Ionic liquid iodinating reagent for mild and efficient iodination of aromatic and heteroaromatic amines and terminal alkynes

Article abstract of DOI:10.1080/00397911.2012.749991

Hexamethylene bis(N-methylimidazolium) bis(dichloroiodate) (HMBMIBDCI), an ionic liquid iodinating reagent, have been prepared and characterized. Its ability to perform iodination reactions with a variety of substrates has been explored. In general, iodination reactions of aromatic and heteroaromatic amines proceed with good yields in the absence of solvent. Reactions of terminal alkynes in the presence of 1,8-diazabicyclo [5.4.O] undec-7-ene and tetrahydrofuran have been investigated as well.

Full text of DOI:10.1080/00397911.2012.749991

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Ionic Liquid Iodinating Reagent for Mild and Efficient
Iodination of Aromatic and Heteroaromatic Amines and
Terminal Alkynes
Mahboobe Nouzarian a , Rahman Hosseinzadeh a & Hamid Golchoubian b
a Department of Organic Chemistry, Faculty of Chemistry , University of Mazandaran ,
Babolsar , Iran
b Department of Inorganic Chemistry, Faculty of Chemistry , University of Mazandaran ,
Babolsar , Iran
Accepted author version posted online: 31 May 2013.
To cite this article: Mahboobe Nouzarian , Rahman Hosseinzadeh & Hamid Golchoubian (2013): Ionic Liquid
Iodinating Reagent for Mild and Efficient Iodination of Aromatic and Heteroaromatic Amines and Terminal Alkynes,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI:10.1080/00397911.2012.749991
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Ionic liquid iodinating reagent for mild and efficient iodination of aromatic and
heteroaromatic amines and terminal alkynes
Mahboobe Nouzarian1, Rahman Hosseinzadeh1,*, and Hamid Golchoubian2
1Department of Organic Chemistry, Faculty of Chemistry, University of Mazandaran,
Babolsar, Iran, 2Department of Inorganic Chemistry, Faculty of Chemistry, University of
Mazandaran, Babolsar, Iran
Corresponding Author; , E-mail: r.hosseinzadeh@umz.ac.ir; Fax: 0098 11253 42350
Abstract
Hexamethylene bis(N-methylimidazolium) bis(dichloroiodate) (HMBMIBDCI), an ionic
liquid iodinating reagent, have been prepared and characterized. Its ability to perform
iodination reactions with a variety of substrates has been explored. In general, iodination
reactions of aromatic and heteroaromatic amines proceed with good yields in the absence
of solvent. Reactions of terminal alkynes in the presence of DBU and THF have been
investigated as well.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
NH2
NH2
HMBMIBDCI
Solvent free
R
R
I
electron rich aromatics
12 examples, up to 85%
* Corresponding Author; E-mail: r.hosseinzadeh@umz.ac.ir; Fax: 0098 11253 42350
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HMBMIBDCI
R
I
R
DBU, THF
R=Aryl, Alkyl
9 examples, up to 90%
KEYWORDS: Iodination; ionic liquid; aromatic and heteroaromatic amines; terminal
alkynes; hexamethylene bis(N-methylimidazolium) bis(dichloroiodate)
INTRODUCTION
Iodo-substituted aromatic compounds are the most reactive intermediates in organic
chemistry.[1,2] They are utilized as building blocks for the synthesis of various
biologically active molecules such as calicheamicine and L-thyroxine.[3]
The most aryl iodides were synthesized by Sandmeyer reaction, which is a multistep
reaction up to 1950. However, investigations through many years have directed to
discovery of new procedures. Direct iodination using I2 is a simple method, but such
reaction is not straightforward and needs the oxidation of iodine to the more reactive
species with a pronounced I+ nature. Some of the reported procedures such as nitric
acid/sulfuric acid,[4] iodic or periodic acid,[5] NaI or KI/oleum,[6a] I2/HgX2,[6b]
