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          Mild and Regiospecific Nuclear Iodination of Methoxybenzenes 
            and Naphthalenes with N-Iodosuccinimide in Acetonitrile
                         Tet Lett 37, 4081-4084 (1996)
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Abstract: A wide range of methoxy substituted benzenes and naphthalenes were 
          regiospecifically iodinated at para position with N-iodosuccinimide in 
          acetonitrile under mild conditions in excellent yields. Methylanisoles 
          afforded only nuclear iodination products. 

Iodination of aromatic compounds has been the subject of numerous studies due to 
the interest of iododerivatives as substrates for reactions involving C-C bond 
formation mainly mediated by transition metals. These derivatives have been used 
in the synthesis of many interesting natural products and bioactive compounds. 
Concerning iodination procedures, the moderate reactivity of iodine with aromatic 
substrates determined the use of different activating agents to effectively 
succeed in the goal. Iodonium donating reagents and other more sophisticated 
procedures have also been employed. The wide range of methods described so far 
revealed the lack of an efficient and general enough procedure.

We recently reported the use of N-bromosuccinimide (NBS) in acetonitrile as a 
mild and excellent nuclear brominating reagent for methoxybenzenes and naphthalenes. 
Seeking for further extension of these results we thought of N-iodosuccinimide 
(NIS) as iodination agent. We report in this letter the ability of NIS to achieve 
nuclear iodination of activated aromatic compounds under very mild conditions and 
in good to excellent yields. Whereas NCS and NBS have been extensively used for 
many years as halogenating agents for aromatic substrates under different 
conditions, aromatic iodinations using N-iodoamides have been used in a lesser 
extent. 

Methoxy aromatic derivatives used in this study were commercially available. These 
compounds were submitted to reaction with NIS in CH3CN at different temperatures. 
The results are collected in the Table. As can be seen, the products obtained in 
all cases resulted from the regiospecific iodination of the aromatic ring. The 
observed regiochemistry was the result of reaction through the presumably more 
electron rich and less sterically encumbered aromatic ring position. Thus, para 
positions of methoxybenzenes (entries 1, 5 and 6) and 4- and 1- position of
methoxynaphthalenes (entries 9 and 10) were exclusively iodinated, whereas the 
ortho-iodination only ocurred when the para position was occupied (entries 4 and 7). 
As was found with NBS, chain iodination products were not detected in the reactions 
of NIS with methylanisoles under refluxing acetonitrile (entries 2-4).

The reactivity of the substrates seems to be associated to the electronic density 
of the aromatic rings. Thus, iodination of 1,3- and 1,4-dimethoxybenzene (entries 
6 and 7) and 1,2,4-trimethoxybenzene (entry 8) took place at rt whereas the 
reactions of methoxybenzenes and naphthalenes (entries 1-4 and 9-10) and 
1,2-dimethoxybenzene (entry 5) required refluxing acetonitrile to be completed. 
It is noteworthy that the activating effect of the substituents is only additive 
when they are not arranged on adjacent carbons. Thus, the influence of a second 
electron-donating substituent situated on a vicinal carbon on the reactivity is 
scarce (compare entries 1 with 2 and 6 with 8) or even negative (compare entries 
1 with 5) when iodination can take place on a free para position. In the case of 
1,2-dimethoxybenzene (entry 5), this could be a consequence of the lower 
activation of the reactive position 4 due to the OMe group situated at C-2 (meta).

We have also checked the influence of solvent polarity on the reactivity. When 
these reactions were performed using CCl4, the reactivity observed was lower than 
in CH3CN. Thus, the reaction of the most reactive substrates in the Table 
(1,3-dimethoxy- and 1,2,4-trimethoxybenzenes) required four days in refluxing CCl4 
to be completed, whereas the less reactive ones (2-methyl- and 2-methoxyanisole) 
were recovered unaltered after 5 days in the same conditions. These results 
evidenced the important role of the solvent polarity to achieve an efficient 
iodination with NIS. A similar effect was observed in bromination with NBS, where 
the reactions in CH3CN were faster than in CCl4. The regioselectivity observed 
(para iodination prefered when possible) revealed the influence of steric grounds 
on the reaction. The different reactivity of the studied aromatic substrates (the 
more electron rich reacted faster) and the effect of solvent polarity on the 
efficiency of the reaction suggested an aromatic electrophilic halogenation-type
mechanism, with the succinimide anion acting as leaving group at the first step 
(formally a SN2 reaction at halogen) and as a base in the subsequent deprotonation 
of the Wheland intermediate. The lower reactivity of NIS with respect to NBS could 
be explained by assuming that the nucleophilic attack on iodine is less favoured 
than on bromine due to the higher size and lower positive charge density of the 
former.

In order to take advantage of this highly regioselective iodination in a controlled 
mixed dihalogenation, we performed the reaction of 4-iodo-3-methylanisole with 
NBS/CH3CN. Unfortunately, the method was not preparatively useful and after 3 days 
at rt we obtained a complex mixture where 6-bromo-4-iodo-3-methylanisole and 
4-bromo-3-methylanisole were detected as major components in a similar proportion, 
indicating that the reactivity of C-4 adjacent to the methyl substituent was as 
large as that of the less hindered C-6 contiguous to the methoxy group. The well 
contrasted higher reactivity of the system NBS/H2SO4 did not allow us to achieve 
the regioselective bromination. The reaction of the above substrate with NBS/p-TsOH 
at rt yielded a ca. 60:40 mixture of the 2-bromo and 6-bromo derivatives. 

In conclusion, the regiospecific nuclear iodination of aromatic methoxy derivatives 
can be efficiently achieved with NIS in CH3CN. These results broaden the range of 
application of N-halosuccinimides and provide a mild and controlled entry into 
substituted aromatic iododerivatives widely used in organic synthesis. We are now 
extending the utilization of this method in the iodination of highly 
functionalizated aromatic derivatives in order to evaluate its compatibility with
a range of functional groups.


Representative procedure:

To a solution of 1 mmol of the aromatic compound in 4 ml of CH3CN, 1.5 mmol NIS was 
added and the reaction was stirred at the desired reaction temperature. After the 
time required in each case, the solvent was evaporated and ether added. The etheral 
phase was washed with aqueous NaHSO3 solution followed by water. The ether layer 
was dried over MgSO4 and evaporated to give the crude compound. 

Examples:

1,4-MeO-benzene, 20°C, 16h, 95% yield (2-iodo)
1,2-MeO-benzene, 82°C, 18h, 85% yield (4-iodo)
Anisole, 82°C, 6h, 95% yield (4-iodo)
1,2,4-MeO-benzene, 20°C, 4h, 95% yield (5-iodo)

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