0-Iodoaniline

In a 3-I. beaker are placed no g. (1.2 moles) of aniline, 150 g. (r.76 moles) of sodium bicarbonate and i 1. of water, and the mixture is cooled to 12-15° th addition of a small amount of ice. The beaker is then fitted with an efficient mechanical stirrer. The blade of a large porcelain spatula should be inserted into the liquid to overcome the rotary motion and thus obtain better mixing. The stirrer is started and 254 g. (i mole) of powdered iodine is added in 15-20 g. portions at intervals of two to three minutes so that all the iodine is introduced during the course of onc-half hour. Stirring is continued for twenty to thirty minutes. By this time the reaction is complete, and the color of the free iodine in the solution has practically disappeared. The crude -iodoaniline, which separates as a dark crystalline mass, is collected on a Biichner funnel, pressed as free from water as possible, and dried in the air. The filtrate may be saved for the recovery of iodine (Note i). 

For the purification of the -iodoaniline, the crude product is placed in a 2-I. flask and i 1. of gasoline (Note 2) is added. The flask is fitted with an air-coolcd reflux condenser and heated in a water bath at a temperature of 75-80° (Note 5). Phe flask should be shaken frequently and about fifteen minutes 

The sodium iodide which remains in the aqueous solution may be converted into iodine as follows To the aqueous filtrate from the -iodoaniline are added 100 cc. of concentrated sulfuric acid and 200 g. of sodium dichromate in 200 cc. of water. The iodine is allowed to settle, washed three times with water by decantation, collected on a filter, and allowed to dry on a watch glass. The yield of crude iodine is 167-179 g. 

The gasoline used was a fractionated product (b. p. 70-150°). Ordinary gasoline may be used, but it has the disadvantage that the higher boiling hydrocarbons are removed very slowly from the / -iodoaniline. 

If a higher temperature is used a tarry material is sometimes formed and a diminished yield results. 

This preparation illustrates the direct iodination of a primary aromatic amine by iodine the sodium bicarbonate removes the hydrogen iodide as formed  

Into a 1-litre beaker, provided with a mechanical stirrer, place 36 - 8 g. (36 ml.) of aniline, 50 g. of sodium bicarbonate and 350 ml. of water cool to 12-15° by the addition of a little crushed ice. Stir the mixture, and introduce 85 g. of powdered, resublimed iodine in portions of 5-6 g, at intervals of 2-3 minutes so that all the iodine is added during 30 minutes. Continue stirring for 20-30 minutes, by which time the colour of the free iodine in the solution has practically disappeared and the reaction is complete. Filter the crude p-iodoaniline with suction on a Buchner funnel, drain as completely as possible, and dry it in the air. Save the filtrate for the recovery of the iodine (1). Place the crude product in a 750 ml. round-bottomed flask fitted with a reflux double surface condenser add 325 ml. of light petroleum, b.p. 60-80°, and heat in a water bath maintained at 75-80°. Shake the flask frequently and after about 15 minutes, slowly decant the clear hot solution into a beaker set in a freezing mixture of ice and salt, and stir constantly. The p-iodoaniline crystallises almost immediately in almost colourless needles filter and dry the crystals in the air. Return the filtrate to the flask for use in a second extraction as before (2). The yield of p-iodoaniline, m.p. 62-63°, is 60 g. 

A good 3ueld of 5-iodo-2-aminotoluene may be obtained by intimately mixing o-toluidine hydrochloride, iodine and calcium carbonate, and then adding water to the mixture. The liberated hydriodic acid reacts at once with the Calcium carbonate and the lij driodide of the base is not formed. 

Triturate 20 g. of dry o-toluidine hydrochloride and 35 5 g. of powdered iodine in a mortar and then grind in 17 -5 g. of precipitated calcium carbonate. Transfer the mixture to a conical flask, and add 100 ml. of distilled water with vigorous shaking of the flask. Allow the mixture to stand for 45 minutes with occasional agitation, then heat gradually to 60-70° for 5 minutes, and cool. Transfer the contents of the flask to a separatory funnel, extract the base with three 80 ml. portions of ether, diy the extract with anhydrous calcium chloride or magnesium sulphate, and remove the excess of solvent. The crude 5-iodo-2-aminotoluene separates in dark crystals. The yield is 32 g. Recrystallise from 50 per cent, alcohol nearly white crystals, m.p. 87°, are obtained. 

Those reactions which are common to both aliphatic and aromatic amines and have been described under Aliphatic Amines (Section 111,123) will not be repeated in this Section except where differences in experimental technique occur. 

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Two extractions usually sufiSce, but if much organic material remains, a third extraction should be made. If the p-iodoaniline from the second and third extractions is coloured, it should be refluxed for a short period in light petroleum solution with a little decolourising carbon and filtered through a hot water funnel (CA U TION inflammable). 

