A. 2-Cyclopentene-1-acetamide. A dry, 250-mL, three-necked, round-bottomed flask is equipped with a magnetic stirring bar, serum stopper, 25-mL pressure equalizing addition funnel, and an argon atmosphere with provision for venting gaseous reaction products (Note 1). The vessel is charged with 20 g (152 mmol) of 2-cyclopentene-1-acetic acid (Note 2) and 25 mL of dry toluene (Note 3). Oxalyl chloride (17.3 mL, 1.3 equiv) is added slowly over a 30-min period by means of the addition funnel, taking care to release any pressure buildup. (Caution: gaseous hydrogen chloride evolution!.) The dark reaction mixture is stirred for an additional 20 min while the second reaction vessel is assembled, then concentrated to about 2/3 volume at the vacuum pump (Note 4).

A 250-mL, three-necked, round-bottomed flask equipped with magnetic stirring bar, serum stopper, dry ice condenser, and argon atmosphere is cooled by means of a dry ice/acetone bath and charged with approximately 150 mL of dry liquid ammonia. The 2-(2-cyclopentenyl)acetyl chloride reaction mixture is added carefully but steadily (Note 5) to the cold and rapidly stirred ammonia by syringe. (Caution: vigorous exothermic reaction!). Residual acid chloride is transferred by rinsing the first vessel with 5 mL of toluene. After the addition the mixture is stirred for an additional 5 min, then 60 mL of dichloromethane is added. The cold bath is removed and the excess ammonia is allowed to escape into the fume hood by stirring the open vessel overnight.

The crude reaction mixture is filtered and the filtrate is reserved. The solids are triturated by stirring vigorously with 100 mL of methanol for 20 min with gentle warming to about 40°C. The solids are filtered and triturated again in the same way. The three organic filtrates are combined and concentrated to near dryness. The resulting semi-solid is redissolved in 100 mL of dichloromethane, filtered to remove residual ammonium chloride, and concentrated to a light brown solid, 18.9 g. The crude product is dissolved in 60 mL of boiling tetrahydrofuran and allowed to crystallize in a −6°C freezer overnight. The amide is collected by filtration, washed with 5 mL of cold ether, and dried under reduced pressure, giving 15.77 g of white flakes, mp 128–129°C. The filtrate is concentrated to about 8 mL, brought to the cloud point by the addition of a few drops of hexane, and cooled in the freezer. Filtration as before gives a second crop of white flakes, 1.46 g, mp 128–129°C (total yield 17.23 g, 90.6%) (Note 6).

B. 8-exo-Iodo-2-azabicyclo[3.3.0]octan-3-one. A dry, 500-mL, three-necked, round-bottomed flask equipped with magnetic stirring bar, serum stopper, 50-mL pressure-equalizing addition funnel, cold water bath, and argon atmosphere is charged with 12.5 g (100 mmol) of 2-cyclopentene-1-acetamide, 29.2 mL (210 mmol) of triethylamine (Note 7), and 80 mL of dry pentane (Note 8). By means of the addition funnel, 41 mL (210 mmol) of trimethylsilyl trifluoromethanesulfonate (Note 9) is slowly added to the cooled and rapidly stirred amide suspension over a 50-min period. After the addition is complete, the reaction mixture is stirred for an additional 20 min at room temperature, then the stirring is stopped, and the two layers are allowed to separate.

A second, dry, 500-mL, three-necked, round-bottomed flask is equipped with magnetic stirring bar, serum stopper, vacuum pump connection, and argon atmosphere. The (top) pentane layer from the first flask, which contains the bis(trimethylsilyl)imidate, is carefully transferred to the second flask by cannula, maintaining the argon atmosphere, and leaving the oily triethylammonium trifluoromethanesulfonate layer behind. This remaining salt is triturated with 30 mL of a dry 2:1 pentane/ether mixture by stirring for 15 min, allowing the layers to separate, then transferring the extract to the second flask as before. The trituration is repeated with a 30-mL portion of anhydrous ether, and the combined extracts in the second flask are concentrated with stirring to about 1/3 volume using the vacuum pump (Note 10).

A third, dry, 500-mL, three-necked, round-bottomed flask equipped with an addition funnel, magnetic stirring bar, serum stopper, cold water bath, and argon atmosphere is charged with 53.3 g (210 mmol) of molecular iodine and 140 mL of anhydrous ether. The mixture is allowed to stir for 10 min to dissolve most of the iodine. The concentrated organic extract in the second flask is now added to the iodine solution with stirring and cooling over 15 min. The reaction mixture warms slightly during the addition, but should not reach reflux. An additional 10 mL of anhydrous ether is used to complete the transfer of the bis(trimethylsilyl)imidate. Near the end of the addition, the oily black layer (which contains the cyclized iminium salt) solidifies, leaving a clear light brown ether supernatant. The serum stopper is carefully removed and the solid residue gently broken up using a spatula. The stopper is replaced and the reaction mixture is allowed to stand for an additional 45 min with occasional swirling by hand. The reaction is quenched by removing the addition funnel and stopper and slowly adding 20 mL of saturated aqueous sodium carbonate. (Caution: vigorous gas evolution!). At this point stirring can be resumed. A 20-mL portion of saturated aqueous sodium sulfite is added slowly (more gas evolution), and the process is repeated until 100 mL each of saturated aqueous sodium carbonate and sulfite have been added. The reaction mixture is filtered, the crude solid iodolactam is reserved, and the organic layer is separated and reserved. The aqueous layer is saturated with sodium chloride and extracted with four, 100-mL portions of dichloromethane. The five organic extracts are combined, dried over anhydrous sodium sulfate, and concentrated to a light brown solid. This residue is dissolved in 20 mL of tetrahydrofuran and hexane is added to the cloud point. Cooling in the freezer gives colorless needles, which are collected and dried under reduced pressure to afford 1.60 g of iodolactam, mp 138–139°C.

The reserved solid from filtration is dried under reduced pressure, dissolved in 65 mL of hot tetrahydrofuran and filtered. The solution is allowed to cool, first at room temperature, then in the freezer. The product (16.77 g, mp 138–139°C) is collected as before. The mother liquor is concentrated to about 10 mL, brought to the cloud point by the addition of hexane, and cooled in the freezer, resulting in an additional crop of 1.70 g, mp 138–139°C. The total amount of iodolactam is 19.80 g, representing a 79% yield from the amide (Note 11).