Organic Syntheses, Vol. 78, pp. 177-188
Checked by Brad M. Savall and William R. Roush.
1. Procedure
2. Notes
1.
(S)-Ethyl lactate
was purchased from Merck, Darmstadt, Germany, in enantiomerically
pure form (ee >> 99%) and was used without further
purification.
2.
O-Benzyl 2,2,2-trichloroacetimidate
was synthesized in
98% yield
according to ref.
5
by addition of
1.0 equiv of benzyl alcohol
(Aldrich Chemical Company, Inc.; previously distilled over calcium
hydride (CaH2) under an atmosphere of argon),
to
1.0 equiv of trichloroacetonitrile
(Aldrich Chemical Company, Inc.; no previous purification)
in the presence of
0.1 equiv of sodium hydride
in
anhydrous diethyl ether.The
resulting viscous, dark brown crude compound showed sufficient purity (> 97%) by
1H NMR and GLC analysis and was used without further purification. The
benzylating agent can be stored at 4°C under an atmosphere of
argon
for several weeks without decomposition or loss of quality. However, the compound
can be further purified by distillation to yield a colorless viscous liquid, or, alternatively,
can be purchased from Aldrich Chemical Company, Inc.
5.
Trifluoromethanesulfonic acid
was purchased from Aldrich Chemical Company, Inc.,
stored and handled under an atmosphere of
argon, and used without
further purification.
6. During the addition of the catalyst an almost colorless precipitate
of
trichloroacetamide forms,
which might dissolve again after a few minutes. If this happens or if the reaction
mixture does not become turbid at all, more
(0.4
mL) trifluoromethanesulfonic acid can be
added.
7. The submitters indicated that extended reaction times are essential
to obtain complete consumption of the starting material and good yields. However,
the checkers observed that the reaction appeared to be complete within several hours
according to TLC analysis.
8. The checkers observed that a crystalline solid (
trichloroacetamide)
formed in the condenser at the beginning of the distillation, and that the distillate
contained small amounts of a precipitated crystalline solid (
trichloroacetamide)
that could be removed by filtration through a
sintered glass funnel.
The checkers obtained
78-83%
yields of product, with material collected from 125 - 135° to maximize the yield of
product.
9. The compound shows the following physical data: R
f
= 0.40 (
0.25 mm silica gel on glass,
diethyl ether/light petroleum = 1:5);
bp:
124-127°C/6 mm,
αD21 : −73.6° (neat), {
[α]D20 : −74.5 (CHCl3,
c 2.94)};
3 31H NMR (300 MHz, CDCl
3)
δ: 1.30 (t, 3 H, J = 7.2), 1.44 (d, 3 H, J = 6.9),
4.05 (q, 1 H, J = 6.8), 4.22 (m, 2 H), 4.45 (d, 1
H, J = 11.8), 4.69 (d, 1 H, J = 11.8), 7.20-7.40 (m, 5 H);
13C NMR (75 MHz,
CDCl
3) δ: 14.2, 18.7, 60.8,
71.9, 74.0, 127.8, 127.9, 128.4,
136.6, 173.2; IR
(film) cm
−1: 2985, 1746, 1455,
1200, 1143; HRMS
calcd for C
12H
17O
3 [M+H] 209.1178, found
209.1183. Anal. Calcd for C
12H
16O
3:
C, 69.21; H, 7.73, Found: C, 69.17; H, 7.74. The O-Bn protected
(S)-ethyl
lactate can be stored without special precautions.
10.
Diethyl ether
was purified by distillation from
sodium benzophenone
ketyl under
argon.
11.
Diisobutylaluminum hydride
(DIBAH) (1 M in hexane) was purchased from Aldrich
Chemical Company, Inc., and used without further purification.
DIBAH should be handled with caution and all operations should be performed by employing
the usual inert gas techniques (cannula, syringe, etc.).
12. To avoid reduction of the generated aldehyde that is more prone
to reduction than the corresponding ester, the reducing agent should be added very
slowly, avoiding any local temperature increase. The reaction mixture should be kept
below −70°C. The checkers used a
three-necked flask equipped
with a
low temperature thermometer to monitor the internal
reaction temperature.
13. It is strongly recommended that the reaction mixture be added
to the beaker containing the ice-cold acid solution with vigorous stirring because
of the strong evolution of
hydrogen gas. Reversing the order
of addition causes freezing of the acid and effects a vigorous evolution of
hydrogen
gas on warming.
