4- Iodoimidazoles

Generally these derivatives are rather unstable and behave as oxidizing and halogenating agents. 1-Iodoimidazoles are more stable than other analogs. 

Most iV-haloimidazoles and their benzo analogues are rather labile compounds, but the iV-iodo compounds are stable probably because the iodonium cation is more stable than other halogen cations. 1-Iodoimidazoles do not dissolve in acids or alkalies and decompose on heating with liberation of iodine. The rearrangement of N- to C-halopyrazoles has been observed and has also been postulated to occur with imidazoles iV-iodoimidazoles may be intermediates in the C-iodination process. 

An AT-dimethylsulfamoyl-protected 4-iodoimidazole is joined with N-tert-butoxy-carbonyl-4-piperidone via a Grignard reaction to give, in good yield after dehydration and elimination of the two protecting groups with concentrated HC1, 4(5)-( 1,2,5,6-tetra-hydropyridin-4-yl)imidazole as dihydrochloride c 151... 

Treating imidazole with iodine in an NaOH solution afforded the complete ring iodination product, 2,4,5-triiodoimidazole. 4-Iodoimidazole was then produced in 75% yield upon selective reductive deiodination, [5]. The same procedure converted 2-methylimidazole and 1-methylimidazole to 4(5)-iodo-2-methylimidazole [6] and 4(5)-bromo-l-methylimidazole [7], respectively. 

By carefully monitoring the pH of the reaction, regioselective diiodination was achieved. Treating imidazole with iodine at pH 12 furnished 2,5-diiodoimidazole. Selective reductive deiodination secured 2-iodoimidazole, which upon bromination afforded 4,5-dibromo-2-iodoimidazole [6],... 

A variant of the Sandmeyer reaction transformed 5-aminoimidazole 3 into the corresponding 5-iodoimidazole 4. Here the diazotization was accomplished using isoamyl nitrite [9,10],... 

Evans et al. prepared organozinc reagent 16 from quantitative metalation of iodide 15 by using an activated Zn/Cu couple in the presence of an ester functionality. Treating 2-iodoimidazole 17 with three equivalents of 16 in the presence of PdCl2(Ph3P)2 afforded adduct 18, which was then transformed into diphthine (19) in five additional steps [17]. 

Most literature precedents assemble the heterobiaryls at the C(4) position. In one instance, however, the substitution took place at the C(5) position. As shown below, treatment of 5-iodoimidazole derivative 4 with (E)-1 -tributylstannylprop- l-en-3-ol (49) in the presence of PdCl2(PhCN)2 led to adduct 50 in 68% yield [33],... 

In contrast, an excellent yield was obtained for the reaction between 5-iodoimidazole and propargyl alcohol in the absence of Cul to install the 5-alkynyl derivative [10, 41], The adduct was then deprotected to 5-alkynyl- l-P-D-ribofuranosylimidazole-4-carboxamide 58, an antileukemic agent. It is noteworthy that if the Sonogashira reaction was conducted in the presence of Cul, the yield dropped to 19%. 

Considerable confusion has existed in the literature since the publication of incorrect structural assignments of 4-iodo- and 4,5-diiodo-imidazoles over 60 years ago (28JPR33). Pauly believed these compounds to be the 2- and 2,4-isomers, respectively, and only recently were the assignments finally corrected (81JOC1781 87AJC1399). Those involved in the field should therefore be wary of many reported structures of bromo- and iodo-imidazoles. For example, 4- (not 2-) iodoimidazole reacted with bromine in chloroform to give 4-bromo-5-iodoimidazole (not the 4-bromo-2-iodo isomer), and there are many other examples (81JOC1781). 

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