In the reaction of aryl and alkenyl halides with 1,3-pentadiene (248), amine and alcohol capture the 7r-allylpalladium intermediate to form 249. In the reactions of o-iodoaniline (250) and o-iodobenzyl alcohol (253) with 1,3-dienes, the amine and benzyl alcohol capture the Tr-allylpalladium intermediates 251 and 254 to give 252 and 255[173-175]. The reaction of o-iodoaniline (250) with 1,4-pen tadiene (256) affords the cyclized product 260 via arylpalladiuni formation, addition to the diene 256 to form 257. palladium migration (elimination of Pd—H and readdition to give 258) to form the Tr-allylpalladium 259, and intramolecular displacement of Tr-allylpalladium with the amine to form 260[176], o-Iodophenol reacts similarly. 

Pyrrole derivatives are prepared by the coupling and annulation of o-iodoa-nilines with internal alkynes[291]. The 4-amino-5-iodopyrimidine 428 reacts with the TMS-substituted propargyl alcohol 429 to form the heterocondensed pyrrole 430, and the TMS is removed[292]. Similarly, the tryptophane 434 is obtained by the reaction of o-iodoaniline (431) with the internal alkyne 432 and deprotection of the coupled product 433(293]. As an alternative method, the 2,3-disubstituted indole 436 is obtained directly by the coupling of the o-alky-nyltrifluoroacetanilide 435 with aryl and alkenyl halides or triflates(294]. 

Transition-Metal Catalyzed Cyclizations. o-Halogenated anilines and anilides can serve as indole precursors in a group of reactions which are typically cataly2ed by transition metals. Several catalysts have been developed which convert o-haloanilines or anilides to indoles by reaction with acetylenes. An early procedure involved coupling to a copper acetyUde with o-iodoaniline. A more versatile procedure involves palladium catalysis of the reaction of an o-bromo- or o-trifluoromethylsulfonyloxyanihde with a triaLkylstaimylalkyne. The reaction is conducted in two stages, first with a Pd(0) and then a Pd(II) catalyst (29). 

Substituted indoles can be prepared from o-bromo or o-iodoanilines by paHadium-cataly2ed cycli2ation of AJ-aHyl derivatives (31). 

Iodoaniline [615-43-0] M 219.0, m 60-61 , pK 2.54. Distd with steam and crystd from benzene/pet ether. 

The selectivity of the cyclization using enamino-esters 18-20 derived from m-halogenated anilines 14-16, provided mixtures of 5- and 7-substituted quinolines. In all of these cases, the cyclization gave either equal amounts of the 5- and 7- isomers or in the case of m-iodoaniline, about a 1 2 ratio was observed. During the time of these publications, it was the desire of the authors to obtain the 7-substituted quinolines, which were potential drugs for the treatment of malaria. 

In an effort toward indolo[3,2-h]carbazoles based on Lewis acid-assisted dimerization of benzotriazole derivatives, the necessary starting materials 197 were prepared in good yields from 1-propargylbenzotriazole and 2-iodoaniline followed by alkylation. In the ensuing dimerization step, compounds 197 were treated with zinc chloride in refluxing dichlorometane to afford the indolo[3,2-h]carbazoles 199 or the dihydro derivatives 198 (Scheme 27). Under similar conditions 197, where R = = H, did not undergo dimerization, which suggests that the alkyl... 

I, 3-diaminobenzene, 2-iodoaniline, and 2,5-diiodo-4-aminotoluene in hydrochloric acid containing stannous chloride the respective rate coefficients were... 

FIGURE 3.4 Schematic drawing of the complex of P-cyclodextrin and p-iodoaniline. ... 

Larock has developed a new catalyst system for the Pd-catalyzed cyclization of olefinic tosylamides. Whereas typical conditions require either stoichiometric amounts of Pd(II) salts or catalytic amounts of Pd(II) in the presence of benzoquinone as a reoxidant, the new catalyst system utilizes catalytic Pd(OAc)2 under an atmosphere of O2 in DMSO with no additional reoxidant <96JOC3584>. Although o-vinylic tosylamides 76 can be cyclized to Af-tosylindoles 77 using this catalyst system, PdCla/benzoquinone is more effective for such cyclizations. Interestingly, in the case of o-allylic tosylanilides, the cyclization can be modulated to afford either dihydroindole or dihydroquinoline products. In a related approach involving a common 7i-aUyl Pd-intermediate, 2-iodoanilines were coupled with vinylic cyclopropanes or cyclobutanes in the presence of a Pd catalyst to afford dihydroindoles <96T2743>. 

Heating of aromatic amines such as 2-iodoaniline 126 with stericaUy hindered carbonyl compounds such as 10-iodocamphor 125 in the presence of Si(OEt)4, 59 and catalytic amounts of sulfuric acid, while distilling off the Hberated ethanol. 

Optimization of the Pd-catalyzed coupling reaction between iodoaniline 28 and bis-trialkylsily 1 butynol ether 29. 

Process development of the synthesis of iodoaniline 28 began with an improved synthesis of l-(4 -aminobenzyl)-l,2,4-triazole (6) (Scheme 4.7), which was prepared in the medicinal chemistry synthesis, albeit with poor regioselectivity (Scheme 4.1). We found that this aniline intermediate 6 could be readily prepared in three steps in >90% overall yield from 4-amino-l,2,4-triazole (30) and 4-nitrobenzyl bromide (4) based on a modified literature procedure [9]. The condensation of 30 and 4 in isopropyl alcohol followed by deamination gave the nitro... 

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