An efficient and regioselective iodination of electron-rich aromatic compounds using N-chlorosuccinimide and sodium iodide

Article abstract of DOI:10.1016/j.tetlet.2009.12.125

An efficient and regioselective method for iodination of electron-rich aromatic compounds was found using N-chlorosuccinimide and sodium iodide in AcOH with short reaction times. This method is also applicable to non-benzenoid aromatic or heteroaromatic c

Full text of DOI:10.1016/j.tetlet.2009.12.125

Tetrahedron Letters 51 (2010) 1364–1366
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Tetrahedron Letters
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An efficient and regioselective iodination of electron-rich aromatic
compounds using N-chlorosuccinimide and sodium iodide
*
*
Takuya Yamamoto , Kozo Toyota, Noboru Morita
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and regioselective method for iodination of electron-rich aromatic compounds was found
using N-chlorosuccinimide and sodium iodide in AcOH with short reaction times. This method is also
applicable to non-benzenoid aromatic or heteroaromatic compounds.
Received 24 October 2009
Revised 21 December 2009
Accepted 22 December 2009
Available online 29 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Iodination
Electrophilic substitution
Aromatic compounds
Thiophenes
Iodoarenes are one of the most important species in organic
synthesis, because they are more reactive than the corresponding
bromides and chlorides. For example, they are used in metal-cata-
lyzed coupling1 reactions such as Heck–Mizoroki,2 Negishi,3 Stille,4
and Suzuki reactions.5 Iodination of aromatic compounds is carried
out normally by using reagents such as I2,6 benzyltriethylammo-
nium dichloroiodate–NaHCO3,7 ICl,8 ICl–Cp2FeB[3,5-(CF3)2C6H3]4,9
N-iodosuccinimide (NIS),10 NIS–CF3SO3H,11 NIS–CF3CO2H,12 NaO-
Cl–NaI.13 However, most of these methods require toxic reagents
or hard conditions. In addition, NIS is expensive than N-chloro-
(NCS) and N-bromosuccinimide (NBS).14
tory results (entries 3 and 4). Other solvents were screened, and
acetic acid was found to be the best one (entries 5 and 6).
We next explored the iodination of several aromatic compounds
with NCS and NaI under the optimized conditions. The results are
summarized in Table 2.16 Methoxy aromatic derivatives gave the
excellent yields of the corresponding iodoarenes with good selectiv-
ity (entries 1–4). The reaction of 1,3,5-triethylbenzene17 proceeded
at 100 °C in the modest yield (entry 5). Iodination of N,N-dimethyl-
anilineproduced p-iodo-N,N-dimethylaniline (7) (entry 6). The reac-
tion of azulene as a non-benzenoidaromatic compound with 2 equiv
of reagents also afforded the expected iodination product 8 (entry 7).
Thus, it is useful to use iodide salts such as sodium iodide com-
pared with using I2, NIS, or other reactive reagents. Recently, Ogivie
et al. reported the iodochlorination of alkynes and alkenes using
NCS in the presence of tetrabutylammonium iodide,15 but iodin-
ation of aromatic compounds were not carried out. Iodination of
aromatic compounds using NCS in the presence of iodide ion is
of interest.
Table 1
Optimization of the reaction conditions of 1a
OMe
OMe
NCS (1 equiv)
NaI (1 equiv)
Here we report the iodination of activated aromatic compounds
with NCS and NaI under mild conditions.
solvent
I
1
2
Our initial exploration was focused on the reaction of anisole (1)
with NCS and NaI in AcOH at room temperature, which proceeded
to afford 2 in 54% yield (Table 1, entry 1). Efficient iodination was
realized at 50 °C for 2 h in 93% yield (entry 2). The other additives
such as KI and tetrabutylammonium iodide did not give satisfac-
Entry
Additive
Solvent
Condition
Yieldb (%)
1
2
3
4
5
6
NaI
NaI
KI
AcOH
AcOH
AcOH
AcOH
MeOH
MeCN
rt, 3 h
54
93
65
67
NR
25
50 °C, 2 h
50 °C, 2 h
Reflux, 2 h
Reflux, 2 h
n-Bu4NI
NaI
NaI
Reflux, 12 h
* Corresponding authors. Tel.: +81 22 795 6560.
E-mail addresses: yamataku@m.tains.tohoku.ac.jp (T. Yamamoto), nmorita-
kamo@hb.tp1.jp (N. Morita).
a
Concentration was 0.1 M.
Isolated yield.
b
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.125

