Tetramethylammonium dichloroiodate: An efficient and environmentally friendly iodination reagent for iodination of aromatic compounds under mild and solvent-free conditions

Article abstract of DOI:10.1021/jo0264628

Tetramethylammonium dichloroiodate (1, TMADCI) as a mild and efficient iodination reagent was prepared. Iodination of different aromatic compounds with this reagent takes place fast and with high yields under solvent-free conditions.

Full text of DOI:10.1021/jo0264628

Tetr a m eth yla m m on iu m Dich lor oiod a te: An Efficien t a n d
En vir on m en ta lly F r ien d ly Iod in a tion Rea gen t for Iod in a tion of
Ar om a tic Com p ou n d s u n d er Mild a n d Solven t-F r ee Con d ition s
Abdol R. Hajipour,*,†,‡ Marty Arbabian,† and Arnold E. Ruoho†
Department of Pharmacology, University of Wisconsin, Medical School, 1300 University Avenue,
Madison, Wisconsin 53706-1532, and Pharmaceutical Research Laboratory, College of Chemistry,
Isfahan University of Technology, Isfahan 84156, IR Iran
arhajipour@facstaff.wisc.edu; haji@cc.iut.ac.ir
Received September 19, 2002
Tetramethylammonium dichloroiodate (1, TMADCI) as a mild and efficient iodination reagent was
prepared. Iodination of different aromatic compounds with this reagent takes place fast and with
high yields under solvent-free conditions.
In tr od u ction
ditions,12 we herein report an extremely convenient
method for the iodination of activated and deactivated
aromatic compounds with TMADCI (1) under solvent-
free conditions. The readily prepared reagent (see Ex-
perimental Section) is a yellow powder, which is stable
and can be stored at room temperature in a dark bottle
for months without loss of its activity; it is soluble in polar
solvents such as methanol, THF, acetonitrile, acetone,
DMF, chloroform, ethyl acetate, and dichloromethane,
but insoluble in solvents such as carbon tetrachloride,
hexane, and diethyl ether (Scheme 1).
Iodobenzene derivatives are valuable, versatile syn-
thetic intermediates, which have found wide applications
in medicine and biochemistry.1 However, iodine is a
weaker electrophile compared to bromine and chlorine.
For this and other reasons (e.g., electrophilic iodination
generates hydrogen iodide, which is both a strong reducer
and a strong acid and can cause protolytic cleavage of
Ar-I), there are few known methods available for direct
iodination of aromatic compounds,1-6 and the hydrogen
iodide generated may be scavenged with alkalis or
pyridine7 or destroyed by the addition of various oxidants
such as mercuric oxides.8
Reactions under solvent-free conditions have received
increasing attention in recent years. The advantage of
these methods over conventional homogeneous reactions
is that they provide greater selectivity, proceed with
enhanced reaction rates, give cleaner products, and
involve simple manipulation.9-11
SCHEME 1
NaI + NaClO + 2HCl 0 °C8 NaICl2 + NaCl + H2O
H2O/20 min
Me4N+Cl- + NaICl2
8 Me4N+Cl2- + NaCl
room temperature
98%
The process involves simple mixing of the aromatic
compound and reagent 1 in a mortar and grinding the
mixture with a pestle to produce a homogeneous powder,
then allowing the mixture to stand for the specified time
(Table 1) at room temperature. This reaction proceeds
rapidly, and purification of products is very simple.
Activated aromatic compounds 2 were converted to the
corresponding iodo-aromatic compounds 3 under solvent-
free conditions at room temperature in excellent yields
in 5-20 min; deactivated aromatic compounds were
Resu lts a n d Discu ssion
In connection with our ongoing program to develop
environmentally benign methods using solvent-free con-
* To whom correspondence should be addressed. Fax: 001-608-262-
1257.
† University of Wisconsin.
‡ Isfahan University of Technology.
(1) Chaikovski, V. K.; Kharlova, T. S.; Filimonov, V. D.; Saryucheva,
T. A. Synthesis 1999, 748.
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1995, 926.
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D. M. P.; Baghurst, D. R. I. Chem. Soc. Rev. 1991, 20, 1. (c) Caddick,
S. Tetrahedron 1995, 51, 10403.
(3) Dolenc, D. Synlet. 2000, 544.
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1995, 1273.
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(6) Merkushev, E. B. Synthesis 1952, 150.
