5-(isobutyloxycarbonylamino)-2-bromothiazole

 

2-Bromothiazole-5-carboxylic acid ethyl ester 17.75g (75.18mmol) was dissolved in THF 300mL and a solution of NaOH 8.6g in water 150mL was added, followed by additional water 150mL. The mixture was stirred vigorously for 45min (the hydrolysis was complete in 15 min) and the obtained homogeneous mixture was concentrated on rotavap to remove THF. The concentrated mixture was acidified with conc. HCl 20mL, the produced acid was allowed to precipitate on ice bath for 1 hour. The precipitate was collected by filtration, washed with ice-cold water, partially dried by suction. The wet paste of the acid was transferred out from the Buchner funnel, into a small beaker and the material was dried thoroughly on highvac for 1 day. Y=15.045g (96%) of the 2-bromothiazole-5-carboxylic acid as a white solid.

2-bromothiazole-5-carboxylic acid 3.78g (18.17mmol) and 3 drops of DMF was suspended in anhydrous chloroform 40mL. Oxalyl bromide 1.85mL (19.68mmol) was added and the mixture was refluxed on oil bath (85C) under a Drierite-filled tube as a gas outlet for 6 hours. The reaction mixture was cooled, diluted with anhydrous toluene 20mL and evaporated to dryness. The residue was dissolved in anhydrous toluene 40mL. TMS-N3 2.90mL (22 mmol) was added (gas evolution) and the mixture was stirred at 70C under Ar for 2 hours. The reaction mixture was cooled to RT, 2,6-lutidine 3.5mL and isobutyl alcohol (anh, 40mL) was added. The mixture was refluxed under Ar on oil bath (120C) for 1 day. The reaction mixture was evaporated . The residue was portioned between ether 150mL and 1M citric acid 150mL, the aqueous phase was re-extracted with ether 150mL. The organic extracts were washed with water 150mL and then with sat. bicarbonate 150mL. The combined extracts were dried (MgSO4) and evaporated. The residue was purified on a column of silica 80g in a EtOAc gradient in hexane, 0 to 50% EtOAc. Y=3.987g of a light yellow oil that gradualy solidified into a white crystalline mass. (78.5% yield from the acid, 75% from the ester).

1H(d6-DMSO, 400MHz): 11.187(br s, 1H), 7.153(s, 1H), 3.926(d, 6.6Hz, 2H), 1.916(app sept, 6.6Hz, 1H), 0.913(d, 6.7Hz, 6H)

The wet paste of 2-bromothiazole-5-carboxylic acid tends to dry into hard chunks; it is a good idea to transfer the wet product before drying it on highvac – the dried acid is difficult to scrape out of a Buchner funnel. The dried and powdered acid is quite static, crushing the chunks of the dried acid is best done with a spatula in a wide-mouth storage bottle.

Oxalyl bromide was used to avoid a halogen scrambling on the thiazole (chlorothiazole acyl chloride is the main product with oxalyl chloride).  

Note: TMS-azide is volatile, latex-permeable and absorbed by skin. Quite a small quantity of TMSN3 can make you very sick very fast. Use double gloves and work with TMSN3 only in the hood, don’t spill it. Don’t try to clean up the spill, just evacuate quickly if it happens. Drinking few shots of vodka can relieve symptoms of moderate azide poisoning, i.e. the azide-induced head-splitting migraine.