Iodination secondary amines

Primary and secondary amines and amides are first chlorinated at nitrogen by the chlorine released by the gradually decomposing calcium hypochlorite. Excess chlorine gas is then selectively reduced in the TLC layer by gaseous formaldehyde. The reactive chloramines produced in the chromatogram zones then oxidize iodide to iodine, which reacts with the starch to yield an intense blue iodine-starch inclusion complex. 

Derivatives of Methylene Violet 6 possessing long aliphatic chains are obtained by oxidative coupling of 3-acetoxyphenothiazine with a secondary amine in the presence of an oxidant such as iodine. The oxidative coupling of phenothiazine with amine is well known but in this case the reaction does not stop there but proceeds further at reflux temperatures to the phenothiazinone 74.9 Reduction of the latter dye and treatment with acetic anhydride yields the ballasted phenothiazine 6. Reaction of 75 with the dye chloroformate 70 yields the ballasted leuco dye developer 76. 

Triazaphospholes do not react with iodine alone but yield the 3,3-diamino-1,2,4,32 -triazaphospholes on the combined action of iodine and a primary or secondary amine (Equation (16)) <91PS(56)17, 92MI422-01). 

The reduction of amides with borane leads to the formation of borane-amine adducts, which can be resistant towards acylating agents or hydrolysis. Such borane complexes can be cleaved either by treatment with a secondary amine (e.g. piperidine, 60 °C [180]), or oxidatively, by treatment with iodine (Entry 3, Table 10.11 [181,182]). 

Stereoselective vicinal diamination of dihydropyridines 309 by electrophilic interaction with iodine in the presence of secondary amines leading to tetrahydropyrimidines 312 is described in [338, 339] (Scheme 3.107). The... 

Methods for the chlorination of secondary amines, secondary amides and imides have been reviewed. Secondary alkylamines can be chlorinated by r-butyl hypochlorite at low temperature, or by sodium hypochlorite or iV-chlorosuccinimide. A(-Bromination and A(-iodination can be brought about using the appropriate halogen, but these N-halodialkylamines are unstable and are rarely isolated. A(-Flu-oroamines and Mfluoroamides are also rare. The A(-fluoroimide (CP3S02)2NF, has, however, been prepared by direct fluorination widi fluorine. It is a stable liquid which shows promise as a fluorinating agent for aromatic compounds. ... 

Cleavage of the AI-PhFl derivatives occurs either with TFA in aqueous organic solvents or by hydrogenolysis over Pd/C,F 51 preferentially in the presence of AcOH.1 When hydrogenation is performed in the presence of B0C2O the corresponding Boc-protected derivatives are obtained directly in excellent yields. A-PhFl derivatives are also cleaved with Li/NHj in THp or in the case of A-PhFl derivatives of secondary amines by iodine in MeOH. ... 

An analogous process has been developed for unbranched aldehydes which can be transformed into a-amino ketones when oxidized in the presence of an secondary amine and iodine, as the mediator, in aqueous terf-butanol. The actual reactive species is probably the enamine which is attacked by iodine cations and subsequently by water. Carbonyl transposition reaction releases iodine anions which can be anodically reoxidized [197]. 

In summary, Honda reported a fonnal synthesis of (-)-TAN1251A in which a hypervalent iodine-promoted cyclization of a tethered secondary amine and phenol was used in the key step for the elaboration of the tricyclic skeleton. 

Hydriodic acid and phosphorus (22), like hydrochloric or hydrobromic acid replaces the hydroxyl of tropine by a halogen atom. The reductive elimination of this iodine atom from iodotropane by nascent hydrogen (Zn + HCl) provided the first preparation of the parent substance, tropane (dihydrotropidine) (I, R = CH3). (A more direct preparation of tropane is by the catalytic reduction of tropidine over platinum black (159a)). Tropane reacts readily with hydrogen chloride at an elevated temperature eliminating methyl chloride with the formation of a new saturated base, nortropane (94). The methyl group eliminated from tropane must have been attached to the nitrogen, for nortropane, in contrast to tropane, forms a well defined A-nitroso derivative. The isolation of methyl chloride and the secondary amine, nortropane, confirms the earlier assumption of the... 

Another useful strategy for the activation of an amide towards hydrolysis involves intramolecular 0-alkylation of the amide carbonyl. An early rendition of this strategy entailed the use of 4-chlorobutanamides in which cleavage was initiated by treatment with silver(I) perchlorate in aqueous acetone. More re-cently the Fraser-Reid group showed that N-pent-4-enoyl derivatives are rapidly and efficiently cleaved under mild conditions by brief treatment with 3 equivalents of iodine in aqueous THF [Scheme 8.29]. These deprotection conditions do not affect oxidisable functionalities including p-methoxybenzyl ethers and alkyl sulfides though allyloxycarbonyl groups appear to be incompatible. Primary and secondary amines are readily protected as N-pent-4-enoyl derivatives by reaction with pent-4-enoic anhydride. 

If the appropriate aniline is available, it is possible to selectively iodinate the Ar by iododediazonization (Coenen et al, 1983). However, it requires harsh conditions and may lead to undesirable by-products (especially with the solvent). An improvement over this method is the use of triazenes (WaUach reaction. Figure 76.5), which are more stable than the corresponding diazonium salts. They are, indeed, isolable and can be stored in the dark (Heindel et al, 1982). They can be decomposed by protic or Lewis acids. The choice of solvent also has great importance, as also do the substituents on the Ar and the secondary amine used. 

Microwave-assisted solid-phase synthesis of purines on an acid-sensitive meth-oxybenzaldehyde (AMEBA)-linked polystyrene has been reported [50]. The heterocyclic scaffold was first attached to the polymer support via an aromatic nucleophilic substitution reaction by conventional heating in l-methyl-2-pyrrolidinone (NMP) in the presence of N,N-diisopropylethylamine. The key aromatic nucleophilic substitution of the iodine with primary and secondary amines was conducted by microwave heating for 30 min at 200 °C in l-methyl-2-pyrrolidone (Scheme 16.28). After reaction the products were cleaved from the solid support by use of trifluoroacetic acid-water at 60 °C. 

A highly efficient a-amination of sterically divergent aldehydes 154 using secondary amines 155 as nitrogen source, iodine as the pre-catalyst and sodium percarbonate as an environmentally benign co-oxidant has been... 

DMP with high purity by the original procedure therefore, a few modifications have been suggested. In addition, DMP has been successfully used in the syntheses of polycyclic heterocyclesand in the removal of thioketals and thioacetals. It should be mentioned that other hypervalent iodine compounds can be used as oxidants as well, especially for the o-iodoxybenzoic acid (IBX), the precursor to DMP, which can oxidize tertiary cyclic allyl alcohol into O, y0-unsaturated cyclic ketones and secondary amines into imines and can convert epoxides or aziridines into corresponding of-hydroxy ketones or Q -amino ketones. 

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