3-Iodobenzoic acid ethyl ester 13.18g (47.7mmol) solution in anh THF (220mL) was cooled to -78C under Ar. After 20 min a 2M solution of isopropylmagnesium chloride in ether 38mL (76mmol) was slowly added along the flask wall over 15 min at -78C. The flask was placed on a -55C bath and stirred at -55C to -40C for 50 min and then at -40C to -34C for 90 min. The reaction mixture was then cooled back to -78C, anhydrous DMF 20mL was slowly added along the flask wall with intense stirring (a slurry formed), the flask was then placed on a -30C bath and the bath was allowed to expire and reach ambient temperature over 2 hours. The reaction was quenched with saturated aq. NH4Cl (250mL), stirred for 45 min, diluted with water 50mL and ether 100mL, shaken, separated. The organic phase was washed with additional sat. NH4Cl (250mL) and sat. NaCl (200mL). The aqueous phases were re-extracted with ether (250mL). The combined organic extracts were dried with MgSO4 and evaporated (down to 1.5 Torr, at 40C). The residue was dried on highvac overnight. Y=8.84g (104%) of the crude aldehyde as a pale yellow oil, 94% pure by HPLC, 1H-NMR.
1H(d6-DMSO, 400MHz): 10.103(s, 1H), 8.447(dd, 1.7Hz, 1.4Hz, 1H), 8.254(dt, d: 7.8Hz, t: 1.5Hz, 1H), 8.170(dt, d: 7.7Hz, t: 1.5Hz, 1H), 7.764(t, 7.7Hz, 1H), 4.367(q, 7.1Hz, 2H), 1.350(t, 7.1Hz, 3H)
4.110g (approx 22.18mmol) of the crude aldehyde from the previous step was dissolved in a mixture of acetic acid 20mL and water 10mL. Thiosemicarbazide 2.50g was dissolved in a mixture of acetic acid 20mL and water 20mL with heating, the hot solution was added into the stirred solution of aldehyde. A white precipitate formed. The stirred mixture was allowed to cool to RT. After 1 hour, the precipitated thiosemicarbazone was collected by filtration, washed with some additional AcOH+water 1:1 mixture (2x10mL), then with copious quantity of water, dried by suction and on highvac. The obtained crude thiosemicarbazone (white solid, 4.73g) was suspended in anhydrous ethanol 250mL, iron(III)chloride hexahydrate 21.6g (80mmol) was added and the mixture was refluxed on an 85C oil bath for 2 hours. Charcoal 1g was then added, the mixture was cooled to RT, filtered and the filtrates were concentrated to a small volume (about 30mL). Meanwhile, EDTA disodium salt 35g (94mmol) was dissolved in a mixture of water 200mL and 28% ammonia 20mL. The concentrated reaction mixture was poured in a thin stream into the vigorously-stirred solution of EDTA. The flask was washed with additional ethanol (2x10mL) then with water (2x25mL); the washings were also added to the mix. After 15 min stirring, the precipitated crude product was collected by filtration, washed with water until nearly-white, then dried by suction and on highvac. The crude product (4.36g) was dissolved in refluxing acetonitrile 250mL, the solution was quickly filtered while hot, the Buchner funnel was washed with some additional hot acetonitrile (50mL) and the filtrates were evaporated. The residue was suspended in acetonitrile 40mL, the solids were collected by filtration, washed with acetonitrile (2x20mL), dried by suction and on highvac. Y= 3.780g (80.5% from semicarbazone, 68.5% overall) of a cream-colored solid, about 96% pure by HPLC.
1H(d6-DMSO, 400MHz): 8.304(t, 1.6Hz, 1H), 7.986(m, 2H), 7.623(t, 7.8Hz, 1H), 7.513(br s, 2H), 4.355(q, 7.1Hz, 2H), 1.348(t, 7.1Hz, 3H); LC/MS(+ESI): 250 (M+1)