(7) Kajiagaeshi, S.; Kakinami, T.; Morrivaki, M.; Tanaka, T.; Fufi-
Saki, S.; Okamoto, T. Bull. Chem. Soc. J pn. 1989, 62, 439.
(8) Serguchev, Yu. A.; Davydova, V. G.; Makhon’kov, D. I.; Chep-
rakov, A. V.; Beletskaya, I. P. Zh. Org. Khim. 1985, 21, 2010.
(9) Caddick, S. Tetrahedron 1995, 51, 10403. (b) Michael, D.; Mingos
P.; Baghurst, D. R. Chem. Soc. Rev. 1991, 20, 1. (c) Gedye, R. J .;
Westaway, K.; Ali, H.; Baldisera, L.; Laberge, L.; Rousell, J . Tetrahe-
dron Lett. 1986, 27, 279. (d) Giguere, R. J .; Bray, T. L.; Duncan, S. M.;
Majetich, G. Tetrahedron Lett. 1986, 27, 4945.
(11) Loupy, A.; Petit, A.; Ramdiani, M.; Yvanaeff, C.; Majdoud, M.;
Labiad, B.; Villemin, D. Can. J . Chem. 1993, 71, 90. (b) Varma, R. S.;
Chatterjee, A. K.; Varma, M. Tetrahedron Lett. 1993, 34, 3207.
(12) Hajipour, A. R.; Mallakpour, S. E. Imanzadeh, G. J . Chem. Res.
1999, 228. (b) Hajipour, A. R.; Mallakpour, S. E. Adibi, H. Chem. Lett.
2000, 460. (c) Hajipour, A. R.; Mallakpour, S. E. Afrousheh, A.
Tetrahedron 1999, 55, 2311. (d) Hajipour, A. R.; Islami, F. Ind. J .
Chem. 1999, 38B, 461. (e) Hajipour, A. R.; Mallakpour, S. E. Iman-
zadeh, G. Chem. Lett. 1999, 99. (f) Hajipour, A. R.; Hantehzadeh, M.
J . Org. Chem. 1999, 64, 8475. (g) Hajipour, A. R.; Mallakpour, S. E.
Backnejad, H. Synth. Commun. 2000, 30, 3855. (h) Hajipour, A. R.;
Mallakpour, S. E.; Afrousheh, A. Phosphorus, Sulfur Silicon 2000, 160,
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10.1021/jo0264628 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/06/2002
8622
J . Org. Chem. 2002, 67, 8622-8624

Tetramethylammonium Dichloroiodate
TABLE 1. Iod in a tion of Ar om a tic Com p ou n d s 2 w ith Rea gen t 1 to Iod oa r en es 3 Un d er Solven t-F r ee Con d ition s a t
Room Tem p er a tu r ea ,b
mp/°C or
bp/°C/Torr (lit.)
entry
Ar-H 2
Ar-I 3
time (min)
yieldc (%)
1
C6H5OMe
4-IC6H4OMe
5
5
100
99
50-53 (51-52)5
63-65 (62.5-63) 13
45-47 (40) 14
64-66 (64-66)3
77-78 (75-76) 5
184-186 (188-189)13
58-60 (56-57)15
142-144
2
C6H5NH2
4-IC6H4NH2
3
3-MeC6H4NH2
3-ClC6H4NH2
1,2-(MeO)2C6H4
C6H5NHCOMe
ClC6H5
4-MeOC6H4CH2OH
4-CHOC6H4OH
1,3,5-C6H3(CH2)3
PhC6H5
C6H5NO2
4-MeC6H4NO2
C6H5CHO
C6H5COOH
C6H5COPh
4-I-3-MeC6H3NH2
4-I-3-ClC6H3NH2
4-I-1,2-(MeO)2C6H3
4-IC6H4NHCOMe
3-I-ClC6H4
3-I-4-MeOC6H3CH2OH
2-I-4-CHOC6H3OH
2-I-1,3,5-C6H2(CH2)3
4-I-PhC6H4
3-I C6H4NO2
2-I-4-MeC6H3NO2
3-IC6H4CHO
3-IC6H4COOH
3-IC6H4COPh
3-I-4-NH2C6H3COOH
3-I-4-NH2C6H3(CH2)2COOH
3-iodo-4-cocaine
4-amino-3-iodococaine
5
99
4
7
5
10
15
10
5
20
20
45
35
30
35
35
25
10
40
20
97
5
100
98
6
7
91
8
100
93
9
113-115 (113-115)16
30-32 (29-30)3
114-115 (113-114)17
35-37 (34-36) 1
54-56 (54-56) 1
55-57 (54-56) 1
186-188 (188-189) 1
40-42 (41-42)18
203-205 (203-204)19
242-243
10
11
12
13
14
15
16
17
18
19
20
87
90
75
82
92
90
80
4-NH2C6H4COOH
4-NH2C6H4(CH2)2COOH
cocaine
86
100
83
gummy oil
195-198
4-aminococaine
92
a
b
Confirmed by comparison with authentic samples (IR, TLC, and NMR).1-8 Molar ratio of 1:2 (1:1). c Yield of isolated pure product
after purification.