14. The resulting viscous colorless crude compound obtained by the
submitters showed sufficient purity (> 97%) by
1H NMR and GLC analysis
to be used without further purification. The submitters report that the aldehyde can
be stored at −20°C under an atmosphere of
argon for several
days without detectable racemization or loss of quality. However, the checkers observed
that some crystalline material resembling aluminum salts formed when the crude aldehyde
was stored in the refrigerator. The salts could be removed by dissolving the product
in
diethyl ether and washing
with
1 N HCl (2 × 50 mL). The
purity of the aldehyde obtained by the checkers was 80% by GC analysis. Nevertheless,
this material gave acceptable results in the following Horner-Wadsworth-Emmons reaction.
If desired, the aldehyde can be purified by distillation to yield a colorless viscous
liquid.
3 The compound shows the following physical
data: R
f = 0.27 (
0.25 mm silica gel
on glass,
diethyl ether/light petroleum
= 1:3);
α: −65.3° (neat)
{
α: −65.9° (neat)};
3 1H
NMR (300 MHz, CDCl
3) δ: 1.31 (d, 3 H, J = 7.2), 3.88
(qd, 1 H, J = 6.9, 1.9), 4.57 (d, 1 H, J = 11.8), 4.67 (d,
1 H, J = 11.8), 7.35 (m, 5 H), 9.64 (d, 1 H, J = 1.6);
13C NMR (75 MHz,
CDCl
3) δ: 15.5, 72.0, 79.4,
127.9, 128.6, 137.3, 203.4;
IR (film) cm
−1: 3448,
2870, 1733, 1455, 1375, 1094;
HRMS calcd for C
10H
16NO
2
[M+NH
4+] 182.1181, found 182.1176.
Anal. Calcd for C
10H
12O
2:
C, 73.14; H,
7.37. Found: C, 68.98; H, 7.52.
15. Because of precipitating lithium phosphates during the course
of the reaction the mixture forms a sticky slurry and so the use of a
large
stirring bar is recommended.
16.
Lithium bromide
was purchased from Fluka Chemical Corp. and dried
for ca. 12 hr at 100-110°C under reduced pressure using a high vacuum pump. The salt
was handled and stored under an atmosphere of
argon with the
exclusion of moisture.
20. To obtain good chemical yields and a very high (E)-selectivity
in the olefination step it seems to be crucial that all of the phosphonate must be
transformed into its chelated lithium derivative before the aldehyde is added. Sometimes
the reaction mixture becomes turbid during cooling but this does not affect reactivity.
21. During the olefination step only very small amounts of the corresponding
(Z)-isomer are formed, which are easily removed by column chromatography on silica
gel. The (Z)-isomer has a slightly higher R
f-value than the (E)-isomer:
R
f(Z) = 0.49 (
0.25 mm silica gel on
glass,
diethyl ether/light petroleum
(v/v) 1:1).
22. The compound shows the following physical data: R
f
= 0.44 (
0.25 mm silica gel on glass,
dimethyl ether/light petroleum (v/v) 1:1);
[α[: −31.9° (CHCl3, c
1.10);
1H
NMR (300 MHz, CDCl
3) δ: 1.31 (d, 3 H, J = 6.6), 4.18
(qdd, 1 H, J = 6.6, 4.8, 1.6), 4.44 (d, 1 H, J = 12.0), 4.48
(d, 1 H, J = 12.0), 6.57 (dd, 1 H, J = 15, 1.5), 6.94 (dd,
1 H, J = 15.3, 4.9), 7.21-7.34 (m, 5 H), 7.48-7.55 (m, 2
H), 7.57-7.64 (m, 1 H), 7.85-7.90 (m, 2 H);
13C NMR (75 MHz,
CDCl
3) δ: 20.0, 71.0, 72.9,
127.5, 127.6, 127.8, 128.4, 129.3,
130.3, 133.4, 137.6, 140.3, 147.0;
IR (film) cm
−1: 3063,
1447, 1307, 1147, 1086, 834;
HRMS calcd for C
17H
22O
3NS
[M+NH
4+] 320.1320, found 320.1310.
Anal. Calcd for C
17H
18O
3S: C, 67.43; H, 6.00. Found:
C, 66.45; H, 6.09. The checkers found that the product solidified when stored at −20°C,
cracking the glass bottle.
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
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