I2/Ag2SO4[6c] and ICl/Hg(OTf)2[7] include highly strong oxidizing agents, powerfully
corrosive acidic media and toxic heavy metals and reagents. A little less challenging
solution is to use sodium hypochlorite as an oxidant on sodium iodide or iodine in the
¯
presence of hydrochloric acid to form benzyltriethylammonium ICl2 salt that is an
¯
efficient electrophilic iodination reagent.[8] Several ammonium ICl2 salts have been
reported for the iodination of aromatic compounds, including: benzyltrimethylammonium
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dichloroiodate,[9] tetramethyl and tetraethylammonium dichloroiodate,[10] poly[N-(2-
aminoethyl)-acrylamido]triethylammonium dichloroiodate.[11]
Similarly iodoalkynes are also important intermediates in organic synthesis.[12] They were
found to possess anti-HIV,[13a] antimicrobial[13b] and fungicidal activities.[13c] A variety of
method have been introduced for preparation of iodoalkynes, for example: iodination of
phenylacetylenes using I2/NH3,[14] I2/DMAP,[15] KI/TBHP,[16] CuI/TBAB/Et3N,[17]
KI/CuI/Et3N/PhI(OAc)2,[18] metallic lithium/I2/ultrasonic,[19] n-BuLi/ZnI2/BTMSPO,[20]
I(Py)2BF4/CH3ONa,[21] BTMSPO/CuI or ZnI2,[22] (collidine)2I+PF6-[23]; iodination of
trimethylsilylacetylenes by AgNO3/NIS,[24] iodination of organotrifluoroborates utilizing
NaI/chloramines-T,[25] iodination of 1-bromoalkynes using CuI [26] and
halodecarboxylation of propiolic acids by NIS/TBATFA.[27] Although some of these
reported procedures are effective, some of them have certain drawbacks, such as
formation of diyne byproduct,[26] use of transition metal catalyst,[17-18] use of moisture
sensitive bases and intermediates[19-20 ] and long reaction time.[15-17]
Ionic liquids are interesting media for greener reaction protocols.[28] Their green feature
depend on their non-volatility, their unique physico-chemical properties such as large
electrochemical window, high thermal and chemical stability, broad range of liquid-state
temperature and desired solvation behavior. Ionic liquids have many applications in
synthetic transformations,[29] electrochemistry,[30] extraction and separation processes[31]
as well as catalysts.[32] In addition, they have important role as non-volatile and reusable
solvents in different reactions, for example they have successfully been used as solvent in
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iodination reactions.[33] Apart from being applied as solvent, they have been shown to
serve as reagent in some reactions[34] but, there is only a few examples that ionic liquid
was used as iodinating reagent for organic compounds.[35]
Recently, we have introduced an ionic liquid oxidant, hexamethylene bis(N-
methylimidazolium) dichlorochromate (HMBMIDCC), for oxidation of benzylic alcohols
¯
under solvent free condition.[34a] To extend our studies, with replacing of ICl2 to
¯
ClCrO3 , we prepared new ionic liquid reagent and it was applied for iodination of
aromatic, heteroaromatic amines and terminal alkynes (Scheme 1).
RESULTS AND DISCUSSION
As part of our continuing studies of using bis imidazolium salts,[34a,36] we report here an
ionic liquid, hexamethylene bis(N-methylimidazolium) bis(dichloroiodate)
(HMBMIBDCI), that functions as an iodinating reagent for aromatic and heteroaromatic
amines in solvent free condition (Scheme 2).
To synthesize HMBMIBDCI (4a), N-methyl imidazole (1a) was initially treated with 1,6-
dichlorohexane (2a) to form hexamethylene bis(N-methylimidazolium) dichloride
(HMBMIDC) (3a) as a white and hygroscopic solid. Then treatment of an aqueous
solution of NaICl2 or iodinemonochloride (ICl) with dichloride 3a resulted in formation
of corresponding dichloroiodate 4a as a yellow-orange solid (Scheme 3).
