4-Iodo-2,6-dimethylbenzenamine

General procedure: A mixture of aromatic/heteroaromatic amine (1 mmol) and 1-butyl-3-methylpyridinium dichloroiodate (BMPDCI) (1.2 mmol) was heated to 80°C for 1-4 h. After completion of the reaction (monitored by TLC), ethyl acetate was added, followed by addition of water. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layer was dried using sodium sulfate and evaporated under vacuum to afford the crude product, which on further column chromatography using silica gel afforded the pure iodinated product as shown in Table 1.General procedure: 1-Methoxy-3, 5-dimethylbenzene(100mg, 0.73 mmol), N-Bromosuccinimide (NBS, 260 mg, 1.46 mmol) and one ball (5 mmdiameter, stainless steel) were transferred to a milling jar (10 mL, stainlesssteel). The ball-milling operation was performed and the progress of reaction was monitored by TLC/To a solution of 2, 6-dimethyl aniline (50 gm) in 1, 4-dioxane (400 ml) and pyridine (40 ml) was added iodine (157.3 gm) slowly at 0°C. The solution was stirred for1 hour at 0°C and the temperature was raised to room temperature. The solution was stirred for 1 hour at room temperature and then added a saturated solution of sodium thiosulfate. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried with anhydrous sodium sulfate and the solvent was evaporated in vacuum to obtain 91.8 gm of 4-iodo-2, 6- dimethyl benzenamine.Example 4 Preparation of 4-iodo-2, 6-dimethyl benzenamine [0083] To a solution of 2, 6-dimethyl aniline (50 gm) in 1, 4-dioxane (400 ml) and pyridine (40 ml) was added iodine (157.3 gm) slowly at 0° C. The solution was stirred for 1 hour at 0° C. and the temperature was raised to room temperature. The solution was stirred for 1 hour at room temperature and then added a saturated solution of sodium thiosulfate. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried with anhydrous sodium sulfate and the solvent was evaporated in vacuum to obtain 91.8 gm of 4-iodo-2, 6-dimethyl benzenamine.Step-I: General procedure: To a solution of the aniline (1, 20.0 mmol) in a mixture of H2O (100 mL) and MeOH(300 mL), was added conc. hydrochloric acid was added until pH was 1–2 (pH strip).Then an aqueous solution of NaICl2 (50percent w/w 1.1–4;.8 molar equiv; for amount, seeTable) was added dropwise and the resulting mixture was stirred with a stirring bar atroom temperature for 3–4 h. Saturated aqueous NaHSO3 was added until negative starchtest was obtained and the product was worked up.When no precipitate was clearly visible in the product mixture, the mixture was madeslightly basic (pH strip) by dropwise addition of an aqueous solution of NaOH (1 M) andextracted with Et2O. The combined organic phases were dried (MgSO4), filtered, and concentratedunder vacuum to give a solid.When a visible precipitate was obtained, the solid was isolated by gravity filtration(each case specified below) and the filtrate was then made slightly basic (pH strip) byaddition of an aqueous solution of NaOH (1 M) and extracted with Et2O. The combinedorganic extracts were dried (MgSO4), filtered, and concentrated under vacuum to afford asolid.All the solids were analysed by TLC (silica gel; varying mixtures of hexanes/ethylacetate). When a solid consisted of several products, the compounds were separated andpurified by flash chromatography (silica gel; hexanes/ethyl acetate 9:1 when not otherwisestated).The products obtained were characterized by mps (and comparison with lit. mps), IR, MS, 1H- and 13C-NMR spectra as well as elemental analysis for all new compounds. Theanisidines gave no products that could be characterized. Anilines 1a–1j gave products assummarized below; most of them are known from the literature.To a suspension of sodium bicarbonate (126 g, 1500 mmol) and 2, 6-dimethylaniline (61.5 mL, 500 mmol) in methanol (700 mL) was added iodine monochloride (1.0 M in dichloromethane, 550 mL, 550 mmol) at room temperature over 1 h. After addition was complete, stirring was continued for 3 h. The reaction was filtered to remove excess sodium bicarbonate and the solvent removed in vacuo. The residue was redissolved in diethyl ether (1.5 L) and treated with hydrochloric acid (2M in ether, 375 mL, 750 mmol). The resulting suspension was stored in the freezer (-15° C.) overnight. The solid was filtered and washed with diethyl ether until it became colorless to give 126.5 g (89percent) as a grey-green powder. 1H-NMR (DMSO-d6) delta 2.33 (s, 6H), 7.48 (s, 2H), 9.05 (bs, 3H); 13C-NMR (DMSO-d6) delta 17.4, 91.5, 133.1, 131.2, 136.9.b) 1, 012 kg of moistened palladium on charcoal (Pd/C 10percent), 9, 361 kg of sodium acetate and 34, 41 kg of N, N-dimethylacetamide were introduced in a reactor and put under nitrogen atmosphere. The mixture was stirred and heated at 140C. 23, 497 kg of 4-iodo-2, 6-dimethyl-benzeneamine, 7, 569 kg of acrylonitrile and 54, 98 kg of N, N- dimethylacetamide were introduced in a second reactor and put under nitrogen atmosphere. The mixture was stirred at room temperature for 30 minutes. The solution of the second reactor was tranferred to the first reactor over 1 hour and the temperature of the first reactor was maintained at 140C. The reaction mixture was stirred at 140C overnight and then allowed to cool to room temperature. The reaction mixture was then filtered (1) and the filter was washed with 95, 1 1 of toluene (2). To the thus obtained organic phase, i. e. (1) + (2), was added 380, 4 [1] of water and the mixture was stirred vigourously. Then agitation was stopped and the phases were separated (3). The water layer was washed once with 95, 1 [1] of toluene and the phases were separated again (4). The combined organic phases, i. e. (3) + (4), were tranferrred to the second reactor and distilled under reduced pressure. 