Chemistry Reference
In-Depth Information
4.3.4.2
Unsymmetrical Phosgene Equivalents
Unsymmetrical equivalents of phosgene are less reactive and the rate and selectiv-
ity of carbonylation can be conveniently controlled by selecting the nature of the
leaving groups and the conditions of consecutive displacements.
Phenyl carbamates
Various N,N
0
-disubstituted ureas 1039, including some chiral compounds, are ef-
ficiently synthesized by the reaction of amines with carbamates 1038, which, in
turn, are prepared from phenyl chloroformate 1037 [760].
PhOCOCl
O
O
1037
R'NH
2
DMSO
RNH
2
Ph
R'H
N
N
HR
O
NHR
DMSO
1038
1039
(78-95 %)
R, R' = aryl, alkyl, cycloalkyl
The reaction occurs at room temperature in 78-95% yield simply by mixing the
reagents in DMSO, the only by-product being phenol, which is easily removable by
an aqueous NaOH wash. The method can also be successfully applied to secondary
amines to generate N,N,N
0
-trisubstituted ureas in 78-89% yield, irrespective of
the steric hindrance of the reagents. The reaction conditions are compatible with a
number of functional groups, such as chiral amines, amino acids, and amino al-
cohols. The rate and yield of the reaction are highly dependent on the solvent used.
The use of DMSO is critical to the mildness of the conditions. Compared to
DMSO, the reaction was found to be much slower in methanol, dioxane, DME, or
dichloromethane, in which carbamate 1038 is not readily soluble. A possible draw-
back of this approach is associated with the use of DMSO as solvent, which is toxic,
a possible carcinogen, and potentially explosive when mixed with some organic
and inorganic reagents [761].
Typical procedure. N-(4-Acetylphenyl)-N
0
,N
0
-dibutylurea [760]:
In a dry 100-mL flask
equipped with an N
2
inlet adapter, a rubber septum, and a magnetic stirring bar,
was placed a solution of phenyl N-(4-acetylphenyl)carbamate 1038 (R
4-AcPh)
(6.38 g, 25 mmol) in DMSO (50 mL). Dibutylamine (4.42 mL, 26.25 mmol) was
then slowly added. The resulting solution was stirred at room temperature for 15
min, and then diluted with EtOAc (250 mL). The resulting mixture was washed
successively with H
2
O(2
ΒΌ
50 mL), 1 m HCl (100 mL), H
2
O (100 mL), 1 m NaOH
(100 mL), and brine (100 mL), dried (MgSO
4
), and concentrated under reduced
pressure to give a crude solid, which was triturated with Et
2
O/hexane to furnish N-
(4-acetylphenyl)-N
0
,N
0
-dibutylurea as a white solid; yield 6.98 g (96%).
Trihaloacetyl chlorides and trihaloacetamides
Trihaloacetyl chlorides 1040 represent a second class of unsymmetrical reagents
1002 which are commercially available at reasonable prices. They can be quantita-
