Simple synthesis of fresh alkyl iodides using alcohols and hydriodic acid

Article abstract of DOI:10.1016/j.tetlet.2008.02.106

A simple synthesis of fresh alkyl iodides using alcohols and hydriodic acid (HI) is reported. The alkyl iodides were obtained in quick and easy work-up with good to excellent yields (66-94%) and very high purities (97-99%). Freshly prepared iodomethane and 1-iodobutane were applied to synthesize biologically relevant 3,7-dimethyladenine and 9-butyladenine, which were characterized thoroughly using 1D and 2D NMR, individually.

Full text of DOI:10.1016/j.tetlet.2008.02.106

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Tetrahedron Letters 49 (2008) 2638–2641
Simple synthesis of fresh alkyl iodides using alcohols and hydriodic acid
Suzane M. Klein a, Cungen Zhang b, Yu Lin Jiang a,*
a Department of Chemistry, College of Arts and Sciences, East Tennessee State University, Johnson City, TN 37614, USA
b Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD 21205, USA
Received 26 April 2007; revised 14 February 2008; accepted 15 February 2008
Available online 7 March 2008
Abstract
A simple synthesis of fresh alkyl iodides using alcohols and hydriodic acid (HI) is reported. The alkyl iodides were obtained in quick
and easy work-up with good to excellent yields (66–94%) and very high purities (97–99%). Freshly prepared iodomethane and 1-iodo-
butane were applied to synthesize biologically relevant 3,7-dimethyladenine and 9-butyladenine, which were characterized thoroughly
using 1D and 2D NMR, individually.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Alcohols; Hydriodic acid; Hydrogen bromide; Hydriodination; Hydrobromination; Alkyl iodides; Alkyl bromides
Alkyl halides are very useful reagents in organic chemis-
try, molecular biology, and chemical biology (Fig. 1).1–4
The alkyl halides have been applied to the synthesis of
effective drugs to treat many deadly human diseases, such
as cancer,5,6 HIV,7 diabetes,8 and arthritis.9 They are also
useful in nano material fabrication and nanotechnolo-
gies.10 To study how alkylators affect human health and
diseases, the alkyl iodides are widely used to the alkylation
of DNA for crystallographic study of DNA repair protein
AlkB1,11 and structural study of DNA repair protein 3-
methyladenine DNA glycosylase I (TAG) using NMR.12
Recently, the alkyl iodides have been used to alkylate pro-
teins directly,13,14 RNA related compounds15 and even live
cells.16
However, most of alkyl iodides are not very stable in
room temperature or even at 4 °C.17–19 They decompose
automatically and quickly, resulting in dark color and
impurities, which could affect the confidence of drawing
conclusions in biological studies, especially in cell death
and phenotype research. Fresh and pure alkyl iodides are
needed in organic chemistry, medicinal chemistry, drug
discovery, and molecular biology.
Alkyl iodides can be synthesized in many ways. A tradi-
tional method is to use the reactions of alcohols with phos-
phorus triiodide to make alkyl iodides.20 However, the
reactions generate toxic H3PO3. Another method is to
apply the cleavages of dialkyl ethers using hydriodic acid,
however, many ethers are not readily available.21 Some
modern methods to synthesize alkyl iodides include the
reaction of alcohols with cesium iodide in the presence of
p-toluenesulfonic acid,22 nucleophilic substitution of alkyl
chlorides with an excess of sodium iodide,23 rapid reaction
of organoboranes with iodine under the presence of a
base,24 and conversion of alcohols to alkyl halides
using halide-based ionic liquids.25 However, none of the
syntheses are cost effective or convenient.
NH2
N
NH3
N
CH3
14C
N
N
N
N
I
N
N
O
14CH3I
H2O
O
DNA
DNA
O
O
O
O
DNA
DNA
Fig. 1. Synthesis of methylated DNA using 14CH3I.1
*
Corresponding author. Tel.: +1 423 439 6917; fax: +1 423 439 5835.
E-mail address: jiangy@etsu.edu (Y. L. Jiang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.106

S. M. Klein et al. / Tetrahedron Letters 49 (2008) 2638–2641
2639
Hydriodic acid and hydrogen bromide can be reusable,
and iodine and bromine can also be recycled from the
acids.26–28 Thus, the application of hydriodic acid and
hydrogen bromide in the synthesis of alkyl iodides and
alkyl bromides should be environmentally benign. The
hydriodic acid had been used to synthesize isotope labeled
iodomethane and iodoethane.29,30 However, the syntheses
either took a long time to complete or resulted in low
yields. Surprisingly, there is no report on the synthesis of
longer aliphatic chain alkyl iodides or benzyl iodide using
the hydriodic acid and the corresponding alcohols.
Alkyl halides should be synthesized easily from alcohols
and hydrogen halides by reflux. However, we found that
the reflux of 1-butanol (2.34 g, 31.5 mmol) with 48%
hydrogen bromide (7 mL) for 4 h on a 120 °C oil bath only
gave low yield of 1-bromobutane (54%) and moderate pur-
ity (93%). The yield of 1-bromobutane was improved to
82% with 90% purity by adding additional sulfuric acid
(98%, 1 mL). Interestingly, we found that 1-iodobutane
could be directly synthesized using 1-butanol and hydriodic
acid (HI, 57%) by reflux without adding an additional acid
in 80% yield with 98% purity (Scheme 1 and Table 1).
The methodology for the synthesis of 1-iodobutane was
also applied to the synthesis of other alkyl iodides (Table
1). Iodomethane and iodoethane were synthesized in 76%
and 72% yields with 99% purities individually using corre-
sponding methanol, ethanol, and hydriodic acid. They were
collected by distillation to flasks on an ice-water bath for
2 h after mixing of the alcohol with hydriodic acid. The
reaction time was only about one fifth of that reported
for the preparation of 13C-iodomethane using 13C-metha-
nol and hydriodic acid.29 Furthermore, besides 1-butanol,
methanol and ethanol, 1-propanol, 1-pentanol, and benzyl
alcohol were also found to be miscible with 57% hydriodic
acid. Their corresponding alkyl iodides, 1-iodopropane, 1-
iodopentane, and benzyl iodide were also synthesized in
good to excellent yields (66%, 83%, and 93%, respectively)
with very high purities (99%, 98%, and 99%, respectively).
However, we found that the alcohols with longer chains
(C6–C8) were immiscible with 57% HI. As a result, the
reflux of the three alcohols with hydriodic acid only gave
moderate to good yields of the corresponding alkyl iodides
(72%, 75%, and 69%, individually) with low purities (82%,
84%, and 77%, individually) (Table 1). To improve the
yields and purities of the alkyl iodides, we added H3PO4
to the reaction mixtures during the hydriodination of these
alcohols. The oil bath temperature was raised to 130 °C. As
a result, all of the three alkyl iodides were then obtained in
excellent yields (90%, 94%, and 92%, individually) with
very high purities (99%, 98%, and 97%, individually).
Furthermore, the freshly prepared iodomethane and 1-
iodobutane were used to make biologically important
known compounds 3,7-dimethyladenine (Scheme 2) and
9-butyladenine (Scheme 3), respectively. The synthesis of
3,7-dimethyladenine was carried out in DMF at room
temperature, by methylating DNA base 3-methyladenine
H3C
NH
NH2
N
N
N
N
CH3I
DMF
N
N
N
CH3
N
CH3
reflux,120 oC or 130 oC
+
ROH
HI
RI
+
H2O
Scheme 2. Synthesis of 3,7-dimethyladenine using freshly made
iodomethane.
Scheme 1. Synthesis of alkyl iodides using alcohols and hydriodic acid.
Table 1
Simple synthesis of fresh alkyl halides using alcohols and HI
57% HI or 48% HBr
reflux, 120 oC or 130 oC
RX (X = I, Br)
ROH
Entry
R
X
Conditions
Oil bath temp (°C)
Yielda (%)
Purityb (%)
1
2
CH3
CH3CH2
I
I
I
I
I
I
I
I
I
I
I
I
Br
Br
Br
Distillation, 2 h
Distillation, 2 h
Reflux, 4 h
Reflux, 4 h
Reflux, 4 h
Reflux, 4 h
Reflux, 4 h (H3PO4)
Reflux, 4 h
Reflux, 6 h (H3PO4)
Reflux, 4 h
Reflux, 8 h (H3PO4)
Reflux, 4 h
120
120
120
120
120
120
130
120
130
120
130
120
120
120
120
76
72
66
80
83
72
90
75
94
69
92
93
54
82
92
99
99
99
98
98
82
99
84
98
77
97
99
93
99
99
3
CH3(CH2)2
CH3(CH2)3
CH3(CH2)4
CH3(CH2)5
CH3(CH2)5
CH3(CH2)6
CH3(CH2)6
CH3(CH2)7
CH3(CH2)7
C6H5CH2
CH3(CH2)3
CH3(CH2)3
C6H5CH2
4
5
6
7
8
9
10
11
12
13
14
15
a
Reflux, 4 h
Reflux, 4 h (H2SO4)
Reflux, 4 h
Isolated yield.
b
Purity based on gas chromatography.

2640
S. M. Klein et al. / Tetrahedron Letters 49 (2008) 2638–2641
NH2
N
N
NH2
N
N
I
N
N
N
H
N
Cs2CO3, DMF
Scheme 3. Synthesis of 9-butyladenine using freshly made 1-iodobutane.
without adding any additional base. The 3,7-dimethylade-
nine was isolated by using HPLC and C-18 reverse phase
column in 60% yield. The 9-butyladenine was synthesized
by alkylating of a DNA base adenine in DMF using 1-
iodobutane in the presence of cesium carbonate. The puri-
fication of the 9-butyladenine was achieved by double re-
crystallization using toluene then 10% ethanol–water solu-
tion, resulting in a final yield of 51%. Without the second
re-crystallization in ethanol–water, the purity of 9-butylad-
enine was never good. Both compounds were characterized
using 1D NMR and 2D NMR (Figs. 2 and 3 for 3,7-dime-
thyladenine and 9-butyladenine, respectively). The 3,7-
dimethyladenine will continually be used in the study of
the DNA repair proteins, such as AlkB1,11 and TAG.12
The 9-butyladenine will be used to inhibit enzymes, such
as kinase p38 gamma.31 The biological investigations using
3,7-dimethyladenine and 9-butyladenine are on the way.
In summary, a novel and simple method for the prepa-
ration of fresh alkyl halides is reported from the readily
available alcohols and hydriodic acid. This method should
find wide application in organic synthesis and drug discov-
ery, using the alkyl iodides to make a variety of chemicals
as drugs to treat many deadly human diseases. The alkyl
iodides will also be very useful in chemical, biology, and
molecular biology studies.
Fig. 3. NMR (400 MHz) COSY spectrum of 9-butyladenine and a typical
hydrogen to hydrogen correlation.
Acknowledgments
This research is supported by the Office of Research and
Sponsored Programs and Department of Chemistry at East
Tennessee State University. We also thank Dr. Mohseni
for assistance in gas chromatography, and Mrs. Susan
Campbell for error-proof reading.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.02.106.
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