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The structure of compound 4a was identified by 1H and 13C NMR spectroscopy as well as
elemental analysis. Iodometric titration was also carried out to confirm the identity of
compound 4a.[37]
To optimize the reaction conditions, aniline as an activated aromatic compound was
chosen as a model substrate. The preliminary reaction conditions applied was based on
the reported results for iodination of anilines using dichloroiodate reagents,[8c,e,9] in a
mixture of CH2Cl2:CH3OH (3:1) solvent. As a result, the initial experiment using aniline
(1mmol), HMBMIBDCI (0.5 mmol) in the presence of calcium carbonate in
CH2Cl2:CH3OH (3:1) at room temperature after 45 min resulted in the formation of 2-
iodo, 4-iodo and 2,4-diiodoaniline without satisfactory regioselectivity. In the next step,
the reaction was performed under solvent free condition at ambient temperature. The
progress of the reaction was monitored by GC that demonstrated the formation of 4-
iodoaniline in 82% yield with high regioselectivity. Therefore, these reaction conditions
were applied for iodination of a wide variety of aromatic and heteroaromatic amines. The
results are summarized in Table 1.
It was observed that anilines with open ortho and para positions were iodinated with high
selectivity on the para position to generate 4-iodo products (Table 1, entries 1-2 and 5-6).
Where the para position is substituted, ortho products were obtained in good yields
(Table 1, entries 3 and 4). In similar reaction conditions, 2-aminopyridine and 2-
aminothiazole resulted in the corresponding monoiodinated products with high selectivity
(Table 1, entries 7 and 8). It is noteworthy to mention that the same optimized reaction
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conditions were successfully applied for iodination of heteroaromatic compounds in
moderate yields (Table 1, entries 9-12). For example, 5-iodo-1-methyl imidazole which is
an important reactant in the synthesis of Xestospon gia, was obtained in 20% yield (Table
1, entry 11). This compound was previously prepared by Panosyan and et al. in four
consecutive steps.[38d] In addition to imidazole derivatives, 3-methylindole was examined
to give selectively 2-iodo-3-methylindole (Table 1, entry 12).
Iodination of terminal alkynes were also studied to prepare iodoalkynes using
HMBMIBDCI as an iodinating reagent (Scheme 4).
To optimize the reaction conditions, the reaction of phenyl acetylene and HMBMIBDCI
was used as a model reaction in a number of bases and solvents. The optimization results
are shown in Table 2.
According to the results, only 19% yield was obtained from the reaction of
phenylacetylene with HMBMIBDCI in the absence of a base. The best result was
achieved when the reaction was conducted in the presence of DBU and NEt3 (Table 2,
entries 2 and 6). However, DBU was chosen as the base of the reaction because in the
presence of NEt3 a dimeric byproduct (diyne) was formed. Among several solvents which
are tested (THF, CH3OH, H2O, CH2Cl2, CH3CN and PhCH3) THF was found to be the
solvent of the choice for iodination of the terminal alkynes. In spite of good yield in
solvents of methanol, water and toluene, these solvents were eliminated due to low
solubility of some acetylenic compounds that provide low yields of desired products (see
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Table 3, entries 6-8). It should be pointed out that aforementioned solvents can be utilized
for soluble acetylenic compounds. The solvent-free condition is not applicable for this
reaction in case of solid terminal acetylenes since the viscosity of the reaction mixture is
too high which hinders the homogenization of the reaction mixture and reduces the yield
of the reaction. Therefore, a wide variety of terminal alkynes using HMBMIBDCI in the
presence of DBU in THF was examined and the results are shown in Table 3.
As it is shown in Table 3, the yields of desired products are excellent (80-90%) for
aromatic alkynes containing either electron-releasing or electron-withdrawing groups in
meta, para or ortho positions (Table 3, entries 2-5). In addition naphthyl, ferrocenyl and
phenylethynyl derivatives of the aromatic alkynes provide corresponding 1-iodoproducts
in good yields (Table 3, entries 6-8). Treatment of aliphatic acetylenes such as 1-hexyne
also afforded 1-iodohex-1-yne in good yields (Table 3, entry 9) but conversion of
propargylic alcohol to the corresponding 1-iodoproduct did not occur. It is interesting to
point out that under these reaction conditions and without using strong bases such as n-
BuLi or Grignard,s reagents which are moisture sensitive, 1-iodoalkynes were obtained in
shorter reaction time with good yields. Moreover, under this reaction conditions and
employing of DBU, a dimeric byproduct was not observed.
