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             Halogenation of methoxybenzenes with N-halosuccinimide
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Procedure for using NIS for iodonating a methoxy benzene:

Dissolve the benzene in DMF at a concentration of 0.1M. cool to 4C on ice bath.
Add DROPWISE 1.2-2 molar equiv. of NIS disolved in a bit of DRY acetone (GP
usually used 20ml/gram NIS) over 30 minutes or so. Remove Ice bath and allow to
react for some time. literature states that the reaction will be over after the
addition, but experience has proved that to be BULLSHIT. If you have TLC
analysis capabilities let the RXN go until it is complete. 24 hours and not much
else will happen for sure. WORKUP: dilute the reaction mix with 2X volume
NaCl/H2O (conc brine) and extract with Ethyl acetate (or ether). Wash the
extract 2-3 times with dil. HCl to remove the DMF, then wash with NaHCO3 and
finally with Na2SO3 (that's sulFITE, not sulFATE) in order to remove the I+ via
oxidation. Dry and evap to get the crude product. Isolation can be tricky.. GP
usually runs the shit through a flash silica column, but GP'd bet you don't have
that kinda equip, sooo distillation would be the easiest method.. under vacuum
of course.

Also, if you can't get ahold of any sulfite, it can be omitted, but there WILL
be some I+ in your mix. It can also be removed by repeatedly distilling hexane
off of your product (I+ is soluable in nonpolar solvents and will distill off
with the solvent). That will work just fine, hell if you're distilling for final
purification it might not even matter.

This reaction works will for Methoxy and other electron rich rings. The more
activation on the ring, the better. Also, it likes the para but will go ortho if
blocked..



The use of NXS (N-Halosucccinimid) are OK for making DOX ore 2-CX from DMA/2-CH.
And you dont need to use CCl4. It can been done in hexane ore P.ether.
The yield is around 80-95% See J.Org.Chem. 1993,58,3072-3075



First of all, GP would like to clairify the DMF/Acetone @ 4C. The reference is:
J. CHEM. SOC. Perkin Trans I, 1985 p2521

Now at first this seems like an odd reference as it's title has nothing to do
with what we want, but upon further investigation we find that they needed an
Iodo derivative of their multiple ringed compound, catechin. They did work with
both OH and OMe substituted catechin, using NIS to Iodinate their intermediate.
This procedure was applied to various phenols in GP's research group, with
varied success. It would seem as though the more electron rich the ring, the
easier iodination occurs. Attempts with methoxy derivatives were not attempted
by GP, so he don't know for sure on those. It DOES work for phenols, some better
than others.

Another procedure:
Tetrahedron Lett. Vol. 37, No. 23, pp. 4081-4084, 1996
This paper is titled: "Mild and Regiospecific Nuclear Iodination of
Methoxybenzenes and Naphthalenes with N-Iodosuccinimide in Acetonitrile"

They apply NIS in MeCN to a good number of Methoxy derivatives, all giving high
yields (85+) of the iodinated products. GP has not seen success with phenols,
but that's not what we are concerned with here now is it..dumb GP.

Next..Tetrahedron Lett., Vol 33, No 20, pp. 2883-2886, 1992

This one is a bit 'out there' but this statement caught GP's eye: "Halogenated
salicylic acid derivatives were prepared by direct halogenation of salicylic
acids in DMF at ambient temp. using NBS or NIS" They are sticking that Iodine on
the ring, so it couldn't hurt investigation.

One more NIS ref:
J. Am. Chem. Soc. Vol 105, No. 9, 1983
This one is strange. They use NIS and NBS on coumarin, which is another big
molecule. This one uses glacial acetic acid as the solvent.


