Phosgenation Reactions - Phosgenations - page 209

there is permanent turbidity. The product is recovered in the form of its triethyl-
ammonium salt after extraction and work-up as in the previously described aque-
ous protocol. N-tert-Butoxycarbonyl-l-phenylalanine has mp 85 C.
When the N-tert-butoxycarbonylation of sterically hindered a-amino acids is car-
ried out under normal conditions, yields of just 40-60% are obtained. The use of
excess Boc 2 O (3-5 equiv.) over 3-4 days gives slightly faster reaction rates, but the
competing hydrolysis means that there is no overall benefit in terms of yield.
However, the use of tetramethylammonium hydroxide leads to enhanced solubility
of the amino acid in dry acetonitrile, and hence tert-butoxycarbonylation under
these conditions leads to excellent yields of the derivatized products [368].
Typical procedure. N-tert-Butoxycarbonylation of a,a-disubstituted glycines [368]. Cau-
tion! Carry out all procedures in an e cient fume cupboard; wear gloves and chemical-
proof safety goggles. The reaction flask is charged with equimolar amounts of the
amino acid (a,a-disubstituted glycine, 10 mmol) and solid tetramethylammonium
hydroxide pentahydrate (1.81 g, 10 mmol). Dry acetonitrile (freshly distilled from
calcium hydride; 5-10 mL mmol 1 ) is added, and the mixture is stirred at room
temperature until a solution is obtained (usually within 30 min). Boc 2 O (0.12
mmol) is then added and the resulting mixture is stirred at room temperature for 2
days. On the third day, a further portion of Boc 2 O (1.2 g, 0.6 mmol) is added and
the mixture is stirred for another day. The acetonitrile is then removed in vacuo,
the residue is partitioned between diethyl ether and water, and the aqueous layer is
acidified to pH 3-4 with saturated aqueous citric acid [prepared by dissolving citric
acid (146 g) in water (100 mL) at 25 C]. The aqueous layer is washed with a fur-
ther portion of diethyl ether, separated, and extracted three times with ethyl ace-
tate. The combined organic extracts are washed with water, dried (magnesium
sulfate), and concentrated. Pure material is usually obtained; when necessary, the
product can be recrystallized from diethyl ether.
S,S-Dimethyldithiocarbonate (DMDTC)
S,S-Dimethyldithiocarbonate (DMDTC) 786 represents a mild and safely handled
reagent structurally similar to phosgene, which is useful in the synthesis of ureas.
DMDTC can be prepared from methanol, carbon disulfide, and dimethyl sulfate by
a two-step sequence [575, 576]. Although dimethyl sulfate is a suspected human
carcinogen, it is relatively non-volatile and with due care can be handled safely in
the laboratory.
In a representative example, DMDTC 786 is allowed to react with 2 equivalents
of benzylamine 787 at 60 C for 24 h in methanol or ethanol to give the symmet-
rical dibenzylurea 788 in 85% yield (route A) [577]. Aliphatic amines 789 bearing
a hydroxy or an amino substituent at the b-org-position react with 786 in dilute
solution to predominantly afford cyclic ureas or carbamates 790 (40-80% yield)
(route C). By increasing the concentration of the starting reagent 789 with respect
to DMDTC, the symmetrical ureas 791 are obtained in high yield (75-100%) with-
out any need for protection and deprotection procedures.