Another advantage of this protocol is reusability of the ionic liquid iodinating reagent
(HMBMIBDCI) which can be reproduced from the reaction residue and be reused. In this
regard, after completion of the reaction, the dark reaction mixture was quenched by
water, and was extracted with Et2O. The aqueous layer was then filtered to separate solid
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CaCO3. The resultant residue, which contains imidazolium salt, was treated with an
aqueous solution of NaICl2 to afford HMBMIBDCI. The resulting reagent was reused for
iodination of aniline under solvent free condition at three successive runs without
appreciable loss in its activity (Table 4).
CONCLUSION
In summary, an efficient and solventless protocol has been developed for iodination of
aromatic and heteroaromatic amines using an ionic liquid iodinating reagent. The
significant advantage of dichloroiodate ionic liquid with respect of reported protocols are
simplicity, considerably fast reaction (0.75-4 h), solvent free condition, ragioselectivity,
high isolated yields of products and reusability of the ionic liquid reagent. In addition,
iodination of terminal alkynes to their corresponding 1-iodoproducts were also achieved
using HMBMIBDCI and DBU in solvent of THF. To the best of our knowledge, we are
not aware of any such use of dichloroiodate ionic liquid reagent for iodination of
acetylenic compounds. Short reaction time, avoiding of a sensitive and strong base, lack
of production of diyne byproduct during the iodination of terminal alkynes, good yields
of products, regeneration of HMBMIBDCI and devoid in application of any special
handling techniques are some other advantages of this protocol, which makes it as a good
alternative to the existing methods.
EXPERIMENTAL
General Information
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Materials were purchased from Fluka and Merck Chemical Companies. 1H and 13C NMR
spectra were obtained on a Bruker Avance instrument at 400 and 100 MHz, respectively
using CDCl3, D2O and DMSO as solvents. Melting points were determined on an Electro
Thermal 9100. All the products were characterized by 1H NMR data, and some of the
products were characterized by GC analyses. GC analyses were performed on a Perkin
Elmer 8500 instrument using a Capillary column 30M with a FID detector under helium
as carrier gas. GC parameters were quantified by the authentic product samples prior to
the analysis. Elemental analyses were performed on a LECO 600 CHN elemental
analyzer. Iodine percentage was determined by iodometric titration. [37]
General Procedure For Preparation Of Hexamethylene Bis(N-Methylimidazolium)
Bis(Dichloroiodate) (HMBMIBDCI) (4a)
Method 1. A mixture of N-methylimidazole (1a) (33.00 mmol, 2.71 g) and 1,6-
dichlorohexane (2a) (15.00 mmol, 2.33 g) was stirred in DMF (10 mL) at 100˚C for 4 h.
After cooling the mixture, the hygroscopic white solid was immediately filtered, washed
with diethyl ether (40 mL), and dried under vacuum to give hexamethylene bis(N-
methylimidazolium) dichloride (HMBMIDC) (3a) (3.30 g, 69%); mp 159-163˚C; 1H
NMR (D2O) δ: 8.61 (s, 2 H), 7.37 (s, 2 H), 7.33 (s, 2 H), 4.09 (t, J = 7.0 Hz, 4 H), 3.79 (s,
6 H), 1.77 (br quin, 4 H), 1.24 (br quin, 4 H); 13C NMR (D2O) δ: 135.80, 123.48, 122.14,
49.36, 35.66, 29.02, 24.81. Then HMBMIDC (3a) (10.30 mmol, 3.30 g) was dissolved in
H2O (20 mL) and was slowly added to an aqueous solution of NaICl2 that was
beforehand prepared.[8] The mixture was cooled to 0˚C and the yellow-orange solid
formed was collected by filtration, washed first with a small quantity of H2O (10 mL) and
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then with Et2O (30 mL) and dried under vacuum to give HMBMIBDCI (4a) (5.0 g,
76%); mp 79-81˚C; 1H NMR (DMSO- d6) δ: 9.08 (s, 2 H), 7.74 (pseudo t, J = 1.6 Hz, 2
H), 7.70 (pseudo t, J = 1.6 Hz, 2 H), 4.14 (t, J = 7.2 Hz, 4 H), 3.85 (s, 6 H), 1.78 (br quin,
4 H), 1.27 (br quin, 4 H). 13C NMR (DMSO- d6) δ: 136.9, 124.11, 122.70, 49.16, 36.26,
29.61, 25.40. Anal calcd for C14H24Cl4I2N4: C 24.73, H 4.15, N 8.24, I 37.32 found: C
24.63, H 3.90, N 8.13, I 36.69.