190, [2 1 of EtOH was added and the mixture was stirred at room temperature. A solution of HCI (6N) in 2-propanol (18, 13 [1)] was added at room temperature and the reaction mixture was stirred overnight at room temperature, followed by filtration (*). The obtained solid was washed with 14, 74 l of 2-propanol (**) and dried under reduced pressure at 50C. Yield: 50-60 percent of the hydrochloric acid salt (1: 1) of the intermediate of formula (II). Additional product (10-15percent) was recuperated by distillation of the filtrate (*) and wash liquid (**) followed by filtration at room temperature.Example 7:Preparation of (E)-3-(4-amino-3, 5-dimethyIphenyl)acrylonitrile hydrochlorideSodium acetate (13.27 gm), palladium on charcoal (0.858 gm) and dimethylacetamide (400 ml) were added and then heated to 140°C under nitrogen atmosphere. A solution of 4-iodo-2, 6-dimethyl benzenamine (20 gm), acrylonitrile (10.72 ml) and dimethylacetamide (200 ml) was added slowly to the reaction mixture. The reaction mixture was maintained for 12 hours at 140°C. The reaction mass was then cooled to room temperature and filtered through celite. The filtrate obtained was treated with water and then the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and sodium chloride solution. The organic layer was dried with sodium sulfate and the solvent was evaporated in vacuum to obtain crude oily residue. To the crude oily residue obtained above was added ethanol (210 ml). The solution was then heated to 60°C and then added a solution hydrochloride in isopropyl alcohol (69.5 ml). The reaction mixture was stirred for 1 hour at 60°C and then cooled to room temperature. The solid obtained was collected by filtration and then dried to obtain 11.5 gm of (E)-3-(4-amino-3, 5-dimethylphenyl)acrylonitrile hydrochloride.Sodium acetate (13.27 gm), palladium on charcoal (0.858 gm) and dimethylacetamide (400 ml) were added and then heated to 140°C under nitrogen atmosphere. A solution of 4-iodo-2, 6-dimethyl benzenamine (20 gm), acrylonitrile (10.72 ml) and dimethylacetamide (200 ml) was added slowly to the reaction mixture. The reaction mixture was maintained for 12 hours at 140°C. The reaction mass was then cooled to room temperature and filtered through celite. The filtrate obtained was treated with water and then the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and sodium chloride solution. The organic layer was dried with sodium sulfate and the solvent was evaporated in vacuum to obtain crude oily residue.To the crude oily residue obtained above was added ethanol (210 ml). The solution was then heated to 60°C and then added a solution of hydrochloride in isopropyl alcohol (69.5 ml). The reaction mixture was stirred for 1 hour at 60°C and then cooled to room temperature. The solid obtained was collected by filtration and then dried to obtain 1 1.5 gm of (E)-3-(4-amino-3, 5-dimethylphenyl)acrylonitrile hydrochloride.Step-II: Preparation of (E)-3-(4-amino-3, 5-dimethylphenyl)acrylonitrile hydrochloride Sodium acetate (13.27 gm), palladium on charcoal (0.858 gm) and dimethylacetamide (400 ml) were added and then heated to 140° C. under nitrogen atmosphere. A solution of 4-iodo-2, 6-dimethyl benzenamine (20 gm), acrylonitrile (10.72 ml) and dimethylacetamide (200 ml) was added slowly to the reaction mixture. The reaction mixture was maintained for 12 hours at 140° C. The reaction mass was then cooled to room temperature and filtered through celite. The filtrate obtained was treated with water and then the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and sodium chloride solution. The organic layer was dried with sodium sulfate and the solvent was evaporated in vacuum to obtain crude oily residue. To the crude oily residue obtained above was added ethanol (210 ml). The solution was then heated to 60° C. and then added a solution of hydrochloride in isopropyl alcohol (69.5 ml). The reaction mixture was stirred for 1 hour at 60° C. and then cooled to room temperature. The solid obtained was collected by filtration and then dried to obtain 11.5 gm of (E)-3-(4-amino-3, 5-dimethylphenyl)acrylonitrile hydrochloride.a) To a solution of 159 g of 4-iodo-2, 6-dimethyl-benzenamine in 650 ml of N, N- dimethylacetamide was added 63.8 g of sodium acetate. The reaction mixture was kept under nitrogen atmosphere. 7 g of moistened palladium on charcoal (Pd/C 10 percent) and 64.4 ml of acrylonitrile was added. The reaction mixture was heated to 130C and stirred overnight. After cooling to room temperature, 0.5 1 of toluene and 0.5 1 of N, N- dimethylacetamide was added. The reaction mixture was filtered over Dicalite and the residue was washed with 0.5 1 of toluene. Water(6 l) was added to the mixture which was stirred for 30 minutes. The layers were separated. To the aqueous layer, [1] 1 of toluene was added and the mixture was stirred for 30 minutes. The layers were separated again. The separated organic layers were collected and the solvent was evaporated. Yield: 123 g of the intermediate of formula (II). The retention time of intermediate (II) on CPSIL8CB (25mx0.32mmx0.5 mum) purged with He with an initial temperature of 40C increased with 10C/minute till a temperature of 300C, was 17.50 minutes for the (Z) isomer and 18.77 minutes for the (E) isomer.

Molecular Weight:247.08
XLogP3:2.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:246.98580
Monoisotopic Mass:246.98580
Topological Polar Surface Area:26
Heavy Atom Count:10
Complexity:104
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes