------------------------------------------------------------------------------- Halogenation of methoxybenzenes with N-halosuccinimide ------------------------------------------------------------------------------- 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 don’t 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. ------------------------------------------------------------------------------- Halogenation of Arenes, Alkenes and Alkynes with HX/H2O2 (or TBHP) Tetrahedron 55(36), 11127-11142 (1999) ------------------------------------------------------------------------------- Standard Procedure for aromatic halogenation: A solution of TBHP(tertbutylhydroperoxide)(70% aqueaous, 0.15mL, 1.17 mmol) was added to a cooled mixture of HBr (48% aqueaous, 0.2 mL, 1.17 mmol) in methanol (5 mL) and the mixture stirred for 5 min. To this cold solution 1.17 mmol of the aromatic is added, stirred for 30 min. and then refluxed for 6 hours. Extract with DCM and they purify by column chromatography. Anisole to 4-BromoAnisole 76% 1,4-dimethoxybenzene to 2-Br-1,4-dimethoxybenzene 89% 4-methylphenol to 2-Bromo-4-methylphenol 74% The following was done with 4 equivalents of TBHP and 4 Eq. HBr 1,4-dimethoxybenzene to 2,5-diBr-1,4-dimethoxybenzene 98% With 4 equivalents of H2O2 and 4 Eq. HBr 1,4-dimethoxybenzene to 2,5-diBr-1,4-dimethoxybenzene 99% With 4 equivalents of H2O2 and 4 Eq. HCl 1,4-dimethoxybenzene to 2,5-diCl-1,4-dimethoxybenzene 73% With 4 equivalents of TBHP and 4 Eq. HCl 1,4-dimethoxybenzene to 2Cl-1,4-dimethoxybenzene 71% This had no detectable dichloro impurity Its too bad they didn't run more reactions with H2O2 ------------------------------------------------------------------------------- Synthesis 676 (1977) - Aromatic halogenation with H2O2, HX, 1 eq CaX2 and a PTC -------------------------------------------------------------------------------