T and I2 [14],
but, to the best of our knowledge, these methods have not
been used with 2-allylaniline type compounds as substrates.
Encouraged by these results, the iodocyclization of N-
tosyl-2-allylanilines 1b-1f has been carried out using 1.2 and
4 equiv. of I2 in water at 50 °C (Eq. 3) [18]. As shown in
Table 2, the corresponding 2-iodomethyl-indolines (2b-2f)
have been obtained, in up to 90% yield [19], with efficiency
and a reaction rate depending on both the structure of the
substrate and the amount of iodide. It should be noted that, in
all aforementioned experiments, the alternative 6-exo
cyclisation was never detected.
*Address correspondence to this author at the Laboratory of Medicinal
Chemistry, Department of Pharmacy, School of Health Sciences, University
of Patras, 26500 Patras, Greece; Tel: (+30) 2610969326; Fax: (+30)
2610310553; E-mail: snikolar@upatras.gr
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

Selective 5-exo-trig Iodocyclization of N-tosyl-2-allylanilines
Letters in Organic Chemistry, 2010, Vol. 7, No. 6 441
MeO
MeO
I2
(2)
H
N
I
N
solvent, 50 °C
Ts
Ts
1a
2a
Equation 2.
Table 1. Iodocyclization of 1a Under Different Conditions
Run
Solvent
I2 (equiv.)
Time (h)
Yield %
1
2
H2O
H2O
4
2
3
81
82
72
69
70
62
81
1.2
1
3
H2O
3
4
H2O/MeCN (1:1)
H2O/MeCN (1:1)
MeCN
1.2
1.2
1.2
1.2
3
5a
16
3
6
7
MeCN
27
aReaction carried out in the presence of NaHCO3 (1.2 equiv.).
R1
R1
R2
R2
I2 (1.2 or 4 equiv.)
H2O, 50 °C
(3)
H
I
R3
R3
N
N
Ts
Ts
2b-2f
1b-1f
b: R1 = R3 = H, R2 = n-Bu. c: R1 = R3 = H, R2 = Cl.
d: R1 = R3 = H, R2 = Me. e: R1 = R2 = R3 = H.
f: R1 = R3 = Me, R2 = H.
Equation 3.
Table 2. Iodocyclization of 1b-1f
Substrate
I2 (equiv.)
Time (h)
Yield (%)
1b
"
1.2
4
3
1
68
90
80
71
79
73
79
84
88
79
1c
"
1.2
4
2
4
1d
"
1.2
4
4
1
1e
"
1.2
4
2.75
1
1f
"
1.2
4
0.5
0.3
In conclusion, 2-iodomethyl-N-tosylindolines can be
obtained from N-tosyl-2-allylanilines using an inexpensive
and efficient procedure requiring only iodine as reagent and
water as solvent.
ACKNOWLEDGEMENTS
The nuclear magnetic resonance and the GC-MS spectra
were carried out in the Center of Instrumental Analysis of

442 Letters in Organic Chemistry, 2010, Vol. 7, No. 6
Batistatos et al.
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SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
Web site along with the published article.
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Physical data for compound 2a: Mp: 146.5-147.5 ºC. IR (KBr) ꢂ
cm-1: 3009, 2920, 2837, 1597, 1487, 1350, 1161, 812, 704, 665,
a
phenyliodine(III)
1
606, 571, 540. H NMR (CDCl3, 400 MHz): ꢀ 2.36 (s, 3H), 2.73-
2.84 (m, 2H), 3.23 (t, J = 10.0 Hz, 1H), 3.62 (dd, J = 9.7, 3.6 Hz,
1H), 3.76 (s, 3H), 4.29-4.35 (m, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.76
(dd, J = 8.8, 2.6 Hz, 1H), 7.18 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.3
Hz, 2H), 7.55 (d, J = 8.8 Hz, 1H). 13C NMR (CDCl3, 100 MHz): ꢀ
11.1, 21.5, 34.9, 55.6, 62.9, 110.9, 113.2, 118.2, 127.2, 129.7,
132.4, 134.3, 134.6, 144.1, 157.6. GC-MS (EI): tR = 14.08; 443
(12) [M+], 288 (44), 161 (100), 146 (18), 130 (4), 118 (5), 105, 91

Selective 5-exo-trig Iodocyclization of N-tosyl-2-allylanilines
Letters in Organic Chemistry, 2010, Vol. 7, No. 6 443
(6). Anal. Calcd. for C17H18INO3S: C, 46.06; H, 4.09; N, 3.16;
Found: C, 45.98; H, 4.07; N, 3.14.
extracted with dichloromethane (3ꢀ10 mL). The combined organic
phases were dried over Na2SO4 and the solvent was removed under
reduced pressure. The crude mixture was purified by silica gel
column chromatography using hexanes-ethyl acetate mixtures as
eluents to afford the corresponding 2-iodomethyl-N-tosyl-indoline
2.
[18]
Typical procedure for the synthesis of 2-iodomethyl-N-tosyl-
indoline derivatives 2a-2f. A mixture of 1 (0.25 mmol) and iodine
(1.2 or 4 mmol) in water (0.5 ml) was stirred at 50 ºC for the
indicated time. The reaction mixture was diluted with
dichloromethane (10 mL) and aqueous saturated Na2S2O3 was
added. The phases were separated and the aqueous layer was
[19]
For spectroscopic data of 2b-2f see Supplementary Material.