Iodination of alcohols using triphenylphosphine/iodine under solvent-free conditions using microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2006.04.036

A straightforward and effective procedure for the conversion of benzylic, allylic and aliphatic alcohols to the corresponding iodides using Ph₃P/I₂ under solvent-free conditions using microwave irradiation is reported.

Full text of DOI:10.1016/j.tetlet.2006.04.036

Tetrahedron Letters 47 (2006) 4191–4196
Iodination of alcohols using triphenylphosphine/iodine under
solvent-free conditions using microwave irradiation
a
a
Abdol Reza Hajipour,a,b, Ali Reza Falahati and Arnold E. Ruoho
*
aDepartment of Pharmacology, University of Wisconsin Med. Sch., 1300 University Avenue, Madison, WI 53706-1532, USA
bPharmaceutical Research Laboratory, College of Chemistry, Isfahan University of Technology, Isfahan 84156,
Islamic Republic of Iran
Received 30 October 2005; revised 11 April 2006; accepted 11 April 2006
Available online 5 May 2006
Abstract—A straightforward and effective procedure for the conversion of benzylic, allylic and aliphatic alcohols to the correspond-
ing iodides using Ph3P/I2 under solvent-free conditions using microwave irradiation is reported.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
iodination of benzylic alcohols.19 Although some of
these methods have convenient protocols with good to
high yields, the majority of these methods suffer from
drawbacks such as the presence of hazardous vapor,
high temperature, long reaction times, moisture sensitiv-
ity of the using reagents, low yields, harsh reaction
conditions, non-commercially available materials and
tedious work-up procedures. Thus introducing new
methods with higher efficiency and selectivity, less toxic-
ity, easy handling and also using inexpensive and com-
mercially available materials are important.
Organic halides are very useful intermediates in organic
synthesis.1 They react with nucleophiles, such as amines
or alkoxides, to give the corresponding substituted
products and can be lithiated to introduce electrophiles
via a halogen–lithium exchange reaction.2 Alkyl iodides
or bromides are widely used for carbon–carbon coupling
reactions, and also act as intermediates in substitution,
elimination and rearrangement reactions. Alkyl iodides
are less stable than the corresponding chloride or bro-
mide and more reactive than the other halides, and in
some cases iodides are the only reactive halides.3 The
most common precursors to alkyl halides are alcohols,
and their conversion into iodides is one of the most
frequently used functional group transformation
reactions.4
2. Results and discussion
In recent years, there has been a growing interest in the
application of microwave irradiation in chemical reac-
tion enhancement,20 because of its cleaner reactions,
decreased reaction time and easier work-up. In continu-
ation of our ongoing efforts in this area and developing
new methods in organic synthesis,20–23 herein we wish to
report an efficient and mild procedure for the iodination
To perform iodination of hydroxyl groups, several
methods have been described using a variety of reagent
systems, such as BF3–Et2O/NaI,5 P2I4,6 P4/I2,7 Cl2SO–
DMF/KI,8 MgI2,9 HI,10 ClSiMe3/NaI,11 R3PI2–Et2O,
or C6H6/HMPA,12 CeCl3Æ7H2O/NaI,13 PPh3/DDQ/
R4N+XÀ,14 KI/BF3ÆEt2O,15 ZrCl4/NaI,16 I2/petroleum
ether,17 and NaI/Amberlyst 15.18 Polymer-supported
triphenylphosphine/I2/ImH has also been used for the
Ph3P/solvent-free
R-I
microwave iradiation
ROH + I2
30-60 sec, 75-94 Yields
Keywords: Iodination; Alcohols; Ph3P; Solvent-free; Microwave.
*
Corresponding author. Tel.: +98 311 391 3262; fax: +98 311 391
2350; e-mail addresses: haji@cc.iut.ac.ir; arhajipour@facstaff.wisc.
edu
R = Aliphatic, Benzylic and Allylic
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.036

