Chemistry Reference
In-Depth Information
Typical procedure. Thiazol-2-ylmethyl isocyanide 1527 [1169]:
In a dry 25-mL round-
bottomed flask was placed N-(thiazol-2-yl)methylformamide (0.5 g, 3.52 mmol) and
to this was added dichloromethane (2 mL) and dry triethylamine (1.15 mL, 8.22
mmol). The mixture was cooled in a ice bath under a positive N
2
pressure. Phos-
gene (for a safe source, see Chapter 7) (3.52 mL of a 1 m solution in dichloro-
methane; 3.52 mmol) was added dropwise. An exothermic reaction was observed; a
precipitate of triethylammonium chloride formed and the mixture turned brown.
After 15 min, saturated Na
2
CO
3
solution (10 mL) was added and a thick glutinous
precipitate formed. The dichloromethane solution was decanted off and the solid
was washed further with dichloromethane (3
10 mL). The combined extracts
were dried over MgSO
4
, concentrated in vacuo, and distilled at 100
C (30 mmHg)
to give thiazol-2-ylmethyl isocyanide 1527 as a pale-brown oil; yield 0.293 g (67%).
Diphosgene
An interesting chiral building block for the synthesis of optically active unusual
amino-hydroxy acids is (
)-8-phenylmenthyl isocyanoacetate 1532 [1170]. It is pre-
pared in optically pure form in 95% yield by dehydration of the corresponding
formamide with diphosgene within ca. 10 h at room temperature.
þ
O
Ph
NC
O
1532
Typical procedure. (
)-8-Phenylmenthyl isocyanoacetate 1532 [1170]:
To 8-phenyl-
menthyl formamidoacetate (480 mg, 1.51 mmol) in anhydrous dichloromethane
(15 mL) was added anhydrous triethylamine (0.45 mL, 3.16 mmol, 2 equiv.). The
mixture was cooled to 0
C in an ice-bath and a solution of diphosgene (0.096 mL,
0.8 mmol, 1.1 equiv.) in anhydrous dichloromethane (2 mL) was added dropwise.
After stirring at 25
C overnight, the mixture was washed with 10% aq. NaHCO
3
solution (2
þ
5 mL) and then with water until the washings were of pH 6-7. The
organic phase was dried over MgSO
4
and the solvent was evaporated in vacuo. The
crude product, which consisted of a mixture of the desired isocyanoacetate 1532
(55%) and the starting material (45%), as determined by
1
H NMR, was then re-
cycled under the same conditions (with 2 equiv. of Et
3
N and 0.5 equiv. of di-
phosgene). After the same work-up, the crude compound, a yellowish viscous
liquid, was obtained. Yield: 411 mg (95%) of 1532; R
f
¼
0
:
6 (Et
2
O/hexane, 1:1);
[a]
D
21
4, CCl
4
).
In the recent patent literature, an application on ''Preparation of alkyl isocyano-
acetates'' from amino acids by dehydration of the corresponding formamides has
been filed [1171].
a-Hydroxycarboxylic acid amides 1536 are formed by TiCl
4
-mediated addition of
isocyanides to aldehydes and ketones 1535 in a Passerini-type reaction [1172]. The
yields of 1536 range from 14% to in excess of 95%. The isocyanides are obtained by
dehydration of the corresponding formylated amino acid esters with diphosgene;
yields 42-91%.
¼þ
20
:
5(c
¼
4
:
