Iodination of Terminal Alkynes Using KI/CuSO4 – A Facile Method with Potential for Radio-
iodination
Trevor Ferris,a Laurence Carroll,a,b Ronnie C Mease,b Alan C Spiveyc and Eric O Aboagye*a
aComprehensive Cancer Imaging Centre, Department of Surgery & Cancer, Hammersmith Campus, Imperial College, London, W12 0HS,UK.
bRussell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
cDepartment of Chemistry, Molecular Sciences Research Hub, 80 Wood Lane, White City Campus, Imperial College, London W12 0BZ, UK
E-mail: eric.aboagye@imperial.ac.uk; Tel: +44 (0)20 8383 3759
Abstract
Herein, we report an efficient new method for the iodination of terminal alkynes using stoichiometric KI and
CuSO4 in a mix of acetonitrile and acetate buffer that holds promise for further development into a method for
radio-iodination.
Introduction
Radio-iodinated probes are useful in the context of biological research, diagnostic imaging and radiotherapy using
125I, 123/4I and 131I, respectively.1 As alkyl iodides are relatively labile under physiological conditions, aryl and
occasionally alkenyl iodides are often preferred for such purposes (Fig. 1).1,2
Figure 1. Clinically used iodo-tracer probes.
The synthesis of these radio-labelled molecules is usually achieved by electrophilic iodo-dehydrogenation (i.e.
Csp2-H
→ C sp2-I) or iodo-demetallation (i.e. C sp2-M → C sp2-I) reactions of appropriate aromatic/alkenyl precursors
using carrier-added molecular iodine or iodide salts in the presence of an oxidant. The former reactions are
generally performed on electron rich aryl precursors and are prone to poor regio- and chemoselectivity,3 whereas
the latter reactions require the preparation of the appropriate aryl metal precursors (e.g. Ar-SnR3) which can be
time consuming and involve toxic reagents (e.g. Cl-SnR3). Moreover, although this type of approach has been used
extensively for the radioiodination of tyrosine containing peptides and proteins,4 the resulting probes often
display poor metabolic stability.5 The metabolic degradation of iodine-containing probes compromises their
effectiveness and leads to an accumulation of iodine in the thyroid and stomach.6 The activity/selectivity profile of
these iodinated derivatives towards their in vivo targets also often differs significantly relative to the non-
iodinated parent peptides and proteins,7 likely due to the steric and electronic perturbation that the iodine atom
has on adjacent functionality e.g. the phenol moiety in the case of tyrosine based probes.8
In view of this situation, we became interested in developing the iodination of terminal alkynes as an alternative
approach to prepare radio-iodinated probes. In particular, we envisioned that this reaction could be highly
chemoselective even in the presence of electron rich aromatic and heteroaromatic rings as well as electron rich
alkenes. Additionally, such a protocol would introduce the iodine atom at a position unlikely to strongly sterically
or electronically perturb adjacent functionality. It was anticipated that the iodoalkenyl products might also display
improved metabolic stability relative to aryl and alkenyl analogues due to the greater strength of Csp-I bonds
relative to Csp2-I bonds.
An ideal radiolabelling protocol would proceed rapidly under mild aqueous conditions (123I has t1/2 = 13 h), would
avoid the use of carrier added molecular iodine to form an electrophilic iodine species due to its
volatility/toxicity,9 and would be amenable to small scale preparations on an automated platform. Although the
literature contains a number of protocols for the iododehydrogenation of terminal alkynes, none of them
appeared well aligned to this aspiration.10-14
Results and Discussion
Cognisant of the method of Tsai and co-workers.11 in which iodination of terminal alkynes is achieved in aqueous
solution using molecular iodine (2 equiv.), triethylamine (3 equiv.), tetrabutylammonium bromide (TBAB, 1 equiv.)
and copper(I) iodide (1-2 mol%), we set out to explore the ability of combinations of various iodine/iodide sources
and copper salts to effect the iodination of ethynylbenzene 1a as a test substrate. In all experiments we used
sodium acetate buffer solution at pH 5 as the medium with bathophenanthrolinedisulfonic acid (BPDS, 1 equiv.)
added to solubilise copper species in this solution (Table 1).