Phosgenation Reactions - Phosgenations - page 461

Typical procedure. 2-tert-Butyl-1,1,3,3-tetramethylguanidine 1779 [1302]: To an oven-
dried, 500-mL, three-necked, round-bottomed flask, equipped with a nitrogen inlet
with gas bubbler, magnetic stirring bar, thermometer, condenser, and a 250-mL
dropping funnel, were added triphosgene (14.8 g, 0.05 mol) and anhydrous toluene
(120 mL). The mixture was kept under argon and cooled to ca. 10 C with the aid of
an external ice bath. A solution of N,N,N 0 ,N 0 -tetramethylurea (18.0 mL, 0.15 mol)
in dry toluene (50 mL) was then slowly added over a period of 30 min. After com-
pletion of the addition, the mixture was allowed to warm to ambient temperature,
and stirring was continued for a further 1 h. During this time, a white precipitate
formed, consisting of the Vilsmeier salt. Then, tert-butylamine (47.3 mL, 0.45 mol)
was slowly added to the mixture over a period of 30 min. After completion of the
addition, the mixture was heated under reflux for 5 h and then cooled to room
temperature. Anhydrous diethyl ether (200 mL) was added and the white precipi-
tate was quickly removed by filtration. This precipitate had to be collected as
quickly as possible to avoid hydrolysis to the starting urea. The precipitate turns
pale-yellow if hydrolysis is occurring. In some instances, additional diethyl ether
(300 mL) was needed to ensure complete transfer of the solids to the filtration ap-
paratus. The precipitate was washed with a further quantity of anhydrous diethyl
ether (300 mL) (the filtrate must be colorless, indicating that all impurities have
been removed) and immediately dissolved in aqueous 25% sodium hydroxide so-
lution (100 mL). The mixture was then extracted with diethyl ether (3 300 mL).

The combined organic layers were dried (potassium carbonate), filtered, and the
solvent was removed under reduced pressure. The resulting colorless liquid was
purified by distillation (bp 88-89 C/36 mmHg) to afford 18.7 g (73%) of 2-tert-
butyl-1,1,3,3-tetramethylguanidine 1779.
Versatile syntheses of 3-chloroisoxazolium chlorides by the reaction of 4-
isoxazolin-3-ones with phosgene or diphosgene have been reported [1308]. 3-
Chloroisoxazolium chlorides were obtained in good yields, and were converted to
4-isoxazoline-3-thiones on treatment with NaSH. Pyrolysis of 3-chloro-2-methyl-
isoxazolium chlorides afforded 3-chloroisoxazoles. In the presence of Bu 3 N, 3-
chloro-2-methyl-5-phenylisoxazolium chloride condensed carboxylic acids with
alcohols or amines to give the corresponding esters or amides in high yields, to-
gether with 2-methyl-5-phenyl-4-isoxazolin-3-one.
When N-substituted formanilides 1780 are treated briefly and sequentially with
oxalyl chloride, Hunig's base, and bromine, isatins 1784 are rapidly formed, many
in good yields. The reaction involves deprotonation of the Vilsmeier reagent, di-
merization of the carbene thus formed, and electrophilic cyclization of the dimer
by the action of bromonium ion followed by aqueous hydrolysis [1309, 1310]. The
reaction sequence has been developed into a simple and e cient one-pot isatin
synthesis from formanilides.
Alternatively, isatins 1784 can be synthesized from secondary aromatic amines
with oxalyl chloride followed by a Friedel-Crafts cyclization [1311].
There are numerous procedures for the conversion of amides and lactams to
thioamides and thiolactams, e.g. using Lawesson's reagent, P 2 S 5 ,H 2 S, R 3 OBF 4 /
NaSH, R 2 PSX, or (Et 2 Al) 2 S. Many of these methods require protracted reaction