Method 2. Following the typical procedure for 3a, the mixture of ICl (20.60 mmol, 3.34
g) in CH2Cl2 (2 mL) was added to an aqueous solution of HMBMIBDCI (3a) (10.30
mmol, 3.30 g) in 0˚C. The yellow-orange solid formed was collected by filtration,
washed with Et2O (50 mL) and dried under vacuum to give HMBMIBDCI (4a) (4.9 g,
74%).
General Procedure For Iodination Of Aromatic And Heteroaromatic Amines
Aromatic amines (1.00 mmol) was treated with hexamethylene bis(N-methyimidazolium)
bis(dichloroiodate) (4a) (0.70 mmol) in the presence of CaCO3 (2.00 mmol) in a 25-mL
round-bottomed flask equipped with a magnetic stirring bar at 30˚C for the time specified
in Table 1. After disappearance of the starting material as monitored by GC, the reaction
mixture was quenched with water (20 mL) and was extracted with Et2O (40 mL) (Step
1). The organic layer was washed with aqueous NaHSO3 (5%, 20 mL), dried over
Na2SO4 and evaporated in vacuum. The crude product was passed through a short column
of silica gel and was recrystallized from CH3OH:H2O (2:1) to afford corresponding
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products shown in Table 1. All products were identified by comparing melting point and
1H NMR with those of authentic samples reported in the literature.
General Procedure For Iodination Of Terminal Alkynes
To a solution of alkyne (0.50 mmol), DBU (0.50 mmol) in THF (2 mL) was added
HMBMIBDCI (4a) (0.35 mmol) and stirred at room temperature for the time specified in
Table 3. The progress of the reaction was monitored by TLC and the reaction mixture
was quenched with aqueous NaHSO3 (5%, 20 mL) and was extracted with Et2O (40 mL).
The organic layer was dried over Na2SO4 and the resultant solution was evaporated under
reduced pressure. The crude product was purified by preparative thin-layer
chromatography. All products were identified by comparing melting point and 1H and 13C
NMR with those of authentic samples reported in the literature.
Recovery Of Hexamethylene Bis(N-Methylimidazoilum) Bis(Dichloroiodate)
(HMBMIBDCI) (4a)
To a separated aqueous layer in step 1 was added a solution of NaICl2 that was
beforehand prepared.[8] The reaction was immediately followed by formation of a yellow
precipitate, which was then filtered, washed with Et2O and dried under vacuum to give
HMBMIBDCI (4a) (67%). The yellow solid obtained was identical in all aspect with the
parent HMBMIBDCI. This procedure was repeated three times for iodination of aniline,
and the yield of the product was nearly the same.
ACKNOWLEDGMENTS
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We thank the Research Council of University of Mazandaran for the partial support of
this work.
Supporting Information:
Full experimental detail, 1H and 13C NMR spectra. This material can be found via the
‘‘Supplementary Content’’ section of this article’s Web page.