T. Yamamoto et al. / Tetrahedron Letters 51 (2010) 1364–1366
1365
Table 2
Iodination of various aromatic compounds with NCS and NaIa
+OH
N Cl
O
OH
N+ Cl
O
N Cl
AcO-
Yieldb (%)
93c
AcOH
Entry
Condition
Product
O
O
MeO
I
1
50 °C, 2 h
13
13'
2
I
NaI
H
+OH
N Cl
OMe
HCl
Aryl-H
2
50 °C, 2 h
91
I-Cl
Aryl-I
15
3
14
O
OMe
I
N
O
O
AcONa
13'
3
4
rt, 1.5 h
87
84
MeO
MeO
4
Scheme 2. Plausible mechanism.
I
50 °C, 2 h
5
Although NCS/NaI system was highly selective for the iodin-
ation of thiophene rings, a reaction of 3-phenylthiophene with
1 equiv of ICl gave a mixture of products in our hands. The NCS/
NaI system appeared to be moderately reactive, compared with
the case of the reaction of ICl.
Et
5
100 °C, 12 h
49d
Et
Et
I
6
7
Furthermore, we investigated the bromination reaction
(Scheme 1). The reaction of anisole (1) with 1 equiv of NCS and
NaBr gave p-bromoanisole (12) (rt, 2 h, 80%).
Me2N
I
6
rt, 1 h
rt, 1 h
80
89
A possible mechanism of iodination of aromatic compounds is
shown in Scheme 2. NCS is activated by AcOH. The iodide ion at-
tacks on the electrophilic chlorine atom of the intermediate 130,
which would generate ICl 14.15 Then, aromatic compounds react
with the electrophilic iodine to generate iodoarenes 15.
In conclusion, an efficient and mild method for the iodination of
electron-rich aromatic compounds using NCS and NaI was accom-
plished. The reagents for iodination are superior in easy handling
as well as availability and cost performance.
I
7e
I
8
S
I
8f,g
rt, 2 h
97
n
-hexyl
9
S
I
I
Acknowledgment
9f
50 °C, 3 h
92
92
Ph
This work was supported in part by the Grants-in-Aid for Scien-
tific Research (No. 20550030) from the Ministry of Education, Cul-
ture, Sports, Science and Technology.
10
S
I
10e
rt, 2 h
S
11
References and notes
a
b
c
d
e
f
NCS (1 equiv), NaI (1 equiv), AcOH (0.1 M).
Isolated yield.
Trace amount of o-iodoanisole was observed.
Starting material was 49% recovery.
NCS (2 equiv), NaI (2 equiv).
1. (a) Carril, M.; Corrae, A.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 4862; (b)
Candra, M.; Pirre Vogel, R. V. Tetrahedron Lett. 2008, 49, 5961.
2. (a) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518; (b) Mizoroki, T.; Mori, K.; Ozaki,
A. Bull. Chem. Soc. Jpn. 1971, 44, 581.
3. Baba, S.; Negishi, E. J. Am. Chem. Soc. 1976, 98, 6729.
4. Azarian, D.; Dua, S. S.; Eaborn, C.; Walton, D. R. M. J. Organomet. Chem. 1976,
117, C55.
NCS (1.5 equiv), NaI (1.5 equiv).
A mixture of AcOH and MeCN (1:1) was used as a solvent.
g
5. Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979.
6. Bothe, R.; Dial, C.; Conaway, R.; Pagni, R. M.; Kabalka, G. W. Tetrahedron Lett.
1986, 27, 2207.
NCS (1 equiv)
NaBr (1 equiv)
OMe
OMe
7. Kosynkin, D. V.; Tour, J. M. Org. Lett. 2001, 3, 991.