4192
A. R. Hajipour et al. / Tetrahedron Letters 47 (2006) 4191–4196
of alcohols using a combination of triphenylphosphine
and iodine under solvent-free conditions using micro-
wave irradiation (Scheme 1).
solvent-free conditions using microwave irradiation.
The mild reaction conditions, short reaction times, good
to high yields, low cost, easy preparation and handling
of silica sulfuric acid are the advantages of this method.
The iodination of benzyl alcohol was selected for opti-
mization of the reaction conditions. Initially, we studied
the conversion of benzyl alcohol (1 mmol, 0.1 mL) to
benzyl iodide with triphenylphosphine (1.0 mmol,
0.26 g) and iodine (1.0 mmol, 0.25 g) in the presence of
various solvents and also under solvent-free conditions
(grinding) with or without microwave irradiation. As
shown in Table 1 in comparison to other conditions
the reaction proceeds rapidly under solvent-free condi-
tion with microwave irradiation and gives an optimal
yield. Therefore, we investigated the iodination of vari-
ous benzylic, allylic and aliphatic alcohols in the pres-
ence Ph3P and iodine (Table 2).
3. Experimental
3.1. General
All reagents were purchased from Merck and Aldrich,
and used without further purification. All yields refer
to isolated products after purification. Products were
characterized by comparison with authentic samples
1
and by spectroscopic data (IR, H NMR and MS anal-
1
ysis). H NMR spectra were recorded at 300 MHz in
CDCl3, unless otherwise stated, relative to TMS
(0.00 ppm). GC analysis was run with Shimadzu GC-
14A. All of the reaction was carried out under hood with
strong ventilation using a domestic Samsung microwave
(South Korea) oven (2450 MHz, 900 W) without any
modification.
A variety of alcohols were smoothly converted to the
corresponding iodides using I2/Ph3P system under
microwave irradiation using a domestic microwave.
The reaction is highly selective for the conversion of
benzylic and allylic alcohols in the presence of aliphatic
alcohols (Table 2). In the case of phenol, the conversion
into the corresponding iodides was not carried out even
after prolonged stirring in acetonitrile. The generality of
the method was examined using alkyl aryl, allyl, alkyl
and also cyclic alcohols. To test the safety of the
method, the iodination of 4-methoxy benzyl alcohol
was successfully scaled-up to 5 mmol without any risks
and decreasing the yield of 4-methoxy benzyl iodide.
3.2. Iodination of 4-bromobenzyl alcohol (typical
procedure)
In a mortar a mixture of 4-bromobenzyl alcohol
(1 mmol, 0.19 g), I2 (1.0 mmol, 0.25 g) and triphenyl-
phosphine (1.0 mmol, 0.26 g) was ground with a pistol
(30 s) to a homogeneous mixture. The mixture was
transferred to a sealed Teflon vessel, and the reaction
mixture was irradiated for the time specified in Table
2. The progress of the reaction was monitored by TLC
or GC. After disappearing the alcohol TLC (n-hexane–
EtOAc, 3:1) the reaction mixture was diluted with ether
(25 mL) and filtered to removed the solids. The organic
layer was washed with an aqueous solution of Na2S2O3
(10%, 10 mL), then H2O (2 · 10 mL). The organic layer
was dried over anhydrous Na2SO4. The solvent was
evaporated under reduced pressure and the mixture of
the products was purified by short column chromatogra-
phy (n-hexane–EtOAc, 3:1). 4-Bromobenzyl iodide was
obtained in 80% (0.237 g) yield as a crystalline white
In order to evaluate the chemoselectivity of this method,
we studied competitive reactions for the iodination of
benzylic alcohols in the presence of phenol and satu-
rated alcohols. The remarkable selectivity of these reac-
tions allowed only benzylic hydroxyl groups to be
iodinated without affecting other OH groups (Table 3,
entries 1–3). We also studied the iodination of benzyl
alcohol versus 4-methoxybenzyl alcohol and 4-nitrobenz-
yl alcohol in the presence of benzyl alcohol. These reac-
tions proceeded with high selectivity showing the
importance of electronic effects upon these reactions
using this technique (Table 3, entries 4 and 5).
1
solid. Mp 57–59 ꢁC; H NMR (FT-300 MHz, CDCl3,
TMS) d = 7.43 (d, J = 8.5 Hz, 2H), 7.26 (d, J =
8.5 Hz, 2H), 4.42 (s, 2H); IR (KBr) cmÀ1: 3020, 2900,
2850, 1590, 1490, 1420, 1200, 1150, 1030, 850, 670;
MS (EI), m/e (relative intensity): 298 (M++2, 3), 296
(M+, 3), 171 (100), 169 (100), 127 (25), 91 (42), 90
(100), 89 (95), 77 (12), 76 (10), 63 (60), 39 (25).
In conclusion, we have developed a simple, direct and
high chemoselective process for the iodination of benz-
ylic, allylic and aliphatic alcohols using Ph3P/I2 under
Table 1. Conversion of benzyl alcohol to benzyl iodide under different
conditions using I2/Ph3P
3.3. Iodination of 4-methoxybenzyl alcohol in the presence
of benzyl alcohol (typical procedure)
Solvent
Time
Benzyl iodide (%)c
Acetonitrilea
1.5 h
5 h
5 h
35
20
10
10
30
55
82
Ethyl acetatea
Diethyl ethera
THFa
In
a mortar a mixture 4-methoxybenzyl alcohol
(1 mmol, 0.138 g), benzyl alcohol (1 mmol, 0.1 mL),
I2 (1.0 mmol, 0.25 g) and triphenylphosphine (1.0 mmol,
0.26 g) was ground with a pistol to a homogeneous mix-
ture. The mixture was transferred to a sealed Teflon ves-
sel and the reaction mixture was irradiated for 60 s. The
progress of the reaction was monitored by TLC or GC.
4-Methylbenzyl iodide was obtained in 90% yield and
benzyl alcohol was intact (Table 3, entry 4).
5 h
Dichloromethanea
Solvent-freeb
1.5 h
10 min
40 s
Microwave irradiation
a Stirring at room temperature in 5 mL of solvents.
b Grinding at room temperature.
c Yields refer to isolated pure products.