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Table 1. Iodination of aromatic and heteroaromatic amines with HMBMIBDCI under
solvent free conditions
Entry
1
Substrate
Product
Time Yield(%
Mp (0C)b
[Ref]
a
)
45 min
82
58-60 [8]
NH2
NH2
NH2
I
NH2
2
3
120 min
60 min
77 83-85 [9c]
85 35-37 [9c]
CH3
CH3
I
NH2
NH2
I
CH3
NH2
CH3
NH2
4
5
90 min
60 min
66
65-66.5
[8]
CH3
CH3
I
CH3
N
CH3
H3C
CH3
84 75-77 [9c]
H3C
CH3
N
I
6
7
8
4 h
180 min
90 min
25
102-105
[8]
N
H
N
H
I
85 1128-130
[38a]
I
N
N
NH2
N
NH2
NH2
S
70
95-96
NH2
S
N
I
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CH3
9
180 min
47
193-
CH3
N
NH
I
N
NH
195[38b]
I
10
11
12
180 min
4 h
50
20
32
178-180
[38c]
N
NH
N
NH
H3C
H3C
N
I
112-115
[38d]
N CH3
N
N CH3
CH3
I
CH3
90 min
103-106
[38e]
I
N
H
N
H
aYields refer to isolated products
bAll products were identified by comparing of melting point and 1H NMR spectra with
those of authentic samples reported in the literature
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Table 2. Iodination of phenyl acetylene with HMBMIBDCI in different bases and
solvents
Entry
Base Solvent a
Time
(min)
90
Yield
(%)b
19
1
2
3
4
-
THF
THF
NEt3
10
80
K2CO3
KOH
THF
10
20
THF
10
22
5 LiOAC.2H2O
THF
10
21
6
7
DBU
KF/Al2O3
DBU
THF
10
90
THF
10
20
8
CH3OH
CH2Cl2
H2O
10
89
9
DBU
10
76
10
11
12
13
DBU
10
90
DBU
CH3CN
PhCH3
-
10
75
DBU
10
90
DBU
10
90
aReaction conditions: Phenyl acetylene (0.5 mmol), Base (0.5 mmol), HMBMIBDCI
(0.25 mmol), Solvent (2 ml), rt.
bYields refer to isolated product, 1-iodoethynylbenzene.
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Table 3. Iodination of terminal alkynes with HMBMIBDCI in the presence of DBU
Mp
Entry Substrate
1
Product
Time (min) Yield% a
(0C)b[Ref]
10
10
90
89
Oil [18]
Oil [16]
I
I
2
H3C
H3C
Br
Br
3
30
80
Oil [15]
I
4
45
45
85
86
95-99 [26]
81-84 [26]
I
I
Br
Br
5
Cl
Cl
MeO
6
75
45
70
70
115-118
MeO
I
116-117
[38f]
I
7
Fe
Fe
8
9
I
60
90
61
60
142-145
Oil [18]
CH3CH2CH2CH2C
CH3CH2CH2CH2C
I
aYields refer to isolated products
bAll products were identified by comparing 1H, 13C NMR and TLC with those of
authentic samples reported in literature.
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Table 4. Recycling studies of iodination of aniline to 4-iodoaniline with HMBMIBDCI
Entry
Cycle
Time (min)
Yield (%)a
1
Fresh
45
45
45
45
82
81
81
81
2
1
2
3
3
4
aYields refer to isolated products
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Scheme 1. Structures of HMBMIDCC and HMBMIBDCI
-
-
ICl2
ClCrO3
N
N
N
+
+
N
+
+
N
-
N
N
-
N
ClCrO3
ICl2
HMBMIBDCI
HMBMIDCC
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Scheme 2. Iodination of aromatic and heteroaromatic amines
NH2
NH2
HMBMIBDCI
Solvent free
R
R
I
R= electron releasing group
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Scheme 3. Preparation of HMBMIBDCI
Cl _
N
N CH3
100oC
Cl
+
+
+
N
N
+
N
H3C
N
Cl
H3C
N
DMF
Cl _
3a
2a
1a
ICl2_
ICl / CH2Cl2
or NaICl2 (aq)
N
CH3
+
N
H3C
N
ICl2_
4a
28

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Scheme 4. Iodination of terminal alkynes
HMBMIBDCI
DBU, THF
R
I
R
R=Aryl, Alkyl
29