TABLE 2. Com p a r ison of Iod in a tion of Som e Ar om a tic Com p ou n d s w ith TMADCI, ICl/Ag2SO4,1 N-Iod osa cch a r in ,20 a n d
2
I2/P b(OAc)4
yield % (min)
entry
substrate
C6H5OMe
TMADCI
ICl/Ag2SO4
85 (60)
N-iodosacchari
I2/Pb(OAc)4
85 (60)
1
2
100 (5)
99 (5)
81 (120)
C6H5NH2
3
4
5
6
7
8
9
10
11
12
C6H5NHCOMe
ClC6H5
4-MeOC6H4CH2OH
C6H5NO2
C6H5COOH
C6H5COPh
C6H5CHO
4-NH2C6H4(CH2)2COOH
cocaine
4-aminococaine
98 (10)
91 (15)
100 (10)
74 (45)
90 (35)
80 (35)
92 (30)
100 (10)
83 (40)
92 (20)
55 (60)
67 (50)
80 (360)
91 (720)
55 (60)
53 (120)
57 (60)
77 (60)
61 (40)
converted to iodobenzene derivatives after 30-45 min at
room temperature in good yield (Scheme 2 and Table 1).
Iodination of aromatic compounds with this reagent
occurred rapidly under solvent-free and very mild condi-
tions, without using base, toxic heavy metal, or oxidizing
reagent. The reagent does not affect oxidizable groups,
such as hydroxyl, aldehyde, or amine. The iodination was
successfully scaled-up to afford multigram quantities of
4-iodoaniline, 4-iodoanisole, and 3-(3-iodo-4-aminophe-
nyl)propionic acid. Even for the scaled-up reaction, this
reaction is mild and is not extremely exothermic. The
tetramethylammonium cation could be recovered in
quantitative yield. After extraction of the iodoaromatic
compounds, the aqueous layer was acidified with 5% HCl
and treated with a fresh bath of the aqueous dichloroio-
date to produce the reagent 1 in quantitave yield.
To evaluate the efficiency of this reaction under solid-
state conditions in comparison to the reaction in solution,
several experiments were performed. We performed the
reaction of 3-(4-aminophenyl)propionic acid in several
solvents, such as methanol, acetone, ether, dichlo-
romethane, and acetonitrile. We determined that aceto-
nitrile is the best solvent for this reaction. When 3-(4-
aminophenyl)propionic acid was treated with 1 molar
ratio of this reagent, the yield was about 10% and many
byproducts were produced after 24 h refluxing. By
increasing the amount of iodination reagent to 2 molar
ratios, the yield of the reaction was not increased. When
3-(4-aminophenyl)propionic acid was treated with 1.5
molar ratio of the iodination reagent in the presence of
1 molar ratio of NaHCO3, 3-(4-amino-3-iodophenyl)-
propionic acid was produced in 40% yield after 14 h
refluxing in a mixture of acetonitrile/methanol (1:1).
SCHEME 2
+
-
+
solvent-free conditions8
Ar-H Me4N Cl2
5-45 min, 65-100%
2
1
+ HCl + Me N+Cl-
Ar-I
3
4
To show the ability of this reagent to iodinate aromatic
compounds, we compared some of our results with those
reported for ICl/Ag2SO4,1 N-iodosaccharin,20 and I2/Pb-
(OAc)42 (Table 2). This reagent is superior to ICl/Ag2SO4,
N-iodosaccharin, and I2/Pb(OAc)4 in term of selectivity,
(13) Orazi, O. O.; Corral, R. A.; Bertorello, H. E. J . Org. Chem. 1963,
30, 1101.
