A direct iodination method with iodine and silver triflate for the synthesis of SPECT and PET imaging agent precursors

Article abstract of DOI:10.1081/SCC-100105877

A direct iodination method with iodine and silver triflate for the synthesis of SPECT and PET imaging agent precursors has been developed.

Full text of DOI:10.1081/SCC-100105877

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A DIRECT IODINATION METHOD WITH IODINE AND
SILVER TRIFLATE FOR THE SYNTHESIS OF SPECT AND
PET IMAGING AGENT PRECURSORS
G. Keith Mulholland a & Qi-Huang Zheng b
a Department of Radiology , Indiana University Medical Center , 975 W. Walnut Street,
IB028C, Indianapolis, IN, 46202-5121, U.S.A.
b Department of Radiology , Indiana University Medical Center , 975 W. Walnut Street,
IB028C, Indianapolis, IN, 46202-5121, U.S.A.
Published online: 16 Aug 2006.
To cite this article: G. Keith Mulholland & Qi-Huang Zheng (2001) A DIRECT IODINATION METHOD WITH IODINE AND
SILVER TRIFLATE FOR THE SYNTHESIS OF SPECT AND PET IMAGING AGENT PRECURSORS, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:20, 3059-3068, DOI: 10.1081/
SCC-100105877
To link to this article: http://dx.doi.org/10.1081/SCC-100105877
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SYNTHETIC COMMUNICATIONS, 31(20), 3059–3068 (2001)
A DIRECT IODINATION METHOD WITH
IODINE AND SILVER TRIFLATE FOR THE
SYNTHESIS OF SPECT AND PET IMAGING
AGENT PRECURSORS
G. Keith MulhollandandQi-Huang Zheng
*
Department of Radiology, Indiana University Medical Center,
975 W. Walnut Street, IB028C, Indianapolis,
IN 46202-5121, USA
ABSTRACT
A direct iodination method with iodine and silver triflate for
the synthesis of SPECT and PET imaging agent precursors
has been developed.
Iodinated aromatic compounds are essential precursors to innumer-
able radioiodinated tracers,1 tritiated compounds, and several PET (posi-
tron emission tomography) imaging agents, including b-[11C]CIT,2
N-fluoroethyl b-CIT, and [11C]iomazenil. The most important aromatic
iodination methodologies3 include: (a) direct iodination with I2; a slow
and reversible reaction with requires the help of an oxidant, metallic
salts4,5 or strong oxidizing acids, (b) iodination with iodide plus an oxidant
or an interhalogen compound such as ICI, (c) the use of electrochemical
*Corresponding author.
3059
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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MULHOLLAND AND ZHENG
reactions, or hypervalent iodine reagents,6 (d) iododemetalation, and (e) the
Sandmeyer diazotization reaction. A problem with the existing iodination
procedures is that many require harsh conditions that can destroy structu-
rally complex and sensitive drug molecules such as those containing amino
and ester functions. Others utilize toxic salts of thallium or mercury which
raise safety and disposal concerns. We recently (re)discovered the iodine and
Silver Triflate (I2-AgOTf) iodination system in response to frustrating and
unsuccessful attempts to iodinate the phenyl tropane precursor of b-CIT by
a published procedure. The reported literature method7 using I2 in HNO3/
H2SO4, gave very poor yields in our hands due to competing ring nitration
and ester hydrolysis. We were familiar with the l2-silver sulfate iodination
system4 and reasoned that substitution of the more organic-soluble AgOTf
for Ag2SO4 might lead to faster reactions. Indeed, we found that the
I2-AgOTf reagent iodinated the b-CIT precursor in CH2Cl2 very smoothly
at room temperature in high yield.8 These impressive results made us
wonder if others had reported the I2-AgOTf reagent. A search found a
single brief communication in 1977,9 that has been largely overlooked in
the subsequent literature.3–6 In view of the limited amount of study of the
reagent, and our favorable initial results, we decided to investigate in more
detail its utility for direct iodination of a variety of compounds of interest as
radiopharmaceuticals SPECT (single photon emission computed tomogra-
phy) and PET imaging agents and precursors.
RESULTS AND DISCUSSION
The I2-AgOTf reagent iodinated a variety of aromatic structures
at room temperature. The progress of the iodination reaction was easily
monitored through the appearance of insoluble AgI and the disappearance
of the dark iodine color. Iodinations of activated molecule could be
‘‘titrated’’ by adding measured concentrations of I2 solution to a solution
of substrate and AgOTf until I2 color just persisted. Electron rich activated
molecules such as methoxybenzenes reacted almost instantaneously. In the
absence of AgOTf, iodination of the same substrates was extremely slow
(days) or totally unsuccessful, even if the substrates are strongly activated
veratroyl derivatives. Unactivated compounds (benzene, toluene) iodinated
within a few minutes. Deactivated compounds (chlorobenzene, nitroani-
soles) iodinated within minutes to a few hours with I2-AgOTf. Mono-iodi-
nation was favored over poly-iodination. In the iodination of benzilic acid
esters, only monoiodo-benzilate esters were produced, even in the presence
of excess I2-AgOTf. Concerning the regiochemistry of the iodination reac-
tion, the para position was favored over the ortho site in nearly all cases.

