Org Prep Daily

July 25, 2007

2-Chloro-5-iodobenzoic acid tert-butyl ester

Filed under: procedures — milkshake @ 6:26 pm

tbu-ester.gif 

2M oxalyl chloride solution in dichloromethane 60mL (120 mmol) was added to a slurry of 2-chloro-5-iodobenzoic acid 19.41g (68.71mmol, Lancaster) in dichloromethane 40mL followed by 4 drops of DMF. The flask was equipped with a Drierite-filled tube as a gas outlet and the mixture was stirred for 4 hours. The homogenous reaction mixture was diluted with toluene 25 mL and evaporated to dryness. The obtained solid acyl chloride was dissolved in anh THF 20mL under Ar and the solution was added dropwise into a stirred slurry of sodium tert-butoxide 7.2g (74.9 mmol, 97%, Aldrich) in anh. THF 150mL at 0C. (The acyl chloride flask and syringe was washed with anh. THF 2x10mL and washing also added to the reaction mixture). The mixture was stirred at 0C for 90 min, warmed up to RT, silica (30g) was added to the reaction mixture followed by water 0.4mL, stirred for 20 min, filtered through a plug of silica (2×1 in) , the silica was washed with additional THF (200mL).  The filtrates were evaporated and the residue was dried on highvac overnight.
Y=22.69g (97.5%) of a pale yellow oil.

1H(d6-DMSO, 400MHz): 7.987(d, 2.2Hz, 1H), 7.862(dd, 8.5Hz, 2.2Hz, 1H), 7.331(d, 8.5Hz, 1H), 1.538(s, 9H)

July 20, 2007

4-(5-Chloro-1,3-benzodioxolyl)-Isocyanate

Filed under: procedures — milkshake @ 4:34 am

isocyanate.gif

4-amino-5-chloro-1,3-benzodioxole 858 mg (5.00 mmol) was dissolved in toluene 20mL and 4M anh. HCl solution in dioxane 1.5mL (6 mmol) was added dropwise. The formed slurry was stirred vigorously for 10 min. Phosgene 20% solution in toluene 15 mL (Fluka, approx 1.9M solution; 28.5 mmol) was added to the mix, the flask was equipped with a Drierite-filled gas outlet tube and the mixture was stirred on oil bath at 70C for 45 min and then at 90C for additional 45 min. (The hydrochloride slurry gradually dissolved with gas evolution). The reaction mixture was cooled to RT, filtered (the fritted funnel was washed with toluene) and the filtrates were evaporated to dryness. The obtained solid residue was dissolved in cyclohexane 10mL with gentle heating, the solution was diluted with hexane 10 mL and allowed to crystallize at RT overnight. The first crop (large needles, 388mg) was obtained by decanting the supernatants and rinsing the precipitate briefly with pentane, then drying on highvac. Cooling the supernatants to -15C in a freezer overnight, a second pure fraction (465mg) crystallized.  Combined yield was 853mg (86%) of coarse light tan needles.

1H(CDCl3, 400MHz, ref. TMS): 6.867(d, 8.4Hz, 1H), 6.605(d, 8.4Hz, 1H), 6.047(s, 2H); 13C(CDCl3, 100MHz, ref TMS): 147.27, 142.41, 128.48(br s), 122.61, 121.92, 115.28(br s), 106.06, 102.63

4-amino-5-chloro-1,3-benzodioxole preparation was posted in Org Prep Daily on Sept 24 (2006)

Using the same procedure,  5-chloro-2,1,3-benzothiadiazol-4-yl isocyanate was prepared from 4-amino-5-chloro-2,1,3-benzothiadiazole (TCI-US) in 59% yield as pale yellow cotton-like fibrous needles (recryst from cyclohexane, to RT).

Note: There was a significant phosgene gas evolution from the heated reaction mixture and phosgene also condensed in the rotavap receiving flask. Using an efficient fume hood and cleaning the rotavap after the evaporation is a necessity: Unlike zombies, the sweet-smelling phosgene gas eats lungs without causing an immediate discomfort.

July 3, 2007

8-iodo-4,7-octadiynoic acid methyl ester

Filed under: Chris Douglas, procedures — milkshake @ 12:58 am

iodoacetylene1.gif

Silver nitrate (0.74 g, 4.40 mmol) was added to a solution of methyl 4,7-octadiynoate (6.77 g, 44.0 mmol) in THF (45 mL).  The suspension was shielded from light and stirred at rt for 5 min.  N-iodosuccinimide (10.1 g, 44.0 mmol) was added to the reaction mixture in one portion and stirring was maintained for 2h.   The reaction mixture was poured into 100 mL water and extracted with Et2O (3´100 mL).  The combined extracts were dried with Na2SO4 and concentrated onto Celite (20 g).  Purification of the resulting powder by flash chromatography (1:10 Et2O:Pentane) gave the title compound as a light and air sensitive colorless powder, 8.52 g (30.4 mmol, 69%).

1H NMR (500 MHz, CDCl3) d 3.70 (s, 3H), 3.30 (t, J = 2.2, 2H), 2.52–2.48 (m, 4H); 13C NMR (125 MHz, CDCl3) d 172.4, 87.9, 79.5, 73.8, 51.8, 33.2, 14.6, 11.8, –4.6; IR (film) 2997, 2950, 1730 cm-1 LRMS (CI, NH4) m/z, 294 (M + NH4)+, 277 (M + H)+, 168.  Calcd for C9H9IO2: C, 39.16; H, 3.29. Found C, 39.37; H, 3.34.

Note: 1-Iodo-phenylacetylene can be easily prepared using the same procedure. The yields can be slightly variable depending on the scale.

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