C O M M U N I C A T I O N S
Figure 2. The halogen exchange reaction performed in a m-xylene/diglyme
solvent mixture of variable composition.
Acknowledgment. We thank the National Institutes of Health
(GM 45906) for supporting this work. We are grateful to Pfizer,
Merck, and Bristol-Myers Squibb for additional funds.
Supporting Information Available: Experimental procedures and
characterization data for all unknown compounds (PDF). This material
References
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Figure 1. (a) Conversion of 5-bromo-m-xylene into 5-iodo-m-xylene using
NaI or KI in n-BuOH or DMF as solvents. Performed with 5.0 mol % CuI,
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using NaI or TBAI (tetrabutylammonium iodide), and the reverse reaction
using NaBr or TBAB (tetrabutylammonium bromide). Performed with 5.0
mol % CuI, 10 mol % ligand 1b, 1.0 equiv of aryl halide, and 1.0 equiv of
the halide salt in DMF at 110 °C.
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mended for the copper-catalyzed halogen exchange (Figure 1a).1a
The rate of the halogen exchange exhibits an interesting dependence
on the total concentration of the halide salts in the solution. Thus,
NaI in DMF is the only combination in Figure 1a that gives a
homogeneous solution initially, and it also provides the lowest rate.
This is further emphasized by Figure 1b, where the completely
soluble tetrabutylammonium halides provide lower rates of halogen
exchange (in either direction) than sodium halides, which give
heterogeneous reaction mixtures. We speculate that a high con-
centration of the halide salts in the solution inhibits the desired
halogen exchange reaction via formation of poorly reactive halo-
cuprate complexes.10Nevertheless, there seems to exist an optimal
range of the halide concentrations because the halogen exchange
reaction is sluggish in nonpolar solvents such as toluene and xylene
that dissolve the iodide salt only sparingly. In those cases,
solubilizing additives, such as diglyme, can be of great benefit
(Figure 2). While neither pure m-xylene nor diglyme is well-suited
as a solvent, the use of a mixture of 5-60% diglyme in m-xylene
gives excellent results. Thus, the success of the current method
relies on a combination of multiple factors, most importantly, on
the proper choice of the ligand, solvent, and halide salt.
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(7) The following conversions of 5-bromo-m-xylene into 5-iodo-m-xylene
were observed after 22 h at 110 °C in dioxane using 2.0 equiv of NaI, 5.0
mol % of CuI, and 10 mol % of a ligand: 1a, 77%; 1b, 99.3%; 2a, 73%;
2b, 98%; 3, 72%; 1,10-phenanthroline, 6%; no ligand, <0.1%.
(8) Aryl chlorides react more slowly than aryl bromides. A 35% conversion
(GC) of 4-chlorotoluene into 4-iodotoluene was observed after 24 h at
130 °C.
In conclusion, we have developed a new method for the
conversion of aryl, heteroaryl, and vinyl bromides into the corre-
sponding iodides utilizing a catalyst system comprising CuI and a
1,2- or 1,3-diamine ligand. Efforts to expand the reaction scope
and to apply it in various problems are in progress in our laboratory.
(9) In a control experiment, only 1% yield (by GC) of 4o was observed if
ligand 3 was omitted.
(10) Liedholm, B.; Nilsson, M. Acta Chem. Scand. A 1984, 38, 555.
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