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Aromatic compounds with electron densities equal to or greater than that of
chlorobenzene could be iodinated by the I2-AgOTf reagent. Benzophenone
was not iodinated under standard conditions at room temperature; it is
apparently too deactivated for the reagent. I2-AgOTf did not react across
the somewhat electron deficient double bond of azalactones. Nor was there
significant iodination of unsubstituted phenyl groups in the oxazoline ring
of azalactones. Molecules containing benzylic alcohol functions appeared to
suffer oxidation by the I2-AgOTf reagent. Some ethers and alcohols appear
to react slowly with the reagent. Reaction solvent choices may be limited.
Dichloromethane and chloroform were tried. The best solvent is dichloro-
methane. Iodination of radiotracers and precursor drugs containing
primary, secondary, and tertiary amines occurred smoothly and in good
to very good yields. Catechol derivatives were iodinated at the 6-position
with I2-AgOTf. The essentially anhydrous and neutral conditions and
methylene chloride reaction medium permits application of this reagent to
a wide range of organic compounds. The results are summarized in Scheme
1, 2, 3 and Table 1. All compounds made here are known compounds.
From a mechanistic point of view, we think the first process is
an activation of the iodine molecule, which is polarized by the soft–soft
interaction with the silver triflate, which increase the electrophilicity of the
iodine and, consequently, its reactivity towards the substrate aromatic
compound. This iodination obeys the orientation rule of an aromatic SE
reaction, and is assumed to take place according to the following mechan-
istic equations (Scheme 4).
In conclusion, we have established a mild, simple, and convenient
method for the direct iodination of a wide range of aromatic compounds
using a combination of iodine and silver triflate.
EXPERIMENTAL
Typical Iodination Procedure
A mixture of aromatic compound (2 mmol), silver triflate (2–4 mmol),
and iodine (2–4 mmol) was stirred together in 10 mL CH2Cl2 in a darkened
fume hood. Alternatively a solution of iodine in methylene chloride or
chloroform could be added dropwise to a CH2Cl2 solution of the first two
ingredients. If the aromatic compound contained a basic amine function,
acetic acid (5 drops) was added to prevent amine-iodine complexation, or an
organic-soluble acid salt form was used. Loss of iodine color and precipita-
tion of AgI occurred as the reaction progressed. Reaction times to com-
pletion ranged from a few minutes to 12 hours, depending upon the degree

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MULHOLLAND AND ZHENG
Scheme 1. Iodination of simple compounds.
of activation of the aromatic ring. Workup: AgI was removed by filtration
and washed with 4 ꢀ 3 mL CH2Cl2. The combined CH2Cl2 solution was
washed with dilure NH4OH, dilute Na2SO3, and water, then dried over
anhydrous Na2SO4, filtered and evaporated under vacuum to give the
crude product. Crude products were analyzed by TLC, HPLC or in some
cases GC. Products were further purified, if necessary, by flash chromato-
graphy with silica gel and hexane/Et2O/iPr2NH mixtures as eluent. Product
percentages were given representative isolated yields. Final products were

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3063
Scheme 2. Substrates which failed to iodinate or gave complex mixtures with
I2-AgOTf.
characterized by some relevant analytical data such as nD,20 mp or 1H NMR
(Bruker QE 300, TMSas an internal standard, CDCl as solvent) in com-
parison with the compounds which are known from the literature.
3
Analytical data for the compounds in Scheme 3 were listed as below.
b-CIT, 1H NMR (CDCl3), d 7.60 (d, 2H, J ¼ 8.4 Hz), 7.02 (d, 2H,
J ¼ 8.1 Hz), 3.73–3.58 (m, 1H), 3.50 (s, 3H), 3.38–3.35 (m, 1H), 2.95–2.86
(m, 2H), 2.60–2.54 (m, 1H), 2.23 (s, 3H), 2.16–2.13 (m, 2H), 1.84–1.75
(m, 3H). b-CINT, 1H NMR (CDCl3), d 7.77–7.67 (m, 3H), 7.41–7.38
(m, 3H), 3.60–3.59 (m, 1H), 3.43 (s, 3H), 3.41–3.39 (m, 1H), 3.18–3.12
(m, 1H), 3.03–3.02 (m, 1H), 2.78–2.66 (m, 1H), 2.24 (s, 3H), 2.28–2.06
(m, 2H), 1.85–1.58 (m, 3H). I-MDM, 1H NMR (CDCl3), d 7.60–7.24
1
(m, 9H), 4.23 (s, 1H), 3.86 (s, 3H). I-QNB, H NMR (CDCl3), d 7.71–7.65
(m, 2H), 7.41–7.21 (m, 7H), 4.98–4.91 (m, 1H), 3.20–3.08 (dd, 1H, J ¼ 15.8,
2.0 Hz), 2.95–2.45 (m, 6H), 2.00–1.98 (m, 1H), 1.64–1.24 (m, 4H). I-TRB,
1H NMR (CDCl3), d 7.65–7.32 (m, 9H), 5.20–5.16 (m, 1H), 3.25–3.18
(m, 2H), 2.42 (s, 3H), 2.14–2.08 (m, 1H), 1.96–1.68 (m, 4H), 1.60–1.47
(m, 4H). I-PB, 1H NMR (CDCl3), d 7.58–7.36 (m, 9H), 5.10–5.04 (m,
1H), 3.49–3.40 (m, 1H), 2.88–2.72 (m, 1H), 2.53–2.48 (m, 4H), 1.83–1.79
(m, 4H).