A. R. Hajipour et al. / Tetrahedron Letters 47 (2006) 4191–4196
4193
Table 2. Conversion of alcohols to the corresponding Iodides using Ph3P/I2 with microwave irradiationa,b
Entry
Substrate
Product
Time (sec)
Yield (%)
CH2OH
CH2OH
CH2I
CH2I
1
40
80
OMe
OMe
2
3
30
50
90
88
CH2OH
CH2I
MeO
MeO
CH2OH
CH2OH
CH2I
CH2I
4
5
6
7
50
30
30
40
95
90.
87
78
MeO
MeO
MeO
MeO
OMe
OMe
CH2OH
CH2I
Me
Cl
Me
Cl
CH2OH
CH2I
CH2OH
CH2I
CH2I
Cl
Cl
8
9
40
30
30
50
50
80
92
80
80
78
CH2OH
CH2OH
CH2OH
Cl
Br
Cl
Br
CH2I
10
11
12
CH2I
O2N
O2N
O2N
O2N
CH2OH
CH2I
OH
I
13
30
90
CH3
CH3
(continued on next page)

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A. R. Hajipour et al. / Tetrahedron Letters 47 (2006) 4191–4196
Table 2 (continued)
Entry
Substrate
Product
Time (sec)
Yield (%)
85
Ph
14
15
Ph
60
5
OH
I
OH
I
0
78
75
90
84
75
CH2CH2OH
CH2CH2I
16
17
18
19
20
50
50
40
50
60
OH
I
OH
I
OH
I
Cyclododecane
Cyclododecyl iodide
a The molar ratio of alcohol/KI/SSA is 1:1.2:1.2.
b Yields refer to pure isolated products and were characterized by comparison of their physical and spectral data (IR, 1H NMR, MS) with authentic
samples.
Table 3. Competitive reaction for selective iodination of different alcoholsa
CH2OH
+
CH2CH2OH
CH2I
+
CH2CH2OH
Ph3P/solvent-free
1
2
microwave iradiation
60 sec
1 mmol
1 mmol
1 mmol
100%
CH2I
80%
CH2OH
OH
OH
Ph3P/solvent-free
+
+
microwave iradiation
60 sec
90%
100%
1 mmol
CH2OH
+
OH
CH2I
+
OH
Ph3P/solvent-free
3
microwave iradiation
60 sec
90%
1 mmol
MeO
1mmol
100%
CH2OH
+
CH2I
+
CH2OH
CH2OH
Ph3P/solvent-free
microwave iradiation
60 sec
4
5
MeO
1 mmol
CH2OH
100%
CH2OH
90%
1 mmol
CH2OH
CH2I
+
Ph3P/solvent-free
+
microwave iradiation
60 sec
O2N
O2N
80%
100%
1 mmol
a The progress of the reaction was determined by GC and TLC analysis.
1 mmol

A. R. Hajipour et al. / Tetrahedron Letters 47 (2006) 4191–4196
4195
3.4. Benzyl iodide
Further financial support from Center of Excellency in
Chemistry Research (IUT) is gratefully acknowledged.
IR (neat) cmÀ1: 3010, 2930, 1595, 1485, 1430, 1070, 835,
750, 660. 1H NMR (FT-300 MHz, CDCl3, TMS)
d = 7.3–7.0 (m, 5H), 3.95 (s, 2H).
References and notes
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1
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1
Acknowledgments
We gratefully acknowledge the funding support received
for this project from the Isfahan University of Techno-
logy (IUT), IR Iran (A.R.H.) and Grant GM 33138
(A.E.R.) from the National Institutes of Health, USA.
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