(14) Potts, K. T. Chem. Commun. 1953, 3711.
(15) Citterio, A. Synth. Commun. 1981, 11, 639.
J . Org. Chem, Vol. 67, No. 24, 2002 8623

Hajipour et al.
MgSO4. Evaporation of the solvent gave corresponding io-
doaromatic derivatives (3). The product was purified by column
chromatography on silica gel using a mixture of hexane/EtOAc
(80:20).
high yields, short reaction time, purity of products, and
ease of workup.
In summary, we report here the preparation of tet-
ramethylammonium dichloroiodate (1) as a mild, inex-
pensive, and selective iodination reagent. This iodination
reagent is easily prepared from cheap and commercially
available starting materials and could be stored for
months without losing its activity. The reagent is soluble
in polar solvents and slightly soluble in nonpolar solvents.
This reagent is an efficient and novel reagent for iodi-
nation of activated and deactivated aromatic compounds
to the corresponding iodobenzene derivatives in the
presence of other oxidizable functional groups under
solvent-free conditions. The reaction does not need any
base, toxic heavy metals, or oxidizing agent. The reagent
can be recovered easily in quantitative yield.
Iod in a tion of An isole. Anisole (50.0 mmol, 5.4 g) was
added to the iodination reagent 1 (14.0 g, 50.0 mmol) in a
mortar. The reaction mixture was ground with a pestle until
a homogeneous powder was obtained, and the mixture was
allowed to stand at RT for 10 min. When TLC (hexane/EtOAc,
80:20) showed complete disappearance of anisole, 50 mL of a
sodium bisulfate (5%) was added to the brown solid. The
reaction mixture was then extracted with ether (3 × 5 mL).
The combined extracts were dried with MgSO4. Evaporation
of the solvent afforded the iodo compound, which was purified
by column chromatography on silica gel using a mixture of
hexane/EtOAc (80:20), to give 11.5 g (98%) of colorless solid,
1
mp 50-53 °C. H NMR: δ 7.35 (d, 2H), 6.45 (d, 2H), 3.85 (s,
3H). 13C NMR: δ 142.81, 136.25, 129.36, 126.65, 112.86, 68.70.
MS: m/z, 234.22 (100%, M+), 108 (100%), 77 (8%), 65 (65%).
Anal. Calcd for C7H7IO: C, 35.90; H, 2.99. Found: C, 35.70;
H, 3.20.
Exp er im en ta l Section
4-Iod o-4-m eth oxyben zyl a lcoh ol: colorless solid, mp
142-144 °C. H NMR: δ 6.9-7.4 (m, 3H), 4.5 (s, 2H), 3.6 (s,
Gen er a l Meth od s. All yields refer to isolated products after
purification by column chromatography. Products were char-
acterized by comparison with authentic samples (IR and 1H
NMR spectra, TLC, melting and boiling points).1-14 All 1H
NMR spectra were recorded at 300 MHz in CDCl3 and CD3-
CN relative to TMS. The IR (KBr) spectra were recorded on a
Shimadzu 435 IR spectrophotometer. All reactions were car-
ried out under solid-state conditions at room temperature.
P r ep a r a tion of Tetr a m eth yla m m on iu m Dich lor oio-
d a te (1, TMADCI). A solution of tetramethylammonium
chloride (10.95 g, 100 mmol) in 100 mL of water was added to
an orange solution of NaICl2 (110 mmol) [prepared from 6%
NaClO (136 mL) or 5.25% NaClO (156 mL), NaI (110 mmol,
16.5 g), and 37% HCl (220 mmol, 22 mL) at 0 °C and stirred
for 30 min at room temperature]. The resulting yellow
precipitate was collected and washed with cooled distilled
water (2 × 50 mL) and ether (2 × 30 mL) and dried in a
desiccator under vacuum over calcium chloride to afford a
yellow powder (26.66 g, 98 mmol, 98% yield), which decom-
posed at 198-200 °C to a dark-brown material. 1H NMR: δ
4.7(s). 13C NMR: δ 29.68 (s). Anal. Calcd for C4H12ICl2N: C,
17.64; H 4.41. Found: 17.45; H, 4.68.
