Ammonia → Meconin

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Since iodine is the least reactive halogen towards electrophilic substitution, direct iodination of aromatic compounds with iodine presents difficulty and requires strong oxidizing conditions. Thus, a large diversity of methods for synthesis of aromatic iodides have been reported [36]. Some of these reported procedures involved harsh conditions such as nitric acid-sulfuric acid system (HNO3/H2SO4), iodic acid (HIO3) or periodic acid (HIO4/H2SO4), potassium permanganate-sulfuric acid system (KMnO4/H2SO4), chromia (CrO3) in acidic solution with iodine, vanadium salts/triflic acid at 100° C., and lead acetate-acetic acid system [Pb(OAc)4/HOAc]. N-iodosuccinimide and triflic acid (NIS/CF3SO3H) has also been reported for the direct iodination of highly deactivated aromatics. In addition, iodine-mercury(II) halide (I2/HgX2), iodine monochloride/silver sulfate/sulfuric acid system (ICl/Ag2SO4/H2SO4), N-iodosuccinimide/trifluoroacetic acid (NIS/CF3CO2H), iodine/silver sulfate (I2/Ag2SO4), iodine/1-fluoro-4-chloromethyl-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (I2/F-TEDA-BF4), N-iodosuccinimide/acetonitrile (NIS/CH2CN), and ferric nitrate/nitrogen tetroxide [Fe(NO2) 3/N2O4] are also routinely employed for iodination. Nonetheless, iodination of noscapine even under the most gentle conditions gave only the hydrolysis products, meconine and cotamine [37]. In addition, direct aromatic iodination of noscapine using thallium trifluoroacetate or iodine monochloride also resulted in bond fission between C-5 and C-3′ under acidic conditions. Thus, different reaction conditions were tried, based upon varying pH, and found that successful introduction of the iodine atom at the desired C-9 position without disrupting other groups and bonds was stringently dependent on the acidity of the reaction media. A low acidic environment was conducive to effect iodination, whereas, higher acidity was detrimental to the iodination reaction. Thus, in this present work, two different complexes of iodine chloride were used for iodination: pyridine-iodine chloride and potassium iododichloride. Although the reaction with potassium iododichloride gave 9-I-nos (5), the yield was low and the desired product was associated with the undesirable hydrolyzed products. A suggestive reason for hydrolysis reaction could be the generation of excess amount of conc. hydrochloric acid in the reagent mixture. Since it was necessary to avoid excess acidity, excess amounts of potassium chloride were employed. Although potassium iododichloride solutions are most conveniently prepared by the addition of commercial iodine chloride to a solution of potassium chloride, it was possible to modify the procedure of Gleu and Jagemann, wherein, an iodide solution was oxidized with the calculated quantity of iodate in the presence of excess potassium chloride [38]. The pyridine-iodine chloride complex was prepared directly from pyridine and potassium iododichloride and this procedure avoided the separate isolation of the pyridine-iodine chloride-hydrogen chloride complex [39]. Thus, 9-I-nos (5) was prepared by treating a solution of noscapine in acetonitrile with pyridine-iodine chloride at room temperature for 6 hours followed by raising the temperature to 100° C. for another 6 hours. After cooling, excess ammonia was added and filtered through a celite pad to remove the black nitrogen triiodide. The filtrate was made acidic with 1 M HCl and filtered to collect the yellow solid, washed with water and air-dried to obtain the desired compound in 76% yield. A valuable advantage of this procedure lies in its applicability for the regioselective aromatic iodination of complex natural products.

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