8. Hubig, S. M.; Jung, W.; Kochi, J. K. J. Org. Chem. 1994, 59, 6233.
9. Mukaiyama, T.; Kitagawa; Matsuo, J. Tetrahedron Lett. 2000, 41, 9383.
10. Carreño, M. C.; García Ruano, J. L.; Miguel, A. G. S.; Urbano, A. Tetrahedron Lett.
1996, 37, 4081.
AcOH, rt, 2 h
80%
Br
1
12
11. Olah, G. A.; Sandford, G. Q. W.; Surya, P. G. K. J. Org. Chem. 1993, 58, 3194.
12. Castanet, A. S.; Colobert, F.; Broutin, P. E. Tetrahedron 2002, 43, 5047.
13. Edgar, K. J.; Falling, S. N. J. Org. Chem. 1990, 55, 5287.
14. (a) Gronowitz, S.; Holm, B. Acta Chem. Scand. 1976, 30, 423; (b) Tanemura, K.;
Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Horaguchi, T. Chem. Lett. 2003, 32,
932.
15. Ho, L. M.; Flynn, B. A.; Ogilvie, W. W. J. Org. Chem. 2007, 72, 977.
16. A typical experimental procedure is as follows: To a mixture of NCS (0.93 mmol)
and NaI (0.93 mmol) in AcOH (4.0 mL) was added a solution of aromatic
compound (0.93 mmol) in AcOH (5.3 mL). The reaction mixture was stirred at
room temperature for several hours. Upon completion, the mixture was poured
into satd aq NaHCO3, and extracted with AcOEt. The organic layer was washed
with brine and dried over MgSO4. The filtrate was concentrated under reduced
pressure, and purified by silica gel chromatography to give the iodoarene
derivative.
Scheme 1. Bromination of anisole (1).
Furthermore, this method is applicable to the heteroaromatic
compounds (entries 8–10). Exclusive regioselective18 iodination19
was performed using AcOH/MeCN = 1:1 as a solvent (entry 8). It
should be noted that the reaction of 3-hexylthiophene with NCS
and NaI in AcOH formed 2-chloro-3-hexylthiophene as a by-prod-
uct along with 9.20 3-phenylthiophene gave 2-iodo-3-phenylthi-
ophene (10) in an excellent yield (entry 9). Treatment of
thieno[3,2-b]thiophene21 with 2 equiv of NCS and NaI afforded
the disubstituted product 11 (entry 10).
17. The reaction of toluene with 1 equiv of NCS and NaI did not proceed.

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T. Yamamoto et al. / Tetrahedron Letters 51 (2010) 1364–1366
18. Gronowitz, S.; Gjos, N.; Kellogg, R. M.; Wynberg, H. J. Org. Chem. 1967, 32, 463.
19. (a) Johnson, A. L. J. Org. Chem. 1976, 41, 1320; (b) Toyota, K.; Okada, K.; Katsuta,
H.; Tsuji, Y.; Morita, N. Heterocycles 2009, 77, 1057.
20. The yields of 3-hexyl-2-iodothiophene (9) and 2-chloro-3-hexylthiophene in
AcOH were 81% and 16%, respectively.
21. (a) Henssler, J. T.; Matzger, A. Org. Lett. 2009, 11, 3144; (b) Fuller, L. S.; Iddon, b.;
Smith, K. A. J. Chem. Soc., Perkin Trans. 1997, 3465; (c) Yasuike, S.; Kurita, J.;
Tsuchita, T. Heterocycles 1997, 45, 1891; (d) Boldt, P.; Bourhill, G.; Braüchle,
C.; Jim, Y.; Kammler, R.; Muller, C.; Rase, J.; Wichem, J. Chem. Commun.
1996, 793.