Iod in a tion of Ar om a tic Com p ou n d s (2) to th e Cor r e-
sp on d in g Iod oa r om a tic Der iva tives (3): Gen er a l P r oce-
d u r e. The aromatic compounds 2 (5.0 mmol) were added to
the iodination reagent 1 (1.4 g, 5.0 mmol) in a mortar. The
reaction mixture was ground with a pestle to produce a
homogeneous powder, and the mixture was left for the time
specified in Table 1 at room temperature. When TLC (hexane/
EtOAc, 80:20) showed complete disappearance of starting
aromatic compounds 2, to the brown solid was added 5 mL of
sodium bisulfate (5%) and the reaction mixture was extracted
with ether (3 × 5 mL). The combined extracts were dried with
1
3H). 13C NMR: δ 140.91, 137.32, 128.38, 126.95, 113.96, 94.37,
64.70, 55.06. MS: m/z, 264.42 (100%, M+), 108 (100%), 93
(60%), 91(100%), 77 (85%), 65 (50%), 39 (25%). Anal. Calcd
for C8H9IO2: C, 36.64; H, 3.4. Found: C, 36.71; H, 3.56.
3-(3-Iod o-4-a m in op h en yl)p r op ion ic a cid : colorless solid,
mp 242-243 °C. 1H NMR: δ 10.2 (s, 1H), 6.7-7.3 (m, 3H),
3.18 (s, 2H), 2.98 (t, 2H), 2.58 (t, 2H). 13C NMR: δ 179.61,
146.51, 140.19, 128.59, 126.41, 119.48, 33.68, 30.59. MS: m/z,
301.52 (100%, M+), 289 (100%), 150 (90%), 104(80%), 93
(100%), 77 (65%), 66 (30%), 51 (25%), 39 (15%). Anal. Calcd
for C9H10INO2: C, 35.88; H, 3.32; N, 4.65. Found: C, 35.69;
H, 3.44; N, 4.58.
3-Iod oben zoyl ecgon in e m eth yl ester : yellow gummy oil.
1H NMR: δ 8.33 (d, J ) 1.8, 1H), 7.98 (m, 1H), 7.86 (d, J )
8.4, 1H), 7.16 (m, 1H), 5.20 (m, 1H), 3.73 (s, 3H, OMe), 3.29
(m, 1H), 3.01 (m, 1H), 2.42 (m, 1H), 2.23 (s, 3H, NMe), 2.20-
1.70 (m, 5H). 13C NMR: δ 180, 170. 149, 138, 135, 120, 118,
117, 65.2, 65.13, 60.78, 50.92, 50.22, 41.31, 35.68, 25.79, 25.50.
MS: m/z, 430 (100%, M+ + 1), 182 (100%), 96 (90%), 94 (80%),
82 (100%), 77 (65%), 66 (30%), 51 (25%), 39 (15%). Anal. Calcd
for C17H20INO4: C, 47.55; H, 4.66; N, 3.26. Found: C, 47.72;
H, 4.80; N, 3.18.
4-Am in o-3-iod oben zoyl ecgon in e m eth yl ester : yellow
1
solid, mp 195-198 °C. H NMR: δ 8.32 (d, J ) 1.8, 1H), 7.80
(dd, J ) 1.8, 8.4 1H), 6.69 (d, J ) 8.4, 1H), 5.25 (m, 1H), 4.50
(br, 2H, NH2), 3.74 (s, 3H, OMe), 3.60 (m, 1H), 3.32 (m, 1H),
3.07 (m, 1H), 2.24 (s, 3H, NMe), 2.46-1.2 (m, 7H). 13C NMR:
δ 175, 170. 150. 135, 132, 128,126.3 126.0, 68.4, 66.23, 61.78,
50.92, 50.22, 41.31, 35.68, 25.79, 25.50. MS: m/z, 445 (100%,
M+ + 1), 182 (92%), 96 (95%), 94 (75%), 82 (80%), 77 (65%),
66 (30%), 51 (25%), 39 (15%). Anal. Calcd for C17H21IN2O4: C,
45.95; H, 4.73; N, 6.31. Found: C, 45.862; H, 4.85; N, 6.24.
Ack n ow led gm en t. We gratefully acknowledge the
funding support received for this project from the
Isfahan University of Technology (IUT), IR Iran (A.R.H.),
and Grant GM 33138 (A.E.R.) from the National Insti-
tutes of Health.
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J . Chem. Soc. 1950, 2824.
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J O0264628
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