Chemistry Reference
In-Depth Information
chloride 451 (0.030 mol), dichloromethane (100 mL), and pyridine (9.8 mL, 0.121
mol). The resulting suspension or solution was cooled in an ice bath for 15 min. A
solution of phosgene (for a safe source, see Chapter 7) (1.93 m in toluene, 20 mL,
0.039 mol) [CAUTION: USE HOOD!] was added by means of a syringe over 20-30
s, and the resulting light-yellow solution was stirred at 0
C for 2 h. The reaction
mixture was extracted twice with cold 0.5 m aqueous HCl (300 mL) and crushed
ice (ca. 300 mL). Each aqueous layer was re-extracted with dichloromethane (100
mL). The combined organic phases were extracted with a mixture of cold saturated
aqueous NaCl solution (300 mL) and crushed ice (ca. 200 mL), dried over MgSO
4
,
filtered, and concentrated in a rotary evaporator to afford the crude isocyanate 452
as a light-brown oil. (During work-up, the isocyanate was only exposed to water for
a total of 5-10 min). The product was purified by kugelrohr distillation under re-
duced pressure.
An earlier publication [312] described the synthesis of d,l-amino acid ester iso-
cyanates (at that time called d,l-carbonyl-amino acid esters) from the corresponding
amino acid ester hydrochlorides by carbonylation with phosgene. Ester hydro-
chlorides of alanine, leucine, phenylalanine 451, aminobutyric acid, phenyl gly-
cine, norvaline, norleucine, benzyl cysteine, methionine, aspartic acid, and gluta-
mic acid were used; yields of isocyanates were 85-97%.
General procedure for d,l-carbonyl alanine ethyl ester [312]:
In a three-necked, round-
bottomed flask fitted with a mechanical stirrer, a gas inlet, and a reflux condenser
were placed abs. toluene (50 mL) and d,l-alanine ethyl ester hydrochloride (dried
over P
2
O
5
at 50
C in vacuo) (15 g). The mixture was warmed by an oil bath, which
was heated to 130-160
C, and, under vigorous stirring, phosgene (for a safe source,
see Chapter 7) was passed in for 1.5 h. HCl was evolved and the hydrochloride was
gradually dissolved. The toluene was then removed by fractional distillation in
vacuo at 45
C and the residue was purified by distillation; bp 69
C (11 Torr),
affording a colorless liquid; yield 13 g (91%). Author's remark: Excess phosgene has
to be passed into a vessel filled with ethanol to make it harmless, and thereby HCl
gas is evolved (see Chapter 7).
Procedures using triphosgene as an equivalent of a solution of phosgene in tol-
uene and either pyridine or aqueous sodium hydrogen carbonate as a base have
been reported [313]. These mild reaction conditions are superior to alternative
methods for the preparation of amino acid ester isocyanates, as described in the
present chapter, which involve either refluxing the amino acid ester hydro-
chloride in toluene for several hours while purging with gaseous phosgene [312]
or treating the amino acid ester hydrochloride with di-tert-butyl dicarbonate and 4-
dimethylaminopyridine (DMAP) [314].
Amino acid ester isocyanates are produced cleanly by this method and can often
be used without purification. If desired, volatile amino acid ester isocyanates, such
as the title compound, can be purified to analytical purity by kugelrohr distillation.
The amino acid ester isocyanates generated by this method are formed without
detectable racemization (
99.5% ee); the enantiomeric purity of the isocyanates
can be checked by trapping with (S)-1-phenylethylamine followed by
>
1
H NMR