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MULHOLLAND AND ZHENG
Scheme 3. Iodination of radiotracer precursors.
Analytical data for the products in Table 1 were listed as below. Entry
1 Product, 1H NMR (CDCl3), d 7.70 (s, 1H), 6.92 (s, 1H), 5.95 (s, 2H), 3.78
(s, 2H), 1.45 (s, 2H). Entry 2 Product, 1H NMR (CDCl3), d 7.70 (s, 1H), 6.94
(s, 1H), 5.96 (s, 2H), 3.85–3.76 (m, 2H), 2.98–2.90 (m, 2H), 1.43 (s, 2H).
Entry 3 Product, 1H NMR (CDCl3), d 7.71 (s, 1H), 6.93 (s, 1H), 3.88 (s, 3H),
3.86 (s, 3H), 3.83–3.80 (m, 2H), 2.96–2.93 (m, 2H), 1.45 (s, 2H). Entry 4
Product, 1H NMR (CDCl3), d 7.70 (s, 1H), 6.94 (s, 1H), 5.97 (s, 2H),
3.66–3.61 (m, 2H), 3.03 (s, 1H), 2.94–2.89 (m, 2H), 2.88 (s, 3H). Entry 5

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3065
Product, 1H NMR (CDCl3), d 7.24 (s, 1H), 6.70 (s, 1H), 6.50 (brs, 1H), 3.88
(s, 3H), 3.85 (s, 3H), 3.61 (dt, 2H, J ¼ 6.5, 6.5 Hz), 2.98 (t, 2H, J ¼ 6.5 Hz).
Entry 6 Product, 1H NMR (CDCl3), d 7.73 (s, 1H), 7.50–7.34 (m, 5H), 6.93
(s, 1H), 5.95 (s, 2H), 3.60–3.55 (m, 2H), 3.01 (s, 1H), 2.94–2.91 (m, 2H), 2.72
(s, 2H). Entry 7 Product, 1H NMR (CDCl3), d 8.11 (s, 1H), 7.71 (s, 1H), 6.92
Table 1. Catechol Derivatives lodinate at the 6-Positiona
(continued )

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MULHOLLAND AND ZHENG
Table 1. Continued
aReaction conditions: 1 : 1 :1 :1 substrate/I2/AgOTf, CH2Cl2, R. T., in
b
a darkened fume hood; isolated yield.
Scheme 4. Mechanistic equation of iodinatior.
1
(s, 1H), 5.98 (s, 2H), 2.46 (s, 3H). Entry 8 Product, H NMR (CDCl3), d
7.98 (s, 1H), 7.70 (s, 1H), 7.50–7.35 (m, 4H), 6.94 (s, 1H), 5.95 (s, 2H), 3.81
1
(s, 3H). Entry 9 Product, H NMR (CDCl3), d 7.77 (s, 1H), 7.58 (s, 1H),
7.50–7.39 (m, 5H), 6.93 (s, 1H), 3.47 (s, 3H), 3.02 (s, 3H). Entry 10 Product,
1H NMR (CDCl3), d 7.23 (s, 1H), 7.15 (s, 1H), 6.98 (s, 1H), 6.77 (s, 2H), 5.97
(s, 2H), 3.89 (s, 6H), 3.86 (s, 3H), 3.75–3.68 (m, 4H), 2.59–2.51 (m, 4H).
1
Entry 11 Product, H NMR (CDCl3), d 7.23 (s, 1H), 6.98 (s, 1H), 5.97
(s, 2H), 4.02 (s, 2H), 3.33 (s, 2H), 2.80 (s, 3H), 0.93 (s, 9H), 0.11 (s, 6H).
1
Entry 12 Product, H NMR (CDCl3), d 7.33 (s, 1H), 6.95 (s, 1H), 3.82

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(s, 3H), 3.65 (t, 1H, J ¼ 8.1 Hz), 3.40 (s, 3H), 3.13 (s, 1H), 2.96 (d, 2H,
J ¼ 7.0 Hz), 1.13 (s, 9H), 1.10 (s, 9H).
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Received in the USA December 4, 2000

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