Organic Syntheses, Vol. 78, pp. 220-224
Submitted by James H. Tsai, Leo R. Takaoka, Noel A. Powell, and James S. Nowick
1.
Checked by Adam Charnley and Steven Wolff.
1. Procedure
A
250-mL, three-necked, round-bottomed flask is equipped
with a
mechanical stirrer and charged with
100
mL of methylene chloride,
100
mL of saturated aqueous sodium bicarbonate,
and
5.50 g (25.5 mmol) of L-phenylalanine
methyl ester hydrochloride (Note
1). The
biphasic mixture is cooled in an
ice bath and stirred mechanically
while
2.52 g (8.42 mmol) of
triphosgene (Note
2) is added
in a single portion. The reaction mixture is stirred in the
ice bath
for 15 min and then poured into a
250-mL separatory funnel.
The organic layer is collected, and the aqueous layer is extracted with three
15-mL portions of methylene chloride.
The combined organic layers are dried
(MgSO4),
vacuum filtered, and concentrated at reduced pressure using a
rotary evaporator
to give a colorless oil. The oil is purified by Kugelrohr distillation (130°C, 0.05
mm) to afford
5.15
g (98%) of methyl
(S)-2-isocyanato-3-phenylpropanoate
as a colorless oil (Notes
3-
6).
2. Notes
2.
Triphosgene was
purchased from Aldrich Chemical Company, Inc.
3. The product has the following properties:
[α]D25 −83.8° (neat); IR (CHCl
3) cm
−1: 2260,
1747;
1H
NMR (400 MHz, CDCl
3) δ: 3.03 (dd, 1 H, ABX pattern, J
AB
= 13.8, J
BX = 7.8), 3.16 (dd, 1 H, ABX pattern, J
AB
= 13.6, J
AX = 4.8), 3.81 (s, 3 H), 4.27 (dd, 1
H, J = 7.8, 4.6), 7.18-7.21 (m, 2 H), 7.27-7.36 (m, 3 H);
13C NMR (125
MHz, CDCl
3) δ: 39.6, 52.8, 58.3,
126.7, 127.2, 128.4, 129.1, 135.4,
170.7. Anal. Calcd for C
11H
11NO
3:
C, 64.38; H, 5.40; N, 6.83. Found: C, 64.18; H, 5.40; N, 6.70.
4. The yield is typically
4.97-5.15
g (
95-98%).
5. The submitters previously reported an optical rotation of
[α]D22 +71.9° (neat)
for
methyl (S)-2-isocyanato-3-phenylpropanoate.
2 This value
does not match the current value of
[α]D25
−83.8° (neat) and is in error. The origin of this discrepancy involves
the path length of the polarimeter cell. With a 5-cm cell, a correct α value
of
−48.15° is obtained. If
a 10-cm cell is used, a spurious positive α value is obtained, which gives rise
to a erroneous positive value of [α]
D.
6. The optical purity of the product was determined to be >99.5%
by trapping with
(S)-1-phenylethylamine
and
1H NMR analysis of the resulting urea adduct, as described in reference
2.
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
This procedure provides a convenient, rapid, high yielding route to amino acid
ester isocyanates..
It is based upon procedures the submitters have previously reported for the preparation
of both amino acid ester isocyanates
2 and peptide isocyanates.
3,4 These procedures use either
triphosgene
or a solution of
phosgene in
toluene
as a one-carbon electrophile and either
pyridine
or
aqueous sodium bicarbonate
as a base. The current procedure uses
triphosgene
and
sodium bicarbonate
to minimize the hazard and toxicity of the reagents and waste products. These mild
reaction conditions are superior to alternative methods for the preparation of amino
acid ester isocyanates, which include refluxing the amino acid ester hydrochloride
in
toluene for several hours
while purging with gaseous
phosgene,
5
or treating the amino acid ester hydrochloride with
di-tert-butyl dicarbonate
and
4-dimethylaminopyridine (DMAP).
6
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
1H
NMR analysis of the resulting urea adducts.
2 If this
method is used to generate isocyanates of peptides, then efficient stirring is necessary
to prevent epimerization of the peptide isocyanates.
3,
4
Amino acid ester isocyanates are useful synthetic building blocks, precursors to
peptides and azapeptides,
7,8
chiral derivatizing agents,
9,10 and reagents
for the preparation of chiral chromatographic media.
11,12 (S)-2-Isocyanato-3-phenylpropanoate
(
phenylalanine methyl ester isocyanate) has been used as a building
block for 1,2,4-triazine azapeptides,
8 and inhibitors
of thermolysin
13
and human leukocyte elastase (HLE).
14
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